Asymmetric thio-claisen rearrangement induced by an enantiopure alkylsulfinyl group. Unusual preference for a boat transition state in the acyclic series

Article abstract of DOI:10.1021/jo015956m

Ketene aminothioacetals 2a-c and 5a-b bearing an enantiopure vinylic alkylsulfinyl substituent were readily prepared from (R)-2-cyclohexylsulfinyl-N,N-dimethylethanethioamide 1 with full control of the geometry of their double bonds. They underwent a Claisen rearrangement upon heating at THF reflux to afford α-sulfinyl ?-unsaturated thioamides 3a-c and 6a-b. With all substrates the asymmetric induction of the sulfinyl group was excellent. The determination of the absolute configurations of thioamides 3a-c and 6a-b was achieved either by X-ray crystallographic analysis or by chemical correlation. The stereochemical course of this [3,3] sigmatropic transposition was explained by an electronic model. Interestingly the Claisen rearrangement of the (ZE)-cinnamyl substrates 5b was shown to proceed through a boat transition state rather than a chair transition state; such a preference is quite unusual for acyclic systems.

Full text of DOI:10.1021/jo015956m

J . Org. Chem. 2001, 66, 7841-7848
7841
Asym m etr ic Th io-Cla isen Rea r r a n gem en t In d u ced by a n
En a n tiop u r e Alk ylsu lfin yl Gr ou p . Un u su a l P r efer en ce for a Boa t
Tr a n sition Sta te in th e Acyclic Ser ies
Ste´phanie Nowaczyk,† Carole Alayrac,*,† Vincent Reboul,† Patrick Metzner,*,† and
Marie-The´re`se Averbuch-Pouchot‡
Laboratoire de Chimie Mole´culaire et Thioorganique (UMR CNRS 6507), ISMRA-Universite´ de Caen,
6 Boulevard du Mare´chal J uin, 14050 Caen, France, and LEDSS (UMR CNRS 5616),
Universite´ J oseph Fourier, BP 53, 38041 Grenoble, France
patrick.metzner@ismra.fr
Received J uly 20, 2001
Ketene aminothioacetals 2a -c and 5a -b bearing an enantiopure vinylic alkylsulfinyl substituent
were readily prepared from (R)-2-cyclohexylsulfinyl-N,N-dimethylethanethioamide 1 with full control
of the geometry of their double bonds. They underwent a Claisen rearrangement upon heating at
THF reflux to afford R-sulfinyl γ-unsaturated thioamides 3a -c and 6a -b. With all substrates the
asymmetric induction of the sulfinyl group was excellent. The determination of the absolute
configurations of thioamides 3a -c and 6a -b was achieved either by X-ray crystallographic analysis
or by chemical correlation. The stereochemical course of this [3,3] sigmatropic transposition was
explained by an electronic model. Interestingly the Claisen rearrangement of the (ZE)-cinnamyl
substrates 5b was shown to proceed through a boat transition state rather than a chair transition
state; such a preference is quite unusual for acyclic systems.
Sch em e 1
In tr od u ction
The Claisen rearrangement is well-established as an
efficient method to achieve one of the main challenges
for chemists, which is the stereoselective formation of
carbon-carbon bonds in acyclic systems. Nevertheless
only a few asymmetric variants of this [3,3] sigmatropic
transposition involving a removable chiral auxiliary have
been proposed so far.1,2 We have recently reported the
first examples of an asymmetric thio-Claisen rearrange-
ment mediated by racemic alkylsulfinyl groups.3 The
control of the relative stereochemistry was excellent, and
a model was proposed to explain the stereochemical
course.
This reaction gave access to R-sulfinyl γ-unsaturated
dithioesters, and in view of the limited number of known
methods4-6 allowing the highly selective allylation of
carbonyl R-alkylsulfinyl compounds we wished to extend
it to the enantiopure series. We chose to examine the
thioamide series rather than the dithioester one because
thioamides are usually more stable and crystallize more
easily. For this purpose we developed an efficient asym-
metric synthesis of the precursor of the Claisen rear-
rangement substrates 2 (Scheme 1), 2-cyclohexylsulfinyl-
N,N-dimethylethanethioamide (R)-1 from diacetone-D-
glucose (Scheme 2), a cheap and accessible source of
chirality.7 We report here the first examples of asym-
metric thio-Claisen rearrangements directed by an enan-
tiopure alkylsulfinyl group and the efficient construction
of molecules bearing two to three asymmetric centers.
The full assignment of the molecular structures by X-ray
crystallographic analysis or chemical correlation is de-
scribed. We show that the stereochemical course of this
reaction performed in the acyclic series unexpectedely
switches in one example from the generally admitted
pseudocyclic chair transition state to the boat transition
state.
† ISMRA-Universite´ de Caen.
‡ Universite´ J oseph Fourier, Grenoble.
Resu lts a n d Discu ssion
(1) Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43-50.
(2) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry
1996, 7, 1847-1882.
Access to Th ioa m id es P ossessin g Tw o Asym -
m etr ic Cen ter s. The substrates of the rearrangement
2 were easily obtained by deprotonation of (R)-1 (98% ee)
with tert-butyllithium and subsequent allylation at the
(3) Alayrac, C.; Fromont, C.; Metzner, P.; Anh, N. T. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 371-374.
(4) Fujita, M.; Ishida, M.; Manako, K.; Sato, K.; Ogura, K. Tetra-
hedron Lett. 1993, 34, 645-648.
(5) De Mesmaeker, A.; Waldner, A.; Hoffmann, P.; Mindt, T. Synlett
1993, 871-874.
(6) Beckwith, A. L. J .; Hersperger, R.; White, J . M. J . Chem. Soc.,
Chem. Commun. 1991, 1151-1152.
(7) Alayrac, C.; Nowaczyk, S.; Lemarie´, M.; Metzner, P. Synthesis
1999, 669-675.
10.1021/jo015956m CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/25/2001

7842 J . Org. Chem., Vol. 66, No. 23, 2001
Nowaczyk et al.
Sch em e 2
prevent such a transformation, 2a -c should not be
isolated. The reaction was thus carried out in one pot,
and a significant increase in the yields of rearranged
products up to 78% was observed (Table 1). Thioamides
3a -c were obtained with an excellent diastereoselectivity
(up to 100:0) with no variation related to the tempera-
ture. In all cases, the 1H NMR signals of the proton linked
to the stereogenic carbon center of the major isomer were
shifted toward lower δ values. The enantiomeric excess
of 3a (96% ee) was determined by HPLC analysis (Daicel
AD column) as identical to that of the precursor (R)-1
(98% ee), demonstrating that the stereopurity of the
sulfinyl group was preserved.
The (SS,2S) configuration of 3a was established by
X-ray crystallographic analysis. The same configuration
was assigned to thioamides 3b-c according to similar
trends observed in the proton NMR spectra.
We also selectively prepared the (SR,2R) enantiomer
of 3a (dr ) 91:9) from the (S) enantiomer of 1 (88% ee),
which was available from the same source of chirality,
diacetone-D-glucose (DAG). Indeed, the reaction of race-
mic cyclohexanesulfinyl chloride13 with DAG led to either
diastereomer of DAG cyclohexanesulfinate 4 according
to the nature of the base employed in agreement with
the methodology described by Alcudia.14 While (S)-DAG
cyclohexanesulfinate 4 was selectively obtained7 with
N,N-diisopropylethylamine, the (R)-isomer of 4 was
preferentially formed with pyridine (Scheme 2). Similarly
both (SS,2S) and (SR,2R) enantiomers of molecules 3b-c
are easily accessible. Moreover we have recently re-
ported15 that the aminolysis of (SS*,2S*)-R-sulfinyl-γ-
unsaturated dithioesters by dimethylamine proceeded
under dynamic kinetic control and led to the correspond-
ing (SS*,2R*)-thioamides with inversion of configuration
at the asymmetric carbon center. Consequently all four
isomers of molecules 3 can be selectively synthesized.
