.Wisniewska et al.Pagethe enantiomers of MCHR1 antagonist 1 and FAAH inhibitor
.Wisniewska et al.Pagethe enantiomers of MCHR1 antagonist 1 and FAAH inhibitor 3 show at least an order of magnitude difference in activity (Figure 1).7a,dNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptPreviously, we developed a stereospecific nickelcatalyzed Kumada cross-coupling of benzylic ethers for the formation of 3benzylic stereocenters.9 In contrast to enantioselective techniques that employ a chiral catalyst with racemic or achiral beginning supplies, stereospecific solutions use an achiral catalyst to translate the stereochemistry on the beginning material towards the solution. As an example, throughout the course of our Kumada coupling, a readily ready enantioenriched secondary ether10 is transformed to a tertiary benzylic stereocenter with all round inversion of configuration. Even though this transformation is very stereoselective and has been utilized in synthesis of medicinal agents with activity against breast cancer and insomnia, the use of DP site Grignard reagents as the coupling companion precludes synthesis of hugely functionalized compounds like 2 and 3 without having recourse to lengthy protecting group methods. Not too long ago, we’ve turned our interest to milder coupling partners in an effort to expand the scope of our reaction.11,12 We chose to concentrate on organozinc reagents due to the fact Negishi reactions are highly functional group tolerant.13 Stereoselective sp2 p3 cross-coupling has been shown for -chiral organozinc reagents, which undergo stereospecific Negishi reactions with aryl and vinyl halides.14 Moreover, the Fu group has created enantioselective alkyl-alkyl cross-coupling reactions using chiral nickel catalysts.15 However, stereospecific sp3 p3 cross-coupling of alkylzinc reagents with enantioenriched electrophiles has not yet been reported. Whilst Kumada reactions advantage from the high nucleophilicity of Grignard reagents, and proceed with easy benzylic ethers, we postulated that cross-coupling of alcohol derivatives using the less nucleophilic organozinc reagents would call for a much more reactive electrophile. Directing CaMK II Storage & Stability groups happen to be made use of in organic synthesis to promote transformations of otherwise unreactive substrates.16,17 Whilst incorporation of your directing group in to the physique with the substrate is often a popular method, it could limit the scope on the transformation. A traceless approach locations the directing functionality on the leaving group. More than the course with the reaction the directing group is cleaved, affording solutions that bear no trace on the directing functionality. Liebeskind demonstrated that traceless directing groups promote the cross-coupling of thioethers by accelerating the transmetallation step (Scheme 1a).18 The pendant carboxylic acid complexes zinc and promotes dissociation in the leaving group, supplying an open coordination web page around the nickel center for transmetallation. Inspired by this perform, we designed traceless directing groups to market the oxidative addition of sluggish electrophiles for Kumada couplings (Scheme 1b).9b,19,20 Magnesium coordination for the 2-methoxyethyl ether moiety is proposed to weaken the benzylic C-O bond, facilitating oxidative addition. We postulated that a related strategy could accelerate cross-coupling reactions with dimethylzinc. A leaving group bearing a pendant ligand could serve two functions (Scheme 1c). Coordination to a zinc reagent could activate the substrate for oxidative addition and facilitate the subsequent transmetallation step. We anticipated that tun.