Stereodivergent synthesis of iminosugars from stannylated derivatives of (S)-vinylglycinol

Article abstract of DOI:10.1021/ol303213r

An original access to iminosugars from a cis/trans mixture of stannylated oxazolidinones 5 is reported. The dehydropiperidines 7-trans and 7-cis were obtained stereoselectively with an RS and SS configuration depending on the order of the Sn-Li transmetalation (followed by electrophilic trapping) and of the ring closing metathesis reactions due to the stereoselective epimerization of the α-aminoanion intermediate. The dehydropiperidines 7-trans and 7-cis were subsequently used for the synthesis of enantiopure homonojirimycin analogs.

Full text of DOI:10.1021/ol303213r

ORGANIC
LETTERS
2013
Vol. 15, No. 1
160–163
Stereodivergent Synthesis of Iminosugars
from Stannylated Derivatives of
(S)‑Vinylglycinol
Alexandre Lumbroso,† Isabelle Beaudet,† Lo¨ıc Toupet,‡ Erwan Le Grognec,*,† and
Jean-Paul Quintard*,†
ꢀ
Universite de Nantes, CNRS, CEISAM, UMR 6230, Faculte des Sciences et des
Techniques, 2, rue de la Houssiniere, BP 92208, 44322 Nantes Cedex 3 France, and
ꢀ
ꢁ
ꢀ
Institut de Physique de Rennes, CNRS, UMR 6251ÀUniversite de Rennes 1,
Campus de Beaulieu, 35042 Rennes Cedex, France
erwan.legrognec@univ-nantes.fr; jean-paul.quintard@univ-nantes.fr
Received November 21, 2012
ABSTRACT
An original access to iminosugars from a cis/trans mixture of stannylated oxazolidinones 5 is reported. The dehydropiperidines 7-trans and 7-cis
were obtained stereoselectively with an RS and SS configuration depending on the order of the SnÀLi transmetalation (followed by electrophilic
trapping) and of the ring closing metathesis reactions due to the stereoselective epimerization of the R-aminoanion intermediate. The
dehydropiperidines 7-trans and 7-cis were subsequently used for the synthesis of enantiopure homonojirimycin analogs.
Iminosugars have found widespread interest due to the
biological properties of this class of compounds as glyco-
sidases inhibitors,1 properties which have been used for the
development of treatment against viral infections such as
human immunodeficiency virus (HIV), human hepatitis C
or dengue virus,2 diabetes,3 tuberculosis,4 cancers,5 and
lysosomal storage disorders.6
These important polyhydroxylated N-heterocycles can
be obtained from natural sugars or from nonsugar
compounds.7,8 The approach starting from natural sugars
allows access to well-defined molecules, but with a lower
flexibility in the modifications of the parent compound,
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Wang, J.-B. Phytomedicine 2007, 14, 353–359. (c) Wrodnigg, T. M.;
Steiner, A. J.; Ueberbacher, B. J. Anti-Cancer Agents Med. Chem. 2008,
8, 77–85.
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4683–4696. (b) Butters, T. D.; Dwek, R. A.; Platt, F. M. Curr. Top. Med.
Chem. 2003, 3, 561–574. (c) Meikle, P. J.; Fietz, M. J.; Hopwood, J. J.
Expert. Rev. Mol. Diagn. 2004, 4, 677–691. (d) Futerman, A. H.; van
Meer, G. Nat. Rev. Mol. Cell Biol. 2004, 5, 554–565. (e) Fan, J. Q. Biol.
Chem. 2007, 389, 1–11. (f) Wennekes, T.; van den Berg, R. J. B. H. N.;
Boot, R. G.; van der Marel, G. A.; Overkleeft, H. S.; Aerts, J. M. F. G.
Angew. Chem., Int. Ed. 2009, 48, 8848–8869. (g) Parenti, G. EMBO Mol.
†
ꢀ
UMR CNRS 6230, CEISAM, Universite de Nantes.
‡
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UMR CNRS 6251À Universite de Rennes 1.
(1) (a) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.;
Nash, R. J. Phytochemistry 2001, 56, 265–295. (b) Asano, N.; Nash,
R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11,
1645–1680. (c) Compain, P.; Martin, O. R. Iminosugars: From Synthesis
to Therapeutic Applications; Wiley: Chichester, 2007. (d) St€utz, A. E.
Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond;
Wiley-VCH: Weinheim, 1999.
€
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Top. Med. Chem. 2003, 3, 513–523. (b) Durantel, D.; Alotte, C.; Zoulim,
F. Curr. Opin. Investig. Drugs 2007, 8, 125–129.
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1054. (b) Tsujino, D.; Nishimura, R.; Taki, K.; Morimoto, A.; Tajima,
N.; Utsunomiya, K. Diabetes Technol. Ther. 2011, 13, 303–308.
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r
10.1021/ol303213r
Published on Web 12/20/2012
2012 American Chemical Society

when compared to the second approach which allows
for instance the preparation of eight 1-deoxynojirimycin
isomers from a single precursor.9 Among the plethora
of strategies, allylmetalation of imines combined with
ring closing metathesis (RCM) has also been widely used
as a key step.10 We have developed a diastereoselective
route toward iminosugars based on a highly syn-selective
allylstannation of an N-acyliminium intermediate by a
γ-silyloxyallyltin.11 However, while desired iminosugars
were synthesized with very high diastereoselectivity, only
racemic mixtures were obtained, limiting the use of this
methodology for the development of new potent therapeu-
tic agents. As part of an ongoing program to synthesize
enantioenriched R-amino stannylated derivatives,12 we
report herein an original, flexible access to enantiopure
iminosugars based on a diastereoselective SnÀLi transme-
talation followed by electrophilic trapping of R-amino
stannylated derivatives of (S)-N-methoxycarbonylvinyl-
glycinol 2 (Scheme 1). The synthesis began with the prepara-
tion of 2-tributylstannyloxazolidine 3 via a transacetalization
reaction13 between diethoxymethyltributyltin 1 and 2.
3 was obtained in good yield (65%) as a 1:1 mixture of
diastereomers (3-trans/3-cis) which were separated to con-
sider possible differences in terms of reactivity.
Ring opening with allyltributyltin in the presence of
BF3 OEt2 at À78 °C afforded azadienol 4 in excellent
3
yield (90 and 98% starting from 3-cis or 3-trans respec-
tively), albeit giving a moderate anti selectivity (4-anti:
4-syn = 63:37 from 3-cis and 70:30 from 3-trans). However,
4-anti and 4-syn were easily separated by column chroma-
tography on silica gel.
Treatment of 4-anti and 4-syn with an excess of sodium
hydride (3 equiv) furnished the desired stannylated oxazo-
lidinones 5-(RS) and 5-(SS) in 85% and 90% yield res-
pectively (Scheme 2).14
Scheme 1. Synthesis of Azadienols 4-syn and 4-anti Starting
from (S)-N-Methoxycarbonyl-vinylglycinol 2
Scheme 2. Synthesis of Stannylated Oxazolidinones 5
We then considered the SnÀLi transmetalation by
n-BuLi at low temperature which can occur with complete
retention of the configuration at the anionic center of an
R-aminoorganotin precursor.12d,15 At higher temperatures,
it is also possible to take advantage of the epimerization of
the anionic center to obtain the desired compounds with
(7) (a) Cipolla, L.; La Ferla, B.; Nicotra, F. Curr. Top. Med. Chem.
2003, 3, 485–511. (b) Ruiz, M.; Ruanova, T. M.; Blanco, O.; Nunez, F.;
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Jurczak, M.; Panfil, I.; Furman, B.; Grzeszczyk, B.; Chmielewski, M. C.
R. Chim. 2011, 14, 102–125. (d) Lenagh-Snow, G. M. J.; Araujo, N.;
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J.; Marrot, J.; Bleriot, Y. Org. Lett. 2012, 14, 870–873. (f) Lenagh-Snow,
Table 1. SnÀLi Transmetalation/Electrophilic Trapping
Sequence on Stannylated Oxazolidinones 5
G. M. J.; Jenkinson, S. F.; Newberry, S. J.; Kato, A.; Nakagawa, S.;
Adachi, I.; Wormald, M. R.; Yoshihara, A.; Morimoto, K.; Akimitsu,
K.; Izumori, K.; Fleet, G. W. J. Org. Lett. 2012, 14, 2050–2053.
