The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.
Remarkable reaction rate and excellent enantioselective direct α‐amination of unmodified aldehydes with various azodicarboxylates was catalyzed by pyrrolidinylcamphor organocatalyst 2a (5 mol‐%) to provide the desired aminated products with excellent chemical yields and high to excellent levels of enantioselectivity (up to >99 % ee) at 0 °C in CH2Cl2.
A series of pyrrolidine-camphor-derived organocatalysts (1-4) were designed and synthesised. These organocatalysts were used for direct α-amination of aldehydes with dialkyl azodicarboxylates to give the desired α-aminated products in high chemical yields (up to 92 %) and with high to excellent levels of stereoselectivity (up to Ͼ99 % ee). The reactions proceeded rapidly (within 5 min) with low catalyst loading (5 mol-%) at ambient temperature. Enantioselective aminations of asymmetric α,α-disubstituted aldehydes in the cata-
Optical resolution of racemic 5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid 2 with L‐amino acid methyl ester via the diastereomers formation was investigated. Treatment of racemic 5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid 2 with L‐valine methyl ester gave diastereomers with a total yield of 86%. The diastereomeric dipeptides can be easily separated by flash column chromatography. Acidic cleavage of the derived diastereomers gave both the optically pure (+)‐(R)‐ and (‐)‐(S)‐5‐oxo‐1‐phenyl‐pyrazolidine‐3‐carboxylic acid ((+)‐(R)‐2 and (‐)‐(S)‐2) with a total yield of 94% and 95%, respectively.
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