Total Asymmetric Synthesis of Doubly Branched Carba-hexopyranoses and Amino Derivatives Starting from the Diels-Alder Adducts of Maleic Anhydride to Furfuryl Esters

The Diels-Alder adducts of maleic anhydride to furfuryl esters were reduced into 7-oxabicyclo[2.2.1]hept-5-ene-1,2-exo,3-exo-trimethanol (±)- 15 and enantiomerically pure (−)- 15 (Scheme 1). The tripivalate of (±)- 15 was converted into (1RS,2RS,3RS,4RS,5SR,6SR)-1,5,6-tris(hydroxymethyl)cyclohexane-1,2,3,4-tetrol ((±)- 23 ; Scheme 2). Reaction of BBr₃ with the triacetate (±)- 30 of (±)- 15 gave (1RS,2RS,5RS,6RS)-5-bromo-6-hydroxycyclohex-3-ene-1,2,3-trimethyl triacetate ((±)- 31 ) at −78°, and (1RS,2RS,5SR,8SR)-2-endo-hydroxy-6-oxabicylo[3.2.1]oct-3-ene-5,8-dimethyl diacetate ((±)- 32 ) at 0° (Scheme 3). Single-crystal X-ray diffraction of (1RS,2RS,5SR,8SR)-2-acetoxy-6-oxabicyclo[3.2.1]oct-3-ene-5,8-dimethyl diacetate ((±)- 33 ) was carried out. Displacement of bromide (+)- 31 (derived from (−)- 15 ) with azide anion gave (+)- 38 which was transformed into (+)-(1R,2R,5S,6S)-5-amino-6-hydroxycyclohex-3-ene-1,2,3-trimethanol ((+)- 40 ) (Scheme 4). Reaction of (±)- 31 with BBr₃ at 0°, followed by azide disubstitution led to (1RS,2RS,5SR,6SR)-5-amino-3-(aminomethyl)-6-hydroxycyclohex-3-ene-1,2-dimethanol ((±)- 45 ). Dihydroxylation of (±)- 38 and further transformations gave (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-1,4,6-trihydroxycyclohexane-1,2,3-trimethanol ((±)- 49 ) and (1RS,2RS,3SR,4RS,5SR,6RS)-2,3-dihydroxy-7-oxabicyclo[4.1.0]heptane-2,3,4-trimethanol ((±)- 55 ) (Schemes 5 and 6). Expoxidation of the 4-nitrobenzoate (±)- 61 of (±)- 38 allowed the preparation of (1RS,2RS,3SR,4RS,5RS)-5-amino-1,4-dihydroxycyclohexane-1,2,3-trimethanol ((±)- 65 ) and of (1RS,2RS,3SR,4RS,5SR,6RS)-5-amino-4-hydroxy-7-oxabicyclo[4.1.0]heptane-1,2,3-trimethanol ((±)- 67 ) (Scheme 7). The new unprotected polyols and aminopolyols were tested for their inhibitory activity toward commercially available glycohydrolases. At 1 mM concentration, 34, 30, and 31% inhibition of β-galactosidase from bovine liver was observed for (+)- 40 , (±)- 65 , and (±)- 67 , respectively.     

Beitrag zur Analytik und Synthese von 3-Hydroxy-4-oxocarotinoiden

Contribution to the Analytical Separation and the Synthesis of 3-Hydroxy-4-oxocarotenoids (3RS,3′RS)-Astaxanthin (= 3,3′-dihydroxy-β,β-carotene-4,4′-dione, 1:1-mixture of racemate and meso-form; 1 ) can be separated into its optical isomers (3S,3′S)- 1a , (3R,3′R)- 1b and meso-(3R,3′S)- 1c via the corresponding diastereomeric di-(?)-camphanates. Some aspects of the configurational stability of astaxanthin are discussed. - HPLC. analysis of the (?)-camphanates of 3-hydroxy-4-oxocarotenoids provides, in suitable cases and supported by spectroscopic data, an analytical method for the simultaneous determination of constitution and chirality.     

