Lewis acid/base catalyzed [2+2]-cycloaddition of sulfenes and aldehydes: A versatile entry to chiral sulfonyl and sulfinyl derivatives

Article abstract of DOI:10.1002/chem.201003542

The first catalytic asymmetric synthesis of β-sultones is reported. This development has enabled a rapid access to a number of highly enantioenriched biologically interesting sulfonyl and sulfinyl compound classes, which makes use of the inherent ring strain of the four-membered heterocycles. The products possess either two vicinal stereocenters, such as in β-hydroxy-sulfonamides, -sulfonates, -sulfones, -sulfonic acids, -sulfinic acids, γ-sultines, and γ-sultones or a single stereocenter, such as in α-branched alkyl or allyl sulfonic acids. This work also represents the first application of sulfene intermediates in asymmetric catalysis. The reactivity of a sulfene normally acting as an electrophile could be reverted by the formation of a nucleophilic zwitterionic sulfene-amine adduct. To achieve a combination of high enantioselectivity and reactivity, cooperative catalytic action of a chiral nucleophilic tertiary amine (the cinchona alkaloid derivative diydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)₂PYR)) and Bi(OTf)₃ or In(OTf)₃ was of primary importance.

Full text of DOI:10.1002/chem.201003542

FULL PAPER
DOI: 10.1002/chem.201003542
Lewis Acid/Base Catalyzed [2+2]-Cycloaddition of Sulfenes and Aldehydes:
A Versatile Entry to Chiral Sulfonyl and Sulfinyl Derivatives
Florian M. Koch[b] and Renꢀ Peters*[a, b]
Dedicated to Professor Dieter Enders on the occasion of his 65th birthday
Abstract: The first catalytic asymmetric
synthesis of b-sultones is reported. This
sultines, and g-sultones or a single ste-
reocenter, such as in a-branched alkyl
or allyl sulfonic acids. This work also
represents the first application of sul-
fene intermediates in asymmetric catal-
ysis. The reactivity of a sulfene normal-
ly acting as an electrophile could be re-
verted by the formation of a nucleo-
philic zwitterionic sulfene–amine
development has enabled
a
rapid
adduct. To achieve a combination of
high enantioselectivity and reactivity,
cooperative catalytic action of a chiral
nucleophilic tertiary amine (the cincho-
na alkaloid derivative diydroquinine
2,5-diphenyl-4,6-pyrimidinediyl diether
access to a number of highly enan-
tioenriched biologically interesting sul-
fonyl and sulfinyl compound classes,
which makes use of the inherent ring
strain of the four-membered heterocy-
cles. The products possess either two
vicinal stereocenters, such as in b-hy-
droxy-sulfonamides, -sulfonates, -sul-
fones, -sulfonic acids, -sulfinic acids, g-
((DHQ)2PYR)) and Bi
ACHTUNGRTENN(UNG OTf)3 or In-
Keywords: carbanions
· coopera-
AHCTUNGERTG(NNUN OTf)3 was of primary importance.
tive catalysis · heterocycles · ring
strain · zwitterions
Introduction
tides, enzymes, or receptors, and 4) the SO2 function can de-
crease the basicity of amino moieties in neighboring posi-
tions to a physiologically acceptable value.[9] Consequently,
several chiral sulfonyl derivatives have been licensed by the
FDA, such as the sulfones dorzolamide (Merck, carbonic an-
hydrase inhibitor), tazobactam (Wyeth, b-lactamase inhibi-
tor), bicalutamide (Astra Zeneca, nonsteroidal antiandro-
gen), or the sulfonamide argatroban (Mitsubishi, anticoagu-
lant).
Sulfenes 1 (systematic name: thioaldehyde S,S-dioxides)[1]
are sulfonyl equivalents of ketenes. In contrast to ketenes,[2]
the use of sulfenes in asymmet-
ric catalysis has not been de-
scribed.[3] This may be partly at-
tributed to the intrinsic instabil-
ity of sulfenes 1 (R1 =H, alkyl,
aryl). Although their existence
For the pharmacological importance of chiral sulfonyl de-
rivatives we became interested in b-sultones 2 (systematic
name: 1,2-oxathietane 2,2-dioxide) as a potential rapid and
divergent entry to different classes of chiral enantioenriched
sulfonyl derivatives. b-Sultones are reactive sulfonyl ana-
logues of b-lactones.[10] In contrast to the latter compounds,
they have been rarely investigated despite their prospective
value as synthetic building blocks.[11] As a result of their in-
herent ring strain, b-sultones are prone to nucleophilic ring-
opening reactions under mild conditions providing either b-
substituted sulfonic acids or b-hydroxy sulfonyl deriva-
tives.[12] The evolution of such ring-opening strategies has so
far been limited by the number of accessible b-sultones 2,
because most b-sultones have been reported to be unstable
at room temperature due to the occurrence of proton shift,
elimination, and rearrangement reactions.[13] b-Sultones con-
taining an a-CH2 moiety have been reported to be particu-
larly unstable due to thermal decomposition. They were
often found to rearrange yielding complex mixtures of iso-
meric unsaturated sulfonic acids and g- and d-sultones.[14]
More stable derivatives are those holding an electron-with-
drawing and sterically demanding CCl3 group at the 4-posi-
was spectroscopically demon-
strated at low temperature,[4]
they cannot be isolated due to rapid di- or oligomeriza-
tion.[5,6]
The use of sulfenes for asymmetric catalysis might offer a
versatile synthetic access to scalemic sulfonyl derivatives.[7]
Sulfonyl analogues of carbonyl derivatives are of increasing
importance in medicinal chemistry,[8] because 1) they mimic
the structural properties of tetrahedral intermediates,
2) they often provide high solubility in water, 3) they act as
hydrogen-bond acceptors to interact, for example, with pep-
[a] Prof. Dr. R. Peters
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
Fax : (+49)711-685-54330
E-mail: rene.peters@oc.uni-stuttgart.de
[b] Dr. F. M. Koch, Prof. Dr. R. Peters
ETH Zꢀrich, Laboratory of Organic Chemistry
Wolfgang-Pauli-Str. 10, 8093 Zꢀrich (Switzerland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003542.
Chem. Eur. J. 2011, 17, 3679 – 3692
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3679

