Pergamon Tetrahedron Letters 40 (1999) 5779-5782 TETRAHEDRON LETTERS A Short Enantiodivergent Synthesis of D-Erythro and L-Threo Sphingosine Noureddine Khiar*, Kamaljit Singht, Mercedes Garda and Manuel Martin-Lomas*. Grupo de CarbohMr~ttos. Instituto de hwestigaciones Quimicas. C.S.I.C., el. Am~rico Vespucio. s/n., Isla de la Cartuja. 41092 Sevilla. Spain Received 13 April 1999; accepted 3 June 1999 ABSTRACT:A new, short (6 steps) and efficientenantiodivergent route to both D-erythro and L threo- sphingosineI and II is disclosed.The high diastereoselection( 100%de) reached in the creationof the C- 3 stereocenterrelies on the use of a sulfoxideas chiral controlling agent in the reduction of the common precursor [3-ketosulfoxide3. The desiredE-alkenepf sphingosines has beenconstructedby the Schlosser modificationof the Wittigreactionbetweenthe aldehyde8 and the phosphonitm salt 9. The relmrted methodologycan easily be extendedto the synthesisof a large number of opticallypuresyn and anti aminoalcoholsstartingfromcommercially availableaminoacids. © 1999ElsevierScience Ltd. All rightsreserved. The receptor mediated enzymatic cleavage of membrane lipids to generate intracellular second messengers is a crucial biological event that has been firmly established in recent years.1 In this connection, the generation of second messengers from inositol-containingglycolipids has been proposed as a general pathway of intracellular signal transduction. 2 The molecular basis of this new pathway of intracellular signaling remains, however, very poorly understood and quite a number of basic chemical and biological aspects have yet to be discovered. We are presently engaged in synthetic and structural studies in this area dealing with both the putative glycan mediators and the corresponding glycolipid precursors) These glycolipids may contain either a diacyl glycerol moiety or a ceramide as a lipophilic region, and both of them behave in turn as an intracellular second messenger. 1,2 The long chain base component of the ceramide moiety, D-erythro sphingosine, has been found itself to be a potent and specific inhibitor of protein kinase C and plays therefore a pivotal role in signal transduction. 4 As a part of our studies in this area) we now report a new, short, highly diastereoselective and enantioselective synthesis of D-erythro and L-threo sphingosine. Because of its biological importance sphingosine has been a long standing synthetic target and a number of syntheses have recently appeared. 5 Our synthetic approach to D-erythro, L-threo sphingosine starts from a common synthetic precursor and uses a sulfoxide as a chirality controlling agent for the construction of both epimers at C-3 in a predictable manner. NH2 _NH2 H~C13H27 H~13H27.; OH OH (2S.3R,4E)-D-erythro sphingosineI (2S.3S,4E)-L-threo sphingosine II Figure 1 Our synthetic approach is shown in scheme 1. Starting from L-serine, three high yielding synthetic manipulations led to the protected serine methyl ester 1.7 Condensation of 1 with 2 equivalents of the carbanion of (R )-(+)-methyl p-tolyl sulfoxide 28 gave the common precursor [3-ketosulfoxide 3 in 70% yield. The diastereoselective reduction of compound 3 by means of DIBALH or DIBALH in the presence of ZnCI29 constitutes the key step in the synthetic sequence. A question may be raised, as to whether the chiral secondary amine protected with a bulky Boc group (o~ to the prochiral ketone) or the chiral sulfinylfunctionalityin compound 3, will control the stereochemical outcome of the reduction reaction (the 2 factors may be expected to operate in opposite directions). 10 0040-4039/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved, PII: S0040.-4039(99)01112-0