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8527–8539.
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Asymmetry 2009, 20, 672–711. (b) Danoun, G.; Ceccon, J.; Greene,
A. E.; Poisson, J.-F. Eur. J. Org. Chem. 2009, 4221–4224. (c) van den
Nieuwendijk, A. M. C. H.; Ruben, M.; Engelsma, S. E.; Risseeuw,
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3959.
entry
5
temp
electrophile
6
yield (SS:RS)c
1
2
3
4
5
6
7
5-(RS)
5-(SS)
À78 °C cyclohexanonea 6a
À78 °C cyclohexanonea 6a
71 (100:0)
47 (100:0)
77 (26:74)
65 (96:4)d
76 (97:3)e
49 (95:5)d
78 (29:71)d
(9) van den Nieuwendijk, A. M. C. H.; van den Berg, R. J. B. H. N.;
Ruben, M.; Witte, M. D.; Brussee, J.; Boot, R. G.; van der Marel, G. A.;
Aerts, J. M. F. G.; Overkleeft, H. S. Eur. J. Org. Chem. 2012, 3437–3446.
(10) (a) Felpin, F. X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693–
5-(SS) À100 °C cyclohexanonea 6a
a
5-(RS)
5-(RS)
5-(SS)
À78 °C CO2
À78 °C CO2
À78 °C CO2
6b
6b
6b
6b
a
a
b
ꢀ
3712. (b) Pearson, M. S. M.; Mathe-Allainmat, M.; Fargeas, V.;
Lebreton, J. Eur. J. Org. Chem. 2005, 2159–2191.
5-(SS) À100 °C CO2
(11) (a) Chevallier, F.; Beaudet, I.; Le Grognec, E.; Toupet, L.;
Quintard, J.-P. Tetrahedron Lett. 2004, 45, 761–764. (b) Chevallier, F.;
Le Grognec, E.; Beaudet, I.; Fliegel, F.; Evain, M.; Quintard, J.-P. Org.
Biomol. Chem. 2004, 2, 3128–3133. (c) Chevallier, F.; Lumbroso, A.;
Beaudet, I.; Le Grognec, E.; Toupet, L.; Quintard, J.-P. Eur. J. Org.
Chem. 2011, 4133–4144.
a Electrophile added 20 min after the addition ofn-BuLi. b Electrophile
added 5 min after the addition of n-BuLi. c Determined by GC analyses.
d Conversion in methyl ester using SOCl2/MeOH. e Using TMSCHN2.
Org. Lett., Vol. 15, No. 1, 2013
161

high stereoselectivities and in particular when stannylated
oxazolidinones are involved.14,15 A different situation was
recently reported using R-stannylated sulfonamides with
cesium fluoride at 100 °C under carbon dioxide pressure
which afford products with inversion of the configuration
through a tin ate complex.16
Transmetalation reactions of stannylated oxazolidinones
5-(RS) and 5-(SS) were performed at À78 or À100 °C using
n-BuLi in THF followed by an electrophilic trapping of the
corresponding anionic species by cyclohexanone or CO2
(Table 1). When starting from 5-(RS), the transmetalation
followed by electrophilic trapping with cyclohexanone
(after 20 min) occurred with complete retention of the
configuration (entry 1) while a complete epimerization of
the anionic center and a lower yield were observed with
5-(SS) (entry 2).17 This result was corroborated by a reac-
tion at À100 °C followed by trapping after 5 min which
exhibits only a partial epimerization (6a-(SS):6a-(RS) =
26:74, entry 3).
At this stage, we also decided to consider the RCM
performed on stannylated oxazolidinones 5 whereas only a
few examples of such a reaction on stannylated oxadienes
have been reported.18 The stannylated oxazolidinones
8-trans and 8-cis were obtained in excellent yields (95%
and 89% yield respectively) using the Grubbs I catalyst
(Scheme 4).
