Asymmetric synthesis of-3-substituted γ- and δ-sultams

Article abstract of DOI:10.1002/ejoc.200500860

An efficient and flexible asymmetric synthesis of various 3-substituted γ- and δ-sultams is described. The key step is a diastereoselective nucleophilic 1,2-addition of various organocerium compounds to the CN double bond of co-SAMP-hydrazonosulfonates. The resulting hydrazines were obtained in good to excellent diastereomeric excesses (de = 78 to ≥ 96 %). Removal of the chiral auxiliary by reductive N,N-bond cleavage afforded the corresponding aminosulfonates without racemisation. Ester hydrolysis and subsequent treatment of the resulting sulfonic acids with phosgene in toluene led to the aminosulfonyl chlorides, which were cyclised to the title compounds in good to excellent overall yields (39-51 %) and high enantiomeric excesses (ee = 78-99 %). The absolute configuration was determined by X-ray structure analysis and is in accordance with the postulated mechanism for the diastereoselective 1,2-addition. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500860

FULL PAPER
DOI: 10.1002/ejoc.200500860
Asymmetric Synthesis of 3-Substituted γ- and δ-Sultams
Dieter Enders,*[a] Alexander Moll,[a] and Jan W. Bats[b]
Keywords: Asymmetric synthesis / Aminosulfonates / Cyclisation / Sulfonamides / Sultams
An efficient and flexible asymmetric synthesis of various 3-
substituted γ- and δ-sultams is described. The key step is a
of the resulting sulfonic acids with phosgene in toluene led
to the aminosulfonyl chlorides, which were cyclised to the
diastereoselective nucleophilic 1,2-addition of various organo- title compounds in good to excellent overall yields (39–51%)
cerium compounds to the CN double bond of ω-SAMP-hy-
drazonosulfonates. The resulting hydrazines were obtained
in good to excellent diastereomeric excesses (de = 78 to Ն
96%). Removal of the chiral auxiliary by reductive N,N-bond
cleavage afforded the corresponding aminosulfonates with-
out racemisation. Ester hydrolysis and subsequent treatment
and high enantiomeric excesses (ee = 78–99%). The absolute
configuration was determined by X-ray structure analysis
and is in accordance with the postulated mechanism for the
diastereoselective 1,2-addition.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
lised in numerous asymmetric reactions.[7] Despite the im-
portance of these heterocycles in medicinal and synthetic
chemistry, the number of methods for the synthesis of dia-
stereo- and enantiomerically pure γ- and δ-sultams is still
limited. Among the various approaches to the title com-
pounds are radical cyclisations,[8] intramolecular alkylations
or sultam formation,[9] intramolecular aziridinations of un-
saturated sulfonamides and rhodium-catalysed amid-
ation,[10] 1,3-dipolar cycloadditions[11] and intramolecular
Heck reactions.[12] Lee et al.[13] and Cooper,[14] for instance,
were able to synthesise chiral γ-sultams by intramolecular
carbanion alkylation starting from the chiral β-amino
alcohols. Furthermore, sultams can be synthesised by intra-
or intermolecular Diels–Alder reactions[15] and ring-closing
metathesis.[1a,16] In 1999, Hanson et al. described the first
synthesis of cyclic sulfonamides with metathesis reac-
tions,[17] and a few years later they reported on the success-
ful enantioselective synthesis of γ-sultams.[18] Moreover,
Metz et al. described the synthesis of bicyclic δ-sultams by
intramolecular Diels–Alder reactions of vinylsulfon-
amides.[19]
Introduction
Compounds containing the sulfonamide function are
well-known for their wide range of biological activities and
especially their cyclic forms, the sultams, are of enormous
importance as pharmaceuticals[1] and agricultural agents.[2]
In Figure 1 three typical drugs are shown bearing the sul-
tam moiety.[3]
As part of our continuous interest in the asymmetric syn-
thesis of sulfur-containing heterocycles,[20] we already de-
scribed the diastereo- and enantioselective synthesis of cis-
3,4-disubstituted β-sultams.[21] In this paper, we wish to re-
port the efficient enantioselective synthesis of 3-substituted
γ- and δ-sultams with the SAMP/RAMP-hydrazone meth-
odology.[22]
Figure 1. Selected sultams with various biological activities.
In addition to their application as pharmaceuticals, sul-
tams have also been used as chiral auxiliaries[4] and rea-
gents[5] with great success. Especially the well-known Op-
polzer–Sultam,[6] easily be prepared from camphor, was uti-
[a] Institut für Organische Chemie, RWTH Aachen,
Landoltweg 1, 52074 Aachen, Germany
Fax: +49-241-8092127
Results and Discussion
E-mail: enders@rwth-aachen.de
As shown in Scheme 1, the desired γ- and δ-hydrazono-
sulfonates (S)-3 could be synthesised on a multigram scale
following a two-step protocol. The methanesulfonate 1 was
[b] Institut für Organische Chemie, Johann Wolfgang Goethe Uni-
versität Frankfurt,
Marie-Curie-Strasse 11, 60439 Frankfurt am Main, Germany
Eur. J. Org. Chem. 2006, 1271–1284
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D. Enders, A. Moll, J. W. Bats
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deprotonated with n-butyllithium at low temperature and
trapped with allylbromide or 4-bromopent-1-ene to afford
the unsaturated substrates 2, which were obtained in good
yields after flash column chromatography (2a, n = 1, 71%;
2b, n = 2, 75%). The alkylation was initially tried using
bromoacetaldehyde diethyl acetal as electrophile, but the
desired aldehyde precursor could not be obtained in this
way.
Scheme 1. Synthesis of γ- and δ-hydrazonosulfonates (S)-3. Rea-
gents and conditions: a) 1. nBuLi, –78 °C, THF, 30 min; 2. RBr,
18 h, –78 °C to room temp.; b) 1. O3, CH2Cl2, –78 °C; 2. PPh3, 1 h;
3. CH2Cl2, 0 °C, SAMP, MgSO4, room temp., 18 h.
Scheme 2. Asymmetric synthesis of γ- and δ-sultams 7. Reagents
and conditions: a) RM/CeCl3, THF, –100 °C to –78 °C, 3 h; b) 1.
BH3·THF, THF, reflux, 4 h; 2. CbzCl, K2CO3, CH2Cl2, reflux,
18 h; c) 1. EtOH/H2O, reflux, 18 h; 2. NaOAc, CH2Cl2, room
temp., 1 h; 3. COCl2 in toluene, CH2Cl2/DMF, room temp., 2 h; d)
1. HBr/AcOH, CH2Cl2, room temp., 3 h; 2. NEt3, 0 °C, 2 h.
Subsequent ozonolysis of the unsaturated sulfonates 2
and treatment with PPh3 led to the corresponding alde-
hydes, which were directly condensed with the chiral auxil-
iary (SAMP) to the ω-hydrazonosulfonates (S)-3 in good
yields by the standard procedure (3a, n = 1, 68%; 3b, n =
2, 76%).[23] With these compounds in hands, we were able
to synthesise the title sultams following the well-established
protocol for the nucleophilic 1,2-addition to aldehyde
SAMP/RAMP-hydrazones with subsequent N–N bond
cleavage, followed by ring closure as depicted in Scheme 2.
For the nucleophilic 1,2-addition to the CN double
bond, organocerium reagents were used. Initial attempts
utilizing commercially available organolithium or Grignard
compounds turned out to be difficult in obtaining the de-
sired hydrazines. Because of their high basicity, mainly eli-
mination of the sulfur substituent was observed. Because
of the lower basicity and the higher nucleophilicity of the
Imamoto reagents, however, this problem could be simply
Table 1. Diastereoselective 1,2-addition of organocerium reagents
to ω-hydrazonosulfonates (S)-3 to afford the ω-hydrazinosulfonates
4.
Product
R
n
Yield [%]
de[a] [%]
(R,S)-4a
(R,S)-4b
(R,S)-4c
(R,S)-4d
(S,S)-4e
(R,S)-4f
(R,S)-4g
(R,S)-4h
(S,S)-4i
Me
Et
nBu
nHex
Ph
1
1
1
1
1
2
2
2
2
92
98
89
78
99
78
94
75
77
82
78
87
90
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
Me
nBu
nHex
Ph
[a] Determined by 13C NMR spectroscopy.
circumvented.[24] The cerium reagents were freshly prepared higher homologues. We assume that the sulfonate moiety
from the corresponding organolithium or Grignard com- and the chiral auxiliary can both be chelating ligands of the
pounds and dehydrated CeCl3 in a transmetallation reac- nucleophile. The disturbing influence of the sulfonate moi-
tion. First trials using the standard conditions[21a] led to ety decreases with growing distance to the hydrazone func-
poor yields and diastereoselectivities. Shorter reaction times tionality, therefore the 1,2-addition to δ-hydrazonosulfon-
(3 h) and hydrolysis at low temperature (–78 °C) were essen- ates proceeds with better diastereoselectivities. To explain
tial for a good asymmetric induction. By the use of these the fact that at least two equivalents of the nucleophile are
optimised conditions we were able to obtain the hydrazines necessary to obtain good asymmetric induction, we assume
4 after aqueous work up and purification by flash column a precoordination of the first equivalent of the organocer-
chromatography in good to excellent yields (77–99%) and ium reagent. As shown in Figure 2, the hydrazone sub-
with high diastereomeric excesses (78 to Ն 96%). The re- strates can act as bidentate (pyrrolidino nitrogen and meth-
sults of the 1,2-additions are summarised in Table 1.
oxy group) and even tridentate (plus sulfonate group) li-
Obviously, the diastereoselectivities are dependent on the gands leading to the steric hindrance of the si-face. The
applied hydrazones and nucleophiles. In general, γ-hydrazo- second organocerium equivalent would then attack the re-
nosulfonates led to lower diastereomeric excesses than their face of the CN double bond as observed.
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Asymmetric Synthesis of 3-Substituted γ- and δ-Sultams
FULL PAPER
ride were also tested but resulted in significantly lower
yields. After aqueous work up and purification by flash col-
umn chromatography the Cbz-protected aminosulfonyl
chlorides 6 were obtained in good yields (72–89%) and high
enantiomeric excesses (78–99%) based on the ee values of
the corresponding aminosulfonates
(Table 3).
5 and sultams 7
Table 3. Conversion of the aminosulfonates 5 to the corresponding
sulfonyl chlorides 6.
Product
n
R
Yield [%]
ee [%]
Figure 2. Proposed transition state for the asymmetric 1,2-addition.
(R)-6a
(R)-6b
(R)-6c
(R)-6d
(S)-6e
(R)-6f
(R)-6g
(R)-6h
(S)-6i
1
1
1
1
1
2
2
2
2
Me
Et
nBu
nHex
Ph
72
74
75
83
80
84
89
77
72
84[a]
78[c]
87[b]
90[b]
93[c]
Many procedures providing amines from their corre-
sponding hydrazines by cleavage of the N,N bond have been
reported.[25] Based on previous experiences[26] we decided
to use the reductive cleavage by the BH3·THF complex
which is a very mild method which not requires the acti-
vation of the N,N bond. For that purpose the hydrazines 4
were dissolved in THF and heated to reflux with a large
excess of the BH3·THF complex. After methanolysis the
corresponding amines were directly protected as benzyl car-
bamates. The ω-aminosulfonates 5 were obtained in good
to very good yields (50–99%) and ee values of 78–99%
(Table 2).
Me
Ն 96[b]
93[c]
nBu
nHex
Ph
93[c]
99[c]
[a] In correlation with the ee value of the corresponding ω-amino-
sulfonate. [b] In correlation with the de value of the corresponding
hydrazines. [c] In correlation with the ee value of the resulting sul-
tams.
Finally the Cbz-protected aminosulfonyl chlorides 6 were
deprotected with HBr/AcOH and the resulting free amines
were cyclised in situ with an excess of triethylamine. The
corresponding 3-substituted sultams 7 were obtained in
good to excellent yields (70–100%) and high enantiomeric
excesses (78–99%, Table 4). The enantiomeric excesses were
Table 2. Hydrazine cleavage with the BH3·THF complex and subse-
quent protection of the amino function to afford the ω-aminosulfo-
nates 5.
Product
R
n
Yield [%]
ee [%]
(R)-5a
(R)-5b
(R)-5c
(R)-5d
(S)-5e
(R)-5f
(R)-5g
(R)-5h
(S)-5i
Me
Et
nBu
nHex
Ph
1
1
1
1
1
2
2
2
2
50
71
99
79
96
58
53
70
98
84[a]
78[a]
Table 4. Cyclisation of ω-aminosulfonyl chlorides 6 to 3-substituted
γ- and δ-sultams 7.
87[b]
90[b]
93[c]
Product
n
R
Yield [%]
ee [%][a]
Me
Ն 96[b]
93[a]
(R)-7b
(R)-7c
(R)-7d
(S)-7e
(R)-7f
(R)-7g
(R)-7h
(S)-7i
1
1
1
1
2
2
2
2
Et
nBu
nHex
Ph
70
99
93
77
82
100
100
72
78
87[b]
90[b]
93
nBu
nHex
Ph
93[c]
99[c]
Me
Ն 96[b]
93
[a] Determined by HPLC on a chiral stationary phase. [b] In corre-
lation with the de value of the corresponding hydrazine. [c] In cor-
relation with the ee value of the resulting sultams.
nBu
nHex
Ph
93
99
The N,N-bond cleavage and the protection of the amino
group was assumed to be free of racemisation in accordance
to earlier results.[25s,25t,27] This was indeed a valid assump-
tion that could be proven in several cases. Thus, the enan-
tiomeric excesses determined by HPLC analysis using a chi-
ral stationary phase are in correlation with the dia-
stereomeric excesses of the corresponding hydrazinosulfo-
nates 4 within the limits of detection. The other ee values
given are based on the ee values of the resulting sultams 7.
In the following step the aminosulfonates 5 were con-
verted into their corresponding sulfonyl chlorides 6. Based
on our previous results[20d] we synthesised the free sulfonic
acid by heating the sulfonate in a mixture of ethanol/water
for 18 h. Without further purification the crude acids were
transferred to their sodium salt, followed by chlorination
with phosgene in toluene. Other chlorinating agents like
[a] Determined by GC on chiral stationary phase (Chirasil-dex).
[b] In correlation with the de value of the corresponding hydrazines.
Figure 3. Crystal structure of the δ-sultam (S)-7i. H atoms at C(4)
and N are represented as small spheres all other H atoms have been
thionyl chloride, phosphorus pentachloride or sulfuryl chlo- omitted for clarity.
Eur. J. Org. Chem. 2006, 1271–1284
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1273

D. Enders, A. Moll, J. W. Bats
FULL PAPER
36 mmol, 1.2 equiv.) as described in GP 1. Compound 2a was ob-
tained as a brown oil after purification by flash column chromatog-
raphy (SiO2, n-pentane/Et2O, 6:1). Yield: 4.72 g (71%); Rf = 0.36
(n-pentane/Et2O, 6:1). 1H NMR (400 MHz, CDCl3): δ = 1.25–1.84
[m, 10 H, (CH2)cyclo], 2.60 (m, 2 H, SCH2CH2), 3.15 (m, 2 H,
SCH2), 4.71 (m, 1 H, OCH), 5.14 (m, 2 H, CH=CH2), 5.84 (m, 1
H, CH=CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.5, 24.8,
32.7 [(CH2)cyclo], 27.8 (SCH2CH2), 50.7 (SCH2), 81.0 (OCH), 117.1
determined by GC on chiral stationary phase by compari-
son with racemic samples.
The absolute configuration of the δ-sultam (S)-7i was de-
termined by X-ray crystallography as depicted in Figure 3.
The observed absolute configuration is in full agreement
with the postulated transition state and our previous results
on nucleophilic 1,2-additions of organolithium-, Grignard-
and organocerium reagents to aldehyde-SAMP-hydra-
zones.[28]
(CH=CH ), 133.7 (CH=CH ) ppm. IR (film): ν = 3080 (w), 2939
˜
2
2
(vs), 2862 (s), 1643 (w), 1451 (m), 1416 (w), 1355 (vs), 1244 (w),
1168 (vs), 1118 (w), 1091 (w), 1032 (w), 1000 (m), 934 (vs), 868 (s),
831 (m), 722 (w), 641 (w), 587 (w), 529 (w), 488 (w), 457 (w) cm–1.
MS (EI, 70 eV): m/z (%) = 136 (12), 94 (5), 84 (7), 83 (100), 82 (90),
81 (12), 79 (5), 67 (49). C10H18O3S (218.31): calcd. C 55.02, H 8.31;
found C 55.44, H 8.55.
