Catalytic Oxidative Processes in Steroid Chemistry ...

Current Organic Chemistry, 2006, 10, 2227-2257

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Catalytic Oxidative Processes in Steroid Chemistry: Allylic Oxidation, Selective Epoxidation, Alcohol Oxidation and Remote Functionalization Reactions Jorge A.R. Salvador*, Samuel M. Silvestre and Vânia M. Moreira Laboratório de Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Rua do Norte, 3000-295 Coimbra, Portugal Abstract: 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, -selective epoxidation, alcohol oxidation and remote functionalization reactions in steroid substrates are reviewed. Focus has been given to catalytic processes because of their major importance from the viewpoint of synthetic organic chemistry.

1. INTRODUCTION Steroid compounds are widely distributed in nature. The living organism, both animal and vegetable, contains steroids which play an important role in its vital activity. Over the last decades, hundreds of steroid compounds have been isolated from natural sources and many thousands of them have been obtained synthetically. Moreover, steroids are challenging substrates for the synthesis of a wide variety of important biologically active molecules. The preparation of steroids containing oxygenated functions in the steroid nucleus is of major importance and can be performed by means of several oxidative processes. Among the available methods, allylic oxidation, -selective epoxidation, alcohol oxidation and remote functionalization reactions were chosen to discuss in this review. Special emphasis has been given to the allylic oxidation of steroidal alkenes to the corresponding enones. The 5-7-keto derivatives are of great importance due to their relevant biological properties. -Selective epoxidation has been considered because the -epoxides are normally difficult to obtain in organic synthesis. Moreover, this functionality has been found in a number of biologically active steroids, particularly the 5,6-epoxides. The oxidation of steroidal saturated, allylic and homoallylic alcohols is also reviewed. Of particular relevance is the synthesis of 4-3-ketones, a typical functionality of the major class of steroidal hormones. Finally, remote functionalization in steroid substrates has been considered. Its practical goal lies in the possibility of obtaining bioactive compounds from readily available sterols or bile acid sources, through regio- and stereoselective remote oxyfunctionalization of unactivated carbons, avoiding multistep syntheses. Environmentally benign and sustainable transformations are now considered to be basic goals and requirements in the development of modern organic synthesis. There has been a growing effort in the replacement of stoichiometric procedures, using classical toxic waste-producing oxidants, with

*Address correspondence to this author at the Laboratório de Química Farmacêutica, Faculdade de Farmácia, Universidade de Coimbra, Rua do Norte, 3000-295 Coimbra, Portugal; Tel: +351 239859950; Fax: +351 239827126. E-mail: [email protected] 1385-2728/06 $50.00+.00

catalytic procedures using environmentally friendly oxidants. These include molecular oxygen, hydrogen peroxide, alkyl hydroperoxides, nitrous oxide and several other systems where there is either no by-product, the by-product is environmentally benign or it can easily be recovered and recycled. For synthetic utility, where high conversion and selectivity are desirable, these oxidants require activation by appropriate, usually metal-based catalysts. Furthermore, it is preferable to carry out these reactions in aqueous media or organic solvents with low environmental load. The recycling of both catalysts and solvents is also highly desirable [1]. For these reasons, in this review focus has been given to catalytic oxidative processes. Each section contains brief mention of the biological relevance of some of the compounds that can be prepared using the reactions chosen and a basic description of the stoichiometric processes involved. The biocatalytic oxidative processes available to perform these reactions have not been included in this review. 2. ALLYLIC OXIDATION Allylic oxidation is a particularly important subject and has attracted interest over many years. This consists of the production of allylic alcohols, esters, ethers and ,unsaturated carbonyl compounds [2]. In this review, focus has been exclusively given to the allylic oxidation of steroidal alkenes to the corresponding enones, mainly because this functionality is present in a large number of biologically active steroids. An example of the former is the oxidation of 5-steroids to their corresponding 5-7-ketones (scheme 1) [3]. These compounds can be found in animal tissues, food products [4] and certain folk medicines [5], and some are known inhibitors of sterol biosynthesis [3a; 4b; 6]. Their greater toxicity towards cancerous than non-cancerous cells [5b] as well as their ability to inhibit cell replication [7] are probably the dominant reasons they are considered potent agents for cancer treatment. 7-Keto-dehydroepiandrosterone (7-keto-DHEA) 8 and some of its derivatives are effective in inducing thermogenic enzymes [8]. Enhancement of memory in old mice by 7keto-DHEA acetate 6 has been reported [9]. This compound is currently available as a nutraceutical [10] and is suggested to be useful in the prevention of primary Raynaud's attacks © 2006 Bentham Science Publishers Ltd.

2228 Current Organic Chemistry, 2006, Vol. 10, No. 17

Salvador et al.

R2

R2

R3

R3

R1

1.....R1=OAc;R2=C8H17;R3=H.....2 3....R1=OAc;R2=COCH3;R3=H....4 5...........R1=OAc;R2,R3=O............6 7............R1=OH;R2,R3=O.............8

R1

O

Scheme 1.

OSO3H

O 3ClH3N

N H2

N H2

OH 9 (Squalamine)

Scheme 2.

[11]. Furthermore, Alzheimer's disease and immune deficient disorders may be effectively treated with these types of compounds [12]. Recently, it has been demonstrated that the 7-keto hybrid steroidal esters of nitrogen mustards have cytogenetic and antineoplasic effects [13]. The existence of the allylic 7-keto group in the skeleton of the 5-steroidal esters leads to an impressive enhancement of their antileukemic activity while the toxicity remains at clinically acceptable levels [14]. These allylic steroidal ketones can be used as intermediates for the preparation of other steroidal derivatives with varying biological activities and, more important, new drug-hormone conjugates such as squalamine 9 (scheme 2) and its derivatives, a new class of naturally occurring antibiotics [3a; 15]. A large number of reagents and methods have been reported for the allylic oxidation of 5-steroidal substrates to the corresponding ,-unsaturated enones (scheme 1). A variety of chromium(VI) reagents have been used in stoichiometric amounts. These include CrO3 in acetic acid [16], t-butyl chromate [17] or sodium chromate in acetic acid [17b], CrO3-pyridine complex [18], CrO3 and 3,5-dimethylpyrazole [19], CrO3 and benzotriazole [20], pyridinium chlorochromate (PCC) [21], pyridinium dichromate (PDC) [21b], PDC-tert-butyl hydroperoxide (TBHP) [22], sodium

dichromate in acetic acid [23], pyridinium fluorochromate [24], 3,5-dimethylpyrazolium fluorochromate(VI) [25] and a combination of a N-hydroxydicarboxylic acid imide with a chromium containing oxidant [26]. However, the large quantities of ecologically and physiologically undesirable chromium reagents involved and the large volume of solvent required in these procedures, in combination with the difficult work-up makes such procedures inconvenient on a commercial scale. Furthermore, problems sometimes occur which limit the application of these procedures such as the acidity of the reagents, their limited solubility in organic solvents, the need for their preparation before each reaction or long reaction times. Other stoichiometric processes have also been reported. These include the use of irradiated solutions in the presence of N-bromosuccinimide in moist solvents [27] or HgBr2 [28], oxygen or an oxygen containing gas in an inert solvent in the presence of a N-hydroxydicarboxylic acid imide [29], 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 [30] and sodium hypochlorite (household laundry bleach) in combination with aqueous TBHP (70% or less) [31]. Steroidal 4-3,6-diketones have been obtained from the corresponding 4-3-ketones (scheme 3) using aqueous R1

R1

O

Scheme 3.

10.......R1=C8H17....11 12.....R1=COCH3....13

O O

Catalytic Oxidative Processes in Steroid Chemistry

Current Organic Chemistry, 2006, Vol. 10, No. 17 2229

Table 1. Catalytic allylic oxidation of 5-steroids by TBHP under homogeneous conditions Substrate

Catalyst

Conditions

Product/Isolated yield

5

CrO3 (0.05 equivs.)

TBHP (7 equivs.), CH2Cl2, r.t., 24 h, 100% conversion

6 / 52%

5

(n-Bu3SnO)2CrO 2 (0.07 equivs.)

TBHP (6 equivs.), CH2Cl2, 40ºC, Ar, 20 h, 92% conversion

6 / 62%

1

C5H5NHCrIVO2 F (0.05 equivs.)

TBHP (7 equivs.), CH2Cl2, r.t., 4 h, 74% conversion

2 / 25%

1

Cr(CO)6 (0.5 equivs.)

TBHP (3 equivs.), CH3CN, reflux, N2 , 15 h

2 / 80%

1

RuCl3.nH2O (0.007 equivs.)

TBHP (10 equivs.), cyclohexane, 15-20ºC, 24 h

2 / 75%

5

Cu (0.03 equivs.)

TBHP (6-7 equivs.), CH3CN, 50ºC, N 2, 16 h

6 / 84%

5

CuI (0.68 equivs.)

TBHP (30 equivs.), CH2Cl2, reflux, PTC, 4 h

6 / 89%

5

Co(OAc)2.4H2O (0.012 equivs.)

TBHP (6 equivs.), CH3CN, 50ºC, N 2, 20 h

6 / 84%

1

Fe(acac)3 (0.1 equivs.)

TBHP (7.7 equivs.), PhH, reflux, Ar, 24 h

2 / 74%

5

BiCl3 (0.1 equivs.)

