An Overview of Partial Synthesis and Transformations of Secosteroids

Send Orders for Reprints to [email protected] Current Organic Chemistry, 2014, 18, 216-259

216

An Overview of Partial Synthesis and Transformations of Secosteroids Katarina Penov Gai, Marija Saka, Suzana Jovanovi-anta* and Evgenija Djurendi Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovia 3, 21 000 Novi Sad, Serbia Abstract: Secosteroids are an important group of modified steroids, which exhibits a variety of different biological activities. Studies on secosteroids have shown that modifications of the rigid tetracyclic steroidal carbon skeleton by cleavage of the internal C-C bonds provides more flexible compounds with new biological properties. The search for steroid compounds analogs with improved biological properties includes ring transformation into seco system. The recent development in the partial syntheses of secosteroids is described herein, as well as studies of methods for modifications of such molecules.

Keywords: Secosteroids, partial synthesis, reactivity, modification. INTRODUCTION Steroidal compounds are a very important class of natural products because of their capability to pass lipophilic membrane, enter the cell and, after binding to the appropriate steroid receptors, express their specific physiological function. The significant biological activity (e.g. antiproliferative, antifouling, antiinflammatory, antimicrobial, ichthyotoxic and antiviral) of many naturally occurring secosteroids, isolated mostly from marine organisms [1-4] or from plants [5, 6] emphasize the importance of this class of organic compounds. Extensive structure–activity relationship (SAR) studies provides a considerable amount of information concerning the biological and/or pharmacological activity of new steroidal compounds, isolated from natural sources or synthesized, as well as the pharmacophore moieties and possible mechanisms of compounds’ biological action. Knowing that even minor changes in steroid structures can cause significant changes in biological activity, large number of research groups worldwide modify steroidal moiety in different ways, trying to find more active compounds, expressing good biological activities, different from original steroids, but with lower side effects. Among the many other derivatives origined from steroids, compounds which underwent cleavage of C-C bond in A, B, C or D ring of the steroid tetracyclic nucleus, called secosteroids, are of great importance, because of a variety of their biological activities. Chemistry of secosteroids includes synthesis and modifications of secosteroidal compounds. Secosteroids are synthons in the in the semi-synthetic steroid research, making the possibility for the modification of the original sterane core and thus for the approach to novel biologically active compounds. Some secosteroids are intermediates in the syntheses of heterosteroids (thia-, oxa- and azasteroids) [7-10], while others are the main goal of the planned syntheses. This review was intended to be a survey on recent partial syntheses and derivatization of secosteroids, but, since there was no review on this topic reported in the literature until now, we did not outlined a time limit in the literature survey. The primary focus of this review will be the new structures and synthetic works, as well

*Address correspondence to this author at the Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovia 3, 21 000 Novi Sad, Serbia; Tel: +381-21-485-2771; Fax: +381-21-455-662; E-mail: [email protected] 1875-5348/14 $58.00+.00

as biological activity of new secosteroids, where available. Since some review papers about vitamin D derivatives exists [11, 12], 9,10-secosterod derivatives syntheses and transformations are not described herein. On the basis of their chemical structures, the reported secosteroids are divided into principal groups, according to the cleaved C-C bond. 1,2-SECOSTEROIDS Shoppee and co-workers [13, 14] reported the synthesis of two 1,2-secocholestane derivatives. Namely, the ozonolysis of the double bond in 5-cholest-1-ene (1) afforded the 1,2-seco-diacid 2, while the pyrolisis of its barium salt yielded the decarboxylation product, A-nor-1-ketone 3. Its reaction with hydroxylamine afforded (E)-oxime 4 exclusively. The Beckmann rearrangement of this compound afforded 1-aza lactam 5 accompanied by A-seco unsaturated nitrile 6 (Scheme 1). 1,3-SECOSTEROIDS Kocor and co-workers [15] described the synthesis of some 1,3seco-2-nor compounds 8-10 which were obtained from 17-methyl1,4,6-androstatrien-17-ol-3-one (7) with hydrogen peroxide in the excess of oxidant and alkali at room temperature. Baeyer-Villiger reaction with epoxidation was a simple method of synthesis of 2oxa-steroid (11) (Fig. 1). 1,10-SECOSTEROIDS Shoppee and co-workers [14] in the reaction of Beckmann rearrangement of 5-cholestan-1-one oxime 12, beside expected 1aza-A-homo-5-cholestan-2-one (13), also synthesized 1,10-seco-1cyano derivative 14 (Scheme 2). Compound 14 under relatively mild conditions by potassium-hydroxide hydrolyzed to the carboxylic acid 15. 2,3-SECOSTEROIDS 2,3-Secosteroids were intermediates in the syntheses of 2-aza5-cholestan-3-one (21) or 3-aza-5-cholestan-2-one (23) [16, 17] from 5-cholestan-3-one (16) (Scheme 3). The compound 19 was obtained from 2,3-secocholestane-2,3-dioic acid cyclic anhydride 18 in three-step procedure [16]. Methanolysis of anhydride occured © 2014 Bentham Science Publishers

An Overview of Partial Synthesis and Transformations of Secosteroids

Current Organic Chemistry, 2014, Vol. 18, No. 2 217

C8H17 O a

b

HOOC

c

COOH H

H

H

HO

3

2

1

H

N d

N

O

+ H

CN

H

H 6

5

4 Scheme 1. Reagents. a: O3, CHCl3 ; b: Ba(OH)2; c: NH 2OH; d: SOCl2, acetone.

OH Me

OH Me

OH Me

HOH2C

OHC

HOH2C

HOOC O

H

H 7

9a 5H 9b 5-H

8a 5H 8b 5-H OH Me

OH Me

OHC O MeOOC O 10

11

Fig. (1). Structures of the starting compound 7, 1,3-seco-2-nor compounds 8-10 and final 2-oxa-steroid 11.

O

H N

C8H17 HO

H

N

13 a b

CN

COOH

H 12 H

H 14

15

Scheme 2. Reagents. a: SOCl2,; b: KOH, acetone.

regioselectively at C-4. An alternative approach of nucleophile to 2carbonyl group was hindered by the presence of 19-methyl group. Diacid 3-monoester 19 was treated with diphenylphosphoryl azide (DPPA) and triethylamine (TEA) to effect a Curtius rearrangement. Finally, the resulting isocyanate 20 was converted to 2-azasteroid 21 by refluxing in wet DMF.

In order to find new ways for the functionalization of the A-ring of the steroid nucleus, the reaction of 5-cholest-2-en-3-yl acetate (24) with ruthenium tetroxide was also carried out and afforded, apart from -hydroxy ketone 25, diketone 26 also and a 2,3secocholestane-2,3-dioic acid (17) (Scheme 4) [18].

218 Current Organic Chemistry, 2014, Vol. 18, No. 2

Gai et al.

C8H17 O a, b

g, h

c

HOOC

MeOOC

O

H2NC

HOOC

O

H

H

O

16

O

H

H

18

17

22

d

H

f

N

O

C

N

O

HOOC

e

MeOOC

O

i

MeOOC

H

H 21

20

N

H

H

H

19

23

Scheme 3. Reagents. a: benzaldehyde or furfural; b: H2O2, KOH, EtOH; c: N,N’-dicyclohexylcarbodiimide (DCC), dioxane; d: MeONa, MeOH,; e: DPPA, TEA; f: H 2O, DMF; g: NH3, PhMe; h: CH2N2 ; i: Br2 , MeONa, MeOH.

C8H17

HO

a AcO

O +

O

H

HOOC

O

H

H

25

24

HOOC

+

H 26

17

Scheme 4. Reagents. a: RuO4 , acetone/H2O.

C8H17 O

O a, b

HO2C HO2C

Cl

C

Cl

C O

H

c

N2HC

C

N2HC

C O

H

H

27

17

28 d

e O

MeO2C MeO2C H

H 30

29

Scheme 5. Reagents. a: MeONa, MeOH; b: (COCl)2, Py, C6H 6; c: CH2N 2, Et2O; d: silver benzoate in TEA, Et2 O, MeOH; e: Th-salt, pyrolysis.

The 2,3-seco-dioic acid 17, also obtained by vigorous oxidation of cholestanol with chromic acid [19], served for obtaining derivatives 27-29 (Scheme 5) [20, 21] and for synthesis of Ahomocholestane-3-one (30) by unambiguous method involving bishomologation of 17 via Arndt-Eistert sequence followed by ring closure of the resulting acid. Namely, treatment of the sodium salt with oxalyl chloride led to the formation of the bis-acid chloride 27, which with etheral diazomethane yielded bis-diazomethyl ketone 28. The Wolff rearrangement of 28, which was catalyzed by silver benzoate-triethylamine, proceeded smoothly in methanolic solution to give the dimethyl ester 29. When the diester was converted to the thorium salt and pyrolyzed, the ketone 30 was obtained.

Dauben and co-workers [22] synthesized A,B-dinorcholestanone (37) and A,B-dinortestosterone (38) to determine the chemical and biological consequences of contracting both the A- and B-rings of the steroidal nucleus. The A,B-dinor analogs 37 and 38 were prepared from the corresponding B-nor steroids by formylation of B-norenones 31 or 32, ozonization of 2-hydroxymethylene ketones 33 or 34, resulting in the selective cleavage of 2,3-bond and cyclization of the formed 2,3-seco diacids 35 or 36 (Scheme 6). Paisley and Weiler [23] described the synthesis of 2,3-seco cyanoaldehyde 40, obtained by Beckmann fragmentation of 2-hydroxy-3-hydroximino-5-androstan-17-yl acetate (39) (Scheme 7).



R

R

The key intermediate for the multistep synthesis of 3-oxa-5 steroid 45 was 2,3-seco iodo formate 44. The Baeyer-Villiger oxidation of ketone 41 with meta-chloroperoxybenzoic acid (MCPBA) in 8-aminopyrene-1,3,6-trisulfonic acid trisodium salt (APTS) gave lactone 42. The reduction of lactone 42 with diisobutylaluminium hydride (DIBAH) yielded lactol 43, which was converted into corresponding iodo formate 44 with a mercury(II) oxide-iodine reagent in benzene, after which the solution was subjected in situ to the photolysis. Compound 45 was obtained by cyclization of formate 44 with methyllithium in THF [24].

HOHC a O

O

33 R = C8H17 34 R = OH

31 R = C8H17 32 R = OH

b

R

R

3,4-SECOSTEROIDS

c

HOOC

O

Schoppee and co-workers [25] described routes for the syntheses of 3- and 4-aza steroids through Curtius, Hofmann or Beckmann rearrangements, where 3,4-seco steroids were the key intermediates (Scheme 9). For the synthesis of 3-aza steroids, Diels acid (46) [19, 26, 27] was converted into the dimethyl ester, which with hydrazine gave the hydrazine salt of the 3-azido-4-acid 48. Compound 48 by nitrous acid was then converted into the 3-azido-4-acid 49. Azide 49 was rearranged in refluxing acetic acid into 50, formed by addition of acetic acid to the precursor 3-isocyanato-4-acid, since thermal decomposition occurred smoothly with elimination of carbon dioxide and acetic acid, to yield the lactam 51.

HOOC 35 R = C8H17 36 R = OH

37 R = C8H17 38 R = OH

Scheme 6. Reagents. a: NaH, HCOOEt; b: O3; c: KCN, Ac2O. OAc

OAc

HO a

OHC NC

N

3,5-SECOSTEROIDS

H

H

OH

39

40

5-Oxo-3,5-seco-4-norcholestan-3-oic acid (52), prepared firstly by Windaus [19] by oxidizing cholest-4-en-3-one with potassium

Scheme 7. Reagents. a: SOCl2, KOH, MeOH.

OMe OMe b

a

O O

OMe

H

42

OMe

41

O

OMe

H

OMe

H

HO

O

c OMe

43

I d

O

OHCO

OMe H

OMe

H

45

44

Scheme 8. Reagents. a: MCPBA, APTS, CH2 Cl2; b: DIBAH, CH2Cl2; c: HgO-I2, Py, C6H6 , h ; d: MeLi, THF.

C8H17 c

d

b HN COOR ROOC a

H2N

N3

CO OOC NH3-NH2

49

48

46 R = H 47 R = Me e

OAc C O

NH HOOC

HN 50

Scheme 9. Reagents. a: MeOH/HCl; b: NH2NH2 ·HCl; c: HNO 2; d: AcOH/Et2O; e: .

CO HOOC

O

51


Gai et al.

C8H17 C8H17 a or b or c or d O HOOC

N R

O 52

53 R = H 54 R = Bn 55 R = Me 56 R = (CH2)2OH

Scheme 10. Reagents. a: NH3 ; b: BnNH 2; c: MeNH 2, EtOH; d: HO(CH 2)2NH2, C6H6 .

