Steroids 69 (2004) 1721

Are the 11-oxo-steroids really so hindered towards organometallic compounds?

Vincent Lecomte a , Elie Stphan a, , Jacqueline Vaissermann b , Grard Jaouen a
b

Laboratoire de Chimie organomtallique, Ecole Nationale Suprieure de Chimie et CNRS, 11 rue Pierre et Marie Curie, 75005 Paris, France Laboratoire de Chimie Inorganique et Matriaux Molculaires et CNRS, Universit Pierre et Marie Curie, 4 place Jussieu, 75252 Paris cedex 05, France Received 9 July 2003; received in revised form 16 September 2003; accepted 22 September 2003

Abstract Allylation of an 11-oxo-steroid, the protected adrenosterone, was studied to examine more closely the steric hindrance of such a ketosteroid. While the face exhibits, as well known, a strong steric hindrance, the side appears to be only relatively hindered. A high diastereoselectivity was observed in the addition of crotyl magnesium bromide. 2003 Elsevier Inc. All rights reserved.
Keywords: Allylation; Ketosteroids; Steric hindrance

1. Introduction The 11-oxo-steroids containing two angular methyl groups in positions 10 and 13 are relatively unreactive with nucleophiles [13]. However, we have shown that it is possible to add aryl and alkyl organolithiums to 1 under mild conditions. The preparation is simple and yields are often very good [4]. Steroids modied in position 11 command the interest of a number of groups worldwide [5] since this is a key position for modication of the biological activity of steroids; for example, to produce an antagonistic effect [6]. But modication of this position, with its sluggish reactivity remains a considerable synthetic challenge. It therefore seemed appropriate to examine more closely the steric hindrance of the 11-oxo-steroids. Allylation reactions are useful in this context. In fact, they can lead to a mixture of linear and branched-chain compounds, and the relative proportion of products formed allows assessment of the steric hindrance of the starting carbonyl compound [79]. To our knowledge, two allylation reactions of a 11-oxo-steroid in the pregnene series have been previously reported (reaction of allyl magnesium bromide [10] and prenyl magnesium bromide [11] with

cortisone-bismethylenedioxy-3-dioxolane). No example in the androstene series has been previously described. 2. Experimental NMR and 13 C NMR spectra were recorded on a 200 MHz Bruker AC 200 spectrometer. Chemical shifts are reported in ppm and referenced to the residual proton resonances of the solvent used. Infrared (IR) spectra were recorded by using a BOMEN MB spectrometer. Mass spectra were obtained on NERMAG R1010C apparatus. Melting points were determined with a Koer hot-stage apparatus and are uncorrected. Thin-layer chromatography (TLC) was performed on Merck silica gel 60 F 254. Silica gel Merck Gerudan SI (4063 m) was used for column chromatography. Elemental analyses were measured at the microanalysis laboratory of the Pierre et Marie Curie University (Paris, France). All solvents and reagents were puried when necessary using standard procedures. The 11-ketosteroid 1 was prepared as previously described [12] from the adrenosterone (Aldrich). The following methods were used for allylation of this steroid. 2.1. Method A
1H

Corresponding author. Tel.: +33-1-44-27-66-98; fax: +33-1-43-26-00-61. E-mail address: stephan@ext.jussieu.fr (E. St phan). e 0039-128X/$ see front matter 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.steroids.2003.09.009

Magnesium (1 mmol, 24.3 mg) was stirred with dry THF in a three-necked ask under argon. One drop of allyl bro-

18 Table 1 Results of the addition of 2ad to 1 Entry 1 2 3 4 5 RMgBr 2a 2b 2c 2c 2d Method A A A B A t (h) 0.7 1 1a 7.5 24

V. Lecomte et al. / Steroids 69 (2004) 1721

Conversion (%)b 100 (3a) 100 (3b) 0 0 23 (4d)

