Steroids absolute configuration

Implicit ia the base names are the absolute configurations at carbons 8 and 12 and the iadicated numbering systems. Derivatives of these parent stmctures are named according to terpene and steroid nomenclature rules (see Steroids Terpenoids). The lengthy and awkward nature of the chemical abstract systematic nomenclature (12) for these compounds has resulted ia the development (13) and use of simplified nomenclature based on common names. 

If a molecule contains several asymmetric C atoms, then the diastereomers show diastereotopic shifts. Clionasterol (28a) and sitosterol (28b) for example, are two steroids that differ only in the absolute configuration at one carbon atom, C-24 Differing shifts of C nuclei close to this asymmetric C atom in 28a and b identify the two diastereomers including the absolute configuration of C-24 in both. The absolute configurations of carboxylic acids in pyrrolizidine ester alkaloids are also reflected in diastereotopic H and C shifts which is used in solving problem 54. 

The recently introduced lanthanide-induced shift (LIS) technique has also found useful application in configurational studies of sulfur compounds. For example, the absolute configurations of a new type of bridged steroidal sulfoxide 203, which is epimeric at sulfur, were... 

It must be stressed, however, that the methyl alkyl sulfoxide rule is not valid for alkyl benzyl and alkyl allyl sulfoxides (222-224), where the electronic, steric, and solvent effects exert influences on the chiroptical phenomena in a way that is difficult to rationalize. This rule was found to be satisfactory and was used for the assignment of absolute configurations of steroidal (200,201,225), penicillin (226), and amino acid (227-230) sulfoxides. 

The amplitude (A) of the exciton Cotton effect is inversely proportional to the square of the interchromophoric distance. Thus, weak exciton split Cotton effects are expected for remote dibenzoates. Nevertheless, exciton Cotton effects were used for the assignment of the configuration of dibenzoates in a steroidal skeleton separated by as many as seven or eight C—C bonds158. In one application, the absolute configuration of Wieland-Miescher ketone (—)-2 was established by the use of the dibenzoate chirality rule for the 4-bromobenzoylated derivatives of the epimeric 1,5-diols 3 and 4, obtained by reduction of (-)-2159. 

All naturally occurring steroids, and the overwhelming majority of those used as drugs, comprise single enantiomers. When written as in the flow schemes that follow, the diagrams depict the absolute configuration. Substiments below the plane of these rather flat molecules are named a while those above that face are named (3, a convention that later spread to many other strucmral classes. 

For the said reasons dihydrolycorine would afford only the methiodide from the I) form therefore bearing the iV-methy] group in the a. (steroid notation) configuration. The absolute configuration a for the methio-dides of the /3 series and /3 for those of the a series, respectively, thus far established by chemical reasoning, is in agreement with the optical rotatory values which are predictable from the octant rule (Fig. 1) for the following reasons. 

CD spectroscopy has historically been of extreme importance in the study of small, optically active organic molecules. David Lightner has provided a review of the CD methods used to establish the absolute configuration of dissymmetric centers, covering both the octant rule as well as the exciton chirality rule. The use of difference CD studies in the characterization of steroids has been detailed by Andras Gergely. 

Orientation, proximity and chromophore are paramount considerations in the Exciton Chirality Rule. Extrachromophoric considerations are relatively unimportant. Thus the CD spectra of bis-p-dimethylaminobenzoates of 5a-cholestan-2a,3/3-diol and (2R,2R)-cyclohex-anediol (both diequatorial diols of the same absolute configuration) are essentially irip.ntir.al (Figure 32). Other steroid diols, whether with vicinal hydroxyls or very distant hydroxyls, give bisignate CE s originating from exciton coupling and with a signed order consistent with the Exciton Chirality Rule (Table XII). 

Theories behind these methods were primarily developed for the determination of the absolute configurations of single molecules, especially steroids, and consist of derivatizing the molecule by substituting two identical chromophores at predetermined sites. Common substituents used as the molecular probes are para-substituted benzoates and polyacenes, e.g. 

