Glycosides of marine invertebrates. XIII. New holothurinogenins of holothurin B1 fromHolothuria floridana

We have isolated for the first time the native aglycone of a triterpene glycoside of the holoturin series — holothurin B₁ — and have established its structure as holost-9-ene-3β,12α,17α-triol. The structures of two new holostane derivatives have been established — holosta-8,11-diene-3β,17α-diol and 3β,17α-dihydroxyholost-9-en-12-one. A scheme of transformation of the native genin of holothurin B₁ under the conditions of the acid splitting of the glycoside has been put forward.     

Oxidative transformations of labdane diols. III. Preparation of acids with a strobane skeleton from larixol

It has been shown that the oxidation of larixol with chromic acid mixture forms methyl 6-oxo-8α,13α-epoxystroban-14β-oate, methyl 6-oxo-8α,13α-epoxystroban-14α-oate, and 6,13-dioxo-14,15-bisnorlabd-7-en-17-oate.     

Research on steroids. 41. Conversion products of 17-alpha-strophanthidins

Pseudostrophanthidin ( 2 ) can be easily prepared by treating strophanthidin ( 1 ) with concentrated hydrochloric acid in the cold [1]. 2 has served as the initial product for the preparation of a number of analogues and homologues of steroid hormones [2] [3]. 17α-Pseudostrophanthidin ( 4 ) is considered a suitable starting material for an extension of these investigations. It was logical to attempt the preparation of 4 from 17α-strophanthidin ( 3 ) under conditions identical with those used in the conversion of 1 into 2. However, these experiments did not lead to 4 but, instead, by way of the unstable 14ξ-chloro-14-deoxy-17α-strophanthidin ( 5 ) to 14-anhydro-17α-strophanthidin ( 6 ). This result is essentially in agreement with findings reported in the literature [5]. To support the structure assigned to 6 , this compound was also prepared by a different, unambiguous, route. Treatment of 3 with thionyl chloride in pyridine gave mainly 3β, 5β-O, Osulfinyl-14-anhydro-17α-strophanthidin ( 8 ), which was converted into 6 by mild hydrolysis. In turn 6 , as obtained via the unstable chloro compound 5 , gave on treatment with thionyl chloride in pyridine a product identical with 8. – 6 was characterized as the 3-acetate 7 . As extension of these experiments, 17α-strophanthidol ( 10 ) [6] was treated with concentrated hydrochloric acid in the cold under conditions similar to those used in the conversion of 3 into 6 by way of 5. This led to the isolation of 14-anhydro-17α-strophanthidol ( 11 ), which could also be obtained by the reduction of 6 with aluminium amalgam. As is known [1] [8], strophanthidinic acid ( 13 ) can be converted into strophanthidinic acid 19,8-lactone ( 14 ) by treatment with concentrated hydrochloric acid in the cold. In view of the negative results obtained in the attempt to transform 3 into 4 under these conditions, the question arose as to whether the conversion of 17α-strophanthidinic acid ( 15 ) into 17α-strophanthidinic acid 19,8-lactone ( 16 ) by the same procedure is also impossible. 15 was prepared by treating 3 with hydrogen peroxide and was characterized as the methyl ester 17 and the methyl ester of the 3-benzoate ( 18 ). 15 and 17 have been mentioned in the literature [5], but the physical constants reported differ from those obtained in this laboratory. It was demonstrated that after treating 15 with concentrated hydrochloric acid in the cold, no 16 could be isolated but, instead, an unstable chloro compound 19 which was converted into 14-anhydro-17α-strophanthidinic acid ( 20 ). 20 was characterized as the methyl ester 21 and the 3-acetate 22 .     

Transformed steroids. 193. Synthesis of 16α,17α-isopropylidene derivatives of pregn-4-ene-9α,16α,17α,21-tetraol-3,20-dione and its 17α-thioanalog

A study was carried out on the pathways for the transformation of 16α,17α-epoxypregn-4-ene-9α,21-diol-3,20-dione to give 16α,17α-isopropylidene derivatives of pregn-4-ene-9α,16α,17α,21-tetraol-3,20-dione and its 17α-thioanalog. The key step in this pathway is thecis-cleavage of the 20-carboethoxyhydrazone of this epoxide by acetic and thioacetic acids and subsequent condensation of the products formed with acetone. This pathway is an efficient approach to the synthesis of the 16α,17α-dioxolane derivative and is equally efficient for preparation of the thioanalog, namely, 16α,17α-isopropylidenepregn-4-ene-9α,16α,21-triol-17α-thiol-3,20-dione, which has already been synthesized by an alternative method.     

