Convergent Synthesis of the ent-ZA'B'C'D'-Ring System of Maitotoxin.

Stereoselective synthesis of the ent-ZA'B'C'D'-ring system of maitotoxin has been accomplished through a convergent strategy utilizing Suzuki-Miyaura cross coupling reaction of ZA'-ring alkylborane and C'D'-ring (Z)-vinyl iodide, and subsequent construction of the B'-ring by reduction of the O,S-acetal.

SmI(2)-induced reductive cyclizations for the synthesis of cyclic ethers and applications in natural product synthesis.

This tutorial review covers SmI(2)-induced reductive cyclizations of beta-alkoxyacrylate, beta-alkoxyvinyl sulfone, and beta-alkoxyvinyl sulfoxide, as methods for efficient construction of cyclic ethers. These cyclizations were developed as tools to aid in the total synthesis of marine polycyclic ethers, whose complex, synthetically challenging structures and potent bioactivities have attracted the attention of numerous synthetic organic chemists. Applications of the methods to total syntheses of various natural products containing cyclic ether are also described.

SmI2-induced cyclizations and their applications in natural product synthesis.

Since the isolation of brevetoxin-B, a red tide toxin, many bioactive marine natural products featuring synthetically challenging trans-fused polycyclic ether ring systems have been reported. We have developed SmI(2)-induced cyclization of beta-alkoxyacrylate with aldehyde, affording 2,6-syn-2,3-trans-tetrahydropyran (THP) or 2,7-syn-2,3-trans-oxepane with complete stereoselection, as a key reaction of efficient iterative and bi-directional strategies for the construction of these polycyclic ethers. This reaction is also applicable to the synthesis of 3-, 5-, and 6-methyl-THPs and 3,5-dimethyl-THP. The synthesis of 2-methyl- and 2,6-dimethyl-THPs was accomplished by means of a unique methyl insertion. Recently, the SmI(2)-induced cyclization was extended to similar reactions using beta-alkoxyvinyl sulfone and sulfoxide. Reaction of (E)- and (Z)-beta-alkoxyvinyl sulfone-aldehyde afforded 2,6-syn-2,3-trans- and 2,6-syn-2,3-cis- THPs, respectively. Reaction of (E)-beta-alkoxyvinyl (R)- and (S)-sulfoxides gave 2,6-anti-2,3-cis- and 2,6-syn-2,3-trans-THPs, respectively. Reaction of (Z)-beta-alkoxyvinyl (R)-sulfoxides gave 2,6-syn-2,3-cis-THP and an olefinic product, while that of (Z)-beta-alkoxyvinyl (S)-sulfoxide afforded a mixture of many products. These SmI(2)-induced cyclizations have been applied to the total syntheses of various natural products, including brevetoxin-B, mucocin, pyranicin, and pyragonicin. Synthetic studies on gambierol and maitotoxin are also introduced.

Discovery of novel antiviral agents directed against the influenza A virus nucleoprotein using photo-cross-linked chemical arrays.

The nucleoprotein (NP) of the influenza virus is expressed in the early stage of infection and plays important roles in numerous steps of viral replication. NP is relatively well conserved compared with viral surface spike proteins. This study experimentally demonstrates that NP is a novel target for the development of new antiviral drugs against the influenza virus. First, artificial analogs of mycalamide A in a chemical array bound specifically with high affinity to NP. Second, the compounds inhibited multiplication of the influenza virus. Furthermore, surface plasmon resonance imaging experiments demonstrated that the binding activity of each compound to NP correlated with its antiviral activity. Finally, it was shown that these compounds bound NP within the N-terminal 110-amino acid region but their binding abilities were dramatically reduced when the N-terminal 13-amino acid tail was deleted, suggesting that the compounds might bind to this region, which mediates the nuclear transport of NP and its binding to viral RNA. These data suggest that compound binding to the N-terminal 13-amino acid tail region may inhibit viral replication by inhibiting the functions of NP. Collectively, these results strongly suggest that chemical arrays are convenient tools for the screening of viral product inhibitors.

Stereoselective synthesis of 2,6-syn-dimethyl-tetrahydropyran derivatives, important segments of marine polycyclic ethers, by unique insertion of the methyl group.

Treatment of 6-methyl-tetrahydropyran derivatives, which have a 1'-mesyloxy group at the C2-side chain, with Me(3)Al effected stereoselective insertion of a methyl group at the C2-position to give 2,6-syn-dimethyl-tetrahydropyran derivatives. This reaction proceeds via removal of the mesyloxy group, 1,2-hydride shift, and stereoselective insertion of a methyl group into the resulting oxonium ion.

Stereoselective synthesis of trans-fused 7,6,6,7-membered tetracyclic ether, corresponding to the EFGH-ring of gambierol and the BCDE-ring of gambieric acids.

