Iridoids utilization

Tissue Cultures, Microbial Transformations.—Little success has rewarded the search for cell cultures that effectively biosynthesize monoterpenes de novo. The most impressive studies utilize cultures from a variety of Mentha spp. yields of oil were some 60 % (w/v) of those in the parent plants, but the monoterpene products were generally more oxidized (i.e. ketones extra C=C bonds predominated). In vitro, oxidation at C-3 of the menthane skeleton was also restricted, apparently owing to an inhibition of the enzymic reduction of the 4(8) double bond in the intermediates formed.925 926 Colchicine stimulated synthesis of essential oil by Mentha cultures.927 Iridoid glucosides have been produced by cultured cells of Gardenia spp.673 Menthone was biotransformed to neomenthol by Mentha suspension cultures,928 and Nicotiana lines oxidized linalool and its derivatives at C-10 to aldehydes and alcohols,929 and also foreign substrates such as a-terpineol (at C-6 and C-7) and /raw.s-/ -menthan-9-en-l-ol (at C-4 and C-10).930... 

An alternate approach to the iridoid core, again developed by Biichi, utilized the [2+2] cycloaddition of cyclopentene 28 and tricarbonyl 29 (Scheme 6). Following photochemical annulation, the resulting cyclobutane 30 underwent a retro-aldol reaction and hemiacetal formation to provide racemic cyclopenta[c]pyran 31. Elaboration of 31 to loganin (16) required 10 additional steps. ... 

A strategy developed by Tietze and coworkers early in his independent career involved the application of intramolecular or intermolecular inverse electron demand hetero-Diels-Alder reactions to iridoid total synthesis. The intermolecular [4+ 2]-cycloaddition of ethyl vinyl ether and unsaturated aldehyde 31 provided acetal 32, which underwent double bond isomerization to afford 33 (Scheme 1) An intramolecular variant of this reaction is discussed in detail later (Scheme 10). More recently, Jacobsen and Chavez extended this work with the enantio- and diastereoselective synthesis of a range of iridoid natural products. Utilizing tridentate Cr(III) catalyst 34, acetal 35 was prepared in 98% ee with good diastereoselectivity (Scheme 1)P... 

Complimenting these [2+2] and [4+2] cycloaddition approaches, is the elegant work of Krische and Jones, who constructed the iridoid core utilizing a (3 + 2) annulation (Scheme 8). Excellent regio- and stereoselectivity were observed for the triphenylphosphine-catalyzed (3 + 2) annulation between enone 36 and butadienoate 37 to yield 38, which was converted to (+)-geniposide (39) in 13 subsequent steps. " ... 

Deoxyloganin (24) has previously been synthesized by Tietze and coworkers, utilizing an intramolecular hetero-Diels-Alder reaction to construct the iridoid core (Scheme 10). The synthesis commenced with conversion of (5)-citronellal (47) to enol ether 48 in seven steps. Knoevenagel condensation of the aldehyde with Meldrum s acid, followed by in situ intramolecular hetero-Diels-Alder reaction afforded pyran 49, with all the carbons required for the natural product core installed. Conversion of 49a, via methanolysis and a reduction/elimination sequence, to lactol acetate 50, was achieved in four steps. Finally, glycosylation and deprotection provided the natural product in a total of 14 steps. 

Gardner, D. R. and F. R. Stermitz, Host plant utilization and iridoid glycoside sequestration by Euphydryas anicia (Lepidop-tera Nymphalidae), J. Chem. Ecol., 14, 2147-2168 (1988). 

Stermitz, F. R., D. R. Gardner, F. J. Odendaal, and P. R. Ehrlich, Euphydryas anicia (Lepidoptera Nymphalidae) utilization of iridoid monoterpenes from Castilleja and Besseya (Scro-phulariaceae) host plants, J. Chem. Ecol., 12, 1459-1468 (1986b). 

Hudlicky and coworkers also reported an elegant synthesis of the iridoid sesquiterpene (-)-specionin, by utilizing the low-temperature anion-accelerated VCP-CP rearrangement developed in their lab. The precursor siloxyvinylcyclopropane 38 was synthesized as a mixture of exo/endo isomers by the cyclopropanation of substituted cyclopentenone 36 with the lithium dienolate 37 derived from4-(dimethyl-tert-butylsilo5q )-2-bromocrotonate tScheme 11.321. Rearrangement of the diastereomeric VCP substrates was achieved by the use of TMSI/HMDS at -78 °C to afford the tricyclic ketone in high yield as a mixture of diastereomers, which was then converted to the natural product. ... 

The extensive isolation of iridoid glycosides from the plants of various families and exploration of their pharmacological potentials provide us new insights for utilization of these wild resources either the pure chemicals or their erode extracts for development of new natural drugs. Recent biosynthetic studies on iridoids also reveal us a new concept for synthesis of iridoid monoterpenoids via MEP pathway rather than well-known MVA pathway for terpenoid and steroid biosynthesis in higher plants. The traditional use of iridoid-rich plants as food, nutraceutical, cosmetic, and pharmaceutical industries is well justified, and their wide-scale use and cultivation may be popularized for maintenance of good health and as potential source of raw materials for pharmaceutical industries. 

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