Triterpenes epoxides

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... 

Double Sharpless epoxidation was also applied to the synthesis of a key intermediate 10 to the meso-compound 11 that is related to teurilene, abioactive polycyclic triterpene isolated from red alga Laurencia obtusa,4 The reaction of ( , )-Bisallylic alcohol 9 gave the bisglycidic alcohol 10 with 80% de and 89% ee for each epoxidation (Scheme 6AA.4). 

Van Tamelen has examined extensively the cyclization of monoepoxide-polyolefins (94). For example, he found (95) that the treatment of racemic epoxide 247 with SnCl in nitromethane provided a major product (35% yield) which was identified as the racemic tetracycle 248. This represents an over all, close simulation of the squalene tetracyclic triterpene bioconversion (except for optical activity). 

Limonoids are C2(, nortriterpenoids deriving from a C30 triterpene precursor. The best known limonoids are the Azadirachta indica (neem tree) antifeedant azadirachtin (C50L C40 C6 -C60(epoxide methylene cross-link) furan) and the Citrus species (Rutaceae) bitter antifeedant limonin (G50L G40 G6 G6 C50L(epoxide)-furan). Limonin gives a delayed bitter taste to Citrus fruit. The limonoids are typically bitter compounds with insect antifeedant activity... 

An impressive cationic domino polycyclization has been developed by Corey and coworkers in their short and efficient enantioselective total synthesis of aegicer-adienol (1-150), a naturally occurring pentacyclic nor-triterpene belonging to the 3-amyrin family [42]. Thus, the treatment of the enantiopure monocyclic epoxy tet-raene 1-147 with catalytic amounts of methylaluminum dichloride induces a ca-tion-JT-tricyclation by initial opening of the epoxide to form the tetracyclic ketone 1-148 in 52 % yield, and its C-14 epimer 1-149 in 23 % yield, after silylation and chromatographic separation (Scheme 1.37). Further transformations led to aegicer-adienol (1-150) and its epimer 1-151. 

Squalene oxidases enantiospecifically and regiospecifically epoxidize the terminal double bond of squalene 1 to give (31S )-squalene epoxide 258. This, in turn, is the precursor of triterpenes and sterols (e.g., 3) in both plants and animals. Squalene oxidases are found in higher forms of life with the probable exception of insects and terrestrial annelids. They are also present in algae and other lower forms with the possible exception of some bacteria. The enzyme system requires molecular oxygen, NADPH and FAD as well as supernatant protein and phospholipids. There is no evidence for the participation of cytochromes P-450. 

Berti et al. found that the tetrasubstituted epoxide derivative (110 equation 44) of the triterpene hopane gave an efficient rearrangement to the ketone (111). 

Various attempts to oxidize 7,8- and 8,9-unsaturated tetracyclic triterpenes such as (1) to the corresponding epoxides by reaction with perbenzoic acid afforded mixtures of epoxide with the 7,9(1 l)-diene. Fried et al. found that the difficulty is eliminated by use of m-chloroperbenzoic acid in chloroform, which gave exclusively... 

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. 

Thus, once the appropriate orientation within the corresponding enzyme occurs, steroids, cucurbitacins, or other triterpenes may be formed. In the case of cucurbitacins, the squalene epoxide adopts a chair-boat-chair conformation, and the cyclization leads to a protostane cation, which is the immediate precursor of the cucurbitanes through a series of 1,2-proton and methyl group shifts, Fig. (4) [40]. 

Both the mixed stems and stem bark, and the stems CHCls-soluble extracts of L. wallichii Kurz, were found to display significant inhibitory activity in a famesyl protein transferase (FPTase) assay system. It has been suggested that inhibitors of this enzyme may be considered as potential anticancer agents for tumors in which products of the ras oncogene contribute to transformation. The bioassay directed fractionation of the two active extracts [213] led to the isolation of the known lupane lactones, ochraceolide A (128), ochraceolide B (129), and the new compound dihydroochraceolide A (135), among other known triterpenes. The structure of 135 was confirmed by reduction of 128, Fig. (37) and the stereochemistry to the epoxide group of 129, not determined when this compound was first isolated from K. ochracea [211], was established by preparation of both epoxide isomers, 129 and the new semisynthetic derivative, 20-epi-ochraceolide B (136) from 128. 

Squalene [(a//- )-2,6,10,15,19,23-hexamethyl-2.6, 10,14,18,22-tetracosahexaene]. The most important aliphatic, acyclic triterpene, C30H50, Mr 410.73, mp. -4.8 to -5.2 C, bp. 284-285°C, formula, see steroids. S. was first isolated from fish liver oils and later detected in plant oils and human fat. It is composed of 6 isoprene units and is formed from activated acetate ( acetyl-CoA) via mevalonic acid. It is an intermediate in the biosynthesis of all cyclic triterpenoids and thus also of the steroids. Its enzymatic cyclization to IanosteroI or cycloartenoI requires molecular oxygen and proceeds through (35)-squalene 2,3-epoxide. lit. Annu. Rev. Biochem. 14,555-585 (1982)"Chem. Soc. Rev. 20,129-147 (1991) - Kaiier, No. 34 Nat. Prod. Rep. 2, 525 - 5W (1985) Phytochemisby 27,628 (1988) (biosy nthe-sis) Stryer 1995,692-695.-/HS290/29 CASHI-02-4]... 

The pentacyclic triterpene skeleton hopane is generated by 2,7-, 6,11-, 10,15-, 14,19-, and 18,22-cyclization of the carbenium ion in a fivefold chair conformation (as drawn) arising from regioselective protonation of the 2,3-double bond of squalene (but not of the 2,3-epoxide). This explains why hopanes are usually not hydroxylated in the 3-position. 

In contrast to the previously discussed mono-, sesqui-, and diterpenes that are biosynthesized by linear condensation of five carbon units, triterpenes arise via dimerization of two famesyl pyrophosphate units to produce an intermediate compound, squalene (1) (Fig. 23.2). Squalene (usually as the 2,3-epoxide) may then be cyclized by several mechanisms from different conformations on an enzyme surface to produce the parent skeletal types of many different kinds of triterpenes that undergo subsequent modification (Banth-orpe and Chari wood, 1980 Harrison, 1985). The structures of many triterpenes and steroids may be explained by the biogenetic isoprene rule see Chapter 18) (Connolly and Hill, 1991). 

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