Scheme 4. Synthesis of Bicyclic Stannylated Oxazolidinones 8
The reactivity of stannylated oxazolidinones 8 was then
examined (Table 2), and contrary to the reaction carried
out with 5-(RS), SnÀLi transmetalation of 8-trans fol-
lowed by electrophilic trapping with cyclohexanone af-
forded pure 7a-cis in 30% yield after complete epimeri-
zation of the anionic center. However, to our delight, using
the same conditions, 8-cis furnished exclusively 7a-cis in
good yield (72%).17 The moderate yield obtained when
starting from 8-trans should be due to a partial decom-
position of the organolithium reagent during the epimer-
ization reaction. Similar results were obtained with CO2
as the electrophile, and 7b-cis was obtained in excellent
Scheme 3. Synthesis of Dehydropiperidines 7
These results are in agreement with a transmetalation
occurring with retention of the configuration at the anionic
center at À100 °C followed by an epimerization which
occurs more easily at higher temperatures (À78 °C) as
already observed for this type of anions.14,15
Table 2. SnÀLi Transmetalation/Electrophilic Trapping
Sequence on Stannylated Oxazolidinones 8
Similar trends were observed when CO2 was used as an
electrophile (entry 4À7), although a slight epimerization of
the stereogenic center was observed when starting from
both 5-(RS) and 5-(SS) and whatever the esterification
reaction used. After purification, diastereopure dienes
6a-(SS) and 6b-(SS) were then successfully transformed
into their dehydropiperidine derivatives 7a-trans17 and
7b-trans by RCM using the Grubbs II catalyst (Scheme 3).
entry
8
temp
electrophilea
7
yield (cis:trans)b
1
2
3
4
8-trans
8-cis
À78 °C cyclohexanone 7a
À78 °C cyclohexanone 7a
30 (100:0)
72 (100:0)
88 (100:0)c
15 (100:0)c,d
8-cis
À78 °C CO2
7b
7b
8-trans À100 °C CO2
ꢀ
(12) (a) Cintrat, J.-C.; Leat, V.; Parrain, J.-L.; Le Grognec, E.;
Beaudet, I.; Toupet, L.; Quintard, J.-P. Organometallics 2004, 23, 943–
a Electrophile added 20 min after the addition of n-BuLi. b Ratio
determined by GC analyses. c The carboxylic acid was not isolated but
converted into its methyl ester using trimethylsilyldiazomethane
(TMSCHN2). d Contaminated by protonated product (E = H).
ꢀ
945. (b) Cintrat, J.-C.; Leat-Crest, V.; Parrain, J.-L.; Le Grognec, E.;
Beaudet, I.; Toupet, L.; Quintard, J.-P. Eur. J. Org. Chem. 2004, 4268–
4279. (c) Coeffard, V.; Cintrat, J.-C.; Le Grognec, E.; Beaudet, I.;
Quintard, J.-P. J. Organomet. Chem. 2006, 691, 1488–1497. (d) Coeffard,
V.; Beaudet, I.; Evain, M.; Le Grognec, E.; Quintard, J.-P. Eur. J. Org.
Chem. 2008, 3344–3351. (e) Coeffard, V.; Le Grognec, E.; Beaudet, I.;
Evain, M.; Quintard, J.-P. J. Org. Chem. 2009, 74, 5822–5838. (f) Viaud,
P.; Coeffard, V.; Thobie-Gautier, C.; Beaudet, I.; Galland, N.;
Quintard, J.-P.; Le Grognec, E. Org. Lett. 2012, 14, 942–945.
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compounds (Patai Series); Rappoport, Z., Marek, I., Eds.; Wiley: Chichester,
U.K., 2004; pp 997À1053. (b) Coldham, I.; Sheikh, N. S. Top. Stereochem.
2010, 26, 253–293. (c) Gawley, R. E. Top. Stereochem. 2010, 26, 93–133.
(d) Coeffard, V.; Beaudet, I.; Quintard, J.-P.; Le Grognec, E. Chirality
2010, 22, 864–869.
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2012, 77, 2159–2168.
(17) The absolute configuration of this compound was confirmed by
X-ray analysis.
(13) Cintrat, J.-C.; Leat-Crest, V.; Parrain, J.-L.; Le Grognec, E.;
Beaudet, I.; Quintard, J.-P. Eur. J. Org. Chem. 2004, 4251–4267.
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162
Org. Lett., Vol. 15, No. 1, 2013

yield (88%) as a pure diastereomer after esterification
under mild conditions using trimethylsilyldiazomethane.
