Asymmetric Dihydroxylation of Alkenes

OHSHIBA Y., YOSHIMITSU T., OGASAWARA K.

A practical route to all possible stereoisomers of the muscarine alkaloids in optically pure forms has been developed starting from a readily accessible chiral starting material.

TSURUOKA A., KAKU Y., KAKINUMA H., TSUKADA I., YANAGISAWA M., NAITO T.

A new series of thiazole-containing triazole antifungals was synthesized and evaluated for antifungal activity against a variety of clinically isolated pathogenic fungi in vitro and against systemic candidosis in vivo. Among these compounds, (+/-)-1-(2,4-difluorophenyl)-1-[4-(2,4-difluorophenyl) thiazol-2-yl]-2-(1H-1,2,4-triazol-1-yl)ethanol (ER24161) showed the most potent and well-balanced in vitro activities and excellent in vivo efficacy. We also achieved an enantioselective synthesis of the more potent enantiomer of ER-24161.

MURATAKE H., TONEGAWA M., NATSUME M.

Formal syntheses of (±)-duocarmycin SA, natural (+)-duocarmycin SA and unnatural (-)-duocarmycin SA were accomplished by way of a tricyclic heteroaromatic compound 10b. For the preparation of 10, an N-oxide route aiming at a process 20 in Chart 3 was first investigated by synthesizing 19, derived from Stille coupling products 13 between bromopyrrole 7a and 3-(tributylstannyl)pyridines 12, but without success. As the second approach, Stille coupling products 9a-c were prepared by condensation between 7a and 2-substituted 3-(trialkylstannyl)pyridines 8a-f. Both 9b and 35, derived from 9c, were converted to their silyl enol ethers and then subjected to a palladium-catalyzed methyl ketone-arylation reaction in the presence of tributyltin fluoride and lithium chloride, affording 10a and 10b in excellent yields, especially from 35. Application to 10b of three successive operations, i.e., i) partial reduction of 10b to dihydropyridine derivatives 11a and 11b, ii) dihydroxylation of the double bonds formed to give 58 and 59, and iii) reductive elimination of the hydroxy groups adjacent to the nitrogen function and the aromatic ring, afforded 6 in fairly good yield. Compound 6 was readily converted to relay compounds 64 and 67, completing total syntheses of (±)-, (+)-, and (-)-duocarmycin SA. Both Sharpless asymmetric dihydroxylation (AD) and Jacobsen's asymmetric epoxidation were applied to 11a and 11b. At the best, 81% ee was observed in the AD reaction of 11a using 2, 5-diphenyl-4, 6-bis(9-O-dihydroquinyl)pyrimidine [(DHQ)2PYR], but the resulting 58 possessed an unnatural absolute configuration.

TOMIOKA K., SHINMI Y., SHIINA K., NAKAJIMA M., KOGA K.

Enantioselective dihydroxylation of E-stilbene afforded (1S, 2S)-1, 2-diphenyl-1, 2-ethanediol in 70% ee by employing a stoichiometric amount of osmium tetroxide-chiral amine 5, prepared from N-methylephedrine and 2-bromopyridine.

ISHIYAMA H., ISHIBASHI M., KOBAYASHI J.

A diastereomer of the C-1-C-9 fragment of amphidinolide C, a potent cytotoxic 25-membered macrolide isolated from a marine dinoflagellate, Amphidinium sp., has been synthesized to provide an authentic sample for use in studies on the degradation of amphidinolide C.

MATSUSHIMA T., MORI M., NAKAJIMA N., MAEDA H., UENISHI J., YONEMITSU O.

The C1-C7 fragment (4) of tedanolide (1) was synthesized starting from methyl (R)-3-hydroxy-2-methyl-propionate via a mismatched but highly efficient Sharpless dihydroxylation of the C1-C7 α, β-unsaturated ester (6) with AD-mix-α.

MATSUSHIMA T., MORI M., ZHENG B., MAEDA H., NAKAJIMA N., UENISHI J., YONEMITSU O.

