Benzylic Photobromination for the Synthesis of Belzutifan: Elucidation of Reaction Mechanisms Using In Situ LED-NMR.

A detailed mechanistic understanding of a benzylic photobromination en route to belzutifan (MK-6482, a small molecule for the treatment of renal cell carcinoma associated with von Hippel-Lindau syndrome) has been achieved using in situ LED-NMR spectroscopy in conjunction with kinetic analysis. Two distinct mechanisms of overbromination, namely, the ionic and radical pathways, have been revealed by this study. The behavior of the major reaction species, including reactants, intermediates, products, and side products, has been elucidated. Comprehensive understanding of both pathways informed and enabled mitigation of a major process risk: a sudden product decomposition. Detailed knowledge of the processes occurring during the reaction and their potential liabilities enabled the development of a robust photochemical continuous flow process implemented for commercial manufacturing.

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

Total synthesis of jiadifenolide.

As a potent neurotrophic agent, the sesquiterpenoid jiadifenolide represents a valuable small-molecule lead for the potential therapeutic treatment of neurodegenerative diseases. A stereocontrolled total synthesis of this densely functionalized natural product is reported, central to which is an adventurous samarium-mediated cyclization reaction to establish the tricyclic core and the adjacent C5 and C6 quaternary stereocenters.

Total synthesis of the antimitotic marine macrolide (-)-leiodermatolide.

Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin-targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we report a highly stereocontrolled total synthesis (3.2% yield) based on a convergent sequence of palladium-mediated fragment assembly and macrolactonization. Boron-mediated aldol reactions were used to configure the three key fragments 2, 5, and 6 by employing the appropriate enantiomer of the lactate-derived ketone 7.

Total synthesis of alotaketal A.

The total synthesis of the cAMP signaling pathway activator (-)-alotaketal A is reported. A convergent approach to the unusual alotane sesterterpenoid skeleton was employed, exploiting a remarkable LiDBB-mediated coupling of an (R)-carvone-derived δ-lactone with an allyl bromide side chain, followed by spiroacetalization.

The stereocontrolled total synthesis of spirastrellolide A methyl ester. Expedient construction of the key fragments.

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 stereocontrolled total synthesis of spirastrellolide A methyl ester. Fragment coupling studies and completion of the synthesis.

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.

A second-generation total synthesis of spirastrellolide A methyl ester.

Marine macrolides: an improved second-generation total synthesis of the anticancer macrolide spirastrellolide A methyl ester has been achieved. The synthesis features a uniformly high level of stereocontrol combined with more expedient fragment assembly, and demonstrates a critical dependence of the crucial macrolactonization step on the substitution pattern of the C22-C24 linker region.

Synthesis of the macrocyclic core of leiodermatolide.

The macrocyclic core (2) of the marine macrolide leiodermatolide (1) has been synthesized in 19 steps through a convergent strategy exploiting boron aldol methodology to install the requisite stereochemistry and a selective Stille coupling reaction for controlled fragment assembly, followed by a Yamaguchi macrolactonization and carbamate introduction at the C9-OH.

Synthesis of polyketide natural products and analogs as promising anticancer agents.

Recent highlights in the synthesis of polyketide natural products and structural analogs as promising anticancer agents are described, focusing on the halichondrins and eribulin (Eisai), together with recently published research on bryostatin, dictyostatin, spongistatin, peloruside, spirastrellolide, palmerolide, reidispongiolide, spirangien and saliniketals. These examples demonstrate the centrality of bioactive polyketides in current and future anticancer drug discovery, and the increasingly key role of efficient total synthesis in providing a sustainable supply of such compounds for drug development.

Synthesis and stereochemical determination of the spirastrellolides.

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.

Total synthesis of (+)-azinothricin and (+)-kettapeptin.

Asymmetric total syntheses of (+)-azinothricin and (+)-kettapeptin have been completed through a common new pathway that exploits a highly chemoselective coupling reaction between the fully elaborated cyclodepsipeptide 5 and the glycal activated esters 3 and 4 at the final stages of both respective syntheses.

Synthesis of A83586C analogs with potent anticancer and beta-catenin/ TCF4/osteopontin inhibitory effects and insights into how A83586C modulates E2Fs and pRb.

The synthesis of three potent new antitumor agents is described: the A83586C-citropeptin hybrid (1), the A83586C-GE3 hybrid (2), and l-Pro-A83586C (3). Significantly, compounds 1 and 2 function as highly potent inhibitors of beta-catenin/TCF4 signaling within cancer cells, while simultaneously downregulating osteopontin (Opn) expression. A83586C antitumor cyclodepsipeptides also inhibit E2F-mediated transcription by downregulating E2F1 expression and inducing dephosphorylation of the oncogenic hyperphosphorylated retinoblastoma protein (pRb).

From nature to the laboratory and into the clinic.

Natural products possess a broad diversity of structure and function, and they provide inspiration for chemistry, biology, and medicine. In this review article, we highlight and place in context our laboratory's total syntheses of, and related studies on, complex secondary metabolites that were clinically important drugs, or have since been developed into useful medicines, namely amphotericin B (1), calicheamicin gamma(1)(I) (2), rapamycin (3), Taxol (4), the epothilones [e.g., epothilones A (5) and B (6)], and vancomycin (7). We also briefly highlight our research with other selected inspirational natural products possessing interesting biological activities [i.e., dynemicin A (8), uncialamycin (9), eleutherobin (10), sarcodictyin A (11), azaspiracid-1 (12), thiostrepton (13), abyssomicin C (14), platensimycin (15), platencin (16), and palmerolide A (17)].

A concise asymmetric total synthesis of aspidophytine.

An expedient asymmetric total synthesis of aspidophytine is reported. A highly convergent strategy involving the sequential annulation of vinyl iodide 5 with indole 6 exploits varying modes of indole reactivity to provide aspidophytine in 23% over six steps from 5.