Synthesis of the amino aldehydes from glycine, tyrosine, and lysine

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Content SYNTHESIS OF THE AMINO ALDEHYDES
FROM GLYCINE, TYROSINE, AND LYSINE
by
Raymond Emment Planck III
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In P a r tia l F u lfil lm ent of the
Requirements for the Degree
MASTER OF SCIENCE
(Chemi s t r y )
Febr ua ry 197 9
UMI Number: EP41666
All rights reserved
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UNIVERSITY O F S O U T H E R N CALIFORNIA
THE GRADUATE SCH O O L
UNIVERSITY PARK
LOS ANGELES, CA LIFO R N IA 9 0 0 0 7
This thesis, written by
and approved by all its members, has been pre
sented to and accepted by the Dean of The
Graduate School, in partial fulfillm ent of the
requirements for the degree of
C
P ? I I
RAYM OND EM M ENT PLANCK III
under the direction of h..±$...Thesis Committee,
MASTER OF SCIENCE
Dean
THESIS COMMITTEE
To Chris
i i
ACKNOWLEDGEMENTS
The author is indebted to Drs. L. Dunkerton and
B. S t r e h l e r for t h e i r guidance, i n s i g h t s , s t i m u l a t i o n ,
and fina nc ial a s s i s t a n c e . The author is grateful to
Dr. W. P. Weber for his guidance and a s s i s t a n c e during
my studies at the University of Southern Califo rn ia.
The author had the benefit of having many challenging
and s tim u la tin g cover sations with Dr. Ming Li and
Mr. Abdelkrim Chihi. The author a p p re c iate s the
patience and understanding of his wife, Chris, during
t h i s course of study. A word of thanks is due to
Ms. Michele Dea for her profes sion al preparation of
t h i s manuscript.
i i i
TABLE OF CONTENTS
Chapter Page
D e d i c a t i o n , , , . , , , . . . . . , , , , , , ii
Acknowledgements i i i
I I n tr oduction, , 1
II Results and Discussion, , 13
Glycine.....................................................................................................13
Reduction. . . , . . , . , . . . , . , 13
O x id a tio n . . . . . , . . , 20
Tyrosine . . , . , , « . . . . . , . , , 28
Reduction. . . . . . . 28
Oxidation. . . , . . . . . . , . . ., . 35
P ro te c tin g Groups. , ............................................. 36
Lysine . . . . . 38
Reduction. . . . . . . . 38
Oxidation. . . . - 41
G1 utamic. Acid and Hi s t i d i n e .................................... 42
Glutamic Acid................................................................. 42
Histid in e . . . . . . . 44
Concl us i o n ............................................................................ 45
III Experimental. . ..................................................... 46
Glycine........................................................... 46
N-phthaloyl glycine (4_8) . . . . . . . 46
N-phthaloyl glycyl c hlo rid e (60_) . . . 46
Cha pter
III (continued)
N-phthaloyl glycine benzyl t h i o e s t e r
(80) . . . . . . . . ......................................
N-( 2 - hydroxyethyl )-phthalimide (B7_). .
N-phthaloyl glycinal (8J[)................................
T y r o s i n e ................................................................. . . .
L- tyr osine methyl e s t e r hydrochloride
(105) .................................................................................
L-tyrosine methyl e s te r (103) ......................
L-tyrosinol hydrochloride (104). . . .
N-CBZ-L-tyrosine methyl e s te r (125). .
N-CBZ-L-tyrosino 1 (126) ......................................
N-CBZ-L-tyrosinal semicarbazone
(127a) ...........................................................................
N-CBZ-L-tyrosinal (127)......................................
L y s i n e ................................................................ . . . .
L-lysine methyl e s t e r dihydrochi oride
(135) .................................................................................
N , N 1 - diCBZ-L-lysine , (1, 37 ) ................................
N,N'-diCBZ-L-lysine methyl e s te r
(138) ...............................................................................
N,N' -diCBZ-L-1ysinol (139) . . . . . .
N,N'-diCBZ-L-lysinal semicarbazone
(1 40a ) ...........................................................................
Chapter Page
III (continued)
N,N'-diCBZ-L-lysinal (1_40) 60
G1 ut ami c ac i d ..................................................... . , . 60
N-CBZ- L-gl ut ami c aci d (141 ) ................................... 60
N-CBZ-glutamic acid anhydride (142), , 61
Histidine.............................. . ...................................... 62
l -N '- d iC B Z -L -h is tid in e methyl este r
(135). ................................... 62
R e f e r e n c e s ........................................................................................... 63
I
v i
CHAPTER I
INTRODUCTION
Peptide sy n th e sis in b io logical systems involves DNA,
RNA, enzymes and amino a cid s. The DNA encodes a sequence
to be synthesized to the messenger RNA (m-RNA) which acts
as a template for the polypeptide chain. After a c t i v a t i o n
by an enzyme ca lled amino acyl s y n th e ta s e , the amino acids
are t ra n s p o r t e d by t r a n s f e r RNA(t-RNA) to the s i t e of
prote in sy n th es is.
Ribosomal RNA (r-RNA) and enzymes in the presence of
m-RNA and the t-RNA amino acid complex forge the growing
peptide chain. The r-RNA t r a n s l a t e s the message (from
the m-RNA) into a polypeptide chain and the t-RNA t r a n s
ports the p a rts of the polypeptides to the s i t e of
sy n th es is. Enzymes provide the a c tiv e s i t e to e f f e c t .
the growth of the polypeptide chain.
There are many methods of sy n th esizin g polypeptides
in the la b o r a to ry using chemical reag en ts. A few of these
methods will be discussed. Scheme 1 shows a general path
of peptide s y n th e s i s . The sequence b a s i c a l l y involves
p r o te c t io n of fun ct iona l groups to cause the chain to
grow in the desired way, and a c t i v a t i o n of the carboxylic
acid in order to cause a peptide bond to form.
The f i r s t method t h a t will be discussed is the dike to-
piperazine method which is used for the synth esis of
1
Carboxyl Component
+ ,
NH3CHR'C02
Amino P r o te c ti on
ANHCHR'C02H
Ca rboxyl Acti vati on
ANHCHR’COB
Amino Component
+nh3chr"co2"
Carboxyl P rote c ti on
nh2chrmco2c
Coup!i n g Reaction (-HB)
ANHCHR1C0NHCHR"C02C
Scheme I. General path for the synth es is of peptides
d i p e p t i d e s. An i l l u s t r a t i v e example is the formation of
glycylglyci ne ethyl e s t e r {]_) by E. Fischer and E. Formeau
(eq. I ) . 1 The method s u f f e r s from the following problems:
lim ited to d i p e p t i d e s , d i f f i c u l t y in hydrolzing diketo-
2
piperazines and loss of op tical a c t i v i t y .
The d-haloacylhaTide and r e l a t e d methods can b e >
best i l l u s t r a t e d by the formation of L -alany!-L -v a line
(12) by E. Fisher and H. Sch ei bler (eq. 2).^ D-os-bromo-
propionic acid (9_) was formed by the react io n of n i t ro s y l
bromide on D-alanine (8). When D-d- bromopro p.ionic; acid was
t r e a t e d with phosphorus pen tach lo rid e , D-a-bromoprbpionyl
chlo rid e (1_0) was obtained which was reacted with
L-valine to y i e l d D - - bromo pro pionyl - L-val 1 n | ' (11 ) / Treat-
ment of 1 _ 1 _ with ammonia yiel ded the desired product 12.
2
HCI'-H
EtOH
H C 1
H C 1
aq. H C1
Li O H
H C 1
(eq, V)
PCI NOBr
Br
L-valine
alkaline
solution
(eq. 2)
This method was useful for ea rly synth es is of many
i n t e r e s t i n g pe ptides. This method suffered from some
f a u lts , e.g. r e s t r i c t i o n of the method to simple mono-
aminoacids, m u ltip le r e c r y s t a 11i z a t i o n s to remove s a l t s ,
and d i f f i c u l t y in obtaining o p t i c a l l y pure pep tid es.^
Another important method was the azlactone method
i l l u s t r a t e d by the synthesis of L-phenyl a 1 any1-L-
glutamic acid (1_7) by M. Bergmann and coworkers (eq. 3).
NH,
HO OH NaOH
o + x (ch3)2co
water
cata ly st
0 co2h
15
selective
16
o co2h
hydrolysis
(eq. 3)
The advantages of t h i s approach are i t allows for the
s y n th e s i s of a number of complex pdlypeptides and a source
of dehydropeptides. The method does s u ffe r from s t e r e o
chemical problems in c e r t a i n instan ce s due to the removal
The acid anhydride method offe red one of the more
useful methods of peptide formation before the development
of s o li d support. The acid anhydride 22_ was formed by
The anhydride 2_4 could be t r e a t e d with the amino acid
method was very water s e n s i t i v e but was very useful for
y i e l d i n g a v a r i e t y of p e p tides.
Perhaps the most successful and useful method is
the so lid - p h a se technique which involves the use of resin
p a r t i c l e s to support the growing peptide chain. This
method has been used to synthes ize p an creatic rib onucle ase
which contains 124 residues. Hence, the method can be
of the nitrogen acetyl group by hot acid.
6
heating the e s t e r - a c i d c hlorid e 2J_ (eq. 4) . ^
0
R 0
H 0
18 19 20
(eq. 4)
Cl (Br)
soci2 , pc i5
or PBr3
R'X
23 22 21
O
e s t e r to y i e l d the de sired peptide 2j5 (eq. 5). This
5
H O
24
0
(eq. 5)
used for the synth es is of long peptide chains. This method
has been automated which incr eases the ease of the s y n th e
sis of long polypeptide chains. Scheme 2 i l l u s t r a t e s the
general p r i n c i p l e of t h i s method to synthe size a t r i p e p t i d y l
chain. This method uses dicy cloh ex ylcarbodiimide as a
condensing agent which dehydrates the acid ( i . e . carboxyl
acti vati on).
All these methods have one thing in common which is
the a c t i v a t i o n of the carbonyl to f a c i l i t a t e peptide bond
formation. This a c t i v a t i o n is required because amino acids
will not react spontaneously to form pep tide s. If heating
is used to remove the water, degradation of the peptides
o c c u r s .
In attempting to design a p r e b i o t i c synth es is of
peptide fragments, a spontaneous r e ac tio n whose r e a c t a n t s
6
Carboxyl-terminal
residue
Resin bead
Incoming N blocked
Dicyclohexylcarbodiimide
amino acid
CBZ— N
CBZ— N‘
acid
Incoming
Dicyclohexylcarbodiimide
OH
CBZ- N Amino Acid
Scheme 2. Solid-phase technique for peptide sy n th e s is.
were simple organic molecules which could have e x i s t e d in
a p r e b i o t i c environment was req uired . The formation of
9
S c h iff bases is usually exothermic. In our l a b o r a t o ry ,
i t was shown t h a t glycine re a c t s spontaneously with a l d e
hydes to y i e l d a S c h iff base e q u i l i b r i u m . ^ Treatment of
these S c h iff bases with basic hydrogen peroxide r e s u l t e d
in the formation of the corresponding amides ^0 (ep- 6).
