Enantioselective syntheses of isoprostane and iridoid lactones intermediates by enzymatic transesterification

Crude Pseudomonas cepacia lipase (Amano PS-30) is a suitable biocatalyst for the kinetic resolution of the 1,2-cis-disubstituted cyclopentanoid building block (3aR*,4R*,6aS*)-(±)-4-hydroxymethyl-3,3a,4,6a-tetrahydrocyclopenta[b]furan-2-one through enantioselective transesterification. Enantiomerically enriched acetic acid (3aS,4S,6aR)-(+)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-4-yl methyl ester was utilized in a formal synthesis of the iridoids (+)-isoiridomyrmecin and (−)-teucriumlactone.     

Enantiospecific first total synthesis of (6S,7R)-silphiperfolan-6-ol

Enantiospecific first total synthesis of the angular triquinane sesquiterpene (6S,7R)-silphiperfolan-6-ol has been accomplished, starting from 2-(3-isopropenyl-2-methylene-1-methylcyclopent-1-yl)acetic acid (readily available from (R)-limonene) employing an efficient, regioselective intramolecular rhodium carbenoid insertion into the CH bond of a tertiary methyl group as the key step.     

Design,synthesis, resolution,and stereochemical assignment of a conformationally rigid chiral ligand derived from anthracene and a dienophile containing a pyridine moiety

The conformationally rigid chiral ligand, trans-12-(pyridin-2-yl)-9,10-dihydro-9,10-ethanoanthracene-11-carboxylic acid ethyl ester, 1, was designed and synthesized in racemic form. Both isomers were successfully obtained in enantiomerically pure form through classical resolution using l-(+)-tartaric acid in acetonitrile. The nature of the diastereomeric complex formed in this resolution was elucidated using single crystal X-ray crystallographic studies. The absolute configuration of (+)-1 was unambiguously assigned as (11S,12S) by single crystal structural analysis of salt 5 formed from (+)-1 and l-(+)-tartaric acid.     

Diastereoselective total synthesis of (+)-morusimic acid B, an amino acid from Morus alba

An efficient, flexible and diastereoselective synthesis of the naturally occurring pyrrolidine amino acid, (+)-morusimic acid B, has been accomplished. Starting from chiral, optically active (+)-(3S)-hydroxy butyric acid methyl ester the key steps of our synthesis are diastereoselective α-alkylation of its dianion to introduce the main part of the side chain, Curtius rearrangement of the hydrazide derivative to a 2-oxazolidinone followed by N→π-cyclization with mercury(II) acetate to generate the cis-2,5-disubstituted pyrrolidine ring. The remote C-3 stereocentre is established after chain elongation with the dianion of methyl acetoacetate and asymmetric hydrogenation of the resulting β-oxoester with Noyori's Ru(II)-(R)-BINAP catalyst.     

A convenient and new approach to the synthesis of ω-heterocyclic amino acids from carboxy lactams through ring-chain-transformation. Part 2: Synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid

Making use of amide activation, a convenient and short path synthesis of optically pure ω-heterocyclic-β-amino acids has been achieved from (1R,3R)- and (1R,3S)-5-oxo-1-(1-phenyl-ethyl)-pyrrolidine-3-carboxylic acid methyl ester. The key step of the synthesis involves a regiospecific ring-chain-transformation of the enaminones when subjected to 1,2-binucleophilic attacks. The method is illustrated by the synthesis of (2R)-/(2S)-2-aminomethyl-3-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)-propionic acid.     

Determination of absolute configuration using vibrational circular dichroism spectroscopy: phenyl glycidic acid derivatives obtained via asymmetric epoxidation using oxone and a keto bile acid

The (+)-enantiomers of the o-Br, m-F and p-CH₃ derivatives of trans phenyl glycidic acid have been obtained from the corresponding trans cinnamic acid derivatives using Oxone and the tri-keto bile acid dehydrocholic acid. Vibrational circular dichroism (VCD) spectroscopy of their methyl esters has been used to determine their absolute configurations. In each case, the absolute configurations of both methyl ester and parent acid were shown to be (2S,3R)-(+)/(2R,3S)-(−).     

