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New resveratrol (trans-3,4',5-trihydroxystilbene) analogs were synthesized and screened for their in vitro cancer chemopreventive potential using various bioassays relevant for the prevention of carcinogenesis in humans: two assays to detect modulators of carcinogen metabolism (Cyp1A inhibition; determination of NAD(P)H/quinone reductase (QR) activity), three assays to identify radical scavenging and antioxidant properties (DPPH, ORAC, superoxide anion radicals in differentiated HL-60 cells), four assays to determine anti-inflammatory and anti-hormonal effects (iNOS, Cox-1 and aromatase inhibition, anti-estrogenic potential). 3,4',5-Tri-O-methyl resveratrol 1a was about sevenfold more active than resveratrol in inhibiting Cyp1A activity, it was a potent inducer of QR activity, and it showed pure anti-estrogenic activity (whereas resveratrol is a known mixed estrogen (ant)agonist with both estrogenic and anti-estrogenic properties). Dual estrogen ant-/agonist activity was restored in the mono-O-benzyl-substituted derivatives 4b (4'-O-benzyl resveratrol) and 5b (3-O-benzyl resveratrol). With respect to aromatase inhibition (Cyp19), which provided the highest number of actives, the benzyl-substituted series was more potent than the methyl-substituted derivatives of resveratrol, and 3-O-benzyl resveratrol 5b was about eightfold more active than resveratrol. Overall, 3,4',5-tri-O-pivaloyl resveratrol oxide 7c was identified as a potent inducer of phase 2 enzymes concomitant with inhibition of LPS-mediated iNOS induction.

Several synthetic combretastatin A4 (CA-4) derivatives were recently prepared to increase the drug efficacy and stability of the natural product isolated from the South African tree Combretum caffrum. A group of ten 3-amino-2-azetidinone derivatives, as combretastatin A4 analogues, was selected through docking experiments, synthesized and tested for their anti-proliferative activity against the colon cancer SW48 cell line. These molecules, through the formation of amide bonds in position 3, allow the synthesis of various derivatives that can modulate the activity with great resistance to hydrolytic conditions. The cyclization to obtain the 3-aminoazetidinone ring is highly diastereoselective and provides a trans biologically active isomer under mild reaction conditions with better yields than the 3-hydroxy-2-azetidinone synthesis. All compounds showed IC(50) values ranging between 14.0 and 564.2 nM, and the most active compound showed inhibitory activity against tubulin polymerization in vitro, being a potential therapeutic agent against colon cancer.

The use of two oxidoreductases (an aldoketo reductase from Escherichia coli JM109 and an alcohol dehydrogenase from Lactobacillus brevis) has demonstrated that it is possible to prepare enatiomerically pure diols in a one-pot operation. The reactions were applied to the synthesis of (1R)-1-[3-(hydroxymethyl)phenyl]ethanol and (1S)-1-phenylethane-1,2-diol, using a two-step procedure. The yield is nearly quantitative and the enantiomeric purity is greater than 95%. A third step has been introduced by adding a cell biocatalyst showing dihydrodiol dehydrogenase activity from Pseudomonas fluorescens N3. This allows for the preparation of 3-[(1R)-1-hydroxyethyl]benzoic acid and (2S)-hydroxy(phenyl)ethanoic acid.

In recent years, phosphonic acids and their derivatives have received increasing attention as analogues of a series of naturally occurring phosphates and as "bio-isosteric phosphorus analogues" of amino acids. Unlike a phosphate group, the phosphonate moiety is not readily hydrolyzed, in a biological environment, by the enzymes involved in the phosphate cleavage. This feature makes these compounds extremely useful in several applications, in metabolic regulation, in enhancement or inhibition studies, in the development of potential drugs against several metabolic disorders. The great potential of these compounds in biological applications resulted in an intense effort directed to the development of efficient synthetic methods for their preparation, with particular attention to stereoselective synthesis. The purpose of this review is to give an up-to-date account of the chemistry, the synthesis and the biological activity of aminophosphonic acids and their derivatives.

