One-pot multicomponent coupling methods for the synthesis of diastereo- and enantioenriched (Z)-trisubstituted allylic alcohols

Abstract

(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)-alpha,alpha,beta-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 alpha- and beta-hydroxy propanal derivatives furnished the expected anti-Felkin addition products via chelation control. Surprisingly, silyl-protected alpha-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. Alpha-ethyl and alpha-cyclohexyl (Z)-trisubstituted allylic alcohols can now be synthesized with excellent levels of enantioselectivity in the presence of diamine inhibitors.

Figure 1

ORTEP drawing 35 (entry 17, Table 4) with 30% probability thermal ellipsoids

Scheme 1

Common Methods to Generate (Z)-Trisubstituted Allylic Alcohols and their Precursors

Scheme 2

Ng and Jamison’s Synthesis of Enantioenriched (Z)-Trisubstituted Allylic Alcohols

Scheme 3

Generation and Trapping of (Z)-Trisubstituted Vinylzinc Intermediates for the Synthesis of (Z)-Trisubstituted Allylic Alcohols

Scheme 4

1,2-Metallate Rearrangements with 1-Halo-1-alkenyl Boranes

Scheme 5

One-Pot Multicomponent Coupling Reaction for the Stereospecific Synthesis of (Z)-Trisubstituted Allylic Alcohols

Scheme 6

Comparison of Alkyl and Hydride Migration.

Scheme 7

Protonalysis of Intermediates in the Generation of Trisubstituted Vinylzinc Species.

Scheme 8

Proposed Mechanism for the Formation of α-Methyl (Z)-Trisubstituted Allylic Alcohols (X=Br or Cl)

Scheme 9

Synthesis of an Intermediate in the Total Synthesis of (−)-Hennoxazole A

Scheme 10

Stereochemical Correlation Between Compounds 19, 25, and 30