Pd-catalyzed steroid reactions

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Contents lists available at ScienceDirect

Steroids journal homepage: www.elsevier.com/locate/steroids

2

Review

5 4 6

Pd-catalyzed steroid reactions

7

Q1

8

Institute of Chemistry, University of Białystok, Hurtowa 1, 15-399 Białystok, Poland

9 10

a r t i c l e

1 7 2 2 13 14 15 16 17 18 19 20 21 22 23 24 25 26

Dorota Czajkowska-Szczykowska, Jacek W. Morzycki ⇑, Agnieszka Wojtkielewicz

i n f o

Article history: Received 7 June 2014 Received in revised form 7 July 2014 Accepted 30 July 2014 Available online xxxx

Q2

a b s t r a c t We review the most important achievements of the last decade in the field of steroid synthesis in the presence of palladium catalysts. Various palladium-catalyzed cross-coupling reactions, including Heck, Suzuki, Stille, Sonogashira, Negishi and others, are exemplified with steroid transformations. Ó 2014 Elsevier Inc. All rights reserved.

28 29 30 31 32

Keywords: Palladium-catalyzed reactions Heck reaction Suzuki reaction Stille reaction Sonogashira reaction Negishi reaction Carbonylation reactions 33

36 35 37 38 39 40 41 42 43 44 45 46 47 48 49

34

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Heck reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Suzuki coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stille reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sonogashira coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Negishi and Kumada coupling reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tsuji–Trost reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Buchwald–Hartwig amination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pd-catalyzed carbonylation, alkoxycarbonylation and aminocarbonylation. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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50 51 Abbreviations: 9-BBN, 9-borabicyclo[3.3.1] nonane; BINAP, 2,20 -bis(diphenylphosphino)-1,10 -binaphthyl; Boc, t-butoxycarbonyl; Cp, cyclopentadienyl; dba, dibenzylideneacetone; DIEA, diisopropylethylamine; DIPA, diisopropylamine; DMAP, 4-dimethylaminopyridine; DME, dimethoxyethane; dppb, 1,4-bis(diphenylphosphino)butane; dppe, 1,2-bis(diphenylphosphino)ethane; dppf, 1,10 -bis(diphenylphosphino)ferrocene; dppp, 1,3-bis(diphenylphosphino)propane; HATU, (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); HMDS, 1,1,1,3,3,3-hexamethyldisilazane; HMPA, hexamethylphosphoramide; MOM, methoxymethyl; MW, microwave irradiation; NMP, 1-methyl-2-pyrrolidinone; Nf, nonafluorobutanesulfonyl; Piv, dimethylpropanoyl; PPA, polyphosphoric acid; TBAF, tetra-n-butylammonium fluoride; THP, tetrahydropyranyl; TES, triethylsilyl or triethylsilane; Tf, trifluoromethanesulfonyl; TMEDA, N,N,N0 ,N0 -tetramethylethylenediamine; TMG, 1,1,3,3-tetramethylguanidine; o-Tol, 2-methylphenyl; Ts, p-toluenesulfonyl. ⇑ Corresponding author. Tel.: +48 85 7457585; fax: +48 85 7457581. E-mail address: [email protected] (J.W. Morzycki).

1. Introduction

52

Transition metal-mediated cross-coupling reactions have revolutionized organic synthesis. Many highly efficient protocols for bond construction have emerged by mastery of such reactions, particularly in multifunctional settings. Among them, palladium-catalyzed carbon–carbon or carbon–heteroatom bond-forming reactions have probably had the largest impact on synthetic organic chemistry and have found many applications in target-oriented synthesis. Their widespread use in organic synthetic applications is due to the mild conditions associated with the reactions together with their tolerance of a wide range of functional groups. Palladium-catalyzed cross-coupling reactions have

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R1 Pd catalyst

H R

+

2

R3

R4

X

R R

base

4

2

R3

R4 = aryl, benzyl, vinyl X = I, Br, Cl, OTf, OTs, N2+

Scheme 1. Heck reaction.

78

changed the practice of the science of synthesis. Three of the main developers, Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki, were awarded the Nobel Prize in Chemistry in 2010 for their contribution to this field. The cross-coupling reactions have been applied to the synthesis of a large number of both natural products and biologically active compounds of complex molecular structures. These reactions are suitable for being carried out on a large scale, and therefore they have found wide applications in fine chemical and pharmaceutical industries. Many review articles devoted to Pd-catalyzed cross-coupling reactions have been recently published [1–6]. However, the last review article on the application of these reactions in steroid synthesis appeared over ten years ago [7]. The present paper covers literature that was published during the past decade; the older papers are only occasionally quoted when appropriate.

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2. Heck reaction

80

The Heck reaction, also known as the Mizoroki–Heck reaction, is the palladium-catalyzed coupling of alkenyl or aryl halides or pseudohalides with alkenes (Scheme 1) in the presence of a base (e.g., tertiary amines, alkali acetates, carbonates, or phosphates). Extensive studies on the Heck reaction since its discovery in 1972 have resulted in optimization of the methodology. The reaction conditions, palladium catalysts that are used and substrates have been examined to afford high efficiency, even with the use of unreactive substrates, such as aryl chlorides [8–11]. Also, the asymmetric variant of the Heck reaction has been explored [12,13]. Nowadays, the Heck reaction is considered to be one of the most versatile and useful carbon–carbon bond-forming methods in modern organic synthesis. It has found many applications at both the laboratory and industrial scale [7,14–16]. In recent years, many examples of employing diastereoselective intramolecular Heck reactions to steroid framework synthesis have been published.

64 65 66 67 68 69 70 71 72 73 74 75 76 77

81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96

Tietze et al. used a combination of Suzuki and Heck reactions for synthesis of the B-norestradiol analog [17]. As substrates, the CD fragment boronic ester and ortho-2-bromobenzylchloride were used; the former was prepared from the Hajos–Wiechert ketone [18] in several steps (Scheme 2). The purpose of the work was to design novel estrogens that bind to the b-unit of the maxi K+-channel located on the surface of the endothelium without showing the hormonal activity of estradiol. It is worth noting that the intramolecular Heck reaction was performed under microwave irradiation, which was superior to the normal thermal reaction. The reaction was catalyzed by Herrmann’s palladacycle and allowed for efficient and completely diastereoselective B-ring closing to afford the desired B-nor-steroid (Scheme 2). A year later, German scientists applied the same strategy to synthesize the spiro-B-norestradiol analog (Scheme 3) [19]. The isomeric B-seco-steroid with a different diene position was prepared from the Hajos–Wiechert ketone. Interestingly, the subsequent intramolecular Heck reaction took place regioselectively with the double bond located in the five-membered ring D. This selective formation of the spiro compound could be explained by the fact that exo-trig additions are favored over the endo-trig ones. Similarly to the example as previously described, the Heck reaction performed under microwave irradiation was much more superior as compared with the normal thermal reaction. The next study, performed by Tietze’s group, proved that the Heck reaction can be successfully used in the synthesis of new steroids with a seven-, eight-, or nine-membered D ring (Scheme 4) [20]. In 2008 the same authors reported the enantioselective total synthesis of the oral contraceptive desogestrel (Scheme 5), in which the steroid core was formed by a sequence of two consecutive Heck reactions [21]. The conversion of the known enantiopure diketone led to the chiral bicycle, the CD ring synthon, which was used for a diastereoselective intermolecular Heck reaction with vinyliodide to give the desired (Z)-B-seco-steroid. In addition to the main product, small amounts of its E isomer and regioisomer were obtained in this coupling. In the following intramolecular Heck reaction of the obtained B-seco-steroid, the tetracyclic steroid ring system was formed to give the intermediate, which was further converted to desogestrel. The Heck cyclization reaction was highly diastereoselective, leading only to the unnatural cis junction of rings B and C.

OtBu

OtBu

Br Br Pd(PPh3)4, NaOH,

+

THF, reflux, 22 h, 72%

B

Cl

O

MeO

O

MeO (o-Tol)2 O Pd P O

1. nBuLi, TMEDA, B(OiPr)3 2. 2,2-dimethylpropane-1,3-diol

OtBu

O P Pd O

nBu4NOAc, DMF, MeCN, H2O, (o-Tol)2 MW 140oC, Herrmann's palladacycle 5 min, 70%

OtBu

OtBu 2 steps

H O

O Br

MeO

Scheme 2. Synthesis of the enantiopure B-norestradiol derivative.

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OtBu

(o-Tol)2 O Pd P O (o-Tol)2

Br

O P Pd O

Herrmann's palladacycle nBu4NOAc, DMF, MeCN, H2O, MW 180oC, 30 min, 73%

MeO OMe

Scheme 3. Tietze’s synthesis of the spiro-B-norestradiol analog.

O O

O

Herrmann's catalyst,

Br

+

nBu4NOAc, DMF, MeCN, H2O, 120 oC

MeO 14%

60%

O

O

O

Br

Herrmann's catalyst,

+

nBu4NOAc, DMF, MeCN, H2O, 120 oC

80% (4:1)

MeO

Scheme 4. Synthesis of D-homoestradiol derivatives.

O

OtBu Br I

+ MeO

O

OtBu Pd(OAc)2, PPh3, Ag2CO3, DMF, 95 oC

OtBu

H OMe

Br

OtBu

H

+

+ Br Br

MeO

77%

H

Herrmann's palladacycle, nBu4NOAc, DMF, MeCN, H2O, 135 oC

MeO

OtBu

OH (o-Tol)2

H

H

H MeO

H

H 94%

H

O O P Pd Pd P O O (o-Tol)2 Herrmann's palladacycle

desogestrel

Scheme 5. Synthesis of desogestrel by a double Heck reaction.

141 142 143 144

The domino Heck inter- and intramolecular reaction was used by Parsons’ group to synthesize the batrachotoxin ring system (Scheme 6) [22]. Treatment of vinyl bromide, a synthon of the AB ring fragment, with cyclopent-2-enone in the presence of

palladium acetate and triethylamine gave the desired tetracyclic compound in 35% yield after 24 h. The analogous reaction carried out under microwave irradiation took 5 min and allowed to increase the yield up to 48%.

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O

O Br

Pd(OAc)2, Et3N,

O

MW, 110 oC, 5 min. (48%)

O MeO O

O

MeO

H

H

H

Scheme 6. Palladium catalyzed ring annulation for synthesis of the batrachotoxin framework.

O

O

X2P

1. BuLi O

Br

Hoveyda-Grubbs 2nd gen. cat.

X2 P Br

Br

3.

MeO

MeO

O

2.

4 steps

Me N 46%, X2 =

MeO

N Me

59%

O

O

Br

Herrmann's catalyst nBu4NOAc,

H

estrone

DMF, MeCN, H2O, 115 oC

H MeO

MeO

100%

58%

Scheme 7. Linclau’s total synthesis of estrone.

C8H17

C8H17

OH

OH

H H

H

O

Pd(PPh3)4, CH3CN, reflux 10

H

15%

I C8H17

10S-iodide

H C8H17

C8H17

OH OH

H

OH H

H Pd(PPh3)4, CH3CN, reflux

OTBS

10

H

64%

I 10R-iodide

H

Scheme 8. Granja’s synthesis of the novel steroid-like polycyclic system.

149 150 151 152 153 154 155 156 157

Recently, Linclau et al. adapted the Heck reaction conditions developed by Tietze to the novel enantioselective synthesis of estrone [23]. In the proposed synthesis, a steroid backbone construction relied on the prior formation of three stereogenic centers (C8, C13, and C14) on a D ring template by a three-component conjugate addition/alkylation process, followed by C- and B-ring cyclizations (Scheme 7). First, the closure of ring C was accomplished by RCM reaction in the presence of a Hoveyda–Grubbs second generation catalyst. The C9–C11 double bond resulting from the RCM

reaction was ideally positioned for the subsequent Heck B-ring closure, which proceeded in quantitative yield under the conditions developed by Tietze. A similar approach based on a combination of RCM and Heck cyclizations was applied by the Granja group for the synthesis of a steroid analog with an eight-membered B ring that mimics the putative transition structure of the isomerization of previtamin D3 to vitamin D3 (Scheme 8) [24]. The CD-ring platform was obtained starting from Grundmann’s ketone readily available from

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OTf O

Bu3Sn

nBu4NOAc, DMF, MeCN, H2O, 120 oC

H

Pd2(dba)3, AsPh3 CuI, LiCl, NMP, 65 oC

14

COOtBu

14

Br

O

(o-Tol)2

O

H

O Pd P O (o-Tol)2

Br O

14β-H or 14α-H

97% (14β-H) 95% (14α-H)

OtBu

O P Pd O

OtBu

MW 170 oC (45 min.) - 200 oC (2 min.) DMF/toluene

14

14

H

H

O

O COOtBu

COOtBu

O

O 73% (14β-H) 79% (14α-H)

83% (14β-H) 15% (14α-H) + Δ5,Δ9-isomer (63%)

Scheme 9. de Meijere’s synthesis of steroid derivatives by the Stille-Heck coupling sequence.

