Copper–Phthalocyanine Conjugates of Serum Albumins as Enantioselective Catalysts in Diels–Alder Reactions

Abstract

Anchoring ligand-bound transition metals to proteins covalently or noncovalently provides conjugates that are of potential interest as enantioselective hybrid catalysts in organic synthesis.[1] Although a number of studies regarding this concept have appeared, examples of truly high enantioselectivity (> 90 % ee) are rare. Indeed, pronounced degrees of asymmetric induction cannot be expected just because the protein environment is chiral. Herein we report Cu II -catalyzed Diels-Alder reactions of azachalcones 1 a-e with cyclopentadiene (2) in an aqueous medium in the presence of appropriate proteins, leading to products 3 [Eq.(1)] with surprisingly high enantiopurities (85-98 % ee). The first transition-metal-catalyzed asymmetric Diels-Alder reactions in water were reported by Engberts and co-workers, who performed the cycloaddition of 1 a with 2 in the presence of water-soluble Cu II complexes of chiral a-amino acids (up to 74 % ee of the major endo product 3 a).[2] More recently Roelfs and Feringa carried out the same reaction also in water with Cu II conjugates of DNA, resulting in a maximum of 53 % ee for endo-3 a (endo/exo 91:9).[3] Moreover, endo/exo selectivity of certain Diels-Alder reactions is known to be influenced by the presence of Bakers yeast, [4] and in another study Colonna et al. showed that enantioselectivity up to 38 % ee can be achieved upon adding bovine serum albumin (BSA) to the aqueous medium.[5] Highly stereoselective Diels-Alder reactions in water were reported to be catalyzed by Diels-Alderases, [6] catalytic antibodies, [7] and ribozymes.[8]In our study we chose the commercially available watersoluble amphiphilic phthalocyanine-copper complex 4 as the achiral catalyst and various serum albumins as the protein hosts.Serum albumins are proteins present at high concentrations in blood plasma, functioning as transport carriers for a wide variety of compounds, including fatty acids, bile acids, bilirubin, and hemin.[9] They are generally robust, readily accessible, and easy to handle. The decision to choose these proteins in our study was also influenced by several previous reports.[ 5,10,11] Kokubo et al. demonstrated that a 1:1 complex of an osmate ester and bovine serum albumin (BSA) functions as a catalyst in the cis dihydroxylation of alkenes (up to 68 % ee).[10] In a novel and systematic study Mahammed and Gross anchored certain water-soluble sulfonylated Fe III -and Mn III -corroles to serum albumins and used the conjugates as catalysts in the H 2 O 2 -based asymmetric sulfoxidation of prochiral thioethers (up to 74 % ee).[11] Previous to the latter study it had been reported that the sodium salts of di-, tri-, and tetrasulfonic acid derivatives of porphyrins, phthalocyanines, and corroles bind strongly to serum albumins in a noncovalent manner, although the exact position of anchoring in the proteins was not elucidated with absolute certainty in all cases.[12] An example of unambiquous assignment was recently reported by Curry and co-workers, who showed that iron-protoporphyrin dim...

Second Generation Artificial Hydrogenases Based on the Biotin‐Avidin Technology: Improving Activity, Stability and Selectivity by Introduction of Enantiopure Amino Acid Spacers

“…[5][6][7][8][9][10] To ensure localization of the catalytic moiety within the macromolecular host, covalent, dative and supramolecular anchoring strategies have successfully been exploited to produce enantioselective hybrid catalysts for ester hydrolysis, [11] dihydroxylation, [12] epoxidation, [13,14] sulfoxidation, [15][16][17][18][19] hydrogenation, [20][21][22][23][24][25][26][27][28] transfer hydrogenation [29,30] and DielsAlder reactions. [31][32][33] Based on Whitesides early report, [20] several groups have been exploiting the biotin-avidin technology to produce artificial hydrogenases for the enantioselective reduction of N-protected dehydroamino acids [21][22][23][24][25][26]28] as well as the reduction via transfer hydrogenation of aromatic ketones. [29,30] For optimization purposes, our group relies both on chemical and on genetic strategies (i.e., chemogenetic) [5] to yield both (R)-and (S)-selective hydrogenases.…”

Artificial Metalloenzymes for Enantioselective Catalysis: Recent Advances

“…[35] The recent structural determination of a hemin&HSA 1:1 conjugate by Curry and co-workers [36] coincided with the development of enantioselective artificial metalloenzymes based on the noncovalent incorporation of corroles and phthalocyanines in serum albumins. [37,38] Gross and co-workers have reported on the incorporation of amphiphilic bis-sulfonated corrole metal complexes in various serum albumins. In particular, [Mn…”

Bimetallic Copper-Heme-Protein-DNA Hybrid Catalyst for Diels Alder Reaction

“…Building upon this idea, Reetz et al designed hybrid proteins by non-covalent attachment of Cu-phtalocyanine to different serum albumins. 12 Such proteins were capable of catalyzing Diels Alder reaction of azachalcones with cyclopentadiene in aqueous medium with high selectivity and e.e. between 85−93 % depending on the albumins used.…”