Conclusion
In summary, we have developed an efficient asymmetric
synthesis of 3-substituted γ- and δ-sultams through the
asymmetric 1,2-addition to the CN double bond of ω-
SAMP-hydrazonosulfonates. Subsequent cleavage of the
chiral auxiliary and Cbz protection led to the correspond-
ing ω-aminosulfonates. After ester hydrolysis and chlorina-
tion of the resulting ω-aminosulfonic acids the desired ω-
aminosulfonyl chlorides were obtained in good yields. De-
protection of the amino group and cyclisation under basic
conditions provided the substituted sultams in good overall
yields (39–51%) and good to excellent enantiomeric ex-
cesses (ee = 78–99%).
Cyclohexyl Pent-4-ene-1-sulfonate (2b): Cyclohexyl methanesulfo-
nate (1, 3.57 g, 20 mmol) was deprotonated with nBuLi (8.0 mL,
24 mmol, 1.2 equiv.) and treated with 4-bromo-1-butene (3.24 g,
24 mmol, 1.2 equiv.) as described in GP 1. Compound 2b was ob-
tained as a brown oil after purification by flash column chromatog-
raphy (SiO2, n-pentane/Et2O, 6:1). Yield: 3.49 g (75%); Rf = 0.50
(n-pentane/Et2O, 6:1). 1H NMR (400 MHz, CDCl3): δ = 1.24–1.97
[m, 12 H, (CH2)cyclo, SO2CH2CH2], 2.21 (m, 2 H, CH2=CHCH2),
3.07 (t, 2 H, J = 7.7 Hz, SO2CH2), 4.70 (m, 1 H, OCH), 5.08 (m, 2
H, CH2=CH), 5.77 (m, 1 H, CH2=CH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 22.7 (SO2CH2CH2), 23.5, 24.9, 32.8 [(CH2)cyclo], 31.9
(CH2=CHCH2), 50.6 (SO2CH2), 80.8 (OCH), 116.4 (CH2=CH),
136.1 (CH =CH) ppm. IR (film): ν = 3078 (w), 2940 (vs), 2862 (s),
˜
2
1641 (m), 1452 (m), 1346 (vs), 1267 (w), 1168 (vs), 1118 (w), 1032
(w), 1000 (m), 935 (vs), 869 (vs), 829 (m), 732 (m), 641 (w), 582
(m), 531 (m), 488 (w) cm–1. MS (EI, 70 eV): m/z (%) = 232 (0.4)
[M+], 151 (9), 133 (6), 96 (5), 84 (6), 83 (100), 82 (100), 81 (10), 69
(26),68 (62), 67 (45). MS (CI): m/z (%) = 233 (2.4) [M+ + 1], 152
(5), 151 (52), 84 (6), 83 (100), 82 (13), 81 (7), 69 (17), 68 (8).
C11H20O3S (232.34): calcd. C 56.87, H 8.68; found C 57.18, H 8.97.
Experimental Section
General Remarks: All reagents were purchased from common com-
mercial suppliers and used from freshly opened containers. Solvents
for chromatography and for work-up were dried and purified by
conventional methods prior to use. Tetrahydrofuran was freshly
distilled from sodium/lead and benzophenone under argon. nBuLi
(1.6  in hexane) was purchased from Merck, Darmstadt. Prepara-
tive flash column chromatography was carried out with Merck sil-
ica gel 60, particle size 0.040–0.063 mm. Optical rotation values
were measured with a Perkin–Elmer P 241 polarimeter, solvents
used were of Merck UVASOL quality. IR spectra: Perkin–Elmer
FT/IR 1750 and Perkin–Elmer FT/IR 1720 X. NMR spectra: Var-
ian VXR 300, Varian Gemini 300 and Varian Inova 400, TMS as
internal standard. MS: Varian MAT 212 (EI, 70 eV, 1 mA) and
Finnigan MAT SSQ 7000 (CI, 100 eV). Microanalyses were ob-
tained with Heraeus, CHN-O-Rapid. High-resolution MS Finnin-
gan MAT, MAT 95. Merck TLC plates silica gel 60 F254 have been
used for TLC analyses and the products were visualized by UV
detection or phosphomolybdic acid (5 wt.-% in EtOH).
General Procedure for the Synthesis of ω-Hydrazonosulfonates (S)-
3 (GP 2): A solution of cyclohexyl sulfonate 2 (1.0 equiv.) in
CH2Cl2 (7 mL/mmol) was treated with ozone at –78 °C until the
solution turned blue. After removal of the excess of ozone the mix-
ture was warmed to room temperature and treated with tri-
phenylphosphane (0.2 g/mmol) and stirred for 1 h. After that the
reaction mixture was concentrated under reduced pressure, the
crude aldehyde was dissolved in CH2Cl2 (3.0 mL/mmol) and
treated with SAMP (1.2 equiv.) and MgSO4 (0.4 g/mmol) at 0 °C.
The reaction mixture was stirred for 18 h at room temperature, af-
ter addition of water the phases were separated and the aqueous
phase was extracted three times with CH2Cl2. The combined or-
ganic phases were dried with MgSO4 and concentrated in vacuo.
The pure product was obtained after purification by flash column
chromatography.
General Procedure for the Synthesis of Sulfonates 2 (GP 1): Cyclo-
hexyl methanesulfonate (1.0 equiv.) was dissolved in abs. THF
(3 mL/mmol) under argon and cooled to –78 °C. nBuLi (1.0 equiv.)
was added dropwise, and the solution was stirred at this tempera-
ture for 30 min. The electrophile was then added to the resulting
red solution and the reaction mixture was warmed to room tem-
perature overnight. After hydrolysis with pH 7 buffer solution
(8 mL/mmol) the mixture was extracted three times with CH2Cl2.
The combined organic phases were dried with MgSO4 and concen-
trated in vacuo. The pure product was obtained after flash column
chromatography (SiO2, pentane/EtO2, 6:1).
Cyclohexyl (S)-(–)-3-[2-(Methoxymethyl)pyrrolidin-1-ylimino]pro-
pane-1-sulfonate [(S)-3a]: The cyclohexyl sulfonate 2a (2.97 g,
13.48 mmol) was treated with ozone at –78 °C and triphenylphos-
phane (3.54 g, 13.50 mmol). The resulting aldehyde was converted
with SAMP (1.97 g, 15.14 mmol, 1.1 equiv.) and MgSO4 (5.18 g) to
the desired hydrazone (S)-3a, which was obtained after flash col-
umn chromatography (SiO2, n-pentane/Et2O, 2:1) as a brown oil.
Yield: 3.03 g (68%); Rf = 0.10 (n-pentane/Et2O, 2:1). [α]2D5 = –8.4
(c = 1.29, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.24–2.04
[m, 14 H, (CH2)cyclo, NCH2CH2CH2], 2.75 (m, 3 H, SO2CH2CH2,
NCHH), 3.30–3.56 (m, 6 H, NCH, NCHH, SO2CH2, OCH2), 3.38
(s, 3 H, CH3), 4.70 (m, 1 H, OCH), 6.60 (t, J = 4.4 Hz, 1 H, N=CH)
Cyclohexyl But-3-ene-1-sulfonate (2a): Cyclohexyl methanesulfo-
nate (1, 5.35 g, 30 mmol) was deprotonated with nBuLi (14.4 mL,
36 mmol, 1.2 equiv.) and treated with allyl bromide (4.35 g,
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Asymmetric Synthesis of 3-Substituted γ- and δ-Sultams
FULL PAPER
ppm. 13C NMR (100 MHz, CDCl3): δ = 22.1 (NCH2CH2), 23.5,
NCH2CH2CHH, OCHCH2), 2.35 (td, J = 9.0 Hz, J = 9.0 Hz, 1 H,
24.8, 32.7 [(CH2)cyclo], 26.5 (NCH2CH2CH2), 27.1 (CHCH2), 49.1, NCHH), 2.63 (m, 1 H, NCH), 3.06 (m, 1 H, CH), 3.11–3.31 (m, 3
49.7 (NCH2, SCH2), 59.2 (OCH3), 63.2 (NCH), 74.4 (OCH2), 80.9
H, SCH2, NCHH), 3.34 (s, 3 H, OCH3), 3.35 (m, 1 H, OCHH),
3.47 (dd, J = 5.2 Hz, J = 9.3 Hz, 1 H, OCHH), 4.69 [m, 1 H,
CH(CH2)cyclo] ppm. 13C NMR (100 MHz, CDCl3): δ = 18.9 (CH3),
(OCH), 131.0 (C=N) ppm. IR (CHCl ): ν = 2937 (vs), 2863 (s),
˜
3
1600 (w), 1453 (s), 1347 (vs), 1167 (vs), 1119 (s), 1002 (w), 933 (vs),
870 (s), 829 (m), 756 (s), 590 (m), 527 (m) cm–1. MS (EI, 70 eV): 21.0 (NCH2CH2), 23.5 24.9, 32.7 [(CH2)cyclo], 26.2
m/z (%) = 332 (5) [M+], 288 (5), 287 (28), 207 (6), 206 (13), 205 (NCH2CH2CH2), 29.1 (CHCH2), 48.0 (SCH2), 52.4 (CH), 57.9
(100), 123 (10). MS (CI): m/z (%) = 334 (7), 333 (37), 332 (11) [M+],
331 (7), 288 (9), 287 (48), 279 (16), 253 (6), 252 (15), 251 (100), 233
(5), 206 (5), 205 (39). C15H28N2O4S (332.46): calcd. C 54.19, H
8.49, N 8.43; found C 54.23, H 8.49, N 8.83.
(NCH2), 59.0 (OCH3), 66.1 (NCH), 75.4 (OCH2), 80.6 [CH-
(CH2)cyclo] ppm. IR (CHCl ): ν = 3019 (m), 2939 (vs), 2864 (s),
˜
3
1452 (m), 1343 (s), 1216 (m), 1165 (s), 1115 (m), 932 (vs), 870 (m),
830 (m), 757 (vs), 668 (m), 531 (w) cm–1. MS (EI, 70 eV): m/z (%)
= 348 (5) [M+], 266 (11), 223 (5), 221 (100), 141 (7), 129 (8), 125
(5), 83 (5), 70 (8), 55 (8). C16H32N2O4S (348.50): calcd. C 55.14, H
9.25, N 8.04; found C 55.31, H 9.70, N 7.40.
Cyclohexyl (S)-(–)-4-[2-(Methoxymethyl)pyrrolin-1-ylimino]butane-
1-sulfonate [(S)-3b]: The cyclohexyl sulfonate 2b (2.16 g,
9.31 mmol) was treated with ozone at –78 °C and triphenylphos-
phane (2.44 g, 9.31 mmol). The resulting aldehyde was converted
with SAMP (1.36 g, 10.45 mmol 1.1 equiv.) and MgSO4 (3.58 g) to
the desired hydrazone (S)-3b, which was obtained after flash col-
umn chromatography (SiO2, n-pentane/Et2O, 2:1) as a brown oil.
Yield: 2.45 g (76%); Rf = 0.14 (n-pentane/Et2O, 2:1). [α]2D5 = –61.2
(c = 1.01, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.25–2.14
[m, 16 H, (CH2)cyclo, SO2CH2CH2CH2, NCH2CH2], 2.37 (m, 2 H,
SO2CH2CH2), 2.73 (m, 1 H, NCHH), 3.15 (m, 2 H, SO2CH2),
3.31–3.56 (m, 4 H, NCH, NCHH, OCH2), 3.38 (s, 3 H, OCH3),
4.69 (m, 1 H, OCH), 6.57 (t, J = 4.9 Hz, 1 H, N=CH) ppm. 13C
Cyclohexyl (R,S)-(–)-3-[2-(Methoxymethyl)pyrrolidin-1-ylamino]-
pentane-1-sulfonate [(R,S)-4b]: Prepared according to GP 3 by 1,2-
addition of CeCl3·7H2O (2.05 g, 5.5 mmol) and ethylmagnesium
bromide (5.5 mL, 5.5 mmol) to the hydrazone (S)-3a (0.382 g,
1.10 mmol). Compound (R,S)-4b was obtained after flash column
chromatography (SiO2, n-pentane/Et2O, 1:1) as a colourless oil.
Yield: 0.392 g (98%); Rf = 0.28 (n-pentane/Et2O, 1:1); de = 78%
(13C NMR). [α]2D5 = –37.8 (c = 1.11, CHCl3). H NMR (400 MHz,
1
CDCl3): δ = 0.87 (t, J = 7.4 Hz, 3 H, CH3), 1.20–2.05 [m, 18 H,
(CH2)cyclo, CH2CH3, SO2CH2CH2, NCH2CH2CH2], 2.31 (td, J =
8.8 Hz, J = 8.8 Hz, 1 H, NCHH), 2.58 (m, 1 H, NCH), 2.80 (m, 1
H, CH), 3.09–3.27 (m, 3 H, SO2CH2, NCHH), 3.29 (s, 3 H, OCH3),
3.31 (m, 1 H, OCHH), 3.42 (dd, J = 5.3 Hz, J = 9.4 Hz, 1 H,
OCHH), 4.65 [m, 1 H, CH(CH2)cyclo] ppm. 13C NMR (100 MHz,
CDCl3): δ = 10.2 (CH3), 21.2 (NCH2CH2), 23.66, 25.06, 25.25,
26.36, 32.94 [(CH2)cyclo, CHCH2, NCH2CH2CH2, CH2CH3], 48.0
(SCH2), 58.21 (NCH2), 58.6 (CH), 59.1 (OCH3), 66.5 (NCH), 75.6
NMR (100 MHz, CDCl3):
δ = 21.5 (SO2CH2CH2), 22.1
(NCH2CH2), 23.5, 24.9, 32.7 [(CH2)cyclo], 26.5 (NCH2CH2CH2),
31.1 (C=NCH2), 49.9 (NCH2), 50.7 (SO2CH2), 59.1 (OCH3), 63.3
(NCH), 74.6 (CH2OCH3), 80.7 (OCH), 134.4 (C=N) ppm. IR
(CHCl ): ν = 2939 (vs), 2863 (vs), 1725 (m), 1601 (w), 1453 (w),
˜
3
1343 (vs), 1168 (vs), 1119 (vs), 1031 (w), 1004 (w), 936 (vs), 869
(vs), 829 (m), 756 (m), 587 (m), 530 (m), 486 (w) cm–1. MS (EI,
70 eV): m/z (%) = 346 (4) [M+], 302 (7), 301 (33), 221 (5), 220 (13),
219 (100), 70 (8). MS (CI): m/z (%) = 350 (11), 349 (33), 348 (71),
346 (12), 345 (12), 303 (6), 302 (11), 301 (38), 298 (10), 293 (26), 267
(13), 266 (38), 265 (100), 219 (28). C16H30N2O4S (346.49): calcd. C
55.46, H 8.73, N 8.09; found C 55.65, H 8.75, N 7.79.
(OCH2), 80.7 [CH(CH2)cyclo] ppm. IR (CHCl ): ν = 2938 (vs), 2866
˜
3
(vs), 1724 (w), 1455 (s), 1347 (vs), 1234 (w), 1166 (vs), 1113 (s),
1032 (w), 1005 (w), 935 (vs), 870 (vs), 830 (m), 756 (w), 590 (w),
531 (w) cm–1. MS (EI, 70 eV): m/z (%) = 362 (7), 280 (14), 236 (11),
235 (100), 155 (6), 129 (10), 125 (5), 70 (12), 55 (6). C17H34N2O4S
(362.53): calcd. C 56.32, H 9.45, N 7.73; found C 56.40, H 9.51, N
7.65.
General Procedure for the Synthesis of ω-Hydrazinosulfonates (GP
3): CeCl3·7H2O (4–5 equiv.) were dehydrated for 2 h at 130 °C in
vacuo (0.1 Torr) and then suspended in dry THF (3.0 mL/mmol)
with sonification. The suspension was stirred overnight at room
temperature. After cooling to –78 °C 4–5 equiv. of lithium- or Grig-
nard reagent were added and stirred for 2 h at this temperature.
To this resulting yellow suspension 1.0 equiv. of hydrazone (S,S)-4,
dissolved in dry THF (4.0 mL/mmol), was added at –100 °C. The
solution was warmed to –78 °C within 3 h. The reaction mixture
was quenched with pH 7 buffer solution at this temperature and
then warmed to room temperature. The mixture was extracted three
times with CH2Cl2, the combined organic layers were dried with
MgSO4 and concentrated in vacuo. The pure hydrazine was ob-
tained after purification by flash column chromatography (SiO2, n-
pentane/Et2O).
