A new synthesis of α-amino acid thioesters by pummerer reaction of 3- substituted-4-sulfinyl-β-sultams

Article abstract of DOI:10.1021/jo981230n

α-Amino acid thioesters were synthesized by the Pummerer reaction of 3- substituted-4-sulfinyl-β-sultams with TFAA. The 3-substituted-4-sulfinyl- β-sultams were prepared from the corresponding β-sultams by sulfenylation with diphenyl disulfide followed by m-CPBA oxidation. Diastereoselective synthesis of β-sultams by 1,3-asymmetric induction in [2 + 2] cycloaddition of a sulfene intermediate and chiral imines in solution-phase was studied, and it was found that N-alkylimines gave better diastereoselectivities than N-aralkylimines. The use of imines derived from (R)- and (S)-α- methylbenzylamine followed by separation of the major and minor diastereomers gave enantiopure 3-substituted-N-methylbenzyl-β-sultams. These β-sultams were then converted to N-methylbenzyl-α-amino acid thioesters via sulfenylation and Pummerer rearrangement with high or complete retention of configuration.

Full text of DOI:10.1021/jo981230n

J . Org. Chem. 1998, 63, 8355-8360
8355
A New Syn th esis of r-Am in o Acid Th ioester s by P u m m er er
Rea ction of 3-Su bstitu ted -4-su lfin yl-â-su lta m s
Tetsuo Iwama,† Tadashi Kataoka,*,† Osamu Muraoka,‡ and Genzoh Tanabe‡
Gifu Pharmaceutical University, 6-1, Mitahora-higashi 5-chome, Gifu 502-8585, J apan, and
Kinki University, Faculty of Pharmaceutical Sciences, 3-4-1, Kowakae, Higashi-osaka,
Osaka 577-0818, J apan
Received J une 24, 1998
R-Amino acid thioesters were synthesized by the Pummerer reaction of 3-substituted-4-sulfinyl-
â-sultams with TFAA. The 3-substituted-4-sulfinyl-â-sultams were prepared from the corresponding
â-sultams by sulfenylation with diphenyl disulfide followed by m-CPBA oxidation. Diastereoselective
synthesis of â-sultams by 1,3-asymmetric induction in [2 + 2] cycloaddition of a sulfene intermediate
and chiral imines in solution-phase was studied, and it was found that N-alkylimines gave better
diastereoselectivities than N-aralkylimines. The use of imines derived from (R)- and (S)-R-
methylbenzylamine followed by separation of the major and minor diastereomers gave enantiopure
3-substituted-N-methylbenzyl-â-sultams. These â-sultams were then converted to N-methylbenzyl-
R-amino acid thioesters via sulfenylation and Pummerer rearrangement with high or complete
retention of configuration.
In tr od u ction
of optically active R-amino acid thioesters7 and examined
1,3-asymmetric induction in [2 + 2] cycloaddition of chiral
imines and a sulfene intermediate. Synthesis of â-sul-
tams using the [2 + 2] cycloaddition of imines and
sulfenes has been given scant attention2 since it was first
reported by Tsuge and Iwanami.8 Recently, Gordeev and
co-workers reported the first examples of diastereoselec-
tive solid-phase synthesis of â-sultams using chiral
imines and activated sulfenes.9 In this paper, we report
the synthesis of R-amino acid thioesters by the Pummerer
reaction of 3-substituted-4-sulfinyl-â-sultams and a pre-
liminary study on diastereoselective synthesis of â-sul-
tams in solution-phase.
â-Sultams, sulfonyl analogues of â-lactams, are unique
four-membered heterocycles containing three different
hetero single bonds, namely, C-N, C-S, and N-S.
Stabilization of the â-sultam ring by π-bond overlap
between the nitrogen lone-pair electrons and the sulfonyl
group is much less than comparable stabilization of the
â-lactam ring.1 In addition, â-sultams are destabilized
by the increased distortion of the â-sultam ring due to
the C-S and N-S bonds which are longer than the
corresponding C-C and C-N bonds of the â-lactam ring.
Therefore, â-sultams have been widely investigated from
both chemical and pharmacological points of view.2 In
previous papers we described the hetero bond cleavage
of the â-sultam ring.3 If the Pummerer reaction of
3-substituted-4-sulfinyl-â-sultams proceeds successfully,
it would become the new method for the C-S bond
cleavage of â-sultams and can be utilized for the synthe-
sis of R-amino acid thioesters. R-Amino acid thioesters
are activated esters4 utilized for peptide synthesis5 as
well as natural product synthesis as versatile intermedi-
ates.6 We intended to apply this method to the synthesis
Resu lts a n d Discu ssion
3-Substituted-4-sulfinyl-â-sultams 4A,B were synthe-
sized as shown in Scheme 1 (Table 1). â-Sultams
(5) For some recent papers, see (a) Sasaki, S.; Shinoya, M.; Koga,
K. J . Am. Chem. Soc. 1985, 107, 3371-3372. (b) Sasaki, S.; Koga, K.
Chem. Pharm. Bull. 1989, 37, 912-919. (c) Schno¨lzer, M.; Kent, S. B.
H. Science 1992, 256, 221-226. (d) Hojo, H.; Know, Y.; Kakuta, Y.;
Tsuda, S.; Tanaka, I.; Hikichi, K.; Aimoto, S. Bull. Chem. Soc. J pn.
1993, 66, 2700-2706. (e) Richter, L. S.; Tom, J . Y. K.; Burnier, J . P.
Tetrahedron Lett. 1994, 35, 5547-5550. (f) Dawson, P. E.; Muir, T.
W.; Clark-Lewis, I.; Kent, S. B. H. Science 1994, 266, 776-779. (g)
Tam, J . P.; Lu, Y. A.; Liu, C. f.; Shao, J . Proc. Natl. Acad. Sci. U.S.A.
1995, 92, 12485-12489. (h) Hojo, H.; Yoshimura, S.; Go, M.; Aimoto,
S. Bull. Chem. Soc. J pn. 1995, 68, 330-336. (i) Aimoto, S.; Hojo, H.;
Yoshimura, S.; Shimizu, N.; Asano, T.; Ikebe, M.; Kokui, T.; Crivici,
A.; Ikura, M. Pept. Chem. 1995, Volume Date 1994, 32nd, 197-200
[Chemical Abstract on CD-ROM, 125: 11415]. (j) Kawakami, T.;
Kogure, S.; Aimoto, S. Bull. Chem. Soc. J pn. 1996, 69, 3331-3338. (k)
Shao, Y.; Lu, W.; Kent, S. B. H. Tetrahedron Lett. 1998, 39, 3911-
3914.
(6) For some recent papers see (a) Fukuyama, T.; Lin, S. C.; Li, L.
J . Am. Chem. Soc. 1990, 112, 7050-7051. (b) Moss, W. O.; J ones, A.
C.; Wisedale, R.; Mahon, M. F.; Molloy, K. C.; Bradbury, R. H.; Hales,
N. J .; Gallagher, T. J . Chem. Soc., Perkin Trans. 1 1992, 2615-2624.
(c) Ho, P. T.; Ngu, K.-y. J . Org. Chem. 1993, 58, 2313-2316. (d)
J ackson, R. F. W.; Palmer, N. J .; Wythes, M. J .; Clegg, W.; Elsegood,
M. R. J . J . Org. Chem. 1995, 60, 6431-6440.
† Gifu Pharmaceutical University.