0 pH 8 -10 \
28a R = CH
28b R = C2H5
28c R = CH(CH3 )2
H2°2
(eq. 6)
e
0
30a R = CH
30b R =
C2H5
30c R = CH(CH3 )2
In the course of developing this re action for sy n th e
t i c , m ech an istic, and p r e b i o t i c purposes, aldehyde d e r i v a
t i v e s of amino acids were req ui red. In a d d i t i o n , these
d e r i v a t i v e s must be so p ro te cted so t h a t e i t h e r the ami no .
or the aldehyde p r o te c t in g group could be removed s e l e c
t i v e l y and under the conditions of S chiff base formation.
8
These prel im inar y experiments showed t h a t the desired
amino aldehydes could be e i t h e r the L co n fig u ra tio n or
racemic. The alpha hydrogens in simple aldehydes are
known to exchange during S c h iff base f o r m a t i o n . ^
A v a r i e t y of methods are found in the l i t e r a t u r e
concerning the sy n th e s is of a amino aldehydes. The
c l a s s i c r ea c tio n is the Rosemund r e a c tio n involving the
acid ch lo rid e . K. Balenovic and coworkers t r e a t e d
S -b e nzyl-N -phthaloyl-L -c yste inyl ch loride (21) with hydro
gen in the presence of Pd-BaSO^ to obtain the corresponding
aldehyde 32 (eq. 7 ) . 11
xylene
100-110
N - 0
67%
(eq. 7)
E. Adams showed t h a t L - h i s t i d i n e methyl e s t e r .dihydro
ch loride (3J3) could be t r e a t e d with 2.5% sodium amalgam to
y i e l d the aldehyde- 34 1 n 50% y ie ld (eq. 8 ) . ^ ' W. Ried and
P. Pfaender t r e a t e d 35^ with LAH followed by heating with
N.N dibenzylamine and t r e a t i n g with 50% s u l f u r i c acid and
methanol to y i e l d the aldehyde 3jj_ (eq. 9 ) . ^
2.5% Na amal.
water
H C 1
50%
c
HNTS
35
1. LA H
2 Heat, 5h
(PhCH2 )2M H IS'
3. H 2S04 , M eO H
CH2Ph
(eq. 9)
36
H. Seki et al . obtained N -ace ty l-L -a la n in a l (3_7) by
t r e a t i n g N -a c e t y l - L-a 1 anine (3_7) with ethyl chioroformate
followed by hydrogen in the presence of Pd on charcoal
14
(e q . 10) The ethyl chioroformate formed the carbonic-
OH
37 38
(eq. 10)
carboxy lic acid anhydride. A. Ito and coworkers were
able to reduce N-CBZ-alanine methyl e s t e r (39) to the
corresponding aldehyde £0 with diisobutylaluminiurn
hydri de ( e q . 1 1 ) . ^
0^ —
CBZ- N
39
DIBAL-H
toluene
hexane
-55°
50%
CBZ- N
(eq. 11)
40
The formation of a-amino-alcohols has been
i n v e s t i g a t e d . G. Poindexter and A. M eye rsin v e stig a te d
thre e d i f f e r e n t reduction methods on L-leucine (£]_) and
1 6
e s t e r d e r i v a t i v e s to obtain L-leucinol (42) (eq. 12).
1 0
LAH-ether
via ethyl e ste r
0
NaBH4, EtOH
O H (eq. 12)
2
via ethyl e ste r
hydrochloride 2
41
BH3-Me2S,-THF
42
The lithium aluminium hydride r e ac tio n used the ethyl
e s t e r as s t a r t i n g material while the sodium borohydride
r e a c t i o n used the ethyl e s t e r hydrochloride as s t a r t i n g
m a t e r i a l .
On the basis of the se l i t e r a t u r e p recedents, the
reduction of N-protected amino acids to t h e i r corresponding
aldehydes and alco ho ls we re i n v e s t i g a t e d . Since glycine
was known to form S c h iff bases, i t was chosen for the
i n i t i a l i n v e s t i g a t i o n . Additional amino acids chosen were
t y r o s i n e (4_3) , ly sin e (44), glutamic acid (4_5) and
h i s t i d i n e (4j5) for use of more s o p h i s t i c a t e d p r o te c t io n
sequences. It is important to keep the side chains i n t a c t
during these r e a c t i o n s . In the f u t u r e , experiments beyond
11
44
N H ,
2
0
0 0
2
45
H
46
2
the scope of these prelim inary s tu d ie s will be conducted.
Then the side chains will be used in the development of
a templating process. These side chains may influence the
sequence of a growing peptide chain under p r e b i o t i c
condi t i o n s .
12
CHAPTER II
RESULTS AND DISCUSSION
Glycine
Reduc tion. Glycine was chosen for i n i t i a l i n v e s t i g a
t i o n . In order to prevent polymerization betw een the
nitrogen of the amine and the aldehyde to be generated
l a t e r , the ni trogen of the amine was prote cted using the
phthaloyl p r o te c t in g group. Following the method of
L. Reese, glycine (47_) was fused with p h th alic anhydride
at 150° to y i e l d N-phthaloyl glycine (48J in 74% y i e l d
(eq. 1 3 ) . 17
h2n
OH
4 7 0 (eq. 13)
Lithium aluminium hydride was chosen as a reducing
agent. G.A. Swan showed th a t the amido e s t e r 49_ could
be t r e a t e d with lithium aluminium (LAH) to y i e l d the
1 8
amino alcohol 50 (eq. 14). A. Rhein and M. J u t i s z
t r e a t e d dibenzoyl arg in in e ethyl e s t e r (5 JJ with LAH to
1 9
obt ai n d ib enzoyl-arg inol (52) (eq. 15). P. Karrer
and coworkers obtained monobenzoyl-L-histindinol (54)
by t r e a t i n g di benzoyl - L-h i s t i di ne methyl e s t e r (5_3) with
2 0
LAH (eq. 16). These examples i l l u s t r a t e d the s t a b i l i t y
of these amides to LAH. These r e s u l t s can be compared
1 3
-H
N-H
LAH
Benzene
Ether
Refl ux
■ N H .
LA H
(eq. 15)
THF
LA H
H N
Ether
Reflux
44%
0 =
(eq. 16)
to the s t a b i l i t y of the following im id e s ' to ' LAH.
When R.H. Wiley t r e a t e d d iacety l glycine ethyl e s t e r
55 with LAH, di ethyl ethanol ami ne (5_6) was obtained
21
(eq. 17). W. Garbrecht obtained 2 , 3-dihydro-1-benz-
[de] - i soqu i no 1 i ne-2-ethanol (58_) in a y i e l d of 68.5% when
0
CH.
CH
CH.
LAH
3 0 55
ether
2 hr
r t
42.8%
CH.
\
• O H
CH.
(eq. 17)
56
N-(8-acetoxyl )-naphthalimide (5 7 ) wa s 'treated with LAH
2 2
(eq. 18). When they attempted the same r e a c tio n on
N- ( B-hydroxyethy 1 ) - napthal imi de (5J3) , 2 , 3 - d ih y d r o - 1 -
b e n z - [ d e j - i soqui nol i ne-2-ethano 1 ('58 ) was not obtained.
0
. n . ^ LAH
>
Ether
soxhlet
.O H
58
(eq. 18)
This in d ic a te d t h a t the LAH reduction of s ele cted
^derivatives of N-phthaloyl glycine might be p ossible.
■Since the r e a c tio n is easy to do, an LAH reduction was
attempted on N-phthaloyl glycinyl c hlorid e (6JD) which was
S0C1
refl ux
PCI
48
0
0
Cl
reflux
benzene
60 (eq. 19)
EtQH \
0
prepared from N-phthaloyl glycine (4J3) e i t h e r using PC15
(93.5% y i e l d ) ^ or using thionyl c hlorid e (78% y i e l d )
2 4 2 5
(eq. 19). ’ Treatment of N-phthaloyl glycinyl ch lorid e
(60) with LAH at 0° in THF yiel ded an oil which appeared
to be decomposition products.
N-phthaloyl glycine ethyl e s t e r (6J_) was prepared by
0 ^
'0 (eq. 20)
60 61_
r e a c t i n g the acid ch lo r id e 6£ with ethanol (eq. 20). The
ethyl e s t e r was t r e a t e d with LAH as per the procedure
p C
of R.B. Moffett, and upon \w6rk-iip decomposition, products
were obtained.
At t h i s p o i n t , i t was determined that the LAH was
probably reducing both the imide and the e s t e r or acid
c h lo rid e . The a t t a c k of LAH on the phthaloyl group
could be explained by the low e le ctr o n de ns ity at
each carbonyl carbon which f a c i l i t a t e d the red uc tion .
1 6
The work-upinvolved the use of aqueous con ditions and
the re was a p o s s i b i l i t y t h a t the products remained in
the aqueous layer.
P. Karrar was able to reduce the following
ethyl e s t e r s t o " th e corresponding al co hols by'
using LAH: phenylalanine (62_), alanine ( 6 4 j , leucine
(5J3), and asparag ine (68) (eq. 21-24).
0
62
LAH ^
Ether
75%
63
(eq
LA H
Ether
85%
65
(eq
LA H
Ether
85% N H ,
(eq
66
67
0 N H
LA H
Ether
70%
N H ,
O H
(eq
69
. 2 1 )
. 22 )
. 23)
. 24)
17
This seemed to i n d i c a t e t h a t a s im i l a r r eactio n might
work for glycine. Glycine methyl e s t e r hydrochloride (70)
was prepared by r e a c t i n g methanol and thionyl chlo rid e
with glycine (47j by the method of S. Gullmann and
t r e a t e d with LAH but no s t a r t i n g material or product
was i s o l a t e d . Both may have remained in the aqueous
s o l u t i o n s used in work-up.
Another reduction t h a t was i n v e s t i g a t e d was Raney
nickel d e su T fu riz a tio n . The t h i o e s t e r s can be prepared
by the r e a c tio n of an acid c h l o r id e with a mercaptan.
M.L. Wolfrom and J.V. Karabinos showed th a t benzoyl
c h lo r id e (7J_) in py ridine could be t r e a t e d with ethyl
R.H. Levin and coworkers prepared a number of s t e r o i d a l
t h i o e s t e r s . ~For' example, 3-a-hydroxy -12-q-ace toxy -nor-
cholanic acid (7j4) was t r e a t e d with thionyl chi or i de, then
ethyl mercaptan to y i e l d 3-a-hydroxy-12 - a-ace to xy-nor-
e t h i o l c h l o n a n a t e (7J5).3^
OH
S0C1
2
0
M eOH
(eq. 25)
47 0 70
7 ^
R.A. Boissonnas (eq. 25). The methyl e s t e r 7_0 was
pyridine
71 72 73
2 9
mercaptan (72J to y i e l d ethyl t h i o l benzoate 73.