(6′RS,8′RS,2E)- und (6′RS,8′SR,2E)-3-Methyl-3-(2y,2′,6′-trimethyl-7′-oxabicyclo[4.3.0]non-9′-en-8′-yl)-2-propenal ([(5RS,8RS)- und (5RS,8SR)-5,8-Epoxy-5,8-dihydro-ionyloinden]acetaldehyd): Synthese und Röntgenstrukturanalyse

Synthesis and X-Ray Structure of (6′RS,8′RS,2E)- and (6′RS,8′SR,2E)-3-Methyl-3-(2′,2′,6′-trimethyl-7′-oxabicyclo[4.3.0]non-9′-en-8′-yl)-2-propenal ([(5RS,8RS)- and (5RS,8SR)-5,8-Epoxy-5,8-dihydro-ionylidene]acetaldehyde) To check our previous spectroscopic assignments of the structures of trans- and cis-substituted furanoid end groups of carotenoid-5,8-epoxides, we now have synthesized the title compounds. An X-ray structure determination of a single crystal of the trans-isomer (±)- -10A is in agreement with the ¹ H-NMR spectroscopic arguments: isomers with Δδ (H? C(7), H? C(8)) = 0.15–0.22 ppm and J > 1.4 for H? C(7) belong to the cis-series; Δδ in trans-compounds is < 0.07 ppm, and H? C(7) appears as a broad singulett.     

A New Approach to the Synthesis of Long-Chain Polypropionates Based on the Diels-Alder Monoadditions of 2,2′-Ethylidenebis[3,5-dimethylfuran]

Acidic condensation of 2,4-dimethylfuran with acetaldehyde provided 2,2′-ethylidenebis[3,5-dimethylfuran] ( 7 ) which added 1 equiv. of methyl bromopropynoate to give a major adduct 8 . Regio- and stereoselective hydroboration of the latter 7-oxanorbornadiene derivative followed by alcohol protection and methanolysis of its β-bromoacrylate moiety gave (1RS,2RS,4RS,5SR,6SR,1′RS)-methyl 4-[1′-(3″,5″-dimethylfuran-2″-yl)ethyl]-3,3-dimethoxy-6-exo-[(2-methoxy)ethoxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptane-2-endo-carboxylate ( 24 ) (Schemes 2 and 3). Reduction of 24 with LiAlH₄, followed by H₂O and MeOH elimination gave the 3-methyl-idene-7-oxanorbornan-2-one derivative 26 which underwent 7-oxa ring opening through a S_N2′ type of reaction with Me₂CuLi (Scheme 4). Stereoselective hydrogenation and ketone reduction provided (1RS, 2SR,3RS,4RS,5RS,6RS,1′SR)-1- [1″-(3 ″,5″-dimethylfuran-2″-yl)]-c-3-ethyl-c-5-[(2-methoxyethoxy)m e-c-ethyl-c-c-5-(2-methoxyethoxy)methoxy]-t-4,t-6-dimethyl-cyclohexane-r-1,c-2-diol ( 32 ), the oxidative cleavage of which with Pb(OAc)₄ generated a 6-oxo-aldehyde 33 (Schemes 4 and 5). Chemoselective protection of 33 and chemo- and stereoselective reductions generated (2RS,3RS,4SR,5SR,6SR,7RS)-7-(3′,5″-dimethylfuran-2′-yl)-2-ethyl-6-hydroxy-4-[(2-methoxyethoxy)methoxy]-3,5-dimethyloct-1-yl pivaloate ( 36 ) and its 4-hydroxy 6-epimer 40 (12 and 13 steps, resp., from adduct 8 ; Scheme 5). Oxidation of the furan ring of 36 led to a (2RS,3SR,4RS,5SR,6RS,7RS)-7-ethyl-3,5,8-trihydroxy-2,4,6-trimethyl-octanoic acid derivative 44 , a polypropionate fragment with six contiguous stereogenic centres (Scheme 6).     

Studies for a Diastereoselective Synthesis of the Tetracyclic Diterpenic Diol Stemarin: A Model Study for a New Preparation of the Key Intermediate and the Synthesis of (+)-18-Deoxystemarin

