Synthesis of Enantiomerically Pure 2-Isoxacephems

Summary. (R,6R,7R)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylic acid and its enantiomer have been prepared. The ring systems were formed from the corresponding enantiomerically pure N-unsubstituted -lactams. The reduction of methyl [(R,2S,3R)-3-(1-acetoxyethyl)-1-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate] has been solved via a hemi-acetal. The structure and the configuration of a new stereogenic center in this intermediate was predicted by using 2D NMR technique and unambiguously proven by x-ray.     

Synthesis of Enantiomerically Pure 2-Isoxacephems

(R,6R,7R)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylic acid and its enantiomer have been prepared. The ring systems were formed from the corresponding enantiomerically pure N-unsubstituted -lactams. The reduction of methyl [(R,2S,3R)-3-(1-acetoxyethyl)-1-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate] has been solved via a hemi-acetal. The structure and the configuration of a new stereogenic center in this intermediate was predicted by using 2D NMR technique and unambiguously proven by x-ray.     

Stereospecific Synthesis of (+)-β-Sesquiphellandrene

The structure and absolute configuration of (−)-β-Sesquiphellandrene ((−)- 1a ) is shown to be (6S)-2-methyl-6-[(1′R)-4-methylidenecyclohex-2-enyl]hept-2-ene by stereospecific synthesis of its enantiomer ((+)- 1a ) and of a further (6S,1′S)-diastereoisomer ((+)- 1b ). Characteristic spectroscopic differences in both diastereoisomeric series are discussed.     

An efficient synthesis of optically active (2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral building block for synthesis of vitamin D and steroids

An efficient synthesis of optically active (2R,3R)-2-methyl-3-[(1R)-1-methylprop-2-enyl]cyclopentanone, a useful chiral building block for synthesis of vitamin D and steroids, has been developed starting from readily accessible optically active secondary propargyl phosphate (R)-2, where the asymmetric Michael addition of a chiral allenyltitanium to alkylidenemalonate 3 is a key reaction.     

Epimeric Isopavine N-Oxides from Roemeria refracta

Roemeria refracta DC. (Papaveraceae) of Turkish origin yielded two novel epimeric N-oxides, (?)-(5R, 11S,14R)-reframidine N-oxide ( = (?)-(5R, 11S,14R)-11,12-dihydro-14-methyl-11,5-(iminomethano)-5H -cyclohepta[1, 2-f: 4, 5-f′]bis[1,3]benzodioxole 14-oxide; 1 ) and (?)-(5R, 11S, 14S)-reframidine N-oxide ( = (?)-(5R, 11S, 14S)-11, 12-dihydro-14-methyl-11, 5-(iminomethano)-5H-cyclohepta[1, 2-f:4, 5-f′]bis[1, 3]benzodioxole 14-oxide; 2 ). The isolated (?)-roelactamine ( = (?)-11, 12-dihydro-14-methyl-11, 5-(iminomethano)-5H-cyclohepta[1, 2-f:4, 5-f′]bis[1, 3]benzodioxol-15-one, 4 ) is the first natural isopavinoid incorporating a lactam group. The epimeric (?)-15-(2-oxopropyl)reframidines ( = (?)-1-[11, 12-dihydro-14-methyl-11, 5-(iminomethano)-5H-cyclohepta[1, 2-f:4, 5-f′]bis[1, 3]benzodioxol-15-y1]propan-2-ones; 5/6 ) and the epimeric (?)-ethyl (reframidin-15-yl)acetates ( = (?)-ethyl [11, 12-dihydro-14-methyl-11, 5-(iminomethano)-5H-cyclohepta[1, 2-f:4, 5-f′]bis[1, 3]benzodioxol-15-y1]acetates; 7/8 ) are probably artifacts. (±)-Coclaurine ( 9 ), (±)-N-methylcoclaurine ( 10 ), (?)-roemeridine ( 11 ), and N-feruloyltyramine ( 12 ) are also isolated from R. refracta together with the previously reported bases. Specific ¹³C-NMR assignments are reported for the first time for the isopavines.     

