# Stereospecific Transition‐Metal‐Free Alkylation of Chiral Non‐Racemic Secondary Tosylates with Cyanohydrins: Convenient Access to Enantiomerically Enriched α‐Tertiary Ketones

## TL;DR

A new chemical method allows the efficient and stereospecific synthesis of enantioenriched α-tertiary ketones without using transition metals.

## Contribution

A transition-metal-free stereospecific alkylation method for synthesizing enantioenriched α-tertiary ketones using cyanohydrins and secondary tosylates.

## Key findings

- The method enables efficient and stereospecific SN2 alkylation of cyanohydrins with chiral secondary tosylates.
- The approach is tolerant of various functional groups and can handle both acyclic and cyclic tosylates.
- The strategy was used to synthesize (R)-cyclamen aldehyde in a concise and stereospecific manner.

## Abstract

A novel stereospecific, transition‐metal‐free alkylation of cyanohydrins with enantiomerically enriched secondary tosylates is described. This method enables the general, efficient, and operationally simple synthesis of enantioenriched α‐tertiary ketones by leveraging the nucleophilicity of cyanohydrin anions, which serve as umpolung carbonyl equivalents to facilitate highly stereospecific SN2 substitutions. Reactions involving alkenyl cyanohydrins proceed through a stereoconvergent olefin synthesis (SCOS) from a geometric E/Z mixture, furnishing stereochemically defined, conjugated α‐tertiary ketones. This methodology exhibits broad functional group tolerance, accommodating unactivated and sterically hindered acyclic and cyclic secondary tosylates. The resulting chiral ketones are configurationally stable and can be readily converted into synthetically versatile intermediates using classical transformations. The utility of this approach is exemplified by a concise, stereospecific synthesis of (R)‐cyclamen aldehyde, underscoring its potential to streamline the preparation of enantioenriched α‐tertiary ketones—structural motifs that feature prominently in both natural and non‐natural products and serve as key intermediates in target‐directed synthesis.

A stereospecific, transition‐metal‐free SN2 alkylation of cyanohydrins with chiral non‐racemic secondary tosylates is reported, providing efficient access to enantioenriched α‐tertiary ketones. The method exhibits broad substrate scope, operational simplicity, and excellent stereospecificity, including stereoconvergent reactions of E/Z mixtures of alkenyl cyanohydrins. The utility of the strategy is demonstrated through a concise synthesis of (R)‐cyclamen aldehyde.