ChemInform Abstract: Recent Developments in Oxidative Processes in Steroid Chemistry

Current Organic Chemistry, 2012, 16, 1243-1276 1243

Recent Developments in Oxidative Processes in Steroid Chemistry

Jorge A.R. Salvadora,b,*

, Samuel M. Silvestrec and Vânia M. Moreira

b

aGrupo de Química Farmacêutica, Faculdade de Farmácia da Universidade de Coimbra, Pólo das Ciências da Saúde, Azinhaga de

Santa Comba, 3000-548, Coimbra, Portugal

bCentro de Química de Coimbra, Faculdade de Ciências e Tecnologia da Universidade de Coimbra, Rua Larga, 3004-535 Coimbra,

Portugal

cHealth Sciences Research Centre, Faculdade de Ciências da Saúde, Universidade da Beira Interior, Av. Infante D. Henrique, 6200-

506 Covilhã, Portugal

Abstract: Oxygenated steroids are bioactive compounds and valuable intermediates in the synthesis of biologically active products and

APIs. This review will cover the literature from 2005/06 to the present concerning allylic oxidation, epoxidation and syn-dihydroxylation

of alkenes, alcohol oxidation, and remote functionalization reactions of steroidal substrates.

Keywords: Alcohol oxidation, Allylic oxidation, Catalysis, Epoxidation, Oxidative processes, Remote functionalization, Steroids, syn-

dihydroxylation.

1. INTRODUCTION

Steroid compounds are widely distributed in nature and are

challenging substrates for the synthesis of a wide variety of impor-

tant biologically active molecules. In this context, the oxidation of

several positions of the steroid core is of great importance and can

be achieved by means of several oxidative methods. In fact, sub-

stantial work has been carried out on the oxidative processes in

steroid chemistry over the last decades. Environmental constraints

and the need to meet the demands of industrial scale production

have empowered the search for more sustainable oxidative proc-

esses with special emphasis on catalysis [1]. Thus, major progress

has been seen in terms of synthesis, recovery, selectivity and effi-

ciency of the catalyst. However, despite the fact that catalysis is

appealing, stoichiometric methods have still not lost interest and

continue to be used especially in the laboratory scale.

We have previously reviewed several catalytic oxidation reac-

tions on steroid substrates. In the first work which covered literature

up to 2005, allylic oxidation, -selective epoxidation, alcohol oxi-

*Address correspondence to this author at the Grupo de Química Farmacêutica, Facul-

dade de Farmácia da Universidade de Coimbra, Pólo das Ciências da Saúde, Azinhaga

de Santa Comba, 3000-548, Coimbra, Portugal, Tel: +351 239 488 400; Fax: +351 239

488 503; E-mail: [email protected]

dation, and remote functionalization reactions were considered. In a

second work, the catalytic processes that lead mainly to the forma-

tion of -epoxides and syn-diols from steroidal alkenes were dis-

cussed considering literature up to 2006. This review is now de-

voted to updating the methods reported for the allylic oxidation of

alkenes to enones, epoxidation, alcohol oxidation, remote function-

alization and syn-dihydroxylation reactions on steroid substrates,

from 2005/06 to present. It is divided into sections according to the

reactions considered and within each section the discussion is made

relative to the positions of the steroid core where the oxygenated

functionalities are introduced. Each section also includes the exam-

ples that highlight the biological and synthetic relevance of some of

the compounds that can be synthesized using these reactions. Bio-

catalytic oxidative processes which are available to perform these

reactions have not been considered herein.

2. ALLYLIC OXIDATION

The production of allylic alcohols, esters, ethers, and , -

unsaturated carbonyl compounds has proven to be an important

reaction for the production of interesting intermediates as well as

compounds with diverse biological activities [2-4]. In the steroid

field and regarding the allylic oxidation of steroidal alkenes to the

corresponding enones, 5-7-ketones are good examples (Scheme 1).

R1

R2

R3

R1

R2

R3

1.....R1=OAc;R2=C8H17;R3=H.....2

3.....R1=OBz;R2=C8H17;R3=H.....4

5......R1=OH;R2=C8H17;R3=H......6

7.......R1=OAc;R2=OH;R3=H.......8

9............R1=OH;R2,R3=O...........10

O

Scheme 1.

1875-5348/12 $58.00+.00 © 2012 Bentham Science Publishers

1244 Current Organic Chemistry, 2012, Vol. 16, No. 10 Salvador et al.

They can be found in nature and are useful in the treatment of dis-

eases such as cancer, Alzheimer disease, and immune deficient

disorders. Also, a number of 5-7-keto steroids have been used not

only as intermediates in the preparation of biologically active

agents but also as the privileged scaffolds or probes in several stud-

ies [5-8].

The allylic oxidation of 5-steroidal substrates to the corre-

sponding , -unsaturated enones has been achieved by several

stoichiometric methods mostly by use of chromium(VI) reagents.

These include CrO3 in acetic acid, t-butyl chromate or sodium

chromate in acetic acid, CrO3-pyridine complex, CrO3 and 3,5-

dimethyl-pyrazole, CrO3 and benzotriazole, pyridinium chloro-

chromate (PCC), pyridinium dichromate (PDC), PDC-tert-butyl

hydroperoxide (TBHP), sodium dichromate in acetic acid, pyridi-

nium fluorochromate, 3,5-dimethylpyrazolium fluorochromate(VI)

and a combination of a N-hydroxydicarboxylic acid imide with a

chromium containing oxidant [9]. A new chromium oxidizing rea-

gent pyridinium-1-sulfonate fluorochromate (PSFC) has been re-

cently reported for the allylic oxidation of cholesteryl acetate 1 and

benzoate 3 (Scheme 1 and Table 1, entry 1) [10]. A system com-

prising CrO3/N-hydroxyphthalimide (NHPI) supported on activated

clay has been reported to effectively oxidize several 5-sterols to

the corresponding 5-7-ketosterols (Scheme 1 and Table 1, entry 2)

[11].

Stoichiometric methods avoiding chromium reagents have also

been reported and include the use of irradiated solutions in the pres-

ence of N-bromosuccinimide in moist solvents or HgBr2, oxygen or

an oxygen containing gas in an inert solvent in the presence of a N-

hydroxydicarboxylic acid imide, sodium hypochlorite in combina-

tion with aqueous TBHP, and a combination of periodic acid or

metal periodate and an alkyl hydroperoxide under normal as well as

elevated pressure of a suitable gas such as air [9]. Among the metal-

free based processes, the combination of sodium chlorite and TBHP

in stoichiometric amounts has been reported to efficiently convert 5-steroids to the corresponding 7-ketone derivatives (Scheme 1

and Table 1, entry 3) [12]. 1-(tert-Butylperoxy)-1,2-benziodoxol-

3(1H)-one and the combination of diacetoxyiodobenzene (DIB) and

TBHP have also been used as efficient oxidants for the allylic oxi-

dation of 5-steroids (Scheme 1 and Table 1, entry 4) [13, 14].

Efforts to eliminate the use of ecologically and physiologically

undesirable chromium reagents as well as the common drawbacks

associated with stoichiometric procedures, especially if used on a

commercial scale, have been made through the development of

catalytic methods to efficiently perform this transformation. Hy-

droperoxides such as TBHP combined with different types of metal

catalysts under homogeneous conditions have been extensively

used to perform allylic oxidations on steroid substrates [9]. Previ-

ously used catalysts include chromium (VI) compounds such as

CrO3, bis-(tributyltin oxide) dioxochromium(VI), tert-

butylchromate, CrO3 in the presence of an amine and PCC (Scheme

1 and Table 1, entries 5 and 6). This last method resulted in im-

provement of the reaction yield [15, 16]. Hexacarbonyl chromium

and Cr(IV) complexes have also been used for this transformation

under catalytic conditions [9] as well as the following metal cata-

lysts: ruthenium trichloride, Cu(I) and Cu(II) salts or Cu metal,

Co(OAc)2, ferric acetylacetonate [Fe(acac)3], and bismuth (III) salts

[9, 17]. Recently, the allylic oxidation of 5-steroidal alkenes to the

corresponding enones (Scheme 1 and Table 1) using

Mn(OAc)3.3H2O and TBHP, under N2 atmosphere has been re-

ported, in good yields (Table 1, entry 7) [18]. Excellent chemose-

lectivity was observed as shown by 17 -hydroxyandrost-5-en-3 -yl

acetate 7 which was oxidized into the corresponding 7-ketone de-

rivative 8 without concomitant oxidation of the secondary hydroxyl

group. The allylic oxidation of several 5-steroids into the corre-

sponding 7-ketone derivatives has also been performed with dirho-

dium caprolactamate and 70% TBHP in water (Table 1, entry 8)

[19]. Using this method, the 3 -hydroxyl group remained un-

changed throughout the procedure. An important intermediate for

the synthesis of vitamin D3 has been prepared from cholesteryl

acetate 1 using an environmentally benign method for the allylic

oxidation comprising O2 in the presence of NHPI and

Co(OAc)2/Mn(OAc)2 (Table 1, entry 9) [20]. An allylic oxidation

method for 5-steroids using TBHP with 2-quinoxalinol salen

Cu(II) complex as catalyst (Catalyst 1, Figure 1) (Table 1, entry 10)

has been very recently reported [21].

N

NN

N OH

O

O

Cu2+

Catalyst 1

Fig. (1).

Several methods have been reported for the allylic oxidation of 5-steroids using a cleaner technology in which the catalysts are

immobilized on heterogeneous supports. This technology eliminates

the difficulty in the separation of the catalysts from the reaction

medium and may allow their recovery and reuse. Previously re-

ported heterogeneous catalysis methods for the allylic oxidation of 5-steroids involve the combination of TBHP and the following

metal catalysts: KMnO4/SiO2 in benzene or chromium(VI) ad-

sorbed on SiO2/ZrO2, cobalt(II), copper(II), manganese(II) and

vanadium(II) immobilized on silica and BiCl3/montmorillonile K-

10 [9]. Metal-free ecofriendly synthetic transformations bear the

advantage of avoiding the use of toxic and expensive metals and are

especially attractive for the preparation of compounds that do not

tolerate metal contamination such as active pharmaceutical ingredi-

ents (APIs). In this context, our group has recently reported that

various 5-steroidal substrates could be selectively oxidized to the

corresponding enones, in good yields, using sodium chlorite associ-

ated with NHPI as catalyst (Scheme 1 and Table 1, entry 11) [12].

Steroidal 4-3,6-diketones can be obtained by allylic oxidation

of the corresponding 4-3-ketones (Scheme 2). This transformation

has been performed with aqueous sodium peroxide, oxidizers with

reversible redox potentials, and sodium hypochlorite in combina-

tion with aqueous TBHP, in stoichiometric amounts. Catalytic

methods for the allylic oxidation of 4-3-ketones have been re-

ported and involve the use of CrO3 in the presence of TBHP and

2,6-dichloropyridine N-oxide (DCPNO) in the presence of the

Ru(IV) porphyrin [RuIV

(2,6-Cl2TPP)Cl2] (TPP=tetraphenylporphy-

rinate) [9]. A recent development in this transformation consisted in

the use of catalytic amounts of both NHPI and 2,2’-azobis(4-

Recent Developments in Oxidative Processes in Steroid Chemistry Current Organic Chemistry, 2012, Vol. 16, No. 10 1245

methoxy-2,4-dimethylvaleronitrile) [V70] for the aerobic oxidation

of androst-4-ene-3,17-dione 11 affording androst-4-ene-3,6,17-

trione 12 in 12% yield, along with 6-hydroperoxyandrost-4-ene-

3,17-dione, in 56% yield (Scheme 2 and Table 2, entry 1) [22]. A

new system comprising dirhodium caprolactamate and 70% TBHP

in water has been applied to the allylic oxidation of several steroidal 4-3-ketones to afford the corresponding

4-3,6-diketones, in mod-

erate to good yields (Scheme 2 and Table 2, entries 2-5). Interest-

ingly, water could be used as the solvent for this reaction [23].

The stoichiometric allylic oxidation with chromium based rea-

gents of 16

-steroidal compounds has afforded the corresponding 16

-15-oxo intermediates for the synthesis of cytotoxic certonardos-

terols 21 and 22 (Scheme 3) [24, 25] and the shark repellent pavon-

inin-4 25 (Scheme 4) [26, 27]. Dihydroeuphol acetate 26 has been

oxidized by a system consisting of meso-5,10,15,20-tetramesityl-

porphyrinate osmium (II) carbonyl complex [Os(TMP)CO] (Cata-

lyst 2, Figure 2) and TBHP to afford 25-hydroxy-7,11-dioxo-euph-

8-en-3 -yl acetate 27 (Scheme 5) [28].

3. EPOXIDATION

Epoxides are versatile intermediates in organic syntheses [29].

