Field of the Invention The present invention relates to novel analogs of the hormone 1cL, 25-dihydroxy vitamin D,. Such analog materials exhibit a pharmacologically desirable combination of <BR> <BR> <BR> high antiproliferative and high transcriptional activity in vitro along with no or low<BR> <BR> <BR> <BR> <BR> <BR> calcemic activity in vivo.

Background of the Invention Because of its extraordinarily high potency in regulating diverse biochemical events vital to good health in humans, la, 25-dihydroxy vitamin D3, also known as calcitriol or 1,25D3, has stimulated the worldwide interest of medical researchers, molecular biologists, pharmacologists, medicinal and organic chemists, and researchers in the area of products for personal care and cancer prevention and/or treatment. This Material corresponds to the structure set forth in Formula I.

Formula I la, 25-dihydroxy vitamin D3 (1,25D3, calcitriol) Numerous references can be cited as showing prior work with respect to vitamin D3 analogues, calcitriol or the like. See, for example: Vitamin D. Chemical. Biochemical and Clinical Update, Proceedings of the Sixth Workshop on Vitamin D, Merano, Italy, March 1985; Norman, A. W., Schaefer, K., Grigoleit, H. G., Herrath, D. V. Eds.; W. de Gruyter; New York, 1985; Brommage, R., DeLucca, H. F., Endocrine Rev. (1985) 6: 491; Dickson, I., Nature (1987) 325: 18; Cancela, L., Theofon, G., Norman, A. W., in Hormones and Their Actions. Part I; Cooke, B. A., King, R. J. B., Van der Molen, H. J. Eds.; Elsevier, Holland, 1988; Tsoukas, D. C., Prowedini, D. M., Manolagas, S. C., Science, (Washington, D. C.) (1984) 224: 1438; Prowedini, D. M., Tsoukas, C. D., Deftoe, L. J., Manolagas, S. C., Science (Washington, D. C.) (1983) 221: 1181; Vitamin D. Chemical Biochemical, and Clinical Endocrinology of Calcium Metabolism, Proceedings of the Fifth Workshop on Vitamin D, Williamsburg, VA, Feb. 1982, Norman, A. W., Schaefer, K., Herrath, D. V., Grigoleit, H. G., Eds., W. de Gruyter, New York, 1982, pp. 901-940; Calverley, M. J. in Vitamin D: Molecular. Cellular, and Clinical Endocrinologv, Norman, A. W., Ed., de Gruyter; Berlin, 1988, p. 51; Calverley, M. J., Tetrahedron (1987) 43: 4609. Vitamin D, A Pluripotent Steroid Hormone : Structural Studies, Molecular Endocrinology and Clinical Applications, ed. Norman, Boullion and Thomasset, 1994, Walter de Gruyter, New York. Calverley and Binderup, Bioorganic & Medicinal Chemistry Letters (1993) 3: 1845. U. S. patents No. 5,274,142; 5,389,622; 5,403,832 and also describe and claim vitamin D3 analogs. The entire contents of each reference and patent cited above and elsewhere in the present application are hereby incorporated by reference.

A major chemical challenge has been to design and synthesize analogs of la, 25- dihydroxy vitamin D3 that retain potent antiproliferative and pro-differentiating activities but that lack hypercalcemic activity. Some synthetic analogs exhibiting such selective physiological activities, like 1 a, 25-dihydroxy-16-ene-23-yne-26,27- hexafluorocholecalciferol developed by Hoffman-La Roche, have been shown to possess very desirable pharmacological properties. Only a few 24-fluoro and 24,24-difluoro analogs of 1,25D3, having natural A-ring substituents and stereochemistry, have been synthesized. They have been shown, however, to be disappointingly similar to 1,25D, in terms of calcemic activity. Although their binding affinity to the vitamin D receptor (VDR) is similar to that of calcitriol, such materials do have longer plasma half-lives.

Given the foregoing, it is clear that there is a continuing need to identify additional synthetic analogs of the hormone la, 25-dihydroxy vitamin D3, which analogs selectively exhibit desirable pharmcological activities but do not exhibit hypercalcemic activity.

Accordingly, it is an object of the present invention to provide novel 1,25D, analogs which are useful for a wide variety of beneficial medicinal and/or personal care product uses but which do not exhibit undesirably high levels of calcemic activity in vivo.

Summarv of the Invention The present invention relates to novel sulfur-containing, and optionally fluorinated, unsaturated and/or oxa-containing analogs of la, 25-dihydroxy vitamin D,. Such analogs have the diastereoisomeric structural formulas set forth as Formulas II, III, IV, V, VI, VII, Vm, IX and X.

Formula II Formula III Formula IV Formula V Formula VI Formula VII Formula VIII Formula IX Formula X In Formulae II-X and other compounds of the invention, the hydroxyl substituents at Position 1 and at position 3 on the A-ring can be such that the analogs are either in the (-), i. e. (la, 3 (3) or the (+), i. e. (lp, 3a), diastereomeric configuration.

The C-0 bonds at these positions are occasionally indicated by wavy lines in structural formulae hereinbelow to indicate that alternative configurations are intended.

Compounds with substituents in the (la, 3 (3) diastereomeric configuration are preferred according to the invention.

The present invention also includes materials which are similar to the compounds of Formulae II-X but which have 23-oxa-25-sulfone, 20-epi-22-oxasulfone; 16-ene-alkenyl sulfone; 16-ene-alkynyl sulfone; and 22E, 24E diene sulfone units.

Compounds represented by Formulae XIV-XVII and XIX are among the preferred compounds of the invention: Formula XIV Formula XV Formula XVI osv 0, \/, o : in I oli Formula XVII Formula XIX Compounds of the invention can be represented by the general formulae XI-XIII and XVIII Formula XI wherein X is H7 or F2 and R is a branched or straight chain lower alkyl (1-6 carbons), an unsubstituted phenyl group or a phenyl group substituted with a lower alkyl or alkoxy group. Compounds wherein R is methyl, t-butyl, phenyl, and methoxyphenyl are especially preferred.

Formula XII wherein X is H2 or F2 and R is a branched or straight chain lower alkyl (1-6 carbons), an unsubstituted phenyl group or a phenyl group substituted with a lower alkyl or alkoxy group. Compounds wherein R is methyl, t-butyl, phenyl, and methoxyphenyl are especially preferred.

Formula XIII wherein n is 1 or 2, and R is a branched or straight chain lower alkyl (1-6 carbons), an unsubstituted phenyl group or a phenyl group substituted with a lower alkyl or alkoxy group. Compounds wherein R is methyl, t-butyl, phenyl, and methoxyphenyl are especially preferred.

Formula XVIII wherein R is a branched or straight chain lower alkyl (1-6 carbons), an unsubstituted phenyl group or a phenyl group substituted with a lower alkyl or alkoxy group. Compounds wherein R is methyl, t-butyl, phenyl, and methoxyphenyl are especially preferred.

Brief Description Of The Drainas Figure 1: Dose response effects of vitamin D3 analogs on keratinocyte proliferation.

No represents the number of cells at zero hours and N, represents the number of cells at 96 hours. KRC 22E, 24Ediene 26S02-1 = compound 23a ; KRC 22E, 24Ediene 26S02-2 = compound 23b ; KRC-20epi 22oxa 26 PMP-1 = compound 15a; KRC-20epi 22oxa 26 PMP-2 = compound 15b.

Figure 2: Effect of 22E, 24E diene sulfone vitamin D3 analog on calcium levels in rat urine. Values shown for control, calcitriol and diene sulfone analog groups, each containing three animals.

Figure 3: Effect of 22E, 24E diene sulfone vitamin D3 analog on weight gain. Weight gain of rats, days 0-7 of treatment is shown for control, calcitriol and diene sulfone analog groups, each containing three animals.

Detailed Description of the Invention In preparing the calcitrol analogs corresponding to Formulas II-VIII, several considerations are taken into account in order to arrive at the desired combination of substitutents which will diminish calcemic activity yet also provide potently pro- differentiating side chains. Position 24 on the side chain is typically the site of side chain metabolic oxygenation. Therefore, it is believed that replacing C-H by stronger C-F bonds at this position should increase lifetime of such an analog in vivo. Further, the atomic size of a fluorine substituent closely matches that of a hydrogen atom, thereby causing no steric hindrance to receptor binding. Further, it is postulated that the presence of two fluorine atoms should increase the lipophilicity of the analog relative to its non-fluorinated counterpart, thereby enhancing rates of absorption and transport in vivo. Further, presence of a t-butylsulfone group at position 24 or 25 is expected to simulate the polar environment in that region characteristic of the natural polar 25-OH group. Finally, a 16- ene carbon-carbon double bond often potentiates antiproliferative activity.

Taking these considerations into account, the sulfur-containing, and optionally fluorine-containing, unsaturated and oxa-containing analogs of the present invention can be prepared via multi-step organic synthesis reaction procedures as set forth hereinafter in Schemes 1,2,3,4,5,6,7,8 and 9. Steps in the reaction process as depicted in the schemes are described in the examples following each scheme.

Unless otherwise noted, in all of the examples, reactions are run in flame-dried round-bottomed flasks under an atmosphere of ultra high purity (UHP) argon. Diethyl ether (ether) and tetrahydrofuran (THF) are distilled from sodium benzophenone ketyl prior to use. Methylene chloride (CH2CI2) is distilled from calcium hydride prior to use.

All other compounds are purchased from Aldrich Chemical Company and used without further purification. Analytical thin-layer chromatography (TLC) is conducted with Silica Gel 60 F254 plates (250 pm thickness, Merck).-Column chromatography is performed using short path silica gel (particle size <230 mesh), flash silica gel (particle size 400-230 mesh), or Florisil (200 mesh). Yields are not optimized. Purity of products is judged to be >95% based on their chromatographic homogeneity. High performance liquid chromatography (HPLC) is carried out with a Rainin HPLX system equipped with two 25 mL/min preparative pump heads using Rainin Dynamax 10 mm x 250 mm (semi- preparative) columns packed with 60 A silica gel (8 pm pore size), either as bare silica or as C-18-bonded silica. Melting points are measured using a Mel-Temp metal-block apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectra are obtained either on a Varian XL-400 spectrometer, operating at 400 MHz for 1H and 100 MHz for 13C or on a Varian XL-500 spectrometer, operating at 500 MHz for 1H and 125 MHz for 13C. Chemical shifts are reported in parts per million (ppm, 5) downfield from tetramethylsilane. Infrared (IR) spectra are obtained using a Perkin-Elmer 1600 FT-IR spectrometer. Resonances are reported in wavenumbers (cm~l). Low and high resolution mass spectra (LRMS and HRMS) are obtained with electronic or chemical ionization (EI or CI) either (1) at Johns Hopkins University on a VG Instruments 70-S spectrometer run at 70 eV for EI and run with ammonia (NH3) as a carrier gas for CI, or (2) at the University of Illinois at Champaign-Urbana on a Finnigan-MAT CH5, a Finnigan-MAT 731, or a VG Instruments 70-VSE spectrometer run at 70 eV for EI and run with methane (CH4) for CI.

Preparation of the Formula II materials is set forth in Scheme 1 as follows.

Scheme 1 Synthesis of Formula II Calcitriol Analogs OHOH ($OTs 1) 03 TSCI If2 OH OU (+)-2 (+)-3 osts Q S TESOTf NaI 2,6-Lutidine Acetone > 90/0 97/0 87% OTES OTES (+)-4 (+) ~5 Ov 20 o 80 ' _ _ 1) n-BuLi,-78'C F n-BuLi,-78*C 2) NFSI,-78°C to r. t. 2) NFSI,-78°C to r. t. 80% H H 80% (two steps) OTES OTES (+)-6 7 00 00 TB C PDC 8 % F F celite 91% OTES OH o o (+)-9 A, s/ 0 H "" O (+)-10 o o ph_Ss NFSI:N-Fluorobenzenesulfonimide N-F Phs 0 O P (O) Ph, 7 1) PhLi 2) (+)-10,66% 3) TBAF, 79% --"" I = t-BuMerSi 0\* 0 0%//0 23 s 23 S F F F F -. in + in H H 3 1 3 i. HO OH OH HO OH 1 2 Formula II Synthesis of the iodide derivative 5 of the C, D-ring is carried out from the calcitriol starting material 1 through intermediates 2,3, and 4 in conventional manner. These steps in the synthesis are described in greater detail in our publication, Journal of Organic Chemistry, 1997, Vol. 62, pp. 3299-3314.

Preparation of the various intermediates 6,7,8,9, and 10 and the Formula II compounds is described in Examples 1 through 5 hereinafter.

Example 1 TES protected C, D-ring sulfone (+)-6 A solution of methyl tert-butyl sulfone (594 mg, 4.40 mmol) and 20 ml of THF was cooled to-78°C, and then 3.1 mL (4.40 mmol, 1.4 M solution in hexane) of n-BuLi was added dropwise to the solution. After 15 minutes, 1.3 mL of HMPA was added and the solution was stirred for another 15 minutes. A precooled (-78°C) solution of iodide 5 (381 mg, 0.87 mmol) in 20 mL of THF was added slowly via cannula. The reaction mixture was then warmed up to room temperature. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous concentrated in vacuo, and then purified by column chromatography (25% EtOAc/hexanes) to give 336 mg (87%) of the desired sulfone (+)-6 as a colorless oil: [a] 25D +45.9° (c 3.3, CHC13);'H NMR (400 MHz, CDCI,) 8 4.02 (d, J= 1.6 Hz, 1H), 3.01-2.90 (m, 1H), 2.85-2.73 (m, 1H), 2.07-1.75 (m, 4H), 1.71-1.50 (m, 4H), 1.41 (s, 9H), (m, 5H), 1.16-1.00 (m, 2H), <BR> <BR> <BR> 0.96-0.89 (m, 15H), 0.54 (q, J = 8.0 Hz, 6H);"C NMR (100 MHz, CDC13) 8 69.46,59.15, 56.56,53.20,43.30,42.44,40.92,34.99,34.76,27.41,26.33,23.76, 23.12,18.56,17.85, 13.74,7.14,5.12; IR (neat, cm-') 2943,2872,1461,1302,1284,1114,1014; HRMS m/z (M') calcd 444. 3093 for C24H4803SSi, found 480.3098.

Example 2 Difluorinated C, D-ring sulfone (+)-8 To a solution of the TES protected C, D-ring sulfone (+)-6 (265 mg, 0.60 mmol) in THF (6.0 mL) was added 0.85 mL of n-BuLi (1.4 M solution in hexane, 1.19 mmol) at- 78°C. After being stirred for 30 minutes, a precooled solution of NFSI (N- fluorobenzenesulfonimide, bought directly from Aldrich, 226 mg, 0.72 mmol) in 5.0 mL of THF was added slowly to the reaction mixture, and then it was warmed up to room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, concentrated in vacuo, and then purified bv column chromatography (25% EtOAc/hexanes) to give a mixture of mono and di-fluorinated sulfones.

The mixture (280 mg) was dissolved in 6.0 mL of THF and the solution was cooled to-78°C. To the solution was added 1.1 mL of n-BuLi (1.4 M solution in hexane, 1.54 mmol) and the reaction mixture was stirred for 30 minutes. A precooled solution of NFSI (386 mg, 1.22 mmol) in 5.0 mL of THF was then added slowly via cannula. The reaction mixture was warmed up to room temperature, quenched with water, extracted with EtOAc, washed with brine and concentrated. Purification by column chromatography (25% EtOAc/hexanes) gave 230 mg (80%) of the desired difluoronated C, D-ring sulfone (+)-8 as a colorless oil: [a]',) +40.7° (c 2.1, CHCl3) ;'H NMR (400 MHz, CDC13) 5 4.02 (d, J = 2.8 Hz, 1H), 2.45 (ddd, J = 35.6,13.6,8.8 Hz, 1H), 2.05-1.75 (m, 5H), 1.70-1.54 (m, 3H), 1.52 (s, 9H), 1.44-1.13 (m, 6H), 1.08 (d, J= 6.0 Hz, 3H), 0.95 (s, 3H), 0.94 (t, J= 8.0 Hz, 9H), 0.55 (q, J= 8.0 Hz, 6H);"C NMR (100 MHz, CDCI,) 8 130.37 (t, J = 289.3 Hz), 69.49,63.29,56.97,53.32,42.58,40.89,35.21 (t, J= 18.3 Hz), 34.72,30.76,27.75,24.48, 56,7.17,5.14;'9F NMR (376 MHz, CDCI3, CFCI, as internal) 8- 94.82 (dd, J = 218.1,35.0 Hz),-97.41 (dd, J = 218.3,30.6 Hz); IR (neat, cm') 2950, 2876,1459,1322,1165,1134,1083,1018; HRMS m/z (M*) calcd 480.2905 for C24H46F203SiS, found 480.2900.

Example 3 Deprotected dinuoronated C, D-ring alcohol (+)-9 A solution of silyl ether (+)-8 (226 mg, 0.47 mmol) in THF (5.0 mL) and 1.2 mL of 1.0 M solution of tetra-n-butylammonium fluoride (TBAF) in THF was stirred overnight at room temperature. The mixture was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, concentrated in vacuo and then purified by column chromatography (25% EtOAc/hexanes) to give 147 mg (85%) of the desired alcohol as a white solid: mp 105-106°C; [α]20D +34.7° (c 1.7, CHCI,); 'H NMR (400 MHz, CDC13) 5 4.07 (d, J= 2.4 Hz, 1H), 2.45 (ddd, J = 35.4,13.6,9.2 Hz, 1H), 2.05-1.74 (m, 6H), 1.64-1.12 (m, 18H), 1.09 (d, J= 6.0 Hz, 3H), 0.97 (s, 3H);"C NMR (100 MHz, CDCI3) 8 130.27 (t, J= 289.3 Hz), 69.42,63.32,56.77,52.82,42.29, 40.51,35.16 (t, J = 18.5 Hz), 33.68,30.76,27.63,24.47,22.61,20.44 (d, J = 2.8 Hz), 17.57,13.53;'9F NMR (376 MHz, CDCl3, CFCl3 as intemal) 8-94.82 (dd, J= 218.1,35.0 Hz),-97.43 (dd, J= 218.1,32.0 Hz); IR (neat, cm') 3564,2939,2869,1317,1133; HRMS m/z (M+) calcd 366.2040 for C18H32F2O3 S, found 366.2047; Anal. Calcd for C, 8H32F2O3S: C, 58.98; H, 8.74. Found: C, 58.45; H, 8.76.

