Desymmetrisation of a meso-N-hydroxyimide via a chiral Lossen reaction

N-[(1S)-10-Camphorsulphonyloxy]norborn-5-ene-endo-2,3-dicarboximide 2 underwent a Lossen type reaction with dicyclohexylmethylamine to furnish endo-2-methoxycarbonyl-endo-3-(methoxycarbonylamino)norborn-5-ene 3, in 84% yield and 33% e.e. (by NMR).     

Mycorrhizin a and chloromycorrhizin a,two antibiotics from a mycorrhizal fungus of monotropa hypopitys L.

Two new compounds, mycorrhizin A and chloromycorrhizin A, have been isolated from a mycorrhizal fungus of Monotropa hypopitys, L. and their structures established as 1(S), 6(S),9(R) - 6 - hydroxy - 8,8 - dimethyl - 4 - (1 - chloro - prop -1 - enyl) - tricyclo[4.4.0.0^1.9] - 7 - oxa - dec - 3 - ene - 2,5 - dione and its 3-chloro derivative. Several derivatives were prepared and characterized.     

Optimisation of a key cross-coupling reaction towards the synthesis of a promising antileishmanial compound

During the course of a research program aimed at identifying novel antileishmanial compounds, a multi-gram synthesis of N-(trans-4-((4-methoxy-3-((R)-3-methylmorpholino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)cyclohexyl)-2-methylpropane-1-sulfonamide ((R)-1) was required. This letter describes optimisation of the reaction conditions and protecting group strategy for a key Buchwald-Hartwig coupling, delivering the required quantities of (R)-1, as well as further compounds in the series.     

Convenient construction of a variety of glycosidic linkages using a universal glucosyl donor

This letter deals with the concept of constructing four types (cis-α, trans-α, cis-β, and trans-β) of glycosidic linkages using a universal glucosyl donor. The selectively protected universal glucosyl donor 8 was synthesized in 36% yield from d-glucose (eight steps). The donor 8 undergoes glycosidation with a primary carbohydrate alcohol 7 to give disaccharide 9 having a 1,2-cis-α-glycosidic linkage in 90% yield. The construction of the corresponding 1,2-trans-α-glycosidic linkage was performed in 68% yield (three steps) from 9. A similar glycosidation of the 2-O-(N-phenylcarbamoyl)-glucosyl donor 6 derived from 8 with 7 gave disaccharide 11 having a 1,2-trans-β-glycosidic linkage in 75% yield. The construction of the corresponding 1,2-cis-β-linkage was performed in 53% yield (three steps) from 11.     

Synthesis and properties of a novel nucleoside derivative possessing a 2,3,5,6-tetraazabenzo[cd]azulene skeleton

We describe herein the synthesis and properties of the novel nucleoside derivative, 4,7-diamino-2-(2-deoxy-β-d-erythro-pentofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulene (1). The palladium catalyzed cross-coupling reaction of 2,4-diamino-5-iodo-7-(2-deoxy-β-d-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (9) with acrylonitrile afforded 2,4-diamino-5-[(E)-1-cyano-2-ethenyl]-7-(2-deoxy-β-d-erythro-pentofuranosyl)pyrrolo[2,3-d]pyrimidine (10) in 77% yield, which was treated with NaOMe in MeOH in the presence of NaSPh to give the desired 1 in 64% yield. Whereas 1 was stable in concentrated ammonia at room temperature, it was gradually hydrolyzed in water to give 4-amino-2-(2-deoxy-β-d-erythro-pentofuranosyl)-2,6-dihydro-7H-2,3,5,6-tetraazabenzo[cd]azulen-7-one (12). Density functional calculations indicated that 12 was 20 kcal/mol more thermodynamically stable than 1 in a model study.     

Practical and efficient synthesis of the (R)-atropisomer of a 4-phenyl 1,2,4-triazole derivative as a selective GlyT1 inhibitor

Herein we describe a novel and efficient method for synthesizing the (R)-atropisomer of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzonitrile 1, a novel GlyT1 inhibitor. The diastereomeric salt formation of 3-[3-ethyl-5-(6-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl]-2-methylbenzoic acid 7 with (1R,2S)-(?)-2-amino-1,2-diphenylethanol afforded the desired (R)-atropisomer. We also report the determination of the absolute configuration of (R)-7 by powder X-ray diffraction.     