Stereoselective synthesis of a trans-fused 7,6,6,7-membered tetracyclic ether, corresponding to the EFGH-ring of gambierol and the BCDE-ring of gambieric acids, was efficiently accomplished via a two-directional approach. The key reactions were SmI(2)-induced double cyclization for construction of the F- and H-rings and SmI(2)-induced cyclization followed by ring expansion for construction of the E-ring.

Synthetic studies on maitotoxin. 2. Stereoselective synthesis of the WXYZA'-ring system.

The stereoselective synthesis of the WXYZA'-ring system of maitotoxin has been accomplished via a linear synthetic approach, in which key reactions were SmI 2-induced cyclization of beta-alkoxyacrylate for the construction of the A'-, Y-, and X-rings and 6- endo cyclization of hydroxy vinylepoxide for that of the Z- and W-rings.

Synthetic studies on maitotoxin. 3. Stereoselective synthesis of the BCDE-ring system.

The stereoselective synthesis of the BCDE-ring system of maitotoxin has been accomplished through a two-directional strategy for the construction of polycyclic ether. The key reactions involve SmI 2-induced double cyclization of a beta-alkoxyacrylate and a double dihydroxylation for construction of the B- and E-rings.

Synthetic studies on maitotoxin. 1. Stereoselective synthesis of the C'D'E'F'-ring system having a side chain.

The stereoselective synthesis of the maitotoxin C'D'E'F'-ring system having a side chain has been accomplished through a convergent strategy. The key reactions include Horner-Wadsworth-Emmons coupling of the C'D'E'-ring and the side chain and subsequent construction of the F'-ring by silane reduction of dihydropyran.

Pyranicin, a non-classical annonaceous acetogenin, is a potent inhibitor of DNA polymerase, topoisomerase and human cancer cell growth.

This report describes the inhibitory activities of the natural and non-natural acetogenins [mucocin (compound 1), jimenezin (compound 2), 19-epi jimenezin (compound 3), muconin (compound 4), pyranicin (compound 5), pyragonicin (compound 6), 10-epi pyragonicin (compound 7), and a gamma-lactone (compound 8)], which were synthesized by us, against DNA polymerase (pol), DNA topoisomerase (topo), and human cancer cell growth. Among the compounds tested, compound 5 was revealed to be the strongest inhibitor of the animal pols and human topos tested, and the IC50 values for pols and topos were 2.3-15.8 and 5.0-7.5 microM, respectively. The compound also suppressed human cancer cell (promyelocytic leukemia cell line, HL-60) growth with the same tendency as the inhibition of pols and topos and the LD50 value was 9.4 microM. Compound 5 arrested the cells at G2/M and G1 phases, and prevented the incorporation of thymidine into the cells, indicating that it blocks DNA replication by inhibiting the activity of pols and topos. This compound also induced apoptosis of the cells. Based on these results, the action mode of compound 5 is discussed.

Convergent synthesis of pyragonicin.

This paper describes a second-generation synthesis of an antitumor tetrahydropyran (THP) acetogenin, pyragonicin. The key step involved an olefin cross-metathesis between the THP segment and the terminal gamma-lactone residue. The coupling reaction in the presence of Grubbs' second-generation catalyst resulted in an unseparable mixture of a desired coupling product and its one-carbon eliminated product while the use of Grubbs' first-generation catalyst afforded the former exclusively. A novel MOM-migrating reaction found in a cyclization reaction is also discussed.

Synthesis of ovalicin starting from D-mannose.

[reaction: see text] A new synthesis of epoxyketone 22 is described that is a key intermediate in Barton's synthesis of ovalicin (2), a powerful anti-angiogenetic inhibitor. The key process for the construction of 22 was ring-closing metathesis of olefins 11 and 12 obtained from 2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose (4) and regioselective desilylation of tri-TES ether 19. Furthermore, an alternative stereoselective route from 22 into 2 has also been developed, and the overall yield of 2 from 4 was 10.0%.

Total synthesis of (+)-batzelladine A and (-)-batzelladine D, and identification of their target protein.

Asymmetric total synthesis of batzelladine A (1) and batzelladine D (2) has been achieved. Our synthesis of batzelladines features 1) stereoselective construction of the cyclic guanidine system by means of successive 1,3-dipolar cycloaddition reaction and subsequent cyclization, 2) direct esterification of the bicyclic carboxylic acid 35 with the guanidine alcohol 8 or 59 to construct the whole carbon skeleton of batzelladines, and 3) one-step formation of the alpha,beta-unsaturated aldehyde 53 from the primary alcohol 47 with tetra-n-propylammoniumperruthenate (TPAP), providing an efficient route to the left-hand bicyclic guanidine alcohol of batzelladine A (1). With the synthetic compounds 1 and 2 in hand, their target protein was examined by using immobilized CD4 and gp120 affinity gels. The results indicated that batzelladines A (1) and D (2) bind specifically to CD4.

