Opening of aryl-substituted epoxides to form quaternary stereogenic centers: synthesis of (-)-mesembrine

[reaction: see text] Cycloalkanones are easily converted into aryl-substituted cyclic alkenes by the addition of an aryl Grignard reagent followed by dehydration. These alkenes are good substrates for asymmetric epoxidation. We have found that the addition of allylic and benzylic Grignard reagents can occur preferentially at the benzylic position of the derived epoxides to give the quaternary stereogenic center. This approach led to a short synthesis of the nanomolar serotonin re-uptake inhibitor (-)-mesembrine.     

Diastereoselective production of homoallylic alcohols bearing quaternary centers from gamma-substituted allylic indiums and ketones

Highly stereoselective In-employed addition of gamma-substituted allylic halides (cyclohexenyl halides, cinnamyl halides, and ethyl 4-bromocrotonate) to ketones is established to produce homoallyl alcohols bearing quaternary centers. The reactivity patterns and relative stability of allylic indiums were studied. The addition of water characteristically affected the reactions. Cyclohexenyl indium addition was completely disturbed, but a clear reaction was observed in the cinnamyl and crotonate-indium addition. In the case of ethyl 4-bromocrotonate, an interesting conversion of a gamma-adduct into an alpha-adduct was observed in anhydrous conditions.     

Enantioselective synthesis of alkyne-substituted quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution reactions with (i-Bu)2(alkynyl)aluminum reagents

A catalytic enantioselective method for the formation of alkyne-substituted all-carbon quaternary stereogenic centers is reported. Additions of alkynylaluminums to alkyl-, aryl-, carboxylic ester-, or silyl-substituted allylic phosphates are promoted by 1.0-5.0 mol % loadings of NHC-Cu complexes derived from air-stable and commercially available CuCl(2)·2H(2)O. The requisite Al-based reagents are prepared through treatment of the corresponding aryl-, heteroaryl-, alkyl-, or alkenyl-substituted terminal alkynes with diisobutylaluminum hydride in the presence of 5.0 mol % Et(3)N at ambient temperature. The desired 1,4-enynes are obtained in up to 98% yield and >99:1 enantiomeric ratio. Selected Au-catalyzed cyclizations involving the alkyne unit of the enantiomerically enriched products are presented as a demonstration of the method's utility in chemical synthesis.     

Selective synthesis of di(propen-1-yl)sulfone and di(propen-1-yl)sulfoxide

Convenient selective methods of synthesis of the title compounds, based on oxidation of di(propen-1-yl)sulfide with 30% H₂O₂, have been developed.Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, 664033 Irkutsk. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 3, pp. 675–679, March, 1992.     

Enantioselective synthesis of cyclic enol ethers and all-carbon quaternary stereogenic centers through catalytic asymmetric ring-closing metathesis

The first examples of catalytic asymmetric ring-closing metathesis (ARCM) reactions of enol ethers are reported. To identify the most effective catalysts, various chiral Mo- and Ru-based catalysts were screened. Although chiral Ru catalysts (those that do not bear a phosphine ligand) promote ARCM in some cases, such transformations proceed in <10% ee. In contrast, Mo-based alkylidenes give rise to efficient ARCM and deliver the desired products in the optically enriched form. Thus, Mo-catalyzed enantioselective transformations allow access to various five- and six-membered cyclic enol ethers in up to 94% ee from readily available achiral starting materials. The first examples of catalytic ARCM that lead to the formation of all-carbon quaternary stereogenic centers are also disclosed. Mechanistic models that offer a plausible rationale for the identity of major enantiomers as well as the observed levels of enantioselectivity are provided. Representative examples demonstrate that the enol ether moiety and the unreacted alkene of the ARCM products can be discriminated with excellent site selectivity (>98%).     

Diastereoselective alkylation and reduction of β-alkoxyacylsilanes: stereoselective construction of three contiguous stereogenic centers

The nucleophilic addition reaction to acylsilanes, having stereogenic centers at the α and β positions, derived from the aldol reaction of dimethyl acetals and acylsilane silyl enol ethers gives the corresponding α-silylalcohols in high yields with excellent diastereoselectivity. The protiodesilylation of α-silylalcohols proceeds with complete retention of the configuration. In addition, the reduction of acylsilanes having stereogenic centers at the α and β positions affords the corresponding α-silylalcohols in good yields with high diastereoselectivity similarly to the nucleophilic addition. And the treatment of acylsilanes having a phenyl group on silicon atom with fluoride ion results in the formation of phenyl carbinol derivatives via migration of the phenyl group with high diastereoselectivity.     

