Field of the Invention

This invention generally relates to use of enynes in palladium catalyzed al ylative cyclizations, and more particularly where a 1,6-enyne or 1,7-enyne is reacted with a aryl halide, a vinyl halide, or an alkyl halide lacking a β-hydrogen in the presence of a palladium catalyst to generate 1,2-bis-alkylidenecyclo- alkanes, such as Vitamin D analogues.

Background of the Invention

As is well known. Vitamin D ₂ (also known as "calciferol") and Vitamin D ₃ (also known as "cholecal- ciferol") are effective in humans as antirachitic nutritional factors. Vitamin D ₂ is obtainable from ergosterol by uv irradiation in a suitable solvent, and Vitamin D ₃ can be obtained by irradiation of its provitamin, 7-dehydrocholesterol. In about the early 1970s, interest developed in lα,25-dihydroxychole- calciferol, which is the polar, biologically active, metabolite of Vitamin D ₃ , due to an extremely rapidly onset of physiological activity. A few years later, another new Vitamin D ₃ analogue, again with rapid onset of physiological activity, was described by Barton et al (lα-hydroxy-Vitamin D ₃ ) . Several of these Vitamin D analogues are illustrated by reference to the Formula 1 structure. In the case of lα,25-dihydroxycholecalciferol, X is hydroxyl as are both R ₂ and R ₃ . For lα-hydroxy-Vitamin D ₃ , X is hydrogen while both R ₂ and R ₃ are hydroxyl.

FORMULA 1

The Formula 1 structure can be further generalized (and often is, particularly in description of syntheses) by more generally representing the side chain R ¹ of the Formula 1 representation is a part.

Vitamin D analogue syntheses have received considerable attention, particularly recently, due to evidence that various Vitamin D ₃ related compounds are hormonally active and may be clinically useful regu¬ lators of various fundamental physiological processes. Thus, for example, 1,25-dihydroxy-Vitamin D ₃ has been shown to modulate the immune function of monocytes and macrophages, Huebel et al., "In-vivo Effect of 1,25- dihydroxy Vitamin D ₃ on Phagocyte Function in Hemodialysis Patients," Kidney International , 40 (5), pp. 927-933 (1991) . Calcipotriol (also known as "MC- 903") is an analogue of the physiologically active metabolite of Vitamin D ₃ , lα,25-dihydoxycholecalciferol, which is indicated as efficacious in reducing in hyperproliferation for psoriasis patients by Arnold et al., "Induction of Epidermal Ornithine Decarboxylase Following Tape Stripping is Inhibited by a Topical Vitamin D ₃ Analogue MC-903," British Journal of Dermatology, 125 (1), pp. 6-8 (1991). Binderup et al..

"20-Epi-Vitamin D ₃ Analogues, A Novel Class of Potent Regulators of Cell Growth and Immune Responses," Biochemical Pharmacology, 42 (8) , pp. 1569-1576 (1991) , found the 20-Epi-Vitamin D ₃ analogues (structurally related to lα,25-dihydroxycholecalciferol) to be very potent inhibitors of T-lymphocyte proliferation induced by interleukin-1 or alloantigen. These 20-epi-Vitamin D ₃ analogues are characterized by an altered stereo¬ chemistry at carbon 20 of the side chain. Thus, various Vitamin D analogues are of potential interest in therapeutic applications, such as the prevention of graft rejections and in the treatment of cancer and auto-immune diseases, as well as in the treatment of psoriasis. These increasingly interesting potential clinical applications of Vitamin D analogues have enhanced interest in simplifying their syntheses. Two strategies for lα-hydroxy-Vitamin D analogues are currently employed. One is based on a biomimetic path from a normal steroid precursor, such as, for example, reported by Barton et al. in their 1973 description of the synthesis of lα-hydroxy-Vitamin D ₃ , J. Am. Chem. Soc. , 95 (8), pp. 2748-2749 (1973). The other current strategy is based on a convergent approach of attaching a preformed ring A system to a CD fragment (Grundmann ketone or an analogue thereof) , such as is illustrated by Posner et al., J. Org. Chem. , 55 , pp. 3967-3969 (1990) .

Accordingly, a simple convergent strategy that can readily be adopted for the synthesis of many Vitamin D analogues, particularly those with differing side chains, would be useful to prepare compounds that are presently clinically useful, as well as analogues for potential clinical uses in this rapidly developing field.

