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Reported herein is the total synthesis of the trisaccharide repeating unit of Streptococcus pneumoniae zwitterionic polysaccharide Sp1 containing a rare sugar, 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose (AAT), and three consecutive 1,2-cis-glycosidic linkages. The total synthesis was completed via highly stereoselective glycosylations and late-stage oxidation as key steps involving a longest linear sequence of 21 steps with 4.4% overall yield.

Herein, we describe the first total synthesis of cochlearol B, a meroterpenoid natural product featuring a 4/5/6/6/6-fused pentacyclic structure. Key steps, oxidative cyclization and subsequent intramolecular [2+2] photocycloaddition, which constructed the pentacyclic structure in highly stereoselective manner, allowed efficient access to cochlearol B with the longest linear sequence of 16 steps, and in 9 % overall yield. Single-crystal X-ray crystallographic analysis clearly confirmed the stereochemistry of cochlearol B.

Herein, we report the total synthesis of the phosphorylated zwitterionic trisaccharide repeating unit of Photorhabdus temperata subsp. cinerea 3240. The efficient route involves regio- and stereoselective assembly of trisaccharide with rare deoxyamino sugar AAT at the nonreducing end, late stage oxidation, and installation of a phosphate linker on the trisaccharide. The total synthesis was completed via a longest linear sequence of 24 steps in 6.5% overall yield.

First total synthesis of the conjugation-ready pentasaccharide repeating unit of Plesiomonas shigelloides strain 302-73 (serotype O1) is reported. The complex target pentasaccharide is composed of all-rare amino sugars such as orthogonally functionalized d-bacillosamine, l-fucosamine, and l-pneumosamine linked through four consecutive α-linkages. The poor nucleophilicity of axial 4-OH of l-fucosamine and stereoselective glycosylations are the key challenges in the total synthesis, which was completed via a longest linear sequence of 27 steps in 3% overall yield.

Zwitterionic polysaccharides isolated from commensal bacteria are endowed with unique immunological properties and are emerging as immunotherapeutic agents as well as vaccine carriers. Reported herein is a total synthesis of the repeating unit of Bacteroides fragilis zwitterionic polysaccharide A1 (PS A1). The structurally complex tetrasaccharide unit contains a rare sugar 2-acetamido-4-amino-2,4,6-trideoxy-d-galactose (AAT) and two consecutive 1,2-cis glycosidic linkages. The repeating unit was efficiently assembled by rapid synthesis of d-galactosamine and AAT building blocks from cheap and abundant d-mannose via a one-pot SN2 displacement of 2,4-bistriflates and installation of all of the glycosidic bonds in a highly stereoselective manner. The total synthesis involves a longest linear sequence of 17 steps with 3.47% overall yield.

A convergent strategy was developed for the synthesis of the C12–C40 segment of (–)-pulvomycin. Key step was a diastereoselective aldol reaction between a chiral ethyl ketone representing the C24–C40 fragment and a chiral aldehyde representing the C12–C23 fragment. Both compounds were prepared from enantiomerically pure building blocks in a convergent fashion. The longest linear sequence commenced with a known d-fucose-derived glycosyl donor and entailed a total number of 16 steps. The desired anti-aldol product was obtained in a total yield of 5% over these steps and contains 12 out of 13 stereogenic centers present in the natural product.

Asperversin A represents the first example of a steroid-sterigmatocystin heterodimer. We report the concise asymmetric total synthesis of this natural product in 11 steps (the longest linear sequence). The polycyclic ring system was constructed by a cascade dialdehyde cyclization and the late stage xanthene formation by a phenol-assisted reductive alkylation and a SNAr reaction. The acetal linkage with ergosterol peroxide was furnished by a glycosylation-inspired approach.

Herein, we report the stereoselective and convergent synthesis of resolvin E4, a newly identified specialized pro-resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV–Vis and LC–MS/MS) data of synthetic resolvin E4 matched those obtained from biologically produced material.

