Indole Alkaloids, Macrocycles and Heterocycles

An enantioselective total synthesis of (-)-terengganensine A, a heptacyclic monoterpene indole alkaloid, was performed. A short sequence allowed to obtain the enantio-enriched target in good overall yield. The synthesis featured a key asymmetric transfer hydrogenation of iminium as well as a complex domino dihydroxylation, oxidative cleavage, triple cyclization, hydrolysis sequence. An excellent stereocontrol was achieved thanks to a strategy based on an in-depth conformational analysis of the substrates.

A divergent synthesis of (-)-vallesamidine and of (+)-1,2-dehydroaspidospermidine was also reported. A key macrocyclic intermediate was obtained in enantio-enriched form as a single diastereoisomer. An enantioselective 1,4-addition on a 3-substituted cyclopent-2-en-1-one, a chiral prolinol-catalyzed aldol reaction as well as a stereoinvertive nucleophilic substitution of a benzylic mesylate with a vinylic boronic acid derivative were responsible for the obtained excellent stereocontrol. From a common intermediate, a complex domino sequence allowed the formal diamination of a cyclopentene and therefore the synthesis of (-)-vallesamidine. Using the same intermediate, a novel TiCl3-promoted reductive cyclization/rearrangement cascade afforded (+)-1,2-dehydroaspidospermidine. Both targets were obtained in 9 to 11 steps and good overall yield with an excellent stereocontrol.

(+)-Peganumine A, was synthesized in 7 steps and excellent overall yield with a good enantioselectivity. After different unsuccessful strategies, an innovative approach was developed for the synthesis of (+)-peganumine A, a structurally uncommon octacyclic carboline dimer. A novel macrocyclization method relying on the use of a omega-isocyanoaldehyde followed by transannular cyclization furnished a tetracyclic alpha-ketoamide in a single step and good yield. As last step, a chiral thiourea-catalyzed enantioselective Pictet-Spengler reaction/transannular cyclization/deprotection domino sequence afforded (+)-peganumine A in excellent enantioselectivity. Overall, the targeted molecule was obtained in a short 7-step sequence and in excellent yields.

We then extended the scope of the macrocyclization. Macrocycles with different ring sizes and ring topologies were synthesized in moderate to good yields. Different isonitrile-based multicomponent reactions were successfully exploited. This new methodology was then successfully applied to the total synthesis of (-)-eurystatin B, a 13-membered cyclic peptide containing an alpha-ketoamide function. An interemediate was cyclized using a 2-component 3-center Passerini reaction to the 13-membered core ring in excellent yield. Our total synthesis allowed the determination of the absolute configuration of (-)-eurystatin B.

We then focused on the development of a novel silver-catalyzed 1,1-aminoacylation of homopropargylamine for the synthesis of proline amide derivatives. Mechanistic studies revealed a silver-catalyzed 5-endo-dig cyclization of homopropargylamines to 2,3-dihydro-1H-pyrrole derivatives followed by an unprecedented on-column 3-component addition of isonitrile and water onto the latter. Wide range of proline amide derivatives was obtained in good yields. The reaction was then extended to primary homopropargylamines. Similarly, a silver-catalyzed 5-endo-dig cyclization afforded a 3,4-dihydro-2H-pyrrole intermediate. Addition of a carboxylic acid and an isonitrile reaction partner initialized an Ugi-Joullié reaction.