ꢀ
Table 1. Investigation of various sterically hindered tertiary amine bases
and solvents in the model reaction of methane- and ethanesulfonyl chlo-
ride (3a/b) with chloral (6a).[a]
tion, which significantly stabilizes the otherwise labile C O
bond.
Already in 1966, the Bayer AG reported that b-sultones
are accessible by a [2+2]-cycloaddition route that utilized
the parent sulfene (R1 =H in 1) as a reactive intermedi-
ate.[15] 10 years later, King and Harding discovered that b-
sultone formation is improved by a large excess of a sterical-
ly nonhindered tertiary amine, such as NMe3.[16] This was at-
tributed to the reversible formation of a reactive zwitterion-
ic intermediate[17,5] from sulfenes and tertiary amines, which
undergoes a cyclocondensation reaction with strongly polar-
ized carbonyl groups.
Based on these findings, we hoped that it should be possi-
ble to conduct b-sultone formation enantioselectively by the
action of a catalytic amount of a scalemic nucleophile 4,
which is regenerated during an internal esterification step
for further turnover (Scheme 1). The reactivity of a sulfene
normally acting as an electrophile would thus be reverted by
the formation of a nucleophilic zwitterion 5.[18]
R1 =
2
Base
Solvent
Yield [%][b]
d.r.[b]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
H
H
H
H
H
2b
2b
2b
2b
2b
2b
2a
2a
2a
2a
2a
2a
2a
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
PMP
THF
22
11
5
4
8
1
15
9
9
4
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
–
–
–
–
–
–
–
toluene
CH2Cl2
Et2O
THF
PMP
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
iPr2NEt
Cy2NEt
tBu(Me)NiPr
PMP
PS
DBU
9
10
11
12
13
0
0
0
H
H
iBu
N
[a] Conditions: 1.1 equiv 3a/b, concentration (6a): 0.17m, addition time
of 3a/b: 0.5 h, additional reaction time: 3 h. [b] Determined by 1H NMR
spectroscopy of the product after aqueous workup with acetophenone as
the internal standard.
in THF and toluene (Table 1, entries 1–2), whereas the use
of CH2Cl2 and Et2O (entries 3–4) could reduce the amount
of product formed. 1,2,2,6,6-Pentamethylpiperidine (PMP)
also resulted in lower product quantities (entries 5–6). Con-
version of the sulfonyl chloride and formation of the hydro-
Scheme 1. Proposed asymmetric formation of b-sultones catalyzed by
enantiopure nucleophiles.
1
chloride salt of the base (as determined by H NMR spec-
troscopic studies) pointed to the generation of methylsul-
fene with these bulky bases. Methanesulfonyl chloride (3a)
was more reactive in CH2Cl2 than ethanesulfonyl chloride
(3b, compare entries 3 and 7 or 6 and 10). Also in that case,
PMP leads to deprotonation of the sulfonyl chloride, where-
as only little cycloaddition product is formed. Proton sponge
(PS, 1,8-bis(dimethylamino)naphthalene) and DBU (1,8-
In this full paper, we describe the detailed development
of a catalytic asymmetric method to prepare highly enan-
tioenriched b-sultones 2 via sulfene intermediates 1[3] and
demonstrate that b-sultones are versatile building blocks for
the rapid preparation of a variety of chiral highly enantioen-
riched sulfonyl or sulfinyl compound classes.
diazabicycloACTHNUGTRNEUNG[5.4.0]undec-7-en) gave no b-sultone at all (en-
tries 11–12), as they did not depronate 3a and are thus not
useful as an achiral auxiliary base.
Results and Discussion
Product formation by using bulky bases was not expected,
because King and Harding had reported that nBu3N in Et2O
is already too hindered to initiate b-sultone formation. Since
formation of a zwitterionic sulfene amine adduct 5 does not
appear to be a very likely scenario with sterically demanding
bases, such as PMP, alternative reaction pathways might
lead to product formation, such as hydrogen-bond activation
of the aldehyde 6 by the generated ammonium species
HNR3 triggering a [2+2]-cycloaddition with 1 or formation
of a carbanion by chloride attack on the sulfene intermedi-
ate.
With 3b and an excess of quinuclidine as a sterically less
demanding nucleophile, racemic b-sultone 2b was isolated
in 91% yield (Table 2, entry 3). The monosubstituted 2a
was formed in lower yield (entry 1), which might reflect the
lower product stability relative to disubstituted b-sultones.
Catalytic nonenantioselective b-sultone formation: Due to
the stability issue we focused on the formation of b-sultones
bearing an electron-withdrawing group at the 4-position. In
our model studies, methane- (3a) and ethanesulfonyl chlo-
ride (3b) were reacted with chloral (6a). To minimize sul-
fene di-/oligomerization, the sulfonyl chlorides were slowly
added by means of a syringe pump to the reaction mixture
at low temperature (ꢀ158C). The reactivity of sterically de-
manding tertiary amine bases in combination with different
solvents was studied first (Table 1). In view of the final goal
to develop an asymmetric procedure, a nucleophilic amine
Nu* 4 would ideally catalyze the process, whereas a non-nu-
cleophilic amine NR3 would generate the sulfene intermedi-
ate. However, even the non-nucleophilic Hꢀnigꢃs base
(iPr2NEt) resulted in significant product formation with 3b
+
3680
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3679 – 3692

