Synthesis of Nitrogen containing Building Blocks with Monothioester Malonates. An Efficient Method for alpha-, beta- and gamma-Amino Acid Derivatives
Final Report Abstract
In summary we have developed a mild organocatalytic method for the synthesis of β^3-amino thioesters through Mannich reactions of MTMs. Nol only β^3- but also β^2.2.3-amino thioesters, that bear a linear all-carbon quaternary stereogenic center adjacent to a tertiary stereocenter, were for the first lime obtained in excellent yields and remarkably high stereoselectivities. Mechanistic studies provided insight into the high stereochemical differentiation between the two ester moieties wilhin the MTMs and showed that the stereochemistry can be controlled by the choice of the substrate. Deprotection of the oxo-ester moiety followed by decarboxylation allowed for access to syn β^2.3 amino thioesters in good diastereoselectivities. Furthermore, we showed the synthetic value of β-amino thioesters as building blocks for coupling reagent-free peptide synthesis. In conclusion we have introduced a route to access synthetically versatile acyclic γ-nitrothioesters with an all-carbon quaternary stereogenic center in high yields and stereoselectivities. The method relies on reactions between y-substituted mono thiomalonates and nitroolefins that proceed under mild organocalalytic conditions and require only low catalyst loadings. The functional groups wilhin the y-nitrothioesters arc orthogonal and can be selectively modified to provide access to many other valuable compounds with all-carbon quaternary stereogenic centers as well as anti-configured y-nitroaldehydes. After the initial proof, MTMs were found to be highly efficient tri-substituted Michael donors. However, it is surprising how finely balanced this reactivity is. Reactions with electrophiles more reactive than the ones describes above, such as diazo-compounds (N-synthons), are so fast that all stereoselectivity is lost, whereas ihe introduction of more steric bulk, such as for bis-substitued (ket)imines, leads to a complete stop of the reaction. We predict that furtherfine-tuning of the MTMs properties will give rise to additional new methods for the constructions of small chains of stereocenters, important for biologically active compounds. Part of this work was highlighted in Synfacts 2014, 10, 641.
Publications
- "Organocatalytic Stereoselective Synthesis of Acyclic γ-Nitro Thioesters with All-Carbon Quaternary Stereogenic Centers.", J. Org. Chem. 2014, 79, 3937-3945
Y. Arakawa, S. P Fritz, H. Wennemers
(See online at https://doi.org/10.1021/jo500403q) - "Stereoselective Metal-free Synthesis of β-Amino Thioesters bearing Tertiary and Quaternary Stereogenic Centers.", Angew. Chem. Int. Ed. 2014
A. Bahlinger. S. P. Fritz, H. Wennemers
(See online at https://doi.org/10.1002/anie.201310532)
