Skip to main content

Access to chiral pyridine derivatives via catalytic asymmetric synthesis

Periodic Reporting for period 1 - ChirPyr (Access to chiral pyridine derivatives via catalytic asymmetric synthesis)

Reporting period: 2017-10-01 to 2019-09-30

The pyridine ring is one of the most important N-containing aromatic heterocycles in drug discovery. Playing a vital role in the field of heterocyclic chemistry, pyridine and its derivatives abundantly exist in nature and are widely used for many applications in medicinal science. The ability of the C=N moiety of a pyridine ring to activate the adjacent alkenyl towards nucleophilic attack (in analogy to carbonyl compounds), offers an attractive opportunity to carry out conjugate nucleophilic additions using carbon-nucleophiles. This concept has been broadly implemented for additions of a variety of nucleophiles to vinyl-substituted pyridines as well as other types of heteroarenes. Catalytic enantioselective addition of carbon-nucleophiles to β-substituted alkenyl pyridines represents a conceptually simple and atom economical method for the preparation of chiral pyridine scaffolds. However, compared to vinyl-pyridines, nucleophilic additions to β-substituted alkenyl pyridines (AP) are much less explored due to the lower reactivity caused by the steric hindrance derived from the β-substituent. As a result of this low reactivity, only few literature examples exists, and they deal with racemic addition of carbon-nucleophiles to β-substituted AP. When catalytic enantioselective synthesis is in consideration, the only two literature reports are restricted to arylation reactions using β-substituted AP with strong electron-withdrawing groups in the aromatic ring under microwave irradiations or at elevated temperature. The shortage of methodologies clearly indicates a need for novel strategies to activate β-substituted AP towards nucleophilic additions. Recently, the Harutyunyan group reported, in Science magazine, a breakthrough in a closely related field: synthesis of chiral heteroarenes via catalytic asymmetric addition of various alkyl, as well as phenyl, Grignard reagents to alkenyl-substituted aromatic N-heterocycles using Cu(I)-catalyst. The scope of explored heteroaromatic substrates included benzoxazoles, benzothiazoles, thiazoles, oxazoles, pyrimidines and triazines. The key strategy was the enhancing of the reactivity of alkenyl-heteroarenes via Lewis acid (L.A.) activation combined with the use of highly reactive carbon-nucleophiles such as Grignard reagents.
The project was started trying to develop a methodology for the synthesis of alkylated alkenyl-N-heteroarenes at non-cryogenic temperatures and high enantioselectivities. While a powerful methodology, only one non-cryogenic example has been reported; the room-temperature addition of EtMgBr to 4-styrilpyridine in the presence of aforementioned chiral copper catalyst and trimethylsilyl bromide, which affords the 1,4-addition product at 73% yield and 91% ee. During this work we discusse the possible extension of this catalytic system to include non-cryogenic, ideally ambient temperatures in this type of reactions.

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.
The ability of the C=N moiety of a pyridine ring to activate the adjacent alkenyl towards nucleophilic attack (in analogy to carbonyl compounds), offers an attractive opportunity to carry out conjugate nucleophilic additions using carbon-nucleophiles. This concept has been broadly implemented for additions of a variety of nucleophiles to vinyl-substituted pyridines as well as other types of heteroarenes. Catalytic enantioselective addition of carbon-nucleophiles to β-substituted alkenyl pyridines represents a conceptually simple and atom economical method for the preparation of chiral pyridine scaffolds. However, compared to vinyl-pyridines, nucleophilic additions to β-substituted AP are much less explored due to the lower reactivity caused by the steric hindrance derived from the β-substituent. As a result of this low reactivity, only few literature examples exists, and they deal with racemic addition of carbon-nucleophiles to β-substituted AP. When catalytic enantioselective synthesis is in consideration, the only two literature reports are restricted to arylation reactions using β-substituted AP with strong electron-withdrawing groups in the aromatic ring under microwave irradiations or at elevated temperature. The shortage of methodologies clearly indicates a need for novel strategies to activate β-substituted AP towards nucleophilic additions.

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.
reactions carried out during the period of the grant