Stereoselective access to β-C-glycosamines by nitro-Michael addition of organolithium reagents

Article abstract of DOI:10.1002/ejoc.201402001

The nitro-Michael addition of organolithium species to 2-nitroglycal derivatives was investigated. This methodology affords straightforward and stereoselective access to C-nitroglycosides, which are excellent precursors to C-N-acetylglycosamines. The corresponding products bearing an aromatic, heteroaromatic, alkynyl, alkenyl, or alkyl moiety were isolated in good yields with excellent selectivities. The β isomer was isolated as a single stereoisomer in most cases, and the structure was clearly elucidated by NMR spectroscopy experiments. Copyright

Full text of DOI:10.1002/ejoc.201402001

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402001
Stereoselective Access to β-C-Glycosamines by Nitro-Michael Addition of
Organolithium Reagents
Thierry Delaunay,[a] Thomas Poisson,*[a] Philippe Jubault,[a] and Xavier Pannecoucke*[a]
Keywords: Synthetic methods / Michael addition / Lithium / Diastereoselectivity / Carbohydrates
The nitro-Michael addition of organolithium species to 2-
nitroglycal derivatives was investigated. This methodology
affords straightforward and stereoselective access to C-nitro-
matic, heteroaromatic, alkynyl, alkenyl, or alkyl moiety were
isolated in good yields with excellent selectivities. The β iso-
mer was isolated as a single stereoisomer in most cases, and
glycosides, which are excellent precursors to C–N-acetyl- the structure was clearly elucidated by NMR spectroscopy
glycosamines. The corresponding products bearing an aro-
experiments.
del–Crafts arylation of glycosyl-based acetamidate,[8]
(3) metal-catalyzed arylation of haloglycosides,[9] and
(4) Lewis acid mediated nucleophilic substitution of an an-
omeric acetate[10] (Scheme 1).
Introduction
Carbohydrates are key components of glycopeptide and
glycolipid structures involved in numerous biological pro-
cesses.[1] Glycoconjugates are present on the cell surface and
are involved in several cellular communication events. For
instance, glycoproteins have shown a key role in several in-
fections owing to the selective recognition of the glycosidic
part of their structure.[2] As a result, carbohydrates are ex-
tremely appealing toward the design of new therapeutics
such as anticancer drugs.[3] Unfortunately, these potent and
promising applications are severely hampered by the low
stability of the glycosidic bond in vivo. The most popular
way to tackle this major drawback is through the replace-
ment of the oxygen atom with a methylene motif to give
non-hydrolizable C-glycosides.[4] Indeed, C-glycosides are
less sensitive to metabolic hydrolysis, and they have been
described to possess interesting biological activities as drug
candidates and inhibitors of carbohydrate-processing en-
zymes. Noteworthy, this strategy has been widely explored,
which led to the design of several elegant methods towards
their synthesis.[5] As part of these C-glycosides, β-C-aryl
glycosides are a very important class of C-glycosides that
are present in several bioactive and natural compounds.[6]
Among all these carbohydrates, 2-amino-2-deoxysugars
are key components of O- and N-glycopeptides, and the
synthesis of their C-analogues is appealing to access meta-
bolic-resistant compounds. The developed strategies to ac-
cess these structures usually focus on (1) radical-based reac-
tion of a halo- or chalcogenoglycoside on olefins,[7] (2) Frie-
Scheme 1. State of the art; EDG = electron-donating group.
[a] Normandie Univ., COBRA, UMR 6014 et FR 3038, Univ.
Rouen, INSA Rouen, CNRS,
1 rue Tesnière, 76821 Mont Saint-Aignan Cedex, France
E-mail: thomas.poisson@insa-rouen.fr
Results and Discussion
xavier.pannecoucke@insa-rouen.fr
http://www.lab-cobra.fr/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402001.
