RESUMEN
Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.
RESUMEN
A practical method for the efficient and enantioselective preparation of versatile ketones and aldehydes that contain an α-quaternary stereocenter is described. Reactions utilize simple carboxylic acid or ester starting materials, a monodentate chiral phosphine, and afford a variety of aryl, alkenyl, alkynyl, and alkyl-substituted ketone and aldehyde products in 25-94 % yield and 90 : 10 to >99 : 1 enantiomeric ratio. Reactions proceed by acyl substitution with in situ formed chiral allylic nucleophiles, and display selectivity and conversion dependence on a protic additive. The utility of the approach is demonstrated through several product transformations.
RESUMEN
A general method for the synthesis of secondary homoallylic alcohols containing α-quaternary carbon stereogenic centers in high diastereo- and enantioselectivity (up to >20:1 dr and >99:1 er) is disclosed. Transformations employ readily accessible aldehydes, allylic diboronates, and a chiral copper catalyst and proceed by γ-addition of in situ generated enantioenriched boron-stabilized allylic copper nucleophiles. The catalytic protocol is general for a wide variety of aldehydes as well as a variety of 1,1-allylic diboronic esters. Hammett studies disclose that diastereoselectivity of the reaction is correlated to the electronic nature of the aldehyde, with dr increasing as aldehydes become more electron poor.
Asunto(s)
Alcoholes/síntesis química , Aldehídos/química , Compuestos Alílicos/síntesis química , Carbono/química , Alcoholes/química , Compuestos Alílicos/química , Boro/química , Catálisis , Ésteres , Estructura Molecular , EstereoisomerismoRESUMEN
A catalytic diastereo- and enantioselective method for the preparation of complex tertiary homoallylic alcohols containing a vicinal quaternary carbon stereogenic center and a versatile alkenylboronic ester is disclosed. Transformations are promoted by 5â mol % of a readily available copper catalyst bearing a bulky monodentate phosphoramidite ligand, which is essential for attaining both high dr and er. Reactions proceed with a wide variety of ketones and allylic 1,1-diboronate reagents, which enables the efficient preparation of diverse array of molecular scaffolds.
Asunto(s)
Alquenos/química , Compuestos de Boro/química , Cobre/química , Cetonas/química , Catálisis , Ligandos , Fosforamidas/química , EstereoisomerismoRESUMEN
A Cu-catalyzed method for the efficient enantio- and diastereoselective synthesis of chiral homoallylic amines bearing a quaternary carbon and an alkenylboron is disclosed. Transformations are promoted by a readily prepared (phosphoramidite)-Cu complex and involve bench-stable γ,γ-disubstituted allyldiborons and benzyl imines; products are obtained in up to 82% yield, >20:1 dr, and >99:1 er. Reactions proceed via stereodefined boron-stabilized allylic Cu species formed by an enantioselective transmetalation. Utility of the 1-amino-3-alkenylboronate products is highlighted by a variety of synthetic transformations.
Asunto(s)
Aminas/síntesis química , Carbono/química , Aminas/química , Catálisis , Cobre/química , Espectroscopía de Protones por Resonancia Magnética , EstereoisomerismoRESUMEN
A single-pot Cu-catalyzed enantio- and diastereoselective tandem hydroboration/borylative cyclization of alkynes with ketones for the synthesis of carbocycles is reported. The reaction proceeds via desymmetrization and generates four contiguous stereocenters, including an all-carbon quaternary center. The method provides rapid access to [6,5]- and [5,5]-bicycles and cyclopentane products. Catalyst-controlled diastereoselectivity by selection of bisphosphine ligand is noted. Utility of the products is demonstrated by site- and chemoselective transformations that afford valuable alkenyl and allyl organoborons.
Asunto(s)
Alquinos/química , Alquinos/síntesis química , Cobre/química , Cetonas/química , Cetonas/síntesis química , Boro/química , Técnicas de Química Sintética , Ciclización , EstereoisomerismoRESUMEN
Catalytic enantioselective synthesis of 1-hydroxy-2,3-bisboronate esters through multicomponent borylation/1,2-addition is reported. Catalyst and substrates are readily available, form both a C-B and C-C bond, and generate up to three contiguous stereocenters. The reaction is tolerant of aryl, vinyl, and alkyl aldehydes and ketones in up to 95% yield, >20:1 dr, and 99:1 er. Intramolecular additions to aldehydes and ketones result in stereodivergent processes. The hydroxy bis(boronate) ester products are amenable to site-selective chemical elaboration.