Biosynthesis of tylophorine and tylophorinine

Administration of 3,4-dihydroxyphenyl[2-¹⁴C] alanine to young Tylophora asthmatica plants revealed that ring B and carbon atoms C₉ and C₇ of tylophorine and tylophorinine are derived from dopa. Tracer experiments with 6,7-diphenylhexahydroindolizines (1–7) and (26) demonstrated that compound 1 is efficiently and specifically incorporated into tylophorine (13) and tylophorinine (16). Compounds (3), (4) and (26) were not metabolized by the plants to form (13) and (16) whereas (5) and (6) were utilized to yield (13) and (16). Compound (2) was very poorly converted into (13) and (16) and thus is not on the major biosynthetic pathway of (13) and (16).     

Gibberellin metabolites from ent-kaura-2,16-dien-19-ol and its succinate in Gibberella fujikuroi

Exposure of ent-kaura-2,16-dien-19-ol (1) or its succinate (2) to resuspended mycelia of G. fujikuroi has produced a complex mixture of acids which after methylation gave the esters of two C₁₉ (24) and (30) and five C₂₀ gibberellins (4, 11, 20, 32 and 33). The triester (32) and the lactone ester (24) have been prepared before from the esters of gibberellin A₁₃ (8) and gibberellin A₄ (26) respectively. The structures of the other metabolites were assigned on spectroscopic data and by chemical transformations. Thus the lactone diester (4) has been converted to the known keto triester (6). The epoxide (11) has been related to gibberellin A₁₄ (14) and the aldehyde (33) has been related to gibberellin A₁₃ trimethyl ester (8) by way of the triol (34). Selective de-epoxidation of the 16,17-epoxy function in diepoxides has provided a route from the dienes (20 and 24) to the epoxides (11 and 30) respectively, but not from the ester of gibberellin A₅ (23) to that of gibberellin A₆ (29). On the other hand the latter can be obtained by epoxidation of gibberellin A₅ methyl ester trifluoroacetate. Backfeeding experiments carried out with the epoxy diacid (12), the diene diacid (21) and the derived diol (39) indicate pathways connecting the various metabolites. The natural gibberellins A₅ and A₆ were shown to be formed in some of the backfeeding experiments.     

Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(−)-apomorphine and (R)-(−)-aporphine via a recycle process of resolution

Efficient preparations of (R)-(−)-apomorphine (R)-1 and (R)-(−)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.     

Regio- and stereospecific models for the biosynthesis of the indole alkaloids—III : The Aspidosperma-Iboga-secodine relationship

In vitro transformation of the Aspidosperma alkaloid (?) tabersonine (1) to (±)-pseudocatharanthine (7) via (+) allocatharanthine (6) and dehydrosecodine A (3) is described as a model for the biochemical interconversion of Aspidosperma and Iboga alkaloids. Facile conversion of 1, 2 and 7 in xylene solution to the carbazole (9) suggests the intermediacy of dehydrosecodines (as 8) in these reactions. In methanol solution the racemic salt (12) is formed in 50% yield from catharanthine at 175°. Further pyrolysis of the salt yields the carbazole (9). Reduction of the salt (12) with NaBH₄ affords (±) dihydrosecodine (16) identical with the natural alkaloid from Rhazya stricta.     

Novel resolution of the anthracyclinone intermediate by the use of (2r, 3r)-(+)- and (2s, 3s)-(-).1,4-bis(4-chlorobenzyloxy)butane-2,3-diol: a simple and efficient synthesis of optically pure 4-demethoxydaunomycinone and 4-demethoxyadriamycinone

(±)-7-Deoxy-4-demethoxydaunomycinone((±)-3) was found to be cleanly resolved by forming a mixture of the diastereomereic acetals((-)-9and(+)-10 or(+)-9 and(-)-10)with the title vicinal-diol(+)-or ( )-5), affording optically pure (R)-( )-3. The resolving agents (( + )- and ( )-5) were readily synthesized from unnatural(2S,3S)-(-)-tartaric acid((-)-6)or D-(-)-mannitol and natural (2R,3R)-(+)-tartaric acid((+)6), respectively. The undesired enantiomer ((S)-(+ )-3) obtained by the optical resolution could be racemized by heating with trifluoromethanesulfonic acid in aq acetic acid. Optically pure (R)-3 was elaborated to optically pure (+)-4-demethoxydaunomycinone ((+)-2b) and (+)-demethoxyadriamycinone ((+)-2a) by featuring highly stereoselective ( ? 20:1) introduction of the OH group into the C₇-position as a key step.     

