Enantioselective Synthesis of Homosphingosine Derivatives from l-Aspartic Acid

Abstract

The sterically demanding 9-phenylfluorenyl N-protection of a number of amino acids allows the formation of amino acid derived β-ketophosphonate reagents and their Horner-Wadsworth-Emmons olefination. In an attempt to develop a synthesis of d-erythro-homosphingosine in enantiopure form, we have shown that the reactivity of the intermediates is influenced by the distinctive conformational requirements of this large protecting group.

Key words

diastereoselectivity - enantioselectivity - sphingosine - ceramide

References

• For reviews on sphingolipids, see:
• 1a Brunner M. Koskinen AMP. Curr. Org. Chem.  2004,  8:  1629 
• 1b Koskinen PM. Koskinen AMP. Methods Enzymol.  1999,  311:  458 
• 1c Koskinen PM. Koskinen AMP. Synthesis  1998,  1075 
• 2a Pruett ST. Bushnev AA. Hagedorn K. Adiga M. Haynes CA. Sullards MC. Liotta DC. Merrill AH. J. Lipid Res.  2008,  49:  1621 
• 2b Smith WL. Merrill AH. J. Biol. Chem.  2002,  277:  25841 
• 3a Koskinen AMP. Krische MJ. Synlett  1990,  665 
• 3b Koskinen PM. Koskinen AMP. Methods Enzymol.  1999,  311:  458 
• 4 Koskinen AMP. Kallatsa OA. Tetrahedron  2003,  59:  6947 
• 5 Pelšs A. Kumpulainen ETT. Koskinen AMP. J. Org. Chem.  2009,  74:  7598 
• 6a Christie BD. Rapoport H. J. Org. Chem.  , 
• 6b Lubell WD. Rapoport H. J. Am. Chem. Soc.  1987,  109:  236 
• 6c Koskinen AMP. Rapoport H. J. Org. Chem.  1989,  54:  1859 
• 6d Koskinen AMP. Schwerdtfeger J. Edmonds M. Tetrahedron Lett.  1997,  38:  5399 
• 7 Koskinen AMP. Koskinen PM. Synlett  1993,  501 
• 8a Shikata K. Niiro H. Azuma H. Tachibana T. Ogino K. Bioorg. Med. Chem. Lett.  2003,  13:  613 
• 8b Shikata K. Niiro H. Azuma H. Ogino K. Tachibana T. Bioorg. Med. Chem.  2003,  11:  2723 
• 8c De Jonghe S. Lamote I. Venkataraman K. Boldin SA. Hillaert U. Rozenski J. Hendrix C. Busson R. De Keukeleire D. Van Calenbergh S. Futerman AH. Herdewijn P. J. Org. Chem.  2002,  67:  988 
• 8d Tarnowski A. Retz O. Bär T. Schmidt RR. Eur. J. Org. Chem.  2005,  1129 
• 9 Koskinen AMP. Koskinen PM. Tetrahedron Lett.  1993,  34:  6765 
• 10 Jamison TF. Rapoport H. Org. Synth.  1993,  71:  226 
• 11 Compound 10 has been reported in the literature, however, without data, see: Kaul R. Brouillette Y. Sajjadi Z. Hansford KA. Lubell WD. J. Org. Chem.  2004,  69:  6131 
• 13 Lee J.-M. Lim H.-S. Chung S.-K. Tetrahedron: Asymmetry  2002,  13:  343 
• 14 Gosselin F. Lubell WD. J. Org. Chem.  1998,  63:  7463 
• 15 Lubell WD. Jamison TF. Rapoport H. J. Org. Chem.  1990,  55:  3511 
• 16 Kovacs J. Kovacs HN. Ballina R. J. Am. Chem. Soc.  1963,  85:  1839 
• 17 Itaya T. Shimizu S. Nakagawa S. Morisue M. Chem. Pharm. Bull.  1994,  42:  1927 
• 18 Garrard EA. Borman EC. Cook BN. Pike EJ. Alberg DG. Org. Lett.  2000,  2:  3639 

12

X-ray crystallography was performed at the University of Jyväskylä with a Nonius Kappa CCD diffractometer. Crystal data for 10: Orthorhombic; P2₁2₁2₁ (No. 19); a = 9.0028 (3) Å, b = 9.4284 (3) Å, c = 25.0491 (8) Å; R1 = 0.0453, wR2 = 0.0847 (I > 2σ). 12: Monoclinic; P2₁ (No. 4); a = 9.8177 (7) Å, b = 8.8352 (5) Å, c = 11.3458 (8) Å, β = 92.366 (3)˚; R1 = 0.0490, wR2 = 0.0955 (I > 2σ). 6a: Orthorhombic; P2₁2₁2₁ (No. 19); a = 14.9329 (6) Å, b = 15.1590 (5) Å, c = 17.2261 (5) Å; R1 = 0.0573, wR2 = 0.0936 (I > 2σ). CCDC 255363-255365 contain the supplementary crystallographic data (excluding structure factors) for this paper. These data can be obtained online free of charge or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ UK [fax: [phone]; or [e-mail]].

19

The stereochemistry was assigned based on analogy with previous reductions, as well as on the coupling constants for similar compounds; see, for example, ref. 8d.