Access to Th ioa m id es P ossessin g Th r ee Asym -
m etr ic Cen ter s. To apply our method to the synthesis
of natural biologically active compounds, we wished to
extend it to the formation of thioamides possessing three
contiguous asymmetric centers. We have shown previ-
ously that the deprotonation of 1 was stereoselective and
that the alkylation of the resulting enethiolate proceeded
with full retention of configuration. Therefore, by using
isomerically pure allylic halides or mesylates, the geom-
etry of both double bonds of the Claisen rearrangement
substrates 5a -b could be controlled. This fulfillment is
quite important as the configuration of the double bonds
involved in the [3,3] sigmatropic transposition is known16,17
to be crucial for the stereochemistry of the newly formed
asymmetric centers. This feature has been often exploited
in synthesis.18-21
Ta ble 1. Cla isen Rea r r a n gem en t of Com p ou n d s
(SS,2S)-2a -c Accor d in g to Sch em e 1
entry
2
R
T (°C)
time
3
dra (%)
yield (%)
1
2
3
4
5
6
2a
2a
2b
2b
2c
2c
H
H
Me
Me
Br
Br
20
66
20
66
20
66
3 d
0.5 h
8 d
2 h
5 d
3a
3a
3b
3b
3c
3c
96:4
95:5b
>98:2
100:0
95:5
60
78
51
76
56
58
0.5 h
96:4
The diastereomeric ratio was measured by 1H NMR analysis
a
b
by integration of the signals of the diastereomeric proton. Crys-
tallization (ethyl acetate/pentane) afforded isomerically pure 3a
(100:0 dr).
sulfur atom of the resulting enethiolate (Scheme 1).8 All
our attempts to deprotonate 1 with other bases failed,
while LDA was efficient with the analogous dithioesters.3
The nature of the base is thus crucial, and this is quite
surprising as the sulfinyl group should enhance the
acidity of the R-located protons. Some precedents can be
found in the literature with related systems.9
The cis-deprotonation8,10 of 1 was exclusively observed,
and as the alkylation of enethiolates is known to proceed
with complete retention of configuration,11,12 only the (Z)-
isomer of ketene aminothioacetals 2a -c was formed. It
is worthy to note that, in the dithioester series, the
enethiolate isomeric ratio was about 90:10 in favor of the
(Z)-isomer.3 The Claisen rearrangement of ketene ami-
nothioacetals 2a -c was slow at room temperature (Table
1, entries 1, 3, and 5) and even slower than in the
dithioester series (less than 2 days). However, while
dithioesters underwent some decomposition upon heat-
ing, the analogous thioamides proved to be stable at
reflux of THF. We were then able to shorten drastically
the rearrangement time of 2a -c from several days to less
than 2 h. Compounds 2a -c are rather sensitive toward
hydrolysis, which gives the amide analogue of 1. To
The enolate of (R)-1 was thus treated with isomerically
pure or enriched crotyl and cinnamyl allylic reagents22-24
to afford (ZZ)- and (ZE)-5a -b quantitatively (Scheme 3).
(13) Youn, J .-H.; Herrmann, R. Synthesis 1987, 72-73.
(14) Fernandez, I.; Khiar, N.; Llera, J . M.; Alcudia, F. J . Org. Chem.
1992, 57, 6789-6796.
(15) Alayrac, C.; Metzner, P. Tetrahedron Lett. 2000, 41, 2537-2539.
(16) Ziegler, F. E. Acc. Chem. Res. 1977, 10, 227-232.
(17) Vittorelli, P.; Winkler, T.; Hansen, H.-J .; Schmid, H. Helv.
Chim. Acta 1968, 51, 1457-1461.
(8) Metzner, P. Synthesis 1992, 1185-1199.
(9) Cinquini, M.; Manfredi, A.; Molinari, H.; Restelli, A. Tetrahedron
1985, 41, 4929-4936 and references therein.
(10) Metzner, P.; Thuillier, A. Sulfur Reagents in Organic Synthesis;
Academic Press: London, 1994.
(11) Beslin, P.; Metzner, P.; Valle´e, Y.; Vialle, J . Tetrahedron Lett.
1983, 24, 3617-3620.
(12) Beslin, P.; Valle´e, Y. Tetrahedron 1985, 41, 2691-2705.
(18) He, S.; Kozmin, S. A.; Rawal, V. H. J . Am. Chem. Soc. 2000,
122, 190-191.
(19) Tamaru, Y.; Furukawa, Y.; Mizutani, M.; Kitao, O.; Yoshida,
Z. J . Org. Chem. 1983, 48, 3631-3639.
(20) Beslin, P.; Perrio, S. Tetrahedron 1993, 49, 3131-3142.
(21) Kurth, M. J .; Beard, R. L. J . Org. Chem. 1988, 53, 4085-4088.

Asymmetric Thio-Claisen Rearrangement
J . Org. Chem., Vol. 66, No. 23, 2001 7843
Sch em e 3
Sch em e 4
isomer of 6a arising from the rearrangement of the (ZE)-
5a substrate was that of the product of the (ZZ)-5a
substrate.
Deter m in a tion of th e Absolu te Con figu r a tion s of
Th ioa m id es 6a -b. It was not possible to obtain crystals
suitable for X-ray analysis of the isomerically pure
thioamides 6a -b obtained from the Claisen rearrange-
ment of (ZZ)-5a -b. They were then converted into the
corresponding amides 7a -b with dimethyldioxirane,25
which was formed in situ from oxone and acetone
(Scheme 4). The reaction proceeded readily at 0 °C
without loss of stereopurity. By a careful addition of
oxone further oxidation such as the transformation of the
sulfinyl moiety to the sulfone function was prevented.
The X-ray crystallographic analysis of amides 7a -b
allowed us to assign the (SS,2S,3R) and (SS,2S,3S)
configuration to thioamides 6a and 6b, respectively. By
contrast, the Claisen rearrangement of (ZE)-5a led to a
mixture of two diastereoisomers of 6a (Table 2), which
could not be separated either by flash chromatography
through silica gel or by crystallization, even after their
transformation into the corresponding amides. The struc-
ture of the minor isomer was known as it corresponded
to the unique product of the Claisen rearrangement of
the (ZZ)-5a substrate. The identification of the major
isomer was then attempted by chemical correlation.
The strategy was to reduce first the sulfinyl moiety of
both isomers to have access to molecules bearing only
two asymmetric centers. The resulting thioamides could
be either enantiomers or diastereomers. In the first case,
as the configuration at the sulfur atom was known, the
full assignment would be made. In the second case, the
removal of two asymmetric centers by reduction of the
carbon-sulfur bond of both isomers would be necessary.
