Steroid sidechain

We used the radical relay process, chlorinating C-9 and then generating the 9(11) double bond, in a synthesis of cortisone 91 [158]. This is a substitute for manufacturing processes in which C-9 or C-ll are hydroxylated by biological fermentation. Also, with templates that directed the chlorination to C-17 of 3a-cholestanol, such as that in 90, we were able to remove the steroid sidechain [159-162]. Using an electrochemical oxidation process, we could direct chlorination by simple chloride ion with an iodo-phenyl template [163]. A general review of the processes with iodophenyl templates has been published [164]. 

In this chapter we will take a look at several syntheses of a sesquiterpene ester called juvabione. We will see that it became a target for synthesis because of structural and biological issues, and became a test molecule for the evaluating methodology for controlling vicinal stereochemistry in acyclic systems. But first let s once again examine the steroid sidechain problem. 

Sterol. A steroid alcohol. Such alcohols contain the common steroid nucleus, plus an 8- to 10-car-bon-atom sidechain and a hydroxyl group. Sterols are widely distributed in plants and animals, both in the free form and esterified to fatty acids. Cholester-... 

Before discussing our synthetic studies, mention should be made of different approaches employed in the synthesis of brassinolide by other investigators. The most practical method would be to start with a readily available steroid having the same carbon skeleton as brassinolide, and then introduce the required functional groups in rings A and B and the sidechain. In the case of 28-homobrassinolide (5), tiie ideal starting compound would be the abundant sterol stigmasterol (4). 

Subsequent to our use of butenolide anions in aldol reactions to construct sidechains of steroids, two groups have reported a similar method for synthesis of brassinolide or its analogs. Kametani and co-workers employed the dianion of 3-isopropyltetronic acid which was reacted with a 20-keto steroid. The aldol product was dehydrated and the product hydrogenated to furnish the brassinolide sidechain (28,29). Zhou and Tian have used the reaction of a C-22 aldehyde derived from... 

We thought to prepare several groups of structures. These would include polar alkyl sidechains and steroid. The attachment of these chains would also vary as shown in the figure below. The problem in this case is the same as that noted in section 3 above, namely that attachment of an amide carbonyl group directly to ferrocene, increases its redox potential and destabilizes the ferricinium cation. 

Most steroids share a common tetracyclic ring system, but are adorned differently in terms of oxidation state at various carbons. The three targets we will consider are only the tip of the iceberg. Fused ring systems with different ring juncture stereochemistry (cis vs trans), different sidechains, and different oxidation patterns are common. A few examples are shown here (see problems for some questions about fiisidic and cholic acids). 

Prostaglandins-26 illustrates how the vicinal stereocontrol exercise just examined within the context of prostaglandins has been applied to the steroid (or terpenoid) sidechain problem we encountered in Chapter 2. Diazoketone 205 (derived from 204) was converted to 206 using an intramolecular car-benoid cyclopropanation of the m-olefin. Opening of the cyclopropane with lithium dimethyl cuprate gave 207 which was then converted to 208. The relationship between 208 and the D-ring of steroids (with appended C17 sidechain) is clear. 

The synthesis continued with reduction of the cyclohexanone to the alcohol oxidation state, taking it out of play for a series of reactions that constructed the sidechain (49 54). The sidechain ketone was then protected as an acetal, and the cyclohexanone was reinstalled by deprotection and oxidation of the cyclohexanol. Regioselective acylation of 55 under conditions of thermodynamic control, followed by reduction of the intermediate /3-ketoester, gave 56 (for comparison see 3 —> 14 on Steroids-3). Formation of the tosylate, a /3-elimination, and ketal hydrolysis completed the synthesis of 14. 

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