RESUMEN
The furanobisindole alkaloid, phalarine, possesses a unique structural framework within the alkaloid family of natural products. Our laboratory recently disclosed the racemic total synthesis of phalarine, featuring an efficient azaspiroindolenine rearrangement; this achievement is revisited in detail. Upon completion of the first-generation total synthesis, we explored some interesting mechanism-level issues with regard to the key azaspiroindolenine rearrangement. These investigations provided valuable insights into the mechanism of racemization during the azaspiroindolenine rearrangement en route to synthetic phalarine. In addition, in the course of these studies, we demonstrated the Pictet-Spengler capture reaction for C(2)-aryl indoles, and successfully isolated the elusive azaspiroindolenine intermediate of the Pictet-Spengler reaction. Key insights into the remarkably subtle stereoelectronics that govern this rearrangement for C(2)-arylated indoles are discussed.
RESUMEN
An enantioselective synthesis of the CGRP antagonist BMS-846372, amenable to large scale preparation, is presented. This new synthesis showcases a chemo- and enantioselective reduction of a cyclohepta[b]pyridine-5,9-dione as well as a Pd-catalyzed alpha-arylation reaction to form the key carbon-carbon bond and set the absolute and relative stereochemistry.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Catálisis , Compuestos Heterocíclicos de 4 o más Anillos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Analogues of cribrostatin IV ( 1) and the potent antineoplastic agent ecteinascidin 743 ( 2) have been synthesized. The cytotoxic activity of these compounds ( 5, 14, 20) has been determined, and the cyanoamine-cribrostatin analogue ( 14) exhibits a 20-fold improvement with regard to the natural product 1.
Asunto(s)
Antineoplásicos Alquilantes/síntesis química , Antineoplásicos Alquilantes/farmacología , Dioxoles/síntesis química , Dioxoles/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/farmacología , Antineoplásicos Alquilantes/química , Dioxoles/química , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Isoquinolinas/química , Estructura Molecular , Relación Estructura-Actividad , Tetrahidroisoquinolinas/química , TrabectedinaRESUMEN
We report the enantioselective total synthesis of cribrostatin IV (1). Key features of this synthesis involve the convergent coupling of two highly functionalized homochiral components followed by a "lynchpin" Mannich cyclization to establish the pentacyclic core (cf. 19 --> 20).