66(P-47) Synthetic Studies on (+)-Lysergic Acid
Details
Lysergic acid, which possesses the common core skeleton of various ergot alkaloids, was isolated in 1934 and its structure was determined in 1954. Because of its interesting biological activities and its application to clinical purposes, lysergic acid and the related compounds have drawn much attention of synthetic chemist for a long time. Since the first total synthesis by Woodward, many synthetic routes to racemic lysergic acid have been developed. However, total synthesis of optically active lysergic acid has not yet been reported. In this paper, we describe a route for the synthesis of methyl lysergate featuring (1) conjugated addition of 2,6-dibromoaryllithium to optically active nitroolefin, and (2) Pd-mediated double cyclization, i.e. intramolecular amination and Heck reaction. First, synthesis of optically active nitroolefin was investigated. Easily accessible 1,3-diol was desymmetrized using lipase PS to give monoacetate (6). A nitrogen function was introduced by means of Mitsunobu reaction to give 8, whose enantiomeric excess was determined to be 88% by HPLC analysis. The terminal olefin was cleaved and the resulting aminoaldehyde was transformed to tetrahyrdropyridine derivative (12). Next, diastereoselective allylation to the acyliminium ion generated from 12 was investigated. Excellent selectivity was observed when acetyl or pivaloyl group was used for the protection of the hydroxy group. The high selectivity implies steric bias due to a neighboring group participation of the acyl groups to the iminium ion moiety (Table 1 and Figure 1). After cleavage of the terminal olefin, condensation of the resultant aldehyde with nitromethane gave nitroolefin (15). Coupling reaction of 2,6-dibromophenyllithium and the nitroolefin proceeded smoothly to give the adduct (16), which was transformed to the double cyclization precursor (17). After extensive investigation of the crucial double cyclization, the desired 4-membered skeleton (18) was formed in good yield. Having successfully constructed the desired framework, the requisite functional group manipulations were executed to furnish methyl paspalate (21), a structural isomer of methyl lysergate. Finally, heating of 21 with silica gel, isomerization of the olefin occurred to give methyl lysergate (22). Since transformation of methyl lysergate to lysergic acid has already been reported by Woodward, we have achieved a formal total synthesis of lysergic acid. Currently, we are undertaking further optimization of the established route.
