Synthesis and biological evaluation of (S)-4-aminoquinazoline alcohols

A simple synthetic method for the preparation of enantiomerically pure (S)-4-aminoquinazoline alcohols from (S)-quinazolinone alcohols by key steps including chlorination, nucleophilic ipso substitution, and deacetylation is presented. Mutagenic and antimutagenic properties of the (S)-4-aminoquinazoline alcohols were investigated by using Salmonella typhimurium TA1535, and Escherichia coli WP2uvrA tester strains at 0.01, 0.1, and 1 μg/plate concentrations. (S)-4-aminoquinazoline alcohols were found to be genotoxically safe at the tested concentrations. Among the tested (S)-4-aminoquinazoline alcohols, the best antimutagenic activity was obtained with a methyl derivative at 0.1 μg/plate dose.     

Synthesis of trifluoromethylated γ- and β-lactones through the palladium-catalyzed cyclocarbonylation

3-Trifluoromethyl-2(5H)-furanones (γ-lactones) and 3-(2,2,2-trifluoroethylidene)-2-oxetanones (β-lactones) were obtained, respectively through the palladium-catalyzed cyclocarbonylation of (Z)-3-iodo-3-trifluoromethyl allylic alcohols and (Z)-2-iodo-3-trifluoromethyl allyl alcohols.     

Enantioselective synthesis of butadien-2-ylcarbinols via (silylmethyl)allenic alcohols from chromium-catalyzed additions to aldehydes utilizing chiral carbazole ligands

The synthesis of chiral, nonracemic butadienylcarbinols by employing intermediate (trimethylsilyl)methylallenic alcohols is described. Allenic alcohols are obtained by treatment of aldehydes with (4-bromobut-2-ynyl)trimethylsilane in the presence of a catalytic amount of CrCl₃ or CrCl₂. Several new tridentate bis(oxazolinyl)carbazole ligands were synthesized and evaluated as the source of chirality. The synthesis of chiral allenic alcohols can be achieved in good yields (58-88%) and enantioselectivities (55-78% ee). Allenic alcohols may be treated with TBAF or 2 M HCl to provide the desired dienes in 43-86% yields. Alternatively, the (trimethylsilyl)methyl allenic alcohols afford iodobutadienyl carbinols when treated with N-iodosuccinimide.     

Syntheses of Enantiopure Aliphatic Secondary Alcohols and Acetates by Bioresolution with Lipase B from <em>Candida antarctica</em>

The lipase B from Candida antarctica (Novozym 435^?, CALB) efficiently catalyzed the kinetic resolution of some aliphatic secondary alcohols: (±)-4-methylpentan-2-ol (1), (±)-5-methylhexan-2-ol (3), (±)-octan-2-ol (4), (±)-heptan-3-ol (5) and (±)-oct-1-en-3-ol (6). The lipase showed excellent enantioselectivities in the transesterifications of racemic aliphatic secondary alcohols producing the enantiopure alcohols (>99% ee) and acetates (>99% ee) with good yields. Kinetic resolution of rac-alcohols was successfully achieved with CALB lipase using simple conditions, vinyl acetate as acylating agent, and hexane as non-polar solvent.     

Catalytic asymmetric transfer hydrogenation of ketones using terpene-based chiral β-amino alcohols

Catalytic asymmetric transfer hydrogenations of aromatic alkyl ketones have been studied using [RuCl₂(p-cymeme)]₂ and terpene-based β-amino alcohols. The limonene derived amino alcohol, (1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(methylamino)cyclohexanol gave the most promising results. Chiral secondary alcohols were obtained in good to excellent yields and moderate enantioselectivities (up to 71%).     

