Table 3 - uploaded by Samuel M. Silvestre
Content may be subject to copyright.
Source publication
The preparation of steroids containing oxygenated functions in suitable positions of the steroid nucleus is of great importance and can be achieved by means of several oxidative processes. In this paper allylic oxidation, β-selective epoxidation, alcohol oxidation and remote functionalization reactions in steroid substrates are reviewed. Focus has...
Citations
... Overall, epoxidation of steroids with trans-anti-trans ring fusions generally leads to the formation of the α-epoxide. This fact can be explained by the preference of the attack by the reagent on the α-side of the steroid scaffold since the β-side is shielded by the two angular methyl groups at C-10 and C-13 [35]. Despite 5α,6αepoxysteroids have generally been obtained by oxidation with the most common peroxyacid 3-chloroperoxybenzoic acid (m-CPBA), MMPP has emerged as an advantageous alternative, considering its higher stability in the solid state and safety in handling. ...
... Overall, epoxidation of steroids with trans-anti-trans ring fusions generally leads to formation of the α-epoxide. This fact can be explained by the preference of the attac the reagent on the α-side of the steroid scaffold since the β-side is shielded by the angular methyl groups at C-10 and C-13 [35]. Despite 5α,6α-epoxysteroids have gene been obtained by oxidation with the most common peroxyacid 3-chloroperoxyben acid (m-CPBA), MMPP has emerged as an advantageous alternative, considerin higher stability in the solid state and safety in handling. ...
Steroids constitute an important class of pharmacologically active molecules, playing key roles in human physiology. Within this group, 16E-arylideneandrostane derivatives have been reported as potent anti-cancer agents for the treatment of leukemia, breast and prostate cancers, and brain tumors. Additionally, 5α,6α-epoxycholesterol is an oxysterol with several biological activities, including regulation of cell proliferation and cholesterol homeostasis. Interestingly, pregnenolone derivatives combining these two modifications were described as potential neuroprotective agents. In this research, novel 16E-arylidene-5α,6α-epoxyepiandrosterone derivatives were synthesized from dehydroepiandrosterone by aldol condensation with different aldehydes followed by a diastereoselective 5α,6α-epoxidation. Their cytotoxicity was evaluated on tumoral and non-tumoral cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, the assessment of the neuroprotective activity of these derivatives was performed in a dopaminergic neuronal cell line (N27), at basal conditions, and in the presence of the neurotoxin 6-hydroxydopamine (6-OHDA). Interestingly, some of these steroids had selective cytotoxic effects in tumoral cell lines, with an IC50 of 3.47 µM for the 2,3-dichlorophenyl derivative in the breast cancer cell line (MCF-7). The effects of this functionalized epoxide on cell proliferation (Ki67 staining), cell necrosis (propidium iodide staining), as well as the analysis of the nuclear area and near neighbor distance in MCF-7 cells, were analyzed. From this set of biological studies, strong evidence of the activation of apoptosis was found. In contrast, no significant neuroprotection against 6-OHDA-induced neurotoxicity was observed for the less cytotoxic steroids in N27 cells. Lastly, molecular docking simulations were achieved to verify the potential affinity of these compounds against important targets of steroidal drugs (androgen receptor, estrogen receptor α, and 5α-reductase type 2, 17α-hydroxylase-17,20-lyase and aromatase enzymes). This in silico study predicted a strong affinity between most novel steroidal derivatives and 5α-reductase and 17α-hydroxylase-17,20-lyase enzymes.
... Naturally occurring steroidal derivatives, such as spirostannic alcohols, are characterized by a hydroxyl group in position 3β-in the A-ring of the cyclopentaneperhydro phenanthrene nucleus, being typical secondary alcohol, and, taking into account this consideration, most common oxidative transformation in steroid chemistry is probably the oxidation of alcohol functionality into carbonyl group [20]. ...
The oxidation of the 3β-hydroxy group in the steroidal substrates obtained from naturally occurring sources, i.e., solanaceae steroidal sapogenins, is an important process in the preparation of ecdysteroid analogs. The need for selective green oxidation methodologies for steroidal alcohols (spirostenols, diosgenine, and derivatives) avoid the use of toxic Cr (VI) derivatives, without the isomerization of the double bond at 5,6 position and also without the oxidative cleavage of the spirocetal moiety is of great methodological significance. Herein, we report the oxidation of spirostanic steroidal alcohols to their carbonyl analogs using hypervalent iodine (III)/TEMPO-4-N-acetoxyamine system. The present method is simple, eco-sustainable, efficient, and high-yielding process for the oxidative transformation of secondary steroidal alcohols without any over-oxidation, isomerization of the double bond, or oxidative cleavage of spirocetalic fragment in different substrates. Therefore, this method does not involve toxic heavy metals and is expected to have wide utility in the oxidation process of these compounds.
