Origin of selectivity in the antibody 20F10-catalyzed Yang cyclization.
The first antibody-catalyzed Yang (Norrish type II) cyclization has been achieved with antibodies that were elicited against cis- and trans-2,3-diaryloxetanes. The photocyclization of 1,4-diarylbutan-1-one produced a single stereoisomer of cis-1,2-diarylcyclobutanol with very high enantioselectivity. The background photochemical reaction in the absence of the antibody yielded only fragmentation products. The antibody 20F10-catalyzed reaction was studied in detail, exploring its selectivity, substituent effects, substrate and hapten binding, kinetic parameters and irradiation wavelength dependence. Quantum mechanical calculations suggest that the activation enthalpy of fragmentation pathway is favored by 7.9 kcal/mol over cyclization pathway. Hapten, substrate, and transition state docking studies on a homology based modeled antibody binding site indicate that the trans hapten, substrate and the cyclization transition state have similar binding modes. By contrast, the fragmentation transition state is bound in a different way, not easily accessible within the lifetime of the bound substrate excited state. Several side chain residues were identified that can act as local sensitizers to enhance the cyclization process.
Saphier
Sigal
S
Department of Chemistry and Institute of Catalysis Science and Technology, Technion--Israel Institute of Technology Technion City, Haifa 32000 Israel.
Hu
Yunfeng
Y
Sinha
Subhash C
SC
Houk
K N
KN
Keinan
Ehud
E
D000595:Amino Acid Sequence; D017151:Antibodies, Catalytic / Q000737:chemistry* / Q000276:immunology; D001665:Binding Sites; D003500:Cyclization; D004797:Enzyme-Linked Immunosorbent Assay; D004988:Ethers, Cyclic / Q000276:immunology*; D006241:Haptens / Q000737:chemistry; D006433:Hemocyanins / Q000737:chemistry / Q000276:immunology; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010777:Photochemistry; D011789:Quantum Theory; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000276:immunology; D013237:Stereoisomerism; D013379:Substrate Specificity; D013816:Thermodynamics
D017151:Antibodies, Catalytic; D004988:Ethers, Cyclic; D006241:Haptens; D012710:Serum Albumin, Bovine; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin; C005287:oxetane