Stereochemical Assignment and First Synthesis of the Core of Miharamycin Antibiotics

Abstract

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Synthesis of Purine Nucleosides from D‐Glucuronic Acid Derivatives and Evaluation of Their Cholinesterase‐Inhibitory Activities

“…Coupling of 3 with silylated 2‐acetamido‐6‐chloropurine was carried out in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) in acetonitrile at 65 °C, conditions that are reported to favour the formation of N 7 purine nucleosides,7c and under microwave irradiation (MW) at 150 W maximum power for 30 min (Scheme ). Thus, β‐linked N 9 purine nucleoside 4 and its N 7 regioisomer 5 were obtained in 52 and 12 % yields, respectively.…”

The Miharamycins and Amipurimycin: their Structural Revision and the Total Synthesis of the Latter

“…Removal of the N-Cbz and iodide via hydrogenolysis over Pd/C followed by condensation of the resultant amine with tri-Boc-l-arginine in the presence of isobutylchloroformate and Et 3 Ni nT HF led to peptidyl nucleoside 22 (66 %). [5,19] Cleavage of the four N-Boc groups with CF 3 CO 2 Ha nd subsequently the esters with LiOH in THF/H 2 Oa t0 8 8C furnished the 4'-deoxy derivative of the revised miharamycin B(23;78% for 2steps). This compound showed similar J values for the protons of the furan core (H-2',-8',and -9')a s those reported for amipurimycin derivative 3 and miharamycin B( 5b).…”

“…These data can be obtained free of charge from The Cambridge Crystallographic Data Centre,F igure 4), thus unambiguously confirming the revised structure.I ti sn oteworthy that the crystal structure adopts aconformer with the lateral chain folding towards the aminopurine moiety,w hich has been proposed as the major conformer in solution by BlØriot, Sinaþ,R auter,a nd co-workers based on NMR spectroscopy. [5] In conclusion, the structure of amipurimycin (2), the peptidyl nucleoside antibiotic with potent inhibitory activities against phytopathogenic fungi, has been unambiguously revised via total synthesis and X-ray diffraction analysis. Theo riginally proposed configurations at C3' and C8' are inverted and those at C6',C2'',and C3'' have been corrected.…”

“…[4] The S configuration at C6' (in 4)w as later determined by modern NMR spectroscopic analysis. [5] Although tremendous efforts have been dedicated to the chemical synthesis of amipurimycin [6] and miharamycin, [5,7] thesuccessful synthesis of the proposed amipurimycins (1a-d)w as only recently achieved by us. [8] However,a pparent discrepancies were found between the NMR spectroscopy data of the synthetic compounds and those recorded for the natural product, leading to aconclusion that the configuration of the tertiary C3' in the originally proposed structure of amipurimycin should be inverted.…”

“…between the chemical shifts of H6' of the 6'S-congeners compared to those of the 6'R-counterparts (Dd = À0.22 to À0.14 ppm) implied the S configuration at C6' in amipurimycin, which is in accordance with the assignment in miharamycins. [5] Furthermore,t he cis-3-aminocyclopentane-2-carboxylic acid residue is likely to have 2''R,3''S configurations, given the fact that only this enantiomer,named cispentacin or FR109615, [11] has been isolated from bacteria. Taken together, the structure of amipurimycin was revised to 2 with 3'S,6 'S, 8'R,2''R,3''S configurations (Figure 1).…”