Using HPLC analysis, we expected to be able to resolve
whether the reduction product was a single molecule or
an enantiomeric mixture. The same strategy could serve
for the determination of the structure of the minor isomer
of thioamide 6b arising from the Claisen rearrangement
of (ZE)-5b (Table 2). We first investigated the selective
reduction of the sulfinyl moiety of molecules 6a -b. Many
methods exist for the conversion of sulfoxides into
sulfides.26 After a short screening of reducing agents,
P4S10 proved to be the most convenient one for the
selective transformation of 6a -b and 3a into thioamides
8a -c (Scheme 5).27 The reaction proceeded readily at
room temperature in CH2Cl2 within 0.5-1 h and the
isolated yields ranged from 59% to 86%. The conversion
of thioamides 6a -b bearing the unknown isomer as
minor component (same dr 90:10:0:0) led to thioamides
8a and 8b as diastereomeric mixtures (dr 90:10 and 84:
Ta ble 2. Cla isen Rea r r a n gem en t of Com p ou n d s 5a -b
Accor d in g to Sch em e 3
T
yield
(%)
entry
5a
R
(ZE)/(ZZ)b (°C) time
6
drc
1
2
3
4
5
6
(ZE)-5a Me
(ZE)-5a Me
(ZZ)-5a Me
(ZE)-5b Ph
(ZE)-5b Ph
(ZZ)-5b Ph
86:14
95:5
0:100
100:0
100:0
4:96
20 4 wks 6a
66 2 h 6a
66 2.5 h 6a
20 3 wks 6b
43 15:85:0:0
64 18:82:0:0
53 100:0:0:0
30 70:30:0:0
53 90:10:0:0
45 100:0:0:0
66 4 h
66 5 h
6b
6b
a
The (ZE) configuration of 5a -b refers to the (Z)-configuration
of the enethiolate moiety and the (E)-configuration of the allylic
b
moiety. The (ZE)/(ZZ) ratio was determined by 1H NMR analysis
by integration of the signals of the vinylic proton of the enethiolate
moiety. c The diastereomeric ratio was measured by 1H NMR
analysis by integration of the signals of the proton linked to the
carbon located R to the cyclohexylsulfinyl group and those of the
methyl groups of the thioamide function.
The Claisen rearrangement of 5a -b was very slow at
room temperature, but as in the case of substrates 2a -
c, it could be accelerated by heating at THF reflux (Table
2). The transposition was slower in the cinnamyl series
(entries 4-6) than in the crotyl series (entries 1-3)
probably as a result of the loss of conjugation between
the phenyl group and the double bond of the allylic
moiety in the course of the rearrangement. The obtained
yields were relatively modest (45-64%) since the full
conversion of the ketene aminothioacetals 5a -b into the
thioamides 6a -b could not be achieved even by prolong-
ing the heating time. Nevertheless the results were
excellent in terms of stereoselectivity since only one or
two diastereomers out of the four possible ones were
formed (Table 2). A single isomer of 6a -b was isolated
in the case of the (ZZ)-substrates 5a -b. The isomeric
purity of the major product of the rearrangement of (ZE)-
substrates 5a and 5b was 64% and 80%, respectively. A
variation of the isomeric ratio of 6b according to the
temperature was observed (entries 4 and 5) and is due
to some decomposition of the minor isomer at THF reflux.
Not only the configuration of the allylic double bond but
also the nature of the allylic substituent had an influence
on the stereochemical course of the rearrangement.
Indeed, while the (ZE)- and (ZZ)-5a substrates led to
distinct isomers of 6a as major products (entries 2 and
3) the corresponding 5b substrates gave access to the
same major isomer of 6b (entries 5 and 6). According to
1H and 13C NMR analysis, the structure of the minor
(22) White, J . D.; Takabe, K.; Prisbylla, M. P. J . Org. Chem. 1985,
50, 5233-5244.
(23) Marvell, E. N.; Li, T. Synthesis 1973, 457-468.
(24) Davis, F. A.; Reddy, R. T. J . Org. Chem. 1992, 57, 2599-2606.
(25) Tang, W.; Abbott, F. S. Chem. Res. Toxicol. 1996, 9, 517-526.
(26) Madesclaire, M. Tetrahedron 1988, 44, 6537-6580.
(27) Still, I. W. J .; Hasan, S. K.; Turnbull, K. Synthesis 1977, 468-
469.

7844 J . Org. Chem., Vol. 66, No. 23, 2001
Nowaczyk et al.
Sch em e 5
Sch em e 6
16, respectively, according to proton NMR analysis). Thus
the (SS,2R,3S) and (SS,2R,3R) respective configurations
for thioamides 6a and 6b should not be considered. To
discriminate between the two last possible structures, the
determination of the absolute configuration of carbon 3
was necessary and required the reduction of the carbon-
sulfur bond. We first prepared the racemic reference28
compounds 9a and 9b by aminolysis of the corresponding
dithioesters29,30 with dimethylamine and found the best
conditions for the separation of their enantiomers on
HPLC (Daicel AD column). The electron-transfer system
SmI2-THF-HMPA has been reported to be quite efficient
for the mild reduction of sulfoxides.31,32 Therefore we
attempted such a reaction with 6a and 6b (same dr 90:
10:0:0) and obtained thioamides 9a -b as enantiomer
mixtures with respective unoptimized yields of 60 and
39% (Scheme 5). The enantiomeric ratio of compounds
9a and 9b was determined by HPLC analysis as 90:10
and 88:12, respectively. According to the results of both
reactions (P4S10 and SmI2), we were able to assign the
(SS,2S,3S) configuration to the major isomer of 6a
obtained from the Claisen rearrangement of (ZE)-5a and
the (SS,2S,3R) configuration to the minor isomer of 6b
arising from the rearrangement of (ZE)-5b.
Ster eoch em ica l Cou r se of th e Cla isen Rea r r a n ge-
m en t of 2 a n d 5. We have demonstrated that the
cyclohexylsulfinyl group was a quite efficient chiral
inducer in the Claisen rearrangement of ketene ami-
nothioacetals 2 and 5. To explain the high level of
selectivity of this reaction, we suggest that it proceeds
under orbital control and that the steric control is not
significant. Such a model has been previously proposed
for the Claisen rearrangement in the racemic dithioester
series.3 A pseudo-cyclic chair transition state is usually
described for [3,3] sigmatropic transpositions in the
acyclic series.16,33-34 To optimize the electronic transfer,
the best donor substituent of the sulfinyl group, the lone
pair, is oriented anti to the electrophilic attack of the
allylic chain. Two transition states deriving from con-
formers A and B are then possible (Scheme 6), and they
only differ in the orientation of the oxygen atom and the
cyclohexyl group. Model B where the cyclohexyl group,
the bulkier substituent,35 is located at the inside position
is sterically disfavored in comparison to model A where
the cyclohexyl group is oriented at the outside position.
Moreover, in model A the oxygen atom of the sulfinyl
group occupies the inside position, which is a stabilizing
electronic factor.4 Model A is thus more favorable than
model B, and it gives access to the major diastereoisomer
of (SS,2S) configuration in agreement with the experi-
mental results.
The stereochemical course of the Claisen rearrange-
ment of the (ZZ)-5a -b substrates that afforded only one
isomer of thioamides 6a -b can be described by the same
pseudo-cyclic chair model A leading to the (SS,2S,3R)-
isomer of 6a and the (SS,2S,3S)-isomer of 6b (scheme in
Supporting Information).
Similarly, in the case of the (ZE)-crotyl substrate 5a
such a chair conformation is preferential, although the
selectivity is lowered probably because of the increase of
steric hindrance within the molecule (scheme in Sup-
porting Information). By contrast the pseudo-cyclic chair
conformation is less suitable in the case of (ZE)-5b as a
result of the disfavorable steric interaction between the
phenyl substituent and the cyclohexyl group. This inter-
action is less pronounced in the pseudo-boat conforma-
tion, which is then more favorable, and the (SS,2S,3S)
isomer of 6b is formed preferentially (Scheme 7). Such a
switch in selectivity is quite unusual in acyclic systems
where boat transition states are usually higher in energy.
The known examples of pseudo-cyclic boat transition
states mostly involve substrates whose allyl bonds are
included in a ring,36 and only a few specific cases have
been reported in the acyclic series.37-39
(28) Takano, S.; Yoshida, E.; Hirama, M.; Ogasawara, K. J . Chem.
Soc., Chem. Commun. 1976, 776-777.
(29) Fujisawa, T.; Umezu, K.; Sato, T. Chem. Lett. 1985, 1453-1456.
(30) De´sert, S.; Metzner, P.; Ramdani, M. Tetrahedron 1992, 48,
10315-10326.
