Asymmetric synthesis of cis-3,4-disubstituted β-sultams

Article abstract of DOI:10.1055/s-2005-865326

The asymmetric synthesis of cis-3,4-disubstituted β-sultams is reported. The protocol is based on the oxidation of 1,2-aminothiols with H ₂O₂ and ammonium heptamolybdate. The chlorination of the resulting β-amino sulfonic acids was a

Full text of DOI:10.1055/s-2005-865326

PAPER
1807
Asymmetric Synthesis of cis-3,4-Disubstituted b-Sultams
A
symmetric Synth
i
esis of
e
cis-3,4-Dis
t
ubstitu
e
b
-Sulta
m
r
s
Enders,* Alexander Moll
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: Enders@rwth-aachen.de
Received 20 January 2005; revised 15 February 2005
Despite these promising applications there are only a few
examples for the synthesis of diastereomerically and
enantiomerically pure b-sultams reported in the literature.
In general, b-sultams can be synthesised by [2+2] cy-
Abstract: The asymmetric synthesis of cis-3,4-disubstituted b-sul-
tams is reported. The protocol is based on the oxidation of 1,2-ami-
nothiols with H2O2 and ammonium heptamolybdate. The
chlorination of the resulting b-amino sulfonic acids was achieved
utilising a solution of phosgene in toluene. The b-aminosulfonyl cloaddition of sulfene intermediates with imines,12 of alk-
enes with N-sulfonylamines13 or by intramolecular
chlorides obtained were cyclised to the title compounds under basic
cyclisation.14
conditions without epimerisation (de, ee ≥96%) and good overall
yields (17–59%). In addition, the N-Cbz-protection of b-sultams
was easily accomplished.
Kataoka et al., for example, described the diastereoselec-
tive [2+2] cycloaddition using mesyl chloride and chiral
imines.15 However, the adaptable substrates are not only
restricted in the choice of substituents, the cycloaddition
also yields unsatisfactory stereoselectivities. Another ac-
cess to enantiomerically pure b-sultams is the ex-chiral-
pool synthesis starting from natural amino acids. Initially
Otto et al. utilised cysteine derivatives16 as precursors, but
recently also embarked on other amino acids followed by
introduction of the sulfur moiety.17
Key words: asymmetric synthesis, reductive cleavage, 1,2-amino-
thiol, ring-closure, 1,2-thiazetidine 1,1-dioxides
1,2-Thiazetidine 1,1-dioxides (b-sultams)1 can be seen as
sulfonyl analogues of b-lactams or cyclic sulfonamides.
The acyclic sulfonamide moiety has been used extensive-
ly as a surrogate for the amide group in the design of pep-
tidomimetics, which have found widespread application
as potent enzyme inhibitors.2 Thus, sultams are interesting
building blocks for the synthesis of new synthetic drugs,
corresponding to b-lactam antibiotics.3 Their reactivity is
usually higher compared to the analogous b-lactam sys-
tems (approx. 103-fold)4 and at least 107-fold more reac-
tive than acyclic sulfonamides.5 Therefore, they are
important subunits for chemical and pharmaceutical ap-
plications.
One of the most reliable approaches is the synthesis of an
open chain precursor with already established stereo-
chemistry, such as b-amino sulfonic acids, and subse-
quent intramolecular ring closure.
Following this strategy we developed an asymmetric syn-
thesis of enantiopure b-sultams. We already reported the
asymmetric synthesis of b-amino sulfonates using asym-
metric Lewis acid catalysed aza-Michael additions to alk-
enyl sulfonic esters as the key step.18 With this precursor
in hand, we were able to synthesise a variety of 3-substi-
tuted b-sultams.19
Page et al. have investigated the biological properties and
reaction mechanisms of nucleophiles influenced by dif-
ferent substituents.6 Extensive theoretical studies on the
alcoholysis of b-sultams were described by Feng and co-
workers.7 According to these results, b-sultams can act as
peptidomimetics in sulfonyltransfer reactions. They are
potent sulfonating agents for a variety of nucleophiles. It
was shown that some of them inactivate serine proteases,
especially N-benzoyl b-sultam is an irreversible inhibitor
of elastase, which is responsible for diseases such as em-
physema, cystic fibrosis and rheumatoid arthritis.8 In ad-
dition, cyclic sulfonamides found application as
agrochemicals.9
Only one further enantioselective synthesis is described in
the literature.20 Baldoli et al. used chiral tricarbonyl(h6-
arene)chromium(0) complexes in the synthesis of 3-sub-
stituted 1,2-thiazetidine 1,1-dioxide derivatives. Howev-
er, the choice of substituents in the C-3 position is
restricted (o-substituted phenyls).
We have also described the flexible asymmetric synthesis
of anti-1,2-benzylsulfanyl amines (S,R)-221 employing
the SAMP/RAMP hydrazone methodology (Scheme 1).22
As part of our continuous interest in the asymmetric syn-
thesis of heterocyles,23 we now wish to report the success-
ful application of sulfanyl amines (S,R)-2 in the diastereo-
and enantioselective synthesis of cis-3,4-disubstituted b-
sultams (S,R)-5.
Furthermore the C–S and C–N bonds can be broken under
different conditions.10 The cleavage of these bonds leads
to taurine derivatives and a wide range of building blocks
for the synthesis of other heterocycles. Moreover, enan-
tiopure b-sultams have been employed as ligands in the
enantioselective hydrogenation of ketones.11
As shown in Scheme 1 the anti-1,2-benzylsulfanyl
amines (S,R)-2 were synthesised with excellent diastereo-
meric and enantiomeric excesses (de, ee ≥96%). Key steps
are the diastereoselective a-alkylation of a-sulfanylated
acetaldehyde-SAMP-hydrazone (S)-1 with various elec-
SYNTHESIS 2005, No. 11, pp 1807–1816
x
x.
x
x
.
2
0
0
5
Advanced online publication: 18.04.2005
DOI: 10.1055/s-2005-865326; Art ID: Z02005SS
© Georg Thieme Verlag Stuttgart · New York

1808
D. Enders, A. Moll
PAPER
Moc
R2
H3CO
#
HN
HN SO2
R2 R1
Moc
R2
#
R1
HN
N
H
ref. 21
N
R1
SBn
17–59%
SBn
(S,R)-2
(S,R)-5
25–73%
SBn
(S)-1
de, ee ≥ 96%
de, ee ≥ 96%
(S,R)-2
de, ee ≥ 96%
R1 = i-Bu, Ph(CH2)2, Bn,
c-Hex(CH2)
c
a
68–99%
Moc
39–83%
+
R2 = Me, n-Bu, n-Hex
Moc
R2
HN
HN
b
Scheme 1 Asymmetric synthesis of anti-1,2-benzylsulfanyl amines
(S,R)-2; Moc = methoxycarbonyl
R1
R1
R2
44–99%
SH
SO2Cl
(S,R)-3
de, ee ≥ 96%
(S,R)-4
de, ee ≥ 96%
trophiles and subsequent nucleophilic 1,2-addition of or-
ganocerium compounds to the hydrazone C=N double
bond. The resulting hydrazines were converted to the cor-
Scheme 2 Synthesis of the disubstituted b-sultams (S,R)-5 starting
responding protected amines by reductive N–N bond from anti-1,2-benzylsulfanyl amines (S,R)-2. Reagents and reaction
conditions: a) Li/NH3, –33 °C, 30 min; b) 1. H2O2, (NH4)6Mo7O21,
cleavage. The relative and absolute configuration was de-
termined by NOE experiments and X-ray structure analy-
sis.
MeOH, 2. NaOAc, CH2Cl2, r.t., 3. COCl2 in toluene, CH2Cl2, DMF,
r.t.; c) 1. CH2Cl2, HBr–AcOH, 7 d, r.t.; 2. Et3N, 2 h, 0 °C
With these compounds in hands, we were able to synthe-
sise the title b-sultams as shown in Scheme 2.
obtained by means of H2O2 in MeOH with an excess of
ammonium heptamolybdate.27
Initial attempts to synthesise the aminosulfonyl chlorides
(S,R)-4 directly starting from aminosulfide (S,R)-2 by ox-
idative chlorination led to decomposition. Therefore, we
decided to follow a two-step protocol. The cleavage of S-
benzyl groups was already described in the literature us-
ing lithium in ammonia.24
The 1,2-amino thiols (S,R)-3 were oxidised to the corre-
sponding amino sulfonic acid (TLC monitoring), which
were directly converted without further purification to
their sodium salts, followed by chlorination utilising a
phosgene solution in toluene. The resulting b-amino-sul-
fonyl chlorides were obtained in good to excellent yields
(44–99%) and without epimerisation (de, ee ≥96%). The
results of oxidation and chlorination are summarised in
Table 2.
Employing this method, we were able to obtain the corre-
sponding 1,2-amino thiols (S,R)-3 after aqueous work up
and purification in good to excellent yields (68–99%) and
without epimerisation (de, ee ≥96%). The results of the re-
ductive cleavage are summarised in Table 1.
The chlorination was also tried with other reagents like
PPh3/SO2Cl2,28 triphosgene29 or PPh3·Cl2,30 but in contrast
to the literature where these conditions showed good re-
sults, we observed a significant lower yield.
In the following step, the thiol moiety has to be oxidised.
We initially tried to use peracetic acid (H2O2–AcOH)25
and perfluoroacetic acid (H2O2–CF3CO2H),26 but these re-
action conditions led to poor yields. The best results were
Afterwards, the Moc-group was cleaved employing HBr–
AcOH.31 The resulting free amines were cyclised in situ
Table 1 Reductive Debenzylation of the anti-1,2-Benzylsulfanyl Amines (S,R)-2 to the Amino Thiols (S,R)-3
3
R1
R2
Yield (%)
dea (%)
≥96
≥96
≥96
≥96
≥96
≥96
≥96
≥96
eeb (%)
≥96
≥96
≥96
≥96
≥96
≥96
≥96
≥96
(S,R)-3a
(S,R)-3b
(S,R)-3c
(S,R)-3d
(S,R)-3e
(S,R)-3f
(S,R)-3g
(S,R)-3h
i-Bu
n-Bu
Me
73
68
94
92
86
93
99
99
Bn
Bn
n-Bu
n-Hex
Me
Bn
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
c-Hex(CH2)
n-Bu
n-Hex
n-Bu
a Determined by 13C NMR spectroscopy.
b Based on the ee values of the enantiopure anti-1,2-benzylsulfanylamines (S,R)-2.
