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Multicomponent synthesis of optically pure aminodicarboxylic acids in water and total synthesis of 15-EPI-benzo-lipoxin A4 and aspirin-triggered neuroproctectin D1/protectin D1

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Multicomponent synthesis of optically pure aminodicarboxylic acids in water and total synthesis of 15-EPI-benzo-lipoxin A4 and aspirin-triggered neuroproctectin D1/protectin D1

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Content MULTICOMPONENT SYNTHESIS OF OPTICALLY PURE AMINODICARBOXYLIC
ACIDS IN WATER
AND
TOTAL SYNTHESIS OF 15-EPI-BENZO-LIPOXIN A4 AND ASPIRIN-TRIGGERED
NEUROPROTECTIN D1/PROTECTIN D1

by

Kevin Michael Kossick

A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTORATE OF PHILOSOPHY
(CHEMISTRY)

December 2022

Copyright 2022 Kevin Michael Kossick
ii
DEDICATION

To my loving parents who mean the world to me.

iii
ACKNOWLEDGEMENTS
First and foremost, I would like to thank my advisor, Professor Nicos A. Petasis, for his
constant support and encouragement throughout my experience in his laboratory. I thoroughly
enjoyed our discussions on chemistry and the stories of his experiences throughout his career.
Our relationship made the challenging moments, whether relating to a research problem or a
personal obstacle, much easier to navigate.
I would also like to thank all of the staff at the Loker Hydrocarbon Research Institute and
elsewhere for their efforts in creating an ideal working environment. All of the conditions
needed to work efficiently have been met, and for that I am grateful.
I have a deep appreciation for the people I’ve worked with in the Petasis lab and friends
I’ve made over the years. A special thanks to Drs. Caroline Black, Caitlyn DeAngelo, Dr. Robert
Nshimiyimana, and Blake Houser is warranted for the many meaningful experiences shared
inside and out of the laboratory. They have all left a lasting impression on me. I would also like
to mention my friends Dr. Sanket Samal and soon-to-be Dr. Adam Ung, whom between the three
of us have likely consumed a metric ton of coffee at the campus Starbucks, and whom have
always been great sources of insight and understanding.
Finally, I must thank my parents, Michael and Marla Kossick, for always being there for
me through the best and worst of times. Without them, I would certainly not be where I am
today. To them I am eternally grateful.

iv
TABLE OF CONTENTS

Dedication ...................................................................................................................................... ii
Acknowledgements ...................................................................................................................... iii
List of Tables .............................................................................................................................. viii
List of Figures ............................................................................................................................... ix
List of Schemes ............................................................................................................................. xi
Abstract ....................................................................................................................................... xiv

CHAPTER 1
Boron-Mediated, Multicomponent Reactions .............................................................................1
1.1 Introduction ...................................................................................................................2
1.1.1 Multicomponent Reactions ............................................................................2
1.1.2 Organoboronic Acids: Structure, and Properties ...........................................5
1.2 Multicomponent Reactions involving Organoboronic Acids .....................................10
1.2.1 Passerini-Type Reaction ..............................................................................10
1.2.2 Petasis Borono-Mannich Reaction ...............................................................11
1.2.3 Petasis-Type Reactions ................................................................................15
1.3 Asymmetric Petasis Borono-Mannich Reactions .......................................................16
1.3.1 Chiral Substrate Control ..............................................................................17
1.3.2 Chiral Auxiliary Control ..............................................................................20
1.3.3 Chiral Catalyst Control ................................................................................22
1.4 References ...................................................................................................................26
v
CHAPTER 2
Diastereoselective Multicomponent Synthesis of Aminodicarboxylic Acids in Water ..........30
2.1 Introduction .................................................................................................................31
2.2 Results and Discussion ...............................................................................................32
2.2.1 Synthesis of Aminocidcarboxylic Acids ......................................................32
2.2.2 Stereoselective Synthesis of Enalaprilat ......................................................38
2.2.3 Potential Sources of Stereoselectivity ..........................................................40
2.2.4 Conformational Dynamics of Aminodicarboxylic Acids in DMSO-d6 .......45
2.3 Conclusions .................................................................................................................52
2.4 Synthetic Preparations ................................................................................................53
2.5 References ...................................................................................................................77

CHAPTER 3
Total Synthesis of 15-epi-Benzo-Lipoxin A4 ..............................................................................79
3.1 Introduction .................................................................................................................80
3.2 Retrosynthetic Analysis ..............................................................................................81
3.3 Results and Discussion ...............................................................................................82
3.4 Conclusions .................................................................................................................84
3.5 Synthetic Procedures ...................................................................................................85
3.6 References ...................................................................................................................90

vi
CHAPTER 4
Total Synthesis of Aspirin-Triggered Neuroprotectin D1/Protectin D1 .................................93
4.1 Introduction .................................................................................................................94
4.2 Retrosynthetic Analysis ..............................................................................................96
4.3 Results and Discussion ...............................................................................................98
4.4 Challenges and Setbacks ...........................................................................................102
4.5 Conclusions ...............................................................................................................105
4.6 Synthetic Procedures .................................................................................................105
4.7 References .................................................................................................................131

APPENDIX ONE
Spectra Relevant to Chapter Two ............................................................................................135
A1.1 General Information ...............................................................................................136
A1.2
1
H-NMR and
13
C-NMR Spectra ............................................................................137
A1.3
1
H-NMR spectra of Compounds 8 and 13 in basic and neutral DMSO-d6 ............161
A1.4 Studies on the Effects on Stereoselectivity in Protic vs. Aprotic Solvents ............162

APPENDIX TWO
Spectra Relevant to Chapter Three..........................................................................................164
A2.1 General Information ...............................................................................................165
A2.2
1
H-NMR Spectra ....................................................................................................166

vii
APPENDIX THREE
Spectra Relevant to Chapter Four ...........................................................................................172
A3.1 General Information ...............................................................................................173
A3.2
1
H-NMR,
1
H-
1
H COSY-NMR and
13
C-NMR Spectra...........................................174

viii
LIST OF TABLES
Table 2.1 Synthesis of Aminodicarboxylic acid derivatives from amino acids ...........................33

Table 2.2 Studies on the reactivity of boronic acids with* differing electronegativities .............35

Table 2.3 Synthesis of functionalized dipeptides in water ...........................................................37

Table 2.4 Studies on the stereoselectivity of various chiral amines.............................................43

Table 2.5 Duration required to reach equilibrium for amino acids of different side chain ..........47

ix
LIST OF FIGURES
Figure 1.1 Examples of biologically active compounds synthesized using the
UGC procedure ................................................................................................................................3

Figure 1.2 a) The structure of boronic acid moiety and a representation of its
vacant p-orbital. b) Lone pair overlap between B(pz) and oxygen lone pairs.
c) Additional C(pz)-B(pz) overlap in alkenyl and aryl boronic acids ...............................................5

Figure 1.3 Crystalline, repeating structure of phenylboronic acid in the solid state ......................7

Figure 1.4 C-B bond lenths correlated with degree of pz-conjugation ..........................................8

Figure 1.5 Selected examples demonstrating the substrate scope for the
Passerini-type multicomponent synthesis of a-hydroxyketones ....................................................11

Figure 1.6 Synthesis of anti- β-amino alcohols via chiral α-hydroxyaldehydes ...........................17

Figure 1.7 Proposed transition states of sulfinyl functionalized intermediates
pre styryl-migration .......................................................................................................................22

Figure 2.1 Concentration versus yield of reactions done via mechanical grinding .....................36

Figure 2.2 ORTEP crystal structure of Enalaprilat 28 .................................................................39
x
Figure 2.3 Computational studies on the geometry of Enalaprilat 28 in water ...........................40

Figure 2.4 Staked 1H NMR spectra of the alkenyl protons of 19 taken in 15-minute
intervals ..........................................................................................................................................48

Figure 2.5 Optimized geometries of 13 via B3LYP/6-31++G** (PCM, DMSO) .......................50

Figure 2.6 Optimized geometries of 10 via B3LYP/6-31++G** (PCM, DMSO) .......................51

Figure 3.1
19
F NMR spectrum of Mosher’s ester 7 (no internal standard was present for
signal referencing) .........................................................................................................................83

xi
LIST OF SCHEMES
Scheme 1.1 Ugi four-component reaction towards α-acetoamido carboxamides ..........................2

Scheme 1.2 Mechanism for the Ugi four-component reaction .......................................................4

Scheme 1.3 a) Adduct formation of boronic acids with water. b) Structure of boronate
anion 13 elucidated via X-ray diffraction ........................................................................................9

Scheme 1.4 Synthesis of naftifine via the Petasis borono-Mannich reaction ...............................12

Scheme 1.5 Efficient two-step synthesis of α-amino acids via Petasis borono-Mannich
reaction and Pd-catalyzed N-debenzylation ...................................................................................13

Scheme 1.6 Synthesis of novel anticoagulant inhibitor of the Tissue Factor/Factor VIIa ...........14

Scheme 1.7 Synthesis of 2-(5-nitroindolin-1-yl)-2-arylacetic acids (22) .....................................15

Scheme 1.8 Proposed mechanism for the synthesis of indol-3-yl-acetic acids ............................16

Scheme 1.9 Synthesis of optically pure, protected δ-amino amino acids via a chiral
functionalized glucose-derived aldehyde .......................................................................................18

xii
Scheme 1.10 Synthesis of (-)- and (+)-conduramine E featuring key asymmetric Petasis
reaction step ...................................................................................................................................19

Scheme 1.11 Chiral sulfonamide facilitated asymmetric synthesis of a key component in
antifungal echinocandins ...............................................................................................................20

Scheme 1.12 Asymmetric synthesis of chiral α-amino methyl esters ..........................................21

Scheme 1.13 Chiral thiourea catalyzed Petasis reactions. a) first asymmetric catalyzed
report requiring precondensation of amines and aldehydes. b) Follow up report utilizing
improved chelating system. c) Proposed chelation intermediates .................................................23

Scheme 1.14 Asymmetric Petasis reactions via chiral BINOL derivatives .................................24

Scheme 1.15 Synthesis of anti- β-amino alcohols via chiral BINOL catalysts.............................25

Scheme 2.1 Pilot reaction for the three-component Petasis borono-Mannich reaction in
water ...............................................................................................................................................32

Scheme 2.2 Synthesis of Enalaprilat (28)* via Pd-catalyzed hydrogenation 27 in water ............38

Scheme 2.3 Equilibrium pathway demonstrating stereodifferential control in the
synthesis of aminodicarboxylic acids in water ..............................................................................42
xiii

Scheme 2.4 Dynamic equilibrium of spiro-like conformers in DMSO-d6 ..................................45

Scheme 3.1 Retrosynthetic analysis of 15-epi-Benzo-lipoxin A4 ................................................81

Scheme 3.2 Total synthesis of 15-epi-Benzo-lipoxin A4 .............................................................82

Scheme 4.1 Biosynthesis of NPD1/PD1 and AT-NPD1/PD1.
5
...................................................94

Scheme 4.2 Retrosynthetic analysis for the production of AT-NPD1/PD1 .................................97

Scheme 4.3 Synthesis of terminal fragment 5 ..............................................................................98

Scheme 4.4 Synthesis of the core fragment ................................................................................100

Scheme 4.5 Joining of the terminal pieces and completion of AT-NPD1/PD1 .........................101

Scheme 4.6 Unsuccessful conversions. a) Low yielding trityl ether deprotection.
b) Suzuki-Miyaura substrate modifications. c) Ordering of terminal fragment couplings ..........104

xiv
ABSTRACT
The first chapter of this dissertation introduces the historical development of the Petasis
borono-Mannich reaction. Topics covered include a brief discussion on the merits and
applications of multicomponent reactions in general, boronic acids and their use in
multicomponent reactions, and asymmetric versions of the Petasis borono-Mannich reactions
involving chiral substrates, catalysts, and auxiliaries towards stereopure compounds of biological
relevance.
The second chapter describes our latest studies on a one-step, multicomponent reaction,
wherein stereopure amino acids, glyoxylic acid monohydrate, and trans-2-phenylvinylboronic
acid are combined to form multifunctionalized amines and amino acid derivatives of biological
interest. Typically performed in organic solvents, our method involves the use of water to
furnish multifunctionalized amino acids in very high diastereoselectivity. We extended the study
to dipeptides to showcase the applicability of our method for process synthesis. L-alanine-L-
proline was converted to its respective functionalized dipeptide in >99% de and 93% yields on
the gram scale, and subsequent aqueous hydrogenation using Pd/C furnished Enalaprilat, the
metabolically generated form of the hypertension blockbuster therapeutic Vasotec. Additionally,
unique conformational isomers of the synthesized products were observed using
1
H-NMR
spectroscopy. The conformational dynamics in solution were studied and elucidated using both
time-dependent
1
H NMR spectroscopy and DFT calculations. To our knowledge, this
conformational system has not been reported in the literature.
Chapter Three discusses a convenient four-step total synthesis of the pro-resolving lipid
mediator, 15-epoi-benzo-lipoxin A4, in 32% overall yield and >99% ee via a Noyori asymmetric
ketone reduction.
xv
Chapter Four discusses a modified convergent synthesis of aspirin-triggered
neuroprotectin D1/protectin D1 (AT-NPD1/PD1). AT-NPD1/PD1 is an analogue of
endogenously derived pro-resolving lipid-mediators that play a key role in the proper resolving
of inflammation. The key benefit to our modified route is that a core unit is synthesized that
shares its structure with the rest of its class of lipid-mediators. Therefore, synthesis of an
abundance of this core unit allows quick and efficient synthesis of AT-NPD1/PD1’s chiral and
structural derivatives, requiring far less steps than the overall synthesis.

1

CHAPTER 1
Boron-Mediated, Multicomponent Reactions

2
1.1 Introduction
1.1.1 Multicomponent Reactions
Multicomponent reactions (MCRs) are useful conversions involving three or more
components that combine to form a single product. The appeal of this relatively new technology
is the exceptionally high atom economy – nearly all atoms within the substrates are retained in
the final product – and extensive diversification is achievable by changing one or more of the
substrates. Additionally, MRCs facilitate the formation of more than one bond, allowing access
to a broad range of complex molecules in a single step without needing transition metal catalysts.
A pioneering example is the Ugi four-component reaction involving an aldehyde, an amine, a
carboxylic acid, and an isocyanide to furnish α-acetoamido carboxamide derivatives.
1

Scheme 1.1: Ugi four-component reaction towards α-acetoamido carboxamides.

One of many key advantages of MCRs is their tolerance for orthogonal reactive
functional groups contained within the structures of the substrates. This allows for further, step-
wise diversification into more complex molecules post-condensation. Thus, what might take a
linear synthetic approach a multitude steps can often be achieved in less than three. A notable
example is the Ugi-deprotection-cyclization (UGC)
procedure, where substrate functional groups are deptrotected post-condensation and are then
reacted to form cyclized products of biological importance. For example, this method was used
3
to synthesize biologically active quinoxalinone (1), benzimidazole (2), benzodiazepinedione (3),
and tetrazolodiazepinone (4) derivatives (Figure 1.1).
2

Figure 1.1: Examples of biologically active compounds synthesized using the UGC procedure.

Several types of MCRs exist. Type I MCRs involve multiple equilibrium pathways
among the reactants and intermediates. Type II MCRs are also equilibrium driven but have a
single, irreversible step leading to the product. Type III MCRs involve multiple irreversible
steps.
2
Type II MCRs will be the focus of this chapter, because they are the most synthetically
attractive due to their ability to achieve high yields and exceptional purity by nature of their
mechanism. These MCRs are interesting mechanistically because of their equilibrium driven
cascade with the irreversible formation of the product occurring last.
The most established and popular type II MCRs involve amines and carbonyl compounds
as two of the key components. A generalized version of the Ugi 4-component reaction
mechanism is shown in Scheme 1.2.
3
Their pathway is initiated upon reversible addition of the
amino nucleophile to the carbonyl moiety to produce a hemiaminal intermediate (5), which is
followed by subsequent liberation of a water molecule and generation of a transient iminium
cation (6) depending on the conditions. The iminium salt favorably undergoes irreversible
addition by a nucleophile to the unsaturated α-carbon to furnish the final compound. Reaction
4
completion is essentially achieved as a result of nucleophilic addition eliminating and further
potential for addition to the unsaturated C-N bonds.
4
In the case of the four-component Ugi
reaction, a final intramolecular acyl transfer reduces the unsaturated C-N bond of the imine
intermediate (7), generating the desired α-aminoacyl amide (8).

Scheme 1.2: Mechanism for the Ugi four-component reaction.

Because irreversibility of carbonyl addition is required for type II MCRs, one of the
main developmental challenges of reactions based on these compounds is identifying third and
fourth components that do not add irreversibly to the carbonyl group. Our group began
exploring the possibility of using boronic acids as the third
component in MCRs of this type due to their tunable electronic properties. One of the
fascinating aspects of boronic acids and esters is that they can behave as electrophiles or
nucleophiles based on their chemical environment. The following section is intended to
introduce boronic acids and their reactivities and illustrate why boronic acids are a particularly
interesting third component.
5
1.1.2 Organoboronic Acids: Structure and Properties
The applicability of organoboronic acids in organic synthesis has expanded impressively
over the course of the mid to late 20
th
century. Since the 1940s, the number of publications
focusing on boronic acids has grown exponentially.
5
Most notable are transition-metal-catalyzed
cross-coupling reactions involving organoboronic acids. The formation of C-C and C-N bonds
in an efficient and general way is of crucial importance to the field of organic synthesis. Likely
the most general and wide reaching approach to C-C and C-N bond formation is the Suzuki-
Miyaura reaction first published in 1981.
6

What has allowed organoboronic acids their broad applications in organic synthesis lies
within the unique structure that sets them apart from compounds composed of the other second
period elements. Organoboronic acids are trivalent boron-containing molecules with one C-B
bond and two hydroxyl groups that functionalize the boron atom. The unique six-electron
valency of boron—of which the electrons are contained within the three sp
2
hybridized C-B and
C-O bonds—result in a stable, two-electron vacancy. Thus, a vacant p-orbital occupies space
orthogonal to its adjacent bonds and imparts unique electronic behavior and Lewis acidic
properties (Figure 1.2a). Unlike the analogous boranes, overlap between boron’s empty p-
orbital and neighboring oxygen lone pairs provides boronic acids with stabilization (Figure
1.2b), allowing them to tolerate broad chemical environments and be less prone to
decomposition.

6

Figure 1.2: a) the structure of boronic acid moiety and a representation of their vacant p-orbital.
b) Lone pair overlap between B(p z) and oxygen lone pairs. c) Additional C(p z)-B(p z) overlap in alkenyl and aryl
boronic acids.

Organoboronic acids bearing alkenyl and aryl carbon substituents have a planar
configuration allowing optimal conjugative overlap between neighboring p-orbitals along the C-
B bond (Figure 1.2c). An X-ray crystal structure of phenylboronic acid demonstrated the overall
planarity of the compound. The geometric configuration and hydrogen bonding capacity of these
types of boronic acids result in regular, repeating units in the solid phase with each B-OH group
forming hydrogen bonding partners with two others (Figure 1.3).
7

7

Figure 1.3: Crystalline, repeating structure of phenylboronic acid in solid phase.

The stability and reactivity of organoboronic acids are partially dependent on the
properties of the carbon moiety bonded to boron. The extent of electron delocalization between
the p-orbital of boron and neighboring carbon group (Figure 1.2c) is the deterministic variable.
Four subgroups of organoboronic acids exist, arranged from lowest to highest stability: alkyl-,
alkenyl-, alkynyl-, and arylboronic acids. Moderate electron delocalization between the pi-
orbitals of the carbon group and the boron’s p-orbital are what give alkenyl-, alkynyl-, and
arylboronic acids their greater stability over alkylboronic acids. This was evidenced by
measuring the C-B bond lengths for a series of arylboronic acids shown in figure 1.4 to assess
the stability of compounds with varying carbon functionalities. Compound 9 and 10 have C-B
bond lengths of 1.568 and 1.556 Å, respectively. The reduction of 0.012 Å corresponds with the
increased electron density within the aromatic system as a consequence of the electron donating
ability of the methoxyl group. The bond length of compound 11 is 1.588 Å, showing a
lengthening of the C-B bond consistent with the strongly electron withdrawing substituents on
8
the ring and diminished delocalization across the C-B π-bond. The inductive effects on the two
derivatives of compound 12 result in bond lengths of 1.573 Å, slightly longer bond length
compared with 9 due to induction.
8

Figure 1.4: C-B bond lengths correlated with degree of p z-conjugation.

By virtue of boron’s vacant p-orbital, completion of its octet can occur via formation of
adducts with Lewis-basic compounds to form relatively stable tetravalent anions. These adducts
are typically formed in-situ under basic conditions. In 1959, studies on the water solubility of
organoboronic acids in high pH solutions led to the elucidation of the quasi-stable tetravalent
boronate anion (13). Previous assumptions were that formation of hydronium ions upon
dissolution of organoboronic acids in basic aqueous solution was the result of water acting as a
Brønsted base. Thus, hydronium ion formation was believed to be a result of deprotonation of an
oxygen atom, generating an anion and retaining a trivalent boron structure. By contrast, it was
determined that indirect proton transfer occurs after complexation with a water molecule to
generate the tetravalent boronate anion (Scheme 1.3a).
9
The crystal structure of 13 has recently
been reported (Scheme 1.3b).
10

9

Scheme 1.3: a) Adduct formation of boronic acids with water. b) Structure of boronate anion 13
elucidated via X-ray diffraction.

Organoboronate anions vary drastically from their neutral counterparts. In their trivalent
form, they act as Lewis Acids. After complexation with a basic molecule, the electronic
character becomes that of a nucleophile in lieu of boron’s negative charge. Under the right
conditions, these anions behave as carbon group transfer nucleophiles.
The key features previously discussed make alkenyl- and arylboronic acids very desirable
reagents for organic synthesis. By virtue of their electronic structure, they are quite stable to
oxidation in ambient conditions, allowing them to be stored on the bench top for extended
durations. Additionally, their negligible toxicity and functional group tolerance make them ideal
for pharmaceutical applications.
11

10
1.2 Multicomponent Reactions Involving Organoboronic Acids
Organoboronic acids have been extensively applied to multicomponent reactions towards
functionalization of unsaturated C-N bonds to provide a broad variety of compounds of
biological interest. Unsaturated C-N bonds have traditionally been functionalized using
organometallic reagents. Many compelling advantages make organoboron compounds an
attractive alternative to these toxic and dangerous reagents. Organoboronic acids exhibit
exceptional chemoselectivity, tolerance towards a broad range of functional group, lower
toxicity, and considerable ease of handling and storage in the laboratory. Additionally,
organoboronic acids used in MCRs give boric acid as the only byproduct, making it an
environmentally feasible synthetic alternative for pharmaceutical chemists. Lastly, a cornucopia
of organoboronic acid derivatives are commercially available at low cost.

