title: 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.
authors.affiliation: P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kerrigan
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Jeon
authors.forename: Young K
authors.initials: YK
authors.lastname: Chen
authors.forename: Luca
authors.initials: L
authors.lastname: Salvi
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Carroll
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Walsh
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis*; D000447:Aldehydes / Q000737:chemistry*; D000480:Alkynes / Q000737:chemistry*; D000498:Allyl Compounds / Q000138:chemical synthesis*; D001880:Boranes / Q000737:chemistry; D002384:Catalysis; D009942:Organometallic Compounds / Q000737:chemistry; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry
chemical_list: D000438:Alcohols; D000447:Aldehydes; D000480:Alkynes; D000498:Allyl Compounds; D001880:Boranes; D009942:Organometallic Compounds; D015032:Zinc