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Enantioselective synthesis of episulfide analogues of L-methionine
oo404039/92 $5.00+ .oo
Tehahedron Letters. Vol. 33, No. 35. Pp. 5047-5050.1992 Printed in Gnat Britain
Pergamon Press Lxd
Enantioselective Synthesis of Episulfide Analogues of GMethionine D. Guillerm and G. Guillerm Laboratoire de Chimie Bioorganique associe au CNR!3, Universite de Reims Champagn+ Ardenne, UPR Sciences, B.P. 347,51062 Reims .
Abstract :
Novel functionaliud steps
The inhibition developing number
amincucid analogues of L-mcthioninc were prepared stereoselectively in three
via iodolactonization of (S)-tram and (S)-cis crotylglycines.
of S-adenosyl
chemotherapeutic
of inhibitors
microorganisms
methionine
transferase
of the enzyme
are known
is an attractive
target for
agents in particular,
to be inhibitors
of the growth
since a
of certain
1 and tumors 2.
The enzyme
catalyses the formation of S-adenosylmethionine
moiety of ATP to the sulfur atom of L-methionine in transmethylation
reactions, polyamine
search for methionine
analogues
Steric, electronic L- methionine,
(EC-2.4.2.13)
agents in general and antitumor
biosynthesis
essential
of S-adenosyl
and regulation
as inhibitors of Sadenosyl
and conformational
by transfer of the adenosyl
3. The importance
requirements
methionine
processes
methionine
stimulated
the
transferase 4.
have been described
to their function as substrates or potent inhibitors
for analogues
of
of the methionine
adenosyl transferase reaction 5 .These results led us to consider that analogues of L-methionine
1
and 2 bearing an epithio function could be good candidates as “active site directed inhibitors” of S-adenosyl transferase..
The route selected
for the enantioselective
availibility
of (S)-tram and (S)-cis enantiomerically
the known
high stereoselectivity
synthesis
of 1 and 2 is based on the ready
pure crotylglycines
of halolactonization
of suitably
and takes advantage
protected
of
y, b-unsaturated
amino acids. (S)sis and (S)-frans crotylglycines
were prepared from the bislactim ether 3 of cycle (D-Val-
Gly) according to the method described by Schollkopf 6 (Scheme I).
5047
0CH3 1. n E3uLL 2
=
3
CH+r
80%
3.H2/Lindlar/CH30H
6
7
80%
4. Ba(OHj2
Scheme I Alklylation in three steps.
of 3 with (E) 1-bromo-Z-butene N-protected
bromo-2-butyne
giving
compound
(trans/ cis = 16/ 1). 6 was converted N-Boc (S)-crotylglycines iodolactones
gave a unique
(S)-cis crotylglycine
compound
was best prepared
6 easily separated
4 which led to acid 5
by alkylation
from a minor
amount
into acid 7 in four steps by classical methods
5 and 7 were submitted
to iodolactonization
of 3 with l-
of the cis isomer 7. (12 ,TI-IF) leading
to
8 (2S, 4S, 5R) [aIzP D = -16.8” (c = 6, CHCl3), mp = 117”-118°C and 9 (2S, 4S, 55) [al’,” =
+49-B” (c = 4, CHCW, mp= 130-131°C
respectively
as major products 8. NHBoc
NHBoc H$_d
&e
COOH
5
o&&L,, 0
85%
8
NHBoc NHBoc H$+-,
&
COOH
7
om’“3 9
80% Scheme
The cis stereochemistry experiments,
corroborating
Ohfume
concerning
C5 was
assigned
for lactones 8 and 9 was assigned the recent
halolactonization on the basis
considerations. The direct synthesis
II
results
of episulfides
of G.M. Whitesides
of 2-amino-4-pentenoic
of the results
by IH NMR analysis
of this author
and NOE
9 and the conclusions
of Y.
acids 10. The stereochemistry
at
10 and also by mechanistic
1 and 2 was then accomplished
as shown in scheme III :
5049
75%
50%
63% 12
10
8
NHBoc
NHBoc
62%
9
11
13
Scheme III 8 and 9 were stereoselectively
transformed
= - 12.4” (c = 2.88, CHC13) 11. Then, opening
CHCl$ and 11 [a{; carbonate
in methanol
episulfides
according
conversion
of epoxides
Thus thiocyanates
allowed
similar
into episulfides
and final purification
overall
yield
from
by Bordwell
by reaction with thiocyanate episulfides
or thiourea
the the
13.
