81703-94-8

A short synthesis of the natural potent cytotoxic agent (-)-muricatacin 1 and related unsaturated lactones from a versatile common intermediate, dienedioate 2, derived from d-mannitol or tartaric acid, is described. The strategy depends upon the desymmetrization of 7 by dihydroxylation and elaboration of the hydroxy alkyl sidechain. A route to unsaturated lactones is also described using a cis selective Wittig reaction. Since the enantiomers of 2 are available from the corresponding tartaric acids, this method provides access to both enantiomers of the described compounds and a wide range of derivatives.

In this report, the originally proposed rupestonic acid (5) and pechueloic acid (3) were efficiently synthesized. The chiral lactone 13, recycled from the degradation of saponin glycosides, was utilized to prepare the key chiral fragment 11. During the exploration of this convergent assembly strategy, the ring-closing metathesis (RCM), SmI2-prompted intermolecular addition, and [2,3]-Wittig rearrangement proved to be effective transformations for the synthesis of subunits.

Several macrocyclization reaction attempts of highly advanced precursors toward a total synthesis of marine diterpene bielschowskysin are disclosed. Biomimetic [2+2]-photocyclization reactions were applied to construct the cyclobutane core in these intermediates, which could be accessed along scalable high-yielding reaction sequences from cheap enantiopure starting-materials. Asymmetric syntheses of various highly functionalized intermediates toward the total synthesis of bielschowskysin (1) are described. In particular a biomimetic [2+2]-photocycloaddition reaction strategy, forming the cyclobutane core, was followed by various macrocyclization reactions attempts. Copyright

SN2′ sequences have been employed for the synthesis of β-branched α-amino acids using 1,2-diastereocontrol for forming C-C bonds. An oxazolidine fragment derived from Garner's aldehyde provides the handle for facial discrimination and acts as a

A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6-9) of phenolic ansamycins. Ansamycin natural products and selected structural analogues were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the heat shock protein 90 with enhanced binding activity (～25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (～100 nM).

A process for preparing an α,β-unsaturated ester of the compound (4), wherein R7 and R8 are the same or different and hydrogen atom, C1-6alkyl group or phenyl group, which comprises oxidizing a glycerol derivative (2), wherein R7 and R8 are the same as defined above, in the presence of a nitroxyl radical compound and a co-oxidant to prepare a glyceraldehyde and then reacting the compound with a phosphonoacetic acid alkyl ester or a (triphenylphosphoranylidene)acetic acid alkyl ester to give the compound (4).

A convenient synthesis of (3R,3aS,6aR)-3-hydroxyhexahydrofuro[2,3-b]furan, a high-affinity non-peptidal ligand for HIV protease inhibitor UIC-94017, is described. This inhibitor is undergoing advanced clinical trials. The synthesis utilizes a novel stereoselective photochemical 1,3-dioxolane addition to 5(S)-benzyloxymethyl-2(5H)-furanone as the key step. The requisite furanone derivative was prepared in high enantiomeric excess by an immobilized lipase-catalyzed selective acylation of (±)-1-(benzyloxy)-3-buten-2-ol and a ring-closing olefin metathesis with Grubbs' catalyst. Optically active bis-THF was converted to protease inhibitor 2 (UIC-94017).

Direct access to bicyclic precursors of octulosonic acids is achieved by treatment of differentially (or not) protected γ,δbis(silyloxy) cis-α,β-epoxy aldehydes with ethyl 2-(trimethylsilyloxy)-2-propenoate in the presence of boron trifluoride-diethyl ether. An X-ray crystallographic structure of a bicycle (compound 33a) was obtained and used to determine the absolute configurations of the different stereogenic centers and thus the diastereoselective preference of the aldol reaction (syn) and the regioselectivity of the epoxide ring-opening (C-6 atom). Functionalization and opening of the bicyclic compound to afford octulosonic analogues in their furanoside forms was studied. An octulosonic 8-phosphate analogue has been synthesized. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

(4S)-4,5-O-Isopropylidenepent-(2Z)-enoate (1) has been prepared on a multigram scale from 1,2: 5,6-di-O-isopropylidene-D-mannitol (4) in a one pot, two step sequence with improved selectivity (16:1 Z:E) and yield (71% Z) over previous literature procedures.

