Synthetic Studies toward Dimeric Indole Alkaloids Based on Convergent Synthetic Strategy

Abstract

The total syntheses of dimeric indole alkaloids, haplophytine, and T988s are described. These dimeric compounds comprising two structurally different indole units are ubiquitous in nature, and many possess pharmaceutically important activities. To realize an efficient chemical synthesis of these dimeric indole alkaloids, the establishment of convergent synthetic strategies and development of new coupling methods are indispensable. The linkage of two highly functionalized units at a late stage of the synthesis frequently induces synthetic problems such as chemoselectivity and steric repulsion. Moreover, although transition metal-catalyzed reactions are usually an effective method for the cross-coupling of two units, the application of these cross-coupling reactions to bond formation involving a sterically hindered C(sp 3) is often difficult. Thus, even with precise modern synthetic methods, it is currently difficult to realize convergent syntheses of dimeric indole alkaloids possessing a quaternary carbon linking two units. To combat these synthetic problems, we developed a synthetic method to link two indole units using an Ag-mediated nucleophilic substitution reaction. In this review, we provide a detailed discussion of convergent synthetic strategies and coupling methods for dimeric indole alkaloids.

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′‐epi‐Leucophyllidine

“…Furthermore, the successful execution of convergent disconnection strategies demand reactions that forge sterically congested C À C bonds between densely functionalized frameworks with complete regio-and stereocontrol. [3] A majority of examples to date rely on biomimetic reactions to accomplish these convergent couplings, but as these reactions are substrate-controlled, the inherent reactivity can be difficult to overturn [4] and prohibitive to analogue synthesis. [5] Leucophyllidine (1) is a heterodimeric bisindole alkaloid that was first isolated from the bark of the Malaysian woody climber Leuconotis griffithi in 2009.…”

Formal Total Syntheses of (+)- and (−)-Aspidophytine from a Common, Homochiral Precursor

“…Significant effort has been devoted to establishing total syntheses of alkaloids 1 and 2 , with the latter being more heavily targeted to date because of its reduced structural complexity and its potential to serve as a precursor to the former. The first total synthesis of (−)-aspidophytine ( 2 ) was reported by Corey in 1999, and some half dozen others have been described in the interim along with approaches to it. , In 2009, the first total syntheses of haplophytine ( 1 ) were described in back-to-back reports from the Fukuyama/Tokuyama and Nicolaou/Chen groups. Some 7 years later, a bio-inspired and more concise synthesis of the same target was reported by Tokuyama and co-workers and so setting an impressive benchmark against which all subsequent efforts must be measured.…”