The GE81112 complex has garnered much interest due to its broad antimicrobial properties and unique ability to inhibit bacterial translation initiation. Herein we report the use of a chemoenzymatic strategy to complete the first total synthesis of GE81112 B1. By pairing iron and α-ketoglutarate dependent hydroxylases found in GE81112 biosynthesis with traditional synthetic methodology, we were able to access the natural product in 11 steps (longest linear sequence). Following this strategy, 10 GE81112 B1 analogues were synthesized, allowing for identification of its key pharmacophores. A key feature of our medicinal chemistry effort is the incorporation of additional biocatalytic hydroxylations in modular analogue synthesis to rapidly enable exploration of relevant chemical space.

Taking advantage of the reliable stereocontrol capability of DMNPA group via long-distance-participation (LDP) effect as well as the mild and efficient deprotection conditions, the first and highly efficient synthesis of digoxin was achieved through a nine-step longest linear sequence with 41% overall yield.

The asymmetric synthesis of ent-fissistigmatin C is successively accomplished in 12 steps (longest linear sequence (LLS)). Relying on the enantioselective coupling of aliphatic aldehyde with 2-hydroxychalcone promoted by cooperative organocatalysts, the pivotal linkage of ent-fissistigmatin C between the flavonoid and the sesquiterpenoid fragment was stereoselectively established. An unprecedented final-stage radical cascade was also featured in this synthesis, which enabled the simultaneous establishment of the trans-decalin framework via forging two consecutive C-C bonds in one step.

The first total synthesis of sanjoseolide (1), which was originally obtained from Dalea frutescens A, was achieved via an efficient route with a longest linear sequence of six steps from the commercially available 2,4-dihydroxyacetophenone in 8.6% overall yield. Meanwhile, a series of sanjoseolide representative analogues were synthesized and assessed for their antiproliferative potency against cancer cells of different origins. Compound 8e inhibited the survival of all tested cancer cell lines in a dose-dependent manner, the IC50 values of the treatment were about 12.8 μM for human cholangiocarcinoma cell lines RBE and 12.7 μM for human cholangiocarcinoma cell lines HCCC-9810, which was more active than sanjoseolide (1). Analysis of the structure-activity relationships revealed that the presence of a trifluoromethyl group may be beneficial in terms of both RBE and HCCC-9810 inhibition.

A short, scalable total synthesis of meayamycin is described by an approach that entails a longest linear sequence of 12 steps (22 steps overall) from commercially available chiral pool materials (ethyl l-lactate, BocNH-Thr-OH, and d-ribose) and introduces the most straightforward preparation of the right-hand subunit detailed to date. The use of the approach in the divergent synthesis of a representative series of O-acyl analogues is exemplified.

We have developed a concise diastereoselective total synthesis of (±)-parvistemonine A. By using a Mukaiyama–Michael addition, an aza-Wittig reaction, a Paal–Knorr pyrrole synthesis, an acid-mediated annulation, and a Mitsunobu reaction as key steps, we achieved a total synthesis in which the longest linear sequence was ten steps and the overall yield was 19.6%. Additionally, the relative stereochemistry of parvistemonine A was confirmed by X-ray crystallographic analysis for the first time.

This work describes the total synthesis of raputindole A (1) through a convergent approach that features (1) an iridium-catalyzed cyclization to assemble the tricyclic core of the northern part, (2) enzymatic resolution to secure the preparation of an enantiomerically pure benzylic alcohol intermediate, and (3) the installation of the isobutenyl side chain via methallylation of the corresponding benzylic carbocation and coupling of the northern and southern parts via the Heck reaction. (+)-Raputindole A (1) was prepared in 10 steps (longest linear sequence) in 3.3% overall yield.

The first synthesis of the tetrasaccharide fragment of the anthracycline natural product Arugomycin is described. A reagent controlled dehydrative glycosylation method involving cyclopropenium activation was utilized to synthesize the α-linkages with complete anomeric selectivity. The synthesis was completed in 20 total steps, and in 2.5% overall yield with a longest linear sequence of 15 steps.

The first total synthesis of antiallergic depsipeptide seongsanamide A has been achieved and also the relative and absolute stereochemistry of the natural product has been confirmed. Highlights of the convergent route include the use of Miyuara borylation, Chan–Evans–Lam coupling for the effective assembly of the isodityrosine subunit and the identification of an effective macrocyclization site in very high conversion. The longest linear sequence leading to seongsanamide A was 12 steps, with an overall yield of 12.7%.

