Delving into the Latest Updates on L-731120 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

SQS

Mechanism

SQS inhibitors(Squalene synthase inhibitors)

Therapeutic Areas

Cardiovascular DiseasesEndocrinology and Metabolic Disease

Active Indication-

Inactive Indication

AtherosclerosisHypercholesterolemia

Originator Organization

Merck & Co., Inc.

Active Organization-

Inactive Organization

Merck & Co., Inc.

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC23H32O7

InChIKeyNLNJIEVMUWDLAZ-NZYMUKNISA-N

CAS Registry2232226-16-1

The development of a flow-assisted synthesis of alkyl citrate natural products is described. The flow route harnesses a number of steps including the generation of ketene silyl acetal, a formal [2 + 2] cycloaddition, and a methanolysis cascade to efficiently generate a highly substituted, and stereodefined tetrahydrofuran intermediate. A heterogeneous pseudo-Finkelstein reaction and zinc-mediated elimination furnish a key alkene alkyl citrate fragment in high yield over a multistep sequence that provides direct entry to compounds such as (-)-CJ-13982 (1), (-)-CJ-13,981 (2), L-731,120 (3), and related natural products. The flow methodology developed in this study enables a new machine-assisted approach toward the efficient and scalable synthesis of the alkyl citrate family of natural products.

20 Jul 2018·Organic LettersQ1 · CHEMISTRY

Synthesis of Alkyl Citrates (−)-CJ-13,981, (−)-CJ-13,982, and (−)-L-731,120 via a Cyclobutene Diester

Q1 · CHEMISTRY

Article

Author: Robertson, Angus ; Rizzacasa, Mark A. ; Sturgess, Dayna ; White, Jonathan M. ; Chen, Zongjia ; Atkin, Liselle

An efficient and step-economic new approach to alkyl citrate natural products from a cyclobutene diester is presented. The key sequence involves a formal [2 + 2]-cycloaddition of a silylketene acetal with dimethylacetylene dicarboxylate to provide the cyclobutene diester 14 with 4.5:1 stereoselectivity. Exposure of diester 14 in acidic methanol effected a hydrolysis, intramolecular oxy-Michael reaction, and cyclobutanone methanolysis cascade to give the triester 15. Iodination and elimination then afforded a key alkyl citrate alkene intermediate, which was converted into the natural products (-)-CJ-13,982 (1), (-)-CJ-13,981 (2), and (-)-L-731,120 (3) via a cross-metathesis and subsequent reduction.

100 Deals associated with L-731120

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