Luca Salvi - One-Pot Multicomponent Coupling Methods for the Synthesis of Diastereo- and Enantioenriched (Z)-Trisubstituted Allylic Alcohols

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      Publication Details (including relevant citation   information):

      J. Am. Chem.   Soc. 2009,   131, 8434-8445.


      (Z)-Trisubstituted allylic alcohols are widespread   structural motifs in natural products and biologically active   compounds but are difficult to directly prepare. Introduced   herein is a general one-pot multicomponent coupling method for   the synthesis of (Z)-α,α,β-trisubstituted allylic   alcohols. (Z)-Trisubstituted vinylzinc reagents are   formed in situ by initial hydroboration of 1-bromo-1-alkynes.   Addition of dialkylzinc reagents induces a 1,2-metalate   rearrangement that is followed by a boron-to-zinc   transmetalation. The resulting vinylzinc reagents add to a   variety of prochiral aldehydes to produce racemic   (Z)-trisubstituted allylic alcohols. When   enantioenriched aldehyde substrates are employed,   (Z)-trisubstituted allylic alcohols are isolated with   high dr (>20:1 in many cases). For example, vinylation of   enantioenriched benzyl-protected α- and β-hydroxy propanal   derivatives furnished the expected anti-Felkin addition   products via chelation control. Surprisingly, silyl-protected   α-hydroxy aldehydes also afford anti-Felkin addition   products. A protocol for the catalytic asymmetric addition of   (Z)-trisubstituted vinylzinc reagents to prochiral   aldehydes with a (−)-MIB-based catalyst has also been developed.   Several additives were investigated as inhibitors of the Lewis   acidic alkylzinc halide byproducts, which promote the background   reaction to form the racemate. α-Ethyl and α-cyclohexyl   (Z)-trisubstituted allylic alcohols can now be   synthesized with excellent levels of enantioselectivity in the   presence of diamine inhibitors.

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