Developing an efficient, concise synthesis of the fungal natural product illudalic acid has been a long-standing challenge, made more pressing by the recent discovery that illudalic acid and analogs are selective phosphatase inhibitors. Syntheses of illudalic acid have become progressively more efficient over the decades yet remain strategically grounded in a 17-step synthesis reported in 1977. Here we validate a two-step process — convergent [4+2] benzannulation and one-pot coordinated functional group manipulations — for preparing the key trifunctional pharmacophore of illudalic acid. The modular building blocks are readily available in 2–3 steps, for a longest linear sequence (LLS) of 5 steps to illudalic acid from 3,3-dimethylcyclopentanone. A small collection of analogous indanes and tetralins featuring the same pharmacophore were prepared by a similar route. These compounds potently and selectively inhibit the human leukocyte common antigen-related (LAR) subfamily of protein tyrosine phosphatases (PTPs). Evidence supporting a postulated covalent ligation mechanism is provided herein.

The total synthesis of dysoxylactam A, a novel 17-membered macrolactam with potent multi-drug-resistant reversing activities, has been achieved, starting from 4-pentene-1-al in a longest linear sequence of 17 steps and 9.5% overall yield. The key transformations consist of iterative aldol and ring-closing metathesis reactions for the construction of the stereochemically enriched polypropionate scaffold and the macrocycle, respectively.

The total synthesis of putative penasulfate A was effectively achieved by a convergent strategy with a longest linear sequence of 14 steps and overall yield of 8.6%. The highlights of our strategy involved an E-selective olefin cross-metathesis, Suzuki cross-coupling, and a copper(I)-catalyzed coupling reaction.

A concise, scalable, six-step (longest linear sequence) synthetic route to ovatodiolide scaffolds was developed for the first time. This protecting-group-free route features tandem ring-opening metathesis/ring-closing metathesis reactions to install the macrocycle-fused butenolide ring and a tandem allylboration/lactonization to build the α-methylene-γ-lactone. Our syntheses have enabled the determination of the hitherto unknown stereochemical configurations of this family of natural products. Preliminary tests of structure-activity relationships were conducted with four natural ovatodiolides and three analogues. Further assays indicated that the synthetic natural product isoovatodiolide can significantly decrease the population of hepatic cancer stem cells and reduce the tumorsphere-forming capability of HepG2 cells.

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis-hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues., (‒)-Morphine is an essential medicine selected by the World Health Organization, however its catalytic asymmetric syntheses have been rarely reported. Here, the authors developed an intramolecular enantioselective Michael addition leading to (‒)-morphine in a longest linear sequence of 16 steps.

Modular, fully synthetic routes to structurally complex natural products provide useful avenues to access chemical diversity. Herein we report a concise route to virginiamycin M2, a member of the group A streptogramin class of natural products that inhibits bacterial protein synthesis. Our approach features a longest linear sequence of six steps from 7 simple building blocks, and is the shortest and highest yielding synthesis of any member of the streptogramin class reported to date. We believe this route will enable access to unexplored structural diversity and may serve as a useful tool to improve the therapeutic potential of the streptogramin class of antibiotics.

In this study, the total synthesis of 3-epi-juruenolide C is achieved in 10 steps (longest linear sequence) starting from ethyl (2E,4S,5S)-4,5-dihydroxy-2-hexenoate. The synthetic highlights of our approach include one-pot regioselective bromination, intramolecular carbonylation using bis(triphenylphosphine)dicarbonylnickel, and face-selective hydrogenation using a homogeneous Wilkinson's catalyst.

Here, we report a formal synthesis of the marine cytotoxic meroterpenoid actinoranone. Key steps include a semipinacol rearrangement/Wittig reaction sequence and a chiral pool approach for the syntheses of the tetralone and the ocatalin fragments, respectively. The presented route provides access to the natural product in 14 steps in the longest linear sequence.

A total synthesis of the marine macrolide biselide A is described that relies on an enantiomerically enriched α-chloroaldehyde as the sole chiral building block. Several strategies to construct the macrocycle are presented including a macrocyclic Reformatsky reaction that ultimately provides access to the natural product in a longest linear sequence of 18 steps. Biological testing of synthetic biselide A suggests this macrolide disrupts cell division through a mechanism related to the regulation of microtubule cytoskeleton organization. Overall, this concise synthesis and insight gained into the mechanism of action should inspire medicinal chemistry efforts directed at structurally related anticancer marine macrolides., A total synthesis of the marine macrolide biselide A is described that relies on an enantiomerically enriched α-chloroaldehyde as the sole chiral building block.

