J. Org. Chem. 1990,55, 243-247
243
Total Synthesis of la-Fluoro-25-hydroxycholecalciferoland -ergocalciferol Shian-Jan Shiuey,* kina Kulesha, Enrico G. Baggiolini,f and Milan R. Uskokovie Roche Research Center, Hoffmann-La Roche Inc., Nutley, New Jersey 07110
Received June 21, 1989
Stereoselective construction of the la-fluoro ring-A synthon 15 is described. The key steps in the synthesis are epimerization of the trans-acetoxy alcohol 1 to cis regioisomer 2 and the stereospecific fluorination of alcohol 10 with inversion to give the intermediate fluoro ester 11. The synthon 15 is used in the convergent synthesis of la-fluoro-25-hydroxycholecalciferoland la-fluoro-25-hydroxyergocalciferol. The vitamin D3 metabolites carrying fluorine-substituted side chains have been successfully used to elucidate metabolic events obligatory to vitamin D activity.' Also, 1-fluorovitaminD, was prepared, and its biological activity was evaluated.* However, the configuration at the C-1 position in this case remained uncertain. Later, the synthesis of la-fluorovitamin D,3 and la-fluoro-25-hydroxyvitamin D34were reported and a difference in the UV spectra between la-fluoro and 10-fluoro analogues was indicated. It was shown that la-fluoro-25-hydroxyvitamin D3 possesses strong phagocytic activity toward human promyelocytic leukemia celh4 Recently, we reported the convergent synthesis of la,25-dihydroxycholecalciferoland la,25-dihydroxyergo~alciferol~ and decided to extend the same strategy to the synthesis of the corresponding lafluoro analogues. Our goal was to synthesize ring-A synthon 15,which possesses a fluorine group stereospecifically attached at the la-position. Once the synthon 15 was made, we planned to couple it with C,D-ring synthons 16 and 19 to produce the title compounds (Scheme I). The synthesis of 15 is illustrated in Scheme 11. For the synthesis of intermediate 9,the known diester 1,5 easily obtained in three steps from (S)-(+)-camone,was subjected to an epimerization reaction with (diethy1amido)sulfur trifluoride (DAST) to give cis-hydroxy acetate 2 in high yield. DAST-induced epimerization of hydroxy group via neighboring-groupparticipation was previously reported? In the present case, a possible mechanism was postulated in Scheme 111. After protection as the carbonate 3 with 2,2,2-trichloroethylchloroformate' and osmium tetraoxide catalyzed oxidation with potassium periodate? thus-obtained methyl ketone 4 was subjected to Baeyer-Villiger oxidation with trifluoroperacetic acid to afford the diacetate 5. Selective deprotection to 6 by mild acid treatment (H+ cation-exchange resin? EtOH, room temperature) followed by silylation'O afforded 7. This substance was selectively deprotected with zinc and potassium dihydrogen phosphate in tetrahydrofuran to give the tertiary alcohol 8,which was successfully dehydrated by Martin's sulfurane" in carbon tetrachloride to give the desired olefin 9 with an exocyclic double bond.5 After deacylation to 10 with sodium ethoxide in ethanol, the mild fluorination was carried out at -95 "C by using (diethy1amido)sulfur trifluoride (DAST) in methylene chloride to give the desired la-fluoride 11 in moderate yield. Compound 11 was efficiently converted to the corresponding 52 isomer 12 by triplet-sensitized photoisomerization5 using 9-fluorenone. This substance was reduced to the allylic alcohol 13 with diisobutylaluminum hydride and then converted to the corresponding allylic chloride 14 by reaction with the complex made from N chlorosuccinimideand methyl sulfide.12 The desired lafluoro ring-A synthon 15 was finally obtained by treatment Deceased September 30,1988.
p
Scheme I
(S)-(+)-carvone
lt
15
'
1
with lithium diphenylphosphidefollowed by oxidation with hydrogen peroxide.13 With the desired synthon 15 at hand, the final convergent formation of 1a-fluoro-25-hydroxycholecalciferol(18) and la-fluoro-25-hydroxyergocalciferol(21)was now within reach (Scheme IV). Wittig-Horner reaction of the lithium anion of 15 with the known C,D-ring synthons 165and 1g5 at -75 "C in tetrahydrofuran provided the protected vitamins 17 and 20 in moderate yields (63% and 50%). The last deprotection step with tetrabutylammonium fluoride in tetrahydrofuran then afforded 18 and 21 respectively in high yields. It is noteworthy that the UV Amax'sof 18 (240 and 268 nm) and 21 (242 and 269 nm) were compatible with the previous finding3l4and different from the conventional ca. 265 nm for 1-desoxy, la-hydroxy, and 10-fluoro vitamins. In summary, a convergent total synthesis of la-fluoro25-hydroxy analogues of cholecalciferol and ergocalciferol (1)(a) Napoli, J. L.; Fivizzani, M. A.; Schnoes, H. K.; DeLuca, H. F. Biochemistry 1978,17,2387.(b) Shiuey, S.-J.; Partridge, J. J.; UskokoviE, M. R. J. Org.Chem. 1988,53,1040. (2)Napoli, J. L.; Fivizzani, M. A.; Schnoes, H. K.; DeLuca, H. F. Biochemistry 1979,18,1641. (3)Ohshima, E.;Takatauto, S.; Ikekawa, N.; DeLuca, H. F. Chem. Pharm. Bull. 1984,32(9),3518. (4)Ohshima, E.;Sai, H.; Takatsuto, S.; Ikekawa, N.; Kobayashi, Y.; Tanaka, Y.; DeLuca, H. F. Chem. Pharm. Bull. 1984,32(9),3525. (5)Baggiolini, E.G.;Iacobelli, J. A.; Hennessy, B. M.; Batcho, A. D.; Sereno, J. F.; UskokoviE, M. R. J. Org. Chem. 1986,51, 3098. (6) (a) Yang, S. S.; Beattie, T. R. J. Org. Chem. 1981,46,1718. (b) Houge-Frydrych, C. S. V.; Pinto, I. L. Tetrahedron Lett. 1989,3349. (7) Windholz, T. B.; Johnston, D. B. R. Tetrahedron Lett. 1967,2555. (8)Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956,21, 478. (9)AG 50W-X4,Bio-Rad Laboratories, Richmond, CA 94804. 1972,94,6190. (10)Corey, E.J.; Venkateswarlu, A. J. Am. Chem. SOC. (11)(a) Martin, J. C.; Arm,R. J.; Franz, J. A.; Perozzi, E. F.; Kaplan, L. J. Org. Synth. 1977,57,22. (b) Martin, 3. C.; Arhart, R. J. J. Am. Chem. SOC. 1971,93,2339,2341,4327. (c) Arhart, R. J.; Martin, J. C. J. Am. Chem. SOC.1972,94,4997,5003. (12)Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 4339. (13)(a) Lythgoe, B.; Moran, T. A.; Nambudiry, M. E. N.; Ruston, S.; Tideswell, J.; Wright, P. W.Tetrahedron Lett. 1975,3863.(b) Lythgoe,
B.; Moran, T. A.; Nambudiry, M. E. N.; Ruston, S.; J. Chem. Soe., Perkin Trans. 1 1976,2386. (c) Toh, H. T.; Okamura, W.H. J. Org. Chem. 1983, 48,1414. (d) Reference 5 of this paper.