Enantioselective synthesis of β-amino acids. Part 9: Preparation of enantiopure α,α-disubstituted β-amino acids from 1-benzoyl-2(S)-tert-butyl-3-methylperhydropyrimidin-4-one,

Double alkylation of enantiopure N,N-acetal pyrimidinone (S)-1, a masked chiral derivative of β-alanine prepared from (S)-asparagine, proceeds with high stereoselectivity to give C(5) disubstituted adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7, and (2S,5S)-7. Acid hydrolysis of these derivatives affords enantiopure α,α-dialkylated β-amino acids (R)-8, (S)-8, (R)-9, and (S)-9 in very good yields.     

(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in Diels–Alder reactions

A study of the Diels–Alder reactions of the esters derived from acrylic, methacrylic, trans-crotonic and trans-cinnamic acid and the chiral auxiliaries (R)- and/or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone (4, 17, 25 and 26, respectively) with different dienes [cyclopentadiene 5, isoprene 8, 11,12-dimethylene-9,10-dihydro-9,10-ethanoanthracene 9 and anthracene 10], catalyzed by titanium tetrachloride, is described. Cyclopentadiene gave adducts with esters (R)- or (S)-4 and (R)-25 with high endo- and facial-diastereoselectivities. Diene 5 reacted with (±)-17 without endo-diastereoselectivity and failed to give a cycloadduct with (±)-26. Isoprene reacted only with ester (S)-4 with high facial-diastereoselectivity. The reaction of 9 with (R)-4 failed, because the diene was not stable under the acid reaction conditions. Adducts derived from 10 and esters (S)-4 and (R)-17 could be obtained with high facial-diastereoselectivity. LiOH-hydrolysis of the adducts derived from esters (R)- or (S)-4 and (R)-25 gave the corresponding enantiopure acids, the chiral auxiliaries being completely recovered unchanged. However, hydrolysis of the adduct derived from 10 and (R)-17, required more drastic basic conditions which partially epimerized the chiral auxiliary. X-Ray diffraction analysis of the adducts derived from 10 and esters (S)-4 and (R)-17, let us establish their relative configurations and, taking into account the absolute configuration of the starting chiral auxiliary, their absolute configurations.     

Deoxygenation reactions of c19-diterpenoid alkaloids

Efficient methods for deoxygenation of secondary and tertiary alcohols of some C₁₉-diterpenoid alkaloids are presented. Delphisine (12) was converted to 1-deoxydelphisine (19) via either 1,2-pyrodelphisine (17) or phenyl thionocarbonate 20. The following alkaloids were deoxygenated via their thiocarbonylimidazolyl derivatives: 14-acetyldelcosine (13) to 14-acetyl-l-deoxydelcosine (22); alkaline hydrolysis of 22 gave 1-deoxydelcosine (23); aconitine (24) to 3-deoxyaconitine (27); yunaconitine (25) to crassicauline A (28). Deoxygenation of 14-acetyldictyocarpine (30) via the chloro-derivative 31 gave 14-acetyl-10-deoxydictyocarpine (34). Reduction of 31 with LiAlH₄ gave the unusual elimination product 32. An improved partial synthesis of hypaconitine (35) from aconitine (24) is also presented.     

Synthesis of (1R,cis,αS)-cypermethrine via lipase catalyzed kinetic resolution of racemic m-phenoxybenzaldehyde cyanohydrin acetate

A technical scale preparation of optically active (1R,cis,αS)-cypermethrine 4 from racemic m-phenoxybenzaldehyde cyanohydrin acetate (RS)-1 and (1R,cis)-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid chloride (1R,cis)-3 is described. Key steps of the new procedure are a lipase catalyzed enantioselective transesterification of (RS)-1 with n-butanol and direct acylation of the mixture of (R)-1 and (S)-cyanohydrin (S)-2 with (1R,cis)-3 to give enantiomerically pure (1R,cis,αS)-4. The unchanged (R)-1 is removed from (1R,cis,αS)-4 by distillation, and is racemized with triethylamine to give (RS)-1 which is returned to the process. The total yield of (1R,cis,αS)-4 referred to (RS)-1 is 80%.     

Synthesis of immunoreagents for measurement of galactosylhydroxylysine

(2S,5R)-(+)-Hydroxylysine (6) was transformed into (−)-succinimidyl ester (13) and conjugated to BSA or KLH to form immunogens (2 and 3) for generation of anti-galactosylhydroxylysine antibodies. Additionally, treatment of (−)-13 with 6-Fln-CH₂NH₂ (16) or acridinium derivative (17) and subsequent hydrolysis gave the fluorescent (4) and chemiluminescent (5) tracers, respectively. These immunoreagents (3,4 and 5,6) are essential for development of assays for diagnosis of osteoporosis.     

