No abstract

The identification of the first small-molecule ligand of the neuronal receptor sortilin and structure determination of the receptor–ligand complex are reported.

The spirastrellolides are a novel family of structurally unprecedented marine macrolides which show promising anticancer properties due to their potent inhibition of protein phosphatase 2A. In the preceding paper, a modular strategy for the synthesis of spirastellolide A methyl ester which allowed for the initial stereochemical uncertainties was outlined, together with the synthesis of a series of suitably functionalised fragments. In this paper, the realisation of this synthesis is described. Two alternative coupling strategies were explored for elaborating the C26-C40 DEF bis-spiroacetal fragment: a modified Julia olefination of a C26 aldehyde with a C17-C25 sulfone, and a Suzuki coupling of a C25 trialkylborane with a C17-C24 vinyl iodide, which also required the development of a double hydroboration reaction to install the C23/C24 stereocentres. The latter proved a significantly superior strategy, and was fully optimised to provide a C17 aldehyde which was coupled with a C1-C16 alkyne fragment to afford the C1-C40 carbon framework. The BC spiroacetal was then installed within this advanced intermediate by oxidative cleavage of two PMB ethers with spontaneous spiroacetalisation, which also led to unanticipated deprotection of the C23 TES ether. The ensuing truncated seco-acid was cyclised in high yield to construct the 38-membered macrolactone under Yamaguchi macrolactonisation conditions, suggesting favourable conformational pre-organisation. Exhaustive desilylation provided a crystalline macrocyclic pentaol, revealing much about the likely conformation of the macrolactone in solution. Attachment of the remainder of the side chain proved challenging, potentially due to steric hindrance by this macrocycle; an olefin cross-metathesis to install an electrophilic allylic carbonate and subsequent π-allyl Stille coupling with a C43-C47 stannane achieved this goal. Global deprotection completed the first total synthesis of (+)-spirastrellolide A methyl ester which, following detailed NMR correlation with an authentic sample, validated the full configurational assignment. A series of simplified analogues of spirastrellolide incorporating the C26-C47 region were also prepared by π-allyl Stille coupling reactions.

Due to a combination of their promising anticancer properties, limited supply from the marine sponge source and their unprecedented molecular architecture, spirastrellolides represent attractive and challenging synthetic targets. A modular strategy for the synthesis of spirastrellolide A methyl ester, which allowed for the initial stereochemical uncertainties in the assigned structure was adopted, based on the envisaged sequential coupling of a series of suitably functionalised fragments; in this first paper, full details of the synthesis of these fragments are described. The pivotal C26-C40 DEF bis-spiroacetal was assembled by a double Sharpless asymmetric dihydroxylation/acetalisation cascade process on a linear diene intermediate, configuring the C31 and C35 acetal centres under suitably mild acidic conditions. A C1-C16 alkyne fragment was constructed by application of an oxy-Michael reaction to introduce the A-ring tetrahydropyran, a Sakurai allylation to install the C9 hydroxyl, and a 1,4-syn boron aldol/directed reduction sequence to establish the C11 and C13 stereocentres. Two different coupling strategies were investigated to elaborate the C26-C40 DEF fragment, involving either a C17-C25 sulfone or a C17-C24 vinyl iodide, each of which was prepared using an Evans glycolate aldol reaction. The remaining C43-C47 vinyl stannane fragment required for introduction of the unsaturated side chain was prepared from (R)-malic acid.

The marine macrolide spirastrellolide A (1, Scheme 1) is a potent and selective protein phosphatase inhibitor, causing premature cell entry into mitosis.[1] Synthetic interest [2] in the spirastrellolides derives not only from their unique molecular architecture, but also from their potential as lead structures for the development of novel anticancer agents. [3] In the preceding communication, [2] we described our optimized and scalable approach to the construction of the key C17-C40 bisspiroacetal intermediate 3, which forms the foundation of our strategy towards these challenging natural products. Herein, we report the completion of the first total synthesis of spirastrellolide A methyl ester (2, Scheme 1), as well as the single-crystal X-ray diffraction analysis of an advanced intermediate that reveals the conformation of the spirastrellolide macrocycle and plays a vital role in our end-game strategy.A summary of our synthetic plan, which was designed to provide maximum flexibility in terms of fragment coupling and diastereomer selection, is outlined in Scheme 1. This optimized retrosynthesis leads to three key subunits-the C17-C40 aldehyde 3, the C1-C16 alkyne 4, and the C43-C47 stannane 5. The planned completion of the total synthesis of spirastrellolide A methyl ester (2) would thus proceed through the union of aldehyde 3 with alkyne 4, with subsequent elaboration to introduce the BC spiroacetal domain, and macrolactonization to generate the 38-membered macrolide core. A series of manipulations at C40 (in the truncated side chain) would precede the end game of the synthesis, which would involve a cross-coupling reaction with stannane 5 to install concurrently the 40E and 43Z double bonds as well as the terminal a-hydroxy ester in structure 2.The first requirement for this synthetic plan was the preparation of the C1-C16 alkyne 4. We have previously reported the synthesis of a close relative of this alkyne [4] by using Jacobsens hydrolytic kinetic resolution of epoxides. [5] Building on this earlier work, installation of a PMB ether was now required at C1 such that our envisaged BC-spiroacetalization step would result in simultaneous deprotection at this position. The most convenient point to undertake this modification was deemed to be the vinyl dibromide 6 (Scheme 2). Thus, selective desilylation at C1 was followed by formation of the PMB ether under mild conditions by using PMB trichloroacetimidate. Subsequent conversion of the vinyl dibromide into the alkyne 4 proceeded uneventfully on treatment with base (66 % yield, over 3 steps). [6] The union of the C1-C16 and C17-C40 subunits through addition of the lithium anion of alkyne 4 to the DEF aldehyde Scheme 1. Spirastrellolide A (1), its methyl ester (2), and retrosynthetic analysis leading to key building blocks 3-5. PMB = para-methoxybenzyl, TBS = tert-butyldimethylsilyl, TES = triethylsilyl.