Periodic Reporting for period 1 - ChirPyr (Access to chiral pyridine derivatives via catalytic asymmetric synthesis)
Reporting period: 2017-10-01 to 2019-09-30
We continue the project with the generation of contiguous stereocenters next to the heterocyclic moieties by sequential asymmetric addition/Mg-aza-enolate trapping reaction. We developed a study on sequential conjugate addition of Grignard reagents to alkenyl-heteroarenes followed by trapping of the resulting enolates, yielding moderate to good diastereoselectivities. Contrary to conventional wisdom, one-pot conjugate addition/trapping using two reactive Michael acceptors in combination with Grignard reagents can proceed via conjugate addition to the least reactive Michael acceptor. This unusual chemoselectivity is triggered by the presence of a Lewis acid, reverting the usual reactivity order of Michael acceptors. We decided to go one step forward using carbenium ions, different Michael acceptors and bromine as electrophiles in the Lewis acid promotion of the enantioselective conjugate addition (CA) of Grignard reagents to unsaturated amides, carboxylic acids and alkenyl heterocycles. During this work we show a simple one-pot conjugate addition-trapping protocol that leads to functionalized molecules starting from unreactive Michael acceptors. This domino reaction of enamides with carbenium ions afforded compounds featuring useful and non-trivial substituent motives.
Finally, the catalytic synthesis of chiral pyridines with quaternary stereocenters was studied. For the purpose of generating all carbon quaternary stereocenters β-to the heteroaromatic moiety, the following β,β-disubstituted 2-alkenyl heteroaromatic compounds were synthesized. Subsequently the copper-catalyzed asymmetric conjugate addition of Grignard reagents to form all-carbon quaternary stereocenters was studied. The copper-catalyzed ACA of Grignard reagents to such substrates could not be performed at the targeted position due to the big steric hindrance. Therefore, in order to achieve the desired enantioenriched all-carbon quaternary stereocenters, new methodologies should be developed.
During thisproject we stated to develop a methodology using non-cryogenic conditions to performed this type of additions where only one exmaple was reported before. Like this way we were be able to synthetized enantionriched heterocyclic compounds with mild reaction conditions.
After that the generation of contiguos stereocenters in this type of substrates was studied using trapping reagents. We showed that chiral silyl ketene aminals and related enolates from carboxylic acids and alkenylheterocycles could be trapped by various electrophiles. Trapping by carbocations was compatible with the excess of TMSOTf and Grignard reagent, which are required for the effective CA to unreactive Michael acceptors. Experiments showed that steric factors were responsible for reactions outcomes. Trapping reaction on alkenylheterocycles allowed use of BF3*OEt2 and TMSOTf. By this one-pot procedure, we obtained multiplefunctionalized products, which are not accessible by other methods.