Introduction

Steroids, as an entrenched class of natural organic compounds, constitute the largest group of pharmaceuticals next to antibiotics. Steroids are employed as drugs for prevention and therapy for disorders like anti-inflammatory, diuretic, anabolic, contraceptive, antiandrogenic, progestational as well as anticancer agents for breast cancer and prostate cancer, and colon cancer (Morzycki 2011; Patel and Savjani 2015; Banday et al. 2010). Safety, less vulnerability to multidrug resistance (MDR) and extreme bioavailability are the important characteristics of steroid-based compounds. Steroids have future in pharmaceutical industry due to their growing significance to deal with a range of medical challenges based on their biological and pharmacological properties.

New synthesis methods are also needed in geochemical and petroleum research to identify fossil steroids as maturity parameters because actual methods involve multiple steps and toxic solvents (Bryselbout et al. 1998; Lichtfouse et al. 1990, 1994, 1998; Lichtfouse and Albrecht 1994). Many methods are available for the synthesis of steroids lack environmental, health concerns and resource conservation (Larsson 2014). Green chemistry has opened up innovative frontiers and prompted rapid improvements using more environment-friendly approaches as alternative sustainable routes for the development and synthetic transformations of steroids (Salvador et al. 2015; Huang et al. 2017; Kaplan et al. 2016; Cichowicz et al. 2015; Peterson 1985; Zlotos 2005; Misra et al. 2015; Wolfling 2007; Gupta and Mahajan 2015; Fenyvesi et al. 2018; Gude and Martinez-Guerra 2018; Dsikowitzky et al. 2017). Some of the imperative C19 and C21 steroid (Mesquita 2012) hormones and their selected analogues are shown in Figs. 1, 2 and 3.

Fig. 1
figure 1

Gonane: the simplest steroid

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Fig. 2
figure 2

Representative steroidal structures of testosterone and oestradiol

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Fig. 3
figure 3

Structure of important C19 and C21 steroid hormones and their selected analogues

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Cholesterol (Fig. 4), an abundant steroid, contains 27 carbons, one hydroxyl group at C3, methyl groups at C13 and C10 designated as 18CH3 and 19CH3 correspondingly and one branch of eight aliphatic hydrocarbons on carbon C17.

Fig. 4
figure 4

Steroidal structures of cholesterol

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Like most of the naturally occurring steroids, cholesterol has B/C and C/D diequatorial trans-fused (Mesquita 2012) rings with configuration at bridgehead position C8, C9, C13 and C14 as shown in Fig. 5: 8β–H, 9α–H, 13β–CH3 and 14α–H. Two possible ring fusions are observed between rings A and B as configuration at C5 varies from one steroid to another. Some steroids are designated as 5α-steroids with A/B diequatorial (5α, 10β) trans-fused rings which explain 5α-configuration of the substituent at C5 position. In contrast, β-configuration of the C5 substituent is characterized by A/B axial–equatorial (5β, 10β) cis-fused rings.

Fig. 5
figure 5

Steroidal structures. a A/B diequatorial trans-fused rings. b A/B axial-equatorial cis-fused rings

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Several oxidative chemical methods (Shan et al. 2009; Ouyang et al. 2014) have been established to provide significant intermediates for the synthesis of various biologically active steroid molecules. In numerous cases, heavy metals, fumed metal oxides, fumed silica are used to catalyze oxidative steps in steroids synthesis. Incorporation of green chemistry principles into some oxidative transformations allows paramount advances in synthetic chemistry when applied to steroidal compounds.

Heterogeneous catalysts

Heterogeneous catalysis plays a foremost part in the production of more than 80% of all chemical products and made a representative contribution to the decrement of environmental pollutants in the contemporary years (Mesquita 2012; Ouyang et al. 2014; Tong and Dong 2009).