Synthesis 2005, No. 11, 1807–1816 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of cis-3,4-Disubstituted b-Sultams
1809
Table 2 Synthesis of the N-Protected 1,2-Aminosulfonyl Chlorides (S,R)-4
4
R1
R2
Yield (%)
dea (%)
≥96
eeb (%)
≥96
(S,R)-4a
(S,R)-4b
(S,R)-4c
(S,R)-4d
(S,R)-4e
(S,R)-4f
i-Bu
n-Bu
n-Bu
Me
99
44
71
99
44
52
Bn
≥96
≥96
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
c-Hex(CH2)
≥96
≥96
n-Bu
n-Hex
n-Bu
≥96
≥96
≥96
≥96
≥96
≥96
a Determined by 13C NMR spectroscopy.
b Based on the ee values of the enantiopure anti-1,2-benzylsulfanyl amines (S,R)-2.
using an excess of Et3N. The title b-sultams (S,R)-5 were Irradiation of the proton at C-4 showed a strong nuclear
obtained in moderate to good yields (39–83%) and excel- Overhauser effect with the proton at C-3. No interaction
lent diastereomeric and enantiomeric excesses (de, ee was observed between the proton at C-3 with the alkyl
≥96%).
side chain at C-4 and the proton at C-4 showed no NOE
effect with the alkyl side chain at C-3. Furthermore the
coupling constant between the protons at C-3 and C-4
(J = 8.4 Hz) indicates the cis-configuration.
In several cases the diastereomeric excess determined by
13C NMR could be confirmed by GC (Table 3). Other
deprotection protocols using TFA and TMSI32 were also
tested but only the N-protected amino sulfonic acids were
obtained.
2
1
H
H
H
HN SO2
H
CH3
H
The enantiomeric excesses given are based on the diaste-
reomeric excesses of the corresponding sulfanyl amines
(S,R)-2. The whole synthetic sequence leading to the b-
sultams was assumed to be free of epimerisation. This was
indeed a valid assumption that could be proven in case of
(S,R)-5d. The corresponding enantiomer (R,S)-5d was
synthesised starting from (R,S)-2d which could be ob-
tained from the RAMP hydrazone following the general
protocol. The ee-values were determined by GC analysis
using a chiral stationary phase and comparison with the
racemic mixture. This enabled us to confirm the epimeri-
sation free course of the b-sultam synthesis.
CH3
H
O2S
3
4
N
H3C
CH3
H3C
H
(S,R)-5a
CH3
Figure 1 NOE connectivity in b-sultam (S,R)-5a
Page et al. already reported that the reactivity of b-sultams
depends on the N-substituent.6
Sultams with N-carbamate or acyl groups show high reac-
tivity against nucleophiles. Therefore, we demonstrated
for one example the conversion of b-sultam (R,S)-5d to its
Cbz-protected derivative (R,S)-6. It was obtained with vir-
The cis-configuration of the disubstituted b-sultams was
proven by an NOE measurement of (S,R)-5a (Figure 1).
Table 3 Cyclization of the 1,2-Aminosulfonyl Chlorides (S,R)-4 to the b-Sultams (S,R)-5
5
R1
R2
Yield (%)
de (%)a
≥96
≥96
≥96
98c
ee (%)b
≥96
(S,R)-5a
(S,R)-5b
(S,R)-5c
(S,R)-5d
(S,R)-5e
(S,R)-5f
i-Bu
n-Bu
n-Bu
Me
50
82
50
64
39
83
Bn
≥96
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
c-Hex(CH2)
≥96
≥98d
n-Bu
n-Hex
n-Bu
≥96
98c
≥96
≥96
a Determined by 13C NMR spectroscopy.
b Based on the ee values of the enantiopure sulfanyl amines (S,R)-2.
c Determined by GC.
d Determined by GC using a chiral stationary phase (Chirasil-dex).
Synthesis 2005, No. 11, 1807–1816 © Thieme Stuttgart · New York

1810
D. Enders, A. Moll
PAPER
(S,R)-(1-Butyl-2-mercapto-4-methylpentyl)carbamic Acid Me-
thyl Ester [(S,R)-3a]
Cbz
HN SO2
n-Bu
N
SO2
a
According to GP 1 compound (S,R)-2a (663 mg, 1.97 mmol) was
debenzylated with Li (68 mg) in NH3 and (S,R)-3a (356 mg, 73%)
was obtained after column chromatography as a colourless oil; Rf
n-Bu
99%
18
0.42 (Et2O–n-pentane, 1:6); de, ee ≥96%; [a]D +16.2 (c = 1.06,
CHCl3).
(R,S)-5d
(R,S)-6
IR (CHCl3): 3332 (m), 2955 (vs), 2868 (s), 1708 (vs), 1516 (vs),
1462 (s), 1365 (m), 1244 (s), 1195 (m), 1113 (m), 1069 (m), 1019
(m), 929 (w), 776 (w), 759 (m) cm–1.
Scheme 3 Synthesis of the N-Cbz-protected b-sultam (R,S)-6.
Reagents and reaction conditions: a) 1. THF, DMPU, –78 °C, n-Bu-
Li, 5 min, 2. CbzCl, –78 °C, 15 min
1H NMR (400 MHz, CDCl3): d = 0.89 [d, J = 6.6 Hz, 3 H,
CH(CH3)2], 0.91 (t, J = 6.6 Hz, 3 H, CH2CH3), 0.97 [d, J = 6.9 Hz,
3 H, CH(CH3)2], 1.25–1.51 (m, 9 H, CH2CH2CH2CH3, CHCH2CH2,
SH), 1.87 [m, 1 H, CH(CH3)2], 3.05 (m, 1 H, SCH), 3.67 (s, 3 H,
OCH3), 3.74 (m, 1 H, CHNH), 4.95 (d, J = 9.0 Hz, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 14.0 (CH3), 21.6, 23.0
[CH(CH3)2], 22.6 (CH2CH3), 25.6 [CH(CH3)2], 28.2, 28.7
(CHCH2CH2), 44.4 (SCH), 44.8 (CHCH2CH), 52.0 (OCH3), 54.7
(CHNH), 156.5 (C=O).
MS (EI, 70 eV): m/z (%) = 247 (0.1) [M+], 145 (8), 144 (100), 88
(25).
MS (CI, CH4): m/z (%) = 248 (14) [M+ + 1], 214 (5), 174 (8), 173
(77), 171 (6), 145 (8), 144 (100), 104 (5), 88 (11), 83 (8), 69 (5).
tually quantitative yield utilising n-BuLi and DMPU
(Scheme 3).
In summary, we have described a versatile and efficient
asymmetric synthesis of cis-3,4-disubstituted b-sultams
starting from anti-1,2-benzylsulfanyl amines. The reac-
tion sequence begins with the reductive cleavage of the
benzyl group. The corresponding amino thiols were ob-
tained with high yields (37–99%) and excellent stereose-
lectivities (de, ee ≥96%). The following oxidation led to
the amino sulfonic acids, which were converted directly to
the aminosulfonyl chlorides in high yields (44–99%) and
without epimerisation. Deprotection of the amino group
and cyclisation under basic conditions led to the b-sultams
in excellent diastereomeric and enantiomeric excesses
(de, ee ≥96%) and moderate to good yields (39–83%).
HRMS: m/z calcd for C12H25NO2S – C5H11S: 144.1025; found:
144.1025.
(S,R)-(2-Mercapto-1-methyl-3-phenylpropyl)carbamic Acid
Methyl Ester [(S,R)-3b]
According to GP 1 compound (S,R)-2b (298 mg, 0.90 mmol) was
debenzylated with Li (34 mg) in NH3 and (S,R)-3b (146 mg, 68%)
was obtained after column chromatography as a colourless oil; Rf
All reagents were purchased from common commercial suppliers
and used from freshly opened containers. Solvents for chromatog-
raphy and workup were dried and purified by conventional methods
prior to use. THF was freshly distilled from sodium–lead and ben-
zophenone under Ar. Preparative flash column chromatography
was carried out with Merck silica gel 60, particle size 0.040–0.063
mm. Optical rotation values were measured using a Perkin-Elmer P
241 polarimeter, solvents used were of Merck UVASOL quality. IR
spectra were obtained with a Perkin-Elmer FT/IR 1760 spectrome-
ter. NMR spectra were measured on Varian VXR 300, Varian Ge-
mini 300 and Varian Inova 400 spectrometers with TMS as an
internal standard. MS data were obtained with Varian MAT 212
(EI, 70 eV, 1 mA) and Finnigan MAT SSQ 7000 (CI, 100 eV) in-
struments. Microanalyses were obtained with a Vario EL element
analyzer. High resolution MS data were measured on a Finningan
MAT, MAT 95 instrument. Merck TLC silica gel 60 F254 plates
have been used for TLC analyses and the products were visualised
by UV detection or phosphomolybdic acid (5 wt% in EtOH). Melt-
ing points were determined on a Tottoli melting point apparatus and
are uncorrected.
18
0.18 (Et2O–n-pentane, 1:6); de, ee ≥96%; [a]D +45.7 (c = 1.12,
CHCl3).
IR (film): 3327 (m), 3062 (w), 3027 (m), 2977 (m), 2946 (m), 1708
(vs), 1516 (vs), 1454 (s), 1380 (m), 1352 (m), 1249 (s), 1192 (m),
1116 (m), 1069 (s), 913 (m), 778 (m), 734 (s), 703 (m), 500 (w)
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.10 (d, J = 6.7 Hz, 3 H, CH3), 2.67
(dd, J = 14.1, 9.3 Hz, 1 H, CHHPh), 2.86 (dd, J = 14.1, 5.9 Hz, 1 H,
CHHPh), 3.27 (m, 1 H, SCH), 3.56 (s, 3 H, OCH3), 3.85 (m, 1 H,
NCH), 5.05 (d, J = 7.7 Hz, 1 H, NH), 7.09–7.26 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): d = 14.8 (CH3), 42.6 (CH2Ph), 47.7
(SCH), 49.7 (NCH), 52.1 (OCH3), 126.8 (pCPh), 128.6, 129.0
(CPh, mCPh), 138.6 (ipsoCPh), 156.1 (C=O).
MS (EI, 70 eV): m/z (%) = 206 (2) [M+ – HS], 205 (15) [M+ – H2S],
164 (9), 131 (7), 102 (100), 91 (15) (C7H7), 58 (15).
