Synthesis of orthogonally protected (R)-and (S)-2-methylcysteine via an enzymatic desymmeterization and curtius rearrangement

Article abstract of DOI:10.1021/jo034170g

A synthesis of differentially protected (R)- and (S)-2-methylcysteines is described. Monomethylation of dimethylmalonate followed by alkylation with tert-butylchloromethyl sulfide gave an achiral diester. Desymmeterization by selective hydrolysis of one e

Full text of DOI:10.1021/jo034170g

Syn th esis of Or th ogon a lly P r otected (R)-
a n d (S)-2-Meth ylcystein e via a n En zym a tic
Desym m eter iza tion a n d Cu r tiu s
Rea r r a n gem en t
Brant L. Kedrowski*
F IGURE 1.
Department of Chemistry, University of
Wisconsin-Oshkosh, 800 Algoma Blvd.,
Oshkosh, Wisconsin 54901
SCHEME 1. P r otected (R)-2-Meth ylcystein ea
kedrowsk@uwosh.edu
Received February 6, 2003
Abstr a ct: A synthesis of differentially protected (R)- and
(S)-2-methylcysteines is described. Monomethylation of di-
methylmalonate followed by alkylation with tert-butylchloro-
methyl sulfide gave an achiral diester. Desymmeterization
by selective hydrolysis of one ester with pig-liver esterase
gave the acid in 97% chemical yield and 91% enantiomeric
excess. Heating this acid with diphenylphosphoryl azide
followed by 4-methoxybenzyl alcohol gave protected (R)-2-
methylcysteine. Alternately, the acid and ester groups were
interchanged and heated with diphenylphosphoryl azide
followed by 4-methoxybenzyl alcohol, giving protected (S)-
2-methylcysteine.
a
Reagents and conditions: (a) LHMDS, t-BuSCH2Cl, THF, 20
h; (b) PLE, pH 7.2 phosphate buffer, 2 N NaOH, 8 h; (c) (i)
diphenylphosphoryl azide (DPPA), Et3N, (CH2Cl)2, reflux, 100 min;
(ii) PMBOH, reflux, 4 h; (d) 10% TFA/CH2Cl2.
The amino acid 2-methylcysteine (1) occurs naturally
in both (R)- and (S)-stereochemical configurations. It is
present in the thiazoline rings (2) of a number of natural
products including mirabazoles A-C,1a,b tantazoles A-F,1b,c
thiangazole,1d,e thiazohalostatin,1f,g yersiniabactin,1h and
4-methylaeruginoic acid.1i
The key to any synthesis of 2-methylcysteine is control
of stereochemistry at the tetrasubstituted R-carbon. A
number of different synthetic strategies have been re-
ported that address this issue. The first reported syn-
thesis of 2-methylcysteine uses valine as a chiral auxil-
iary to direct the thiomethylation of an alanine derivative
at its R-position.2 Two other methods utilize strategies
based on the principles of self-regeneration of stereo-
centers3 to stereoselectively thiomethylate an alanine
derivative4 and methylate a cysteine derivative5 at their
R-positions, respectively. The forth method accesses
2-methylcysteine by nucleophilic opening of the â-lactone
derived from (R)- or (S)-N-(t-Boc)-2-methylserine with a
thiolate nucleophile.6a,b Finally, 2-methylcysteine has
been synthesized from 2-methylglycidol, by way of
2-methylserine.7a,b With the exception of the methods
reported by Fukuyama and Goodman,6a,b all of these
methods utilize starting materials from the chiral
pool.
Our synthetic efforts toward the tantazoles and mira-
bazoles required significant quantities of both enanti-
omers of 2-methylcysteine, with orthogonal protection of
all functionalities. Furthermore, we wanted a method
that was as short as possible and utilized inexpensive
starting materials to facilitate large-scale preparations.
Therefore, we developed the synthesis of 2-methyl-
cysteine described in Scheme 1.
Dimethyl malonate was monomethylated by a litera-
ture procedure8 to give dimethyl 2-methylmalonate (3).
This compound was then deprotonated with lithium bis-
(trimethylsilyl)amide (LHMDS) in THF and alkylated
with tert-butylchloromethyl sulfide9 to give achiral diester
4.
