First stereoselective synthesis of serinol-derived malyngamides and their 1′-epi-isomers

A stereoselective synthesis of 1a {N-[(1R)-2-hydroxy-1-methoxy-methyl ethyl]-(4E,7S)-7-methoxy-4-eicosenamide} has been accomplished in 10 steps from 1-tetradecanol for the first time in 28% overall yield. The key steps involved the coupling reaction of a chiral alkyne with a protected bromide in the presence of t-BuLi, as well as the amidation reaction of (4E,7S)-7-methoxyeicos-4-enoic acid with (R)-methoxyamino alcohol. Acetylation of 1a finished the preparation of 1b {N-[(1S)-2-acetyloxy-1-methoxy-methyl ethyl]-(4E,7S)-7-methoxy-4-eicosenamide}. Their 1′-epi-isomers have also been synthesized with a similar strategy.     

Stereoselective carbon–carbon bond forming reactions of chiral cyclopent-2-enone and cyclopentene-1-methanol,both spiro-connecting a 1,2:5,6-di-O-isopropylidene-α-d-glucofuranosyl ring

The conjugate additions of a variety of organocopper reagents or dimethyl malonate anion to a spirocyclic cyclopent-2-enone connecting a 1,2:5,6-di-O-isopropylidene-α-d-glucofuranosyl ring as a constituent of the spiro structure, namely (1S,3R,4R,5R)-3,4-(isopropylidenedioxy)-1-[(1R)-1,2-(isopropylidenedioxy)ethyl]-2-oxa-spiro[4.4]non-6-en-8-one, proceeded stereoselectively in some cases affording a variety of β-functionalized cyclopentanone derivatives. The thermal treatment of (1S,3R,4R,5R)-7-(hydroxymethyl)-3,4-(isopropylidenedioxy)-1-[(1R)-1,2-(isopropylidenedioxy)ethyl]-2-oxaspiro[4.4]non-6-ene, another d-glucose-derived spirocyclic substrate, with triethyl orthoacetate in the presence of a catalytic amount of acid afforded the Claisen rearrangement product with a high level of diastereoselectivity.     

5a-Carba-β-D-, 5a-Carba-β-L- and 5-Thio-β-L-xylopyranosides as New Orally Active Venous Antithrombotic Agents

Mitsunobu displacement of (−)-(1S,4R,5S,6S)-4,5,6-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohex-2-en-1-ol ((−)- 12 ; a (−)-conduritol-F derivative) with 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one ( 16 ) provided a 5a-carba-β-D -pyranoside (+)- 17 that was converted into (+)-4-ethyl-7-[(1′R,4′R,5′S,6′R)-4′,5′,6′-trihydroxycyclohex-2′-en-1′-yloxy]-2H-1-benzopyran-2-one ((+)- 5 ) and (+)-4-ethyl-7-[(1′R,2′R,3′S,4′R)-2′,3′,4′-trihydroxycyclohexyloxy]-2H-1-benzopyran-2-one ((+)- 6 ). The 5a-carba-β-D -xyloside (+)- 6 was an orally active antithrombotic agent in the rat (venous Wessler's test), but less active than racemic carba-β-xylosides (±)- 5 and (±)- 6 . The 5a-carba-β-L -xyloside (−)- 6 was derived from the enantiomer (+)- 12 and found to be at least 4 times as active as (+)- 6 . (+)-4-Cyanophenyl 5-thio-β-L -xylopyranoside ((+)- 3 ) was synthesized from L -xylose and found to maintain ca. 50% of the antithrombotic activity of its D -enantiomer. Compounds (±)- 5 , (±)- 6 , and (−)- 6 are in vitro substrates for galactosyltransferase 1.     

Cyclocondensations of (+)-camphor derived enaminones with hydrazine derivatives

Reactions of 3-[(E)-(dimethylamino)methylidene]-(+)-camphor and (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one with hydrazine derivatives were studied. Treatment of 3-[(E)-(dimethylamino)methylidene]-(+)-camphor with hydrazines afforded the corresponding fused pyrazoles. Similarly, fused pyrazoles were obtained upon reaction of (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one with ortho-unsubstituted phenylhydrazines, while reactions with ortho-substituted phenylhydrazines and with hydrazine hydrochloride resulted in ‘ring switching’ type of transformation to furnish 2-aryl-4-[(1S,3R)-3-hydroxy-2,2,3-trimethylcyclopentyl]-1,2-dihydro-3H-pyrazol-3-ones.     