Steroid epoxides can be found in nature, being participants or prod-

ucts of selective biological oxidations. Several natural and synthetic

- and -epoxysteroids have relevant biological activities which

account for the interest in their stereoselective synthesis along the

years [30-36]. It is well established that the stereochemistry of ep-

oxidation reactions on steroidal substrates is modulated by the

shielding of the -side of the steroid nucleus by the two angular

methyl groups at C10 and C13 (Figure 3), and that therefore the -

epoxide is invariably the major reaction product. Steroidal -

epoxides have been traditionally obtained by use of peroxyacids

[37]. -Epoxides can be obtained by using a combination of KMnO4

Table 1. Allylic Oxidation of 5-steroids

Entry Substrate Reaction Conditions Product/Yield Ref.

1 1 PSFC (5 eq.), CH3CN, r.t., 120 min. 2 / 85% [10]

2 5 CrO3/NHPI activated clay (3.2 eq./Cr6+

content), CH2Cl2, r.t., 24-48 h 6 / 52% [11]

3 1 NaClO2 (1.2 eq.), TBHP (10 eq.), CH3CN, 60ºC, 80 h 2 / 66% [12]

4 1 PhI(OAc)2 (3 eq.), TBHP (4 eq.), nPrCO2nBu, Mg(OAc)2·4 H2O, 0ºC, 5 h 2 / 82% [14]

5 1 CrO3 (0.05 eq.), Py (0.1 eq.), TBHP (7 eq.), PhCF3, r.t., 31 h 2 / 76% [15]

6 1 PCC (0.025), TBHP (7 eq.), CH2Cl2, 40ºC, 50 h 2 / 78% [15]

7 1 Mn3O(OAc)9 (0.1 eq.), TBHP (5 eq.), EtOAc, MS3Å, N2, r.t., 48 h 2 / 87% [18]

8 1 Rh2(cap)4 (0.01 eq.), TBHP (5 eq.), CH2ClCH2Cl, 40ºC, 20 h 2 / 80% [19]

9 1 NHPI (0.1 eq.), Co(OAc)2 (0.005 eq.), Mn(OAc)2 (0.005 eq.), O2 (1 atm), acetone, r.t., 8 h 2 / 76% [20]

10 1 Catalyst 1 (0.01 eq.), TBHP (10 eq.), CH3CN/CHCl3, 70ºC, 12 h 2 / 62% [21]

11 1 NHPI (0.1 eq.), NaClO2 (1.5 eq.), 1,4-dioxane/H2O (3:1), 50ºC, 25 h 2 / 60% [12]

O O11...........R1,R2=O...........12

13.......R1=OH;R2=H.......14

15.....R1=C8H17;R2=H.....16O

R2

R1R1

R2

Scheme 2.

Table 2. Catalytic Allylic Oxidation of 4-3-ketone Steroids

Entry Substrate Catalyst Reaction Conditions Product/Yield Ref.

1 11 NHPI (0.2 eq.), V-70 (0.05 eq.) O2 (1 atm), CH3CN, 30ºC, 48 h

12 / 12%

+ 6-OOH derivative

( : =1:1) / 56%

[22]

2 11 Rh2(cap)4 (0.01 eq.) TBHP (10 eq.), CH2ClCH2Cl, 40ºC, 40 h 12 / 80% [23]

3 11 Rh2(cap)4 (0.01 eq.) TBHP (10 eq.), H2O, 40ºC, 40 h 12 / 62% [23]

4 13 Rh2(cap)4 (0.01 eq.) TBHP (8 eq.), CH2ClCH2Cl, 40ºC, 16 h

14 / 28%

+ oxidation at the 17-position /

40-50%

[23]

5 15 Rh2(cap)4 (0.01 eq.) TBHP (8 eq.), H2O, 25ºC, 48 h 16 / 50% [23]


H

H

OAc

R1O

OR2

H

H

OAc

R1O

OR2

H

H

HO

OH

OH

R

21 / Certonardosterol D2: 22, R=OH

22 / Certonardosterol D3: R=CH2OH

O

17.................................................R1=R2=MOM...................................................18 / 76%

[NOS (4 eq.), Na2Cr2O7.2H2O (1.5 eq.), acetone, 50˚C, overnight]

19...................................................R1=R2=TBS....................................................20 / 74%

[NHPI (8.4 eq.), Na2Cr2O7.2H2O (4.2 eq.), acetone, 40˚C, overnight]

Scheme 3.

BzO

H

H

OBz

BzO

H

H

OBz

OCrO3 (24.1 eq.), 3,5-DMP (24.1 eq.)

24 / 62%

CH2Cl2, Ar, -20˚C, 5h

HO

H

H

OAc

OO

OH

OH

OH

AcHN

23

25 / Pavoninin-4

Scheme 4.


N

N N

N

Os

CO

Catalyst 2

Fig. (2).

with metal salts. Metal-catalyzed epoxidations of steroidal olefins

using alkyl peroxides have been an object of interest. Also, a num-

ber of processes involving the use of green oxidants such as H2O2

and O2 and several catalysts have been reported for the epoxidation

of steroidal olefins [9, 38].

Several steroidal compounds with interesting biological activi-

ties such as aromatase or steroid sulfatase inhibition, anti-HIV ac-

tivity, as well as several bioactive oxysterols have been prepared by

means of 4,5-epoxysteroid intermediates [9]. Also, several 4 ,5 -

steroidal epoxides have been found to be cytotoxic against breast

and prostate cancer cell lines [32] whereas 4 ,5 -progesterone ep-

oxides were reported to inhibit 5 -reductase [33].

The selective preparation of 4 ,5 -epoxysteroids from several

steroid alkenes was accomplished using dimethyldioxirane

(DMDO), KMnO4/CuSO4.5H2O, perfluoro-cis-2-butyl-3-

propyloxaziridine, Ti(OiPr)4/TBHP/(D)- or (L)-diethyltartrate

(DET) in stoichiometric conditions and with catalytic Fe(TPFPP)Cl

(TPFPP=5,10,15,20-tetrakis(pentafluorophenyl porphyrinate)/H2O2

[17, 38]. The epoxidation of 4-steroidal olefins bearing allylic and

homoallylic hydroxyl groups by TBHP which is commonly per-

formed with VO(acac)2 as catalyst, affords compounds with the

desired stereochemistry due to the syn-stereodirecting effect caused

by the hydroxyl groups, an effect usually observed. The most com-

mon method for this reaction, however, involves the use of per-

oxyacids such as peroxybenzoic acid and m-chloroperoxybenzoic

acid (MCPBA) [17, 38]. Recently, the efficient preparation of 4,5-

epoxides from several 4-steroidal olefins (Scheme 6 and Table 3)

was performed using the safe and readily available magnesium

bis(monoperoxyphthalate) hexahydrate (MMPP) as oxidant sus-

pended in acetonitrile, at reflux temperature. This process was ap-

plied to cholest-4-en-3 -ol 28 and to cholest-4-en-3 -ol 31 and a

syn-stereodirecting effect was observed with the corresponding

epoxides being obtained in high yields and selectivities (Table 3,

entries 1 and 2) [39, 40]. A similar stereodirecting effect was ob-

served in the epoxidation of cholesta-4,6-dien-3 -ol 34 with

MCBPA (Table 3, entry 3) [41]. Using cholest-4-en-3 -yl acetate

R

A B

C D

3

10

13

19

18

17

H

5 -Steroid:

-face

-face

56

12

4 7

89

1112

14 1516

H

Fig. (3).

AcOH

AcOH

O

O

OH

Os(TMP)CO (0.005 eq.),

TBHP (20 eq.)

27 / 48%

PhH, MS4A, reflux, 72h

26

Scheme 5.

R3

28...........R1=H;R2=OH;R3=C8H17......................................29 + 30

31...........R1=OH;R2=H;R3=C8H17......................................32 + 33

34.........R1=OH;R2=H;R3=C8H17;6...................................35 + 36

37..........R1=OAc;R2=H;R3=C8H17.....................................38 + 39

15...............R1,R2=O;R3=C8H17..........................................40 + 41

42..............R1,R2=O;R3=COCH3........................................43 + 44

13..................R1,R2=O;R3=OH...........................................45 + 46

R1

R2

H

O

R1

R2O

R1

R2

Scheme 6.


37 as substrate for the MMPP epoxidation (Table 3, entry 4) a

slower reactivity was however found to occur when compared to

the previous allylic alcohols, and the corresponding 4 ,5 -epoxide

38 was preferentially formed probably due to steric hindrance and

the lack of coordination between MMPP and the allylic hydroxyl

group. The epoxidation of the 4-3-ketones cholestenone 15, pro-

gesterone 42, and testosterone 13 (Scheme 6 and Table 3, entries 5-

7) with this MMPP procedure afforded the corresponding epoxides,

in low to moderate yields, and the -isomer was predominant [39,

40]. The combination of an iron(II) salt with 4,4´,4´´-trichloro-

2,2´:6´,2´-terpyridine produced an effective catalyst (Catalyst 3,

Figure 4) for the epoxidation of several alkenes, including testos-

terone 13, in the presence of oxone. After 2 hours at room tempera-

ture this steroid substrate was selectively oxidized to the corre-

sponding epoxide with an : ratio of 3:1, and the unprotected hy-

droxyl group remained unchanged (Table 3, entry 8) [42].

N

O-PEG-OCH3

NN

ClCl

Fe

N

NN

ClCl

O-PEG-OCH3

2+

PEG = polyethylene glycol

Catalyst 3

Fig. (4).

The -selective epoxidation of several 4-steroids can be per-

formed by stoichiometric processes including the use of alkaline

H2O2, Fe(acac)3/H2O2, TBHP/LiOH, MoO5 HMPTA

(HMPTA=hexamethylphosphoric triamide), DMDO and

KMnO4/metal sulphates and by catalytic methods such as the fol-

lowing combination of reagents under homogeneous conditions:

Mn(III) porphyrins/H2O2, ruthenium porphyrins/DCPNO or hetero-

geneous conditions: manganese(III) porphyrin/iodosylbenzene

(PhIO) [9, 17]. The ruthenium(II) TFPP carbonyl complex

[Ru(TFPP)CO] covalently attached to functionalized silica (Cata-

lyst 4, Figure 5) has been found to efficiently catalyze the -

selective epoxidation of several steroids with DCPNO as oxidant.

When applied to cholestenone 15 (Scheme 6), this supported Ru

catalyst also afforded the corresponding 4 ,5 -epoxide 41 with

99% selectivity, however with low conversion and yield (Table 3,

entry 9) [43].

Mixtures of 5 ,6 - and 5 ,6 -epoxysteroids are present in sev-

eral naturally occurring compounds, such as the anticancer witha-

nolides [34] and various epoxysitosterols isolated from Rhododen-

dron formosanum [44]. Several other 5 ,6 -epoxysteroids can also

be found in marine sponges [45, 46] and soft corals [47], for in-

stance, and have shown interesting cytotoxicities. In addition, some

naturally occurring secosterols [9, 48], stoloniferones [35] and

sinugrandisterols [49] have the 5 ,6 -epoxide functionality. Both

5 ,6 - and 5 ,6 -epoxysterols have been found to exhibit selective

cytotoxic activity against a panel of tumor cell lines [36, 40]. The

N

N N

N

F F

F

F

F

F

FF

F

F

F

Ru

CO

Catalyst 4

F F

F

F

FF

F

F

NH

SiO2

Fig. (5).

Table 3. Epoxidation of 4-steroids

Entry Substrate Reaction Conditions Product/Yield Ratio : Ref.

1 28 MMPP (1.1 eq.), CH3CN, reflux, 5 min. 29 + 30 / 81% 84:16 [39]


3 34 MCPBA (1.16 eq.), CHCl3, N2, r.t., 18 h

36 / 48%

+ 4 ,5 ,6 ,7 -diepoxy derivative /

12%

- [41]


5 15 MMPP (4.1 eq.), CH3CN, reflux, 5 h 40 + 41 / 53% 85:15 [39]



8 13 Catalyst 3 (0.05 eq.), oxone (1.3 eq.),

CH3CN, H2O, NH4HCO3, r.t., 2 h 45 + 46 / 84% 75:25 [42]

9 15

Catalyst 4 (0.01 eq.), DCPNO (2 eq.),

CH2Cl2, N2, 40ºC, 72 h,

42% conversion

40 + 41 / 32% 1:99 [43]


epoxystigmastanes (22R,23R)-5 ,6 -oxido-3 -,22,23-trihydroxy-

stigmastane and the analog 5 ,6 -epoxide are moderately toxic

towards MCF-7 cells [50]. Moreover, steroidal 5 ,6 - and 5 ,6 -

epoxides of 17-picolyl and picolinylidene androstane derivatives

have been synthesized as potential aromatase inhibitors and some

5 ,6 -epoxide picolinylidene derivatives inhibited the growth of

MDA-MB-231 and PC-3 cells [32]. Epoxysteroids are also interest-

ing intermediates in the preparation of several bioactive steroids [9,

38] as exemplified by the synthesis of the cardioactive steroid oua-

bain from a 5 ,6 -epoxysteroid [51].

