Total Synthesis of the Antimitotic Bicyclic Peptide Celogentin C

• Published in: Journal of the American Chemical Society Vol. 132; no. 3; pp. 1159 - 1171
• Main Authors: Ma, Bing, Banerjee, Biplab, Litvinov, Dmitry N, He, Liwen, Castle, Steven L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.01.2010; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Molecular Conformation; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Physical Sciences; Science & Technology; Stereoisomerism; CELOSIA-ARGENTEA; SEEDS; CENTRAL TRYPTOPHAN RESIDUE; ASYMMETRIC-SYNTHESIS; DIELS-ALDER REACTIONS; REDUCTION; ALPHA-AMINO-ACIDS; KNOEVENAGEL CONDENSATION; NITRO; STEPHANOTIC ACID
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja909870g

An account of the total synthesis of celogentin C is presented. A right-to-left synthetic approach to this bicyclic octapeptide was unsuccessful due to an inability to elaborate derivatives of the right-hand ring. In the course of these efforts, it was discovered that the mild Braslau modification of the McFadyen−Stevens reaction offers a useful method of reducing recalcitrant esters to aldehydes. A left-to-right synthetic strategy was then examined. The unusual Leu−Trp side-chain cross-link present in the left-hand macrocycle was fashioned via a three-step sequence comprised of an intermolecular Knoevenagel condensation, a radical conjugate addition, and a SmI2-mediated nitro reduction. A subsequent macrolactamization provided the desired ring system. The high yield and concise nature of the left-hand ring synthesis offset the modest diastereoselectivity of the radical conjugate addition. Formation of the Trp−His side-chain linkage characteristic of the right-hand ring was then accomplished by means of an indole−imidazole oxidative coupling. Notably, Pro−OBn was required as an additive in this reaction. Detailed mechanistic investigations indicated that Pro−OBn moderates the concentration of NCS in the reaction mixture, thereby minimizing the production of an undesired dichlorinated byproduct. The natural product was obtained after macrolactamization and deprotection. The chemical shifts of the imidazole hydrogen atoms exhibited significant dependence on temperature, concentration, and pH. Antitumor screening indicated that celogentin C inhibits the growth of some cancer cell lines.