Total synthesis of the proposed structure for pyragonicin.

[structure: see text] The total synthesis of acetogenin 1 reported for pyragonicin and its 10-epimer 32 is described. The common THP ring system was stereoselectively constructed through a SmI(2)-induced reductive cyclization of beta-alkoxy acrylate 5 followed by Mitsunobu inversion, and each chiral center at C-10 was created by Brown's asymmetric allylation. Compound 1 had spectroscopic data consistent with that of natural pyragonicin, but a different optical rotation.

Total synthesis of brevetoxin-B.

Brevetoxin-B (BTX-B), produced by the red tide organism, Gymnodium breve Davis, is the first member of marine polycyclic ethers to be structurally elucidated and one of the most potent neurotoxins. The structural feature is a trans-fused polycyclic ether ring system with 23 stereocenters. Its unique, complex structure and potent biological activity have attracted the attention of synthetic organic chemists. Total synthesis of BTX-B has been accomplished via the coupling of the ABCDEFG and IJK-ring segments, each ether ring of which was stereoselectively and efficiently constructed on the basis of SmI2-induced intramolecular cyclization, 6-endo-cyclization of hydroxy epoxide, ring-closing olefin metathesis, and SmI2-induced intramolecular Reformatsky-type reaction. Several kinds of double reactions at the left and right sides were efficiently used through the synthesis.

Precise structural elucidation of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase alpha.

The X-ray crystal structure of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase alpha, has previously been reported. We show that dehydroaltenusin exists in an equilibrium mixture of two tautomers possessing gamma-lactone or delta-lactone in polar solvents by NMR experiments. Acetylation of dehydroaltenusin afforded two types of diacetates and two types of monoacetate, possessing gamma-lactone or delta-lactone, respectively. The inhibitory activities of these acetate derivatives against DNA polymerase alpha were all much weaker than that of dehydroaltenusin.

Synthetic studies on macroviracin A: a rapid construction of C(42) macrocyclic dilactone corresponding to the core.

The C(2)-symmetric macrodiolide core 2 of an antiviral agent, macroviracin A (1), was constructed in a single step by the intermolecular macrodimerization of C(22)-hydroxy carboxylic acid 3 with 2-chloro-1,3-dimethylimidazolinium chloride and DMAP in the presence of sodium hydride (NaH). The use of potassium hydride instead of NaH caused the intramolecular cyclization, predominantly providing the corresponding monomer 26. The acid 3 was synthesized through a series of reactions such as the coupling reaction of acetylene 5 and oxirane 6, stereoselective glycosidation with the trichloroacetimidate method, and Jones oxidation.

Pheromone gland-specific fatty-acyl reductase of the silkmoth, Bombyx mori.

The C10-C18 unsaturated, acyclic, aliphatic compounds that contain an oxygenated functional group (alcohol, aldehyde, or acetate ester) are a major class of sex pheromones produced by female moths. In the biosynthesis of these pheromone components, the key enzyme required to produce the oxygenated functional groups is fatty-acyl reductase (FAR). This enzyme converts fatty-acyl pheromone precursors to their corresponding alcohols, which, depending on the moth species, can then be acetylated or oxidized to the corresponding aldehydes. Despite the significant role this enzyme has in generating the species-specific oxygenated constituents of lepidopteran sex pheromones, the enzyme has yet to be fully characterized and identified. In experiments designed to characterize a pheromone-gland-specific FAR in the silkmoth, Bombyx mori, we have isolated a cDNA clone encoding a protein homologous to a FAR from the desert shrub, Simmondsia chinensis, commonly known as jojoba. The deduced amino acid sequence of this clone predicts a 460-aa protein with a consensus NAD(P)H binding motif within the amino terminus. Northern blot analysis indicated that 2-kb transcripts of this gene were specifically expressed in the pheromone gland at 1 day before adult eclosion. Functional expression of this gene in the yeast Saccharomyces cerevisiae not only confirmed the long-chain FAR activity, but also indicated a distinct substrate specificity. Finally, the transformed yeast cells evoked typical mating behavior in male moths when cultured with the pheromone precursor fatty acid, (E,Z)-10,12-hexadecadienoic acid.

Total synthesis of a cytotoxic acetogenin, pyranicin.

[structure: see text] The first total synthesis of a new cytotoxic acetogenin, pyranicin (1), is described. SmI(2)-induced reductive cyclization of beta-alkoxy acrylate 4 proceeded stereoselectively to give 16,20-syn-19,20-trans-THP derivative 14, which was efficiently transformed into the 19,20-cis-THP derivative 18 through Mitsunobu lactonization. Wittig reaction of the phosphonium salt 2 obtained therefrom with butenolide 3 at -78 degrees C followed by reduction and deprotection afforded 1 in good overall yield.