Example 4 C, D-ring ketone (+)-10 To a solution of the C, D-ring alcohol (+)-9 (74 mg, 0.20 mmol) in CH2CI2 (5.0 mL) were added 150 mg of oven-dried celite and pyridinium dichromate (PDC, 152 mg, 0.40 mmol) at room temperature. The reaction mixture was stirred overnight and then passed through a 2 cm pad of flash silica gel and washed with EtOAc. The filtrate was concentrated and purified by column chromatography (25% EtOAc/hexanes) to give 67 mg (91%) of the desired C, D-ring ketone (+)-10 as a colorless solid: mp 106-107°C; [α]25D +15.7° (c 3.5, CHCl3) ;'H NMR (400 MHz, CDC13) 5 2.51-2.33 (m, 2H), 2.30-2.14 (m, 2H), 2.12-2.04 (m, IH), 2.04-1.80 (m, 5H), 1.72 (m, 1H), 1.64-1.42 (m, 12H), 1.33 (m, 1H), 1.12 (d, J = 6. 0 Hz, 3H), 0.65 (s, 3H);"C NMR (100 MHz, CDCI,) 8 211.56,129.93 (t, J= 289.4 Hz), 63.31,61.99,56.63,49.90,40.98,38.95,35.20 (t, J= 18.5 Hz), 30.79, 27.75,24.35,24.02,20.54 (d, J= 2.6 Hz), 19.14,12.49;'9F NMR (376 MHz, CDCI,, CFCl3 as intemal) 5-94.87 (ddd, J= 6 Hz),-97.46 (ddd, J= 219.0,30.5, 8.5 Hz); IR (neat, cm-1) 3013,1708,1314,1208; HRMS m/z (M') calcd 364.1884 for C,, HO, S, found 364.1884; Anal. Calcd for C18H30F2O3S: C, 59. 31; H, 8.24. Found: C, 59.42; H, 8.27.

Example 5 Analogs Formula II A solution of 102 mg (0.18 mmol) of racemic phosphine oxide (A-ring) in 2.0 mL of anhydrous THF was cooled to-78°C and treated with 94 µL (0.15 mmol, 1.6 M solution in THF) of phenyllithium under argon atmosphere. The mixture turned reddish orange and was stirred for 30 min at-78°C. To the solution was added dropwise a solution of 45 mg (0.12 mmol) of the C, D-ring ketone (+)-10 (dried azeotropically three times with benzene and held under vacuum for at least 24 h prior to use) in 1.0 mL of anhydrous THF. The reaction kept going on at-78°C until the reddish orange color faded to yellow (about 4 hours). The reaction was quenched by adding 3.0 mL of a 1: 1 mixture of 2 N sodium potassium tartrate and 2 N K, CO, solution. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous MgSO"concentrated in vacuo, and then purified by column chromatography (97% hexanes/ether) to afford 59 mg (66%) of the coupled product as a colorless oil.

The coupled product (59 mg, 0.081 mmol) was dissolved in 3.0 mL of anhydrous THF, and to this solution were added TBAF (0.32 mL, 0.32 mmol, 1.0 M solution in THF) and 46 µL (0.32 mmol, 4 equiv) of Et, N. The reaction was run in darkness overnight, then quenched with water and extracted with EtOAc. The organic portions were washed with brine, dried over anhydrous MgSO4, concentrated in vacuo and then purified by silica gel chromatography (90% EtOAc/hexanes) to give 32 mg (79%) of a mixture of two diastereomers as a white solid. One portion (16 mg) of the diastereomers was separated by reverse phase HPLC (C-18 semipreparative column, 52% MeCN/H2O, 3.0 mL/min) to afford 5.7 mg (19%) of Formula II-1 (1α, 3ß, tR 100.8 min) as a foaming solid and 4.1 mg (14%) of Formula 11-2 (1 p, 3a, tR 95.8 min) as a colorless oil. Formula II-1: [α]25D <BR> <BR> <BR> +17. 4° (c 0.6, CHCI,);'H NMR (400 MHz, CDCI,) 5 6.37 (d, J= 11.2 Hz, IH), 6.01 (d, J = 11.6 Hz, 1H), 5.33 (s, 1H), 4.99 (s, 1H), 4.44 (m, 1H), 4.23 (m, 1H), 2.83 (dd, J= 12.4, 3.6 Hz, 1H), 2.66-2.38 (m, 2H), 2.31 (dd, J= 13.4,6.6 Hz, 1H), 2.10-1.20 (m, 24H), 1.12 (d, J= 6.0 Hz, 3H), 0.59 (s, 3H);"C NMR (100MHz,CDC)8 147.78,142.73,133.42, 130.24 (t, J= 288.0 Hz), 70,56.55,46.17, 45.46,43.02,40.57,35.13,31.43,29.17,27.96,24.48,23.67,22.40, 20.76,12.09;"F NMR (376 MHz, CDCI3, CFCI, as internal) 8-94.87 (dd, J= 217.7,37.2 Hz),-97.39 (dd, J= 219.0,28.0 Hz); UV (EtOH) #max 263 nm (E 12,225); IR (neat, cm-') 3695,3601,2931, 2872,1596,1467,1308,1132,1043; HRMS m/z (M') calcd 500.2772 for CHO, S, found 500.2774. Formula II-2 : [a] 25D +8.5 (c 0.4, CHCl3) ;'H NMR (400 MHz, CDCI,) 8 6.38 (d, J= 11.2 Hz, 1H), 6.01 (d, J= 11.2 Hz, 1H), 5. 32 (s, 1H), 5.00 (s, 1H), 4.45 (m, 1H), 4.22 (m, 1 H), 2.83 (dd, J= 12.8,4.4 Hz, 1H), 2.62 (dd, J= 12.8,4.7 Hz, 1H), 2.46 (m, 1H), 2.29 (dd, J= 13.4,7.4 Hz, 1H), 2.20-1.20 (m, 24H), 1.12 (d, J= 6.0 Hz, 3H), 0.59 (s, 3H);"C NMR (100 MHz, CDCI,) 8 147.41,142.76,133.29,130.24 (t, J= 289.3 Hz), 00,63.36,56.70,56.52 46.17,45.69,42.97,40.55, 35.32 (t, J= 17.8 Hz), 14,27.94,24.47,23.65,22.42,20.74,12.09;'9F NMR <BR> <BR> <BR> (376 MHz, CDCl3, CFCl3 as intemal) 8-94.81 (dd, J = 220.7,29.7 Hz),-97.38 (dd, J= 215.8,26.7 Hz); UV (EtOH) A"E"263 nm (e 12,200); IR (neat, cm-') 3695,3613,2919, 1596,1308,1126,1043. HRMS m/) calcd 500.2772 for C., 7H,, F, O, S, found 500.2784.

Preparation of the Formula III materials is set forth in Scheme 2 as follows: Scheme 2 Synthesis of Formula III Calcitriol Analogs OTs CN CHO KCN DIBAH fT\ f r DMSO 0°C, toluene LL/ H 80% 95% H OTES OTES OTES (+)-4 (+)-12 OH I C. O Su n-BuLi -78°c, 99%. Imidazole'_pA 95% 91%'' OTES OTES (+)-13 (+)-14 Ph Ph oTEHs oh 92% PDC oyes oh 92% OTES pHH (+)-15 (+)-16 Ph O O O H (+)-17 P (O) Ph2 1) PhLi 2) (+)-17,54% / 3) TBAF, 90% "..

Formula III Synthesis of the iodide derivative 14 of the C, D-ring is carried out from the sulfone starting material 4 and proceeds through intermediates 11,12, and 13 as set forth in Scheme 2. These steps in the synthesis are described in greater detail in the following experimental sections.

Preparation of the various intermediates 15,16, and 17 and the Formula III compounds is described in Examples 6 through 9 hereinafter.

Example 6 TES protected 25-phenyl C, D-ring sulfone (+)-15 To a solution of methyl phenyl sulfone (181 mg, 1.16 mmol) and THF (10 mL) was added 0.83 mL (1.16 mmol) of a 1.4 M solution of n-BuLi in hexane at-78°C. After 15 minutes, 0.3 mL of HMPA was added and the solution was stirred for another 15 minutes at-78°C. A precooled (-78°C) solution of iodide 14 (105 mg, 0.23 mmol) in 3.0 mL of THF was added slowly via cannula. The reaction mixture was then warmed up to room temperature. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous MgS04, and concentrated to give a crude product that was purified by column chromatography (25% EtOAc/hexanes) to give 105 mg (95%) of the desired sulfone (+)-15 as a colorless oil: [a] 25D +44. 1° (c 1.3, CHCl3) ;'H NMR (400 MHz, CDCI,) 8 7.94-7.86 (m, 2H), 7.70-7.52 (m, 3H), 4.00 (d, J= 2.4 Hz, 1H), 3.03 (m, 2H), 1.93-1.46 (m, 7H), 1.44-1.22 (m, 5H), 1.22-0.96 (m, 5H), 0.92 (t, J = 8.0 Hz, 9H), 0.85 (s, 3H), 0.83 (d, J = 6.4 Hz, 3H), 0.53 (q, J = 7.9 Hz, 6H);"C NMR (100 MHz, CDCI3) S 129.39,128.15,69.45,56.88,56.51,53.14,42.27,40.85,35.10, 34.72,34.54,27.43,23.07,19.45,18.47,17.79,13.64,7.10,5.07; IR (neat, cm-1) 2949, 1087,1025; HRMS m/z (M*) calcd 478. 2937 for C27H4603SiS, found 478.2932.

Example 7 Deprotected 25-phenyl C, D-ring sulfone (+)-16 A flame-dried 5 mL flask was charged with 105 mg (0.22 mmol) of the silyl ether (+)-15,2.0 mL of anhydrous THF'and 0.55 mL (0.55 mmol) of a 1.0 M solution of TBAF in THF. The resulting reaction mixture was stirred overnight at room temperature, and then it was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, concentrated in vacuo and then purified by chromatography (20% EtOAc/hexanes) to give 79-mg (99%) of the desired alcohol (+)-16 as a colorless oil: la]'D'31. 8* (c 3.0, CHC13);'H NMR (400 MHz, CDCI3) 6 7. 92-7. 84 (m, 2H), 7.63 (t, J= 7.4 Hz, 1H), 7.58-7.50 (m, 2H), 4.02 (d, J= 2.4 Hz, 1H), 3.02 (m, 2H), 1.92 (d, J =13.2 Hz, 1H), 1.85-1.67 (m, 4H), (m, 12H), 0.86 (s, 3H), 0.82 (d, J = 6.8 Hz, 3H);"C NMR (100 MHz, CDCI,) 8 139.32,133.75,129.38,128.10, 95,40.42,35.05,34.42,33.65,27.25,22.55,19.39,18.35, 17.51,13.61; IR (neat, cm-1) 3539,2937,2872,1446,1305,1147,1086; HRMS m/z (M+) calcd 364.2072 for C,, H3, 0, Slfound 364.2069.

Example 8 C, D-ring ketone (+)-17 To a solution of the C, D-ring alcohol (+)-16 (68 mg, 0.19 mmol) in CH2Cl2 (5.0 mL) were added 140 mg of oven-dried celite and pyridinium dichromate (PDC, 140 mg, 0.38 mmol) at room temperature. The reaction mixture was stirred overnight and then passed through a 2 cm pad of flash silica gel and washed with EtOAc. The filtrate was concentrated and purified by silica gel chromatography (50% EtOAc/hexanes) to give 62 mg (92%) of the desired C, D-ring ketone (+)-17 as a colorless oil: [a] 25D +10.8° (c 3.4, CHCI,);'H NMR (400 MHz, CDCI,) 8 7.94-7.82 (m, 2H), 7.63 (t, J= 7.4 Hz, 1H), 7.58- 7.48 (m, 2H), 3.02 (m, 2H), 2.39 (dd, J= 11.6,7.2 Hz, 1H), (m, 2H), 2.10-1.26 (m, 12H), 1.26-1.02 (m, 2H), 0.89 (d, J= 6.4 Hz, 3H), 0.57 (s, 3H);"C NMR (100 MHz, CDCI,) 8 01, 53,12.56; IR (neat, cari') 2943,2872, 1708,1443,1378,1302,1143,1079; HRMS m/z (M') calcd 362.1916 for C2, H3aO3S, found 362.1910.

Example 9 Analogs Formula III Racemic phosphine oxide (A-ring, 102 mg, 0.18 mmol) was dissolved in 2.0 mL of anhydrous THF and cooled to-78°C under argon atmosphere. To this solution was added 94 uL (0.15 mmol) of phenyllithium (1.8 M solution in THF) dropwise. The mixture turned deep reddish orange and persisted. After stirring at-78°C for 30 minutes, a precooled (-78°C) solution of C, D-ring ketone (+)-17 (44 mg, 0.12 mmol) dissolved in 1.0 mL of anhydrous THF was added dropwise via cannula. The reaction kept going on until the reddish orange color faded to yellow (about 4 hours). The reaction was quenched by adding 3.0 mL of a 1: 1 mixture of 2 N sodium potassium tartrate and 2 N K2CO3 solution.

The reaction mixture was allowed to warm to room temperature, extracted with EtOAc, washed with brine, dried over anhydrous MgS04, filtered, concentrated in vacuo, and then purified by column chromatography (20% EtOAc/hexanes) to afford 47 mg (54%) of the coupled product as a colorless oil.

The coupled product (47 mg, 0.065 mmol) was dissolved in 3.0 mL of anhydrous THF with 38 gL of Et, N, and to this solution was added 0.26 mL (0.26 mmol) of TBAF (1.0 M solution in THF) at room temperature. The reaction was run in darkness overnight, then extracted with EtOAc, washed with brine, dried over anhydrous MgSO4, concentrated in vacuo and then purified by column chromatography (90% EtOAc/Hexanes) to give 29 mg (90%) of a mixture of two diastereomers as a colorless oil. One portion (20 mg) of the diastereomers was separated by reverse phase HPLC (C-18 semipreparative column, 51% MeCN/H20,3.0 mL/min) to afford 9.1 mg (22%) of Formula III-1 (la, 3p, tR 66.4 min) and 2.6 mg (6%) of Formula III-2 (1 ß, 3a, tR 63.7 min) as colorless oils. Formula III-1: [« 325D +23.0° (c 1.0, CHCI3);'H NMR (400 MHz, CDCI,) 8 7.96-7.88 (m, 2H), 7.66 (t, J= 7.4 Hz, 1H), 7.62-7.54 (m, 2H), 6.36 (d, J= 11.2 Hz, 1H), 6.00 (d, J= 11.2 Hz, 1H), 5.32 (s, 1H), 4.99 (s, 1H), 4.42 (m, 1H), 4.22 (m, 1H), 3.04 (m, 2H), 2.81 (dd, J= 12.0,3.6 Hz, 1H), 2.59 (dd, J= 13.2,3.2 Hz, 1H), 2.31 (dd, J= 13.4,6.6 Hz, 1H), 2.08-1.04 (m, 18H), 0.88 (d, J= 6.4 Hz, 3H), 0.51 (s, 3H);"C NMR (100 MHz, CDCI,) 8 147.80,143.11, 139.48,133.84,133.20,129.48,128.23,125.13,117.32,112.02,71.0 3,67.05,56.92, 56.44, 56.33,46.07,45.45,43.04,40.60,36.02,34.70,29.22,27.81,23.73, 22.41,19.55, 18.74,12.19; W (EtOH) ? ?264 nm (s 15,100); IR (neat, cm-1) 3683,3601,2931,2861, 1596,1443,1378,1302,1149,1079,1043; HRMS m/z (M) calcd 498.2804 for C30H4204S, found 498.2818. Formula 111-2: [a]"D-2. 7* (c 0.3, CHCl3) ;'H NMR (400 MHz, CDCI3) 5 7.98-7. 88 (m, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.62-7. 54 (m, 2H), 6.38 (d, J= 11.6 Hz, 1H), 5.99 (d, J = 11.6 Hz, 1H), 5.31 (s, 1H), 4.99 (s, 1H), 4.44 (m, 1H), 4.21 (m, 1H), 3.05 (m, 2H), 2.82 (d, J= 13.2 Hz, 1H), 2.61 (dd, J= 13.2,3.6 Hz, 1H), 2.29 (dd, J= 13.0,7.4 Hz, 1H), 2.20-1.06 (m, 18H), 0.89 (d, J= 6.8 Hz, 3H), 0.51 (s, 3H);"C NMR (100 MHz, CDCI,) S 133.09,129.49,128.24,125.14, 08,45.67,43.02,40.59,36.02, 34.71,29.20,27.81,23.71,22.44,19.56,18.75, 12.19 ; W (EtOH) X. 263 nm (E 13,600); IR (neat, cm-') 3695,3613,2966,1596,1449,1384,1249,1043; HRMS m/z (M) calcd 498.2804 for C30H42O4S, found 498.2814.

Preparation of the Formula IV materials is set forth in Scheme 3 as follows: Scheme 3 Synthesis of Formula IV Calcitriol Analogs OH SOTS (CH20) n 1) TsCl, DMAP, 87% Me2AICI 2) TESOTf, Lutidine if 82% H 98% H OH OH OTES (+)-18 (+)-19 (+)-20 CN CHO KCN DMAH DIBA. H DMSOtoluene-780C, 96% 89% H 0°c, 89% OTES OTES (+)-21 (+)-22 OH Q.-P OH I O,,. O S \ I2. Ph3P n-BuLi Imidazole . OTES OTES 92% OYES 92/o (+)-23 (+)-24 . u O O Tg O 0 pDC cl 99% celite, 94% OTES OH (+)-25 (+)-26 < x, OaHz 0 0 Formula IV Synthesis of the iodide derivative 24 of the C, D-ring is carried out from the 17-ene starting material 18 and proceeds through intermediates 19,20,21,22, and 23 as set forth in Scheme 3. These steps in the synthesis are described in greater detail in J. Med. Chem.

1999, Vol. 41, pp. 3008-3014.

Preparation of the various intermediates 25,26, and 27 and the Formula IV compounds are described in Examples 10 through 13 hereinafter.