A one-pot, fluoride-promoted Wittig reaction was developed. The reactions of ethyl α-bromoacetate with aliphatic, aromatic, and heteroaromatic aldehydes in the presence of tri-n-butylphosphine and tetrabutylammonium fluoride produced α,β-unsaturated esters in good to excellent yields and E-stereoselectivity. Under the same conditions, reactions of ethyl α-bromopropionate, α-bromo acetonitrile, and α-bromoacetophenone with aliphatic and aromatic aldehydes in the presence of tri-n-butylphosphine and tetrabutylammonium fluoride produced the expected α,β-unsaturated derivatives in good E-stereoselectivity. The protocol was extended to semistabilized ylides and applied to the synthesis of some combretastatin analogs.

New resveratrol (trans-3,4',5-trihydroxystilbene) analogs were synthesized and screened for their in vitro cancer chemopreventive potential using various bioassays relevant for the prevention of carcinogenesis in humans: two assays to detect modulators of carcinogen metabolism (Cyp1A inhibition; determination of NAD(P)H/quinone reductase (QR) activity), three assays to identify radical scavenging and antioxidant properties (DPPH, ORAC, superoxide anion radicals in differentiated HL-60 cells), four assays to determine anti-inflammatory and anti-hormonal effects (iNOS, Cox-1 and aromatase inhibition, anti-estrogenic potential). 3,4',5-Tri-O-methyl resveratrol 1a was about sevenfold more active than resveratrol in inhibiting Cyp1A activity, it was a potent inducer of QR activity, and it showed pure anti-estrogenic activity (whereas resveratrol is a known mixed estrogen (ant)agonist with both estrogenic and anti-estrogenic properties). Dual estrogen ant-/agonist activity was restored in the mono-O-benzyl-substituted derivatives 4b (4'-O-benzyl resveratrol) and 5b (3-O-benzyl resveratrol). With respect to aromatase inhibition (Cyp19), which provided the highest number of actives, the benzyl-substituted series was more potent than the methyl-substituted derivatives of resveratrol, and 3-O-benzyl resveratrol 5b was about eightfold more active than resveratrol. Overall, 3,4',5-tri-O-pivaloyl resveratrol oxide 7c was identified as a potent inducer of phase 2 enzymes concomitant with inhibition of LPS-mediated iNOS induction.

During the investigation of ester derivatives (juvenogens, biochemically activated insect hormonogenic compounds) of biologically active alcohols with potential application in insect pest control, a need for availability of all existing stereoisomers of ethyl N-{2-[4-(2-butanoyloxycyclohexyl)methyl]phenoxy}ethyl carbamate occurred. They were synthesized from their chiral precursors, the corresponding stereoisomers of 2-(4-methoxybenzyl)cyclohexyl butanoate, by removing their protecting group (methyl), and by subsequent condensation of the aromatic hydroxyl moiety with ethyl N-(2-bromoethyl) carbamate. The requested enantiomers of 2-(4-methoxybenzyl)cyclohexyl butanoate were obtained by a Candida antarctica lipase-mediated transesterification and chiral resolution of the respective racemic cis- and trans-isomers of 2-(4-methoxybenzyl)cyclohexanol either directly or after a subsequent chemical esterification of the chiral precursor. In this synthesis, two convenient butanoic acid activating esters, vinyl butanoate and 2,2,2-trifluoroethyl butanoate, were employed, and the chiral precursors in the synthesis of the target molecules were obtained in 41-48% yields (i.e., 82-96% conversion), and with enantiomeric purity ee=96-98%, respectively. The enantiomeric purity of the products was determined by chiral HPLC analysis, and their absolute configuration was assigned on the basis of analyzing the (1)H and (19)F NMR spectra of their diastereoisomeric Mosher acid (3,3,3-trifluoromethyl-2-methoxy-2-phenylpropanoic acid) esters.

Highly selective enzymatic reductions of aldehydes to the corresponding alcohols was performed using an E. coli JM109 whole cell biocatalyst. A selective enzymatic method for the reduction of aldehydes could provide an eco-compatible alternative to chemical methods. The simplicity, fairly wide scope and the very high observed chemoselectivity of this approach are its most unique features.