Interestingly, complete epimerization was also observed
at À100 °C (entry 4, Table 2). It is worth noting that
previous reports using (À)-sparteine showed that the
resulting competitive chelation of this external chiral
ligand can strongly modify the stereochemical course of
the reaction depending on the nature of the electrophilic
trapping reagent.19 In the present work, the configura-
tional preference in the epimerization step (when allowed
by temperature conditions) is substrate dependent and
only controlled by the respective stability of the obtained
intramolecularly chelated anionic species.
Scheme 5. Access to Homonojirimycin Analogs 11 and 12
With compounds 7-trans and 7-cis in hand, their mod-
ification into iminosugars was examined through a dihy-
droxylation/deprotection sequence. First, the dihydroxyla-
tion was achieved with osmium tetroxide in the presence
of N-methyl morpholine N-oxide20 affording the expected
diols which were subsequently converted into their aceto-
nide derivatives 9 for easier characterization (Table 3).
Compounds 9b-cis-exo and 9b-trans-endo were
finally reduced into the corresponding N-methyl 2,
6-bis(hydroxymethyl) piperidines using lithium aluminum
hydride. Subsequent acid promoted deprotection fur-
nished 2-deoxy-N-methyl β-homoallonojirimycin analog
11 and 2-deoxy-N-methyl R-homogalactonojirimycin ana-
log 12 (Scheme 5).
In summary, the proposed strategy constitutes an effi-
cient, stereodivergent route toward cis and trans de-
hydropiperidine scaffolds (7-cis/7-trans) starting from a
common key intermediate 5 by modifying the order of the
transmetalation/electrophilic trapping and of the RCM
reactions.
Table 3. Stereoselective Dihydroxylation of 7-trans/7-cis
The use of the appropriate precursor, 5-(RS) and 5-(SS),
for the preparation of 7-trans and 7-cis respectively led to
higheryieldsbut had no effecton the stereochemicalcourse
of the reaction. Therefore, the transmetalation/RCM
(orvice versa) sequence can be achieved from diastereomeric
mixtures of 5 or its azadienol precursor 4. Finally, the
application of this methodology to the preparation of
homonojirimycin analogs (11/12) exemplified the useful-
ness and efficiency of this method for the stereoselective
synthesis of iminosugars.
entry
7
electrophile
9
yield (exo:endo)a
1
2
3
4
7a-cis
C6H10OH
CO2Me
9a-cis
85 (>98/2)
79 (95/5)
7b-cis
9b-cis
7a-trans
7b-trans
C6H10OH
CO2Me
9a-trans
9b-trans
94 (15/85)
78 (17/83)
a Ratio determined from 1H NMR or by GC analyses of the crude.21
Good to excellent diastereoselectivities in favor of the
exo (entries 1, 2, Table 3) or endo (entries 3, 4, Table 3)
isomers were observed depending on the stereochemistry
of the starting material (cis or trans). These stereochemical
results are consistent with the structure of the dehydropi-
peridines 7a/b. Indeed, in 7a/b-cis, the presence of the E
group (C6H10OH/CO2Me) on the concave face of the
bicyclic system induces a nearly exclusive approach of
osmium tetroxide on the convex face, while, for 7a/b-trans,
the presence of the E group on the convex face allows a
preferred approach of osmium tetroxide on the concave
face, but with lower selectivity.21
Acknowledgment. The authors are grateful to Institut de
Chimie des Substances Naturelles (CNRS, Gif-sur-Yvette)
for a Ph.D. Fellowship (A.L.), Chemtura (Bergkamen) for
the gift of organotin starting materials, and CNRS and
ꢀ
Universite de Nantes for financial support. They also wish
to acknowledge M.-J. Bertrand (CEISAM, UMR CNRS
6230) for GC analyses.
Supporting Information Available. Experimental pro-
cedures, characterizations, and NMR spectra of the prod-
ucts; X-ray analysis for 6a-(SS), 7a-cis, 7a-trans, and
9b-trans-endo. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Chem. Soc. 1997, 119, 6919–6920.
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(b) Beak, P.; Johnson, T. A.; Kim, D. D.; Lim, S. H. Top. Organomet.
Chem. 2003, 5, 139–176.
(21) See Supporting Information for details and X-ray analysis of 9b-
trans-endo.
(20) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973–1976.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 1, 2013
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