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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.

Sodium monobenzoxyborohydride, which is easily prepared from sodium borohydride and benzoic acid in THF in situ, is treated with α-picoline in THF under mild conditions to give α-picoline–borane in an excellent yield. This method can be a practical preparation for α-picoline–borane.

The formal total synthesis of aspergillide A 1 is described. The cross-metathesis of enone 6 with 6-hepten-2-ol derivative 5 provided E-olefin 15 corresponding to the C4–C14 backbone of 1. The CBS asymmetric reduction of 15 gave allyl alcohol 16, which was transformed into β-alkoxyacrylate 4 which had a formyl group. SmI2-induced reductive cyclization of 4 gave a 2,6-syn-2,3-trans THP derivative 3 in good yield. After methoxymethylation of 3, the resulting compound 19 was submitted to desilylation and hydrolysis, to afford Fuwa’s key intermediate 2 for the total synthesis of 1.

SmI 2 -induced reaction of ( E )- and (Z)-β-alkoxyvinyl sulfones onto an aldehyde function afforded 2,6- syn -2,3- trans - and 2,6- syn -2,3- cis -tetrahydropyran-3-ols, respectively, via stereoselective cyclization. This reaction was applied to the synthesis of 2-methyl-tetrahydropyran, corresponding to the N-ring of gymnocin-A, and 2- exo -methylene-tetrahydropyran, a key intermediate for convergent synthesis of polycyclic ethers based on the Suzuki–Miyaura reaction.

A convenient method for N-protection of amino acid derivatives with a benzyl group by reductive alkylation of amino acid derivatives with α-picoline-borane is described. Amino acid esters or amino alcohols were treated with aryl aldehydes in methanol/acetic­ acid in the presence of α-picoline-borane to give N-benzyl-protected amino acid derivatives in good yields.

SmI 2 -induced reaction of ( E )-β-alkoxyvinyl ( R )- and ( S )-sulfoxides with aldehydes effected a highly stereoselective intramolecular cyclization to give 2,6- anti -2,3- cis - and 2,6- syn -2,3- trans -tetrahydropyran-3-ols, respectively. The reaction of ( Z )-( R )-isomer gave 2,6- syn -2,3- cis -tetrahydropyran-3-ol and a ring-opened product, and that of ( Z )-( S )-isomer yielded many products.

Total synthesis of theopederin B, isolated from marine sponge, was accomplished by coupling pederic acid, as the left half, with trioxodecaline amine as the right half. Key reactions for synthesizing the amine were SmI 2 -promoted Reformatsky reaction, stereoselective allylation followed by Sharpless asymmetric epoxidation for construction of the functionalized side chain, and 1,3-dioxane ring construction followed by azide insertion.

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.

Stereoselective synthesis of (−)-centrolobine, an anti-Leishmania agent, was accomplished via an intramolecular Barbier-type reaction of iodo-ester with n- or t-butyllithium followed by Lewis acid-promoted Et3SiH reduction of the resulting hemiacetal.

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.

The 13C-labelled putative erythromycin biosynthetic intermediates, ((2S,3S,4S,5R,6R,7R)-3,6,7-trihydroxy-2,4,6-trimethyl[1-13C]nonan-5-olide and S-2-acetylaminoethyl (2R,3S,4S,5R,6S,7R)-3,5,6,7-tetrahydroxy-2,4,6-trimethyl[1-13C]nonanethioate), which would be useful for the investigation of the chain elongation mechanism in erythromycin biosynthesis, were efficiently synthesized via aldol condensation of aldehyde derived from (2S,3R,4R,5R)-tert-butyldimethylsilyloxy-5-3,4-O-isopropylidene-2,4-dimethylheptanol, which was obtained in our previous work on erythromycin A synthesis, and sodium [1-13C]propionate (after conversion to ester). Copyright © 2008 John Wiley & Sons, Ltd.

