Syntheses of (+)- and (–)-Methyl 8-Epinonactate and (+)- and (–)-Methyl Nonactate

In four synthetic steps, (+)- and (–)-methyl 8-epinonactate ((+)- and (–)− 4 ) have been derived from (+)- and (–)-7-oxabicyclo[2.2.1]heptan-2-one ((+)- and (–)− 9 ), respectively. The (+)- and (–)-methyl nonactate ((+)- and (–)− 3 ) were obtained from (+)- and (–)− 4 , respectively, by Mitsunobu displacement reactions. Optical resolution of (±)− 9 via chromatographic separation of the corresponding N-methyl-S-alkyl-S-phenylsulfoximides 24 and 25 yielded the starting materials (+)- and (–)− 9 , respectively.     

Synthesis of Aristotelia-Type Alkaloids. Part XIII. Total syntheses of (+)-makonine, (+)-aristotelinone,and (+)-11,12-didehydroaristoteline

The oxidative transformation of synthetic (+)-aristoteline ((+)- 6 ) into other metabolites which had been isolated from Aristotelia species was investigated. Thus, treatment of (+)- 6 with I₂ as the single oxidant furnished the naturally occurring indole alkaloids (+)-makonine ((+)- 9 ),(+)-aristotelinone ((+)- 11 ), or (+)-11, 12-didehydroaristoteline ((+)- 7 ) in good yields, the selectivity of the oxidation process depending on the chosen reaction conditions.     

Optical resolution of 7-oxabicyclo[2.2.1]hept-21-ene derivatives. Diastereoselectivity in the formation of cyanohydrine-brucine complexes

A new, practical method for the optical resolution of bicyclic ketones if illusttrated by the preparation of (+)-(1R,4R)-7-oxabicyclo[2.2.1]bept-5-en-2-one ((+)- 1 ) and (+)-(1R, 2S,4R)-2-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yul acetate ((+)- 4 ). It involves the diastereoselective formation of a brucine complex with the corresponding cyanhydrine mixture.     

Synthesis of Aristotelia-Type Alkaloids. Part XII. Total synthesis of (−)-tasmanine. Stereoelectronic factors that control the rearrangement of 3H-indol-3-ol derivatives to oxindoles ( = 1,3-dihydro-2H-indol-2-ones) or to pseudoindoxyls ( =1,2-dihydro-3H-indol-3-ones)

The oxidative transformation of (+)-aristoteline ((+)- 5 ) into its metabolites, the recently synthesized indole alkaloids (?)-serratoline ((?)- 6 ), (+)-aristotelone ((+)- 2 ), and (?)-alloaristoteline ((?)- 22 ), was investigated in more detail. It was demonstrated that the diastereoface selectivity of the reaction of (+)- 5 with 3-chloroperbenzoic acid can be altered by variation of the solvent as well as by addition of CF₃COOH. The chemoselectivity of the 1,2-rearrangement of the intermediate 3H-indol-3-ol derivatives could be controlled as follows: treatment of 3H-indol-3-ols with aqueous polyphosphoric acid led to the pseudoindoxyl ( = 1,2-dihydro-3H-indol-3-one) derivatives, whereas an analogous treatment of the corresponding O-benzoates furnished exclusively the corresponding, constitutionally isomeric 2-oxindole ( = 1,3-dihydro-2H-indol-2-one) products. Exploitation of these and related findings led to efficient total syntheses of the Aristotelia alkaloid (?)-tasmanine ((?)- 1 ) and of the corresponding unnatural epimer (+)- 12 , as well as of the two pseudoindoxyls (+)-aristotelone ((+)- 2 ) and (?)-2-epiaristotelone ((?)- 11 ). All these transformations were carried out with synthetic (+)-aristoteline ((+)- 5 ) as the single indole alkaloid precursor.     

Almazole C,a New Indole Alkaloid Bearing an Unusually 2,5-Disubstituted Oxazole Moiety,and its putative biogenetic peptidic precursors,from a senegalese delesseriacean seaweed

From product isolation and biomimetic synthesis – which also establishes absolute configurations – the known oxazole alkaloids almazoles A ((+)- 1 ) and B ((+)- 2 ) seem to arise in a Senegalese delesseriacean seaweed from, in seuence, the new modified peptide prealmazole C ((+)- 4 ) and the oxazole alkaloid almazole C ((+)- 3a ). N,N-Dimethyl-L -phenylalaninamide ((+)- 7 ) and the new peptides (+)- 5 and (+)- 6 , as well as a series of known small units, are also involved. In all cases, the oxazole ring is peculiarly 2,5-inserted.     

