Lactone synthesis oxygen nucleophiles

Palladium-catalyzed lactonization with CO insertion is a useful method that has been developed over the years to become an important tool in organic synthesis. The most straightforward approach consists of an oxidative addition of Pd(0) to a vinyl/aryl halide or a pseudohalide (e.g., triflate) followed by insertion of carbon monoxide and subsequent intramolecular attack of the oxygen nucleophile onto the carbonyl, with regeneration of the Pd(0) catalyst. An appropriate base is necessary to trap the acid released during the reaction (Scheme 1). 

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

The Michael addition of nucleophiles to coumarins catalyzed by solid bases provides an interesting approach to the synthesis of 4-substituted 3,4-dihydrocumarins, because with the conventional Michael catalysts the alkaline hydrolysis of the 8-lactone predominates (Scheme 44). Results were obtained when the Michael addition of diethyl malonate to coumarin was catalyzed by the activated Ba(OH)2 292). An unusual 1,2-addition-elimination process at the C = 0 bond was observed. The mechanism of this reaction was explained on the basis of the microcrystalline structure of the catalyst. It was suggested that the rigid coumarin molecule interacts with the Ba ions through the lone-pair electrons of both oxygen atoms of the... 

An interesting methodology to highly oxygenated p)razolidines and indolizidines from 2,3-unsaturated sugar lactones was presented by Chmielewski [84]. The synthesis was initiated by a 1,4-addition of nitrogen nucleophiles to unsaturated lactones 93, which resulted in formation of appropriate heterocyclic derivative 94 (O Scheme 38). 

Anionic polymerization has an essential role in the polyester synthesis from lactones because it enables the correct design of the polymer s molecular weight, structure and properties. As has been widely reviewed, the anionic ROP of four-membered lactone monomers takes place by the nucleophilic attack of a negatively charged initiator on the carbonyl carbon, or on the carbon atom adjacent to the endocyclic ether oxygen atom, resulhng in linear polyester (Scheme 9.5). 

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