Aziridines steroid

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. 

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... 

Aziridines can best be obtained by ring closure of amine derivatives which contain a tm 5-oriented leaving group at the -position, see (89). The variable conformational and steric influences in the steroid skeleton limit the generality of a particular synthetic method and necessitate a selection of reagents based on the position of fusion of the aziridine ring. 

Iodine isocyanate was used to synthesize the first steroidal aziridine, 2, 3 -iminocholestane (95). from 5a-cholest-2-ene (91). This reaction sequence which is believed to proceed through a three-membered ring iodonium ion (92) illustrates the limitation of pseudohalogen additions for the synthesis of -aziridines. The iodonium complex forms from the least hindered side (usually alpha) and is opened tmK5-diaxially to give a -oriented nitrogen function. The 3a-iodo-2 -isocyanate (93) is converted by treatment with... 

Iodine azide, on the other hand, forms pure adducts with A -, A - and A -steroids by a mechanism analogous to that proposed for iodine isocyanate additions. Reduction of such adducts can lead to aziridines. However, most reducing agents effect elimination of the elements of iodine azide from the /mwj -diaxial adducts of the A - and A -olefins rather than reduction of the azide function to the iodo amine. Thus, this sequence appears to be of little value for the synthesis of A-, B- or C-ring aziridines. It is worthy to note that based on experience with nonsteroidal systems the application of electrophilic reducing agents such as diborane or lithium aluminum hydride-aluminum chloride may yet prove effective for the desired reduction. Lithium aluminum hydride accomplishes aziridine formation from the A -adducts, Le., 16 -azido-17a-iodoandrostanes (97) in a one-step reaction. The scope of this addition has been considerably enhanced by the recent... 

A convenient route to steroidal aziridines from the diaxial IN3-olefin adducts, e.g., (99), which undergo elimination with lithium aluminum hydride, was developed by Galle and Hassner. Upon treatment with trialkyl phosphite, these adducts are converted to A-phosphorylated aziridines which are reduced by lithium aluminum hydride to the free steroidal aziridine. 

The properties of chlorine azide resemble those of bromine azide. Pon-sold has taken advantage of the stronger carbon-chlorine bond, i.e., the resistance to elimination, in the chloro azide adducts and thus synthesized several steroidal aziridines. 5a-Chloro-6 -azidocholestan-3 -ol (101) can be converted into 5, 6 -iminocholestan-3l -ol (102) in almost quantitative yield with lithium aluminum hydride. It is noteworthy that this aziridine cannot be synthesized by the more general mesyloxyazide route. Addition of chlorine azide to testosterone followed by acetylation gives both a cis- and a trans-2iddMct from which 4/S-chloro-17/S-hydroxy-5a-azidoandrostan-3-one acetate (104) is obtained by fractional crystallization. In this case, sodium borohydride is used for the stereoselective reduction of the 3-ketone... 

Many a,/ -unsaturated keto steroids undergo conjugate addition and thereby provide a unique route to aziridines. Treatment of 3j5-hydroxypregna-5, 16-diene-20-one acetate (48) with methoxyl-or ethoxylamine in ethanol under... 

The photolytic and thermolytic decomposition of azides in the presence of olefins has been applied to aziridine synthesis. However, only a limited number of steroid aziridines have been prepared in this manner. The patent literature reports the use of cyanogen azide at ca. 50° for 24 hours in ethyl acetate for the preparation of an A-nor- and a B-norsteroidal aziridine. The addition is believed to proceed via a triazoline. The reaction of cholest-2-ene with ethyl azidoformate takes place in a nonselective manner to produce a mixture of substances, including C—H insertion products. 

The oxidation of certain steroidal <5,e-unsaturated amines with either N-chlorosuccinimide or lead tetraacetate yields bridged aziridines, see structure (117)... 

A number of nonfused steroidal aziridines have been synthesized. The reduction of the azirine (118) over a platinum catalyst yields the spiro aziridine (119). Several aziridine derivatives of the type (120) have been... 

Oxime 26 was prepared from 5,ll-dihydro-dibenzo[a,d]cyclohepten-10-one. The Hoch-Campbell reaction of 26 with 3-dimethylaminopropylmagnesium bromide produced aziridine 27 in 46% yield after acidic workup. Extension of the Hoch-Campbell reaction to steroids has also been reported. Thus, treatment of 3(3-hydroxy-5-pregnen-20-one oxime (28) with methylmagnesium iodide furnished a mixture of diastereomers, 20ot/20P,21-imino-20-methyl-5-pregnen-3P-ol (29) in a 50% combined yield and a 3 1 ratio. On the other hand, homo-adamantan-4-one oxime (30) was transformed to homo-adamantano[4,5-b]-2 -ethylaziridine (31) in 76% yield upon the action of... 

Navarro D, Ledn L, Chirino R, Fernandez L, Pestano J, Dlaz-Chico BN (1998) The two native estrogen receptor forms of 8S and 4S present in cytosol from human uterine tissues display opposite reactivity with tamoxifen aziridine and the estrogen response element. J Steroid Biochem Mol Biol 64 49... 

In this molecule only the bond between the steroid skeleton and the aziridine moiety can rotate freely. A molecular mechanics conformational analysis resulted in two low energy conformations (Fig. 9.4, see p. 264), both of which had almost identical potential energy, as calculated in the Tripos force field [10]. 

More recent developments in the field of the Pirkle-type CSPs are the mixed r-donor/ r-acceptor phases such as the Whelk-Of and the Whelk-02 phases.The Whelk-Of is useful for the separation of underiva-tized enantiomers from a number of families, including amides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes, ketones, carboxylic acids, alcohols and non-steroidal anti-inflammatory drugs.It has been used for the separation of warfarin, aryl-amides,aryl-epoxides and aryl-sulphoxides. The phase has broader applicability than the original Pirkle phases. The broad versatility observed on this phase compares with the polysaccharide-derived CSPs... 

Interestingly, Morrow et al. have reported that the steroidal 1-azirine (29) is hydrogenated to the aziridine (169) using platinum oxide.15,16... 

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