Asymmetric synthesis of β-amino cyclohexyl sulfonates, β-sultams and γ-sultones

Article abstract of DOI:10.1055/s-2003-41029

An efficient asymmetric synthesis of β-aminocyclohexyl sulfonates, β-sultams and γ-sultones has been developed. The key step of the synthesis is the Lewis acid catalyzed aza-Michael addition of the enantiopure hydrazines SAMP [(S)-1] or RAMBO [(R,R,R)-2] to alkenylcyclohexyl sulfonates 3. This leads to β-hydrazino sulfonates 4a-k in moderate to good yields (41-85%) and diastereomeric excesses (de = 44-90%). The epimers were separated by preparative HPLC. Subsequent reductive N-N bond cleavage with BH ₃·THF and protection of the resulting amines with CbzCl gave N-Cbz-protected β-aminocyclohexyl sulfonates 6a-k in moderate to good yields (38-68% over 2 steps) and high enantiomeric excesses (ee ≥ 96%). α-Alkylation of 6 with various electrophiles afforded α-alkyl-β -aminocyclohexyl sulfonates 10a-g in good to excellent yields (67-92%) and moderate to high diastereomeric excesses (de = 71-93%). After alkylation with allyl iodide, the first asymmetric iodosultonization was achieved with high selectivities. Compounds 6g-k were also cyclized in a four-step synthesis to highly enantio-enriched 3-substituted-1,2-thiazetidine 1,1-dioxides (β-sultams) 9a-e.

Full text of DOI:10.1055/s-2003-41029

1856
PAPER
Asymmetric Synthesis of -Amino Cyclohexyl Sulfonates, -Sultams and
-Sultones
A
symmetric Synth
i
esis of
e
Sulfonates,
t
-Sult
e
amsand
-
r
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 3 June 2003; revised 25 June 2003
Dedicated to Professor Wolfgang Steglich on the occasion of his 70th birthday.
As we have described in a previous communication, the
Abstract: An efficient asymmetric synthesis of -aminocyclohexyl
aza-Michael addition provides an efficient access to tau-
sulfonates, -sultams and -sultones has been developed. The key
step of the synthesis is the Lewis acid catalyzed aza-Michael addi-
tion of the enantiopure hydrazines SAMP [(S)-1] or RAMBO
rine derivatives.6 As shown in Scheme 1, the reaction
starts with 1,4-addition of enantiopure nitrogen nucleo-
[(R,R,R)-2] to alkenylcyclohexyl sulfonates 3. This leads to -hy- philes to alkenyl sulfonates, followed by cleavage of the
drazino sulfonates 4a–k in moderate to good yields (41–85%) and
chiral auxilaries. This leads to chiral -amino sulfonates,
diastereomeric excesses (de = 44–90%). The epimers were separat-
which can be used in the synthesis of 3-substituted 1,2-thi-
ed by preparative HPLC. Subsequent reductive N–N bond cleavage
azetidine 1,1-dioxides ( -sultams) and -sultones.
with BH3·THF and protection of the resulting amines with CbzCl
gave N-Cbz-protected -aminocyclohexyl sulfonates 6a–k in mod-
O
O
erate to good yields (38–68% over 2 steps) and high enantiomeric
excesses (ee 96%). -Alkylation of 6 with various electrophiles
afforded -alkyl- -aminocyclohexyl sulfonates 10a–g in good to
excellent yields (67–92%) and moderate to high diastereomeric ex-
cesses (de = 71–93%). After alkylation with allyl iodide, the first
asymmetric iodosultonization was achieved with high selectivities.
Compounds 6g–k were also cyclized in a four-step synthesis to
highly enantio-enriched 3-substituted-1,2-thiazetidine 1,1-dioxides
( -sultams) 9a–e.
*
+
R2N-NH2
S
R1
OR2
aza-Michael addition,
cleavage of chiral auxiliary
*
-R2N
H2N
O
O
S
R1
OR2
*
Key words: asymmetric synthesis, Michael addition, sulfonates
-
α−allylation,
sultams -sultones, hydrazines
cyclization
iodosultonization
O
O
H2N
*
HN SO2
R1
S
There is constant need for the synthesis of unnatural ami-
no acids, since these compounds can provide new biolog-
ical activities and their peptides are attractive targets for
drug discovery. The best-known -aminosulfonic acid is
taurine, which is important for the evolution of the central
nervous system of many mammals. Moreover, derivatives
like 2-amino-2-phenylethanesulfonic acid,1 a potential
GABAB receptor antagonist or flavocristamides A and B,2
which have inhibitory activity against DNA polymerase
, demonstrate the demanding interest for the asymmetric
synthesis of taurine derivatives.
*
O
R1
*
R3
Scheme 1 Asymmetric synthesis of -aminocyclohexyl sulfonates,
-sultones and -sultams by aza-Michael addition
-Sultams are the sulfonyl analogues of -lactams. There-
fore, they are interesting building blocks for the synthesis
of new antibiotics, corresponding to -lactam antibiotics.7
But so far none of the synthesized compounds have shown
remarkable antibacterial activities.
Furthermore, the exchange of - or -amino acids in pep-
tides for -aminosulfonic acids or the synthesis of -sul-
fonopeptides have drawn great attention.3 White et al.
designed -sulfonopeptides as inhibitors of D-alanyl-D-
alanine transpeptidase containing taurine instead of a pen-
ultimate amino acid.4 Liskamp et al. synthesized oligo-
petido sulfonamides on solid-phase starting from -amino
acids in order to analyze their secondary and tertiary
structure as well as their biological activity.5
Due to their higher reactivity compared to -lactams (ap-
prox. 103-fold more reactive),8 -sultams are important
compounds from a chemical and pharmacological point of
view. For example, N-benzoyl -sultam is an irreversible
inhibitor of porcine pancreatic elastase (PPE).9 PPE is re-
lated to the human neutrophil elastase (HNE), which caus-
es diseases such as emphysema, cystic fibrosis and
rheumatoid arthritis. Furthermore, it has been found that
the C–S and C–N bonds can be broken under different ex-
perimental conditions, thus making -sultams interesting
building blocks for the synthesis of other heterocyclic sys-
tems.10
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 13 08 2003.
Art Id.1437-210X,E;2003,0,12,1856,1868,ftx,en;Z07703SS.pdf.
DOI: 10.1055/s-2003-41029
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymetric Synthesis of Sulfonates, -Sultams and -Sultones
1857
The term sultone was first introduced by Erdmann in Table 1 Aza-Michael Addition of SAMP [(S)-1] to 1-(E)-Alkenyl-
1888.11 Since then sultones have emerged as valuable het-
cyclohexyl Sulfonates 3
erocyclic intermediates. They are very reactive towards
4
R
Yield (%)
dea (%)
nucleophiles and are therefore used as sulfoalkylating
agents.12 Propane sultone found application in industry as
modifier of proteins, fungicides, fire-resistant polymers,
oil additives, emulsifying agents and cation exchange res-
ins.13
(R,S)–4a
(R,S)–4b
(R,S)–4c
(R,S)–4d
(R,S)–4e
Me
78
74
73
41
66
44 ( 96)b
55 ( 96)b
58 ( 96)b
80 ( 96)b
60 ( 96)b
Et
n-Pr
i-Pr
Ph(CH2)2
We now wish to report our results on the asymmetric syn-
thesis of -sultams and -sultones, starting from enan-
tioenriched -aminosulfonates.
a Determined by 13C NMR spectroscopy.
The first aza-Michael addition of primary and secondary
amines to ethenesulfonates was published in 1970.14
Progress has been made in the last years towards the aza-
Michael addition,15 but to our knowledge we have de-
scribed the first enantioselective 1,4-addition with enan-
tiopure nitrogen-nucleophiles to alkenyl sulfonates.6
b After HPLC on chiral stationary phase (Daicel AD 2).
Table 2 Aza-Michael Addition of RAMBO [(R,R,R)-2] to 1-(E)-
Alkenylsulfonic Esters 3
As shown in Scheme 2, (S)-1-amino-2-methoxymeth-
ylpyrrolidine [SAMP, (S)-1]16 or (R,R,R)-2-amino-3-
4
R
Yield (%)
dea (%)
(S,R,R,R)–4f
(S,R,R,R)–4g
(S,R,R,R)–4h
(S,R,R,R)–4i
(S,R,R,R)–4j
(S,R,R,R)–4k
Me
77
85
62
65
44
63
64 ( 96)b
77 ( 96)b
82 ( 96)b
80 ( 96)b
90 ( 96)b
78 ( 96)b
methoxymethyl-2-azabicyclo[3.3.0]octane
[RAMBO,
(R,R,R)-2]17 could be added to (E)-alkenylcyclohexyl sul-
fonates 3 in the presence of catalytic amounts of zinc bro-
mide in moderate to good yields and moderate to good
diastereomeric excesses (Tables 1 and 2). The excess of
(S)-1 or (R,R,R)-2 can be recovered after column chroma-
tography. , -Unsaturated sulfonates 3 were obtained by
modification of the Horner–Wadsworth–Emmons olefi-
nation reported by Masamune et al.18 and Rathke et al.19
Et
n-Pr
n-Bu
i-Pr
Ph(CH2)2
a Determined by 13C NMR spectroscopy.
bAfter HPLC on chiral stationary phase (Daicel AD 2).
CbzHN
O
O
O O
*
+
R2N-NH2
S
S
*
R
OHex-c
R
OHex-c
3 steps
(S)-1 or (R,R,R)-2
6a-k
ee ≥ 96%
3
Sm(OTf)3, LiBr, Cu(OTf)2, Eu(OTf)3, AgOTf], starting
with ytterbium triflate [Yb(OTf)3], which has shown good
results in the addition of (S)-1 and (R,R,R)-2 to alkenylsul-
fones.20 For our system zinc bromide proved to be the best
Lewis acid.
43-68%
( 2 steps)
a
41-85%
c
*
R2N
H2N
NH
*
O
O
O
O
b
After the aza-Michael addition, the epimers could be sep-
arated by preparative HPLC to yield virtually diastereo-
merically pure -hydrazinocyclohexyl sulfonates 4a–k. In
the following step the chiral auxiliary was removed by ra-
cemization-free reductive N–N bond cleavage utilizing
BH3·THF.21 After workup and column chromatographic
purification the auxiliaries [in the case of SAMP: (S)-
(methoxymethyl)pyrrolidine] could be recovered as its N-
Cbz derivative and - after deprotection, nitrosation and re-
duction - reused in further asymmetric reactions. The re-
sulting crude amines 5 were not purified, but directly
protected with CbzCl to yield N-Cbz-protected -ami-
nocyclohexyl sulfonates 6a–k in moderate to good yields
and high enantiomeric excesses (Table 3). Other protect-
ing groups, e.g. FmocCl, BnBr or BOC-anhydride have
been tested without satisfying results.
S
S
*
R
OHex-c
R
OHex-c
5
4a-k
de = 44-90% (≥ 96%)*
*after HPLC
ee ≥ 96%
OCH3
OCH3
*
R2N-NH2 =
N
N
NH2
NH2
(S)-1 (SAMP)
(R,R,R)-2 (RAMBO)
R = Me, Et, n-Pr, i-Pr, n-Bu, Ph(CH2)2
Scheme 2 Enantioselective synthesis of N-Cbz-protected -amino-
cyclohexyl sulfonates. Reagents and conditions: a) ZnBr2, MeOH,
r.t.; b) BH3·THF, THF, reflux; c) CbzCl, Na2CO3, CH2Cl2–H2O (4:1),
reflux
Addition of a Lewis acid to the reaction mixture is essen-
tial. Therefore we tested different Lewis acids [Yb(OTf)3,
Zn(OTf)2, Sn(OTf)2, Pr(OTf)3, CeCl3, Sc(OTf)3, SnCl4,
ZrCl4, TiCl4, FeCl3, MgCl2, MgBr2, ZnF2, ZnBr2,
The relative configuration of the new stereogenic center
was determined by NOE experiments on the major dia-
stereoisomer of (R,S)-4d (Figure 1) and (S,R,R,R)-4j. The
(R,S)- or (S,R,R,R)-configuration follows from the known
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

