Asymmetric reduction of α-(trimethylsilyl)methyl-β-ketosulfoxide with DIBAL under basic conditions

Article abstract of DOI:10.1021/jo034285k

The reaction of the α-carbanion of p-tolyl 2-(trimethylsilyl)ethyl sulfoxide with esters followed by reduction with DIBAL gave α-(trimethylsilyl)methyl-β-hydroxysulfoxides with high stereoselectivity. The stereoselective reaction was demonstrated to proceed through a dynamic kinetic resolution pathway via a six-membered cyclic transition state involving Si-O interaction. These reactions provide a convenient route for the synthesis of optically pure allylic alcohols.

Full text of DOI:10.1021/jo034285k

rate of each diastereomer with a reducing agent (dynamic
kinetic resolution). In contrast, reduction of R-alkylated
â-ketosulfoxides under similar basic conditions shows
only low stereoselectivity.3 There is no report on the
reduction of R-alkylated â-ketosulfoxides with DIBAL
through a dynamic kinetic resolution pathway. Recently,
we have reported reactions of the R-sulfinyl carbanion
of â-(trimethylsilyl)ethyl sulfoxide as a powerful chiral
inducer,6,7 in which Si-O interaction in the transition
state has been demonstrated. We now report a highly
stereoselective reduction of R-(trimethylsilyl)methyl-â-
ketosulfoxides that proceeds through a dynamic kinetic
resolution pathway, involving a transition state stabilized
by the Si-O interaction.
We examined the reaction of the R-sulfinyl carbanion,
derived from p-tolyl â-(trimethylsilyl)ethyl sulfoxide 1,6a
with various esters and subsequent in situ reduction of
the produced R-(trimethylsilyl)methyl-â-ketosulfoxides 4
with various reducing agents. We also studied a similar
reaction of R-alkyl p-tolyl sulfoxides 2 and 3. The results
are summarized in Table 1.
Asym m etr ic Red u ction of
r-(Tr im eth ylsilyl)m eth yl-â-k etosu lfoxid e
w ith DIBAL u n d er Ba sic Con d ition s
Shuichi Nakamura, J un-ichi Nakayama, and
Takeshi Toru*
Department of Applied Chemistry, Nagoya Institute of
Technology, Gokiso, Showa-ku, Nagoya, 466-8555, J apan
toru@ach.nitech.ac.jp
Received March 5, 2003
Abstr a ct: The reaction of the R-carbanion of p-tolyl 2-(tri-
methylsilyl)ethyl sulfoxide with esters followed by reduction
with DIBAL gave R-(trimethylsilyl)methyl-â-hydroxysulfox-
ides with high stereoselectivity. The stereoselective reaction
was demonstrated to proceed through a dynamic kinetic
resolution pathway via a six-membered cyclic transition
state involving Si-O interaction. These reactions provide a
convenient route for the synthesis of optically pure allylic
alcohols.
A THF solution of â-(trimethylsilyl)ethyl sulfoxide 1
was treated with LDA (1.3 equiv)8 at -78 °C and
subsequently reacted with ethyl benzoate (1.5 equiv),
forming â-ketosulfoxide 4a . Without isolation of 4a ,
DIBAL (1.6 equiv) was added to this solution at -78 °C.
