Dynamic Approaches Towards Catalyst Discovery

MICROREVIEW DOI: 10.1002/ejoc.200901338 Dynamic Approaches towards Catalyst Discovery Giulio Gasparini,[a] Marta Dal Molin,[a] and Leonard J. Prins*[a] Keywords: Catalyst discovery / Dynamic combinatorial chemistry / Supramolecular catalysis / Noncovalent interactions / Molecular recognition Catalyst development is a challenging task, caused by the tion as it allows for self-assembly and self-selection pro- subtle effects that determine whether a catalyst is efficient or cesses. Synthesis is restricted to the building blocks after not. Success is enhanced by using methodology that relies which diversity is simply generated upon mixing. Self-selec- to a smaller extent on rational design. Combinatorial high- tion of the best catalyst by the target reaction relieves the throughput approaches allow for a systematic exploration of burden of rational design. Molecular systems exhibiting ca- chemical space, but require an easy synthetic access to struc- talysis as an emerging property due to a cooperative inter- turally diverse catalysts. The use of dynamic or reversible play of the molecular components are envisioned for the fu- chemistry for the construction of catalysts is an attractive op- ture. 1. Introduction noncovalent[5] or a combination[6]), to connect these subunits offers a series of unique advantages and possibilities Catalyst discovery is one of the central themes of chemis- that will be discussed here. try because of the growing need for highly efficient and se- In this review we describe our own contributions in this lective chemical transformations with a low environmental area embedded within the context of other dynamic ap- [1] impact. Catalyst discovery is very challenging as it re- proaches towards catalyst discovery. Three classes of cata- quires the identification of species able to stabilize elusive lysts will be discussed, distinguished in name by their char- and transient transition states along the reaction pathway. acteristic property (Figure 1). Self-assembled catalysts are Combinatorial approaches have been introduced that per- formed through noncovalent interactions between the mo- mit the high-throughput synthesis and screening of cata- lecular subunits. Self-selected catalysts, which have been the [2,3] lysts. Here, the difficulty lies in the accessibility of struc- main focus of our studies, are identified upon the spontane- turally diverse libraries of ligands. In that respect, catalytic ous response of a dynamic combinatorial library against a systems composed of small, easily modifiable subunits are transition state analogue for the reaction of interest. Fi- advantageous. The use of dynamic chemistry, i.e. chemistry nally, a new class of self-evolving catalysts is defined to de- [4] relying on reversible bond formation (either covalent, scribe complex dynamic networks of molecules with catalytic properties. It should be emphasized that this is by no [a] Department of Chemical Sciences, University of Padova Via Marzolo 1, 35131 Padova, Italy means an exhaustive review and only selected examples are Fax: +39-049-8275239 provided that serve to illustrate key concepts. E-mail: [email protected] Giulio Gasparini (left) was born in 1981 and studied Chemistry at the University of Padua, where he obtained his degree in 2005. In 2008, he received his PhD degree working on catalyst discovery using dynamic covalent capture, under the supervision of Prof. Paolo Scrimin and Dr. Leonard Prins. He is currently covering a postdoctoral position in the group of Prof. Giulia Licini, studying triphenolamine adducts as chiral catalysts for sulfoxidation reactions. Marta Dal Molin obtained her degree in Chemistry at the University of Padova in 2008. The same year she joined Prof. Scrimin’s group starting her PhD project under the supervision of Dr. Leonard Prins. The area of her research is the study of molecular recognition processes using a dynamic combinatorial approach. Leonard Prins (right) obtained his PhD degree in 2001 from the University of Twente, Netherlands, under the supervision of David Reinhoudt. After postdoctoral periods with Peter Dervan (Caltech) and Giulia Licini (Padova), he is currently an assistant professor at the University of Padova, Italy. He has been awarded the H. J. Backerprize 2001 (Royal Dutch Chemical Society) and the “Ciamician” medal 2009 (Italian Chemical Society) and is a recipient of an ERC starting grant 2009. His research interests are the application of dynamic chemistry for receptor and catalyst discovery and the development of multivalent enzyme-like catalysts. Eur. J. Org. Chem. 2010, 2429–2440 © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2429 MICROREVIEW G. Gasparini, M. Dal Molin, L. J. Prins asymmetric hydrogenation catalyst through complex formation with a biotin ligand functionalized with an achiral (di- phosphane)rhodium(I) complex. The idea behind this approach was that the protein would provide a chiral environ- ment for the achiral catalyst. Indeed, the supramolecular construct gave enantioselectivities up to around 40% for the reduction of α-acetamidoacryclic acid with no apparent loss of catalytic activity. Much more recently, this system was re-visited and optimized by Ward et al.