Synthesis of Polypropionate Fragments Containing Tertiary-Alcohol Moieties. Cross-aldolisations with lithium enolates of 7-oxabicyclo[2.2.1]heptan-2-one derivatives

The Diels-Alder adduct of 2,4-dimethylfuran to 1-cyanovinyl (1′R)-camphanate ((+)-(1R,2S,4R)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′R)-camphanate ((+)- 1 )) was converted into (+)-2,7-dideoxy-2,4-di-C-methyl-L -glycero- ((+)- 6 ) and -D -glycero-L -altro-heptono-1,4-lactone ((+)- 7 ), into (?)-(3R,4R,5R,6S)-3,4:5,7-bis(isopropylidenedioxy)-4,6-dimethylheptan-2-one ((?)- 22 ), and into (+)-(2R,3R,4R,5S,6S)-3,4:5,6-bis(isopropylidenedioxy)-2,4-dimethylheptanal ((+)- 34 ). Condensation of ((+)- 34 with the lithium enolate of (?)-(1R,4R,5S,6R)-6-exo-[(tert-butyl)dimethylsilyloxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1] heptan-2-one ((?)- 38 ; derived from (+)- 1 ) gave a 3:2 mixture of aldols (+)- 39 and (+)- 40 (mismatched pairs of a α-methyl-substituted aldehyde and (E)-enolate) whereas the reaction of (±)- 34 with (±)- 38 gave a 10:1 mixture of aldols (±)- 41 and (±)- 39 . A single aldol, (?)- 44 , was obtained to condensing (+)- 34 with the lithium enolate of (+)-(1S,4S,5S,6S)-5-exo-(benzyloxy)-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptan-2-one ((+)- 43 ; derived from (?)-(1S,2R,4S)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′S)-camphanate ((?)- 3 )). All these cross-aldolisations are highly exo-face selective for the bicyclic ketones. The best stereochemical matching is obtained when the lithium enolates and α-methyl-substituted aldehydes can realize a ‘chelated transition state’ that obeys the Cram and Felkin-Anh models (steric effects). Polypropionate fragments containing eleven contiguous stereogenic centres and tertiary-alcohol moieties are thus prepared with high stereoselectivity in a convergent fashion. The chiral auxiliaries ((1R)- and (1S)-camphanic acid) are recovered at the beginning of the syntheses.     

Neue Synthese von (−)-(R)-Cembren A,Synthese von (+)-(R)-Cembrenen und (+)-(S)-Cembren

Novel Synthesis of (?)-(R)-Cembrene A, Synthesis of (+)-(R)-Cembrenene and (+)-(S)-Cembrene A novel synthesis of (?)-(R)-cembrene A ((?)- 3 ) was developed using the Sharpless epoxidation for the introduction of the chiral center. Furthermore, the synthesis of (+)-(R)-cembrenene ((+)- 4 ) showed that this cembranoid must have the (R)-configuration and not, as previously reported, the (S)-configuration. Selective hydrogenation of (+)- 4 afforded (+)-(S)-cenibrene ((+)- 5 ).     

Synthesis and Circular Dichroism of Optically Pure (±)-(1S,2S,5S)-5-Methoxy-3,4,6,7-tetramethylidenebicyclo[3.2.1]oct-2-yl Derivatives. Baker's Yeast Reduction of 4-Methoxy-5,6,7,8-tetramethylidenebicyclo[2.2.2]octan-2-one

Baker's yeast reduction of 4-methoxy-5,6,7,8-tetramethylidenebicyclo[2.2.2]octan-2-one ( 11 ) under fermenting conditions afforded (?)-(1S,2S,4R)-4-methoxy-5,6,7,8-tetramethylidenebicyclo[2.2.2]octan-2-ol ((?)- 13 ) in 60% yield with an e.e. > 99.5%. Its methanesulfonate (?)- 14 was hydrolyzed and rearranged with high stereo-selectivity into (+)-(1S,2S,5S)-5-methoxy-3,4,6,7-tetramethylidenebicyclo[3.2.1]octan-2-ol ((+)- 15 ). The absolute configuration of (?)- 13 was deduced from the CD spectrum of its 4-(dimethylamino)benzoate ((+)- 22 ) applying the chiral exciton-coupling method. The CD spectrum of (+)- 15 and of its (tert-butyl)dimethylsilyl ether ((+)- 23 ) showed exciton-split type of Cotton effects attributed to through-space interactions between the s-gauche-buta-diene and s-cis-butadiene chromophores of these systems.     

