Elucidation of the mechanisms governing the thermal diastereomerization of bioactive chiral 1,3,4-thiadiazoline spiro-cyclohexyl derivatives towards their anancomeric stereoisomers

Menta S.; Carradori S.; Siani G.; Secci D.; Mannina L.; Sobolev A. P.; Cirilli R.; Pierini M.

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Elucidation of the mechanisms governing the thermal diastereomerization of bioactive chiral 1,3,4-thiadiazoline spiro-cyclohexyl derivatives towards their anancomeric stereoisomers

机译：阐明治疗生物活性手性1,3,4-噻二唑啉螺旋环己基衍生物朝向其对照立体异构体的机制

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The kinetics of the thermal isomerization of some diastereomers of three chiral 1,3,4 thiadiazoline derivatives, selected as case studies of structures resulting from mono-alkyl substitution of the anancomeric 4-acetyl-2-acetamido-1,3,4-thiadiazolinyl-spiro-cyclohexane (TsC) framework, have been investigated in order to elucidate the possible mechanistic pathways and the structural factors responsible for the observed spiro-junction lability. The insertion of a methyl or a t-butyl group on the C2 or C3 position with respect to the spiro junction generates two stereogenic centres, so that two pairs of enantiomers exist. The first-order rate constants for the isomerization of the less stable enantiomers into the most stable ones have been measured in different solvents and at different temperatures through batch-wise kinetic determinations. The obtained data have been successfully rationalized by DFT calculations and Linear Solvation Energy Relationships (LSER) analyses. The achieved elucidation should make it possible to plan a more rational synthesis of this kind of pharmacologically active compounds, thus affording a practical tool that is useful for controlling the involved stereochemistry and spiro-junction lability.

机译：三种手性1,3,4噻二唑啉衍生物的一些非对映异构体的热异构化的动力学，选择了由金刚间4-乙酰基-2-乙酰氨基-1,3,4-噻二唑啉基的单烷基取代引起的结构的案例研究已经研究了-Piro-Cyclohexane（TSC）框架，以阐明可能的机械途径和负责观察到的螺纹连接损伤的结构因素。在C2或C3位置上的甲基或叔丁基的插入相对于螺螺杆杆的位置产生两个立体中心，因此存在两对对映体。用于在不同溶剂和不同温度下通过批量动力学测定来测量较稳定的对映体的异构化的一定稳定性常数。所获得的数据通过DFT计算和线性溶剂化能量关系（LSER）分析成功地进行了合理化。实现的阐明应该使得可以规划更合理的这种药理学活性化合物，因此提供了一种用于控制所涉及的立体化学和螺螺纹韧性的实用工具。

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《RSC Advances》 |2016年第75期|共11页
作者
Menta S.; Carradori S.; Siani G.; Secci D.; Mannina L.; Sobolev A. P.; Cirilli R.; Pierini M.;
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Sapienza Univ Roma Dipartimento Chim &

Tecnol Farmaco Ple Aldo Moro 5 I-00185 Rome Italy;

Univ G dAnnunzio Dept Pharm G DAnnunzio Via Vestini 31 I-66100 Chieti Italy;

Univ G dAnnunzio Dept Pharm G DAnnunzio Via Vestini 31 I-66100 Chieti Italy;

Sapienza Univ Roma Dipartimento Chim &

Tecnol Farmaco Ple Aldo Moro 5 I-00185 Rome Italy;

Sapienza Univ Roma Dipartimento Chim &

Tecnol Farmaco Ple Aldo Moro 5 I-00185 Rome Italy;

CNR Area Ric Roma Ist Metodol Chim Lab Risonanza Magnet AnnalauraSegre Via Salaria Km 29-300 I-00015 Monterotondo Italy;

Ist Super Sanita Dipartimento Farmaco Viale Regina Elena 299 I-00161 Rome Italy;

Sapienza Univ Roma Dipartimento Chim &

Tecnol Farmaco Ple Aldo Moro 5 I-00185 Rome Italy;

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1. Elucidation of the mechanisms governing the thermal diastereomerization of bioactive chiral 1,3,4-thiadiazoline spiro-cyclohexyl derivatives towards their anancomeric stereoisomers [J] . Menta S., Carradori S., Siani G., RSC Advances . 2016,第75期

机译：阐明治疗生物活性手性1,3,4-噻二唑啉螺旋环己基衍生物朝向其对照立体异构体的机制
2. Efficient synthesis of chiral Δ2-1,3,4-thiadiazolines from α-pinene and verbenone [J] . Sarmiento G.P., Rouge P.D., Fabian L., Tetrahedron, Asymmetry: The International Journal for Repid Publication on all Aspects of Asymmetry in Orgainc, Inorganic, Organometallic, Physical and Bio-Organic Chemistry . 2011,第20a22期

机译：由α-pine烯和马鞭草酮高效合成手性Δ2-1,3,4-噻二唑啉
3. Synthetic studies on mitotic kinesin Eg5 inhibitors: Synthesis and structure-activity relationships of novel 2,4,5-substituted-1,3,4-thiadiazoline derivatives [J] . YamamotoJ., AmishiroN., KatoK., Bioorganic and Medicinal Chemistry Letters . 2014,第16期

机译：有丝分裂驱动蛋白Eg5抑制剂的合成研究：新型2,4,5-取代-1,3,4-噻二唑啉衍生物的合成与构效关系
4. Separations of Chiral Pharmaceuticals: Direct Experimental Probing and Molecular Modeling for Elucidating the Molecular Recognition Mechanism of Amylose tris(3,5- dimethylphenylcarbamate) [C] . Rahul B. Kasat, Siao Yee Wee, Ji Xian Loh American Institute of Chemical Engineers Annual Meeting . 2007

机译：手性药物的分离：直接实验探测和分子建模，用于阐明淀粉糖三的分子识别机制（3,5-二甲基苯胺酸）
5. I. A1,3- strain enabled retention of chirality during Bis-cyclization of β-ketoamides: Asymmetric synthesis and bioactivity of salinosporamide a and derivatives II. Optimization of an Organic syntheses procedure: asymmetric nucleophile-catalyzed aldol-lactonization with aldehyde acids [D] . Nguyen, Henry 2010

机译：I. A1,3-菌株能够在β-酮基酰胺的双环化过程中保留手性：salinosporamide a和衍生物II的不对称合成和生物活性。有机合成程序的优化：醛酸不对称亲核催化醛醇内酯化
6. Elucidation of the Enantiodiscrimination Properties of a Nonracemic Chiral Alignment Medium through Gel‐based Capillary Electrochromatography: Separation of the Mefloquine Stereoisomers [O] . Dr. Ayat Allah Al‐Massaedh, Dr. Manuel Schmidt, Prof. Dr. Ute Pyell, 2016

机译：通过基于凝胶的毛细管电色谱法阐明非消旋手性取向介质的对映异构特性：甲氟喹立体异构体的分离
7. The Anancomeric Character of the Pharmacophore 1,3,4-Thiadiazoline Framework in Chiral Spiro-Cyclohexyl Derivatives: Effects on Stereochemistry and Spiro-Junction Lability. Thermodynamic Aspects [O] . -1

机译：手性螺环己基衍生物中药物1,3,4-噻二唑啉框架的综合体特征：对立体化学和螺螺纹韧性的影响。热力学方面

Elucidation of the mechanisms governing the thermal diastereomerization of bioactive chiral 1,3,4-thiadiazoline spiro-cyclohexyl derivatives towards their anancomeric stereoisomers

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