1,23-DIHYDROXYVITAMIN D COMPOUNDS

Abstract: Novel 1,23-dihydroxyvitamin D compounds, a process for preparing such compounds of novel intermediates in such process. As indicated by its binding affinity for the 1 alpha ,25-dihydroxyvitamin D3 receptor protein, the compounds of this invention would function as effective substitutes for vitamin D and certain vitamin D metabolites for the regulation of calcium and phosphorous metabolism and for treatment of bone-related diseases.

Description: Description 1,23-D-Uaydroxyvitamin D Compounds Technical Field This invention relates to hydrαxylated vitamin D analogs. More specifically, this invention relates to novel la ,23-d__hyd-X-Xyvii-aιi-in D cαrpounds, and to methods and novel intermediates utilized for their preparation. -_a<-^grσund For the regulation of calcium and phosphate metabolism in the animal or human and for the regulation of normal bone grcwth, development and maintenance, the metabolites of vit-Ξimin D are essential agents. In the normal animal or human, these bone-related processes are regulated by la ,25-dibydrαxyvitamin D3, a metabolite formed from vitamin D3 by hydrαxylation at carbon 25 and then at carbon 1. This discovery has stimulated much ac±ivity aimed at preparing the natural metabolite and structural analogs thereof * Results of these efforts are sumπarized in several reviews (e.g. Yakhimαvich, Russian Chem. Rev. 49, 371 (1980) ; DeLuca et. al. Topics in Current Chemistry, Vol. 83, p. 1 * (1979); Ann. Rev. Biochem. 5>2, 411 (1983)) . Important exaπples of synthetic analogs of the natural hormone include lcr-hydroxyvit-amin D 3 (U.S. Patent 3,741,996) , l^hydroxyvitamin D 2 (U.S. Patent 3,907,843), 3-deαxγ-lαr,25-di]-ydrσJcyvit--_i-__n D 3 (U.S. Patent 4,264,512), 10,19-dihyd__O-lorhydrO_<^ita-iύn D- coπpounds (U.S. Patent 4,159,326) , 1^,24-dihydroxyvitamin D 3 (U.S. Patent 4,022,891), 24,24-difl\aoro-l-?,25-iihydroxyvita-t± D 3 (U.S. Patents 4,226,788, 4,284,577), 26,26,26,27,27,27-hexafluorc-lα ,25-dihyd__oxyvitaιτιin D 3 (U.S. Patent 4,358,406) and other side-chain or ring A fluoro analogs (U.S. Patents 4,069,321; 4,224,230? 4,307,025). ' OMPI Disclosure of Invention A class of analogs not known heretofore are lα,23-d_ibyd__O-<yvii_a-T-in D cx-mpounds. These compounds r characterized by hydroxy substitution at carbons 1 and 23 (instead of carbon 25) of the vitamin D skeleton, have new- been prepared by chemical processes as set forth herein. Specifically, the novel ccmpcfunds of this invention may be represented by the formulae shown belσwr wherein R. and R~ are selected frcm the group consisting of hydrogen and alkyl and where X, , X~ and X, are selected frcm hydrogen or a hydrα-^-^rotecting group. -0-qportant examples of such analogs are the αxrpour-ds where R, is hydrogen and Ky is isobutyl (i.e. la ,23-di_--yd_-Oxyvitamin D 3 and its 5,6-trans-isomer) , or where . is hydrogen and R_ is methyl, ethyl, propyl, isopropyl or butyl, as well as the cortpounds where both. . and « represent an alkyl group, e.g. where . and R- are methyl, or where R. is methyl, and R, is ethyl, propyl, butyl or isobutyl. In this specification and in the claims, the word "alkyl" denotes a lower hydrocarbon radical of frcm 1 to 5 carbons, in all isomeric forms, e.g. methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, pentyl, etc. A hyd__c*y-protecting group is any of the cannon organic groupings used for protection of hydrαxy functions, e.g. acyl, alkylsilyl, iiEthoxy-irethyl, tetrahyd__x_pyranyl. Of particular interest are acyl protecting groups, i.e. alkancyl groups of from 1 to 5 carbons, such as formyl, acetyl, propionyl, etc. or ar tatic acyl groups such as benzcyl, or halo, nitro, or alkyl substituted benzσyl groups, or carboxyalkanoyl groups of from 1 to 6 carbons, such as oxalyl, alonyl, succinyl, valeryl, adipyl or diglycolyl. The analogs identified above are thus characterized by possessing the irrportant - Hbydroxy (or protec ed-hydroxy) group and by side chain st_mctures having a 23-hydroxy (or protected hydroxy) __uncti_on which may be primary, secondary or tertiary, i.e. the hydrocarbon substituents R, and R- at carbon 23 may be both hydrogen, or hydrogen and alkyl, or both alkyl, as illustrated below: It is also to be noted that when in the above structures the two substituents at carbon 23 are both alkyl these alkyl groups may be identical or different, e.g. R, and R~ may both represent methyl, ethyl, isopropyl, butyl, etc., or they may represent any ccπibination of two different substituents such as irethyl and ethyl, methyl and isopropyl, ethyl and propyl, etc. In the compounds of this invention, the side chain hydrαxy group, which occurs in the natural metabolite, lxx ,25-dihydroxyvitar-άn D_, at the 25-ρosition, occurs at the 23-position. Despite this irtportant strructural change, it has been found that the 1,23-di ydroxy analogs of this invention exhibit pronounced bio-potency as expressed, in particular, by their high binding affinity to the cytosolic receptor protein in intestine, a property which is known to be iirportant for high in vivo activity. The 1,23-dihydroxy cαrpounds can be prepared by a series of process steps which are more fully described below and in the process schematics. The cατιpcunds can be prepared from a coirron starting material, such as the cyclσvitamin D-23-aldehyde of structure la shown in Process Scheme I. In this formula, the radical Z represents a lcwer hydrocarbon radical (alkyl) as defined above. Generally and conveniently, Z represents methyl, but hcπologs where Z is, for exaπple, ethyl, propyl, isopropyl, etc. are also suitable starting materials for the present process. This starting material may be converted to the desired final products illustrated above by three major process steps: a) __nt-- duc_ion of the desired C-23 substituents (R-, R-) by alkylation or reduction.; b) introduction of the C-l -hydrαxy function, and c) solvolysis to obtain the 5,6-cis and 5,6-trans lor,23-d-_hyd__oxyvitamin D products. In principle, these three main process steps can be carried out in any desired order (e.g. C-23-substituent -lnt--Oduction, followed by - r-hyd-_Osylation, followed by solvolysis, or lα-1ydroxylation, followed by solvolysis, followed by 23-substituent -mtrcduction, etc.) , and the choice of a specific sequence of steps is a matter