Marine polycyclic ethers exemplified by brevetoxin B, a red tide toxin, have a unique trans-fused polycyclic ether ring system. Their synthetically challenging complex structures and potent bioactivities have attracted the attention of numerous synthetic organic chemists. We have already developed several efficient methods for synthesis of cyclic ethers based on the SmI2-induced reductive cyclization of β-alkoxyacrylate, β-alkoxyvinyl sulfone, and β-alkoxyvinyl sulfoxide with high stereoselectivity. Iterative and two-directional strategies for the construction of polycyclic ethers were developed based on the above methods. Several convergent strategies for the synthesis of polycyclic ethers were also developed based on acetylide-triflate coupling, acetylide-aldehyde coupling, or intramolecular Barbier reaction, respectively. Total syntheses of brevetoxin B, mucocin, and pyragonicin were accomplished as application of the developed methods.

An efficient 13C-labelling synthesis of the putative erythromycin biosynthetic intermediate, S-2-acetylaminoethyl (2R,3R,4R,5R)-3,5-diacetoxy-2,4-dimethyl-4-([13C]methoxy)heptanethioate, which would be useful for the investigation of the chain elongation mechanism in erythromycin biosynthesis, was achieved by utilizing iodo[13C]methane and (2S,3R,4R,5R)-4-hydroxy-3,5-O-isopropylidene-2,4-dimethylheptanol, obtained in our previous studies on erythromycin A synthesis. Copyright © 2008 John Wiley & Sons, Ltd.

SmI2-induced reductive cyclization of optically active (E)- and (Z)-β-alkoxyvinyl sulfoxides with aldehyde was developed for the construction of several stereoisomers of tetrahydropyran derivatives.

SmI 2 -induced reductive cyclization of ( E )- and ( Z )-β-alkoxyvinyl sulfones with aldehyde stereoselectively afforded 2,6- syn -2,3- trans - and 2,6- syn -2,3- cis -tetrahydropyrans, respectively. The product having a sulfonylmethyl group was converted to a cyclic ether having a methyl group by reduction with Raney-Ni.

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.

[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%.

A new function that effectively takes into account ring structural environments achieves extensive highly accurate prediction of 13C NMR chemical shift in the CAST/CNMR system. The approach adapts a fast and flexible ring perception algorithm and a new CAST coding method for the ring information. 13C NMR chemical shift prediction is performed for complicated polycyclic natural products and their synthetic intermediates as the demonstration, which shows the reliability of the function in extending the scope of the practically accurate 13C NMR prediction for wide range of organic compounds.

A novel approach to natural β-hydroxy-γ-lactone 2 from 2,5-anhydro- d -mannitol ( 1 ) is described. The key reactions in this synthesis include stereoselective methylation of aldehyde 3 with lithium dimethylcuprate, an intramolecular radical cyclization of seleno carbonate 11 and an intermolecular cross-metathesis of 3-allyl-4-hydroxy-γ-lactone 16 with 1-tridecene.

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.

First total synthesis of dehydroaltenusin, a natural enzyme inhibitor, is described. The key step involves Suzuki-couplig reaction of aryl triflate prepared from 2,4,6-trihydroxy benzoic acid with a catechol-derived boronic acid. The synthetic sample was evaluated as a potent inhibitor against an eukaryotic DNA polymerase α.

Accurate, practical prediction of 13 C NMR chemical shifts has been achieved with a new system, CAST/CNMR, taking account of stereochemistry. The CAST/CNMR system has solved the critical problem of the accurate distinction of differences and similarities in stereochemical structures around a specific carbon, which has not yet been achieved by any other database-oriented system for prediction of 13 C NMR chemical shifts. CAST/CNMR uses a three-dimensional structural database together with a 13 C NMR spectral database. Absolute/relative configurational and conformational structural information are described by the CAST (CAnonical-representation of STereochemistry) coding method. This paper provides an overview of the CAST/CNMR system, and describes its application to two natural products as examples.