Cyclohexyl (R,S)-(–)-3-[2-(Methoxymethyl)pyrrolidin-1-ylamino]-
heptane-1-sulfonate [(R,S)-4c]: Prepared according to GP 3 by 1,2-
addition of CeCl3·7H2O (2.24 g, 6.0 mmol) and nBuLi (2.4 mL,
6.0 mmol) to the hydrazone (S)-3a (0.499 g, 1.5 mmol). Compound
(R,S)-4c was obtained after flash column chromatography (SiO2,
n-pentane/Et2O, 1:1) as a colourless oil. Yield: 0.520 g (89%); Rf =
0.44 (n-pentane/Et2O, 1:1); de = 87% (13C NMR). [α]2D5 = –28.8 (c
= 0.99, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J =
7.4 Hz, 3 H, CH3), 1.20–2.05 [m, 22 H, (CH2)3CH3, (CH2)cyclo
,
SO2CH2CH2, NCH2CH2CH2], 2.38 (td, J = 8.8 Hz, J = 8.8 Hz, 1
H, NCHH), 2.63 (m, 1 H, NCH), 2.92 (m, 1 H, NHCH), 3.10–
3.52 (m, 5 H, SO2CH 2, CH2O, NCHH), 3.35 (s, 3 H, OCH3), 4.68
[m, 1 H, CH(CH2)cyclo] ppm. 13C NMR (100 MHz, CDCl3): δ =
14.1 (CH3), 21.1 (NCH2CH2), 23.0 (CH2CH3), 23.5, 24.9, 32.8
[(CH2)cyclo], 26.3 (NCH2CH2CH2), 26.7 (CH2CH2CH3), 28.0
(SO2CH2CH2), 32.2 (CH2CH2CH2CH3), 47.9 (SCH2), 57.2
(NCH2), 58.3 (CH), 59.0 (OCH3), 66.5 (NCH), 75.6 (OCH2), 80.6
Cyclohexyl (R,S)-(–)-3-[2-(Methoxymethyl)pyrrolidin-1-ylamino]bu-
tane-1-sulfonate [(R,S)-4a]: Prepared according to GP 3 by 1,2-ad-
dition of CeCl3·7H2O (1.86 g, 5.0 mmol) and MeLi (3.14 mL,
5.0 mmol) to the hydrazone (S)-3a (0.333 g, 1.0 mmol). Compound
(R,S)-4a was obtained after flash column chromatography (SiO2,
n-pentane/Et2O, 2:1) as a colourless oil. Yield: 0.321 g (92%); Rf =
0.10 (n-pentane/Et2O, 2:1), de = 82% (13C NMR), [α]2D5 = –26.1 (c
= 1.34, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.03 (d, J =
6.3 Hz, 3 H, CH3), 1.22–1.45 (m, 3 H, OCHCH2CH2CHH), 1.47–
[CH(CH2)cyclo] ppm. IR (CHCl ): ν = 2935 (vs), 2862 (vs), 1720
˜
3
(m), 1453 (s), 1411 (w), 1346 (vs), 1168 (vs), 1117 (m), 1004 (w),
937 (vs), 869 (s), 831 (m), 531 (m) cm–1. MS (EI, 70 eV): m/z (%)
= 390 (6) [M+], 308 (16), 265 (6), 264 (13), 263 (100), 129 (12), 70
(11), 55 (8). HRMS, C19H38N2O4S: calcd. 390.2552; found
390.2551.
1.69 (m, 4 H, NCH2CH2CHH, OCHCH2CH2CHH), 1.69–1.81 (m, Cyclohexyl (R,S)-(–)-3-[2-(Methoxymethyl)pyrrolidin-1-ylamino]-
4 H, NCH2CH2, OCHCH2CH2), 1.85–2.03 (m, 5 H, CHCH2, nonane-1-sulfonate [(R,S)-4d]: Prepared according to GP 3 by 1,2-
Eur. J. Org. Chem. 2006, 1271–1284
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1275

D. Enders, A. Moll, J. W. Bats
FULL PAPER
addition of CeCl3·7H2O (2.24 g, 6.0 mmol) and nHexLi (2.3 mL,
6.0 mmol) to the hydrazone (S)-3a (0.499 g, 1.5 mmol). Compound
(R,S)-4d was obtained after flash column chromatography (SiO2,
n-pentane/Et2O, 1:1) as a colourless oil. Yield: 0.492 g (78%); Rf =
0.5 (n-pentane/Et2O, 1:1); de = 90% (13C NMR). [α]2D5 = –34.3 (c
SO2CH2CH2CH2, NCH2CH2CH2. (CH2)cyclo], 2.35 (m, 1 H,
NCHH), 2.59 (m, 1 H, NCH), 2.89 (m, 1 H, CHNH), 3.09 (m, 2
H, SO2CH2), 3.30–3.38 (m, 4 H, NCHH, OCHH), 3.36 (s, 3 H,
OCH3), 3.49 (m, 1 H, OCHH), 4.70 (m, 1 H, OCH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 19.4 (CH3), 20.2 (SO2CH2CH2),
= 1.16, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 21.0 (NCH3CH2), 23.5, 24.8, 32.8 [(CH2)cyclo], 26.1
6.9 Hz, 3 H, CH3), 1.24–2.12 [m, 26 H, (CH2)5CH3, (CH2)cyclo (NCH2CH2CH2), 34.2 (SO2CH2CH2CH2), 51.6 (SO2CH2), 53.5
SO2CH2CH2, NCH2CH2CH2], 2.38 (td, J = 8.8 Hz, J = 8.8 Hz, 1 (NHCH), 57.8 (NCH2), 59.0 (OCH3), 66.0 (NCH), 75.1 (OCH2),
H, NCHH), 2.64 (m, 1 H, NCH), 2.92 (m, 1 H, NHCH), 3.10– 80.7 (OCH) ppm. The structure was corroborated by the reactions
3.29 (m, 3 H, SO2CH2, NCHH), 3.34 (s, 3 H, OCH3), 3.36 (m, 1 involved in the next step.
H, OCHH), 3.46 (m, 1 H, OCHH), 4.69 [m, 1 H, CH(CH2)cyclo
,
]
Cyclohexyl (R,S)-4-[2-(Methoxymethyl)pyrrolidin-1-ylamino]octane-
1-sulfonate [(R,S)-4g]: Prepared according to GP 3 by 1,2-addition
of CeCl3·7H2O (1.863 g, 5.0 mmol) and nBuLi (3.1 mL, 5.0 mmol)
to the hydrazone (S)-3b (347 mg, 1.0 mmol). Compound (R,S)-4g
was obtained after flash column chromatography (SiO2, n-pentane/
Et2O, 1:1) as a yellow oil. Yield: 379.7 mg (94%); Rf = 0.16 (n-
pentane/Et2O, 1:1); de Ն 96% (13C NMR). [α]2D5 = –29.0 (c = 1.11,
ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1 (CH3), 21.0
(NCH2CH2), 22.6 (CH2CH3), 23.5, 24.9, 32.8 [(CH2)cyclo], 25.8
(NCH2CH2CH2), 26.3, 26.7, 29.5, 31.8, 32.5 [CHCH2, (CH2)4-
CH2CH3], 47.8 (SCH2), 57.1 (CH), 58.1 (NCH2), 58.9 (OCH3),
66.4 (NCH), 75.5 (OCH2), 80.5 [CH(CH2)cyclo] ppm. IR (CHCl3):
ν = 2932 (vs), 2860 (vs), 1720 (m), 1455 (s), 1346 (vs), 1168 (vs),
˜
1115 (m), 1004 (w), 935 (vs), 869 (s), 830 (m), 756 (s), 589 (w), 530
(m) cm–1. MS (EI, 70 eV): m/z (%) = 418 (6), 336 (19), 293 (6), 292
(15), 291 (100), 289 (5), 235 (6), 211 (8), 129 (13), 125 (13), 83 (6),
82 (5), 70 (10), 67 (7), 55 (9), 45 (5). C21H42N2O4S (418.63), calcd.
C 60.25, H 10.11, N 6.69; found C 59.93, H 10.45, N 6.46.
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 6.9 Hz, 3
H, CH3), 1.25–1.98 [m, 24 H, CH3CH2CH2CH2, SO2CH2CH2CH2,
NCH2CH2CH2. (CH2)cyclo], 2.28 (m, 1 H, NCHH), 2.61 (m, 1 H,
NCH), 2.77 (m, 1 H, CHNH), 3.10 (m, 1 H, SO2CH2), 3.26–3.53
(m, 4 H, NCHH, OCH2), 3.36 (s, 3 H, OCH3), 4.71 (m, 1 H, OCH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3CH2), 20.0
(SO2CH2CH2), 21.0 (NCH3CH2), 23.1 (CH3CH2), 23.5, 24.9, 32.8
[(CH2)cyclo], 26.2 (NCH2CH2CH2), 27.7 (CH3CH2CH2), 31.7, 32.6
(SO2CH2CH2CH2, CH3CH2CH2CH2), 51.9 (SO2CH2), 58.0
(NCH2), 58.1 (NHCH), 59.1 (OCH3), 66.3 (NCH), 75.2 (OCH2),
80.8 (OCH) ppm. The structure was corroborated by the reactions
involved in the next step.
Cyclohexyl (S,S)-(+)-3-[2-(Methoxymethyl)pyrrolidin-1-ylamino]-3-
phenylpropane-1-sulfonate [(S,S)-4e]: Prepared according to GP 3
by 1,2-addition of CeCl3·7H2O (2.24 g, 6.0 mmol) and PhLi
(3.41 mL, 6 mmol) to the hydrazone (S)-3a (0.499 g, 1.50 mmol).
Compound (S,S)-4e was obtained after flash column chromatog-
raphy (SiO2, n-pentane/Et2O, 1:1) as a colourless oil. Yield: 0.616 g
(99%); Rf = 0.31 (n-pentane/Et2O, 1:1); de Ն 96% (13C NMR).
[α]2D5 = +23.4 (c = 1.01, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.24–1.36 (m, 3 H, OCHCH2CH2CHH), 1.43–1.62 (m, 4 H,
NCH2CH2CHH, OCHCH2CH2CHH), 1.70 (m, 4 H, NCH2CH2,
OCHCH2CH2), 1.88 (m, 3 H, NCH2CH2CHH, OCHCH2), 2.21
(m, 1 H, CHCHH), 2.34 (m, 1 H, CHCHH), 2.44 (td, J = 8.6 Hz,
J = 8.7 Hz, 1 H, NCHH), 2.67 (m, 1 H, NCH), 2.99 (dd, J =
7.4 Hz, J = 8.5 Hz, 3 H, SCH2), 3.23 (m, 1 H, NCHH), 3.27 (s, 3
H, OCH3), 3.42 (m, 1 H, OCHH), 3.48 (m, 1 H, OCHH), 4.01 (dd,
J = 5.0 Hz, J = 8.0 Hz, 1 H, CH), 4.60 [m, 1 H, CH(CH2)cyclo],
7.24–7.38 (m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3): δ =
21.0 (NCH2CH2), 23.5, 24.8, 32.7 [(CH2)cyclo], 26.4
(NCH2CH2CH2), 29.4 (CHCH2), 48.2 (SCH2), 57.9 (NCH2), 58.9
(OCH3), 62.2 (CH), 66.2 (NCH), 75.5 (OCH2), 80.8 [CH-
(CH2)cyclo], 127.4, 127.4, 128.3 (CPh), 141.4 (ipso-CPh) ppm. IR
Cyclohexyl
(R,S)-4-[2-(Methoxymethyl)pyrrolidin-1-ylamino]de-
cane-1-sulfonate [(R,S)-4h]: Prepared according to GP 3 by 1,2-ad-
dition of CeCl3·7H2O (7.45 g, 20.0 mmol) and nHexLi (7.7 mL,
20.0 mmol) to the hydrazone (S)-3b (1.73 g, 5.0 mmol). Compound
(R,S)-4h was obtained after flash column chromatography (SiO2,
n-pentane/Et2O, 1:1) as a yellow oil. Yield: 1.62 g (75%); Rf = 0.33
(n-pentane/Et2O, 1:1); de Ն 96% (13C NMR). 1H NMR (400 MHz,
CDCl3): δ = 0.89 (t, J = 7.2 Hz, 3 H, CH3), 1.24–2.05 [m, 28 H,
CH3 (CH2)5, SO2CH2CH2CH2, NCH2CH2CH2, (CH2)cyclo], 2.25
(m, 1 H, NCHH), 2.60 (m, 1 H, NCH), 2.76 (m, 1 H, NHCH),
3.11 (m, 3 H, NCHH, SO2CH2), 3.30–3.50 (m, 2 H, OCH2), 3.35
(s, 3 H, OCH3), 4.70 (m, 1 H, OCH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.1 (CH3), 19.9 (SO2CH2CH2), 21.0 (NCH2CH2),
22.6
(CH2CH3),
23.5,
24.9,
26.1
32.8
[(CH2)cyclo],
25.5
29.7
(CHCl ): ν = 3454 (w), 3061 (m), 3028 (m), 2939 (vs), 2863 (vs),
˜
3
(CH2CH2CH2CH2CH3),
(NCH2CH2CH2),
1687 (m), 1603 (w), 1494 (w), 1451 (s), 1348 (vs), 1266 (w), 1236
(w), 1168 (vs), 1114 (s), 1030 (w), 1004 (w), 933 (vs), 871 (vs), 829
(m), 758 (vs), 703 (s), 531 (m) cm–1. MS (EI, 70 eV): m/z (%) = 411
(7), 410 (28) [M+], 394 (11), 328 (7), 283 (21), 281 (11), 215 (8), 214
(12), 203 (34), 197 (9), 130 (16), 129 (100), 117 (17), 106 (7), 105
(47), 84 (24), 83 (37), 77 (8), 70 (9), 67 (9), 55 (11), 54 (7), 46 (7),
45 (16). MS (CI): m/z (%) = 411 (21), 410 (15), 409 (10), 363 (19),
357 (17), 330 (14), 329 (78), 327 (14), 311 (7), 281 (9), 245 (7), 243
(10), 217 (6), 216 (11), 214 (100), 203 (6), 197 (14), 132 (15), 129
(18), 105 (12). C21H34N2O4S (410.57) calcd. C 61.43, H 8.35, N
6.82; found C 61.32, H 8.14, N 6.64.
(CH2CH2CH2CH3), 31.6, 31.9 (CH2CH2CH3, SO2CH2CH2CH2),
35.4 (CH2CH2CH2CH2CH2CH3), 51.8 (SO2CH2), 57.9 (NCH2),
58.0 (NHCH), 59.0 (OCH3), 66.2 (NCH), 75.1 (OCH2), 80.8
(OCH) ppm. The structure was corroborated by the reactions in-
volved in the next step.
Cyclohexyl
(S,S)-4-[2-(Methoxymethyl)pyrrolidin-1-ylamino]-4-
(phenyl)butane-1-sulfonate [(S,S)-4i]: Prepared according to GP 3
by 1,2-addition of CeCl3·7H2O (7.45 g, 20.0 mmol) and PhLi
(11.8 mL, 20.0 mmol) to the hydrazone (S)-3b (1.20 g, 3.46 mmol).
