Asymmetric Synthesis of <i>N</i>‑Boc‑(<i>R</i>)‑Silaproline via Rh-Catalyzed Intramolecular Hydrosilylation of Dehydroalanine and Continuous Flow <i>N</i>‑Alkylation

An asymmetric synthesis of a silicon-containing proline surrogate, <i>N</i>-Boc-(<i>R</i>)-silaproline (<b>1</b>), is described. Starting from <i>N</i>-Boc-dehydroalanine ester, deprotonation, followed by <i>N</i>-alkylation with chloromethyldimethylsilane under flow conditions, afforded the <i>N</i>-alkylated product <b>8</b> in 91% yield. An unprecedented enantioselective (NBD)₂RhBF₄/Josiphos 404-1 catalyzed 5<i>-endo-trig</i> hydrosilylation afforded the silaproline ester in 85–90% yield and >95% ee. Subsequent saponification and salt formation upgraded <b>1</b> to >99% ee

Synthesis of ((3<i>R</i>,6<i>R</i>)‑6-Methylpiperidin-3-yl)methanol via Biocatalytic Transamination and Crystallization-Induced Dynamic Resolution

An asymmetric synthesis of orexin receptor antagonist MK-6096 piperidine core, ((3<i>R</i>,6<i>R</i>)-6-methylpiperidin-3-yl)­methanol (<b>3</b>), is described. The target is synthesized in four steps and 40% overall yield from methyl vinyl ketone and diethyl malonate. The key operation is a practical crystallization-induced dynamic resolution for the conversion of a trans/cis mixture of lactam acid <b>17</b> into the desired trans-lactam acid salt in >95% de and 91% yield. The substrate lactam acid mixture was prepared via a solvent-free Michael reaction and a practical biocatalytic transamination process

Asymmetric Synthesis of Cyclic Indole Aminals via 1,3-Stereoinduction

A general and efficient asymmetric synthesis of cyclic indoline aminals was developed with a high level of 1,3-stereoinduction through a dynamic crystallization-driven condensation. Dehydrogenation of the indoline aminals with potassium permanganate produced the corresponding cyclic indole aminals in high yields and excellent enantioselectivities. This general methodology was successfully applied to the synthesis of a wide variety of chiral cyclic indoline aminals and indole aminals with aromatic and aliphatic functional groups

Unusual Pyrimidine Participation: Efficient Stereoselective Synthesis of Potent Dual Orexin Receptor Antagonist MK-6096

An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (<b>1</b>) is described. Key steps for the <i>trans</i>-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a <i>trans</i>-selective Mukaiyama aldol, and a regioselective pyridyl S_NAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described

Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin

A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (<b>1</b>) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael–lactolization–dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps

Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an <i>anti</i>-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales

Asymmetric Synthesis of a Glucagon Receptor Antagonist via Friedel–Crafts Alkylation of Indole with Chiral α‑Phenyl Benzyl Cation

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an <i>anti</i>-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales

Asymmetric Synthesis of <i>cis</i>-2,5-Disubstituted Pyrrolidine, the Core Scaffold of β₃‑AR Agonists

A practical, enantioselective synthesis of <i>cis</i>-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields <i>syn</i>-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the <i>cis</i>-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β₃-AR agonists is synthesized in 38% overall yield