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. 2010 Mar 31;132(12):4399-408.
doi: 10.1021/ja910717p.

Overriding Felkin control: a general method for highly diastereoselective chelation-controlled additions to alpha-silyloxy aldehydes

Gretchen R Stanton  1 , Corinne N Johnson, Patrick J Walsh
Affiliations

Overriding Felkin control: a general method for highly diastereoselective chelation-controlled additions to alpha-silyloxy aldehydes

Gretchen R Stanton et al. J Am Chem Soc. .

Abstract

According to the Felkin-Anh and Cram-chelation models, nucleophilic additions to alpha-silyloxy aldehydes proceed through a nonchelation pathway due to the steric and electronic properties of the silyl group, giving rise to Felkin addition products. Herein we describe a general method to promote chelation-control in additions to alpha-silyloxy aldehydes. Dialkylzincs, functionalized dialkylzincs, and (E)-disubstituted, (E)-trisubstituted, and (Z)-disubstituted vinylzinc reagents add to silyl-protected alpha-hydroxy aldehydes with high selectivity for chelation-controlled products (dr of 10:1 to >20:1) in the presence of alkylzinc halides or triflates, RZnX. With the high functional group tolerance of organozinc reagents, the mild Lewis acidity of RZnX, and the excellent diastereoselectivities favoring the chelation-controlled products, this method will be useful in the synthesis of natural products. A mechanism involving chelation is supported by (1) NMR studies of a model substrate, (2) a dramatic increase in reaction rate in the presence of an alkylzinc halide, and (3) higher diastereoselectivity with larger alkyl substituents on the alpha-carbon of the aldehyde. This method provides access to chelation-controlled addition products with high diastereoselectivity previously unavailable using achiral organometallic reagents.

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Figures

Figure 1
Figure 1
Felkin-Ahn and Cram-chelation models
Scheme 1
Scheme 1
Overriding Substrate Control with Enantioenriched Stoichiometric Additives (A-C) and Catalysts (D).
Scheme 2
Scheme 2
One-pot Synthesis of (Z)-Disubstituted Allylic Alcohols in the Presence of BF3•OEt2 with unexpected anti-Felkin Stereoselectivity.
Scheme 3
Scheme 3
Evans’ Proposal for Chelation-Control with Aluminum Lewis Acids in the Asymmetric Mukayama Aldol Reaction (PG=protecting group).
Scheme 4
Scheme 4
One-pot Generation of (Z)-Trisubstituted Allylic Alcohols with High Diastereoselectivity.
Scheme 5
Scheme 5
Synthesis of RZnX via Conproportionation.
See this image and copyright information in PMC

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