0022-326319011955-0243$02.50/0 0 1990 American Chemical Society
244
J. Org. Chem., Vol. 55, No. 1, 1990
Shiuey e t al. Scheme 11"
4 R'=COMe 5 R'=OAc 6 R'=OH
3 R = C@CH&Cb
2
- bAC 9
yo,"'
13 R=CHzOH 14 R=CHpU 15 R = CH2POPh2 a (a) DAST/CH2C12,86%; (b) C1CO2CH2CCl3, DMAP/Pyr, 100%; (c) OsO,, KI04/THF-H20, 83%; (d) (CF3C0)20,HzOz,KH2P04/ CH2Cl2, 93%; (e) AG 50W-X4/EtOH, 58%; (0 t-BuMe2SiC1,imidazole/DMF, 96%; (g) Zn, KH2P04/THF-H20, 100%; (h) Ph,S[OC(CF&Ph]2/CCld,99%; (i) EtONa/EtOH, 87%; (j) DAST/CH2C12,-95 "C, 60%; (k) 9-fluorenone,hv/t-BuOMe, 85%; (1) DIBAL-H, PhCH,, 83%; (m) NCS/DMS/CH2C12,93%; (n) Ph,PLi/THF, -75 " C and then 5% H2O2/CH2Cl2, 49%.
Scheme I11
was developed.
Experimental Section Materials and Methods. Melting points were measured on a Buchi-Tottoli apparatus in open capillary tubes and are uncorrected. Infrared spectra were obtained on a Digilab Model FTS-15E spectrometer. Proton NMR spectra were recorded on a Varian XL-400 (400 MHz) or Varian XL 200 (200 MHz) instrument in CDC13. Chemical shifts are reported in parts per million downfield from internal TMS. Mass spectra data were obtained on a Varian MAT CH-5 instrument. Ultraviolet absorption spectra were measured with a Cary Model 14 spec-
trometer and optical rotations with a Perkin-Elmer 241 polarimeter. Chromatographic purifications were carried out with EM Merck silica gel (60, particle size 0.040-0.063 mm). All chromatographed products were homogeneous by silica gel TLC. [2 5 - ( lE,2a,3a,5a)]-[3-(Acetyloxy)-2-hydroxy-2-met hyl5-(1-methylethenyl)cyclohexylidene]aceticAcid Ethyl Ester (2). To a mixture of 32.6 mL (0.246 mol) of (diethy1amido)sulfur trifluoride and 490 mL of dry methylene chloride at -75 "C was added dropwise a solution of 25.3 g (0.0854 mol) of 1 in 490 mL of dry methylene chloride. The mixture was stirred at -75 O C for 1.5 h and at 0 "C for 1.5 h under argon. The mixture was then poured with stirring into a mixture of saturated aqueous NaHC03 and ice chips. The mixture was extracted with methylene chloride. The organic phase was washed with water and brine and dried (Na2S04).After evaporation under reduced pressure, the residual oil was purifed by column chromatographyon silica gel using ethyl acetate-hexane (1:2) to afford 21.4 g (86%) of 2 as an oil: -121.5' (c 1.00, CHCl,); IR (CHCl,) 3590, 1718, 1648 cm-'; MS, m / z 253 (M+ - CH,CO, l),236 (3), 190 (13), 43 (100);*H NMR 8 1.30 (t, J = 8 Hz, 3 H, CHZCHJ, 1.39 (s, 3 H, CH,), 1.78 (9, 3 H, CH3), 2.14 (s, 3 H, CH,CO), 2.33 (m, 1 H, CH of CH2),3.75 (m, 1 H, CH of CH2),4.21 (4,J = 8 Hz, CH2CH3),4.67 (m, 1 H, CHO), 4.81 (br s, 2 H, olefinic CH2),5.91 (s, 1 H, olefinic CH). Anal. Calcd for C,,H,O,: C, 64.84; H, 8.16. Found: C, 64.83; H, 8.24. [2 5 4 lE,2a,3a,5a)]-[3-(Acetyloxy)-2-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-2-methyl-5-( I-methyletheny1)cyclo-
Scheme IV (rPOPh2
15
n-Bu4NF
n-BuU
THF
Y = t-BuMezSi I
la-Fluoro-25-hydroxycholecalciferoland -ergocalciferol hexylidenelaceticAcid Ethyl Ester (3). To a solution of 21.4 g (72.2 mmol) of 2 in 1 L of dry pyridine a t 25 "C were added 102 mL (74.1mmol) of 2,2,2-trichloroethylchloroformate and 7.64 g (62.5 mmol) of 4-(dimethy1amino)pyridine. The mixture was stirred a t 25 "C for 3 days under an argon atmosphere and then quenched with water at 0 "C. The mixture was stirred at room temperature for 1 h and evaporated to remove most of pyridine. The residue was partitioned between methylene chloride and water. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2S04),and evaporated to dryness. The residue was chromatographed on silica gel, with methylene chloride as the eluent, to give 34.3 g (100%) of 3 as an oik [aIz5D -106" (c 0.7, CHCI,); IR (CHC1,) 1750, 1720, 1651 cm-'; MS, m / z 470 (M+),14 410 (22), 382 (9), 364 (12), 337 (24), 43 (100); 'H NMR 6 1.29 (t, J = 8 Hz, 3 H, CH&HJ, 1.66 (s,3 H, CH3), 1.75 (9, 3 H, CH3), 2.14 (s, 3 H, CH,CO), 3.89 (m, 1 H), 4.18 (4, J = 8 Hz, 2 H, CH,CH,), 4.58-4.86 (m, 4 H, CH, of OCH2C1, and olefinic CH,), 5.96 (s, 1 H, olefinic CH). Anal. Calcd for ClSHz5O7Cl3:C, 48.37; H, 5.34; C1, 22.55. Found: C, 48.07; H, 5.38; C1, 22.80. [2S-(lE,2a,3a,5a)]-[5-Acetyl-3-(acetyloxy)-2-[[ (2,2,2-trichloroethoxy)carbonyl]oxy]-2-methylcyclohexy~dene]acetic Acid Ethyl Ester (4). To a solution of 5.00 g (10.6 mmol) of 3 in 142 mL of a 1:l mixture of tetrahydrofuran-water were added 3.73 mL of a 1% aqueous solution of osmium tetraoxide and 5.60 g (24.3 mmol) of potassium periodate. The mixture was stirred vigorously for 16 h at 25 "C. A 1% aqueous solution of osmium tetraoxide (3.73mL) and 5.60 g (24.3"01) of potassium periodate were added, and the reaction was continued for 15 h a t 25 "C. The mixture was diluted with brine until two layers were formed. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with 10% aqueous sodium bisulfite, followed by water and brine. After the mixture was dried (Na2S04)and the solvents were evaporated, the residue was chromatographed on silica gel, with 30% ethyl acetate-hexane as the eluent, to give 4.16 g (83%) of 4 as an oil: [aIz5D -51.3" (c 1.0, CHCI,); IR (CHCl,) 1760, 1715, 1657 cm-'; MS, m / z 366 (M+- HOAC- EtOH)," 237 (a), 220 (12), 178 (25), 43 (100);'H NMR 6 1.30 (t,J = 8 Hz, 3 H, CHZCH,), 1.68 (9, 3 H, CH3), 2.16 (s, 3 H, CH,CO), 2.23 (s, 3 H, CH,CO), 2.57 (m, 1 H), 4.08 (br d, J = 13 Hz, 1 H), 4.19 (4, J = 8 Hz, 2 H, CHZCH,), 4.64-4.78 (m, 3 H, CHO and CH,O), 6.02 (s, 1 H, olefinic CH). Anal. Calcd for C18H2308C13:C, 45.64; H, 4.89; C1, 22.45. Found: C, 45.82; H, 5.06; C1, 22.60. [25 -( lE,2a,3a,5a)]-[3,5-Bis(acetyloxy)-2-[ [ (2,2,2-trichloroethoxy)carbonyl]oxy]-2-met hylcyclohexylidene]acetic Acid Ethyl Ester (5). To a mixture of 0.725 mL (26.6 mmol) of 90% hydrogen peroxide and 18 mL of dichloromethane, cooled to 0 "C, was added a solution of 3.84 mL (27.2 mmol) of trifluoroacetic anhydride in 21 mL of dichloromethanedropwise with vigorous stirring over a 15-min period. After stirring at 0 "C for 10 min, 11.2 g of finely pulverized, anhydrous potassium dihydrogen phosphate was added and the resulting suspension stirred for 10 min at 0 "C and then treated dropwise at 0 "C with a solution of 4.16 g (8.79 mmol) of 4 dissolved in 25 mL of dichloromethane. The addition was carried out over a 25-min period. The resulting mixture was stirred for 23 h a t 0 "C and then quenched with 250 mL of a 10% aqueous sodium sulfite solution. The mixture was extracted with dichloromethane. The combined organic extracts were washed sequentially with water, saturated aqueous NaHCO,, and brine. After drying (Na2S04) and evaporation in vacuo, the residue was chromatographed on silica gel, with 40% ethyl acetate-hexane as the eluent, to afford 4.01 g (93%) of 5 as an oil: [aIz5D -68.8" (c 0.40, CHCI,); IR (CHCl,) 1742, 1720, 1655 cm-'; MS, m/z 488 (M+),14360 (l),194 (ll),177 (loo),43 (96);'H NMR 6 1.29 (t,J = 8 hz,3 H, CH,CH,), 1.67 (s,3 H, CH3), 2.07 (9, 3 H, CH,CO), 2.16 (5, 3 H, CHSCO), 2.22 (m, 1 H, CH of CH2),4.10 (br d, J = 13 Hz, 1 H, CH of CH2), 4.21 (q, J = 8 Hz, 2 H, CH,CH,), 4.68-4.84 (m, 4 H, CHzO and 2 CHO), 6.10 (s, 1 H, olefinic CH). Anal. Calcd for Cl8HZ3OsCl3:C, 44.15; H, 4.73; C1, 21.72. Found: C, 44.40; H, 4.77; C1, 21.54. (14) The peak observed on off-scale scan only.