... The addition, removal and modification of functional groups to, from and at these starting materials is of central importance when producing the wide variety of steroidal drugs. These modifications are achieved using conventional organic synthesis and/or microbial whole-cell biotransformations [5,6]. Cytochrome P450 enzymes (P450s, CYPs) are the key biocatalysts of steroid biotransformation and catalyze hydroxylation, epoxidation, aromatization and side chain removal [2]. ...
Two unspecific peroxygenases (UPO, EC 1.11.2.1) from the basidiomycetous fungi Marasmius rotula and Marasmius wettsteinii oxidized steroids with hydroxyacetyl and hydroxyl functionalities at C17 - such as cortisone, Reichstein's substance S and prednisone - via stepwise oxygenation and final fission of the side chain. The sequential oxidation started with the hydroxylation of the terminal carbon (C21) leading to a stable geminal alcohol (e.g. cortisone 21-gem-diol) and proceeded via a second oxygenation resulting in the corresponding α-ketocarboxylic acid (e.g. cortisone 21-oic acid). The latter decomposed under formation of adrenosterone (4-androstene-3,11,17-trione) as well as formic acid and carbonic acid (that is in equilibrium with carbon dioxide); fission products comprising two carbon atoms such as glycolic acid or glyoxylic acid were not detected. Protein models based on the crystal structure data of MroUPO (Marasmius rotula unspecific peroxygenase) revealed that the bulky cortisone molecule suitably fits into the enzyme's access channel, which enables the heme iron to come in close contact to the carbons (C21, C20) of the steroidal side chain. ICP-MS analysis of purified MroUPO confirmed the presence of magnesium supposedly stabilizing the porphyrin ring system.
... Due to interest in "green" or environmentally benign chemistry, chemists have questioned the ethics of earlier catalysts. Environmental and health concerns have motivated the search for new oxidants and catalysts [18]. From chromium based catalysts, the next phase in steroidal allylic oxidation manifested through more environmentally friendly metallic catalysts that use TBHP as an oxygen donor. ...
Introduction of α, β-unsaturated ketones to Δ5 steroidal olefins changes the characteristics and biological function of those compounds. Several synthetic methods have been reported to accomplish carbonyl introduction to Δ5 steroidal olefins. Herein, this short review will catalogue many of those oxidative methods, particularly those proceeding through a peroxide intermediate and/or use chromium complexes as reagents.
... Perhaps, the oxidation of alcohols is the most common oxidative transformation in steroid chemistry [40,41]. In fact, a large variety of relevant natural and synthetic steroids have carbonyl groups and this functionality is frequently an intermediate in the synthesis of a large variety of bioactive steroids. ...
... Thus, over the years several oxidative processes for this transformation have been developed. The most known oxidants are transition metals, particularly chromium(VI) reagents, however, several other oxygen-and halogen-based oxidants as well as other oxidizing conditions, frequently combined with suitable catalysts, have also been described [40,41]. ...
... Other described oxidative procedures that allow these transformations involves the use of oxidants such as isolated or in situ generated dioxiranes, aziridines and peroxides, frequently combined with adequate promoters. Due to their advantages, catalytic epoxidations have been object of interest in more recent years, and several procedures using more environmentally friendly oxidants such as alkyl peroxides, H 2 O 2 and even O 2 in combination with metal and non-metal catalysts have been reported [40,41]. ...
Steroid compounds are widely distributed in nature and are challenging substrates for the synthesis of a wide variety of important biologically active molecules. These include the sex hormones , corticosteroids and mineralocorticoids hormones, bile acids, vitamin D derivatives, cardiotonic steroids, among others, that have shown great therapeutic value for a broad array of medical conditions. Due to their biological and synthetic relevance, several chemical processes for the preparation and/or functionalization of the steroid nucleus have been developed. In some of those processes, green chemistry principles have been incorporated, allowing significant advances in synthetic chemistry applied to steroid compounds. In this review, a selection of the most relevant applications of pharmaceutical green chemistry in steroid synthesis, using chemical methods will be presented. Special emphasis will be given to catalytic processes, specially involving the use of heterogeneous catalysts, microwave technologies and ionic liquids as solvents. This review is organized according to the reaction type that include oxidation and reduction reactions, protection/deprotection transformations, glycosylations, rearrangements, olefin methathesis, preparations of heterocycles using different strategies and miscellaneous reactions. Biocatalytic methods applied to steroid synthesis are out of the scope of this review.
