Steroids: reactions and partial synthesis

Contents

• 1 Introduction

• 2 Estrogens

• 3 Androgens

• 4 Pregnanes

• 5 Cholic acids

• 6 Cholestanes

• 7 Vitamin D

• References

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Abstract

Covering: January to December 2003

This article reviews the progress in the chemistry of the steroids that was published between January and December 2003. The reactions and partial synthesis of estrogens, androgens, pregnanes, cholic acid derivatives, cholestanes and vitamin D analogues are covered. There are 152 references.

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1 Introduction

This review follows the pattern of its predecessor¹ with sections on the chemistry of the major skeletal types of steroids. There has been continued progress in the development of compounds which inhibit stages in steroid metabolism, particularly the C-17(20) lyase, in defining the structural requirements for binding to the steroid receptors and in establishing structure–activity relationships for the neurosteroids that target the GABA_A receptor.

A review of the synthesis, physical and biological properties of enantiomeric steroids has appeared.²Ent-desmosterol and ent-cholesterol have been prepared³ from ent-androst-4-ene-3,17-dione in order to study sterol–lipid interactions. A review has appeared⁴ covering the use of transition metal catalysts in steroid synthesis. Although steroid total synthesis is outside the scope of this article, it is worth noting that a new strategy for a convergent steroid synthesis has been described.⁵ A review has also appeared⁶ covering chemical approaches to the study of transcription, a topic which included steroid examples.

2 Estrogens

The receptor interactions involving anti-estrogens and the role of selective estrogen receptor modulators in medicine has been reviewed.⁷ NMR studies on the conformations adopted by estrogen receptor ligands has been reported.⁸ 2-Methoxyestradiol has tumour growth inhibitory properties. A new short synthesis has been described⁹ based on the oxidation of estradiol bis-THP ether by hydrogen peroxide in the presence of a strong base. An efficient synthesis of estrieno[2,3-b]- and [3,4-c]-pyrroles 1 by a palladium-catalysed amination has been reported.¹⁰

Some observations have been made¹¹ on the hydrolytic behaviour of the ethylene ketals of 5α,10α-epoxy-9(11)-estrenes and their 5α-hydroxy-11β-alkyl counterparts. The X-ray crystal structure of the alkene 2, obtained from the reduction of the aromatic ring of 13-ethyl-3-ethoxygona-1,3,5(10)-triene-11α,17β-diol, has revealed¹² the presence of products from this reaction with an unusual 10α-hydrogen atom. Some novel estratrienones have been obtained¹³ by oxidation at the benzylic C-6 and C-9 positions with t-butyl hydroperoxide in the presence of cobalt acetate. Estrogen esters with groups at C-7α, C-11β and C-15α have been used¹⁴ to probe the structural requirements of the estrogen receptor. The synthesis has been reported¹⁵ of a 7α-substituted estradiol–biotin chimera 3 that heterodimerizes the estrogen receptor with a streptavidin protein in a yeast.

The synthesis of a ring B aromatic 13-azasteroid has been described.¹⁶ Although they have a lower binding affinity, some normal and 13-epi-D-homoestrone derivatives are recognized by the estrogen receptor.¹⁷ The stereochemistry of the addition reactions to the 16,17-double bond of 3-methoxy-13α-estra-1,3,5(10),16-tetraene has been examined¹⁸ and the conformation of the four 16,17-diols has been established.¹⁹ A stereoselective synthesis of the isomeric trans 16-hydroxymethyl-3-methoxy-13α-estra-1,3,5(10)-trien-17-ols (e.g.4) and their halogenation, has been reported.^20,21 The synthesis and anti-neoplastic activity of 16-arylidene derivatives of estrone, e.g.5, have been described.²² Syntheses have been reported of estradiol–adenosine²³ and estradiol–taxol²⁴ conjugates.

The modification of ring D of estrone has continued to be of interest in the context of its effects on estrogen metabolism and on the binding of the steroid to the estrogen receptor. Some medium-sized ring D derivatives of estrone, e.g.6, have been obtained²⁵ by a combination of intramolecular Heck and Grignard reactions. The sulfamate 7 has been shown²⁶ to be a potent inhibitor of a steroid sulfatase. The receptor binding activity of 17α-arylestradiols has been examined.²⁷ The synthesis of ¹¹C labelled compounds in the estradiol series has been reported,²⁸ while 17α,20E/Z-[¹²⁵I]-iodovinyl derivatives of 7α-cyanoestradiol²⁹ and 7α-cyano-19-nortestosterone³⁰ have been prepared as radioligands for the relevant steroid receptors. Some 4′-substituted cinnamylestradiol derivatives 8 have been evaluated³¹ as probes for the estrogen receptor binding domain. Various 17α-substituted estradiolpyridin-2-yl hydrazine complexes with rhenium have also been prepared³² as potential ligands for labelling the estrogen receptor.