1.2.1 Passerini-Type Reaction
A recent report by Yang et al highlighted a three-component Passerini-type synthesis of
α-hydroxyketones—compounds with a scaffold commonly occurring in natural products and
pharmaceuticals—using aldehydes, isocyanides and arylboronic acids.
12
The scope of suitable
aldehydes and boronic acids were explored and the method was shown to tolerate a broad range
of substrates, affording products in moderate to good yields (Figure 1.5). Late-stage
modification of complex bioactive or therapeutic compounds was explored due to the excellent
functional group tolerance typical of MCRs and the nature of the reagents used.

11

Figure 1.5: Selected examples demonstrating the substrate scope for the Passerini-type multicomponent
synthesis of α-hydroxyketones.

1.2.2 Petasis Borono-Mannich Reaction
Most relevant to this dissertation is the three-component Petasis borono-Mannich reaction
reported in 1993 by Petasis and Arkitopoulou.
13
This process was originally investigated as a
step-wise reaction involving preformed adducts of amines and paraformaldehyde with addition
12
of a suitable alkenylboronic acid. Due to troubles surrounding incomplete condensation between
amine and the carbonyl component, a novel process involving a vigorously stirred mixture of all
three components lead to the discovery of the three-component Petasis borono-Mannich reaction
(also referred to simply as the Petasis reaction). Their first reported application involved the
synthesis of naftifine (16)—a very active topical antimycotic—using N-methyl-1-(naphthalen-1-
yl)methanamine (14), trans-2-phenylvinyl boronic acid (15), and formaldehyde as the
components (Scheme 1.4).

Scheme 1.4: Synthesis of naftifine via the Petasis borono-Mannich reaction.

Petasis and Zavialov reported a simple convergent method towards the synthesis of non-
natural α-amino acids by employing various amines, alkenylboronic acids and glyoxylic acid
(Scheme 1.5).
14
The key feature of this method is the ability to design the α-amino acid by
varying the boronic acid and amine employed. Chiral amines lead to exceptional stereocontrol
upon nucleophilic attack by the organoboronate at the unsaturated C-N α-carbon. The amine was
strategically chosen so that palladium catalyzed benzyl cleavage would furnish an N-
unsubstituted homophenylalanine HCl.

13

Scheme 1.5: Efficient two-step synthesis of α-amino acids via Petasis borono-Mannich reaction and
Pd-catalyzed N-debenzylation .

Zhang, et. al. utilized the Petasis borono-Mannich reaction to synthesize novel
anticoagulant inhibitors of the Tissue Factor/Factor VIIa (21) (Scheme 1.6). The key
intermediate (20) was obtained through Petasis borono-Mannich reaction of glyoxylic acid
monohydrate (17), boc-protected 1,6-aminoisoquinoline (18), and (4-fluoro-3-
methoxy)phenylboronic acid (19). Enantiomerically pure compounds were obtained by chiral
resolution.
15

14

Scheme 1.6: Synthesis of novel anticoagulant inhibitor of the Tissue Factor/Factor VIIa.

Secondary amines have also been used to generate biologically interesting compounds
(Scheme 1.7). A series of 2-(5-nitroindolin-1-yl)-2-arylacetic acids (22) were synthesized in a
single step using glyoxylic acid monohydrate (17), various arylboronic acids (23), and 5-
nitroindoline (24) in the presence of a catalytic amount of trifluoroacetic acid to accelerate the
reaction.
16

15

Scheme 1.7: Synthesis of 2-(5-nitroindolin-1-yl)-2-arylacetic acids (22).

1.2.3 Petasis-Type Reactions
The Petasis reaction is notable for its ability to generate a C-C and C-N bond without the
need for transition metal catalysts. Roughly a decade after its discovery, variants of the Petasis
reaction have been reported involving carbon-based nucleophilic substrates towards the
generation of two C-C bonds. Naskar et al developed a method replacing traditionally used
amino nucleophiles with N-substituted indoles (Scheme 1.8).
17
According to their proposed
mechanism, nucleophilic addition to glyoxylic acid monohydrate occurs at C3 of the indol (23)
generating the adduct (24), followed by complexation between the pz orbital of the
phenylboronic acid derivative (25) and the carboxylate to generate a boronate complex (26).
Electrons from the activated C-B bond then adds to the proximal unsaturated C-C bond
generating the product (27).

16

Scheme 1.8: Proposed mechanism for the synthesis of indol-3-yl-acetic acids.

1.3 Asymmetric Petasis Borono-Mannich Reactions
Asymmetric Petasis borono-Mannich reactions usually involve stereogenic centers on
one or more substrates involved in the condensation. Most common examples involve aldehydes
with stereogenic hydroxy functionalized α-carbons which give exclusively anti-selectivity.
These reactions reliably give optically pure products with >99% diastereoselectivity. The use of
chiral amines have been reported, but with lower stereodifferentiation due to mechanistic
considerations discussed in the following section.
Chiral organoboronic esters have also seen use, with less frequency. These components contain
stereogenic carbons within the ester moiety. Further discussion on these reagents is beyond the
scope of this dissertation. Another means of inducing stereocontrol involves chiral auxiliaries,
which will also be discussed in the following section.
17
1.3.1 Chiral Substrate Control
One of the most reliable and useful means of stereodifferential control involve chiral α-
hydroxyaldehydes and their derivatives, which furnish anti products exclusively. Petasis and
Zavialov reported a novel approach towards anti- β-amino alcohols with >99% de using chiral α-
hydroxyaldehydes (Figure 1.6).
18
A broad range of vinyl- and arylboronic acids, primary and
secondary amines, and chiral α-hydroxyaldehydes were screened, achieving good to excellent
yields and >99% de in all cases.

Figure 1.6: Synthesis of anti- β-amino alcohols via chiral α-hydroxyaldehydes.
Lenci et. al. utilized α-D-glucodialdofuranose (29) derived from commercially available
glucose diacetonide (28) as the aldehyde component to functionalize the C-6 carbon with >99%
de, providing a short route towards optically pure, protected δ-amino acids.
19
Amines and α,β-
18
unsaturated organoboronic acids were screened with moderate yields achieved. Optically pure,
polyfunctional protected δ-amino acid (31) was synthesized from 30 in 48% yield over two steps.

Scheme 1.9: Synthesis of optically pure, protected δ-amino amino acids via a chiral
functionalized glucose-derived aldehyde.

Partha and Shaw utilized the Petasis borono-Mannich reaction in the total synthesis of
(+)- and (-)-conduramine E using chiral α-hydroxyaldehydes derived from carbohydrates
(Scheme 1.10).
20
(+)-conduramine E (34) was synthesized via hemiacetal (32) derived from D-
galactose. Compound 32 was treated with tert-butylamine and trans-2-phenylvinyl boronic acid
to give the unsaturated amino alcohol (33). Further functionalization provided optically pure 34
in six additional steps.
19
The synthesis of (-)-conduramine E (37) involved conversion of D-mannose into the
corresponding aldehyde (35) in five steps and was subsequently treated with tert-butylamine and
trans-2-phenylvinyl boronic acid to give stereopure amine (36). Five additional steps furnished
optically pure 37.

Scheme 1.10: Synthesis of (-)- and (+)-conduramine E featuring key asymmetric Petasis reaction step.

20
1.3.2 Chiral Auxiliary Control
Novel approaches involving chiral sulfonamide auxiliaries have been investigated.
Hutton and coworkers reported a stereoselective approach to the synthesis of a key component in
naturally occurring antifungal echinocandins.
21
Using tert-butylsulfinamide (38) as the source of
stereocontrol in conjunction with trans-2-phenylvinylboronic acid derivatives and glyoxylic acid
monohydrate furnished the desired compound (39) in upwards of 20:1 dr.

Scheme 1.11: Chiral sulfonamide facilitated asymmetric synthesis of a key component in
antifungal echinocandins.

Xu and Li synthesized β, γ-unsaturated α-amino acids achieving high diastereoselectivity
via chiral sulfinamides (40), glyoxylic acid monohydrate, and vinylboronic acids (Scheme
21
1.12).
22
82% de was achieved in the absence of Lewis-acid additives. Introduction of InBr3
resulted in an impressive increase in selectivity as high as 99% de. A series of vinylboronic
acids were demonstrated to give N-sulfinyl α-amino acids (41) bearing unique R-groups. Post-
condensation, the sunfinyl group was cleaved using thionyl chloride in methanol to give α-amino
methyl esters (42).

Scheme 1.12: Asymmetric synthesis of chiral α-amino methyl esters.

Xu and Li proposed a plausible explanation for stereocontrol based on previously
reported crystal structures and theoretical calculations on relevant systems, in addition to
diastereofacial selectivities observed in their previous metal-chelation work.
23
Indium chelation
between carboxylate and amine gives a 5-membered ring (TS-1) with the N-sulfinyl moiety in a
synperiplanar configuration. This configuration makes styryl migration from the Re-face
preferable due to steric repulsion between the boronate phenylvinyl and tert-butyl groups.

22

Figure 1.7: Proposed transition states of sulfinyl functionalized intermediates pre-styryl migration.

1.3.3 Chiral Catalyst Control
Enantioselective organocatalysis has become an essential tool for synthetic chemists. Not
only do they have the ability to enrich the optical purity of a given conversion, they can also
provide novel substrate activation similarly seen from their organometallic counterparts,
typically without need for special operative procedures.
The first organocatalyzed asymmetric Petasis-type reaction was reported in 2007 by
Yamaoka et al and involved chiral thiourea (45) activation of preformed condensation product
(46) between quinoline (43) and phenyl chloroformate (44) in the presence of trans-2-
phenylvinyl boronic acid (Scheme 1.14a).
24
Bifunctional chelation of 46 and boronic acid by
optically pure 45 induces facial selectivity for alkenyl transfer generating functionalized
quinolines 47 with R-stereoconfiguration in as high as 94% ee.
The same group later developed an asymmetric synthesis of N-aryl amino acid
derivatives without need for preformed condensation adducts via novel, chiral hydroxy-thiourea
catalysts derived from their previous study (Scheme 1.14b).
26
In their report, glyoxylsaeure-
dimethylamid (48) and 2,4-dimethoxyaniline (49) were treated with trans-2-phenylvinylboronic
23
acid diisopropyl ester (50) and catalytic amount of hydroxy-thiourea catalyst (51) achieving N-
aryl amino acids (52) in upwards of 92% ee. In comparison with their previous study, the
presence of basic amino or imino groups within the catalyst likely prevent chelation of adducts
with lone-pair containing nitrogen.

Scheme 1.13: Chiral thiourea catalyzed Petasis reactions.
a) first asymmetric catalyzed report requiring precondensation of amines and aldehydes. b) Follow up report
utilizing improved chelating system. c) Proposed chelation intermediates.
24
A pioneering development in asymmetric Petasis borono-Mannich reactions involves the
use of chiral BINOL-derived catalysts. Schaus and Lou developed the first BINOL-catalyzed
asymmetric Petasis borono-Mannich reaction to afford chiral α-amino acids.
26
By using
organoboronic esters in place of acids, they took advantage of ligand exchange between the more
facile ester groups with the BINOL hydroxyl groups to form the axially chiral tetravalent
boronate anion.
27

Scheme 1.14: Asymmetric Petasis reactions via chiral BINOL derivatives.
25
Enantiopure β-amino alcohols with anti diastereoselectivity can be synthesized via α-
hydroxyaldehydes. Its limitation is the inability to achieve β-amino alcohols in a syn
diastereoselective fashion due to the method’s intrinsic anti selectivity. Schaus and coworkers
developed the first method towards both anti- and syn- β-amino alcohols by adapting their
previous work on BINOL-derivatives.
28

Scheme 1.15: Synthesis of anti- β-amino alcohols via chiral BINOL catalysts.
26
1.4 References
[1] (a) Ugi, I.; Angew. Chem. Int., 1959, 71, 386; (b) Ugi, I.; Angew. Chem. Int. 1962, 1, 8-
21. (c) Dömling, A.; Ugi, I.; Multicomponent Reactions with Isocyanides. Angew. Chem.
Int. Ed. 2000, 39, 18, 3168-3210.
[2] Dömling, A.; Wang, W.; Wang, K.; Chemistry and Biology of Multicomponent
Reactions Chem. Rev. 2012, 112, 3083-3135.
[3] Rocha, R. O.; Rodrigues, M. O.; Neto, B. A. D.; Review on the Ugi Multicomponent
Reaction Mechanism and the Use of Fluorescent Derivatives as Functional
Chromophores. ACS Omega, 2020, 5, 972-979.
[4] Zhu, J.; Bienaymé, H.; Multicomponent Reactions, chapter 7: Multicomponent
Reactions with Organoboron Compounds, pp. 199-223, 1
st
ed.; Wiley-VCH, 2005.
[5] Hall, D.; Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine
and Materials, in preface, vol.; 1, 1
st
ed.; Wiley-VCH, 2011.
[6] Miyaura, N.; Yanagi, T.; Suzuki, A.;The Palladium-Catalyzed Cross-Coupling
Reaction of Phenylboronic Acid with Haloarenes in the Presence of Bases. Synth.
Commun. 1981, 11, 513-519.
[7] Retting, S. J.; Trotter, T.; Crystal and molecular structure of phenylboronic acid,
C6H5B(OH)2 Can. J. Chem., 1977, 55, 3071-3075.
[8] (a) Cambridge Crystallographic Database Compound (CCDC) number 222652
(www.ccdc.cam.ac.uk). (b) Soundararajan, S.; Duesler, E. N.; Hageman, J. H.;
Structure of 4-carboxy-2-nitrobenzeneboronic acid. Acta. Crystallogr. 1993, C49,
690-693.
27
[9] Lorand, J. P.; Edwards, J. O.; Polyol Complexes and Structure of the Benzeneboronate
Ion. J. Org. Chem., 1959, 24, 769-774.
[10] Cammidge, A. N.; Goddard, V. H. M.; Gopee, H.; Harrison, N. L.; Hughes, D. L.;
Schubert, C. J.; Sutton, B. M.; Watts, G. C.; Whitehead, A. J.; Aryl Trihydroxyborates:
Easily Isolated Discrete Species Convenient for Direct Application on Coupling
Reactions. Org. Lett. 2006, 8, 4071-4074.
[11] Hall, D.; Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine
and Materials, in ch. 13, vol.; 3, 1
st
ed.; Wiley-VCH, 2011.
[12] Yang, K.; Zhang, F.; Fang, T.; Li, C.; Li, W.; Song, Q.; Passerini-type reactions of
boronic acids enables α-hydroxyketones synthesis. Nat. Commun. 2021, 12, 441.
[13] Petasis, N. A.; Akritopoulou, I.; The boronic acid mannich reaction: A new method for
the synthesis of geometrically pure allylamines. Tet. Lett. 1993, 34, 583-586.
[14] Petasis, N. A.; Zavialov, I. A.; A New and Practical Synthesis of α-Amino Acids from
Alkenyl Boronic Acids. J. Am. Chem. Soc. 1997, 199, 445-446.
[15] Zhang, X.; Jiang, W.; Jacutin-Porte, S.; Glunz, P. W.; Zou, Y.; Cheng, X.; Hirschl, A. H.;
Wurtz, N. R.; Luettgen, J. M.; Rendina, A. R.; Luo, G.; Harper, T. M.; Wei, A.;
Anumula, R.; Cheney D. L.; Knabb, R. M.; Wong, P. C.; Wexler, R. R.; Priestley, R. S.;
Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and
Selective TF-FVIIa Inhibitors. ACS Med. Chem. Lett., 2014, 5, 2, 188-192.
[16] Zhang, J.; Yun, F.; Xie, R.; Cheng, C.; Chen, G.; Li, J.; Tang, P.; Yuan, Q.; Petasis three-
component reaction accelerated by trifluoroacetic acid: synthesis of indoline-derived
glycenes. Tet. Lett., 2016, 57, 3916-3919.
28
[17] Naskar, D.; Neogi, S.; Roy, A.; Mandal, A. B.; Novel Petasis boronic acid reactions with
indoles: synthesis of indol-3-yl-aryl-acetic acid. Tett. Let. 2008, 49, 6762-6764.
[18] Petasis, N. A.; Zavialov, I. A.; Highly Stereocontrolled One-Step Synthesis of anti-β-
Amino Alcohols from Organoboronic Acids, Amines, and α-Hydroxy Aldehydes. J. Am.
Chem. Soc. 1998, 120, 45, 11798-11799.
[19] Lenci, E.; Puglielly, R. B.; Bucaletti, E.; Innocenti, R.; Trabocchi, A.; A Glucose-Derived
α-Hydroxy Aldehyde for the Petasis Reaction: Facile Access to Polyfunctional δ-Amino
Acids. Eur. J. Org. Chem., 2020, 4227-4234.
[20] Ghosal, P.; Shaw, A. K.; A Chiron Approach to Aminocytitols by Petasis-Boronno-
Mannich Reactions: Formal Synthesis of (+)-Conduramine E and (-)-Conduramine E. J.
Org. Chem., 2012, 77, 7627-7632.
[21] Churches, Q. I.; White, J. M.; Hutton, C. A.; Synthesis of β,γ-Dihydroxyhomotyrosines
by a Tandem Petasis-Asymmetric Dihydroxylation Approach. Tet. Lett., 2011, 13, 11,
2900-2903.
[22] Xu. M. H.; Li, Y.; Lewis Acid Promoted Highly Diastereoselective Petasis Borono-
Mannich Reaction: Efficient Synthesis of Optically Active β,γ-Unsaturated α-Amino
Acids Org. Lett. 2012, 14, 8, 2062-2065.
[23] (a) Owens, T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A.; Synthesis, Utility, and
Structure of Novel Bis(sulfinyl)imidoamidine Ligands for Asymmetric Lewis Acid
Catalysts. J. Am. Chem. Soc. 2001, 123, 1539.; (b) Owens, T. D.; Souers, A. J.; Ellman, J.
A.; The preparation and utility of bis(sulfinyl)imidoamidine ligands for the copper-
catalyzed Diels-Alder reaction. J. Org. Chem. 2003, 68, 3.; (c) Schenkel, L. B.; Ellman, J.
A.; Novel Sulfinyl Imine Ligands for Asymmetric Catalysis. Org. Lett., 2003, 5, 545 (d)
29
Tietze, L. F.; Schuffenhauer, A.; Synthesis of Tetrahydro- and Dihydropyridines by
Hetero Diels-Alder Reaction of Enantiopure α,β-Unsaturated Sulfinimines. Eur. J. Org.
Chem., 1998, 1629.; (e) Bharatam, P. V.; Uppal, P.; Kaur, A.; Kaur, D.; Theoretical
investigations on the conformational preferences of sulfinimines. J. Chem. Soc., Perkin
Trans., 2000, 2, 43.
[24] Yamoka, Y.; Miyabe, H; Takemoto, Y.; Catalytic Enantioselective Petasis-Type
Reactions of Quinolines Catalyzed by a Newly Designed Thiourea Catalyst. J. Am.
Chem. Soc. 2007, 129, 6686-6687.
[25] Inokuma, T.; Suzuki, Y.; Sakaeda, T.; Takemoto, Y.; Synthesis of Optically Active N-
aryl Amino Acid Derivatives through the Asymmetric Petasis Reaction Catalyzed by a
Novel Hydroxy-Thiourea Catalyst. Chem. Asian. J. 2011, 6, 2902- 2906.
[26] Lou, S.; Schaus, S. E.; Asymmetric Petasis Reactions Catalyzed by Chiral Biphenols. J.
Am. Chem. Soc., 2008, 130, 6922-6923.
[27] Lou, S.; Moquist, P. N.; Schaus, S. E.; Asymmetric Allylboration of Acyl Imines
Catalyzed by Chiral Diols. J. Am. Chem. Soc., 2007, 129, 15398-15404.
[28] Muncipinto, G.; Moquist, P. N.; Schreiber, S. L.; Schaus, S. E.; Catalytic
Diastereoselective Petasis Reactions. Angew. Chem. Int. Ed., 2011, 50, 8172-8175.

30

CHAPTER 2
Diastereoselective Multicomponent Synthesis of Aminodicarboxylic Acids in Water

31
2.1 Introduction
Chapter One introduced the Petasis borono-Mannich reaction and covered its features and
applications—most of which are relevant to pharmaceutical synthesis and green chemistry—that
make it a valuable synthetic alternative to traditional reactions. It is exceptionally atom
economical, high yielding, and generates C-C and C-N bonds without the need for transition
metal catalysts, all of which make this reaction particularly suited for process synthesis. Recent
developments on asymmetric Petasis reactions have added to its relevance considerably.
Stereoselective conversions are crucial in the development of compounds intended for
pharmaceutical use. Asymmetric reactions—particularly those that achieve over 99% diastereo-
or enantioselectivity—eliminate the considerable time and resources required to separate
stereoisomers from one another.
Another important aspect in the development of process synthesis is minimizing its
environmental impact. Over the past several decades, many have highlighted concerns about the
impact that excessive toxic chemical waste produced on a global scale may have. Thus,
considerable investigations towards less toxic alternative solvents and reagents have accelerated.
One of the most obvious and impactful strategies is the replacement of toxic organic solvents
with water.
Herein, results on our highly diastereoselective, aqueous, three-component synthesis of
aminodicarboxylic acids will be discussed. We are delighted to contribute to the growing body
of research on aqueous based Petasis borono-Mannich reactions.
1
It is also hoped that these
results will prompt further investigation into the parameters guiding stereocontrol in the Petasis
borono-Mannich reaction.

32
2.2 Results and Discussion
2.2.1 One-Step, Multicomponent Synthesis of Aminodicarboxylic Acid Derivatives
To test the feasibility of the reaction of interest, benzylamine (1) with a slight excess of
trans-2-phenylvinylboronic acid (2) and glyoxylic acid monohydrate (3) were stirred at 40 °C in
water for 48 hours (Scheme 2.1). The insolubilities of 1 and 2 resulted in a heterogeneous, white
suspension, so the solution was stirred vigorously to ensure efficient conversion. Due to
insolubility of the product, aminocarboxylic acid (4) was easily recovered via filtration and
subsequent washing with a minimal volume of acetone to remove unreacted 2 from the filtered
solid. Compound 4 was isolated in 77% yield without optimization of conditions.

Scheme 2.1: Pilot reaction for the three-component Petasis borono-Mannich reaction in water.

Glycine and β-alanine were reacted with 2 and 3 to afford 5 and 6, respectively, at 60 °C
in water for 48 hours (Table 2.1). Compounds 5 and 6 were isolated in good yields via filtration
and subsequent washing with ethyl acetate. Likewise, 7 was successfully isolated in 72% yield
after reaction of 3-aminobenzoid acid with 2 and 3 under the aforementioned conditions.
33

Table 2.1: Synthesis of aminodicarboxylic acid derivatives from amino acids.

