Aldol lactonization domino reactions

Scheme 2.61. Syntnesis of (-)-panclicin D (2-258) and okinonellin B (2-261) employing the domino Mukaiyama aldol/lactonization reaction sequence.

Romo and coworkers [1] have extensively studied the domino Mukaiyama-aldol-lactonization reaction of aldehydes and thiopyridyl silyl S,0-ketene acetals,... 

Scheme 8.2 Domino aldol/lactonization/oxoniumion formation/reduction reaction [4].

Isotetronic acids were readily assembled through an organocatalyzed domino aldol-lactonization reaction starting from a-keto carboxylic acids and aldehydes [5]. As chiral organocatalyst, the proline-derived benzimidazol pyrrolidine 8 was employed, which proved superior to proUne itself Electron-poor aldehydes were both more reactive and selective. Thus, as a typical example, pyruvate was converted into isotetronic acid 10 in 77% yield and 83% ee upon treatment with para-nitrobenzyldehyde (9) and 10mol% 8 (Scheme 8.3). 

Scheme 8.3 Domino aldol-lactonization reaction for the assembly of isotetronic acids [5].

Domino reduction/aldol cydization was applied for the synthesis of ( )-fredericamydn A 44, a potent antitumor and antibiotic agent, by Kelly et al. [18] in 1988 (Scheme 9.10). DIBAL-H (diisobutylaluminum hydride) reduction of lactone 45 afforded an intermediate 46 having both enolate and aldehyde. Subsequent cychzation via aldol reaction gave a diastereomeric mixture of spiro hydroxy ketone 47, which was further converted into ( )-fredericamycin A 44 by sequential organic transformations. A similar strategy was employed by Mehta et al. [19] for the synthesis of bicyclo[3.3.1]nonan-9-one core of hyperforin, an antidepressant. 

A mechanistic rationalization for this reaction is presented in Scheme 5.48. Domino process is initiated with generation of key intermediate 152, which undergoes a 1,4-addition of a deprotonated oxindole to form 153. After H-migration and following aldol reaction with another molecule of alkynyl aldehyde, intermediate 155 is formed. Subsequent lactonization delivers prodnct 66 and regenerates NHC for the next catalytic cycle. The stereochemistry of the products may be determined by the most sterically favored chair transition state in 155. 

Scheme 7.54 Domino Michael-lactone-opening-aldol-dehydration reaction catalysed by chiral amine catalysis and platinum catalysis followed by esterification.

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