Synthesis of some diol DErivatives as potential reagents in steroid chemistry

APTEFF, 34, 1–148 (2003) UDC 66.091.3 : 547.92 BIBLID: 1450–7188 (2003) 34, pp. 111–118 Original scientific paper SYNTHESIS OF SOME DIOL DERIVATIVES AS POTENTIAL REAGENTS IN STEROID CHEMISTRY Katarina M. Penov Gaši, Ksenija N. Kuhajda, Stanko M. Cvjetićanin, Evgenija A. Đurendić, Ljubica D. Medić-Mijačević, Vjera M. Pejanović and Marija N. Sakač The multistage syntheses of the p-toluenesulphonyloxy esters [1-benzyloxy-4-p-toluenesulphonyloxybutane (3a), 1-benzyloxy-6-p-toluenesulphonyloxyhexane (3b) and 1-benzyloxy-10-p-toluenesulphonyloxydecane (3c)], alkyl chlorides [1-benzyloxy-4-chlorobutane (4a), 1-benzyloxy-6-chlorohexane (4b) and 1-benzyloxy-10-chlorodecane (4c)], as well as alkyl iodides [1-benzyloxy-4-iodobutane (5a), 1-benzyloxy-6-iodohexane (5b) and 1benzyloxy-10-iododecane (5c)] with the terminal O-benzyl groups starting from 1,4butanediol (1a), 1,6-hexanediol (1b) and 1,10-decanediol (1c) were carried out. The possibilities of formation and addition of the corresponding Grignard reagent to the C17 carbonyl group of dehydroepiandrosterone were investigated. KEY WORDS: 1,4-butanediol, 1,6-hexanediol and 1,10-decanediol derivatives INTRODUCTION The possibility of rendering low molecular weight steroids antigenic by coupling them to proteins, prompted the synthesis of different steroid haptens for immunoassays (1-8). Clutton et al. (9) have applied the hapten principle to prepare thyroxyl derivatives of proteins and then demonstrated that these elicited antisera capable of inhibiting the physiological action of thyroglobulin. Previous attempts to apply this principle to steroids have been unsuccessful, but later a number of radioimmunoassay systems have been developed for the determination of steroid hormones. The aim of this work was to obtain some derivatives of 1,4-butanediol, 1,6-hexanediol and 1,10-decanediol as potential reagents for the synthesis of some novel steroidal haptens. Dr. Katarina M. Penov Gaši, Prof., Dr Ksenija N. Kuhajda, Prof. Stanko M. Cvjetićanin, M.Sc.; Dr. Evgenija A. Đurendić, Prof.; Dr. Ljubica D. Medić-Mijačević, Sen. Res. Fell.; Dr. Vjera Pejanović, Sen. Res. Fell.; Dr. Marija N. Sakač, Assist. Prof., Department of Chemistry, Faculty of Sciences, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia and Montenegro 111 All mentioned diols were transformed into monohalogen derivatives and could serve for linking with steroids. EXPERIMENTAL NMR spectra were taken on a Bruker AC 250E spectrometer operating at 250 MHz (proton) and 62.9 MHz (carbon), using standard Bruker software; the tetramethylsilane peak (δ 0.00) was used as reference in CDCl3 for 1H NMR, whereas the central carbon line of chloroform-d was set at 77.0 ppm for carbon-13 NMR. The extracts were dried over anhydrous sodium sulphate and removal of solvents was carried out under reduced pressure. All reagents used were analytical grade commercially available substances. General procedure for the synthesis of compounds 2a-2c A mixture consisting of 1,n-alkanediols [n = 4 (1a; 1.0 ml, 12 mmol); n = 6 (1b; 1.0 g, 8.5 mmol) and n = 10 (1c; 1.0 g, 5.7 mmol)], benzyl chloride (0.6 ml, 5.2 mmol) and potassium hydroxide (0.52 g, 9.2 mmol) in anhydrous dioxane (7 ml, for 2a and 2b) or in a mixture of anhydrous dioxane-dimethyl sulphoxide (1:1; 10 ml, for 2c) was refluxed with stirring for 3h. After cooling and filtration, the mixture was diluted with water (10 ml) and extracted with dichloromethane. The obtained crude products were purified on a silica gel column. 