18
M.W. Cronyn and J. Jiu obtained hippuraldehyde 71_
by t r e a t i n g t h i o h i p p u r i c acid (76) with Raney nickel
31
(eq. 28). M.L. Wolfrom and J.V. Karabinos showed that
aldehydes could be obtained by Raney nickel d e s u l f u r i z a -
t i o n . For i n s t a n c e , ethyl thi ol benzoate ( 7_S) was refluxed
with Raney nickel in 70% ethanol to y i e l d benzaldehyde
(79) in a y i e l d of 62% (eq.’ 2 9 ) . 29
76
While waiting for the a r r i v a l of ethyl mercaptan, the
benzyl thi ol e s t e r of glyci ne (8(3) was prepared by the
3 0
method of R.H. Levin and coworkers (eq. 30).
N-phthaloyl glyc'inyl ch lori de (60J was rea ct ed with benzyl
mercaptan to y i e l d the benzyl t h i o e s t e r 80^ in 65%
y i e l d .
Following the procedure of M.L. Wolfrom, N-phthaloyl
glycine benzyl t h i o e s t e r (80J and a W-2 Raney nickel
ethanol s l u r r y f a i l e d to y i e l d the des ired aldehyde a f t e r
1 9
2 9
4-1/2 hours of r e fl u x i n q (eq. 31). S t a r t i n g material
was iso la ted. The re act ion was repeated and refluxed for
24 hours with the same r e s u l t .
0
0 80 81
Following the procedure of M. Cronyn and coworkers,
a s o lu t i o n of benzyl thio e s t e r 80^ in acetone and water
was refluxe d for 1 hour with Ra-Ni which upon work up
31
yiel ded s t a r t i n g m a t e r ia l. The reactio n was repeated
and a f t e r r e f l u x i n g 15 hours y ie lded s t a r t i n g m a t e r ia l.
Oxi dati on. There are many l i t e r a t u r e examples of
ox idation of alco ho ls to the corresponding carbonyl
compounds using chromium t r i o x i d e . M.A. Wuonola and
R.B. Woodward showed t h a t an amide alcohol 82^ when
2 0
(eq. 32)
83
t r e a t e d with aqueous CrO^, and pyridine gave the keto
alcohol <33 (eq. 32).^2,33 They also t r e a t e d the amido
alcohol 84 with aqueous CrO^ and py ridine to y i e l d the
keto alcohol 85^ (eq. 33).
C02ch3
CrO.
\
N
1
N
/ >
C02CH3
85
(eq. 33)
The f i r s t oxidation i n v e s t i g a t e d was the Jones
o x id a tio n . The s t a r t i n g material for the Jones oxidation
was N - (2 - hydroxyet hyl ) - pht ha 1 i mi de (8_7) which was prepared
by fusing p h t h a l i c anhydride with 2 - aminoethano1 in an
oil bath at 1 5 0 ° . ^ The Jones ox idation using
N-(2 hydroxyethyl )-phthal imide (87_) as a s t a r t i n g
21
0
0
H 2N
OH
0
0
N
(eq. 34)
86 0 87
material was i n v e s t i g a t e d under a v a r i e t y of c o n d itio n s,
a ll of which f a i l e d to y i e l d the desired aldehyde. In
a l l cases he- cl a s s.i c. co 1 or ' c han ge for the Jones oxidation
was ■ observed-, b u t ' no organic products could be i s o l a t e d
using standard work-up procedures.
R.H. Mueller and coworkers converted the amino alcohol
88 into aminoketone 8J9 using Jones reagent (eq. 35).
After encountering i s o l a t i o n problems using the normal
workup, they solved the problem by using amalgamated
zinc in the presence of trisodium c i t r a t e . Upon normal
work-up, the oxidant forms C r ( I I I ) hydroxide as a
g e latin o u s mass. In order to overcome th is problem, the
amalgamated zinc reduces the C r ( I I I ) to C r (II) which
complexes with the c i t r a t e to form a water soluble
complex. 35
Jones
O H Reagent
(eq. 35)
88 89
22
This procedure was used in the work-up of the Jones
oxidation on the amino alcohol 8_7. The f i r s t attempt
involved work-up wi th e th e r followed by methylene c hlorid e .
The e t h e r y ielded an oil and the methylene ch lorid e
yie ld ed a, solid,, both of which were n e i t h e r s t a r t i n g
material or product. The second attempt upon work-up with
methylene ch lo rid e yi el ded a yellow s o li d which'was the
aminoalcohol (small amount) contaminated with an uniden
t i f i a b l e compound.
The f a i l u r e of Jones oxidation might be due to two
things. F i r s t , the aldehyde might have g r e a t e r s o l u b i l i t y
in water than in e ther or methylene c h l o r i d e , and remained
in the aqueous l a y e r. Second, over-oxidation could have
occurred and the corresponding acid could have been
formed. The acid (N-phthaloyl glycine) is more soluble
in water than in e t h e r or methylene chlor ide.
The second oxidation i n v e s t i g a t e d was the Moffatt
oxidat ion which involves the tra n sfo rm a tio n of an alcohol to
the aldehyde using dimethyl sulfoxide (DMSO) and dicyclo-
hexylcarbodiimide (DCC). K.E. P f i t z n e r and J.G. Moffatt
t r e a t e d 3 ‘-0 -a cety l thymidine (90_) with DMSO and DCC to
obtain 3 ’-0 -a c e ty l th ym idine-5 1-a 1dehyde ( 9J_) (eq.
3 6),36 ,38 jh e y were able to oxidize the a lk a lo id
spegazz i n i di ne dimethyl e th e r (92_) to 3 - dehydrospegazz in i -
dine dimethyl e t h e r (930 in 83% y i e l d by using DMSO and
DCC (eq. 3 7 ) . 37
23
H O
D M SO
>
0=CH
D C C
90%
OAc
OAc
(eq. 36)
M e
O M e
CH.
D M SO
(eq. 37)
D CC
8 H e% ° 4
M eO
O M e
C H
92 93
When methyl-3-benzamid o - 4 ,6 - 0 - b e n z y l idine-3-deoxy-
a-D-gl ucopyranos ide (940 was subjec ted to the Moffatt
oxi da t i on, the corresponding ketone 95_, was obtained
3 9
(eq. 38). The corresponding a l t r o s i d e 9j5 of ££ was
t r e a t e d with DMSO and DCC to y i e l d 95_ (eq. 3 8 ) . ^ A
number of oth e r r e l a t e d compounds were subjec ted to the
Moffatt o xidatio n by the same au thors.
P.J. Beeby synthes ize d c e p h a l o s p o r i n - 4 - a l dehydes
98 and 100 from the corresponding alcohols using the
Moffatt ox idation {eqs, 39, 4 0 ) . 40 These r e a c tio n s
in d ic a te d t h a t i t might be f e a s i b l e to syn thes iz e the
desired aldehyde from the alcohol 87.
The oxidat ion of the amino alcohol 87^ following the
P.J. Beeby procedure using DMSO and DCC y ie lded a
2 5
DMSO,DCC
(eq. 39)
80%
OAc
C = 0
(eq. 40)
OAc
62% as
acetal
.O A c
N
— 0
100
26
DM SO, D C C
N
0
81
H
0 (eq. 41 )
mixture of the aldehyde, alcohol and dicyclohexyl urea as
40
i d e n t i f i e d by PMR and t i c . The i s o l a t i o n of the de sired
aldehyde using c r y s t a l l i z a t i o n techniques and chroma
tography proved impossible. The dicyclohexylurea appeared
to have nearly the same s o l u b i l i t y as the aldehyde.
41 42 43
The Swern ox idat ion ’ ’ offe red the p o s s i b i l i t y
of overcoming the di cy clohexylurea problem in the Moffatt
o x id a tio n . D. Swern and co-workers showed th at a v a r i e t y
of alcohols including 1 -adamantan emet hatio 1 (1 01 )r co ul d be
oxidized by DMSO and t r i f l uoroacet'ic anhydride (TFAA) to
41
CHO
the corresponding aldehyde 102.
CHo0H
101
D M SO
TFAA
102
(eq. 42)
The amino alcohol 8_7 was t r e a t e d with DMSO and TFAA
41
according to the procedure of D. Swern and coworkers.
PMR and t i c i n d ic a te d t h a t the desired product 8J_ was
formed. Attempts a t p u r i f i c a t i o n by column chromatography
f a i l e d to s e p a ra te the aldehyde from the side products
2 7
e.g. alkyl t r i f l u o r o a c e t a t e s and alkyl methy1thiomethy1
e t h e r s .
•Tyros i ne
Reduction. The f i r s t reduction i n v e s t i g a t e d was the
LAH reduction of ty r o s i n e methyl e s t e r (103) to y ield
tyro sin o l hydrochloride 104 (eq. 43). Tyro si n e'methyl
0
LAH . / V ~ ~ )H
H O
1 03
THF
N H 2 -HC1
104
(eq. 43)
e s t e r was prepared following the procedure of S. Gullmann
28 •
and R.A. Boissonnas. L-Tyrosine (4_3) was t r e a t e d with
thionyl c h lo r id e and methanol to y i e l d L-tyrosine methyl
e s t e r hydrochloride ( 105) (72.2%) (eq. 44). L-Tyrosine
0
S0C1?
M eOH
(eq. 44)
nh2 - hci
43 105
methyl e s t e r hydrochloride ( 105) was t r e a t e d with t r i -
ethylamine in ethyl a c e t a t e to y i e l d the methyl e s t e r
10 3 '' in a y i e l d of 82% (eq. 45).
As mentioned in the glycine se ctio n on r e d u c tio n s,
q u i t e a few LAH reduc tions of amino acid methyl and
2 8
H O
N H 2-HC1
105
Et3N:
EtOAc
(eq. 45)
ethyl e s t e r s to the corresponding alcohols are found in
the l i t e r a t u r e . P. Karrer and coworkers reduced L-tyrosine
methyl e s t e r ( 103) with LAH to obtain L-ty rosinol hydro
c h lo r id e ( 104) in a y i e l d of 6 5 . 5 % . ^ The reactio n
0
H O
103
LAH
Ether
Solvent
(eq. 46)
104
co nditions involved e ther as a solven t and a Soxhlet
app ar at us. L-tyrosino l hydrochloride ( 104) was prepared
in a y i e l d of 44.3% following t h e i r procedure except THF
was used as a so lv en t.
The lower y i e l d could be explained in a number of
ways. The s t a r t i n g material was unstab le at elevated
temperatures for long periods of time due to decomposition.