Summary of the Invention

In one aspect of the present invention, an alkylative cycloaddition method is provided permitting the formation of substituted bis(alkylidene)cycloalkanes as reaction products in which a 1,6 enyne or a 1,7-enyne is reacted with a selected compound RX. The alkylative cycloaddition is performed in the presence of a palladium catalyst and is characterized by remarkable diastereoselectivity. One application of this alkyla- tive cycloaddition method is wherein the selected compound RX is an E-bromomethylene derivative of Grundmann's ketone. Thus, a highly geometrically pure bromoolefin having the structure

(where R, is to be a Vitamin D analogue side chain) is useful as a Vitamin D analogue by reaction with a 1,7 enyne (and with the generation of a new carbon-carbon bond to cyclize the enyne) . A particularly preferred embodiment for application of the alkylative cycloaddition method is in the convergent synthesis of Vitamin D analogues with a side chain R,, such as by forming reaction products having the structure

where R, is the Vitamin D analogue side chain, R ₂ is hydrogen, fluorine, hydroxyl, lower alkoxy, or a removable protecting group, and R ₃ is hydrogen, fluorine, hydroxyl, lower alkoxy, or a removable protecting group.

Detailed Description of the Preferred Embodiments

Substituted 1,2-bis(alkylidene)cycloalkanes are valuable building blocks in chemical syntheses as well as interesting substances in their own right. Broadly, an alkylative cycloaddition of this invention provides entry to substituted bis-alkylidenecycloalkanes possessing Z stereospecificity as is illustrated by Reaction (1) .

REACTION .1.

c ciiteA rtαc on | σ< r ? ^{rt A} r- ^CI (S or & ^bw r ^' ,™, )

Briefly, a 1,6 or 1,7 enyne (designated here as "pre A") is reacted with a compound RX (sometimes hereinafter referred to as "pre CD" for the application to Vitamin D analogues) in the presence of a palladium catalyst to form a substituted bis(alkylidene)cyclo- alkane as reaction product in an alkylative cyclo¬ addition. (Where R of RX is vinyl, then a cyclohexa- diene can be obtained after thermal cyclization.) RX is a halide (preferably bromide or iodide) where R is a vinyl, an aryl, or an alkyl lacking a β-hydrogen. This new method for ring construction permits an extremely wide selection of available choices for the R moiety and permits introduction of both electron donating and withdrawing substituents on the terminal olefinic carbon of the enyne in order to prepare bis-alkylidenecyclo¬ alkanes with five and six membered rings.

There are various alternatives to the reaction conditions in performing the Reaction (1) synthesis. In one method, we have reacted pre A and pre CD in the presence of two mole percent Pd(OAc) ₂ , four mole percent Ph ₃ P(TPP) and one eq. of silver carbonate (as base) . Heating eventually to 75°C leads to the desired alkylated cycloadduct. In another alternative, we have changed the catalyst to two mole percent (dba) ₃ Pd ₂ -CHCl ₃ and four mole percent tri-o-tolylphosphine (TOT) . We have also replaced silver carbonate with triethylamine. In a third variation, we have used five mole percent Pd(0Ac) ₂ , fifteen mole percent (TPP) and varying amounts of triethylamine (such as from 1 eq. to a 1:1 mixture with the solvent) in refluxing toluene. Accordingly, various reaction conditions can be used to accomplish the reaction (1) alkylative cycloaddition, although the palladium catalyst should be a palladium zero complex in its active state, and with at least some of the ligands being trivalent phosphorous compounds such as phosphines or phosphites.

Table 1 summarizes some of the different enynes and some of the different RX compounds in which we have demonstrated successful alkylative cyclizations. (The designation "TBDMS" stands for the removable protecting group tert-butyldimethylsilyl; of course, a variety of removable protecting groups are known and useful) .

σ~

Our particularly preferred mode of carrying out this invention is as a new convergent strategy in which ring A of Vitamin D analogues is created from the pre A, acyclic unit as a result of attaching this unit to a Grundmann's ketone derivative (as pre CD) while utilizing a Pd catalyzed alkylative enyne cyclization, as illustrated in Reaction (2) .

REACTION 12 ,

(wherein R-, is a Vitamin D analogue side chain, R ₂ is hydroxyl, lower alkoxy, fluorine, or a removable protecting group, and R ₃ is hydrogen, hydroxyl, lower alkoxy, fluorine, or a removable protecting group) .