A novel glyceryl ester (glyceryl dendryphiellate A), a trinor-eremophilane (dendryphiellin A1), and eremophilanes (dendryphiellin E1 and E2) from the marine deuteromycete Dendryphiella salina (SUTHERLAND) PUGH et NICOT

Continuing studies of the global extracts from cultures of the marine deuteromycete Dendryphiella salina have led to the isolation of novel compounds that add to the scarce list of marine fungal metabolites. Besides (22E)-ergosta-4.6,8(14),22-tetraen-3-one which, though known from basidiomycetes, was unknown in the sea, they are an unusual glyceryl ester, i.e. glycer-1-yl dendryphiellale A (= (+)-(2R)-2,3-dihydroxyprop-l-yl (6S,2E,4E)6-methylocta-2,4-dienoate; (+)- 1 ), a trinor-eremophilane, i.e. dendryphiellin A1 ( = (+)-(3R*,4E,6E)-7-{[(1R*,2S*,7R*,8aR*)-1,2,6,7,8,8a-hexahydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2yl]oxycarbonyl}-3-methylhepta-4,6-dienoic acid; (+)- 11 ), and two eremophilanes, i.e. dendryphiellin El ( = (+)-(1R*, 2S*, 7S*,8aR*)-1,2,6,7,8,8a-hexahydro-1,8a-dimethyl-7-(1-methylethenyl)-6-oxonaphthalen-2-yl(6S,2E,4E)-6-methyl-octa-2,4-dienoate; (+)- 13 ) and dendryphiellin E2 ( = (+)-(1R*, 2S*, 8aR*)-1,2,6,7,8,8a-hexahydro-7-isopropyl-idene-1,8a-dimethyl-6-oxonaphthalen-2-yl (6S,2E,4E)-6-Methylocta-2,4-dienoate; (+)- 14 ). Absolute configurations have been established for (+)- 1 via total synthesis and for the acid portion of (+)- 13 and (+)- 14 via transesterification in NaOMe/MeOH which gave in both cases melhyl dendryphiellate A ((+)- 16 ) of known configuration and the free alcoholic moiety of (+)- 14 , i.e. (+)- 17 .     

Synthesis of methyl (E)-2-[(3S,4S)-4-hydroxy-3-(pent-3-yloxy)-pyrrolidin-2-ylidene]propanoate and its unusual recyclization

Methyl (2E,4S,5S)-5-hydroxy-6-mesyloxy-2-methyl-4-(pent-3-yloxy)hex-2-enoate was synthesized from l-tartaric acid. Attempted substitution of the mesyloxy group by the reaction with NaN₃ directly led to methyl (E)-2-[(3S,4S)-4-hydroxy-3-(pent-3-yloxy)pyrrolidin-2-ylidene]propanoate. The latter on treatment with CF₃COOH and then NaOH gave methyl (2E)-2-methyl-4-[(S)-oxiran-2-yl]-4-(pent-3-yloxy)but-2-enoate.     

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.     

Enantioselective synthesis of Fmoc-l-3-(2-benzothienyl)alanine (2-BtAla) via diastereoselective alkylation of a glycine equivalent

Stereoselective alkylation of the anion derived from (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with 2-chloromethylbenzothiophene afforded the corresponding trans-monosubstituted product, (2S,5R)-2-((1-benzo[b]thiophen-2-yl)methyl)-3,6-dimethoxy-5-(propan-2-yl)-2,5-dihyropyrazine in 88% yield. Hydrolysis of the alkylated product using 40% TFA/H₂O at 0?°C and subsequent protection of the α-amino functional group with Fmoc-OSu afforded Fmoc-l-3-(2-benzothienyl)alanine methyl ester in 88% yield. Hydrolysis of the methyl ester with aqueous LiOH gave Fmoc-l-3-(2-benzothienyl)alanine in 62% overall yield.     

