Merging Asymmetric Henry Reaction with Organocatalytic Cascade Reaction for the Construction of a Chiral Indolizidine Alkaloid Skeleton

A sequential reaction combining the
copper-catalyzed asymmetric Henry reaction with the organocatalytic
Michael addition–hemiacetalization cascade reaction was developed.
The C1-symmetric chiral diamine L1–copper complex was responsible for the first highly
enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective organocatalyst for the second cascade
reaction between chiral β-nitro alcohol and α,β-unsaturated
aldehydes. Via rational design and combination of the two independent
catalytic systems, good yields and excellent enantioselectivities
and diastereoselectivities were achieved for a broad substrate scope
under mild reaction conditions. The synthetic utility of this sequential
catalytic asymmetric cascade reaction was demonstrated as an alternative
and straightforward stereoselective synthesis strategy for chiral
indolizidine alkaloid and its analogues.