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Brackow J.,Carbogen Amcis AG | Pabel J.,Ludwig Maximilians University of Munich | Mayer P.,Ludwig Maximilians University of Munich | Polborn K.,Ludwig Maximilians University of Munich | Wanner K.T.,Ludwig Maximilians University of Munich
Tetrahedron | Year: 2010

Three novel sulfur containing chiral bicyclic carboxylic acids were synthesized from d-camphoric acid. Two of these compounds were briefly evaluated for their potency as chiral auxiliaries in Asymmetric Electrophilic α-Amidoalkylation (AEαA) reactions. © 2010 Elsevier Ltd. All rights reserved.


Fritschi S.P.,University of Zurich | Fritschi S.P.,Carbogen Amcis AG | Linden A.,University of Zurich | Heimgartner H.,University of Zurich
Helvetica Chimica Acta | Year: 2016

The synthesis of α-benzamido-α-benzyl lactones 23 of various ring size was achieved either via ‘direct amide cyclization’ by treatment of 2-benzamido-2-benzyl-ω-hydroxy-N,N-dimethylalkanamides 21 in toluene at 90 – 110° with HCl gas or by ‘ring transformation’ of 4-benzyl-4-(ω-hydroxyalkyl)-2-phenyl-1,3-oxazol-5(4H)-ones under the same conditions. The precursors were obtained by C-alkylations of 4-benzyl-2-phenyl-1,3-oxazol-5(4H)-one (15) with THP- or TBDMS-protected ω-hydroxyalkyl iodides. Ring opening of the THP-protected oxazolones by treatment with Me2NH followed by deprotection of the OH group gave the diamides 21, whereas deprotection of the TBDMS series of oxazolones 25 with TBAF followed by treatment with HCl gas led to the corresponding lactones 23 in a one-pot reaction. © 2016 Wiley-VHCA AG, Zürich


Gersbach P.,ETH Zurich | Jantsch A.,ETH Zurich | Jantsch A.,CSL Behring GmbH | Feyen F.,ETH Zurich | And 5 more authors.
Chemistry - A European Journal | Year: 2011

The total synthesis of the mycobacterial toxins mycolactones A/B (1 a/b) has been accomplished based on a strategy built around the construction of the mycolactone core through ring-closing metathesis. By employing the Grubbs second-generation catalyst, the 12-membered core macrocycle of mycolactones, with a functionalized C2 handle attached to C11, was obtained in 60-80 % yield. The C-linked upper side chain (comprising C12-C20) was completed by a highly efficient modified Suzuki coupling between C13 and C14, while the attachment of the C5-O-linked polyunsaturated acyl side chain was achieved by Yamaguchi esterification. Surprisingly, a diene containing a simple isopropyl group attached to C11 could not be induced to undergo ring-closing metathesis. By employing fluorescence microscopy and flow cytometry techniques, the synthetic mycolactones A/B (1 a/b) were demonstrated to display similar apoptosis-inducing and cytopathic effects as mycolactones A/B extracted from Mycobacterium ulcerans. In contrast, a simplified analogue with truncated upper and lower side chains was found to be inactive. RCM.... What else? The total synthesis of the mycobacterial toxins mycolactones A/B (1 a/b) has been accomplished based on the construction of the mycolactone core through ring-closing olefin metathesis (RCM) of diene 2 (see scheme). Synthetic 1 a/b showed similar apoptosis-inducing and cytopathic effects as natural mycolactones A/B. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Altmann K.-H.,ETH Zurich | Cachoux F.,University of Bern | Feyen F.,Carbogen Amcis AG | Gertsch J.,Pierre Fabre | And 2 more authors.
Chimia | Year: 2010

Epothilones are bacterial macrolides with potent microtubule-stabilizing and antiproliferative activity, which have served as successful lead structures for the discovery of several clinical candidates for cancer treatment. Overall, seven epothilone-type agents have been advanced to clinical evaluation in humans so far and one of these has been approved by the FDA in 2007 for clinical use in breast cancer patients. Notwithstanding these impressive numbers, however, the structural diversity represented by the collection of epothilone analogs that have been (or still are) investigated clinically is rather limited and their individual structures show little divergence from the original natural product leads. In contrast, we have elaborated a series of epothilone-derived macrolactones, whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of conformationally constrained side chains, the removal of the C(3)-hydroxyl group, and the replacement of C(12) with nitrogen. The latter modification leads to aza-macrolides that may be described as 'non-natural natural products'. © Schweizerische Chemische Gesellschaft.


Walker A.J.,Glaxosmithkline | Adolph S.,Carbogen AMCIS AG | Connell R.B.,Glaxosmithkline | Laue K.,Carbogen AMCIS AG | And 5 more authors.
Organic Process Research and Development | Year: 2010

Control of trace inorganics and an understanding of reaction kinetics and impurity generation proved critical in allowing safe and reliable scale-up of a high-temperature Claisen reaction in support of multikilogram manufacture of a key chromene intermediate 4. Implementation of a Medicinal Chemistry route allowed for rapid early phase delivery of 1 to support early clinical studies. © 2010 American Chemical Society.

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