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Asymmetric Hydroformylation-Initiated Tandem Sequences for Syntheses of (+)-Patulolide C, (−)-Pyrenophorol, (+)-Decarestrictine L, and (+)-Prelog Djerassi Lactone

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journal contribution
posted on 02.01.2015 by Roberto M. Risi, Andrew M. Maza, Steven D. Burke
Four different Rh-catalyzed asymmetric hydroformylation (AHF) tandem reactions have been developed in the context of the total syntheses of (+)-patulolide C, (−)-pyrenophorol, (+)-decarestrictine L, and (+)-Prelog–Djerassi lactone. A total synthesis of (+)-patulolide C has been accomplished in three steps utilizing a Rh­(I)-catalyzed Z-selective anti-Markovnikov hydroacetoxylation of a known alkyne to give a Z-enol acetate with excellent selectivity. An AHF/intramolecular Wittig olefination cascade was utilized to set the C4-hydroxyl stereochemistry, E-olefin geometry, and form the macrolactone. In addition, both (−)-pyrenophorol and (+)-decarestrictine L have been synthesized from the enantiomeric (4R)- and (4S)-4-(tert-butyldimethylsiloxy)-1-pentyne in five and four steps, respectively. These syntheses feature Ru­(II)-catalyzed Z-selective anti-Markovnikov hydroacetoxylation of terminal alkynes followed by AHF/Wittig olefination sequences to rapidly establish functionality and stereogenicity. A synthesis of (+)-Prelog–Djerassi lactone was accomplished in three isolations from the known 1-vinyl-4-methyl-2,6,7-trioxabicyclo[2.2.2]­octane ortho ester. An AHF/crotylation tandem sequence has been developed to set the C2–C4 stereochemistry. An asymmetric hydrogenation was employed to set the C6 stereochemistry, resulting in an especially efficient enantioselective synthesis from achiral starting material. In summary, these syntheses have greatly improved efficiency in terms of atom-economy, catalytic stereoselective transformations, inexpensive reagents, step-counts, and overall yield when compared with previous synthetic attempts.