Etherification of hydroxysteroids via triflates

Tetrahedmn Lettet-s, Vol. 35, No. 28, Pp. 5075-5076, 1994 Elsevier Scimce Ltd Printed in Gnat Britain oo40-4039/94 $7*00+0.00

Pergamon oo40-4039(94)00972-4

Etherification of Hydroxysteroids vfu T.riflatesl Anatoly M. Belostotskii and Alfred Hasst~” chanistry~~Bar-Ilanunivc&t$RamatGan529oo,I?irael

Absbwk Tr@latesof satwatedalcoholsare ua@l in the a@Won of 3- anti 17-hydtvzyste~vids in thepmettce of hindered am&w. The ethe@ation

is successjldeven in those caseswhere other alkyladng @ents are none#uMt.

Steroidal or fatty acid esters of biologicslly active compound@ i~~~luding anti-AIDS agent@ have shown in many cases enhanced activity. Since esters sre too easily degradable In viva. steroidal ethers contaiuing additional functions are desirable. Yet, the known methods of e&&cation are limited in the steroidal feld, e.g., Williamson ether synthh is often unsum@d even for M&&red 3-hydroxystemids~. Reactions via tosylates~7 are not always effective (see below) and diam compounds are useful only if the simplest diazo alkanes sre employed~. Oxidative displacement of iodo compounds~ cannot be applied to steroids containing isolated double bonds and oxidative displacement of 3-tosylhydrazinosteroidss is not stereosekctive. Only knzyl ethers are available by the use of sodium hydrogen telltide and phenyl imidinium saltsg. We now report that triflates of aliphaiic alcohols can serve ss convenient reagents for etheritkation of hydmxysteroids. Both 3-hydroxysteroids and more hindemd 17-hydroxystcroids can be e&.ritkd in moderate yield, and the use of bifunctionsl uiflateziwas efTectivealso in cases where the above mentioned allcylatingagents wereinferior. For in&mce smong the 2’,3’,4’J’diisopropylidene galactose derivatives (DIG-X) neither the iodide fat0 nor the tosylate lb‘10 reacted with the sodium salt of 3@hydroxy-5-androstene-17-one 4 (nitromethane, reflux). By contrast, Feaction of steroid 4 with 1.5-2 equiv. of @iflate2a11 in the presence of 2,6-d&reti-butylpyridine 5 formation of ethers tip was achieved by (nitromethane, teflux 3 h) led to ether 6a in 61% yieldt2. Siiy, heating of 4 with Wlates 2b,c13 in nitrometha~ in the pnsence of 5 or of 1,2,2,6$Qemamethylpipekiine 7 (60-650, 1.5 h). The unstable hiflate 2d was generated in sizu iu the pence of 1.1 equiv. of 7 and when tmated with 0.5 equiv. of steroid alcohol 4 in the presence of 1 equiv. of 7 (nitromethane, 60-650.1 h) followed by hydrolysis of the product, etbez 6d was obtained in 67% yield.

JI&?z& ROTf

&&_ Ho” O@#SWR=DKi

Ib: RYz.H&Cl

ObZR=(CH&Cl

at:R=(CH&Br

6c,@czR=(Cl-l&Br

2d:R=(CH&OlBS

X 1r:X=l

g;;;gy 3: X=:oH

M:R=(C&)&H

1 I DIG-X +k

m choice of smine as proton acceptor is importantz the yield decreasesasthesterichindranceofthe aminegrouprliminiskn.Thus,tbeyieldsof6b~9o,32,or2%wbeD~aminewas7,luti~andpyridine, “spect’ve’y. The yields of tic were 63,47 and 3% when amine 5, huidine and pykline, respectively. were used. Obviously, in the csae of less hindered amines, qua&n&&n of the amine function competes effectively (e.g., lutidine is methylated by methyl fluorosulfate at room tempmtd3). In the case of 3mhydroxy steroids the yield of the emon product ia lowerz the methyl ester of Uocholic acid 8 gives in the reaction with triflates 2a or 2c m&r the above conditions the products 9a or 9c in 36 and 39% yield, respectively.

