Nakadomarin A, isolated approximately a decade ago from an Okinawan sea sponge, has an impressive architecture with a tetracyclic core containing an 8-membered heterocycle on one side and a 15-membered ring on the other. The potential anticancer, antifungal, and antibacterial activities of this marine alkaloid, coupled with its extremely limited availability and structural complexity, make its synthesis an important and formidable challenge. Kerr and Young present an asymmetric synthesis of nakadomarin A starting from commercially available D-mannitol. Their synthesis of this manzamine family member showcases the utility of a nitrone/cyclopropane cycloaddition to generate the pyrrolidine functionality within the tetracyclic core. Eva J. Gordon, Ph.D.

The ipomoeassins, a family of five cytotoxic glycoresins, were isolated from extracts of an endangered species of the morning glory, Ipomoea squamosa, from the Suriname rainforest. Toward exploration of the anticancer potential of these intriguing glycoconjugates, Fürstner and coworkers report the first total syntheses of ipomoeassin B and ipomoeassin E. A key aspect of these syntheses entailed early installation of a C-silylated (protected) cinnamic acid ester. Ring closing metathesis was used to construct the macrolactone ring, which the protected cinnamate ester tolerated. This unit also survived a subsequent hydrogenation step and was successfully deprotected under mild conditions. Eva J. Gordon, Ph.D.

FR901464, a natural product isolated from the Pseudomonas genus of bacteria, possesses potent antitumor activity. This compound is of particular interest because it appears to kill cancer cells by a mechanism different from that of other known anticancer agents. Koide and coworkers now present the most efficient construction of FR901464 to date. Their convergent synthesis relies on early installation of a spiroepoxide functionality and an impressive diene-ene cross-coupling as the final step. Furthermore, degradation studies of the right fragment of FR901464 enabled the design of an FR901464 analog with dramatically increased stability and picomolar potency. Eva J. Gordon, Ph.D.

Papulacandin D is a member of a family of glycolipids that possess potent activity against several fungal pathogens responsible for increased mortality among immunocompromised individuals. The potential clinical applications of the papulacandins have stimulated efforts toward their synthesis, focusing on facile generation of the tricyclic spiroketal ring system. Denmark and coworkers report an efficient, convergent synthesis of papulacandin D, employing a palladium catalyzed, silicon-based cross-coupling reaction to generate the key spirocyclic C-aryl glycopyranoside and an enantioselective allylation reaction using a chiral bisphosphoramide Lewis basic catalyst for installation of the C(7'') stereocenter in the lipid chain. Eva J. Gordon, Ph.D.

Jerangolid D, produced by the myxobacterium Sorangium cellulosum, is a natural product with intriguing antifungal activity. Markó and coworkers report the first total synthesis of jerangolid D. The convergent synthesis is based on connection of three fragments: a lactone, a sulfone, and a dihydropyran. A modified Julia olefination, in which reaction between a phenyl sulfonyl carbanion and a ketone-bearing dihydropyran is followed by reductive elimination with samarium diiodide, is first used to join the sulfone and the dihydropyran pieces. A Kociensky–Julia olefination is used to couple the resulting dihydropyran fragment with an aldehyde-bearing lactone, yielding jerangolid D. Eva J. Gordon, Ph.D.

Spirotenuipesines A and B, natural products isolated from the fungus Paecilomyces tenuipes, have demonstrated potential to promote the differentiation of neurons, an activity that could find application in the treatment of neurodegenerative disorders. To facilitate exploration of their mechanism of action and potential clinical use, Danishefsky and Dai present total syntheses of spirotenuipesines A and B. The bicyclic ring system was constructed using an intramolecularly tethered cyclopropanation followed by radical initiated fragmention. The syntheses hinge on a stereoselective Diels–Alder reaction to generate the spirocyclic enone intermediates. A key ring closing metathesis early in the synthesis greatly simplified generation of the dienophile for the Diels–Alder sequence. Lactone reduction, chemospecific dihydroxylation, nucleophilic methylation, and deprotection led to the generation of the fully synthetic, racemic natural products. Eva J. Gordon, Ph.D.

The growing family of dimeric pyrrole–imidazole alkaloids exhibits a wide range of biological properties, including antibacterial and antiviral activities. Baran and coworkers report their development of a synthetic program focusing on the construction of these structurally and biologically intriguing compounds. Based on the hypothesis that sceptrin could serve as a precursor to other members of the family, total syntheses of five dimeric pyrrole–imidazole alkaloids were achieved. Notably, use of protecting groups was kept to a minimum by exploiting the inherent reactivity of the 2-aminoimidazole functionality. Furthermore, examination of the oxaquadricyclane fragmentation used in the spectrin synthesis enabled the first enantioselective syntheses of spectrin and ageliferin to be achieved. Eva J. Gordon, Ph.D.