Biocatalytic reduction of a racemic selenocyclohexanone by Brazilian basidiomycetes

An efficient synthesis of the chiral cyclic secondary alcohols, trans-2-(phenylseleno)cyclohexanol 1a and cis-2-(phenylseleno)cyclohexanol 1a, was obtained by enzymatic reduction of 2-(phenylseleno)cyclohexanone 1 using whole fungal cells. Five strains of white-rot basidiomycetes were examined; Irpex lacteus CCB 196, Pycnoporus sanguineus CCB 196, Trametes rigida CCB 285, Trametes versicolor CCB 202 and Trichaptum byssogenum CCB 203. Cells of T. rigida CCB 285 gave alcohols cis-(RS)-1a and trans-(SS)-1a in high enantiomeric excesses (ca. 99%).     

Template synthesis of a macrocycle with a mixed NHC/phosphine donor set

Reaction of cis-[ReCl(NHC)(CO)₄] cis-[1] (NHC = NH,NH-substituted saturated cyclic diaminocarbene) with diphosphine (2-F-C₆H₄)₂P-CH₂CH₂-P(C₆H₄-2-F)₂2 yields complex fac-[Re(NHC)(2)(CO)₃]Cl fac-[3]Cl. Deprotonation of the NH,NH-NHC ligand in fac-[3]Cl with KOtBu leads to an intramolecular nucleophilic aromatic substitution of one fluorine atom from each -P(C₆H₄-2-F) group by the NHC ring nitrogen atoms with formation of complex fac-[4]Cl bearing a facially coordinated [11]ane-P₂C^NHC ligand. Reaction of cis-[MnBr(NHC)(CO)₄] cis-[5] (NHC = NH,NH-substituted saturated cyclic diaminocarbene) with diphosphine 2 yields complex [MnBr(NHC)(2)(CO)₂] [6] without substitution of the bromo ligand and with the phosphine donors from the bidentate diphosphine occupying one cis and one trans position to the NHC donor.     

Synthesis and isolation of a monoamine having a thermodynamically stabilized pseudo-chirotopic nitrogen

We have synthesized a tricyclic monoamine, (1S,4R)-(E)-7,3′-heptenylene-2,3:5,6-dibenzo-7-azabicyclo[2.2.1]heptane (1), by applying a ring-closing metathesis reaction in the key step of the synthetic route and by using preparative chiral HPLC for the separation. The X-ray crystallographic analysis of its salt with (1R)-camphor-10-sulfonic acid showed that the geometry and absolute configuration are (E) and (1S,4R), respectively. The theoretical calculations revealed that the inversion of the nitrogen atom at the 7-position of (1S,4R)-(E)-1 thus isolated takes place through a very slow process and that the configuration of the N(7) is highly biased to (R), indicating that (1S,4R)-(E)-1 is a thermodynamically controlled N-pseudo-chirotopic compound ((1S,4R,7R): (1S,4R,7S) = 99.68:0.32 at 120 °C).     

Hexitol derivatives containing a 1,4-oxathiane ring—III : Rearrangement of a sulfone on treatment with LAH

Treatment of 2,5 - anhydro - 3,4 - di -O- mesyl - 1,6 - thioanhydro - D - glucitol S,S-dioxide (1) with LAH afforded (1S,6R)-2-thiabicyclo[4.1.0]heptane S,S-dioxide (2) and its (4R) - 4 -hydroxy derivative 3 in a ratio of 46:6. Sodium - dihydro - bis(2 - methoxy - ethoxy) - aluminate afforded the same compounds in a ratio of 15:22. The corresponding sulfide 5 underwent no rearrangement under similar conditions. The structure of the products was established by IR, PMR, CMR and MS. A probable reaction mechanism is discussed.     

