Library lactones

The major components are series of homologous trimers, tetramers, and pentamers of the three acids 44-46, along with smaller quantities of dimers, hexamers, and heptamers. Furthermore, the secretion contains several isomers of each oligomer, furnishing a combinatorial library of several hundred macro-cyclic polyamines [51, 52]. Using repeated preparative HPLC fractionation, the most abundant trimeric, tetrameric and pentameric earliest-eluting compounds were isolated. One and two-dimensional H NMR spectroscopic analyses showed that these molecules were the symmetric macrocyclic lactones 48, 49, and 50 (m, n, o, p, q=7) derived from three, four or five units, respectively, of acid 46. Moreover, using preparative HPLC and NMR methods, various amide isomers, such as 53,54, and 55 (Fig. 9) were also isolated and characterized [51,52]. 

Figure 25 /3-Lactones and /3-lactams as natural product-derived probes for ABPP. (a) A biomimetic /3-lactone probe library with an alkyne tag and several diversity elements, (b) /3-Lactam probes derived from known antibiotics and synthetic approaches.

The attachment of a,fi-unsaturated carbonyl compounds to polymeric supports via silyl-enol ether has been employed in some combinatorial libraries. Thus, a,(3-unsaturated lactones (316, 321) can be enolized by KHMDS, then trapped by polystyrene-bound silylchlorides (315) [311]. The resulting furans (317, 322) reacted with methylacrylate to give only endo adducts (319, 323) (Scheme 67). 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

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