(1 S ,2 S )-1-Amino-2-hydroxy-1,2,3,4-tetrahydronaphthalene, synthesized via a chemoenzymatic approach from naphthalene, has been successfully used as a chiral auxiliary in Reformatsky-type reactions between the corresponding α-bromoacyloxazolidinone and carbonyl compounds.

Recombinant Escherichia coli based on Pseudomonas fluorescens N3 naphthalene dioxygenase (NDO) was used in two liquid phase bioconversions to produce 1,2-dihydro-1,2-dihydroxy naphthalenes derived from substituted naphthalenes. Five different organic phases (dodecane, silicon oil CR100, dioctyl phthalate, 1-dodecanol, 2-undecanone) were used at different ratios with respect to water and containing different substrate concentrations. The results show different phase effects in terms of both rates and other experimental variables. The differences between substrates are very interesting, showing rate increases from 0.9 to 4 times. The choice of the phase to some extent depends on the substrate, but dodecane shows to be a general effective phase for all the substrates © 2004 Elsevier B.V. All rights reserved.

Monooxygenation of styrene derivatives using recombinant E. coli biocatalyst is an efficient way to prepare the corresponding oxiranes. The electronic and geometric effects of the ring substituents are described and show the relaxed specificity of the enzyme and its high stereoselectivity Monooxygenation of styrene derivatives using recombinant E. coli biocatalyst is an efficient way to prepare the corresponding oxiranes. The electronic and geometric effects of the ring substituents are described and show the relaxed specificity of the enzyme and its high stereoselectivity. © 2004 Elsevier Ltd. All rights reserved.

A series of stilbenoid analogues of resveratrol (trans-3,4',5-trihydroxystilbene) with a stilbenic or a bibenzylic skeleton have been prepared by partial synthesis from resveratrol and dihydroresveratrol. The synthesized compounds have been evaluated for their ability to modulate voltage-gated channels.

A new and stereoselective synthesis of isosteric phosphono analogues of glycosyl phosphates is reported. Appropriately protected glyconolactones, easily available from the parent sugars are reacted with ethyl-α-iodomethylphosphonate in THF in the presence of a soluble low-valent cobalt–phosphine complex, either in stoichiometric or sub-stoichiometric amounts, in the latter case in the presence of magnesium metal. The use of magnesium metal alone works, but in a less efficient and predictable way. The intermediate addition product can be subsequently deoxygenated with triethylsilane in the presence of boron trifluoride.

(2R)-2-Amino-8-methoxy-1,2,3,4-tetrahydronaphthalene, a useful precursor of the 5-hydroxytryptamine receptor agonist 8-OH-DPAT((2R)-2-(dipropylamino)-8-hydroxytetrahydronaphthalene), has been synthesized from 1-methoxynaphthalene through a chemoenzymatic protocol. The same protocol has been subsequently applied to the synthesis of other (2R)-2-amino-1,2,3,4-tetrahydronaphthalenes. (C) 2002 Published by Elsevier Science Ltd.

(1S,2S)-2-Hydroxy-1-amino-1,2,3,4-tetrahydronaphthalene, (1R,2R)-1-hydroxy-2-amino-1,2,3,4-tetrahydronaphthalene, (1S,2R)-1,2-diamino-1,2,3,4-tetrahydronaphthalene, (2R,3S)-2-hydroxy-3-amino-1,2,3,4-tetrahydronaphthalene and (2S,3S)-2,3-diammino-1,2,3,4-tetrahydronaphthalene have been synthesized from (1R,2S)-1,2-dihydroxy-1,2-dihydronaphthalene. The latter was obtained, using a protocol reported in a previous paper, from naphthalene using an Escherichia coli recombinant strain containing the naphthalene dioxygenase gene cloned from Pseudomonas fluorescens N3.