Example 10 TES protected C, D-ring sulfone (+)-25 A solution of methyl t-butyl sulfone (118 mg, 0.87 mmol) and THF (3.0 mL) was cooled to-78°C and treated dropwise under argon with 0.61 mL (0.85 mmol) of a 1.4 M solution of n-BuLi in hexane. The solution was stirred for 15 minutes at-78°C. To the solution was added 0.3 mL of HMPA and then the solution was stirred for another 15 minutes. A precooled (-78°C) solution of iodide 24 (78 mg, 0.17 mmol) in 2.0 mL of THF was added slowly via cannula. The reaction mixture was then warmed up to room temperature. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous concentrated in vacuo, and then purified by column chromatography (20% EtOAc/hexanes) to give 73 mg (92%) of the desired sulfone (+)-25 as a colorless oil: [α]25D +18.5° (c 7.3, CHCI,);'H NMR (400 MHz, CDCI,) 8 5.26 (s, 1H), 4.10 (d, J= 2. 0 Hz, 1H), 2.87 (t, J=7. 8Hz, 2H), 2.24 (t, J = 13. 2 Hz, 1H), 2.07 (m, 1H), 1.94-1.76 (m, 4H), 1.72-1.56 (m, 4H), 1.55-1.28 (m, 13H), 0.99 (s, J= 5.2 Hz, 3H), 0.93 <BR> <BR> <BR> <BR> (t, J = 7.8 Hz, 9H), 0.54 (q, J = 7.9 Hz, 6H);"C NMR (100 MHz, CDC13) 5 159.41, 120.15,68.85,58.73,54.99,46.61,45.68,35.71,35.64,34.83,31.55 ,30.68,23.39,22.16, 18.87,18.77,17.98,6.88,4.84; IR (neat, cm') 1026; HRMS m/z (M) calcd 456.3093 for CH,, 0, SSi, found 456.3090.

Example 11 Deprotected C, D-ring sulfone (+)-26 To a solution of silyl ether (+)-25 (83 mg, 0.18 mmol) in THF (3.0 mL) was added 0.45 mL (0.45 mmol) of a 1.0 M solution of TBAF in THF, and then it was stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, concentrated in vacuo and then purified by chromatography (20% EtOAc/hexanes) to give 61 mg (99%) of the desired alcohol (+)-26 as a colorless oil: Cal"D +4.2° (c 1.5, CHCI,); <BR> <BR> <BR> <BR> 'H NMR (400 MHz, CDCl3) 6 5. 30 (d, J= 1.2 Hz, 1H), 4.15 (s, 1H), 2.87 (t, J= 8.0 Hz, 2H), 2.25 (t, J= 13.4 Hz, 1H), 2.07 (m, 1H), 2.00-1.45 (m, 12H), 1. 38 (s, 9H), 0.99 (d, J= 6.8 Hz, 3H);"C NMR (100 MHz, CDCI,) 8 159. 23, 120.26,68.94,58.75,54.31,46.28, 15,23.38,22.06,18.88,18.37,17.71; IR (neat, cl-') 3519,2919,1461,1367,1284,1108; HRMS m/z (M) calcd 342. 2229 for C, 9H"O, S, found 342.2235.

Example 12 C, D-ring ketone (+)-27 To a solution of the C, D-ring alcohol (+)-26 (60 mg, 0.18 mmol) in CH2Cl2 (5. 0 mL) were added 130 mg of oven-dried celite and pyridinium dichromate (PDC, 132 mg, 0.35 mmol) at room temperature. The reaction mixture was stirred overnight and then passed through a 2 cm pad of flash silica gel and washed with EtOAc. The filtrate was concentrated and purified by column chromatography (50% EtOAc/hexanes) to give 56 mg (94%) of the desired C, D-ring ketone (+)-27 as a colorless oil: (al"D +14.7° (c 5.2, CHC1,);'H NMR (400 MHz, CDCI,) 5 5.27 (t, J= 1.4 Hz, 1H), 2.86 (t, J= 7.8 Hz, 2H), 2.81 (m, 1H), 2.40 (ddt, J= 15.8,10.6,1.4 Hz, 1H), 2.29-2.19 (m, 2H), 2.17-1.90 (m, 4H), 1.90-1.58 (m, 5H), 1.56-1.40 (m, 1H), 1. 36 (s, 9H), 1.04 (d, J= 6.8 Hz, 3H), 0.77 (s, 3H); <BR> <BR> <BR> <BR> "C NMR (100 MHz, CDCI) 5 210.72,157.10,120.67,62.92,58.73,53.64,45.37,40.35, 35.40,34.24,32.64,26.95,23.86,23.31,21.47,18.79,17.24; IR (neat, cm-1) 2954, 1713, 1455,1367,1284,1108; HRMS m/z (M+) calcd 340.2072 for C,, H3, 03S, found 340.2073.

Example 13 Analogs Formula IV A solution of 108 mg (0.19 mmol) of racemic phosphine oxide (A-ring) in 2.0 mL of anhydrous THF was cooled to-78°C and treated with 107 µL (0.16 mmol, 1.5 M solution in THF) of phenyllithium under argon atmosphere. The mixture turned reddish orange and was stirred for 30 min at-78°C. To the solution was added dropwise a solution of 40 mg (0.12 mmol) of the C, D-ring ketone (+)-27 in 1.0 mL of anhydrous THF. The reaction kept going on until the reddish orange color faded to yellow (about 5 hours). The reaction was quenched by adding 3.0 mL of a 1: 1 mixture of 2 N sodium potassium tartrate and 2 N KCO, solution. The reaction mixture was extracted with EtOAc, washed <BR> <BR> <BR> <BR> with brine, dried over anhydrous MgS04, concentrated in vacuo, and then purified by column chromatography (20% EtOAc/hexanes) to afford 37 mg (45%) of the coupled product as a colorless oil.

The coupled product (37 mg, 0.053 mmol) was dissolved in 3.0 mL of anhydrous THF, and to this solution were added 0.21 mL (0.21 mmol) of a 1.0 M solution of TBAF in THF and 29 µL (0.21 mmol) of triethylamine. The reaction was run in darkness overnight, then extracted with EtOAc, washed with brine, dried over anhydrous MgSO4, concentrated in vacuo and then purified by silica gel chromatography (90% EtOAc/hexanes) to give 19 mg (76%) of a mixture of two diastereomers as a colorless oil.

The diastereomers were separated by reverse phase HPLC (C-18 semipreparative colurnn, 49% MeCN/H20,3.0 mL/min) to afford 6.3 mg (11%) of Formula IV-1 (1 a, 3i, tR 47. 9 min) and 4.1 mg (7%) of Formula IV-2 (1 (3, 3a, t 43.2 min) as colorless oils. Formula IV-1: [a]"D +6. 7° (c 0.6, EtOH);'H NE (400 MHz, CDCI,) 6 6.37 (d, J= 11. 2 Hz, 1H), 6.11 (d, J= 10.4 Hz, 1H), 5.34 (s, 2H), 5.01 (s, 1H), 4.45 (m, 1H), 4.24 (m, 1H), 3.00-2.75 (m, 3H), 2.60 (d, J= 12.8 Hz, 1H), 2.40-1.50 (m, 16H), 1.40 (s, 9H), 1.05 (d, J= 6.8 Hz, 3H), 0.69 (s, 3H) ;13C NMR (100 MHz, CDCl3) 8 158.85,147.62,142.31,133.09,124.83, 120.84,116.91,111.64,70.63,66.86,58.81,58.31,50.04,45.62,45. 14,42.82,35.53, 35.28,32.65,29.39,28.74,23.57,23.46,21.59,18.73,16.98; UV (EtOH) Aw 263 nm (e 12,000); IR (neat, cm-1) 3425,2919,1284,1108,1049; HRMS m/z (M) calcd 476.2960 for C28H44O4 found 476.2952. Formula IV-2: [α]25D-8.9°(c 0.5, EtOH);'H NMR (400 <BR> <BR> <BR> MHz, CDCI,) 8 6.39 (d, J= 11. 2 Hz, 1H), 6.09 (d, J=10.6 Hz, 1H), 5.32 (s, 2H), 5.01 (d, J= 1.6 Hz, 1H), 4.45 (m, 1H), 4.22 (m, 1H), 2.94-2.76 (m, 3H), 2.62 (m, 1H), 2.42-1.46 (m, 16H), 1.41 (s, 9H), 1.05 (d, J= 6.8 Hz, 3H), 0.68 (s, 3H);"C NMR (100 MHz, CDCl3) <BR> <BR> <BR> 8 158.84,147.02,142.40,132.88,124.89,120.83,116.91,113.00,71.5 5,66.74,58.82, 65,29.43,28.73,23.56,23.47,21.61, 18.72,16.99; UV (EtOH) #max264nm(# 13,200); IR (neat, cm-') 3401,2919,1455,1284, 1108,1049; HRMS mlz (M) calcd 476.2960 for C28H44O4S, found 476.2955.

Preparation of the Formula V materials is set forth in Scheme 4 as follows: Scheme 4 Synthesis of Formula V Calcitriol Analogs '-,,10 S- 1<. n-BuLi OI) n-BuLi,-79'C THF-HIYIPA,-78'C to r. L 2) NFST,-780C to r. L OTES 92% OTES 58% F F F F F F) F) p p. I. BAF O PDC J O'O TBAF fL ° ° PDC 66% ceinte 78% H (+)-28 (+)-29 F F t/ " \ O fi (+)-30 P (O) Ph2 1) PhLi 2) (+)-30,84% 3) TBAF, 96% po ou Formula V Scheme 4 begins with the same iodide derivative 24 and the next intermediate 25 as set forth in Scheme 3. Preparation of the various intermediates 28,29, and 30 and the Formula V compounds is described in Examples 14 through 17 hereinafter.

Example 14 Difluorinated C, D-ring sulfone (+)-28 To a solution of the TES protected C, D-ring sulfone (+)-25 (56 mg, 0.12 mmol) in THF (3.0 mL) was added 0.18 mL (0.29 mmol) of a 1.6 M solution of n-BuLi in hexane at -78°C. After being stirred for 30 minutes, a precooled (-78°C) solution of NFSI (N- fluorobenzenesulfonimide, 77 mg, 0.24 mmol) in 1.0 mL of THF was added slowly to the reaction mixture, and then it was warmed up to room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, and concentrated in vacuo. Purification by column chromatography (20% EtOAc/hexanes) gave a mixture of mono and di-fluorinated sulfones.

The mixture (58 mg) was dissolved in THF (3.0 mL) and the solution was cooled to-78°C. To the solution was added 0.18 mL of n-BuLi (1.6 M solution in hexane, 0.29 mmol) and the reaction mixture was stirred for 30 minutes at-78°C. A precooled (-78°C) solution of NFSI (96 mg, 0.30 mmol) in 1.0 mL of THF was then added slowly via cannula. The reaction mixture was warmed up to room temperature, quenched with water, extracted with EtOAc, washed with brine and concentrated. Purification by column chromatography (20% EtOAc/hexanes) gave 35 mg (58%) of the desired difluoronated C, D-ring sulfone (+)-28 as a colorless oil: [a] (c 3.5, CHCl3) ;'H NMR (400 MHz, CDCI3) S 5.30 (d, J= 1.2 Hz, 1H), 4.11 (d, J= 2. 0 Hz, 1H), 2.45-2.02 (m, 4H), 1.94- 1.58 (m, 9H), (m, 10H), 1.02 (d, J= 6.8 Hz, 3H), 1.00 (s, 3H), 0.95 (t, J= 8.0 Hz, 9H), 0.56 (q, J= 7. 9 Hz, 6H) ; 13C NMR (100 MHz, CDCl3) # 158. 80,129.63 (t, J= 287.9 Hz), 120.94,69.08,63.30,55.28,46.81,35.92,35.10,31.65,30.99,29.02 (t, J= 19.3 Hz), 49,18.91,18.25,7.17,5.11;'9F NMR (376 MHz, CDC1,, CFCl3 as internal) 8-97.76 (t, J= 16.9 Hz); IR (neat, cm~') 2955,2933,2876,1458,1324,1136, 1082,1029; HRMS m/z (M') calcd 492.2905 for C. 6F20, SSi, found 492.2907.

Example 15 Deprotected difluoronated C, D-ring alcohol (+)-29 A solution of silyl ether (+)-28 (89 mg, 0. 18 mmol) in THF (2.0 mL) and 0.45 mL of 1.0 M solution of TBAF in THF was stirred overnight at room temperature. The mixture was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, concentrated in vacuo and then purified by column chromatography (20% EtOAc/hexanes) to give 45 mg (66%) of the desired alcohol as a colorless oil: [a]'D +3. 4° (c 3.8, CHCI,);'H NMR (400 MHz, CDCI,) 8 5.34 (t, J= 1.4 Hz, 1H), 4.16 (s, 1H), 2.34-1.36 (m, 23H), 1.03 (d, J = 6.8 Hz, 3H), 1.02 (s, 3H);"C NMR (100 MHz, CDCl3) 8 158. 62,129.52 (t, J= 287.7 Hz), 121.04,69.19,63.29,54.57, 46.47,35.57,33.96,31.63,30.42,28.96 (t, J= 19.8 Hz), 26.93,24.32,22.37,18.50,17.96; "'F NMR (376 MHz, CDCI"CFCl3 as internal) 8-97.83 (m); IR (neat, cm-1) 3568,2930, 2870,1458,1320,1134; HRMS m/z (M') calcd 378.2040 for C19H32F2O3S, found 378.2047.

Example 16 C, D-ring ketone (+)-30 A flame-dried 5 mL flask was charged with 40 mg (0.11 mmol) of the C, D-ring alcohol (+)-29,3.0 mL of anhydrous THF, 100 ma of oven-dried celite and 100 mg (0.27 mmol) of PDC. The reaction mixture was stirred overnight at room temperature and then passed through a 2 cm pad of flash silica gel and washed with EtOAc. The filtrate was concentrated and purified by column chromatography (20% EtOAc/hexanes) to give 31 mg (78%) of the desired C, D-ring ketone (+)-30 as a colorless oil: [a] 25D +12. 9° (c 3.4, <BR> <BR> <BR> CHCl3) ;'H NMR (400 MHz, CDCI3) 6 5.33 (d, J= 1.2 Hz, 1H), 2.83 (dd, J=10. 4,6.4 Hz, 1H), 2.45 (dd, J= 15.6,10.8 Hz, 1H), 2.36-1.56 (m, 12H), 1.50 (s, 9H), 1.09 (d, J= 6.8 Hz, 3H), 0.80 (s, 3H);"C NMR (100 MHz, CDCl3) 8 210.87,156.51,129.38 (t, J= 287.8 Hz), 50,32.64,28.85 (t, J= 19.6 Hz), 27.31,26.90, <BR> <BR> <BR> 24.31,24.14,21.70,17.47;'9F NMR (376 MHz, CDCI3, CFCl3 as internal) 8-97.79 (m); IR (neat, cm-') 2939,2873,1718,1458,1377,1320,1130; HRMS mAz (M*) calcd 376.1884 for C19H30F2O3S, found 376.1889.

Example 17 Analogs Formula V Racemic phosphine oxide (A-ring, 89 mg, 0.15 mmol) was dissolved in 2.0 mL of anhydrous THF and cooled to-78°C under argonzatmosphere. To this solution was added 100 LL (0.16 mmol) of phenyllithium (1.6 M solution in THF) dropwise. The mixture turned deep reddish orange and persisted. After stirring at-78°C for 30 minutes, a precooled (-78°C) solution of C, D-ring ketone (+)-30 (30 mg, 0.080 mmol) dissolved in 1.0 mL of anhydrous TE was added dropwise via cannula. The reaction kept going on until the reddish orange color faded to yellow (about 4 hours). The reaction was quenched by adding 3.0 mL of a 1: 1 mixture of 2 N sodium potassium tartrate and 2 N K2CO3 solution. The reaction mixture was allowed to warm to room temperature, extracted with EtOAc, washed with brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo, and then purified by column chromatography (10% EtOAc/hexanes) to afford 50 mg (84%) of the coupled product as a colorless oil.

The coupled product (50 mg, 0.067 mmol) was dissolved in 3.0 mL of anhydrous THF with 37 µL of Et, N, and to this solution was added 0.27 mL (0.27 mmol) of TBAF (1.0 M solution in THF) at room temperature. The reaction was run in darkness ovemight, then extracted with EtOAc, washed with brine, dried over anhydrous MgS04, concentrated in vacuo and then purified by column chromatography (90% EtOAc/Hexanes) to give 33 mg (96%) of a mixture of two diastereomers as a colorless oil. The diastereomers were separated by reverse phase HPLC (C-18 semipreparative column, 52% MeCN/H20,3.0 mL/min) to afford 16.6 mg (41%) of Formula V-1 (la, 3 (3, tR 145.3 min) as a foaming solid and 7.0 mg (17%) of Formula V-2 (lp, 3a, tR 129.2 min) as a colorless oil.

