Steroid Framework Research Articles

Molecular Recognition of Deoxycholic Acids by Pyrene-Appended .GAMMA.-Cyclodextrin Connected with a Rigid Azacrown Spacer.

A γ-cyclodextrin (γ-CyD) derivative (1) having a pyrene moiety, connected through a 4, 13-diaza-18-crown-6 ether moiety to γ-CyD, was synthesized and evaluated for guest binding and sensing properties. In aqueous solution, 1 existed as an association dimer in which the secondary hydroxyl sides faced each other to accommodate two pyrene moieties. Photo-induced electron transfer (PET) between the amino group and the excited pyrene moiety regulated the monomer fluorescence intensity of 1. The monomer-dimer equilibrium and the PET indicated that 1 may be used as a host capable of detecting guest complexation by changes in fluorescence intensity from the pyrene moiety. Deoxycholic acids were found to be good guests for detection by 1, and deoxycholic acid itself induced different fluorescence changes compared to the other deoxycholic acids. This indicated that 1 could recognize the position of the hydroxy groups on the steroidal framework. The azacrown part may participate in the guest selectivity for the deoxycholic acids by regulating the distance between the amino group and the pyrene moiety, modifying PET efficiency.

Construction of the Steroid Framework via a Functionalized Macrocyclic Compound

A palladium-catalyzed intramolecular coupling process leads to a functionalized macrocycle suitable for a double transannular cyclization. The resulting steroid framework, and its stereo- and regioisomers, are identified by analysis of the NMR-spectroscopic data.

A novel strategy for the enantioselective synthesis of the steroidal framework using cascade ring expansion reactions of small ring systems-asymmetric total synthesis of (+)-equilenin

Enantioselective synthesis of (+)-equilenin ( 1) utilizing a novel strategy is described. The key steps are two cascade ring expansion reactions of small ring systems; 1) chiral (salen)Mn III complex-catalyzed cascade reaction of cyclopropylidene; 2) Pd II-mediated cascade reaction of the cyclobutanol.

Construction of the Steroid Framework via a Functionalized Macrocyclic Compound

A palladium-catalyzed intramolecular coupling process leads to a functionalized macrocycle suitable for a double transannular cyclization. The resulting steroid framework, and its stereo- and regioisomers, are identified by analysis of the NMR-spectroscopic data.

Computer-Aided Organic Synthesis – SESAM: A Simple Program to Unravel “Hidden” Restructured Starting Materials Skeleta in Complex Targets

We describe the SESAM program whose aim is to help the chemist in exploring new synthetic strategies for complex structures by locating simple, non-obvious but effective starting materials. The program works at the skeletal level and attempts to map simply modified starting materials into the skeletal surface of the target. SESAM has been tested on taxol and steroid frameworks.

Computer-Aided Organic Synthesis – SESAM: A Simple Program to Unravel “Hidden” Restructured Starting Materials Skeleta in Complex Targets

We describe the SESAM program whose aim is to help the chemist in exploring new synthetic strategies for complex structures by locating simple, non-obvious but effective starting materials. The program works at the skeletal level and attempts to map simply modified starting materials into the skeletal surface of the target. SESAM has been tested on taxol and steroid frameworks.

Homologous Series of Liquid Crystalline Steroidal Lipids

Steroids are an important source of chiral mesophases. The melting behavior and mesomorphic properties of homologous series of steroidal derivatives have been extracted from the literature, tabulated, and discussed. The tables provide the reader with an evaluated compilation of the type of mesophases found for the individual compounds, including their transition temperatures. Where the literature gives more than one set of data for a specific substance, one has been chosen as the main reference, but all alternatives are listed in the footnotes. The data can be used for statistical analysis to show the specific role of substructures within the steroidal framework.

