A General Organocatalytic Enantioselective Malonate Addition to α,β‐Unsaturated Enones

Abstract

A general enantioselective organocatalytic conjugate addition procedure of a variety of malonates to alpha,beta-unsaturated enone systems is presented. The reaction is efficiently catalysed by the pyrrolidinyl tetrazole catalyst 1. Cyclic, acyclic and aromatic enones can be used and the reaction with ethyl malonates 3 b provides the Michael addition products in high yields with good to excellent enantioselectivities. Since only 1.5 equivalents of malonate are used as a reagent, the reaction is readily scaled and practical to operate. Furthermore, the malonate addition products can be easily mono decarboxylated without loss in enantiomeric excess by enzymatic or sodium hydroxide mediated methods.

Novel guanidinyl pyrrolidine salt-based bifunctional organocatalysts: application in asymmetric conjugate addition of malonates to enones

“…Moreover, good to high enantioselectivities were obtained when both dimethylmalonate and diethylmalonate were used. 11,12 Only very recently, Zhao and Yang reported a highly efficient strategy using primary-secondary diamine catalysts. 13 Indeed the use of 20 mol % of catalyst gave the desired products in a relatively short reaction time (24 h) in excellent yields (up to 99%) and enantioselectivities (up to 99% ee) for a wide range of acyclic enones.…”

A Tetrakis(tetrazolyl) Analogue of EDTA

“…[19,20] But its incorporation into multidentate ligands that leads to five-membered chelate rings upon complexation has not yet been attempted. In the domains of medicinal chemistry and drug design, [21,22] and lately also more frequently in organocatalysis, [23][24][25][26] the tetrazole moiety is of particular interest as a carboxylic acid "isoster". [27] Here, it is usually established in situ with the corresponding inconveniences (reactant incompatibility, yield).…”

Asymmetric Organocatalytic Reactions of α,β-Unsaturated Cyclic Ketones

“…Thus, piperidine was added to the reaction mixture for this purpose (entry 1, Table 1) [20,21]. As reported below, nitroalkanes (pK a MeNO 2 = 10) need weaker bases.…”

“…All malonates and cyclic enones react generally smoothly to generate adducts with high yields and excellent enantioselectivities, except 2-cyclopentenone, which gives 88%, 64%, 47% yield and 30%, 63%, 55% ee under Ley [21], Ye [24], and Yoshida [27] This difficulty has been overcome using a chiral diamine-acid combination catalyst in methanol [23]. At the HF/6-31G(d) level of theory, the transition states C has a minimum of energy over transition states, where methanol or malonate are not involved in hydrogen bonding with the catalyst.…”