Substituent increments for the 1H-NMR. Chemical shifts of the 18- and 19-methyl protons of steroids. Part I: 9beta, 10alpha(retro)-steroids

This paper reports 261 substituent increments for the ¹H? NMR. chemical shifts (solvent: CDCl₃) of the 18- and 19-methyl protons of 9β, 10α(retro)-steroids relative to 5β,9β,10α,-androstane. The increments were calculated by a least-squares procedure from 1334 spectra of 759 different steroids.     

Substituent increments for the 1H-NMR. Chemical shifts of the 18- and 19-methyl protons of steroids. Part II: 9alpha, 10beta(normal)-steroids

In Part II of this series we report 292 substituent increments for the ¹H-NMR. chemical shifts (solvent: CDCl₃) of the 18- and 19-methyl protons of 9α,10β(normal)-steroids relative to 5α,9α,10β,-androstane. The increments were calculated by a least-squares procedure from 988 spectra of 681 different steroids.     

Photochemistry of the vitamin D series. II. Wavelength dependence of photoisomerization of precalciferol

In addition to the known ring opening at shorter wavelengths it was found that ring opening in Δ^5,7-steroids occurs also at λ > 300 nm. Ring closure of the corresponding seco- steroids in this region was confirmed. The existence of three rotational isomers with respect to the 5,6-bond is assumed to be responsible for the observed wavelength dependency of the photoisomerizations of previtamin D. In this case the 5,6-s-trans isomer should absorb uv light at shorter wavelengths yielding tachysterol whereas the two 5,6-rotational isomers with skew conformation should absorb at longer wavelengths yielding lumisterol and ergosterol, respectively.     

The x-ray structure analysis of 17-beta-bromoacetoxy-9-beta, 10-alpha-androst-4-en-3-on

The structure of 17β-bromacetoxy-9β, 10α-androst-4-en-3-one has been determined by three-dimensional X-ray crystallographic methods. The crystals of the restrosteroid belong to the orthorhombic space group P2₁2₁2₁ with four molecules per unit cell. The cell constants are a = 11.32 Å, b = 13.71 Å and c = 12.52 Å. The absolute configuration of the molecule has been determined by the anomalous dispersion method. Bond length, bond angles and distances of atoms from ‘best planes’ are given. Ring A represents a distorted half-chair, ring B and C a chair and ring D an envelope conformation. The molecule shows, contrary to normal 9α, 10β-steroids, a bent shape.     

5α-24-Norcholestan-3β-ol and (24Z)-Stigmasta-5,7,24(28)-trien-3β-ol,Two New Marine Sterols from the Pacific Sponges Terpios zeteki and Dysidea herbacea

The steroidal components of 2 marine sponges, Terpios zeteki (from Hawaii) and Dysidea herbacea (from Australia) were fractionated through a combination of chromatographic methods, including reversed phase HPLC., and were analyzed by a combination of physical methods, including high resolution GC.-MS. and 360 MHz ¹H-NMR. T. zeteki contains 6 conventional 5α-stanols which comprise 91% of the sterol mixture, and traces (0.5%) of a new C₂₆ sterol, 5α-24-norcholestan-3β-ol. Minor amounts of conventional Δ⁵-sterols (6.5%) and of a single Δ⁴-3-ketosteroid (1.5%) were also present. In contrast, the Australian sponge (D. herbacea) contains 3 Δ^5,7-sterols which comprise 1.5% of the sterol mixture, and one new C₂₉ sterol, (24 Z)-stigmasta-5,7,24(28)-trien-3β-ol, as the major component (75%). In addition, minor amounts of conventional 5α-stanols (0.5%), Δ⁵-sterols (5%) and 5α-Δ⁷-sterols (18%) were present in this complex sterol mixture. The possible dietary or endosymbiotic origins of these sterols are discussed.     