OtBu (o-Tol)2 O Pd P O (o-Tol)2

O 2 steps (75%)

O P Pd O

H

N PhSO2

Br

dppb, Et3N, DMF, H2O, 105oC

N PhSO2

COOtBu

Br

OH

OtBu

2 steps (59%)

H

H N

N PhSO2

COOtBu

PhSO2

COOH

92%

Scheme 10. Synthesis of the steroidal d-amino acid.

167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188

vitamin D. After alkylation and allylation of the Grundmann’s ketone, a diene suitable for metathetic cyclization, as a mixture of C10-epimers, was obtained. Its RCM reaction in the presence of a Grubbs first generation catalyst led to the formation of the target eight-membered ring. To construct the A ring, (Z)-vinyl iodide (as a separated 10S- and 10R-isomer), required for the Heck cyclization, was prepared by known procedures from the tricyclic RCM product. The Heck reaction of (10R)-iodide with tetrakis(triphenylphosphine)-palladium(0) yielded the desired product as a single isomer in 64% yield. By contrast, applying the same reaction conditions to (10S)-iodide afforded the tetracyclic product in only 15% yield. The use of other catalyst systems, such as Pd(OAc)2/PPh3/Et3N, did not provide any improvement. These differences in the reactivity of the epimeric iodides seem to be due to the conformational restrictions introduced by the eight-membered ring fused to the CD-bicyclic system. de Meijere demonstrated that a sequence of Stille and Heck cross-coupling reactions and subsequent thermal 6p-electrocyclization provided easy access to the steroidal compounds by a convergent A + CD ? ACD ? ABCD strategy (Scheme 9) [25–27]. The highly chemoselective Stille couplings on the triflate moiety of several 2-bromo-cyclohex-1-enyl triflates with cis- and

trans-fused bicyclo[4.3.0]-nonenylstannanes furnished the corresponding tricyclic bromobutadienes in good to excellent yields (70–97%). These were subjected to Heck reactions with tert-butyl acrylate to provide pentasubstituted tricyclic 1,3,5-hexatrienes. A significant increase in efficiency of the Heck coupling process could be achieved by applying a protocol with a precatalyst on the basis of Herrmann’s palladacycle prepared from Pd(OAc)2 and P(o-Tol)3 with added triarylphosphines as co-ligands (73–90% yield). Upon heating these hexatrienes cyclized to yield various unsaturated steroid analogs as single diastereomers. The described methodology appeared to be useful in the synthesis of new enantiomerically pure steroidal d-amino acids which were interesting enough to be tested as novel heterocyclic steroid analogs and as d-amino acids to be incorporated into peptidomimetics (Scheme 10) [28]. In the case of tricyclic bromodienes with the A ring containing a nitrogen atom, the best results for the Heck reactions were obtained with the palladacycle and dppb as coligand in the presence of triethylamine as a base. These conditions were significantly superior to the sole use of palladacene. The application of the palladium complex with a co-ligand for stabilization to avoid premature decomposition of the catalytically active species had not been reported before and allowed for a significant

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OH

OH

H

H Br

Pd(PPh3)4, Et3N, toluene, reflux

+

TBSO TBSO

OTBS

OTBS

R

R

Scheme 11. A tandem intermolecular carbopalladation/intramolecular Heck cyclization strategy for the synthesis of 2-substituted 1a,25-(OH)2 vitamin D3.

X

OH N

n

HO

ONf

X

N

n

1. NaH, THF, rt

Pd(OAc)2, BnEt3NCl, NaHCO3

2. NfF, THF, rt 73%

DMF, 90 oC

1. H2, Pd/C

N

X

n

O

n

H

2. Py-SO3, DMSO, Et3N

69% (n = 1, X = CH2) 75% (n = 2, X = CH2) 89% (n = 1, X = NBoc)

H

SmI2, HMPA,

OH

X

N

tBuOH, THF, rt

H

N

46% (n = 1, X = CH2) 46% (n = 2, X = CH2) 75% (n = 1, X = NBoc)

OH

33% (n = 1, X = CH2) 33% (n = 2, X = CH2) 55% (n = 1, X = NBoc)

Scheme 12. Reissig’s synthesis of azasteroids.

211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233

reduction in the amount of palladium precatalyst necessary for complete conversion of the reactants. This protocol could be a convenient alternative to particularly tuned ligands that are either expensive or time-consuming when specifically prepared. A stunning application of the tandem process consisting of intermolecular carbopalladation and intramolecular Heck cyclization can be found in the construction of ring A and the triene unit of the vitamin D skeleton in a single operation. Thus, CD-ring-bearing bromomethylene and enyne, as the A-ring precursor, were coupled using Pd(PPh3)4 in the presence of triethylamine (Scheme 11). This approach, first developed by Trost in 1992 [29], appeared to be very versatile in the synthesis of various vitamin D analogs. Many research groups adapted this methodology to prepare vitamin D3 derivatives for biological studies in good yields. According to Trost’s strategy, Kubodera’s group synthesized all possible diastereoisomers at 1-, 3- and 20-positions of 1a,25-dihydroxy2b-(3-hydroxypropoxy)vitamin D3 [30–33] as well as their 24R and 24S-hydroxy derivatives [34]. In order to obtain vitamin D derivatives which have strong activity for enhancing bone growth, Saitoh and Kittaka designed C-2 and C-4 variously substituted vitamin D derivatives [35–40]. 2a- and 2b-N-substituted analogs of 1a,25-(OH)2D3 were obtained similarly by other Japanese scientists [41].

A combination of Heck reaction and SmI2-HMPA induced cyclization was used for the synthesis of azasteroids with unnatural cis–cis annulation of rings B, C, and D (Scheme 12) [42]. The Heck reactions of quinolyl nonaflate (nonafluorobutanesulfonate, Nf) with 2-vinylcycloalkan-1-ols or their azacycle analogs, Q3 followed by oxidation and hydrogenation, smoothly give the desired c-heteroaryl substituted ketones – substrates to SmI2HMPA promoted cyclization. Hetaryl nonaflates employed in the Heck transformation, although not yet routinely explored in the cross-coupling reactions, exhibited several advantages over the corresponding triflates. They are very stable, easily purified by crystallization or column chromatography, and easily prepared using commercially available, non-toxic and cost-effective nonafluorobutanesulfonyl fluoride (NfF). The major products of Heck reactions were unsaturated alcohols which were transformed into the desired ketones by oxidation with the PySO3 complex in DMSO followed by hydrogenation. The well-known palladium-catalyzed migration of the double bond of allylic and homoallylic alcohols in Heck processes [43], in the case of the obtained homoallylic alcohols, was observed to a small extent. Apart from the intramolecular Heck reaction, which was extensively used for a steroid backbone construction, its intermolecular variant provided a convenient tool for steroid functionalization.

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O COOMe

I 1. H2, Pd/C, EtOAc (98%) 2. NH2NH2 H2O, Et3N, MeOH (98%)

H

3. I2, Et3N, THF, rt 98%

H

COOMe Pd(OAc)2, K2CO3, DMF, rt, 77%

AcO 16-DPA R1

R1

R2

R2

COOMe H

Pd/C, MeOH, TES, 10 min.

COOMe H

+

R1 = Me, R2 = H and R1 = H, R2 = H

R1 = Me, R2 = H and R1 = H, R2 = H

H2, Pd/C, EtOAc, 90%

COOMe

COOMe

H

H

+ (8 : 2)

Scheme 13. Pore’s construction of the steroidal side chain from 16-DPA.

C8H17 C8H17

CN CN

Pd(OAc)2, P(o-Tol)3, Bu3N

Pd(OAc)2, P(o-Tol)3, Bu3N

CH3CN, MW, 150 oC, 54%

CH3CN, MW, 150 oC, 54%

H

H

H NC

OTf KCN, 18-crown-6, Pd(PPh3)4, 75 oC, 40%

NC

C8H17

H CN

Scheme 14. Synthesis of novel steroid analogs containing the nitrile moiety. 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272

Use of the Heck reaction for the attachment of various side chains to the steroidal skeleton is advantageous due to mild reaction conditions, high stability of the reagents and a variety of readily available steroidal ketones that are converted smoothly to the corresponding enol triflates or vinyl iodides – the cross coupling partners in the Heck reaction. A recent example of the application of the intermolecular Heck reaction for a side-chain extension was published by Pore et al. in 2009 [44]. The scientists reported the construction of a steroidal side chain at C-20 of 16-dehydropregnenolone acetate (16-DPA). The key steps of the stereoselective side-chain synthesis were the palladium catalyzed C–C bond-forming Heck reaction of the C-20 vinyl iodide with methyl acrylate and transfer hydrogenation with triethylsilane and Pd/C (Scheme 13). An intermolecular variant of Heck coupling was also employed by Mayer’s group for the preparation of seco-steroid analogs con-

R1 BY2 + R2

X

Pd catalyst Base

R1 R2

Scheme 15. Suzuki reaction.

taining a nitrile function attached to the bicyclic ring system as a potential reactive group to bind covalently to proteins (Scheme 14) [45]. For this purpose, Grundmann’s ketone was converted to vinyl triflate under kinetic control following a protocol worked out by De Riccardis et al. [46]. The Heck reaction of vinyl triflate and acrylonitrile, catalyzed by tri-o-tolylphosphine and palladium(II) acetate under microwave irradiation, gave a mixture of E- and Z-cyanodiene isomers in moderate yield. In an analogous manner, the Heck reaction was performed with but-3-enenitrile to obtain the homologous nitrile. Another seco-steroid analog bearing a nitrile group attached directly to the bicycle was obtained in a reaction with potassium cyanide and 18-crown-6 ether catalyzed by tetrakis(triphenylphosphine)-palladium(0).

273

3. Suzuki coupling

287

The Suzuki (or Suzuki–Miyaura) cross-coupling reaction is one of the most powerful and environmentally friendly methods for the selective construction of carbon–carbon bonds, and it has

288

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ArB(OH)2 "Pd", base, 79-98%

O

O Br

Ar

O

ArB(OH)2 "Pd", base, 84-99%

O

O

Ar

Br O OAc

ArB(OH)2 5% Pd(dppb)Cl2 K2CO3, 100 oC, 43-100%

O

O Ar

Cl

Scheme 16. Arylation of 4- or 6-halogenated unsaturated ketones.

O O ArB(OH)2 "Pd", base

O

O Br

Ar

HC(OMe)3

H2O, HCl

ArB(OH)2 "Pd", base

MeO

MeO Br

Ar

Scheme 17. Suzuki arylation of 6-bromo-D3,5-steroid enol ethers.