New ceramides from the flower of Albizia julibrissin

A new ceramide and its glycoside were isolated from the flower of Albizia julibrissin. Their structures were established as(2S,3S,4R,8E)-2-[(2'R)-hydroxyhexadecanoylamino]-8-tetra-cosene-1,3,4-triol (Ⅰ) and 1-O-β-D-glucopyranosyl-(2S,3S,4R,8E)-2-[(2'R)-hydroxy-hexade-canoylamino]-8-tetracosene-1,3,4-triol (H) on the basis of chemical and spectroscopic studies.     

Uncommon transformations of methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate initiated by bases

Methyl (1S,2S,3R,4R)-2,3-isopropylidenedioxy-5-iodomethyl-2-tetrahydrofurylacetate prepared in two stages from D-ribose acetonide underwent a series of uncommon transformations under the treatment with bases providing the following different products depending on the base applied: methyl 3-(5-acetyl-2,2-dimethyl-1,3-dioxol-4-yl)propionate (DBU), methyl 2,3-isopropylidenedioxy-7-oxabicyclo[2.2.1]heptane-6-carboxylate (t-BuOK), methyl {(5R)-2,2-dimethyl-5-[(2R)-oxiranyl]-1,3-dioxolan-4-ylidene}propionate and methyl-(E)-3-{(4S,5R)-2,2-dimethyl-5-[(1R)-(2-oxiranyl)]-1,3-dioxolan-4-yl}-2-propenoate (t-BuOK and LDA).     

The use of (−)-8-phenylisoneomenthol and (−)-8-phenylmenthol in the enantioselective synthesis of 3-functionalized 2-azabicyclo[2.2.1]heptane derivatives via aza-Diels-Alder reaction

The asymmetric aza-Diels-Alder reaction of the (1R)-8-phenylmenthyl or (1R)-8-phenylisoneomenthyl glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding pure [(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylates (80 or 69% yield, respectively). Reduction of these cycloadducts with LiAlH₄ afforded pure (−)-[(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol. Furthermore, a reaction sequence based on Barbier-Wieland degradation of both (1S,3-exo)-adducts afforded pure (+)-(1R)-2-benzoyl-2-azabicyclo[2.2.1]heptan-3-one. In the course of the two transformation sequences referred, the chiral auxiliaries were recovered in a virtually quantitative way.     

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.     

Asymmetric synthesis of conformationally constrained 4-hydroxyprolines and their applications to the formal synthesis of (+)-epibatidine

This report describes the synthesis of enantiomerically pure (1S,3S,4R)- and (1S,3R,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acids, two new conformationally constrained 4-hydroxyprolines, using a straightforward synthetic route and starting from (−)-8-phenylmenthyl 2-acetamidoacrylate. The easy transformation of the pure (1S,3S,4R)-3-hydroxy-7-azabicyclo[2.2.1]heptane-1-carboxylic acid into (1R,4S)-N-Boc-7-azabicyclo[2.2.1]heptan-2-one constitutes a new formal synthesis of (+)-epibatidine.     

3,6-Thioanhydro sugar derivatives. An enantiospecific synthesis of (2R,3R,4S)-3-benzyloxy-4-hydroxy-2-[(R)-1-benzyloxy-4-hydroxybutyl]thiolane as the key intermediate for thioswainsonine

Methyl 2-O-benzyl-3,6-thioanhydro-α-D-mannopyranoside ( 9 ) was obtained in eight steps from the commercially available methyl α-D-glucopyranoside. Compound 9 was transformed into (2R,3R,4S)-3-benzyloxy-4-hydroxy-2-[(R)-1-benzyloxy-4-hydroxybutyl]thiolane ( 14 ) by acid hydrolysis of its 2,4-di-O-benzyl derivative 10 followed by reaction of the not isolated 2,4-di-O-benzyl-3,6-thioanhydro-D-mannose ( 11 ) with ethoxycarbonylmethylenetriphenylphosphorane to give an = 1:1 E/Z mixture of the corresponding α,β-unsaturated ester ( 12 ). Finally, catalytic hydrogenation of 12 to ethyl (R)-4-benzyloxy-4-[(2′R)3′R,4′S)-3′-benzyloxy-4′-hydroxythiolan-2′-yl]butanoate ( 13 ) and subsequent reduction with lithium aluminum hydride gave the title compound 14 .     

