2120-91-4Relevant academic research and scientific papers
Stereoselective Cyclopropanation of Electron-Deficient Olefins with a Cofactor Redesigned Carbene Transferase Featuring Radical Reactivity
Carminati, Daniela M.,Fasan, Rudi
, p. 9683 - 9697 (2019/10/19)
Engineered myoglobins and other hemoproteins have recently emerged as promising catalysts for asymmetric olefin cyclopropanation reactions via carbene-transfer chemistry. Despite this progress, the transformation of electron-poor alkenes has proven to be very challenging using these systems. Here, we describe the design of a myoglobin-based carbene transferase incorporating a non-native iron-porphyrin cofactor and axial ligand, as an efficient catalyst for the asymmetric cyclopropanation of electron-deficient alkenes. Using this metalloenzyme, a broad range of both electron-rich and electron-deficient alkenes are cyclopropanated with high efficiency and high diastereo- A nd enantioselectivity (up to >99% de and ee). Mechanistic studies revealed that the expanded reaction scope of this carbene transferase is dependent upon the acquisition of metallocarbene radical reactivity as a result of the reconfigured coordination environment around the metal center. The radical-based reactivity of this system diverges from the electrophilic reactivity of myoglobin and most of the known organometallic carbene-transfer catalysts. This work showcases the value of cofactor redesign toward tuning and expanding the reactivity of metalloproteins in abiological reactions, and it provides a biocatalytic solution to the asymmetric cyclopropanation of electron-deficient alkenes. The metallocarbene radical reactivity exhibited by this biocatalyst is anticipated to prove useful in the context of a variety of other synthetic transformations.
Origin of High Stereocontrol in Olefin Cyclopropanation Catalyzed by an Engineered Carbene Transferase
Tinoco, Antonio,Wei, Yang,Bacik, John-Paul,Carminati, Daniela M.,Moore, Eric J.,Ando, Nozomi,Zhang, Yong,Fasan, Rudi
, p. 1514 - 1524 (2019/02/03)
Recent advances in metalloprotein engineering have led to the development of a myoglobin-based catalyst, Mb(H64V,V68A), capable of promoting the cyclopropanation of vinylarenes with high efficiency and high diastereo- and enantioselectivity. Whereas many enzymes evolved in nature often exhibit catalytic proficiency and exquisite stereoselectivity, how these features are achieved for a non-natural reaction has remained unclear. In this work, the structural determinants responsible for chiral induction and high stereocontrol in Mb(H64V,V68A)-catalyzed cyclopropanation were investigated via a combination of crystallographic, computational (DFT), and structure-activity analyses. Our results show the importance of steric complementarity and noncovalent interactions involving first-sphere active site residues, heme-carbene, and the olefin substrate in dictating the stereochemical outcome of the cyclopropanation reaction. High stereocontrol is achieved through two major mechanisms: first, by enforcing a specific conformation of the heme-bound carbene within the active site, and second, by controlling the geometry of attack of the olefin on the carbene via steric occlusion, attractive van der Waals forces, and protein-mediated π-π interactions with the olefin substrate. These insights could be leveraged to expand the substrate scope of the myoglobin-based cyclopropanation catalyst toward nonactivated olefins and to increase its cyclopropanation activity in the presence of a bulky α-diazo-ester. This work sheds light on the origin of enzyme-catalyzed enantioselective cyclopropanation, furnishing a mechanistic framework for both understanding the reactivity of current systems and guiding the future development of biological catalysts for this class of synthetically important, abiotic transformations.
Stereoselective Enzymatic Synthesis of Heteroatom-Substituted Cyclopropanes
Brandenberg, Oliver F.,Prier, Christopher K.,Chen, Kai,Knight, Anders M.,Wu, Zachary,Arnold, Frances H.
, p. 2629 - 2634 (2018/04/14)
The repurposing of hemoproteins for non-natural carbene transfer activities has generated enzymes for functions previously accessible only to chemical catalysts. With activities constrained to specific substrate classes, however, the synthetic utility of these new biocatalysts has been limited. To expand the capabilities of non-natural carbene transfer biocatalysis, we engineered variants of Cytochrome P450BM3 that catalyze the cyclopropanation of heteroatom-bearing alkenes, providing valuable nitrogen-, oxygen-, and sulfur-substituted cyclopropanes. Four or five active-site mutations converted a single parent enzyme into selective catalysts for the synthesis of both cis and trans heteroatom-substituted cyclopropanes, with high diastereoselectivities and enantioselectivities and up to 40 000 total turnovers. This work highlights the ease of tuning hemoproteins by directed evolution for efficient cyclopropanation of new substrate classes and expands the catalytic functions of iron heme proteins.
Short Syntheses of Furan and Catechol Derivatives. A Synthesis of Hydrourushiol
Wenkert, Ernest,Alonso, Miguel E.,Buckwalter, Brian L.,Sanchez, Eduardo L.
, p. 2021 - 2029 (2007/10/02)
The copper-catalyzed decomposition of ethyl diazopyruvate in enol ethers is shown to yield alkoxydihydrofuroates, whose exposure to acid leads to ethyl α-furoates.The latter are also the products of the copper-induced interaction of ethyl diazopyruvate with acetylenes.The conversion of one furoate into a furan and another into a furanoid terpene system is described.The Fetizon oxidation of primary β-alkoxycyclopropylcarbinols is shown to give alkoxydihydrofurans.The formation of a masked, 1,2,5-triketo system by the copper-assisted decomposition of 1-diazo-3,3-dimethoxy-2-butanone in n-butyl vinyl ether and subsequent acid-catalyzed unraveling of the resultant β-alkoxycyclopropyl ketone are portrayed.Ring scission of the intermediate in methanolic acid at elevated temperature yields veratrole.Utilization of this method of synthesis of aromatic compounds of the catehol type in the synthesis of hydrourushiol is illustrated.