(35) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds; J ohn Wiley: New York, 1994.
(36) Cave, R. J .; Lythgoe, B.; Metcalfe, D. A.; Waterhouse, I. J .
Chem. Soc., Perkin Trans. 1 1977, 1218-1228.
(37) Kurth, M. J .; Yu, C.-M. J . Org. Chem. 1985, 50, 1840-1845.
(38) Ireland, R. E.; Wilcox, C. S. Tetrahedron Lett. 1977, 33, 2839-
2842.
(31) Handa, Y.; Inanaga, J .; Yamaguchi, M. J . Chem. Soc., Chem.
Commun. 1989, 298-299.
(32) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693-2698.
(33) Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 5, pp 827-873.
(34) Doering, W. v. E.; Roth, W. R. Tetrahedron 1962, 18, 67-74.
(39) Maruoka, K.; Yamamoto, H. Synlett 1991, 793-794.

Asymmetric Thio-Claisen Rearrangement
J . Org. Chem., Vol. 66, No. 23, 2001 7845
Sch em e 7
Further transformation of compounds 3 and 6 is in course
with the aim of synthesizing biologically active com-
pounds.
Exp er im en ta l Section
Solvents were dried immediately prior use. Dry THF was
distilled from sodium/benzophenone under N2. Commercial
reagents were used directly as received. All reactions were
monitored by TLC carried out on analytical silica gel TLC
plates purchased from Merck silica gel and visualized with
UV light and iodine. Preparative flash liquid chromatography
was performed with Merck 60 silica gel (63-200 µm) in the
eluting solvents indicating below. 1H NMR spectra were
recorded on 250 and 400 MHz spectrometers. 13C NMR spectra
were determined with the same spectrometers operating with
broad band 1H decoupling. Elemental analyses were performed
by the Service Central d’Analyse of CNRS at Vernaison or by
the “Service d’Analyse de l’ICSN” at Gif sur Yvette for C, H,
N, and O or by LCMT for C, H, S, N, and O. Melting points
are uncorrected.
Cyclohexanesulfinyl chloride was prepared from cyclohex-
anethiol according to the literature.13 It was obtained in 94%
yield after distillation [bp (°C/mm) 65-66/0.075 (lit.13 62-64/
0.07)].
(S)-4 was obtained according to our previous procedure7 from
diacetone-D-glucose and i-Pr2NEt. (R)-1 was prepared7 from
(S)-4 with 91% yield and 98% ee (using 0.33 equiv of N,N-
dimethylethanethioamide instead of 0.25).
Th ioa m id es 3a -c. Only the signals of the minor isomer
that were clearly identified are given. The (SS,2S) configura-
tion of both 3b and the major isomer of 3c was deduced from
that of the major isomer of 3a .
Con clu sion
The stereocontrolled thio-Claisen rearrangement medi-
ated by a cyclohexylsulfinyl group afforded diastereo- and
enantioenriched R-sulfinyl γ-unsaturated thiocarbonyl
compounds possessing two or three contiguous asym-
metric centers. Excellent diastereoselectivities were
achieved by the ability of the cyclohexylsulfinyl group as
chiral auxiliary and by the full control of the geometry
of the double bonds of the Claisen rearrangement sub-
strates 2 and 5. Excellent enantioselectivities were
obtained using diacetone-D-glucose, an easily available
and inexpensive source of chirality. Moreover diacetone-
D-glucose gave selective access to both enantiomers of the
substrates 2 and 5. Thus our method allows the control
of both relative and absolute stereochemistries in acyclic
series. It can be considered as an alternative to the
palladium-catalyzed regio- and stereoselective allylation
reaction.40-42 Indeed, while this reaction has proven high
efficiency in the preparation of enantiopure phenyl-
substituted allyl compounds, it is not optimal for the
synthesis of the methyl analogues.43 Quite unexpectedly,
the thio-Claisen rearrangement was stereodiverging in
the crotyl series and stereoconverging in the cinnamyl
series. The stereochemical course of this reaction was
mostly explained by a pseudocyclic chair transition state,
but an unusual switch to a boat transition state was
observed with the (ZE)-cinnamyl substrates 5b.
(SS,2S)-2-Cycloh exylsu lfin yl-N,N-dim eth ylpen t-4-en eth -
ioa m id e (3a ). Typ ica l P r oced u r e. (R)-1 (107 mg, 0.46 mmol)
was diluted in freshly distilled THF (3 mL), and a 1.64 M
solution of t-BuLi in pentane (285 µL, 0.47 mmol) was slowly
added at -40 °C under nitrogen. After 1 h of stirring at -40
°C and 15 min at 0 °C allyl bromide (45 µL, 0.52 mmol) was
added at -40 °C, and the reaction mixture was allowed to
warm to room temperature over 1.5 h. The reaction mixture
was heated at THF reflux for 0.5 h and then cooled to 0 °C
before hydrolysis (5 mL). The aqueous phase was acidified with
diluted sulfuric acid and extracted with CH2Cl2 (5 mL, three
times); the combined organic layers were washed with water
(5 mL), dried over MgSO4, and then concentrated to dryness
for analysis. Flash chromatography on silica gel (ethyl acetate)
afforded 98 mg (78% yield, dr 95:5) of 3a as a pale yellow solid.
Crystallization (ethyl acetate/pentane) afforded isomerically
pure 3a (100% de). Its (SS,2S) configuration was assigned by
X-ray crystallographic analysis. Its enantiopurity (96% ee) was
measured by HPLC on a Chiralpack AD Daicel column (n-
hexane/i-PrOH 96:4, λ ) 280.9 nm). Mp 76 °C; [R]26 -396 (c
D
1
) 1.02, CHCl3); H NMR (250 MHz, CDCl3) δ 1.10-2.15 (m,
The Claisen rearrangement products 3a -c and 6a -b
are stable molecules bearing several important functional
groups that can be selectively modified without altering
the diastereopurity. A large diversity of transformations
are possible and give access to versatile synthons. For
example the reduction of compounds 6a -b and 3a with
P4S10 afforded new R-sulfanyl γ-unsaturated thioamides
8a -c, while the oxidation of 6a -b by dimethyldioxirane
led to the corresponding amides 7a -b. Compounds 6a -b
are also precursors of enantioenriched pent-4-enethioa-
mides 9a -b bearing an asymmetric center in â-position.
10H), 2.84 (tt, J ) 3.8 Hz, J ) 12.0 Hz, 1H), 3.05-3.15 (m,
2H), 3.36 (s, 3H), 3.48 (s, 3H), 4.13 (dd, J ) 6.2 Hz, J ) 8.5
Hz, 1H), 5.08-5.30 (m, 2H), 5.67-5.85 (m, 1H); 13C NMR (62.9
MHz, CDCl3) δ 22.6, 25.5, 25.6, 26.2, 28.7, 36.8, 42.3, 44.2,
54.7, 68.3, 119.6, 133.0, 196.9; IR (KBr) ν ) 3072, 2932, 2854,
2362, 1518, 1450, 1396, 1266, 1142, 1036, 918 cm-1; MS (70
eV, EI) m/z (%) 274 (MH+, 1), 247 (2), 190 (1), 108 (21), 83
(56), 55 (100), 45 (42). Anal. Calcd for C13H23NOS2: C, 57.12;
H, 8.49; N, 5.13; O, 5.86; S, 23.41. Found: C, 56.99; H, 8.55;
N, 5.18; O, 6.03; S, 23.35. 1H NMR signals of the (SS,2R) minor
isomer (250 MHz, CDCl3) δ 3.44 (s, 3H), 3.56 (s, 3H), 4.51 (dd,
J ) 3.6 Hz, J ) 10.3 Hz, 1H), 5.29-5.47 (m, 2H), 5.85-6.03
(m, 1H).