As previously mentioned, the selective preparation of 5 ,6 -

epoxysteroids has been performed by the reaction of 5-steroids

with isolated peroxyacids such as peroxybenzoic, p-(metoxy-

carbonyl)peroxybenzoic, pentafluoroperoxybenzoic, MCPBA and

monoperphthalic acids or by the in situ generation of the peroxya-

cid [17, 38]. Recently, the preparation of 5 ,6 -epoxides from

several 5-steroidal olefins (Scheme 7 and Table 4) was performed

with MMPP as oxidant suspended in acetonitrile, at reflux tempera-

ture. This process afforded excellent yields and good chemo-, regio-

and stereoselectivities within very short reaction times (Table 4,

entries 1-4). For example, with substrates such as stigmasterol 56

and 16-dehydropregnenolone 62, in spite of the presence of a sec-

ondary hydroxyl group and an additional double bond, only stereo-

selective 5 ,6 -epoxidation was observed (Table 4, entries 2 and

3). However, with cholest-5-ene-3 ,4 -diol 49 as substrate, a syn-

stereodirecting effect of the allylic 4-hydroxyl group was observed

favoring the attack by the -face, thus preferentially yielding the

cis-diastereoisomer 51 (Table 4, entry 4) [39, 40]. A similar stereo-

directing effect was found to occur due to hydrogen bonding be-

tween an hydroxyl group of the substrate and the oxidant, was ob-

served in the MCPBA epoxidation of several 5-sterols bearing

allylic [52] and homoallylic hydroxyl groups [51]. 5 ,6 -

Epoxysteroids can also be selectively prepared in stoichiometric

conditions with the MoO5 HMPTA complex, 2-hydroperoxyhexa-

fluoro-2-propanol, Ti(OiPr)4 and TBHP, sodium perborate in gla-

cial acetic acid, perfluoro-cis-2-butyl-3-propyloxaziridine, oxazirid-

R1

C8H17

R1 R1O

R R RO O

O

C8H17

O

66 6765

O

5............R1=OH;R2=H..............................47 + 48

49........R1=OH;R2=OH.............................50 + 51

1..........R1=OAc;R2=H..............................52 + 53

3..........R1=OBz;R2=H..............................54 + 55

R2

HO

O

HO HO

O

63 6462

O

R2 R2

56............R=OH........................................57 + 58

59...........R1=OAc......................................60 + 61

Scheme 7.


inium tetrafluoroborate, 18

O2/isobutyraldehyde, and with dioxiranes

either isolated or generated in situ [38]. The reaction of dioscin

pivalate 68 with the in situ generated DMDO, by the combination

of acetone and oxone in the presence of NaHCO3, selectively af-

forded the corresponding 5 ,6 -epoxide-16 -hydroxy derivative 69

(Scheme 8) [53]. Under similar reaction conditions, t-

butyldimethylsilyldiosgenin afforded, however, a 1:1 mixture of -

and -epoxides [54, 55]. Catalytic methods described for the -

selective epoxidation of 5-steroids include the following combina-

tions of oxidant/catalyst: NaOCl/Mn(TPP)OAc, several hydroper-

oxides/Mo(CO)6, H2O2/Fe(ClO4)3 or methyltrioxorhenium (MTO),

urea-hydrogen peroxide (UHP)/MTO, O2 with 2-methylpropanal/

homogeneous Co(II) complexes, and O2 with benzhydrol/NHPI

combined with hexafluoroacetone [38]. The known combination of

TBHP and catalytic VO(acac)2 has also been reported for the prepa-

ration of 5,6-epoxysteroids in which a syn-stereodirecting effect is

usually observed [56, 57].

Peroxyacids have been used for the epoxidation 5-steroids

with stereo impediments on the -face to afford 5 ,6 -

epoxysteroids. 5 ,6 -Epoxides have also been prepared with chro-

myl diacetate however along with by-products. The treatment of 5-

steroids with H2O2 in the presence of iron(II), iron(III), and tita-

nium(III) ions led to mixtures of 5 ,6 - and of the 5 ,6 -epoxides

With perfluoro-cis-2,3-dialkyloxaziridine, several 3 -substituted-5-steroids afforded the 5 ,6 -epoxides as major reaction products,

whereas cholesterol 5 and stigmasterol 56 mainly led to the corre-

sponding 5 ,6 -epoxides [9]. A stoichiometric, nonetheless very

efficient, method for the preparation of 5 ,6 -epoxides from 5-

steroids (Scheme 7) is the use of biphasic systems involving

KMnO4 and metal sulphates, nitrates or other metal salts. The most

commonly used combinations are KMnO4/CuSO4·5H2O [58-60]

and KMnO4/Fe2(SO4)3 [17, 61, 62]. Recently, it was proposed that

the effective epoxidizing reagent in the combination of

KMnO4/CuSO4·5H2O was Cu(MnO4)2 because the observed stereo-

selectivities when using Cu(MnO4)2 were similar to those obtained

with the same substrates studied with the KMnO4/CuSO4·5H2O

system. With 1.5 equivalents of Cu(MnO4)2 interesting regioselec-

tivities were observed with cholesta-3,5-diene 65 and stigmasteryl

acetate 59 and the corresponding 5 ,6 -epoxides were obtained

(Scheme 7 and Table 4, entries 5 and 6) [63]. The combination of

KMnO4/CdSO4 was recently reported to afford -epoxides from

several cholestene derivatives, in high yields and selectivities [64].

A high number of catalytic processes for the -selective epoxi-

dation of 5-steroids have been reported and revised previously [9].

These include the use of molecular oxygen as oxidant either with

the Groves catalyst or combined with a sacrificial aldehyde (Mu-

kayiama reaction conditions) and a catalyst such as several metal

complexes including porphyrins, diketones, Fe-salen, and Ru-

bioxazoline, all under homogeneous conditions. The use of fluori-

nated solvents is an interesting approach to more sustainable proce-

dures and Mn(OAc)3 and a Ru-pyridine-benzimidazole complex

bearing perfluorinated "ponytails" were reported as catalysts for this

reaction, under Mukayiama conditions. Heterogeneous catalysts

mainly bearing cobalt as the metal centre have also been reported

for the effective preparation of 5 ,6 -epoxides from 5-steroids

using O2 combined with a sacrificial aldehyde. The obvious advan-

tage associated with the use of heterogeneous catalysts is that they

can potentially be recovered and reused. In addition to O2, other

combinations of oxidant/catalyst have been reported for this reac-

tion including: t-pentyl hydroperoxide/MoCl5, cumene hydroperox-

ide (CHP)/2,3,7,8,12,13,17,18-octachloro-5,10,15,20-tetraaryl-

porphyrinatoiron(III) chloride, H2O2/pertungstate salts or porphyrin

complexes of either Mn(III) or Fe(III), or 2,4-bisperfluoro-

octylphenyl butylselenide, MMPP/manganese tetra-o-dichloro-

phenylporphyrin complexes, N2O/dioxo(tetramesityl-porphyrinato)

ruthenium(VI) complex, sodium perborate in glacial acetic

acid/KMnO4, oxone/chiral ketones, DCPNO/homogeneous and

heterogeneous Ru-porphyrins, and PhIO/heterogeneous Mn-

porphyrins [9]. Recently, the -selective epoxidation of several 5-

steroids (Scheme 7 and Table 4) with heterogeneous Ru catalysts

has been reported [43, 65, 66]. The ruthenium(II) 5,10,15,20-

tetrakis(pentafluorophenyl)porphyrin carbonyl complex [Ru(TFPP)

CO] covalently attached to the functionalized silica (Catalyst 4,

Figure 5) efficiently catalyzed the -selective epoxidation of several

RO

O

O

68

O

O

PivO

OPiv

O

O

OPiv

PivO

Me

PivOO

OPiv

PivO

Me

PivO

R =

RO

O

O

69

OH

O

RO

O

O

OH

O

Oxone (8-13 eq.),

acetone

CHCl3, H2O,

NaHCO3,

Na2EDTA,

r.t., 10h

70

90% yield

Scheme 8.


steroids with DCPNO as oxidant, in good yields and excellent se-

lectivities (Table 4, entry 7) [43]. The porphyrin [RuII(F20-TPP)CO]

covalently attached to poly(ethylene glycol) (Catalyst 5, Figure 6)

was found to be an efficient catalyst for the DCPNO epoxidation of

cholesteryl acetate 1 to afford the 5 ,6 -epoxide 53, in very high

yield and complete selectivity (Table 4, entry 8) [65]. Cholesteryl

benzoate 3 was selectively epoxidized to the corresponding 5 ,6 -

epoxide 55 using an SiO2-supported Ru-monomer complex as cata-

lyst (Catalyst 6, Figure 7), under Mukayiama reaction conditions

(Table 4, entry 9) [66].

N

N N

N

F F

F

F

F

F

FF

F

F

F

Ru

CO

Catalyst 5

F F

F

F

FF

F

F

O

O

H3C

n

Fig. (6).

An interesting reactivity was observed with the diene A-

homosteroid 71 using a chiral and bulky fructose-derived ketone as

catalyst and oxone as oxidant in which the epoxidation stereoselec-

tively occurred in the A-ring, affording the -epoxide 72 as the only

product (Scheme 9). With MCPBA a mixture of the 5,6-epoxide

and the 3,4:5,6-diepoxide was observed. The epoxide 72 is an in-

termediate in the synthesis of a neuroactive steroid almost as active

as allopregnenolone [67].

5 ,10 -Epoxy-9(11)

-estrenes (Scheme 10) are valuable syn-

thetic intermediates in the obtention of several 11 -substituted-19-

norsteroids which have important biological activities such as po-

tent antiprogestational properties [38, 68]. Stoichiometric amounts

Table 4. Epoxidation of 5-steroids






5 65 Cu(MnO4)2 (1.5 eq.), t-BuOH/CH2Cl2, 23ºC, 1.5 h 66 + 67 / 46% 10:90 [63]

6 59 Cu(MnO4)2 (1.5 eq.), t-BuOH/CH2Cl2, 23ºC, 1 h 60 + 61 / 99% 14.3:85.7 [63]

7 1 Catalyst 4 (0.01 eq.), DCPNO (2 eq.), CH2Cl2, N2, 40ºC, 72 h 52 + 53 / 97% 7:93 [43]

8 1 Catalyst 5 (0.001 eq.), DCPNO (1.1 eq.), CH2Cl2, 50ºC, 24 h 53 / 95% - [65]

9 3 Catalyst 6 (0.005 eq.), O2 (1 atm), IBA (1 eq.), 24 h, 67% conversion 54 + 55 22:78 [66]

OH OHO

O

O

O

O

O(0.3 eq.)

Oxone (5.28 eq.), t-butylammonium acetate,

Na2(EDTA), K2CO3 aq., CH3CN/DME (1:2),

r.t., 30 min.

DME = dimethoxyethane

72 / 35%

O

71

Scheme 9.

N NH

O2

SC4H6

XO

OO

SiO2

Ru Cl

Catalyst 6

Fig. (7).


of MCPBA have been used to epoxidize 5(10),9(11)-estradiene

derivatives in relatively low yields and selectivities. In this context,

3,3-ethylenedioxo-(8S,13S,14R)-7-oxa-estra-5(10),9(11)-dien-17-

one 73 has been epoxidized with MCPBA to the corresponding

5 ,10 -epoxy derivative 74, with improved selectivity (Table 5,

entry 1) [68]. The use of catalytic amounts of FeII-phthalocyanine

combined with PhIO and hexahaloacetones combined with H2O2

(Table 5, entry 2) [69] or UHP has also been reported for this trans-

formation [38]. The phase-transfer catalyzed enantioselective ep-

oxidation of 3,3-ethylenedioxo-17 -(1-propynyl)estra-5(10),9(11)-

dien-17 -ol 79 using chiral ammonium salts derived from Chin-

chona alkaloids (e.g. catalyst 7, Figure 8) has been reported in the

presence of hexahaloacetones and H2O2, which improved the :

ratio of isomers to 7:1 (Table 5, entry 3) [70].

N

HO N+

H

H

Br-

H3CO

Catalyst 7

Fig. (8).

The 14 ,15 -epoxide function can be found in several naturally

occurring bioactive compounds such as the antitumor steroid gym-

nasterone B [71], the cytotoxic cinobufagin [72], and gedunins [73],

steroidal compound used in traditional medicines for the treatment

of enteritis, dysentery, and itching. Catalytic amounts of VO(acac)2

and TBHP and MCPBA have been used for the epoxidation of 14

-

steroids [38, 74]. In the synthesis of gymnasterone B, the 7 -

hydroxy-14

-derivative 82 was epoxidized by TBHP and Ti(iPrO)4,

in good yield and complete stereoselectivity due to the syn-directing

effect of the 7 -hydroxyl group (Scheme 11) [71].

The regio- and stereoselective epoxidation of the 17

- and 20

-

steroidal olefins 84 and 87 (Schemes 12 and 13) bearing allylic

hydroxyl groups using TBHP and VO(acac)2 as catalyst was also

described, and a syn-stereodirecting effect caused by the hydroxyl

group was observed. However, with compound 84 and using

MCPBA as oxidant only compound 85 was obtained, in 40% yield.

This compound has been highlighted as a lead molecule for the

synthesis of novel neuroprotective agents [75].