Synthesis,structure, and acylation of dihydroquinopimaric acid hydroxy derivatives

Reduction conditions of methyl dihydroquinopimarate with sodium borohydride and lithium aluminum hydride were established. As a result of the reduction 14β-hydroxy, 17α-hydroxy, 14β,17α-dihydroxy, and 14β,17α,21α-trihydroxy derivatives were obtained. The structure of methyl esters of 14β-acetoxy- and 17α-hydroxydihydroquinopimaric acid was established by XRD and NMR methods. Mono-, di-, and triacylates were obtained from the diterpene alcohols.     

Extended hopane derivatives in sediments: identification by 1H NMR

The sedimentary C₃₂ hopanoic acid $\text{3a}$, one of the most abundant in nature and of probable bacterial origin, has been isolated for the first time as a single component and characterised by ¹H NMR. The 17αH,21βH configuration of the C₃₁ alkane has been similarly confirmed.     

Degradation of deoxycholic acid by Pseudomonas Sp. NCIB 10590

The microbial degradation of deoxycholic acid 1 by Pseudomonas NCIB 10590 has been studied and two major products have been isolated and identified as 12β-hydroxyandrosta-1,4-dien-3,17-dione 2 and 12α-hydroxypregna-1,4-dien-3-one-20-carboxylic acid 9. Three minor products were isolated and evidence is given for the following structures: 12α-hydroxyandrosta-1,4-dien-3,17-dione 4, 12β-hydroxyandrosta-4-en-3,17-dione 7 and 12?, 17?-dihydroxyandrosta-1,4-dien-3-one 8.     

Alcaloïdes stéroïdiques—CLXXVIII: synthèse d'azides tertiaires—VIII: Synthèse d'azido et d'amino-14β cardénolides

The use of hydrazoic acid in the presence of BF₃-etherate allows the synthesis of the potentially interesting 14β-amino cardenolides. The 17βH configuration allows a quantitative yield of the 14β-azido cordenolide, but by this method, the 17αH configuration does not. However, the synthesis of the 14β-azido cardenolide of 17αH configuration can be achieved by the elaboration of a 14β-azido 17αH-pregnane.     

Metabolism of methyltestosterone in the greyhound

Gas chromatography/mass spectrometry and selective derivatisation techniques have been used to identify urinary metabolites of methyltestosterone following oral administration to the greyhound. Several metabolites were identified including reduced, mono‐, di‐ and trihydroxylated steroids. The major metabolites observed were 17α‐methyl‐5β‐androstane‐3α‐17β‐diol, 17α‐methyl‐5β‐androstane‐3α,16α,17β‐triol, and a further compound tentatively identified as 17α‐methyl‐5z‐androstane‐6z,17β‐triol. The most abundant of these was the 17α‐methyl‐5β‐androstane‐3α,16α,17β‐triol. This metabolite was identified by comparison with a reference standard synthesised using a Grignard procedure and characterised using trimethylsilyl (TMS) and acetonide‐TMS derivatisation techniques. There did not appear to be any evidence for 16β‐hydroxylation as a phase I metabolic transformation in the greyhound. However, significant quantities of 16α‐hydroxy metabolites were detected. Selective enzymatic hydrolysis procedures indicated that the major metabolites identified were excreted as glucuronic acid conjugates. Metabolic transformations observed in the greyhound have been compared with those of other mammalian species and are discussed here. Copyright © 2009 John Wiley & Sons, Ltd.     

Thiosteroids—XXXV : Diastereomers of steroidal thiolsulfinates

17β-Hydroxy-5α-androstan-2α,3α-anti(R)-episulfoxide on treatment with methanol and ethanol in the presence of a trace amount of sulfuric acid gave diastereomers of bis((2β-methoxy- and 2β-ethoxy-17β-hydroxy-5α-androstan-3α-yl) disulfide S-monoxides respectively. The absolute configuration of the compounds was established by their Grignard reactions leading to diastereomeric phenyl sulfoxides stereoaspecifically.     

