Catalytic asymmetric oxa-Diels-Alder reaction of acroleins with simple alkenes.

The catalytic asymmetric inverse-electron-demand oxa-Diels-Alder (IODA) reaction is a highly effective synthetic method for creating enantioenriched six-membered oxygen-containing heterocycles. Despite significant effort in this area, simple α,ß-unsaturated aldehydes/ketones and nonpolarized alkenes are seldom utilized as substrates due to their low reactivity and difficulties in achieving enantiocontrol. This report describes an intermolecular asymmetric IODA reaction between α-bromoacroleins and neutral alkenes that is catalyzed by oxazaborolidinium cation 1f. The resulting dihydropyrans are produced in high yields and excellent enantioselectivities over a broad range of substrates. The use of acrolein in the IODA reaction produces 3,4-dihydropyran with an unoccupied C6 position in the ring structure. This unique feature is utilized in the efficient synthesis of (+)-Centrolobine, demonstrating the practical synthetic utility of this reaction. Additionally, the study found that 2,6-trans-tetrahydropyran can undergo efficient epimerization into 2,6-cis-tetrahydropyran under Lewis acidic conditions. This structural core is widespread in natural products.

Formal Nitrene Insertion into the ß-Vinyl C-H Bond of Acroleins: Synthesis of Enaminals.

An efficient formal nitrene insertion reaction into the ß-vinyl C-H bond of acroleins with an electron-rich organic azide was developed. The reaction protocol can produce secondary enaminals in high yield with a broad substrate scope. In the reaction, acid mediated [3 + 2] cycloaddition of organic azides with an acrolein generated intermediate protonated triazolines, which were selectively decomposed into enaminals with addition of a weakly Brønsted basic reagent such as methanol. The resulting secondary enaminal could be easily reduced into a γ-amino alcohol under mild hydrogenation conditions.

Catalytic Diastereoselective Hetero-Diels-Alder Reaction of α-Haloacroleins with Alkenes: Construction of 3,4-Dihydropyran.

In this Letter, a catalytic diastereoselective hetero-Diels-Alder reaction of α-haloacroleins with less polarized alkenes was developed, and the resulting 3,4-dihydropyrans were produced in high yields with a broad substate scope. Mechanism studies showed that 3,4-dihydropyran was produced from the ring expansion of cyclobutane, which was generated in the ring contraction of the initially formed unstable 3,4-dihydropyran conformer.

Catalytic Enantioselective [2+2] Cycloaddition of α-Halo Acroleins: Construction of Cyclobutanes Containing Two Tetrasubstituted Stereocenters.

A catalytic enantioselective formal [2+2] cycloaddition between α-halo acroleins and electronically diverse arylalkenes is described. In the presence of (S)-oxazaborolidinium cation as the catalyst, densely functionalized cyclobutanes containing two vicinal tetrasubstituted stereocenters were produced in high yields and high diastereoselectivities with excellent enantioselectivities. Mechanistic studies revealed that the cis isomer could be transformed into the trans isomer via an enantiocontrolled process. A gram-scale reaction of this catalytic method was used to demonstrate its synthetic potential.

Catalytic asymmetric insertion of diazoesters into aryl-CHO bonds: highly enantioselective construction of chiral all-carbon quaternary centers.

This paper describes a catalytic enantioselective route to synthesize functionalized all-carbon quaternary acyclic systems via a boron Lewis acid-promoted formal C-C insertion of diazoesters into aryl-CHO bonds. In the presence of chiral (S)-oxazaborolidinium cation 1d as a catalyst, the reaction proceeded in good yield (up to 83%) with good regioselectivity (up to 88:12) and excellent enantioselectivity (up to 99% ee). The synthetic potential of this method was illustrated by conversion of the products to both α- and ß-amino esters.

Oxazaborolidinium ion-catalyzed cyclopropanation of α-substituted acroleins: enantioselective synthesis of cyclopropanes bearing two chiral quaternary centers.

A catalytic synthetic route to highly functionalized chiral cyclopropane derivatives was developed by Michael-initiated cyclopropanation of α-substituted acroleins with aryl- and alkyl diazoacetates. In the presence of chiral (S)-oxazaborolidinium cation 1b as a catalyst, the reaction proceeded in high yield (up to 93%) with high to excellent diastereoselectivity (up to 98% de) and enantioselectivity (up to 95% ee).

Highly enantioselective mukaiyama aldol reactions catalyzed by a chiral oxazaborolidinium ion: total synthesis of (-)-inthomycin C.

A cationic oxazaborolidinium-catalyzed asymmetric Mukaiyama aldol reaction of (1-methoxy-2-methyl-propenyloxy)-trimethylsilane with various aldehydes including α,ß-disubstituted acroleins has been developed in high yields and enantioselectivities. The synthetic utility of this methodology was demonstrated in the first short synthesis of naturally occurring inthomycin C in high enantiopurity.

Catalytic enantioselective 1,3-dipolar cycloadditions of alkyl diazoacetates with alpha,beta-disubstituted acroleins.

A catalytic route to highly functionalized chiral 2-pyrazolines by an asymmetric 1,3-dipolar cycloaddition reaction of ethyl diazoacetate with alpha-substituted and alpha,beta-disubstituted acroleins has been developed; in the presence of chiral (S)-oxazaborolidinium ion as catalyst, the reaction proceeded with high to excellent enantioselectivities (up to 99% ee).