Synthesis of <i>P</i>‑Chiral Dihydrobenzooxaphosphole Core for BI Ligands in Asymmetric Transformations

An efficient and practical synthesis of enantiomerically pure <i>P</i>-chiral dihydrobenzooxaphosphole (BOP) core <b>1</b> is developed that is amenable to large scale preparation of the related ligand series. The unique epimerization of the <i>P</i>-chiral center of the undesired (<i>R</i>,<i>R</i>)-diastereomeric phosphine oxide <b>19</b> through chlorination followed by crystallization makes this chemical resolution method achieve 65% yield of desired (<i>R</i>,<i>S</i>)-diastereomer <b>12</b>

A Highly Convergent and Efficient Synthesis of a Macrocyclic Hepatitis C Virus Protease Inhibitor BI 201302

A highly convergent large scale synthesis of a 15-membered macrocyclic hepatitis C virus (HCV) protease inhibitor BI 201302 was achieved, in which the key features are the practical macrocyclization by Ru-catalyzed ring-closing metathesis (0.1 mol % Grela catalyst, 0.1–0.2 M concentration) and the efficient sulfone-mediated S_NAr reaction

Development of an Enantioselective Hydrogenation Route to (<i>S</i>)‑1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-amine

A highly enantioselective enamide hydrogenation route to the title amine was developed. Highlights of the synthesis include an efficient two-step synthesis of a 2-sulfonyl 4-pyridyl ethyl ketone, a simple enamide synthesis by direct condensation of propionamide with a ketone, catalytic asymmetric enamide hydrogenation employing the in-house-developed ligand MeO-BIBOP, and a mild epimerization-free deprotection of a propionamide using Koenig’s procedure

Carbamoyl Anion Addition to <i>N</i>‑Sulfinyl Imines: Highly Diastereoselective Synthesis of α‑Amino Amides

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral <i>N</i>-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η² coordination of lithium by the carbonyl group

Carbamoyl Anion Addition to <i>N</i>‑Sulfinyl Imines: Highly Diastereoselective Synthesis of α‑Amino Amides

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral <i>N</i>-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η² coordination of lithium by the carbonyl group

Carbamoyl Anion Addition to <i>N</i>‑Sulfinyl Imines: Highly Diastereoselective Synthesis of α‑Amino Amides

Carbamoyl anions, generated from N,N-disubstituted formamides and lithium diisopropylamide, add with high diastereoselectivity to chiral <i>N</i>-sulfinyl aldimines and ketimines to provide α-amino amides. The methodology enables the direct introduction of a carbonyl group without the requirement of unmasking steps as with other nucleophiles. The products may be converted to α-amino esters or 1,2-diamines. Iterative application of the reaction enabled the stereoselective synthesis of a dipeptide. Spectroscopic and computational studies support an anion structure with η² coordination of lithium by the carbonyl group

An Enantioselective Synthesis of an 11-β-HSD‑1 Inhibitor via an Asymmetric Methallylation Catalyzed by (<i>S</i>)‑3,3′‑F₂‑BINOL

An efficient asymmetric synthesis of 11-β-HSD inhibitor <b>1</b> has been accomplished in five linear steps and 53% overall yield, starting from the readily available 3-chloro-1-phenylpropan-1-one. The key feature of the synthesis includes an asymmetric methallylation of 3-chloro-1-phenylpropan-1-one catalyzed by the highly effective organocatalyst (<i>S</i>)-3,3′-F₂-BINOL under solvent-free and metal-free conditions

Preparative Synthesis via Continuous Flow of 4,4,5,5-Tetramethyl-2-(3-trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane: A General Propargylation Reagent

A scalable process for the preparation of 4,4,5,5-tetramethyl-2-(3-trimethylsilyl-2-propynyl)-1,3,2-dioxaborolane from trimethylsilylpropyne, isopropyl pinacol borate, and <i>n</i>-butyllithium is described. Problems associated with implementing a typical aqueous workup and batch process into production due to borolane “ate” equilibration and protonolysis are presented. To address these issues, a continuous-flow and distillation process was developed which efficiently produced 297 kg of the key propargylation reagent

Asymmetric Methallylation of Ketones Catalyzed by a Highly Active Organocatalyst 3,3′‑F₂‑BINOL

(<i>S</i>)-3,3′-F₂-BINOL has been synthesized for the first time and demonstrated as a highly active organocatalyst for asymmetric methallylation of ketones. Up to 98:2 enantioselectivity and 99% yield were obtained with 5 mol % catalyst loading. The catalyst (<i>S</i>)-3,3′-F₂-BINOL could be easily recovered and reused

Zinc Catalyzed and Mediated Asymmetric Propargylation of Trifluoromethyl Ketones with a Propargyl Boronate

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the <i>N</i>-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist <b>BI 653048</b>. A mechanism for the boron–zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones