s t e r o i d s 7 1 ( 2 0 0 6 ) 1091–1096

avai lab le at www.sc iencedi rec t .com

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D-homoannulation of 17�,21-dihydroxy-20-ketosteroids (corticosteroids)

Angelo Liguori ∗, Francesca Perri, Carlo SicilianoDipartimento di Scienze Farmaceutiche, Universita degli Studi della Calabria, Via P. Bucci cubo 15/c,I-87036 Arcavacata di Rende, CS, Italy

a r t i c l e i n f o

Article history:

Received 4 August 2006

Received in revised form

9 October 2006

Accepted 12 October 2006

Keywords:

D-homosteroids

17,21-Dihydroxy-20-keto steroids

Corticosteroids

a b s t r a c t

Synthetic corticosteroids are widely used as anti-inflammatory agents. Mechanisms of their

degradation continue to be studied. D-ring homoannulation is a well-known metabolic path-

way for steroids in vivo. The rearrangement with aluminium trichloride of the commercial

anti-inflammatory drugs hydrocortisone, cortisone and dexamethasone is here presented.

The structures of the corresponding 17a-keto-17-hydroxy-D-homosteroids are established

by mono- and two-dimensional NMR analysis. Inversion of the �-configuration of C-16 is

observed in the Lewis acid assisted D-homoannulation of dexamethasone.

© 2006 Elsevier Inc. All rights reserved.

Rearrangement

Aluminium trichloride

groups takes place initially and is followed by migration of

Cyclic sulfites

1. Introduction

The D-ring rearrangement (D-homoannulation) of 17-hydroxy-20-keto steroids was discovered in 1938 [1] and hasthoroughly been studied ever since [2]. D-ring homoannu-lation is a known metabolic route for steroids in vivo [3,4].Furthermore this rearrangement has been observed underrelatively mild conditions and during the storage of theclinically useful C21-steroids [5–7].

Treatment of 17-hydroxy-20-keto steroids with Lewis acidsyielded 17a-keto-17�-hydroxy-D-homosteroids [8]. The metal-catalyzed rearrangement of 16�-substituted 17-hydroxy-20-

keto steroids provided the corresponding 17a-keto-17�-hydroxy-D-homo isomers as single rearrangement products[9]. These reactions were highly stereoselective [10].

∗ Corresponding author. Tel.: +39 0984 492042; fax: +39 0984 492855.E-mail address: A.Liguori@unical.it (A. Liguori).

0039-128X/$ – see front matter © 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.steroids.2006.10.001

The Lewis acid-catalyzed D-homoannulation of triam-cinolone (9�-fluoro-11�,16�,17�,21-tetrahydroxypregna-1,4-diene-3,20-dione) has been reported to afford the 17a-keto-17-hydroxy-D-homo derivate [11], despite to the data publishedin previous studies [12] in which the substance arising fromD-homoannulation of triamcinolone has originally been for-mulated as the 17-keto-17a-hydroxy-D-homo isomer ratherthan the 17a-keto-17-hydroxy product.

The mechanism of the rearrangement of 17-hydroxy-20-keto steroids could be regarded as a pinacol-like transposition[10]. Chelation of Lewis acids by the 20-keto and 17�-hydroxyl

the C(16)–C(17) bond [13,14] (Fig. 1). The oxygen functional-ities are forced to a cis orientation through coordination tothe metal core of the Lewis specie, yielding the 17a-keto-

1092 s t e r o i d s 7 1 ( 2 0 0 6 ) 1091–1096

-ho

Fig. 1 – Mechanism of the Lewis acid-induced D

D-homosteroids with the hydroxyl group at C-17 in the �-orientation [15].

17-Hydroxy-20-keto steroids have extensively beenexploited in order to obtain D-homosteroids, compoundswhich continue to be very attractive in view of their medicinalimportance [16]. Nevertheless, there are no reports in theliterature dealing with the metal-assisted rearrangementof simple corticosteroids. These molecules possess the 21-hydroxyl group which could coordinate to the Lewis acid,thus controlling the stereochemistry of the rearrangement.