TBHP (10 equivs.), CH3CN, 70ºC, 20 h

6 / 88%

sodium peroxide [32], oxidizers with reversible redox potentials, mostly tetrazolium salts [33] and sodium hypochlorite (household laundry bleach) in combination with aqueous TBHP (70% or less) [31] in stoichiometric amounts. 2.1. Catalytic Allylic Oxidation of 5-Steroids 2.1.1. Mediated by t-Butyl Hydroperoxide Of particular preparative interest is the use of hydroperoxides such as TBHP combined with different types of metal catalysts to perform allylic oxidations (Table 1 and Table 2). Muzart et al. reported the first application of CrO3 as catalyst to synthesize 5-7-ketones (scheme 1) in yields ranging from 32% to 61%. Epoxidation of the double bond occurred as a minor reaction pathway [34]. Similar results were reported using either bis-(tributyltin oxide) dioxochromium(VI) or Cr(IV) complexes as catalysts [35]. High-yield conversions of 5-steroids into the corresponding 5-7-ketones were reported using hexacarbonyl chromium [36] or ruthenium trichloride [37] as catalysts. These methods can be successfully applied to substrates carrying a free secondary hydroxyl group. Despite the good yields obtained, the toxicity of the chromium compounds and the high cost of the ruthenium catalysts has motivated the search for more environmentally friendly methods based on the use of copper catalysts such as Cu(II) and Cu(I) salts or Cu metal. Thus, several 3-acetoxy5-steroids have been oxidized to the corresponding 5-7keto derivatives (scheme 1) in yields ranging from 70 to

84%. The best result was obtained with copper powder (Aldrich, 150 mesh) as catalyst, which is transformed into a soluble copper compound in situ [38]. The copper-catalyzed oxidation by TBHP under phase transfer conditions has been applied in this type of allylic oxidation, affording high yields in short reaction times [39]. Cobalt acetate has also been reported to be an effective catalyst for the selective oxidation of unsaturated steroids using TBHP in yields ranging from 40 to 86% [40]. These reactions are very selective compared to those reported by Kimura et al., carried out using Fe(acac)3 as catalyst and TBHP as the oxidant [41]. Under similar oxidative conditions the use of Mo(CO)6 led to the epoxidation of cholesteryl acetate 1 [42]. A common difficulty associated with the homogeneous procedures reported so far is the separation step required for the removal of the catalysts, which cannot be easily recovered and reused. The imobilization of inorganic reagents and catalysts useful in organic reactions on heterogeneous supports is a very important area in clean technology. Several methods have been reported for the allylic oxidation of 5-steroids (scheme 1) using heterogeneous catalysts. These include TBHP in the presence of a catalytic amount of KMnO4/SiO 2 in benzene [43] or chromium(VI) adsorbed on SiO2/ZrO 2 [44]. The use of cobalt(II), copper(II), manganese(II) and vanadium(II) immobilised on mesoporous silica (Fig. 1) for this kind of allylic oxidation has also been reported recently. Very good yields and high selectivity were achieved. In addition, the catalysts could be easily recovered and reused


Salvador et al.

O

-O

O Si

O O

M2+

CH2CH2 O-

CH3 O

Catalyst 1 M2+=Co2+ Catalyst 2 M2+=Mn2+ Catalyst 3 M2+=V2+ O

H Si

O O Catalyst 4 M

N

C

C

O O-

H

-O M2+

N

CH3 O

2+=Co2+

Catalyst 5 M2+=Cu2+ Catalyst 6 M2+=Mn2+

Fig. (1).

[45]. Jurado-Gonzalez et al. reported similar results using TBHP and catalytic amounts of cobalt(II) alkyl phosphonate modified silica (Fig. 2) [46].

be especially effective and led to a significant increase in chemoselectivity when compared to other processes [36b; 37; 38; 40].

Fig. (2). Catalyst 7.

2.1.2. Mediated by Iodoxybenzene The oxidation of 3-cholesteryl benzoate 14 to the corresponding 4-ketone derivative 15 (Table 3) has been performed by iodoxybenzene (PhIO2) and a catalytic amount of 2,2’-dipyridyldiselenide in 67% yield (scheme 4) [48]. The same conversion has been achieved using PhIO2 combined with perfluorooctylseleninic acid in trifluoromethylbenzene under reflux. This catalyst was recovered by fluorous extraction in the form of bis(perfluorooctyl) diselenide, which itself served as a convenient catalyst precursor [49].

In spite of its heavy metal status, bismuth is considered safe when compared to the copper and cobalt catalysts reported in previous papers, as it is non-toxic and noncarcinogenic. The increasing concern about environment and the need for green reagents has prompted research on the use of homogeneous or heterogeneous bismuth salts as catalysts combined with TBHP for the allylic oxidation of 5-steroids (scheme 1) [47]. The use of BiCl3 as catalyst was shown to

2.2. Catalytic Allylic Oxidation of Other Unsaturated Steroids The use of TBHP combined with CrO3 as catalyst has been reported for the oxidation of cholest-4-en-3-one 10 to cholest-4-ene-3,6-dione 11 (scheme 3). When dichloromethane was used as solvent, only 25% yield [34] was obtained whereas the use of benzotrifluoride afforded 70% yield in the same reaction [50]. Both cholest-4-en-3-one 10

O O

Si OH

O P O- Na+ ONa+

Co(OAc)2.4H2O

Cobalt(II) phosphonate modified silica

Table 2. Catalytic allylic oxidation of 5-steroids by TBHP under heterogeneous conditions Substrate 1

1

5

5

5

Catalyst

Conditions

Product/Isolated yield 2 / high yield

KMnO4/SiO2

TBHP (4.2 equivs.),

(0.046 equivs.)

PhH, 50ºC, Ar, 4-6 h

CrVI /SiO 2/ZrO2 (0.02 equivs.)

TBHP (2 equivs.),

2 / 48%

PhH, r.t., 30 h

5

TBHP (6 equivs.),

(0.003 equivs.)

CH3CN, 55ºC, N 2, 18 h

7

TBHP (6 equivs.),

(0.096 equivs.)

CH3CN, 50ºC, N 2, 48 h

BiCl3 /K-10

TBHP (10 equivs.),

(0.1 equivs.)

CH3CN, 70ºC, 13 h

6 / 86%

6 / 86%

6 / 89%



C8H17

C8H17

Catalyst, PhIO2

BzO

BzO

O

14

15

Scheme 4. Table 3. Catalytic allylic oxidation of 3 -cholesteryl benzoate 14 by iodoxybenzene Substrate

Catalyst

Conditions


14

2,2´-dipyridyldiselenide

PhIO2 (3 equivs.),

15 / 67%

(0.1 equivs.)

PhH, 80ºC, 10 h

+

85% conversion

7-keto derivative / 18%

Perfluorooctylseleninic

PhIO2 (3 equivs.),

15 / 65%

acid (0.1 equivs.)

PhCF3 , reflux, N 2

Bis(perfluorooctyl)

PhIO2 (3 equivs.),

diselenide (0.1 equivs.)

PhCF3 , reflux, N 2

14

14

and pregn-4-ene-3,20-dione 12 were oxidized respectively to cholest-4-ene-3,6-dione 11 and pregn-4-ene-3,6,20-trione 13 by 2,6-dichloropyridine N-oxide (2,6-Cl2pyNO) and dichlororuthenium(IV) complex of meso-tetrakis(2,6-dichlorophenyl)porphyrin [RuIV(2,6-Cl2tpp)Cl2] as catalyst [51]. The oxidation of lanost-8-en-3-yl acetate 16 with 2,6Cl2pyNO catalyzed by (5,10,15,20-tetramesitylporphyrinate) ruthenium(II) carbonyl complex [Ru(TMP)CO] (Fig. 3) and HBr afforded a mixture of the 7-oxo derivative 17 as the major product along with 11-hydroxy-7-oxo derivative 18 and 25-hydroxy-7,11-dioxo derivative 19 (scheme 5) [52].

N

N

II Ru CO

N

N

Catalyst 8: Ru(TMP)CO

Fig. (3).

Androst-4-en-17-yl acetate 20 has been oxidized to the 4-3-ketone derivative 21 in 70% yield with catalyst 4 (Fig. 1) and TBHP [40]. A similar yield has been reported in the

15 / 61%

oxidation of androst-4-en-17-yl benzoate 22 using catalyst 5 (Fig. 1) and TBHP (scheme 6) (Table 4) [45]. Both catalysts could easily be recovered and reused. 3. -SELECTIVE EPOXIDATION The high degree of stereoselectivity associated with most syntheses and reactions of epoxides accounts for their enormous synthetic utility. In general, epoxidation of steroids with trans-anti-trans ring fusions mainly leads to the formation of the -epoxide. The preferred attack by the reagent on the -side of the steroid nucleus can be attributed to shielding of the -side of the molecules by the two angular methyl groups at C-10 and C-13. Steroidal 5,6-epoxides are readily available through the epoxidation of 5-steroids with peracids [53]. In contrast, steroidal 5,6-epoxides and their derivatives are difficult to obtain with high selectivity. The -selective epoxidation of 5-steroids is of great importance because the 5,6-epoxide functionality is present in several naturally occurring compounds, such as withanolides (Fig. 4) which have been studied for their anti-inflammatory [54], antitumor, cytotoxic [55], immunomodulating [56] activities and for their potential in protection against CCl4-induced hepatotoxicity [57]. They have also been reported to induce phase-II enzymes in animal models, which is considered to be one of the mechanisms in cancer chemoprevention [55b; 58]. Several steroids isolated from the Okinawan soft coral C. viridis have also shown growth inhibition towards HeLa S3 cells and human diploid cells in vitro [59]. A 9,11secosteroid containing the 5,6-epoxide ring, isolated from the Octocoral P. violacea displayed cytotoxic activity against human (A-549, HT-29, MEL-28) and mouse (P-388) tumor cells lines [60]. Cholesterol-5,6-epoxide induces apoptosis in U937 cells [61]. In addition, bracteosin A, bracteosin B and with-


Salvador et al.

[Ru(TMP)CO] (0.0042 equivs.) 2,6-Cl2pyNO (3 equivs.), HBr, dry PhH, MS 4Å, 50˚C, 48 h, 88% conversion

AcO 16

AcO

O HO 17 / 56%

AcO

O 18 / 16% OH

O

AcO

O 19 / 16%

Scheme 5.

R1

R1

Catalyst, t-BuOOH CH3CN, N2, 55˚C O

20....R1=OAc....21 22....R1=OBz....23

Scheme 6. Table 4. Catalytic allylic oxidation of 4-steroids 20 and 22 by TBHP Substrate

Catalyst

Conditions


20

4 (0.0095 equivs.)

TBHP (6 equivs.), CH3CN, N2, 55ºC, 3 h

21 / 70%

22

5 (0.0038 equivs.)

TBHP (6 equivs.), CH3CN, N2, 55ºC, 10 h

23 / 72%

OH H

OH

O

O O

O

OH

Fig. (4).

O

24 (Withanolide D)

aferin A 25 (Fig. 4) exhibited evident inhibitory potential against cholinesterase enzymes in a concentration-dependent fashion [62]. Recently, withaferin A 25 has also been

O

O

OH

O

25 (Withaferin A)

reported as an important candidate for the treatment of neurodegenerative diseases since it is able to reconstruct neuronal networks [63].