An approach to an asymmetric synthesis of stemofoline

A stereoselective Mannich reaction between an (S)-tert-butylsulfinimine and methyl (S)-4-benzyloxy-3-methylbutanoate followed by treatment with acid and N-protection was used to prepare methyl (2R,3S)-2-[(S)-2-benzyloxy-1-methylethyl]-3-tert-butoxycarbonylamino-6-methylenedecanoate. This was taken through to methyl (4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-5-tert-butoxycarbonylamino-3,8-dioxododecanoate which on treatment with trifluoroacetic acid cyclised stereoselectively to give (1R,2S,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-tert-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane, a potential precursor of stemofoline. Reduction and N-deprotection of this ketone gave (1R,2S,3R,4R,5S)-4-[(S)-2-benzyloxy-1-methylethyl]-1-butyl-2-methoxycarbonyl-8-azabicyclo[3.2.1]octan-3-ol the structure of which was confirmed by X-ray diffraction.     

Isolation,structural elucidation and cytotoxicity evaluation of a new pentahydroxy-pimarane diterpenoid along with other chemical constituents from Aerva lanata

Aervalanata possesses various useful medicinal and pharmaceutical activities. Phytochemical investigation of the plant has now led to the isolation of a new 2α,3α,15,16,19-pentahydroxy pimar-8(14)-ene diterpenoid (1) together with 12 other known compounds identified as β-sitosterol (2), β-sitosterol-3-O-β-D-glucoside (3), canthin-6-one (4), 10-hydroxycanthin-6-one (aervine, 5), 10-methoxycanthin-6-one (methylaervine, 6), β-carboline-1-propionic acid (7), 1-O-β-D-glucopyranosyl-(2S,3R,8E)-2-[(2′R)-2-hydroxylpalmitoylamino]-8-octadecene-1,3-diol (8), 1-O-(β-D-glucopyranosyl)-(2S,3S,4R,8Z)-2-[(2′R)-2′-hydroxytetracosanoylamino]-8(Z)-octadene-1,3,4-triol (9), (2S,3S,4R,10E)-2-[(2′R)-2′-hydroxytetracosanoylamino]-10-octadecene-1,3,4-triol (10), 6′-O-(4″-hydroxy-trans-cinnamoyl)-kaempferol-3-O-β-D-glucopyranoside (tribuloside, 11), 3-cinnamoyltribuloside (12) and sulfonoquinovosyldiacylglyceride (13). Among these, six compounds (8–13) are reported for the first time from this plant. Cytotoxicity evaluation of the compounds against five cancer cell lines (CHO, HepG2, HeLa, A-431 and MCF-7) shows promising IC₅₀ values for compounds 4, 6 and 12.     

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.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Diastereoselective synthesis of 5-benzylthio- and 5-mercaptohexahydropyrimidin-2-ones

A three-stage diastereoselective synthesis of (4R^∗,5R^∗,6S^∗)-5-mercapto-4-methyl-6-phenylhexahydropyrimidin-2-one has been developed. The first stage involves the formation of 4-hydroxy-5-(4-methoxybenzylthio)-4-methyl-6-phenylhexahydropyrimidin-2-one by the reaction of N-[(phenyl)(tosyl)methyl]urea with the sodium enolate of 1-(4-methoxybenzylthio)propan-2-one. Reduction of the obtained compound by NaBH₄-CF₃COOH and removal of the p-methoxybenzyl protecting group results in the target compound.     

