Die kristall- und molekülstruktur von 10,11-(4',5'-dimethylbenzo)-9,12-dithia- trans-bicyclo[6.4.0]dodeca-2,4,6,10-tetraen,einem trans-annelierten cycloocta-1,3,5-trien

The compound 10,11 - (4',5' - dimethylbenzo) - 9,12 - dithia - trans - bicyclo[6.4.0]dodeca - 2,4,6,10 - tetraen (1a) has been determined by X-ray analysis from three-dimensional film data and refined by least-squares techniques to R = 0.10. The dimensions of the unit cell containing 4 molecules are a = 10.61(2) Å, b = 6.53(1) Å, c = 19.96(2) Å),β = 102.2(1)o, the space group is P2₁/c. The heterocyclic and the carbocyclic rings are trans - annelated. Consequently the included angles of the bridgehead atoms deviate from the ideal tetrahedral angles and the bond between the atoms C(9) and C(16) is significantly shortened. The cyclooctatriene ring has a distorted boat conformation.     

The conversion of 3,4-cis- to 3,4-trans-cannabinoids

An investigation of the conversion of Δ¹-3,4-cis-THC 1a to Δ⁶-3,4-trans-THC 2a with BBr₃ is described. By use of 1a of known optical purity it was determined that the main epimerization occurs at C-4. The small loss of optical purity observed during formation of 2a results from either competitive epimerization at C-3 or a racemization process. The conversion of 3,4-cis- to 3,4-trans-HHCs proceeds with exclusive C-4 inversion.     

Stereoselective syntheses of 20-epi cholanic acid derivatives from 16-dehydropregnenolone acetate

A stereoselective total synthesis of naturally occurring 20-epi cholanic acid derivatives has been realized, starting from readily available 16-dehydropregnenolone acetate. The key step of these syntheses involves an ionic hydrogenation of a C-20,22-ketene dithioacetal and deoxygenation of steroidal C-20 tert-alcohols, to set up the unnatural C(20R) configuration with 100% stereoselectivity. The unnatural C-22 aldehydes with C(20R) stereocenters thus obtained were elaborated to 20-epi cholanic acid derivatives. Two derivatives of 20-epi cholanic acid were synthesized and their structures have been confirmed by single crystal X-ray analysis. Catalytic hydrogenation of 16-dehydropregnenolone acetate and 16-dehydropregnenolone in ethanol affords C-5,C-16 tetrahydro products. Crystal structure analysis of one of these products revealed C-5α and C-17α configurations of the hydrogen atoms.     

Zur lokalisierung funktioneller gruppen mit hilfe der massenspektrometrie—VIII : 6-hydroxy-androstan-3,17-dione und 6,17β-dihydroxy-androstan-3-one

5β-androstan-3-ones carrying a 6α-OH group show in their mass spectra a key-ion indicating the loss of water and C-1 to C-4 as C₄H₅O? particle. 6β-OH isomers lose instead C-1 to C-4 in form of C₄H₇O?.In 6α-hydroxy-androstan-3-ones differentiation between the connection of the A/B-ring system is possible, because in 5α-isomers the loss of C-3 to C-7 occurs as a C₅H₆O₂ particle, while the 5β-isomers lose the same C atoms as a C₅H₇O? unit.Compounds with a 6β-OH group in an A/B trans connected ring system show a tendency for thermal water elimination. After rearrangement of the double bond in 4,5 position the typical fragments for 3-keto-Δ⁴-steroids are obtained.Occasionally a strong influence of a 6-OH group on fragmentation reactions in the D-ring system is observed: The presence of a 6α-OH group in an androstan-3,17-dione enhances the loss of C-16 and C-17 in the form of acetaldehydenol. Also the connection of the A/B-ring system may have a considerable influence on this type of reaction: In 6,17β-dihydroxy-androstan-3-ones only by trans connection of the A/B-ring system, C-16 and C-17 are lost with high probability after water elimination.     