(SS,2S)-2-Cycloh exylsu lfin yl-N,N-d im eth yl-4-m eth yl-
p en t-4-en eth ioa m id e (3b). Prepared from (R)-1 (765 mg,
3.28 mmol) and methallyl iodide (664 mg, 3.65 mmol). Flash
chromatography on silica gel (ethyl acetate) afforded 713 mg
(76% yield, dr 100:0) of 3b as a yellow oil. The enantiopurity
(90% ee) of a sample of 3b (de 86%) was measured by HPLC
on a Chiralpack AD Daicel column (hexane/i-PrOH 95:5, λ )
(40) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1999, 96, 395-
422.
(41) Pfaltz, A.; Lautens, M. In Comprehensive Asymmetric Catalysis;
Springer: Berlin, 1999; pp 834-884.
(42) Williams, J . M. J . Synlett 1999, 705-710.
(43) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 99-102.

7846 J . Org. Chem., Vol. 66, No. 23, 2001
Nowaczyk et al.
1
280.9 nm). [R]21 -262 (c ) 0.5, CHCl3); H NMR (250 MHz,
the reaction mixture was allowed to warm to room tempera-
ture over 1.75 h. The reaction mixture was heated at THF
reflux for 0.5 h and then cooled to 0 °C before hydrolysis (10
mL). The aqueous phase was acidified with diluted sulfuric
acid and extracted with CH2Cl2 (10 mL, three times). The
combined organic layers were washed with water (10 mL),
dried over MgSO4, and then concentrated to dryness to afford
264 mg of crude product as orange oil. Flash chromatography
on silica gel (ethyl acetate) afforded 221 mg (81% yield, dr 91:
9) of (SR,2R)-3a as a pale yellow oil. A second flash chroma-
tography and a crystallization (ethyl acetate/petroleum ether
1/4) were necessary to obtain isomerically pure 3a (>99% de).
Its enantiopurity (>99% ee) was measured by HPLC on a
D
CDCl3) δ 1.15-2.00 (m, 10H), 1.79 (s, 3H), 2.84 (tt, J ) 2.3
Hz, J ) 7.4 Hz, 1H), 2.98-3.15 (m, 2H), 3.35 (s, 3H), 3.47 (s,
3H), 4.17 (dd, J ) 2.1 Hz, J ) 6.8 Hz, 1H), 4.84 (s, 1H), 4.87
(s, 1H); 13C NMR (62.9 MHz, CDCl3) δ_22.6, 25.3, 25.4, 26.0,
28.6, 23.2, 39.8, 42.0, 44.1, 54.5, 67.9, 114.9 141.1, 197.3; IR
(NaCl) ν 3076, 2932, 2854, 2362, 1518, 1450, 1394, 1036 cm-1
;
MS (70 eV, EI) m/z (%) 288 (MH+, 1), 258 (4), 156 (84), 88
(51), 83 (61), 55 (100), 41 (90). Anal. Calcd for C14H25NOS2:
C, 58.51; H, 8.77; N, 4.88; S,22.27. Found: C, 58.62; H, 8.70;
N,4.91; S, 22.03.
(SS,2S)-4-Br om o-2-cycloh exylsu lfin yl-N,N-d im et h yl-
p en t-4-en eth ioa m id e (3c). Prepared from (R)-1 (100 mg, 0.43
mmol) and 2,3-dibromopropene (65 µL, 0.5 mmol). Flash
chromatography on silica gel (ethyl acetate) afforded 87 mg
(58% yield, dr 96:4) of 3c as a solid: 1H NMR (250 MHz, CDCl3)
δ 1.10-2.06 (m, 10H), 2.64-2.84 (m, 1H), 3.30-3.68 (m, 2H),
3.48 (s, 3H), 3.49 (s, 3H), 4.44 (dd, J ) 3.2 Hz, J ) 10.8 Hz,
1H), 5.48 (s, 1H), 5.78 (s, 1H); 13C NMR (62.9 MHz, CDCl3) δ
23.3, 25.6, 25.7, 26.3, 28.9, 42.9, 44.5, 44.7, 55.6, 66.7, 121.8,
128.5, 196.0; IR (NaCl) ν 3444, 3096, 2932, 2854, 1628, 1518,
1450, 1416, 1394, 1302, 1272, 1042, 994, 894, 612 cm-1; MS
(70 eV, EI) m/z (%) 352 (MH+, 1), 272 (3), 230 (19), 140 (75),
83 (100), 55 (1), 44 (1); HRMS found 351.03257, C13H22NOS2-
Chiralpack AD Daicel column (n-hexane/i-PrOH 96:4, λ )
1
280.9 nm). [R]26 +321 (c ) 1, CHCl3).). The H and 13C NMR
D
data are identical to those previously reported for (SS,2S)-3a .
(SS,2S,3S)-2-Cycloh exylsu lfin yl-N,N-d im eth yl-3-m eth -
ylp en t-4-en eth ioa m id e (6a ). Typ ica l P r oced u r e. (R)-1 (99
mg, 0.42 mmol) was diluted in freshly distilled THF (3 mL),
and a 1.5 M solution of t-BuLi in pentane (300 µL, 0.45 mmol)
was slowly added at -40 °C under nitrogen. After the reaction
had been stirred for 1 h at -40 °C and for 15 min at 0 °C, a
solution of (E)-4-bromobut-2-ene (61 mg, 0.52 mmol) diluted
in THF (1 mL) was then added at -40 °C, and the reaction
mixture was allowed to warm to room temperature over 1.5
h. The reaction mixture was heated at THF reflux for 2 h and
then hydrolyzed (5 mL) at 0 °C. The aqueous phase was
acidified with diluted sulfuric acid and extracted with CH2Cl2
(5 mL, 3 times). The combined organic layers were washed
with water, dried over MgSO4, and then concentrated to
dryness for analysis. Flash chromatography on silica gel (ethyl
acetate) afforded 79 mg (64% yield, dr 18:82:0:0) of 6a as a
Br (M+) requires 351.03276; H NMR signals of the (2R,SS)
1
minor isomer (250 MHz, CDCl3) δ 3.51 (s, 3H), 4.94 (dd, J )
3.0 Hz, J ) 9.9 Hz, 1H); 13C NMR signals of the minor isomer
(62.9 MHz, CDCl3) δ 22.6, 25.7, 26.4, 28.6, 42.1, 46.0, 55.7,
63.0, 121.7, 128.3.
1,2:5,6-Di-O-isop r op ylid en e-R-D-glu cofu r a n osyl (R)-Cy-
cloh exa n esu lfin a te (4). To a cooled (-50 °C) solution of
freshly distilled cyclohexanesulfinyl chloride (7.00 g, 42 mmol,
1.6 equiv) in 25 mL of anhydrous THF was added dropwise
and with vigorous stirring a mixture of diacetone-D-glucose
(6.83 g, 26.3 mmol, 1 equiv) and pyridine (2.60 mL, 31.5 mmol,
1.2 equiv) in dry THF (20 mL). The reaction mixture was
stirred at -50 °C for 2.5 h and then quenched with water (100
mL). The aqueous layer was extracted with ethyl acetate (70
mL, three times). The combined organic extracts were succes-
sively washed with 5% aq HCl (100 mL), 2% aq NaHCO3 (100
mL), and brine (100 mL), dried over MgSO4, and concentrated
to dryness to afford the crude sulfinate (11.10 g) as a colorless
oil. The diastereomeric ratio was determined by 1H NMR
analysis: (R)/(S) ) 90/10. (R)-4 was isolated as a colorless oil
(8.49 g, 83% yield) after crystallization of (S)-4 from ethyl
acetate/petroleum ether 1/4. 1H NMR (CDCl3, 250 MHz) δ 1.30,
1.32, 1.42 and 1.50 (4 s, 12 H), 1.18-2.06 (m, 10 H), 2.65 (m,
1 H), 3.94-3.98 (m, 2 H), 4.10-4.18 (m, 2 H), 4.71 (d, J ) 1.7
Hz, 1H), 4.80 (d, J ) 3.5 Hz, 1H), 5.91 (d, J ) 3.5 Hz, 1H).