The stereoselective syntheses of the aminodicarboxylic acids 8-16 in Table 2.1 were done
using various L- and D-amino acids with slight excess of 2 and 3. To our surprise, L-alanine
afforded 8 in >99% diastereoselectivity. In all subsequent cases, products were isolated in >99%
de. Amino acids bearing alkyl and aryl side chains were well tolerated by the reaction
conditions, affording 8-16 in moderate to good yields. Amino acids bearing heteroatoms on
their side chains proved more challenging. L-sarcosine, L-threonine, L-tryptophan, L-lysine, and
34
several others were reacted with 2 and 3 requiring more complicated purification procedures and
were emitted from the study. Only amino acids with oxygen containing side chains lead to
considerable product formation. Unlike the aliphatic amino acids, these aminodicarboxylic acid
derivatives are soluble in water, limiting the efficient purification by filtration. No attempt was
made to develop a purification procedure for these types of derivatives. On the other hand, L-
tyrosine with 2 and 3 led to precipitation of 16, which was isolated via filtration in moderate
yield after 48 hours at 60°C.
Compound 13 was synthesized on the gram scale and isolated in 80% yield and >99% de,
demonstrating an improvement between small and gram scale reactions and the feasibility of
adopting a macro scale industrial procedure.
Trans-2-phenylvinyl boronic acid derivatives bearing electron donating and withdrawing
substituents were tested to determine whether varying electron densities of the organoboronate
anions would be well tolerated by the given conditions (Table 2.2). Trans-2-(3-
fluorophenyl)vinyl boronic acid and its 4-fluoro analogue were reacted with 3 and L-
phenylalanine to afford 17 and 18 in moderate yields, respectively. The filtered solid required
suspension and sonication in acetone to remove excess organoboronic acid. This process led to
considerable loss of recovery by solvation of the products in acetone. Instead, ethyl acetate
proved to be a better alternative for purification. No attempt was made at further recovery of
compound solubilized in the filtrate. Compound 19 was synthesized from L-phenylalanine, 3,
and trans-2-(3-methoxyphenyl)vinyl boronic acid in 63% yield and >99% de after sonication in
acetone. We suspect that lack of variation in yields between boronic acids of different
electronegativities can be attributed to a solvation equilibrium unrelated to the relative reactivity
35
of the boronate anions. We believe that under forced conditions, a deviation in percent yield
would correlate with relative reactivity of the boronic acid component.

Table 2.2: Studies on the reactivity of boronic acids of differing electronegativities.

We were interested in studying the effect of concentration on the rate of reaction (Figure
2.1). A series of reactions between L-phenylalanine, 2, and 3 using various amounts of water at
room temperature for 7 hours were conducted via periodic mechanical grinding. As expected, a
trend in percent yield and concentration was observed. Most notably was the result of recovering
13 in 44% yield using minimal water. We suspect that modification and optimization may allow
access to an efficient industrial procedure towards the generation of aminodicarboxylic acids
using minimal solvent and energy. Additionally, L-phenylalanine, 2, and 3 in water at 1 mM was
left in a sonicater under argon for 24 hours, resulting in 42% yield and >99% de.
36

Figure 2.1: Concentration and yield of reactions done by mechanical grinding.

Dipeptides were studied next. L-alanyl- L-phenylalanine and L-phenylalanyl- L-
phenylalanine were coupled with 2 and 3 to afford 20, and 23 in 82 and 88% yield, respectively
(Table 2.3). In both cases, >99% diastereoselectivity was achieved. Interestingly, unlike the
amino acid derivatives, work-up required no washing of the filtered solid with organic solvent to
remove excess 2. By contrast, 26 was isolated in only 32% yield, >99% de, and required work-
up via flash chromatography to give a pasty, white semi-solid. Our compound of interest, 27,
was isolated in 93% yield after optimization, and 91% yield on the gram scale with >99%
diastereoselectivity. Work-up of 27 conveniently required only filtration and no subsequent
washing with solvent.
37

Table 2.3: Synthesis of functionalized dipeptides in water.

These dipeptide derivatives exhibited their own unique
1
H and
13
C NMR behavior.
2

Compounds 16 and 17 exist as two distinct conformational isomers due to amide C-N bond
induced planarity. Unique cis and trans signals in one-to-one ratio were present in their
respective
1
H and
13
C spectra. No evidence of exchange between the previously discussed
38
conformers was found (See section 2.2.4). As previously reported for the enalapril maleate salt,
21 showed a pH dependent preference for the trans isomer due to electrostatic repulsion of
proximal carboxyl groups. At higher pH, carboxylate repulsion is increased due to the negative
charges on both carboxylates and the trans-cis ratio is higher. In contrast, the trans-cis ratio is
smaller at lower pH. In addition, the existence of intramolecular hydrogen bond induced
conformers was evident in the spectra of 21, with small signals going through exchange.

2.2.2 Stereoselective Synthesis of Enalaprilat
Compound 27 was efficiently hydrogenated using 5% Pd/C at 10 wt. % loading under H2
at room temperature. We were delighted to determine that the reaction could be done with water
as the solvent as well. Enalaprilat (28) was isolated with full retention of stereochemistry
(Scheme 2.2). After filtering off the palladium catalyst, 28 crystalized from solution to give 22%
yield. Flash chromatography of the filtrate afforded the remainder of 28 to give a total of 72%
yield.

Scheme 2.2: Synthesis of Enalaprilat via Pd-catalyzed hydrogenation 27 in water.

A single crystal of 28, readily prepared by our process, was analyzed via X-ray
diffraction to give the ORTEP structure represented in Figure 2.2. The structure shows
39
preference for the cis isomer, with hydrogen bonding occurring between the benzyl carboxyl
group and amide oxygen moieties with the ammonium hydrogens, showing further support for
the existence of intermolecular hydrogen bonding conformers (See section 2.2.4). Further, this
structure confirms the S-stereogenic center generated in in the three-component reaction
reaction.

Figure 2.2: ORTEP crystal structure of Enalaprilat 28.

B3LYP/6-31++G**(PCM, H2O) calculations were conducted on a random structure of 28
to give a high-energy trans structure of which all subsequent energies were related (Figure 2.3).
First, rotation about the C4-C5 bond to give the geometry seen in the crystal structure gave an
increase of 0.16 kcal/mol. The C1-N1 and N1-C2 were rotated 60° to allow for optimal
hydrogen bonding between amide and carboxylate oxygen with ammonium hydrogens
corresponding to a drop in 0.47 kcal/mol. Subsequently, the C2-N2 bond was rotated 180° to
give the more stable cis conformer, dropping the energy by 3.53 kcal/mol. Due to repulsive
interaction between amide oxygen with carboxylate anion, no additional trans structures were
analyzed. A further drop in 0.60 kcal/mol was achieved by rotating the N1-C2 bond to realign
40
N-H and C2-O dihedral angle for optimal hydrogen bonding. Lastly, the optimal position of the
homobenzyl moiety was probed by rotation about the C1-C6 bond to give a corresponding drop
in 1.3 kcal/mol. Overlay of the crystal structure with the calculated lowest energy conformer
shows backbone structural similarities with a deviation in position of the homobenzyl group.

Figure 2.3: Computational studies on the geometry of Enalaprilat 28 in water.

2.2.3 Potential Sources of Stereoselectivity
We believe the high stereoselectivity observed has several plausible mechanistic
explanations. The first involves the nature of the “ate” complex studied computationally by
Candeias et al and its interactions with the solvent shell.
3
The stereoselectivity observed for the
Petasis reaction via chiral amines has demonstrated examples of steric stereodifferentiation. The
difference herein being choice of solvent. The high capacity for hydrogen bond formation
between these compounds and their respective intermediates with water molecules results in a
net stabilization of a series of intermediates generated along the equilibrium pathway. Of key
importance is the stabilization of the final intermediate preceding the final irreversible C-C bond-
41
forming step shown in Scheme 2.3. In conjunction with this, the ability for equilibrium-based
reverse reactions to occur amplifies stereo-differentiation at this final step. Steric restriction
upon generation of the ate-complex (29), combined with net-stabilization by solvation, likely
contributes greatly to stereodifferentiation. The (R)-intermediate likely experiences steric
repulsion between the hydroxyl group of the boronate ion and the amino acid side chain, greatly
slowing equilibrium along this pathway.
Another possible factor involves complexation of boron with the amino acid anionic
carboxylate oxygen in 29. Although complexation between boron and a hydroxyl group is much
stronger—as seen with chiral α-hydroxyaldehydes
4
—evidence for this interaction is presented in
the diminished stereodifferentiation when using chiral α-methylbenzylamine. We tested several
chiral amines to probe their stereodifferential control, and their results are shown in Table 2.4.

42

Scheme 2.3: Equilibrium pathway demonstrating stereodifferential control in the synthesis of aminodicarboxylic
acids in water.

The (S)-intermediate may experience further stabilization via a more optimized hydrogen
bonding system with a water molecule of the shell. For example, a hydrogen bond bridge
between the intermediate alcohol, a water molecule, and the carboxylic acid of the amino acid
moiety may contribute to the preference for the
43

Table 2.4: Studies on the stereoselectivity of various chiral amines.

pathway towards the generation of the (S) hydroxyl carbon center since this bridge cannot form
for the (R) alcohol. This indirect hydrogen bonding interaction may be present during attack of
the amino acid on glyoxylic acid, lowering the energy of the transition state. Experiments of the
reported conditions with non-hydrogen bonding solvents in place of water led to racemic
products, suggesting a strong link between the solvent’s hydrogen bonding ability and
stereodifferentiation.
A third consideration is the possibility of H-bond attraction between the hydroxyl groups
of the boronic acid and both carboxyl moieties of the (S) intermediate to help facilitate
generation of the ate-complex, which is in direct competition with strongly solvating water
44
molecules. Contrarily, the (R) intermediate can only facilitate the formation of the “ate
complex” via hydrogen bond-assisted direction using a single carboxyl moiety from the
glyoxylic acid side. It can be surmised that competition between boronic acid and water favors
“ate complex” formation when enough hydrogen bonding partners are present for the hydroxyl
groups on the boronic acid.
The result in a non-polar and / or weakly hydrogen bonding environment is expected to
increase the reactivity of the intermediates due to absence of hydrogen bonding, as well as a
diminished ability for the reverse reactions to occur. This diminishes potential for stereo-
differentiation between the stereogenic carbon of the alcohol upon formation of the ate complex
due to energetically similar intermediates.
To test this hypothesis, a series of reactions were done with varied choice of solvent at
room temperature. As expected, DCM lead to the generation of both (R) and (S) isomers of 13 in
racemic or near 1:1 ratio. Somewhat surprisingly, EtOAc lead to the same result, suggesting that
the strength of the hydrogen bond is a crucial variable. Acetone and MeOH produced the (S)
stereocenter in 55% yield and >99% de.
Surprisingly, the reaction done in H2O under otherwise identical conditions resulted in
the expected >99% de, but only 5% yield. We attribute this result to the solvation strength of
water. We envisage a series of stabilized, ionic intermediates through the equilibrium driven
pathway, limiting the rates of reaction due to the possibility of long-lived intermediates
drastically stabilized by the solvent network.

45
2.2.4 Conformational Dynamics of Aminodicarboxylic Acids in DMSO-d6
The structure of these compounds, coupled with weak solvation in polar aprotic solvents,
leads to interesting
1
H and
13
C NMR behavior. Intramolecular hydrogen bonding between both
carboxyl moieties and charged ammonium protons results in a pair of stable, spiro-like
conformers, which are easily detected using NMR spectroscopy. Scheme 2.4 illustrates a
plausible conversion pathway.
5

Scheme 2.4: Dynamic equilibrium of spiro-like conformers in DMSO-d 6.

These conformers have unique
1
H and
13
C signals within their respective NMR spectra.
Consequently, products 8-19 showed additional, small resonances with identical J-couplings and
multiplicity to their respective parent signals when analyzed in DMSO-d6. These signals were
46
initially mistaken with formation of undesired diastereomers during the reaction, but change in
integral ratio over time at room temperature between respective signals indicated the presence of
equilibrium-based conversion. The major and minor signals progress toward a roughly one-to-
one ratio at different rates for each of the aminodicarboxylic acids depending on the bulkiness of
their amino acid side chains. We speculate that the final, irreversible reaction step between imine
and the organoborate anion produces the major conformer, which precipitates from solution
before any solution-based exchange is able to occur. Upon dissolution in solvents like DMSO,
equilibrium is then facilitated.
As stated, we noted that exchange between conformers occurs at rates dependent on the
size of the amino acid side chain. Table 2.5 provides the time needed for compounds 8, 10, 12,
and 13 to reach equilibrium. In particular, the level of substitution at the β-carbon appears to be
responsible for the rate of exchange. Equilibrium for 8 was reached after less than 1 hour.
Substitution with larger alkyl and aryl moieties increased the rate considerably. Comparison of
12 and 13 shows a relationship between the steric bulk of the entire side-chain of the amino acid
moiety, requiring 3 and 8 hours, respectively. Compound 10 did not achieve equilibrium after 24
hours, indicating that the level of substitution at the amino acid β-carbon restricts the rate to a
greater extent than the overall size of the side chain. We suspect that there is some steric
restriction when traversing the conversion pathway. Another possibility is an increased entropic
factor governed by solvent reorganization upon conversion.

47

Table 2.5: Duration required to reach equilibrium for amino acids of different side chain.

The stacked
1
H NMR spectra of 13 taken at regular intervals of 15 minutes are provided
in Figure 5. An alkenyl proton signal was chosen for clarity. Changes in ratio are uniform for
each signal throughout the spectrum of a given compound.
The structures of these conformers and the nature of their conversion were evidenced by
experiments done in basic and acidic DMSO-d6. Interestingly, when sufficient base is added to
the sample, single, sharp
1
H signals are observed, indicating that only the expected diastereomer
was formed (these spectra can be found in the supporting information). The deprotonated form
loses the ability to form stable, intramolecularly hydrogen-bonded rings allowing quick
exchange.

48

Figure 2.4: Staked 1H NMR spectra of the alkenyl protons of 19 taken in 15-minute intervals.

We suspect that exchange can only occur as a direct result of deprotonation, followed by
pyramidal inversion of the amine. The 5-membered intramolecularly hydrogen bonded ring
structure prevents rotation about the C-N bond as illustrated in Figure 2.4. To test this
hypothesis, 8 was dissolved in acidic and basic DMSO-d6 (TFA and NaOD). Basic solution of 8
required only 55 minutes to reach equilibrium, in contrast to the 1.5 hours required in neutral
DMSO-d6. By contrast, equilibrium was not achieved after sitting in solution for 2 weeks for 8
in acidic solution.
49
To gain further evidence for the proposed conformation equilibria, sequential geometry
optimization and energy calculations at the B3LYP/6-31++G**(PCM, DMSO) level showed
hydrogen bonding between both carboxyl moieties with the ammonium hydrogens for
compounds 13 and 10 (Figure 2.6 and Figure 2.7, respectively).
6
The compounds were
modeled in their zwitterionic form. Because the peptide carboxyl group is anionic in the crystal
structure of Enalaprilat (Figure 2.2), the carboxyl groups on the amino acid were modeled as
anions.
From a random initial geometry, the conformational space of 13 was probed through a
systematic manipulation of 4 dihedral angles: d(O1C1C2N1), d(C1C2N1H1), d(C2N1C3C4),
and d(N1C3C4O2). The conformers shown in Figure 7 correspond to the two lowest energy
geometries for 13.

50

Figure 2.5: Optimized geometries of 13 via B3LYP/6-31++G** (PCM, DMSO).

51

Figure 2.6: Optimized geometries of 10 via B3LYP/6-31++G** (PCM, DMSO).

52
2.3 Conclusions
Herein, we have reported the three-component synthesis of aminodicarboxylic acid
derivatives and their dipeptide derived analogues using water as the solvent. Our conversions
have achieved moderate to excellent yields and in all cases have achieved >99%
diastereoselectivity. Using L-alanine-L-proline, we successfully synthesized Enalaprilat, the
metabolically generated form of Vasotec, in 67% overall yield and >99% diastereoselectivity.
Our results also demonstrated that aminodicarboxylic acids exhibit unique
conformational dynamic equiblibria in DMSO-d6 via intramolecular hydrogen bonding between
terminal carboxylic groups and ammonium protons. As far as we are aware, this system has not
been reported in the literature.
1
H NMR experiments and computational geometry minimizations
have provided supplemental evidence for our proposed conformational system.

53
2.4. Synthetic Preparation
General Information. All material was purchased from commercial suppliers and was used as
received without further purification. All
1
H NMR spectra were obtained using a Mercury 400
MHz spectrometer. All
13
C spectra were obtained using a Varian 600 MHz NMR spectrometer.
The NMR chemical shift values refer to DMSO-d6 (δ (
1
H), 2.50 ppm; δ (
13
C) 39.52 ppm). Mass
spectra were obtained on a Bruker micrOTOF-Q. Elemental analysis data was obtained on a
FLASH 2000 organic elemental analysis instrument.

General Procedure for the Synthesis of Aminodicarboxylic Acid Derivatives (4-19). Amino
acid (1.00 mmol), trans-2-phenylvinylboronic acid (1.2 mmol), and glyoxylic acid monohydrate
(1.2 mmol) were added to a rbf equipped with a stir bar. The flask was evacuated and backfilled
with argon three times, and distilled water (0.12-0.15 M) was added to the reaction vessel. The
solution was vigorously stirred at 60 °C in an oil bath for ~48 hours unless otherwise stated. The
crude was then filtered and washed with cold ethyl acetate to yield pure aminodicarboxylic acid
derivatives 4-19.

54
2-(benzylamino)-4-phenylbut-3-enoic acid (4)

40 °C. White solid, 413 mg, 86% yield from 196 mg (1.83 mmol) benzylamine, 339 mg 2 (2.22
mmol) 2, and 234 mg (2.49 mmol) 3 in 13 mL deionized H2O.
1
H NMR (400 MHz, DMSO-d6):
δ 7.25-7.44 (m, 10H), 6.65 (d, J = 15.7 Hz, 1H), 6.24 (dd, J = 8.1, 16.0 Hz, 1H), 3.92 (s, 2H),
3.86 (dd, J = 0.9, 8.1 Hz, 1H).
13
C{
1
H} NMR (151 MHz, DMSO-d6): δ 169.19, 136.15, 135.38,
133.31, 129.18, 128.69, 128.40, 127.91, 127.85, 126.30, 124.71, 63.30, 49.28. HRMS (ESI-TOF)
calc. for C17H16NO2

[M]
-
: 266.1187; found: 266.1190.

(1-carboxy-3-phenylallyl)-glycine (5)

55 °C, 51 hr. Light pink solid, 175 mg, 62% yield from 89.9 mg (1.20 mmol) glycine, 229 mg
(1.57 mmol) 2, and 132 mg (1.44 mmol) 3 in 7 mL deionized H2O.
1
H NMR (400 MHz, DMSO-
d6): δ 7.25-7.45 (m, 5H), 6.68 (d, J = 15.9 Hz, 1H), 6.19 (dd, J = 8.2, 15.9 Hz, 1H), 4.03 (d, J =
Hz, 1H), 3.36 (s, 2H).
13
C{
1
H} NMR (151 MHz, DMSO-d6): δ 170.75, 167.91, 136.00, 133.86,
128.74, 127.93, 126.53, 124.57, 62.56, 47.03.

55
(1-carboxy-3-phenylallyl)-β-alanine (6)

50 °C, 47 hr. White solid, 268 mg, 69% yield from 87.7 mg (0.984 mmol) beta-alanine, 181 mg
(1.23 mmol) 2, and 175 mg (1.25 mmol) 3 in 6.25 mL deionized H2O.
1
H NMR (400 MHz,
DMSO-d6): δ 7.42 (d, J = 7.4 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 6.71 (d,
J = 15.9 Hz, 1H), 6.18 (dd, J = 8.5, 15.9 1H), 3.98 (d, J = 8.5 Hz, 1H), 2.92-2.99 (m, 2H), 2.58-
2.63 (m, 2H).
13
C{
1
H} NMR (151 MHz, DMSO-d6): δ 172.22, 168.24, 135.95, 134.25, 128.72,
127.98, 126.33, 123.70, 64.00, 41.20, 31.28. HRMS (ESI-TOF) calc. for C13H14NO4

[M]
-
:
248.0928; found: 248.0932.

((S,E)-1-carboxy-3-phenylallyl)-3-aminobenzoid acid (7)

50 °C. 22 hr. White solid, 163.2 mg, 72% yield, >99% de from 75.3 mg (0.549 mmol) 3-
aminobenzoic acid, 108 mg (0.729 mmol) 2, and 81.2 mg (0.882 mmol) 3 in 4.5 mL deionized
H2O.
1
H NMR (400 MHz, DMSO-d6): δ 7.44 (d, J = 7.2 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.26
(t, J = 7.4 Hz, 2H), 7.18-7.22 (m, 2H), 6.91 (dt, J = 2.1, 2.1, 7.5 Hz, 1 H), 6.78 (d, J = 17.0 Hz,
1H), 6.40 (dd, J = 6.5, 16.0 Hz, 1H), 4.76 (dd, J = 1.1, 6.5 Hz, 1H).
13
C{
1
H} NMR (151 MHz,
56
DMSO-d6): δ 172.81, 167.75, 147.40, 136.03, 131.89, 131.40, 128.95, 128.74, 127.93, 126.40,
125.50, 117.59, 117.10, 113.33, 58.05.

((S,E)-1-carboxy-3-phenylallyl)-L-alanine (8)

50 °C. White solid, 31.9 mg, 16% yield, >99% de from 71.6 mg (0.804 mmol) L-alanine, 150 mg
(1.01 mmol) 2, and 89.1 mg (0.968 mmol) 3 in 6 mL deionized H2O.
1
H NMR (400 MHz,
DMSO-d6, conformer A): δ 7.42-7.45 (m, 2H), 7.32-7.36 (m, 2H), 7.25-7.28 (m, 1H), 6.71 (d, J
= 15.9 Hz, 1H), 6.15-6.21 (dd, J = 8.1, 15.9 Hz, 1H), 4.03 (d, 8.2 Hz, 1H), 3.37 (q, J = 7.0 Hz,
1H), 1.27 (d, J = 6.9 Hz, 3H).
1
H NMR (400 MHz, DMSO-d6, conformer B): δ 7.42-7.45 (m,
2H), 7.32-7.36 (m, 2H), 7.25-7.28 (m, 1H), 6.64 (d, 15.8 Hz, 1H), 6.18-6.24 (dd, J = 7.8, 15.9
Hz, 1H), 3.98 (d, 7.8 Hz, 1H), 3.33 (q, 7.06 Hz, 1H), 1.26 (d, J = 7.1 Hz, 3H).
13
C{
1
H} NMR
(151 MHz, DMSO-d6, mixture of conformers): δ 174.72, 174.38, 171.78, 171.42, 136.11,
133.27, 132.89, 128.82, 128.68, 128.66, 128.56, 128.26, 128.21, 127.92, 127.83, 126.40, 126.39,
126.00, 125.40, 61.64, 61.52, 53.60, 53.37, 18.03, 17.25. HRMS (ESI-TOF) calc. for C13H14NO4

[M]
-
: 248.0928; found: 248.0932.

