Synthesis of (5S*,4aS*,7aS*)-5-hydroxyhexahydro-cyclopenta[c]pyran-3(1H)-one

(5S*,4aS*,7aS*)-5-Hydroxyhexahydrocyclopenta[c]pyran-3(1H)-one, the promising isoprostane building block, was synthesized using intramolecular [3+2] cycloaddition of silyl nitronate generated from 4-benzyloxy-3-nitroocta-2,7-diene on the key step.     

New synthesis of (5S*,7aS*)-5-benzyloxy-5,6,7,7a-tetrahydrocyclopenta[c]pyran-3(1H)-one

To increase the efficiency of the recently suggested total synthesis of iso- and neuroprostanes, a possibility of transformation of its side products, i.e., syn- and anti-2-[(2S*,5S*)-2-benzyloxy-5-hydroxymethyl-Z-cyclopentylidene]ethanaldoximes, to (5S*,7aS*)-5-benzyloxy-5,6,7,7a-tetrahydrocyclopenta[c]pyran-3(1H)-one was studied.     

Furopyridines. XVIII. Photocycloaddition of furo[2,3-c]pyridin-7(6H)-one with acrylonitrile

The photocycloaddition of furo[2,3-c]pyridin-7(6H)-one ( 1 ) and its N-mefhyl derivative ( 1-Me ) to acrylonitrile has been studied. The structures of the photoadducts isolated by colum chromatography were determined by the nuclear magnetic resonance spectroscopy and single crystal X-ray analysis. The cyclo-addition of 1 afforded an adduct 2 at the carbonyl oxygen and 8-cyano-8,9-dihydrofuro[d]azocin-7(6H)-one ( 3 ), and the addition of 1-Me the N-methyl derivative 3-Me of 3 , (9S*)-9-cyano-6-methyl-3a,7a-dihydro-3a,7a-ethanofuro[2,3-c]pyridin-7(6H)-one ( 4 ), (2S*, 2aR*, 7bR*)- ( 5 ) and (1R*, 2aS*, 7bS*)-2-cyano-3-methyl-4-oxo-1,2,2a,3,4,7b-hexahydrocyclobuta[e]furo[2,3-c]pyridine ( 6 ).     

New aspects of reactions of methyl (thio)ureas with benzil

New pathways of reaction between 1-methylthiourea or 1-methylurea and benzil bring about new derivatives of (2S*,3aR*,6aS*)-perhydro-3aH-[1,3]dioxolo[4,5-d]imidazole and racemic (4S*,5R*)-4-alkoxy-5-hydroxy-1-methyl-4,5-diphenylimidazolidine-2-thiones. Some of the obtained urea-and thiourea derivatives were characterized by X-ray diffraction, which showed their supramolecular organization governed by the directionality of hydrogen bonds at the acceptor side C=O or C=S groups.     

Regioselectivity in the formation of norbornene-fused pyrazoles: preparation of 1-substituted derivatives of 4,5,6,7-tetrahydro-1H-4,7-methanoindazole

The structural characteristics of (±)-(exo,exo)-3-(hydroxymethylene)-5,6-(isopropylidenedioxy)bicyclo[2.2.1]heptan-2-one make the reactions between this β-diketone and hydrazines particularly interesting for elucidating the mechanism of pyrazole formation. The isolation and X-ray structure determination of two 5-hydroxy substituted Δ²-pyrazolines [(±)-(3aR*,4R*,5R*,6S*,7R*,7aR*)-7a-hydroxy-5,6-(isopropylidenedioxy)-3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-indazole] and [(±)-(3aS*,4R*,5R*,6S*,7R*,7aR*)-7a-hydroxy-5,6-(isopropylidene-dioxy)-1-phenyl-3a,4,5,6,7,7a-hexa-hydro-4,7-methano-1H-indazole] has been determinant for proposing a mechanism. Besides B3LYP/6-31G* calculations have been carried out on all intermediate dihydroxypyrazolidines and 5-hydroxypyrazolines. Finally, the annular tautomerism of the NH-methanotetrahydroindazoles has been studied both experimentally (¹³C NMR) and theoretically: the Mills-Nixon effect favours the 2H-tautomer.     

Diastereoselective 1,3-Dipolar Cycloaddition of Nitrones to 1<Emphasis Type="Italic">H</Emphasis>-Pyrrole-2,3-diones. Synthesis of pyrrolo[3,2-<Emphasis Type="Italic">d</Emphasis>]isoxazoles

1H-pyrrol-2,3-diones react with nitrones affording substituted pyrrolо[3,2-d]isoxazoles. The structures of ethyl (3R*,3aR*,6aR*)-6-benzyl-3-(4-bromophenyl)-4,5-dioxo-2,6a-diphenylhexahydro-3aHpyrrolo[ 3,2-d]isoxazole-3a-carboxylate and dimethyl (3R*,3aR*,6aS*)-3-(4-bromophenyl)-4,5-dioxo-2,6-diphenyltetrahydro-3aH-pyrrolo[3,2-d]isoxazole-3a,6a(4H)-dicarboxylate were proved by single-crystal X-ray analysis.     

