Steroid biosynthesis, scheme

The most important oxirane, from an anthropocentric viewpoint, is probably squalene oxide (72), a precursor of lanosterol (73) and thus of the maligned but essential cholesterol (74 Scheme 87) 78MI50501). The cyclization of (72) to (73) represents nucleophilic tr-attack on oxirane carbon cf. Section 5.05.3.4.3(t)()), and the process has also been extensively investigated in vitro (68ACR1). Oxiranes are even more ubiquitous in steroid biosynthesis than had been thought, for a cholesterol epoxide has been shown to be a product of mammalian steroid biosynthesis <81JA6974). 

The scheme for steroid biosynthesis is the same in both plants and animals up to the formation of the carbocation 3-2. The biosynthesis diverges at this point in animals the methyl group at Cg migrates to afford lanosterol (4-1) as an isolable product (Scheme 2.4). The first steroidal product that can be isolated in plants, cycloartenol (4-2), features a cyclopropyl ring fused on to ring B at carbons 9,10. 

Isotope incorporation experiments have demonstrated the essential correctness of the scheme presented m this and preceding sections for terpene biosynthesis Considerable effort has been expended toward its detailed elaboration because of the common biosyn thetic origin of terpenes and another class of acetate derived natural products the steroids... 

Pharmacologically active allenic steroids have already been examined intensively for about 30 years [5], Thus, the only naturally occurring allenic steroid 107 had been synthesized 3 years before its isolation from Callyspongia diffusa and it had been identified as an inhibitor of the sterol biosynthesis of the silkworm Bombyx mori (Scheme 18.34) [86d], At this early stage, allenic 3-oxo-5,10-secosteroids of type 108 were also used for the irreversible inhibition of ketosteroid isomerases in bacteria, assuming that their activity is probably caused by Michael addition of a nucleophilic amino acid side chain of the enzyme at the 5-position of the steroid [103, 104]. Since this activity is also observed in the corresponding /3,y-acetylenic ketones, it can be rationalized that the latter are converted in vivo into the allenic steroids 108 by enzymatic isomerization [104, 105],... 

Scheme 18.34 Allenic steroids as inhibitors of sterol biosynthesis.

Most of the more recently described allenic steroids bear an allene group at the 17-position, which was usually formed by an SN2 substitution [106] or reduction [86d] process of a suitable propargylic electrophile. Thus, reduction of the pro-pargylic ether 109 with lithium aluminum hydride followed by deprotection of the silyl ether resulted in the formation of the allenic steroid 110, which irreversibly inhibits the biosynthesis of the insect moulting hormone ecdysone (Scheme 18.35) [107]. 

Alternative, also stereoselective, routes to allenic steroids take advantage of cationic cyclization reactions [108] or [2,3]-sigmatropic rearrangements [109]. For example, the allenic Michael acceptor 112 was prepared with 57% chemical yield by reaction of mestranol (111) with diethyl chlorophosphite and was found to inhibit the sterol biosynthesis of the pathogen responsible for Pneumocystis carinii pneumonia (PCP), the most abundant AIDS-related disease (Scheme 18.36) [110]. 

In view of the importance of mevalonate in the biosynthesis of terpenes and steroids, it is not surprising that numerous syntheses of mevalonolactone are available. These are briefly itemized in the detailed procedure for the synthesis of (i ,S)-mevalonolactone labelled at C-2 with 13C (Scheme 215) (81OS(60)92>. 

The concentration of dolichyl phosphate in eukaryotic tissues is very low and is probably rate-limiting for the glycosylation processes. Variation of the concentration in the endoplasmic-reticulum membranes is a possible way of controlling the rate of glycosylation. It is important to point out that the early steps in the dolichol biosynthesis are common to such other prenyl derivatives in plants as steroids, essential oils, hormones, phytol, and carotenes (see Scheme 1), and parameters affecting those reactions that may control the dolichol to dolichyl phosphate step could be another mechanism for regulation of the level of dolichyl phosphate. 

Steroid hormones are produced in the adrenal cortex and the sex glands. All such hormones originate from cholesterol. Figure 16.4 shows the overall scheme for steroid hormone biosynthesis that is applicable to all tissues. The final products may be divided into the following groups mineralocorticoids (e.g., aldosterone), produced by the zona glomerulosa of the adrenal cortex glucocorticoids (e.g., cortisol), produced by the zona fasciculata of the adrenal cortex and the... 