Carotenoids of Rhizobia. IV. Isolation and structure elucidation of the carotenoids of a mutant of Rhizobium lupini

The structures of the main carotenoid pigments from the mutant 1-207 of Rhizobium lupini were elucidated by spectroscopic techniques (UV./VIS., CD., 270 MHz ¹H-NMR., and MS.). Ten carotenoids were identified, namely β,β-carotene ( 1 ), β,β-caroten-4-one (echinenone, 2 ), β,β-carotene-4,4′-dione (canthaxanthin, 3 ), (3S)-3-hydroxy-β,β-caroten-4-one ((3S)-3-hydroxyechinenone, 4 ), (2R, 3R)-β,β-carotene-2,3-diol ( 5 ), (3S)-3-hydroxy-β,β-carotene-4,4′-dione ((3S)-adonirubin, 6 ), (2R, 3S)-2,3-dihydroxy-β,β-caroten-4-one ( 7 ), (2R, 3S)-2,3-dihydroxy-β,β-caroten-4,4′-dione ( 8 ), (2R, 3S, 2′R, 3′R)-2,3,2′,3′-tetrahydroxy-β,β-caroten-4-one ( 9 ) and the corresponding (2R, 3S, 2′R, 3′S)-4,4′-dione ( 10 ). Structures 5, 7, 8 and 10 have not been reported before. From the observed carotenoid pattern it is concluded that in this mutant the oxidation to 4-oxo compounds is favoured compared to the hydroxylation at C(3) and C(2).     

Concise,efficient and highly selective asymmetric synthesis of (+)-(3S,4R)-cisapride

A concise asymmetric synthesis of the gastroprokinetic agent (+)-(3S,4R)-cisapride {(+)-(3S,4R)-N(1)-[3′-(4″-fluorophenoxy)propyl]-3-methoxy-4-(2″′-methoxy-4″′-amino-5″′-chlorobenzamido)piperidine} from commercially available starting materials has been developed. The key step of this synthesis employs the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl 5-[N-3′-(4″-fluorophenoxy)propyl-N-allylamino]pent-2-enoate and in situ enolate oxidation with (?)-camphorsulfonyloxaziridine to set the (3S,4R)-configuration found within the piperidine ring of the product. This synthesis proceeds in 9 steps from commercially available 1-(4′-fluorophenoxy)-3-bromopropane with an overall yield of 19%.     

First asymmetric synthesis of a C2-symmetric 2-endo,6-endo-disubstituted bispidine

The enantioselective synthesis of a C₂-symmetric 2-endo,6-endo-disubstituted bispidine (3,7-diazabicyclo[3.3.1]nonane) has been accomplished for the first time. The key step was a Michael addition of the protected β-amino ester methyl (R)-3-{N-benzyl-N-[(S)-1-phenylethyl]amino}-3-phenylpropionate to its α-methylene derivative delivering an anti,anti-configured α,α′-methylene-bridged bis(β-amino ester) as the major diastereomer. Deprotection, reduction and cyclisation furnished (1R,2R,5R,6R)-2,6-diphenyl-3,7-bis((S)-1-phenylethyl)-3,7-diazabicyclo[3.3.1]nonane in six steps and 15% overall yield.     

Efficient stereoselective synthesis of enantiopure cis- and trans-1,2,4-trisubstituted piperidines

Enantiomerically pure (2R,4S)- and (2R,4R)-2-[(S)-1,2-dibenzyloxyethyl]-4-[2-(diphenylmethoxy)ethyl]-1-[(S)-1-phenylethyl]piperidines cis-1 and trans-1 have been synthesised from N-[(S)-1-phenylethyl]-(S)-2,3-di-O-benzylglyceraldimine in six steps in 31% and 18% overall yields, respectively. The efficiency of the synthetic strategy developed for the synthesis of these compounds relies on: (a) the totally diastereoselective tandem Mannich–Michael reaction between Danishefsky’s diene and the starting glyceraldimine, (b) the high yielding Wadsworth–Emmons reaction of the 4-piperidone intermediate and (c) the diastereodivergent reduction of the exocyclic C–C double bond at C₄ of the piperidine ring. These transformations led to 1,2,4-trisubstituted piperidines with two new stereogenic centres with excellent stereoselectivity.     

Transformations of peroxide ozonolysis products of (1R,3R)-p-menth-4-en-3-ol in the presence of pyridine

Ozonolysis of (1R,3R)-p-menth-4-en-3-ol in methylene chloride or methanol in the presence of pyridine afforded a mixture of equimolar amounts of epimeric 1-[(2R,4S,6S)- and 1-[(2S,4S,6S)-6-hydroxy-4-methyltetrahydro-2H-pyran-2-yl]-2-methylpropan-1-ones. A probable reaction mechanism is discussed.