J. Org. Chem., Vol. 55, No. 1, 1990 245 [25-(LE,2a,3a,5a)]-[3-(Acetyloxy)-2-[ [(2,2,2-trichloroethoxy )carbonyl]oxy ]-5- hydroxy-2-methylcyclohexylidene]acetic Acid Ethyl Ester (6). To a solution of 17.7 g (36.1 mmol) of 5 in 460 mL of ethanol was added 88.4 g of cation-exchange resin AG 50W-X4 (200-400 mesh) washed with ethanol, and the suspension was stirred at 25 "C under argon for 21 h. The resin was filtered and washed with ethanol. The combined filtrates were evaporated to dryness. The residue was chromatographed on silica gel, with 40% ethyl acetatehexane as the eluent, to give 3.4 g of the desired product (6) and 11.65 g of the recovered starting material (5). The same procedure was repeated with the recovered starting material three more times to give 9.35 g (58%) of 6 as an oik [a]%D -68.2" (c 0.56, CHClJ; IR (CHCld 3605,1758, 1723,1655 cm-'; MS, m/z 446 (M+,l),386 (18), 358 (16), 43 (100); 'H NMR 6 1.30 (t, J = 8 Hz, 3 H, CH,CH,), 1.67 (s, 3 H, CH,), 1.91 (s, 1 H, OH), 2.14 (s, 3 H, CH,CO), 3.80 (br s, 1 H, CHO), 4.00 (br d, J = 13 Hz, 1 H, CH of CH2), 4.20 (4, J = 8 Hz, 2 H, CH,CH,), 4.65-4.84 (m, 3 H, CHO and CH,O), 6.05 (s, 1 H, olefinic CH). Anal. Calcd for C16H2108C13:C, 42.93; H, 4.73; C1, 23.76. Found: C, 43.18; H, 4.90; C1, 23.46. [2 5 4lE,2a,3~~,5a)]-[3-(Acetyloxy)-2-[ [(2,2,2-trichloroethoxy)carbonyl]oxy]-5-[ [ (1,l-dimethylethyl)dimethylsilyl]oxy]-2-methylcyclohexylidene]aceticAcid Ethyl Ester (7). To a solution of 13.3 g (29.8 mmol) of 6 in 260 mL of dry N,Ndimethylformamide were added 8.96 g (59.4 mmol) of tert-butyldimethylsilyl chloride and 8.10 g (119 mmol) of imidazole, and the resulting mixture was stirred at room temperature under argon for 18 h. Crushed ice was then added, and after being stirred for 1 h, the mixture was evaporated in vacuo to dryness. The residue was partitioned between water and ether. The aqueous layer was extracted with ether. The combined ether extracts were washed with water and brine and dried (Na2S0,), and the solvent was evaporated in vacuo. The residue was purified by chromatography over silica gel, using ether-hexane (1:2) as the eluent, to give 16.0 g (96%)of 7 as an oik [a]%D -66.3" (c 0.57, CHCI,); IR (CHCl,) 1758,1720,840cm-'; MS, m/z 545 (M+ - CH3, 21), 503 (24), 469 (5),443 (20),415 (16), 269 (37), 43 (100);'H NMR 6 0.05 (s, 3 H, SiMe), 0.07 (5, 3 H, SiMe), 0.88 (s, 9 H, CMe3),1.26 (t,J = 8 Hz, 3 H, CH,CH,), 1.60 ( s , 3 H, CH,), 2.11 (s, 3 H, CH,CO), 3.66 (br s, 1 H, CHO), 3.97 (br d, 1 H, CH of CH,), 4.17 (4, J = 8 Hz, 2 H, CH,CH,), 4.57 (m, 1 H, CHO), 4.73 (s, 2 H, CH,CCl,), 5.97 (s, 1 H, olefinic CH). Anal. Calcd for C22H3508C13Si:C, 47.02; H, 6.28; C1, 18.93. Found: C, 46.88; H, 6.30; C1, 18.96. [2S-(lE,2a,3a,5a)]-[3-(Acetyloxy)-2-hydroxy-5-[ [(1,l-dimet hylethyl)dimethylsilyl]oxy]-2-methylcyclohexylidene]acetic Acid Ethyl Ester (8). To a solution of 15.9 g (28.3mmol) of 7 in 900 mL of dry tetrahydrofuran were added 99.8 g of zinc dust and 200 mL of 1 M solution of potassium dihydrogen phosphate, and the mixture was stirred for 4.5 h at 25 "C. After filtration, the filtrate was evaporated under reduced pressure to remove most of the solvent. The remaining aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with water and brine. After drying (Na2S04)and evaporation in vacuo, the residue was chromatographed on silica gel, with 40% ethyl acetate-hexane as the eluent, to afford 11.1 g (100%)of 8 as an oik [D]%D -64.3" (c 0.55, CHCI,); IR (CHClJ 3585,1730,1713,1651,838 cm-'; MS, m/z 371 (M+ - CH,, 5), 353 (2), 329 (ll),269 (66), 43 (100); 'H NMR 6 0.05 (s, 3 H, SiMe), 0.06 (s, 3 H, SiMe), 0.85 (s, 9 H, CMe,), 1.28 (t,J = 8 Hz, 3 H, CH,CH,), 1.54 (s, 3 H, CH,), 2.01 (m, 2 H, CH,), 2.09 (s, 3 H, CH,CO), 2.84 (m, 1 H, CH of CH,), 3.40 (m, 1 H, CH of CH,), 3.76 (br s, 1H, CHOSi), 4.18 (q, J = 8 Hz, 2 H, CH2CH3),4.63 (m, 1 H, CHOAc), 6.00 (s, 1 H, olefinic CH). [3R-( lE,3a,5a)]-[3-(Acetyloxy)-2-methylene-5-[ [(1,l-dimethylethyl)dimethylsilyl]oxy]cyclohexylidene]acetic Acid Ethyl Ester (9). To a solution of 9.34 g (24.2 mmol) of 8 in 230 mL of anhydrous carbon tetrachloride at 0 "C was added a solution of 40.0 g (59.5 mmol) of bis[a,a-bis(trifluoromethy1)benzenemethanolato]diphenylsulfur in 340 mL of anhydrous carbon tetrachloride under argon. After the addition, the cooling bath was removed and the mixture stirred at 25 "C for 1.5 h. Crushed ice and water were then added, and after being stirred for 25 min, the mixture was extracted with methylene chloride. The combined organic phases were washed with water and brine, dried (Na#04),
