Steroidal skeleton

In polycyclic systems the Birch reduction of C—C double bonds is also highly stereoselective, e.g. in the synthesis of the thermodynamically favored trans-fused steroidal skeletons (see p. 104 and p. 278). 

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

Intramolecular reaction can be used for polycyclization reaction[275]. In the so-called Pd-catalyzed cascade carbopalladation of the polyalkenyne 392, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion takes place twice, followed by the alkene insertion twice. The last step is the elimination of/3-hydrogen. In this way, the steroid skeleton 393 is constructed from the linear diynetriene 392(276]. 

A typical steroid skeleton is shown along with the numbenng scheme used for this class of compounds Specify in each case whether the designated substituent is axial or equatorial... 

Repeat Problem 3 35 for the stereoisomenc steroid skeleton having a cis ring fusion between the first two nngs... 

Steroidal and Nonsteroidal Estrogens. Modification of the basic steroid skeleton and the nature of the functional groups in the B, C, and D rings while maintaining the phenoHc A-ring has continued to be a primary approach in the development of new estrogens with unique biological profiles. 

This explosion in steroid chemistry both stimulated and was aided by the development of conformational analysis (10). Many basic, physical organic chemistry principles were estabUshed as a result of the study of the logically predictable chemistry of the rigid perhydro-l,2-cyclopentenophenanthrene, steroid skeleton. 

Bde salts, cholesterol, phosphoHpids, and other minor components are secreted by the Hver. Bile salts serve three significant physiological functions. The hydrophilic carboxylate group, which is attached via an alkyl chain to the hydrophobic steroid skeleton, allows the bile salts to form water-soluble micelles with cholesterol and phosphoHpids in the bile. These micelles assist in the solvation of cholesterol. By solvating cholesterol, bile salts contribute to the homeostatic regulation of the amount of cholesterol in the whole body. Bile salts are also necessary for the intestinal absorption of dietary fats and fat-soluble vitamins (24—26). 

When used at room temperature in the presence of an active platinum catalyst in an inert solvent, e.g., acetone or ethyl acetate, oxygen will oxidize nonhindered, saturated hydroxyl groups and exposed allylic alcohols. This reagent has found extensive use in sugar chemistry and is particularly suited for the selective oxidation of either 3a- or 3j -alcohols of steroids. Other hydroxyl groups on the steroid skeleton are much less sensitive to oxidation. As a result, this reaction has been used extensively in research on polyhydroxy cardiac-active principles, e.g., the cardenolides and bufadienolides, where the 3-hydroxyl group is easily oxidized without extensive oxidation or dehydration of other hydroxyl groups. The ordinarily difficult selective oxidation of the... 

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. 

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. 

The most extensive use of enamine halogenations has, hctwever, been in the attachment of fluorine to the steroid skeleton (499-503). The formation of a ]6-fluoro-17-ketosteroid by the reaction of perchlorofluoride with a 17-enamide has also been reported (504). 

A highly efficient construction of the steroidal skeleton 166 is reported by Kametani and coworkers111 in the intramolecular Diels-Alder reaction of the a, jS-unsaturated sulfone moiety of 165 (equation 117). Thus, when the sulfone 165 is heated in 1,2-dichlorobenzene for 6h, the steroidal compound 166 can be obtained in 62% yield. The compound 166 produces estrone (167) by elimination of benzenesulfinic acid and subsequent hydrogenation of the formed double bond. The stereoselectivity of the addition reflects a transition state in which the p-tosyl group occupies the exo position to minimize the steric repulsion between methyl and t-butoxy groups and the o-quinodimethane group as shown in equation 117. 

The y-lactone ring of the steroid skeleton forms an intermediate cardenohde anion in alkaline medium that nucleophilically adds to the 3,5-dinitrobenzoic acid in the position ortho to the two nitro groups. A mesomerically stabilized red-violet anion is produced (Meisenheimer complex). 

A highly efficient construction of the steroidal skeleton 166 is reported by Kametani and coworkers in the intramolecular Diels-Alder reaction of the ot, jS-unsaturated sulfone... 

Entry 9 uses the oxaborazolidine catalysts discussed on p. 505 with 2-bromopropenal as the dienophile. The aldehyde adopts the exo position in each case, which is consistent with the proposed TS model. Entry 10 illustrates the use of a cationic oxaborazolidine catalyst. The chirality is derived from trans-1,2-diaminocyclohcxanc. Entry 12 shows the use of a TADDOL catalyst in the construction of the steroid skeleton. Entry 13 is an intramolecular D-A reaction catalyzed by a Cu-Ws-oxazoline. Entries 14 and 15 show the use of the oxazaborolidinone catalyst with more complex dienes. 