MS (CI, CH4): m/z (%) = 268 (14), 240 (39) [M+ + 1], 208 (16), 205
(8), 165 (79), 159 (11), 131 (100), 105 (34), 102 (28), 76 (18), 61
(12).
Preparation of 1,2-Aminothiols 3; General Procedure 1 (GP 1)
To liquid NH3, (50 mL/mmol), which was placed in a three necked
flask fitted with a dry ice condenser, small pieces of lithium wire (5
mmol) were added. The 1,2-benzylsulfanyl amines (S,R)-2 (1
mmol) were dissolved in anhyd THF (10 mL/mmol) and added to
this dark blue solution at –78 °C. The cooling bath was removed and
the solution was kept under reflux (–33 °C) for 30 min. The reaction
was quenched with solid NH4Cl and NH3 was evaporated at r.t. The
residue was dissolved in a mixture of CH2Cl2 and H2O (1:1), the or-
ganic layer was separated and the aqueous phase extracted with
CH2Cl2. The combined organic phases were dried with MgSO4 and
concentrated under reduced pressure. The crude products were pu-
rified by column chromatography (silica gel, Et2O–n-pentane).
HRMS: m/z calcd for C12H17NO2 – H2S: 205.1103; found:
205.1104.
(S,R)-[1-(1-Mercapto-2-phenylethyl)pentyl]carbamic Acid
Methyl Ester [(S,R)-3c]
According to GP 1 compound (S,R)-2c (840 mg, 2.34 mmol) was
debenzylated with Li (81 mg) in NH3 and (S,R)-3c (619 mg, 94%)
was obtained after column chromatography as a colourless solid;
mp 62 °C; Rf 0.21 (Et2O–n-pentane, 1:6); de, ee ≥96%; [a]D18 +50.0
(c = 1.05, CHCl3).
IR (KBr): 3304 (vs), 3064 (m), 3032 (m), 2953 (vs), 2864 (m), 1709
(vs), 1687 (vs), 1602 (w), 1548 (vs), 1497 (m), 1454 (m), 1439 (m),
1349 (m), 1293 (s), 1270 (s), 1248 (vs), 1191 (m), 1115 (m), 1074
Synthesis 2005, No. 11, 1807–1816 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of cis-3,4-Disubstituted b-Sultams
1811
(w), 1042 (m), 958 (m), 938 (w), 817 (w), 777 (w), 748 (s), 722 (m),
700 (s), 680 (s), 503 (w), 466 (w) cm–1.
Ph), 3.70 (s, 3 H, OCH3), 3.90 (m, 1 H, CHNH), 5.05 (s, 1 H, NH),
7.16–7.33 (m, 5 H, PhH.).
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 6.1 Hz, 3 H, CH3),
1.25–1.50 [m, 6 H, (CH2)3CH3], 1.60 (m, 1 H, SH), 2.74 (dd, J = 9.9,
13.8 Hz, 1 H, CHHPh), 3.02 (dd, J = 5.2, 13.9 Hz, 1 H, CHHPh),
3.30 (m, 1 H, SCH), 3.66 (s, 3 H, OCH3), 3.81 (m, 1 H, CHNH),
4.92 (d, J = 9.2 Hz, 1 H, NH), 7.18–7.34 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.6 (CH2CH3), 28.1
(CH2CH2CH3), 29.0 (CHCH2CH2), 42.3 (CH2Ph), 47.8 (SCH), 52.2
(OCH3), 54.5 (NCH), 126.7 (pCPh), 128.5, 129.1 (oCPh, mCPh),
138.6 (ipsoCPh), 156.6 (C=O).
13C NMR (75 MHz, CDCl3): d = 14.7 (CH3), 33.7 (CH2Ph), 38.2
(CH2Bn), 46.2 (SCH), 50.1 (NCH), 52.1 (OCH3), 126.1 (pCPh),
128.4, 128.5 (oCPh, mCPh), 141.2 (ipsoCPh), 156.1(C=O).
MS (EI, 70 eV): m/z (%) = 253 (2) [M+], 178 (13), 103 (6), 102
(100), 91 (11), 58 (7).
HRMS: m/z calcd for C13H19NO2S: 253.1136; found: 253.1137.
(S,R)-[1-(1-Mercapto-3-phenylpropyl)pentyl]carbamic Acid
Methyl Ester [(S,R)-3f]
MS (EI, 70 eV): m/z (%) = 247 (7), 206 (5), 145 (8), 144 (100), 115
(5), 91 (11), 88 (28), 59 (6).
MS (CI, i-C4H9): m/z (%) = 284 (6), 283 (18), 282 (100) [M+ + 1],
144 (6).
According to GP 1 compound (S,R)-2f (2.38 g, 6.18 mmol) was de-
benzylated with Li (215 mg) in NH3 and (S,R)-3f (1.70 g, 93%) was
obtained after column chromatography as a colourless solid; mp 64
22
°C; Rf 0.26 (Et2O–n-pentane, 1:6); de, ee ≥96%; [a]D –6.0 (c =
1.16, CHCl3).
Anal. Calcd for C15H23NO2S (281.41): C, 64.02; H, 8.24; N, 4.98.
Found: C, 64.09; H, 7.95; N, 4.92.
IR (KBr): 3677 (w), 3311 (vs), 3056 (m), 3027 (m), 2956 (s), 2859
(s), 1713 (s), 1684 (vs), 1603 (w), 1538 (vs), 1497 (m), 1456 (m),
1382 (w), 1367 (w), 1294 (m), 1252 (s), 1189 (m), 1126 (w), 1083
(m), 1018 (m), 932 (w), 913 (w), 885 (w), 783 (m), 756 (m), 707
(m), 652 (m), 499 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 6.9 Hz, 3 H, CH3),
1.18–1.41 (m, 6 H, CH2CH2CH2CH3), 1.46 (m, 1 H, SH), 1.72 (m,
1 H, CHHBn), 1.98 (ddd, J = 4.4, 6.6, 14.0 Hz, 1 H, CHHBn), 2.69
(ddd, J = 6.9, 10.3, 13.8 Hz, 1 H, CHHPh), 2.95 (m, 2 H, SCH,
CHHPh), 3.67 (s, 3 H, OCH3), 3.80 (m, 1 H, NCH), 4.86 (d, J = 9.3
Hz, 1 H, NH), 7.17–7.32 (m, 5 H, PhH).
13C NMR (100 MHz, CDCl3): d = 14.0 (CH3), 22.6 (CH2CH3), 28.1
(CH2CH2CH3), 29.0, 33.8 [CH2(CH2)2CH3, CH2Bn], 37.8 (CH2Ph),
46.2 (SCH), 52.1 (OCH3), 55.0 (NCH), 125.9 (pCPh), 128.3, 128.3
(oCPh, mCPh), 141.3 (ipsoCPh), 156.4 (C=O).
MS (EI, 70 eV): m/z (%) = 295 (1) [M+], 145 (8), 144 (100), 91 (11,
C7H7), 88 (10).
(S,R)-[1-(1-Mercapto-2-phenylethyl)heptyl]carbamic Acid
Methyl Ester [(S,R)-3d]
According to GP 1 compound (S,R)-2d (486 mg, 1.22 mmol) was
debenzylated with Li (42 mg) in NH3 and (S,R)-3d (347 mg, 92%)
was obtained after column chromatography as a colourless oil; Rf
18
0.23 (Et2O–n-pentane, 1:6); de, ee ≥96%; [a]D +37.5 (c = 1.01,
CHCl3).
IR (KBr): 3329 (vs), 3062 (m), 3027 (m), 2924 (vs), 2856 (s), 1695
(vs), 1603 (w), 1541 (vs), 1455 (m), 1383 (m), 1337 (m), 1298 (m),
1263 (s), 1231 (m), 1195 (m), 1095 (vs), 1027 (vs), 928 (m), 803 (s),
752 (s), 699 (s), 543 (w), 467 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 (t, J = 6.9 Hz, 3 H, CH3),
1.10–1.40 [m, 10 H, (CH2)5CH3], 1.54 (m, 1 H, SH), 2.69 (dd, J =
9.6, 13.8 Hz, 1 H, CHHPh), 2.95 (dd, J = 5.5, 14.1 Hz, 1 H, CHH-
Ph), 3.23 (m, 1 H, SCH), 3.60 (s, 3 H, OCH3), 3.75 (m, 1 H, CHNH),
4.77 (d, J = 9.6 Hz, 1 H, NH), 7.12–7.28 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): d = 13.0 (CH3), 21.6 (CH2CH3), 24.9,
28.1, 28.3, 30.7 [(CH2)4CH3], 41.3 (CH2Ph), 46.7 (SCH), 51.1
(OCH3), 53.5 (NCH), 125.7 (pCPh), 127.5, 128.0 (oCPh, mCPh),
137.6 (ipsoCPh), 155.6 (C=O).
MS (CI, CH4): m/z (%) = 296 (27) [M+ + 1], 264 (12), 215 (7), 187
(100), 144 (41), 131 (11), 117 (21).
HRMS: m/z calcd for C16H25NO2S: 295.1606; found: 295.1607.
(S,R)-[1-(1-Mercapto-3-phenylpropyl)heptyl]carbamic Acid
Methyl Ester [(S,R)-3g]
MS (EI, 70 eV): m/z (%) = 276 (1.6) [M+ – HS], 275 (5), 173 (10),
172 (100), 91 (15) [C7H7], 88 (42), 76 (5), 59 (7), 55 (14).
According to GP 1 compound (S,R)-2g (353 mg, 0.85 mmol) was
debenzylated with Li (31 mg) in NH3 and (S,R)-3g (272 mg, 99%)
was obtained after column chromatography as a colourless solid;
mp 44 °C; Rf 0.22 (Et2O–n-pentane, 1:9); de, ee ≥96%; [a]D26 –4.3
(c = 1.14, CHCl3).
MS (CI, CH4): m/z (%) = 350 (6), 338 (15), 311 (13), 310 (69), 308
(12), 292 (19), 291 (5), 290 (5), 280 (7), 279 (6), 278 (38), 276 (15),
263 (19), 249 (18), 237 (5), 236 (12), 235 (100), 234 (8), 233 (8),
229 (8), 201 (40), 172 (32), 131 (18), 117 (11), 76 (11).