C8H17

C8H17

Doorenbos and Wu [29] attempted to synthesize 4-aza steroids from 4-oxa-5-cholestan-3-one (57) by its reaction with corresponding amines (Scheme 11), but they obtained only 5-hydroxy3,5-seco-4-nor-3-cholestanamides (58-62). All attempts to cyclize the amides resulted in the re-creation of starting compound (57). The lactone 57 was also reduced to 3,5-seco-4-norcholestane-3,5diol (63). Rao and co-workers [30] published a versatile procedure for preparing A-lactone 65 from 17-hydroxy-4-nor-5-oxo-3,5-seco-3androstanoic acid (64) (Fig. 2) using a reagent composed of acetic anhydride and perchloric acid in ethyl acetate. Compound 64 was obtained from testosterone via oxidation method using suitable reagent KMnO4/NaIO4 [31-34] in presence of Na2CO3.

b HOH2C O

O

HO H

H

57

63

a C8H17

OAc

OH

RHNOC HO

H 58 R = H 59 R = Me 60 R = NH2 61 R = CH2CH2OH 62 R = Bn

HOOC O

O

64

O

65

Fig. (2). Structures of the starting compound 64 and final product 65.

Scheme 11. Reagents. a: RNH2; b: LiAlH4, EtOH.

3,5-Seco derivative 67 was the key intermediate in the syntheses of finasteride (72) and dutasteride (74), inhibitors of 5reductase, used for the treatment of benign prostatic hypertrophy. The compound 67 was obtained by oxidation of 66 with KMnO4/NaIO4. Its ammonium salt upon pyrolysis yielded 5-4-aza

permanganate, served as starting compound for syntheses of the corresponding enamine lactams 53-56. Compound 52 in the reaction with ammonia, benzylamine, methylamine or ethylamine at elevated temperatures afforded corresponding lactams [28]. COOMe O

a

b

c

HO O

O

O 66

H

67 O

O

H N

H

O H

73 R = t-Bu 74 R = 1,4-bis-trifluoromethyl-benzene

H

68

H 69a 5H 69b 5H

d

H N

COOH

e

f

N

N

R

R

O

O

N

N

O H

H 71 R = t-Bu 72 R = 1,4-bis-trifluoromethyl-benzene

N H

H 70

Scheme 12. Reagents. a: KMnO4, NaIO 4, t-BuOH; b: NH4OAc; c: Pd/C, AcOH; d: NaOH; e: alkylamine, DCC; f: DDQ, BSTFA, dioxane.



lactam 68. The 5-hydrogenation gave 69. Saponification of compound 69a yielded acid 70, followed by condensation with appropriate alkyl amine in the presence of DCC to give 71 and 72, which upon oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) yields the respective steroids 73 and 74 as shown in (Scheme 12) [35]. The 5-oxo-4-nor-3,5-secosteroid-3-oic acids 52, 64 and 75-78 served as precursors for the syntheses of 4-azalactams 53, 79-83, using urea, catalysed by Lewis acid under microwave irradiation [36]. The starting compounds 52, 64 and 75-78 were obtained from 4-cholesten-3-one, testosterone, 24-ethyl-cholest-4,22-dien-3-one, testosterone acetate, progesterone and androst-4-ene-3,17-dione respectively, by oxidation using NaIO4 or KMnO4 in presence of Na2CO3 (Scheme 13). R

R a

COOH O

O

N H 53 R =

52 R = 64 R = OH

79 R = 75 R = 80 R = OH 81 R = OAc 82 R = COMe 83 R = O

76 R = OAc 77 R = COMe 78 R = O

Aggarwal and co-workers [37] described the syntheses of 17oxo-17a-aza-D-homo-3,5-secosteroids 92-95 using diosgenin (84) as a starting material. Diosgenin was converted to 17-oxo-3,5-seco4-norandrostan-3-oic acid (90) in following steps: Oppeanuer oxidation, Lemieux-von Rudolff oxidation, Wolff-Kishner reduction, Marker degradation, oximation and Beckmann rearrangement. 17Oxo-3,5-seco-3-acid 90 was then converted to D-homolactame 92 via oxime 91. The resulted seco acid 92 was then treated with thionyl chloride and the respective amines to get the desired 3,5secosteroidal amides (94, 95) (Scheme 14). 4,5-SECOSTEROIDS Schoppee and Roy [38] reported in 1963 the synthesis of 4,5seco derivative 97 by Beckmann fragmentation of 5-hydroxy-4hydroximino-cholestan (96), which after hydrolysis gave acid 98 (Scheme 15). The B-nor-4,5-seco compounds 101-106 were intermediates in the synthesis of 3-hydroxy-17-dimethyl-t-butylsilyloxy-5-azaandrostane (108) from B-nor-17-oxoandrost-5-en-3-yl acetate (99) [39]. The key step was fragmentation of B-nor-17-dimethyl-tbutylsilyloxy-androst-4-en-3-yl acetate (100) by ozonolysis, followed by reductive opening of the ozonide bridge (Scheme 16). The Eschenmoser fragmentation [40-46] of ,-epoxy ketones 110 afforded 4,5-seco-keto acetylene 111 (Scheme 17) [47]. The compound 111, after partial hydrogenation of triple bond, was converted into compound 112, which with hydroxylamine gave oxime 113. 5,10-SECOSTEROIDS In the oxidative C5-C10 -fragmentation of 5-hydroxy steroid [48-52] compound 114 in the reaction with iodine and lead

Scheme 13. Reagents. a: urea, BF3·Et2O, MW.

O

O

O

O

O a

O b COOH O

O

HO

85

84

c O

R

R

COOH

COOH

COOH 90 R = O 91 R = NOH f

e

88 R = O 89 R = NOH

87

H

H N

O

d

f

e

86

N

O

O

h

R

COR

N g

92 R = OH 93 R = Cl

R'

C O 94 R = H, R' = CH2CH2Me 95 R = H, R' = CHMe2

Scheme 14. Reagents. a: Al(i-PrO)3 , cyclohexanone, toluene,; b: KMnO4, NaIO4, t-BuOH/H2O (9:1); c: NH2NH2 · H2O, NaOH, diethylene glycol; d: MeNH2 · HCl, Ac2 O, Py; e: NH2OH · HCl, Py; f: SOCl2 , C6H6; g: SOCl2 ; h: alkyl amine, CH2Cl2.


Gai et al.

b

a

O COOH

O CN

OH NOH

96

98

97

Scheme 15. Reagents. a: SOCl2 , or HCl/Et2O; b: HCl,-AcOH (1:1).

O

OSiMe2tBu

7 steps

a

b O

99

100

c HOOC AcO

HC AcO

AcO

AcO

101

f

e

Ph2HCOOC AcO

O

O

Ph2HCOOC AcO

R

H

N O

102 103 R = O 104 R = NOH

d

h

g N HOOC H AcO

N

AcO O

105

O

106

N

HO O

107

108

Scheme 16. Reagents. a: 1. O3, 2. (Me)2 S; b: KMnO4, t-BuOH/NaH2 PO4 ; c: Ph2 CN2; d: NH 2OH/EtOH; e: SOCl2/ether; f: 1. KOH/MeOH, 2. HCl; g: Ac2O/Py; h: LiAlH 4/dioxane.

OH a

O

O 109

c

b

O O

110a 5,6 110b 5,6

R 111 d

112 R = O 113 R = NOH

Scheme 17. Reagents.a: H2O2 /MeOH, NaOH; b: TsNHNH 2, AcOH; c: H2, Lindlar; d: NH2OH, EtOH.

tetraacetate gave two diastereomeric (Z)- and (E)-1(10)-unsaturated 5,10-secosteroidal 5-ketones 115a and 115b (Scheme 18) [50] as the main products. Both compounds were utilized for the synthesis of an impressive number of new 5,10-seco steroidal derivatives, potentially useful for the development of new pharmacological tools. In this reaction compounds 116-118 were by-products. Khripach and co-workers [53] used 3 ,17 -diacetoxy-5,10secoandrost-1(10)-en-5-one (115b) to obtain a new secosteroidal compound 119 containing a cyclopentenone ring (Scheme 19) in reaction with BF3·Et2O, followed by cleavage of the macrocycle. It is evident that intramolecular rearrangement took place under used conditions.

Batzold and Robinson [54] described the synthesis of 5,10seco-19-norcholest-5-yne-3,10-dione (120) and its estryne (121) and 19-nor pregnyne (122) analogues which were obtained after Tanabe-Eschenmoser fragmentation of 5 ,10 -epoxy-6-oxo steroids. Starting from 5,10-seco acetylenic steroids 120-122 (Fig. 3), some specific inhibitors of the 5-3-keto steroid isomerase of P. testosteroni were designed and synthesized. Thus, the enzyme converts 5-3-oxo steroids to the corresponding 4-3-oxo steroids by the removing the 4 proton which is transferred intramoleculary to the 6 position, most plausibly via enol intermediate. If compounds such as 120 proved to be subtrates for the enzyme, the same process should generate the reactive 4,5-dien-3-one system.



H

H +

+ AcO

AcO

AcO

O

O

OH

H

H AcO

AcO I

116

+

+ 114

OH

115b

115a

a

AcO

+

H

OAc

O

I

117a

AcO

O

O

117b

118

Scheme 18. Reagents. a: Pb(OAc)4 , I2, C6H6 .

OAc OAc

H AcO

H

a

H

O

H

H

some of them was confirmed by partial syntheses. A partial synthesis of secosteroid 127 started from 5-cholest-7-ene-3,5,6-triol (125) (Scheme 20) [56]. In particular, the reaction of the polyhydroxylated sterol 125 with lead tetraacetate in acetic acid gave 5oxo-5,6-seco-6-al derivative 126. Reduction of this product yielded the compound 127 and its 5 epimer 128. The authors [57] have repeated this procedure in 5-ergostane serie.

119

O 115b

OAc Scheme 19. Reagents. a: BF3·Et2O, CHCl3 .

a R

HO HO

O

O CHO

HO OH 125

126 b

O 120 R = C1817, 121 R = O 122 R = CH3CO, Fig. (3). Structures of the compounds 120-122.

HO O

O

HO

HO OH 127

HO

OH 128

O

O

Scheme 20. Reagents. a: Pb(OAc)4 , AcOH; b: LiAlH4 .

O

C

O

C

123

124

Fig. (4). Structures of the compounds 123 and 124.

Zerhouni and co-workers [55] found that (4R)-5,10-secoestra4,5-diene-3,10,17-trione (123) and (4R)-5,10-seco-19-norpregna4,5-diene-3,10,20-trione (124) were noncompetetive and possibly irreversible inhibitors of epididymal 5-reductase (Fig. 4). 5,6-SECOSTEROIDS Nine 3,5,6-trihydroxylated 5,6-secosteroids, isolated by Sica and co-workers [56, 57] from the marine sponge Hippospongia communis differ only in their side chains A stereochemistry of

The ozonization of cholesterol in aqueous dispersion afforded epidioxy-5,6-seco-triol 129 and, efter decomposition of this compound, 5,6-seco-6-a1dehyde 130 and 5,6:5,10-disecolactone131 (Fig. 5) [58]. Acetic anhydride/pyridine treatment of the epidioxide 129 resulted in rearrangement, yielding 5,6:5,10-disecolactones 133 and 136. Acetylation of homologue 132 and its 3-acetate also involved rearrangement to disecolactones, including 134 and 135. These results established that 5,6-secosterol formation was the major ozonization process and that “anomalous” lactone products are derived by rearrangement of initially formed epidioxides (Scheme 21). Lin and co-workers [59] reported that 3-sterols, exemplified by 4-(2-propenyl)-5-cholestan-3-ol (LY295427), have potent hypocholesterolemic activity. In order to examine the effect of


O

Gai et al.

O

OH

O

O

HO

HO

HO

CHO

CHO

OH

O 130

129

131

Fig. (5). Structures of the compounds 129-131.

O

O

O

HO OH

CHO OR

O 133

129 R = H 132 R = Me a

OH

O HO O

O -ROH

CH OR

HO

CHO O

129a R = H 132a R = Me

OAc

O AcO

131

OAc

O CH

CH O 134 R = H 135 R = Me

OR

O

OAc 136

Scheme 21. Reagents. a: Ac2O, Py.

flexibility of the 3-hydroxy-bearing A-ring on the activity, 4-(2propenyl)-5,6-secocholestan-3-ol (148), a B-ring seco analog of LY295427, was synthesized from cholest-4-en-3-one (138) (Scheme 22) [60]. In the first attempt, the olefin 139 was subjected to the reductive ozonolysis. Obtained products were the 5,6epoxide 140 and the desired seco aldehyde 141. To improve the yield of the key aldehyde 141, olefine 139 was treated with osmium tetroxide in the presence of pyridine to give the 5,6-dihydroxy ketal 142a and its 5,6-dihydroxy isomer 142b. A mixture of 142a and 142b was then oxidatively cleaved with sodium periodate to afford the seco aldehyde 141. Compound 141 was not stable and tended to undergo intramolecular aldol condensation; therefore, it was immediately subjected to selective reduction of the aldehyde group to provide the keto alcohol 143. By Grieco’s protocol [61], compound 143 was treated sequentially with o-nitrophenylselenocyanate and tri-n-butylphosphine to give a selenide, which was readily converted to the olefin 144 after

treatment with m-chloroperoxybenzoic acid. Catalytic hydrogenation of 144 delivered 145. Reduction of the keto group of 145 and subsequent acid-catalyzed deprotection of the ethylenedioxy ketal, accompanied by the concurrent dehydration, furnished the enone 146. Compound 146 was subjected to the reductive alkylation to yield a separable mixture of allylated ketones 147a and 147b. Finally, the desired compound 148 was obtained as the sole product after the reduction of 147a with K-selectride (Scheme 22). 5,6-Secosteroids were suitable as intermediates in the syntheses of 6-azasteroids. For example, 6-azacholest-4-en-3-one (151) was synthesized from 4-cholesten-3-one (138) through 5,6-seco-5-keto6-acid (149) (Scheme 23) [62]. The acid was converted to the acid chloride followed by reaction with sodium azide to give acyl azide 150. Heating of 150 to 80 °C generated the isocyanate 150a which was immediately treated with aqueous acid yielding the 6azasteroid 151.



