The biosynthesis of the alkaloids of croton sparsiflorus morong

Incorporation of tyrosine, dopa, dopamine, 4-hydroxyphenylpyruvic acid, (±)-, norcoclaurine-1-carboxylic acid, -norcoclaurine, -coclaurine, and -N-methylcoclaurine into N-methylcrotsparine, N-methylcrotsparinine and N-methylsparsiflorine in Croton sparsiflorus Morong has been studied. The evidence supports the direct oxidative coupling of (+)-, and (-)-N-methylcoclaurines to give N-methylcrotsparine and N-methylcrotsparinine respectively. Tracer experiment show that N-methylcrotsparine undergoes dienone-phenol rearrangement to give N-methylsparsiflorine. A double labelling experiment with (±)-N[¹⁴C]methyl[1-³H]coclaurine demonstrated that the H atom at the asymmetric centre in the 1-benzylisoquinoline precursor is retained in the bioconversion. The intermediacy of norcoclaurine-1-carboxylic acid and specific incorporation of dehydro-N-methylcoclaurinium salt into the bases have been demonstrated.     

The structure,absolute configuration and biosynthesis of nortiliacorinine a

The incorporation of (±)-norcoclaurine, (±)-coclaurine, (±)-N-methylcoclaurine and dehydro-N-methylcoclaurine into nortiliacorinine A in Tiliacora racemosa colebr has been studied and specific utilisation of the (±)-coclaurine demonstrated. The evidence supports oxidative dimerization of two coclaurine units to give nortiliacorinine A. Experiments with (±)-N-methylcoclaurine and (±)-[1-³H, N-¹⁴CH₃]N-methylcoclaurine established that only one N-methylcoclaurine unit is specifically utilised to constitute that “half” of the base which had phenolic OH group in the benzylic portion and further demonstrated that the H atom at the asymmetric centre in the 1-benzylisoquinoline precursor is retained in the bioconversion into nortiliacorinine A. Double labelling experiment with (±)-[1-³H, 6,0-¹⁴CH₃]N-methylcoclaurine showed that O-Me function of the precursor is lost in the bioconversion into nortiliacorinine A. Parallel feedings of (+)-(S)- and (-)-(R)-N-methyl-coclaurines and (-)-(S)-, and ( + )-(R)-coclaurines revealed that the stereo-specificity is maintained in the biosynthesis of nortiliacorinine A from 1-benzylisoquinoline precursors and established ‘S,S’-configuration at the two asymmetric centres in nortiliacorinine A.     

The biosynthesis of nornuciferine-I(2-methoxy-6aα-aporphine-1-ol)

The incorporation of (±)-norcoclaurine, (±)-coclaurine, (±)-N-methylcoclairine, (±)-N-methylnorcoclaurine into nornuciferine-I in Croton sparsiflorus morong has been studied, and the specific utilization of the (±)-N-methylcoclaurine demonstrated. The evidence supports the direct oxidative coupling of (+)-(S)-N-methylcoclaurine to give N-methylcrotsparine, which in turn is shown to be a specific precursor of nornuciferine-I. The experiments also show that N-methylcrotsparine is reduced to N-methylcrotsparinol and it is N-methylcrotsparinol-I which is preferentially dehydrated and rearranged to nornuciferine-I.     

Biosynthesis of magnoflorine and laurifoline

The incorporation of (±)-, nor-laudanosoline, nor-protosinomenine, nor-orientaline, norreticuline and reticuline and reticuline methiodide into magnoflorine and laurifoline has been studied and specific incorporation of nor-reticuline and reticuline demonstrated. Parallel feeding experiments with (+)-S and (?)-(R)-reticulines demonstrated specific incorporation of (+)-(S)-isomer into these bases.     

Biosynthesis of (+)-,(-)- and (±)-tetrahydropalmatines

Specific incorporation of didehydroreticuline and reticuline into (±)- (+)-, and (-)-tetrahydropalmatines in Cocculus laurifolius and of (R)- and (S)-reticulines into (R)- and (S)-tetrahydropalmatines respectively has been demonstrated. Feeding of[l-³H, 4'-methoxy-¹⁴C]reticuline suggested that reticuline was not converted in the plants into didehydroreticuline and racemisation of optically active forms of tetrahydropalmatine did not take place via dehydrotetrahydropalmatine     

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.     