... Among these transformations, allylic oxidations are of high interest because the olefinic starting materials are readily available as cheap bulk chemicals and many interesting derivatives such as terpenes are available from renewable sources [3][4][5]. In addition, the resulting allyl alcohols [6][7][8][9][10] or α,βunsaturated carbonyl compounds are attractive synthetic targets of high economic and scientific interest [11][12][13][14][15][16][17]. Allylic oxidations of olefins to enones have classically been performed with strong oxidants such as chromium or other metal-based reagents [18,19]. ...
Allylic oxidations of olefins to enones allow the efficient synthesis of value-added products from simple olefinic precursors like terpenes or terpenoids. Biocatalytic variants have a large potential for industrial applications, particularly in the pharmaceutical and food industry. Herein we report efficient biocatalytic allylic oxidations of spirocyclic terpenoids by a lyophilisate of the edible fungus Pleurotus sapidus. This ''mushroom catalysis'' is operationally simple and allows the conversion of various unsaturated spirocyclic terpenoids. A number of new spirocyclic enones have thus been obtained with good regio- and chemoselectivity and chiral separation protocols for enantiomeric mixtures have been developed. The oxidations follow a radical mechanism and the regioselectivity of the reaction is mainly determined by bond-dissociation energies of the available allylic CH-bonds and steric accessibility of the oxidation site.
... The mechanism of chromium-catalyzed allylic oxidations with tert-butyl hydroperoxide has been discussed but is a matter of some controversy. 17 Most likely, a mechanism similar to the one depicted in Scheme 23 is operative (section 4.2). Herein, the t-BuOO· radical is responsible for the initial abstraction of an allylic hydrogen. ...
... 16,17 Table 3 gives an overview of common reagent combinations for the allylic oxidation of cholesteryl acetate (50) using tert-butyl hydroperoxide as a source of oxygen together with catalytic amounts of different chromium reagents. 17,[74][75][76][77][78] These protocols usually provide a good level of chemoand regioselectivity and give enones like 51 in moderate to good yields along with small amounts of epoxides like 52. ...
... Following these lines, PDC and PCC have also been used with great success as catalytic chromium sources (entries 7-9). 77,91,92 As alternatives to chromium(VI) oxide, tert-butyl chromate 17 and bis(tributyltin oxide)dioxochromium(VI) 78,88,[93][94][95] have also been used as catalytic chromium sources with some success (entries 10 and 11). The catalytic use of potassium dichromate for allylic oxidation is not as common as the use of chromium(VI) oxide, but for the allylic oxidation of α-isophorone (68) ...
Allylic oxidations of olefins to enones are C-H functionalizations and are valuable organic transformations that permit the synthesis of value-added products from simple precursors. A variety of stoichiometric and catalytic metal-based methods are available for these conversions. In addition, metal-free and biocatalytic protocols are gaining in importance. This review summarizes the available oxidation methods and compares their regio- and chemoselectivities. 1Introduction 2Chromium-Based Oxidation 2.1Stoichiometric Methods 2.2Catalytic Methods 2.3Chromium on Solid Support 3Regio- and Chemoselectivity of Allylic Oxidations 4Other Metal-Based Oxidations 4.1Copper Reagents 4.2Rhodium Reagents 4.3Selenium Reagents 4.4Cobalt Reagents 4.5Ruthenium Reagents 4.6Palladium Reagents 4.7Iron Reagents 4.8Other Metal Reagents 5Metal-Free and Biocatalytic Methods 5.1Metal-Free Methods 5.2Biocatalytic Methods 6Conclusion
... The allylic oxidation of 5 -steroidal substrates to the corresponding ,-unsaturated enones has been achieved by several stoichiometric methods mostly by use of chromium(VI) reagents. These include CrO 3 in acetic acid, t-butyl chromate or sodium chromate in acetic acid, CrO 3 -pyridine complex, CrO 3 and 3,5- dimethyl-pyrazole, CrO 3 and benzotriazole, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), PDC-tert-butyl hydroperoxide (TBHP), sodium dichromate in acetic acid, pyridinium fluorochromate, 3,5-dimethylpyrazolium fluorochromate(VI) and a combination of a N-hydroxydicarboxylic acid imide with a chromium containing oxidant [9] . A new chromium oxidizing reagent pyridinium-1-sulfonate fluorochromate (PSFC) has been recently reported for the allylic oxidation of cholesteryl acetate 1 and benzoate 3 (Scheme 1 andTable 1, entry 1) [10] . ...