As a part of our work in the steroid chemistry [17–19],we now propose the study of the Lewis acid-induced D-homoannulation of corticosteroids.

2. Experimental

2.1. General

All solvents were purified and dried by standard proceduresand distilled prior to use. Commercially available reagentswere purchased from Aldrich Chemical Co. and were usedwithout further purification. Melting points were determinedon a Kofler hot-stage apparatus (Reichert Thermovar, Ger-many) and are uncorrected. Proton nuclear magnetic reso-nance (1H NMR) spectra, and proton homodecoupling exper-iments were recorded at 300 MHz on a Bruker Avance 300spectrometer (Bruker BioSpin International, Switzerland). Car-bon nuclear magnetic resonance (13C NMR) spectra, and DEPTexperiments were recorded at 75.5 MHz on the same instru-ment. 2D NOESY spectra were obtained with the optimizedmixing time of 200 ms. Chemical shift values are expressed ası (ppm) relative to the residual proton of the solvent perdeu-teriodimethylsulfoxide (DMSO-d6) fixed at 2.50 ppm (centralline of the quintet) for 1H NMR spectra, and relative to DMSO-d6 fixed at 39.51 ppm (central line of the septet) for 13C NMRspectra. 19F NMR spectra were recorded at 470.5 MHz, ona Bruker Avance 500 spectrometer (Bruker BioSpin Interna-tional, Switzerland), in deuteriochloroform (CDCl3) as solvent.Fluorine chemical shift are expressed as ı (ppm) relative tothe trichlorofluoromethane used as internal standard. All 1Dand 2D 1H, 13C, and 19F NMR spectra were recorded at 298 K,using standard pulse sequence programs from the BrukerBioSpin firm. All coupling constants (J) are reported in Hz.

Elemental analysis were performed on a Perkin-Elmer Elemen-tal Analyzer. Reaction mixtures were monitored by thin layerchromatography (TLC) using Silica gel 60-F254 precoated glassplates (Merck, Darmstadt, Germany). Kieselgel 60H without

moannulation of 17-hydroxy-20-keto steroids.

gypsum purchased from Merck, was used for short-columnflash chromatography (SCFC). All reactions were performedusing flame dried glassware and under an inert atmosphere(dry N2).

2.2. Synthesis of D-homosteroids 2a, 2b, and 4

The appropriate corticosteroid 1a, 1b, or 3 (1 mmol) was dis-solved in dry 1,4-dioxane (20 ml) and aluminium trichloride(3 mmol) was added. The mixture was stirred under refluxfor 90 min, until TLC analysis of the reaction mixture (diethylether/methanol 98:2 v/v) showed complete conversion of theprecursor into the corresponding D-homosteroid. The organicsolvent was removed under vacuum and the residue wastreated with water and extracted with ethyl acetate (3× 25 ml).The combined organic layers were washed once with brine anddried over Na2SO4. The solvent was removed under vacuumand the solid residue was subjected to chromatographic purifi-cation (diethyl ether/methanol 98:2 v/v) to afford the respec-tive D-homoannulated product 2a, 2b, or 4.

2.2.1. 11ˇ,17˛-Dihydroxy-17ˇ-hydroxymethyl-D-homoandrosta-4-ene-3,17a-dione (2a)Yield: 87%. Yellow solid; mp 192–196 ◦C. Rf = 0.31 (eluent mix-ture: diethyl ether/methanol 98:2 v/v); (found: C, 69.79; Hand 8.31; C21H30O5 requires: C, 69.59 and H, 8.34%). 1H NMR(DMSO-d6, 300 MHz): ı 5.57 (s, 1H, H4), 4.82 (s, 1H, 17-OH),4.61 (m, 1H, CH2OH), 4.42 (d, J = 3.2 Hz, 1H, 11-OH), 4.22 (m,1H, H11), 3.49 (m, 2H, CH2OH), 1.70–2.51 (m, 13H), 1.22–1.58[m, 6H (C18 + C19) + 2H], 0.87–1.02 (m, 2H). 13C NMR (DMSO-d6,75.5 MHz): ı 213.66 (C17a), 198.45 (C3), 172.62 (C5), 121.63 (C4),77.06 (C17), 67.56 (CH2OH), 65.79 (C11), 54.61, 48.24 (C14), 42.20,39.33, 34.35, 33.92, 32.36, 32.17, 31.83, 31.29, 20.93, 20.73, 20.49,17.45.