* Address correspondence to this author. Phone: 920 424-3488.
Fax: 920 424-2042.
(1) (a) Carmeli, S.; Moore, R. E.; Patterson, G. M. L. Tetrahedron
Lett. 1991, 32, 2593. (b) Carmeli, S.; Paik, S.; Moore, R. E.; Patterson,
G. M. L.; Yoshida, W. Y. Tetrahedron Lett. 1993, 34, 6681. (c) Carmeli,
S.; Moore, R. E.; Patterson, G. M. L.; Corbett, T. H.; Valoriote, F. A. J .
Am. Chem. Soc. 1990, 112, 8195. (d) J ansen, R.; Kunze, B.; Reichen-
bach, H.; J urkiewicz, E.; Hunsmann, G.; Ho¨fle, G. Liebigs Ann. Chem.
1992, 357. (e) J ansen, R.; Schomburg, D.; Ho¨fle, G. Liebigs Ann. Chem.
1993, 701. (f) Yamagishi, Y.; Matsuoka, M.; Odagawa, A.; Kato, S.;
Shindo, K.; Mochizuki, J . J . Antibiot. 1993, 46, 1633. (g) Shindo, K.;
Yamagishi, Y.; Kawai, H. J . Antibiot. 1993, 46, 1638. (h) Drechsel, H.;
Stephan, H.; Lotz, R.; Haag, H.; Zaehner, H. Liebigs Ann. Org. Bioorg.
Chem. 1995, 10, 1727. (i) Ryoo, I.; Song, K.; Kim, J .; Kim, W.; Koshino,
H.; Yoo, I. J . Antibiot. 1997, 50, 256.
(4) (a) Karady, S.; Amato, J . S.; Weinstock, L. M. Tetrahedron Lett.
1984, 25, 4337. (b) Walker, M. A.; Heathcock, C. H. J . Org. Chem. 1992,
57, 5566.
(5) Mulqueen, G. C.; Pattenden, G.; Whiting, D. A. Tetrahedron
1993, 49, 5359.
(6) (a) Fukuyama, T.; Xu, L. J . Am. Chem. Soc. 1993, 115, 8449. (b)
Smith, N. D.; Goodman, M. Org. Lett. 2003, 5, 1035.
(7) (a) Shao, H.; Zhu, Q.; Goodman, M. J . Org. Chem. 1995, 60, 790.
(b) Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett. 1995,
36, 3639.
(8) Hosokawa, T.; Yamanaka, T.; Itotani, M.; Murahashi, S. J . Org.
Chem. 1995, 60, 6159.
(2) Groth, U.; Scho¨llkopf, U. Synthesis 1983, 1, 37.
(3) For a review see: Seebach, D.; Sting, A. R.; Hoffmann, M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2708.
(9) Beight, D. W.; Mehdi, S.; Koehl, J . R.; Flynn, G. A. Bioorg. Med.
Chem. Lett. 1996, 6, 2053.
10.1021/jo034170g CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/23/2003
J . Org. Chem. 2003, 68, 5403-5406
5403

SCHEME 2. P r otected (S)-2-Meth ylcystein ea
The next step involved an enzymatic hydrolysis of one
ester of 4 with pig-liver esterase (PLE). Compound 4 was
treated with PLE in a pH 7.2 phosphate buffer, with
rapid stirring. The PLE was used as supplied [EC 3.1.1.1,
pH 8 suspension in 3.2 M (NH4)2SO4], at a loading level
of 90 units per mmol of substrate. This enzyme level was
selected because it gave convenient reaction times;
however, lower loading levels also seem feasible. The
acidity of the mixture was monitored throughout the
reaction, and 2 N NaOH solution was added dropwise
as needed to maintain a constant pH of 7.2. The reaction
started off as biphasic, but became nearly homogeneous
near the end. The reaction’s end point could be estimated
by monitoring the amount of NaOH consumed, and by
the rate of pH change. After 1 equiv of NaOH had been
consumed, the rate of pH change slowed dramatically,
indicating a nearly complete reaction. The acid (5) was
isolated by extraction as a white solid.
