Journal of the American Chemical Society
ARTICLE
Scheme 4. Catalyst-Controlled Stereoselective Synthesis of
1,3-Diols
’ ASSOCIATED CONTENT
S
Supporting Information. Characterization of new com-
b
pounds and experimental procedures. This material is available
’ AUTHOR INFORMATION
Corresponding Author
nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp
’ ACKNOWLEDGMENT
This work was financially supported by a Grant-in-Aid for
Scientific Research (S) from JSPS (M.S.) and Grant-in-Aid for
Innovative Areas from MEXT (N.K.). N.K. thanks the Sumitomo
Foundation for financial support. R.Y. thanks JSPS for a pre-
doctoral fellowship.
’ REFERENCES
(1) General review of asymmetric aldol reactions: (a) Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004. (b) Geary,
L. M.; Hultin, P. G. Tetrahedron: Asymmetry 2009, 20, 131.
(2) Reviews of direct catalytic asymmetric aldol reactions: (a)
Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187. (b) Alcaide,
B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595. (c) Notz, W.; Tanaka, F.;
Barbas, C. F., III Acc. Chem. Res. 2004, 37, 580. (d) Mukherjee, S.; Yang,
J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. See also ref 1a.
(3) Trost, B. M. Science 1991, 254, 1471.
nucleophiles, affording the corresponding ketone 12 and ketoester
13 by treatment with MeLi and Li ester enolate at À78 °C,
respectively. Activation of the thiocarbonyl moiety with TFAA
gave the corresponding amide 14.26 It is worth noting that no
epimerization proceeded during the activation of thioamide in
these transformation reactions. Amino alcohol 15 was obtained by
directly subjecting the aldol product 3ca to the reduction with
Red-Al in ether at room temperature. The second aldol reaction of
the thus-obtained sample with 94% ee aldehyde 9 demonstrates
the application of the present aldol methodology to the enantio-
selective synthesis of 1,3-diols via catalyst-controlled stereoselec-
tion (Scheme 4).27,28 A second aldol reaction with thioacetamide
1b was attempted using 10 mol % (R)-catalyst in DMF at À60 °C,
affording predominantly syn-diol (3S,5R)-16 with excellent en-
antioselectivity. On the other hand, subjecting the same substrate
set to (S)-catalyst delivered anti-diol (3S,5R)-16 with high stereo-
selectivity, indicating that stereoselectivity of the newly con-
structed stereogenic center was largely controlled by chirality of
the catalyst.
(4) Handbook of Green ChemistryÀGreen Catalysis; Anastas, P. T,
Crabtree, R. H., Eds.; Wiley-VCH: Weinheim, 2009.
(5) There are numerous examples of direct aldol reactions using
aldol donors bearing electron-withdrawing R-substituents that are read-
ily enolized under mild basic conditions.
(6) Direct catalytic asymmetric aldol (-type) reactions using aldol
donors at the carboxylic acid oxidation state without electron-with-
drawing R-substituents. Alkylnitriles: (a) Suto, Y.; Tsuji, R.; Kanai, M.;
Shibasaki, M. Org. Lett. 2005, 7, 3757. Activated amides:(b) Saito, S.;
Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 8704. β,γ-Unsaturated ester:
(c) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 10842. 5H-oxazol-4-ones:(d) Misaki, T.; Takimoto, G.; Sugimura,
T. J. Am. Chem. Soc. 2010, 132, 6286. (e) Direct catalytic asymmetric
aldol reaction of thiazolidinethiones where the use of stoichiometric
amount of silylating reagent was essential: Evans, D. A.; Downey, C. W.;
Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706.
’ CONCLUSIONS
(7) For the use of thioamide as pronucleophile in enantioselective
CÀC bond-forming reactions, see: Iwasawa, N.; Yura, T.; Mukaiyama,
T. Tetrahedron 1989, 45, 1197.
In conclusion, we developed a direct catalytic asymmetric
aldol reaction of thioacetamides promoted by a soft Lewis acid/
hard Brønsted base cooperative catalyst. As a result of the highly
chemoselective deprotonation of thioamide through a softÀsoft
interaction, the desired aldol products were produced in a highly
stereoselective manner, even with R-nonbranched enolizable
aldehydes. The addition of phosphine oxide to the above-
mentioned catalyst constituted a soft Lewis acid/hard Brønsted
base/hard Lewis base ternary catalyst, enhancing the catalytic
activity in THF to enable the syn-selective direct catalytic
asymmetric aldol reaction of thiopropionamides. Because of
the substantial effect of phosphine oxide and the presence of
the retro-aldol reaction, stringent control of the phosphine oxide
was essential to achieve high stereoselectivity. Divergent trans-
formation of the thioamide functionality showcases the synthetic
utility of the present catalysis, culminating in the catalyst-
controlled stereoselective synthesis of both syn and anti 1,3-diols
via iterative direct aldol reactions.
(8) For the use of thioamide as pronucleophile in diastereoselective
CÀC bond-forming reactions, see: (a) Tamaru, Y.; Harada, T.; Nishi, S.;
Mizutani, M.; Hioki, T.; Yoshida, Z. J. Am. Chem. Soc. 1980, 102, 7806.
(b) Goasdoue, C.; Goasdoue, N.; Gaudemar, M.; Mladenova, M. J.
Organomet. Chem. 1981, 208, 279. (c) Goasdoue, C.; Goasdoue, N.;
Gaudemar, M. Tetrahedron Lett. 1983, 24, 4001. (d) Goasdoue, C.;
Goasdoue, N.; Gaudemar, M. J. Organomet. Chem. 1984, 263, 273.
(9) For use of thioamides in catalytic asymmetric reactions CÀC
bond-forming reactions, see: (a) Suzuki, Y.; Yazaki, R.; Kumagai, N.;
Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 5026. (b) Iwata, M.;
Yazaki, R.; Suzuki, Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 18244. (c) Iwata, M.; Yazaki, R.; Kumagai, N.; Shibasaki, M.
Tetrahedron: Asymmetry 2010, 21, 1688. (d) Yazaki, R.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 10275.
(10) Jagodziꢀnski, T. S. Chem. Rev. 2003, 103, 197.
(11) Recent reviews on cooperative catalysis. Lewis acid/Brønsted
base: (a) ref 2a. (b) Matsunaga, S.; Shibasaki, M. Bull. Chem. Soc. Jpn.
2008, 81, 60. Lewis acid/Lewis base:(c) Kanai, M.; Kato, N.; Ichikawa,
5559
dx.doi.org/10.1021/ja200250p |J. Am. Chem. Soc. 2011, 133, 5554–5560