Novel 4,15-polyether analogues of macrocyclic trichothecenes

Following the development of the appropriate protecting group chemistry, the preparation of the 4,15-polyether analogues 17–20, 23–25, and 29–31 of macrocyclic trichothecenes from T-2 toxin (2) and neosolaniol (3) is described.     

Efficient and practical synthesis of both enantiomers of 6-silyloxy-3-pyranone derivatives

Lipase catalyzed kinetic resolution of racemic cis-6-(tert-butyldimethylsilyloxy)-3,6-dihydro-2H-pyran-3-ol (rac)-1 was achieved in high enantiomeric excess. Transesterification of (rac)-1 with vinylacetate in ^tBuOMe yielded the alcohol (3S,6R)-1 in 99.0% ee, whereas (3R,6S)-1 was obtained, in 99.0% ee, by the lipase catalyzed ester hydrolysis of acetate (3R,6S)-2, which was obtained along with the transesterification. Both (3S,6R)-1 and (3R,6S)-1 were subjected to oxidation to provide the corresponding 6-silyloxy-3-pyranone (6R)-3 and (6S)-3, respectively. Application to the synthesis of 7, which is the key intermediate of asymmetric synthesis of pseudomonic acid A 9 is also described.     

Benzisoxazolium cations—II : Reaction with anthranilic acid: Intramolecular reaction of an N-aroyl-N-alkylsalicylamide

Reaction of 2-ethylbenzisoxazolium fluoborate (1) with anthranilic acid gives O-aroylsalicylamide (5a) and the quinazolone (6a), whose structure is established by an unambiguous synthesis of its methyl ether (6b). The O-aroyl amide (5a), formed via the ketoketenimine (Scheme 1) from the salt 1, undergoes O→N migration to the imide (8) which through an intramolecular reaction followed by dehydration is converted to the quinazolone 6a (Scheme 2). Independently the O-aroyl amide (5a) could be transformed to the quinazolone (6a) under basic conditions. The formation of quinazolone (6a) suggests the labile N-alkyl-N-aroyl isomer (8), which is expected to be in equilibrium with the O-aroyl isomer (5a), is captured. (Scheme 2).     

Total synthesis of (+)-myxothiazols A and Z

The first synthesis of (+)-myxothiazol A 1 was achieved based on a modified Julia olefination between (3,5R)-dimethoxy-(4R)-methyl-6-oxo-(2E)-hexenamide 3, corresponding to the left side of the final molecule, and 4-(2″-benzothiazolyl)sulfonylmethyl-2′-[(1′″R),6′″-dimethylhepta-(2′″E),(4′″E)-dienyl]-2,4′-bithiazole 6, corresponding to the right side. The synthesis of (+)-myxothiazol Z 2 was also achieved based on modified Julia olefination between (3,5R)-dimethoxy-(4R)-methyl-6-oxo-(2E)-hexenoate 4, corresponding to left side of the final molecule, and (S)-sulfone 6.     

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.     

Chemoenzymatic synthesis of calcilytic agent NPS-2143 employing a lipase-mediated resolution protocol

The kinetic resolution of chlorohydrin (±)-6 has been successfully carried out via a lipase-mediated transesterification with vinyl acetate in organic as well as ionic liquid media to yield (R)-alcohol 6 and (S)-acetate 7 in high enantioselectivity. An enantioconvergent synthesis has also been achieved by a Mitsunobu esterification of a mixture of (R)-alcohol 6 and (S)-acetate 7 in one pot to convert the (R)-alcohol 6 to (S)-acetate 7. (S)-Acetate 7 has been hydrolyzed by LiOH·H₂O to give epoxide (R)-2. This enantiopure epoxide has been used as a chiral precursor for the synthesis of calcilytic agent NPS-2143.     