The enyne used can be substituted or unsubstituted. For example, the saturated carbons of the enyne can be substituted with heteroatom substituents such as halogen, oxygen (ethers, silyl ethers, etc.), and nitrogen (such as dialkylamino) . Thus, use of the term "1,6 or 1,7 enyne" is broadly meant to include substituted enynes. Further, considerable variety in the R ₁ moiety is possible (which means that analogues of Grundmann's ketone varying in the side chain can correspondingly tolerate quite a broad range of side chains) . A number of literature articles have illustrated such side chain variations, which are intended to be included within the scope of

the subject invention. For example, the following articles have described some of the various such side chains, the disclosures of which are incorporated herein by reference: Chodynski and Kutner, Steroids , 56 , 311 (1991); Gill et al.. Steroids , 48 , 93 (1986); Gill et al., J. Med. Chem. , 33 , 480 (1990); Onisks et al., J ^" . Biol . Chem. , 254 , 3493 (1979) ; Sai et al., Chem. Pharm. Bull . , 33 , 878 (1985); Tamaka et al., Arch. Biochem. Biophys. , 218 , 314 (1982); Corradins et al., Arch Bioche-ri. Biophys . , 208 , 273 (1981); Esvelt and De Luca, Arch Biochem. Biophys . , 206 , 403 (1981); Holick et al., J. Biol . Chem. , 250 , 226 (1975); and Ostrem and De Luca, Steroids , 49 , 73 (1987) .

The simple convergent strategy illustrated by Reaction (2) can readily be adopted for the synthesis of many of the hydroxylated Vitamin D analogues which differ in the side chain through Grundmann's ketone analogues. The ability to use a simple acyclic unit such as pre A as the precursor for the A ring also facilitates variations of substituents on the A ring.

The following examples are intended to illustrate, but not limit, the scope of this invention. Example 1 outlines asymmetric synthesis of a suitable pre A for preparing a Vitamin D analogue.

EXAMPLE 1

At -78°C, ozone in oxygen is bubbled into a solution of l,l-diethoxy-but-3-ene (2.88 g, 20 mmol.) in dichloromethane (40 mL) until a blue color persists. The flask is then purged with oxygen for 30 minutes. To this cold solution is added triphenylphosphine (5.25 g, slight excess) in one portion, and the cold bath is removed. After 2 hours stirring at room temperature, the solution is dried (Mg30 ₄ ) and concentrated. The triphenylphosphine oxide present in the oily residue is

crystallized by successive addition of pentane (20 mL) and ethyl ether (50 mL) , and removed by filtration. The resulting pentane/ethyl ether solution of 3,3-diethoxy- propanal is redried (MgS0 ₄ ) , and dropwise added to a propargyl Grignard solution (prepared from 40 m ol. propargyl bromide and 50 mmol. magnesium in 50 mL ethyl ether) at 0°C. The reaction is instantaneous. After 15 minutes stirring at room temperature, water (5 mL) is slowly added. After decantation and extraction of the wet salts with ethyl ether (2 x 20 mL) , the combined organic phases are dried (MgS0 ₄ ) , concentrated, and distilled (Kugelrohr) to afford 2.71 g of 1,1-diethoxy- hex-5-yne-3-ol as an oil (73% from 1,l-diethoxy-but-3- ene, bp=140-145°C/0.1 mmHg) . IR (neat): 3450, 3298, 2977, 2931, 1376, 1346

¹ H NMR (200 MHz): 1.21 (t, 6H, J=7Hz) , 1.82 and 1.95 (complex AB, 2H) , 2.06 (t, 1H, J=2.5Hz), 2.33 and 2.43 (complex B, 2H) , 3.45-3.80 (m, 4H) , 3.95 (m, 1H) , 4.72 (t, 1H, J=6.5Hz).

¹³ C NMR: 14.8, 14.9, 26.7, 38.9, 61.2, 62.0, 66.6, 70.3, 80.6, 101.6.

To the above material (1.86 g, 10 mmol) in dry DMF (10 mL) are successively added imidazole (2.1 g, 3 eq.) and tert-butylchlorodiphenyl silane (4.12 g, 1.5 eq.). The resulting pale brown solution is heated at 65°C for 18 hours then cooled down, and poured into a suspension of water (30 mL) and pentane (100 mL) . The organic phase is separated, and the aqueous phase extracted with pentane (2 x 20 mL) . The combined organic phases are washed with water (10 mL) , dried (MgS0 ₄ ) , and concentrated. Chromatography of the oily residue (ethyl ether/hexanes, 1/5) affords the tert- butyldiphenylsilyl ether (3.52 g, 83%) as a colorless oil.

IR (neat): 3311, 2973, 2932, 2859, 1473, 1428, 1377 cm ^*1 .

¹ H NMR (200 MHz): 1.06 (s, 9H) , 1.08 (t, 3H,

J=7HZ) , 1.12 (t, 3H, J=7HZ) , 1.86-2.08 (m, 3H) , 2.23 and 2.34 (complex AB, 2H) , 3.17-3.62 (m, 4H) , 4.00 (m, 1H) ,

4.68 (bt, 1H, J=6.5Hz), 7.30-7.50 and 7.65-7.75 (2m,

10H) .

¹³ C NMR: 15.0, 15.1, 19.1, 26.8, 27.0, 60.3, 61.0, 68.3, 70.4, 80.9, 100.1, 127.7, 127.8, 129.8, 133.8, 134.2, 136.1.

