Synthesis of the I-K Fused Polyether Array of CTX3C and Related Ciguatoxins by Use of a Gold-Catalyzed Cyclization Reaction.

The I-K fragment (C31-C49) of the ciguatoxin CTX3C has been synthesized from a simple chiral pool derived tetrahydropyranyl alcohol. An efficient gold-catalyzed cyclization reaction of a γ'-hydroxy ynone has been used to accomplish efficient closure of ring K under mild conditions. The resulting vinylogous ester has been elaborated to give a complete tricyclic fragment bearing the dimethyl-substituted side chain required for assembly of the LM spirocyclic acetal portion of the target.

Synthesis of the A-F Fragment of the Pacific Ciguatoxin CTX3C by Iterative Ring-Closing Metathesis and Tsuji-Trost Allylation.

The fully functionalized A-F fragment of the Pacific ciguatoxin CTX3C has been synthesized from a derivative of D-glucal, which serves as the B-ring. Rings A and C were introduced to either side of ring B by ring-closing diene and enyne metathesis (RCM). The seven-membered D-ring and eight-membered E-ring were assembled by iterative use of a six-step reaction sequence in which RCM was used for ring construction and Tsuji-Trost allylation was employed for subsequent stereoselective functionalization. The nine-membered F-ring was formed by use of an RCM reaction and bears the functionality required for attachment of the I-M fragment and subsequent closure of rings G and H.

Synthetic Studies on Amphidinolide F: Exploration of Macrocycle Construction by Intramolecular Stille Coupling.

Exploration of an ambitious new strategy for the total synthesis of the cytotoxic marine natural product amphidinolide F is described, which features fabrication of the core structure from four readily accessible fragments and macrocycle construction through C9-C10 bond formation by intramolecular Stille coupling between an alkenyl iodide and alkenyl stannane. Efficient stereoselective synthesis of each of the four building-blocks and subsequent coupling of them to produce the requisite cyclization precursor has been accomplished, but suitable conditions for high-yielding palladium-mediated closure of the macrocycle to produce the fully protected amphidinolide F ring system have yet to be identified.

Convergent Synthesis of the C1-C29 Framework of Amphidinolide F.

The complete carbon framework of the macrocyclic marine natural product amphidinolide F has been prepared by a convergent synthetic route in which three fragments of similar size and complexity have been coupled. Key features of the syntheses of the fragments include the stereoselective construction of the tetrahydrofuran in the C1-C9 fragment by oxonium ylide (free or metal-bound) formation and rearrangement triggered by the direct generation of a rhodium carbenoid from 1-sulfonyl-1,2,3-triazole, the highly diastereoselective aldol reaction between a boron enolate and an aldehyde with 1,4-control to prepare the C10-C17 fragment, and the formation of the tetrahydrofuran in the C18-C29 fragment by intramolecular nucleophilic ring opening of an epoxide with a hydroxyl group under acidic conditions.

Synthesis of the Prototypical Cyclopropyl Dipeptide Mimic and Evaluation of Its Turn-Inducing Capability.

The (+) and (-) enantiomers of a new turn-inducing cyclopropyl dipeptide mimic have been synthesized and evaluated. The mimic derives its turn-inducing capabilities solely from the cyclopropyl group and without the conformational biasing that would be provided by side-chain substituents. The mimic and peptide-mimic hybrids prepared from it have been studied using a combination of spectroscopic techniques (NMR, IR, and CD). The dipeptide mimic itself displays intramolecular hydrogen bonding in organic solvents, which differs from that observed in natural peptide turns. In contrast, more elaborate peptide-mimic hybrids exhibit hydrogen bonding characteristics that vary with solvent but are consistent with structures found in the tetrapeptide portion (i → i + 3) of a native ß-turn.

Stereoselective Synthesis of the I-L Fragment of the Pacific Ciguatoxins.

The I-L ring system found in all the Pacific ciguatoxins has been prepared from a tricyclic precursor in a highly stereoselective manner. Subtle differences in the reactivity of the enones present in the seven- and eight-membered rings of the tricyclic ether starting material have been exploited to allow selective protection of the enone in the eight-membered ring. Subsequent distereoselective allylation of the seven-membered ring has been accomplished by a palladium-mediated Tsuji-Trost reaction. The K-ring methyl and hydroxyl groups have been installed in a highly stereoselective manner by sequential conjugate reduction and enolate oxidation reactions. Ring L has been constructed by a use of a novel relay ring-closing metathesis reaction to complete the tetracyclic framework, which possesses the functionality necessary for elaboration of rings I and L and the introduction of ring M.