1858
D. Enders et al.
PAPER
Table 3 Synthesis of N-Cbz-Protected Amines 6a–k
In an earlier communication we have described a four step
asymmetric synthesis of 3-substituted -sultams.26 Cleav-
age of the sulfonates (S)-6g–k in order to achieve free ac-
ids succeeded by refluxing in a mixture of EtOH–H2O
(Scheme 3). Without further purification the crude acids
were transferred to their sodium salts. The Cbz-protected
-aminosulfonyl chlorides (S)-7a–e were synthesized by
adding a solution of phosgene in toluene in good yields
(62–74% over 2 steps) and high enantiomeric excesses (ee
96%, Table 4). The enantiomeric excesses were deter-
mined for the -sultams (S)-9a–e synthesized in the last
step.
6
R
Yielda (%)
eeb (%)
96
(R)–6a
(R)–6b
(R)–6c
(R)–6d
(R)–6e
(S)–6f
(S)–6g
(S)–6h
(S)–6i
Me
68
53
43
61
53
56
53
38
63
57
56
Et
96
n-Pr
i-Pr
96
96
Ph(CH2)2
Me
96
96
Et
96
CbzHN
R
HN SO2
O
O
n-Pr
n-Bu
i-Pr
96
S
OHex-c
4 steps
R
96
(S)-6g-k
(S)-9a-e
ee ≥ 96%
ee ≥ 96%
(S)–6j
(S)–6k
a Over 2 steps.
96
29-78%
over 2 steps
Ph(CH2)2
96
a
62-74%
c
b Determined by HPLC (Daicel AD 2).
CbzHN
H2N
O
O
O O
b
S
S
R
Cl
R
Cl
(S)-7a-e
ee ≥ 96%
(S)-8a-e
absolute configuration of SAMP [(S)-1] or RAMBO
[(R,R,R)-2].
As shown in Scheme 2, N-Cbz-protected -aminocyclo-
hexyl sulfonates 6a–f can now be cyclized to 3-substituted
-sultams.
R = Et, n-Pr, i-Pr, n-Bu, Ph(CH2)2
Scheme 3 Enantioselective synthesis of -sultams. Reagents and
conditions: a)1. EtOH, H2O, reflux r.t., 2. NaOAc, DMF, 3.
CH2Cl2, 20% COCl2 in toluene; b) 33% HBr in HOAc, r.t. c) NEt3,
0 °C r.t.
The cyclization of -aminosulfonyl chlorides has been
carried out quite often.22 For example Otto et al. synthe-
sized different -sultams to analyze their biological activ-
ities compared to -lactam antibiotics.7
Table 4 Synthesis of Cbz-Protected -Aminosulfonyl Chlorides
(S)-7a–e
Another approach to -sultams is the [2+2] cycloaddition
of a sulfene intermediate with chiral imines.23 Due to the
increasing interest in chemical libraries of small and reac-
tive biological compounds Gordeev et al. investigated the
[2+2] cycloaddition on a solid phase support.24
(S)-7
R
Yielda (%)
eeb (%)
96
(S)-7a
Et
64
74
67
64
62
(S)-7b
n-Pr
i-Pr
96
To the best of our knowledge, only one enantioselective
synthesis of -sultams exists. Baldoli et al. used chiral tri-
(S)-7c
96
6
(S)-7d
n-Bu
Ph(CH2)2
96
carbonyl( -arene)chromium(0) complexes in the synthe-
sis
of
3-(2-phenyl-substituted)
N-tert-butyl-1,2-
(S)-7e
96
thiazetidine 1,1-dioxide derivatives. The products are
enantiomerically pure, but restricted in the C-3 position
(o-substituted phenyls).25
a Over 2 steps.
b Based on the ee values of 9.
The Cbz-protected -aminosulfonyl chlorides were
deprotected utilizing HBr·AcOH, resulting in -aminosul-
fonyl chlorides, which were cyclized in situ using an ex-
cess of triethylamine (Scheme 3).
OCH3
CH3
H
N
N
SO3Hex-c
H3C
H
H
C-3 Substituted -sultams (S)-9a–e were obtained in
moderate to good yields (29–78% over 2 steps) and high
enantiomeric excesses (ee 96%, Table 5). The enantio-
meric excesses were determined by GC on a chiral sta-
tionary phase (Daicel AD) by comparison with racemic
samples. As shown in Table 5, the -sultams containing
Figure 1 NOE connectivitiy in (R,S)-4d
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

PAPER
Asymetric Synthesis of Sulfonates, -Sultams and -Sultones
1859
Table 6
fonates 10a–g
-Alkylation of N-Cbz-Protected -Aminocyclohexyl Sul-
longer alkyl chains were obtained in higher yields, due to
their increasing stability towards hydrolysis.
10
R1
R2X
Yield
(%)
dea (%)
Table 5 Synthesis of 3-Substituted -Sultams (S)-9a–e
(S)-9
R
Yielda (%)
eeb (%)
96
(R,R)-10a
(R,R)-10b
(R,R)-10c
Et
Et
Et
MeI
67
79
71 ( 96)b
(S)-9a
Et
29
68
47
78
55
BnBr
93
90
(S)-9b
n-Pr
i-Pr
96
2-Methylallyl 87
bromide
(S)-9c
96
(R,R)-10d
(R,R)-10e
(R,R)-10f
(S,S)-10g
n-Pr
allyl iodide
EtI
92
83
89
86
91
(S)-9d
n-Bu
Ph(CH2)2
96
n-Pr
85 ( 96)b
(S)-9e
96
a Over 2 steps.
i-Pr
allyl iodide
allyl iodide
90
90
b Determined by GC on chiral stationary phase (Daicel AD) by com-
parison with racemic samples.
Ph(CH2)2
a Determined by 13C NMR spectroscopy.
b After HPLC (Chiracel-OD).
Besides the synthesis of -aminosulfonates and -sulta-
ms, we investigated the -alkylation of 6 with various
electrophiles. As shown in Scheme 4 (Table 6), 2.2 equiv-
alents of LDA were necessary, due to the formation of a
dianion species. The four equivalents of the correspond-
ing electrophile had no side effects, for example, no alkyl-
ation at the nitrogen atom occurred. Only in the case of the
most reactive electrophile, methyl iodide, we obtained a
small amount of double -alkylated product. The yields of
the -alkylation reactions were good to excellent (67–
92% over 2 steps) and only twice we decided to separate
the diastereoisomers by preparative HPLC [(R,R)-10a,
(R,R)-10e], due to a lower selectivity (de = 73–85%).
1.) EtOH, H2O,
CbzHN
reflux
O
O
CbzHN
O
O
2.) 20% COCl2 in
toluene
S
S
Ph
OHex-c
CH2
Ph
Cl
CH2
87%
(S,S)-10g
de = 90%
(S,S)-11
de = 90%
Scheme 5 Conversion of the -aminocyclohexyl sulfonate (S,S)-
10g to the sulfonyl chloride (S,S)-11
The addition of electrophiles is controlled by the already
existing stereocenter and always resulted in anti-products,
which was confirmed by a NOE experiment on (R,R)-10a.
Addition of HMPA, DMPU or LiCl to the reaction mix-
ture had no significant effect on yields or selectivities.
Only a few diastereoselective syntheses of -sultones are
described in literature. For example Yamamoto et al. pub-
lished a synthesis of -sultones using an intramolecular
Michael addition of -alkylsulfonyloxy- , -unsaturated
esters involving higher order cyano copper or silver
amides as a base.27 Another example is the intramolecular
stereocontrolled Diels–Alder reaction of vinyl sulfonates
by Metz et al.28 Furthermore, the first auxiliary controlled
enantioselective synthesis of -sultones was developed in
our group.29
CbzHN
CbzHN
O
O
O O
a
S
S
*
R1
*
OHex-c
R1
*
OHex-c
67-92%
R2
10a-g
de = 71-93%
6
ee ≥ 96%
R1 = Et, n-Pr, i-Pr, Ph(CH2)2
R2 = Me, Et, Allyl, Bn
The ‘halolactonization’ reaction is a valuable tool in
asymmetric synthesis of lactones,30 but to the best of our
knowledge no substrate-controlled stereoselective io-
dosultonization has been described in the literature. As
shown in Scheme 6, after cleavage of the sulfonate the cy-
clization was obtained by addition of three equivalents io-
dine to the sodium salts at –78 °C. The yields of the -
sultones were good (76–77% over 2 steps) and complete
induction of the new stereocenter was achieved. Cycliza-
tion of (R,R)-10c failed, probably due to steric reasons.
Scheme 4
-Alkylation of N-Cbz-protected -aminocyclohexyl
sulfonates. Reagents and conditions: a) LDA, R2X, –78 °C
The -alkyl- -aminocyclohexyl sulfonates 10a–g can be
used in the synthesis of new -sultams. As shown in
Scheme 5 no epimerization in the -position occurred,
during the conversion of the sulfonate to the sulfonyl
chloride.
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

1860
D. Enders et al.
PAPER
(2R,2 S)-2-{[2 -(Methoxymethyl)pyrrolidine-1 yl]amino}pro-
CbzHN
O
O
CbzHN
O
O
pane-1-cyclohexyl Sulfonate [(R,S)-4a]
S
S
*
*
R
OHex-c
*
a
Reaction of 3 (0.409 g, 2 mmol) and SAMP (S)-1 (0.781 g, 6 mmol)
R
O
*
gave 0.521 g (78%) of pure (R,S)-4a; [ ]D24 –60.6 (c = 1.1, CHCl3).
CH2
76-77%
*
I
IR (CHCl3): 2937, 2863, 2826, 1452, 1345, 1263, 1195, 1168, 1119,
1032, 1004, 937, 894, 871, 829, 799, 770, 643, 598, 566, 532, 489
cm–1.
10f,g (de = 90%)
R = i-Pr, Ph(CH2)2
12a,b (de = 90%)
1H NMR (400 MHz, C6D6):
= 0.90–1.80 (m, 14 H,
Scheme 6 Enantioselective synthesis of -sultones by iodosultoni-
CH2CH2CH2CHN, CH2, c-Hex), 1.16 (d, 3 H, J = 6.32 Hz,
CH3CH), 2.20 (q, 1 H, J = 8.79 Hz, CHHCH2CH2CHN), 2.61 (m, 1
H, CH2CH2CH2CHN), 2.85 (dd, 1 H, J = 14.29, 5.50 Hz,
CHHSO2), 3.10–3.60 (m, 6 H, CHHCH2CH2CHN, CH2O, CHNH,
CHHSO2, NH), 3.18 (s, 3 H, OCH3), 4.63 (m, 1 H, CH, c-Hex).
13C NMR (100 MHz, C6D6): = 19.84 (CH3CH), 21.28, 23.43,
24.99, 26.97 (OCHCH2CH2CH2, NCH2CH2CH2), 32.83, 32.89
(OCHCH2), 50.33 (CHNH), 56.60 (CH2SO2), 57.06 (NCH2), 58.70
(OCH3), 66.06 (NCHCH2O), 75.66 (CH2O), 80.10 (OCH).
zation. Reagents and conditions: a) EtOH, H2O, reflux
r.t., THF,
–78 °C, I2
The relative configuration of the new stereogenic center
was determined by NOE analysis on the major diastereo-
isomer of (R,R)-12a (Figure 2).
MS (EI, 70 eV): m/z (%) = 334 (1, [M+]), 332 (5), 287 (17), 221 (7),
207 (27), 206 (9), 205 (100), 169 (6), 141 (7), 125 (45), 123 (6), 115
(26), 84 (8), 83 (52), 73 (11), 71 (76), 69 (6), 57 (7), 56 (14), 55 (57),
45 (42).
CH3
H
SO2
H3C
O
H
H
HN
I
H
Cbz
Anal. Calcd for C15H30N2O4S (334.48): C, 53.86; H, 9.04; N, 8.38.
Found: C, 53.77; H, 8.94; N, 8.64.
Figure 2 NOE connectivity in (S,R,R)-12a
(2R,2 S)-2-{[2 -(Methoxymethyl)pyrrolidine-1 yl]amino}bu-
tane-1-cyclohexyl Sulfonate [(R,S)-4b]
In summary, we have developed a novel asymmetric syn-
thesis of -aminocyclohexyl sulfonates, -sultams and -
sultones. Starting with the aza-Michael addition of the
enantiopure hydrazines SAMP or RAMBO to alkenyl sul-
fonates, N–N-cleavage of the hydrazine 1,4-adducts and
protection of the resulting amines leads to the N-Cbz-pro-
tected -aminocyclohexyl sulfonates of high enantiomer-
ic purity. After -alkylation of the sulfonates and
iodosultonization a novel class of -sultones is obtained
(de = 71–93%). In addition, the sulfonates can directly be
cyclized to highly enantio-enriched 3-substituted -sulta-
ms.
Reaction of 3 (0.437 g, 2 mmol) and SAMP (S)-1 (0.781 g, 6 mmol)
gave 0.516 g (74%) of pure (R,S)-4b; [ ]D24 –88.1 (c = 1.1, CHCl3).
IR (CHCl3): 3401, 2937, 2864, 1671, 1454, 1343, 1265, 1248, 1194,
1167, 1119, 1032, 1004, 936, 870, 831, 643, 596, 531 cm–1.
1H NMR (300 MHz, CDCl3): = 0.92 (t, 3 H, J = 7.42 Hz,
CH3CH2), 1.20–2.05 (m, 16 H, CH2CH2CH2CHN, CH3CH2, CH2, c-
Hex), 2.31 (q, 1 H, J = 8.59 Hz, CHHCH2CH2CHN), 2.61 (m, 1 H,
CH2CH2CH2CHN), 3.03 (br s, 1 H, NH), 3.12 (m, 1 H, CHHSO2),
3.10–3.60 (m, 5 H, CHHCH2CH2CHN, CH2O, CHNH, CHHSO2),
3.36 (s, 3 H, OCH3), 4.72 (sept, 1 H, J = 4.13 Hz, CH, c-Hex).
13C NMR (75 MHz, CDCl3): = 9.27 (CH3CH2), 20.88, 23.47,
24.86, 25.78, 25.88 (OCHCH2CH2CH2, CH3CH2, NCH2CH2CH2),
32.77, 32.80 (OCHCH2), 53.71, 56.88 (CH2SO2, NCH2), 55.56
(CHNH), 59.05 (OCH3), 65.93 (NCHCH2O), 74.41 (CH2O), 81.15
(OCH).
Melting points were measured with a Büchi 510 apparatus and are
1
not corrected. IR: Perkin Elmer FT 1750 spectrometer. H NMR
MS (EI, 70 eV): m/z (%) = 348 (6, [M+]), 266 (14), 221 (100), 219
(10), 129 (10), 71 (5), 55 (10), 45 (8).
spectra (300, 400, 500 MHz) and 13C NMR spectra (75, 100 MHz):
Varian VXR 300, Varian Gemini 300, Varian Inova 400 and Varian
VXR 500 spectrometer, internal standard TMS. MS: Varian MAT
212 and Finnegan MAT SSQ 7000 spectrometer (EI 70 eV). Ele-
mental analyses: Heraeus CHN-O-RAPID and Elementar Vario EL.
GC: Siemens Sichromat 2 and 3, FID, using SE-54, OV1-CB, OV-
5 or OV-17 capilliary columns. Optical rotations: Perkin-Elmer P
241 polarimeter. THF, CH2Cl2, MeOH and diisopropylamine were
dried and distilled prior to use by standard procedures. n-BuLi (1.6
molar solution in hexane), BH3·THF (1 M solution in THF) and
ZnBr2 were purchased from Merck and Aldrich. The pH 7 buffer
was prepared from NaOH (11.6 g) and KH2PO4 (68 g) in H2O (1 L).
All experiments were performed under argon.
Anal. Calcd for C16H32N2O4S (348.51): C, 55.14; H, 9.25; N, 8.04.
Found: C, 55.12; H, 9.66; N, 8.15.
(2R,2 S)-2-{[(2 -(Methoxymethyl)pyrrolidine-1 yl]amino}pen-
tane-1-cyclohexyl Sulfonate [(R,S)-4c]
Reaction of 3 (0.232 g, 1 mmol) and SAMP (S)-1 (0.39 g, 3 mmol)
gave 0.265 g (73%) of pure (R,S)-4c; [ ]D24 –64.1 (c = 1.0, CHCl3).
IR (CHCl3): 2937, 2870, 2827, 1455, 1345, 1264, 1168, 1119, 1096,
1032, 1002, 937, 871, 829, 643, 598, 566, 532 cm–1.
1H NMR (300 MHz, CDCl3): = 0.94 (t, 3 H, J = 7.42 Hz,
CH3CH2), 1.20–2.05 (m, 18 H, CH2CH2CH2CHN, CH3CH2CH2,
CH2, c-Hex), 2.32 (q, 1 H, J = 8.90 Hz, CHHCH2CH2CHN), 2.62
(m, 1 H, CH2CH2CH2CHN), 2.90 (br s, 1 H, NH), 3.10–3.60 (m, 5
H, CHHCH2CH2CHN, CHHO, CHNH, CH2SO2), 3.35 (s, 3 H,
OCH3), 3.48 (dd, 1 H, J = 9.40, 3.95 Hz, CHHO), 4.71 (sept, 1 H,
J = 3.95 Hz, CH, c-Hex).
-Hydrazinocyclohexyl Sulfonates 4a–k; General Procedure
ZnBr2 (0.2 equiv) and the corresponding sulfonate 3 were dissolved
in anhyd MeOH (1 mL/mmol 3). (S)-1 or (R,R,R)-2 was added after
10 min and the reaction mixture was stirred for 7–14 d at r.t. The so-
lution was poured into a mixture of n-pentane and Et2O (2:1, 30 mL/
mmol 3) to precipitate the Lewis acid. After filtration through
Celite, the product was purified by column chromatography (silica
gel, n-pentane–Et2O) to afford 4a–k as colorless oils.
13C NMR (75 MHz, CDCl3):
= 14.12 (CH3CH2), 18.26
(CH3CH2), 20.92, 23.43, 24.84, 25.95 (OCHCH2CH2CH2,
NCH2CH2CH2), 32.71, 32.76 (OCHCH2), 35.24 (CH3CH2CH2),
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