Formula V-1: [α]25D +0.1° (c 1.7, CHC1,);'H NMR (400 MHz, CDCI,) 8 6.36 (d, J= 11.2 Hz, 1H), 6.10 (d, J= 11.2 Hz, 1H), 5.40-5.30 (m, 2H), 5.00 (s, 1H), 4.43 (dd, J= 8.0,4.4 Hz, 1H), 4.23 (m, 1H), 2.81 (dd, J= 12.0,4.0 Hz, 1H), 2.59 (dd, J= 13.2,2.8 Hz, 1H), 2.43-2.13 (m, 5H), 2.09-1.96 (m, 2H), 1.95-1.63 (m, 9H), 1.51 (s, 9H), 1.07 (d, J= 6.8 Hz, 3H), 0.68 (s, 3H);"C NMR (100 MHz, CDCI,) 5 158.19,147.85,142.36,133.43,129.60 (t, J= 287. 7 Hz), 124.99,121.67,117.21,111.88,70.82,67.07,63.34,58.52,50.18,45 .35, 43.02,35.42,32.58,29.65,28.94,28.70 (t, J= 19.6 Hz), 26.81,24.36,23.77,21.79,17.05; <BR> <BR> <BR> <BR> 19F NMR (376 MHz, CDC13, CFC13 as intemal) 8-97.86 (m); UV (EtOH) 1""x 263 nm (s 16,100); IR (neat, cm') 3601,2931,2837,1455,1314,1126,1043; HRMS m/z (M+) calcd 512.2772 for C28H42F2O4S, found 512.2781. Formula V-2: [α]25D-24.1° (c 0.7, CHCl3) ;'H <BR> <BR> <BR> <BR> <BR> NMR (400 MHz, CDCl3) 5 6.39 (d, J= 11.2 Hz, 1H), 6.10 (d, J = 11.2 Hz, 1H), 5.35 (t, J = 1.2 Hz, 1H), 5.32 (s, 1H), 5.01 (d, J= 2.0 Hz, 1H), 4.44 (dd, J= 6.0,4.0 Hz, 1H), 4.22 (m, 1H), 2.82 (dd, J = 11.8,4.2 Hz, 1H), 2.62 (dd; J = 13.2,4.0 Hz, 1H), 2.42-2.12 (m, 5H), 2.10-1.96 (m, 2H), 1.95-1.55 (m, 9H), 1.52 (s, 9H), 1.07 (d, J= 6.8 Hz, 3H), 0.68 (s, <BR> <BR> <BR> <BR> 3H);"C NMR (100 MHz, CDCI,) 5 158.20,147.22,142.49,133.18,129.62 (t, J= 288.0 Hz), 94, 35.40,32.58,29.70,28.94,28.69 (t, J = 19.1 Hz), 26.82,24.38,23.77,21.81,17.07; 19F NMR (376 MHz, CDCI,, CFCI, as internal) 5-97.88 (m); UV (EtOH) 263 nm (E 15,000); IR (neat, cm-1) 3683,3601,2931,1314,1132,1043; HRMS m/z (M+) calcd 512.2772 for C28H42F2O4S, found 512.2776.

Preparation of the Formula VI materials is set forth in Scheme 5 as follows: Scheme 5 Synthesis of Formula VI Calcitriol Analogs 0.. 0 Ph n-BuL ! 0 THF THF-HWA, 88% OTES OTES (+)-24 (+)-31 o PceDtCte ~ XPh Ph OH ouzo PDC ai j"I 95% OU O (+32 (+)-33 P (O) Ph2 1) PhLi 2) (+>33, 73% 3) TBAF, 96% po ou Formula VI Scheme 5 begins with the same iodide derivative 24 as set forth in Schemes 3 and 4. Preparation of the various intermediates 31,32 ; and 33 and the Formula VI compound is described in Examples 18 through 21 hereinafter.

Example 18 TES protected 16-ene-25-phenyl C, D-ring sulfone (+)-31 A solution of methyl phenyl sulfone (147 mg, 0.95 mmol) and THF (3. 0 mL) was cooled to-78°C, and then 0.60 mL (0.96 mmol, 1.6 M solution in hexane) of n-BuLi was added dropwise to the solution. After 15 minutes, 0.2 mL of HMPA was added and the solution was stirred for another 15 minutes. A precooled (-78°C) solution of iodide 24 (85 mg, 0.19 mmol) in 1.0 mL of THF was added slowly via cannula. The reaction mixture was then warmed up to room temperature. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous concentrated in vacuo, and then purified by column chromatography (20% EtOAc/hexanes) to give 79 mg (88%) of the desired sulfone (+)-31 as a colorless oil: [a] ZSp +14. 7° (c 7.8, CHCI,);'H NMR (400 MHz, CDCI,) 8 7.92-7.84 (m, 2H), 7.63 (t, J= 7.4 Hz, 1H), 7.54 (t, J= 7.6 Hz, 2H), 5.15 (t, J= 1.2 Hz, 1H), 4.08 (d, J= 2.0 Hz, 1H), 3.04 (m, 2H), 2.15 (t, J= 13.0 Hz, 1H), (m, 3H), 1.73-1.22 (m, 10 H), 0.95 (t, J= 8.0 Hz, 9H), 0.92 (d, J= 6.8 Hz, 3H), 0.87 (s, 3H), 0.55 (q, J= 8.0 Hz, 6H);"C NMR (100 MHz, CDC13) 8 159.31,139. 19, 03,56.58,55.15,46.72,35.82,35.06,35.02,31.52, 30.82,22.50,21.25,18.86,18.16,7.14,5.07; IR (neat, crri') 2953,2874,1447,1319, 1306,1148,1082,1028; HRMS m/z (M') calcd 476.2780 for C27H44O3SSi, found 476.2787.

Example 19 Deprotected 25-phenyl C, D-ring sulfone (D)-32 A solution of silyl ether (+)-31 (78 mg, 0.16 mmol) in THF (2.0 mL) and 0.41 mL of 1.0 M solution of TBAF in THF was stirred overnight at room temperature. The mixture was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, concentrated in vacuo and then purified by column chromatography (20% EtOAc/hexanes) to give 55 mg (93%) of the desired alcohol (60)- <BR> <BR> <BR> 32 as a colorless oil: [α]25D-0.8° (c 5.8, CHCl3) ;'H NMR (400 MHz, CDCl3) 8 7.92-7.84 (m, 2H), 7.63 (t, J= 7.4 Hz, 1H), 7.58-7.50 (m, 2H), 5.20 (t, J= 1.4 Hz, 1H), 4.13 (d, J= 2.4 Hz, 1H), 3.04 (m, 2H), 2.18 (t, J= 13.2 Hz, m), 2.02-1.18 (m, 13H), 0.93 (d, J= 6.8 Hz, 3H), 0.92 (s, 3H);"C NMR (100 MHz, CDCI3) 8 159.20,139.21,133.78,129.37, 128.20,120.51,69.12,56.54,54.49,46.43,35.52,35.04,33.98,31.6 0,30.32,22.34, 21.20,18.49,17.89; IR (neat, cm') 3535,2926,2864,1447,1305,1147,1086; HRMS m/z (M) calcd 362.1916 for C2, H3,, OISI found 362.1913.

Example 20 C, D-ring ketone (+)-33 To a solution of the C, D-ring alcohol (+)-32 (55 mg, 0.15 mmol) in CHCl (3.0 mL) were added 114 mg of oven-dried celite and pyridinium dichromate (PDC, 114 mg, 0.30 mmol) at room temperature. The reaction mixture was stirred overnight and then passed through a 2 cm pad of flash silica gel and washed with EtOAc. The filtrate was concentrated and purified by column chromatography (50% EtOAc/hexanes) to afford 52 <BR> <BR> <BR> mg (95%) of the desired C, D-ring ketone (+)-33 as a colorless oil: [3035]25D +11. 2° (c 5.1, CHCI,);'H NMR (400 MHz, CDCI,) 8 7.88-7.82 (m, 2H), 7.63 (t, J= 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 5.18 (t, J= 1.4 Hz, 1H), 3.03 (t, J= 7.8 Hz, 2H), 2.77 (dd, J= 10.8,6.4 Hz, 1H), 2.38-2.20 (m, 3H), (m, 10H), 0.98 (d, J= 6.8 Hz, 3H), 0.67 (s, 3H);"C NMR (100 MHz, CDCI,) 8 210.93,157.03,139.13,133.83,129.38,128.13,120.91,63.10, 56. 37,53.80,40.58,34.87,34.40,32.58,27.14,24.07,21.80,21.05,17. 32; IR (neat, cm-1) HRMS m/z (M) calcd 360.1759 for C,, H,, O, S, found 360.1758.

Example 21 Analogs Formula VI A solution of 89 mg (0.15 mmol) of recemic phosphine oxide (A-ring) in 2.0 mL of anhydrous THF was cooled to-78°C and treated with 100 fiL (0.15 mmol, 1.5 M solution in THF) of phenyllithium under argon atmosphere. The mixture turned reddish orange and was stirred for 30 min at-78°C. To the solution was added dropwise a solution of 52 mg (0.14 mmol) of the C, D-ring ketone (+)-33 in 1.0 mL of anhydrous THF. The reaction kept going on until the reddish orange color faded to yellow (about 4 hours). The reaction was quenched by adding 3.0 mL of a 1: 1 mixture of 2 N sodium potassium tartrate and 2 N K. C03 solution. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous MgS04, citrate in vacuo, and then purified by column chromatography (20% EtOAc/hexanes) to afford 76 mg (73%) of the coupled product as a colorless oil.

The coupled product (76 mg, 0.10 mmol) was dissolved in 3.0 mL of anhydrous THF, and to this solution were added TBAF (0.41 mL, 0.41 mmol, 1.0 M solution in THF) and 59 µL of Et, N. The reaction was run in darkness overnight, then quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous concentrated in vacuo and then purified by column chromatography (90% EtOAc/hexanes) to give 52 mg (96%) of a mixture of two diastereomers as a colorless oil. The diastereomers were separated by reverse phase HPLC (C-18 semipreparative column, 50% MeCN/H20,3.0 mL/min) to afford 19.1 mg (28%) of Formula VI-1 (la, 3p, tR 59.3 min) and 12.7 mg (18%) of Formula VI-2 (1ß,3α,tR 53.6 min) as colorless oils. Formula VI-1: la]"D-1. 60 <BR> <BR> <BR> <BR> (c 1.9, CHCI,);'H NMR (400 MHz, CDCI,) 8 7.94-7.86 (m, 2H), 7.65 (t, J= 7.4 Hz, 1H), 7.60-7.52 (m, 2H), 6.35 (d, J = 11.2 Hz, 1H), 6.08 (d, J = 11.2 Hz, 1H), 5.35 (d, J= 1.6 Hz, 2H), 5.01 (s, 1H), 4.44 (dd, J = 8.0,4.0 Hz, 1H), 4.23 (m, 1H), 3.05 (t, J = 8.0 Hz, 2H), 2.79 (dd, J= 12.4,4.4 Hz, 1H), 2.59 (dd, J= 13.2,2.8 Hz, 1H), 2.40-2.26 (m, 2H), 2.20-2.00 (m, 3H), 2.00-1.84 (m, 2H), 1.84-1.20 (m, 9H), 0.98 (d, J= 6.8 Hz, 3H), 0.58 (s, <BR> <BR> <BR> <BR> 3H);"C NMR (100 MHz, CDCI,) 5 158. 80,147.93,142.36,139.30,133.81,133.43, 47,56.57,50.16.45.31, UV (EtOH) #max 264 nm (E 12,400); IR (neat, cm') 3613,2919,2837,1443,1302,1143,1043; HRMS m/z (M+)<BR> calcd 496.2647 for C,, H, (, 04S, found 496.2635. Formula VI-2 : [a]-22. 8° (c 1.3, CHCl3) ;'H NMR (400 MHz, CDC13) 8 7.94-7.86 (m, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.60- 7.52 (m, 2H), 6.38 (d, J = 11.2 Hz, 1H), 6.07 (d, J = 11.2 Hz, 1H), 5.33 (s, 1H), 5.23 (d, J = 1.2 Hz, 1H), 5.01 (d, J = 1.6 Hz, 1H), 4.46 (dd, J = 5.6,4.0 Hz, 1H), 4.22 (m, 1H), 3.05 (t, J= 8.0 Hz, 2H), 2.80 (dd, J= 11.6,4.0 Hz, 1H), 2.62 (dd, J = 13.0,3.8 Hz, 1H), 2.36- 2.24 (m, 2H), 2.20-1.86 (m, 5H), 1.84-1.20 (m, 9H), 0.98 (d, J= 6.8 Hz, 3H), 0.58 (s, 3H); "C NMR (100 MHz, CDCI,) 5 129.42, 92,58.48,56.59,50.18,45.72,42.99, 91,23.72,21.79,21.01,17.11; W (EtOH) 264 nm (e 16,400); IR (neat, cm-') 3601,2919,2849,1443,1302,1143,1085,1043; HRMS m/z (M+) calcd 496.2647 for C30H40O4S, found 496.2650.

Preparation of the Formula VII materials is described in Scheme 6 as follows: Scheme 6 Synthesis of Formula VII Calcitriol Analogs $ vssS X '' (1) LDA .,, 0 chu F F (2) F/S, H H + OYES (3) CIP (0) (OEt) =, OTES 71 Y. (+34-E (+)-3i-Z E: Z-3: 2 F F a y /iiSW/ySW H TgpF H O PDC u' 54% Ce 0% H H OYES OH OTES OH F F t H eH 0 'tu 0 (93SE P (O) Ph2 1) PhLi 2) (+)-36-E, 67% 3) 10°/a HF-EtOH 80% "ow o 0E Formula Vll Scheme 6 begins with the same protected-aldehyde derivative 22 as set forth in Scheme 3 above. Preparation of the various intermediates 34-E, 34-Z, 35-E, and 36-E, and the Formula VII compounds is described in Examples 22 through 25 hereinafter.

Example 22 TES protected C, D-ring sulfone (+)-34-E A solution of 5.0 mL of 1B and 0.53 mL of n-BuLi (1.5 M solution in THF, 0.80 mmol) was cooled to-78°C, and then 0.11 mL (0.80 mmol) of diisopropylamine was added dropwise to the solution. After 15 minutes, monofluorinated methyl tert-butyl sulfone (58.4 mg, 0.38 mmol) was added via cannula and the resulted reaction mixture was stirred for another 15 minutes. Diethyl chlorophosphate (52 1L, 0.36 mmol) was added and the reaction was stirred at-78°C for one hour. A precooled (-78°C) solution of TES protected aldehyde 22 (75.0 mg, 0.22 mmol) in 1.0 mL of THF was added slowly via cannula. The reaction mixture was then warmed up to room temperature. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried over anhydrous MgSO"concentrated in vacuo, and then the mixture (75 mg, 71%) was separated by column chromatography (2% Et2O/hexanes) to give 45 mg of the desired E isomer and 30 mg of the Z isomer as colorless oils. (+)-34-E: [a] 25D +28.2° (c 2.8, CHCl3) ;'H NMR (400 MHz, CDCI,) 8 6.05 (dt, J = 32.8,7.6 Hz, 1H), 5.31 (t, J= 1.6 Hz, 1H), 4.11 (d, J = 2.4 Hz, 1H), 2.54-2.18 (m, 4H), 1.98-1.20 (m, 17H), 1.06 (d, J= 6.8 Hz, 3H), 1.00 (s, 3H), 0.94 (t, J= 8.0 Hz, 9H), 0.56 (q, J= 8.0 Hz, 6H) ;"C NMR (100 MHz, CDC13) 8 158.62, 151.81 (d, J= 294.8 Hz), 122.33 (d, J= 6.4 Hz), 19,46.95,35.98, 35.01,31.41,31.33,30.96,23.47,22.16,19.05,18.22,7.15,5.10;'9 F NMR (376 MHz, <BR> <BR> <BR> CDCI3, CFC13 as internal) 8-119.77 (d, J = 33.5 Hz); IR (neat, cm') 2954,2931,2860, 1666,1455,1320,1132,1026; HRMS m/z (M+) pending.

Example 23 Deprotected C, D-ring alcohol (+)-35-E A solution of silyl ether (+)-34-E (73.5 mg, 0.16 mmol) and TBAF (0.39 mL, 1.0 M solution in THF, 0. 39 mmol) in 2.0 mL of THF was stirred for 4 hours at room temperature. The mixture was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, concentrated in vacuo and then purified by column chromatography (50% EtOActhexanes) to give 30 mg (54%) of the desired alcohol as a colorless oil: [a]' +6. 8" (c 1.9, CHCl3) ;'H NMR (400 MHz, CDCl3) 8 6.05 (dt, J= 33.2,7.8 Hz, 1H), 5.36 (t, J= 1.6 Hz, 1H), 4.17 (d, J= 2.0 Hz, 1H), 2.55- 2.20 (m, 4H), 2.06-1.30 (m, 17H), 1.06 (d, J= 6.8 Hz, 3H), 1.03 (s, 3H);"C NMR (100 MHz, CDCI,) 8 158.45,151.92 (d, J= 295.2 Hz), 122.07 (d, J = 6.3 Hz), 121.51,69.14, 59.72,54.52,46.63,35.64,34.03,31.34,31.32,30.45,23.48,22.14, 18.64,17.93;"F <BR> <BR> <BR> NMR (376 MHz, CDCI1, CFC1, as internal) 8-119.62 (d, J = 33.5 Hz); IR (neat, cm-') 3542,2919,2872,1666,1455,1137,1114; HRMS m/z (M+) pending.

Example 24 C, D-ring ketone (+)-36-E A flame-dried 5 mL flask was charged with 30.0 mg (0. 084 mmol) of the C, D-ring alcohol (+)-35-E, 3.0 mL of anhydrous CH2C12,70 mg of oven-dried celite and 63.0 mg (0.17 mmol) of PDC. The reaction mixture was stirred overnight at room temperature and then passed through a 2 cm pad of flash silica gel and washed with EtOAc. The filtrate was concentrated and purified by column chromatography (50% EtOAc/hexanes) to give 24.0 mg (78%) of the desired C,D-ring ketone (+)-36-E as a colorless oil: [α]25D +26.0° (c 2.4, CHCl3) ;'H NMR (400 MHz, CDC13) 8 6.03 (dt, J= 32.8,7.6 Hz, 1H), 5.35 (t, J= 1.2 Hz, 1H), 2.85 (dd, J= 10.8,6.6 Hz, 1H), 2.60-2.20 (m, 6H), 2.18-1.60 (m, 5H), 1.38 (s, 9H), 1.13 (d, J = 6.4 Hz, 3H), 0.80 (s, 3H); 13C NMR (100 MHz, CDCI3) 6 210.70, 156.35,152.31 (d, J= 295.7 Hz), 121.95,121.38 (d, J= 6.4 Hz), 63. 15,59.74,53.90, 40.60,34.56,32.24,31.25,27.34,24.12,23.47,21.62,17.54;'9F NMR (376 MHz, CDCI3, CFCI3 as internal) õ-119.06 (d, J = 33.1 Hz); IR (neat, cm) 2943,1713,1666,1455, 1314,1120,1038; HRMS mlz (M) pending.

