Enantioselective Total Synthesis of (−)‐Martinellic Acid

Abstract

An enantioselective total synthesis of martinellic acid is described. The pyrroloquinoline alkaloid core is efficiently prepared from a quinoline, employing a method which relies on a newly developed Cu‐catalyzed enantioselective alkynylation using the chiral imidazole‐based biaryl P,N ligand StackPhos to establish the absolute stereochemistry. The remaining carbon atoms are then installed by means of a diastereoselective Pd‐catalyzed decarboxylative allylation and the synthesis is completed after straightforward functional‐group manipulation. This new synthetic method enables the most concise enantioselective synthesis of this important class of molecules to date.

Enantioselective Copper‐Catalyzed Quinoline Alkynylation

“…While compounds such as 12 g could be desilylated and further functionalized, this methodology should obviate the need for such manipulations and enable highly convergent synthetic strategies to tetrahydroquinolines. [14] However,f or synthetic applications the absolute configuration of the products needs to be determined. To do so,w ea pplied our methodology to the synthesis of three tetrahydroquinoline alkaloids,( + +)-galipinine (13), [18] (+ +)-cuspareine (14), [19] and (À)-angustureine (4), [5] which are natural products isolated from the bark of Galipea officinalis Hancock, and have welldocumented absolute configuration and optical rotation data.…”

“…As part of al igand development program exploring the use of StackPhos (9), [13] we became interested in the question of how to catalytically install alkynes at the quinoline C2 with stereocontrol, thus envisioning an ew synthetic approach to martinellic acid (1). [2,14] P, Nligands such as QUINAP (7)and PINAP (8)h ave been reported for copper-catalyzed alkyne addition reactions.I nterestingly,w hile Taylor and Schreiber reported the use of 7 in the enantioselective addition to isolated dihydroisoquinolinium salts, [15] satisfactory results were not obtained in the related reaction of the fully aromatic quinolines. [16] After ligand screening, Arndtsen and co-workers found 8 to be the best ligand, but the highest selectivity reported was 84 % ee.…”

Synthesis of the Hexahydropyrrolo-[3,2-c]-quinoline Core Structure and Strategies for Further Elaboration to Martinelline, Martinellic Acid, Incargranine B, and Seneciobipyrrolidine

“…Another approach towards martinellic acid was presented by Pappoppula and Aponick in 2015 [ 51 ]. Their synthesis commenced from quinoline 39 , which was synthesized in two steps from benzocaine (40) in 79% yield following a literature procedure ( Scheme 6 ) [ 52 ].…”

Lanthanide‐Catalyzed Reversible Alkynyl Exchange by Carbon–Carbon Single‐Bond Cleavage Assisted by a Secondary Amino Group

“…[17] Propargylamines are versatile building blocks in organic synthesis and as tructural feature of many biologically active compounds and natural products. [18,19] Although many methods for the synthesis of propargylamines have been devel-…”