PAPER
Asymetric Synthesis of Sulfonates, -Sultams and -Sultones
1861
54.10, 56.95 (CH2SO2, NCH2), 54.33 (CHNH), 58.91 (OCH3),
(2S,2 R,4 R,5 R)-2-[(2 -Aza-3 -methoxymethylbicyclo[3.3.0]oc-
65.92 (NCHCH2O), 74.42 (CH2O), 80.89 (OCH).
MS (EI, 70 eV): m/z (%) = 362 (8, [M+]), 280 (16), 236 (12), 235
(100), 129 (10).
tane-2 yl)amino]propane-1-cyclohexyl Sulfonate [(S,R,R,R)-4f]
Reaction of 3 (0.613 g, 3 mmol) and RAMBO (R,R,R)-2 (1.532 g,
9 mmol) gave 0.865 g (77%) of pure (S,R,R,R)-4f; [ ]D28 +5.3
(c = 1.0, CHCl3).
Anal. Calcd for C17H34N2O4S (362.53): C, 56.32; H, 9.45; N, 7.73.
Found: C, 56.29; H, 9.19; N, 7.66.
IR (CHCl3): 2939, 2862, 1451, 1346, 1264, 1249, 1196, 1169, 1119,
1096, 1033, 1004, 938, 911, 893, 870, 831, 790, 757, 704, 643, 624,
602, 564, 533, 490, 460 cm–1.
1H NMR (300 MHz, CDCl3): = 0.92–2.10 (m, 18 H, CH2CH2CH2,
CHCH2CHN, CH2, c-Hex), 1.17 (d, 3 H, J = 6.32 Hz, CH3CH),
2.45 (m, 1 H, CHCHN), 2.70 (m, 1 H, CHCH2CHN), 2.92 (dd, 1 H,
J = 13.46, 6.86 Hz, CHHSO2), 3.04 (m, 1 H, CHCHN), 3.32 (s, 3 H,
OCH3), 3.34 (dd, 1 H, J = 9.89, 4.94 Hz, CHHO), 3.40–3.58 (m, 3
H, CHHO, CHHSO2, CHNH), 4.70 (sept, 1 H, J = 4.12 Hz, CH, c-
Hex).
13C NMR (75 MHz, CDCl3): = 19.17 (CH3), 23.74, 24.12, 25.11
(OCHCH2CH2CH2, CH2CH2CH2), 33.06, 33.27, 33.51, 35.46
(OCHCH2, CH2CH2CH2, CHCH2CHN), 38.37 (CHCHN), 50.28
(CHNH), 56.83 (CH2SO2), 59.18 (OCH3), 68.84 (NCHCH2O),
75.20 (CHCHN), 75.99 (CH2O), 81.32 (OCH).
MS (EI, 70 eV): m/z (%) = 374 (4, [M+]), 327 (9), 292 (8), 249 (5),
248 (11), 247 (100), 246 (5), 245 (41), 169 (14), 165 (16), 67 (10),
55 (8), 45 (11).
(2R,2 S)-2-{[2 -(Methoxymethyl)pyrrolidine-1 yl]amino}-3-me-
thylpropane-1-cyclohexyl Sulfonate [(R,S)-4d]
Reaction of 3 (3.252 g, 14 mmol) and SAMP (S)-1 (5.468 g, 42
mmol) gave 2.08 g (41%) of pure (R,S)-4d; [ ]D24 –87.7 (c = 1.0,
CHCl3).
IR (CHCl3): 2940, 2869, 2826, 1499, 1455, 1344, 1247, 1196, 1167,
1117, 1033, 995, 935, 870, 830, 774, 733, 643, 600, 564, 530 cm–1.
1H NMR (300 MHz, CDCl3): = 0.80 (d, 3 H, J = 6.87 Hz,
CH3CH), 0.91 (d, 3 H, J = 7.14 Hz, CH3CH), 1.20–2.05 (m, 14 H,
CH2CH2CH2CHN, CH2, c-Hex), 2.26 (m, 2 H, CHHN, CH3CH),
2.58 (m, 1 H, NCHOCH2), 2.84 (dd, 1 H, J = 14.56, 8.89 Hz,
CHHSO2), 2.96 (br s, 1 H, NH), 3.06 (d, 1 H, J = 14.56 Hz,
CHHSO2), 3.34 (s, 3 H, OCH3), 3.39 (dd, 1 H, J = 9.06, 5.77 Hz,
CHHO), 3.48 (m, 2 H, CHHO, CHHN), 3.86 (m, 1 H, CHNH), 4.73
(sept, 1 H, J = 3.85 Hz, CH, c-Hex).
13C NMR (75 MHz, CDCl3): = 15.11, 18.94 [(CH3)2CH], 20.70,
23.40, 24.83, 25.57 (OCHCH2CH2CH2, NCH2CH2CH2), 28.01
[(CH3)2CH], 32.72, 32.75 (OCHCH2), 50.16 (CH2SO2), 55.96
(NCH2), 58.42 (CHNH), 58.95 (OCH3), 65.62 (NCHCH2O), 73.88
(CH2O), 81.01 (OCH).
Anal. Calcd for C18H34N2O4S (374.54): C, 57.72; H, 9.15; N, 7.49.
Found: C, 58.07; H, 8.96; N, 7.58.
(2S,2 R,4 R,5 R)-2-[(2 -Aza-3 -methoxymethylbicyclo[3.3.0]oc-
tane –2 yl)amino]butane-1-cyclohexyl Sulfonate [(S,R,R,R)-4g]
Reaction of 3 (0.655 g, 3 mmol) and RAMBO (R,R,R)-2 (1.532 g,
9 mmol) gave 0.99 g (85%) of pure (S,R,R,R)-4g; [ ]D24 +23.4
(c = 1.0, CHCl3).
MS (EI, 70 eV): m/z (%) = 362 (7, [M+]), 280 (18), 236 (11), 235
(100), 129 (10).
Anal. Calcd for C17H34N2O4S (362.53): C, 56.32;, H, 9.45; N, 7.73.
Found: C, 56.29; H, 9.53; N, 7.83.
IR (CHCl3): 2939, 2862, 1452, 1346, 1272, 1245, 1196, 1168, 1118,
1032, 1004, 936, 868, 830, 788, 642, 601, 530 cm–1.
(2R,2 S)-2-{[2 -(Methoxymethyl)pyrrolidine-1 yl]amino}-4-
phenylbutane-1-cyclohexyl Sulfonate [(R,S)-4e]
Reaction of 3 (2.944 g, 10 mmol) and SAMP (S)-1 (3.905 g,
30 mmol) gave 2.802 g (66%) of pure (R,S)-4e; [ ]D24 –55.7
(c = 1.0, CHCl3).
1H NMR (300 MHz, CDCl3): = 0.91 (t, 3 H, J = 7.41 Hz,
CH3CH2), 1.01–2.10 (m, 20 H, CH3CH2, CH2CH2CH2,
CHCH2CHN, CH2, c-Hex), 2.50 (m, 1 H, CHCHN), 2.70 (m, 1 H,
CHCH2CHN), 3.07 (dd, 1 H, J = 14.28, 5.22 Hz, CHHSO2), 3.08
(m, 1 H, CHCHN), 3.26 (dd, 1 H, J = 9.62, 6.60 Hz, CHHO), 3.32
(s, 3 H, OCH3), 3.30–3.43 (m, 2 H, CHHSO2, CHNH), 3.53 (dd, 1
H, J = 9.07, 4.94 Hz, CHHO), 4.70 (sept, 1 H, J = 4.12 Hz, CH, c-
Hex).
13C NMR (75 MHz, CDCl3): = 9.42 (CH3CH2), 23.71, 24.42,
25.11, 25.35 (OCHCH2CH2CH2, CH3CH2, CH2CH2CH2), 33.04,
33.28, 33.94, 35.56 (OCHCH2, CH2CH2CH2, CHCH2CHN), 38.94
(CHCHN), 54.47 (CH2SO2), 55.15 (CHNH), 59.16 (OCH3), 68.67
(NCHCH2O), 75.57 (CHCHN), 75.86 (CH2O), 81.25 (OCH).
IR (CHCl3): 3085, 3061, 3026, 2938, 2862, 1603, 1496, 1454, 1344,
1265, 1169, 1118, 1031, 1003, 935, 870, 829, 747, 700, 644, 595,
533, 489, 457 cm–1.
1H NMR (400 MHz, CDCl3):
= 1.20–2.08 (m, 16 H,
NCH2CH2CH2, PhCH2CH2, CH2, c-Hex), 2.33 (q, 1 H, J = 8.79 Hz,
CHHN), 2.80 (br s, 1 H, NH), 2.61–2.78 (m, 3 H, PhCH2CH2,
CHN), 3.18 (dd, 1 H, J = 14.29, 4.12 Hz, CHHSO2), 3.25 (dd, 1 H,
J = 14.29, 7.42 Hz, CHHSO2), 3.30 (m, 1 H, CHHN), 3.31 (s, 3 H,
OCH3), 3.34 (dd, 1 H, J = 9.07, 6.04 Hz, CHHO), 3.40 (m, 1 H,
CHNH), 3.50 (dd, 1 H, J = 9.07, 4.12 Hz, CHHO), 4.70 (m, 1 H,
CH, c-Hex), 7.15–7.30 (m, 5 H, C6H5).
MS (EI, 70 eV): m/z (%) = 388 (5, [M+]), 306 (12), 263 (5), 262
(13), 261 (100), 169 (15), 67 (7), 55 (8), 45 (5).
13C NMR (100 MHz, CDCl3): = 21.24 (NCH2CH2CH2), 23.69,
25.07 (OCHCH2CH2CH2), 26.39 (NCH2CH2CH2), 31.45 (PhCH2),
32.95, 33.02 (OCHCH2), 34.52 (PhCH2CH2), 54.36 (CHNH), 54.42
(CH2SO2), 57.16 (CH2N), 59.26 (OCH3), 66.15 (NCHCH2O), 75.04
(CH2O), 81.40 (OCH), 126.14, 128.59, 128.62 (CH, Ph), 141.89 (C,
Ph).
Anal. Calcd for C19H36N2O4S (388.57): C, 58.73; H, 9.34; N, 7.21.
Found: C, 59.06; H, 9.84; N, 7.44.
(2S,2 R,4 R,5 R)-2-[(2 -Aza-3 -methoxymethylbicyclo[3.3.0]oc-
tane-2 yl)amino]pentane-1-cyclohexyl Sulfonate [(S,R,R,R)-4h]
Reaction of 3 (1.859 g, 8 mmol) and RAMBO (R,R,R)-2 (4.086 g,
24 mmol) gave 1.997 g (62%) of pure (S,R,R,R)-4h; [ ]D24 +17.7
(c = 1.0, CHCl3).
MS (EI, 70 eV): m/z (%) = 424 (7, [M+]), 342 (16), 299 (6), 298
(18), 297 (100), 129 (17), 91 (5), 70 (6).
IR (CHCl3): 2937, 2863, 1451, 1347, 1265, 1240, 1195, 1168, 1119,
1033, 1004, 937, 869, 833, 791, 643, 603, 531 cm–1.
1H NMR (300 MHz, CDCl3): = 0.94 (t, 3 H, J = 7.42 Hz,
CH3CH2), 1.00–2.14 (m, 22 H, CH3CH2CH2, CH3CH2CH2,
CH2CH2CH2, CHCH2CHN, CH2, c-Hex), 2.50 (m, 1 H, CHCHN),
2.69 (m, 1 H, CHCH2CHN), 3.06 (m, 2 H, CHCHN, CHHSO2),
Anal. Calcd for C22H36N2O4S (424.60): C, 62.23; H, 8.54; N, 6.60.
Found: C, 62.33; H, 8.80; N, 6.69.
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