Synthesis of podophyllotoxin analogues: δ-lactone-containing picropodophyllin, podophyllotoxin and 4′-demethyl-epipodophyllotoxin derivatives

Non-epimerizable cis and trans δ-lactone analogues of podophyllotoxin have been prepared. Thus the synthesis of the cis isomer 4 has been achieved in 8 steps and 4% overall yield from podophyllotoxin 1 via the reduction of the γ lactone ring into the trans diol, selective protection of the 4-OH and 11-OH as a benzylidene acetal, and Wittig elongation at C-13 with inversion of configuration at C-2. Same elongation at C-13 but via the formation of a mesylate and introduction of a cyano group, led to the trans δ-lactone 5 (7 steps from 1 and 6% overall yied) with a small amount of its C-4 epimer 6. The synthesis of non-epimerizable δ-lactone analogues of 4′-demethyl-epipodophyllotoxin 7 and of 4-demethyl podophyllotoxin 8 are also reported. The synthesis of 7 and 8 was based upon the reduction of the γ-lactone ring of 4′-demethyl-4-epipodophyllotoxin followed by selective protection at C-11 and elongation at C-13. (8-15% and 4% overall yields). Compounds 4, 5 and 7 did not display relevant cytotoxicity in vitro against L1210 murine leukemia.     

The stereochemistry of 2,4-disubstituted γ-butyrolactones and 2,4,6-trisubstituted-5,6-dihydro-4H-1, 3-oxazines

2,4-Disubstituted butyrolactones and 2,4,6-trisubstituted-5,6 dihydro-4H-1,3-oxazines show similar features in their ¹H and ¹³C- NMR spectra. Two geminal ring hydrogens of cis isomers give rise to a complex ABXY spectra when the substituent is alkyl or aryl. In spectra of trans isomers these patterns are degenerated. When R is OMe(in 4) or OCOMe (in 6) the difference in chemical shifts of geminal protons and vicinal coupling constants cannot be used for diagnosis. In ¹³C spectra ring carbons C-2 and C-3 in lactones and C-4 and C-5 in oxazine of trans isomers show a small but consistent shift to higher fields.     

Steroid photochemistry : The photocycloaddition of an enone and dienone to norbornene and norbornadiene

The photocycloaddition of a steroidal 4-en-3-one and a 4,6-dien-3-one to bicyclo[2.2.1]heptene and bicyclo[2.2.1]heptadiene has been studied. The photocycloaddition to norbornene furnished only the trans-4α,5β-cyclobutane, while the enone gave a mixture of cis and trans-[2+2] adducts as well as the first example of hydrogen transfer in this series to form a 4-(2-norbornanyl 1)-conjugated enone. The photocycloaddition of the dienone to norbornadiene formed the 4-(7-norbornenyl)-dienone by a 1,4-hydrogen shift as the major product, together with lesser amounts of the unrearranged trans-4α,5β-[2+2]-cyclobutane. On the other hand, the cycloaddition of the enone to norbornadiene yielded the 4α-(7-norbornene)-β,γ-enone as the major product; accompanied again by the unrearranged trans-[2+2]-adduct. In addition, the 4α,5α-cis-[3+2] adduct was obtained and was formed by rearrangement of the norbornenyl radical portion of the intermediate diradical.     

Conformational analysis—XXVIII : Four-component equilibria in 1,3-dioxanes. Ring deformations and the chair-twist free energy difference

Four-component equilibria in substituted 1,3-dioxanes were applied to the determination of conformational energies not accessible by conventional equilibration, with the following conclusions: 1. The difference in free energy between the chair and twist forms of 2,2,trans - 4,6 - tetramethyl - 1,3 -dioxane is 7·4 kcal/mol. 2. Equatorial Me substituents at C-4,6 exert a palpable buttressing effect on the corresponding axial substituents. 3. Equatorial substituents at C-2 exert a similar buttressing effect on the geminal axial substituent. 4. The effect of equatorial t-Bu substitution or gem-dimethyl substitution at C-5 on conformational energy seems to be of minor importance. The more complex effects of equatorial 4-t-Bu substitution are discussed.     

Synthesis of highly modular bis(oxazoline) ligands by Suzuki cross-coupling and evaluation as catalytic ligands

New bis(oxazoline) ligands (BOXs) containing biaryl substitutents at the C-4 position and H or CH₂OR substituents at the C-5 position have been synthesized using Suzuki cross-coupling as the main tool for structural diversity. Copper, zinc, and palladium complexes of the prepared BOXs have been evaluated in the following catalytic asymmetric processes: Acylation with kinetic resolution of trans-1,2-cyclohexanediol (Cu), enantioselective Friedel-Crafts alkylation of indole (Zn), and enantioselective alkylation of 3-acetoxy-1,3-diphenylpropene (Pd).     

