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With 21 unknown stereocentres embedded in spatially separated stereoclusters, the cytotoxic polyketide hemicalide represents a seemingly intractible structural assignment problem. Herein, through the targeted synthesis of configurationally defined fragments, as well as "encoded" mixtures of diastereomers, the stereochemical elucidation of the C31-C46 region of hemicalide is achieved. Detailed NMR spectroscopic analysis of candidate fragments and comparison with the related hemicalide data strongly supported a 31,32- syn , 32,36- anti and 42,46- anti relationship. In combination with previous work on hemicalide, this reduces the number of possible structural permutations down to a more manageable eight diastereomers.

The structural complexity and biological importance of macrolide natural products has inspired the development of innovative strategies for their chemical synthesis. With their dense stereochemical content, high level of oxygenation and macrocyclic cores, we viewed the efficient total synthesis of these valuable compounds as an aspirational driver towards developing robust methods and strategies for their construction. Starting out from the initial development of our versatile asymmetric aldol methodology, this personal perspective reflects on an adventurous journey, with all its trials, tribulations and serendipitous discoveries, across the total synthesis, in our group, of a representative selection of six macrolide natural products of marine and terrestrial origin - swinholide A, spongistatin 1, spirastrellolide A, leiodermatolide, chivosazole F and actinoallolide A.

The actinoallolides are a family of polyketide natural products isolated from the bacterium Actinoallomurus fulvus. They show potent biological activity against trypanosomes, the causative agents of the neglected tropical diseases human African trypanosomiasis (sleeping sickness) and Chagas disease, while exhibiting no cytotoxicity against human cell lines. Herein, we give a full account of our strategy evolution towards the synthesis of this structurally unique class of 12-membered macrolides, which culminated in the first total synthesis of (+)-actinoallolide A in 20 steps and 8% overall yield. Subsequent late-stage diversification then provided ready access to the congeneric (+)-actinoallolides B-E. Enabled by this flexible and efficient endgame sequence, we also describe the design and synthesis of a photoaffinity probe based on actinoallolide A to investigate its biological mode of action. This will allow ongoing labelling studies to identify their protein binding target(s).

Characterization of the complex molecular scaffold of the marine polyketide natural product phormidolide A represents a challenge that has persisted for nearly two decades. In light of discordant results arising from recent synthetic and biosynthetic reports, a rigorous study of the configuration of phormidolide A was necessary. This report outlines a synergistic effort employing computational and anisotropic NMR investigation, that provided orthogonal confirmation of the reassigned side chain, as well as supporting a further correction of the C7 stereocenter.

The aplyronines are a family of highly cytotoxic marine natural products with potential application in targeted cancer chemotherapy. To address the severe supply issue, function-oriented molecular editing of their macrolactone scaffold led to the design of a series of simplified aplyronine analogues. Enabled by a highly convergent aldol-based route, the total synthesis of four analogues was achieved, with a significant improvement in step economy versus previous compounds, and their cancer cell growth inhibition in the HeLa cell line was determined. The modular strategy presented offers a means for significantly shortening their chemical synthesis to facilitate the continued development of this promising class of anticancer agent.

As part of our ongoing studies towards the total synthesis of phormidolide A (1), we explored the chelation-controlled vinylmetal addition of iodide 2 to aldehyde 3 to install the reported 17S configuration. While the stereochemical outcome of this reaction was opposite to that expected, detailed NMR comparisons with the previously reported triacetonide derivative of phormidolide A (18) highlighted that the major adduct was a better match to the natural product. The synthesis of three model acetonides and detailed spectroscopic comparisons to the triacetonide derivative of phormidolide A supports a reassignment of seven of the 11 stereocentres in phormidolide A (1a).

The patellazoles are a family of complex marine macrolides that exhibit potent cytotoxicity against cancer cell lines. However, despite extensive characterisation efforts, their full stereochemical assignment has remained elusive. We report our approach towards the synthesis-enabled structural elucidation of patellazole B (4), a 24-membered macrolide with 16 stereocentres and a signature thiazole-containing side chain. Our plan hinges upon isolating the unknown stereocentres into a single C20-C25 fragment to facilitate the flexible assembly of various possible diastereomers of an advanced C1-C25 fragment. Towards this end, a highly convergent and modular synthesis of one candidate diastereomer 37, corresponding to the patellazole B macrocyclic skeleton, has been achieved based on the strategic application of stereocontrolled aldol methodology, combined with Suzuki and Heck cross-coupling reactions.

