Non-aromatic nitrogen-and oxygen-containing heterocycles such as piperidines and pyrans are prevalent components of natural products and pharmaceutical drugs. Although it has been a workhorse as a synthetic method for assembling unsaturated sp 2 -hybridized substrates, transition metal-catalysed cross-coupling chemistry is traditionally not a suitable approach to prepare chiral non-aromatic heterocycles. Several mechanistic issues hamper the coupling of stereogenic secondary sp 3 -hybridized carbon-metal centres. Moreover, use of unsymmetrical allylic boronates in the Suzuki Miyaura cross-coupling is further complicated by the possibility of forming two regioisomeric products. Here we address this two-pronged problem and demonstrate that chiral enantiomerically enriched heterocyclic allylic boronates can be coupled with high stereochemical retention with a wide variety of aryl and alkenyl halides to independently afford both regioisomeric 2-and 4-substituted dihydropyrans and dehydropiperidines in high selectivity. A divergent mechanism is proposed where regiochemistry is governed by the nature of the ligands on the palladium catalyst. This scalable method is applied to the efficient preparation of the neuroactive alkaloid anabasine and the antidepressant drug paroxetine.
Multicomponent reactions (MCR), transformations employing three or more simple substrates in a single and highly atom-economical operation, are very attractive in both natural product synthesis and diversity-oriented synthesis of druglike molecules. Several popular multicomponent reactions were designed by combining two well-established individual reactions that utilize mutually compatible substrates. In this regard, it is not surprising that the merging of two reactions deemed as workhorses of stereoselective synthesis, the Diels-Alder cycloaddition and carbonyl allylboration, would produce a powerful and highly versatile tandem MCR process. The idea of using 1,3-dienylboronates in [4 + 2] cycloadditions as a means to produce cyclic allylic boronates was first reported by Vaultier and Hoffmann in 1987. In their seminal study, a 1-boronodiene was reacted with electron-poor alkenes, and the intermediate cycloadducts were isolated and added to aldehydes in a separate step leading to α-hydroxyalkylated carbocycles via a highly diastereoselective allylboration reaction. The one-pot three-component variant was realized in 1999 by Lallemand and co-workers, and soon after groups led by Hall and Carboni reported heterocyclic variants of the tandem [4 + 2] cycloaddition/allylboration to prepare α-hydroxyalkylated piperidine and pyran containing compounds, respectively. These classes of heterocycles are ubiquitous in Nature and are important components of pharmaceuticals. This Account summarizes the development and evolution of this powerful multicomponent reaction for accessing nonaromatic heterocycles and its many applications in natural products synthesis and drug discovery. The aza[4 + 2]cycloaddition/allylboration MCR was first optimized in our laboratory using 4-boronylhydrazonobutadienes and N-substituted maleimides, and it was exploited in the preparation of combinatorial libraries of polysubstituted imidopiperidines that feature as many as four elements of chemical diversity. Biological screening of these druglike imidopiperidine libraries unveiled promising bioactive agents such as A12B4C3, the first reported inhibitor of the human DNA repair enzyme, polynucleotide kinase-phosphatase (hPNKP). Related applications of this MCR in target-oriented synthesis also led to total syntheses of palustrine alkaloids. The inverse electron-demand oxa[4 + 2] cycloaddition/allyboration variant can take advantage of Jacobsen's chiral Cr(III)salen catalyst, affording a rare example of catalytic enantioselective MCR, one that provides a rapid access to α-hydroxyalkyl dihydropyrans in high enantio- and diastereoselectivity. This process exploits 3-boronoacrolein pinacolate as the heterodiene with ethyl vinyl ether or various 2-substituted enol ethers, along with a wide variety of aldehydes in the allylation stage. This versatile methodology was deployed in total syntheses of thiomarinol antibiotics, goniodiol and its derivatives, and the complex anticancer macrolide palmerolide A. More recent work from our laboratory centered on the...
Oxygen-containing heterocycles such as pyrans are a common substructure present in a variety of natural products and pharmaceutical drugs. Highly functionalized 4- and 6-aryl/heteroaryl dihydropyran derivatives are assembled by a highly stereoselective, ligand-controlled regiodivergent sp(3)-sp(2) Suzuki-Miyaura cross-coupling of a 2-ethoxy dihydropyranyl boronate derived from a catalytic enantioselective inverse-electron-demand oxa[4 + 2] cycloaddition. The scope and selectivity of this method were assessed along with an application to a concise total synthesis of the diarylheptanoid natural product diospongin B.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.