Chiral separation and analysis by molecular propeller effect

 描述(由申请人提供)：在这项SBIR第一阶段提案中，我们建议测试一种新的手性分离技术，用于绝对立体化学的快速分离、纯度分析和鉴定。这项技术将为手性化学研究和工业节省大量成本和时间--(1)通过消除对昂贵的手性固定相的需求，(2)通过显著缩短分离方法的开发和(3)通过使用用于性能预测和立体化学测定的预测软件。目前用于手性拆分和分析的技术，如高效液相色谱、X射线结晶学和振动圆二色谱，都是耗时、昂贵或保真度较低的。最近，我们利用旋转电场实验验证了分子螺旋桨效应的存在，并演示了手性分离和绝对构型确定。在这个项目中，我们建议研究利用剪切流对分子施加旋转的替代方法，这种方法具有多种优点，如不需要分子的高偶极矩、溶剂的低极性和较强的电场。简而言之，当暴露在剪切流中时，左旋手性分子和右旋手性分子旋转并充当分子推进器，沿着垂直于剪切面的方向推进，但由于它们的相反手向相反的方向推进。螺旋桨效应作为一种流体力学现象，不依赖于与化学基质的特定相互作用，因此可以使用理论模型可靠地确定任何新的手性分子的平移运动的方向和速度，从而提供关于预期性能的先验信息，并使绝对构型的分配成为可能。这种基于分子螺旋桨效应的手性分离分析方法，将为手性分离分析提供一种廉价、易用的台式仪器。由于单一对映体化合物普遍证明的优势，FDA要求对大多数新药的每个对映体都需要单独进行评估，从而增加了对新的手性分离和分析技术的需求。如果更多的学术界和工业界的研究人员能够在先导化合物发现的早期阶段进行手性分离和分析，将对药物发现和商业化的速度产生积极的影响。具体目标是：(1)设计和构建基于剪切流动的原理验证装置；(2)展示至少5个手性分子的对映体浓缩和绝对立体化学测定；研究设计参数的权衡，如剪切速率、溶剂类型、粘度和温度；以及研究用于高保真绝对构型确定的预测软件的最佳算法。该项目的长期目标是开发一种简单易用、低成本的方法和设备，既能加快制药行业的药物发现和开发速度，又能利用手性化合物在其他行业中找到应用，如农业、食品和营养食品。

 DESCRIPTION (provided by applicant): In this SBIR Phase I proposal we propose to test a novel chiral separation technology for rapid separation, purity analysis and identification of absolute stereochemistry. The technology will enable significant cost and time savings for chiral chemistry research and industry - (1) by eliminating the need for expensive chiral stationary phases, (2) by significantly shortening separation method development and (3) through the use of predictive software for performance prediction and stereochemistry determination. Current techniques for chiral resolution and analysis such as high-performance liquid chromatography, x-ray crystallography and vibrational circular dichroism are time consuming, expensive or low fidelity. Recently we have experimentally validated the existence of a molecular propeller effect using rotating electric fields and demonstrated both chiral separation and absolute configuration determination. In this project we propose to investigate alternative means of imposing rotation on the molecules using shear flows which offers multiple advantages such as no requirements for high dipole moment of the molecule, low polarity of the solvent and strong electric fields. Briefly, when exposed to shear flow the left and right-handed chiral molecules rotate and act as molecular propellers, propelling along the direction perpendicular to shear plane but into opposite directions due to their opposite handedness. The propeller effect, as a hydrodynamic phenomenon does not rely on specific interactions with a chemical matrix, therefore the direction and velocity of translational motion for any new chiral molecule can be reliably determined using theoretical modeling, thus providing a priori information about expected performance, as well as enabling the assignment of absolute configuration. The proposed method, relying on the molecular propeller effect will enable the development of an inexpensive and easy-to-use benchtop instrument for chiral separation and analysis. The FDA, due to the generally proven advantages of single enantiomer compounds, mandates that for most new drugs each enantiomer needs to be evaluated separately thereby increasing the need for new chiral separation and analysis techniques. The rate of drug discovery and commercialization will be positively impacted if more researchers, both in academia and industry are able to afford chiral separation and analysis at earlier stages of lead discovery. The Specific Aims are: (1) design and build a shear flow-based proof-of-principle device; and (2) demonstrate enantiomeric enrichment and absolute stereochemistry determination of at least five chiral molecules; investigate design parameter tradeoffs such as shear rate, type of the solvent, viscosity and temperature; and investigate optimal algorithms for predictive software for high fidelity absolute configuration determination. The long-term goal of the project is to develop a simple-to-use and low-cost method and device that will both accelerate the rate of drug discovery and development by pharmaceutical industry and also find applications in other industries using chiral compounds such as agricultural, food and nutraceuticals.