R2

R2

R3

R3

R1

R1

O

26..........R1=OH;R2=C8H17;R3=H............27 1...........R1=OAc;R2=C8H17;R3=H...........28 3..........R1=OAc;R2=COCH3;R3=H..........29 5.................R1=OAc;R2,R3=O..................30 31..........R1=Cl;R2=C8H17;R3=H..............32

33.........R1=OH.........34 35.........R1=OAc.......36

R1

R1

O

H H3C

H

O

H3C

O

CH3

CH3

O O

AcO AcO

O

37

38

Scheme 7. R3

R3

R4

R1

R1

R2

R2

Scheme 8.

R4

O

39........R1=R2=H;R3=OAc;R4=H........40 41.......R1=R2=H;R3=C8H17;R4=H.......42 43.............R1,R2=O;R3,R4=O...............44

Steroidal 5,6-epoxides have been obtained by peracid epoxidation of 3-halo-5-steroids [64]. Reaction of 7bromocholesteryl benzoate with m-chloroperbenzoic acid (MCPBA) also yielded the corresponding 5,6-epoxide [65]. Stoichiometric epoxidation of 5-steroids (scheme 7) has also been performed using chromyl diacetate, although in moderate yields, along with by-products [66]. Mixtures of 5,6- and of the 5,6-epoxides were obtained by treatment of 5-steroids with hydrogen peroxide in the presence of iron(II), iron(III), and titanium(III) ions [67]. A number of research groups have shown that 5,6-epoxides can be obtained from 5-steroids (scheme 7) using biphasic systems involving potassium permanganate and metal sulphates, nitrates or other metal salts [68]. A new system

consisting of KMnO4/Fe(ClO4)3.nH2O has recently been reported to afford these epoxides in high yields in the presence of NaH2PO4.3H2O [69]. On treatment with perfluoro-cis-2,3-dialkyloxaziridine, several 3-substituted5-steroids produced the 5,6-epoxides as major products, whereas cholesterol 26 and stigmasterol 33 mainly led to the 5,6-epoxides [70]. Stoichiometric processes for the -selective epoxidation of 4-steroids (scheme 8) include the use of Fe(acac)3-H2O2 [67a], TBHP/LiOH [32b], MoO5.HMPTA (HMPTA=hexamethylphosphoric triamide) [71], dimethyldioxirane (DM DO) [72] and KMnO4/metal sulphates [68d; 73]. The selective epoxidation of 4-3-ketones such as substrate 43 has been performed with alkaline hydrogen peroxide [53].


3.1. Catalytic -Selective Epoxidation of 5-Steroids 3.1.1. Mediated by Oxygen or Air The use of either molecular oxygen or air as the oxidant in the presence of metalloporphyrin catalysts is of great industrial interest (Table 5). The epoxidation of 5-steroids by air and [RuVI(O)2tmp] (Fig. 5) has been reported to produce the 5,6-epoxide in good yields, in a stereospecific manner. Under these conditions, the reactions proceeded slowly and cholesterol 26 was found to inhibit the catalytic system [74]. When applied to conjugated 5(6), 7(8) steroidal diene systems, a 1:1 mixture of the and epoxides was obtained in a non-stereoselective process. However, stigmasteryl acetate 35 has been readily epoxidized under the same conditions, in a highly regioselective and stereoselective fashion, to the 5,6-epoxide 36 (scheme 7) [75].

N

O

N

Ru N

O

N

Salvador et al.

Bis(dipivaloylmethanato)manganese (II), [Mn(dpm)2] was particularly effective and has also been applied to a series of cholesterol derivatives affording yields ranging from 77 to 93% [79]. Similar conversions were achieved with molybdenyl(VI) acetylacetonate as catalyst under the same reaction conditions [80]. Catalytic -stereo and regioselective epoxidation of 5-steroid derivatives (scheme 7) has been effected by ruthenium(II) bioxazoline complex (RuCl2(biox)2) (Fig. 6) under aerobic conditions [81]. Chandrasekaran et al. reported the use of a μ-dimethoxobridged diferric salen derivative (Fig. 7) for the conversion of 5-steroids to the corresponding 5,6-epoxides, in high yields (85-92%) and selectivities [82]. Manganese(III) acetate dihydrate has been used as a catalyst for the epoxidation of steroidal olefins with O2 and pivalaldehyde as a sacrificial reductant, in a fluorinated solvent (perfluoro-2butyltetrahydrofuran) (FC-75) [83]. An efficient ruthenium catalyzed biphasic epoxidation of 3-chloro-cholest-5-ene 31 with oxygen/isopropylaldehyde has been reported in the presence of a pyridine-benzimidazole ligand bearing perfluorinated "ponytails" (Rf2 Bimpy) [84]. The fluorinated phase was reused several times without any apparent loss of activity, always resulting in the full con-version of the substrate. Despite the good yields and selecti-vities reported with these different metal catalysts in homogeneous reaction conditions, a difficult separation step is usually needed to remove the catalysts, which cannot easily be reused.

O

N

Cl

N

O

N

O

Ru O

N

Cl

Fig. (5). Catalyst 9. Fig. (6). Catalyst 10.

The epoxidation of both cholesterol 26 and cholesteryl acetate 1 with catalytic systems using air as the oxygen source, isobutyraldehyde as the reductant (Mukaiyama conditions) and nickel, iron or manganese porphyrins as catalysts has also been investigated. In the presence of (5,10,15,20-tetraphenylporphyrinato)nickel(II) [Ni(tpp)], the -selective epoxidation of cholesteryl acetate 1 has been enhanced to more than 80% [76]. The major drawback of these methods is the synthesis of the porphyrin catalyst, which is not always straightforward. Similar results have been reported using metal complexes as catalysts (Table 5). Catalytic amounts of bis[1,3-bis(pmethoxyphenyl)-1,3-propanedionato]nickel(II) complex, [Ni (dmp)2] smoothly monooxygenated 5-steroids to the corresponding epoxides in almost quantitative yields on treatment with isobutyraldehyde under an atmospheric pressure of oxygen at room temperature [77]. Tris[1,3-bis(p-methoxyphenyl)-1,3-propanedionato]iron(III) [Fe(dmp)3] was found to be an excellent catalyst for the oxygenation of cholesteryl acetate 1 to the corresponding 5,6-epoxide in 86% yield with moderate stereoselectivity (ratio / isomers 29/71) [78]. Under similar reaction conditions nickel(II), iron(III) palladium(II), ruthenium(III), cobalt(II) and manganese(II) complexes coordinated with 1,3-diketones, afforded the hindered 5,6-epoxides as major isomers from cholesteryl benzoate.

N O

N Fe

O

MeO O

OMe Fe

N

O N


Mastrorilli et al. [85] reported the use of polymerizable -ketoesterate complexes such as Fe(AAEMA)3, Ni(AA EMA)2 and Co(AAEMA)2 as catalytic centres (AAEMA-= deprotonated form of 2-(acetoacetoxy)ethyl methacrylate), as potential hybrid epoxidation catalysts with a view to laying the foundations for effecting these reactions under heterogeneous conditions. Epoxidation of both cholesterol 26 and cholesteryl acetate 1 proceeded smoothly using O2/isobutyraldehyde and nanostructured amorphous cobalt oxide on mesoporous silica (CoO-MCM-41) composite as catalyst in



Table 5. Catalytic -stereoselective epoxidation of 5-steroids by O2 under homogeneous conditions

Substrate

Catalyst

Conditions

Product/ Isolated yield

Ratio of isomers (:)

1

9 (0.044 equivs.)

Air, PhH, dark, 20ºC, 5 h

28 / 85%

99:1

1

Ni(tpp) (0.1 equivs.)

Air, isobutyraldehyde, CH2Cl2, dark, r.t., 1 d

28 / quant. yield

82:18

1

Ni(dmp)2 (0.025 equivs.)

O2 (1 atm), isobutyraldehyde, CH2ClCH2Cl, r.t., 5 h

28 / 84%

76:24

1

Fe(dmp)3 (0.01 equivs.)


28 / 86%

71:29

1

Mn(dpm)2 (0.0094 equivs.)


28 / 83%

81:19

1

MoO2(acac)2 (0.1 equivs.)


28 / 82%

83:17

5

10 (0.025 equivs.)

O2 (1 atm), isobutyraldehyde, CH2Cl2, NaHCO3, 25ºC, 5 h

30 / 96%

96:4

1

11 (0.02 equivs.)

O2 (1 atm), isobutyraldehyde, CH2Cl2, 25ºC, 10 h

28 / 92%

80:20

26

Mn(OAc)3.2H2O (0.04 equivs.)

O2 (bubbling), pivalaldehyde, FC-75/toluene, 25ºC, 4 h

27 / 75%

74:26

31

RuCl3.nH2O/ Rf2Bimpy (0.01 equivs.)

O2 (1 atm), isopropylaldehyde, C8F17Br/PhCl, 40ºC, 2.5 h

32 / 94%

60:40

1

Co(AAEMA) 2 (0.008 equivs.)


28 / 87%

68:32

Table 6. Catalytic -stereoselective epoxidation of 5-steroids by O2 under heterogeneous conditions

Conditions

Product/ Isolated yield

Ratio of isomers (:)

CoO-MCM-41

O2 (1 atm),

28 / 80%

78:22

(0.02 equivs.)

isobutyraldehyde,

30 / 89%

81:19

Substrate

Catalyst

1

CH2ClCH2Cl, NaHCO 3, 28ºC, 4 h 5

4

O2 (1 atm),

(0.024 equivs.)

isobutyraldehyde, CH2ClCH2Cl, r.t., 5 h

high yields with preferential formation of the 5,6-epoxide (ratio / 69:31 and 78:22, respectively) (Table 6) [86]. A large variety of 5-steroids, with different functional groups and side chains, were conveniently converted to the corresponding 5,6-epoxides (scheme 7) in high yields and degree of stereoselectivity, using silica supported cobalt catalysts 1, 4 (Fig. 1) and molecular oxygen as the oxidant. The catalysts were easily recovered and reused (Table 6) [87].