291 292 293 294 295 296 297 298 299 300 301 302

found extensive use in the synthesis of significant products such as drugs, fine chemicals, and optical devices [7,47]. The advantages of Suzuki coupling over other reactions are the availability of common boronic acids, mild reaction conditions, and the less toxic nature of these reactions than other similar ones. Enormous effort has been devoted to this reaction as a result of the remarkably wide range of substrates that are tolerated and the stability of organoboron compounds in air and water. Excellent results can be obtained either with a Pd(0) or Pd(II) precatalyst in the presence of ligands or additives, as well as under ligand-free conditions (Scheme 15). Potential aromatase inhibitors, 4- and 6-aryl-substituted derivatives of androst-4-ene-3,17-dione and 17a-hydroxyprogesterone,

have been prepared by Lukashev et al. using the Suzuki–Miyaura cross-coupling reaction from the corresponding 4- or 6-halosteroids (Scheme 16) [48,49]. While the reaction with bromo-derivatives is catalyzed by Pd(PPh3)2Cl2, coupling with chlorosteroids requires the use of Pd(dppb)Cl2 or Pd(dppf)Cl2; K2CO3 or K3PO4 were used as bases in these reactions. Yields were good to excellent. The method can be applied for the preparation of 6-arylated steroids with the aryl group attached to the sp3-hybridized C-6 atom (Scheme 17) [48,50]. Although the Suzuki reaction of the allylic substrate led only to the dehydrobrominated product, Pd(PPh3)2Cl2 or Pd(dppf)Cl2 coupling of the corresponding methyl enol ether with arylboronic acids in aqueous dioxane afforded excellent yields of arylated products. In situ hydrolysis of enol ether with concentrated HCl provided a convenient route to 6a-aryl-substituted androstanes. A convenient method for preparation of 3b-acetoxy-6-iodocholest-5-ene from cholesterol was also elaborated [51]. This compound was used as a key intermediate for the synthesis of 6arylated cholesterol derivatives, as potential drugs, using a Suzuki cross-coupling reaction (Scheme 18). Richardson et al. described the synthesis of novel 3-aryl indoles as progesterone receptor antagonists [52]. These analogs were prepared from 2-bromo-6-nitro indole in a few steps using Suzuki cross-coupling as the key step (Scheme 19). 1-Alkyl-3-bromo6-nitroindoles were coupled to aryl boronic acids to give 1-alkyl-3-aryl-6-nitroindoles. The nitro group was then reduced by using standard conditions followed by reaction with methanesulfonyl chloride to give final compounds for biological assays. Alternatively, 3-bromo-6-nitroindole was converted to the pinacolboryl derivative. This allowed direct coupling of more readily available aryl bromides without conversion to the corresponding boronic acids. The coupling of aryl bromides worked well when using standard Suzuki conditions. This was followed by reduction and sulfonylation to give the final compounds. A general method for direct and stereoselective synthesis of epoxypolyenes via the Suzuki–Miyaura cross-coupling reaction of 1-iodoalkenes with B-alkylboron compounds was described by De Clercq [53]. It allows for straightforward and convergent assembly of compounds that are structurally similar to (3S)-oxidosqualene, an important intermediate in steroid biosynthesis. The starting (S)-methyloctalone was transformed to the dicyclohexylboron intermediate using the Grieco-Sharpless elimination protocol (Scheme 20) [54]. Suzuki–Miyaura cross-coupling of this compound with the known iodoalkene using the Pd(dppf)Cl2 catalyst afforded the tetraene product. This advanced intermediate was subjected again to the analogous procedure using (S)-epoxide, derived from the previously used iodoalkene, for the cross-coupling step, and yielding the (3S)-oxidosqualene analog. Novel chemical entities have been prepared via the Suzuki reaction (Scheme 21) as AC-ring substrate mimetics of CYP17, a key enzyme in androgen biosynthesis, which catalyzes both the 17a-hydroxylation of pregnenolone and progesterone and the subsequent cleavage of the C17–C20 bond to yield the 17-oxo androgens being the precursors of testosterone [55,56]. The inhibition of CYP17 is a promising alternative to the current treatment of prostate cancer. Also, a series of compounds that mimic steroidal A and B rings with proper substituents have been obtained using the Suzuki cross-coupling reaction [57,58]. Tetracyclic 3-methanesulfonamide turned out to be a highly potent inhibitor at nanomolar concentrations [59]. The glucocorticoid receptor (GR) is a member of the steroid family of nuclear hormone receptors that is involved in modulating a variety of immunological and metabolic signaling pathways upon glucocorticoid binding. A new series of GR modulators has been reported [60] with a 2,2-dimethyl-3-phenyl-N-(thiazol or thia-

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303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368

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ArB(OH)2 Pd(OAc)2, PPh3, K2CO3, DMF, 29-79%

AcO

AcO Ar

I

Scheme 18. Synthesis of 6-aryl-substituted cholesterol derivatives.

O B

O

N

O2N

R' aryl bromide, Pd(PPh3)4, Na2CO3, LiOH, toluene

bis(pinacolato)diboron, PdCl2(dppf)2 CH2Cl2, KOAc, DMSO

CN

CN

R''

R''

Br

ArB(OH)2, Pd2(dba)3, [(tBu)3PH]BF4, KF, THF

1. H2, Pd/C, THF

N

O2N

2. MsCl, Py, CH2Cl2

N

O2 N

R'

N

MeSO2NH R'

R'

Scheme 19. Synthesis of progesterone receptor antagonists.

O

O (3S)-oxidosqualene

(3S)-oxidosqualene analog

O BCy2

OH O

1. o-NO2C6H4SeCN, PMe3 2. H2O2, rt

steps

3. Cy2BH, rt

Ph2t-BuSiO

Ph2t-BuSiO O

I Pd(dppf)Cl2, Ph3As, Cs2CO3, 40 h, rt, 80% O I

(3S)-oxidosqualene analog

Pd(dppf)Cl2, Ph3As, Cs2CO3, 18 h, rt, 70%

Cy2B

1. TBAF 2. o-NO2C6H4SeCN, PMe3 3. H2O2, rt 4. Cy2BH, rt

Ph2t-BuSiO

Scheme 20. Synthesis of the (3S)-oxidosqualene analog. 369 370 371 372

diazol-2-yl)propanamide core and the basic imidazo[1,5-a]pyridine ring, which serves as a replacement for the A–B ring of the steroid scaffold (Scheme 22). Suzuki coupling reactions of the key bromo intermediate with arylboronic acids were carried out using

the homochiral bromo compound (no information was provided which enantiomer was used). Areno- and heteroareno-annelated steroids were proposed by Watanabe et al. as compounds with potential anti-inflammatory,

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R3 N

N

N

Y

R Aryl-B(OH)2, Pd(Ph3)4

Y Br

N

2

X

Na2CO3, toluene, reflux, 4 h

X

X, Y = CH or N; R1, R2, R3 = H, OMe, F, NH2

R1

OH

OH

O

O B

NH-R Pd(PPh3)4, Na2CO3, toluene, reflux, 2 h

HO

HO

Br R = COCH3 or SO2CH3 NH-R

Scheme 21. Synthesis of substrate mimetics of enzyme CYP17.

O

S X

COOH

N H 1. ArB(OH)2, Pd(dppf)Cl2, K3PO4, CH2Cl2, DMF, 90 oC

N N

N

N N

2. 2-aminothiazole or 2-amino-1,3,4-thiadiazole, HATU, DIEA, DMF

Br

Ar

Ar = Ph or 4-F-Ph; X = CH or N

Scheme 22. Synthesis of glucocorticoid receptor modulators.

Hetaryl

CHO

MeO Ph3P=CHCOR, CHCl3, 100 oC

hetaryl-B(OH)2 Pd(PPh3)2Cl2, PPh3, Na2CO3, DME

Br

Hetaryl

O

CHO

R Pd(PPh3)2Cl2, hetaryl-B(OH)2, Ph3P=CHCOR, Na2CO3, DME

MeO

MeO

X

diphenylether, Δ

for example:

O S

S

R CO2Me

CO2Me

diphenylether, 160 oC, 15 h

MeO

Scheme 23. Synthesis of heteroareno-annelated steroids by the sequence: Suzuki coupling, Wittig reaction, and thermal intramolecular cyclization.

377 378 379

antibacterial and antimicrobial activities [61]. Certain bioactive benzoannelated pentacyclic and hexacyclic terpenoids were isolated from natural sources [62–65]. 17-Thienyl- and

17-benzo[b]thienyl-3-hydroxyestra-1,3,5(10),16-tetraenes were synthesized by either sequential or one-pot Suzuki cross-coupling and Wittig olefination reactions (Scheme 23). At 160 °C, hetero-

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R

+

Pd(OAc)2, K3PO4,

R-B(OH)2

R = phenyl, 4-fluorophenyl, 3-(trifluoromethyl)phenyl or 2-(cyanomethyl)phenyl

THF, rt

CHO

CHO

X = Cl or Br X

X

CHO

C8H17

CHO OHC

AcO

AcO

X C8H17

Suzuki coupling/aldol condensation cascade

O

Br

NC

O B

Pd(OAc)2, K3PO4,

+

DMF, MW

CN

CHO

CN

Scheme 24. Reactions of b-halo a,b-unsaturated aldehydes with boronic acids. Synthesis of polycyclic aromatic hydrocarbons through a Suzuki–Miyaura cross-coupling/ aldol condensation cascade.

Br

X N

O

X= (HO)2BX, PdCl2(PPh3)2, Na2CO3, THF, 80 oC

N

X=

N

67%

77%

N

S O

X=

O

X= 33%

68%

Scheme 25. Synthesis of steroid 5a-reductase inhibitors with Suzuki–Miyaura cross-coupling as a key step.

C8H17

C8H17 1. KHMDS, -78 oC

Pd(dppf)Cl2, K3PO4, DMF, 89%

Tf

2.

N

H

C8H17

N

(-)

H

Tf

OMe Me

OTf

O

H

B

-70 oC to rt, 60%

Br Me

Me

MeO o

tBuLi, -78 C, 9-BBNOMe, 2h

MeO MeO

Scheme 26. High-yielding sp2–sp3 cross-coupling of the CD-ring platform with phenethyl bromide – the A-ring synthon.

383 384 385 386 387 388 389 390 391 392 393 394 395

aryl substituted steroids undergo thermal intramolecular cyclization to produce E-ring heteroareno-annelated estranes. Simple and efficient ligand-free Suzuki cross-coupling reactions of steroidal and nonsteroidal b-halo a,b-unsaturated aldehydes with boronic acids have been described. A range of boronic acids varying in their electronic character was used for coupling (Scheme 24) [66]. This protocol was extended to the direct onepot synthesis of polycyclic aromatic hydrocarbons through a Suzuki–Miyaura cross-coupling/aldol condensation cascade reaction under microwave irradiation. In search for novel inhibitors of human steroid 5a-reductase, various heterocyclic substituents were introduced to the tricyclic core via Suzuki–Miyaura cross-coupling reactions (Scheme 25)

I Hetaryl

Pd(PPh3)4, hetaryl-B(OH)2 Na2CO3, benzene, MeOH, reflux, 11-47%

HO

Scheme 27. Heteroarylation of 17-iodoandrost-16-enes.

[67]; 3-pyridyl, 2-furanyl, and 2-thienyl derivatives were easily prepared performing couplings with the suitably substituted boronic acids at 80 °C under Pd(PPh3)2Cl2 catalysis in THF with Na2CO3

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OTES

Br

O

+

B

OH

R

R 1. Pd(PPh3)2Cl2, K3PO4, THF, 55% (R=CH3) or 85% (R=COOCH3)

O

2. TBAF, THF

R = CH3 or COOCH3 TBSO

OTBS

HO

OH

Scheme 28. Synthesis of 6-substituted analogs of 1a,25-dihydroxy-19-norvitamin D3.