A concise, multigram synthesis of (4R)-2-[(1′R2′S)-1′, 2′-methano-3′-(/er/-butyldiphenylsiloxy)propyl]-4-hydroxymethyl-4, 5-dihydrothiazole has been achieved, and this compound has been used for the production of a range of analogues of the anti-mitotic a

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An asymmetric synthesis of the chiral β-lactone precursor of the HMG-CoA synthase, inhibitor L-659,699, is described, which involves as the key step an asymmetric [2,3]-Wittig rearrangement to control the stereogenic centers at the ring carbons (C2' and C

The synthetic studies on gymnodimine, a shellfish toxin, are described. This marine toxin consists of 16-membered carbocycle, tetrahydrofuran, and spiro-imine moieties. Our synthetic strategy involves the stereoselective allylation of tetrahydrofuran compound and the exo-selective intramolecular Diels-Alder reaction.

Oxidative ruthenium catalysis (0.07 molequiv RuCl3*(H2O)3, 1.5 molequiv NaIO4, EtOAc/CH3CN/H2O 3:3:1), beyond the usual C-C bond cleavage to give dicarbonyls, have been shown to syn-dihydroxylate a wide range of alkenes (except for strained bicyclic alkenes, sterically hindered trisubstituted alkenes, and most tetrasubstituted alkenes) to give vicinal diols rapidly (within minutes) and efficiently.The minor products are the usual oxidative fission products, namely, ketones and aldehydes or carboxylic acids, and sometimes ketols.Longer reaction times lower the yields of most diols, probably owing to oxidative glycol cleavage.Reactions with substrates containing one or more electron-withdrawing groups in conjugation with or adjacent to the alkene moiety are generally slower but give better yields.The diastereoselectivity of the present "flash" dihydroxylation, anti to the existing α-stereogenic center, with cycloalkenes is excellent whereas that with acyclic alkenes is moderate to poor.Sodium metaperiodate is still the best co-oxidant for the catalytic reaction.Aqueous acetonitrile (approximately 86percent) as an alternative solvent system was found to give better yields of 1,2-diols than the original solvent system in some cases. - Keywords: alkenes, catalysis, dihydroxylations, electrophilicity, ruthenium compounds.

Enantiomeric synthesis of cyclopropyl carbocyclic nucleosides has been accomplished. The key intermediates 7 and 9 were synthesized from D- glyceraldehyde acetonide 1, which was converted to the α,β-unsaturated ester 2 and then reduced to give allylic alcohol 3a. Stereoselective construction of the cyclopropyl ring of 3a and 3b followed by oxidation gave acid 5, which was treated under Curtius rearrangement conditions to obtain the urea intermediate 7. The urea intermediate was utilized to prepare uracil 14, thymine 15, and cytosine 18 nucleosides. The purine derivatives were prepared from cyclopropylamine 9 by condensation with 4,6-dichloro-5-form- amidopyrimidine or 4,6-dichloro-2-aminopyrimidine.

Reductive cleavage of various types of C-O and C-N bonds tethered to α,β-unsaturated esters and halomethyls was mediated with magnesium in methanol, which provided a facile method for the synthesis of δ-hydroxy or δ-amino β,γ-unsaturated esters and allylic alcohols.Regardless of the geometry (E or Z) of the α,β-unsaturated esters, 1a-b, 5a-c, 11, 13, and 23, the cleavage product obtained was exclusively the E isomer of the corresponding deconjugated hydroxy and amino esters.The steric bias and ring strain of 15, 17, and 21 gave rise to a product mixture of E and Z isomers.

