Structural Elucidation, Synthesis and Study of the Chlorosulfolipids

描述(申请人提供)：自然界在生物合成中广泛使用氯；到目前为止，已鉴定出2000多种氯化天然产品。许多这些氯化次生代谢物显示出强大而多样的生物活性，但从自然来源获得的数量很少。氯原子的存在给这些化合物带来了什么好处，这一重大问题仍有待回答。回答这个问题的能力取决于氯化化合物合成的有效战略，而这一领域目前的复杂程度很低。氯磺脂是一类立体化学复杂的烷烃，显示了许多含氯的立体生成中心，代表了一类特别有趣的多氯化分子。当人们食用受污染的贻贝时，某些氯硫脂被确定为腹泻性贝类中毒的病原体，其他的是许多淡水藻类细胞和鞭毛膜中唯一的极性脂类。这些化合物在烷烃链的两端带有两个极性硫酸盐基团，是稳定膜的主要成分，这真的很耐人寻味。据认为，这些化合物可能比最初预期的要广泛得多，可能在藻类物种中普遍存在。相对和绝对的立体化学只对贻贝衍生的脂类建立。到目前为止，几乎没有关于这些具有挑战性的目标的合成的研究，或者对它们的构象行为，或者它们的本体或膜性质的研究，还没有报道。Ochromonas Danica的细胞膜和鞭毛膜主要由氯硫脂组成，基本上不含磷脂；这些多氯天然产物在许多淡水藻类中都有发现。我们建议用核磁共振方法阐明丹参主要氯硫脂的相对和绝对立体化学。然后我们将通过合成来验证立体化学分配。这些努力已经取得了实质性的成功。一条通向这一脂质靶标的对映体选择性路线将被开发出来，它也将适用于首次合成富含对映体的氯硫脂贻贝毒素。我们将回顾相关的多氯天然产物Malhamensilipin A，并用光谱方法确定其立体化学，并通过合成证实这些结果。我们还将重新分离和确定几种氯化程度较低的丹尼卡脂的结构，并合成具有代表性的成员。合成的氯磺脂的溶液构象将用核磁共振波谱和计算模型进行研究。这部分研究的目的是加深我们对多氯烷烃构象的了解，并获得根据烷烃链上残留氯的数量和立体化学来控制分子形状(构象)的预测能力。最后，我们将使用UCI马丁实验室目前正在开发的尖端固态核磁共振方法来研究合成产生的氯磺脂。我们将使用可变角度旋转(VAS)和切换角度旋转(SAS)等实验来了解这些脂分子在生理相关(散装)条件下的动力学。这项建议中的研究的长期影响将包括为多氯天然产物的立体选择性合成提供更有效的战略，以及更好地了解多氯代烷的反应性。我们还将从控制分子形状的强大新策略中受益，分子形状与功能密切相关。最后，这项研究可能开始阐明膜设计中的一种进化转向，这种转向导致了许多淡水藻类以氯硫脂为基础的细胞膜。

DESCRIPTION (provided by applicant): Nature makes extensive use of chlorine in biosynthesis; to date, over 2000 chlorinated natural products have been identified. Many of these chlorinated secondary metabolites display potent and varied biological activities, but are available from natural sources in only minute quantities. The significant question as to what advantage is conferred upon these compounds by the presence of the chlorine atom remains to be answered. The ability to answer this question is dependent upon effective strategies for the synthesis of chlorinated compounds, and the current level of sophistication in this field is low. The chlorosulfolipids, a family of stereochemically complex alkanes that display numerous chlorine-bearing stereogenic centers, represent one particularly intriguing class of polychlorinated molecules. Certain chlorosulfolipids have been established as causative agents of Diarrhetic Shellfish Poisoning when people have consumed tainted mussels, and others are the exclusive polar lipids in the cell and flagellar membranes of many species of freshwater algae. That these compounds, which bear two polar sulfate groups at opposite ends of the alkane chain, are major components of stable membranes is truly intriguing. It is thought that these compounds could be much more widespread than originally expected, and might be pervasive among algal species. The relative and absolute stereochemistry has only been established for the mussel-derived lipids. To date, few studies toward the synthesis of these challenging targets, or investigations into their conformational behavior, or their bulk or membrane properties, have been reported. The cell and flagellar membranes of the alga Ochromonas danica are largely composed of chlorosulfolipids and contain essentially no phospholipids; these polychlorinated natural products have been found in numerous freshwater algae species. We propose to elucidate the relative and absolute stereochemistry of the major chlorosulfolipid from O. danica by NMR methods. We will then verify the stereochemical assignment by synthesis. These endeavors have already met with substantial success. An enantioselective route to this lipid target will be developed, and it will also be adapted to the first synthesis of enantioenriched chlorosulfolipid mussel toxin. We will revisit the related polychlorinated natural product malhamensilipin A, and determine its stereochemistry by spectroscopic methods, and confirm these results by synthesis. We will also reisolate and determine the structure of several of the less chlorinated O. danica lipids and synthesize representative members. The solution conformations of the chlorosulfolipids synthesized will be studied using NMR spectroscopy and with computational modeling. The goal of this portion of the research is to further our understanding of the conformations of polychlorinated alkanes, and to garner a predictive ability to control molecular shape (conformation) according to the number and stereochemistry of chlorine residues along an alkane chain. Finally, we will study the chlorosulfolipids generated by synthesis using cutting edge solid-state NMR methods currently in development in the Martin lab at UCI. We will use variable angle spinning (VAS) and switched angle spinning (SAS) experiments, among others, to learn about the dynamics of these lipid molecules in physiologically relevant (bulk) conditions. The long-term impact of the research in this proposal will include the availability of more effective strategies for the stereoselective synthesis of polychlorinated natural products, and a greater understanding of the reactivity of polychlorinated alkanes. We will also benefit from powerful new strategies for the control of molecular shape, which is intimately tied to function. Finally, this research could begin to shed light on an evolutionary diversion in membrane design that resulted in the chlorosulfolipid-based cell membranes of many freshwater algae.