3.1.2. Mediated by Other Oxidants On oxidation with t-pentyl hydroperoxide in the presence of MoCl5, dehydroepiandrosterone and diosgenin acetates 5, 37 (scheme 7) formed mixtures of epoxides in which the 5,6-isomer predominated [71]. 2,3,7,8,12,13,17,18-Octachloro-5,10,15,20-tetraarylporphyrinatoiron(III) chloride catalyzed the -selective epoxidation of cholesteryl acetate 1 with cumene hydroperoxide (CumOOH), either with or without N-methylimidazole [88].


Salvador et al.

Several methods have been reported for this reaction using hydrogen peroxide as the oxidant. These include the selective epoxidation of cholesteryl acetate 1 using pertungstate salts [89] or porphyrin complexes of Mn(III) and Fe(III) as catalysts (Fig. 8). Porphyrins with bulky, electronwithdrawing groups in the ortho positions of the meso phenyls and with Mn(III) as the central metal ion afforded the -selective epoxidation of cholesteryl acetate 1 preferentially. [Mn(TDCPP)Cl] (catalyst 12, Fig. 8) was found to be the best catalyst for this conversion affording 79% yield and 90% -selectivity [90]. The readily prepared 2,4-bisperfluorooctylphenyl butylselenide catalyzes the epoxidation of various olefins, including the -selective epoxidation of 3-chloro-cholest-5-ene 31 with hydrogen peroxide in a fluorous biphasic system. The catalyst could be reused several times without decrease in the yield of the reaction or increase in the reaction time [91]. Z

Z

Z

Z

Y

Y

Y

Y

Cl N

X Z

N M

Z

N

N Z

Z

Y

Y Y

Y

Z

Z

Z

Z Catalyst 12 Catalyst 13 Catalyst 14 Catalyst 15

Mn(TDCPP)Cl M=Mn; X=H, Y=Cl; Z=H Mn(βNO2TDCPP)Cl M=Mn; X=NO2, Y=Cl; Z=H Mn(TPFPP)Cl M=Mn; X=H, Y=Z=F Fe(TPFPP)Cl M=Fe; X=H, Y=Z=F

Fig. (8).

Magnesium monoperoxyphtalate, which shows good stereoselectivity for the epoxidation of cholesterol 26 in the absence of catalyst, exhibits fair -stereoselectivity for the epoxidation of various 5-steroids in the presence of manganese tetra-o-dichlorophenylporphyrin complexes [92]. The -selective epoxidation of cholesteryl acetate 1 was performed using the tetraphenylporphinatoiron(III)chlorideiodosylbenzene system, with good / ratios, although yields were poor [93]. In the presence of a catalytic amount of dioxo(tetramesityl-porphyrinato)ruthenium(VI) complex (Fig. 5), nitrous oxide (N2O) oxidized 5-steroids into the corresponding 5,6-epoxides in good to high yields (30-99%) and high selectivities (>99%) [94]. In this study, coordinating solvents such as THF, EtOH and CH3 CN afforded no products. A variety of aromatic solvents were examined and fluorobenzene was found to be the most suitable for this reaction (99% yield and >99% -selectivity). Using dehydroepiandrosterone acetate 5 as substrate, sodium perborate in

glacial acetic acid produced a mixture of the 5,6- and 5,6-epoxides, containing predominatly the -epoxide. However, in the presence of catalytic amounts of potassium permanganate, the reaction was much faster and the stereoselectivity was reversed, with the -epoxide predominating. Thus, a number of 5-steroids, including some with substituents at C4, were epoxidized under these conditions [95]. A whole range of 5-steroids with different functional groups such as hydroxyl, carbonyl, acetyl or ketal, as well as different side chains, were conveniently converted to the corresponding synthetically and biologically interesting 5,6-epoxides (scheme 7) with excellent selectivities and high yields using chiral ketones as catalysts and oxone as the terminal oxidant [96]. Dichlororuthenium(IV)-porphyrin complexes were reported to be powerful catalysts for the epoxidation of steroids with 2,6-Cl2pyNO under mild conditions. By employing dichlororuthenium(IV) complex of meso-tetrakis(2,6-dichlorophenyl)porphyrin as catalyst, the epoxidation of 5-steroids could be completed within 0.5 or 1h and displayed up to 99% -selectivity and up to 97% epoxide yield [51]. Attachment of poly(ethylene glycol) (PEG) or dendritic wedges to homogenous metal catalysts has endowed the catalyst molecule with a soluble, well-defined nanoscale structure, allowing facile separation of the catalyst from the products by membrane or nanofiltration techniques with no loss of the advantages of homogeneous catalysts. Furthermore, the dendritic wedges induced regioselectivity or shape selectivity of the catalyst by creating a proper environment around the metal centre and also stabilized the catalytic centre. Thus, Che et al. used poly(ethylene glycol) (PEG) attached to a ruthenium porphyrin via a covalent ether bond (Fig. 9) to achieve the epoxidation of cholesteryl acetate 1 with 2,6-Cl2pyNO in high overall yield (90%) and with complete -selectivity [97]. Dendritic ruthenium(II) porphyrins were used to perform the -selective epoxidation of cholesteryl esters in high yields and selectivities [98]. An "octopus" manganese porphyrin with polyglycol chains catalyzed the -selective epoxidation of cholesterol derivatives with iodosylbenzene (PhIO) [99]. The epoxidation of cholesterol 26 and stigmasterol 33 with PhIO catalyzed by 5,10,15,20-tetrakis-,,,-[O-(4N-methylisonicotinamido)phenyl]porphyrinatomanganese(III) acetate in phospholipid vesicles was achieved in moderate yields and high -selectivities [100]. Manganese(III) 5,10,15-tris(tolyl)20-(4-hydroxyphenyl) porphyrin covalently attached to Merrifield's peptide resin (MPR) (Fig. 10) exhibited high reactivity and -selectivity towards the epoxidation of cholest-5-ene derivatives with PhIO. This catalyst was consecutively reused four times without detectable catalyst leaching and afforded over 90% epoxide yield and over 99% -selectivity [101]. 3.2. Catalytic -Selective Epoxidation of Other Unsaturated Steroids The oxidation of both androst-4-en-17-yl acetate 39 and cholest-4-ene 41 to the corresponding 4,5-epoxides (scheme 8) has been achieved using hydrogen peroxide as the oxidant and Mn(III) porphyrins with bulky, electronwithdrawing groups in the ortho positions of the meso phenyls as catalysts (Fig. 8) [90]. When progesterone 12 was



Cl

CO N

N Ru

OCH2CH2O

Cl N

N

Cl


Me

N

N Mn

CH2O

Me N

N

Me


subjected to oxidation with 2,6-Cl2pyNO, catalyzed by (5,10,15,20-tetramesitylporphyrinate)ruthenium(II) carbonyl complex (Fig. 3) and HBr, a mixture of the corresponding 4,5-epoxide 45 and the 6-oxo derivative 13 was obtained in 65% and 10% yield, respectively (scheme 9) [52]. Also, androst-4-ene-3,17-dione 43 was oxidized to the 4,5epoxide derivative 44 (scheme 8) by 2,6-Cl2pyNO and dichlororuthenium(IV) complex of meso-tetrakis(2,6-dichlorophenyl)porphyrin, [RuIV(2,6-Cl2tpp)Cl2] as catalyst in 89%

overall yield [51]. The same substrate was oxidized by PhIO and manganese(III) 5,10,15-tris(tolyl)-20-(4-hydroxyphenyl) porphyrin covalently attached to Merrifield's peptide resin (MPR) (Fig. 10). This catalyst allowed 23% conversion of the substrate and more than 99% of -stereoisomer product [101]. Treatment of an estratetraene derivative 46 with 2,6Cl2pyNO (Table 7) and a dendritic ruthenium(II) porphyrin as catalyst produced the 17,19-epoxide derivative 47 in COCH3

COCH3

COCH3

[Ru(TMP)CO] (0.0042 equivs.) + O

12

Scheme 9.

2,6-Cl2pyNO (3 equivs.), HBr, dry PhH, MS 4Å, 50˚C, 48 h, 75% conversion

O

O O

45 / 65%

O 13 / 10%


Salvador et al.

O

MeO dendritic ruthenium(II) porphyrin

47

2,6-Cl2pyNO, CH2Cl2, 40˚C

[RuIV(2,6-Cl2tpp)Cl2] or

MeO

[RuIV(tmp)Cl2] 46

O

2,6-Cl2pyNO, CH2Cl2, 40˚C

MeO O 48

Scheme 10. Table 7. Catalytic -stereoselective epoxidation of estratetraene derivative 46 by 2,6-Cl2pyNO Substrate

Catalyst

Conditions


46

dendritic ruthenium(II)

2,6-Cl2pyNO (1.1 equivs.),

47 / 95%

porphyrin

CH2Cl2, 40ºC, N2 , 48 h

(0.001 equivs.) 46

[RuIV(2,6-Cl2tpp)Cl2]

2,6-Cl2pyNO (4 equivs.),

(0.001 equivs.)

CH2Cl2, 40ºC, Ar, 8 h

48 / 90%

99% conversion 46

IV

[Ru (tmp)Cl2]

2,6-Cl2pyNO (4 equivs.),

(0.001 equivs.)