Efforts towards the first total synthesis of (-)-oxazolomycin B and (+)-oxazolomycin C from the intermediate of our previous synthesis of (+)-neoxazolomycin are reported. The syntheses were achieved in a longest linear sequence of 25 steps from the amino acid serine in 3.6 and 2.7 % overall yields, respectively. The efficiency of our approach is derived from silyl triflate-mediated reductive oxazolidine ring-opening and Fürstner's Ru-catalyzed hydrosilylation and protodesilylation reactions. The obtained spectra and optical rotations were in good agreement with those of natural products, thus confirming the structures.

The total synthesis of decarboxyaltenusin (5’-methoxy-6-methyl-[1,1’-biphenyl]-3,3’,4-triol), a toxin produced by various mold fungi, has been achieved in seven steps in a yield of 31% starting from 4-methylcatechol and 1-bromo-3,5-dimethoxybenzene, where the longest linear sequence consists of five steps. The key reaction was a palladium-catalyzed Suzuki coupling of an aromatic boronate with a brominated resorcin derivative.

The synthesis and biological evaluation of truncated spirastrellolide A analogues comprised of the southern hemisphere against protein phosphatase 2A are described. A convergent synthesis was designed featuring two gold-catalyzed cyclization reactions, specifically, a dehydrative cyclization of monoallylic diols for the synthesis of the tetrahydropyran (A-ring) and a regioselective spiroketalization for the efficient generation of the [6,6]-spiroketal (B, C-ring system). The synthesis of the southern hemisphere of spirastrellolide A was achieved involving the longest linear sequence of 19 steps. A total of eight spirastrellolide A analogues were synthesized, and preliminary PP2A enzyme assay inhibition studies were performed for the first time on analogues of the southern hemisphere. Several analogues showed inhibition, which is a positive indication and perhaps suggests that the unsaturated spiroketal fragment might be crucial to induce PP2A inhibition.

Holostane glycosides are characteristic metabolites of sea cucumbers, which possess various biological activities. Here, we report the synthesis of two representative congeners, namely, pervicoside B and C, starting from lanosterol with the longest linear sequence of both 34 steps and in 0.3% overall yields. The flexible synthetic approach has enabled us to expeditiously prepare 16 analogues for preliminary studies on the key structural features influencing their antiproliferative activities against tumor cells. A simplified disaccharide is found to be as potent as natural tetrasaccharides, which can be used as a lead for future studies.

A new route to MK-4482 was developed. The route replaces uridine with the more available and less expensive cytidine. Low-cost, simple reagents are used for the chemical transformations, and the yield is improved from 17% to 44%. A step is removed from the longest linear sequence, and these advancements are expected to expand access to MK-4482 should it become a viable drug substance.

A next generation total synthesis of vancomycin aglycon is detailed that was achieved in 17 steps (longest linear sequence, LLS) from the constituent amino acid subunits with kinetically-controlled diastereoselective introduction of all three elements of atropisomerism. In addition to new syntheses of three of the seven amino acid subunits, highlights of the approach include a ligand-controlled atroposelective one-pot Miyaura borylation-Suzuki coupling sequence for introduction of the AB biaryl axis of chirality (>20:1 dr), an essentially instantaneous and scalable macrolactamization of the AB ring system nearly free of competitive epimerization (>30:1 dr), and two room temperature atroposelective intramolecular S(N)Ar cyclizations for sequential CD (8:1 dr) and DE ring closures (14:1 dr) that benefit from both preorganization by the preformed AB ring system and subtle substituent effects. Combined with a protecting group free two-step enzymatic glycosylation of vancomycin aglycon, this provides a 19-step total synthesis of vancomycin. The approach paves the way for large scale synthetic preparation of pocket modified vancomycin analogues that directly address the underlying mechanism of resistance to vancomycin.