Model compounds, containing rings C and D, or A, C, and D of lysergic acid, were compared with polycyclic compounds of the steroid series, whose absolute configuration, with respect to the spatial arrangement corresponding to C-5 of lysergic acid, was known. 

Figure 26. Exciton chirality method for the determination of the absolute configuration of steroidal diols. The clockwise (+) and counterclockwise (-) directionality of two dipoles is determined by the configuration of the diol.

Figure 26 shows the formula, conformation, and absolute configuration of veratridine (52). The structure and conformation of the C27-steroidal base is very similar to that determined for zygacine (C32H49N08) another Veratrum alkaloid (53). Variations in the pharmacological effects of Veratrum alkaloids appear to be dependent on the substituents attached to the essentially rigid molecular framework. The numerous intramolecular hydrogen bonds that enhance the molecular rigidity are indicated in Fig. 26. The positions of all the hydrogen atoms have been located for the veratridine molecule and the intramolecular donors and acceptors are identified as...

The absolute configuration at C-24 in some ecdysteroids has been established by C n.m.r.Assignments are reported also for some steroidal alkaloids, ° and for a series of twelve 5a-cardenolides. ... 

C.d. data recorded for a series of 5a-cholestane-3/3,6a-diol di-(4-chloro-benzoates) with additional substituents at C-4 have indicated that the diterpenoids caryoptin, 3-epicaryoptin, and clerodin have the same absolute configuration. C.d. data are reported for four isomeric steroidal 3-spiro-isoxazolidine[2,3- i]oxadiazolines, together with X-ray data confirming the structure (26) for one of them. These compounds result from 1,3-dipolar cycloadditions between benzonitrile oxide and the 3-methylene-steroid. An interpretation of the c.d. data at ca. 250 nm attributes the Cotton effect to coupled benzenoid transitions. A new sector rule is proposed for the c.d. of 2,2-dialkyl-l,3-oxathiolans (ketone hemithioacetals), which are essentially of thio-ether type with c.d. bands in the regions of 240 and 220 nm. 

Circular Dichroism. The salicylidene-imino chirality rule has been applied to cyclic steroidal amines. This rule was previously used to correlate the absolute configuration of cyclic terpenoid amines with the signs of the observed Cotton effects near 255 and 315 nm in their circular dichroism spectra. Similar considerations were used to interpret the c.d. spectra of fV-salicylidene derivatives of steroidal cyclic amines. These spectra were reported but no simple interpretation was possible. 

The 9(10-> l9)-abeo analogue (6) of oestrone methyl ether has been shown by X-ray crystallography to have the normal 9a -configuration, but because of the chair conformation of the enlarged ring b the molecule differs considerably in shape from oestrone methyl ether. X-Ray, n.m.r., and o.r.d. data establish the structures and absolute configurations of a series of insect-repellent steroids isolated from Nicandra physaloides. The structure and conformation of the 6-sila-steroid (7) have been determined. ... 

A full account has appeared of the study of absolute configurations of vicinal diols and amino-alcohols by c.d. measurements in solutions containing nickel acetylacetonate [Ni(acac)2] or the n.m.r. shift reagent [Pr(dpm)3]. Examples of steroidal derivatives examined include 2,3-, 3,4-, 5,6-, 16,17-, 17a,20j8-, and side-chain diols. 

Immobilization does not destroy hydroxylase activity. llg-Hydroxyla-tion of 17a,21-dihydroxy-pregn-4-ene-3,20-dione by Culvularia falcata supported in polyacrylamide has been reported.31 This flow procedure was coupled with a polyacrylamide-immobilized Al>2-dehydrogenase of Arthrobac-ter simplex so that the cortisol produced was converted directly into the more active corticoid, prednisolone. The Al 2-dehydrogenase of A. simplex has also been employed for resolving synthetic steroids and for determining their absolute configurations.32... 

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