399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436

aq as a base. The couplings were completed in 4–24 h and afforded products in 67–77% yield. Synthesis of the E-styryl derivative was achieved in a slightly different way by using the boronic ester prepared by the addition of catecholborane to phenyl acetylene. In the synthesis of a natural product, ()-astrogorgiadiol, the Grundmann’s ketone was used. Its kinetic enol triflate was chosen as the CD-ring platform on which an A-ring synthon was cross-coupled with an sp2–sp3 bond (Scheme 26) [68]. The kinetic enolate was prepared using KHMDS at 78 °C and trapped after 2 h with the triflate donor (Comins reagent). As the A-ring synthon 2-(20 -methyl-50 -methoxyphenyl)ethyl bromide was used. Slightly modified Marshall’s conditions were used for Suzuki–Miyaura coupling. Bromide was converted to methoxy boronate through an addition of 9-BBNOMe before reacting it with triflate. The product is an intermediate in the synthesis of ()-astrogorgiadiol. Suzuki coupling of 17-iodoandrosta-5,16-dien-3b-ol and 17-iodoandrosta-4,16-dien-3-one with different heteroaryl boronic acids (2- or 3-furanyl, thienyl, benzofuranyl and benzothienyl boronic acid derivatives) was carried out under usual Suzuki conditions (Pd(PPh3)4, Na2CO3, and MeOH). The C17-heteroaryl steroids were obtained in moderate yields (Scheme 27) [69]. The synthesis of analogs of 1a,25-dihydroxy-19-norvitamin D3 bearing different substituents at C-6 was accomplished by the Suzuki–Miyaura cross-coupling reaction of a bicyclic organoboron derivative (CD-ring fragment) with the respective alkenyl halides (A-ring synthons) [70]. The CD-ring boronate ester was prepared from the corresponding Grundmann’s ketone according to the known procedure [71], while the chiral A-ring synthons were obtained from quinic acid (Scheme 28). A similar approach was also applied for the synthesis of 1a,25-dihydroxyvitamin D3 analogs with hydroxyalkyl substituents at C-12 [72]. Palladium catalyzed cross couplings of carboxylic anhydrides with arylboronic acids have emerged as a convenient alternative for the preparation of arylketones [73,74]. The fact that the starting carboxylic anhydride can be generated in situ from the corresponding carboxylic acids allowed the design of attractive one-pot

R1

Sn(alkyl)3

+

R2

X

Pd catalyst

R1 R2 + XSn(alkyl)3

Scheme 30. Stille reaction.

procedures for the preparation of phenylketones in high to good yields. In addition, the high stability and wide functional group tolerance of arylboronic acid make this cross coupling a versatile synthetic alternative for the synthesis of aryl ketones. Palladium-catalyzed cross coupling of phenyboronic acid with acetylated bile acids (Scheme 29) in which the carboxylic groups have been activated by formation of mixed anhydrides with pivalic anhydride afforded moderate to good yields of 24-phenyl-24-oxosteroids [75].

437

4. Stille reaction

446

The Stille (or Migita–Kosugi–Stille) coupling reaction involves a reaction between organotin compounds (organostannanes) and organic halides (Cl, Br, I) or pseudohalides (e.g., OTf, OSO2CF3), using the Pd(0) or Pd(II) catalyst (Scheme 30) [76–78]. The group attached to trialkyltin is usually allyl, alkenyl or aryl. Stannanes are stable in air and moisture, but their main drawback is high toxicity [79] of the tin compounds used. The reaction can successfully be applied to syntheses of compounds furnished with a variety of functional groups, i.e., alcohols, ketones, enones, esters, lactones, nitriles, epoxides or nitro groups. The reaction conditions are mild, but low polarity of the tin compounds and the resulting poor solubility in water are a major drawback. The most common additives to the Stille reaction are: copper iodide, cesium fluoride, or lithium chloride, as these have been found to be powerful rate accelerants [80]. This method was applied for the preparation of steroidal derivatives of maleimides, i.e., tetracyclic analogs bearing a fivemembered A-ring with nitrogen at the 2-position (Scheme 31) [81]. The starting Grundmann’s ketone was first converted to vinyl triflate, which was subjected to Stille coupling with vinyltributyl-

447

O COOH

3

R

3

R

Ph

Piv2O, THF, Pd(OAc)2, Ph-B(OH)2 AcO

R2

H R1

61-83%

AcO

R2

H R1

R1, R2, R3 = H or OAc

Scheme 29. Synthesis of 24-oxo-24-phenyl steroids.

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Pd(PPh3)4,LiCl, CH2=CH_Sn(Bu)3

1. NaHMDS, THF, -78 °C, 1 h

Grundmann’s ketone

2. Phenyl triflimide, -78 °C to rt, 2.2 h 67%

THF, 75 °C, 2 h, 98%

H

H

OTf

O X

toluene, 120 °C, 12 h, 41-81%

N

R

X O

O X

R

H

N

H

X

X = CH or N; R = H, Me, Et or Pr

O

Scheme 31. Synthesis of ring A-modified cytotoxic steroid analogs.

OtBu OTf

OtBu

OtBu

O O

3 steps

[Pd2(dba)3], CuI, LiCl NMP, 90 °C, 12 h

O

H

O

Bu3Sn H cis (73%) or trans (60%) OtBu

O Me

OtBu O

H

H H

O O

C 77%

H N

cis, α

O

N

cis, β

OtBu

O Me

N

Me

CN

Ph

H

O H

O

D 62% dr 1.5:1 or 1:1.5

+

trans (77%)

cis (73%)

N

N

O

O

O

NC N N

A 79%

B 84%

OtBu

OtBu

Me H

H

H

Diels-Alder conditions H

A: benzene, 100-130 °C, 12 h C: dichloromethane, 22 °C, 12 h

H

H

N

B: toluene, 110 °C, 16 h

O

N H

CN

H

D: benzene, 100 °C, 14 h

O H

CN

N

N O

O Ph

Me

Scheme 32. Stille coupling reactions leading to cis/trans tricyclic dienes and Diels–Alder reactions yielding selected novel enantiomerically pure steroidal compounds. 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483

tin, and catalyzed by Pd(PPh3)4 and LiCl to afford 1,3-diene – the key intermediate ready for successive Diels–Alder cycloaddition. A similar approach was used by the de Meijere group – the CDring fragment was linked to the A-ring by a Stille cross-coupling reaction of cyclohexenyl triflates with enantiomerically pure bicyclo-[4.3.0]nonenylstannanes [82]. Synthesis of the B-ring was finally completed by using a Diels–Alder reaction of the resulting tricyclic 1,3-dienes (Scheme 32). Novel steroid analogs with interesting functionalities for further elaboration were obtained. The enantiomerically pure Hajos–Parrish–Wiechert–Sauer ketone was used as the starting material for this synthesis. Finally, some of the compounds were deprotected in two steps to provide samples for biological testing. The 1,3-dioxolane moieties were cleaved with p-toluenesulfonic acid in aqueous acetone to furnish 3-oxosteroids. The ethynyltestosterone derivatives were obtained via a Stille coupling reaction using the appropriate iodo-organometallics and

17a-ethynyltestosterone stannyl derivatives (Scheme 33) [83]. The synthesized complexes retained a modest affinity for the androgen receptors. The ferrocenyl derivatives of ethynyltestosterone showed a strong antiproliferative effect on hormone-independent prostate cancer cells PC-3 with IC50 values of 4.7 lM – these results were slightly better than those found for the most active ferrocenyl derivative of nonsteroidal antiandrogen nilutamide (with an IC50 value of 5.4 lM). The complexes (C5H4I)Re(CO)3 and (C5H4I)Mn(CO)3, as shown in Scheme 33, were more reactive than their iodoferrocene counterpart. A similar result was obtained when Stille coupling (Scheme 34) was carried out with 17a-(tributylstannylethynyl)estradiol [84]. New steroidal 17-diazines (17-pyrazine and 17-pyrimidine) were rationally synthesized employing Stille cross-coupling of 17-iodoandrosta-5,16-dien-3b-ol with tributylstannyl diazines as a key reaction (Scheme 35) [85]. The synthesis started from dehydroepiandrosterone, which was converted to the correspond-

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OH H

SnBu3

nBu3SnOMe 130 °C, 5 h, 56%

O

O

OH

Pd(MeCN)2Cl2, DMF rt, 3 h

MLn MLn = Re(CO)3 (90%) Mn(CO)3 (75%) FeCp (36%)

I MLn

O

Scheme 33. Synthesis of 17a-ethynyltestosterone organometallic androgen receptors.

OH

OHC

MLn

CHO MLn OH

I

(S)

(R)

HO

SnBu3

MLn = (R)-Re(CO)3 (30%); (S)-Re(CO)3 (50%) (R)-Mn(CO)3 (68%); (S)-Mn(CO)3 (43%) (R) or (S) FeCp (0%) OHC OH

Pd(MeCN)2Cl2, DMF rt, overnight

I HO

CHO

MLn

MLn (R) (S)

HO

Scheme 34. Synthesis of o-formylcyclopentadienyl metal complexes of 17a-ethynylestradiol.

N N

O

I

(2-tributylstannyl)pyrazine Pd(PPh3)4

2 steps

DMF, 120 °C, 20 h, 15%

N

HO

N

dehydroepiandrosterone

(5-tributylstannyl)pyrimidine Pd(PPh3)4 DMF, 120 °C, 20 h, 15%

Scheme 35. Syntheses of steroidal 17-diazines (17-pyrazine and 17-pyrimidine).

501 502 503 504

ing 17-hydrazone by treatment with hydrazine hydrate and hydrazine sulfate in ethanol [86]. The steroidal hydrazone was reacted with iodine in the presence of 1,1,3,3-tetramethylguanidine yielding the vinyl 17-iodide. The following palladium-catalyzed

cross-coupling reactions of the resulting D16 steroids with 2-(tributylstannyl)pyrazine or 5-(tributylstannyl)pyrimidine proceeded to give 3b-hydroxy-17-(pyraz-2-yl)-androsta-5,16-diene and 3b-hydroxy-17-(pyrimid-5-yl)-androsta-5,16-diene, respectively.

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N

method A

COOEt

toluene, 100 °C, 8 h, 82%

45%

H

COOEt N

I

N

16 COOEt

H

N Pd(PPh3)4 toluene, 100 °C, 6 h

H

N one-pot procedure

method B

COOEt

H 46-51%

COOEt

+

toluene, 100 °C, 8 h

COOEt N

H +

N

16 H

COOEt , N method C

COOEt

H

N

SnBu3

11-20%

Pd(PPh3)4

COOEt toluene, 100 °C, 6-30 h

Scheme 36. Syntheses of [16,17-c]-10 ,20 ,30 ,60 -tetrahydro-10 ,20 -pyridazines.

Br

N

Bu3SnCH=CH2, Pd(OAc)2, PPh3, Et3N

N

O

N

H2/(PPh3)3RhCl benzene, 40 °C, 6 h, 75%

95 °C, 24 h, 43%

O Me

O Me

Me

Scheme 37. Synthesis of 8-ethyl-4-methyl-2,3,5,6,-tetrahydro-(1H)-benzo[c]quinolizin-3-one – a potent 5a-reductase 1 inhibitor.

C8H17

NC C8H17

H

42%

NC Bu3SnCH=CH2 Pd(PPh3)4, LiCl

H

THF, 75 °C, 2 h, 98%

NC

H

CN

H

C8H17

+

toluene, 110 °C, 12 h

OTf NC H NC

H 23%

Scheme 38. Synthetic route to tricyclic dinitriles.

509 510 511 512 513 514 515 516 517 518 519 520 521

The low yields of these two transformations may be due to instability of the stannyldiazine reagents under the reaction conditions that were employed. Three different methods (Scheme 36) of the synthesis of new steroidal [16,17-c]tetrahydropyridazine derivatives have been presented recently [87]. 16a- and 17b-isomer mixtures were obtained by consecutive Stille coupling and the hetero-Diels–Alder reaction. 17-Iodo-5aandrost-16-ene was first reacted with vinyltributyltin in the presence of Pd(PPh3)4 and then with diethyl azodicarboxylate to produce tetrahydropyridazines (method A). An inseparable mixture of two isomers in an approximate 2:1 ratio was also formed in a one-pot procedure (method B). Even the Lewis acid (AlCl3, ZnCl2) catalysis did not alter the stereoselectivity of cycloaddition. Unfortunately, the domino reac-

tion (method C) turned out to be the least efficient, which can be explained by partial deactivation of the catalyst as a result of the coordination of dienophile to palladium. However, the one-pot reaction could effectively be used for the conversion of other steroidal 17iodo-16-enes to the corresponding tetrahydropyridazines, e.g., compounds with the lactam A-ring. New 5a-reductase 1 (5aR-1) inhibitors evaluated as a potent drug in a treatment of diseases such as acne and alopecia in men and hirsutism in women were synthesized using the Pd-catalyzed cross-coupling process [67]. It was proven that a more planar overall structure of 19-nor-10-azasteroids, lacking the D ring and with a benzene ring incorporated in place of the C ring, makes compounds such as benzo[c]quinolizin-3-one derivatives selective

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R1

H

+

R2

X

base

R1

R2

Scheme 39. Sonogashira reaction.

