Tetracyclic oxindoles

The foregoing degradations, when considered in conjunction with the spectrographic properties of the molecule and the proved presence of one O-methyl group, resulted in the provisional formulation of mitraphylline as V, i.e., as the tetracyclic oxindole analog of ajmalicine (56). This expression was based on the molecular formula C21H26N2O4, and on the assumption that the molecule contains a carbomethoxy group. 

Tetracyclic heteroyohimbines (COntinue d) Tetracyclic oxindoles (continued) ... 

A detailed study of the previously uninvestigated U. borneensis was also carried out. The major alkaloids were the tetracyclic oxindoles isorhynchophylline, rhynchophylline, isocorynoxeine, and corynoxeine accompanied by minor yohimbine alkaloids, pseudoyohimbine, alloyohimbine and 3-epi-P-yohimbine (81). The unique and predominant occurrence... 

An ingenious new approach to the synthesis of pseudotabersonine (707) has been developed by Carroll and Grieco (391). Here the intermediate oxindole 708 was constructed by a remarkable process in which the anion from the precursor oxindole 709 was alkylated by Grieco s spiroaziridinium triflate 710. A-Benzylation of the product 711, followed by a reverse Diels-Alder fragmentation, then an intramolecular aza-Diels-Alder cyclization, gave the tetracyclic oxindole 708. Introduction of the three-carbon unit into position 2 in 70iB was achieved by condensation with 2-lithio-l,l-diethoxy-2-... 

H3CO2C—C=CH0CH3) chromophore. IR and PMR spectral properties of the tetracyclic oxindole alkaloids are collected in Tables IV and... 

The tetracyclic oxindole alkaloids possess four asymmetric centers (C-3, C-7, C-15, and C-20) and therefore can exist as sixteen possible diastereoisomers. However, since all naturally occurring indole alkaloids of the corynane type possess a C-15a hydrogen [17), the total number of isomers is restricted to eight. Taking into consideration the asymmetric... 

Beckett et al. 49) found no significant relationship between mass spectral fragmentation and stereochemistry in a number of tetracyclic oxindole alkaloids. The relative abundance of the main mass spectral fragments in the spectra of rhynchophylline and isorhynchophylline seem to be independent of the stereochemistry at C-7. 

Condensation of the unstable, highly functionalised aldehydo-ester (162) with 2-hydroxytryptamine gave a mixture of three stereo-isomeric, tetracyclic oxindole esters (163). The major isomer, when heated with polyphosphoric acid, underwent cyclisation, hydrolysis, decarboxylation, and further cyclization, to give the hexacyclic ketone (164), reduction of which gave (+)-19-hydroxyaspidofractinine (Scheme 29), identical (except in optical rotation) with an authentic sample prepared from minovincine. Kuehne s versatile biomimetic synthesis has been further... 

Although some researchers have reported that two che-motypes (chemically distinct types of a plant species) of cat s claw are recognized, one containing pentacyclic oxin-dole alkaloids (POA) and the other containing tetracyclic oxindole alkaloids (TOA) (Laus et al. 1997), others have indicated that such chemotypes are not typically found and that cat s claw contains both POAs and TOAs (Taylor 2002a, 2002b). 

The anticancer effect of cat s claw can be partly attributed to the pentacyclic oxindole alkaloids that are likely accompanied by tetracyclic oxindole alkaloids, some of which are calcium channel blockers and hence hypotensive (Bacher et al. 2006 Garcia Prado et al. 2007 Laus et al. 1997 Reinhard 1999 Shi et al. 2003). 

A total synthesis of strychnofoline (277), a bisindole constituted from the union of a tetracyclic oxindole and a tryptamine unit, and previously isolated from S. usambarensis (165), has been recently reported (166). A key feature of the synthesis is the convergent assembly of the tetracyclic core containing the oxindole moiety 276 through the ring-expansion reaction of a spiro[cyclopropan-l,3-oxin-dole] 274 and a cyclic imine 275, as shown in Scheme 21. 

Extracts of U. rhynchophylla have been shown to be anticonvulsive, antioxidant, neuroprotective, and cytotoxic [34, 38-40]. Some of these activities are attributed to the tetracyclic oxindole alkaloids rhynchophylline and isorhynchophylline. They have been shown to inhibit NMDA receptors [41], These receptors are transducers of postsynaptic signals in the central nervous system of mammals. Inhibitors of NMDA receptors could be used to treat disorders caused by excessive activation of this pathway, like cerebral ischemia, Parkinson s, and Huntington s diseases [42]. 

The synthesis commences with alkylation of oxindole 120 with spiroaziri-dinium triflate 109, providing the 3,3-disubstituted 121 in 53% yield (cf. Scheme 2.17). Treatment of 121 with boron trifluoride etherate at 100°C in toluene initiates the tandem retro Diels-Alder/intramolecular aza Diels-Alder process, leading to spiro-tetracyclic oxindoles 122 and 123 (1.5/1) in 61% yield. Addition of 2-lithio-l,l-diethoxy-2-propene to oxindole 122 provides carbinolamine 124 (95%). Exposure of 124 to p-toluenesulfonic acid in acetone-water followed by treatment with excess triethylamine in acetonitrile at 80°C effects the biomimetic transformation to adduct 126, which possesses the pentacyclic carbon framework of pseudotabersonine. This unique two-step one-pot transformation generates the inherently unstable dihydropyridine portion of dehydrosecodine 125, which participates in an intramolecular reverse electron-demand Diels-Alder reaction, providing 126 in 50% yield. The total synthesis is completed by transformation of the formyl group into the requisite carbomethoxy unit followed by N-benzyl deprotection (Scheme 2.19). 

FIGURE 49.16. Chemical structures of (A) pentacyclic and (B) tetracyclic oxindole alkaloids. 

Arbain and coworkers [35] discovered unusual indole monoterpenoid gluco-alkaloid, characterized by a glucose moiety on the benzenoid ring. Recent studies reported an unusual oxindole alkaloid, macrophylUonium (1.23), pair of new tetracyclic oxindole alkaloids, macrophyllines A and B (1.24 and 1.25) with significant vasodilating activity [36]. 

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