Meso-Chimonanthine

The synthesis of racemic chimonanthine has been realised in two ways. In the first case an ethereal solution of the Grignard derivative of N tryptamine (15) is treated with ferric chloride. Hydrolysis gives unchanged (15), racemic chimonanthine [racemic (7)] in 19 % yield, and meso-chimonanthine (8) in... 

Menozzi C, Dalko PI et al (2006) Concise s3mthesis of the (+/—)-Nb-desmethyl-meso-chimonanthine. Chem Commun (Cambridge, U K). 4638-4640... 

The 5-exo intramolecular Heck reaction has been employed to construct both meso-chimonanthine 105 and (-)-chimonanthine 106 (Scheme 16). The synthetically most challenging structural features of these bispyrroloindoline alkaloids are their vicinal quaternary centers. The synthetic plan relies on two sequential 5-exo carbopallada-tions to stereoselectively produce pentacycles 102 and 104 from closely related intermediates. Heck cyclization of 100 requires a challenging tetrasubstituted alkene insertion to provide 101. A second 5-exo carbopalladation reaction adjacent to the newly formed quaternary center installs the second quaternary center and oxindole unit. The tartrate-derived ene-diamide 100 underwent bis-5-cJct) carbopalladation when... 

This was followed shortly by a stereo- and enantiocontrolled synthesis of (—)-chimonanthine (154) and calycanthine (150) as well as a second route to meso-chimonanthine (152). The central step in this synthesis features the use of a double Heck cyclization to create vicinal quaternary carbon centers in high yields and with complete stereocontrol 124). The synthesis commenced with a double alkylation of the lithium dienolate of dimethyl succinate 194 and tartrate-derived diiodide 195 to give a diastereomeric mixture of the saturated diesters. Subsequent oxidation of the diesters, followed in succession by aminolysis, A-benzylation, removal of the benzyl ethers, and silylation, provided the cyclization substrate 197, which on Heck cyclization yielded a single product, 198, a pentacyclic bisoxindole, subsequently shown to have the meso relationship of the two oxindole groups. Further manipulations of 198 led eventually to the diazide derivative 199, which can be processed to we.so-chimonanthine (152), following the procedure established in the preceding synthesis (Scheme 14). 

As a prelude to discussing the implementation of this bold plan towards 1, we thought that we would start our discussions by mentioning a few aspects of the route that the Overman group had developed previously to access their key starting material, meso-chimonanthine (3). Scheme 3 provides the steps of this creative total synthesis in which the most important reaction was unquestionably the conversion of 17 into 20, since this operation was responsible for generating the two adjacent quaternary centers of the target molecule. 

With these two steieogenic centers set beautifully through this creative approach, meso-chimonanthine (3) was then obtained in a few additional operations from 20 to ultimately provide a reliable route capable of delivering the natural product in an overall yield of 34%. As an additional option for obtaining supplies of this compound, the Overman group could also turn to a 3-step... 

Scheme 3. Overman s total synthesis of meso-chimonanthine (3).

Overman LE, Larrow JF, Steams BA, Vance JM (2000) Enantioselective Constmction of Vicinal Stereogenic Quaternary Centers by Dialkylation Practical Total Syntheses of (-i-)-and meso-Chimonanthine. Angew Chem Int Ed 39 213... 

The indole alkaloids have provided a rich source of synthetic challenges over many years, and novel approaches and chemistry still flow from this source. Natural products derived only from tryptamine, the key feature being indole-C3—C3 and N—C2 links (the cyclotryptamines), are exemplified by chimonanthine. Overman s synthesis of meso-chimonanthine (106) (2000AGE213) was followed by the use of this substance to prepare hodg-kinsine (108) (Scheme 14) (2003AGE2528), just one of several outstanding alkaloid syntheses from the Overman laboratory. 

Psychotria colorata (Willd. ex Roem. Schult.) Miill. Arg. Hodgkinsine, (+)-Chimonanthine, meso-Chimonanthine, and Psychotridine... 

Lathrop SP, Movassaghi M. Application of diazene-directed fragment assembly to the total synthesis and stereochemical assignment of (+)-desmethyl-meso-chimonanthine and related heterodimeric alkaloids. Chem Sd. 2014 5 333-340. 

N-methyltryptamine (dipterine) has been converted into its Grignard derivative and oxidized in situ with ethereal ferric chloric to yield dl- along with a trace of meso-chimonanthine. These were the expected products since they were produced under conditions where no possibility for hydrolytic ring opening was provided. In a different approach, N-methoxycarbonyl 3-2 -aminoethyloxindole was dimerized by means of iodine in tetra-hydrofuran to furnish two isomeric dimers which were reduced separately with lithium aluminium hydride which converted the — NHCOOMe to — NHMe and the oxindole to the carbinolamine. 

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