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and in some cases competitive inhibitors of 5aR-1. The Stille crosscoupling reaction (Scheme 37) was exploited for the introduction of a small-sized lipophilic group into position 8 in 8-bromo-4methyl-2,3,5,6,-tetrahydro-(1H)-benzo[c]-quinolizin-3-one, employing tributylvinylstannane as the nucleophilic reagent in the presence of Pd(OAc)2 and PPh3 in anhydrous Et3N. The subsequent selective hydrogenation of the vinyl moiety, leaving the enaminone moiety unaltered, was achieved by using the Wilkinson catalyst. The synthesis of isomeric tricyclic dinitriles (Scheme 38) showing cytotoxic activities on human leukemia HL-60 cells was described by Mayer [88]. First, vinyl triflate, readily obtained from Grundmann’s ketone, was reacted with vinyltributyltin in the presence of tetrakis(triphenylphosphine)-palladium(0) and lithium chloride to obtain 1,3-diene in excellent yield. The Stille reaction was followed by [4+2]-cycloaddition which led to a trans-dinitrile as a separable 2:1 mixture of the isomers. The obtained compounds demonstrated completely different cytotoxicity. While the bottom compound (Scheme 38) was completely inactive, its isomer, the top one, showed an interesting IC50 value of 12 lM.

555

5. Sonogashira coupling

556

The Sonogashira cross-coupling reaction has been recognized as very useful in the formation of carbon–carbon bonds [89] and has

557

been employed in a wide variety of areas. The coupling is performed between terminal alkynes and aryl or vinyl halides or pseudohalides (e.g., OTf), using a palladium catalyst, a copper(I) salt co-catalyst, and an amine base (Scheme 39). The reactions do not need rigorous conditions to occur, that is why they can be applied to the synthesis of complex molecules [90–92]. Nevertheless, in most cases this transformation requires anhydrous and anaerobic conditions because the copper acetylides undergo homocoupling if exposed to air [93], but occasionally it shows its utility in aqueous media and under aerobic conditions [94]. Sonogashira coupling can be completed at room temperature and using a mild base. The palladium catalyst, Pd(PPh3)2Cl2 in original, is often replaced by Pd(PPh3)4, Pd(OAc)2, NaPdCl4, Pd(MeCN)2Cl2, PdCl2, and PdI2 and can be combined with phosphines (e.g., PtBu3, PCy3) to increase the efficiency of the reaction. For this purpose the copper(I) co-catalyst is also changed (for e.g., Ag2O) [95]. The Sonogashira cross-coupling reaction has been successfully adopted to the four-step synthesis of aminosteroid derivatives [96], an important subclass of steroids that display interesting biological properties which are mostly used in the area of anesthesia [97,98]. The compounds were obtained in good overall yields and diastereoselectivities. The Sonogashira reaction proceeded between appropriate haloaldehyde and trimethylsilylacetylene in the presence of Pd(dppf)Cl2 and CuI as catalysts, in a mixture of anhydrous Et3N and THF (Scheme 40). This step was followed by the addition of an allylzinc reagent to Ellman’s tert-butylsulfinimine and completed with the Pauson–Khand reaction of homoallylic amine, bearing a pendant triple bond in its carbon backbone to construct the cyclopentenone ring. Modified Sonogashira reactions have been employed in the synthesis of ferrocene-labeled steroids exhibiting many interesting features, e.g., liquid crystalline properties [99] or even antitumor O S

O

O

tBu H

HN TMS

O X

R

TMS H Pd(dppf)Cl2, CuI

1) (R)-tBuSONH2 Ti(OEt)4, CH2Cl2, 12 h

Et3N/THF, 80 °C

2)

TMS

ZnBr

THF, -60 °C, 3 h R 3) Co2(CO)8 toluene, rt then 80 °C

R

(a) R = H, X = I (b) R = OMe, X = Br

(a) R = H, 51 %, > 20:1 dr (b) R = OMe, 28 %, 15:1 dr

Scheme 40. Application of the Sonogashira cross-coupling reaction to the synthesis of amino steroid derivatives.

OH

OH

or

or O HO O

OH R I

+

O

Fe

OH

O

Pd(PPh3)2Cl2/CuI CO (1-25 bar)

Fe

THF, Et3N, 60 °C 12-20 h, 27-66%

R = Me or Et

Scheme 41. Palladium-catalyzed carbonylative Sonogashira coupling of steroids with iodoferrocene.

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OTHP

O O 5 steps 69%

8

H

H 8 Grubbs 1st gen. cat. CH2Cl2, reflux 16 h, 55% TBSO

Estrone TBSO

OTHP H

COOMe I CuI, Et3N, Pd(PPh3)4

10

1. H2, 10% Pd/C, EtOAc, rt, 16 h 2. LDA, TMSCHN2 THF, -78 °C, 1 h then reflux, 3 h 59%

NHBoc

benzene, 40 °C, 3 h, 95%

TBSO NH2 NHBoc

OTHP

R OTHP

12

COOMe

10

1. Deprotection 2. Hydrogenation 3. Hydrolysis or reduction

(a) R = COOMe (b) R = COOH (c) R = CH2OH

HO

Scheme 42. Synthesis of simplified substrate/cofactor hybrid inhibitors of type 1 17b-hydroxysteroid dehydrogenase EM-1745.

OH I

Epiandrosterone

, Pd(PPh3)4

I

1. Protection

CuI, DIEA, THF 40 °C, 1 h, 48%

2. HC C Mg Cl, THF, rt, 22 h, 71%

TBSO H

OH

OH TBSO

O

O

1. Deprotection 2. Mitsunobu esterification 3. Ring-closing metathesis 27% over 3 steps

O

O

TBSO OH

OH E/Z = 1:1

Scheme 43. Synthetic route to macrocyclic molecular rotors derived from epiandrosterone.

590 591 592 593 594 595 596 597 598 599 600 601 602 603

activity (Scheme 41) [100]. The carbonylative coupling of ethynylsteroids and iodoferrocene was carried out in the presence of the most widely used Pd(PPh3)2Cl2/CuI catalytic system. Furthermore, moderate CO (1, 15 or 25 bar) pressures have been used in order to convert iodoferrocene into alkynyl ketones and to avoid homo-coupling of the terminal acetylene reaction partner. It should be mentioned that the absence of the CuI co-catalyst and the use of higher CO pressure resulted in lower yields [101]. The Sonogashira coupling reaction was also applied in the efficient and convergent synthesis of simplified substrate/cofactor hybrid inhibitors of type 1, 17b-hydroxysteroid dehydrogenase EM-1745 [102,103]. Poirier developed a new approach for this purpose involving a cross-metathesis and a cross-coupling reaction as key steps. Estrone was converted into 3-tert-butyldimethylsilyl-

oxy-17b-(tetrahydro-2H-pyran-2-yl-oxy)-16b-allyl-estra1,3,5(10)-triene [104] and was then reacted with 10-undecenal in the presence of Grubbs first generation catalyst (Scheme 42). Hydrogenation followed by treatment with LDA and trimethylsilyl-diazomethane provided a terminal alkyne ready for Sonogashira coupling. This step was performed with aryl iodide using Pd(PPh3)4, CuI, and Et3N and gave the desired product in an excellent 95% yield. Cleavage of all three protecting groups in acidic solutions and hydrogenation of the alkyne, followed by hydrolysis or hydride reduction, allowed to obtain the designed hybrid inhibitors. On the other hand, Tietze and his group applied the Sonogashira cross-coupling reaction in the syntheses of estrogen analogs containing different substituents at rings A and D by using the Pd(PPh3)4, CuI, and iPr2NH catalytic system [105,106].

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R

O

O

I2, DMAP, Py, CCl4

Pd(PPh3)4, CuI 1-Alkyne, DIEA

rt, 15 h, 93-98%

HO

O

THF, reflux, 4 h 92-93%

HO

HO

H

H

H (a a) 3α-OH, 5β-H, R =

(a a) 3α-OH, 5β-H (b b ) 3β-OH, 5α-H

OH

(b b ) 3β-OH, 5α-H, R = OH

Scheme 44. Synthesis of 21-alkynyl-18,21-cyclodinorchol-18(21)-en-20-ones.

R O

OTf

PhN(Tf)2, KHMDS THF, -78 °C, 2 h

1-Alkyne Pd(PPh3)4, AgOAc, DIEA DMF, rt, 30 min

97-98%

86-98%

R=

OH

OH

,

or

OCH3

Scheme 45. Pd(PPh3)4/AgOAc-catalyzed preparation of 17-alkynylsteroids through corresponding triflates.

Br

Br

O

HC C-CH2-OTBS Pd(PPh3)2Cl2

HN

4 steps 49%

Et3N, DMF, 65 °C 75%

O

Br

HN

TBSO

O

O

O

HO 1. H2, Lindlar's cat. CH2Cl2, rt, 95%

HN

1. MsCl, Et3N CH2Cl2

2. HF-Py, THF, rt, quant.

O O

N

2. NaH, THF 40% over 2 steps

O O

Scheme 46. Synthesis of the azaviridin analog from 3,4-dibromofuran via the furanoquinolone intermediate.

618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635

Research groups from Mexico and Poland also reported the possibility of using this method in the synthesis of macrocyclic molecular rotors, linked by the D rings with triple bonds at their C17 positions to a 1,4-phenylene rotator, which can potentially be used in optoelectronics [107]. This synthesis was started with 3b-hydroxy-5a-androstan-17-one, which was first protected as the tert-butyldimethylsilyl ether and then reacted with ethynylmagnesium chloride to stereoselectively afford 17a-ethynyl-17bol (Scheme 43). A subsequent reaction of the product with 1,4-diiodobenzene following the Sonogashira protocol using Pd(PPh3)4, CuI, and DIEA as a base yielded an acyclic dimer in 48% yield. After removing the silyl-protecting groups with tetrabutylammonium fluoride, Mitsunobu esterification of the hydroxyl groups at C3 with inversion of configuration was carried out using 3-butenoic acid, diethyl azodicarboxylate, and triphenylphosphine. The final ring-closing metathesis in the presence of Grubbs second generation catalyst afforded an E/Z diastereoisomeric mixture in a ratio of ca. 1:1 due to the nonstereoselective course of this reac-

tion. The molecular rotors were separated and their dynamics were studied. Straightforward and efficient two-step syntheses of a series of conjugated alkynyl 18,21-cyclo-dinorcholenones were described by Wang et al. in 2011 [108]. 22-Iodo-18,21-cyclodinorcholenones were prepared from 18,21-cyclodinorcholenones with I2/DMAP/ pyridine. Sonogashira cross-coupling reactions of these compounds and appropriate 1-alkynes catalyzed by Pd(PPh3)4, CuI in the presence of DIEA were carried out in high yields (80–94%). The obtained products showed measurable anticancer activity against the KB, HeLa, MKN-28, and MCF-7 cell lines that were tested. Scheme 44 presents selected structures of obtained 22-alkynyl-18,21-cyclodinorcholenones. A year earlier, Wang revealed a novel and operationally simple coupling reaction for highly efficient synthesis of D-ring unsaturated 17-alkynylsteroids by employing 17-steroidal triflates and alkynes using a new Pd(PPh3)4/AgOAc catalytic system in the presence of DIEA in DMF (Scheme 45) [109]. First, treatment of ste-

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OH

R

OH R I

COOH

Et3N, MeCN, 50 °C, 20 h

H H

H

H

Pd(PPh3)4 (10 mol%) CuI (10-20 mol%), 60-78%

HO

H HO

O H

O

R = H, Me, Ph, C6H4Ph

Scheme 47. Formation of c-alkylidene butenolides from 17-ethynylestradiol.

O

O

R

, 100 °C

Pd(PPh3)4, CuI, piperidine, dioxane, water or Pd(PPh3)4, AgCl, piperidine, dioxane, water, Bu4N+Br-

MeO Br

MeO

95-100%

R = Ph or CH2OH R

Scheme 48. Alkynylation of 6-bromo-3-methoxyandrosta-3,5-dien-17-one with terminal acetylenes.

