The first example of a reagent-controlled enantioselective Pictet-Spengler reaction is demonstrated. Using diisopinocampheylchloroborane as a chiral Lewis acid catalyst, the Pictet-Spengler reaction of N(b)-hydroxytryptamine with aldehydes gave the corresponding 2-hydroxytetrahydro-beta-carbolines in up to 90% ee. The enantioselective Pictet-Spengler reaction catalyzed by chiral binaphthol-derived Brønsted acid-assisted Lewis acids, with up to 91% ee, is also demonstrated.
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.
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