Methods for a stereoselective preparation of compounds of type 2b , a key intermediate of a previous synthesis of the tetracyclic diterpene stemarin ( la ), have been tested on model compounds 5a, 5c , and 8a . Thus, (±)-(1RS,6SR,8SR,11SR)-hydroxytricyclo[6.2.2.0^l,6]dodecan-9-one ( 5a ) was transformed by the Mitsunobu reaction into (±)-(1RS,6SR,8SR,11RS)-11-(benzoyloxy)tricyclot[6.2.2.0^1,6]dodecan-9-one ( 6b ; Scheme 2). The latter was also obtained from (±)-(1RS,6SR,8SR,11RS)-11-[(4)-toluenesulfonyloxy]tricyclo[6.2.2.0^1,6]dodecan-9-one ( 5c ) by the action of Et₄N (PhCOO) in acetone. Compound 6b was then converted into (±)-(1RS,6RS,8RS,9RS)-tricyclo[6.2.2.0^1,6]dodecan-9-ol ( 8b ), a model for 2b . Compound 8b was also prepared from its epimer 8a by the Mitsunobu reaction via ester 7b . The inversion of configuration of bicyclo[2.2.2]octan-2-ols or derivates was not previously described. The model studies paved the way to the diastereoselective synthesis of (+)-18-deoxystemarin ( 1b ) via 12β-hydroxy-13-methyl-9β,13β-ethano-9β-podocarpan-15-one ( 10a ) and 13-methyl-9β,13β-ethano-9β-podpcarpan-12α-ol ( 11b ).     

Technische Verfahren zur Synthese von Carotinoiden und verwandten Verbindungen aus 6-Oxo-isophoron. IV. Neues Konzept für die Synthese von (3RS, 3′RS)-, (3S, 3′S)- und (3R, 3′R)-9,9′-dicis-7,8,7′,8′-Tetradehydroastaxanthin

Technical Procedures for the Synthesis of Carotenoids and Related Compounds from 6-Oxo-isophorone. IV. A Novel Concept for the Synthesis of (3RS, 3′RS)-, (3S, 3′S)- and (3R, 3′R)-9,9′-dicis-7,8,7′,8′-Tetradehydroastaxanthin Starting from readily available intermediates of the synthesis of astaxanthin, (3RS, 3′RS)-, (3R, 3′R)- and (3S, 3′S)-9,9′-di-cis-tetradehydroastaxanthin ( 1, 1a and 1b , resp.) were synthesized, 1 and 1b for the first time. Key features of this concept are: a) use of the unprotected, acetylenic phosphonium salts 8–12 , b) a two-step synthesis with 47% overall yield, and c) good chemical and optical purity of the end products.     

Relative configuration,absolute configuration and absolute structure of three isomeric 8‐benzyl‐2‐[(4‐bromophenyl)(hydroxy)methyl]‐8‐azabicyclo[3.2.1]octan‐3‐ones

The title compounds, C₂₁H₂₂BrNO₂, are isomeric 8‐benzyl‐2‐[(4‐bromophenyl)(hydroxy)methyl]‐8‐azabicyclo[3.2.1]octan‐3‐ones. Compound (I), the (±)‐exo,syn‐(1RS,2SR,5SR,9SR) isomer, crystallizes in the hexagonal space group R, while compounds (II) [the (+)‐exo,anti‐(1R,2S,5S,9R) isomer] and (III) [the (±)‐exo,anti‐(1RS,2SR,5SR,9RS) isomer] crystallize in the orthorhombic space groups P2₁2₁2₁ and Pna2₁, respectively. The absolute configuration was determined for enantiomerically pure (II). For the noncentrosymmetric crystal of (III), its absolute structure was established. In the crystal structures of (I) and (II), an intramolecular hydrogen bond is formed between the hydroxy group and the heterocyclic N atom. In the crystal structure of racemic (III), hydrogen‐bonded chains of molecules are formed via intermolecular O—H...O interactions. Additionally, face‐to‐edge π–π interactions are present in the crystal structures of (I) and (II). In all three structures, the piperidinone rings adopt chair conformations and the N‐benzyl substituents occupy the equatorial positions.     

Stereoselective Double Functionalization of Iron-Carbonyl Complexes of 5,6,7,8-Tetramethylidenebicyclo[2.2.2]oct-2-ene. Crystal Structure and Absolute Configuration of (–)-trans-μ-[(2S,5R,7S)-C,5,6,C-η:C,7,8,C-η-(6,7,8-trimethylidene-5-((Z)-2-oxopropylidene)-2-bicyclo[2.2.2]octyl acetate)]-bis(tricarbonyliron)