of convenience dictated in part by the nature of the specific target cαrpσund to be prepared, as will be evident to those skilled in the art. For example, lcHiydrαxylatiσn of compound la with Se0 2 and a l^drcperoxide (e.g. H_0 or an alkyl I-ydroperoxide) according to the procedure of DeLuca et al., U.S. Patent 4,195,027, gives the lαrbydroxy intermediate 2a (X,=H) . This compound is then solvolyzed, preferably in a " medium containing an organic ca__boxylic acid (e.g. acetic, formic, propionic acid, see DeLuca et al., U.S. Patent 4,260,549) to obtain in admixture the 5,6-cis-vitamin D compound represented by structure 3a (X,=H; X_=-acyl) and the 5,6-trans coitpound of structure 4a (X^H, X^cyl) , where the acyl group (X corresponds to the acyl moiety of the acid used in the solvolysis reaction. These cis and trans c-απpounds can be separated at this stage (e.g. by ch_-Oπat_ography using thin O PI layer plates, or high performance columns) to give compounds 3a and 4a individually. These C-3-monoacylates can be used directly for the next step of the process, or, if desired, the 3-0-acyl groups in coπpounds 3a or 4a can be removed by base hydrolysis (e.g. 5%-10% KOH) to give 3a and 4a where X, and X~ = H, or the free 1-hydrαxy group may be acylated tinder conventional conditions to provide 3a and 4a where X. and 2 are acyl groups, which may be the same or different. Treatment of c * αrιpσund 3a (where X, and X 2 may be acyl or H) with a reductant (e.g. NaBH. or L.LA1H, or similar reducing agent) provides one of the desired analogs, cα_rpound 3b (where R, is hydrogen and X, and X« may be acyl or hydrogen, depending on the nature of 3_a and the reductant used, and X 3 is hydrogen) . Analogous reduction of the trans compound 4a gives analog 4b where R-. represents hydrogen (see Process Scheme I) . Any acyl groups present in 3b or 4b thus prepared may be removed by simple base hydrolysis to obtain the corresponding free hydroxy cαrpounds. A suitable alternative sequence to the above compounds is for example, reduction of la to provide inteririediate 3J3 (R,=H) followed by lcsrhydroxylation to 2b (R,-=H) and solvolysis and final acyl hydrolysis. Likewise, a sequence involving reduction of 2a to the corresponding C-23-prirtary alcohol (2b, R,=H) followed by solvolysis can be used effectively. The preparation of 23-monoalkyl analogs can be achieved by alkylation of the intermediate 3a (X.. and X 2 =acyl or H) with an alk l-Grignard reagent in an ether solvent at a temp¬ erature ranging from 0°C to reflux, or the corresponding.) alkyl-lithiu reagents (methyl lithium, ethyl lithium, etc.) to provide the analogs of general structure 3b where . is an alkyl group _-ni-roduced by the Grignard or a-Lkyl-lithium ... OMPΓ ^ isopropyBlgBr, ^ (R = isc . propyl} 3a ^-^ 3b (R^butyl) 3a pentyl MBi^ 3b (R^ pentyl) In all of the above exairples, X, and ^ in compound ' 3a may be hydrogen or acyl, whereas X-, X-, and X^ in the product of type 3b are all hydrogen, since acyl groups (if present in the starting material) are removed during the Grignard reaction step. . Analogous aUcylation of the 5,6-trans αarpound 4a gives the 5,6-trans-l,23-dihydroxy analogs of structure 4b where R, is an alkyl group. As shown in Process Scheme I, the C-23-alkyl analogs of structure 3b or 4b (where .=alyl) can also be conveniently prepared by an alternative route. Thus initial reaction of cyclovitamin D starting material ^a with the appropriate Grignard or alkyl lithium reagent, gives the 23-hydroxy- cyclovitamin intermediate of structure lb (where R 3 ==a-_kyl and X 3 =H) . Suitable Grignard reagents are for example, metiiylmagnesium bromide, ethyl magnesium bromide, propyl- and isopropylmagnesium bromide, butyl- and isobutyl magnesium bromide, or sec. butyl magnesium b__cmide, and the use of such reagents then gives a series of 23-l^droxy compounds of general structure lb, where R. is the alkyl group (i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or sec. butyl, respectively) introduced by the Grignard reagent. Subsequent _ r-hydrαjylation of lb, under the conditions cited above, then provides the corresponding lα.,23-d-U * -ydroxy cyclovitamin D compound of structure 2b (where R.-=alkyl and X.. and X^ are hydrogen) . Solvolysis of cαrpound 2b, using conditions analogous to those described above gives the 3-0-acyl derivatives of the compounds represented by s-r-_Euctures 3b and 4b (R =alkyl, X, and X 3 =H, X =acyl) , as a mixture. Separation of this mixture provides analogs 3b and the 5,6-trans analog 4b in pure form (where R.=alkyl, X, and X 3 =ff, X 2 =acyl) . Acyl hydrolysis then gives the corresporiding free hydroxy coirpounds. If desired, the mixture of the 3-0- acyl derivatives of 3b and 4b as obtained by the solvolysis reaction may also be hydrolyzed directly to give a mixture of 3b and 4b (where X, , X~ and X 3 =H) , which is then separated to provide the desired cis cc_π _>und 3b (R.=alkyl, X,, X~, X 3 =H) and the trans compound 4b (Ir ^alkyl, X. , X~, X 3 =H) . For the preparation of 1,23-dihydrαxy ccπpσunds featuring a tertiary 23-hydrαxy group, i.e. the cαrpσunds where both of the C-23-substituents R. and - represent an alkyl group (and where Ε and IFL may be the same or different) , an extension of the above process, more specifically depicted in Process Scheme II, can be used. This involves the oxidation of the secondary 23-hydroxy group in a cyclovitamin D intermediate of general structure lb (where .=alkyl, and X 3 =H) to obtain the corresponding 23-ke-bD-intermediate, i.e. the compounds of general structure lc, shown in Process Scheme II, where R, is the same alkyl group present in the precursor of formula-lb. This oxidation is accomplished with mild oxidants suitable for hydroxy to ketone conversions, for example, c-hrcmium oxide reagents (e.g. pyridinium dic±tro ate, in d-tmethylforinamide solution) or sulfur triαxide pyridine complex in dimsthyl- sulfoxide and triethylamine, at about room temperature or below. Subjecting this keto intermediate of structure lc to a reaction with a Grignard reagent (alkyl magnesium halide) or with an organo-røetal reagent (alkyl-lithium) under conditions analogous to those used for the conversion of la to 3±>, then provides a 23-tertiary hydroxy cyclovitamin -Lnter ediate, i.e. a compound of general struσtu__e 1Δ in which X_ is hydrogen and where both 1? and R_ represent an alkyl group (which may be Process Scheme I OMPI Process Scheme II the same or different, depending on the nature of R-, present in compound lc and the nature of the alkyl group in the Grignard reagent or organo-metal reagent used for the conversion of lc to Id ) . For example: !b (R^, oxidativ^ icethylMgBr (I^-^fe) lc ( ^=^) Id (R 1 =R 2 =Me) lb R^th l) oxidativ propγlMgB^ lb (R χ =Me) ? 