Diastereoselective Petasis-borono-Mannich Crotylation Reactions of Chiral α-Heteroatom (F, OBz, OH) Aldehydes: Rapid Access to Valuable Mono and Bicyclic Heterocyclic Scaffolds

• Published in: Chemistry : a European journal 2023-09, Vol.29 (53), p.e202301701-e202301701
• Main Authors: Chevis, Philip J, Chao, Chi Bong Eric, Richardson, Christopher, Hyland, Christopher, Lee, Richmond, Pyne, Stephen G
• Format: Article
• Language: English
• Subjects: Aldehydes; Amines; Chemistry; Conformation; Scaffolds; Stereoselectivity; Tetrahydropyridines
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202301701

The crotylation reactions of chiral α-F, α-OBz and α-OH aldehydes under Petasis-borono-Mannich conditions using (E)- or (Z)-crotylboronates and primary amines resulted in γ-addition products in high dr and high er. α-F and α-OBz aldehydes gave 1,2-anti-2,3-syn and 1,2-anti-2,3-anti, products, respectively while an α-OH aldehyde gave 1,2-syn-2,3-syn products. The stereochemical outcomes of reactions of the former aldehydes can be explained using a six-membered ring transition state (TS) model in which a Cornforth-like conformation around the imine intermediate is favoured resulting in 1,2-anti products. The 2,3-stereochemical outcome is dependent upon the geometry of the crotylboronate. These TS models were also supported by DFT calculations. The stereochemical outcomes of reactions employing an α-OH aldehyde can be rationalised as occurring via an open-TS involving H-bonding in the imine intermediate between the α-OH group and the imine N atom. Representative products were converted to highly functionalized 1,2,3,6-tetrahydropyridines and 3H-oxazolo[3,4-a]pyridine-3-ones which will be valuable scaffolds in synthesis.