Journal of Natural Products Vol. 49, No. I , pp. 35-47, Jan-Feb 1986
35
ANTIBIOTIC STRUCTURE AND BIOSYNTHESIS JOHN
W. WESTLEY
Smith Kline and French Laboratories, IS00 Spn’ng Garden Street, Philadelphia, Pennsylvania 19101
Class
Sub-class
l a - 1 Monovalent . . . . Non-spiroketal -2 Spiroketal Dispiroketal -3 16-1 Monovalent glycoside . Spiroketal Two spiroketals -2 2a Divalent . . . . . . . 2b Divalent glycoside . . Pyrrole ether . . . . . 3 Acyl tetronicacid . . . 4
Number Reported 2 17 15 17 8 8 2 3 2
Examples alborixin (12), X-206 (13) lonomycin ( 14), monensin (4) noboritomycin (15), salinomycin (16) carriomycin (17), septamycin (18) dianemycin (l9), lenoremycin (20) lasalocid (2 l), lysocellin(22) antibiotic 60 16 (23), X- 14868B (29) calcimycin (25), X-l4547A(26) tetronomycin (27), M- 139603 (28)
Figure 1. Until the discovery of antibiotics X-l4868A,B,C, and D (24), all of the monovalent glycoside class (I 6) of polyether antibiotics contained the identical sugarlike moiety, 2,3,5-trideoxy-4-0-methyI-~-erythrohexapyranose (4-0-methyl‘Presented as a plenary lecture at the “Biologically Active Nitrogen-Containing Natural Products: Structure, Biosynthesis, and Synthesis” Symposium of International Research Congress on Natural Products at the University of North Carolina, Chapel Hill, North Carolina, July 7-12, 1985.
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Antibiotic Structure and Biosynthesis
Antibiotic
Molecular weight
Lasalocid . . . . . . . . . . .
5 90
Monensin . . . . Nigericin . . . . Salinomycin . . Dianemycin . . . Antibiotic X-206
67 1 724 750 866 870
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39
Cation selectivity
'Lyotropic series (with ionic radii in nanometers) are: Cs+ (0.169)>Rb+ (0.148)>K+ (0. 133)>Naf (0.095)>Lif (0.060) and BaZ+(0.135)>Srz+ (0.113)>Caz+ (0.099)>Mgz+ (0.097).
Lasalocid can be distinguished from the other five polyether antibiotics listed in Table 2 by the ability to transport divalent cations in addition to the effect on alkaline metals exhibited by all the polyether antibiotics. This is the basis of classificationfor the divalent antibiotics illustrated in Figure 3. The last two classes of polyether antibiotics are structurally distinct from all the other polyethers. They are the pyrrole ethers (Figure 4 ) , which all contain a pyrrole-2-carbonyl function, and the most recently discovered, class 4 polyethers, also known as the acyl tetronic acids (Table 1). These latter antibiotics differ from all other polyethers in that they lack a carboxlic acid moiety. As illustrated in the structure of tetronomycin (27), the carboxlic group is replaced by an acylidene tetronic acid, and another distinguishing characteristic is the presence of a trisubstituted cyclohexane ring representing the first example of a homocyclic aliphatic ring in a polyether antibiotic (Figure 5). The complex structures of these different classes of polyether antibiotics has presented a considerable challenge to several chemists involved in the total synthesis of these unique natural products (33). The structure of lasalocid was published in 1970 (2 l), and in that same year, the first report on the biosynthesis of that versatile divalent polyether antibiotic also appeared (34). Since that time, many studies on polyether biosynthesis have been reported, including a number of reviews (35). From these reports, a universal biosynthetic scheme has emerged. The major building blocks for the skeletons of all the polyethers are acetate, propionate, and butyrate, and, in the case ofpolyethers contain-
40
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