[13] using streptavidin rather than avidin and by modulating the spacer connecting biotin to the rhodium complex. Additionally, it was shown that the catalytic performance of the construct could be im- proved (reaching enantioselectivities up to 96 %) by altering the protein structure via site-directed mutagenesis. A limitation of the use of proteins is that alteration of the protein structure is time-consuming and, more import- Figure 1. Schematic representations of (a) self-assembled, (b) self- antly, that only one enantiomer is available. The modulation selected, and (c) self-evolving catalysts. of transition metal complexes by means of noncovalent interactions with small synthetic molecules is much more flexible and also easy amendable to combinatorial screening. 2. Self-Assembled Catalysts The potential of this approach is nicely illustrated by the following supramolecular approaches towards the construc- Enzymes have been, and continue to be, a fascinating tion of diphenylphosphane ligands (Figure 2). inspiration for chemists interested in the development of The initial discoveries by the groups of Kagan[14] and catalysts. The superb interplay of functional groups in the Knowles[15] that the use of chiral diphosphanes led to con- active site of enzymes with the substrate and the transition siderably higher enantioselectivities in the Rh-catalyzed state has led chemists to propose, often ingenious, artificial asymmetric hydrogenation of olefins compared to mono- systems able to mimic (at least part of) these recognition dentate phosphanes caused a longstanding domination of events.[7,8] Such supramolecular systems have served as bidentate ligands in this field. This general belief was over- model systems to explain phenomena observed in enzymes thrown less than a decade ago by independent observations and have permitted very detailed studies that have contrib- by the groups of Reetz,[16] Pringle,[17] and Feringa[18] that uted to a mechanistic understanding of the reaction path- chiral monodentate phosphonites and phosphoramidites ways involved. Although occasionally also catalytic effi- gave excellent levels of enantioselectivity. This aroused great ciencies have been obtained that come close to the values interest, which was further enhanced by the observation of the natural counterparts, as a general rule the artificial that mixtures of monodentate ligands behaved better than systems do not live up to the expectations and industrial the pure ligands by themselves.[19,20] It should be noted that applications are rare.[9] the mixed ligand approach had already been applied in An alternative starting point for self-assembled catalysts other catalyst systems,[21] for instance mixtures of achiral are transition-metal-based catalysts, which are of funda- salen-MnIII complexes and chiral amines for asymmetric mental industrial importance.[10] Here, the scope is to alter epoxidation,[22] conformationally flexible bis(phosphanyl)- or fine-tune the properties of known organometallic cata- biphenyl ligands with resolved 1,2-diamino-1,2-diphenyl- lysts via the creation of supramolecular constructs.[11] The ethane bound to ruthenium for enantioselective hydrogena- intrinsic advantage compared to de novo enzyme develop- tion,[23] and achiral bis(sulfonamides) and chiral titanium ment is evident: one starts with an catalytic core unit which alkoxide complexes for the asymmetric addition of alkyl ensures a basic reactivity or selectivity. Already more than groups to aldehydes.[24] Together with a much easier syn- three decades ago Whitesides et al.[12] reported in a seminal thetic accessibility of monodentate compared to bidentate contribution on the conversion of the protein avidin into an ligands, this stimulated and permitted combinatorial Figure 2. Heteromeric covalent bidentate ligands (I), monodentate ligands (II), noncovalent bidentate ligands (III) and templated bidentate ligands (IV). 2430 www.eurjoc.org © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2010, 2429–2440 Dynamic Approaches towards Catalyst Discovery searches for optimal ligand combinations.[25] In this con- upon the addition of rhodium. Also this system displayed text, a key contribution by the group of Breit[26] illustrated a catalytic behaviour in the rhodium-catalyzed hydro-

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