Anal. Calc'd for c ₂₆ H ₃₆ 0 ₃ Si: C,73.54%; H,8.54%. Found: C,73.75%; H,8.74%.

To a stirred suspension of the just described ketal (0.51 g, 1.2 mmol) in THF (5 mL) and water (1 L) is added trifluoroacetic acid (2 mL) . The reaction mixture becomes homogeneous. After 1.5 hours stirring at room temperature, the reaction mixture is poured into a suspension of potassium carbonate (5 g) , water (20 mL) , and ethyl ether (50 mL) . After decantation, the aqueous phase is extracted with ethyl ether (2 x 30 mL) , and the combined organic phases are washed with 10% aqueous NaCl, dried (MgS0 ₄ ) , and concentrated to afford 0.41 g of material (98/2 mixture of 3-tert-butyldiphenyl silyloxy-hex-5-yne-l-al and the ketal by GC analysis) , which is immediately dissolved in dry THF (7 mL) , and cooled to -78°C. To this solution is dropwise added vinyl magnesium bromide (IM solution in THF, 3 mL) and the resulting suspension stirred for 30 minutes at -78°C. Water (1 mL) is then slowly added, then the temperature raised to room temperature. The organic phase is separated by decantation, and the moist inorganic salts are extracted with ethyl ether (2 x 20 mL) . The combined organic phases are dried (MgS0 ₄ ) and concentrated. Chromatography of the oily residue (ethyl ether/pentane 1/3) affords the product of Formula 2 structure:

FORMULA 2

The Formula 2 product was obtained as 0.355 g of diastereoisomeric mixtures designated "2a" and "2b" (ca. 1.5:1). Total yield 78%. 1.79 g of this mixture is separated by MPLC (hexanes/ethyl ether, 4/1) to afford successively:

590 mg of minor anti isomer (2b)

100 mg of diastereomeric mixture 980 g of major syn isomer (2a) .

The stereoisomeric purity of each isolated isomer is greater than 95% (no peak detected by H NMR) . IR (neat, mixture): 3410 (broad), 3298, 2912, 2851, 2117, 1585, 1465, 1420 cm ^"1 . Data for where 3R*,5R* (that is, mixture 2a)

Colorless oil.

¹ H NMR (300 MHz): 1.05 (s, 9H) , 1.78-1.95 (m,

3H) , 2.28 (complex AB, 2H) , 4.03 (bq, IH, J=7Hz) , 4.31

(m, IH) , 5.02 (bd, IH, J=llHz) , 5.13 (bd, IH, J=17Hz) , 5.76 (ddd, IH, 3=6 , 11, and 17Hz) , 7.32-7.47 and 7.65-

7.75 (2m, 10H) .

¹³ C NMR: 19.0, 26.7, 26.9, 42.7, 70.4, 70.7 (double peak) , 80.7, 114.5, 127.8, 127.9, 130.0, 130.1, 133.3, 133.9, 136.0, 140.8. Anal. Calc'd for C ₂₄ H _3fJ 0 ₂ Si: C,76.14%; H,7.99%.

Found: C,76.13%; H,8.07%.

Data for where 3S*,5R* (that is, mixture 2b) Colorless oil.

¹ H NMR (300 MHz): 1.05 (s, 9H) , 1.71 (complex AB, 2H) , 190 (t, IH, J=2Hz) , 2.33 (complex AB, 2H) , 4.11

(m, IH) , 4.36 (m, IH) , 5.03 (bd, IH, J=llHz) , 5.18 (bd.

IH, J=17HZ) , 5.79 (ddd, IH, J=6, 11, and 17Hz) , 7.32- 7.48 and 7.65-7.75 (2m, 10H) .

¹³ C NMR: 19.0, 26.3, 26.8, 42.0, 69.2, 69.6 70.6, 80.5, 114.2, 127.9, 128.0, 130.1, 130.2, 133.3, 133.7, 136.1, 141.1.

Anal. Calc'd for C ₂₄ H ₃₀ O ₂ Si: C,76.14%; H,7.99%. Found: C,76.36%; H,7.77%.

The relative stereochemistry of the two isomers was established by NMR analysis, as illustrated by Example 2, with kinetic resolution of the racemic allylic alcohol (3S*,5R*) giving virtually quantitative recovery of the desired scalemic alcohol (3S,5R) of 98% ee, with the resolution being illustrated by Example 3.