O a

138

c O

O

O O

O

HO

139

O

OH

OH

142a

142b

b

d

O

O

HO

O

O

O

O

H

O

O

O

R

h

O 140

141

141 R = CH2CHO

e

143 R = CH2CH2OH

f

144 R = CH=CH2

g

O 146

145 R = CH2Me i

O

O 147a

147b

j

HO 148 Scheme 22. Reagents. a: HOCH 2CH2OH, p-toluenesulfonic acid (PTSA), toluene; b: O3, MeOH, CH 2Cl2, Me 2S; c: OsO4, Py; d: NaIO4, THF, H2O; e: NaBH4, THF, MeOH; f: 2-nitrophenylselenocyanate, Bu3P, THF; MCPBA, CaCO 3, CH2Cl2; g: PtO2, H 2, EtOAc; h: LiAlH4, THF; 2.5N HCl; i: Li, NH3, t-BuOH, THF, allyl iodide; j: K-selectride, THF.

Kasal [63] synthesized a series of 6-substituted 7norepiallopregnanolone derivatives. A key compound in these syntheses was 3-acetoxy-5,20-dioxo-5,6-secopregnan-6-oic acid (154). Seco acid 154 was obtained from 20-oxopregn-5-en-3-yl acetate (152) in two ways (Scheme 24). The oxidation of 152 with CrO3 in AcOH led to the product of allylic oxidation 155 and an

inseparable mixture of acid 154 and the product of the C17–C20bond cleavage, 20,21-dinor acid 156. However, if the alkene 152 was first converted into diol 152, the 5,6-seco steroid production 154 was cleanly carried out under milder conditions. On treatment of acid 154 with benzoyl chloride in pyridine and then pyrolysis of compound 157, 20-oxo-7-norpregn-5-en-3-yl acetate (158) was


Gai et al.

C8H17

e, f

a, b, c, d O O

O

138

CO2H

O 149

g, h O

O O

O

CON3

O

O

NCO 150a

150 C8H17

O

N H

151

Scheme 23. Reagents. a: HOCH2CH 2OH, PTSA, toluene; b: O3, MeOH, CH2Cl2; c: Zn, AcOH; d: NaClO2 , 2-methyl-2-butene, Na2HPO4, t-BuOH, H2O; e: (COCl)2 , Py, CH 2Cl2; f: NaN3 , acetone, H2O; g: toluene, 80 °C; h: HCl, 4M in THF.

obtained. Compound 158 served for a synthesis of other 7norepiallopregnanolones.

b

5,7-SECOSTEROIDS AcO

HO

AcO 153

OH

COOH

O 154

a O

AcO

AcO

155 O

c

AcO AcO

6,7-SECOSTEROIDS

O

152

O

COOH

O 156

COOH 154 d

e

AcO

AcO

O O

157

The synthesis of 3-oxygenated 6-azaandrostanes was achieved from 3-hydroxyandrost-5-ene-7,17-dione via 5,7-seco-6-nor derivatives 160 and 161. The oxidation of t-butyldimethylsilyl ether 159 with ruthenium tetroxide afforded B-seco acid 160 (Scheme 25) [64]. The reaction of its methyl ester 161 with ammonia afforded the mixture of epimeric lactam carbinols 162, which after dehydration and oxidation of the resulting enamide yielded enon lactam 163.

Miljkovi and co-workers [65] developed a method for a partial synthesis of 6,7-seco estradiol system from estradiol derivatives. They selected 3-methoxy-17-hydroxyestra-1,3,5(10)-trien-6-one (164) as starting material (Scheme 26). Oximination of 164 gave a mixture of isomeric oximino ketones in which the main product 165 was isolated by crystallization and its anti-geometry of oximino group was determined by X-ray analysis [66]. Reduction of 165 stereospecifically afforded a syn--hydroxy oxime 166 [67], which underwent Beckmann fragmentation reaction whereupon the secocyanoaldehyde 167 was obtained (Scheme 26). 6,7-Secoestranes served as intermediates in the syntheses of 6and 7-azaestrane lactams [68]. Reaction started from 3methoxyestra-1,3,5(10),6-tetraen-17-yl acetate 168, which by oxidative cleavage gave 6,7-seco-dioic acid 169 (Scheme 27). This key intermediate was converted via diester 170 into mono-ester 171. The Curtius rearrangement of this compound, followed by hydrolysis of the intermediate isocyanate 172 and cyclization, yielded 6-azaestrane lactam 173. A similar route was applied for the synthesis of 7-azaestrane lactam [68].

158

Scheme 24. Reagents. a: MCPBA; HClO4, THF; b: Jones reagent, acetone, toluene; c: CrO3, AcOH; d: BzCl, Py; e: pyrolysis.

7,8-SECOSTEROIDS Suginome and Shea [69] reported a transformation of 7-oxo3,5-cyclo-5-cholestan-7-one (174) into a methyl 3,5-cyclo-7,8-



O

a t-BuMe2SiO

O

c CO2R

O

t-BuMe2SiO

159 b

160 R = H 161 R = Me

d, e t-BuMe2SiO

HO

N

O

O

N H

H

O

163

162 Scheme 25. Reagents. a: RuO4, NaIO4; b: CH 2N2 ; c: NH 3, MeOH; d: AcOH, CHCl3; e: CrO3 , Py.

diene (178) was obtained by photosensitized oxidation of 3acetoxylanost-8-ene (177) (Scheme 29).

OAc

OAc a MeO

N

MeO

OH

a

O

O 164

MeO

165

CO2R2 CO2R1

MeO 168

b

169 R1 = R2 = H

b,c

170 R1 = R2 = Me

d,e

171 R1 = H, R2 = Me

c MeO

f

CN C H

N

MeO OH

O

OH

g

166

167

Scheme 26. Reagents. a: AmONO, t-BuOK, t-BuOH; b: NaBH4, MeOH; c: SOCl2.

seco-5-cholestan-7-oate (175) and 3,5-cyclo-7-oxa-5cholestane (176) by irradiation in the presence of oxygen (Scheme 28). The ketone 174 in methanol saturated with oxygen was irradiated with a Hanovia 450-W mercury arc through a Pyrex filter. When compound 174 was photolyzed in the absence of oxygen 7,8seco derivative 175 was the exclusive product [70]. 8,9-SECOSTEROIDS In the partial synthesis of 8,9-secosteroids, reported by Fox and co-workers [71], 3-acetoxy-8,9-oxido-8,9-secolanosta-7,9(11)-

MeO

N H 173

O

MeO

172

Scheme 27. Reagents. a: NaIO 4, KMnO4 , acetone; b: SOCl2 , CHCl3, Py; c: MeOH; d: NaOH, H 2O, dioxane; e: Ac2O, Py; f: DPPA, TEA, toluene; g: Py, H2O.

9,11-SECOSTEROIDS Many of 9,11-seco steroids were investigated, partially because of a variety of biologically active naturally occurring compounds with 9,11-seco steroidal moiety, while others were intermediates in the syntheses of oxa, thia or aza steroidal compounds with a hetero atom in the C-ring of the steroidal skeleton.

C8H17

C8H17

C8H17

a O 174 Scheme 28. Reagents. a: MeOH, O2 , h.

COOMe NCO

COOMe

O

175

176


Gai et al.

the isocyanate 184 to the imine 185, was prepared in two ways: via appropriate chloride 182, or directly from the acid 181. In the field of steroidal estrogens it was found that compounds with nitrogen-containing residue at 11-position proved themselves as antiestrogens. Syntheses of amide derivatives of 9,11-secoestra1,3,5(10)-trien-11-oic acid containing alkyl or aromatic amine residues (188-198) were carried out by the treatment of 186 (obtained by chromium trioxide oxidation of 3-methoxyestra-1,3,5-(10)-trien17-yl acetate [73]) with aliphatic amines such as n-propyl amine, n-butyl amine, 2-phenyl ethyl amine etc., in presence of hydroxy benzotriazole (HOBT), through condensation of respective amines with ester of 11-oic acid prepared in situ. Otherwise, by treatment of 186 with dicyclohexyl carbodiimide (DCC) corresponding cyclohexyl amide derivative of the 11-oic acid (187) was achieved. (Scheme 31) [74]. Knowing that among various modiﬁcations of steroidal moiety, substitution of aryl residue at the 11 position of seco-steroidal compounds could lead to the development of compounds with altered hormonal proﬁle, Gupta and co-workers [75] synthesized 11aryl-substituted 3-methoxy-9,11-secoestra-1,3,5(10)-trienes with ester function at position C-11 as modified estrogens (Scheme 32). During these syntheses intramolecular cyclization of 17-acetoxy3-methoxy-9,11-secoestra-1,3,5(10)-triene-11-oic acid 186 under different Friedel–Crafts reaction conditions occurred.

a O AcO

AcO

H

H

177

178

Scheme 29. Reagents. a: Py, O2 , hematoporphyrin, p-nitrobenzenesulphonyl chloride, h.

An efficient synthesis of 11-aza analogue of dihydrotestosterone (185) from 5-androst-9,l1-ene-3,17-dione (179), through a pathway implying a Curtius-type rearrangement of a 9,11-seco 9oxo derivatives 180-182 and C-nor-9,12-seco derivative 183 was described (Scheme 30) [72]. Starting compound (179) was obtained from adrenosterone in four synthetic steps. Ozonolysis of 5androst-9,l1-ene-3,17-dione (179) and oxidation with hydrogen peroxide gave the seco keto aldehyde 180, accompanied by the diketo acid 181. The diketo acid 181 also was formed by the oxidation of aldehyde 180 with Jones’ reagent. The acid azide 183 which, in turn, was subjected to a Curtius-type rearrangement, leading via R CO

O

O

O

a

b

O

O

N3C

O

O

C

N

O

O +

O

O H

H 183

180 R = H 181 R = OH 182 R = Cl

179

184 c O N

O

H 185

Scheme 30. Reagents, a: O3; H2O 2; b: (COCl)2, NaN3, C6H 6 or TEA and ethyl chloroformate; c: HCl.

O HN

O

OAc

C

HO

OAc

C

HN

C

MeO

MeO 187

O

b

a

MeO

R

186

Scheme 31. Reagents. a: DCC, CH2Cl2, TEA, amine; b: HOBT, CH2Cl2, TEA, amine.

188-198

188 R = n-propyl OAc 189 R = n-butyl 190 R = buthylmethyl 191 R = n-octyl 192 R = n-dodecyl 193 R = phenyl 194 R = benzyl 195 R = phenethyl 196 R = phenpropyl 197 R = p-anisidyl 198 R = m-anisidyl


OH

HO


OAc

HO c

a

O

O

MeO

OH

MeO O

MeO 201

MeO 186

d

199 e

b H

O

OH

O

O O

OH

O

MeO

MeO

MeO

OH

Ph Ph

200

202

O O

MeO 203 Scheme 32. Reagents. a: HCl, MeOH; b: PhMgBr, ether; c: NaOH, MeOH; d: PhLi, THF; e: phenol or anisole with polyphosphoric acid or BF3·OEt2 or SnCl4.

