N-叔丁氧羰基-D-丝氨酸(Β-内酯) | 126330-77-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: N-叔丁氧羰基-D-丝氨酸(Β-内酯)
• 中文别名: N-叔丁氧羰基-D-丝氨酸(b-内酯)；(R)-(2-氧代-3-氧杂环丁基)氨基甲酸叔丁酯
• 英文名称: N-(tert-butyloxycarbonyl)-D-serine β-lactone
• 英文别名: Boc-D-serine lactone；(R)-3-(t-butoxycarbonylamino)oxetan-2-one；N-Boc-D-serine β-lactone；N-Boc-L-serine β-lactone；(R)-tert-Butyl (2-oxooxetan-3-yl)carbamate；tert-butyl N-[(3R)-2-oxooxetan-3-yl]carbamate
• CAS: 126330-77-6
• 化学式: C₈H₁₃NO₄
• 分子量: 187.196
• InChiKey: HRJDEHQWXAPGBG-RXMQYKEDSA-N

物化性质

• 熔点：
  121-122℃
• 沸点：
  319℃
• 密度：
  1.18±0.1 g/cm3(Predicted)
• 闪点：
  147℃

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 海关编码：
  2932209090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  存放于惰性气体中，并保持在低于0°C的环境，避免接触湿气（可能导致分解）。应避免加热。

反应信息

• 作为反应物：
  描述：

  N-叔丁氧羰基-D-丝氨酸(Β-内酯) 生成 丁氧羰基-D-二氨基二酸羟基
  参考文献：
  名称：

  KUCHARCZYK, N.;BADET, B.;LE, GOFFIC F., SYNTH. COMMUN., 19,(1989) N-10, C. 1603-1609

  摘要：

  DOI：
• 作为产物：
  描述：

  BOC-L-丝氨酸 在 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 为溶剂， 生成 N-叔丁氧羰基-D-丝氨酸(Β-内酯)
  参考文献：
  名称：

  Total Synthesis of the Cyclic Heptapeptide Argyrin B:  A New Potent Inhibitor of T-Cell Independent Antibody Formation

  摘要：

  [GRAPHICS]The total synthesis of Argyrin B (1) is presented using a synthetic plan that is convergent and flexible and conserves the stereogenic centers. The unusual amino acid 4-methoxy tryptophan (6) was obtained via an enzymatic resolution. Cyclization followed by oxidative elimination of the phenylseleno cysteine to the sensitive dehydroalanine afforded synthetic 1.

  DOI：

  10.1021/ol017184m

文献信息

• Novel Easily Recyclable Bifunctional Phosphonic Acid Carrying Tripeptides for the Stereoselective Michael Addition of Aldehydes with Nitroalkenes
  作者：Margery Cortes-Clerget、Olivier Gager、Maelle Monteil、Jean-Luc Pirat、Evelyne Migianu-Griffoni、Julia Deschamp、Marc Lecouvey

  DOI：10.1002/adsc.201500794

  日期：2016.1.7

  A novel bifunctional organocatalyst library combining both aminocatalysis and phosphonic acid activation was used for the first time as an efficient tool for the stereoselective Michael addition of aldehydes with several aromatic nitroalkenes with good selectivities up to 95:5 dr and 93:7 er. Due to their high water solubility, the catalysts were easily recyclable and could be reused over several cycles

  首次将结合了氨基催化和膦酸活化的新型双功能有机催化剂库作为有效的工具，用于醛与几种芳香族硝基烯烃的立体选择性迈克尔加成反应，选择性高达95：5 dr和93：7 er。由于它们的高水溶性，这些催化剂易于回收利用，并且可以在多个循环中重复使用，而没有任何明显的选择性损失。
• Exploring the dNTP -binding site of HIV-1 reverse transcriptase for inhibitor design
  作者：Weijie Gu、Sergio Martinez、Abhimanyu K. Singh、Hoai Nguyen、Jef Rozenski、Dominique Schols、Piet Herdewijn、Kalyan Das、Steven De Jonghe