Example 25 Analogs Formula VII Racemic phosphine oxide (A-ring, 48.9 mg, 0.084 mmol) was dissolved in 2.0 mL of anhydrous THF and cooled to-78°C under argon atmosphere. To this solution was added 65 µL (0.08 mmol) of phenyllithium (1.2 M solution in THF) dropwise. The mixture turned deep reddish orange and persisted. After stirring at-78°C for 30 minutes, a precooled (-78°C) solution of C, D-ring ketone (+)-36-E (24.2 mg, 0.068 mmol) dissolved in 1.0 mL of anhydrous THF was added dropwise via cannula. The reaction kept going on until the reddish orange color faded to yellow (about 4 hours). The reaction was quenched by adding 3.0 mL of a 1: 1 mixture of 2 N sodium potassium tartrate and 2 N K2CO3 solution. The reaction mixture was allowed to warm to room temperature, extracted with <BR> <BR> <BR> <BR> EtOAc, washed with brine, dried over anhydrous MgSO"filtered, concentrated in vacuo, and then purified by column chromatography (8% EtOAc/hexanes) to afford 33 mg (67%) of the coupled product as a colorless oil.

The coupled product (31 mg, 0.043 mmol) was dissolved in 2.0 mL of anhydrous ethanol, and then 0.34 mL of HF (49% solution in water) was added and the resulted reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with diluted NaHCO, solution and extracted with EtOAc, washed with brine, dried over anhydrous MgS04, concentrated in vacuo and then purified by column chromatography (80% EtOAc/Hexanes) to give 17.0 mg (80%) of a mixture of two diastereomers as a colorless oil. The diastereomers were separated by reverse phase HPLC (C-18 semipreparative column, 52% MeCN/H20,3.0 mL/min) to afford 5.7 mg (17%) of Formula VII-1 (la, 3ß, tR 77.3 min) as a foaming solid and 4.2 mg (12%) of Formula VII-2 (Ip, 3a, tR 70.4 min) as a colorless oil. Formula VII-1: [a] 25D +3.2° (c 0.57, CHCl3) ;'H NMR (400 MHz, CDCI,) 8 6.36 (d, J = 11.2 Hz, 1H), 6.10 (d, J= 10.8 Hz, 1H), 6.05 (dt, J= 33.2,7.6 Hz, 1H), 5.37 (s, 1H), 5.34 (t, J= 1.6 Hz, 1H), 5.00 (s, 1H), 4.44 (dd, J= 7.8,4.2 Hz, 1H), 4.24 (m, 1H), 2.82 (dd, J= 12.2,4.6 Hz, 1H), 2.60 (d, J= 13.6 Hz, 1H), 2.54-1.18 (m, 23H), 1.10 (d, J= 6.4 Hz, 3H), 0.69 (s, 3H);"C NMR (100 MHz, CDCI,) 8 158.03,152.01 (d, J= 295.3 Hz), 147.86,142.11,133.56,124.97,122.12, 121.88 (d, J= 6.3 Hz), 117.36,111.90,70.89,67.07,59.73,58.51,50.20,45.37,43.08, 35.46,32.30,31.26,29.66,28.90,23.72,23.50,21.52,17.21 ;19F NMR (376 MHz, CDCl3, CFCI3 as internal) # -119. 50 (d, J = 33.1 Hz); UV (EtOH) Aw 263 nm (E 14,700); IR (CHCl3, cm-1) 3707, 3601,2919,1654,1455,1314,1220,1038; HRMS m/z (M+) pending.

Formula VII-2: [α]25D -16.7° (c 0.42, CHCl3) ;'H NMR (400 MHz, CDCl3) 8 6.38 (d, J= 11.6 Hz, 1H), 6.09 (d, J= 10.4 Hz, 1H), 6.05 (dt, J= 6 Hz, 1H), 5.37 (s, 1H), 5.33 (s, 1H), 5.01 (d, J= 1.6 Hz, 1H), 4.46 (m, 1H), 4.22 (m, 1H), 2.82 (dd, J= 12.0,4.4 Hz, 1H), 2.62 (dd, J= =13. 2,3.6 Hz, 1H), 2.56-1.20 (m, 23H), 1.10 (d, J= 6.8 Hz, 3H), 0.69 (s, 3H) ; 13C NMR (100 MHz, CDCl3) 8 158.03,152.01 (d, J= 295.7 Hz), 147.34,142.20, 133.38,125.02,122.12,121.89 (d, J= 5.9 Hz), 73,58.51, 23.71,23.51,21.54,17.23;'9F NMR (376 MHz, CDCI,, CFCl3 as internal) 8-119.51 (d, J = 32.0 Hz); UV (EtOH) #max 263 nm (e 14,900); IR (CHCl3, cm-1) 3601,2919,2849,1655,1455,1314,1214,1038; HRMS m/z (M+) pending.

Preparation of the Formula VIII materials is described in Scheme 7 as follows: Scheme 7 Synthesis of Formula Vin Calcitriol Analogs . J r-sH w/ Çß~ r\ SeOrH202 t SeOZ-HZO= DBU, sealed tube 90% OIES 130°C, 50% OTES (+)-24 (+)-37 I\ *o O% N 410 S S (1)rr-BuLi)-78°C F F TBAF a (2) NFSL-78*C to rt 66% 80% H OTES 0'fES (+)-38 (+)-39 04"0 N% 41 S a 89% H H OH 0 (+)-40 (+}. 41 P (O) Ph2 1) PhLi t1(+)-41,84% <3) TBAF, 96% f"y 3) TBAF, 96% FormulaV'III Scheme 7 begins with the same iodide derivative 24 as set forth in Schemes 3,4, and 5. Preparation of the various intermediates, 37,38,39,40, and 41, and the Formula VIII compounds is described in Examples 26 through 29 hereinafter.

Example 26 Difluorinated C, D-ring sulfone (+)-39 To a solution of the TES protected C, D-ring sulfone (+)-38 (64 mg, 0.15 mmol) in THF (3. 0 mL) was added 0.29 mL (0.58 mmol) of a 2.0 M solution of n-BuLi in pentane at-78°C. After being stirred for 30 minutes, a precooled (-78°C) solution of NFSI (N- fluorobenzenesulfonimide, 127 mg, 0.41 mmol) in 1.0 mL of THF was added slowly to the reaction mixture, and then it was warmed up to room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, and concentrated in vacuo. Purification by column chromatography (20% EtOAc/hexanes) gave a mixture of mono and di-fluorinated sulfones.

The mixture was dissolved in THF (3.0 mL) and the solution was cooled to-78°C.

To the solution was added 0.29 mL of n-BuLi (2.0 M solution in pentane, 0.58 mmol) and the reaction mixture was stirred for 30 minutes at-78°C. A precooled (-78°C) solution of NFSI (127 mg, 0.41 mmol) in 1.0 mL of THF was then added slowly via cannula. The reaction mixture was warmed up to room temperature, quenched with water, extracted with EtOAc, washed with brine and concentrated. Purification by column chromatography (20% EtOAclhexanes) gave 55 mg (80%) of the desired difluoronated C, D-ring sulfone (+)-39 as a colorless oil: [α]25D +21.9° (c 5.5, CHC1,);'H NMR (400 MHz, CDCI,) 8 5.37 (s, 1H), 4.12 (s, 1H), 2.68-2.18 (m, 4H), 1.96-1.30 (m, 17H), 1.12 (d, J= 5.6 Hz, 3H), 1.04 (s, 3H), 0.94 (t, J= 7. 8 Hz, 9H), 0.56 (q, J=8.0 Hz, 6H);"C NMR (100 MHz, CDCI,) 8 158.94,129.52 (t, J= 289.2 Hz), 36,35.94,35.05,31.00, 25.44,24.44,23.91,22.89,19.01,18.22,7.13,5.11;"F NMR (376 MHz, CDC13, CFCI3 as internal) 8-96.24 (ddd, J= 219.2,31.9,6.6 Hz),-97.83 (ddd, J = 219.6,29.9,5.5 Hz); IR (neat, ci") 2934,2876,1458,1320,1134,1029; HRMS m/z (M*) pending.

Example 27 Deprotected difluoronated C, D-ring alcohol (+)-40 A solution of silyl ether (+)-39 (55 mg, 0. 11 mmol) in THF (2.0 mL) and 0.29 mL (0. 29 mmol) of 1.0 M solution of TBAF in THF was stirred overnight at room temperature. The mixture was quenched with water and extracted with EtOAc. The combined organic portions were washed with brine, dried, concentrated in vacuo and then purified by column chromatography (20% EtOAc/hexanes) to give 27 mg (66%) of the desired alcohol as a colorless oil: [α]25D +9.3° (c 2.7, CHC1,);'H NMR (400 MHz, CDCI,) 8 5.41 (d, J = 1.2 Hz, 1H), 4.17 (d, J = 2.4 Hz, 1H), 2.72-2.20 (m, 4H), 2.06-1.32 (m, 17H), 1.13 (d, J = 6.0 Hz, 3H), 1.06 (s, 3H);"C NMR (100 MHz, CDC13) 8 158.70, 129.45 (t, J= 289.7 Hz), 121.75,69.17,63.38,54.45,47.01,35.96 (t, J= 18.6 Hz), 35.60, 34. 00,30.46,25.44,24.42,22.89,18.57,17.94; NMR (376 MHz, CDC13, CFC13 as <BR> <BR> <BR> <BR> internal) 8-96.22 (ddd, J = 219.6,32.4,8.0 Hz), 8-97.76 (ddd, J= 219.6,29.7,6.8 Hz); IR (neat, cm') 3566,3448,2931,2860,1455,1314,1126; HRMS mlz (M*) pending.

Example 28 C, D-ring ketone (+) 41 A flame-dried 5 mL flask was charged with 27 mg (0.074 mmol) of the C, D-ring alcohol (+)-40,3.0 mL of anhydrous THF, 100 mg of oven-dried celite and 69 mg (0.19 mmol) of PDC. The reaction mixture was stirred overnight at room temperature and then passed through a 2 cm pad of flash silica gel and washed with EtOAc. The filtrate was concentrated and purified by column chromatography (20% EtOAc/hexanes) to give 24 <BR> <BR> <BR> mg (89%) of the desired C, D-ring ketone (+) 41 as a colorless oil: [a] 25D +17. 5° (c 2.5,<BR> <BR> <BR> <BR> <BR> CHCI,);'H NMR (400 MHz, CDCl3) 8 5.41 (s, 1H), 2.84 (dd, J= 10.4,6.4 Hz, 1H), 2.74-<BR> <BR> <BR> <BR> 2.22 (m, 6H), 2.16-1.74 (m, 5H), 1.51 (s, 9H), 1.19 (d, J= 6.4 Hz, 3H), 0.84 (s, 3H);"C NMR (100 MHz, CDCl3) 5 210.76,156.38,129.20 (t, J= 289.9 Hz), 122.29,63.47,63.12, <BR> <BR> <BR> 54.14,40.62,36.03 (t, J= 18.5 Hz), 34.54,27.36,26.48 (t, J= 2.7 Hz), 24.41 (t, J= 2.6<BR> <BR> <BR> <BR> <BR> Hz), 24.11,22.56,17.50;"F NMR (376 MHz, CDCI"CFCI, as internal) 8-96.20 (ddd, J<BR> <BR> <BR> <BR> <BR> = 219.8,28.9,9.2 Hz), # -97. 49 (ddd, J = 219.8,28.9,10.3 Hz); IR (neat, cri') 2943, 1713,1314,1132; HRMS m/z (M+) pending.

Example 29 Analogs Formula VIII Racemic phosphine oxide (A-ring, 43.4 mg, 0.075 mmol) was dissolved in 1.0 mL <BR> <BR> of anhydrous THF and cooled to-78°C under argon atmosphere. To this solution was added 58 uL (0.070 mmol) of phenyllithium (1.2 M solution in THF) dropwise. The <BR> <BR> <BR> mixture turned deep reddish orange and persisted. After stirring at-78°C for 30 minutes, a<BR> <BR> <BR> <BR> <BR> precooled (-78°C) solution of C, D-ring ketone (+)-41 (24.8 mg, 0.068 mmol) dissolved in 1.0 mL of anhydrous THF was added dropwise via cannula. The reaction kept going on until the reddish orange color faded to yellow (about 4 hours). The reaction was quenched by adding 3.0 mL of a 1: 1 mixture of 2 N sodium potassium tartrate and 2 N K2CO, solution. The reaction mixture was allowed to warm to room temperature, extracted with EtOAc, washed with brine, dried over anhydrous filtered, concentrated in vacuo, and then purified by column chromatography (10% EtOAc/hexanes) to afford 37.2 mg (75%) of the coupled product as a colorless oil.

The coupled product (37.2 mg, 0.051 mmol) was dissolved in 3.0 mL of anhydrous <BR> <BR> <BR> THF with 29 liL of Et, N, and to this solution was added 0.20 mL (0.20 mmol) of TBAF (1.0 M solution in THF) at room temperature. The reaction was run in darkness overnight, then extracted with EtOAc, washed with brine, dried over anhydrous MgS04, concentrated in vacuo and then purified by column chromatography (90% EtOAc/Hexanes) to give 18.6 mg (73%) of a mixture of two diastereomers as a colorless oil. The diastereomers were separated by reverse phase HPLC (C-18 semipreparative column, 52% MeCN/H, O, <BR> <BR> <BR> 3.0 mL/min) to afford 7.4 mg (22%) of Formula VIII-1 (la, 3p, tR 90.7 min) as a foaming solid and 4.3 mg (13%) of Formula VIII-2 (1/3,3a, tR 84.3 min) as a colorless oil. Formula VIII-1: [α]25D +2.1° (c 0.7, CHCI,);'H NMR (400 MHz, CDCl3) 8 6.37 (d, J = 11.6 Hz, 1H), 6.10 (d, J= 11.2 Hz, 1H), 5.42 (s, 1H), 5.33 (s, 1H), 5.00 (s, 1H), 4.44 (dd, J = 7.2,4.0 Hz, 1H), 4.24 (m, 1H), 2.82 (dd, J =11. 8,4.2 Hz, 1H), 2.74-2.50 (m, 3H), 2.44-2.16 (m, 5H), 2.10-1.48 (m, 16H), 1.17 (d, J= 6.8 Hz, 3H), 0.72 (s, 3H) ;13C NMR <BR> <BR> <BR> <BR> (100 MHz, CDCl3) 5 158.32,147.83,142.25,133.45,129.44 (t, J = 290.0 Hz), 125.03, 111.92,70.91,67.08,63.40,58.42,50.50,45.39,43.05,35.98 (t, J= 18.6 Hz), 35.44, 26.49,24.45,23.71,22.42,17.14 ; 19F NMR (376 MHz, CDCl3, <BR> <BR> <BR> <BR> CFCI, as internal) 8-96.17 (ddd, J= 218.6,32.0,8.1 Hz), S-97. 64 (ddd, J= 219.8,29.7,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 8.5 Hz); UV (EtOH) A",, 263 nm (c 16,900); IR (CHCI,, cm ') 3601,2931,2849,1649, 1602,1455,1314,1132,1043; HRMS m/z (M+) pending. Formula VIII-2: [α]25D-19.3° (c 0.4, CHC13);'H NMR (400 MHz, CDCI,) 8 6.38 (d, J= 11. 2 Hz, 1H), 6.09 (d, J= 11.2 Hz, 1H), 5.42 (s, 1H), 5.32 (s, 1H), 5.01 (d, J = 1.2 Hz, 1H), 4.45 (m, 1H), 4.22 (m, 1H), 2.82 (dd, J=12. 0,4.4 Hz, 1H), 2.74-2.50 (m, 3H) ;-2.44-2.16 (m, 5H), 2.10-1.48 (m, 16H), <BR> <BR> <BR> <BR> 1.17 (d, J = 6. 8 Hz, 3H), 0.72 (s, 3H) ;"C NMR (100 MHz, CDCI,) 5 158.34,147.32, 142.32,133.26,129.45 (t, J= 294.7 Hz), 125.07, 122.26, 117.29,113.07,71.70,66.99, 63.40,58.41,50.51,45.73,42.98,35.99 (t, J= 18.6 Hz), 35.43,29.70,28.89,26.49,24.46, <BR> <BR> <BR> <BR> 23.71,22.42,17.14;'9F NMR (376 MHz, CDCI,, CFC13 as internal) 8-96.17 (dd, J=<BR> <BR> <BR> <BR> <BR> <BR> <BR> 222.0,28.4 Hz), 8-97.69 (dd, J= 219.6,28.9 Hz); UV (EtOH) #max 262 nm (e 14,000); IR (CHCl3, cm-1)3601, 2931,2849,1455,1314,1132,1038; HRMS m/z (M+) pending.

Preparation of the Formula IX materials is described in Scheme 8 as follows: Scheme 8 Synthesis of Formula IX Calcitriol Analogs o., o. u CHO $ n-BuLi. 9 < 1) MsCI. DMAP 16 76% 2) DBU, 94% TES TEST (+)-22 42 25 /, S../... S ; o HF-MeCN PDC 16 16 TESO HO" TESO H HO H (+)-43E (+)-44E O H % 0 16 16 OH (+)-45E P (O) Ph2 ) 1) PhLi 2)(+)-45E, 88% 4 3) 10% HF-EtOH 91% EO . OE (t) A MA Formula IX Scheme 8 begins with the same aldehyde derivative as set forth in Schemes 3 and 6. Preparation of the various intermediates, 42,43E, 44E, and 45E, and the Formula IX compounds is described in Examples 30 through 34 hereinafter.

Example 30 16-Ene-23-Hydroxy-25-Sulfones 42 To a solution of methyl t-butylsulfone (103 mg, 0.76 mmol) in 10 mL of was added 0.52 mL of n-BuLi (1.60 M, 0.83 mmol) dropwise at-78°C. After 1 h at-78°C, a solution of aldehyde (+)-22 (45 mg, 0.13 mmol) in 10 mL of THF was added dropwise at -78°C. After 2 h at-78°C, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (50 mLx3). The combined organic portions were washed with brine (30 mL), dried over MgS04 and concentrated. The crude product was purified by flash column chromatography (33% EtOAc/hexanes) to give 45 mg (76%) of diastereomeric alcohols 42 as colorless oils: 1 H NMR (400 MHz, CDCl3) 8 5.33 and 5. 27 (two s, 1H), 4.48 and 4.38 (two s, IH), 4.12 (s, IH), 3.47 and 3.37 (two s, IH), 3.09-2.94 (m, 2H), 2.41 (m, 1H), 2.26 (m, IH), 1.91-1.41 (m, 13H), 1.42 and 1.41 (two s, 9H), 1.04 (m, 6H), 0.95 and 0.94 (t, J= 8.0 Hz, 9H), 0.56 and 0.55 (q, J= 8.0 Hz, 6H); IR (neat, cm 1) 3523,2932,1290,1114; HRMS m/z (M) calcd 472.3043 for C25H4804SSi, found 472. 3037.