4. ALCOHOL OXIDATION

The oxidation of steroidal hydroxyl groups is perhaps the most

common oxidation in steroid chemistry. A large variety of naturally

occurring steroids have carbonyl groups as is the case of the major

steroidal hormones, such as testosterone 13, progesterone 42, corti-

sol and aldosterone which have a characteristic 4-ene-3-ketone

moiety. In addition, the preparation of steroidal ketones from the

oxidation of the corresponding alcohols is a very common step in

the synthesis of a large variety of bioactive steroids [9, 37, 76-87].

In agreement with the biological and synthetic importance of ster-

oidal ketones, a large number of procedures have been described

and applied to the oxidation of steroidal alcohols into their corre-

sponding ketone derivatives. These include the use of transition-

metal based oxidants the most common of which are chromium(VI)

reagents, however the use of manganese, ruthenium, osmium, pal-

ladium, molybdenum, bismuth and silver oxidants has also been

described. Oxygen-based oxidants such as O2, O2/reductant, TBHP

and peroxyacids, usually combined with several metal catalysts,

either in homogeneous or in heterogeneous conditions, have also

been reported for this transformation. The use of halogen based

oxidants like bromine, chlorine, and iodine derivatives such as

Dess-Martin periodinane, either in stoichiometric or catalytic condi-

tions, combined with metal or non-metal catalysts has been de-

XO

O

XO

O

O

XO

O

O

R1

R2

73.....................R1,R2=O;X=O............................................74 + 75

76...................R1,R2=O;X=CH2..........................................77 + 78

79...........R1=OH;R2=propynyl;X=CH2..............................80 + 81

Scheme 10.

Table 5. Epoxidation of estra-5(10),9(11)-diene Derivatives


1 73 MCBPA (1.5 eq.), NaHCO3, CH2Cl2, -30ºC, 16 h 74 + 75 / 70% 8:1 [68]

2 76 CF3COCF3 (0.5 eq.), H2O2 (1.5 eq.), Na2HPO4, CH2Cl2, 0ºC to r.t., 18 h 77 + 78 / 53% only [69]

3 79 CF3COCF3 (0.3 eq.), H2O2 (1.6 eq.), catalyst 7 (0.1 eq.), CH2Cl2, Py, r.t., 48 h 80 + 81 / 76.5% 7:1 [70]


scribed. Other oxidizing conditions such as the known Swern and

Oppenauer reaction conditions, as well as the use of 2,3-dichloro-

5,6-dicyano-1,4-benzoquinone (DDQ), N2O and other reagents

have also been previously reported [9]. Recent methods for the

oxidation of several steroidal alcohols to corresponding ketones

will be discussed in this section together with examples of the bio-

logical relevance of the synthesized steroids using these methods.

The use of molecular oxygen combined with heterogeneous

catalysts is highly desirable from both economic and environmental

viewpoint and has been applied to the oxidation of alcohols to car-

bonyl compounds [88, 89]. 5 -Cholestan-3 -ol 90 has been effec-

tively oxidized to cholestanone 91 (Scheme 14 and Table 6) under

aerobic conditions using heterogeneous nanoparticle catalysts that

can be recovered and reused. Thus, this reaction can be catalyzed

by gold nanoparticles immobilized in aluminum oxyhydroxide (Ta-

ble 6, entry 1) [90] or supported in hydrotalcite (Table 6, entry 2)

[91], and by palladium nanoparticles entrapped in aluminum hy-

droxide [92]. The oxidation of 3 -hydroxy-5 -pregnan-20-one 92

was effected under aerobic conditions with in situ generated Pd

nanoparticles from Pd(O2CCF3)2 and neocuproine and aqueous

solvent. After 4 hours, 59% conversion of the substrate and 99%

selectivity for the the 3-keto derivative 93 was observed, using 5

mol% of the catalyst (Table 6, entry 3) [93]. An interesting alterna-

tive to aerobic conditions is the use of a readily available organic

molecule instead of oxygen as the hydrogen acceptor, thus over-

coming safety concerns linked to the use of flammable solvents.

The low loading supported copper catalyst Cu/Al2O3, in the pres-

ence of styrene as hydrogen acceptor, was used in the oxidation of

3 - and 3 -hydroxy-5 -pregnan-20-one 94 and 96, and 3 - and 3 -

hydroxy-5 -androstan-17-one 98 and 100 (Scheme 14 and Table 6,

entries 4-7). It was interesting to observe that the oxidation is faster

when the hydroxyl group is in the 3 -position, both in 5 - and 5 -

series evidencing that the hydroxyl group has to be as unhindered as

possible to effectively adsorb on the catalytic surface [94]. 5 -

Cholestan-3 -ol 90 was oxidized to cholestanone 91 with hydrotal-

cite-supported copper nanoparticles and mesitylene (Table 6, entry

8) [95]. The use of hydrotalcite-supported silver nanoparticles was

also reported for the same transformation, however p-xylene was

used instead of mesitylene (Table 6, entry 9) [96]. Another interest-

ing oxidant used was TBHP, which efficiently oxidized alcohols

such as 5 -cholestan-3 -ol 90 to cholestanone 91 using a chromium

exchanged zeolite (CrE-ZSM-5) as heterogeneous catalyst (Table 6,

H

TBDPSO OH

O

O

H

TBDPSO OH

O

O

O

TBHP, Ti(iPrO)4

83 / 87%

tBuOH/H2O 1:1, r.t. 20h

82

Scheme 11.

HO

CH2OH

CH2OH

O

CH2OH

O

84 85 86

VO(acac)2 (cat.), TBHP.......70% yield......................85:86 2:1

MCPBA............................... 40% yield........................only 85

Scheme 12.

OH

HO

O

O

OH OH HH

VO(acac)2 (0.044 eq.),

TBHP (3 eq.)

CH2Cl2, r.t., 12h

68% yield 2:1

87 88 89

Scheme 13.


entry 10). However, it was demonstrated that this reaction was, at

least partially, homogeneously catalyzed by leached chromium

[97]. The use of ionic liquid-supported reagents allows recovery

and recycling. In this context, the non-volatile and odorless organo-

sulfoxide anchored on imidazolium ionic liquid scaffold 102 (Fig-

ure 9) was used in the oxidation of 5 -cholestan-3 -ol 90 to chole-

stanone 91, in 85% yield, under Swern oxidation conditions (Table

6, entry 11). The corresponding sulfide could be recovered and

reused after re-oxidation with periodic acid [98].

N+N

SO

TfO-

102

Fig. (9).

Hypervalent iodine reagents have widespread applications in

the oxidation of alcohols to ketones because of their selectivity and

simplicity [99]. Thus, the oxidation of 5 -cholestan-3 -ol 90 was

performed using PhIO with catalytic Yb(OTf)3 and 2,2,6,6-

tetramethylpiperidine-1-oxyl (TEMPO), affording cholestanone 91,

in 94% yield, after 2 hours of reaction (Scheme 14 and Table 6,

entry 12) [100]. 4,4´-Bis(dichloroiodo)biphenyl in combination

with tetraethylammonium bromide (TEAB) at room temperature

was also reported for the oxidation of the 3 -hydroxyl group of the

same substrate leading to the 3-keto derivative, however in 30%

isolated yield (Table 6, entry 13) [101].

The concomitant oxidation of the 3 - and 12 -hydroxyl groups

of substrate 103 with catalytic tetra-n-propylammonium perruthen-

ate (TPAP) combined with N-methylmorpholine-N-oxide (NMO)

was described and the corresponding diketone 104 (Scheme 15)

was obtained as an intermediate in the synthesis of (+)-

cephalostatin 1 105, an important antitumour agent [82]. The 11-

hydroxyl group of prednisolone acetate 106 was oxidized with o-

iodobenzoic acid (IBX) in DMF, affording prednisone acetate 107,

in very high yield (Scheme 16) [102]. This system was also very

efficient for the oxidation of the 17 -hydroxyl group of estrone

methyl ether 108 (Table 7, entry 1) [102]. Recently, other methods

have been described for the oxidation of the 17 -hydroxyl group to

the corresponding 17-keto steroid (Scheme 17 and Table 7). Thus,

the Moffatt-Swern oxidation of testosterone 13 was efficiently per-

formed in a continuous flow microreactor system, allowing an an-

R3R3

90.................5 -H;R1=OH;R2=H;R3=C8H17;R4=H...............91

92...............5 -H;R1=H;R2=OH;R3=COCH3;R4=H..............93

94...............5 -H;R1=H;R2=OH;R3=COCH3;R4=H..............95

96...............5 -H;R1=OH;R2=H;R3=COCH3;R4=H..............97

98.......................5 -H;R1=H;R2=OH;R3,R4=O.....................99

100.....................5 -H;R1=OH;R2=H;R3,R4=O...................101

R1

R2

R4R4

O

H H

Scheme 14.

Table 6. Oxidation of Steroidal Saturated 3-alcohols


1 90 Au/AlO(OH) (0.03 eq.), O2 (1 atm), PhCH3, Cs2O3, 25ºC, 72 h 91 / 83% [90]

2 90 Au/HT (0.0045 eq.), air (1 atm), PhCH3, 80ºC, 10 h 91 / 98% [91]

3 92 Pd(O2CCF3)2/neocuproine (0.05 eq.), NaOAc (0.5 eq.),

50 bar 8% O2/N2, (EtO)2CO/H2O, 100ºC, 4 h, 59% conversion 93 / (99% selectivity) [93]

4 94 Cu/Al2O3 (~0.2 eq.), styrene, PhCH3, N2, 90ºC, 24 h, 41% conversion 95 / (75% selectivity) [94]



7 100 Cu/Al2O3 (~0.18 eq.), styrene, PhCH3, N2, 90ºC, 2.5 h, 100% conversion 101 / (96% selectivity) [94]

8 90 Cu/HT (0.073 eq.), mesitylene, Ar, 150ºC, 17 h, 84% conversion 91 / (96% selectivity) [95]

9 90 Ag/HT (0.0009 eq.), p-xylene, Ar, 130ºC, 96 h, 83% conversion 91 / (>99% selectivity) [96]

10 90 CrE-ZSM-5 (0.002 eq.), TBHP (4 eq.), PhCH3, 80ºC, 9 h 91 / 83% [97]

11 90 Compound 102 (3 eq.), (COCl)2 (3 eq.), CH2Cl2, CH3CN, -78ºC, 1.5 h and Et3N 91 / 85% [98]

12 90 Yb(OTf)3 (0.02 eq.), TEMPO (0.05 eq.), PhIO (1.3 eq.), CH2Cl2, 0 to 25ºC, 2 h 91 / 94% [100]

13 90 4,4´-Bis(dichloroiodo)biphenyl (0.55 eq.), TEAB (1.1 eq.), CH2Cl2, r.t., 25 min. 91 / 30% [101]


drost-4-ene-3,17-dione 11 production rate of 64g·h-1

[103]. The

alcohol oxidation of nandrolone 112 was effected under aerobic

conditions with in situ generated Pd nanoparticles from

Pd(O2CCF3)2 and neocuproine with full conversion, after 4 hours of

reaction and 5 mol% of the catalyst (Table 7, entry 2) [93]. 17 -

Estradiol 110 was selectively oxidized to estrone 111 under anaero-

bic conditions, with 2,4-dichlorotoluene as both the oxidant and the

solvent, and using a (N-heterocyclic carbene)-Nio complex as cata-

lyst, which was generated in situ from the combination of

[Ni(cod)2] (cod=1,5-cyclooctadiene) and IPr·HCl (IPr·HCl=1,3-bis-

(2,6-diisopropylphenyl) imidazolium chloride) (Table 7, entry 3)

[104].

The 20-carbonyl group is characteristic of well known steroids

such as pregnenolone and progesterone 42 as well as their deriva-

tives and can be obtained through the oxidation of a 20-hydroxy

precursor. 20-Oxopregnane derivatives are also intermediates in the

preparation of several bioactive steroids namely (Z)-volkendousin

116 (Scheme 18), a natural cytotoxic steroid [83] and candicanoside

A 121 (Scheme 19), a potent antitumor saponin with a rearranged

side chain [84, 85]. Thus, the described synthesis of these two com-

pounds involves the oxidation of a 20-hydroxy intermediate into the

corresponding 20-ketone using pyridinium dichromate (PDC) and

pyridinium chlorochromate (PCC), respectively (Schemes 18 and

19). The use of 4,4´-bis(dichloroiodo)biphenyl in combination with

TEAB was also reported for the oxidation of the 20-hydroxyl group

of a pregnane derivative affording the 20-ketone compound, al-

though in relatively low isolated yield [101].

The oxidation of the 21-hydroxyl group of (20S)-20-

methylpregnane derivatives to the corresponding aldehydes (and/or

carboxylic acids) has also been reported (Scheme 20 and Table 8).

This transformation allows the preparation of intermediates for the

synthesis of bulk steroids such as progesterone 42 and corticoster-

HO

OH

H

TBDPSO

HO

H

TBDPSO

HO

O

O

TPAP (0.1 eq.),

NMO (5 eq.)

104 / 69% or over

CH2Cl2, MS4A,

25˚C, 30 min.