246 J. Org. Chem., Vol. 55, No. 1, 1990
and evaporated to dryness. The residue was chromatographed on silica gel, with methylene chloride as the eluent, to give 8.82 g (99%) of 9 as an oil: [(Y]=D +1.78" (c 0.46, CHCl,); IR (CHCl,) 1730,1708, 1640,838 cm-'; MS, m / z 368 (M+),14353 (5), 323 (4), 311 (12),251 (E),177 (21), 75 (100); 'H N M R 6 0.05 (s,3 H, SiMe), 0.06 (s, 3 H, SiMe), 0.86 (s, 9 H, CMe,), 1.28 (t, J = 8 Hz, 3 H, CH,CH3), 1.68 (m, 1 H, CH of CH2),2.13 (s, 3 H, CH,CO), 2.21 (m, 1 H, CH of CH,), 2.29 (m, 1 H, CH of CH,), 3.81-3.95 (m, 2 H, CHO and CH of CHZ), 4.18 (4, J = 8 Hz, 2 H, CHZCH,), 4.98 (s, 1H, olefiic CH), 5.21 (s, 1H, olefinic CH), 5.33 (m, 1H, CHO), 5.95 (9, 1 H, olefinic CH). [3R-(lE,3a,5a)]-[3-Hydroxy-5-[ [ (1,l-dimethylethy1)dimethylsilyl]oxy]-2-methylenecyclohexylidene]acetic Acid Ethyl Ester (10). To a stirred 10.5 mL 1.09 M solution of sodium ethoxide in ethanol at 0 "C was added a solution of 8.82 g (23.9 mmol) of 9 in 1.3 L of anhydrous ethanol under argon. The mixture was stirred at 25 "C for 30 min and then cooled to 0 "C. After being neutralized with acetic acid-ether (1:2), the solvent was evaporated in vacuo. The residue was partitioned between saturated aqueous NaHCO, and methylene chloride. The aqueous phase was extracted with methylene chloride. The combined organic phases were washed with brine, dried (Na2S04),and evaporated to dryness. The residue was chromatographedon silica gel, with ethyl acetate-hexane (1:7) as the eluent, to give 6.80 g (87%) of 10 as an oil: [a]"D -6.2" (c 0.15, CHCI,); IR (CHCl,) 3465,1703,1638,838 cm-'; MS, m / z 311 (M+- CH3,2), 281 (2), 269 (16), 241 ( l l ) , 223 (15), 75 (100); 'H NMR 6 0.11 (s, 6 H, SiMe,), 0.87 (s, 9 H, CMe,), 1.28 (t, J = 8 Hz, 3 H, CH,CH,), 1.96 (m, 1 H, CH of CH,), 2.15 (m, 1 H, CH of CH,), 2.45 (m, 1 H, CH of CH,), 3.88 (br d, J = 13 Hz, 1 H, CH of CH,), 4.06-4.26 (m, 3 H, CHzCH3and OH), 4.35 (br s, 2 H, 2 CHO), 5.05 (s, 1H, olefinic CH), 5.16 (s, 1 H,olefinic CH), 6.07 (s, 1H, olefinic CH). [3 5 -( lE,38,5a)]-[ 3-Fluoro-5-[ [ ( 1,l-dimethylethy1)dimethylsilyl]oxy]-2-methylenecyclohexylidene]acetic Acid Ethyl Ester (11). To a solution of 6.80 g (20.8 mmol) of 10 in 1.1 L of dry methylene chloride at -95 "C (mixture of acetone and liquid nitrogen) was added dropwise 21.2 mL (174 mmol) of (diethylamid0)sulfurtrifluoride over a 10 min-period under argon. The mixture was stirred at -95 "C for 30 min, and then the cooling bath was removed. The mixture was then poured with stirring into a mixture of saturated aqueous NaHC0,-methanol (21) and ice chips. The mixture was extracted with methylene chloride. The combined organic phases were washed with water and brine, dried (Na2S04),and evaporated to dryness. The residue was chromatographed on silica gel, with methylene chloride-hexane (1:l) as the eluent, to afford 4.09 g (60%) of 1 1 as an oil: IR (CHCl,) 1708,1640,838 cm-'; MS, m / z 641 (2M+ - CH,, l), 599 (14), 579 (5), 447 (17), 328 (l),75 (100); 'H NMR 6 0.08 (s, 6 H, %Mez), 0.87 (s, 9 H, CMe,), 1.29 (t, J = 8 Hz, 3 H, CH2CH3), 1.98-2.14 (m, 2 H, CH,), 2.98 (m, 1 H, CH of CH,), 3.10 (br d, J = 13 Hz, 1 H, CH of CH,), 4.08-4.16 (m, 3 H, CH2CH3and CHO), 5.20 (s, 1H, olefinic CH), 5.25 (br d, J = 48 Hz,1H, CHF), 5.98 (s, 1 H, olefinic CH). Anal. Calcd for Cl7HSO3FSi: C, 62.16; H, 8.90; F, 5.78. Found C, 62.40; H, 8.96; F, 5.60. [3 5 -( lZ,38,5a)]-[ 3-Fluoro-5-[[ (1,l-dimethylethy1)dimet hylsilyl]oxy]-2-methylenecyclohexylidene]aceticAcid Ethyl Ester (12). A solution of 4.09 g (12.45 