14 which
on HP 20 SS resin led to episulfides
N-Boc (S)-truns-crotylglycine
into
concerning
12 (2S, 4% 55) [al’,” = -22.2” (c =
= + 107.3” (c = 1.94, CHCb)
= + 48” (c = 0.6, H20) I5 .Episulfides
O.lN) and 2 [c&f
of the thiocyanates
to one proposed
10 and 11 gave respectively
= + 61.15” (c=3.1,
10 [IX];
of the lactone ring using sodium
a “one pot” transformation
to a mechanism**
1.8, CHC13) and 13 ( 2S, 4R, 5R) [a]K deprotection
into thiocyanates
1 [cI]~
1 and 2 were obtained
and 15 % overall
yield
after
classical
= + 8.4” (c=l, HCl respectively
in 20 %
from N-Boc (S)-cis-
crotylglycine. Biological
activity of these compounds
will be reported
elsewhere.
REFERENCES AND FOOTNDTES 1.
C.J. Abshire,
2.
(a) J.R. Sufrin, Anticancer
R. Pineau. Can. J. Biochem. 451637 (1%7). J.B. Lombardini.
Mol. Pharmacol.
22 752 (1982). (b) R.M.
Res. 5 1 (1985). (c) J.R. Sufrin, J.B. Lombardini,
Bernacki,
C. Porter.
Borchardt,
C.R. Craveling,
In Biological
Methylation
and
P.M. Ueland, eds) Humana
3.
G.L. Cantoni. J. Biol. Chem 204 403 (1953).
4.
J.B Lombardini,
P. Talalay Advances
Drug
Design
Clifton, N.J..
in Enzyme regulation
Hoffman
D.L. Kramer, Vitauts Alks, R.S.
9 349(1971).
373-84,
1985 (R.T.
5.
(a) A.W. Coulter, J.B. Lombardini, Lombardini.
Biochemistry
R.T. Borchardt, 6.
of S-Adenosyl
C.R. Creveling,
K.H. Pospischil,
Westphalen,
Methionine
(1974). (b) J.R. Sufrin, J.B.
and related
Compounds
(E. Usdin,
eds 687-690 1982 Mac Millan Pres. London.
U. Groth, C. Deng. Angew Chem. Int. Ed 20 798 (1981) ; U. Schr)llkopf, W.
U. Schiillkopf, Hartwig,
P. Talalay. Mol. Pharm. Q293
H. Kehne. Synthesis
C. Deng. Synthesis
966 (1981) ; U. Schollkopf,
969 (1981). U. Sch6llkopf,
U. Groth, K.O.
H.J. Neubauer.
Synthesis
861
(1982). 7.
Compounds relation
4 and 6 exibit a ~JHz-H~ of respectively
between
HZ and H5 in the bislactim
3.36 Hz and 3.25 Hz, typical of the trans
ether system.
5 JH~+I~ = 15.25 Hz ; 7 JI-&H~= 10.9 Hz. 8.
8 MS (DCI/NH3)356
(MH)+ >H NMR, sppm, CD@
12.5,9.7 Hz; 1.98,3H, d, J = 6.5 Hz ; 3.05, Hh, 5.10 N-H. 9 MS (DCI/NI-+)
: 1.42,9H,
s ;
1.87, H3& ddd, J = 12.5,
m ; 4.15, W, I-Q and I-&,m ; 4.40, lH, Ha m ;
356 (MH)+ >H NMR, bppm, CD@ : 1.40,9H, s ; 1.92,3H, d, J = 6.5 Hz and
H3~;2.90,Hbm;
4.25,2H,HqandH5,m;4.5O,H~m;5.20N-H.
9
H.K. Chenault,
10.
Y. Ohfume,
11.
