(2-hydroxybenzyl)phosphine oxides (2-HOBPOs) have recently been reported to serve as organocatalysts for the stereospecific coupling of aliphatic aclohols and acidic pronucleophiles (akin to a Mitsunobu reaction, but with no additional reagents). Herein, I report the use of an addition-rearrangment coupling (ARC) reaction to directly access dozens of systematically varied 2-HOBPOs in a single step from commercially available precursors (salicylaldehydes and secondary phosphines). The efficiency and generality of the synthetic method allowed for structure-activity-relationship (SAR) studies, which from which it was determined that substutuents on both the phenolic portion and the phosphine oxide portion can exert significant influence on the turnover frequency (TOF) and substrate scope of each catalyst. It also appears to be possible to control which step is turnover-limiting, offering differing selectivity profiles. Key mechanistic insights from experimental and computational modeling will be discussed, and design principles will be proposed.

Structure-activity relationships for varied phosphine oxide organocatalysts for the stereospecific coupling of aliphatic alcohols and acidic pronucleophiles

ACS Spring 2022

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