The C1-C12 part (4) of tedanolide (1) was synthesized starting from methyl (R)-3-hydroxy-2-methylpropionate (11a) via a coupling between the C1-C7 aldehyde (6) and the C8-C11 iodoalkene (7a). For a synthesis of 6, a mismatched but highly efficient Sharpless dihydroxylation of the alpha, beta-unsaturated ester (15) with AD-mix-alpha was successfully applied. Compound 7a was synthesized using hydrozirconation to the alkyne (32).

van Maarseveen J.H., Oberyé E.H., Bolster M.B., Scheeren H.W., Kruse C.G.

Fensholdt J., Wengel J., Dahl O., Hvistendahl G., Leskelä M., Polamo M., Homsi M.N., Kuske F.K., Haugg M., Trabesinger-Rüf N., Weinhold E.G.

Novel 5'-C-hydroxymethyl substituted derivatives of thymidine have been prepared by dihydroxylation of the 5'C-methylene nucleoside 1. Osmium tetraoxide catalysed dihydroxylation of 1 afforded a 3:2 epimeric mixture of diols 2, whereas asymmetric dihydroxylation using AD-mix-alpha and AD-mix-beta resulted in mixtures 3 and 4 of the two epimeric diols, both enriched with the same diastereomer. Nucleosides 2 were transformed into phosphoramidites 8 which were used for solid phase synthesis of oligodeoxynucleotides (ODNs) containing 5'-C-(hydroxymethyl) functionalised thymidine monomers. This novel class of C-hydroxymethyl modified ODN-analogues exhibited promising affinity towards both complementary DNA and RNA as well as resistance towards 3'-exonucleolytic degradation.

Nymann K., Jensen L., Svendsen J.S., Anthonsen T., Gawinecki R., Häfelinger G., Homsi M.N., Kuske F.K., Haugg M., Trabesinger-Rüf N., Weinhold E.G.

Tanner D., Harden A., Johansson F., Wyatt P., Andersson P.G., Zhang S.Y., Zhao S.H., Ciglic M.I., Haugg M., Trabesinger-Rüf N., Weinhold E.G.

The chiral bis(aziridines) 4, 6 and 7 have been synthesized and evaluated as chelating ligands for a variety of asymmetric transformations mediated by metals. The processes studied were the asymmetric addition of osmium tetroxide to olefins, copper-catal

Bodas M.S., Kumar P.

A concise enantioselective synthesis of (2S,3S)-3-hydroxypipecolic acid 1 starting from 1,4-butanediol using Sharpless asymmetric dihydroxylation and the regioselective nucleophilic opening of a cyclic sulfate as the key steps is described.

McNamara C.A., King F., Bradley M.

Sharpless asymmetric dihydroxylation ligands were synthesized using a triazine spacer group in two, high yielding steps from cheap, readily available starting materials. The ligands, gave good enantioselectivities in the asymmetric dihydroxylation of alkenes and may provide a very economic alternative to current systems.

Sayyed I.A., Sudalai A.

A simple and effective procedure for the enantioselective synthesis of two important neurotransmitter drugs, that is, (S)-3,4-dihydroxyphenylalanine ( l -DOPA) and (R)-N,α-dimethyl-N-2-propynylbenzeneethaneamine [(R)-selegiline], is described by employing the Sharpless asymmetric dihydroxylation (AD) as a key step to introduce chirality.

DeClue M.S., Siegel J.S.