‡ Kinki University.
(1) Koller, W.; Linkies, A.; Rehling, H.; Reuschling, D. Tetrahedron
Lett. 1983, 24, 2131-2134.
(2) For reviews, see (a) Iwama, T.; Kataoka, T. Rev. Heteroatom
Chem. 1996, 15, 25-60. (b) Harris, P. A. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Elsevier Science Inc.: Oxford, 1996; Vol. I, p 1009. (c) Chanet-Ray, J .;
Vessiere, R. Org. Prep. Proced. Int. 1986, 18, 157-178. (d) Dittmer,
D. C.; Sedergran, T. C. In Small Ring Heterocycles; Hassner, A., Ed.;
J ohn Wiley and Sons: New York, 1985, Part 3, Chapter 5, pp 431-
768. (e) Timberlake, J . W.; Elder, E. S. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
New York, 1984; Vol. 7, pp 449-489.
(3) (a) Kataoka, T.; Iwama, T. Tetrahedron Lett. 1995, 36, 245-248.
(b) Kataoka, T.; Iwama, T. Tetrahedron Lett. 1995, 36, 5559-5562. (c)
Kataoka, T.; Iwama, T.; Takagi, A. Tetrahedron Lett. 1996, 37, 2257-
2260. (d) Iwama, T.; Takagi, A.; Kataoka, T. Chem. Pharm. Bull. 1998,
46, 757-766. (e) Iwama, T.; Kataoka, T.; Muraoka, O.; Tanabe, G.
Tetrahedron 1998, 54, 5507-5522.
(4) (a) Wieland, T.; Scha¨fer, W.; Bokelman, E. J ustus Liebigs Ann.
Chem. 1951, 573, 99-105. (b) Farrington, J . A.; Hextall, P. G.; Kenner,
G. W.; Turner, J . M. J . Chem. Soc. 1957, 1407-1413.
(7) Williams, R. M. In Synthesis of Optically Active R-Amino Acids;
Pergamon: New York, 1989.
(8) Tsuge, O.; Iwanami, S. Bull. Chem. Soc. J pn. 1970, 43, 3543-
3549.
(9) Gordeev, M. F.; Gordon, E. M.; Patel, D. V. J . Org. Chem. 1997,
62, 8177-8181.
10.1021/jo981230n CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

8356 J . Org. Chem., Vol. 63, No. 23, 1998
Iwama et al.
Sch em e 1
sulfoxide by the use of 4 equiv of TFAA. In the cases of
4c,f, steric hindrance of the tert-butyl group prevented
amidation of 7 with excess TFAA. Treatment of a
mixture of the four diastereomers 6A,B and 4d A,B also
provided 7d and 8d in 63% and 15% yields, respectively
(entry 11). In all cases, a trace amount of diphenyl
disulfide was isolated.
A proposed mechanism is shown in Scheme 3. The
alcohol 10 is produced by hydrolysis of a Pummerer
product 9 formed from 4 and TFAA. Water during
workup may cause the hydrolysis. The amide anion 11
is generated by the ring destruction of 10 with the C-S
(C-SO2) bond cleavage followed by elimination of sulfur
dioxide to give thioester 7. A small amount of 8 would
be obtained by amidation of 11 with excess TFAA.
Diphenyl disulfide is probably obtained by the C-S (C-
SPh) bond cleavage with the formation of a â-sultam-4-
one 12 although we could not isolate 12.
Thioesters are activated compounds of carboxylic acids,
and R-amino acid thioesters have been utilized for peptide
synthesis5 as well as natural product synthesis as ver-
satile intermediates.6 Therefore, enantioselective syn-
thesis of R-amino acid thioesters is necessary. 1,3-Asym-
metric induction was examined in [2 + 2] cycloaddition
of a sulfene intermediate and chiral imines 13, prepared
from the corresponding chiral amines and aldehydes
(Scheme 4, Table 3). The use of N-aralkylimines showed
moderate diastereoselectivity (entries 1-5), and that of
N-alkylimines showed good diastereoselectivity (entries
6-8). The best selectivity was given in the case of N-(1-
tert-butylethyl)imine (entry 8). The diastereoselectivity
would be dependent on the size and conformation of the
N-substituents in the imines. Reactions of imines bear-
ing an ether group resulted in the formation of a complex
mixture (entries 9 and 10). Diastereomers of compounds
14a -e bearing an N-aralkyl group were separable by
silica gel column chromatography.
The stereochemistry of the major isomers was deter-
mined by X-ray crystallographic analysis of 14h as a
representative (see Supporting Information). The rela-
tive configuration is syn-form as drawn in Scheme 5. The
stereoselectivity in the 1,3-asymmetric induction is ex-
plained as follows: a sulfene intermediate, generated
from mesyl chloride and an imine, reacts with another
imine 15, which is the most stable conformer by A1,3
strain,14 from the opposite face to the bulky tert-butyl
group to form a syn-isomer. Contribution of a less stable
conformer 16 to the formation of an anti-isomer would
be negligible. The stereochemistry of the major of 14a ,b
is deduced to be syn from this mechanism.
prepared by [2 + 2] cycloaddition of a sulfene and
imines3c,d,8 were treated with 3 equiv of LDA at -78 °C
in THF followed by 1 equiv of diphenyl disulfide at -78
°C for 1 h to give 3,4-trans-4-sulfenyl-â-sultams 2 as
major products accompanied by 3,4-cis-isomers 3.10 The
cis-isomers 3 were obtained as inseparable mixtures with
the starting materials 1 except for 3e.10 The use of 1
equiv of LDA generates a mixture of monoanion and
dianion of the â-sultams which makes reactions compli-
cated,11 and an excess amount of LDA is required for
formation of the sole dianion and for clean reactions. It
is necessary to quench reactions at -78 °C; for example,
when the reaction of 1f was quenched at room temper-
ature instead of at -78 °C, a ring-opened product 5 was
obtained in 67% yield as a major product together with
a trace amount of 2f (entry 7). Treatment of 3,4-trans-
4-sulfenyl-â-sultams 2 with m-CPBA in CH2Cl2 provided
3,4-trans-4-sulfinyl-â-sultams 4A,B as mixtures of ste-
reoisomers at the sulfoxide moiety. Oxidation of 3,4-cis-
isomer 3d containing 1d with m-CPBA gave a mixture
of four diastereomers, 3,4-trans-4-sulfinyl-â-sultams
4d A,d B and 3,4-cis-4-sulfinyl-â-sultams 6A,B, due to
isomerization of the latter to the former.12
The Pummerer reaction of 3,4-trans-4-sulfinyl-â-sul-
tams 4A,B with TFAA was examined (Scheme 2, Table
2). Treatment of 4a A with 1 equiv of TFAA in CH2Cl2
at room temperature for 12 h resulted in the recovery of
the sulfoxide (entry 1).13 A reaction of 4a A with 2 equiv
of TFAA for 24 h gave an R-amino acid thioester 7a and
its amido derivative 8a in low yields (entry 2).13 Thioesters
7 were obtained in good yields accompanied with amides
8 except for 8c,f regardless of the configuration of the
We applied this thioester synthesis to chiral â-sultams
prepared by 1,3-asymmetric induction described above
(Scheme 6). Sulfoxides 19 and 23 were prepared by
sulfenylation of 14 followed by m-CPBA oxidation of
trans-isomers 17 and 21, respectively. The sulfoxides
19A,B and 23A,B were obtained as two separable ste-
reoisomers at sulfoxide group (alphabets A and B mean
stereoisomers at sulfoxide moiety). Treatment of 19 and
23 with 4 equiv of TFAA gave chiral R-amino acid
thioesters 20 and 24, respectively, in high yields. Slight
epimerization of the R-chiral center of R-phenyl thioesters
20a and 24a was observed under the reaction conditions,
and the diastereomeric excess was >90%, determined by
(10) The stereochemistry was determined from the coupling con-
stants between 3- and 4-protons. In general, cis-isomers show greater
coupling constants by 1.5-2.0 Hz than trans-isomers.2a,d For example,
the 1H NMR spectrum of 2b showed a couple of doublets at δ 3.86 and
4.69 (owing to 3- and 4-protons) with J ) 6.8 Hz, and a couple of
doublets at δ 4.69 and 5.65, with J ) 8.3 Hz assignable to 3- and
4-protons of 3b, were observed in the 1H NMR spectrum of a mixture
of 3b and 1b. The cis-isomers 3 can be converted to the trans-isomers
2 by treatment with LDA in THF at -78 °C.
