Chiral Phosphoric Acid Catalyzed Highly Enantioselective Desymmetrization of 2-Substituted and 2,2-Disubstituted 1,3-Diols via Oxidative Cleavage of Benzylidene Acetals

Abstract

A highly enantioselective catalytic protocol for the desymmetrization of a wide variety of 2-substituted and 2,2-disubstituted 1,3-diols is reported. This reaction proceeds through the formation of an "ortho ester" intermediate via oxidation of 1,3-diol benzylidene acetal by dimethyldioxirane (DMDO) and the subsequent proton transfer catalyzed by chiral phosphoric acid (CPA). The mechanism and origins of enantioselectivity of this reaction are identified using DFT calculations. The oxidation by DMDO is rate-determining, and the phosphoric acid significantly accelerates the proton transfer; the attractive interactions between the benzylidene part of the substrate and the 2,4,6-triisopropyl group of CPA are the key to high enantioselectivity.

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…To further understand the origin of stereoselectivity for the KR of 1-6 catalyzed by A,a nd to probe the role of different non-covalenti nteractions, we next analyzed truncatedm odels of the stereochemistry-determining acyl transfer TS structures. [104][105][106][107] In particular, we considered structures in which the p-p + interaction involving the B-ring of the substrate wase liminated and in which the acetate counterion wasr emoved (see Table 2). First, we note that the energy differenceb etween the stereochemistrycontrolling TS structures follows the same trend as the free energy difference.…”

“…Notably, this finding is consistent with the drastically different selectivities of 5 and 6 , despite the presence of a β′ OMe in both. To further understand the origin of stereoselectivity for the KR of 1 – 6 catalyzed by A , and to probe the role of different non‐covalent interactions, we next analyzed truncated models of the stereochemistry‐determining acyl transfer TS structures . In particular, we considered structures in which the π–π + interaction involving the B‐ring of the substrate was eliminated and in which the acetate counterion was removed (see Table ).…”

Nonenzymatic enantioselective synthesis of all-carbon quaternary centers through desymmetrization

“…35 Dimethyldioxirane (DMDO) was used in combination with catalyst 85 (TRIP) to selectively oxidize benzylidene acetals 82 to esters such as 84 via the proposed intermediate 83 in excellent yields and good enantiopurity. DFT calculations showed that the rate determining step was oxidation by DMDO and that aryl-aryl interactions between the substrate and catalyst are responsible for the high enantioselectivities seen.…”

Discovery and enantiocontrol of axially chiral urazoles via organocatalytic tyrosine click reaction

“…1b , compound D ), we turned our attention to construct the chiral urazoles in an atroposelective approach via tyrosine click-like reaction. In this scenario, three major challenges would be encountered: (1) the selection of suitable catalyst to interact with the substrates in high efficiency to inhibit the very strong background reaction; (2) the choice of an appropriate chiral catalyst prompt to efficiently induce remote axial enantiocontrol at the distant position via organocatalytic desymmetrization strategy 13 14 15 16 17 18 19 ; (3) the use of mild reaction conditions to circumvent the axial rotation. Recently, some strategies have been successfully developed for the organocatalytic synthesis of axially chiral compounds 20 21 22 23 24 25 26 27 28 29 30 31 32 33 .…”