Macrolactonization strategy

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. 

The greater stability of 120 relative to 123 induced us to center our efforts on luzopeptin E2. It seemed logical to examine first a macrolactonization strategy involving cyclodimerization of 125, because we estimated that the coupling of acid 124 with amine 49 would not be subject to the stereochemical difficulties alluded to in the introduction, and that no base treatment would be necessary subsequent to the union of 124 and 49 through peptide bond formation. Recall that peptides incorporating mhv are base-sensitive this property was likely to be carried over into 125. 

Based on information accrued during the stereochemical elucidation, macrolactone 85 was identified as a viable synthetic intermediate (Scheme 12). The authors were cognizant of the potential challenges that could arise. First, the required formation of a trisubstituted alkene in a projected Horner-Emmons macrocyclization was without strong precedent. Also, this strategy would necessitate a stereoselective reduction of the Cl5 ketone, which was predicted to be feasible based on MM2 calculations. 

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. 

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. 

A convergent strategy was chosen, which allows the introduction of modifications at nearly every position of the macrolactone. During the research more than 350 active epothilone analogues were synthesized and it was found that the side chains at C-15 and C-6 are responsible for the tolerability and efficacy. ... 

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). 

Chattopadhay and Pattenden adopted a similar strategy in an attempt to assemble the entire carbon skeleton of 1195 (Scheme 1.399). Here, the authors prepared 1567 and 1568 independently from 1543. It was anticipated that a late-stage macrolactonization of 1567 or 1568 would then give rise to entire carbon skeleton. Unfortunately, this strategy was frustrated by the disappointingly low yields (5-10%) encountered during this crucial step. 

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