Leiopathic Acid,a Novel Optically Active Hydroxydocosapentaenoic Acid,and related compounds,from the black coral Leiopathes sp. of Saint Paul Island (S. Indian Ocean)

The antipatharian Leiopathes sp., collected around Saint Paul Island, is shown here to contain, in relatively high amounts, the novel fatty acid leiopathic acid ( = (+)-(10R,7Z,11E,13Z,16Z,19Z)-10-hydroxy-7,11,13,16,19-docosapentaenoic acid; (+)- 1 ), besides (+)-(8R,5Z,9E,11Z,14Z,17Z)-8-hydroxy-5,9,11,14,17-icosapentaenoic acid ((+)- 11 ) and (+)-(8R,5Z,9E,11Z,14Z,)-8-hydroxy-05,9,11,14-icosatetraenoic acid ((+)- 16 ) and their ethyl ester (+)- 2 , (+)- 12 , and (+)- 17 .     

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.     

Total Syntheses of (−)-Conduritol B ((−)-1L-Cyclohex-5-ene-1,3/2,4-tetrol) and of (+)-Conduritol F((+)-1D-Cyclohex-5-ene-1,2,4/3-tetrol). Determination of the Absolute Configuration of (+)-Leucanthemito

The ‘naked sugar’ (+)-(1R,2R4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-sn-2-exo-yl acetate ((+)- 4 ) was converted (7 steps, 45% overall) with high stereoselectivity into (?)-(4R,5S,6R)-4,5,6-tris{[(tert-butyl)dimethylsilyl]oxy}cyclohex-2-en-1-one ((?)- 11 ). Reduction of (?)- 1 with NaBH₄- CeCl₃ · 7 H₂O, followed by deprotection of the silyl ether moieties gave (+)-conduritol F ((+)- 1 ; 47%) whose characteristics were identical to those of natural (+)-leucanthemitol. Reduction of (?)- 11 with DIBAH, followed by deprotection of the silyl ether moiety led to (?)-conduritol B ((?)- 3 ; 51 %).     

Synthese von (+)-Abscisinsäure

Synthesis of (+)-Abscisic Acid . Starting from (4S)-4-hydroxy-2,6,6-trimethylcyclohex-2-enone ( 2 ), a short synthesis of the natural (+)-abscisic acid ((+)- 1 ) has been accomplished.     

(+)-(1S, 3S, 6S, 8S)-und (−)-(1R, 3R, 6R, 8R)-4, 9-Twistadien: Synthese und Bestimmung der absoluten Konfiguration

(+)-(1S, 3S, 6S, 8S)-and (?)-(1R, 3R, 6R, 8R)-4, 9-Twistadiene: Synthesis and Absolute Configuration A synthesis and the determination of the absolute configuration of (+)-(1S, 3S, 6S, 8S)- and (?)-(1R, 3R, 6R, 8R)-4, 9-twistadiene ((+)- and (?)- 4 , respectively) is described. Their chiroptical properties are compared with those of saturated twistane ((+)- and (?)- 5 ) as well as with those of the unsaturated and saturated 2, 7-dioxatwistane analogs (+)- and (?)- 9 , and (+)- and (?)- 10 , respectively, which also are compounds of known absolute configurations.     