Compound (S,S)-4i was obtained after flash column chromatog-
raphy (SiO2, n-pentane/Et2O, 1:1) as a yellow oil. Yield: 1.13 g
Cyclohexyl
(R,S)-4-[2-(Methoxymethyl)pyrrolidin-1-ylamino]pen-
1
tane-1-sulfonate [(R,S)-4f]: Prepared according to GP 3 by 1,2-ad-
dition of CeCl3·7H2O (1.863 g, 5.0 mmol) and MeLi (3.1 mL,
5.0 mmol) to hydrazone (S)-3b (347 mg, 1.0 mmol). Compound
(R,S)-4f was obtained after flash column chromatography (SiO2, n-
pentane/Et2O, 1:1) as a yellow oil. Yield: 283 mg (78%); Rf = 0.16
(n-pentane/Et2O, 1:1); de = 82% (13C NMR). 1H NMR (300 MHz,
(77%), Rf = 0.29 (n-pentane/Et2O, 1:1); de Ն 96% (13C NMR). H
NMR (400 MHz, CDCl3):
δ
=
1.24–1.98 [m, 18 H,
SO2CH2CH2CH2, NCH2CH2CH2, (CH2)cyclo], 2.35 (td, J = 8.5 Hz,
J = 8.8 Hz, 1 H, NCHH), 2.61 (m, 1 H, NCH), 2.99 (m, 2 H,
SO2CH2), 3.14 (dd, J = 5.8 Hz, J = 9.3 Hz, 1 H, OCHH), 3.24 (s,
3 H, OCH3), 3.30 (m, 1 H, NCHH), 3.39 (dd, J = 4.7 Hz, J =
CDCl3): δ = 1.03 (d, J = 6.1 Hz, 3 H, CH3), 1.25–2.02 [m, 18 H, 9.3 Hz, 1 H, OCHH), 3.85 (dd, J = 4.9 Hz, J = 8.0 Hz, 1 H,
1276
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1271–1284

Asymmetric Synthesis of 3-Substituted γ- and δ-Sultams
FULL PAPER
CHNH), 4.59 [m, 1 H, CH(CH2)cyclo], 7.28–7.32 (m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.2 (CH3), 23.5, 24.8,
ppm. 13C NMR (100 MHz, CDCl3): δ = 20.4 (SO2CH2CH2), 21.0 32.7 [(CH2)cyclo], 28.3 (CH2CH3), 29.2 (CHCH2), 48.7 (SCH2), 51.6
(NCH2CH2), 23.4, 24.8, 32.6 [(CH2)cyclo], 26.3 (NCH2CH2CH2), (CH), 66.7 (CH2Ph), 81.1 (OCH), 127.8, 128.0, 128.4 (CPh), 136.2
34.2 (SO2CH2CH2CH2), 51.4 (SO2CH2), 57.7 (NCH2), 58.8 (ipso-CPh), 156.1 (C=O) ppm. IR (KBr): ν = 3362 (vs, br.), 3037
˜
(OCH3), 63.6 (NCH), 66.0 (NHCH), 75.1 (OCH2), 80.8 (OCH), (w), 2936 (s), 2869 (m), 1696 (vs), 1525 (vs), 1452 (m), 1414 (w),
127.1, 127.5, 128.0 (CPh), 142.6 (ipso-CPh) ppm. The structure was
corroborated by the reactions involved in the next step.
1385 (w), 1355 (s), 1299 (s), 1266 (m), 1233 (vs), 1170 (vs), 1093
(m), 1069 (m), 1043 (w), 1000 (m), 939 (vs), 893 (w), 867 (m), 833
(m), 778 (w), 755 (w), 729 (m), 695 (m), 645 (m), 601 (m), 537 (m),
515 (w), 458 (w) cm–1. MS (EI, 70 eV): m/z (%) = 302 (5), 301 (27),
272 (8), 228 (19), 192 (9), 165 (6), 148 (15), 146 (6), 109 (6), 108
(78), 106 (15), 92 (8), 91 (100), 83 (5), 55 (6). MS (CI): m/z (%) =
384 (9), 312 (5), 304 (6), 303 (16), 302 (100), 301 (21), 286 (12), 284
(20), 272 (5), 259 (10), 258 (66), 228 (7), 193 (9), 119 (8), 108 (20),
106 (5), 92 (5), 91 (69). C19H29NO5S (383.50): calcd. C 59.51, H
7.62, N 3.65; found C 59.37, H 7.73, N 3.59.
General Procedure for the N,N-Bond Cleavage and Protection of the
Amino Group (GP 4): The hydrazine 4 (1.0 equiv.) was dissolved in
dry THF (10.0 mL/mmol), then BH3·THF (12 equiv.) was added,
and the solution was heated to reflux for 4 h. The reaction mixture
was cooled to 0 °C, hydrolysed with methanol (30 mL/mmol) and
heated for another 20 min. The solvent was removed under reduced
pressure, and the residue was dissolved in CH2Cl2 (17 mL/mmol),
treated with K2CO3 (5.3 equiv.) and CbzCl (5.2 equiv.) and heated
to reflux for 18 h. After that, the reaction mixture was quenched
with water and the aqueous portion was extracted three times with
CH2Cl2. The combined organic layers were dried with MgSO4 and
the solvent was removed in a rotary evaporator. The residue was
purified by flash column chromatography (SiO2, n-pentane/Et2O).
Cyclohexyl
(R)-(+)-3-(Benzyloxycarbonylamino)heptanesulfonate
[(R)-5c]: Prepared as described in GP 4; N–N bond cleavage of
hydrazine (R,S)-4c (520 mg, 1.33 mmol) with BH3·THF (16.0 mL,
12 equiv.) afforded the crude amine, which was directly converted
into the carbamic acid benzyl ester (R)-5c by treatment with
K2CO3 (0.97 g, 7.05 mmol) and CbzCl (0.99 mL, 6.92 mmol).
Compound (R)-5c was obtained as a colourless oil after flash col-
umn chromatography (SiO2, n-pentane/Et2O, 1:1). Yield: 542 mg
(99%), Rf = 0.49 (n-pentane/Et2O, 1:1); ee = 87% (based on the de
value of the corresponding hydrazine). [α]2D5 = +1.58 (c = 1.01,
Cyclohexyl
(R)-(–)-3-(Benzyloxycarbonylamino)butanesulfonate
[(R)-5a]: Prepared as described in GP 4; N–N bond cleavage of the
hydrazine (R,S)-4a (0.081 g, 0.23 mmol) with BH3·THF (2.8 mL,
12 equiv.) afforded the crude amine, which was directly converted
into the carbamic acid benzyl ester (S)-5a by treatment with K2CO3
(168 mg, 1.22 mmol) and CbzCl (0.17 mL, 1.20 mmol). Compound
(R)-5a was obtained as a colourless oil after flash column
chromatography (SiO2, n-Pentan/Et2O, 2:1). Yield: 44 mg (50%);
Rf = 0.11 (n-pentane/Et2O, 2:1); ee = 84% (determined by HPLC
on chiral stationary phase, Daicelod M). [α]2D5 = –3.2 (c = 1.09,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 7.4 Hz, 3
H, CH3), 1.23–2.20 [m, 18 H, CHCH2, (CH2)3CH3, (CH2)cyclo],
3.14 (t, J = 8.3 Hz, 2 H, SCH2), 3.64 (m, 1 H, CH), 4.67 (m, 1 H,
OCH), 4.79 (br. d, J = 9.1 Hz, 1 H, NH), 5.09 (s, 2 H, OCH2), 7.34
(m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9 (CH3),
22.4 (CH2CH3), 23.5, 24.8, 32.7 [(CH2)cyclo], 27.9 (CH2CH2CH3),
29.6 (CHCH2), 35.1 (CH2CH2CH2CH3), 48.6 (SCH2), 50.2 (CH),
66.7 (CH2Ph), 81.0 (OCH), 127.8, 128.0, 128.4 (CPh), 136.2 (ipso-
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.20 (d, J = 6.3 Hz, 3
H, CH3), 1.22–1.99 [m, 10 H, (CH2)cyclo], 2.00 (m, 2 H, CHCH2),
3.12 (t, J = 8.0 Hz 2 H, SCH2), 3.83 (m, 1 H, CH), 4.68 (m, 1 H,
OCH), 4.83 (br. s, 1 H, NH), 5.08 (s, 2 H, OCH2), 7.34 (m, 5 H,
PhH) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.2 (CH3), 31.0
(CHCH2), 23.4, 24.8, 32.7 [(CH2)cyclo], 46.0 (CH), 48.6 (SCH2),
66.7 (CH2Ph), 81.1 (OCH), 127.9, 128.0, 128.4 (CPh), 136.1 (ipso-
CPh), 156.0 (C=O) ppm. IR (CHCl ): ν = 3501 (m, br.), 3337 (m),
˜
3
3029 (w), 2937 (vs), 2862 (s), 1701 (vs), 1530 (vs), 1453 (s), 1415
(m), 1346 (vs), 1241 (s), 1166 (vs), 1106 (m), 1074 (w), 1035 (m),
932 (vs), 869 (s), 831 (m), 756 (vs), 698 (m), 667 (w), 529 (w) cm–1.
MS (EI, 70 eV): m/z (%) = 330 (5), 329 (25), 272 (15), 228 (25), 220
(12), 194 (9), 176 (18), 146 (5), 108 (55), 107 (12), 92 (9), 91 (100),
83 (5), 55 (8). HRMS, C21H33NO5S: calcd. C21H33NO5S – C6H10
= 329.1297; found 329.1298.
CPh), 155.6 (C=O) ppm. IR (CHCl ): ν = 3065 (w), 3034 (w), 2939
˜
3
(vs), 2863 (s), 2362 (w), 2336 (w), 1347 (vs), 1289 (w), 1248 (vs),
1166 (vs), 1093 (m), 1064 (s), 1027 (m), 932 (vs), 870 (s), 831 (m),
750 (s), 699 (m), 669 (w), 587 (m), 534 (w), 463 (w) cm–1. MS (EI,
70 eV): m/z (%) = 369 (0.5), 288 (5), 287 (28), 152 (5), 134 (12), 109
(8), 108 (100), 107 (23), 92 (6), 91 (82), 83 (5), 70 (5), 55 (9). MS
(CI): m/z (%) = 370 (6), 316 (5), 290 (6), 289 (15), 288 (100), 287
(11), 272 (9), 270 (10), 244 (30), 180 (7), 119 (6), 108 (10), 91 (39),
83 (6). C18H27NO5S (369.47): calcd. C 58.51, H 7.37, N 3.79; found
C 58.36, H 7.15, N 3.62.
Cyclohexyl
(R)-(+)-3-(Benzyloxycarbonylamino)nonanesulfonate
[(R)-5d]: Prepared as described in GP 4; N–N bond cleavage of
hydrazine (R,S)-4d (691 mg, 1.65 mmol) with BH3·THF (3.5 mL,
12 equiv.) afforded the crude amine, which was directly converted
into the carbamic acid benzyl ester (R)-5d by treatment with
K2CO3 (1.22 g, 8.75 mmol) and CbzCl (1.22 mL, 8.58 mmol).
Compound (R)-5d was obtained as a colourless solid after flash
column chromatography (SiO2, n-pentane/Et2O, 1:1). Yield:
Cyclohexyl
(R)-(+)-3-(Benzyloxycarbonylamino)pentanesulfonate
[(R)-5b]: Prepared as described in GP 4; N–N bond cleavage of 573.5 mg (79%); Rf = 0.25 (n-pentane/Et2O, 2:1); ee = 90% (based
hydrazine (R,S)-4b (0.149 g, 0.41 mmol) with BH3·THF (5.0 mL, on the de value of the corresponding hydrazine). [α]2D5 = +1.0 (c =
1
12 equiv.) afforded the crude amine, which was directly converted
into the carbamic acid benzyl ester (R)-5b by treatment with
K2CO3 (300 mg, 2.17 mmol) and CbzCl (0.30 mL, 2.13 mmol).
Compound (R)-5b was obtained as a colourless solid after flash
column chromatography (SiO2, n-pentane/Et2O, 2:1). Yield: 0.113 g
(71%); Rf = 0.34 (n-pentane/Et2O, 2:1): ee = 78% (determined by
HPLC on chiral stationary phase, Daicelod M). [α]2D5 = +1.9 (c =
1.15, CHCl3); m.p. 54 °C. H NMR (400 MHz, CDCl3): δ = 0.88
(t, J = 6.9 Hz, 3 H, CH3), 1.23–2.15 [m, 22 H, CHCH2, (CH2)
5CH3, (CH2)cyclo], 3.14 (t, J = 8.2 Hz, 2 H, SCH2), 3.64 (m, 1 H,
CH), 4.67 (m, 1 H, OCH), 4.81 (br. d, J = 9.1 Hz, 1 H, NH), 5.08
(s, 2 H, OCH2), 7.34 (m, 5 H, PhH) ppm. 13C NMR (75 MHz,
CDCl3):
δ = 14.0 (CH3), 22.5 (CH2CH3), 23.5, 24.9, 32.7
[(CH2)cyclo], 29.6 (CHCH2), 25.8, 29.0, 31.7, 35.5 [(CH2)4CH2CH3],
48.7 (SCH2), 50.3 (CH), 66.8 (CH2Ph), 81.2 (OCH), 128.0, 128.2,
1
1.46, CHCl3); m.p. 74 °C. H NMR (400 MHz, CDCl3): δ = 0.93
(t, J = 7.4 Hz, 3 H, CH3), 1.20–1.90 [m, 12 H, CH2CH3,
128.6 (CPh), 136.5 (ipso-CPh), 156.3 (C=O) ppm. IR (KBr): ν =
˜
(CH2)cyclo], 1.95 (m, 1 H, CHCHH) 2.09 (m, 1 H, CHCHH), 3.14 3527 (w), 3471 (w), 3347 (s), 3064 (m), 3033 (m), 2933 (vs), 2860
(t, J = 8.3 Hz 2 H, SCH2), 3.64 (m, 1 H, CH), 4.68 (m, 1 H, OCH), (s), 2796 (w), 2759 (w), 2724 (w), 2697 (w), 1690 (vs), 1527 (vs),
4.75 (br. s, 1 H, NH), 5.09 (s, 2 H, OCH2), 7.35 (m, 5 H, PhH) 1455 (s), 1344 (vs), 1283 (w), 1241 (s), 1197 (w), 1166 (vs), 1112
Eur. J. Org. Chem. 2006, 1271–1284
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1277

D. Enders, A. Moll, J. W. Bats
FULL PAPER
(m), 1057 (m), 1038 (s), 1002 (w), 930 (vs), 867 (s), 831 (s), 803 (w), Cyclohexyl
(R)-(–)-4-(Benzyloxycarbonylamino)octanesulfonate
777 (m), 752 (m), 699 (s), 652 (m), 599 (s), 572 (m), 523 (m), 492 [(R)-5g]: Prepared as described in GP 4; N–N bond cleavage of the
(m) cm–1. MS (EI, 70 eV): m/z (%) = 439 (1) [M+], 358 (5), 357
(18), 272 (15), 248 (10), 228 (23), 222 (11), 204 (18), 146 (5), 108
(50), 107 (10), 92 (9), 91 (100), 83 (5), 55 (8). MS (CI): m/z (%) =
440 (7), 386 (9), 360 (8), 359 (24), 358 (100), 357 (11), 356 (7), 342
(11), 340 (12), 315 (9), 314 (38), 250 (6), 108 (6), 91 (26).