Many steroids isolated from various marine organisms that expressed diverse biological activities (e.g. antitumor or antiinflammatory) have oxo function at position C-9. In order to study the role of C-9 oxo group, Kongkathip and co-workers [76] synthesized various types of 9,11-secosteroids with or without an oxo function at C-9, containing different side-chains: spiroketal moiety, acetyl side chain or cholesterol-like chain and evaluated the anticancer activity of these compounds. This study revealed that presence of a cholesterol-type side chain plays a major role in the anticancer activity of these compounds, as well as oxo-function at C-9 (Schemes 33-35). 9,11-Secosteroids with spiroketal ring were synthesized from 9,11-dehydrotigogenin and its acetate (204 and 205) (Scheme 33), which by ozonolysis and treating with PPh3 gave keto-aldehydes 206 and 207. The reduction of 206 and 207 with NaBH4 afforded 9,11-seco 11-alcohol derivatives with oxo (208-210) or alcohol group (211-213) in position 9. On the other hand, treatment of ketoaldehydes 206 and 207 with hydroxylamine gave the 11-oxime 214, which upon treatment with DDQ provided keto nitrile 215 [76]. Selective hydrogenation of 216 using Raney nickel as catalyst proceeded predominantly at the sterically less hindered double bond at C-16, giving D-ring saturated derivative, which underwent ozonolysis, affording appropriate 9,11-seco derivative 217 (Scheme 34). This compound was selectively reduced at 11-formyl group with NaBH4, and dehydropyran compound 218 was obtained as a

result of nucleophilic attack of the 11-hydroxy group, formed under reduction conditions, to the 20-keto side chain [76]. The syntheses of 9,11-secosteroids containing cholesterol-like side chain with different degrees of oxidation at C-9 (219-223) are also shown in (Scheme 34) [76]. 20-Ketosterol 216 served as starting compound in multistep syntheses of such derivatives. This derivatization included prolongation of side chain and ozonolytic cleavage of the 9(11) double bond. In order to investigate the influence of the side chain absence, 9,11-secosteroids lacking side chains in steroidal skeleton were synthesized from the same 20-ketosterol 216 (Scheme 34). This conversion included Beckman rearrangement upon reaction with pacetamidobenzenesulfonyl chloride in pyridine and subsequently removing of 17-keto group by thioketalisation and then desulphurization of the formed derivative. The opening of C-ring was achieved in the same manner as previously described, giving 9,11seco 9-oxo 11-hydroxy derivatives 224 and 225. The syntheses of 9,11-secosteroids containing different functional groups on the cholesterol-like side chain (227-237) are shown in (Scheme 35) [76]. The 9(11) steroidal derivative 226 served as starting compound in the synthesis of this kind of compounds, directly or over 22-hydroxy derivative 231. Both compounds 226 and 232 in the reaction conditions of ozonolysis underwent cleavage of the 9(11) double bond, giving 9,11-seco-9-keto-11-aldehydes 227 and 233, respectively. The selective reduction of these compounds


Gai et al.

O

O

O

b

RO

RO

204 R = H

O

d

AcO

H

H a

HON

CHO

H

206 R = H 207 R = Ac

205 R = Ac

214

c

e

R2O

CN

208 R1 = R2 = H, R3 = O a

R3

209 R1= Ac, R2 = H, R3 = O

O

210 R1 = R2 = Ac, R3 = O 211 R1 = R2 = H, R3 = OH, H a

R1O

212 R1 = Ac, R2 = H, R3 = OH, H AcO

213 R1 = R2 = Ac, R3 = OH, H

H

H 215

Scheme 33. Reagents. a: Ac2O, Py; b: O3 , CH 2Cl2, then PPh3; c: NaBH 4, EtOH in CH2 Cl2 ; d: NH 2OH, EtOH; e: DDQ, dioxane.

HO R1 R2

AcO

219 R1 = isopropyl, R2 = O 220 R1 = isobutyl, R2 = O 221 R1 = isopropyl, R2 = OH, H 222 R1 = isobutyl, R2 = OH, H 223 R1 = isopropyl, R2 = H, H

H

HO O

R O

AcO

AcO

H

H

224 R = O 225 R = H, H

216

O CHO O

AcO

Scheme 34. Reagents. a: NaBH4 , 30% EtOH, CH 2Cl2 .

O O a

AcO H

H

217

218



O

OR d

AcO

H

231 R = H 232 R = Ac

c

226 a

a O

OAc

CHO

CHO

O

O

227

233

b

RO

b

O HO

OR1

O R2

c

228 R = H 229 R = Ac

R 1O

+ HO

e

H 234 R1 = Ac, R2 = O 235 R1 = H, R2 = O

e

236 R1 = Ac, R2 = OH, H 237 R1 = H, R2 = OH, H

O

OH

230 Scheme 35. Reagents. a: O3 , CH 2Cl2, then PPh3; b: NaBH4 , EtOH in CH2Cl2 ; c: Ac2O, Py; d: NaBH4, MeOH; e: KOH, MeOH.

afforded different diol, triol and tetraol compounds (230 and 234237).

from 11-oxaestrone 244, over 9,11-seco 9-oxo 11-acid (246) and Cnor-9,12-seco derivatives 247 and 248.

9,12-SECOSTEROIDS

11,13-SECOSTEROIDS

The synthesis of 11-oxa-5-androstane-3,17-dione (243) from C-nor-9,12-seco 9-oxo 12 acid 238, over C-nor-9,12-seco derivatives 241 and 242 was described [77] (Scheme 36). This synthesis included a multistep conversion of C-seco derivatives in order to introduce oxygen atom in the C-ring of the steroidal skeleton. The starting compound in this reaction scheme, 238 was produced by same researchers from 11-oxo-5-androstan-3,17-dione, over many synthetic intermediates, including epoxide, bromohydrin, monoketal, acetonide and 9-en-12-one derivatives. The synthesis of 11-oxaestradiol (249), product with antifertility activity and very low uterotropic potency, was reported by Engel and co-workers [78] (Scheme 37). 11-Oxaestradiol was synthesized

The syntheses of 12-oxa (255), 12-aza (257) and 12-thia (260) steroids from 12-oxo-3,7,24-trimethoxy-5-cholane (251), Ibrahim-Ouali and co-workers [79] led through some C-nor-11,13-seco derivatives, where iodo formate 254 served as key intarmediate (Scheme 38). Namely, 254 was obtained from lactol 253, which was subjected to the hypoiodide photolysis. The cyclization of formate 254 with methyllithium in THF afforded a novel 12-oxa steroid 255 (Scheme 38). On the other hand, compound 254 was converted into its diiodo derivative 256, by treatment with trimethylsilyl iodide in carbon tetrachloride, which with benzylamine in dioxane afforded Nbenzyl 12-aza-5-steroid 257. The synthesis of 12-thia steroid 260


Gai et al.

OR2 R1OOC O

O MeOOC O

OR2

MeOOC O

a, b

O

O

c O

RO

O

H 238 R = R1 = R2 = H 239 R = Ac, R1 = R2 = H

H

O

H

240

241

d OH

O

O

O

OH

O e, f O O

O

H

H 242

243 Scheme 36. Reagents. a: CH2 N2, Et2O; b: Jones reagent, acetone; c: PTSA.

COOH O

O O

O

a

O

Cl

OH

O

b

H3CO

H3CO

RO

Cl

244 R = H 245 R = Me

247

246

c OH O

OH

d, e

H3CO

RO

248

249 R = H 250 R = Me

Scheme 37. Reagents. a: chromic acid, AcOH, H2O; b: Pb(OAc)4 , CCl4, trityl chloride; c: NaBH4, MeOH; d: NaOMe, MeOH; e: BBr3, CH2Cl2.

was achieved in three steps from iodo formate 254, over two secoiodo derivatives: hydroxy- (257) and mesyloxy (258) (Scheme 38). 12,13-SECOSTEROIDS A ring-closing metathesis approach was used for obtaining secosteroidal macrocycle from cholic acid (261) or methyl-cholate (262). The Bayer-Villiger reaction of ketocholane 264 was used for the ring expansion to obtain compound 265. This reaction was followed by C-ring fragmentation affording the pentahydroxysecocholane product 266, which, in form of diallyl adduct 267 underwent cyclization reaction, providing a mixture of geometric isomers of the secosteroidal macrocycle 268 (ratio E:Z = 8:2) (Scheme 39). This combination of secocholanic skeleton with varied types of macrocycles, produces high levels of skeletal diversity and complexity [80].

13,14-SECOSTEROIDS Bjelakovi and co-workers [81] described the syntheses of 13,14-secosteroids, a type of modified steroids containing a ninemembered ring. Oxidations of 14-hydroxy-5-cholestan-3-yl acetate (270) with lead tetraacetate under thermal (Scheme 40) or photolytic conditions (Fig. 6) proceeded mainly by fragmentation of the C(13)-C(14) bond to give, as the primary products, 13,18didehydro-13,14-seco derivative 271 and (E)- 12-13,14-seco ketone 276, respectively. Further transformations of these compounds under the same conditions afforded, in addition, the acetoxy derivatives 272-274 (from 271), and the D-homo-C-nor compound 277. The photolytic lead-tetraacetate oxidation of 270, carried out by irradiation with a high-pressure mercury lamp, in benzene solution in the presence of CaCO3, resulted in a reversible fragmentation


O


HO

O

OMe

O

O b

a

OMe

OMe MeO

H 251

OMe 253

252

c

CHO OMe

MeO

OMe

d

MeO

OMe

H 255

O

I

O

OMe

H 254

g e

I

MsO

h

I

259

I

I

HO

OMe

OMe

OMe

256

258

i

f Ph

S OMe

260

N OMe

257

Scheme 38. Reagents. a: MCPBA, PTSA, CH 2Cl2; b: DIBAH, CH2 Cl2 ; c: HgO-I2, Py, C6H 6, h ; d: MeLi, THF; e: (Me)3 Si-CCl4 ; f: BuNH2, dioxane; g: DIBAH, CH 2Cl2; h: MsCl, Py; i: Na2 S·H 2O, MeCN.

involving scission and recombination of the C(8)-C(14) bond, followed by formation of compounds 275 - 277 (Fig. 6). Khripach and co-workers [82] reported a synthetic methodology for the synthesis of 13,14-seco-steroids with substituents at C14 and C-17 (Scheme 41). They started from 15-en-17-one estradiol derivative, in which molecule they introduced 14-hydroxy group. Compound 278 was achieved, whose tosylate 279 underwent cleavage of 13,14 C-C bond, giving 14-oxo 13,14-seco-steroid 280. The hydride reduction of 280 proceeded smoothly with formation of only one isomer 281 using NaBH4, Ca(BH4)2, or LiAlH4 (Scheme 41). The hydroboration-oxidation of 281 also led to only one product 282 [82]. Acetylation of diol 282 afforded mixture of monoand diacyloxy derivatives 283 and 284.

The syntheses of 13,14-seco steroids starting from easily available (13S)-13-iodo-6 -methoxy-3,5-cyclo-13,14-seco-5androsta-14,17-dione (286) were described by Khripach and coworkers [83] (Scheme 42). Starting compound 286 was synthesized by the radical oxidation of 17-functionalized 14-hydroxy steroid 285 [84]. Radical dehalogenation of 286 with Bu3SnH resulted in diketone 287 (inseparable mixture of C-13 epimers). A good yield of the product was obtained by treatment of iodo ketone 286 with hydroxylamine. The reaction led to oximination of the 17-keto group with simultaneous deiodination at C-13 to give 288. Hydride reduction of 288 gave alcohol 289. Acetylation of hydroxyoxime 289 gave the diacetate 290, and treatment of this compound with TiCl3 led to the desired acetoxyketone 291 (Scheme 42).


Gai et al.

O

O

OH

OH OR

OMe

b

H H

H

HO

H

OH

MeO

H

H OMe

H

261 R = H 262 R = Me

a

263 O

O

O OMe

O O

d

H

OMe

e

H

H MeO

c

H

H

H

OMe

H

MeO

H OMe

H

264

265

O

O

OH

O

O HO

OH

HO

f

H H MeO

H

H H

H

OMe

H

HO

g

MeO

H

RO

OMe

H

266

H

H

OR H

267

268 R = Me 269 R = H

h

Scheme 39. Reagents. a: MeOH, PTSA; b: MeI, NaH, THF; c: PCC, MW; d: MCPBA, PTSA, CH2Cl2; e: LiAlH4 , THF; f: allyl bromide, KH, DMF; g: GrubbsII catalyst, CH2Cl2; h: ISi(Me)3 , CHCl3 .

CH2 C8H17

+

O

C8H17 AcO

CH2 C8H17

AcO

271

H

O H

OAc

272

a OAc CH2 C8H17

OH AcO

CH2 C8H17 OAc

H 270

+ O AcO

H

O

OAc AcO

H

273

274

Scheme 40. Reagents. a: Pb(OAc)4 , C 6H6 .

H

C8H17 O

H OH

O AcO

AcO H

275


CH2 C8H17

AcO H

276

H

277



OTs

OH

b

a OH MeO

c O

OH MeO

MeO 278

280

279 OH d, e

HO

MeO

f

HO

MeO 281

282 OAc

OAc AcO

HO + MeO

MeO

284

283 Scheme 41. Reagents. a: PTSA; b: NaCH 2S(O)Me; c: LiAlH4 ; d: BH 3; e: H2 O2; f: Ac2O.

O

O

O

I OH

OMe

285

a

b

O

OMe

O

OMe

286

287

c NOH

O

NOR OR

d

OAc f

O

OMe

OMe

288

289 R = H 290 R = Ac

OMe e

291

Scheme 42. Reagents. a: Pb(OAc)4 , I2; b: Bu3SnH; c: NH 2OH; d: Ca(BH4 )2; e: Ac2O; f: TiCl3.