a
Reagents and conditions: (a) t-BuOH, H2SO4, MgSO4, CH2Cl2,
24 h; (b) LiOH, H2O, THF, (n-Bu)4NHSO4; (c) (i) DPPA, Et3N,
(CH2Cl)2, reflux, 100 min; (ii) PMBOH, reflux, 4 h.
form.2,11 The magnitude of the reported optical rotation
of ent-7 compares very favorably with that of 7 obtained
in this study, and is opposite in sign.12
To determine the optical purity of 5, a salt with (S)-
R-methylbenzylamine was formed and analyzed by H
The conversion of acid 5 into protected (S)-2-methyl-
cysteine involves swapping the ester and acid function-
alities, followed by a Curtius rearrangement. In Scheme
2 the acid 5 was converted into ester 8 by treatment with
acid adsorbed on magnesium sulfate and tert-butyl
alcohol.13 Saponification of the methyl ester with lithium
hydroxide gave acid 9. Finally, 9 was subjected to the
Curtius rearrangement conditions used previously, and
gave protected (S)-2-methylcysteine (10) in 92% yield.
1
NMR. For comparison, racemic 5 was synthesized from
4 by saponification with lithium hydroxide. The resulting
racemic acid was treated with 1 equiv of (S)-R-methyl-
benzylamine and analyzed by 1H NMR. The resulting
diastereomeric salts contained several well-resolved peaks,
including methyl ester peaks at 3.58 and 3.56 ppm.
Through integration of these peaks, the ratio of enanti-
omers obtained in the PLE reaction was determined to
be 96% in favor of (R)-2-methylcysteine, for an enantio-
meric excess (ee) of 91%.
There are several literature accounts of 2,2-disubsti-
tuted malonate diesters being selectively hydrolyzed by
PLE.6a,10a,b The selectivity of the reaction reportedly
depends greatly on substrate substitution. The most
favorable results are obtained when the malonate di-
esters contain a methyl group in the 2-position and the
other 2-substituent is bulky. Such substrates are reported
to favor formation of the (R)-enantiomer, which was also
observed in this study. It has also been reported that
using DMSO as a cosolvent can help improve selectivity
in some reactions with PLE. However, with 4 a decline
in both chemical and optical yields was observed with
use of a 5% DMSO cosolvent.
The acid 5 was next treated with diphenylphosphoryl
azide and triethylamine in 1,2-dichloroethane, which
resulted in rapid formation of an acyl azide (not iso-
lated). Refluxing this solution promoted a Curtius re-
arrangement to the corresponding isocyanate (not iso-
lated), which was treated with p-methoxybenzyl alcohol
(PMBOH) to give 6. These reactions resulted in retention
of configuration to give protected (R)-2-methylcysteine.
The sequence was carried out without predrying of
solvents and reagents. The choice of alcohol (PMBOH)
used in this reaction was based on the ease with which
the resulting carbamate is cleaved with mild acid. Other
alcohols could potentially be used, which would alter the
properties of the resulting nitrogen protecting group.
To confirm the absolute stereochemistry of 6, and to
check its optical purity, it was converted to compound 7.
The enantiomer of 7 (ent-7) is known in optically pure
In summary, we have developed syntheses of orthogo-
nally protected (R)- and (S)-2-methylcysteine from di-
methyl malonate that proceed in four steps and six steps,
respectively. Key steps in this sequence include an
enzymatic desymmeterization of an achiral malonate
diester and a Curtius rearrangement to selectively form
the carbon-nitrogen bond. This new method is amenable
to large-scale preparations and should prove useful in
future syntheses of 2-methylcysteine-containing com-
pounds.