2.2.2. 17˛-Hydroxy-17ˇ-hydroxymethyl-D-homoandrosta-4-ene-3,11,17a-trione (2b)Yield: 80%. Yellow solid; mp 134–137 ◦C. Rf = 0.30 (eluent mix-ture: diethyl ether/methanol 98:2 v/v); (found: C, 69.81 andH, 7.85; C21H28O5 requires: C, 69.98 and H, 7.83%). 1H NMR(DMSO-d6, 300 MHz): ı 5.62 (s, 1H, H4), 4.95 (s, 1H, 17-OH),4.80 (m, 1H, CH2OH), 3.77 (dd, J = 9.5, 6.3 Hz, 1H, CH2OH), 3.47(dd, J = 9.5, 6.3 Hz, 1H, CH2OH), 1.79–2.54 (m, 14H), 1.43–1.67(m, 3H), 1.32 (s, 3H, CH ), 0.92 (s, 3H, CH ). 13C NMR (DMSO-

3 3

d6, 75.5 MHz): ı 212.05 (C11), 209.75 (C17a), 198.72 (C3), 169.37(C5), 123.70 (C4), 78.98 (C17), 71.61, 67.69 (CH2OH), 63.42, 61.52,51.96, 50.40, 47.94, 38.12, 38.06, 34.37, 33.73, 31.86, 31.32, 18.63,15.77.

0 0 6 ) 1091–1096 1093

21YmH(J14J1(716C2((

2Do

Tdbr6epvtwr(a

mrı

Table 1 – Conversion of steroids 1a and 1b into theD-homo derivatives 2a and 2b

R1 R2 Yield (%)

s t e r o i d s 7 1 ( 2

.2.3. 9˛-Fluoro-11ˇ,17˛-dihydroxy-17ˇ-hydroxymethyl-6ˇ-methyl-D-homoandrosta-1,4-diene-3,17a-dione (4)ield: 78%. Pale yellow solid; mp 138–141 ◦C. Rf = 0.34 (eluentixture: diethyl ether/methanol 98:2 v/v); (found: C, 67.47 and, 7.43; C22H29FO5 requires: C, 67.33 and H, 7.45%). 1H NMR

DMSO-d6, 300 MHz): ı 7.26 (d, JH1H2 = 10.2 Hz, 1H, H1), 6.20 (dd,

H1H2 = 10.2 Hz, JH2H4 = 1.8 Hz, 1H, H2), 5.99 (m, 1H, H4), 5.43 (m,H, 11-OH), 4.89 (s, 1H, 17-OH), 4.55 (t, J = 5.6 Hz, 1H, CH2OH),.11 (m, 1H, H11), 3.67 (dd, J = 10.3, 5.6 Hz, 1H, CH2OH), 3.24 (dd,= 10.3, 5.6 Hz, 1H, CH2OH), 2.24–2.68 [m, 3H (H15 + H16) + 2H],.87–2.09 (m, 3H), 1.62 (m, 1H), 1.41–1.50 [m, 3H (H19) + 2H], 1.24s, 3H, H18), 0.86 (d, J = 6.9 Hz, 3H, 16-CH3). 13C NMR (DMSO-d6,5.5 MHz): ı 212.81 (C17a), 185.62 (C3), 167.35 (C5), 152.93 (C1),29.57 (C2), 124.27 (C4), 102.34 (d, JCF = 174.6 Hz, C9), 77.36 (C17),9.97 (d, JCF = 32.1 Hz, C11), 62.58 (CH2OH), 48.37 (d, JCF = 23.1 Hz,10), 44.34, 38.44, 36.58, 34.62 (d, JCF = 19.8 Hz, C8), 30.67, 29.60,8.89, 26.96 (d, JCF < 0.4 Hz, C7), 23.58 (d, JCF = 4.4 Hz, C19), 17.8616-CH3), 15.68 (C18). 19F NMR (CDCl3, 470.5 MHz): ı −136.07dd).