Chiral Sulfonyl and Sulfinyl Derivatives
FULL PAPER
Table 2. Investigation of achiral nucleophilic tertiary amine bases.[a]
The poor enantioselectivities
observed might be surprising at
first sight given the high ee
values obtained in the forma-
tion of b-lactones via ketene-
derived zwitterionic enolates.
However, fundamental structur-
al differences between the an-
ticipated sulfene–amine adducts
5 and ketene-derived zwitter-
ionic enolates 7 as reactive in-
R1 =
2
Nucleophilic base [equiv]
Auxiliary base [equiv]
Yield [%][b]
d.r.[b]
1
2
3
H
a
b
b
b
b
c
c
c
d
d
d
e
e
e
f
quinuclidine (1.05)
DABCO (1.05)
quinuclidine (1.05)
quinuclidine (0.10)
DABCO (0.20)
quinuclidine (1.45)
quinuclidine (0.10)
DABCO (0.20)
quinuclidine (1.45)
quinuclidine (0.10)
DABCO (0.20)
quinuclidine (1.45)
quinuclidine (0.10)
DABCO (0.20)
quinuclidine (1.45)
quinuclidine (0.10)
DABCO (0.20)
–
–
–
35
49
91
78
80
82
79
31
51
48
64
64
58
51
87
71
32
–
Me
Me
Me
Me
Et
>100:1
40:1
4[c]
5[c]
6
iPr2NEt (1.45)
NEt3 (1.45)
–
iPr2NEt (1.45)
NEt3 (1.45)
–
iPr2NEt (1.45)
NEt3 (1.45)
–
iPr2NEt (1.45)
NEt3 (1.45)
–
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
11:1
>50:1
>50:1
90:1
50:1
>100:1
termediates
are
expected
(Scheme 2). Whereas in the
case of 7, both enolate C atoms
are sp2-hybridized, the S atom
in 5 and presumably also the a-
C atom are pyramidalized, in
analogy to the majority of sul-
fone carbanions bearing one
alkyl group at the a-C atom as
the only substituent.[20–22] This
implies that diastereomeric
zwitterionic species (5A and
5A’) are formed, whereas in
the ketene case the cinchona al-
kaloid is supposed to bind se-
7[c]
8[c]
9
Et
Et
nPr
nPr
nPr
Cl
Cl
Cl
Bn
Bn
Bn
10[c]
11[c]
12
G
13[c]
14[c]
15
E
ACHTUNGTRENNUNG
16[c]
17[c]
f
f
iPr2NEt (1.45)
NEt3 (1.45)
[a] Conditions: 1.1 equiv 3, scale: 0.67 mmol 6a, concentration (6a): 0.17m, addition time of 3: 2.5 h, additional
reaction time: 15 min. [b] Yield of isolated product. [c] Scale: 61.5 mmol 6a, concentration (6a): 0.51m.
With increasing size of the sulfonyl chloride, the reactivity
somewhat decreased (entries 6, 9, and 12). Notably, a pri-
mary chloride in R1 was well tolerated in the presence of
the nucleophilic base (entry 12).
The use of catalytic amounts of quinuclidine in combina-
tion with iPr2NEt as an auxiliary base resulted in only slight-
ly lower yields in most cases and excellent diastereoselectivi-
ties (Table 2, entries 4, 7, 10, 13, and 16). To prepare the rac-
emic diastereomerically almost pure products on a larger
scale (61.5 mmol chloral), quinuclidine and iPr2NEt can also
be replaced with the more cost-efficient 1,4-diazabicyclo-
lectively trans to the residue R in 7 to minimize unfavorable
steric interactions.[2] The absolute configuration of the b-sul-
tone products 2 primarily depends on the reactive configura-
tion of the zwitterion at the a-position. Compounds 5A and
5A’ are diastereomeric species, even if their a-C atom is
planar (planar chirality, expected for aromatic residues R1),
due to the existence of favored Ca–S conformations whereby
the lone pair at the a-C atom should be arranged gauche to
both sulfonyl oxygen atoms as a result of a stabilizing nC–
s*SN interaction leading to a hindered Ca–S rotation. This
would be in analogy to nC–s*SR interactions, which are
known to stabilize sulfone carbanions.[23] The strength of
these interactions increases with the electron-withdrawing
character of the S-substituent and should thus play a major
role in the present case of a sulfonylammonium species. We
ACHTUNGTRENNUNG[2.2.2]octane (DABCO; 20 mol%) and NEt3 (entries 5, 8,
11, 14, and 17). An important factor during scale-up is effi-
cient stirring of the suspension at an increased concentration
(0.51 rather than 0.17m).
ꢀ
assume a staggered conformation around the S N bond, in
Cinchona alkaloid catalyzed b-sultone formation: The trans-
fer to chiral quinuclidine organocatalysts[19]—cinchona alka-
loid derivatives—turned out to be a nontrivial task. With
10 mol% of various quinine derivatives in combination with
PMP as the stoichiometric base in CH2Cl2 at ꢀ158C, the dis-
ubstituted b-sultone 2b was usually formed in low yield
(Table 3, entries 1–6) and with almost no enantioselectivity
(eeꢁ11%). A better yield was obtained with the more rigid
b-ICD (entry 7), but also in this case nearly racemic product
was formed. A lack of enantioselectivity was also noticed
with methanesulfonyl chloride (3a, entries 8–11). On the
other hand, the reactivity was higher in that case (compare
entries 1 and 9 or 2 and 10) with the exception of b-ICD
(compare entries 7 and 11).
which the R1HCꢀ moiety should be positioned in a way so
as to reduce repulsive interactions with the catalyst back-
bone. This requires that the sterically more hindered posi-
tions would be adopted by the sulfonyl oxygen atoms. How-
ever, in both diastereomers 5A and 5A’ there would be one
unfavorable double-gauche pentane interaction of R1 with a
ꢀ
N C bond of the quinuclidine core explaining why none of
them is strongly preferred as the reactive species and enan-
tioselectivity is low.
Lewis acid/base catalyzed enantioselective b-sultone forma-
tion: To enhance the reactivity of the catalytic system, the
effect of activation by Lewis acid co-catalysts was investigat-
ed. Initial experiments in the presence of 20 mol% of Sc-
AHCTUNGRTEG(NNUN OTf)3 revealed that both yield and ee values were improved
Chem. Eur. J. 2011, 17, 3679 – 3692
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3681

R. Peters and F. M. Koch
Table 3. Investigation of various cinchona alkaloid derivatives as nucleo-
philic catalysts.[a]
Scheme 2. Comparison of the expected structure of the proposed sulfene
zwitterions 5A/5A’ with the ketene derived enolate 7. The antiperiplanar
ꢀ
orientation of the N S bond and the nonbonding orbital at the a-C atom
is favored for stereoelectronic reasons.
Table 4. Investigation of a cooperative Lewis acid/base activation.[a]
Mn+
NR3*
Yield [%][b]
ee [%][c]
d.r.[b]
10:1
51:1
>100:1
23:1
1[d]
2
3
ScIII
ScIII
ScIII
ScIII
ScIII
ScIII
ScIII
LiI
BQd
BnQ
MeQ
TMSQ
T
10
26
12
26
9
41
19
7
ꢀ35
20
24
40
15
4
5[d]
6[d]
7
8
9
26:1
28:1
22:1
60:1
R1 =
NR3*
Yield [%][b]
ee [%][c]
d.r.[b]
N
51
ꢀ14
ꢀ2
ꢀ6
50
55
62
39
70
59
17
ꢀ6
ꢀ7
ꢀ5
ꢀ3
ꢀ2
31
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
H
BQd
BnQ
MeQ
TMSQ
G
0
1
8
2
4
23
61
9
36
48
19
–
–
N
n.d.
11
n.d.
n.d.
6
9
0
0
9
>50:1
>100:1
>50:1
>50:1
>50:1
>100:1
–
MgII
SnII
R
9
>100:1
79:1
59:1
>100:1
66:1
>100:1
74:1
>100:1
>100:1
>100:1
38:1
>100:1
>100:1
87:1
>100:1
>100:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
E
47
33
25
27
45
57
16
9
CuII
ZnII
AlIII
InIII
N
N
A
R
b-ICD
BQ
BQd
BnQ
b-ICD
N
BiIII
YIII
G
9
10
11
H
H
H
–
–
–
N
NdIII
SmIII
EuIII
GdIII
ErIII
YbIII
Me3SiIV
ZrIV
N
0
N
6
8
[a] Conditions: 1.1 equiv 3a/b, concentration (6a): 0.17m, addition time
of 3b: 2 h, additional reaction time: 2 h. [b] Determined by 1H NMR
spectroscopy of the product after aqueous workup with acetophenone as
the internal standard. [c] Determined by HPLC analysis.
E
G
12
14
26
18
31
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
N
21
39
N
[a] Conditions: 1.1 equiv 3b, concentration (6a): 0.17m, addition time of
3b: 2.5 h, additional reaction time: 1 h. [b] Determined by H NMR spec-
troscopy of the product after aqueous workup with acetophenone as the
internal standard. [c] Determined by HPLC analysis. Negative ee values
should indicate the formation of (ent)-2b as the major enantiomer.
[d] 1.21 equiv of PMP were used.
1
(Table 4, entries 1–6). BnQ, for example, which gave almost
no product in the absence of a Lewis acid (Table 3, entry 2),
provided 2b in a yield of 26% (Table 4, entry 2). The best
yield (41%) and enantioselectivity (ee=51%) was found
with diydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether
((DHQ)2PYR;[24] Table 4, entry 6).[25] A screening of various
Lewis acids (entries 8–24) in the presence of this chiral nu-
cleophile revealed that most metal triflate salts, for example,
were thus selected as the most promising co-catalysts for
further studies.
those of LiI, MgII, CuII, ZnII, AlIII, YIII, lanthanides
(III),
A final optimization of the reaction conditions (stoichi-
ometry, temperature, co-catalyst amount) was performed
with propanesulfonyl chloride (3c), which was found to
permit higher enantioselectivity relative to ethanesulfonyl
chloride (3b), but was also less reactive (compare Table 5,
Me3SiIV, or ZrIV resulted in a decreased reactivity, whereas a
few, namely SnII (entry 10), InIII (best ee value, entry 14),
and BiIII (best yield, entry 15) improved the product forma-
tion. The latter two also improved the enantioselectivity and
3682
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Chem. Eur. J. 2011, 17, 3679 – 3692