Absolute configuration of (−)-4-methylheptan-3-ol,a pheromone of the smaller european elm bark beetle,as determined by the synthesis of its (3R,4R)-(+)- and (3S,4R)-(+)-isomers

Nerol and geraniol were stereoselectively converted to (±)-threo- and (±)-erythro-4-methylheptan-3-ol respectively. (R)-(+)-Citronellic acid was converted to a mixture of (3R,4R)-(+)-threo- and (3S,4R)-(+)-erythro-isomers which was separable by GLC. These syntheses established the absolute configuration of the naturally occurring (?)-4-methylheptan-3-ol to be 3S,4S.     

The absolute configuration of (+)- and (−)-1-phenylundec-4-yn-3-ols. Synthesis of (R)-4-dodecanolide,a component of the defensive secretion of rove beetle Bledius mandibullaris

Hydrogenation of the triple bond of (+)-1-phenylundec-4-yn-3-ol (obtained from (+)-[η⁶-(3-hydroxyundec-4-yn-1-yl)benzene]chromium tricarbonyl) with the NaBH₄-NiCl₂·6H₂O reagent system in MeOH leads to (?)-1-phenylundecan-3-ol. Ozonolysis of the phenyl ring in the corresponding acetate gives (R)-(?)-acetoxydodecanoic acid, lactonization of which leads to the known (R)-(+)-4-dodecanolide. The starting (+)-1-phenylundec-4-yn-3-ol was thus shown to have the S-configuration.     

Synthesis of (+)-1,3:2,5-dianhydroviburnitol ((+)-(1R,2R,3S,5R,6S)-4,7-dioxatricyclo[3.2.1.03,6]octan-2-ol)

Epoxidation of (?)-(1R,2R,4R)-2-endo-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl acetate ((?)-5) followed by saponification afforded (+)-(1R,4R,5R,6R)-5,6-exo-epoxy-7-oxabicyclo[2.2.1]heptan-2-one ((+)-7). Reduction of (+)-7 with diisobutylaluminium hydride (DIBAH) gave (+)-1,3:2,5-dianhydroviburnitol ( = (+)-(1R,2R,3S,4R,6S)-4,7-dioxatricyclo[3.2.1.0^3,6]octan-2-ol; (+)-3). Hydride reductions of (±)-7 were less exo-face selective than reductions of bicyclo[2.2.1]heptan-2-one and its derivatives with NaBH₄, AlH₃, and LiAlH₄ probably because of smaller steric hindrance to endo-face hydride attack when C(5) and C(6) of the bicyclo-[2.2.1]heptan-2-one are part of an exo oxirane ring.     

Resolution of (±)-[2.2]paracyclophane-4,12-dicarboxylic acid

The resolution of (±)-[2.2]paracyclophane-4,12-dicarboxylic acid (±)-1 has been realized through the diastereomeric esters of (1S)-hydroxymethyl-4,7,7-trimethyl-2-oxabicyclo-[2.2.1]heptan-3-one, simply separated by flash chromatography and hydrolyzed with ^tBuOK/H₂O. (R)-(−)-1 and (S)-(+)-1 were obtained in high enantiomeric excesses (>97%) while the determinations of the absolute configurations of (R)-1 and (S)-1 were carried out by X-ray diffraction.     

Raman optical activity of tartaric acid and related molecules

The Raman optical activity spectra of (2R, 3R) (+)- and (2S,3S) (?)-tartaric acid, (2R, 3R) (+)-dimethyl tartrate, (2R,3R) (?)-2,3-butanediol and (2S, 3S) (+)-dibenzoyl tartaric acid are presented. A large couplet at about 500cm^?1 in the first three molecules, which probably originates in deformations of a chiral structural unit, might serve as an indicator of conformation and absolute configuration.     

Biosynthesis of tetrahydropalmatine and palmatine

The incorporation of (±)-norlaudanosoline, norprotosinomenine, nororientaline, norlaudanidine, reticuline and laudanosine into tetrahydropalmatine and palmatine has been studied, and specific utilization of reticuline demonstrated. Feeding of (±)-[N-methyl-¹⁴C] reticuline showed that C atom 8 of tetrahydropalmatine and palmatine are formed by oxidative cyclisation of the N-Me group of reticuline. Parallel experiments with (R)-; and (S)-, reticulines demonstrated specific incorporation of (R)- isomer into these bases. Feeding experiments also revealed that the plants can convert tetrahydropalmatine into palmatine with high efficiency.     