Mammalian Alkaloids: Configurations of Optically Active Salsoline- and 3′,4′-Dideoxynorlaudanosoline-1-carboxylic Acids

Synthesis of the optical isomers of (±)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate ((±)- 2 ) was accomplished by reaction of (±)- 2 with (+)-(R)-1-phenylethyl isocyanate, separation of the urea diastereoisomers (?)- 4A and (+)- 4B , and alcoholysis of the ureas in refluxing BuOH. Optically active isoquinoline-carboxylates 2A , B and hydantoins 8A , B isolated were characterized. The absolute configuration of the reaction products was established by X-ray analysis of the optically active hydantoin (+)- 8A . Hydrolysis of the methyl isoquinolinecarboxylates 2A , B with 48% HBr soln. at reflux afforded the desired optically active 3′,4′-dideoxynorlaudanosoline-1-carboxylic acids 1A , B required for enzyme-inhibition studies. Details of the X-ray diffraction analysis of (+)-methyl salsoline-1-carboxylate hydrobromide ((+)- 11A ·HBr) prepared earlier are included. CD spectra of (+)-(S)-methyl 6,7-dimethyl-3′,4′-dideoxynorlaudanosoline-1-carboxylate hydrobromide ((+)- 2A . HBr) and (?)-(R)-methyl salsoline-1-carboxylate hydrochloride ((?)- 11B ·HCl) confirmed the assignment of their (S)- and (R)-configurations, respectively.     

Absolute Configuration of 3-Substituted 1-Azabicyclo[2.2.1]heptanes

The l-azabicyclo[2.2.1]heptan-3-exo-ol ( 2 ) was resolved by fractional crystallisation of its hydrogen tartrate salts. The enantiomers (+)- and (?)- 2 were oxidised to the ketones (?)- 4 and (+)- 4 , respectively (Scheme). CD spectroscopy suggested that (?)- 4 possesses the (1R,4S)-configuration. This absolute configuration was confirmed by single-crystal X-ray diffraction of the derivative (+)-(1R,4R)-3-(1,3-dithian-2-ylidene)-1-azabicyclo [2.2.1]-heptane ((+)- 5 ).     

Synthese des Dysidins

Synthesis of Dysidin The synthesis of dysidin ((?)- 1 ), the enantiomer of a metabolite of the marine sponge Dysidea herbacea, is described. To effect the synthesis, (±)-5-isopropyl-4-methoxy-3-pyrrolin-2-one ( 7 ) is converted to its lithium salt and reacted with (?)-(5R,2E)-3-methoxy-5-trichloromethyl-2-hexenoyl chloride ((-)- 11 ) to give (?)- 1 and its diastereoisomer (+)-5-epidysidin ((+)- 12 ) epimeric at C(5) of the pyrrolinone ring. The (?)-acyl chloride (?)- 11 has been synthesized from (+)-(R)-3-(trichloromethyl)butanoic acid ((+)- 8 ) via the intermediates (+)- 9 and (?)- 10 , the pyrrolinone 7 from N-benzyl-oxycarbonyl-L-valine via the intermediate 5 . The enantiomers of acid 8 have been resolved by fractional crystallization of their diastereoisomeric N-(1-phenylethyl)amides. The (R)-chirality of (+)- 8 was determined by comparing the ¹H-NMR spectra of the diastereoisomeric N-(1-phenylethyl)amides 16 and 17 , made from (+)- 8 by substituting deuterium for chlorine, with the spectra of the N-(1-phenylethyl)amides 14 and 15 of known absolute configuration. This correlation shows that literature value (R) for (?)- 8 is in error. Therefore, the structural formulae of (?)-dysidenin and (+)-isodysidenin, two other metabolites of D.herbacea, have to be changed to their mirror images as shown in formulae (?)- 3 and (+)- 4 , respectively.     

Synthesis of Aristotelia-Type Alkaloids. Part XV. Total synthesis of (+)-hobartinol

Synthetic (+)-makomakine ( 6 ) was transformed in six steps into (+)-17R,18R)-17,18-dihydrohobartine-17,18-diol ((+)- 5 ) with an overall yield of 38% (Scheme 2). This compound was shown to be identical with natural hobartinol, a monoterpene indole alkaloid from Aristotelia australasica, originally believed to be the (17S)-epimer 1 . At the same time, the synthesis of (+)- 5 delineates the hitherto unknown absolute configuration of this metabolite.     