2-Nitroglycals are versatile building blocks for the
synthesis of 2-amino-2-deoxyglycosides.[11] Basically, these
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T. Delaunay, T. Poisson, P. Jubault, X. Pannecoucke
SHORT COMMUNICATION
versatile compounds are mainly used in the course of was performed at 0 °C and allowed to reach room tempera-
Michael addition reactions with “soft” nucleophiles such as ture (Table 1, entries 6 and 7). Finally, an organozinc deriv-
alcohols,[11c–11e] thiols,[11f] malonates,[11g] N-nucleo- ative was found to be unreactive in our hands, regardless
philes,[11h,11i] and others.[11j–11m] Quite surprisingly, a sole of the reaction temperature (Table 1, entry 8). Having these
report dealt with the addition of allylzinc and vinylmagne- optimized conditions in hand, we turned our attention to
sium species onto this backbone with modest α/β stereose- the scope of the reaction by using 2-nitroglucal 1a as the
lectivity,[12,13] whereas the addition of lithiated dithiane was substrate and various organolithium derivatives (Table 2).
reported on a single 2-nitroglucal derivative without a yield
First, electron-rich aryllithium reagents were engaged un-
der our reaction conditions. Pleasingly, aryllithiums bearing
and with complete β selectivity.[14]
Herein, we report our efforts towards the development a dioxolane or a methoxy moiety afforded corresponding β
of a nitro-Michael addition of organolithium reagents to adduct 2b and 2c in 65 and 67% yield, respectively. Note-
2-nitroglycals.[15] This methodology affords straightforward worthy, in the case of the methoxy derivative, we were able
and stereoselective access to β-C-alkynyl, alkenyl, and alkyl to isolate 5% of the corresponding α derivative. Then, 4-
glycosamines and β-C-aryl glycosamines as well. At the fluorophenyllithium was tested, which led to the corre-
outset of the project, we attempted the reaction of 2-nitro- sponding β-glycoside in modest yield (32%) as a single iso-
glucal 1a with several organometallic derivatives under vari- mer along with several degradation products. Gratefully,
ous conditions (Table 1).
heteroaromatic derivatives reacted smoothly with ni-
troglucal derivative 1a. Pyridine derivatives 2e and 2f were
isolated in good yields of 66 and 45%, respectively, as single
diastereoisomers, whereas electron-rich thiophene and
furan derivatives gave exclusively β-isomers 2g and 2h in 63
and 37% yield, respectively.[17] Then, we turned our atten-
tion to the alkynyl and alkenyl derivatives. Pleasingly, the
organolithium species derived from phenylacetylene reacted
well to provide β-adduct 2i in 51% yield, whereas lithiated
trimethylsilylacetylene afforded β-isomer 2j in 61% yield
along with 18% of the α isomer. Then, vinyllithium and
propenyllithium were used to give products 2k and 2l in 53
and 65% yield, respectively. In the last case, small quantities
of the α-addition product were isolated in 9% yield. Finally,
our methodology was extended to aliphatic organolithium
species. MeLi was added to glucal 1a to afford β-isomer 2m
as the sole product in 68% yield. nBuLi reacted nicely with
1a to give β-glycoside 2n exclusively, whereas TMSCH2Li
furnished corresponding addition product 2o in 56% yield.
In summary, aromatics, heteroaromatics, alkynes, alkenes,
and alkyls were all suitable nucleophiles for this transfor-
mation, and they gave stereoselectively β-C-glucosamines
2a–o.
Table 1. Optimization study.[a]
Entry
1
M
Li
Solvent
THF
T [°C]
Additive
–
Yield[b] [%]
55
–78 to
–40
–78
–78
–78
–78
–78
0 to r.t.
–78 to r.t.