4-Benzyloxy-1-butanol (2a) According to the general procedure as described above, crude compound of 2a was obtained from 1a. Pure compound 2a was obtained after column chromatography (tolueneEtOAc, 1:1), as an oil, in a yield of 43%. 1H NMR (CDCl3, δ): 1.69 (m, 4H, H-2, H-3); 3.52 (t, 2H, J=5.0 Hz, H-4); 3.62 (t, 2H, J=7.5 Hz, H-1); 4.52 (s, 2H, Bn); 7.26-7.36 (several signals, 5H, Ar H). 13C NMR (CDCl3, δ): 26.53, 29.94, 62.48, 70.24, 72.93, 127.53128.32 (5Ar H), 138.04 (Ar H). 6-Benzyloxy-1-hexanol (2b) Crude compound 2b was prepared from 1b under the same experimental conditions as described above. Pure compound 2b was obtained after column chromatography (toluene-EtOAc, 3:1), as an oil, in a yield of 39%. 1H NMR (CDCl3, δ): 1.51 (2m, 8H, H-2, H-3, H-4, H-5); 3.47 (t, 2H, J=7.5 Hz, H-6); 3.63 (t, 2H, J=7.5 Hz, H-1); 4.50 (s, 2H, Bn); 7.26-7.35 (several signals, 5H, Ar H). 13C NMR (CDCl3, δ): 25.56, 25.99, 29.69, 32.69, 62.90, 70.32, 72.88, 127.47-128.32 (5Ar H), 138.63 (Ar H). 10-Benzyloxy-1-decanol (2c) According to the above general procedure, before diluting the reaction mixture with water, dimethyl sulphoxide was removed by vacuum distillation. Pure compound 2c was obtained from 1c after column chromatography (toluene), as an oil, in a yield of 40.5%. 1 H NMR (CDCl3, δ): 1.56 (m, 16H); 3.47 (t, 2H, J=5.0 Hz, H-10); 3.63 (t, 2H, J=5.0 Hz, H-1); 4.51 (s, 2H, Bn); 7.34-7.43 (several signals, 5H, Ar H). 13C NMR (CDCl3, δ): 25.68, 112 26.13, 29.36, 29.40, 29.48, 29.71, 32.74, 38.94, 62.98, 70.47, 72.80, 127.42-130.46 (5Ar H), 138.64 (Ar H). General procedure for the synthesis of compounds 3a-3c and 4a-4c n-Benzyloxy-1-alkanols [n = 4 (2a; 0.9 g, 5.1 mmol); n = 6 (2b; 0.1 g, 0.55 mmol) and n = 10 (2c; 0.8 g, 3.1 mmol)] were dissolved in absolute pyridine (10, 4 or 8 ml) and solutions were left at 0°C for 15-20 min. After that a cooled solution (0°C) of p-toluenesulphonyl chloride (2.8 g, 14.7 mmol for 2a; 0.3 g, 1.63 mmol for 2b and 1.8 g, 9.2 mmol for 2c) in absolute pyridine (4 or 8 ml) was added dropwise, and the mixture was stirred for 12 h at room temperature. When the reaction was completed, ice was added and the mixture was stirred for 30 min. The mixture was then poured into ice (300 g), cold HCl (1:1) was added to pH 4-5 and extracted with dichloromethane. The extract was dried, and after evaporation of solvent it was chromatographed on silica gel column using toluene as eluent. 1-Benzyloxy-4-p-toluenesulphonyloxybutane (3a) and 1-benzyloxy-4-chlorobutane (4a) By following the general procedure, pure compounds 3a (yield 41%) and 4a (yield 19.5%) were obtained as oils. Compound 3a: 1H NMR (CDCl3, δ): 1.66 (2m, 4H, H-2, H-3); 2.35 (s, 3H, Ts); 3.37 (t, 2H, J=2.5 Hz, H-1); 4.03 (t, 2H, J=2.5 Hz, H-4); 4.41 (s, 2H, Bn); 7.27-7.80 (several signals, 9H, Ar H). 13C NMR (CDCl3, δ): 20.81 (Ts), 25.26, 25.96, 68.61, 69.90, 72.04, 126.77-144.05 (12Ar H). Compound 4a: 1H NMR (CDCl3, δ): 1.92 (2m, 4H, H-2, H-3); 3.55-3.64 (m, 2H, H1, H-4); 4.58 (s, 2H, Bn); 7.40-7.45 (several signals, 5H, Ar H). 13C NMR (CDCl3, δ): 26.65, 29.12, 44.43, 68.86, 72.29, 127.02-127.86 (5Ar H), 138.18 (Ar H). 1-Benzyloxy-6-p-toluenesulphonyloxyhexane (3b) and 1-benzyloxy-6-chlorohexane (4b) By following the general procedure, pure compounds 3b as an unstable oil (yield 47%) and 4b as an oil (yield 22%) were obtained from compound 2b. Compound 3b: 1H NMR (CDCl3, δ): 2.45 (s, 3H, Ts); 3.45 (t, 2H, J=5.0 Hz, H-1); 4.02 (t, 2H, J=5.0 Hz, H-6); 4 (...truncated)