10 MS (DCI/NI-I$287
J. Dahmer, G.M. Whitesides,
K. Hori, M. Sakaitani, Tetrahedron
J. Am. Chem. Sot. 1116354 (1989). Lett 22 6079 (1986).
(MH)+ >H NMR, bppm, CDC13 : 1.40,9H, s ; 1.60,3H, d, J = 7 Hz ;
2.07,1H,ddd,J=12,12,10.5Hz;2.~,lH,m;3.45dq,J=7Hz,7Hz;948,H~and~,m;5.30 N-H. 11 MS (DCI/NH3)287
(MH)+ >H NMR, 6ppm, CDQ
: 1.45,9H, s ; 1.68,3H,
d, J = 7H.z ;
2.12, lH, ddd, J = 12,12,10.5 Hz ; 2.%, lH, m ; 3.40, lH, dq, J = 7 Hz, 7Hz ; 4.45, H2 and I-&m ; 5.20 N-H. 12.
JH~_H~ observed assigned
: 7.05 Hz (12) and 5.48 Hz (13) are in accord with cis and trans
values
episulfide
structures.
13.
F.G. Bordwell
and H.M. Andersen
14.
12 J@ (DCI/NH3)287
J. Am. Chem. Sot. 75 4959 (1953).
(MH)+. IH NMR, bppm, CD@ : 1.40,9H, s ; 1.47,3H, d, J = 5.8 Hz ;
1.85, lH, m ; 2.35, lH, m ; 2.89, lH, m ; 2.95, lH, m ; 3.70,3H, s ; 4.45, lH, m ; 5.25 N-H. 13 MS (DCI/NH3)287
(MH)+ >H NMR, 8ppm, CDC13 : 1.46,9H, s ; 1.50,3H, d, J = 5.48 Hz ;
1.9, lH, m ; 2.3, lH, m ; 2.56, lH, m ; 2.62 dq J = 5.48 Hz ,548 Hz; 3.75,3H, s ; 4.47 ; lH, m ;5.3 15.
N-H. 1 lHNMR,bppm,D20:
150,3H,d,
J=5.85Hz;1.99,1H,m;2.56,1H,m;3.18,2H,m;3.90,
lH,t, J = 6.65 Hz. 2 1HNMR,
6ppm,D20:
1.41,3H,d,
4.09, lH, dd, J = 6.25,8.75 Hz.
(Received in France 21 May 1992)
J=7.05Hz;2.42,2H,m;3.18,1H,m;3.60,1H,m;
Tehahedron Letters. Vol. 33, No. 35. Pp. 5047-5050.1992 Printed in Gnat Britain
Pergamon Press Lxd
Enantioselective Synthesis of Episulfide Analogues of GMethionine D. Guillerm and G. Guillerm Laboratoire de Chimie Bioorganique associe au CNR!3, Universite de Reims Champagn+ Ardenne, UPR Sciences, B.P. 347,51062 Reims .
Abstract :
Novel functionaliud steps
The inhibition developing number
amincucid analogues of L-mcthioninc were prepared stereoselectively in three
via iodolactonization of (S)-tram and (S)-cis crotylglycines.
of S-adenosyl
chemotherapeutic
of inhibitors
microorganisms
methionine
transferase
of the enzyme
are known
is an attractive
target for
agents in particular,
to be inhibitors
of the growth
since a
of certain
1 and tumors 2.
The enzyme
catalyses the formation of S-adenosylmethionine
moiety of ATP to the sulfur atom of L-methionine in transmethylation
reactions, polyamine
search for methionine
analogues
Steric, electronic L- methionine,
(EC-2.4.2.13)
agents in general and antitumor
biosynthesis
essential
of S-adenosyl
and regulation
as inhibitors of Sadenosyl
and conformational
by transfer of the adenosyl
3. The importance
requirements
methionine
processes
methionine
stimulated
the
transferase 4.
have been described
to their function as substrates or potent inhibitors
for analogues
of
of the methionine
adenosyl transferase reaction 5 .These results led us to consider that analogues of L-methionine
1
and 2 bearing an epithio function could be good candidates as “active site directed inhibitors” of S-adenosyl transferase..
The route selected
for the enantioselective
availibility
of (S)-tram and (S)-cis enantiomerically
the known
high stereoselectivity
synthesis
of 1 and 2 is based on the ready
pure crotylglycines
of halolactonization
of suitably
and takes advantage
protected
of
y, b-unsaturated
amino acids. (S)sis and (S)-frans crotylglycines
were prepared from the bislactim ether 3 of cycle (D-Val-
Gly) according to the method described by Schollkopf 6 (Scheme I).