Synthesis of N-allyl- and N-acyl-2-vinylindoline

Heating a mixture of (2R*,3R*)- and (2R*,3S*)-2-[(1S*)-1-iodoethyl]-3,5-dimethyl-1-[(2-nitrophenyl) sulfonyl]indolines with N-isopropylpiperidine in xylene resulted in (2S*,3R*)-3,5-dimethyl-1-[(2-nitrophenyl) sulfonyl]-2-vinylindoline. The latter reacted with thiophenol to afford (2S*,3R*)-3,5-dimethyl-2-vinylindoline, whose reaction with allyl halides or acetyl bromide gave rise to N-allyl-, N-propenyl-, or N-acetyl derivatives. Nitration of 1-acetyl-3,5-dimethyl-2-vinylindoline yielded ortho-nitro derivative.     

Synthesis and molecular structure of di(4-hydroxy-2,6-diisoborn-2-ylphenyl)methane

Di(4-hydroxy-2-{(1R*,2S*,4S*)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl}-6-{(1S*,2R*,4R*)-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl})methane was synthesized by condensation of the meso-diastereomer of 2,6-diisobornylphenol with paraformaldehyde under acid catalysis. The product structure as a meso-forms was confirmed by XRD analysis.     

Efficient synthesis of new tricyclic pyrano[3,2-c]pyridine derivatives

Reaction between arylidenemalononitriles and acetoacetanilide in the presence of piperazine hydrate in methanol at room temperature affords new tricyclic pyrano[3,2-c]pyridine derivatives of (rac-1S*,2R*,3R*,7R*,8R*,11R*)-2,11-diaryl-4,10-diimino-8-methyl-5-phenyl-6-oxo-9-oxa-5-azatricyclo-[5.3.1.0^3,8]undecane-1,3-dicarbonitrile family in yields of 55–84%. The molecular structures of the products were confirmed by X-ray crystallography and NMR spectroscopy.     

Five-membered 2,3-dioxo heterocycles: LXXVII. [4 + 2]-Cycloaddition of alkyl vinyl ethers to 3-aroylpyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazine-1,2,4(4<Emphasis Type="Italic">H</Emphasis>)-triones

[4 + 2]-Cycloaddition of 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4(4H)-triones to alkyl vinyl ethers gave substituted stereoisomeric (1R*,16R*)- and (1S*,16R*)-16-alkoxy-14-aryl-3,15-dioxa-10-azatetracyclo[8.7.0.0^{1, 13}.0^{4, 9}]heptadeca-4,6,8,13-tetraene-2,11,12-triones.     

Effect of salts on the reaction direction of (2R*,3R*)-2-[(1R*)-1-iodoethyl)]-3-methyl(3,5-dimethyl)-1-(4-methylphenylsulfonyl)-2,3-dihydro-1H-indoles with dimethylformamide

Transformations of (2R*,3R*)-2-[(1R*)-1-iodoethyl)-3,5-dimethyl-1-(4-methylphenylsulfonyl-2,3-dihydro-1H-indole on heating in boiling dimethylformamide in the presence of various salts were studied.     

Synthesis of 1′-substituted and 1′,3′-disubstituted (±)-2R*, 11bS*-9,10-Dimethoxy-1,3,4,6,7,11 b-Hexahydrospiro-[benzo[a]quinolizin-2,5′-imidazolidine]-2′,4′-diones

The results of the reaction between (±)-2R*,11bS*-2-alkyl(aryl)amino-1,3,4,6,7,11b-hexahydrobenzo[a]-quinolizine-2-carbonitriles 2 and isocyanates under a variety of experimental conditions are discussed. The ureides 3 and iminohydantoins 4 thus obtained were used to prepare N₃-monosubstituted and N₁,N₃-disubstituted derivatives of the (±)-2R*,11bS*-9,10-dimethoxy-1,3,4,6,7,11b-hexahydrospiro[benzo[a]quinolizin-2,5′-imidazolidine]-2′,4′-dione system 1 . The stereochemistry of these compounds is discussed, on the basis of spectroscopic evidence and study of their chemical reactivity.     

Stericaliy Congested Molecules: 2,2′-[(Biaryldiyl)bis(oxy)]bis[1,3,2-oxazaphospholidines]

The original suggestion that a through-space mechanism was operative in the seven-bond J(P, P) coupling constant of 30.3 Hz observed for 3.3′-bis(1,1-dimethylethyl)-2,2′-[3,3′,5,5′-tetrakis(1,1-dimethylethyl)-1,1′-biphenyl-2,2′-diyl]bis(oxy)}bis[1,3,2-oxazaphospholidine] ( 1a )) was investigated. In the solid-state CP-MAS ³¹PNMR spectrum of 1a , two nonequivalent P -atoms were observed; sufficient resolution could not be obtained to determine whether P, P coupling was present. The preparation and spectral data of the N-methyl analogue 1b and of the acyclic N-isopropyl analogue 6 (Scheme 1) provided evidence that a) the essentially exclusive formation (R*, R*,S*)- 1a in the reaction of the disodium biphenyldiolate 3a with the phosphorochloridite 4a is the result of significant differences in the free energy of activation (ΔG*) for the formation of the various diastereoisomers due to the steric congestion within the molecule and that b) the magnitude of the observed P,P coupling is dependent upon the degree of conformational freedom within the molecule. In the ³¹P-NMR spectrum of the P-sulfide 7 , which was prepared by the reaction of la with sulfur, 2s resonances were observed that strongly suggested that the lone electrons pair on P are involved in the mechanism for the transmission of coupling data. The (4S,5R) -12 and (4R, 5S) -12 of la were prepared in a three-step reaction sequence starting from the corresponding enantiomerically pure norephredine 8 (Scheme 2). Both (4S, 5R)- and (4R, 5S) -12 were obtained as a diastereoisomer mixture that differ by the configuration of the axis of chirality, i.e., (R*R*,R*)- and (R*,S*,R*) -12 were obtained. The major diastereoisomer was obtained upon recrystallization, and the atropisomers were observed to equilibrate in solution by monitoring the H? C(5) resonance in the ¹H-NMR with time (ΔG° = 0.4 kcal/mol; Fig. 2). The process observed corresponds to the restricted rotation about the central single bond of the biphenyl system. The isolation of an atropisomer with only a single ortho substituent on each aryl ring is quite rare. In the ¹³C-NMR spectrum of both (R*,R*,R*)- and (R*,S*,R*) -12 , C(5) is two-bond-coupled to the oxazaphospholidine P-atom (²J(C(5),P((2)) = 8.5 Hz) that is further virtually coupled to the P-atom of the other oxazaphospholidine ring (7J(P(2),P(2′)) = 30 Hz; ⁹J(C(5),P(2′)) = 0 Hz; δ(P(2)) = δ(P(2′)) = 136 ppm. In the ³¹P-NMR spectrum of (R*,R*,S*) -12 , which was prepared from the racemic chloridite (mixture of three diastereoisomers was obtained), a ⁷J(P(2),P(2′) of 36 Hz was observed. These observations provide strong evidence that seven-bond P,P coupling occurs in all three diastereoisomers of 12 . The observed P,P coupling is both independent of the configuration of the chiral axis and the configuration of the asymmetric P-centers. This independence of P,P coupling upon the configuration on P implies also the independence of the observed coupling upon the orientation of the lone-pair of electrons on P provided that the conformations of the diastereoisomers are similar in solution. The X-ray crystal structure of the complex formed from 1a and dichloro(cycloocta-1,5-diene)platinum(II) was obtained and the solid-state structure discussed. The major diastereoisomer of (4S,5R) -12 was used as a chiral ligand in asymmetric hydrosilylation and hydrogenation reactions (Scheme 3).     

Synthesis of Pyrano[4′,3′:2,3]pyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]quinoxalines by Reaction of Aroylpyrroloquinoxalines with Alkyl Vinyl Ethers

Thermally induced [4 + 2]-cycloaddition of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones with alkyl vinyl ethers afforded mixtures of diastereoisomeric (5S*,6aR*)- and (5R*,6aR*)-5-alkoxy-3-aryl-5,6-dihydropyrano[ 4′,3′: 2,3]pyrrolo[1,2-a]quinoxaline-1,2,7(8H)-triones.     

Hetero-Diels–Alder Reaction of Aroylpyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]quinoxalinetriones with Styrene

Hetero-Diels–Alder reaction of 3-aroylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones with styrene afforded diastereoisomeric (5R*,6aR*)- and (5S*,6aR*)-3,5-diaryl-5,6-dihydropyrano[4′,3′:2,3]pyrrolo[1,2-a]-quinoxaline-1,2,7(8H)-triones.     