2o (R 1 =Me) Id (R 1 =4fe, ^rσ l 3b ( ^) q ^a i^ ^ {Rι=φfe) butylMgBr Δ (R j ^Me, R 2 =butyl> oxidativi propy-L gBr h (R^th l) ISO i * l lcc (S-=et±yl) Id (R^thyl, lb (R^ropyl) i≡ - ^ <P =prαpyl) ^^ Id (R^rcpyl, R^butyl) lb (R 1 =isopro P yl) *M**^ lc (R^i-s^rqpyl) sec ' ^^ Id (R- isopropyl, R =sec.butyl) lb (R 1 =butyl) -^^ lc (R,=butyl) ethylMgB^ Id (R^utyl, ^th l) OMPI lb (R 1 =sec. butyl) oa dativ lc (R χ =sec. butyl) ethylMqB^ Id (R-=sec. butyl, Ir^-^thyl . The 23-hydroxy .function may be acylated to provide the oo__rεsponding acylαxy derivative (Id, where X =acyl) but such acylation is not required for the conversions which follow. Subsequent allylic hydroxylation of the tertiar-hydroxy cαrpound of type Id (R, and R=alkyl and X 3 =hydrogen or acyl) at carbon 1, using the conditions (Se0 2 /hydropercκide) mentioned above then provides the corresponding 1#,23- dihydroxy cyclovitamin D compound (or the 23-acylates) of st-_ucture 2d (R_ and . Further conversion of the latter intermediate along the lines described above for the case of the 23-secondary-hydroxy analog, namely, solvolysis to cfotain a mixture of 5,6-cis and 5,6-trans-l,23-dihydroxy- vitamin D compounds as the 3-0-acylates, separation of this mixture, to give the pure 3-0-acylates (compounds 3_d and 4d, where X-,=hydrogen, X^acyl, and X 3 =hydrogen or acyl) and hydrolysis of the acyl groups in each coπpound to obtain the lα,23-d-_bydrcκyvitamin D analog of structure 3d and the 5,6-trans-lo,,23-dihydroxyvitamin D compound of structxire 4d (where R. and i . represent alkyl, and where X. , X , and X^ are hydrogen) . As shown in Process Scheme II, the 23-keto intermediate (lc, R-=alkyl) may also be directly lα-hydroxylated to give compound 2c (R ==alkyl, X ==H) , and solvolysis of that material, followed by separation of the cis and trans isαrers (3c and 4c) and alkylation of each then provides an alternative route to the tertiary 23-hydroxy products (3d and 4d, where R_ and 1*2 are alkyl) , whereas hydride reduction of 3c or 4c would provide the secondary 23-hydroxy cc_rpouhds of structures 3b or OMPI 4b respectively (Process Scheme I) where R, is alkyl. These process steps are conducted in a fashion analogous to the equivalent process steps (i.e. the conversion of la-» 2a-» 3a/4a, etc.) alr ady described above. The reaction sequences described in the preceding and outlined in Process Schemes I and II thus provide the full array of the 23-ρrima-_y, secondary or tertiary _L«,23- dil-ydrαxyvitamin D compounds indicated by the general st_-uctures shown above. It should be noted that certain of the analogs discussed above, for exaπple, 23-primary or 23-tertiary lΛ,23-d-l_-ydrαxyvitamin D analogs can also be prepared conveniently from an alternative starting material, namely the -te-hydroxyvitamin D-23-esters (!__*,3β-d_t_hydrαxy- 24-nor-9,10-seco-5,7,10(19)-cholatrien-23-oic acid alkyl esters) , represented by the st-_ucture shown below: Such esters are known compounds (DeLuca et al. U.S. Patent 4,209,634) . Reduction of the 23-ester function in the cαπpσund shewn above with, for example, lithium aluminum hydride, produces directly the corresponding 23-p-_Lmary alcohol, i.e. the lff,23-d__hyd__αxyvitamin D analog of st_nιcture 3b (Process Scheme I) where R.,, X.. , X^ and X- are hydrogen.. Mternatively, treatment of the ester shewn above with an alkyl Grignard reagent leads to the 23-tertiary alcohol, i.e. the lαr,23-αj_hyd__oxyvit_a_τ-in D ccπpound of structure 3d (Process Scheme II) where R- and 1^ are both alkyl, and whereby, in this case, the two alkyl groups introduced are necessarily identical. The 5,6-cis-vitamin l- y ,23-d-Lhydroxyvitam__n D analogs thus prepared from the 23-ester shown above can be transformed into the corresponding 5,6-trans-isomers (general structure 4b or OMPI 4d) by the iodine-catalyzed double bond isαrerization procedure of Verloop et al. [Rec. Trav. Chim. Pays-Bas 78, 1004 (1969)]. If the hydroxy-protected derivatives of products 3b, 4b, 3d or 4d are desired for therapeutic or other applications, they can be prepared from the free hydroxy compounds by conventional derivatization reactions known in the art. For example, a C-ompσund of structure 3b or 3d, where X,, X 2 and X3 represent hydrogen is readily acetylated to give the corresponding 1,3,23-tri-acetate, by -treatment with acetic anhydride in pyridine and other acylates of 3b and 3d or 4b and 4d are similarly prepared by treatment with the appropriate acyl anhydride or acyl chloride at room temperature or elevated temperature according to known procedures. In addition, it should be noted that the 3-0-acyl derivatives of the compounds of general structures 3_ and 4_ (X. and X 3 =H, X 2 =aσyl) are of course obtained as irrmediate products of the solvolysis reaction, and other partially or completely acylated derivatives of the final products can be obtained if desired by the use of acylated intermediates in the reaction process. For example, intermediate lb or Id (where R, and ~ represent alkyl, and X 3 =H) can be acylated by standard procedures to the 23-acyl derivative (cαrpound lb or Id, where X =acyl) and from these intermediates after hydroxylation to 2b or 2d, respectively (X,=H, X=acyl) and solvolysis, the 3,23-diacyl compounds 3b or 3d (where - and X 3 are acyl groups which nay be the same or different, and X,=H) and 4b or 4d (X 2 and X 3 =acyl, X,=H) are obtained. Similarly, acylation of the 23-acylates of 2b or 2d (Xv=H, X 3 =acyl) to the corresponding 1,23-diacyl intermediate (cαtpounds 2b or 2d, where X. and X 3 =acyl) would provide, after.solvolysis, the 1,3,23-tri-O-acylated products of structures 3b, 4b or 3d, 4d. Alternatively, selective acylation of the dihydroxy compounds 2b or 2d (X, and 3 =H) to QMPI the 1-0-acyl -Intermediate (2b or 2d, where X j =acyl, ^H) followed by solvolysis yields l,3-di-0-acyl derivatives (X-^ and of the final products (3b, 4b, 3d, 