A concise synthetic method towards (−)-swainsonine and its 8-epimer by using palladium-catalyzed asymmetric hydroamination of alkoxyallene as the key strategy

Pd-Catalyzed Hydroamination of Alkoxyallenes with Azole Heterocycles: Examples and Mechanistic Proposal

“… 1 These reactive structures have been used as key intermediates in the synthesis of biologically active heterocycles and natural products. 2 Examples from our group include the stereoselective synthesis of the natural product l -baikiain 2b and a formal total synthesis of the alkaloid quinolizidine 233A. 2c , 3 To follow up on these results, we envisioned that also aromatic nitrogen nucleophiles, so-called azole heterocycles, would be of particular interest as reactants in such hydroaminations.…”

Total Synthesis of ( + )-Swainsonine, (–)- Swainsonine, ( + )-8-epi-Swainsonine and ( + )- Dideoxy-Imino-Lyxitol by an Organocatalyzed Aldolization/Reductive Amination Sequence

“…After completing the synthesis of both ( + )-swainsonine ( 1) and ( + )-8-epi-swainsonine (18), further efforts were made in order to increase the efficiency of both syntheses, by introducing the already oxygenated fragment, instead of the allyl group, to aldehyde 3: in addition to improving the overall redoxeconomy of the synthesis, the addition of the modified Grignard reagent 19 was expected to be diastereoselective, obviating the separation of isomers. Indeed, the reaction of 3 with 19 produced the expected adduct 20, as a single stereoisomer in 87% yield (Figure 5).…”

“…In addition, the addition of allyl magnesium bromide can proceed with allylic rearrangement (which may decrease stereoselectivity of the reaction), which is not possible for 19. Finally, hydrogenation of 20 under acidic conditions led to one pot total deprotection and reductive amination to afford ( + )-8-epi-swainsonine (18) in excellent yield (94%), thus shortening the first-generation synthesis by as much as 4 steps.…”

“…The synthesis of ( + )-swainsonine (1) required the epimerization of the secondary alcohol 20, which was accomplished under Mitsunobu conditions (Figure 6), as previously described for 9-anti. Surprisingly, the hydrolysis/hydrogenation protocol which was successfully applied for the synthesis of 8-epi-swainsonine (18), was not useful for the diastereoisomer 21. An attempt to hydrolyze the acetal functionality in 21 by treatment with 2 M HCl resulted in the formation of dimeric compound 22; this transformation proceeds via an interesting sequence involving the Mannich reaction of the swainsoninederived iminium ion with the corresponding enamine, as previously described by Nagasawa, Asakawa and collaborators.…”

“…[28][29][30][31][32] The main advantages of our approach include good to excellent reagent-controlled stereoselectivity in aldol addition, as well as substrate-controlled stereoselectivity in reductive amination thus allowing preparation of both natural and unnatural iminosugar stereoisomers. Previously, we reported a concise synthesis of ( + )-swainsonine (1) and ( + )-8-epi-swainsonine (18) based on this synthetic concept 16 ; herein, we provide a full account on this research.…”