Chiral Sulfonyl and Sulfinyl Derivatives
FULL PAPER
Table 5. Optimization of the reaction conditions with propanesulfonyl
Table 6. Investigation of the effect of BiACTHNGUTERNNUG
(OTf)3 activation.[a]
chloride (3c).[a]
x mol%
Bi(OTf)3
Tactivation Bi [8C]
ACTUHGTNNRE(NUG OTf)3
Yield
[%][b]
ee
d.r.[b]
M
equiv M
equiv 3c
G
T
Yield
ee
d.r.[b]
G
[%][c]
[8C] [%][b] [%][c]
1
2
3
4
5
18
18
36
36
36
140
–
140
120
100
51
7
65
36
32
85
88
92
95
84
>100:1
>100:1
>100:1
>100:1
>100:1
1
2
3
4
5
6
7
8
9
Bi 0.18
In 0.18
Bi 0.18
Bi 0.18
In 0.18
Bi 0.18
Bi 0.18
Bi 0.18
Bi 0.18
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
ꢀ15
4
39
36
42
51
28
36
36
36
23
27
26
65
40
90
97
85
85
94
90
87
88
90
85
89
92
74
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
>100:1
[a] Conditions: 2.75 equiv 6a, concentration (6a): 0.34m, addition time of
3c: 2.5 h, additional reaction time: 15 min. [b] Determined by 1H NMR
spectroscopy of the product after aqueous workup with acetophenone as
the internal standard. [c] Determined by HPLC analysis.
10 Bi 0.18
11 Bi 0.18
12 Bi 0.36
13 In 0.36
ꢀ40
ꢀ15
ꢀ15
Table 7. Scope of the title reaction.[a]
[a] Conditions: concentration (6a): 0.34m, addition time of 3c: 2.5 h, ad-
ditional reaction time: 15 min. [b] Determined by 1H NMR spectroscopy
of the product after aqueous workup with acetophenone as the internal
standard. [c] Determined by HPLC analysis.
Entry R1
R2
Product Bi Yield d.r.[c]
ee
or [%][b]
In
[%][d]
entries 1–2 with Table 4, entries 14–15). In the case of Bi-
ACHTUNGTRENNUNG
1[e,f]
2[e,f]
3
Me
Me
Et
Et
Pr
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
2b
2b
2c
2c
2d
2d
2e
2e
2 f
2 f
2g
2g
2a
2a
Bi
In
Bi
In
Bi
In
Bi
In
Bi
In
Bi
In
Bi
In
Bi
In
Zn
78
61
65
29
47
36
87
58
60
57
83
69
82
36
52
62
23
96:1
>100:1
>100:1
>100:1
>50:1
>50:1
>50:1
15:1
22:1
12:1
>100:1 >99
>100:1 >99
67
78
92
97
83
89
95
81
91
84
ACHTUNGTRENNUNG
(entry 5). An excess of 3c (entries 7–9) or working at higher
or lower temperatures (entries 10–11) did not improve the
product yield. With a larger amount of the Lewis acid co-
catalyst the product yield was increased to a synthetically
useful level (entry 12). Note that the unusual (co-)catalyst
amounts of 9 or 18/36% are simply caused by the change of
the stoichiometry relative to Table 4, in which the catalyst
amount refers to 6a and not to the sulfonyl chloride 3c.
4[e]
5
6
7
8
9
10
11
12
Pr
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CH2Ph
CH2Ph
MeOC6H4O
MeOC6H4O
H
G
ACHTUNGTRENNUNG
13[e,f]
14[e,f]
15[g]
16[g]
17[g]
CCl3
CCl3
–
–
2:1
22
16
90
90
77
To achieve reproducible results activation of Bi
(OTf)3 at 1408C under high vacuum is indispensable.
Table 6 summarizes results obtained with different batches
of Bi(OTf)3. With commercial nonactivated ꢄanhydrousꢃ Bi-
(OTf)3, only traces of b-sultone 2c were obtained (Table 6,
ACHTUNGRTEN(NUNG OTf)3 or
H
InACHTUNGTRENNUNG
MeOC6H4O
MeOC6H4O
MeOC6H4OAHCUTNGTRENNUNG
R
A
2.5:1
>100:1
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] Conditions: 2.75 equiv 6a, concentration (6a): 0.34m, addition time of
3: 2.5 h, additional reaction time: 15 min. [b] Yield of the isolated prod-
ucts. [c] d.r. determined by 1H NMR spectroscopy. [d] Determined by
HPLC analysis. [e] 18 mol% of MACHTNUTRGNE(UNG OTf)3 were used. [f] iPr2NEt was used
instead of PMP. [g] Sulfonyl chloride and aldehyde were simultaneously
added by syringe pump.
entry 2). Batches activated at 120 or 1008C (entries 4–5) led
to diminished product yields relative to batches activated at
1408C (entry 3).
It has been reported that BiACHTNUTRGNENG(U OTf)3 starts to decompose at
temperatures of 80–1008C.[26] For that reason, we have per-
formed TG-MS (thermogravimetry–mass spectroscopy)
measurements that revealed that decomposition starts only
above 2508C, which shows that the reported activation
method is reliable. Moreover, microanalysis of the batches
activated at 1408C showed a deviation of <0.2% for both C
and S from the theoretical value, whereas the commercial
material contained 4.0 weight% of H2O.
stituted b-sultones 2b–h with ee values of 78 to >99% and
d.r. values of 22:1 to >100:1 for the best combination of
(DHQ)2PYR with either Bi
ACHUTGTNNERNUG(OTf)3 or InACHTGNUTRENNUNG
Bi(OTf)3 provided better yields (47–87%) than InACHTUNGTRENNUNG
G
(28–69%), whereas in terms of enantioselectivity a clear-cut
trend is not obvious. Surprisingly, the product 2e with a
chloroethyl substituent R1 allowed for the highest yield de-
spite its anticipated alkylating properties (Table 7, entry 7).
The optimized reaction conditions were then applied to a
number of sulfonyl chlorides (Table 7) providing the disub-
Chem. Eur. J. 2011, 17, 3679 – 3692
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3683