The biomimetic hydroxylation of C-12 to afford 9 using a copper complex and oxygen, with the 17-pyridinyl imine as a directing group, has been examined.³³ Some 17β-estradiol dimers linked via an alkyl chain between C-17α have been shown³⁴ to have cytotoxic activity against human cancer cell lines that are responsive to estrogens.

3 Androgens

Methods have been reported for the regioselective aminolysis of steroidal 2α,3α-epoxides catalysed by gadolinium triflate³⁵ and for the preparation of 3β-amino-5α-androstan-17-one.³⁶ A regioselective Candida antarctica lipase catalysed hydrolysis of the diacetate 10 to the mono-ol 11 has provided³⁷ the basis for a convenient synthesis of the ring A lactone of oxandrolone. The stereochemistry of some reactions of 2-methylene and 2-hydroxymethylene-5α-androstanes has been described.^38,39

The structure–activity relationships of some 3-deoxyandrogens, e.g.12, as aromatase inhibitors have been evaluated.⁴⁰ The nitrone 13 has been examined⁴¹ as a transition state mimic of an enolate intermediate in the formation of 5α-dihydrotestosterone by testosterone 5α-reductase. The oxime ether 14 has been shown⁴² to be a novel Na⁺,K⁺-ATPase inhibitor and this compound may have application in the treatment of heart failure.

Some thermodynamic features of the isomerization of androst-5-ene-3,17-dione to androst-4-ene-3,17-dione have been examined.⁴³ The microwave-induced enol-acetylation of steroidal ketones has been reported.⁴⁴ Some unusual steroidal polyquinane hybrids, e.g.15, have been described.⁴⁵ The proton chemical shifts of androstane amines have been assigned.⁴⁶

Some structural requirements for binding to the androgen receptor have been determined⁴⁷ using some androst-16-enes. The partial syntheses of androst-16-ene-3β,5α-diol and 3β,5α,6β-triol⁴⁸ and of some cytostatic ring B lactams⁴⁹ have been described. The stereochemical factors affecting the 1,2-addition of Grignard reagents to steroidal unsaturated ketones and the oxidation of 3-hydroxy-3-methyl-Δ⁴-steroids have been examined.^50,51

Androstanes have continued to provide useful substrates for defining the structural requirements for microbiological hydroxylations. Studies on the biotransformation of 3α,17β- and 3β,17α-dihydroxy-5α-androstanes,⁵² 4,4-dimethylandrost-5-enes,⁵³ 5β-methylestr-9-enes,⁵⁴ des ring D androstanes,⁵⁵ 17-chloroandrosta-4,16-dien-3-one,⁵⁶ and 4-formylandrostanes⁵⁷ have all been reported. The extent of the double bond migration in the Westphalen rearrangement of des ring D androstenes has been examined.⁵⁸

The syntheses of some equine metabolites of the anabolic steroid, norethandrolone 16, have been reported.⁵⁹ Solvent effects have been shown⁶⁰ to play a role in the addition of organolithium reagents to hindered C-11 ketones. The preparation and X-ray crystal structure of 16-acetylandrosta-4,16-diene-3-one 17 has been reported.⁶¹ The conditions for the abnormal Beckmann rearrangement of steroidal C-17 oximes have been optimized⁶² for the fragmentation of ring D to form 18. 16,17-Secosteroids with aminomethylene-2-pyridine structures have been used⁶³ as chiral ligands for the copper ion activation of oxygen.

The palladium-catalysed aminocarbonylation of 17-iodoandrost-16-enes⁶⁴ in ionic liquids and the X-ray structures of 16-amino-D-homosteroids have been reported.⁶⁵ The Cu/Fe-mediated hydrogenation of 17-halo-16-enes in the presence of hydrazine has also been reported.⁶⁶

Androgens containing various 17-azole substituents have been examined as inhibitors of the hydroxylase in the 17(20)-lyase and as potential agents for prostatic cancer therapy.^67,68 Some 5α,13α-D-azasteroids have been prepared⁶⁹ as potential precursors of GABA_A receptor modulators. Improvements in the phosphorylation of alcohols with titanium t-butoxide as the catalyst have been made⁷⁰ using steroidal 17β-alcohols as examples. The synthesis of two new haptens of 16α-hydroxydehydroepiandrosterone has been reported.⁷¹