Since THF has a higher boiling point than e ther and the
r e a c tio n co n d itio n s involved four days o f > e f l u x i n g , some
of the s t a r t i n g material might have decomposed. Also
the procedure involved a tedious e x t r a c t i o n using 60°
water of a gelatin o u s mass. Some of the product might
have remained trapped in the gelat inous mass.
2 9
Due to the tedious nature and time involved in the
LAH reduction of t y ro s in e methyl e s t e r , other methods
of reduction were i n v e s t i g a t e d , H. Seki and coworkers
rep orted the sodium boro hydride reductions of the f o l
lowing ethyl e s t e r hydr ochlorides to the corresponding
a lc o h o ls: L-tryptophan (106), L-methionine ( 108),
L-threonine ( 110), L-iso le u c in e ( 112) and L-phenyl-
al anin e ( 114) (eq. 47-51).
Cl
45
nh2 -hci
NaBH„
75% EtOH
0-10
8 hr
77%
(eq. 47)
107
N H 2 - H C 1
1 08
NaBH,
75% EtOH
refl ux
2 days
67%
/ S
(eq. 48)
109
O H 0
N H 2H C 1
110
N H 2 ’H C 1
112
NaBH,
75% EtOH
0 - 10 °
2 days
47%
NaBH
4
75% EtOH
5.5 hr
re f 1 u x
63%
2 111
113
(eq. 49)
(eq. 50)
3 0
YJ
N H2'HC1
114
NaBH,
5Q% EtOH
Ref1ux
4.5 hr
84%
)
63 (eq. 51)
Phenylalanine ethyl e s t e r hydrochloride (114) was
used as a model compound. Phenylalanine ethyl e s t e r
hydrochloride ( 114) was prepared by a modi fica tion of
2 8
the procedure of S. Gullmann and R.A. Boissonnas, in
t h a t 100% EtOH was used in ste a d of methanol. D,L-3-
phenylalanine ( 115) was t r e a t e d with ethanol and thionyl
chlo rid e to y i e l d the ethyl e s t e r hydrochloride 114
S0C1
100% EtOH
24 hr N H 2 -HC1
(eq. 52)
115 114
in a y i e l d of 93.2%. The ethyl e s t e r hydrochloride was r e
flu x'e'd wi th' four moles of NaBH^ in 50% EtOH for 4.5 hours
to y i e l d D, L-phenylalanino 1 {63) ( 55.1 % y i e l d ) . When
s ubje c te d to the reaction c o n d i t i o n s , L -tyrosine methyl
e s t e r hydrochloride ( 105) f a i l e d to y i e l d the des ired
alcohol 116, t h a t is, 116 was not i s o l a t e d .
0
NaBH„
nh2 - hci
50% EtOH
ref! ux
4.5 hr
(eq. 53)
105 116
31
A. Ito and coworkers prepared the following N-CBZ
aminoa1cohols by reducing the corresponding CBZ-amino
acid e s t e r s with NaBH^ in ethanol: N-CBZ-nitroargininol
(118), N-CBZ-leucinol ( 1 2 0 ) , N-CBZ-phenyl a 1 an i nol (12 2 ),
and N-CBZ-S-BZL-cysteinol (124) (eqs. 54-57).
1 5
This
CBZNH
o2n / " V
NaBH,
EtOH
r.t.
3 hr
H H
o2n'
N ^ z' N
Y
N H
118
(eq. 54)
NHCBZ
NaBH,
EtOH
r. t.
3 hr
H (eq. 55)
119 120
NaBH,
EtOH
r. t .
3 hr
(eq. 56)
3 2
123
NaBH
EtOH
r .t.
3 hr
4
124
(eq. 57)
i n d ic a te d t h a t a s im i l a r r ea c tio n might work for N-CBZ-
t y r o s i n e methyl e s t e r ( 125).
Following the procedure of A. Ito and c o w o r k e r s ^
N-CBZ-L-tyrosi ne methyl e ste r ( 12 5 ) was prepared in a y i e l d
of 69.5% by t r e a t i n g a sodium carbonate s o lu tio n of
0
HO
105
CBZ-C1
NaHCO
NaOH
0 °
(eq. 58)
L - t y r o si n e methyl e s t e r hydrochloride ( 105) with CBZ-C1
and NaOH.
N-CBZ-L-tyrosinol (126) was prepared by a modified
1 5
version of the procedure of A. Ito . N-CBZ-L-tyrosine
methyl e s t e r (12 5 ) was t r e a t e d with NaBH^ to give the
corresponding alcohol 126 in a y i e l d of 68.8% (eq. 59).
125 CBZ
(eq. 59)
3 3
This alcohol was su b jec te d to the Swern oxi dat ion as
discussed l a t e r in the o xidation section (cjf. p, 35),
A t h i r d r e a c t i o n t h a t was i n v e s t i g a t e d involved the
reagent d i i s o b u t y l a 1uminum hydride (DIBAL-H). DIBAL-H
can be used to reduce an e s t e r to an alcohol with the
aldehyde as an i n te rm e d ia te . The us efulnes s of th is
reag ent l i e s in the f a c t th at at low temperature ( i . e .
-50°C) the aldehyde can be i s o l a t e d as the major reduction
p r o d u c t .
A. Ito and coworkers t r e a t e d N-CBZ-L-tyrosine methyl
e s t e r ( 125) with DIBAL-H in an argon atmosphere to obtain
N-CBZ-L-tyrosinal ( 12 7) (eg. 6 0 ) . ^ The aldehyde was
0 x -"' DIBAL-H
H O
toluene
hexane
125
CBZ
H O
(eq. 60)
127
CBZ
sep arat ed from the r e a c t i o n mixture by column chroma
tography with s i l i c a gel a f t e r i t was converted to i t s
semicarbazone. The aldehyde was regen erated by tre atme nt
with formaldehyde and acid. The reason for the formation
of the semicarbazone before column chromatography was
t h a t the unprotected aldehyde racemizes through e n o l i z a -
1 5
tion during co ntact with s i l i c a gel. The semi carbazone
prevents t h i s racemization from oc curring.
34
N-CBZ-L-tyrosine methyl e s t e r ( 12 5 ) was t r e a t e d with
DIBAL-H at -60° to y i e l d the aldehyde 127 according to
the procedure of A. I t o . ^ 6 The r e a ctio n mixture was
t r e a t e d with semicarbazide hydrochioride and chroma
tographed to y i e l d the semicarbazone of 127 in 10.2%.
A. Ito and coworkers rep orted a y i e l d of 42%.
Oxi dati o n . As mentioned e a r l i e r , D. Swern and
coworkers using DMSO and TFAA were able to e f f e c t the
o xidation of many alcohols to the corresponding alde-
41 42 43
hydes. ’ ’ The same procedure worked on N-( 2 - hydroxy-
ethy 1 )-p ht hal i mi de (87.) to y i e l d the corres pond i ng aldehyde
81 which could not be p u r i f i e d . It seemed t h a t the same
procedure might work on N-CBZ-L-tyrosinol ( 126) without
the s e p a ra tio n problems encountered e a r l i e r .
41 42
Following procedure A of D. Swern and coworkers ’
N-CBZ-L-tyrosinol (12 6 ) was oxidized by DMSO and TFAA
to the aldehyde 12 7 . The p u r i f i c a t i o n of the aldehyde
0
(eg. 61 )
ch2c i2
126 127
was attempted by s i l i c a gel chromatography but f a i l e d to
y i e l d the pure aldehyde. A PMR'spectrum of the reaction mixture
i n d i c a t e d t h a t only 52% of the alcohol had reacted to form
35
the aldehyde.
P r o te c ti n g Groups. O r i g i n a l l y , i t was determined
t h a t the phthaloyl nitro gen p r o t e c t i n g group would be
used on t y r o s i n e . Following the method used for glycine
1 7
(eq. 62), L-ty ro sin e (£3) was heated with p h t h a l i c
anhydride in an attempt to obtain N -p h th a lo y l-L -ty ro sin e
V /
( 128). The d esir ed product 128 was not i s o l a t e d .
J.C. Sheehan and coworkers t r e a t e d L-threonine ( 129)
with p h t h a l i c anhydride in dioxane with heating (105°)
for 5 hours to obtain N -p h thalo yl-L -threonine ( 130) in a
y i e l d of 94% (eq. 6 3 ) . ^ When the same method was
ap plied to t y r o s i n e , no N - p h th a lo y l- L -ty r o sin e was
obtained.
0
dioxane
A.K. Bose rep orted a procedure for the synthes is of
N-phthaloyl phenylalanine ( 131) from phenylalanine ( 115)
using p h t h a l i c anhydride, t o l u e n e , and t r i e t h y l amine
36
(eq. 64)
48,49
Using the same method, A.K, Bose and
0
115
to!uene
N(C2H 5 )3
refl ux
2 hrs
\
( e q - 64)
coworkers prepared the N-phthaloyl d e r i v a t i v e s of g ly cin e,
4 9
a l a n i n e , and d ie t h y l -L -g l u t a m a t e . This method was
ap plied to L-ty ro sin e but f a i l e d to y i e l d the des ired
p r o d u c t .
F.E. King and D.A.A. Kidd prepared N-phthaloyl
diet hyl glutamate (134) by r e a c t i n g p h t h a l i c anhydride
and diethyl glutamate ( 132) in ether to give diethyl
0-carboxybenzoyl-L-glutamate ( 133) which was refluxed
with e i t h e r 4% e t h a n o l i c hydrogen ch lo rid e or thionyl
c hlorid e to y i e l d 134 (eq. 6 5 ) . ^ ’^ ’^ This procedure
/0
0 I ,u I u
_ (eq. 65)
V
H 2N
0
(CH2 )
132
2 '2Y
0
ether
(ch2 )2
0-
133 0
4% ethanolic hydro
gen chloride or S0C12
0
37
was t r i e d on ty ro s i n e but f a i l e d to y i e l d the desired
p r o d u c t .
At t h i s p o i n t , i t was decided to s e l e c t another
p r o t e c t i n g group. A number of reasons led to th is
d e c isio n . F i r s t , the d i f f i c u l t y encountered in placing
the phthaloyl group on t y r o s i n e . Second, the phthaloyl
group was removed by hydrazine which might r e a c t with
some of the aldehyde in the desired product. Third,
in some instance s ( e s p e c i a l l y fusion) racemization of
the s t a r t i n g m ate ria l might occur.
The CBZ n itro g e n p r o t e c t i n g group was chosen for
a number of reason s. It could be easily ' put on the
n itrogen with no racem ization. It would be removed
in a mild matter t h a t would not destroy the other
functio na l groups in the amino acid d e r i v a t i v e . Also the
work of A. Ito and coworkers came to our a t t e n t i o n and
i t appeared t h a t CBZ might be a good choice based on
1 5 46
t h e i r work. ’ The CBZ group would aid in the
s o l u b i l i t y of the various d e r i v a t i v e s in organic solve nts
li k e methylene c h l o r id e and e t h e r .