Synthesis and analytical properties of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid

2-Methoxy-2-(9-phenanthryl)propionic acid was synthesized as a novel chiral resolving agent. The absolute configuration of (+)-2-methoxy-2-(9-phenanthryl)propionic acid was determined to be S by using X-ray structural analysis of the (1R,2S,5R)-menthyl ester. In the crystal, the methoxyl and carbonyl groups of the ester are in a syn-periplanar position. The syn-periplanar conformations of (1R,2S,5R)-menthyl esters were also observed by the NMR analyses in CDCl₃. The utility of (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid was exemplified by the resolution of (±)-3-octanol.     

Stereoselective synthesis of new (+)-1-{(1R,3R,6S)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl}ethan-1-one derivatives

A procedure was developed for the stereoselective synthesis of aminated derivatives of (+)-1-{(1R,3R,6S)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl}ethan-1-one. The configuration of the side-chain chiral center in (+)-1-{(1R,3R,6S)-4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-yl}ethan-1-ol was determined by X-ray analysis. Diketene and Meldrum’s acid were proposed as initial compounds for the synthesis of, respectively, 3-oxobutanoic and malonic acid esters having a 1-ethyl-4,7,7-trimethylbicyclo[4.1.0]hept-4-ene fragment.     

Arylacetic acid derivatization of 2,3- and internal erythro-squalene diols. Separation and absolute configuration determination

We have studied a new approach for the resolution and absolute configuration determination of the enantiomers of squalene diols as intermediate precursors in the chemical synthesis of different squalene oxides (SOs); (3R)- and (3S)-2,3-SO, (6R,7R)- and (6S,7S)-6,7-SO, and (10R,11R)- and (10S,11S)-10,11-SO. Monoderivatization of the corresponding racemic squalene diol intermediates with pure stereoisomers of (S)-(+)-methoxyphenyl acetic acid ((S)-(+)-MPA), (S)-(+)-9-anthrylmethoxyacetic acid ((S)-(+)-9-AMA) and (S)-(+)-acetoxyphenylacetic acid ((S)-(+)-APA) afforded the diastereomeric esters which could be easily separated by column flash chromatography with silica gel. In addition, the absolute configuration for these diastereoisomers of the derivatized diols was advantageously inferred from ¹H NMR data according to the models depicted for these derivatizing chiral agents. In order to demonstrate the absolute configuration assignment of the different stereoisomers, (S)-(+)-AMA showed the larger Δδ by ¹H NMR, however, (S)-(+)-MPA esters were much more stable derivatives.     

The absolute stereochemistry of cascarillic acid

((1S,2R)-2-Hexylcycloprop-1-yl)acetic acid has been synthesised from cis-1,2-dihydroxymethylcyclopropane and shown to be identical to cascarillic acid obtained from cascarilla essential oil.     

Synthesis of 2,5-diaryl-1,3-oxazoles containing a carbamate group

Acetophenones containing a methoxycarbonylamino group in position 2, 3, or 4 of the aromatic ring reacted with phenylglycine in the presence of 2 equiv of iodine and 0.5 equiv of sulfanilic acid in DMSO at 100°C for 6 h to give methyl [2(3,4)-(2-phenyl-1,3-oxazol-5-yl)phenyl]carbamates. The reaction was presumed to involve intermediate formation of methyl [(iodoacetyl)phenyl]carbamate. This was confirmed by the isolation of methyl [2-(iodoacetyl)phenyl]carbamate in the reaction of methyl (2-acetylphenyl)carbamate with iodine in glacial acetic acid and its subsequent transformation to methyl [2-(2-phenyl-1,3-oxazol-5-yl)-phenyl]carbamate.     

A practical synthesis of enantiopure β-methyltryptophan ethyl ester for a preparation of diabetes drug

A practical synthesis of (2R,3S)- and (2S,3R)-β-methyltryptophan ethyl ester (β-MeTrp-OEt) has been developed. Racemic threo-β-MeTrp-OEt was diastereoselectively prepared via crystallization-induced diastereomer transformation (CIDT) of the α-nitro equivalent of β-MeTrp-OEt. The enantiomers were resolved via diastereomeric salt formation using a half equivalent of (R)-2-(4-hydroxyphenoxy)propionic acid. The process allowed a diabetes drug candidate N-[(1R,2S)-1-({5-[(dimethylamino)methyl]-2-ethoxyphenyl}aminocarbonyl)-2-(1H-indol-3-yl)propyl]-4-phenyl-1-piperidinecarboxamide to be prepared in good yield with high quality.     

