Asymmetric Total Synthesis of Cladosporin and Isocladosporin

Abstract

The first asymmetric total syntheses of cladosporin and isocladosporin were accomplished in 8 steps with 8% overall yield and 10 steps with 26% overall yield, respectively. The relative configuration of isocladosporin was determined via this total synthesis.

An Efficient Formal Total Synthesis of Cladosporin

“…The structure was confirmed by spectroscopic data analysis and the absolute stereochemistry of lactone compound 12 was confirmed by single‐crystal X‐ray crystallographic analysis (Scheme ) 17. Hydrogenation of lactone compound 12 by using a catalytic amount of PtO 2 in ethyl acetate under a H 2 atmosphere led to desired compound 13 in 95 % yield, the spectral ( 1 H and 13 C NMR) and analytical data {[ α ] D 25 = +73.4 ( c = 1.3, CHCl 3 ), ref 7. [ α ] D 22 = +76.5 ( c = 2.0, CHCl 3 )} of which were in good agreement with the reported values; this constitutes a formal total synthesis of 1 .…”

“…The absolute stereochemistry of 1 was determined by researchers at Merck3e and Vederas et al4 Grove et al established the general features of its biosynthesis in A. flavus by administration of [1‐ l3 C]acetate and [2‐ 14 C]malonate 5. The relative configuration of isocladosporin ( 2 )6 was confirmed through the asymmetric total synthesis of 1 and 2 7. The structural features of 1 and 2 are comprised of a 2,6‐disubstituted tetrahydropyran (THP) ring and a δ‐valerolactone with a fused 1,3‐dihydroxybenzene ring (Figure 1).…”

Protein Translation Enzyme lysyl-tRNA Synthetase Presents a New Target for Drug Development against Causative Agents of Loiasis and Schistosomiasis

“…Poor bioavailability is the main limitation in development of cladosporin as a lead molecule [34]. Chemical synthesis protocols for cladosporin are now available which can aid in structure-guided rational synthesis of more drug-like cladosporin derivatives [41]. Apart from loiasis and schistosomiasis, suitable derivatization of cladosporin for better ADME (absorption, distribution, metabolism, and excretion) properties will be highly valuable for drug development against host of parasitic infections including malaria and feasibly trypanosomosis (given the conservation in active site residues that recognize cladosporin, Fig 6B and 6C) [15].…”

The growing pipeline of natural aminoacyl-tRNA synthetase inhibitors for malaria treatment

“…Indeed, the observation of the presence of an ample space within the PfLysRS active site allowed further chemical derivatization of cladosporin, facilitated by the available total synthetic route of the molecule. 23,24 Dual inhibitors of both cytosolic and apicoplastic targets represent an attractive strategy to reduce emergence of resistance, and combine the slow clearance that results from apicoplastic delayed death with the rapidity of action of cytosolic translation inhibition. 37 aaRS have been identified in P. falciparum, 25 23 of which present a signal peptide for import into the apicoplast.…”