Of neo-clerodanes

From another Argentinian Baccharis species, B. articulata, three diterpenes of neo-clerodane type, articulin, Fig. (3), articulin acetate and barticulidiol, Fig. (4), together with the known bacchotricuneatin A, Fig. (5), were isolated [22,23],... 

Teucrium species are a rich source of neo-clerodane diterpenes which can be used as chemotaxonomic markers for the genus. TTiey possess therapeutic properties and are used as folk medicine in many parts of the world. 

The stereochemistry at C-12 is also very important. This chiral centre of neo-clerodane diterpenoids, C-12 was assumed to have (S) configuration. This view was maintained after X-ray analysis and, chemical correlations with the compounds of known absolute stereochemistry. Hence, Teucrium diterpenoids were invariably found with C-12S configuration. However, recent studies, using H NOE difference techniques [24,25], have shown that S configuration at C-12 is by no means a common stereochemical property. During the investigation... 

The structures of all these compounds were established by spectral data including 2D NMR techniques. X-ray analysis were performed for compounds 60 (alysine A) and 139 (alysine B) in order to be sure of their stereochemistry. All six compounds had typical substitutions of neo-clerodane diterpenes, only instead of a monosubstituted fiiran, they all have a, P-disubstituted furan ring, which was the first isolation of such type of compounds. 

M. S. J. Blaney, W. M. Oxirane-opening reactions of some 6,19-oxygenated 4a,18-epoxy-neo-clerodanes isolated from teucrium. Biogenesis and antifeedant activity of their derivatives. Tetrahedron 1994, 50, 5451-5468. 

E-isolinaridial and E-isolinaridial methylketone are two neo-clerodane diterpenoids isolated from the aerial parts of Linaria saxatilis var. glutinosa (Schrophulariaceae). Benrezzouk et al. evaluated these compounds on multiple inflammation pathways and found that they were not COX-1/COX-2 inhibitors [139]. However, E-isolinaridial and E-isolinaridial methylketone were dual inhibitors against purified phospholipase A2 and 5-lipoxygenase. E-isolinaridial and E-isolinaridial methylketone showed potent inhibition of cell-free 5-LOX enzyme with IC50 values of 0.42 pM and 1.41 pM,... 

The clerodanes are a notable example of feeding deterrents2 and further examples have been discovered recently. The natural insect antifeedant clerodin (100) forms the basis of the name of this type of diterpenes called the neo-clerodane diterpenes. Ateo-clerodanes are compounds with a clerodane skeleton and exactly the same absolute configuration as clerodin. Those that have the opposite absolute configuration are referred to as ent-neo- cl erod an es. 

Characteristic constituents from the Baccharis genus, one member of the Compositae, are the neo-clerodane type diterpenes. For example, the aerial parts of B. trinervis, a representative of which is used in South American folk medicine, furnished 24 neo-clerodane type diterpenes, many of them new, e.g., methyltrineracetal, Fig. (1) and epi-methyltrineracetal, Fig. (2) [19],... 

Jakupovic et al. [34] investigated some representatives of the genus Baccharis which grow in Texas and Mexico, and seven new e /-clerodane diterpenoids have been described from Baccharis pteronioides D. C. Novel neo-clerodane diterpenoids were also isolated from the aerial parts of B. genistelloides, which were collected in the area of Sao Paulo and neighbouring states of Brazil [35-37] and from Baccharis scoparia (L.) Sw., a species widespread in the Caribbean Islands [38],... 

According to Rowe s nomenclature [14], the hydrogen at C-lOa being and methyl at C-5 P(Me-19) indicate clerodane, the reverse en/-clerodane structure. Roger [ 15] assigned en/-/jeo-clerodane for the former and neo-clerodane for the latter type of stmctures. In the present day, clerodane and neo-clerodane names are used commonly. Most of the diterpenoids isolated from Teucrium species have neo-clerodane structures. 

In case of the presence of an acetyl group at C-3 together with 4, 18-oxirane ring in a neo-clerodane diterpenoid, the H NMR spectrum clearly... 

In Teucrium diterpenoids C-6 position is also very important. Almost all of the neo-clerodane diterpenes have an oxygen function at that location, either as a hydroxyl, acetyl or a ketone, and sometimes as an ether function. In somecases, C-6 hydroxyl group forms a lactone with C-18 methylene group as in compounds 7, 14, 16. The hydroxyl or the acetyl groups could possess a or P stereochemistry. When the literature is studied, there are some discrepancies for the chemical shifts of the C-6 proton, either a or 3, it appears in the lowfield or highfield, as observed in compounds 77 and 78. 