Exp er im en ta l Section
Dim eth yl 2-ter t-Bu tylsu lfa n ylm eth yl-2-m eth ylm a lon a te
(4). A 1 M solution of LHMDS in THF (95.4 mL, 95.4 mmol)
was cooled to 0 °C under an atmosphere of N2. A solution of
dimethyl 2-methylmalonate (13.94 g, 95.40 mmol) in THF (28
mL) was added over 5 min, with stirring. After an additional
15 min, tert-butylchloromethyl sulfide (14.55 g, 104.9 mmol, 1.1
equiv) was added dropwise over 5 min, with stirring. The cooling
bath was removed and the solution was stirred at room tem-
perature for 20 h. The solution was then diluted with ether (330
mL), washed twice with 1 N HCl, washed with brine, dried over
MgSO4, and filtered, and the solvents were evaporated under
vacuum. The resulting liquid was vacuum distilled (74-80 °C,
0.26 Torr), giving the clear colorless liquid product (18.12 g,
76%): TLC Rf 0.35 (4:1 hexane/Et2O); IR (NaCl, cm-1) 2957,
1739, 1459, 1290, 1238, 1172, 1110; 1H NMR (CDCl3, δ ppm)
3.74 (s, 6 H), 3.04 (s, 2 H), 1.50 (s, 3 H), 1.31 (s, 9 H); 13C NMR
(CDCl3, δ ppm) 171.5, 54.0, 52.6, 42.3, 33.5, 30.6, 19.8; FAB
LRMS m/z (M + H) 249. Anal. Calcd for C11H20O4S: C, 53.20;
H, 8.12; S, 12.91. Found: C, 53.34; H, 8.44; S, 13.12.
(11) The authors synthesized the compound in (S)-form but mis-
takenly refer to it as (R).
(12) For 7 obtained in this study [R]25D +19.6 (c 1.00, EtOH), purity
91% ee. Reported value for ent-7 [R]20 -16.3 (c 1.00, EtOH), reported
D
(10) (a) Luyten, M.; Mu¨ller, S.; Herzog, B.; Keese, R. Helv. Chim.
Acta 1987, 70, 1250. (b) Zhu, L.; Tedford, M. C. Tetrahedron 1990, 46,
6587.
purity >95% ee.2
(13) Wright, S. W.; Hageman, D. L.; Wright A. S.; McClure, L. D.
Tetrahedron Lett. 1997, 38, 7345.
5404 J . Org. Chem., Vol. 68, No. 13, 2003

(R)-2-ter t-Bu t ylsu lfa n ylm et h yl-2-m et h ylm a lon ic Acid
Mon om eth yl Ester (5). Diester 4 (17.74 g, 71.43 mmol) was
mixed with 0.1 N NaH2PO4 solution (713 mL) and adjusted to
pH 7.2 with 2 N NaOH. Pig-liver esterase [EC 3.1.1.1, 1.8 mL
of a suspension in 3.2 M (NH4)2SO4, 6430 units] was added, and
the heterogeneous mixture was stirred rapidly. The pH was
maintained between 7 and 7.2 by addition of 2 N NaOH, with
stirring. After 8 h the reaction had consumed 1 molar equiv of
NaOH and the pH change slowed dramatically. The reaction was
worked up by addition of 2 N NaOH to reach pH 9, and the
mixture was washed once with ether. The pH was then adjusted
to 2 by addition of 2 N HCl, and the mixture was extracted with
ether three times. The combined extracts were washed with
brine, dried over MgSO4, and filtered, and the ether was removed
under vacuum to give the product as a clear colorless oil that
crystallized (16.26 g, 97%, 91% ee): TLC Rf 0.26 (16:4:1 hexane/
Et2O/AcOH); mp 43-45 °C; [R]26D -1.0 (c 1.00, CHCl3); IR (NaCl,
cm-1) 3100 (br), 2961, 1738, 1723, 1460, 1292, 1239, 1206, 1164,
1114; 1H NMR (CDCl3, δ ppm) 3.78 (s, 3 H), 3.08 (d, J ) 12.0
Hz, 1 H), 3.02 (d, J ) 12.0 Hz, 1 H), 1.54 (s, 3 H), 1.32 (s, 9 H);
1H NMR as the salt of (S)-R-methylbenzylamine (CDCl3, δ ppm)
7.42-7.29 (m, 5 H), 6.69 (br s, 3 H), 4.30 (m, 1 H), 3.58 (s,
-OCH3, major S,R-diastereomeric salt, 3 H), 3.56 (s, -OCH3,
minor S,S-diastereomeric salt, 4% the intensity of the major
isomer), 2.99 (d, J ) 11.6 Hz, 1 H), 2.79 (d, J ) 11.6 Hz, 1 H),
1.57 (d, J ) 6.8 Hz, 3 H), 1.27 (apparent s, 12 H); 13C NMR
(CDCl3, δ ppm) 176.6, 171.3, 54.1, 52.8, 42.4, 33.3, 30.5, 19.8;
FAB LRMS m/z (M + H) 235, (M - isobutene) 179. Anal. Calcd
for C10H18O4S: C, 51.26; H, 7.74; S, 13.69. Found: C, 51.24; H,
7.77; S, 13.53.