1. Br

OH

NBoc N

NH

OH

NBoc

N

NH

O

O

(H3C)3C O O Pd(OAc)2, PPh3, CuI DIPA, 2 h, 55 °C, 94% 2. TFA, CH2Cl2 50 min, rt, 86%

HO

(H3C)3C

HO ReBr(CO)3(H2O)3, NaHCO3 EtOH/H2O 3 h, rt, 95%

OH NH NH N OC Re OC OC O

OH

O

NH NH N OC Re OC OC O

H2/Lindlar's cat. EtOH 12 h, rt, 70%

O OH

NH NH N OC Re OC OC O

H2/10% Pd/C EtOH 4 h, rt, 98%

HO

O

Scheme 49. Synthesis of estradiol complexes.

654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670

roid-17-ones with PhN(Tf)2 and KHMDS in dried THF at 78 °C for 2 h gave the corresponding steroidal 17-triflates in high yields (97–98%), and the following Sonogashira coupling of these compounds with various 1-alkynes yielded the desired D-ring unsaturated 17-alkynyl steroids (86–97%). Interestingly, the applied catalyst arrangement proved to be better for vinyl triflates than for aryl triflates. This general approach provides high yield access to D-ring unsaturated 17-alkynylsteroids that are key intermediates for the preparation of some biologically important steroids with a modified side chain. Another type of synthesis including the Sonogashira coupling step was described by Wright [110]. He designed a new class of non-natural furanosteroids which were more chemically stable analogs of viridins, i.e., potent inhibitors of phosphoinositide-3kinases. The synthesis of azaviridins entails replacement of the C10 quaternary carbon with a nitrogen atom. The starting 3,4-dibromofuran was converted in four steps to bromofuranoquinolone

in good overall yield (Scheme 46). The Sonogashira coupling reaction of this compound with a protected propynyl alcohol using Pd(PPh3)4/Et3N led to alkyne, which was converted to the allylic alcohol through reduction and deprotection. The final ring closure was achieved in moderate yield by initial conversion to highly labile mesylate followed by a reaction with sodium hydride. c-Alkylidene butenolides bearing a steroid moiety were synthesized by the stereoselective sequential cross-coupling lactonization procedure from functionalized terminal alkynes and 3-iodopropenoic acid derivatives (Scheme 47) [111]. For the reaction of 17-ethynylestradiol with various 3-substituted 3-iodopropenoic acids, a catalytic system Pd(PPh3)4/CuI/Et3N in acrylonitrile was employed with different amounts of CuI. In general, the yields were better when a higher amount of Cu(I) salt was used. Lukashev announced an efficient method for the synthesis of 6-alkynyl-substituted androstane derivatives in which the tradi-

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OH

OH

I Pd(PPh3)2Cl2, CuI, CsCO3 THF/H2O (25:1) 24 h, reflux, 35%

HO

HO

Scheme 50. Synthesis of 17-(9-m-carboranylethynyl)estra-1(10),2,4-triene-3,17b-diol.

OH OHC

2'

Mn(CO)3 CHO I Mn(CO)3 OH

(S)

HO Pd(PPh3)2Cl2, Cu(OAc)2 H2O DIPA, reflux, 2h

(R) 45%

CHO OH

5'

I

Mn(CO)3

HO

CHO Mn(CO)3 (R)

(S) 45%

HO

Scheme 51. Application of the Sonogashira cross-coupling reaction in the synthesis of hormone complexes bearing a disubstituted cymantrene group.

Fe

TfO

C

CH

Pd(PPh)4, CuI, Et3N DMF, rt, 24 h, 87% or Pd(PPh)2Cl2, CuI, DIPA DMF, rt, 24 h, 65%

Fe =

Fe

Scheme 52. Cross-coupling reaction between cholesta-3,5-dien-3-yl triflate and ethynylferrocene.

688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706

tionally used CuI co-catalyst in the Sonogashira coupling reaction was replaced by AgCl (Scheme 48). The exchange showed an increase in activity of this catalytic system [112]. Also, different Pd-catalysts were tested for these transformations. A further boost in reactivity was achieved by the addition of 40 mol% Bu4N+Br, thus providing complete conversion of the starting halide. In 2006 Arterburn et al. reported syntheses of a new class of tridentate pyridin-2-yl hydrazine Re/99mTc chelates that exhibit strong binding affinity to the estrogen receptors, GPR30 and ERa/ b, and evaluated intracellular binding with a functional cell-based receptor-mediated signaling assay [113]. The exploited Sonogashira cross-coupling reaction (Scheme 49) performed in the presence of Pd(OAc)2/PPh3/CuI in Et2NH on the protected chelate with 17aethynylestradiol, followed by deprotection and Re(CO)+3 labeling gave a linear alkyne complex in a high 95% yield. The following stereospecific hydrogenation using Lindlar’s catalyst produced a complex containing (Z)-ethene linkage in 70% yield, whereas hydrogenation with Pd/C gave a saturated alkane-linked complex in 98% yield.

Syntheses of carborane-containing steroids in which the carborane fragment is linked to the steroid skeleton through an acetylene bridge were reported by Beletskaya et al. [114]. Sonogashira cross-couplings of 2-iodo-p-carborane and 9-iodo-m-carborane with ethynyl derivatives of steroids gave carboranylethynylsubstituted estrogens and androgens, e.g., the reaction of 9-iodom-carborane with 17a-ethynylestradiol under classical reaction conditions yielded the corresponding carboranylethynyl estradiol derivative (Scheme 50). It is noteworthy to mention that boiling aqueous THF and using cesium carbonate as a base was applied to avoid decomposition of the carborane polyhedron, even so the yield of the final product was fairly moderate (35%). 17a-Ethynylestradiol was also used in the synthesis of (S) and (R)-17a-(20 -formylcymantrenylethynyl)estradiol by Sonogashira cross-coupling (Scheme 51). The reaction occurred between ethynylestradiol and optically pure (S)- and (R)-1-formyl-2-iodocymantrenes [115]. In the article the authors presuppose the tethering of a planar chiral organometallic moiety of ethynylestradiol in view of further application in breast cancer treatment. For this

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OH

11 11

CH3

CH3I N

N

(a) Pd(PPh3)4/CuI/ CH3CN, 10 min, 80°C, 4-6% (b) Pd(PPh3)4/Ag2O MeO THF, 10 min, 80°C, 4% (c) Pd(PPh3)4/TBAF THF, 10 min, 80°C, 0.4% (d) Pd2(dba)3/AsPh3/ TBAF THF, 3 min, 60 °C, 49—64%

MeO

Scheme 53. Pd-catalyzed cross-coupling of mestranol with [11C]methyl iodide.

18

OH

OH

18F

F

I

Pd(PPh3)4/CuI/Et3N THF, 20 min, 110°C

RO

RO

R = H, 65—88% R = Me, 34—64%

Scheme 54. Sonogashira cross-coupling of 17a-ethynylestradiol or mestranol with 4-[18F]fluoroiodobenzene.

OH

H

Pd(PPh3)2Cl2, CuI, Et2NH, DMF MW: 300W, 120 °C, 5 min, 98%

2 steps 6% H

H

OTf

HO

NC

Scheme 55. Synthesis of bicyclic nitrile as a potential drug against human leukemia HL-60 cells.

726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751

purpose the coupling reaction was performed in diisopropylamine in the presence of PdCl2(PPh3)2 and Cu(OAc)2 monohydrate, and both products were obtained in moderate yields (45%). Since some ferrocene labeled compounds (e.g., oligonucleotides) have emerged as important, versatile tools for the development of bioelectronic gene-sensing systems, a coupling of ethynylferrocene with a steroid derivative was attempted by Coutouli-Argyropoulou [116]. The synthesis of 3-(2-ferrocenylethynyl)cholesta-3,5-diene was carried out by the Sonogashira coupling reaction (Scheme 52). In this regard two methods were employed in which Pd(0) and Pd(II) were used with different bases. The 3-(2-ferrocenylethynyl)cholesta-3,5-diene was obtained in 87% and 65% yields, respectively. A Sonogashira-like coupling reaction of terminal alkynes, such as mestranol, with [11C]methyl iodide was studied [117]. The elaborated method can be utilized in positron emission tomography (PET), imaging techniques in nuclear medicine and drug research to produce 11C-labeled radiotracers. Several reaction conditions for sufficient palladium-catalyzed cross-coupling of mestranol with [11C]methyl iodide were tested (Scheme 53). The classical conditions of the reaction could not be applied for cross-coupling with [11C]MeI since it was immediately consumed by the amine base that was used (e.g., Et3N). In order to circumvent this problem, an alternative non-nucleophilic base was used, namely 1,8bis(dimethylamino)naphthalene, which is known to withstand alkylation even under harsh reaction conditions. However, only

less than 6% of the product was obtained. Second, silver(I) oxide or tetrabutylammonium fluoride were employed as activators. Again the yields were poor. Then Pd2(dba)3 as the Pd(0)-source and AsPh3 as a more readily dissociating co-ligand were used. These reaction conditions proved to be crucial, as the product was obtained in 49–64% yield. For the same purpose a similar strategy was adopted in the synthesis of 17a-(4-[18F]fluorophenyl)ethynyl-substituted steroids (Scheme 54) [118]. The cross-coupling reactions were performed between 17a-ethynyl-3,17b-estradiol and 17a-ethynyl-3-Omethyl-3,17b-estradiol with 4-[18F]fluoroiodobenzene, at 110 °C for 20 min using THF as a solvent and triethylamine as a base. These transformations gave products in yields up to 88%. Synthesis of a bicyclic nitrile as a novel seco-steroid that was tested for its cytotoxic activity on human leukemia HL-60 cells was described by Mayer [88]. First, Grundmann’s ketone, a common building block for introduction of the CD ring pattern of steroids, was easily converted into vinyl triflate and then coupled under Sonogashira conditions with but-3-yn-1-ol using bis(triphenylphosphine)-palladium(II) dichloride in the presence of CuI (Scheme 55). The resulting acetylenic alcohol was mesylated and converted to the pent-4-ynenitrile derivative with sodium cyanide. However, the desired product was obtained in a poor overall yield. Ultimately, mononitrile showed only very low antitumor activity, even weaker than that of the starting acetylenic alcohol.

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HN

O

Ph 4 steps 6%

Br

Ph N

N

Pd(PPh3)2Cl2, CuI, Et3N

N

H2, Pd/BaSO4, Py rt, 16 h, 89%

reflux, 6 h, 31%

O

O

O

Me

Me

Me

Scheme 56. Synthetic route to 8-Z-styryl-4-methyl-2,3,5,6,-tetrahydro-(1H)-benzo[c]-quinolizin-3-one.

R1 MX1 +

R 2 X2

Pd or Ni catalyst

R1 R2

Scheme 57. Negishi and Kumada reactions: M = Zn (Negishi) or Mg (Kumada).

778 779 780 781 782

19-Nor-10-azasteroidal 5a-reductase inhibitors were obtained by varying the group at position 8 using the Sonogashira protocol [67] since their potency was found to be dependent on the presence and bearings of double bonds on the A ring and on the type and number of substituents located at positions 1, 4, 5, 6, and 8

[119]. Starting from commercially available 3,4-dihydroquinolin2(1H)-one (Scheme 56), 8-bromo-4-methylbenzo[c]quinolizin-3one was obtained in four steps in 6% overall yield. Then a lipophilic substituent was placed in the C ring by the Sonogashira coupling reaction. The 8-bromo-substituted compound was reacted with phenylacetylene using Pd(PPh3)2Cl2/CuI as a catalyst and Et3N as a base and solvent. The alkynyl derivative was obtained in 31% yield and then hydrogenated over Lindlar’s catalyst to afford the Z-alkenyl derivative in a satisfactory yield.

