Of macroline

The partial synthesis70 of macroline (136) from normacusine B (140) was inspired by its postulated biosynthesis from a sarpagine-type precursor. Normacusine B (140), prepared by a previously published route from perivine, was protected at the primary alcohol group and then methylated on Na. Direct epoxidation of the product (141) failed however, osmylation gave the desired diol together with the related oxindole obtained by simultaneous oxidation of the indole double-bond, followed by rearrangement. Conversion of these diols into the related epoxides gave a mixture of (142) and (143), from which the desired epoxide (142) could be separated satisfactorily by fractional crystallization. 

Pandicine (312), an air-sensitive, amorphous alkaloid from the leaves of Pandacastrum saccharatum Pichon, has a novel structure composed of macroline and highly oxygenated tabersonine units.135 Its structure was elucidated mainly by comparison of its H and 13C n.m.r. spectra with those of the macroline unit in villalstonine and the oxygenated tabersonine unit in cryophylline. There is at present no definitive proof for the relative stereochemistry of the two components of the pandicine molecule that depicted in (312) is simply based on the stereochemistry deduced for related monomers, namely talcarpine and hazuntinine. Presumably the ease of oxidation of pandicine is due to the facile formation of the quinonoid species (313). 

Finally, the more important arguments leading to the structure of macroline (215), C21H26O2N2, will be discussed the presence of the groupings... 

The mass spectrum of the ketone (222) shows, as does that of macroline (215) (see Scheme 14), the peaks mje 197 and 170. The macroline peaks at mje 251 and 208 are now shifted 12 mass units lower to mje 239 and 196, i.e. ketone (222) contains, instead of >C=CH2, the grouping >CH2. Structure (222) contains nine C-bonded exchangeable protons. The distribution shown in ( H9-222) has been confirmed mass spectrometrically. 

In connection with the biogenetic origin of alstonisidine it is of interest to note that 0-benzoylvincamajine (42) has been shown to occur in the closely related A. macrophylla (42) and trimethoxybenzoyl-quebrachidine (44) in A. constricta (35). It is thus possible that alstonisidine arises by Mannich condensation of macroline (57) with quebrachidine to give an intermediate similar to 69, which is then converted into alstonisidine by closure of the amino ketal function (39). 

On the basis of this evidence the structure XVIII was proposed as a working hypothesis for the structure of macroline this proved to be capable of providing a rational explanation of the mass spectra ofmacroline and its derivatives and was ultimately shown to be correct. The mass spectrum of macroline indicates that two prominent fragmentation processes occur. The first of these leads to the jS-carbolinium ion XXb at... 

In later experiments the acid hydrolysis of macralstonine was carried out using shorter reaction times (0.5 hour) and the monomeric products were separated from the dimeric and polymeric material by high-vacuum distillation. The products thus obtained were alstophylline (XXVIII), macroline (XVIII), the ketone XLIII, and its cyclic anhydro derivative, XLIV. No trace of the methoxyketone (XXXI) could be found. The presence of XLIV was perhaps not surprising since this ketone also arises by distillation of XLIII under the same conditions. However, a comparison of the results of these two hydrolyses is instructive. After brief reaction times alstophylline is produced but not the methoxyketone XXXI the latter must therefore arise by subsequent hydrolysis of alstophylline. In contrast the ketone XLIII is not generated by further reaction of macroline (XVIII) with hydrochloric acid since under these reaction conditions macroline gives only resinous products. Hence both macroline and the ketone XLIII must be obtained directly... 

The structure XLIX for macrosalhine and L for anhydromacrosalhine methine are strongly. supported by their behavior on electron impact. When introduced into the mass spectrometer macrosalhine chloride undergoes thermal Hofmann degradation and the mass spectrum ob.scrved is that of the methine base LII, C21H26N2O2, M 338, which is an isomer of macroline (XVIII). As expected, several of the peaks in the... 

The biomimetic transformation of macroline into alstonerine, previously reported in brief, has now been described in detail. Additional, related interconversions simultaneously reported include the reduction of alstonerine (164) by means of sodium borohydride, followed by acid treatment, which gave Nb-methyl-Nb,21-secotalpinine (165), and the two-fold reductive rearrangement of alstonisine (166) into talpinine (167) (Scheme 23). 

Advances in the chemistry of macroline, sarpagine, and ajmaline-related indole alkaloids 06T8655. 

Cook has also carried out a synthesis of 11-methoxymacroline (350), which was then transformed into alstophylline (340), which in view of LeQuesne s previous demonstration of biomimetic alstophylline-macroline coupling to macralstonine (336) (234,235), and Cook s previous synthesis of ( + )-macroline (226,227), constituted a total synthesis of macralstonine (336). Similarly, the synthesis of ( + )-A -methylsarpargine (351) constituted a total synthesis of the bisindole macralstonidine (352), in view of LeQuesne s biomimetic macroline-A -methylsarpagine coupling (236). The synthesis of A -methylsarpagine and 11-methoxymacroline, required preparation of the appropriate methoxytetracyclic ketones 353 and 354 (the methoxysubstituted versions of the tetracyclic ketone 348 used above in the Cook synthesis of (+ )-macroline), which served as versatile templates for elaboration to alstophylline (340) and A -methylsarpagine (351). 

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