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A series of vinylogous amphetamine analogs was synthesized and examined for their activity at biogenic amine transporters and serotonin-2 receptor (5-HT2) subtypes. (1S,3E)-1-Methyl-4-phenyl-but-3-enylamine (S-6) is a potent dual dopamine/serotonin (DA/5-HT) releaser with no activity at 5-HT2 receptors. This unique profile of actions suggests that analog S-6 is a viable lead compound for identifying new structural classes of DA/5-HT releasers with therapeutic benefit and reduced abuse liability.

Chemical modifications of the I287C mutant of a Burkholderia cepacia lipase afforded various I287C-X conjugates, among which I287C-PAA bearing an N-phenylacetamide (PAA) moiety showed excellent enantioselectivity and catalytic activity for secondary alcohols. Site-directed chemical modifications are powerful tools to control enantioselective biocatalysis.

The first catalytic enantio- and diastereoselective synthesis of 1,2-hydroxyboronates is reported. Reactions are promoted by a readily available chiral monodentate phosphoramidite-copper complex in the presence of an alkyl 1,1-diboron reagent. Products contain two contiguous stereogenic centers and are obtained in up to 91% yield, >98:2 d.r., and 98:2 e.r. The reaction is tolerant of aryl and vinyl aldehydes, and the 1,2-hydroxyboronate products can be transformed into versatile derivatives. Mechanistic experiments indicate control of absolute stereochemistry of the α-boryl component.

A simple, iron-based catalytic system allows for the inter- and intramolecular arylation of unactivated secondary alcohols. This transformation expands the substrate scope beyond the previously required activated alcohols and proceeds under mild reaction conditions, tolerating air and moisture. Furthermore, the use of an enantioenriched secondary alcohol provides an enantioenriched product for the intramolecular reaction, thereby offering a convenient approach to nonracemic products.

The first asymmetric synthesis of a synthetic cannabinoid levonantradol was accomplished, and the 3-D solution structure of its core architecture was confirmed by NMR and computational methods. The Royal Society of Chemistry 2013.

Borylation of alkyl halides with diboron proceeded in the presence of a copper(I)/Xantphos catalyst and a stoichiometric amount of K(O-t-Bu) base. The boryl substitution proceeded with normal and secondary alkyl chlorides, bromides, and iodides, but alkyl sulfonates did not react. Menthyl halides afforded the corresponding borylation product with excellent diastereoselectivity, whereas (R)-2-bromo-5-phenylpentane gave a racemic product. Reaction with cyclopropylmethyl bromide resulted in ring-opening products, suggesting the reaction involves a radical pathway.

Treatment of alkenes such as 3-hexene, 3-octene, and 1-cyclohexyl-1-butene with the N-heterocyclic carbene (NHC)-derived borane 2 and catalytic HNTf 2 (Tf = trifluoromethanesulfonyl (CF3SO2)) effects hydroboration at room temperature. With 3-hexene, surprisingly facile migration of the boron atom from C(3) of the hexyl group to C(2) was observed over a time scale of minutes to hours. Oxidative workup gave a mixture of alcohols containing 2-hexanol as the major product. A similar preference for the C(2) alcohol was observed after oxidative workup of the 3-octene and 1-cyclohexyl-1-butene hydroborations. NHC-borenium cations (or functional equivalents) are postulated as the species that accomplish the hydroborations, and the C(2) selective migrations are attributed to the four-center interconversion of borenium cations with cationic NHC-borane-olefin π-complexes.

A facile method for the synthesis of tetralins has been described which uses various substituted phenylpentane-1,4-diones as starting material with a combination of TiCl4/Et3SiH. The synthesis involves three reactions under mild conditions. A mechanism has been proposed for the reductive cyclization through ionic hydrogenation, and titanium(IV) chloride catalyzed cyclization.

A copper-catalyzed methodology to functionalize remote sp3 C-H bonds in alkyl hydroperoxides is presented. The atom-transfer chlorination utilizes simple ammonium chloride salts as the chlorine source, and the internal redox process requires no external redox reagents.

This comprehensive study describes the influence of substituents at the aryl moiety on SmI2-mediated intramolecular ketyl-aryl coupling reactions. Differently substituted γ-aryl ketones were employed as precursors, which were directly prepared

A new chiral bisphosphine, (S,S)-2,2″-bis[(diethylphosphino)methyl]- 1,1″-biferrocene [(S,S)-EtTRAP-H], was synthesized in seven steps in 45% overall yield from ferrocenyloxazoline derived from (S)-valinol. The new chiral phosphine has only planar chirality, and is able to form a trans-chelate metal complex. (S,S)-EtTRAP-H is an effective ligand in rhodium-catalyzed asymmetric hydrosilylation of ketones (up to 94% ee). In particular, the hydrosilylation of 2-octanone yielded (S)-2-octanol with 77% ee.

The present invention relates to novel dihydro-[1,2,3]triazolo-[4,5-d]pyrimidin-7-one, to processes for their preparation and to their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.

