Synthesis of (−)‐Hobartine and Related Indole Alkaloids

Abstract

SummaryAn improved method for obtaining optically pure (S)-( 1-p -menthen-8-yl)amine (12) has led to expedient syntheses of two hypothetical biogenetic intermediates on the way to aristoteline (7), namely (S)-N-(l-p-menthen-8-yl)-2-(3-indolyl)ethylamine (3) and (S)-N-(l-p-menthen-8-yl)-2-(3-indolyl)ethylideneamine (4). The latter has been transformed into (-)-hobarthe (6) in 64 % yield via a stereoselective biomimetic cyclization by treatment with HCOOH. This unambiguous synthesis establishes the hitherto unknown absolute configuration of (-)-hobartine (6). Several model cyclization reactions of N-substituted a -(terpen-%yl)imine derivatives yielding unsaturated 3-azabicyclo-[3.3. llnonane compounds are described. Aristoteline (7) was isolated in 1975 by Bick et al. [l] from the New Zealand plant Aristotelia serrata as the first member of a novel group of indole alkaloids. The same authors determined its pentacyclic structure by X-ray crystallography. Subsequently, this natural product was detected in other plants [2] [3] together with several related alkaloids'), of which two, the tetracyclic compounds makomakine (5) and hobartine (6) (Scheme I ) , are on the same oxidation level as aristoteline (7).The outstanding feature of this alkaloid family is that most of its members embody an intact monoterpene unit, whereas the vast majority of the known mevalonoid indole alkaloids originate from secologanin which arises from an oxidative cleavage of a preformed cyclopentane monoterpene. (cf. e.g. [ 141 and ref. therein). A plausible pathway to the aristoteline family has been proposed by Bick et al. [15] and, in a slightly modified version, by Hesse et al. [3]. Their proposal which is relevant to the present discussion is shown in Scheme I :According to Scheme I cyclization of nerylpyrophosphate (2) in the presence of tryptamine (1) leads to 3 as the first biogenetic intermediate containing all C-atoms of the aristoteline-type alkaloids. To date, this compound has not been detected in natural sources, but an oxidized version of its skeleton is present in frutico-') Presented in part at the 'Herbstversammlung

Synthesis of Aristotelia‐Type Alkaloids. Part VIBiomimetic Synthesis of (+)‐Aristofruticosine

“…-Commercially available (S)-perilla alcohol (5) served as convenient starting material and was transformed into amino alcohol 10 via the route shown in Scheme 2. Regioselective oxymercuration (121 of benzoate 6 furnished alcohol 7 which was then transformed into the corresponding azide 8 upon treatment with HN,/ BF, [9] [13]. Subsequent reduction with NaHTe [14] led to the amino benzoate 9 which was saponified to furnish the target molecule 10.…”

“…This compound could also be obtained directly through reduction of the intermediate azido benzoate 8 with LiAlH,. Whereas condensation of 9 and 10 with indole-protected indole-3-acetaldehyde 12 [l 11 readily led to the expected imines 13 and 14 (Scheme 3 ) , these intermediates did not react further to the desired hobartine derivatives under our established cyclization conditions [9] [ll]. Since this lack of reactivity can hardly be explained by steric hindrance arguments, we suspect that the strongly electronegative allylic 0-substituents reduce the nucleophilicity of the olefinic double bond to such an extent that the desired cyclization process can not compete with other, imine-decomposition reactions6).…”

Biomimetic Synthesis of Alkaloids Derived from Tryptophan: Indolemonoterpene Alkaloids

“…Accordingly, nucleophilic attack of tryptamine (5) on the α-terpinyl cation arising from the cyclization of linalyl or neryl diphosphate should give rise to an α-terpinyltryptamine (12) unit possessing the same skeleton as the natural alkaloid (+)-fruticosimine (13), which only differs in its oxidation level. Dehydrogenation of the putative α-terpinyltryptamine unit 12 should generate an aldimine intermediate (14), which should cyclize upon protonation to makomakine (15), aristoteline (16), or hobartine (17), which are the major alkaloids isolated from Aristotelia species (Scheme 3.3).…”

“…Following the work of Stevens, several syntheses of Aristotelia alkaloids were performed, through an initial condensation of (S)-(−)-α-terpinylamine (21) with various indole substrates, including tryptophyl bromide (22) [12] and indol-3-ylacetaldehyde (23) (Figure 3.3) [13]. This latter approach proved particularly successful, since most of the Aristotelia alkaloids isolated to date could be prepared in the group of Borschberg [14], by condensation of unprotected or protected indol-3-ylacetaldehyde (23) with α-terpinylamine (21), terpinyl-derived amino-alcohols, or synthetic equivalents such as phenylthioterpinylamines.…”

Synthesis of Aristotelia‐type alkaloids. Part VII. Syntheses of (±)‐sorelline, (±)‐serratenone, and (±)‐aristotelin‐19‐one

“…Srhemr I 1 3 R = suitable protecting group thetic approach towards these metabolites has been reported. A retrosynthetic analysis along the lines of our biomimetic strategy [ 11 [9] [ 101 leads back to the imine 3 (Scheme 1 ) and finally to the two building blocks 4 and 5 [lo]. Besides the desired building block (i)-4, two side products were isolated from the above reaction.…”