RESUMEN
We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically enriched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize valuable substituted azoles in a regioselective manner by capping (e.g., acylation) of the equilibrating azole-aldehyde adduct. With the use of a prolinol-derived DMAP catalyst as the chiral Lewis base, the products can be obtained in high chemical yield and with high enantiomeric excess. The DKR was performed on a multikilogram scale to produce a tetrazole prodrug fragment for a leading clinical candidate that posed formidable synthesis challenges.
Asunto(s)
Azoles/síntesis química , Ésteres/síntesis química , Bases de Lewis/química , Aldehídos/química , Alcanosulfonatos/síntesis química , Alcanosulfonatos/química , Azoles/química , Catálisis , Ésteres/química , Cinética , Estereoisomerismo , TetrazolesRESUMEN
Despite the longstanding importance of polyketide natural products in human medicine, nearly all commercial polyketide-based drugs are prepared through fermentation or semi-synthesis. The paucity of manufacturing routes involving de novo chemical synthesis reflects the inability of current methods to concisely address the preparation of these complex structures. Direct alcohol C-H bond functionalization via"C-C bond forming transfer hydrogenation" provides a powerful, new means of constructing type I polyketides that bypasses stoichiometric use of chiral auxiliaries, premetallated C-nucleophiles, and discrete alcohol-to-aldehyde redox reactions. Using this emergent technology, total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, were accomplished. These syntheses represent the most concise routes reported to any member of the respective natural product families.
Asunto(s)
Productos Biológicos/síntesis química , Policétidos/síntesis química , Productos Biológicos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Brioestatinas/síntesis química , Brioestatinas/química , Catálisis , Eritromicina/análogos & derivados , Eritromicina/síntesis química , Eritromicina/química , Humanos , Hidrogenación , Macrólidos/síntesis química , Macrólidos/química , Estructura Molecular , Policétidos/química , Rifamicinas/síntesis química , Rifamicinas/química , EstereoisomerismoRESUMEN
The Pt-catalyzed diboration of cyclic alkenes is extended to unsaturated heterocycles and bicyclic compounds and can be accomplished in a diastereoselective fashion. The optimal procedures, substrate scope, and diastereoselectivity were investigated, and examples employing both homogeneous and heterogeneous catalysis were examined. Lastly, application to the construction of the nucleoside analog (±)-aristeromycin was conducted.
RESUMEN
Intramolecular amination of organoboronates occurs with a 1,2-metalate shift of an aminoboron "ate" complex to form azetidines, pyrrolidines, and piperidines. Bis(boronates) undergo site-selective amination to form boronate-containing azacycles. Enantiomerically enriched azacycles are formed with high stereospecificity.
RESUMEN
The first described reaction between N-tosylhydrazone and SO2 is reported to provide alkyl sulfonamides in the presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed in moderate to excellent yields. Primary and secondary aliphatic amines are accommodated in this reaction, which provides a novel route to sulfonamides.
Asunto(s)
Hidrazonas/química , Sulfonamidas/síntesis química , Aldehídos/química , Aminas/química , Catálisis , Cetonas/química , Estructura Molecular , Sulfonamidas/química , Dióxido de Azufre/químicaRESUMEN
The ruthenium catalyst derived from Ru3(CO)12 and triphos [Ph2P(CH2CH2PPh2)2] promotes the direct C-C coupling of isoprene with aryl substituted hydantoins 1a1f at the diene C4-position to furnish products of n-prenylation 2a2f. A mechanism involving hydantoin dehydrogenation followed by diene-imine oxidative coupling to furnish a transient aza-ruthencyclopentene is proposed.
Asunto(s)
Butadienos/química , Hemiterpenos/química , Hidantoínas/química , Pentanos/química , Rutenio/química , Alquilación , Catálisis , Complejos de Coordinación/química , Hidrogenación , PrenilaciónRESUMEN
The cyclometalated π-allyliridium 3,4-dinitro-C,O-benzoate complex modified by (R)- or (S)-Cl,MeO-BIPHEP promotes the transfer hydrogenative coupling of allyl acetate to ß-stereogenic alcohols with good to excellent levels of catalyst-directed diastereoselectivity to furnish homoallylic alcohols. Remote electronic effects of the C,O-benzoate of the catalyst play a critical role in suppressing epimerization of the transient α-stereogenic aldehyde.