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Investigating Sequence Space: How Important is the Spatial Arrangement of Functional Groups in the Asymmetric Aldol Reaction Catalyst H‐Pro‐Pro‐Asp‐NH 2 ?
Author(s) -
Revell Jefferson D.,
Wennemers Helma
Publication year - 2008
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.200800053
Subject(s) - chemistry , aldol reaction , catalysis , sulfonyl , hexafluorophosphate , combinatorial chemistry , amine gas treating , methylene , organic chemistry , stereochemistry , medicinal chemistry , alkyl , ionic liquid
H‐Pro‐Pro‐Asp‐NH 2 1 is a versatile catalyst for asymmetric aldol reactions. Within the catalyst structure, both the N‐terminal secondary amine and the carboxylic acid are crucial for efficient catalysis. Here, the importance of the arrangement of these two functional groups towards each other was examined. Several analogues of H‐Pro‐Pro‐Asp‐NH 2 were prepared in which the secondary amine and the carboxylic acid occupy different positions. Evaluation of their catalytic properties revealed that the placement of these two functional groups is highly critical for efficient catalysis. Even seemingly small structural modifications, for example, one methylene group more or less, can modify the catalytic properties significantly. The results demonstrate the difficulty in rationally designing a peptidic catalyst and the value of combinatorial smart screening methods for catalyst discovery. Abbreviations: Fmoc=9‐fluorenylmethoxycarbonyl; HCTU=2‐(6‐chloro‐1 H ‐benzotriazole‐1‐yl)‐1,1,3,3‐tetramethyluronium hexafluorophosphate; MSNT=1‐(mesitylene‐2‐sulfonyl)‐3‐nitro‐1 H ‐1,2,4‐triazole; TNBS=2,4,6‐trinitrobenzenesulfonic acid.