Evaluation of two approaches for the synthesis of functional sphingosines with mirror symmetric order of reduction and metathesis steps.

Two mirror-symmetric approaches for the chemical synthesis of sphingosines 1via olefin metathesis can be distinguished. The widely used approach D is based on the head group with an allylic alcohol moiety and leads to the formation of sphingosines in moderate yields. An alternative pathway E, involving a head group with a vinyl ketone moiety, has been described but is currently not used, although the metathesis of such olefins occurs with high yields of cross-coupling products. Based on a systematic comparison, we show that the new pathway E provides up to 3.4-fold higher yield and is a practically superior strategy compared to the currently used pathway D at the metathesis step. In pathway D, we observed allylic isomerization of the starting hydroxyl-containing head group 3a to the saturated ketone 17 on a Grubbs 2nd generation catalyst. On the one hand, this isomerization reduces the efficiency of metathesis. On the other hand, the Grubbs catalyst was found to be effective for the isomerization of allylic alcohols to ketones in the absence of a base. The second isomerization along route D was detected at the stage of metathesis product formation, where migration of the double bond along the aliphatic chain to the distant π-system occurred. Pathway E is free of the isomerization side reaction. In the final step of sphingosine 1 synthesis, we observed the formation of N-trifluoroacetylsphingosines 24 upon removal of Boc protection with trifluoroacetic acid. The use of HCl eliminates this transacylation reaction.