mmol) of 1 1 and 0.3 g of fluorenone in 500 mL of tert-butyl methyl ether was irradiated for 1 h with a Hanovia 450-W mercury lamp using a uranium glass filter. During the photolysis, a gentle stream of argon was passed through the solution. The solvent was removed in vacuo and the residue chromatographed on silica gel, with cyclohexane-methylene chloride (1:l) as the eluent, to give 3.46 g (85%) of 12 as an oil: [ c ~ ] ~+18.4" D ( C 0.09, CHCl,); IR (CHCl3) 1718,1640,838 cm-'; MS, m / z 328 (M+,l l ) , 313 (3), 308 (2), 283 (51, 271 (85), 151 (631, 75 (100); 'H NMR 6 0.07 ( 8 , 6 H, SiMe,), 0.87 (s, 9 H, CMe,), 1.25 (t, J = 8 Hz, 3 H, CH,CH,); 1.85-2.02 (m, 1 H, CH of CH,), 2.15 (m, 1 H, CH of CHz), 2.27 (m, 1 H, CH of CH,), 2.49 (m, 1 H, CH of CH,), 4.13 (4, J = 8 Hz, 2 H, CHzCH3),4.22 (br s, 1H, CHO), 5.18 (br d, J = 48 Hz, 1H, CHF), 5.24 (s, 1 H, olefinic CH), 5.32 (s, 1H, olefinic CH), 5.73 (s, 1 H, olefinic CH). [35-(12,3fi,5a)]-[3-Fluoro-5-[ [ (1,l-dimethylethy1)dimethylsilyl]oxy]-2-methylenecyclohexylidene]ethanol(13). To a solution of 1.17 g (3.57 mmol) of 12 in 20 mL of dry toluene
Shiuey et al. at -75 "C was added dropwise a 5.8-mL (10.2 mmol) 1.76 M solution of diisobutylaluminum hydride in toluene over a period of 10 min. After addition, stirring was continued for 40 min at -75 "C. The reaction mixture was then quenched by adding rapidly 190 mL of 2 N potassium sodium tartrate. The organic phase was separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried (Na2S04)and the solvents evaporated in vacuo. The residue was chromatographed on silica gel, with 10% ethyl acetate-hexane as the eluent, to afford 0.850 g (83%) of 13 as an oil: +53.9" (c 0.16, CHCl,); IR (CHCl,) 3620, 838 cm-'; MS, m/z 286 (M+),14271 (l), 229 (5), 209 (7), 137 (49), 75 (100); 'H NMR 6 0.08 (s, 6 H, SiMez), 0.88 (s, 9 H, CMe,), 1.90 (m, 1 H, CH of CHJ, 2.08-2.28 (m, 2 H, CHd, 2.48 (m, 1H, CH of CHJ, 4.16 (m, 2 H, CH,O), 4.28 (br s, 1 H, CHO), 4.95 (s, 1 H, olefinic CH), 5.09 (br d, J = 48 Hz, 1 H, CHF), 5.31 (s, 1 H, olefinic CH), 5.64 (br t, J = 6 Hz, olefinic CH). Anal. Calcd for C15Hn02FSi: C, 62.89; H, 9.50; F, 6.63. Found C, 62.60; H, 9.39; F, 6.33. [ 1R-(lfi,32,5a)]-[[3-(2-Chloroethylidene)-5-fluoro-4methy lenecyclohexylloxy ](1,l-dimethylethy1)dimet hylsilane (14). A solution of 0.782 g (5.85 mmol) of N-chlorosuccinimide in 22 mL of methylene chloride was treated dropwise at 0 "C and under argon with 0.484 mL (6.60 mmol) of dimethyl sulfide over 15 min. A white, voluminous precipitate formed. After the addition, the mixture was stirred for an additional 15 min at 0 "C, then cooled at -20 "C, and treated dropwise with a solution of 0.839 g (2.93 "01) of 13 in 10 mL of methylene chloride. After an additional 30 min of being stirred at -20 "C, the reaction mixture was allowed to come to room temperature. The mixture was washed with water and brine and dried (Nafi04). The solvent was evaporated in vacuo and the residue chromatographed on silica gel, with 3% ethyl acetate-hexaneas the eluent, to give 0.833 g (93%) of 14 as an 03: [ C Y ] ~ D+73.0° (C 0.28, CHCl,); IR (CHClJ 1643,838cm-'; 'H N M R 6 0.08 (s,6 H, SiMeJ, 0.88 (s,9 H, CMed, 1.84-2.03 (m, 1 H, CH of CH,), 2.12 (br s, 1 H, CH of CH,), 2.24 (m, 1 H, CH of CH,), 2.48 (br d, J = 13 Hz, 1 H, CH of CH,), 4.06-4.26 (m, 3 H, CHO and CH,Cl), 5.10 (br d, J = 48 Hz, 1 H, CHF), 5.16 (s, 1H, olefinic CH), 5.35 (s, 1H, olefinic CH), 5.63 (br t, J = 6 Hz, 1 H, olefinic CH). [3 5 - ( 12,3a,58)]-[ 2-[3-Fluoro-5-[ [( 1,l-dimethylet hy1)dimethylsilyl]oxy]-2-methylenecyclohexylidene]ethyl]diphenylphosphine Oxide (15). To a solution of 1.78 g (5.84 mmol) of 14 in 146 mL of dry tetrahydrofuran at -75 "C, under argon, was added dropwise 22.0 mL (7.44 mmol) of a 0.338 M solution of lithium diphenylphosphide in tetrahydrofuran until the orange color developed. After addition of 6 mL of water, the reaction mixture was allowed to reach room temperature and the solvent evaporated in vacuo. The residue was dissolved in 60 mL of methylene chloride and stirred