Total Synthesis and Structural Revision of Antibiotic CJ‐16,264

Abstract

The total synthesis and structural revision of antibiotic CJ-16,264 is described. Starting with citronellal, the quest for the target molecule featured a novel bis-transannular Diels–Alder reaction that casted stereoselectively the decalin system and included the synthesis of six isomers before demystification of its true structure.

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

“…With both fragments (+)- 21 and (−)- 22 in hand, the latter obtained from ( S )-citronellal as previously described, 2 their coupling proceeded well under the influence of BEt 3 to afford alcohol (+)- 37 as a single diastereoisomer and in 82% yield as shown in Scheme 3. Comparison of the spectral data and optical rotation of (+)- 37 matched those previously obtained for the same compound, 2 confirming its absolute stereochemistry, including that at C8′.…”

“…Summarized in retrosynthetic format, and shown in Figure 3, our original total synthesis of antibiotic CJ-16,264 [(+)- 1 ] 2 utilized racemic iodo pyrrolizidinone fragment (±)- 21 and enantiopure aldehyde (−)- 22 , the latter obtained from ( S )-citronellal ( 25 ) via intermediates 23 and 24 . Racemic pyrrolizidinone (±)- 21 was prepared following the procedure reported by Danishefsky et al 5c and summarized in Figure 4A [ 26 + 27 → 28 → (±)- 29 → (±)- 21 , 38% overall yield from 27 ].…”

“…1 The ability of pathogenic bacteria to evolve beyond our latest and most powerful antibacterial agents made the fight against them particularly challenging and, thus far, continuous. 1 Antibiotic CJ-16,264 [(+)- 1 : revised structure; 2 (+)- 1a : originally assigned structure, 3 Figure 1] is one of the latest antibacterial agents to be discovered from Nature. 3 Isolated from fungus CL39457, antibiotic CJ-16,264 exhibits potent antibacterial properties (MIC = 0.78 μ g mL −1 against Staphylococcus aureus 01A1120; MIC = 0.39 μ g mL −1 against Moraxella catarrhalis 87A1055, and MIC = 6.25 μ g mL −1 against Escherichia coli 51A1051 with altered permeability) and cytotoxic properties (IC 90 = 8.0 μ g mL −1 against HeLa cells).…”

“…3 Other members of this class of antibiotics include CJ-16,367 ( A ), 3 pyrrolizilactone ( B ), 4 UCS-1025A ( C ), 5 and UCS-1025B ( D ) 5a,b (Figure 1). The first total synthesis of antibiotic CJ-16,264 has recently been reported from our laboratories, 2 an accomplishment that also led to its structural revision. The chemical detective work that led to the identification of the correct structure of antibiotic CJ-16,264 [(+)- 1 ] was accompanied by the synthesis of a number of isomers of the natural product [(−)- 1 , (−)- 1b , (−)- 1c , (+)- 1c , and (+)- 1d , Figure 2B].…”

“…In this article we report an improved synthesis of CJ-16,264 [(+)- 1 ], which includes an enantioselective synthesis of the pyrrolizidine structural domain of the molecule (as opposed to its racemic form employed in our first synthesis). 2 In addition, herein we describe the design, synthesis, and biological evaluation of an array of racemic analogues [i.e., (±)- 2 –(±)- 6 , 7 , and (±)- 8 –(±)- 12 , Figure 2A] and a series of enantiopure analogues [i.e., (−)- 13 , (+)- 7 , (+)- 8 , and (−)- 14 –(+)- 20 , Figure 2B] for bioactivity comparison purposes. These investigations resulted in improvements of our original synthesis 2 and enabled the identification of a number of equipotent, or even more potent, and yet significantly less complex than the natural product, antibacterial agents.…”