New functional chiral P-based ligands and application in ruthenium-catalyzed enantioselective transfer hydrogenation of ketones

Metal-catalyzed asymmetric transfer hydrogenation is a powerful and practical method for the reduction of ketones to produce the corresponding secondary alcohols, which are valuable building blocks in the pharmaceutical, perfume, and agrochemical industries. Hence, a series of novel chiral β-amino alcohols were synthesized by chiral amines with regioselective ring opening of (S)-propylene oxide or reaction with (S)-(+)-2-hydroxypropyl p-toluenesulfonate by a straightforward method. The chiral ruthenium catalytic systems generated from [Ru(arene)(μ-Cl)Cl]₂ complexes and chiral phosphinite ligands based on amino alcohol derivatives were employed in asymmetric transfer hydrogenation of ketones to give the corresponding optically active alcohols; (2S)-1-{[(2S)-2-[(diphenylphosphanyl)oxy]propyl][(1R)-1-phenylethyl]amino}propan-2-yldiphenylphosphinitobis[dichol-oro(η⁶-benzene)ruthenium(II)] acts an excellent catalyst in the reduction of α-naphthyl methyl ketone, giving the corresponding alcohol with up to 99% ee. The substituents on the backbone of the ligands were found to have a remarkable effect on both the conversion and enantioselectivity of the catalysts. Furthermore, this transfer hydrogenation is characterized by low reversibility under these conditions.     

Pd-catalyzed nucleophilic allylic alkylation of aliphatic aldehydes by the use of allyl alcohols

Under catalysis of Pd(OAc)₂-(P-n-Bu)₃, Et₂Zn promotes a variety of allyl alcohols to undergo nucleophilic allylation of aliphatic aldehydes and ketones at room temperature and provides homoallyl alcohols in 60-90 and ca. 60% isolated yield, respectively. The reaction is irreversible and kinetically controlled, and unique regio- and stereoselectivities observed for the allylation with unsymmetrically substituted allyl alcohols are discussed.     

Biginelli reaction starting directly from alcohols

An efficient of one-pot oxidative access to 3,4-dihydropyrimidin-2-(1H)-ones directly from aromatic alcohols under mild conditions is reported. The protocol involves 1-methylimidazolium hydrogen sulphate [Hmim]HSO₄ catalyzed oxidation of aromatic alcohols to aromatic aldehydes with NaNO₃ followed by their cyclocondensation with 1,3-dicarbonyl compounds and urea in the same reaction vessel at 80 °C within 2-4 h to afford 3,4-dihydropyrimidin-2-(1H)-ones in 55-97% overall yields. Thus, the present work utilizing alcohols instead of aldehyde in Biginelli reaction is a valid and green alternative to the classical synthesis of 3,4-dihydropyrimidin-2-(1H)-ones.     

One-pot synthesis of N-alkyl purine and pyrimidine derivatives from alcohols using TsIm: a rapid entry into carboacyclic nucleoside synthesis

A convenient and efficient one-pot N-alkylation of nucleobases from alcohols using N-(p-toluenesulfonyl)imidazole (TsIm) is described. In this method, treatment of alcohols with a mixture of purine or pyrimidine nucleobase, TsIm, K₂CO₃, and triethylamine in refluxing DMF regioselectively furnishes the corresponding N-alkyl nucleobases in good yields. This methodology is highly efficient for various structurally diverse primary alcohols.     

Asymmetric synthesis of secondary benzylic alcohols via arene chromium tricarbonyl complexes

(Aryl aldehyde)- and (aryl ketone)-chromium tricarbonyl complexes ortho-substituted with the chiral auxiliary O-methyl-N-(α-methylbenzyl)hydroxylamine undergo diastereoselective addition of Grignard reagents and Super-Hydride^®, respectively, to give the corresponding secondary alcohols in high diastereoisomeric purity. These compounds may be easily decomplexed and deprotected to give the corresponding enantiopure amino alcohols.     