Synthesis and study of hydrazones of 17α-hydroxyprogesterone and 17α-hydroxypregna-4,6-diene-3,20-dione and their 17α-acylated derivatives

It has been shown that under mild conditions the reactions of 17α-hydroxy 3,20-diones of the pregnane series with acid hydrazides lead to the formation of 3-monohydrazones, while under severe conditions 3,20-dihydrazones are formed regardless of whether a C₄–C₅ ethylenic bond or a chain of conjugation of C₄–C₅ and C₆–C₇ ethylenic bonds is present in the steroid molecule. The reaction of 17α-acetoxy 3,20-diketones of the pregnane series with acid hydrazides takes place only with the formation of 3-monohydrazones. An investigation of the gestagenic action of some of the compounds synthesized has shown that the presence of a 3-keto group in the steroids of the pregnane series is not necessary for the retention of this effect. The replacement of the keto group at carbon atom 3 by an azomethine group does not abolish the gestagenic action.     

(-)-(S)-Nakinadine B: first asymmetric synthesis

(-)-(S)-Nakinadine B has been synthesized for the first time (in 9 steps and 17% overall yield from commercially available atropic acid) using the conjugate addition of lithium dibenzyl-amide to an N-α-phenylacryloyl SuperQuat derivative with in situ diastereoselective enolate protonation as the key step.     

Glycosylation of cardenolides. VIII. Structures of the by-products of the synthesis by the orthoester method of strophanthidol rhamnosides

The by-products formed in the preparation of strophanthiodol 19-rhamnoside and 3, 19-bisrhamnoside by the orthoester method are 3β,5-dihydroxy-8,19-epoxy-5β,14β, 17α-card-20(22)-enolide and its 3-α-L-rhamnoside. 3β,5-Dihydroxy-8,19-epoxy-5β, 14α,17β-card-20(22)-enolide has been obtained by the action of a solution of HBr in nitromethane on strophanthidol.     

Combination of carbon isotope ratio with hydrogen isotope ratio determinations in sports drug testing

Carbon isotope ratio (CIR) analysis has been routinely and successfully applied to doping control analysis for many years to uncover the misuse of endogenous steroids such as testosterone. Over the years, several challenges and limitations of this approach became apparent, e.g., the influence of inadequate chromatographic separation on CIR values or the emergence of steroid preparations comprising identical CIRs as endogenous steroids. While the latter has been addressed recently by the implementation of hydrogen isotope ratios (HIR), an improved sample preparation for CIR avoiding co-eluting compounds is presented herein together with newly established reference values of those endogenous steroids being relevant for doping controls. From the fraction of glucuronidated steroids 5β-pregnane-3α,20α-diol, 5α-androst-16-en-3α-ol, 3α-Hydroxy-5β-androstane-11,17-dione, 3α-hydroxy-5α-androstan-17-one (ANDRO), 3α-hydroxy-5β-androstan-17-one (ETIO), 3β-hydroxy-androst-5-en-17-one (DHEA), 5α- and 5β-androstane-3α,17β-diol (5aDIOL and 5bDIOL), 17β-hydroxy-androst-4-en-3-one and 17α-hydroxy-androst-4-en-3-one were included. In addition, sulfate conjugates of ANDRO, ETIO, DHEA, 3β-hydroxy-5α-androstan-17-one plus 17α- and androst-5-ene-3β,17β-diol were considered and analyzed after acidic solvolysis. The results obtained for the reference population encompassing n?=?67 males and females confirmed earlier findings regarding factors influencing endogenous CIR. Variations in sample preparation influenced CIR measurements especially for 5aDIOL and 5bDIOL, the most valuable steroidal analytes for the detection of testosterone misuse. Earlier investigations on the HIR of the same reference population enabled the evaluation of combined measurements of CIR and HIR and its usefulness regarding both steroid metabolism studies and doping control analysis. The combination of both stable isotopes would allow for lower reference limits providing the same statistical power and certainty to distinguish between the endo- or exogenous origin of a urinary steroid.     

Synthesis of 16,17-seco-steroids with iminomethyl-2-pyridine and aminomethylene-2-pyridine structures as chiral ligands for copper ions and molecular oxygen activation

Starting from 16-oximino-3-methoxy-estra-1.3.5(10)-trien-17-one, the 16,17-seco-13α-carbaldehyde with a 16-nitrile function and its corresponding carboxylic acid have been synthesized via a Beckmann fragmentation. The corresponding 13α-amine is available by Curtius degradation of the carboxylic acid. Condensation of the carboxaldehyde with 2-(aminomethyl)pyridine and the primary amine with pyridine-2-carboxaldehyde gave the corresponding iminomethyl-2-pyridine and the aminomethylene-2-pyridine compounds. Copper-mediated ligand hydroxylations with molecular oxygen were not successful. Reasons for this are discussed.     

