Synthesis of 8-epi-l-swainsonine, related C6 alkylated derivatives and their α-l-rhamnosidase inhibition

l-Swainsonine (l-SWN) is a known inhibitor of α-l-rhamnosidase (IC50 0.13 µM), but its isomers have not been thoroughly investigated. In the present study, we focused on the 8-epi-l-SWN (6) and its analogues 9a–c and synthesized them from chiral lactam 1 as a common intermediate. 8-epi-l-SWN (6) showed moderate inhibition (IC50 87 µM), but this was about 670-fold lower than l-SWN. The introduction of a (6S)-C-methyl group into 6 significantly reduced its α-l-rhamnosidase inhibitory activity (9b: IC50 329 μM). On the other hand, among the analogues 9a–c, (6R)-C-benzyl 8-epi-l-SWN 9c was approximately 8.7 times better than (6R)-C-methyl-8-epi-l-SWN 9a. These results suggest that the α-l-rhamnosidase inhibitory activity may be further enhanced by introducing a long or bulky substituent at the C6 position of l-SWN.