Pyrimidines-19: Ring transformation of 5-nitrouracil into nitroresorcinols

The first intermolecular right transformation of a uracil derivative into the benzene system is reported. Treatment of 1,3-dimethyl-5-nitrouracil (1) with acetone in NaOMe/MeOH afforded 6-acetonyl-5,6-dihydro-1,3-dimethyl-5-nitrouracil (6) which was converted into 4-nitroresorcinol (5) upon treatment with NaOEt/EtOH at reflux. Reaction of1 with butanone gave two major products, 3-(5,6-dihydro-1,3-dimethyl-5-nitrouracil-6-yl)butanone (7) and the 1-(uracil-6-yl)butanone isomer (8). Prolonged treatment of7 with NaOEt/EtOH afforded 4-methyl-6-nitro-resorcinol (9) whereas8 was converted into 2-methyl-4-nitro-resorcinol (10). Treatment of1 with diethyl acetonedicar?ylate in NaOEt/EtOH afforded diethyl-2-(5,6-dihydro-1,3-dimethyl-5-nitrouracil-6-yl)-acetonedicar?ylate (2). Prolonged treatment of2 with NaOEt/EtOH at reflux afforded (5,6-dihydro-1,3-dimethyl-6-nitrouracil-6-yl)-acetate (3). Apparently,2 underwent a retroClaisen reaction to give3. Reaction of1 with ethyl acetoacetate in NaOEt/EtOH gave adduct isomers4 which underwent transformation reaction to give eventually 6-nitroresorcinol (5).     

Isomerization of 2,5-divinyltetrahydropyran and acid-catalyzed rearrangements of isomeric novel dihydropyrans

2,5-Divinyltetrahydropyran (1) can be isomerized using a ruthenium trichloride- triphenylphosphine catalyst to give 3,4-dihydro-3-vinyl-6-ethyl-2H-pyran (2) and 3,4-dihydro-3- ethylidene-6-ethyl-2H-pyran (3). These products give a variety of rearranged products on treatment with acid. The course of the reactions can be controlled by reaction conditions to give 4-ethyltoluene (5) or 3-hydroxymethyl-1-octen-6-one (4) from 2, and 3,4-dihydro-2-methyl-3-methylene-(6-ethyl-2H- pyran (7), 2,3,4-trimethyl-2-cyclohexen-1-one (8), or 3-hydroxymethyl-2-octen-6-one (6) from 3. All of these products (4–8) can be explained as arising by the initial opening of the dihydropyran to generate an unsaturated hydroxy ketone which then cyclizes to carbocyclic products.     

Studies on fungal metabolites—XXXII: A renewed investigation on (−) flavoskyrin and its analogues

1-Oxo-1,2,3,4-tetrahydroanthraquinone (4a), and its 8-hydroxy-(4b) and 8-hydroxy-6- methyl (4c) derivatives were dimerized to the compounds formulated as (6a), (6b) and (6e), respectively. The structure of 6a was confirmed by X-ray crystallographic analysis.By the analogy with these dimers and NMR spectral analysis, a revised structure (7) was proposed for (?) flavoskyrin, a yellow metabolite of Penicillium islandicum NRRL 1175. A biosynthetic scheme involving Diels-Alder type cyclo-addition (π4s + π2s) was proposed for (?) flavoskyrin.     

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.     

Chromatographic enantioseparation of racemic α-(1-naphthyl)ethylammonium perchlorate by a Merrifield resin-bound enantiomerically pure chiral dimethylpyridino-18-crown-6 ligand

Three novel chiral pyridino-18-crown-6 ligands (S,S)-1, (S,S)-2 and (S,S)-3 were prepared and (S,S)-1 was attached to a Merrifield resin. The resulting adsorbent (S,S)-5 was used as a chiral stationary phase in the chromatographic enantioseparation of racemic α-(1-naphthyl)ethylammonium perchlorate. Also, a new chiral pyridono-18-crown-6 ligand (S,S)-6, used for the synthesis of (S,S)-1 and (S,S)-2, was prepared in two different ways.     

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.     

Chemoenzymatic total synthesis of cryptocaryalactone natural products

A new chemoenzymatic route for the preparation of cryptocaryalactones natural products using a kinetic resolution process as the key step is described. Novozyme-435 catalyzed hydrolysis of the prochiral (±)-monoester 7 afforded the precursors of cryptocaryalactones with high enantiomeric excess and excellent yields. The compounds (4S,6S)-7 and (4R,6R)-7 were converted to (+)-(6R,2′S)-cryptocaryalactone (1) and (?)-(6S,2′R)-cryptocaryalactone (2), respectively by employing Wittig-olefination, lactonization and acylation reactions.     

