Spiroligozymes for Transesterifications: Design and Relationship of Structure to Activity

• Published in: Journal of the American Chemical Society Vol. 134; no. 44; pp. 18345 - 18353
• Main Authors: Kheirabadi, Mahboubeh, Çelebi-Ölçüm, Nihan, Parker, Matthew F. L, Zhao, Qingquan, Kiss, Gert, Houk, K. N, Schafmeister, Christian E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.11.2012; Amer Chemical Soc
• Subjects: Alcohols - chemistry; Biocatalysis; Biomimetic Materials - chemistry; Catalysis; Chemistry; Chemistry, Multidisciplinary; Esterification; Methanol - chemistry; Models, Molecular; Physical Sciences; Pyridines - chemistry; Science & Technology; Vinyl Compounds - chemistry; CATALYSIS; COMPUTATIONAL DESIGN; THERMOCHEMISTRY; ENZYMES; AB-INITIO; ATOMIC CHARGES; ORGANOCATALYSIS; NONCOVALENT INTERACTIONS; ENERGIES; SOLVATION
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja3069648

Transesterification catalysts based on stereochemically defined, modular, functionalized ladder-molecules (named spiroligozymes) were designed, using the “inside-out” design strategy, and mutated synthetically to improve catalysis. A series of stereochemically and regiochemically diverse bifunctional spiroligozymes were first synthesized to identify the best arrangement of a pyridine as a general base catalyst and an alcohol nucleophile to accelerate attack on vinyl trifluoroacetate as an electrophile. The best bifunctional spiroligozyme reacted with vinyl trifluoroacetate to form an acyl-spiroligozyme conjugate 2.7 × 103-fold faster than the background reaction with a benzyl alcohol. Two trifunctional spiroligozymes were then synthesized that combined a urea with the pyridine and alcohol to act as an oxyanion hole and activate the bound acyl-spiroligozyme intermediate to enable acyl-transfer to methanol. The best trifunctional spiroligozyme carries out multiple turnovers and acts as a transesterification catalyst with k 1/k uncat of 2.2 × 103 and k 2/k uncat of 1.3 × 102. Quantum mechanical calculations identified the four transition states of the catalytic cycle and provided a detailed view of every stage of the transesterification reaction.