C23H37NO5S (439.61): calcd. C 62.84, H 8.48, N 3.19; found C
62.73, H 8.15, N 3.22.
hydrazine (R,S)-4g (380 mg, 0.94 mmol) with BH3·THF (11.3 mL,
12 equiv.) afforded the crude amine, which was directly converted
into the carbamic acid benzyl ester (S)-5e by treatment with K2CO3
(688.3 mg, 4.98 mmol) and CbzCl (0.70 mL, 4.89 mmol). Com-
pound (R)-5g was obtained as a colourless oil after flash column
chromatography (SiO2, n-pentane/Et2O, 1:1). Yield: 211.2 mg
(53%); ee = 93% (determined by HPLC chiral stationary phase);
Rf = 0.21 (n-pentane/Et2O, 2:1). [α]2D5 = –7.5 (c = 1.07, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 5.69 Hz, 3 H,CH3), 1.24–
2.00 [m, 20 H, (CH2)cyclo, SO2CH2CH2CH2, CH3CH2CH2CH2],
3.10 (m, 2 H, SO2CH2), 3.62 (m, 1 H, NHCH), 4.58 (d, J = 9.4 Hz,
1 H, NH), 4.68 (m, 1 H, OCH), 5.09 (s, 2 H, OCH2), 7.26–7.37 (m,
5 H, PhH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 20.2
(SO2CH2CH2), 22.5 (CH3CH2), 23.5, 24.9, 32.8 [(CH2)cyclo], 28.0
(CH3CH2CH2), 33.8 (CH3CH2CH2CH2), 35.1 (SOCH2CH2CH2),
50.6 (NHCH), 51.1 (SO2CH2), 66.6 (OCH2), 81.0 (OCH), 128.0,
128.1, 128.5 (CPh), 136.6 (ipso-CPh), 156.2 (C=O) ppm. IR
Cyclohexyl (S)-(–)-3-Benzyloxycarbonylamino-3-(phenyl)propane-
sulfonate [(S)-5e]: Prepared as described in GP 4; N–N bond cleav-
age of hydrazine (S,S)-4e (0.218 g, 0.53 mmol) with BH3·THF
(6.4 mL, 12 equiv.) afforded the crude amine, which was directly
converted into the carbamic acid benzyl ester (S)-5e by treatment
with K2CO3 (0.388 g, 2.81 mmol) and CbzCl (0.39 mL,
2.76 mmol). (S)-5e was obtained as a colourless solid after flash
column chromatography (SiO2, n-pentane/Et2O, 1:1). Yield: 0.213 g
(96%); Rf = 0.51 (n-pentane/Et2O, 1:1); ee Ն 96% (based on the
de value of the corresponding hydrazine). [α]2D5 = –17.4 (c = 1.03,
(CHCl ): ν = 3336 (m), 3029 (m), 2938 (vs), 2862 (s), 1703 (vs),
˜
3
1
CHCl3); m.p. 114 °C. H NMR (300 MHz, CDCl3): δ = 1.26–2.00
1530 (vs), 1454 (s), 1414 (m), 1346 (vs), 1240 (s), 1166 (vs), 1109
(m), 1048 (w), 1005 (w), 934 (vs), 870 (s), 829 (m), 755 (vs), 699
(m), 593 (w), 530 (w) cm–1. MS (EI, 70 eV): m/z (%) = 204 (38),
160 (26), 92 (7), 91 (100). MS (CI): m/z (%) = 426 (6) [M+ + 1],
344 (11), 250 (22), 227 (6), 206 (13), 205 (6), 173 (10), 142 (14), 137
(5), 107 (6), 91 (45), 84 (7), 83 (100), 82 (18), 82 (70), 79 (10), 69
[m, 10 H, (CH2)cyclo], 2.34 (m, 2 H, CHCH2), 3.08 (m, 2 H, SCH2),
4.67 [m, 1 H, CH(CH2)cyclo], 4.79 (m, 1 H, OCH), 5.08 (d, J =
6.2 Hz, 2 H, OCH2), 5.21 (d, J = 8.4 Hz, 1 H, NH), 7.26–7.40 (m,
10 H, PhH) ppm. 13C NMR(75 MHz, CDCl3): δ = 23.5, 24.8, 32.7
[(CH2)cyclo], 30.5 (CHCH2), 48.7 (SCH2), 54.1 (CH), 67.1 (CH2Ph),
81.4 (OCH), 126.3, 128.2, 128.2, 128.6, 129.1 (CPh), 136.1, 140.4
(20), 67 (12). HRMS, C22H35NO5S: calcd. C22H35NO5S
C8H16SO2 = 249.1365; found 249.1366.
–
(ipso-CPh), 155.7 (C=O) ppm. IR (KBr): ν = 3366 (s, br.), 3088
˜
(w), 3062 (w), 3034 (m), 2993 (m), 2937 (s), 2863 (m), 1693 (vs),
1519 (vs), 1453 (m), 1417 (w), 1360 (vs), 1341 (vs), 1290 (m), 1253
(vs), 1236 (vs), 1163 (vs), 1045 (s), 937 (vs), 876 (s), 829 (m), 801
(w), 759 (s), 700 (s), 629 (w), 585 (m), 561 (m), 532 (s), 489 (w)
cm–1. MS (EI, 70 eV): m/z (%) = 349 (8), 258 (8), 241 (7), 240 (39),
215 (5), 213 (45), 200 (5), 197 (9), 196 (33), 132 (19), 116 (9), 108
(13),107 (13), 92 (8), 91 (100), 55 (7). C23H29NO5S (431.54): calcd.
C 64.02, H 6.77, N 3.25; found C 64.17, H 6.55, N 3.09.
Cyclohexyl
(R)-(–)-4-(Benzyloxycarbonylamino)decanesulfonate
[(R)-5h]: Prepared as described in GP 4; N–N bond cleavage of the
hydrazine (R,S)-4h (696 mg, 1.61 mmol) with BH3·THF (19 mL,
12 equiv.) afforded the crude amine, which was directly converted
into the carbamic acid benzyl ester (R)-5h by treatment with
K2CO3 (1.18 g, 8.53 mmol) and CbzCl (1.19 mL, 8.4 mmol). (R)-5h
was obtained as a colourless oil after flash column chromatography
(SiO2, n-pentane/Et2O, 1:1). Yield: 511 mg (70%); ee Ն 96% (based
on the de value of the corresponding hydrazine); Rf = 0.36 (n-pen-
tane/Et2O, 1:1). [α]2D5 = –1.6 (c = 0.98, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H, CH3), 1.23–2.15
[m, 24 H, SO2CH2CH2CH2, (CH2)5CH3, (CH2)cyclo], 3.10 (m, 2 H,
SO2CH2), 3.63 (m, 1 H, CH), 4.55 (br. d, J = 9.2 Hz, 1 H, NH),
4.69 (m, 1 H, OCH), 5.09 (s, 2 H, OCH2), 7.30–7.39 (m, 5 H,
PhH) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0 (CH3), 20.2
(SO2CH2CH2), 22.5 (CH2CH3), 23.5, 24.8, 32.7 [(CH2)cyclo], 25.8
[CH2(CH2)3CH3], 29.1 [CH2(CH2)2CH3], 31.7 (CH2CH2CH3), 33.8
(SO2CH2CH2CH2), 35.3 [CH2(CH2)4CH3], 50.6 (CH), 51.0
(SO2CH2), 66.6 (OCH2), 81.0 (OCH), 127.8, 127.9, 128.3 (CPh),
Cyclohexyl
(R)-(–)-4-(Benzyloxycarbonylamino)pentanesulfonate
[(R)-5f]: Prepared as described in GP 4; N–N bond cleavage of the
hydrazine (R,S)-4f (196 mg, 0.56 mmol) with BH3·THF (6.4 mL,
12 equiv.) afforded the crude amine, which was directly converted
into the carbamic acid benzyl ester (R)-5f by treatment with K2CO3
(409.1 mg, 2.96 mmol) and CbzCl (0.41 mL, 2.91 mmol). Com-
pound (R)-5f was obtained as a colourless solid after flash column
chromatography (SiO2, n-pentane/Et2O, 2:1). Yield: 122 mg (58%);
ee Ն 96% (based on the de value of the corresponding hydrazine);
Rf = 0.14 (n-pentane/Et2O, 2:1). [α]2D5 = –5.8 (c = 0.99 in CHCl3).
1H NMR (400 MHz, CDCl3): δ = 1.15 (d, J = 6.6 Hz, 3 H, CH3),
1.25–1.98 [m, 14 H, (CH2)cyclo, SO2CH2CH2CH2], 3.10 (m, 2 H,
SO2CH2), 3.74 (m, 1 H, NHCH), 4.67 (m, 1 H, OCH), 4.81 (d, J
= 8.2 Hz, 1 H, NH), 5.08 (s, 2 H, OCH2), 7.28–7.36 (m, 5 H, PhH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 20.3 (SO2CH2CH2), 21.1
(CH3), 23.4, 24.8, 32.7 [(CH2)cyclo], 35.2 (CH3CHCH2), 46.3
(NHCH), 51.0 (SO2CH2), 66.4 (OCH2), 80.9 (OCH), 127.8, 127.9,
136.4 (ipso-CPh), 156.0 (C=O) ppm. IR (CHCl ): ν = 3364 (m),
˜
3
3027 (m), 2935 (vs), 2860 (vs), 1706 (vs), 1528 (vs), 1454 (s), 1410
(w), 1345 (vs), 1236 (s), 1165 (vs), 1115 (m), 1057 (m), 1004 (w),
933 (vs), 871 (s), 829 (m), 757 (vs), 700 (m), 667 (w), 593 (w), 529
(w) cm–1. MS (EI, 70 eV): m/z (%) = 372 (6), 371 (20), 287 (9), 286
(53), 248 (21), 243 (10), 242 (62), 236 (14), 225 (11), 205 (6), 204
(38), 108 (18), 107 (8), 92 (8), 91 (100), 83 (5), 67 (6). MS (CI):
m/z (%) = 454 (6), 354 (9), 264 (17), 221 (10), 173 (8), 108 (22), 107
(14), 95 (8), 92 (9), 91 (74), 84 (5), 83 (70), 82 (69), 81 (100), 80
(13), 79 (31), 69 (18), 67 (61). HRMS, C24H39NO5S: calcd.
C24H39NO5S – C6H10 = 371.1766; found 371.1765.
128.3 (CPh), 136.3 (ipso-CPh), 155.6 (C=O) ppm. IR (CHCl ): ν =
˜
3
3376 (s), 3066 (w), 3031 (m), 2940 (vs), 2863 (s), 2362 (m), 2335
(m), 1703 (vs), 1653 (m), 1528 (vs), 1455 (s), 1413 (w), 1343 (vs),
1244 (vs), 1165 (vs), 1070 (s), 1030 (m), 1006 (w), 933 (vs), 870 (s),
830 (m), 756 (vs), 700 (m), 668 (w), 589 (w), 532 (w) cm–1. MS (EI,
70 eV): m/z (%) = 383 (1) [M+], 301 (22), 178 (15), 166 (10), 134 Cyclohexyl (S)-(–)-4-(Benzyloxycarbonylamino)-4-(phenyl)butane-
(25), 108 (65), 107 (19), 92 (8), 91 (100), 83 (5), 55 (6). MS (CI):
m/z (%) = 384 (13) [M+ + 1], 330 (9), 304 (7), 303 (19), 302 (100),
301 (7), 286 (10), 284 (16), 259 (7), 258 (41), 119 (6), 108 (5), 91
(28). HRMS, C19H29NO5S: calcd. 383.1766; found 383.1768.
sulfonate [(S)-5i]: Prepared as described in GP 4; N–N bond cleav-
age of the hydrazine (S,S)-4i (1.13 g, 2.67 mmol) with BH3·THF
(32 mL, 12 equiv.) afforded the crude amine, which was directly
converted into the carbamic acid benzyl ester (S)-5i by treatment
1278
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1271–1284

Asymmetric Synthesis of 3-Substituted γ- and δ-Sultams
with K2CO3 (1.96 g, 14.25 mmol) and CbzCl (1.97 mL, (11), 259 (5), 258 (35), 206 (8), 119 (10), 108 (7), 92 (7), 91 (100).
FULL PAPER
13.88 mmol). (S)-5i was obtained as a colourless oil after flash col-
umn chromatography (SiO2, n-pentane/Et2O, 1:1). Yield: 1.18 g
(98%); ee: Ն 96% (determined by HPLC on chiral stationary
phase); Rf = 0.25 (n-pentane/Et2O, 1:1). [α]2D5 = –15.9 (c = 1.00,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.18–1.89 [m, 14 H,
SO2CH2CH2CH2, (CH2)cyclo], 3.06 (m, 2 H, SO2CH2), 4.64 (m, 2
H, NHCH, OCH), 5.06 (m, 2 H, OCH2), 5.39 (br. s, 1 H, NH),
7.22–7.36 (m, 10 H, PhH) ppm. 13C NMR (75 MHz, CDCl3): δ =
20.6 (SO2CH2CH2), 23.4, 24.8, 32.7 [(CH2)cyclo], 34.8
(SO2CH2CH2CH2), 50.8 (SO2CH2), 54.8 (NHCH), 66.7 (OCH2),
81.0 (OCH), 126.2, 127.5, 127.9, 128.3, 128.6 (CPh), 136.3, 141.3
HRMS, C12H16ClNO4S: calcd. 305.0489; found 305.0488.
(R)-(+)-3-(Benzyloxycarbonylamino)pentane-1-sulfonyl
Chloride
[(R)-6b]: According to GP
5 compound (R)-5b (223.8 mg,
0.58 mmol) was dissolved in ethanol (17.4 mL) and water
(0.58 mL). After refluxing for 18 h, sodium acetate (53.0 mg,
0.65 mmol) was added, the resulting sodium sulfonate was dis-
solved in CH2Cl2 (5.8 mL abs.) and DMF (0.07 mL abs.) and con-
verted with phosgene solution (0.58 mL, 20% in toluene) to the
corresponding sulfonyl chloride (R)-6b, which could be isolated af-
ter column chromatography (SiO2, n-pentane/Et2O, 2:1) as a
colourless solid. M.p. 71 °C; yield: 139 mg (74%); Rf = 0.51 (n-
pentane/Et2O, 1:1); ee = 82% (determined by HPLC chiral station-
ary phase). [α]2D5 = +3.0 (c = 0.61, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 0.97 (t, J = 7.4 Hz, 3 H, CH3), 1.56 (m, 2 H, CH2CH3),
2.02 (m, 1 H, CHHCH), 2.27 (m, 1 H, CHHCH), 3.74 (m, 3 H,
SCH2, CH), 4.62 (d, J = 8.8 Hz, 1 H, NH), 5.10 (s, 2 H, OCH2),
7.36 (m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3): δ = 10.3
(CH3), 28.4, 30.1 (CH2CHCH2), 51.2 (CH), 62.7 (SCH2), 67.0
(OCH2), 128.0, 128.2, 128.5 (CPh), 135.9 (ipso-CPh), 156.1 (C=O)
(ipso-CPh), 155.6 (C=O) ppm. IR (CHCl ): ν = 3336 (m), 3028
˜
3
(m), 2942 (vs), 2863 (m), 1706 (vs), 1527 (s), 1454 (m), 1413 (w),
1344 (s), 1237 (m), 1167 (s), 1122 (w), 1053 (m), 1030 (m), 1004
(w), 932 (s), 870 (m), 831 (w), 756 (vs), 701 (s), 667 (w), 587 (w),
528 (m) cm–1. MS (EI, 70 eV): m/z (%) = 568 (6), 512 (85), 327
(11), 326 (47), 325 (44), 318 (9), 241 (8), 240 (43), 228 (18), 213 (8),
212 (9), 211 (15), 197 (5), 196 (34), 151 (7), 150 (7), 147 (7), 132
(8), 131 (7), 130 (10), 129 (5), 120 (8), 108 (24), 107 (15), 106 (7),
105 (18), 104 (8), 92 (7), 91 (66), 83 (8), 82 (56), 81 (13), 79 (21),
78 (5), 77 (15), 68 (5), 67 (100), 65 (9), 56 (8), 54 (63), 54 (10), 52
(9), 51 (5). MS (CI): m/z (%) = 446 [M+ + 1, 2], 225 (7), 214 (10),
213 (65), 152 (9), 131 (15), 108 (12), 107 (6), 105 (5), 95 (5), 92 (7),
91 (74), 84 (6), 83 (100), 82 (60), 81 (97), 80 (5), 79 (12), 69 (29),
67 (52). HRMS, C24H31NO5S: calcd. 445.1922; found 445.1923.
ppm. IR (KBr): ν = 3346 (vs), 3068 (w), 3036 (w), 2965 (s), 2929
˜
(s), 2858 (m), 1687 (vs), 1529 (vs), 1454 (s), 1369 (vs), 1297 (s),
1243 (vs), 1165 (vs), 1090 (s), 1067 (m), 1038 (m), 996 (m), 932 (m),
841 (w), 777 (m), 752 (s), 724 (m), 695 (m), 659 (w), 608 (s), 527
(vs), 496 (s), 461 (w) cm–1. MS (EI, 70 eV): m/z (%) = 319 (2) [M+],
148 (5), 109 (6), 108 (74), 107 (7), 92 (8), 91 (100), 65 (5). MS (CI):
m/z (%) = 320 (10) [M+ + 1], 276 (5), 220 (22), 181 (6), 119 (7), 108
(7), 92 (9), 91 (100). HRMS, C13H18ClNO4S: calcd. 319.0645;
found 319.0642.
General Procedure for the Synthesis of ω-Aminosulfonyl Chlorides
(GP 5): The aminosulfonate 5 (1.0 equiv.) was dissolved in ethanol
(30 mL/mmol) and water (1 mL/mmol) and refluxed for 18 h. After
cooling to room temperature sodium acetate (1.1 equiv.) was
added, and the solution was stirred for 1 h at room temperature.
The solvent was removed and the obtained sodium sulfonate was
directly converted into the corresponding sulfonyl chloride. There-
fore, the residue was dissolved in abs. CH2Cl2 (10 mL/mmol) and
abs. DMF (0.12 mL/mmol). Then a solution containing 20% phos-
gene in toluene (1.0 mL/mmol) was added, and the mixture was
stirred for 2 h at room temperature. The solution was concentrated,
and the crude product was purified by column chromatography
(SiO2, n-pentane/Et2O).
(R)-(+)-3-(Benzyloxycarbonylamino)heptane-1-sulfonyl
Chloride
[(R)-6c]: According to GP compound (R)-5c (99.5 mg,
5
0.24 mmol) was dissolved in ethanol (7.2 mL) and water (0.24 mL).
