An aryl-end-capped dodecayne has been prepared using a four-fold fluoride-mediated dechlorosilylation of a masked dodecayne precursor containing four beta-chlorovinylsilane residues that serve as masked alkynes; the unstable dodecayne product has been characterised by UV-vis absorption spectroscopy and 'matrix-free' MALDI-TOF mass spectrometry.

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The synthesis of nemorosone, a polyprenylated acylphloroglucinol isolated from Clusia rosea, was achieved by means of a bridgehead substitution process, involving initial iodination and subsequent lithium-iodine exchange followed by acylation. The difficulties in the bridgehead substitution are discussed, and a probable explanation proposed, based on molecular modelling.We have recently been interested in the synthesis of members of the polyprenylated acylphloroglucinol (PPAP) family of natural products, which possess myriad intriguing biological properties, and which are characterized by a bicyclo[3.3.1]nonane-trione core structure bearing additional acyl and prenyl substituents, for example, garsubellin A (1), hyperforin (2), clusianone (3), and nemorosone (4, Figure 1). 1-3The strategy employed in our total synthesis of clusianone (3) involved the generation of a C-1-substituted bicyclic intermediate 5, using an Effenberger annulation, and then bridgehead prenylation at the C-5 bridgehead position, to give 6 in 91% yield (Scheme 1, equation 1). 2cNotably, this transformation occurred in the presence of an unsubstituted C-3 position, which was substituted via a subsequent lithiation. We also demonstrated some generality to this type of bridgehead substitution in closely related catechinic acid intermediates. 4In their independent studies of PPAP synthesis, the Danishefsky group also employed bridgehead substitution, initially in a synthesis of garsubellin, 2b and more recently in syntheses of clusianone and nemorosone (e.g. Scheme 1, equation 2). 2gIn these cases the strategy employed required bridgehead substitution at C-1, which is adjacent to a quaternary carbon bearing gem-dimethyl substitution. The Danishefsky protocol involves initial bridgehead iodination, using a combination of LDA, TMSCl, and iodine, followed by magnesium-iodine exchange and quenching with PhCHO. Overall, this procedure provides low to modest yields of the bridgehead acylated materials (obtained after oxidation), and also requires the installation of a C-3 blocking silyl substituent.Recently, we required access to nemorosone in order to study the apparent antitumour properties of this compound. 5 We asked if direct bridgehead acylation at C-1 (in an intermediate such as 7) might be possible, and wondered why substitution at this position appears so much more difficult than at C-5. Herein we describe our synthesis of nemorosone and an experimental and computational study that clarifies some aspects of the key bridgehead substitution reaction.The O-methylated trione 9, described in our recent paper, 2d was available in gram quantities via an Effenberger annulation approach 6 (Scheme 2). Although, in our hands, clean C-3 prenylation could be effected on this compound using LTMP-Li(2-Th)CuCN and prenyl bromide (78%), this was not a productive route forwards, since the product underwent a subsequent metallation, not at the desired C-1 bridgehead, but on the newly installed C-3 prenyl substituent. 2d Thus, blocking of C-3 by installation of...

A strategy for the synthesis of members of the prenylated indole alkaloid family is described, which involves a radical cascade process of an appropriately substituted diketopiperazine (DKP) core structure. Several approaches to the generation of the initial radical were explored, with the most successful involving treatment of a sulfenyl substituted DKP under classical reductive conditions by heating with Bu3SnH and a radical initiator. The required, fully substituted, radical precursor DKP structures were prepared using regio- and stereocontrolled enolate chemistry of simpler proline-tryptophan derived DKPs. The new approach allowed rapid access to a key polycyclic indoline structure, which was converted into either of the natural products stephacidin A or notoamide B.