CH2Cl2, 40ºC, Ar, 8 h

48 / 88%

99% conversion

95% yield with a complete -stereoselectivity [98]. The same oxidation was performed with 2,6-Cl2pyNO in the presence of either [RuIV(2,6-Cl2tpp)Cl2] or [RuIV(tmp)Cl2]. However, with these catalysts, the CH2 group at the 6position in B-ring was concomitantly oxidized to the 6ketone derivative 48 (scheme 10) [51]. 4. ALCOHOL OXIDATION The oxidation of steroidal saturated, allylic and homoallylic alcohols is an important process in steroid chemistry. A typical feature of major steroidal hormones, such as testosterone, progesterone, cortisol and aldosterone is the 4ene-3-ketone functionality [102]. The conversion of steroidal 5-3-alcohols to the corresponding 4-3-ketones represents the last step in the commercial synthesis of a variety of hormones [102-103]. Furthermore, a large number of steroids having 4-ene-3-ketone system are known to be substrates or active-site directed inhibitors for the aromatase enzyme system [104]. Cholest-4-en-3-ones markedly inhibit

body weight gain and body fat accumulation, as well as the levels of serum triglycerides and cholesterol in animals without inducing any clinical abnormalities [105]. Steroidal 4-3,6-diketones are naturally occuring substances found in several plants [106] and marine sponges [107]. Moreover, 4-3,6-diketones are of special interest because of their biological properties [108]. Thus, two oxygenated desmosterols 49, 50 (Fig. 11) isolated from the red alga Galaxaura marginata and a synthetic oxygenated desmosterol 51 were shown to exhibit significant cytotoxicity against several cancer cell lines [109]. Also, two oxygenated fucosterols, 52, 53 isolated from the brown alga Turbinaria conoides, were cytotoxic against the same cancer cell lines [110]. 6-Oxoandrostenedione is clinically used for treatment of estrogen-dependent breast cancer [111]. Classical methods for the oxidation of steroidal saturated, allylic and homoallylic alcohols include the use of Cr(VI) reagents [112] such as Jones reagent [112-113], diethyl ether/CrO3 reagent in the presence of celite [114], chromyl



OOH

R1

R1= 49 52 OOH

O 50

O

O

HOO 53

51

Fig. (11).

chloride adsorbed on silica/alumina [115], CrO3-pyridine complex [112b; 116], pyridine oxodiperoxychromium(VI) [117], 4-(dimethylamino)pyridinium chlorochromate [118], pyridinium fluorochromate or benzyltrimethylammonium chlorochromate [119], benzotriazole-CrO3 complex [120], CrO3 and 3,5-dimethyl-pyrazole [121], PCC [122], PDC, [122l; 123], and sodium chromate [112]. Activated DMSO [112; 124], aluminum alkoxides/ hydride acceptors (Oppenauer reaction) [112; 125], N-halo compounds [112; 126], AgCO3/celite [112b; 127], KMnO4 [68f; 128], MnO2 [112], and 2,3-dichloro-5,6-dicyanobenzoquinone [112] have also been used. Other stoichiometric oxidative processes involve the use of tertiary butyl hypochlorite [112a], Pt/O2 [112], bismuth(V) [129], OsO4 and RuO4 [112b; 130], H2O2 and ammonium molybdate [131], molybdenum-peroxo complexes [132], trichloroacetaldehyde/Al2O3 [133], chlorine/p yridine [134], sodium hypochlorite [135], calcium hypochlorite [136], dioxotrichlororuthenate(VI) and dioxodichlorobipyridylruthenate(VI) [137], oxoammonium salts [138], hypervalent iodine reagents [139], tetra-n-propylammonium perruthenate/N-methylmorpholine-N-oxide (TPAP/ NMO) [140], palladium(II) salts [141], perfluoro-cis-2,3-

dialkyloxaziridines [142], DMDO [143], electrochemical oxidation [144] and trimethylamine-N-oxide in the presence of an iron carbonyl [145]. The stoichiometric methods previously mentioned often require one or more equivalents of these relatively expensive oxidizing agents. Moreover, some of these processes generate equal amounts of metal waste and therefore, developing selective and efficient processes using catalytic and non toxic oxidants for the oxidation of steroidal alcohols is of paramount importance for both economic and environmental reasons. 4.1. Catalytic Oxidation of Steroidal Saturated 3Alcohols to the 3-Ketone 4.1.1. Mediated by t-Butyl Hydroperoxide Treatment of androstane-3,17-diol 54 with tert-butyl hydroperoxide (TBHP) in the presence of chromium hexacarbonyl catalyst (Cr(CO)6) afforded androstane-3,17dione 55 in high yield (scheme 11). Also, all three alcohol groups of methyl cholate 56 were oxidized to give the triketone derivative 57 [36b]. 5-Cholestan-3-ol 58 has been oxidized to the corresponding 3-ketone 59 (scheme 12) using CrO3 with an excess of aqueous TBHP, in 56% yield O

OH Cr(CO)6 (0.25 equivs.), t-BuOOH (3 equivs.) CH3CN, reflux, 19 h O

HO

55 / 80%

54 COOMe

OH

COOMe

O

Cr(CO)6 (0.25 equivs.), t-BuOOH (4 equivs.) CH3CN, reflux, 19 h HO

OH H 56

Scheme 11.

O

H

O 57 / 81%


R3

Salvador et al.

R3

R4

R1

R4

O

R2 58........R1=OH;R2=H;R3=C8H17;R4=H........59 60...............R1=OH;R2=H;R3,R4=O.............55 61...............R1=H;R2=OH;R3,R4=O.............55

Scheme 12.

[146]. A better yield was obtained (95%) when benzotrifluoride was used as solvent instead of dichloromethane [50]. Other methods reported for this reaction include the use of pentafluorobenzeneseleninic acid which becomes catalytic in the presence of TBHP in 90% yield [147], Fe(NO3)3.9H2O and TBHP [148] and methylalumoxane/TBHP, in 85% yield [149]. In addition, the oxidation of the same steroid substrate occurred under microwave irradiation with TBHP in the presence of 3Å molecular sieves (MS) as catalyst. However, only 30% yield was obtained with 58% recovery of the starting material [150]. A low yield was also obtained in the oxidation of 5-cholestan-3-ol 58 with K-10 montmorillonite/TBHP [151]. 4.1.2. Mediated by Oxygen or Air A combination of Pd(OAc)2/pyridine/MS 3Å catalyzed the aerobic oxidation of 5-cholestan-3-ol 58 in toluene, in 92% yield [152]. The use of palladium(II) acetate in the presence of a novel perfluoroalkylated-pyridine ligand, with oxygen in a fluorinated biphasic system composed of toluene and perfluorodecalin, has been reported for the same catalytic oxidation. The fluorinated phase containing the active palladium species could be easily separated and reused several times without significant loss of catalytic activity [153]. A heterogenized Pd catalyst, Pd(II)-hydrocalcite (palladium(II) acetate-pyridine complex supported by hydrocalcite) catalyzed the aerobic oxidation in toluene of 5-cholestan-3-ol 58 in 93% yield using atmospheric pressure of air as a sole oxidant under mild conditions. The catalyst was easily prepared using only commercially available reagents and could be reused several times [154]. Aerobic oxidation of alcohols using molecular oxygen in the presence of an aldehyde has also been reported. Thus, ruthenium-cobalt bimetallic catalyst in the presence of acetaldehyde efficiently converted 5-cholestan-3-ol 58 to its 3-keto derivative 59 [155]. 1-Sitosterol 62 underwent

selective oxidation to give the corresponding ketone 63 with a cobalt(II) Schiff's base complex (Fig. 12) in the presence of 2-methylpropanal (scheme 13) [156]. Homogeneous and heterogeneous catalytic oxidation of 5-cholestan-3-ol 58 in the presence of 2-methylpropanal has been described. The homogeneous conditions used consisted of a catalytic amount of Co(acac)2 with an excess of 2-methylpropanal at 40ºC and molecular oxygen as the oxidant. A copolymer obtained by reaction of Co(AAEMA)2 [AAEMA =deprotonated form of 2-(acetoacetoxy)ethyl methacrylate)] with N,N-dimethylacrylamide and N,N’-methylenebisacrylamide in N,N-dimethylformamide was used as catalyst for the same reaction under heterogeneous conditions. This catalyst can be recycled and reused [157]. R1 N

HO

62

Scheme 13.

O

Co

O R1

N R2

Catalyst 18: CoSANSE: R1=CH2OH; R2=CO2Me

Fig. (12).

4.1.3. Mediated by Other Oxidants 3-Hydroxy-5-androstan-17-one 60 has been oxidized to the corresponding 3,17-diketone 55 (scheme 12) using a slight excess of sodium metaperiodate in the presence of a catalytic amount of ruthenium tetraoxide [158]. Sodium bromate has been found to be effective for the oxidation of 5-cholestan-3-ol 58 to the 3-keto derivative 59 in the presence of cerium(IV) ammonium nitrate as catalyst in 97% yield [159]. The same reaction has also been performed with

Catalyst 18 (0.05 equivs.) O2 (1 atm), 2-methylpropanal (2 equivs.), CH3CN, MS 3Å, r.t., 15-17 h

R2

O

63 / 62%



peracetic acid/RuCl3.nH2O under mild conditions with high efficiency [160], with pyridinium dichromate-Me3SiO OSiMe3 system [161] and with DMSO catalyzed by a (polystyrene-catecholato)oxorhenium complex (Fig. 13) [162]. In the latter case, the supported [Re(catecholato)] catalyst could be recovered and used repeatedly without loss of activity. A hydride transfer reaction catalyzed by CuCl.phen (phen=1,10-phenanthroline) with t-BuOOCN= NCOOt-Bu (DBAB) in the presence of K2CO3 has been reported. Thus, 5-cholestan-3-ol 58 has been oxidized to the corresponding 3-keto derivative 59 in anaerobic conditions, in 90% yield [163]. Reaction of hydrogen peroxide catalyzed by methyltrioctylammonium tetrakis (oxodiperoxotungsto)phosphate3- under two-phase conditions also performed the oxidation of 5-cholestan-3-ol 58 [164]. The same oxidant was used in the conversion of 17methylandrostane-3,17-diol 64 to the corresponding 3keto derivative 65 catalyzed by sodium tungstate, under phase transfer conditions (scheme 14) [139h]. N-tertButylbenzenesulfenamide catalyzed the oxidation of 5lanosta-8,24-dien-3-ol 66 to the corresponding 3-ketone 67 using N-chlorosuccinimide in the presence of K2CO3 and MS 4Å at temperatures ranging from 0ºC to room temperature (scheme 15) [165]. 5-Cholestan-3-ol 58 and 3-hydroxy-5-androstan17-one 61 were oxidized to the 3-keto compounds 59, 55 (scheme 12) in a hydrogen transfer reaction catalyzed by

O

O N H

O


Pd(PPh3)4 with bromobenzene and K2CO3 in DMF, under homogeneous conditions. The same substrates were also oxidized using polymer-anchored palladium(II) chloride catalysis, under heterogeneous conditions [166]. The oxidation in high yield of 5-cholestan-3-ol 58 has been carried out using RuCl2(PPh3)3 and NMO [167]. Tetran-butylammonium perruthenate (TBAP) and TPAP with NMO have been reported as mild catalytic oxidants for the high yield conversion of lanost-8-en-3-ol 68 to lanost-8-en3-one 69 (scheme 16) (Table 8) [168]. RuCl2(PPh3)3 catalyzed oxidation of 5-cholestan-3-ol 58 by PhIO led to the 3-ketone 59 in 85% yield [169]. Similar yields have been reported using the same oxidant and ytterbium(III) nitrate as catalyst [170]. Catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) have been used in combination with [bis(acetoxy)iodo]benzene (BAIB) as stoichiometric oxidant in the conversion of 5-cholestan-3-ol 58 to the corresponding 3-ketone 59, in 80% yield [171]. The same oxidant OH

Na2WO4 (0.27 equivs.) H2O2 (1.5 equivs.; dropwise addition) toluene, PTC, 95˚C, 24 h

O 65 / 82%

Scheme 14.

