Thioester macrolactonization

Termination of polyketide biosynthesis typically involves the TF mediated cleavage of the ACP-bound thioester, followed by cyclization to generate a macrolactone. Alternatively, the TF catalyzes the simple hydrolysis of the thioester to generate a linear free acid product. Here, we consider two of the relatively few known examples of polyketide natural products that are neither a macrocycle nor a free acid, but instead terminate with a double bond. 

Macrocyclic motifs are usually essential for the unique biological properties of natural products. In most cases, linear NRP and PK scaffolds are cyclized to form macrolactones or macrolactams prior to further post-modification. Macrocyclization is usually carried out by cyclases towards the end of elongation. For example, in the biosynthesis of the antibiotic tyrocidine A, a linear enzyme-bound decapeptide is cyclized via an intramolecular SN2 reaction between the N-terminal amine nucleophile and the C-terminal thioester, which is covalently linked to the synthase [reactions (a) and (b), Scheme 8.3] [22], This cyclase shows great versatility. Not only does it catalyze the formation of macrolactams of ring sizes from 18 to 42 atoms from... 

Masamune et al. [42] developed the macrolactonization of to-hydroxy r-butyl thioester with Hg(OCOCp3)2 in MeCN at room temperature, and this method accomplished the first total synthesis of methynolide [1]. They further developed an alternative method using a phosphoric acid mixed anhydride, which was apphed to the synthesis of narbonolide [43] and tylonolide [44]. 

Attempts at altering polyketide chain length have resulted in a number of abridged lactones. By repositioning the thioester domain in DEBS to the C-terminal end of module 5, a 12-membered macrolactone analog of 10-deoxymethynolide, the aglycon precursor to methymycin, was produced [28],... 

The isolated TE domain from the tyrocidine (tyc) NRPS has recently been shown to catalyze the macrocyclization of unnatural substrates to generate a variety of cyclic peptides. In conjunction with standard solid-phase peptide synthesis, Walsh and coworkers demonstrated a broad substrate tolerance for peptidyl-N-acetylcysteamine thioesters by the tyrocidine TE [41,42], Cyclization of peptide analogs, where individual amino acids were replaced with ethylene glycol units, was observed with high efficiency. In addition, hydroxyacid starter units were readily cyclized by the isolated TE domain to form nonribosomal peptide-derived macrolactones. More recently, Walsh and coworkers have demonstrated effective cyclization of PEGA resin-bound peptide/polyketide hybrids by the tyrocidine TE domain [43], Utilization of a pantetheine mimic for covalent attachment of small molecules to the resin, serves as an appropriate recognition domain for the enzyme. As peptide macrocyclizations remain challenging in the absence of enzymatic assistance, this approach promises facile construction of previously unattainable structures. 

Since the PKS (polyketide synthase) gene cluster for actinorhodin (act), an antibiotic produced by Streptomyces coelicolor[ 109], was cloned, more than 20 different gene clusters encoding polyketide biosynthetic enzymes have been isolated from various organisms, mostly actinomycetes, and characterized [98, 100]. Bacterial PKSs are classified into two broad types based on gene organization and biosynthetic mechanisms [98, 100, 102]. In modular PKSs (or type I), discrete multifunctional enzymes control the sequential addition of thioester units and their subsequent modification to produce macrocyclic compounds (or complex polyketides). Type I PKSs are exemplified by 6-deoxyerythronolide B synthase (DEBS), which catalyzes the formation of the macrolactone portion of erythromycin A, an antibiotic produced by Saccharopolyspora erythraea. There are 7 different active-site domains in DEBS, but a given module contains only 3 to 6 active sites. Three domains, acyl carrier protein (ACP), acyltransferase (AT), and P-ketoacyl-ACP synthase (KS), constitute a minimum module. Some modules contain additional domains for reduction of p-carbons, e.g., P-ketoacyl-ACP reductase (KR), dehydratase (DH), and enoyl reductase (ER). The thioesterase-cyclase (TE) protein is present only at the end of module 6. 

Masamune used the S-tert-butyl ester as an intermediate in the total synthesis of 6-deoxyerythronolide B (17), and activation of the thioester by a heavy metal efficiently promoted cyclization to form the desired polyoxygenated macrolactone (Scheme 5.3) [25]. 

Chapter Synthesis of 12- to 16-Membered-Ring Lactones is dedicated to the synthesis of 12- to 16-membered ring lactones. In this chapter, M. Kalesse and M. Cordes present an overview of the macrocyclization of seco-acids as well as new effective procedures to access 12- to 16-membered ring lactones such as ringclosing metatheses of alkynes and olefins. The authors also report the use of ketene sources and benzodioxinones to produce macrocyclic lactones. Nitrile oxide-olefin cycloaddition, intramolecular C-H oxidative macrolactonization, and Yamaguchi and Mukaiyama macrocyclization as well as macrolactonization via thioester or using phosphorus reagents are described. 

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