Steroid oxiranes reactions

Some deviations from this normal route which involves an oxirane intermediate occurred in sterically hindered ketones. For example, 2,2,6,6-tetramethyl-4-piper-idine underwent a-methoxylation (20%) [19], whereas cholestanone yielded a product of Favorski-type rearrangement [21], In 17-acetylated steroids the reaction with DIB-MeOH-KOH was normal but in 17-hydroxy-17-acetyl-steroids intramolecular cyclization occurred with formation of oxetanones [22] ... 

The role of steric factors has been examined in the opening of polyfluorinated oxiranes. Accounts have been given of the alcoholysis of steroid oxiranes and their transformation with phenol.The kinetics of the reactions of oxiranes with alcohols and phenols have been reported in a number of publications. The catalytic influence of transition metals has been examined. A secondary deuterium isotope effect has been studied in the course of methanolysis, and the solvent effect has been considered in reactions with phenols. ... 

The reactions can be performed more simply with hydrochloric acid and hydro-bromic acid. The reaction between terpene oxides and hydrochloric acid has been examined, for example, in the cases of p-mentadiene dioxide, a-3,4-epoxy-carane, and a-4,5-epoxycarane. Studies have been made of the reactions of steroid oxiranes with hydrochloric acid and hydrobromic acid. The acidic opening of compounds containing two oxirane rings can be carried out selectively and in good yield (Eq. 309). ... 

Ganem has described a novel allylic alcohol to haloepoxide transformation (26) (28) using t-butylhypochlorite as the oxidant. This is the first known case where anchimeric participation by the hydroxyhalonium ion, as in (27), is invoked. The reaction, which has an analogy with iodolactonization, is susceptible to conformational and stereochemical requirements, since the octalin (29) gave a low yield of (30). Mild conditions for the preparation of (mostly steroidal) oxirans... 

The reaction of vinyloxiranes with malonate proceeds regio- and stereose-lectively. The reaction has been utilized for the introduction of a 15-hydroxy group in a steroid related to oogoniol (265)(156]. The oxirane 264 is the J-form and the attack of Pd(0) takes place from the o-side by inversion. Then the nucleophile comes from the /i-side. Thus overall reaction is sT -StM2 type, in the intramolecular reaction, the stereochemical information is transmitted to the newly formed stereogenic center. Thus the formation of the six-membered ring lactone 267 from 266 proceeded with overall retention of the stereochemistry, and was employed to control the stereochemistry of C-15 in the prostaglandin 268[157]. The method has also been employed to create the butenolide... 

The high degree of stereoselectivity associated with most syntheses and reactions of oxiranes accounts for the enormous utility of these systems in steroid syntheses. Individual selectivity at various positions in the steroid nucleus necessitates the discussion of a collection of uniquely specific reactions used in the synthesis of steroidal epoxides. The most convenient and generally applicable methods involve the peracid, the alkaline hydrogen peroxide and the halohydrin reactions. Several additional but more limited techniques are also available. 

In general, epoxidation of steroids with trans-anti-trans ring fusions leads to exclusive formation of the a-oxirane. Steroid Reactions lists examples of exclusive a-epoxide formation from 2-, 4-, 6-, 7-, 8(9)-, 14-, 16- and 17(20)-unsaturated steroids. Further examples of a-epoxidation of steroid 1-enes, 3-enes, 8-enes, 9(ll)-enes, 8(14)-enes and 16-enes have been reported. The preferred attack by the reagent on the a-side of the steroid nucleus can be attributed to shielding of the -side of the molecules by the two angular methyl groups. 

In analogy with the peracid attack on steroidal double bonds, the formation of the bromonium ion, e.g., (81a), occurs from the less hindered side (usually the a-side of the steroid nucleus) to give in the case of the olefin (81) the 9a-bromo-l l -ol (82). Base treatment of (82) provides the 9 5,1 l S-oxide (83). Similarly, reaction of 17/3-hydroxyestr-5(10)-en-3-one (9) with A -bromosuccinimide-perchloric acid followed by treatment with sodium hydroxide and sodium borohydride furnishes the 3, 17 5-dihydroxy-5a,l0a-oxirane. As mentioned previously, epoxidation of (9) with MPA gives the 5, 10 -oxirane. °... 

