Structural studies on lipiarmycin I. Characterization by 1H and 13C NMR spectroscopy and isolation of methyl 2-O-methyl-4-O-homodichloroorsellinate-.BETA.-rhamnoside.

Abstract

1H and 13C NMR spectral studies of lipiarmycin in CDCI , and in pyridine-d; provided evidence for the six partial structures I-VI and the two sugar units 1 and 2. Acid methanolysis led to the isolation of methyl 2-O-methyl-4-O-homodichloroorsellinate-,3-rhamnoside, whose structure was determined by spectroscopic methods.Lipiarmycinl.2) is a chlorine containing antibiotic produced by Actinoplanes deccanensis ATCC 21983, active mainly against Gram-positive bacteria. While the weak in vivo activity delayed further developments, its mechanism of action has been the subject of many studies'-''.In a previous paper2) the preliminary characterization of lipiarmycin was reported, showing the presence of a sugar moiety and of many branched aliphatic chains. Furthermore, homodichloroorsellinic acid was isolated after acid hydrolysis. In this paper we report the structure elucidation of the sugar components and of the two compounds obtained by hydrolysis. In addition, the partial structures of some aliphatic moieties are deduced from 270 MHz 1H and 67.88 MHz 13C NMR spectroscopy.From elemental analysis and osmometric data, supported by 1H and 13C NMR spectroscopy, lipiarmycin has the molecular formula C52H72C1201e-1e• Spectroscopic Studies Fig. 1 shows the IR spectrum of lipiarmycin in CDC13. Absorption bands at 3600, 3560, 3540 and 3500 cm-1 are assigned by deuteration to OH functions, the last three of them being intramolecularly H-bonded. The spectrum shows three carbonyl absorptions at 1730 and 1690 cm-1, unchanged after deuteration, and at 1660 cm-I which shifts to 1640 cm-1 after deuteration.The band at 1690 cm'' is then assigned to a conjugated C=O and that at 1660 cm-1 to a C=O ester conjugated and H-bonded; the band at 1730 cm-1 is due to an aliphatic ester. In the double bond region a band at 1590 cm-1 (1580 cm-I after D,O addition) is associated with an aromatic moiety carrying one or more phenolic groups. These latter functions are confirmed by the presence of 6,0 bands at 1410 and 1220 cm-1 shifted by deuteration. Finally, the strong band at 1070 cm-1 (o _0) can be assigned to the anomeric group of a sugar. Table 1, where the various H-bearing groups are labelled with alphabetical letters. Examination of the 1H NMR data in CDCI, indicates that the total number of protons is 72 of which 5 are exchangeable. Furthermore, the exchangeable H at 5 11.5 is attributed to a phenolic OH

Total Synthesis of the Tiacumicin B (Lipiarmycin A3/Fidaxomicin) Aglycone

“…3:1 mixture of two closely related macrolides, lipiarmycin A3 and lipiarmycin A4, whose gross chemical structures were determined in 1987. [5] The complete relative and absolute configuration of 1 (from Dactylosporangium aurantiacum) was elucidated in 2005 by X-ray crystallographic analysis; [6] importantly, most recently, 1 has been shown to be identical to lipiarmycin A3. [7] The structure of tiacumicin B (1) features an 18-membered macrolactone core with four chiral centers and a high degree of unsaturation; an additional, hydroxy-bearing ste-reogenic center is present in the short side chain attached to C17.…”

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

“…The producer strain was isolated on February 29th, 1972 – in a leap year – and accordingly, the produced compounds were named lipiarmycins. Preliminary structural studies on lipiarmycin identified the rhamnoside‐dichlorohomoorsellinate moiety as well as the modified noviose as important structural features ( Figure ) . However, lipiarmycin was later reported to actually be composed of two compounds, lipiarmycin A3 ( 1 ) and A4 ( 9 ), whose structures were finally elucidated after extensive NMR and degradation studies .…”

Final Demonstration of the Co-Identity of Lipiarmycin A3 and Tiacumicin B (Fidaxomicin) through Single Crystal X-ray Analysis

“…Although its chemical–physical properties, its biological activity [2,3], and its NMR characterization [4] were thoroughly described within a few years, this material was only recognized to be a mixture of two related products in 1987, when the first comprehensive study [5] on the chemical structure determination of lipiarmycin was published. Based on chemical degradations and NMR studies, the two antibiotics extracted from Actinoplanes deccanensis —named lipiarmycin A3 ( 1 ) and lipiarmycin A4 ( 2 )—proved to be characterized by a common 18-membered macrolactone attached to two glycosyl moieties, namely 2- O -methyl-4- O -homodichloro-orsellinate-β- d -rhamnose and 4- O -isobutyrate-5-methyl-β-rhamnose.…”