Practical Synthesis of threo-(S,2S)- and erythro-(1R,2S)-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) from l-Serine

Abstract

Both L-threo and D-erythro-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) were synthesized stereoselectively from L-serine.1-Phenyl-2-acylamino-3-morpholino-1-propanol (1 and 2) was developed as an inhibitor of sphingolipid synthesis by Radin and Inokuchi, and is expected to be a useful compound for treating tumors. 1 Very recently, 1 was reported to be effective in inhibiting the growth of malaria parasite by inhibiting sphingomyelinase. 2 Although some structure-activity relationships of 1 and 2, with regard to the inhibition of sphingolipid synthesis, have been reported, the effect of the stereo centers on this activity is still unclear. 3 We are interested in further modification of these compounds and decided to develop a practical route for the synthesis of this type of compound in a stereo-defined manner. Scheme 1As a chiral starting material, we chose Garner aldehyde (4), since both enantiomers of the aldehyde are readily available from D-and L-serine by simple four-step procedures, 4 and because the stereoselective addition of alkyl and aryl metals to 4 has been reported previously. 5 Therefore, we examined the nucleophilic addition of phenyl metal reagents to 4 in the absence and presence of metal salts. However, we could not achieve a high level of selectivity (syn:anti=1:<4, Table 1), 6 and separation of the isomers 3 by column chromatography was difficult.Next, we turned our attention to the stereoselective reduction of ketone 5, which was obtained in 94% yield from the mixture of syn-and anti-3 by Dess-Martin oxidation. 7 Reduction of ketone 5 by Red-Al and borohydride reagents gave syn-3 as a major diastereomer (Table 2). Among these reagents, NaBH 4 and nBu 4 NBH 4 gave syn-3 with relatively high selectivity (syn/anti= ~11/ 1). Reduction with K-and L-Selectride proceeded at a lower temperature, and the highest syn selectivity (syn/anti=23/1) was observed in reduction using K-Selectride. 8 In contrast to the above results, high anti selectivity (syn/anti=1/40) was observed when ketone 5 was reduced by DIBAH in THF at 0 °C in quantitative yield. 8 Optically pure syn-and anti-3 were obtained by simple recrystallization from petroleum ether. Therefore, both diastereomers of 3 were synthesized in a highly selective manner.

A concise and simple synthesis of 1-hydroxy-phenethylamine derivatives: Formal synthesis of naturally occurring norephedrine, virolin and 3-hydroxy-2-phosphonylmethoxypropyl adenine

“…Reduction of 2a with LiAlH 4 in THF furnished the syn alcohol 1a exclusively without a trace of any anti isomer 1a 1 (scheme 1). 5 Due to the presence of rotamers the NMR spectra of the compounds described showed complicated patterns which has already been explained by Nishida et al 5 in details.…”

Development of Environmentally Benign Organometallic Catalysis for Drug Discovery and Its Application

“…To overcome these problems, modern synthetic methods for quinoline using a transition metal-catalyst, such as ruthenium, palladium, rhodium, iron, copper, manganese or cobalt, have been investigated. In our continuing study of the RCM reaction and our approaches to the synthesis of novel antimalarial agents, 87) we developed a novel method for synthesizing substituted 1,2-dihydroquinolines using ene-ene metathesis and silyl or alkyl enol ether-ene metathesis, which proceeds under mild conditions and gives an excellent yield. This process leads to spontaneous air oxidation to quinoline after deprotection.…”

“…Formal synthesis of chloroquine, chinine, PPMP-quinine hybrid 21) : Encouraged by these results, we applied this novel method to the synthesis of key intermediates of antimalarial agents, such as quinine, [88][89][90][91][92] chloroquine, 93,94) and PPMP-quinine hybrid, 87) which are shown in Chart 7.…”

Preparation of nitrogen-containing heterocycles using ring-closing metathesis (RCM) and its application to natural product synthesis

“…1,1 0 -(2,2 0 -Bisacylamino)binaphthalenes (23)(24)(25) were synthesized by the reaction of chiral binaphthyldiamine with mixed anhydride of the corresponding acid, which then treated with ruthenium-carbene catalyst (B) under various conditions (Table 4).…”

“…Encouraged by these results, we applied this novel method to the synthesis of key intermediates of anti-malarial agents, such as quinine [25], chloroquine [26], and PPMP-quinine hybrid [24], which are shown in Scheme 6.…”