Through synthesising both candidate diastereomers of a model C1-C28 fragment of the potent cytotoxic marine polyketide hemicalide, an assignment of the relative configuration between the C1-C15 and C16-C26 regions has been achieved. By detailed NMR comparisons with the natural product, the relative stereochemistry between these two 1,6-related stereoclusters is elucidated as 13,18-syn rather than the previously proposed 13,18-anti relationship. A flexible and modular strategy using an advanced C1-C28 ketone fragment 22 is outlined to elucidate the remaining stereochemical features and achieve a total synthesis.

The aplyronines are a family of antimitotic marine macrolides that disrupt cytoskeletal dynamics by dual targeting of both actin and tubulin. Given their picomolar cytotoxicity profile and unprecedented mode of action, the aplyronines represent an excellent candidate as a novel payload for the development of next-generation antibody-drug conjugates (ADCs) for cancer chemotherapy. Enabled by an improved second-generation synthesis of the macrolactone core 5, we have achieved the first total synthesis of the most potent congener aplyronine D together with a highly stereocontrolled synthesis of aplyronine A. To facilitate step economy, an adventurous site-selective esterification of the C7 hydroxyl group was performed to install the N,N,O-trimethylserine pharmacophore to directly afford aplyronines A and D. Toward the assembly of ADCs incorporating an aplyronine warhead, the C29-ester derivative 4 featuring an Fmoc-amino substituted linker attached to the actin-binding tail region was also prepared by adapting this flexible endgame.

Using the DP4f GIAO-NMR method, the stereochemistry of hemicalide was computationally analysed, resulting in a reassignment at C18 as supported by improved NMR shift correlations with a model C13-C25 fragment 23. An advanced C16-C28 subunit 6 of this potent anticancer agent was then synthesised with the revised 18,19-syn relationship.

The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic protocols were employed to assemble a series of increasingly elaborate fragments. The controlled preparation of suitable C1-C19 and C20-C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres respectively, was first achieved. An adventurous C19-C20 fragment union was then explored to construct the entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type aldol protocols proved unrewarding. A protected C1-C38 polyol 93 was subsequently prepared, setting the stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work, asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for controlled fragment assembly and coupling with predictable stereoinduction from the enolate component.

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.

Two new peloruside congeners (3 and 4) were isolated from wild and aquacultured collections of the New Zealand marine sponge Mycale hentscheli. Small-scale reactions on peloruside A (1) have been performed, which along with the isolation of 3 and 4, give further insight into the bioactive pharmacophore of 1.

A hybrid library of the marine natural products dictyostatin and discodermolide, incorporating the taxol or taxotere side chains, were synthesised; preliminary biological evaluation in the PANC-1 cancer cell line revealed significant antiproliferative activity, demonstrating that a macrolide scaffold is an effective surrogate for the baccatin core of taxol.

This Highlight summarises synthetic efforts towards the marine sponge-derived antimitotic agent spirastrellolide A and its congeners, including the first total synthesis by Paterson and co-workers.

The first total synthesis of (-)-spirangien A, a cytotoxic and antifungal polyketide of myxobacterial origin, is reported; this exploits a Stork-Wittig olefination and double Stille cross-coupling sequence to install the sensitive pentaene side chain onto a fully elaborated spiroacetal core, leading initially to the methyl ester of spirangien A.

A concise total synthesis of the antiproliferative macrolide (+)-neopeltolide has been completed, utilising a Jacobsen hetero Diels-Alder reaction to install the trisubstituted tetrahydropyran ring.

A potent dictyostatin-discodermolide hybrid was designed and synthesised; it showed enhanced cell growth inhibitory activity relative to discodermolide in four human cancer cell lines including the Taxol-resistant NCI/ADR-Res cell line.

Initially isolated in trace quantities from deep-sea sponges, the structurally related polyketides discodermolide and dictyostatin share the same microtubule-stabilizing antimitotic mechanism as Taxol. Discodermolide has been the focus of intense research activity in order to develop a practical supply route, and these efforts ultimately allowed its large-scale synthesis and the initiation of clinical trials as a novel anticancer drug. Similarly, the re-isolation and synthesis of dictyostatin continues to stimulate the biological and chemical communities in their quest for the development of new chemotherapeutic agents. This comprehensive review chronicles the synthetic endeavours undertaken over the last 15 years towards the development and realization of practical chemical syntheses of discodermolide and, more recently, dictyostatin, focusing on the methods and strategies employed for achieving overall stereocontrol and key fragment unions, as well as the design and synthesis of novel hybrid structures.

The optimisation of a synthetic strategy towards the ABC segment of the cytotoxic macrolide spirastrellolide A is reported, together with its application to the synthesis of two diastereomeric C(1)-C(22) fragments for stereochemical correlation purposes with a putative spirastrellolide degradation product.

A 22-membered macrocyclic discodermolide/dictyostatin hybrid has been designed and synthesised; biological evaluation against a range of human cancer cell lines revealed significant levels of growth inhibition.