Synthesis and reactivity of a 1,4-dihydropyrazine derivative

N,N-Bis-(tert-butoxycarbonyl)-2,5-bis-methoxycarbonyl-1,4-dihydropyrazine can be obtained in high yield by treatment of the methyl ester of N-(4-toluenesulfonyl)-N-(tert-butoxycarbonyl)-α,β-didehydroalanine with dimethylaminopyridine and potassium carbonate. This compound was used as substrate in Michael addition reactions with several types of nucleophiles. The electrochemical behaviour of this pyrazine derivative was also studied by cyclic voltammetry and by controlled potential electrolysis.     

The unexpected conversion of a thiophene ring into a pyrrole ring via a putative nitrene intermediate

Triethylphosphite induced reductive cyclisation of 1-(2-nitrophenyl)-3,5-di(2-thienyl)pyrazole 6 afforded the expected 1,3-di(2-thienyl)pyrazolo[1,2-a]benzotriazole 7 (14%) together with an unexpected product which was shown to be a 2-(2-thienyl)pyrazolo[1,5-a]pyrrolo[2,1-c]quinoxaline 8 derivative (27%). A mechanism for the extrusion of sulfur during the transformation of heterocycle 6 into product 8 is proposed.     

Synthesis of a d,d- and l,d-heptose-containing hexasaccharide corresponding to a structure from Haemophilus ducreyi lipopolysaccharides

The synthesis of a linear hexasaccharide, 2-(4-trifluoroacetamidophenyl)ethyl (β-d-galactopyranosyl)-(1→4)-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-(1→3)-(β-d-galactopyranosyl)-(1→4)-(d-glycero-α-d-manno-heptopyranosyl)-(1→6)-(β-d-glucopyranosyl)-(1→4)-l-glycero-α-d-manno-heptopyranoside, corresponding to a structure found in Haemophilus ducreyi LPS, is described. A Barbier reaction between benzyloxymethyl chloride and a properly protected 6-aldo-1-thio-mannopyranoside yielded both the d,d- and the l,d-heptopyranoside (2 and 3, ratio 2:3), which were separated and both used in the synthesis. p-Methoxybenzyl and chloroacetyl groups were employed as temporary protecting groups, selectively removed in the presence of the persistent benzyl, acetyl, benzoyl and isopropylidene groups by treatment with DDQ/H₂O and hydrazine dithiocarbonate, respectively. Thioglycosides were utilised as donors throughout using either NIS/TfOH or DMTST as promoters. The introduction of the spacer into thioglycoside 5 was high-yielding (95%) but with low stereoselectivity (α:β 5:3). All other glycosylations are completely stereoselective. The target hexasaccharide is obtained via a 3+3 block approach with the yield in the final NIS/TfOH-promoted coupling between an N,N-diacetyl-trisaccharide thioglycosyl donor 20 and a 4′′-OH trisaccharide acceptor 13 being 75%.     

Synthesis of aromatic carbamates derivatives with a chromen-2-one fragment

Condensation of methyl N-(3-hydroxyphenyl)carbamate with ethyl trifluoromethylacetoacetate, 2-methoxyethyl acetoacetate in the presence of conc. sulfuric acid, and also with acetonedicarboxylic acid formed in situ from citric acid under the action of conc. sulfuric acid afforded chromene derivatives. The esterification of 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}acetic acid with methanol in the presence of TsOH provided the corresponding ester. The oxidation of its α-methylene group with selenium dioxide led to the formation of methyl 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}-2-oxo-acetate entering into a condensation with o-phenylenediamine resulting in a derivative with a dihydroquinoxaline fragment. The reaction of phenyl N-(4-formylphenyl)carbamate with 3-acetyl-2H-chromen-2-one in butanol in the presence of catalytic quantity of piperidine and acetic acid furnished 4-[(E)-3-oxo-2H-chromen-3-yl)-1-propenyl]phenyl N-phenylcarbamate.     