The 6,6-spiroacetal segment of spirofungin A, an antifungal antibiotic isolated from Streptomyces violaceusniger Tu 4113, was efficiently prepared via the coupling reaction of the Weinreb amide and the alkyne which are readily available from the common intermediate. The synthesis includes the unsymmetrization through a stereoinversion at the C11 position and the transacetalization as the key steps.

An antitumor acetogenin, muconin, was synthesized through a coupling reaction of a THF–THP segment and a terminal butenolide. The key reactions include successive ether-ring formation reaction under acidic and basic conditions or one-pot double cyclization promoted by TBAF and stereoselective reduction of acyclic ketones adjacent to the 2,6-cis THP with Zn(BH4)2.

The pentacyclic guanidine compounds 4 and 5 were stereoselectively synthesized as novel ptilomycalin A and crambescidin analogs. The synthetic method involves successive 1,3-dipolar cycloaddition reactions which effectively access the key intermediates, trans- and cis-2,5-disubstituted pyrrolidine 8 having hydroxyl groups at the p-positions on their side chains. Among the analogs synthesized, 4b and 5b exhibited significant inhibitory activity against Ca 2 + -ATPase.

Various derivatives of reveromycin A, a novel inhibitor of eukaryotic cell growth, were prepared and their inhibitory effects on both isoleucyl-tRNA synthetase activity and in vitro protein synthesis, and activities on the morphological reversion of src(ts)-NRK cells were assayed. The C5 hydroxyl group and C24 carboxyl group are particularly important for these activities.

An antitumor acetogenin, muconin, was synthesized through a coupling reaction of a THF–THP segment and a terminal butenolide. The key reactions include 6- exo cyclization of an epoxy tetraol, regioselective cyclization of hydroxy tosylate, and stereoselective reduction of an acyclic ketone adjacent to the 2,6- cis THP ring with Zn(BH 4 ) 2 .

A simple and efficient synthesis of (+)-benzoylpedamide, the right half of pederin, was achieved in 16 steps with a 35% overall yield from (S)-malic acid. The key steps include the SmI2-mediated intramolecular Reformatsky reaction, stereoselective allylation, the Sharpless asymmetric dihydroxylation, and amidation. The total synthesis of pederin was accomplished via coupling of the left and right halves.

A highly efficient strategy for the iterative synthesis of a trans -fused polycyclic ether ring system has been developed. The new iterative method involves SmI 2 -induced reductive intramolecular cyclization of an aldehyde and a β-alkoxy acrylate as the key step, producing a 2,3- trans -tetrahydropyran or oxepane ring. The syntheses of trans -fused 6,6,6-tricyclic, 6,7,6-tricyclic, and 6,7,7,6-tetracyclic ethers were effectively achieved based on the newly developed method.

Accurate recognition of differences and similarities in stereochemical structures is achieved by extended CAST (CAnonical-representation of STereochemistry) coding method. Using the CAST notations, complete search of partial structures as well as whole structures by matching with the query in any level from a specific atom considering planar, configurational, and conformational information has been achieved. Differences and similarities of stereochemistry in four aldopentoses of D-xylose, D-ribose, D-arabinose, and D-lyxose, which have three chiral centers, are clearly represented by the extended CAST. Applications for some organic compounds containing more complicated stereochemical structures are also demonstrated.

Symmetrical pentacyclic guanidines 1a–c and 2 which contain the core skeleton of 13,14,15-isocrmbescidine 800, have been synthesized. In the presence of catalytic amounts of these guanidines 1, the reaction rate of the conjugate addition of pyrrolidine (9) to γ-crotonolactone (10) could be enhanced depending upon the size of the cavities and substituents on tetrahydropyran rings of 1 and 2.

