Macrolactonization strategy macrolactone synthesis

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]. 

A Stille type coupling strategy has been utilised to complete a total synthesis of epothilone E. The vinyl iodide 30 and the thiazole stannane 31 were coupled to give the macrolactone 32 which is a precursor to natural epithilone E. The thiazole stannane 31 was prepared from 4-bromo-2-hydroxymethylthiazole via treatment of the lithiated protected 4-bromO 2-hydroxymethylthiazole with tributylstannyl chloride. This Stille coupling approach was also used to prepare a range of epothilone B analogues <99BMC665>,... 

For the cyclization to the 16-membered macrolactone structure of epothilones C and D (= desoxyepothilones A and B, resp. [26]), three different strategies have been used successfully so far (1) Ring-closing olefin metathesis (RCM) between C12 and Cl3. RCM is a comparably new method in total synthesis and underwent enor-... 

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. 

In Section II, the synthetic strategies for macrolide synthesis are introduced and focus in particular on asymmetric synthesis of 1,3-diol, synthetic methodology for macrolactone, and glycosidation. In Section III, the total synthesis of selected macrolide antibiotics is introduced FK506 (tacrolimus 1), rapamycin (sirolimus 2), avermectins (3), altohyrtins (spongistatins 4), and epothilones (5) (Fig. 1). Several other synthesized macrolides are also illustrated. 

Shortly thereafter, Ghosh and Liu" reported a convergent and enantioselective synthesis of 1183. In their strategy, macrolactonization of 1259 is the key step for assembling the core structure. Further disconnection of 1259 then revealed the oxazole dienylamine 1203 (R = CH3), D-alanine, and the 5-hydroxy-2-alkenoic acid 1228 as intermediate synthetic targets (Scheme 1.322). 

A further synthesis of hypothemycin (481) was published by the group of Winssinger in 2009 (384). They used a partial solid-phase strategy with a benzylic sulfide linker to build up the resorcylic macrolactone. The applied macrolacto-nization step proceeded extremely efficiently and epoxidation of LL-Zl640-2 (567) with dimethyldioxirane afforded hypothemycin with excellent regio- and stereoselectivity, but in a poor yield. 

In 2004, Myers and Haidle reported a convergent and modular total synthesis of cytochalasin B (1088) and the [lljcytochalasan L-696,474 (1139) (742), using a late-stage macrocyclization step involving an intramolecular Horner-Wadsworth-Emmons olefination. Their strategy is applicable for the synthesis of cytochalasans of different ring sizes, as exemplified by these two total syntheses. Both macrolactone and macrocarbocyclic cytochalasans can lead back retrosyntheticaUy to the same precursors. The synthesis of the tricyclic isoindolone precursor to cytochalasin B (1088) and L-696,474 (1139) is shown in Scheme 14.1. 

The synthetic sequence involving formation of a thioether, oxidation to the corresponding sulfone and the RBR need not be performed consecutively, although it almost invariably is when applied to the synthesis of complex targets. An example in which divorcing the sulfone preparation from the RBR was actually beneficial to the synthetic strategy is seen in the total synthesis of the resorcylic acid macrolactone (RAL) aigialomycin D by Harvey and coworkers. ... 

Recently, Shishido has achieved the third total synthesis of (+)-lasonolide A, and their synthetic strategy was based on the introduction of the side chain via Lee s protocol, the successful Yamaguchi macrolactonization, and the... 

Hoye achieved the total synthesis of (-)-dactylolide via two distinct macro-cyclization strategies, involving Ti(IV)-mediated macrolactonization of an epoxy-acid (route A) and a RCM macrocyclization (route B) (Scheme 29). The czs-2,6-disubstituted-4-methylene tetrahydropyran was constructed by Prins... 

Having completed the synthesis of 13-demethyllyngbyaloside B (5), we were now in a position to tackle the parent natural product, lyngbyaloside B (1). Our initial synthesis plan for 1 followed that of 5, basically relying on the esterification/RCM strategy for the construction of the macrocyclic skeleton (Scheme 7). Thus, it was conceived that the macrolactone 36 would be available from the tertiary alcohol 37 and the carboxylic acids 9a,b. 

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. 

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... 

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