A number of testosterone analogs with a 13,14-secosteroidal fragment (292-296) was prepared from compound 286 (Scheme 43) [85]. The key steps involved stereoselective deiodination of the starting compound 286 with triphenylphosphine and selective protection of the 17-keto group with trimethylsilylcyanide, giving compound 293. Removal of iodine at C-13 proceeded with inversion of the configuration at C-13, which was established by X-ray crystallography. The obtained compounds containing flexible C,Dring fragments, which were of great interest for comparative studies in biological tests together with testosterone and other steroids with a rigid tetracyclic skeleton. Preparation of a number of different 13,14-seco steroids described in paper [85] is presented here by few examples (Scheme 43).

13,17-SECOSTEROIDS Fenselau and co-workers [86] described the preparation of several 13,17-seco-nitriles from 17-oximino steroids (Scheme 44). The reaction of estrone methyl ether oxime 297 with dimethyl sulfoxide and dicyclohexylcarbodiimide in the presence of trifluoroacetic acid led to the very rapid formation of two products in roughly equal amounts: the lactam 298 and 13,17-seco-nitrile 299, the result of a second-order Beckmann rearrangement. The formation of equal amounts of lactam 298 and nitrile 299 is interesting, since a number of 17-oximino steroids was subjected to Beckmann rearrangement under a variety of conditions with formation, generally in high yield, of only the corresponding lactams. A


Gai et al.

O

NC

O

OSiMe3 b

a

I O

OMe

O

O

OMe

286

c

H

H

OMe

292

293 OH

O

NC OSiMe3 d, e

OH

f, g

OAc

OAc

HO OMe

OMe

294

296

295

Scheme 43. Reagents. a: Ph3 P; b: (Me)3SiCN, Ph3 P, THF; c: Ca(BH4) 2; d: Ac2O; e: Bu 4NF; f: L-selectride; g: PTSA.

NOH

H N

O

CH2 CN

a + MeO

MeO

297

MeO

298

NOR

H N

299

O

CH2 CN

a + AcO

AcO

AcO

302

300 R = H 301 R = Ac

303

Scheme 44. Regents. a: DMSO, DCC, trifluoroacetic acid (TFA).

similar reaction of 17-oximinoandrost-5-ene derivative 300 led to the formation of the lactam 302 and the unsaturated nitrile 303 (Scheme 44). Seco-nitrile 299 served as starting compound in the formation of many 17a-aza and 17-amino steroids [87]. 13,17-Seco steroids 305-310 were prepared by Mammato and Eadon [88]. Beckmann rearrangement of 5-androstan-17-one oxime (304) with p-toluenesulfonyl chloride in dry pyridine gave an 11% yield of the “abnormal“ Beckmann product 13,17-seco-17nitrile 305 (Scheme 45). NOH

was predominant. Thin layer chromatography on silica gel impregnated with 10% silver nitrate removed the exocyclic isomer 309, while removal of the endocyclic impurity of 310 was postponed until the acetates were converted to the hydrocarbons [88] (Fig. 7). OR OR

H

CH2 a

306 R = H 307 R = Ac

OAc

H

308

CN OAc

H

304

H

OAc

305

Scheme 45. Reagents. a: TsCl, Py.

Lithium aluminum hydride reduction of D-homo-17a-oxa-5androstan-17-one gave 13,17-seco-diol 306. Pyrolysis of the diacetate 307 gave a mixture of three alkene acetates, where isomer 308

H

309

H


310



Morrison and co-workers [89] investigated the photochemical reactions of steroids 311 and 313 which bear a dimethylphenylsiloxy (DPS) group and additional ketone or olefin functionalities. The DPS group was used to harvest photons in order to direct the excitation energy to the remote target acceptor groups. The products of photochemical reactions were 13,17-secosteroids 312 and 314 (Scheme 46). O a

DPS

H

O

DPS O

311

O

312

O a

O

O H

O

H

H

DPS

DPS

313

314

Scheme 46. Reagents. a: h/266 nm, MeCN, TEA.

Siddiqui and co-workers [90] described the approach in the synthesis of selena, tellura, and thia lactones of estrane series via corresponding 13,17-secosteroids 317 and 318. The Baeyer-Villiger oxidation of 3-acetoxy-1,3,5(10)-estratrien-17-one derivative 315 with perbenzoic acid in the presence of p-toluenesulfonic acid afforded 17a-oxa-D-homo-derivative 316. The lactone ring was cleaved by reaction with hydrobromic acid in acetic acid to give 13,17-seco-13-bromo-acid 317. Treatment of 317 with thionyl chloride gave chloride 318, that in the reaction with selenium and sodium borohydride in ethanol gave 17a-selena-D-homo-derivative 319. Similarly, the reaction of 318 with tellurium and sodium borohydride gave 17a-tellura-D-homo-steroid 320. Incorporation of sulfur in the steroidal nucleus was achieved through the cyclization reaction of D-seco-13-bromo derivative 318 with sodium sulfide (Scheme 47).

The partial synthesis of 18-norestradiol (331) via WittigSchöllkopf cyclization of an appropriately functionalized D-secosteroid 326, obtained from estrone (322) was described by Kuhl and co-workers [91]. The crucial hydration of the C13=C17 bond in an anti-Markovnikov sense was achieved via a diastereoselective hydroboration procedure (328329). The synthesis involves several 13,17-secosteroids (323-327) (Scheme 48). 14,15-SECOSTEROIDS Starting from 3 -acetoxy-5-androstan-17-one (332), by specific D-ring modification, followed by the A-ring 1,4-diene-3-one system formation, some D-nor-14,15-seco steroidal derivatives were formed [92]. The aldehyde 334 was prepared from 332 through conversion to the enol acetate 333 which underwent ozonolysis, hydrolysis to the free acid and esterification with diazomethane. Decarbonylation of 334 with Wilkinson’s catalyst gave the 14-methyl compound 335. Alternatively, conversion of 334 to the enol acetates 336 (a mixture of E and Z isomers), followed by ozonolysis, provided the 14-formyl compound 337, which was decarbonylated to give 15,16-dinor-14,15-seco compound 338 (Scheme 49). Hu and co-workers [93] described the synthesis of 14,15secosteroid 346 starting from 15,16-dinor-14,15-seco steroid derivative 339 (Scheme 50) [92]. It was selectively hydrogenated in the presence of Wilkinson’s catalyst to yield enone 340. Compound 340 via ketal 341 was reduced to alcohol 342. Oxidation of 342 with pyridinium chlorochromate (PCC) gave aldehyde 343, which reacted with lithium-(trimethylsilyl)acetylide to obtain compound 344. The trimethylsilyl group was then removed under basic conditions and the ketal group was removed under acidic conditions in a one-pot reaction to yield compound 345. Oxidation of 345 with Jones reagent produced diketone 346. 16,17-SECOSTEROIDS Miescher [94] investigated a group of substances which are very closely related to the natural estrogens, and thus collected new information on the hormone specificity problem. Doisynolic acid (347) was obtained by melting estrone (322) with potassium hydroxide. Similarly, fusion of equilenin (348) with potassium hydroxide gave two optically active bisdehydro-doisynolic acids 349a (+) and 349b (-) (Scheme 51).

O O

O b

a

AcO

AcO 315

316

Br

COR

X

d or e or f

AcO

AcO 317 R = OH 318 R = Cl

c

Scheme 47. Reagents. a: PBA, PTSA; b: HBr, AcOH; c: SOCl2; d: Se, NaBH4; e: Te, NaBH4; f: Na2 S.

319 X = Se 320 X = Te 321 X = S

O


Gai et al.

O CH2

a, b, c, d H H HO

H

325

k H

PPh3 Br

Br

H

H

j

O H

H Br

H

H

H

H 327

326 H

H 324

i

O

h

OH

H

323

H H

COOMe

H

322 CH2

H

H H

OH

H

f, g

CH2

e

H 328

OH

OH

H l

H

H

+ H

H

H

H

H

H

H3CO

329

H

HO 330

331

Scheme 48. Reagents. a: Me2SO 4, K2CO 3, Me2 CO; b: NH2OH·HOAc, EtOH; c: DCC, TFA, DMSO, CCl4 ; d: NaOH, H2 O, EtOH, then CH2N 2 in Et2O; e: LiAlH4 , THF; f: TEA, MsCl,CH2 Cl2 ; g: LiBr, acetone; h: O 3, CH 2Cl2, MeOH, then Me2 S; i: PPh3; j: H3CSOCH2 Na, DMSO; k: catecholborane, LiBH4, C6H 6, EtOH, NaOH, H 2O2 ; l: DIBAH, C 6H6. O

OAc a

COOMe

COOMe

b, c

d Me

CH2CHO 332 AcO

335

334

333

a

H COOMe COOMe

d

COOMe

b

CH

CHO AcO

336

337 H

OAc

338

Scheme 49. Reagents.a: CH2=C(Me)OAc, PTSA; b: O3, CH2 Cl2-HOAc; c: CH2N2, Et2O; d: (Ph3 P)3 RhCl, PhCN.

COOMe

COOMe

COOMe

a

c

b O O

O

O

340

339

341 OH

CH2OH

CHO d

O

e O

O

O

342

TMS

O 343

O

344 f

O

OH

g H O

H O

346

345

Scheme 50. Reagents. a: H2, (Ph 3P) 3RhCl; b: HOCH 2CH2OH, PTSA; c: LiAlH4 ; d: PCC; e: lithium-(trimethylsilyl) acetylide; f: OH- followed by H3O+; g: Jones reagent.



O

The program which began with the investigation of ring-D seco steroids related to some estrogenolic acids an example of which is doisynolic acids led to the synthesis of 17-oxa-D-homo steroids and related seco steroids derived from different estrane derivatives (Scheme 52) [95]. The synthesis began with the ozonolysis of the enol acetate 357 followed by hydrolysis to the aldehyde acid 358. Azeotropic distillation of water from a dilute solution of 358 in toluene containing p-toluenesulfonic acid (PTSA) gave the enol lactone 359. Miljkovi and co-workers [96] reported the results of the studies undertaken in order to explore the possibility of using the Beckmann fission reaction for the synthesis of ring-D seco steroids (Scheme 53). 3-Hydroxy-androst-5-en-17-one was converted into the corresponding 16-oximino derivative 360 [97]. The NaBH 4 reduction of oximino-ketone 360 afforded only oximino-alcohol 361. The 17-orientation was assumed on the basis of the well known stereochemical course of the NaBH4 reduction of 17-keto group in steroids [98]. The Beckmann cleavage of 361 using ptoluenesulfonyl chloride (TsCl) in pyridine at 0 °C afforded the unstable cyanoaldehyde 362, isolated as the 2,4dinitrophenylhydrazone 363, that was converted afterwards into to the known lactone 365 [99-101]. Knowing that estrogens show hypocholesterolemic activity [95], Miljkovi and Petrovi [102] investigated the Beckmann fragmentation reaction in the estrane series. A starting material was 16-oxime 367 and its chemical transformations were performed .in similar reaction conditions as earlier (Scheme 54) [96]. In this case, the primary fragmentation product 369 was easily isolated and purified by direct crystallization. By the action of gaseous hydrogen chloride on the aquous solution of 370 in methylene chloride the lactone 371 was obtained [99], which was also independently pre-

COOH a C2H5 HO

HO

347

322 O

COOH

a

C2H5 HO

HO

349a (+) 349b (-)

348 Scheme 51. Reagents. a: KOH.

Compounds with substituted carboxyl group of the (-)bisdehydro-doisynolic acid (351-356, Fig. 8) showed that replacement of carboxyl group changes estrogenic activity of the starting compound 350. Similarly, a number of 16,17-seco androstane derivatives were synthesized [94]. 350 R = CH2COOH 351 R = COMe 352 R = COCH2OCOMe 353 R = CHO 354 R = CH2OH 355 R = Me 356 R = C2H5

R C2H5 MeO


O

OAc COOH a, b

O

c CHO

MeO

MeO

MeO

357

358

359

Scheme 52. Reagents. a: O3; b: OH¯; c: PTSA.

O

OH N

a

CHO

b

c

CH=NNHR

N

OH

CN

OH

H

H

H

361

362

HO 360

CN H 363 R = 2,4-dinitrophenyl

d

O

H

e

CH2OH

O

CN H

HO 365

364

Scheme 53. Reagents. a: NaBH4 , MeOH; b: TsCl, Py; c: 2,4-dinitrophenylhydrazine, EtOH; d:NaBH4 , MeOH; e: KOH, MeOH.


Gai et al.

O

OH H

O a

b

CN

OH

OH

H

CHO

c N

N H

H

H

367

368

369

MeO 366

d

f, g

O

H

e

CH2OH

O

CN H

MeO 371

370

Scheme 54. Reagens. a: i-AmONO, t-BuOK; b: NaBH 4, MeOH, H 2O; c: TsCl, Py; d: NaBH 4, MeOH; e: HCl, CH 2Cl2, H2O; f: HOCH2CH 2OH, OH¯; g: H3O+.

pared by a simple procedure directly from oxime 368 and potassium hydroxide in boiling ethylene glycol, in a stream of nitrogen. The Beckmann fragmentation product 369 was reduced by LiAlH4 giving the products 372 and 373, by a presumed neighboring group participation of 17-OH group in the intermediary formed 16-imino derivative (A). The structure of 373 was proved by an alternative synthetic route by reducing 371 with di-isobutylaluminium hydride (DIBAH) [103] (Scheme 55).

