Multicomponent Hetero-[4 + 2] Cycloaddition/Allylboration Reaction: From Natural Product Synthesis to Drug Discovery
Dennis G Hall, Taras Rybak, Tristan Verdelet
Acc Chem Res. 2016 Nov 15;49(11):2489-2500.
PMID: 27753496
Abstract:
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 regio- and stereoselective Suzuki-Miyaura cross-coupling of the dihydropyranyl boronates, thus providing a glimpse of the potential for new multicomponent variants that merge hetero[4 + 2] cycloadditions of 1-borylated heterodienes with transition metal-catalyzed transformations. This stereoselective MCR strategy holds great promise for provoking continuing applications in complex molecule synthesis and drug discovery, and is likely to inspire new and innovative MCR-based approaches to nonaromatic heterocycles.
Chemicals Related in the Paper:
| Catalog Number |
Product Name |
Structure |
CAS Number |
Price |
| AP1005129805 |
A12B4C3 |
 |
1005129-80-5 |
Price |