Lys i ne
Redu ction. The f i r s t reduction i n v e s t i g a t e d was the
sodium borohydride red uction of L- lysine methyl e s t e r
d ih y d roc hlo ride ( 135) to the corresponding alcohol 136
3 8
(eq. 66). As mentioned in the t y ro s i n e sec tion a. number
NaBH,
nh2 - hci
H C 1 • H 2N
135
75% EtOH
refl ux
4.5 hr
(eq. 66)
136
of amino acid e s t e r hyd rochlorides have been reduced to
the corresponding alcohols by H. Seki and coworkers
45
using sodium borohydride.
L-Lysine methyl e s t e r d ihydro c hlo ride ( 135) was
prepared by a mod ification of the procedure of S. Gullmann
2 8
and R.A. Boissonnas. L-lysine (4_4) was t r e a t e d with
thionyl c h lo r id e and methanol to y i e l d the methyl e s t e r
S0.C1,
M eOH
(eq. 67)
nh2 - hci
hci-h2n
dihydrochi orid e 1 35 (99%). An ethanol solu tio n of the
e s t e r 135 was reflux ed with sodium borohydride for 4.5
hours to y i e l d an u n i d e n t i f i a b l e compound.
Another reduct ion t h a t was examined was the NaBH^
reduction of N, N1 - diCBZ-L-1ysine methyl e s t e r . The
s t a r t i n g mat er ia l was prepared in the following way.
Treatment of L-lysine (44_) with CBZ-C1 yiel ded the
N,N'-diCBZ-acid 137 which was t r e a t e d with diazomethane
3 9
ether
0 °
HNCBZ
CBZ-Cl
NaOH
HNCBZ
137 0
(eq. 68)
to y i e l d the methyl e s t e r 138 in 73% y ield (eq. 68)
55
Treatment of the e s t e r 138 with NaBH^ r e s u l t e d in the
formation of N, N1 - diCBZ-L-1 ysinol ( 139) following the
1 5
procedure of A, Ito and coworkers.
CBZ CBZNH
0 . NaBH.
100% EtO
r . t.
3 h
CBZNH
138 (eq. 69)
The reduction of the diCBZ-L-lysine methyl e s t e r
( 138) with DIBAL-H in hexane following the method of
A. Ito and coworkers y i e l d e d a mixture of the aldehyde
140 and the alcohol 139. After tre atm e nt of the r e a c t i o n
mixture with semicarbazide hydrochloride and column
chromatography with s i l i c a g e l , the semicarbazone of 140
was obtained in a y i e l d of 28.7% (eq, 70).
CBZNH
DIBAL-H
138
toluene
hexane
-55°
(eq. 70)
CBZNH
140
40
A. Ito and coworkers reported th at the semicarbazone
can be converted to the aldehyde by tre at ment with
30
formaldehyde in the presence of acid. This procedure
was t r i e d and y i e l d e d a mixture of the aldehyde 140 and
i t s semicarbazone. PMR indicated t h a t .42% of the semi-
carbazone had re acted to y i e l d the aldehyde 140. The
procedure was repeated on the product mixture with no
a d d i t i o n a l conversion.
All of the d i - CBZ-1ys ine d e r i v a t i v e s were o i l s .
Many attempts at c r y s t a l l i z a t i o n of these d e r i v a t i v e s
e s p e c i a l l y the methyl e s t e r f a i l e d to y i e l d a s o lid
d e r i v a t i v e . The d i f f i c u l t y of c r y s t a l l i z i n g these
d e r i v a t i v e s are noted in the l i t e r a t u r e and in all cases
53 54
the o i l s were used in subsequent s te p s . 5
O x i d a t i o n . The Swern oxidation using DMSO and TFAA
y ielded the aldehyde of N-( 2 - hydroxyethy1 ) - phtha 1imide
(87) and N-CBZ-L-tyrosine (80). The same procedure was
t r i e d on N,N'-diCBZ-L-lysinol (139) . N,N'-diCBZ-L-lysinol
(139) was t r e a t e d with DMSO and TFAA according to the
procedure of D. Swern and coworkers to y i e l d a mixture
of the aldehyde 140, alcohol 139 and side products
(eq. 71 ).^^ ,42,43 r e a c ^-jon mj xt ure was t r e a t e d with
d i l u t e HC1, sodium carbonate and water during work-up.
This appeared to remove most of the side products from
the r e a c tio n mixture as in d icated by PMR.
41
CBZNH
D M S O
TFAA
139
CBZNH
(eq. 71 )
PMR in d ic a te d t h a t the sample co n s is te d of 31% a l d e
hyde. It was assumed t h a t the r e s t of the mixture c o n s i s
ted of the alcoho l. The semicarbazone of the aldehyde was
prepared before column chromatography. Column chromato
graphy afforded the semi carbazone in a y ie ld of 6.7%.
Glutamic Acid and H istid in e
G1utami c Acid. The s y n th e s i s ch allenge presented by
glutamic acid will be the s e l e c t i v e reduction of the
a - c a r b o x y l i c acid in the presence of the side chain
carbo xy lic acid group. The a e s t e r (142), the y e s t e r
(148), and the d i e s t e r (145) have been prepared as shown
i n eqs. 71 -73.
^ ^ N H C B Z
57 ,59, 60
EtOH
■ >
Sealed Tube
120-1 30°
4 h
NHCBZ (eq. 71)
H O
N H ,
H C 1
O H EtOH
Et20
(eq. 72)
143
42
H C 1
144
NH2'HC1
145
(eq. 73)
The f i r s t step for glutamic acid involved the forma
tion of the alpha methyl e s t e r . L-glutamic acid (45)
H O
N H .
45 ! 2
QH
CBZ-C1
TjaHCOT
NaOH d
h2o
(eq. 74)
146
NHCBZ
was disso lv ed in a sodium bicarbo nat e s o lu tio n and t r e a t e d
with CBZ-C1 and sodium hydroxide according to the p roce
dure of S. Goldschmidt, and C. Jutz to y i e l d N-CBZ-L-
glutamic acid ( 146) in a y i e l d of 72% (eq. 74).
According to the procedure of W.J. LeQuesne and G.T.
Young, N-CBZ-L-glutamic acid ( 146) was t r e a t e d with a c e t i c
anhydride to y i e l d N-CBZ-glutamic acid anhydride (147)
in a y i e l d of 93.4% (eq. 7 5 ) . ^
HO
146
NHCBZ
(eq. 75)
0 ^ O^n)
147
In the f u t u r e , the alpha e s t e r 142 could be prepared
by t r e a t i n g the anhydride 141 with ethanol in a sealed
tube according to the procedure of W.J. LeQuesne and
5 7
G.T. Young (eq. 73). At t h i s p o i n t , two options are
43
a v a i l a b l e in an attempt to sy n th e siz e the aldehyde.
F i r s t , the ethyl e s t e r 142 could be t r e a t e d with DIBAL-H
1 5
according to the procedure of A. Ito and coworkers.
The second option involves t r e a t i n g the ethyl e s t e r
142 with sodium borohydride to y i e l d the alcohol. The
alcohol could be su b jec te d to the Swern o x i d a t i o n . ^ ^ ^
H i s t i d i n e . H i s ti d i n e o f f e r s some s y n t h e t i c problems
involving the imidazole ring. The imidazole ring might
not be s ta b l e to some of the reag ents t h a t yie ld e d
desired products in the g ly c in e , t y r o s i n e , and l y sin e
sequen c e s .
Following the procedure of A. Patchornik and
coworkers, L - h i s t i d i n e (46.) was t r e a t e d with CBZ-C1 and
sodium hydroxide to y i e l d the 1 ,N1-diCBZ -L-histidine
( 148) which was immediately t r e a t e d with diazomethane in
e t h e r to y i e l d the methyl e s t e r 149 (eq. 76).^®
In the f u t u r e , two d i f f e r e n t paths to the aldehyde
are a v a i l a b l e based on the work reported in t h i s manuscript.
F i r s t , the e s t e r 149 could be sub jec ted to a DIBAL-H
reduct ion to obtain the aldehyde. Second, the methyl
e s t e r 149 could be reduced to the alcohol with sodium
borohydride. The r e s u l t i n g alcohol could be su b jec te d to
a Swern o xid ation to y i e l d the aldehyde.
._________________ 44
I 2 H20 I
0
A o h
H 46 0° / CBZ
:bz
148
ch2n2
ether
. i NH
1 |
CBZ CBZ
149
Conclusion. Based on the resear ch conducted, the best
method for o b ta in in g the aldehydes of ty r o s i n e and ly sin e
was tre at ment of the CBZ-methyl e s t e r s with DIBAL-H in
toluene and hexane at -50°, Preparation of the semicarba-
zone before s i l i c a gel chromatography p a r t i a l l y sim p l i f i e d
the p u r i f i c a t i o n of the d e s ir e products. For t y ro s i n e and
l y s i n e , the best method of o b ta in in g the alcohol was the
tre atm e n t of the CBZ-methyl e s t e r with sodium borohydri de
in 100% ethanol. Future resear ch will include optim iz ati on
of the semicarbazone h y d r o ly s i s , use of Na-Hg amalgam to
reduce e s t e r s to aldehydes, and r e i n v e s t i g a t i o n of the Raney
nickel d e s u l f u r i z a t i o n of the t h i o e s t e r s .
45
CHAPTER III
EXPERIMENTAL
PMR sp e c t ra were reocrded on a Varian T-60 s p e c t r o
meter. PMR s pectra in d ica ted as 100 Hz were recorded on
a Varian XL-100 spectrometer. IR spectra were determined
on a Perkin-Elmer 281 spectrophotometer and c a l i b r a t e d
a g a i n s t known peaks in a po lystyrene film. Melting points
were taken on a Fisher-Johns apparatus and are uncorrected.
G1yc i ne
N-Phthaloyl glycine ( 4 8 ) . This compound was prepared by
the general method of L. Reese, 17 A f i n e l y ground mixture
of glycine (9.59 g, 127.7 mmol) and p h th alic anhydride
(19.64 g, 139.3 mmol) was heated in an oil bath at 150° for
45 min. A yellow solid r e s u l t e d when the r e a c tio n mixture
cooled. R e c r y s t a l l i z a t i o n from m ethan ol:water (5:3) yiel ded
the acid £8 (18.98 g, 73.5%) as white c r y s t a l s : mp 195-197°
[ l i t . 17 mp 1 92-1 94 ° C]. PMR ( CDC13 : DMSO-dg, 1:1) 6 4.1
(s ,2 H) , 6.0 (br s, 3H), 7.6 (s, 4H). IR ( KBr) 3300-2400,
1750-1600, 1605, 1460, 1410, 1380 cm- 1 .
I
N-phthaloyl glycyl c h l o r id e ( 6 0 ) . Method 1. This compound
was prepared by the method of J.C. Sheenhan and V.S.
