| A general catalytic enantioselective approach for the allylic alkylation of unstabilized enolate is described in this work. In the presence of a proper enantiopure chiral palladium catalyst, an allyl enol carbonate releases one molecule of carbon dioxide and generates an enolate nucleophile together with a pi-allylpalladium electrophile. The recombination of those two gives an allylated ketone product (either cyclic or acyclic) possessing an alpha-stereogenic center (either tertiary or quaternary) in high yield and high regio- and enantioselectivity. The decarboxylative asymmetric allylic alkylation reaction (DAAA) features by its extremely mild conditions, broad substrate scope and great functional group compatibility.;To simplify the synthesis of substituted ally) enol carbonates, BF3 complexes of imidazolides are found to be safer and more readily available equivalents of chloroformates, reacting with sodium or potassium enolates at the O-terminal in high regioselectivity. The DAAA reactions of substituted allyl enol carbonates are particularly noteworthy since two adjacent all carbon stereogenic centers are formed simultaneously in high yield, dr and ee under extremely mild conditions.;This chemistry is extended to the asymmetric alkylation of alpha-heteroketones. Either an tertiary hydroxyaldehyde or a secondary hydroxyketone can be selectively produced in high yield and ee from the DAAA reaction of a certain allyl 1,2-enediol carbonate in the presence of different ligands. The power of the method is demonstrated by the concise asymmetric formal synthesis of (S)-oxybutynin (5 steps, 30% yield, 99% ee), an anticholinergic medication used to relieve urinary and bladder difficulties.;This chemistry is also successfully extended to vinylogous esters and thioesters. The products are versatile synthons for organic synthesis, serving as masked 1,3-dicarbonyl compounds in which the two ketone groups and adjacent carbons may be selectively functionalized.;The DAAA reaction of acylimidazoles allows us to have a reliable access to other carbonyl compounds including esters, thioesters, amides, etc. This is especially meaningful since there is no general catalytic protocol for the access of these synthetically important compounds. As a demonstration, we synthesize cetiedil (7 steps, 77% yield, 90% ee), a drug possessing analgesic, local anaesthetic and antispasmodic activities and currently prescribes in Europe for the condition of ischemic leg pain.;The first catalytic enantioselective allylic alkylation of lactams and piperidine-2,6-diones is also described. The products are very useful intermediates for the synthesis of indole alkaloids, such as vincamine (formal synthesis, 9 steps, 44% yield, 90% ee; compared with the chiral auxiliary approach 15 steps, 2.6% yield, 89% ee), epieburnamonine (11 steps, 25%, 90% ee) and vallesamidine (on-going).;The mechanism of the palladium catalyzed DAAA reaction of unstabilized enolates is investigated. Although unstabilized enolates are considered as "hard" nucleophiles, our experimental results indicate that the alkylation step is an "outer sphere" SN2 substitution reaction, similar to the addition of most "soft" nucleophiles to pi-allylpalladium complex. |
