Human immunodeficiency virus-1 (HIV-1) infection currently requires lifelong therapy with drugs that are used in combination to control viremia. The indole-3-glyoxamide 6 was discovered as an inhibitor of HIV-1 infectivity using a phenotypic screen and derivatives of this compound were found to interfere with the HIV-1 entry process by stabilizing a conformation of the virus gp120 protein not recognized by the host cell CD4 receptor. An extensive optimization program led to the identification of temsavir (31), which exhibited an improved antiviral and pharmacokinetic profile compared to 6 and was explored in phase 3 clinical trials as the phosphonooxymethyl derivative fostemsavir (35), a prodrug designed to address dissolution- and solubility-limited absorption issues. In this drug annotation, we summarize the structure-activity and structure-liability studies leading to the discovery of 31 and the clinical studies conducted with 35 that entailed the development of an extended release formulation suitable for phase 3 clinical trials.
Aromatic bisvinyl ethers, prepared by the condensation of bisphenols with 2‐chloroethyl vinyl ether in the presence of sodium hydroxide, are a new class of thermosetting monomers. These new materials can be polymerized cationically by using diaryliodonium salts as photo and thermal initiators to produce crosslinked resins whose physical and thermal characteristics resemble those of epoxy resins.
The transition metal-catalyzed asymmetric allylic alkylation of unsymmetrically substituted allyl derivatives has recently emerged as an effective method for the preparation of optically active branched regioisomers in high enantioselectivity and regioselectivity. [1] Results of these studies are in contrast to the traditional palladium-catalyzed reactions that predominantly afford the linear regioisomeric product. [2,3] Particularly interesting is the molybdenum-catalyzed asymmetric allylic alkylation method developed by Trost, which has emerged as one of the most promising methods for obtaining optically active branched regioisomeric products, Scheme 1. [1c,4] Indeed, high enantio-and regioselectivities have been achieved for a range of allylic substrates with various malonate nucleophiles.
Scheme 1. Trost's asymmetric allylic alkylation reactionOur primary interest in the described reaction arose from our desire to utilize the chiral unsymmetrically substituted ªbranchedº allylic derivative 3 as a key intermediate in the synthesis of a lead drug candidate (Scheme 2). The results published by Trost suggest that the molybdenum-catalyzed asymmetric allylic alkylation methodology would provide the desired product 3 in good enantio-and regioselectivities. However, it became clear that direct implementation of the reaction to large-scale
Asymmetric catalysis by transition metal complexes has emerged as an important tool for the synthesis of optically active compounds for both academia and industry. The study of asymmetric catalysis and subsequent utility in organic synthesis requires that the chiral catalysts and/or ligands be available in sufficient quantities. This is especially true for the pharmaceutical industry, since large quantities are often needed to prepare a drug candidate to support clinical trials. Accordingly, the development of practical syntheses of these chiral catalysts and/or ligands becomes of great importance.Transition metal-catalyzed allylic alkylations using chiral ligands is an elegant method for inducing asymmetry into achiral compounds. [1] Enantioselective alkylation of unsymmetrically substituted allylic substrates is a challenging problem, due to regioselectivity issues. [2] Trost has recently reported exceptional results with a chiral molybdenum catalyst prepared from ligand 2 [3] which gave a branched-to-linear ratio of 49 : 1 and an ee of 99% in the alkylation of methyl (E)-1-phenylallyl carbonate with dimethyl sodiomalonate. In order to further investigate a molybdenum-catalyzed asymmetric alkylation reaction for the preparation of a key intermediate in the synthesis of a new drug candidate, we needed to prepare multigram quantities of 1 and 2. Scheme 1.
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