AK-2285GP_published_mainmanuscript

AK-2285GP_published_mainmanuscript - Issue in Honor of...

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Issue in Honor of Prof. Alain Krief ARKIVOC 2007 (x) 232-244 A convergent approach for the synthesis of fluorinated sphingosine analogues Harriet Teare, a Florian Huguet, a Matthew Tredwell, a Sébastien Thibaudeau, a Sajinder Luthra, b and Véronique Gouverneur a * a University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA (UK) b Hammersmith Imanet Ltd (part of GE Healthcare), Hammersmith Hospital, Du Cane Road, London, UK W12 0NN E-mail: veronique.gouverneur@chem.ox.ac.uk Dedicated to Professor Alain Krief on the occasion of his 65 th birthday Abstract An improved route to a fluorinated analogue of sphingosine has been developed starting from Garner’s aldehyde with two cross-metathesis couplings and an electrophilic fluorodesilylation as the key steps. This approach eliminates the problem of double bond transposition encountered with strategies relying on the nucleophilic fluorinating reagent DAST and supplies the target compound as well as a fluorinated intermediate amenable to functional variations at three sites. Keywords: Allylsilane, fluorine, sphingosine, metathesis Introduction Sphingomyelin 1 , an abundant membrane phospholipid, is metabolized into lipid mediators such as ceramide 2 , sphingosine 3 , and sphingosine-1-phosphate 4 (S1P). The concept that sphingolipid metabolism is an important source of signaling lipids has gained considerable acceptance. 1 The importance of this metabolic pathway is underscored by its impact on cell death, stress responses and animal development in unicellular and multicellular eukaryotes. ISSN 1424-6376 Page 232 © ARKAT-USA, Inc.
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Issue in Honor of Prof. Alain Krief ARKIVOC 2007 (x) 232-244 C 13 H 27 OH O P O NH O C 15 H 31 NMe 3 + O - C 13 H 27 OH OH NH O C 15 H 31 C 13 H 27 OH OH NH 2 C 13 H 27 OH OPO(OH) 2 NH 2 sphingomyelin 1 ceramide 2 sphingosine 3 sphingosine-1-phosphate 4 Figure 1. Signaling lipids derived from sphingomyelin metabolism. One of these metabolites, sphingosine-1-phosphate 4 acts as an extracellular mediator by activating a family of protein-coupled receptors (S1PR1-5). 1 The generality of sphingosine-1- phosphate signaling is supported by recent findings that S1PRs are required for a multitude of physiological processes, including heart and vascular development, angiogenesis, and immune cell trafficking. 2 These remarkable findings on the role of sphingolipids led to the development of numerous protocols for their syntheses. 3 Sphingolipids all feature a common structural motif, which consists of a non-racemic chiral 4,5-unsaturated 2-amino 1,3-diol biosynthetically derived from L-serine. Structural variations occur with the substituents attached to the primary alcohol and the amino group. Metabolites with additional modifications on the main carbon chain have also been identified. Many diversity-oriented approaches have been devised and validated for the synthesis of sphingolipids. However, convergent synthetic routes to sphingolipid analogues are still in demand to further probe the physiological and pathological significance of sphingolipid metabolism. Several groups have prepared fluorosphingosine
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AK-2285GP_published_mainmanuscript - Issue in Honor of...

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