(11) Mu¨ller, M.; Otto, H.-H. Arch. Pharm. (Weinheim, Ger.) 1991,
324, 15-17.
(12) 3,4-cis-4-Sulfinyl-â-sultams 6A,B gradually isomerized to trans-
isomers 4d A,d B during purification with silica gel column chroma-
tography. The 1H NMR spectrum of the mixture showed four couples
of doublets at δ 4.44 and 5.37 with J ) 8.3 Hz, δ 4.92 and 5.23 with J
) 7.8 Hz (6A,B), δ 4.70 and 4.91 with J ) 4.9 Hz, and δ 4.24 and 4.85
with J ) 5.4 Hz (4d A,d B) owing to 3- and 4-protons. No trans-isomers
4A,B isomerized to cis-isomers with silica gel column chromatography.
(13) The 1H NMR spectrum of the recovered sulfoxide showed
isomerization of the sulfoxide moiety. Two sets of doublet assigned to
3- and 4-protons of 4a A and 4a B were observed in the spectrum.
1
the H NMR spectra.15 No epimerization was observed
(14) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860.

Synthesis of R-Amino Acid Thioesters
J . Org. Chem., Vol. 63, No. 23, 1998 8357
Ta ble 1. Syn th esis of 3-Su bstitu ted -4-su lfin yl-â-su lta m s
entry
1
1
R1
R2
Ph
2 and 3 (%yield)a
4b (%yield)a
1a
c-C6H11
2a (72)
4a A (58), 4a B (16)
3a (trace)c
2b (57)
3b (12)c
2c (67)
2
3
4
5
1b
1c
1d
1e
n-Bu
Ph
4bA (49), 4bB (47)
4cA (75), 4cB (20)
4d A (53), 4d B (20)
4eA (64), 4eB (33)
4fA (54), 4fB (38)
t-Bu
Ph
3c (7)c
2d (66)
3d (18)c
2e (72)
c-C6H11
c-C6H11
p-tolyl
o-tolyl
3e (18)
6
1f
1f
c-C6H11
c-C6H11
t-Bu
t-Bu
2f (92)
7d
2f (t),e 5 (67)
a
b
Isolated yield unless otherwise mentioned. A,B: Diastereomers at sulfoxide moiety. c The compound was obtained as an inseparable
mixture with the starting material. The yield was estimated by the 1H NMR spectrum. The reaction was quenched at rt. e t: Trace.
d
Sch em e 2
Sch em e 3
Ta ble 2. Th e P u m m er er Rea ction of
3-Su bstitu ted -4-su lfin yl-â-su lta m s
TFAA
(equiv)
Productsa
(%yield)b
entry
4
R1
R2
1c
2e
3
4
5
6
7
8
9
10
11
12
13
14
15
4a A
4a A
4a A
4a B
4bA
4bB
4cA
4cB
4d A
4d B
4d ,6g
4eA
4eB
4fA
c-C6H11 Ph
1.0
2.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
recoveryd
7a , 8a (low yield)f
7a (72), 8a (13)
7a (79), 8a (14)
7b (74), 8b (10)
7b (73), 8b (9)
7c (93)
n-Bu
t-Bu
Ph
Ph
Sch em e 4
7c (97)
c-C6H11 p-tolyl
7d (73), 8d (9)
7d (79), 8d (8)
7d (63), 8d (15)
7e (71), 8e (10)
7e (73), 8e (7)
7f (81)
c-C6H11 o-tolyl
c-C6H11 t-Bu
2-n -Bu tyl-3-p h en yl-1,2-th ia zetid in e 1,1-d ioxid e (1b):
colorless prisms (from CH2Cl2-hexane), mp 66-68 °C; 1H
NMR (CDCl3) δ: 0.84 (3 H, t, J ) 7.3 Hz), 1.29-1.41 and 1.43-
1.59 (each 2 H, m), 2.81 (1 H, ddd, J ) 6.8, 8.3, and 13 Hz),
3.22 (1 H, ddd, J ) 5.9, 7.8, and 13 Hz), 3.95 (1 H, dd, J ) 6
and 12.2 Hz), 4.21 (1 H, dd, J ) 6 and 7 Hz), 4.37 (1 H, dd, J
) 7 and 12 Hz), 7.35-7.43 (3 H, m), 7.49 (2 H, dd, J ) 2 and
8 Hz); 13C NMR (CDCl3) δ: 13.5, 20.2, 30.1, 45.9, 51.1, 65.9,
126.7, 129.1, 129.1, 137.4; MS (FAB) m/z (rel int %): 240 (100,
M+ + 1); IR νmax (KBr) cm-1: 1305, 1135 (SO2). Anal. Calcd
for C12H17NO2S: C, 60.22; H, 7.16; N, 5.85. Found: C, 60.05;
H, 7.14; N, 5.78.
4fB
7f (82)
a
b
A trace amount of (PhS)2 was isolated in all cases. Iso-
lated yield. c Reaction time: 12 h. Isomerization of the sulfoxide
d
moiety was observed. e Reaction time: 24 h. f Yields of 7a and 8a
were not calculated. A considerable amount of the starting
material was recovered. Isomerization of the sulfoxide moiety was
observed. g Mixture of 3,4-cis- 6A,B and 3,4-trans-â-sultams 4d A,B
was used.
in the 1H NMR spectra in the cases of R-tert-butyl
thioesters 20b and 24b.
(3R ,1′R )-2-(r-Me t h ylb e n zyl)-3-p h e n yl-1,2-t h ia ze t i-
d in e 1,1-d ioxid e (syn -14a ): colorless prisms (from
1
CH2Cl2-hexane), mp 131-133 °C; H NMR (CDCl3) δ: 1.60
(3 H, d, J ) 7 Hz), 3.93-4.00 (2 H, m), 4.29-4.36 (1
H, m), 4.48 (1 H, q, J ) 7 Hz), 6.97-7.15 (10 H, m);
13C NMR (CDCl3) δ: 21.7, 50.3, 58.9, 65.6, 126.8, 128.0,
128.2, 128.2, 128.4, 137.6, 138.1, an aromatic carbon is
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. IR
spectra were recorded by KBr (solids) and NaCl (liquids)
methods. 1H NMR spectra were recorded in a CDCl3 solution
with tetramethylsilane as an internal standard. 13C NMR
spectra were obtained with CDCl3 (77.0 ppm) as an internal
standard. Mass spectra were recorded with a direct-insertion
probe at 70 eV. All chromatographic isolations were ac-
complished with either Kieselgel 60 (Merck) or BW-127ZH
(Fuji Silysia) for column chromatography or Kieselgel 60 PF254
containing gypsum (Merck) for preparative TLC.
overlapped; MS (FAB) m/z (rel int %): 288 (100, M+
+
1); IR νmax (KBr) cm-1
: 1325, 1140 (SO2). Anal. Calcd
for C16H17NO2S: C, 66.87; H, 5.96; N, 4.87. Found: C,
66.65; H, 5.98; N, 4.87.
