Efficient asymmetric synthesis of 3-substituted β-sultams

Article abstract of DOI:10.1016/S0040-4039(02)00980-2

The asymmetric synthesis of 3-substituted 1,2-thiazetidine 1,1-dioxides by cyclization of β-amino-sulfonyl chlorides is reported. The synthesis is based on the aza-Michael addition of (R,R,R)-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane (RAMBO) to al

Full text of DOI:10.1016/S0040-4039(02)00980-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5109–5111
Efficient asymmetric synthesis of 3-substituted b-sultams
Dieter Enders* and Stefan Wallert
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule, Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Received 8 May 2002; accepted 23 May 2002
Abstract—The asymmetric synthesis of 3-substituted 1,2-thiazetidine 1,1-dioxides by cyclization of b-amino-sulfonyl chlorides is
reported. The synthesis is based on the aza-Michael addition of (R,R,R)-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]octane
(RAMBO) to alkenyl–sulfonates. © 2002 Elsevier Science Ltd. All rights reserved.
1,2-Thiazetidine 1,1-dioxides (b-sultams) are the sulfo-
nyl analogues of b-lactams. They contain three different
heteroatom bonds: NꢀS, SꢀC and NꢀC. Cleavage of
these bonds leads to a wide range of interesting build-
ing blocks for the synthesis of other heterocyclic sys-
tems or b-amino-sulfonic acids.1
To the best of our knowledge only one stereoselective
synthesis of b-sultams exists. Baldoli et al. used chiral
tricarbonyl(h6-arene)chromium(0) complexes in the
synthesis of N-tert-butyl-3-(2-phenyl substituted)-1,2-
thiazetidine 1,1-dioxide derivatives.6 The products are
enantiomerically pure, but restricted in the C-3 position
(o-substituted phenyls).
Due to their higher reactivity compared to b-lactams
(approx. 103-fold more reactive),2 b-sultams are impor-
tant compounds from a chemical and pharmacological
point of view.
We now wish to report an efficient four step asymmet-
ric synthesis of 3-substituted b-sultams according to
Scheme 1. In an earlier publication we presented the
synthesis of b-amino-cyclohexyl sulfonates 2.7 The key
step of this synthesis, as shown in Scheme 2, is the
Lewis acid catalyzed aza-Michael addition of (R,R,R)-
2 - amino - 3 - methoxymethyl - 2 - azabicyclo[3.3.0]octane
(RAMBO) to alkenylsulfonic esters 1.
Especially, the synthesis of highly substituted b-sultams
has been investigated thoroughly.3 In addition, a major
effort has been placed upon the search of new antibi-
otics among these b-sultams, corresponding to the b-
lactam antibiotics. But so far none of the synthesized
compounds have shown remarkable antibacterial
activities.
4 steps
O2S NH
NHCbz
R
O
O
Less attention was paid to the synthesis of lower substi-
tuted b-sultams, even though at least one of them has
shown biological activities: N-benzoyl b-sultam is an
irreversible inhibitor of the human neutrophil elastase
(HNE). HNE has been implicated in the development
of diseases such as emphysema, cystic fibrosis and
rheumatoid arthritis.4
S
R
c-HexO
ee ≥ 96%
ee ≥ 96%
R = Et, n-Pr, i-Pr, n-Bu, (CH2)2Ph
Scheme 1.
Enantiopure 3-substituted b-sultams have also found
RAMBO (ref. 7)
application in enantioselective catalysis.5
NHCbz
R
O
O
O
O
S
S
c-HexO
c-HexO
R
3 steps
(S)-2, ee ≥ 96%
1
Keywords: asymmetric synthesis; b-sultams; 1,2-thiazetidine 1,1-diox-
ides; alkenyl sulfonates; Michael addition.
R = Et, n-Pr, i-Pr, n-Bu, (CH2)2Ph
* Corresponding author. Tel.: +49(241)8094676; fax: +49(241)
8092127; e-mail: enders@rwth-aachen.de
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00980-2

5110
D. Enders, S. Wallert / Tetrahedron Letters 43 (2002) 5109–5111
Subsequent NꢀN bond cleavage of the generated
hydrazines utilizing BH3·THF, and protection of the
amines with CbzCl, N-Cbz-protected b-amino-sulfonic
esters (S)-2 were obtained in good yields and excellent
enantiomeric excesses (ee]96%).