Insights into the Synthesis of Steroidal A‐Ring Olefins

The classical synthesis, followed by purification of the steroidal A‐ring Δ¹‐olefin, 5α‐androst‐1‐en‐17‐one ( 5 ), from the Δ¹‐3‐keto enone, (5α,17β)‐3‐oxo‐5‐androst‐1‐en‐17‐yl acetate ( 1 ), through a strategy involving the reaction of Δ¹‐3‐hydroxy allylic alcohol, 3β‐hydroxy‐5α‐androst‐1‐en‐17β‐yl acetate ( 2 ), with SOCl₂, was revisited in order to prepare and biologically evaluate 5 as aromatase inhibitor for breast cancer treatment. Surprisingly, the followed strategy also afforded the isomeric Δ²‐olefin 6 as a by‐product, which could only be detected on the basis of NMR analysis. Optimization of the purification and detection procedures allowed us to reach 96% purity required for biological assays of compound 5 . The same synthetic strategy was applied, using the Δ⁴‐3‐keto enone, 3‐oxoandrost‐4‐en‐17β‐yl acetate ( 8 ), as starting material, to prepare the potent aromatase inhibitor Δ⁴‐olefin, androst‐4‐en‐17‐one ( 15 ). Unexpectedly, a different aromatase inhibitor, the Δ^3,5‐diene, androst‐3,5‐dien‐17‐one ( 12 ), was formed. To overcome this drawback, another strategy was developed for the preparation of 15 from 8 . The data now presented show the unequal reactivity of the two steroidal A‐ring Δ¹‐ and Δ⁴‐3‐hydroxy allylic alcohol intermediates, 3β‐hydroxy‐5α‐androst‐1‐en‐17β‐yl acetate ( 2 ) and 3β‐hydroxyandrost‐4‐en‐17β‐yl acetate ( 9 ), towards SOCl₂, and provides a new strategy for the preparation of the aromatase inhibitor 12 . Additionally, a new pathway to prepare compound 15 was achieved, which avoids the formation of undesirable by‐products.     

Conversion of 11-keto-9-beta, 10-alpha-steroids on 10-alpha-compounds. Synthesis of 10-alpha-cortisone, 11-oxo-10-alpha-progesterone, 10-alpha-androsterone and analogs of 11-hydroxy-compounds

Isomerisation of 11-keto-9β, 10α(retro)-steroids by acid or base led to the thermo-dynamically more stable 11-keto-10α-isomers, which have not yet been described in the literature. This epimerisation at C-9 constitutes a new route for the synthesis of 10α-steroids. The steric factors responsible for this isomerisation are discussed.     

Reaktionen von Steroiden mit Dialkylaminoschwefeltrifluoriden. I. 11β-Hydroxysteroide. Über STeroide, 233. Mitteilung

Reactions of Steroids with Dialkylaminosulfur Trifluorides. I. 11β-Hydroxysteroids. Reactions of three types of 11β-hydroxy steroids with dialkylaminosulfur trifluorides (DAST) have been studied. 9Δ-unsubstituted 11-alcohols are dehydrated with DAST to Δ⁹⁽¹¹⁾-unsaturated compounds under very mild conditions. 9α-Chloro-11β-hydroxy steroids are quantitatively fluorinated in position 11 yielding the known 9α-chloro-11β-fluoro derivatives. Finally, 9α, 11Δ-fluorohydrins at 0–25° are selectively transformed with DAST into Δ¹¹-9α-fluorides. When the latter reaction is run at lower temperature, the corresponding 11-piperidinesulfinates, products of partial hydrolysis of the alkoxy-dialkylaminosulfur difluoride intermediates postulated by Middleton, can be isolated in high yields. A rational explanation of the results is presented.     

