CAMDOL-enabled diastereoselective synthesis of α-substituted phosphonates

• Published in: Chemical communications (Cambridge, England) England), 2024-02, Vol.6 (14), p.1924-1927
• Main Authors: Huang, Yu, Zhang, Yulong, Pan, Li, Wu, Qian, Li, Ning, Shi, Enxue, Xiao, Junhua
• Format: Article
• Language: English
• Subjects: Alkylation; Analgesics; Phosphonates; Phosphonic acids; Stereoselectivity; Substitutes; Substrates; Synthesis
• ISSN: 1359-7345; 1364-548X
• DOI: 10.1039/d3cc05436e

Enantiopure α-substituted phosphonic acids are widely utilized as drugs, pesticides, and ligands. Despite numerous synthetic approaches having been investigated, precise construction of P -adjacent chiral tertiary carbon centres by the employment of recoverable chiral auxiliaries is traditional and still one of the most reliable and practical synthetic methodologies so far. Herein, we present a highly diastereoselective synthesis of α-substituted phosphonates via the unique CAMDOL-derived P-substrates by an efficient sequential deprotonation with LiHMDS and alkylation/arylation with RI. A wide range of 30 structurally diverse α-substituted phosphonate products, including the well-known P-analogues of naproxen and ibuprofen, were thus afforded conveniently in up to 92% yields and 99 : 1 diastereomeric ratios. The related chiral phosphonic acid could be easily obtained by simple acidic hydrolysis with fully recovered auxiliary. This CAMDOL-enabled asymmetric synthetic protocol exhibits comparative advantages over known chiral-induction methods with easy accessibility and compatibility of furnishing a variety of C-stereogenic centres in the proximity of the phosphorus atom, including some rare examples. Development of a highly diastereoselective synthetic approach to α-substituted phosphonates via CAMDOL-derived P-substrates by sequential deprotonation with LiHMDS and alkylation/arylation with RI to afford a range of structurally diverse products in up to 92% yields and 99 : 1 d.r.