Physicochemical properties and inclusion complex formation of δ-cyclodextrin

δ-Cyclodextrin (CD) is a cyclic oligosaccharide composed of nine α-1,4-linked d-glucose units. Its physicochemical properties have been characterized only in terms of its X-ray crystal structure (Fujiwara et al., 1990). A method for the purification of δ-CD was examined, and its physicochemical properties and complexation abilities were elucidated and compared with those of α-, β-, and γ-CD (Kobayashi et al., 1986; Miyazawa et al., 1993). Purification of δ-CD from the commercially available CD powder was mainly carried out with the combined treatment of HPLC and column chromatographies. The molecular weight of δ-CD was determined by FAB-MS, and the cyclic structure of δ-CD was identified by 1H-NMR and 13C-NMR. The aqueous solubility of δ-CD was greater than that of β-CD but less than that of α-CD or γ-CD. No surface activity of δ-CD was observed. δ-CD did not exhibit any hemolytic activity at 4.0 × 10 −2 M δ-CD, which was close to its saturated solution. The acid-catalyzed hydrolysis increased in the following order: α-CD < β-CD < γ-CD < δ-CD. δ-CD did not show any significant solubilization effect on most of the slightly soluble or insoluble drugs in water. However, in the case of a large guest molecule such as spironolactone (SP) and digitoxin, which have a steroidal framework, the enhancement of solubility of the guest molecule by δ-CD was greater than that by α-CD. The solubility of SP increased about 30-fold in the presence of δ-CD (4.5 × 10 −2 M), showing the features of an A l type phase diagram.

Substituted methyl 5β‐cholan‐24‐oates. I—17O NMR spectral characterization

AbstractMethyl esters of four common bile acids, 3α‐hydroxy‐5‐β‐cholan‐24‐oic (lithocholic) acid, 3α, 7α‐dihydroxy‐5β‐cholan‐24‐oic (chenodeoxycholic) acid, 3α,12α‐dihydroxy‐5β‐cholan‐24‐oic (deoxycholic) acid and 3α,7α,12α‐trihydroxy‐5β‐cholan‐24‐oic (cholic) acid, and 14 acetylated, trifluoroacetylated, mesylated and oxo derivatives of methyl 5β‐cholan‐24‐oates were prepared and their 17O NMR spectra recorded. In spite of their relatively high molecular masses and the rigid molecular structure of the steroid skeleton, most of the oxygens included in these structures gave well resolved 17O NMR resonance lines at natural abundance in 0.25–0.5 M acetonitrile solutions at 75°C. In agreement with the present 17O NMR results, molecular mechanics calculations revealed that a hydroxy substituent located at the 3α‐position clearly differs from the hydroxyls at the 7α‐ and 12α‐positions. This is due to the fact that the 3α‐hydroxyl possessing only two γ‐carbons at antiperiplanar positions is less shielded than the other hydroxyls influenced also by the shielding effects of γ‐gauche carbons. The spectral deconvolution of the overlapping signals of the 7α‐ and 12α‐hydroxyls is based on a computer‐aided method or on chemical substitutions. The oxo groups located at the longitudinal (3‐oxo) vs. transversal (7‐ and 12‐oxo) axes of the steroid framework show very different quadrupolar relaxation properties and 17O NMR linewidths owing to the strong anisotropy of overall molecular motion. In contrast, the 17O NMR linewidths of all 3α‐, 7α‐ and 12α‐hydroxyls are very similar and clearly smaller than those of the corresponding oxo groups, revealing that their quadrupolar relaxation is merely determined by their internal rotation rather than by the overall molecular motion.

