Anhydrides macrolactonization

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. 

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... 

This synthesis is shown in Scheme 13.59. Two enantiomerically pure starting materials were brought together by a Wittig reaction in Step C. The aldol addition in Step D was diastereoselective for the anti configuration, but gave a 1 1 mixture with the 6S, 1R-diastereomer. The stereoisomers were separated after Step E-2. The macrolactonization (Step E-4) was accomplished by a mixed anhydride (see Section 3.4.1). The final epoxidation was done using 3-methyl-3-trifluoromethyl dioxirane. 

Macrocycles are often not easy to form, especially when they include many substituents. The applied procedure to synthesize macrolactones was introduced by Yamaguchi and co-workers and has since been used extensively.21 First the acid is transformed into the mixed anhydride 26. Refluxing the anhydride in toluene will yield the desired macrocycle. The attack of the alcohol at the trichlorobenzoic acid carbonyl moiety is not favored because of steric hindrance by the chlorine substituents ortho to the acid. Therefore the ring is closed selectively. Usually in macrocyclizations high dilution conditions are applied, too, in order to avoid intermolecular reactions. 

Macrolactonization.1 High dilution is usually essential for macrolactonization, but the 14-membered lactone, 9-dihydroerythronolide A (3), can be obtained in almost quantitative yield by lactonization of the seco-acid 2 via the mixed anhydride formed with 2,4,6-trichlorobenzoyl chloride (1) with triethylamine and 4-dimethyl-... 

Another useful reagent for macrolactonization via mixed phosphoric anhydride is N,N- bis(2-oxo-3-oxazolidinyl)phosphordiamidic chloride (BOP-Cl, 64), which was used by Corey and coworkers [41] in the first synthesis of aplasmomycin (67), a novel boron-containing macrocyclic antibiotic. As shown in Scheme 21, the linear precursor 65 was treated with 3 equiv of BOP-Cl (64) and 7 equiv of triethylamine in dichloromethane at 23 °C for 6 h to give the dilactone 66 in 71% yield. 

In the classical procedure, the mixed anhydride is formed in THF in the presence of NEts. After filtration of NEtsHCl and evaporation of the solvent, the mixed anhydride is diluted in toluene and slowly added by syringe pump to a highly diluted solution of DMAP in toluene at 80 °C or under reflux/ The mixed anhydride is attacked by DMAP with formation of a cationic intermediate which forms the macrolactone by nucleophilic attack of the hydroxyl group. The mode of action is depicted below. The reaction proceeds with retention of the configuration at C-co. 

Accordingly, treatment of 129 with potassium f-butoxide and pseudoacid 107 gave a 58% yield of the required ( ,Z)-muconic ester 130. Macrolactonization was then achieved via the mixed pivaloyl anhydride in the presence of 4-pyrrolidinopyridine to afford verrucarin (124) in 60% yield along with its ( , )-muconate isomer 131 (30%). The latter could be isomerized with 12 in benzene to provide additional 124 (61%) contaminated with another muconic ester isomer. 

Masamune et al. [42] developed the macrolactonization of to-hydroxy r-butyl thioester with Hg(OCOCp3)2 in MeCN at room temperature, and this method accomplished the first total synthesis of methynolide [1]. They further developed an alternative method using a phosphoric acid mixed anhydride, which was apphed to the synthesis of narbonolide [43] and tylonolide [44]. 

Retronecine, in turn, can be converted to (— )-integerrimine (970) by coupling its cyclic stannoxane 968 with anhydride 969 followed by macrolactonization [211]. 

Yamaguchi s methynolide synthesis is based on the coupling of the C1-C7 (13) and Cg-Cii (14) segments, both of which are prepared from the resolved compounds, and the macrolactonization using the mixed anhydride prepared by use of 2,4,6-trichlorobenzoyl chloride and dimethylaminopyridine (Yamaguchi method). 

Extension of the traditional Yamaguchi/Corey-Nicolaou/Keck macrolactonization protocols (see Scheme 2.1) [5] to catalytic variants can address some of the drawbacks of classical methods. Mixed anhydrides can undergo cyclization with Lewis adds such as Sc,1i, Zr, and Hf [125,126].Trostetol. reported the use of ethoxyacetylene as a stoichiometric activating agent, installed via Ru catalysis [127], later applied to the synthesis of apicularen A (Scheme 2.67) [128]. 

Scheme 6.4 Mixed anhydride method of Yamaguchi for macrolactonization...

To a solution of 2-methyl-6-nitrobenzoic anhydride (MNBA, 8.1 mg, 0.0234 mmol) and DMAP (7.1 mg, 0.0585 mmol) in toluene (10 mL) was slowly added hydroxy carboxylic acid (17.1 mg, 0.0195 mmol) in toluene (10 mL) at 80 °C by syringe pump over a 4-h period. After stirring for additional 6 h at the same temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes/EtOAc, 8/1) to afford macrolactone 2.332 (13.5 mg, 81 %). 

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