Starting from aspartic acid a stereoselective synthesis of enantiomerically pure 4-aminopiperidin-2-ones which can serve as conformationally restrained B-amino acid equivalents in peptidomimetics is described. The synthesis is based on the regioselective functionalization of the l,4-bis-electrophile 2b and a diastereoselective introduction of various side chain equivalents into the lactam a-position of 4b,c. Conformationally locked peptide surrogates have been utilized extensively in the design and development of enzyme inhibitors or neuroreceptor ligands.l-4 This strategy afforded valuable information regarding the elucidation of the biologically active conformation of peptides and led to drug candidates with remarkable affinity, selectivity and metabolic stability.5 Among the numerous developments in this field, incorporating the a-amino carboxamide moiety of a peptide backbone into a Freidinger lactam (I) has proven very successful.6-10On the other hand, B-amino acid derived substructures and the investigation of B-peptides led to interesting peptidomimetics.l1-13 As far as we know, a combination of these two strategies was not reported yet. As part of our efforts on the synthesis of enantiopure B-amino acid derivatives, 14.15here we report the first stereoselective synthesis of 4aminopiperidin-2-ones as lactam-bridged analogs with a B-amino carboxamide substructure (Homo-Freidinger lactams, II). Applying this approach, our initial results on lactam-constrained mimetics of the dopamine receptor modulating peptide Pro-Leu-Gly-NH216 are presented. The synthesis of aN-protected 4-aminopiperidine in enantiomerically pure form was planned starting from natural aspartic acid (1). Taking advantage of our recently described methodology we were able to functionalize regioselectively the dibenzyl protected aminobutanediol 2a.17-20 Thus, activation of 2a by MesCl gave the bis-electrophile 2b which could be transformed into the azido nitrile 3a by subsequent substitution with LiCN and NaN3. Due to an activating anchimeric participation of the dibenzylamino group the leaving group in position 1 is exclusively displaced by the nucleophile which is added first. The formation of regioisomers was not observed. Chemoselective reduction of the azide functionality in the presence of the nitrile group was accomplished under Staudinger conditions 21giving the amino nitrile 3b in 81 % yield. Alternatively, a more direct preparation of 3b is possible when liquid NH3 is used as the "second nucleophile" instead of NaN3.22 Lactamization of the amino nitrile 3b was induced by HClIMeOH. The reaction sequence is highly practical and efficient providing the amino lactam 4a in 58 % overall yield, based on (S)-aspartic acid (I), as well as the (R)-configured enantiomer of 4a (ent-4a) when commercially available (R)-aspartic acid (ent-I) is used as the starting material. ,¢°OH OH H2N ° 28: X = H 2b: X=Mes 1. UCN (1.2 eq) THF / DMF, RT. 3h 2b 2. NaN3, DMF, RT, 17h •

中文翻译：

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Homo-Freidinger 内酰胺类：天冬氨酸中 4-Aminopiperidin-2-one 衍生物的立体选择性合成

描述了从天冬氨酸开始立体选择性合成对映异构纯 4-氨基哌啶-2-酮，其可在肽模拟物中用作构象受限的 B-氨基酸等价物。该合成基于 l,4-双亲电试剂 2b 的区域选择性功能化和将各种侧链等价物非对映选择性引入 4b,c 的内酰胺 a 位。构象锁定肽替代物已广泛用于酶抑制剂或神经受体配体的设计和开发。l-4 该策略为阐明肽的生物活性构象提供了有价值的信息，并导致了具有显着亲和力、选择性和代谢性的候选药物稳定性。5 在该领域的众多发展中，将肽主链的 a-氨基甲酰胺部分结合到 Freidinger 内酰胺 (I) 中已证明非常成功。6-10另一方面，B-氨基酸衍生的亚结构和 B-肽的研究导致了有趣的肽模拟物。l1- 13 据我们所知，尚未报告将这两种策略结合使用。作为我们合成对映体纯 B-氨基酸衍生物的努力的一部分，14.15 在这里，我们报告了 4aminopiperidin-2-ones 作为内酰胺桥连类似物与 B-氨基甲酰胺亚结构（Homo-Freidinger 内酰胺，II）的首次立体选择性合成. 应用这种方法，我们展示了多巴胺受体调节肽 Pro-Leu-Gly-NH216 的内酰胺约束模拟物的初步结果。计划从天然天冬氨酸 (1) 开始合成对映体纯形式的 N 保护的 4-氨基哌啶。利用我们最近描述的方法，我们能够对二苄基保护的氨基丁二醇 2a.17-20 进行区域选择性功能化。因此，通过 MesCl 激活 2a 得到双亲电试剂 2b，通过随后用 LiCN 和NaN3。由于二苄基氨基的活化嵌合参与，1位的离去基团仅被首先加入的亲核试剂取代。未观察到区域异构体的形成。在腈基团的存在下，叠氮化物官能团的化学选择性还原在施陶丁格条件 21 下完成，得到氨基腈 3b，产率为 81%。或者，当使用液态 NH3 作为“第二亲核试剂”而不是 NaN3 时，更直接地制备 3b 是可能的。22 氨基腈 3b 的内酰胺化是由 HClIMeOH 诱导的。基于 (S)-天冬氨酸 (I) 以及 4a (ent-4a) 的 (R)-构型对映异构体，该反应序列非常实用且高效，以 58% 的总收率提供氨基内酰胺 4a可用的(R)-天冬氨酸(ent-I)用作起始材料。,¢°OH OH H2N° 28: X = H 2b: X = Mes 1. UCN (1.2 eq) THF / DMF, RT。3h 2b 2. NaN3, DMF, RT, 17h • 基于 (S)-天冬氨酸 (I) 以及 4a (ent-4a) 的 (R)-构型对映异构体，该反应序列非常实用且高效，以 58% 的总收率提供氨基内酰胺 4a可用的(R)-天冬氨酸(ent-I)用作起始材料。,¢°OH OH H2N° 28: X = H 2b: X = Mes 1. UCN (1.2 eq) THF / DMF, RT。3h 2b 2. NaN3, DMF, RT, 17h • 基于 (S)-天冬氨酸 (I) 以及 4a (ent-4a) 的 (R)-构型对映异构体，该反应序列非常实用且高效，以 58% 的总收率提供氨基内酰胺 4a可用的(R)-天冬氨酸(ent-I)用作起始材料。,¢°OH OH H2N° 28: X = H 2b: X = Mes 1. UCN (1.2 eq) THF / DMF, RT。3h 2b 2. NaN3, DMF, RT, 17h •