Asymmetric Total Synthesis of Vindorosine, Vindoline, and Key Vinblastine Analogues

Abstract

Concise asymmetric total syntheses of vindoline (1) and vindorosine (2) are detailed based on a unique intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to control the facial selectivity of the initiating Diels-Alder reaction and set the absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced three rings and four C-C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural products in a single step. Implementation of the approach for the synthesis of 1 and 2 required the development of a ring expansion reaction to provide a 6-membered ring suitably functionalized for introduction of the Δ 6,7 -double bond found in the core structure of the natural products. Two unique approaches were developed that defined our use of a protected hydroxymethyl group as the substituent that controls the stereochemical course of the cycloaddition cascade. In the course of these studies, several analogues of vindoline were prepared containing deep-seated structural changes presently accessible only by total synthesis. These analogues, bearing key modifications at C6-C8, were incorporated into vinblastine analogues and used to probe the unusual importance (100-fold) and define the potential role of the vinblastine Δ 6,7 -double bond.

Multi-Bond Forming Processes in Efficient Synthesis

“…[76,77] The research group of Boger has championed a complementary method of ylide formation to that of Padwa's in an uncatalysed, pericyclic intramolecular sequence featuring a hetero-Diels-Alder, retro-Diels-Alder, and dipolar cycloaddition. Two very recent applications of this strategy are in the asymmetric syntheses of vindoline and vindorosine, [78] and (þ)-fendleridine and (þ)-1-acetylaspidoalbidine. [79] Each features a similar domino sequence of pericyclic reactions, generating, in the case of vindorosine (Scheme 6), three rings, four carbon-carbon bonds, and six stereocentres, in 55 % yield after reduction.…”

“…[ Scheme 6. Domino sequence in the synthesis of vindorosine by Boger et al [78,79] (IMDA, intramolecular Diels-Alder. )…”

Regio-selective chlorination of vinca alkaloids catalyzed by Lewis acid

“…CH 2 Cl 2 was used as a polar and noncoordinating solvent, and NCS was used as a chlorinating reagent. The reaction was performed at ambient temperature in the presence of the various Lewis acids, such as AlMe 2 Cl, AlCl 3 , ZnCl 2 , BF 3 .Et 2 O, FeCl 2 , FeCl 3 , SnCl 4 , TiCl 4 , Ti(OPr i ) 4 , and Yb(OTf) 3 . The results exhibited either no desired product or unidentified complicated products under these conditions.…”

“…To this aim, tremendous efforts have been devoted, including recent achievements in the vinblastine-binding site study [3], the de novo total synthesis of vinblastine [4][5][6][7] and the modification of vinca alkaloids [8][9][10][11][12][13][14][15][16][17][18]. Many studies demonstrate that the minor difference in the structure among these vinca alkaloids could often result in significant difference in their potency and clinical toxicity [8][9][10][11][12][13][14][15][16][17].…”

Structure elucidation of indole–indoline type alkaloids: A retrospective account from the point of view of current NMR and MS technology

“…1) and the biological activities of the aforementioned bisindoles that went to market, it is apparent that relatively small structural changes lead to significantly different oncological and toxicological profiles. For this reason the bisindole family has been, and continues to be, an important but difficult field of chemical research that has given rise to many inventive and elegant synthetic solutions, and keeps providing new challenges [3][4][5][6][7][8].…”