  DOI：10.1016/j.ejmech.2021.113785

  日期：2021.12

  HIV-1 reverse transcriptase (RT) plays a central role in the viral life cycle, and roughly half of the FDA-approved anti-HIV drugs are targeting RT. Nucleoside analogs (NRTIs) require cellular phosphorylation for binding to RT, and to bypass this rate-limiting path, we designed a new series of acyclic nucleoside phosphonate analogs as nucleoside triphosphate mimics, aiming at the chelation of the catalytic

  HIV-1 逆转录酶 (RT) 在病毒生命周期中发挥着核心作用，FDA 批准的抗 HIV 药物中大约有一半针对 RT。核苷类似物 (NRTIs) 需要细胞磷酸化才能与 RT 结合，为了绕过这个限速路径，我们设计了一系列新的无环磷酸核苷类似物作为三磷酸核苷模拟物，旨在螯合催化 Mg 2+离子通过膦酸盐和/或羧酸基团。开发了新的合成程序来获取这些核苷膦酸盐类似物。与 HIV-1 RT/dsDNA 复合的 X 射线结构表明它们的结合模式与我们之前报道的化合物系列的结合模式不同。讨论了链长、手性和接头原子的影响。对这些新化合物的详细结构了解为设计新型 HIV-1 RT 抑制剂提供了机会。
• Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site
  作者：Susan Matthew、Qi-Yin Chen、Ranjala Ratnayake、Charles S. Fermaintt、Daniel Lucena-Agell、Francesca Bonato、Andrea E. Prota、Seok Ting Lim、Xiaomeng Wang、J. Fernando Díaz、April L. Risinger、Valerie J. Paul、Maria Ángela Oliva、Hendrik Luesch

  DOI：10.1073/pnas.2021847118

  日期：2021.3.2

  Natural products provide the inspiration for most drugs, and marine natural products, in particular, are emerging as promising new therapeutics with new targets or mechanisms of action. Pharmacological targeting of tubulin dynamics has been a validated strategy for cancer therapy for decades, yielding structurally diverse natural products and derivatives, including paclitaxel, vincristine, maytansine, and eribulin, targeting six known and different binding sites. We discovered a chemical scaffold from marine cyanobacteria that targets a seventh tubulin binding site. We report the entire spectrum of the discovered chemical and biological novelties, including the isolation, structure determination, and chemical synthesis of the natural product, and the investigation of its mechanism of action, target identification, and binding mode elucidation at the atomic level.

  天然产物为大多数药物提供灵感，尤其是海洋天然产物正逐渐成为具有新靶点或作用机制的有前途的新疗法。数十年来，药理学上针对微管动力学的靶向治疗一直是癌症治疗的验证策略，产生了结构多样的天然产物和衍生物，包括紫杉醇、长春碱、马丹霉素和依立必利，靶向六个已知且不同的结合位点。我们发现了一种来自海洋蓝藻的化学骨架，靶向第七个微管结合位点。我们报告了所发现的化学和生物新颖性的整个范围，包括天然产物的分离、结构确定和化学合成，以及对其作用机制、靶点识别和在原子水平上结合方式的阐明的调查。

• Synthesis of the stereoisomers of a novel antibacterial agent and interpretation of their relative activities in terms of a theoretical model of the penicillin receptor
  作者：Saul Wolfe、Caijun Zhang、Blair D. Johnston、Chan-Kyung Kim