Ritter reaction with Starbon®400-SO3H catalyst

In steroid chemistry, Starbon®400-SO3H is used to catalyze acidic reactions like esterification of organic acids in aqueous medium, acylation of alcohols, amines and alkylations of aromatics (Budarin et al. 2007; Xing et al. 2007). It is a sulfonated mesoporous carbonaceous material prepared from mesoporous expanded starch as a precursor. In this ambience, using Starbon®400–SO3H catalyst in Ritter reaction of 5β, 6β-epoxy-17-oxoandrostan-3β-yl acetate with nitriles sustained vic-N-acylamino-hydroxy products for the development of new chemical processes. Stereoselective trans-dial nucleophilic advance at C5 by the α-face in case of 5β, 6β-epoxy-17-oxoandrostan-3β-yl acetate and other 5β, 6β-epoxy steroids (5β, 6β-epoxy-20-oxopregnan-3β-yl acetate) and 5β, 6β-epoxycholestan-3β-yl acetate is attained for the corresponding acylamino-hydroxy products in a remarkable yield (Scheme 1).

Scheme 1
scheme 1

Ritter reaction conditions with Starbon®400-SO3H catalyst

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The trans-diaxial ring opening of 5α,6α-epoxycholestan-3β-yl acetate with nucleophilic attack at C6 and C5 positions (Scheme 2) through β- and α-face afforded a mixture of stereoisomers, the 6β-acetamido-5α-hydroxycholestan-3β-yl acetate 8 and stereoisomer 6.

Scheme 2
scheme 2

Ritter reaction catalyzed by Starbon®400-SO3H for 5α,6β-epoxycholestan-3β-yl acetate

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Allylic oxidation with heterogeneous catalyst

Conventionally, allylic oxidation of Δ5-steroids has been achieved with various obnoxious and environmentally unsafe complexes (Scheme 3) like CrO3-pyridine, chromium trioxide, pyridinium dichromate (PDC), pyridinium chlorochromate (PCC), sodium chromate and sodium dichromate (Wendell and Edward 2016; Salvador et al. 2006, 2012; Bulman Page and McCarthy 1991; Salvador and Silvestre 2005; Salvador et al. 2011).

Scheme 3
scheme 3

Allylic oxidation of ∆5-steroids to ∆5-7-oxosteroids

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In recent times, several heterogeneous catalysts such as KMnO4/SiO2 in benzene or chromium (VI) adsorbed on SiO2/ZrO2, cobalt (II), copper(II), manganese(II) and vanadium(II) immobilized on silica and BiCl3/montmorillonite K-10 in combination with tert-butyl hydroperoxide as an oxidant have been used for allylic oxidation of Δ5-steroids. As environmentally safe advances, the oxidation of steroidal olefins compounds to α,β-enones has also been conceded with household bleach and aqueous tert-butyl hydroperoxide at ambient temperature. Dirhodium caprolactamate ([Rh2(cap)4]) catalyst in the presence of 70% tert-butyl hydroperoxide in water has been reported recently for the preparation of several steroids (Scheme 4) like Δ4-3,6-ketones (Doyle et al. 2012).

Scheme 4
scheme 4

Allylic oxidation of ∆5-3-ketone-steroids to corresponding ∆4-3,6-diketone-steroids

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Allylic oxidation with dirhodium (II, II) caprolactamate

Recently, Doyle et al. (2012) profoundly depicted the methods for achieving the efficient allylic oxidation of 7-keto steroidal molecules applying dirhodium (II, II) paddlewheel complexes and in particular dirhodium carboximate (Fig. 6) and t-BuOOH as catalysts under aqueous conditions in comparison to anhydrous methods.

Fig. 6
figure 6

Structure of dirhodium (II, II) caprolactamate

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Oxidation of alkenes at allylic position to unsaturated carbonyl compounds is achieved by hydrogen abstraction by t-butylperoxy radicals produced from dirhodium (II) complexes. The proposed reaction mechanism for Rh2(cap)4-mediated allylic oxidation is described in (Fig. 7) taking cyclohexene as the substrate. The oxidation reactions of steroids (testosterone, 4-androstene-3,17-dione, 4-cholesten-3-one) performed by 70% aqueous solution of tert-butyl hydroperoxide (T-HYDRO®) catalyzed by Rh2(cap)4 are shown in Scheme 5.