EXAMPLE 2

To a stirred solution of alcohol (3R*, 5R*) (190 mg, 0.5 mmol) in THF (2 mL) was added tetrabutyl- ammoniumfluoride (IM solution in THF, 0.6 mL, 1.2 eq.) at 0°C. After 1.5 hours stirring at this temperature, the reaction mixture is diluted with hexanes (2 mL) , and filtered over silica gel (hexanes/ethylacetate, 1/1) to afford 63 mg of pale yellow oil (90%, IR 3300 and 3360 cm ^" ) which is dissolved in 2,2-dimethoxypropane (2 mL) . To the resulting solution is added camphorsulfonic acid (10 mg, ca. 0.01 eq.) and the mixture is stirred overnight at room temperature, then poured into ethyl ether (20 mL) , and washed with 5% aqueous NaHC0 ₃ . The organic phase is dried (MgS0 ₄ ) , and carefully concentrated to afford 48 mg of acetonide as a colorless volatile oil.

IR (neat): 3312, 2933, 2924, 2855, 1464, 1380

-1 cm .

¹ H NMR (200 MHz): 1.2-1.4 (m, IH) , 1.40 (s, 3H) , 1.45 (s, 3H) , 1.71 (dt, IH, J=2.5 and 13Hz) , 1.99

(t, IH, J=2.5Hz), 2.24 (ddd, IH, J=2.5, 7.5, and 17Hz) ,

15

2.46 (ddd, IH, J=2.5, 5.5, and 17Hz) , 4.00 (dddd, IH, J=2.5,5.5, 7.5, and 11.5Hz), 4.35 (dddt, IH, J=1.5, 2.5, 6, and 11.5Hz), 5.12 (dt, IH, J=1.5 and 11Hz) , 5.26 (dt, IH, J=1.5 and 17Hz) , 5.81 (ddd, IH, J=6, 11, and 17Hz) . ¹³ C NMR: 19.6 (CH3) , 26.0, 29.9 (CH3) , 35.7,

67.4, 70.1, 70.4, 80.1, 99.0, 112.4, 115.8, 138.6.

MS and peak match: m/z=165.0924 (100%, M+- CH ₃ , calculated 165.0915), 105, 83, 79, 66.

EXAMPLE 3

To a stirred suspension of freshly activated molecular sieves (400 mg) , racemic allyl alcohol (3S*, 5R*) (1.4 g, 3.7 mmol, azeotropically dried prior to use), and D(+)-dicyclohexyltartrate (unnatural, 1.39 g, 1.2 eq. , recrystallized four times) in dichloromethane (30 mL, distilled from calcium hydride prior to use) is added at 20°C dropwise freshly distilled titanium isopropoxide (1.1 mL, 1 eq.). The reaction mixture is swirled for 30 minutes at this temperature then tert- butylhydroperoxide (3M in isoctane, 0.82 mL, 0.66 eq. , dried over sieves prior to use) is added by syringe at -40°c.

The reaction mixture is placed in the freezer (-20°C without stirring) for 19 days, then poured in an ice cooled suspension of ferrous sulfate heptahydrate (17.5 g) , tartaric acid (9 g) , water 120 mL) , and dichloromethane (100 L) . The organic layer is separated, and the aqueous phase extracted with dichloromethane (3 x 100 mL) . The organic phases are combined, washed with brine, dried, and concentrated.

Chromatography of the residue (pentane/ethyl ether, 2:1, Rf=0.6) affords 642 mg (46%) of optically enriched product (3S, 5R) . [o] -19.7 (c 1.25, CH ₂ C1 ₂ ) .

¹ H NMR analysis of the S(+)-O-methylmandelic ester:

Methoxy group (s, 3H) ; major isomer 3.35 ppm minor isomer 3.32 ppm The integration shows a 100:1 ratio (98% ee) .

The scalemic protected enyne illustrated by

Formula 3 below and sometimes referred to as "Enyne 5" was prepared as illustrated by Example 4.

EXAMPLE 4

To a stirred solution of the alcohol from Example 1 (3R*, 5R*) (3a, 378 mg, 1 mmol.) and imidazole (210 g, 3 eq.) in dry DMF (3 L) is added tert-butyl chlorodimethylsilane (225 mg, 1.5 eq.). The resulting pale brown solution is heated at 55°C for 3 hours then cooled, and poured into a suspension of water (30 mL) and ethyl ether (50 mL) . The organic layer is separated and the aqueous phase extracted with ethyl ether (2 x 20 mL) . The combined organic phases are washed (20 mL of water) , dried (MgS0 ₄ ) , and concentrated. The oily residue is chromatographed (hexanes/ethylacetate 20/1) to afford 430 mg of syn 4-0-terbutyldiphenylsilyl-6-0- tert-butyldimethylsilyl-oct-l-yne-7-ene-4,6-diol. Yield 87-88%.