Synthesis of both RP and SP enantiomers of unsymmetrical methylphosphonates based on a new approach utilizing a P-ester bond with α-hydroxyacids

Condensation of methyl methylphosphonochloridate with the dilithium salt of 2-methyllactic acid gave P-racemic methylphosphonates which unexpectedly contained two units of α-hydroxyacid linked via carboxylic ester bond. The racemic mixture was chromatographically separated via diastereomeric salts with quinine or cinchonine to give, based on the X-ray analysis, pure (R_P)-(+) and (S_P)-(−) enantiomers. Both enantiomers were immobilized on the ArgoGel^®–OH solid support. Condensation of methyl methylphosphonochloridate with α-hydroxyacid methyl esters [2-methyllactate, (S_C)-(−)-lactate, methyl (S_C)-(+) and (R_C)-(−)-mandelates] gave chromatographically inseparable 1:1 mixtures of diastereomers in 63–69% yields. A basic hydrolysis of the latter resulted in a selective and unexpected cleavage of the P–OMe group in a quantitative yield [(S_C)-(+) and (R_C)-(−)-mandelates, (S_C)-(−)-lactate] or simultaneous cleavages of P–OMe and C(O)OMe groups (2-methyllactate).     

Resolution of omeprazole by inclusion complexation with a chiral host BINOL

Both (S)-(−)- and (R)-(+)-enantiomers of omeprazole were directly resolved by inclusion complexation with a chiral host compound (S)-(−)- or (R)-(+)-2,2′-dihydroxy-1,1′-binaphthyl in high enantiomeric excess (>99% e.e.).     

Skipped diynes—VII : Stereospecific thermal isomerization of a tetraethynyldimethylenecyclobutane

1,1-Bis(t-butylethynyl)-3-t-butylchloroallene (1) dimerizes stereospecifically at ca 25° to give Z - 1 - (t - butylchloromethylene) - 2- bis(t - butylethynylmethylene) - 3 - t - butyl - 3 - chloro - 4,4 -bis(t - butylethynyl)cyclob Z-I in the solvent bis(2 - ethoxyethyl) ether. Rate data for 100° are k = 111 × 10^?6 sec^?1, ΔH^≠ = 30·8 ± 1 kcal/mole and ΔS^≠ = 15 ± 3 eu. It is proposed that the dimerization of 1 produces a bisallyl diradical in an orthogonal conformation from which conrotatory paths lead to Z-I or trans-II. The observations on this system are used to construct a useful, if simplistic, approach to rationalize or predict product distributions in reactions such as allene dimerizations, 1, 2 - dimethylenecyclobutane rearrangements, etc, which proceed through the bisallyl diradical. On the graph which connects all of the species (or on the energy surface which contains all of the species) the first products should be those which are one allowed reaction step away from a given diradical. Applications and exceptions to this concept of favored kinetic control are discussed.     

A chemoenzymatic synthesis of both enantiomers of a cis-lignan lactone

The stereoselective acetylation of meso-2,3-bis(3,4-dimethoxybenzyl)butanediol by vinyl acetate in the presence of Candida antarctica lipase in benzene gave the corresponding (+)-(2S,3R) monoester (ee ≥98%). Transesterification of meso-2,3-bis(3,4-dimethoxybenzyl)butyl diacetate, in the presence of the same enzyme, by ethanol in benzene/isopropyl ether gave the corresponding (−)-(2R,3S) monoester (ee ≥98%). Both enantiomers of the known cis-2,3-bis(3,4-dimethoxybenzyl)butyrolactone were synthesized from these monoesters.     

Synthesis,resolution and absolute configuration of a tolperisone metabolite

1-(4′-Hydroxymethyl-phenyl)-2-methyl-3-(piperidine-1-yl)-propane-1-one M2, a metabolite of tolperisone, was synthesised in a solvent-free Mannich reaction. The optical resolution was carried out by diastereoisomeric salt formation and separation, for which three resolving agents ((2R,3R)-O,O′-dibenzoyl tartaric acid, (2R,3R)-O,O′-di-p-toluoyl tartaric acid and (R)-2-hydroxy-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide (anicyphos)) were found. The absolute configuration of M2 was determined by the single-crystal X-ray diffraction method.     

Improved synthetic methods of CP-060S,a novel cardioprotective drug

Two synthetic methods of CP-060S, (−)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amino]propyl]-1,3-thiazolidin-4-one (−)-1, have been developed. The first method involved preparative HPLC resolution of bromo-intermediate 4. The second one involved resolution of 1 by crystallization of the corresponding diastereomeric salt.