A single diastereomer 5a A out of four possible diaster-
eomeric â-hydroxysulfoxides 5a shown in Scheme 1 was
formed in 60% yield.9 The unreduced â-ketosulfoxide 4a
was isolated in 38% yield in a syn/anti ratio of 79:21
(entry 1). On the other hand, the one-pot reduction of 4a
with other reducing agents such as LiAlH4, L-selectride,
and NaBH4 gave two diastereomeric products 5a A and
5a B but with low stereoselectivities (entries 2-4). The
reaction of 1 with other esters and subsequent reduction
with DIBAL also gave â-hydroxysulfoxides 5bA-d A as
single diastereomers together with unreduced â-ketosul-
foxides 4b-d (entries 5-7). In contrast to the highly
stereochemical outcome in the reduction of R-(trimeth-
ylsilyl)methyl-â-ketosulfoxides 4a-d, reduction of R-alkyl-
â-ketosulfoxides 4e and 4f with DIBAL showed low
stereoselectivity on the carbon R to the sulfinyl group
giving the diastereomeric products 5e and 5f in an A/C
ratio of 74:26 and 72:28, respectively (entries 8 and 9).11
It is well-known that reduction of â-ketosulfoxides with
diisobutylaluminum hydride (DIBAL) gives â-hydrox-
ysulfoxides with high diastereoselectivity.1 The DIBAL
reduction of a diastereomeric mixture of R-substituted
â-ketosulfoxides, which possibly affords four diastereo-
meric isomers, shows high selectivity with respect to
carbonyl face selection, but the products are generally
obtained as an inseparable mixture of the diastereo-
mers.2,3 This often becomes a disadvantage of the above
type of reduction in terms of the stereoselective synthesis
of â-hydroxysulfoxides. Highly stereocontrolled synthesis
of R-substituted â-hydroxysulfoxides has been partly
achieved: Ogura4 and Guanti5 with their co-workers have
independently reported that reduction of R-(alkylthio)-
â-ketosulfoxides with NaBH4 or LiAlH4 in the presence
of tertiary amines such as triethylamine gives the
products with high stereoselectivity. They have assumed
that the highly diastereoselective outcome can be as-
cribed to the rapid equilibrium between the diastereo-
meric R-substituted â-ketosulfoxides through abstraction
and addition of an R-proton as well as to the reaction
* To whom correspondence should be addressed. Phone/Fax:
(+)81-52-735-5217.
(6) (a) Kusuda, S.; Ueno, Y.; Toru, T. Tetrahedron 1994, 50, 1045-
1062. (b) Toru, T.; Nakamura, S.; Takemoto, H.; Ueno, Y. Synlett 1997,
449-450. (c) Nakamura, S.; Watanabe, Y.; Toru, T. J . Chem. Soc.,
Perkin Trans. 1 1999, 3403-3404. (d) Ghorai, B. K.; Herndon, J . W.;
Lam, Y. Org. Lett. 2001, 3, 3535-3538. (e) Nakamura, S.; Uchiyama,
Y.; Ishikawa, S.; Fukinbara, R.; Watanabe, Y.; Toru, T. Tetrahedron
Lett. 2002, 43, 2381-2383. (f) Chambert, S.; De´sire´, L.; De´cout, J .-L.
Synthesis 2002, 2319-2334.
(7) (a) Nakamura, S.; Takemoto, H.; Ueno, Y.; Toru, T.; Kakumoto,
T.; Hagiwara, T. J . Org. Chem. 2000, 65, 469-474. (b) Nakamura, S.;
Watanabe, Y.; Toru, T. J . Org. Chem. 2000, 65, 1758-1766. (c)
Nakamura, S.;. Toru, T. J . Synth. Org. Chem., J pn. 2002, 60, 115-
124.
(1) (a) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985,
26, 435-438. (b) Kosugi, H.; Konta, H.; Uda, H. J . Chem. Soc., Chem.
Commun. 1985, 211-213. (c) Solladie´-Cavallo, A.; Suffert, J .; Adib.
A.; Solladie´, G. Tetrahedron Lett. 1990, 31, 6649-6652.
(2) (a) Carreno, M. C.; Ruano, J . L. G.; Martin, A. M.; Pedregal, C.;
Rodrigues, J . H.; Rubio, A.; Sanchez, J .; Solladie´, G. J . Org. Chem.
1990, 55, 2120-2128. (b) Bueno, A. B.; Carreno, M. C.; Ruano, J . L.
G.; Pena, B.; Rubio, A.; Hoyos, M. A. Tetrahedron 1994, 50, 9355-
9364. (c) Ruano, J . L. G.; Maestro, M. C.; Sanchez, F. Tetrahedron:
Asymmetry 1995, 6, 2299-2312. (d) Ruano, J . L. G.; Maestro, M. C.;
Barros, D.; Gonzalez, A. M. Tetrahedron: Asymmetry 1996, 7, 1819-
1828.
(8) Larger amount of LDA lowered the yield of 5a .
(3) Barros, D.; Carreno, M. C.; Ruano, J . L. G.; Maestro, M. C.
Tetrahedron Lett. 1992, 33, 2733-2736.
(9) To confirm the product distribution, four diastereomeric isomers
5a A-D were separately prepared by the reaction of the R-carbanion
derived from the corresponding â-hydroxysulfoxide with (iodomethyl)-
trimethylsilane.
