This invention relates to a hitherto unknown class of compounds which shows strong activity in inducing dif¬ ferentiation and inhibiting undesirable proliferation of certain cells, including cancer cells and skin cells, to pharmaceutical preparations containing these compounds, to dosage units of such preparations, and to their use in the treatment of diseases characterized by abnormal cell dif¬ ferentiation and/or cell proliferation.

The compounds of the invention constitute a novel class of vitamin D analogues and are represented by the general formula I

in which formula (and also throughout the remainder of this disclosure) X stands for hydrogen, lower alkyl, halogen or hydroxy; Y stands for hydrogen or hydroxy; R 1 and R2, which may be the same or different, stand for lower alkyl, option¬ ally substituted with halogen or hydroxy (but with the pro- viso that R 1 and R2 cannot both be methyl when X is other than lower alkyl), or, taken together with the carbon atom numbered 25, R 1 and R2 can form a saturated or unsaturated

C,-C _Q carbocyclic ring (including an aromatic ring) which may optionally be substituted at any possible position(s)

with lower alkyl, halogen or hydroxy; R stands for hydro- gen or lower alkyl ; R 4 and R5 represent either each hydro¬ gen, or when taken together constitute a bond, with the result that a double bond connects carbon atoms numbered 22 and 23; and the two undulated bonds to carbon 24 indi¬ cate that both R and S_ forms at this centre are within the scope of the invention. In the context of this invention the expression "lower alkyl" indicates a straight or bran¬ ched saturated or unsaturated carbon chain with a content of from 1 to 6 carbon atoms.

As it can be seen, the compounds of formula I, depen¬ ding on the meanings of R , R , R , R and R , and/or X, contain one or more additional asymmetric carbon atoms and/or double bonds, and may thus form stereoisomeric forms. The invention covers all these compounds in pure form and also mixtures of them. It should be noted, however, that our investigations indicate a notable difference in activ¬ ity between the stereoisomeric forms. In addition, deriva¬ tives of I in which one or more of the hydroxy groups are masked as groups which can be reconverted to hydroxy groups in vivo are also within the scope of the invention ("bio- reversible derivatives or pro-drugs of I")

Especially preferred are compounds of formula I in which Y is hydroxy and R stands for hydrogen or methyl, and in particular compounds in which R 4 and R5 taken to¬ gether represent a bond, especially in such a way that the resulting 22,23-double bond has the trans configuration. The term "bioreversible derivatives or prodrugs of I" includes, but is not limited to, derivatives of the com- pounds of formula I in which one or more hydroxy groups have been transformed into -O-acyl or -O-glycosyl groups, such masked groups being hydrolyzable _in vivo.

It has recently been shown that certain vitamin D deri¬ vatives, in particular 1 , 2-5 (OH) -.D-. ( lot,25-dihydroxy-vitamin D,) are able to stimulate the differentiation of cells and inhibit excessive cell proliferation, and it has been sug¬ gested that these compounds might be useful in the treat-

ment of diseases characterized by abnormal cell prolifera¬ tion and/or cell differentiation such as leukemia, myelo- fibrosis and psoriasis. However, the well known potent effects of these compounds on calcium metabolism prohibit the use of higher doses, which will give rise to hypercal- ce ia. Thus, these compounds are not completely satisfactory for use as drugs in the treatment of e.g. psoriasis or leukemia, which may require continuous administration of the drug in relatively high doses. It has now surprisingly turned out that the compounds of the invention have a favourable therapeutic index and are particularly useful in the treatment of human and vet¬ erinary disorders which are characterized by abnormal cell proliferation and/or cell differentiation, such as certain dermatological disorders including psoriasis and certain cancer forms, e.g. leukemia and myelofibrosis.

A number of cells, including skin cells and cancer cells, contain receptors for 1,25(OH)_.D- . The compounds of the invention have thus been tested in vitro for their ability to interact with the receptor in such cells, and for their effect on the proliferation and differentiation of such cells (e.g. the human monocytic tumour cell line U 937). I_n vivo, the compounds were tested after p.o. and i.p. administration to rats for effects on calcium meta¬ bolism. The compounds were compared with 1,25(OH)_D--.j.n the n vitro experiments and with let(OH)D.. and 1,25(OH)_D-. in the in vivo experiments.

From the above tests, it was shown that e.g. compound 59* binds strongly to the receptor and is a potent inhibitor of cell proliferation and inducer of cell differentiation in vitro. In vivo, compared to l,25(OH) ₂ D- and lα(OH)D ₃ , it showed only weak vitamin D activity and could be admini¬ stered at much higher doses without having any toxic effects. Thus, a favourable separation of the biological effect on cell differentiation/proliferation and on calcium meta-

* See Table 2

bolism has been clearly demonstrated.

Compound I can be prepared by total synthesis, or, more conveniently, by partial synthesis from readily avail¬ able precursors, either steroidal, for example dinorcholenic acid, ergosterol, stigmasterol, or seco-steroidal e.g. vitamin D ^' . The route described below by way of example utilises vitamin D_ as starting material, and is considered to be the most flexible of the routes explored to date, being very suitable for the synthesis of a large number of compounds represented by formula I. However, it should be noted that the synthesis of a particular compound on a pro¬ duction scale may well be more conveniently carried out from an alternative starting material and/or by an alternative route. Two such routes are outlined later on. The compound i can readily be obtained in crystalline form by crystalli¬ zation from common organic solvents or mixtures thereof, as well known in the art.

The synthetic strategy involves the modification of the ring D side chain present in the (seco-)steroidal pre- cursor to a lS _^ -formylethyl group followed by elaboration of the new side chain present in the particular target com¬ pound I. At some stage in the synthesis the rest of the full vitamin D skeleton must be elaborated. The way this is done in practice depends on the starting material and the new side chain in question, and in addition the order of some of the reaction steps can be altered with the result that not all the possible intermediates can be exemplified here. Furthermore, the nature of the various activating groups, protecting groups, and methods for masking the _ triene moiety can be different to those exemplified. How¬ ever, any such changes still fall within the scope of this invention.

One synthetic route will now be described in detail. In the reaction scheme, the triene moiety of the vitamin D nucleus is masked as the adduct with SO- (other dienophiles which can be used include for example 4-phenyl-l,2,4-triazol- ine-3,5-dione and phthalazine-1,4-dione, as known in the art) and the ring A hydroxyl groups are protected as tert-butyl-

dimethylsilyl (t-BuMe-Si) ethers (other suitable protecting groups are well known in the art and include the etherifying and esterifying groups e.g. as described in "Protective Groups in Organic Synthesis", T.W. Greene, Wiley, New York, 1981). The coupling of the aldehyde function with a side chain fragment is done at the 5 ,6-trans vitamin stage (other possibilities include the cis-vita in stage or masked triene stage, the requisite aldehyde being obtained by altering the order of reactions). The incorporation of the side chain fragment involves a Wittig reaction (other types of coupling, e.g. aldol reaction, or reaction with a sulphone anion, followed by elimination or reductive elimination, are well known in the art), the ylide being a triphenyl- phosphorane (other types of ylide being well known in the art). Finally, [X] represents either X of formula I, or a protected or masked derivative which can be converted to X at some stage in the synthesis (and not necessarily the last stage as indicated oτι the Scheme).

As shown on the Reaction Scheme which follows, the synthesis involves the preparation of the important key intermediate 12 which is used to prepare compounds of for¬ mula I in which Y stands for OH. The corresponding com¬ pound I in which Y = H is prepared analogously from 13. An alternative key intermediate is the corresponding 5 ,6-cis aldehyde 14, which can be used analogously to 13 or 12 in the subsequent step on the Scheme to give the cor¬ responding 5,6-cis isomer of II and hence III. Reaction h_ then converts these isomers directly to the corresponding V. The continuation of the synthesis after 12 or 13 (or 14) requires the reaction with a side chain fragment (D), the synthesis of which can be achieved for example by the fol¬ lowing route:-

Th side chain fragments shown in Table I are selected for the purposes of illustration and are described in the , Preparations.

Table I

Side Chain Fragment (D) X or [X]

D(i) -(CH ₂ ) ₂ - H

D(ii) -(CH ₂ ) ₄ - H

D(iii) -(CH ₂ ) ₅ - H

D(iv) CH. CH. CH.

D(v) =CH-(CH=CH)

The ketone A, if not commercially available, may -be * prepared by literature methods and is converted to the bromomethyl ketone B by literature methods. In some cases B are commercially available starting materials.

In the Preparations, the starting materials/inter¬ mediates A, B and C (if described) are also given corre¬ sponding suffixes (i) - (v) to indicate the nature of R ,

2 R and [X] (e.g. for the sequence A(i) → B(i) → C(i) -> D(i))

In order to describe -further the invention, but not in any way to limit it, the details for the synthesis of some particular examples of compounds of formula I are given,

For the purpose, the Reaction Scheme and Notes should be read with reference to Tables 1 and 2 and to the Prepa¬ rations and Examples.

Notes to Reaction Scheme

On the Scheme, Z' represents an optionally protected hydroxy group, and Z also represents an optionally protected hydroxy group (which maybe the same or different to Z ' ) unless it is stated that Z = H, in which case Z represents hydrogen.

For the specific numbered compounds described in Table 2 and in the Preparations and Examples, Z ¹ = t-BuMe-SiO, and Z = Z ¹ unless stated otherwise, which requires step "b" to be a tert-butyldimethylsilylation reaction e.g. with t-BuMe~SiCl - imidazole) and step "j" to be a de-tert- butyldimethylsilylation reaction (e.g. with n-Bu NF).

a. SO-; b. Optional hydroxyl protection reaction; c. NaHCO^ (boiling EtOH); d-. SeO- - N-methylmorpholine N-oxide (MeOH-CH C1-) ; e. (i) 0- (ii) PPh ; f. Side chain frag¬ ment D (see Table 1); g. 1 ,4-Reduction under suitable conditions with a selective reducing agent, e.g. Na-S-O. under phase transfer conditions; h. Formal source of

"R 3 (^) " - when R3 = H; e.g. NaBH. or other reducing agent; when R = alkyl, e.g. Grignard or other organo- metallic reagent. A radiolabel can be conveniently introduced at this stage by using a suitable source of radioactive R ³ (e.g. for R ³ = ³ H or ¹⁴ CH ) ; i. hX - triplet sensitizer; j. Optional hydroxyl deprotection reaction(s) ; k. Any necessary reaction (sequence) for converting [x] to X.