(S)-2-(Cycloh exylsu lfin yl)-N,N-d im eth yleth a n eth ioa -
m id e (1). To a cooled (-78 °C) solution of N,N-dimethyl-
ethanethioamide (1.86 g, 18 mmol, 3 equiv) in dry THF (22
mL) was added dropwise a 2 M solution of NaHMDS in THF
(8.7 mL, 17.4 mmol, 2.9 equiv). The reaction mixture was
stirred at -78 °C for 1 h, and then a solution of (R)-4 (2.34 g,
6 mmol, 1 equiv) in dry THF (15 mL) was added dropwise.
The reaction was monitored by thin-layer chromatography. It
was complete after 1.5 h and quenched by addition of a H2O/
THF (1/4) mixture at -78 °C. The reaction mixture was worked
up by addition of diluted aq H2SO4 solution (pH 1), followed
by extraction with CH2Cl2 (50 mL, four times). The combined
organic layers were washed with brine, dried over MgSO4, and
then concentrated to dryness. Purification by column chroma-
tography (silica gel, ethyl acetate then 10% MeOH) afforded
1.33 g (95% yield) of the (S)-enantiomer of 1 as a white solid
(mp 82 °C). Its enantiopurity (88% ee) was measured by HPLC
on a Chiralpack AD Daicel column (n-hexane/i-PrOH 90:10, λ
1
yellow solid: mp 64 °C; H NMR (250 MHz, CDCl3) δ 1.01-
2.01 (m, 10H), 1.31 (d, J ) 6.9 Hz, 3H), 2.96 (tt, J ) 3.8 Hz, J
) 11.9 Hz, 1H), 3.22-3.36 (m, 1H), 3.39 (s, 3H), 3.49 (s, 3H),
4.14 (d, J ) 6.4 Hz, 1H), 5.02-5.32 (m, 2H), 5.80-6.04 (m,
1H); 13C NMR (62.9 MHz, CDCl3) δ 17.5, 22.9, 25.7, 25.8, 26.4,
28.9, 40.5, 42.9, 44.3, 55.1, 71.7, 116.7, 140.3, 202.3; IR (KBr)
ν 3078, 2930, 2854, 2362, 1508, 1040 cm-1; MS (70 eV, EI)
m/z (%) 287 (M+, 13), 198 (11), 171 (16), 97 (18), 83 (36), 69
(71), 55 (100), 43 (99). Anal. Calcd for C14H25NOS2: C, 58.51;
H, 8.77; N, 4.88; S, 22.27. Found: C, 58.39; H, 8.81; N, 5.28;
S, 22.53.
(SS,2S,3R)-2-Cycloh exylsu lfin yl-N,N-d im eth yl-3-m eth -
ylp en t-4-en eth ioa m id e (6a ). Obtained from (R)-1 (310 mg,
1.34 mmol) and (Z)-4-bromobut-2-ene (235 mg, 1.74 mmol).
Flash chromatography on silica gel (ethyl acetate) afforded 202
mg (53% yield, dr 100:0:0:0) of 6a as a yellow solid. Its
(SS,2S,3R) configuration was deduced from that of the corre-
sponding amide 7a : 1H NMR (250 MHz, CDCl3) δ 1.02-2.00
(m, 10H), 1.38 (d, J ) 6.6 Hz, 3H), 2.91-3.06 (m, 1H), 3.27-
3.45 (m, 1H), 3.38 (s, 3H), 3.46 (s, 3H), 3.98 (d, J ) 6.2 Hz,
1H), 5.07 (d, J ) 10.2 Hz, 1H), 5.17 (d, J ) 17.1 Hz, 1H), 5.84-
6.02 (m, 1H); 13C NMR (62.9 MHz, CDCl3) δ 18.1, 22.8, 25.7,
25.8, 26.4, 28.7, 42.0, 42.7, 44.1, 55.3, 72.7, 116.4, 139.6, 196.1.
Further characterization of 6a was made on the corresponding
amide 7a .
(SS,2S,3S)-2-Cycloh exylsu lfin yl-N,N-d im et h yl-3-p h e-
n ylp en t-4-en eth ioa m id e (6b). Obtained from (R)-1 (157 mg,
0.67 mmol) and (Z)-3-phenylprop-2-enyl methane sulfonate
(156 mg, 0.74 mmol). Flash chromatography on silica gel (ethyl
acetate) afforded 106 mg (45% yield, dr 100:0:0:0) of 6b as a
solid. Its (SS,2S,3S) configuration was deduced from that of
the corresponding amide 7b: mp 91 °C; [R]19D -140 (c ) 0.98,
CHCl3); 1H NMR (250 MHz, CDCl3) δ 1.10-2.15 (m, 10H), 2.44
(s, 3H), 2.88 (tt, J ) 3.7 Hz, J ) 12.0 Hz, 1H), 3.32 (s, 3H),
4.27 (d, J ) 5.3 Hz, 1H), 4.35 (dd, J ) 5.3 Hz, J ) 7.9 Hz, 1H),
5.34 (d, J ) 10.0 Hz, 1H), 5.40 (d, J ) 16.9 Hz, 1H), 6.84 (ddd,
J ) 7.9 Hz, J ) 10.0 Hz, J ) 16.9 Hz, 1H), 7.15-7.50 (m, 5H);
13C NMR (62.9 MHz, CDCl3) δ 22.7, 25.5, 25.6, 26.2, 28.7, 41.2,
43.6, 49.7, 54.3, 72.3, 118.6, 127.7, 128.7, 129.0, 134.9, 140.8,
193.6; IR (NaCl) ν 3426, 3030, 2930, 2854, 1512, 1450, 1392,
1274, 1114, 1030, 990, 742, 702 cm-1; MS (70 eV, EI) m/z (%)
349 (M+, 0.8), 265 (1), 249 (3), 218 (100), 184 (68), 127 (30),
) 280.9 nm). The H and 13C NMR data are identical to those
1
previously reported7 for (R)-1.
(SR ,2R )-2-Cycloh e xylsu lfin yl-N ,N -d im e t h ylp e n t -4-
en eth ioa m id e (3a ). (S)-1 (233 mg, 1 mmol) was diluted in
freshly distilled THF (2 mL), and a 1.5 M solution of t-BuLi
in pentane (670 µL, 1 mmol) was slowly added at -40 °C under
nitrogen. After 50 min of stirring at -40 °C and 45 min at -5
°C, allyl bromide (95 µL, 1,1 mmol) was added at -40 °C, and

Asymmetric Thio-Claisen Rearrangement
J . Org. Chem., Vol. 66, No. 23, 2001 7847
115 (37), 88 (70), 83 (55), 55 (96), 44 (62); HMRS found
350.1622, C19H28NOS2 (MH+) requires 350.1612.
This reaction was also carried out with (R)-1 (171 mg, 0.73
mmol) and (Z)-3-bromo-1-phenylpropene (164 mg, 0.83 mmol)
and afforded 102 mg (40% yield, dr 100:0:0:0) of 6b.