(()-2-ter t-Bu t ylsu lfa n ylm et h yl-2-m et h ylm a lon ic Acid
Mon om eth yl Ester (5). Diester 4 (53.0 mg, 0.213 mmol) was
mixed with MeOH (0.25 mL) and 2 N NaOH (0.12 mL), and the
solution was stirred for 4 h at 40 °C. MeOH was evaporated and
the aqueous layer was acidified to pH e2 with 2 N HCl and
extracted three times with ether. The combined extracts were
washed with brine, dried over MgSO4, and filtered, and the ether
was removed by rotovapping. The product was purified by flash
chromatography (75:25:2 hexane/EtOAc/AcOH), giving the pure
racemic product as a clear colorless oil (38.0 mg, 76%): 1H NMR
as a 1:1 mixture of diastereomeric salts of (S)-R-methylbenzyl-
amine (CDCl3, δ ppm) 7.42-7.28 (m, 10 H), 6.47 (br s, 6 H), 4.30
(m, 2 H), 3.58 (s, 3 H, -OCH3, S,R-diastereomeric salt), 3.56 (s,
3 H, -OCH3, S,S-salt), 2.99 (d, J ) 11.6 Hz, 1 H, S,R-salt), 2.96
(d, J ) 12.0 Hz, 1 H, S,S-salt), 2.79 (d, J ) 11.6 Hz, 1 H, S,R-
salt), 2.76 (d, J ) 12.0 Hz, 1 H, S,S-salt), 1.57 (d, J ) 6.8 Hz, 6
H), 1.27 (apparent s, 21 H), 1.24 (s, 3H).
complete. Addition of H2O (3 mL), with stirring, discharged the
color. The CH2Cl2 was evaporated, and the remaining aqueous
layer was washed once with hexane. The aqueous layer was
decanted from
a sticky residue and treated with aqueous
ammonia to pH 9. The mixture was extracted twice with CH2Cl2,
and the combined extracts dried over Na2SO4 and filtered. The
solution was rotovapped, and the resulting liquid was purified
by flash chromatography (1:1 hexane/EtOAc), giving the product
as a clear colorless liquid (82.7 mg, 72%): [R]25 +19.6 (c 1.00,
D
EtOH); IR (NaCl, cm-1) 3372, 2962, 1738, 1459, 1198, 1161,
1097; 1H NMR (CDCl3, δ ppm) 3.67 (s, 3H), 2.91 (d, J ) 12.0
Hz, 1 H), 2.63 (d, J ) 12.0 Hz, 1 H), 1.87 (br s, 2H), 1.34 (s, 3
H), 1.25 (s, 9 H); 13C NMR (CDCl3, δ ppm) 176.6, 57.8, 52.2, 42.1,
38.7, 30.7, 26.4; FAB LRMS m/z (M + H) 206.2. Anal. Calcd for
C9H19NO2S: C, 52.65; H, 9.33; N, 6.82; S, 15.62. Found: C, 52.33;
H, 9.61; N, 6.59; S, 15.40.