4d) and analogous 1,3-diacylates can be obtained by the 1,3-di-acylation of carpounds of type 3a and 3c (or 4a and 4c) followed by borohydride reduction of the aldehyde or keto group. It is to be noted also that whenever the substituents . and 1*2 at carbon 23 in the -ύκive-described c rpounds are not identical, said coπpαunds will generally occur as a mixture of ά^iastereccners (the 23R and 23&-epimers) and thus final - products 3b and 4b (or 3d and 4d) will be otained as mixtures of epimers, characterized by the Rαr S sterreochemistry at carbon 23. If desired, these epimers may be separated (preferably by high performance liquid chromatography at the stage of the final p-_oduct) to obtain the 23R and the 23S epimers in pure form. For example, reaction of aldehyde la with iscbutylmagnesium bromide gives the cyclαvitamin D intermediate lb (R-=isobutyl) as- a mixture of the 23R and 23S-epimers. Further conversion of that mixture, by la -hydrox laticn, solvolysis and acyl hydrolysis as discussed above, then provides four carpounds, the 23R and £3 epimers of 3b (R,=isobutyl) and the 23R and _S epimers of 4b (R,=isobutyl). These αaπrpounds can be .separated, advantageously by high pressure liquid cl-αxmatography, to obtain each of the epimers in pure form. However, in many pharmaceutical applications, these C-23-epimers of 3b and 4b (or 3d and 4d) nay also be used as the epimeric mixtures and separation is essential only when the pure 23-R and S-isomers are desired. The starting material, the cyclovitamin D-23-aldehyde of structure la utilized in Process Scheme I is itself a novel compound. Its preparation is described below by an illustrative working example. OMPI The lα,23-d-Lhydroxyvitamin D analogs of this invention exhibit high binding affinity for the lα.,25-d:Uydrσxyvita_r_in D 3 receptor protein occurring in intestine and other vitamin D responsive tissues. Present evidence indicates that effective binding of a vitamin D metabolite or analog to this protein is a key step for expression of in vivo activity. Consequently, the remarkable binding potency of the corrpounds of this invention indicate that they can be used effectively as substitutes for the kncwn vitamin D metabolites for the regulation of calcium and phosphorus metabolism in mammals and for the prevention or cure of bone-related diseases. The present invention is more specifically described by the following exairples which are intended to be illustrative only. In the examples, chemical products identified by ' numbers (e.g. compound la, 2a, 3b, 4d, etc.) refer to the structures similarly numbered in Process Schemes I or II. All the products and intermediates shown in Process Schemes I and II, are novel corrpounds. Exaπple 1 Preparation of starting material, cyclovitamin D-23-aldehyde of structure la (Z=Me) : An ethanolic ethereal solution of diazαmethane (CHJSL) , generated f om N-methyl-N-nit-_oso-p-toluenesulfonamide (CH 3 C 6 H 4 S0 2 N(CH 3 )NO; Diazald) , was added dropwise to a suspension of (20SJ-3β-acetcxy-5-preo^ene-20-carboxylic acid (10.0 g, 25.7 πtnole; m.p. 228-231°C) in 1:9 ethanol-ether at room temperature until all the solids dissolved and pale yellow color due to an excess diazcraethane persisted. Excess diazαπethane was removed with a stream of N 2 until the solution became colorless. Removal of solvent provided the desired methyl ester, (20 )-3β-acetoxy-5-pregnene-20- carboxylic acid methyl ester (10.3 g; Rf 0.63 on silica gel in 3:7 ethyl acetate-hexane; m.p. 140-142°C) in 99.4% yield. Mass spectrum, m/e (relative intensity) 402 (M , 0) , 342 (100), 327 (10), 283 (4), 255 (6), 239 (5), 234 (11), 221 OMPI (12), 213 (5); NMR (CDC1 3 ) S 0.70 (s, 18-^), 1.02 (s, 19- j )r 1.19 (d, J=6.8 Hz, 21-iy , 2.03 (s, 3-OCOOy , 4.60 (m, 3-H) , 5.37 (br d, J=4.8 Hz, 6-H) . Conversion of this product to the corresponding 5,7-diene ester was accαrplished by treating a stirred solution of the above cαnpound (10.0 g, 24.8 imole) in dry hexane (150 ml) containing finely divided sodium bicarbonate (10.0 g) and preheating to 80°C under nitrogen with 1,3-d-LbrαrD- 5,5-d_-_re-t-_^.l_-ydantoin (Dibrαπantin; 3.62 g, 12.4 imole) . After 20 minutes, the reaction was worked up in the usual manner. s-Collidine (2,4,6-tr-_methylpyridiι_e; 6 g, 49.6 imole) was added slowly to a stirred solution of the 7-bromo intermsdiate in dry xylene (100 ml) . After heating at reflux under nitrogen for 90 minutes, the resulting mixture, containing 5,7-diene and 4,6-diene was dissolved in dry dioxane (120 ml) and heated at 70°C under nitrogen. After addition of p-toluenesulfonic acid (1 g) in dry dioxane (30 ml) , heating was continued for 30 minutes. orkup by fractional crystallization from ethyl acetate-hexane provided - the 5,7-diene product (6.77 g; Rf 0.59 on silica gel in 1:1 ethyl acetate-hexane) in 68.0% yield: UV (C^OH) 293 πm, 282, 272, 263; mass spectrum, m/e (relative intensity) 400 (M*, 2) , 340 (100) , 325 (19) , 281 (7) , 253 (15), 237 (14), 211 (8), 158 (61); NMR (CDC1 3 ) δ0.64 (s, lβ-iy, 0.96 (s, 19-H 3 ), 1.23 (d, J=6.6 Hz, 21-Hg , 2.04 (s, 3-OC0CH 3 ), 3.67 (s, 22-0000^), 4.71 ( , 3-H), 5.40 (m(sharp) , 7-H), 5.58 (m(sharp), 6-H). Hydrolysis of the 3β-acetcxy function was accomplished by treating a stirred solution of the above pi-Oduct (2.4 g, 6.0 i ole) in 3:7 methanol-ether (70 ml) with finely powdered anhydrous potassium carbonate (2.5 g, 18.0 imole) at room terrperature under nitrogen for 5 hr. The mixture, diluted with ether (100 irύ.) , was washed with water (3x30 ml) , the washings were back-extracted with ether (1x50 ml) , and the cαnbined extracts were washed with saturated aqueous sodium chloride (2x30 ml) , dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 2.14 g (99.6% yield) of the hydroxy-ester, having the structure: UV (EtQH). 