ß-Turn Mimics by Chemical Ligation.

We report a simple reductive amination protocol to ligate two peptides, while simultaneously installing a ß-turn mimic at the ligation junction. This strategy uses commercially available materials, mild chemical conditions, and a chemoselective ligation reaction of unprotected peptide substrates accessed through standard solid phase methods. This system was implemented in a designed ß-hairpin system, and biophysical analysis demonstrates effective mimicry of the ß-turn.

Bidirectional Synthesis of the IJK Fragment of Ciguatoxin CTX3C by Sequential Double Ring-Closing Metathesis and Tsuji-Trost Allylation.

A novel four-step bidirectional strategy has been used to synthesize the IJK fragment of the marine polyether natural product CTX3C from a simple monocyclic precursor in a concise and efficient manner. The four-step bidirectional sequence involves ring-closing metathesis, alcohol oxidation, enol carbonate formation, and palladium-mediated Tsuji-Trost allylation.

Total Syntheses of 11-Acetoxy-4-deoxyasbestinin†D, 4-Deoxyasbestinin†C, Asbestinin-10, -20, -21 and -23.

Six members of the asbestinin family of marine diterpene natural products have been synthesized in an efficient and stereoselective manner from a single oxa-bridged intermediate. Five of these natural products have not been synthesized previously and the structures of four of them have been confirmed as those proposed originally or following revisions to the original structures. The fifth natural product-asbestinin-21-has been shown to be a diastereomer of the compound that had been proposed previously.

Synthesis of the Core Framework of the Cornexistins by Intramolecular Nozaki-Hiyama-Kishi Coupling.

A new and direct approach to the construction of the core framework of the herbicidal natural products cornexistin and hydroxycornexistin has been developed. Formation of the nine-membered carbocycle found in the natural products has been accomplished by an intramolecular Nozaki-Hiyama-Kishi reaction between a vinylic iodide and an aldehyde. Good yields of carbocyclic products were obtained from the reaction, but diastereomeric mixtures of allylic alcohols were produced. The cyclisation reaction was successful irrespective of the relative configuration of the stereogenic centres in the cyclisation precursor.

Synthesis of fused tricyclic systems by thermal Cope rearrangement of furan-substituted vinyl cyclopropanes.

A novel method for the stereoselective construction of hexahydroazuleno[4,5-b]furans from simple precursors has been developed. The route involves the use of our recently developed Brønsted acid catalysed cyclisation reaction of acyclic ynenones to prepare fused 1-furanyl-2-alkenylcyclopropanes that undergo highly stereoselective thermal Cope rearrangement to produce fused tricyclic products. Substrates possessing an E-alkene undergo smooth Cope rearrangement at 40 °C, whereas the corresponding Z-isomers do not react at this temperature. Computational studies have been performed to explain the difference in behaviour of the E- and Z-isomers in the Cope rearrangement reaction. The hexahydroazuleno[4,5-b]furans produced by Cope rearrangement have potential as advanced intermediates for the synthesis of members of the guaianolide family of natural products.

Stereoselective Synthesis of Medium-Sized Cyclic Ethers by Sequential Ring-Closing Metathesis and Tsuji-Trost Allylation.

Fully functionalized medium-sized cyclic ethers, of the type found in fused polyether natural products, have been prepared by sequential ring-closing diene metathesis, conversion of the resulting cyclic enone into an allylic enol carbonate, and Tsuji-Trost allylation using a chiral palladium complex. Very high levels of diastereocontrol, favoring the diastereomer in which there is a cis relationship between the allyl group at C-2 of the medium-ring ether and the substituent at C-7/C-8, are obtained in cases where catalyst control and substrate control are matched.

Trialkylphosphine-Mediated Synthesis of 2-Acyl Furans from Ynenones.

A novel reaction for the synthesis of 2-acyl furans is reported. The reaction is believed to proceed by sequential addition of a trialkylphosphine to an ynenone, 5-exo-dig cyclization to form the furan, and oxidation of the resulting phosphonium ylide with molecular oxygen. Many common functional groups are tolerated during the reaction, and the products are obtained in good to excellent yield under the mild conditions. This methodology offers efficient access to biologically important compounds, including fused polycyclic compounds and furaldehydes, from simple starting materials.