Organocatalytic asymmetric synthesis of 3(2H)-furanones with adjacent quaternary and tertiary stereocenters

An efficient stereoselective Michael addition of simple 3(2H)-furanones to α,β-unsaturated ketones has been described. The protocol provides a facile and efficient access to complex 3(2H)-furanones containing adjacent quaternary and tertiary stereocenters in high yields (up to 99%) with good diastereoselectivities (up to 86:14) and excellent enantioselectivities (up to 98% ee) under mild conditions.     

Synthesis of symmetrical di(pyrimidin-2-yl)-1,2,4-triazoles and di(pyrimidin-2-yl)-1,2,4,5-tetrazines

The reactions of pyrimidine-2-carbonitrile and 4,6-dimethylpyrimidine-2-carbonitrile with hydrazine hydrate were investigated. Intermediates in the route of successive transformations of pyrimidine-2-carbonitrile (pyrimidine-2-carbamidrazone and 1,2-bis[amino(pyrimidin-2-yl)methylidene]hydrazine) into trinuclear heterocyclic compounds, viz., symmetrical di(pyrimidin-2-yl)-1,4-dihydro-1,2,4,5-tetrazines and di(pyrimidin-2-yl)-4H-1,2,4-triazol-4-amines (potential polydentate ligands), were isolated. The oxidative dehydrogenation of di(pyrimidin-2-yl)-1,4-dihydro-1,2,4,5-tetrazines afforded the corresponding 3,6-di(pyrimidin-2-yl)-1,2,4,5-tetrazines.     

Enantiospecific synthesis of vicinal stereogenic tertiary and quaternary centers by combination of configurationally-trapped radical pairs in crystalline solids

[reaction: see text] Photochemical irradiation of crystalline (2R,4S)-2-carbomethoxy-4-cyano-2,4-diphenyl-3-butanone 1 led to highly efficient decarbonylation reactions. Experiments with optically pure and racemic crystals showed that the intermediate radical pairs undergo a highly diastereo- and enantiospecific radical-radical combination that leads to the formation of two adjacent stereogenic centers in good chemical yield and with high chemical control. Reactions with chiral crystals occurred with quantitative enantiomeric yields and >95% diastereomeric yields.     

Asymmetric synthesis of quaternary centers. Total synthesis of (-)-malyngolide

[structure] The deracemization of 3-nonyl-3,4-epoxybut-1-ene with Pd(0) in the presence of chiral ligands using p-methoxybenzyl alcohol as a nucleophile proceeds regio- and enantioselectively to form the monoprotected vinylglycidol in 99% ee. This chiral building block was converted in seven steps to (-)-malyngolide, an antibiotic showing significant activity against Mycobacterium smegmatis and Streptococcus pyogenes. An interesting aspect involves controlling the diastereoselectivity of protonation of an enolate via a distal hydroxyl group.     

5-phenyl-2H-tetrazol-2-ylmethyl ketones in the synthesis of tetrazolylalkanols and tetrazolyl(hydroxy)alkylphosphonates

The reduction of 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanone with sodium tetrahydridoborate gave 1-(5-phenyl-2H-tetrazol-2-yl)propan-1-ol and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanol, respectively. Only 1-(5-phenyl-2H-tetrazol-2-yl)propan-2-one was reduced with baker’s yeast with an appreciable yield. 1-(5-Phenyl-2H-tetrazol-2-yl)propan-2-one and 1-phenyl-2-(5-phenyl-2H-tetrazol-2-yl)ethanone reacted with diethyl phosphonate in the presence of potassium fluoride to produce the corresponding diethyl [hydroxy(5-phenyl-2H-tetrazol-2-yl)alkyl]phosphonates.     

