Hydroxy esters macrolactonization

Lipases also catalyze the intramolecular transesterification (lactonization) of hydroxy esters. Macrolactonization of a racemic hydroxy ester in the presence of PSL provided the corresponding (R)-lactone (Figure 6.22). This compound is the naturally occurring enantiomer of the pheromone produced by the merchant grain beetle [70]. Chemical macrolactonizations require high dilution to minimize... 

The simplest way of macrolactonization is the use of acid or base catalysis so that after the ring closure no tedious separation of the lactone from auxiliary by-products is required. However, there are only very few such examples. The 16-membered macrolide ring of milbemycin 3 is closed very efficiently by simply treating the hydroxy ester (349) with potassium hydride. OH deprotonation induces ring formation with retention of configuration to (350 equation 125). 

Treatment of ( )-hydroxy ester 32 with lipase P (Amano) affected the enantioselective macrolactonization to give the pheromone of the rusty grain beetle (R)-33, although the yield was only 17% (Figure 24.17) [20]. 

Macrolactonization. This acetylene reacts selectively with the carboxyl group of an (o-hydroxy carboxylic acid (2) to form a stable hydroxy enol ester 3. Addition of 10-camphorsulfonic acid or mercury(II) trifluoroacctate results in lactonization to macrolactones (4). 

Although Bu2SnO is a powerful catalyst for cyclization of co-hydroxy and co-amino carboxylic acids [294], treatment of co-hydroxy trifluoroethyl esters with Bu jSnOMe catalysis resulted in macrolactonization and/or diolide formation in different ratios, depending on chain lengths and reaction conditions (Scheme 12.166) [295]. In this reaction inter- and/or intramolecular transesterification occurred between trifluoroethyl esters and alkoxytrialkyltin generated by rapid exchange of the alkoxytin catalyst with the terminal alcohol. By use of this procedure as a final key step a 12-membered macrocyclic otonecine diester was obtained (Scheme 12.167) [296]. 

The total synthesis by the Ireland group was accomplished via Michael addition of the C8-C20 segment to the C21-C34 segment having a pipecolic ester moiety, and macrolactonization (Fig. 5). Their synthetic feature is that the C21-C24 a -allyl P-hydroxy ketone system is masked as 6,6-spiroketal during the synthesis and the labile a,p-diketoamide hemlketal system is prepared by oxidation of a masked enediol at a late stage. 

Danishefsky s first macrolactonization [142d] to 5a was carried out using 568 (Scheme 81), which was prepared starting from 562. The Cl-ClO ester 562 was synthesized from acetal 561 (Scheme 79). After hydrolysis of the acetal 561, the resulting aldehyde was subjected to aldol reaction with t-butyl acetate to give a-and p-alcohols in a 2 1 ratio. The desired a-alcohol was further converted to TBS ester 562 in standard fashion. As shown in Scheme 81, Suzuki coupling of 562 and 565 followed by hydrolysis of the ester afforded hydroxy carboxylic... 

An alternative route by the Danishefsky group was developed [142e-g] (Scheme 84). The aldol reaction of ethyl ketone 580, prepared from P-keto ester 579, with aldehyde 581 stereoselectively afforded 582 (dr = 5.4 1). After Troc protection followed by hydrolysis of the enol ether, Suzuki coupling with 583 followed by TBS deprotection gave the desired (12Z)-olefin 584. The Noyori reduction of the P-keto ester 584 gave 3a-alcohol with high stereoselectivity, which was converted into hydroxy carboxylic acid 585. Macrolactonization of 585 was accomplished by the Yamaguchi method, and subsequent deprotection and DMDO oxidation efficiently afforded epothilone B (5b). 

TE domain is able to catalyze the macrocyclization of oo-hydroxy fatty acid ethyl esters to afford 17- to 28-membered lactones [35]. One would hope that in the future a rather general TE domain will be identified or optimized via directed evolution, which could compete with the chemical Yamaguchi macrolactonization. 

A novel synthesis of (+)-mtegerrinecic acid lactone, the necic acid component of the macrolactone pyrrolizidine alkaloid integerrimine 53, has been reported by White and Jayasinghe, wherein lactonization of a 6-hydroxy acid was used for the ring closure [46] (Scheme 9). Reduction of epoxide 49 derived from / -(+)-P-citronellol and subsequent protection gave bis-3,5-DNB ester 50. Oxidative cleavage of the double bond afforded the carboxylic acid which upon saponification of the esters and acidification resulted in spontaneous lactonization to provide lactone 52. 

Macrolactonization. When a carboxylic acid is treated with 2,2 -dipyridyl disulfide in the presence of Triphenylphosphine, the corresponding 2-pyridinethiol ester is formed. Corey and Nicolaou have developed an efficient method for the synthesis of macrocyclic lactones based on these 2-pyridinethiol esters. When an m-hydroxy thiolester is heated in refluxing xylene under high dilution conditions (10 M, typically accomplished with syringe pump techniques), macrolactonization occurs, liberating triphenylphosphine oxide and pyridinethione. The reaction is quite general and is believed to proceed by a double activation mechanism in which the basic 2-pyridinethiol ester simultaneously activates both the hydroxy and the carboxylic acid moieties with a single proton transfer. It has been shown that the cyclization rate is not affected by the presence of acids, bases, or any of the possible reaction contaminants. ... 

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