Ex-Chiral Pool Synthesis of Aminooxazepinones as Conformationally Restricted b-Amino Acid Analogs

Starting from natural asparagine, an efficient synthesis of the dibenzyl protected 6-amino-l,3-oxazepin-4-one (7) is reported. According to NMR based conformational studies, the lactam-bridged J3-amino acid analog (7) adopts preferentially a twisted boat structure. The incorporation of the described molecular scaffold to give a constrained J3-analog of the dopamine receptor modulating peptide Pro-Leu-Gly-NHl is described as an application in the field of medicinal chemistry. In search for increased target selectivity and pharrnakokinetics, great efforts in peptide-based drug design are made by developing non-peptidic structural modifications..5 Among these, lactam-bridged peptidomimetics are of special relevance since their conformational constraints give interesting insights into the bioactive conformations of both, natural ligands and binding sites.6.s As an example, the y-Iactam restricted analog (1) of the dopamine receptor modulating peptide Pro-Leu-Gly-NHz (PLG) displayed modulating activities superior to PLG, indicating that a type-II J3-tum might be bioactive conformation.9.,o Structure activity relationship studies in our laboratory are based on J3-amino acid derived PLG analogs including the incorporation of J3-proline as well as 4-aminopiperidin-2-one as a Homo-Freidinger lactam (2).11.12 As an extension of our efforts on the synthesis of conformationally restrained J3-amino acid equivalents, here we report the construction of enantiopure 6-aminoI ,3-oxazepin-4-ones from natural asparagine and the application of this novel molecular scaffold for the respective PLG analog (3). \X~NH2 0+ do ... , N g ceO .. / \N--rr NO· N ~ ° I I ° NH H R NH H The synthesis of the :\'N-dibenzyl protected chiral building block (7) was planned from natural asparagine employing the B-homoserine derivative (5)1~ as a cyclization precursor. In practice, asparagine was readily tranformed into the protected ester (4) by reaction with benzyl bromide in aqueous K:CO~ solution. If the reaction is performed at room temperature benzylation of the amide function and formation of a cyclic imide can be precluded. Since most of the product precipitates under these conditions this one-pot preparation is superior to the earlier published two-step sequence including reductive alkylation and subsequent esterification.I.'16 Chemoselective reduction of the ester group of 4 by LiAlH~ at O°C gave the hydroxy amide (5). Formation of the cyclic N/O-acetal (7) could be accomplished by reaction of 5 with dimethoxypropane under acidic conditions. This transacetalization turned out to be very sensitive to the employed cyclization conditions. Thus, refluxing of 5 in neat dimethoxypropane using TsOH as a catalyst afforded the acyclic OIO-acetal (8) in 37 c,-c yield. On the other hand, using toluene as a solvent ga\e a chromatographically separable mixture of the oxazepinone (7) (25 %) and the y-lactone (6) (30 %) besides traces of8 (1-2 o/c) after 4 h reflux. Lowering the reaction temperature resulted in 45 % of the lactone (6)17 and a strongly decreased yield of the target compound (7). When heating the pure educts in toluene I TsOH, almost quantitative lactone formation could be observed directly from the B-homoserine (5) as well as by ring-contraction of the oxazepinone (7). The selectivity of the reaction could be improved when pyridinium p-toluenesulfonate (PPTS) was used as a mild catalyst instead of TsOH. Under these conditions, only small amounts of the by-products were formed and 35 % of the pure building block (7) \\as isolated. In the presence of PPTS, selective cyclization of the OIO-acetal (8) to give 7 proved also possible. 0XjOH NH2 ,\ H N' 2 ° )

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