# Stereoselective Pudovik reaction of aldehydes, aldimines, and nitroalkenes with CAMDOL-derived H-phosphonate

## TL;DR

The paper introduces a new chiral H-phosphonate derived from CAMDOL that improves the efficiency of stereoselective Pudovik reactions for making bioactive phosphonates.

## Contribution

A novel CAMDOL-derived H-phosphonate is developed for efficient and stereoselective Pudovik reactions with diverse substrates.

## Key findings

- CAMDOL-PHO enables high dr values (up to 99:1) and yields (up to 97%) in Pudovik reactions.
- The method produces α-hydroxyl, α-amino, and β-nitro phosphonates with broad substrate scope.
- DFT and experimental studies confirm CAMDOL-PHO's superiority in forming P-adjacent stereogenic centers.

## Abstract

Optically pure phosphonates featuring an α-functional motif serve as core structures of versatile pharmaceuticals. Pudovik reaction employing P-stereogenic H-phosphonates derived from recyclable chiral auxiliary (CA) is one of the most practical and efficient asymmetric synthetic strategies. Although several centre and axial CAs have been investigated in this field, the development of novel chiral H-phosphonates has remained largely unexplored over the past 25 years. Here, we developed a kind of H-phosphonate (CAMDOL-PHO) derived from camphor-derived 2,3-diol (CAMDOL). Stereoselective Pudovik reactions of CAMDOL-PHO with diverse aldehydes, aldimines, and nitroalkenes were well developed, affording a library of molecules of α-hydroxyl, α-amino, and β-nitro phosphonates respectively with high dr values (up to 99:1) and yields (up to 97%) as well as broad scopes. Comparative DFT and experimental studies demonstrated that CAMDOL-PHO possessed significant superiority to install the P-adjacent C-stereogenic centre, mainly benefiting from its unique diphenyl-substituted camphor skeleton with an angular methyl group.

Optically pure phosphonates are crucial in pharmaceuticals, yet the development of chiral H-phosphonates has been stagnant for decades. Here, the authors report an H-phosphonate derived from camphor-derived 2,3-diols (CAMDOL), that enables efficient stereoselective Pudovik reactions and yields diverse bioactive molecules, with significant implications for asymmetric synthesis.