Stereoselective Organocatalytic Synthesis of γ,γ‐Disubstituted Butenolides

Abstract

A direct highly diastereo‐ and enantioselective asymmetric doubly vinylogous 1,6‐Michael addition reaction of 3‐methyl‐4‐nitro‐5‐alkenyl isoxazoles with γ‐substituted deconjugated butenolides has been successfully developed with the help of Cinchona derived squaramides. This novel strategy has been utilized to synthesize a range of enantiopure γ,γ‐disubstituted butenolide molecules bearing remote contiguous quaternary and tertiary stereocenters in yield up to 76% with ee up to 98% and dr up to ≥20:1.

Cinchona Derivatives as Bifunctional H‐bonding Organocatalysts in Asymmetric Vinylogous Conjugate Addition Reactions

“…Later, Chimni et al. also published a similar work with quinine‐based catalyst C17a and slightly different reaction conditions [44b] …”

Asymmetric Phase Transfer Catalysed Michael Addition of γ-Butenolide and N-Boc-Pyrrolidone to 4-Nitro-5-styrylisoxazoles

“…Compounds 1 are stable solids and reacted in Michael reactions as an acceptor. A special feature of compounds 1 is the presence of two electrophilic centres that can be independently reacted [29,30], with the exocyclic "soft" one that found extensive application in 1,6-conjugate enantioselective additions particularly under organocatalytic conditions [44][45][46][47][48][49][50][51][52][53]. Compounds 1 were also used in a large-scale industrial context, for example in the preparation of active pharmaceutical ingredients (APIs) (R)-Baclophen [54] and (S)-Pregabalin [55].…”

Unravelling the Development of Non-Covalent Organocatalysis in India

“…Chiral quinine squaramide catalysts 3A and 3C have been used by Chimni and co-workers in asymmetric 1,6-Michael addition reactions of 3-methyl-4-nitro-5-alkenylisoxazoles 163 with γ-substituted deconjugated butenolides 17 and pyrazolin-5-ones 164 to furnish the corresponding products 166 and 165 , respectively, with excellent enantioselectivities (Scheme 55 ). 102 103 They also demonstrated the use of squaramide catalyst 3A for the enantioselective decarboxylative addition reaction of β-ketoacids 168 to isatin imines 167 , resulting in chiral 3-aminooxindoles 169 in high yields and excellent enantioselectivities (Scheme 56 ). 104 Chimni proposed a transition state in which the isatin imine 167 is activated by double H-bonding through the N–H bonds of the squaramide catalyst 3A , with the β-ketoacid 168 being activated by the tertiary amine, thereby making the Re face of the imine accessible for nucleophilic attack.…”