After refluxing for 18 h, sodium acetate (22.4 mg, 0.27 mmol) was
added, the resulting sodium sulfonate was dissolved in CH2Cl2
(2.4 mL abs.) and DMF (0.03 mL abs.) and converted with phos-
gene solution (0.24 mL, 20% in toluene) to the corresponding sul-
fonyl chloride (R)-6c, which could be isolated after column
chromatography (SiO2, n-pentane/Et2O, 2:1) as a colourless solid.
M.p. 89 °C; yield: 62.8 mg (75%); Rf = 0.60 (n-pentane/Et2O, 1:1);
ee = 87% (based on the de value of the corresponding hydrazine).
(R)-(+)-3-(Benzyloxycarbonylamino)butane-1-sulfonyl
Chloride
[(R)-6a]: According to GP compound (R)-5a (86.6 mg,
5
1
[α]2D5 = +7.0 (c = 1.00, CHCl3). H NMR (300 MHz, CDCl3): δ =
0.23 mmol) was dissolved in 6.9 mL ethanol and 0.23 mL water.
After refluxing for 18 h, sodium acetate (21.5 mg, 0.26 mmol) was
added, the resulting sodium sulfonate was dissolved in CH2Cl2
(2.3 mL abs.) and DMF (0.03 mL abs.) and converted with phos-
gene solution (0.23 mL, 20% in toluene) to the corresponding sul-
fonyl chloride (R)-6a, which could be isolated after column
chromatography (SiO2, n-pentane/Et2O, 2:1) as a colourless solid.
M.p. 82–84 °C; Yield: 50.3 mg (72%); Rf = 0.30 (n-pentane/Et2O,
2:1); ee = 84% (based on the ee value of the corresponding sulfo-
nate). [α]2D5 = +1.7 (c = 1.01, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 1.25 (d, J = 6.7 Hz, 3 H, CH3), 2.08 (m, 1 H, CHHCH), 2.22
(m, 1 H, CHHCH), 3.70 (m, 2 H, SO2CH2), 3.90 (m, 1 H, CH),
4.70 (br. s, 1 H, NH), 5.10 (s, 2 H, OCH2), 7.36 (m, 5 H, PhH).
13C NMR (75 MHz, CDCl3): δ = 21.4 (CH3), 32.0 (CHCH2), 45.7
(CH), 62.7 (SCH2), 67.1 (CH2Ph), 128.2, 128.4, 128.7 (CPh), 136.1
0.90 (m, 3 H, CH3), 1.25–1.56 [m, 6 H, (CH2)3CH3], 2.02 (m, 1 H,
CHHCH), 2.25 (m, 1 H, CHHCH), 3.74 (m, 3 H, SCH2, CH), 4.72
(br. s, 1 H, NH), 5.10 (s, 2 H, OCH2), 7.33–7.40 (m, 5 H, PhH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9 (CH3), 22.3
(CH2CH3), 27.9, 30.5, 35.1 [CH2CH(CH2)2], 49.8 (CH), 62.6
(SCH2), 67.0 (OCH2), 127.9, 128.2, 128.4 (CPh), 135.9 (ipso-CPh),
156.0 (C=O) ppm. IR (KBr): ν = 3334 (vs), 3061 (w), 2950 (m),
˜
2861 (m), 1692 (vs), 1539 (vs), 1454 (m), 1369 (vs), 1300 (s), 1249
(s), 1161 (s), 1109 (m), 1072 (w), 1032 (m), 937 (w), 908 (w), 777
(m), 748 (m), 729 (m), 696 (m), 672 (m), 557 (s), 538 (m), 487 (m)
cm–1. MS (EI, 70 eV): m/z (%) = 347 (2), 109 (5), 92 (8), 91 (100).
MS (CI): m/z (%) = 350 (5), 348 (14), 304 (5), 249 (5), 248 (26),
119 (8), 108 (7), 92 (8), 91 (100), 65 (5). C15H22ClNO4S (347.85):
calcd. C 51.79, H 6.37, N 4.03; found C 51.73, H 6.69, N 3.86.
(ipso-CPh), 155.9 (C=O) ppm. IR (KBr): ν = 3307 (s, br.), 3070 (R)-(+)-3-(Benzyloxycarbonylamino)nonane-1-sulfonyl
Chloride
˜
(m), 2978 (w), 2792 (w), 1687 (vs), 1544 (vs), 1454 (m), 1376 (vs),
[(R)-6d]: According to GP 5 compound (R)-5d (141.3 mg,
1293 (m), 1254 (vs), 1164 (vs), 1092 (s), 1059 (s), 1022 (m), 932 (m), 0.32 mmol) was dissolved in ethanol (9.6 mL) and water (0.32 mL).
884 (w), 843 (w), 1022 (m), 932 (m), 884 (w), 843 (w), 762 (m), 730 After refluxing for 18 h, sodium acetate (29.7 mg, 0.36 mmol) was
(w), 699 (m), 593 (m), 530 (s), 487 (w) cm–1. MS (EI, 70 eV): added, the resulting sodium sulfonate was dissolved in CH2Cl2
m/z (%) = 305 (3) [M+], 109 (8), 108 (100), 107 (15), 92 (7), 91 (94), (3.2 mL abs.) and DMF (0.04 mL abs.) and converted with phos-
79 (7), 65 (6). MS (CI): m/z (%) = 306 (4) [M+ + 1], 302 (29), 284 gene solution (0.32 mL, 20% in toluene) to the corresponding sul-
Eur. J. Org. Chem. 2006, 1271–1284
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1279

D. Enders, A. Moll, J. W. Bats
FULL PAPER
fonyl chloride (R)-6d, which could be isolated after column
chromatography (SiO2, n-pentane/Et2O, 2:1) as a colourless solid.
m.p. 85 °C; Yield: 100.0 mg (83%); Rf = 0.42 (n-pentane/Et2O, 2:1);
ee = 90% (based on the de value of the corresponding hydrazine).
128.1, 128.2, 128.6 (CPh), 136.4 (ipso-CPh), 155.9 (C=O) ppm. IR
(KBr): ν = 3312 (vs), 3044 (w), 2976 (m), 2952 (m), 2913 (m), 1685
˜
(vs), 1537 (vs), 1459 (m), 1371 (vs), 1298 (m), 1252 (vs), 1165 (vs),
1098 (m), 1063 (s), 981 (w), 931 (m), 843 (w), 822 (w), 732 (s), 732
(s), 701 (m), 652 (m), 579 (w), 539 (s), 512 (s) cm–1. MS (EI, 70 eV):
m/z (%) = 319 (3), 134 (14), 109 (6), 108 (72), 107 (6), 92 (7), 91
[α]2D5 = +5.8 (c = 1.03, CHCl3). H NMR (300 MHz, CDCl3): δ =
1
0.88 (t, J = 6.4 Hz, 3 H, CH3), 1.25–1.56 [m, 10 H, (CH2)5CH3],
2.02 (m, 1 H, CHHCH), 2.26 (m, 1 H, CHHCH), 3.74 (m, 3 H, (100), 65 (5). MS (CI): m/z (%) = 320 (10) [M+ + 1], 119 (8), 108 (6),
SCH2, CH), 4.62 (d, J = 9.1 Hz, 1 H, NH), 5.10 (s, 2 H, OCH2),
92 (7), 91 (100). HRMS, C13H18ClNO4S: calcd. 319.0645; found
7.36 (m, 5 H, PhH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 319.0645.
(CH3), 22.5 (CH2CH3), 25.8, 28.9, 30.6, 31.6, 35.5 [CH2CH(CH2)
(R)-(–)-4-(Benzyloxycarbonylamino)octane-1-sulfonyl Chloride [(R)-
4], 49.9 (CH), 62.8 (SCH2), 67.1 (OCH2), 128.2, 128.4, 128.7 (CPh),
6g]: According to GP 5 compound (R)-5g (128.0 mg, 0.30 mmol)
was dissolved in ethanol (9.0 mL) and water (0.30 mL). After re-
fluxing for 18 h, sodium acetate (26.8 mg, 0.33 mmol) was added,
the resulting sodium sulfonate was dissolved in CH2Cl2 (3.0 mL
abs.) and DMF (0.04 mL abs.) and converted with phosgene solu-
tion (0.30 mL, 20% in toluene) to the corresponding sulfonyl chlo-
ride (R)-6g, which could be isolated after column chromatography
(SiO2, n-pentane/Et2O, 2:1) as a colourless solid. M.p. 69 °C; yield:
97.5 mg (89%), Rf = 0.20 (n-pentane/Et2O, 2:1); ee = 93% (based
136.1 (ipso-CPh), 156.3 (C=O) ppm. IR (KBr): ν = 3695 (w), 3674
˜
(w), 3653 (w), 3312 (vs, br.), 3066 (w), 2957 (s), 2927 (s), 2853 (m),
1689 (vs), 1541 (vs), 1451 (m), 1369 (vs), 1299 (m), 1262 (vs), 1165
(s), 1118 (w), 1064 (m), 1030 (m), 965 (w), 913 (w), 753 (m), 730
(m), 694 (m), 606 (w), 575 (m), 535 (s), 499 (m), 462 (w) cm–1. MS
(EI, 70 eV): m/z (%) = 375 (3) [M+], 245 (7), 204 (10), 109 (6), 108
(76) 92 (9), 91 (100). MS (CI): m/z (%) = 375 (0.8) [M+], 204 (7),
109 (5), 108 (62), 92 (8), 91 (100). C17H26ClNO4S (375.91): calcd.
C 54.32, H 6.97, N 3.73; found C 54.66, H 6.77, N 3.25.
on the ee value of the corresponding sulfonate). [α]2D5 = –8.1 (c =
1
(S)-(–)-3-Benzyloxycarbonylamino-3-(phenyl)propane-1-sulfonyl 0.57, CHCl3). H NMR (300 MHz, CDCl3): δ = 0.90 (br. s, 3 H,
Chloride [(R)-6e]: According to GP 5 compound (R)-5e (42.2 mg,
0.10 mmol) was dissolved in ethanol (3.0 mL) and water (0.10 mL).
After refluxing for 18 h, sodium acetate (9.1 mg, 0.11 mmol) was
added, the resulting sodium sulfonate was dissolved in CH2Cl2
(1.0 mL abs.) and DMF (0.01 mL abs. ) and converted with phos-
gene solution (0.60 mL, 20% in toluene) to the corresponding sul-
fonyl chloride (R)-6e, which could be isolated after column
chromatography (SiO2, n-pentane/Et2O, 1:1) as a colourless solid.
m.p. 74 °C; Yield: 28 mg (80%); Rf = 0.43 (n-pentane/Et2O, 1:1);
ee Ն 96% (based on the de value of the corresponding hydrazine).
CH3), 1.25–1.82 (m, 8 H, SO2CH2CH2CH2, CH3CH2CH2CH2),
2.09 (m, 2 H, SO2CH2CH2), 3.60–3.85 (m, 3 H, SO2CH2, CH),
4.58 (d, J = 8.9 Hz, 1 H, NH), 5.11 (s, 2 H, OCH2), 7.30–7.38 (m,
5 H, PhH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 21.0
(SO2CH2CH2), 22.5 (CH3CH2), 28.0 (CH3CH2CH2), 33.4
(CH3CH2CH2CH2), 35.2 (SO2CH2CH2CH2), 50.3 (NHCH), 65.0
(SO2CH2), 66.8 (OCH2), 128.1, 128.3, 128.6 (CPh), 136.4 (ipso-
CPh), 156.3 (C=O) ppm. IR (KBr): ν = 3319 (s), 3065 (w), 3033
˜
(w), 3942 (s), 2857 (m), 1695 (vs), 1545 (vs), 1459 (m), 1413 (w),
1357 (s), 1248 (s), 1163 (s), 1111 (m), 1081 (w), 1054 (w), 1021 (m),
911 (w), 843 (w), 757 (s), 734 (s), 694 (m), 523 (s), 486 (w) cm–1.
MS (EI, 70 eV): m/z (%) = 361 (2) [M+], 262 (5), 260 (16), 176 (18),
1
[α]2D5 = –23.1 (c = 0.62, CHCl3). H NMR (300 MHz, CDCl3): δ =
2.54 (m, 2 H, CH2CH), 3.69 (m, 2 H, SCH2), 4.85 (m, 1 H, NH),
5.10–5.17 (m, 3 H, CH, OCH2), 7.36 (m, 10 H, PhH) ppm. 13C 108 (30), 92 (8), 91 (100). MS (CI): m/z (%) = 362 (7) [M+ + 1],
NMR (75 MHz, CDCl3): δ = 31.1 (CH2CH), 53.7 (CH), 62.4 358 (18), 314 (6), 251 (16), 250 (100), 248 (7), 207 (9), 206 (45), 204
(SCH2), 67.3 (OCH2), 126.3, 128.2, 128.4, 128.6, 129.4 (CPh), (17), 186 (6), 142 (24), 119 (14), 114 (9), 107 (5), 92 (7), 91 (94), 83
135.9, 139.5 (ipso-CPh), 155.8 (C=O) ppm. IR (KBr): ν = 3345 (5), 79 (9), 65 (6). C16H24ClNO4S (361.88): calcd. C 53.10, H 6.68,
˜
(vs), 3063 (m), 3032 (m), 2997 (m), 2939 (m), 1693 (vs), 1523 (vs), N 3.87; found C 53.45, H 6.82, N 4.14.
1444 (m), 1372 (vs), 1290 (m), 1246 (vs), 1162 (vs), 1046 (s), 925
(R)-(–)-4-(Benzyloxycarbonylamino)decane-1-sulfonyl Chloride [(R)-
6h]: According to GP 5 compound (R)-5h (58.8 mg, 0.13 mmol)
was dissolved in ethanol (3.9 mL) and water (0.13 mL). After re-
(m), 842 (m), 754 (s), 700 (s), 647 (w), 596 (m), 513 (s) cm–1. MS
(EI, 70 eV): m/z (%) = 376 (1), 276 (8), 240 (15), 232 (5), 196 (23),
132 (18), 117 (8), 108 (33), 107 (7), 92 (8), 91 (100), 65 (6). MS
fluxing for 18 h, sodium acetate (11.8 mg, 0.14 mmol) was added,
(CI): m/z (%) = 668 (2), 364 (14), 320 (8), 268 (14), 240 (9), 228 (6),
the resulting sodium sulfonate was dissolved in CH2Cl2 (1.3 mL
abs.) and DMF (0.02 mL abs.) and converted with phosgene solu-
213 (30), 207 (19), 152 (28), 119 (14), 118 (7), 116 (60), 92 (8), 91
(100), 65 (5). C17H18ClNO4S (367.84): calcd. C 55.50, H 4.93, N
tion (0.80 mL, 20% in toluene) to the corresponding sulfonyl chlo-
3.81; found C 55.37, H 5.13, N 3.66.