An efficient synthesis of the C(26)-C(40) tricyclic [5,6,6]-bis-spiroacetal segment of the marine macrolide spirastrellolide A has been developed, exploiting a novel double Sharpless asymmetric dihydroxylation/spiroacetalisation sequence.

By relying on asymmetric boron-mediated aldol reactions, solid phase methodology for the stereoselective synthesis of highly substituted spiroacetals was developed and applied to the preparation of a complex AB-spiroacetal subunit of the antimitotic agent spongistatin 1 (altohyrtin A).

The convergent synthesis of the C1-C15 AB-spiroacetal subunit of altohyrtin A/spongistatin 1 is described. This highly stereocontrolled synthesis relies on matched boron aldol reactions of chiral methyl ketones, under Ipc(2)BCl mediation, to establish the C5, C9 and C11 stereocentres, and formation of the desired thermodynamic spiroacetal under acidic conditions. The scalable synthetic sequence developed provided access to multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4.

The antimitotic marine macrolide altohyrtin A/spongistatin 1 has been synthesised in a highly convergent and stereocontrolled manner, thus contributing to the replenishment of the largely exhausted material from the initial isolation work. Coupling of the AB- and CD-spiroacetal subunits by a stereoselective aldol reaction was achieved by using either a lithium (67 : 33 dr) or boron enolate (90 : 10 dr). A highly (Z)-selective Wittig coupling was used to unite the northern hemisphere aldehyde with the southern hemisphere phosphonium salt . Deprotection and subsequent regioselective macrolactonisation on a triol seco-acid completed the synthesis of altohyrtin A. Two structural analogues were also prepared and evaluated as growth inhibitory agents against a range of human tumour cell lines, including Taxol-resistant strains, alongside altohyrtin A and paclitaxel (Taxol), revealing that dehydration in the E-ring is tolerated and results in enhanced cytotoxicity (at the low picomolar level), whereas the presence of the full C44-C51 side-chain appears to be crucial for biological activity.

Stereocontrolled syntheses of the C16-C28 CD-spiroacetal subunit of altohyrtin A/spongistatin 1 , relying on kinetic and thermodynamic control of the spiroacetal formation, are described. The kinetic control approach resulted in a slight preference (60 : 40) for the desired spiroacetal isomer. The thermodynamic approach allowed ready access to the desired spiroacetal by acid-promoted equilibration, chromatographic separation of the C23 epimers and resubjection of the undesired isomer to the equilibration conditions. This scalable synthetic sequence provided multi-gram quantities of , thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4 of this series.

The fully functionalised C29-C51 southern hemisphere of altohyrtin A/spongistatin 1 , incorporating the E- and F-ring tetrahydropyran rings and the unsaturated side chain, has been synthesised in a highly convergent and stereocontrolled manner. Key steps in the synthesis of this phosphonium salt include four highly diastereoselective, substrate-controlled, boron aldol reactions to establish key C-C bonds and accompanying stereocentres, where the introduction of the chlorodiene side chain and the C47 hydroxyl-bearing centre were realised by exploiting remote stereoinduction from the F-ring tetrahydropyran.

The convergent syntheses of the C(1-32) and C(33-46) domains of phorboxazole B are described. An iterative cyclocondensation strategy exploited the Jacobsen hetero-Diels-Alder (HDA) reaction as a platform for the synthesis of both the C(5-9) and C(11-15) tetrahydropyran rings. The use of 2-silyloxydiene coupling partners bearing an increasing resemblance to the phorboxazole skeleton was found to lead to a reduction in diastereoselectivity, however, in the case of the C(11-15) ring. The coupling of aldehyde and 2-silyloxydiene by this route provided a C(1-32) fragment which was elaborated to the macrolide core of phorboxazole B. The synthesis of the C(33-46) domain involved a Nozaki-Kishi coupling of aldehyde 31 and vinyl iodide 39. The syntheses of 31 and 39 were highly diastereoselective: an Evans [Cu(Ph-pybox)](SbF6)2-catalysed Mukaiyama aldol reaction formed the cornerstone of the synthesis of 31 whilst a Nagao-Fujita acetate aldol reaction provided a convenient means of installing the sole stereogenic centre of 39.

The relative stereochemistry of the 22-membered marine macrolide dictyostatin, a Taxol-like antimitotic agent, was determined based on a combination of extensive high field NMR studies, including J-based configuration analysis, and molecular modelling.

Simplified analogues of the potent antimitotic marine macrolide spongistatin 1/altohyrtin A were synthesised and evaluated as growth inhibitory agents against a range of human tumour cell lines, including Taxol-resistant strains, revealing that E-ring dehydration leads to enhanced cytotoxicity at the low picomolar level while truncation of the side-chain at C46 results in a drastic decrease in activity.