57
((S,E)-1-carboxy-3-phenylallyl)-L-2-aminobutyric acid (9)

60 °C. White solid, 284.9 mg, 63% yield, >99% de, from 177 mg (1.72 mmol) L-2-aminobutyric
acid, 282 mg (1.90 mmol) 2, and 191 mg (2.07 mmol) 3 in 8.0 mL deionized H2O.
1
H NMR (400
MHz, DMSO-d6, conformer A): δ 7.7.41-7.44 (m, 2H), 7.33 (t, J = 7.6, 7.6 Hz, 2H), 7.24-7.27
(m, 1H), 6.65 (d, J = 15.8 Hz, 1H), 6.20 (dd, J = 7.6, 15.9 Hz, 1H), 3.91 (dd, J = 1.2, 7.6 Hz, 1H),
3.16 (t, J = 6.1 Hz, 1H), 1.60-1.68 (m, 2H), 0.89 (t, 7.4 Hz, 3H).
13
C{
1
H} NMR (151 MHz,
DMSO-d6, conformer A): δ 174.78, 172.42, 136.16, 132.67, 128.60, 127.79, 126.40, 126.35,
61.66, 59.34, 25.45, 9.98.
1
H NMR (400 MHz, DMSO-d6, conformer B): δ 7.7.41-7.44 (m, 2H),
7.33 (t, J = 7.6, 7.6 Hz, 2H), 7.24-7.27 (m, 1H), 6.69 (d, 15.9 Hz, 1H), 6.17 (dd, J = 8.1, 15.9 Hz,
1H), 3.99 (dd, J = 1.1, 8.1 Hz, 1H), 3.25 (t, J = 6.1 Hz, 1H), 1.60-1.68 (m, 2H), 0.89 (t, J = 7.4
Hz, 3H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, conformer B): δ 174.39, 172.04, 136.07, 133.05,
128.60, 127.89, 126.39, 125.99, 62.10, 59.31, 24.82, 9.75. HRMS (ESI-TOF) calc. for
C14H18NO4

[M]
+
: 264.1230; found: 264.1158.

58
((S,E)-1-carboxy-3-phenylallyl)-L-valine (10)

52 hr. White solid, 196 mg, 78% yield, >99% de from 106 mg (0.905 mmol) L-valine, 176 mg
(0.987 mmol) 2, and 102 mg (1.10 mmol) 3, in 6.0 mL of deionized H2O.
1
H NMR (400 MHz,
DMSO-d6, conformer A): δ 7.42 (m, 2H), 7.33 (m, 2H), 7.26 (m, 1H), 6.64 (d, J= 15.8 Hz, 1H),
6.10-6.16 (dd, J = 8.2, 15.9 Hz, 1H), 3.85 (dd, J = 0.9, 8.2 Hz, 1H), 2.99 (d, J = 5.1 Hz, 1H), 1.91
(m, 1H), 0.90 (m, 6H).
1
H NMR (400 MHz, DMSO-d6, conformer B): δ 7.42 (m, 2H), 7.33 (m,
2H), 7.26 (m, 1H), 6.64 (d, J= 15.8 Hz, 1H), 6.14-6.20 (dd, J = 7.8, 15.4 Hz, 1H), 3.79 (dd, J =
1.1, 7.5 Hz, 1H), 2.94 (d, J = 5.1 Hz, 1H), 1.91 (m, 1H), 0.90 (m, 6H).
13
C{
1
H} NMR (151 MHz,
DMSO-D6, mixture of conformers): δ 175.17, 172.96, 172.74, 136.22, 136.13, 132.63, 132.26,
128.64, 128.20, 127.81, 127.70, 126.92, 126.36, 126.35, 63.69, 63.63, 63.23, 61.91, 30.85, 30.78,
19.39, 19.04, 18.09, 17.94. HRMS (ESI-TOF) calc. for C15H18NO4

[M]
-
: 276.1241; found:
276.1253.

59
((R,E)-1-carboxy-3-phenylallyl)-D-norvaline (11)

60 °C. White solid. 148.7 mg, 49% yield, >99% de from 127.0 mg (1.08 mmol) D-norvaline, 188
mg (1.27 mmol) 2, and 136 mg (1.48 mmol) 3 in 4.0 mL deionized H2O.
1
H NMR (400 MHz,
DMSO-d6, Conformer A): δ 7.41-7.44 (m, 2H), 7.34, (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H),
6.68 (d, J = 15.9 Hz, 1H), 6.17 (dd, J = 8.0, 15.9 Hz, 1H), 3.98 (d, J = 8.0 Hz, 1H), 3.26 (t, J =
6.3 Hz, 1H), 1.53-1.62 (m, 2H), 1.3-1.42 (m, 2H), 0.87 (t, J = 7.32 Hz, 3H).
13
C{
1
H} NMR (151
MHz, DMSO-d6, conformer A): δ. 174.86, 172.20, 136.08, 132.88, 128.66, 127.86, 126.19,
62.18, 57.97, 34.09, 18.29, 13.72.
1
H NMR (400 MHz, DMSO-d6, Conformer B): δ 7.41-7.44
(m, 2H), 7.34, (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 6.64 (d, J = 15.6 Hz, 1H), 6.19 (dd, J
= 7.6, 15.8 Hz, 1H), 3.88 (d, J = 8.4 Hz, 1H), 3.18 (t, J = 6.4 Hz, 1H), 1.53-1.62 (m, 2H), 1.3-
1.42 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, conformer B): δ.
175.25, 172.50, 136.15, 132.58, 127.77, 126.47, 126.37, 61.60, 57.76, 34.62, 18.44, 13.69.
HRMS (ESI-TOF) calc. for C15H20NO4

[M]
+
: 278.1387; found: 278.1434.

60
((S,E)-1-carboxy-3-phenylallyl)-L-leucine (12)

50 °C. White solid, 103 mg, 47% yield, % de from 99.1 mg (0.755 mmol) L-leucine, 137 mg
(0.928 mmol) 2, and 87.0 mg (0.945 mmol) 3 in 5.0 mL deionized H2O.
1
H NMR (400 MHz,
DMSO-d6, conformer A): δ 7.43 (t, J = 6.8 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 7.3
Hz,1H), 6.67 (d, J = 15.3 Hz, 1H), 6.14-6.20 (dd, J = 7.6, 15.8 Hz, 1H), 3.96 (d, 7.9 Hz, 1H),
3.24 (t, J = 7.0 Hz, 1H), 1.77-1.86 (m, 1H), 1.39-1.47 (m, 2H), 0.82 (d, J = 6.6 Hz, 6H).
1
H NMR
(400 MHz, DMSO-d6, conformer B): δ 7.43 (t, J = 6.8 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.25 (t,
J = 7.3 Hz, 1H), 6.64 (d, 15.5 Hz, 1H), 6.14-6.20 (dd, J = 7.6, 15.8 Hz, 1H), 3.85 (d, J = 7.6 Hz,
1H), 3.16 (t, J = 7.0 Hz, 1H), 1.77-1.86 (m, 1H), 1.39-1.47 (m, 2H), 0.87 (d, 6.8 Hz, 6H).
13
C{
1
H} NMR (151 MHz, DMSO-D6, mixture of conformers): δ 175.97, 175.63, 172.63,
172.48, 136.15, 136.12, 132.50, 128.67, 128.64, 127.75, 126.65, 126.60, 126.38, 126.32, 62.27,
61.48, 56.90, 56.38, 41.96, 41.59, 24.27, 22.82, 21.70, 24.27, 22.63, 22.11, 21.70. HRMS (ESI-
TOF) calc. for C16H20NO4

[M]
-
: 290.1398; found: 290.1410.

61
((S,E)-1-carboxy-3-phenylallyl)-L-phenylalanine (13)

White solid, 51.6 mg, 68% yield, >99% de, from 38.6 mg (0.234 mmol) L-phenylalanine, 38.2
mg (0.257 mmol) 2, and 26.4 mg (0.281 mmol) 3 in 2.5 mL deionized H2O.
1
H NMR (400 MHz,
DMSO-d6, conformer A): δ 7.18-7.41 (m, 10H), 6.57 (d, J = 16.9 Hz, 1H), 6.08-6.14 (dd, J =
7.9, 15.9 Hz, 1H), 3.91 (d, J = 8.3 Hz 1H), 3.48 (t, J = 6.5 Hz, 1H), 2.81-2.99 (m, 2H).
1
H NMR
(400 MHz, DMSO-d6, conformer A): δ 7.18-7.41 (m, 10H), 6.37 (d, J = 15.9, 1H), 6.05-6.11
(dd, J = 6.9 , 15.9 Hz, 1H), 3.82 (d, J = 6.9 Hz, 1H), 3.39 (t, J = 5.4 Hz, 1H), 2.81-2.99 (m, 2H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, mixture of conformers): δ 174.85, 174.58, 172.83, 138.08,
137.74, 136.15, 136.10, 132.57, 131.66, 129.37, 129.25, 128.62, 128.56, 128.10, 128.05, 127.79,
127.63, 126.82, 126.56, 126.37, 126.31, 126.28, 61.73, 61.04, 59.69, 59.50. HRMS (ESI-TOF)
calc. for C19H18NO4

[M]
-
: 324.1241; found: 324.1255.

62
((R,E)-1-carboxy-3-phenylallyl)-D-cyclohexylalanine (14)

White solid, 150 mg, 63% yield, >99% de from 124 mg (0.722 mmol) D-cyclohexylalanine, 129
mg (0.870 mmol) 2, and 103 mg (1.12 mmol) 3 in 4.0 mL deionized H2O.
1
H NMR (600 MHz,
DMSO-d6, conformer A): δ 7.42 (d, J = Hz, 2H), 7.34 (t, J = Hz, 2H), 7.25 (t, J = Hz, 1H), 6.64
(d, J = 15.8 Hz, 1H), 6.18 (dd, J = 7.5, 15.8 Hz, 1H), 3.85 (d, J = 7.5 Hz, 1H), 3.19 (dd, J = 5.7,
8.2 Hz, 1H), 1.50-1.73 (m, 6H), 1.39-1.50 (m, 2H), 1.05-1.22 (m, 3H), 0.75-0.91 (m, 2H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, conformer A): δ 175.93, 172.48, 136.17, 132.47, 128.69,
127.79, 126.52, 126.32, 61.50, 55.77, 40.40, 33.54, 33.19, 32.07, 26.07, 25.68.
1
H NMR (600
MHz, DMSO-d6, conformer A): δ 7.41 (d, J = 5.43 Hz, 2H), 7.34 (t, J = Hz, 2H), 7.25 (t, J = Hz,
1H), 6.66 (d, J = 16.0 Hz, 1H), 6.17 (dd, J = , Hz, 1H), 3.95 (d, J = 8.1 Hz, 1H), 3.28 (app. t, J =
6.6, 8.2 Hz, 1H), 1.50-1.73 (m, 6H), 1.39-1.50 (m, 2H), 1.05-1.22 (m, 3H), 0.75-0.91 (m, 2H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, conformer B): δ 175.39, 172.23, 136.12, 132.80, 128.67,
127.87, 126.52, 126.38, 62.33, 56.28, 39.90, 33.48, 32.93, 32.38, 25.82, 25.75. HRMS (ESI-
TOF) calc. for C19H26NO4

[M]
+
: 332.1856; found: 332.1924.

63
((S,E)-1-carboxy-3-phenylallyl)-L-1-naphthylalanine (15)

White solid, 120 mg, 55% yield, >99% de from 126 mg (0.585 mmol) L-1-naphthylalanine, 116
mg (0.785 mmol) 2, and 69.8 mg (0.758 mmol) 3 in 4.0 mL deionized H2O.
1
H NMR (400 MHz,
DMSO-d6, conformer A): δ 8.09-8.11 (m, 1H), 7.92-9.94 (m, 1H), 7.81-7.84 (m, 1H), 7.48-7.50
(m, 1H), 7.39-7.48 (m, 2H), 7.30-7.33 (m 2H), 7.22-7.26 (m, 1H), 7.17-7.20 (m, 1H), 7.03-7.04
(d, J = 7.2 Hz, 1H), 6.41 (d, J = 15.9 Hz, 1H), 6.09 (dd, J = 7.8, 15.9 Hz, 1H), 3.83 (d, J = 7.8 Hz,
1H), 3.62 (t, J = 7.0 Hz, 1H), 3.39 (, J = Hz, 2H), 3.27 (dd, 7.8, 13.5 Hz, 1H).
13
C{
1
H} NMR
(151 MHz, DMSO-d6, conformer A): δ. 175.11, 172.64, 135.99, 133.92, 133.42, 132.65, 131.59,
128.63, 128.42, 127.80, 127.50, 127.08, 126.32, 126.13, 126.02, 125.57, 125.41, 123.61, 61.80,
59.16, 36.22.
1
H NMR (400 MHz, DMSO-d6, conformer B): δ 8.09-8.11 (m, 1H), 7.92-9.94 (m,
1H), 7.81-7.84 (m, 1H), 7.48-7.50 (m, 1H), 7.39-7.48 (m, 2H), 7.30-7.33 (m 2H), 7.22-7.26 (m,
1H), 7.17-7.20 (m, 1H), 7.03-7.04 (d, J = 7.2 Hz, 1H), 6.14 (d, J = 15.8 Hz, 1H), 5.97 (dd, J =
6.6, 15.9 Hz, 1H), 3.80 (d, 5.8 Hz, 1H), 3.48-3.54 (m, 3H).
13
C{
1
H} NMR (151 MHz, DMSO-d6,
conformer B): δ 174.60, 172.69, 135.96, 134.24, 133.47, 131.55, 131.39, 128.62, 128.42, 127.85,
127.52, 127.14, 127.08, 126.26, 126.00, 125.49, 125.34, 123.54, 60.91, 59.23, 36.40. HRMS
(ESI-TOF) calc. for C23H22NO4

[M]
+
: 376.1543; found: 375.1471.

64
((S,E)-1-carboxy-3-phenylallyl)-L-tyrosine (16)

70 °C, 50 hr. White solid, 223 mg, 45% yield, >99% de from 263 mg (1.45 mmol) L-tyrosine,
275 mg (1.86 mmol) 2, and 165 mg (1.79 mmol) 3 in 10 mL deionized H2O.
1
H NMR (400
MHz, DMSO-d6, conformer A): δ 9.19 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 7.79 Hz, 2
H), 7.25 (t, J = 7.1 Hz, 1H), 7.01 (d, J = 7.9 Hz, 2H), 6.66 (d, J = 4.8 Hz, 2H), 6.39 (d, J = 15.9
Hz, 1H), 6.09 (dd, J = 6.8, 16.1 Hz), 3.81 (d, J = 6.99 Hz, 1H), 3.31 (t, J = 5.7 Hz, 1H), 2.70-2.86
(m, 2H).
1
H NMR (400 MHz, DMSO-d6, conformer B): δ 9.19 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H),
7.33 (t, J = 7.79 Hz, 2 H), 7.25 (t, J = 7.1 Hz, 1H), 6.99 (d, J = 7.8 Hz, 2H), 6.65 (d, J = 7.9 Hz,
2H), 6.57 (d, J = 16.0 Hz, 1H), 6.11 (dd, J = 7.8, 15.8 Hz, 1H), 3.88 (d, J = 7.9 Hz, 1H), 3.40 (t, J
= 6.4 Hz, 1H), 2.70-2.86 (m, 2H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, mixture of conformers):
δ 174.89, 174.51, 172.76, 172.64, 155.84, 136.20, 136.10, 132.48, 131.66, 130.23, 130.13,
128.62, 128.57, 127.91, 127.76, 127.60, 126.78, 126.58, 126.35, 126.32, 114.94, 114.87, 61.83,
61.14, 59.92, 59.82, 37.97, 37.55. HRMS (ESI-TOF) calc. for C19H18NO5

[M]
-
: 340.1190; found:
340.1206.

65
((S,E)-1-carboxy-3-(3-fluorophenyl)allyl)-L-phenylalanine (17)

120 hr. White solid, mg, % yield, >99% de from 126 mg (0.763 mmol) L-phenylalanine, 152 mg
(0.916 mmol) trans-2-(3-fluorophenyl)vinyl boronic acid, and 116 mg (1.26 mmol) 3 in 3.0 mL
deionized H2O.
1
H NMR (400 MHz, DMSO-d6, conformer A): δ 7.04-7.37 (m, 9H), 6.60 (d, J =
15.8 Hz, 1H), 6.21 (dd, J = 7.4, 11.8 Hz, 1H), 3.92 (d, J = 7.8 Hz, 1H), 3.47 (t, 6.6 Hz, 1H), 2.81-
2.99 (m, 2H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, conformer A): δ 174.64, 172.69, 138.79 (d,
J = 5.8 Hz), 137.72, 131.35 (d, J = 2.1 Hz), 130.51, 129.27, 128.66, 128.13, 126.33, 122.75 (d, J
= 2.3 Hz), 114.46 (d, J = 21.2 Hz), 112.66 (d, J = 21.8 Hz), 61.59, 59.53, 38.39.
1
H NMR (400
MHz, DMSO-d6, conformer B): δ 7.04-7.37 (m, 9H), 6.36 (d, J = 15.8 Hz, 1H), 6.18 (dd, J = 6.9,
15.8 Hz, 1H), 3.84 (d, 6.5 Hz, 1H), 3.47 (t, 6.6 Hz, 1H), 2.81-2.99 (m, 2H).
13
C{
1
H} NMR (151
MHz, DMSO-d6, conformer B): δ 174.90, 172.66, 163.42, 161.49, 138.84 (d, J = 5.8 Hz),
138.14, 130.57, 130.42 (d, J = 4.6 Hz), 129.43, 128.40, 128.07, 126.30, 114.29 (d, J = 23.1 Hz),
122.62 (d, J = 21.3 Hz), 60.91, 59.77, 38.82. HRMS (ESI-TOF) calc. for C19H19FNO4

[M]
-
:
344.1293; found: 344.1355.

66
((S,E)-1-carboxy-3-(4-fluorophenyl)allyl)-L-phenylalanine (18)

White solid, 167.6 mg, 63% yield, >99% de from 126 mg (0.765 mmol) L-phenylalanine, 150
mg (0.908 mmol) trans-2-(4-fluorophenyl)vinyl boronic acid, 109 mg (1.18 mmol) 3 in 3.0 mL
deionized H2O.
1
H NMR (400 MHz, DMSO-d6, conformer A): δ 7.43-7.47 (m, 2H), 7.20-7.29
(m, 5H), 7.15 (t, J = 8.9 Hz, 2H), 6.59 (d, J = 15.9 Hz, 1H), 6.04-6.10 (dd, J = 7.8, 15.9 Hz, 1H),
3.91 (d, J = 7.1 Hz, 1H), 3.48 (t, J = 6.5 Hz, 1H), 2.85-2.96 (m, 2H).
13
C{
1
H} NMR (151 MHz,
DMSO-d6, mixture of conformers): δ 206.48, 174.86, 174.62, 172.81, 162.67, 160.73, 138.09,
137.74, 132.71, 131.32, 130.42, 129.37, 129.24, 128.34, 128.26, 128.24, 128.18, 128.09, 128.04,
126.80, 126.29, 115.54, 115.47, 115.36, 115.30, 61.68, 60.96, 59.49, 38.40, 30.68. HRMS (ESI-
TOF) calc. for C19H17FNO4

[M]
-
: 342.1147; found: 342.1157.

67
((S,E)-1-carboxy-3-(4-methoxyphenyl)allyl)-L-phenylalanine (19)

White solid, 171 mg, 63% yield, >99% de from 127 mg (0.769 mmol) L-phenylalanine, 169 mg
(0.949 mmol) trans-2-(4-methoxyphenyl)vinyl boronic acid, 97.7 mg (1.06 mmol) 3 in 3.0 mL
deionized H2O.
1
H NMR (400 MHz, DMSO-d6, conformer A): δ 7.32-7.35 (m, 2H), 7.25-7.29
(m, 2H), 7.18-7.22 (m, 3H), 6.88-6.90 (m, 2H), 6.52 (d, J = 15.8 Hz, 1H), 5.92-5.98 (dd, J = 7.9,
15.9 Hz, 1H), 3.87 (d, 7.9 Hz, 1H), 3.75 (s, 3H), 3.47 (t, 6.53 Hz, 1H), 2.84-2.95 (m, 2H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, mixture of conformers): δ 174.82, 174.57, 173.00, 172.95,
159.01, 158.88, 138.06, 137.75, 132.24, 131.35, 129.35, 129.24, 128.78, 128.71, 128.09, 128.05,
127.67, 127.58, 126.29, 124.25, 123.99, 114.03, 113.98, 61.83, 61.11, 59.59, 59.44, 55.11, 38.75,
38.36. HRMS (ESI-TOF) calc. for C20H20NO5

[M]
-
: 354.1347; found: 354.1358.

68
General Procedure for the Synthesis of Aminodicarboxylic Acid Derivatives (20-27).
Dipeptide (1.00 mmol), trans-2-phenylvinylboronic acid (1.2 mmol), and glyoxylic acid
monohydrate (1.2) mmol were added to a rbf equipped with a stir bar. The flask was evacuated
and backfilled with argon three times, and distilled water (4 mL) was added to the reaction
vessel. The solution was vigorously stirred at 50 °C in an oil bath for 48 hours unless otherwise
stated. The crude was then filtered and washed with cold acetone to yield aminodicarboxylic
acid derivatives 20-27.

((S,E)-1-carboxy-3-phenylallyl)-L-alanyl-L-phenylalanine (20)

60 °C White solid, 145 mg, 82% yield, >99% de from 105 mg (0.444 mmol) L-alanyl-L-
phenylalanine, 75.0 mg (0.505 mmol) 2, 63.7 mg (0.692 mmol) 3 in 2.5 mL deionized H2O.
1
H
NMR (400 MHz, DMSO-d6, cis+trans isomers): δ 8.26 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 8.2 Hz,
1H), 7.13-7.38 (m, 10H), 6.58 (dd, J = 1.1, 18.0 Hz, 1H), 6.38 (d, J = 15.8 Hz, 1H), 6.15 (dd, J =
7.1, 16.0 Hz, 1H), 6.07 (dd, J = 8.1, 15.9 Hz, 1H), 4.44-4.56 (m, 1H), 3.80 (dd, J = 1.1, 7.4 Hz,
1H), 3.54 (dd, J = 0.7, 8.1 Hz, 1H), 3.24 (q, J = 6.9 Hz, 1H), 3.20 (q, J = 6.9, 1H), 3.13 (dd, J =
4.8, 14.0 Hz, 1H), 3.06 (d, J = 5.2, 13.8 Hz, 1H), 2.92 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H). 1.12 (d,
J = 7.0 Hz, 3H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, cis-trans isomers): δ 173.29, 173.06,
172.77, 172.68, 172.37, 171.83, 137.49, 137.13, 136.19, 136.16, 132.91, 131.96, 129.17, 129.02,
69
128.62, 128.60, 128.26, 128.19, 128.12, 127.73, 126.43, 126.35, 126.19, 126.12, 61.93, 61.22,
55.49, 53.54, 52.75, 52.64, 36.69, 36.56, 18.90, 18.73. HRMS (ESI-TOF) calc. for C22H23N2O5

[M]
-
: 395.1612; found: 395.1615.