293 nm, 282, 272, 263; mass spectrum, m/e (relative intensity) 358 (M + , 100) , 343 (5) , 340 (8), 325 (81), 299 (54), 253 (12), 237 (19), 211 (18), 143 (51); NMR (CDC1 3 ) 60.64 (s, 18-H 3 ), 0.95 (s, 19-fi j ) , 1.21 (d, J=6.8 Hz, 21-H 3 ) , 3.66 (s, 22-0000^) , 5.39 (m(sharp) , 7-H) , 5.57 (m(sharp) , 6-H) . A solution of the above 5,7-diene ester (1.5 g; 2x0.75 g, 4.18 mraole) in 1:4 dry benzene-ether (150 ml) was irradiated under nitrogen in a jacket around a double-walled, water-cooled quartz rumersion well equipped with a nitrogen bubbler, a magnetic stirrer, and a Vycor filter using a Hanovia 608A36 quartz medium-pressure mercury vapor ultraviolet lamp. The reaction was monitored by high performance liquid chromatography (HPDC; Zorbax Sil analytical column), using 1% isopropanol-hexane at 265 nm. The quasi-photostetionary state mixture contained lumisterol (8%) , previtamin (63%) , and provitamin (29%) which were eluted at 31 ml, 43 ml, and 53 ml, respectively. This mixture in ethanol, freshly distilled under nitrogen and saturated with nitrogen just prior to use, was heated to 70°C for 3 hours under nitrogen, then cooled, and concentrated in vacuo. Purification by chrc_matography on Florisil (magnesium silicate; MgO 15.5%, Si0 2 84%, a 2 _=C * 4 0.5%) using ethyl acetate-hexane (stepwise elution; 5 to 25%) afforded the OMPI vitamin ester (0.774 g, 51.6% yield) of the structure shown below: This compound was characterized by the following physical data: UV (CJi M) 265 nm; mass spectrum, ra/e (relative intensity) 358 (M + , 75), 340 (8), 325 (26), 299 (13), 253 (14), 237 (10), 211 (10), 136 (100), 118 (98); NMR (CDC-^)<T 0.56 (s, 18-R j ), 1.20 (d, J=6.8 HZ, 21-H 3 ) , 3.65 (s, 22-OOθαy, 3.94 (m, 3-H), 4.80 (d, J=1.2 Hz, 19^-H), 5.04 (d, J=1.2 Hz, 19E-H), 6.03 (d, J=11.2 Hz, 7-H) , 6.23 (d, J=11.2 Hz, 6-H). A solution of the above vitamin ester (500 mg, 1.4 imole) in dry pyridine (5 ml) was treated with freshly recrystallized p-toluenesulfαnyl chloride (530 g, 2.8 imole) at 5°C under nitrogen for 24 hours. The mixture was poured over ice, then extracted with ether (3x20 ml) . The combined extracts were washed successively with 3% aqueous hydrochloric acid (2x10 ml) , water (1x10 ml) , saturated aqueous sodium bicarbonate (1x10 ml) , saturated aqueous sodium chloride (2x10 ml) , then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to yield the corresponding 3-p-toluenesulfonyl derivative (690 mg; Rf 0.56 on silica gel in 1:1 ethyl acetate-hexane) in 96.4% yield. Mass spectrum, m/e (relative intensity) 512 (M + , 7) , 358 (16) , 340 (88) , 325 (23), 299(5), 281 (6), 253 (30), 158 (63), 118 (88), 91 (100); NMR (CDC1 3 ) S 0.54 (s, 18-H 3 ) , 1.20 (d, J=6.8 Hz, 21-H 3 ) , 2.46 (s, S-OSO^g^CH- j ) , 3.66 (s, 22-COCCH 3 ) , 4.70 ( , 3-H0, 4.81 (br s, 19Z-H), 5.04 (br s, 19E-H) , 5.97 (d, J=11.6 Hz, 7-H), 6.10 (d, J=11.6 Hz, 6-H), 7.34 (d, J=8.4 Hz, 3-0SO 2 C 6 H 4 CH 3 ) , 7.81 (d, J=8.4 Hz, 3-OS0 2 C 6 H 4 CH 3 ) . The above toluenesulfonyl intermediate was then solvolyzed by addition (600 mg, 1.17 imole) to a stirred suspension of finely divided sodium bicarbonate (600 mg) in anhydrous mathanol (20 ml) . The mixture was heated to 55°C ■ under nitrogen for 15 hours. The usual workup, followed by chraiiatograpby on silica gel using 30% ethyl acetate-hexane (double elution) , provided 300 mg; 68.8% yield of the cyclovitamin D ester having the structure below: cøoctf j The product can be further purified by HP C (Zorbax Sil se ipreparative column) using 0.2% isopropanol-hexane. The product was characterized by the following data: mass spectrum, m/e (relative intensity) 372 (M , 17) , 340 (100) , 253 (48), 221 (40), 135 (41), 119 (72); NMR (CDCL j ) 50.54 (s, 18-H 3 ), 0.74 ( , 3-H), 0.91 ( , 4-H) , 1.20 (d, J=7.2 Hz, 21-H 3 ), 3.25 (s, 6R-OCH,), 3.65 (s, 22-CCCCH 3 ) , 4.15 (d, J=8.8 Hz, 6-H), 4.88 (br s 19^-H) , 5.00 (d, J=8.8 Hz, 7-H), 5.02 (br s, 19E-H). A stirred solution of the above product (250 mg, 0.67- rπrole; Rf 0.72 on silica gel in 5:95 irethanol-chloroform) in ether was treated with lithium aluminum hydride, saturated in ether, at room temperature under nitrogen for 15 minutes. The usual workup gave the corresponding 22-alcohol (200 irg; Rf 0.58 on silica gel in 5:95 irethaiiol-chloroform) in 86.5% 4 . yield. Mass spectrum, m/e (relative intensity) 344 (M , 13) , 312 (40) , 253 (19) , 193 (33) , 135 (60) , 119 (81) ; NMR (CEC1 3 ) S 0,56 (s, 18-iy, 0.74 (m, 3-H), 0.92 (m, 4-H) , 1.06 (d, J=6.3 Hz, 21-H- j ), 3.26 (s, 6R-OCH 3 ), 3.66 (dd, J=2.8 Hz and 10.4 Hz, 22-iy, 4.17 (d, J=9.2 Hz, 6-H), 4.89 (br s, 19Z-H) , 5.01 (d, J=9.2 Hz, 7-H), 5.04 (br s, 19E-H) . A stirred solution of the above alcohol (160 mg, 0.46 mmole; Rf 0.26 on silica gel in 3:7 ethyl acetate-hexane) in dry pyridine (5 ml) , cooled on an ice bath, was treatedwith freshly recrystallized p-toluenesulfonyl chloride * (180 mg, 0.92 mmole) under nitrogen for 3 hours. Several chips of ice were added, and the mixture was stirred for 5 miiiutes to decompose the excess p-toluenesulfσπyl chloride. The mixture was then poured into ice-cold water (5 ml), and extracted with ether (3x20 ml) . The combined extracts were washed sequentially, with water (3x10 ml) , saturated aqueous sodium bicarbonate (1x10 ml) and saturated aqueous sodium chloride (2x10 ml) , then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to yield the 22-p-toluenesulfonate derivative (210 mg, Rf 0.46 on silica gel in 3:7 ethyl acetate-hexane) in 90.6% yields mass spectrum, m/e (relative intensity) 498 (M + , 19) , 483 (11) , 466 (27), 294 (8), 135 (36), 119 (55), 91 (100). A stirred solution of the above p-toluenesulfonyl intermediate (180 mg, 0.36 mmole) in dry dimethyl sulfoxide (10 ml) was treated with sodium cyanide (36 g, 0.72 imole) at 80°C under nitrogen for 2 hours. The mixture was allowed to cool to room temperature, stirred for 1 hour, then poured over ice-saturated aqueous ar onium chloride (10 ml) , and extracted with hexane (3x30 ml) . The ccmbined extract was washed with water (3x20 ml) , saturated aqueous sodium chloride (2x20 ml) , then dried over anhydrous magnesium sulfate, filtered (it can also be decolorized with activated charcoal, then filtered through Celite as a filter-aid) , and concentrated in vacuo. Purification by chi matography on silica gel using 20% ethyl acetate-hexane (double elution) presided the desired cyclovitamin D-22-nitrile (100 mg; Rf 0.49 on silica gel in 3:7 ethyl acetate-hexane) in 78.3% yield. This product has the structure shown below. + Mass spectrum, m/e (relative intensity) 353 (M , 25) , 338 (4) , 321 (100), 306 (31), 135 (16), 119 (56); NMR (CDC1 3 ) $ 0.57 (s, 18-H 3 ), 0.75 (m, 3-H), 0.92 (m, 4-H) , 1.18 (d, J=6.8 Hz, 21-H , 3.26 (s, 6R-CCR , 4.15 (d, J=9.3 Hz, 6-H), 4.88 (br s, 19Z-H), 5.02 (d, J=9.3 Hz, 7-H), 5.04 (br s, 19E-H) . A stirred solution of the above nitrile (90 mg, 0.25 mmole) in dry