Syntheses of Steroid Side Chains

Ikekawa [73] described the synthesis of two new vitamin Dj derivatives such as compound 332. Introduction of a double bond resulted from a Claisen- 

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The stereocontroUed syntheses of steroid side chains for ecdysone, cmstecdysone, brassinoHde, withanoHde, and vitamin D have been reviewed (185). Also, other manuscripts, including reviews on the partial synthesis of steroids (186), steroid dmgs (187—189), biologically active steroids (190), heterocychc steroids (191), vitamin D (192), novel oxidations of steroids (193), and template-directed functionali2ation of steroids (194), have been pubhshed. 

Aside from the stoichiometric construction of steroidal side chains by the reaction of alkenylzirconium derivatives with steroidal 7r-allylpalladiums, a one-pot synthesis of a-famesene and its 6Z-isomer from generanyl and neryl chlorides, respectively, reported in 1981 appears to be the first example of natural product syntheses via Pd-catalyzed allylation (Scheme 21). 

Classical syntheses of steroids consist of the stepwise formation of the four rings with or without angular alkyl groups and the final construction of the C-17 side-chain. The most common reactions have been described in chapter 1, e.g. Diels-AIder (p. 85) and Michael additions (p. 

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

The 29-fluorophytosterols, members of a new class of selective pro-insecticides, have been synthesized and examined m vivo in tobacco hornworms. Dealkylation at C-24 of the steroid side chain by insects releases the latent poison fluoroacetate, resulting in dose-dependent reductions in growth rate, maximum weight, and survival when fed at 1 to 100 ppm to Manduca sexta. 

Similar types of alkylation have been applied in syntheses of other steroidal side-chains, including that of 22-trans-26,27-dinorergosta-5,22-dien-3j8-ol (387), a novel marine sterol. In addition, the Wittig reaction has been used to prepare various possible polyene intermediates in phytosterol biosynthesis. The aldehydes (389) and (390) were prepared (Scheme 26) from stigmasterol acetate (388b) by modification of a known procedure. These aldehydes were then alkylated with a variety of ylides derived from phosphonium salts, leading to a series of polyenes (391) and (392). ... 

Novel compounds of alkaloid type with a heterocycle in the steroid side-chain have been synthesized by reaction between the acid chlorides (472) and pyrrolemag-nesium iodide. Reduction followed by selective dehydrogenation converted the acylpyrrole (473) successively into the pyrrolidine (474) and 23(N)-unsaturated (475) derivatives. ... 

The syntheses of labelled lanosterol, cycloartenol, and parkeol derivatives for use in biosynthetic studies have been described. Terminal labelling of the side-chain [25- C] or [26,27- H6] was achieved by the formation of Wittig intermediates with the trisnortriterpenoid units followed by reaction with labelled acetone. Methods for the removal of one or both methyl groups from 4,4-dimethyl-steroids have been published. Lanosterol has been degraded to the trimethyl-pregnenolone (54). 

Cholesterol and its fatty-acid esters enter the intestinal cells and are combined with proteins to form lipoproteins that are carried to the tissues, especially the brain, by the blood. In addition, cholesterol is synthesized from acetate ion by human beings, in amount about 1000 mg per day. The daily food intake may provide 500 to 1000 mg (an egg, a high-cholesterol food, contains about 250 mg). Cholesterol is broken down at a rate equal to the intake, and is eliminated in the bile as bile acids. The bile acids have a carboxyl group at the end of the side chain for example, cholic acid, C24H40O5, differs from cholesterol in having the side chain —CH(CHa)CH2CH2COOH at Cl7, as well as hydroxyl groups at C7 and C13. The bile acids are steroids other important steroids are hormones (Section 14-10). 

Methods of Introducing Side Chains. The side chains introduced in the total synthesis of steroids must be sterically oriented in a suitable manner and contain functional groupings providing for subsequent cyclization. Table 3 gives an idea of the use of various methods for the building up and extension of side chains. According to this table, the main reactions involved are organometallic syntheses, the Michael reaction, and various alkylation reactions. 

Since all the most important natural steroids have already been obtained by total synthesis, each reaction in the steroid series can in fact now be regarded as a "formal total synthesis" of the products formed in it. Such a situation requires the drawing of the clearest possible boundaries between the partial and total synthesis of steroids. In our opinion, the term total synthesis can be applied only to those investigations in which the construction of the side chains distinguishing the classes of steroid compounds was connected organically with the construction of the steroid skeleton (as is the case in the syntheses of aldosterone and conessine). From this point of view, it must be regarded as incorrect to describe as total syntheses, for example, the syntheses of equilin, diosgenin, and tomatidine these syntheses deliberately start from natural steroids and must be classified as partial syntheses. In view of what has been said, in this book our main attention is devoted to the construction of the steroid skeleton and not to the introduction of side chains. The broad development of the chemistry of the heterocyclic steroids has made it necessary also to consider the main methods for the total synthesis of azasteroids, oxasteroids, and thiasteroids. 

For those cases where the steroidal side chains had an extra chiral center at C-24, several compounds of known stereochemistry were synthesized and used as model systems. This was the case for two naturally occurring marine steroids from a starfish and an ophiuroid 87.6 and 87.7, respectively (see Figure 87). 

Early efforts to partially synthesize 20-keto and 17a-hydroxy-20-keto steroids led to ring D-expanded products isomeric with the desired compounds. Darzens condensation of 3/5-hydroxyandrost-5-en-17-one acetate (75) with ethyl a,a-dichloropropionate, followed by alkali treatment and decarboxylation, gives both the expected 3j5-hydroxypregn-5-en-20-one (78) and an isomer now known to be 17a-methyl-D-homo-17-ketone (79).36,37a alternative route for the introduction of the two carbon side chain, Ruzicka... 

The steric bulk of steroid structures prevents their use as the only organic side group present. However, mixed-substituent polymers that contain both steroidal side groups and amino acid ester or other cosubstituent units can be readily synthesized. If a saturated A ring is present in the steroid, linkage to the polymer chain is complicated by side reactions that result from dehydration of the steroid (chlorophosphazenes are powerful dehydrating agents). 

Testiculat androgens are synthesized in the interstitial tissue by the Leydig cells. The immediate precursor of the gonadal steroids, as for the adrenal steroids, is cholesterol. The rate-limiting step, as in the adrenal, is delivery of cholesterol to the inner membrane of the mitochondria by the transport protein StAR. Once in the proper location, cholesterol is acted upon by the side chain cleavage enzyme P450scc. The conversion of cholesterol to pregnenolone is identical in adrenal, ovary, and testis. In the latter two tissues, however, the reaction is promoted by LH rather than ACTH. 

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