369

CH2OH

CH2OH

a, b

CH2NH3 Cl

+

C=N H A

372

c

O

O

O 371

AlH3

H OH

373

Scheme 55. Reagents. a: LiAlH4; b: H 2O, HCl; c: DIBAH.

Starting from 17-oxo-16,17-seco-16-nitrile 362 some biologically active D-seco steroids were synthesized [104, 105]. Protection of the 17-oxo function of compound 362 yielded compounds 474 and 475 (Scheme 56) [104]. The Oppenauer oxidation of 374 or its oxidation with H2O2 in alkaline conditions gave the respective compounds 376 and 380. Epoxidation of compound 376 yielded a mixture of 4,5- and 4 ,5 -epoxides 377a and 377b and a mixture of 4,5- and 4 ,5 -epoxy-carboxamides 378a and 378b. Opening of the oxirane ring of a mixture of compounds 377a and 377b with formic acid afforded the 4-hydroxy derivative 379. Compounds 374, 376, 379 and 380 showed a strong cytotoxicity against prostate cancer PC-3 cells. The reduction of compound 374 with NaBH4 yielded hydroxy derivatives 382a and 382b (Scheme 57) [105]. Acetylation of com-

pound 382b afforded compound 383. When compound 374 reacted with DDQ the result was compound 384 with 1,4,6-triene-3-oxosystem. Compound 385 was obtained from compound 384 after deprotection at C-13 with formic acid. Compound 386 with 3,6dioxo-4-ene system and carboxylic function at C-13 atom was obtained by oxidation of compound 362 with Jones reagent. Starting from compound 387 (3 -acetoxy-derivative of 413), 16,17-seco nitrile 390 was synthesized by a three-stage procedure (Scheme 58) [106]. Firstly, the formyl group of compound 387 was reduced to yield the alcohol 388. Compound 388 was further transformed to the mesyloxy derivative 389, which was reduced to the compounds 390-392. Compound 393 was obtained by hydrolysis of 390 and after the Oppenauer oxidation afforded 3-oxo-16,17secoandrost-4-ene-16-nitrile (394). Some 17-oxo-17-substituted-16,17-seco-16-nitriles 398-401 were obtained by Beckmann fragmentation with TiCl3 or Ac2O of the corresponding 17-substituted-17 -hydroxy-16-oximes 395397. The NaBH4 reduction of 398 and 399 afforded seco cyanoalcohols 402 and 403 (Scheme 59) [107-109]. Similarly, starting from oximino-ketone 360 the synthesis of 16,17-seco-17-butyl-17-oxo androstene derivatives was achieved also [110]. The starting compound for the syntheses of 16,17secoandrostane ketones with 1,4-dien-3-one, 4,6-dien-3-one and 1,4,6-trien-3-one systems was 4-en-3-one derivative 404, obtained by Oppenauer oxidation from 399 (Scheme 60) [111]. Dehydrogenation of compound 404 with 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil) gave three products: 405-407, but with DDQ in benzene or dioxane, the corresponding derivatives 405 i.e. 407 were obtained [107]. On the other hand, epoxidation of compound 404 resulted in a mixture of and isomers 408a and 408b. Opening of the oxirane rings of the mixture of 408a and 408b by the action of formic acid yielded the 4-hydroxy-4-en derivative 409. Beckmann fragmentation of 16-oximino alcohols 361 or 395 with methyl salicylate yielded corresponding D-seco derivatives 362 and 399. Simultaneous fragmentation and acylation of compound 361 resulted in 3 -salicyloyl-D-seco derivative 410 (Scheme 61) [112]. Anti-oxidant assay of the synthesized compounds 362 and 410 indicated strong radical scavenging capacity. Compound 362 also exhibited strong cytotoxicity against PC-3 cell line.



O

O H

O H

CN

CONH2

HO

O

380

381

f

d

O 374

O O H

+

H

b

CN

O

O

CN

CN

HO

HO

(CH2)2OH

O H

a

375

374

362

c O

O O H CONH2

O

O

O O H

O H

d

CN

+ O

CN

O

O

376 377a 4,5epoxy 377b 4,5epoxy

378a 4,5epoxy 378b 4,5epoxy

e O H CN

O OH 379 Scheme 56. Reagents. a: HOCH2CH 2OH, PTSA, 37-40 °C, 40 min.; b: HOCH2CH2OH, PTSA, 45-50 °C, 1 h 75-80 °C, 1 h; c: cyclohexanone, Al(i-PrO)3 ; d: 30% H2O 2, NaOH, MeOH; e: HCOOH; f: cyclohexanone, Al(t-BuO)3, xylene.

Saka and co-workers reported the synthesis of 16,17-secoestra1,3,5(10)-triene derivative with 4-[2-(dimethylamino)ethoxy]phenyl group in the position 17, the same function as the one present in the molecule of Tamoxifen (TAM, a well-known nonsteroidal antiestrogen, used for the treatment of estrogen-receptor-positive tumors) [113] (Scheme 62). Starting from16-hydroximino derivative 411 [114], D-seco steroid 413a was synthesized (Scheme 62). Reduction of 413a with sodium borohydride yielded secocyano alcohol 414a, as well as the secoamino alcohol 415a when reduction was performed in the presence of cobalt(II) salt. Deprotection of the C-3 hydroxy group in compounds 413a-415a by catalytic hydrogenolysis resulted in the corresponding 3-hydroxy derivatives 413b-415b.

Starting from oximino ketones 360 or 367 D-seco derivatives 400, 401 and 421-427 were synthesized and used for synthesis of 16-amino-D-homo steroid derivatives in the androstane and estrane series, 428-435 (Scheme 63) [107]. First step in the synthesis of the D-homo steroid derivatives 428-435 was a stereospecific addition of -picolyllithium, benzyllithium, methylmagnesiumiodide or ethylmagnesiumiodide to the C-17 carbonyl group of oximino ketones 360 or 367 or a reduction of C-17 carbonyl group, whereupon products 361, 395-397 and 416-420 were obtained (Scheme 63) [96, 107, 109, 115-117]. “One-pot” fragmentation-cyclization reaction of the oximino-alcohols 361, 395-397, and 416-420 with potassium hydroxide in refluxing ethylene glycol or with potassium t-butoxide in tbutylalcohol gave D-homo derivatives 428-435 (Scheme 63) [108].


Gai et al.

O O H CN

AcO 383 d

O

O

O H CN

c

376

O H CN

+

HO

HO 382a

382b O

O

b

O H

H

CN

CN

f

e

374

O

O 384

385 O

a OH CN g

362

O O 386 Scheme 57. Reagents. a: HOCH 2CH2OH, PTSA; b: cyclohexanone, Al(i-PrO)3; c: NaBH4, EtOH; d: Ac 2O, Py; e: DDQ, dioxane; f: HCOOH; g: Jones reagent.

O CN

OH a

CN

OMs

b

CN

AcO

AcO

AcO 388

387

Me

Me CN

Me CN

+

CN

+

AcO

AcO

389 c

AcO 391

392

390 d

Me

Me CN

O

e

CN

HO 394

Scheme 58. Reagents. a: NaBH4 , EtOH; b: MsCl, Py; c: NaBH3CN, DMSO; d: EtONa, EtOH; e: cyclohexanone, Al(i-PrO)3.

393



O

a or b or c

360

H

OH R1

R1

d or e

OH

g

R1

CN

N

CN

OH R2O 395 R1 = Me 396 R1 = Et 397 R1 = Ph

398 R1 = Me, R2 = Ac 399 R1 = Me, R2 = H 400 R1 = Et, R2 = H 401 R1 = Ph, R2 = H

402 R1 = Me, R2 = Ac 403 R1 = Me, R2 = H

f

Scheme 59. Reagents. a: MeMgI, ether, THF; b: EtMgI, ether, THF; c: PhLi, ether, THF; d: TiCl3 , HCl, EtOH; e: Ac2O, Py; f: EtONa, EtOH; g: NaBH 4, EtOH.

O Me

O

CN Me CN

HO 399 O 405 a O

O Me

Me

b

CN

CN

O

O

406

404 c

O Me

O

CN Me CN

O 407

O

O 408a 4,5-epoxy 408b 4,5-epoxy d O Me CN

O OH 409 Scheme 60. Reagents. a: Al(t-BuO)3, cyclohexanone; b: chloranil, PTSA, xylene for 405, 406 and 407; DDQ, C6H 6 for 405 or DDQ, dioxane for 407; c: 30% H2O2, NaOH, MeOH; d: HCOOH.


Gai et al.

OMe

H

HO R

O

a

N

R

OH

HO N O

HO

C O

361 R = H 395 R = Me

361a R = H 395a R = Me

c

O

O H

b

R

CN

CN

O

HO 410

C

362 R = H 399 R = Me

O

OH Scheme 61. Reagents. a: methyl salicylate, Na, toluene, reflux, 1 h; b: methyl salicylate, Na, toluene, reflux, 15 h; c: methyl salicylate, Na, toluene, reflux, 18 h.

O(CH2)2NMe2 HO

O a

N

N OH

OH BnO

BnO

412

411 O(CH2)2NMe2

b

CHOH

O(CH2)2NMe2

O

c

CN

CN

RO

RO

413

414

d

In formulae 413-415: a R=Bn b R=H

O(CH2)2NMe2

CHOH

e

CH2NH2

RO 415 Scheme 62. Reagents. a: {4-[2-(dimethylamino)ethoxy]phenyl}magnesium bromide, THF, then NH4Cl; b: TsCl, Py, h; c: NaBH4, MeOH; d: NaBH 4, CoCl2, MeOH, then HCl, H2O; e: H2 , 10% Pd/C, EtOH.



O j R3 CN R1 or R2 f or g or h O

OH R3

a or b or c or d N

421 R2 series, R3 = CH2Py 422 R1 series, R3 = Bn (3-OAc) 423 R1 series, R3 = Bn (3-OH) 424 R1 series, R3 = Me (3-OTs) 425 R2 series, R3 = Me 400 R1 series, R3 = Et 426 R2 series, R3 = Et (3-OTs) 401 R1 series, R3 = Ph 427 R2 series, R3 = Bn

e or f N

OH R1 or R2 360 R1 = The residual part of 3hydroxy-16-oximinoandrost-5-ene-17-one 367 R2 = The residual part of 3methoxy-16oximino-estra1,3,5(10)-trien-17-one

OH R1 or R2 416 R1 series, R3 = CH2Py 417 R2 series, R3 = CH2Py 418 R1 series, R3 = Bn 419 R2 series, R3 = Bn 395 R1 series, R3 = Me 420 R2 series, R3 = Me 396 R1 series, R3 = Et 361 R1 series, R3 = H 397 R1 series, R3 = Ph

e or f

O R3 i NH2 R1 or R2

428 R1 series, R3 = Py 429 R2 series, R3 = Py 430 R1 series, R3 = Ph 431 R1 series, R3 = Ph (3-OAc) 432 R2 series, R3 = Py 433 R1 series, R3 = H 434 R2 series, R3 = H 435 R1 series, R3 = Me

Scheme 63. Reagents. a: -PyCH2 Li, THF; b: BnLi, THF; c: MeMgI, ether, THF; d: EtMgI, ether, THF; e: KOH, HOCH2 CH2OH; f: t-BuOK, t-BuOH; g: TsCl, Py; h: Ac2O, Py; EtONa, EtOH; i: Ac2O, Py; j: KOH, MeOH.