Reaction Scheme

less polar isomer: _1 more polar isomer: 2

Reaction Sch

Table 2

Compounds Indicated on the Reaction Scheme and/or Referred to by Number in the Preparations and Examples

Table 2 continued

Notes. (a) Where "bond" appears in the last column, the trans configuration of the 22,23-double bond is to be understood; (b) Each formula I, IV, V, VI and

VIII (and IX and XI, see later) represents two sep- arate numbered compounds. These differ only in their absolute configuration at C-24. In the Prep¬ arations and Examples, no attempt has been made to identify these configurations, but it is clearly indicated which of the two isomers is concerned in relative terms by differentiating unambiguously between their physical and/or spectroscopic prop¬ erties (when possible) and/or by correlation with a particular starting material.

The compounds I may also be synthesized from ster¬ oidal precursors. Such an approach is illustrated in the conversion of the compound VΙI(a) or VΙI(b) (both available from dinorcholenic acid acetate) into the "pre-vitamin" VΙII(a) or VΙII(b), respectively, as outlined below:-

VIII (a) Y=0H VIII (b) Y=H

Side Chain Fragment (D) (see text) (dimethyl sulphoxide, 100°C);

(ii) N-bromosuccinimide (CC1., reflux);

(iii)(a) Bu ₄ NBr, then (b) Bu ₄ NF (tetrahydrofuran ⁽ THF ⁾ , 20°C); (iv) 4-Phenyl-l,2,4-triazoline-3,5-dione (CHC1-, 20°C);

(v)* Na ₂ S ₂ O ₄ /(C ₁₀ H ₂₁ ) ₃ NMeCl/NaHCO ₃ PhH-H*O reflux); either (vi) ⁺ NaBH ₄ /C Cl ₃ (THF-MeOH, 0°C) (for R ⁵ = H); or (vii) ⁺ R ³ MgBr or R ³ Li (THF, -10°C ^{) (} for R ³ - ^c _n ^H 2n+l _• n = 1-6); (viii) LiAlH (THF, reflux);

(ix) Irradiation with medium-pressure Hg lamp through a Vycor filter (PhH~EtOH, 0°C)

* If step (v) is included, the compounds VIII having R =

R = H are produced; if step (v) is omitted, the com- pound VIII having R 5, R4 = bond .(trans) are produced.

+ Chromatographic separation of C-24 epimers may be conve¬ niently effected after stage (vi) or (vii).

The pre-vitamin VIII may be partially converted to the corresponding compound I by keeping in an inert solvent (e.g. ether, ethanol or benzene, or a mixture) at ^" a temperature from about 0°C to 100°C, preferably from about 20°C to about 80°C until equilibrium is reached or until an acceptable, less complete, conversion has been achieved (e.g. from two weeks at 20°C to a few minutes at 80°C). This equi¬ libration may also be performed on a hydroxy-protected deri- vative of VIII, such as an acylated or trialkylsilylated derivative to give the corresponding derivative of I which is converted to I by conventional deprotection reaction(s).

Implicit in the routes to the compound I illustrated heretofore is the key reaction establishing the 24-hydroxy group from a 24-oxo compound. The reactions exemplified all give rise to a mixture of diastereoisomers at this centre, which means that a separation step is required unless ^' the particular compound I can be administered as a mixture. However, biological results have shown that of a pair of C-24 diastereoisomeric compounds I, one isomer is normally more active than the other. It is therefore

advantageous to increase the proportion of the intermediate having the C-24 configuration corresponding to the more active compound I. This is possible by using a diastereo- selective organometallic reagent (for R = alkyl) or reduc- ing agent (for R = H) . Methodology for the latter, reduct¬ ive, reaction especially is now highly developed, and is particularly well applicable to compounds in which the 22,23- double bond is present in the 24-oxo intermediate.

Thus, the proportion of for example either compound IV (see Reaction Scheme) in the mixture, obtained by reducing compound II or III, can be increased by the use of for ex¬ ample the one or the other antipode of a chiral reducing agent. Examples of this type or reaction are reviewed for example in "Asymmetric Synthesis" , ed. J.D. Morrison, Academic Press, London, Volume 2, 1983.

An alternative practical approach to an efficient reduction process is to recycle the undesired C-24 isomer (either in essentially puxe form or admixed -with smaller amounts of the desired isomer) after separation of either essentially all or just some of the desired isomer. This recycling is achieved by a mild oxidation back to the 24-oxo compound. For example, either compound 26 or 27 (or a mix¬ ture) is readily reconverted to 16 by reaction with active manganese dioxide. it should be noted however that a minor amount of the less active C-24 isomer of I in admixture with the more active isomer does not interfere with the efficacy of the formulated drug.

A second alternative synthesis of compound I is illu- strated in the coupling of an optionally hydroxy-protected form of the "top-half" fragment IX of the molecule with the anion derived from the protected "bottom-half" fragment X to give XI, followed by conventional deprotection step(s) and any necessary modification of [x],

IX X

In formulae IX, X and XI, Z' is protected OH, e.g. t-BuSiMe-O; Z is either H or protected OH, e.g. t-BuSiMe_0; W is either

? ^c ~ OH or protected OH, e.g. t-BuSiMe-O; and [x] is either X of formula I or a group which can be converted to X.

The present compounds are intended for use in pharma¬ ceutical compositions which are useful in the treatment of human and veterinary disorders which, as mentioned above,

30 are characterized by abnormal cell-proliferation and/or differentiation.

The amount required of a compound of formula I (here¬ inafter referred to as the active ingredient) for therapeutic effect will, of course, vary both with the particular com-

35 pound, the route of administration and the mammal under treat¬ ment. The compounds of the invention can be administered

by the parenteral, enteral or topical routes. They are well absorbed when given enterally and this is the preferred form of administration in the treatment of systemic disorders. In the treatment of dermatological disorders like psoriasis, topical forms like ointments, creams or lotions are preferred, In the treatment of systemic disorders daily doses of from 1-1000 μg, preferably from 2-250 μg, of a compound of for¬ mula I are administered. In the topical treatment of der¬ matological disorders, ointments, creams or lotions contain- ing from 1-1000 μg/g, and preferably from 10-500 μg/g, of a compound of formula I are administered. The oral compo¬ sitions are formulated, preferably as tablets, capsules, or drops, containing from 0.5-500 μg, preferably from 1-250 μg, of a compound of formula I, per dosage unit. While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. Conveniently, the active ingredient -compr-ises from 1 ppm to 0.1%.by weight of the formulation. By the term "dosage unit" is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, re¬ maining as a physically and chemically stable unit dose com¬ prising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers. The formulations, both for veterinary and for human medical use, of the present invention comprise an active ingredient in association with a pharmaceutically, acceptable carrier therefor and optionally other therapeutic ingre- dient(s). The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the for¬ mulations and not deleterious to the recipient thereof.

The formulations include e.g. those in a form suit¬ able for oral, rectal, parenteral (including subcutaneous, intramuscular and intravenous), and topical administration. The formulations may conveniently be presented in

dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingre¬ dients. In general, the formulations are prepared by uni- formly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a sus¬ pension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emul¬ sion. The active ingredient may also be administered in the form of a bolus, electuary or paste.

A tablet may be made by compressing or moulding the . active ingredient optionally with one or more accessory in- gredients. Compressed tablets may be prepared by compres¬ sing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixedv. with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding, in a suitable machine, a mixture of the pow¬ dered active ingredient and a suitable carrier moistened with an inert liquid diluent.

Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.

Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient.

Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments,

lotions, applications; oil-in-water or water-in-oil emul¬ sions such as creams, ointments or pastes; or solutions or suspensions such as drops.

In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavour¬ ing agents, binders, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.

The compositions may further contain other therapeut- ically active compounds usually applied in the treatment of the above mentioned pathological conditions.

The invention will now be further described in the following non-limiting Preparations and Examples:

Preparations and Examples. General.

The compounds referred to in the Preparations and Examples are to be identified by number (Compounds 15*-73 via Table 2) with the corresponding formulae in the Reac- tion Scheme or elsewhere in which Z'=t-BuMe-SiO, and Z=Z' unless otherwise stated.

For ^' -the cognate Preparations and Examples, only dif¬ ferences in the procedure and the new data are noted.

Analytical thin layer chromatography (TLC) was per- formed on Merck plates pre-coated with silica gel 60 F--.- The approximate Rf values quoted are only meant to be used for distinction in relative terms between pairs of isomers. Analytical high-performance liquid chromatogra¬ phy was performed on Lichrosorb Si 60 normal phase column (4 mm i.d. x 25 cm) at a flow rate of 3.5 ml/min. with 2% methanol in dichloromethane as eluant. The quoted reten¬ tion times, T _R , are used only for distinction in relative terms between pairs of isomers, and are not necessarily exactly reproducible. Nuclear magnetic resonance (NMR) (<5) spectra were run at 100 MHz for solutions in CDC1- using either TMS (<5 = 0) or CHC1-. (δ = 7.25) as internal stan¬ dard. Coupling constants are given in Hertz and are ap¬ proximated to the nearest unit. Mass spectra m/z) were run at 70 eV and only the highest mass signal and base peak are quoted. Organic solutions were dried over dried mag¬ nesium sulphate.

