Biogenetically modeled synthesis via an indole acrylic ester. Total synthesis of (+-)-minovine

Abstract

The details of a total synthesis of (+)-minovine (3), patterned upon biogenetic considerations, are discussed.n 1962 Wenkert4 postulated that a protonated form I of dihydropyridine acrylic ester 2a might play an integral role in the biosynthesis of Aspidosperma and Zboga alkaloids. In recent years, in citro experiments have been reported with alkaloids of these classes in an attempt to verify the intermediacy of the acrylic esters 2b.j During this period secodine ( l a ) and 16,17dihydrosecodin-17-01 (lb) have been isolated6 and syn-the~ized.",~ Moreover, secodine has been shown to incorporate in Give into the Aspidosperma n u c l e~s .~~~ It was our intention to investigate the viability of the addition of an endocyclic enamine to a 2,2'-indole acrylic ester followed by a Mannich c10sure.~ Although the ultimate test would have been the construction of acrylic ester 2b or 2c, prudence dictated that the manipulation of such a reactive functionality would be best accommodated by isolating the reactive moieties in separate substrates and only at the designated time to allow their chemical union.Whereas an appropriate endocyclic enamine 412 was already at hand from previous work, it was necessary to consider a suitable means of constructing a (1) For a preliminary account of this work, see A considerable amount of controversy has arisen over these results. We leave the reader to formulate his own opinions.(6) (a) G.2,2'-indole acrylic ester. Since it was known13 that N-methylindole is capable of undergoing lithiation at the 2 position, it was an easily accessible method of appropriate functionalization of the indole nucleus which mandated that minovine (3) be a convenient test of the biogenetic-like sequence. la. R = CH. b. R = CH-OH H CO-CH , A s p id o s p e r m a (tabersonine) b.14,15 dehydro; Z = H, 2a.14,15 dehydro: Z = 0 c.14,15 dihydro; Z = H2 3I b o g a ( c a t h a r a n t h i n e ) When ethyl oxalate was added dropwise to an ethereal solution of the lithioindole, only trace amounts of the desired ethyl 1-methyl-2-indole glyoxylic ester 5a could be detected, the two major products being the diketone 6 and the hydroxy ketone 7. Since it was apparent that the glyoxylic ester was undergoing further reactions, the situation was ameliorated by the slow addition of the lithium reagent to an excess of ethyl oxalate in ether. The major product from the inverse addition was the glyoxylate 5a which was directly converted to its crystalline free acid 5b by saponification of the reaction mixture, which served to allow facile chemical separation from both neutral species 6 and 7. Treatment of the glyoxylic acid with ethereal diazomethane provided the methyl ester 5c as a yellow oil whose nuclear magnetic resonance spectrum revealed two three-proton singlets at 6 3.95 and 3.99 (NCHB and (13)

Generation and Intermolecular Reactions of 2-Indolylacyl Radicals

“…For our study we selected indoleglyoxylic acids 3a − c , and their oxidative decarboxylation was tested toward pyridines 6 and 7 under the above conditions (Scheme ) , mixtures of C-4 ( 8 , 10 ) and C-6 ( 9 , 11 ) acylation products were generally obtained.…”

Total Synthesis of Aspidosperma and Strychnos Alkaloids through Indole Dearomatization

“…A retrosynthetic disconnection of the C‐ring of the pentacyclic core of Aspidosperma and Strychnos alkaloids at first sight seems trivial. Nevertheless, this transformation should be deemed difficult, given the poor yields in separate communications of Potier and co‐workers and Ziegler et al., based on a seemingly straightforward dearomative S N 2 cyclization (Scheme ).…”

Aspidosperma Terpenoid Alkaloids — Biosynthetic Origin, Chemical Synthesis and Importance

“…In 1978 was published a work that introduced a conceptually new approach to the synthesis of Aspidosperma-type alkaloids, the photocyclization-rearrangement or heteroatom directed photoarylation of anilinocyclohexanones, exemplified by the synthesis of the indolines A and B shown in figure 8 [57], this concept being expanded many years later, with the demonstration of different techniques of photo-induced reactions [58][59][60]. Given the biosynthetic route proposed by Wenkert [30], a group from Yale University developed a synthetic route for obtaining the alkaloid minovine in a biogenetically modeled way (figure 9), refined many years later by the same group [61,62]. Based on the fact that the Aspidosperma alkaloids share common structural features, a group from the Chinese Academy of Synthesis developed a strategy to aspidophytine enantioselective and stereo-controlled synthesis that could be applied to the synthesis of several other alkaloids of this family by simply varying the initial aniline (figure 10) [63].…”