Fig. 7
figure 7

Preferred reaction mechanism for Rh2(cap)4-mediated allylic oxidation

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Scheme 5
scheme 5

Allylic oxidation of ∆4-3-ketone-steroids to corresponding ∆4-3,6-diketone-steroids with dirhodium (II, II) caprolactamate

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Allylic oxidation with bismuth (III) and cobalt (II) salts

Latterly, environment-friendly catalysts such as bismuth (III) and cobalt (II) salts played a key role in the allylic oxidations of steroids at the 7-position in organic synthesis of pharmaceutical interest. Allylic oxidation of a variety of Δ5-steroids using bismuth (III) salts-based several heterogeneous bismuth catalysts in combination with t-BuOOH has been reported by Salvador et al. (2006, 2012), Bulman Page and McCarthy (1991) and Salvador and Silvestre (2005). BiCl3/t-BuOOH catalyst system is used for allylic oxidation of Δ5-steroids to produce corresponding Δ5-7-oxosteroids (Salvador et al. 2011; Parish et al. 2004) and proved to be very (Scheme 6) selective as momentous epoxidation of the double bond and secondary hydroxyl group oxidation can be avoided. Further BiCl3/t-BuOOH system used in the allylic alcohol oxidation (Scheme 7) of androst-4-ene-3β,17β-diol provided an important hormone testosterone in 45% yield.

Scheme 6
scheme 6

Bismuth (III) salt-catalyzed allylic oxidation of ∆5-steroids

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Scheme 7
scheme 7

Selective allylic alcohol oxidation of steroids by BiCl3/t-BuOOH

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Allylic oxidation of steroids at 7-position with heterogeneous Co(II) catalysts 1, 2, 3 has also been reported as a sustainable method (Fig. 8) (Salvador and Clark 2001).

Fig. 8
figure 8

Structure of silica-supported Co(ll) heterogeneous catalysts

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It is pertinent to mention that thermal and chemical stability of employed supports all through the reaction process and batch reactions during the separation phase, accessibility and good dispersions of the active sites in an organic reaction arbitrates the performance of the supported catalyst. Frequently used inorganic supports are zeolites, silica, polymers, hydroxyapatite, zirconia, carbons, and all these supports have high surface areas (100–1000 m2/g) with average pore diameters ranging from the micro-zeolites to some micro-porous silica (Gupta and Paul 2014). Δ5-steroids can be selectively oxidized at the allylic position to 5-en-7-ones in high yield using silica-supported cobalt acetate along with t-butyl hydroperoxide as an oxidant. Under similar reaction conditions, catalysts 2 and 3 can be recycled with small decline in the product yield (80% for recycled catalyst 2 and 81% for recycled catalyst 3) (Salvador and Clark 2001). The catalytic method is also effective in the presence of an oxidative vulnerable secondary alcohol group (Scheme 8), as well as when applied to unsaturated Δ4-steroids, the steroid 33 is oxidized to the alcohol product 34 with impressive selectivity (71%) and 36 gives the testosterone acetate 37 in 70% yield.

Scheme 8
scheme 8

Allylic oxidation of ∆5-steroids to corresponding ∆5-7 ketone-steroids with silica-supported Co(II) heterogeneous catalyst

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Bismuth reagents

Over the last decade, bismuth (III) salts (Salvador and Silvestre 2005, 2006) for the design of eco-catalysts and a large number of methods involving the use of Bi(III) compounds in organic synthesis of pharmaceutical interest have been reported (Salvador and Silvestre 2006). Bi2O3/CH3COOH along with in situ preparation of efficient and selective oxidant Bi(OAc)3 causes selective oxidation of α-hydroxy ketone to corresponding diketo due to its chemical selectivity in various steroids. Further dehydrohalogenated 20, 21-diketo product 41 was accomplished from oxidation of 20,21-ketol group of a 21-chloromethyl-pregnane (Angello et al. 1963) derivative (Scheme 9) in Bi2O3/CH3COOH mixture. Bi2O3/CH3COOH system has also been used for the oxidation of the 11-keto-12β hydroxyl moiety (Scheme 10) of a hecogenin derivative (Djerassi et al. 1954) for the preparation of an intermediate in the synthesis of cortisone.

Scheme 9
scheme 9

Bi2O3/AcOH oxidation of the 20, 21 ketol group of a 21-chloromethyl-pregnane derivative

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Scheme 10
scheme 10

Bi2O2/AcOH oxidation of the 11-keto-12β-hydroxy moiety of a hecogenin derivative

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Acylation of cholesterol with bismuth (III) salts

Recently, several bismuth (III) salt catalysts have been reported for acylation (Orita et al. 2000, 2001; Stephens et al. 2003), and Bi(OTf)3·xH2O in the presence of acetic anhydride (Scheme 11) is used for the acetylation of cholesterol. Regardless of sterically hindered 12α-hydroxy group, all the three hydroxyl groups of cholic acid methyl ester are remarkably converted to the analogous acetoxy groups in outstanding yield.