.3. Synthesis of 9˛-fluoro-11ˇ-hydroxy-16ˇ-methyl--homoandrosta-1,4-diene-3,17a-dione-17-spiro-5′-(2′-xide-1′,3′-dioxathiolane) (5)

o a solution of the D-homosteroid 4 (1 mmol) in dryichloromethane (10 ml), containing sodium hydrogen car-onate (13 mmol), thionyl bromide (4 mmol) was added. Theesulting heterogeneous mixture was stirred under reflux for0 min, until TLC analysis of the reaction mixture (diethylther/methanol 98:2 v/v) showed complete conversion of therecursor into the corresponding cyclic sulfite 5. The sol-ent was removed under reduced pressure conditions andhe residue was dissolved in dichloromethane. The mixtureas filtered and the solvent evaporated to dryness. The solid

esidue was then subjected to chromatographic purificationdiethyl ether/methanol 98:2 v/v), to afford 5 as a pale yellowmorphous solid.

Yield: 89%. Rf = 0.39 (eluent mixture: diethyl ether/ethanol 98:2 v/v); (found: C, 60.21 and H, 6.20; C22H27FO6S

equires: C, 60.26 and H, 6.21%). 1H NMR (DMSO-d6, 300 MHz):7.26 (d, JH1H2 = 10.1 Hz, 1H, H1), 6.21 (dd, JH1H2 = 10.1 Hz,

Scheme 1 – Conversion of steroids 1a and 1b

2a OH H 872b O O 80

JH2H4 = 1.89 Hz, 1H, H2), 6.01 (m, 1H, H4), 5.57 (sbroad, 1H,OH), 4.86 (d, J = 9.08 Hz, 1H, CH2OSO2), 4.77 (d, J = 9.08, 1H,CH2OSO2), 4.14 (m, 1H, H11), 2.52–2.71 (m, 2H), 2.23–2.41 (m,2H, H15 + H16), 1.72–2.10 (m, 4H), 1.41–1.52 [m, 3H (H19) + 2H],1.32 (s, 3H, H18), 1.19–1.30 (m, 1H), 0.89 (d, J = 7.5 Hz, 3H, 16-CH3). 13C NMR (DMSO-d6, 75.5 MHz): ı 206.12 (C17a), 185.57(C3), 166.90 (C5), 152.93 (C1), 129.66 (C2), 124.37 (C4), 100.99(d, JCF = 172.1 Hz, C9), 92.56 (C17), 70.76 (CH2OSO2), 69.53 (d,JCF = 29.5 Hz, C11), 46.34 (d, JCF = 22.7 Hz, C10), 37.93, 36.92,34.00, 33.54 (d, JCF = 20.4 Hz, C8), 30.48, 28.92, 28.51, 27.05 (d,JCF < 0.4 Hz, C7), 23.48 (d, JCF = 5.3 Hz, C19), 18.13 (16-CH3), 15.70(C18).