From T. massiliense [55], six neo-clerodanes were isolated, two of which have hydroxymethylene and the other four acetoxymethylene groups at C-19. In all six compounds, C-6 substituents have P-stereochemistry. The H NMR spectra of all six compounds (86-91) were recorded in CDCI3, so it is easy to compare their chemical shifts. The chemical shift of C-19 hydroxymethylene groups were around 8 4.00-4.30 while its acetyl derivatives at o 4.35-4.80 (Table 9). 

In 108, the position of the tertiary hydroxyl group at C-10 was decided from the C NMR spectrum. C-10 hydroxyl showed paramagnetic shift at C-1 (A6 + 7.9 ppm), C-5 (A6 + 3.8) and at C-9 (A6 + 5.2) which are 3 carbons with respect to closely related neo-clerodane derivatives lacking the tertiary alcohol function, such as teuflavin (113) obtained from T. flavum subsp. glaucum [65]. 

From Teucrium oliverianum [34,68] the two C-10 hydroxylated neo-clerodane diterpenes were isolated, teucrolivins B (115) and A (116). Both possess a C-103 hydroxyl group appeared at 8 81.53 and 81.73, respectively, the 3-configuration of them was supported by NOE experiments, which showed that C-20 methyl group and the H-1 a proton must be close (3.7 % NOE enhancement in H-1 a when the Me-20 protons were irradiated). The NOE experiments summarized in Table 15 clearly revealed that the relative stereochemistry of the substituents of decalin ring of teucrolivin B is that depicted in its formula 115. 

From T. sandrasicum [69] two C-10 P-hydroxylated and one a-hydroxylated neo-clerodane diterpenes were isolated, sandrasin A (117), 6-deacetylsandrasin A (118) and sandrasin B (119), All three compounds had C-12R configuration. This configuration was deduced by the observation of a NOE between Me-17 and H-12 which was extensively studied previously [25,29]. The C-10 hydroxyl group induced paramagnetic shifts on C-1, C-5 and C-9 with respect to those of closely related neo-clerodane diterpenes either lacking or with an a-hydroxyl... 

In two different studies with the aerial parts of Teucrium alyssi/olium [35,64], we have isolated six new rearranged neo-clerodane diterpenes alysines D and E (110-111) and 3-deacetylalysine B (140). 

Teucrium species are used in folk medicine as diuretic, diaphoretic, carminative, astringent, stimulant and tonic, antiseptic, antipyretic and antiinflammatory agents. T. cubense [92] for example is used against stomach aches and as an amoebacide. Teucjaponin A(32) obtained from T. japonicum [33] was shown to be antifeedant for the larve of Prodenia litura. Its threshold concentration for inhibitory activity was about 400 ppm in the leaf disk test. Generally neo-clerodane diterpenes posses insect antifeedant activity and they are used as antifungal, antitumor and antibacterial agents [56,63]. The antitumor activity of T. bicolor [52] was reported. The antifeedant activity of neoclerodanes is mentioned in a... 

Clerodanes.—The reversal of the absolute configuration assigned to clerodin has led to some controversy over that assigned to the ajugarins. They now appear to have the neo-clerodane absolute stereochemistry. Teucrium (Labiatae) species have continued to be a source of new clerodanes. Eriocephalin, isolated from T. eriocephalum, was assigned the structure (24) on the basis of an X-ray analysis and the structure (25) has been assigned to a clerodane from T. polium. 

Paquette and Efremov used a ring-closing metathesis strategy in their first total synthesis of the rearranged neo-clerodanes, teubrevin G and teubrevin These compounds feature a cycloctanene core fused and... 

Similar processes have been designed and utilized extensively by Barriault and coworkers for efforts in natural product synthesis. An impressive example of this strategy was utilized for the synthesis of the neo-clerodane skeleton of teucrolivin A. Thermal rearrangement of 92 under microwave irradiation results in a tandem sequence featuring an oxy-Cope rearrangement, followed by the Claisen rearrangement and subsequent ene reaction to give 93. 

L6pez-01guin J., De la Torre M.C., Ortego F., Castanera P., Rodriguez B. Structure-activity relationship of natural and synthetic neo-clerodane diterpenes from Teucrium against Colorado potato beetle larvae. Phytochemistry, 50 749-753 (1999). 

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