The Friedel-Crafts monoacylation of trans-η-[(1RS,2RS,4SR,5SR,6RS,7SR,8SR)-C,5,6,C-η:C,7,8,C-η-(5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octyl acetate)]-bis(tricarbonyliron) ((±)- 5 ) is highly stereoselective and yields trans-η-[(1RS,2RS,4RS,5SR,6RS,7RS,8SR)-C,6-η,oxo-σ:C,7,8,C-η-(6,7,8-trimethylidene-5-((Z)-2-oxopropylidene)-2-bicyclo[2.2.2]octyl acetate)]-bis(tricarbonyliron) ((±)- 8 ) which equilibrates with the trans-η-[(1RS,2RS,4RS,5SR,6RS,7RS,8SR)-C,5,6,C-η:C,7,8,C-η-(6,7,8-trimethylidene-5-((Z)-2-oxopropylidene)-2-bicyclo[2.2.2]octyl acetate)]-bis(tricarbonyliron) ((±)- 9 ) on heating. Optically pure (–)- 9 has been prepared from the corresponding optically pure alcohol (+)- 4 . The structure and absolute configuration of (–)- 9 was established by single-crystal X-ray diffraction.     

Trennung und absolute Konfiguration der C(8)-epimeren (all-E)-Neochrome (Trollichrome) und -Dinochrome

Separation and Absolute Configuration of the C(8)-Epimeric (app-E)-Neochromes (Trollichromes) and -Dinochromes The C(8′)-epimers of (all-E)-neochrome were separated by HPLC and carefully characterized. The faster eluted isomer, m.p. 197.8–198.3°, is shown to have structure 3 ((3S,5R,6R,3′S,5′R,8′R)-5′,8′-epoxy-6,7-dodehydro-5,6,5′,8′-tetrahydro-β,β-carotene-3,5,3′-triol). To the other isomer, m.p. 195-195.5°, we assign structure 6 , ((3S,5R,6R,3′S,5′R,8′R)-5′,8′-epoxy-6,7-didehydro-5,6,5′,8′-tetrahydro-β,β-carotene-3,5,3′-triol). The already known epimeric dinochromes (= 3-O-acetylneochromes) can now be formulated as 4 and 5 , (‘epimer 1’ and its trimethylsilyl ether) and 7 and 8 , (‘epimer 2’ and its trimethylsilyl ether), respectively.     

The Diels-Alder Reactivity of 2,2′-Ethylidenebis[3,5-dimethylfuran] and Exploratory Chemistry of the Mono-adducts

In the presence of Me₃Al, 1-cyanovinyl acetate added to 2,2′-ethylidenebis[3,5-dimethylfuran] ( 1 ) to give a 20:10:1:1 mixture of mono-adducts 4,5,6 , and 7 resulting from the same regiocontrol (‘para’ orienting effect of the 5-methyl substituent in 1 ). The additions of a second equiv. of dienophile to 4–7 were very slow reactions. The major mono-adducts 4 (solid) and 5 (liquid) have 2-exo-carbonitrile groups. The molecular structure of 4 (1RS,1′RS,2SR,4SR)-2-exo-cyano-4-[1-(3,5-dimethylfuran-2-yl)ethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl acetate) was determined by X-ray single-crystal radiocrystallography. Mono-adducts 4 and 5 were saponified into the corresponding 7-oxanorbornenones 8 and 9 which were converted with high stereoselectivity into (1RS,1′SR,4RS,5RS,6RS)-4-[1-(3,5-dimethyl furan-2-yl)ethyl]-6-exo-methoxy-1,5-endo-dimethyl-7-oxabicyclo [2.2.1]heptan-2-one dimethyl acetal ( 12 ) and its (1′RS-stereoisomer 12a , respectively. Acetal hydrolysis of 12a followed by treatment with (t-Bu)Me₂SiOSO₂CF₃ led to silylation and pinacol rearrangement with the formation of (1RS,1′RS,5RS,6RS)-4-[(tert-butyl)dimethy lsilyloxy]-1-(3,5-dimethylfuran-2-yl)ethyl]-5-methoxy-6-methyl-3-methylidene- 2-oxabicyclo[2.2.1]heptane ( 16 ). In the presence of Me₃Al, dimethyl acetylenedicarboxylate added to 12 giving a major adduct 19 which was hydroborated and oxidized into (1RS,1′RS,2″RS,3″RS,4SR,4″RS,5 SR,6SR)-dimethyl 5-exo-hydroxy-4,6-endo-dimethyl-1-[1-(3-exo,5,5-trimeth oxy-2-endo,4-dimethyl-7-oxabicyclo[2.2.1]hept-2-yl)ethyl]-7-oxabicyclo [2.2.1]hept-2-ene-2,3-dicarboxylate ( 20 ). Acetylation of alcohol 20 followed by C?C bond cleavage afforded (1′RS,1″SR,2RS,2′″SR,3RS, 3″SR,4RS,4″SR,5RS)-dimethyl {3-acetoxy-2,3,4,5-tetrahydro-2,4-dimethyl-5-[1-(3-exo,5,5-trimethoxy ?2-endo,4-dimethyl-7-oxabicyclo[2.2.1]hept-1-yl)-ethyl]furan-2,5-diyl} bis[glyoxylate] ( 24 ).     