5047
0CH3 1. n E3uLL 2
=
3
CH+r
80%
3.H2/Lindlar/CH30H
6
7
80%
4. Ba(OHj2
Scheme I Alklylation in three steps.
of 3 with (E) 1-bromo-Z-butene N-protected
bromo-2-butyne
giving
compound
(trans/ cis = 16/ 1). 6 was converted N-Boc (S)-crotylglycines iodolactones
gave a unique
(S)-cis crotylglycine
compound
was best prepared
6 easily separated
4 which led to acid 5
by alkylation
from a minor
amount
into acid 7 in four steps by classical methods
5 and 7 were submitted
to iodolactonization
of 3 with l-
of the cis isomer 7. (12 ,TI-IF) leading
to
8 (2S, 4S, 5R) [aIzP D = -16.8” (c = 6, CHCl3), mp = 117”-118°C and 9 (2S, 4S, 55) [al’,” =
+49-B” (c = 4, CHCW, mp= 130-131°C
respectively
as major products 8. NHBoc
NHBoc H$_d
&e
COOH
5
o&&L,, 0
85%
8
NHBoc NHBoc H$+-,
&
COOH
7
om’“3 9
80% Scheme
The cis stereochemistry experiments,
corroborating
Ohfume
concerning
C5 was
assigned
for lactones 8 and 9 was assigned the recent
halolactonization on the basis
considerations. The direct synthesis
II
results
of episulfides
of G.M. Whitesides
of 2-amino-4-pentenoic
of the results
by IH NMR analysis
of this author
and NOE
9 and the conclusions
of Y.
acids 10. The stereochemistry
at
10 and also by mechanistic
1 and 2 was then accomplished
as shown in scheme III :
5049
75%
50%
63% 12
10
8
NHBoc
NHBoc
62%
9
11
13
Scheme III 8 and 9 were stereoselectively
transformed
= - 12.4” (c = 2.88, CHC13) 11. Then, opening
CHCl$ and 11 [a{; carbonate
in methanol
episulfides
according
conversion
of epoxides
Thus thiocyanates
allowed
similar
into episulfides
and final purification
overall
yield
from
by Bordwell
by reaction with thiocyanate episulfides
or thiourea
the the
13.
14 which
on HP 20 SS resin led to episulfides
N-Boc (S)-truns-crotylglycine
into
concerning
12 (2S, 4% 55) [al’,” = -22.2” (c =
= + 107.3” (c = 1.94, CHCb)
= + 48” (c = 0.6, H20) I5 .Episulfides
O.lN) and 2 [c&f
of the thiocyanates
to one proposed
10 and 11 gave respectively
= + 61.15” (c=3.1,
10 [IX];
of the lactone ring using sodium
a “one pot” transformation
to a mechanism**
1.8, CHC13) and 13 ( 2S, 4R, 5R) [a]K deprotection
into thiocyanates
1 [cI]~
1 and 2 were obtained
and 15 % overall
yield
after
classical
= + 8.4” (c=l, HCl respectively
in 20 %
from N-Boc (S)-cis-
crotylglycine. Biological
activity of these compounds
will be reported
elsewhere.
REFERENCES AND FOOTNDTES 1.
C.J. Abshire,
2.
(a) J.R. Sufrin, Anticancer
R. Pineau. Can. J. Biochem. 451637 (1%7). J.B. Lombardini.
Mol. Pharmacol.
22 752 (1982). (b) R.M.
Res. 5 1 (1985). (c) J.R. Sufrin, J.B. Lombardini,
Bernacki,
C. Porter.
Borchardt,
C.R. Craveling,
In Biological
Methylation
and
P.M. Ueland, eds) Humana
3.
G.L. Cantoni. J. Biol. Chem 204 403 (1953).
4.
J.B Lombardini,
P. Talalay Advances
Drug
Design
Clifton, N.J..
in Enzyme regulation
Hoffman
D.L. Kramer, Vitauts Alks, R.S.
9 349(1971).
373-84,
1985 (R.T.
5.
(a) A.W. Coulter, J.B. Lombardini, Lombardini.