IR (KBr): 3327 (s), 3056 (w), 3027 (w), 2926 (vs), 2854 (s), 1694
(vs), 1605 (w), 1542 (vs), 1500 (m), 1458 (m), 1302 (s), 1267 (s),
1201 (m), 1122 (m), 1067 (m), 1019 (w), 777 (w), 753 (s), 702 (m),
659 (m), 598 (w), 499 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.10 (d, J = 6.6 Hz, 3 H, CH3),
1.24–1.47 [m, 11 H, SH, (CH2)5CH3], 1.72 (ddd, J = 4.6, 9.9, 14.9
Hz, 1 H, CHHBn), 1.99 (m, 1 H, CHHBn), 2.69 (ddd, J = 6.6, 9.9,
13.5 Hz, 1 H, CHHPh), 2.95 (m, 2 H, SCH, CHHPh), 3.66 (s, 3 H,
OCH3), 3.80 (m, 1 H, CHNH), 5.05 (d, J = 8.8 Hz, 1 H, NH), 7.16–
7.32 (m, 5 H, PhH).
HRMS: m/z calcd for C17H27NO2S – H2S: 275.1885; found:
275.1886.
(S,R)-(2-Mercapto-1-methyl-4-phenylbutyl)carbamic Acid
Methyl Ester [(S,R)-3e]
According to GP 1 compound (S,R)-2e (154 mg, 0.45 mmol) was
debenzylated with Li (16 mg) in NH3 and (S,R)-3e (98 mg, 86%)
was obtained after column chromatography as a colourless oil; Rf
26
0.17 (Et2O–n-pentane, 1:9); de, ee ≥96%; [a]D –16.0 (c = 1.06,
CHCl3).
IR (CHCl3): 3331 (m), 3060 (w), 3026 (m), 2939 (s), 2858 (m),
2563 (w), 1712 (vs), 1603 (w), 1513 (vs), 1453 (s), 1350 (m), 1246
(s), 1193 (m), 1113 (m), 1082 (s), 777 (m), 750 (m), 701 (s), 619
(w), 498 (w) cm–1.
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.6 (CH2CH3), 26.0,
29.2, 29.4, 31.7 [(CH2)4CH2CH3], 33.9 (CH2Ph), 37.9 (CH2Bn),
46.2 (SCH), 52.1 (OCH3), 55.1 (NCH), 126.1 (pCPh), 128.5, 128.5
(oCPh, mCPh), 141.3 (ipsoCPh), 156.7 (C=O).
1H NMR (300 MHz, CDCl3): d = 1.10 (d, J = 6.7 Hz, 3 H, CH3), 1.25
(s, 1 H, SH), 1.71 (m, 1 H, CHHBn), 1.95 (m, 1 H, CHHBn), 2.70
(ddd, J = 6.6, 9.6, 13.6 Hz, 1 H, CHHPh), 2.95 (m, 2 H, SCH, CHH-
MS (EI, 70 eV): m/z (%) = 324 (0.4) [M+], 173 (9), 172 (100), 91
(7), 88 (27).
Synthesis 2005, No. 11, 1807–1816 © Thieme Stuttgart · New York

1812
D. Enders, A. Moll
PAPER
MS (CI, CH4): m/z (%) = 324 (17) [M+], 322 (7), 292 (12), 243 (6),
216 (14), 215 (84), 173 (9), 172 (100), 145 (6), 131 (17), 117 (28),
91 (7), 88 (12).
(CHCH2CH), 52.3, 52.4 (OCH3, CHNH), 80.9 (SCH), 156.6
(C=O).
MS (EI, 70 eV): m/z (%) = 256 (5), 145 (8), 144 (100), 114 (9), 88
HRMS: m/z calcd for C18H29NO2 – C2H5NO2: 248.1599; found:
(25), 76 (5), 69 (6).
248.1599.
MS (CI, CH4): m/z (%) = 338 (5), 316 (16), 314 (42) [M+ + 1], 311
(11), 310 (71), 308 (5), 282 (5), 278 (17), 252 (9), 250 (6), 215 (13),
214 (100), 212 (5), 145 (6), 143 (80), 139 (5), 88 (7).
(S,R)-[1-(2-Cyclohexyl-1-mercaptoethyl)pentyl]carbamic Acid
Methyl Ester [(S,R)-3h]
According to GP 1 compound (S,R)-2h (50 mg, 0.12 mmol) was de-
benzylated with Li (4.4 mg) in NH3 and (S,R)-3h (38 mg, 99%) was
obtained after column chromatography as a colourless oil; Rf 0.49
(Et2O–n-pentane, 1:6); de, ee ≥96%; [a]D25 +9.0 (c = 1.39, CHCl3).
IR (film): 3328 (m), 2923 (vs), 2852 (vs), 1705 (vs), 1531 (vs), 1450
(s), 1348 (m), 1245 (s), 1194 (m), 1095 (m), 1019 (m), 942 (w),890
(w), 778 (m), 717 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.90 (t, J = 6.8 Hz, 3 H, CH3),
1.00–1.77 [m, 20 H, CH2CH(CH2)cyclohexyl, CH2CH2CH2CH3,
(CH2)cyclohexyl, SH] 3.09 (m, 1 H, SCH), 3.67 (s, 3 H, OCH3), 3.65–
3.78 (m, 1 H, CHNH), 4.89 (m, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 14.0 (CH3), 22.6 (CH2CH3), 26.1,
26.2, 26.5, 28.2, 28.7, 32.4, 33.7 [CHCH2CH2, (CH2)cyclohexyl], 35.0
(CHcyclohexyl), 43.6 (SCH), 52.0 (OCH3), 54.9 (CHNH), 156.5
(C=O).
MS (EI, 70 eV): m/z (%) = 287 (0.1) [M+], 145 (9), 144 (100), 88
(17), 55 (5).
Anal. Calcd for C12H24NO4SCl (313.84): C, 45.92; H, 7.71; N, 4.46.
Found: C, 46.35; H, 7.49; N, 4.56.
(S,R)-[1-(1-Chlorosulfonyl-2-phenylethyl)pentyl]carbamic
Acid Methyl Ester [(S,R)-4b]
According to GP 2 compound (S,R)-3c (281 mg, 1.00 mmol) was
converted to (S,R)-4b which could be isolated after column chroma-
tography as a colourless oil (137 mg, 44%); Rf 0.91 (Et2O–n-pen-
tane, 1:1); de, ee ≥96%; [a]D25 +10.6 (c = 0.33, CHCl3).
IR (CHCl3): 3414 (m), 3328 (m), 3064 (m), 3028 (m), 2958 (vs),
2865 (s), 1721 (vs), 1604 (w), 1517 (vs), 1455 (vs), 1370 (vs), 1245
(s), 1194 (m), 1162 (vs), 1120 (w), 1075 (m), 1038 (m), 936 (w),
756 (vs), 701 (s), 638 (m), 580 (m), 525 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 7.2 Hz, 3 H, CH3),
1.25–1.45 [m, 4 H, (CH2)2CH3], 1.55 (m, 1 H, CHCHHCH2), 2.90
(m, 1 H, CHCHHCH2), 3.09 (m, 2 H, CH2Ph), 3.64 (s, 3 H, OCH3),
3.99 (m, 1 H, SCH), 4.27 (m, 1 H, NCH), 5.14 (d, J = 9.1 Hz, 1 H,
NH), 7.22–7.42 (m, 5 H, PhH).
Anal. Calcd for C15H29NO2S (287.46): C, 62.67; H, 10.17; N, 4.87.
Found: C, 63.03; H, 10.10; N, 5.15.
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 22.1 (CH2CH3), 28.7
(CH2CH2CH3), 29.3, 34.3 (CHCH2CH2, CH2Ph), 51.6 (NCH), 52.4
(OCH3), 82.6 (SCH), 127.9 (pCPh), 128.9, 129.2 (oCPh, mCPh),
134.6 (ipsoCPh), 156.2 (C=O).
Synthesis of the 1,2-Aminosulfonyl Chlorides 4; General Proce-
dure 2 (GP 2)
MS (EI, 70 eV): m/z (%) = 248 (10), 247 (5), 190 (15), 173 (15),
145 (8), 144 (100), 131 (5), 130 (11), 117 (20), 116 (5), 115 (11), 91
(33), 88 (27), 76 (7), 59 (6).
The amino thiols (S,R)-3 (1.0 mmol) were dissolved in MeOH (4.8
mL/mmol) and ammonium heptamolybdate (1.4 mmol) was added.
After that aq H2O2 solution (4.8 mL/mmol) was added dropwise and
the mixture was stirred for 2 d (TLC control). After addition of Pd/
C in order to destroy the excess of H2O2 and stirring for 30 min, the
reaction mixture was filtered over celite. The solution was concen-
trated under reduced pressure and the corresponding crude amino
sulfonic acid was dissolved in CH2Cl2. NaOAc (1.1 mmol) was add-
ed and the mixture was stirred for 1 h at r.t. The solvents were re-
moved and the crude sodium salts were dissolved in anhyd CH2Cl2
(10 mL/mmol) and anhyd DMF (0.12 mL/mmol). Then a solution
containing 20% phosgene in toluene (4.1 mL/mmol) was added and
the mixture was stirred for 2 h at r.t. The solution was concentrated
and the crude product was purified by column chromatography (sil-
ica gel, Et2O–n-pentane).
MS (CI, CH4): m/z (%) = 348 (3), 312 (13), 287 (6), 286 (32), 285
(17), 284 (100), 282 (7), 252 (8), 251 (5), 250 (29), 249 (13), 248
(74), 247 (8), 201 (6), 190 (6), 175 (7), 174 (7), 173 (34), 144 (41),
119 (6), 117 (7), 91 (9), 76 (19), 75 (8), 65 (21).
HRMS: m/z calcd for C15H22NO4SCl – SO2Cl: 248.1650; found:
248.1650.
(S,R)-(2-Chlorosulfonyl-1-methyl-4-phenylbutyl)carbamic
Acid Methyl Ester [(S,R)-4c]
According to GP 2 compound (S,R)-3e (90 mg, 0.36 mmol) was
converted to (S,R)-4c which could be isolated after column chroma-
tography as a colourless oil (82 mg, 71%); Rf 0.25 (Et2O–n-pentane,
1:1); de, ee ≥96%; [a]D25 +40.7 (c = 1.11, CHCl3).