We developed biocatalysts carrying naphthalene dioxygenase and dihydrodiol dehydrogenase genes cloned from plasmid pN3 of Pseudomonas fluorescens N3 involved in naphthalene degradation, as an alternative approach to the production of hydroxylated compounds by chemical synthesis. Naphthalene dioxygenase is responsible for hydroxylation of the hydrocarbon into the corresponding 1,2-dihydro-1,2-dihydroxy derivative and dihydrodiol dehydrogenase is involved in the subsequent transformation into the 1,2-dihydroxy derivative. The first reaction strictly requires the presence of oxygen, essential for the dioxygenation reaction, while the second one can also be performed in anaerobic conditions that are optimal to avoid the easy oxidation of bioconversion products. Consequently, we constructed biocatalysts carrying the genes responsible for the biotransformation of hydrocarbons, inducible under aerobic and anaerobic conditions. We cloned the dioxygenase gene under its promoter, inducible by salicylic acid and the dihydrodiol dehydrogenase under the Pnar promoter of Escherichia coli, inducible by nitrate, in a nitrogen atmosphere, in order to develop biological systems with the possibility of controlling the expression of the cloned genes by the shift from aerobic to anaerobic conditions. Bioconversion experiments performed in aerobic conditions showed dihydrodiol production and dehydrogenase repression; as soon as cultures were switched to nitrogen, dihydrodiol dehydrogenation with an efficient production of 1,2-dihydroxyderivatives was observed. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

The cascade use of enzymatic activities allows for the preparation of enantiomerically pure epoxides. In particular, using whole-cell biocatalysts we can prepare both (−)-[3-(oxiran-2-yl)phenyl]methanol and (−)-3-(oxiran-2-yl)benzoic acid in one-pot, two or three steps procedure. The yield is quantitative and enantiomeric purity greater than 95%. The selected biocatalysts contain a styrene monoxygenase from Pseudomonas fluorescens ST and a naphthalene dihydrodiol dehydrogenase from P. fluorescens N3, cloned and expressed in Escherichia coli .

The detailed investigation of Astralagus trigonus DC roots, led to the isolation of a new cycloartan-3β, 16β diglucoside, whose structure was elucidated by extensive use of 1D- and 2D- high field (600 MHz) NMR techniques. The NaBH 4 reduction of the natural 6-oxo 3β, 16β diglucoside, previously isolated from the same plant, afforded the 6-epi-derivative of the new compound. The conformational preference of both these compounds has been investigated by high field 1 H NMR spectroscopy and molecular modeling techniques.

Low-valent cobalt complexes were used in Reformatsky-type additions of α-halophosphonates to carbonyl compounds (ketones and aldehydes) to yield a variety of β-hydroxyphosphonates.

3,3′-(1,2-ethanediyl)bis[2-substituted-1,3-thiazolidin-4-one] derivatives display different biological activities depending on the configuration of the 2,2′ centers and on the substitution at C2, C2′. In this context, 3,3′-(1,2-ethanediyl)bis[2-(2′-(5′-methyl)thienyl)-1,3-thiazolidin-4-one] (6b) and 3,3′-(1,2-ethanediyl)bis[2-(3′-pyridyl)-1,3-thiazolidin-4-one] (8b) have been prepared. Their structural and conformational features, which can be related to the biological activity, have been investigated by X-ray diffraction and molecular modeling techniques.

Summary: The anticancer activity of a novel pure 1,4-Diaryl-2-azetidinone (1), endowed with a higher solubility than the well known Combretastatin A4, is tested in mice. We previously reported that Compound (1) showed specific antiproliferative activity against duodenal and colon cancer cells, inducing activation of AMP-activated protein kinase and apoptosis. Here we estimate that the maximum tolerated dose in a mouse model is 40 mg/kg; the drug is well tolerated both in single dose and in repeated administration schedules. The drug displays a significant antitumor activity and a tumor growth delay when administered at the MTD both in single and fractionated i.v. administration in a mouse xenograft model of colorectal cancer. Arrest of tumor growth and relapse after drug suspension are parallel to modification in glucose demand as shown by PET studies with [18∈F] FDG. These data strongly support Compound (1) as a promising molecule for in vivo treatment of colorectal cancer.

Low-valent cobalt complexes were used in Reformatsky-type additions of α-haloesters and in aldol-type reactions of α-haloketones to ( R )-2,3- O -cyclohexylideneglyceraldehyde. Addition products were obtained in good yield with reasonable to high diastereoselection. The addition of methyl 4-bromocrotonate, which took place exclusively at the γ-carbon, was regioselective.