The total synthesis of the potent respiratory chain inhibitor ajudazol A was accomplished by a concise strategy in 17 steps (longest linear sequence). The modular approach was based on a direct oxazole functionalization strategy involving a halogen dance reaction for selective halogenation in combination with a challenging combination of sp2-sp2 and sp2-sp3 Negishi cross coupling reactions. The applicability of this strategy for analogue synthesis was demonstrated by the synthesis of a simplified as well as stabilized ajudazol analogue.

In a 2016 screen of natural product extracts a new family of natural products, the cahuitamycins, was discovered and found to inhibit the formation of biofilms in the human pathogen Acinetobacter baumannii. The molecules contain an unusual piperazate residue that raises structure/function and biosynthesis questions and resemble iron-trafficking virulence factors from A. baumannii, suggesting a connection between metal homeostasis and biofilm-mediated pathogenicity. Here we disclose the first total synthesis of the reported structure of cahuitamycin A in a twelve-step longest linear sequence and 18% overall yield. Comparison of spectral data of the authentic natural product and synthetic target compound demonstrate that the reported structure is distinct from the isolated metabolite. Herein, we propose an alternative structure to reconcile our findings with the isolation report, setting the stage for future synthetic and biochemical investigations of an important class of natural products.

The natural product koningic acid (KA) is a selective covalent inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a critical node in the glycolysis pathway. While KA is available commercially, sources are limited and its cost becomes rapidly prohibitive beyond the milligram scale. Additionally, a practical and flexible synthetic route to KA and analogs remains to be developed. Here we detail a new route that is operationally safer, scalable and offers a five-step reduction in the previously reported longest linear sequence.

Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey-Chaykovsky-type reaction, and a modified Horner-Wadsworth-Emmons Z-selective olefination. We also discuss a Z-E isomerization during the α,β-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps.

Stitching alkynes into bryostatin 3 The bryostatin family of marine natural products has been explored for a wide variety of pharmaceutical applications but remains challenging to source. The general structure comprises a macrocycle that contains three smaller, six-membered rings. Bryostatin 3 is distinguished by the added complexity of a fourth, fused lactone ring. Trost et al. report a convergent synthesis of this complex molecule, taking advantage of alkyne coupling reactions to stitch together three main fragments and asymmetric dihydroxylation and propargylation reactions to set stereochemistry. Science , this issue p. 1007

A convergent sequence to access the indole alkaloid (±)-melokhanine E in 12-steps (8-step longest linear sequence) and an 11% overall yield is reported. The approach utilizes two cyclopropane moieties as reactive precursors to a 1,3-dipole and imine species to enable stereoselective construction of the core scaffold through a formal [3 + 2] cycloaddition. The natural product was evaluated for its antimicrobial activity based on isolation reports; however, no activity was observed. The reported efforts serve as a synthetic platform to prepare an array of alkaloids bearing this core structural motif.

Herein, we report the synthesis of the entire acyclic carbon framework toward (±)-furanocembranoid 1 via the longest linear sequence of 12 steps from commercially available linalool and diethyl 2-isopropylmalonate. Key to the success of this synthetic approach is a silver-catalyzed enyne-annulation reaction for the formation of 2,4-disubstituted furan motif of unique furanocembranoid 1, isolated from Croton oblongifolius. Construction of macrocycle has also been explored using the ring-closing metathesis reaction.

A diverted total synthesis effort is described that is designed to prepare potent cytotoxins based on the actin-binding natural product bistramide A. The major focus of this study is the preparation of analogues that contain oxygenation at the C29 position, which is necessary for a key reaction in the sequence but is not present in the natural product. This process showed that C29 ketone analogues are accessed more readily and show similar potency compared to the natural product. The ability to incorporate C29 oxygenation and to replace a secondary alcohol by a primary alcohol allowed for the development of a more convergent approach that provides a potent analogue in just eight steps in its longest linear sequence.

The structure proposed in the literature for caldoramide, a formal pentapeptide metabolite of the marine cyanobacterium Caldora penicillata, was synthesised in 12 steps and 16% yield (longest linear sequence from isoleucine) following the strategy of a stepwise consecutive extension of an N-oligopeptidyl chain on a tetramate anchor. The synthetic product differed from the natural isolate in optical rotation, some NMR data, and cytotoxicities. Its antiproliferative effect on three human cancer cell lines was distinctly lower than that of related dolastatin 10 and belamide A.