The archazolids, produced by the myxobacterium Archangium gephyra, are inhibitors of vacuolar-type ATPases. Malfunction of these enzymes has been implicated in cancer, osteoporosis, and renal acidosis, suggesting that the archazolids may have therapeutic potential against a number of diseases. Menche and coworkers present the first total synthesis of archazolid A, and also establish its relative and absolute configuration. Their convergent synthesis relies on assembly of three building blocks. A stereoselective, boron-mediated aldol condensation is used to connect the first two fragments and sets the (Z,Z,E)-triene functionality, and a diastereoselective Heck coupling unites the third piece. Finally, a Horner–Wadsworth–Emmons macrocyclization completes the generation of this structurally unique macrolactone. Eva J. Gordon, Ph.D.

Stephacidin A is a fungal metabolite with potential anticancer activity. Its [2.2.2] diazaoctane ring system is shared with several other alkaloids such as stephacidin B and notoamide B, suggesting related biosynthetic pathways. To facilitate exploration of the biosynthesis of these complex, prenylated indole alkaloids, Williams and coworkers have developed concise routes for the total syntheses of (−)-stephacidin A, (+)-stephacidin B, and (+)-notoamide B. Notable features of these syntheses include the use of an S_N2′ cyclization to form the [2.2.2] bridged bicyclic ring system, development of an improved route toward the pyranoindole ring system, and extensive use of microwave reaction technology to improve reaction times and yields. Eva J. Gordon, Ph.D.

Palmerolide A is 20-membered macrolide containing a distinct polyunsaturated N-acyl dienamine side chain. Isolated from an antarctic marine animal, access to natural sources of palmerolide A is extremely limited. To facilitate exploration of its antitumor activity, De Brabander and coworkers developed a total synthesis of the originally proposed structure of palmerolide A. The unique macrolide was constructed from three fragments using a Suzuki coupling, an esterification, and a Horner–Wadsworth–Emmons-mediated marcrocyclization. Installation of the terminal enamide unit was accomplished using a Curtius rearrangement sequence. Surprisingly, it was discovered that the proposed structure of palmerolide A is a diastereomer of the natural product. De Brabander and coworkers subsequently deduced the correct relative stereochemistry and synthesized (−)-palmerolide A, the enantiomer of the natural product. Eva J. Gordon, Ph.D.

Salvinorin A, a diterpene isolated from the Mexican plant Salvia divinorum, is a selective κ opioid receptor agonist with potent hallucinogenic properties. Structurally distinct from other known psychoactive substances, salvinorin A has intriguing therapeutic potential. Evans and coworkers report the first synthesis of this unique natural product. The key step of this convergent synthesis is the transannular bis-Michael reaction cascade that forms the tricyclic core of the natural product. Eva J. Gordon, Ph.D.

Saxitoxin is a bis-guanidinium poison notorious for causing paralytic shellfish poisoning in red tides. A potent inhibitor of voltage-gated sodium channels, saxitoxin is also a valuable pharmacological tool for identification and exploration of sodium channels. Du Bois and coworkers present their synthetic strategies for the asymmetric synthesis of (+)-saxitoxin, illuminating a path for generation of saxitoxin analogs. Two routes to (+)-saxitoxin were developed, the shortest of which required only 14 linear steps. Key aspects include two methods for generation of a unique nine-membered ring guanidine intermediate, one employing a rhodium-catalyzed C–H amination and the other a stereoselective acetylide dianion–nitrone addition sequence. Eva J. Gordon, Ph.D.

The frondosins are a family of 14-carbon terpenoids isolated from the marine sponge Dysidea frondosa of Micronesia. In addition to demonstrated anti-HIV activity, the frondosins inhibit the function of interleukin-8, a chemokine involved in the inflammatory response. Trost and coworkers report the first total synthesis of (+)-frondosin A, the most potent member of the frondosin family, and establish its absolute stereochemistry. Key features of the synthesis include the formation of a bicyclo[5.3.0] ring system with high regio- and diastereoselectivity using a ruthenium-catalyzed [5+2] cycloaddition, followed by a Claisen rearrangement and ring expansion reaction to furnish the [5.4.0] frondosin core. Eva J. Gordon, Ph. D.