Preparation 1. Compound 5_ (via Compounds 1_ and/ or 2_, 3_' ^an< ^ i. ⁾ Vitamin D- (12.5 g) was dissolved in liquid SO-

(50 ml) and the mixture stirred under reflux for 30 min. The SO- was distilled off, and the residue was dried in vacuo to give a foam. This was dissolved in N,N-dimethyl- formamide (100 ml), and imidazole (4.5 g) and tert-butyl- dimethylsilyl chloride (5 g) were added. The mixture was stirred under N- for 90 min. and then partitioned between ethyl acetate and water. The organic layer was

washed with water, dried and concentrated to give a mix¬ ture of 1. and 2 as a crystalline solid which was tritu¬ rated with ethanol, filtered off, and dried _. in vacuo. A portion of the mixture was separated by chromato- graphy (silica; 30% ether in petroleum ether as eluant) to give pure 1_, less polar isomer, needles (from dichloro- methane-ethanol ) , δ 0.06 (6 H, s), 0.67 (3 H, s), 0.88 (9 H, s), 1.03 (3 H, d, J 7Hz) , 3.64 (2 H, broad s), 4.0

(1 H, m), 4.4-4.8 (2 H, 2 broad d, J 10 Hz) and 5.2 (2 H, m) ; m/z 510 M ⁺ -S0 ₂ ) and 119, and pure 2_, more polar isomer, needles (from dichloromethane-ethanol ). δ 0.06 (6 H, s), 0.58 (3 H, s), 0.88 (9 H, s), 1.03 (3 H, d, J 7Hz) , 3.65 (2 H, broad s), 3.95 (1 H, m), 4.5-4.9 (2 H, 2 broad d, J 10 Hz), and 5.2 (2 H, m) ; m/z 510 (M ⁺ - S0 ₂ ) and 119] The product (the pure isomers can also be used se¬ parately) was suspended in 96% ethanol (25Q ml) and sodium hydrogen carbonate (20 g) added. The stirred mixture was heat-ed under reflux for 100 min under N _~ , cooled, partial¬ ly concentrated iri vacuo, and partitioned between ethyl acetate and water. The organic layer was washed with water, dried and concentrated to give 3 , δ 0.07 (6 H, s), 0.57 (3 H, s), 0.88 (9 H, s), 1.02 (3 H, d, J 6 Hz), 3.85 (1 H m), 4.64 (1 H, broad s), 4.91 (1 H, broad s), 5.2 (2 H, m), 5.85 (1 H, d, J 11 Hz), and 6.47 (1 H, d, J 11 Hz) . This was dissolved in dichloromethane (160 ml) con¬ taining dried N-methyl morpholine N-oxide (15 g). The stirred solution was heated under reflux under N- and a solution of selenium dioxide (3 g) in methanol (160 ml) was added rapidly. Heating under reflux was continued for 50 min. before the reaction mixture was cooled, diluted with more dichloromethane, washed with water, dried and concentrated to give 4, of sufficient purity for use in the next stage. Q_n analytical sample was obtained after chromatography (silica gel; 15% ether in petroleum ether as eluant), λmax (EtOH) 270 nm; δ 0.07 (6 H, s), 0.57

(3 H, s), 0.87 (9 H, s), 1.02 (3 H, d, J 7 Hz), 4.2 (1 H, m) _. 4.5 (1 H, ), 4.94 (1 H, broad s), 5.06 (1 H, broad s),

5.2 (2 H, m), 5.86 (1 H, d, J 11 Hz), and 6.51 (1 H, d, J

11 Hz).] This ¹ was dissolved in N,N-dimethylformamide (80 ml ) _r and imidazole (3.8 g) and tert-butyldimethylsilyl chloride

(4.5 g) was added. The mixture was stirred under N- for

90 min. and then partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, dried and concentrated to give a crystalline solid which was purified by chromatography on silica (eluting with 2% ether in petroleum ether) followed by recrystallisation from ether-ethanol to g ^ive -5 as colourless needles,"Amax

(EtOH) 270 nm; δ 0.07 (12 H, s), 0.57 (3 H, s), 0.88 (9 H, s), 0.91 (9 H, s), 1.03 (3 H, d, J 7), 4.22 (1 H, broad s). 4.54 (1 H, broad dd, J 5 and 9 Hz), 4.97 (2 H, m), 5.20 (2 H, m), 5.82 (1 H, d, -J 11 Hz), and 6.47 (1 H, d, J 11 Hz); m/z 640 (M ⁺ ) and 248.

Preparation 2: Compounds 6_ and 7_

5_ (4.0 g) was dissolved in diethyl ether (10 ml) and liquid S0-. (50 ml) and the mixture was stirred under re¬ flux for 30 min. The SO- and ether were distilled off, and the residue was dried in vacuo to give white needles, showing two spots on thin layer chromatography (silica; 10% ether in petroleum ether as eluant) corresponding to 6_ (Rf ca. 0.25) and 7_ (Rf ca. 0.1). (Found: C, 67.97;

H, 1 ⁰ .26 ^; S, 4.37. ^C 4o ^H 72°4 ^{S Si} 2 ^rec 3 ^{uires C} ' 68.12 ^; H,

10.29; S, 4.55%); v>max (CHC1-3) 1310 and 1160 cm ^"1 ; δ 0.05 (12 H, broad s), 0.57 and 0.65 (3 H, 2 s), 0.87 (9 H, s), 0.8.8 (9H, s) _. 3.4-4.1 (2 H, broad ABq, J 16 Hz), 4.17 (1 H, m), 4.35 (1 H, m) 4.7 (2 H, m) and 5.2 (2 H, m) . Pure 6_ and 7_ were separated from a sample of the mixture by chromatography )silica; 20% ether in petroleum ether as eluant): 6_, δ 0.65 (3 H, s) and 4.67 (2 H, m) ; 7_, δ 0.57 (3 H, s) and 4.5-4.9 (2 H, 2 br d, J 10).

Preparation 3: Compounds j3 and 9_

The mixture of 6_ and 7_ from Preparation 2 (4.4 g) was dissolved in dichloromethane (120 ml) and methanol (40 ml). The stirred solution was cooled to -60°C and trea- ted with ozonised oxygen until TLC showed essentially com¬ plete consumption of starting materials. The solution was then purged with N- and triphenyl phosphine (2.5 g) was added. After warming slowly to room temperature, the reaction mixture was diluted with more dichloromethane, washed with water, dried and concentrated. The residue was purified by chromatography (silica gel; 30% ether in petroleum ether as eluant). 8_ and 9_ can be collected se¬ parately or, more conveniently, as a mixture, which crystallises and was used directly in Preparation 6. The data refer to the separated isomers. First eluted was — 8, obtained as white need.les; max (CHCl3,) 1720 (alde- hyde), 1310 and 1160 cm ; δ 0.06 (12 H, broad s), ^' θ.70 (3 H, s), 0.87 and 0.88 (18 H, 2 s), 1.13 (3 H, d, J 7Hz), 3.45-4.1 (2 H, broad AB q, J 16 Hz), 4.2 (1 H, m) , 4.35 (1 H, m), 4.7 (2 H, m) , and 9.58 (1 H, d, J 3 Hz). Se¬ cond elut,ed was —9, max (CHCl3,) 1720 (aldehyde), 1310 and

1160 cm ^" ; δ 0.07 (12 H, broad s), 0.61 (3 H, s), 0.88 and 0.89 (18 H, 2 H), 1.14 (3 H, d, J 7 Hz), 3.45-4.1 (2 H, broad AB q, J 16 Hz), 4.15 (1 H, m), 4.4 (1 H, m), 4.5-4.95 (2 H, 2 broad d, J 10 Hz), and 9.57 (1 H, d, J

3 Hz) . It should be noted that the use of the pure iso¬ mers 6_ and 7_ separately as starting materials in this Preparation gives respectively 8 _^ and 9_ free from the other isomer.

Preparation 4: Compound 1_0

The use of compound 1_ (from Preparation 1) (3.6 g) as starting material instead of 6_ and/or 7_ in Prepara¬ tion 3, but using 50% ether in petroleum ether as eluant for the chromatography step, gave 1_0, δ 0.04 (6 H, br s),

0.70 (3 H, s), 0.86 ( 9 H, s), 1.13 (3 H, d, J 7), 3 63 (2 H, br s), 4.0 (1 H, m), 4.4-4.85 (2 H, 2 br, d, J 10) and 9.58 (1 H, d, J 3) .

Preparation 5 : Compound 11

The use of compound 2_ (from Preparation 1) (3.5 g) as starting material instead of 6_ and/or 7_ i- Prepara¬ tion 3, but using 50% ether in petroleum ether as eluant for the chromatography step, gave 1_1_, δ 0.04 (6 H, br s), 0.60 (3 H, s), 0.87 (9 H, s), 1.14 (3 H, d, J 7), 3.65 (2 H, br s), 4.0 (1 H, m), 4.5-4.95 (2 H, 2 br d, J 10) and 9.56 (1 H, d, J 3) .

Preparation 6 : Compound 1_2_ The mixture of 8_ and 9_ from Preparation 3 (the pure isomers may also be used separately, but there 'is no ad¬ vantage in separating them since both give 1_2 on elimina¬ tion of S0-) (1.12 g) was suspended in 96% ethanol (50 ml) and sodium hydrogen carbonate (2 g) added. The stirred mixture was heated under reflux under N_ for 100 min. , cooled, partially concentrated in vacuo, and partitioned between ethyl acetate and water. The organic layer was washed with water, dried, and concentrated to give Y2_ of sufficient purity for subsequent use. An analyti- ^■'■ " cal sample was obtained after chromatography (silica gel;

5% ether in petroleum ether as eluant) and crystallization from ethanol; needles ,, m.p. 113-5°C; Λ max (EtOH) 270 nm; » _aχ (CHC1-) 1720 era ^" (aldehyde); δ 0.08 (12 H, s), 0.61 (3 H, s), 0.88 and 0.92 (18 H, 2 s) 1.16 (3 H, d, J 7 Hz), 4.2 (1 H, m), 4.5 (1 H, m) , 4.98 (2 H, m) , 5.85 (1 H, d, j 11 Hz), 6.46 (1 H, d, J 11 Hz), and 9.60 (1 H, d, J 3 Hz), m/z 572 (M ⁺ ) and 248.

