Mechanism and Origins of Stereoselectivity of the Aldol-Tishchenko Reaction of Sulfinimines.

Aneta Turlik,Mark Light,Kaori Ando,K N Houk,Emma Alcock,Gerard P Mcglacken,Pamela Mackey

doi:10.1021/acs.joc.0c02862

Abstract

Density functional theory computations have elucidated the mechanism and origins of stereoselectivity in McGlacken’s aldol-Tishchenko reaction for the diastereoselective synthesis of 1,3-amino alcohols using Ellman’s t-butylsulfinimines as chiral auxiliaries. Variations of stereochemical outcome are dependent on the nature of the ketone starting materials used, and the aspects leading to these differences have been rationalized. The intramolecular hydride transfer step is the rate- and stereochemistry-determining step, and all prior steps are reversible.

Highlights

Density functional theory computations have elucidated the mechanism and origins of stereoselectivity in McGlacken’s aldol-Tishchenko reaction for the diastereoselective synthesis of 1,3-amino alcohols using Ellman’s t-butylsulfinimines as chiral auxiliaries
In 2015, McGlacken and co-workers reported the stereoselective synthesis of 1,3-amino alcohols through an aldolTishchenko process (Scheme 1).[4]
Synthesis of 1,3-Diols via the Aldol-Tishchenko Reaction imparted through the use of t-butylsulfinimines, the Ellman auxiliaries.[5]

Summary

The Journal of Organic Chemistry

The second-lowest-energy transition state (TS-2b, ΔΔG⧧ = 0.6 kcal/mol) leads to the stereochemistry analogous to that observed in the acetophenone-derived substrates In this transition state structure, an unfavorable steric interaction exists between the equatorial methyl group and the t-Bu group of the sulfinimine, with a distance of 2.34 Å between these two groups. A similar DFT analysis was performed for the acetophenone derived reaction (Figure 4) In this case, transition state TS-3b leading to formation of minor product (S,R,R)-8 is higher in energy than transition state TS-3a-E, which leads to formation of the major product, by 2.4 kcal/mol. Transition state TS-3b leading to formation of minor product (S,R,R)-8 is higher in energy than transition state TS-3a-E, which leads to formation of the major product, by 2.4 kcal/mol NMR and X-ray data for dimethylcyclopentanone reactions; energies and geometries of computed structures (PDF)

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■ ACKNOWLEDGMENTS

Findings

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