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). ... 

Reversible acylation is important in biochemical reactions, and sulfur functions as an activator in many such processes. Coenzyme A (41) is an acyl group carrier which is involved in lipid oxidation and the biosynthesis of lipids and steroids. The active form of coenzyme A is the thiol ester (acyl coenzyme A) (42), which is more stable than coenzyme A (41) and hence functions as an efficient acyl group donor for a substrate RH (Scheme 26). 

Willadsen and Eggerer (75) have studied the stereochemistry of the enzyme acetyl CoA acetyltransferase, a key enzyme in both the terminal step in C-3 oxidation of fatty acids and the initial step in the biosynthesis of terpenes and steroids. The enzyme, when incubated separately with (2S)-[2-2Hi,2-3Hi]aceto-acetyl CoA and the (2R) isomer gave two moles of acetyl CoA as depicted in Scheme 17. Eggerer et al. (76) utilized the enzyme enoyl CoA hydratase to convert properly labeled crotonyl CoA, via syn addition, to the doubly isotopically labeled 3-hydroxyacyl CoA derivatives needed in this study. A discussion of this unique type of hydration has been presented by Rose (9). The labeled... 

ScHEME XI. Biosynthesis of steroid hormones. / -450-catalyzed monooxygenase reactions... 

Figure 7-12 outlines the terminal steps in the complex sequence of both the biosynthesis of cholesterol and ergosterol. The synthesis, starting with acetate, leads to the common steroid precursor lanosterol.9 Thus, in the case of cholesterol, the scheme involves steps for the reduction of the A24 double bond, and the oxidation and removal of the 14a methyl group and of both methyls at C-4. This is followed by isomerization of the A8 double bond of the resultant zygmosterol to the A5 position, affording desmesterol, and finally cholesterol. 

The next step in the biosynthesis of steroids features an unusual head-to-head coupling reaction of two famesol pyrophosphates (OPP, not shown in diagram) to afford the alicyclic triterpene squalene 3-1, a compound found in shark liver oil (Scheme 2.3). Note that this product is in fact symmetrical about the newly formed bond. The next reaction in the sequence, which has only recently been uncovered, comprises oxidation of the terminal double bond to an epoxide. Opening of the oxirane leads to a domino-like series of ring-closing reactions and also concomitant migration of methyl groups. This chain reaction can be, and in fact has been, duplicated in the laboratory in the absence of enzymes. This series of reactions leads to the hypothetical steroidal carbocation 3-2. 

Steroidal Alkaloids.—Further study on the biosynthesis of Veratrum alkaloids has been published (for earlier work see refs. 224 and 225). The results obtained with dormant rhizome slices of V. grandiflorum were that (a) labelled verazine (207) gave rise to radioactive rubijervine (211) and hakurirodine (210), a new alkaloid isolated from dormant tuber slices, and (b) labelled etioline (208), a probable progenitor of solanidine (209), was not incorporated into either alkaloid. It was concluded that the biosynthetic pathway to solanidine (209) branches from that to rubijervine (211) at verazine (207) (see Scheme 25). 

The conversion of oxidosqualene 50 to lanosterol 52, the so-called squalene folding in the biosynthesis of steroids has initiated much research efforts (Scheme 10) [23]. This process is catalyzed by the enzyme lanosterol synthase, which controls precisely the formation of four rings and six new stereocenters. According to the pioneering work by Eschen-moser and Stork the cyclization proceeds in a concerted fashion due to favorable orbital overlap [24, 25]. In contrast Nishizawa et al. were able to trap several cationic intermediates 55-57 from a related model system 54... 

From cholesterol 4.18) biosynthesis leads through truncation of the side-chain and other modifications to mammalian steroid hormones, e.g. oestrone 4.22) [11, 33]. Vitamin D3 4.24) is obtainable by photochemically mediated electrocyclic ring-opening of 7-dehydrocholesterol 4.23), followed by a thermal 1,7-sigmatropic hydrogen shift (Scheme 4.7) [34, 35]. The ecdysone insect moulting... 

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