Totalsynthese von Steroiden. 1. Mitteilung. rac-17β-Hydroxydes-A-androst-9-en-5-on

In connection with earlier work on the synthesis of 9β, 10α-steroids, a new and practical synthesis of rac-17α-hydroxy-des-A-androst-9-en-5-one ( 19 ) has been developed, based on a novel stereoselective condensation of 7-hydroxy-1-nonen-3-one ( 3 ) with 2-methyl-cyclopentane-1, 3-dione ( 9 ) and subsequent transformations of the resulting tricyclic diene ether 12 .     

Terpenoids—LXXI: Chemical studies of marine invertebrates—XIV. Four representatives of a novel sesquiterpene class—the capnellane skeleton

The isolation and complete structure determination of four marine sesquiterpenoids: Δ⁹⁽¹²⁾-capnellene-8β,10α-diol (1), Δ⁹⁽¹²⁾-capnellene-3β,8β,10α-triol (3), Δ⁹⁽¹²⁾-capnellene-5α,8β,10α-triol (5), Δ⁹⁽¹²⁾-capnellene-2ξ,8β,10α-triol (7) from the soft coral Capnella imbricata is described. These alcohols are the first members of a fundamentally new sesquiterpene class consisting of three 5-membered fused rings which we have named capnellane (A).     

The Course of the Catalytic Hydrogenation/Isomerization Reaction of Steroidal Ring B Olefins in the 13β- and 13α-Series

The course of the catalytic hydrogenation and isomerization (H₂/Raney-Ni/dioxane or H₂/Pd/C/EtOH) of Δ^5.7-, Δ⁷-, Δ⁸-, and Δ⁸⁽¹⁴⁾-steroid olefins was shown to depend strongly on the configuration at C(13). The known hydrogenation/isomerization of reactions of Δ^5.7-dienes in the 13β-series to Δ⁷-(H₂/Raney-Ni/dioxane) and Δ⁸⁽¹⁴⁾-olefins (H₂/Pd/C/EtOH) were also confirmed in the 3β, 19-epoxy-13β- and 3-Oxo-19-acetoxy-13β-steroid series (e.g. 32 → 35 → 37 , Scheme 3). On the other hand, in the corresponding 13α-steroid series the same reactions afforded the Δ⁷-. and the Δ⁸-olefins (mixture of products with H₂/Raney-Ni/dioxane; quantitatively the Δ⁸-compounds with H₂/Pd/C/EtOH; s. e.g. Scheme 3). A similar dependence on the C(13) configuration was observed in the allylic oxidation of these olefins with SeO₂ (Fieser's test, see Table), and in the acid catalyzed opening of the 7α, 8α-epoxides (e.g. 60 → 62 + 63 in the 13β-series, and 56 → 64 + 65 in the 13α-series, Scheme 8).     

Photochemische Reaktionen 42. Mitteilung [1]. Photoisomerisierung von α, β-Epoxyketonen II Der sterische Verlauf der Umlagerung von 3-Oxo-4, 5-oxido-Steroiden

The photorearrangement previously described [3] of saturated and Δ¹-unsaturated 3-oxo-4,5-epoxy-10β-steroids to 3,5-dioxo-10(5 →4)-abeo compounds proceeds most likely via a radical 1,2-alkyl shift (Chart 1). The similar rearrangements of the related 10α-epoxyketone 10 and the 4-methyl-epoxyketones 13 , 15 , 16 , 20 and 21 to the corresponding 3,5-diketones occurred without epimerization at the migrating carbon atom (C-10) and the site of substitution (C-4) (Chart 3). The stereochemical control of the rearrangement is in agreement with the earlier proposed mechanism of a concerted alkyl radical shift in these alicyclic systems.     

The course of the transformation of steroid 3,5-dienamines with formaldehyde

Reaction of steroidal 3,5-dienamines (including 9β,10α- and 19-nor-compounds) with formaldehyde gave 6-hydroxymethyl derivatives as major products. The latter compounds are valuable intermediates for the preparation of 6-methyl-3-keto-Δ^4,6-steroids.     