(2 R ,3 R )-Dihydroxy-tetrahydronaphthalene, prepared via an efficient chemoen-zymatic procedure from naphthalene, has been successfully tested, as a chiral auxiliary in diastereoselective conjugate additions of lithium dialkylcuprates to α,β-unsaturated esters and in stereoselective alkylations of β-ketoesters.

(2R, 3R)-dihydroxy-tetrahydronaphthalene 4 has been prepared via an efficient three-step synthesis from cis -(1R, 2S)-dihydroxy-1,2-dihydronaphthalene 1 . The latter was obtained by bioconversion of naphthalene by a modified strain of Pseudomonas fluorescens . The diol 4 has been successfully tested in a conjugate asymmetric addition of lithium dibutyl cuprate to the monocrotonate 7 .

Several conduritol and conduramine analogues have been synthesized from β-substituted naphthalenes via a chemoenzymatic approach, in a high regio- and stereocontrolled way.

3,3′(1,2-Ethanediyl)bis(2-halophenyl-thiazolidin-4-one) derivatives display different pharmacological activities depending on the configuration of the 2,2′ centers and on the oxidation state of the sulfur atoms. Quantum-chemical calculations on the 3-fluorophenyl-substituted configurational isomers are reported here, together with the X-ray structure of the 1∶1 dioxide derivative. This crystallizes in the monoclinic space group P21/c, with four molecules per unit cell and cell dimensions:a=18.917(3),b=9.003(2),c=12.062(2)A, β=96.20(3)°. The compound, which has an approximate center of symmetry in the middle of the ethylene chain and two asymmetric carbon atoms of opposite chiralities, is the (2R,2′S-meso) (or 2S,2′R-meso) stereoisomer.

A series of low-valent cobalt complexes of mono- and poly-dentate phosphorus donors (phosphines and phosphinites) was screened for effectiveness as mediators of the Reformatsky-type addition of benzaldehyde and tert -butyl α-bromoacetate in tetrahydrofuran at room temperature. The results are discussed in terms of the donor properties of the ligands and reactant ratios. With the triphenylphosphine-cobalt 2:1 system, the reaction gave addition product in high yields and excellent purity, providing a convenient alternative to the classical Reformatsky reaction.

A series of novel 1,4-diaryl-2-azetidinones were synthesized and evaluated for antiproliferative activity, cell cycle effects and apoptosis induction. Strong cytotoxicity was observed with the best compounds (±)-trans-20, (±)-trans-21 as well as enantiomers (+)-trans-20 and (+)-trans-21, which exhibited IC50 values of 3-13 nM against duodenal adenocarcinoma cells. They induced inhibition of tubulin polymerization and subsequent G2/M arrest. This effect was accompanied by activation of AMP-activated protein kinase (AMPK), activation of caspase-3 and induction of apoptosis. Additionally, the most potent compounds displayed antiproliferative activity against different colon cancer cell lines, opening the route to a new class of potential therapeutic agents against colon cancer.

Alexandroside I, a new cycloartane triterpene glycoside was isolated from Astragalus alexandrinus. Its structure was established as 3-O-β- d -glucopyranosyl-9β,19-cyclolanost-3β,6α,16β,24(R),25 pentaol on the basis of spectroscopic and chemical methods. Four known glycosides, astraversianins VI, X, XIV and XV, were also isolated.

The stereochemistry of the 3,3′-(1,2-ethanediyl)bis[2-(3-fluorophenyl)-1,3-thiazolidine-4-one] configurational isomers ( 2R,2′R 2S,2′ S and 2R,2′S meso ) has been investigated by 1 H-NMR techniques in solution, by X-ray diffraction methods in the solid state and by quantum chemical methods as the free molecule. The racemic compound, which has antagonistic activity at both H 1 and H 2 receptors, is found to prefer a gauche conformation in CDCl 3 solution, in the solid state and in the free molecule. The inactive meso stereoisomer is centrosymmetric in the crystalline state with an antiperiplanar conformation of the ethylene chain, whereas in CDCl 3 solution it exists as a rapidly interconverting mixture of 3 rotamers. The free molecule presents 2 gauche and 1 anti -periplanar conformations (differing by 1.3–2.4 kcal/mol). Some relationships between stereochemistry and activity are discussed.

