- Development of an asymmetric hydrogenation route to (S)- N -Boc-2,6-dimethyltyrosine
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An improved, simpler and potentially more economical route to (S)-N-Boc-2,6-dimethyltyrosine 1, based on a previously published route, is presented. Key modifications were to prepare the dehydroaminoacid hydrogenation substrate 6 in a one-pot process directly from serine methyl ester and 4-iodo-3,5-dimethylphenyl acetate 4 and to identify a significantly more active asymmetric hydrogenation catalyst that allowed a 5-fold reduction in catalyst loading.
- Praquin, Celine F. B.,De Koning, Pieter D.,Peach, Philip J.,Howard, Roger M.,Spencer, Sarah L.
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experimental part
p. 1124 - 1129
(2012/01/06)
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- Novel ligands lacking a positive charge for the δ- and μ-opioid receptors
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Recently we reported using minilibraries to replace Lys [somatostatin (SRIF) numbering] of the potent somatostatin agonist L-363,301 (c[-Pro-Phe-D- Trp-Lys-Thr-Phe-]) to generate the potent neurokinin receptor (NK-1) antagonist c[-Pro-Phe-D-Trp-p-F-Phe-Thr-Phe-]. This novel cyclic hexapeptide did not bind the SRIF receptor. Thus, a single mutation converted L-363,-301, a SRIF agonist with potency ca. 2-8 times the potency of SRIF in laboratory animals, into a selective NK-1 receptor antagonist with an IC50 of 2 nM in vitro. During the screening of the same libraries for ligands of the δ- opioid receptor, we identified four compounds (1-4) which represent a new class of δ-opioid antagonists, some of which were also NK-1 receptor antagonists. The most potent δ-opioid antagonist, c[-Pro-1-Nal-D-Trp-Tyr- Thr-Phe-] (2), showed a K(e) value of 128 nM in the mouse vas deferens assay and a δ-receptor binding affinity constant of 152 nM in the rat brain membrane binding assay. These results are of interest because they represent a novel class of δ-opioid antagonists and, like two previously reported δ- opioid antagonists, they lack a positive charge. To examine further the requirement for a positive charge in the δ-opioid ligands, we prepared two analogues of the β-casomorphin-derived mixed μ-agonist/δ-antagonist, H- Dmt-c[-D-Orn-2-Nal-D-Pro-Gly-] (7), in which we eliminated the positive charge either through formylation of the primary amino group (5) or by the deletion of this N-terminal amino group (6). These latter compounds proved to be δ-opioid antagonists with K(e) values in the 16-120 nM range, as well as fairly potent μ-opioid antagonists (K(e) ? 200 nM). These six compounds provide the most convincing evidence to date that there is no requirement for a positive charge in μ- and δ-opioid receptor antagonists. In addition, cyclic, hexapeptide 4 lacks a phenolic hydroxyl group. Taken together, these data suggest that the prevailing assumptions about δ- and μ-opioid receptor binding need revision and that the receptors for these opioid ligands have much in common with the NK-1 and somatostatin receptors.
- Schiller, Peter W.,Berezowska, Irena,Nguyen, Thi M.-D.,Schmidt, Ralf,Lemieux, Carole,Chung, Nga N.,Falcone-Hindley, Margaret L.,Yao, Wenqing,Liu, Josephine,Iwama, Seiji,Smith III, Amos B.,Hirschmann, Ralph F.
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p. 551 - 559
(2007/10/03)
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- A convenient asymmetric synthesis of the unnatural amino acid 2,6-dimethyl-L-tyrosine
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The title compound was prepared in high optical purity by a five-step synthesis from 3,5-dimethylphenol on a kilogram scale. The key steps were a modified palladium-catalyzed coupling of an aryl iodide with methyl 2-acetamidoacrylate and hydrogenation of the resulting sterically hindered dehydroamino acid 4 using [Rh(1,5-COD)(R,R-DIPAMP)]BF4 as catalyst.
- Dygos,Yonan,Scaros,Goodmonson,Getman,Periana,Beck
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p. 741 - 743
(2007/10/02)
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