Stereoselective Synthesis of 5a-Ethyl-1,2,3,3a,4,5,5a,6,9a,9b-decahydro- 1,3,4-trihydroxy-3a-(hydroxymethyl)-7H-benz[e]inden-7-one Derivatives

Homochiral Diels-Alder cyclodimerization of (±)-6-ethenyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-ol ( 1 ) followed by oxidation gives (1RS,4RS,4aSR,4bSR,5RS,8RS,8aRS)-8a-ethenyl-1,3,4,4a,4b,5,6,8,8a,9-decahydro-1,4:5,8-diepoxyphenanthrene-2,7-dione ( 18 ). Selective hydrogenation followed by epoxidation produced (1RS,4RS,4aRS,5aRS,6aRS,7RS,10RS,10aSR,10bRS)-6a-ethyl-1,4,5a,6,6a,7,9,10,10a,10b-decahydro-1,4:7,10-diepoxyphenanthro[8a,9-b]oxirene-3,8-dione ( 21 ), which was solvolyzed (Me₃SiOSO₂CF₃, Piv₂O) with concomitant pinacol rearrangement involving an acyl-group migration to give a 6-oxo-7-oxabicyclo[2.2.1]hept-2-yl cation intermediate, which finally generated (1RS,3SR,3aRS,4SR,5aRS,6RS,9RS,9aSR,9bSR)-5a-ethyl-1,4,5,5a,6,7,8,9,9a,9b-decahydro-7,10-dioxo-3H-6,9-epoxy-1,3a-ethanonaphtho[1,2-c]furan-3,4-diyl bis(2,2-dimethylpropanoate) ( 24 ). Photo-reductive 7-oxa bridge opening of 24 , followed by water elimination and silylation, provided (1RS,3SR,3aRS,4SR,5aSR,9aSR,9bSR)-7-{[(tert-butyl)dimethylsilyl]oxy}-5a-ethyl-1,4,5,5a,9a,9b-hexahydro-10-oxo-3H-1,3-ethanonaphtho[1,2-c]furan-3,4-diyl bis(2,2-dimethylpropanoate) ( 34 ). Reduction of 34 with NaBH₄ in MeOH followed by desilylation and alcohol protection produced (1RS,3RS,3aRS,4SR,5aSR,9aSR,9bSR)-5a-ethyl-2,3,3a,4,5,5a,6,7,9a,9b-decahydro-1,3-bis(methoxymethoxy)-3a-[(methoxymethoxy)methyl]-7-oxo-1H-benz[e]inden-4-yl 2,2-dimethylpropanoate ( 5 ), a polyoxy-substituted decahydro-1H-benz[e]indene derivative with cis-transoid-trans junction for the two cyclohexane and the cyclopentane rings bearing an angular 3a-(oxymethyl) substituent.     

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.     

Acid-Promoted Rearrangements of N-Substituted 8-Oxa-3-azatricyclo[3.2.1.02′4] octane-6,7-dicarboxylates: Remote Substituent Effects on the Regioselectivity of the N-Acylaziridine/Dihydrooxazone Rearrangement

