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PubMed1986

Synthesis and analgesic evaluation of 4-(2-heptyloxy)-7-[(Z)-(3-hydroxycyclohexyl)]indole: a caveat on indole-phenol bioisosterism.

The synthesis of 4-(2-heptyloxy)-7-[(Z)-(3-hydroxycyclohexyl)]indole (7) is described. Compound 7 was tested for analgesic properties in the phenylbenzoquinone writhing test and was found to be essentially devoid of activity. In contrast, cis-3-[4-(2-heptyloxy)-2-hydroxyphenyl]cyclohexanol (8), the analogue in which the pyrrolo ring is replaced by a hydroxyl group, had an ED50 of 8.3 mg/kg, sc, in the same model. The absence of bioisosterism between the pyrrolo ring and the phenolic hydroxyl group, in this instance, is discussed in terms of the circumstances that control the manifestation of bioisofunctionality between a pyrrolo ring and a phenolic hydroxyl group, which functions as a hydrogen-bond donor.

Analgesics↗
PubMed1997

N-hydroxyalkyl derivatives of 3 beta-phenyltropane and 1-methylspiro[1H-indoline-3,4'-piperidine]: vesamicol analogues with affinity for monoamine transporters.

As part of our ongoing structure-activity studies of the vesicular acetylcholine transporter ligand 2-(4-phenylpiperidino)cyclohexanol (vesamicol, 1), 22 N-hydroxy(phenyl)alkyl derivatives of 3 beta-phenyltropane, 6, and 1-methylspiro[1H-indoline-3,4'-piperidine], 7, were synthesized and tested for binding in vitro. Although a few compounds displayed moderately high affinity for the vesicular acetylcholine transporter, no compound was more potent than the prototypical vesicular acetylcholine transporter ligand vesamicol. However, a few derivatives of 6 displayed higher affinity for the dopamine transporter than cocaine. We conclude that modification of the piperidyl fragment of 1 will not lead to more potent vesicular acetylcholine transporter ligands.

Anesthetics, Local↗
PubMed1999

Hydroxylated decahydroquinolines as ligands for the vesicular acetylcholine transporter: synthesis and biological evaluation.

Analogues of the potent anticholinergic 2-(4-phenylpiperidino)cyclohexanol (vesamicol, 1) in which the cyclohexyl fragment was replaced with an N-acyl or N-alkyl trans-decahydroquinolyl moiety were synthesized and evaluated as potential ligands for the vesicular acetylcholine transporter (VAChT). The binding of compounds, such as 18, 20, and 21, was both stereospecific and of comparable magnitude to that of the closely related vesamicol analogue 2,3-trans-4a, 8a-trans-3-hydroxy-2-(4-phenylpiperidino)-1,2,3,4,5,6,7, 8-decahydronaphthalene (6) which displays subnanomolar affinity for this transporter. However, these compounds also demonstrated high affinities for sigma(1) and sigma(2) receptors and thus failed to show significantly improved selectivity over previously reported vesamicol analogues.

Acetylcholine↗
PubMed2002

Directing abilities of alcohol-derived functional groups in the hydroformylation of olefins.

The hydroformylation of allylic and homoallylic alcohols and their derivatives using cationic and neutral rhodium complexes has been examined. The highest diastereoselectivity (87:13) was observed in the reaction of 1-methoxymethoxy-2-methylenecyclohexane. Higher yields and similar selectivities were obtained in the reaction of the TBDMS-protected alcohol. The major diastereomer results from hydroformylation syn to the functional group, which would suggest a directing effect. However, hydroformylation of 3-methylene-1-cyclohexanol derivatives occurs on the face opposite to the directing group in the major isomer. These data, in addition to the results of hydroformylation of 1-methyl-2-methylenecyclohexane, suggest that inherent conformational preferences are of significant importance in determining the product distribution and that the directing power of simple alcohols and their derivatives is moderate at best under the conditions examined in this study.