Diastereoselective formation of 2-fluoro-2-trifluoromethyl-3,4-alkadienamides from propargyl alcohols and hexafluoropropene-diethylamine adduct (PPDA)

Treatment of propargyl alcohols (1) with hexafluoropropene-diethylamine adduct (PPDA) affords N,N-diethyl-2-fluoro-2-trifluoromethyl-3,4-alkadienamides (2) that are produced by the Claisen rearrangement of intermediary 2-alkynyl 1-(N,N-diethylamino)-2,3,3,3-tetrafluoro-1-propenyl ethers. Starting from propargyl alcohols bearing a triple bond at the terminal position, the corresponding products (2) were formed with a high stereoselectivity.     

Base-catalyzed cross coupling of secondary alcohols and aryl-aldehydes with concomitant oxidation of alcohols to ketones: An alternative route for synthesis of the Claisen-Schmidt condensation products

Base-catalyzed C–C cross coupling of secondary alcohols and aryl-aldehydes was achieved, when an alcoholic solution of an aryl-aldehyde was stirred under reflux for 45 h in the presence of a catalytic (20 mol%) amount of K₂CO₃. The consistent formation of α,α′-bis-(benzylidene) alkanones was obtained in moderate to good yields using various secondary alcohols and substituted aryl-aldehydes. Herein, α,α′-bis-(benzylidene)alkanones, which are the classical products of Claisen-Schmidt (cross aldol) condensation, have been synthesized via an alternative strategy using secondary alcohols. Bis-(benzylidene) alkanones are an integral part of various drug regimes and the production of bis-(benzylidene) alkanones without using any precious metal is a major outcome of the present reaction.     

An efficient access to (Z)-β-fluoroallyl alcohols based on the two carbon homologation of aromatic aldehydes by Horner–Wadsworth–Emmons reaction with 2-(diethoxyphosphinyl)-2-fluoro-ethanethioic acid,S-ethyl ester followed by reduction with sodium borohydride

We describe a biomimetic approach to (Z)-β-fluoroallyl alcohols based on the two carbon homologation of aromatic aldehydes to α-fluorocinnamic thioesters by Horner–Wadsworth–Emmons reaction with 2-(diethoxyphosphinyl)-2-fluoro-ethanethioic acid, S-ethyl ester, followed by reduction with sodium borohydride in mild conditions. The α-fluorothioesters were obtained in a good yield by condensing the aldehydes with the lithium anion of 2-(diethoxyphosphinyl)-2-fluoro-ethanethioic acid, S-ethyl ester in THF at ?78 °C. The (E,Z)-α-fluorocinnamic thioester mixtures were then cleanly reduced with double bond isomerisation to the corresponding (Z)-β-fluoroallyl alcohols by NaBH₄ at room temperature. This methodology may be applied to highly functionalized aldehydes as exemplified by the straightforward access to (Z)-β-fluoroconiferin, a strong inhibitor of lignin polymerization from O-glucosylated vanillin.     

A general method for the synthesis of enantiopure aliphatic chain alcohols with established absolute configurations. Part 2, via catalytic reduction of acetylene alcohol MαNP esters

A general method for synthesizing enantiopure (100% ee) aliphatic alcohols with established absolute configurations has been developed and applied to alcohols CH₃(CH₂)_n–CH(OH)–(CH₂)_mCH₃, the enantiomeric discrimination of which is the most difficult, if m = n + 1 and n is large. Racemic saturated alcohols with short chains could be directly enantioresolved as (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid) esters by HPLC on silica gel, and their absolute configurations were simultaneously determined by ¹H NMR diamagnetic anisotropy. However, the application of this powerful MαNP ester method to alcohols with long chains was difficult, because of smaller values of the separation factor α. In such cases, the use of the corresponding acetylene alcohol MαNP esters was crucial. Acetylene alcohol MαNP esters were largely separated by HPLC on silica gel, and their absolute configurations were unambiguously determined by ¹H NMR as reported in the Part 1 paper. The MαNP esters obtained with established absolute configurations were catalytically hydrogenated to yield saturated alcohol MαNP esters. It was evidenced that no racemization occurred at the stereogenic center of the alcohol moiety during catalytic hydrogenation, by the coinjection of MαNP esters in HPLC. From the MαNP esters obtained, enantiopure (100% ee) aliphatic chain alcohols with established absolute configurations were recovered. Although the [α]_D values of these alcohols were too small for the identification of the enantiomers, it was clarified that the analytical HPLC of MαNP esters is useful for identification in most cases.     