Ketene-S,S-acetals-V : The reactions of α-keto and α-cyanoketene-S,S-acetals with guanidine and thiourea: a new general synthesis of alkoxy-pyrimidines

The ketoketene-S,S-acetals (5a–c) react with guanidine and thiourea in the presence of alcoholic sodium alkoxides to give 2-amino- and 2-mercapto-4-alkoxy-5-aryl-6-methyl-pyridimidines (6a–k) respectively in good yields. The α-cyanoketene-S,S-acetals (9a–d) similarily gave 5-substituted-2,4-diamino-6-alkoxy-pyridimidines (10a–e) with guanidine in 50–60% overall yields. The unexchanged 2,4-diamino-5-p-chlorophenyl-6-methylthio-pyrimidine (11) was prepared from 9c as a typical example using identifical conditions described for 7. The synthesis of 5,6-fused pyrimidines (14a–f), (19) and (23a–e) was also accomplished using the cyclic ketene-S,S-acetals (13a–c) and (22a–b). The present method is found to be more convenient and efficient than reported methods for alkoxy and methylthiopyrimidines.     

Synthesis of an octamethyl-18-crown-6 derivative and the X-ray crystal structure of its 2:1 complex with borane-ammonia

The synthesis of 2,2,3,3,11,11,12,12-octamethyl-1,4,7,10,13,16-hexaoxacyclooctadecane (2) from pinacol (3) by a sequence of reactions (3→4→5→6+5→2) involving alkylation (3→ 4), ozonolysis and reduction (4→5), tosylation (5→6), and cyclisation (5+6→2) is reported. With borane-ammonia, the octamethyl-18-crown-6 derivative 2 forms a crystalline 2:1 complex, (BH₃NH₃)₂ · 2. X-Ray crystallography reveals the two guest BH₃NH₃ molecules are hydrogen bonded in a centrosymmetric manner to the opposite faces of the host 2, which adopts an all-gauche (ag⁺a ag^-a)₃ conformation.     

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.     

Lipase-catalyzed kinetic resolution of tetronic acid derivatives bearing a chiral quaternary carbon: total synthesis of (S)-(−)-vertinolide

We have developed a chemoenzymatic synthesis of (S)-vertinolide 1 with a chiral quaternary carbon atom at C5. In the kinetic resolution of tetronic acid precursor 6, lipase PS-D furnished the recovered alcohol 6 with an (R)-stereochemistry in a ratio of 95% ee, whereas lipase AY gave (S)-alcohol 6 with 93% ee. Chemical transformations of (S)-alcohol 6 provided (S)-vertinolide 1 in 33% yield in five steps with no loss of enantiomeric excess.     

Synthese von spiroverbindungen—V: (±)-Acorenon aus (±)-Acorenon-B durch konfigurationsinversion am Spirochiralitätszentrum

The sesquiterpene ketone (±)-acorenone-B (1) formerly obtained by total synthesis was converted by Wharton reaction of its epoxy ketone 4 into (±)-acorenone (6). The stereochemical correlation of 1 with 6 by configurational inversion at the spirochirality center C-5 also represents the first synthesis of 6.     

Deoxygenation reactions of C19-diterpenoid alkaloids

Efficient methods for deoxygenation of secondary and tertiary alcohols of some C₁₉-diterpenoid alkaloids are presented. Thus deltaline (1) was converted to delpheline (2) or to 10-deoxydeltaline (7); deltamine (8) to 6-deoxydetamine (10); and delpheline (2) to 6-deoxydelpheline (12). An unusual elimination product 4 was formed when chloro-derivative 3 was reduced with LiAlH₄.     

Search for a simpler synthetic model system for intramolecular 1,3-dipolar cycloaddition to the 5,6-double bond of a pyrimidine nucleoside

In search for a simpler model system for the study of intramolecular thermal reactions between the base and 5'-functionalized sugar moiety in nucleosides, 1-(3-azidopropyl)uracil (2), 1-(4-azidobutyl) pyrimidines (12 and 13) and 1-(5-azidopentyl)-uracil (14) was synthesized through the corresponding ω-benzoyloxy-(6,7 and 8) and ω-hydroxyalkyl-pyrimidines (9,10 and 11). Heating 2 gave 1,N⁶-trimethylene-6-aminouracil (4), while heating 12 and 13 gave N¹-C₆ cleaved addition products. 15 and 16, respectively. 15 was regiospecifically transformed to 1,2,3-triazole derivatives, 17,18 and 19. Heating 1-(4-azidobutyl)-5-bromouracil (20) yielded 3,9-tetramethylene-8-azaxanthine (22). 9 with NBA gave 1,0⁶-tetramethylene-5-bromo-6-hydroxy-5,6-dihydrouracil (24) and the 5-brominated analog of 9 (25). The 4-functionalized butyl side chain proved to serve as a substitute for the 5'-functionalized sugar moiety in pyrimidine ribonucleosides.