N-chlorosuccinimide (1.1 equivs.) N-t-butylbenzenesulfenamide (0.1 equivs.) CH2Cl2, K2CO3, MS 4Å, r.t., 1 h

HO

O

66

67 / 94%

Scheme 15.

TBAP or TPAP, NMO CH2Cl2, MS 4Å, r.t. HO

O 68

Scheme 16.

Cl OPPh3

CH3

64

O Re

OH

HO

O

69

CH3


Salvador et al.

Table 8. Catalytic oxidation of lanost-8-en-3-ol 68 by NMO Substrate

Catalyst

Conditions

Product/Isolated yield 69 / 86%

68

TBAP

NMO (1.5 equivs.), CH2Cl2,

(0.05 equivs.)

MS 4Å, r.t., 6 h

TPAP

NMO (1.5 equivs.), CH2Cl2,

(0.05 equivs.)

MS 4Å, r.t., 1.5 h

68

was used in this conversion in the presence of ruthenium [bis(oxazolinylpyridine)-(pyridine-2,6-dicarboxylate)] (Fig. 14) as catalyst, in high yields [172].

O

O

N N

N Ru

O

O N

O

O


4.2. Catalytic Oxidation of other Steroidal Saturated Alcohols 5,6-Dihydroxycholestan-3-yl acetate 70 has been oxidized to 5-hydroxycholestan-6-one-3-yl acetate 71 using a large excess of sodium metaperiodate in the presence of a catalytic amount of ruthenium tetraoxide (scheme 17) [158]. Oxidation of 17-hydroxysteroids with TBHP

69 / 81%

catalyzed by Zr(O-n-Pr)4 afforded the 17-keto derivatives. Also, 11-hydroxy-19-norandrost-4-ene-3,17-dione has been oxidized to 19-norandrost-4-ene-3,11,17-trione with further addition of both oxidant and catalyst [173]. Both testosterone 72 and 17-hydroxy-5-androst-2-ene 73 were oxidized by NMO and RuCl2(PPh3)3 as catalyst (scheme 18) [167]. TBAP and TPAP with NMO have been reported as mild catalytic oxidants for the high yield conversion of 17hydroxy-5-androstan-3-one 75 to the corresponding 17ketone 55 (scheme 19) [168]. The combination of TPAP and NMO has been used to generate ketones from 3-, 11-, 15-, 17- and 20-hydroxysteroids [174]. Dichlororuthenium(IV) complex of meso-tetrakis(2,6dichlorophenyl)porphyrin has been used as a catalyst for the rapid oxidation of testosterone 72 to androst-4-ene-3,17dione 43 (scheme 18) in 99% yield with 2,6-Cl2pyNO under mild conditions [51]. -Estradiol 76 was oxidized to the 17keto derivative 77 by DMSO and (polystyrene-catecholato) oxorhenium complex as catalyst (Fig. 13, scheme 20) [162]. N-tert-Butylbenzenesulfenamide catalyzed the oxidation of 17-hydroxy-5-androstan-3-one 75 to the corresponding 17-ketone 55 (scheme 19) using N-chlorosuccinimide in the presence of K2CO3 and MS 4Å [165]. Testosterone 72 (scheme 18) and 17-hydroxy-5-androstan-3-one 75 C8H17

C8H17 RuO4 (0.0036 equivs.), NaIO4 (large excess) CCl4, r.t. AcO

AcO OH

OH

OH

70

Scheme 17.

O

71 / 76% O

OH

O

O 72

43 O

OH RuCl2(PPh3)3 (0.0084 equivs.), NMO (2 equivs.) dry acetone, r.t., 2 h

Scheme 18.

73

74 / 83%



O

OH

O

O

55

75

Scheme 19. O

OH Catalyst 19 (0.05 equivs.), DMSO (1.5 equivs.) toluene, reflux, 4 h HO

HO 76

77 / 98%

Scheme 20.

(scheme 19) were oxidized using bromobenzene and K2CO 3 in DMF catalyzed by Pd(PPh3)4 under homogeneous conditions and with polymer-anchored palladium(II) chloride under heterogeneous conditions [166].

SO2C8F17 N AlMe O

4.3. Catalytic Oxidation of Steroidal Allylic Alcohols: 4 3-Alcohols to the 4-3-Ketone 19-Nortestosterone 79 has been synthesized from the 3hydroxy derivative 78 in 84% yield in a clean and environmentally benign process using Pd/C as catalyst under an ethylene atmosphere (scheme 21) (Table 9) [175]. The same authors have reported the reaction can be carried out using nitrobenzene as the hydrogen acceptor and Pd/C as catalyst, although lower yields were obtained. However, under these conditions, testosterone 72 was obtained from the 3-hydroxy derivative 80 in 82% yield (Table 9) [176]. A modified aluminium catalyst (Fig. 15) was found to be highly effective for Oppenauer oxidation of cholest-4-en-3-ol to the corres-


ponding enone 10 in 97% yield using acetone as hydride acceptor [177a]. Muzart et al. reported the same conversion by sodium percarbonate in the presence of catalytic amounts of both molybdenyl(VI) acetylacetonate and Adogen 464 [177b]. In the presence of dioxo(tetramesityl-porphyrinato)ruthenium(VI) complex as catalyst (Fig. 5), N2 O quantitatively oxidized cholest-4-en-3-ol 81 to cholest-4en-3-one 10 (scheme 22) [94b; 178]. OH

OH R1

Pd/C (50 wt% of 10% Pd/C), hydrogen acceptor

R1

CH3CN HO

O

78.......R1=H.......79 80......R1=CH3....72

Scheme 21. Table 9. Catalytic oxidation of substrates 78 and 80 using a hydrogen acceptor Substrate 78

78

80

Catalyst

Conditions

Product/Isolated yield 79 / 84%

Pd/C

ethylene atmosphere,

(50 wt% of 10% Pd/C)

CH3CN, 50ºC, 4.5 d

Pd/C

nitrobenzene (0.33 equivs.),

(50 wt% of 10% Pd/C)

CH3CN, 80ºC, 3 d

Pd/C

nitrobenzene (0.33 equivs.),

(50 wt% of 10% Pd/C)

CH3CN, 80ºC, 3 d

79 / 63%

72 / 82%


Salvador et al.

C8H17

C8H17 Catalyst 9 (0.05 equivs.), N2O (10 atm) 1,2-dichloroethane, 120˚C, 7.5 h

HO

O

81

10 / quantitative yield

Scheme 22. C8H17

C8H17 RuCl2(PPh3)3 (0.0084 equivs.), NMO (2 equivs.) dry acetone, r.t., 2 h O

HO 82

83 / 87%

Scheme 23. C8H17

C8H17 OsO4 (0.004 equivs.), t-BuOOH (2 equivs.) t-BuOH/H2O, NEt4OH, 0˚C, 12 h

H

H

OH

O

84

85 / 85% C8H17

C8H17 OsO4 (0.004 equivs.), t-BuOOH (2 equivs.) t-BuOH/H2O, NEt4OH, r.t., 12 h

HO

HO O

OH 86

87 / 70% C8H17

C8H17 OsO4 (0.004 equivs.), t-BuOOH (2 equivs.)

OH

AcO

Scheme 24.

OH

t-BuOH/H2O, NEt4OH, 0˚C, 12 h

88

4.4. Catalytic Oxidation of Other Steroidal Allylic Alcohols The oxidation in high yields of 5-cholest-1-en-3-ol 82 has been performed using RuCl2(PPh3)3 and NMO (scheme 23) [167]. 3,5-Cyclocholest-7-en-6-ol 84 was oxidized with TBHP and catalytic amounts of OsO4 in the presence of aqueous NEt4OH to 3,5-cyclocholest-7-en-6-one 85 in a good yield. 5-Cholest-7-ene-3,6-diol 86 and 7,8dihydroxycholest-5-en-3-yl acetate 88 were selectively oxidized to 3-hydroxy-5-cholest-7-en-6-one 87 and 3,8-dihydroxycholest-5-en-7-one 89, under the same conditions (scheme 24) [179].

OH

HO

O 89 / 66%

4.5. Catalytic Oxidation of Steroidal Homoallylic Alcohols: 5-3-Alcohols to the 5-3-Ketone, 4-3Ketone or 4-3,6-Diketone Several systems have been applied to the conversion of cholesterol 26 to the corresponding cholest-5-en-3-one 90 (scheme 25). These include peroxyacetic acid and a catalytic amount of 2,4-dimethylpentane-2,4-diol cyclic chromate in 84% yield [180], dioxygen in the presence of ethyl 2oxocyclopentanecarboxylate catalyzed by a cobalt(II) Schiff's base complex (Fig. 12) in 55% yield [181], BAIB as stoichiometric oxidant with catalytic amounts of TEMPO in 80% yield [171], CH3 CN and CCl4 with Mn(acac)3 as catalyst in 80% yield [182], and N-chlorosuccinimide in the



C8H17

C8H17

O

HO

90

26

Scheme 25.

