ORGANIC LETTERS
Diastereoselective Aldol Additions to r-Amino-β-silyloxy Aldehydes. Divergent Synthesis of Aminodiols
2005 Vol. 7, No. 5 893-895
Per Restorp and Peter Somfai* KTH Chemistry, Organic Chemistry, SE-100 44 Stockholm, Sweden
[email protected] Received January 13, 2005
ABSTRACT
A divergent protocol for substrate-controlled diastereoselective synthesis of aminodiols has been developed using nucleophilic Mukaiyama aldol additions to r-amino-β-silyloxy aldehydes. The merged stereochemical impact on the diastereoselectivity of the polar r- and β-substituents is highlighted.
Nucleophilic carbonyl addition reactions can be ranked among the premier transformations in organic synthesis for stereoselective C-C bond formation. Asymmetric induction can in general be realized in the presence of proximal stereogenic centers, which can provide a diastereofacial discrimination at the CdO π-faces, and much work has been devoted toward elucidating the underlying factors. The influence of R- or β-substituents on the stereochemical outcome of additions to CdO bonds have been well studied and can be rationalized by steric and electronic effects1 or chelation to adjacent heteroatoms.2 However, the stereochemical outcome in additions to more complex systems, containing multiple adjacent stereocenters, is more difficult to predict and has only received scarce attention. Recently, Evans et al. reported that the stereochemical outcome of nucleophilic additions to β-alkoxy-R-methyl aldehydes are (1) No´gradı´, M. In StereoselectiVe Synthesis; VCH: New York, 1986. (b) Mander, L. N. In Stereochemistry of Organic Compounds; Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York, 1994; pp 875-894. (c) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191-1223. (2) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462-468. (b) Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833-4835. (c) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am. Chem. Soc. 2001, 123, 10840-10852. 10.1021/ol0500719 CCC: $30.25 Published on Web 02/02/2005
© 2005 American Chemical Society
influenced by the stereochemistry of both stereocenters and that their stereodirecting effects can be mutually reinforcing or attenuating.3 This study showed that in anti-β-alkoxy-Rmethyl aldehydes the stereocenters operate in concert and nucleophilic additions afford uniformly high diastereoselectivities in favor of the Felkin-Anh products. In contrast, additions to syn-β-alkoxy-R-methyl aldehydes proceed with variable levels of aldehyde π-facial selectivity depending on the steric demands of the nucleophile and solvent polarity. These findings were qualitatively rationalized by using an integrated stereoinduction model,3 based on the Felkin-Anh4 and the 1,3-polar induction models,5 that correctly accounts for the combined effects of both the R-methyl and β-alkoxy substituents. This methodology has successfully been implemented in the synthesis of complex organic structures.6 (3) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.; Livingston, A. B. J. Am. Chem. Soc. 1995, 117, 6619-6620. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322-4343. (4) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 58285835. (b) Anh, N. T. Top. Curr. Chem. 1980, 88, 145-162. (c) Che´rest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199-2204. (5) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron Lett. 1984, 25, 729732. (b) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537-8540.
Scheme 1.
a
Stereodivergent Synthesis of Aminodiolsa
Table 1. Diastereoselective Mukaiyama Additions to Anti-R,β-Substituted Aldehydes 1a-da
R′ ) Bn or H. entry
subst
Lewis acid
yieldb (%)
dr (3/4)c
products
1 2 3 4 5d
1a 1a 1b 1c 1d
BF3‚OEt2 TiCl4 BF3‚OEt2 BF3‚OEt2 BF3‚OEt2
91 85 94 92 81
92:8 90:10 >98:2