((S,E)-1-carboxy-3-phenylallyl)-L-phenylalanyl-L-alanine (21)

White solid. 47.9 mg, 62% yield, >99% de from 53.0 mg (0.224 mmol) L-phenylalanyl-L-
alanine, 37.1 mg (0.251 mmol) 2, and 32.4 mg (0.352 mmol) 3 in 3.0 mL deionized H2O.
1
H
NMR (400 MHz, DMSO-d6, major isomer): δ 8.10 (d, J = 7.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H),
7.38 (d, J = 7.3 Hz, 2H), 7.32 (t, J = 6.0 Hz, 3H) 7.20-7.27 (m, 5H), 6.57 (d, J = 15.8 Hz, 1H),
6.13 (dd, 6.13 Hz, 1H), 4.17 (p, J = 7.0, 6.9 Hz, 1H), 3.82 (d, J = 7.7 Hz, 1H), 3.39 (t, J = Hz,
1H), 2.95 (dd, J = 4.9, 13.9 Hz, 1H), 2.81 (dd, J = 7.9, 13.8 Hz, 1H), 1.14 (d, J = 7.2 Hz, 3H).
13
C{
1
H} NMR (125 MHz, DMSO-d6, major isomer): δ 174.01, 172.84, 172.38, 137.76, 136.17,
132.19, 129.35, 128.70, 128.60, 128.08, 127.75, 126.81, 126.57, 126.31, 62.18, 60.73, 47.16,
17.35. HRMS (ESI-TOF) calc. for C22H25N2O5

[M]
+
: 397.1758; found: 397.1820.

70
((S,E)-1-carboxy-3-phenylallyl)-L-leucyl-L-alanine (22)

White solid. 82.3 mg, 23% yield, 80% de from 203 mg (1.00 mmol) L-leucyl-L-alanine, 174 mg
(1.18 mmol) 2, and 111 mg (1.21 mmol) 3 in 5.0 mL deionized H2O.
1
H NMR (400 MHz,
DMSO-d6): δ 8.31 (d, J = 7.3 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H), 7.25 (t,
J = 7.3 Hz, 1H), 6.59 (d, J = 15.8 Hz, 1H), 6.16 (dd, J = 7.8, 15.8 Hz, 1H), 4.23 (p, J = 7.4, 7.5
Hz, 1H), 3.77 (d, J = 7.8, 1H), 3.18 (t, J = 7.1 Hz, 1H), 1.77-1.84 (m, 1H), 1.32-1.40 (m, 2H),
3.34 (d, 7.3 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H).
13
C{
1
H} NMR (151
MHz, DMSO-d6, major isomer): δ 174.01, 173.48, 172.46, 136.31, 132.82, 128.70, 127.78,
126.41, 61.26, 56.87, 47.42, 42.35, 24.07, 23.13, 22.01, 17.22. HRMS (ESI-TOF) calc. for
C19H27N2O5

[M]
+
: 363.1914; found: 363.1986.

71
((S,E)-1-carboxy-3-phenylallyl)-L-phenaylalanyl-L-phenylalanine (23)

White solid, 193 mg, 88% yield, >99% de from 145 mg (0.465 mmol) L-phenylalanyl-L-
phenylalanine, 84.2 mg (0.569 mmol) 2, and 68.6 mg (0.745 mmol) 3 in 5.5 mL deionized H2O.
1
H NMR (400 MHz, DMSO-d6, cis-trans isomers): δ 8.36 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 8.4
Hz, 1H), 7.08-7.36 (m, 15H), 6.49 (d, J = 15.9 Hz, 1H), 6.12 (d, J = 15.7 1H), 6.07-6.13 (m, 1H),
5.89 (dd, J = 7.0, 15.9 Hz, 1H), 4.52 (m, 1H), 3.76 (dd, J = 1.0, 7.3, 1H), 3.44 (dd, J = 0.9, 7.0,
1H), 3.13 (dd, J = 4.5, 13.8 Hz, 1H), 2.53-2.98 (m, 4H).
13
C{
1
H} NMR (151 MHz, DMSO-d6,
cis-trans isomers): δ 173.02, 172.90, 172.83, 172.72, 172.55, 172.27, 138.43, 137.56, 137.10,
137.56, 136.14, 136.13, 131.91, 131.73, 129.28, 129.23, 129.16, 129.03, 128.58, 128.52, 128.13,
127.96, 127.71, 127.56, 126.64, 126.44, 126.30, 126.24, 126.21, 126.09, 61.79, 61.32, 60.19,
59.83, 52.86, 52.59, 36.83. 36.67. HRMS (ESI-TOF) calc. for C28H27N2O5

[M]
-
: 471.1925;
found: 471.1926.

72
((S,E)-1-carboxy-3-phenylallyl)-L-valyl-L-tyrosine (24)

60 °C. 46 hr. White solid, 98.5 mg, 50% yield, >99% de from 108 mg (0.385 mmol) L-valyl-L-
tyrosine, 52.2 mg (0.353 mmol) 2, and 49.2 mg (0.534 mmol) 3 in 2.0 mL deionized H2O.
1
H
NMR (400 MHz, DMSO-d6): δ 7.94 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.31 (t, J = 7.2
Hz, 2H), 7.23 (t, J = 7.6 Hz, 1H), 6.93 (d, 7.7 Hz, 2H), 6.62 (d, J = 8.3 Hz, 2H), 6.50 (d, J = 16.0,
1H), 6.15 (dd, J = 7.5, 16.0 Hz, 1H), 4.38 (q, J = 5.3 Hz, 1H), 3.69 (d, J = 7.4 Hz, 1H), 2.88 (dd,
J = 4.8, 14.2 Hz, 1H), 2.80 (d, J = 5.6 Hz, 1H), 2.73 (dd, J = 8.8, 13.5 Hz, 1H), 1.74-1.82 (m,
1H), 0.80 (dd, 6H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, cis+trans isomers): δ 172.99, 172.88,
172.80, 172.75, 172.52, 172.23, 155.91, 155.80, 137.59, 137.11, 136.17, 131.95, 130.19, 130.18,
129.22, 129.08, 128.61, 128.56, 128.23, 128.16, 127.74, 127.62, 127.32, 126.59, 126.47, 126.45,
126.33, 126.21, 115.05, 114.88, 61.94, 61.62, 60.37, 60.09, 52.90, 52.60, 38.48, 37.82, 36.89,
36.70.

73
((S,E)-1-carboxy-3-phenylallyl)-L-tyrosyl-L-phenylalanine (25)

55 °C. White solid. 44.2 mg, 46% yield, >99% de from 64.8 mg (0.197 mmol) L-tyrosyl-L-
phenylalanine, 36.1 mg (0.244 mmol) 2, and 24.7 mg (0.268 mmol) 3 in 1.4 mL deionized H2O.
1
H NMR (400 MHz, DMSO-d6, cis+trans isomer): δ 8.27 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.6
Hz, 7.18-7.35 (m, 9H), 7.08 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 8.4 Hz, 2H), 6.68 (d, 8.0 Hz, 1H),
6.64 (d, J = 8.2 Hz, 2H), 6.48 (d, J = 15.9 Hz, 1H), 6.13 (d, J = 15.0 Hz, 1H), 6.10 (dd, J = 8.1,
15.1 Hz, 1H), 4.44-4.55 (m, 1H), 3.73 (d, J = 7.7 Hz, 1H), 3.47 (d, J = 7.3 Hz, 1H), 3.18-3.23 (m,
2H), 3.12 (dd, J = 4.8, 13.7 Hz, 1H), 2.87-3.00 (m, 2H), 2.73 (td, J = 4.3, 12.6, 12.9 Hz, 1H),
2.61 (dd, J = 7.5, 13.9 Hz, 1H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, cis+trans isomer): δ
173.02, 172.85, 172.82, 172.73, 172.52, 172.26, 155.87, 155.77, 137.56, 137.08, 136.15, 131.91,
130.16, 129.19, 129.06, 128.59, 128.56, 128.54, 128.24, 128.14, 127.73, 127.60, 127.33, 126.58,
126.46, 126.44, 126.31, 126.28, 126.23, 115.02, 114.85, 61.88, 61.61, 60.30, 60.07, 52.85, 52.55,
40.06, 38.48, 37.83, 36.86, 36.67. HRMS (ESI-TOF) calc. for C29H29N2O5

[M]
+
: 489.2020;
found: 489.2071.

74
((S,E)-1-carboxy-3-phenylallyl)-L-phenylalanyl-L-proline (26)

40 °C. White solid, 52 mg, 32% yield (determined via
1
H NMR, LCMS), >99% de from 100 mg
(0.381 mmol) L-phenylalanyl-L-proline,
1
H NMR (400 MHz, DMSO-d6, cis+trans isomers): δ
7.19-7.43 (m, 10H), 6.61-6.65 (d, J = 15.8 Hz, 1H), 5.93-5.99 (dd, J = 15.7, 9.2 Hz, 1H), 3.94-
3.98 (dd, J = 8.7, 3.8 Hz, 1H), 8.80-3.83 (d, J = 8.9 Hz, 1H), 3.58-3.54 (dd, J = 7.9, 5.6 Hz, 2H),
3.34-3.37 (m, 1H), 2.76-2.80 (m, 1H), 2.63-2.68 (m, 1H), 1.79-1.83 (m, 2H), 1.55-1.70 (m, 2H),
1.55-1.70 (m, 2H), 1.45-1.53 (m, 1H), 1.27-1.35 (m, 1H).
13
C{
1
H} NMR (151 MHz, DMSO-d6,
cis+trans isomers): δ 172.78, 171.62, 139.74, 136.21, 131.13, 128.59, 128.51, 128.33, 127.68,
127.65, 127.50, 126.25, 65.96, 63.41, 63.01, 60,94, 58.40.

75
((S,E)-1-carboxy-3-phenylallyl)-L-alanyl-L-proline (27)

White solid, 108 mg, 93% yield, >99% de from 62.4 mg (0.335 mmol) L-phenylalanyl-L-
phenylalanine, 60.0 mg (0.405 mmol) 2, and 38.8 mg (0.421 mmol) 3 in 2.2 mL deionized H2O.
1
H NMR (400 MHz, DMSO-d6, trans isomer): δ 7.25-7.45 (m, 5H), 6.67 (d, J = 16.8 Hz, 1H),
6.18 (dd, J = 8.3, 15.8 Hz, 1H), 3.84 (dd, J = 3.9, 8.6 Hz, 1H), 3.62 (d, J = 8.9 Hz, 1H), 3.55 (q, J
= 6.8 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 1.48-1.79 (m, 4H), 1.15 (d, J = 6.8 Hz, 3H).
1
H NMR
(400 MHz, DMSO-d6, cis isomer): δ 7.25-7.45 (m, 5H), 6.60 (d, J = 15.8 Hz, 1H), 6.01 (dd, J =
9.0, 15.8 Hz, 1H), 4.03 (dd, J = 3.8, 8.5 Hz, 1H), 3.59 (d, J = 9.0 Hz, 1H), 3.51 (q, J = 6.7 Hz,
2H), 1.19 (d, J = 6.8 Hz, 3H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, trans isomer): δ 173.08,
171.26, 135.92 132.98, 128.67, 128.52, 126.57, 126.47, 63.05, 58.44, 51.66, 45.86, 28.08, 24.14,
17.43.
13
C{
1
H} NMR (151 MHz, DMSO-d6, cis isomer): δ 173.74, 172.98, 136.11, 133.49,
128.52, 127.95, 125.69, 61.84, 58.39, 51.67 46.06, 28.45, 24.39, 17.52. HRMS (ESI-TOF) calc.
for C18H21N2O5

[M]
-
: 345.1456; found: 345.1465.

76
Hydrogenation of 27 to form 28. Compound 27 (415 mg, 1.20 mmol), and 10 wt.% Pd/C (5%
Pd on carbon powder, wet support) were added to a rbf equipped with a stir bar. 20 mL DI water
was added and the resulting heterogeneous solution was sonicated for 10 minutes to afford a
grey, opaque solution. The headspace was evacuated and backfilled with H2 gas 3 times and the
solution was left to stir at rt until completely black, which required under 5 hours. The black
solution was filtered directly onto 3 quantitative filter papers, and the clear filtrate was
condensed via rotoevaporator to afford 414.2 mg of white solid, which was chromatographed
with silica gel in a 1:1 DCM/MeOH solution to afford 298 mg (72 % yield) of 28 as a white
solid.

Enalaprilat (28)

1
H NMR (400 MHz, DMSO-d6, trans isomer): δ 7.15-7.29 (m, 5H), 4.28 (dd, J = 4.2, 8.8 Hz,
1H), 3.78 (q, J = 6.7 Hz, 1H), 3.37 (q, J = 6.7 Hz, 1H), 3.53 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 6.2
Hz, 1H), 2.56-2.69 (m, 2H), 2.09-2.18 (m, 2H), 1.80-1.93 (m, 5H), 1.19 (d, J = 6.7 Hz, 3H).
13
C{
1
H} NMR (151 MHz, DMSO-d6, trans isomer): δ 173.09, 170.83, 141.64, 128.24, 125.76,
125.70, 59.03, 58.47, 52.99, 46.21, 46.14, 34.10, 31.24, 28.46, 21.69, 17.16. HRMS (ESI-TOF)
calc. for C18H23N2O5

[M]
-
: 347.1612; found: 347.1632.

77
2.5 References
[1] (a) Candeias, N. R.; Veiros, L. F.; Afanso, C. A. M.; Góis, P. M. P.; Water: A suitable
Medium for the Petasis Borono-Mannich Reaction. Eur. J. Org. Chem. 2009, 1859-1863.
(b) Candeias, N. R.; Cal, P. M. S. D.; André, V.; Duarte, M. T.; Veirós, L. F.; Góis, P. M.
P.; Water as the reaction medium for multicomponent reactions based on boronic acids.
Tetrahedron 2010, 14, 3, 2736-2745. (c) Candeias, N. R.; Paterna, R.; Cal, P. M. S. D.;
Góis, P. M. P.; A Sustainable Protocol for the Aqueous Multicomponent Petasis Borono-
Mannich Reaction. J. Chem. Educ. 2012, 89, 6, 799-802.
[2] Lee, Y. C.; Jackson, P. L.; Jablonsky, M. J.; Muccio, D. D.; Pfister, R. R.; Haddox, J. L.;
Sommers, C. I.; Anantharamaiah, G. M.; Chaddha, M.; NMR conformational analysis of
cis and trans proline isomers in the neutrophil chemoattractant, N-acetyl-proline-glycine-
proline. Biopolymers 2001, 58, 6, 548-561.
[3] Souza, R. Y.; Bataglion, G. A.; Ferreira, D. A. C.; Gatto, C. C.; Eberlin, M. N.; Neto, B.
A. D.; Insights on the Petasis Borono-Mannich multicomponent reaction Mechanism.
RSC. Adv. 2015, 5, 76337-76341.
[4] Tao, J.; Li, S.; Theoretical Study on the Mechanism of the Petasis-type Boronic Mannich
Reaction of Organoboronic Acids, Amines, and α-Hydroxy Aldehydes. Chin. J. Chem.
2010, 28, 41-49.
[5] This model was developed with the help of late Prfoessor John D. Roberts’ collective
work on intramolecularly hydrogen bonding systems. Rudner, M. S.; Kent, D. R.;
Goddard, W. A.; Roberts, J. D.; Intramolecular Hydrogen Bonding in Disubstituted
Ethanes: General Considerations and Methodology in Quantum Mechanical Calculations
78
of the Conformational Equilibria of Succinamate Monoanion. J. Phys. Chem. A 2005,
109, 9083-9088.
[6] Computational calculations were done using USC’s High-Performance Computing (HPC)
resources.

79

CHAPTER 3
Novel, Stereoselective Synthesis of 15-epi-Benzo-Lipoxin A4

80
3.1 Introduction
The compound discussed herein—(5S,6R,15R)-benzo-lipoxin A4 (15-epi-benzo-
LXA4)—is a structural analogue of naturally occurring pro-resolving lipoxins (LX), which were
discovered in 1984 by Serhan et al.
1
These compounds are biosynthetically generated from cell
wall derived arachedonic acid via lipoxygenase oxidation when damage is detected in the body.
LXs serve as chemical signals to dampen the biochemical cascade that triggers production of
pro-inflammation compounds when the process of inflammation is complete. The major
complication is that lipid mediators are rapidly metabolized within the cell, attenuating their
purpose and causing a biochemical feedback loop prolonging inflammation.
2
15-epi-LXA4, an aspirin-triggered analogue, has recently demonstrated promising
therapeutic activity towards diseases related to chronic inflammation in the body.
3
The chemical
instability of LX analogues in cellular environments have generated interest in ways to prolong
their half-life through structural modification without compromising binding affinity. Another
key factor is making the therapeutic of interest easy to synthesize. It was discovered that
replacing the tetraene moiety of 15-epi-LXA4 with a fused benzene ring increased thermal
stability and allowed for an efficient convergent synthesis versus its naturally occurring
analogue.
4

Herein, a considerably improved convergent synthesis of 15-epi-benzo-LPX4 is reported.
The final compound was furnished in 32% overall yield, and the C15 stereocenter was generated
with greater than 99% enantioselectivity via a Noyori asymmetric ketone reduction.

81
3.2 Retrosynthetic Analysis
A straightforward retrosynthetic analysis of 15-epi-benzo-LXA4 (6) is shown in Scheme
3.1 below. The complete scaffold can easily be prepared via Suzuki-Miyaura coupling between
suitable reactive groups. We chose vinylboronic acid pinacol ester (3) and aryl bromide (2) as
reaction partners to undergo palladium catalyzed C-C coupling. The pinacol ester can be
generated from a terminal alkyne via hydroboration using Schwartz reagent. Lastly, the alkyl
chain can be attached via Grignard reagent by treatment with pentylmagnesium bromide and the
corresponding active acyl chloride (1).

Scheme 3.1: Retrosynthetic analysis of Benzo-lipoxin A4 analogue.
82
3.3 Results and Discussion
Prior to functionalizing acyl chloride (1), the pinacol ester (3) was prepared in excellent
yields via hydroboration with pinacolborane in solvent free conditions and elevated temperature
from the commercially purchased terminal alkyne shown in Scheme 3.2.
5
Next, 1 was treated
with a slow addition of 0.95 equivalents of pentylmagnesium bromide to afford the ketone (2) in
excellent yields and no appreciable double addition byproduct.
6

Scheme 3.2: Total synthesis of R,R,S-Benzo-lipoxin A4 analogue.

Compounds 3 and 2 were then coupled via palladium catalyzed Suzuki-Miyaura coupling under
specialized conditions to afford ortho-scaffold (4) in good yields.
7

83
Reduction of the ketone to furnish alcohol (5) with R-stereoconfiguration was achieved via
Noyori asymmetric hydrogenation in moderate yields and 99% enantioselectivity.
Stereoconfiguration of the hydroxyl carbon post Noyori asymmetric reduction was assumed to be
R based on literature precedent
8
(before completion of 6, a structurally analogous compound (7)
was synthesized and asymmetrically reduced to determine the stereoselectivity, which was
determined to be >99% ee via
19
F-NMR spectroscopic analysis after derivatization with
Mosher’s acid chloride [Figure 3.1]).
9
Completed Benzo-lipoxin A4 6 was deptrotected in
excellent yields using tetrabutylammonium fluoride at low temperature.
10
Stereo- and chemical
purity of 6 was assessed via LC-MS analysis.
11
Structural confirmation of 6 was done by our
collaborators via LC-MS analysis versus an authentic sample.

Figure 3.1:
19
F NMR spectrum of Mosher’s ester 7 (no internal standard was present for signal referencing).
84
3.4 Conclusions
Benzo-lipoxin A4 analogue 6 was successfully synthesized in 33% overall yields and
>99% ee using an efficient four-step synthesis. Addition of pentylmagnesium bromide to acyl
chloride 1 was well tolerated and no appreciable over addition was observed. The mild Suzuki-
Miyaura coupling conditions provided 4 in good yields. Purification of 4 proved difficult, but
this issue was mitigated by the resulting difference in polarities between the alcohol of 5 and
unreacted 3 after Noyori asymmetric reduction, making purification via column chromatography
straightforward. The chemical and optical purity of 6 was determined to be acceptable for
biological testing (>98%) via LC-MS analysis versus an authentic sample. It is hoped that the
efficiency and good overall yields will result in continued application towards other Benzo-
lipoxin analogues in future studies.

85
3.5 Synthetic Procedures
Methyl-(5S,6R,E)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-
bis((triethylsilyl)oxy)oct-7-enoate (3)

An rbf equipped with a stir-bar, a three-way valve adapter, and an argon filled balloon was flame
dried and back-filled with argon. The apparatus was sealed and transferred to a nitrogen glove
box, and was charged with alkyne (1.61 g, 3.88 mmol) and pinacolborane (2.01 g, 15.7 mmol).
The apparatus was resealed, evacuated for five minutes, and back-filled with argon. The rbf was
then submerged in an oil bath set to 90°C and stirred for 78 hours. The mixture was condensed
under low pressure to remove excess pinacolborane, and chromatographed through a 25 g
Biotage Sfär Silica – 60μm column with a 1-50% EtOAc in hexanes gradient system. Product
was visualized via permanganate stained TLC plates, which gave yellow spots. Fractions
containing product were condensed under reduced pressure to give 3 as a clear, colorless oil
(1.88 g, 89% yield).
Rf (SiO2, 30% EtOAC in hexanes, permanganate stain) = 0.79;
1
H-NMR (400 MHz, CDCl3): δ
6.59 (dd, J = 18.0, 5.6 Hz, 1H), 5.62 (dd, J = 18.2, 1.5 Hz, 1H), 4.02 (ddd, J = 5.7, 4.3, 1.4 Hz,
1H), 3.66 (s, 3H), 3.59 (m, 1H), 2.29 (t, J = 7.5 Hz, 2H), 1.74 (m, 1H), 1.61 (m, 2H), 1.48 (m,
2H), 1.26 (d, J = 1.5 Hz, 14H), 0.93 (ddd, J = 8.3, 7.7, 5.6 Hz, 18H), 0.59 (m, 12H). Ref. KK-72-
261-665.
86
1-(2-bromophenyl)hexan-1-one (2)

An rbf equipped with a stir bar, three-way valve adapter, and an argon filled balloon was flame
fried and back-filled with argon. Once the rbf cooled, 2-bromobenzoyl chloride 1 (1.50 mL, 11.5
mmol) was added via syringe, followed by anhydrous THF (37 mL) to give a pale-yellow
solution. The rbf was submerged in a dry ice-acetone bath, which was measured at -78°C. After
leaving to cool, a 2.0 M solution of pentylmagnesium bromide (6.00 mL, 13.1 mmol) in diethyl
ether was added drop-wise in portions over the course of 50 minutes. After an additional hour of
stirring, the solution was brought to room temperature and left to stir for 25 minutes. Then, 10
mL of 1.0 M HCl in water was added. The THF was removed under low pressure and the
product was extracted twice with large portions of ether, and the organic phases were dried over
MgSO4 and condensed under reduced pressure to give 2.82 g of pale yellow oil (2.8 g, 92% pure
from
1
H-NMR analysis, 8% -COOH byproduct, 96% crude yield, 89% calculated yield). A small
portion was purified for analytical analysis via reverse phase HPLC in 90:100 ACN to water
solvent system, affording 2 as clear, colorless oil.
Rf (SiO2, 10% EtOAC in hexanes, UV) = 0.55;
1
H-NMR (400 MHz, CDCl3): δ 7.59 (m, 1H),
7.35 (m, 2H), 7.28 (m, 1H), 2.90 (td, J = 7.41, 7.39, 1.0 Hz, 2H), 1.71 (m, 2H), 1.35 (m, 4H),
0.90 (m, 3H). Ref. KK-72-203-606.