Sarain A, an alkaloid isolated from the marine sponge Reniera sarai, possesses significant biological properties including antibacterial, insecticidal, and antitumor activities. Overman and coworkers present their synthetic efforts culminating in the total, enantioselective synthesis of (−)-sarain A. The extraordinary architecture of sarain A is comprises a diazatricycloundecane core with five contiguous stereogenic centers, a saturated 13-membered macrocycle, a 14-membered ring containing a skipped-triene and a vicinal diol functional group, and a tertiary amine–aldehyde proximity interaction. Ring forming reactions, including an enoxysilane-N-sulfonyliminium ion cyclization, a ring-closing metathesis reaction, and an intramolecular Stille macrocyclization, figure prominently in this synthesis of (−)-sarain A. Eva J. Gordon, Ph.D.

The indole alkaloid communesin F, isolated from a marine fungal strain of Penicillium, is structurally related to the cytotoxic communesins A and B. Qin and coworkers present the first total synthesis of any member of the communesin family, (±)-communesin F. The structure is made up of a fused ring system, including one seven-membered ring. Notable features of this highly stereoselective synthesis include an intramolecular cyclopropanation of an indole, followed by a ring opening and ring closing sequence to construct the key pentacyclic substructure. The quaternary carbon center was formed via a 3,3-rearrangement, and the final azepine ring was established via an acid-catalyzed cyclization. Eva J. Gordon, Ph.D.

Platensimycin is a promising new antibiotic effective against several drug-resistant strains of Gram-positive bacteria. The ether oxygen in platensimycin is known to participate in a hydrogen bonding interaction with a threonine residue in its target protein. Nicolaou and coworkers present the synthesis and biological evaluation of carbaplatensimycin, a platensimycin analog containing a carbon atom in place of the ether oxygen. The synthesis made use of an enantiomerically enriched aldehyde intermediate from their earlier platensimycin synthesis, which was elaborated to the desired carbocycle and then converted to the final product following a similar pathway employed for platensimycin. The biological activity of carbaplatensimycin compared with that of platensimycin confirmed the important contribution of the ether oxygen in binding to the protein target. Eva J. Gordon, Ph.D.

Okilactomycin, a novel polyketide isolated from the bacteria Streptomyces griseoflavus, displays significant cytotoxicity against several human cancer cell lines. Smith and coworkers report the first total synthesis of (−)-okilactomycin, and establish the absolute stereochemistry of the natural product as (+)-okilactomycin. Key structural elements of this complex antitumor antibiotic include a 13-membered macrocycle, a highly functionalized cyclohexene ring, a spirocenter, and a 2,6-cis-tetrahydropyranone moiety. Notable features of the Smith synthesis include use of a Petasis–Ferrier union/rearrangement to assemble the 2,6-cis-tetrahydropyranone functionality and a ring closing metathesis to generate the 13-membered ring. Eva J. Gordon, Ph.D.

Elatol is a member of the chamigrene subclass of sesquiterpenes, a large family of compounds that exhibit a range of interesting biological activities. Stoltz, Grubbs, and coworkers present the first total synthesis of (+)-elatol, one of the most widely studied compounds of this class. In addition to the spiro[5.5]undecone core that characterizes the chamigrenes, elatol incorporates two quaternary all carbon centers, one of which is a stereocenter, and a fully substituted chlorinated olefin. This very concise synthesis features an enantioselective decarboxylative allylation to generate the all carbon stereocenter, and a ring-closing metathesis to construct the tetrasubstituted chlorine-containing alkene and the spirocyclic core of the natural product. Eva J. Gordon, Ph.D.

The cyathane diterpenoid (−)-erinacine E, produced by edible mushrooms of the Hericium species that have been used in Chinese medicine, has recently been reported as a κ-opioid receptor agonist. Nakada and coworkers report the first total synthesis of erinacine E, whose complex structure includes a hexacyclic ring system with ten stereogenic centers and a 5-6-7 tricyclic cyathane skeleton fused with a tricyclic 2,9-dioxatricyclo[5.2.2.0]undecane system. The key step in the Nakada synthesis is an intramolecular aldol reaction coupled with the 1,2-migration of a benzoyl ester protecting group, resulting in formation of the strained skeleton. A similar aldol cyclization is hypothesized to occur in the biosynthesis of erinacine E. Eva J. Gordon, Ph.D.

Mycolactone F is a polyketide macrolide isolated from the fish pathogen Mycobacterium marinum. Related mycolactones from M. ulcerans cause Buruli ulcer skin disease in humans, and intriguing heterogeneity in their structures may be related to the potency of clinical isolates from different parts of the globe. Kishi and coworkers report the total synthesis of mycolactone F. Because the stereochemistry of the two hydroxyls on the side chain fatty acid was ambiguous, both the proposed structure of mycolactone F and its remote diastereomer, which differed only in the configuration of the hydroxyls, were synthesized. Subsequent development of an HPLC method using chiral columns enabled the stereochemistry of the natural product to be determined. Eva J. Gordon, Ph.D.