(10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3: an improved synthesis via 19-nor-10-oxo-vitamin D

An efficient synthetic route to (10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3 was developed. The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5E)-19-nor-10-oxo-vitamin D derivative. The 10-oxo-compound was obtained via a 1,3-dipolar cycloaddition reaction of (5E)-1alpha,25-dihydroxyvitamin D with in situ generated nitrile oxide followed by ring cleavage of the formed isoxazoline moiety with molybdenum hexacarbonyl. Conversion of the keto group of (5E)-19-nor-10-oxo-vitamin D to the E and Z fluoromethylene group was achieved through a two-step sequence involving a reaction of lithiofluoromethyl phenyl sulfone followed by the reductive desulfonylation of the alpha-fluoro-beta-hydroxy sulfone. The dye-sensitized photoisomerization of the (5E)-19-fluorovitamin D afforded the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3.     

Synthesis of (10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3: compounds to probe vitamin D conformation in receptor complex by 19F-NMR

To study the interaction of vitamin D with its receptor by 19F-NMR, (5Z,10Z)- and (5Z,10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3 were synthesized starting from vitamin D2 via electrophilic fluorination of vitamin D-SO2 adducts as the key step. Regio- and stereoselective electrophilic fluorination at C(19) of vitamin D-SO2 adducts was achieved under the conditions using (PhSO2)2NF and bulky bases. The stereochemistry of the addition and elimination of SO2 of various vitamin D derivatives was studied in detail. SO2 causes Z-E isomerization of the 5,6-double bond of vitamin D and adds to the resulting (5E)-isomer from the sterically less hindered side opposite to the substituent at C(1). Elimination of SO2 from 19-substituted vitamin D-SO2 adducts proceeded exclusively in a suprafacial manner with respect to the diene part under either thermal or reductive conditions. Dye-sensitized photochemical isomerization of 19-fluorovitamin D derivatives was studied in detail. The rapid isomerization at the 5,6-double bond was followed by the slow isomerization at the 10,19-double bond to yield the (5E,10Z)-isomer (by nomenclature of the 1-OH derivatives) as the major product. (10Z)- and (10E)-19-Fluorovitamin Ds were also interconverted thermally probably via the corresponding previtamin D by 1,7-sigmatropic isomerization.     

Statistical analysis of (13)C and (15)N NMR chemical shifts from GIAO/B3LYP/6-311 + + G** calculated absolute shieldings

The (13)C and (15)N absolute shieldings of 28 compounds have been calculated at the GIAO/B3LYP/6-311 + + G** level to complete a collection of data already published. This has allowed us to devise new equations relating delta and sigma for these nuclei based on 461 points ((13)C) and 70(72) points ((15)N).     

Pronounced stereospecificity of 1H, 13C, 15N and 77Se shielding constants in the selenophenyl oximes as shown by NMR spectroscopy and GIAO calculations

In the ¹H and ¹³C NMR spectra of 1‐(2‐selenophenyl)‐1‐alkanone oximes, the ¹H, the ¹³C‐3 and ¹³C‐5 signals of the selenophene ring are shifted by 0.1–0.4, 2.5–3.0 and 5.5–6.0 ppm, respectively, to higher frequencies, whereas those of the ¹³C‐1, ¹³C‐2 and ¹³C‐4 carbons are shifted by 4–5, ～11 and ～1.7 ppm to lower frequencies on going from the E to Z isomer. The ¹⁵N chemical shift of the oximic nitrogen is larger by 13–16 ppm in the E isomer relative to the Z isomer. An extraordinarily large difference (above 90 ppm) between the ⁷⁷Se resonance positions is revealed in the studied oxime isomers, the ⁷⁷Se peak being shifted to higher frequencies in the Z isomer. The trends in the changes of the measured chemical shifts are well reproduced by the GIAO calculations of the ¹H, ¹³C, ¹⁵N and ⁷⁷Se shielding constants in the energy‐favorable conformation with the syn orientation of the? C?N? O? H group relative to the selenophene ring. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis and NMR spectroscopy (1H 13C) of 1-(2′-benzothiazolyl)-3(5),4-polymethylenepyrazoles and related compounds

A series of 3(5),4-trimethylene and 3(5),4-tetramethylenepyrazoles (tetrahydroindazoles) have been prepared from 2-acylcyclanones using two methods: direct reaction with a substituted hydrazine and through an NH-pyrazole followed by nucleophilic substitution. The results mainly concern the 2-benzothiazolyl substituent, but 2,4-dinitrophenyl derivatives were also studied for comparison. The orientation of the reactions (isomer ratio), the deshielding in ¹H nmr of the 5-methyl and 5-methylene signals when a benzothiazolyl residue is at position 1, and the ring strain effect on heterocyclic carbons chemical shifts, are discussed.     

A Convenient Synthesis of (1 1E, 13E)-11, 13-Hexadecadienal and (11Z, 13E)-Hexadecadienal

A simple method for synthesizing (11E, 13E)-11, 13-hexadecadienal 7, a component of the female sex pheromone of cabbage webworm, and its geometrical isomer (11Z, 13E)-11, 13-hexadecadienal 8 is described.     