4 Pregnanes

Some general patterns have been identified⁷² in the wavelength dependence of various photochemical reactions of pregna-1,4-diene-3,20-dione 19. An efficient process has been developed⁷³ for the production of the key steroid intermediate, 16-dehydropregnenolone 20, from diosgenin. A synthesis has been reported⁷⁴ of 5,7-dienes related to pregnane-3,17α,20-triols which are abnormal steroid metabolites. Methods have been developed⁷⁵ for the synthesis of 6β-hydroxycortisol labelled with stable isotopes. Some pregna-1,4,6-trienones, e.g.21, have been evaluated⁷⁶ as inhibitors of testosterone 5α-reductase. The conjugate addition of p-aminothiophenol to pregnane-4,6-dien-3-ones has been observed.⁷⁷

The 6,19-methanoprogesterone 22 has been prepared.⁷⁸ Neurosteroids have continued to attract interest. The GABA_A receptor activity of the 6,19-oxidopregnane analogue 23 has been examined.⁷⁹ Some other pregnanes with conformationally constrained side chains, e.g.24, have also been prepared⁸⁰ as analogues of neurosteroids with GABA modulatory activity. The synthesis of 11,12-aziridino analogues, e.g.25 of neuroactive steroids has also been reported.⁸¹ Dysfunction of glucocorticoid receptors in the brain has been associated with some neuropsychiatric disorders. Some novel arylpyrazolocorticosteroids have been developed⁸² for imaging these receptors.

16-Dehydropregnenolone acetate has provided the starting material for the preparation of 16β-halo⁸³ and 16α-methyl⁸⁴ derivatives of cyproterone and for the formation of a pyrone 26 by a 4 + 2 cycloaddition.⁸⁵

21,21-Difluoro-3β-hydroxypregna-5,20-diene and the corresponding 5,16,20-triene have been shown⁸⁶ to be inhibitors of the 17(20)-lyase. The Grob fragmentation of ring D to give the aldehyde 27⁸⁷ and the base-catalysed cleavage of the dihydroxyacetone side chain of the corticosteroids⁸⁸ have been examined. Aerial oxidation of the corticosteroid side chain in the presence of copper acetate has been shown⁸⁹ to lead to dimers based on 17,21-acetals. The preparation of 21,21-dimethylprogesterone⁹⁰ and the conformation of the side chain of 21-alkylpregnanes⁹¹ have been examined.

5 Cholic acids

The application of residual dipolar couplings in the NMR spectrum to the assignment of conformation has been explored⁹² with sodium cholate. The preparation of fluorinated derivatives of cholic acids has been explored⁹³ in the context of the synthesis of squalamine analogues. The marine sterol 3β,6α-dihydroxy-5α-cholan-23-one has been synthesized.⁹⁴ The conversion of cholic acid to the unsaturated 6-ketone 28⁹⁵ and the synthesis of the lactone 29⁹⁶ have been described.

Metal complexing has been explored⁹⁷ as a tool for controlling the self assembly and gelation properties of cholic amide–phenthroline gelating agents. A review has appeared⁹⁸ of steroids as the organising components in anion receptors. A cholapod quaternary ammonium salt containing pendant urea groups has been examined⁹⁹ in the context of anion recognition. Desoxycholic acid–copper phosphite complexes have been explored¹⁰⁰ as ligands for the enantioselective conjugate addition of diethyl zinc to acyclic enones.

Clathrates based on cholic acid have been used¹⁰¹ to form complexes with the o-, m- and p-xylenes. The X-ray structure of an inclusion complex between ursodeoxycholic acid and phenanthrene has been described.¹⁰²

The addition of metal cyanides to the p-toluenesulfonyl hydrazones of aldehydes has been explored¹⁰³ as a method of one-carbon homologation on the steroid side chain, as in the formation of 30. The properties of a model trans-membrane ionophore based on the dimer 3β,6α,7β-trihydroxy-bisnorchol-16-ene 22-terephthalate have been examined.¹⁰⁴ The synthesis of ester-linked lithocholic acid dimers has been reported.¹⁰⁵ Some novel steroidal dendrons have been obtained¹⁰⁶ from 3α-trifluoroacetoxy-5β-cholan-24-oyl chloride and the benzyl ester of 2,2-bis(hydroxymethyl)propionic acid. The complexing properties of some cholane–porphyrin conjugates have been examined.¹⁰⁷ The anti-malarial, anti-mycobacterial and anti-proliferative activity of phenyl-substituted tetraoxanes, e.g.31, have been examined.¹⁰⁸ The photochemical rearrangement of the C-3 o-nitrobenzyl ethers of cholic acid to o-nitrosohemiacetals has been observed.¹⁰⁹

6 Cholestanes

Evidence has been provided¹¹⁰ for the effect of cholesterol in a membrane on unravelling neighbouring phospholipids by acting as a a rigid hydrophobic template and maximizing the hydrophobic interactions. The interactions of cholesterol with cyclodextrins in solution has been studied¹¹¹ by NMR methods.