O

O

RCH2ZnBr Pd(PPh3)2Cl2, DMF, 20 oC

O

O Br R

R = Ph (88%) R = 2-ClC6H4 (85%) R = 4-MeC6H4 (95%) R = 2-MeOC6H4 (84%) R = Me3Si (94%)

R

I

RCH2ZnBr Pd(PPh3)2Cl2, DMF, 20 oC

O

R = Ph (83%) R = 2-ClC6H4 (70%) R = Me3Si (98%)

O

Scheme 58. Alkylation of halogen-substituted steroids with organozinc compounds.

R1 R1 H H

1. Pd(PPh3)4, Et3N, -40 oC, rt., THF

BrZn

R2

+

2. nBu4NF, THF

R2 TfO

HO TIPSO

OTIPS

OH

70% (R1 = H, R2 = H) 76% (R1 = H, R2 = CH3) 76% (R1 = OMOM, R2 = H)

Scheme 59. Synthesis of vitamin D3 analogs by the tandem cyclization-Negishi coupling process.

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OTf Ph 1. MOMCl, DIEA, DMAP, DCM, rt

PhMgBr, Pd(PPh3)4, THF, 25-50 oC

2. PhN(Tf)2, KHMDS, THF, -78 oC

HO

88%

MOMO H

H

97%

5% HCl, THF, rt

17-phenyl-5α-androst-16-en-3α-ol (98%)

Scheme 60. Synthesis of 17-phenyl-5a-androst-16-en-3a-ol by Kumada coupling.

R

X

R

Pd catalyst

Nu

R

Nu

Pd'' X = OAc, Cl, OC(=O)OR', etc.

X

π-allyl complex Scheme 61. Tsuji–Trost reaction.

OtBu

1. KHMDS, BEt3 Cl

OH

H

H

H

2. Cl Pd(PPh3)4

Cl

OtBu

O

O

H

H

H

88%

O

OH

H

H

OtBu H 1. KHMDS, BEt3 Br 2.

H

Pd(PPh3)4

H O

H

H 82%

O

Scheme 62. Palladium-catalyzed alkylation of Hajos-Parrish indenone to construct the rearranged steroid ring systems.

792

6. Negishi and Kumada coupling reactions

793

Negishi and Kumada couplings are the other versatile palladium- or nickel-catalyzed C–C bond forming reactions (Scheme 57). Since their discovery [120–123], the scope and conditions of these methods have been widely developed, thus making them some of the most powerful tools available to organic chemists [124,125]. They have also been found to be useful in steroid synthesis. Negishi coupling is a cross-coupling reaction involving an organozinc compound, an organic halide, and a nickel or palladium catalyst creating a new carbon–carbon covalent bond. When a Grignard reagent is used instead of the organozinc compound, the reaction is called Kumada coupling. The Negishi reaction of halogen-substituted steroids with benzyl- and alkylzinc halides has been studied by Latyshev (Scheme 58) [126], who developed a general procedure for the introduction of hydrophobic alkyl groups into positions 3, 6, and 17 of the steroid molecules. Recently, Negishi coupling has been applied to the synthesis of 1a,25-dihydroxyvitamin D3 and its analogs, 1a-hydroxyvitamin D3 and 1a-hydroxy-6-methylvitamin D3 [127,128]. The key step of the developed strategy was a Pd-catalyzed tandem cyclizationNegishi coupling process in which ring A and the triene unit of the vitamin D skeleton were constructed under mild conditions (Scheme 59).

794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815

In 2008 an efficient and simple protocol for preparation of the neurosteroid antagonist, 17-phenyl-5a-androst-16-en-3a-ol, from androsterone using palladium-catalyzed coupling of steroidal vinyl triflate and the Grignard reagent was elaborated by researchers from China (Scheme 60) [129]. The Kumada reaction performed under Pd(PPh3)4 promotion appeared to be superior as compared to the other Pd-catalyzed couplings, i.e., Suzuki, Stille, and Negishi reactions.

816

7. Tsuji–Trost reaction

824

The Tsuji–Trost reaction (also called Trost allylic alkylation) is a palladium-catalyzed substitution reaction involving a substrate that contains a leaving group in an allylic position (Scheme 61). The palladium catalyst first coordinates with the allyl group and then undergoes oxidative addition, forming the p–allyl complex. This complex can then be attacked by a nucleophile, resulting in the substituted product. To expand the structure–activity studies of neuroactive steroids acting at c-aminobutyric acid type A receptors, Covey et al. developed two new protocols for the synthesis of cyclopenta[b]anthracene and cyclopenta[b]phenanthrene neurosteroid analogs using stereo- and regioselective potassium enoxyborate alkylation in the presence of Pd(PPh3)4 as a key step (Scheme 62) [130].

825

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OPiv (MeOOC)2HC 3β

+

Ligand L PdCl2, NaCl, conc. HCl

NaCH(COOMe)2

rt, under CO

THF, rt

HO

Pd Cl

(MeOOC)2HC

2

65% (trans : cis = 3:1)

3α

65% (3β:3α = 1:99, L = PPh3) 64% (3β:3α = 1:99, L = PBu3) 38% (3β:3α = 4.1:1, L = dppe) 87% (3β:3α = 1:5.3, L = dppb)

Scheme 63. The ligand effect in a reaction of the steroidal g3-allylpalladium chloride dimer with malonate.

O

Pd2(dba)3, PPh3 HCOOH, Et3N, dioxane, reflux (49%) O

O

O

O

NHBoc

Ph

H

OH

O

O

OBz

H

OH

Scheme 64. The reductive Tsuji–Trost step of the synthesis of a new steroid as a potential mimic of antitumor taxoids.

R2 X R1

+

HN R3

R2

Pd catalyst N

base, ligand R1

Scheme 65. Buchwald–Hartwig amination.

839 840

841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857

858

8. Buchwald–Hartwig amination

861

During the last decade, the Pd(0)-catalyzed amination process has proven to be quite valuable due to the ease with which a variety of complicated N-containing heterocycles or carbocycles can rapidly be constructed in good yields utilizing mild reaction conditions. The development of the Buchwald–Hartwig reaction allowed for facile synthesis of aryl amines via palladium-catalyzed cross-coupling of amines with aryl halides (Scheme 65), thus replacing the harsher methods (the Goldberg reaction, nucleophilic aromatic substitution, etc.) to some extent. 3-Aminoestrone, a non-natural C-18 steroid, has been described as a key intermediate for the synthesis of biologically active steroid derivatives that can be used, for example, for the treatment of prostate and breast cancers. Poirier et al. [133] reported a new, efficient pathway starting with estrone triflate with Pd(0)-catalyzed amination as the key reaction. To introduce the nitrogen atom at position C3 of estrone, they used benzophenone imine as a convenient ammonia equivalent. In 2003 Zhang and Sui [134] reported the preparation of 3-aminoestrone by using benzylamine and slightly modified amination conditions [Pd(OAc)2, BINAP, and NaOtBu in toluene at 100 °C, 24 h]. However, the reaction resulted in a very low yield of the desired amino derivative due to the hydrolysis of triflate under alkaline reaction conditions. As a consequence, the authors

862

859 860

R3

X = I, Br, Cl, OTf, ONf R1, R2, R3 = alkyl, aryl, H

838

allowed to avoid the formation of 4,6-dien-3-one, which was formed as a by-product by dehydration of an intermediate allylic alcohol.

In 2008 Shimizu reported the effects of ligands in the palladium-catalyzed allylation of nucleophiles, such as active enolates. As a model system, a nucleophilic reaction of the steroidal g3-allylpalladium chloride complex prepared from an androst4-en-3b,17b-diol derivative with a malonate anion was chosen. The study showed that stereochemistry in the nucleophilic reaction of the g3-allylpalladium chloride dimer was dependent on the added phosphines; for example, the 3a-derivative was obtained in the presence of PPh3 in 65% yield, whereas the 3b-isomer was formed as the major product when the dppe ligand was used (Scheme 63) [131]. The new steroidal compounds bearing phenylisoserine and benzoate side chains of docetaxel, as potential mimics of antitumor taxoids, were readily obtained from 4-androstene-3,17-dione by a reductive Tsuji–Trost one-pot reaction [132]. The reductive Trost reaction was performed on steroidal 6a,7a-epoxide under standard conditions (i.e., with Pd2(dba)3, triphenylphosphine, formic acid, and triethylamine) to form the desired 7a-OH group in a regioselective manner (Scheme 64). The influence of the solvent on the reaction course was studied. Dioxane and THF were found to be the best solvents, as their usage

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O

NfF, Et3N

O

Pd(OAc)2, BINAP tBuONa, NH2R

HO

NfO

RHN H2, Pd/C

O

EtO

OEt

OH

1. MsCl, Et3N 2. PPA, toluene 3. NaBH4, MeOH 4. KOH, EtOH

N H

R = Bn, 65% R = H, 82% R = CH2CH(OEt)2, 57%

OH

+ N H

HN 58%; ratio 2:1

Scheme 66. Pd-catalyzed amination of estrone followed by Bischler indole synthesis.

O

O

HN

Br O

O

H

H

X H2N

X NH2

Pd(dba)2, BINAP

N H

tBuONa, dioxane, reflux

Br

Scheme 67. Synthesis of a macrocycle using Pd-catalyzed amination.

O Nu

I

+

CO

+ NuH +

Pd(0)

+ R3NHI

R3N

Nu = NR'R'' (aminocarbonylation), OR' (alkoxycarbonylation), OH (hydroxycarbonylation)

Scheme 68. Carbonylation of an iodoalkene functionality in the presence of various nucleophiles.

885 886 887 888

replaced triflate by the corresponding nonaflate, which possessed stronger stability toward base hydrolysis. The Buchwald–Hartwig amination of estrone triflate was later optimized with respect to the best phosphine ligand, Pd source, solvent, and other reaction

conditions. The three-step procedure using X-Phos as an optimal ligand afforded 3-aminoestrone with an overall yield of about 55% [135]. Applying the palladium-catalyzed amination of estrone nonaflate with NH2CH2CH(OEt)2 as an amine source afforded the corresponding 3-aminoestrone derivative, which was subjected to acid-catalyzed Bischler conditions (Scheme 66). Estrieno[2.3-b]pyrrole and its regio-isomer [3.4-c]pyrrole were obtained in a 2:1 ratio. Both steroidal indoles were further transformed to their 17b-OH derivatives. Palladium-catalyzed amination of bis(3-bromophenyl) ether of 5b-cholane-3a,24-diol with different polyamines leads to new macrocycles comprising one steroid and one polyamine fragments [48,136,137]. Attempts at synthesis of macrocyclodimers contain-

O O

a

O

b

RO H

H

MeOOC

c

H

MeOOC

H

R = Tf or Nf a) LDA, NfF or Tf2NPh, THF; b) CO, Et3N, Pd(OAc)2, PPh3, MeOH, DMF, 52 or 69%; c) H2, Pd/C

Scheme 69. Pd-catalyzed alkoxycarbonylation of 5a-pregnan-3-one derivatives.

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CONu

Pd(OAc)2, PPh3 CO, NuH

HO

HO CONu

I

Pd(OAc)2, PPh3 CO, NuH

MeO

MeO

CONu

I

Pd(OAc)2, PPh3 CO, NuH

MeO

MeO

NuH = amines, alcohols, water

Scheme 70. Carbonylation of vinyl 17-iodides in 13a-androstane, 13a-estrane, 13a- and 13b-D-homoestrane series.

O H

H

steps

H

I

+

I

H

H

H

H

H O

Pd(OAc)2, PPh3

NR'R''

NR'R'' H

O

HCOOH, Pd/C

+

CO, HNR'R'', Et3N, DMF, 48-77%

H

O

H

NR'R'' H

Scheme 71. Synthesis of 17a-methyl-16a-carboxamido-18-norandrostanes.

903 904

905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921

ing two steroid and two polyamine fragments have also been undertaken (Scheme 67).