The Crystal and Molecular Structure of 3-Oxo-17β-acetoxy-Δ4-14α-methyl-8α, 9β, 10α, 13α-estrene

The crystal and molecular structure of 3-oxo-17β-acetoxy-Δ⁴-14α-methyl-8α, 9β, 10α, 13α-estrene, C₂₁H₃₀O₃, has been determined by X-ray diffraction analysis. The crystals belong to the orthorhombic space group P2₁2₁2₁, with the cell dimensions a = 12.093 Å, b = 19.667 Å, c = 7.746 Å; Z = 4. Intensity data were collected at room temperature with an automatic four-circle diffractometer. The structure was solved by direct methods and the parameters were refined by least-squares analysis. All the hydrogen atoms were included in the refinement. The final R value was 0.038 for 1413 observed reflections. The conformation of ring A is intermediate between a half-chair and a 1, 2-diplanar form. The hydrogens at C(9) and C(10) are anti, the B/C ring junction is trans, and rings B and C adopt chair conformations. Ring D is cis fused and is halfway between C₂ and C_s forms.     

Studies on biaxial stretching of polypropylene film. IV. Overall orientation during one-step biaxial stretching and its application to the estimation of the principal refractive indices of isotactic polypropylene

Polypropylene film was biaxially stretched in one step in air at 140°C or 152°C, and the deformation was studied optically. A linear relation held between Δn_ss and v_A^?½ for v_A > 10, at both temperatures, where Δn_ss is the birefringence with respect to the normal to the film and v_A is the degree of stretching expressed as the factor by which the area of the film is increased. Extrapolation of data in this linear region yielded a value of 20 × 10^?3 for ?Δn_ss at infinite v_A. Since it is presumed that the polypropylene molecules lie completely parallel to the film surface when the film is stretched infinitely, ?Δn_ss at v_A^?½ = 0 must be just half Δn°, the intrinsic birefringence in the case of completely parallel orientation. Thus, Δn° must be 40 × 10^?3. This value was obtained experimentally in uniaxial stretching when the birefringence with respect to the direction of drawing was extrapolated to infinite extension. Similar relations held between n_p, the average of the refractive indices in the two stretching directions, and v_A, and between n_ss, the index normal to the film, and v_A. By similar extrapolations, (1/2)(n′_γ + n′_β) and n′_β = n*_α′ were estimated, and thence nα′ was obtained. Here, n′_α and n′_β are the refractive indices along the c axis (molecular chain axis) and b axis. All these optical parameters refer to a density of 0.900 g/cm³. Hence by applying a density correction to those values, the principal refractive indices and the intrinsic birefringence of polypropylene crystal were evaluated as follows: n_α = 1.5522, n_β = n*_α = 1.5106 and Δn_c° = 4.16 × 10^?3, where n*_α is the refractive index prependicular to the b and c axes of the crystal.     

Metathesis reactions of Δ-steroids

Metathesis reactions of Δ²²-steroids are studied. The cross metathesis reactions of model Δ²²-steroids with excess of simple alkenes are sluggish or do not occur at all. In contrast, derivatives of both trans- and cis-Δ²²-cholesterol undergo ring closing metathesis reactions but the former reacts faster. However, the side chain double bond in stigmasterol and ergosterol is too crowded for metathesis reactions promoted by currently available catalysts.     

Molecular calculations with the nonempirical ab initioMODPOT,VRDDO, and MODPOT/VRDDO procedures. IX. Carcinogenic benzo(a)pyrene and its metabolites using a MERGE technique