IR (CHCl3): 3409 (s), 3325 (s), 3062 (m), 3027 (m), 2951 (s), 2867
(m), 1718 (vs), 1604 (w), 1520 (vs), 1454 (vs), 1366 (vs), 1250 (vs),
1161 (vs), 1066 (m), 946 (w), 755 (vs), 702 (s), 628 (s), 537 (m),
499 (w), 469 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40 (d, J = 7.1 Hz, 3 H, CH3), 2.13
(ddd, J = 5.5, 9.0, 14.5 Hz, 1 H, CHHCH2Ph), 2.51 (m, 1 H,
CHHCH2Ph), 2.86 (ddd, J = 7.7, 7.7, 14.0 Hz, 1 H, CHHPh), 2.96
(ddd, J = 5.5, 9.0, 14.2 Hz, 1 H, CHHPh), 3.70 (s, 3 H, OCH3), 3.88
(m, 1 H, SCH), 4.38 (m, 1 H, NCH), 5.41 (s, 1 H, NH), 7.15–7.36
(m, 5 H, PhH).
(S,R)-(1-Butyl-2-chlorosulfonyl-4-methylpentyl)carbamic Acid
Methyl Ester [(S,R)-4a]
According to GP 2 compound (S,R)-3a (367 mg, 1.48 mmol) was
converted to (S,R)-4a which could be isolated after column chroma-
tography as a colourless solid (413 mg, 99%); mp 97 °C; Rf 0.91
(Et2O–n-pentane, 1:1); de, ee ≥96%; [a]D25 +60.1 (c = 1.01, CHCl3).
IR (KBr): 3340 (vs), 2960 (vs), 2871 (s), 1696 (vs), 1540 (vs), 1466
(s), 1365 (vs), 1315 (w), 1295 (w), 1255 (s), 1232 (m), 1193 (m),
1163 (s), 1115 (m), 1061 (m), 1041 (m), 1013 (m), 962 (w), 932 (w),
835 (w), 783 (m), 716 (m), 637 (vs), 533 (s), 504 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.91 (t, J = 6.9 Hz, 3 H, CH3), 1.04
[d, J = 4.9 Hz, 3 H, CH(CH3)2], 1.07 [d, J = 6.2 Hz, 3 H, CH(CH3)2],
1.20–1.60 (m, 6 H, CH2CH2CH2CH3), 1.75–2.02 [m, 3 H,
CH2CH(CH3)2], 3.72 (s, 3 H, OCH3), 3.97 (m, 1 H, SCH), 4.05 (m,
1 H, CHNH), 5.28 (d, J = 9.7 Hz, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 15.9 (CH3), 30.1 (CH2Bn), 32.7
(CH2Ph), 47.5 (NCH), 52.4 (OCH3), 80.9 (SCH), 126.6 (pCPh),
128.3, 128.6 (oCPh, mCPh), 138.9 (ipsoCPh), 155.8 (C=O).
MS (EI, 70 eV): m/z (%) = 319 (13) [M+], 219 (12), 164 (23), 145
(29), 144 (12), 129 (10), 128 (11), 117 (5), 116 (6), 115 (13), 105
(5), 104 (5), 103 (6), 102 (100), 91 (24), 76 (7), 65 (5), 59 (5), 58 (7).
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 21.3, 23.3 [CH(CH3)2],
22.1 (CH2CH3), 25.8 [CH(CH3)2], 28.9, 29.1 (CHCH2CH2), 36.8
Synthesis 2005, No. 11, 1807–1816 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of cis-3,4-Disubstituted b-Sultams
1813
MS (CI, CH4): m/z (%) = 318 (6), 317 (17), 316 (100), 315 (8), 284
(17), 252 (7), 220 (20), 145 (16), 102 (6).
(S,R)-[1-(1-Chlorosulfonyl-2-cyclohexylethyl)pentyl]carbamic
Acid Methyl Ester [(S,R)-4f]
According to GP 2 compound (S,R)-3h (220 mg, 0.77 mmol) was
converted to (S,R)-4f which could be isolated after column chroma-
tography as a colourless oil (143 mg, 52%); Rf 0.90 (Et2O–n-pen-
tane, 1:1); de, ee ≥96%; [a]D25 +20.0 (c = 0.14, CHCl3).
IR (CHCl3): 3410 (m), 3334 (m), 3017 (m), 2928 (vs), 2856 (vs),
1719 (vs), 1518 (vs), 1452 (s), 1367 (vs), 1244 (s), 1162 (s), 1117
(m), 1023 (w), 758 (vs), 640 (m), 530 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.91 (t, J = 7.1 Hz, 3 H, CH3),
0.75–1.77 [m, 18 H, CHHCH(CH2)cyclohexyl, CH2CH2CH2CH3,
(CH2)cyclohexyl], 2.00 [m, 1 H, CHHCH(CH2)cyclohexyl], 3.71 (s, 3 H,
OCH3), 4.03 (m, 2 H, CHNH, SCH), 5.25 (d, J = 9.6 Hz, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 22.1 (CH2CH3), 25.7,
26.0, 26.2, 28.9, 29.2 32.0, 33.8, 35.5, [CH2CH2CH2CH3,
CH2CH(CH2)cyclohexyl], 34.9 [CH(CH2)cyclohexyl], 52.5 (OCH3,
CHNH), 80.2 (SCH), 156.5 (C=O).
HRMS: m/z calcd for C13H18NO4SCl – Cl: 284.0957; found:
284.0955.
(S,R)-[1-(1-Chlorosulfonyl-3-phenylpropyl)pentyl]carbamic
Acid Methyl Ester [(S,R)-4d]
According to GP 2 compound (S,R)-3f (120 mg, 0.41 mmol) was
converted to (S,R)-4d which could be isolated after column chroma-
tography as a colourless solid (147 mg, 99%); mp 65 °C; Rf 0.92
(Et2O–n-pentane, 1:1); de, ee ≥96%; [a]D25 +50.8 (c = 1.01, CHCl3).
IR (KBr): 3337 (vs), 3062 (w), 3026 (m), 2956 (vs), 2932 (s), 2869
(m), 1694 (vs), 1603 (w), 1532 (vs), 1452 (s), 1366 (vs), 1306 (w),
1258 (vs), 1190 (m), 1159 (vs), 1119 (m), 1068 (m), 1020 (m), 967
(w), 915 (m), 854 (w), 782 (m), 753 (m), 704 (s), 632 (vs), 533 (s),
483 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 6.9 Hz, 3 H, CH3),
1.18–1.48 (m, 4 H, CH2CH2CH3), 1.58 (m, 1 H, CHCHHCH2), 1.76
(m, 1 H, CHCHHCH2), 2.13 (m, 1 H, CHHCH2Ph), 2.51 (m, 1 H,
CHHCH2Ph), 2.93 (m, 2 H, CH2Ph), 3.77 (s, 3 H, OCH3), 3.88 (m,
1 H, SCH), 4.21 (m, 1 H, NCH), 5.31 (d, J = 9.7 Hz, 1 H, NH), 7.20–
7.34 (m, 5 H, PhH).
MS (CI, CH4): m/z (%) = 356 (21), 355 (11), 354 (55), 352 (5), 350
(8), 255 (16), 254 (100), 252 (9), 222 (7), 144 (36), 65 (6).
Anal. Calcd for C15H28NO4SCl (353.91): C, 50.91; H, 7.97; N, 3.96.
Found: C, 51.33; H, 8.40; N, 4.41.
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 22.1 (CH2CH3), 28.7
(CH2CH2CH3), 29.6 (CH2CH2CH2CH3), 29.9 (CH2Bn), 32.7
(CH2Ph), 52.1 (NCH), 52.5 (OCH3), 81.2 (SCH), 126.8 (pCPh),
128.6, 128.8 (oCPh, mCPh), 139.2 (ipsoCPh), 156.5 (C=O).
Cyclisation of the 1,2-Aminosulfonyl Chlorides 4 to the b-Sul-
tams 5; General Procedure 3 (GP 3)
The amino sulfonyl chlorides (S,R)-4 were dissolved in CH2Cl2 (20
mL/mmol) and a 33% solution of HBr in AcOH (6.0 equiv) was
added. After stirring for 7 d at r.t. the reaction mixture was cooled
to 0 °C and Et3N (12mL/mmol) was added using a syringe pump.
The solution was stirred for 2 h while it was allowed to warm to r.t.
After the addition of water and separation of the organic layer the
aqueous phases were extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and the solvent was removed under
reduced pressure. The b-sultams were isolated after chromatograph-
ic purification (silica gel, Et2O–pentane).
MS (EI, 70 eV): m/z (%) = 361 (7), 262 (12), 187 (6), 186 (5), 170
(11), 164 (24), 145 (9), 144 (100), 131 (7), 130 (7), 129 (16), 117
(9), 115 (14), 114 (11), 104 (5), 91 (21), 88 (24), 76 (12), 59 (5).
Anal. Calcd for C16H24NO4SCl (361.88): C, 53.10; H, 6.68; N, 3.87.
Found: C, 53.28; H, 6.75; N, 3.77.
(S,R)-[1-(1-Chlorosulfonyl-3-phenylpropyl)heptyl]carbamic
Acid Methyl Ester [(S,R)-4e]
According to GP 2 compound (S,R)-3g (148 mg, 0.46 mmol) was
converted to (S,R)-4e which could be isolated after column chroma-
tography as a colourless solid (80 mg, 44%); mp 55 °C; Rf 0.92
(Et2O–n-pentane, 1:1); de, ee ≥96%; [a]D25 +46.3 (c = 1.01, CHCl3).
IR (KBr): 3981 (m), 3939 (m), 3880 (w), 3816 (w), 3691 (w), 3634
(w), 3310 (vs), 3062 (m), 3031 (m), 2929 (vs), 2860 (s), 1694 (vs),
1604 (w), 1546 (vs), 1455 (s), 1359 (vs), 1314 (m), 1268 (s), 1248
(s), 1193 (m), 1159 (s), 1126 (m), 1066 (s), 1030 (m), 971 (w), 891
(w), 853 (w), 783 (m), 739 (s), 697 (s), 640 (vs), 534 (vs), 498 (s),
475 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.88 (t, J = 6.6 Hz, 3 H, CH3),
1.20–1.50 [m, 8 H, (CH2)4CH3], 1.60 (m, 1 H, NHCHCHH), 1.65
(m, 1 H, NHCHCHH), 2.14 (ddd, J = 6.1, 8.8, 14.6 Hz, 1 H, CHH-
Bn), 2.50 (m, 1 H, CHHBn), 2.92 (m, 2 H, CH2Ph), 3.71 (s, 3 H,
OCH3), 3.90 (m, 1 H, SCH), 4.20 (m, 1 H, CHNH), 5.24 (d, J = 9.6
Hz, 1 H, NH), 7.22–7.36 (m, 5 H, PhH).