The first total synthesis of viscumneoside III, a promising anti-angina pectoris dihydroflavone O-glycoside isolated from Viscum coloratum was described here. Trichloroaceti-midate was employed as the apiofuranosyl donor to construct the key building block of homoeriodictyol-7-O-β- d -apiosyl-(1 → 2)-β-D-glycoside (1). The longest linear sequence (from 2 to 1) in the synthetic route required thirteen steps and afforded the final product 1 with an overall yield of 6.3%.

Bongkrekic acid (BKA) is a strong inhibitor of adenine nucleotide translocase (ANT), inducing inhibition of adenosine triphosphate synthesis. We designed and synthesized simplified benzene-ring-containing BKA analogs. The key reaction is the one-pot double Sonogashira reaction, which forms the main skeleton. The analogs were efficiently synthesized in 8–10 longest linear sequence steps. This synthetic method can be applied for the preparation of other analogs having different combinations of carbon chain lengths. Furthermore, the allyloxy group on the benzene ring can be easily replaced by other functional groups. Our preliminary biological evaluation based on mitochondrial inhibitory effects revealed the high potency of the analogs bearing the same carbon chain length as that of BKA. In particular, the prefunctionalized analogs are potential ANT inhibitors.

This communication details the first total synthesis of the 13-membered macrolide, (−)-Melearoride A, as well as unnatural (+)-Melearoride A. The synthesis features a concise 13 step synthesis (11 steps longest linear sequence) that offers flexible stereo-control and multiple opportunities for unnatural analog synthesis to delve into antifungal SAR. The route features a cuprate addition, an Evans asymmetric alkylation, and a ring-closing metathesis (RCM) to close the 13-membered macrocyclic core.

Significant development and scale-up work was completed on the synthesis of an antibody drug conjugate payload based on the tubulysin natural products. This work included the development of new routes to the tubuvaline and tubuphenylaniline portions of the molecules, as well as extensive optimization of the solid phase peptide synthesis used to assemble the molecule. The initial route (21 steps longest linear sequence, 0.01% overall yield) was improved to a new, more robust route (19 steps longest linear sequence, 2.4% overall yield) affording a 240-fold increase in overall yield and allowing delivery of over 86 g of the required molecule.

The total synthesis of nannocystin Ax in an overall yield of 11% with 14 steps as the longest linear sequence is reported. Nannocystin Ax is a cytotoxic 21-membered depsipeptide and was isolated from the myxobacterial genus Nannocystis sp. The synthesis uses a vinylogous Horner-Wadsworth-Emmons reaction (HWE) and a vinylogous Mukaiyama aldol reaction (VMAR) as the key steps for the construction of the polyketide fragment. The macrocycle was closed via a macrolactamization reaction using COMU.

The polyhydroxylated 18-membered lichen macrolide (+)-aspicilin was synthesized in 12 steps and 17% yield (longest linear sequence) starting from d-mannose and (S)-propylene oxide as the source of the stereogenic centers. Key steps were a palladium-catalyzed Csp3X–Csp3ZnX Negishi cross-coupling affording an ω-hydroxy hemiacetal which was macrocyclized via a domino addition–Wittig olefination reaction with the cumulated ylide Ph3PCCO. This synthetic approach also allowed a regioselective glycosylation of 6-OH of aspicilin with d-desosamine, a quick entry to chimeric macrolides with potential antibiotic activity.

The first total synthesis of greensporone C, a cytotoxic 14-membered resorcylic acid lactone, has been accomplished via a longest linear sequence of 16 steps in 3.3% overall yield. The key features of the synthesis include Mitsunobu esterification and ring-closing metathesis to construct the macrocycle and establish the ( E )-olefin geometry, respectively. Our synthesis also confirmed the absolute stereochemistry of the natural product.

An enantiospecific synthesis of the C20–C32 central core of the phorboxazole scaffold, including the non-macrocyclic oxazole is detailed in 17 steps (longest linear sequence) from methacrolein in 7.8% overall yield. All of the stereocenters are communicated from a single Evans aldol reaction, and the final compound is suitably functionalized for further elaboration to the natural products.