87
Methyl-(5S,6R,E)-8-(2-hexanoylphenyl)-5,6-bis((triethylsilyl)oxy)oct-7-enoate (4)

A 4-dram vial equipped with a stir-bar, a three-way valve adapter, and an argon filled balloon
was flame dried and back-filled with argon. The apparatus was sealed and transferred to a
nitrogen glove box, and was charged with 2 (138 mg, 0.541 mmol), 3 (352 mg, 0.649 mmol),
Pd(OAc)2 (8 mg, 0.03 mmol), cataCXium Fsulf (32 mg, 0.043 mmol), and potassium phosphate
tribasic (343 mg, 1.62 mmol). Inside the nitrogen glove box, tert-amyl alcohol (2.0 mL) was
added, and the apparatus was resealed and removed from the box. The argon balloon was
reattached and the apparatus was evacuated for several minutes, and then back-filled with argon.
The orange, heterogeneous solution was stirred at room temperature for 30 minutes. The vial was
submerged in an oil bath set to 63°C and stirred for 27 hours to give a light-brown,
heterogeneous solution. The product was extracted from the reaction crude with several portions
of DCM, dried over MgSO4, and chromatographed through a 10 g Biotage Sfär Silica – 60μm
column with a 3-40% EtOAc in hexanes gradient system. Fractions containing product,
visualized at 254 and 280 nm, were collected and condensed under reduced pressure to give 4 as
a pale-yellow, clear oil (140 mg; 81% 4, 19% unreacted 3, 93% crude yield; 75% calculated
yield from
1
NMR signal integration).
1
H-NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 7.9, 1.2 Hz, 1H), 7.50 (dd, J = 7.7, 1.4 Hz, 1H), 7.41
(td, J = 7.8, 7.7, 1.3 Hz, 1H), 7.29 (td. J = 7.6, 7.5, 1.2 Hz, 1H), 6.88 (dd, J = 16.0, 0.9 Hz, 1H),
6.14 (dd, J = 15.9, 7.2 Hz, 1H), 4.09 (ddd, J = 7.4, 3.5, 1.1 Hz, 1H), 3.72 (ddd, J = 6.4, 5.5, 3.4
88
Hz, 1H), 3.66 (s, 3H), 2.84 (td, J = 7.2, 7.1, 0.9 Hz, 2H), 2.30 (t, J = 7.6, 3H), 1.76 (m, 2H), 1.67
(m, 3H), 1.47 (m, 3H), 1.33 (m, 4H), 0.94 (m, 18H), 0.62 (m, 12H). Ref. KK-72-258-661.

Methyl-(5S,6R,E)-8-(2-((R)-1-hydroxyhexyl)phenyl)-5,6-bis((triethylsilyl)oxy)oct-7-enoate
(5)

A 4-dram vial was flame dried and left to cool in a nitrogen filled glove box. Once room
temperature, it was charged with 4 (78.6 mg, 0.133 mmol), (S)-RUCY-XylBINAP (excess), and
potassium phosphate tribasic (excess). Isopropyl alcohol (0.50 mL) was added in the glove box.
The vial was sealed with a three-way valve adapter and removed from the glove box to be
connected to an hydrogen containing triple-layer balloon setup. The apparatus was then
evacuated for several minutes and backfilled with H2, and stirred for 50 minutes at room
temperature. The crude was chromatographed with a 10 g Biotage Sfär Silica – 60μm column
with a 2-30% EtOAc in hexanes gradient system. Fractions containing product were collected
and condensed under reduced pressure to afford 5 as a clear, colorless oil (38.3 mg, >99% ee,
49% yield).
1
H-NMR (600 MHz, CD3OD) δ 7.47 (dd, J = 7.8, 1.4 Hz, 1H), 7.40 (dd, J = 7.8, 1.4 Hz, 1H),
7.26 (td, J = 7.6, 7.5, 1.4 Hz, 1H), 7.21 (td, J = 7.51, 7.49, 1.5 Hz, 1H), 6.90 (d, J = 15.8, 1.0 Hz,
1H), 6.10 (dd, J = 15.8, 7.2 Hz, 1H), 4.96 (dd, J = 7.5, 5.5 Hz, 1H), 4.22 (ddd, J = 7.2, 3.2, 1.2
Hz, 1H), 3.79 (ddd, J = 7.0, 4.9, 3.2 Hz, 1H), 3.64 (s, 3H), 2.33 (t, J = 7.4 Hz, 2H), 1.77 (m, 1H),
89
1.67 (m, 3H), 1.50 (m, 3H), 1.31 (m, 5H), 1.00 (td, J = 8.0, 7.9, 6.6 Hz, 18H), 0.87 (t, J = 6.9 Hz,
3H), 0.68 (qt, J = 8.2, 1.4 Hz, 12H). Ref. KK-72-260-663.

Methyl (5S,6R,E)-5,6-dihydroxy-8-(2-((R)-1-hydroxyhexyl)phenyl)oct-7-enoate (6)

A 4-dram vial in a nitrogen glove box was charged with 5 (24.5 mg, 0.0413 mmol), and
anhydrous THF (3.0 mL). The vial was capped with a Teflon-disked cap and the headspace was
flushed with argon. The vial was submerged in an ice water bath and left to cool for 10 minutes
while stirring. A 1.0 M solution of TBAF (approximately 80 μL) in THF was added and the
solution was stirred for 45 minutes and brought to room temperature. The solution was allowed
to stir at room temperature for no more than 10 minutes. Saturated NH4Cl (approximately 1 mL)
was added and the solution was agitated, extracted with ether three times. The collected organic
phase was dried over MgSO4 and condensed. The oil was chromatographed through a 10 g
Biotage Sfär Silica – 60μm column with a 40-70% EtOAc in hexanes gradient system. Fractions
containing product, visualized at 254 and 280 nm, were collected and condensed under reduced
pressure to give a clear, colorless oil (94% conversion, >99% stereoretention).
1
H-NMR (400 MHz, CD3OD) δ 7.46 (m, 2H), 7.25 (td, J = 7.6, 7.5, 1.6 Hz, 1H), 7.20 (td, J =
7.5, 7.4, 1.6 Hz, 1H), 6.98 (d, J = 15.3 Hz, 1H), 6.17 (dd, J = 15.6, 6.9 Hz, 1H), 4.99 (t, J = 6.5
Hz, 1H), 4.10 (ddd, J = 6.9, 4.8, 1.3 Hz, 1H), 3.73 (m, 1H), 3.60 (m, 1H), 2.37 (t, J = 7.2, 2H),
1.87 (m, 2H), 1.66 (m, 4H), 1.44 (m, 2H), 0.89 (m, 3H). Ref. KK-71-273-677.
90
3.6 References
[1] Serhan, C. N.; Hamberg, M.; Samuelsson, B.; Trihydroxytetraenes: A novel series
of compounds formed from Arachidonic acid in human leukocytes. Biochem.
Biophys. Res. Commun. 1984, 118, 3, 943-949.
[2] Tiberi, M.; Chiurchiù, V.; Specialized Pro-resolving Lidip Mediators and Glial Cells:
Emerging Candidates for Brain Homeostasis and Repair. Front. Cell. Neurosci. 2021, 15,
673549.
[3] (a) Serhan, C. N.; Savill, J.; Resolution of inflammation: the beginning programs the
ends. Nat. Immunol. 2005, 6, 1191-1197. (b) Ortiz-Muñoz, G.; Mallavia, B.; Bins, A.;
Headley, M.; Krummel, M. F.; Looney, M. R.; Aspirin-triggered 15-epi-lipoxin A4
regulates neutrophil-platelet aggregation and attenuates acute lung injury in mice. Blood.
2014, 124, 17, 2625-2634. (c) Kain, V.; Liu, F.; Kozlovskaya, V.; Ingle, K. A.; Bolisetty,
S.; Agarwal, A.; Khedkar, S.; Prabhu, S. D.; Kharlampieva, E.; Halade, G. V.; Resolution
Agonist 15-epi-Lipoxin A4 Programs Early Activation of Resolving Phase in Post-
Myocardial Infarction Healing. Sci. Rep. 2017, 7, 9999. (d)Sekheri, M.; Kebir, D. E.;
Edner, N.; Filep, J. G.; 15-Epi-LXA4 and 17-epiRvD1 restore TLR9-mediated impaired
neutrophil phagocytosis and accelerate resolution of lung inflammation. Proc. Natl. Acad.
Sci. U.S.A. 2020, 117, 14, 7971-7980.
[4] For studies regarding benzo-LXA2 stability, see: Sun, Y.-P.; Tjonahen, E.; Keladjian, R.;
Zhu, M.; Yang, R.; Recchiuti, A.; Pillai, P. S.; Petasis, N. A.; Serhan, C. N.; Anti-
inflammatory and pro-resolving properties of benzo-lipoxin A4 analogs. Prostaglandins
Leukot. Essent. Fatty Acids. 2009, 81, 357-366.
91
[5] Horino, Y.; Aimono, A.; Abe, H.; Pd-Catalyzed Three-Component Reaction of 3-
(Pinacolatoboryl)allyl Acetates, Aldehydes, and Organoboranes: A New Entry to
Stereoselective Synthesis of (Z)-anti-Homoallylic Alcohols. Org. Lett. 2015, 17,
2824-2827.
[6] O’Sullivan, T. P.; Vallin, K. S. A.; Shah, S. T. A.; Fakhry, J.; Maderna, P.; Scannell, M.;
Sampaio, A. L. F.; Perretty, M.; Godson, C.; Guiry, P. J.; Aromatic Lipoxin A4 and
Lipoxin B4 Analogues Display Potent Biological Activities. J. Med. Chem. 2007, 50,
5894-5902. (A modified procedure was used involving pentylmagnesium bromide that
was purchased commercially as a 2.0 M solution in hexanes.)
[7] The procedure used was provided by a research contract organization. Information
regarding phosphine cataCXium ligands can be found here: Fleckinstein, C. A.; Plenio,
H.; Aqueous cross-coupling: highly efficient Suzuki-Miyaura coupling of N-heteroaryl
halides and N-heteroarylboronic acids. Green Chem. 2007, 9, 1287-1291.; Fleckenstein,
C. A.; Plenio, H.; 9-Fluorenylphosphines for the Pd-Catalyzed Sonogashira, Suzuki, and
Buchwald-Hartwig Coupling Reactions in Organic Solvents and Water. Chem. Eur. J.
2007, 13, 2701-2716.; Fleckenstein, C. A.; Plenio, H. Highly Efficient Suzuki-Miyaura
Coupling of Heterocyclic Substrates through Rational Reaction Design. Chem. Eur. J.
2008, 14, 4267-4279.
[8] Matsumura, K.; Arai, N.; Hori, K.; Saito, T.; Sayo, N.; Okhuma, T.; Chiral
Ruthenabicyclic Complexes: Precatalysts for Rapid, Enantioselective, and Wide-Scope
Hydrogenation of Ketones. J. Am. Chem. Soc. 2011, 133, 10696-10699.
92
[9] Nakane, S.; Yoshinaka, S.; Iwase, S.; Shuto, Y.; Bunse, P.; Wünsch, Tanaka, S.;
Kitamura, M.; Synthesis of fluspidine via asymmetric NaBH4 reduction of silicon
enolates of β-keto esters. Tetrahedron, 2018, 74, 5069-5084.
[10] Ogawa, N.; Amano, T.; Kobayashi, Y.; Synthesis of Optically Active Maresin 2 and
Maresin 2n-3 DPA. Synlett, 2021, 32, 295-298.
[11] Refer to appendix for chromatographic data.

93

CHAPTER 4
Total Synthesis of Aspirin-Triggered Neuroprotectin D1/Protectin D1

94
4.1 Introduction
Neuroprotectin D1/protectin D1 (NPD1/PD1) is a compound produced endogenously via
enzymatic oxidation of docosahaexanoic acid (DHA), and has a critical role in the resolution of
inflammation (Scheme 4.1).
1
Initial studies elucidated its potent action in the protection of the
brain and retina from oxidative stress, and was appropriately termed neuroprotectin D1 as a
result.
2
A year later, additional protective roles in non-neuronal tissues were discovered for the
same compound, leading to a broader designation of NPD1/PD1.
3
The role of NPD1/PD1 differ
fundamentally from conventional anti-inflammation therapeutics. Instead of inhibiting the
process of inflammation by deactivating inflammatory response enzymes, NPD1/PD1, as well as
other lipid mediators, act as stop-signals when inflammation has properly run its course.
4

Scheme 4.1: Biosynthesis of NPD1/PD1 and AT-NPD1/PD1.
5

95
The biosynthesis of an analogue of NPD1/PD1 produced by endogenous oxidation by
cyclooxygenase-2 (COX-2) in the presence of aspirin was later elucidated.
4
This analogues,
called aspirin-triggered neuroprotectin D1/protectin D1 (AT-NPD1/PD1), differs from
NPD1/PD1 by the stereoconfiguration at the C17 hydroxyl group, the aspirin-triggered analogue
having R-stereoconfiguration.
5
The group responsible for its discovery proved enhanced potency
of AT-NPD1/PD1 as an anti-inflammatory-pro-resolving compound.

96
4.2 Retrosynthetic Analysis
Our strategy for the preparation of aspirin-triggered neuroprotectin D1/protectin D1 (AT-
NPD1/PD1) involves a three-fold convergent synthesis utilizing core fragment 19 with two
sequentially added terminal fragments 5 and 20 (Scheme 4.1). The primary advantage of this
strategy is that it provides access to other chiral and / or structural analogues with R-
stereoconfiguration at the C10 carbon from a core fragment holding an advanced position in the
synthetic pathway. Divergent syntheses from 19 may allow the production a broad range of
analogues in a highly efficient manner.
Final product 24 can be generated via Suzuki-Miyaura between terminal fragment 5 and
the C14 position of 22. The stereoretentive nature of Suzuki-Miyaura couplings with regards to
alkenyl systems allows a convenient approach to generating the cis-trans-trans network along
C16 through C11. The cis π bond at C4-C5 can be achieved through Wittig olefination between
an in-situ generated ylid on core fragment 19 and aldehyde 20. Formation of core fragment 19
can be achieved through an epoxide ring opening reaction between silyl protected glycidol 9 and
terminal alkyne 8 in the presence of Lewis acid and alkyllithium base.
Previous total syntheses of AT-NDP1/PD1 have involved a series of Sonogashira
couplings to generate C5-C6 and C14-C15 alkynes followed by mild reductions via Lindlar’s
catalyst.
7
Complications arise due to the particularly activated nature of the conjugated system at
C11 through C16, and thus reduction of the C15-C16 triple bond exhibit a propensity for over-
reduction. By contrast, our strategy generates the C14-C15 bond via Suzuki-Miyaura coupling
between 5 and 22 avoiding this complication. The stereoretentive nature of this reaction
regarding alkenyl systems allows installation of the required C15-C16 cis bond and eliminates
the need for further reduction.
97

Scheme 4.2: Retrosynthetic analysis for the production of AT-NPD1/PD1.
98
4.3 Results and Discussion
The synthesis of AT-NPD1/PD1 involved independent, multistep routes to generate three
key fragments: the core fragment 19 with terminal C15 and C5 reactive sites, aldehyde 20, and
cis-iodide 5. The synthesis of the 5 is shown in Scheme 4.2 and will be discussed first, followed
by the synthesis of core fragment 19.
Synthesis of cis-iodide 5 began with an L-proline catalyzed stereoselective aminoxylation
of commercially available cis-4-heptanol 1, followed by a hydroboration oxidation using sodium
borohydride followed by zinc dust affording (R)-diol 2 in very good yields and high
enantioselectivity.
8
A double protection of the 2 with two equivalents of triethylsilyl chloride
was achieved in very good yields. The primary silyl ether of 3 was selectively oxidized under
Swern conditions to afford 4 in good yields. Finally, the aldehyde was homologated via Wittig
type reaction in the presence of (iodomethyl)thriphenylphosphonium iodide to afford the cis-
iodide 5 in moderate yields.
9

Scheme 4.3: Synthesis of terminal fragment 5.
99
Construction of core fragment 19 is shown in Scheme 4.3 and began with parallel silyl
protections of but-3-yn-1-ol and (S)-(-)-glycidol with tert-butyldimethylsilyl chloride and
triethylsilyl chloride, respectively.
10
The silyl ethers underwent epoxide ring opening in the
presence of boron trifluoride etherate and n-butyl lithium to produce alkyne 10 in good yields.
11

To homologate the terminal alcohol at C11, a series of orthogonal silyl protections and
deprotections were required. First, the free alcohol at C10 was protected with tert-
butyldiphenylsilyl chloride in good yields, and a competitive deprotection of C11 primary
triethylsilyl ether was done in the presence of 5% formic acid in methanol and a one-to-one
mixture of dichloromethane and methanol at low temperatures.
12
Although triethylsilyl ethers
are preferentially cleaved over tert-butyldimethylsilyl ethers, some double deprotection was
observed. Thus, special care was taken to selectively remove the triethylsilyl group by periodic
reaction monitoring via thin layer chromatography and maintaining low temperatures. Next,
reduction of the alkyne of 12 was done in excellent yields using Lindlar’s catalyst in the presence
of hydrogen gas, as well as a small volume of quinoline to prevent further reduction
f
. Oxidation
of free alcohol 13 was carried out using Dess-Martin periodinane and dichloromethane in the
presence of pyridine for reaction acceleration.
13
Ambient conditions afforded aldehyde 14 in
excellent yields. A Wittig homologation was performed using (triphenylphosphoranylidene)
acetaldehyde in toluene under argon atmosphere to afford 15 in good yields.
14
To stabilize the
reactive terminal for further conversions at C5, the homologated aldehyde was converted to
terminal alkyne 16 in excellent yields in the presence of a large excess of both lithium
diisopropylamide and trimethylsilyl diazomethane under rigorously controlled temperature and
moisture free conditions.
15
With a stabilized terminal C14 position in hand, attention was then
brought to further modification of C5 to generate thriphenylphosphonium bromide for Wittig
100
olefination with 20. Removal of the tert-butyldimethylsilyl ether was achieved using
camphorsulfonic acid in a one to one mixture of dichloromethane and methanol, affording free
alcohol 17 in very good yields.16 Bromination using carbon tetrabromide in dichloromethane
afforded 18 in moderate yields,
17
and subsequent substitution with triphenylphosphene under
microwave assisted conditions afforded completed core fragment 19 in good yields.
18

Scheme 4.4: Synthesis of the core fragment.

101
With phosphonium bromide 19 in hand, Wittig olefination with the corresponding
aldehyde 20 was done (Scheme 4.4).
19
A one-step synthesis of 20 from its bromide precursor
was done under microwave-assisted conditions in the presence of sodium hypochlorite and
2,2,6,6-tetramethyl-1-piperidinyloxy free radical in excellent yields.
20
The terminal alkyne was
treated with a neat mixture of Schwartz’ reagent with pinacolborane and triethylamine at
elevated temperatures to generate trans-pinacolborane 22 in moderate yields.
21
A Suzuki-
Miyaura coupling between 22 and 5 was done using cesium carbonate and
tetrakis(triphenylphosphene) palladium(0) in a mixture of water and tetrahydrofuran to afford 23
in moderate yields.
22
Purification of the product proved difficult, thus deprotection using
tetrabutylammonium fluoride and a subsequent hydrolysis to generate the carboxylic acid of
were done sequentially on the crude without purification until the final step to afford the final
compound (R,R-NPD1/PD1 24).

Scheme 4.5: Joining of the terminal pieces and completion of AT-NPD1/PD1.

102
4.4 Challenges and Setbacks
The synthesis of AT-NPD1/PD1 involved some failures and complications that required
rerouting and reordering to our initial strategy (Scheme 4.5). These low-yielding or failed
conversions seem appropriate to note considering the possibility of further development down
the road. Thus, the following discussion is intended to explain the logic behind some of the
conversions and the choice of ordering along the synthetic route discussed above.
1. Concerns surrounding the strongly basic conditions required to open the epoxide ring of 7
led previous researchers to convert the primary alcohol of 7 into a robust trityl ether. As
expected, good yields were achieved in the presence of a highly reactive alkyllithium
reagent and Lewis base. Unfortunately, removal of the trityl group using zinc dibromide
proved cumbersome and resulted in diminished yields for unknown reasons.
23
Because
differential stabilities were required for the selective deprotection at the C11 silyl ether,
tert-butyldimethylsilyl ether was obviously not an option. There was a concern that the
next best option, triethylsilyl ether, would not tolerate alkyllithium conditions. Treatment
of 9 with n-butyllithium and boron trifluoride etherate was unexpectedly well tolerated
and led to only slightly diminished yield (74% yield for the trityl ether, to 69% yield for
9). Subsequent protection of C10 alcohol and deprotection of 11 with a 5% solution of
formic acid in methanol afforded the desired alcohol 12 in good yields, proving to be
much more feasible.
2. Due to circumstances and urgency, the initially planned Suzuki-Miyaura coupling
involved a trans iodide at C14 on the core fragment and a cis-pinacolborane
functionalized analogue of terminal fragment 5. The strategy involved conversion of 4
into terminal alkyne 5a via Bestmann-Ohira reagent,
24
followed by borylation using n-
103
butyllithium to generate 5c
25
and subsequent reduction via Schwartz reagent to furnish
the desired terminal fragment 5d.
26
Conversion of 5c provided no product under several
different sets of conditions. This was suspected to be the result of steric congestion
between the bulky zirconium complex and geminal silyl ether. To get around this, the
location of iodide and boronate ester was exchanged, and the procedure described above
to install the cis-iodide on the terminal fragment proved effective. Likewise, 21 was
efficiently functionalized with the boronate ester via Schwartz reagent, and the Suzuki-
Miyaura coupling between the two major fragments was achieved successfully.
Additionally, these improvements conveniently lead to a decrease in four reaction steps
to synthesize 5.
3. Unexpectedly, the ordering of key C-C bond forming steps between terminal fragments 5
and 20 with the core fragment was non-trivial. The initial strategy involved the Suzuki
coupling being done first, with Wittig olefination being carried out as the final key step.
Attempts at Wittig olefination palladium-coupled fragment 23a were unsuccessful. The
source of failure is not precisely known, but it is suspected that the increased degree of
freedom of 23a make the substrate fold upon itself at very low temperatures and shroud
the reactive center at C5. Another possibility involves the undesired cleavage of the
triethylsilyl ether under strongly basic conditions. Attempts of selective deprotection and
re-protection with tert-butyldiphenylsilyl chloride still failed. Wittig olefination of
terminal alkyne 19 tolerated the given conditions, affording the homologated fragment,
albeit in low yields.
104

Scheme 4.6: Unsuccessful conversions. a) Low yielding trityl ether deprotection.
b) Suzuki-Miyaura substrate modifications. c) Ordering of terminal
fragment couplings.