13C NMR (100 MHz, CDCl3): d = 14.0 (CH3), 22.5 (CH2CH3), 26.6,
28.7, 29.8, 31.5 [(CH2)4CH2CH3], 29.9, (CH2Bn), 32.7 (CH2Ph),
52.0 (NCH), 52.4 (OCH3), 81.2 (SCH), 126.6 (pCPh), 128.3, 128.4
(oCPh, mCPh), 139.0 (ipsoCPh), 156.3 (C=O).
(S,R)-3-Butyl-4-isobutyl[1,2]thiazetidine-1,1-dioxide [(S,R)-5a]
According to GP 3 the compound (S,R)-4a (157 mg, 0.5 mmol) was
cyclised to the b-sultam (S,R)-5a. After column chromatography the
product was obtained as a yellow oil (55 mg, 50%); Rf 0.26 (Et2O–
n-pentane, 1:1); de, ee ≥96%; [a]D25 –10.2 (c = 1.27, CHCl3).
IR (CHCl3): 3283 (vs), 2957 (vs), 2871 (vs), 1713 (s), 1524 (m),
1465 (vs), 1388 (m), 1301 (s), 1160 (vs), 1078 (m), 986 (w), 876
(w), 823 (w), 793 (m), 748 (s), 663 (s), 527 (m), 475 (m) cm–1.
1H NMR (500 MHz, CDCl3): d = 0.92 (t, J = 7.0 Hz, 3 H, CH3), 0.98
[d, J = 6.7 Hz, 3 H, CH(CH3)2], 1.00 [d, J = 6.7 Hz, 3 H, CH(CH3)2],
1.23 (m, 1 H, CHHCH2CH3), 1.36 (m, 3 H, CHHCH2CH3), 1.57 (m,
1 H, CHCHHCH), 1.62 (m, 2 H, CHCH2CH2), 1.76 [sept, J = 7.0
Hz, 1 H, CH(CH3)2], 2.03 (ddd, J = 6.1, 11.0, 14.3 Hz, 1 H, CHCH-
HCH), 3.62 (ddd, J = 3.9, 8.2, 9.6 Hz, 1 H, NCH), 4.56 (dddd, J =
0.9, 4.3, 8.6, 11.3 Hz, 1 H, SCH), 5.34 (s, 1 H, NH).
13C NMR (125 MHz, CDCl3): d = 14.0 (CH3), 21.8, 22.5
[CH(CH3)2], 22.2 (CH2CH3), 26.8 [CH(CH3)2], 28.2 (CH2CH2CH3),
30.5 (CHCH2CH2), 33.1 (CHCH2CH), 45.5 (NCH), 74.0 (SCH).
MS (EI, 70 eV): m/z (%) = 219 (0.8), 177 (6), 176 (69), 161 (13),
144 (9), 140 (6), 120 (28), 113 (6), 112 (63), 99 (7), 98 (36), 97 (13),
95 (6), 86 (15), 84 (12), 83 (9), 82 (14), 81 (46), 79 (5), 71 (5), 70
(29), 69 (21), 67 (6), 58 (6), 57 (100), 56 (67), 55 (27), 54 (6).
MS (EI, 70 eV): m/z (%) = 389 (8) [M+], 198, (8), 173 (9), 172
(100), 164 (15), 131 (8), 129 (12), 117 (6), 115 (8), 114 (9), 104 (5),
91 (20), 88 (31), 76 (14), 55 (6).
Anal. Calcd for C10H21NO2S (219.34): C, 54.76; H, 9.65; N, 6.39.
Found: C, 54.29; H, 10.03; N, 6.66.
MS (CI, CH4): m/z (%) = 393 (8), 392 (37), 391 (24), 390 (100), 389
(11), 388 (12), 358 (5), 354 (13), 326 (15), 291 (13), 290 (61), 289
(19), 288 (5), 243 (6), 216 (6), 215 (37), 172 (50), 164 (6), 131 (6),
117 (5), 91 (8), 88 (7), 76 (9), 65 (6).
(S,R)-4-Benzyl-3-butyl[1,2]thiazetidine-1,1-dioxide [(S,R)-5b]
According to GP 3 the compound (S,R)-4b (47 mg, 0.14 mmol) was
cyclised to the b-sultam (S,R)-5b. After column chromatography
HRMS: m/z calcd for C18H28NO4SCl – Cl: 354.1739; found:
354.1739.
Synthesis 2005, No. 11, 1807–1816 © Thieme Stuttgart · New York

1814
D. Enders, A. Moll
PAPER
the product was obtained as a yellow oil (29 mg, 82%); Rf 0.22
(Et2O–n-pentane, 1:2); de, ee ≥96%; [a]D25 –20.9 (c = 0.56, CHCl3).
IR (KBr): 3285 (vs), 3063 (m), 3028 (m), 2957 (vs), 2864 (s), 1604
(w), 1497 (m), 1457 (s), 1305 (vs), 1164 (vs), 1073 (m), 1031 (w),
969 (m), 880 (w), 757 (vs), 700 (vs), 666 (s), 584 (m), 540 (w), 485
(m) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, J = 7.2 Hz, 3 H, CH3),
1.23–1.50 (m, 4 H, CH2CH2CH3), 1.59–1.80 (m, 2 H, CHCH2CH2),
3.07 (dd, J = 5.5, 15.1 Hz, 1 H, CHHPh), 3.45 (dd, J = 9.9, 15.1 Hz,
1 H, CHHPh), 3.70 (m, 1 H, NCH), 4.80 (m, 1 H, SCH) 5.33 (s, 1
H, NH), 7.26–7.36 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): d = 13.9 (CH3), 22.3 (CH2CH3), 28.2
(CH2CH2CH3), 30.5, 30.7 (CHCH2CH2, CH2Ph), 45.7 (NCH), 76.3
(SCH), 127.2 (pCPh), 128.5, 129.0 (oCPh, mCPh), 136.4 (ipsoCPh).
(m, 1 H, CHCHHCH2), 1.98 (dddd, J = 4.5, 8.0, 8.9, 13.9 Hz, 1 H,
CHHCH2Ph), 2.44 (dddd, J = 5.2, 8.7, 11.6, 13.6 Hz, 1 H,
CHHCH2Ph), 2.68 (ddd, J = 8.2, 8.2, 13.9 Hz, 1 H, CHHPh), 2.92
(ddd, J = 4.9, 8.9, 13.8 Hz, 1 H, CHHPh), 3.59 (ddd, J = 4.2, 8.5,
9.9 Hz, 1 H, NCH), 4.45 (dddd, J = 1.7, 4.4, 8.4, 11.4 Hz, 1 H,
SCH), 5.51 (s, 1 H, NH), 7.20–7.34 (m, 5 H, PhH).
13C NMR (100 MHz, CDCl3): d = 13.9 (CH3), 22.3 (CH2CH3), 27.0
(CH2Bn), 28.2 (CH2CH2CH3), 30.4 (CH2CH2CH2CH3), 33.7
(CH2Ph), 45.4 (NCH), 74.4 (SCH), 126.6 (pCPh), 128.6, 128.7
(oCPh, mCPh), 139.9 (ipsoCPh).
MS (EI, 70 eV): m/z (%) = 202 (45), 186 (15), 176 (7), 169 (11), 160
(5), 159 (6), 150 (6), 147 (11), 146 (80), 145 (28), 144 (64), 143
(10), 133 (5), 131 (5), 130 (10), 129 (60), 128 (11), 121 (5), 120
(12), 118 (19).
MS (CI, CH4): m/z (%) = 296 (13), 270 (6), 269 (17), 268 (100)
MS (EI, 70 eV): m/z (%) = 253 (4) [M+], 196 (35), 189 (14), 188
(77), 160 (5), 147 (18), 146 (19), 133 (21), 132 (100), 130 (12), 129
(9), 128 (5), 117 (9), 115 (11), 105 (22), 104 (34), 103 (10), 98 (7),
91 (26), 84 (11), 78 (5), 77 (5), 56 (10).
[M+], 244 (5), 232 (16), 205 (11), 204 (69), 202 (5), 187 (8).
Anal. Calcd for C14H21NO2S (267.39): C, 62.89; H, 7.92; N, 5.24.
Found: C, 62.49; H, 7.98; N, 4.77.
MS (CI, CH4): m/z (%) = 255 (13), 254 (30), 219 (5), 218 (12), 191
(14), 190 (100), 188 (6), 173 (13), 150 (5), 86 (5).
(S,R)-3-Hexyl-4-phenethyl[1,2]thiazetidine-1,1-dioxide [(S,R)-
5e]
According to GP 3 the compound (S,R)-4e (70 mg, 0.18 mmol) was
cyclised to the b-sultam (S,R)-5e. After column chromatography the
product was obtained as a yellow oil (20 mg, 39%); Rf 0.52 (Et2O–
n-pentane, 1:1); de, ee ≥96%; [a]D25 +4.21 (c = 0.67, CHCl3).
IR (CHCl3): 3279 (vs), 3063 (m), 3026 (m), 2927 (vs), 2856 (vs),
2735 (w), 2687 (w), 2658 (w), 2633 (w), 2305 (w), 1710 (s), 1603
(m), 1528 (m), 1497 (m), 1457 (s), 1378 (m), 1304 (vs), 1161 (vs),
1132 (vs), 1030 (m), 807 (m), 752 (vs), 701 (vs), 669 (s), 619 (s),
524 (m), 484 (w) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 7.1 Hz, 3 H, CH3),
1.15–1.50 [m, 10 H, (CH2)5CH3], 1.98 (m, 1 H, CHHCH2Ph), 2.45
(dddd, J = 4.9, 8.4, 11.6, 13.6 Hz, 1 H, CHHCH2Ph), 2.69 (ddd, J =
8.0, 8.0, 13.6 Hz, 1 H, CHHPh), 2.94 (ddd, J = 5.0, 8.9, 13.6 Hz, 1
H, CHHPh), 3.59 (ddd, J = 4.2, 8.4, 10.1 Hz, 1 H, NCH), 4.47
(dddd, J = 1.7, 4.7, 8.4, 11.4 Hz, 1 H, SCH), 5.23 (s, 1 H, NH), 7.20–
7.34 (m, 5 H, PhH).