(4) Ogura, K.; Fujita, M.; Inaba, T.; Takahashi, K.; Iida, H.
Tetrahedron Lett. 1983, 24, 503-506.
(5) Guanti, G.; Narisano, E.; Pero, F.; Banfi, L.; Scolastico, C. J .
Chem. Soc., Perkin Trans. 1 1984, 189-193.
(10) Absolute configuration of 5c was determined by comparison of
the 1H NMR spectral data with the reported data; see ref 3.
10.1021/jo034285k CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/07/2003
5766
J . Org. Chem. 2003, 68, 5766-5768

TABLE 1. Red u ction of r-Su bstitu ted â-Ketosu lfoxid es 1-3 w ith Va r iou s Red u cin g Agen ts
sulfoxide
R
yield (%)
diastereomeric ratioa
A:B:C:D
entry
reducing agent
R′
4
5
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
3
CH2SiMe3
CH2SiMe3
CH2SiMe3
CH2SiMe3
CH2SiMe3
CH2SiMe3
CH2SiMe3
CH3
Ph
Ph
Ph
Ph
DIBAL
LiAlH4 c
NaBH4
L-Selectride
DIBAL
DIBAL
DIBAL
DIBAL
DIBAL
4a : 38b
4a : 30
4a : 30
4a : 45
4b: 35d
4c: 43b
4d : 40e
4e: 17f
4f: 47f
5a : 60
5a : 62
5a : 65
5a : 51
5b: 30
5c: 52
5d : 55
5e: 83
5f: 51g
>98:0:0:0
65:35:0:0
55:45:0:0
64:36:0:0
>98:0:0:0
>98:0:0:0
>98:0:0:0
74:0:26:0
72:0:28:0
CH3
n-C5H11
(CH3)2CH
CH3
CH2CMe3
Ph
a
b
Diastereomeric ratio was determined by the 1H NMR spectrum. Syn/anti ratio was determined to be 79:21 by the 1H NMR spectrum.
c Reaction was carried out in EtOH. Syn/anti ratio was 60:40. e Syn/anti ratio was 65:35. f Syn/anti ratio was 58:42. g Absolute configuration
d
of 5f has not been determined.
SCHEME 1
These results show the important role of the â-silyl group
in the stereochemical outcome.
To obtain more information on the reaction mecha-
nism, we performed the reduction of â-ketosulfoxide 4a ,
which was isolated as a diastereomeric mixture in a ratio
of 79:21 at the stage of the reaction of lithiated 1 with
ethyl benzoate in THF at -78 °C (Scheme 1). The DIBAL
F IGURE 1. Stereoselective course to form 5A under dynamic
reduction of 4a in THF at -78 °C gave 5a in 96% yield
kinetic resolution control.
in an A/B/C/D ratio of 75:0:21:4. On the other hand, when
4a was first treated with 0.3 equiv of LDA and then with
DIBAL in THF at -78 °C, a single diastereomer 5a A was
obtained in 64% yield as in the case of in situ reduction
of 4a without isolation, together with recovered 4a in a
ratio of 75:25.
(11) Another possible pathway, i.e., enolate formation with LDA
selectively from anti-4a and reduction occurring only from syn-4a , can
be ruled out: a solution of 4a with a syn/anti ratio of 79:21 was treated
with a smaller amount (0.1 equiv) of LDA at -78 °C and subsequently
quenched with water. The syn/anti ratio of 4a thus obtained was the
same as that of the starting 4a . The product 4a should be composed
of a higher content of syn-4a than that of the starting 4a in the above
mechanism.
These results show that the reduction proceeds through
a dynamic kinetic resolution pathway (kA > kB, kC, kD in
Figure 1), where very rapid equilibrium between syn-4a
and anti-4a occurs through formation of the enolate in
the presence of LDA and syn-4a is selectively reduced to
give 5a A.11
J . Org. Chem, Vol. 68, No. 14, 2003 5767

(Figure 2).12,13 The transition state TS-1 derived from
syn-4 has a lower activation energy than TS-2 from anti-
4, because TS-1 involves the Si-O interaction stabilizing
the partially negative charge on the carbonyl oxygen.