An efficient method for cross-coupling using phthalate-tethered ring-closing metathesis was developed. Based on this method, the stereocontrolled syntheses of both (R,R)- and (S,R)-1-methoxypentadecane-2,9-diol ( 17 , 20 ) were achieved from (R)-1-undecen-5-ol ( 4e ) and (R)-1-methoxy-5-hexen-2-ol ( 13 ).

[structure: see text]. The stereoselective syntheses of the C'D'E'F'-ring system of maitotoxin and the FG-ring system of gambierol were accomplished. The key steps involve 6-endo-cyclization of methylepoxide, SmI2-induced reductive cyclization, 6-endo-cyclization of vinylepoxide, and formation of the lactone ring.

The stereoselective synthetic methods for anti - and syn -fused tricyclic guanidine compounds 4a and 4b were developed based on a successive 1,3-dipolar cycloaddition. Through these synthetic studies, the stereochemistry of the left-hand tricyclic guanidine unit of batzelladine F ( 3 ) was confirmed as a syn -fused one, which is identical with the structure reported by the Murphy and Snider groups.

The EFG-ring system of brevetoxin-B, having an α-methyl group on the D-ring, was stereoselectively synthesized based on the stereoselective Michael addition of the α-methyl group, novel ring-expansion reaction, and 6-endo-cyclizations of the vinylepoxide and methylepoxide.

The classification and prediction of the roles for reagents in reactions are presented. The same dimensional representation of various reagents independent of the number of atoms was achieved by selecting representative factors by the FRAU (Field-characterization for Reaction Analysis and Understanding) system. Training of a self-organizing model considering both negative and absent data was accomplished by modifying the original counter-propagation (CP) type of Kohonen neural network to treat absent data differently from negative data. The modified CP Kohonen neural network successfully classified the reagents and produced a reagent-roles correlation model that gives good answers predicting roles of the reagents.

The stereoselective total synthesis of reveromycin A (1), a potent inhibitor of eukaryotic cell growth, has been accomplished on the basis of the stereocontrolled construction of the 6,6-spiroketal system, efficient succinylation of the tert-alcohol under high pressure, and the introduction of the unsaturated side chains.

An l-lactate dehydrogenase that requires coenzyme NADH catalyzes the enantioselective reduction of pyruvate to l-lactate in anaerobic glycolysis. As the first homochiral ansa-type NADH models, we designed the bridged NADH models 10a−c having a parapyridinophane structure for strictly mimicking the stereospecificity of hydrogen transfer in the biological asymmetric reduction with NADH. These models were synthesized in several steps from the corresponding bridged nicotinate 5 prepared by our novel pyridine-formation reaction of formyl-substituted (vinylimino)phosphorane 4 with methyl propiolate. The bridged NADH models 10a−c effected excellent biomimetic reduction at various temperatures in the presence of magnesium ion to achieve both the enantioselective and stereospecific reduction of the pyruvate analogues 12u−z into chiral lactate analogues 13u−z with 88−99% ee. The high enantioselectivity was almost completely dependent on the planar chirality of 10a−c but not on the nature of the substituents of thei...

A very efficient convergent strategy for the construction of the trans -fused 6-6-6-6-membered tetracyclic ether ring system was developed based on the acetylide-triflate coupling of two tetrahydropyrans, oxidation of the alkyne group to an α-diketone, double cyclization to 6,6,6,6-membered tetracyclic diacetal, and stereoselective reduction of the diacetal with Et 3 SiH–TMSOTf.

MePdCl[3-methyl-5-(2-pyridinyl)pyrazole] (1 and 2), PdCl2[3-methyl-5-(2-pyridinyl)pyrazole] (3), and bis{MePd[3-methyl-5-(2-pyridinyl)pyrazole]} (4) were synthesized, and structural assignment was performed by 1H-, 13C-, 15N-NMR spectroscopy. By comparison of their 15N-NMR spectra, the relationship between bond strength of the palladiumnitrogen bond and chemical shift was analyzed. X-ray diffraction analysis of 4 was also achieved.