Synthesis of macrocyclic precursors of lankacidins using Stille reactions of 4-(2-iodo-alkenyl)azetidinones and related compounds for ring closure

In the context of a proposed total synthesis of lankacidins, the synthesis of 4-(2-iodo-alkenyl)azetidinones and their participation in Stille coupling reactions have been investigated. 1-tert-Butyldimethylsilyl-4-(2-iodoethenyl)azetidinone was found to undergo a Stille coupling reaction with a 3-hydroxy-1-tributylstannylhepta-1,5-diene to give an acceptable yield of the corresponding conjugated diene but the analogous reaction with a 3-tert-butyldimethylsilyloxy-1-tributylstannylhepta-1,5-diene was unsuccessful. A series of 4-[(E)-2-iodoprop-1-enyl]azetidinones, a ring-opened ester and a lactone were also found to undergo Stille reactions with 3-tributylstannylprop-2-enol albeit with variable yields. Asymmetric syntheses of methyl (2R,3R,5S)-3-tert-butyldimethylsilyloxy-2-methyl-5-(2-trimethylsilylethoxy)methoxy-6-oxohexanoate, (3R,4S)-1-tert-butyldimethylsilyl-4-[(E)-2-iodoprop-1-enyl]-3-methylazetidin-2-one, and (5S,2E,6E)-5-tert-butyldimethylsilyloxy-2-methyl-1-phenylsulfonyl-7-tributylstannylhepta-2,6-diene and their incorporation into macrocyclic precursors of the lankacidins were then investigated. Key reactions were a Julia reaction between the aldehyde and the sulfone to form the 12,13-double-bond, a stereoselective acylation of the azetidinone, and formation of macrocycles using intramolecular Stille reactions in the presence of a free hydroxyl group at C(8) (lankacidin numbering).     

SYNTHESIS OF ANELLATED ANHYDROPYRANOSES ON THE BASIS OF 1,6-ANHYDRO-3-DEOXY-4-METHYLSULFANYL-3-[(METHYLSULFANYL)METHYLENE]-β-D-ERYTHRO-HEXOPYRANOS-2-ULOSE

(Z)-1,6-Anhydro-3-deoxy-4-methylsulfanyl-3-[(methylsulfanyl)methylene]-β-D-erythro-hexopyranos-2-ulose (1) reacted with diethyl malonate, 1,3-diketones, N-aryl-3-oxobutyramides and dialkyl 3-oxoglutarate, respectively, in the presence of potassium carbonate and crown ether to yield diethyl 2-(1,6-anhydro-4-methylsulfanyl—D-arabino-hex-2-ulopyranos-3-ylmethylene) malonate (2), 1-{(1R,2S,8S,9R)-2-hydroxy-4-methyl-8-methylthio-3,11,12- trioxatricyclo7.2.1.0^2,7dodeca-4,6-dien-5-yl} ethanone (3), (1R,2S,12S,13R)-2-hydroxy-12-methylthio-3,15,16-trioxatetracyclo[11.2.1. 0^2,11. 0^4,9] hexadeca- 4(9),10-dien-8-one (4), (1R,8S,9R)-5-acetyl-3-aryl-8-methylthio-11,12-dioxa- 3-azatricyclo-[7.2.1.0^2,7]dodeca-2(7),5-dien-4-ones (5,6) and dialkyl (1R,8S,-9R)-4-hydroxy-8-methylthio-11,12-dioxatricyclo[7.2.1.0^2,7]dodeca-2(7),3,5-triene-3,5-dicarboxylates (7,8), respectively.     

Vitamin-B12-Catalyzed C,C-Bond Formation. Synthesis of a california red scale pheromone

A Mixture of (3S,6R)- and (3R,6R)-3-methyl-6-(1-methylethenyl)dec-9-enyl acetate ( 1a and 1b , respectively)– 1a being a pheromone of the California red scale – is synthesized in 14 steps from (+)-(R)-limonene ( 4 ). The key step is the reductive vitamin- B ₁₂-catalyzed coupling of (R)-5-(2-iodoethyl)-6-mehtylhept-6-en-2-one ethylene acetal ( 8 ) and methyl crotonate ( 3 ).     

Chiral cyclohexene block from <Emphasis Type="Italic">R</Emphasis>-(−)-carvone

The oxidation with SeO₂ of a methyl group linked to an sp²-hybridized carbon in the product of the intramolecular iodoetherification of cis-carveol afforded (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]-oct-3-en-4-carbaldehyde and [(1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-yl]methanol that were oxidized to methyl (1R,5R,7S)-7-iodomethyl-7-methyl-6-oxabicyclo[3.2.1]oct-3-en-4-carboxylate. The latter by the Zn-promoted opening of the γ-oxide ring was converted into the target chiral block, methyl (4R,6R)-6-hydroxy-4-(prop-1-en-2-yl)cyclohex-1-encarboxylate.     