R. Peters and F. M. Koch
A substituent R1 is necessary for high enantioselectivity as
entries 13–14 show for which methanesulfonyl chloride was
used.
8 for the addition of the zwitterionic sulfene–amine adduct
5 to aldehyde 6 depicted in Scheme 4 might explain the high
diastereomeric excess for a sterically demanding group R2.
Assuming an anti-periplanar arrangement of the sulfonyl
group and the developing alcoholate, the gauche orientation
of R1 and R2 in the alternative transition-state 9 would
cause stronger repulsive interactions than in the favored
transition-state 8.
Further limitations not shown in Table 7 were found for
sulfonyl chlorides with R1 =Cl or Ph. In these cases, only
traces of product were formed and the major product with
R1 =Ph was stilbene.[16] With R1 =CF3, only the N-sulfony-
lated catalyst was isolated, presumably since the resulting
zwitterionic carbanion is not nucleophilic enough in the
presence of the acidifying CF3 group. Moreover, a,a-disub-
stituted sulfonyl chlorides did not provide b-sultones with a
quaternary stereocenter at the a-position,[27] as either the
sulfonyl chloride did not react (two a-alkyl substituents) or
a tetrasubstituted E-stilbene (one a-aryl and one a-alkyl
substituent) was obtained.
The optimized reaction conditions can also be adapted to
alternative electron-poor aldehydes as demonstrated for
ethyl glyoxylate (6b, Table 7, entries 15–16). Yield and enan-
tioselectivity are preparatively useful, whereas the diastereo-
selectivity is diminished. Both diastereomers can be separat-
ed by column chromatography. Almost complete diastereo-
Scheme 4. Explanation of the high cis diastereoselectivity for the forma-
tion of b-sultones 2 catalyzed by tertiary amines.
selectivity was attained with ZnACHTUNRGTNEUNG(OTf)2, but at the expense of
yield and enantioselectivity (ee=77%, entry 17).
To avoid polymerization of 6b under the reaction condi-
tions, both the sulfonyl chloride and the aldehyde were
slowly and simultaneously added to the reaction mixture by
a syringe pump. In general, the product formed from ethyl
glyoxylate was found to be much more sensitive than the
chloral-derived cycloadducts showing decomposition/oligo-
merization under acidic conditions and elimination with
amine bases, such as NEt3. Nonactivated aldehydes did not
react to the title compounds: aromatic aldehydes did not
react at all, whereas aliphatic aldehydes R2CHO with R2 =
n-Hept or (CH2)2Ph underwent a trimerization to diastereo-
merically pure 1,3,5-trioxanes under the reaction condi-
tions.[28]
The absolute configuration was established to be R,R by
the first X-ray crystal structure analysis of a monocyclic b-
sultone (Figure 1), which also confirmed the cis configura-
tion of the cycloaddition products.[29] The ring system of 2c
is almost completely flat with a dihedral angle of 1.38. The
ꢀ
C-S-O angle of 82.78 reflects the high ring strain. The C O
bond length of 147.0 pm is almost identical to a b-CCl3-sub-
stituted b-lactone (146.2 pm).[30]
The relative configuration of b-sultones 2b and 2h was
1
determined by H NMR-NOE spectroscopic experiments re-
vealing a cis connectivity of both ring protons (Scheme 3).
The original tentative assignment of a trans configuration
for 2b and 2c by King and Harding[16] thus needs to be cor-
rected.
Figure 1. Ortep representation of b-sultone 2c in the crystal structure
(50% probability ellipsoids, H atoms are omitted for clarity.
Scheme 3. Determination of the relative configuration of b-sultones 2 by
NOE experiments.
From a mechanistic point of view, at least two scenarios
might in principal account for the product formation
(Scheme 5): A) the proposed formation of a sulfene-derived
zwitterionic intermediate 5 or B) the formation of a zwitter-
ionic chloral–amine adduct 11, which undergoes a cyclocon-
densation reaction with the corresponding sulfene 1 or sulfo-
nyl chloride 3.[31]
The strong preference for the cis-configured isomer is not
the direct consequence of the catalyst geometry, since the
cis isomers are also almost exclusively formed in the none-
nantioselective methodology described above (Table 2). The
conformational analysis of the assumed open transition-state
3684
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Chem. Eur. J. 2011, 17, 3679 – 3692