2 3
Frank. To a s o lu t i o n of N-phthaloyl glycine (9.5 g,
46.3 mmol) in benzene (200 mL) was added phosphorus penta-
c h lo r id e (15.16 g, 72.8 mmol). The r e s u l t i n g solu tio n was
46
heated in an oil bath at 55° for 1 hour. Evaporation of
the solve nt gave 6_0 as white c r y s t a l s (10.38 g, 93.5%).
Method 2. In t h i s method, 60^ was prepared by the procedure
2 5 24
of K. Balenovic et al . and S. Gabriel. A s o lu tio n of
N-phthaloyl glycine (7.00 g, 34.1 mmol) in thionyl c h l o r id e
(17 ml, 233 mmol) was heated in an oil bath at r e fl u x for
1 hour. The solve nt was evaporated to y i e l d a s o li d .
Recrystal 1 izat ion from benzene .-hexane (1:1) yie lded 6J3
(6.39 g, 78.2%) as a white s o l i d : mp 80-83°C [ l i t .
mp 85-86° C]. NMR ( CDC13 ) 6 4.9 (s, 2H), 7.8 (d, J = 1 Hz,
4 H). IR ( KBr) 2980, 2950 , 1 805, 1 770, 1 750-1 620 , 1 61 0,
1 470, 1 400, 1 370, 1 31 0 cm""' . This compound was also i d e n t i
fied by i t s r e ac tio n with ethanol to y i e l d the ethyl ester.;
N-phthaloyl glycine benzyl t h i o e s t e r ( 8 0 ) . This compound
was prepared by the procedure of R.H. Levin and cowork-
30
er s. To a solu tio n of N-phthaloyl glycyl c h l o r id e
(0.77 g, 3.4 mmol) and pyridine (0.4 mL, 3.2 mmol) in
benzene (10 mL) was added benzyl mercaptan (4.5 mL, 3.83
mmol) dropwise. The r e s u l t i n g pink s o lu tio n was allowed
to stand for 1 h. The s o lu t i o n was p a r t i t i o n e d between
e t h e r (15 mL) and water (15 mL), the la yers were s e p a r a t e d ,
and the aqueous layer was washed with ether (2 x 15 mL).
The combined ether layers were washed su c c e ss iv e ly with J
water (30 mL), 1% HC1 (30 mL), 1% NaOH (30 mL), and water |
(30 mL). Drying and evaporation of the ether gave 80_ j
(.711 g, 66.4%) as a c l e a r g la ss . PMR (.CDCI3) 6 4.1
(s, 2 H) , 4.5 (s, 2H) , 7.1 (s, 5H), 7.6 (d, 0=1 Hz, 4H).
IR (CDC13 ) 3090, 3060, 3030, 3010, 2930, 1800-1760,
1750-1650, 1600, 1500, 700 cm"1 .
N-(2-hydroxyethyV)-phthalimide ( 8 7 ) . This compound was
prepared by modifying the procedure of L. Reese. 17 A mix
ture of p h t h a l i c anhydride (12.34 g, 83.3 mmol) in
2-ami noethanol (5 mL, 82.8 mmol) was heated in an oil
bath at 150° for 30 min. Upon cooling, a whiti sh green
s o l i d was obtained which was dis solved in chloroform, and
f i l t e r e d . Evaporation of the chloroform y i e l d e d 87_
(9.8 g, 61.9%) as w h i t e ’c r y s t a 1s : mp 125-127°. PMR
(CDC13 ) 6 2.7 (s, 1H), 3.8 (s, 4H), 7.6 (d, 0 = 1 Hz, 4H).
IR ( KBr) 3460, 3100-3000, 2940, 2880, 1765, 1740-1615,
1600, 1055, 1030, 1010, 990 cm"1 .
N-phthaloyl glycinal ( 8 1 ) . Method 1 is a v a r i a t i o n of the
40
procedure of P.O. Beeby. To a s t i r r e d s o lu t i o n of
N , N1 - dicyclohexy1carbodiimide (4.16 g, 20.2 mmol) in DMS0
(50 mL) under a nitrogen atmosphere was added N-( 2 - hydroxy-
e t h y l ) - p h t h a l i m i d e . After 8 min, d i c h i o r o a c e t i c acid
(.5 mL) and ethyl a c e t a t e (30 mL) were added. After the
s o lu t i o n was f i l t e r e d , the solv ent was evaporated. Evapora
tion of some of the DMS0 by vacuum d i s t i l l a t i o n y ie ld e d a
yellow s o lid which was dis solved in methylene ch lo rid e .
48
After the s o lu t i o n was f i l t e r e d , the solvent was removed
to y i e l d a yellow s o lid which by pmr cons i s t e d of the
aldehyde 8J_, DMSO and d i c y c l o h e x y l u r e a . Chromatography
( s i l i c a gel, methylene c h lo rid e ) f a i l e d to y i e l d 8_T in a
pure form.
Method 2. This procedure was a mod ific ati on of the
41 42 4 3
method used by D. Swern and coworkers. ’ ’ To a
s t i r r e d s o l u t i o n of DMSO (7.1 mL, 100 mmol) in methylene
c h lo r id e (10 mL) c h i l l e d to -55° was added slowly a s o l u
tion of t r i f 1u o roacetic anhydride (11.0 mL, 77.9 mmol) in
methylene ch lo r id e (5 mL). After 15 min had elapsed a
s o lu t i o n of N-(2 - h y d ro x y e t h y l )-phthalimide (9.52 g, 49.8
mmol) in methylene c hlorid e (100 mL) and acetone (15 mL)
was added. After 30 more min had ela p se d , t r i e t h y l a m i n e
(20 mL) was added. After standing at room temperature
for 90 min, the so lv en t was removed to y i e l d a yellow
s o lu tio n which was vacuum d i s t i l l e d to remove some of
the DMSO. Chromatography ( s i l i c a gel, methylene c h lo rid e :
methanol ( 1 : 1)) f a i l e d to improve the p u r i t y of 8 1 .
Tyrosine
L-t.yrosine methyl e s t e r hyd rochloride ( 1 0 5 ) . This com
pound was prepared by a m o dificati on of the procedure of
2 8
S. Gullmann and R.A. Boissonnas. To a s o lu tio n of
methanol (60 mL) in a bath at -25° was added thionyl
c hlorid e (12 mL, 165 mmol) slowly, then L-ty rosine
(6.13 g, 33.9 mmol) was added. After removal from the
4 9
bath, the s o l u t i o n was s t i r r e d at room temperature for 24 ft.
The so lv en t was removed, and the residue was dis solved in
methanol. Addition of methylene c hlo rid e r e s u l t e d in the
p r e c i p i t a t i o n of 105 (5.6 g, 72.2%) as a white s o l i d :
mp' 1 85-188° [ l i t . 61 mp 190°]. PMR (CDC13 :DMS0-dg , 1:1)
6 3.1 (d, 0=3 Hz, 2 H), 3.6 (s, 3H), 4.0 ( t, 0 = 3 Hz, 1H),
6.7 (q, 0=4 Hz, 4H), 8.6 (br s, 3H), IR ( KBr) 3600-3200,
3200-2640, 2640-2480, 1740, 1610, 1590, 1510-1490 cm"1 .
L - ty r o sin e methyl e s t e r ( 1 0 3 ) . To a suspension of L-tyro-
since methyl e s t e r hydrochloride (4,4 g, 19 mmol) in ethyl
a c e t a t e (200 mL) was added t r i e t h y l amine (10 mL). After
s t i r r i n g for 2 h at room tem p eratu re, the s o lu t i o n was f i l
t e r e d to remove t r i e t h y l amine hydrochloride as a s o li d .
Evaporation of the f i l t r a t e so lv en t yielded 103 (3.04 g,
r ,o
82%) as a yellow s o l i d : mp 127-128° [ l i t . mp 133-135°].
PMR (CDC13 ) 6 2.7 (t, J = 2 Hz, 2H), 3.5 (s, 3H), 3.8
(br s, 3 H) , 6.5 (q, J = 4 Hz, 4H). IR (KBr) 3360 , 3300 ,
3200-2300, 1700, 1620, 1520, 1490 cm- 1 ,
L - ty rosinol hydrochioride ( 1 0 4 ) . This compound was pre-
44
pared by the method of P. Karrer and coworkers. L-tyro-
since methyl e s t e r (9,6901 g, 49.7 mmol) was placed in
the thimble of a Soxhet apparatus with the fla sk con
t a i n i n g a suspension of l ith iu m aluminum hydride (12.48 g,
3 3 0.8 mmol) in THF (150 mL). The mixture re fluxed for
_______________ 50,
4 days and then was quenched by the slow ad d itio n of 1,2-
dimethoxyethane (200 mL), e th e r (500 mL), and water (200
mL). After s e p a ra tio n of l a y e r s , the mixture was e x t r a c t e d
with water (5 x 100 mL at 60°). The water wash was evapor
ated to y i e l d a residue which was dissolved in methanol
(500 mL). Adjustment of the s o lu t i o n pH to 6 with ox a lic
acid r e s u l t e d in the formation of a p r e c i p i t a t e which was
removed by f i l t r a t i o n . The removal of the solv ent yielded
a resid u e which was dissolved in ethanol (300 mL) cont ai n-
ing a l i t t l e cone, HC1, The volume of the s o lu tio n was
reduced to 50 mL. The addit ion of 100% ethanol (10 mL),
methylene c h l o r id e (150 mL), and ether (300 mL), and p l a c e
ment in a r e f r i g e r a t o r r e s u l t e d in the formation of 104
(4.4667 g, 44.3%) as cream colored c r y s t a l s : mp 150-154°
[ l i t . 48 mp 167-167.5°]. PMR ( CDC13 : DMS0-dg, 1:1) 6 2 . 5 - 3 .8
(m, 6H), 4 . 8 - 5 . 9 (br s, 2H), 6,7 (q, J = 9 Hz, 4H) 7.6-8.1
(br s, 3H), IR (KBr) 3600- 3340 , 3340-2700 , 1 580 cm"1 .
N-CBZ-L-tyrosine methyl e s t e r ( 1 2 5 ) . This compound was
1 5
prepared by the method of A, Ito and coworkers. To a
s o lu tio n o f sodium bica rbon at e (5.595 g) in water (40 mL)
in an ice bath was added L-tyrosine methyl e s t e r hydro -
c h l o r id e (2,4338 g, 10.5 mmol) and ethyl a c e t a t e (50 mL),
To t h i s s o lu t i o n was added CBZ-C1 (2.5 mL, 17,5 mmol)
slowly. The s o lu t i o n was s t i r r e d for 1.75 h and then the
s o l u t i o n was a c i d i f i e d to pH 2 with d i l u t e HC1. After the
_____________________________
layers were s e p a r a t e d , the aqueous la yer was e x t r a c t e d with
ethyl a c e t a t e (2x). The combined e x t r a c t s were dried with
sodium s u l f a t e , and evaporated to y i e l d an o i l . The oil
was dissolved in methylene c hlo rid e and Skelly 'A1 pentanes,
seeded, and placed in a r e f r i g e r a t o r which r e s u l t e d in the
formation of 1 25 (2.5069 g, 69.5%) as white c r y s t a l s :
mp 87-88°. PMR (C DC13 ) 6 3.1 (d, J = 6 Hz, 2H), 3.8 (s, 3H),
4.6 (m, 1H), 5.2 (s, 1H), 5.8 (s, 2H), 6.9 (q, J=10 Hz, 4H)
7.5 (s, 5H). IR (KBr) 3600- 3380, 3320 , 1 720, 1 690 cm- 1 .