Synthesis and properties of bis(heteroazulen-3-yl)methyl cations and bis(heteroazulen-3-yl)ketones

The synthesis and properties of a novel type of bis(heteroazulen-3-yl)methyl cations, bis(2-oxo-2H-cyclohepta[b]furan-3-yl)methyl cation salt and nitrogen analogues, (9a-c·PF₆⁻) and (9a-c·BF₄⁻), as well as bis(heteroazulen-3-yl)ketones (12a-d) are studied. The synthetic method was based on a TFA-catalyzed electrophilic aromatic substitution on the heteroazulenes (6a-d) with paraformaldehyde to afford the corresponding disubstituted methane derivatives 7a-d, followed by oxidative hydrogen abstraction with DDQ, and subsequent exchange of the counter-anion by using aq. HPF₆ or aq. HBF₄. In addition, the reaction of 7a-d with 2.2 equiv. amounts of DDQ afforded carbonyl compounds 12a-d. The delocalization of the positive charge of 9a-c was evaluated by the ¹H and ¹³C NMR spectral data. The thermodynamic stability of cations 9a-c was evaluated to be in the order 9a<9b<9c on the basis of their reduction potentials measured by cyclic voltammetry (CV) and pK_R+ values (2.6-10.3) obtained spectrophotometrically. The reduction waves of cations 9a-c were irreversible, suggesting the dimerization of the radical species generated by one-electron reduction. This was demonstrated by the reduction of 9a·BF₄⁻ with Zn powder to give dimerized product 14a. In addition, the quenching of 9a·BF₄⁻ with MeOH/NaHCO₃ gives ether derivative 15a, which is proposed for the precursor for synthesizing tris(heteroazulene)-substituted methyl cations bearing two different heteroazulene-units.     

Acid catalyzed rearrangements of aryl 3-(2-nitroaryl)oxiran-2-yl ketones

Russian Chemical Bulletin - Studies of chemical behavior of aryl 3-(2-nitrophenyl)oxiran-3-yl ketones in acidic medium revealed the possible occurrence of two competitive rearrangements leading to...     

Diastereoselective synthesis of (R*,R*)-ethyl 2-[1H-indol-3-yl(phenyl)methyl]-3-oxobutanoate

Russian Chemical Bulletin -     

Efficient and selective synthesis of alkoxy substituted di(pyridin-2-yl)amines and N-arylpyridin-2-ylamines

The formation of alkoxy substituted di(pyridin-2-yl)amines and N-arylpyridin-2-ylamines by nitro group reduction is described. Unexpected substitution of ortho with the amino at C-6 was observed during the reduction using SnCl₂·2H₂O in different alcohols. The influence of the nature of the atom at the 3- and 5-positions of nitro-substituted di(pyridin-2-yl)amines and N-arylpyridin-2-ylamines was investigated.     

FeCl3-catalyzed efficient synthesis of di(5-methylfuran/thiophen-2-yl)isatin analogues

A simple, inexpensive, environmentally friendly, and high yield protocol is described for the synthesis of (5-methylfuran/thiophene-2-yl)isatin by the reaction of 2-methylfuran/2-methylthiophene with isatin/isatin imine in the presence of FeCl₃. The present protocol is ideal for the direct introduction of 2-methylfuran/2-methylthiophene onto isatin at 3-position with complete regioselectivity.     

Solvent-free microwave assisted synthesis of substituted (E)-phenyl{3-(2-[1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-4-yl]vinyl)benzofuran-2-yl}methanones and their antimicrobial activity

Russian Journal of General Chemistry - New substituted (E)-phenyl{3-(2-[1-phenyl-3-(thiophen-2-yl)-1H-pyrazol-4-yl]vinyl)benzofuran-2-yl}methanones have been synthesized from substituted...     

The synthesis of a series of (α-amino)indol-3-yl ketones

A series of [(α-amino)indol-3-yl]-2-methyl-1-propanones and [(α-amino)indol-3-yl]cyclopentylmethanones has been synthesized by a variety of reductive reactions performed on the corresponding series of (α-azido)-indol-3-yl ketones. One of the more interesting reductive procedures involved the palladium-catalyzed decomposition of formic acid with the formation of hydrogen in situ. The (α-azido)ketones were prepared in excellent yield by the displacement of the tertiary bromine atom from the (α-bromo)ketones using sodium azide in N,N-dimethylformamide. Bromination was accomplished by using either cupric bromide in ethyl acetate/chloroform or phenyltrimethylammonium tribromide in tetrahydrofuran.