Asymmetric hydrosilylation of simple ketones with diphenylsilane proceeded at -40 °C in the presence of a rhodium complex (0.001 - 0.01 molar amount) coordinated with a trans-chelating chiral bisphosphine ligand bearing linear alkyl substituents on the phosphorus atoms, (R,R)-(S,S)-Et-, Pr-, or BuTRAP, giving the corresponding optically active (S)- secondary alcohols with up to 97% ee. The asymmetric hydrosilylation using TRAP ligands with bulkier P-substituents resulted in much lower enantioselectivities. The EtTRAP-rhodium catalyst was also effective for asymmetric hydrosilylation of keto esters with a coordination site for a rhodium atom (up to 98% ee). Optically active symmetrical diols were obtained with up to 99% ee from the corresponding diketones via the asymmetric reduction using 2.5 molar amounts of diphenylsilane.

A Bacillus megaterium strain was isolated from topsoil by a selective screening procedure with allylbenzene as a xenobiotic substrate. This strain performed the hydroxylation chemoselectively (no arene oxidation and overoxidized products) and enantioselectively (up to 99% ee) in the benzylic and nonbenzylic positions of a variety of unfunctionalized arylalkanes. Salycilate and phenobarbital, which are potent inducers of cytochrome P-450 activity, changed the regioselectivity of the microbial CH insertion, without an effect on the enantioselectivity. The biotransformation conditions were optimized in regard to product yield and enantioselectivity by variation of the oxygen-gas supply and the time of the substrate addition. The different product distributions (α- versus β-hydroxylated product) that are obtained on induction of cytochrome P-450 enzyme activity demonstrate the involvement of two or more hydroxylating enzymes with distinct regioselectivities in this biotransformation. An oxygen-rebound mechanism is assumed for the cytochrome P-450-type monooxygenase activity, in which steric interactions between the substrate and the enzyme determine the preferred face of the hydroxy-group transfer to the radical intermediate.

Asymmetric hydrosilylation of simple terminal alkenes (RCH=CH2) with trichlorosilane at 40 deg C in the presence of 1*10-3 or 1*10-4 molar amounts of palladium catalyst prepared in situ from 3-C3H5)>2 and (S)-2-diphenylphosphino-2'-methoxy-1,1'-binaphthyl ((S)-MeO-MOP) proceeded with unusual regioselectivity and with high enantioselectivity to give high yields of 2-(trichlorosilyl)alkanes together with a minor amount of 1-(trichlorosilyl)alkanes.Optically active alcohols, RCH(OH)CH3, were obtained by oxidation of the carbon-silicon bond.Regioselectivities for forming 2-silylalkanes over 1-silylalkanes and enantiomeric purities of alcohols are as follows: R=n-C4H9: 89/11, 94percent ee (R).R=n-C6H13: 93/7, 95percent ee (R).R=n-C10H21: 94/6, 95percentee (R).R=PhCH2CH2: 81/19, 97percentee (S).R=PhCH2CH2CH2: 80/20, 92percent ee (R).R=cyclo-C6H11: 66/34, 96percent ee (R).A similar hydrosilylation of 1-alkenes, 4-pentenyl benzoate and 1,5-heptadiene gave corresponding 2-alkanols of 90percent ee and 87percent ee, respectively, the ester carbonyl and the internal double bond remaining intact.

Absorption of a variety of acids to chromatographic silica gel results in substantial enhancement of their catalytic activity-affording easily prepared, environmentally benign heterogeneous acids that are highly effective in mediating a number of processes.This was shown for the isomerization of allene 1 and dimerization of the corresponding 1,3-diene 2; cyclization of (R)-citronellal (5), the related diester 10, and 1,5-cyclooctadiene (15); Rupe rearrangement of alkynol 18; and Friedel-Crafts cyclodehydration of alcohols 21.By contrast, commercially available Nafion-H was significantly less effective as a heterogeneous acid catalyst.Chromatographic alumina displayed enigmatic behavior, showing enhanced acidity on the adsorption of HCl but little or no acidity on the adsorption of a variety of other types of acid.The results are discussed in terms of the surface structures of silica gel and alumina.

The electroreduction of nonconjugated aromatic ketones gave intramolecularly coupled products.The best result was obtained using an Sn cathode in i-PrOH containing tetraalkylammonium salt as a supporting electrolyte.This reductive cyclization proceeded with remarkable stereoselectivity, and the cis isomer was obtained exclusively.A variety of new bi- and polycyclic compounds were synthesized.The reaction mechanism was studied, and it was suggested that the anion radical generated by one-electron transfer to a carbonyl group attacks an aromatic ring intramolecularly.The choice of counter cation of the anion radical was critical for the reductive cyclization.Other reductive methods employing metal reducing agents were also studied.Reduction with Na in HMPA-THF gave the same cyclized product, though the yield was lower than that with the electroreduction.

