Herein, we report a short and efficient synthetic pathway that uses intramolecular cyclization reactions of readily synthesized and densely functionalized amino alcohols. The research illustrates the implementation of a strategy that enables the synthesis, in only three to five steps, of a diverse collection of single-isomer small molecules whose members have over 15 different types of skeleton. In the future, this research should also enable the consequences of the unique structural features of the compounds in small-molecule screens to be determined. [1,2] We used the Petasis three-component, boronic acid Mannich reaction [3] followed by an amine propargylation to yield b-amino alcohols 1. These compounds bear polar (amino, hydroxy, ester) and nonpolar (alkene, alkyne, cyclopropane) functionalities strategically placed as handles for subsequent skeletal diversification reactions (Scheme 1).
The Petasis reaction of (S)-lactol 2 a (from l-phenyllactic acid), l-phenylalanine methyl ester (3 a), and (E)-2-cyclopropylvinylboronic acid (4) proceeded smoothly under ambient conditions in EtOH to afford the anti diastereomer 5 aa exclusively in 85 % yield. [4] The same conditions but with (R)lactol 2 b afforded the corresponding (2R,3S) isomer 5 ba exclusively (Scheme 2). These reactions indicate that the secondary hydroxy group adjacent to the intermediate imines directs the stereochemical outcome of the reaction, overriding any directing effects of the stereocenter in 3 a. [3b]