103

N

N

O

O

OO

OH

H

H

H

OH

OH

HO

HO

H

H

H

H

O(+)-Cephalostatin 1 / 105

Scheme 15.

HO

O

O

OAc

OH

O

O

OAc

OHO

IBX (1.2 eq.)

106 107 / 99%

DMF, r.t, 5h

Scheme 16.


R

OH

O

R

O

13..........R=CH3.........11

112..........R=H..........113

OH

RO MeO

O

108.........R=CH3........109

110...........R=H..........111

O

Scheme 17.

Table 7. Alcohol Oxidation of 17-hydroxysteroids


1 108 IBX (1.2 eq.), DMF, r.t, 4 h 109 / 98% [102]

2 112 Pd(O2CCF3)2/neocuproine (0.05 eq.), NaOAc (0.5 eq.),

50 bar 8% O2/N2, (EtO)2CO/H2O, 100ºC, 4 h, 100% conversion 113 [93]

3 110 [Ni(cod)2] (0.05 eq.), IPr·HCl (0.05 eq.), PhCl, KOtBu, 2,4-dichlorotoluene, 25ºC, 90 min 111 / 96% [104]

O

O

OH

O

PDC (2 eq.)

HO

OH

O

116 / (Z)-volkendousin

CH2Cl2, MS,

0˚C, 4.5h

114 115 / 87%

Scheme 18.


OMe

R2

R3

R1

117.................R1=I;R2=H;R3=OH.........PCC (1 eq.)..........118 / >50%

119.............R1=OAc;R2=OH;R3=H.......PCC (2 eq.)..........120 / 92%

OMe

R1

PCC, NaOAc

O

O

O

OO

O

O

OH

HOHO

HO

HOOH

121 / Candicanoside A

CH2Cl2, MS4A, r.t., 2h

Scheme 19.

oids, and can be important in the preparation of adequate steroidal

lateral chains starting from the aldehyde. Thus, an industrial proce-

dure for the oxidation of the 21-hydroxyl group to the correspond-

ing aldehyde involved the use of NaOCl as oxidant combined with

KBr and the catalyst 4-hydroxy-TEMPO [105]. The use of

stoichiometric o-iodobenzoic acid in DMF also efficiently oxidized

(20S)-21-hydroxy-20-methylpregna-1,4-dien-3-one 122 to the cor-

responding aldehyde 123, in 90% yield (Table 8, entry 1) [102]. In

the context of the synthesis of brassinosteroids (BRs) and ana-

logues, the direct oxidation of the 21-hydroxyl group to the corre-

sponding carboxylic acid has been reported. Thus (20S)-3,6-dioxo-

20-methyl-5 -pregnane-20-carboxylic acid 131 has been prepared

in 84% yield by the oxidation of a triol precursor 130 with the Jones

reagent (Table 8, entry 2). The same authors also reported the ap-

plication of the Swern method for the oxidation of other (20S)-21-

hydroxy-20-methylpregnanes (e.g. substrate 124, Table 8, entry 3),

affording the corresponding aldehydes, in good yields [106, 107].

(20S)-6,6-Ethylenedioxy-20-methyl-5 -pregn-2-en-21-ol 126, an

intermediate in the preparation of BRs with cytotoxic activity, was

oxidized using the Dess-Martin reagent to (20S)-6,6-ethylendioxy-

5 -pregn-2-en-20-carboxaldehyde 127, in 76% yield (Table 8, entry

4) [86]. Alcohol oxidation at this position of the steroid core

(Scheme 20 and Table 8) was also reported in the preparation of

potential antitumor agents such as certonardosterols 21 and 22 [24,

25] OSW-1 analogues [108] and parathiosterols [87]. Thus, the

oxidation of compound 132, an intermediate in the synthesis of the

estrane derivative of OSW-1, with PDC led to the corresponding

aldehyde 133, in 66% yield (Table 8, entry 5) [108]. A similar

transformation was described in the preparation of the certonardos-

terols D2 and D3 precursors 137 and 139, however using Dess-

Martin periodinane as reagent instead of PCC (Table 8, entries 6

and 7) [24, 25]. In the synthesis of parathiosterols, the oxidation of

several (20S)-21-hydroxy-20-methylpregnanes (substrates 122, 140,

134 and 128) (Scheme 20 and Table 8, entries 8-11) to the corre-

sponding carboxylic acids has been performed in two steps in

which the alcohols were oxidized to the aldehydes with PDC and

then after treatment with NaClO2 and catalytic TEMPO/NaOCl the

carboxylic acids were obtained. The direct conversion of the pri-

mary hydroxyl group at C-21 to the acid was precluded by steric

hindrance [87].

Remarkable reactivities were observed in the preparation of in-

termediates for the synthesis of bile acid derivatives [109, 110].

With the Jones reagent, 5 -cholane-3 ,7 ,16 ,24-tetraol 142 was

oxidized to the triketo carboxylic acid. However, with a TEMPO

catalyzed N-chlorosuccinimide (NCS) oxidation in a biphasic mix-

ture using a phase transfer catalyst (PTC), the selective formation of

3 ,7 -dihydroxy-5 -cholane-O-24,16 -lactone 143 (Scheme 21)

occurred [110]. A similar reactivity was observed in the aerobic

oxidation of the analogue 5 -cholane-3 ,7 ,12 ,16 ,24-pentol 144

catalyzed by TEMPO and CuCl in DMF. Interestingly, the selective

oxidation of the 7 -hydroxyl group of 3 ,7 ,12 -trihydroxy-5 -cholane-O-24,16 -lactone 145 was performed using N-

bromosuccinimide (NBS), afforded the 7-keto derivative 146, in

88% yield [109]. PCC also selectively oxidized the 7 -hydroxyl

group of methyl cholate and this reaction was fastened by high-

intensity ultrasound (HIU) or microwave irradiation (MW). The use

of KMnO4 and K2Cr2O7 to oxidize this substrate yielded the trike-

tones however with partial degradation. Both pure NaOCl (13-14%)

and NaOCl (7%) in the presence of catalytic amounts of Cr(VI),

under HIU or MW, oxidized methyl 3,7-diacetoxycholate [111].

The preparation of cholesten-26-oic acids via, for instance, the

oxidation of the primary 26-hydroxyl group (Scheme 22 and Table


OH

H

H

OH

R1O

OR2

H

H

O

R1O

OR2136.......R1=R2=MOM.......137

138........R1=R2=TBS.........139

OMOM OMOM

R1

R2

R3 R4

O

R1

R2

R3 R4

122.................... 1,4;R1,R2=O;R3=R4=H....................123

124............5 - ;R1,R2=R3,R4=ethylenedioxy...........125

126............... 2,5 - ;R3,R4=ethylenedioxy...............127

128..................... 4;R1,R2=O;R3=R4=H......................129

H

OH

HO

OHH

O

OH

O

O

OH

RO

O

RO

132.......... 16;R=TBS...........133

134..........R=TBDMS...........135

H

OH

HOH

O

O

130 131

140 141

Scheme 20.

Table 8. Oxidation of the 21-hydroxyl group of (20S)-20-methylpregnane Derivatives


1 122 IBX (1.2 eq.), DMF, r.t., 3.5 h 123 / 90% [102]

2 130 Jones reagent, acetone, 15 min. 131 / 84% [106]

3 124 DMSO (14.3 eq.), (COCl)2 (10.5 eq.), CH2Cl2, Ar, -70ºC, 1 h and Et3N 125 / 89% [106]

4 126 Dess-Martin reagent (1.1 eq.), CH2Cl2, 20 min. 127 / 76% [86]

5 132 PDC (5 eq.), CH2Cl2, MS4Å, r.t., 24 h 133 / 66% [108]

6 136 Dess-Martin reagent (3.7 eq.), CH2Cl2, 0ºC, 30 min. 137 / 99% [24]

7 138 Dess-Martin reagent (4 eq.), pyridine, CH2Cl2, Ar, 0ºC to r.t., 1 h 139 / 99% [25]

8 122 PDC (3.3 eq.), DMF, MS, r.t., 5 h 123 / 99% [87]

9 140 PDC (3.3 eq.), DMF, MS, r.t., 5 h 141 / 82% [87]

10 134 PDC (3.3 eq.), DMF, MS, r.t., 5 h 135 / 82% [87]

11 128 PDC (3.3 eq.), DMF, MS, r.t., 5 h 129 / 73% [87]


CH2OH

H

HO

R

OH

142.........R=H.......TEMPO (0.05 eq.), BnNEt3+, CH2Cl2, H2O,.........143 / 63%

NaHCO3/K2CO3, pH=8.6, NCS (5 eq.), 4h

144........R=OH.......CuCl (0.4 eq.), TEMPO (0.4 eq.), .......................145 / 78%

O2 (1 atm), DMF, r.t, 3h

H

HO

R

O O

H

HO

R

O O

NBS (1.4 eq.),

acetone-H2O,

r.t., 10 min.

R=OH

146 / 88%

OH OH

O

Scheme 21.

HO

OH

H

O

H

OH

147........25R........148

149........25S.........150

O

TBSO

OH O

H

TBSO

151...............R1,R2=O; 4;25R...............152

153..............R1,R2=O; 4;25S.................154

155..........R1=OAc;R2=H; 5;25R...........156

157..........R1=OAc;R2=H; 5;25S...........158

OH

R1

R2

O

R1

R2

OH

159 160

Scheme 22.

9) is also of major relevance. Recently, two 25S-cholesten-26-oic

acids were isolated from the Indonesian soft coral Minabea sp

[112]. Moreover, the oxidation of several steroidal 26-alcohols has

been used as a key step in the preparation of dafacronic acids,

known cholesterol derived hormones which control the life cycle of

the pathogenic nematode Caenorhabditis elegans [113-115]. Using

the Jones reagent, the carboxylic acid is obtained and in some cases

concomitant oxidation of the 3-hydroxyl group also occurs (Scheme

22 and Table 9, entries 1-4). The Swern oxidation of the silyl-

protected alcohol 159 afforded however the corresponding aldehyde

160 (Table 9, entry 5), which was then oxidized to the carboxylic

acid with NaClO2 [113, 115]. In the preparation of useful steroids


for biosynthetic studies of cholic acids the oxidation of the 26-

hydroxyl group of the cholestene derivatives 151, 153, 155 and 157

was performed with NaClO2, catalyzed by TEMPO and NaOCl, and

afforded the corresponding carboxylic acids, in moderate yields

(Scheme 22 and Table 9, entries 6-9) [116].

The oxidation of 5-3 -hydroxy steroids to the corresponding

5-3-keto derivatives (Scheme 23 and Table 10) has found an inter-

esting application in the synthesis of bis-diosgenin pyrazine dimers

as new cephalostatin analogues [117]. Thus, the combination of

PCC with CaCO3 in stoichiometric amounts efficiently converted

diosgenin 161 into 25R-spirost-5-en-3-one 162, in 80% yield (Table

10, entry 1). This oxidation has also been performed with chro-

mium reagents on cholesterol 5 to afford cholest-5-en-3-one 163. In

this context, the use of CrO3 supported on NaHSO4.H2O (Table 10,

entry 2) [118], cetyltrimethylammonium dichromate (CTADC)

[119], and 3-carboxypyridinium trifluoroacetatochromate

(CPTFAC) (Table 10, entry 3) and 3-carboxypyridinium

trichloroacetatochromate (CPTCAC) has been reported [120]. Mo-

lecular iodine was used as an efficient catalyst for the oxidation of

cholesterol 5 to cholest-5-en-3-one 163 using PhI(OAc)2 as oxidant,

in 92% yield (Table 10, entry 4) [121]. 17,17-

Ethylenedioxyandrost-5-en-3 -ol 164 was also oxidized to the cor-

responding 5-3-keto derivative 165, in quantitative yield, using the

Dess-Martin periodinane, another hypervalent iodine reagent (Table

10, entry 5) [75]. The oxidation of cholesterol 5 to cholest-5-en-3-

one 163 was performed using KBrO3 in the presence of

Fe(HSO4)3/wet SiO2 in either acetonitrile or in a solvent-free proc-

ess, in high yields (Scheme 23 and Table 10, entries 6 and 7) [122].