presence of K2CO3 and MS 4Å with N-tert-butylbenzenesulfenamide as catalyst in 92% yield [165]. Allyl methyl carbonate and RuH2(PPh3)4 have been used for the same oxidation leading to 52% yield. However, cholest-4-en-3-one 10 was obtained in 18% yield by thermally induced isomerization [183]. The use of TBHP and transition metals incorporated in the mesoporous sieve MCM-41 has also been reported as catalyst for the oxidation of cholesterol 26 although in low conversion. When Zr-MCM-41 was used, cholest-5-en-3-one 90 was the main product, whilst the incorporation of Ti led to the formation of 5,6-epoxycholesterol as the major product [184]. Cholesterol 26 has been oxidized to cholest-4-en-3-one 10 (scheme 26) using mesityl bromide as the oxidant and palladium acetate/triphenylphosphine as catalyst in the presence of K2CO3 [185]. Also, the use of MnO2 in the presence of a catalytic system consisting of a ruthenium catalyst (Fig. 16) and 2,6-di-tert-butylbenzoquinone, in 40% yield has been reported [186]. The biomimetic oxidation of cholesterol 26 and sitosterol 92 with H2O2 catalyzed with anionic water soluble iron(III) 5,10,15,20-tetraarylporphyrins (Fig. 17) in aerosol OT (AOT) reverse micelles under different reaction conditions has been described. The 4-3-ketone derivatives 10 and 93 were the major products obtained although yields were relatively modest [187]. The oxidation of cholesterol 26 to cholest-4-en-3-one 10 has also been performed under Oppenauer conditions using the following catalyst-hydride acceptor systems: t-BuOSmI2cyclohexanone [188], bidentate aluminum-pivalaldehyde (Fig. 18) [189], triruthenium dodecacarbonyl/triphenylphosphine-diphenylacetylene [190] and RuCl2[S-BINAP]diphenylacetylene (Fig. 19). This latter system has also been applied to the conversion of dehydroepiandrosterone 7 to androstenedione 43 in good yield (scheme 26) [191]. Several 3-hydroxy-5-steroids were efficiently oxidized to the corresponding 4-3-ketone derivatives (scheme 26) by acetone under reflux in the presence of a catalytic system consisting of either RuCl2(PPh3)3 and K2CO3 or catalyst 22 (Fig. 16) [192]. Polyaniline-supported molybdenum-catalyzed aerobic oxidation of cholesterol 26 to cholest-4-en-3-one 10 in 72% yield has been reported. This heterogeneous catalyst could be recycled and reused [193]. The oxidation of 3-hydroxy-5-cholestenes, -pregnenes and -androstenes to the corresponding 4-3,6-diketones (scheme 27) has been achieved in high yields by a one-step procedure using TPAP with NMO as co-oxidant, under sonochemical conditions [194]. The use of hydrogen

H

O

Ph

O

Ph Ru OC

Ph

Ph

Ph

Ph

Ph

Ru Ph

H CO

CO

OC

Fig. (16). Catalyst 22. Z

Y

Y'

Y

X

X X

X N

Y

N FeIII

Z

N

N Y'

Z X

X X

Y'

X

Y'

Y Z

Catalyst 23 X=Y=Y'=H, Z=SO3Na Catalyst 24 X=Z=CH3, Y=H, Y'=SO3Na Catalyst 25 X=Cl, Y=Z=H, Y'=SO3Na

Fig. (17).

peroxide and a manganese complex based on 1,4,7trimethyl-1,4,7-triazacyclononane [Mn2O3(tmtacn)2](PF6)2 as catalyst has also been reported [195]. Catalytic oxygenation of cholesterol 26 with a platinum black catalyst under moderate pressure (20-25 atm) of oxygen afforded cholest-4ene-3,6-dione 11 (scheme 27) in poor yield [196]. 5. REMOTE FUNCTIONALIZATION The direct remote functionalization of steroids with high predictability and specificity has long been attempted, and constitutes an area of increasing interest. It involves the achievement of selective reactions at arbitrarily large distances from any functional groups of the substrate [197]. Several reviews on the subject have been published [197198]. The predominant target in many studies has been 25hydroxycholesterol due mainly to its interesting biological properties and its ability to be dehydrated to desmosterol, which can be further chemically modified. 25-Hydroxy-


R1

Salvador et al.

R1

R2

26........R1=C8H17;R2=H.......10 91 ......R1=COCH3;R2=H......12 7................R1,R2=O..............43

HO

R2

O

Catalyst 25 in AOT reverse micelles H2O2, isooctane, w0=12 (pH 7.0), r.t., 12 h

HO 92

O 93 / 52%

Scheme 26. AlMe2

Me2Al O

O

Me

Me

Fig. (18). Catalyst 26. PH2 Cl

P Ru P

Cl PH2

Catalyst 27 [S-BINAP]-RuX2

Fig. (19).

cholesterol is known to be a very potent inhibitor of 3hydroxy-3-methyl-glutaryl CoA reductase, a key regulatory enzyme in cholesterol biosynthesis [198c]. Furthermore, the C-25 hydroxylation of cholestane derivatives is a key step in the synthesis of the 1,25-dihydroxyvitamin D3 [199]. Several 5-hydroxysteroids occur in nature [200]. C-5 Oxyfunctionalization of steroids represents a key step in the conversion of bile acids into androgen and progestogen hormones [102; 201]. Selective C-9 hydroxylation is important because 9-hydroxysteroids can be dehydrated to introduce the C-9(11) double bond which permits synthesis R1

HO

Scheme 27.

of corticosteroids with oxygen at C-11 and fluorine at C-9, an important class of medicinal compounds [202]. Several stoichiometric procedures for remote functionalization reactions in steroids have been reported. Breslow et al. have attempted to mimic the regioselectivity of enzymatic processes in which selective oxidation of unactivated positions in substrates is directed by the geometry of the enzyme-substrate complex [198a]. This "remote oxidation" was firstly achieved using attached reagents or templates to steroid substrates to direct photochemical and free radical processes, using a combination of both geometric and reactivity control. Thus, directed photochemical reactions and chlorinations, including the "radical relay mechanism", in steroid substrates were reported [198d]. "Meta"-substituted tetraphenylporphyrins attached to 5-androstan-3ol derivatives have shown to lead to oxidation in the presence of PhIO [203]. Hydroxylations at either C(9) and/or C(12) of the steroid nucleus have been carried out by "ortho"-substituted porphyrins attached to the C(17) position of 5-androstane [204]. The use of manganese(III) salen (N,N'-bis-(salicylideneamino)ethane) complexes attached to steroid substrates also mediated the hydroxylation of unactivated carbons with PhIO as the oxygen atom source [205]. Tri- or bidentate ligands with N-donor atoms for copper complexation covalently attached to the steroid nucleus have been used as directing groups for the regio- and stereoselective hydroxylation of nonactivated C-H bonds of steroid substrates, using molecular oxygen as the oxidant. Hydroxylations in the -position relative to the central Natom occurred in relatively low yields [206]. More recently, R1

R2

26........R1=C8H17;R2=H........11 91 ......R1=COCH3;R2=H......13 7................R1,R2=O..............94

O O

R2



O

O Cl8TPPFeIIICl

HO

(0.01 equivs.)

O 43

O O

CumOOH (0.25 equivs.), N-methylimidazole, dry CH2Cl2, 25˚C, 12 h

CH

O 95 / 31.3% O

96 / 15.7% O

HO 97 / 32.1%

Scheme 28.

OH Mn(III) catalyst (0.025 equivs.), O2

HO 26

ascorbic acid (50 equivs.), Tris pH 8.6 buffer, r.t., 15 h

HO 98 / 2%

Scheme 29.

-hydroxylations have been performed with better yields [206-207]. Other stoichiometric procedures have been reviewed by Reese [198e] and include: the hypohalite reaction, nitrite photolysis (Barton reaction), ketone irradiations, the nitrene reaction, the Hoffmann-Loffler-Freytag reaction, the lead tetraacetate reaction (LTA), anodic oxidation, the free radical decomposition of peracids, peroxide reactions and the use of dioxiranes [208], perfluorodialkyloxaziridine, ceric ammonium nitrate (CAN), chromium trioxide and hypervalent organoiodine reagents [209]. The use of ozone absorved on silica gel has been reported for the synthesis of 1,25dihydroxyvitamin D3 [199a] and also for the C-25 functionalization of cholestane derivatives [210]. 5.1. Catalytic Remote Functionalization The interesting Gif systems [211] (iron catalyst-metallic zinc-pyridine-aqueous acetic acid) have been applied by Barton et al. to a series of cholestane derivatives. In almost all cases, the 20-ketone was obtained as the major product although yields were generally low [212]. However, when the process was applied to cholest-4-en-3-one 10 below 0ºC, less side-chain cleavage occurred and 25-hydroxycholest-4en-3-one was obtained as the major product [213]. The oxidation of androst-4-ene-3,17-dione 43 with CumOOH, catalyzed by chloroiron(III)-5,10,15,20-tetraarylporphinate/ N-methylimidazole systems was reported by Chauhan et al. An oxidation of C-19 was observed along with aromatization of the A-ring (scheme 28) [214]. A steroidal manganese(III) porphyrin positioned in a synthetic bilayer assembly was

used in the selective 25-hydroxylation of cholesterol 26 (scheme 29). Thus, chloro[,,,-meso-tetrakis[o-(3-hydroxy-5-cholenamido)phenyl]porphyrinato]manganese(III) was used to perform this reaction under aerobic conditions with ascorbic acid as the reducing agent, in low yield but good selectivity [215]. The oxidation of steroid compounds with 2,6-Cl2pyNO catalyzed by ruthenium porphyrins (Fig. 3), in the presence of HBr has also been investigated. The best results have been obtained in the oxidation of 5steroids to the corresponding 5-hydroxy derivatives [216]. The remote oxyfunctionalization of methyl 3-acetoxy5-cholan-24-oate 99 and methyl 3-oxo-5-cholan-24-oate 102 with 2,6-Cl2pyNO catalyzed by (5,10,15,20-tetramesitylporphyrinate)ruthenium(II) carbonyl complex (Fig. 3) and HBr afforded the corresponding 5-hydroxy compounds 100, 103 along with 5,20S-dioxygenated derivatives 101, 104 (as the -lactones) and 20S-mono derivative 105 (scheme 30) [217]. More recently, the same system has been applied to a series of 3-oxobile acids 106, 108, 112. The remote oxyfunctionalization of the methyl ester-peracetylated derivatives of 3-oxobile acids with a 12-acetoxyl group 106 resulted primarily in 5-hydroxylation, while (20S)-24,20-lactonization predominated for 3-oxobile acids having 3-oxo and 7-acetoxyl substituents 108, 112 (scheme 30) [218]. Complete domination by the geometry of the catalystsubstrate complex was first achieved in the selective hydroxylations of steroids by use of a mimic of the enzyme class cytochrome P-450 [198d]. Biomimetic regioselective template-directed functionalizations in steroid substrates


Salvador et al.

