Hapalindole

A cytotoxic alkaloid has been isolated from the filamentous species Hapalosi-phon forUinalis strain V-3-1. This isolate was made from soil samples collected in the Marshall Islands in 1981. This strain produces the lipophilic compound hapalindole A, which has a broad range of antialgal and antimycotic activity (9). OscUlatoria acutissima strain B-1, isolated from a freshwater pond in Oahu, was found to produce two novel macrolide compounds termed acutiphycin and 20, 21-didehydroacutiphycin. These macrolides show cytotoxicity (KB and NIH/3T3) and antitumor activity (Murine Lewis lung carcinoma) (10). 

H. fontinalis Strain V-3-1 (Marshall Islands) Hapalindole A Substituted indole alkaloid... 

Richter utilized a reductive amination in their synthesis of the natural product (+)-hapalindole Q [294], Employing 10 equivalents of sodium cyanoborohydride and 40 equivalents of ammonium acetate in a methanol/THF mixture (150 °C, 2 min), the primary amine was obtained as a 6 1 mixture of diastereomers. Transformation to the isothiocyanate completed the total synthesis of (+)-hapalindole Q (Scheme 6.150). 

The scope of the dienophile partner within the Diels-Alder reaction was further expanded in an insightful synthesis of (H-)-hapalindole Q by Kerr and co-workers [216]. Cycloaddition of A-protected indole 166 and substituted diene 167 catalysed by imidazoMinonium salt 12 HC1 (40 mol%) gave the densely functionalised Diels-Alder adduct 168 (35% yield 93% ee), which was converted to the target alkaloid (169) in eight steps (Scheme 67). 

Klein D, Daloze D, Braekman JC, Hoffmann L, Demoulin V (1995) New Hapalindoles from the Cyanophyte Hapalosiphon laingii. J Nat Prod 58 1781... 

Becher PG, Keller S, Jung G, Siissmuth RD, Jiittner F (2007) Insecticidal Activity of 12-epi-Hapalindole J Isonitrile. Phytochemistry 68 2493... 

Scheme 1 Biosynthesis of the fischerindoles and hapalindoles according to Moore...

Some crucial details of this biosynthetic proposal have recently been challenged. In particular, it has been proposed that the role of 12 as an intermediate is unlikely because of the absence of architectures similar to that of 12 among the known natural members of the hapalindole-fischerindole-welwitindolinone family. Instead, fischerindole I has been proposed as the actual precursor to welwitindolinone A 6, a hypothesis that is supported by synthetic studies (Sect. 5.2) [11]. 

Since the first publication, amine-catalyzed Diels-Alder reactions of a,/ -unsaturated aldehydes have been investigated in much detail [15, 26-33]. Catalyst immobilization studies on solid support [26, 27], as well as in ionic liquids [29], have shown advantages for amine recycling, while partially maintaining good levels of asymmetric induction [34]. The use of this reaction in total synthesis has allowed the rapid preparation of (+)-hapalindole Q, a tricyclic alkaloid natural product containing four contiguous stereocenters (Scheme 3.2) [28]. 

Scheme 7.10 In situ deprotonation of an interfering acidic group allowing an overall protecting group-free synthesis of hapalindole Q.

An oxidative heterocoupling reaction between indoles and ketones was reported that provided a facile route into a-indolylketones <04JA7450>. Treatment of indole and carvone 194 with lithium hexamethyidisilazane (LiHMDS) and the oxidant, copper 2-ethylhexanoate, produced 3-substituted indole 195. The latter was converted into hapalindole Q 196. 

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