Total Synthesis of Celogentin C by Stereoselective CH Activation

Abstract

the most potent isolate (IC50= 0.8 mm ; IC= inhibitory concentration) from the celogentin/moroidin family, whose members possess inhibitory activity against tubulin polymerization. Its highly unusual architecture, which is characterized by the direct linkages of Trp C6 to Leu Cb, and Trp C2 to His N1 (Figure 1), and its biological activity have prompted a number of synthesis studies. Although N-linkedHis residues are known to occur in other macrocyclic peptides, the Leu-Trp linkage is extremely rare and poses a difficult synthetic challenge. To access the key Leu-Trp motif, Moody and Bentley, and Campagne et al., applied asymmetric hydrogenation conditions to dehydroamino acid precursors. Enantioand/or diastereoselectivities ranged from 1:1 to 16:1 for these 10–14 step sequences. More recently, Castle and coworkers developed a novel Knoevenagel condensation/radical conjugate addition approach to the Leu-Trp linkage. They completed the first celogentin synthesis through an elegant NCS-mediated Trp-His C N coupling by utilizing the major diastereomer product, albeit in modest enantioand diastereoselectivity. Herein, we report a highly stereoselective and efficient synthesis of celogentin C using a novel palladiumcatalyzed C H functionalization strategy. The highly constrained structure of 1 is probably assembled in vivo from the much simpler linear peptide precursor through a series of enzymatic oxidative cross-links (Figure 1). Inspired by these simple yet powerful transformations found in nature, we envisioned developing a synthetic equivalent of these processes in a direct approach to celogentin. Our synthetic strategy relied on the direct regioand stereoselective activation of the b C H bond of a Leu moiety and on the subsequent coupling of the derived C Pd species with a suitable Trp partner. The recent report by Corey et al. of the carboxamide-directed b C H functionalization of amino acids served as the starting point for our venture. Corey demonstrated that the b C H bond of the Nphthaloyl amino acid 8-aminoquinoline amide can be efficiently activated and then arylated with simple aryl iodides under Pd(OAc)2 catalysis, a procedure built on the seminal discovery of Daugulis and co-workers for the functionalization of inactivated sp C H bonds. The quinoline moiety serves as a chelating auxiliary for palladium coordination, and promotes the formation of trans-palladacycle intermediate 4. This palladium(II) intermediate presumably undergoes crosscoupling with an aryl iodide partner to provide the final arylated product which has an erythro stereochemical preference. To our delight, we were able to achieve the high-yielding and highly stereoselective 6-indolylation of N-phthaloyl leucine (Scheme 1a). Upon simple heating of precursors 2 (2.0 equiv) and 3 (1.0 equiv), with Pd(OAc)2 (0.2 equiv), and AgOAc (1.5 equiv), at 110 8C in tBuOH, the desired diastereomer 5 was formed exclusively, and the slight excess of 2 could be largely recovered. About 3% of deiodinated side product 6 was also generated. Although the quinoline carboxamide serves as an effective auxiliary in arylation chemistry, its efficient removal under mild conditions would be required for this process to become a useful tool for natural product synthesis. However, the cleavage of the amide linkage was particularly problematic, owing to both steric hindrance and the lability of the Nphthaloyl group. This phthaloyl group, which provides both bis-protection of the a-amino group and steric bias, is critical Figure 1. Celogentin C and our synthetic strategy.