Steroid oxiranes

Oxiranes are more readily detected by infrared spectroscopy than aziridines and thiiranes. Bands for steroid oxiranes appear consistently either between 800-900 cm or 1035-1050 cm h The oxirane band at 1250 cm is not... 

A review of the IR frequencies of the three-membered heterocycles is found in Katritzky and Ambler. The IR frequencies were more recently studied by Potts. " George recorded the IR spectra of 16 straight-chain oxiranes for analytical purposes and reported their refractive indices too. IR (4000-200cm" ) and Raman spectra have been taken in the solid and the liquid phases for the conformational examination of alkyl-substituted oxiranes. Studies have been made of the steric structure of oxirane-carboxaldehydes and the low-temperature oxidation of cyclohexene in the presence of Co" chelates. Analyses have been carried out on the IR spectra of oxiranes in the region of 850 cm" and the vibrational energy levels. Steroid oxiranes have likewise been subjected to IR investigation. Hirose published the rotational spectra of 10 oxiranes together with their evaluation and, in conjunction with the microwave spectra, determined thero,r, andr, structures of the compounds. 

New results have likewise been reported on the acid-catalyzed rearrangement of steroid oxiranes. " Three different types of rearrangements are depicted in Eqs. 136-138. A new fragmentation is observed and isopropyl group migration occurs besides the oxirane -> carbonyl isomerization (Eq. 136). ... 

On the action of BF3, a steroid oxirane undergoes rearrangement to a tetrahydro-furan. 7-Lactones are formed from oxirane by nucleophilic ring-opening (Eqs. 192-194). ° ... 

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). ... 

The process in Eq. 315, the transformation of a steroid oxirane with acetic acid or benzoic acid, is regio- and stereoselective. ... 

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 most important oxirane, from an anthropocentric viewpoint, is probably squalene oxide (72), a precursor of lanosterol (73) and thus of the maligned but essential cholesterol (74 Scheme 87) 78MI50501). The cyclization of (72) to (73) represents nucleophilic tr-attack on oxirane carbon cf. Section 5.05.3.4.3(t)()), and the process has also been extensively investigated in vitro (68ACR1). Oxiranes are even more ubiquitous in steroid biosynthesis than had been thought, for a cholesterol epoxide has been shown to be a product of mammalian steroid biosynthesis <81JA6974). 

This chapter will deal exclusively with three-membered rings containing the hetero atoms O, S and N, and fused to the steroid skeleton. Because of the conformational requirements in steroids, not all of the usual methods of synthesis of three-membered rings are applicable to the fused ring system. For the synthesis of steroids to which an aziridine, oxirane or thiirane is attached either in the side chain or at a ring position but not directly fused to the nucleus, the methods discussed in this chapter, as well as others, are applicable. 

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. 

Several steroid olefins, especially A -steroids, do not give exclusive a-epoxidation. The a-oxirane usually predominates in the epoxidation mixture, its proportion varying from 50% to 90% or greater when either perbenzoic acid or monoperphthalic acid is employed. The claims that the ratio of a- to p-epoxide is high in compounds containing a keto group d or a j5-substituent at may be misleading since epoxidation of 17a,20 20,... 

However, suitably located hydroxyl and acetoxyl functions can assist the cisoid approach of the peracid reagent. While 4jS-acetoxycholest-5-ene gives a 9 1 ratio of the a- and jS-epoxides, the 4a-acetoxy-5-ene yields the a-epoxide exclusively. The directive effect can be used to prepare and /9-oxiranes from A -steroids as illustrated by the epoxidation of (16) and (18). 

For steroids bearing two trisubstituted double bonds, such as A - and 11 -dienes, e.g. (35), the 5,6-oxirane is formed preferentially. The 9(ll)-double bond in -dienes, e.g. (38), is usually attacked first by... 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

The procedure involving a-halo ketone intermediates has been used for the synthesis of 11, 12 - and oxiranes of 5a-steroids... 

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. °... 

Although steroidal spiro oxiranes are difficult to obtain stereochemically pure by peracid epoxidations of exocyclic methylenes,the recently developed methylene transfer reagents, dimethylsulfonium methylide and di-methylsulfoxonium methylide in tetrahydrofuran, proved useful in the stereoselective transformation of steroid ketones to a- and -oxiranes, (87) and (88), respectively. ... 

In nuclear magnetic resonance (NMR) spectra the protons of the oxirane ring are usually shifted out of the steroid methylene envelope. Tori et al have tabulated the relationships of the angular methyl proton resonances and the oxirane proton signals with respect to location and configuration of the oxirane group. 

The effect of an a-substituted oxirane group on the optical rotatory dispersion of steroidal ketones should be interpreted with caution an inverted octant rule for a-epoxy ketones has been proposed/although recent data indicate that the normal octant rule may still be valid. 

A variety of conditions has been used to prepare oxiranes from trans-hxomo-hydrins. In general, bromohydrins are heated in a solution of 5-10% methanolic potassium hydroxide for 30 min to 8 hr. Longer reflux times are required for bromohydrins which are not anti-coplanar, e.g., diequatorial bromohydrins. A 5 % solution of potassium acetate in boiling ethanol can be used to cyclize steroidal bromohydrins containing base sensitive groups. The use of 1.1 equivalents of sodium methoxide per equivalent of steroid in methanol solution is especially recommended for 9a-bromo-l lj5-hydroxy steroids. 

Acyl-oxirane der Steroid-Reihe werden bei 0° im wesentlichen zu /3-Hydroxy-keto-nen reduziert4 ... 

The tetracyclic alcohol 179 is produced by the action of boron trifluoride etherate or tin(IV) chloride on the oxirane 178 (equation 85)95. A similar cyclization of the oxirane 180 yields DL-<5-amyrin (181) (equation 86)96. In the SnCLt-catalysed ring-closure of the tetraene 182 to the all-fraws-tetracycle 183 (equation 87) seven asymmetric centres are created, yet only two of sixty-four possible racemates are formed97. It has been proposed that multiple ring-closures of this kind form the basis of the biosynthesis of steroids and tetra-and pentacyclic triterpenoids, the Stork-Eschenmoser hypothesis 98,99. Such biomimetic polyene cyclizations, e.g. the formation of lanosterol from squalene (equation 88), have been reviewed69,70. 

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). 

An alternative route to such 6-(l-hydroxyalkyl)-substituted pteridines including 106 is from 2,4,5-triamino-6-butoxypyrimidine 107 and 2-formyloxiranes 108 in which the stereochemical properties are emphasized by the inclusion of the 17-steroidal ester <1992S303>. L-Biopterin 106 was synthesized from the oxirane 108 and 107 via a 5,6-dihydropteridine intermediate which was oxidized in situ to afford the product (Scheme 21). Syntheses of oxiranes and the condensation mechanism in the context of molecular orbital calculations were discussed. The field has been reviewed <1998H(48)1255>. 

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