Palladium-Catalyzed α‑Arylation of Sultams with Aryl and Heteroaryl Iodides

Palladium­(0)-catalyzed conditions for the α-arylation of sultams with aryl and heteroaryl iodides have been developed. Arylation of 3-substituted 1,3-propanesultams gave rise to high yields and high diastereomeric ratios, leading to the thermodynamically favored <i>cis</i> product. The arylation was broadly applicable to various electron-rich and electron-poor (hetero)­aromatic iodides

Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084

An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals

A Practical, Protecting-Group-Free Synthesis of a PI3K/mTOR Inhibitor

We report a practical and protecting-group-free synthesis amenable to produce multikilogram amounts of PI3K/mTOR inhibitor <b>GDC-0980</b>. The route employed metalation/formylation and reductive amination followed by a metal catalyzed Suzuki–Miyaura cross-coupling. The metalation was performed via triarylmagnesiate intermediates allowing formylation under noncryogenic conditions. 2-Picoline·BH₃ was employed to replace Na­(OAc)₃BH in the reductive amination and to eliminate the use of molecular sieves. A concise one-step synthesis was developed for the selective monoamidation of piperazine with (<i>S</i>)-lactate to produce the piperazine lactamide starting material. The boronic acid was produced from 2-amino-5-bromopyrimidine in a one-step and protecting-group-free approach. The final crystallization in 1-propanol and water afforded the API in 59% overall yield in four steps and >99% purity by HPLC

Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib

A highly efficient asymmetric synthesis of the Akt kinase inhibitor ipatasertib (<b>1</b>) is reported. The bicyclic pyrimidine <b>2</b> starting material was prepared via a nitrilase biocatalytic resolution, halogen–metal exchange/anionic cyclization, and a highly diastereoselective biocatalytic ketone reduction as key steps. The route also features a halide activated, Ru-catalyzed asymmetric hydrogenation of a vinylogous carbamic acid to produce α-aryl-β-amino acid <b>3</b> in high yield and enantioselectivity. The API was assembled in a convergent manner through a late-stage amidation/deprotection/monohydrochloride salt formation sequence

Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up

Herein, the first-generation process to manufacture Akt inhibitor Ipatasertib through a late-stage convergent coupling of two challenging chiral components on multikilogram scale is described. The first of the two key components is a <i>trans</i>-substituted cyclopentylpyrimidine compound that contains both a methyl stereocenter, which is ultimately derived from the enzymatic resolution of a simple triester starting material, and an adjacent hydroxyl group, which is installed through an asymmetric reduction of the corresponding cyclopentylpyrimidine ketone substrate. A carbonylative esterification and subsequent Dieckmann cyclization sequence was developed to forge the cyclopentane ring in the target. The second key chiral component, a β²-amino acid, is produced using an asymmetric aminomethylation (Mannich) reaction. The two chiral intermediates are then coupled in a three-stage endgame process to complete the assembly of Ipatasertib, which is isolated as a stable mono-HCl salt

Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up

Herein, the first-generation process to manufacture Akt inhibitor Ipatasertib through a late-stage convergent coupling of two challenging chiral components on multikilogram scale is described. The first of the two key components is a <i>trans</i>-substituted cyclopentylpyrimidine compound that contains both a methyl stereocenter, which is ultimately derived from the enzymatic resolution of a simple triester starting material, and an adjacent hydroxyl group, which is installed through an asymmetric reduction of the corresponding cyclopentylpyrimidine ketone substrate. A carbonylative esterification and subsequent Dieckmann cyclization sequence was developed to forge the cyclopentane ring in the target. The second key chiral component, a β²-amino acid, is produced using an asymmetric aminomethylation (Mannich) reaction. The two chiral intermediates are then coupled in a three-stage endgame process to complete the assembly of Ipatasertib, which is isolated as a stable mono-HCl salt