1862
D. Enders et al.
PAPER
3.32 (s, 3 H, OCH3), 3.30–3.60 (m, 4 H, CHHSO2, CHNH, CH2O),
4.71 (sept, 1 H, J = 3.84 Hz, CH, c-Hex).
Anal. calcd for C20H38N2O4S (402.60): C, 59.67; H, 9.51; N, 6.96.
Found: C, 59.47; H, 9.42; N, 7.17.
13C NMR (75 MHz, CDCl3): = 14.60 (CH3CH2), 18.61 (CH3CH2),
23.84, 24.50, 25.23 (OCHCH2CH2CH2, CH2CH2CH2), 33.16,
33.42, 33.88, 35.10, 35.72 (OCHCH2, CH3CH2CH2, CH2CH2CH2,
CHCH2CHN), 38.93 (CHCHN), 54.01 (CHNH), 55.00 (CH2SO2),
59.23 (OCH3), 68.81 (NCHCH2O), 75.58 (CHCHN), 75.91
(CH2O), 81.24 (OCH).
(2S,2 R,4 R,5 R)-2-[(2 -Aza-3 -methoxymethylbicyclo[3.3.0]oc-
tane-2 yl)amino]-4-phenylbutane-1-cyclohexyl Sulfonate
[(S,R,R,R)-4k]
Reaction of 3 (1.324 g, 4.5 mmol) and RAMBO (R,R,R)-2 (2.298 g,
13.5 mmol) gave 1.317 g (63%) of pure (S,R,R,R)-4k; [ ]D24 +20.7
(c = 1.0, CHCl3).
MS (EI, 70 eV): m/z (%) = 402 (8, [M+]), 320 (15), 277 (6), 276
(14), 275 (100), 169 (15), 67 (5).
IR (CHCl3): 3061, 3026, 2939, 2862, 1496, 1452, 1345, 1238, 1216,
1196, 1169, 1118, 1031, 1002, 934, 869, 830, 756, 700, 643, 599,
531 cm–1.
1H NMR (300 MHz, CDCl3): = 1.00–2.12 (m, 20 H, CH2CH2CH2,
CHCH2CHN, PhCH2CH2, CH2, c-Hex), 2.45–2.74 (m, 4 H,
PhCH2CH2, OCH2CHN, CHCHN), 3.10 (m, 1 H, CHHO), 3.12 (dd,
1 H, J = 14.29, 5.22 Hz, CHHSO2), 3.28 (s, 3 H, OCH3), 3.20–3.60
(m, 4 H, CHCHN, CHNH, CHHSO2, CHHO), 4.70 (sept, 1 H,
J = 3.85 Hz, CH, c-Hex), 7.18–7.32 (m, 5 H, C6H5).
Anal. Calcd for C20H38N2O4S (402.60): C, 59.67; H, 9.51; N, 6.96.
Found: C, 59.50; H, 9.64; N, 7.16.
(2S,2 R,4 R,5 R)-2-[(2 -Aza-3 -methoxymethylbicyclo[3.3.0]oc-
tane-2 yl)amino]hexane-1-cyclohexyl Sulfonate [(S,R,R,R)-4i]
Reaction of 3 (0.246 g, 1 mmol) and RAMBO (R,R,R)-2 (0.51 g,
3 mmol) gave 0.271 g (65%) of pure (S,R,R,R)-4i; [ ]D24 +18.6
(c = 0.8, CHCl3).
13C NMR (75 MHz, CDCl3):
= 23.74, 24.43, 25.13
IR (film): 2938, 2862, 1452, 1346, 1264, 1247, 1196, 1168, 1119,
1096, 1032, 1004, 937, 870, 829, 790, 733, 643, 601, 530 cm–1.
(OCHCH2CH2CH2, CH2CH2CH2), 31.42, 33.04, 33.09, 33.26,
33.88, 34.11, 35.64 (OCHCH2, PhCH2CH2, CH2CH2CH2,
CHCH2CHN, PhCH2CH2), 39.00 (CHCHN), 53.64 (CHNH), 54.77
(CH2SO2), 59.21 (OCH3), 68.62 (NCHCH2O), 75.61 (CHCHN),
75.92 (CH2O), 81.35 (OCH), 126.19, 128.68 (CH, Ph), 141.90 (C,
Ph).
1H NMR (300 MHz, CDCl3): = 0.92 (t, 3 H, J = 6.87 Hz,
CH3CH2), 1.00–2.14 (m, 24 H, CH3CH2CH2CH2, CH2CH2CH2,
CHCH2CHN, CH2, c-Hex), 2.50 (m, 1 H, CHCHN), 2.70 (m, 1 H,
CHCH2CHN), 3.06 (m, 2 H, CHCHN, CHHSO2), 3.32 (s, 3 H,
OCH3), 3.30–3.60 (m, 4 H, CHHSO2, CHNH, CH2O), 4.71 (sept, 1
H, J = 3.84 Hz, CH, c-Hex).
MS (EI, 70 eV): m/z (%) = 464 (4, [M+]), 382 (9), 339 (7), 338 (20),
337 (100), 170 (2), 169 (18), 91 (7), 67 (8), 55 (5), 45 (6).
13C NMR (75 MHz, CDCl3): = 14.27 (CH3CH2), 23.08, 23.68,
Anal. Calcd for C25H40N2O4S (464.67): C, 64.62; H, 8.67; N, 6.03.
Found: C, 64.63; H, 8.67; N, 6.07.
24.31,
25.10,
27.33
(OCHCH2CH2CH2,
CH3CH2CH2,
CH2CH2CH2), 32.45, 33.02, 33.31, 33.74, 35.58 (OCHCH2,
CH3CH2CH2CH2, CH2CH2CH2, CHCH2CHN), 38.75 (CHCHN),
54.04 (CHNH), 54.83 (CH2SO2), 59.10 (OCH3), 68.68
(NCHCH2O), 75.46 (CHCHN), 75.82 (CH2O), 81.13 (OCH).
N-Cbz-Protected -Aminocyclohexyl Sulfonates 6a–k; General
Procedure
The -hydrazino sulfonates 4a–k were dissolved in anhyd THF
(10 mL/mmol 4a–k). BH3·THF (10 equiv, 1.0 M in THF) was add-
ed and the reaction mixture was refluxed for 5 h. After cooling to
r.t., the solution was slowly quenched with MeOH (3 mL/mmol 4a–
k). The solvents were carefully evaporated under reduced pressure
and the mixture was treated again with MeOH (30 mL/mmol 4a–k).
The solution was refluxed for 30 min after which the solvent was re-
moved. The crude amines were dissolved in a mixture of CH2Cl2
and H2O (4:1, 10mL/mmol 4a–k). After the addition of Na2CO3 (6
equiv) and CbzCl (3 equiv), the reaction mixture was refluxed for
1–3 d. Then the organic layer was separated and the aqueous phase
was extracted three times with CH2Cl2 (30 mL/mmol 4a–k). The
combined organic layers were washed with sat. aq Na2CO3 and
NaCl solutions. After drying (MgSO4), the solvent was evaporated
and the products were purified by column chromatography (silica
gel,; n-pentane–Et2O) to afford 6a–k as colorless solids.
MS (EI, 70 eV): m/z (%) = 416 (8, [M+]), 334 (16), 289 (100), 169
(19), 67 (6), 55 (7), 45 (5).
Anal. Calcd for C21H40N2O4S (416.62): C, 60.54; H, 9.68; N, 6.72.
Found: C, 60.72; H, 10.14; N, 6.54.
(2S,2 R,4 R,5 R)-2-[(2 -Aza-3 -methoxymethylbicyclo[3.3.0]oc-
tane-2 yl)amino]-3-methylbutane-1-cyclohexyl Sulfonate
[(S,R,R,R)-4j]
Reaction of 3 (0.697 g, 3 mmol) and RAMBO (R,R,R)-2 (1.532 g,
9 mmol) gave 0.531 g (44%) of pure (S,R,R,R)-4j; [ ]D24 +17.2
(c = 0.9, CHCl3).
IR (CHCl3): 2940, 2863, 1498, 1452, 1351, 1264, 1238, 1196, 1168,
1118, 1095, 1004, 937, 870, 830, 734, 641, 601, 567, 503 cm–1.
1H NMR (300 MHz, CDCl3): = 0.83 (d, 3 H, J = 6.86 Hz,
CH3CH), 0.89 (d, 3 H, J = 7.14 Hz, CH3CH), 1.00–2.14 (m, 18 H,
CH2CH2CH2, CHCH2CHN, CH2, c-Hex), 2.39 (m, 1 H, CH3CH),
2.57 (m, 1 H, CHCHN), 2.70 (m, 1 H, CHCH2CHN), 2.88 (dd, 1 H,
J = 14.56, 9.06 Hz, CHHSO2), 3.05 (dd, 1 H, J = 14.56, 2.48 Hz,
CHHSO2), 3.10 (m, 1 H, CHCHN), 3.27 (dd, 1 H, 9.06, 6.87 Hz,
CHHO), 3.32 (s, 3 H, OCH3), 3.46 (m, 1 H, CHNH), 3.57 (dd, 1 H,
J = 9.06, 3.85 Hz, CHHO), 4.73 (sept, 1 H, J = 3.85, CH, c-Hex).
2-Benzyloxycarbonylaminopropane-1-cyclohexyl Sulfonate
[6a/f]
Reaction of (R,S)-4a (0.334 g, 1 mmol) or (S,R,R,R)-4f (0.187 g, 0.5
mmol) with BH3·THF and CbzCl gave 0.242 g (68%) of pure (R)-
6a or 0.100 g (56%) of pure (S)-6f; mp 85 °C; [ ]D24 +8.5 [c = 0.9,
CHCl3; for (R)-6a].
13C NMR (75 MHz, CDCl3): = 15.53, 18.79 [(CH3)2CH], 23.67,
24.97, 25.10 (OCHCH2CH2CH2, CH2CH2CH2), 27.12 [(CH3)2CH],
32.81, 33.00, 33.04, 35.20, 35.43 (OCHCH2, CH2CH2CH2,
CHCH2CHN), 40.01 (CHCHN), 51.01 (CH2SO2), 58.00 (CHNH),
59.28 (OCH3), 68.31 (NCHCH2O), 75.56 (CH2O), 75.97
(CHCHN), 81.33 (OCH).
IR (KBr): 3356, 2934, 2865, 1694, 1541, 1455, 1382, 1343, 1327,
1271, 1256, 1208, 1197, 1172, 1108, 1053, 935, 893, 875, 835, 729,
695, 648, 595, 568, 528, 476 cm–1.
1H NMR (400 MHz, CDCl3): = 1.43 (d, 3 H, J = 6.87 Hz,
CH3CH), 1.20–2.00 (m, 10 H, CH2, c-Hex), 3.23 (dd, 1 H,
J = 14.01, 4.74 Hz, SO2CHH), 3.23 (dd, 1 H, J = 14.15, 4.74 Hz,
SO2CHH), 4.22 (sept, 1 H, J = 6.68 Hz, CHNH), 4.72 (sept, 1 H,
J = 3.84 Hz, CH, c-Hex), 5.10 (s, 2 H, OCH2), 5.15 (d, 1 H, J = 9.34
Hz, NH), 7.28–7.38 (m, 5 H, C6H5).
MS (EI, 70 eV): m/z (%) = 402 (6, [M+]), 320 (14), 277 (7), 276
(15), 275 (100), 169 (18), 67 (6), 55 (2).
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