Preparations of dimethyl (1RS,2SR,4RS,5SR,6SR,7RS)- and dimethyl (1 RS,2SR,4RS,5SR,6RS,7SR)-8-oxa-3-azatricyclo[3;2.1.0²⁴] octane-6,7-dicarboxylate 15 and 18 , resp.) and of their N-(tert-butyloxy)carbonyl ( 14 , 17 ) and V-benzoyl ( 16 , 19 ) derivatives are described. While treatment with nucleophilic acids (HCl, HBr. A^cOH) of the exo, exo-diesters 14 and 16 gave the corresponding products 23–27 of aziridine trans -addition, the exo, endo -diesters 17 and 19 led to the corresponding amino-lactones 63 (methyl (1RS,2RS,3SR,6RS,7SR,9RS)-2-{[(tert-butyloxy)carbonyl] amino}-5-oxo-4,8-dioxatricyclo[4.2.1.0 ³⁷] nonane-9-carboxylate) and 64 (methyl (1RS,2RS,3SR,6RS,7SR,9SR)-2-(benzoylamino)-5-oxo-4,8-dioxatricyclo[4.2.1.0 ^3′7] (nonane-9-carboxylate). Under non-nucleophilic acidic conditions, the N-benzoylaziridine 16 was rearranged quantitatively into dimethyl (1RS,2SR,26SR,67SR,7SR,8SR,9SR)-4-phenyl-5,10-dioxa-3-azatricyclo[4.3.1.0^2′7] dec-3-ene-8,9-dicarboxylate( 31 ), and 19 into dimethyl (1RS,2SR,26SR,67SR,7SR,8SR,9SR)-4-phenyl-3,10-dioxa-5-azatricyclo [5.2.1.0^2′6] dec-4-ene-8,9-di-carboxylate ( 65 ). Possible mechanisms of these highly selective reactions and rearrangements are discussed.     

Reisolation of Carotenoid 3,6-Epoxides from Red Paprika (Capsicum annuum)

Cucurbitaxanthin A (= (3S,5R,6R,3′R)-3,6-epoxy-5,6-dihydro-β,β- carotene-5,3′-diol; 5 ), cucurbitaxanthin B (= (3S,5R,6R,3′S,5′R,6′S)-3,6,5′, 6′-diepoxy-5,6,5′,6′-tetrahydro-β,β-carotene-5,3′-diol; 6 ), the epimeric cucurbitachromes 1 and 2 (= (3S,5R,6R,3′S,5′R,8′S)- and (3S,5R,6R,3′S,5′R,8′R)-3,6,5′, 8′-diepoxy-5,6,5′,6′-tetrahydro-β,β-carotene-5,3′-diol, resp.; 9/10 ), cycloviolaxanthin (= (3S,5R,6R,3′S,5′R,6′R)-3,6,3′, 6′-diepoxy-5,6,5′,6′-tetrahydro-β,κs-carotene-5,5′-diol; 8 ), and capsanthin 3,6-epoxide (= (3S,5R,6R,3′S,5′R)-3,6-epoxy-5,6-dihydro ?5,3′-dihydroxy-β,κ-caroten-6′-one; 7 ) were isolated from red spice paprika (Capsicum annuum var. longum) and characterized by their ¹H- and ¹³C-NMR, mass, and CD spectra.     

Synthesis of racemic and enantiomerically pure 2′-thia-2′,3′-dideoxycytidine as potential anti-hepatitis B virus agents

A novel class of nucleosides with the C₁, atom bonded to three hetero atoms was synthesized. 2′-Thia-2′,3′-dideoxycytidine was the pilot compound of this series. (±)-β-2′-Thia-1′,3′-dideoxycytidine ( 6 ) and (±)-α-2′-thia-2′,3′-dideoxycytidine ( 7 ) were synthesized from (±)-3-mercapto-1,2-propanediol. The synthesis of the enantiomerically pure 2′-thia-2′,3′-dideoxycytidines (α-D-form, β-D-form, α-1-form and β-L-form) from optically pure (S)-(2,2-dimethyl-1,3-dioxalan-yl)methyl p-toluenesulfonate ( 8 ) and its (R)-isomer 18 was also described. The preliminary biological results showed that (+)-β-D-2′-thia-2′,3′-dideoxycytidine ( 26 ) was the most active against human hepatitis B virus with an ED₅₀ of 3 μM.     

