Michael J. Zacuto

Synthesis of the HCV Protease Inhibitor Vaniprevir (MK-7009) Using Ring-Closing Metathesis Strategy

A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.

Asymmetric synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraine.

A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of this organocatalytic transformation was the identification of a dual acid cocatalyst system, which allowed striking a balance of the reaction efficiency and product stability effectively. As such, via an iminium species, the necessnary C-6 stereogenicity was practically established in one operation in >95% ee. Furthermore, we enlisted an unprecedented Doebner-Knoevenagel coupling, which was also via an iminium species, to efficiently construct the C3-C4 bond with desired functionality. In order to prepare telcagepant (1) in high quality, a practical new protocol was discovered to suppress the formation of desfluoro impurities formed under hydrogenation conditions to <0.2%. An efficient lactamization facilitated by t-BuCOCl followed by a dynamic epimerization-crystallization resulted in the isolation of caprolactam acetamide with the desired C3 (R) and C6 (S) configuration cleanly. Isolating only three intermediates, the overall yield of this cost-effective synthesis was up to 27%. This environmentally responsible synthesis contains all of the elements required for a manufacturing process and prepares telcagepant (1) with the high quality required for pharmaceutical use.

Asymmetric synthesis of a potent, aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV inhibitor.

A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.

One-step synthesis of 1-chloro-3-arylacetone derivatives from arylacetic acids.

A practical one-step method has been developed to prepare α-chloroketones from readily available, inexpensive phenylacetic acid derivatives. The method utilizes the unique reactivity of an intermediate Mg-enolate dianion, which displays selectivity for the carbonyl carbon of chloromethyl carbonyl electrophiles. Decarboxylation of the intermediate occurs spontaneously during the reaction quench. The utility of the reaction products has been demonstrated through the total synthesis of the natural product cimiracemate B.