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Asymetric Synthesis of Sulfonates, -Sultams and -Sultones
1863
13C NMR (100 MHz, CDCl3): = 20.10 (CH3CH), 23.68, 25.04
(OCHCH2CH2CH2), 32.91, 32.99 (OCHCH2), 43.96 (CHNH),
56.28 (CH2SO2), 67.05 (OCH2), 81.93 (OCH), 128.31, 128.42,
128.77 (CH, Ph), 136.47 (C, Ph), 155.57 (OCNH).
MS (CI, isobutane): m/z (%) = 356 (74, [M+ + 1]), 274 (100).
HRMS: m/z calcd for C17H25NO5S – C6H5 (273.07, M+): 273.0671;
6d or 0.371 g (57%) of pure (S)-6j; mp 102 °C; [ ]D24 +8.8 [c = 1.0,
CHCl3; for (R)-6d].
IR (KBr): 3374, 2938, 2906, 2868, 1698, 1531, 1469, 1453, 1411,
1387, 1331, 1304, 1273, 1241, 1195, 1171, 1128, 1104, 1035, 1025,
1004, 934, 890, 877, 829, 751, 726, 695, 641, 591, 569, 534, 526,
482 cm–1.
found: 273.0670.
1H NMR (400 MHz, CDCl3): = 0.93 (d, 3 H, J = 6.86 Hz, CH3),
0.98 (d, 3 H, J = 6.86 Hz, CH3), 1.19–2.15 (m, 11 H, CH2, c-Hex,
CH3CH), 3.26 (dd, 1 H, J = 14.63, 4.12 Hz, CHHSO2), 3.36 (dd, 1
H, J = 14.56, 7.14 Hz, CHHSO2), 3.92 (m, 1 H, CHNH), 4.72 (sept,
1 H, J = 4.28 Hz, CH, c-Hex), 5.11 (s, 2 H, OCH2), 5.19 (d, 1 H,
J = 9.34 Hz, NH), 7.28–7.37 (m, 5 H, C6H5).
13C NMR (100 MHz, CDCl3): = 18.53, 19.63 [(CH3)2CH], 23.82,
25.19 (OCHCH2CH2CH2), 31.48 [(CH3)2CH], 33.04, 33.12
(OCHCH2), 53.28 (CH2SO2), 53.39 (CHNH), 67.15 (OCH2), 81.83
(OCH), 128.22, 128.32, 128.72 (CH, Ph), 136.57 (C, Ph), 156.00
(OCNH).
2-Benzyloxycarbonylaminobutane-1-cyclohexyl Sulfonate [6b/
g]
Reaction of (R,S)-4b (1.394 g, 4 mmol) or (S,R,R,R)-4g (1.749 g,
4.5 mmol) with BH3·THF and CbzCl gave 0.783 g (53%) of pure
(R)-6b or 0.881g (53%) of pure (S)-6g; mp 99 °C; [ ]D24 +8.6
[c = 0.9, CHCl3; for (R)-6b].
IR (CHCl3): 3354, 3035, 2969, 2936, 2868, 2852, 1692, 1660, 1588,
1537, 1499, 1453, 1441, 1421, 1411, 1385, 1343, 1333, 1320, 1282,
1265, 1240, 1195, 1168, 1115, 1092, 1056, 1020, 993, 967, 934,
892, 877, 859, 832, 774, 745, 727, 694, 649, 591, 567, 533, 481,
457 cm–1.
MS (CI, isobutane): m/z (%) = 383 (6, [M+]), 303 (13), 302 (80),
168 (7).
1H NMR (300 MHz, CDCl3): = 0.96 (t, 3 H, J = 7.15 Hz, CH3),
1.20–2.00 (m, 12 H, CH2, c-Hex, CH3CH2), 3.25 (dd, 1 H,
J = 14.01, 4.26 Hz, CHHSO2), 3.40 (dd, 1 H, J = 14.01, 4.26 Hz,
CHHSO2), 4.00 (m, 1 H, CHNH), 4.70 (m, 1 H, CH, c-Hex), 5.10
(s, 2 H, OCH2), 5.38 (d, 1 H, J = 8.24 Hz, NH), 7.28–7.38 (m, 5 H,
C6H5).
13C NMR (75 MHz, CDCl3): = 10.74 (CH3CH2), 23.71, 25.08
(OCHCH2CH2CH2), 26.98 (CH3CH2), 33.01, 32.93 (OCHCH2),
49.60 (CHNH), 54.80 (CH2SO2), 67.02 (OCH2), 81.87 (OCH),
128.26, 128.39, 128.78 (CH, Ph), 136.63 (C, Ph), 156.00 (OCNH).
HRMS: m/z calcd for C19H29NO5S (383.18, M+): 383.1766; found:
383.1766.
2-Benzyloxycarbonylaminohexane-1-cyclohexyl Sulfonate [6i]
Reaction of (S,R,R,R)-4i (0.708 g, 1.7 mmol) with BH3·THF and
CbzCl gave 0.426 g (63%) of pure (S)-6i; mp 114 °C; [ ]D24 –12.1
(c = 1.0, CHCl3).
IR (KBr): 3360, 3034, 2930, 2863, 2185, 1696, 1535, 1454, 1411,
1329, 1254, 1217, 1193, 1169, 1109, 1038, 1006, 935, 875, 832,
774, 731, 694, 644, 602, 569, 541, 526, 486, 456 cm–1.
1H NMR (300 MHz, CDCl3): = 0.89 (t, 3 H, J = 7.28 Hz, CH3),
1.20–2.00 (m, 16 H, CH2, c-Hex, CH3CH2CH2CH2,
CH3CH2CH2CH2, CH3CH2CH2CH2), 3.28 (dd, 1 H, J = 14.29, 4.12
Hz, CHHSO2), 3.40 (dd, 1 H, J = 14.56, 5.77 Hz, CHHSO2), 4.07
(m, 1 H, CHNH), 4.71 (m, 1 H, CH, c-Hex), 5.10 (s, 2 H, OCH2),
5.31 (d, 1 H, J = 8.79 Hz, NH), 7.28–7.38 (m, 5 H, C6H5).
MS (EI, 70 eV): m/z (%) = 370 (1, [M+]), 288 (5), 287 (38), 214 (6),
108 (72), 107 (83), 92 (7), 91 (100), 83 (6), 79 (5), 65 (7), 55 (18).
Anal. Calcd for C18H27NO5S (369.48): C, 58.51; H, 7.37; N, 3.79.
Found: C, 58.70; H, 7.33; N, 3.59.
2-Benzyloxycarbonylaminopentane-1-cyclohexyl Sulfonate [6c/
h]
Reaction of (R,S)-4c (0.363 g, 1 mmol) or (S,R,R,R)-4h (0.201 g,
0.5 mmol) with BH3·THF and CbzCl gave 0.165 g (43%) of pure
(R)-6c or 0.072 g (38%) of pure (S)-6h; mp 98 °C; [ ]D24 +9.8
[c = 1.0, CHCl3; for (R)-6c].
13C NMR (75 MHz, CDCl3):
(CH3CH2CH2CH2), 23.71, 25.07 (OCHCH2CH2CH2), 28.37
(CH3CH2CH2CH2), 32.95, 33.02 (OCHCH2), 33.53
= 14.19 (CH3), 22.52
(CH3CH2CH2CH2), 48.20 (CHNH), 55.15 (CH2SO2), 67.06
(OCH2), 81.88 (OCH), 128.29, 128.42, 128.79 (CH, Ph), 136.58 (C,
Ph), 155.93 (OCNH).
MS (EI, 70 eV): m/z (%) = 397 (1, [M+]), 315 (22), 214 (7), 108
(100), 107 (17), 92 (8), 91 (91), 83 (10), 82 (7), 67 (13), 57 (11), 55
(18).
IR (KBr): 3365, 3035, 2993, 2929, 2869, 2850, 1698, 1535, 1460,
1359, 1331, 1290, 1260, 1225, 1195, 1170, 1109, 1059, 1039, 1027,
1006, 935, 878, 830, 731, 694, 635, 605, 526, 457 cm–1.
1H NMR (400 MHz, CDCl3): = 0.94 (t, 3 H, J = 7.28 Hz, CH3),
1.20–2.00 (m, 14 H, CH2, c-Hex, CH3CH2CH2, CH3CH2CH2), 3.29
(dd, 1 H, J = 14.43, 4.26 Hz, CHHSO2), 3.42 (dd, 1 H,
J = 14.42, 5.63 Hz, CHHSO2), 4.09 (m, 1 H, CHNH), 4.72 (sept, 1
H, J = 4.12 Hz, CH, c-Hex), 5.10 (s, 2 H, OCH2), 5.22 (d, 1 H,
J = 8.24 Hz, NH), 7.28–7.37 (m, 5 H, C6H5).
Anal. Calcd for C20H31NO5S (397.54): C, 60.43; H, 7.86; N, 3.52.
Found: C, 60.01; H, 8.05; N, 3.65.
2-Benzyloxycarbonylamino-4-phenylbutane-1-cyclohexyl Sul-
fonate [6e/k]
Reaction of (R,S)-4e (0.425 g, 1 mmol) or (S,R,R,R)-4k (1.394 g, 3
mmol) with BH3·THF and CbzCl gave 0.236 g (53%) of pure (R)-
6e or 0.842 g (63%) of pure (S)-6k; mp 121 °C; [ ]D24 +14.4
[c = 1.0, CHCl3; for (R)-6e].
13C NMR (100 MHz, CDCl3):
= 13.62 (CH3CH2), 19.28
(CH3CH2), 23.47, 24.83 (OCHCH2CH2CH2), 32.71, 32.78
(OCHCH2), 35.58 (CH3CH2CH2), 47.74 (CHNH), 54.91 (CH2SO2),
66.83 (OCH2), 81.62 (OCH), 128.05, 128.18, 128.54 (CH, Ph),
136.30 (C, Ph), 155.65 (OCNH).
IR (KBr): 2936, 2863, 1533, 1498, 1454, 1328, 1294, 1247, 1214,
1127, 1049, 1010, 930, 875, 742, 700, 614 cm–1.
MS (CI, isobutane): m/z (%) = 384 (100, [M+ + 1]), 303 (12), 302
(75), 250 (7), 168 (5), 91 (5).
HRMS: m/z calcd for C19H29NO5S (383.18, M+): 383.1766; found:
383.1766.
1H NMR (400 MHz, CDCl3): = 1.20–2.20 (m, 12 H, CH2, c-Hex,
PhCH2CH2), 3.26 (dd, 1 H, J = 14.56, 4.12 Hz, CHHSO2), 2.68 (m,
2 H, PhCH2CH2), 3.40 (dd, 1 H, J = 14.56, 5.76 Hz, CHHSO2), 4.07
(m, 1 H, CHNH), 4.68 (m, 1 H, CH, c-Hex), 5.10 (s, 2 H, OCH2),
5.37 (d, 1 H, J = 8.51 Hz, NH), 7.24–7.36 (m, 5 H, C6H5).
13C NMR (100 MHz, CDCl3): = 23.82, 25.18 (OCHCH2CH2CH2),
32.60 (PhCH2CH2), 33.03, 33.08 (OCHCH2), 35.44 (PhCH2CH2),
2-Benzyloxycarbonylamino-3-methylbutane-1-cyclohexyl Sul-
fonate [6d/j]
Reaction of (R,S)-4d (1.088 g, 3 mmol) or (S,R,R,R)-4j (0.684 g, 1.7
mmol) with BH3·THF and CbzCl gave 0.701 g (61%) of pure (R)-
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