Photoinduced molecular transformations. Part 133. New photoinduced deconjugation of steroidal α,β-unsaturated cyclic ketone oxime into the β,γ-unsaturated isomer involving stereospecific proton transfer

Irradiation of 1-methyl-5α-cholest-1-en-3-one oxime or its 4,4-dimethyl derivative in either a protic or an aprotic solvent gave 1-methylene-5α-cholestan-3-one oxime or the corresponding 4,4-dimethyl derivative, arising from an unprecedented photodeconjugation of α,β-enone oximes into the β,γ-isomers. Neither the expected isoxazole derivative (a product in the photoreaction of 5α-cholest-1-en-3-one oxime or its 4,4-dimethyl derivative) nor the unsaturated lactam that arises from a photo-Beckmann rearrangement was formed. Deuterium-labelling studies on the photoreactions of 1-methyl-5α-cholest-1-en-3-one oxime established that either a proton or a deuteron is stereospecifically introduced at the 2α-position of the steroidal oxime in this photodeconjugation. A pathway which involves the sterospecific addition of either a proton or deuteron to the photogenerated, twisted double bond of the oximes from the rear side of the steroidal framework, followed by the loss of a proton or deuteron from the 1-methyl group of the resulting carbocation intermediate, is proposed regarding the formation of β,γ-unsaturated oximes from the excited α,β-unsaturated oximes.

Photoinduced molecular transformations. Part 134. Photoinduced stereospecific addition of methanol to 5β-cholest-1-en-3-one oxime and photoinduced deconjugation of its 1-methyl derivative involving stereospecific proton transfer

Irradiation of 5β-cholest-1-en-3-one oxime 14 in methanol gave 1α-methoxy-5β-cholestan-3-one oxime 16, arising from the photoaddition of methanol to the double bond of the enone oxime. 1α-Methoxy-5β-cholestan-3-one 17 as well as 10β-methoxy-5(10→1)abeo-1β(H),5β,10α(Me)-cholestan-3-one 15, arising from a skeletal rearrangement of 5β-cholest-1-en-3-one (generated from the oxime), were the accompanying products in this photoreaction. Deuterium-labelling studies confirmed that the formation of 1α-methoxy-5β-cholestan-3-oxime 16 involves a stereospecific syn addition of methanol to the photogenerated, twisted, ground-state double bond of the oximes B from the rear side of the steroidal framework.Irradiation of 1-methyl-5β-cholest-1-en-3-one oxime 23 in methanol, on the other hand, gave almost exclusively 1-methylene-5β-cholestan-3-one oxime 24, arising from photodeconjugation of the α,β-double bond to the β,γ-position. A deuterium-labelling study established that deuterium is stereospecifically introduced at the 2β-position of 1-methyl-5β-cholest-1-en-3-one oxime 23 in the photodeconjugation in methanol[2H]ol while deuterium is stereospecifically introduced at the 2α-position in the photodeconjugation of its 5α-isomer 6. These results are fully consistent with our previously proposed pathway concerning the photodeconjugation of 1-methyl-5α-cholest-1-en-3-one oxime 6; the stereospecific addition of a proton to the photogenerated, twisted double bond of the oxime D from the rear side of the steroidal framework was followed by the loss of a proton from the 1-methyl group of the resulting carbocation intermediate. Neither the isoxazole derivative, a product in the photoreaction of 5α-cholest-1-en-3-one oxime 1, nor the unsaturated lactam from a photo-Beckmann rearrangement was formed in the photoreactions of either 5β-cholest-1-en-3-one oxime 14 or its 1-methyl derivative 23.

Aldosterone antagonists. 4. Synthesis and activities of steroidal 6,6-ethylene-15,16-methylene 17-spirolactones

Several steroidal 6,6-ethylene-15,16-methylene 17-spirolactones were synthesized to find new progestogens that exhibit both progestational and antimineralocorticoidal activities. The influence of substituents in the 10- and 13-position of the steroidal framework on both properties was investigated. It was found that only compound 12, carrying methyl groups at the 10- and 13-positions, possesses high progestational and antimineralocorticoidal activity.

