One-pot multicomponent coupling methods for the synthesis of diastereo- and enantioenriched (Z)-trisubstituted allylic alcohols.
(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.
Kerrigan
Michael H
MH
P. Roy and Diana T. Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, USA.
Jeon
Sang-Jin
SJ
Chen
Young K
YK
Salvi
Luca
L
Carroll
Patrick J
PJ
Walsh
Patrick J
PJ
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
D000438:Alcohols; D000447:Aldehydes; D000480:Alkynes; D000498:Allyl Compounds; D001880:Boranes; D009942:Organometallic Compounds; D015032:Zinc