9. Pd-catalyzed carbonylation, alkoxycarbonylation and aminocarbonylation The iodoalkene functionality undergoes various carbonylation reactions in the presence of amines, alcohols or H2O as an HX-type nucleophile. This allows for facile synthesis of the corresponding amides, esters or carboxylic acids, respectively. Alkenyl iodides may be replaced by other good leaving groups; and instead of tertiary amines, analogous phosphines may be used (Scheme 68). Steroidal 3-carboxylic acids were prepared from the corresponding 3-ketones by palladium-catalyzed alkoxycarbonylation using triflates or nonaflates as the leaving groups [138]. The alkoxycarbonylation reaction was followed by hydrogenation of the double bond and hydrolysis (Scheme 69). Steroidal 17b-carboxamides in the natural 13b series are 5areductase inhibitors. Transition metal-catalyzed homogeneous reactions (e.g., aminocarbonylations) have efficiently been used for functionalization of the steroidal skeleton. Both androstane

and estra-1,3,5(10)-triene carboxamides in the 13b series were obtained in high yields as reported earlier [7]. Also, 17-carboxamido-13a-androsta-5,16-dienes [139] and 17-carboxamido-13a-estra-1,3,5(10),16-tetraenes [140] can be synthesized in high yields by palladium-catalyzed carbonylations of the corresponding steroidal 17-iodo-16-ene derivatives (Scheme 70). As a surrogate of the analogous enol-triflate, the iodoalkene substrate is readily accessible from the corresponding 17-ketone via the 17-hydrazone. The high reactivity of the palladium-acyl intermediates allows for facile synthesis of steroidal 17-carboxamides. The palladium(0)-catalyzed reaction proved highly tolerant to the structural diversity of the amines, however, the highest reactivities were observed with sterically less hindered primary amines, including amino acids. Also, reactions with methanol (or water) worked better than with higher alcohols. Analogous 17-aminocarbonylation was also carried out in 13a- and 13b-D-homoestrane systems from the corresponding vinyl iodides [141]. While the aminocarbonylation reactions were practically completed in the 13b series in a reasonable reaction time, under mild conditions and in high isolated yields, the corresponding substrate of 13a-configuration has shown decreased reactivity resulting in moderate to low yields. However, under high

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NNH2

H2NNH2

O

H2NN O NR1R2

I

Pd(OAc)2, PPh3

I2, TMG

CO, HNR1R2

1 2

R RN

R1, R2 = H, tBu; H, CH(CH3)COOCH3; or -(CH2)5-

I O

Scheme 72. Synthesis of 3,17-dicarboxamido-androst-3,5,16-trienes via aminocarbonylation of the corresponding 3,17-diiodoandrost-3,5,16-triene derivative as keyintermediate.

CO2Et

I O NH2 , CO

H N

O

H N

N N

ferrocenyl azide, CuSO4, Na-ascorbate

N Fe

CH2Cl2, H2O, 77%

Pd(OAc)2, PPh3, Cs2CO3, dioxane, 64%

OH

Scheme 73. Synthesis of ferrocene labeled steroidal 17-carboxamides.

O H2N

I

+

CO

R

H N

R

Pd(OAc)2, PPh3

+ O

Et3N, dioxane 61-88%

OMe

O

R = phenyl or ferrocenyl

OMe

Scheme 74. Synthesis of steroid-b-lactam and steroid-b-lactam-ferrocene conjugates. 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967

carbon monoxide pressure, excellent yields can be obtained even in the 13a series. Similar aminocarbonylation of steroidal 11-iodo-9(11)-ene afforded 11-carboxamido-androst-9(11)-ene derivatives in moderate to high isolated yields [142]. Also, 12-carboxamido- and 12carboxy-11-spirostanes were synthesized from the corresponding 12-iodo-11-ene derivative by palladium-catalyzed carbonylation reactions under mild reaction conditions [143]. A mixture of steroidal 16-iodo-16-ene and 16-iodo-15-ene derivatives were obtained from the 16a,17a-epoxide in several steps (Scheme 71). Aminocarbonylation of the steroidal alkenyl iodides was carried out using different primary and secondary amines as nucleophiles. The products, 16-carboxamido-16-ene and 16-carboxamido-15-ene derivatives, were obtained in good yields [144]. The reduction of the above two unsaturated carboxamides resulted in the same product, 17a-methyl-16a-carboxamido18-norandrostane. 3,17-Dicarboxamido-androst-3,5,16-triene derivatives possessing various amine moieties were synthesized under mild conditions using palladium-catalyzed homogeneous aminocarbonylation as key reaction (Scheme 72). Compounds containing the corresponding iodoalkene functionalities, i.e., 17-iodo-16-ene and 3-iodo-3,5-diene structural motifs, were used in the amino-

carbonylation and the N-nucleophiles were varied systematically. Three amines, such as tert-butylamine, piperidine and methyl alaninate were used as N-nucleophiles in the aminocarbonylation. All variations of 3,17-dicarboxamides were synthesized using this methodology [145,146]. Different steroids with the 17-iodo-16-ene functionality were converted to ferrocene labeled steroidal 17-carboxamides via a two-step reaction sequence (Scheme 73) [147]. The first step involved the palladium-catalyzed aminocarbonylation of vinyl iodides with prop-2-yn-1-amine as the nucleophile in the presence of the Pd(OAc)2/PPh3 catalytic system. In the second step, the product N-(prop-2-ynyl)-carboxamides underwent a facile azide–alkyne cycloaddition with ferrocenyl azides in the presence of CuSO4/ sodium ascorbate to produce the steroid–ferrocene conjugates. Steroid-b-lactam and steroid-b-lactam-ferrocene conjugates were synthesized via palladium-catalyzed carbonylation of steroidal 17-iodo-16-enes in the presence of 3-amino-azetidin-2-ones (Scheme 74) [148]. 3-Amino-azetidin-2-one derivatives served as nucleophiles in the aminocarbonylation reaction. A set of new steroid dimers linked through D rings were synthesized [149] via catalytic diaminocarbonylation of 17-iodo5a-androst-16-ene in the presence of palladium–phosphine in situ prepared catalysts and aliphatic or aromatic diamines as N-nucleophiles (Scheme 75). Dimeric steroidal compounds con-

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O

O HN

NH

I

NH

NH

CO, Pd(OAc)2, PPh3

H H2 N

NH2 NH

NH

H

H

NH2

NH2

=

H2N

H2 N NH2

81%

NH2

95%

91%

48%

Scheme 75. Catalytic diaminocarbonylation of 17-iodo-5a-androst-16-ene.

OAc COOMe OMe

O

COOMe

O

O

MeOOC O

O

base, MeOH

HClaq, MeOH

CO, MeOH

O

O

Pd(MeCN)2Cl2, p-benzoquinone

O

or OAc

MeO

Scheme 76. Synthesis of spiro furanone via Pd(II)-mediated cyclization–carbonylation of propargylic esters.

O TfO

P R1 O

O

R2 H(O)PR1R2 Pd(OAc)2, dppp, DIEA dioxane, MW (19 - 52%)

O

O

Scheme 77. Pd-catalyzed phosphination under microwave irradiation. 992 993 994 995 996 997 998 999 1000 1001 1002

taining 17,170 -dicarboxamide spacers were obtained through highly chemoselective reactions in good yields. Oxidative cyclization–carbonylation of propargylic esters mediated by Pd(II) afforded cyclic orthoesters that were hydrolyzed into c-acetoxy-b-ketoesters (Scheme 76) [150]. When these intermediates were treated with a basic condition, Knoevenagel–Claisen type condensation took place, and spiro furanone derivatives were obtained in good yields. These reactions were applied in the synthesis of steroid derivatives with a spiro furanone fragment present in the vasorelaxant and bradycardiac active compounds.

1003

10. Miscellaneous

1004

The palladium-catalyzed coupling reaction was employed by Jiang et al. to introduce a phosphorus group onto the aromatic ring

1005

COOMe

COOMe HPPh2 Pd(OAc)2, K2CO3 DMF, 100 oC

P(O)Ph2

Scheme 78. Reaction of steroidal a,b-unsaturated esters with HPPh2.

of 11b-aryl-substituted steroids [151]. The best results of the phosphination reaction were obtained in the presence of Pd(OAc)2/ dppp/DIEA under microwave irradiation conditions (Scheme 77). The obtained products with phosphorus-containing aryl were evaluated for progesterone receptor (PR) antagonist activity. Hungarian researchers R. Skoda-Foldes and L. Kollar have also synthesized steroidal phosphine oxides by the sequence of Pd(OAc)2

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Br

R1

R2 NH2

R1 CHO

+

+

N Pd(OAc)2, PPh3, Na2CO3 Al2O3, MW (600 W), 10 min.

R2

AcO

AcO

Scheme 79. Multicomponent synthesis of steroidal D-ring fused substituted pyridines.

R Br

HS CHO

S Pd(OAc)2, PPh3, Na2CO3

+

DMF, 120 oC

H2N

N

R 72% (R = H) 69% (R = Cl) 74% (R = CF3)

AcO

Scheme 80. Pd(OAc)2-catalyzed synthesis of steroidal benzo[b][1,4]thiazepine.

OH O N

H

N

Pd(OOCCF3)2, NaOAc (EtO)2CO/H2O (1:1), 50 bar, 8% O2/N2, 100 oC

mol% catalyst 1% 5%

O

yield 25% 100%

O

N

N

Pd(OOCCF3)2, NaOAc (EtO)2CO/H2O (1:1), 50 bar, 8% O2/N2, 100 oC

HO

O

59%

Scheme 81. Aerobic oxidation of nandrolone and 3a-hydroxy-5a-pregnan-20-one in the presence of a palladium catalyst.

1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031

and base-catalyzed addition of HPPh2 to the C–C double bond of a,bunsaturated steroidal esters followed by autoxidation (Scheme 78) [152]. The desired 16a-phosphinyl-17b-methoxycarbonyl derivatives were formed stereoselectively and isolated in moderate to good yields. Because the addition of diphenylphosphine oxide under the same conditions resulted in the formation of the same products, an inverted order of transformations (oxidation–addition sequence) could also be considered. In 2013 the palladium-catalyzed multi-component synthesis of steroidal A- and D-ring fused pyridines was described by scientists from India [153]. A solvent-free three-component reaction of steroidal b-halovinyl aldehyde, alkyne and benzylamine in the presence of Pd(OAc)2 under microwave irradiation led to the target steroidal pyridine in high yield (Scheme 79). It is worth noting that all of the reactions of b-bromovinyl aldehydes with unsymmetrical alkynes and benzylamine afforded only one regioisomer of the pyridine derivative. A wide variety of alkyl-, aryl- and ester-substituted alkynes underwent this highly regioselective reaction to give good yields of the desired steroidal pyridines.

Similarly, steroidal b-bromovinyl aldehydes in the presence of Pd(OAc)2 reacted with various 2-aminothiophenols to afford steroid-fused benzo[b][1,4]hiazepines in good yields (Scheme 80) [154]. Apart from the above reviewed Pd-promoted reactions of steroids, Pd-catalyzed hydrogenation [155–158], deuteration [159], tritiation [160] and hydrogenolysis [161,162] are routinely and widely used in steroid synthesis. Recently, also selective aerobic oxidation of steroidal secondary alcohols, nandrolone and 3a-hydroxy-5a-pregnan-20-one, to corresponding ketones was reported (Scheme 81) [163]. The reaction proceeded in the presence of a catalyst formed in situ by a reaction of palladium(II) salts with the neocuproine ligand. It was shown that the active species was not the expected homogeneous Pd(II) complex but rather Pd nanoparticles stabilized by the neocuproine ligand and the co-solvent.

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11. Conclusion

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This review article compiled recent advances in homogeneous palladium catalysis involving steroids as substrates. The growing number of cross-coupling reaction types and different Pd-catalyzed steroid transformations has allowed chemists to carry out straightforward syntheses of complex steroid molecules and other natural products. Several steps in the conventional multi-step synthesis of a target compound may frequently be replaced by a single selective catalytic step, resulting in a large increase in the total yield. Pd-catalyzed reactions are chemo-, regio-, and stereoselective, and therefore they are widely used for the synthesis of biologically active compounds, i.e., pharmaceutically important steroids. Due to the rapid development of homogeneous catalysis, it is expected that synthetic methods employing Pd-catalyzed steroid transformations, including procedures for application in largescale syntheses, will become even more important in the years to come.

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Acknowledgments

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Financial support from the Polish National Science Centre (DEC2011/02/A/ST5/00459) is gratefully acknowledged.

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