Hydroxy acids, macrolactonization

The 15-hydroxy acids 10a and 10b (Scheme 2) were cyclized with the reliable Yamaguchi (2,4,6-trichlorobenzoylchloride, TEA, DMAP, toluene) [10, 11, 13, 16] and Keck methods (DCC, DMAP, DMAPxHCl, CHCI3) [23, 28]. Both delivered the macrolactones in good to excellent yields, the first (90 % 9b and 78 % 9c) being superior to the latter. 

Ley et al. [22] recently applied this method to the total synthesis of the antibiotic ( + )-milbemycin jSi(ii). Thus, hydroxy acid 31 was cyclized to macrolactone 32 in good yield (more than 49%) by slow addition (over 9 h) of a solution of 31 and triethylamine in acetonitrile to a refluxing solution of 28 in acetonitrile (Scheme 11). Another recent application of the Mukaiyama method is due to White and Bolton [23],... 

In the total synthesis of the macrolide antibiotic methymycin 49), Masamune and coworkers [28] developed a new macrolactonization method which makes use of the electrophilicity of Hg(II) toward bivalent sulfur. It involves the S -f-butyl thiolester 44 of the hydroxy acid 41 and employs mercuric trifluoroacetate as an activating agent. The required S -r-butyl thiolester 44 can be prepared in high... 

Macrolactonization can also be achieved by the Mitsunobu reaction [44] with inversion of the configuration of the alcohol. The reaction principle and mechanism are demonstrated in Scheme 24. Addition of triphenylphosphine to diethyl azodicarboxylate (DEAD, 73) forms a quaternary phosphonium salt 74, which is protonated by hydroxy acid 11, followed by phosphorus transfer from nitrogen to oxygen yielding the alkoxyphosphonium salt 76 and diethyl hydrazinedicarboxy-late 75. Then, an intramolecular Sn2 displacement of the important intermediate 76 results in the formation of the lactone 15 and triphenylphosphine oxide. 

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. 

Also, macrolactonization of hydroxy acids is achieved using a polymer bound carbo-diimide." " ... 

Long chain tu-hydroxy acids, such as 653, are converted to the corresponding macrolactones 654 in 95 % yield using DMAP hydrochloride. ... 

The total synthesis of a novel fungicidal natural product, (-)-hectochlorin, was accomplished by J.R.P. Cetusic and co-workers. The final step in their synthetic route was the Keck macrolactonization under the original conditions developed by Keck et al. The substrate hydroxy acid was dissolved in ethanol-free CHCI3 and was slowly added to a chloroform solution of DCC, DMAP and DMAP-HCI at reflux temperature. 

Corey, E. J., Brunelle, D. J. New Reagents for Conversion of Hydroxy-Acids to Macrolactones by Double Activation Method. Tetrahedron Lett. 1976, 17, 3409-3412. 

Keck, G. E., Sanchez, C., Wager, C. A. Macrolactonization of hydroxy acids using a polymer-bound carbodiimide. Tetrahedron Lett. 2000, 41, 8673-8676. 

The high reactivity of this polymeric-related DCC 5 is particularly noticeable in the macrolactonization reaction of 12, 13, 15 and 16-carbon to-hydroxy acids 6 (Scheme 7.2). Here, the combination of carbodiimide 5 and DMAP gave rise to the corresponding macrolactones 7 in identical yields to when DCC was used-the yield being even higher for the 13-membered lactone 7a (only a 32% yield was obtained using DCC) [16]. 

Total synthesis of the antibiotic globomycin is achieved via macrolactonization, from the key intermediate 50. Coupling of hydroxy acid 48 and amide 49 is mediated by DEPC without protection of the hydroxyl group in 48.20... 

Mitsunobu et al. [46] reported an efficient macrolactonization using diethyl azodicarboxylate (DEAD) and Ph3P. In the case of (o-hydroxy acids having a secondary alcohol, this cyclization takes place with inversion of the configuration of the alcohol. In the total synthesis of latrunculin A (82) and B, the Mitsunobu reaction was used for the macrolactonization of the seco-acid 81 with inversion of the secondary alcohol [47]. 

A variety of specialized reagents have been developed for macrolactonization reactions. Two of the more important are the Corey-Nicolaou reagent, 2,2 -dipyridyl disulfide (232)10 jjjg Mukaiyama reagent, which is 2-chloro-l-methylpyridinium iodide (233). A number of related reagents have been developed, including imidazole disulfide 234 [2,2 -dithio-(4-ferf-butyl-l-isopropylimidazole)]l 2 and imidazole 235 [N-(trimethylsilyl)imidazole].l 3 All of these reagents are effective for the cyclization of co-hydroxy acids, as shown in Table 6.1. For comparison, available cyclization results with DEAD and 234 are included. In this table, a hydroxy acid is converted to a lactone (219). 

Two other important methods are described in Fig. 7. The first is a macrolactonization mediated by the Mitsunobu reaction. In this case, in contrast with the preceding examples, the hydroxyl functional group is activated, and the carboxylate group behaves as a nucleophile. The reaction of the hydroxy acid with diethyl... 

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