To prove the postulated mechanism, i.e. the assumption that Dhomo compounds are formed from the intermediate seco cyano ketones, the mentioned D-homo derivatives starting from the corresponding 16,17-seco compounds 400, 401 and 421-427 were synthesized (Scheme 63) [108]. The 13-carboxilyc acid of the seconitrile was also synthetized in the estrane series, as well as some amines and amides [118]. Starting from 16,17-seco derivatives of 5-androstene, the Dhomo lactones 441-443 were synthesized (Scheme 64) [119, 120]. Reduction of the seco cyano ketones 398, 399, 401, 422, 423 and 436 with sodium borohydride in MeOH yielded the corresponding 17-methyl, 17-phenyl and 17-benzyl seco-cyano alcohols 402, 403, 437-440. Compound 437 or its 3 -acetoxy derivative 438 reacted with KOH in ethylene glycol, while acidification of the reaction mixture yielded lactone 441. In case of compound 438, a simultaneous hydrolysis of the 3 -acetoxy group took place. Similarly, lactones 442 and 443 were obtained from the cyano alcohols 439 or 440, and 402 or 403, respectively. Lactones 441-443 showed an inhibitory activity against the enzyme aromatase. Hydroximino ketone 411 was used by Saka and co-workers [121] for the synthesis of several 17-methyl-16,17-secoestratriene derivatives (Scheme 65). In the first step of the synthesis, hydroximino ketone 411 was transformed into 444, the Beckmann fragmentation of which gave seco derivative 445. Reduction of 445a with sodiumborohydride yielded 446a, whose configuration at the newly formed chiral center was established by X-ray structural analysis. Catalytic hydrogenation of compound 445a yielded 446b and 448b. Petrovi and co-workers [122] reported the synthesis of 17tosyl, -chloro-, bromo-, and -iodo- derivatives 450a, 452a, 453a, and 454a, prepared directly from secocyanoalcohol 449a [114], while the 17-fluoro-derivative 451a was obtained from tosylate

450a in the reaction with tetrabutyl ammonium fluoride (Scheme 66). The corresponding 3-hydroxy derivatives of these compounds were produced by action of hydrogen in presence of Pd/C [123], except the 3-hydroxy-17-iodo derivative 454b, which was obtained from 3-hydroxy-17-tosyloxy derivative 450b. Some of these compounds express high afinity for estrogen receptors [124]. Among all examined compounds, 3-hydroxy-17-bromo-16,17secoestra-1,3,5(10)-triene-16-nitrile (453b) was of special interest, because of its antiestrogenic activity, with no estrogenic properties. For this reason an alternative pathway for the synthesis of this compound was performed [125]. It included preparing the tosylate 450b, its deprotection of 3-OH group and introducing of 17-bromo function by tetrabutylammonium bromide to give 453b. Similar chemical transformations of 3 -acetoxy derivative of compound 364 was performed by Penov Gai and co-workers [126], whereby corresponding 17-halo-16,17-seco-5-androstene derivatives were obtained. The secocyanoalcol 449b served as precursor in the synthesis of 3-benzyloxy-hemisuccinate and hemiglutarate, expressing antiaromatase and antiestrogenic potency [127]. Steroidal triazoles via intramolecular 1,3-dipolar cycloaddition of a steroidal 16,17-seco-17-diazo-16-nitrile system were synthesized (Scheme 67) [128]. Secocyanoaldehydes 362 and 455 were transformed into the corresponding tosylhydrazones 456 and 457. The reactions were carried out in refluxing ethanol to afford hydrazones 456 and 457. Thus, addition of NaOH in dioxane/H2O, NaBH4 in ethanol, or LiAlH4 in dioxane, to tosylhydrazones 456 and 457 yielded the sodium salts 456a and 457a, further heating of which at reflux gave the 17-diazo compounds 458 and 459. These in situ formed diazo compounds underwent intramolecular 1,3dipolar cycloaddition to give the D-ring fused triazole derivatives 460 and 461. In the case of compound 461 the benzyl protection


Gai et al.

O

HO R2

H R2

a

CN

CN

R1O

R1O 401 R1 = H, R2 = Ph 436 R1 = Ac, R2 = Ph 423 R1 = H, R2 = Bn 422 R1 = Ac, R2 = Bn 398 R1 = Ac, R2 = Me 399 R1 = H, R2 = Me

437 R1 = H, R2 =Ph 438 R1 = Ac, R2 = Ph 439 R1 = H, R2 = Bn 440 R1 = Ac, R2 = Bn 402 R1 = Ac, R2 = Me 403 R1 = H, R2 = Me

b H

R O O

HO 441 R = Ph 442 R = Bu 443 R = Me Scheme 64. Reagents. a: NaBH4 , MeOH; b: KOH, HOCH2CH 2OH; HCl, H2 O.

HO

O

Me N

N

a

OH

OH BnO

BnO

444

411 b

Me

Me

CHOH O

d

CH2NH2

CN

HO

RO

448

445

c In formulae 445 and 446: a R=Bn b R=H Bn=benzyl

Me

Me OH H

H O

+

CN

O BnO

RO 446

447a

Scheme 65. Reagents. a: MeMgI, ether, THF, then NH4 Cl, H2O; b: Ac2O, Py; c: NaBH4 , MeOH; d: H 2, 10% Pd/C, MeOH, CH2Cl2.

d



CH2OH a

CN

CH2 I

CH2 OTs

d

CN

CN RO

HO 450

449

454b

b

c

CH2 X

CH2 F

CN

CN

RO

For 450-453: a R = Bn bR=H

d

RO 452 X = Cl 453 X = Br 454a X = I

451

Scheme 66. Reagents. a: TsCl, Py; b: Bu4NF·3H2O, EtCOMe; c: CBr4 or CCl4 , Ph3 P, Py, or I2 , Ph3 P, imidazole; d: Bu4NI, EtCOMe; e: H2, Pd/C/CH2Cl2, MeOH.

O

N

NH

Ts Na

H

H

a

CN

N

b

CN

R1 or R2

R1 or R2

456 R1 series 457 R2 series

455 R2= The residual part of 3benzyloxy-17-oxo16,17-secoestra-1,3,5(10)triene-16-nitrile

Ts

CN

R1 or R2

362 R1= The residual part of 3-hydroxy-17-oxo16,17-secoandrost-5-ene16-nitrile

N

N

456a R1 series 457a R2 series

N CH

N

N

N

CN R1 or R2

R1 or R2 458 R1 series 459 R2 series

N

N

N H

N

HO

N

BnO 460

N

N H

N

c

HO 461

N

462

Scheme 67. Reagents. a: TsNHNH2, EtOH; b: NaOH, dioxane/H2O, NaBH4 , EtOH, or LiAlH4 , dioxane; c: H2, 10% Pd/C, MeOH, CH2 Cl2 .

H


Gai et al.

N

O

CN

O a

N

CN

AcO

AcO

466

463

N

O

CN

O a

N

CN

MeO

MeO

467

464 N

O

CN

O a

N

CN

N

N O

465

N

O

N

468

Scheme 68. Reagents. a: P(OEt)3.

CN

CN

CN c

a CN

CN

O

HO 469

EtO 473

470 b

b

b

CN

CN

CN CN

O

CN

CN

CN

O

O 471

472

474

Scheme 69. Reagents. a: Al(i-PrO) 3, cyclohexanone; b: DDQ; c: PTSA, triethyl orthoformate.

was removed by catalytic hydrogenolysis in the presence of 10% Pd/C, which resulted in the steroidal triazole 462. Triazole 460 showed potent antiproliferative activity against prostate cancer PC3 cells. N-Oxide compounds 463-465 were synthesized by Jindal and co-workers [129] to investigate the reaction with triethyl phosphite. Furazan N-oxide fused to D-ring gave dinitriles 466-468 (Scheme 68). Yadav and co-workers [130] reported in 2012 the synthesis of 16,17-seco-16,17-dinitriles 470-474 (Scheme 69). 3-Acetoxy16,17-seco-5-androstene-16,17-dinitrile 466 (Scheme 68) [129] was handy for this purpose. Alkaline hydrolysis of 16,17-dinitrile 466 under mild reaction conditions afferded 3-hydroxy-16,17-seco-5androstene-16,17-dinitrile (469).

Oppenauer oxidation of the 3-hydroxy-16,17-dinitrile 469 afforded 3-oxo-16,17-seco-4-androstene-16,17-dinitrile (470). For the preparation of the 1,4,6-triene derivative 471 the 3-hydroxy derivative 469 was dehydrogenated by refluxing with DDQ in anhydrous dioxane. Further, it was tried to obtain 1,4-diene derivative 472 by dehydrogenating of 3-hydroxy derivative 469 with DDQ, but the product was found to be a mixture of compounds 471 and 472. For the preparation of 3-oxo-4,6-diene derivative 474, the enone 470 was treated with triethyl orthoformate in presence of ptoluenesulfonic acid in dry dioxane to yield 473, which was dehydrogenated using DDQ in aqueous acetone to afford the desired 3oxo-16,17-seco-4,6-androstadiene-16,17-dinitrile (474). The D-seco derivatives 470-472 and 474 having unsaturation at C-4, C-1 and C4 or C-4 and C-6 along with carbonitrile function in ring-D showed very strong aromatase inhibition (Scheme 69).



O R3 N3

HO

R2

R1O

H

H

476a R1 = -OAc, 476b R1 = -OAc, 477a R1 = -OAc, 477b R1 = -OAc, 478a R1 = -OAc, 478b R1 = -OAc,

475a 3-OH 475b 3-OH

R2 = CN , R2 = CN, R2 = CONH2, R2 = CONH2, R2 = CONH2, R2 = CONH2,

R3 = COOH R3 = COOH R3 = COOH R3 = COOH R3 = COOMe R3 = COOMe


O O COOH

a

COOMe

b

O COOMe

COOH AcO

O 482

481

480

479 Scheme 70. Reagents. a: HIO4 ; b: CH2N2 .

OAc R

OTs CH2

a

O

c

I H MeO

MeO 483

MeO 484 R = CHO 485 R = CH2OH

b

486 d

O

O MeO

OBz

O

e

COOEt MeO

488

487

Scheme 71. Reagents. a: MeONa, MeOH; b: NaBH4 , MeOH; c: I2, NaHCO 3, Et2O/H2O; d: 1,8-diazabicyclo[5,4,1]undec-7-ene; e: ethyl Obenzoyldiformylacetate, toluene, CH2Cl2.

Takahashi and Satoh [131] reported the synthesis of 16,17secosteroids 476-478 from -azido ketones 475a and 475b (Fig. 9). Namely, treatment of -azido steroidal ketones 475a and 475b with bromine in acetic acid gave seco-carboxylic acids 476a and 476b. When 475a and 475b were allowed to react under the above conditions for a long period of time, the seco-amides 477a and 477b were formed by hydrolysis. The cleavage reaction was also useful for introduction of a nitrogen atom into the steroid D-ring. Treatment of the seco-amides 477a and 477b with diazomethane in ether gave the methyl esters 478a and 478b. The unusual activity of some D-ring-seco estrogens led Reich and co-workers [132] to prepare several seco steroids related to dehydroepiandrosterone (DHEA) and to test them for ability to mimic thyroid hormone and 7-oxo-DHEA (479) as inducers of thermogenic enzymes in rats’ liver (Scheme 70). For the syntheses

of secosteroids 481 and 482, the 16,17-dione 480 was used, which was obtained from dehydroepiandrosterone-acetate via 7-oxodehydroepiandrosterone acetate (479) [132, 133]. The coupling of two or more natural products to make hybrids leads to an almost inexhaustible reservoir of new types of compounds with diverse structures. Tietze and co-workers [134, 135] made a new type of pharmacologically interesting hybrid natural product 488 from estrone and the highly biologically active mycotoxin talaromycin B, which in vitro tests demonstrated strong cytotoxic activity against human cancer cells (Scheme 71) [134]. The combination of a toxin with a steroid was chosen in light of the fact that steroids are able to penetrate the cell membrane and bind to the cell nucleus [136, 137]. For the synthesis of compound 488 the Dsecoestrone aldehyde 484 was used which is available from estrone via compound 483 [138].


Gai et al.

H

O

O

a

O R

H

C6H4NH2 490

MeO

MeO

489

484 b

490-494 R X

R

a b c d e f g h i j k

N

N

c

MeO MeO

492 491

R H o-Me p-Me m-Me o-OMe p-OMe m-OMe o-Br p-Br m-Br p-NO2

X H N

N R

R

MeO

MeO 494

493

Scheme 72. Reagents. a: Meldrum’s acid, ethylenediamine diacetate (EDDA); b: H2 N-C6H 4-R (490); c: SnCl4, ZnBr2 or PTSA.

Secoestrone aldehyde 484 served as the starting compound in the synthesis of many seco- and homosteroids. Wölfling and coworkers [139] reported syntheses of steroidal tetrahydroquinolines starting from secoestrone aldehyde 484 and substituted anilines 490 (Scheme 72) [139]. For the formation of the steroid alkaloid analogues from the aldehyde 484, the appropriate D-seco arylimines 491 underwent a hetero Diels-Alder reaction during treatment with a Lewis or a Brønsted acid via the corresponding D-seco iminium ions 492. The preparation of steroid alkaloid analogues 494 is also depicted in Scheme 72. The reaction of the estrone derivative 484 with Meldrum’s acid led to 489 in a highly efficient domino reaction with excellent selectivity and yield [140]. Starting from 484 or its 3-benzyloxy analog, new Dhomoestrone derivatives containing halogen in position 16 were prepared by treatment of appropriate secoaldehyde with some Lewis acid [141]. Allyl derivatives of 484 were starting compounds in the synthesis of the steroid derivatives with modified, 7-membered D-ring [142]. Further, starting from 484 and its 16-saturated analog, many 9,13-bridged D-secoestrone alkaloids were synthesized by the treatment with aniline or substituted aniline derivatives in the presence of different Lewis and Brønsted acids, in a domino-type process [143], as well as different amino- and imino derivatives 9,13bridged steroidal azacycles [144]. Secoestrone aldehyde 484 and its 13-analog were transformed into the 16-methylated and 16-halomethylated tetrahydropyran and -Lactone D-homoestrone derivatives [145], -alkenyl phenylhy-

drazones [146] and halogen-containing D-homoestrone and 13a-Dhomoestrone derivatives over some D-seco intermediates [147]. Frank and co-workers [148] showed that secoestrone aldehyde 484 undergoes intramolecular nitrone 1,3-dipolar cycloaddition with both hydroxylamine and N-methylhydroxylamine to produce a single isoxazolidine isomer in each case (Scheme 73). The ringclosures of the hydrazones and the aldazine derived from the secoaldehyde 484 lead to fused N-containing heterocycles via Lewis acid-induced cyclization of the intermediate azomethine imines (Scheme 74) [148]. Synthesis of isoxazolidine derivatives 498 and 499 by internal nitrone 1,3-dipolar cycloaddition and heterocyclic estrone derivatives 503, 504 and 506 via corresponding D-seco derivatives 501, 502 and 505 obtained from 484 and 500 or hydrazine, are presented in Schemes 73 and 74. Tietze and co-workers [149] reported the syntheses of steroids with a seven-, eight- or nine-membered D-rings from a D-secoestrone derivatives by a Grignard and an intramolecular Heck reaction (Scheme 75). Namely, Grignard reaction of 484 with the Mgcompound derived from 507 gave the secondary alcohols 509a and 509b as a 1.9:1 mixture of two diastereomers. In a similar way, the alcohols 510a and 510b were obtained from 484 with the Grignard reagent derived from 508. Oxidation of 509a and 509b led to the ketone 512 and that of 510a and 510b to the ketone 513 respectively. In addition, the acetates 511a and 511b from 509a and 509b were prepared. The Heck reaction of 509a and 511-513 employing the palladacycle trans-di(-acetato)-bis[o-(di-otolylphosphino)benzyl]dipalladium(II) as a catalyst, led to the seven-, eight- or nine-membered D-ring estrone derivatives [149].



