A Chiral Base Desymmetrisation-Ring-Closing Metathesis Route to Chiral Azaspirocycles: Synthesis of Core Structures Related to Pinnaic Acid and Halichlorine

Abstract

A range of highly functionalised chiral azaspirocycles was synthesised, starting from a piperidine diester that is available in 90% ee from a chiral base desymmetrisation. The approach depends upon the use of Grignard addition reactions or a Claisen rearrangement to provide intermediates capable of undergoing ringclosing metathesis. A number of intermediates related to the core structure of pinnaic acid were synthesised by concise routes using the approach.Natural products incorporating azaspirocyclic structures, such as the well known histrionicotoxin family [e. g. histrionicotoxin (1)], have long attracted the interest of synthetic chemists. 1 A more recently disclosed structure is pinnaic acid (2), which has stimulated substantial activity due to its potency as an inhibitor of cPLA 2 (phospholipase A 2 ). 2 The closely related alkaloid, halichlorine (3), found to inhibit VCAM-1 (vascular cell adhesion molecule-1), was isolated around the same time and has also sparked a great deal of interest ( Figure 1). 3 Figure 1Since these compounds exhibit potentially useful biological activity, synthetic approaches, which deliver highly functionalised azaspirocycles, of various ring size combinations, in a stereocontrolled fashion are of intense current interest. 4-6 Some time ago we described a new type of chiral lithium amide base reaction, which provided chiral polyfunctional piperidines with high levels of stereocontrol. 7 In the present paper we describe how one such piperidine can be usefully transformed into a range of azaspirocyclic systems, with a focus on compounds closely related to the pinnaic acid core structure. 8The previously described desymmetrisation reaction involves enolisation of the readily available piperidine diester 4 with chiral base 5, and subsequent alkylation to give products such as the allyl derivative 6, Scheme 1. 9 Scheme 1Subsequent differentiation of the ester functions was then carried out by reduction of 6 to the corresponding diol, selective protection of the less hindered primary alcohol, oxidation and Peterson olefination. This sequence provided quantities of a,b-unsaturated ester 7, and we initially hoped to develop this compound to a spirocyclic system by establishing a novel cyclisation protocol for linking the terminus of the allyl group to the b-position of the enoate.The first plan was to effect regioselective hydrometallation of the allylic appendage to give a terminal organometallic, which, on activation by transmetallation, would then undergo intramolecular Michael addition. In the event, a series of studies, focussed on the combination of initial hydroboration or hydrozirconation, followed by transmetallation chemistry using zinc or copper, failed to provide an effective means of ring-closure. 10,11 As a back-up tactic we expected that conversion of the allyl group into a terminal halide, or similar, would allow