Biochemistry
R.T. Borchardt, 6.
of S-Adenosyl
C.R. Creveling,
K.H. Pospischil,
Westphalen,
Methionine
(1974). (b) J.R. Sufrin, J.B.
and related
Compounds
(E. Usdin,
eds 687-690 1982 Mac Millan Pres. London.
U. Groth, C. Deng. Angew Chem. Int. Ed 20 798 (1981) ; U. Schr)llkopf, W.
U. Schiillkopf, Hartwig,
P. Talalay. Mol. Pharm. Q293
H. Kehne. Synthesis
C. Deng. Synthesis
966 (1981) ; U. Schollkopf,
969 (1981). U. Sch6llkopf,
U. Groth, K.O.
H.J. Neubauer.
Synthesis
861
(1982). 7.
Compounds relation
4 and 6 exibit a ~JHz-H~ of respectively
between
HZ and H5 in the bislactim
3.36 Hz and 3.25 Hz, typical of the trans
ether system.
5 JH~+I~ = 15.25 Hz ; 7 JI-&H~= 10.9 Hz. 8.
8 MS (DCI/NH3)356
(MH)+ >H NMR, sppm, CD@
12.5,9.7 Hz; 1.98,3H, d, J = 6.5 Hz ; 3.05, Hh, 5.10 N-H. 9 MS (DCI/NI-+)
: 1.42,9H,
s ;
1.87, H3& ddd, J = 12.5,
m ; 4.15, W, I-Q and I-&,m ; 4.40, lH, Ha m ;
356 (MH)+ >H NMR, bppm, CD@ : 1.40,9H, s ; 1.92,3H, d, J = 6.5 Hz and
H3~;2.90,Hbm;
4.25,2H,HqandH5,m;4.5O,H~m;5.20N-H.
9
H.K. Chenault,
10.
Y. Ohfume,
11.
10 MS (DCI/NI-I$287
J. Dahmer, G.M. Whitesides,
K. Hori, M. Sakaitani, Tetrahedron
J. Am. Chem. Sot. 1116354 (1989). Lett 22 6079 (1986).
(MH)+ >H NMR, bppm, CDC13 : 1.40,9H, s ; 1.60,3H, d, J = 7 Hz ;
2.07,1H,ddd,J=12,12,10.5Hz;2.~,lH,m;3.45dq,J=7Hz,7Hz;948,H~and~,m;5.30 N-H. 11 MS (DCI/NH3)287
(MH)+ >H NMR, 6ppm, CDQ
: 1.45,9H, s ; 1.68,3H,
d, J = 7H.z ;
2.12, lH, ddd, J = 12,12,10.5 Hz ; 2.%, lH, m ; 3.40, lH, dq, J = 7 Hz, 7Hz ; 4.45, H2 and I-&m ; 5.20 N-H. 12.
JH~_H~ observed assigned
: 7.05 Hz (12) and 5.48 Hz (13) are in accord with cis and trans
values
episulfide
structures.
13.
F.G. Bordwell
and H.M. Andersen
14.
12 J@ (DCI/NH3)287
J. Am. Chem. Sot. 75 4959 (1953).
(MH)+. IH NMR, bppm, CD@ : 1.40,9H, s ; 1.47,3H, d, J = 5.8 Hz ;
1.85, lH, m ; 2.35, lH, m ; 2.89, lH, m ; 2.95, lH, m ; 3.70,3H, s ; 4.45, lH, m ; 5.25 N-H. 13 MS (DCI/NH3)287
(MH)+ >H NMR, 8ppm, CDC13 : 1.46,9H, s ; 1.50,3H, d, J = 5.48 Hz ;
1.9, lH, m ; 2.3, lH, m ; 2.56, lH, m ; 2.62 dq J = 5.48 Hz ,548 Hz; 3.75,3H, s ; 4.47 ; lH, m ;5.3 15.
N-H. 1 lHNMR,bppm,D20:
150,3H,d,
J=5.85Hz;1.99,1H,m;2.56,1H,m;3.18,2H,m;3.90,
lH,t, J = 6.65 Hz. 2 1HNMR,
6ppm,D20:
1.41,3H,d,
4.09, lH, dd, J = 6.25,8.75 Hz.
(Received in France 21 May 1992)
J=7.05Hz;2.42,2H,m;3.18,1H,m;3.60,1H,m;