Thomas B. Poulsen

Catalytic Asymmetric Friedel−Crafts Alkylation Reactions—Copper Showed the Way

2. The Incubation Period 2904 3. Alkylation with Activated Alkenes 2905 3.1. Copper Complexes 2905 3.2. Other Metal Complexes 2907 3.3. Organocatalysis 2907 4. Alkylation with Carbonyl Compounds 2908 4.1. Copper Complexes 2908 4.2. Other Metal Complexes 2909 4.3. Organocatalysis 2910 5. Alkylation with Imines 2911 5.1. Copper Complexes 2911 5.2. Organocatalysis 2912 6. Miscellaneous 2913 7. Conclusion and Perspectives 2914 8. Acknowledgments 2914 9. Note Added in Proof 2914 10. References 2914

A versatile catalyst for asymmetric reactions of carbonyl groups working purely by activation through hydrogen bonding: Mukaiyama-aldol, hetero Diels–Alder and Friedel–Crafts reactions

Bis-sulfonamides are demonstrated to be promising candidates for the efficient activation of carbonyl compounds through hydrogen bonding. Exemplified by three carbonyl addition reactions: Mukaiyama-aldol, hetero Diels-Alder and Friedel-Crafts reactions we show that bis-triflamides or bis-nonaflamides of commercially available chiral diamines act as chiral Brønsted-acid catalysts, leading to the optically active products in moderate to excellent yields and with enantioselectivities up to 73% ee.

Manipulating the torsion of molecules by strong laser pulses.

We demonstrate that strong laser pulses can induce torsional motion in a molecule consisting of a pair of phenyl rings. A nanosecond laser pulse spatially aligns the carbon-carbon bond axis, connecting the two phenyl rings, allowing a perpendicularly polarized, intense femtosecond pulse to initiate torsional motion accompanied by an overall rotation about the fixed axis. We monitor the induced motion by femtosecond time-resolved Coulomb explosion imaging. Our theoretical analysis accounts for and generalizes the experimental findings.

Organocatalytic asymmetric allylic carbon–carbon bond formation

Organocatalytic allylic C-C bond-forming addition of activated alkylidenes to alkyl and aryl nitroalkenes has been achieved with high diastereo- and enantioselectivity. Chiral tertiary amine catalysts are used to give allyl intermediates which exhibit gamma-selectivity in the C-C bond forming step. The reactions proceed with up to >99:1 syn:anti ratio for both the alkyl- and aryl nitroalkenes with up 96% and 98% ee, respectively. The products of this conjugate addition are transformed into a range of intermediates, such as optically active conjugated dienes and 1-substituted tetralones, which are difficult to access via alternative methods.

Direct catalytic asymmetric aldol reactions of pyruvates: scope and mechanism

The direct aldol reaction of 2-ketoesters catalyzed by chiral bisoxazoline copper(II) complexes has been investigated. First the direct homo-aldol reaction of ethyl pyruvate is reported which proceeds to give diethyl 2-hydroxy-2-methyl-4-oxoglutarate. This was isolated as the more stable optically active isotetronic acid in good yield and enantiomeric excess in the absence of bases such as amines. Detailed investigations of the use of different chiral Lewis acids as the catalyst, amines, ratios of chiral bisoxazoline copper(II) salts:amine, and solvents gave up to 96% ee of the isotetronic acid. Then the reaction was extended to a cross-aldol reaction of various 2-ketoesters with activated carbonyl compounds to give the cross-aldol adduct with excellent enantiomeric excess. Furthermore, the synthesis of the isotetronic acids was investigated from these cross-aldol adducts giving important information about the formation of the stereogenic centers during the aldol reaction. Based on the absolute configuration of the homo-aldol adduct the mechanism for the aldol reaction is discussed.

Binding Sites for Acylated Trehalose Analogs of Glycolipid Ligands on an Extended Carbohydrate Recognition Domain of the Macrophage Receptor Mincle.

The macrophage receptor mincle binds to trehalose dimycolate on the surface of Mycobacterium tuberculosis. Signaling initiated by this interaction leads to cytokine production, which underlies the ability of mycobacteria to evade the immune system and also to function as adjuvants. In previous work the mechanism for binding of the sugar headgroup of trehalose dimycolate to mincle has been elucidated, but the basis for enhanced binding to glycolipid ligands, in which hydrophobic substituents are attached to the 6-hydroxyl groups, has been the subject of speculation. In the work reported here, the interaction of trehalose derivatives with bovine mincle has been probed with a series of synthetic mimics of trehalose dimycolate in binding assays, in structural studies by x-ray crystallography, and by site-directed mutagenesis. Binding studies reveal that, rather than reflecting specific structural preference, the apparent affinity of mincle for ligands with hydrophobic substituents correlates with their overall size. Structural and mutagenesis analysis provides evidence for interaction of the hydrophobic substituents with multiple different portions of the surface of mincle and confirms the presence of three Ca2+-binding sites. The structure of an extended portion of the extracellular domain of mincle, beyond the minimal C-type carbohydrate recognition domain, also constrains the way the binding domains may interact on the surface of macrophages.

The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle

We demonstrate that the natural product brartemicin, a newly discovered inhibitor of cancer cell invasion, is a high-affinity ligand of the carbohydrate-recognition domain (CRD) of the C-type lectin mincle.

Organocatalysis with endogenous compounds: Towards novel non-enzymatic reactions

The aldol reaction of the endogeneous compounds acetone and methylglyoxal has been studied using organocatalysis in relation to biologically relevant non-enzymatic reactions. Under preparative conditions, 3-hydroxy-2,5-hexadione, known as Henzes ketol, is formed in high yield and with enantioselectivities up to 88% ee. Furthermore, Henzes ketol is also formed under simulated physiological conditions at micromolar scale, indicating that this reaction might take place in living organisms.

Total Synthesis and Biological Evaluation of Rakicidin A and Discovery of a Simplified Bioactive Analogue

We report a concise asymmetric synthesis of rakicidin A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem-like leukemia cells. Key transformations include a diastereoselective organocatalytic cross-aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist-type Horner-Wadsworth-Emmons (HWE) macrocyclization, and a new DSC-mediated elimination reaction to construct the sensitive APD portion of rakicidin A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity.

Synthesis of ent-BE-43547A1 reveals a potent hypoxia-selective anticancer agent and uncovers the biosynthetic origin of the APD-CLD natural products

Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products.