Synthesis of Homochiral beta-Branched-Chain Amino Acids

描述(申请人提供)：许多非蛋白生成氨基酸已被证明对抑制生物降解和提高多肽和模拟多肽药物的生物活性是有用的。尽管支链氨基酸侧链相互作用在确定多肽结构中的重要性，但很少有非遗传编码的支链氨基酸(BCAA)在商业上可用。手性支链可以通过微妙地改变侧链形状来微调生物活性。例如，D-异亮氨酸取代提供了更特异和有效的胰岛素和加压素拮抗剂，以及有效的短抗血管生成多肽。β-甲基芳基氨基酸的支链碳结构对活性有很大影响。因此，β-手性支链氨基酸可以为生物活性多肽构象提供更好的模型，并极大地提高多肽治疗的活性和作用时间。 大多数β-手性支链氨基酸的合成都是从立体随机构筑碳骨架开始，然后拆分非对映异构体，最后拆分对映体。在D-异亮氨酸的情况下，改进这一低效合成策略的多次尝试只导致了昂贵、复杂的过程，难以放大。人们对不太常见的支链氨基酸的兴趣很高，但商业来源目前无法以可接受的成本提供药物开发所需的数量。在开发一种可扩展的酶促工艺将L-异构体干净地异构化为D-异构体的过程中，我们意识到获得具有正确侧链支链构型的氨基酸骨架是制备任何β-支链的关键问题，因为立体定向的异构化可以定量地将α-异构体混合物转化为同手性产物。我们将比较直接的甘氨酸阴离子烷基化和两种新的环丙烷开环方法的合成和经济上的优点，以制造带有β-手性支链的氨基酸。然后，α-碳同分异构体将通过先例的化学酶过程均匀地制造D-或L。

DESCRIPTION (provided by applicant): Many nonproteogenic amino acids have proved useful for inhibiting biodegradation and improving biological activity in peptides and peptidomimetic drugs. Few non-genetically encoded branched-chain amino acids (BCAAs) are commercially available, despite the importance of BCAA side-chain interactions in determining polypeptide structure. Chiral branches permit fine-tuning of biological activity by subtly changing side-chain shapes. For example, D-isoleucine substitution gives more specific and effective insulin and vasopressin antagonists, and potent short antiangiogenic peptides. Branch-carbon configurations of beta-methyl arylamino acids strongly affect activity. Thus beta-chiral BCAAs can provide better models for bioactive polypeptide conformations and greatly improve both activity and duration of action in peptide therapeutics. Most syntheses of beta-chiral BCAAs begin by stereorandomly building carbon skeletons, then separating diastereomers and finally enantiomers. In the case of D-alloisoleucine, numerous attempts to improve on this inefficient synthetic strategy have only resulted in expensive, complex processes which are difficult to scale up. Interest in less-common branched-chain amino acids is high, but commercial sources are currently not providing the quantities needed for drug development at acceptable cost. In developing a scalable enzymatic process to cleanly isomerize L-Ile to D-allo-Ile, we realized that obtaining amino acid frameworks with the correct side-chain branch configuration is the crucial problem in making any beta-branched BCAA, because stereo directed epimerizations can quantitatively convert alpha-isomeric mixtures to homochiral )roducts. We will compare the synthetic and economic merits of straightforward glycine anion alkylations with two novel cyclopropane ring-opening procedures for making amino acids with beta-chiral branches. alpha-Carbon epimers will then be made uniformly D- or L- by well-precedented chemoenzymatic processes.