The same conditions applied on optically enriched allyl alcohol of Example 3 (98% ee, 100 mg, 0.264 mmol.) afforded the scalemic protected enyne anti isomer of syn 4-0-terbutyldiphenylsilyl-6-0-tert- butyldimethylsilyl-oct-l-yne-7-ene-4,6-diol (117 mg, 90%, [α] -5.3 (c 1.74, CH ₂ Cl ₂ ) IV-3, Formula 3:

FORMULA 3

Colorless viscous oil.

¹ H NMR (300 MHz): -0.06 (s, 3H) , -0.03 (s, 3H) , 0.81 (S, 9H) , 1.07 (s, 9H) , 1.58-2.06 (m, 3H) , 2.31

(complex AB, 2H) , 3.94 (bq, IH, J=5.5Hz), 4.09 (bq, IH,

J=6.5HZ), 4.90-5.06 (m, 2H) , 5.63 (ddd, IH, J=6.5, 11, and 17Hz) , 7.32-7.48 and 7.65-7.75 (2m, 10H) .

¹³ C NMR: -5.1, -4.4, 17.9, 19.1, 25.7, 26.8, 27.2, 45.0, 69.1, 70.2, 71.7, 81.2, 114.3, 127.8, 127.7, 129.8, 134.2, 134.4, 136.1, 141.8.

Anal. Calc'd for C^H^O^i^ C,73.11%; H,9.00%. Found: C,72.91%; H,8.86%.

IR Tneat) : 3313, 3073, 2957, 2931, 2858,

-1

2132, 1590 ,, 11447733,, 11442288 ccmm ^"1 .

MS (GC-MS) : mz = 381, 313, 307, 209, 199,

171.

Grundmann's ketone has the structure illustrated by Formula 4:

FORMULA 4

Example 5 illustrates an geometrically controlled bromoolefination of Grundmann's ketone.

EXAMPLE 5

To a suspension of bromomethyltriphenyl- phosphonium salt (545 mg, 5 eq.) in THF (3 mL) is added sodium hexamethyldisilazide (IM in THF, 1.2 L, 4.8 eq.) at -60°C. The suspension becomes bright yellow after 1 hour. The Grundmann's ketone (Formula 4, X=H) is added in 0.5 mL of THF, and the cold bath is removed after a few minutes. After 1 hour stirring at room temperature, hexanes (10 mL) are added and the suspension is filtered over a small pad of silica, washing with hexanes. After concentration the oily residue is chromatographed (pentane) to afford the bromide (Formula 5, X=H) as a colorless viscous oil (53 mg, 62%) :

FORMULA 5

E/Z ratio: 30:1

[α] _p ⁵ for this mixture: +103, c 1.63, CH ₂ C1 ₂ IR (neat) : 2952, 2869, 1632, 1467 cm ^"1 .

¹ H NMR (200 MHz): 0.52 (s, 3H) ; 0.83 (d, 6H, J=7Hz) ; 0.90 (d, 3H, J=6Hz) ; 0.95-2.22 (m, 19H) ; 2.85 (m, IH) ; 5.62 (bs, IH) .

¹³ C NMR: 11.6, 18.6, 21.8, 22.4, 22.6, 23.6, 27.4, 27.8, 30.9, 35.9 (double peak) , 39.3, 39.7, 45.4, 55.8 (double peak) , 97.4, 145.5.

MS with peak match: m/z=342.1750 and 340.1746 (M+, each 1%, calculated 342.1745 and 340. 1765), 229, 227, 207, 147, 105.

Anal. Calc'd for C ₁₉ H ₃₃ Br: C,66.85; H,9.74. Found: C,67.00; H,9.49.

The bromoalkene product obtained from Example 5 is a particularly preferred pre CD in practice of this invention with a particular R., side chain. However, as earlier discussed, substrates bearing different R., side chains can readily be utilized in practicing this invention. Notice in Example 5 the surprisingly high E selectivity in the E/Z ratio of 30:1. Even a 10:1 ratio would typically be considered as "substantially geometrically pure" bromoolefin.

Example 6 illustrates the convergent reaction of the enyne from Example 4 with the bromoolefin of Example 5.

EXAMPLE 6A

Pd ₂ (dba) ₃ CHCl ₃ (25 mg, 10%) and triphenyl- phosphine (40 mg, 30%) are mixed under nitrogen in freshly distilled toluene (2.5 mL) and triethylamine

(2.5 mL) . After 15 minutes, a solution of the Example

4 enyne (156 mg, 0.316 mmol) and the bromide of Example

5 (162 mg, 1.5 eq.) in 0.5 mL fresh toluene is added by gas tight syringe. The resulting yellow solution is vigorously refluxed (120°C) for 1.5 hours, then cooled and filtered over a small pad of silica gel, washing with pentane. After concentration, the oily residue is chromatographed (pentane/dichloromethane, 10:1) to afford successively:

49 mg of recovered starting bromide

33 g of "previtamin", among some other impurities. 160 mg of the vitamin having the removable silyl protecting groups. The "previtamin" fraction is heated under N ₂ in toluene, at 80°C for 1 hour, then cooled, and combined with some impure fractions of vitamin. After concentration and flash chromatography (same conditions as above), some 17.5 mg of additional silyated vitamin have been isolated, combined with the first crop, and kept under vacuo for 3 hours to remove any trace of solvent. Total mass of silyated vitamin product 181 mg (76%)

Data for vitamin product Colorless viscous oil.