The synthesis of a natural product family: from debromoisolaurinterol to the aplysins

Total syntheses of (±)-aplysin 1, (±)-debromoaplysin 2, (±)-isoaplysin 3, (±)-aplysinol 4, (±)-debromoaplysinol 5, (±)-aplysinal 6, (±)-isolaurinterol 7 and (±)-debromoisolaurinterol 8 are described. Key features are a diastereoselective, sulfur mediated radical cyclisation of diene 12 to give 35; a new radical to polar crossover sequence mediated by Bu₃Sn that transforms diene 12 into (±)-debromoisolaurinterol 8; and a series of biomimetic cyclisation and oxidation reactions.     

A new group of isoquinoline alkaloids : The secoberbines

The new isoquinoline alkaloid (?)-peshawarine (1) has been isolated from Hypecoum parviflorum Kar. & Kir. (Papaveraceae). Its synthesis in the racemic form from coptisine (6b) involves a novel approach to cyclic hemiacetals in which the key step is the transformation of the aldehyde (±)-aobamine (10b) into the hemiacetal 12b using ethyl chloroformate. (±)-Corydalisol (11b) and (±)-canadaline (10a) have also been synthesized for the first time. The absolute configuration of (?)-1 was determined by chemical correlation with (+)-rhoeagenine methiodide (20). The chirality of the alkaloid (+)-canadaline (10a) has also been established by analogy to (+)-corydalisol (11b). (?)-Peshawarine (1), (+)-canadaline (10a), (+)-corydalisol (11b), and aobamine (10b), as well as hypecorine (22) and hypecorinine (23), are members of a new group of isoquinoline alkaloids, the secoberbines.     

Synthesis of adamantane derivatives—38: Synthesis of 1,3-bishoadamantane via ring-expansion of homoadamantan-2-one and homoadamant-4-en-2-one

The ring expansion of homoadamant-4-en-2-one (7) via the corresponding aminomethyl alcohol (9) gave 1,3-bishomoadamant-7-en-4-one (10) as the major product which was converted to 1,3-bishomoadamant-4-ene (14) and 1,3-bishomoadamanta-4,7-diene (16) via the alcohols 13 and 15. Catalytic hydrogenation of 14 and 16 afforded 1,3-bishomoadamantane (2). The ring expansion of homoadamantan-2-one (17) via the aminomethyl alcohol (19) afforded a 9:1 mixture of 1,3-bishomoadamantan-4-one (12) and 5-one (20). The same mixture was also obtained directly from 17 on treatment with diazomethane. The Wolff-Kishner reduction of 12 and 20 gave also 2.     

Photochemistry of dienones—X: Photochemistry of (e)-β-ionone oxime ethyl ether

(E)-β-ionone oximc ethyl ether [(E, E)-4] upon direct irradiation with λ either254or 313 nm yields the geometrical isomer (E, Z)-4 and (Z)-retro-γ-ionone oxime ethyl ether (Z,E)-5 as the sole primary products, illustrating (E)-(Z) isomerization (φ₃₁₃ =0.49) and a 1, 5-hydrogen shift (φ313 =0.15) respectively. From studies with triplet photosensitizers and with ethyl iodide (to enhance the singlet-triplet intersystem crossing) it is concluded that these two products in the direct irradiation result only from the singlet excited state, and that the inter-system crossing quantum yield is relatively low. Upon prolonged irradiation of (E,E)-4 with λ 313 nm the eventual products are (Z,E)-5 and (Z,Z)-5, whereas with λ 254 nm they are (E,E)-5 and [(Z,E)-5 and/or (E,Z)-5]. Upon triplet photosensitization (E,E)-4 undergoes only (E)-(Z) isomerization, leading to a mixture of all the four geometrical isomers of4. From the dependence of the geometrical isomer distribution in the photostationary state on the triplet energy of the sensitizer the triplet energies of (E,E)-4, (E, Z)-4, (Z, E)-4, and (Z, Z)-4 have been determined to be ca 55, < 55,57, and 57 $\text{kcal}\text{mol}$ respectively.     

An efficient enantiocontrolled synthesis of (+)-4-demethoxydaunomycinone

A chromatography-free, seven-step synthesis of the title compound (3) is described. The tetracyclic carbon skeleton is elaborated by a Diels-Alder strategy in which the 6a,7- and 1O.1Oa-bonds are constructed the epoxy-tetrone (9) and the D-glucose-derived diene (10b) serving as precursors. Interestingly, the cycloaddition reaction leads mainly to the “desired” cycloadduct (11b), revealing a notable diastereofacial reactivity of the diene (10b). Hydrolysis of the cycloadduct (11b) leads to the epoxy-pentone (12b) which is reduced to the dihydroxy-trione (13b). The reaction of the last-cited compound with ethynylmagnesium bromide affords a mixture of the ethynyl-diones (20b) and (21b), the latter compound arising from the precursor (13b) by a prior epimerisation at the 10a-position. The mixture of ethynyldiones (20b) and (21b) is converted into the anthracycline (14b) by the action of lead (IV) acetate. By a hydrolysis-hydration sequence, the anthracycline (14b) is transformed into (+)-4-demethoxydaunomycinone (3).     