Proof of the Absolute Configuration of (−)-(S)-2-Hydroxy-β-ionone by correlation with ursolic acid and with (−)-trans-verbenol

(?)-(S)-2-Hydroxy-β-ionone ( 33 ), (+)-(2 S, 6 S)-2-hydroxy-α-ionone ( 34 ), and their acetates 35 and 36 have been synthesized from (+)-(S)-6-methylbicyclo [4.3.0]-non-1-ene-3, 7-dione ( 3 ). The key intermediate (+)-(1 R, 3 S, 6 S)-2, 2, 6-trimethyl-7-oxobicyclo [4.3.0]non-3-yl acetate ( 7 ) was correlated with a degradation product of the pentacyclic triterpene ursolic acid ( 16 ). Compound 33 was also synthesized by an alternative route starting from (?)-trans-verbenol ( 42 ).     

Preliminary studies on a novel synthesis of β-amino acids: stereocontrolled transformation of d- and l-glyceraldehyde into 3-amino-2-(2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)propanoic acids

A stereocontrolled synthesis of the methyl ester of (2S)-3-amino-2-((4′S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)propanoic acid from d-glyceraldehyde is described for the first time. This method involves the stereoselective Michael addition of the lithium salt of tris(phenylthio)methane to (S)-2,2-dimethyl-4-((E)-2-nitrovinyl)-1,3-dioxolane followed by hydrolysis of the resulting (4S)-2,2-dimethyl-4-((2′S)-3′-nitro-1′,1′,1′-tris(phenylthio)propan-2′-yl)-1,3-dioxolane to (2S)-methyl 2-((4′S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)-3-nitropropanoate, which was finally reduced to the target compound. A similarly stereocontrolled transformation of l-glyceraldehyde into (2R)-methyl 3-amino-2-((4′R)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl)propanoate is also described.     

Synthesis and characterization of novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and dihydro-alkylthio-benzyloxopyrimidine (S-DABO) analogs containing a benzo[<Emphasis Type="Italic">d</Emphasis>]thiazol moiety

A series of novel dihydro-alkylthio-benzyloxopyrimidine (S-DABO) and 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio)thymine (HEPT) analogs bearing a (benzo[d]thiazol-2-yl)methyl moiety at the C⁶ position of the pyrimidine core have been synthesized. 5-Allyl-6-{(benzo[d]thiazol-2-yl)methyl}-2-thiouracil and 5-allyl-6-{(benzo-[d]thiazol-2-yl)methyl}uracil were alkylated to give, respectively, S²- and N¹- ethoxymethyl and -methylthiomethyl uracil derivatives. 5-Allyl-6-[(benzo[d]thiazol-2-yl)methyl]-2-thiouracil was also alkylated by S² with methyl bromoacetate and hydrolyzed to the corresponding acid.     

New atropoisomeric alkenylphenylglycine derivatives: Synthesis of (5R*)- and (5S*)-isomers of (1R*,3aR*,4S*,11S*)-3a,5,9,11-tetramethyl-4,5-dihydro-3aH-1,4-methano[1,3]oxazolo[3,2-a]quinolin-2-one

We synthesized methyl ester of N-(1-methylbut-2-en-1-yl)-N-phenylglycine which underwent acid catalyzed aromatic amino Claisen rearrangement to provide methyl-N-[2-(1-methylbut-2-en-1-yl)phenyl]glycinate. A mixture of syn- and anti-atropisomeric methyl-N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycinates was obtained either by the reaction of this ester with acetyl bromide or by the reaction of the sodium salt of N-acetyl-2-(1-methylbut-2-en-1-yl)-4-methylaniline with methyl bromoacetate. Upon saponification of the synthesized ester mixture the syn-atropisomer of N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycine was isolated by fractional crystallization. Treatment of the obtained acids with acetic anhydride, ethyl chloroformate, dicyclohexylcarbodiimide or isopropenylacetate leads to compounds of 4,5-dihydro-3aH-methano[1,3]oxazolo[3,2-a]quinolin-2-one structure.