Reactions of N- and C-alkenylanilines: VI. Synthesis of 6-methyl-2-[(E or Z)-1-propenyl]anilines and the corresponding anilides and their reaction with bromine

Isomerization of 2-allyl-6-methylaniline by the action of potassium hydroxide at 300°C afforded cis and trans isomers of 2-methyl-6-(1-propenyl)aniline which were converted into the corresponding carbamates by treatment with ethyl chloroformate. Ethyl 2-methyl-6-(1-propenyl)phenylcarbamates reacted with bromine to give mixtures of 4-(1-bromoethyl)-8-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and ethyl 2- methyl-6-(1,2-dibromopropyl)phenylcarbamates. Treatment of the same compounds with N-bromosuccinimide resulted in formation of 2-ethoxy-4H-3,1-benzoxazine derivatives. The reaction of N-{6-methyl-2-[(Z)- 1-propenyl]-phenyl}methanesulfonamide gave a mixture of stereoisomeric N-[6-methyl-2- (1,2-dibromopropyl)-phenyl]-methanesulfonamides.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 12, 2004, pp. 1815–1818.Original Russian Text Copyright © 2004 by Afonkin, Sotnikov, Gataullin, Spirikhin, Abdrakhmanov.For communication V, see [1].     

Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes. Part 6: synthesis and incorporation into peptides of the first reported 2,3-dihydroxycyclopentanecarboxylic acid

Herein we report the intramolecular alkylation of nitronates of methyl-5-O-benzyl-3,6-deoxy-6-nitro-β-d-glucofuranoside and methyl-5-O-benzyl-3,6-deoxy-6-nitro-α-d-glucofuranoside into the corresponding 2-oxabicyclo[2.2.1]heptane derivatives. Similarly, methyl-3-O-benzyl-5-deoxy-5-nitromethyl-β-d-xylofuranoside and methyl-3-O-benzyl-5-deoxy-5-nitromethyl-α-d-xylofuranoside were cyclized to (1R,3R,4S,5R,7R)-7-benzyloxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane and (1R,3S,4S,5R,7R)-7-benzyloxy-3-methoxy-5-nitro-2-oxabicyclo[2.2.1]heptane, respectively. These 2-oxabicyclo[2.2.1]heptane derivatives were eventually transformed into enantiopure methyl (1S,2S,3R,4S,5R)-2-amino-2,3-dihydroxycyclopentanecarboxylate and this novel β-amino acid was incorporated into peptides.     

Synthetic studies directed toward the pseurotins. Part II. Synthesis of related highly functionalized furan-3(2H)-ones

The synthesis of 2,2-bis(hydroxymethyl)-4-methyl-5-phenylfuran-3(2H)-one ( 9 ), 5-[(1S,2S,Z)-1,2-(ethylidenedioxy)hex-3-enyl]-2,2-bis(hydroxymethyl)-4-methylfuran-3(2H)-one ( 24 ), and 5-[(1S,2S,Z)-1,2-(ethylidenedioxy)hex-3-enyl]-2-(hydroxymethyl)-4-methylfuran-3(2H)-one ( 28 ), which represent more advanced, suitably functionalized intermediates for the synthesis of pseurotin A ( 1 ), a secondary metabolite of Pseudeurotium ovalis STOLK , is described.     

Synthesis and biological evaluation of N-thia-carba-thymidine as an antiherpetic agent

As a continuation of our project aimed at the search for new antiviral agents, the synthesis and biological evaluation of N-thia-carba-thymidine ((1R,2S,4S,5S)-5-methyl-1-{6-thia-4-hydroxy-5-[(hydroxy)-methyl]bicyclo[3.1.0]hex-2-yl}-1,3-dihydropyrimidine-2,4-dione; compound 8) was carried out employing the carbocyclic enantioenriched intermediate (1R,4S)-4-phenylmethoxy-3-[(phenylmethoxy)methyl]cyclopent-2-en-1-ol, which in turn was prepared from (3R,4S) phenylmethoxy-3-[(phenylmethoxy)methyl]-cyclopent-1-ene. The title compound resulted to be a very potent antiherpetic agent exhibiting a similar potency to acyclovir as shown. The synthetic approach to obtain this carbanucleoside required a novel strategy to introduce a thiirane group fused to a functionalized five-membered ring.     

Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris

A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.     

Asymmetric nitrogen

The molecular structure of 3-methyl-1-((S)-1-tosylprolyl)1,2-diazacyclohex-2-ene, the product of the reaction of 5-methyl-1,6-diazabicyclo[3.1.0]hexane with (S)-N-tosylproline chloride, has been established by X-ray structural analysis. The pyrrolidine cycle has a half-chair conformation with the pyramidal nitrogen atom; the tosyl and pseudo axial carbamoyl groups havetrans orientations. The diazacyclohexene cycle has an envelope conformation with folding along the C(7)...C(9) line. The stereochemistry of the transition state of the above-mentioned reaction is discussed.For the previous communication, see Ref. 1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 500–503, March, 1995.     

