Phosphazene Catalyzed Addition to Electron-Deficient Alkynes: The Importance of Nonlinear Allenyl Intermediates upon Stereoselectivity

Abstract

An ONIOM(QM/MM) study on the mechanism of the Michael addition to triple bonds catalyzed by chiral diiminophosphorane catalysts has been performed to understand the stereoselectivity of the product olefin. Our results are consistent with the experimental enantioselectivity, but more importantly, reveal that the Z vs E preference depends on the influence of the catalyst upon the geometry of the allenyl enolate formed in the addition step. These intermediates show an innate preference for a (Z)-configuration, although this can be suppressed by steric interactions due to a catalyst. This leads to two distinct mechanisms in which the kinetic basis for (E) or (Z)-stereoselectivity is determined by a different step. Bifunctional iminophosphorane catalysts are found to use steric interactions to override innate stereoelectronic effects of the allenyl enolate reactive intermediate.

Phosphine Organocatalysis

“…The mechanisms of this transformation and of the related additions were very recently investigated through computational studies. 885…”

Experimental and Theoretical Investigation of the Reaction of Amines with Methyl Propiolate

“…Theoretical investigation of the catalytic Michael addition of azlactone and 5 H ‐oxazol‐4‐one to methyl propiolate showed that the Z/E diastereoselectivity of the products is also controlled by the relative orientation of the catalyst and the Michael donor. In view of this, we explored a third route also, which involved attack of 1‐methylpiperazine ( 3 a ) on methyl propiolate from the side opposite to the complexing amine molecule (Figure ).…”

Catalyst‐Enabled Site‐Divergent Stereoselective Michael Reactions: Overriding Intrinsic Reactivity of Enynyl Carbonyl Acceptors

“…Having identified the catalyst capable of promoting a 1,4‐selective reaction with rigorous control of stereoselectivity, we turned our attention to search for a catalyst effective for overturning the regiochemical preference to 1,6‐selectivity while conserving a comparable level of stereocontrol, thereby establishing a site‐divergent stereoselective Michael reaction protocol. Toward this end, we used the P ‐spiro chiral triaminoiminophosphorane 2 as a catalyst, considering the unique ability of its conjugate acid 2 ⋅H to recognize both a nucleophile and an electrophile through hydrogen‐bonding interactions, thus providing an unusual mutual orientation in the transition state for the subsequent bond formation ,. Interestingly, the reaction of 3 a with 4 in the presence of the l ‐valine‐derived 2 a in Et 2 O at 0 °C selectively afforded 1,6‐γ‐ Z , E ‐ 5 a ( vi ) in high yield with excellent enantioselectivity (Table , entry 8).…”