MHz, CDCl3) δ 19.0, 25.6, 26.0, 26.02, 33.7, 34.5, 42.2, 43.2,
44.6, 45.4, 114.7, 140.7, 202.5; IR (NaCl) ν 3076, 2928, 2852,
1638, 1516, 1448, 1390, 1276, 1146, 1096, 1068, 996, 918 cm-1
;
MS (70 eV, EI) m/z (%) 271 (M+, 1), 255 (0.8), 236 (1), 216
(30), 208 (23), 193 (87), 188 (99), 157 (95), 156 (100), 142 (33),
The same (SS,2S,3S) isomer of 6b was also obtained from
(R)-1 (100 mg, 0.43 mmol) and (E)-3-bromo-1-phenylpropene
(96 mg, 0.49 mmol). Flash chromatography on silica gel (ethyl
acetate) afforded 80 mg (53% yield, dr 90:10:0:0) of 6b. Only
the signals of the (SS,2S,3R) minor isomer that were clearly
identified are given: 1H NMR (250 MHz, CDCl3) δ 2.73 (s, 3H,
NMe), 3.23 (s, 3H, NMe); 13C NMR (62.9 MHz, CDCl3) δ 41.4
(NMe), 43.9 (NMe), 75.0 (SOCH), 117.6 (CH2d).
88 (24), 83 (13), 55 (82), 41 (47); HRMS found 271.1463, C14H25-
NS2 (M+) requires 271.1428. Anal. Calcd for C14H25NS2: C,
61.94; H, 9.28; N, 5.16; S, 23.62. Found: C, 61.87; H, 9.43; N,
5.55; S, 23.51. 1H NMR signals of the (2S,3S) minor isomer
(400 MHz, CDCl3) δ 1.06 (d, J ) 6.6 Hz, 3H), 3.44 (s, 3H),
3.51 (s, 3H); 13C NMR signals of the (2S,3S) minor isomer (100
MHz, CDCl3) δ 115.4, 141.1.
(2S,3S)-2-Cycloh exylsu lfa n yl-N,N-d im eth yl-3-p h en yl-
p en t-4-en eth ioa m id e (8b). Obtained from (SS,2S,3S)-6b (dr
100:0:0:0, 237 mg, 0.68 mmol). Flash chromatography on silica
gel (petroleum ether/ethyl acetate 8:2) afforded 134 mg (59%
(SS,2S,3R)-2-Cycloh exylsu lfin yl-N,N-d im eth yl-3-m eth -
ylp en t-4-en a m id e (7a ). Typ ica l P r oced u r e. (SS,2S,3R)-6a
(93 mg, 0.32 mmol) was diluted in acetone (4.5 mL). Sodium
bicarbonate (107 mg, 1.26 mmol) and water (450 µL) were
added, and the mixture was stirred at 0 °C. Then 0.5 equiv of
oxone (100 mg, 0.16 mmol) was first added. After 15 min of
stirring, 0.25 equiv of oxone was added every 15 min (4 × 50
mg, 0.32 mmol). Water (5 mL) was then added. The aqueous
phase was extracted with ethyl acetate (5 mL, three times).
The combined organic layers were dried over MgSO4 and then
concentrated to dryness to afford 66 mg (75% yield, dr 100:0:
0:0) of a white solid. Its (SS,2S,3R) configuration was assigned
by X-ray crystallographic analysis after crystallization (ethyl
acetate/petroleum ether): mp 95 °C; [R]19D -160 (c ) 1, CHCl3);
1H NMR (250 MHz, CDCl3) δ 1.10-2.05 (m, 10H), 1.30 (d, J
) 7.0 Hz, 3H), 2.60-2.75 (m, 1H), 2.98-3.20 (m, 1H), 2.98 (s,
3H), 3.11(s, 3H), 3.82 (d, J ) 6.3 Hz, 1H), 5.10 (d, J ) 10.5
Hz, 1H), 5.17 (d, J ) 17.1 Hz, 1H), 5.84-5.99 (m, 1H); 13C
NMR (62.9 MHz, CDCl3) δ 18.5, 23.1, 25.4, 25.5, 26.0, 28.2,
35.7, 38.4, 38.5, 55.8, 66.4, 116.1, 139.0, 167.5; IR (KBr) ν 3222,
3070, 2924, 2854, 1620, 1496, 1456, 1404, 1258, 1128, 1044,
992, 910, 518, 456 cm-1; MS (70 eV, EI) m/z (%) 272 (MH+, 2),
214 (2), 189 (33), 172 (4), 141 (45), 134 (100), 126 (53), 105
(18), 72 (57), 55 (41), 44 (21).
yield) of 8b as a white solid: mp 120 °C; [R]18 -17 (c ) 1,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.91-1.61 (m, 10H), 1.77
(m, 1H), 3.45 (s, 3H), 3.46 (m, 1H), 3.49 (s, 3H), 4.30 (br s,
1H), 5.04-5.08 (m, 2H), 6.08 (br s, 1H), 7.26-7.34 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 25.6, 26.06, 32.9, 34.7, 42.0, 43.7,
45.0, 53.9, 57.2, 117.4, 127.1, 128.4, 129.3, 138.2, 141.1, 202.4;
IR (KBr) ν 3058, 3026, 2924, 2848, 2364, 1636, 1514, 1450,
1446, 1414, 1390, 1274, 1206, 1114, 998, 990, 770, 704, 668,
526 cm-1; MS (70 eV, EI) m/z (%) 333 (M+, 2), 250 (4), 219
(100), 204 (10), 186 (21), 134 (17), 128 (18), 117 (17), 88 (55),
55 (27), 44 (19); HRMS found 333.1574, C19H27NS2 (M+)
requires 333.1585.
Starting from (SS,2S,3S)-6b (dr 90:10:0:0, 10 mg, 0.029
mmol), 8b (7 mg, 73% yield) was obtained after flash chroma-
tography (CH2Cl2). The diastereomeric ratio was determined
1
by H NMR analysis: (2S,3S)/(2S,3R) 84:16.
(S)-2-Cycloh exylsu lfa n yl-N,N-d im et h ylp en t -4-en et h -
ioa m id e (8c). Obtained from (SS,2S)-3a (123 mg, 0.45 mmol).
Flash chromatography on silica gel (CH2Cl2) afforded 100 mg
(86% yield) of 8c as a yellow oil: [R]18 -137 (c ) 1.9, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 1.27-1.98 (m, 10H), 2.62-2.69
(m, 1H), 2.97 (m, 1H), 3.07 (br s, 1H), 3.43 (s, 3H), 3.50 (s,
3H), 4.03 (br s, 1H), 5.03-5.14 (m, 2H), 5.76-5.86 (m, 1H);
13C NMR (100 MHz, CDCl3) δ_25.6, 26.0, 26.1, 34.2, 34.7, 41.0,
41.8, 43.0, 45.30, 45.34, 117.4, 135.4, 202.0; IR (NaCl) ν 3074,
2928, 2850, 1638, 1508, 1448, 1390, 1276, 1140, 1088, 998, 918
cm-1; MS (70 eV, EI) m/z (%) 257 (M+, 1), 255 (1), 236 (0.4),
216 (1), 214 (3), 208 (2), 193 (7), 174 (28), 156 (10), 143 (100),
142 (100), 127 (13), 114 (12), 88 (12), 55 (34), 44 (74); HRMS
found 257.1221, C13H23NS2 (M+) requires 257.1272.
