Squalene formation from acetate

It now appears that the de novo formation of pregnane derivatives in nature proceeds almost certainly by the side-chain cleavage of preformed sterols rather than by direct formation from acetate. The existence of an alternate pathway for the formation of pregnane compounds from acetate along routes not involving the prior transformation to squalene and its cyclization has not been demonstrated. No-... 

The structure of presqualene alcohol has been established beyond reasonable doubt by three independent rational syntheses (Chapter 4). " As the last isolable intermediate between acetate and squalene to be formulated, its structure has been a subject of controversy since its isolation in 1966, Its formulation therefore represents a major advanee which makes it possible to eonsider its mode of formation from famesol and its transformation into squalene. Enzymie... 

Animals accumulate cholesterol from their diet, but are also able to biosynthesize it from acetate. The pioneering work that identified the key intermediates in the complicated pathway of cholesterol biosynthesis was carried out by Konrad Bloch (Harvard) and Feodor Lynen (Munich), corecipients of the 1964 Nobel Prize for physiology or medicine. An important discovery was that the triterpene squalene (see Figure 26.6) is an intermediate in the formation of cholesterol from acetate. Thus, the early stages of cholesterol biosynthesis are the same as those of terpene biosynthesis described in Sections... 

The increased accumulation of anthocyanins in hypocotyls of mevinolin-treated radish seedlings ( 9) certainly does not simply reflect the routing away of acetate units from sterois (cf. Figure 1) but also reflects a more general response of plants upon treatment with chemicals (95). Inhibitors (see also below) affecting later steps in phytosterol synthesis seem to affect various other products of the isoprenoid pathway before and after squalene formation (95). Secondary effects of such growth... 

Bromohydration, Bromolactonization, and Other Additions to C=C. The preferred conditions for the bromohydration of afkenes involves the portionwise addition of solid or predissolved NBS (recrystallized) to a solution of the alkene in 50-75% aqueous DME, THF, or f-butanol at 0 °C. The formation of dibromide and a-bromo ketone byproducts can be minimized by using recrystallized NBS. High selectivity for Markovrukov addition and anti stereochemistry results from attack of the bromonium ion intermediate by water. Aqueous DMSO can also be used as the solvent however, since DMSO is readily oxidized under the reaction conditions, significant amounts of the dibromide byproduct may be produced. In the bromohydration of polyalkenic compounds, high selectivity is regularly achieved for attack of the most electron-rich double bond (eq 20). With famesol acetate, squalene, and other polyisoprenes, choice of the optimum proportion of water is used to effect the selective bromohydration at the terminal double bond (eq 21), and the two-step sequence shown is often the method of choice for the preparation of the corresponding epoxides. ... 

This reaction was first reported by Johnson et al. in 1970. It is a highly stereoselective synthesis of y,5-unsaturated esters from the reaction between allylic alcohols and an orthoester in the presence of a trace amount of weak acid, such as propionic acid. Because this reaction is the modification or variant of the Claisen Rearrangement, it is often referred to as the Johnson orthoester Claisen rearrangement. Occasionally, this reaction is also known as the Claisen-Johnson orthoester rearrangement, " or Johnson orthoester protocol. This reaction involves the formation of mixed orthoester from allyl alcohol and the added orthoester, which loses an alcoholic component to form a ketene acetal then migrates to unsaturated carbonyl compounds via the Claisen Rearmagement with high syn selectivity. Posner further extended this reaction to use sulfonyl orthoester. Overall, this reaction has been applied to the synthesis of a variety of complicated natural products, such as squalenes. ... 

Several studies, in part contradictory, are available concerning the influence of nicotinic acid on cholesterol biosynthesis. Perry (1960) reported from work with rat liver slices a decreased incorporation of C-acetate into cholesterol with high concentrations of nicotinic acid in the medium Schade and Saltman (1959) had obtained similar results in rabbits fed with nicotinic acid. On the other hand, Merrill and Lemley-Stone (1957) found increased cholesterol synthesis in liver slices of rats fed nicotinic acid, while Duncan and Best (1960) reported that nicotinic acid has no effect on C-acetate incorporation. Parsons (1961 a) studied the effects of nicotinic acid and niacin on incorporation of C-acetate in man, and stated that considerably less conversion into serum cholesterol (free and esterifled) and into erythrocyte cholesterol occurred during nicotinic acid administration. The concept of inhibition of cholesterol synthesis is also held by Goldsmith (1962) the point of inhibition supposedly occurs before the formation of squalene, because sterol intermediates between squalene and cholesterol could not be detected in serum. 

By incubation or perfusion of placental tissue Math acetate, this precursor is transformed into squalene, lanosterol, and cholesterol (Levitz et al., 1962, 1964 Van Leusden and Villee, 1965 C. A. Villee, 1967, 1969). On the other hand, placental perfusion with mevalonate results in the formation of squalene and lanosterol, but not of cholesterol (Tjcvitz et al., 1962). However, the in vi(7 o conversion of both acetate and mevalonate to cholesterol was found by Zelen-ski and Villee (1966) using a preparation of minced human term placenta. Tliese authors suggest that the formation of cholesterol from these precursors is through different metabolic pathways. 

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