O H C

N

OH

a

MeO

MeO 484

495

c

b R N H C

R

O

N O MeO

496 R = H 497 R = Me

498 R = H 499 R = Me

Scheme 73. Reagents. a: NH2OH; b: BF3 ·OEt2; c: MeNHOH.

R2

R1 R1 BF3 CH

N

NH

N

-BF3 -2 H

R2

N

MeO

502

503 b

-2 H H C

N

H N

R2

R1

R1 N

N

R2 MeO 501

MeO 504

OMe

a

H O

H H

CH

H

N

N

CH

c OMe

MeO

MeO 484

H2N

H N

505

H

b

H H

R1

R2

500-506

R1

R2

a b c

H H NO2

H OMe NO2

N

500 MeO 506 Scheme 74. Reagents. a: H2N-NH-C6H 3R1 R2 (500); b: BF3·OEt2; c: NH 2NH2 .

N


Gai et al.

O OR

H

O c

a n

n

Br

Br

MeO 484

Br n

512 n = 1 513 n = 0

509a (17S), n = 1, R = H 509b (17R), n = 1, R = H 510a (17S), n = 0, R = H 510b (17R), n = 0, R = H

Br b

507 n = 1 508 n = 0

511a (17S), n = 1, R = Ac 511b (17R), n = 1, R = Ac

Scheme 75. Reagents. a: 507 or 508, Mg, Et2O; b: Ac2O, Py; c: Dess-Martin reagent, CH2Cl2.

O

O O O

a

OR2 b

R 1O

RO 514 R = H 515 R = Ac

516 R = H 517 R = Ac

518 R1 = H, 519 R1 = Ac, 520 R1 = Ac, 521 R1 = H,

R2 = H R2 = H R2 = Ac R2 = Me

c H

OR3

R 3O

CH3

OR2

+

H CH3

OR2 524 R1 = Ac, R2 = Ac, R3 = H 525 R1 = Ac, R2 = Ac, R3 = Ts 526 R1 = H, R2 = H, R3 = H

522 R1 = Ac, R2 = Ac, R3 = H 523 R1 = Ac, R2 = Ac, R3 = Ts d

R4

R1O 527 R1 = H, R4 = O 528 R1 = Ac, R4 = O 529 R1 = Ac, R4 = (OMe)2 Scheme 76. Reagents. a: H2O 2, OH¯; b: aluminium amalgam; c: KBH4, EtOH; d: KOH, MeOH.

The synthetic route for the preparation of seco-pregnane derivative 527, using Grob fragmentation as the key step was described (Scheme 76) [150]. This seco-steroid contains a formyl group and an unsaturated side-chain in a sterically favourable position, and was therefore a promising starting material for the syntheses of novel condensed steroid heterocycles. Epoxide 516 was obtained by treating of pregnane derivative 515 with hydrogen peroxide in alkaline solution. A reductive epoxide ring opening reaction of 516 in the presence of aluminium amalgam allowed the stereoselective

formation of 518. The 20-carbonyl function of 520 was reduced with potassium borohydride. 20R-Hydroxypregn-5-ene and 20Shydroxypregn-5-ene derivatives (522 and 524) were formed in a ratio of 19:1. Treating of compound 522 with p-toluenesulfonyl chloride in pyridine afforded 523. When compound 523 was treated with potassium hydroxide in methanolic solution, the Grob fragmentation led selectively to seco-pregnane aldehyde 527 (Scheme 76) [150].



a O

N

N

R1

H AcO

AcO 531

R1

528

b H

N N

R2O

N

N

H

BF3

R1

AcO 533 R2 = Ac 534 R2 = H

532 R1

530-534

R1 H Me OMe Cl NO2 CF3

a b c d e f

NHNH2 530 Scheme 77. Reagents. a: 530a-f, MeOH; b: BF3·OEt2 .

O

R

O 23

C

25

O O

HO O

a

O

I

+

O

CHO 536a 17(R) 536b 17(S)

AcO

537

535a 23(R) or 535b 23(S) O 25

O

S

C

23

HO O

O O

a

I

O

+

O

CHO AcO

H

538a 23(R) or 538b 23(S)

539a 17(R) 539b 17(S)

540

Scheme 78. Reagents. a: Pb(OAc)4 , I2, CCl4 , h.

Magyar and co-workers [151] were interested in the syntheses of various kinds of tetrahydroquinolines condensed to the androstane skeleton, as a part of a program of steroid hybrids research. Steroidal aryliminium salts were prepared from D-seco-pregnene aldehyde 528, and their BF3·OEt2-catalyzed reactions were studied. The phenylhydrazones 531 of unsaturated D-secopregnenealdehyde 528 underwent BF3·OEt2-induced intramolecular 1,3-dipolar cycloaddition to afford new pyrazoline-fused androst-5ene derivatives 533 under extremely mild conditions (Scheme 77) [152]. Pyrazolines 533a-f were deacetylated in alkaline MeOH to furnish the corresponding 3-OH derivatives 534a-f, which were subjected to pharmacological investigation.

The chemistry of spirostanes was intensively studied during past period [153-155] in order to find an efficient route to medicinally important steroids by degradation of plant sapogenins [156]. The recent revival of interest in the chemistry of spirostanes stems from studies on cephalostatins [157, 158] and the natural products isolated from plants used in traditional medicine [159]. Although many spirostane based natural products were known for several decades, methods for their synthesis are rather limited. However, Jastrzbska and co-workers [160] studied reactions of 23R- and 23S-23-spirostanols in the 25R and 25S series (535a, 535b, 538a and 538b) with lead tetraacetate-iodine, whereby D-seco-iododialde-


Gai et al.

O

O COOH CHO

H H H3CO

H

H

b

H H

H 542

541

366

O

COOH CH2OH

a

H3CO 543

c

O

H

O H H

H H3CO

COCl CH2OH

d

H 545

544

Scheme 79. Reagents. a: NaBH4 , MeOH; b:Sc(OTf) 3, molecular sieves, MeCN, THF; c: (COCl)2 , C6H6; d: TEA, C6H 6.

OR OR O

O

O

Cr O

CHO

OMe 551 R = H 552 R = TES

OMe d OR

OR

COOEt

O

OH a

c

OMe

OMe

OMe 546

OH

b

547 R = H 548 R = TES

549 R = H 550 R = TES TES

e TES OH

O

O

CHO +

553

OMe

552

OMe

Scheme 80. Reagents. a: MeMgI; b: chlorotriethylsilane (TESCl), DMF, imidazole; c: OsO4 ; d: PDC; e: DMSO, (COCl)2, TEA.

hydes (536a, 536b, 539a and 539b as well as lactones 537 and 540) were obtained (Scheme 78). More lactones were formed in the 25S series. Interestingly, similar products were formed irrespective of the configuration of the 23-hydroxy group. There was an apparent difference between the axial and equatorial alcohols in the reaction rate; the former being faster (especially, the reaction of compound 538b). The Dseco-iododialdehydes (formed as mixtures of epimers in a ratio close to 1:1) were separated and fully characterized, but their configuration at C-17 was not unequivocally established.

The syntheses of some D-dihomo-oxasteroid derivatives started from 16,17-secoestrone carboxylic acid 541, which was a minor product from transformation of estrone 3-methyl ether to 3methoxy-16-methylidene-estrone [161-163]. Reduction of 541 with sodium borohydride in methanol resulted in the 16,16a-unsaturated alcohol 542. The direct ring closure of 542 with a catalytic amount of scandium(III)-triflate led to the unsaturated 16-methyl derivative 543. The in situ formation of chloride 544 with oxalyl chloride and subsequent triethylamine-induced intramolecular cyclization led to lactone 545 (Scheme 79).



R3

R3 OH

OMs

a

CN

CN R1 or R2

R1 or R2

388 R1 = The residual part of 3-acetoxy-17-hydroxy16,17-secoandrost-5-ene-16nitrile, R3 = H 402 R1, R3 = Me 554 R2 = The residual part of 3benzyloxy-17-hydroxy16,17-secoestra-1,3,5(10)triene-16-nitrile, R3 = H 555 R2, R3 = Me

389 R1, R3 = H 556 R1, R3 = Me 557 R2, R3 = H 558 R2, R3 = Me b R3 N

N

C

N

N

R1 or R2 389a R1, R3 = H 556a R1, R3 = Me 557a R2, R3 = H 558a R2, R3= Me

R3

R3 N

N

N

N N

N N

N AcO 559 R3=H 560 R3= Me

BnO 561 R3=H 562 R3= Me

Scheme 81. Reagents. a: MsCl, aps. Py; b: NaN3, hexamethylphosphoramide (HMPA) for serie R3 = H or NaN3 , CuCl, HMPA for serie R = Me.

Morzycki and co-workers [164] described in 2010 the unexpected synthesis of the D-seco-aldehyde 551 during attempts to invert configuration at C16 in triol 549 (Scheme 80). Namely, reaction of the unsaturated ester 546 with excess methylmagnesium iodide provided the tertiary alcohol 547, which was converted into the triol 549 with a slight excess of osmium tetroxide. Similar osmylation of the triethylsilylether 548 (22-O-TES-ether) gave the monoprotected triol 550. The pyridinium dichromate (PDC) oxidation of 549 produced the D-seco-aldehyde 551. The formation of this product probably occurred by fragmentation of a cyclic chromate ester (Scheme 80), an intermediate resembling that involved in the oxidation of cis-diols with periodic acid [165]. It is clear that the C22 tertiary hydroxyl group does not influence the course of this reaction since PDC oxidation of 550 (22-O-TES-ether) at room temperature gave the protected D-secoaldehyde 552 as the sole product. Compound 552 was obtained also by Swern oxidation [166] of the 16,17-dihydroxy-22-O-TES-ether 550 in addition to the desired 16-ketone 553 (Scheme 80). “Click” chemistry of D-seco nitriles was used to synthesize a new class of pentacyclic D-homo-fused steroidal tetrazoles [167]. Namely, androstane and estratriene 16,17-seco-16-nitrile-17-

mesyloxy derivatives 389 and 556-558 were converted to their corresponding tetrazoles 559-562 via in situ generated 16,17-seco-17azido-16-nitriles. D-Homo fused estrane tetrazoles 561 and 562 expressed specific, selective antiproliferative effect against estrogen receptor positive breast adenocarcinoma cells (Scheme 81). CONCLUSION The significant biological activity of many naturally occurring or synthesized steroidal compounds prompts researchers to create and synthesize new steroidal derivatives with altered biological activity, compared to the parent compounds. The methods for the syntheses of the modified steroidal compounds available to date are numerous and diverse. Very interesting, biologically potent, classes of steroidal derivatives are secosteroids - compounds which underwent cleavage of C-C bond in A, B, C or D ring of the steroidal moiety. The results achieved so far demonstrate that the cleavage of C-C bond, jointly with introduction of different substituents could contribute in the biological potency of the modified steroids significantly. The partial syntheses of secosteroids, as well as the modifications of these class of molecules have been reviewed herein, cov-


ering quite long period of time. The biological activities of the secosteroidal compounds for which data are available have been presented in this review.

Gai et al. [25]

[26] [27]

CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.

[28] [29] [30]

ACKNOWLEDGEMENTS This project was supported by the Ministry of Education, Science and Technological Development, Republic of Serbia (Grant No. 172021). REFERENCES [1] [2] [3]

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Received: April 19, 2013

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Accepted: July 30, 2013

An Overview of Partial Synthesis and Transformations of Secosteroids

An Overview of Partial Synthesis and Transformations of Secosteroids

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