(SS,2S,3S)-2-Cycloh exylsu lfin yl-N,N-d im et h yl-3-p h e-
n ylp en t-4-en a m id e (7b). Obtained from (SS,2S,3S)-6b (116
mg, 0.33 mmol) as white crystals (90 mg, 81% yield, dr 100:
0:0:0). Its (SS,2S,3S) configuration was assigned by X-ray
crystallographic analysis after crystallization (ethyl acetate/
petroleum ether): mp 130 °C; [R]21 -92 (c ) 0.5, CHCl3); 1H
D
NMR (250 MHz, CDCl3) δ 1.10-2.05 (m, 10H), 2.30 (s, 3H),
2.48-2.62 (m, 1H), 2.86 (s, 3H), 4.03 (d, J ) 5.4 Hz, 1H), 4.24
(dd, J ) 5.4 Hz, J ) 9.3 Hz, 1H), 5.32 (d, J ) 10.0 Hz, 1H),
5.34 (d, J ) 17.1 Hz, 1H), 6.51 (ddd, J ) 9.3 Hz, J ) 10.0 Hz,
J ) 17.1 Hz, 1H), 7.15-7.40 (m, 5H); 13C NMR (62.9 MHz,
CDCl3) δ 23.1, 25.5, 26.0, 28.2, 35.5, 37.2, 48.2, 55.5, 66.3,
119.1, 127.5, 128.2, 129.0, 134.9, 140.9, 166.7; IR (KBr) ν 2984,
2954, 2930, 2852, 1628, 1492, 1452, 1414, 1400, 1256, 1178,
1128, 1108, 1040, 994, 928, 758, 702, 602, 512 cm-1; MS (70
eV, EI) m/z (%) 334 (MH+, 1), 251 (7), 234 (1), 214 (2), 203 (8),
201 (8), 189 (3), 157 (7), 141 (2), 134 (100), 105 (15), 72 (30),
55 (18). Anal. Calcd for C19H27NO2S: C, 68.43; H, 8.17; N, 4.20;
S, 9.60. Found: C, 68.60; H, 8.22; N, 4.59; S, 9.91.
(S)-N,N-Dim eth yl-3-m eth ylp en t-4-en eth ioa m id e (9a ).28
Typ ica l P r oced u r e. To a solution of (SS,2S,3R)-6a (dr 90:
10:0:0, 79 mg, 0.27 mmol) in HMPA (0.275 mL, 1.58 mmol)
was added slowly a solution of SmI2 (0.58 mmol) in THF [5.8
mL, freshly prepared from 1,2-diiodoethane (282 mg, 1 mmol)
and samarium (301 mg, 2 mmol) in THF (10 mL)]. The
resulting mixture was stirred at room temperature, and the
reaction was monitored by TLC. After 1.5 h, the reaction
mixture was hydrolyzed by addition of a 0.1 M aqueous
solution of HCl (5 mL) and then extracted with ethyl acetate
(5 mL, three times). The combined organic layers were washed
with water (5 mL), a saturated aqueous solution of sodium
thiosulfate (5 mL), and brine (5 mL), dried over MgSO4, and
concentrated to dryness. Flash chromatography on silica gel
(petroleum ether/ethyl acetate 8:2) afforded 26 mg (60% yield)
of 9a as a colorless oil. The enantiomeric ratio of 9a was
determined by HPLC analysis on a Daicel Chiralpack AD
column (n-hexane/i-PrOH 99:1, λ ) 275.7 nm): (S)/(R) 90:10;
1H NMR (250 MHz, CDCl3) δ 1.12 (d, J ) 6.5 Hz, 3H), 2.73-
2.98 (m, 3H), 3.32 (s, 3H), 3.50 (s, 3H), 4.95-5.08 (m, 2H), 5.83
(ddd, J ) 6.7 Hz, J ) 10.3 Hz, J ) 17.0 Hz, 1H); 13C NMR
(62.9 MHz, CDCl3) δ 19.5, 38.3, 42.2, 44.8, 49.6, 113.6 142.6,
202.8; IR (NaCl) ν 3076, 2964, 2930, 2870, 1640, 1520, 1456,
1392, 1284, 1124, 1054, 998, 916, 854, 720, 676 cm-1; MS (70
eV, EI) m/z (%) 157 (M+, 100), 142 (71), 128 (13), 88 (55), 44
(56).
Com p ou n d s 8a -c. Conformational changes of the molecule
1
within the NMR time scale resulted in broad signals. The H
NMR signal of CHR for 8a -b (R ) Me, Ph) was hidden by
the NCH3 signals.
(2S,3R)-2-Cycloh exylsu lfa n yl-N,N-d im eth yl-3-m eth yl-
p en t-4-en eth ioa m id e (8a ). Typ ica l P r oced u r e. P4S10 (117
mg, 0.26 mmol) was added slowly to a stirred solution of
(SS,2S,3R)-6a (dr 90:10:0:0, 150 mg, 0.52 mmol) in CH2Cl2 (4
mL) at room temperature. The reaction was monitored by TLC.
After 45 min, the CH2Cl2 layer was separated, and the residual
inorganic reagent was shaken with water (2 mL) and CH2Cl2
(3 mL, three times). The combined organic extracts were
washed once with water (5 mL) and evaporated to dryness.
Flash chromatography on silica gel (CH2Cl2) afforded 113 mg
(80% yield) of 8a as a yellow oil. The diastereomeric ratio was
determined by 1H NMR analysis: (2S,3R)/(2S,3S) 90:10; 1H
NMR (400 MHz, CDCl3) δ 1.20-2.02 (m, 10H), 1.28 (d, J )
6.6 Hz, 3H), 2.91 (m, 1H), 3.39 (s, 3H), 3.45 (s, 3H), 4.01 (br s,
1H), 4.95-5.08 (m, 2H), 5.76-5.85 (m, 1H); 13C NMR (100
(S)-N,N-Dim eth yl-3-p h en ylp en t-4-en eth ioa m id e (9b).
Obtained from (SS,2S,3S)-6b (dr 90:10:0:0, 50 mg, 0.14 mmol).
After 2.5 h of stirring, the reaction was stopped, although it

7848 J . Org. Chem., Vol. 66, No. 23, 2001
Nowaczyk et al.
was not complete. Flash chromatography on silica gel (petro-
leum ether/ethyl acetate 8:2) afforded 12 mg (39% yield) of 9b
as a yellow oil; 10 mg of starting material was recovered (dr
90:10:0:0, 20%). The enantiomeric ratio of 9b was determined
by HPLC analysis on a Daicel Chiralpack AD column (n-
Ack n ow led gm en t. We gratefully acknowledge the
CNRS and the “Re´gion Basse-Normandie” for financial
support to S.N., Margareth Lemarie´ for HPLC analysis
of 9b, and Pascale Gancel for technical assistance.
1
hexane/i-PrOH 98:2, λ ) 278.1 nm): (S)/(R) 88:12; H NMR
(400 MHz, CDCl3) δ 2.96 (s, 3H), 3.17 and 3.25 (AB of ABX,
2H, J AB ) 12.7 Hz, J AX ) 8.0 Hz, J BX ) 6.9 Hz), 3.39 (s, 3H),
4.15-4.21 (m, 1H), 5.08-5.15 (m, 2H), 6.12 (ddd, J ) 6.7 Hz,
J ) 10.4 Hz, J ) 17.0 Hz, 1H), 7.22-7.31 (m, 5H); 13C NMR
(62.9 MHz, CDCl3) δ 41.9, 44.8, 48.4, 49.9, 115.2 127.0, 128.0,
128.6, 140.1, 142.6, 202.1; IR (NaCl) ν 3080, 3060, 3026, 2974,
2932, 2360, 2340, 1636, 1600, 1520, 1452, 1392, 1284, 1072,
918, 758, 702 cm-1; MS (70 eV, EI) m/z (%) 219 (M+, 100), 204
(49), 186 (22), 158 (11), 131 (11), 115 (27), 105 (17), 88 (39), 70
(16), 68 (10), 44 (57); HRMS found 219.10809, C13H17NS (M+)
requires 219.10816.
Su p p or tin g In for m a tion Ava ila ble: Scheme for the
rearrangement of keteneaminothioacetals (ZZ)-5a -b and
(ZE)-5a . Experimental procedures and typical H NMR data
for aminoketenethioacetals 2a -c and 5a -b. X-ray crystal-
lographic data for compounds 3a and 7a -b and HPLC isomer
analyses of 9a -b. This material is available free of charge via
the Internet at http://pubs.acs.org. *Fax: +33 231 452 877.
1
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