Triterpene oxide

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. 

Epoxyfarnesol was first prepared by van Tamelen, Stomi, Hessler, and Schwartz 4 using essentially this procedure. It is based on the findings of van Tamelen and Curphey5 that N-bromosuccinimide in a polar solvent was a considerably more selective oxidant than others they tried. This method has been applied to produce terminally epoxidized mono-, sesqui-, di-, and triterpene systems for biosynthetic studies and bioorganic synthesis.6 It has also been applied successfully in a simple synthesis of tritium-labeled squalene [2,6,10,14,18,22-Tetracosahexaene, 2,6,10,15,19,23-hexamethyl-, (all-E)-] and squalene-2,3-oxide [Oxirane, 2,2-dimethyl-3-(3,7,12,16,20-pentamethyl-3,7,ll,-15,19-heneicosapentaenyl)-, (all-E)-],7 and in the synthesis of Cecropia juvenile hormone.8... 

These results do not prove that the ester is an essential intermediate in aqueous solution even though it is present, but the result with the hindred triterpene is convincing In this case the esterification step, which is normally fast, has become rate-determining and the disappearance of the isotope effect must mean that C-H cleavage occurs after the formation of the ester and not independently of it. The generality of this result is apparent from the stopped-flow investigation of isopropanol oxidation ... 

This enantiomeric specificity has been of interest in other contexts, and stereospecific biotransformation has been observed. Examples include the enantiomeric oxidation of sulfides to sulfoxides (Chapter 11, Part 2) and steroid and triterpene hydroxylation (Chapter 7, Part 2). 

The structure-activity relation of triterpene QMs on the anti-inflammatory effect has been investigated with a series of analogues by comparing inhibition of the IL-1 (3 production in the LPS-induced monocytes.93-94 Clearly, the conjugated QM structure with alkenes is essential for the observed inhibition, and similar inhibitory effect was found with derivatives that are capable to form the conjugated QM through hydrolysis and/or oxidation.93-94 Also, the presence of the E ring in the triterpene QM structure is an additional contributor. 

Sea cucumbers (Holothuroidea, Echinodermata) appear to be unique in their mode of squalene oxide (37) cyclization. Tritium-labeled lanosterol (33), cycloartenol (32) and parkeol (38) were individually administered to the sea cucumber Holothuria arenicola. While the former two triterpenes were not metabolized [22], parkeol was efficiently transformed into 14x-methyl-5a-cho-lest-9(l l)-en-3/ -ol (39) (Scheme 3). Other A1 sterols present in H. arenicola were not found to be radioactive and were thus assumed to be of dietary origin. The intermediacy of parkeol was confirmed by the feeding of labeled mevalonate (23) and squalene (26) to the sea cucumber Stichopus californicus [15]. Both precursors were transformed into parkeol, but not lanosterol nor cycloartenol, aqd to 4,14a-dimethyl-5a-cholest-9(ll)-en-3/J-ol (40) and 14a-methyl-5a-cholest-9(ll)-en-3/ -ol. Thus, while all other eukaryotes produce either cycloartenol or lanosterol, parkeol is the intermediate between triterpenes and the 14-methyl sterols in sea cucumbers. 

Figure 5.3 GALDI mass spectra of the samples depicted in Figure 5.2 photoaged for 300 h hydroxydammarenone (a) and the equimolar mixture (b) [39], Photoageing results in strong oxidation and degradation of the initial triterpenes. Progressive oxidation can be followed by mass increments of 16 and 14 Da. Signals marked with crosses at m/z 413, 469, 483, and 507 are contaminants in the spectrometer. Signals with crosses at m/z <460 may have small contributions from contaminants...

Ring A diosterols.3 The ring A diosterols (3 and 4) of triterpenes can be prepared from the A2-alkene (1) by osmylation to form the two possible cis-diols (2), which on Swern oxidation give the a-diketone (3). The same diketone is also obtained by Swern oxidation of the 2(3,3a-diol, the product of peracid oxidation followed by acid cleavage. The diketone 3 rearranges to the more stable diosphenol (4) in the presence of base. 