... A system comprising CrO 3 /N-hydroxyphthalimide (NHPI) supported on activated clay has been reported to effectively oxidize several 5 -sterols to the corresponding 5 -7-ketosterols (Scheme 1 andTable 1, entry 2) [11]. Stoichiometric methods avoiding chromium reagents have also been reported and include the use of irradiated solutions in the presence of N-bromosuccinimide in moist solvents or HgBr 2 , oxygen or an oxygen containing gas in an inert solvent in the presence of a Nhydroxydicarboxylic acid imide, sodium hypochlorite in combination with aqueous TBHP, and a combination of periodic acid or metal periodate and an alkyl hydroperoxide under normal as well as elevated pressure of a suitable gas such as air [9] . Among the metalfree based processes, the combination of sodium chlorite and TBHP in stoichiometric amounts has been reported to efficiently convert 5 -steroids to the corresponding 7-ketone derivatives (Scheme 1 andTable 1, entry 3) [12] . ...
... Efforts to eliminate the use of ecologically and physiologically undesirable chromium reagents as well as the common drawbacks associated with stoichiometric procedures, especially if used on a commercial scale, have been made through the development of catalytic methods to efficiently perform this transformation. Hydroperoxides such as TBHP combined with different types of metal catalysts under homogeneous conditions have been extensively used to perform allylic oxidations on steroid substrates [9] . Previously used catalysts include chromium (VI) compounds such as CrO 3 , bis-(tributyltin oxide) dioxochromium(VI), tertbutylchromate , CrO 3 in the presence of an amine and PCC (Scheme 1 andTable 1 , entries 5 and 6). ...
Oxygenated steroids are bioactive compounds and valuable intermediates in the synthesis of biologically active products and APIs. This review will cover the literature from 2005/06 to the present concerning allylic oxidation, epoxidation and syn-dihydroxylation of alkenes, alcohol oxidation, and remote functionalization reactions of steroidal substrates.
... D 5 -7-keto-steroids are important naturally occurring molecules that are useful in the treatment of diseases such as cancer, Alzheimer's disease, and immune and metabolic disorders, and as synthetic intermediates in the preparation of other biologically active agents [39,[78][79][80]. The most common way to prepare D 5 -7-keto-steroids is by the allylic oxidation of the corresponding D 5 -steroids, which can be efficiently performed using the combination of t-BuOOH with several homogenous or heterogeneous bismuth catalysts. ...
In recent years, the chemical potential of bismuth and bismuth compounds has been actively exploited. Bismuth salts are known for their low toxicity, making them potential valuable reagents for large-scale synthesis, which becomes more obvious when dealing with products such as active pharmaceutical ingredients or synthetic intermediates. Conversely, bismuth compounds have been widely used in medicine. After extensive use in the treatments of syphilis and other bacterial infections before the advent of modern antibiotics, bismuth compounds remain important for the treatment of several gastrointestinal disorders and also exhibit antimicrobial properties and cytotoxic activity, among others. This review updates relevant advances in the past few years, concerning the application of bismuth reagents and catalysts in innovative synthetic processes for the preparation of compounds of medicinal interest, as well as the preparation, biological evaluation and potential medicinal uses of bismuth compounds.
... The allylic oxidation of Δ 5 -steroids [42,43] using several homogeneous or heterogeneous bismuth catalysts in combination with t-BuOOH has been recently reported [44,45]. BiCl 3 was found to be the best catalyst and several Δ 5 -steroids were converted into the corresponding Δ 5 -7-oxosteroids in good to high yields (Scheme 5). ...
Steroid and terpene chemistry still have a great impact on medicinal chemistry. Therefore, the development of new reactions or "greener" processes in this field is a contemporaneous issue. In this review, the use of bismuth(III) salts, as "ecofriendly" reagents/catalysts, on new chemical processes involving steroids and terpenes as substrates will be focused. Special attention will be given to some mechanistic considerations concerning selected reactions.