A formal synthesis of squalamine from desmosterol has been reported.¹¹² The anti-viral activity of the disulfate of 23,3α-dihydroxy-5α-cholestane has been noted.¹¹³ The reactions of the oxetane 32 have been studied¹¹⁴ as a model for aspects of taxol chemistry. The oxidative fragmentation of 5α-hydroxy-1-oxo-cholestan-3β-yl acetate to form 33, and of some 5-hydroxy-B-norcholestan-3β-yl acetates to give 5,10-secosteroids such as 34, together with their acid-catalysed reactions, have been examined.^115–117

The allylic oxidation of cholesteryl acetate has been examined using t-butylhydroperoxide and silica modified with a cobalt alkylphosphonate¹¹⁸ or copper iodide in acetonitrile.¹¹⁹ Some further epoxides have been isolated¹²⁰ from the autoxidation of isotachysterol. The synthesis of deuteriated samples of 7α- and 26-hydroxycholesterol for use in studying the bile acid pathway has been described.¹²¹

The sperm-activating factor 35 of the ascidian Ciona intestinalis, has been synthesized.¹²² A synthesis of the follicular fluid meiosis activating sterol, 3β-hydroxy-4,4-dimethyl-5α-cholesta-8,14,24-triene, has been reported¹²³ in the context of improving in vitro fertilization. The synthesis of the B-noraldehyde, orostanal 36, has attracted interest¹²⁴ because it induces apoptosis in HL-60 cells.

A computer program for predicting ¹³C NMR chemical shifts which takes into account stereochemistry has been applied¹²⁵ in the ecdysone series. The brassinolide plant hormones have continued to attract interest with reports on novel methods of constructing the side chain,¹²⁶ and the synthesis of B-homo analogues,¹²⁷ C-28 homo analogues,¹²⁸ and labelled brassinolides.¹²⁹ The anti-tumour activity of the marine sterol aragusterol A has provided the stimulus for the synthesis¹³⁰ of some analogues, 37, from cholic acid. The tumour-inhibiting properties of the dimeric steroids of the cephalostatin series has also continued to stimulate synthetic methodology.^131,132 Methyl protodioscin¹³³ and some rhamnosylated diosgenin glucosides¹³⁴ have been synthesized from diosgenin in the course of studies on steroidal cytostatic agents.

A number of modifications of the spiroketal ring system of the steroidal sapogenins such as diosgenin have been reported including the unusual cleavage of the diol 38 to the 22→16-lactone,¹³⁵ the formation of C-26 dithioketals¹³⁶ and the opening of the spiroketal with trifluoroacetyltrifluoromethanesulfonate to form 39¹³⁷ and the cleavage with boron trifluoride–acetic anhydride.¹³⁸ The synthesis of the aglycone of 26-O-deacetylpavoninin 5 40 from diosgenin has been reported.¹³⁹ Distinctions between the 25R and 25S spirostanes have been made¹⁴⁰ using their NMR spectra. The azasterol analogue 41 has been shown¹⁴¹ to be an inhibitor of the 24-methyl transferase in Leishmania species.

7 Vitamin D

The organic chemistry of vitamin D analogues has been reviewed.¹⁴² 1α,25-Dihydroxyvitamin D₃ (calcitriol) may exert some of its biological activity by binding to a nuclear receptor and initiating gene transcription whilst other effects involving calcium homeostasis may involve interactions with a membrane receptor. The synthesis of analogues modified on rings C and D to differentiate between these binding sites has been reported.¹⁴³ The thermal isomerization of vitamin D₃¹⁴⁴ and the photoconversion of 25-hydroxytachysterol to 25-hydroxyprevitamin D₃¹⁴⁵ have been examined.

The rigid acetylenic side chain analogue 42 of calcitriol has been shown¹⁴⁶ to induce vitamin D receptor transcriptional activity whilst 1α-hydroxyvitamin D₃ 26→23-lactones e.g.43, have antagonistic activity at the vitamin D receptor.^147,148 Functionalization of C-12 of 1α,25-dihydroxyvitamin D₃ modifies the affinity for the vitamin D receptor. The analogue with a 12-methyl substituent possessed a high affinity for the receptor.¹⁴⁹

A number of novel hapten derivatives of 1α,25-dihydroxyvitamin D₃ have been prepared.¹⁵⁰ Compounds linked through C-16 expose both ring A and the side chain, to maximize antibody specificity. A number of new strategies for the synthesis of vitamin D analogues have been described.^151,152

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