Polysiloxane acts as a modular scaffold for macromolecular reagent development. Two separate components were covalently integrated into one material, one constituent provided reagent functionality, the other modulated solubility. In particular cinchona alkaloid based ligands used in the osmium tetroxide catalyzed asymmetric dihydroxylation (AD) reaction were covalently attached to commercially available polysiloxane. To enhance the reactivity of these polymeric ligands, multifunctional reagents were designed to include both the cinchona alkaloid and an alkoxyethylester solubilizing moiety providing random co-polymers. While the mono-functional materials led to heterogeneous conditions, the bi-functional polymers resulted in homogeneous reaction mixtures. Although both reagent types provided diol products with excellent yield and selectivity (>99% ee in nearly quantitative yield) the homogeneous analog has nearly twice the reactivity. Every repeat unit in the heterogeneous material was functionalized along the polysiloxane backbone while approximately half of these sites contained ligand in the homogeneous version. This approach led to macromolecular catalysts with high loadings of ligand and therefore materials with very low equivalent weights. Although these polymers are highly loaded they do maintain reactivity on a par with their free ligand counterpart. Using straightforward purification techniques (i.e. precipitation, simple filtration, or ultrafiltration) these polymeric ligands were easily separated from diol product and reused multiple times. Polysiloxane is a viable support for the catalysis of AD reactions and may provide a generally useful backbone for other catalytic systems.

Baldassarre S.M., Sato H.S., Louise A.P., Summer L.L., Wilson B.P., Hemric B.N.

Chen J., Zhang J., Sun Y., Xu Y., Yang Y., Lee Y., Ji W., Wang B., Nam W., Wang B.

Dixon G.J., Rodriguez M.R., Chong T.G., Kim K.Y., Downey C.W.

In the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine, α,α-disubstituted aldehydes condense with electron-rich aromatic aldehydes to yield β,β-disubstituted styrenes. More electron-rich aromatic aldehydes react more rapidly and in higher yield. Preliminary results suggest that the reaction may proceed via the ionization and formal deformylation of an aldol intermediate.

Makai S., Falk E., Morandi B.

Unprotected, primary 2-azidoamines are versatile precursors to vicinal diamines, which are among the most common motifs in biologically active compounds. Herein, we report their operationally simpl...

Wu B., Zhang S., Hong T., Zhou Y., Wang H., Shi M., Yang H., Tian X., Guo J., Bian J., Roache J., Delgado P., Mo R., Fridrich C., Gao F., et. al.

The scalable synthesis of an FXI (Factor XI) inhibitor employing multiple emerging technologies is described. The reduction of ketone to chiral alcohol was established through a biocatalysis approa...

Jin S., Sun S., Yu J., Cheng J.

The silver-promoted phosphonation/alkynylation of vinyl in α-aryl α-alkynyl allylic alcohols with phosphine oxide was developed, affording a series of α-alkynyl γ-ketophosphine oxides in moderate to good yields. This procedure involved the radical 3-exo-dig cyclization, proceeding with the radical 1,2-alkynyl migration rather than the aryl migration.

Michalak S.E., Nam S., Kwon D.M., Horne D.A., Vanderwal C.D.

Haterumaimide J (hatJ) is reportedly the most cytotoxic member of the lissoclimide family of labdane diterpenoids. The unusual functional group arrangement of hatJ-C18 oxygenation and C2 chlorination-resisted our efforts at synthesis until we adopted an approach based on rarely studied terminal epoxide-based cation-π bicyclizations that is described herein. Using the C2-chlorine atom as a key stereocontrol element and a furan as a nucleophilic terminator, the key structural features of hatJ were rapidly constructed. The 18-step stereoselective synthesis features applications of chiral pool starting materials, and catalyst-, substrate-, and auxiliary-based stereocontrol. Access to hatJ and its acetylated congener hatK permitted their biological evaluation against aggressive human cancer cell lines.

Qin T., Li J., Xie M., Qu G., Guo H.

An efficient method to construct chiral acyclic nucleosides via Sharpless asymmetric dihydroxylation of N-allylpyrimidines or N-alkenylpurines is reported. A range of chiral acyclic nucleosides with two adjacent hydroxyl groups present on the side chains could be produced in good yields (up to 97% yield) and excellent enantioselectivities (90-99% ee). The synthetic utility of the reaction was demonstrated by the catalytic asymmetric synthesis of ( S)-Cidofovir and ( R)-Buciclovir.

Hao B., Gunaratna M.J., Zhang M., Weerasekara S., Seiwald S.N., Nguyen V.T., Meier A., Hua D.H.