IR (neat): 2952, 2930, 1471, 1428, 1361, 1252

-ι cm .

¹ H NMR (300 MHz): 0.01 and 0.03 (2s, 6H) ;

0.51 (s, 3H) ; 0.80-2.03 (m, 49H) ; 2.18 (dd, IH, J=6.5 and 13Hz); 2.30 (bd, IH, J=13Hz) ; 2.79 (bd, IH, J=13Hz) ; 4.23 (m, IH) ; 4.47 (m, IH) ; 4.88 (bs, IH) ; 5.22 (bs, IH) ; 6.09 (AB, 2H, J=12Hz) ; 7.30-7.45 and 7.63-7.72 (2m, 10H) .

¹³ C NMR: -5.4, 5.1, 11.7, 18.1, 18.6, 19.0, 22.0, 22.4, 22.6, 23.4, 23.7, 25.7, 26.8, 27.5, 27.8, 28.8, 36.0, 29.3, 40.5, 44.4, 45.0, 45.7, 56.3, 56.6, 68.7, 71.2, 110.5, 117.9, 123.7, 127.7, 127.8, 129.7 (double peak) , 134.4, 134.8, 135.1, 136.0, 136.1, 141.3, 149.0.

EXAMPLE 6B

(Desilylation of Example 6A product) To a stirred solution of the silyated vitamin product (181 mg, 0.24 mmol) in THF (l mL) is added dropwise tetrabutylammonium fluoride (IM in THF, 2 mL, large excess) at room temperature. The solution is stirred for 40 hours then eluted through a small pad of silica gel (ethylacetate) . After concentration the oily residue is chromatographed (ethyl acetate) to afford 75 mg of pale yellow solid (79%, mp=131°c, pure by ¹ H NMR) . A portion of this material is recrystallized from pentane to afford α-calcidiol as white crystals (mp=133- 134°C), illustrated by Formula 6, X=H:

FORMULA 6

[α] .2 _D 5 +26.5, c 0.89, ethyl ether.

IR (neat): 3400 (broad), 2954, 2869, 1645,

1631, 1605, 1467, 1377, 1366, 1054, 959, 909 cm ^"1 .

UV (ethyl ether) : λmax=263 nm, e=18800.

¹ H NMR (400 MHZ): 0.55 (3H, s) ; 0.98 (6H, 2d, J=6.5Hz); 0.92 (3H, 2d, J=5Hz) ; 0.95-1.73 (m, 18H) ; 1.83-2.05 (m, 4H) ; 2.32 (dd, IH, J=7 and 13.5Hz); 2.60 (dd, IH, J=3.5 and 13.5Hz); 2.82 (bd, IH, J=11.5Hz);

4.23 (m, IH) ; 4.43 (m, IH) ; 5.01 (bs, IH) ; 5.32 (bs, IH) ; 6.02 (d, IH, J=12Hz) ; 6.39 (d, IH, J=12Hz) .

¹³ C NMR: 11.8, 18.5, 22.1, 22.4, 22.6, 23.4, 23.7, 27.5, 27.8, 28.9, 36.0, 39.3, 40.3, 42.7, 45.1, 45.8, 56.3, 56.5, 66.8, 70.8, 111.9, 117.0, 125.2, 132.9, 143.6, 147.8.

MS with peak match: m/z=400.3342 (5%, M+, calculated 400.3341); 382.3215 (68%, M+-H ₂ 0, calculated

382.3236); 364.3103 (77%, M+-2H ₂ 0, calculated 36 .3130) ; 349.2880 (M+-2H ₂ 0-CH ₃ , calculated 349.2895); 251 (41%) ;

209 (41%); 195 (48%); 157 (47%); 141 (83%); 131 (50%).

Examples 7 and 8 give an analogous preparation as has just been described but with hydroxyl at the carbon position 25 of this particular R. side chain to illustrate that side chain variations are readily accommodated in practicing the inventive method.

