RESUMEN
A new synthesis of LYS228, fitting for further process development for commercial manufacture, is described. The key features of this synthesis include development of new protocols for acylation reactions, application of an asymmetric hydrogenation via dynamic kinetic resolution, and a late-stage ring closure to form ß-lactam 1.
Asunto(s)
Antibacterianos , Monobactamas , Hidrogenación , Estereoisomerismo , beta-LactamasRESUMEN
A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Amidas/química , Técnicas de Química Sintética , Lactamas/química , Fenol/químicaRESUMEN
Aryl fluorosulfonates are developed as a deoxyfluorinating reagent in the transformation of primary and secondary alcohols into the corresponding alkyl fluorides. These reagents feature easy availability, low-cost, high stability and high efficiency. Diverse functionalities including aldehyde, ketone, ester, halogen, nitro, alkene, and alkyne are well tolerated under mild reaction conditions.
RESUMEN
A practical synthetic strategy to a chiral azabicycclooctanyl derivative (1), a potent DPP-4 inhibitor, starting from a commercially available nortropine is described. The stereogenic center of 1 was established employing a modified protocol of Ellman's diastereoselective addition of a benzylic nucleophile to tert-butanesulfinimine. Other key steps include Corey-Chaykovsky reaction, Meinwald rearrangement, and CDMT-promoted amide bond formation involving a sterically hindered amine 2.
Asunto(s)
Compuestos de Azabiciclo/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Aldehídos/química , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Butanos/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Iminas/química , Estereoisomerismo , Compuestos de Sulfonio/químicaRESUMEN
In explorations toward the total synthesis of the antitumor anthrapyran natural product kidamycin, the regioselective introduction of aminosugars angolosamine and vancosamine as C-arylglycosides has been accomplished onto hydroxylated anthrapyran aglycones. Specifically, the 9,11-dihydroxylated anthrapyran A undergoes sequential glycosylations with angolosamine synthon B and vancosamine synthon C to regio- and stereoselectively afford bis-C-glycoside D corresponding to the C-glycoside pattern of kidamycin.
Asunto(s)
Aminoglicósidos/química , Antineoplásicos/química , Glicósidos/química , Glicosilación , Estructura Molecular , EstereoisomerismoRESUMEN
The aglycone structures 1 and 2, respectively corresponding to the antitumor antibiotic natural products altromycin and kidamycin, have been efficiently synthesized from a common advanced intermediate 3. A series of Claisen condensations and aromatizations affords the anthracene section of 3, followed by annulation of the pyrone ring. The functional groups of 3 can be manipulated for enantioselective introduction of the epoxide side-chain of altromycin aglycone 1, as well as synthesis of the kidamycin aglycone 2. [reaction: see text]