(3S ,1′R )-2-(r-Me t h ylb e n zy l)-3-p h e n y l-1,2-t h ia ze t i-
d in e 1,1-d ioxid e (a n ti-14a ): colorless prisms (from EtOAc-
hexane), mp 105-108 °C; 1H NMR (CDCl3) δ: 1.49 (3 H, d, J
) 6.8 Hz), 3.94 (1 H, dd, J ) 5 and 12.2 Hz), 4.26 (1 H, dd, J
) 5 and 7.8 Hz), 4.30 (1 H, q, J ) 6.8 Hz), 4.39 (1 H, dd, J )
7.8 and 12.2 Hz), 7.24-7.44 (10 H, m); 13C NMR (CDCl3) δ:
20.9, 49.1, 57.4, 65.8, 126.9, 127.3, 128.0, 128.6, 128.9, 129.0,
137.8, 140.2; MS (FAB) m/z (rel int %): 288 (67, M+ + 1), 105
(100); IR νmax (KBr) cm-1: 1315, 1145 (SO2). Anal. Calcd for
Syn th esis of â-Su lta m s 1 a n d 14 by [2 + 2] Cycloa d -
d ition . â-Sultams 1 and 14 were synthesized according to
the literature.3d,e
(15) In prolonged reaction or prolonged workup, the diastereomeric
excess decreased to ca. 75% in the worst case. Rapid workup and
purification are necessary to minimize epimerization.
C
16H17NO2S: C, 66.87; H, 5.96; N, 4.87. Found: C, 66.71; H,
5.94; N, 4.94.

8358 J . Org. Chem., Vol. 63, No. 23, 1998
Iwama et al.
Ta ble 3. 1,3-Asym m etr ic In d u ction in th e [2 + 2] Cycloa d d ition of a Su lfen e In ter m ed ia te a n d Ch ir a l Im in esa
entry
R1
R2
Ph
14 (%Yield)b
1
2
3
4
5
6
7
8
9
(R)-R-methylbenzyl
(S)-R-methylbenzyl
(R)-R,4-dimethylbenzyl
rac-1-(1-naphthyl)ethyl
rac-1-indanyl
rac-1-cyclohexylethyl
(1R,2R,3R,5S)-isopinocampheyl
rac-1-tert-butylethyl
rac-1-(methoxymethyl)propyl
(R)-2-(methoxymethyl)pyrrolidinyl
14a , (70, 42% de)c
14b, (32, 45% de)c
14c, (72, 44% de)c
14d , (53, 47% de)c
14e, (36, 50% de)c
14f, (60, 67% de)d
14 g, (54, 80% de)d
14h , (67, >95% de)d
complex mixture
complex mixture
t-Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
a
b
2 equiv of imines were used based on MsCl. Isolated yield based on MsCl. Diastereomeric exsess was calculated by the 1H NMR
spectrum of the reaction mixture. c Separable stereoisomers. Inseparable stereoisomers.
d
Sch em e 5
12.2 Hz), 4.50 (1 H, q, J ) 7 Hz), 7.30 (1 H, t, J ) 7.3 Hz),
Sch em e 6
7.37 (2 H, t, J ) 7.3 Hz), 7.47 (2 H, d, J ) 7.3 Hz); 13C NMR
(CDCl3) δ: 19.0, 25.8, 33.6, 55.5, 58.4, 58.7, 127.8, 127.9, 128.5,
140.2; MS (EI) m/z (rel int %): 267 (1, M+), 105 (100); IR νmax
(KBr) cm-1: 1315, 1150 (SO2). Anal. Calcd for C14H21NO2S:
C, 62.89; H, 7.92; N, 5.24. Found: C, 62.62; H, 8.06; N, 5.18.
(3R,1′S)-3-ter t-Bu t yl-2-(r-m et h ylb en zyl)-1,2-t h ia zet i-
d in e 1,1-d ioxid e (a n ti-14b): colorless leaves (from EtOAc-
1
hexane), mp 105-109 °C; H NMR (CDCl3) δ: 0.87 (9 H, s),
1.81 (3 H, d, J ) 7 Hz), 3.10 (1 H, dd, J ) 5 and 8 Hz), 3.78 (1
H, dd, J ) 5 and 12 Hz), 3.94 (1 H, dd, J ) 8 and 12 Hz), 4.51
(1 H, q, J ) 7 Hz), 7.30 (1 H, t, J ) 7 Hz), 7.38 (2 H, t, J ) 7
Hz), 7.49 (2 H, d, J ) 7 Hz); 13C NMR (CDCl3) δ: 20.0, 25.9,
33.8, 53.0, 58.3, 58.8, 127.7, 127.7, 128.7, 140.4; MS (EI) m/z
(rel int %): 267 (3, M+), 105 (100); IR νmax (KBr) cm-1: 1295,
1145 (SO2). Anal. Calcd for C14H21NO2S: C, 62.89; H, 7.92;
N, 5.24. Found: C, 62.61; H, 8.04; N, 5.17.
(3R*,1′R*)-2-(1-ter t-Bu t ylet h yl)-3-p h en yl-1,2-t h ia zet i-
d in e 1,1-d ioxid e (syn -14h ): colorless needles (from EtOAc-
1
hexane), mp 148-151 °C; H NMR (CDCl3) δ: 0.99 (9 H, s),
1.35 (3 H, d, J ) 6.8 Hz), 2.58 (1 H, q, J ) 6.8 Hz), 3.91 (1 H,
dd, J ) 5.9 and 12 Hz), 4.31 (1 H, dd, J ) 7.8 and 12 Hz), 4.39
(1 H, dd, J ) 5.9 and 7.8 Hz), 7.37-7.43 (3 H, m), 7.49 (2 H,
d, J ) 7.8 Hz); 13C NMR (CDCl3) δ: 11.6, 27.6, 34.5, 48.4, 64.8,
65.3, 127.7, 129.3, 129.5, 137.7; MS (EI) m/z (rel int %): 267
(1, M+), 210 (100); IR νmax (KBr) cm-1: 1305, 1140 (SO2). Anal.
Calcd for C14H21NO2S: C, 62.89; H, 7.92; N, 5.24. Found: C,
62.62; H, 7.90; N, 5.19.
Su lfen yla tion of â-Su lta m s 1 a n d 14. Gen er a l P r oce-
d u r e. To a solution of LDA (3 mmol, prepared from 3 mmol
of diisopropylamine (0.39 cm3) and 3 mmol of nBuLi in hexane)
in dry THF (10 cm3) was added dropwise a solution of â-sultam
1 or 14 (1 mmol) in THF (2-4 cm3) at -78 °C under argon.