On the formation of homo-azasteroidal esters of N,N-bis(2-chloroethyl)aminobenzoic acid isomers and their antitumor activity

The N, N-bis(2-chloroethyl)aminobenzoate isomers and the 4-methyl-3-N, N-bis(2-chloro-ethyl)aminobenzoate of 3β-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam, 3α-hydroxy-13α-amino-13,17-seco-5α-androstan-17-oic-13,17-lactam, 3α-hydroxy-13α-amino-13,17-seco-5-androsten-17-oic-13,17-lactam and 17β-hydroxy-3-aza-A-homo-4α-androsten-4-one, have been prepared and their biological activity evaluated against P388 leukemia in vivo and Ehrlich Ascites tumor (EAT), P388 and L1210 leukemias and Baby Hamster cells (BHK) in vitro. The esters in which the alkylating congener is linked to the lactam alcohol in the axial position are inactive in vivo in P388 leukemia, while compounds 1, 4, 6, 13, 14 and the alkylating congeners 17, 18 and 20 are active. The effect of the homo-azasteroidal of N, N-bis(2-chloroethyl)aminobenzoic acid isomers and of 4-methyl-3-N, N-bis(2-chloroethyl)aminobenzoic acid on the incorporation of the radioactive precursor into the DNA of L1210, P388 leukemias, Ehrlich ascites tumor and, baby Hamster kidney cells was investigated. Higher inhibitory effects on the incorporation of the radioactive precursor was obtained with the ortho derivatives, yielding <70% inhibition of thymidine incorporation in all tumor lines tested.     

The incubation of 13α,17-dihydroxystemodane with Cephalosporium aphidicola

The biotransformation of 13α,17-dihydroxystemodane (3) with the fungus Cephalosporium aphidicola afforded 13α,17,18-trihydroxystemodane (4), 3β,13α,17-tri-hydroxystemodane (5), 13α,17-dihydroxy-stemodan-18-oic acid (6), 3β,11β,13α,17-tetra-hydroxystemodane (7), 11β,13α,17,18-tetrahydroxystemodane (8) and 3β,13α,17,18-tetra-hydroxystemodane (9). The hydroxylation at C-18 of the substrate points to a biosynthetically-directed transformation, because aphidicolin (2) is hydroxylated at this carbon. However, the C-3(β) and C-11(β) hydroxylations seem to indicate a xenobiotic biotransformation.     

Steroidal imidazopyridines and lactam imidazopyridines

Condensation of 17β-acetoxy-2α-bromo-5α-androstan-3-one with unsubstituted and substituted amino-pyridines, gives the corresponding 17β-acetoxy-5α-androstanimidazo[1,2-a]pyridines. Treatment of 16α-bromo-3-aza-A-homo-4α-androsten-4,17-dione with 2-aminopyridine or methyl-2-aminopyridine produces the corresponding 3-aza-A-homo-4α-androsten[16,17:2′,3′]imidazo[1,2-a]pyridines. Similarly, from 2α-bromo-17β-acetamido-5α-androstan-3-one and methylaminopyridine the 17β-acetamido-5α-androstan[2,3:2′,3′]imidazo[1,2-a]methylpyridine has been obtained. The structure of the compounds was apparent from their chemical properties and spectral data (ir, uv and nmr).     

Oxydation photochimique d'amines tertiaires et c'alcaloïdes XI: Photooxydation sensibilisée de la corynanthéidine. Transformation de dérivés de type corynanthéine en dérivés de type sarpagine

1 - Benzenesulfonyl - 17 - methoxy - 5α - cyano - 16ζ, 17 - 2α, 7α - tetrahydrocorynantheidine 21c, which was obtained by photosensitized oxidation of 1 - benzenesulfonyl - 17 - methoxy - 16ζ, 17 - 2α, 7α - tetrahydro-corynantheidine 20d effected in the presence of KCN, has been transformed into 1- benzene - sulfonyl - 2α, 7α - 20α, 19 - tetrahydro - 10 - deoxysarpagine 24b. A mechanism is proposed for the formation of 6α - hydroxy - 5α - cyano - 2α, 7α - dihydrocroynantheidine when 1-trifluoroacetyl - 2α, 7α - dihydro - corynantheidine was irradiated in the presence of rose bengale, oxygen and KCN.     

Total synthesis of verbalactone: an efficient, carbohydrate-based approach

A carbohydrate-based strategy for the total synthesis of verbalactone has been described. (3R,5R)-3,5-dihydroxydecanoic acid was dimerised under Yamaguchi conditions to provide verbalactone in an overall yield of 17% starting from 3-deoxy-1,2:5,6-di-O-isopropylidine-α-d-glucofuranose.