The enantioselective addition of water to olefins in an aqueous environment is a common transformation in biological systems, but was beyond the ability of synthetic chemists. Here, we present the first examples of a non-enzymatic catalytic enantioselective hydration of enones, for which we used a catalyst that comprises a copper complex, based on an achiral ligand, non-covalently bound to (deoxy)ribonucleic acid, which is the only source of chirality present under the reaction conditions. The chiral β-hydroxy ketone product was obtained in up to 82% enantiomeric excess. Deuterium-labelling studies demonstrated that the reaction is diastereospecific, with only the syn hydration product formed. So far, this diastereospecific and enantioselective reaction had no equivalent in conventional homogeneous catalysis.

A new approach for the fully chemoselective α-arylation of amides is presented. By means of electrophilic amide activation, aryl groups can be regioselectively introduced α- to amides, even in the presence of esters and alkyl ketones. Mechanistic studies reveal key reaction intermediates and emphasize a remarkably subtle base effect in this transformation.

Total synthesis, stereochemical elucidation and biological evaluation of Ac(2)SGL; a 1,3-methyl branched sulfoglycolipid from Mycobacterium tuberculosis Geerdink, Danny; ter Horst, Bjorn; Lepore, Marco; Mori, Lucia; Puzo, Germain; Hirsch, Anna; Gilleron, Martine; de Libero, Gennaro; Minnaard, Adriaan 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: 2012Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Geerdink, D., ter Horst, B., Lepore, M., Mori, L., Puzo, G., Hirsch, A. K. H., ... Minnaard, A. J. (2012). Total synthesis, stereochemical elucidation and biological evaluation of Ac(2)SGL; a 1,3-methyl branched sulfoglycolipid from Mycobacterium tuberculosis. Chemical Science, 4(2), 709-716. DOI: 10.1039/c2sc21620e 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. Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), continues to represent a challenging pathogen causing many deaths. A reason for the persistence of this pathogen is the cell-envelope composition, which consists of long-tailed (glyco)lipids, involved in the modulation of the host immune response. Diacylated sulfoglycolipid Ac 2 SGL (1), found in the cell envelope, is a potent antigen that stimulates the immune response towards TB. This observation suggests the application of 1 as part of a vaccine. Here, we report the first asymmetric total synthesis of 1. Two approaches were developed for the synthesis of hydroxyphthioceranic acid (4), its polypropionate part, thereby establishing the absolute stereochemistry of the C17 hydroxyl function to be of (R)-configuration. Subsequently, 4 was regioselectively connected to the trehalose core and after selective sulfation and a final fourfold deprotection step, pure 1 was obtained. The identity of synthetic and natural 1 was confirmed by NMR and mass analysis, Furthermore, synthetic 1 shows identical biological function to 1 and activates CD1b-restricted and Ac 2 SGL-specific T cells that are highly sensitive to minimal structural modifications of 1 with the same potency. A modeling study is presented to point out the structural features of 1 that are important for binding to the antigen-presenting molecule CD1b and to the T-cell receptor. IntroductionTuber...

The asymmetric synthesis of diarylmethyl amines is of great importance because they are present in a variety of pharmacologically active structures.[1] Among other methods for performing the catalytic asymmetric synthesis of diarylmethyl amines, [2] the recently developed rhodium-catalyzed asymmetric arylation of aldimines is an important strategy. [3] Excellent enantioselectivities have been reported for the addition of aryl stannane [4] and aryl titanium [5] reagents. Aryl boronic acids have received increasing attention as arylating reagents because they are readily available, stable, and compatible with a large variety of functional groups, and they produce nontoxic by-products. [6,7] So far, three groups have reported on the rhodium(i)-catalyzed asymmetric addition of aryl boron reagents to aldimines. Tomioka and coworkers described the first enantioselective addition of aryl boronic acids and their boroxine trimers to benzaldimines using the chiral amidophosphane ligand 1 (Boc = tert-butyl-Enantioselectivities above 90 % were obtained through steric tuning of substituents on both the substrate and the boron reagent. Hayashi and co-workers reported excellent enantioselectivities for the addition of aryl boroxines to N-tosyl-and N-nosylbenzaldimines employing chiral diene ligands (i.e. 2 and 3).[9] Recently, Ellman and coworkers reported an example of high enantioselectivity for the addition of aryl boronic acids to N-diphenylphosphinoyl benzaldimine using deguphos as a chiral ligand.[10]From a synthetic point of view, the current methodology still presents some major drawbacks. Often large amounts of boronic acid (2-5 equiv) and catalyst (at least 3 mol %) are required to obtain full conversion. Moreover, the removal of the protecting groups is either not straightforward, [10,11] or requires environmentally unfriendly reagents.[9b]We envisioned a more efficient and versatile synthetic method for this transformation that relies on the combination of a new catalyst and protecting group. Herein we report the development of a highly active rhodium(i) catalyst that allows the efficient asymmetric synthesis of diarylmethyl amines under mild conditions without extensive hydrolysis of the aryl boronic acid (Scheme 1). Furthermore, we present N,Ndimethylsulfamoyl as an inexpensive, low-molecular-weight protecting/activating group for this reaction and describe an efficient method for its removal. [12] We focused on monodentate phosphoramidites 4,[13] a class of low-cost, readily available chiral ligands, which have been applied successfully in the related rhodium-catalyzed asymmetric conjugate addition of aryl boronic acids to enones. [14] Although it has been observed that the two reactions have different ligand requirements, [9a] phosphoramidites are easily tunable because of their modular composition and are therefore well suited to a combinatorial approach in the design of asymmetric catalysts. [15] Scheme 1. Rhodium/phosphoramidite-catalyzed addition of aryl boronic acids 6 to N,N-dimethylsulfamoyl-protected a...

We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C−H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (−)‐quinine, the first synthesis of unnatural (+)‐quinine, and also provides access to unprecedented C3‐aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (−)‐quinine both in vitro and in mice infected with Plasmodium berghei.