Scheme 11
scheme 11

Acetylation and pivaloylation of cholesterol with bismuth (III) salts

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Tetrahydropyranylation of cholesterol with bismuth (III) salts

Tetrahydropyranylation of the secondary hydroxyl groups in cholesterol derivatives (Stephens et al. 2003; Khan et al. 2005) has been achieved with 3,4-dihydro-2H-pyran in the presence of Bi(OTf)3·xH2O (Scheme 12).

Scheme 12
scheme 12

Bismuth(lll) salt-catalyzed tetrahydropyranylation of cholesterol

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Microwave-assisted steroid synthesis

The short reaction times and expanded reaction range offered by microwave-assisted organic synthesis are appropriate to the increased demands in chemical industry.

Microwave-promoted one-pot synthesis of novel A-ring-fused steroidal dehydropiperazines

Microwave irradiation-based preparation of ring-A-fused 3,4-position steroidal dehydropiperazine is recently reported by Borthakur et al. (2008). In one-pot reaction, annulations are commenced from easily available 3-keto-4-en steroids (testosterone acetate, 4-androsten-3,17-dione, progesterone, 24-ethyl 4, 22-cholestadiene-one) with ethylenediamine in environmentally innocuous manner. Base-catalyzed aerial oxidation of the C6 methylene group is key stage pursued by cyclocondensation of ethylenediamine via Michael addition reaction to afford dehydropiperazine adducts 49a–f (Scheme 13). In the proposed mechanism for the formation of dehydropiperazine derivatives (Scheme 14) under basic conditions, enolate intermediate facilitates aerial oxidation of C6 allylic protons to afford diketo intermediate followed by cyclocondensation of ethylenediamine with diketo intermediate pursued with Michael addition and autooxidation.

Scheme 13
scheme 13

Synthesis of steroidal dehydropiperazines from corresponding 3-keto-4-en steroids

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Scheme 14
scheme 14

Proposed mechanism for the formation of dehydropiperzine derivative

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Microwave-promoted deprotection of 3-one-oximes to 3-keto steroids

A catalytic procedure using 10% BiCl3 under microwave irradiation for deprotection of 5α-cholestan-3-one-oxime for the generation of the corresponding 3-keto-steroid, e.g., 5α-cholestan-3-one in 80% yield has been reported (Boruah et al. 1997) (Scheme 15).

Scheme 15
scheme 15

Microwave-promoted deprotection of 3-one-oximes to 3-keto steroids

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Similarly, microwave-based green chemistry has been used for a variety of condensations such as deprotection, esterification and silylation reactions in steroids (Lidstrom et al. 2001), Wittig olefination of 3-ketosteroids, (Spinella et al. 1997) basic amide hydrolysis (Dayal and Ertel 1998) using alkali, silylation reaction (Lidstrom et al. 2001) of secondary alcohol using tert-butyldimethylsilyl chloride (TBDMS) and esterification (Lami et al. 1999) of acids using methanesulfonic acid (Scheme 16).

Scheme 16
scheme 16

Microwave-promoted Wittig olefination, esterification, amide hydrolysis, silylation in steroids

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Microwave-promoted preparation of steroidal chalcones

In 2012, Kakati et al. (2013), Silvestre et al. (2016), Bianchi and Baulieu (2012) and Ornelas et al. (2005) reported a solvent-free coupling of pregnenolone acetate with different aldehydes to build up a library of novel pregnenolone steroidal hybrids possessing potential antimicrobial activities against pathogens (Scheme 17). Claisen–Schmidt condensation of pregnenolone acetate with variously substituted benzaldehydes has been carried out in the presence of I2–Al2O3 as catalyst under microwave reaction conditions.

