Convergent Synthesis of the Renin Inhibitor Aliskiren Based on C5–C6 Disconnection and CO₂H–NH₂ Equivalence

Abstract

A novel synthesis of the renin inhibitor aliskiren based on an unprecedented disconnection between C5 and C6 was developed, in which the C5 carbon acts as a nucleophile and the amino group is introduced by a Curtius rearrangement, which follows a simultaneous stereocontrolled generation of the C4 and C5 stereogenic centers by an asymmetric hydrogenation. Operational simplicity, step economy, and a good overall yield makes this synthesis amenable to manufacture on scale.

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

“…More recently a novel synthesis of aliskiren was proposed by Cini and co‐workers based on an unprecedented C5‐C6 disconnection, which was carried out on a multigram scale in nine steps. Also in this case a key Curtius rearrangement step was involved …”

“…Also in this case ak ey Curtius rearrangement step was involved. [84] Acid 137,b earing the adjacent OH functionality protected as acetyl derivative, possessed all of the features required for application of the Curtius rearrangement withoutt he risk of a concurring lactonizationr eaction. It was reactedw ith DPPAi n the presence of benzyla lcohol.…”

Enantioselective Synthesis of Ozanimod, the Active Pharmaceutical Ingredient of a New Drug for Multiple Sclerosis

“…Following our interest in optimizing the synthesis of API for important medicines, [14][15][16] we tried to design a new approach to Ozanimod 1 based on catalytic introduction of the stereogenic center, reduction of unrequired steps and limited use of protective groups and dangerous solvents.…”

Design and synthesis of chiral and regenerable [2.2]paracyclophane-based NAD(P)H models and application in biomimetic reduction of flavonoids

“…including stereoselective hydrogenation in the synthesis of Aliskiren, which is a hypertension drug. 5 Inspired by the achievements based on [2.2]paracyclophane, 5,6 we envisioned that the [2.2]paracyclophane-based chiral and regenerable NAD(P)H models should be an excellent candidate. For the chiral and regenerable NAD(P)H models, some requirements must be taken into account: (1) no substituent on the active site (CH]N and CH]NH); otherwise, low reactivity would be observed due to steric hindrance; (2) the CH of active sites must be close to the planar stereogenic center, which is favourable for stereocontrol of hydride transfer.…”