Abstract
It was recently reported that a (2-hydroxybenzyl)phosphine oxide (2-HOBPO) can serve as a phosphorus-centered catalyst for the stereo-invertive coupling of aliphatic alcohols and acidic pronucleophiles (akin to a Mitsunobu reaction, but without additional reagents). Herein, we report an improved synthesis, which provides direct access to systematically varied 2-HOBPOs in a single step from commercially available precursors (salicylaldehydes and secondary phosphines). The efficiency and generality of the synthetic method enabled limited structure–activity relationship (SAR) studies, from which it was determined that substituents on both the phenolic and phosphine oxide portions can exert significant influence on the turnover frequency (TOF) of each catalyst. Importantly, for all catalytically active 2-HOBPOs examined, the molecularity of catalyst in the rate law of the alcohol coupling was determined to be <1. Thus, for high catalyst loadings, differences in catalytic activity between 2-HOBPOs appear to be dominated by differences in catalytic auto-inhibition, while for low catalyst loadings, differences are attributed to inherent differences in the energetic span of the catalytic cycle, ignoring off-cycle species, in good agreement with density functional theory (DFT) modeling at the ωB97X-D/6-311G(d,p) level.
Highlights
The Mitsunobu reaction (Figure 1a) is of particular importance in the fields of synthetic organic chemistry and medicinal chemistry and is the topic of several reviews [1–3]. This protocol allows aliphatic alcohols to serve as electrophiles for SN 2 substitution, and in cases in which the O-bound carbon atom of the alcohol is a stereocenter, the reaction is highly selective for inverting the configuration of the stereocenter
Multiple stable alternative ground states for the 1a/2,4-DNBA/2-phenylpropanol system were identified (Table 1, rows 1–5), including several that were found to be more stable than the lowest ground state identified by Houk and co-workers (GS A) [9]
The observed rate law appears to be in agreement with the mechanism proposed by Houk and co-workers, while being inconsistent with that proposed by Denton and co-workers
Summary
The Mitsunobu reaction (Figure 1a) is of particular importance in the fields of synthetic organic chemistry and medicinal chemistry and is the topic of several reviews (from the perspective of synthetic organic chemists) [1–3] This protocol allows aliphatic alcohols to serve as electrophiles for SN 2 substitution, and in cases in which the O-bound carbon atom of the alcohol is a stereocenter, the reaction is highly selective for inverting the configuration of the stereocenter. The Mitsunobu protocol is a powerful and selective synthetic tool, this reaction suffers from very poor atom economy (often
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