vigorously with 120 mL of a 5% hydrogen peroxide solution for 45 min. The methylene chloride layer was separated and the aqueous phase extracted with methylene chloride, and the combined organic extracts were washed with 2 N aqueous sodium sulfite, water, and brine and then dried (Na,S04). Evaporation of the solvent and chromatographic purification of the residue on silica gel using ethyl acetate-hexane (1:l) gave 1.35 g (49%) of 15 as an oil: [a]25D +50.2" ( c 0.84, CHCI,); IR (CHCl,) 835, 692 cm-'; UV ,A, (ethanol) 223 (c 22770), 258 (19501, 265 (1750), 272 nm (1280); MS, m / z 470 (M+),14455 (4), 450 (a), 413 (98), 338 (9), 75 (100); 'H NMR 6 0.02 (e., 6 H), 0.84 (s, 9 H), 1.76-1.93 (m, 1 H), 2.16 (m, 2 H), 2.42 (br d, 1H), 3.28 (m, 2 H), 4.01 (m, 1H), 5.02 (dm, J = 44 Hz, 1 H), 5.14 (s, 1H), 5.30 (s, 1H), 5.5 (m, 1 H),7.5 (m, 6 H), 7.73 (m, 4 H). Anal. Calcd for C2,H,02FPSi: C, 68.91; H, 7.71; F, 4.04. Found: C, 68.69; H, 7.80; F, 3.88. [[ (La,38,52,7E)-3-[ [ (1,l-Dimethylethyl)dimethylsilyl]oxy]-l-fluoro-9,10-secocholesta-5,7,10( 19)-trien-25-yl]oxy]trimethylsilane (17). To a solution of 210 mg (0.446 mmol) of 15 in 6 mL of dry tetrahydrofuran was added dropwise at -75 "C 0.26 mL (0.42 mmol) of a 1.6 M solution of n-butyllithium in hexane. After the deep orange mixture was stirred for 6 min, a solution of 98 mg (0.28 mmol) of 165 in 6 mL of dry tetrahydrofuran was added dropwise. The mixture was stirred at -75 "C for 5 h and quenched by addition of a 1:l mixture of 2 N aqueous potassium hydrogen tartrate and 2 N aqueous potassium
J. Org. Chem. 1990,55, 247-250 bicarbonate. The mixture was extracted with ethyl acetate, and the organic phase was washed with brine, dried (Na2S04),filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel using ethyl acetate-hexane (1:15), to give 106 mg (63%) of 17 as a glass: IR (CHCI,), 1633,1600 (C=C), 841 (SiMe,) cm-'; MS, m / z 604 (M+),14584 (lo), 452 (4), 131 (78),77 (100);W A- (ethanol) 243 (e 15330),268 n m (15790); 'H NMR b 0.08 (s, 6 H, SiMeJ, 0.10(s, 9 H, SiMe3), 0.56(s, 3 H, CH,), 0.88(s, 9 H, CMe3), 0.93 (d, J = 7 Hz, 3 H, CHCH,), 1.20 (s, 6 H, CMe2),2.51 (m, 1 H), 2.82 (br d, J = 13 Hz, CH of CHJ, 4.16(br m, 1 H, CHO), 5.09(s, 1 H, olefinic CH), 5.10(dm, J = 48 Hz, 1 H, CHF), 5.36(s, 1 H, olefinic CH), 6.03(d, J = 12 Hz, 1 H, olefinic CH), 6.35(d, J = 12 Hz, 1 H, olefinic CH); exact 604.4507,found 604.4503. mass calcd for C36H6502FSi2 la-Fluoro-25-hydroxycholecalciferol (18). To a solution of 101 mg (0.167mmol) of 17 in 10 mL of dry tetrahydrofuran was added 0.83 mL (0.83mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 20 "C for 15 h under argon. After dilution with 20 mL of water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na#04), and evaporated to dryness. The crude product obtained was purified by column chromatography on silica gel using ethyl acetate-hexane (1:1.3)as the eluent, to afford 63 mg (90%) of la-fluoro-25-hydroxycholecalciferol (18)as a foamy glass: [a]25D +80.7" (c 0.15, MeOH); IR (CHCl,), 3610 (OH), 1644,1600( C 4 ) cm-'; MS, m / z 418 (M+),14398 (15),380 (42),362 (28),347 (6), 59 (100);UV,,A (ethanol) 240 (t 13620),268 nm (13390);'H NMR 6 0.55(s,3 H, CH3), 0.94(d, J = 7 Hz, 3 H, CHCHJ, 1.22 (s, 6 H, CMe2),2.19(m, 1 H), 2.31(m, 1 H), 2.63(dm, J = 13 Hz, 1 H), 2.82 (br d, J = 13 Hz, 1 H), 4.23(br s, 1 H, CHO), 5.11(s, 1 H, olefinic CH), 5.14(dm, J = 48 Hz, 1 H, CHF), 5.40(s, 1 H, olefinic), 6.03 (d, J = 12 Hz, 1 H, olefinic CH), 6.42(d, J = 12 Hz, 1 H, olefinic CH); exact mass calcd for C2,H4,02F418.3247, found 418.3242. [ [(l(r,3&52,7E,22E)-3-[[ (1,l-Dimethylethy1)dimethylsilyl]oxy]- l-fluoro-9,10-secoergosta-5,7,10( 19),22-tetraen-25yl]oxy]trimethylsilane (20). In a manner analogous to the
247