After 30 min, diphenyl disulfide (218 mg, 1 mmol) in THF (1-2
cm3) was added dropwise to it, and the whole was stirred at
-78 °C for 1 h. The reaction was quenched by addition of
saturated aqueous NH4Cl (0.5 cm3) at -78 °C, and the mixture
was warmed to room temperature. Additional saturated
aqueous NH4Cl (5 cm3) and water (5 cm3) were added to it,
and the organic layer was separated. The water layer was
extracted twice with EtOAc (10 cm3). The organic layer and
the extracts were combined, washed with saturated aqueous
NaCl (20 cm3), dried (MgSO4), and evaporated under reduced
(3S,1′S)-3-ter t-Bu t yl-2-(r-m et h ylb en zyl)-1,2-t h ia zet i-
d in e 1,1-d ioxid e (syn -14b): colorless leaves (from EtOAc-
1
hexane), mp 148-152 °C; H NMR (CDCl3) δ: 0.85 (9 H, s),
1.76 (3 H, d, J ) 7 Hz), 3.27 (1 H, dd, J ) 5.9 and 8.3 Hz),
3.76 (1 H, dd, J ) 5.9 and 12.2 Hz), 3.94 (1 H, dd, J ) 8.3 and

Synthesis of R-Amino Acid Thioesters
J . Org. Chem., Vol. 63, No. 23, 1998 8359
pressure. The residue was purified by column chromatography
on silica gel with EtOAc-hexane (1:20-1:10 v/v).
128.3, 128.5, 128.6, 128.7, 129.5, 131.8, 132.2, 133.5, 140.1,
an aromatic carbon is overlapped; MS (FAB) m/z (rel int %):
396 (2, M+ + 1), 154 (100); IR νmax (KBr) cm-1: 1315, 1160
(SO2). Anal. Calcd for C22H21NO2S2: C, 66.81; H, 5.35; N,
3.54. Found: C, 66.64; H, 5.46; N, 3.40.
tr a n s-2-Cycloh exyl-4-(p h en ylsu lfen yl)-3-p-tolyl-1,2-th i-
a zetid in e 1,1-d ioxid e (2d ): colorless prisms (from EtOAc-
1
hexane), mp 102-104 °C; H NMR (CDCl3) δ: 1.11-1.26 (4
H, m), 1.47-1.61 (4 H, m), 1.72 (1 H, br d, J ) 13 Hz), 2.03 (1
H, br d, J ) 12 Hz), 2.37 (3 H, s), 3.21 (1 H, m), 3.96 (1 H, d,
J ) 6.3 Hz), 4.97 (1 H, d, J ) 6.3 Hz), 7.21 (2 H, d, J ) 8 Hz),
7.26-7.31 (3 H, m), 7.38-7.41 (4 H, m); 13C NMR (CDCl3) δ:
21.2, 24.2, 24.4, 25.3, 30.4, 31.9, 56.8, 57.5, 82.5, 126.5, 128.4,
129.4, 129.7, 131.6, 131.8, 134.1, 139.1; MS (FAB) m/z (rel int
%): 388 (7, M+ + 1), 154 (100); IR νmax (KBr) cm-1: 1310, 1155
(SO2). Anal. Calcd for C21H25NO2S2: C, 65.08; H, 6.50; N,
3.61. Found: C, 64.91; H, 6.57; N, 3.60.
Syn th esis of 4-Su lfin yl-â-su lta m s 4, 19, a n d 23. Gen -
er a l P r oced u r e. To a solution of a 4-sulfenyl-â-sultam 2, 17,
or 21 (0.5 mmol) in CH2Cl2 (10-20 cm3) was added mCPBA
(70-85% purity, 0.5 mmol) at 0 °C. After 1-3 h, saturated
aqueous NaHCO3 (10 cm3) was added to it, and the organic
layer was separated. The water layer was extracted once with
CH2Cl2 (10 cm3). The organic layer and the extracts were
combined, washed with saturated aqueous NaCl (10 cm3), dried
(MgSO4), and evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel with
EtOAc-hexane (1:10-1:3 v/v).
tr a n s-2-Cycloh exyl-4-(p h en ylsu lfin yl)-3-p-tolyl-1,2-th i-
a zetid in e 1,1-Dioxid e (4d ). Major isomer 4d A: colorless
prisms (from EtOAc-hexane), mp 161-164 °C; 1H NMR
(CDCl3) δ: 1.11-1.29 (4 H, m), 1.43-1.77 (5 H, m), 2.01 (1 H,
br d, J ) 12 Hz), 2.29 (3 H, s, Me), 3.31-3.37 (1 H, m), 4.70 (1
H, d, J ) 4.9 Hz), 4.91 (1 H, d, J ) 4.9 Hz), 7.05 (2 H, d, J )
7.8 Hz), 7.22 (2 H, d, J ) 7.8 Hz), 7.48-4.79 (3 H, m), 7.67-
6.69 (2 H, m); 13C NMR (CDCl3) δ: 21.1, 24.1, 24.3, 25.3, 30.4,
31.8, 48.5, 56.8, 92.5, 124.2, 126.6, 129.6, 129.7, 132.2, 134.3,
138.8, 140.4; MS (FAB) m/z (rel int %): 404 (12, M+ + 1), 154
(100); IR νmax (KBr) cm-1: 1320, 1165 (SO2), 1055 (SO). Anal.
Calcd for C21H25NO3S2: C, 62.50; H, 6.24; N, 3.47. Found: C,
62.30; H, 6.30; N, 3.30.
tr a n s-3-ter t-Bu tyl-2-cycloh exyl-4-(p h en ylsu lfen yl)-1,2-
th ia zetid in e 1,1-d ioxid e (2f): colorless prisms (from CH2-
Cl2-hexane), mp 106-108 °C; 1H NMR (CDCl3) δ: 1.05 (9 H,
s), 1.02-1.25 (3 H, m), 1.58-1.87 (5 H, m), 1.98 (1 H, br d, J
) 13 Hz), 2.22 (1 H, br d, J ) 12 Hz), 3.01-3.09 (1 H, m), 3.10
(1 H, d, J ) 5.9 Hz), 4.89 (1 H, d, J ) 5.9 Hz), 7.30-7.38 (3 H,
m), 7.50 (2 H, dd, J ) 2 and 8 Hz); 13C NMR (CDCl3) δ: 25.2,
25.4, 26.2, 26.5, 28.6, 31.4, 34.6, 58.7, 59.1, 75.5, 128.5, 129.5,
132.0, 132.1; MS (FAB) m/z (rel int %): 354 (2, M+ + 1), 290
(100); IR νmax (KBr) cm-1: 1305, 1165 (SO2). Anal. Calcd for
C
18H27NO2S2: C, 61.15; H, 7.70; N, 3.96. Found: C, 60.97; H,
7.68; N, 3.87.