Preparation 7: Compound _. 13_

The use of compound 10 or U. (or a mixture) (0.9 g) as starting material instead of 8. and/or 9. in Preparation 6 gave L3, δ 0.06 (6 H, s), 0.61 (3 H, s), 0.88 (9 H, s), 1.14 (3 H, d, J 7), 3.85 (1 H, m) , 4.65 (1 H, br s), 4.91 (1 H, br s), 5.88 (1 H, d, J 11), 6.48 (1 H, d, J 11), and 9.59 (1 H, d, J 3).

Preparation 8: Bromoacetylcyclopropane (B(i)) To a stirred, ice-cooled solution of acetylcyclopro- pane (A(i) ) (22 g) in methanol (150 ml) was added bromine (40 ) at such a rate that the temperature was maintained below 20°C. Stirring was then continued at room tempera¬ ture for 30 min. before water (75 ml) was added. After a . further 15 min. the mixture was diluted with water (225 ml) and extracted with ether. The ether extracts were washed with saturated sodium carbonate solution, water, and dried. After removing the solvent n vacuo, the re¬ sidue was distilled to give B(i) , b.p. 71-73°C/13 mmHg, δ 0.9-1.3 (4 H, m) , 2.05-2.35 (1 H, m) and 4.02 (2 H, s).

Preparation 9: Cyclopropylcarbonylmethyltriphenyl- phosphonium bromide (C(i) )

Starting material (B(i) ) , and triphenylphosphine were mixed in equimolar amounts and allowed to react spon¬ taneously. The resulting solid cake was dissolved in di¬ chloromethane and treated with ether to precipitate pure C(i) as colourless needles, m.p. 204-205°C, δ 1.02 (4 H, m), 2.75 (1 H, m), 5.89 (2 H, d, J 12 Hz), and 7.45-8.0 (15 H, m) .

Preparation 10: Cyclopentylcarbonylmethyltriphenyl- phosphonium bromide (C(ii) )

Method: as Preparation 9; starting material: bromo- acetylcyclopentane (B(ii)).

Preparation 11: Cyclohexylcarbonylmethyltriph'enyl- phosphonium bromide (C(iii) ) .

Method: as Preparation 9; Starting material: Bro o- acetylcyclohexane (B(iii) ) ; Data: m.p. 244-7°C.

5 Preparation 12: Pivaloylmethyltriphenylphospho- nium bromide (C(iv) ) .

Method: as Preparation 9; Starting material: Bromome- thyl tert—butyl ketone (B(iv) ) , Data: m.p. 234-7°C.

10 Preparation 13: Phenacylmethyltriphenylphosphonium bromide (C(v) ) .

Method: as Preparation 9; Starting material: phe- nacyl bromide (B(v) ) ; Modification: B(v) and triphenyl- phosphine were predissolved and combined in toluene solu- •* 15 tion with stirring. After the spontaneous reaction,

C(v) was filtered off and washed with ether; Data: m.p. > 260°C.

Preparation 14: Cyclopropylcarbonylmethylenetri- 20 phenylphosphorane (D(i) ) .

Starting material (C(i) ) (3 g) was dissolved in di¬ chloromethane (30 ml), and the solution was extracted- with sodium hydroxide solution (2 N, 20 ml ) . The organic layer was washed with water, dried and concentrated _in vacuo to 2 .give a product which was purified by recrystallisation from dichloromethane-acetone to give D(i) as needles, m.p. 181-182°C, δ 0.60- (2"H, _o) , 0.85 (2 H, m), 1.75 1 H, m) , 3.77 (1 H, br d, J 26) and 7.1-7.8 (15 H, m) .

30 Preparation 15: Cyclopentylcarbonylmethylenetri- phenylphosphorane (D(ii) ) .

Method: as Preparation 14; Starting material: C(ii) ; Data: m.p. 159-60°C, δ 1.3-2.0 (8 H, m) , 2.75 (1 H, m) , 35 3.7 (1 H, d, J 27) and 7.2-7.8 (15 H, m) .

Preparation 16: Cyclohexylcarbonylmethylenetri- phenylphosphorane (D(iii) ) .

Method: as Preparation 14? Starting material: C(iii) ; -Data: m.p. 159-61°C, δ 1.0-2.45 (11 H, m) , 3.65 (1 H, m), and 7.2-7.9 (15 H, m) .

Preparation 17: Pivaloylmethylenetriphenylphos- phorane (D(iv) )

Method: as Preparation 14; Starting material: C(iv) : Data: m.p. 182-3°C, δ 1.20 (9H, s), 3.78 (1 H, d, J 27) and 7.2-7.8 (15 H, m).

Preparation 18: Phenacylmethylenetriphenylphos- phorane (D(v) ) .

Method: as Preparation 14;. Starting material: C(v) ; Modification: recrystallisation from dichloromethane-ether; Data: m.p. 183-4°C, δ 4.41 (1 H, d, J 25) and 7.2-8.0 (20H, m) .

Preparation 19: Compound 16.

A solution stirred under N_ of the aldehyde _12_ (0.93 g) and the phosphorane D(i) (1 g) in dimethyl sul- phoxide (20 ml) was heated at 95°C for 90 min. then 105°C for 120 min. After cooling, the reaction solution was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, dried, and concen- trated iri vacuo to give a residue which was purified by chromatography (silica gel; 10% ether in petroleum ether as eluant) to give 1_6_, colourless plates (from ether- methanol ) , m.p. 122-123°C; _{mra ^} (EtOH) 270 nm, δ 0.06 (12 H, s), 0.59 (3 H, s), 0.87 and 0.90 (18 H, 2 s), 1.13 (3 H, d, J 7), 4.2 (1 H, m) , 4.5 (1 H, m) , 4.96

(2 H, m), 5.8 (1 H, d, J 11 Hz), 6.14 (1 H, d, J 16 Hz), 6.45 (1 H, d, J 11 Hz), and 6.78 (1 H, dd, J 9 and 16 Hz); m/z 638 (M ⁺ ) and 248.

Preparation 20: Compound 15.

Method: as Preparation 19; Aldehyde: 1_3_ (1.06 g); Phosphorane: D(i) (1.64 g); Data: δ 0.06 (6 H, s)., 0.60 (3 H, s), 0.88 (9 H, s), 1.13 (3 H, d, J 7), 3.85 (1 H, m), 4.65 U H, br s), 4.92 (1 H, br s), 5.85 (1 H, d, J 11), 6.14 (1 H, d, J 16), 6.47 (1 H, d, J 11) and 6.78 (1 H, dd, J 9 and 16).

Preparation 21 : Compound 17

Method: as Preparation 19; Aldehyde: _12 _^ (1.62 g); Phosphorane: D(ii) (2.60 g); Reaction conditions: 16 h at 110°C; Chromatography eluant: 5% ethyl acetate in pe¬ troleum ether; Data: δ 0.06 (12 H, s), 0.58 (3 H, s), 0.87 and 0.90 (each 9 H, s), 1.1 .(3 H, d, J 7), 4.2 (1 H, m), 4.5 (1 H, m) , 4.96 (2 H, m) , 5.81 (1 H, d, J 11) 6.44 (1 H, d, J 11) and 6.79 (1 H, dd, J 9 and 15).

Preparation 22: Compound 18.

Method: as Preparation 19; Aldehyde: 1_2 (1.0 g); Phosphorane: D(iii) (1.3 g); Reaction conditions: 4 h at 100°C followed by 2 h at 110°C; Chromatography elu¬ ant: 5% ethyl acetate in petroleum ether; Data: δ 0.06 (12 H, s), 0.58 (3 H, s), 0.87 and 0.90 (each 9 H, s), 1.1 (3 H, d, J 7), 4.2 (1 H, m), 4.5 (1 H, m) , 4.96' ^" (2 H, m). 5.81 (1 H, d, J 11), 6.44 (1 H, d, J 11) and 6.79 (1 H, dd, J 9 and 15) .

Preparation 23: Compound 19.

Method: as Preparation 19; Aldehyde: 1_2 (1.1 g); Phosphorane: D(iv) (2.1 g); Reaction conditions: 16 h at 110°C ; Chromatography eluant: 5% ether in petroleum ether; Data: δ 0.06 (12 H, s), 0.58 (3 H, s), 0.87 and 0.90 (each 9 H, s), 1.10 (3 H, d, J 7), 1.15 (9 H, s), 4.2 (1 H, m) , 4.52 (1 H, m), 4.96 (2 H, m) , 5.81 (1 H, d, J 11), 6. ^* 40 (i H, d, J 15), 6.44 (1 H, d, J 11), and 6.80 (1 H, dd, J 9 and 15) .

Preparation 24: Compound 20.

Method: as Preparation 19; Aldehyde: 1_2 (0.96 g); Phosphorane: D(v) (1.86 g); Reaction conditons: 16 h at 110°C; Chromatography eluant: 5% ether in petroleum ether; Data: δ 0.07 (12 H, s), 0.56 (3 H, s), 0.87 and 0.90 (each 9 H, s), 1.17 (3 H, d, J 7), 4.2 (1 H, m) , 4.55 (1 H, m) , 4.97 (2 H, m), 5.82 (1 H, d, J 11), 6.45 (1 H, d, J 11), 6-.87 (2 H, m), 7.5 (3 H, m) and 7.9 (2 H, m) .

Preparation 25: Compound 21.