N-CBZ-L-tyrosino! ( 1 2 6 ), This compound was prepared
by a m o dificati on of the procedure of A. Ito and co-
w o r k e r s . ^ To a s o lu t i o n of sodium borohydride (1,2416 g,
32,8 mmol) in ethanol (50 mL) in an ice bath was added
to a s o lu tio n of N-CBZ-L-tyro s i ne methyl e s t e r (1,0428 g,
3,2 mmol) in ethanol (10 mL). The s o lu tio n was s t i r r e d
at room temperature for 3,5 h. Ethyl a c e t a t e (50 mL) and
water (40 mL) were added to the s o l u t i o n , and the s o l u
ti o n volume was reduced and water (25 mL) was added.
The s o lu t i o n was e x t r a c t e d with methylene c h lo r id e once.
The e x t r a c t was washed with IN HCl, washed with water,
dried with sodium s u l f a t e , and evaporated to y i e l d an oil
which s o l i d i f i e d to give 126 (,6563 g, 68.8%) as white
c r y s t a l s : mp 88-90° [ l i t . ^ ® mp 92-96°]. PMR (CDCl^)
6 3.1 (d, J = 6 Hz, 2 H), 3.8 (s , 3H), 4.6 (m, 1H), 5,2
(s, 4 H) , 5.8 (s, 2 H) , 6,9 (q, J = 10 Hz, 4H), 7.5 (s, 5H).
52
IR (KBr) 3600-3380, 3320, 1720, 1690 cm'1 ,
N-CBZ-L-tyrosinal semicarbazone ( 1 2 7 a ) , This procedure
is a m o d ific a tio n of the method used by A. Ito and
46
coworkers. To a s o lu t i o n of N-CBZ-L-tyrosine methyl
e s t e r (3.8175 g, 11.6 mmol) in toluene (200 mL) in a
d r y -i c e - i s o p r o p a n o l bath at -60°, 1 M DIBAL-H in hexane
(23.5 mL) was added slowly over a period of 25 minutes,
under a n itro g e n atmosphere with s t i r r i n g . After s t i r
ring the s o lu t i o n for 25 min, 2N HC1 (80 mL) was added,
and the s o l u t i o n was removed from the dry ice- isoprop an ol
bath and allowed to warm to room tem perature. The layers
were s e p a r a t e d , and the aqueous layer was washed with
ethyl a c e t a t e . The combined organic e x t r a c t s were washed
with water, dried with s'odium s u l f a t e , and evaporated
(bath temperature l e s s than 40°) to y i e l d a yellow o i l .
The yellow oil was disso lv ed in 70% ethanol (30 mL) and
combined with a s o l u t i o n of 70% ethanol co ntaining sodium
a c e t a t e (.9431 g) and'semi carbazi de hydrochloride (1.112 g).
This s o l u t i o n was heated in a oil bath at 98° for 5 min.
The solv ent was removed to y i e l d a white residue which was
e x t r a c t e d with ethyl a c e t a t e (3 x 30 mL). The combined
e x t r a c t s were washed with water, dried with sodium s u l f a t e ,
and evaporated to y i e l d a yellow o i l . The oil was
chromatographed ( s i l i c a gel, ethyl a c e t a t e ) to give 12 7a
(.421 g, 10.2%) as a white s o l i d : mp 1 76-1 77° [ l i t . 46 m p .
53
171-173°]. PMR (Varian XL-100) ( CDC13 : DMSO-dg, 4:1.) 6 2.8-
3.4 {m, .5 H), 4.3 (d, J = 4 Hz, 2H) , 5.. 0 (s, 2H), 5.6 (br s ,
1H),. 7.2 (d, J= 3 Hz , 2 H ) , 7.5 (d, J = 1 Hz, 2H ) , 7.7 ( s , 5H).
IR (KBr) 3500- 3390 , 3390.-2500 ,. 1 750-1 620 cm” 1 .
N-CBZ-L-tyrosina1 ( 1 2 7 ) . This compound was prepared by
a m o d ific a tio n of the procedure of D. Swern and cowork-
41 4 ?
e r s. * A s o lu tio n of dimethyl sulfoxide (0.2 mL, 2.8
mmol) in methylene chlo rid e (2 mL) was c h i l l e d in a dry
i c e - i s o p r o p a n o 1 bath at -65°. TFAA (.3995 g, 1.899 mmol)
in methylene ch lo r id e (.5 mL) was added with s t i r r i n g to
the DMSO s o l u t i o n . After 10 min, a s o lu t i o n of N-CBZ-L-
t y ro s i n o l (0.3239 g, 1.08 mmol) in methylene c hlo rid e
(15 mL) (dropwise add itio n of DMSO aided in d iss o lv in g
the a lc ohol) was added over a period of 8 minutes to the
re a c tio n mixture. After s t i r r i n g for 35 min, t r i e t h y l -
amine (2 mL) was added to the s o l u t i o n , the solutdon was
removed from the bath and s t i r r e d at room temperature for
50 min. The so lv en t was evaporated and the r e s u l t i n g oil
was placed under vacuum over nigh t. The next day, the oil
was placed under vacuum for 6 hr while in an oil bath at
55°. The oil was chromatographed ( s i l i c a gel, methylene
chio ride:metha no l , 98:2) which f a i l e d to y i e l d the pure
12 7 . Pmr a n aly sis in d ic a te d t h a t 5 2.6% of the s t a r t i n g
m ateria l had r e a c te d to form the aldehyde. PMR (CDCl^)
6 4.9 (s, 2H), 6.7 (q, J=4 Hz, 4H), 7.1 (s, 5H), 9.4 (s) .
Lys i ne
L-l.ysine methyl e s t e r dih y d ro c h io rid e ( 1 3 5 ). This com
pound was prepared by a m o d ifica tio n of the procedure of
2 8
S. Gullmann and R.A. Boissonnas. To a s o lu tio n of
methanol (50 mL) in a bath at -20° was added thionyl
c h l o r i d e (8.0 mL, 109.7 mmol) slowly with s t i r r i n g ,
then L-lysine (4.4302 g, 30.34 mmol) was added. After
removal from the bath, the s o lu tio n was s t i r r e d at room
temperature for 24 h. The solv ent was removed, and
the re sid u e was dissolv ed in methanol. Addition of e th er
r e s u l t e d in the p r e c i p i t a t i o n of 135 (7.0244 g, 99.8%)
as a white s o l i d : mp 204-206°, Pmr (D^O) 6 1 . 1- 2.1
(br s, SH), 3.0 ( t , J=3 Hz, 3H), 3.9 (s, 3H). IR (KBr)
3400-3300, 3300-2300, 2060-1900, 1735, 1500, 1230 cm- 1 .
N, N1-d ic arb obenzoxy-L-1ysine ( 1 3 7 ) . This compound was
55
prepared by the method of R.A. Boissonnas and coworkers.
To a s o l u t i o n of L-lysine (2.0090 g, 13.76 mmol) in 2N
NaOH (7 mL) and water (7 mL) in a bath at -5° was added
benzyl ch 1oroformate (7.2 mL, 50.4 mmol) slowly with s t i r
rin g. Simultaneous add itio n of 4N NaOH maintained the
pH a t 10. The CBZ-C1 s o lu t i o n and the NaOH s o lu t i o n were
maintained at 0° during the a d d i t i o n . After 15 minutes
of s t i r r i n g , 3N HC1 (14 mL) was added to the s o l u t i o n .
The r e a c t i o n mixture was e x t r a c t e d with e t h e r (2x). The
combined e t h e r e x t r a c t s were washed with IN HC1 and then
with water. The e ther was e x t r a c t e d with IN NH^OH (1 x 40
55
mL) and with IN NH^OH (2 x 20 mL). The combined NH^OH
laye rs were washed with e t h e r , and then a c i d i f i e d with
3N HC1 in the presence of et her (40 mL) and ice (30 g),
and the layers sep a ra te d . The aqueous lay er was washed
with e t h e r which a f t e r sep a ra tio n was combined with the
e t h e r layer from t h e a c t d i f i c a t i o n step. The combined
e t h e r la yers were washed with water, dried with sodium
s u l f a t e , and evaporated to y i e l d a syrup. Several attempts
at c r y s t a l l i z a t i o n f a i l e d so the syrup was used without
f u r t h e r p u r i f i c a t i o n in the next step.
N , N ' -diCBZ-L-lysine methyl e s t e r ( 1 3 8 ) . This compound was
prepared by a modified version of the procedure used by
1 5
A. Ito and coworkers. To a s o lu tio n of N, N' -diCBZ-L-
l y s i n e obtained from the previous step in e t h e r (15 mL)
cooled in an ice bath was added diazomethane in e ther until
the yellow color of diazomethane p r e s i s t e d . The r e ac tio n
p s s t i r r e d for 3 h at 0°. The solven t was evaporated
to y i e l d an oil which could not be c r y s t a l l i z e d . The oil
was subjected to chromatography ( s i l i c a gel, methylene
c h lorid e ) to y i e l d 138 (4.308 g, 73%) as a syrup which
could not be c r y s t a l l i z e d . PMR (CDC1^ ) 6 1 .3 -2 .3 (br s,
8H), 3.3 (d, J=5 Hz, 1H), 3.8 (s, 3H), 4.2 (br s, 1H), 5.2
(s, 4H) , 5.8 (d, J = 6 Hz, 1H), 7.4 (s, 10H), IR (KBr)
3500-3200, 3000-2720, 1760-1660 cm'1.
56
N,Nl -diCBZ-L“ 1ysinol ( 1 3 9 ) , To a s o lu tio n of sodium
borohydride (3.3957 g, 89.76 mmol) in 100% ethanol
(150 mL) c h i l l e d in an ice bath was added a cold s o l u
tion of N,N'-diCBZ-L-1ysine methyl e s t e r (3.8894 g, 9.1
mmol) in 100% ethanol (30 mL). After s t i r r i n g the s o l u
tion at room temperature for 3 h, ethyl a c e t a t e (100 mL)
and water (120 mL) were added. After the volume of the
s o l u t i o n was reduced, water (50 mL) was added. The s o l u
tion was e x t r a c t e d with methylene ch lo rid e (5 x 50 mL).