Chiral Sulfonyl and Sulfinyl Derivatives
FULL PAPER
Scheme 5. Potential reactive intermediates for the formation of b-sul-
tones 3 catalyzed by tertiary amines.
Figure 2. Effect of reaction temperature on enantiomeric excess for the
*
formation of 2b (for conditions see Table 4, entries 14 and 15; : Bi-
ACHUTNGRENNUG CAHTUNGTRENNUGN
(OTf)3, R2 =0.9991; ꢅ: In(OTf)3, R2 =0.9991).
Sulfene formation under the described reaction conditions
was verified by deuteration experiments.[32] When sulfonyl
chlorides 3b–c were treated with PMP, (DHQ)2PYR, and
Lewis acid co-catalyst in the presence of H3COD, the mono-
deuterated esters 12 were selectively formed as determined
by GCMS (Scheme 6). Double deuteration was not detected
thus excluding a random deprotonation process. The deuter-
ation level was not influenced by the Lewis acid co-catalyst.
Incomplete deuteration is ascribed to D/H-exchange be-
tween MeOD and the ammonium salt formed during the
sulfene formation event.
Table 8. Investigation of the effect of the addition time of propanesulfon-
yl chloride (3c).[a]
Addition time of 3c
[min]
Reaction time after com-
plete
Yield
[%][b]
ee
[%][c]
addition of 3c [min]
1
2
3
4
5
5
30
60
150
5
15
15
15
15
150
12
18
28
51
44
>99.5
92
91
85
95
[a] Conditions: 2.75 equiv 6a, concentration (6a): 0.34m. [b] Determined
1
by H NMR spectroscopy of the product after aqueous workup with ace-
tophenone as the internal standard. [c] Determined by HPLC analysis.
Scheme 6. Deuterium labeling experiments to prove the existence of sul-
fene intermediates by the formation of monodeuterated ester 12.
ished yields (Table 8, entry 1). Under these conditions, the
concentration of the reactive sulfene intermediates was in-
creased favoring pathway A. A prolonged reaction time
after complete sulfonyl chloride addition also led to dimin-
ished enantioselectivity (compare entries 5 and 1). Also this
result can be explained by a decreasing sulfene concentra-
tion by dimerization and oligomerization.
Unusual temperature characteristics were found for the
model reaction of b-sultone formation employing ethylsul-
fonyl chloride (3b) and chloral (6a). The ee values reached
a maximum at ꢀ258C by using In
using Bi(OTf)3 as co-catalyst. They decreased at both higher
or lower temperatures (Figure 2).[33]
A
ACHTUNGTRENNUNG
These results might be attributed to a simultaneous com-
peting action of both pathways A and B (Scheme 5). The
following finding points to the mechanistic scenario A as the
major reaction pathway in CH2Cl2 at ꢀ158C: the results
listed in Table 5, entry 4 (see also Table 8, entry 4) were ob-
tained by addition of a solution of the sulfonyl chloride 3c
to the reaction mixture over a period of 2.5 h by using a sy-
ringe pump to maintain low concentrations of sulfene, so as
to avoid sulfene dimerization and oligomerization.[34] Stir-
ring was then continued for an additional 15 min before the
reaction mixture was quenched. However, if the addition
time of 3c was reduced to just 5 min, the ee values were no-
tably increased from 85 to 99.5% at the expense of dimin-
The improved product formation when using certain
metal triflate co-catalysts can be attributed to activation of
the aldehyde by coordination of the carbonyl group and/or
stabilization of the sensitive sulfene–amine adduct. Coordi-
nation of both reactants might lead to a highly organized
transition state explaining the enhanced enantioselectivity.
We speculate that the coordination mode of the metal
center might be similar as in lithiated sulfone carbanions, in
which the lithium ion binds to both sulfonyl oxygen
atoms.[35] By that the bulk of the sulfonyl moiety would be
seriously increased effecting a change of the preferred con-
formation so as to minimize repulsive interactions with the
catalyst core (Scheme 7).[36] The two alternative configura-
Chem. Eur. J. 2011, 17, 3679 – 3692
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3685