  DOI：10.1139/v94-134

  日期：1994.4.1

  2,2-Dimethyl-3-(2′-hydroxypropyl)-5-carboxy-Δ³ -1,4-thiazine (1) is a designed antibacterial agent. Based on an analysis of how penicillin complexes to and reacts with a model of a penicillin-binding protein, 1 contains a functional group (C=N) that can react with a serine hydroxyl group of the receptor according to the putative reaction Enz-OH + C = N → Enz-O-C-NH. Compound 1 also contains additional substituents that are designed to position the O-H and C=N groups relative to one another in the enzyme–substrate complex in a geometry that attempts to reproduce the optimum geometry of approach of two such reactants. A most important assumption is that this optimum geometry can be computed ab initio. In a first preparation of 1, (±)-5-methyl-4-hexene-2-ol (2) was converted to the lithium salt of (±)-2-mercapto-2-methyl-5-tert-butyldimethylsiloxy-3- hexanone (7), which was condensed with the N-tert-butoxycarbonyl-D- and L-serine-β-lactones (3). The synthesis was completed by deprotection with formic acid and cyclization in water. The R and S enantiomers of 2 have now been obtained, and the absolute configuration of the alcohol established, by reaction of the R- and S-propylene oxides with an organometallic reagent prepared from β,β-dimethylvinyl bromide. The R alcohol has also been secured by lipase-catalyzed transesterification with trifluoroethyl butyrate, and chemical hydrolysis of the trifluoroethyl ester. The R and S enantiomers of 2 were converted to the R and S enantiomers of 7, and these were condensed with the R and S enantiomers of 3 to yield each of the stereoisomers of the chemically unstable 1 in ca. 95% optically pure form. Antibacterial activity resides in the 5S,8R and 5S,8S isomers. These findings are shown to be consistent with the theoretical model. It is hoped that the stability of the lead structure 1 can be improved, to allow binding experiments with penicillin recognizing enzymes to proceed.

  2,2-二甲基-3-(2'-羟丙基)-5-羧基-Δ³-1,4-噻嗪（1）是一种设计的抗菌剂。根据对青霉素与青霉素结合蛋白模型的复合物如何反应的分析，1含有一个功能基团（C=N），可以根据假定的反应Enz-OH + C = N → Enz-O-C-NH与受体的丝氨酸羟基反应。化合物1还包含额外的取代基，旨在将O-H和C=N基团相对于酶-底物复合物中的位置设计成一种几何构型，试图重现两种反应物的最佳接近几何构型。一个最重要的假设是这种最佳几何构型可以从头计算。在对1的第一次制备中，（±）-5-甲基-4-己烯-2-醇（2）被转化为（±）-2-巯基-2-甲基-5-叔丁基二甲基硅氧基-3-己酮（7）的锂盐，然后与N-叔丁氧羰基-D-和L-丝氨酸-β-内酯（3）缩合。合成完成后，用甲酸去保护，然后在水中环化。2的R和S对映体现已被获得，并通过R-和S-丙烯氧化物与由β，β-二甲基乙烯基溴制备的有机金属试剂反应，确定了醇的绝对构型。R醇也通过脂肪酶催化的三氟乙基丁酸酯转酯化和三氟乙基酯的化学水解获得。2的R和S对映体转化为7的R和S对映体，然后与3的R和S对映体缩合，以在约95%光学纯度形式中产生化学不稳定的1的各立体异构体。抗菌活性存在于5S,8R和5S,8S异构体中。这些发现与理论模型一致。希望可以改进引物结构1的稳定性，以便进行与识别青霉素的酶的结合实验。
• Interactive design and synthesis of a novel antibacterial agent
  作者：Saul Wolfe、Haolun Jin、Kiyull Yang、Chan-Kyung Kim、Ernest McEachern