A new class of poly-N-vinylpyrrolidinones containing an asymmetric center at C5 of the pyrrolidinone ring were synthesized from l-amino acids. The polymers, particularly 17, were used to stabilize nanoclusters such as Pd/Au for the catalytic asymmetric oxidations of 1,3- and 1,2-cycloalkanediols and alkenes, and Cu/Au was used for C-H oxidation of cycloalkanes. It was found that the bulkier the C5 substituent in the pyrrolidinone ring, the greater the optical yields produced. Both oxidative kinetic resolution of (±)-1,3- and 1,2-trans-cycloalkanediols and desymmetrization of meso cis-diols took place with 0.15 mol % Pd/Au (3:1)-17 under oxygen atmosphere in water to give excellent chemical and optical yields of (S)-hydroxy ketones. Various alkenes were oxidized with 0.5 mol % Pd/Au (3:1)-17 under 30 psi of oxygen in water to give the dihydroxylated products in >93% ee. Oxidation of (R)-limonene at 25 °C occurred at the C-1,2-cyclic alkene function yielding (1S,2R,4R)-dihydroxylimonene 49 in 92% yield. Importantly, cycloalkanes were oxidized with 1 mol % Cu/Au (3:1)-17 and 30% H2O2 in acetonitrile to afford chiral ketones in very good to excellent chemical and optical yields. Alkene function was not oxidized under the reaction conditions. Mechanisms were proposed for the oxidation reactions, and observed stereo- and regio-chemistry were summarized.

Corey E.J., Kürti L.

Morris C.L., Hu Y., Head G.D., Brown L.J., Whittingham W.G., Brown R.C.

Trienes and dienynes containing one electron-deficient double bond were shown to undergo regio- and stereoselective oxidative cyclization in the presence of permanganate ion to afford 2,5-bis-hydroxyalkyltetrahydrofurans (THF diols). The THF diols produced retained either alkene or alkyne functionalities, which provided convenient handles for the metal oxo-mediated introduction of an adjacent THF ring with overall control of relative and absolute stereochemistry. Adjacent bis-THFs possessing threo-cis-threo-trans-erythro, threo-cis-threo-trans-threo, threo-cis-threo-cis-erythro, threo-cis-erythro-cis-threo, or threo-cis-erythro-trans-threo relationships were synthesized by appropriate selection of alkene geometry and methodology for the closure of the second ring. The threo-cis-threo-cis-erythro stereochemical arrangement is embodied within the bis-THF core units of a number of Annonaceous acetogenins including membrarollin, while trilobacin has a threo-cis-erythro-trans-threo configured core. As an application of the selective oxidative cyclization approach, a total synthesis of membrarollin was completed in 17 linear steps from dodecyne. The C21,C22 double epimer of membrarollin was also synthesized in 15 linear steps and without recourse to the use of hydroxyl group protection.

West R., Wang Y., Atkinson J.

The study of the dynamic and structural role of lipids in membranes is commonly accomplished using 2H NMR and neutron diffraction. This necessarily requires the availability of specifically deuterated lipids. Our interest in the behaviour of tocopherols and tocotrienols in phospholipid membranes has shown that the tocotrienols, unsaturated forms of vitamin E, have very different effects on membrane properties as judged by differential scanning calorimetry (DSC). We report here the preparation of deuterated forms of α-, β-, and γ-tocotrienols where the terminal methyl groups on the isoprenoid side chains have been replaced with trideuteromethyl groups, thus incorporating six deuterium atoms per molecule. Starting from the naturally occurring tocotrienols, the terminal alkene can be selectively hydrobrominated with NBS, transformed to a diol and oxidatively cleaved to give a chain truncated aldehyde. The full chain length is then restored by reaction with the ylide formed by deprotonation of triphenyl-(1,2,2,2-tetradeutero-1-trideuteromethyl-ethyl)-phosphonium bromide. Copyright © 2008 John Wiley & Sons, Ltd.

Noe M.C., Letavic M.A., Snow S.L.