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Title: Asymmetric synthesis of Crispine A: constructing tetrahydroisoquinoline scaffolds using pummerer cyclizations

Author
item ROTTE, SATEESH CHANDRA - University Of Mississippi
item CHITTIBOYINA, AMAR - University Of Mississippi
item KHAN, IKHLAS - University Of Mississippi

Submitted to: European Journal of Organic Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2013
Publication Date: 10/1/2013
Citation: Rotte, S.K., Chittiboyina, A.G., Khan, I.A. 2013. Asymmetric synthesis of Crispine A: constructing tetrahydroisoquinoline scaffolds using pummerer cyclizations. European Journal of Organic Chemistry. 28:6355-6360.

Interpretive Summary: Crispine A is a naturally occurring tetrahydroisoquinoline alkaloid isolated from Carduus crispus. Traditionally, C. crispus has been used in Chinese folk medicine for the treatment of colds, stomach-ache and rheumatism. Moreover; some C. crispus extracts have been reported to show significant cytotoxic properties against SKOV3, HeLa and KB human cancer cell lines. We wished to test it against the NCI 60 different cell line panel. We have demonstrated a concise (6 steps), total synthesis of both enantiomers of crispine A by employing Keck asymmetric allylation and Pummerer rearrangement as crucial steps. This led to the synthesis tetrahydroisoquinoline core in high yield and paves way for the synthesis of various structurally similar alkaloids in an efficient manner, to investigate their intriguing biological properties. Neither compound showed any promising cytotoxicity in any cell line in the preliminary screening at single dose.

Technical Abstract: For the first time, a concise, linear and protecting group-free stereoselective synthesis of both enantiomers of crispine A have been achieved in six steps with an overall yield of less than or equal to 20%,starting from commercially available veratraldehyde. Asymmetric Keck allylation and trifluoroacetic anhydride mediated Pummerer rearrangement were the key transformations used to construct the tetrahydroisoquinoline core.