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

Abstract

A tactical combination of either (S)- or (R)-proline catalyzed aldol reaction followed by intramolecular reductive amination enabled the synthesis of a chiral pyrrolidine derivative with 3 contiguous stereocenters in only 2 synthetic steps, starting from achiral precursors. This product, obtainable in both enantiomeric forms, was further exploited as a common intermediate in total syntheses of the biologically active iminosugars: ( + )-swainsonine, (–)-swainsonine, ( + )-8-epi-swainsonine, and ( + )-dideoxy-imino-lyxitol.

(–)-Swainsonine (ent-1, Figure 1) ¹ is a biologically active polyhydroxylated indolizidine iminosugar,^2–4 with high potential for application in pharmacy and medicine, due to its diverse biological activities: swainsonine inhibits Golgi α-mannosidase II,^5–8 exhibits anticancer^9,10 and anti-prion ¹¹ activity and has been tested as a therapeutic option for immunological disorders.^12,13 It has attracted significant attention from the synthetic community, resulting in more than 50 total syntheses.^14–21 Additionally, in order to enhance the biological activity, several structural analogs of (–)-swainsonine (ent-1) have also been synthesized.^22–27 Over the past several years, we have successfully utilized tactical combination of organocatalyzed aldolization and reductive amination as a key step in asymmetric synthesis of several iminosugars.^28–32 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.

Figure 1.

Retrosynthetic analysis of ( + )-swainsonine (1).

Results and Discussion

Our retrosynthetic strategy for the enantioselective synthesis of ( + )-swainsonine (1) is outlined in Figure 1. The piperidine ring in 1 could be constructed by reductive amination from pyrrolidine derivative 2, which in turn could be obtained by organometallic addition to aldehyde 3. Aldehyde 3 might arise from 1,3-dioxane 5, through an epimerization/oxidation sequence (via dioxolane 4). Disconnection of the pyrrolidine ring in compound 5 by reductive amination gives aldol 6—a compound which could be produced enantioselectively by proline-catalyzed aldol addition of 2,2-dimethyl-1,3-dioxan-5-one (7, dioxanone) to amino aldehyde 8.^33–37 As our synthesis starts from achiral precursors, both enantiomers of swainsonine and 8-epi-swainsonine would be available simply by switching from (S)- to (R)-proline as a catalyst in the aldol reaction.

The synthesis started with asymmetric aldol reaction between dioxanone 7 and double-protected amino aldehyde 8 (Figure 2). When (S)-proline was employed as a catalyst, a smooth reaction occurred and anti-aldol 6 was obtained in good yield (66%), as a single diastereoisomer. An attempt to perform the aldol reaction with a single-protected Cbz-aminoacetaldehyde resulted in a prolonged reaction time, incomplete conversion of the starting material, low diastereoselectivity and poor yield (20%-30%). Exposure of aldol 6 to hydrogenation conditions led to deprotection and subsequent reductive amination in situ; after reprotection, the pyrrolidine derivative 5 was obtained. As a consequence of the bicyclic structure of the imine intermediate, the reductive amination proceeded with good substrate-controlled diastereoselectivity (12/1). As a result of a tactical combination of the aldolization and reductive amination, the trisubstituted pyrrolidine derivative 5, with the required configuration at all 3 newly formed contiguous stereocenters, was expeditiously synthesized in optically pure form. The absolute configuration of this compound was confirmed by a single-crystal x-ray analysis. ³⁸

Figure 2.

Synthesis of pyrrolidine derivative 3 and subsequent allylation reaction.

A greater thermodynamic stability of dioxolane 4 (with respect to 1,3-dioxane 5) was exploited as a driving force for the epimerization of dioxane 5 under acidic conditions, and after subsequent oxidation of primary alcohol 4 with Dess-Martin periodinane, the aldehyde 3 was isolated in good yield (72% over 2 steps). Aldehyde 3 served as a substrate for the planned organometallic allyl addition. The Zn- and In-mediated reactions afforded the homoallylic alcohol 9 in good yields; however, it was obtained as a mixture of 2 diastereoisomers with the predominance of the undesired one (9-anti), which would not lead to swainsonine, but to its 8-epimer. Predominant formation of the 9-anti isomer can be rationalized by the coordination between metal and carbamate oxygen, resulting in the attack of allyl nucleophile from the less hindered face of the molecule.^39–41 Thus, the inversion of the stereochemical outcome would be unlikely even with a different protecting group on nitrogen.