The combined methylene c h l o r id e layers were washed with
IN HC1 , dried with sodium s u l f a t e , and evaporated to
y i e l d 139 (3.4370 g, 94.6%) as an oil which could not
be c r y s t a l l i z e d . PMR (CDClg) 6 1 .2 -1 .9 (br s, 8H), 2.6
(br s, 2 H), 3.2 (d, J = 5 Hz, 1H), 3.4 (s, 1H), 3.6 (s, 2H),
5.1 (s, 4H), 7.3 (s, 10H). IR (KBr) 3620-3120, 3100-2720,
1740-1600 cm- 1 .
N,N'-diCBZ-L-lysinol semicarbazone (1 4 0 a ) . The procedure
used to prepare t h i s compound was th a t of A. I to and
1 5
coworkers. To a s o lu tio n of N,N'-diCBZ-L-lysine methyl
e s t e r (10.0313 g, 23.4 mmol) in toluene (100 mL) in a
dry ice-iso p ro p a n o l bath at -60°, was added 1 M DIBAL-H
in hexane (42 mL) slowly over a period of 20 minutes under
nitorg en atmosphere with s t i r r i n g . After s t i r r i n g the
s o lu t i o n for 25 minutes, 2N HC1 (100 mL) was added, and
the s o lu t i o n was removed from the dry ice-iso propanol
5 7
bath and allowed to warm to room temperature. The lay ers
were sep arat ed and the aqueous lay er was washed with
ethyl a c e t a t e (3x). The combined organic la yers were
washed with water, dried with sodium s u l f a t e , and
evaporated (bath temperature less than 40°) to y i e l d a
yellow o i l . To a s o lu tio n of the yellow oil in 70%
ethanol (70 mL) was added semi ca rbazide hydrochloride
(2.0177 g, 18.09 mmol), and sodium a c e t a t e (1.4945 g).
This s o lu t i o n was heated in an oil bath a t 94° for 5 min
and evaporated to y i e l d an o i l . The oil was washed with
chloroform and a white s o li d r e s u l t e d which was washed
with chloroform. The combined chloroform washes were
washed with water, drie d with sodium s u l f a t e , and e vapora
ted to y i e l d a yellow o i l . The oil was chromatographed
( s i l i c a ge l, ethyl a c e t a t e ) to give 140a (3.2182 g, 28.7%)
as a o i l . PMR (CDC13) 6 1 .2 -2 .0 (br s, 10H), 3.1-3.4
(br s, 2H), 5.4 (s, 4H), 7.4 (s, 10H). IR (KBr) 3860-3100,
3060, 3000-2799 (2930, 2960), 1840-1610 (middle 1730-1660),
1 575 , 1 550-1 470 cm"1 .
N,N'-diCZB-L-lysinal semicarbazone (1 4 0 a ) . Method 2. This
compound was prepared by the procedure of D. Swern and
coworkers. 41 A s o lu tio n of dimethyl sulfoxid e (1.5 mL,
21.1 mmol) in methylene c h l o r id e (10 mL) was c h i l l e d to
-65° with a dry ic e-iso p ro p a n o l bath. TFAA (2.1 mL, 15
mmol) in methylene c h l o r id e (5 mL) was added with s t i r r i n g
58
over a period of 9 minutes. After 10 min of s t i r r i n g ,
a s o lu t i o n of N,N'-diCBZ-L-lysinol (4.41 g, 11.0 mmol) in
methylene c h l o r id e (10 mL) was added over a period of
12 minutes. After s t i r r i n g an a d d i t i o n a l 5min, the r e a c
tion mixture (T = -65°) was removed from the dry ice-
isopropanol bath and s t i r r e d at room temperature for
95 min. Then N , N' - d i i s o p r o p y 1e t h y 1 amine (5 mL) was added
over a period of 10 minutes. The organic layer was washed
with water (20 mL) which was backwashed with methylene
c h l o r id e (5 mL). The combined methylene ch lo rid e laye rs
were washed with d i l u t e HC1 , d i l u t e sodium ca rbonate, and
water, then dried with magnesium s u l f a t e . Evaporation of
the solv ent y i e l d e d an oil which was dissolved in 70%
EtOH (28-mL). After adding semicarbazide hydrochioride
(1.03 g) and sodium a c e t a t e (0.85 g), the r e s u l t i n g
s o lu t i o n was heated in an oil bath at 96° for 5 minutes.
The solven t was evaporated to y i e l d a white oil which was
e x t r a c t e d with methylene ch lo r id e (1 x 50 mL) and
ethyl a c e t a t e (3 x 30 mL). The combined organic la yers
were washed with water, dried with sodium s u l f a t e and
evaporated to y i e l d an o i l . Column chromatography ( s i l i c a
ge l, ethyl a c e t a t e ) yie ld e d 140a (0.3534 g, 6.7%) as an
o i l . Spectra data was the same as the data for 140a
generated from the DIBAL-H r e a c t i o n .
5 9
N, N1 - diCBZ-L-1ysin al ( 1 4 0 ) . This compound's p re p a ratio n
1 5
was attempted using the method of A. Ito and coworkers.
To a s o lu tio n of N, N' - diCBZ-L-1y s i n a 1 semicarbazone
(1.0232 g) in 100% ethanol (30 mL) was added 0.5 N HC1
(12 mL) and 37% formaldehyde (3 mL) with s t i r r i n g at
room temperature. A fte r s t i r r i n g for 2 hours, water
(30 mL) was added and the s o lu tio n was e x t r a c t e d with
ethyl a c e t a t e (3 x 50 mL). The combined e x t r a c t s were
washed with w at er , dried with sodium s u l f a t e and evap ora
ted to y i e l d an oil which c o n s is te d of the aldehyde and
the s t a r t i n g m a t e r i a l . The PMR in d i c a t e d th a t 42% of the
s t a r t i n g material had been converted to the aldehyde.
The procedure was rep ea te d on the oil which did not
improve the p u r i t y of the product.
G1utami c Aci d
N-CBZ-L-glutamic acid ( 1 4 1 ) . This compound was prepared
56
by the method of S. Goldschmidt and C. Jutz . L-glutamic
acid (22.0018 g, 149.5 mmol) and sodium bicarbona te
(25.0693 g) were disso lv ed in water (115 mL) and placed
in an ice bath with s t i r r i n g . CBZ-C1 (24 mL, 168 mmol)
was added slowly while 2N NaOH (app. 75 mL) was added
sim ultan eo us ly to maintain the pH between 8-9. After
f i l t r a t i o n , the s o lu t i o n was e x t r a c t e d with e th e r
(4 x 50 mL). The aqueous la y e r was a c i d i f i e d to pH = 2
with 4H HC1 and e x t r a c t e d with ethyl a c e t a t e (3 x 50 mL).
The ethyl a c e t a t e layers were combined, washed with 2N
60
HC1, dried with sodium s u l f a t e , and evaporated to y i e l d
a t h ic k o i l . The oil was disso lv ed in a l i t t l e ethyl
a c e t a t e and Skelly 'A' pentanes we re added until the
s o lu tio n became t u r b i d . C r y s t a l l i z a t i o n was induced by
s t i r r i n g and s c r a t c h i n g to y i e l d 141 (30.24 g, 71.9%)
as a white s o l i d : mp 116-117° [1 i t . 56' mp 120-121°]. PMR
(CDC1 3 : DMS0-d6 , 1:1) 6 1 . 9-2 . 7 (br s', 4H), 4 . 2 - 4 .6 (br s,
1 H, 5.2 (s , 2 H ) , 5 •. 7 - 6 . 0 ' (b r . s , • 1 H ) , 7.4 (s , 5H), 10.3
(s, 2H). IR (KBr) 3600^3300 (3400), 3300-2980, 2980-2200,
1 71 0, 1 695, 1 550 , 1 530 , 1 435 , 1 370 cm"1.
N-CBZ-glutamic acid anhydride ( 1 4 2 ) . This compound was
5 7
prepared by the method of W.J. LeQuesne and G.T. Young.
A suspension of N-CBZ-L-glutamic acid (10.266 g, 35.6
mmol) in a c e t i c anhydride (35 mL) was s t i r r e d at room
temperature for 90 min. The so lv e n t was evaporated with
a water bath at 50° which caused the suspension to become
a c l e a r l i q u i d before evapo ration of all of the solv ent.
The r e s u l t i n g oil was disso lv ed in chloroform (20 mL) to
which e t h e r (30 mL) was added to produce a white s o lu tio n
which f a i l e d to c r y s t a l i z e a f t e r 2 days in a r e f r i g e r a t o r .
Several more at tem pts at c r y s t a l l i z a t i o n f a i l e d . The oil
was i d e n t i f i e d as L42 (8.75 g, 93.4%). PMR (CDC 13) 6
1 . 8 -2 . 0 (br s, 2H), 2 .3 -2 . 9 (br s, 2H), 4 .0 -4 .2 ( br s,
1H), 4.8 (s, 2H), 5.9 (d, J = 4 Hz, 1H), 7.0 (s, 5H). IR
(KBr) 3600-3120, 3100-3000, 2900-2700, 1820, 1770, 1740-
61
1650 cm"1 .
Histidine
1 ,N1-diC BZ-L -h isti din e methyl e s t e r ( 1 4 5 ) . This compound
was prepared by the method of A. Patchornik and cowork-
c o
e r s. To a s o lu t i o n at 0° of L - h i s t i d i n e (3.9032 g,
25.2 mmol) in water (10 mL) and 2N NaOH (10 mL), CBZ-C1
(9.0 mL, 63.0 mmol) was added in portions with s t i r r i n g .
Simultaneously, 2N NaOH was added -to maintain the pH
between 9 and 10. After s t i r r i n g for 15 min, the s o lu tio n
was a c i d i f i e d (pH = 2) with 4N HC1 to y i e l d a white s o li d .
After s e p a r a t i o n , the white s o li d was dissolved in methanol
in an attempt to r e c r y s t a l 1ize which f a i l e d . After the
removal of the s o lv e n t, the oil was dissolved in methanol
and t r e a t e d at 0° with diazomethane unt il the yellow
co lor p r e s i s t e d , The s o lu t i o n was s t i r r e d ove rnight to
y i e l d a white p r e c i p i t a t e which was removed by f i l t e r a -
tio n . Ether was added to the s o lu tio n in an attempt at
c r y s t a l l i z a t i o n which f a i l e d . The solven t was removed
to y i e l d 145 (9.29 g, 94%) as an o i l . PMR (CDClg) 6
3.2 (s, 1H), 3.5 (s, 2 H) , 4.4 (s, 3H)', 5.0 (s, 3H),
7.0 (s, 14 H) . IR (KBr) 3680-2300 , 1 900-1 650, 1 620-1 570,
1560-1480 cm"1 .
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Creator Planck, Raymond Emment (author)

Core Title Synthesis of the amino aldehydes from glycine, tyrosine, and lysine

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