ride (R)-6h, which could be isolated after column chromatography
(R)-(–)-4-(Benzyloxycarbonylamino)pentane-1-sulfonyl
Chloride
(SiO2, n-pentane/Et2O, 1:1) as a colourless solid. m.p. 51 °C; Yield:
[(R)-6f]: According to GP 5 compound (R)-5f (77.6 mg, 0.20 mmol) 38.9 mg (77%); Rf = 0.4 (n-pentane/Et2O, 1:1); ee = 93% (based
was dissolved in ethanol (6.0 mL) and water (0.20 mL). After re-
fluxing for 18 h, sodium acetate (17.8 mg, 0.22 mmol) was added,
the resulting sodium sulfonate was dissolved in CH2Cl2 (2.0 mL
abs.) and DMF (0.02 mL abs.) and converted with phosgene solu-
tion (0.20 mL, 20% in toluene) to the corresponding sulfonyl chlo-
ride (R)-6f, which was isolated after column chromatography (SiO2,
n-pentane/Et2O, 2:1) as a colourless solid. M.p. 88 °C; yield:
54.3 mg (84%); Rf = 0.09 (n-pentane/Et2O, 2:1); ee Ն 96% (based
on the de value of the corresponding hydrazine). [α]2D5 = –7.8 (c =
on the ee value of the corresponding sultam). [α]2D5 = –3.7 (c = 1.02,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.88 (t, 3 H, J = 6.9 Hz,
CH3), 1.25–1.80 [m, 12 H, (CH2)5CH3, SO2CH2CH2CH2], 2.09 (m,
2 H, SO2CH2CH2), 3.68 (m, 2 H, SO2CH2), 3.80 (m, 1 H, CHNH),
4.51 (d, 1 H, J = 8.5 Hz, NH), 5.10 (s, 2 H, OCH2), 7.36 (m, 5
H, PhH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 21.0
(SO2CH2CH2CH2), 22.5 (CH2CH3), 25.8 (CH2CH2CH2CH2CH3),
29.1
(CH2CH2,
CH2CH3),
31.7
(CH2CH2CH3),
33.7
(SO2CH2CH2), 35.4 (CH2CH2CH2CH2CH2CH3), 50.3 (NHCH),
0.65, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.23 (d, J = 65.0 (SO2CH2), 66.8 (OCH2), 128.1, 128.2, 128.6 (CPh), 136.5
6.7 Hz, 3 H,CH3), 1.63 (m, 2 H, SO2CH2CH2), 2.09 (m, 2 H, (ipso-CPh), 156.3 (C=O) ppm. IR (KBr): ν = 3331 (s), 2930 (vs),
HNCHCH2), 3.70 (m, 3 H, CH3CH, SO2CH2), 4.65 (d, J = 6.7 Hz, 2858 (s), 2361 (m), 2342 (m), 1776 (m), 1691 (vs), 1538 (vs), 1457
˜
1 H, NH), 5.09 (s, 2 H, OCH2), 7.33–7.37 (m, 5 H, PhH) ppm. 13
NMR (75 MHz, CDCl3): δ = 21.1 (CH3), 21.2 (SO2CH2CH2CH2),
C
(s), 1362 (vs), 1249 (vs), 1164 (vs), 1118 (m), 1065 (m), 741 (s), 696
(m), 575 (m), 525 (s) cm–1. MS (EI, 70 eV): m/z (%) = 389 (4), 304
34.8 (SO2CH2CH2), 46.2 (NHCH), 65.0 (SO2CH2), 66.8 (OCH2), (8), 262 (10), 261 (5), 260 (27), 245 (8), 204 (23), 149 (5), 108 (36),
1280
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1271–1284

Asymmetric Synthesis of 3-Substituted γ- and δ-Sultams
FULL PAPER
92 (9), 91 (100). MS (CI): m/z (%) = 480 (5), 420 (5), 419 (18), 418
(CH3), 28.9 (CH2CH3), 29.4 (SCH2CH2), 48.1 (SCH2), 56.6 (CH)
(6), 417 (6), 416 (11), 392 (9), 391 (6), 390 (24), 359 (5), 331 (5), ppm. IR (film): ν = 3625 (w), 3562 (w), 3274 (s), 2967 (s), 2880
˜
329 (5), 328 (10), 327 (9), 326 (29), 325 (5), 313 (5), 293 (6), 291
(m), 1460 (m), 1399 (m), 1299 (vs), 1186 (m), 1141 (vs), 1054 (w),
(6), 290 (26), 248 (15), 246 (8), 240 (11), 204 (10), 196 (7), 152 (6), 1020 (v), 976 (m), 925 (m), 847 (m), 740 (m), 667 (w), 595 (m), 482
119 (9), 108 (8), 92 (8), 91 (100), 65 (29). HRMS, C18H28ClNO4S:
calcd. 389.1428; found 389.1427.
(m) cm–1. MS (EI, 70 eV): m/z (%) = 190 (2), 152 (5), 152 (5), 151
(11), 150 (100), 120 (9), 69 (13). MS (CI): m/z (%) = 150 (12), 122
(5), 121 (9), 120 (100), 57 (5), 56 (22). C5H11NO2S (149.21): calcd.
C 40.25, H 7.43, N 9.39; found C 40.66, H 7.48, 9.30. The NMR
spectroscopic data are in accordance with those reported in the
literature.[13]
(S)-(–)-4-Benzyloxycarbonylamino-4-(phenyl)butane-1-sulfonyl
Chloride [(S)-6i]: According to GP 5 compound (S)-5i (903 mg,
2.0 mmol) was dissolved in ethanol (60.0 mL) and water (2.0 mL).
After refluxing for 18 h, sodium acetate (185 mg, 2.25 mmol) was
added, the resulting sodium sulfonate was dissolved in CH2Cl2
(20.0 mL abs.) and DMF (0.24 mL abs.) and converted with phos-
gene solution (12.18 mL, 20% in toluene) to the corresponding sul-
fonyl chloride (S)-6i, which could be isolated after column
chromatography (SiO2, n-pentane/Et2O, 1:1) as a colourless solid.
M.p. 88 °C; yield: 432 mg (56%); Rf = 0.30 (n-pentane/Et2O, 1:1);
ee Ն 96% (based on the de value of the corresponding hydrazine).
(R)-(+)-3-Butyl-1,2-thiazolidine 1,1-Dioxide [(R)-7c]: According to
GP 6 the compound (R)-6c (62.8 mg, 0.18 mmol) was cyclised to
the sultam (R)-7c with HBr/AcOH (0.20 mL, 33 %) and NEt3
(2.16 mL). After flash column chromatography (SiO2, n-pentane/
Et2O, 1:2) the product was obtained as a yellow oil. Yield: 31.5 mg
(99%); Rt = 8.36 min (CP-Sil-8, 100–10–300); Rf = 0.26 (n-pentane/
Et2O, 1:2); ee = 87% (based on the de value of the corresponding
hydrazine). [α]2D5 = +7.4 (c = 0.76, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 0.92 (t, J = 6.9 Hz, 3 H, CH3), 1.30–1.41 (m, 4 H,
CH2CH2CH3), 1.52–1.67 (m, 2 H, CH2CH2CH2CH3), 2.07 (m, 1
H, SCH2CHH), 2.51 (dddd, J = 3.8 Hz, J = 6.3 Hz, J = 8.0 Hz, J
= 13.2 Hz, 1 H, SCH2CHH), 3.11 (ddd, J = 8.0 Hz, J = 9.9 Hz, J
= 12.9 Hz, 1 H, SCHH), 3.22 (ddd, J = 3.8 Hz, J = 8.8 Hz, J =
12.9 Hz,1 H, SCHH), 3.58 (m, 1 H, CH), 4.24 (d, J = 5.5 Hz, 1 H,
NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9 (CH3), 22.4
(CH2 CH3 ), 28.2 (CH2 CH2 CH3 ), 29.9 (SCH2 CH2 ), 35.6
1
[α]2D5 = –26.6 (c = 0.98, CHCl3). H NMR (300 MHz, CDCl3): δ =
2.0 (m, 4 H, SO2CH2CH2CH2), 3.67 (m, 2 H, SO2CH2), 4.73 (m,
1 H, NH), 5.10 (m, 3 H, CHNH, OCH2), 7.28–7.40 (m, 10 H, PhH)
ppm. 13C NMR (100 MHz, CDCl3): δ = 21.3 (SO2CH2CH2CH2),
34.0 (SO2CH2CH2), 54.5 (NHCH), 64.6 (SO2CH2), 66.8 (OCH2),
126.1, 127.9, 128.0, 128.3, 128.8 (CPh), 136.0, 140.8 (ipso-CPh),
155.6 (C=O) ppm. IR (KBr): ν = 3346 (vs), 3032 (m), 2936 (s),
˜
2876 (m), 1687 (vs), 1531 (vs), 1455 (m), 1412 (m), 1355 (vs), 1238
(s), 1166 (vs), 1127 (m), 1052 (s), 1024 (m), 947 (w), 911 (w), 838
(w), 752 (vs), 701 (s), 651 (m), 580 (w), 543 (s), 505 (s) cm–1. MS
(EI, 70 eV): m/z (%) = 319 (5), 274 (24), 249 (10), 248 (59), 240 (7),
230 (16), 205 (8), 204 (56), 196 (5), 92 (8), 91 (100), 71 (5). MS
(CI): m/z (%) = 382 (8) [M+ + 1], 359 (7), 321 (21), 320 (100), 319
(6), 318 (16), 313 (6), 290 (5), 288 (5), 285 (6), 277 (5), 276 (29),
274 (20), 250 (22), 249 (8), 248 (45), 240 (11), 231 (8), 230 (5), 213
(9), 212 (44), 206 (19), 204 (33), 184 (9), 160 (7), 154 (5), 152 (7),
142 (11), 131 (5), 119 (10), 114 (5), 92 (7), 91 (88), 83 (5), 71 (5),
65 (7). HRMS, C18H20ClNO4S: calcd. C18H20NO4SCl – C7H7O
274.0305; found 274.1483.
(CH CH CH CH ), 48.0 (SCH ), 55.2 (CH) ppm. IR (CHCl ): ν
˜
2
2
2
3
2
3
= 3518 (w), 3265 (vs), 2932 (vs), 2865 (vs), 1726 (w), 1462 (m),
1399 (m), 1300 (vs), 1186 (s), 1079 (w), 1018 (w), 927 (m), 855 (w),
739 (m), 655 (w), 596 (m), 476 (m) cm–1. MS (EI, 70 eV): m/z (%)
= 178 (1) [M+ + 1], 177 (1) [M+], 122 (5), 120 (100), 56 (12). MS
(CI): m/z (%) = 206 (5), 180 (5), 179 (9), 178 (100) [M+ + 1], 120 (5).
HRMS: C7H15NO2S: calcd. 177.0824; found 177.0823, C7H15NO2S
(177.26): calcd. C 47.43, H 8.53, N 7.90; found C 47.82, H 8.41, N
8.19.
(R)-(+)-3-Hexyl-1,2-thiazolidine 1,1-Dioxide [(R)-7d]: According to
GP 6 the compound (R)-6d (54.6 mg, 0.15 mmol) was cyclised to
the sultam (R)-7d using HBr/AcOH (0.16 mL, 33%) and NEt3
(1.80 mL). After flash column chromatography (SiO2, n-pentane/
Et2O, 1:2) the product was obtained as a colourless solid. M.p.
41 °C; yield: 28.5 mg (93 %); Rf = 10.73 min (CP-Sil-8, 100–10–
300); Rf = 0.32 (n-pentane/Et2O, 1:2); ee = 90% (based on the de
value of the corresponding hydrazine). [α]2D5 = +8.9 (c = 0.77,
General Procedure for the Synthesis of γ- and δ-Sultams (GP 6):
The aminosulfonyl chlorides 6 were dissolved in CH2Cl2 (20 mL/
mmol) and a 33% solution of HBr in AcOH (1.1 mL/mmol.) was
added. After stirring for 3 h at room temperature the reaction mix-
ture was cooled to 0 °C, and NEt3 (12 mL/mmol) was added using
a syringe pum.p. The solution was stirred for 2 h while it was
warmed to room temperature. After the addition of water and sepa-
ration of the organic layer the aqueous phases were extracted with
CH2Cl2. The combined organic layers were dried with MgSO4 and
the solvent was removed under reduced pressure. The sultams were
isolated after flash column chromatographic (SiO2, n-pentane/
Et2O).
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 6.6 Hz, 3
H, CH3), 1.20–1.42 [m, 8 H, (CH2)4CH3], 1.60 [m, 2 H, CH2(CH2)4-
CH3], 2.07 (ddd, J = 8.9 Hz, J = 9.6 Hz, J = 13.3 Hz, 1 H,
SCH2CHH), 2.50 (ddd, J = 4.0 Hz, J = 7.9 Hz, J = 13.3 Hz, 1 H,
SCH2CHH), 3.10 (ddd, J = 8.0 Hz, J = 9.9 Hz, J = 12.9 Hz, 1 H,
SCHH), 3.20 (ddd, J = 3.8 Hz, J = 8.5 Hz, J = 12.9 Hz, 1 H,
SCHH), 3.58 (m, 1 H, CH), 4.21 (br. s, 1 H, NH) ppm. 13C NMR
(R)-(+)-3-Ethyl-1,2-thiazolidine 1,1-Dioxide [(R)-7b]: According to
GP 6 the compound (R)-6b (138 mg, 0.43 mmol) was cyclised to
the sultam (R)-7b with HBr/AcOH (0.47 mL, 33 %) and NEt3 (75 MHz, CDCl3): δ = 14.0 (CH3), 22.5 (CH2CH3 ), 26.1
(5.16 mL). After flash column chromatography (SiO2, n-pentane/
Et2O, 1:2) the product was obtained as a yellow oil. Yield: 45 mg
[CH2(CH2)3CH3], 29.0 (CH2CH2CH2CH3), 29.9 (SCH2CH2), 31.6
(CH2CH2CH3), 36.0 [CH2(CH2)4CH3], 48.1 (SCH2), 55.3 (CH)
(70%), Rt = 5.94 (Cp-Sil-8, 100–10–300); Rf = 0.16 (n-pentane/ ppm. IR (KBr): ν = 3920 (w), 3860 (w), 3754 (w), 3689 (w), 3655
˜
Et2O, 1:2); ee = 78 % (determined by GC on chiral stationary
phase, Chiralsil-dex). [α]2D5 = +6.5 (c = 0.26, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.00 (t, J = 7.4 Hz, 3 H, CH3), 1.65 (m, 2
H, CH2CH3), 2.09 (m, 1 H, SCH2CHH), 2.52 (dddd, J = 4.1 Hz,
(w), 3414 (m), 3315 (vs), 3030 (m), 2959 (vs), 2925 (vs), 2855 (s),
1742 (w), 1469 (m), 1429 (w), 1388 (s), 1347 (s), 1304 (m), 1279
(m), 1182 (s), 1143 (vs), 1078 (m), 1046 (w), 1007 (w), 956 (w), 920
(m), 860 (m), 828 (w), 793 (w), 735 (s), 635 (m), 584 (m), 477 (s)
J = 6.3 Hz, J = 8.0 Hz, J = 13.2 Hz, 1 H, SCH2CHH), 3.11 (ddd, cm–1. MS (EI, 70 eV): m/z (%) = 122 (5), 121 (5), 120 (100), 56 (10).
J = 8.2 Hz, J = 9.9 Hz, J = 12.9 Hz, 1 H, SCHH), 3.23 (ddd, J =
4.1 Hz, J = 8.8 Hz, J = 12.9 Hz,1 H, SCHH), 3.52 (m, 1 H, CH),
MS (CI): m/z (%) = 207 (13), 206 [M+ + 1, 100], 123 (5), 120 (20).
HRMS, C9H19NO2S: calcd. C9H19NO2S – C6H13 120.0119; found
4.40 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 10.4 120.0120.
