Chimonanthines

Relying on this expectation, we carried out the reaction of 19 with 85 % HCOOH, and discovered the exclusive formation of ( )-169 (44%) (99H1237), which has the same skeleton as the alkaloids folicanthine (253a) and chimonanthine (253b)... 

These epipolythiodiketopiperazine alkaloids, together with the calycanthaceous alkaloids (Fig. 9.1b), form a superfamily of natural products termed the dimeric hexahydropyrroloindole alkaloids [6-8]. The main dichotomy within this superfamily arises from the biogenetic elaboration of tryptamine versus tryptophan building blocks. The tryptamine-based calycanthaceous alkaloids, boasting members such as chimonanthine (7), calycanthine (9), and folicanthine (8), are largely plant derived and have a long and rich history in the context of natural product synthesis [7, 9]. 

Scheme 9.2 Prior approaches to the C3-C3 linked dimers, (a) Hendrickson s oxidative dimerization approach to chimonanthine. (b) Scott s oxidative dimerization of tryptamines. (c) Overman s intramolecular Heck reaction, (d) Overman s asymetric alkylation...

The isolation of calycanthine (9) in 1888 by Eccles [28] and the subsequent proposition for its origins in the oxidative dimerization of tryptamine by Woodward [29] and Robinson [30] had prompted several key synthetic studies based on a biomimetic approach. Hendrickson was the first to experimentally verify the plausibility of forming the C3-C3 linked dimers through an oxidative radical dimerization strategy (Scheme 9.2a). He demonstrated that the sodium enolate of a tryptamine-derived oxindole could be oxidized with iodine to afford a mixture of three possible stereoisomers. The racemic product was isolated in 13 % yield, while the meso product was isolated in 8 % yield. Global reduction of the oxindole and carbamates afforded the first synthetic samples of chimonanthine (7) [9a],... 

Scott was able to leverage the same type of methodology in an impressive display in which /V-methyltryptamine was dimerized directly to afford chimonanthine (7) (Scheme 9.2b) [9c]. Deprotonation of the indole 1H proton with methyl Grignard followed by treatment with FeCl3 accomplished the singleelectron oxidation and dimerization of the indole moiety. The racemic and meso stereoisomeric products were obtained as a mixture in 19 % and 7 % yields, respectively. Takayama later found hypervalent iodine to be a superior oxidant, affording yields of 17 % and 30 %, respectively [9j]. In both cases, however, as in the case of Hendrickson s example, stereocontrol could not be achieved. 

The octacyclic dimer (+)-94 could be obtained in short order from the tetracyclic bromide (+)-93 via a Co(I)-mediated reductive dimerization protocol first implemented in our prior syntheses of (+)-chimonanthine (7), (+)-folicanthine (8), and (—)-calycanthine (9) [7]. Simple exposure of intermediate (+)-93 to tris (triphenylphosphine)cobalt(I) chloride [48] in acetone under anaerobic conditions rapidly afforded dimer (+)-94 in 46 % yield. While higher yields (52 % yield) could be obtained in tetrahydrofuran on small scale, performing the reaction in acetone reproducibly afforded higher yields on gram scales. Notably, the product was obtained in similar efficiency on multi-gram scale (43 % yield on 8-g scale)... 

A twofold intramolecular Heck reaction has been employed as a key step for the synthesis of the skeleton of the natural product (—)-chimonanthine 58 (Scheme 19). The synthetically most challenging structural features of this bispyrro-loindoline alkaloid are its two adjacent quaternary centers. They were both built up by intramolecular double-bond carbopalladations, which stereoselectively produced the pentacycle 57 from the f72-symmetrical bis[A-(2-iodophenyl)-cyclohexane-1,2-dicarboxamide 55 via the intermediate 56. The key intermediate 57 was thus obtained as a single enantiomer in 90% yield. 

Scheme 19 A twofold intramolecular Heck reaction en route to the bispyrroloindoline alkaloid (-)-chimonanthine 58. ...

Calycanthine and chimonanthine have been found to occur in Palicourea fendleri 142 this is the second report of the occurrence of calycanthine in the genus Palicourea. The structure of the antibiotic chetomin (241) has been elucidated,143 mainly by 1SN and 13C n.m.r. spectroscopy on 15N-enriched material obtained from the culture of Chaetomium cochliodes in a nutrient medium containing Na15N03. 

The reactions of physostigmine also show some similarities (e.g., facile reduction cleavage of the pyrrolo ring) to those of folicanthine, calycan-thidine, and chimonanthine, which are now known to possess the structures of bis(pyrrolo[2,3,-6]indoles) (27, 28, 29, 30, 31, 32a, 32b see also Chapter 16 of this volume). 

The rather remarkable alkaloid hodgkinsine from Hodgkinsonia frutescens C. T. White is almost certainly related to the chimonanthine-folicanthine pair. This relation is the more remarkable because Hodgkinsonia F. Muell. belongs to the family Rubiaceae, which does not have obvious affinities with Calycanthaceae. 

A remarkable synthesis of meso- and racemic chimonanthine has recently been published (30). The sodium salt of the urethane (XVI) was dimerized by oxidation with iodine in tetrahydrofuran. Two diastereo-isomeric dimers (XVII R = CH2CH2.CC Et) were obtained XVIIa, mp 243°-245°, and XVIIb, mp 214°-216°. Reduction of the former with LiAlH4 in tetrahydrofuran yielded an isomer of calycanthine (mp 240°-243°) which was regarded as retaining one of the indole nuclei. Similar reduction of the second isomer (XVIIb) yielded optically inactive chimonanthine (mp 202°-203°) whose IR- and mass-spectra were identical with those of the natural base. 

Chimonanthine (172),242 isolated from leaves of Chimonanthus fragrans Lindle (Calicanthaceae), is an example of naturally occurring dimeric indole alkaloids of type C. 

One other indole alkaloid, reminiscent in structure of the pseudophrynamines, has been isolated from amphibians, namely, chimonanthine 14) (XVII). Chimonanthine was accompanied in the dendrobatid poison-dart... 

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