Preparation of anti-1,3-Amino Alcohol Derivatives Through an Asymmetric Aldol-Tishchenko Reaction of Sulfinimines

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

“…We first examined the propiophenone-derived sulfinimine, which formed product 6′ in 87% yield and 84:16 dr (Figure ). In this case, one major diastereomer was observed out of a possible eight. The absolute stereochemistry of the major diastereomer was confirmed by X-ray crystallographic analysis as the ( S , R , R , R )-diastereomer.…”

“…Compound 9 was prepared using 2,2-dimethylcyclopentanone (1.12 mL, 8.9 mmol) and ( S )- tert -butanesulfinamide (1.08 g, 8.9 mmol) according to the previously reported procedure . The crude compound was purified using column chromatography on silica gel (3:1, hexane:EtOAc) to give the title compound 9 as a pale yellow oil (1.19 g, 62%).…”

“…In 2015, McGlacken and co-workers reported the stereoselective synthesis of 1,3-amino alcohols through an aldol-Tishchenko process (Scheme ). Diastereoselectivity was imparted through the use of t -butylsulfinimines, the Ellman auxiliaries . After an initial aldol reaction ( 1 to 2 ), the resulting alkoxide reacts with another equivalent of the aldehyde ( 2 to 3 ), followed by an intramolecular hydride transfer, to produce the sulfinamide ( 4 ).…”

“…Experimental studies of the aldol-Tishchenko reaction by McGlacken and co-workers have shown that the steps leading to the final intramolecular reduction step are reversible, and that the reduction step determines the stereochemical outcome of the reaction . Thus, our calculations were focused on the reduction step in order to determine why a change in stereochemistry was observed between the propiophenone substrates compared to the acetophenone and dimethylcyclopentanone substrates, as well as what factors control selectivity.…”

“…To investigate the origin of stereoselectivity for this reaction, eight transition states were located, three of which are shown in Figure . McGlacken and co-workers had tentatively assigned the stereochemistry by analogy to the propiophenone substrate, the ( S , R , R , R )- 6′ , because a crystal structure could initially not be obtained . This stereochemistry would be obtained from a fully equatorial arrangement of the substituents during the six-membered ring transition state.

6 DFT studies of the transition states for hydride transfer in the dimethylcyclopentyl series.

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