Eur. J. Org. Chem. 2006, 1271–1284
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1281

D. Enders, A. Moll, J. W. Bats
FULL PAPER
(S)-(–)-3-Phenyl-1,2-thiazolidine 1,1-Dioxide [(S)-7e]: According to
GP 6 the compound (S)-6e (95.6 mg, 0.26 mmol) was cyclised to
3 H, CH3), 1.16–1.45 (m, 5 H, SO2CH2CH2CHH, CH3CH2CH2),
1.49 (m, 2 H, CH3CH2CH2CH2), 1.81 (dq, J = 14.0 Hz, J = 2.7 Hz,
the sultam (S)-7e with HBr/AcOH (0.28 mL, 33 %) and NEt3 1 H, SO2CH2CH2CHH), 2.19 (m, 2 H, SO2CH2CH2), 2.87 (m, 1
(3.12 mL). After flash column chromatography (SiO2, n-pentane/
H, SO2CHH), 3.19 (dt, J = 13.2 Hz, J = 3.6 Hz, 1 H,SO2CHH),
Et2O, 1:2) the product was obtained as a colourless solid. M.p. 3.44 (m, 1 H, NHCH), 4.06 (d, J = 9.3 Hz, 1 H,NH) ppm. 13C
77 °C; yield: 39.7 mg (77 %); Rf = 11.52 min (CP-Sil-8, 100–10– NMR (100 MHz, CDCl3): δ = 13.9 (CH3), 22.3 (CH3CH2), 22.9
300); Rf = 0.19 (n-pentane/Et2O, 1:2); ee = 93% (determined by
(SO2CH2CH2), 27.5 (CH3CH2CH2), 30.3 (SO2CH2CH2CH2), 35.3
GC on chiral stationary phase, Chiralsil-dex). [α]2D5 = –33.8 (c =
(CH CH CH CH ), 49.2 (SO CH ), 56.7 (CH) ppm. IR (KBr): ν
˜
3
2
2
2
2
2
0.32, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.40 (m, 1 H, = 3970 (w), 3945 (m), 3900 (w), 3880 (w), 3803 (m), 3777 (m), 3756
SCH2CHH), 2.76 (m, 1 H, SCH2CHH), 3.20 (ddd, J = 7.7 Hz, J (m), 3737 (m), 3675 (m), 3631 (w), 3439 (vs), 3258 (vs), 3170 (w),
= 10.5 Hz, J = 12.7 Hz, 1 H, SCHH), 3.34 (ddd, J = 3.9 Hz, J =
8.0 Hz, J = 12.7 Hz, 1 H, SCHH), 4.73 (m, 2 H, NH, CH), 7.30–
3132 (w), 3072 (w), 2942 (vs), 2869 (vs), 2770 (m), 2723 (w), 2703
(w), 2682 (w), 2648 (w), 2613 (w), 2560 (w), 2536 (w), 2457 (w),
7.42 (m, 5 H, PhH) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.1 2234 (w), 2198 (w), 2128 (w), 2095 (w), 2026 (w), 1704 (w), 1626
(SCH2CH2), 48.1 (SCH2), 58.0 (CH), 125.8, 128.2, 128.8 (CPh),
(s), 1499 (m), 1460 (s), 1415 (s), 1384 (m), 1310 (vs), 1242 (m), 1185
(s), 1144 (vs), 1067 (m), 1026 (m), 951 (vs), 882 (s), 764 (vs), 677
(s), 623 (m), 578 (m), 515 (s) cm–1. MS (EI, 70 eV): m/z (%) = 191
140.0 (ipso-CPh) ppm. IR (KBr): ν = 3933 (s), 3878 (m), 3842 (m),
˜
3821 (m), 384 (w), 3769 (w), 3751 (w), 3692 (m), 3654 (m), 3622
(m), 3593 (m), 3568 (m), 3479 (s), 3449 (vs), 3414 (s), 3384 (s), 3268 (2) [M+], 135 (9), 134 (100), 70 (6). MS (CI): m/z (%) = 193 (13),
(vs), 3032 (m), 3001 (w), 2942 (s), 2864 (m), 2763 (w), 2698 (w), 192 (100) [M+ + 1], 134 (7). C8H17NO2S (191.29): calcd. C 50.23,
1604 (w), 1495 (s), 1459 (s), 1372 (m), 1285 (vs), 1175 (s), 1137 (vs),
1045 (s), 1007 (s), 977 (w), 931 (vs), 840 (m), 804 (w), 760 (vs), 737
(s), 700 (vs), 613 (m), 588 (m), 523 (m) cm–1. MS (EI, 70 eV):
m/z (%) = 197 (14) [M+], 169 (45), 106 (9), 105 (100), 104 (74), 78
H 8.96, N 7.32; found C 50.11, H 9.27, N 7.23
(R)-(+)-3-Hexyl-1,2-thiazinane 1,1-Dioxide [(R)-7h]: According to
GP 6 the compound (R)-6h (74.1 mg, 0.19 mmol) was cyclised to
the sultam (R)-7h with HBr/AcOH (0.21 mL, 33 %) and NEt3
(2.28 mL). After flash column chromatography (SiO2, n-pentane/
Et2O, 1:2) the product was obtained as a colourless solid. M.p.
75 °C; yield: 41.7 mg (100%); Rf = 0.34 (n-pentane/Et2O, 1:2); Rt
= 11.49 min (CP-Sil-8, 100–10–300); ee = 93% (determined by GC
on chiral stationary phase, Chiralsil-dex). [α]2D5 = +14.8 (c = 0.52,
(12), 77 (11), 51 (6). MS (CI): m/z (%) = 199 (14), 198 (100) [M+
+
1], 120 (13), 117 (25), 105 (5). C9H11NO2S (197.25): calcd. C 54.80,
H 5.62, N 7.10; found C 55.00, H 5.80, N 6.76. The NMR spectro-
scopic data are in accordance with those reported in the litera-
ture.[13]
1
(R)-(–)-3-Methyl-1,2-thiazinane 1,1-Dioxide [(R)-7f]: According to
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3
GP 6 the compound (R)-6f (54.3 mg, 0.17 mmol) was cyclised to H, CH3), 1.15–1.53 [m, 11 H, SO2CH2CH2CHH, CH3(CH2)5], 1.81
the sultam (R)-7f with HBr/AcOH (0.18 mL, 33 %) and NEt3
(2.04 mL). After flash column chromatography (SiO2, n-pentane/
(dq, J = 14.1 Hz, J = 3.4 Hz, 1 H, SO2CH2CH2CHH), 2.20 (m, 2
H, SO2CH2CH2), 2.85 (m, 1 H, SO2CHH), 3.20 (dt, J = 13.4 Hz,
Et2O, 1:1) the product was obtained as a colourless solid. M.p. J = 3.7 Hz, 1 H, SO2CHH), 3.45 (m, 1 H, CH), 3.99 (br. s, 1 H,
143 °C; yield: 20.8 mg (82%); Rf = 0.10 (n-pentane/Et2O, 1:1); ee
Ն 96% (based on the de value of the corresponding hydrazine).
NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0 (CH3), 22.5
(CH3CH2), 23.1 (SO2CH2CH2), 25.4 (CH3CH2CH2CH2CH2), 29.0
(CH3CH2CH2CH2), 30.5 (SO2CH2CH2CH2), 31.6 (CH3CH2CH2),
35.8 [CH3(CH2)4CH2], 49.4 (SO2CH2), 57.7 (CH) ppm. IR (KBr):
1
[α]2D5 = –3.1 (c = 0.55, CHCl3). H NMR (300 MHz, CDCl3): δ =
1.18–1.26 (m, 1 H, SO2CH2CH2CHH), 1.23 (d, J = 6.4 Hz, 3 H,
CH3), 1.80 (dq, J = 14.1 Hz, J = 2.7 Hz, 1 H, NHCHCHH), 2.22 ν = 3676 (m), 3630 (w), 3452 (s), 3258 (vs), 3204 (w), 3174 (w),
˜
(m, 2 H, CHCH2CH2), 2.85 (m, 1 H, SO2CHH), 3.18 (dt, J = 3135 (w), 3108 (w), 3074 (w), 3036 (w), 2923 (vs), 2853 (vs), 2371
13.4 Hz, J = 3.7 Hz, 1 H, SO2CHH), 3.60 (m, 1 H, NHCH), 4.03 (w), 2345 (w), 2312 (w), 1732 (m), 1627 (m), 1500 (w), 1460 (s),
(br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.5 (CH3), 1415 (m), 1382 (w), 1311 (vs), 1242 (m), 1184 (s), 1143 (vs), 1076
23.1 (SO2CH2CH2), 32.1 (SO2CH2CH2CH2), 48.9 (SO2CH2), 52.5
(m), 1028 (w), 1000 (w), 949 (s), 888 (m), 769 (vs), 678 (s), 582 (m),
(CH) ppm. IR (KBr): ν = 3976 (m), 3942 (m), 3896 (m), 3870 (m), 520 (s), 463 (m) cm–1. MS (EI, 70 eV): m/z (%) = 220 (3), 136 (5),
˜
3828 (m), 3761 (m), 3685 (s), 3629 (m), 3593 (m), 3448 (vs), 3207 135 (9), 134 (100), 70 (8). MS (CI): m/z (%) = 248 (5), 222 (6),
(vs), 3137 (m), 3100 (m), 3078 (m), 3048 (m), 2981 (s), 2938 (s), 221 (16), 220 (100), 218 (5), 134 (15). HRMS, C10H21NO2S: calcd.
3849 (s), 2797 (w), 2756 (w), 2709 (w), 2680 (w), 2646 (w), 2553
(w), 2527 (w), 2451 (w), 2214 (w) 2179 (w), 2122 (w), 2081 (w),
2025 (w), 1947 (w), 1847 (w), 1775 (w), 1707 (m), 1639 (s), 1500
(m), 1458 (s), 1433 (s), 1307 (vs), 1282 (vs), 1161 (vs), 1126 (vs),
1069 (s), 952 (vs), 887 (m), 857 (m), 779 (vs), 683 (m), 575 (s), 533
(s), 498 (s) cm–1. MS (EI, 70 eV): m/z (%) = 149 (7) [M+], 135 (10),
134 (100), 107 (5), 70 (12), 57 (14), 56 (7). MS (CI): m/z (%) = 152
(6), 151 (11), 150 (100) [M+ + 1], 134 (5). HRMS, C5H11NO2S:
calcd. 149.0511; found 149.0508. The analytical data are in accord-
ance with those reported in the literature.[10b]
219.1293; found 219.1292.
(S)-(–)-3-Phenyl-1,2-thiazinane 1,1-Dioxide [(S)-7i]: According to
GP 6 the compound (S)-6i (272.3 mg, 0.71 mmol) was cyclised to
the sultam (S)-7i with HBr/AcOH (0.76 mL, 33 %) and NEt3
(8.52 mL). After flash column chromatography (SiO2, n-pentane/
Et2O, 1:2) the product was obtained as a colourless solid. M.p.
149 °C; yield: 107.8 mg (72%); Rf = 0.28 (n-pentane/Et2O, 1:2); Rt
= 12.36 min (CP-Sil-8, 100–10–300); ee = 99% (determined by GC
on chiral stationary phase, Chiralsil-dex). [α]2D5 = –16.5 (c = 0.91,
CHCl3). 1H NMR (300 MHz, CDCl3 ): δ = 1.73 (m, 1 H,
SO2CH2CH2CHH), 2.05 (m, 1 H, SO2CH2CH2CHH), 2.33 (m, 2
H, SO2CH2CH2), 3.01 (m, 1 H, SO2CHH), 3.24 (dt, J = 13.4 Hz,
(R)-(–)-3-Butyl-1,2-thiazinane 1,1-Dioxide [(R)-7g]: According to
GP 6 the compound (R)-6g (40.9 mg, 0.11 mmol) was cyclised to
the sultam (R)-7g with HBr/AcOH (0.12 mL, 33 %) and NEt3 J = 3.5 Hz, 1 H, SO2CHH), 4.32 (br. s, 1 H, NH), 4.58 (ddd, J =
(1.32 mL). After flash column chromatography (SiO2, n-pentane/
2.5 Hz, J = 6.9 Hz, J = 11.9 Hz, 1 H, CH), 7.02–7.16 (m, 5 H,
Et2O, 1:1) the product was obtained as a colourless solid. PhH) ppm. 13C NMR (75 MHz, CDCl3): δ = 23.3 (SO2CH2CH2),
M.p.86 °C; yield: 22.5 mg (100%), Rf = 0.14 (n-pentane/Et2O, 1:1); 31.4 (SO2CH2CH2CH2), 49.1 (SO2CH2), 60.1 (NHCH), 126.4,
Rt = 13.18 min (CP-Sil-8, 60–10–300); ee = 93% (determined by
128.5, 129.0 (CPh), 139.7 (ipso-CPh) ppm. IR (KBr): ν = 3988 (w),
3953 (m), 3912 (m), 3860 (w), 3801 (s), 3697 (w), 3626 (s), 3595
˜
GC on chiral stationary phase, Chiralsil-dex). [α]2D5 = –20.6 (c =
0.65, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.90 (t, J = 7.1 Hz, (m), 3450 (vs), 3307 (m), 3259 (vs), 3161 (w), 3108 (m), 2946 (vs),
1282
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1271–1284

Asymmetric Synthesis of 3-Substituted γ- and δ-Sultams
FULL PAPER
2853 (s), 2687 (w), 2633 (w), 2606 (w), 2534 (w), 2492 (w), 2426
(w), 2375 (w), 2344 (m), 2306 (w), 2270 (w), 1886 (m), 1832 (w),
1727 (w), 1600 (vs), 1501 (m), 1453 (s), 1428 (s), 1384 (w), 1335
(vs), 1286 (s), 1237 (m), 1142 (vs), 1029 (s), 939 (vs), 850 (m), 746
(vs), 696 (s), 557 (s), 516 (m), 464 (s) cm–1. MS (EI, 70 eV): m/z (%)
= 212 (10), 211 (19), 183 (6), 147 (37), 146 (63), 130 (5), 120 (9),
119 (100), 118 (73), 106 (9), 105 (54), 104 (99), 103 (5), 91 (11), 79
(6), 78 (17), 77 (23), 70 (16), 69 (10), 51 (11). MS (CI): m/z (%) =
214 (6), 213 (15), 212 (100), 195 (9), 147 (8), 146 (11), 134 (39), 131
(24), 119 (18), 118 (6), 105 (6), 104 (8). C10H13NO2S (211.28):
calcd. C 56.89, H 6.20, N 6.63; found C 56.85, H 6.20, N 6.63.
[1]
a) S. Hanessian, H. Sailes, E. Therrien, Tetrahedron 2003, 59,
7047; b) L. Zhuang, J. S. Wai, M. W. Embrey, T. E. Fisher,
M. S. Egbertson, L. S. Payne, J. P. Guare Jr, J. P. Vacca, D. J.
Hazuda, P. J. Felock, A. L. Wolfe, K. A. Stillmock, M. V.
Witmer, G. Moyer, W. A. Schleifer, L. J. Gabryelski, Y. M. Leo-
nard, J. J. Lynch Jr, S. R. Michelson, S. D. Young, J. Med.
Chem. 2003, 46, 453; c) M. Inagaki, T. Tsuri, H. Jyoyama, T.
Ono, K. Yamada, M. Kobayashi, Y. Hori, A. Arimura, K. Ya-
sui, K. Ohno, S. Kakudo, K. Koizumi, R. Suzuki, M. Kato, S.
Kawai, S. Matsumoto, J. Med. Chem. 2000, 43, 2040; d) R. A.
Miller, G. R. Humphrey, D. R. Lieberman, S. S. Ceglia, D. J.
Kennedy, E. J. J. Grabowski, P. J. Reider, J. Org. Chem. 2000,
65, 1399.
X-ray Crystallographic Study: (S)-7i (C10H13NO2S, M = 211.27).
Suitable crystals were obtained by crystallisation from dichloro-
methane. The compound crystallises in the monoclinic space group
P21 with cell dimensions a = 5.3012(9), b = 9.278(3), c =
10.3577(19) Å and β = 97.790(16)°. With Z = 2 and V =
504.73(19) Å3 a calculated density of dcalcd. = 1.390 g/cm3 results.
[2]
[3]
A. R. Katritzky, J. Wu, S. Rachwal, B. Rachwal, D. W. Mac-
omber, T. P. Smith, Org. Prep. Proced. Int. 1992, 24, 463.
a) G. J. Wells, M. Tao, K. A. Josef, R. Bihovski, J. Med. Chem.
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A
single crystal (colourless block with dimensions
0.18×0.20×0.40 mm) was measured with a Siemens Smart dif-
fractometer at a temperature of about 161 K. Repeatedly measured
reflections remained stable. Data collection covered the range –7 Յ
h Յ 8, –13 Յ k Յ 13 and –15 Յ l Յ 15 up to θmax = 32.6°. An
empirical absorption correction with the program SADABS (Sheld-
rick, 2000) gave a correction factor between 0.938 and 1.000.
Equivalent reflections were averaged. Friedel opposites were not
averaged. R(I)int = 0.021. The structure was determined by direct
methods using program SHELXS. 3246 unique reflections [I Ͼ
2σ(I)] were included in the full-matrix, least-square refinement on
F2 involving 179 parameters. Refinement with the program
SHELXL-97 converged at R(F) = 0.027 and wR(F2) = 0.067. The
H atoms were taken from a difference synthesis and were refined
with individual isotropic thermal parameters. The final difference
density was between –0.29 and +0.35 e·Å3. The absolute configura-
tion of the molecule was confirmed by the value of the Flack x-
parameter [x = 0.06(5)]. The saturated six-membered ring has a
chair conformation. The phenyl group and the S–O(1) bond are in
equatorial positions with respect to this six-membered ring. The S–
O(2) and N–H bond are both in axial positions. The N atom has
a pyramidal conformation, the sum of the three valence angles
about N is 335°. The phenyl ring is approximately planar, the mean
deviation of the C atoms from the benzene plane is 0.007 Å. The
shortest intramolecular contact distance is 2.53 Å between H(6)
and N. The N–C(4)–C(5)–C(6) torsion angle is –12.9(2)° and shows
the phenyl ring to be almost coplanar with the C(4)–N bond. The
molecules are connected by intermolecular N–H···O hydrogen
bonds to chains parallel to the a-direction. Neighboring chains are
connected by a weak intermolecular C–H···O and a very weak
intermolecular C–H···π(phenyl) interaction.
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CCDC-286031 [for (S)-7i] contains the supplementary crystallo-
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Acknowledgments
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 Flor-
ian Pontzen for his skilful experimental contribution as an under-
graduate student.
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Received: November 3, 2005
Published Online: December 29, 2005
1284
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Eur. J. Org. Chem. 2006, 1271–1284