Synthesis of potential metabolites of the brain imaging agents methyl (1R,2S,3S,5S)-3-(4-Iodophenyl)-8-alkyl-8-azabicyclo[3.2.1]octane-2-carboxylate

The synthesis of potential hydroxy metabolites of the brain imaging agents methyl (1R,2S,3S,5S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate and methyl (1R,2S,3S,5S)-3-(4-iodophenyl)-8-(3-fluoropropyl)-8-azabicyclo[3.2.1]octane-2-carboxylate are reported. The nitration of iodophenyltropanes 1 or 2 with nitronium tetrafluoroborate afforded the nitro compounds 3 or 4 which were reduced with iron powder to the corresponding amino compounds 5 and 6 . The final hydroxylated products 7 and 8 were obtained via a modified Sandmeyer reaction.     

Synthesis of some new tertiary amines and their application as co-catalysts in combination with l-proline in enantioselective Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone

A chiral benzodiazepine derivative 1 was synthesized starting from o-nitrobenzoyl chloride and methyl l-prolinate hydrochloride. Diastereomeric (1R,2R,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3a and (1S,2S,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3b were synthesized starting from (S)-α-phenylethylamine and cyclohexene oxide via ring-opening, diastereomer separation and N-methylation. (S,S)-octahydrodipyrrolo[1,2-a:1′,2′-d]pyrazin 5 was synthesized from methyl l-prolinate. Chiral tertiary amines 1, 3a, 3b and 5 almost cannot catalyze the Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone (MVK). However, they functioned as efficient catalysts for this reaction in the presence of l-proline. The corresponding adducts were obtained in good yields with enantioselectivity of 83% ee, 81% ee, 51% ee and 66% ee, respectively.     

Intermediates of Asymmetric Oxidation Processes Catalyzed by Vanadium(V) Complexes

The [VO(acac)₂]/Schiff base [R-2-(N-3,5-di-tert-butylsalicylidene)amino-2-phenyl-1-ethanol, S-2-(N-3,5-di-tert-butylsalicylidene)amino-3,3-dimethyl-1-butanol, S-2-(N-3,5-di-tert-butylsalicylidene)amino-3-methyl-1-butanol, or R-2-(N-3,5-di-tert-butylsalicylidene)amino-3-phenyl-1-propanol]/H₂O₂ catalytic systems for the asymmetric oxidation of sulfides and the [VO(acac)₂]/(3bR,4aR)-2-(3,4,4-trimethyl-3b,4,4a,5-tetrahydrocyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)ethanol/tert-butyl hydroperoxide/TBHP and VO(OAlkyl)₃/[2,2]paracyclophane-4-carboxylic acid N-(1,1-dimethylethyl)-N-hydroxamide/TBHP catalytic systems for the asymmetric epoxidation of allylic alcohols were studied using ¹³C, ⁵¹V, and ¹⁷O NMR spectroscopy. The key intermediates of these systems (peroxo and alkylperoxo complexes of vanadium(V)) were detected, their structures in solution were studied, and the reactivity was evaluated.     

Determination of the absolute configuration of the male aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, of the stink bug Erysarcoris lewisi (Distant) as 2Z,6R,1′S,5′S by its synthesis

Lipase-catalyzed asymmetric acetylation of a mixture of (6R,1′S,4′S,5′R)- and (6R,1′R,4′R,5′S)-7′-norsesquisabinen-4′-ol (3) afforded a separable mixture of the recovered former and the acetate of the latter. The recovered alcohol was oxidized to (6R,1′S,5′R)-sesquisabina ketone (2), whose absolute configuration could be assigned by its CD comparison with (1R,5S)-sabina ketone (4). Conversion of (6R,1′S,5′R)-sesquisabina ketone (2) to the bioactive pheromone revealed the stereostructure of the male aggregation pheromone of the stink bug Erysarcoris lewisi (Distant) to be (2Z,6R,1′S,5′S)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol (sesquisabinen-1-ol, 1).     

Enantioselective addition of β-keto phosphinate to ω-nitrostyrene in the presence of optically active nickel(II) complex

Synthesis was performed of individual methyl [(S,2R,3S)-4-nitro-1-oxo-1,3-diphenylbutan-2-yl]-(phenyl)phosphinate from racemic β-keto phosphinate and ω-nitrostyrene under the catalysis by nickel(II) complex with (1R,2R)-N,N'-dibenzylcyclohexane-1,2-diamine.