Kinetic resolution is an important method for the separation of racemates into their component enantiomers. Thiols are precursors to a variety of organosulfur compounds, with high utility in both chemistry and chemical biology, yet there is a surprising dearth of methodologies for their direct and efficient catalytic kinetic resolution. Here, we demonstrate an organocatalytic process involving the highly enantioselective desymmetrization of an achiral electrophile with the simultaneous kinetic resolution of a racemic thiol. The preparative potential of the methodology is exemplified by the synthesis of a drug precursor antipode in excellent yield and enantioselectivity as a by-product of a process that also resolves a sec-thiol substrate with a selectivity of S = 226 (that is, both thiol antipodes produced in >95% ee at 51% conversion). In a second example a racemic sec-thiol representing the stereocentre-containing core of the anti-asthma drug (R)-Montelukast was resolved with synthetically useful selectivity under mild conditions.
Simple pyridinium salt derivatives have been (rather unexpectedly) shown to promote highly efficient acetalization reactions of both aldehydes and ketones at ambient temperature. The optimum catalyst is aprotic, yet it can promote the formation of benzaldehyde dimethyl acetal at 0.1 mol % loading more efficiently than a protic Brønsted acid catalyst with a pKa of 2.2. The process is of wide scope with respect to both the nucleophilic and electrophilic components, and the ionic catalyst can be readily recovered by precipitation and reused without loss of activity.
A new class of bifunctional organocatalyst promotes the chemoselective reduction of diketone electrophiles at catalytic loadings in the presence of an inorganic co-reductant.Enzymatic manipulation of the NAD(P) + /NAD(P)H redox couple in biotransformations is a fundamental competency common to all living cells. 1 In biological systems levels of these cofactors are maintained through both continual degradation/biosynthesis 2 and the coupling of oxidation/reduction reactions to sustain a redox balance.1,2 A considerable difficulty associated with the exploitation of biocatalytic reduction in preparative chemistry has been the need for the use of stoichiometric quantities of the expensive and significantly unstable (in solution) NADH cofactor. In response to this challenge several approaches to cofactor regeneration in preparative biooxidations/reductions 3 have been developed, the most practical of which involve either a single (A, Fig. 1) 4 or binary (B, Fig. 1) 5 enzyme system using either isolated enzymes or whole cells.The excellent activity/selectivity of enzymatic reductase systems has inspired the development of de-novo designed small organic molecules for biomimetic reduction which can be categorised as being either chiral nicotinamide-based reagents 6 or chiral NADHanalogue dependant organocatalysts. [7][8][9] Benchmark systems in the former category of NADH model are reagents, capable of effecting highly enantioselective reduction of activated ketones at stoichiometric loadings in the presence of Mg 2+ ions (100 mol%) and are not regenerated, while the second class of reductase mimic can promote efficient reductions of a,b-unsaturated electrophiles 7-9 and imines 10 with impressive levels of stereoinduction at catalytic loadings (1-20 mol%) in the presence of stoichiometric loadings of an achiral Hantzsch dihydropyridine hydride donor.We have been engaged in the design of (thio)urea based bifunctional catalysts capable of activating electrophilic reaction components through hydrogen bond donation 11 and were intrigued by the possibility of extending this strategy to include organocatalytic reductions. 12 In particular, the development of a completely new class of bifunctional organocatalyst incorporating both a substrate-activating (thio)urea moiety and an organic hydride donor (as opposed to a binary catalyst system, e.g. Hantzsch ester and Mg 2+/organocatalyst) was appealing due to the increased potential for synergistic cooperation between the catalyst's functional components and for an increased measure of control (in a catalyst design context) over the catalyst-substrate interaction. To make the proposed process veritably catalytic in all organic components we also undertook to develop a conceptually novel artificial reductase system in which a NADH-model hydride donor could be both generated and recycled in situ by simple, chemical means.With this in mind we prepared (thio)ureas 3-11 and evaluated their performance as promoters of the hitherto unknown (in an organocatalytic context) reduction of be...
Enantioselective synthesis of beta(2)-amino acids using rhodium-catalyzed hydrogenation Hoen, Rob; Wegman, Theodora; Procuranti, Barbara; Lefort, Laurent; de Vries, Johannes G.; Minnaard, Adriaan; Feringa, B.L. IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2007Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Hoen, R., Tiemersma-Wegman, T., Procuranti, B., Lefort, L., de Vries, J. G., Minnaard, A. J., & Feringa, B. L. (2007). Enantioselective synthesis of beta(2)-amino acids using rhodium-catalyzed hydrogenation. Organic & Biomolecular Chemistry, 5(2), 267-275. DOI: 10.1039/b615131k Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. A series of protected b 2 -dehydroamino acids has been prepared in three steps from commercially available starting materials in good yields. These were used as substrates in rhodium-catalyzed asymmetric hydrogenation applying a mixed ligand system of monodentate phosphoramidites and phosphines. Optimization of the catalyst structure was achieved by high throughput experimentation. High enantioselectivities were obtained (up to 91%) with full conversion for a number of b-amino acids. IntroductionSince the seminal reports on the use of monodentate ligands in the highly enantioselective rhodium-catalyzed asymmetric hydrogenation by the groups of Pringle, 1a Feringa, De Vries, Minnaard 1b and Reetz, 1c the number of studies on the use of monodentate ligands increased spectacularly.2 Furthermore, the fact that two monodentate ligands coordinate to the metalcentre in the catalytically active species, was exploited by Reetz and coworkers 3 and our own group 4 to show that mixtures of monodentate ligands can be used in the hydrogenation to enhance selectivities and reactivity. 5In recent years, we have focused on the development of new catalytic systems for asymmetric hydrogenations, 6 and considerable effort has been directed towards the exploration of new substrate classes. 8 Interesting features of these molecules are that they can fold in a predictable way to form secondary structures in solution, they show resistance to cleavage by peptidases and other metabolic transformations and mimic a-peptides in protein-protein and peptide-protein interacti...
Aprotic pyridinium ions incorporating electron-withdrawing substituents on the aromatic ring are powerful catalysts for the acetalization of aldehydes and the formation of dithianes, dithiolanes, dioxanes, and dioxolanes. Under optimum conditions the best catalyst can be used at a loading as low as 0.1 mol% and can outperform a Brønsted acid catalyst with a pK a of 2.2.
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