A New Strategy for the Synthesis of Chiral β-Alkynyl Esters via Sequential Palladium and Copper Catalysis

Abstract

A new strategy for the synthesis of chiral β-alkynyl esters which relies on sequential Pd and Cu catalysis is reported. Terminal alkynes bearing aryl-, alkyl-, and silyl-groups can be employed without prior activation yielding a wide range of important chiral building blocks. The reaction sequence utilizes a robust Pd(II)-catalyzed hydroalkynylation of ynoates with terminal alkynes providing geometrically-pure ynenoates which are readily reduced by CuH. In contrast to previous reports, where additions to ynenoates proceed with marginal preference for the 1,6-pathway, this conjugate reduction occurs with high 1,4-selectivity yielding β-alkynyl esters with excellent levels of enantioselectivity. Importantly, the method tolerates a wide range of functionality, including allylic carbonates and carbamates, and thus allows for rapid elaboration of the β-alkynyl esters into a variety of chiral, substituted heterocycles.

Mutually Complementary Metal‐ and Organocatalysis with Collective Synthesis: Asymmetric Conjugate Addition of 1,3‐Carbonyl Compounds to Nitroenynes and Further Reactions of the Products

“…The mixture was warmed to room temperature and extracted with EtOAc. The combined organic phases were dried over Na 2 SO 4 , filtered, concentrated under vacuum, and purified by column chromatography on silica gel (petroleum ether/ethyl acetate as eluents) to afford the compound 11 ;6 yiele: 16 mg (78%). 1 H NMR (300 MHz, CDCl 3 ): δ =7.40 (m, 2 H), 7.32 (m, 3 H), 4.09 (t, J =8.1 Hz, 1 H), 3.78 (t, J =7.5 Hz, 1 H), 3.37 (t, J =8.1 Hz, 1 H), 2.87 (m, 1 H), 2.73 (m, 1 H), 1.56 (brs, 9 H).…”

“…While these reports stand out as pioneering efforts, they have limitations such as the requirement of the use of aromatic alkynes,2 sterically shielded TMS (trimethylsilyl)acetylene,3 a stoichiometric chiral mediator4 or a complex catalyst system and a relative high temperature (50 °C)5. Thus, the development of a new catalytic asymmetric strategy to construct chiral β‐alkynyl acids,6 especially a novel type of multifunctional chiral β‐alkynyl acids with both biological and pharmacological potential as well as versatile synthetic utilities is highly desirable.…”

Ene‐Reductase: A Multifaceted Biocatalyst in Organic Synthesis

“…[50] The α,β-unsaturated aldehydes with a conjugated triple bond at the γ-position were selectively reduced to homologous alkynyl products (Scheme 3c) which traditionally required harsh and/or metal-catalysed reaction conditions. [51][52][53] The classical synthetic modification of (R)carvone to the reduced (2R,5R)-dihydrocarvone asymmetrically was devised by Paul and co-workers, [54] employing an enereductase FOYE-1, obtained from an acidophilic iron oxidizer OYE. The FOYE-1 showed excellent organic solvent tolerance and thermal stability up to 40 °C in the reduction of (R)-carvone to (2R,5R)-dihydrocarvone which are valuable chiral motifs of various biologically active natural products.…”

Asymmetric synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives via sequential palladium and copper catalysis

“…We previously reported preliminary results toward this end, highlighting the utility of dual Pd and CuH catalysis in the synthesis of selected examples of chiral β-alkynyl esters. 24 Herein, we provide a comprehensive account describing not only the development of that process but also further progress in this area. These subsequent studies have enabled significant expansions in both the scope and the synthetic utility of this sequential catalysis strategy.…”