Stereocontrolled Introduction of the Quaternary Stereogenic Centre in Lyngbyatoxin A

In our study of the enantioselective total synthesis of Lyngbyatoxin A, we have focused first on the stereocontrolled introduction of the quaternary stereogenic centre. The key step in the synthesis involves an enantiospecific Lewis-acid mediated rearrangement of chiral vinyl epoxides, a methodology developed by Jung et al(1). For model studies, the requisite vinyl epoxides were obtained by Sharpless asymmetric epoxidation of the corresponding allylic alcohols, followed by a TPAP oxidation and a Wittig reaction. It was observed that the choice of protective group on the indole nitrogen in had a major impact on the regioselectivity of the rearrangement reaction. Boron trifluoride mediated rearrangement of the allyl and benzyl protected indoles provided only the undesired product (the methyl ketone) resulting from vinyl-migration, whereas the tosyl protected indole gave products resulting from hydrogen and indole migration respectively, in a 3:2 relationship; the desired aldehyde was thus the minor product. In order to benefit from the regioselectivity of the benzyl protected indole, we synthesised the isomeric vinyl epoxide. To our satisfaction the only product from the rearrangement reaction was the desired aldehyde resulting from vinyl migration. The aldehyde functionality then serves as a convenient “handle” for further elaboration. 1) Jung, M. E.; D'Amico, D. C. J. Am. Chem. Soc. 1995, 117, 7379-7388.