Journal Article↗
PubMed2001

Radical and non-radical mechanisms for alkane oxidations by hydrogen peroxide-trifluoroacetic acid.

The oxidation of cyclohexane by the H2O2-trifluoroacetic acid system is revisited. Consistent with a previous report (Deno, N.; Messer, L. A. Chem. Comm. 1976, 1051), cyclohexanol forms initially but then esterifies to cyclohexyl trifluoroacetate. Small amounts of trans-1,2-cyclohexadiyl bis-(trifluoroacetate) also form. Although these products form irrespective of the presence or absence of O2, dual mechanisms are shown to operate. In the absence of O2, the dominant mechanism is a radical chain reaction that is propagated by CF3. abstracting H from C6H12 and SH2 displacement of C6H11. on CF3CO2OH. The intermediacy of C6H11. and CF3. is inferred from production of CHF3 and CO2 along with cyclohexyl trifluoroacetate, or CDF3 when cyclohexane-d12 is used. In the presence of O2, fluoroform and CO2 are suppressed, the reaction rate slows, and the rate law approaches second order (first order in peracid and in C6H12). Trapping of cyclohexyl radicals by quinoxaline is inefficient except at elevated (approximately 75 degrees C) temperatures. Fluoroform and CO2, telltale evidence for the chain pathway, were not produced when quinoxaline was present in room temperature reactions. These observations suggest that a parallel, nonfree radical, oxenoid insertion mechanism dominates when O2 is present. A pathway is discussed in which a biradicaloid-zwiterionic transition state is attained by hydrogen transfer from alkane to peroxide oxygen with synchronous O-O bond scission.

Journal Article↗
PubMed2003

New convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling between A-ring and C,D-ring parts.

A new convergent method for the synthesis of 1alpha,25-dihydroxyvitamin D(3) and its analogues has been developed that involves efficient preparation of the A-ring part 1a, (Z)-(3S,5R)-1-bromomethylene-3,5-bis(tert-butyldimethylsilyloxy)-2-methylenecyclohexane, starting from epichlorohydrin (4) and its Suzuki-Miyaura coupling reaction with the C,D-ring part 12. Thus, (R)-4 was converted to (3S,5R)-5-(tert-butyldimethylsilyloxy)-8-(trimethylsilyl)-oct-1-en-7-yn-3-ol (3a) through a ten-step reaction sequence in 49% overall yield. Compound 3a thus obtained was treated with a Ti(O-i-Pr)(4)/2 i-PrMgCl reagent and then with NBS to afford (Z)-(1S,2S,5R)-2-bromomethyl-3-[bromo(trimethylsilyl)methylene]-5-(tert-butyldimethylsilyloxy)cyclohexanol (10a) in 51% yield, from which 1a was obtained in 87% yield by sequential treatment with TBSCl/imidazole, DBU, and Cs(2)CO(3). The resulting A-ring intermediate 1a was reacted with alkenylboronate 12 in the presence of a PdCl(2)(dppf) catalyst to furnish 1alpha,25-dihydroxyvitamin D(3) in 82% yield after protodesilylation. Similarly, all of the other three possible stereoisomers of A-ring parts 1b, 1c, and 1d were prepared, from which 1-epi-, 3-epi-, and 1,3-di-epi-1alpha,25-dihydroxyvitamin D(3) were synthesized by coupling with 12 in excellent yield, respectively. Starting from 1a and 1c, des-C,D-1alpha,25-dihydroxyvitamin D(3) analogues, retiferol 13 and its 3-epi derivative, were also prepared, respectively.

Calcitriol↗
PubMed2004

Thermodynamics of the molecular and chiral recognition of cycloalkanols and camphor by modified beta-cyclodextrins possessing simple aromatic tethers.