1864
D. Enders et al.
PAPER
47.86 (CHNH), 55.19 (CH2SO2), 67.17 (OCH2), 82.04 (OCH),
126.41, 128.28, 128.41, 128.63, 128.75, 128.77 (CH, Ph), 136.53,
140.85 (C, Ph), 155.84 (OCNH).
MS (EI, 70 eV): m/z (%) = 445 (1, [M+]), 363 (11), 272 (32), 211
(42), 168 (25), 130 (7), 129 (38), 124 (18), 108 (6), 107 (6), 105 (6),
104 (11), 92 (13), 91 (100), 83 (8), 82 (9), 79 (6), 67 (17), 65 (6), 55
(13), 54 (16).
MS (EI, 70 eV): m/z (%) = 320 (0.2, [M+]), 109 (8), 108 (100), 107
(12), 92 (7), 91 (29), 79 (7), 65 (8).
Anal. Calcd for C13H18ClNO4S (319.81): C, 48.82; H, 5.67; N, 4.38.
Found: C, 48.40; H, 5.74; N, 4.28.
(S)-2-Benzyloxycarbonylamino-3-methylbutane-1-sulfonyl
Chloride [(S)-7c]
Reaction of (S)-6j (0.307 g, 0.8 mol) and 20% COCl2 in toluene (0.8
mL, 0.8 mol) gave 0.171 g (67%) of pure (S)-7c; mp 111 °C; [ ]D
+17.2 (c = 1.0, CHCl3).
Anal. Calcd for C24H31NO5S (445.58): C, 64.69; H, 7.01; N, 3.14.
Found: C, 64.63; H, 7.44; N, 3.06.
24
N-Cbz-Protected -Aminocyclohexylsulfonyl Chlorides 7a–e
and (S,S)-11; General Procedure
IR (KBr): 3328, 3033, 2978, 2893, 1692, 1544, 1467, 1356, 1338,
1301, 1251, 1165, 1130, 1112, 1039, 1009, 970, 851, 776, 752, 728,
696, 676, 567, 533 cm–1.
1H NMR (300 MHz, CDCl3): = 0.93 (d, 3 H, J = 6.81 Hz, CH3),
0.98 (d, 3 H, J = 6.82 Hz, CH3), 2.04 (m, 1 H, CH3CH), 3.84 (dd, 1
H, J = 14.06, 3.07 Hz, CHHSO2), 4.00 (dd, 1 H, J = 14.28, 8.13 Hz,
CHHSO2), 4.15 (m, 1 H, CHNH), 5.10 (s, 2 H, OCH2), 5.35 (d, 1 H,
J = 8.79 Hz, NH), 7.26–7.40 (m, 5 H, C6H5).
N-Cbz-Protected -aminocyclohexyl sulfonates (S)-6g–k, (S,S)-
10g were dissolved in a mixture of EtOH [30 mL/mmol 6g–k, (S,S)-
10g] and H2O [1 mL/mmol 6g–k, (S,S)-10g] and refluxed for 4 h.
After cooling to r.t., NaOAc (1.1 equiv) was added and the solution
was stirred for 1 h. The solvents were removed under reduced pres-
sure and the crude sodium salts were dissolved in anhyd CH2Cl2
(10 mL/mmol 6g–k, (S,S)-10g) and anhyd DMF (0.12 mL/mmol
6g–k, (S,S)-10g). Then a solution, containing 20% COCl2 in toluene
[1 mL/mmol 6g–k, (S,S)-10g] was added dropwise and the mixture
was stirred for 2 h at r.t. Products were purified by column chroma-
tography (silica gel, n-pentane–Et2O) to afford 7a–e, (S,S)-11 as
colorless solids.
13C NMR (75 MHz, CDCl3): = 18.33, 19.61 [(CH3)2CH], 32.04
[(CH3)2CH], 53.82 (CHNH), 67.44 (OCH2), 67.51 (CH2SO2),
128.25, 128.46, 128.78 (CH, Ph), 136.37 (C, Ph), 156.00 (OCNH).
MS (EI, 70 eV): m/z (%) = 319 (6, [M+]), 108 (67), 91 (100), 65 (7).
Anal. Calcd for C13H18ClNO4S (319.81): C, 48.82; H, 5.67; N, 4.38.
Found: C, 48.89; H, 5.63; N, 4.09.
(S)-2-Benzyloxycarbonylaminobutane-1-sulfonyl Chloride [(S)-
7a]
Reaction of (S)-6g (0.222 g, 0.6 mmol) and 20% COCl2 in toluene
(0.6 mL, 0.6 mmol) gave 0.117 g (64%) of pure (S)-7a; mp 104 °C;
[ ]D24 –13.2 (c = 0.8, CHCl3).
(S)-2-Benzyloxycarbonylaminohexane-1-sulfonyl Chloride
[(S)-7d]
Reaction of (S)-6i (0.358 g, 0.9 mmol) and 20% COCl2 in toluene
(0.9 mL, 0.9 mmol) gave 0.229 g (64%) of pure (S)-7d; mp 98 °C;
[ ]D26 –8.3 (c = 1.1, CHCl3).
IR (KBr): 3324, 2971, 2934, 1693, 1544, 1499, 1458, 1350, 1313,
1286, 1247, 1165, 1116, 1092, 1055, 994, 967, 835, 777, 743, 730,
697, 534 cm–1.
1H NMR (400 MHz, CDCl3): = 0.98 (t, J = 7.14 Hz, 3 H, CH3),
1.76 (m, 1 H, CH3CH2), 3.86 (d, 1 H, J = 10.12 Hz, CHHSO2), 4.06
(d, 1 H, J = 6.59 Hz, CHHSO2), 4.11 (m, 1 H, CHCH2SO2), 5.10 (s,
2 H, OCH2), 5.33 (m, 1 H, NH), 7.28–7.38 (m, 5 H, C6H5).
IR (KBr): 3328, 3067, 3032, 2956, 2927, 2861, 1693, 1545, 1456,
1363, 1295, 1259, 1218, 1161, 1125, 1107, 1051, 1029, 834, 776,
732, 696, 670, 608, 528, 455 cm–1.
1H NMR (400 MHz, CDCl3): = 0.89 (t, 3 H, J = 7.28 Hz, CH3),
1.33 (m, 4 H, CH3CH2CH2CH2, CH3CH2CH2CH2), 1.71 (m, 2 H,
CH3CH2CH2CH2), 3.86 (dd, 1 H, J = 14.01, 4.12 Hz, CHHSO2),
4.08 (dd, 1 H, J = 14.29, 6.60 Hz, CHHSO2), 4.18 (m, 1 H, CHNH),
5.10 (s, 2 H, OCH2), 5.29 (d, 1 H, J = 7.69 Hz, NH), 7.28–7.38 (m,
5 H, C6H5).
13C NMR (100 MHz, CDCl3):
= 10.36 (CH3CH2), 26.61
(CH3CH2), 49.96 (CHNH), 66.96 (OCH2), 68.30 (CH2SO2), 127.86,
128.09, 128.38 (CH, Ph), 135.86 (C, Ph), 155.38 (OCNH).
MS (EI, 70 eV): m/z (%) = 306 (2, [M+]), 126 (6), 108 (51), 107
(20), 105 (11), 99 (6), 92 (9), 91 (100), 79 (7), 77 (7), 65 (7), 58 (7).
13C NMR (100 MHz, CDCl3):
(CH3CH2), 27.91 (CH3CH2CH2), 33.06 (CH3CH2CH2CH2), 48.59
(CHNH), 66.96 (OCH2), 68.61 (CH2SO2), 127.87, 128.10, 128.38
(CH, Ph), 135.86 (C, Ph), 155.31 (OCNH).
= 13.83 (CH3CH2), 22.09
Anal. Calcd for C12H16ClNO4S (305.78): C, 47.14; H, 5.27; N, 4.58.
Found: C, 47.29; H, 5.39; N, 4.52.
MS (EI, 70 eV): m/z (%) = 334 (1, [M+]), 216 (8), 197 (6), 181 (17),
179 (7), 167 (8), 165 (7), 128 (12), 127 (5), 126 (45), 125 (8), 112
(6), 108 (5), 92 (8), 91 (88), 83 (8), 69 (6), 65 (31).
(S)-2-Benzyloxycarbonylaminopentane-1-sulfonyl Chloride
[(S)-7b]
Reaction of (S)-6h (0.307 g, 0.8 mmol) and 20% COCl2 in toluene
(0.8 mL, 0.8 mmol) gave 0.189 g (74%) of pure (S)-7b; mp 106 °C;
[ ]D24 –4.7 (c = 1.0, CHCl3).
Anal. Calcd for C14H20ClNO4S (333.84): C, 50.37; H, 6.04; N, 4.20.
Found: C, 50.19; H, 5.73; N, 4.19.
IR (KBr): 3309, 3071, 2965, 2925, 2871, 1690, 1551, 1462, 1368,
1291, 1265, 1229, 1166, 1119, 1098, 1056, 1016, 907, 835, 750,
729, 694, 674, 599, 581, 532 cm–1.
1H NMR (400 MHz, CDCl3): = 0.93 (t, 3 H, J = 7.41 Hz, CH3),
1.40 (m, 2 H, CH3CH2), 1.70 (m, 2 H, CH3CH2CH2), 3.86 (dd, 1 H,
J = 14.29, 4.12 Hz, CHHSO2), 4.06 (dd, 1 H, J = 14.28, 6.54 Hz,
CHHSO2), 4.20 (m, 1 H, CHNH), 5.10 (m, 2 H, OCH2), 5.32 (d, 1
H, J = 7.97 Hz, NH), 7.28 (m, 5 H, C6H5).
(S)-2-Benzyloxycarbonylamino-4-phenylbutane-1-sulfonyl
Chloride [(S)-7e]
Reaction of (S)-6k (0.356 g; 0.8 mmol) and 20% COCl2 in toluene
(0.8 mL, 0.8 mmol) gave 0.189 g (62%) of pure (S)-7e; mp 116 °C;
[ ]D24 –11.4 (c = 1.0, CHCl3).
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.
13C NMR (100 MHz, CDCl3):
(CH3CH2), 35.81 (CH3CH2CH2), 48.74 (CHNH), 67.38 (OCH2),
69.06 (CH2SO2), 128.28, 128.52, 128.81 (CH, Ph), 136.29 (C, Ph),
155.78 (OCNH).
= 13.88 (CH3CH2), 19.50
1H NMR (400 MHz, CDCl3): = 2.10 (m, 2 H, PhCH2CH2), 2.68
(m, 2 H, PhCH2CH2), 3.83 (dd, 1 H, J = 14.00, 3.99 Hz, CHHSO2),
4.04 (dd, 1 H, J = 14.15, 6.73 Hz, CHHSO2), 4.15 (m, 1 H,
CHCH2SO2), 5.09 (s, 2 H, OCH2), 5.41 (d, J = 8.24 Hz, 1 H, NH)
7.10–7.36 (m, 10 H, C6H5).
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

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Asymetric Synthesis of Sulfonates, -Sultams and -Sultones
1865
13C NMR (100 MHz, CDCl3): = 32.46, 35.26 (PhCH2CH2), 48.64
(CHNH), 67.49 (OCH2), 68.94 (CH2SO2), 126.69, 128.35, 128.62,
128.88, 128.93 (CH, Ph), 136.30, 140.32 (C, Ph), 155.80 (OCNH).
(S)-3-Propyl-1,2-thiazetidine 1,1-Dioxide [(S)-9b]
Reaction of (S)-7b (0.320 g, 1 mmol) with a solution of HBr in
HOAc and Et3N gave 0.051 g (68%) of pure (S)-9b; [ ]D24 +5.8
(c = 1.0, CHCl3).
MS (EI, 70 eV): m/z (%) = 381(1, [M+]), 290 (34), 186 (30), 142
(10), 129 (23), 108 (6), 104 (7), 91 (100), 65 (10).
IR (film): 3291, 2961, 2934, 2874, 1466, 1414, 1382, 1308, 1224,
1189, 1159, 1114, 1070, 810, 783, 659, 499, 466 cm–1.
1H NMR (300 MHz, CDCl3): = 0.96 (t, 3 H, J = 7.25 Hz, CH3),
1.36 (m, 2 H, CH3CH2CH2), 1.74 (m, 2 H, CH3CH2CH2), 3.63 (m,
1 H, CHNH), 3.87 (dd, 1 H, J = 12.52, 5.50 Hz, CHHSO2), 4.31
(ddd, 1 H, J = 12.52, 7.69, 3.08 Hz, CHHSO2), 5.56 (s, 1 H, NH).
Anal. Calcd for C18H20ClNO4S (381.88): C, 56.61; H, 5.28; N, 3.67.
Found: C, 56.69; H, 5.50; N, 3.36.
(S,S)-5-Benzyloxycarbonylamino-7-phenylhept-1-en-4-sulfo-
nyl Chloride [(S,S)-11]
Reaction of (S,S)-10g (0.243 g, 0.5 mmol) and 20% COCl2 in tolu-
ene (0.5 mL, 0.5 mmol) gave 0.184 g (87%) of pure (S,S)-11.
13C NMR (75 MHz, CDCl3): = 13.97 (CH3CH2CH2), 19.68
(CH3CH2CH2), 38.38 (CH3CH2CH2), 41.08 (CHNH), 65.16
(CH2SO2).
MS (EI, 70 eV): m/z (%) = 149 (2, [M+]), 106 (100), 69 (21), 56
(18).
IR (KBr): 3406, 3333, 3063, 3030, 2929, 2861, 1692, 1643, 1532,
1453, 1372, 1299, 1247, 1163, 1039, 997, 930, 753, 699, 633, 589,
540, 491, 473 cm–1.
1H NMR (300 MHz, CDCl3): = 2.12 (m, 2 H, PhCH2CH2), 2.40–
2.95 (m, 4 H, PhCH2CH2, CH2CHSO2), 3.86 (m, 1 H, CHSO2), 4.38
(m, 1 H, CHNH), 5.13 (d, 2 H, J = 2.72 Hz, OCH2), 4.95–5.32 (m,
3 H, CH2CHCH2, NH), 5.75 (m, 1 H, CH2CHCH2), 7.10–7.38 (m,
10 H, C6H5).
13C NMR (75 MHz, CDCl3): = 32.33, 32.67, 34.93 (PhCH2CH2,
CH2CHSO2), 50.89 (CHNH), 67.38 (OCH2), 79.56 (CHSO2),
120.56 (CH2CHCH2), 126.42, 128.45, 128.67 (CH, Ph), 131.78
(CH2CHCH2), 136.09, 140.22 (C, Ph), 156.03 (OCNH).
MS (EI, 70 eV): m/z (%) = 421 (2, [M+]), 332 (7), 330 (17), 266 (8),
226 (6), 224 (6), 169 (14), 162 (5), 126 (9), 92 (9), 91 (100), 82 (7),
65 (8).
Anal. Calcd for C5H11NO2S (149.21): C, 40.25; H, 7.43; N, 9.39.
Found: C, 40.16; H, 7.51; N, 9.68.
(S)-3-(1-Methylethyl)-1,2-thiazetidine 1,1-Dioxide [(S)-9c]
Reaction of (S)-7c (0.320 g, 1 mmol) with a solution of HBr in
HOAc and Et3N gave 0.070 g (47%) of pure (S)-9c; mp 87 °C;
[ ]D24 +10.2 (c = 1.0, CHCl3).
IR (KBr): 3675, 3653, 3334, 3048, 2965, 2932, 2881, 1738, 1703,
1654, 1624, 1472, 1413, 1383, 1343, 1298, 1231, 1199, 1148, 1121,
1036, 1013, 987, 929, 882, 801, 762, 682, 602, 507 cm–1.
1H NMR (400 MHz, CDCl3): = 0.94 (d, 3 H, J = 6.59 Hz, CH3),
0.98 (d, 3 H, J = 6.59 Hz, CH3), 1.90 (m, 1 H, CH3CH), 3.33 (m, 1
H, CHNH), 3.93 (dd, 1 H, J = 12.64, 6.04 Hz, CHHSO2), 4.22 (ddd,
1 H, J = 12.64, 7.97, 3.85 Hz, CHHSO2), 5.51 (s, 1 H, NH).
Anal. Calcd for C21H24ClNO4S (421.94): C, 59.78; H, 5.73; N, 3.32.
Found: C, 59.45; H, 5.69; N, 3.54.
13C NMR (100 MHz, CDCl3): = 18.27, 18.76 [(CH3)2CH], 33.95
[(CH3)2CH], 46.91 (CHNH), 63.35 (CH2SO2).
MS (EI, 70 eV): m/z (%) = 149 (1, [M+]), 108 (5), 106 (100), 69
-Sultams 9a–e; General Procedure
To a mixture of N-Cbz-protected -aminocyclohexyl sulfonyl chlo-
ride (S)-7a–e in CH2Cl2 (20 mL/mmol (S)-7a–e) was added a 33%
solution of HBr in HOAc (1.5 equiv). After stirring for 3 h at r.t., the
reaction mixture was cooled to 0 °C and Et3N was added (12 mL/
mmol (S)-7a–e). The solution was stirred for 2 h while it warmed up
to r.t. After separation of the organic layer, the aqueous phase was
extracted with CH2Cl2 [3 × 30 mL/mmol (S)-7a–e]. The combined
organic layers were dried (MgSO4) and the solvent was removed
under reduced pressure. Products were purified by column chroma-
tography (silica gel, n-pentane–Et2O) to afford 9a,b,d as colorless
oils and 9c,e as colorless solids.
(10), 55 (6), 45 (6).
Anal. Calcd for C5H11NO2S (149.21): C, 40.25; H, 7.43; N, 9.39.
Found: C, 40.26; H, 7.81; N, 9.09.
(S)-3-Butyl-1,2-thiazetidine 1,1-Dioxide [(S)-9d]
Reaction of (S)-7d (0.167 g, 0.5 mmol) with a solution of HBr in
HOAc and Et3N gave 0.064 g (78%) of pure (S)-9d; [ ]D24 +6.8
(c = 1.1, CHCl3).
IR (CHCl3): 3171, 3019, 2976, 2932, 2875, 1716, 1380, 1217, 1045,
758, 668, 615 cm–1.
(S)-3-Ethyl-1,2-thiazetidine 1,1 Dioxide [(S)-9a]
Reaction of (S)-7a (0.306 g, 1 mmol) with a solution of HBr in
HOAc and Et3N gave 0.039 g (29%) of pure (S)-9a; [ ]D24 +8.6
(c = 0.7, CHCl3).
1H NMR (400 MHz, CDCl3): = 0.92 (t, 3 H, J = 6.87 Hz, CH3),
1.22–1.42 (m, 4 H, CH3CH2CH2), 1.76 (m, 2 H, CH3CH2CH2CH2),
3.60 (m, 1 H, CHNH), 3.87 (dd, 1 H, J = 12.63, 5.50 Hz, CHHSO2),
4.30 (ddd, 1 H, J = 12.37, 7.80, 3.02 Hz, CHHSO2), 5.45 (s, 1 H,
NH).
13C NMR (100 MHz, CDCl3): = 13.90 (CH3CH2CH2), 22.20
(CH3CH2CH2), 28.09 (CH3CH2CH2), 35.75 (CH3CH2CH2CH2),
40.92 (CHNH), 64.78 (CH2SO2).
IR (CHCl3): 3552, 3290, 3031, 2967, 2935, 2879, 2854, 1744, 1462,
1414, 1383, 1316, 1234, 1192, 1159, 1052, 981, 956, 927, 901, 793,
759, 665, 628, 505 cm–1.
1H NMR (300 MHz, CDCl3): = 0.97 (t, 3 H, J = 7.47 Hz, CH3),
1.80 (m, 2 H, CH3CH2), 3.57 (m, 1 H, NHCH), 3.87 (dd, 1 H,
J = 12.53, 5.50 Hz, CHHSO2), 4.30 (ddd, 1 H, J = 12.75, 7.69, 3.07
Hz, CHHSO2), 5.40 (s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 164 (2, [M+ + 1]), 122 (6), 106 (100), 70
(9), 67 (8), 57 (10), 56 (23), 55 (13).
13C NMR (75 MHz, CDCl3): = 10.07 (CH3), 29.03 (CH3CH2),
42.10 (CHNH), 64.34 (CH2SO2).
Anal. Calcd for C6H13NO2S (163.24): C, 44.15; H, 8.03; N, 8.58.
Found: C, 43.93; H, 8.00; N, 8.73.
MS (EI, 70 eV): m/z (%) = 135 (4) [M+], 106 (100), 56 (15).
HRMS: m/z calcd for C4H9NO2S (135.04, M+): 135.0354; found:
(S)-3-(2-Phenylethyl)-1,2-thiazetidine 1,1-Dioxide [(S)-9e]
Reaction of (S)-7e 0.191 g (0.5 mmol) with a solution of HBr in
HOAc and Et3N gave 0.058 g (55%) of pure (S)-9e; mp 95 °C;
[ ]D24 +3.6 (c = 1.0, CHCl3).
135.0354.
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