A mixture of ljj (200 mg), sodium hydrogen carbonate (0.5 g), sodium dithionite (Na-S-0.) (0.5 g), and methyltri- decylammonium chloride (0.05 g) in toluene (10 ml) and water (10 ml) under nitrogen was stirred vigorously at 80°C for i h and then 85°C for 30 min. After cooling, the reaction mixture was partitioned between ether and water, and the organic layer was washed with water, dried and concentrated' in vacuo. The residue was purified by chromatography on silica gel (eluant: 10% ether in petroleum ether) to give 21, colorle _s ₁ s p ^c lates (from ether-methanol ) ; m.p. 93-94°C, v max

1700 cm ^" ; δ0.06 (12 H, s), 0.55 (3 H, s), 0.87 and 0.90

(each 9 H, s), 4.2 (1 H, m), 4.5 (1 H, m). 4.96 (2 H, m), 5.82 (1 H, d, J 11) and 6.45 (1 H, d, J 11); m/z 640 (M ⁺ ) and 248.

Preparation 26: Compounds 24 and 25.

An ice-cooled, stirred solution of 2_1_ (225 mg) in te- trahydrofuran (3 ml), wa.s diluted with methanol (8 ml ) and treated with sodium borohydride (140 mg) portionwise over 5 min. After a further 10 minutes, the reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water, dried, and concen¬ trated in_ vacuo. The residue was crystallised from ether- methanol to give 2_4 and 2. as needles. 2Λ_ and 2_5 have es- sentially superimposable NMR-spectra:

δ 0.06 (12 H, s), 0. 5.-0.65 (4 H, m), 0.55 (3 H, s), 0.86 and 0.90 (each 9 H, s), 4.2 (1 H, m) , 4..55- (1 H, m) , 4.96 (2 H, m),.5.81 (1 H, d, J 11.5) and 6.46 (1 H, d, J 11.5).

Preparation 27: Compounds 26 and 27.

To an ice-cooled, stirred solution of starting mate¬ rial 1_6_ (100 mg) in tetrahydrofuran (10 ml) under nitrogen was added sodium bis(2-methoxyethoxy)aluminium hydride (70% solution in toluene) dropwise until TLC showed essentially complete consumption of starting material. The reaction mixture was then partitioned between ethyl acetate and sodi¬ um hydroxide solution (I N), and the organic layer was washed with water, dried, and concentrated. The residue was puri- fied by chromatography (silica gel; 10% ethyl acetate in pe- troleum ether as eluant) to give the title compounds. First eluted isomer was 2_6, δ 0.06 [ 12 H, s), 0.15-0.65 (4 H, m), 0.57 (3 H, s), 0.87 and 0.90 (18 H, 2 s), 1.05 (3 H, d, J 7 Hz), 3.45 (1 H, m), 4.2 (1 H, m) , 4.55 (1 H, m) , 4.96 (2 H, m), 5.51 (2 H, m), 5.82 (1 H, d, J 11 Hz) and 6.47 (1 H, d, j il Hz). This was followed by the more polar isomer 27, δ 0.06 (12 H, s), 0.15-0.65 (4 H, m) , 0.57 (3 H, s), 0.87 and 0.90 (18 H, 2 s), 1.05 (3 H, d, J 7 Hz), 3.45 (1 H, m) , 4.2 (1 H, m), 4.55 (1 H, m) , 4.96 (2 H, m) , 5.47 (2 H,..m), 5.82 (1 H, d, J 11 Hz) and 6.47 (1 H, d, J 11 Hz). fit is notable that a characteristic difference in the position and pattern of the two proton muliplet δ ca.. 5.5 in the NMR spectra is observed for each of the pairs of 24-epimers _. 26/27, .38/3_9, 5_4/55 and 58/53.] 2_6 and 27_ were each ob¬ tained as needles from petroleum ether-methanol, m.p. 117- 118°C and 122-123°C, respectively.

Preparation 28: Compounds 26 and 27 (alternative method)•

An ice-cooled, stirred solution of starting material 16 (0.82 g) in tetrahydrofuran (1 ml) was diluted with 0.4 N

CeCl-_.6H-0 in methanol (4 ml ) and further with methanpl (2 ml), and treated with sodium borohydride (0.15 g), por- tionwise over 5 min. After a further 10 min., the reaction mixture was partitioned between ethyl acetate and water and the organic .layer was washed with water, dried, and concen¬ trated iri vacuo. The residue was purified as described in Preparation 27, to give separately crystalline 2_6 and 27.

Preparation 29: Compounds 22 and 23

Method: as Preparation 27; Starting material: 15; Data: 2_2 (less polar isomer), δ 0.07 (6 H, s), 0.57 (3 H, _s ), 0.15-0.65 (4 H, m), 0.88 (9 H, s), 1.05 (3 H, d, J 7), 3.45 (1 H, m), 3.85 ( 1 H, m) , 4.64 (1 H, broad s), 4.91 (1 H, broad s) 5.50 (2 H, m), 5.85 (1 H, d, J 11) and 6.47 (1 H, d, j 11); 2_3 (more polar isomer), £ _> 0.07 (6 H, s), 0.57 (3 H, s), 0.15-0.65 (4 H, m), 0.88 (9 H, s), 1.05 (3 H, d, J 7), 3.45 (1 H, m), 3.85 (1 H, m),. 4.64 (1 H, broad s), 4.91 (1 H,* broad s), 5.46 (2 H, m), 5.85 (1 H, d J 11) and 6.47 (1 H, d, J 11).

Preparation 30: Compounds 2_8_ and 29.

Method as Preparation 28; Starting material: 1_7 (0.65 g); Data: 2_8_ (less polar isomer) ;needles (from ether- methanol); δ 0.06 (12 H, s), 0.56 (3 H, s), 0.87 and 0.90 (each 9 H, s), 1.04 (3 H, d, J 7), 3.81 (1 H, m) , 4.2 (1 H, m), 4.55 (1 H, m), 4.96 (2 H, m), 5.46 (2 H, m) , 5.82 (1 H, d, J 11) and 6.45 (1 H, d, J 11); 2_9 (more polar isomer); needles (from ether-methanol); δ 0.06 (-12 H, s) , 0.56 ( 3 H, s), 0.87 and 0.90 (each 9 H, s), 1.05 (3 H, d, J 7), 3.78 (1 H, m), 4.2 (1 H, m), 4.55 (1 H, m), 4.96 (2 H, m) , 5.42 (2 H, m), 5.82 (1 H, d, J 11) and 6.45 (1 H, d, J 11).

Preparation 31: Compounds 30 and 31.

Method: as Preparation 28; Starting material: 1_8. (0.6 g); Data: .30 (less polar isomer); Needles (from me- thanol), m.p. 107-108°C; δ 0.06 (12 H, s), 0.56 (3 H, s), 0.87 and 0.90 (each 9 H, s), 1.05 (3 H, d, J 7), 3.75 (1 H,

m i.), 4.2 (1 H, m), 4.55 (1 H, m), 4.96 (2 H, m) , 5.44 (2 H, m i!), 5.81 (1 H, d, J 11) and 6.45 (1 H, d, J 11); 31_ (more polar isomer); needles (from methanol ) , m.p. 85-86°C; δ

0.06 (12 H, s), 0.56 (3 H, s), 0.87 and 0.90 (each 9 H, s), 1.05 (3 H, ^* d, J 7), 3.73 (1 H. m) , 4.2 (1 H, m) , 4.55 (1 H, m), 4.96 (2 H, m), 5.41 (2 H, m) , 5.81 (1 H, d, J 11), and

6.45 (1 H, d. J 11) .

Preparation 32: Compounds 3_2_ and 3_3_

Method: as Preparation 28; Starting material: 1? (0.5 g); Data: _3__ (less polar isomer); needles (from metha¬ nol); δ 0.06 (12 H, s), 0.57 (3 H, s), 0.87 (9 H, s), 0.90 (18 H, s), 1.05 (3 H, d, J 7), 3.7 (1 H, m) , 4.2 (1 H, m) , 4.55 (1 H, m), 4.96 (2 H, m) , 5.48 (2 H, m) , 5.82 (1 H, d, j il) and 6.45 (1 H, d, J 11); _33_ (more polar isomer); needles (from methanol); δ 0.06 (12 H, s), 0.57 (3 H, s), 0.87.(9 ^' H, s),0.90 (1-^ H, s). 1.05 (3 H, d, J 7), 3.65 (1 H, m), 4.2 (1 H, ), 4.55 (1 H, ), 4.96 (2 H, ) , 5.45 (2 H, m), 5.82 (1 H, d, J 11) and6.45 (1 H, d, J 11).

Preparation 33: Compounds 3_4_ and 35.

Method: as Preparation 28; Starting material: 20_

(197 mg); Modification: only 2 ml of CeCl-. solution used;

Data: 34 (less polar isomer; δ 0.06 (12 H, s), 0.57 (3" H, — s), 0.87 and 0.91 (each 9 H, s), 1.06 (3 H, d, J 7), 4.2

(1 H, m), 4.55 (1 H, m) , 4.96 (2 H, m) , 5.16 (1 H, m) , 5.63

(2 H, m), 5.81 (1 H, d, J 11), 6.46 (1 H, d, J 11) and 7.34

(5 H, m) ; 35. (more polar isomer); δ 0.06 (12 H, s), 0.55

(3 H, s), 0.87 and 0.91 (each 9 H, s), 1.08 (3 H, d, J 7), 4.2 (1 H, m). 4.55 (1 H, m) , 4.96 (2 H, m). 5.16 (1 H, m) ,

5.61 (2 H, m), 5.81 (1 H, d, J 11), 6.46 (1 H, d, J 11) and

7.34 (5 H, m) .