Example 31 16,23-Diene-25-Sulfone (+)-43E To a solution of alcohols 42 (42 mg, 0.089 mmol) in 10 mL of dry CH2C12 was added 0.20 mL of triethylamine and methanesulfonyl chloride (0.050 mL, 0.65 mmmol) at 0°C. The mixture was stirred for 1 h at 0°C. The solution was concentrated in vacuo. The residue was diluted with brine (20 mL) and extracted with EtOAc (30 mLx3). The combined organic portions were dried over MgS04 and concentrated. The crude mesylates were used for the next step without further purification.

To a solution of the mesylates in 7 mL of dry benzene was added 1,8- diazabicyclo [5.4.0] undec-7-ene (0.050 mL, 0.33 mmol). The solution was gently refluxed for 15 min and then allowed to cool to room-temperature. The reaction mixture was diluted with brine (20 mL) and extracted with EtOAc (30 mLx3). The combined organic portions were dried over MgS04 and concentrated. The crude product was purified by flash chromatography (33% EtOAc/hexanes) to give 38 mg (94%) of the unsaturated sulfone (+)-43E as a colorless oil: [a] 25D +20.0 (c 1.4, CHC13); 1H NMR (400 MHz, CDCl3) 8 6.81 (dt, J= 14.8,7.6 Hz, 1H), 6.23 (d, J= 15.2 Hz, 1H), 5.29 (s, 1H), 4.11 (s, 1H), 2.51 (m, 1H), (m, 3H), 1.91 (m, 2H), (m, 10H), 1.04 (d, J= 6.4 Hz, 3H), 1.01 (s, 3H), 0.94 (t, J= 8.0 Hz, 9H), 0.56 (q, J= 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) 8 158.38,150.43,124.31,121.34,68.75,58.17,54.95,46.75,38.76,35 .78, 83,18.84,17.96,6.88,4.83; IR (neat, cm~l) 2932,1294, 1115; HRMS m/z pending.

Example 32 16,23-Diene-8-Hydroxy-25-Sulfone (+) 44E To a solution of the sulfone (+)-43E (24 mg, 0.053 mmol) in 10 mL of acetonitrile was added hydrofluoric acid (2% in H20,0.10 mL, 0.10 mmol) at 0°C. After 2 h at 0°C, the reaction mixture was quenched with saturated NaHC03 solution (20 mL) and extracted with EtOAc (30 mLx3). The combined organic layers were washed with brine (30 mL), dried over MgS04 and concentrated. The crude product was purified by flash chromatography (50% EtOAc/hexanes) to give 17 mg (94 %) of the alcohol (+)-44E as a coloress oil: [a] 25D +5.9 (c 2.9, CHC13); 1H NNM (400 MHz, CDCl3) 8 6.82 (dt, J= 15.2,7.6 Hz, 1H), 6.25 (dt, J= 15.2,1.6 Hz, 1H), 5.35 (s, 1H), 4.18 (s, 1H), 2.54-2.22 (m, 4H), 2.02-1.52 (m, 14H), 1.35 (s, 9H), 1.06 (d, J= 8.0 Hz, 3H), 1.05 (s, 3H); 13C NMR <BR> <BR> <BR> <BR> (100 MHzCDC13) 8 158.30,150.22,124.45,121.45,68.89,58.19,54.31,46.46,38.72, 35.47,33.79,30.99,30.22,23.28,21.84,18.46,17.70; IR (neat, cm 1) 3526,2927,1290, 1120; HRMS w7iZ (M+NH4+) calcd 358.2416 for Cl9H3203S, found 358.2408.

Example 33 16,23-Diene-8-Keto-25-Sulfone (+)-45E To a solution of the alcohol (+)-44E (28 mg, 0.083 mmol) in 10 mL of dry CH2C12 was added 57 mg of oven dried celite and pyridinium dichlomate (57 mg, 0.15 mmol) at rt. After 16 h, the reaction mixture was filtered through a flash silica gel pad, and then eluted with EtOAc. The filtrate was concentrated and purified by flash chromatography (50% EtOAc/hexanes) to give 25 mg (89%) of the ketone (+)-45E as a <BR> <BR> <BR> colorless oil: [a] 25D +22.2 (c 2.0, CHC13); 1 H NMR (400 MHz, CDCl3) b 6.78 (dt, J= 15.2 7.6 Hz, 1H), 6.25 (d, J= 15.2 Hz, 1H), 5.33 (s, 1H), 2.85 (m, 1H), 2.55-2.27 (m, 6H), 2.15-1.74 (m, 7H), 1.33 (s 9H), 1.11 (d, J= 6.4 Hz, 3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) 8 210.43,156.21,149.49,124.89,121.80,62.89,58.19,53.69,40.34,3 8.56, 34.35,27.09,23.86,23.25,21.35,17.32; IR (neat, cm 1) 2935,1715,1289,1113; HRMS miz (M+NH4+) calcd 356. 2259 for Ci9H3003S, found 356.2266.

Example 34 16,23-Diene-25-Sulfone Analogs (-)-Formula IX-1 and (-)-Formula IX-2 To a solution of racemic phosphine oxide ()-A (60 mg, 0.10 mmol) in 1 mL of anhydrous THF was treated dropwise with phenyllithium (1.22 M in cyclohexane-ether, 0.082 mL, 0.10 mmol) at-78°C. The resulting reddish orange solution was stirred at- 78°C for 30 min and then a solution of the ketone (+)-45E (24 mg, 0.071 mmol) in 1 mL uf anhydrous THF was added dropwise. The reaction mixture was stirred until reddish color turned to pale yellow, and then quenched with 3 mL of a 1: 1 mixture of 2 N sodium potassium tartrate solution and 2 N K2C03 solution. The aqueous layer was extracted with EtOAc (50 mLx3). The combined organic portions were washed with brine (50 mL), dried over MgS04, and concentrated. The residue was purified by preparative TLC (EtOAc) to give 44 mg (88%) of the coupled prduct as a colorless oil.

To a solution of the coupled product (44 mg, 0.062 mmol) in 2 mL of anhydrous ethanol was added hydrofluoric acid (49% in H20,0.50 mL, 12.3 mmol). The solution was stirred at rt for 2 h in dark. The reaction mixture was quenched with NaHC03 solution (20mL) and the aqueous layer was extracted with EtOAc (30 mLx3). The combined organic portions were washed with brine (20 mL), dried over MgS04, and concentrated. The residue was purified by preparative TLC (EtOAc) to give 27 mg (91%) of diastereomeric diols Formula IX as colorless oils. The diastereomers were separated by reverse phase HPLC (C-18 semi preparative column, 52% MeCN/48% H20,3 mL/min) to give 12mg (36%) of ()-Formula IX-1 (1a, 3 (3, tR 30.2 min) and 9 mg (27%) of (-)-Formula IX-2 (1 (3,3a, tR 27.1 min) as colorless oils. (-)-Formula IX-1: [a] 25D- 2.5 (c 1.1, CHC13); 1H NMR (400 MHz, CDCI3) 8 6.81 (dt, J=15. 2,7.4 Hz, 1H), 6.36 (d, J= 11.2 Hz, 1H), 6.24 (d, J= 15.2 Hz, 1H), 6.10 (d, J= 11.6 Hz, 1H), 5.34 (two s, 2H), 5.00 (s, 1H), 4.44 (m, 1H), 4.24 (m, 1H), 2.88 (dd, J=12. 4,4.2 Hz, 1H), 2.61-2.48 (m, 3H), 2.38-2.14 (m, 7H), 2.06-1.51 (m, 18H), 1.34 (s, 9H), 1.09 (d, J= 6.4 Hz, 3H), 0.70 (s, 3H); <BR> <BR> <BR> 13C NMR (100 MHz, CDC13) 5 157.86,150.15,147.63,141.81,133.37,124.70,124.50, 122.98,117.14,111.64,70.62,66.83,58.28,58.21,50.02,45.12,42. 84,38.64,35.29, 67,23.49,23.29,21.29,17.03; IR (neat, ciri 1) 3606,2931,1291,1113; <BR> <BR> <BR> W (EtOH) kmax 263 nm (s 11,793); HRMS m/z pending. (-)-Formula IX-2: [a] 25D- 10.9 (C 0.8, CHC13); 1H NMR (400 MHz, CDC13) 5 6.81 (dt, J= 15.2,7.6 Hz, 1H), 6.38 (d, J= 11. 6 Hz, 1H), 6.24 (d, J= 15. 2 Hz, 1H), 6.09 (d, J= 11. 2 Hz, 1H), 5. 35 and 5.33 (two s, 2H), 5.01 (s, 1H), 4.46 (m, 1H), 4.23 (m, 1H), 2.83 (dd, J= 12.8,4.0 Hz, 1H), 2.64-2.48 (m, 3H), 2.34-2.15 (m, 7H), (m, 20H), 1.35 (s, 9H), 1.09 (d, J= 6.4 Hz, 3H), <BR> <BR> <BR> 0.69 (s, 3H)); 13C NMR (100 MHz, CDC13) 8 157.86,150.15,147.09,141.91,133.18, 117.14,112.82,71.42,66.74,58.28,58.22,50.03,45.47,42.78, 38.64,35.28,32.01,29.47,28.66,23.48,23.30,21.32,17.05; IR (neat, cm-1) 3606,2931, 1291,1112; W (EtOH)#max 263 nm (s 11,572);. HRMS? n/z Preparation of the Formula X materials is described in Scheme 9 as follows: Scheme 9 Synthesis of Formula X Calcitriol Analogs fY TBAT r\ Ac: 0 f- 0 0 0 TBAF Ac2O > TESO quantitative HO 94 DMAP HO 94% ACO (+)-46 47 48 O O 'TMSO'IMSOTf TMSCI Et3Si 49 53% 50 52% r /O//O 1)NaOH, EtOH 2) PDC, celite H quantitative AcO 52 51 Formula X Scheme 9 begins with a ketone derivative 46, the preparation of which is described in Posner et al; J. Ors. Chem. Vol. 62.1997 at pp. 3299-3314 and also uses t-butyl, 3- hydroxypropyl sulfone 49 as a ragent. Preparation of the various intermediates 51 and 52 and the Formula X compounds is described in Examples 35 through 40 hereinafter.

Example 35 Hydroxy Ketone 47 To a solution of (triethylsilyloxy) ketone (+)-46 (78 mg, 0.225 mmol) in 5 mL of THF at 0 °C was added 338 uL (0.338 mmol, 1.0 M in THF) of tetrabutylammonium fluoride dropwise via syringe. The reaction mixture was brought to rt and stirred for 5 h, after which the solvent was evaporated. The crude mixture was purified by column chromatography (20% EtOAclhexanes) to give 48 mg of the desired hydroxy ketone 47 in quantitative yield: 1H NMR (CDC13) õ 4.07 (m, IH), 2.45 (t, J = 8.8 Hz, 1H), 2.05 (s, 3H), 0.82 (s, 3H); 13C NMR (CDC13) # 209.4,68.5,64.1,52.6,43.3,39.4,33.3,31.4, 22.5,21.6,17.3,15.1; [a] 25D, IR, HRMS pending.

Example 36 Acetoxy Ketone 48 To a solution of hydoxy ketone 47 (48 mg, 0.245 mmol) in 2.2 mL of CH2C12 at 0 °C was added DMAP (1 mg, 0.03 mmol), pyridine (44 µL, 0.539 mmol), and Ac20 (46 µL, 0.489 mmol) sequentially and the resulting solution stirred for 8 h while warming to rt.

Following concentration, the reaction mixture was passed through flash silica gel (10% EtOAc/hexanes) to afford acetoxy ketone 48 as a pale yellow oil (55 mg, 94%): 1H NMR (CDCl3) # 5. 08 (m, 1H), 2.42 (t, J = 8. 8 Hz, IM, 2.02 (s, 3H), 1.94 (s, 3H), 0.73 (s, 3H); 13C NMR (CDC ! 3) 5 43.1,38.8,31.3,30.1,22.5,21.4, [«] 25D, IR, HRMS pending Example 37 t-Butyl 3-(Trimethylsilyloxy)-propyl Sulfone(Trimethylsilyloxy)-propyl Sulfone 50 To a solution oft-Butyl 3-hydroxypropyl sulfone1 49 (1.01 g, 5.60 mmol) in 25 mL of CH2C12 was added Et3N (1.17 mL, 8.40 mmol) and then TMSCI (0.78 mL, 6.16 mL).

The resulting solution was stirred for I h, cooled to 0 °C, and quenched with saturated NaHC03 (5 mL). After warining, the reaction mixture was diluted with H20 (10 mL), extracted with CH2Cl2 (3 x 15 mL), dried over Na2SO4, filtered, and concentrated to a red oil. Rapid column chromatography (25% EtOAc/hexanes) afforded the desired product 50 as a clear, colorless oil (0.75 g, 53% from 2-methyl-2-propanethioll): 1H NMR <BR> <BR> <BR> <BR> (CDC13) 6 3.71 (t, J = 5.8 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H), 2.07 (m, 2H), 1.40 (s, 9H), 0.09 (s, 9H) ; 13C NMR (CDC13) 5 60.7,58.8,42.5,23.8,23.3,-0.63; IR (neat, cm 1) 2959,2906,2875,1301-1249,1113; HRMS submitted Example 38 Acetoxy Sulfone 51 To a solution of ketone 48 (24 mg, 0.101 mmol) in 1 mL of CH2C12 at-78 °C was added 35 mg (0.138 mmol) of (trimethylsilyl) ether 50 in 0.350 mL of CH2C12. To this solution was added TMSOTf (0.019 mL, 0.105 mmol) via syringe and the resulting solution stirred at-78 °C for 1 h. Et3SiH (0.017 mL, 0.105 mmol) was added via syringe and the reaction mixture brought to rt. After 4 h, the reaction was ceased by the addition of a saturated NaHCO3 solution (I mL). This mixture was diluted with H20 (10 mL), extracted with CH2C12 (3X), dried over MgS04, filtered, concentrated, and passed through flash silica gel (25% EtOAc/hexanes) to afford the acetoxy sulfone 51 as a clear, colorless oil (21.0 mg, 52% : 1H NMR (CDC ! s) 8 5.14 (m, 1H), 3.69 (dt, J = 9.2,6.0 Hz, 1H), 3.35 (dt, J = 9.2,6.0 Hz, 1H), 3.30 (m, IH), 3.04 (t, J = 7.8 Hz, 2H), 2.13 (m, 2H), 2.03 (s, 3H), 1.83 (m,! H), 1.41 (s, 9H), 1.05 (d, J = 6.0 Hz, 3H), 0.88 (s, 3H); 13 C NMR <BR> <BR> <BR> <BR> (CDC13) 8 170.8,77.7,71.1,65.8,58.8,56.6,50.9,43.2,41.8,40.0,30.6,24.7 ,23.4, 22.8,21.7,21.4,18.1,17.8,13.7; [a] i5, IR, HRMS pending Example 39 C, D-Ring Ketone 52 To a solution of acetoxy sulfone 51 (18 mg, 0.045 mmol) in 2 mL of EtOH was added 10 M NaOH (aq) (I mL) dropwise. After stirring for 3 h, the reaction mixture was cooled to 0 °C, diluted with Et20 (ImL), neutralized with 10% HC ! (aq) (I mL), extracted with EtOAc (3 x 5 mL), the combined organics washed with brine, dried over MgS04, filtered, and concentrated to afford the crude alcohol (16 mg). This alcohol (16 mg) was then dissolved in 4 mL CH2Cl2, and to this solution was added celite (25 mg) and PDC (25 mg, 0.067 mmol). After stirring for 12 h, the suspension was passed through a short plug of celite and rinsed with CH2Cl2. The filtrate was then concentrated and passed through a short plug of flash silica gel (35% EtOAc/hexanes) to give the desired ketone 52 (16 mg) as a white solid in quantitative yield. 1H NMR (CDCl3) # 3.69 (dt, J = 9.2,6.0 Hz, iH), 3.36 (dt, J = 9.2,6.0 Hz, IH), 3.29 (m, IH), 3.01 (dt, J = 7.7,3.0 Hz, 2H), 2.45 (dd, J = 11.2,7.2 Hz, 1H), 1.41 (s, 9H) 1.08 (d, J = 6.0 Hz, 3H), 0.64 (s, 3H); 13C NMR (CDC13) S 211.8,77.5,65.9,61.4,58.9,56.7,49.8,42.9,41.1,39.0,25.0,24.1 ,23.4,21.7,19.3, 18.2,13.1; mp, [a] 25D, IR, HRMS pending Example 40 20-Epi-22-osa-26-sulfone Formulas X-1 and X-2 Racemic phosphine oxide (')-A (51 mg, 0.087 mmol) was dissolved in 1 mL of THF and cooled to-78 °C under argon. To this solution was added 51 gL (0.086 mmol, 1.69 M in cyclohexanelEt20) of PhLi dropwise via syringe. The deep orange solution was stirred for 30 min, at which time a cold solution of C, D-ring ketone 52 (31 mg, 0.082 mmol) in 0.7 mL of THF was added dropwise via cannula. The resulting solution was stirred at-78 °C in the dark for approximately 4 h and then quenched with 3 mL of a 2: 1 (v: v) mixture of 2 N sodium potassium tartrate and 2 N potassium carbonate. Upon warming to rt, the reaction mixture was extracted with EtOAc (3 x 20 mL), dried over MgS04, filtered, concentrated and purified by silica gel column chromatography (20% EtOAc/l% NEt3/hexanes) to afford 43 mg (72% based on 52) of the coupled product as a yellow oil. This oil was immediately dissolved in 10 mL of THF with 20 µL of NEt3. To this solution was added 178 uL (0.178 mmol, 1.0 M in THF) of tetrabutylammonium fluoride dropwise via syringe. The reaction mixture was stirred for 16 h in the dark, after which the solvent was evaporated and the crude mixture purified by column chromatography (1% NEt3/EtOAc) to give 21 mg (71%) of a mixture of two diastereomers Formula X-1 and Formula X-2. This diastereomeric mixture was purified by reversed-phase HPLC (C-18 semipreparative column, 40% MeCN/H20,3 mIJmin) giving Formula X-1 (la, 3B, IR 70.7 min) and Formula X-2 (1ß, 3a, tR 66.6 min): Formula X-1 <BR> <BR> <BR> (1α, 3ß) : 1H NMR (CDC13) 6 6. 38 (d, J = 11.2 Hz, IH), 6.00 (d, J = 11.2 Hz, 1H), 5.32 (m, 1H), 4.99 (m, IH), 4.46. 40 (m, IH), (m, 1H), 3.70 (dt, J = 9.2,6.0 Hz, IH), 3.34 (dt, J = 9.2,6.0 Hz, 1H), 3.29 (m, 1H), 3.03 (m, 2H), 2.83 (dd, J = 13.2,4.4 Hz, IH), 2.60 (dd, J= 13.2,3. 6 Hz, 1H), 2.29 (dd, J = 13.4,6.4 Hz, IH), 1.41 (s, 9H) 1.08 <BR> <BR> <BR> (d, J = 5. 6 Hz, 3H), 0.55 (s, 3H); 13C NMR, LTV, [a] 25D-50.8 (c 4.4, CHC13) ; Formula X-2 (1B, 3a): 1H NMR (CDCl3) # 6. 39 (d, J= 11.6 Hz, IH), 5.99 (d, J= 11.2 Hz, IM, 5.31 (m, 1H), 5.00 (m, 1H), 4.47-4.41 (m, IH), 4.26-4.19 (m, IH), 3.71 (dt, J = 9.2,6.0 Hz, IH), 3.35 (dt, J = 9.2,6.0 Hz, 1H), 3.29 (m, 1H), 3.04 (m, 2H), 2.83 (dd, J = 13.2, 4.0 Hz, 1H), 2.61 (dd, J=13. 2,4.0 Hz, IH), 2.30 (dd, J= 13.0,7.6 Hz, 1H), 1.41 (s, 9H) 1.08 (d, J = 5.6 Hz, 3H), 0.55 (s, 3H); 13C NMR, UV, [α]25D-36. 2 (c 3.0, CHC13).