Mechanistic and Synthetic Studies on the Formation of 1,2,4-Trioxanes Related to Arteannuin. Photooxygenation of a bicyclic dihydropyran

The photooxygenation of (4R,4aS,7R)-4,4a,5,6,7,8-hexahydro-4,7-dimethyl-3H-2-benzopyran ( 16 ) was performed in (i) MeOH, (ii) acetaldehyde, and (iii) acetone at ?78°. The products obtained respectively were (i) (2R)-2-[(1S,4R)-4-methyl-2-oxocyclohexyl]propyl formate ( 17 ; 72% yield), (ii) 17 (54.5%), (1R,4R,4aS,7R)-3,4,4a,5,6,7-hexahydro-4,7-dimethyl-1H-2-benzopyran-2-yl hydroperoxide ( 19 ; 16.7%), a 12:1 ratio of (3R,4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,7,10-trimethyl-6H-[2]benzopyrano[1,8a-e]-1,2,4-trioxane ( 20 ) and its C(3)-epimer 21 (17%), together with evidence for the 1,2-dioxetane ( 22 ) originating from the addition of dioxygen to the re-re face of the double bond of 16 , and iii) unidentified products and traces of 22 . Addition of trimethylsilyl trifluoromethanesulfonate (Me₃SiOTf) to the acetone solution of 16 after photooxygenation afforded (4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,3,7,10-tetramethyl-6H-[2]benzopyrano[1,8a-e]-1,2,4,-trioxane ( 23 , 40%). The photooxygenation of 16 in CH₂Cl₂ at ?78° followed by addition of acetone and Me₃SiOTf afforded 17 (11%), 23 (59%), and (4aR,7R,7aS,10R,11aR)-7,7a,8,9,10,11-hexahydro-3,3,7,10-tetramethyl-6H-[2]benzopyrano[8a,1-e]-1,2,4-trioxane ( 24 ; 5%. Repetition of the last experiment, but replacing acetone by cyclopentanone, gave 17 (16%), (4′aR,7′R,7′aS,10′R,11′aR)-7′,7′a,8′,9′,10′,11′-hexahydro-7′,10′-dimethylspiro[cyclopentane-1,3′-6′H-[2]benzopyrano[1,8a-e]-1,2,4-trixane] ( 25 ; 61%), and (4′aR,7′R,7′aS,10′R,11′aR)-7′,7′a,8′,9′,10′,11′-hexahydro-7′,10′-dimethylspiro[cyclopentane-1,3′-6′H-[2]benzopyrano[8a,1-e]-1,2,4-trixane] ( 26 , 4%). The X-ray analysis of 23 was performed, which together with the NMR data, established the structure of the trioxanes 20, 21, 24, 25 , and 26 . Mechanistic and synthesis aspects of these reactions were discussed in relation to the construction of the 1,2,4-trioxane ring in arteannuin and similar molecules.     

Photochemische Umsetzung von optisch aktiven 2-(1′-Methylallyl)anilinen mit Methanol

Photochemical Reaction of Optically Active 2-(1′-Methylallyl)anilines with Methanol It is shown that (?)-(S)-2-(1′-methylallyl)aniline ((?)-(S)- 4 ) on irradiation in methanol yields (?)-(2S, 3R)-2, 3-dimethylindoline ((?)-trans- 8 ), (?)-(1′R, 2′R)-2-(2′-methoxy-1′-methylpropyl)aniline ((?)-erythro- 9 ) as well as racemic (1′RS, 2′SR)-2-(2′-methoxy-1′-methylpropyl) aniline ((±)-threo- 9 ) in 27.1, 36.4 and 15.7% yield, respectively (see Scheme 3). By deamination and chemical correlation with (+)-(2R, 3R)-3-phenyl-2-butanol ((+)-erythro- 13 ; see Scheme 4) it was found that (?)-erythro- 9 has the same absolute configuration and optical purity as the starting material (?)-(S)- 4 . Comparable results are obtained when (?)-(S)-N-methyl-2-(1′-methylallyl)aniline ((?)-(S)- 7 ) is irradiated in methanol, i.e. the optically active indoline (+)-trans- 10 and the methanol addition product (?)-erythro- 11 along with its racemic threo-isomer are formed (cf. Scheme 3). These findings demonstrate that the methanol addition products arise from stereospecific, methanol-induced ring opening of intermediate, chiral trans, -(→(?)-erythro-compounds) and achiral cis-spiro [2.5]octa-4,6-dien-8-imines (→(±)-threo-compounds; see Schemes 1 and 2).     