Preparation 34: Compounds 3j6 and 37. A stirred solution of 1_6 (146 mg) in tetrahydrofuran (4 ml ) under nitrogen was cooled to about -20°C and treated

dropwise with methyl-lithium (ca. 1 M solution in ether) until- TLC showed essentially complete consumption of star¬ ting material. The reaction mixture was then partitioned between ether and water and the organic layer was washed with water, dried, and concentrated. The residue was cry¬ stallised from ether-methanol containing a trace of triethyl- amine to give 3_6 and 3_7 as needles. Compounds 3_6_ and 3J7 have essentially superimposable NMR spectra: δ 0.06 (12 H, s), 0.15-0.65 (4 H. m), 0.56 (3 H, s), 0.87 and 0.90 (each 9 H, s), 1.03 (3 H, d, J 7), 1.27 (3 H, s), 4.2 (1 H, m), 4.55 (1 H, m), 4.96 (2 H, m) , 5.31 (1 H, d, J 16), 5.54 (1 H, dd, J 7, 16), 5.81 (1 H, d, J 11) and 6.46 (1 H, d, J 11).

Preparation 35: Compound 1^ (from recycling of 26 and 27) .

A solution of either 2_6_, ^7, or a mixture of these two compounds (0.5 g) in dichloromethane (30 ml) was stirred under nitrogen at room temperature with active manganese dioxide (4.0 g) for 6 h. The reaction mixture was filtered, concentrated and the residue purified as in Preparation 19 to give crystalline 16.

Preparation 36: Compound 38. A solution of starting material 2_6_ (21 mg), anthracene (4 mg) and triethylamine (1 drop) in toluene (5 ml) under N- in a Pyrex flask was irradiated with light from a high pres¬ sure ultra-violet lamp, type TQ 150Z2 (Hanau) at room tem¬ perature for 100 min. The solution was filtered, concen- trated _in vacuo and the residue purified by chromatography (silica gel; 15% ethyl acetate in petroleum ether as eluant) to give 38., δ 0.06 (12 H, s), 0.15-0.65 (4 H, m), 0.55 (3 H, s), 0.88 (18 H, s), 1.05 (3 H, d, J 7 Hz), 3.5 (1 H, m), 4.2 (1 H, m), 4.35 (1 H, m) , 4.85 (1 H, m) , 5.17 (1 H, m) , 5.50 (2 H, m), 5.99 (1 H, d, J 12 Hz) and 6.24 (1 H, d, J 12 Hz).

It should be noted that in the eluant system specified,-above, 38 is less polar than and distinguishible on TLC from 39.

Preparations 37-51: Compounds 39 - 53. Using the method of Preparation 36, the following starting materials IV (20-30 mg) were converted to the cor¬ responding products V, which were each purified by chromato¬ graphy using the eluant system specified (the entry in the 'Eluant' column indicates the percentage of the more polar component of either an ethyl acetate (EtOAc) or ether (Et-0) in petroleum ether mixture) :-

Prepar¬

V IV Eluant Data (for V) aattiioonn

³⁷ _1 27 15% EtOAc δ 0.06 (12 H, s), 0.15-

0.65 (4 H, m), 0.55 (3 H _. s), 0.88 (18 H, s), 1.05(3H, d, J 7), 3.45(1 H, m), 4.2 (1H, m), 4.35 (1 H, m) , 4.85 (1H, m), 5.17 (1 H, m) , 5.46 (2H, m) , 5.99 (1 H, d, J 12) and 6.24 (1 H d, J 12).

38 40 22 15% EtOAc δ 0.06 (6 H, s), 0.15-0. _.. 65

(4 H, m), 0.56 (3 H, s), 0.89 (9 H, s), 1.05 (3 H, d, J 7) , 3.5 (1 H, m), 3.85 (1 H, m) - 4.8 (1 H, m) , 5.0 (1 H, m) , 5.50 (2 H, m) and 6.1 (2 H, ABq, J 11) .

39 41 23 15% EtOAc δ 0.06 (6 H, s), 0.15-0.65

(4 H, m), 0.56 (3 H,s) ,

0.89 (9 H, s), 1.05 (3 H, d,

J 7), 3.45 (1 H, m), 3.85 (1 H, m), 4.8 (1 H, m) , 5.0 (1

H, m) , 5.47 (2 H, m) and 6.1 (2 H, ABq, J 11).

Prepar- _{y ιγ E} ι _{uant Data} (for V) ation

40 ____ ____ ° ^{% Et} 2° ^δ °- ^{06 (12 H} ' ^s) ' °- ^{55 (3 H} ' s), 0.88 (18 H, s), 1.04 (3 ^' . H, d, J 7), 3.81 (1 H, m) ,

4.2 (1 H, m), 4.35 (1 H, m) ,

4.85 (1 H, m) , 5.45 (2 H, m) ,

5.99 (1 H, d, J 12) and 6.24

(1 H, d, J 12). 41 4 2_9 10% Et ₂ 0 δ 0.06 (12 H, s), 0.55 (3H, s) , 0.88 (18 H, s) , 1.04 (3

H, d, J 7) , 3.78 (1 H, m) ,

4.2 (1 H, m) , 4.35 (1 H, m) ,

4.85 (1 H, m) , 5.41 (2 H, m) , 5'.99 (1 H, d, J 12) and 6.24 .

(1 H, d, J 12) .

42 4_4 2 ^{10% Et} 2° ^δ °- ^{06 (12 H} ' ^s) ' °' ^{55 (3 H} '

^{* '} s) , 0.88 (18 H, s) , 1.04

(3 H, d, J 7) , 3.75 (1 H, m) , . 4.2 (1 H, m) , 4.35 (1 H, m) ,

4.86 (1 H, m) , 5.16 (1 H, m) , 5.43 (2 H, m) , 5.99 (1 H, d,

J 12) and 6.24 (1 H, d, J 12)

43 45 31 10% Et ₂ 0 δ 0.06 (12 H, s), 0.55 (3 H, s) , 0.88 (18 H, s) , 1.04 ^" (3

H, d, J 7) , 3.73 (1 H, m) , 4.2 (1 H, m), 4.35 (1 H, m)., 4.86 (1 H, m) , 5.16 (1 H, m) , 5.41 (2 H, m) , 5.99 (1 H, d, J 12) and 6.24 (1 H, d, J 12)

44 ϋ 22 1° ^{% Et} 2° ^δ °- ^{06 (12 H} ' s ⁾ . 0.55 ⁽ 3 H, s) , 0.88 (18 H, s) , 0.90 (9 H, s) , 1.04 (3 H, d, J 7) , 3.67 (1 H, m) , 4.2 (1 H, m) , 4.35 (1 H, m) , 4.86 (1 H, m) , 5.16 (1 H, m) , 5.47 (2 H, m) , 5.99 (1 H, d, J 12) and 6.24 (1 H, d, J 12) .

Prepar¬

VI Eluant Data (for V) ation

45 47 33 10% Et ₂ 0 δ 0.06 (12 H, s) , 0.55 (3 H, s) , 0.88 (18 H, s) , 0.90 (9 H, s) , 1.04 (3 H, d, J 7), 3.63 (1 H, m) , 4.2 (1 H, m) , 4.35 (1 H, m) , 4.86 (1 H, m) , 5.16 (1 H, m) , 5.43 (2 H, m) , 5.99 (1 H, d, J 12), and 6.24 (1 H, d, J 12) .

46 48 34 10% Et ₂ 0 δ 0.08 (12 H, s) , 0.56 (3 H, s) , 0.90 (L8 H, s) , 4.2 (1 H, m), 4.4 (1 H, m) , 4.87 (1 H, m), 5.17 (2 H, m) , 5.61 (2 H, ' m) , 6.02 (1 H, d, J 11), 6.26 . (1H, d,J 11) and 7.34 (5 H,m)..

47 49 35 10% Et ₂ 0 δ 0.08 (12 H, s ^" ) , 0.56 (3 H, s) , 0.90 (18 H, s) , 4.2 (1 H, m) , 4.4 (1 H, m) , 4.87 (1 H, m), 5.17 2 H, m) , 5.59 (2 H, m) , 6.02 (1 H, d, J 11), 6.26 (1H, d,J 11) and 7.34 (5 H,m) .

48 50 24 30% Et 0 δ 0.06 (12 H, s) , 0.15-0.65 (4 H, m) , 0.54 (3 H, s) ^' , ^'* 0.88 (18 H, s) ,

4.18 (1 H, m) , 4.37 (1 H, m) , 4.86 (1 H, m) , 5.17 (1 H, m) , 6.00 (1 H, d, J 12) and 6.24 (1 H, d, J 12) .

49 51 25 30% Et ₂ 0 δ 0.06 (12 H, s) , 0.15-0.65 (4 H, m) , 0.54 (3 H, s) , 0.88 (18 H, s) ,

4.18 (1 H, m) , 4.37 (1 H, m) , 4.86 (1 H, m) , 5.17 (1 H, m) , 6.00 (1 H, d, J 12) and 6.24 (1 H, d, J 12).

Prepar¬

V VI Eluant Data (for V) ation

50 22. li 20% Et-0 δ 0.06 (12 H, s) , 0.15-0.65

5 • (4 H, m) , 0.55 (3 H, s) , 0.88 (18 H, S), 1.02 (3 H, d, J 7), 1.26 (3 H, s) , 4.2 (1 H, m) , 4.35 (1 H, m), 4.85 (1 H, m) , 5.17 (1 .H, m), 5.31 (1 H, d,

10. J 16), 5.54 (1 H, dd, J 7, 16),

5.99 (1 H, d, J 12) and 6.24 (1 H, d, J 12) . 51 21 11 20% Et ₂ 0 δ 0.06 (12 H, s), 0.15-0.65

(4 H, m) , 0.55 (3 H, s) , 0.88

15 (18 H, s) , 1.02 (3 H, d, J 7),'

1.26 (3 H. s) , 4.2 (1 H, m) , 4.35 (1 H, m) , 4.85 (1 H, m) , 5.17 (1 H, m), 5.31 (1 H, d, J 16), 5.54 (1 H, dd, J 7, 16),

20 5.99 (1 H, d, J 12) and 6.24

(1 H, d, J 12) .

