The stereoselective formation of 5 contiguous chiral centers in a single pot reaction is demonstrated using an aldol, aldol–Tishchenko reaction of N - tert -butyl sulfinimines. One diastereoisomer (from 32 possibilities) predominates, and a series of cyclic and acyclic 3-amino-1,5-diol derivatives are synthesized in good yields (up to 80%) and excellent diastereoselectivities (up to >98:2 dr). Investigations support two reversible aldol steps, and multiple intermediates which are funnelled through a remarkably selective, irreversible, Tishchenko reduction, in a Curtin–Hammett phenomenon. DFT calculations using a disolvated (THF) model reveal the factors controlling stereoselectivity in the final irreversible Tishchenko step.

Procedures yielding ( S )‐2‐Methyl‐ N ‐(1‐phenylethylidene)propane‐2‐sulfinamide 3 as two fractions of a yellow solid and (1 S ,3 S )‐1‐((( S )‐ tert ‐butylsulfinyl)amino)‐4‐methyl‐1‐phenylpentan‐3‐yl isobutyrate as a pale yellow oil are presented. A discussion on 1,3‐aminoalcohols as useful synthetic intermediates and building blocks concludes the chapter.

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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.

Herein, we present a highly diastereoselective method to furnish acyclic 3‐amino‐1,5‐diol derivatives using a tandem double‐aldol‐Tishchenko protocol (dr up to >99 : 1) using a butanone derived sulfinylimine. In most cases only 1 diastereomer predominates, from a possible 16. The reaction is also regioselective. In addition, the highly challenging cyclobutanone and 3‐pentanone derivatives are also amenable to a double‐aldol‐Tishchenko reaction, although the dr values are modest. Despite that, clean single diastereomers can be isolated, which should prove very useful in medicinal chemistry and other areas. Detailed DFT calculations support the observed stereoselectivities in all cases, providing a rationale for the excellent dr values in the butanone series and the moderate values for the 3‐pentanone class.