HRMS: m/z calcd for C13H19NO2S: 253.1137; found: 253.1136.
(S,R)-3-Methyl-4-phenylethyl[1,2]thiazetidine-1,1-dioxide
[(S,R)-5c]
According to GP 3 the compound (S,R)-4c (71 mg, 0.22 mmol) was
cyclised to the b-sultam (S,R)-5c. After column chromatography the
product was obtained as a yellow oil (25 mg, 50%); Rf 0.12 (Et2O–
n-pentane, 1:2); de, ee ≥96%; [a]D25 –17.6 (c = 0.50, CHCl3).
IR (CHCl3): 3288 (s), 3063 (m), 3023 (vs), 2978 (s), 2934 (s), 2860
(m), 2402 (w), 1712 (s), 1603 (m), 1512 (s), 1454 (s), 1386 (w),
1310(s), 1218 (vs), 1163 (s), 1125 (w), 1080 (m), 1030 (w), 930
(m), 829 (w), 755 (s), 702 (s), 667 (s), 578 (w), 509 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.33 (d, J = 6.3 Hz, 3 H, CH3), 1.95
(m, 1 H, CHHBn), 2.45 (m, 1 H, CHHBn), 2.69 (dt, J = 7.9, 13.7
Hz, 1 H, CHHPh), 2.91 (ddd, J = 5.2, 9.1, 14.0 Hz, 1 H, CHHPh),
3.79 (m, 1 H, NCH), 4.46 (m, 1 H, SCH), 5.09 (s, 1 H, NH), 7.20–
7.34 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.5 (CH2CH3), 26.1,
27.0, 28.8, 30.7, 31.6 [CH2Bn, (CH2)4CH2CH3], 33.6 (CH2Ph), 45.4
(NCH), 74.4 (SCH), 126.6 (pCPh), 128.6, 128.7 (oCPh, mCPh),
139.9 (ipsoCPh).
13C NMR (100 MHz, CDCl3): d = 16.7 (CH3), 26.9 (CH2Bn), 33.4
(CH2Ph), 41.1 (NCH), 74.3 (SCH), 126.6 (pCPh), 128.6, 128.7
(oCPh, mCPh), 139.8 (ipsoCPh).
MS (EI, 70 eV): m/z (%) = 225 (1.5), 170 (10), 160 (22), 145 (7),
144 (28), 143 (19), 129 (29), 128 (18), 118 (19), 117 (46), 115 (12),
108 (8), 107 (7), 106 (77), 105 (6), 104 (6), 92 (9), 91 (100), 77 (5),
70 (33), 65 (16), 57 (50), 56 (7), 55 (5), 51 (5).
MS (EI, 70 eV): m/z (%) = 230 (50), 214 (10), 172 (10), 170 (11),
147 (10), 146 (100), 145 (14), 144 (10), 143 (7), 141 (9), 140 (82),
130 (8), 129 (6), 128 (45), 127 (18), 126 (7), 120 (11), 118 (17), 117
(37), 115 (12), 114 (65), 110 (5), 106 (50), 105 (6), 104 (17), 92 (8),
91 91), 84 (10), 81 (5), 77 (5), 71 (5), 70 (21), 69 (10), 68 (6), 67
(7), 65 (12).
MS (CI, CH4): m/z (%) = 227 (8), 226 (63), 190 (16), 163 (11), 162
(100), 160 (7), 145 (29).
MS (CI, CH4): m/z (%) = 324 (5), 297 (11), 296 (54), 260 (20), 233
(16), 232 (100), 230 (13), 215 (8), 146 (9), 140 (6), 117 (8), 114 (8).
HRMS: m/z calcd for C11H15NO2S: 225.0824; found: 225.0824.
(S,R)-3-Butyl-4-phenethyl[1,2]thiazetidine-1,1-dioxide [(S,R)-
5d]
HRMS: m/z calcd for C16H25NO2S – SO2H: 230.1909; found:
230.1908.
According to GP 3 the compound (S,R)-4d (119 mg, 0.33 mmol)
was cyclised to the b-sultam (S,R)-5d. After column chromatogra-
phy the product was obtained as a colourless solid (57 mg, 64%);
mp 88 °C; Rf 0.48 (Et2O–n-pentane, 1:1); de = 98% (GC); ee ≥98%
(GC); [a]D25 –10.5 (c = 0.97, CHCl3).
(S,R)-3-Butyl-4-cyclohexylmethyl[1,2]thiazetidine-1,1-dioxide
[(S,R)-5f]
According to GP 3 the compound (S,R)-4f (63 mg, 0.18 mmol) was
cyclised to the b-sultam (S,R)-5f. After column chromatography the
product was obtained as a colourless solid (39 mg, 83%); mp 70 °C;
IR (KBr): 3309 (vs), 3083 (m), 3063 (m), 3026 (m), 2931 (vs), 2858
(vs), 1876 (w), 1707 (vs), 1603 (m), 1528 (m), 1497 (m), 1456 (vs),
1384 (m), 1333 (s), 1289 (vs), 1167 (vs), 1139 (s), 1074 (m), 1027
(w), 977 (w), 900 (w), 852 (w), 811 (m), 752 (s), 726 (s), 700 (vs),
676 (s), 590 (w), 524 (m), 489 (m), 458 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 7.1 Hz, 3 H, CH3),
1.15–1.40 (m, 4 H, CH2CH2CH3), 1.55 (m, 1 H, CHCHHCH2), 1.62
25
Rf 0.56 (Et2O–n-pentane, 1:1); de = 98% (GC); ee ≥96%; [a]D
–
28.3 (c = 0.90, CHCl3).
IR (KBr): 3441 (s), 3401 (s), 3270 (vs), 3109 (w), 3086 (w), 2925
(vs), 2849 (vs), 2797 (w), 2372 (w), 2342 (w), 1721 (w), 1625 (m),
1444 (m), 1383 (m), 1291 (vs), 1171 (vs), 1131 (m), 1079 (m), 980
Synthesis 2005, No. 11, 1807–1816 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of cis-3,4-Disubstituted b-Sultams
1815
(w), 935 (w), 901 (w), 875 (w), 795 (m), 752 (s), 671 (m), 578 (w),
537 (m), 471 (m) cm–1.
run Keul for her skilful experimental contribution as an undergra-
duate student.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, J = 7.1 Hz, 3 H, CH3),
1.00–1.80 [m, 18 H, CHHCHcyclohexyl, (CH2)3CH3, (CH2)cyclohexyl],
2.01 [ddd, J = 6.0, 11.2, 14.5 Hz, 1 H, CHHCH(CH2)cyclohexyl], 3.61
(ddd, J = 3.9, 8.2, 12.6 Hz, 1 H, NCH), 4.58 (ddd, J = 3.8, 8.8, 12.1
Hz, 1 H, SCH) 5.25 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.4 (CH2CH3), 26.1,
26.3, 28.2, 30.4, 32.0, 32.7, 33.2 [CH(CH2)2, (CH2)cyclohexyl], 36.1
[CH(CH2)cyclohexyl], 45.5 (NCH), 73.7 (SCH).
References
(1) Iwama, T.; Kataoka, T. Rev. Heteroat. Chem. 1996, 15, 25.
(2) (a) Moree, W. J.; van der Marel, G.; Liskamp, R. J. J. Org.
Chem. 1995, 60, 5157. (b) de Bont, D. B. A.; Sliedregt-Bol,
K. M.; Hofmeyer, L. J. F.; Liskamp, R. M. J. Bioorg. Med.
Chem. 1999, 7, 1043.
(3) (a) Otto, H. H.; Schwenkkraus, P. Tertrahedron Lett. 1982,
23, 5389. (b) Cavagna, F.; Koller, W.; Linkies, A.; Rehling,
H.; Reuschling, D. Angew. Chem., Int. Ed. Engl. 1982, 7,
548; Angew. Chem. 1982, 7, 549. (c) Müller, M.; Otto, H.
H. Liebigs Ann. 1991, 171. (d) Liu, Z.; Takeuchi, Y.
Heterocycles 2002, 56, 693.
MS (EI, 70 eV): m/z (%) = 259 (0.6), 202 (7), 178 (6), 176 (39), 152
(8), 139 (8), 138 (51), 137 (6), 135 (5), 124 (5), 121 (14), 120 (18),
113 (7), 112 (72), 110 (5), 109 (9), 108 (6), 98 (18), 97 (7), 96 (8),
95 (26), 94 (5), 93 (9), 86 (27), 84 (19), 83 (16), 82 (15), 81 (18), 79
(9), 71 (6), 70 (55), 69 (13), 68 (5), 67 (20), 58 (7), 57 (100), 56 (71),
55 (36), 54 (8).
MS (CI, CH4): m/z (%) = 261 (8) [M+ + 2], 260 (51) [M+ + 1], 224
(16), 197 (14), 196 (100), 195 (8), 194 (23), 150 (5), 138 (9), 112
(8).
(4) Baxter, N. J.; Rigoreau, L. J. M.; Laws, A. P.; Page, M. I. J.
Am. Chem. Soc. 2000, 122, 3375.
(5) Baxter, N. J.; Laws, A. P.; Rigoreau, L.; Page, M. I. J. Chem.
Soc., Perkin Trans. 2 1996, 2245.
(6) (a) Hinchliffe, P. S.; Wood, J. M.; Davis, A. M.; Austin, R.
P.; Beckett, R. P.; Page, M. I. J. Chem. Soc., Perkin Trans. 2
2001, 1503. (b) Wood, J. M.; Hinchliffe, P. S.; Laws, A. P.;
Page, M. I. J. Chem. Soc., Perkin Trans. 2 2002, 938.
(c) Ahmed, N.; Tsang, W. Y.; Page, M. I. Org. Lett. 2004, 6,
201.
Anal. Calcd for C13H25NO2S (259.41): C, 60.19; H, 9.71; N, 5.40.
Found: C, 60.11; H, 10.03; N, 5.04.