5075

5076

E-on of 17&l1ydroxystetoids 10 and 14 by 2-4 equiv. of haloalkanol nithues 2b and 2e, tespectively.wasalsocarriedoutinthe~of7underfbeabove~~conditionsandledtothe products 12 and 15. Similarly, when in situ genera&d hitlate 2d was treated with 0.5 equiv. of steroid alcohol 11 in thepresence of 1 equiv. of 7 foBowed by hydrolysis of theproduct ether 13 was obtained. lozR=TBs, X=OH@) 11:R=(CH&Br, X-OH@) lLR=ms. x=qcH&cl@) rxR=(CH&Ek, x=qcH&OH(p) 2OzR=Ac, X=OlY(g) 21:R=Ac, X=1(a)

14: x = OH (p) 1s: x = qc*)& lo:X=OTf(fl) 19:X=&(a)

(B)

The yields of the products 12.13 and 15 were 35,37 and 27% respectively. The lower yields of the more hindemd 17~alkoxy &&a&es in comparison to those of 3palkoxy sterokb is consistent with the assumption that tritlate decomposition competes with etherifkation. Attempts to obtain cc-ethers from @Mates of ~hydroxystemids and 3 were unsucce&uL Cholestanol @Mateled to cholest-2-ene, white the trigate 16 gave an i-steroid marrangement product 17 (42%) and ether 6a (21%) or a 3&3g’-his s&roidaJ ether (40%) and 4 (60%) in the ma&on with water. Testosterone uitlate 18 in m&on with akmholsgave a mixtureof productsWead of a0 expectedet&r. Gn the otherhand softer nucleophiles likeBt@Br or BqN*I’ converte4 18 to 17a-bromide 19 (64%) or 20 to a-iodide 21(108%).

AcAnowIedgenGnt:WethanLtheIsrael~~ofScienceandTechnologyforagrantin support of this work. References and Notes 1. Syntktic methodr 42. For paper ld see: Hassner, A.; Smgh, S.; Sharma, R; Maurya,R. Tetrahedron, 1993,41.2317. ‘2. Audus, K. L.; Chikhale, P. J.; Miller, D. W.; Thompson, S. E.; Borchatdt, R T.. A& Drug Res. 1992.23, 2-64. 3. Boutorin, AS.,; GusZova,L. V.; Ivanova, E. M.; Kobetx, N. D.; Zarytova, V. F.; Ryte, A. S.; Yurchenko, L. V.; Vlassov, V. V., FEB.9 Len. 1989,254,129-132. 4. Host&q K Y.; Ricbman, D. D.; Carson, D.A.; Stuhmilk, L. M.; van Wijlc, G. M.T.; van den Bosch, H., Antimicrob. Agents Chemotherapy 1992,36,2025-2029. 5. Greenhouse, R; Muchowski, J. hf. CM. J. Chem 19411,28,1025-1027. 6. Sripada, P. K., J. Lipid Res. l!XI6,27,352-353. 7. Halperin, G.; Gatt, S.. Steroids, W&35,39-42. 8. Balhni. R, Clunr Ind 1983.N 8,317-318. 9. Barmtt, A G. M.; Read, R. W.; Barton, D. H. R., J. Chem Sot., Perkin Z l980,2184-2190. 10. Raymond, A L.; Schroeder, E F., J. Amer. Chem Sot. 1948,70.2785-2781. 11. Binkley, R W.; Ambrose. M. G.; Hehemann, D. G., 3. Org. Chem I-, 45; 4387-439 1. 12. All isolated steroids were identified by tH, *3c NMR and mass-spectra. The data of t3C-NMR spectrum ate given for compound 6n (CDCJ# 37.21 (C 1); 28.42 (C 2); 79.56 (C 3); 39.09 (C 4); 141.34 (C 5); 12.62 (C 6); 31.56 (C 7); 31.50 (C 8); 50.33 (C 9); 37.01 (C 10); 20.39 (C 11); 30.86 (C 12); 47.55 (C 13): 51.85 (C 14); 21.90 (C 15); 35.84(C 16);220.92(C 17);13.56(C 18); 19.43(C 19);96.36 (C 1’);70.72(C 2’); 70.64(C 3’);71.18(C 49;67.12(C 5’); 66.86(C 6’); 108.94.108.23 (JzMez);26.02. 25.93,24.86,24-l1 (Me). 13. TrifHtea were obtaim?d from alcohols and tritlic anhydride in the pmaence of an amine: Stang, PJ.; Hanack, M.; Subramanian, L. R, Syndhcsis. 19%2,85-126. (Received in UK 7 February 1994; revised 13 May 1994; accepted 20 May 1994