With this in mind, we focused on searching for the most selective method for the production of “undesired” diastereoisomer 9-anti, which would be subsequently isomerized into the required 9-syn stereoisomer. After some experimentation, the highest diastereoselectivity was obtained with allyl-Grignard reagent at rt in THF (dr = 5:1). Notably, under Mitsunobu conditions (Ph₃P, DEAD), an intramolecular substitution at the newly created stereocenter in 9-anti occurred, to give the cyclic carbamate 10; in this modified Mitsunobu protocol the Cbz group served as an internal nucleophile (Figure 3). After hydrolysis of cyclic carbamate 10 and nitrogen reprotection, the desired 9-syn product was obtained in 60% yield from 9-anti. The secondary hydroxyl group in 9-syn was then protected as a TBS-ether, and the terminal alkene 11 was converted to primary alcohol 12 by an hydroboration/oxidation protocol. Oxidation of 12 with Dess-Martin periodinane afforded aldehyde 2, which upon exposure to hydrogenation conditions gave the bicyclic product of a reductive amination, 13. A global deprotection under acidic conditions provided ( + )-swainsonine (1), identical to the natural product in all respects. The same reaction sequence was used for the preparation of ( + )-8-epi-swainsonine (18), starting from 9-anti stereoisomer (Figure 4).

Figure 3.

Epimerization of 9-anti to 9-syn and completion of the synthesis of ( + )-swainsonine (1).

Figure 4.

Completion of the synthesis of ( + )-8-epi-swainsonine (18).

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 redox-economy 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). The increased diastereoselectivity of the reaction (as compared to allyl magnesium bromide) can be explained by the internal coordination of the Grignard reagent 19, which increases steric bulk and further disfavors nucleophilic attack on the aldehyde from the Si-face. 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.

Figure 5.

The improved synthesis of ( + )-8-epi-swainsonine (18).

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 swainsonine-derived iminium ion with the corresponding enamine, as previously described by Nagasawa, Asakawa and collaborators. ²⁶ In addition, catalytic hydrogenation under mildly acidic conditions gave N-ethylated product 23.^42,43 Apparently, intramolecular hydrogen bonding induced considerable changes in the conformation and reactivity of 21 (with respect to 20); for the cyclization of 21 to occur, it was crucial to finely tune the acidity and the reducing power of the reaction medium. After some experimentation, we found that catalytic hydrogenation in the presence of excess HCl affords ( + )-swainsonine (1) in excellent yield.

Figure 6.

The improved synthesis of ( + )-swainsonine (1).

As an additional benefit of the represented synthetic approach, the optical antipode of intermediate 5 was separately synthesized by the same procedure, but using (R)-proline as a catalyst. This pyrrolidine derivative was then converted to ( + )-dideoxy-imino-lyxitol (24, DIL) in 2 steps (Figure 7). DIL (24) is another member of a class of biologically active pyrrolidine iminosugars: it was found to inhibit Golgi α-mannosidase II ⁴⁴ and β-galactocerebrosidase. ⁴⁵

Figure 7.

Synthesis of ( + )-dideoxy-imino-lyxitol (24).

Conclusions

In summary, the catalytic enantioselective synthesis of 3 biologically active iminosugars was accomplished from 2 commercially available, achiral precursors. The synthesis hinges on a tactical combination of 2 reactions: organocatalyzed aldol addition which proceeds as a catalytic asymmetric reaction, and reductive amination. This approach allows for a quick assembly of the pyrrolidine core with a defined absolute configuration of 3 newly formed stereocenters, resulting in highly efficient total synthesis of ( + )-swainsonine (1), (–)-swainsonine (ent-1) (9 steps, 24% overall yield), ( + )-8-epi-swainsonine (18) (7 steps, 28% overall yield) and ( + )-dideoxy-imino-D-lyxitol 24 (5 steps, 45% overall yield).

Supplemental Material

sj-docx-1-npx-10.1177_1934578X221091672 - Supplemental material for Total Synthesis of ( + )-Swainsonine, (–)- Swainsonine, ( + )-8- epi -Swainsonine and ( + )- Dideoxy-Imino-Lyxitol by an Organocatalyzed Aldolization/Reductive Amination Sequence

Supplemental material, sj-docx-1-npx-10.1177_1934578X221091672 for Total Synthesis of ( + )-Swainsonine, (–)- Swainsonine, ( + )-8- epi -Swainsonine and ( + )- Dideoxy-Imino-Lyxitol by an Organocatalyzed Aldolization/Reductive Amination Sequence by Milos Trajkovic, Milos Pavlovic, Filip Bihelovic, Zorana Ferjancic and Radomir N Saicic in Natural Product Communications