3. Results and discussion

The potent anti-inflammatory drug hydrocortisone(11�,17�,21-trihydroxy-pregna-4-ene-3,20-dione) 1a, a rep-resentative 17,21-dihydroxy-20-keto steroid, was chosenas a model system to exploit the reaction with aluminiumtrichloride. Hydrocortisone 1a (1 mmol) was dissolved indry 1,4-dioxane and treated with aluminium trichloride(3 mmol) under reflux for 90 min (Scheme 1). After a simplework-up, chromatographic purification of the crude reactionproduct afforded a yellow solid in 87% yield. The compoundthus obtained was characterized as the 11�,17�-dihydroxy-17�-hydroxymethyl-D-homoandrosta-4-ene-3,17a-dione (2a)(Table 1).

The structure of 2a was assigned by mono-dimensional1H and 13C NMR spectroscopy. The 1H NMR spectrum of 2arecorded in perdeuteriodimethylsulfoxide at 298 K, showed

the typical signals attributable to the A-ring proton H4, res-onating at 5.57 ppm. Furthermore, a doublet at 4.42 ppm anda multiplet centred at 4.22 ppm were indicative for the 11-OHand the H-11, respectively. This assignment was confirmed by

into the D-homo derivatives 2a and 2b.

1094 s t e r o i d s 7 1 ( 2 0 0 6 ) 1091–1096

om

Fig. 2 – D-ring proton connectivities fr

isotopic exchange. After addition of deuterium oxide, the 11-OH resonance disappeared, generating a more simple signalfor the H-11. The four protons of the C-17 hydroxyl group andthe C-17 hydroxymethyl chain showed one singlet at 4.82 ppmfor the 17-OH and two multiplets centred at 4.61 and 3.49 ppm,for the methylene and hydroxyl groups, respectively. The res-onances due to both the hydroxy functions were assigned

by isotopic exchange, which also simplified the C-17 hydrox-ymethyl signals into a couple of doublets.

The configuration of the C-17 in the compound 2a (Fig. 2)was unambiguously established by the NOE involving the

Scheme 2 – Conversion of dexamethasone 3 into the D-homostederivative 5.

NOESY data for compounds 2a and 5.

methylene protons of the C-17 substituent, the 16�-proton andthe 18-protons in the NOESY spectrum recorded in perdeuteri-odimethylsulfoxide at 298 K. The three marked connectivitiesestablished that all three features lie on the �-face of the D-ring, for which a chair conformation is invoked. Thus, theNOESY analysis successfully assigned the �-position to thehydroxymethyl group placed on the C-17.

The Lewis acid-induced D-homoannulation was extendedto cortisone (17�,21-dihydroxy-pregna-4-ene-3,11,20-trione)1b (Scheme 1). In particular, 1b was treated with aluminiumtrichloride under the same conditions adopted for 1a, and the

roid 4 and synthesis of the corresponding cyclic sulfite

0 0 6

copat

srLwtc

m1aTtoh3

fppmpetcTspruop4oDtestwssaotpiwd5imott

r

s t e r o i d s 7 1 ( 2

orresponding 17a-keto-17�-hydroxy-D-homo isomer 2b wasbtained in 80% yield after chromatography (Table 1). Com-ound 2b was subjected to mono-dimensional 1H and 13C NMRnalysis to elucidate its structure, and the stereochemistry ofhe C-17 was attributed in analogy to that featured by 2a.

In the literature [8], 16�-methyl-17-hydroxy-20-ketoteroids are reported to be apparently stable and poorlyeactive under the experimental conditions used for theewis acid-induced D-homoannulation [20,21]. Therefore,e evaluated the influence of a methyl group placed at

he 16�-position on the course of the D-homoannulation oforticosteroid systems.

Dexamethasone (9�-fluoro-11�,17�,21-trihydroxy-16�-ethylpregna-1,4-diene-3,20-dione) 3, a 17,21-dihydroxy-

6�-methyl-20-keto steroid characterized by a potentnti-inflammatory activity, was chosen as a model system.reatment of 3 with aluminium trichloride under experimen-al conditions similar to those selected for the rearrangementf 1a and 1b, afforded 9�-fluoro-11�,17�-dihydroxy-17�-ydroxymethyl-16�-methyl-D-homoandrosta-1,4-diene-,17a-dione (4) in 78% yield, after chromatography (Scheme 2).