Scheme 17
scheme 17

Microwave-promoted synthesis of chalconoyl pregnenolones

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Microwave-promoted preparation of steroidal ring-D-fused–quinoline hybrid

Efficient synthesis of novel steroidal D- and A-ring-fused–quinoline hybrids in the estrone and 5α-androstane series has been reported by Frank et al. by the reaction of β-chlorovinyl aldehydes with different aryl amines in polar aprotic solvent under microwave conditions (Scheme 18) (Baji et al. 2016). The electronic and steric characters of the substituents on the anilines and different reactivities of rings D and A sterane skeleton control the rates and yields of the desired products in one-pot catalyst-free syntheses. For the preparation of D-fused quinoline derivatives, simultaneous addition of POCl3 and DMF to an ice-cold solution of estrone 3-methyl ether in chloroform followed with subsequent reflux afforded a β-chlorovinyl aldehyde with the Vilsmeier–Haack reagent, together a 17-chloro-derivative as by product. The microwave-assisted solvent-free reaction of β-chlorovinyl aldehyde (LaFrate et al. 2008) with aniline containing electron-donating groups (EDG) in the para-position on the aromatic moiety furnished the corresponding products in reasonable yields which may be attributed to the higher rigidity and sterically more hindered character of the five-membered ring D, primarily due to the presence of angular methyl group on C13.

Scheme 18
scheme 18

Microwave-promoted synthesis of steroidal ring-D-fused–quinoline hybrid

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Microwave-promoted preparation of steroidal ring-A-fused–quinoline hybrid

For similar reactions on ring A of sterane skeleton, 17β-acetoxy-5α dihydrotestosterone was reacted with Vilsmeier–Haack reagent via Method A to afford bis-formylated as the main product with minor desired β-chlorovinyl aldehyde. The desired β-chlorovinyl aldehyde was obtained by means of Method B in 78% yield by performing the reaction with Vilsmeier–Haack reagent at 25 °C for 2 h. Distinctly substituted anilines with electron-donating groups (EDGs) readily underwent cyclization with β-chlorovinyl aldehyde in dimethylformamide (DMF) to furnish ring-A-fused quinolines (Gogoi et al. 2012) in excellent yields (Scheme 19) when the reaction was carried out under microwave irradiation.

Scheme 19
scheme 19

Microwave-promoted synthesis of steroidal ring-A-fused–quinoline hybrid

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Microwave-assisted Baeyer–Villiger oxidation of steroidal ketones

Baeyer–Villiger oxidation of several steroids in the presence of catalyst Ca[B(C6F5)4]2 and hydrogen peroxide under microwave irradiation turned out the corresponding esters/lactones as reported by Borah and Chowdhury (2011). Baeyer–Villiger oxidation of 17-oxo-5α-androstan-3β-yl acetate by meta-chloroperoxybenzoic acid (MCPBA) under microwave irradiation is shown in Scheme 20.

Scheme 20
scheme 20

Baeyer–Villiger oxidation of steroidal ketone to steroidal lactones

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Microwave-assisted synthesis of steroidal oxime ethers

Incorporation of one or more hetero-atoms in the steroid moiety to produce novel steroidal derivatives with diverse applications has also been achieved using microwave irradiation. In this context, Alam and Lee (2015) reported the synthesis of biologically active steroidal oxime ether 7-(2′-aminoethoxyimino)-cholest-5-ene and its derivatives via facile microwave-assisted green solvent-free reaction technology. The new convenient sustainable, reproducible protocol with short reaction time resulted in a remarkable improvement in the synthetic efficiency (85–93%) and high purity using basic alumina as a solid support (Scheme 21).

Scheme 21
scheme 21

Microwave-based synthesis of steroidal oxime ethers

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Biotransformations

A large number of steroids have been synthesized by exploiting microorganisms for biotransformations. Enzymes catalyzed reactions in microbial transformations include chemical reactions like oxidation, reduction, hydrolysis and degradation, formation of C–C or C-hetero-bonds. Several advantages in selecting microbial reactions as alternative to conventional synthesis are (a) to functionalize specific positions in the molecule which are not normally possible by chemical methods and (b) stereospecific or regiospecific introduction of oxygen functionality or other substituent.

Microbial hydroxylation by Aspergillus and Rhizopus species

For the first time, Hosseinabadi et al. (2015) reported that various sites of steroid precursors can be hydroxylated with different Asperigillus species, which is difficult to attain by chemical methods for the production of valuable steroids with diverse pharmacological properties, e.g., three valuable hydroxylated metabolites: 11α-hydroxyprogesterone, 14α-hydroxyprogesterone and 21-hydroxyprogesterone can be obtained after bioconversion of progesterone (a C21 steroid hormone) by filamentous fungi Aspergillus brasiliensis (Fig. 9). Moreover, hydroxylation at specific positions in steroids increases the biological activity, e.g., products of 11α-hydroxylation and 14α-hydroxylation in the corticosteroid synthesis possess anticancer properties (Fernandes et al. 2003; Zohri and Galil Abdel 1999).