2-ter t-Bu t yl-N-cycloh exyl-1-p h en ylsu lfen ylvin ylsu l-
fon a m id e (5): colorless prisms (from EtOAc-hexane), mp
1
104-110 °C; H NMR (CDCl3) δ: 1.11-1.33 (5 H, m), 1.27 (9
H, s), 1.53-1.58 (1 H, m), 1.66-1.71 (2 H, m), 1.81-1.84 (2 H,
m), 3.03-3.07 (1 H, m), 4.43 (1 H, br d, J ) 7.3 Hz), 7.15-
7.33 (5 H, m), 7.62 (1 H, s); 13C NMR (CDCl3) δ: 24.9, 25.4,
29.9, 34.2, 35.6, 53.4, 126.5, 127.4, 129.3, 131.8, 135.4, 162.2;
MS (EI) m/z (rel int %): 353 (27, M+), 191(100); IR νmax (KBr)
Minor isomer 4d B: colorless prisms (from EtOAc-hexane),
mp 146-151 °C; 1H NMR (CDCl3) δ: 1.06-1.27 (4 H, m), 1.39-
1.69 (5 H, m), 1.96 (1 H, br d, J ) 12 Hz), 2.30 (3 H, s), 3.25-
3.30 (1 H, m), 4.24 (1 H, d, J ) 5.4 Hz), 4.85 (1 H, d, J ) 5.4
Hz), 7.01-7.03 (4 H, m), 7.48-4.57 (3 H, m), 7.73 (2 H, dd, J
) 1.5 and 8 Hz); 13C NMR (CDCl3) δ: 21.1, 23.9, 24.1, 25.2,
30.2, 31.7, 50.7, 56.9, 93.2, 125.6, 126.3, 129.6, 129.7, 132.8,
cm-1: 3270 (NH), 1320, 1155 (SO2). Anal. Calcd for C18H27
-
NO2S2: C, 61.15; H, 7.70; N, 3.96. Found: C, 61.09; H, 7.74;
N, 3.99.
133.4, 139.0, 139.0; MS (FAB) m/z (rel int %): 404 (16, M+
+
(3R,4S,1′R)-2-(r-Meth ylben zyl)-3-ph en yl-4-(ph en ylsu lfe-
n yl)-1,2-th ia zetid in e 1,1-d ioxid e (17a ): colorless prisms
(from CH2Cl2-hexane), mp 96-98 °C; 1H NMR (CDCl3) δ: 1.65
(3 H, d, J ) 7 Hz), 3.62 (1 H, d, J ) 6.8 Hz), 4.45 (1 H, q, J )
7 Hz), 5.07 (1 H, d, J ) 6.8 Hz), 6.96-7.16 (10 H, m), 7.28-
7.30 (3 H, m), 7.37-7.39 (2 H, m); 13C NMR (CDCl3) δ: 21.8,
58.2, 59.3, 82.4, 127.0, 128.1, 128.1, 128.3, 128.4, 128.5, 128.6,
129.5, 131.3, 132.1, 136.2, 137.2; MS (FAB) m/z (rel int %):
396 (2, M+ + 1), 105 (100); IR νmax (KBr) cm-1: 1320, 1160
(SO2). Anal. Calcd for C22H21NO2S2: C, 66.81; H, 5.35; N,
3.54. Found: C, 66.73; H, 5.39; N, 3.53.
1), 154 (100); IR νmax (KBr) cm-1: 1320, 1165 (SO2), 1060 (SO).
Anal. Calcd for C21H25NO3S2: C, 62.50; H, 6.24; N, 3.47.
Found: C, 62.27; H, 6.27; N, 3.32.
tr a n s-3-ter t-Bu tyl-2-cycloh exyl-4-(p h en ylsu lfin yl)-1,2-
th ia zetid in e 1,1-Dioxid e (4f). Major isomer 4fA: colorless
needles (from CH2Cl2-hexane), mp 187-191 °C; 1H NMR
(CDCl3) δ: 0.85 (9 H, s), 1.19-1.26 (3 H, m), 1.62-1.85 (5 H,
m), 2.18 (2 H, br d, J ) 12 Hz), 3.13-3.20 (1 H, m), 3.87 (1 H,
d, J ) 3.9 Hz), 4.59 (1 H, d, J ) 3.9 Hz), 7.56-7.60 (3 H, m),
7.74-7.76 (2 H, m); 13C NMR (CDCl3) δ: 25.3, 25.4, 26.1, 26.3,
29.9, 31.4, 33.9, 55.0, 59.2, 88.2, 124.4, 129.7, 132.1, 141.3; MS
(FAB) m/z (rel int %): 370 (25, M+ + 1), 154 (100); IR νmax
(KBr) cm-1: 1310, 1160 (SO2), 1055 (SO). Anal. Calcd for
(3R,4R,1′R)-2-(r-Meth ylben zyl)-3-ph en yl-4-(ph en ylsu lfe-
n yl)-1,2-th ia zetid in e 1,1-d ioxid e (18a ): colorless needles
1
(from CH2Cl2-hexane), mp 151-154 °C; H NMR (CDCl3) δ:
C
18H27NO3S2: C, 58.50; H, 7.36; N, 3.79. Found: C, 58.21; H,
1.63 (3 H, d, J ) 7 Hz), 4.45 (1 H, d, J ) 9.2 Hz), 4.63 (1 H, q,
7.41; N, 3.71.
J ) 7 Hz), 5.60 (1 H, d, J ) 9.2 Hz), 7.04-7.33 (15 H, m); 13
C
Minor isomer 4fB: colorless needles (from CH2Cl2-hexane),
mp 185-187 °C; 1H NMR (CDCl3) δ: 0.96 (9 H, s), 1.13-1.23
(3 H, m), 1.64-1.82 (5 H, m), 2.00 (1 H, br d, J ) 13 Hz), 2.13
(1 H, br d, J ) 12 Hz), 3.05-3.11 (1 H, m), 3.59 (1 H, d, J )
4.9 Hz), 4.68 (1 H, d, J ) 4.9 Hz), 7.58-7.59 (3 H, m), 7.79-
7.82 (2 H, m); 13C NMR (CDCl3) δ: 25.3, 25.4, 26.1, 26.2, 29.4,
31.4, 34.4, 54.6, 59.3, 86.0, 125.5, 129.6, 132.4, 139.2; MS (FAB)
m/z (rel int %): 370 (34, M+ + 1), 154 (100); IR νmax (KBr)
NMR (CDCl3) δ: 21.3, 54.9, 57.9, 81.1, 128.0, 128.2, 128.4,
128.8, 129.4, 131.8, 132.1, 134.3, 137.7, three aromatic carbons
are overlapped; MS (FAB) m/z (rel int %): 396 (3, M+ + 1),
105 (100); IR νmax (KBr) cm-1: 1310, 1165 (SO2). Anal. Calcd
for C22H21NO2S2: C, 66.81; H, 5.35; N, 3.54. Found: C, 66.68;
H, 5.50; N, 3.37.
(3S,4R,1′R)-2-(r-Meth ylben zyl)-3-ph en yl-4-(ph en ylsu lfe-
n yl)-1,2-th ia zetid in e 1,1-d ioxid e (21a ): colorless oil; 1H
NMR (CDCl3) δ: 1.49 (3 H, d, J ) 7 Hz), 3.90 (1 H, d, J ) 5.9
Hz), 4.31 (1 H, q, J ) 7 Hz), 5.08 (1 H, d, J ) 5.9 Hz), 7.24-
7.44 (15 H, m); 13C NMR (CDCl3) δ: 21.0, 57.1, 57.9, 82.7,
126.9, 127.3, 128.1, 128.7, 128.7, 129.2, 129.3, 129.5, 131.1,
cm-1: 1315, 1175 (SO2), 1055 (SO). Anal. Calcd for C18H27
-
NO3S2: C, 58.50; H, 7.36; N, 3.79. Found: C, 58.22; H, 7.36;
N, 3.65.