Ab initio MODPOT /VRDDO calculations have been carried out on carcinogenic benzo(a)pyrene and its metabolites. The MODPOT /VRDDO method incorporates two very desirable options into our fast ab initio Gaussian programs: MODPOT —ab initio effective core model potentials—and a charge-conserving integral prescreening approximation which we named VRDDO (variable retention of diatomic differential overlap). For orbital energies and population analyses the MODPOT /VRDDO results agree to essentially three decimal places with completely ab initio calculations using the same valence atomic basis set. For this series of very closely related congeners a new MERGE technique was implemented that allows reuse of integrals of a common skeletal fragment. Since our program computes integrals efficiently by blocks, reusing information common to the block, it was more difficult to implement a MERGE technique than for integral programs which calculate the integrals one-byone. The MODPOT /VRDDO calculations were performed for benzo(a)pyrene (BP), BP oxides, BP dihydrodiols, and BP dihydrodiol epoxides. The metabolites investigated were BP-7,8-oxide, BP-4,5-oxide, BP-7,8-dihydrodiol [cis(e, a), cis(a, e), trans(e, e), and trans(a, a)], and BP-7,8-dihydrodiol-9,10-epoxide [β,β,β (the most stable), β,β,α; α,α,β, and α,α,α all derived from cis-BP-7,8-dihydrodiol and β,α,β; α,β,β and α,β,β derived from trans-BP-7,8-dihydrodiol]. Several different conformations were calculated for each of the BP dihydrodiols and BP dihydrodiol epoxides. Calculations were carried out for the opening of the C₉—O—C₁₀ epoxide ring both toward C₉ and C₁₀ for the, most stable β,β,β isomer of BP-7,8-dihydrodiol-9,10-epoxide. Opening the epoxide ring between C₁₀ and O leads to a more stable intermediate than opening the epoxide ring between C₉ and C₁₀. However, there is no buildup of positive charge in C₁₀ as has been postulated by some cancer researchers, but rather the C₁₀ becomes slightly more negative. Nor is there a buildup of negative charge on the O atom. rather it becomes slightly less negative. As the epoxide ring is opened further than 90° for the O—C₉—C₁₀ or O—C₁₀—C₉ angles, there appears to be a possible mixing of configurations that is being investigated further.     

Novel synthesis of (−)-trans-Δ9,11-tetrahydrocannabinol

Addition of hydrogen chloride gas to a solution of Δ⁸-tetrahydrocannabinol in dry dichloromethane at -60° in the presence of zinc chloride results in the formation of a higher concentration of 9-α-chlorohexa-hydrocannabinol (75%) than the thermodynamically more stable 9-β-chlorohexahydrocannabinol (25%). The two isomers can be separated by reverse-phase hplc. Elimination of hydrogen chloride from 9-α-chlorohexa-hydrocannabinol using potassium t-amylate under anhydrous conditions gives exclusively Δ^9,11-tetrahydrocannabinol in overall yield of 65%.     

Glycosides of marine invertebrates. VIII. Steroid glycosides of the holothurianIsostichopus badionotus

The steroid glycoside fraction ofIsostichopus badionotus, consisting of a mixture of D-xylosides of steroid alcohols, has been isolated by column chromatography on silica gel. The mixture of aglycones obtained after acid hydrolysis was separated with the aid of argentation chromatography into several fractions. GLC-MS analysis, and also the use of IR and¹³C NMR spectroscopy has shown that the steroid glycosides ofI. badionotus are xylosides of Δ⁰-, Δ⁷-, Δ²²-, and Δ^7.22-, C₂₇-, C₂₈-, and C₂₉-steroids of the cholestane series.     

Solution conformation and dynamics of L-6-methylperhydroimidazo[1,5-c]thiazole-5,7-dione (γ-thiaprolinehydantoin). A 1H and 13C NMR study

The solution conformation of L-6-methylperhydroimidazo[1,5-c]thiazole-5,7-dione (γ-thiaprolinehydantoin) has been determined from an extensive ¹H and ¹³C NMR study, allowing the extraction of vicinal inter-proton and carbon-hydrogen coupling constants. The major conformation of the thiazolidine ring is an envelope with C-δ as the flap exo (δ^?). In solution the preferred solid state (twist) conformer with C-α exo and C-β endo (_α^βT) is only a minor contributor. ¹³C spin–lattice relaxation data reveal the flexibility of the thiazolidine ring.