Via synthesis procedures similar to those set forth in the examples herein, it is possible to prepare related 23-oxa-25-sulfones and 20-epi-22-oxa-sulfones. Such compounds have the generic structures shown in Formulas XI and XII as follows: FormulaXI <BR> <BR> 23-oxa-25-suifones FormulaXII <BR> <BR> 20-eni-22-oxa-sulfones Via conventional organic synthesis procedures starting from materials described herein, it is also possible to prepare related 16-ene-alkenylsulfones and 16-ene- alkynylsulfones. Such compounds have the generic structure shown in Formula Xm as follows: Formula XIII 16-ene-alkenvisulfones and 16-ene-alkvnvlsulfones Scheme 10 Synthesis of 20-Epi-22-oxi-26-p-methoxyphenyl Sulfone Analogs 15 a and 15b: 0 OH 0OH LiAI (..'H 1. KH, lh TBSO H H 2. TsO TBSO w (+) 1 95 % <.. <0 63 % ., H v v p 1. oxone, MeOH : H20 i tome 2. TBAF, A Oye + 90% ()-14 20 a22 A P (O) Ph2-v vZ6 \ ... I I 1. PhLi 2. (-) 14 I H" TBSCJ OTBS 3. TBAF lí ()-8 64 % 3 1 HO OH KRC-20-epi-22-oxa-26-PMP-1, (I a, 3p), (-)-15a (27%) KRC-20-epi-22-oxa-26-PMP-2, (I P, 3a), (_) _15b (15%) FormulaXIV Example 41 4- [ (Methoxy) phenyl]-3-tosyloxypropyl Sulde 10. To a solution of NaOH (0.572 g, 14.3 mmol) in EtOH (12 mL) at 0 °C was added dropwise via syringe 4- methoxythiophenol (1.75 mL, 14.3 mmol) over 2 min. The resulting solution was warmed to n and stirred for 30 min. Upon dropwise addition of 3-chloro-1-propanol (1.19 mL, 14.3 mmol), the reaction mixture was heated to reflux and stirred overnight. The resulting suspension was filtered to remove NaCI, which was rinsed thoroughly with CH2CI2. The filtrate was neutralized with 1 M HCI (12 mL), diluted with H2O (20 mL), extracted with CH2C12 (3 x 20 mL), washed with H2O, dried over Na2SO4, filtered, and concentrated to a pale yellow oil which solidified on standing.

A portion of this pale yellow solid (613 mg, 2.66 mmol) was dissolved in CH2Cl2 (17 mL) and cooled to 0 °C. To this solution was added DMAP (390 mg, 3.19 mmol) and TsCI (558 mg, 2.93 mmol), and the resulting solution was allowed to stir with gradual warming to rt overnight. The reaction mixture was quenched with 10% HCI (5 mL), partitioned between CH2C12 and H2O, extracted with CH2Cl2 (3 x 20 mL), dried over Na, S04, filtered, concentrated, and purified by column chromatography (30-50% EtOAc/hexanes) to give the desired tosylate (448 mg, 44%) as a clear oil:'H NMR <BR> <BR> <BR> <BR> <BR> (CDCl3) 5 7.77 (dt, J = 8.4,1.6 Hz, 2H), 7.34 (m, 2H), 7.27 (dt, J = 9.0,2.2 Hz, 2H), 6.82 (dt, J = 9.0,2.2 Hz, 2H), 4.13 (t, J = 6.0 Hz, 2H), 3.78 (s, 3H), 2.80 (t, J = 7.0 <BR> <BR> <BR> <BR> <BR> Hz, 2H), 2.44 (s, 3H), 1.86 (m, 2H);"C NMR (CDC13) 6 159.10,144.77,133.58, 68.61,55.26,31.62,28.35,21.59; IR (neat) <BR> <BR> <BR> <BR> <BR> 3063,2957,2834,1594,1571,1494,1462,1441,1359,1284,1244,1187, 1174,1096, 1030; HRMS: calcd for C, 7H2004S2 352.0803, found 352.0804.

Example 42 R-Alcohol (+)-12. To a stirred solution of (r-butyldimethylsilyloxy) ketone (+)-111 (803 mg, 2.59 mmol) in THF (50 mL) at-78 °C was added lithium tri-tert- butoxyaluminohydride (7.76 mL, 1.0 M in THF) dropwise via syringe. The reaction mixture was brought to rt slowly overnight. The reaction was quenched with a saturated aqueous NH, CI solution (15 mL) and the resulting mixture was extracted with EtOAc (3 x 25 mL), dried with brine and MgS04, filtered, and concentrated. The crude mixture was purified on short path silica gel (5-10% EtOAc/hexanes) to give 658 mg (81%) of the desired R-alcohol (+)-12 and 113 mg (14%) of the S-alcohol, both having spectroscopic and physical characteristics analogous to those reported previously. z Example 43 83- [ (t-Butyldimethylsilyl) oxy] 20-epi-22-oxa-26-p-methoxyphenyl Sulfone (+)-13. Potassium hydride (63 mg of a 35 wt. % dispersion in mineral oil- approximately 22 mg, 0.54 mmol dry weight) was rinsed and dried according to methods described by Brown. 3 To a suspension of the resulting dry KH in THF (1.0 mL) was added a solution of alcohol (+)-12 (50 mg, 0.16 mmol) in THF (2.2 mL) dropwise via syringe. The resulting yellow solution was stirred for 1 h. Then tosylate 10 (123 mg, 0. 32 mmol) in THF (0.88 mL) was added via syringe. After 3 h, the reaction was cautiously diluted with EtOAc and H20, and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over MgS04, filtered, concentrated and purified on flash silica gel (2-5% EtOAc/hexanes) to afford 50 mg (63%) of the desired ether (+)-13 <BR> <BR> <BR> with 11 mg (22%) of recovered alcohol (+)-12: D +1.63 (c 3.0, CHCI3);'H NMR<BR> <BR> <BR> <BR> <BR> (CDCI3) 6 7.34 (dt, J = 9.0,2.2 Hz, 2H), 6.83 (dt, J = 9.0,2.2 Hz, 2H), 4.00 (m, 1H), 3.79 (s, 3H), 3.62 (dt, J = 0 Hz, 1H), 3.31-3.22 (m, 2H), 2.91 (t, J = 7.2 Hz, 2H), 2.02 (dt, J = 12.4,2.8 Hz, 1H), 1.85-1.05 (m, 13H), 1.04 (d, J = 6.0,3H), 0.93 (s, 3H), 0.89 (s, 9H), 0.01 (s, 3H),-0.01 (s, 3H);'3C NMR (CDC13) 8 158.75,133.02, 29,52.61,42.00,40.56,34.59,32.94, 17.63,14.46,-4.79,-5.19; IR (neat) 3002, 1019; HRMS: calcd for C28Hy8O3SSi 492.3093, found 492.3093.

Example 44 C, D-Ring Ketone (-)-14. Oxone' (20% aqueous solution: 68 mg, 0.11 mmol in 275 KLL HO) was added dropwise to a stirred solution of ether (+)-13 in MeOH (1.0 mL).

The resulting solution was stirred for 2 d, with additional oxone# solution being added to consume starting material. Upon dilution with H, O and extraction with CHC13, the combined organics were dried, filtered and concentrated to give a crude mixture of sulfones (C8-OTBS: C8-OH), which was immediately dissolved in THF (3.5 mL) and treated with TBAF (400 RL, 1.0 M in THF). The resulting solution was stirred at reflux for 2 d, with additional TBAF solution being added to consume starting material. The reaction mixture was cooled to rt, diluted with EtOAc and H20 (10 mL each), extracted with EtOAc (3 x 10 mL), dried, filtered, and concentrated to give crude hydroxy sulfone which was carried forward.

To crude hydroxy sulfone in CH2C12 (8 mL) was added celitee (57 mg) and PDC (57 mg, 0.15 mmol) and the resulting brown suspension was stirred overnight. Upon filtration through celite*, the reaction mixture was concentrated and passed through a short pad of flash silica gel (40% EtOAc/hexanes) to afford the desired C, D-ring ketone (-)-14 as a pale yellow oil (37 mg, 90% from (+)-13): [a] D-40.8 (c 3.0, CHC13);'H NMR <BR> <BR> <BR> (CDC13) b 7.80 (dt, J = 9.2,2.2 Hz, 2H), 7.00 (dt, J = 9.2,2.2 Hz, 2H), 3.86 (s, 3H), 3.54 (dt, J = 9.2,6.2 Hz, 1H), 3.28-3.06 (m, 5H), 2.45-2.38 (dd, J = 11.2,7.6 Hz, 1H), 2.28-1.07 (m, 12H), 1.01 (d, J = 6. 0,3H), 0.57 (s, 3H);'3C NMR (CDC13) 8 37,77.41,65.38,61.31,56.59,55.63,53.97, 49.68,41.01,38.85,24.91,24.03,23.92,19.25,18.09,12.98; IR (neat) 2961,2874, 1089,1023; HRMS: calcd for C22H3205S 408.1970, found 408.1976.

Example 45 20-Epi-22-oxa-26-p-methoxyphenyl Sulfone Analogs 15a and 15b. Racemic phosphine oxide ()-8 (78 mg, 0.13 mmol) was dissolved in 1.3 mL of THF and cooled to-78 °C under argon. To this solution was added 88 pu (0.13 mmol, 1.5 M in cyclohexane/Et2O) of PhLi dropwise via syringe. The deep orange solution was stirred for 30 min, at which time a cold (-78 °C) solution of C, D-ring ketone (-)-14 (36 mg, 0.087 mmol) in 1.2 mL of THF was added dropwise via cannula. The resulting solution was stirred in the dark at-78 °C for approximately 3 h, and for an additional 1 h at-60 °C. The reaction mixture was quenched with 3 mL of a 2: 1 (v: v) mixture of 2 N sodium potassium tartrate and 2 N potassium carbonate. Upon warming to rt, the reaction mixture was diluted with H2O, extracted with EtOAc (4 x 20 mL), dried over MgS04, filtered, concentrated and purified by silica gel column chromatography (20% EtOAc/hexanes- <0.1 % NEt3) to afford 40 mg (64% based on (-)-14) of the coupled product as a yellow oil.

This oil was immediately dissolved in THF (10 mL) with 10 pL of NEt3. To this solution was added 170 liL (0.17 mmol, 1.0 M in THF) of tetrabutylammonium fluoride dropwise via syringe. The reaction mixture was stirred for 16 h in the dark, after which the solvent was evaporated and the crude mixture purified by column chromatography (1% NEt3/EtOAc) to give 27 mg (90%) of a mixture of two diastereomers 15a and 15b. This diastereomeric mixture was purified by reversed-phase HPLC (C-18 semipreparative column, 43% MeCN/H20,3 mLIrriin) giving 15a (27%, tR 93.8 min) and 15b (15%, tR 88.9 min): 15a (I a, 3B): [a] 25 14.6 (c 2.5, CHC13);'H NMR (CDC13) 8 7. 81 (dt, J = 8.8,2.0 Hz, 2H), 7.01 (dt, J = 8.8,2.0 Hz, 2H), 6.37 (d, J = 11 Hz, 1H), 5.98 (d, J = 11 Hz, 1H), 5.31 (m, IH), 4.98 (m, 1H), (m, 1H), 4.26-4.19 (m, IH), 3.54 (dt, J = 9.2,6.2 Hz, 1H), 3.28-3.06 (m, 5H), 2.85-2.76 (dd, J = 12.2,3.0 Hz, 1H), 2.63-2.54 (dd, J = 12.2,3.0 Hz, 1H), 2.34-2.26 (dd, J = 13.3,6.8 Hz, 1 H), 2.06- 1.04 (m, 19H), 1.01 (d, J = 6.0,3H), 0.49 (s, 3H);'3C NMR (CDC13) 8 163.65, 147.61,142.86,132.98,130.63,130.17,124.88,117.02,114.40,111. 73,78.19, 70.77,66.80,65.45,56.66,55.75,55.67,54.12,45.71,45.21,42.84, 40.34,29.06, 25.04,24.01,23.49,22.40,18.22,12.63; IR (neat) 3706-3115 (br), 3019,2945,2872, 1109, 1088,1057,1027; UV (MeOH) #max 240 (# 20,102), 264 nm (£ 13,165); HRMS: calcd for C3, H", 06S 544.2859, found 544.2857.15b (1B, 3a): [a] 25D -43. 0 (c 4.1, CHCl3) ; 'H NMR (CDCl3) # 7.81 (dt, J = 8.8,2.0 Hz, 2H), 7.01 (dt, J = 8.8,2.0 Hz, 2H), 6.38 (d, J = 11.2 Hz, 1H), 5.98 (d, J = 11.2 Hz, 1H), 5.30 (m, 1H), 4.99 (m, 1H), 4.46-4.40 (m, 1H), (m, 1H), 3.55 (dt, J = 9.2,6.2 Hz, 1H), 3.28-3.06 (m, 5H), 2.85- 2.76 (dd, J = 12.2,3.0 Hz, 1H), 2.63-2.54 (dd, J = 12.2,3.0 Hz, 1H), 2.34-2.26 (dd, J = 13.3,6.8 Hz, 1H), 2.06-1.04 (m, 19Ii), 1.01 (d, J = 6.0,3H), 0.49 (s, 3H); 13C NMR (CDC13) 163.65,147.29,142.93,132.82,130.65,130.18,124.91,117.01, 66,55.75,55.67,54.12,45.72,45.44, 42.82,40.33,29.03,25.04,24.01,23.48,22.43,18.22,12.65; IR (neat) 3686-3076 (br), 2947,2926,2871,1595,1578,1498,1458,1438,1372,1317,1296,1260, 1220, <BR> <BR> <BR> <BR> 1139,1109,1089,1053,1025; W (MeOH) 240 (E 17, 201), 261 nm (E 10,346); HRMS: calcd for C3, H4"06S 544.2859, found 544.2857.

Example 46 20-Epi-22-oxa-25-difluoro-26-tert-butyl Sulfone Analogs 25a and 25b: O 5 P (O) Ph2 1. n-BuLi F F 2. 40 ., H F F I Formula XV (+)-8 3. HF, EtOH H OH KRC-20-epi-22-oxa-25-F 2. 26-SO2-1, (la, 3p), 25a (31%) KRC-20-tpi-22-oxa-25-F z-26-S02-2, (lp, 3a), 25b (9%) 20-Epi-22-oxa-25-difluoro-26-tert-butyl Sulfone Analogs 25a and 25b.

Racemic phosphine oxide ()-8 (70 mg, 0.12 mmol) was dissolved in 1.2 mL of THF and cooled to-78 °C under argon. To this solution was added 80 JIL of n-BuLi (0.12 mmol, 1.53 M in hexanes) dropwise via syringe. The deep red solution was stirred for 1 h, at which time a cold (-78 °C) solution of C, D-ring ketone (-)-24 (24 mg, 0.061 mmol) in 1.0 mL of THF was added dropwise via cannula. The resulting solution was stirred at-78 °C in the dark for approximately 3 h, then slowly warmed to-40 °C over 2 h. The reaction mixture was quenched with H, O (I mL), warmed to rt, extracted with Et2O (3 x 10 mL), washed with brine, dried over MgS04, filtered, concentrated and purified by silica gel column chromatography (5-40% EtOAc/hexanes) to afford 43 mg of the coupled product as a clear oil.