Application of chiral bidentate NMR solvents for assignment of the absolute configuration of alcohols: scope and limitation

The ¹³C NMR behaviors of several cyclic and biaryl secondary alcohols as well as acyclic tertiary alcohols have been studied in the chiral bidentate NMR solvent BMBA-p-Me (1). An empirical rule has been advanced to correlate the absolute configuration of each type of alcohols with the ¹³C chemical shift behaviors in (R,R)- and (S,S)-BMBA-p-Me.     

Intermolecular-medium and intramolecular-weak hydrogen bonding chains in the crystals of chiral trifluoromethylated amino alcohols

A structural feature of hydrogen bonding chains found in the crystals of trifluoromethylated amino alcohols is reported. Hydrogen bondings of 3-(N,N-dialkylamino)-1,1,1-trifluoro-2-propanols construct chiral spiral hydrogen bonding chains. Lone pairs on the nitrogen atoms of the amino alcohols participate in two hydrogen bondings. Detailed structural analysis of the hydrogen bonds of the 3-(N,N-dimethylamino)-1,1,1-trifluoro-2-propanol suggested that the chain built up with alternating intermolecular-medium and intramolecular-weak hydrogen bonds. The medium intermolecular hydrogen bond, which transfers a proton from the hydroxy group to the amino nitrogen, would make a tentative zwitterionic form of the molecule. Then, electrostatic attraction between the charges in the zwitterion centers induced a weak intramolecular hydrogen bond.     

Halogenative kinetic resolution of β-amido alcohols: chiral BINAP-mediated SN2 displacement of hydroxy groups by chlorides with inversion of stereochemistry

A series of optically active cyclic trans-β-amido alcohols were obtained by the non-enzymatic kinetic resolution of the corresponding racemic amido alcohols using commercially available (S)-BINAP and NCS by S_N2 halogenation of the hydroxy group. The product, cis-β-amido chloride, was also obtained in optically active form with an inversion of stereochemistry.     

Halogenative kinetic resolution of β-aryloxy cyclic alcohols: chiral BINAP-mediated SN2 displacement of hydroxy groups by chlorides with inversion of stereochemistry

A series of optically active cyclic trans-β-aryloxy alcohols have been obtained by non-enzymatic kinetic resolution of the corresponding racemic aryloxy cyclic alcohols using commercially available (S)-BINAP and NCS by S_N2 halogenation of a hydroxy group. The product, cis-β-aryloxy chlorides, was also obtained in optically active form with inversion of the stereochemistry.     

PCC-mediated novel oxidation reactions of homobenzylic and homoallylic alcohols

A new PCC-mediated carboncarbon bond cleavage reaction during oxidation of homobenzylic alcohols leading to the formation of benzylic carbonyl compounds has been observed. Homobenzylic alcohols with no benzylic substitution (R¹=H) gave benzylic aldehydes without further oxidation, while those with benzylic substitution (R¹=Me, Et, Ar) gave benzylic ketones. In contrast, homoallylic alcohols gave products arising from double bond migration, cis- to trans-olefin isomerization and/or allylic oxidation.     

N-(Phenylselenomethyl)phthalimide as new reagent for mild protection of alcohols as Pim-ethers

A mild activation of N-(phenylselenomethyl)phthalimide by iodonium ion in the presence of alcohols to give the corresponding O-phthalimidomethyl derivatives (Pim-ethers) is provided. Simple cleavage of the phthalimido group with ethylenediamine is also reported thus making this approach a new and efficient method of protecting alcohols.