Highly stereocontrolled synthesis of marine sesquiterpene upial was achieved from D-mannitol via fragmentation reaction of tricyclic compound 10 and samarium(II) iodide-induced cyclization of diformate 2.Key Words: total synthesis; marine sesquiterpene; u

Additions of various methylcopper reagents to the homochiral acylic vinyloxiranes A14, A15, B6-B9, and C5, C6 were performed in order to evaluate E/Z and syn/anti preferences.The unsubstituted oxiranes A14 and A15 gave a mixture of SN2 and SN2' substitution products with the four reagents examined, LiMe2Cu, LiMeCuCN, BrMgMe2Cu, and LiMeCuI*BF3.The more highly substituted systems B6-B9 derived from geraniol and C5, C6 derived from nerol yielded only SN2' products.The (Z)-allylic alcohol derivatives B8 and C6 and LiMeCuCN gave the best anti/syn ratios (99:1 and 97:3, respectively).In both cases the newly formed double bond was exclusively E.

Very efficient enantioselective syntheses of (1R)-trans-and cis-hemicaronaldehydes precursors of (1R)-trans chrysanthemic acid and its (1R)-cis dibromovinyl analogue starting from natural tartaric acid or D-mannitol are described.They are based on the rea

In-situ-generated phthalimidonitrene was added to five α,β-unsaturated esters containing a chiral secondary O-function at C(γ).The additions were fully suprafacial, inasmuch as the (E)-isomers 1 afforded only the trans-aziridines 2 and 3 (J(β,γ)=4.8-5.1 Hz) and the (Z)-isomers 4 only the cis-aziridines 5 and 6 (8.2-8.5 Hz).The products 2, 3, 5, and 6 where shown to possess the arabino-, xylo-, ribo-, and lyxo-configuration, respectively, by X-ray structure analysis of 2b, 2d, and 6a.The diastereoface selectivity of the nitrene addition, induced by the chiral substructure around C(γ), resulted in more 2 than 3 from 1, but more 6 than 5 from 4, which means that the preference of attack at the double bond switches from one side to the other depending on the C=C configuration.The preferences were higher at lower temperature.The aziridines 2a, 2d, and 3d exhibit 1H-NMR-visible isomerism at the ring N-atom; the major (78-95percent) invertomer A is always the one with the phthalimido group in trans-position to the (larger) substructure around C(γ).The other aziridines only show 1H-NMR signals of one invertomer, which - by steric reasoning - ought to be A; this is confirmed by a 1H-NMR argument for 3a, 5a, 6a, 5c, and 6c.

The 1,3-dipolar cycloaddition of the azomethine ylide (2) with homochiral cyclic dipolarophiles proceeds with high facial selectivity, whereas for homochiral acyclic dipolarophiles, the ?-facial selectivity and mode of cycloaddition is dependent on the structure of the dipolarophile.

The δ-alkoxyallylstannanes (4) and (5) react stereoselectively on heating with p-nitrobenzaldehyde to provide the homoallylic alcohols (14) - (17), with (14) : (15) = 82 : 18; (16) : (17) = 73 : 27

(S)-5-Hydroxy-2-penten-4-olide (5) was synthesized in three steps starting from D-mannitol bis(acetonide) (1), via D-glyceraldehyde acetonide (2) by Z-selective Wittig reaction, acid-catalyzed lactonization and crystallization with a total yield of 40percent.

Both (R) - and (S)-1,2-isopropylideneglyceraldehydes (1) and (18) are shown to be useful, inexspensive chiral starting materials for syntheses of α-methylene-γ-butyrolactones (15) and (28) which are potential intermediates for biologically important sesquiterpene lactones.

(R)-N-Benzyl-4--2-azetidinone (10) and (S)-4--2-azetidinone (17) were enantioselectively synthesized from the benzylamino ester 3, which was prepared by the highly stereoselective 1,4-addition of benzylami

1,2-Isopropylidene D-glyceraldehyde (3) is shown to be a useful and inexpensive chiral starting material for a synthesis of γ-butyrolactones (8), (10) and (12) which are potential intermediates for secologanin and sesquiterpene lactones.