These products have now been used in the synthesis of
highly enantioenriched 3-substituted b-sultams. As
shown in Scheme 3, cleavage of the sulfonates (S)-2 to
achieve the free sulfonic acids succeeded by refluxing in
ethanol. Without further purification, the crude acids
were transferred to their sodium salts, followed by
chlorination utilizing a COCl2 solution in toluene.
Chlorination by means of SOCl2 or PCl5 resulted in low
yields.
Scheme 4.
Table 2. Synthesis of 3-substituted b-sultams (S)-4a–e
(S)-4
R
Yield (%)a
ee (%)b
(S)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
Et
n-Pr
i-Pr
n-Bu
(CH2)2Ph
29
68
47
78
55
]96
]96
]96
]96
]96
After work-up, the Cbz-protected b-amino-sulfonyl
chlorides (S)-3a–e were obtained in good yields (62–
74% over two steps) and high enantiomeric excesses
(ee]96%, Table 1). The enantiomeric excesses are
based on those determined for the b-sultams (S)-4a–e.
a Over two steps.
b Determined by GC on chiral stationary phase (Daicel AD) by
comparison with racemic samples.
The Cbz-protected b-amino-sulfonyl chlorides were
deprotected utilizing HBr·HOAc, resulting in b-amino-
sulfonyl chlorides, which were cyclized in situ using an
excess of NEt3 (Scheme 4).
As shown in Table 2, the b-sultams with longer alkyl
chains were obtained in higher yields. This behaviour
might be explained with their increasing stability
towards hydrolysis. All of the synthesized b-sultams
were stable under argon-atmosphere at −20°C for sev-
eral weeks.
Other deprotecting reagents (e.g. BCl3) were also tested,
but for the given system the best results were obtained
with HBr·HOAc.
3-Substituted b-sultams (S)-4a–e were obtained in mod-
erate to good yields (29–78% over two steps) and high
enantiomeric excesses (ee]96%, Table 2). The enan-
tiomeric excesses were determined by GC on chiral
stationary phase (Daicel AD) by comparison with
racemic samples.
Conclusion
In summary, we have developed an efficient asymmetric
synthesis of 3-substituted b-sultams. The reaction
sequence starts with the cleavage of N-Cbz-protected
b-amino-sulfonic esters to the corresponding sulfonic
acids, followed by chlorination to yield b-amino-sulfo-
nyl chlorides. After deprotection of the amino group
and cyclization, the b-sultams are obtained in excellent
enantiomeric purity.8–10
a) EtOH, reflux, 15 h,
NaOAc, rt, 1 h
b) COCl2 in toluene,
CH2Cl2, rt, 2 h
NHCbz
R
O
O
NHCbz
R
O
O
S
S
62-74%
Cl
c-HexO
Acknowledgements
(S)-3a-e, ee ≥ 96%
(S)-2, ee ≥ 96%
This work was supported by the Deutsche Forschungs-
gemeinschaft (SFB 380) and the Fonds der Chemischen
Industrie. We thank Degussa AG, BASF AG, Bayer
AG and Aventis Pharma for the donation of chemicals.
R = Et, n-Pr, i-Pr, n-Bu, (CH2)2Ph
Scheme 3.
Table 1. Synthesis of Cbz-protected b-amino-sulfonyl chlo-
rides (S)-3a–e
References
(S)-3
R
Yield (%)a
ee (%)b
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(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
Et
n-Pr
i-Pr
n-Bu
(CH2)2Ph
64
74
67
64
62
]96
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]96
]96
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a Over two steps.
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b Based on the ee values of 4.
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(12 mL/mmol (S)-3a–e). The solution was stirred for 2 h
while it was allowed to warm up to room temperature.
After separation of the organic layer the aqueous phase
was extracted with CH2Cl2 (3×30 mL/mmol (S)-3a–e).
After drying over MgSO4 the solvent was evaporated and
the products were purified by column chromatography
(SiO2, n-pentane/diethylether) to afford (S)-4a–e.
