Tandem Intramolecular Diels-Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Initial Scope and Applications.

A summary of the development and initial studies on the scope of a powerful tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles is detailed and provides the foundation for its subsequent use in organic synthesis. Implemented with substrates in which both the initiating dienophile and subsequent dipolarophile are tethered to the 1,3,4-oxadiazoles, the studies expanded the scope of oxadiazoles that participate in the reaction cascade, permitted the use of differentiated dienophiles and dipolarophiles, extended their use to unsymmetrical dienophiles and dipolarophiles, provided exclusive control of the cycloaddition regioselectivities, and imposed exquisite control on the cycloaddition stereochemistry. As key reactivity and stereochemical features of the reactions were being defined, the cascade cycloaddition reaction was implemented in the total synthesis of a series of alkaloids including (-)-vindoline, (-)-vindorosine, the closely related natural products (+)-4-desacetoxyvindoline and (+)-4-desacetoxyvindorosine, natural minovine, (+)-N-methylaspidospermidine, (+)-spegazzinine, (-)-aspidospermine, and a number of key analogues.

Total Synthesis of (-)-Vindoline and (+)-4-epi-Vindoline Based on a 1,3,4-Oxadiazole Tandem Intramolecular [4 + 2]/[3 + 2] Cycloaddition Cascade Initiated by an Allene Dienophile.

It is reported that an allene dienophile can initiate a tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles, that the intermediate cross-conjugated 1,3-dipole (a carbonyl ylide) can participate in an ensuing [3 + 2] dipolar cycloaddition in a remarkably effective manner, and that the reaction can be implemented to provide the core pentacyclic ring system of vindoline. Its discovery improves a previous total synthesis of (-)-vindoline and was used in a total synthesis of (+)-4-epi-vindoline and (+)-4-epi-vinblastine that additionally enlists an alternative series of late-stage transformations.

Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties.

Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure-function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues. With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold.

New insights into the mechanism and an expanded scope of the Fe(III)-mediated vinblastine coupling reaction.

A definition of the scope of aromatic substrates that participate with catharanthine in an Fe(III)-mediated coupling reaction, an examination of the key structural features of catharanthine required for participation in the reaction, and the development of a generalized indole functionalization reaction that bears little structural relationship to catharanthine itself are detailed. In addition to providing insights into the mechanism of the Fe(III)-mediated coupling reaction of catharanthine with vindoline suggesting the reaction conducted in acidic aqueous buffer may be radical mediated, the studies provide new opportunities for the preparation of previously inaccessible vinblastine analogs and define powerful new methodology for the synthesis of indole-containing natural and unnatural products.