25

30

5

Preparation 52: Compound 14a (Z=Z'^OSiMe-Bu ^" *-) .

Method: as Preparation 36; Starting material: 1_2 (28 mg); Modification: the triethylamine was omitted; Chromatography eluant: 5% ether in petroleum ether; δ 0.06 (1-2 H, s), 0.59 (3 H, s), 0.88 (18 H, s), 1.14 (3 H, d, J 7), 4.2 (1 H, m), 4.4 (1 H, m), 4.86 (1 H, m) , 5.17 (1 H, m) , 5.99 (1 H, d, J 12), 6.24 (1 H, d, J 12) and 9.58 (1 H, d, J 3) .

Preparation 53: Compound 14b (Z=H, '_.0SiMe-,Bu ) .

Method: as Preparation36 ; Starting material: 22 (24 mg); Modification: the triethylamine was omitted; Chromatography eluant: 5% ether in petroleum ether; δ 0.06 _^ (6 H, s). 0.60 (3 H, s),0.88 (9 H, s), 1.14 (3 H, d, J 7), . 3.85 (1 H, m), 4.78 (1 H, m) , 4.99 (1 H, m) , 6.1 (2 H, ABq, J 11) and 9.59 (1 H, d, J 3) .

Preparation 54: Compound 54♦

A solution of starting material 2_L (30 mg) and tetra- butylammonium fluoride (60 mg) in tetrahydrofuran (5 ml ) was heated at 60°C under N_ for 60 min. After cooling, the reac¬ tion solution was partitioned between ethyl acetate and 2% sodium hydrogen carbonate solution, and the organic layer was washed with water, dried and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate as eluant) to give —54, 'A max (EtOH) 265 nm, δ 0.15-0.65 (4 H, m.

0.58 (3 H. s), 0.8-1.1 (1 H, m) . 1.05 (3 H, d, J 7), 3.5 (1 H, m), 4.2 (1 H, m), 4.5 (1 H, m) , 4.97 (1 H, m) , 5.11 (1 H, m), 5.51 (2 H, m), 5.88 (1 H, d, J 11) and 6.57 (1 H, d, J 11) .

Preparation 55: Compound 55.

Method: as Preparation 54; Starting material: 2 (26 mg); A , I_,α_,X__ (EtOH) 265 nm, δ 0.15-0.65 (4 H, m) , 0.58 (3 H, s). 0.8-1.1 (1 H, m) , 1.05 (3 H, d, J 7), 3.45 (1 H,

m), 4.5 (1 H, m), 4.97 (1 H, m), 5.11 (1 H, m) , 5.48 (2 ^* H, m), 5.88 (1 H, d, J 11) and 6.57 (1 H, d, J 11).

Preparation 56: Equilibration of compounds 2 ^an< 73 • A ^b solution of £ (73 mg) in ethanol (20 ml) was heated under reflux under nitrogen for 40 min. After cooling, the solvent was removed in vacuo, and the residue purified by chromatography (silica gel, ethyl acetate as eluant) to return 2 followed by the more polar 22, δ 0.15-0.65 (4 H, m), 0.72 (3 H, s), 0.8-1.1 (1 H, m), 1.05 (3 H, d, J 7),

3.45 (1 H, m), 4.2 (2 H, m), 5.47 (3 H, m) and 5.83 (2 H, m).

Example 1 : (1 'E,3R,5 /7E,2QR)-9,10-seco-20-(3 ^l> - cyclopropyl-3'-hydroxyprop-1 '-enyl)-

3-hydroxypregna-5,7,10(19)-triene, isomer A (Compound 5_6_) .

A solution of starting material 4_0 (37 mg) and te- trabutylammonium fluoride (90 mg) in tetrahydrofuran

(4 ml ) was heated under reflux under N_ for 1 h. After cooling, the reaction solution was partitioned between ethyl acetate and 2% sodium hydrogen carbonate solution, and the organic layer was washed with water, dried and concentrated. The residue was purified by chromatography (silica gel; 50% ethyl acetate in petroleum ether as elu¬ ant) to give 56, (EtOH) 265 nm, δ 0.15-0.65 (4 H, m)

0.55 (3 H, s), 1.05 (3 H, d, J 7), 3.5 (1 H, m) , 3.94 (1 H, m), 4.81 (1 H, m), 5.02 (1 H, m) , 5.50 (2 H, m), 6.01 (1 H, d, J 11) and 6.24 (1 H, d, J 11).

Example 2: (1 'E,3R, 2 7E,20_R)-9,10-seco-20-(3 '- cyclopropyl-3'-hydroxyprop-1 '-enyl )- 3-hydroxypregna-5,7,10(19)-triene, isomer B (compound 57) .

Method: as Example 1; Starting material: 42 (40 mg); Data: _,_., (EtOH) 265 rim, δ 0.15-0.65 (4 H, m), 0.55 (3 H, s), 1.05 (3 H, d, J 7), 3.45 (1 H, m) , 3.94 (1-H, m), 4.81 (1 H, m), 5.02 (1 H, m), 5.47 (2 H, m) , 6.01 (1 H, d, J ID and 6.24 (1H, d, J 11).

Example 3: (1S,1 'E,3R,5 E,20R)-(9,10)-seco-20-

-(3 '-cyclopropyl-3*-hydroxyprop-1 '-enyl)- 1,3-dihydroxypregna-5,7,10(19)-triene, isomer A (compound 58) .

Method: as Example 1; Starting material: 21 (1 mg); Chromatography eluant: ethyl acetate; Data: T _R

10.4 min, 'Xmax (EtOH) 265 nm, δ 0.15-0.65 (4 H, m) , 0.56

(3 H, s), 0.75-1.1 (1 H, m) , 1.05 (3 H, d, J 7 Hz), 3.47, (1 H, m), 4.2 (1 H, ), 4.4 (1 H, m) , 4.99 (1 H, m) ,

5.31 (1 H, m), 5.50 (2 H, m) , 5.99 (1 H, d, J 11 Hz) and 6.36 (1 H, d, J 11 Hz); m/z 412 (M ⁺ ) and 134.

Example 4: Compound (alternative method)

A solution of 5_4_ (15 mg), anthracene (4 mg) and tri- ethylamine (20 mg) in toluene (5 ml ) under N- in a Pyrex flask was irradiated with light from a high pressure ultra¬ violet lamp, type TQ 150Z2 (Hanau) at room temperature for 100 min. The solution was concentrated n vacuo and the residue purified by chromatography (silica gel; ethyl acetate as eluant) to give 58.

Example 5: (IS,1 'E,3R,5 _> 7E,2OR)-(9,10)-seco-20- -(3 '-cyclopropyl-3 '-hydroxyprop-1 '- enyl )-1,3-dihydroxypregna-5,7,10(19)- . triene, isomer B (compound 59.) .

A solution of 22 ( 45 mg) and tetrabutylammonium fluoride (90 mg) in tetrahydrofuran (4 ml ) was heated under reflux under N- for 60 min. After cooling, the reaction solution was partitioned between ethyl acetate and 2% sodium hydrogen carbonate solution, and the orga¬ nic layer was washed with v/ater, dried and concentrated. The residue was purified by chromatography (silica gel; ethyl acetate as eluant) followed by crystallisation ^' -"from methyl formate to give ^as needles, m.p. 166-168 °C, R 9.2 min, ^Λ 1 max (EtOH) 265 nm, δ 0.15-0.65 (4 H, m) ,

0.56 (3 H, s), 0.75-1.1 (1 H, m) , 1.05 (3 H, d, J 7 Hz), 3.45 (1 H, m), 4.2 (1 H, m), 4.4 (1 H, m) , 4.99 (1 H, m), 5.31 (1 H, m), 5.47 (2 H, m) , 5.99 (1 H, d, J 11 Hz), and

6.36 (1 H, d, J 11 Hz); m/z 412 (M ) and 134

Example 6: Compound 2 (alternative method)

.A solution of 5_2 (15 mg) , anthracene (4 mg) and tri¬ ethylamine (20 mg) in toluene (5 ml ) under N- in a Pyrex flask was irradiated with light from a high pressure ultra-

violet lamp, type TQ 150Z2 (Hanau) at room temperature for 100 min. The solution was concentrated in. vacuo and the residue purified by chromatography (silica gel; ethyl acetate as eluant) to give 59.

Example 7: Compound 59 (alternative method).

A solution of 1 (125 mg) in ether (9 ml) was kept under nitrogen in the dark at about 20°C for 10 days. The solvent was removed 22. vacuo and the residue purified by chromatography (silica gel; ethyl acetate as eluant) fol- lowed by crystallisation from methyl formate to give 59.

Example 8: (IS,1 'E,3R,52/7E,20R)-(9,10)-seco-20-

-(3 -cyclopentyl-3'-hydroxyprop-1 '-enyl)-

1,3-dihydroxypregna-5,7,10(19)-triene, isomer A (compound 60!

Method: as Example 1; Starting material 4_2 (49 mg); Chromatography eluant: ethyl acetate; Data:A IT13.X

(EtOH) 265 nm; δ 0.56 ^' (3 H, s), 1.03 (3 H, d, J 7), 3.8 (1 H, m), 4.2 (1 H, m) , 4.4 (1 H, m) , 4.98 (1 H, m) , 5.31 (1 H, m), 5.45 (2 H, m) , 5.99 (1 H, d, J 12) and 6.36 (1 H, d. J 12); m/z 440 (M ⁺ ) and 134; T _R 8.2 min.

