P- Amyrin

The first synthesis of a P-amyrin derivative was accomplished by a convergent route which depended on cation-olefin cyclization to form the critical central ring. The plan of synthesis was largely guided by the selection of SM goals for the A/B and E ring portions of the target. 

Pentacyclosqualene, the symmetrical hydropicene corresponding to squalene, has not been made by acid-induced cation-olefin cyclization of squalene, despite considerable experimental study. A simple, convergent synthesis of pentacyclosqualene using cation-olefin cyclization to generate ring C was developed. The C30-framework was constructed by radical coupling to a tetracyclic intermediate that was also used for the synthesis of onoceradiene. 

It was found later that the electrolytic coupling reaction gave better yield with the acetate corresponding to B, since fragmentation was a major side reaction of the y-hydroxy acid B (Ref. 2). 

Divergence of Enzymatic and Biomimetic Chemical Cyclization Reactions.297 

The Synthesis of Prostaglandins-, J. Wiley-Interscience New York, 1977. 

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Fig. 27. Total synthesis of P-amyrin [559-70-6] (256) via a carbocationic cyclization, where TMS = trimethylsilyl.

Knob (southern Canterbury Administrative Region see Fig. 2.11) and cycloartenol methyl ether [58] was found in plants from Clarke River, whereas four other collections failed to yield any TMEs. Similarly, populations of C. rigida (Raoul) Zotov from eastern South Island do not synthesize TMEs, whereas those from western South Island were shown to accumulate p-amyrin methyl ether [59]. An additional difference between populations from these two sites lies in the capacity of the former to produce short-chain wax components, as opposed to long-chain compounds from the latter (Cowlishaw et al., 1983). Different chemodemes were also described for C. cheesemanii (Hackel ex Cheesem.) Zotov plants from North Island exhibited lupeol methyl ether as the dominant compound along with lesser amounts of arun-doin and two unidentified compounds, whereas populations from the South Island had arundoin as the major compound with lesser amounts of lupeol methyl ether. 

The plant is known to produce norbisabolane diterpenes, including phyllanthusols A and B, which are both cytotoxic (36). From the bark, pentacyclic triterpenoids, phyl-lanthol, and olean-12en-3[3-ol (p-amyrin) have been isolated (37). Note lupane- and oleanane-type triterpenoids isolated from the bark of Phyllanthus flexuosus, such as olean-12-en-3 (3,15 a-diol, olean-12-en-3 [3,15 a,24-triol, lupeol, and betulin inhibited the enzymatic activity of topoisomerase II activity with IC50 values in the range of 10 to 39 p.M (38). 

Tirucallol, p amyrin, germanicol, lupeol, 3 hydroxy malabarica 14(26), 1 7 ,21 triene C30H50O... 

The use of HMDS as a derivatization reagent in the analysis of triterpenoid resins has been less explored. The TMS derivatives of triterpenoids bearing hydroxyl groups [a-amyrine, p-amyrine and hop-22(29)-en-3p-ol] have been identified in the triterpenic fraction of Burseraceae resins, thus demonstrating that HMDS combined with Py-GC/MS is effective in the derivatization of triterpenoid compounds [59]. However, the range of structures that can be fully derivatized and detected must be extended and, in order to get comprehensive results comparable with those coming from the well assessed off-line GC/MS procedures, general improvements in the on-line trimethylsilylation-pyrolysis method are needed. 

Characterization of P-Amyrin Synthase from Avena strigosa - A Novel... 

Fig. 5.1 Cyclization of 2,3-oxidosqualene to sterols and triterpenoids. The 2,3-oxidosqualene cyclase enzymes that catalyse the formation of the different products are indicated LS, lanosterol synthase CS, cycloartenol synthase LuS, lupeol synthase PAS, P-amyrin synthase aAS, a-amyrin synthase.