Yield (%)c 90 80 17

130.0, 137.6 ppm. IR (KBr): 3508 cm1 . MS (EI, 70 eV): m/z = 430 [M+ ], 412 [MH2 O+ ], 389, 368, 346, 327, 284, 99, 69, 55, 41. C26 H38 O5 (430.27): calculated C 72.53, H 8.90; found C 72.78, H 9.17 2.2.2. 11-Hydroxy-11-(1-methyl-prop-2-ene)-3,3,17,17(ethylenedioxy)-androst-5-ene (3b) White powder: mp 114 C, 80% yield (100% conversion); 1 H NMR (200 Hz, CDCl ): = 1.05 (s, 3H, C(18)-H), 3 1.08 (d, J = 6.7 Hz, 3H, C(20)-H), 1.29 (m, 2H), 1.23 (s, 3H, C(19)-H), 1.542.15 (m, 14H), 2.34 (dt, J = 3.4, 12.2 Hz, 1H), 2.62 (dq, J = 2.5, 14.3 Hz, 1H), 2.93 (dq, J = 6.8, 8.8 Hz, 1H, C(20)-H), 3.803.98 (m, 8H, ketal), 5.10 (dd, J = 2.2, 17.8 Hz, 1H, C(23)-Htrans ), 5.13 (dd, J = 2.2, 9.6 Hz, 1H, C(23)-Hcis ), 5.32 (m, 1H, C(6)-H), 5.74 (ddd, J = 9.0, 16.2, 10.8 Hz, 1H, C(22)-H) ppm. 13 C NMR (50 MHz, CDCl ): = 15.1, 16.9, 21.2, 23.5, 3 31.0, 32.9, 33.2, 33.8, 37.3, 40.3, 41.7, 43.9, 49.0, 49.7, 50.6, 64.164.9 (ketal), 78.3 (C(11)), 108.8, 117.6 (C(23)), 119.7, 121.4 (C(6)), 141.2 (C(22)), 142.8 (C(5)) ppm. IR (KBr): 3541 cm1 . MS (EI, 70 eV): m/z = 444 [M+ ], 426 [MH2 O+ ], 389, 346, 327, 284, 99, 89, 55, 43. C27 H40 O5 (444,29): calculated C 72.94, H 9.07; found C 73.10, H 8.88. 2.2.3. 11-Hydroxy-11-cinnamyl-3,3,17,17(ethylenedioxy)-androst-5-ene (4d) White powder: mp 120 C, 17% yield (23% conversion); 1 H NMR (200 MHz, CDCl ): = 1.04 (s, 3H, C(18)-H), 3 1.35 (m, 2H), 1.43 (s, 3H, C(19)-H), 1.692.17 (m, 14H), 2.35 (dt, 1H), 2.42 (dd, 1H, C(20)-H), 2.61 (dq, 1H), 2.95 (dd, J = 13.7, 7.6 Hz, 1H, C(20)-H), 3.78-3.99 (m, 8H, ketal), 5.33 (m, 1H, C(6)-H), 6.26 (ddd, J = 6.6, 7.5, 15.9 Hz, C(21)-H), 6.45 (d, J = 15.9 Hz, C(22)-H), 7.18-7.4 (m, 5H, arom.) ppm. 13 C NMR (50 MHz, CDCl3 ): = 14.9, 21.3, 23.6, 31.1, 33.1, 33.2, 33.9, 38.1, 41.3, 41.7, 44.5, 47.1, 49.5, 51.2, 55.3, 64.2, 64.4, 65.1, 108.8, 119.6, 121.7, 126.1, 126.3, 127.2, 128.5, 134, 137.4, 142.4 ppm. IR (KBr): 3494 cm1 . MS (ICP/NH3 ): m/z = 524 [M+NH4 ]+ , 507 [M+ H]+ . 2.2.4. X-ray crystallographic study of (3b) This compound crystallized in the orthorhombic P21 21 21 space group with a = 6.515(2) , b = 17.637(4) , c = 20.435(7) , V = 2348(1) 3 , Z = 4. Data collection was performed at room temperature with a Enraf-Nonius CAD4 diffractometer using the monochromated Mo K radiation. Data were corrected for Lorentz and polarization effects. No absorption correction was applied. The structure was solved by direct methods using SHELXS [14]; all other calculations used CRYSTALS [15]. Atomic scattering factors and anomalous dispersion terms were taken from D.T. Cromer [16]. Full-matrix least squares renements based on F and a Chebychev weighting scheme [17] were performed. All non-hydrogen atoms were anisotropically rened. Hydrogen atoms were introduced in calculated positions (except the oxygen-bonded one, which

a No addition under reux by method A after 1 h, nor at room temperature after 15 h. b Determined by means of 1 H NMR. c As an isolated product.