(S)-ter t-Bu t yl Met h yl 2-ter t-Bu t ylsu lfa n ylm et h yl-2-
m eth ylm a lon a te (8). Concentrated H2SO4 (0.203 mL, 3.62
mmol) was added dropwise to a stirred suspension of anhydrous
MgSO4 (1.75 g, 14.50 mmol) and CH2Cl2 (14 mL). This resulted
in some solid clumping, which was broken up mechanically, and
stirring was continued for 15 min. A solution of acid 5 (0.849 g,
3.62 mmol) in CH2Cl2 (4.2 mL) and then t-BuOH (1.74 mL, 18.1
mmol) were added dropwise, with stirring. The flask was tightly
stopped and the reaction mixture was stirred for 24 h. The
mixture was vacuum filtered, and the MgSO4 was rinsed with
CH2Cl2. The filtrate was then washed with saturated aqueous
NaHCO3 and brine, dried over MgSO4, filtered, and rotovapped
to a liquid. Purification by bulb-to-bulb distillation (∼100 °C,
0.3 Torr) gave 8 as a clear colorless liquid (0.7711 g, 73%): TLC
Rf 0.57 (6:1 hexane/Et2O); [R]25D -7.6 (c 1.00, CHCl3); IR (NaCl,
cm-1) 2974, 1733, 1368, 1293, 1245, 1159, 1111; 1H NMR (CDCl3,
δ ppm) 3.70 (s, 3 H), 2.98 (d, J ) 12.0 Hz, 1 H), 2.95 (d, J ) 12.0
Hz, 1 H), 1.42 (s, 12 H), 1.28 (s, 9 H); 13C NMR (CDCl3, δ ppm)
171.9, 170.0, 81.8, 54.5, 52.3, 42.0, 33.3, 30.6, 27.7, 19.6; EI
LRMS m/z (M+) 290, (M - isobutene) 234, (M - 2 isobutenes)
178. Anal. Calcd for C14H26O4S: C, 57.90; H, 9.02; S, 11.04.
Found: C, 57.78; H, 9.14; S, 11.25.
(S)-2-ter t-Bu t ylsu lfa n ylm et h yl-2-m et h ylm a lon ic Acid
Mon o-ter t-bu tyl Ester (9). Diester 8 (0.548 g, 1.89 mmol) was
dissolved in THF (9.5 mL) and H2O (2.4 mL) was added, followed
by LiOH‚H2O (0.158 g, 3.78 mmol). The mixture was stirred for
20 h, and tetra-n-butylammonium hydrogensulfate (3.2 mg,
0.0094 mmol, 0.5 mol %) was then added. After another 28 h of
stirring at room temperature, the reaction was complete. THF
was evaporated, and the reaction was diluted with water and
acidified to pH 3 with 2 N HCl. The mixture was extracted three
times with ether, and the combined extracts were washed with
brine, dried over MgSO4, and filtered. Rotary evaporation gave
the product as a clear colorless oil that crystallized (0.453 g,
(R )-N -4-Me t h o x y b e n zy lo x y c a r b o n y l-S -t er t -b u t y l-2-
m eth ylcystein e Meth yl Ester (6). Acid 5 (0.748 g, 3.19
mmol) was dissolved in 1,2-dichloroethane (5.5 mL) and Et3N
(738 µL, 5.30 mmol) was added followed by diphenylphosphoryl
azide (700 µL, 3.25 mmol), with stirring. After 15 min at room
temperature the solution was heated at reflux for 100 min, after
which it was converted completely to the isocyanate by TLC.
Next, liquefied p-methoxybenzyl alcohol (660 µL, 5.30 mmol) was
added and refluxing was resumed for 4 h. The solution was
concentrated giving a yellow oil, which was purified directly by
flash chromatography (6:1 hexane/EtOAc). This gave the product
as a clear colorless oil (1.03 g, 87%): TLC Rf 0.10 (4:1 hexane/
87%): mp 58-59 °C; [R]25D -4.4 (c 1.00, CHCl3); IR (NaCl, cm-1
)
3252, 2974, 1736, 1710, 1368, 1158; 1H NMR (CDCl3, δ ppm)
8.95 (br s, 1 H), 2.94 (d, J ) 12.0 Hz, 1 H), 2.90 (d, J ) 12.0 Hz,
1 H), 1.39 (s, 3 H), 1.38 (s, 9 H), 1.23 (s, 9 H); 13C NMR (CDCl3,
δ ppm) 177.0, 169.8, 82.2, 54.4, 42.0, 33.2, 30.5, 27.7, 19.6; FAB
LRMS m/z (M+) 276.1.
