Lactones nitrile oxide intramolecular cycloadditions

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. 

One of the very first uses of the intramolecular nitrile oxide cycloaddition involved the synthesis of macrocyclic lactones. Asaoka et al. (238) conceived this approach to the 16-membered ring antibiotic A26771B (277). Nitro compound 274 [obtained from 11-acetoxydodecanal (273)] was dehydrated with 4-chlorophenyl isocyanate-triethylamine and this was followed by dipolar cycloaddition, which gave isoxazoline 275 as a 4 1 mixture of diastereomers (Scheme 6.100). 

The routes leading from lactone A have the advantage of a chiral source of starting materials. With the two chiral centers at C24 and C25 set, the problem reduces down to elaborating the B ring with the appropriate substituents. An early solution was provided in an unusual cyclization of the B ring via an intramolecular Michael addition to the unsaturated aldehyde formed from a nitrile oxide 1,3-dipolar cycloaddition to the allyl methyl ketal of lactone A [76]. This clever use of relative stereocontrol provided by the highly constrained and predictable transition states of both key reactions unfortunately resulted in a low yield. A more conventional approach conceptualized the addition of a sulfoxide [77] to 2 to yield a masked diol-ketone precursor which cyclizes under acidic catalysis. Elimination of the sulfoxide permitted the introduction of the hydroxy substituent at C19 of the spiroketal. 

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