  DOI：10.1139/v94-133

  日期：1994.4.1

  β-Lactam compounds act on penicillin-recognizing enzymes via acylation of the hydroxyl group of an active site serine. When the resulting acyl enzyme is kinetically stable, as in the case of a penicillin-binding protein (PBP), the biosynthesis of a bacterial cell wall is inhibited, and death of the organism results. The de novo design of an antibacterial agent targeted to a PBP might be possible if the three-dimensional structural requirements of the equilibrium (i.e, fit) and catalytic (i.e. reactivity) steps of the aforementioned enzymatic process could be determined. For a model of the active site of a PBP from Streptomyces R61, the use of molecular mechanics calculations to treat "fit," and ab initio molecular orbital calculations to treat "reactivity," leads to the idea that the carboxyl group (G₁) and the amide N-H (G₂) of the antibiotic are hydrogen bonded to a lysine amino group and a valine carbonyl group in the enzyme–substrate complex. These two hydrogen bonds place the serine hydroxyl group on the convex face of the antibiotic, in position for attack on the β-lactam ring by a neutral reaction, catalyzed by water, that involves a direct proton transfer to the β-lactam nitrogen. Molecular orbital calculations of structure–reactivity relations associated with this mechanism suggest that C=N is bioisosteric to the β-lactam N-C(=O), comparable to a β-lactam in its reactivity with an alcohol, and that the product RO(C-N)H is formed essentially irreversibly (−ΔE > 10 kcal/mol). Accordingly, structures containing a G₁ and a G₂ separated by a C=N, and positioned in different ways with respect to this functional group, have been synthesized computationally and examined for their ability to fit to the PBP model. This strategy identified a 2H-5,6-dihydro-1,4-thiazine substituted by hydroxyl and carboxyl groups as a target for chemical synthesis. However, exploratory experiments suggested that the C=N of this compound equilibrates with endocyclic and exocyclic enamine tautomers. This required that the C2 position be substituted, and that the hydroxyl group not be attached to the carbon atom adjacent to the C=N. These conditions are met in a 2,2-dimethyl-3-(2-hydroxypropyl)-1,4-thiazine, which also exhibits the necessary fit to the PBP model. Two epimers of this compound have been synthesized, from D- and L-serine. The compound derived from L-serine is not active. The compound derived from D-serine exhibits antibacterial activity, but is unstable, and binding studies with PBP's have not been performed. It is hoped that these studies can be carried out if modification of the lead structure leads to compounds with improved chemical stability.

  β-内酰胺化合物通过酰化活性位点丝氨酸的羟基作用于青霉素识别酶。当产生的酰酶在动力学上是稳定的，如青霉素结合蛋白（PBP）的情况下，细菌细胞壁的生物合成被抑制，导致生物体的死亡。如果能确定青霉素结合蛋白的三维结构要求（即平衡的适合性）和催化（即反应性）步骤的需求，可能会实现针对PBP的抗菌剂的全新设计。对来自链霉菌R61的PBP的活性位点模型，使用分子力学计算处理“适合性”，并使用从头算分子轨道计算处理“反应性”，得出一个想法，即抗生素的羧基（G1）和酰胺N-H（G2）与酶-底物复合物中的赖氨酸氨基团和缬氨酸羰基团形成氢键。这两个氢键将丝氨酸羟基置于抗生素的凸面上，处于通过中性反应由水催化的直接质子转移至β-内酰胺氮原子的位置。与这种机制相关的结构-反应关系的分子轨道计算表明，C=N与β-内酰胺N-C(=O)是生物等同物，与醇类反应时与β-内酰胺相当，产物RO(C-N)H基本上是不可逆的（−ΔE > 10 kcal/mol）。因此，含有由C=N分隔的G1和G2的结构，并以不同方式相对于这个功能团定位的结构已经通过计算合成并检验其适合于PBP模型的能力。这种策略确定了一个被羟基和羧基取代的2H-5,6-二氢-1,4-噻嗪作为化学合成的目标。然而，探索性实验表明，该化合物的C=N与内环和外环烯胺互变异构体平衡。这要求对C2位置进行取代，并且羟基不能连接到邻近C=N的碳原子。这些条件在2,2-二甲基-3-(2-羟基丙基)-1,4-噻嗪中得到满足，该化合物还展现出与PBP模型的必要适合性。这种化合物的两个对映体已经从D-丝氨酸和L-丝氨酸合成。从L-丝氨酸衍生的化合物不活跃。从D-丝氨酸衍生的化合物表现出抗菌活性，但不稳定，并且尚未进行与PBP的结合研究。希望如果引物结构的修改导致具有改善化学稳定性的化合物，这些研究可以进行。