EXAMPLE 7

To a suspension of bromomethyltriphenyl- phosphonium bromide (6.54 g, 5 eq.), in dry THF (20 L) at -78°C is added sodium hexamethyldisilazide (IM in THF, 15 mL, 5 eq.) by syringe over 5 minutes. Vigorous stirring is continued at this temperature for 1 hour to give a bright yellow slurry. The hydroxylated Grundmann's ketone (Formula 4, X=OH, 840 mg, 3 mmol.) in dry THF (10 L) is added and the cold bath immediately removed. After about 30 minutes at room temperature, the dark brown reaction mixture is poured into a suspension of ethyl ether (100 mL) and water (30 mL) . The aqueous phase is extracted with ethyl ether (2 x 25 L) . The combined organic phases are washed with water (20 mL) , dried (MgS0 ₄ ) , and concentrated to afford 5 g

23 of semisolid material. Careful chromatography (pentane/ethylether, 3:1) affords 490 mg (46%) of bromoolefin of Formula 5, X=0H. ¹ H NMR shows the presence of 2% of Z isomer and 4% of cis fused isomer.

The product is a colorless oil which becomes yellow upon standing at 4 ^β C for 24 hours, without noticeable change of the NMR spectrum.

[o] +91.4°. (c 2.79, CH ₂ C1 ₂ )

IR (neat): 340 (broad), 2962, 1631, 1467,

¹ H NMR (300 MHz): 0.56 (s, 3H) , 0.93 (d, 3H, J=6Hz) , 0.85-2.05 (m, 24H, including a singlet, 6H, at 1.21 ppm), 2.88 (m, IH) , 5.64 (bs, IH) .

¹³ C NMR: 11.6, 18.6, 20.6, 21.8, 22.4, 27.4, 29.0, 29.2, 30.9, 35.8, 36.2, 44.2, 45.4, 55.7, 55.8, 71.0, 97.4, 145.4.

Anal . Calc ' d for C ₁₉ H ₃₃ BrO: C, 63 . 86% ; H, 9 . 31% . Found: C, 63. 66% ; H, 9.46% .

EXAMPLE 8

(Obtention of calcitriol)

To a suspension of Pd ₂ (dba) ₃ CHCl ₃ (30 mg, 10% Pd) and triphenylphosphine (recrystallized from ethanol, 47 mg, 30%) is added freshly distilled toluene (2 mL) and triethylamine (3 mL) . The mixture is vigorously stirred for about 10 minutes at room temperature. The solution of bromide of Example 7 (327 mg, 1.5 eq.) and enyne of Example 4 (299 mg, 0.61 mmol.) in toluene (1 mL) is added by gas tight syringe. The orange mixture is refluxed for 2 hours (oil bath at 125°C) then cooled, and 5 mL of pentane are added. The resulting suspension is filtered over a small pad of silica, eluting with ethyl ether, and concentrated. Rapid chromatography of the yellow residue (ethyl ether/pentane, 2:1) affords 650 mg of a mixture of protected vitamin, protected

previtamin, and bromide of Example 7, which is not separated by subjected to desilylation by addition (under nitrogen and in the dark) of tetrabutylammonium fluoride (0.5M in THF, 6 mL, ca. 5 eq.) . The resulting black solution is stirred for 30 hours at room temperature, then directly chromatographed (ethyl acetate) to afford 132 mg (52% from enyne of Example 4) of fairly pure calcitriol (Formula 6, X=OH) as a white solid. The latter is recrystallized from chloroform to afford 103 mg of very pure calcitriol as white crystals.

Mp=109-114°C.

[α] _p ⁵ +45.3 (c 0.44, ethanol) . IR (neat): 1652, 1627, 1470, 1364, 1320,

1140, 1075, 1054, 915, 909 cm ^"1 .

¹ H NMR (400 MHz, acetone-d ₆ ) : 0.57 (s, 3H) , 0.96 (d, 3H, J=6Hz), 1.06 (m, IH) , 1.13 (s, 6H) , 1.21- 2.10 (m, 19H) , 2.27 (dd, IH, J=7 and 13.5Hz) , 2.49 (bd, J=13Hz) , 2.74 (m, IH, overlapped with the water peak at 2.80) , 4.16 (m, IH) , 4.38 (m, IH) , 4.85 (bs, IH) , 5.31 (bs, IH) , 6.08 (d, IH, J=12HZ) , 6.28 (d, IH, J=12Hz) . ³ C NMR (acetone-d ₆ ) : 12.3, 19.2, 21.4, 23.0, 24.2, 28.3, 29.5, 36.9, 37.4, 41.3, 44.3, 45.3, 46.3, 46.4, 57.0, 57.4, 66.8, 70.0, 70.5, 110.8, 118.8, 123.9, 136.5, 141.3, 150.6.

It is to be understood that while the invention has been described above in conjunction with preferred specific embodiments, the description and examples are intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims.