Tetrahydroalstonine

Leonard and Elderfield have also carried out degradation experiments with alstonine and its tetrahydride. On fusion with potassium hydroxide at 300-350° in nitrogen, alstonine furnishes barman (p. 490) and indefinite basic and acidic fractions. Tetrahydroalstonine on like treatment produces barman, worharman, and three unidentified bases, each of which fluoresces blue in alcoholic hydrochloric acid Base A, C4,H4gN2, m.p. 171-5 to 172-5°, forms a picrate, m.p. > 267° is probably a substituted -carboline. Base B, or 18 3, gives apicrate, m.p. 261° (dec.). Base C,... 

Tetrahydroalstonine gives with the Adamkiewicz test, as modified by Harvey et al., a colour similar to that given by yohimbine, which is taken to indicate the presence of a tetrahydro-/3-carboline ring system. Further, the ultra-violet absorption curves for yohimbine and tetrahydroalstonine... 

The sodium borohydride reduction of the preequilibrated mixture obtained from 4,21-dehydrogeissoschizine chloride (32) resulted in four isositsirikine isomers (46, 47, 48, 602) besides tetrahydroalstonine and 19-epiajmalicine. A... 

Microbial transformations of four heteroyohimbine stereoisomers [ajmalicine (81a) tetrahydroalstonine (81b), isoajmalicine (81c), and akumigine (81d)] yielded mixtures of 10- and 11-hydroxylation products (786) (Scheme 21). Microorganisms known for their abilities to metabolize indole alkaloids, steroids, and antibiotics were intitially screened, and seven cultures were further used for preparative-scale incubations with alkaloid substrate. The microorganisms used and yields (by HPLC) of metabolites obtained from 81a-81d are shown in Table HI. 

Leaf organ cultures of C. roseus have also been described 118). A typical 2.5-g fresh weight inoculum produced 29 g fresh weight of leaf material after 35 days dedifferentiated tissue was absent. The alkaloids found included ajmalicine (39), sitsirikine (48), tetrahydroalstonine (39), serpentine (40), and vindoline (3). 

The work by Scott and Lee 165) on the isolation of a crude enzyme system from a callus tissue culture of C. roseus was followed by studies of Zenk et al. on an enzyme preparation from a cell suspension system which produced indole alkaloids 166). The cell-free preparation was incubated with tryptamine and secologanin (34) in the presence of NADPH to afford ajmalicine (39), 19-epiajmalicine (92), and tetrahydroalstonine (55) in the ratio 1 2 0.5. No geissoschizine (35) was detected. In the absence of NADPH, an intermediate accumulated which could be reduced with a crude homogenate of C. roseus cells in the presence of NADPH to ajmalicine (39). Thus, the reaction for the formation of ajmalicine is critically dependent on the availability of a reduced pyridine nucleotide. 

The intermediate which accumulated in the absence of NADPH was identified as 20,21-dehydroajmalicine (76) and given the trivial name ca-thenamine 167). It was labeled to the extent of 52% after feeding [2- C]tryptamine in the absence of NADPH, and reduction with NaBH4 afforded tetrahydroalstonine (75). Intermediacy in the enzymatic reaction was also established through conversion to the ajmalicine isomers with... 

In vivo feeding experiments with singly and doubly labeled strictosidine (33) in C. roseus shoots afforded labeled ajmalicine (39), serpentine (40), vindoline (3), and catharanthine (4). Vincoside (85, page 37) was not incorporated into the alkaloids, suggesting that it was biologically inert 188). Brown and co-workers 190) conducted somewhat parallel studies examining the precursor relationship of strictosidine in C. roseus. Incorporation into tetrahydroalstonine (75), ajmalicine (39), catharanthine (4), and vindoline (3) was observed. 

A similar vinylogous Mannich reaction has been used by Martin in the total syntheses of the heteroyohimboid alkaloids (—)-ajmalicine and (—)-tetrahydroalstonine <1995JOC3236>. An attempted synthesis of an opioid analgesic 2,4-dibenzyl-3,7-diazabicyclo[3.3.1]nonan-9-one-l,5-dicarboxylate (piperidone) by a double Mannich reaction of oxoglutarate, 2 equiv of phenylacetaldehyde, and methylamine did not give the expected product but instead gave rise to an unexpected [l,6]naphthyridine derivative (Scheme 57) <1998PHA442>. 

The above structure/activity tendency is seen again in heteroyohimbine alkaloids. Tetrahydroalstonine (83) exhibits considerable selectivity towards presynaptic ct2-adrenoceptors but raubasine (ajmalicine) (84)... 

Cathenamine (100) has been identified as an early intermediate in terpenoid indole alkaloid biosynthesis (cf. Vol. 8, p. 27). It has also been isolated from Guettarda eximia. Another alkaloid, 4,21-dehydrogeissoschizine (99), has now been isolated from this plant it is readily converted into (100) in alkaline solution.29 On incubation with an enzyme preparation from Catharanthus roseus cell cultures in the presence of NADPH at pH 7, (99) was converted into ajmalicine (102), 19-ep/-ajmalicine (103), and tetrahydroalstonine (104), which are the normal products with this enzyme preparation. In the absence of NADPH, cathenamine (100) accumulated.30 The reaction to give (100) proceeded linearly with time, and was dependent on the concentration of protein and substrate. No conversion occurred in the absence of enzyme. 

Brown s one-pot synthesis54" affords mainly (19S)-heteroyohimbine alkaloids (e.g. tetrahydroalstonine) by a kinetically controlled process involving preferential formation of an ( )-alkene (61 ) from the initially formed dienamine... 

Fig. 7 Chemo-enzymatic formation of tetrahydroalstonine from tryptamine and secologanin by an enzyme extract from engineered E. coli harbouring a dual vector expressing both, STR1 and SG cDNAs from R. serpentina cell suspension cultures followed by chemical reduction. Due to simultaneous expression of STR1 and SG cDNAs, the intermediate strictosidine does not accumulate...

Rauniticine oxindole A (77) Rauniticine pseudoindoxyl (77) Tetrahydroalstonine (77) Tetrahydroalstonine A/-oxide (77) Uncarine A (77)... 

A brief, selective review of epimerizations in the isoquinoline and indole alkaloid series inevitably gives prominence to epimerizations at C-3 of tetrahydro-/3 -carbo-line derivatives, in particular of reserpine and reserpic acid lactone the epimerizations involved in Brown s synthesis33/ of Afa-methyl-tetrahydroalstonine and 3/3-H,20/3 -H-lVa-methyldihydrogeissoschizine, from ATb-benzyl-lVa-methylvincoside, are also discussed.69... 

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