The use of O2 in subcritical water in the absence of catalysts also

oxidized cholesterol 5 to cholest-5-en-3-one 163 (Table 10, entry 8)

[123], as well as H2O2 in the presence of amberlite IRA 400 resin,

as PTC, and sodium tungstate (Table 10, entry 9) [124]. This last

Table 9. Oxidation of the Primary 26-hydroxyl group of Cholestane Derivatives


1 147 Jones reagent (5 eq.), acetone, 0ºC, 1 h 148 / 74% [114]

2 149 Jones reagent (5 eq.), acetone, 0ºC, 90 min. 150 / 89% [115]

3 151 Jones reagent (5 eq.), acetone, 0ºC, 1 h 152 / 79% [114]

4 153 Jones reagent (5 eq.), acetone, 0ºC, 90 min. 154 / 65% [115]

5 159 DMSO (4 eq.), (COCl)2 (2 eq.), CH2Cl2, -78ºC, 20 min., and Et3N 160 / >89% [115]

6 151 NaClO2 (~2 eq.), NaOCl (cat.), TEMPO (0.1 eq.), phosphate buffer, pH=6.86, THF, CH3CN, H2O,

35ºC, 5.5 h 152 / 48% [116]


35ºC, 5.5 h 154 / 51% [116]


35ºC, 5.5 h 156 / >55% [116]


35ºC, 5.5 h 158 / >48% [116]

HO

5...................R1=C8H17;R2=H................163

164............R1,R2=ethylenedioxy............165

166...............R1=COCH3;R2=H..............167

O

HO

O

O

O

O

O

R1 R1

R2 R2

161 162

Scheme 23.


procedure was also used to convert pregnenolone 166 into pregn-5-

ene-3,20-dione 167, an important intermediate for the preparation

of 17 -substituted-5-ene-3,20-dione corticosteroids, in 73% yield

(Table 10, entry 10) [124]. The Oppenauer-type oxidation of cho-

lesterol 5 with (hydroxycyclopentadiene)iron dicarbonyl hydride as

catalyst (Catalyst 8, Figure 10) and acetone as hydrogen acceptor

has been reported to afford cholest-5-en-3-one 163 (Table 10, entry

11) [125].

OH

TMS

TMS

Fe

OC H

CO

Catalyst 8

Fig. (10).

5. REMOTE FUNCTIONALIZATION

The direct remote functionalization involves the achievement of

selective reactions at arbitrarily large distances from any functional

groups of the substrate and is an area of increasing interest. In the

context of steroid chemistry, remote functionalization reactions can

allow the preparation of relevant bioactive compounds and/or their

intermediates, namely steroids bearing hydroxyl groups [126, 127].

The specific hydroxylation at C-5 is an important example in this

context because several naturally occurring steroids bear a 5-

hydroxyl group. In addition, oxyfunctionalization at C-5 is a key

step in the conversion of bile acids into some steroid hormones. For

instance, 25-hydroxycholestane derivatives are important as potent

inhibitors of cholesterol biosynthesis and can be useful in the prepa-

ration of relevant compounds, namely vitamin D derivatives. Func-

tionalization at C-19 is yet another very important example because

it allows the synthesis of estrogens from androgens and has there-

fore been exploited in the development of aromatase inhibitors [37,

76-81]. Several stoichiometric procedures previously reported to

perform remote functionalization reactions in steroid chemistry

include the hypohalite, Barton, nitrene, Hoffmann-Loffler-Freytag

and lead tetraacetate (LTA) reactions, the free radical decomposi-

tion of peracids, and the use of perfluoro-cis-2-n-butyl-3-n-

propyloxaziridine, ceric ammonium nitrate (CAN), chromium triox-

ide and ozone adsorbed on silica gel [126].

An interesting approach for the selective oxidation of inacti-

vated positions is the mimetization of the regioselectivity of enzy-

matic processes in which the reaction is directed by the geometry of

the enzyme-substrate complex. In fact, Breslow et al. developed a

system involving the use of reagents or templates attached to ster-

oid substrates to direct photochemical and free radical processes

towards the inactivated positions, using a combination of both

geometric and reactivity control [126, 128, 129]. Recent examples

of the application of this type of remote functionalization can be

found in the preparation of intermediates in the synthesis of xesto-

bergsterols, known potent inhibitors of histamine release [74], pa-

voninin-4 25, a shark repellent [27, 130] and bile acid derivatives

[109, 110]. Another known process for the remote functionalization

of steroids is the use of Mn-porphyrin or salen complexes cova-

lently attached to the steroid framework in combination with PhIO

to perform remote hydroxylations [127] . More recently,

Schonecker et al. developed an aerobic process for the regio- and

stereoselective - or -hydroxylations of non-activated C-H bonds

of steroid substrates mediated and directed by copper complexes of

tri- or bidentate ligands with N-donor atoms attached to the steroid

nucleus [9, 131]. This reaction has been applied in the synthesis of

an intermediate of (+)-cephalostatin 1 105 in which trans-

androsterone 100 was treated with 2-(aminomethyl)pyridine and

tosylic acid to form the corresponding steroidal bidentate ligand

168 that, after formation of a Cu(I) complex, directed an aerobic

hydroxylation towards C-12, in 25% yield, after hydrolytic work-up

(Scheme 24) [82].

Hypervalent organoiodine reagents have also been used for

stoichiometric remote functionalization reactions [132-134]. An

example is the combination of PhI(OAc)2 and I2 under photolytic

[135] or sonochemical conditions [17, 136] which have been useful

for the functionalization of steroids at C-19. The application of

Suarez reaction conditions (PhI(OAc)2 /I2/h ) to 11 -

hydroxypregnanes led to the corresponding 1,11-epoxypregnanes,

in high yields, by intramolecular remote reaction (Scheme 25)

[137]. For example, when applied to 20-oxo-11 -hydroxy-5 -

pregnan-3 -yl acetate 174, this system led to 1 ,11 -epoxy-20-oxo-

5 -pregnan-3 -yl acetate 175, in 80% yield. This epoxide is a syn-

thetic intermediate for a neurosteroid analog, more active than

Table 10. Oxidation of 5-3 -hydroxysteroids to the Corresponding

5-3-ketones


1 161 PCC (0.83 eq.), CaCO3 (0.83 eq.), CH2Cl2, r.t., 30 min. 162 / 80% [117]

2 5 CrO3/NaHSO4·H2O (0.5 eq.), r.t., 2 min. 163 / 80% [118]

3 5 CPTFAC (1 eq.), CH2Cl2, r.t., 2 h 163 / 76% [120]

4 5 PhI(OAc)2 (1.1 eq.), I2 (0.1 eq.), CH3CN, 25ºC, 2h 163 / 92% [121]

5 164 Dess-Martin reagent (2 eq.), CH2Cl2, r.t., 1 h 165 / quant. [75]

6 5 KBrO3 (1.5 eq.), Fe(HSO4)3/wet SiO2 (1 eq.), CH3CN, r.t., 19 min. 163 / 95% [122]

7 5 KBrO3 (1.5 eq.), Fe(HSO4)3/wet SiO2 (1 eq.), r.t., 10 min. 163 / 98% [122]

8 5 O2 (15 bar), subcritical H2O, 120ºC, 2 h 163 / 90% [123]

9 5 H2O2 (6 eq.), Na2WO4 (0.1 eq.), Amberlite IRA 400, CH3CN, 80ºC, 6 h 163 / 73% [124]

10 166 H2O2 (6 eq.), Na2WO4 (0.1 eq.), Amberlite IRA 400, CH3CN, 80ºC, 5 h 167 / 73% [124]

11 5 Catalyst 8 (0.03 eq.), acetone, 60ºC, 24 h 163 / 72% [125]


O

HOH

N

HO

H

N

O

HO

H

OH

2-(aminomethyl)pyridine

(5 eq.), TsOH

Cu(OTf)2 (1.2 eq.), benzoin,

Et3N, acetone, Ar, r.t., 4h,

then O2 (1 atm), 24h,

then HCl, NH4OH

168 / 89%

PhCH3, 110˚C, 4h

169 / 25%

100

Scheme 24.

O

O

HO

HO

O

H

O

171 / 66%

R1,R2

HO

H

AcO

R1,R2

H

O

172..........R1= -OAc;R2=H..........173 / 89%

174.................R1,R2=O................175 / 80%

AcO

a) Reaction conditions: PhI(OAc)2 (~1.2), I2 (1 eq.),

h (300W), CH2Cl2, 25˚C, 20 min.

170

a)

a)

Scheme 25.

pregnanolone as a GABAA receptor modulator, potentially useful in

the management of conditions such as epilepsy, anxiety and insom-

nia [138]. Dioxiranes are versatile oxidizing reagents in organic

chemistry [1, 139] and have also been useful in the selective oxida-

tion of inactivated positions in steroid chemistry. When applied to

several cholane derivatives, stereoselective remote oxidation was

performed by isolated DMDO and, according to the substrate and

reaction conditions, the corresponding 5-, 14- and 17-monohydroxy

derivatives were prepared, in low to moderate yields. In some cases,

dihydroxy derivatives and other products were also formed [140-

143]. Under similar conditions, 5 -cholestan-3 -yl acetate, 5 -

stigmastan-3 -yl acetate and 5 -ergostan-3 -yl acetate were mainly

oxidized at the tertiary carbons of the lateral chain [140]. The pow-

erful oxidizing agent methyl(trifluoromethyl)dioxirane has been

applied in the oxidation of 5 -androstane-3 ,6 ,17 -triyl triacetate

176 and after 28% conversion, the 14 -hydroxy and the 12-keto

derivatives 177 and 178 were formed, in practically equal amounts

(Scheme 26) [144]. It is likely that the acetoxyl group at C6 signifi-

cantly affected the selectivity of the process as the reaction of 5 -

androstan-3 -yl acetate with DMDO resulted in the exclusive for-

mation of the 14 -hydroxy derivative [144]. Recently, 5 ,6 -

dibromo-25-hydroxycholestan-3 -yl acetate 180 was prepared, in


45% isolated yield, from 5 ,6 -dibromocholestan-3 -yl acetate 179

using ethyl(trifluoromethyl)dioxirane generated in situ from 1,1,1-

trifluoro-2-butanone and Oxone®

(Scheme 27). This compound was

used as intermediate for the synthesis of interesting bioactive oxys-

terols [145]. The intramolecular oxidation of unactivated C-H

bonds by in situ generated dioxiranes was also studied. Thus, by

introducing appropriate tethers, regioselective hydroxylation of

steroid ketones have been achieved at C-17, C-16 and C-5 using

Oxone®

as oxidant. Using a trifluoromethyl benzophenone tether,

the yield of the oxidation at C-5 is very low however it is the first

example of the use of a covalently linked dioxirane for the regiose-

lective hydroxylation at C-5 (Scheme 28) [146]. More recently,

direct hydroxylation of tertiary C-H bonds was achieved by a de-

tachable dioxirane precursor containing a trifluoromethyl ketone

moiety and an ethylene tether. Oxone®

treatment of this ketone

moiety bound to the 3 -position of the steroid core led to the regio-

and stereoselective introduction of a 5 -hydroxyl group, in moder-

ate yields, and without concomitant Baeyer-Villiger reaction

(Scheme 28) [147].

Catalytic processes for direct remote functionalization reactions

include the Gif system, the combination of CHP with chloroi-

ron(III)-5,10,15,20-tetraarylporphinate/N-methylimidazole, and a

steroidal manganese(III) porphyrin in a synthetic bilayer assembly

in aerobic conditions using ascorbic acid as the reducing agent [9,

126, 127]. The remote oxidation of steroid compounds with

DCPNO catalyzed by ruthenium porphyrins in the presence of HBr

AcO

OAc

H

OAc

H

AcO

OAc

OH

OAc

HAcO

OAc

H

OAc

H

O

TFDO (0.6 eq.)

~1:1

CH2Cl2, 0˚C,

4h, 28% conv.

176 177 178

Scheme 26.

Br

AcO

Br

Br

AcO

Br

OH

CH2Cl2, r.t., 12h

179

1,1,1-trifluorobutanone (100 eq.),

oxone (10 eq.), NaHCO3

180 / 45%

Scheme 27.

C8H17

H

OO

F3C

H

C8H17

H

HOOH

Oxone,

NaHCO3

182 / 3%

H

OH

Oxone (5 eq.),

NaHCO3 (15 eq.)

Na2.EDTA,

184 / 47%

OF3C

O

O

H

OOH

OF3C

O

O

+ other products

CH3CN/H2O,

r.t., 41 days

tBuOH/H2O,

r.t., 1 day

181

183

Scheme 28.


AcO

H

H

O

AcO

OH

H

O

AcO

H

H

186 / 29%

O

187 / 35%

+ 14 -OH

derivative

188 (3%)

Os(TMP)CO

(0.004 eq.),

TBHP (20 eq.)

PhH, MS4A,

reflux, 96h

185

Scheme 29.

H

R1

R2 R3

R4

R5

OH

R1

R2 R3

R4

R5

+

R6 R6

R6 = CH2CH2COOCH3

OH

R1

R2 R3

R4

R5

+

R6

Other products

189...............R1=H;R2=OAc;R3=R4=R5=H...................190 / 32%........+.......191 / 9%..............+ 5 -OOH (192) / 9%

193.....................R1,R2=O;R3=R4=R5=H.......................194 / 8%................................................+ 4-3-ketone (195) / 10%

+ 3,4-seco-3,4-dioc acid (196) / 35%

197.........R1=H;R2=OAc;R3=OAc;R4=R5=H................198 / 47%........+.......199 / 6%

200........R1=H;R2=OAc;R3=H;R4=OAc;R5=H.............201 / 20%........+.......202 / 16%.............+ 14 -OH (203) / 8%

204..........R1=H;R2=OAc;R3=R4=H;R5=OAc...............205 / 28%........+.......206 / 5%...............+ 5 -OH-16-ketone (207) / 9%

208.......R1=H;R2=OAc;R3=OAc;R4=H;R5=OAc.........209 / 27%...............................................+ 15-ketone (210) / 9%

+ 16-ketone (211) / 7%

+ 5 -OH-16-ketone (212) / 4%

a)

a) Reaction conditions: Os(TMP)CO (0.004 eq. for substrates 189 and 193; 0.005 eq.

for substrates 197, 200, 204 and 208), TBHP (20 eq.), PhH, MS4A, reflux, 96h

Scheme 30.

