Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents

Abstract

An improved and enantioselective total synthesis of antibiotic CJ-16,264 through a practical kinetic resolution and an iodolactonization reaction to form the iodo pyrrolizidinone fragment of the molecule is described. A series of racemic and enantiopure analogues of CJ-16,264 was designed and synthesized through the developed synthetic technologies and tested against drug-resistant bacterial strains. These studies led to interesting structure–activity relationships and the identification of a number of simpler, and yet equipotent, or even more potent, antibacterial agents than the natural product, thereby setting the foundation for further investigations in the quest for new anti-infective drugs.

Total Synthesis Endeavors and Their Contributions to Science and Society: A Personal Account

“…40,41,[83][84][85][86][87] The third category includes molecules whose originally reported structure was later challenged based on biosynthetic considerations 88 [e.g., maitotoxin (74), Figure 7, stereogenic centers within gold-colored oval] and later confirmed by us as the correct one. 89 The fourth, and most common, category of structural elucidation through total synthesis is that involving revision of one or more stereochemical configurations and/or structural motifs (functional groups) [e.g., 21, 120, and 121 (Figure 14e), [90][91][92][93][94][95] 22 (Figure 14g), 85,86 24 (Figure 14h), [96][97][98] 30 and 31 (Figure 14n), [99][100][101][102][103] 33 (Figure 14j), 104 37 (Figure 14o), [105][106][107] 39 (Figure 14p), 108,109 44 (Figure 14r), 110 46 (Figure 14q), 111 47 (Figure 14s),…”

“…186 Thus, in addition to providing sufficient quantities of the rare, in some instances, natural products themselves, we devoted time and effort toward analogue design, synthesis, and biological evaluation. Rich in molecular diversity and biological investigations, these value-added efforts yielded a number of promising compounds, including those within the antibiotic families of vancomycin (17, Figure 16l), 187,188 platensimycin (23, Figure 16m), [189][190][191][192][193][194][195][196] antibiotic BE-43472B (32, Figure 16o), 49,50 biyouyanagins A and B (127 and 33, Figure 16p), 114 dithiodiketopiperazines (326 and 327, Figure 16q), 161 antibiotic CJ-16,264 (39, Figure 16u), 109 and viridicatumtoxin B (37, Figure 16s). 106,107 Even maitotoxin (74, Figures 7 and 16t) did not escape our paradigm of analogue design, synthesis, and biological evaluation.…”

Skeletal Analogues of UCS1025A and B by Cyclization of Maleimides: Synthesis and Biological Activity

“…As currently reported, there are only a small number of members of this class, pyrrolizilactone, 1 UCS1025A and B, 2 and CJ-16264, 3 all possessing a similar core, but which differ in the nature of the acyldecalin unit (Figure 1). Studies of the biosynthesis, 4 synthesis, [5][6][7] and SAR 8 of UCS1025A have already been reported, and similarities with tetramates containing decalin systems been identified. 9 Of significance is that the antibacterial bioactivity of these systems, with MIC values of typically 1-15 g/mL against Gram-positive MDR strains and some Gram-negative ones, is promising; 3 limited SAR analysis with three CJ-16,264 stereoisomers shows MIC values of 2-16 g/mL against MRSA, E. faecelis, and E. faecium, values which are modest but encouraging.…”

Enantioselective Synthesis of Pyrrolizidinone Scaffolds through Multiple-Relay Catalysis

“…Specifically, the pyrrolizidinone subunit deserves a special mention as recently isolated pyrrolizidinone-containing compounds display a wide range of biological activities. In this context, compound CJ-16,264 (Figure , A ) and penibruguieramine A (Figure , B ) exhibit potent antibacterial properties, while UCS1025A is a strong inhibitor of telomerase (Figure , C ) . One of the simplest pyrrolizidinone derivatives, pyrrolam A (Figure , D ), presents herbicidal activity, whereas conjugation with a sugar provides the antifungal properties of burnettramic acids (Figure , E ) .…”