Circular Dichroism of Tricarbonyl(diene)iron Complexes. The Octant Rule Applied to Ketones Perturbed by Remote Fe(CO)3 Groups. Crystal Structure of (±)-Tricarbonyl[(1RS,4RS,5RS,6SR)-C5,6,C-η-(5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octanone)]iron

The preparation and the CD spectra of optically pure (+)-trans-μ-[(1R,4S,5S,6R,7R,8S)-C,5,6,C -η : C,7,8,C-η-(5,6,7,8-tetramethylidene-2-bicyclo [2.2.2]octanone)]bis(tricarbonyliron) ((+)- 7 ) and (+)-tricarbonyl[(1S,4S,5S,6R)-C-5,6,C-η-(5,6,7,8,-tetramethylidene-2-bicyclo[2.2.2]octanone)]iron ((+)- 8 ), and of its 3-deuterated derivatives (+)-trans-μ-[(1R,3R,4S,5S,6R,7R,8S)-C,5,6,C-η : C,7,8,C-η-5,6,7,8-tetramethylidene(3-D)-2-bicyclo[2.2.2]-(octanone)]bis(tricarbonyliron) ((+)- 11 ) and (+)-tricarbonyl[(1S,3R,4S,5S,6R)-C-5,6,C- η-(5,6,7,8-tetramethylidene(3-D)-2-bicyclo[2.2.2]octanone)]iron ((+)- 12 ) are reported. The chirality in (+)- 7 and (+)- 8 is due to the Fe(CO)₃ moieties uniquely. The signs of the Cotton effects observed for (+)- 7 and (+)- 8 obey the octant rule (ketone n→π*_CO transition). Optically pure (?)-3R-5,6,7,8-tetramethylidene(3-D)-2-bicyclo[2.2.2]octanone ((?)- 10 ) was prepared. Its CD spectrum showed an ‘anti-octant’ behaviour for the ketone n→π*_CO transition of the deuterium substituent. The CD spectra of the alcoholic derivatives (?)-trans-μ-[(1R,2R,4S, 5S,6R,7R,8S)-C,5,6,C-η : C,7,8,C- η-(5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octanol)]bis(tricarbonyliron) ((?)- 2 ) and (?)-tricarbonyl- [(1S,2R,4S,5S,6R)- C,5,6,C- η-(5,6,7,8-tetramethylidene-2-bicyclo[2.2.2]octanol)]iron ((?)- 3 ) and of the 3-denterated derivatives (?)- 5 and (?)- 6 are also reported. The CD spectra of the complexes (?)- 2 , (?)- 3 , (+)- 7 , and (+)- 8 were solvent and temperature dependent. The ‘endo’-configuration of the Fe(CO)₃ moiety in (±)- 8 was established by single-crystal X-ray diffraction.     

An Unexpected Asymmetric Reduction of 4-(1-Nitro-2-oxocyclododecyl)butan-2-one. Determination of the absolute configuration of (‒)-15-hexadecanolide

Reduction of the carbonyl group in the side chain of 4-(1-nitro-2-oxocyclododecyl)butan-2-one ( 3 ) with organoboron complexes are influenced by the chiral center, in 4-position with respect to the carbonyl C-atom, to which the NO₂ group is attached, a rare type for an asymmetric reduction. Independent of the (R)- or (S)-configuration of the Alpine-Hydride, (+)- 3 is reduced only to the (15S)-nitrolactone (+)- 5 and, after subsequent transformations, to (+)-(-S)-15-hexadecanolide ((+)- 1 ), enantiomer of the naturally occurring (?)- 1 .     

Über die Konstitution von Loroglossin. Vorläufige Mitteilung

The Constitution of Loroglossine. Loroglossine, a characteristic constituent of orchids, is shown to be bis-[4-(β-D -glucopyranosyloxy)-benzyl]-(2 R, 3 S)-2-isobutyl-tartrate ( 1 ). Hydrolysis and esterification gave 1 mol-equiv. of dimethyl (+)-2-isobutyl-erythro-tartrate ((+)-3) and 2 mol.-equiv. of a glucoside which, after acetylation, gave 4 , identical with a synthetic sample. The erythro configuration of (+)- 3 by oxidation of isobutyl-maleic acid with osmium tetroxide and subsequent esterification. The absolute configuration of (+)- 3 was based on Horeau experiments and NMR. data of the diastereomeric mixture of its esters 7 and 8 with S (+)- and R (?)-α-phenylbutyric acid respectively.