In the presence of samarium iodide diethyl iodomethylphosphonate reacts with esters to afford β-ketophosphonates. The protocol has been applied to sugar lactones to afford in fairly good yields intermediates that are useful precursors for a variety of potentially bioactive compounds, such as the C -glycosyl analogue of thymidine 5′-(β- l -rhamnosyl)diphosphate.

In the presence of samarium iodide α-halophosphonates react with aliphatic carbonyl compounds (aldehydes and ketones) to afford β-hydroxyphosphonates in fairly good yields under neutral and mild conditions. Lower yields are obtained with aromatic carbonyl compounds.

A conformational analysis of (+)-spathulenol and its related stereoisomers was performed using the semiempirical program mndo . The obtained theoretical results were tested by checking the agreement of a selected calculated property ( 3 j H-H ) with the experimental value. The theoretical values of the vicinal coupling constants were calculated for all possible stereoisomers of spathulenol, including the ones not yet isolated, to allow their identification as natural and/or synthetic products. A biogenetic study was then undertaken using both the “saddle” technique, as implemented in the ampac package, and the coordinate reaction method. According to the results obtained, both spathulenol and allospathulenol should originate from two different conformations of a germacradiene precursor with both double bonds in the E configuration.

The cardiac activity of a series of milrinone analogues, 2-substituted 3-acyl-1,6-dihydro-6-oxo-5-pyridinecarbonitriles, 1,6,3,2,11,12-hexahydro-6,3-dioxo-5-quinolinecarbonitriles, the correlated carboxylic acids, 2-substituted 3-acyl-6(1H)-pyridones, and 7,8-dihydro-2,5(1H,6H)-quinolinediones, was evaluated in spontaneously beating and in electrically driven atria from reserpine-treated guinea pigs. Their effects were compared with those induced by amrinone and milrinone in both the atria preparations. Compounds SF28 (3-acetyl-1,6-dihydro-2-methyl-6-oxo-5-pyridinecarbonitrile) and SF40 (7,8-dihydro-7-methyl-2,5(1H,6H)-quinolinedione) were the most effective positive inotropic agents. An inhibition of the negative influence exerted by endogenous adenosine on heart preparations seems to be involved in their contractile activity. SF38 (3-benzoyl-2-phenyl-6(1H)-pyridinone), on the contrary, reduced the contractile force and the frequency rate of guinea pig atria with a mechanism not related to an activation of cholinergic or purinergic inhibitory receptors on the heart. X-ray analysis carried out on the three model compounds, SF28, SF40 (positive inotropic agents), and SF38 (negative inotropic agent), and molecular modeling evidenced that the change from phenyl (SF38) to methyl (SF28) or the introduction of a side cyclic aliphatic chain (SF40) results in a variation of conformational preference and topography which may address the different molecules toward distinct receptor pockets according to the resulting inotropic effect.

There is increasing interest in C-glycosyl compounds because of their potential as enzyme inhibitors’ and chirons for the synthesis of complex natural products2. C-Glycosylation procedures variously involve sigmatropic rearrangements”, addition of a carbon nucleophile at an anomeric centre4, reactions of glycosyl radicals5 or carbanions”, and nucleophilic addition to glycals’. We now report on the reactions of the Reformatsky reagent tert-butoxycarbonylmethylzinc bromide with the acetylated glycals l-4. This reagent was chosen as a model since it is a stable, easily accessible, crystalline compound’, the CH,COO’Bu residue can be easily transformed, and a CH,COOH substituent is “bioisosteric” with a phosphate group’.

Single-crystal X-ray work has been carried out on the 2-benzyl-5-cyano-1,6-dihydro-6-oxo-3-methoxycarbonyl pyridine compound 1f. It crystallizes in the triclinic system space group P 1 . Minimum energy conformations of 2-(alkyl or arylalkyl) 5-cyano-1,6-dihydro-6-oxo-3-pyridine carboxylates showing different biological activity have been calculated by the semiempirical MNDO and AM1 methods. A most critical factor for the different inotropic activities (positive or negative) of compounds 1a–1f seems to be related to the location and the steric requirements of a ‘pocket’ in the receptor boundary that limit the size of the substituent at position 2.

