Macrolactonization methods

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... 

The second reaction is a macrolactonization which is performed with retention of configuration at C-15. Therefore the acid component has to be activated and the Yamaguchi-Yonemitsu macrolactonization method was chosen. For the detailed mechanism see the Key Chemistry of this chapter. Typical conditions are TCBC, EtsN, THF,... 

Erythronolide B, the biosynthetic progenitor of the erythromycin antibiotics, was synthesized for the first time, using as a key step a new method for macrolactone ring closure (double activation) which had been devised specifically for this problem. Retrosynthetic simplification included the clearance of the stereocenters at carbons 10 and 11 and the disconnection of the 9,10-bond, leading to precursors A and B. Cyclic stereocontrol and especially the Baeyer-Villiger and halolactonization transforms played a major role in the retrosynthetic simplification of B which was synthesized starting from 2,4,6-trimethylphenol. 

Sc(OTf)3, AcOH, p-nitrobenzoic anhydride or Sc(OTf)3, AC2O, 66- >95% yield. The lower yields are obtained with allylic alcohols propargylic alcohols give higher yields. Phenols are effectively acylated with this catalyst, but at a much slower rate than simple aliphatic alco-hols. The method was shown to be superior to most other methods for macrolactonization with minimum diolide formation. 

The first total synthesis of erythronolide B (1) by Corey stands as an event of great historical significance in synthetic chemistry it provides a powerful illustration of the utility of Corey s methods of macrolactonization and it demonstrates, in a particularly insightful way, the value of using readily accessible six-membered ring templates for the assembly of contiguous arrays of stereo-genic centers. 

Use of 2,4,6-trichlorobenzoyl chloride, Et3N, and DMAP, known as the Yamaguchi method,128 is frequently used to effect macrolactonization. The reaction is believed to involve formation of the mixed anhydride with the aroyl chloride, which then forms an acyl pyridinium ion on reaction with DMAP.129... 

Macrolactonization of CD-hydroxyl-acid using 2,2 -dipyridyl disulfide. Also known as Corey-Nicolaou double activation method. 

Although RCM gives brilliant results for the synthesis of medium-ring carbo-cycles, it is also effective for the synthesis of macrocyclic lactone as shown in Eqs. (6.25)-(6.27). Prior to RCM, macrolactonization was the most common method for the synthesis of macrocyclic lactone. However, we can now obtain the desired macrocyclic lactone from diene having an ester moiety in a chain by RCM followed by hydrogenation ... 

Macrolactonization The original conditions of Steglich esterification are ineffective for lactonization of co-hydroxy carboxylic acids. However, addition of a soluble amine hydrochloride as a proton-transfer agent results in a useful method... 

The process for preparing macrolactones described in the text is impractical. Instead of this process one uses a continuous method with a syringe pump a solution of the hydroxycar-boxylic acid is added very slowly—that is, in the course of hours or days—i nto a small flask, which contains > 1 equivalent of the activator and, if necessary, just enough triethylamine to neutralize any released HC1. The rate at which the acid is added is regulated such that it is equal to or smaller than the lactonization rate. This is called pseudo high dilution. At the end of the reaction the lactone solution can be relatively concentrated, e. g., 10 mmoEL, at least 10,000 times more concentrated than without the use of this trick. 

Besides conformational disarming, one-pot methods also benefit from building blocks that are electronically disarmed. Biao Yu and coworkers utilized this effect in the one-pot assembly of the 19-membered macrolactone-containing tricolorin A (16) (Scheme 6.3) [13, 14], The key design of their synthesis is the chemoselective activation and coupling of the perbenzylated donor 7 to the bis-acyl-containing disarmed bifunctional acceptor 12. The subsequent glycosylation of macrolactone 14 in the same flask formed the protected tricolorin A15 in 43% overall yield, which was deprotected to provide tricolorin A (16). 

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 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],... 

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