Fig. 9
figure 9

Structure of progesterone and its metabolite

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Further, a 31-step chemical synthesis of cortisone (Scheme 22) from bile acid has been achieved with regiospecific and enantiospecific microbial hydroxylation (Peterson 1985).

Scheme 22
scheme 22

Cortisone synthesis

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β-oxidation cycle reactions

Accessibility of raw materials is one of the fundamental challenges associated for the production of steroidal drugs so majority of steroid-based drugs are synthesized by semi-synthetic routes (Dewick 2009). Biological transformations of natural substrates via β-oxidation reactions (Swizdor et al. 2012) are the focus of synthetic routes for biologically active compounds. The pharmaceutical industry is involved significantly in the selective degradation of sterol side chain (Fig. 10) because this results in the formation of steroid intermediates of therapeutic application which can be used as building blocks for the advance synthesis of bioactive steroids.

Fig. 10
figure 10

Structures of (phyto)sterols with a saturated side chain

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Microbiological degradation of side chain of sterols

In majority of steroids, double bond at C5 and a hydroxyl group at 3β-position can be easily converted to a 4-en-3-oxo moiety. Selective degradation of the 17β aliphatic (Smith 1984; Dunn et al. 2010) side chain of many sterols which is not possible effectively by chemical means can be carried out with microbial transformation due to selectivity of enzymes. Several strains of gram-positive (Pseudomonas, Rhodococcus, Mycobacterium, Streptomyces, Brevibacterium) and gram-negative (Pseudomonas, Comamonas, Bukholderia, Chromobacterium) bacteria can utilize sterols as the sole carbon source and produce carbon dioxide and water as the final product of microbial degradation of sterols (Scheme 23). The other identified metabolites are synthetically useful C19 steroids: androsta-4-en-3,17-dione (AD), androsta-1,4-dien-3,17-dione (ADD), 9α-hydroxy-androsta-1,4-dien-3,17-dione(9α-hydroxy-ADD) and other C22 products: 20-carboxy-pregna-4-en-3-one, 20-carboxy-pregna-4,17(20)-dien-3-one. AD is obtained as the outcome of oxidative degradation of the side chain of cholesterol after subsequent cleavage of propionyl-CoA, acetyl CoA and propionyl -CoA, respectively.

Scheme 23
scheme 23

Microbial catabolic pathway of cholesterol (valuable steroid drug intermediates)

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Biotransformation of resibufogenin and cinobufagin by Pseudomonas aeruginosa

Pseudomonas aeruginosa as 1.860 present versatile means of biotransformation for structural modification of resibufogenin and cinobufagin to four (Hegazy et al. 2015; Zhan et al. 2003) dehydrogenated products, 3-keto-resibufogenin 87, 3-keto-cinobufagin 85, 3-keto deacetylcinobufagin 90 and deacetyl cinobufagin 88 shown in Scheme 24.

Scheme 24
scheme 24

Biotransformation pathways of resibufogenin and cinobufagin by Pseudomonas aeruginosa

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Conclusion

Steroid chemistry has been the focus of research for over one hundred years. With every passing day, there are reports of the isolation, characterization and synthesis of new compounds of new biological evaluations. The attention given to steroid molecules is justified by their biological properties that make them useful in medicinal chemistry. Although there are abundant conventional chemical reactions known with wide applicability in steroid chemistry, these reactions often suffer from disadvantages such as handling toxic, sensitive and expensive reagents, difficult workups, low yields, weak selectivity and lack of catalytic methods. For these reasons, the development of new chemical processes in steroid chemistry that use environmental-friendly, cheap and easily available reactants as well as mild reaction conditions would be of great interest. Green chemistry addresses such challenges by providing novel environmentally and ecologically benign reactions that can maximize the production of the desired products and minimize side reactions. The incorporation of the discussed procedures in the design of large-scale synthetic approaches for the preparation of selected steroids in a near future is very well expected.