Cholesterol oxidative rearrangement

Squalene is also an intermediate in the synthesis of cholesterol. StmcturaHy, chemically, and biogeneticaHy, many of the triterpenes have much in common with steroids (203). It has been verified experimentally that squalene is the precursor in the biosynthesis of all triterpenes through a series of cyclization and rearrangement reactions (203,204). Squalene is not used much in cosmetics and perfumery formulations because of its light, heat, and oxidative instabiUty however, its hydrogenated derivative, squalane, has a wide use as a fixative, a skin lubricant, and a carrier of Hpid-soluble dmgs. 

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

Oestrone lacks one of progesterone s methyl groups, probably removed in the body as CO2 after oxidation. In 1946, Carl Djerassi, a man whose work led directly to the invention of the contraceptive pill, showed that another derivative of cholesterol could be rearranged to the oestrone analogue 1-methyloestradiol—notice how the methyl group has this time migrated to an adjacent carbon atom. At the same time, the dienone has become a phenol. 

In comparison to some of the other activation methods however, the dimethyl sulfoxide-acetic anhydride procedure has certain disadvantages. The method often requires the use of long reaction times (1 24 h), which can result in many side reactions, especially with sensitive substrates. Notable in this respect is that it is not uncommon for this procedure to result in the formation of substantial yields of the thiomethyl ethers obtained from the Pummerer rearrangement product as described above. In fact upon attempted oxidation of cholesterol with this system, the major product obtained was the corresponding (methylthio)methyl ether. Acetates may also be formed if the alcohol is unhindered. For example the sugar derivative (9) reacts under these conditions to form an enol acetate (derived from the requir carbonyl compound) in 40% yield contaminated with 30% of the acetate (10 equation S). ... 

Chiral centers, more than one, lljf Chiral stereomer, 69 Cholesterol, chirality in, 81 Cinnamaldehyde, 328 Cis-trans interconversion, 111 Cis-trans isomerism, in cyclic compounds, 163 Claisen condensation, 394 rearrangement, 439 Cleavage, oxidative, 117 Clemmensen reduction, 219, 311 Coenzyme A, 354 Collins reagent, 264 Collision frequency, 39 Configuration, 72 relative, 76 Conformation, 51 Conformational diastereomers, 78 enantiomers, 78 stereomers, 78... 

Diagnosis of unsaturation types. A -Cholestenyl acetate is oxidized by selenium dioxide in acetic acid-benzene to give 7a-acetoxy-A -cholestene (2), probably by allylic hydroxylation at C14, allylic rearrangement, and acetylation. Since oxidation occurs readily at room temperature whereas cholesterol is attacked only at 55-60°, the reaction can be used to detect small amounts of A -cholestenol... 

The enzyme-catalyzed polycyclization of squalene 135 produces dammaradienol 138, which is known to be the precursor of cholesterol. In the process, squalene oxide is the intermediate, which adopts the conformation as shown in 137, and rearranges, under acid catalysis, to 138 [20, 21]. Note that in the transformations 131 —> 133 and 137 —> 138, many SN2 reactions take place in tandem for the sole reason of stereoelectronically driven well-organized geometrical orientations of the reacting functional groups. Note that all the double bonds are trans, and also that two such consecutive bonds are 1,5-related to each other. 

Oxidation of polyunsaturated fatty acids (PUFA) in lipoproteins may be mediated by reactive species such as radicals, transition metals, other electrophiles, and by enzymes. Once initiated, oxidation of lipids may proceed by a chain reaction, illustrated in Fig. 4 (R5). In step I, an oxidant captures an electron from a PUFA to produce a lipid radical. In step 2, after rearrangement, the conjugated diene radical reacts rapidly with singlet oxygen to produce a lipid peroxide radical, which is the kinetically preferred reaction (step 3) (B5). The chain can be terminated if the lipid radical reacts with an antioxidant to produce a stable peroxide (step 4). Otherwise, the peroxyl radical can react with another polyunsaturated fatty acid as shown in step 5 to perpetuate a chain reaction. The chain reaction requires production of lipid peroxides, giving it the name peroxidation. Fatty acids oxidized in the core are largely triglycerides and cholesterol esters, while toward the outer layer fatty acids in phospholipids are oxidized. 

The Opening of Squalene-2,3-Epoxide Steroids are tetracyclic compounds that serve a wide variety of biological functions, including hormones (sex hormones), emulsifiers (bile acids), and membrane components (cholesterol). The biosynthesis of steroids is believed to involve an acid-catalyzed opening of squalene-2,3-epoxide (Rgure 14-6). Squalene is a member of the class of natural products called terpenes (see Section 25-8). The enzyme squalene epoxidase oxidizes squalene to the epoxide, which opens and frams a carbocation that cyclizes under the control of another enzyme. The cyclized intermediate rearranges to lanosterol, which is converted to cholesterol and other steroids. 

Under exposure to sunlight the cholesterol in the skin is oxidized to 7-dehydrocholesterol, which is immediately rearranged to vitamin D3. 

---