A Facile, Six-Step Process for the Synthesis of (3S,5S)-3-Isopropyl-5-((2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1-carboxylic Acid tert-Butyl Ester, The Key Synthetic Intermediate of Aliskiren

A facile, six-step process for the synthesis of (3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2yl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester from (S)-4-benzyloxazolidin-2-one 2 in an overall 50% yield is reported. The key transformations include: a highly efficient diastereoselective epoxidation, Lewis acid-catalyzed ring-opening with bromide, an SN2 reaction using NaN3, and a tandem reduction−cyclization reaction. ■ INTRODUCTION Aliskiren (1) is the first of a new class of orally effective direct renin inhibitors which was approved by the U.S. Food and Drug Administration (FDA) in 2007 and marketed by Novartis AG (Rasilez, Enviage, Sprimeo, and Tekturna). Although it has received a warning and contraindication from the U.S. FDA in 2012 because of the potential risk of renal failure and angioedema, its superior blood pressure-lowering efficacy and unique chemical structure still capture the interest of pharmaceutical companies and synthetic chemists. The difficulty and challenge of synthesizing aliskiren lie in the construction of its four chiral centers (Scheme 1). Lots of effort and several synthetic approaches toward the synthesis of aliskiren have been reported in the recent literature. Göschke et al. provided a protocol that the core 4,5-(S)-amino-hydroxy was introduced by halo-lactonization and the following azidation. Rüeger et al. reported in 2000 a convergent synthetic route, the key reaction employed the coupling of Grignard reagent with the diastereomeric pure γ-lactone and enantioselective reduction. The linchpin of Sandham’s synthesis routes was the enantioselective Grignard addition to the amide spiroacetal, which was introduced by the pseudoephedrine chiral auxiliary. Dondoni and colleagues synthesized the core chiral β-amino alcohol segment via the Grignard addition to the pseudoephedrine spiroanellated γbutyolactone derivative. Göschke et al. reported another convergent synthesis of aliskiren in 2003, in which the key chiral amine was introduced by the alkylation of the chiral Schöllkopf dihydropyrazine. Ma’s synthetic route was based on the approach reported by Göschke along with modifications. Hanessian devised a “macrocycle route” toward aliskiren, include a chllenging RCM reaction to produce a ninemembered unsaturated lactone, a highly enantioselective catalytic Du Bois aziridination, and a regioand diastereoselective aziridine ring opening to a vicinal amino alcohol. Prasad et al. described a 12-step synthesis of aliskiren that features a Curtius rearrangement to transform carboxylic acid to the benzyl carbamate via the isocyanate. Ko reported a total synthesis of aliskiren, in that route they used the symmetric trans-cisoid−trans-bis latone as a key precursor. Among the synthetic approaches reported, the convergent routes that disconnect aliskiren into three independent segments are the most effective and convenient (Scheme 1). As part of our continuing interest in developing efficient and practical processes for the synthesis of active pharmaceutical ingredients (API) and intermediates, we now report a facile and convergent six-step approach toward the synthesis of (3S,5S)-3-isopropyl-5-((2S,4S)-4-isopropyl-5-oxo-tetrahydrofuran-2-yl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (Segment B), the key synthetic intermediate of aliskiren