Chromatography yielded also a limited number of mixedractions enriched in compound 4 and containing a secondroduct. 1H NMR analysis of these fractions, confirmed theresence of resonance signals attributable to a possible iso-er, likely an epimer, of 4. Unfortunately, this minor com-

ound resulted to be not separable from 4 by chromatography,ven under different sets of eluent gradients. The structure ofhe D-homoannulated steroid 4 was completely assigned byonventional mono-dimensional 1H and 13C NMR techniques.he 1H NMR spectrum of 4 recorded in perdeuteriodimethyl-ulfoxide at 298 K showed the signals attributable to the A-ringrotons H1, H2, and H4, resonating at 7.26, 6.20, and 5.99 ppm,espectively. The resonances of all hydroxyl groups of 4 werenequivocally assigned by isotopic exchange. After additionf deuterium oxide to the sample, the complicated multi-let at 5.43 ppm, the singlet at 4.89 ppm, and the triplet at.55 ppm, attributable to the 11-OH, the 17-OH, and the OHf the C-17 hydroxymethyl chain, respectively, disappeared.euterium exchange simplified the signal multiplicity of both

he 17-methylene protons, resonating at 3.67 and at 3.24 ppmach one as a doublet, while without isotopic exchange theyhowed two clear doublets of doublets. The complicated mul-iplet centred at 4.11 ppm, after addition of deuterium oxide,as assigned to the H-11. After isotopic exchange, this proton

howed in fact a slightly simplified multiplet, featuring thecalar coupling with the H-12 couple and the fluorine atomt C-9. Finally, the 19F NMR spectrum of 4 recorded in deuteri-chloroform at 298 K, showed only one doublet of doublet cen-red at −136.07 ppm. The C-17 stereochemistry of the D-homoroduct 4 was assigned after conversion into the correspond-

ng cyclic sulfite [22] derivative 5 (Scheme 2). Treatment of 4ith SOBr2 provided, after chromatographic purification, theesired compound 5 in 89% yield. Formation of the derivative, in which both the C-17 oxygen functionalities are blocked

n a structure more rigid than in 4, made easier the assign-

ent of the C-17 configuration. Intense NOESY signals were

bserved for compound 5 (Fig. 2), clearly showing the through-he-space correlations existing between the 4′-methylene pro-ons, 18-protons, 15�-proton and the methyl group at the C-16.

) 1091–1096 1095

Nevertheless, the NOESY spectrum did not show correlationbetween 18-protons and the C-16 methyl group. All connectiv-ities observed for the 4′-protons, confirmed the �-orientationfor the methylene group. In particular, the strong correlationobserved between the 4′-protons and the C-16 methyl sub-stituent, suggested for the latter an equatorial orientation. TheNOESY data collected for 5 clearly identified the C-17 configu-ration of the precursor 4.

4. Conclusions

D-ring homoannulation represents a very important processbecause it shows analogies with a possible metabolic pathwayin vivo and/or a decomposition route observed for corticos-teroids which are widely used as potent anti-inflammatorydrugs. For the first time a metallic Lewis acid has beenemployed for the rearrangement of simple corticosteroids.The D-homosteroids prepared from corticosteroids by treat-ment with aluminium trichloride are characterized by a well-defined C-17 stereochemistry. Inversion of the C-16 configura-tion observed for 4 indicates that the C(16)–C(17) bond break-ing occurs during the rearrangement of 3. Presumably, a car-banion at C-16 is developed as an intermediate, which couldinvert its original configuration before the D-homoannulationstep. This structural elaboration of corticosteroid D-ring opensup the obtainment of new steroidal analogs. Both the hydroxyland hydroxymethylene functions at C-17 could further beelaborated to obtain more complex molecules of potential bio-logical interest.

Acknowledgement

This work was supported by grants from Ministero Italianodell’Universita e della Ricerca (MIUR).

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