Synthese von optisch aktiven,natürlichen Carotinoiden und strukturell verwandten Naturprodukten. V. Synthese von (3R, 3′R)-, (3S, 3′S)- und (3R,3′S; meso)-Zeaxanthin durch asymmetrische Hydroborierung. Ein neuer Zugang zu Optisch aktiven Carotinoidbausteinen. Vorläufige Mitteilung

Synthesis of Optically Active Natural Carotenoids and Structurally Related Compounds. V. Synthesis of (3R, 3′R)-, (3S, 3′S)- and (3R,3′S; meso)-zeaxanthin by Asymmetric Hydroboration. A New Approach to Optically Active Carotenoid Building Units The synthesis of (3R, 3′R)-, (3S, 3′S)- and (3R,3′S; meso)-zeaxanthin ( 1 ), ( 19 ) and ( 21 ) is reported utilizing asymmetric hydroboration as the key reaction. Thus, safranol isopropenylmethylether ( 4 ) is hydroborated with (+)- and (?)-(IPC)₂BH to give the optically pure key intermediates 5 and 7 resp., which are transformed into the above-mentioned C₄₀-compounds.     

One‐Pot,Asymmetric and Diastereoselective Four‐Component Synthesis of Polyfunctional (Z)‐Alkenyl Methyl Sulfones with Three Stereogenic Centers

The reaction of 1‐(trimethylsilyloxy)cyclopentene ( 9 ) with (±)‐1,3,5‐triisopropyl‐2‐(1‐(RS)‐{[(1E)‐2‐methylpenta‐1,3‐dienyl]oxy}ethyl)benzene ((±)‐ 4a ) in SO₂/CH₂Cl₂ containing (CF₃SO₂)₂NH, followed by treatment with Bu₄NF and MeI gave a 3.0 : 1 mixture of (±)‐(2RS)‐2{(1RS,2Z,4SR)‐2‐methyl‐4‐(methylsulfonyl)‐1‐[(RS)‐1‐(2,4,6‐triisopropylphenyl)ethoxy]pent‐2‐en‐1‐yl}cyclopentanone ((±)‐ 10 ) and (±)‐(2RS)‐2‐{(1RS,2Z)‐2‐methyl‐4‐[(SR)‐methylsulfonyl]‐1‐[(SR)‐1‐(2,4,6‐triisopropylphenyl)ethoxy]pent‐2‐en‐1‐yl}cyclopentanone ((±)‐ 11 ). Similarly, enantiomerically pure dienyl ether (−)‐(1S)‐ 4a reacted with 1‐(trimethylsilyloxy)cyclohexene ( 12 ) to give a 14.1 : 1 mixture of (−)‐(2S)‐2‐{(1S,2Z,4R)‐2‐methyl‐4‐(methylsulfonyl)‐1‐[(S)‐1‐(2,4,6‐triisopropylphenyl)ethoxy]pent‐2‐enyl}cyclohexanone ((−)‐ 13a ) and its diastereoisomer 14a with (1S,2R,4R) or (1R,2S,4S) configuration. Structures of (±)‐ 10 , (±)‐ 11 , and (−)‐ 13a were established by single‐crystal X‐ray crystallography. Poor diastereoselectivities were observed with the (E,E)‐2‐methylpenta‐1,3‐diene‐1‐ylethers (+)‐ 4b and (−)‐ 4c bearing ( 1 S )‐1‐phenylethyl and (1S)‐1‐(pentafluorophenyl)ethyl groups instead of the Greene's auxiliary ((1S)‐(2,4,6‐triisopropylphenyl)ethyl group). The results demonstrate that high α/β‐syn and asymmetric induction (due to the chiral auxiliary) can be obtained in the four‐component syntheses of the β‐alkoxy ketones. The method generates enantiomerically pure polyfunctional methyl sulfones bearing three chiral centers on C‐atoms and one (Z)‐alkene moiety.     

Dibothrioclinin I and II,epimers from Gerbera piloselloides (L.) Cass

Dibothrioclinin I and II, namely (+)‐(11R,12S,25R,27S)‐ and (±)‐­(11RS,12RS,25RS,27SR)‐3,3,7,17,21‐penta­methyl‐4,12,18,26‐tetraoxahepta­cyclo­[15.11.1.0^2,15.0^5,14.0^6,11.0^19,28.0^20,25]­nona­cosa‐5(14),6,8,10,19(28),20,22,24‐octaene‐13,27‐dione, respectively, are C₃₀H₂₈O₆ epimers which are derived from two bothrioclinin moieties joined so as to create an additional six‐membered ring. Structurally, the epimers differ only by inversion at one C atom of a central ring junction and the corresponding six‐membered rings have similar conformations in each mol­ecule, except for one ring adjacent to this inversion site.