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.

Public Health Relevance

The proposed research is relevant to public health because of the importance of organohalogen chemistry to drug discovery. Though the current halogen of choice for pharmaceutical development is fluorine, the use of chlorine in drug compounds has been increasing. The strategies for stereoselective chlorination and the improved understanding of the properties of chlorinated molecules advanced in this proposal will therefore benefit pharmaceutical research. The chlorosulfolipids, which are the targets of the described synthesis efforts, are the causative agents of Diarrhetic Shellfish Poisoning (DSP) when humans ingest mussels containing these natural products. Access to enantioenriched synthetic mussel toxin might aid in the discovery of the original source and biosynthesis of these compounds;this knowledge could aid in the prevention of DSP outbreaks. Finally, the chlorosulfolipids derived from algae might be a truly important evolutionary diversion in membrane design;although the direct link to public health is not completely clear, this important research area will likely have implications much beyond our current proposal.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Schools of Arts and Sciences
United States
Zip Code
Chung, Won-jin; Vanderwal, Christopher D (2016) Stereoselective Halogenation in Natural Product Synthesis. Angew Chem Int Ed Engl 55:4396-434
White, Alexander R; Duggan, Brendan M; Tsai, Shiou-Chuan et al. (2016) The Alga Ochromonas danica Produces Bromosulfolipids. Org Lett 18:1124-7
Quinn, Ryan K; Könst, Zef A; Michalak, Sharon E et al. (2016) Site-Selective Aliphatic C-H Chlorination Using N-Chloroamides Enables a Synthesis of Chlorolissoclimide. J Am Chem Soc 138:696-702
Daub, Mary Elisabeth; Prudhomme, Jacques; Le Roch, Karine et al. (2015) Synthesis and potent antimalarial activity of kalihinol B. J Am Chem Soc 137:4912-5
Tartakoff, Samuel S; Vanderwal, Christopher D (2014) A synthesis of the ABC tricyclic core of the clionastatins serves to corroborate their proposed structures. Org Lett 16:1458-61
Chung, Won-Jin; Vanderwal, Christopher D (2014) Approaches to the chemical synthesis of the chlorosulfolipids. Acc Chem Res 47:718-28
Vogel, Carl V; Pietraszkiewicz, Halina; Sabry, Omar M et al. (2014) Enantioselective divergent syntheses of several polyhalogenated Plocamium monoterpenes and evaluation of their selectivity for solid tumors. Angew Chem Int Ed Engl 53:12205-9
Chung, Won-jin; Carlson, Joseph S; Vanderwal, Christopher D (2014) General approach to the synthesis of the chlorosulfolipids danicalipin A, mytilipin A, and malhamensilipin A in enantioenriched form. J Org Chem 79:2226-41
Chung, Won-Jin; Carlson, Joseph S; Bedke, D Karl et al. (2013) A synthesis of the chlorosulfolipid mytilipin A via a longest linear sequence of seven steps. Angew Chem Int Ed Engl 52:10052-5
Bedke, D Karl; Vanderwal, Christopher D (2011) Chlorosulfolipids: structure, synthesis, and biological relevance. Nat Prod Rep 28:15-25