COOCH3

O

COOCH3

O

O R5

R5

+ R4

R1 R2

H

R3

R2

99......R1=H;R2=OAc;R3=R4=R5=H......100 / 54%

R4 R2

R3

OH

+

R1

R4

R1

O

R5

R5

+

R1

R3

OH

R4 R2

101 / 11%

H

R3

+ 5β-OH-15-ketone derivative / 11%

102.........R1,R2=O;R3=R4=R5=H...........103 / 30%

+

104 / 19%

+

105 / 17%

+ Δ4-3-ketone derivative / 3% + Δ4-3-ketone

106.....R1,R2=O;R3=R4=H;R5=OAc.......107 / 25%

derivative / 19% 108.....R1,R2=O;R3=OAc;R4=R5=H.......109 / 19%

+

110 / 9%

+

111 / 21%

+ Δ4-3-ketone derivative / 8%

112...R1,R2=O;R3=H;R4=OAc;R5=H.....113 / 18%

+

114 / 3%

+

115 / 29%

+ Δ4-3-keto-20(S)24,20-γ-lactone derivative / 10%

Scheme 30.

S

X

X

X

X

X X

X N

X

N Mn

S

N

N X

S X

X X

X

X

X

X

S Catalyst 28: X=H Catalyst 29: X=F

=cyclodextrin

Fig. (20).

were achieved by Breslow et al. who created true enzyme mimics in which substrates, reversibly bound to a metalloporphyrin with defined geometry, were catalytically functionalized with full geometric control and many catalytic turnovers.

Using PhIO as the oxidant, the selective 6hydroxylation of a diester of androstane-3,17-diol, with tert-buthylphenyl hydrophobic binding groups and solubilizing sulfonate groups 116 (scheme 31) was first achieved with catalyst 28 (Fig. 20), a manganese porphyrin linked to



O O

N H

SO3H

O O HO3S

O

N H

H

H

O H 116 PhIO, Catalyst, r.t.

O O

N H

SO3H

O O HO3S

O

N H

H

H

O H

OH

117

Scheme 31.

-cyclodextrin by phenyl linkers, in c.a. 40% conversion and at least 4 turnovers [219]. Metal ligands such as pivalate anion or pyridine were added to the system to coordinate to and block one face of the catalyst. No further oxidation of the 6-hydroxy to the 6-keto compound occurred although in solution in the absence of special binding, steroidal secondary alcohols are readily oxidized to ketones by metalloporphyrin catalysts.

Perfluorination of the phenyl rings of the catalyst 28 produced catalyst 29 (Fig. 20), which led to 187 catalytic turnovers for the same process [220]. The electron withdrawing effect of fluorine atoms increased the rate of the catalytic process and stabilized the porphyrin system to oxidative destruction. 2000 Turnovers were achieved for this conversion by incorporation of a pyridine moiety that could complex the manganese in the catalyst 30 centre (Fig. 21)

S

F

F

F

F

F F

F N Mn

S N F

S N F

F

H

F N

N


F

N

O


Salvador et al.

S F

F

F

F F

F

F

N

F

N Mn

S

S N

N

F

F

F

F

NO2


[221]. Catalyst 31 (Fig. 22) with a nitrophenyl group as the fourth substituent performed the 6-hydroxylation of substrate 116 with 3000 turnovers (scheme 31). Selective 9-hydroxylation of the triply bound substrate 118 was reported using catalyst 29 (Fig. 20) and excess

oxidizing agent with at least 10 catalytic turnovers (scheme 32) [222]. With substrate 120, in the presence of catalyst 29 (Fig. 20) and PhIO as the oxidant, the formation of the 9hydroxylated species occurred although an almost equal O O

N H

SO3H

O O HO3S

N H

O H O

H O

H

O

O N H

118 PhIO (10 equivs.), Catalyst 29 (0.01 equivs.), water, pyridine, r.t., 2 h 40 min.

SO3H

O O

N H

O O HO3S

N H

O OH O

H O

H

O

O 119

Scheme 32.

N H

SO3H

SO3H



Y

S

X

X

X X

X

X

N Mn

Y

Y N

N

X

X

S

S

N

X

X

X

X

S

Y

Catalyst 32: X=H; Y=CH Catalyst 33: X=F;Y=N

Fig. (23). O

O

O HO3S

N H

O OH O

O

HO

O

OH

O N H

SO3H

120

121

Scheme 33.

amount of a second product, the C-15 hydroxylated alcohol, was formed. When catalyst 32 (Fig. 23) was used, better selectivity was achieved despite the low turnover. A more robust catalyst 33 performed the hydroxylation of substrate 120 to produce triol 121 after hydrolysis, with 90 turnovers and again with essentially complete selectivity for hydroxylation at C-9 (scheme 33) [223]. The fact that the intrinsic reactivities of double bonds and to some extent, of alcohol groups, can be overcome by geo-

metric control has been demonstrated by the hydroxylation of both lithocholic 122 and lithocholenic acids 123 (Fig. 24) using catalyst 29 (Fig. 20). Lithocholic acid 122 has been found to strongly bind to -cyclodextrin because of its A,B ring cis fusion [224]. No added esters groups were needed to perform the hydroxylation of either lithocolic 122 or lithocholenic acids 123 with this catalyst. However, the reaction was not completely selective. Thus, hydroxylations in ring A, B and C occurred. Some oxidation of the 3O

O

OH

OH

HO

HO H

Fig. (24).

122 (litocholic acid)

H 123 (litocholenic acid)


Salvador et al. X N

X N

N X

N X S F

F

F

F

NX XN

XN F

F

F N

NX

N Mn

S

S XN

N

N F

XN

F

F

F

NX

F

NX F

F

F

F S X N

X N

N X

N X

Catalyst 34: X= COCH2NMe3+, Cl-

Fig. (25).

hydroxyl to a ketone has also been observed. No oxidation occurred in the central position of the steroid, either in the double bond or allylic to it, in lithocholenic acid 123. The fact that ring C of the steroid structure is buried inside the cyclodextrin ring of the porphyrin suppresses attack on the more reactive double bond in favour of hydroxylation of unactivated methylene groups [198d; 221; 222b]. Catalyst 34 (Fig. 25) has been synthesized with a manganese-porphyrin unit linked to four hydrophobic cyclophane binding groups and has shown somewhat higher catalytic turnovers before it is destroyed. However, it is less

selective in terms of product formation. 30% Conversion of the substrate 116 to the 6-hydroxylated product 117 with 400 catalytic turnovers has been achieved (scheme 31). 10% Conversion of this substrate to the 15-hydroxylated product was observed, which had not been previously reported using the cyclodextrin-based catalysts [225]. The aromatic steroid equinelin acetate 124 has been hydroxylated at C-6 with good catalytic turnover by PhIO, catalyzed by chloro[5,10,15,20-tetrakis(pentafluorophenyl) porphyrinato]manganese(III) [Mn(TFPP)Cl] (scheme 34) [226].

O

O

O HO

[Mn(TFPP)Cl] (0.02 equivs.)

AcO

Scheme 34.

124

PhIO (5 equivs.), CH2Cl2, 23˚C, 12 h, 57% conversion

+ AcO

AcO OH 125 / 42%

126 / 15%



here. In the presence of Cu2+ ions, a manganese porphyrin having four 2,2'-bipyridyl groups on its meso positions (Fig. 26) catalyzed the regioselective oxidation of steroid substrates carrying auxiliary metal coordinating groups. The androstanolone derivative 127 was initially oxidized in the presence of catalyst 35 using 10 equivalents of PhIO (scheme 35). Products 128–130 all derived from oxidation on the D ring of the steroid were obtained in 10, 3, and 7% yield, respectively, with 20% total conversion. The epiandrosterone derivative 131 appeared to be slightly less reactive than 127 and was selectively oxidized to the 6-hydroxy derivative 132, with very low conversion (3%) [227].

N

N

Cl-

N

N

N

N +Mn N

N

N

N

6. CONCLUDING REMARKS AND FUTURE PERSPECTIVES Substantial work has been carried out on the oxidative processes in steroid chemistry over the last decades. Their importance lies in their application to the synthesis of complex compounds or intermediates in their synthesis with interesting biological activities, in more simple, facile and less expensive steps. Environmental constraints and the need to meet the demands of industrial scale production have empowered the search for catalytic oxidative processes. Thus, major progress has been seen in terms of catalyst synthesis/ recovery, selectivity and efficiency. However, despite the fact that catalysis is appealing, stoichiometric methods have

N

N


Some selectivity in steroid hydroxylation promoted by complexes in which catalyst and substrate are linked by a bridging copper ion has also been reported. However, these systems were not as selective as the ones previously reported O

O

L

L

O

O O L

Catalyst 35 (0.45 equivs.)

O

PhIO (10 equivs.),

O

Cu

2+,

OH OH

O +

CH3CN/CH2Cl2,

127

128 / 10%

Ar, r.t., 16 h, 20% conversion

O

O +

129 / 3% L

O

O O 130 / 7%

O

O

Catalyst 35 (0.2 equivs.) PhIO (10 equivs.),

O

L O

Cu2+, CH3CN/CH2Cl2,

131

Ar, r.t., 16 h, 3% conversion L=

Scheme 35.

N

N

O

L O

OH 132 / 3%


still not lost interest and continue to be used especially in the laboratory scale. Catalysts are sometimes difficult to synthesize, are unstable, display a low number of turnovers or do not allow easy work-ups. It is also important for the catalysts to be easily recycled and reused although this is not always the case. Therefore, the future will probably lie in the continuous improvement of these methods, as well as in the development of new catalytic steroidal oxidative processes involving the combination of homogeneous or heterogeneous catalysis with new green technologies such as sonochemistry, microwaves or ionic liquids. ACKNOWLEDGEMENTS Jorge A.R. Salvador thanks Universidade de Coimbra for financial support. Samuel M. Silvestre thanks Fundação para a Ciência e a Tecnologia for a grant (SFRH/BD/ 11087/2002). Vânia M. Moreira thanks Fundação para a Ciência e a Tecnologia for a grant (SFRH/BD/12508/2003). We are grateful to Prof. Maria Luísa Sá e Melo and Prof. Maria Manuel Cruz Silva (Centro de Estudos Farmacêuticos, Universidade de Coimbra) and Prof. Hugh Burrows (Departamento de Química, Universidade de Coimbra), for the helpful discussions with which they kindly privileged us.

Salvador et al. [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36]

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[54] [55]

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