A Concise Enantioselective Synthesis of (S)-Preclamol via Asymmetric Catalytic Negishi Cross-Coupling Reaction

Abstract

A novel, concise, and efficient enantioselective synthesis of (S)-preclamol (87% ee, 51% total yield) has been developed. The key steps of this synthetic approach included cobalt-catalyzed asymmetric catalytic cross-coupling of α-bromo ester with arylzinc and the reduction of chiral ester to diol with a tertiary carbon atom. Moreover, it was demonstrated that our enantioselective Negishi cross-coupling was a powerful tool to construct stereogenic benzylmethyl center in chiral drugs on a gram scale.

Enantioselective Cross‐couplings between Halide Derivatives and Organometallics by Using Iron and Cobalt Catalysts: Formation of C−C Bonds

“…In addition, in 2019, Zhong et al further expanded this protocol to the synthesis of (S)-preclamol with a 51 % total yield and an er of 93.5 : 6.5. [16] In addition, Zhong et al applied this cobalt-catalyzed enantioselective Negishi cross-coupling to the synthesis of high Scheme 6. Iron-catalyzed enantioselective couplings of alkyl halides and organoboron reagents.…”

“…In addition, in 2019, Zhong et al. further expanded this protocol to the synthesis of ( S )‐preclamol with a 51 % total yield and an er of 93.5 : 6.5 [16] …”

“…In addition, in 2019, Zhong et al further expanded this protocol to the synthesis of (S)-preclamol with a 51 % total yield and an er of 93.5 : 6.5. [16] In addition, Zhong et al applied this cobalt-catalyzed enantioselective Negishi cross-coupling to the synthesis of high enantio-enriched (R)-cinacalcet, a clinical drug for the treatment of hyperparathyroidism (Scheme 11). [17] Fluorine-containing compounds are of high significance in pharmaceutical, agricultural and material industries.…”

Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines

“…Asymmetric chemical synthetic approaches for the preparation of 3-substituted and 3,4-disubstituted piperidines include those based on metalation/cross-coupling, − Grignard Michael addition, ring closure, and transition-metal-catalyzed dearomatization of pyridines. − However, limitations are associated with all of these approaches, including high reaction temperatures, sensitivity to moisture, lack of availability of starting materials, and the use of expensive noncommercial chiral ligands. , Among reported methods, the catalytic asymmetric dearomatization of pyridines is achieved by quaternization-activation of the pyridine nitrogen, permitting access to mild reduction methods to chiral piperidines (Figure B, left). ,− Whilst nature has yielded pyridine synthases to prepare pyridines, an effective biocatalyst for their dearomatization is yet to be discovered. With this in mind, we sought to combine mild chemical reduction of pyridiniums to tetrahydropyridines (THPs) with the exquisite stereoselectivity of a biocatalytic cascade to reduce the final CC bond as an efficient strategy for asymmetric dearomatization of activated 3- and 3,4-substituted pyridines (Figure C).…”

Synthesis of stereoenriched piperidines via chemo-enzymatic dearomatization of activated pyridines

“…Asymmetric chemical synthetic approaches f or the preparation of 3-substituted and 3,4-disubstituted piperidines include those based on metalation/cross-coupling (11)(12)(13)(14), Grignard Michael addition (15), ring-closure (16), and transition-metal-catalyzed dearomatization of pyridines (17)(18)(19)(20). However, limitations are associated with all of these approaches, including high reaction temperatures, sensitivity to moisture, lack of availability of starting materials and the use of expensive non-commercial chiral ligands (11,21).…”