The complex stability constants (K(S)) and thermodynamic parameters (DeltaG degrees, DeltaH degrees, and TDeltaS degrees ) for 1:1 inclusion complexation of beta-cyclodextrin (beta-CD) derivatives, 6-O-phenyl-beta-CD (2) 6-O-(4-formyl-phenyl)-beta-CD (3), 6-O-(4-nitrophenyl)-beta-CD (4), 6-O-(4-bromophenyl)-beta-CD (5), 6-O-(4-chlorophenyl)]-beta-CD (6), and 6-O-(4-hydroxybenzoyl)-beta-CD (7) with representative guest molecules, cyclic alcohols (cyclopentanol, cyclohexanol, cycloheptanol, cyclooctanol), (+/-)-borneol, and (+/-)-camphor, have been determined by means of titration microcalorimetry in an aqueous phosphate buffer solution (pH = 7.20) at 298.15 K. The results obtained indicate that the introduction to beta-CD of an aromatic ring bearing different substituent groups significantly enhances the molecular binding ability and moderately alters the chiral discrimination ability for the guests examined here, displaying the highest enantioselectivity of up to 4.01 for the inclusion complexation of 6 with (+/-)-camphor. The enhanced molecular/chiral discrimination ability caused by derivatization is attributed solely to increased positive entropy changes due to the expanding hydrophobic interaction and desolvation effects. The binding modes of host-guest interactions derived from ROESY spectroscopy data show that the resulting complex of 4 and (+)-borneol possesses better induced-fit interaction as compared to (-)-borneol, which is responsible for the enhanced molecular/chiral recognition ability.

Alcohols↗
PubMed1997

Applications of High-Temperature Aqueous Media for Synthetic Organic Reactions.

Preparative organic synthesis was investigated in aqueous media at temperatures up to 300 degrees C. Experiments were conducted with a recently disclosed pressurized microwave batch reactor (MBR) or in conventionally heated autoclaves. Thirty-six examples are presented. Among these, methods were developed for a Fischer synthesis, an intramolecular aldol condensation that was scaled up, decarboxylation of indole-2-carboxylic acid, Rupe rearrangement of 1-ethynyl-1-cyclohexanol, isomerization of carvone to carvacrol, and conversion of phenylacetylene to acetophenone. The applicability of high-temperature water was also demonstrated for biomimetic processes important in food, flavor, and aroma chemistry and for tandem reactions such as formation of 2-methyl-2,3-dihydrobenzofuran from allyl phenyl ether. When addition of acid or base was necessary, less agent was usually required for high-temperature processes than for those at and below boiling, and the reactions often proceeded more selectively. In some instances the requirement was orders of magnitude lower, with obvious consequences for safe, economic processing and for lowering costs of effluent disposal. The diversity of reactions indicates that high-temperature aqueous media could play an increasingly important role in the development of new preparative processes.

Journal Article↗
PubMed1997

Enantiopure N-Acyldihydropyridones as Synthetic Intermediates: Asymmetric Synthesis of (-)-Septicine and (-)-Tylophorine.

A concise asymmetric synthesis of (-)-septicine (1) and (-)-tylophorine (2) was accomplished with a high degree of stereocontrol in eight and nine steps, respectively. Addition of 4-(1-butenyl)magnesium bromide to 1-acylpyridinium salt 3, prepared in situ from 4-methoxy-3-(triisopropylsilyl)pyridine and the chloroformate of (-)-trans-2-(alpha-cumyl)cyclohexanol, gave a 91% yield of diastereomerically pure dihydropyridone 7. Oxidative cleavage of 7 and subsequent reduction provided alcohol 6 in 81% yield. Conversion of 6 to the chloride followed by treatment with sodium methoxide gave indolizidinone 9 in high yield. Bromination and conjugate reduction of 9 with L-Selectride, and trapping the intermediate enolate with N-(5-chloro-2-pyridyl)triflimide, provided bromovinyl triflate 11. Palladium-catalyzed cross-coupling of excess (3,4-dimethoxyphenyl)zinc bromide and 11 gave (-)-septicine (1). On the basis of this synthesis, (-)-1 was assigned the Rconfiguration. Reaction of 1 with vanadium(V) trifluoride oxide in TFA/CH(2)Cl(2) effected oxidative coupling to give a 68% yield of (-)-tylophorine (2).

