Total synthesis of (+)-swainsonine and (+)-8-epi-swainsonine

Article abstract of DOI:10.1039/c4ra11978a

Enantioselective synthesis of (+)-swainsonine was achieved in 9 steps, with 24% overall yield. The key feature of the synthesis is the tactical combination of reactions: organocatalyzed aldolization/reductive amination, which allows for a rapid construction of highly functionalized heterocyclic systems. In a similar way (+)-8-epi-swainsonine was synthesized (7 steps, 28%).

Full text of DOI:10.1039/c4ra11978a

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Total synthesis of (+)-swainsonine and (+)-8-epi-
swainsonine†
Cite this: RSC Adv., 2014, 4, 53722
*
*
Milos Trajkovic, Vesna Balanac, Zorana Ferjancic and Radomir N. Saicic
Received 12th September 2014
Accepted 14th October 2014
DOI: 10.1039/c4ra11978a
www.rsc.org/advances
Enantioselective synthesis of (+)-swainsonine was achieved in 9 steps, catalytic asymmetric approach. The retrosynthetic blueprint is
with 24% overall yield. The key feature of the synthesis is the tactical represented in Scheme 1. Disconnection of the piperidine ring
combination of reactions: organocatalyzed aldolization/reductive in 1 by reductive amination gives pyrrolidine derivative 2, which
amination, which allows for a rapid construction of highly function- would be obtained by homologation of aldehyde 3. The
alized heterocyclic systems. In a similar way (+)-8-epi-swainsonine synthetic predecessor of 3 – dioxolane 4 – should be a thermo-
was synthesized (7 steps, 28%).
dynamically more stable isomer of 1,3-dioxane 5, on its turn
obtainable by reductive amination of aldol 6. This latter
compound would be assembled by an organocatalyzed12 aldol
addition of dioxanone (7)13 to amino aldehyde 8. The key feature
of this synthetic concept would be the tactical combination of
reactions: organocatalyzed aldolization/reductive amination,
which we recently applied in the synthesis of hyacinthacine
analogues.14 Both enantiomers of swainsonine would be avail-
able from the same starting compounds, using enantiomeric
organocatalysts.
Iminosugars, also known as azasugars, or iminocyclitols, are a
class of alkaloids that has attracted considerable attention from
the scientic community, due to their promising biological
activity.1 These compounds inhibit enzymes involved in carbo-
hydrate processing, which may have therapeutic potential for
treatment of various diseases, such as cancer, diabetes, obesity,
or viral infections.1c Indolizidine alkaloids are an important
subclass of this family,2 where swainsonine (ent-1)3 occupies a
prominent place. This alkaloid, rst isolated in 1973,4 was
found to be a potent inhibitor of mannosidases,5 and has
entered in phase II clinical trials for the treatment of renal
carcinoma.6 It was also found to be a potent and strain-selective
inhibitor of infection by prions – infectious agents responsible
for neurodegenerative disorders such as Creutzfeldt–Jacob
disease and kuru.7 Intensive synthetic efforts toward this
compound have resulted in more than 50 syntheses, most of
them relying on a chiron approach, using sugars, amino acids,
or hydroxy acids as starting compounds.8,9 Of interest is not only
swainsonine, but also its structural analogues (including the
optical antipode, which is a strong and specic inhibitor of
naringinase),9i,10 for the studies of structure activity
relationship.11
The synthesis commenced with (S)-proline-catalyzed aldol
addition of dioxanone (7) to aminoacetaldehyde derivative 8,
which produced the desired adduct 6 in 66% yield, as a single
diastereoisomer (Scheme 2). For the reasons of atom-economy,
We set out to develop an enantioselective synthesis of
swainsonine that would start from achiral precursors, using a
Faculty of Chemistry, University of Belgrade, Studentski trg 16, POB 51, 11158
Belgrade 118, Serbia. E-mail: rsaicic@chem.bg.ac.rs
† Electronic supplementary information (ESI) available: Experimental procedures,
spectral data and copies of NMR spectra for all compounds, CIF le for compound