benzene (10 ml) was cooled on an ice bath under nitrogen before diisctoutylaluminum hydride ([(CH 3 ) 2 CHCH 2 ] 2 A--H 0.25 ml, 1.5 mole solution in toluene) was added slowly. The ice bath was removed after the addition was complete and the reaction was allowed to proceed at rcom temperature for 30 minutes. Sufficient amount of methanol was then added carefully to decompose the aluminum salt complex, the mixture was poured over ice water, phases were separated, and the aqueous phase was extracted with ether (3x10 ml) . The combined organic phase was washed with saturated aqueous sodium chloride (2x10 ml) , dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel using 25% ethyl acetate-hexane (double elution) afforded the desired cyclcvitamin D-23-aldehyde having structure la (Z=Me) (Process Scheme I) (81 irg; Rf 0.52 on silica gel in 3:7 ethyl acetate-hexane) in 89.2% yield: mass spectrum, m/e (relative intensity) 356 (M + , 9) , 324 (27) , 135 (20), 119 (61); NMR (CDC1 3 ) 50.59 (s, 18-H 3 ) , 0.75 (m, 3-H), 0.92 (m, 4-H), 1.03 (d, J=6.4 Hz, 21-H 3 ) , 3.27 (s, δR-CCH j ) , 4.17 (d, J=9.3 Hz, 6-H), 4.89 (br s, 19Z.-H) , 5.01 (d, J=9.3 Hz, 7-H), 5.04 (br s, 19E-H) , 9.76 (m, 23-CHO) . Example 2 Hyd__oxylation of la to 2a: Freshly distilled tert-butyl hydroperoxide ((CEy 3 CCOH; 13 mg, 0.14 mmole) was added to a stirred suspension of selenium dioxide (Se0 2 ; 3.9 mg, 0.035 imole) in dry irethylene chloride (10 ml) under nitrogen. The mixture was stirred at room temperature until hαmogeneous (30 inin) , cooled on an ice bath, and c^cΛcsvita in D aldehyde la. (Z=*5e) (25 g, 0.07 mmole) in dry irethylene chloride (1 ml) was added. The ice bath was then removed, and the reaction was allowed to proceed at room teπperature for 1 hour. The reaction mixture was quenched by addition of 10% NaOH, diluted with, ether and the phases (organic and aqueous) separated. The residue obtained by evaporation of the organic phase was subsequently ch-Xiratographed on silica gel using 40% ethyl acetate-hexane to give the _Ua--hydroxy cyclovitamin D aldehyde of structure 2a, where Z=Me, X-,=H, (10 mg) in 38.2% yield: mass spectrum, m/e (relative intensity) 372 (M + , 21) , 340 (42) , 299 (24) , 135 (100) . Example 3 Solvolysis of 2a to 3_a and 4a: A stirred solution of product 2a as obtained in Example 2 (8 g, 0.02 imole) in glacial acetic acid (0.5 ml) was heated to 55°C under nitrogen for 15 minutes. The resulting reaction product was poured over ice, neutralized with sodium bicarbonate and extracted with ether. Evaporation of the ether extract gave the mixture of the 3β-acetates (corrp- .sing coπpounds 3a and 4a, where X-^H and X 2 =acetyl) which was redissolved in ether (1 ml) and treated with 10% potassium hydroxide in πethanol at room teπperature under nitrogen for 15 minutes. The resulting product mixture was purified by high performance liquid chromatography (HPLC; Zorbax Sil semipreparative column, 6.2 mm x 25 cm) using 5% isopropanol-hexane, to give compound 3a ( ^ and X^H) : UV (C -LOHJ . ^^ 265 nm; mass spectrum, m/e (relative intensity) 358 (M + , 28), 340 (15), 152 (49), 134 (100); NMR (CDCl^O. β l (s, 18-iy, 1.04 (d, J=6.6 Hz, 21-H 3 ) , 4.24 (m, 3-H), 4.44 ( , 1-H), 5.01 (d, J=1.2 Hz, 19JS-H) , 5.34 (d, J=1.2 Hz, 19E-H) , 6.03 (d, J=11.2 Hz, 7-H), 6.38 (d, J=11.2 Hz, 6-H), 9.76 (m, 23-CHO); and cαrpound 4a (X χ and X^H) : ϋV (C^OHJ ^ ∞χ 273 nm; mass spectrum, m/e (relative intensity) 358 (M , 13) , 340 (5), 152 (24), 134 (100); NMR (CDCy $ 0.62 (s, 18-H 3 ) , 1.04 (d, J=6.4 Hz, 21-iy , 4.25 (m, 3-H) , 4.50 (m, 1-H) , 4.98 (br s, 19Z-H), 5.13 (br s, 19&-H) , 5.89 (d, J=10.8 Hz, 7-H), 6.58 (d, j=10.8 Hz, 6-H), 9.76 (m, 23-CHO). Example 4 Al_ylation of JLa to give lb: Isobutylmagnesium bromide ((CH 3 ) 2 CHCH 2 MgBr) was prepared as follows: The apparatus was dried in an oven just prior to use. A 100 ml three-necked round bottom flask, was fitted with a coil-type condenser, a dropping funnel with a pressure- equalizing side tube, and a magnetic stirrer. A trap was provided to the top of the condenser through a three-way tube. High purity dry nitrogen was introduced at the top of the condenser to be allowed to sweep through the apparatus and to escape at the mouth of the dropping funnel. A slight positive pressure of nitrogen was πaintained when the funnel was closed as indicated by bubbles in the trap. Magnesium turnings (1.2 g, 0.05 mole) were placed in the flask, nitrogen was passed through for 30 minutes to displace air and to ensure elimination of any moisture, and isobutyl bromide ((CH 3 ) 2 CHCH 2 Br 6.8 g, 0.05 mole) in ether was introduced dropwise through the funnel with stirring after the nitrogen flow was reduced to a barely perceptible rate. The reaction was allowed to proceed for 4 hours. The final volume was adjusted to 50 ml. Isobutylmagnesium bromide (0.5 ml, 0.5 rmole; 1.0 mole solution in ether) was added slowly to a stirred solution of la (35 mg, 0.1 mmole) (see Exairple 1) in ether (10 ml) under nitrogen. The ir xture was refluxed at room teπperature for 24 hours, then saturated aqueous armonii-m chloride was added slowly frcm a dropping funnel at a rate controlled by the rapidity of refluxing to reach a point where a clear separation occurs. The mixture was allowed to settle for several minutes, the supernatant was decanted, and the precipitate was washed with several portions of fresh ether. The ccπbined ethereal solutions were dried over anhydrous magnesium, sulfate, filtered, and concentrated in vacuo. Ch_-θπatograpihy on silica gel using 20% ethyl acetate-hexane (double elution) gave product h ^ (R^isobutyl, 3 =H, Z=Me) (27 mg; Rf 0.50 on silica gel in 3:7 ethyl acetate-hexane) in + 66.3% yield: mass spectrum, me (relative intensity) 414 ( , 16), 382 (83), 253 (50)-, 135 (45), 119 (95). Treatment of compound la with ethylmagnesium bromide, under conditions analogous to those described above, gives product lb (R--""ethyl, X, *5 ^, Z=methyl) . Treatment of corrpound la (Z=methyl) with, iscpropyliragnesium bromide, under the above described coi-ditions, gives product lb (R.