The crystal structure of diiodo((o-methylthiophenyl)diphenylphosphine)palladium(II), a complex exhibiting a large structural trans influence

The crystal structure of the title compound has been determined by conventional X-ray diffraction techniques. The red diamond-shaped crystals are monoclinic, space group P2₁/n, a 8.914(4), b 16.090(12), c 14.991(5) Å, β 95.97(2)°, V 2138.44 ų, Z = 4. Refinement by full-matrix least-squares methods employed anisotropic thermal parameters for all non-hydrogen atoms and isotropic temperature factors for hydrogen atoms, and returned final residuals of R = 0.028 and R_w = 0.028.The complex is monomeric, with a square planar coordination geometry comprising the S and P atoms of the bidentate (o-methylthiophenyl)diphenylphosphine ligand and the two iodine atoms. The PdI distance trans to P is 2.658(1) Å whereas that trans to S is 2.602(1) Å. The difference of 56 standard deviations illustrates the greater structural trans influence of phosphine over thioether donors. The PdP and PdS distances of 2.250(2) and 2.288(2) Å, respectively, are normal. Two phenyl hydrogen atoms approach the Pd atom in the axial regions above and below the square plane at distances of 2.98 and 2.99 Å.     

Methyl (E)-2-(2-phenylcyclopropylidene)acetate: Synthesis, isomerization, and reaction with 1,3-diphenyl-2-benzofuran

Treatment of 3-methyl-2-phenylcycloprop-2-ene-1-carboxylic acid with potassium tert-butoxide induced its isomerization into trans-2-methylidene-3-phenylcyclopropane-1-carboxylic acid which was converted into methyl ester, and heating of the latter for 1 h in toluene gave methyl (E)-2-(2-phenylcyclopropylidene)acetate. Thermal isomerization of methyl (E)-2-(2-phenylcyclopropylidene)acetate on prolonged heating in toluene afforded 5-methoxy-3-methyl-2-phenylfuran, and the reaction with 1,3-diphenyl-2-benzofuran resulted in [4 + 2]-cycloaddition at the exocyclic double bond.     

Diastereoselective approach to trans-5-hydroxy-6-substitutedethanone-2-piperidinones: Scalable syntheses of (+)-febrifugine and (+)-halofuginone

An efficient diastereoselective approach to access trans-5-hydroxy-6-substitutedethanone-2-piperidinones skeleton has been developed through sequential addition-deprotection-cyclization process involving aldimine 6 with substituted acetones. The diastereoselectivity of substitution at C-6 position of 2-piperidinone was controlled by α-siloxyl group and chiral sulfinamide moiety. In addition, the utility of this effective approach is demonstrated by the scalable syntheses of (+)-febrifugine (2) and (+)-halofuginone (4).     

Binuclear versus mononuclear copper complexes as catalysts for asymmetric cyclopropanation of styrene

A number of (S)-(−)-2-amino-1,1-diaryl-1-propanol compounds have been synthesized. They were used to form the binuclear copper complexes through a spontaneous assembly of the individual components, the β-aminoalcohol, 2-hydroxy-5-methyl-1,3-benzenedialdehyde, and copper acetate monohydrate, in methanol. These binuclear complexes were examined as asymmetric catalysts for cyclopropanation of styrene by ethyl diazoacetate. Moderate improvement in enantioselectivity has been observed for the binuclear versus mononuclear copper complexes. The e.e. values up to 87% for trans and 93% for cis products and the ratio between trans and cis products up to 9:1 have been obtained.     

From oxides of internal perfluoroolefins to fluorocontaining camphor thiazolinylhydrazones

The reaction of oxides of internal trans- and cis-perfluoroolefins with (1S, 4S)- or racemic camphor thiosemicarbazone leads to the formation of trans- and cis-isomers of (1S, 4S)- or racemic camphor 5′-fluoro-4′-hydroxy-4′,5′-di(perfluoroalkyl)-1′,3′-thiazolinyl-2′-hydrazones, respectively. Unsymmetrical dodecafluoro-2,3-epoxyhexane yields a mixture of regioisomeric hydrazones. The molecular structure of the trans-isomer of (1S, 4S)-camphor 5′-fluoro-4′-hydroxy-4′,5′-bis(trifluoromethyl)-1′,3′-thiazolinyl-2′-hydrazone has been established by X-ray crystallography. The quite rare example of cocrystallization of two diastereomers of the latter in homochiral crystal (sp. group P2₁) has been revealed.     