1866
D. Enders et al.
PAPER
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.
Hz, CHHCHSO2), 3.50 (m, 1 H, CHSO2), 3.97 (m, 1 H, CHNH),
4.79 (sept, 1 H, J = 4.12 Hz, CH, c-Hex), 5.12 (s, 2 H, CH2Ph), 5.27
(d, 1 H, J = 9.06 Hz, NH), 7.18–7.38 (m, 10 H, C6H5).
1H NMR (400 MHz, CDCl3): = 2.08 (m, 2 H, PhCH2CH2), 2.68
(m, 2 H, PhCH2CH2), 3.59 (m, 1 H, CHNH), 3.81 (dd, 1 H,
J = 12.64, 5.49 Hz, CHHSO2), 4.22 (ddd, 1 H, J = 12.63, 7.69, 3.30
Hz, CHHSO2), 5.50 (s, 1 H, NH), 7.13–7.32 (m, 5 H, C6H5).
13C NMR (100 MHz, CDCl3): = 32.69 (PhCH2CH2), 37.76
(PhCH2CH2), 40.80 (CHNH), 65.14 (CH2SO2), 126.77, 128.56,
128.98 (CH, Ph), 139.97 (C, Ph).
13C NMR (100 MHz, CDCl3): = 11.01 (CH3CH2), 23.39, 24.84,
26.73 (OCHCH2CH2CH2, CH3CH2), 32.68, 32.77 (OCHCH2),
33.19 (CH2CHSO2), 51.86 (CHNH), 66.43 (CHSO2), 66.82
(OCH2), 81.53 (OCH), 127.07, 128.01, 128.13, 128.51, 128.80,
129.25 (CH, Ph), 136.50, 137.13 (C, Ph), 156.27 (OCNH).
MS (EI, 70 eV): m/z (%) = 459 (1, [M+]), 304 (11), 297 (11), 296
(52), 295 (15), 266 (7), 222 (4), 205 (7), 192 (32), 148 (24), 145
(18), 143 (8), 108 (6), 107 (6), 92 (8), 91 (100), 55 (7).
MS (EI, 70 eV): m/z (%) = 211 (1, [M+]), 130 (100), 106 (32), 91
(44), 77 (12), 65 (12), 51 (7).
Anal. Calcd for C25H33NO5S (459.61): C, 65.32; H, 7.24; N, 3.05.
Found: C, 64.82; H, 7.31; N, 3.27.
Anal. Calcd for C10H13NO2S (211.28): C, 56.85; H, 6.20; N, 6.63.
Found: C, 56.58; H, 6.56; N, 6.22.
(R,R)-5-Benzyloxycarbonylamino-6-methylhept-1-en-4-cyclo-
hexyl Sulfonate [(R,R)-10c]
Reaction of (R)-6d (0.230 g, 0.6 mmol) and allyl iodide (0.403 g,
2.4 mmol) gave 0.231 g (89%) of pure (R,R)-10c.
-Alkylation of N-Cbz-Protected -Aminocyclohexyl Sulfonates
10a–g; General Procedure
-Aminocyclohexyl sulfonates 6 were dissolved in anhyd THF
(3 mL/mmol 6) and added to a solution of LDA (2.2 equiv) in anhyd
THF (10 mL/mmol 6) at –78 °C. The mixture was warmed up to
–45 °C and after 15 min cooled down to –78 °C. After 45 min at this
temperature, the corresponding electrophile (4.0 equiv) was added
slowly to the reaction mixture. The reaction was quenched after ca.
16 h at –78 °C with pH 7 buffer and the aqueous phase was extract-
ed with CH2Cl2 (3 × 30 mL/mmol 6). The combined organic layers
were washed with sat. aq NaHCO3 and NaCl solutions, dried
(MgSO4) and the solvent was removed under reduced pressure.
Products were purified by column chromatography (silica gel, n-
pentane–Et2O) to afford 10a–g as colorless oils.
IR (CHCl3): 3425, 3068, 3027, 2941, 2864, 1724, 1641, 1588, 1514,
1453, 1418, 1332, 1227, 1164, 1116, 1027, 1001, 924, 893, 866,
824, 756, 698, 666, 572, 547 cm–1.
1H NMR (400 MHz, CDCl3): = 0.97 (d, 3 H, J = 6.60 Hz, CH3),
0.99 (d, 3 H, J = 6.59 Hz, CH3), 1.20–2.00 (m, 10 H, CH2, c-Hex),
2.16 (m, 1 H, CH3CH), 2.47 (m, 1 H, CHCHHCH), 2.75 (m, 1 H,
CHCHHCH), 3.42, (dt, 1 H, J = 9.61, 3.30 Hz, CHSO2), 3.76 (dt, 1
H, J = 10.43, 2.47 Hz, CHNH), 4.81 (sep, 1 H, J = 4.12 Hz, CH, c-
Hex), 5.12 (d, 2 H, J = 5.49 Hz, CH2Ph), 5.14 (m, 2 H,
CH2CHCH2), 5.47 (d, 1 H, J = 10.32 Hz, NH), 5.82 (m, 1 H,
CH2CHCH2), 7.25–7.38 (m, 5 H, C6H5).
13C NMR (100 MHz, CDCl3): = 19.88, 20.29 [(CH3)2CH], 23.34,
24.79 (OCHCH2CH2CH2), 31.36 [(CH3)2CH], 32.29, 32.63, 32.80
(OCHCH2, CH2CHSO2), 56.48 (CHNH), 62.52 (CHSO2), 66.68
(OCH2), 81.02 (OCH), 119.41 (CH2CHCH2), 127.71, 127.84,
128.26 (CH, Ph), 132.82 (CH2CHCH2), 136.40 (C, Ph), 156.36
(OCNH).
MS (EI, 70 eV): m/z (%) = 423 (2, [M+]), 380 (19), 341 (13), 298
(18), 254 (64), 108 (7), 91 (100), 55 (9).
HRMS: m/z calcd for C22H33NO5S (423.21, M+): 423.2079; found:
423.2079.
(R,R)-3-Benzyloxycarbonylaminopentane-2-cyclohexyl Sul-
fonate [(R,R)-10a]
Reaction of (R)-6b (0.111 g, 0.3 mmol) and MeI (0.170 g,
1.2 mmol) gave 0.077 g (67%) of pure (R,R)-10a; [ ]D25 +24.3
(c = 0.7, CHCl3).
IR (CHCl3): 3367, 3032, 2939, 2862, 1720, 1522, 1454, 1339, 1283,
1235, 1169, 1091, 1029, 972, 928, 865, 825, 792, 753, 698, 634, 600
cm–1.
1H NMR (400 MHz, CDCl3): = 0.98 (t, 3 H, J = 7.41 Hz,
CH3CH2), 1.20–2.00 (m, 12 H, CH2, c-Hex, CH3CH2), 1.42 (d, 3 H,
J = 7.14 Hz, CH3CH), 3.44 (m, 1 H, CHSO2), 4.00 (m, 1 H, CHNH),
4.76 (sept, 1 H, J = 4.12 Hz, CH, c-Hex), 5.12 (d, 2 H, J = 1.65 Hz,
CH2Ph), 5.22 (d, 1 H, J = 9.34 Hz, NH), 7.28–7.40 (m, 5 H, C6H5).
(R,R)-5-Benzyloxycarbonylaminooct-1-en-4-cyclohexyl Sul-
fonate [(R,R)-10d]
Reaction of (R)-6c (0.115 g, 0.3 mmol) and allyl iodide (0.202 g,
1.2 mmol) gave 0.117 g (92%) of pure (R,R)-10d.
13C NMR (100 MHz, CDCl3):
= 11.04 (CH3CH2), 12.49
(CH3CH), 23.44, 24.86, 25.63 (OCHCH2CH2CH2, CH3CH2), 32.65,
32.78 (OCHCH2), 54.26 (CHNH), 59.48 (CHSO2), 66.85 (OCH2),
81.34 (OCH), 127.96, 128.15, 128.53 (CH, Ph), 136.39 (C, Ph),
156.36 (OCNH).
IR (CHCl3): 3422, 3375, 3066, 3032, 2937, 2863, 1722, 1641, 1515,
1453, 1335, 1252, 1224, 1167, 1108, 1054, 1025, 1002, 926, 865,
825, 754, 698, 603, 576 cm–1.
1H NMR (300 MHz, CDCl3): = 0.92 (t, 3 H, J = 7.18 Hz,
CH3CH2), 1.20–2.05 (m, 14 H, CH2 ,c-Hex, CH3CH2CH2,
CH3CH2CH2), 2.52 (m, 1 H, CHHCHSO2), 2.74 (m, 1 H,
CHHCHSO2), 3.27 (m, 1 H, CHSO2), 4.18 (m, 1 H, CHNH), 4.79
(sept, 1 H, J = 4.20 Hz, CH, c-Hex), 5.10 (s, 2 H, CH2Ph), 5.16 (m,
2 H, CH2CHCH2), 5.31 (d, 1 H, J = 9.15 Hz, NH), 5.79 (m, 1 H,
CH2CHCH2), 7.28–7.40 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): = 13.90 (CH3CH2), 19.96 (CH3CH2),
23.64, 25.10 (OCHCH2CH2CH2), 31.84 (CH2CHSO2), 32.99, 33.03
(OCHCH2), 35.89 (CH3CH2CH2), 50.46 (CHNH), 64.91 (CHSO2),
67.07 (OCH2), 81.66 (OCH), 119.45 (CH2CHCH2), 128.24, 128.38,
128.76 (CH, Ph), 133.65 (CH2CHCH2), 136.70 (C, Ph), 156.41
(OCNH).
MS (EI, 70 eV): m/z (%) = 383 (1, [M+]), 302 (7), 301 (42), 228
(19), 192 (5), 148 (15), 109 (7), 108 (91), 107 (14), 91 (100), 55 (7).
Anal. Calcd for C19H29NO5S (383.51): C, 59.51; H, 7.62; N, 3.65.
Found: C, 59.09; H, 7.56; N, 3.99.
(R,R)-3-Benzyloxycarbonylamino-1-phenylpentane-2-cyclo-
hexyl Sulfonate [(R,R)-10b]
Reaction of (R)-6b (0.111 g, 0.3 mmol) and benzyl bromide (0.205
g, 1.2 mmol) gave 0.109 g (79%) of pure (R,R)-10b.
IR (CHCl3): 3372, 3063, 3030, 2938, 2861, 1720, 1604, 1515, 1454,
1333, 1281, 1230, 1166, 1122, 1076, 1029, 1000, 971, 925, 865,
823, 790, 754, 699, 664, 634, 515 cm–1.
1H NMR (400 MHz, CDCl3): = 0.96 (t, 3 H, J = 7.42 Hz,
CH3CH2), 1.20–2.00 (m, 12 H, CH2, c-Hex, CH3CH2), 2.97 (dd, 1
H, J = 14.01, 9.61 Hz, CHHCHSO2), 3.34 (dd, 1 H, J = 14.28, 3.85
MS (EI, 70 eV): m/z (%) = 423 (4, [M+]), 341 (24), 298 (6), 260
(11), 254 (29), 234 (5), 206 (17), 162 (22), 109 (7), 108 (40), 92 (9),
91 (100), 83 (5), 82 (6), 67 (10), 55 (10).
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

