Strategy macrolactonization reaction

Chemoselective carbonylation of a vinyl iodide 34 with alcohol containing a vinyl bromide moiety 35 has been successfully employed for the solid-phase synthesis of a macrosphelide precursor 36 [43]. After the 4-methoxyphenylmethyl (MPM) group was removed, the palladium-catalyzed carbonylative macrolactonization of the vinyl bromide 37 achieved the synthesis of the macrosphelide-supported derivative 38 (Scheme 9.13). The combinatorial synthesis of a 122-member macrosphelide library has been performed by the three-component strategy based on the palladium-catalyzed chemoselective carbonylation/macrolactonization reaction. 

Then, a macrolactonization reaction (Scheme 2.5) was reported by White in 2006 [10]. The strategy provided medicinal chemists with a useful tool to prepare macrolactonization of m-alkenoic acids via Pd-catalyzed C-H activation... 

Our strategy for the synthesis of (+)-dactylolide (2.217) is outlined in Scheme 2.69. We envisioned that the 20-membered macrolactone in 2.332 could be constructed by intramolecular iV-heterocyclic carbene (NHC)-catalyzed oxidative macrolactonization of co-hydroxy aldehyde 2.333. Intramolecular NHC-catalyzed oxidative esterification reactions have been recognized as an attractive tool and rapidly growing area in the synthetic community. Indeed, several examples of these reactions have recently been reported [208-216], which clearly provide a new opportunity for the development of catalytic acyl transfer agents in macrolactonization reactions of co-hydroxy aldehydes in the presence of oxidants. The substrate for the macrolactonization reaction would be derived firom the cyanohydrin alkylation of 2,6-dr-tetrahydropyran enal 2.335 with dienyl chloride 2.334. 2,6 -di-tetrahydropyran enal would in turn be constructed by employing the 1,6-oxa conjugate addition reaction of co-hydroxy 2,4-dienal 2.336. Despite the... 

The synthesis of the disaccharide subunit 85 of tricolorin A, a cytotoxic resin glycoside isolated from lpomoea tricolor, provides a unique opportunity to compare the efficiency of an RCM-based macro cyclization reaction with that of a more conventional macrolactonization strategy. Furthermore, this specific target molecule challenges the compatibility of the catalysts with various functional groups. 

Nicolaou et al. were the first to report the successful use of RCM to prepare the 16-membered macrolactone nucleus of the epothilones and present a strategy for their total synthesis based on this reaction. The approach involved formation of the C12,C13 olefin and is outlined in Scheme 2 [12,13]. 

In order to overcome the problem, the inverse strategy was followed. Chromium-Reformatsky reaction between 76-derived C8 aldehyde and a 68-derived ester afforded all four possible C6,C7-diastereomers, which can be independently processed to epothilone D5 diastereomers (including the natural one) by the macrolactonization route. 

Leighton s synthetic strategy is shown in Scheme 43. Side chain 200 was introduced by the Still-modified (Z)-selective Honer-Emmons reaction forming the C2 -C3 double bond. Macrolactonization leading to 201 was carried out by using the Yamaguchi procedure, and C17 asymmetric carbon was constructed by alkenylzinc addition to an aldehyde in 202. The 2,6-trans-tetrahyderopyran was synthesized by the Hosomi-Sakurai reaction to a lactol. 

The synthetic strategy is based on Yamaguchi macrolactonization, metal alkynylide addition at C17, Mukaiyama-aldol Prins reaction of vinyl ether 219 with aldehyde 218 forming 2,6-d5-tetrahydropyran, Hosomi-Sakurai reaction giving 2,6-tran5-tetrahydropyran, asymmetric center formation via Myers alkylation at C12 and Noyori reduction at C15 and C3 (Scheme 47). 

The Wipf s synthesis of the leucascandrolide macrolactone relied on a convergent strategy with the two requisite fragments 2.81 and 2.82. The late stage macro-cyclization utilized the Mitsunobu reaction of the seco-acid. The synthesis began... 

The basics and the synthetic potential of olefin metathesis has been recently presented in a comprehensive handbook and several reviews [58]. Thus, this chapter will be restricted to demonstrate the scope and flexibility of this type of reaction in the total synthesis of a complex natural product skeleton such as epothilone. The first total syntheses of these antitumor-active 16-membered macrolactones were based on a ringclosing metathesis (RCM) strategy (Scheme 11.36) [73]. Grubbs catalyst 143 has been used for the construction of the endocydic 1,2-disubstituted C12-C13 double bond in epothilone C 148 that, after epoxidation, affords epothilone A 150 [74]. In this approach, ruthenium carbene 143 is more efiident than Schrock molybdenum catalyst 142b [75a[. However, the RCM-route to epothilone D 149, the desoxy precursor of epothilone B 151 bearing a trisubstituted C=C bond, requires the molybdenum carbene catalyst 142b attempts to initiate ring-closure with 143 failed [75]. 

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