Carbon-13 pulse fourier transform NMR : Conformational preference of the hydroxyl and the acetoxyl group in 2-methyl-2-cyclohexenol and its acetate

¹³C Fourier transform NMR of cis and trans 5 - t - butyl - 2 - methyl - 2 - cyclohexenol, 2 -methyl - 2 - cyclohexenol and their acetates has been examined indicating that the pseudo-axial orientation of the hydroxyl and the acetoxyl group at the allylic position is favoured in 2 - methyl - 2 -cyclohexenol and its acetate.     

Structure and synthesis of a newly discovered terpenoid isolated from Lavandin oil: Trans-5-hydroxy-2-isopropenyl-5-methylhex-3-enyl acetate

A newly discovered component of the oil of Lavandin abrialis has been shown by spectroscopic data to be trans-5-hydroxy-2-isopropenyl-5-methylhex-3-enyl acetate (I). A synthesis of this material is described.     

Efficient microwave-assisted three-component one-pot preparation of 1-aryl-4-(2-acetoxyethyl)piperazines and 1-aryl-4-(2-acetoxyethyl)piperidines

A highly efficient one-pot, three-component microwave-assisted procedure has been developed for the preparation of 1-(para-substituted-aryl)-4-(2-acetoxyethyl)piperazines and 1-(para-substituted-aryl)-4-(2-acetoxyethyl)piperidines. Microwave-accelerated heating of electron-deficient aryl halides and potassium acetate with either 1,4-diazabicyclo[2.2.2]octane (DABCO) or quinuclidine at 180 °C for 120 min provided the title products in good yields and with general substrate scope. Similarly, subjection of potassium pthalimide instead of potassium acetate to the same conditions provided good yields of 1-arylpiperazines and 1-arylpiperidines containing a 2-phthalimidoethyl substituent at the C-4 position.     

Asymmetric torsional potential function and conformational analysis of furfural by far infrared and Raman spectroscopy

The far i.r. (400-50 cm⁻¹) spectra of gaseous and solid furfural (2-furancarboxaldehyde), c-C₄H₃O (CHO), have been recorded. Additionally, the Raman (3500-20 cm⁻¹) spectra of the gas and liquid have been obtained at variable temperatures and the spectrum of the solid at 25 K. These data have been interpreted on the basis that the molecule exists in two different conformations in the fluid states and that the conformation which has the two oxygen atoms oriented in a trans configuration, OO-trans, is most stable (ΔH ⩽ 1 kcal/mol) in the gas; however, the conformation which has the two oxygen atoms oriented cis, OO-cis, is preferred in the liquid (ΔH = 1.07 ± 0.03 kcal/mol) and is the only rotamer present in the spectra of the solid. The asymmetric torsional fundamental for the OO-trans rotamer has been observed at 146.25 cm⁻¹ in the far i.r. spectrum of the vapor and has five accompanying “hot bands”. The corresponding fundamental for the OO-cis rotamer has been observed at 127.86 cm⁻¹ along with a “hot band” which occurs at 127.46 cm⁻¹. From these data a cosine-based potential function governing internal rotation of the CHO top has been determined and the potential coefficients have values of V₁ = 173 ± 2, V₂ = 3112 ± 20, V₃ = 113 ± 2 and V₄ = −198 ± 6 cm⁻¹. This potential is consistent with an enthalpy difference between the more stable OO-trans and high energy OO-cis conformers being 286 ± 24 cm⁻¹ (818 ± 67 cal/mol) and a trans to cis barrier height of 3255 ± 20 cm⁻¹ (9.31 ± 0.06 kcal/mol). These results are compared to the corresponding quantities obtained previously from microwave spectroscopy and theoretical methods.     

A practical synthetic route to 4′-alkylaristeromycin derivatives: 4′-methylaristeromycin

(−)-(1S,4R)-4-Hydroxy-2-cyclopenten-1-yl acetate provided a convenient entry point for a 16-step chiral preparation of 4′-methylaristeromycin. This procedure is adaptable to a number of carbocyclic nucleosides with a diversity of substitution at C-4′ and C-5′ and a variety of heterocyclic bases.     

Molecular structure and rotational isomerism in glyoxylicacid from microwave spectroscopy and ab initio calculations

An improved substitution structure for glyoxylic acid in the hydrogen bonded trans-1 form is presented. By means of microwave double resonance spectroscopy, the trans-2 form, with a zig-zag chain of atoms HOCCH, was identified. Using trans-2 dipole moment components calculated by ab initio SCF theory, the energy of the trans-2 form is found to be 1.2 ± 0.5 kcal mole^?1 higher than that of the trans-1 form. The ab initio energy difference (?1.0 kcal mole^?1) has the wrong sign.