Methods of Synthesis of Thia Analogues of Gonasteroids

Abstract The voluminous literature that appeared on thiasteroids, especially after the publication of our earlier review on this subject,1 prompted us to highlight exclusively the recent progress achieved in the total syntheses of a large variety of thia analogues of gonasteroids otherwise known as thiagonanes. These modified steroids have drawn the attention of steroid chemists for the following reasons: (i) their preparation itself constitutes a stimulating exercise to the organic chemist, often demanding development of new synthetic approaches of general utilitarian value; (ii) the investigations concerning the reaction mechanisms and stereochemistry, based on the steroidal framework, provide fundamentally significant and often fascinating chemical problems; (iii) as common with conformationally rigid molecules, the spectral properties, especially in 1H and 13C NMR, of these heterogonasteroids may reveal quite interesting features. The introduction of a heteroatom like sulfur, oxygen or nitrogen in pla...

Long‐acting contraceptive agents: X‐Ray study of levonorgestrel esters

AbstractThe X‐ray crystal structure determinations of levonorgestrel (1) and its esters (2) to (7) have been performed in order to assign the molecular features and attempt to correlate the conformation of the molecules with their long‐acting contraceptive activity.In the most active compounds, i.e., levonorgestrel butyrate (4), cyclopropylcarboxylate (6), and cyclobutylcarboxylate (7), the unusual orientation of the ester chains seems to affect the entire steroid framework. The stereochemistry of ring A is only slightly modified while the tetracyclic skeleton exhibits a more planar conformation than that of levonorgestrel (1) or the other esters (2), (3), and (5), and the ester grouping shields the 0 (17) ester position much more in esters (4), (6), and (7). Since levonorgestrel (1) and norethisterone (8) have very similar conformations, additional factors, different from the molecular geometry, seem to be responsible for the dramatic long‐acting contraceptive properties associated with these esters.

Conformational studies. Part 10. Crystal and molecular structure of 17β-iodoacetoxy-4,4-dimethyl-5α-androst-7-en-3-one

The crystal and molecular structure of the title compound, (2), C23H33O3I, has been determined by single-crystal X-ray techniques. Crystals are trigonal, space group P32, with six molecules per unit cell (two independent molecules per asymmetric unit) of dimensions a= 22.982(3) and c= 7.547(1)Å. The structure was solved by the heavy-atom method and refined by least-squares calculations to R 0.064 for 1 686 observed reflections. The steroid frameworks of both molecules have essentially the same conformations, the only differences being in the orientations of the 17β-iodoacetoxy-side-chains. Ring A of the steroid skeleton has a very flattened chair conformation, ring B is a distorted half-chair, ring C a flattened chair, and ring D a distorted envelope.

Steroids and steroidases XVII (1). Delineation of some factors involved in the formation and disaggregation of steroid micelles in aqueous solutions using acid-catalyzed isomerization of Δ 5-3-ketones as a convenient kinetic method for monitoring the processes

Some of the factors involved in the formation and disaggregation in aqueous solutions of micelles of Δ 5-3-keto-steroids possessing 17β-H, CH 3, CH 2CH 3, CH(CH 3) 2 and C 8H 17 substituents have been evaluated using both light-scattering and acid-catalyzed isomerization kinetic techniques. The latter method has been shown to be a convenient and sensitive probe for monitoring the degree of substrate aggregation and for determining the conditions under which complete solvation occurs. Studies of the relative effectiveness of organic solvents, particularly of homologous alcohols, in causing micelle break-up have indicated that disruption of the steroid aggregates occurs by solvation of the hydrophobic skeleton by the organic solvent. The steroid micelles appear to resemble those of nonionic surfactants or lipids and a general structure for the aggregates in aqueous solution is proposed in which overlap of the hydrophobic steroid framework is maximized.

Search for substantial barriers to internal rotation about the ring-substituent bond in 5α-cholestan-6β-yltrimethylammonium iodide, N-(5α-cholestan-6β-yl)-N-methylacetamide, and 1-(5α-cholestan-6β-yl)-tetrazole

A satisfactory demonstration of substantial barriers to internal rotation about the ring-substituent bonds in certain 6β-substituted 5α-cholestanes was not possible, in the main probably because of too high flexibility in the steroid framework.