PAPER
Asymetric Synthesis of Sulfonates, -Sultams and -Sultones
1867
Anal. Calcd for C22H33NO5S (423.57): C, 62.38; H, 7.85; N, 3.31.
Found: C, 62.82; H, 8.17; N, 3.55.
(d, 1 H, J = 9.89 Hz, NH), 5.77 (m, 1 H, CH2CHCH2), 7.15–7.37
(m, 10 H, C6H5).
13C NMR (100 MHz, CDCl3): = 23.33, 24.78 (OCHCH2CH2CH2),
31.55 (PhCH2CH2), 32.67, 32.62 (OCHCH2, CH2CHSO2), 35.23
(PhCH2CH2), 50.08 (CHNH), 64.60 (CHSO2), 66.80 (OCH2), 81.47
(OCH), 119.07 (CH2CHCH2), 125.86, 127.83, 127.98, 128.21,
128.24, 128.33, (CH, Ph), 132.99 (CH2CHCH2), 136.18, 140.68 (C,
Ph), 155.87 (OCNH).
MS (EI, 70 eV): m/z (%) = 485 (1, [M+]), 403 (5), 394 (8), 313 (5),
312 (30), 251 (12), 224 (6), 208 (15), 169 (58), 126 (6), 91 (100), 82
(11), 67 (12), 65 (5), 55 (15).
(R,R)-4-Benzyloxycarbonylaminoheptane-3-cyclohexyl Sul-
fonate [(R,R)-10e]
Reaction of (R)-6c (0.115 g, 0.3 mmol) and EtI (0.187 g, 1.2 mmol)
gave 0.103 g (83%) of pure (R,R)-10e; [ ]D25 +8.4 (c = 1.0, CHCl3).
IR (film): 3423, 3372, 3064, 3033, 2938, 2864, 1722, 1516, 1454,
1331, 1257, 1230, 1167, 1096, 1061, 1025, 1025, 1004, 927, 867,
823, 790, 777, 736, 699, 647, 604, 577, 457 cm–1.
1H NMR (400 MHz, CDCl3): = 0.93 (t, 3 H, J = 7.42 Hz,
CH3H2CH2), 1.10 (t, 3 H, J = 7.42 Hz, CH3CHCH2), 1.20–2.10 (m,
10 H, CH2, c-Hex), 3.12 (m, 1 H, CHSO2), 4.19 (m, 1 H, CHNH),
4.79 (sept, 1 H, J = 4.12 Hz, CH, c-Hex), 5.11 (s, 2 H, CH2Ph), 5.35
(d, 1 H, J = 9.89 Hz, NH), 7.25–7.38 (m, 5 H, C6H5).
Anal. Calcd for C27H35NO5S (485.64): C, 66.78; H, 7.26; N, 2.88.
Found: C, 66.30; H, 7.08; N, 3.21.
Sultones 12a,b; General Procedure
13C NMR (100 MHz, CDCl3): = 12.07, 13.67 (CH3CH2CH2,
CH3CH2CH), 19.79 (CH3CH2CH2), 20.67 (CH3CH2CH2), 23.38,
24.84 (OCHCH2CH2CH2), 32.74, 32.77 (OCHCH2), 35.88
(CH3CH2CH), 50.03 (CHNH), 66.56 (CHSO2), 66.72 (OCH2),
80.92 (OCH), 127.74, 127.90, 128.31 (CH, Ph), 136.23 (C, Ph),
156.11 (OCNH).
MS (EI, 70 eV): m/z (%) = 411 (1, [M+]), 330 (5), 329 (30), 286 (5),
242 (29), 206 (15), 162 (29), 136 (11), 119 (6), 108 (49), 107 (9), 91
(100), 55 (9).
N-Cbz-Protected -aminocyclohexyl sulfonate (R,R)-10f or (S,S)-
10g was dissolved in a mixture of EtOH (30 mL/mmol 10) and H2O
(1 mL/mmol 10) and refluxed for 4 h. After cooling to r.t., NaOAc
(1.1 equiv) was added and the solution was stirred for 1 h. The sol-
vents were removed under reduced pressure and the crude sodium
salts were dissolved in anhyd THF (6 mL/mmol 10) and cooled to
–78 °C. Iodine (3.0 equiv) was added and the reaction mixture was
stirred overnight while it warmed up to r.t. Then the solution was di-
luted with CH2Cl2, washed with sat. aq NaHCO3 and 10% Na2S2O3
solution and dried (MgSO4). Products were purified by column
chromatography (silica gel, n-pentane–Et2O) to afford 12a,b as col-
orless solids.
Anal. Calcd for C21H33NO5S (411.56): C, 61.29; H, 8.08; N, 3.43.
Found: C, 60.94; H, 8.38; N, 3.55.
(S,R,R)-[1-(5-Iodomethyl-2,2-dioxo-2 6-[1,2]oxathiolan-3-yl)-2-
methylpropyl]carbamic Acid Benzyl Ester [(S,R,R)-12a]
Reaction of (R,R)-10f (0.191 g, 0.45 mmol) and I2 (0.342 g,
1.35 mmol) gave 0.162 g (77%) of pure (S,R,R)-12a; [ ]D25 –27.7
(c = 1.0, CHCl3).
(R,R)-5-Benzyloxycarbonylamino-2-methylhept-1-en-4-cyclo-
hexyl Sulfonate [(R,R)-10f]
Reaction of (R)-6b (0.296 g, 0.8 mmol) and 2-methylprop-2-ene
bromide (0.432 g, 3.2 mmol) gave 0.295 g (87%) of pure (R,R)-10f.
IR (film): 3420, 3373, 3071, 3034, 2939, 2863, 1721, 1651, 1516,
1453, 1333, 1276, 1230, 1166, 1123, 1087, 1051, 1031, 976, 925,
866, 824, 776, 740, 699, 522 cm–1.
1H NMR (300 MHz, CDCl3): = 0.96 (t, 3 H, J = 7.42 Hz,
CH3CH2), 1.20–2.00 (m, 12 H, CH3CH2, CH2, c-Hex), 1.72 (s, 3 H,
CCH3), 2.51 (dd, 1 H, J = 14.34, 9.89 Hz, CHHCHSO2), 2.63 (dd,
J = 14.59, 3.71 Hz, 1 H, CHHCHSO2), 3.43 (m, 1 H, CHSO2), 4.05
(m, 1 H, CHNH), 4.79 (sept, J = 4.21 Hz, 1 H, CH, c-Hex), 4.89 (d,
2 H, J = 16.82 Hz, CCH2), 5.10 (s, 2 H, CH2Ph), 5.35 (d, 1 H,
J = 9.64 Hz, NH), 7.29–7.37 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): = 11.10 (CH3CH2), 21.69 (CH3C),
23.38, 24.87 (OCHCH2CH2CH2), 26.33 (CH3CH2), 32.78, 32.72
(OCHCH2), 35.08 (CH2CHSO2), 52.15 (CHNH), 62.12 (CHSO2),
66.75 (OCH2), 81.33 (OCH), 115.04 (CCH2), 128.01, 128.09,
128.48 (CH, Ph), 136.55 (C, Ph), 140.10 (CH3C), 156.21 (OCNH).
IR (film): 3340, 3287, 3030, 2965, 2933, 1695, 1530, 1453, 1371,
1336, 1289, 1263, 1169, 1108, 1089, 1061, 1010, 976, 871, 838,
779, 754, 700, 600 cm–1.
1H NMR (400 MHz, CDCl3): = 1.01 (d, 3 H, J = 6.59 Hz, CH3),
1.11 (d, 3 H, J = 6.59 Hz, CH3), 2.14 (m, 2 H, CH3CH
CHHCHSO2), 2.78 (m, 1 H, CHHCHSO2), 3.19 (dd, 1 H,
J = 10.16, 8.24 Hz, CHHI), 3.19 (dd, 1 H, J = 10.16, 4.95 Hz,
CHHI), 3.83 (m, 2 H, CHNH, CHSO2), 4.60 (m, 1 H, CHCH2I),
5.14 (d, 2 H, J = 7.69 Hz, CH2Ph), 5.44 (d, 1 H, J = 10.44 Hz, NH),
7.32–7.39 (m, 5 H, C6H5).
13C NMR (100 MHz, CDCl3): = 3.47 (CHCH2I), 19.51, 20.17
[(CH3)2CH], 31.36 [(CH3)2CH], 34.30 (CH2CHSO2), 55.88,
(CHNH), 59.92 (CHSO2), 67.09 (CH2O), 78.14 (SOCHCH2I),
127.86, 128.10, 128.40 (CH, Ph), 136.02 (C, Ph), 156.50 (OCNH).
MS (EI, 70 eV): m/z (%) = 423 (1, [M+]), 260 (24), 216 (6), 206
(10), 192 (5), 148 (9), 108 (12), 107 (12), 91 (100), 55 (10).
MS (EI, 70 eV): m/z (%) = 467 (19, [M+]), 424 (6), 380 (22), 108
(49), 91 (100), 65 (6).
Anal. Calcd for C22H33NO5S (423.57): C, 62.38; H, 7.85; N, 3.31.
Found: C, 62.18; H, 7.62; N, 3.66.
Anal. Calcd for C16H22INO5S (467.32): C, 41.12; H, 4.74; N, 3.00.
Found: C, 41.34; H, 5.22; N, 2.84.
(R,S,S)-[1-(5-Iodomethyl-2,2-dioxo-2 6-[1,2]oxathiolan-3-yl)-3-
phenylpropyl]carbamic Acid Benzyl Ester [(R,S,S)-12b]
Reaction of (S,S)-10g (0.146 g, 0.3 mmol) and I2 (0.229 g,
0.9 mmol) gave 0.121 g (76%) of pure (R,S,S)-12b; [ ]D22 +12.2
(c = 1.0, CHCl3).
(S,S)-5-Benzyloxycarbonylamino-7-phenylhept-1-en-4-cyclo-
hexyl Sulfonate [(S,S)-10g]
Reaction of (S)-6k (0.267 g, 0.6 mmol) and allyl iodide (0.404 g,
2.4 mmol) gave 0.251 g (86%) of pure (S,S)-10g.
IR (CHCl3): 3421, 3063, 3632, 3027, 2939, 2861, 1720, 1513, 1452,
1334, 1234, 1165, 1031, 1001, 924, 893, 866, 826, 756, 699, 667
cm–1.
1H NMR (400 MHz, CDCl3): = 1.20–2.13 (m, 12 H CH2, c-Hex,
PhCH2CH2), 2.45–2.77 (m, 4 H, PhCH2CH2, CH2CHSO2), 3.27 (m,
1 H, CHSO2), 4.23 (m, 1 H, CHNH), 4.76 (sept, 1 H, J = 4.70 Hz,
CH, c-Hex), 5.12 (s, 2 H, CH2Ph), 5.14 (m, 2 H, CH2CHCH2), 5.40
IR (film): 3337, 3061, 3029, 2931, 2861, 1695, 1533, 1498, 1451,
1343, 1281, 1263, 1244, 1214, 1161, 1066, 973, 853, 780, 739, 698,
603, 474 cm–1.
1H NMR (400 MHz, CDCl3): = 2.10 (m, 3 H, PhCH2CH2,
CHHCHSO2), 2.70 (m, 3 H, PhCH2CH2, CHHCHSO2), 3.15 (dd, 1
H, J = 10.39, 8.16 Hz, CHHI), 3.38 (dd, 1 H, J = 10.39, 5.19 Hz,
Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York

1868
D. Enders et al.
PAPER
CHHI), 3.68 (m, 1 H, CHSO2), 4.06 (sept, 1 H, J = 5.19 Hz,
CHNH), 4.54 (m, 1 H, CHCH2I), 5.14 (d, 2 H, J = 4.94 Hz, CH2Ph),
5.51 (d, 1 H, J = 10.14 Hz, NH), 7.08–7.40 (m, 10 H, C6H5).
13C NMR (100 MHz, CDCl3): = 3.55 (CHCH2I), 32.31, 33.94,
34.81 (CH2CHSO2, PhCH2CH2), 49.50 (CHNH), 62.27 (CHSO2),
67.18 (CH2O), 78.20 (SOCHCH2I), 126.34, 128.09, 128.34, 128.41,
128.45, 128.60 (CH, Ph), 136.17, 140.25 (C, Ph), 156.36 (OCNH).
(13) (a) Metz, P. J. Prakt. Chem. 1998, 340, 1. (b) Buglass, A.
J.; Tillet, J. G. The Chemistry of Sulfonic Acids, Esters and
their Derivatives; Patai, S.; Rappoport, Z., Eds.; Wiley:
Chichester, 1991, Chap. 19. (c) Roberts, D. W.; Williams,
D. L. Tetrahedron 1987, 43, 1027.
(14) Berre, A.; Etienne, A.; Dumaitre, B. Bull. Soc. Chim. Fr.
1970, 946.
(15) (a) Meyle, E.; Keller, E.; Otto, H. H. Liebigs Ann. 1985,
802. (b) Wilken, J.; Thorey, C.; Gröger, H.; Haase, D.; Saak,
W.; Pohl, S.; Muzart, J.; Martens, J. Liebigs Ann./Recl. 1997,
2133. (c) King, J. F.; Loosmore, S. M.; Aslam, M.; Lock, J.
D.; McGarrity, M. J. J. Am. Chem. Soc. 1982, 104, 7108.
(d) Berre, A.; Delacroix, A.; Gressin, J. C.; Masson, J. C.
Bull. Soc. Chim. Fr. 1976, 1845. (e) Liskamp, R. M. J.;
Ameijde, J. Tetrahedron Lett. 2000, 41, 1103. (f) Makara,
G. M.; Ma, Y. Tetrahedron Lett. 2001, 42, 4123.
(16) (a) Enders, D. In Asymmetric Synthesis, Vol. 3; Morrison, J.
D., Ed.; Academic Press: Orlando, 1984, 275. (b) Enders,
D.; Fey, P.; Kipphardt, H. Org Synth. 1987, 65, 173.
(c) Enders, D.; Fey, P.; Kipphardt, H. Org Synth. 1987, 65,
183. (d) Review: Job, A.; Janeck, C. F.; Bettray, W.; Peters,
R.; Enders, D. Tetrahedron 2002, 58, 2253.
MS (EI, 70 eV): m/z (%) = 529 (3, [M+]), 439 (14), 438 (78), 421
(8), 377 (7), 333 (36), 295 (32), 290 (21), 289 (11), 168 (21), 167
(15), 108 (18), 107 (11), 105 (5), 91 (100), 79 (15), 77 (8), 65 (8).
Anal. Calcd for C21H24INO5S (529.39): C ,47.65; H, 4.57; N, 2.65.
Found: C, 48.15; H, 4.93; N, 2.50.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380) and the Fonds der Chemischen Industrie. We thank De-
gussa AG, BASF AG, Bayer AG and Aventis Pharma for donation
of chemicals.
(17) Martens, J.; Lübben, S. Liebigs Ann. 1990, 949.
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Masamune, S.; Roush, W. R.; Skai, T. Tetrahedron Lett.
1984, 25, 2183.
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Synthesis 2003, No. 12, 1856–1868 © Thieme Stuttgart · New York