FIGURE 1.4 Proposed biosynthetic route for the biosynthesis of (A) squalene oxide (squalene-2,3-oxide) via the isoprenoid pathway and (B) triterpene saponins of the dammarane-type and oleanane-type from squalene oxide. PP, diphosphate group GPS, geranyl phosphate synthase FPS, farnesyl phosphate synthase NADPH, nicotinamide adenine dinucleotide phosphate. 

As described above, the cyclization of squalene oxide is a biosynthetic branching point not only for phytosterols and triterpenes but also for dammarane- and oleanane-type ginsenosides. In ginseng, the enzyme... 

A good example of the simplicity and power of the chemistry to rapidly construct complex systems is provided by the Kolbe dimerization of (55) as the key step of a total synthesis of the triterpene (+)-Q -onocerin (57 Scheme 14) [33], Thus, oxidation of (+)-hydroxy keto acid (55) in methanol containing a trace of sodium methoxide and at a temperature of 50 C, followed by acylation and chromatography, provided (+)-diacetoxydione (56) in a 40% yield. 

By using betulin as substrate, some mechanistic studies were performed and it was demonstrated that these reactions are catalyzed by Brpnsted acid species generated in situ from the hydrolysis of Bi(0Tf)3-.vH20. This process was also applied to other terpenic compounds. The sesquiterpene ( )-caryophyllene oxide originated clov-2-en-9a-ol by a cariophyllene-clovane rearrangement (Scheme 41) whereas 3-oxo- l 8a-olean-28- l 3(3-olide was obtained from oleanonic acid (Scheme 42). With this triterpene derivative, only 28,13(3-lactonization occurred, with inversion of the configuration of the stereocenter at C18 [133],... 

As part of the total synthesis of the triterpene (+)-a-onocerin, one of the first total syntheses in which RuO played a key role, a diphenylethyleneacetoxyketone was oxidised to the corresponding acetoxyketoacid by RuO /aq. Na(10yacetone. Aromatic ring oxidation was also involved (cf. 3.3.1 below) [219]. An oxidative cyclisation of a 1,5-diene to a diol by RuCl3/Na(10 )/wet SiO /THF formed part of the synthesis of the antitumour agent cw-solamin [220]. 

The all-tra 5 -squalene (C30H50), discovered in shark liver oil in the 1920s, is a triterpene, but one in which the isoprene rule at violated in one point. Rather than a head-to-tail arrangement of six units of isoprene, there appear to be farnesyl units that have been connected tail to tail. Almost aU steroids are biosynthesized from cholesterol. Cholesterol is biosynthesized from squalene, which is first converted to lanosterol. The conversion of squalene to the steroid skeleton is an oxirane, squalene-2,3-oxide, which is transformed by enzymes into lanosterol, a steroid alcohol naturally found in wool fat. The whole process is highly stereoselective. 

Matsuda, H., T. Kageura, I. Toguchida, T. Murakami, A. Kishi, and M. Yoshikawa. 1999. Effects of sesquiterpenes and triterpenes from the rhizome of Alisma orientate on nitric oxide production in lipopolysaccharide-activated macrophages absolute stereostructures of alismaketones-B 23-acetate and -C 23 acetate. Bioorg. Med. Chem. Lett. 9 3081-3086. 

Most animal steroids arise from cholesterol, which in turn is derived from squalene. This C30 triterpene, whose biosynthesis is described in Section B, is named after the dogfish Squalus in whose liver it accumulates as a result of blockage in oxidation to cholesterol. Squalene is also a prominent constituent of human skin lipids. Its conversion to cholesterol, which takes place in most animal tissues,117/154-156 is initiated by a microsomal enzyme system that utilized 02 and NAD-PH to form squalene 2,3-oxide (Fig. 22-6, step a). 

Soulier et al. (35) isolate eight triterpenic alcohols from sal and illipe butters besides other compounds. They separate these compounds after saponification of the fatty matter and fractionation of the unsaponifiable on an aluminium oxide column (hydrated at 5%). Two successive HPLC separations and a TLC-AgN03 permit the isolation of highly purified fractions. Through the use, among others, of the H-NMR and MS techniques, they identify nine... 

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