mide and a crystal of iodine were added. A solution of 1 (0.34 mmol) and allyl bromide (total quantity 0.5 mmol, 0.04 ml) in 4 ml THF was then slowly introduced. Stirring was continued for 40 min at reux temperature. The reaction mixture was treated with water and the organic phase was separated, washed, and dried with anhydrous MgSO4 . The product was puried on a silica gel chromatographic column (petroleum benzine/ethyl acetate 8/2) to give a white powder in 90% yield. 2.2. Method B Magnesium (2.5 mmol, 60.7 mg) was stirred with dry Et2 O (3 ml) in a three-necked ask under argon. One drop of prenyl bromide and a crystal of iodine were added. A solution of prenyl bromide (total quantity 0.5 mmol, 0.07 ml) in 3 ml Et2 O was then slowly introduced. Stirring was continued for 2 h at 10 C. Then, a solution of 1 (0.3 mmol, 116 mg) in 1 ml of dry THF was slowly added at 10 C. After this addition, the cooling bath was removed, and the reaction mixture was stirred at reux temperature for 7.5 h. The reaction mixture was then treated as before. The prenyllithium was prepared from prenyl phenyl ether according to [13]. Table 1 summarizes the results obtained. In each case, only one addition product was obtained as indicated by 13 C NMR. The conguration is based on comparison between the addition of allyl derivatives and phenyl, alkyl derivatives, each proceeding at the least hindered face [4]. 2.2.1. 11-Hydroxy-11-allyl-3,3,17,17-(ethylenedioxy)androst-5-ene (3a) White powder: mp 104 C, 90% yield (100% conversion); 1 H NMR (200 MHz, CDCl ): = 1.03 (s, 3H, C(18)-H), 3 1.201.42 (m, 5H), 1.39 (s, 3H, C(19)-H), 1.592.14 (m, 11H), 2.26 (dt, J = 2.9, 11.3 Hz, 1H), 2.35 (dd, J = 6.9, 13.4 Hz, 1H), 2.55-2.73 (m, 2H), 3.77-3.99 (m, 8H, C(acetal)-H), 5.07 (dd, J = 2.2, 14.4 Hz, 1H, C(22)-Htrans ), 5.15 (dd, J = 2.2, 7.9 Hz, 1H, C(22)-Hcis ), 5.31 (m, 1H, C(6)-H), 5.85 (m, 1H, C(21)-H) ppm. 13 C NMR (50 MHz, CDCl3 ): = 10.1, 16.5, 18.8, 26.2, 28.1, 28.4, 29.1, 33.0, 36.5, 36.8, 39.6, 42.0, 44.6, 47.2, 49.7, 59.460.2 (C(acetal)), 71.7 (C(11)), 104.0, 114.13, 114.8, 116.8,

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was found on a difference Fourier map) and were allocated on overall isotropic displacement parameter. Using 1724 reections with I > 3(I), the renement converged with nal values R = 0.0624 and wR = 0.0770, GOF = 1.16. Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-209747. Copies of the data can be obtained free of charge at http://www.ccdc.cam.ac.uk/conts/retrieving.html or on application to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK [Fax: (internat.) +44-1223/336-033); E-mail: deposit@ccdc.cam.ac.uk].

3. Results and discussion Addition of allylic compounds of magnesium to the ketone in position 11 of the protected adrenosterone 1 (Scheme 1) was studied with allyl-, crotyl-, prenyl-, and cinnamyl-magnesium bromides 2ad. Addition of substituted allyl magnesium groups to the prochiral ketones tends to lead to formation of several products, including the branched-chain diastereoisomeric alcohols 3 and the linear alcohols 4 as suggested in Scheme 1. Table 1 summarizes the results obtained from a Barbier-Grignard reaction in reuxing THF by method A or if necessary, by method B, which involved preparation of the Grignard reagent followed by addition of the steroid. With the Barbier-Grignard reaction, addition of allyl magnesium bromide 2a and crotyl magnesium bromide 2b was complete in 40 min and 1 h, respectively, in reuxing THF, and gave the alcohols 3a and 3b (Table 1, entries 1, 2). Under the same conditions, cinnamylmagnesium bromide 2d underwent partial addition to 1 after 24 h (Table 1, entry 5) to give 4d. In contrast, the prenyl derivative 2c did not add to 1. Several experiments, not documented here, were carried out with 2c; no addition product was observed in THF, diethyl ether/toluene, or diethyl ether/THF mixtures with organomagnesium or organolithium reagents at room temperature or when heated to reux. Addition occured exclusively on the face of the steroid. Moreover, the addition products of the crotyl magnesium