Journal Article↗
PubMed1997

Enantiopure N-Acyldihydropyridones as Synthetic Intermediates: Asymmetric Syntheses of Indolizidine Alkaloids (-)-205A, (-)-207A, and (-)-235B.

Concise asymmetric syntheses of indolizidine alkaloids (-)-205A, (-)-207A, and (-)-235B were accomplished with a high degree of stereocontrol in eleven steps. Addition of 4-(1-butenyl)magnesium bromide to 1-acylpyridinium salt 5, prepared in situ from 4-methoxy-3-(triisopropylsilyl)pyridine and the chloroformate of (+)-trans-2-(alpha-cumyl)cyclohexanol, gave a 91% yield of diastereomerically pure dihydropyridone 6. Oxidative cleavage of 6 and subsequent reduction provided alcohol 7 in 81% yield. Removal of the chiral auxilliary and TIPS group (NaOMe; 10% HCl), N-acylation with BnOCOCCl, and treatment with NCS/Ph(3)P gave chloride 10. Methylation at C-3, copper-mediated conjugate addition of 4-(benzyloxy)butylmagnesium bromide, and vinyl triflate formation provided 13 in a stereoselective fashion. Catalytic reduction of the vinyl triflate moiety, simultaneous cleavage of the benzyl ether and Cbz groups, and cyclization to give amino alcohol 14 was effected via a one-pot reaction. Oxidation of 14 with the Dess-Martin reagent gave a 97% yield of amino aldehyde 4. Synthesis of each of the three title alkaloids was accomplished in one step from 4. The Seyferth-Gilbert reaction provided a 41% yield of (-)-205A. The appropriate Wittig olefination of 4 gave indolizidines (-)-207A and (-)-235B in 70% and 86% yield, respectively.

Journal Article↗
PubMed1998

The Alcoholysis Reaction of Isocyanates Giving Urethanes: Evidence for a Multimolecular Mechanism.

A kinetic and mechanistic investigation of the catalyzed alcoholysis of isocyanates was undertaken. Both experimental and theoretical results showed that the alcoholysis should be understood by a multimolecular intervention of the alcohols. The alcoholysis of isocyanate was examined experimentally for 2-propanol and cyclohexanol in low and high concentrations. It is suggested that either two or three molecules of the alcohol are implicated from the kinetic study, while the reaction with trimers becomes dominant at high alcohol concentrations. In accordance with these results, theoretical study suggests an active participation of at least three alcohol molecules in a reacting supersystem, giving rise to a genuine effect. The detailed reaction mechanism for the alcoholysis reaction by methanol and methanol clusters (HN=C=O + n(CH(3)OH), n = 1-3) was modeled by ab initio methods, both in the gas phase and in solution. The nucleophilic addition occurs in a concerted way across the N=C bond of the isocyanate rather than across the C=O, similar to the isocyanate hydrolysis. The bulk solvent effect, which is treated by a polarizable continuum model (PCM), does not affect the preference of the alcohol to attack across the N=C bond as pointed out by the gas-phase values.

Journal Article↗
PubMed1998

Efficient Fluorination with Tetrabutylammonium Dihydrogen Trifluoride in a Novel Approach toward 1-alpha-Fluoro-25-hydroxy-vitamin D(3) Analogues.

The known, but hardly accessible, A-ring phosphine oxide 20, a building block for 1-alpha-fluoro-25-hydroxy-vitamin D(3), was prepared by a new route in gram amounts from (S)-(+)-carvone in 20 steps and 0.6% overall yield. Fluorine was introduced at an early stage by the completely regio- and stereoselective trans-diaxial opening of key-epoxide 5 with neat tetrabutylammonium dihydrogen trifluoride at 95 degrees C. The required 2-carbon chain extension of cyclohexanol 13 was accomplished in moderate yield via S(N)' substitution with cesium phenylselanyl acetate followed by Ireland-Claisen rearrangement of the resulting ester 15. Spontaneous elimination of the derived phenyl selenoxide led stereorandomly to a 1:1 mixture of dienoates E/Z-17, which was transformed into 20 as previously described.