Genetic analysis indicates that two of the 10 sad mutants of A. strigosa that we isolated represent different mutant alleles at the Sadi locus.6 These mutants accumulate radiolabelled 2,3-oxidosqualene but not p-amyrin when the roots are fed with 14C-labelled precursor mevalonic acid, suggesting that the triterpenoid pathway is blocked between 2,3-oxidosqualene and P-amyrin.34 The roots of these mutants also lack detectable P-amyrin synthase activity, but, like the wild type and the other mutants, are unimpaired in cycloartenol synthase (CS) activity and sterol biosynthesis.34 The transcript levels for AsbASl are substantially reduced in roots of sadl mutants, while AsCSl transcript levels are unaffected,35 suggesting that the sadl mutants are either mutated in the AsbASl gene itself or in a gene involved in its regulation. 

KUSHIRO, T., SHIBUYA, M., EBIZUKA, Y P-Amyrin synthase. Cloning of oxidosqualene cyclase that catalyzes the formation of the most popular triterpene among higher plants, Eur. J. Biochem., 1998,256,238-244. 

Among the recent outstanding contributions to the chemistry of natural products is the conformational analysis designed by Derek Barton. He used it for the structural determinations of many complex molecules such as P-amyrin and cycloartenol. Robert B. Woodward was involved in the structural determinations of penicillin, strychnine, patalin, terramycin, aureomycin and the synthesis ofVitamin B12. 

The betulinic acid level in the E. florida leaves increased significantly in the May, June, Jully (autumn - winter) and, September, October and November (winter) which was mainly due to the accumulation of this compound in vegetal tissue. Some authors related with the pentacyclic triterpenes, just as betulinic, acid ursolic, acid, p-amyrine and lupeol, are supposed to be toxic to insects, due to their ability to inhibit acyl chain packing in the lipid bilayers of the insect membranes [Rodriguez et al, 1997 Prades et al., 2011]. 

Among five triterpenoids isolated from Calendula officinalis flowers, P-amyrin (119), faradiol (232), i /-taraxasterol (238), taraxasterol (239), and lupeol (238), the diol 232 was the most active. It showed a dose-dependent effect with a potency that equals that of indomethacin (5) in the topical anti-inflammatory assay with croton oil [33]. Esterification at C-3 of 232 with a fatty acid reduced the activity by more than 50% [33] consistent with our observation in the TPA-induced assay described above. The anti-inflammatory properties, as determined by croton oil-induced edema of mouse ear, of faradiol-3-O-myristate (233) and its 3-O-palmitate (234), the main components of lipophilic extracts of C. officinalis flowers, were shown to be contribute significantly to the pronounced antiphlogistic activity of the lipophilic extracts of C. officinalis flowers [34]. 

Johnson in 1993 described an approach to racemic p-amyrin involving application of a biomimctic polyene cyclization.7 In the same year Corey accomplished the enantioseleetive synthesis of compound 4. a key intermediate that opened the way to stereoselective preparation of compounds I, 2. and 3 8 A key step in the synthesis of P-amyrin (1) was the introduction of chiral oxazaboroli-dines for enantioseleetive carbonyl reduction. Ba ed on these methods, generation of an enantiomerically pure epoxide and its stereoselective cationic cyclization led to the pentacyclic system of structure 1 Diastereoselective cyclopropanation and an intramolecular protonation of a carbanion represent other interesting steps in this total synthesis. 

Stereoselective l.4-reduction oi the 1.3-butadiene system to olefin 57 lakes place tinder the conditions of the Birch reduction. Intramolecular protonation of the intermediate carbanion at the 18-position to give 57 occurs with high selectivity syn to the hydroxymethy-iene group Conversion into phosphoric acid derivative 58 and cleavage of the phosphoric acid amide group under (he conditions of the Bcnkeser reduction provides compound 5921 Fluonde ion causes the release of free p-amyrin (1) in a final step I Li, NH3(iyTllF (1/1.75), -78 C 93%. 

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