Confinement-Controlled, Either syn- or anti-Selective Catalytic Asymmetric Mukaiyama Aldolizations of Propionaldehyde Enolsilanes.

Tynchtyk Amatov,Markus Leutzsch,Hui Zhou,Rajat Maji,Nobuya Tsuji,Benjamin List,Lucas Schreyer

doi:10.1021/jacs.1c07447

Abstract

Protected aldols (i.e., true aldols derived from aldehydes) with either syn- or anti- stereochemistry are versatile intermediates in many oligopropionate syntheses. Traditional stereoselective approaches to such aldols typically require several nonstrategic operations. Here we report two highly enantioselective and diastereoselective catalytic Mukaiyama aldol reactions of the TBS- or TES- enolsilanes of propionaldehyde with aromatic aldehydes. Our reactions directly deliver valuable silyl protected propionaldehyde aldols in a catalyst controlled manner, either as syn- or anti- isomer. We have identified a privileged IDPi catalyst motif that is tailored for controlling these aldolizations with exceptional selectivities. We demonstrate how a single atom modification in the inner core of the IDPi catalyst, replacing a CF3-group with a CF2H-group, leads to a dramatic switch in enantiofacial differentiation of the aldehyde. The origin of this remarkable effect was attributed to tightening of the catalytic cavity via unconventional C–H hydrogen bonding of the CF2H group.

Highlights

Protected aldols with either syn- or anti- stereochemistry are versatile intermediates in many oligopropionate syntheses
The first diastereo- and enantioselective examples by Denmark utilized trichlorosilyl enolsilanes under Lewis base catalysis.[14]
From such a vantage point, exploitation of the unique reactivity of IDPi catalysts in the Mukaiyama cross-aldol reaction with propionaldehyde-derived enolsilanes would be even more valuable as it generates two stereogenic centers simultaneously, which are present in many bioactive polyketides (Figure 1).[18]

Summary

■ ACKNOWLEDGMENTS

The authors thank Benjamin Mitschke for his help with figures and several members of the group for our internal crowd reviewing. We thank the technicians of our group and the members of our NMR, MS, X-ray, and chromatography groups for their excellent service.

■ REFERENCES

Findings

Extremely Active Organocatalysts Enable a Highly Enantioselective