This oil was immediately dissolved in 3.0 mL of EtOH. To this solution was added 100 pL of an aqueous HF solution (49% wt) dropwise via syringe. The reaction mixture was stirred for 4 h in the dark, which, after general aqueous workup and column chromatography (75% EtOAc/hexanes), yielded 30 mg [93% from (-)-24] of a mixture of diastereomers 25a and 25b. This diastereomeric mixture was purified by reversed-phase HPLC (C-18 semipreparative column, 49% MeCN/H20,3 min) giving 10 mg (31%) of 25a (la, 3ß, tR 111 min) and 3.0 mg (9%) of 25b (1ß, 3α, tR 105 min): 25a (la, 3B):'H NMR (CDCl3) # 6.38 (d, J = 11 Hz, 1H), 5.99 (d, J = 11 Hz, 1H), 5.32 (m, 1H), 4.99 (m, 1H), (m, 1H), (m, IH), 3.84 (m, 1H), 3.51 (m, 1H), 3.31 (m, 1H), 2.82 (dd, J = 16,4.3 Hz, IH 1H), 2.60 (m, 3H), 2.31 (dd, J = 18, 8.8 Hz, 1H), 1.52 (s, 9H) 1.09 (d, J = 5.6 Hz, 3H), 0.54 (s, 3H);'3C NMR (CDC13) 8 56,70.80,66.83,60.05,56.58, 47,29.12,25.09,24.14,23.52,22.42,18.12, 12.53; HRMS: calcd for C28H44F205S 530.2878, found 530.2877; 25b (IB, 3a) :'H NMR (CDC13) 8 6.40 (d, J = 12 Hz, 1H), 5.98 (d, J = 12 Hz, 1H), 5.31 (m, 1H), 5.00 (m, 1H), 4.44 (m, 1H), 4.23 (m, 1H), 3.85 (m, 1H), 3.52 (m, 1H), 3.31 (m, 1H), 2.82 (dd, J = 16,4.3 Hz, 1H 1H), 2.59 (m, 3H), 2.29 (dd, J = 18,8.8 Hz, 1H), 1.52 (s, 9H) 1.09 (d, J = 6.0 Hz, 3H), 0.54 (s, 3H);"C NMR (CDC13) 8 147.28,143.18,132.68, 06,56.58,55.82,45.78,45.48, 42.82,40.16,31.48,29.10,25.09,24.14,23.52,22.45,18.13,12.55; HRMS: calcd for C28H44F205S 530.2878, found 530.2877;'9F NMR, UV, [α]25D, IR pending.

Through the use of similar methods, 27-t-butyl sulfone and 26-methyl sulfone analogs can be synthesized as shown in Schemes 11 and 12.

1Fernandez, B.; Perez, J. A. M.; Granja, J. R.; Castedo, L.; Mourino, A. J. Org. Chem.

1992,57,3173-3178.

2 Posner, G. H.; White, Dolan, P.; Kensler, T. W.; Yukihiro, S.; Guggino, S. E. Biorg.

Med. Chem. Lett. 1994,4,2919-2924.

3 Brown, C. A. J. Org. Chem. 1974,39,3913-3918.

Scheme 11 Synthesis of 27-t-Butyl Sulfone Analogs o Vitamin D2 H AcO H (+)-4 1) NaOH, EtOH 2) HO Cl _ HO k TMSOTf HS 3) m-CPBA"S Et3SiH 4) TMSCI, Et3N 77% -50% 5 l p OS S dH 0'° I) NaOH, EIOH $°<5> 2) PDC, celite oh ° quantitative 7 6 7 6 p27 s H 4c *", 0 ,/P (O) Ph2 W/ 1) n-BuLi |l H 2) 7 Formula XVI 3) THF HO OH (i). 18 HOOH KRC-20-epi-22-oxa-27-SO2tBu-1, (I cL, 30), 8a KRC-20-epi-22-oxa-27-SO2'Bu-2, (lß, 3a), 8b Scheme 12 Synthesis of 26-Methyl Sulfone Analogs OH VitaminD2 H TBSO (+)-8 A. 1) oxonce KH 2) TsCI, Et3N tao HOnSo b TsOX B.TsCLEtaN B. 9, X = S02, 31 % B. 10, X= S,] 00% 0 O OX ., H., H 1) THF, 0 2) TPAP, NMO, ! H MS (4A), CH3CN H 62% 13 A. 11, X = SO2, NDP B. 12, X= S, 90% O, O S,-,, 26 P (O) Ph2 1) n-BuLi Jj H 2) 13 3) TBAF Formula XVII ()-18 HO OH KRC-20-epi-22-oxa-26-SO2Me-l, (la, 3ß), 14a KRC-20-epi-22-oxa-26-SO2Me-2, (lß, 3a), 14b rxample 4/ 22E, 24E-diene sulfones can be synthesized by the method shown in Scheme 13.

Analogous compounds in which the r-butyl group is replaced by an alternat lower alkyl group or by an unsubstituted phenyl or a phenyl substituted with a lower alkyl or alkoxy can be made with modifications which will be evident to persons of skill in the art.

Scheme 13 Synthesisof 22E, 24E-Diene-26-tert-butyl Sulfone Analogs 23a and 23b 1. NaOH, EtOH 2.Br BsO SL ' (n-Bu0) 3. oxone) MeOH : HzO 4. Br2, CCIe 16 17 5. Et3N, THF 26% (E isomer) 95% CHO 0 0 , O 10 H 17 LO'B NMO, TESO H-78°C-rt H 2. TPAP, : TESO 4 A MS p H (+)-20 93% (+)-21 100% (+)-22 . \JC P (O) Ph2 toSC 1. PhLi 2. (+). 22 TBSg GOTBS 3. HF, EtOH gt 40% 3 OU KRC. 22E, 24E-diene-26-S0 2-1, (1 a, 3ß), (+)-23a (20 %) KRC-22E, 24E-diene-26-SO 2-2, (15,3a), (+)-23b (5%) FormulaXIX E-3-Bromo-1-propenyl t-butyl sulfone 16. To a solution of NaOH (2.40 g, 60.0 mmol) in ethanol (50 mL) at 50 °C was added dropwise via syringe 2-methyl-2- propanethiol (6.76 mL, 60 mmol) over 2 min. The resulting solution was stirred for 30 min while cooling to rt. Upon dropwise addition of allylbromide (5.19 mL, 60 mmol), the reaction mixture was heated to reflux and stirred overnight. The resulting suspension was filtered to remove NaBr, which was rinsed thoroughly with Et20. The filtrate was neutralized with 1 M HCI (50 mL), diluted with H2O (100 mL), extracted with Et2O (3 x 25 mL), washed with H20, dried over Na2SO4, filtered, and concentrated to a pale yellow oil by removing EtOH and Et2O via slow distillation.

This pale yellow oil (7.81 g theor.) was dissolved in 215 mL of MeOH and cooled to 0 °C. To this solution was added a 26% oxone solution (55.3 g, 90.0 mmol in 150 mL H2O) dropwise via addition funnel. The resulting suspension was allowed to stir with gradual warming to rt overnight. The reaction mixture was diluted with 150 mL H20, extracted with CHC13 (3 x 75 mL), washed with H2O and brine (150 mL each), dried over Na, SO,, filtered, and concentrated to give essentially pure allyl t-but sulfone as a clear oil.

A portion of this sulfone (1.00 g, 6.16 mmol) was dissolved in CCI4 (40 mL), treated with bromine (0.317 mL, 6.16 mmol) for 3 h, and concentrated to give the desired dibromide (1.46 g, 74%) as a pale orange solid (mp 75-80 °C) from cold Et2O/hexanes, clean enough for the following transformation.

The dibromide was dissolved in THF (50 mL), cooled to 0 °C, and treated with Et3N (0.945 mL, 6.78 mmol) overnight, while gradually warming to rt. The reaction mixture was neutralized with dilute HCI, diluted with H2O, extracted with Et2O (3 x 25 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (10-20% Et20/pentane) to give 16 (385 mg, 26% two steps) as white crystals: mp 60-62 °C;'H NMR (CDCI3) õ 7.00 (dt, J = 15,6.8 Hz, 1H), 6.55 (dt, J = 15,1.2 Hz, 1H), 4.07 <BR> <BR> (dd, J = 6.8,1.2 Hz, 2H), 1.38 (s, 9H);'3C NMR (CDC13) 8 143.82,127.63,58.94, 27.36,23.23; IR (neat) 1305,1275,1109,982; Anal. Calcd for C7H, 3BrO2S : C, 34.86; H, 5.43. Found: C, 34.98; H, 5.32.

Di-n-butylphosphonate 17. A stirred solution of tri-n-butyl phosphite (5 mL) and sulfone 16 (370 mg, 1.53 mmol) was heated to 130 °C for 12 h, cooled to rt, concentrated and purified on silica gel (75% EtOAc/hexanes) to give 519 mg (95%) of 16 as a clear oil: 'H NMR (CDCI3) 8 7.00 (dt, J = 15,8.0 Hz, 1H), 6.38 (ddt, J = 15,4.6,1.2 Hz, 1H), 4.03-3.92 (m, 4H), 2.76 (ddd, J = 25,8.0,1.2 Hz), 1.62-1.53 (m, 4H), 1.38-1.30 (m, 4H); 1.29 (6H), 0.85 (t, J = 7.2 Hz, 6H);'3C NMR (CDC13) 8 140.23 (d, J = 11 Hz), 128.24 (d, J =14 Hz), 66.18 (d, J = 6.8 Hz), 58.69,32.47 (d, J = 6.1 Hz), 29.97 (d, J = 140 Hz), 27.36,23.18,13.52; IR (neat) 2961,2935,2874,1633,1477,1464,1289, 1246,1114,1024,983; Anal. Calcd for C,, H3, 0, PS: C, 50.83; H, 8.82; S, 9.05.

Found: C, 50.64; H, 8.65; S, 8.91.

8ß-[(Triethylsilyl)[(Triethylsilyl) oxy]-22E, 24E-diene 26-tert-Butyl Sulfone (+)-21.

A solution of lithium tert-butoxide (1.0 M in THF, 0.491 mL, 0.491 mmol) was added via syringe to a cold (-78 °C) solution of phosphonate 17 (175 mg, 0.493 mmol) in THF (1.0 mL). The mixture was warmed slightly to effect solution, then retumed to-78 °C. The resulting yellow solution was delivered via cannula to a stirred solution of aldehyde (+)-20 (64.0 mg, 0.197 mmol) in THF (1.5 mL) at n. After 10 min. the solvent was removed and the residual brown oil was flash chromatographed (8% EtOAc/hexanes) to give 86 mg of (+)-21 (93%) as a moist solid: [a] 25 +77.9 (c 4.0, CHCl3); 1H NMR (CDCl3) # 7.11 (m, IH), 6.14 (t, J = 15 Hz, 1H), 6.09 (m, 2H), 4.02 (m, 1H), 2.27-2.17 (m, 1H), 1.96-1.89 (m, 1H), 1.89-1.74 (qt, J = 13,3.8 Hz, 1H), 1.35 (s, 9H), 1.04 (d, J = 6.8 Hz, 3H), 0.93 (t, J = 8.0 Hz, 9H), 0.93 (s, 3H), 0.54 (q, J = 8.0 Hz, 6H);'3C NMR (CDCI3) õ 153.66,147.16,123.71,120.43,69.20,58.55,55.83,52.87,42.38,40 .61, 40.10,34.52,27.39,23.32,22.94,19.35,17.62,13.75,6.90,4.88; IR (neat) 2950, 2935,2873,1638,1458,1300,1114,1018,1004; HRMS: calcd for C26H4803SSi: 468.3093, found 468.3094.

C, D-Ring Ketone (+)-22. An aqueous solution of HF (0.500 mL, 10% wt) was added dropwise to a stirred solution of (+)-21 in HO: THF (1.00 mL H2O: few drops of THF to effect solution) and the resulting solution stirred at rt for 2 d (two additional 0.500 mL portions of 10% HF were added over this period to consume starting material). The reaction mixture was then carefully neutralized (sat. NaHCO3), diluted with H2O, and extracted with CH2C12 (3 x 10 mL). The combined organics were dried (Na2SO4), filtered and concentrated to give the desired hydroxy sulfide as a white solid.

To crude hydroxy sulfide in CH2C12 (3 mL) was added 4-methymorpholine N- oxide (NMO, 58.0 mg, 0.492 mmol) and powdered molecular sieves (4A), followed by tetrapropylammonium perruthenate (TPAP, 4.30 mg, 0.0123 mmol). After stirring for 15 min, the reaction mixture was filtered, concentrated and passed through a short pad of flash silica gel (20 % EtOAc/hexanes) to afford the desired keto sulfone (+)-22 as a white foam (79 mg, quantitative from (+)-21):'H NMR (CDC13) 8 7.08 (dd, J = 15,10 Hz 1H), 6.15 (t, J = 15 Hz, 1H), 6.08 (m, 2H), 2.43 (m, 1H), 2.29-2.15 (m, 3H), 1.32 (s, 9H), 1.08 (d, J = 6.4 Hz, 3H), 0.63 (s, 3H);'3C NMR (CDC13) 8 211.39,152.05,146.59, 124.38,121.21,61.62,58.57,55.62,49.85,40.86,40.12,38.71,27.4 6,23.94,23.30, 19.61,19.06,12.72; IR (neat) 2955,2934,2872,1708,1638,1587,1461,1296,1278, 1111,1001,824; HRMS: calcd for C20H3203S : 352.2072, found 352.2066.

22E, 24E-Diene-26-tert-butyl Sulfone Analogs 23a and 23b. Racemic phosphine oxide ()-8 (78.0 mg, 0.134 mmol) was dissolved in 1. 34 mL of THF and cooled to-78 °C under argon. To this solution was added 97.0 iL of PhLi (0.134 mmol, 1.38 M in cyclohexane/Et2O) dropwise via syringe. The deep orange solution was stirred for 30 min, at which time a cold solution of C, D-ring ketone (+)-22 (31.0 mg, 0.0880 mmol) in 1.00 mL of THF was added dropwise via cannula. The resulting solution was stirred in the dark at-78 °C for approximately 4 h, then slowly warmed to 40 °C over 2h.

The reaction mixture was quenched with 3 mL of a 2: 1 (v: v) mixture of 2 N sodium potassium tartrate and 2 N potassium carbonate. Upon warming to rt, the reaction mixture was diluted with HO, extracted with EtOAc (4 x 20 mL), dried over MgSO4, filtered, concentrated and purified by silica gel column chromatography (10-50% EtOAc/hexanes- <0.1% Et, N) to afford 33 mg (90% based on (+)-22) of the coupled product as a yellow oil.

This oil was immediately dissolved in 1.50 mL of EtOH, cooled to 0 °C, and treated with HF (0.100 mL, 49% aqueous). This solution was slowly warmed to rt and treated with additional HF (0.100 mL) to complete the deprotection. After aqueous work-up the resulting white film was flash chrmatographed (1% NEt/EtOAc) to afford 17.3 mg (77% for deprotection) of a mixture of diastereomers 23a and 23b. This diastereomeric mixture was purified by reversed-phase HPLC (C-18 semipreparative column, 46% MeCN/H2O, 3 mL/min) giving 8.8 mg of 23a (20%, tR 115 min) and 2.1 mg of 23b (5%, tR 111 min).

23a (la, 3B): [a] D +97 (c 7.5, CHC13);'H NMR (CDC13) 8 7.12 (m, 1H), 6.37 (d, J = 11 Hz, 1H), 6.16 (t, J = 15 Hz, 1H), 6.11 (m, 2H), 6.01 (d, J = 11 Hz, 1H), 5.32 (m, 1H), 4.99 (m, 1H), 4.46-4.40 (m, 1H), 4. 26-4. 19 (m, 1H), 2.83 (dd, J = 12,3.7 Hz, 1H), 2.59 (dd, J = 14,3.2 Hz, 1H), 1.36 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H), 0.57 (s, 58,146.98,142.43,133.24,124.78,124.00, 120.74,117.30,111.83,70.80,66.81,58.60,56.09,55.63,46.06,45. 23,42.83, 40.69,40.26,28.97,27.45,23.45,23.35,22.24,19.69,12.29; IR (neat) 3598-3148 (br), 1588,1457,1295,1108; HRMS: calcd for C29H4404S 488.2960, found 488.2950.23b (ils, 3a): D +32 (c 1.0, CHCl3) ;'H NMR (CDCl3) 8 7.12 (m, 1H), 6.38 (d, J = 11 Hz, 1H), 6.16 (t, J = 15 Hz, 1H), 6.11 (m, 2H), 6.01 (d, J= 11 Hz, 1H), 5.32 (m, 1H), 4.99 (m, 1H), (m, 1H), (m, 1H), 2.84 (dd, J = 12,3.8 Hz, 1H), 2.61 (dd, J = 14,3.2 Hz, IH), 1. 36 (s, 9H), 1.09 (d, J = 6.8 Hz, 3H), 0.57 (s, 3H);'3C NMR (CDC13) 5 153.13,147.27,147.01,142.52, 75,58.61,56.10,55.64, 46.07,45.45,42.83,40.70,40.25,29.00,27.44,23.45,23.38,22.28, 19.71,12.32; IR (neat) 3568-3087 (br), 3016,2954,2928,2872,1637,1588,1457,1295,1109; HRMS: calcd for C29H44O4S 488.2960, found 488.2944. UV pending.

Example 48 Assay of pharmacological activities The compounds of the invention have been compared with calcitriol for biological activity.

The compounds were tested for growth inhibition of murine keratinocyte cells (cell line PE) and for the inhibition of TPA-induced ornithine decarboxylase (ODC) activity as described in U. S. Patent No. 5,830,885.

The cell line PE was derived from a papilloma induced in female SENCAR mice by a standard skin initiation/promotion protocol (Carcinosenesis, 7: 949-958 (1986), the entire contents of which are hereby incorporated by reference) and was chosen for its particular sensitivity to the induction of ornithine decarboxylase (ODC) activity by the extensively characterized tumor promoter TPA. The PE cell line culture medium used in the tests consisted of Eagle's minimal essential medium without calcium chloride supplemented with 8% chelexed fetal calf serum and 1 % antibiotic- antimycotic and the addition of CaCl2 to 0.05 mM Cl++.

The results are shown in Figure 1, and indicate that the compounds of the invention inhibit cell proliferation, compounds 23a and 15a being nearly as effective as calcitriol.

The compounds were also tested for their effect on calcium excretion and weight gain in rats according to the methods described in Posner et al., J. Med. Chem.

41: 3008-3014 (1998). The results are shown in Figures 2 and 3, and demonstrate that the compounds of the invention do not inhibit weight gain nor stimulate calcium secretion in contrast to calcitriol.

Thus, compounds according to the invention exhibit the antiproliferative effects of vitamin D3 without the associated effects on calcium excretion and weight gain exerted by vitamin D3. Accordingly, they should prove valuable as therapeutic agents in diseases where excessive cell proliferation and/or failure of cells to differentiate may occur, including but not limited to psoriasis and cancer. External or internal administration of the compounds of the invention can be made in accord with the condition to be treated using methods known to those of ordinary skill in the medical and veterinary arts, with appropriate dosages determined by routine experimentation.