105
4.5 Conclusions
An efficient total synthesis of AT-NPD1/PD1 has been achieved using a three-fold
convergent strategy. Since the core fragment is holding an advanced position along the synthetic
route, it is hoped that other chiral and structural analogues having R-stereoconfiguration at C10
can be synthesized very conveniently. From the core fragment, only three simple and high
yielding steps are required to begin generation of the C-C bond at the C5 terminus via Wittig
olefination. From there, a simple hydroboration unlocks the C14 terminus to undergo Suzuki-
Miyaura coupling, and two additional, simple steps are required to furnish the analogue of
choice. It is hoped that this route will allow a simpler alternative to synthesizing these complex
molecules.

4.6 Synthetic Procedures
General Information. All materials were purchased from commercial suppliers and were used
as received without further purification. Reactions were done under inert atmosphere using a
standard flame drying and argon backfilling procedure unless otherwise stated. In these cases,
the procedure was repeated three times prior to charging the reaction vessel with materials.
Anhydrous solvents were purchased from Sigma-Aldrich and used without further manipulation.
All
1
H NMR spectra were obtained using a mercury 400 MHz spectrometer and referenced to
CDCl3, CD3OD, CO(CD2)2, and C6D6 at 7.26, 3.31, 2.05, and 7.16 ppm, respectively. All
13
C
spectra were obtained using a Varian 600 MHz NMR spectrometer and referenced to CDCl3 and
C6D6 at 77.16 and 128.06 ppm, respectively.

106
(S,Z)-hept-4-ene-1,2-diol (2a)

Nitrosobenzene (2.733 g) and D-proline (317.5 mg) were dissolved in chloroform (20 mL) at
room temperature. The teal-colored solution was cooled to 0°C and cis-4-heptenal (10 mL) was
added drop-wise and was left to stir for 1 hour. At this time, the solution turned to a dark amber
color. A cooled solution of sodium borohydride 2.841 g) in 100 proof ethanol (230 mL) was
added via cannula transfer, giving a light-orange, cloudy solution. After 1 hour, sodium
bicarbonate was added in small portions until bubbling subsided, and the solution was
condensed, re-dissolved in ethyl acetate, and washed with brine. The organic phase was dried
over MgSO4 and condensed to give an amber oil.
The previous material and zinc dust (16.118 g) was dissolved in 3:1 ethyl acetate/acetic acid
solution (200 mL) and stirred at room temperate overnight. The solution was filtered through a
plug of celite, condensed, and chromatographed (20-95% ethyl acetate in hexanes) to afford the
title compound as a clear, colorless oil (3.089 g, 93% yield).

(R,Z)-hept-4-ene-1,2-diol (2)

The procedure used to produce the (S)-derivative was followed to afford the title compound as a
clear, amber oil (3.559 g, 78% yield).
107
(S,Z)-3,3,8,8-tetraethyl-5-(pent-2-en-1-yl)-4,7-dioxa-3,8-disiladecane (3a)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added imidazole
(1.722 g), DMAP (141 mg), and anhydrous DCM (40 mL). The solution was cooled to 0°C in
an ice bath and (S)-diol (1.8471 g) in 10 mL of anhydrous DCM was added followed by
triethylsilyl chloride (4.25 mL), drop-wise, to give a cloudy white solution. The solution was
warmed to room temperature and left to stir for 16 hours. An excess of DCM was added and the
solution was washed with brine. The organic phase was dried over MgSO4, condensed, and the
resulting oil was chromatographed (1-10% ethyl acetate in hexanes). Fractions were condensed
under vacuum in an 80°C water bath to afford the title compound as a colorless oil (3.610 g, 89%
yield).
1
H-NMR (400 MHz, CDCl3): δ 5.36-5.48 (m, 2H), 3.69 (p, J = 5.7 Hz, 1H), 3.42-3.52
(m, 2H), 2.29-2.36 (m, 1H), 2.12-2.19 (m, 1H), 2.01-2.08 (m, 2H), 0.95 (t, J = 7.7 Hz, 18H),
0.56-0.63 (m, 12H), 0.49-0.55 (q, J = 7.8 Hz, 3H).

(R,Z)-3,3,8,8-tetraethyl-5-(pent-2-en-1-yl)-4,7-dioxa-3,8-disiladecane (3)

The procedure used to produce the (S)-derivative was followed to afford the title compound as a
pale-yellow oil (7.924 g, 87% yield).

108
(S,Z)-2-((triethylsilyl)oxy)hept-4-enal (4a)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added anhydrous
DCM (20 mL) and DMSO (3.5 mL), and the solution was cooled to -78°C. Oxalyl chloride (2.2
mL) in anhydrous DCM (25 mL) was added drop-wise via syringe. The resulting mixture was
stirred for 15 minutes, and a solution of protected diol (1.989 g) in anhydrous DCM (5 mL) was
added slowly. After 10 minutes, the solution was warmed to -40°C and stirred for 1.5 hours.
The solution was cooled back to -78°C and DIPEA (excess) was added drop-wise, and the
resulting solution was allowed to warm to room temperature. The mixture was diluted with
DCM and washed with saturated NH4Cl, and the organic phase was washed with brine. The
organic material was condensed via rotary evaporator using a water bath cooled with ice, and the
residue was purified via column chromatography to afford the title compound as a yellow oil
(618 mg, 46% yield).
1
H-NMR (400 MHz, CDCl3): δ 9.60 (s, 1H), 5.54 (m, 1H), 5.34-5.41 (m,
1H), 3.69-3.99 (dt, J = 1.8, 6.24 Hz, 1H) 2.40 (t, J = 5.9 Hz, 2H), 2.01-2.07 (m, 2H), 0.96 (t, J =
7.9 Hz, 9H), 0.95 (t, J = 7.6 Hz, 3H) 0.60-0.65 (q, J = 8.1 Hz, 6H).

109
(R,Z)-2-((triethylsilyl)oxy)hept-4-enal (4)

The procedure used to produce the (S)-derivative was followed to afford the title compound as a
pale-yellow oil (621.3 mg, 73% yield).
1
H-NMR (400 MHz, CD3OD): δ 9.55 (d, J = 1.3 Hz,
1H), 5.49-5.53 (m, 1H), 5.35-5.40 (m, 1H), 4.09-4.11 (dt, J = 1.3, 6.2 Hz, 1H), 2.42 (m, 2H),
2.07 (dp, J = 1.8, 7.5 Hz, 2H), 0.98 (t, J = 8.9 Hz, 9H), 0.97 (t, J = 7.6 Hz, 3H), 0.63-0.67 (q, J =
8.2 Hz, 6H).

triethyl(((S,1Z,5Z)-1-iodoocta-1,5-dien-3-yl)oxy)silane (5a)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added PPh3CH2I2
(656 mg) and anhydrous THF (4.0 mL). Hexamethyl disilazide (1.0 M in THF, 400 uL) was
added and the solution was cooled to -78°C. HMPA (a few drops), followed by the TES-
protected aldehyde (103 mg) as a 0.2 M solution in anhydrous THF were added and left to stir
for 1 hour. The solution was brought to room temperature and quenched with saturated NH4Cl
and the mixture was extracted with diethyl ether. The combined organic phases were dried over
MgSO4 and condensed. The residue was purified via column chromatography to afford the title
compound as a colorless oil (71.6 mg, 46% yield).
1
H-NMR (400 MHz, C6D6): δ 6.02 (t, J = 7.6
110
Hz, 1H), 5.78-5.80 (dd, J = 1.0, 7.6 Hz, 1H), 5.49-5.64 (m, 2H), 4.53-4.58 (dddd, J = 1.1, 5.7,
6.6, 7.7 Hz, 1H), 2.29-2.44 (m, 2H), 2.04 (m, 2H), 1.03 (t, J = 7.6 Hz, 9H), 0.92 (t, J = 7.5 Hz,
3H), 0.64-0.70 (dq, J = 0.6, 8.0 Hz, 6H).
13
C-NMR (400 MHz, CDCl3): δ 144.57, 134.26,
124.27, 80.22, 75.72, 35.22, 21.14, 14.45, 7.16, 5.41.

triethyl(((R,1Z,5Z)-1-iodoocta-1,5-dien-3-yl)oxy)silane (5)

The procedure used to produce the (S)-derivative was followed to afford the title compound as a
colorless oil (80.9 mg, 49% yield).
1
H-NMR (400 MHz, C6D6): δ 6.02 (t, J = 7.6 Hz, 1H), 5.78-
5.80 (dd, J = 1.0, 7.6 Hz, 1H), 5.49-5.64 (m, 2H), 4.53-4.58 (dddd, J = 1.0, 5.7, 6.7, 7.7 Hz, 1H),
2.29-2.44 (m, 2H), 2.00-2.08 (m, 2H), 1.03 (t, J = 7.6 Hz, 9H), 0.92 (t, J = 7.5 Hz, 3H), 0.64-0.70
(dq, J = 0.6, 8.0 Hz, 6H).

111
(but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (8)

but-3-yn-1-ol (7.49 g) and anhydrous DCM (120 mL) were added to a flame dried, argon back-
filled rbf equipped with a stir bar. DMAP (3.7 g) and imidazole (15.0 g) were added through the
neck of the rbf and the solution was cooled in an ice bath. Tert-butyldimethylsilyl chloride (18
g) was added slowly through the neck of the flask and the head space of the vessel was purged
with argon. The resulting mixture was allowed to warm to room temperature and stirred for
several hours, and the mixture was washed with saturated NH4Cl and the mixture was extracted
with DCM, and the combined organic phases were dried over MgSO4. The organic solution was
condensed and purified via column chromatography to afford the title compound as a clear oil
(17.5 g, 89% yield).

(R)-triethyl(oxiran-2-ylmethoxy)silane (9)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added (S)-(-)-
glycidol (5.0 g) and anhydrous DCM (67 mL). The solution was cooled in an ice bath and
DMAP (825 mg, mmol) and imidazole (5.97 g) were added through the neck of the flask.
Triethylsilyl chloride (11.8 mL) in anhydrous DCM (15 mL) was added drop-wise via syringe,
and the resulting mixture was allowed to warm to room temperature and stir for 1.7 hours. The
112
solution was washed with water and the mixture was extracted with DCM. The combined
organic phases were dried over MgSO4, condensed, and purified via column chromatography to
afford the title compound as a clear, colorless oil (10.62 g, 84% yield).

(R)-3,3-diethyl-13,13,14,14-tetramethyl-4,12-dioxa-3,13-disilapentadec-8-yn-6-ol (10)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added (R)-TBS-
protected alkyne (3.745 g) in anhydrous THF (25 mL), and the solution was cooled to -78°C. n-
Butyl lithium in hexanes (8.0 mL, 2.5 M) was added drop-wise via syringe, and the resulting
solution was allowed to stir for 35 minutes. BF3OEt2 (2.51 mL) was added, and after 5 minutes
(S)-TES-protected glycidol (2.677 g) in anhydrous THF (5 mL) was added slowly, drop-wise.
After 2.2 hours, the solution was warmed to 0°C and the solution was quenched with saturated
NH4Cl and extracted with diethyl ether. The combined organic phases were dried over MgSO4,
condensed, and purified via column chromatography to afford the title compound as a faintly
pale oil (3.67 g, 69% yield).
1
H-NMR (400 MHz, CDCl3): δ 3.68-3.70 (m, 3H), 3.57-3.61 (m,
1H), 2.35-2.40 (m, 4H), 0.97 (dt, J = 1.2, 7.9 Hz, 9H), 0.89 (s, 9H), 0.60-0.64 (m, 9H), 0.07 (s,
6H).
13
C-NMR (600 MHz, CDCl3): δ 79.53, 72.07, 70.58, 67.13, 65.50, 62.35, 32.92, 32.09,
26.04, 25.43, 23.59, 23.32, 22.74, 18.49, 14.19, 6.86, 4.51, -5.14.

113
(R)-10-((tert-butyldiphenylsilyl)oxy)-13,13-diethyl-2,2,3,3-tetramethyl-4,12-dioxa-3,13-
disilapentadec-7-yne (11)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added imidazole (995
mg), DMAP (350 mg), and anhydrous DCM (15 mL). The solution was cooled to 0°C, and a
solution of unprotected alcohol (3.67 g) in anhydrous DCM (5 mL) was added followed by
tertbutyl diphenylsilyl chloride (3.03 mL) drop-wise. The white, heterogeneous solution was
warmed to room temperature and stirred for 1.5 hours. The mixture was washed with NH4Cl and
the solution was extracted with DCM. The combined organic phases were dried over MgSO4,
condensed, and purified via column chromatography to afford the title compound as a clear,
colorless oil (4.715 g, 79%).

114
(R)-7-((tert-butyldimethylsilyl)oxy)-2-((tert-butyldiphenylsilyl)oxy)hept-4-yn-1-ol (12)

A solution of DCM/methanol (1:1, 40 mL) and formic acid (4 mL) was cooled to 0°C in an ice
bath. (R)-protected alcohol (6.412 g) in DCM was added slowly and the solution was allowed to
stir at 0°C for 1 hour. 10% sodium bicarbonate solution was added and the organic solvents
were removed under vacuum. The crude was extracted with DCM 3 times, and the organic
phase was dried over MgSO4, condensed, and the resulting oil was chromatographed with 5-25%
ethyl acetate/hexanes gradient to afford the title compound as a clear, colorless oil (2.931 g).
1
H-NMR (600 MHz, CDCl3) δ 7.66-7.69 (m, 4H), 7.44 (tt, 7.6, 1.4 Hz, 2H), 7.37-7.40 (m, 4H),
3.88-3.92 (m, 1H), 3.61-3.64 (m, 4H), 2.37-2.43 (m, 1H), 2.26-2.31 (m, 3H), 1.08 (s, 9H), 0.87
(s, 9H), 0.04 (s, 6H);
13
C-NMR (600 MHz, CDCl3) δ 135.98, 135.82, 133.69, 133.66, 130.06,
127.97, 127.84, 79.41, 72.63, 65.72, 62.26, 27.12, 26.03, 23.99, 23.27, 19.45, 18.46, 6.73, 5.95, -
5.15.

115
(R,Z)-7-((tert-butyldimethylsilyl)oxy)-2-((tert-butyldiphenylsilyl)oxy)hept-4-en-1-ol (13)

To an rbf equipped with a stir bar was added primary alcohol (1.137 g), Lindlar’s catalyst (0.8
g), ethyl acetate (15 mL) and quinoline (5 drops). The vessel was evacuated and back-filled with
hydrogen gas three times, and the solution was left to stir at room temperature for 45 minutes.
The solution volume was doubled with ethyl acetate and passed through a micro-filter. The
clear, colorless solution was condensed to afford the title compound as a clear, colorless oil
(1.035 g, 91% yield).
1
H-NMR (400 MHz, CDCl3): δ 7.67-7.70 (m, 4H), 7.42-7.45 (m, 2H),
7.37-7.40 (m, 4H), 5.31-5.42 (m, 2H), 3.79-3.82 (sextet, J = 4.8 Hz, 1H), 3.53 (t, J = 6.8 Hz, 3H),
2.18-2.34 (m, 2H), 2.08-2.12 (dq, J = 1.5, 6.8 Hz, 2H), 1.08 (s, 9H), 0.88 (s, 9H), 0.03 (s, 6H).
13
C-NMR (600 MHz, CDCl3) δ 136.03, 135.86, 134.03, 133.93, 129.96, 129.93, 128.84, 127.90,
127.81, 126.33, 73.71, 65.53, 62.93, 31.86, 31.06, 27.18, 26.13, 19.47, 18.56, 6.73, 5.96, -5.15.

116
(R,Z)-7-((tert-butyldimethylsilyl)oxy)-2-((tert-butyldiphenylsilyl)oxy)hept-4-enal (14)

To an rbf equipped with a stir bar was added DCM (14 mL) and alcohol (213 mg). The vessel
was cooled in an ice bath, and Dess-Martin periodinane (362 mg) was added followed by
pyridine (8 drops). The light-blue, heterogeneous solution was allowed to warm to room
temperature, and stirred under ambient atmosphere for 1 hour. To the brown solution was added
NaHCO3/Na2SO4 solution (1:1, 40 mL), and the biphasic mixture was diluted with DCM, and
several extractions using DCM were performed. The combined organic phases were dried over
MgSO4 and condensed with celite via rotary evaporation in a cooled water bath. The solid
residue was purified via dry-load column chromatography to afford the title compound as a pale,
yellow oil (196.1 mg, 92% yield).
1
H-NMR (400 MHz, CDCl3): δ 9.56, (s, 1H), 7.63-7.67 (m),
7.35-7.47 (m), 5.43-5.54 (m, 2H), 4.06-4.09 (m, 1H), 3.53-3.57 (m, 2H), 2.34-2.50 (m, 2H),
2.14-2.19 (m, 2H), 1.12 (s, 9H), 0.89 (s, 9H), 0.04 (s, 6H).
13
C-NMR (600 MHz, CDCl3) δ
203.43, 135.95, 133.20, 133.11, 130.20, 129.42, 127.97, 124.70, 77.84, 62.71, 31.38, 31.28,
27.07, 26.09, 19.48, 18.47, -5.15.
117
(R,2E,6Z)-9-((tert-butyldimethylsilyl)oxy)-4-((tert-butyldiphenylsilyl)oxy)nona-2,6-dienal
(15)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added aldehyde
(1.353 g), toluene (45 mL), and (triphenylphosphoranylidene)acetaldehyde (1.326 g). The vessel
containing the heterogeneous, orange mixture was equipped with a reflux condenser and argon
balloon setup, and was allowed to stir vigorously in an oil bath externally measured to be 85°C.
After 2.5 hours, the dark red solution was allowed to reach room temperature. The solution was
condensed and the residue was purified via column chromatography to afford the title compound
as a pale, yellow oil (1.035 g, 73% yield).
1
H-NMR (400 MHz, CDCl3): δ 9.45 (d, J = 8.1 Hz, 1H), 7.67-7.68 (d, J = 6.8 Hz, 4H), 7.60-7.61
(d, 6.8 Hz, 4H), 7.34-7.46 (m, 12H), 6.68-6.72 (dd, J = 4.9, 15.6 Hz, 1H), 6.18-6.22 (ddd, J =
1.4, 7.9, 15.6 Hz, 1H), 5.32-5.48 (m, 2H), 4.46-4.49 (m, 1H), 3.48-3.51 (dt, J = 1.3, 6.75, 6.82
Hz, 2H), 2.24-2.35 (m, 2H), 2.02-2.06 (m, 2H), 1.09 (s, 9H), 0.87 (s, 9H), 0.02 (s, 6H).
13
C-NMR
(600 MHz, CDCl3): δ 193.63, 158.88, 136.00, 135.93, 131.18, 130.11, 129.45, 127.87, 124.97,
72.40, 62.71, 35.33, 31.24, 27.12, 26.08, 19.46, 18.48, -5.15.
118
(R,Z)-5-((E)-but-1-en-3-yn-1-yl)-2,2,12,12,13,13-hexamethyl-3,3-diphenyl-4,11-dioxa-3,12-
disilatetradec-7-ene (16)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added anhydrous
THF (6mL) and lithium diisopropylamide (2.7 mL, 2.0 M). The bright yellow solution was
cooled to -78°C, and trimethylsilyl diazomethane (2.7 mL, 2.0 M) was added drop-wise. After
30 minutes, a solution of homologated aldehyde (288 mg) in anhydrous THF (11 mL) was added
drop-wise and left to stir. After 1 hour, the vessel was warmed to 0°C and left to stir for an
additional 1.3 hours. The solution was quenched with saturated NH4Cl and stirred open to
ambient atmosphere 1 hour to allow excess diazomethane evaporate. The solution was extracted
with ether and the combined organic phases were dried over MgSO4 and condensed. The residue
was purified via column chromatography to afford the title compound as a clear, colorless oil
(255.4 mg, 89% yield).
1
H-NMR (400 MHz, CDCl3): δ 7.61-7.69 (m, 8H), 7.34-7.42 (m, 12H),
6.16-6.22 (dd, J = 5.5, 15.7 Hz, 1H), 5.54-5.58 (d, J = 15.9 Hz, 1H), 5.28-5.48 (m, 2H), 4.20-
4.23 (m, 1H), 3.49 (t, J = 6.4 Hz, 3H), 2.83 (s, 1H), 2.13-2.31 (m, 3H), 2.03-2.07 (m, 3H), 1.07
(s, 9H), 0.88 (s, 9H), 0.02 (s, 6H).
119
(R,3Z,7E)-6-((tert-butyldiphenylsilyl)oxy)deca-3,7-dien-9-yn-1-ol (17)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added alkyne ( 821
mg) and a solution of DCM (30 mL) and methanol (30 mL). The vessel was cooled to 0°C in an
ice bath, and 10-CSA (340 mg) was added. After stirring at 0°C for 1 hour, triethylamine (200
μL) was added to quench the mixture. The solution was warmed to room temperature,
condensed, and chromatographed to afford the title compound (518 mg, 81% yield).