Enantiomerically pure chiral phenazino-crown ethers: synthesis,preliminary circular dichroism spectroscopic studies and complexes with the enantiomers of 1-arethyl ammonium salts

Enantiomerically pure chiral crown ethers containing the phenazine unit [(R,R)-2–(S,S)-8] were prepared by two types of cyclization reactions. Ligands (R,R)-2, (R,R)-3, (S,S)-4, (R,R)-5, (R,R)-6 and (R,R)-7 were prepared from phenazine-1,9-diol 9 and the appropriate ditosylates (S,S)-10–(S,S)-15 in weak basic conditions with complete inversion of configuration. Ligands (S,S)-2, (S,S)-7 and (S,S)-8, however, were prepared from 1,9-dichlorophenazine 19 and the appropriate diols (S,S)-16–(S,S)-18 in strong basic conditions with retention of configuration. Enantiomeric recognition of most of the chiral ligands with α-(1-naphthyl)ethylammonium perchlorate (NEA) and α-phenylethylammonium perchlorate (PEA) has been studied by CD spectroscopy.     

Enantioselective synthesis of β-amino acids. Part 10: Preparation of novel α,α- and β,β-disubstituted β-amino acids from (S)-asparagine

Perhydropyrimidinone (S)-1 is alkylated with very high diastereoselectivity to give trans products (2S,5R)-3, (2S,5R)–4 and (2S,5R)-5. Dialkylation of (S)-1 also proceeds with complete stereoselectivity to afford adducts (2S,5R)-6, (2S,5S)-6, (2S,5R)-7 and (2S,5S)-7. Hydrolysis (6N HCl, 100°C) of monoalkylated derivative (2S,5R)-3 gives enantiopure α-substituted β-amino acid (R)-8. Hydrolysis of dialkylated adducts 6 and 7 affords enantiopure α,α-disubstituted β-amino acids (R)- or (S)-9 and (R)- or (S)-10. Related iminoester (2S,6S)-2 is alkylated with complete diastereoselectivity to give products (2S,6S)-11–13 whose hydrolysis under relatively mild conditions (2N CF₃CO₂H, CH₃OH, 100°C) affords enantiopure N-benzoylated β,β-disubstituted β-amino acid esters (S)-14–16, with intact double bonds in the olefinic substituents.     

Resolution of 1-phenyl-2-(p-tolyl)ethylamine via diastereomeric salt formation

(S)-1-Phenyl-2-(p-tolyl)ethylamine (S)-1, used for the industrial scale resolution of chrysanthemic acids, was obtained via resolution of the racemate with the hemiphthalate of (S)-isopropylidene glycerol (R)-2. The maximum experimental efficiency [69% yield and >99% e.e. of (S)-1] was achieved by a simple precipitation of (S)-1·(R)-2 from the solution of the 1:1 diastereomeric salt mixture in 93/7 isopropanol/water at saturation of the more soluble (R)-1·(R)-2 salt. Such an experimental efficiency was consistent with 0.79 maximum theoretical resolvability, derived from the solubilities of the two diastereomeric salts, and with DSC data, which indicated that the (S)-1·(R)-2/(R)-1·(R)-2 system is a binary mixture exhibiting an eutectic with composition approximately corresponding to a 0.2 molar ratio of (S)-1·(R)-2.     

Asymmetric synthesis of (S)-(−)-tetrahydropalmatine and (S)-(−)-canadine via a sulfinyl-directed Pictet–Spengler cyclization

(S)-(?)-Tetrahydropalmatine 2 and (S)-(?)-canadine 4 were synthesized in three steps from (S)-6, in 33% and 34% overall yield, respectively. Thus, condensation of the (S)-(E)-sulfinylimines 10 and 11 with the carbanion derived from (S)-6 gave the tetrahydroisoquinolines 12 and 13, respectively, which upon TFA induced N-desulfinylation, and subsequent microwave assisted Pictet–Spengler cyclization effected both cyclization and C-desulfinylation producing (S)-(?)-tetrahydropalmatine 2 and (S)-(?)-canadine 4 in optically pure form.     

Synthesis of (±)-averufanin,1noraverufanin and bis-deoxyaverufanin

Alkylation of xanthopurpurin (8) by 2-hydroxy-6-methyltetrahydropyran (6a and 6b) produced bis-deoxyaverufanin (9). This reaction was first carried out in aqueous sodium bicarbonate solution. Use of (S)-(?)-proline in dimethylformamide gave a quantitative yield of 9. With this method, 1,3,6,8-tetrahydroxyanthraquinone (4) was alkylated by 2-hydroxytetrahydropyran (15). Chromatography of the reaction mixture produced noraverufanin (17) along with a dialkytation product 18. Synthesis of (±)-averufanin (12) with 42% yield was achieved.