Development of an Asymmetric Trimethylenemethane Cycloaddition Reaction: Application in the Enantioselective Synthesis of Highly Substituted Carbocycles

Abstract

A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane with electron-deficient olefins has been developed. The synthesis of novel phosphoramidite ligands was critical in this effort, and the preparation and reactivity of these ligands is detailed. The evolution of the ligand design, commencing with acyclic amine-derived phosphoramidites and leading to cyclic pyrrolidine and azetidine structures is discussed. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired methylenecyclopentanes with high levels of enantioselectivity. The donor scope was also explored and substituted systems were tolerated, including one bearing a nitrile moiety. These donors were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing three stereocenters in high enantioselectivity and complete diastereoselectivity.

Enantioselective Construction of Pyrrolidines by Palladium-Catalyzed Asymmetric [3 + 2] Cycloaddition of Trimethylenemethane with Imines

“…The proposed process would extend the scope of our previously developed cycloaddition with olefin substrates 18 to imines, thereby providing a new method for the generation of chiral pyrrolidines. Prior to this work, the asymmetric reaction had been studied in the Trost group.…”

Catalytic enantioselective synthesis of quaternary carbon stereocentres

“…Enantioselective cycloadditions of palladium-trimethylenemethane (Pd-TMM) complexes have been developed extensively over many years by Trost and co-workers. 15 In this way, a variety of functionalized cyclopentene derivatives containing quaternary stereocenters can be accessed directly. For example, the catalytic-enantioselective cycloaddition of propylidene oxindole 16 and TMM donor 17 was the central step in the total synthesis of (−)-marcfortine C ( 18 ) (Fig.…”

Enantioselective Catalytic Reactions with N-Acyliden Penta-atomic Aza-heterocycles. Heterocycles as Masked Bricks To Build Chiral Scaffolds

“…Catalytic Enantioselective 1,3-Nitrone Dipolar Cycloaddition between Nitrones 196 and 3-Substituted 1-(3,5-Dimethyl-1H-pyrazol-1-yl)prop-2-yn-1-one (3′) or Substituted 1-(3,5-Dimethyl-1H-pyrazol-1-yl)prop-2-en-1-ones (3) Recently, the reaction with 2-[(trimethylsilyl)methyl]allyl acetate (214) was extended to a series of 3-substituted 1-(1H-pyrrol-1-yl)prop-2-en-1-ones (1), with the complex between Pd 2 (dba) 3 The results, reported in Table 28 (entries 1−7), show excellent yields and enantioselectivities for all of the substituents, except the case with R = 2-furyl (entry 6). 96 The mechanism is outlined in the left part of Scheme 56 in which Pd(0) promotes ionization of the allylic acetate functionality in 214 to give [214a/Pd/XXXV], followed by desilylation, promoted by the displaced acetate, to afford the zwitterionic [214b/Pd/XXXV] complex. This nucleophilic Pd-TMM species adds to 1 giving the intermediate [(S)-215/Pd/ XXXV/1], which collapses through intramolecular cyclization to the product 216.…”

“…Its nucleophilic addition to 1 gives (1S,2R,3R)-218, again with excellent yields, diastereo-, and enantioselectivities ( Table 28, entries 8−17). 96 The absolute configuration can be rationalized by the geometry optimized structure of the [217b/Pd/XXXV] complex, in which one of the BINOL aryl rings acts as a wall, forcing the approach to the β-Re face of 1.…”