R. Peters and F. M. Koch
action product under the reported conditions when using
Me2NH. To avoid solvolysis of b-sultones, ring opening with
amines should thus be conducted in aprotic solvents and in
CH2Cl2 b-hydroxysulfonamide 14 was obtained in 65% yield
as a single diastereomer (Scheme 8).
Scheme 7. Rationale for the reactive configuration of sulfene–
(DHQ)2PYR adducts in the presence of BiIII (or alternatively InIII).
Scheme 8. Ring-opening with morpholine to give a b-hydroxysulfonamide
14.
tions 13 and 13’ should now differ to a stronger degree
based on a significant repulsive interaction of R1 and the
quinoline part in 13’. This would explain the effect that the
enantioselectivity greatly improved changing R1 from
methyl to a sterically more demanding substituent, whereas
with R1 =H nearly racemic product is formed. In the latter
case, enantioselectivity would solely depend on the enantio-
face discrimination of the aldehyde; however, with R1 ¼H
preference for one reactive sulfene–amine adduct configura-
tion decides the enantioselectivity outcome, whereas the
configuration at the former carbonyl carbon atom is con-
trolled by the inherent diastereoselectivity of the process.
The unexpected behavior in EtOH in the presence of pri-
mary or secondary amines offered the possibility to prepare
the corresponding b-hydroxysulfonates. Similar reactivity
was also found with alcohols in the presence of tertiary
amine bases, such as NEt3 (Table 9). Ethylsulfonates 15a
(R1 =H) and 15c (R1 =Et) were formed in 90 and 54%
yields, respectively (Table 9, entries 1–2). The lower yield
for 15c is caused by formation of the corresponding tetrae-
thylammonium sulfonate salt, because 15c acted as an alky-
lating agent. The alkylation can be avoided at room temper-
ature by the use of sterically more hindered tertiary amines,
such as nBu3N, iPr2NEt, or PMP, but at the expense of low
conversions. Formation of the ammonium salt side product
was not observed for the preparation of 15a or during ring
opening with 2-phenylethanol, which furnished sulfonates
16a–d in 62–90% yields (entries 3–6). The latter compounds
were used for ee determination of the corresponding b-sul-
tones by HPLC analysis.
Derivatization of enantioenriched b-sultones by ring open-
ing: Enantiopure b-hydroxysulfonyl derivatives are attrac-
tive synthetic targets as they exhibit in several cases a varie-
ty of biological activities and are promising for the treat-
ment of diseases, such as diabetes, peripheral vascular dis-
ease, cardiac failure, Alzheimerꢃs disease, atherosclerosis,
thrombosis, neurodegenerative disorders, or pain.[37–39] Ring-
opening reactions of b-sultones 2 with various nucleophiles
were, therefore, investigated.
In 1978, the ring opening of racemic monosubstituted b-
sultone 2a by various primary and secondary amines in
Et2O/EtOH was reported to give b-hydroxysulfonamides
(e.g. BnNH2: 71% yield; Me2NH: 90% yield).[12d] Unfortu-
nately no NMR spectroscopic data were published to con-
firm these results. In our hands ethylsulfonate 15a (see
Table 9) was obtained instead in 90% yield as the main re-
Nucleophilic ring opening with PhMgBr, which has al-
ready been reported for the racemic sultones 2a and 2b,
gave the enantioenriched b-hydroxysulfones 17 in good
yields without epimerization or racemization (Table 10).
Again a chloroethyl substituent as R1 (Table 10, entry 4) was
well tolerated.
The trichloromethyl group in the 4-postion of 2 could be
hydrolyzed by aqueous 1m NaOH to furnish the mixed sul-
Table 9. Formation of b-hydroxysulfonates 15 by alcoholysis of b-sul-
tones 2a–d.[a]
Table 10. Formation of b-hydroxysulfones 17 by Grignard addition to b-
sultones 3.
R1
R
15
equiv NEt3 t [h] T [8C] Yield [%][a]
R1
17
equiv PhMgBr
t [h]
Yield [%][a]
1[b]
2
3
4
5
H
Et
H
Me
Et
Et
Et
15a
15c
1.1
10
1
17
2
23
23
23
23
50
50
90
54
90
84
62
76
1
2
3
4
5
H
Me
Et
17a
17b
17c
17e
17 f
1.0
1.5
1.5
3.0
3.0
2
15
2
17
2
79
84
92
82
90
BnCH2 16a
BnCH2 16b 1.0
BnCH2 16c 1.0
1.0
14
3
18
Cl
N
6
nPr BnCH2 16d 1.0
Bn
[a] Yield of isolated product. [b] Me2NH was used instead of NEt3.
[a] Yield of isolated product.
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Chiral Sulfonyl and Sulfinyl Derivatives
FULL PAPER
fonic/carboxylic acid 18 after filtration over an acidic cation
exchange resin (Scheme 9).[40] Dissolving the product in
MeOH led to instantaneous formation of monoester 19. The
sulfonic acid moiety was used to form ammonium salt 20,
which was isolated by precipitation in 88% yield over three
steps.
Scheme 10. Partial dechlorination of CHCl2-substituted b-sultone 21c.
Scheme 11. Partial dechlorination of the CCl3 group in the acyclic sulfo-
nate 16c.
Scheme 9. Formation of b-hydroxysulfonic acid 18 under basic conditions.
The trichloromethyl group in b-sultones 2 also offers a va-
riety of other possibilities for further functionalization. As
our studies have revealed b-sultones 2 carrying a CCl3 sub-
stituent can be reduced chemo- and regioselectively at three
different sites. The trichloromethyl group can for instance
be partially reduced by Bu3SnH furnishing dichloromethyl-
substituted b-sultones 21 (Table 11). Notably, R1 =(CH2)2Cl
was well tolerated under the conditions of radical formation
(Table 11, entry 3).
rivatives are important in asymmetric synthesis[43] and are
known as versatile synthetic intermediates.[44] Chiral sulfi-
nates have, for example, been intensively used as the pri-
mary source for chiral sulfoxides.[45] Moreover, they have eli-
cited interest in medicinal chemistry.[46] Scalemic b-hydroxy-
sulfinic acids were recently reported as potent drug candi-
dates for the treatment of reflux disease.[47] We have found
that exposure of a,b-disubstituted b-sultones 2 to LiAlH4 in
Et2O at ambient temperature provides b-hydroxysulfinic
acids 26 within a few minutes in good yield and without par-
tial epimerization (Table 12).
Table 11. Partial dechlorination of CCl3-substituted b-sultones 2.[a]
ꢀ
Table 12. Chemoselective reduction of the S O bond of CCl3-substituted
b-sultones 3 with LiAlH4.
R1
21
Yield [%][b]
1
2
3
Et
nPr
ACHTUNGTRENNUNG(CH2)2Cl
21c
21d
21e
83
66
69
Entry
26
R1
Yield [%][a]
d.r.[b]
20:1
>50:1
>50:1
>50:1
>50:1
[a] Concentration (2): 0.033m. [b] Yield of isolated product.
1
2
3
4
5
26b
26c
26d
26e
26 f
Me
Et
nPr
73
90
77
71
86
1
AHCTUNGTRENNUNG
The dichloro derivative 21c was treated with Bu3SnH/
BEt3 in toluene at room temperature furnishing monochloro
derivative 22, which was found to be robust enough for pu-
rification by column chromatography (Scheme 10).
Similarly, also the acyclic sulfonate 16c was selectively
transformed to either the di- or the monochloro derivatives
23 or 24 depending upon the reaction conditions
(Scheme 11).[41]
[a] Yield of isolated product. [b] Determined by H NMR spectroscopy.
To evade over-reduction to the corresponding thiol, a
large excess of the hydride source and extended reaction
times had to be avoided. The free acids were obtained by
purification with an ion-exchange resin. Although sulfinic
acids have been reported to be unstable even in the absence
of oxygen due to disproportionation, the here reported b-hy-
droxysulfinic acids 26 are remarkably stable and do not
In addition to partial dechlorination one can reduce the
cyclic sulfonic esters 2 to provide b-hydroxysulfinic acids 26
ꢀ
by S O bond cleavage taking advantage of the high ring
strain of the four-membered heterocycles.[42] Sulfinic acid de-
Chem. Eur. J. 2011, 17, 3679 – 3692
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3687