(3R,4S,1′R)-2-(r-Meth ylben zyl)-3-p h en yl-4-p h en ylsu lfi-
n yl-1,2-t h ia zet id in e 1,1-Dioxid e (19a ). Major isomer
19a A: colorless prisms (from CH2Cl2-hexane), mp 139-141
°C; 1H NMR (CDCl3) δ: 1.62 (3 H, d, J ) 6.3 Hz), 4.57 (1 H, d,
J ) 5 Hz), 4.61 (1 H, q, J ) 6.3 Hz), 4.78 (1 H, d, J ) 5 Hz),
6.94 (2 H, d, J ) 7 Hz), 7.01-7.08 (6 H, m), 7.12 (2 H, d, J )
7 Hz), 7.39-7.40 (3 H, m), 7.57-7.60 (2 H, m); 13C NMR
(CDCl3) δ: 21.9, 49.2, 58.8, 92.5, 124.1, 126.9, 128.2, 128.3,
128.3, 129.6, 132.1, 137.0, 137.3, 140.0, two aromatic carbons
are overlapped; MS (FAB) m/z (rel int %): 412 (13, M+ + 1),
125 (100); IR νmax (KBr) cm-1: 1330, 1165 (SO2), 1045 (SO).
132.4, 136.1, 139.8; MS (FAB) m/z (rel int %): 396 (2, M+
+
1), 154 (100); IR νmax (KBr) cm-1: 1320, 1165 (SO2). Anal.
Calcd for C22H21NO2S2: C, 66.81; H, 5.35; N, 3.54. Found: C,
66.64; H, 5.46; N, 3.36.
(3S,4S,1′R)-2-(r-Meth ylben zyl)-3-ph en yl-4-(ph en ylsu lfe-
n yl)-1,2-th ia zetid in e 1,1-d ioxid e (22a ): colorless prisms
(from CH2Cl2-hexane), mp 95-97 °C; 1H NMR (CDCl3) δ: 1.63
(3 H, d, J ) 7 Hz), 4.38 (1 H, q, J ) 7 Hz), 4.62 (1 H, d, J ) 8.3
Hz), 5.64 (1 H, d, J ) 8.3 Hz), 7.26-7.36 (10 H, m), 7.42 (5 H,
s); 13C NMR (CDCl3) δ: 21.2, 54.6, 57.0, 81.0, 127.2, 128.1,

8360 J . Org. Chem., Vol. 63, No. 23, 1998
Iwama et al.
Anal. Calcd for C22H21NO3S2: C, 64.21; H, 5.14; N, 3.40.
Found: C, 64.11; H, 5.17; N, 3.40.
S-P h en yl 2-(cycloh exyla m in o)-3,3-d im eth ylbu ta n e-
th ioa te (7f): white solid (from hexane), mp 40-42 °C; 1H NMR
(CDCl3) δ: 1.03 (9 H, s), 1.00-1.31 (5 H, m), 1.51 (1 H, br s),
1.59-1.62 (1 H, m), 1.72-1.75 (2 H, m), 1.85 (1 H, br d, J )
12 Hz), 1.93 (1 H, br d, J ) 12 Hz), 2.46-2.53 (1 H, m), 3.19
(1 H, s), 7.36-7.42 (5 H, m); 13C NMR (CDCl3) δ: 24.6, 25.0,
26.1, 27.2, 32.8, 34.4, 34.4, 55.6, 73.9, 129.0, 129.0, 129.4, 134.3,
203.5; MS (FAB) m/z (rel int %): 306 (21, M+ + 1), 154 (100);
IR νmax (KBr) cm-1: 3360 (NH), 1680 (CO). Anal. Calcd for
Minor isomer 19a B: colorless prisms (from CH2Cl2-hex-
1
ane), mp 199-202 °C; H NMR (CDCl3) δ: 1.59 (3 H, d, J )
6.8 Hz), 3.88 (1 H, d, J ) 6 Hz), 4.54 (1 H, q, J ) 6.8 Hz), 4.94
(1 H, d, J ) 6 Hz), 6.74 (2 H, d, J ) 7 Hz), 6.95-7.08 (8 H, m),
7.40-7.48 (3 H, m), 7.65 (2 H, dd, J ) 1 and 8 Hz); 13C NMR
(CDCl3) δ: 21.9, 52.2, 59.1, 93.2, 125.4, 126.7, 128.1, 128.3,
128.3, 128.4, 129.7, 132.8, 135.8, 137.0, 138.9, an aromatic
carbon is overlapped; MS (FAB) m/z (rel int %): 412 (39, M+
+ 1), 125 (100); IR νmax (KBr) cm-1: 1300, 1165 (SO2), 1060
(SO). Anal. Calcd for C22H21NO3S2: C, 64.21; H, 5.14; N, 3.40.
Found: C, 63.94; H, 5.17; N, 3.38.
C
18H27NOS: C, 70.77; H, 8.91; N, 4.59. Found: C, 70.60; H,
8.91; N, 4.47.
(2R,1′R)-S-P h en yl 2-(r-m eth ylben zyla m in o)p h en yl-
1
th ioa ceta te (20a ): light yellow oil; H NMR (CDCl3) δ: 1.43
(3S,4R,1′R)-2-(r-Meth ylben zyl)-3-ph en yl-4-(ph en ylsu lfi-
n yl)-1,2-t h ia zet id in e 1,1-Dioxid e (23a ). Major isomer
23a A: white powder (from EtOAc-hexane), mp 160-162 °C;
1H NMR (CDCl3) δ: 1.53 (3 H, d, J ) 6.8 Hz), 4.41 (1 H, q, J
) 6.8 Hz), 4.80 and 4.82 (each 1 H, d, J ) 4 Hz), 7.25-7.34
(10 H, m), 7.46-7.48 (3 H, m), 7.66-7.68 (2 H, m); 13C NMR
(CDCl3) δ: 21.4, 49.1, 57.5, 92.8, 124.2, 125.7, 127.0, 127.1,
128.2, 128.8, 129.0, 129.7, 132.2, 136.0, 139.8, 140.3; MS (FAB)
m/z (rel int %): 412 (23, M+ + 1), 154 (100); IR νmax (KBr)
(3 H, d, J ) 7 Hz), 2.22 (1 H, br s), 3.98 (1 H, q, J ) 7 Hz),
4.35 (1 H, s), 7.27-7.35 (15 H, m); 13C NMR (CDCl3) δ: 24.4,
57.0, 70.1, 126.7, 127.3, 127.4, 128.2, 128.6, 128.8, 128.8, 129.0,
129.1, 134.4, 138.1, 144.4, 201.3; MS (FAB) m/z (rel int %):
348 (38, M+ + 1), 105 (100); IR νmax (NaCl) cm-1: 3345 (NH),
1695 (CO). Anal. Calcd for C22H21NOS: C, 76.05; H, 6.09; N,
4.03. Found: C, 76.12; H, 6.19; N, 4.03.
(2R,1′S)-S-P h en yl
2-(r-m eth ylben zyla m in o)-3,3-d i-
m eth ylbu tan eth ioate (20b): light yellow oil; 1H NMR (CDCl3)
δ: 1.06 (9 H, s), 1.39 (3 H, d, J ) 6.4 Hz), 1.98 (1 H, br s), 3.22
(1 H, s), 3.90 (1 H, q, J ) 6.4 Hz), 7.23-7.40 (10 H, m); 13C
NMR (CDCl3) δ: 22.5, 27.1, 34.9, 57.0, 74.3, 126.9, 127.1, 128.4,
128.6, 129.0, 129.1, 134.3, 145.8, 202.0; MS (FAB) m/z (rel int
%): 328 (64, M+ + 1), 190 (100); IR νmax (KBr) cm-1: 3340
(NH), 1695 (CO). Anal. Calcd for C20H25NOS: C, 73.35; H,
7.69; N, 4.28. Found: C, 73.45; H, 7.83; N, 4.25.
cm-1: 1315, 1165 (SO2), 1045 (SO). Anal. Calcd for C22H21
-
NO3S2: C, 64.21; H, 5.14; N, 3.40. Found: C, 63.94; H, 5.24;
N, 3.26.