5. CCDC 1009272. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ra11978a
Scheme 1 Retrosynthetic analysis of (+)-swainsonine (1).
53722 | RSC Adv., 2014, 4, 53722–53724
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Scheme 3 Side reactions during attempted reductive amination of 12.
M HCl resulted in reductive amination and produced (+)-8-epi-
swainsonine (13) in high yield. The congurational inversion of
the newly created secondary alcohol stereocenter in 10, as
required for the synthesis of 1, was accomplished under modi-
ed Mitsunobu conditions: the Cbz group served as an internal
nucleophile, thus obviating the need for the addition of
carboxylic acid, which is usually used as an external nucleophile
in the reactions of this type. Aer the hydrolysis of cyclic
carbamate 11, aminoacetal 12 was subjected to the hydrogena-
tion conditions in highly acidic medium, to provide in excellent
yield (+)-swainsonine (1) identical to the natural product in all
respect (except for the sense of optical rotation). It is of note that
for the cyclization of 12 to occur, a ne balance between the
acidity and the reducing power of the reaction medium is
required. An attempt to hydrolyze the acetal functionality in 12
by treatment with 2 M HCl resulted in the formation of dimeric
compound 14 (64%, Scheme 3).17 To our surprise, catalytic
hydrogenation of 12 under mildly acidic conditions gave N-
ethylated product 15 (37%, Scheme 3).18
Scheme
swainsonine (13).
2 Total synthesis of (+)-swainsonine (1) and (+)-8-epi-
we also attempted to perform the aldol addition with a single-
protected Cbz-aminoacetaldehyde (i.e., substituting hydrogen
for benzyl in compound 8). These attempts gave inferior results:
lower diastereoselectivity, extended reaction time, incomplete
conversion and the low yield (20–30%); in addition, the corre-
sponding aldol product was unstable and decomposed on
purication. Upon exposure to a hydrogen atmosphere in the
presence of palladium on charcoal, aldol 6 underwent double
deprotection followed by a reductive amination, to give a pyr-
rolidine derivative which was reprotected in situ and isolated as
a Cbz-derivative 5. The product was obtained as a mixture of two
easily separable diastereoisomers with the predominance of the
desired one (5 : 71%; epi-5 (not represented): 6%), correspond-
ing to the hydrogen delivery from the sterically less shielded,
convex face of the bicyclic imine intermediate. The absolute
conguration of this compound was conrmed by a single-
crystal X-ray analysis.15 Acetone-derived dioxolanes are known
to be more stable than the corresponding dioxanes; therefore, 5
was isomerized in the presence of a catalytic amount of p-TsOH
to primary alcohol 4, which was further oxidized with Dess–
Martin periodinane to aldehyde 3. Homologation of 3 was
accomplished in high yield via addition of Grignard reagent 9,
with the formation of a single diastereoisomer 10. The observed
stereochemical outcome of the reaction can be explained by the
coordination of the metal with the carbamate oxygen followed
by the nucleophilic attack from the sterically less shielded
face.16,11d,e Exposure of 10 to the hydrogenation conditions in 2
Conclusions
To summarize, total synthesis of (+)-swainsonine (1) was ach-
ieved from the commercially available achiral precursors in 9
steps with 24% overall yield, which compares favorably (in
terms of yield and step-economy) with all previous asymmetric
syntheses of this compound. In addition, (+)-8-epi-swainsonine
was also synthesized by the shortest route reported so far (7
steps, 28% overall yield). The key feature of the syntheses
described is the tactical combination of reactions: organo-
catalyzed aldolization/reductive amination, which allows for an
expedient entry into optically pure heterocycles.
Acknowledgements
This work was supported by the Serbian Ministry of Education,
Science and Technological Development (Project no. 172027) and
by the Serbian Academy of Sciences and Arts (Project no. F193).
Notes and references
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