The products 5a -d could be converted to optically
active allylic alcohols on treatment with tetrabutylam-
monium fluoride (TBAF, 1.1 equiv) in THF at room
temperature (method A) or on heating in benzene at
reflux for 30 min in the presence of pyridine (method
B).6a-c,e,7,14 The optical purities of the products 6-10 were
1
determined by H NMR analyses of the corresponding
MTPA esters. No racemization occurred during this
reaction. Thus, the chiral p-tolyl â-trimethylsilylethyl
sulfoxide 1 serves as a “chiral vinyl anion equivalent”.
In summary, the R-carbanion derived from p-tolyl
2-(trimethylsilyl)ethyl sulfoxide was reacted with esters
and subsequently with DIBAL to give the single diaste-
reomer of the â-hydroxysulfoxide. The reaction was
demonstrated to proceed through a cyclic transition state
involving the Si-O interaction. These reactions provide
a convenient route for the synthesis of optically pure
allylic alcohols.
F IGURE 2. Assumed transition state in reduction of 4 with
DIBAL.
SCHEME 2
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research (No. 11650890)
from the Ministry of Education, Science, Sports and
Culture, J apan, and the Sasakawa Scientific Research
Grant from The J apan Science Society.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation and spectroscopic characterization
of products 4a -f, 5a -f, and 6-10. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O034285K
Reduction of R-(silylethyl)-â-ketosulfoxides 4a -d with
DIBAL showed high stereoselectivity not only on the
carbonyl face but also on the carbon R to the sulfinyl
group. These results would be due to the interaction
between the silicon and the carbonyl oxygen, such
interaction in the transition state being demonstrated in
our previous reports.7 The in situ reduction of 4a using
other reducing agents such as LiAlH4, L-selectride, and
NaBH4 gave 5a A and 5a B, which were derived from syn-
4a . It is reasonable that the DIBAL reduction proceeds
through a cyclic transition state, because the highly
stereoselective DIBAL reduction of â-ketosulfoxides in
the presence of a Lewis acid such as ZnCl2 is well
rationalized by a conformationally rigid six-membered
cyclic intermediate involving chelation of a Lewis acid
with the sulfinyl and the carbonyl oxygens.1 We assumed
a six-membered cyclic transition state involving the
chelation with a lithium cation, possibly derived from
lithium ethoxide and/or the lithium enolate formed
during the reaction, where DIBAL approaches from the
direction of the sulfinyl lone pair to give product 5A
(12) Ruano and co-workers have reported that reduction of a
diastereomeric mixture of 4e with DIBAL in the presence of ZnCl2
proceeds more stereoselectvely, via a six-membered cyclic transition
state, than that without ZnCl2 to give 5eA and 5eC; see ref 3. This
stereochemical outcome is in good accord with that shown in entry 8
(Table 1). The DIBAL reduction of â-ketosulfoxides in the presence of
a catalytic amount of ZnCl2 also proceeds through a chelated model to
give â-hydroxysulfoxides with high stereoselectivities; see ref 1c. These
results support a six-membered cyclic transition state in the DIBAL
reduction of 4 in the presence of lithium cation.
(13) Solladie´ and co-workers have assumed
intermediate in reduction of â-ketosulfoxides with LiAlH4; see refs 1a
and 2a.
a lithium-chelated
(14) Several methods for the preparation of chiral secondary allylic
alcohols have been reported. For the kinetic resolution in asymmetric
epoxidation, see: (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.;
Yamada, Y.; Ikeda, M.; Sharpless, K. B. J . Am. Chem. Soc. 1981, 103,
6237-6240. (b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S.-Y.;
Masamune, H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-
5780. For the asymmetric reduction of R,â-unsaturated ketones, see:
(c) Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J . Am. Chem.
Soc. 1984, 106, 6717-6725. For the kinetic resolution in asymmetric
hydrogenation, see: (d) Kitamura, M.; Kasahara, I.; Manabe, K.;
Noyori, R.; Takaya, H. J . Org. Chem. 1988, 53, 708-710. For the
enantioselective addition of a vinylzinc reagent, see: (e) Oppolzer, W.;
Radinov, R. N. Helv. Chim. Acta 1992, 75, 170-173.
5768 J . Org. Chem., Vol. 68, No. 14, 2003