Spectroscopic characterization of the 1-substituted 3,3-diphenyl-4-(2'-hydroxyphenyl)azetidin-2-ones: application of (13)C NMR, (1)H-(13)C COSY NMR and mass spectroscopy

The article deals with spectroscopic characterization of azetidin-2-ones. The presence of substituents like hydroxyl, fluoro, methoxy and benzhydryl, etc., on the azetidin-2-one ring significantly affects the IR absorption and (13)C NMR frequencies of the carbonyl group present in these compounds. The presence of an ester carbonyl group or too many methine protons in the molecule has been observed to limit the scope of IR and (1)H NMR spectroscopy in unambiguous assignment of the structure. The application of (13)C NMR, 2D NMR ((1)H-(13)C COSY) and mass spectroscopy in characterization of complex azetidin-2-ones is discussed. An application of the latter two techniques is described in deciding unequivocally between an azetidin-2-one ring and chroman-2-one ring structure for the product obtained by treatment of the 1-substituted 3,3-diphenyl-4-[2'-(O-diphenylacyl)hydroxyphenyl]-2-azetidinones with ethanolic sodium hydroxide at room temperature.     

Structural study of 2-(1-oxo-1 H-inden-3-yl)-2H-indene-1,3-dione by DFT calculations, NMR and IR spectroscopy

Computational studies have been carried out at the DFT-B3LYP/6-31G(d) level of theory on the structural and spectroscopic properties of 2-(1-oxo-1 H-inden-3-yl)-2H-indene-1,3-dione (OID). Experimental studies were conducted on these parameters, including X-ray, FT-IR and 13C NMR spectroscopy. The optimized geometries of OID and its bonding characteristics as well as IR and NMR spectra have been calculated and analyzed. It was observed that the bond lengths and angles in the molecule, obtained by X-ray, IR and NMR at the level of theory, were in a good agreement with those of the experiment. The correlation between the theoretical and the experimental vibrational frequencies and the chemical shifts of the OID molecule were 0.994 and 0.991, respectively. The agreement mutually verified the accuracy of the experimental method and the validity of the applied mathematical model.     

Capturing intermediate structures of Alzheimer's beta-amyloid, Abeta(1-40), by solid-state NMR spectroscopy

Molecular structures of diffusible amyloid intermediates, commonly observed in misfolding of amyloid proteins into fibrils, have attracted broad interest because the intermediates may be potent neurotoxins responsible for amyloid diseases such as Alzheimer's disease (AD) and because the intermediate structures provide an experimental basis for defining the misfolding pathway. However, owing to the intrinsically unstable and noncrystalline nature of the systems, traditional approaches such as X-ray crystallography and solution NMR have been ineffective for elucidating molecular-level structures of the amyloid intermediates. We present a novel approach using solid-state NMR (SSNMR) that permitted the first site-resolved structural measurement of an intermediate species in fibril formation for a 40-residue Alzheimer's beta-amyloid peptide, Abeta(1-40). In this approach, we combined detection of conformation and morphology changes by fluorescence spectroscopy and electron microscopy and quantitative structural examination for freeze-trapped intermediates by SSNMR. The results provide the initial evidence that a spherical amyloid intermediate of 15-30 nm in diameter exists prior to fibril formation of Abeta(1-40) and that the intermediate involves well-ordered beta-sheets in the C-terminal and hydrophobic core regions. The SSNMR-based approach presented here could be applied to intermediate species of diverse amyloid proteins.     

A practical, stereospecific route to 18-, 19-, and 20-hydroxyeicosa-5(Z),8(Z),11(Z),14(Z)-tetraenoic acids (18-, 19-, and 20-HETEs)

Suzuki-Miyaura cross-coupling of cis-vinylbromide 6, obtained in three steps from diol 4, with functionalized boranes provides a practical, stereospecific route to the title CYP P450 eicosanoids.     

Cyclization of 3-methoxy-8, 14-seco-D-homoestra-1, 3, 5(10), 9(11)-tetraene-14, 17a-dione into D-homoestrone derivatives

Conclusions In the cyclization of 3-methoxy-8, 14-seco-D-homoestra-1,3,5,(10),9(11)-tetraene-14, 17a-dione (I) the stereoisomeric 14-hydroxy-3-methoxy-D-homoestra-1,3,5(10),9(11)-tetraen-17a-ones (III) and (IV) are formed at first, and after dehydration and isomerization these are converted into 3-methoxy-D-homoestra-1,3,5(10),8,14-pentaen-17a-one (II). The ketol (IV) is much more readily dehydrated than the ketol (III) and is probably themain intermediate product in the cyclization of the diketone (I).Translated from Izvestiya Akadeemii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1413–1416, August, 1965 Original article submitted June 24, 1963     

Automated structure verification based on a combination of 1D (1)H NMR and 2D (1)H - (13)C HSQC spectra