=iscpropyl, X 3 =H, Z=methyl) . Exaπple 5 HycTro_ylation of lb to 2b: Freshly distilled tert-butyl bydroperoxide ((C^ CCOH; 11 mg, 0.12 imole) was added to a stirred suspension of selenium dioxide (SeC ; 3.3 mg, 0.03 mmole) in dry irethylene chloride (10 ml) under nitrogen. The mixture was stirred at room temperature until homogeneous (30 minutes) , cooled on an ice bath, and product lb (R^isobutyl) from Exairple 4 (25 g, 0.06 mmole) dissolved in dry irethylene chloride (1 ml) , was added. The ice bath was then removed, the reaction was allowed to proceed at room temperature for 1 hour, and 10% aqueous sodium hydroxide (5 ml) was added to quench the reaction. The mixture was diluted with ether (30 ml), phases were separated, and the organic phase was washed successively with 10% aqueous sodium hydroxide (3x5 ml) , water (2x5 ml) , saturated aqueous sodium chloride (2x5 ml) , then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification by chromatography on silica gel using 40% ethyl acetate-hexane yielded 12.2 mg (41%) of product 2b (R-=isobutyl, X, and X 3 =H, Z=-Me): mass spectrum, m/e (relative intensity) 430 (M + , 22) , 412 (5) , 398 (44) , 380 (15), 357 (17), 135 (100); NMR (CDCL j ) £ 0.57 (s, I β -tt j ) , 0.64 (t, J=4.6 Hz, 3-H), 0.92 (d, J=6.5 Hz, 26-^ and 27-1^), 0.98 (d, J=6.4 Hz, 21-iy, 3.26 (s, δR-OC j ) , 3.79 ( , 23-H) , 4.20 (m, 6-H), 4.23 (m, 1-H), 4.98 (m, 7-H), 5.17 (d, J=1.2 HZ, 192HH), 5.24 (d, J=1.2 Hz, 19E-H) . Exairple 6 Solvolysis of 2b to 3b and 4b: A stirred solution of the product of Exairple 5 (10 mg, 0.023 imole) in glacial acetic acid (0.5 ml) was heated to 55°C at reflux under nitrogen for 15 minutes. The mixture was poured over ice, then ice-cold saturated aqueous sodium bicarbonate was added cautiously to neutralize, and the mixture was extracted with ether (3x10 ml). The ccxribined extract was washed with water (1x5 ml) , saturated aqueous sodium chloride (2x5 ml) , then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The mixture of the 3β-acetates (σαrpounds 3b and 4b, where R,-=isobutyl, X. and X^H, X^acetyl) .in ether (1 ml) was treated with 10% potassium hydroxide in metha ol at room temperature under nitrogen for 15 minutes. Saturated aqueous sodium chloride (5 ml) was then added, the mixture was extracted with ether (3x10 ml) . The combined extract was washed with water (2x5 ml) , saturated aqueous sodium chloride (2x5 ml) , then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The isomers cis and trans were separated by high performance liquid chrαnatography (HP C; Zorbax Sil semipreparative column, 6.2 nm x 25 cm)- using 5% isopropanol-hexane to give compound 3b (R-.-=isobutyl, X , X2, X 3 =5i, 23R-stereochsπistry) : UV (C^OH) ^ 265 nm; mass spectrum, m/e (relative intensity) 416 (M , 17) , 398 (12) , 380 (5) , 152 (38) , 134 (100) ; NMR (CDCL j ) S 0.58 (s, 18-IL) , 0.92 (d, J=6.4 Hz, 26-^ and 27-H j ) , 0.98 (d, J=6.4 Hz, 21-^) , 3.79 (m, 23-H) , 4.24 (m, 3-H) , 4.44 (m, 1-H) , 5.01 (br s, 19J3-H) , 5.33 (br s, 19E-H) , 6.03 (d, J=11.2 Hz, 7-H) , 6.39 (d, J=11.2 Hz, 6-H) , and the .5,6-trans coπpound 4b 18-a j ) , 0.93 (d, J=δ.8 Hz, 26-H-. and 27-H j O, 0.99 (d, J=6.8 Hz, 21-iy , 3.79 (m, 23-H) , 4.24 (ra, 3-H) , 4.50 (m, 1-H) , 4.98 (d, J=1.2 Hz, 19^-H) , 5.13 (d, J=1.2 Hz, 19E-H) , 5.89 (d, J=11.2 Hz, 7-H) , 6.59 (d, J=11.2 Hz, 6-fi) , as well as the 23&-isomer of 3b: (C 2 lCOH) -^^ ^ 265 nm; mass spectrum, m/e (relative intensity). 416 (M + , 24) 398 (89) , 380 (35) , 152 (100) , 134 (73) . Exairple 7 Preparaticm of ccπpound 3d (R =R 2 =-Me) from 23-ester: Methyl-magnesium bromide (CH 3 MgBr; 0.05 ml, 3 mole solution in ether) was added drqpwise to a solution of (5Z,7E) -(1S,3R) -l,3-dihydroxy-24-nor-9,10-seco- 5,7,10 (19) -cholatrien-23-oic acid methyl ester (1 mg) in ether (5 ml) under nitrogen. The mixture was heated at reflux for 10 minutes, cooled, and saturated aqueous aimonium chloride was added slowly. The reaction mixture was worked up in the usual way, and the p-_oduct was purified by high performance liquid chromatography (HP C; Microporasil semipreparative column) using 8% isopropanol to afford o rpound 3d (R-=R 2 -=Φ_s, X 1 =X 2 -=X 3 =H) (Rd 0.48 on silica gel in 15:85 methanol-chloroform) : ϋV (C BLOH) _^ 265 nm; mass spectrum, m/e (relative intensity) 388 (M + , 7) , 370 (52) , 352 (50) , 337 (9) , 269 (11) , 267 (9) , 251 (15) , 152 (31) , 134 (100) ; NMR (CDC1 3 ) § 0.60 (s, 18-H j ) , 1.08 (d, J=6.4 Hz, 21-YL , 1.24 (s, 26-^ and 27-H- j ) , 4.25 (m, 3-H) , 4.45 (m, 1-H), 5.02 (br s, 19Z-H) , 5.35 (br s, 19E-h) , 6.04 (d, J=12.0 Hz, 7-H), 6.40 (d, J-=12.0 Hz, 6-H). Example 8 Preparation of ccπpound 3b (R,=H) frcm 23-ester: Lithium aluminum hydride, saturated in ether, was added slowly to a stirred solution of (5^,7E)-(15,3R)-l,3-dihydroxy- 24-nor-9,10-secc-5,7,10(19)-cholantrien-23-oic acid methyl ester (1 mg) in ether (2 ml) at room teirperature under nitrogen. The reaction was allowed to proceed for 5 minutes. The usual workup, followed by high performance liquid ch-xπiatography (HPLC; Microporasil semipreparative column) using 8% isopropanol-hexane, produced compound 3b (R,=-H; X 1 =X,=X 3 -=H) (Rf 0.45 on silica gel in 15:85 methanol- chloroform): UV (CJsLOH) -^- g ..265 nm; mass spectrum, m/e (relative intensity) 360 (M + , 8) , 342 (51) , 324 (49) , 269 (11), 251 (25), 152 (33), 134 (100); NMR (CDCl-^) S 0.58 (s, 18-H , 0.98 (d, J=6.2 Hz, 21-H j ) , 3.71 (br m, 23-H 2 ) , 4.25 (m, 3-H), 4.45 (m, 1-H), 5.03 (br s, 19Z-H) , 5.34 (br s, 19E-H), 6.03 (d, J=11.2 Hz,.7-H), 6.40 (d, J=11.2 Hz, 6-H). Exairple 9 Oxidation of lb to lc: A stirred solution of the cyclcvitamin D-23-alcohol (3b, (1 equivalent) in dry N,N-dimethylfθ-_mamide (1 ml) was cooled on an ice bath under nitrogen before pyridi ium dichromate (7 equivalent) was added. The reaction was allowed to proceed at 5°C under nitrogen for 8 hr., then the mixture was poured over ice water (3 ml) and extracted with ether (3 5 ml) . The cαrbined extract was washed sequentially with water (1 3 ml) and saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel using 30% ethyl acetate-hexane provided the ketone 3c (R,=isobutyl, Z=methyl); mass spectrum, m/e (relative intensity) 412 (M + , 25) , 380 (32) , 365 (7) , 161 (36) , 150 (66) , 135 (20) , 133 (19) , 131 (21) , 121 (27) , 119 (46) , 118 (100) . Exairple 10 Alkylation of lc to Id: Methylmagnesium bromide (O -gBr, 2.8 M solution in ether; 20 equivalent) was added to a stirred solution of the ketone lc (R-=isobutyl, Z=methyl) in ether (0.5 ml) at room teπperature under nitrogen. The mixture was heated at reflux overnight, cooled, and