Highly Enantioselective Catalytic Hetero-Diels-Alder Reaction with Inverse Electron Demand

Abstract

Valuable substrates for the synthesis of natural products, compounds 3 (R =alkyl, aryl, alkoxy; R , R =alkyl) are formed from β,γ-unsaturated α-keto esters 1 and vinyl ethers 2 by the title reaction [Eq. (1)]. Copper(II) bisoxazolines act as catalysts, and in many cases enantiomeric excesses higher than 99.5 % are achieved.

Chemistry of α-Oxoesters: A Powerful Tool for the Synthesis of Heterocycles

“…397 Moreover, there are other reports on the [4 + 2] heterocycloaddition between β,γ-unsaturated α-oxoesters and vinyl ethers leading to THP-2-carboxylates in the literature. 395,398 In addition to vinyl ethers, enamines were also investigated in the HDA reaction with β,γ-unsaturated α-oxoesters to synthesize THF-2-carboxylates bearing an amine substituent at C−6. 399 In this context, Eiden and Winkler 400 performed the HDA reaction between a variety of β,γ-unsaturated α-oxoesters and enamines, in absolute MeOH, leading to the corresponding Gohier et al 401 developed the Lewis acid-mediated HDA reaction between β,γ-unsaturated α-oxoesters and β-substituted N-vinyl-1,3-oxazolidin-2-ones to afford the corresponding cycloadducts, THF-2-carboxylates 837.…”

5.10 Hetero-Diels–Alder Reactions

“…Chiral bis(oxazoline)-copper(II) complexes 58 are the catalysts that are most frequently used for inverse electron-demand hetero-DielsAlder reactions, such as those of b,g-unsaturated a-keto esters and a,b-unsaturated acyl phosphonates. [46][47][48][49][50][51] The ester and phosphonate groups activate the heterodienes as the substrate for a hetero-Diels-Alder reaction by lowering the LUMO. In addition, they provide a second 'docking point' for coordination to the chiral copper(II) LA.…”

Catalytic Enantioselective Cycloaddition Reactions of Carbonyl Compounds

“…Our development of the catalytic enantioselective inverse electron-demand cycloaddition reaction [49], which was followed by related papers by Evans et al [38,48], focused in the initial phase on the reaction of mainly b, c-unsaturated a-keto esters 53 with ethyl vinyl ether 46a and 2,3-dihydrofuran 50a (Scheme 4.34).…”

“…The enantioselective cycloaddition of the b, c-unsaturated a-keto esters 53 with ethyl vinyl ether 46a and 2,3-dihydrofuran 50a catalyzed by 21b (X = OTf) or the water complex 27 (Scheme 4.24) proceeds with high yield and diastereo-and enantioselectivity [38,48,49]. The reaction tolerates a broad range of R 1 substituents, such as alkyl, aryl, alkoxy, and thiobenzyl.…”