H

AcO

OAc

COOMe

H

COOMe

OH

COOMe

OH

COOMe

O

214 / 28%

215 / 11%

216 / 7%

213

Os(TMP)CO

(0.004 eq.),

TBHP (20 eq.)

PhH, MS4A,

reflux, 96h

Scheme 31.

has also been described. The use of the RuII(TMP)CO complex as

catalyst under these reaction conditions has been applied to several

5 - and 5 -steroids, including bile acid derivatives, and mainly

monohydroxy derivatives were prepared, in low to moderate yields.

The best results have been obtained in the oxidation of 5 -steroids

to the corresponding 5 -hydroxy derivatives [9]. Recently, the

combination of TBHP with the catalyst OsII(TMP)CO complex

(Catalyst 2, Figure 2) was found to be yet another efficient oxidant

for C-H carbons in steroid substrates. When applied to 20-oxo-5 -

pregnan-3 -yl acetate 185 (Scheme 29) and several 5 -cholanes

(Scheme 30) regioselective oxyfunctionalization at C-5 was com-

mon to all substrates, however in some cases, oxidative degradation

also occurred [148, 149]. When applied to methyl hyodeoxycholate

diacetate 213, with an equatorially oriented 6 -acetoxyl group, a

much different regioselectivity was observed, with the correspond-

ing 14-hydroxyl derivatives being obtained as the main reaction

products (Scheme 31). 5 -Cholestan-3 -yl acetate 217 [148] and

5 -cycloartan-3 -yl acetate 220 [28] mainly afforded their corre-


H

AcO

H

AcO

OH

+ 5 -OH derivative

219 (16%)

218 / 33%

AcOH

AcOH

OH

a) Reaction conditions: Os(TMP)CO (cat.),

TBHP (20 eq.), PhH, MS4A, reflux, 96h

cat. 0.005 eq.

221 / 50%

a)

cat. 0.004 eq.

a)

217

220

Scheme 32.

N

N N

N

Mn

S

S

S

S

F

F

F

F

FF

F F

F

F F

F

F F

F F

=cyclodextrin

NH

O

COOH

SH

NH

O

COOH

O (CH2)6SH

or

R

R

S-

OO

Mn3+

S

F F

F F

R =

Catalyst 9

Catalyst 10

222 223

Fig. (11).


H H

O

O

O

O NH

SO3H

O

NH

O

HO3S

H H

O

O

O

O NH

SO3H

O

NH

O

HO3S

OH

H2O2, Catalyst 9 +

thiol ligands 222 or 223,

or Catalyst 10, r.t.

H

H

224

225

Scheme 33.

sponding 25-hydroxy derivatives 218 and 221 (Scheme 32) under

similar reaction conditions.

Important advances in the selective oxidation of the inactivated

positions in steroid substrates have been achieved by Breslow et al.

who created true P-450 enzyme mimics that allow the hydroxyla-

tion of steroids directed by geometric control. These systems are

based on manganese porphyrins carrying cyclodextrin groups aim-

ing to bind hydrophobic substrates in water and allow their selec-

tive hydroxylation. Thus, androstane ester derivatives with tert-

butylphenyl hydrophobic binding groups and water-solubilizing

sulfonate groups were remotely functionalized in water using PhIO

as oxidant. With adequate substrates and catalysts, selective and

interesting 6 - and 9 -hydroxylations were achieved with this

method. Further improvements in reaction yields, selectivities and

catalytic turnovers as well as applications to other steroidal sub-

strates have been described [17, 126, 128, 129]. A problem with

these systems is that more sustainable oxidants such as H2O2 failed

to perform these hydroxylation reactions, probably because they

were not strong enough to oxidize the metal to its oxo state in wa-

ter. Better electron donors to the oxo metal species than imidazole

or water such as thiol ligands were then added to the catalyst, either

hydrophobically bound or covalently attached (Figure 11), allowing

the use of H2O2 in the 6 -hydroxylation of the diester of andro-

stane-3 ,17 -diol 224 (Scheme 33), although in modest yields

[150].

Another strategy for the biomimetic remote hydroxylation of

steroids consisted in the use of pyridine recognition fragments at-

tached to a Mn-porphyrin catalyst which is able to bind the sub-

strate, also containing pyridine groups, by forming a complex with

Cu(II). However, this system was not as selective as the ones previ-

ously reported [127], probably due to low intrinsic reactivity and

low stability of the catalyst. An improvement to this system has

been recently reported in which a novel Mn-porphyrin unit linked

to two 2,2´-bipyridyl groups and two pentafluorophenyl groups, in a

trans fashion on its four meso positions (Catalyst 11, Figure 12),

was used as catalyst for the 6 -hydroxylation of the -

phosphonoacetyl diester of androstane-3 ,17 -diol 226, using PhIO

as oxidant (Scheme 34). -Phosphonoacetyl groups bound to the

substrate can also complex Cu(II) ions with the advantage of avoid-

ing the inactivating N-oxidation of the previously used pyridyl

groups. In addition, this system may be more practical since it does

not require water as solvent and substrate water solubility for effec-

tive catalyst/substrate binding [151].

N

N N

NN

NN

N

+Mn

Cl-

F

F

F

F

F

F

F

F

F

F

Catalyst 11

Fig. (12).


O

O

H

O

P

O

ONa

ONa

O

PNaO

O

ONa

PhIO (10 eq.), Cat. 11,

Cu2+, H2O/tBuOH

3N NaOH aq.,

16h

HO

OH

HOH

r.t., dark, 3h+ 10% other

products226

227 / 90%

Scheme 34.

OH

HO

HO

H

OH OH

OH

H

OH

O

HO

H

OH OH

OH

H

OH

O

OH

HO

HO

H

O

OH

HO

HO

HO

Integristerone A / 228

228

OsO4,

ligand

Pyridine, a)............................56%..........+..............27%..................+..................7%

DHQ-PE, b)...........................97%..........+...............3%...................+..................0%

(DHQ)2-PHAL, b)................92%...........+...............6%...................+..................2%

DHQD-PE, b).......................15%...........+..............46%..................+.................19%

(DHQD)2-PHAL, b)..............50%..........+..............30%..................+.................19%

229 230 231

Reaction conditions:

a) OsO4 (4.62 eq.), pyridine, 4h

b) OsO4 (4 eq.), ligand (4 eq.), tBuOH-THF-H2O, 5h

Scheme 35.

6. syn-DIHYDROXYLATION

The most commonly used reagent to perform syn-

dihydroxylation reactions is osmium tetroxide [152], either in

stoichiometric or catalytic amounts, combined with oxidants such

as H2O2, NMO, and K3Fe(CN)6. Apart from this reagent, there are

only a few other transition-metal complexes which are capable of

dihydroxylating olefins in a selective manner, including alkaline

KMnO4 under stoichiometric conditions, and catalytic RuO4 gener-

ated from RuCl3 and hypochlorite or periodate. More recently, the

use of manganese, iron [153], cobalt [154], molybdenum [155] or

palladium catalysts [156] has been described to convert olefins into

cis-1,2-diols, however with low selectivity. Thus, despite the high

volatility and short-term toxicity, osmium-based reagents remain

the choice for this reaction. In the field of asymmetric dihydroxyla-

tions, the known and versatile Sharpless asymmetric dihydroxyla-

tion (AD), involving the use of derivatives of naturally occurring

cinchone alkaloids as ligands for osmium in order to control and

achieve high stereoselectivities, is dominant [38, 152, 153]. This

transformation is of major interest because the cis-1,2-diol func-

tionality has been found in numerous bioactive steroids and their

analogues. In addition, the syn-dihydroxylation of alkenes allows

the preparation of several intermediates in the synthesis of steroids

with diverse biological activities [157-162]. Several interesting

reactivities and selectivities have been recently reported in steroid

chemistry concerning this reaction. In the synthesis of integrister-

one A 228 and analogues, a small group of ecdysteroids, an asym-

metric 1-dihydroxylation of the 3 -hydroxy-5 -steroid 229 was

required (Scheme 35). When a combination of OsO4 and pyridine in

stoichiometric amounts was used, the 1 ,2 -diol 228 was prepared,


in 56% yield, along with the corresponding 1 ,2 -derivative 230

(27%) and its 5 -epimer 231 (7%). This result led to the study of

the effect of several chiral ligands in place of pyridine on the ratio

obtained of these three products and it was observed that with dihy-

droquinidine (DHQD) as the ligand, the 1 ,2 -diol-5 -steroid 230

was found to the major reaction product and that C-5 epimerization

occurred more readily. The best result was obtained with dihydro-

quinine phenantryl ether (DHQ-PE) as the ligand, with integrister-

one A 228 being obtained with 97% selectivity (Scheme 35) [163].

Other ecdysteroids have been prepared by stereoselective dihy-

droxylation in other positions of the steroid nucleus, as is the case

of the 2,3-double bond, as previously reported [161, 164, 165]. 5 -

Steroids predominantly afford the corresponding 2 ,3 -diols

whereas 2 ,3 -diols are preferentially obtained from 5 -steroids

[164, 165]. An exception was observed in the dihydroxylation of

the double bond of 5 -fluorocholest-2-en-6-one 232 with the cata-

lytic OsO4/NMO system that afforded the corresponding 2 ,3 - and

2 ,3 -diols 233 and 234 in a 1:1 ratio (Scheme 36). In this work, it

was been observed that the syn-diol derivative 5 -fluoro-6E-

hydroximino-cholestane-2 ,3 -diol 235 has interesting cytotoxicity

against several cancer cell lines [166].

Our group has previously reviewed the syn-dihydroxylation of

several 4-steroids using osmium-based processes in which mix-

tures of 4 ,5 - and 4 ,5 -diols were generally obtained [38]. In the

presence of catalytic OsO4/NMO, 10 -hydroxyestra-1,4-dien-3,17-

dione 236 afforded the corresponding 4 ,5 -diol 237, after 5 days,

in 50% yield (Scheme 37) [167]. With (22E)-stigmasta-4,22-dien-3-

one 238 and under similar reaction conditions, it was observed that

the lateral chain double bond was more reactive than the conjugated

double bond, with (22S,23S)-22,23-dihydroxystigmast-4-en-3-one

239 being obtained as the main product (62% yield) along with the

corresponding 4 ,5 ,22S,23S-tetraol 240 (30% yield) (Scheme 38).

C8H17

F

O

F

O

F

O

HO

HO

HO

HO

1:1

OsO4 (0.4 eq.),

NMO (34 eq.)

THF/tBuOH/H2O,

dark, Ar, 0˚C, 80 h

30% yield232 234233

C8H17

F

N

OH

HO

HO

235 / 5 -Fluoro-6E-hydroximinocholestane-2 ,3 -diol

Scheme 36.

O

O

OH

O

O

OH

OHOH

OsO4 (0.046 eq.), NMO (4 eq.)

237 / 50%

acetone/H2O/tBuOH, 5 days

236

Scheme 37.

OH

HO

OH

HO

238 239 /62% 240 / 30%

O O

O

OH

OH

CH3SO2NH2,

NaHCO3,

THF/H2O/tBuOH,

50˚C, 24h

OsO4 (0.02 eq.),

NMO (0.72 eq.)

Scheme 38.


This 22,23-dihydroxystigmastane derivative can be useful in the

management of herpetic pathology probably due to its immuno-

modulatory effects [168]. The same group also reported the synthe-

sis of other immunomodulating stigmastanes with a 22,23-diol moi-

ety [169, 170]. Thus, using K2OsO4/K4Fe(CN)6/(DHQD)2-PHAL

(PHAL=phtalazine), (22E)-3 -fluor-5 -hydroxy-stigmast-22-en-6-

one 241 afforded a 2.2:1 mixture of the corresponding 22S,23S- and

22R,23R-diols 242 and 243, after 9 days (Scheme 39) [170].