Entry 15 creates a portion of the steroid skeleton and also illustrates the use of a furan ring as a diene. 

Scheme 10.1 gives some representative examples of laboratory syntheses involving polyene cyclization. The cyclization in Entry 1 is done in anhydrous formic acid and involves the formation of a symmetric tertiary allylic carbocation. The cyclization forms a six-membered ring by attack at the terminal carbon of the vinyl group. The bicyclic cation is captured as the formate ester. Entry 2 also involves initiation by a symmetric allylic cation. In this case, the triene unit cyclizes to a tricyclic ring system. Entry 3 results in the formation of the steroidal skeleton with termination by capture of the alkynyl group and formation of a ketone. The cyclization in Entry 4 is initiated by epoxide opening. 

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]. 

Malacria and co-workers76 were the first to report the transition metal-catalyzed intramolecular cycloisomerization of allenynes in 1996. The cobalt-mediated process was presumed to proceed via a 7r-allyl intermediate (111, Scheme 22) following C-H activation. Alkyne insertion and reductive elimination give cross-conjugated triene 112 cobalt-catalyzed olefin isomerization of the Alder-ene product is presumed to be the mechanism by which 113 is formed. While exploring the cobalt(i)-catalyzed synthesis of steroidal skeletons, Malacria and co-workers77 observed the formation of Alder-ene product 115 from cis-114 (Equation (74)) in contrast, trans-114 underwent [2 + 2 + 2]-cyclization under identical conditions to form 116 (Equation (75)). 

From these examples, one should recognize that the building of the complex steroid skeleton of estrone has been made rather simple when various o-xylylene generation and trapping methods are applied ll5 118). 

The highly evolved catalyst 20 combines several features that have proved successful in simpler cases. The ionic sulfonate groups make the substrate sufficiently soluble for the reaction to be run in water. (The four hydrophilic cyclodextrins perform the same service for the catalyst.) The target reaction, the seledive oxidation of the steroid skeleton, goes back to the early days of enzyme models,1711 and the choice of porphyrin and of manganese as the metal cation are based on many years experience. The aryl groups are perfluorinated because an earlier version of the catalyst suffered self-oxidation. 

The presence of a 5-hexenyl substituent in 28i allowed the o-quinodimethane 229b to be captured in an intramolecular Diels-Alder reaction, producing 230, having a tetracyclic steroidal skeleton, in a single operation (Scheme 20.47) [33, 34], The fused tetracyclic 5,6,6,5-ring system was likewise produced from 34f and 34g. 

Scheme 20.47 Thermally induced one-step construction of the steroidal skeleton.

Another interesting alkaloid is tubocurarine chloride (14), with a bisbenzyliso-quinoline structure. It is the active principle of tubocurare, an arrow poison used by Indians in South America and medicinally used as a muscle relaxant. However, the source, the leaves of the tropical rainwood liane Chondodenron tomento-sum, is not easily accessible and the compound exhibits unwanted side-effects. Investigations showed that the basic structure can be replaced by an appropriate steroid skeleton with two nitrogen substituents at the right distance (see next section). 

Since the predatory water beetles cannot biosynthesise the steroid skeleton de novo, steroidal precursors must be obtained from exogenous sources. Bacillus-strains, isolated from the foregut of the water beetle Agabus affinis, were tested for their ability to transform steroids [101]. After incubation with androst-4-en-3,17-dione two Bacillus strains produced 13 different transformation products. Hydroxylation took place at C6, C7, Cll and C14 resulting in the formation of 6fi-, 7a-, 1 la-, and 14a-hydroxyandrost-4-en-3,17-diones. After incubation with pregnenolone the two Bacillus strains produced a variety of steroids among which 7a-hydroxypregnenolone was the major product [102]. 

C-21 methyl protons. The C-3 and C-16 melhine protons appeared at 8 3.82 and 4.99, respectively. The downfield chemical shift values of C-3 and C-6 methine protons were indicative of the presence of geminal oxygen functionahties. The C-6 resonated at 8 5.36 while the sp hybridized C-28 methylene protons resonated as two singlets, integrating for one proton each, at 8 5.56 and 6.06. A combination of H and C-NMR spectral data indicated to us that compound 11 has a steroidal skeleton. A detailed interpretation of broad C-NMR and DEPT spectra revealed the presence of three metlyl, ten methylene, eight methine and five quaternary carbon atoms in 11. The stereochemistry at various chiral centers was estabhshed with the aid of NOESY spectrum. 

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