The marked stereoselectivities and clean solid-state reactions of oxiranes were used for synthetic purposes in the steroid field. The stereospecifically obtained trans-chlorohydrins 147 ensue quantitatively from the crystalline 5a,6a-epoxides 146 with gaseous HCl [77]. Similarly, the crystalline 16a,17a-epoxide 148 reacts with gaseous HCl to yield exclusively the traws-chlorohydrin 149 which easily loses HCl to re-form the starting epoxide 148. Therefore, an equilibrium situation is reached in that case [77] (Scheme 16). 

The kinetics of the reaction of fert-BuOK with aryl-substituted oxiranes follow a linear Taft correlation. Steroid 5a,6a- and 5(3,6/3-oxiranes react with pyridine to give 97 (Eq. 113). ... 

Simple aliphatic oxiranes can be converted to fluorohydrin with hydrogen fluoride only with great difficulty, but the reaction can be carried out in systems with rigid conformations (e.g., steroids, 9,10-epoxydecalin). Good yields can be attained from cyclopentene and cyclohexene oxides with 42% pyridine-polyhydrogen fluoride and in a series of terpene oxides with an amine-hydrogen fluoride complex. ... 

Oxiranes yield oxazolines with nitriles in the presence of strong acids. The reaction proceeds with inversion, with complete stereospecificity. A new application of the Ritter reaction has been reported the opening of epimeric steroid-16,17-oxiranes in acidic medium with acetonitrile. The reactions of unsaturated hydroxynitriles formed from a-ethylenic oxiranes have been investigated. Numerous publications have appeared on the kinetics of reactions with carboxylic acids and their derivatives. ° ... 

Apparently contradictory results in the Tiffeneau-Demjanov expansion of ring have been only partially clarified from separate study of the epimeric 3-aminomethyl-3-ols (491) derived from 5a-cholestan-3-one, 17j5-hydroxy-5a-androstan-3-one, and the related trans-2-decalyl derivatives. The three reported products, the A-homo-3-one (492), A-homo-4-one (493), and the oxiran (494), are formed in differing proportions (Table 3). The same products arise from reaction between the 3-oxo-steroids and diazomethane it is clear from... 

The reaction between diazomethane and 3-oxo-steroids is catalysed by alu-mina. The 5 -3-ketone gave a 5 -A-homo-4-one, and the 5a-compound afforded an oxiran (50%) and A-homo-ketones. [The unusually high proportion of oxiran here, implying the intermediate with an equatorial diazomethyl group, probably results from an anti-conformation of the diazo- and hydroxy-groups... 

The next step in the biosynthesis of steroids features an unusual head-to-head coupling reaction of two famesol pyrophosphates (OPP, not shown in diagram) to afford the alicyclic triterpene squalene 3-1, a compound found in shark liver oil (Scheme 2.3). Note that this product is in fact symmetrical about the newly formed bond. The next reaction in the sequence, which has only recently been uncovered, comprises oxidation of the terminal double bond to an epoxide. Opening of the oxirane leads to a domino-like series of ring-closing reactions and also concomitant migration of methyl groups. This chain reaction can be, and in fact has been, duplicated in the laboratory in the absence of enzymes. This series of reactions leads to the hypothetical steroidal carbocation 3-2. 

Attempts to effect the direct addition of 2-lithio-l,3-dithian to 17-keto-steroids have met with limited success. On the other hand, reactions of 17-spiro-epoxides were found to provide convenient access to homopregnane derivatives. Whereas treatment of the 17-ketoandrostene (188) with dimethylsulphoxonium methylide gave an inseparable mixture of the two epimers (189) and (190), reaction of (188) with dimethylsuphonium methylide afforded exclusively the 17j3-oxiran (189) in high yield. Opening of the epoxide of (189) with 2-methyl-1,3-dithianyl anion proceeded smoothly to give the 17)S-hydroxy-dithian (191). 

Miscellaneous Reactions of Oxirans.—The first successful enzymatic cyclization of a non-natural squalene has been disclosed. (18Z)-Oxidosqualene (188), which does not possess the naturally occurring a -trans stereochemistry, was caused to cyclize, in the presence of 2,3-epoxysqualene sterol cyclase, to (205)-epinorlanosterol (189). The polyene oxide (190) underwent an uncommon tricyclization in CH2CI2 containing Bp3-OEt2 to form the cw-fused A/B-ring 18-nor-steroid (191) (25%) this compound was found to be identical with a material derived by treatment of a naturally occurring steroid with BF3. 

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