Example 9: (IS,1 'E,3R, 57 _L ,7E,20RH9,10)-seco-20- ^'

-(3'-cyclopentyl-3 '-hydroxyprop-1 '-enyl ) ^• l,3-dihydroxypregna-5,7,10(19)-triene, isomer B (compound 61).

Method: as Example 1; Starting material 21 (31 mg); Chromatography eluant: .ethyl acetate; Data:^ (EtOH) 265 nm; δ 0.55 (3 H, s), 1.03 (3 H, d, J 7), 3.77 (1 H, m), 4.2 (1 H, m) , 4.4 (1 H, m) , 4.98 (1 H, m), 5.31 (1 H, m), 5.41 (2 H, m) , 5.99 (1 H, d, J 12) and 6.36

(1 H, d, J 12); m/z 440 (M ⁺ ) and 134; 6.6 min.

R

Example 10 : ( 1 S , 1 ' E , 3R , 5^, 7E , 2QR ) - ( 9 , 10 ) -seco-20-

-(3 '-cyclohexyl-3 '-hydroxyprop-1 ' -enyl )- 1 , 3-dihydroxypregna-5,7,10(19)-triene, isomer A (compound 62). Method: as Example 1; Starting material: 4_4_

(40 mg); Chromatography eluant: ethyl acetate; Data: λ • I _* ϊ.lc_l-X,, (EtOH) 265 nm; δ 0.56 (3 H, s), 1.04 (3 H, d, J 7),

3.75 (1 H, m), 4.2 (1 H, m) , 4.4 (1 H, m) , 4.98 (1 H, m) , 5.31 (1 H, m), 5.43 (2 H, m), 5.99 (1 H, d, J 12), 6.36 (1 H, d, J 12); m/z 454 (M ⁺ ) and 134; T _R 7.2 min.

Example 11: (1S,1 'E, 3R, 52 E,20R)-( 9, 10)-seco-20-

-( 3 ^• -cyclohexyl-3 ' -hydroxyprop-1 ' -enyl )- 1 , 3-dihydroxypregna-5,7,10(19 )-triene, isomer B (compound 63 ) .

Method: as Example 1; Starting material: 4J5 (41 mg); Chromatography eluant: ethyl acetate; Data: 1 , _v (EtOH) 265 nm; δ 0.56 (3 H, s), 1.04 (3 H, d, J 7), 3.73 (1 H, m), 4.2 (1 H, m) , 4.4 (1 H, m) , 4.98 (1 H, m), 5.31 (1 H, m), 5.40 (2 H, m) , 5.99 (1 H, d, J 12), 6.36 (1 H, d, J 12); m/z 454 (M ⁺ ) and 134 ; T _α 5.8 min.

Example 12: (1S,1 'E, 3R,5Z, 7E, 2QR)-( 9, 10)-seco-20-

-(4 ' ,4 '-dimethyl-3 ' -hydroxybut-1 '-erryl )- 1 , 3-dihydroxypregna-5, 7, 10( 19 )-triene, isomer A (compound 64 ) .

Method: as Example 1; Starting material: 6_ (29 mg); Chromatography eluant: ethyl acetate; Data: T ₀ 8.2 min, λ (EtOH) 265 nm, δ 0.56 (3 H, s), 0.89 (9 H, s), 1.04 (3 H, d, J 7), 3.67 (1 H, m) , 4.2 (1 H, m) , 4.41 (1 H, m), 4.99 (1 H, br s), 5.31 (1 H, m) , 5.47 (2 H, m), 6.00 (1 H, d, J 11) and 6.37 (1 H, d, J 11).

Example 13: (IS,1 'E,3R,5 /7E ,20RJ-(9,10)-seco-io-

-(4' ,4'-dimethyl-3'-hydroxybut-1 '-enyl)- 1,3-dihydroxypregna-5,7,10(19)-triene, isomer B (compound 6_2) . Method: as Example 1; Starting material: 7_

(27 mg); Chromatography eluant: ethyl acetate; Data:

T_. 6.8 min, λmsx (EtOH) 265 nm, δ 0.56 (3 H, s), 0.88

(9 H, s), 1.04 (3 H, d, J 7), 3.63 (1 H, m) , 4.2 (1 H, m) , 4.40 (1 H, m), 4.99 (1 H, br s), 5.31 (1 H, m) , 5.43 (2H, m), 6.00 (1 H, d, J 11) and 6.36 (1 H, d, J 11).

Example 14: (IS, 1 'E,3R,5 7E,20R)-(9,10)-seco-20- -(3'-hydroxy-3-phenylprop-l '-enyl )- 1,3-dihydroxypregna-5,7,10(19)-triene, isomer A (compound 66) .

Method: as Example 1; Starting material: 43

(29 mg); Chromatography eluant: - ethyl acetate; Data:

T„R 8.2 min. ,λmax (EtOH) 265 nm, δ 0.56 (3 H, s), 1.04

(3 H, d, J 7), 4.2 (1 H, m), 4.40 (1 H, m) , 4.98 (1 H, m) , 5.12 (1 H, m), 5.31 (1 H, m) , 5.60 (2 H, m) , 6.00 (1 H, d, J 11), 6.36 (1 H, d, J 11) and 7.33 (5 H, m) .

Example 15: (IS,1 'E,3R,5 / E,20R)-(9,10)-seco-20- -(3'-hydroxy-3-phenylprop-l '-enyl. - 1,3-dihydroxypregna-5,7,10(19)-triene, isomer B (compound 67) .

Method: as Example 1; Starting material: 9

(42 mg) ; Chromatography eluant: ethyl acetate; Data:

T-R 7.2 min., λmax (EtOH 265 nm, δ 0.54 (3 H, s), 1.06 (3 H, d, J 7), 4.2 (1 H, m) , 4.42 (1 H, m) , 4.97 (1 H, m) , 5.13 (1 H, m), 5.30 (1 H, m) , 5.59 (2 H, m) , 5.99 (1 H, d, J 11), 6.36 (1 H, d, j ^' ll) and 7.33 (5 H, m) .

Example 16: (IS,3R,5 / E,2QR)-(9,10)-seco-20-(3 '- cyclopropyl-3'-hydroxypropyl )-1, 3-di- hydroxypregna-5,7,10(19)-triene, isomer A (compound 68) . Method: as Example 1; Starting material: 5_0 (40 mg); Chromatography eluant: ethyl acetate; Data: A _,_. (EtOH) 265 nm, δ 0.15-0..65 (4 H, m) , 0.54 (3 H, s), 0.93 (3 H, d, J 7), 4.2 (1 H, m) , 4.4 (1 H, m), 4.99 (1 H, m), 5.31 (1 H, m) , 5.99 (1 H, d, J 12) and 6.36 (1 H, d, J 12) .

Example 17: ( IS,3R,5 /7E,20R)-(9,10)-seco-20-(3'- cyclopropyl-3 '-hydroxypropyl )-l,3-di- hydroxypregna-5,7,10(19)-triene, isomer B (compound 69) .

Method: as Example 1; Starting material: 1 (22 mg) ; Chromatography eluant: ethyl acetate;

Datai λ , _. (EtOH) 265 nm, δ 0.15-0.65 (4 H, m) , 0.54 (3 H, s), 0.93 (3 H, d, J 7), 4.2 (1 H, m) , 4.4 (1 H, ), 4.99 (1 H, m) , 5.31 (1 H, m), 5.99 (1 H, d, J 12) and 6.36 (1 H, d, J 12) .

Example 18: (1S,1 'E, 3R, 5Z ,7E,20R)-(9, 10)-seco-20-

-(3 '-cyclopropyl-3 '-hydroxy-but-1 '-enyl )- 1,3-dihydroxypregna-5,7,10( 19)-triene, isomer A (compound 7_0) .

Method: as Example 1; Starting material: 2

(19 g); Chromatography eluant: ethyl acetate;

Data: λ (EtOH) 265 nm, δ 0.15-0.65 (4 H, m) , ' max 0.55 (3 H, s), 1.02 (3 H, d, J 7), 1.26 (3 H, s), 4.2

(1 H, m), 4.4 (1 H, m) , 5.31 (1 H, d, J 16), 5.31 (1 H, m), 5.54 (1 H, dd, J 7 and 16), 5.99 (1 H, d, J 12) and 6.36 (1 H, d, J 12) .

Example 19: (IS,1 'E,3 ,5jS,7E,20R)-(9,10)-seco-2Q-

-(3'-cyclopropyl-3 '-hydroxy-but-1 '-enyl)- 1,3-dihydroxypregna-5,7,10(19)-triene, isomer B (compound 71 ) .

Method: as Example 1; Starting material: 1 (17 mg); Chromatography eluant: ethyl acetate;

Data: λ______ (EtOH) 265 nm, δ 0.1-5-0.65 (4 H, ) ,

0.55 (3 H, s), 1.02 (3 H, d, J 7), 1.26 (3 H, s), 4.2

(1 H, m), 4.4 (1 H, m) , 5.31 (1 H, d, J 16), 5.31 (1 H, m), 5.54 (1 H, dd, J 7 and 16), 5.99 (1 H, d, J 12) and 6.36 (1 H, d, J 12) .

Example 20: Dermatological Cream Containing 59.

In 1 g almond oil was dissolved 1 mg 22.. To this solution was added 40 g of mineral oil and 20 g of self- - emulsifying beeswax. -The mixture was heated to liquify. After the addition of 40 ml hot water, the mixture was mixed well. The resulting cream contains approximately 10 μg of 59 per gram of cream.

Example 21 Capsules containing 59.

59 was dissolved in a triglyceride of a medium chain fatty acid to a final concentration of 50 μg 5 ^' 9Vml oil. 10 Parts by weight of gelatine, 5 parts by weight glycerine, 0.08 parts by weight potassium sorbate, and 14 parts by weight distilled water were mixed together with heating and formed into soft gelatine capsules. These were then filled each with 100 μl of the 2 in oil solu¬ tion, such that each capsule contained 5 μg 59.