(S )-N -4-Me t h o x y b e n zy lo x y c a r b o n y l-S -t er t -b u t y l-2-
m eth ylcystein e ter t-Bu tyl Ester (10). Acid 9 (0.374 g, 1.35
mmol) was dissolved in 1,2-dichloroethane (2.7 mL) and Et3N
(369 mL, 2.71 mmol) was added followed by diphenylphosphoryl
azide (350 mL, 2.706 mmol), with stirring. After 15 min at room
temperature the solution was heated at reflux for 100 min, after
which it was converted completely to the isocyanate by TLC.
Next liquefied p-methoxybenzyl alcohol (337 mL, 2.71 mmol) was
added and refluxing was resumed for 4 h. The solvent was
evaporated giving a yellow oil, which was purified by flash
chromatography (6:1 hexane/EtOAc). This gave the product as
an oil, which crystallized upon standing. Recrystallization from
hexane gave the product as fine white needles (0.512 g, 92%):
Et2O); [R]26 +5.3 (c 1.00, CHCl3); IR (NaCl, cm-1) 3362, 2958,
D
1739, 1724, 1515, 1304, 1247, 1176, 1054; 1H NMR (CDCl3, δ
ppm) 7.30 (AA′XX′ pattern, J ) 8.8 Hz, 2 H), 6.89 (AA′XX′
pattern, J ) 8.8 Hz, 2 H), 5.73 (br s, 1 H), 5.02 (s, 2 H), 3.81 (s,
3 H), 3.77 (br s, 3 H), 3.31 (br d, J ) 12.0 Hz, 1 H), 3.01 (d, J )
12.0 Hz, 1 H), 1.64 (s, 3 H), 1.27 (s, 9 H); 13C NMR (CDCl3, δ
ppm) 173.4, 159.4, 154.6, 129.8, 128.4, 113.8, 66.3, 59.6, 55.2,
52.7, 42.2, 34.8, 30.7, 23.4; FAB LRMS m/z (M + H) 370, (M -
PMB) 248, (PMB) 121. Anal. Calcd for C18H27NO5S: C, 58.51;
H, 7.37; N, 3.79; S, 8.68. Found: C, 58.76; H, 7.43; N, 3.51; S,
8.92.
TLC Rf 0.32 (6:1 hexane/EtOAc); mp 78-79 °C; [R]24 +6.8 (c
D
(R)-S-ter t-Bu tyl-2-m eth ylcystein e Meth yl Ester (7). Car-
bamate 6 (0.206 g, 0.557 mmol) was dissolved in CH2Cl2 (5.0
mL), and TFA (0.56 mL) was added, with stirring. The solution
developed an intense purple color, and after 30 min was
1.00, CHCl3); IR (NaCl, cm-1, CDCl3) 2975, 1716, 1514, 1247;
1H NMR (CDCl3, δ ppm) 7.27 (AA′XX′ pattern, J ) 8.6 Hz, 2
H), 6.85 (AA′XX′ pattern, J ) 8.6 Hz, 2 H), 5.75 (br s, 1 H), 4.99
(s, 2 H), 3.80 (s, 3 H), 3.32 (br d, J ) 11.9 Hz, 1 H), 2.95 (d,
J . Org. Chem, Vol. 68, No. 13, 2003 5405

J ) 11.9 Hz, 1 H), 1.44 (s, 9 H), 1.25 (s, 9 H); 13C NMR (CDCl3,
δ ppm) 172.0, 159.5, 154.7, 129.9, 128.8, 113.9, 82.4, 66.2, 59.9,
55.3, 42.1, 34.8, 30.9, 27.9, 23.7.
Berkeley, for providing generous financial support and
facilities.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal conditions and 1H NMR data for all new compounds,
including spectra used for enantiomeric purity determinations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t . The author thanks the Na-
tional Institutes of Health (GM 46057) and the
College of Letters and Science, University of Wis-
consin, Oshkosh for funding this work and pro-
fessor Clayton H. Heathcock, University of California,
J O034170G
5406 J . Org. Chem., Vol. 68, No. 13, 2003