Synthetic studies towards pinnaic acid and halichlorine

Abstract

The current research project focused on the development of a novel, flexible and efficient synthetic strategy towards the synthesis of the core structure of the marine alkaloids pinnaic acid (1) and halichlorine (3) utilising Spirocyclic nitrone (181) as a common key intermediate. The common key intermediate spirocyclic nitrone (181) was synthesized in multi-gram quantities in an overall yield of 35% from l,5-dibromopentane (193) in six steps. The synthetic utility of nitrone (181) as a common key intermediate for the syntheses of (1) and (3) was probed by examination of the yield, regio and Stereofacial selectivity arising from the intermolecular l,3-dipolar cycloaddition with simple dipolarophiles (196) and nucleophilic addition of Grignard reagents (199). This investigation afforded isoxazolidines (197) and MTydroxylamines (201) with undesired stereochemistry at C-5 of the natural product. Nevertheless, compounds with desired relative stereochemistry were obtained by a tandem oxidation/reduction strategy. The successful synthesis of the azaspiro[4.5]decane core structure of pinnaic acid (1) is described utilising an intermolecular l,3-dipolar cycloaddition of spirocyclic nitrone (181) and dipolarophile (234) as a key C-C bond formation step to give isoxazolidine (235). Inversion of stereochemistry at C-3a' of this isoxazolidine (235) occurred smoothly to give azaspirodecane (237). The introduction of the requisite (E)-olefm (251) was achieved via the formation of mesylate (255) from alcohol (253a). Stereoselective installation of the C-14 Stereocentre of pinnaic acid (1) was attempted via formation oflactam (260) and this compound was synthesised in 21 steps in overall yield of 3% from l,5-dibromopentane (193). Unfortunately all attempts to methylate the lactam (260) were unsuccessful. The more complex tricyclic quinolizidine core structure Ofhalichlorine (3) is also reported. This synthesis proceeds by intermolecular l,3-dipolar cycloaddition of spirocyclic nitrone (181) and dipolarophile (276) to give isoxazolidine (277). Selective protection of diol (277) followed by inversion of stereochemistry at C-3a' of isoxazolidine (277) gave azaspirodecane (290). The formation of quinolizidine core structure (297) Ofhalichlorine (3) was effected via the formation of the secondary mesylate (296) followed by intramolecular cyclisation. The simple analogue of halichlorine (3), macrocycle (316) was successfully synthesized by conversion of protected hydroxy acid (301) into diene (315) followed by RCM using 10 mol% loading of Grubbs’ second generation catalyst (13) under the microwave irradiation.