vindorosine and vindoline

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.

Topics: Stereoisomerism; Vinblastine

Catharanthus roseus (L.) G. Don is a plant of the Catharanthus genus of Apocynaceae which has been reported to have therapeutic effects of detoxication and anticancer. In order to further study the alkaloid constituents of C. roseus, the aerial parts of the plant were extracted with 95% EtOH, and then treated with 2% H2SO4 and NH3H2O to obtain total alkaloids. The total alkaloids were separated and purified by column chromatography over silica gel and prepared by high performance liquid chromatography (HPLC). Their structures were elucidated on the basis of physicochemical properties and spectral data. A new alkaloid together with five known compounds were isolated and identified as vindolinine B (1), lochnericine (2), horhammericine (3), vindorosine (4), vindoline (5), and coronaridine (6). Compound 1 is a new compound and named as vindolinine B.

Topics: Antineoplastic Agents, Phytogenic; Catharanthus; Ibogaine; Indole Alkaloids; Molecular Structure; Plant Components, Aerial; Plants, Medicinal; Vinblastine

A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as N-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).

Topics: Alkaloids; Antineoplastic Agents; Cyclization; Molecular Structure; Stereoisomerism; Vinblastine

Vindoline, C(25)H(32)N(2)O(6), and 16-demethoxyvindoline, C(24)H(30)N(2)O(5), both of which are naturally occurring biologically active products derived from plants, are important as possible starting materials for the synthesis of valuable anticancer antibiotics, viz. vincristine and vinblastine, and other pharmaceuticals. The vindoline framework consists of two five- and three six-membered condensed rings. One of the six-membered rings adopts a boat conformation, one adopts a sofa conformation and the third is planar. Both five-membered rings have envelope structures. The intramolecular hydrogen bonds present in the structures are characteristic of vinca alkaloids.

Topics: Alkaloids; Antibiotics, Antineoplastic; Catharanthus; Plants, Medicinal; Vinblastine