Carbocyclic nucleosides from enantiomeric, α-pinane-based aminodiols

Starting from (1R,2S,3S,5R)- and (1S,2R,3R,5S)-6,6-dimethylspiro[bicyclo[3.1.1]heptane-2,2’-oxiran]-3-ol (?)-8 and (+)-8, two comparative syntheses were developed for pinane-based chiral carbocyclic nucleosides. The regioselective ring opening of the spiro-oxirane ring of (?)-8 and (+)-8 with NaN₃ resulted in azidodiols (?)-9 and (+)-9. Catalytic reduction of (?)-9 and (+)-9 furnished chiral aminodiols (?)-10 and (+)-10, which were transformed by linear synthesis to purine-type nucleosides 16–18 through pyrimidine intermediates. Regioselective ring opening of the oxirane ring of (?)-8 and (+)-8 resulted in adenine-, cytosine- and uracil-based carbocyclic nucleosides 19–21 in a single-step synthesis.     

Synthese und Bestimmung des Chiralitätssinns von (+)-(R)-1-Azabicylo[3.3.1]nonan-2-on

Synthesis and Determination of the Chirality Sense of (+)-(R)-1-Azabicyclo[3.3.1]nonan-2-one Optically active (+)-(R)-1-azabicyclo[3.3.1]nonan-2-one ((+)- 1 ) of known absolute configuration is synthesized in the following way: Resolution of (±)-piperidin-3-ethanol ((±)- 2 ) by fractional recrystallization of its diastereoisomeric salts with (+)-3-bromocamphor-8-sulfonic acid from EtOH gave a less soluble salt that yielded(+)- 2 . The chirality sense of (+)- 2 was shown to be (R) by chemical correlation with the enantiomers of 3-oxocyclopentaneacetic acid ((±)- 8 ) of known absolute configuration. This correlation was effected by a Beckmann rearrangement of the oxime (R)-9 to the pyridone (S)- 10 followed by a direct reduction with LiAlH₄ to give the enantiomer (?)-(S)- 2 that was characterized as its benzyloxycarbonyl derivative (?)-(S)- 3 . The alcohol (+)-3 was converted via (+)- 4 into the nitrile (+)-5 which gave by hydrogenolysis and hydrolysis the (R)-configurated hydrochloride (+)- 6 which was cyclized to the bicyclic (5R)-lactam (+)- 1 in 67% yield by heating with 2 equiv. of dibutyltin(IV) oxide in toluene. The nonplanar amide function in (+)- 1 with the substituents at the N-atomarranged in a trigonal pyramid causes two rather intense Cotton effects at 242 (Δ?_max = +19.5) and 211 nm(Δ?_max = ?17.9) in the CD spectrum. If the molecules of (+)- 1 do exist mainly in the chair-twistboat conformation, the amide chromophore is pyramidally deformed in a sense defined by the absolute configuration at C(5). Therefore, the CD spectrum of the (5R)-lactam (+)- 1 can be used to test theories describing the chiroptical properties of distorted amides.     

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.     

Syntheses of pyridin-4-ylium chirons: applications in a synthesis of (+)-coniine

The compounds (3R,5S)-(+)-5-methyl-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide 4 and (3R,5S)-(+)-5-n-propyl-3-phenyl-2,3,5,6,7,8-hexahydro-oxazolo[3,2-a]pyridin-4-ylium iodide 5 were synthesized in two steps starting from the bicyclic thiolactam trans (3R,2aS)-(−)-5-thio-3-phenyl-2,3,6,7,8,2a-hexahydro-oxazolo[3,2-a]pyridine 1. In addition, starting from 5 an enantiospecific synthesis of (+)-coniine 7 was achieved.     

Stereoselective synthesis of the both enantiomers of disparlure,the pheromone of the gypsy moth

The both enantiomers of disparlure [(7R, 8S)-(+)-epoxy-2-methyloctadecane and its (7S,8R)-(?)-isomer] were synthesized from (2R, 3R)-(+)-tartaric acid in a stereoselective manner. (+)-Disparlure was found to be biologically active.     

Oxidation of bicyclic monoterpene ketones with Caro’s acid

Previously unknown seven-membered lactones, (1R,1??R,5S,5??S)-5,5??-oxybis(1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one), 2,2-dimethyl-1,6-dioxaspiro[2.6]nonan-7-one, 4-(1-hydroxy-1-methylethyl)-7-methyloxepan-2-one, and (4R,4??R,7S,7??S)-4,4??-[oxybis(propane-2,2-diyl)]bis(7-methyloxepan-2-one), were synthesized by the Baeyer-Villiger reaction using Caro??s acid as a result of oxidative and skeletal transformations of bicyclic monoterpene ketones, (+)-camphor, (+)-nopinone, and (?)-isocaranone.     

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 both the enantiomers of endo-brevicomin,the aggregation pheromone of Dryocoetes autographus

(1R,5S,7S)-(+)-endo-Brevicomin (7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane) and its (1S,5R),7(R)-(?)-isomer were synthesised employing the Sharpless asymmetric epoxidation as the key-step.