Total Synthesis of 7-epi-Pukalide and 7-Acetylsinumaximol†B.

Convergent total syntheses of the furanocembranoids 7-epi-pukalide and 7-acetylsinumaximol B have been achieved using a one-pot Knoevenagel condensation and thioether-mediated furan-forming reaction. Furan formation proceeds via a sulfur ylide and results in rapid introduction of structural complexity during the coupling of two highly functionalised fragments. The targets have been prepared in 16 steps from (R)-perillyl alcohol.

Total Synthesis of (-)-Nakadomarin†A.

A highly efficient 12-step synthesis of the marine alkaloid (-)-nakadomarin A has been accomplished. The key advanced intermediate, a tetracyclic ketone derivative, was constructed in just seven steps using a sequence that includes an asymmetric Pauson-Khand reaction, an Overman rearrangement reaction, a ring-closing metathesis reaction, and an amination reaction. Late introduction of the furan ring during the synthesis of (-)-nakadomarin A means that the key tetracyclic ketone derivative has the potential to serve as an advanced intermediate for the synthesis of related marine alkaloids.

Synthesis of the A-D Ring System of the Gambieric Acids.

The A-D fragment of gambieric acids A and C has been synthesized using an asymmetric Tsuji-Trost allylation reaction to couple the two key segments. The A ring fragment has been prepared by a short and highly efficient route involving diastereoselective Lewis acid mediated alkylation of an acetal. Iterative ring-closing metathesis reactions have been used to construct cyclic ethers and assemble the tricyclic B-D fragment.

Synthesis of cyclopropyl-substituted furans by brønsted Acid promoted cascade reactions.

Chloroacetic acid promotes an efficient and diastereoselective intramolecular cascade reaction of electron-deficient ynenones to deliver products featuring a 2,3,5-trisubstituted furan bearing a fused cyclopropyl substituent at the 5-position. Synthetically relevant polycyclic building blocks featuring rings of various sizes and heteroatoms have been synthesized in high yield using this mild acid-catalyzed reaction.

Synthesis of four diastereomers of sclerophytin†F and structural reassignment of several sclerophytin natural products.

Synthesis of the triol that has been proposed to be the marine natural product sclerophytin F has been completed along with the syntheses of three diastereomers. Comparison of the NMR spectroscopic data for all four compounds to the data reported for the natural product reveals that sclerophytin F is not the 3S diastereomer of sclerophytin A as proposed by Friedrich and Paquette. Re-analysis of the NMR spectroscopic data for known sclerophytin natural products and synthetic analogues leads to the conclusion that sclerophytins E and F are the same compound. This finding has allowed structural reassignment of several other cladiellin natural products.

Empirical evidence of the efficiency and efficacy of fat taxes and thin subsidies.

This study summarizes the empirical literature on fat taxes and thin subsidies to assess their efficiency and efficacy as instruments of public policy to control obesity. Three specific types of taxes are studied in the literature: food group taxes; nutrient taxes; and nutrient index taxes. Anumber of studies use food expenditure data to assess the impact of various taxes on obesity and therefore only indirectly measure the impacts of taxes and subsidies on obesity. These studies generally conclude that food group taxes, nutrient taxes and nutrient index taxes have a small impact on the purchases of food and the nutrients purchased. Other studies use the body mass index as the explanatory variable and thus measure the impacts of taxes on body mass index directly. Nutrient taxes are found to be more effective than food group taxes, although even for nutrient taxes, the effects are small. In general, thin subsidies seem to offer more effective control of obesity than obesity taxes. However, due to the small effects of both fat taxes and thin subsidies, they are not recommended as instruments of food and nutrition policy.

Total synthesis of the purported structure of sclerophytin F.

The synthesis of the compound that has been proposed to be the natural product sclerophytin F has been completed from a known vinylogous carbonate. The synthetic strategy relied upon rearrangement of a catalytically generated ylide-like intermediate to produce an oxabicyclo[6.2.1]-5-undecen-9-one and an intermolecular Diels-Alder reaction to construct the complete tricyclic core found in the natural product. Comparison of the spectroscopic data for synthetic material to that reported for sclerophytin F shows that the natural product does not have the revised structure possessing the 3S configuration (*) proposed previously.