treated with saturated aque αs amoronium chloride until a clear precipitate separated. The supernatant was then decanted, the precipitate was washed with fresh ether, and the combined ethereal solutions were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel using 30% ethyl acetate-hexane provided the tertiary alcohol Id (R =iscfoutyl, R 2 =_retbyl, X 3 =""H, Z=methyl) ; mass spectrum, m/e (relative intensity) 428 (M + , 21) , 410 (8) , 396 (7) , 381 (7) , 150 (46) , 135 (20) , 133 (26) , 131 (27) , 121 (26) , 119 (49) , 118 (75) . Exairple 11 Conversion of Id to 3_d and 4d: Treatment of compound Id (R-=isdbutyl, R^^^πe hyl, Z==-_rethyl) as obtained in Exairple 10 , with selenium, dioxide and tert-butyl l^droperoxide, under the coriditions described in Exairple 5, provides the corresponding 2d (R =isobutyl, R ==metbyl, X-^H, and Z=methyl) . Solvolysis of this material, followed by acyl hydrolysis and separation of cis and trans isαrers, as described in Exairple 6, gives coirpound 3d (R 1 =isobutyl, 2=--methyl, X^X^X^H and c rpσund Exairple 12 Conversion of ^c to 3c and 4c: Cαrpound lc (R-=iscbutyl, Z=methyl) as obtained in Example 9 is converted to the l__r-hydroxy derivative 2c (R-^isobutyl, γ=R, Z==methyl) under conditions analogous to those described in Exairple 2. Cαrpound 2c is solvolyzed using the conditions described in Exairple 3 to obtain in admixture the acetates 3c and Ac (where R =isαbutyl, X,=H, X =acetyl) . The acetates are hydrolyzed as described in Exairple 3 and the corresponding free hydroxy cαrpounds are separated by high performance liquid c-t-rαratography to obtain compound 3c Exairple 13 Reduction of 3a and 4a to 3b and 4b: Aldehyde 3a (X^X-sH) in diethyl ether was treated with an alcoholic solution of NaBH.. After 1 hr. the reaction π xture was worked up in the usual fashion, to obtain after thin layer chromatographic purification of the p-.od.uct, the 23-alcohol 3b (R-,=H, X^X^X^H) identical with the material obtained in Exairple 8. The exactly analogous reduction of the 5,6-trans-23-aldehyde 4a (X-^X^H) provides the 5 , 6-trans-alcohol of st__ucture 4b (R-,=H, -,-=X 2 -=X 3 =H) . Exairple 14 Alkylation of cαrpound 3a to 3b: A stirred solution of the aldehyde 3a (X.=X_=H) (1 equivalent) in ether (0.5 ml) was treated with etby-dragnesium bromide (CJEI ς MgBr, 2.8 M solution in ether; 20 equivalent) at room temperature under nitrogen for 4 hr. Saturated aqueous aimonium chloride was added drσpwise. The usual workup then gave the 23-alcohol (3b, R-=ethyl, X =X = =H) ; mass spectrum, m/e (relative intensity) 388 (M + , 11) , 370 (6) , 357 (3) , 152 (34) , 134 (100) .

Claims: Claims Cαrpounds selected from the group consisting of wherein 1^ and Ε are each selected f ran the group consisting of hydrogen and alkyl, and where X. , "X~, and X- are selected from the group rønsisting of hydrogen and acyl. 2. Cαtpounds according to Claim 1 wherein J and _ are both hydrogen. 3. A cctrpound according to Claim 2 wherein each of X, , X 2 and , is hydrogen. 4. Cαrpounds according to Claim 1 wherein each of R, and 1? is alkyl. 5. A cαrpound according to Claim 4 wherein R» and 2 are methyl and X-. ' , X~, X, are hydrogen. 6. C-C-ipounds according to Claim 1 wherein R. is alkyl and 2 is hydrogen. 7. Cαrpounds according to Claim 6 wherein R. is selected from methyl, ethyl, or propyl. 8. Compounds accθ-_ding to Claim 6 wherein -, is isobutyl. 9. 1 ,23-di_nyd_-θxyvitamin D 3 . 10. 1 ,23-dihydroxy-5,6-trans vitamin D_ 11. Compounds selected fran the group consisting of wherein Z is alkyl and each of X, and X 3 are hydrogen or acyl and where each of R, and R- is selected from the group consisting of hydrogen and alkyl. 12. Compounds according to Claim 11 where Z is irethyl. 13. Cαrpounds according to Claim 12 where R, and =^ are both hydrogen. 14. Cαrpounds according to Claim 12 where R- is alkyl and , is hydrogen. 15. Cαπpounds according to Claim 12 where R, and R2 are alkyl. 16. Cαrpounds selected frcm the group consisting of wherein Z is alkyl, X, is hydrogen or acyl and R. is hydrogen or alkyl. 17. Cαrpounds according to Claim 16 where Z is irethyl. 18. Cαrpounds according to Claim 17 where R, is hydrogen. 19. Cαrpσui-ds according to Claim 17 where R, is alkyl. 20. Cαrpounds according to Claim 19 where R. is isobutyl. - J EX; OMPI 21. Cαrpounds selected from the group consisting of wherein X. and S are hydrogen or acyl and , is hydrogen or alkyl. 22. Cαrpounds according to Claim 21 where R. is hydrogen. 23. Cαrpounds according to Claim 21 where R, is alkyl. 24. A c rpσund accoi-ding to Claim 22 where X. and X j are hydrogen. 25. A cαπpound according to Claim 23 where X- and X2 are hydrogen. 26. A process for preparing the corrpounds of Claim 1 which comprises subjecting a cyclovitamin D cαrpound having the formula wherein R_ is selected from hydrogen or alkyl and Z is alkyl to reduction with a hydride reducing reagent or to a reaction with an alkyl Grignard reagent, thereby cbtaining a cαrpound having the formula wherein each of R, and Ε is hydrogen or alkyl and Z is alkyl, subjecting said cαrpound, or, optionally, said 23-acylαxy derivative obtained by acylating said ccampound, to _tø-hydroxylation treatπent with Se0 2 and a hydroperσxide to obtain the corresponding - r-hydroxylated cαrpound, subjecting said l r-hydroxy derivative to solvolysis in a iredium containing an organic acid whereby the 5,6-cis and 5 , ' 6-trans cαrpcunds having the fori rαLa wherein R. and ^ have the meaning defined above, X, is hydrogen, X~ is acyl and X_ is hydrogen or acyl are obtained in admixture, separating said compounds and, optionally, either removing any acyl groups present to obtain the corresponding free hydroxy cαrpound, or, acylating free-hydroxy groups to obtain the cσ__responding acylσxy derivative. 27. The process of Claim 25 wherein acyl removal of any acyl groups precedes separation of the 5,6-cis and 5,6-trans compounds. 28. The process of Claims 25 wherein the lor-hydroxylation solvolysis is carried out prior to the reduction or Grignard-reaction step.

Inventors: DELUCA HECTOR F, LEE SEOK-HO, SCHNOES HEINRICH K, DELUCA, HECTOR, F., LEE, SEOK-HO, SCHNOES, HEINRICH, K.
Applicants: WISCONSIN ALUMNI RES FOUND, WISCONSIN ALUMNI RESEARCH FOUNDATION
Application year: 1984
Main classification: C07J9
IPC codes: A61K31, A61P3, C07C67, C07C401, C07J9