Issue in Honor of Prof. Alexandru T. Balaban ARKIVOC 2005 (x) 285-291
that lead directly to the desired products; (ii) non-stereoselective methods that result in racemic mixtures, which are subsequently subjected to resolution. All these methods were described at milligram-scale and no attempts were made previously to produce safingol at a larger scale. 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 (eight steps);5 the eight-step procedure starting from palmytoyl chloride having the asymmetric borane reduction of an a-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. The synthesis of the threo 2-nitro-octadecane-1,3-diol by nitroaldol condensation, reduction of the nitroaldol to racemic dihydrosphingosine and subsequent optical resolution8-10 illustrate the second type of syntheses. The most appealing procedure is the enantioselective nitroaldol condensation/reduction. An optically active BINOLlanthanium complex was the catalyst used to induce stereoselectivity in the condensation of hexadecanal with nitroethanol. However, the preparation of the catalyst was a three-step synthesis,4,11 which raises a series of technological problems, such as continuous cooling for more than 160 hours at temperatures below –40 °C. Although the amount of catalyst required for the reaction is low (10 mol %), the starting materials required for its preparation are quite expensive. Moreover, the synthesis of the chiral catalyst and its ligand are restricted by a recent patent.12
Although a previously described diastereoselective synthesis7 reported an overall yield of the reaction of ca. 30 % and seems appealing and elegant, the starting oxazolidine-type synthetic auxiliary had to be obtained by a multi-step synthesis, which makes it unsuitable for large-scale manufacture.13,14
Non-stereoselective syntheses are mostly alternatives to the Henry nitroaldol condensation (Scheme 1). This classic method is performed under diverse catalytic conditions and has been frequently reviewed.15,16 The synthesis of 2-nitrooctadecane-1,3-diol starting from 2 and 3 has been described earlier, for both diasteromers and their mixtures.8-10 The mixture of nitrodiol diastereomers (4 + 5 and 7 + 9) was recrystallized from various solvents to give one single isomer. Diastereoselective methods described for the nitroaldol condensation,15-17 usually do not apply to long chain aldehydes.18 Methods based on stereoselective syntheses, although successful on small scale, often failed to reproduce the expected purity on larger scale.19 Finally, the reduction of the nitroaldol to the racemic mixture (1+6) followed by resolution has been described earlier.8,10
ISSN 1424-6376 Page 286 ©ARKAT USA, Inc
