Synthesis of Sphingosine‐1‐phosphonate and Homosphingosine‐1‐phosphonate

Abstract

In the first approach to homosphingosine‐1‐phosphonate, D‐glucofuranose was selectively deoxygenated at C‐5. Bond cleavage between C‐1 and C‐2 afforded a 5‐deoxy‐D‐threo‐pentose intermediate. (E)‐Selective Wittig reaction with a C14‐chain gave a C19‐intermediate, which was readily transformed into homosphingosine. Formation of a cyclic urethane containing the 3‐amino and the 4‐hydroxy group of the C19‐intermediate permitted regioselective introduction of the phosphonate group at C‐1, thus affording the target molecule after deprotection. In a second and shorter route, C18‐sphingosine was converted to a cyclic urethane containing the 2‐amino and the 3‐hydroxy group of the C18‐chain. C1‐Chain extension by a hydroxymethyl group by introduction of cyanide led to the same C19 cyclic urethane as obtained in the first route. Similarly, the C18 cyclic urethane led to the other target molecule, namely sphingosine‐1‐phosphonate. The third and shortest route to homosphingosine‐1‐phosphonate could be based on regioselective 1‐O‐tosylation of 1,2,3‐(trihydroxy)octadec‐4‐ene. Transformation into a 1,2‐epoxide, then combination of C1‐chain extension and introduction of a phosphonate group with methylphosphonate as reagent, and finally azide introduction, led after functional group liberation to the target molecule. As shown, also truncated derivatives are readily accessible by this route. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Chemical Synthesis of a Very Long-Chain Fatty Acid, Hexacosanoic Acid (C26:0), and the Ceramide Containing Hexacosanoic Acid

“…The amide group of 12 was reduced with LiBH4 to give alcohol 13 (59% yield from 10) (16). The azide group of 13 was reduced by the Staudinger reaction to give amine 14 in 82% yield (17,18). Spectral data of known compounds 9-14 were identical with those reported.…”

Chemical Tools to Investigate Sphingolipid Metabolism and Functions

“…As mentioned above, S1P is a SL metabolite formed by the action of SphK that has emerged as a potent bioactive agent for its ability to control numerous aspects of cell physiology both at intra‐ and extracellular levels 196. Metabolically stable surrogates of Sph and dihydro Sph of different chain lengths, designed by replacement of the phosphate group by a phosphonate,197–199 or a phosphoramide moiety200 have been described in the literature (Figure 32). No biological activity has been reported for these compounds, except for the Sph phosphonate analogue (Figure 32), which is a highly toxic competitive inhibitor of S1P lyase ( K i 5 μ M , determined from a tritium‐labeled compound),201 and the 2‐vinyl Sph analogue (Figure 32, no stereochemistry is defined), which is also a potent inhibitor of S1P lyase (IC 50 2.4 μ M ) 202…”

Asymmetric synthesis of $\boldsymbol{\gamma}$ -aminophosphonates: The bio-isosteric analogs of $\boldsymbol{\gamma}$ -aminobutyric acid

“…The TBDMS group was removed and the resulting hydroxyl was bromi-nated using LiBr after mesylation to furnish bromo intermediate 119 which was phosphonated using Arbuzov reaction followed by hydrolysis to obtain the γ -aminophosphonic acid derivative/homosphingosine-1-phosphonate 120 (scheme 25). 50 An alternative approach involving nucleophilic attack for formation of C-N bond involves an S 2 N substitution mechanism. Two reports using this route to γ -aminophosphonylation have been published.…”