Isomerisation-Michael reaction

Scheme 7.71 Tandem isomerisation-Michael reaction catalysed by iridium catalysis and chiral amine catalysis.

The retrosynthesis involves the following transformations i) isomerisation of the endocyclic doble bond to the exo position ii) substitution of the terminal methylene group by a more stable carbonyl group (retro-Wittig reaction) iii) nucleophilic retro-Michael addition iv) reductive allylic rearrangement v) dealkylation of tertiary alcohol vi) homolytic cleavage and functionalisation vii) dehydroiodination viii) conversion of ethynyl ketone to carboxylic acid derivative ix) homolytic cleavage and functionalisation x) 3-bromo-debutylation xi) conversion of vinyl trimethylstannane to methyl 2-oxocyclopentanecarboxylate (67). 

Benzyl bromides 15 derived from either salicylaldehydes or 2-methylphenols by reaction with alkyl propynoates afford 277-1 -benzopyrans on treatment with tetrahydrothiophene and K2CO3. A sulfonium ylide is proposed which initiates a Michael addition - elimination -substitution sequence. When CS2CO3 is used as the base, 477-1-benzopyrans result almost exclusively, presumably through isomerisation of the 277-1-benzopyran. The protocol thus offers access to both chromene isomers through simple variation of the reaction conditions <06OL3853>. The Cu-catalysed intramolecular O-arylation of a-(2-bromobenzyl)-P-keto esters in refluxing THF offers a useful route to 2-substituted 477-l-benzopyran-3-carboxylates <06JOC6427>. 

The reaction of cyanide with a protected 5-bromouridine is instructive under mild conditions a cine-substituted product is obtained via a Michael addition followed by p-elimination of bromide, but at higher temperatures, conversion of the 6- into the 5-cyano-isomer is observed, i.e. the product of apparent, direct displacement of bromide is obtained. The higher-temperature product arises via an isomerisation involving another Michael addition, then elimination of the 6-cyano group. 

A short and highly diastereoselective synthesis of tetrahydropyran-4-ones was recently reported hy the group of Tong. Reductive 1,2-oxazoline N-O cleavage in 71 with Sml2 followed by acid-catalysed 6-e do-trig oxa-Michael cyclisation of the crude product furnished q n-tetrahydropyran-4-one 72 (Scheme 25). Extended reaction times resulted in improved yields and diastereoselectivities, presumably due to a retro-oxa-Michael/ oxa-Michael isomerisation. The total synthesis of ( )-diospongin Awas completed in a 20% overall yield. 

In 2010, Jorgensen et al. developed an enantioselective tandem reaction of propargylated malononitriles with cyclic enones sequentially catalysed by a cinchona alkaloid-derived primary amine catalyst in the presence of (J )-mandelic acid as an additive for the first Michael step, and a gold catalyst for the second tandem exo-dig cyclisation-isomerisation reaction. " As shown in Scheme 7.62, the corresponding chiral bicyclic enones were achieved in good yields and high enantioselectivities of up to 96% ee, albeit low to moderate diastereoselectivities (34-66% de). 

Scheme 7.62 Tandem Michael-q clisation-isomerisation reaction catatysed by chiral amine catalysis and gold catalysis.

On the other hand, Alexakis et al. have developed a sequential reaction exploiting the compatibility between a cationic iridium catalyst and chiral diphenylprolinol trimethylsilyl ether. The role of the iridium complex was proposed to isomerise the starting allylic primary alcohols into the corresponding aldehydes in the presence of H2, while the chiral amine catalyst promoted the a-functionalisation of these aldehydes through reaction with vinyl sulfone to give the corresponding Michael adducts as a mixture of syn-and (Z h -diastereomers obtained in moderate yields, moderate to excellent... 

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