The synthesis of ethyl or methyl 4-substituted or unsubstituted 2-(dimethylamino)-5-pyrimidinecarboxylates 10-20, which is mainly carried out by reaction of ethyl or methyl 2-[(dimethylamino)methylene]-3-oxoalkanoates with 1,1-dimethylguanidine, is described. The above esters were hydrolyzed to the relative carboxylic acids 21-30, which were decarboxylated to the corresponding 2,4-disubstituted pyrimidines 31-40. All the new synthesized pyrimidines were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Their effects were compared to those induced by milrinone in both atria preparations. Compound 28 (4-benzyl-2-(dimethylamino)-5-pyrimidinecarboxylic acid) was the most effective positive inotropic agent, while the corresponding methyl ester 17 reduced both the contractile force and the frequency of guinea pig atria. An antagonism toward the negative influence exerted by endogenous adenosine on the heart seems to be involved in the contractile activity of compound 28. By contrast, compound 17 might be partial agonist at the purinergic inhibitory (A1) receptor. X-ray analysis carried out on 17 and 28 and molecular modeling investigations extended also to related derivatives allowed a possible rationalization between structure and inotropic activity for this series of compounds.

The dicyclopenta[a,d]cyclooctane skeleton is obtained by a very mild Cope arrangement of the highly functionalized divinylcyclobutane derivative 10 .

There is increasing interest in C-glycosyl compounds because of their potential as enzyme inhibitors’ and chirons for the synthesis of complex natural products2. C-Glycosylation procedures variously involve sigmatropic rearrangements”, addition of a carbon nucleophile at an anomeric centre4, reactions of glycosyl radicals5 or carbanions”, and nucleophilic addition to glycals’. We now report on the reactions of the Reformatsky reagent tert-butoxycarbonylmethylzinc bromide with the acetylated glycals l-4. This reagent was chosen as a model since it is a stable, easily accessible, crystalline compound’, the CH,COO’Bu residue can be easily transformed, and a CH,COOH substituent is “bioisosteric” with a phosphate group’.

(E)-3-(beta-D-Glucopyranosyloxy)-4',5-dihydroxystilbene (resveratrol 3-beta-D-glucoside, piceid), (Z)-2',3'-dihydroxy-3,4,4',5-tetramethoxystilbene (combretastatin A-1), (Z)-3'-hydroxy-3,4,4',5-tetramethoxystilbene (combretastatin A-4), (Z)-2'-hydroxy-3-4-4'-5-tetramethoxystilbene (combretastatin iso-A-4), alpha, beta-dihydro-2',3'-dihydro-2',3'-dihydroxy-3,4,4',5-tetramethoxystilb ene (combretastatin B-1), the corresponding glucosides, and related compounds have been synthesized via Wittig reactions followed by glucosylation under phase-transfer catalysis. Most of the compounds synthesized have been tested with respect to biological activity (cytostatic, cytotoxic, antimitotic, neurotoxic, antiplatelet, aggregation activity).

(2 R ,3 R )-Dihydroxy-tetrahydronaphthalene, prepared via an efficient chemoen-zymatic procedure from naphthalene, has been successfully tested, as a chiral auxiliary in diastereoselective conjugate additions of lithium dialkylcuprates to α,β-unsaturated esters and in stereoselective alkylations of β-ketoesters.

Low-valent cobalt complexes were used in Reformatsky-type additions of α-halophosphonates to carbonyl compounds (ketones and aldehydes) to yield a variety of β-hydroxyphosphonates.

Low-valent cobalt complexes were used in Reformatsky-type additions of α-haloesters and in aldol-type reactions of α-haloketones to ( R )-2,3- O -cyclohexylideneglyceraldehyde. Addition products were obtained in good yield with reasonable to high diastereoselection. The addition of methyl 4-bromocrotonate, which took place exclusively at the γ-carbon, was regioselective.