The best known application of the syn-dihydroxylation reaction

to steroid chemistry is most likely the synthesis of BRs. Natural

BRs have been isolated from several plants where they act as phy-

tohormones and regulate various vital processes. As BRs are active

plant-growth stimulators, they are promising agents to increase the

harvest of agricultural crops which explains intense research in the

synthesis of BRs and analogues over the years [162]. In addition,

some BRs exert antiviral action [158], bear cytotoxic activity

against several cell lines as well as activity on GABAA receptors

[86]. Due to the fact that naturally occurring BRs are

2 ,3 ,22R,23R-tetraols, the syn-dihydroxylation of 2- and

22-

steroid precursors, both together and separately, has been exploited

in the synthesis of BRs and bioactive analogues [162]. The 2 ,3 -

diol was usually obtained as the only isomer, either in stoichiomeric

or catalytic conditions, from several different 2-5 -steroids, when

osmium-based processes were used [38, 86, 171-176]. An exception

was however seen in the dihydroxylation of 6-oxo-5 -androst-2-en-

17 -yl acetate 244 with catalytic OsO4/NMO in which a 5:2 mix-

ture of the 2 ,3 - and 2 ,3 -diols 245 and 246 was obtained

(Scheme 40). This result led authors to use the combination

OsO4/K3Fe(CN)6/DHQD-CLB (CLB=p-chlorobenzoate) for this

reaction and with this system the : stereoselectivity was im-

proved to 9:1 [177]. The dihydroxylation of 5 -fluoro-6-

oxoandrost-2-en-17 -yl acetate 247 with catalytic OsO4/NMO af-

forded a 2:3 mixture of the 2 ,3 - and 2 ,3 -diols 248 and 249

(Scheme 41) [178]. In the dihydroxylation of 5 -hydroxycholest-2-

en-6-one with OsO4/NMO the corresponding 2 ,3 -diol was also

the major reaction product [179] and when applied to 2-5 -

hydroxy-6-ketone steroids this system afforded the 2 ,3 -diol de-

rivatives almost exclusively [180].

In syn-dihydroxylations of the 22

-bond, several previous stud-

ies revealed that the specific substitution at C-24 strongly influ-

OH

HO

241

F

F CH3SO2NH2, K2CO3,

THF/H2O/tBuOH,

r.t., 9 days,

OH

O

O

OH

OH

HO

~2.2:1

K2OsO4 (0.14 eq.),

K4Fe(CN)6 (3.29 eq.),

(DHQD)2-PHAL (0.57 eq.)

76% yield

242 243

Scheme 39.

OH

OAc

O

H

OAc

HO

HO

O

H

OAc

HO

HO

OsO4 (0.07 eq.), NMO (1.15 eq.), acetone/H2O, 5h.....................96%.............5 : 2

K2OsO4.2H2O (0.02 eq.), DHQD-CLB (0.1 eq.),

K3[Fe(CN)6] (3 eq.), CH3SO2NH2, K2CO3, tBuOH/H2O, 24h....96%.............9 : 1

244 245 246

Scheme 40.

O

F

OAc

OF

OAc

HO

HO

OF

OAc

HO

HO

OsO4 (0.1 eq.),

NMO (10.25 eq.)

~2 : 3

80% yield

247 248 249

acetone/THF/

2-methyl-2-propanol/

H2O, 5h

Scheme 41.


enced the observed ratio of diols obtained. For example, in the ab-

sence of chiral ligands, 22

-steroids with (24S)-24-ethyl substituents

afforded the (22S,23S)-22,23-diol almost exclusively, whereas with 22

-steroids bearing (24R)-24-methyl substituents, mixtures of

(22S,23S)- and (22R,23R)-22,23-diols were obtained [181]. Re-

cently, the application of catalytic OsO4/NMO in the syn-

dihydroxylation of (22E)-3 -11 -dihydroxy-5 -ergost-22-en-6-one

250 afforded the 22R,23R- and 22S,23S-diols 251 and 252 in a

1:1.5 ratio (Scheme 42). With (22E)-11 -hydroxy-5 -ergost-2,22-

dien-6-one 253 this system led to a 1:1.8 mixture of the correspond-

ing 2 ,3 ,22R,23R- and 2 ,3 ,22S,23S-tetraols 254 and 255 [176].

However, using Sharpless AD it became possible to control and

achieve high stereoselectivities in this 22

-dihydroxylation. In fact,

in the presence of NMO or K3Fe(CN)6 as oxidants, using DHQD

derivatives, the (22R,23R)-22,23-diols were preferentially obtained

[38, 107, 172, 174, 175, 182]. Interestingly, in the dihydroxylation

of the 2- and

22-bonds of BR precursors 256, 258 and 260 with

perfluoroalkyl side chains using OsO4/NMO without a chiral

ligand, it was observed that the reaction takes place preferentially

on the more electron-rich double bond in the A ring affording

2 ,3 -dihydroxylation (Scheme 43). The side chain of the tetraols

obtained after full conversion bear the R,R-diol configuration [86].

In a study aiming at the preparation of stigmasterol oxidation

products, the dihydroxylation of i-stigmasterol methyl ether 262

with OsO4/NMO afforded the corresponding 22S,23S-diol 263

along with a small amount of the 22R,23R-diastereomer 264

(Scheme 44). In the presence of OsO4/NMO and DHQD-PHN the

dihydroxylation was directed towards the more hindered upper face

of the molecule, and the major reaction product was the 22R,23R-

diol 264 [58]. The dihydroxylation of 16

-steroids has been per-

formed aiming at the preparation of intermediates for the synthesis

of several potential antitumor agents [82, 183]. Stoichiometric

KMnO4 was used to selectively convert 20-oxopregna-5,16-dien-

3 -yl pivaloate into its 16 ,17 -diol derivative, in high yield [184].

OSW-1 is an acylated cholestane diglycoside isolated from Orni-

thogalum saundersid which has extremely potent cytotoxicity

against various human cancer cells and little toxicity to normal

cells. In the synthesis of OSW-1 and analogues, the dihydroxylation

of several 16

-steroid intermediates (Scheme 45) has been per-

formed with stoichiometric OsO4 and pyridine, always affording the

H

O H

O

HO

OH

HO

OH

HO

HO

HO

H

OH

O

H

O

HO

HO HO

HO

OH

HO

OH

HO

HO

HO

HO

HO

1 : 1.5251250

1 : 1.8

255254253

252

OsO4 (0.35 eq.),

NMO (7.13 eq.)

THF/tBuOH/

H2O, Ar, r.t.,

100h

THF/tBuOH/

H2O,Ar, r.t., 72h

83% yield

94% yield

OsO4 (0.4 eq.),

NMO (8.12 eq.)

Scheme 42.

Rf

O

H

256..........Rf = n-C6F13.............257 / 68%

258...........Rf = n-C3F7..............259 / 50%

260............Rf = i-C3F7...............261 / 46%

OsO4 (0.15 eq.), NMO (3.43 eq.),

2-methyl-2-propanol/acetone/

THF/H2O, Ar, r.t., 16h

Rf

OH

OH

HO

HO

HO

Scheme 43.


OCH3

OH

HO

OH

HO

OsO4 (cat.), NMO,

tBuOH/THF/H2O,

r.t., 11 days

OsO4 (cat.), NMO,

DHQD-PHN,

tBuOH/THF/H2O,

r.t., dark, 5 days

263 / 47%

264 / 30%

262

Scheme 44.

TBSO

O

O

TBSO

O

O

OH

OH

O

O

TBSO

O

O

OH

OH

TBSO

MOMO

OH

O

S

OH

MOMO

O

S

265........... 5............OsO4 (1.94 eq.), Et2O, Py, -60˚C to r.t., 3h................266 / 50%

267.........5 -H.........OsO4 (~2 eq.), Et2O, Py, -78˚C to r.t., 10h.................268 / 58%

OsO4 (1.5 eq.), Et2O, Py

OsO4 (1.2 eq.),

CH2Cl2, Py

272 / 99%

270 / 83%

r.t., 4h

Ar, -78˚C, 8h

AcO

AcO

OTBS

TBDPSO

TMSO

HAcO

AcO

OTBS

TBDPSO

TMSO

H

OH

OHK2OsO4.2H2O (0.01 eq.),

(DHQ)2-PHAL (0.03 eq.),

K3Fe(CN)6 (3 eq.)

269

271

273 274 / 95%

MeSO2NH2, K2CO3,

tBuOH, H2O, 24h

Scheme 45.


OAc

O

BzO

H

AcO

H

OsO4 (0.02 eq.),

(DHQ)2-PHAL (0.1 eq.),

K3Fe(CN)6 (3 eq.) O

BzO

H

OH

OH

O

BzO

H

OH

OH

5 : 1275

K2CO3, tBuOH/H2O,

0˚C, 8h

>95% yield 276 277

Scheme 46.

16 ,17 -diols, in good yields [108, 183, 185, 186]. The syn-

dihydroxylation of steroid alkenes is a reaction of major importance

in the synthesis of cephalostatins and ritterazines, natural products

of marine origin that were found to have potent antitumor proper-

ties [187-189]. In a recently described synthesis of (+)-cephalostatin

1 105 the dihydroxylation of the 16

-steroid 273 was performed

using the Sharpless AD with K2OsO4·2H2O/K3Fe(CN)6/

(DHQ)2PHAL and the corresponding 16 ,17 -diol derivative 274

was prepared, in 95% yield (Scheme 45) [82]. In the synthetic

preparation of the C14,15-dihydro-C22,25-epi north unit of cepha-

lostatin 1 105 from commercially available hecogenin acetate via

multiple reductions and oxidations, the 25,26-dihydroxylation of

several intermediates has been studied. Thus, with the Sharpless

AD procedure, the pretended 25R-stereoisomer was selectively

obtained using (DHQ)2PHAL as ligand (Scheme 46) [190].

7. CONCLUDING REMARKS AND FUTURE PERSPEC-

TIVES

Oxidative processes are vital processes in steroid chemistry.

Many intermediates prepared by oxidation of steroidal substrates

are steps towards biologically active products and APIs. Despite the

several advances in allylic oxidation, epoxidation and syn-

dihydroxylation of alkenes, oxidation of alcohols, and remote func-

tionalization reactions, classical methods are still the most com-

monly used for the oxidation of steroids, especially on a laboratory

scale. Stoichiometric homogeneous processes which sometimes

require toxic and unstable reagents have obvious disadvantages and

therefore, the pursuit for more sustainable methods is mandatory in

this field in a near future. Heterogenenous catalysis, metal-based

free processes, oxidants such as O2 and H2O2, alternative solvents

as well as novel technologies will continue to be areas of intense

research which should be more extensively applied to steroid chem-

istry.

CONFLICT OF INTEREST

Declared none.

ACKNOWLEDGEMENTS

Jorge A. R. Salvador wishes to thank Universidade de Coimbra

for financial support. Samuel M. Silvestre and Vânia M. Moreira

wish to thank Fundação para a Ciência e a Tecnologia for financial

support (SFRH/BPD/41612/2007 and SFRH/BPD/45037/2008).

ABBREVIATIONS

Ac = Acetyl

acac = Acetylacetonate

AD = Asymmetric Dihydroxylation

APIs = Active Pharmaceutical Ingredients

BRs = Brassinosteroids

Bu = Butyl

CAN = Ceric ammonium nitrate

cap = Caprolactamate

CHP = Cumene hydroperoxide

CLB = p-Chlorobenzoate

cod = 1,5-Cyclooctadiene

CPTCAC = 3-Carboxypyridinium trichloroacetatochro-

mate

CPTFAC = 3-Carboxypyridinium trifluoroacetatochro-

mate

CTADC = Cetyltrimethylammonium dichromate

DCPNO = 2,6-Dichloropyridine N-oxide

DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

DET = Diethyltartrate

DHQ-PE = Dihydroquinine phenantryl ether

DHQD = Dihydroquinidine

DIB = Diacetoxyiodobenzene

DMDO = Dimethyldioxirane

Et = Ethyl

HIU = High-intensity ultrasound

HMPTA = Hexamethylphosphoric triamide

HT = Hydrotalcite

IBA = Isobutyraldehyde

IBX = o-Iodobenzoic acid

IPr·HCl = 1,3-Bis-(2,6-diisopropylphenyl) imida-

zolium chloride

LTA = Lead tetraacetate

MCPBA = m-Chloroperoxybenzoic acid

Me = Methyl

MMPP = Magnesium bis(monoperoxyphthalate)

hexahydrate

MOM = Metoxymethyl

MTO = Methyltrioxorhenium

MW = Microwave irradiation

NBS = N-bromosuccinimide

NCS = N-chlorosuccinimide

NHPI = N-hydroxyphthalimide

NMO = N-methylmorpholine-N-oxide

OAc = Acetoxy

OiPr = Isopropoxide


OTf = Triflate

PCC = Pyridinium chlorochromate

PDC = Pyridinium dichromate

PHAL = Phtalazine

PhIO = Iodosylbenzene

PSFC = Pyridinium-1-sulfonate fluorochromate

PTC = Phase transfer catalyst

Py = Pyridine

TBDPS = tert-Butyldiphenylsilyl

TBHP = tert-Butyl hydroperoxide

TBS = tert-Butyldimethylsilyl

TEAB = Tetraethylammonium bromide

TEMPO = 2,2,6,6-Tetramethylpiperidine-1-oxyl

TMP = Tetramesitylporphyrinate

TMS = Trimethylsilyl

TPAP = Tetra-n-propylammonium perruthenate

TPFPP = 5,10,15,20-Tetrakis(pentafluorophenyl)

porphyrinate

TPP = Tetraphenylporphyrinate

UHP = Urea-hydrogen peroxide

V70 = 2,2’-azobis(4-methoxy-2,4-

dimethylvaleronitrile)

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Received: January 10, 2011 Revised: August 19, 2011 Accepted: August 23, 2011

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ChemInform Abstract: Recent Developments in Oxidative Processes in Steroid Chemistry

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