(((R,3E,7Z)-10-bromodeca-3,7-dien-1-yn-5-yl)oxy)(tert-butyl)diphenylsilane (18)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added alcohol (518.8
mg) and DCM (2.0 mL). Carbon tetrabromide (290 mg) was added and the reaction vessel was
cooled to 0°C in an ice bath. Triphenylphosphene (234 mg) was added and the reaction was
120
stirred at 0°C for 1.2 hours. The solution was warmed to room temperature, condensed, and
chromatographed to afford the title compound (376.3 mg, 63% yield).

bromo((R,3Z,7E)-6-((tert-butyldiphenylsilyl)oxy)deca-3,7-dien-9-yn-1-yl)triphenyl-λ
5
-
phosphane (19)

To a flame dried and argon backfilled microwave reactor vial equipped with a stir bar was added
bromide (376 mg), triphenylphosphene (253 mg), and an anhydrous solution of acetonitrile (6
mL) and toluene (2 mL). The mixture was stirred at 105°C under microwave irradiation for 12
hours. The reaction had not reached completion, so the mixture was stirred for an additional 2
hours at 120°C under microwave irradiation. The mixture was condensed and purified via
column chromatography to afford the title compound as a dark yellow oil (414.4 mg, 71% yield).
121
ethyl (R,4Z,7Z,11E)-10-((tert-butyldiphenylsilyl)oxy)tetradeca-4,7,11-trien-13-ynoate (21)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added alkyne (210
mg) in a solution of still-dried THF (5 mL). After cooling the reaction vessel to -78°C,
NaHMDS (300 μL, 1.0 M solution) was added drop wise to produce a brick-red solution. After
3 hours stirring at -78°C, aldehyde (60 mg) in still-dried THF (0.6 mL) was added drop wise.
The mixture was allowed to stir for 40 minutes, and was then warmed to room 0°C, quenched
with NH4Cl, and extracted with ether. The combined organic phases were dried over MgSO4
and condensed. Column chromatography afforded the title compound as an oil (29.7 mg, 21%
yield).
1
H-NMR (400 MHz, C6D6): δ 7.70-7.76 (m, 4H), 7.18-7.24 (m, 6H), 6.24-6.29 (dd, J =
5.0, 15.9 Hz, 1H), 5.71-5.76 (m, 1H), 5.25-5.38 (m, 4H), 4.21-4.25 (m, 1H), 3.93-3.98 (q, J = 7.1
Hz, 2H), 2.58 (d, J = 2.3 Hz, 1H), 2.53-2.60 (m, 2H), 2.26-2.31 (m, 2H), 2.41-2.20 (m, 4H),
1.19-1.21 (d, 8.3 Hz, 2H), 1.14 (s, 9H), 0.97 (t, J = 7.1 Hz, 3H).
122
ethyl (R,4Z,7Z,11E,13E)-10-((tert-butyldiphenylsilyl)oxy)-14-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)tetradeca-4,7,11,13-tetraenoate (22)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added alkyne (29.7
mg, mmol), pinacolborane (1 mL), CpZr2HCl (12 mg), and triethylamine (10 μL). The reaction
vessel was submerged in an oil bath measured at 60°C. After 4 hours, the solution was cooled to
room temperature, and the reaction mixture was diluted with DCM and passed through a micro-
filter. The crude was condensed and chromatographed to afford the semi-pure title compound as
a clear, colorless oil.
123
ethyl (4Z,7Z,10R,11E,13E,15Z,17R,19Z)-10-((tert-butyldiphenylsilyl)oxy)-17-
((triethylsilyl)oxy)docosa-4,7,11,13,15,19-hexaenoate (23)

To an rbf equipped with a stir bar was added boronate (~37 mg) in THF (3 mL), iodide (26 mg),
PdPPh3 (14 mg), Cs2CO3 (43 mg), and water (0.75 mL). The solution was sparged with argon
for 30 minutes, evacuated, and back-filled with argon. The mixture was left to stir at room
temperature for 24 hours. The solution was diluted with water and extracted with ether. The
combined organic phases were dried over MgSO4, filtered, and condensed. Column
chromatography was done to afford the semi-pure title compound as an oil (27.3 mg, 63% crude
yield).
1
H-NMR (400 MHz, C6D6): δ
124
ethyl (4Z,7Z,10R,11E,13E,15Z,17R,19Z)-10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoate
(23a)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added protected diol
(~27 mg) in anhydrous THF (2.0 mL). The reaction vessel was submerged in an ice water bath
and TBAF (60 μL, M) was added drop wise and the solution was left to stir for 5.5 hours. Ice
water was added to the solution and an ether extraction was performed. The combined organic
phases were dried with MgSO4 and condensed via rotary evaporator using an ice cooled water
bath, and the residue was used for the following NaOH hydrolysis without further purification.

125
(R,Z)-2,2,12,12,13,13-hexamethyl-3,3-diphenyl-5-((1E,3E)-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)buta-1,3-dien-1-yl)-4,11-dioxa-3,12-disilatetradec-7-ene (24)

To a flame dried rbf equipped with a stir bar and backfilled with argon was added alkyne (243
mg), pinacol borane (560 μL), and Schwartz’ reagent Cp2ZrHCl (36 mg) in a nitrogen glove box.
The vessel was removed from the glove box and re-backfilled with argon. Triethylamine (70
μL) was added last via syringe, and the vessel was submerged in an oil bath measured at 60°C
and stirred for 2.5 hours under argon. The solution was condensed in celite and purified via dry-
loaded column chromatography to afford the title compound as a clear, colorless oil (243 mg,
63% yield).

126
(5R,6Z,8E,10E,12R,14Z)-12-((tert-butyldiphenylsilyl)oxy)-3,3-diethyl-19,19,20,20-
tetramethyl-5-((Z)-pent-2-en-1-yl)-4,18-dioxa-3,19-disilahenicosa-6,8,10,14-tetraene

To an rbf equipped with a sir bar was added a solution of THF and water (3:1, 15 mL), borane
(126.8 mg), vinyl iodide (56.9 mg), tetrakis(triphenylphosphene)palladium(0) (93.0 mg), and
Cs2CO3 (138 mg). The resulting solution was sparged with nitrogen for 30 minutes, and the
vessel was backfilled with argon. The solution was left the stir vigorously for 4 hours. The
solution was diluted with water and the mixture was extracted with diethyl ether. The combined
organic phases were dried over MgSO4 and condensed. The resulting residue was semi-purified
via column chromatography to afford the title compound as a pale yellow oil (91.5 mg, 78%
crude yield). Material was used for next reaction without further purification.

127
(3Z,6R,7Z,9E,11E,13R,15Z)-18-((tert-butyldimethylsilyl)oxy)-13-((tert-
butyldiphenylsilyl)oxy)octadeca-3,7,9,11,15-pentaen-6-ol

To an rbf equipped with a stir bar and backfilled with argon was added a DCM/MeOH solution
(1:1, 1.5 mL) and crude TES-protected alcohol (97 mg). The vessel was submerged in an ice
bath and a solution of formic acid in methanol (350 μL, 67% v/v) was added drop-wise, slowly,
via syringe, and the solution was left to stir for 1.5 hours. The vessel was allowed to warm to
room temperature and stir for 2 hours. Triethylamine (250 μL) was added at 0°C and the
solution was concentrated via rotary evaporation and purified via column chromatography to
afford the title compound as a clear, colorless oil (56.0 mg, 68% yield).

128
(5R,6Z,8E,10E,12R,14Z)-12-((tert-butyldiphenylsilyl)oxy)-2,2,19,19,20,20-hexamethyl-5-
((Z)-pent-2-en-1-yl)-3,3-diphenyl-4,18-dioxa-3,19-disilahenicosa-6,8,10,14-tetraene

To an rbf equipped with a stir bar and backfilled with argon was added a solution of free alcohol
(27 mg) in DCM (2.0 mL), DMAP (1.0 mg, mmol), imidazole (5.0 mg), and tert-
butyldiphenylsilyl chloride (40 μL). The resulting solution was left to stir at room temperature
under argon for 2.5 hours. The solution was washed with water and a microextraction using
DCM was done, followed by drying of the organic phase over MgSO4. The solution was
condensed and the residue was purified via column chromatography to afford the title compound
as a clear, colorless oil (34 mg, 92% yield).

129
(3Z,6R,7E,9E,11Z,13R,15Z)-6,13-bis((tert-butyldiphenylsilyl)oxy)octadeca-3,7,9,11,15-
pentaen-1-ol

To a flame dried rbf equipped with a stir bar was added a solution TBS-protected alcohol (34
mg) in DCM/MeOH (1:1, 4 mL), and the vessel was backfilled with argon and submerged in an
ice bath. A solution of 10-CSA (9.0 mg) in MeOH (1 mL) was added via syringe, and the
solution was allowed to stir at 0°C for 1.5 hours. Several drops of triethylamine were added and
the solution was condensed and purified via column chromatography to afford the title
compound as a pale-yellow oil (26.0 mg, 88% yield).

130
(3Z,6R,7E,9E,11Z,13R,15Z)-6,13-bis((tert-butyldiphenylsilyl)oxy)octadeca-3,7,9,11,15-
pentaenal

To an rbf equipped with a stir bar was added a solution of alcohol (26.6 mg) in DCM (1.5 mL),
and the vessel was submerged in an ice bath. Dess-Martin periodinane (31.8 mg) and pyridine (2
drops) were added and the solution covered with fail and stirred at room temperature for 40
minutes. A solution of saturated NaHCO3 and Na2SO4 (1:1) was added to quench the reaction
and the resulting mixture was extracted with DCM. The combined organic phases were dried
over MgSO4 and condensed via rotary evaporation in a cooled water bath. The residue was
purified via column chromatography to afford the title compound as a yellow oil (17.9 mg, 68%
yield).

131
4.7 References
[1] Serhan, C. N.; Gotlinger, K.; Hong, S.; Lu, Y.; Siegelman, J.; Baer, T.; Yang, R.;
Colgan, S. P.; Petasis, N. A.; Anti-Inflammatory Actions of Neuroprotectin
D1/Protectin D1 and its Natural Stereoisomers: Assignments of Dihydroxy-
Containing Docosatrienes. J. Immunol. 2006, 176, 1848-1859.
[2] Mukherjee, P. K.; Marcheselli, V. L.; Serhan, C. N.; Bazan, N. G.; Neuroprotectin
D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment
epithelial cells from oxidative stress. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 8491-8496.
[3] Ariel, A.; Li, P.-L.; Wang, W.; Tang, W.-X.; Fredman, G.; Hong, S.; Gotlinger, K. H.;
Serhan, C. N.; The Docosatriene Protectin D1 is Produced by T H 2 Skewing and
Promotes Human T Cell Apoptosis via Lipid Raft Clustering. J. Biol. Chem. 2005, 280,
43079-43086.
[4] Petasis, N. A.; Yang, R.; Winkler, J. W.; Zhu, M.; Uddin, J.; Bazan, N. G.; Serhan, C. N.;
Stereocontrolled total synthesis of Neuroprotectin D1/Protectin D1 and its aspirin-
triggered stereoisomer. Tet. Lett. 2012, 53, 1695-1698.
[5] Bennett, M.; Gilroy, D. W.; Lipid Mediators in Inflammation. Microbiol. Spectr. 2016, 4,
6.
[6] Serhan, C. N.; Fredman, G.; Yang, R.; Karamnov, S.; Belayev, L. S.; Bazan, N. G.; Zhu,
M.; Winkler, J. W.; Petasis, N. A.; Novel Pro-resolving Aspirin-Triggered DHA
Pathway. Chem. Biol. 2011, 18, 976-987.
[7] Petasis, N. A.; Yang, R.; Winkler, W. J.; Zhu, M.; Uddin, J.; Bazan, N. G.;
Serhan, C. N.; Stereocontrolled total synthesis of Neuroprotectin D1/Protectin D1
and its aspirin- triggered stereoisomer. Tet. Lett. 2012, 53, 1695-1698.
132
[8] Donohoe, T. J.; Lindsay-Scott, P. J.; Parker, J. S.; Callens, C. K. A.; New Modes for the
Osmium-Catalyzed Oxidative Cyclization. Org. Lett. 2010, 12, 5, 1060-1063.
[9] Shirokane, K.; Wada, T.; Makoto, Y.; Minamikawa, R.; Takayama, N.; Sato, T.; Chida,
N.; Total Synthesis of (±)-Gephyrotoxin by Amide-Selective Reductive Nucleophilic
Addition. Angew. Chme. Int. Ed. 2014, 53, 512-516.
[10] For protections involving ClSiEt3, see: Petasis, N. A. Trihydroxy polyunsaturated
eicosanoids. EP 2 022 755 A3. 2003. For protections involving ClSi
t
BuMe2, see: Yi, J.;
Sun, Y. Y.; Xiao, B.; Liu, L.; Nickel-Catalyzed Sonogashira Reactions of Non-activated
Secondary Alkyl Bromides and Iodides. Angew. Chem. Int. Ed. 2013, 52, 12409-12413.
[11] Chandra, T.; Broderick, W. E.; Broderick, J. B.; Chemoselective Deprotection of
Triethylsilyl Ethers. Nucleosides Nucleotibes Nucleic Acids 2009, 28, 1016-1029.
[12] Martín, M. J.; Coella, L.; Fernández, R.; Reyes, F.; Rodríguez, A.; Mucia, C.; Garranzo,
M.; Mateo, C.; Sánchez-Sancho, F.; Bueno, S.; Eguilior, C. de: Andres, F.; Munt, S.;
Carmen, C.; Isolation and First Total Synthesis of PM050489 and PM060184, Two New
Marine Anticancer Compounds. J. Am. Chem. Soc. 2013. 135, 10164-10171.
[13] Shao, N.; Huang, X.; Palani, A.; Aslanian, R.; Buevich, A.; Piwinski, J.; Huryk, R.;
Seidel-Dugan, C.; New Applications of PhI(OAc)2 in Synthesis: Total Synthesis and
SAR Development of Potent Antitumor Natural Product Psymberin/Irciniastatin A.
Synthesis 2009, 17, 2855-2872.
[14] Winkler, J. W.; Uddin, J.; Serhan, C. N.; Petasis, N. A.; Stereocontrolled Total
Synthesis of the Potent Anti-inflammatory and Pro-resolving Lipid Mediator
Resolvin D3 and Its Aspirin-Triggered 17R-Epimer. Org. Lett. 2012, 15, 7, 1424-1427.
133
[15] Morita, M.; Wu, S.; Kobayashi, Y.; Stereocontrolled synthesis of resolving D1. Org.
Biomol. Chem. 2019, 17, 2212-2222.
[16] Tungen, J. E.; Aursnes, M.; Vik, A.; Synthesis of Ieodomycin D. Synlett 2016, 27,
2497-2499.
[17] Zhang, C.; Santiago, C. B.; Kou, L.; Sigman, M. S.; Alkenyl Carbonyl Derivatives in
Enantioselective Redox Relay Heck Reactions: Accessing α ,β-Unsaturated Systems. J.
Am. Chem. Soc. 2015. 137, 7290-7293.
[18] Herrera, H.; Barros-Parada, W.; Flores, M. F.; Fuentes-Contreras, E.; Bergmann, J.:
Synthesis and Field Test of a Pheromone Analog of Chilecomadia Valdiviana. J. Chil.
Chem. Soc. 2018, 63, 2, 4019-4022.
[19] Saito, S.; Yamazaki, T.; Kobayashi, Y.: Stereoselective ozonolysis of TMS-
substituted Allylic alcohol derivatives and synthesis of 14R,15S- and 14S,15S-
diHETE. Org. Biomol. Chem. 2018, 16, 7636-7647.
[20] A microwave assisted variation of the following procedure was done: Fournet, G.;
Balme, G.; Barieux, J. J.; Gore, J.: Carbopalladation des Alkylidenecyclopropanes-II
Capure Intramoleculaire de L’Organopalladique Intermediaire. Tetrahedron 1988, 18,
5821-5832.
[21] Wang, L.; Wang, L.; Li, M.; Chong, Q.; Meng, F.; Cobalt-Catalyzed Diastereo- and
Enantioselective Reductive Allyl Additions to Aldehydes with Allylic Alcohol
Derivatives via Allyl Radical Intermediates. J. Am. Chem. Soc. 2021, 143, 12755-12765.
[22] For health and safety reasons, the following procedure was modified by replacing
thalium(I) carbonate with cesium(I) carbonate: Wang, L.-L.; Kirchning, A.: Total
synthesis of elansolids B1 and B2. Beilstein J. Org. Chem. 2017, 13, 1280-1287.
134
[23] Saito, T.; Fuwa, H.; Sasaki, M.; Toward the Tital Synthesis of Goniodomin A, An Actin-
Targeting Marine Polyether Macrolide: Convergent Synthesis of the C15-C36 Segment.
Org. Lett. 2009, 22, 5274-5277.
[24] Paterson, I.; Steadman neé Doughty, V. A.; McLeod, M. D.; Trieselmann, T.;
Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-
mediated aldol reactions of chiral ketones. Tetrahedron 2011, 67, 10119-10128.
[25] Possémé, F.; Deligny, M.; Carreaux, F.; Carboni, B.: (E)-α-Substituted γ-
Alkoxyallylboronic Esters as New Reagents: Synthesis and Reactivity toward
Aldehydes. J. Org. Chem. 2006, 72, 984-989.
[26] Kawai, N.; Abe, R.; Matsuda, M.; Uenishi, J.; Synthesis of Chiral 1-Substituted
Tetrahydroisoquinolines by the Intramolecular 1,3-Chirality Transfer Reaction
Catalyzed by Bi(OTf)3. J. Org. Chem. 2011, 76, 2101-2114.

135

APPENDIX ONE
Spectra Relevant to Chapter Two

136
A1.1 General Information
All
1
H NMR and
13
C NMR spectra were taken in DMSO-d6 referenced to 2.50 ppm and
39.52 ppm for
1
H-NMR and
13
C-NMR, respectively.
1
H NMR spectra were taken from a
Mercury 400 MHz spectrometer, and
13
C NMR spectra were taken from a 600 MHz Varian
spectrometer at room temperature.

137
A1.2
1
H-NMR and
13
C-NMR Spectra

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161
A1.3
1
H-NMR spectra of Compounds 8 and 13 in basic and neutral DMSO-d

Compound 8 in DMSO-d6 and ammonium hydroxide at pH 11-12 (top), and neutral DMSO-d6 (bottom)

Compound 13 in DMSO-d6 and ammonium hydroxide at pH 11-12 (top), and neutral DMSO-d6 (bottom)
162
A1.4 Studies on the Effect on Stereoselectivity in Protic vs. Aprotic Solvents

Solvent Time (hr) temp % yield % de
dichloromethane 20 rt <30 racemic
ethyl acetate 20 rt <50 racemic
methanol 20 rt 55 >99%
acetone 21 rt 55 >99%
water 24 rt 5 >99%

A series of experiments were executed using L-phenylalanine, 2, and 3 in varying
solvent systems in an attempt to determine if water plays a roll in the high
diastereoselectivity observed. The formation of 13 racemate was achieved when non-, or
weak-, hydrogen-bonding solvents were employed (table shown above). Contrarily,
moderate to strong hydrogen bonding solvents facilitated the formation of 13 in moderate
yields under similar conditions, and >99% de was achieved, indicating such a roll exists.
163

164

APPENDIX TWO
Spectra Relevant to Chapter Three

165
A2.1 General Information
All
1
H-NMR and were taken on a Mercury 400 MHz spectrometer at room temperature.
Deuterated solvents used include CDCl3 and CD3OD, which were referenced at 7.26 and 3.31
ppm, respectrively.

166
A2.2
1
H-NMR Spectra

1
H NMR (400 MHz, CDCl3)

167

1
H NMR (400 MHz, CDCl3)

168

1
H NMR (400 MHz, CDCl3)

169

1
H NMR (600 MHz, CD3OD)

170

1
H NMR (400 MHz, CD3OD)

171

172

APPENDIX THREE
Spectra Relevant to Chapter Four

173
A3.1 General Information
All
1
H-NMR spectra were taken on a Mercury 400 MHz spectrometer, and
13
C-NMR
spectra were taken on a Varian 600 MHz spectrometer at room temperature. Deuterated solvents
used were CDCl3, CD3OD, and DMSO-d6, and their proton signals were referenced at 7.26, 3.31,
and 2.50 ppm, respectively. Carbon signals were referenced at 77.16, 49.00, and 39.52,
respectively.

174
A3.2
1
H-NMR,
1
H-
1
H COSY NMR and
13
C NMR Spectra

1
H NMR (400 MHz, CDCl3)

175

1
H NMR (400 MHz, CDCl3)

176

1
H NMR (400 MHz, CD3OD)

177

1
H NMR (400 MHz, C6D6)

13
C NMR (600 MHz, C6D6)
178

1
H NMR (400 MHz, C6D6)

179

1
H NMR (400 MHz, CDCl3)

13
C NMR (600 MHz, CDCl3)
180

1
H NMR (400 MHz, CDCl3)

13
C NMR (600 MHz, CDCl3)
181

1
H NMR (400 MHz, CDCl3)

13
C NMR (600 MHz, CDCl3)
182

1
H NMR (400 MHz, CDCl3)

13
C NMR (600 MHz, CDCl3)
183

1
H NMR (400 MHz, CDCl3)

13
C NMR (600 MHz, CDCl3)
184

1
H NMR (400 MHz, CDCl3)

1
H-
1
H COSY NMR (400 MHz, CDCl3)
185

1
H NMR (400 MHz, CDCl3)

1
H-
1
H COSY NMR (400 MHz, CDCl3)
186

1
H NMR (400 MHz, C6D6)

Abstract (if available)

Abstract The first chapter of this dissertation introduces the historical development of the Petasis borono-Mannich reaction. Topics covered include a brief discussion on the merits and applications of multicomponent reactions in general, boronic acids and their use in multicomponent reactions, and asymmetric versions of the Petasis borono-Mannich reactions involving chiral substrates, catalysts, and auxiliaries towards stereopure compounds of biological relevance.
The second chapter describes our latest studies on a one-step, multicomponent reaction, wherein stereopure amino acids, glyoxylic acid monohydrate, and trans-2-phenylvinylboronic acid are combined to form multifunctionalized amines and amino acid derivatives of biological interest. Typically performed in organic solvents, our method involves the use of water to furnish multifunctionalized amino acids in very high diastereoselectivity. We extended the study to dipeptides to showcase the applicability of our method for process synthesis. L-alanine-L-proline was converted to its respective functionalized dipeptide in >99% de and 93% yields on the gram scale, and subsequent aqueous hydrogenation using Pd/C furnished Enalaprilat, the metabolically generated form of the hypertension blockbuster therapeutic Vasotec. Additionally, unique conformational isomers of the synthesized products were observed using 1H-NMR spectroscopy. The conformational dynamics in solution were studied and elucidated using both time-dependent 1H NMR spectroscopy and DFT calculations. To our knowledge, this conformational system has not been reported in the literature.
Chapter Three discusses a convenient four-step total synthesis of the pro-resolving lipid mediator, 15-epoi-benzo-lipoxin A4, in 32% overall yield and >99% ee via a Noyori asymmetric ketone reduction.
Chapter Four discusses a modified convergent synthesis of aspirin-triggered neuroprotectin D1/protectin D1 (AT-NPD1/PD1). AT-NPD1/PD1 is an analogue of endogenously derived pro-resolving lipid-mediators that play a key role in the proper resolving of inflammation. The key benefit to our modified route is that a core unit is synthesized that shares its structure with the rest of its class of lipid-mediators. Therefore, synthesis of an abundance of this core unit allows quick and efficient synthesis of AT-NPD1/PD1’s chiral and structural derivatives, requiring far less steps than the overall synthesis.

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Creator Kossick, Kevin Michael (author)

Core Title Multicomponent synthesis of optically pure aminodicarboxylic acids in water and total synthesis of 15-EPI-benzo-lipoxin A4 and aspirin-triggered neuroproctectin D1/protectin D1

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Degree Conferral Date 2022-12

Publication Date 08/22/2022

Defense Date 07/08/2022

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag amino acids,conformational dynamics,intramolecular hydrogen bonding,lipid mediators,lipoxins,multicomponent reaction,neuroprotectin,OAI-PMH Harvest,peptidomimetics,Petasis reaction,pro-resolving,stereoselective,synthesis in water,three component reaction,water

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Contributor Electronically uploaded by the author (provenance)

Advisor Prakash, Surya (committee chair), Petasis, Nicos (committee member), Sideris, Constantine (committee member)

Creator Email kkossick@usc.edu,nucleophobe2022@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC111379828

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