Minor isomer 23a B: white powder (from EtOAc-hexane),
mp 158-161 °C; 1H NMR (CDCl3) δ: 1.48 (3 H, d, J ) 6.8
Hz), 4.17 (1 H, d, J ) 4.9 Hz), 4.31 (1 H, q, J ) 6.8 Hz), 4.93
(1 H, d, J ) 4.9 Hz), 7.09 (2 H, d, J ) 7 Hz), 7.20-7.30 (8 H,
m), 7.47-7.55 (3 H, m), 7.70 (2 H, d, J ) 8 Hz); 13C NMR
(CDCl3) δ: 21.2, 51.5, 57.7, 93.3, 125.6, 126.8, 127.1, 128.2,
128.7, 129.1, 129.3, 129.7, 132.7, 135.3, 139.0, 139.6; MS (FAB)
m/z (rel int %): 412 (21, M+ + 1), 154 (100); IR νmax (KBr)
(2S,1′R)-S-P h en yl 2-(r-m eth ylben zyla m in o)p h en yl-
1
th ioa ceta te (24a ): light yellow oil; H NMR (CDCl3) δ: 1.38
(3 H, d, J ) 7 Hz), 2.42 (1 H, br s), 3.70 (1 H, q, J ) 7 Hz),
4.36 (1 H, s), 7.27-7.41 (15 H, m); 13C NMR (CDCl3) δ: 24.2,
55.2, 70.1, 127.0, 127.3, 128.0, 128.2, 128.4, 128.6, 128.8, 129.0,
129.2, 134.5, 137.8, 144.2, 199.3; MS (FAB) m/z (rel int %):
348 (51, M+ + 1), 210 (100); IR νmax (NaCl) cm-1: 3340 (NH),
1700 (CO). Anal. Calcd for C22H21NOS: C, 76.05; H, 6.09; N,
4.03. Found: C, 76.14; H, 6.16; N, 4.08.
cm-1: 1335, 1170 (SO2), 1050 (SO). Anal. Calcd for C22H21
-
NO3S2: C, 64.21; H, 5.14; N, 3.40. Found: C, 64.08; H, 5.21;
N, 3.22.
Th e P u m m er er Rea ction of 4-Su lfin yl-â-su lta m s 4, 19,
a n d 23. Gen er a l P r oced u r e. To a solution of a 4-sulfinyl-
â-sultam 4, 19, or 23 (0.2 mmol) in CH2Cl2 (1 cm3) was added
TFAA (113 µdm3, 0.8 mmol) at room temperature. After 20
h, CH2Cl2 (6 cm3) and 1% aqueous NH3 (6 cm3) were added to
the reaction mixture, and the organic layer was separated. The
water layer was extracted once with CH2Cl2 (10 cm3). The
organic layer and the extracts were combined, washed with
saturated aqueous NaCl (10 cm3), dried (MgSO4), and evapo-
rated under reduced pressure. The residue was purified by
preparative TLC with EtOAc-hexane (1:10-1:5 v/v).
S-P h en yl 2-(cycloh exyla m in o)-p-tolylth ioa ceta te (7d ):
colorless oil; 1H NMR (CDCl3) δ: 1.11-1.25 (5H, m), 1.62-
1.70 (4 H, m), 1.96 (2 H, m), 2.34 (3 H, s), 2.54 (1 H, m), 4.63
(1 H, s), 7.17 (2 H, d, J ) 8.3 Hz), 7.32 (2 H, d, J ) 8.3 Hz),
7.35 (5 H, s); 13C NMR (CDCl3) δ: 21.1, 24.9, 25.0, 26.0, 33.4,
33.6, 55.2, 69.7, 127.5, 128.7, 129.0, 129.5, 134.4, 135.6, 138.0,
201.4, an aromatic carbon is overlapped; MS (FAB) m/z (rel
int %): 340 (26, M+ + 1), 154 (100); IR νmax (NaCl) cm-1: 3340
(NH), 1690 (CO). Anal. Calcd for C21H25NOS: C, 74.30; H,
7.42; N, 4.13. Found: C, 74.27; H, 7.50; N, 4.09.
(2S,1′S)-S-P h en yl
2-(r-m eth ylben zyla m in o)-3,3-d i-
m eth ylbu tan eth ioate (24b): light yellow oil; 1H NMR (CDCl3)
δ: 0.97 (9 H, s), 1.35 (3 H, d, J ) 6.4 Hz), 2.01 (1 H, br s), 2.91
(1 H, s), 3.88 (1 H, q, J ) 6.4 Hz), 7.28 (1 H, t, J ) 7 Hz), 7.34
(2 H, t, J ) 7 Hz), 7.39 (2 H, d, J ) 7 Hz), 7.42 (5 H, s); 13C
NMR (CDCl3) δ: 25.3, 27.1, 34.3, 56.7, 74.0, 127.1, 127.2, 128.3,
128.6, 129.1, 129.2, 134.2, 144.8, 203.0; MS (FAB) m/z (rel int
%): 328 (31, M+ + 1), 190 (100); IR νmax (KBr) cm-1: 3345
(NH), 1695 (CO). Anal. Calcd for C20H25NOS: C, 73.35; H,
7.69; N, 4.28. Found: C, 73.35; H, 7.85; N, 4.26.
Ack n ow led gm en t. This work was supported in part
by Grants-in-Aid for Scientific Research No. 08304037
and 09771915 from the Ministry of Education, Science,
Sports, and Culture.
Su p p or tin g In for m a tion Ava ila ble: Spectra data (1H
NMR, 13C NMR, IR, and MS) and assignment of 1H NMR
signals for 1b, 1c, 2, 4, 5, 7, 8, 14, 17-24 and X-ray
crystallographic analysis data for 14h (41 pages). This mate-
rial is contained in libraries on microfiche, immediately follows
this article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
S-P h en yl 2-(N-cycloh exyltr iflu or oa ceta m id o)-p-tol-
1
ylth ioa ceta te (8d ): colorless oil; H NMR (CDCl3) δ: 1.06-
1.09 (1 H, m), 1.24-1.43 (3 H, m), 1.56-1.75 (4 H, m), 1.89 (1
H, br d, J ) 13 Hz), 2.10 (1 H, br d, J ) 12 Hz), 2.39 (3 H, s),
3.92 (1 H, m), 4.94 (1 H, s), 7.21 (2 H, d, J ) 7.8 Hz), 7.35-
7.41 (7 H, m); MS (FAB) m/z (rel int %): 436 (19, M+ + 1),
326 (100); IR νmax (NaCl) cm-1: 1685 (CO), 1205, 1140 (CF3).
Anal. Calcd for C23H24F3NO2S: C, 63.43; H, 5.55; N, 3.22.
Found: C, 63.17; H, 5.72; N, 3.09.
J O981230N