Synthesis of macrolactones

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

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. 

Scheme 4.37 Synthesis of macrolactone through four-component domino ARC coupling employing linchpins 176 and 188.

Trost and co-workers (Trost, 1998) used a variety of palladium catalysts to effect allylic alkylation reaction. Synthesis of macrolactones from corresponding carboxylic acid catalyzed by palladium complex is a 100% atom-efficient reaction (Fig. 3.3). The reaction, as it occurs at room temperature, is also an example of catalysis reducing energy usage. 

In 1980, Venkataraman and Wagle [43] reported cyanuric chloride (Scheme 6.2) in the synthesis of macrolactones from the corresponding seco-acids, whose mechanism is closely related to the Corey-Nicolaou method. 

In 1981, Mitsunobu [60] described the extension of their method of ester preparation for the synthesis of macrolactones using a mixture of Ph3 P and diethyl azodicarboxylate (DEAD) as dehydrating agent. 

MacrocycHzation for the synthesis of macrolactones was also achieved by C-C bond formation using a variety of techniques (Scheme 6.5). Oxidative acetylene coupling for exaltolide 12, as reported by Bergelson et al. [61], nickel-carbonyl-mediated coupling of allyhc dibromides by Corey and Kirst [62], palladium-catalyzed... 

Another excellent method for the synthesis of macrolactones by oxidation reaction was reported by Tan et al. [72] via oxidative ring expansion of polycyclic enol ethers and enamines, effectively mediated by NaI04 and catalytic amount of RuClj or RUO2 (Scheme 6.9). 

Hf(0Tf)4 was also reported to possess unique reactivity characteristics relative to other Lewis acids. Recent reports indicated that it is capable to catalyze hydrolysis reactions even in the presence of excess water [41]. An example is its capacity to catalyze the efficient direct macrolactonization of secondary acids in high yields (Equation (8.20)). Water was the sole by-product of this reaction. In addition to synthesis of macrolactones and benzolactones this catalyst allowed intermolecular direct esterifications of carboxylic acids and alcohols. 

For lactonization (eq 6), including the synthesis of macrolactones, BOP-Cl is a useful reagent. 

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