Macrolactonization 8-lactone synthesis

Methods for lactone synthesis by transition metal catalysis involving C—O formation developed over the past 50 years have demonstrated much promise. Indeed, lactones have inspired the discovery of new organometallic transformations, design of metal catalysts, and detailed understanding of reaction mechanisms. Issues of waste minimization and stereoselectivity have been addressed. Future developments for chiral lactone synthesis will likely focus on establishing efficient transformations with broad scope and application in complex molecule total synthesis, especially in regards to macrolactonization where entropic costs often plague intramolecular reactivity with undesired intermolecular reactions. 

Prior to the synthesis of the epothilones, the use of RCM for the preparation of macrolactones had received little attention [5]. In part, this could be attributed to the generally held assumption that only conformational biased precursors would undergo cyclization. Although several examples of macro-RCM had been reported, notably by Pandit [9],Hoveyda [10] andFurstner [11], preparation of the densely functionalized 16-membered lactone core of the epothilones was not a trivial undertaking. Preliminary studies focused on the preparation and cyclization of model substrates in order to assess the viability of the RCM approach and to provide precedent for subsequent, more ambitious, synthetic endeavors. 

Although RCM gives brilliant results for the synthesis of medium-ring carbo-cycles, it is also effective for the synthesis of macrocyclic lactone as shown in Eqs. (6.25)-(6.27). Prior to RCM, macrolactonization was the most common method for the synthesis of macrocyclic lactone. However, we can now obtain the desired macrocyclic lactone from diene having an ester moiety in a chain by RCM followed by hydrogenation ... 

It should be noted that TE-catalyzed cyclization is not Umited to the synthesis ofmacrocycUc peptides by catalyzing the formation of a C—N bond. These enzymes are also responsible for the cyclization of NRP depsipeptide and PK lactone. Indeed, a didomain excised from fengydn synthase was able to catalyze the formation of a macrolactone through the formation of a C—O bond [39]. Several cyclases from PKSs have also been characterized to be functional. For example, when a TE from picromycin synthase was fused to an erythromycin module (DEBS module 3), the resulting hybrid was able to convert a diketide and 2-methylmalonyl-CoA to a triketide ketolactone (Scheme 7.12) [40]. However, their in vitro activity is in... 

Synthesis of 12- and 13-membered sulfur-containing lactones by homolytic macrocyclization of mercaptoacetic esters and alkynes has been investigated [95S307]. Reaction of the mercaptoester 245 with alkynes using triethyl borane radical initiation gave the macrolactones 247 and 248 in low yield [95TL2293], Remote asymmetric induction is observed during the cyclization. 

A further reaction mechanistically similar to the Mitsunobu reaction as shown in Scheme 26, with the use of AT,iV-dimethylformamide dineopentylacetal (80), can also be employed for macrolactonization [47]. Takei and coworkers [48] applied it to the synthesis of the macrocyclic antibiotic A26771B (55). As shown in Scheme 27, treatment of the linear precursor 82 with 80 in refluxing dichloromethane for 7 h afforded the lactone 83 (39% yield). 

The hydroxy part of a hydroxy acid can also be activated for macrolactonization. Vedejs et al. [60] applied such a strategy to the synthesis of the macrocychc pyrrolizidine alkaloid monocrotaline 108). Thus, the seco acid derivative 106 was first mesylated with MsCl/EtjN in dichloromethane, and the crude product was added over 3 h to an excess of tetrabutylammonium fluoride trihydrate in acetonitrile at 34 °C to effect ring carboxy deprotection and ring closure to give 107 in 71% yield (Scheme 36). It has been noted that the active intermediate of this kind of lactonization may be an allylic chloride rather than a mesylate [61a], In addition, an intramolecular nucleophilic displacement process of chloride from an a-chloro ketone moiety by a remote carboxylate has been recently reported as an efficient approach to macrocychc keto lactones [61 bj. 

The problem of macrolactonization became especially crucial in the 1960s as intensive studies were directed at the synthesis of biologically active antibiotics containing the macrocyclic lactone (macrolide) moiety. As a result of these studies,the problem of macrolactonization, regardless of the size of lactone ring or the complexity of the acyclic precursor, was solved. 

R.S. Coleman and co-workers have developed a stereoselective synthesis of the 12-membered diene and triene lactones characteristic of the antitumor agent oximidines I and II, based on an intramolecular Castm-Stephens coupling. The effectiveness of this protocol rivals the efficiency of standard macrolactonization. The stereoselective reduction of the internai alkyne afforded the 12-membered ( ,Z)-diene lactone in good yield. 

This hydrostannation/coupling/lactonization approach has been used in fhe synthesis of macrolactone component of apicularen derivatives (Scheme 12.113) [215]. 

The synthetic plan to achieve the total synthesis of avermectin involves the preparation of the aldehyde fragment (A) from D-glucal tripivalate (114), and the ketone fragment (B) from D-ribose aldehyde(125). Coupling of (A) and (B) gives the macrolactone (C). The resulting lactone is reacted with disaccharide (D) to form avermectin A [119]. 

A highly effective method for the construction of macrolactone ring ii is the intramolecular lactonization of the corresponding seco-acid i (Fig. 2). Thus, various effective methods for the synthesis of macrolactones were developed during the 1970s and 1980s and have been successfully apphed to the total synthesis of macroUde antibiotics. In the 1990s, new methods for macrolactonization were reported [35] however, they have not yet been applied frequently to macrolide synthesis. Thus, in this section, the established methods applied to macrolide synthesis are introduced, and selected recent applications are shown in Scheme 12 and Section III.F. 

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