Synthesis of Biologically Relevant Molecules
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Complex polycyclic molecular scaffolds containing multiple stereocenters, as found in many natural products, present particularly appealing targets for synthetic chemists. In addition to the academic challenge of selectively constructing these intricate frameworks, many such compounds display valuable bioactivities, making them important starting points for drug discovery. As in many aspects of contemporary organic synthesis, catalysis plays a key role in many MBFTs toward biologically relevant molecules (BRMs). Recently developed catalytic methodologies allow novel types of C–C bond formations and/or unprecedented control over the stereochemical outcome of the reaction. This chapter focuses on MBFTs based on recent developments in organocatalysis and transition metal catalysis, as well as multicomponent chemistry. It also aims to demonstrate the scope and synthetic potential of the above-mentioned classes of MBFTs in the synthesis of BRMs, with illustrative examples ranging from natural products to complex pharmaceuticals.Keywords:
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Chiral γ‐nitroaldehydes 1 are easily accessible by the organocatalytic Michael addition of aldehydes to nitroalkenes. In this paper, we report the organocatalytic fluorination of 1 with N ‐fluorobenzenesulfonimide (NFSI) leading to the highly stereoselective construction of a challenging quaternary fluorinated stereocenter at the α position of α,α‐dialkyl aldehydes. The reaction takes place via a chiral trisubstituted enamine, so far rather unexplored in the field of organocatalysis. Fluorinated products 3 are direct precursors of chiral monofluorinated 3,4‐polysubstituted pyrrolidines. Mechanistic details are discussed with the aid of computational results.
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This work has demonstrated that a previously unexplored approach to separation of enantiomers via formation of diastereomeric derivatives with three stereogenic centers has obvious practical potential and deserves further systematic study. The design reported here is based on the unusual application of a configurationally unstable stereogenic nitrogen, which plays a key role in setting up the stereochemical match between the three stereogenic centers in the corresponding products.
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Nitrogen stereocenters are common chiral units in natural products, pharmaceuticals, and chiral catalysts. However, their research has lagged largely behind, compared with carbon stereocenters and other heteroatom stereocenters. Herein, we report an efficient method for the catalytic asymmetric synthesis of Tröger's base analogues with nitrogen stereocenters via palladium catalysis and home-developed GF-Phos. It allows rapid construction of a new rigid cleft-like structure with both a C- and a N-stereogenic center in high efficiency and selectivity. A variety of applications as a chiral organocatalyst and metallic catalyst precursors were demonstrated. Furthermore, DFT calculations suggest that the NH···O hydrogen bonding and weak interaction between the substrate and ligand are crucial for the excellent enantioselectivity control.
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A highly enantioface-selective silaboration of allenes having stereogenic centers at the α-positions of the double bonds has been achieved using a combination of a chiral silylborane (−)-2 and a chiral Pd/(R)-3 catalyst. The chiral reagent system efficiently controlled the stereochemistry of the new stereogenic centers even in the reactions of mismatched combinations.
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Abstract A highly diastereo‐ and enantio‐selective method for the asymmetric synthesis of molecules containing helicenes and stereogenic axes was developed based on organocatalysis. Various compounds bearing both helical and axial stereogenic elements were obtained in excellent enantioselectivities. The mechanism study revealed that the reaction proceeded through two stages: 1) The first cyclization produces a reaction intermediate containing a stereogenic axis. 2) The dynamic kinetic resolution of helix reaction intermediate following with cyclization generates a helix and another stereogenic axis.
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