A method for structure validation based on the simultaneous analysis of a 1D (1)H NMR and 2D (1)H - (13)C single-bond correlation spectrum such as HSQC or HMQC is presented here. When compared with the validation of a structure by a 1D (1)H NMR spectrum alone, the advantage of including a 2D HSQC spectrum in structure validation is that it adds not only the information of (13)C shifts, but also which proton shifts they are directly coupled to, and an indication of which methylene protons are diastereotopic. The lack of corresponding peaks in the 2D spectrum that appear in the 1D (1)H spectrum, also gives a clear picture of which protons are attached to heteroatoms. For all these benefits, combined NMR verification was expected and found by all metrics to be superior to validation by 1D (1)H NMR alone. Using multiple real-life data sets of chemical structures and the corresponding 1D and 2D data, it was possible to unambiguously identify at least 90% of the correct structures. As part of this test, challenging incorrect structures, mostly regioisomers, were also matched with each spectrum set. For these incorrect structures, the false positive rate was observed as low as 6%.     

2beta-(N-substituted piperazino)-5alpha-androstane-3alpha,17beta-diols: parallel solid-phase synthesis and antiproliferative activity on human leukemia HL-60 cells

Leukemia is the most common cancer affecting children. A steroid possessing a methylpiperazine nucleus was recently reported to inhibit the proliferation of HL-60 leukemia cells. To speed up the development of this promising potential new drug, we generated libraries of analogues using parallel solid-phase organic synthesis (SPOS). A 6-step sequence of reactions, starting from dihydrotestosterone, afforded a steroidal 2,3alpha-epoxide, which was selectively opened to give, after N-Fmoc protection, a diol with suitable stereochemistry. The difference of reactivity between 3alpha-OH and 17beta-OH was then used to allow the regioselective coupling of 17beta-OH to chloro-activated butyldiethylsilane polystyrene. We next generated three libraries of 2beta-piperazinyl-5alpha-androstane-3alpha,17beta-diol N-derivatives with 1, 2, or 3 levels of molecular diversity in acceptable yields and purities for our biological screening assay. Several members of these libraries were more potent than the lead compound, especially five members with a proline as the first level of diversity and a cyclohexylcarbonyl, methylbutyryl, cyclohexylacetyl, cyclopentylpropionyl, or hexanoyl as the second level of diversity. They efficiently inhibited HL-60 cell proliferation with IC50 values of 0.58, 0.66, 1.78, 1.98, and 2.57 microM, respectively. The present work demonstrates the potential of our SPOS approach for the optimization of a new class of cytotoxic agents.     

Synthesis of new aromatic (C17-C20)-locked side-chain analogues of calcitriol (1alpha,25-dihydroxyvitamin D(3))

The synthesis of four new analogues of calcitriol (1alpha, 25-(OH)(2)-D(3)) possessing aromatic and conjugated double bond units at the side chain are described. The triene system is introduced using the Lythgoe-Hoffmann La Roche convergent Wittig-Horner approach. The key steps in the preparation of the requisite upper fragments are the introduction of the side chain with the E-conjugated aromatic system and its photochemical conversion to the Z counterpart.     

Syntheses and characterization of mu,eta(1),eta(1)-3,5-di-tert-butylpyrazolato derivatives of aluminum

The 3,5-di-tert-butylpyrazolato (3,5-tBu(2)pz) derivatives of aluminum [(eta(1),eta(1)-3,5-tBu(2)pz)(mu-Al)R(1)R(2)](2) (R(1) = R(2) = Me 1; R(1) = R(2) = Et, 2; R(1) = R(2) = Cl, 3; R(1) = R(2) = I, 4; [(eta(2)-3,5-tBu(2)pz)(3)Al], 5; [Al(2)(eta(1),eta(1)-3,5-tBu(2)pz)(2)(mu-E)(C triple bond CPh)(2)] (E = S (6), Se (7), Te (8)) have been prepared in good yield. Compounds 1 and 2 were obtained by the reactions of H[3,5-tBu(2)pz] with Me(3)Al and Et(3)Al, respectively. Reaction of [(eta(1),eta(1)-3,5-tBu(2)pz)(mu-Al)H(2)](2) with the pyrazole H[3,5-tBu(2)pz] gave [(eta(2)-3,5-tBu(2)pz)(3)Al] (5). The reaction of [(eta(1),eta(1)-3,5-tBu(2)pz)(mu-Al)R(2)](2) (R = H, Me) and I(2) yielded 4, while the reaction of 1 equiv of K[3,5-tBu(2)pz] and AlCl(3) afforded 3. In addition, the reaction of [Al(2)(eta(1),eta(1)-3,5-tBu(2)pz)(2)(mu-E)H(2)] and HC triple bond CPh gave 6, 7, and 8. All compounds have been characterized by elemental analysis, NMR, and mass spectroscopy. The molecular structure analyses of compounds 1, 3, 6, and 7 by X-ray crystallography showed that complexes 1 and 3 are dimeric with two eta(1),eta(1)-pyrazolato groups in twisted conformation while 6 and 7 with two eta(1),eta(1)-pyrazolato groups display a boat conformation.