Competition experiments and measurements of enantioselectivities were used to develop a simple active-site model (Figure 1) for resolutions of β-hydroxy-α-methylene carbonyl compounds III via acyl transfers mediated by lipase from Pseudomonas sp. (AK). Further experiments were used to test and refine this model with respect to resolutions of allylic, propargylic, homopropargylic, and other alcohols (Tables I-IV, respectively). The model proved extremely reliable for predicting the sense of the asymmetric induction, and the combined data collected in this paper give an indication of what structural features of the substrates can be correlated with high enantioselectivities in these resolutions. Furthermore, the results account for the conspicuous reversal of enantioselectivity previously observed in resolutions of γ-hydroxy-α,β-unsaturated esters 35. Kinetic resolutions of two substrates (allenol 14 and dienol 9) via asymmetric epoxidations were performed for comparison with the methodology presented in this paper.

The mechanism of dimethylpyrrolidinium (DMP(+1)) mediation of the reductive cyclization of 6-hepten-2-one at a mercury electrode was studied.The initial step of the reduction involves formation of a solid composite, (DMP)Hg5, which then transfers an electron to the ketone, regenerating DMP(1+) and Hgo.The ketyl radical anion cyclizes to form a primary alkyl radical, which can either abstract a hydrogen atom from the solvent, dimethylformamide, or be reduced to the corresponding carbanion.Protonation gives 1,2-dimethylcyclopentanol.Both direct and DMP(1+)-mediated reductions of 7-octen-2-one, 5-phenyl-2-pentanone, and 6-heptyn-2-one were studied.All three compounds give cyclic alcohols when the reduction is mediated by DMP(1+).The former two compounds give the corresponding straight-chain alcohols when reduced directly.The latter gives the same cyclized product upon both direct or DMP(1+)-mediated reduction.Redox catalysis studies show that DMP(1+) is a remarkably effective catalysts for the reduction of ketones.The effectiveness of the catalysis correlates with the expected rates of cyclization of the unsaturated ketones and is consistent with a mechanism involving mediation by solid (DMP)Hg5.Redox catalysis studies of the reduction of cyclohexanones indicate that DMP(1+)-mediated reductions are accelerated by increasing , and the results are discussed in terms of a mechanism leading to pinacol formation.

1,2,3,4,4a,4b,5,6,7,8,8a,12b-Dodecahydro-7-(oxo, hydroxy or amino)-9-hydroxy-11-(alkyl, alkoxy or alkoxyalkyl)triphenylenes, 2,3,3a,3b,4,5,6,7,7a,11b-decahydro-6-(oxo, hydroxy or amino)-8-hydroxy-10-(alkyl, alkoxy or alkoxyalkyl)-1H-cyclopenta[1]phenanthrenes, 2,3,4,4a,4b,5,6,7,8,8a-decahydro-7-(oxo, hydroxy or amino)-9-hydroxy-11-(alkyl, alkoxy, alkoxyalkyl, aralkyl, aralkoxy, aryloxyalkyl or aralkoxyalkyl)-1H-pyrido[1,2-f]phenanthridines, and 1,2,3,3a,3b,4,5,6,7,7a-decahydro-6-(oxo, hydroxy or amino)-8-hydroxy-10-(alkyl, alkoxy or alkoxyalkyl)pyrrolo[1,2-f]phenanthridines and derivatives are valuable as central nervous system active agents or as intermediates to compounds having such activity.

Tricyclic benzo fused compounds of the formula STR1 and pharmaceutically acceptable cationic and acid addition salts thereof, wherein n is zero, 1 or 2, and t is 1 or 2; M is CH or N, R1 is H or certain acyl groups; Q is CO2 R4, COR5, C(OR7)R5 R6, CN, CONR9 R10, CH2 NR9 R10, CH2 NHCOR11, CH2 NHSO2 R12, 5-tetrazolyl or when n is 1, Q and OR1 together form a lactone or certain reduced derivatives thereof; and Z is certain alkyl, alkoxy, alkoxyalkyl, aralkyl, aralkoxy, aryloxyalkyl or aralkoxyalkyl groups, are valuable central nervous system active agents, methods for their use, pharmaceutical compositions containing them and certain intermediates therefor.

The ketones, 4-benzyloxy-1-(furan-3'-yl)pentan-1-one and 4-benzyloxy-1-(furan-3'-yl(butan-1-one, have been prepared by generating the required alkyllithium reagent in the presence of lithium furan-3-carboxylate.The latter ketone has been transformed to 4-(furan-3'-yl)-1-methylbutyltriphenylphosphonium iodide.

5-Phenyl-2S-pentanol is synthesized stereospecifically from S ethyl lactate. The method provides easily purified 5-phenyl-2S-pentanol useful in the synthesis of central nervous system active (CNS) agents such as levonantradol.

Resolution of racemic 5-phenyl-2-pentanol via the hemiphthalate ester, followed by diastereomer salt formation with (+)-brucine, separation of the brucine salt of (S)-5-phenyl-2-pentanol hemiphthalate and recovery of the (S)-alcohol therefrom. The (S)-5-phenyl-2-pentanol is a valuable intermediate for organic synthesis.

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