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

Abstract

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)-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-metallate rearrangement that is followed by a boron-to-zinc transmetallation. 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.

Practical Catalytic Asymmetric Synthesis of Diaryl-, Aryl Heteroaryl-, and Diheteroarylmethanols

“…Although enantioselectivities reached 93%, yields ranged from 8-31% when Ph 2 Zn was generated from PhLi and ZnBr 2 43. Furthermore, we had difficulties with reproducibility using DiMPEG in combination with the MIB-based catalyst for enantioselective vinylation of aldehydes 72,73…”

Overriding Felkin Control: A General Method for Highly Diastereoselective Chelation-Controlled Additions to α-Silyloxy Aldehydes

“…Greater insight into our unexpected stereoselectivities in Scheme 2 was obtained when ( Z )-trisubstituted vinylzinc reagents were added to TBS or TIPS protected α-hydroxy propanals 50,51. ( Z )-trisubstituted vinylzinc intermediates were generated from 1-bromo-1-alkenylboranes.…”

“…Instead of addition of a hydride source ( t -BuLi), a dialkylzinc reagent was added to first promote the 1,2-metallate rearrangement and then to effect the transmetallation to generate the ( Z )-trisubstituted vinylzinc intermediates 50. Addition of α−silyloxy aldehydes to the resultant vinylzinc solution led to anti-Felkin addition products with very high diastereoselectvity (dr >20:1) 51. Importantly, no BF 3 •OEt 2 was employed in this process.…”

Cobalt-Catalyzed Enantioselective Vinylation of Activated Ketones and Imines

“…Out of the various strategies, asymmetric vinylation is arguably the most general one to access allylic alcohols and amines of various substitution patterns, including tertiary alcohols and amines (Scheme ). The catalytic asymmetric addition of preformed vinyl zinc reagents to aldehydes, , imines, and even ketones has been well-established and found wide use in the total synthesis of complex molecules (Scheme a) . This approach, however, involves the tandem hydrometalation–transmetalation of alkynes to afford organozinc reagents and thus necessitates the use of two stoichiometric metallic reagents.…”