(R,S)-3-Butyl-1,1-dioxo-4-phenethyl-1-[1,2]thiazetidine-2-car-
boxylic Acid Benzyl Ester [(R,S)-6]
For N-protection (R,S)-5d (31 mg, 0.12 mmol) was dissolved in an-
hyd THF (2 mL), under Ar atmosphere. n-BuLi (0.08 mL, 1,3
mmol) was added at –78 °C followed after 5 min by dropwise addi-
tion of CbzCl (2.0 equiv). The reaction mixture was stirred for an-
other 15 min at this temperature. The mixture was allowed to warm
to r.t. and hydrolysed with brine. The aqueous layer was extracted
with CH2Cl2, the organic phase was dried (MgSO4) and evaporated
in vacuo. After column chromatography the protected b-sultam
(S,R)-6 was obtained as a colourless oil (52 mg, 99%); Rf 0.50
(7) He, M.; Zhu, F.; Feng, D.; Cai, Z. Chem. Phys. Lett. 2003,
377, 13.
(8) (a) Page, M. I.; Laws, A. P. Tetrahedron 2000, 56, 5631.
(b) Beardsell, M.; Hinchliffe, P. S.; Wood, J. M.; Wilmouth,
R. C.; Schofield, C. J.; Page, M. I. Chem. Commun. 2001,
497. (c) Hinchliffe, P. S.; Wood, J. M.; Davis, A. M.; Austin,
R. P.; Beckett, R. P.; Page, M. I. Org. Biomol. Chem. 2003,
1, 67. (d) Page, M. I. Acc. Chem. Res. 2004, 37, 297.
(9) Katritzky, A. R.; Wu, J.; Rachwal, S.; Rachwal, B.;
Macomber, D. W.; Smith, T. P. Org. Prep. Proced. Int.
1992, 24, 463.
25
(Et2O–n-pentane, 1:2); de, ee ≥96%; [a]D +110.7 (c = 0.51,
CHCl3).
IR (CHCl3): 3065 (m), 3030 (m), 2957 (s), 2867 (m), 1957 (w),
1735 (vs), 1603 (w), 1497 (m), 1455 (s), 1387 (vs), 1344 (vs), 1304
(vs), 1214 (m), 1176 (vs), 1141 (vs), 1029 (w), 953 (w), 906 (w),
866 (w), 753 (vs), 699 (s), 593 (m), 556 (s), 475 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.87 (t, J = 7.1 Hz, 3 H, CH3),
1.22–1.40 (m, 4 H, CH2CH2CH3), 1.59 (m, 1 H, CHCHHCH2), 1.87
(m, 1 H, CHCHHCH2), 2.00 (m, 1 H, CHHCH2Ph), 2.44 (dddd, J =
4.7, 8.0, 12.9, 14.3 Hz, 1 H, CHHCH2Ph), 2.68 (ddd, J = 8.2, 8.2,
13.7 Hz, 1 H, CHHPh), 2.95 (ddd, J = 5.0, 8.8, 13.8 Hz, 1 H, CHH-
Ph), 4.02 (ddd, J = 6.8, 6.8 , 8.8 Hz, 1 H, NCH), 4.45 (ddd, J = 3.8,
8.8, 12.1 Hz, 1 H, SCH), 5.23 (d, J = 12.4 Hz, 1 H, OCHHPh), 5.30
(d, J = 12.4 Hz, 1 H, OCHHPh), 7.20–7.42 (m, 10 H, PhH).
(10) (a) Kataoka, T.; Iwama, T.; Takagi, A. Tetrahedron Lett.
1996, 37, 2257. (b) Iwama, T.; Kataoka, T.; Muraoka, O.;
Tanabe, G. Tetrahedron 1998, 54, 5507. (c) Iwama, T.;
Ogawa, M.; Kataoka, T.; Muraoka, O.; Tanabe, G.
Tetrahedron 1998, 54, 8941.
(11) Trentmann, W.; Mehler, T.; Martens, J. Tetrahedron:
Asymmetry 1997, 8, 2033.
(12) (a) Szymonifka, M. J.; Heck, J. V. Tetrahedron Lett. 1989,
30, 2869. (b) Grunder, E.; Leclerc, G. Synthesis 1989, 135.
(c) Grunder-Klotz, E.; Ehrhardt, J.-D. Tetrahedron Lett.
1990, 32, 751. (d) Gordeev, M. F.; Gordon, E. M.; Patel, D.
V. J. Org. Chem. 1997, 62, 8177.
(13) (a) Atkins, G. M. Jr.; Burgess, E. M. J. Am. Chem. Soc. 1967,
89, 2502. (b) Burgess, E. M.; Williams, W. M. J. Am. Chem.
Soc. 1972, 94, 4386. (c) Atkins, G. M. Jr.; Burgess, E. M. J.
Am. Chem. Soc. 1972, 94, 6135.
(14) (a) Schwenkkraus, P.; Otto, H.-H. Arch. Pharm. (Weinheim,
Ger.) 1993, 326, 519. (b) Schwenkkraus, P.; Otto, H.-H.
Liebigs Ann. Chem. 1994, 251. (c) Barton, W. R. S.;
Paquette, L. A. Can. J. Chem. 2004, 82, 113.
13C NMR (100 MHz, CDCl3): d = 13.8 (CH3), 22.5 (CH2CH3), 26.6
(CH2Bn), 28.3 (CH2CH2CH3), 29.4 (CHCH2CH2), 33.8 (CH2Ph),
49.8 (NCH), 68.5 (OCH2Bn), 73.4 (SCH), 126.6, 127.8, 128.3,
128.4, 128.6, (CPh), 134.7, 139.9 (ipsoCPh).
MS (EI, 70 eV): m/z (%) = 401 (1.5), 246 (15), 234 (5), 202 (29),
180 (11), 130 (5), 129 (7), 124 (9), 117 (9), 107 (14), 105 (5), 104
(17), 92 (9), 91 (100), 65 (5).
(15) Iwama, T.; Kataoka, T.; Muraoka, O.; Tanabe, G. J. Org.
Chem. 1998, 63, 8355.
(16) Schwenkkraus, P.; Merkle, S.; Otto, H.-H. Liebigs Ann./
Anal. Calcd for C22H27NO4S (401.52): C, 65.81; H, 6.78; N, 3.49.
Found: C, 66.16; H, 6.54; N, 3.71.
Recl. 1997, 1261.
(17) (a) Meinzer, A.; Breckel, A.; Thaler, B. A.; Manicone, N.;
Otto, H.-H. Helv. Chim. Acta 2004, 87, 90. (b) Röhrich, T.;
Thaher, B. A.; Otto, H.-H. Monatsh. Chem. 2004, 135, 55.
(c) Röhrich, T.; Thaher, B. A.; Manicone, N.; Otto, H.-H.
Monatsh. Chem. 2004, 135, 979.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg 440, Sonderforschungsbereich 380) and the
Fonds der Chemischen Industrie. We would like to thank Degussa
AG, BASF AG and Bayer AG for donations of chemicals and Heid-
(18) Enders, D.; Wallert, S. Synlett 2002, 304.
Synthesis 2005, No. 11, 1807–1816 © Thieme Stuttgart · New York

1816
D. Enders, A. Moll
PAPER
(25) Brouwer, A. J.; Monnee, M. C. F.; Liskamp, R. M. J.
(19) Enders, D.; Wallert, S. Tetrahedron Lett. 2002, 43, 5109.
(20) Baldoli, C.; Del Buttero, P.; Perdicchia, D.; Pilati, T.
Tetrahedron 1999, 55, 14089.
Synthesis 2000, 1579.
(26) Cremer, H. R.; Sartori, P. Chem.-Ztg 1989, 11, 325.
(27) Bernard, A. M.; Cerioni, G.; Piras, P. P.; Seu, G. Synthesis
1990, 871.
(21) Enders, D.; Moll, A.; Schaadt, A.; Runsink, J.; Raabe, G.
Eur. J. Org. Chem. 2003, 3923.
(22) Review: Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.;
Enders, D. Tetrahedron 2002, 58, 2253.
(28) Huang, J.; Widlanski, T. S. Tetrahedron Lett. 1992, 33,
2657.
(23) Recent examples: (a) Enders, D.; Wallert, S. Synthesis 2003,
1856. (b) Enders, D.; Gries, J.; Kim, Z.-S. Eur. J. Org.
Chem. 2004, 4471. (c) Enders, D.; Nolte, B.; Runsink, J.
Tetrahedron: Asymmetry 2002, 13, 587. (d) Enders, D.;
Braig, V.; Raabe, G. Can. J. Chem. 2001, 79, 1528.
(e) Enders, D.; Thiebes, C. Synthesis 2000, 510. (f) Enders,
D.; Kirchhoff, J. H. Synthesis 2000, 2099. (g) Enders, D.;
Del Signore, G. Heterocycles 2004, 64, 101. (h) Enders, D.;
Harnying, W.; Vignola, N. Eur. J. Org. Chem. 2003, 3939.
(i) Münch, A.; Wendt, B.; Christmann, M. Synlett 2004,
2751.
(29) Reynolds, R. C.; Crooks, P. A.; Maddry, J. A.; Akhtar, M. S.;
Montgomery, J. A.; Secrist, J. A. III J. Org. Chem. 1992, 57,
2983.
(30) Kataoka, T.; Iwama, T.; Setta, T.; Takagi, A. Synthesis 1998,
423.
(31) (a) Wani, M. C.; Campbell, H. F.; Brine, G. A.; Kepler, J. A.;
Wall, M. E. J. Am. Chem. Soc. 1972, 94, 3631. (b)Deroose,
F. D. P.; De Clercq, J. J. Org. Chem. 1996, 60, 321.
(c) Skyler, D.; Heathcock, C. H. Org. Lett. 2001, 3, 4323.
(32) Ksander, G. M.; deJesus, R.; Yuan, A.; Fink, C.; Moskal, M.;
Carlson, E.; Kukkola, P.; Bilci, N.; Wallace, E.; Neubert, A.;
Feldman, D.; Mogelesky, T.; Poirier, K.; Jeune, M.; Steele,
R.; Wasvery, J.; Stephan, Z.; Cahill, E.; Webb, R.;
Navarrete, A.; Lee, W.; Gibson, J.; Alexander, N.; Sharif,
H.; Hospattankar, A. J. Med. Chem. 2001, 44, 4677.
(24) (a) Corrie, J. E. T.; Hlubucek, J. R.; Lowe, G. J. Chem. Soc.,
Perkin Trans. 1 1977, 1421. (b) Holler, T. P.; Ruan, F.;
Spaltenstein, A.; Hopkins, P. B. J. Org. Chem. 1989, 54,
4570.
Synthesis 2005, No. 11, 1807–1816 © Thieme Stuttgart · New York