R. Peters and F. M. Koch
have to be stored as a salt. After several months at ꢀ188C
under N2 the material was basically unchanged.
Sulfinic acid 26e carrying a 2-chloroethyl substituent R1
could either be isolated after acidic workup (Table 12,
entry 4) or cyclized to g-sultine 25 by quenching with water.
To our knowledge, this is the first reported example for the
formation of a g-sultine by nucleophilic displacement of a
halide with a sulfinate oxygen.[48] g-Sultines were recently
reported as a new class of flavor compounds. 3-Propyl-g-sul-
tine was for instance identified in the extracts of the yellow
passion fruit as an enantiomerically pure epimeric mixture
with respect to the configuration at S.[49] In our case, a 2.9:1
diastereomeric mixture was formed, which is separable by
column chromatography. In the major epimer, the S=O
bond adopts the axial position as determined by X-ray crys-
tal structure analysis (Figure 3).[50,51] The five-membered
Scheme 13. Chemoselective reduction of b-sultone 22 by LiBH4 to give
sulfonic acid 28.
If the reduction of b-sultones 2 was performed under hy-
drogenation conditions (p(H2)=1 atm) by using a catalytic
amount of Pd/C (2 mol%) in EtOH, dichloroallylsulfonic
acids 29 were obtained in high yield without significant race-
mization of the remaining stereocenter (Table 13). Only few
enantioselective methods for the synthesis of a-substituted
sulfonic acids have been report-
ed so far,[54] although enantio-
merically pure sulfonic acid de-
rivatives often display interest-
ing biological activities.[55] Fur-
ther dechlorination, hydrogena-
tion, or isomerization of the
generated C,C double bond
were much slower under the
described reaction conditions
than the initial reaction.
Two mechanistic scenarios
might account for the product
formation that are depicted in
Figure 3. X-ray crystal structure of the major isomer of g-sultine 25 with an axial sulfinyl group. The unit cell
contains two slightly different conformers.
Table 13. Chemoselective formation of dichloroallylsulfonic acids 29 with
Pd/C/H2.
rings adopt distorted envelope conformations in the solid
state (two slightly different conformers in a unit cell) and
the hydroxyl groups form inter- rather than intramolecular
hydrogen bonds with the sulfinyl moieties (209 and 220 pm)
resulting in polymeric chains.[52]
Following a reported procedure for the oxidation of sul-
tines, the diastereomeric mixture of g-sultine 25 was oxi-
dized to provide g-sultone 27 in 87% yield as a single dia-
stereomer confirming that the epimers of 25 have a different
configuration at the S atom (Scheme 12).[48c,53]
29
R1
2: ee
Yield 29
29: ee
[%][b]
[%][a]
[%][b]
1
2
3
4
5
6
29b
29c
29d
29e
29 f
29g
Me
Et
nPr
87
>99
89
94
99
94
95
95
80
89
99
85
>99
86
94
99
T
C
>99
>99
[a] Yield of isolated product. [b] Determined by HPLC analysis after
esterification with TMS-diazomethane.
Scheme 12. Oxidation of g-sultine 25 to g-sultone 27.
Scheme 14: the reaction could either proceed by oxidative
addition of Pd0 to the trichloromethyl group followed by b-
elimination (path A) or alternatively oxidative addition
might involve the four-membered ring system providing an
oxypalladacycle intermediate 31 (path B).[56] In both cases
PdII would be formed, which is then reduced with H2 to re-
generate Pd0. HCl generated during this process protonates
the corresponding Pd-sulfonates.
By decreasing the size of the substituent in the 4-position
from CCl3 to CH2Cl and changing the reducing agent to
ꢀ
LiBH4, the C O bond is selectively cleaved by a nucleophil-
ic hydride attack and sulfonic acid 28 is generated in a yield
of 75% (Scheme 13).
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Chiral Sulfonyl and Sulfinyl Derivatives
FULL PAPER
Scheme 16. Chemoselective formation of allylsulfonic acid 34 by a Finkel-
stein reaction of 22 and subsequent treatment with Mg.
was then directly treated with Mg without further purifica-
tion to form 34 in quantitative yield and without racemiza-
tion of the remaining stereocenter.
Scheme 14. Mechanistic alternatives for the formation of dichloroallyl
sulfonic acids 29.
Conclusion
Treatment of allylsulfonic acid 29c with MeLi, nBuLi, or
PhLi at ꢀ788C for 15 min provided racemic allenesulfonic
acid 32 in almost quantitative yield (Scheme 15).
The first catalytic asymmetric synthesis of b-sultones has
been developed. This methodology enables a rapid access to
a number of highly enantioenriched sulfonyl and sulfinyl
compound classes, which makes use of the inherent ring
strain of the four-membered heterocycles. Most of the ring-
opening products comprising one or two vicinal stereocen-
ters are still hardly accessible in a stereoselective way by al-
ternative means. This work also represents the first applica-
tion of sulfene intermediates in asymmetric catalysis. The re-
activity of a sulfene normally acting as an electrophile has
been reverted by the formation of a nucleophilic zwitterion-
ic sulfene–amine adduct. To achieve a combination of high
enantioselectivity and yield, the cooperative catalytic action
of a chiral nucleophilic tertiary amine ((DHQ)2PYR) and
Scheme 15. Formation of allenesulfonic acid 32.
Monochloroallylsulfonic acids 33 were not available by
hydrogenation of the dichloromethyl-substituted b-sultones
21 due to over-reduction of the generated C,C double bond.
However, treatment of 21 with Zn and HOAc in THF at
608C furnished 33 without racemization of the remaining
stereocenter as a mixture of the E and Z isomers (2.5–3.2:1,
Table 14).
BiACTHNUTRGENN(UG OTf)3 or InCAHTUNGTREN(NUGN OTf)3 was necessary.
Experimental Section
General procedure for the asymmetric formation of b-sultones 2: A sus-
pension of M(OTf)3 (0.137 mmol, 0.36 equiv; M=Bi: 90 mg; M=In:
AHCTUNGTRENNUNG
Table 14. Chemoselective formation of monochloroallylsulfonic acids 33
by Zn/HOAc.
77 mg) in CH2Cl2 (1 mL) was sonicated at room temperature for 15 min
and was subsequently cooled to ꢀ158C (EtOH/ice bath). Then a solution
of chloral (6a, 99 mL, 1.018 mmol, 2.75 equiv) in CH2Cl2 (0.5 mL) was
added. After 5 min, a solution of (DHQ)2PYR (30 mg, 0.034 mmol,
0.091 equiv) in CH2Cl2 (0.5 mL) was added followed after an additional
5 min by a solution of PMP (89 mL, 0.493 mmol, 1.32 equiv) in CH2Cl2
(0.5 mL). After another 15 min of stirring at ꢀ158C, a solution of the cor-
responding sulfonylchloride 3 (0.371 mmol, 1 equiv) in CH2Cl2 (0.5 mL)
was added dropwise by syringe pump over a period of 2.5 h. After com-
plete addition, the reaction mixture was stirred at ꢀ158C for an addition-
al 15 min. Prior to aqueous workup the suspension was diluted with
methyl tert-butyl ether (MTBE). The precipitate was filtrated off and
washed 4ꢅ with MTBE. The filtrate was subsequently sequentially
washed with saturated aqueous sodium ethylenediaminetetraacetic acid
(Na2EDTA; 25 mL), H2SO4 (0.05m, 2ꢅ20 mL), and H2O (2ꢅ10 mL). The
combined organic layers were dried over MgSO4, filtrated, and the sol-
vent removed in vacuo. Additional procedures, NMR spectra, and HPLC
data are given in the Supporting Information.
21
R
Yield 33 [%][b]
E/Z[c]
ee [%][d]
1
2
3
21c
21d
21e
Et
nPr
ACHTUNGTRENNUNG(CH2)2Cl
91
82
92
3.2:1
2.9:1
2.5:1
97
86
96
[a] Concentration (21): 0.025m. [b] Yield of isolated product. [c] Deter-
mined by 1H NMR spectroscopy. [d] Determined for the E isomer by
HPLC analysis.
To form the unchlorinated allylsulfonic acid 34, it was
necessary to displace chloride in 22 by iodide by a Finkel-
stein reaction (Scheme 16). The resulting primary iodide
Chem. Eur. J. 2011, 17, 3679 – 3692
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3689

R. Peters and F. M. Koch
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Acknowledgements
This work was financially supported by the Swiss National Science Foun-
dation (SNF, Ph.D. fellowship to F.M.K.) and F. Hoffmann-La Roche. We
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Chem. Eur. J. 2011, 17, 3679 – 3692

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[34] Despite the oligomerization tendency, we have not detected the for-
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(DHQ)2PYR might in addition act as a ligand coordinating to BiIII
in the active species.
Chem. Eur. J. 2011, 17, 3679 – 3692
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3691

R. Peters and F. M. Koch
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Received: December 8, 2010
Published online: March 1, 2011
3692
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 3679 – 3692