9. Selected analytical and spectroscopic data of compounds
(S)-3 and (S)-4. Analytic data of compound (S)-3e: 1H
NMR (400 MHz, CDCl3): l=2.10 (m, 2H, CH2CH2Ph),
2.67 (m, 2H, CH2CH2Ph), 3.83 (dd, J=14.0 Hz, J=3.9
Hz, 1H, SO2CHH), 4.05 (dd, J=14.2 Hz, J=6.7 Hz, 1H,
SO2CHH), 4.15 (m, 1H, SO2CH2CH), 5.09 (s, 2H,
OCH2), 5.42 (d, J=8.2 Hz, 1H, NH), 7.10–7.36 (m, 10H,
Har); 13C NMR (100 MHz, CDCl3): l=32.5, 35.3, 48.6,
67.5, 68.9, 126.7, 128.4, 128.6, 128.9, 128.9, 136.3, 140.3,
155.8; MS (EI): m/z 381, 290, 186, 142, 129, 108, 104, 91,
65; IR (KBr): 3676, 3653, 3590, 3331, 3062, 3030, 2927,
2861, 1695, 1541, 1498, 1454, 1383, 1356, 1285, 1255,
1212, 1166, 1083, 1049, 907, 847, 774, 743, 697, 608, 528
cm−1; Anal. calcd for: C18H20ClNO4S: C, 56.61; H, 5.28;
N, 3.67. Found: C, 56.69; H, 5.50; N, 3.36%.
4. Beardsell, M.; Hinchliffe, P. S.; Wood, J. M.; Wilmouth,
R. C.; Schofield, C. J.; Page, M. I. J. Chem. Soc., Chem.
Commun. 2001, 497–498.
5. Trentmann, W.; Mehler, T.; Martens, J. Tetrahedron:
Asymmetry 1997, 8, 2033–2043.
6. Baldoli, C.; Del Buttero, P.; Perdicchia, D.; Pilati, T.
Tetrahedron 1999, 55, 14089–14096.
7. Wallert, S.; Enders, D. Synlett 2002, 304–306.
8. General procedure for the preparation of compounds
(S)-3 and (S)-4.
Synthesis of N-Cbz-protected b-amino-sulfonyl chlorides
(S)-3a–e: N-Cbz-protected b-amino-sulfonates (S)-2 were
dissolved in EtOH (30 mL/mmol (S)-2) and refluxed for
15 h. After cooling to room temperature, 1.1 equiv.
NaOAc were added and the reaction mixture was stirred
for 1 h. The solvent was removed under reduced pressure
and the crude sodium salts were dissolved in abs. CH2Cl2
(10 mL/mmol (S)-2) and abs. DMF (0.12 mL/mmol
(S)-2) under argon atmosphere. Then a solution, contain-
ing 20% COCl2 in toluene (1 mL/mmol (S)-2) was added
dropwise to the reaction mixture. After stirring for 2 h at
room temperature the products were purified by column
chromatography (SiO2, CH2Cl2) to afford b-amino-sulfo-
nyl chlorides (S)-3a–e.
1
Analytic data of compound (S)-4e: H NMR (400 MHz,
CDCl3): l=2.08 (m, 2H, CH2CH2Ph), 2.67 (m, 2H,
CH2CH2Ph), 3.59 (m, 1H, NHCH), 3.81 (dd, J=12.6 Hz,
J=5.5 Hz, 1H, SO2CHH), 4.22 (ddd, J=12.6 Hz, J=7.7
Hz, J=3.3 Hz, 1H, SO2CHH), 5.50 (s, 1H, NH), 7.13–
7.33 (kB, 5H, Har); 13C NMR (100 MHz, CDCl3): l=
32.7, 37.8, 40.8, 65.1, 126.8, 128.6, 129.0, 140.0; MS (EI):
m/z=211, 130, 106, 91, 77, 65, 51; IR (KBr): 3676, 3654,
3632, 3273, 3032, 2925, 2856, 1656, 1604, 1497, 1456,
1384, 1331, 1302, 1265, 1231, 1203, 1156, 1098, 1083,
1060, 1031, 972, 934, 805, 753, 701, 629, 572, 519, 479
cm−1; Anal. calcd for: C10H13NO2S: C, 56.85; H, 6.20; N,
6.63. Found: C, 56.58; H, 6.56; N, 6.22%.
Synthesis of b-sultams (S)-4a–e: b-amino-sulfonyl chlo-
rides (S)-3a–e were dissolved in CH2Cl2 (20 mL/mmol
(S)-3a–e). A 33% HBr in HOAc-solution was added (1.5
equiv.). After stirring for 3 h at room temperature the
reaction mixture was cooled to 0°C and NEt3 was added
10. All new compounds showed suitable spectroscopic data
(NMR, MS, IR) and correct elemental analyses.