bromide 2b and of the cinnamyl magnesium bromide 2d were 100%; in one case, the branched-chain diastereoisomer 3b with the 11R-20R conguration was formed, and in the other case, the linear diastereoisomer 4d with the E-11S conguration was formed. In the case of 3b, the conguration of carbon 20 was determined by X-ray crystallography, and the structure of the corresponding alcohol is shown in Scheme 2. The conguration of 4d was determined by 1 H NMR, given the coupling constant 3 Jtrans = 15.8 Hz observed between the ethylene protons. Addition of the allyl-Grignards 2b [18] and 2c [9] or other allylic organometallic reagents (zinc or lithium) [18,19] of type 2d to hindered ketones is often reversible. The branched-chain alcoholate, a kinetic product, tended to give the linear alcohol, depending on the degree of steric hindrance. For cyclic ketones, Chrest and Felkin were able to distinguish the reactivity of the axial and equatorial faces [20]. In the case of hindered cyclic ketones, Dimitrov recently described the allylation of camphor (exclusively endo attack) and fenchone (exo attack) by crotyl magnesium bromide [21]. The reaction with camphor gave branched-chain products with poor diastereoselectivity (32%). The reaction with fenchone gave a single linear Z product. In terms of stereochemistry, the addition of crotyl magnesium bromide 2b to prochiral ketones may give branched-chain alcohols with syn or anti relative conguration (Scheme 3). In the acyclic series, Sjholm observed poor diastereoselectivity in this reaction, except for ketones possessing a bulky tertiary-butyl group (max 84% de) [22]. In these cases, the preferred anti conguration of the addition product occurred, according to Sjholm, by transition states of the type TS1 and TS2 (Scheme 3) in which interactions between tertiary-butyl (RL ) and the methyl group of the Grignard were minimized. Steroid 3b, described in this paper, had the anti relative conguration, and its TS1 and TS2 transition states (RL = C-9 and RS = C-12 cf. Scheme 1) were in accord with the observed stereochemistry. The much lower reactivity of 2d may have resulted from an interaction between RS and the phenyl group; the branched-chain product thus formed gradually led to the formation of 4d. This reactiv-

Scheme 1. General reaction of substituted allyl magnesium bromides with 1.

20

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Scheme 2. X-ray structure of 3b.

Scheme 3. Transition states leading to 3b.

ity was similar to that of the cinnamylzinc bromide with acyclic hindered ketones (mediocre yields and slow conversion to the linear alcohol when heated in THF) [19]. The observed failure to react with 2c was probably due to a gauche interaction between RL and the extra methyl group. Steroid 1 was less reactive than the diisopropyl ketone for which yields of 3045% in alcohol have been reported in the reaction of prenylmagnesium chloride in THF [9]. It may also be pointed out that 1 was less reactive toward prenyl magnesium bromide than an 11-oxo-steroid in the pregnene series [11]. In that case, the addition of 2c to the cortisone-bismethylenedioxy-3-dioxolane proceeded with 59% yield. Thus it appears that different substitutions at the position 17 may have affected the reactivity of the position 11, probably as a result of modied steric strains in the transition states. It is thus now possible to rationalize the respective degrees of steric hindrance of the two faces of the 11-oxo-steroid 1: the face may be considered as a relatively hindered ketone; an organomagnesium reagent with minimal

steric requirement (2b) gave a branched-chain addition product. In contrast, if the size of the nucleophile was increased (as in 2d), a considerable increase in the proportion of the linear product was observed to the point (2c) where there was no addition. Addition to the face (axial addition) was impossible because of the two angular methyls. These studies demonstrated the possibility of facile access, after deprotection and selective reduction, to a series of 11-substituted testosterones, whose biological properties will be assessed in a future study. Moreover, the high chirality transfer of 1, observed in particular with 3b, suggests the possibility of using an 11-substituted steroid as a chiral inducer in asymmetric synthesis.

Acknowledgements The authors wish to thank B. McGlinchey for her assistance in translating the manuscript.

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