Journal Article↗
PubMed1999

SmI(2)/Pd(0)-Mediated Intramolecular Coupling between Propargylic Esters and Tethered Aldehydes or Ketones.

A SmI(2)/Pd(0)-promoted intramolecular coupling between propargylic esters and carbonyl compounds is described. The reaction affords homopropargyl cycloalkanol products. Cyclopentanols are formed in high yields when ketones are employed as the carbonyl components, but aldehydes are found not to be suitable partners in these reactions. Particularly remarkable is the efficient formation of products with adjacent functionalized quaternary centers. These cyclizations take place with low diastereoselectivity about the newly created propargylic and carbinol stereogenic centers except when these two centers are quaternary or in the presence of groups capable of both chelating trivalent samarium and facilitating retroaldol-aldol-type equilibria in the product. In this latter case, the strategic combination of chemoselective carbonyl addition and SmI(2)/Pd(0)-promoted cyclization provides ready and convenient stereocontrolled access to functionalized cyclopentanols from unprotected 1,5-dicarbonyl starting materials. The analogous formation of cyclohexanols is limited by low cyclization yields and lack of stereoselectivity.

Journal Article↗
PubMed2000

Assignment of the absolute configuration of alpha-chiral carboxylic acids by 1H NMR spectroscopy

The prediction of the absolute configuration of alpha-chiral carboxylic acids from the 1H NMR spectra of their esters with (R)- and (S)-ethyl 2-hydroxy-2-(9-anthryl) acetate [(R)- and (S)-9-AHA, 5] is discussed. Low-temperature NMR experiments, MM, semiempirical, and aromatic shielding effect calculations allowed the identification of the main conformers and showed that, in all esters studied, conformer ap is the most stable. A simple model for the assignment of the absolute configuration from NMR data is presented, and its reliability is corroborated with acids 6-31 of known absolute configuration. In addition to 5, other auxiliary reagents with open (32-38) and cyclic (39-42) structures have also been studied. trans-(+)- and (-)-2-phenyl-1-cyclohexanol (41) was found to be particularly efficient and produced delta delta RS values similar to those of 5.

Journal Article↗
PubMed2000

Trifluoromethyl-substituted indenyl rhodium and iridium complexes are highly selective catalysts for directed hydroboration reactions

Rhodium and iridium catalysts containing trifluoromethyl-substituted indenyl ligands (Ind'MCod, Ind' = C9H7, (1-CF3)C9H6, (2-CF3)C9H6, (1,3-CF3)2C9H5) have been developed for the directed hydroboration of 4-(benzyloxy)cyclohexene to cis-3-(benzyloxy)cyclohexanol. Compared to unsubstituted complexes, trifluoromethyl substitution yields a 3-10% increase in selectivity which is attributed to the strong electron-withdrawing effect of the trifluoromethyl group. Rhodium complexes give selectivities of 74-84%, and iridium complexes give high levels of selectivity (93-98%).

Journal Article↗
PubMed2001

Nickel-catalyzed intramolecular homoallylation of omega-dienyl aldehyde.

[reaction: see text] In the presence of a catalytic amount of Ni(acac)(2), Et(3)B and Et(2)Zn nicely promote a reductive homoallylic cyclization of omega-dienyl aldehydes and provide 2-allylcyclopentanols and -cyclohexanols with high stereoselectivity in excellent yield. The reaction requires only two kinds of commercially available, inexpensive reagents, Ni(acac)(2) and Et(2)Zn or Et(3)B, and completes at room temperature within 30 min with Et(2)Zn and 1-2 days with Et(3)B. No ligand additives (e.g., phosphine, nitrogen compounds) are required.

Journal Article↗