Total synthesis of naphthoindolizidine alkaloid derivatives

Abstract

The two optical antipodes, (11aS)- and (11aR)-2,3-dimethoxynaphtho[1,2-b] indolizidine (41a and 41b) were synthesized through the pyroglutamate route to confirm the stereospecific synthesis. The amount of racemization for the optical antiopdes was checked in three ways: i) measurement of specific rotation values ($[\alpha]_D$)ii) $^1H$-NMR shift experiment with $Eu(tfc)_3$ iii) HPLC separation of the enantiomers on a chiral column and determined to be 2.4(41a) and 2.2\%(41b), respectively. (11as)-2,3-dimethoxy-6-hydroxymethylnaph-tho[1,2-b]indolizidine (63) which can be used to determine the absolute configuration of C-11a position in natural Vincetene(1) was synthesized from 40a in an optically active form. To introduce the 3``-hydroxy-2``-cis-butenyl side chain at C-6 position, the aldehyde (66) was condensed with acetone to obtain the trans-enone(67) in good yield. The trans-enone was isomerized to cis-enone(68), and subsequent reduction of the two carbonyl groups in 68 by $LiAlH_4$ afforded 69. As a result, diastereomeric mixture (SS+SR) of Vincetene was synthesized from 2,3-dimethoxynaphthalene(11) through 19 steps, and all the spectral data were in agreement with the reported data. The optical properties of the synthesized Vinctene(69) could not be obtained because of the intrinsic unstability of 69.