N-Trifluoroacetyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline ozonides

A three-component condensation of aromatic amine, aldehyde, and cyclopentadiene with subsequent N-trifluoroacetylation leads to 4- and 4,8-substituted N-trifluoroacetyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolines. Ozonation of the double bond in the latter produced the corresponding isomeric stable ozonides having (1R*,4S*,5aR*,6S*,11bR*)-configuration and differing in inversion at the carboxamide nitrogen atom.     

Hetero-Diels–Alder reaction of 3-aroylpyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazines with styrene. Synthesis of pyrano[4′,3′: 2,3]pyrrolo[2,1-<Emphasis Type="Italic">c</Emphasis>][1,4]benzoxazines

The hetero-Diels–Alder reaction of 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with styrene afforded mixtures of diastereoisomeric (10R*,11aR*)- and (10S*,11aR*)-8-aryl-10-phenyl-10,11-dihydropyrano[4′,3′: 2,3]pyrrolo[2,1-c][1,4]benzoxazine-6,7,12-triones.     

Enantioselective syntheses of isoprostane and iridoid lactones intermediates by enzymatic transesterification

Crude Pseudomonas cepacia lipase (Amano PS-30) is a suitable biocatalyst for the kinetic resolution of the 1,2-cis-disubstituted cyclopentanoid building block (3aR*,4R*,6aS*)-(±)-4-hydroxymethyl-3,3a,4,6a-tetrahydrocyclopenta[b]furan-2-one through enantioselective transesterification. Enantiomerically enriched acetic acid (3aS,4S,6aR)-(+)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-4-yl methyl ester was utilized in a formal synthesis of the iridoids (+)-isoiridomyrmecin and (−)-teucriumlactone.     

New Monoterpene-Substituted Dihydrochalcones from Piper aduncum

Five New unusual monoterpene-substituted dihydrochalcones, the adunctins A–E (1″S)-1-{2′-hydroxy-4′-methoxy-6′-[4″-methyl-1″-(1?-methylethyl)cyclohex-3″ -en-1″ -yloxy]phenyl}-3-phenylpropan-1-one ( 1 ), (5aR*,8R*,9aR*)-3-phenyl-1-[5′,8′,9′,9′a-tetrahydro-3′-hydroxy-1′-methoxy-8′-(1″-methylethyl)-5′-a-methyldibenzo-[b,d]furan-4′-yl]propan-1-one ( 2 ), (2′R*,4″S*)-1-{6′-hydroxy-4′-methoxy-4″-(1?-methylethyl)spiro[benzo[b]-furan-2′(3′H),1″ -cyclohex-2″ -en]-7′-yl}-3-phenylpropan-1-one ( 3 ), (2′R*,4″R*)-1-{6′-hydroxy-4′-methylethyl-4″-(1?-methylethyl)spiro[benzo[b]furan-2′(3′H),1″-cyclohex-2″-en]-7′-yl}-3-phenypropan-1-one ( 4 ), and (5′aR*,6′S*, 9′R*,9′aS*)-1-[5′a,6′,7′,8′,9′a-hexahydro-3′,6′-methoxy-6′-methyl-9′-(1″-methylethyl)dibenzo[b,d]-furan-4′-yl]-3-phenylpropan-1-one ( 5 ) were isolated from the leaves of Piper aduncum (Piperaceae) by preparative liquid chromatography. In addition, (?)-methyllindaretin ( 6 ), trans-phytol, and α-tocopherol ( = vitamin E) were also isolated and identified. The structures were elucidated by spectroscopic methods, including 1D- and 2D-NMR spectroscopy as well as single-crystal X-ray diffraction analysis. The antibacterial and cytotoxic potentials of the isolates were also investigated.     

New atropoisomeric alkenylphenylglycine derivatives: Synthesis of (5R*)- and (5S*)-isomers of (1R*,3aR*,4S*,11S*)-3a,5,9,11-tetramethyl-4,5-dihydro-3aH-1,4-methano[1,3]oxazolo[3,2-a]quinolin-2-one

We synthesized methyl ester of N-(1-methylbut-2-en-1-yl)-N-phenylglycine which underwent acid catalyzed aromatic amino Claisen rearrangement to provide methyl-N-[2-(1-methylbut-2-en-1-yl)phenyl]glycinate. A mixture of syn- and anti-atropisomeric methyl-N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycinates was obtained either by the reaction of this ester with acetyl bromide or by the reaction of the sodium salt of N-acetyl-2-(1-methylbut-2-en-1-yl)-4-methylaniline with methyl bromoacetate. Upon saponification of the synthesized ester mixture the syn-atropisomer of N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycine was isolated by fractional crystallization. Treatment of the obtained acids with acetic anhydride, ethyl chloroformate, dicyclohexylcarbodiimide or isopropenylacetate leads to compounds of 4,5-dihydro-3aH-methano[1,3]oxazolo[3,2-a]quinolin-2-one structure.