preparation of 17,when 102 mg (0.217mmol) of la-fluoro A-ring synthon 15 was coupled with 54.7mg (0.150mmol) of 19: 46 mg (50%) of 20 was obtained as a glass: MS, mlz 616 (M+),14596 (3),581 (l), 539 (l), 506 (2),464 (2),131 (100);'H NMR b 0.08 (s, 6 H, &Mez),0.10(s, 9 H, SiMe,), 0.56 (s, 3 H, CH,), 0.88(s, 6 H, CMe,), 0.94(d, J = 7 Hz, 3 H, CHCH,), 1.01(d, J = 7 Hz, 3 H, CHCH,), 1.11 (s, 3 H, CH,), 1.16(s, 3 H, CH,), 2.50(m, 1 H,CH of CH2),2.83 (br d, J = 13 Hz, 1 H, CH of CH2),4.16(br m, 1 H, CHO), 5.08 (s, 1 H, olefinic CH), 5.10(dm J = 48 Hz, 1 H, CHF), 5.20 (s, 1 H, olefinic CH), 5.15-5.36(m, 3 H, olefinic CH), 6.01 (d, J = 12 Hz, 1 H, olefinic CH), 6.33(d, J = 12 Hz, 1 H, olefinic CH). la-Fluoro-25-hydroxyergocalciferol (21). In a manner analogous to the preparation of 18,when 44 mg (0.071mmol) of 20 was reacted with tetrabutylammonium fluoride in tetrahydrofuran, 28 mg (91%) of 21 was obtained as a glass: [a]25D +98.5' ( c 0.13,MeOH); IR (CHC1,) 3605 (OH), 1650,1600( C 4 ) cm-'; MS, m / z 410 (M+ - HF),14392 (76),374 (7),269 (40),251 UV ,A, (ethanol) 242 (c 15320),269 nm (15100); (30),59 (100); 'H NMR 6 0.56 (s, 3 H, CH,), 1.00(d, J = 7 Hz, 3 H, CHCH,), 1.04(d, J = 7 Hz, 3 H, CHCH3) 1.13(s,3 H, CH3), 1.17(s,3 H, CH,), 2.63 (dm, J = 13 Hz, 1 H, CH of CH2),2.83(dm, J = 13 Hz, 1 H, CH of CH2),4.23(br s, 1 H, CHO), 5.11(s, 1 H, olefinic CH), 5.14(dm, J = 48 Hz, 1 H, CHF), 5.26-5.43(m, 3 H, olefinic CH), 6.03(d, J = 12 Hz, 1 H, olefinic CH), 6.41(d, J = 12 Hz, 1 H, olefinic CH); exact mass calcd for CBHa02F 430.3247,found
430.3219.
Acknowledgment. We thank the staff of the Physical Chemistry Department of Hoffmann-La Roche Inc. for the determination of physical and analytical data. Registry No. 1,81506-17-4; 2,123836-51-1; 3, 123836-52-2; 4,123836-53-3; 5,123836-54-4; 6,123836-55-5; 7,123836-56-6; 8, 123836-57-7; 9,123836-58-8; 10,123836-59-9; 11,123836-60-2; 12, 123930-10-9; 13,123836-61-3; 14,123836-62-4; 15,123836-63-5; 16,81506-41-4; 17,123836-64-6; 18, 95586-94-0; 19,95716-69-1; 20,123836-65-7; 21, 123836-66-8; ClC02CH2CC13, 17341-93-4.
Benz[ flindene Louis A. Carpino* and Yao-Zhong Lin Department of Chemistry, University of Massachusetts, Amherst, Massachusetts 01003 Received May 31, I989
A convenient route to benz[flindene (1) has been developed in which 2-methylnaphthalene is brominated sequentially in the a-position and the methyl group followed by application of a standard malonic ester route to propionic acid 10. Cyclization of 10via the acid chloride gave 11 (76%). Simultaneous reduction of the carbonyl group and hydrogenolysis of the aryl bromide linkage of 11 gave secondary alcohol 12 in 55.4% yield. Sulfuric acid dehydration of 12 gave 1 (85%). Less successful routes to 1 involved dithionite reduction of unsaturated sulfones 6. Dihydro derivative 7 could be synthesized in 72% yield by magnesium/methanol reduction of 5b.
Curiously, benzlflindene (1) is only fleetingly referenced in the chemical literature. Although this relatively simple and potentially very useful isomer of fluorene has been cited only as a constituent of tobacco smoke,' the ultraviolet spectrum and melting point determined on a sample contaminated with 3% of its dihydro derivative are recorded in a UV handbook.2
1
(1)Severson, R. F.;Snook, M. E.;Arrendale, R. F.; Chortyk, 0. T. Anal. Chem. 1976,48,1866.
Our interest in 1 relates to its possible use as a building block in the development of modified base-sensitive amino-protecting groups of the FMOC type.3 In the present paper we describe a reliable route to hydrocarbon 1. Retroanalytically, it is clear that benz[flindene is po(2)Ultrauiolet Atlas of Organic Compounds; Plenum Press: New York, 1966;Vol. 4, Spectrum E1/40. We are indebted to Dr. 0. T. Chortyk for pointing out this reference. The submitter of the sample for UV analysis, Dr. E. A. Johnson, National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hertfordshire, U.K., has kindly informed us that the sample in question was synthesized by the oxidation of benzlflindane (Johnson, E.A. J. Chem. SOC. 1962,994)by means of dichlorodicyanoquinone and had mp 162-163 "C after recrystallization from ethanol and sublimation in vacuo. We learned of this work only after completion of the present study. (3) Carpino, L. A. Acc. Chem. Res. 1987,20,401.
0022-3263/90/1955-0247$02.50/00 1990 American Chemical Society
