Abstract
LS-threo-Dihydrosphingosine, an antineoplastic and antipsoriatic drug, has been synthesized by the Henri reaction of hexadecanal and 2-nitroethanol followed by catalytic hydrogenation of the dl-threo-2-nitro-1,3-octadecanediol and resolution of the racemic dl-threo-dihydrosphingosine. Selection of solvents for recrystallization of mixtures of dl-threo and erythro diastereoisomers proved to be of critical importance for the 100-gram scale preparation of the target compound.
Highlights
(2S,3S)-2-Amino-1,3-octadecanediol (L-threo-dihydrosphingosine or safingol, CAS # 15639-506) (1), an antineoplastic and antipsoriatic drug,[1] has been extensively studied for its role in cell regulation, signal transduction,[2] and inhibition of protein kinase C.3
The two-step enantioselective nitroaldol condensation (Henri reaction) of hexadecanal (2) with nitroethanol (3), followed by hydrogenation to Ls-threo-dihydrosphingosine;[4] the total synthesis departing from 2(Z)-2-buten-1,4-diol;[5] the eight-step procedure starting from palmytoyl chloride having the asymmetric borane reduction of an α-oxoketoxime trityl ether as a key step;[6] and the diastereoselective synthesis via addition of N-hexyl magnesium bromide to the chiral 2,2-dimethylpropionic acid 4(S)-formyl-2,2-dimethyloxazolidin-3-yl ester,[7] are procedures belonging to the first category
Based on preliminary experiments, involving optimization of the catalyst and solvent, we have developed a simple three-step procedure for the 100-g scale production of safingol starting from commercially available hexadecanal, following the chemistry indicated in Scheme 1
Summary
(2S,3S)-2-Amino-1,3-octadecanediol (L-threo-dihydrosphingosine or safingol, CAS # 15639-506) (1), an antineoplastic and antipsoriatic drug,[1] has been extensively studied for its role in cell regulation, signal transduction,[2] and inhibition of protein kinase C.3. The synthesis of the threo 2-nitro-octadecane-1,3-diol by nitroaldol condensation, reduction of the nitroaldol to racemic dihydrosphingosine and subsequent optical resolution[8,9,10] illustrate the second type of syntheses. Diastereoselective methods described for the nitroaldol condensation,[15,16,17] usually do not apply to long chain aldehydes.[18] Methods based on stereoselective syntheses, successful on small scale, often failed to reproduce the expected purity on larger scale.[19] the reduction of the nitroaldol to the racemic mixture (1+6) followed by resolution has been described earlier.[8,10]
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