2
3
4
5
6
7
8
Li
Li
Li
Li
MgBr
MgBr
ZnCl
THF
DME
Et2O
THF
THF
THF
THF
–
–
–
71
56
24
HMPA[c] n.r.[d]
–
–
–
n.r.[d]
48 (63:37)[e]
n.r.[d]
[a] Reaction conditions: 1a (0.16 mmol), C6H5–M (0.24 mmol), sol-
vent (2 mL). [b] Yield of isolated product. [c] HMPA = hexameth-
ylphosphoric triamide. [d] n.r.: no reaction. [e] The β/α ratio was
1
determined by H NMR spectroscopy.
Noteworthy, the stereochemistry of the precursor of the
1
An initial attempt was performed with phenyllithium as C-analogue of glucosamine was determined by H NMR
the nucleophile. To our delight, if the reaction was per- spectroscopy experiments (Figure 1).
formed at –78 °C and quenched at –40 °C β-arylglycoside
First, the determination of the coupling constant be-
2a was isolated in 55% yield as a single diastereoisomer tween H1 and H2 (3J = 9.7 Hz) clearly implied a trans rela-
(Table 1, entry 1). A slight modification of the reaction tionship, as did the coupling between H2 and H3 (3J =
quench temperature allowed 2a to be isolated in 71% yield 9.7 Hz). The 3J(H3,H4) coupling (3J = 9.7 Hz) also indi-
(Table 1, entry 2). Noteworthy, no formation of the C2 epi- cated a trans relationship between both protons. Finally, a
mer of 2a was observed, probably because protonation of NOE experiment clearly pointed out a 4C1 conformation of
the latent nitroenolate occurred to deliver the more thermo- the glycoside, as depicted in Figure 1. Beyond doubt, the β
dynamically stable product.[16] Then, a solvent survey re- selectivity of the reaction was demonstrated as well as the
vealed that THF was the best solvent; for instance, Et2O 4C1 conformation of the addition product.
resulted in the isolation of the β isomer in 24% yield. Note-
Then, we checked the efficiency of our methodology on
worthy, the addition of HMPA (1.5 equiv.) inhibited the re- 2-nitroglycals 1b and 1c derived from galactal and arabinal,
action (Table 1, entry 5). Finally, the nature of the organo- respectively (Table 3).
metallic derivative was examined. Interestingly, by using the
First, 2-nitrogalactal 1b was engaged under our reaction
corresponding Grignard reagent no reaction occurred at conditions with methyllithium as a nucleophile. Pleasingly,
–78 °C, whereas the corresponding product was isolated in product 2ba was isolated in 75% yield with a 65:35 ratio of
48% yield as a 63:37 mixture of β/α adducts if the reaction the α/β isomers. This lower diastereoselectivity relative to
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Stereoselective Access to β-C-Glycosamines
Table 2. Scope of the reaction.[a]
[a] Reactions conditions: 1a (0.16 mmol), R–Li (0.24 mmol), THF (2 mL), –78 °C, 2 h, then NH4Cl. [b] Yield of the isolated α isomer.
Table 3. Extension of the reaction to other glycals.
Figure 1. Conformational analysis of 2m.
that generally observed with 2-nitroglucal derivatives might
be explained by the steric repulsion between the incoming
nucleophile and the axial C4 stereogenic center. Thus, we
propose that the addition of the lithiated nucleophile should
occur either on the less-hindered α side of the 5H4 con-
4
former of 1b or on the α side of the sterically favored H5
conformer. A similar trend was observed with phenyl-
lithium as a nucleophile, and corresponding addition prod-
[a] Ratio of the α and β isomers.
uct 2bb was isolated in 32% yield with poor α/β diastereo-
selectivity (59:41). Then, we turned our attention to 2-nitro- meric ratio (β as a major product). Finally, phenyllithium
arabinal 1c. Methyllithium reacted smoothly to give ad- was used, and β-isomer 2cb was isolated in 19% yield as a
dition product 2ca in 59% yield with a 76:24 diastereoiso- single isomer along with several unidentified byproducts.
Eur. J. Org. Chem. 2014, 3341–3345
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T. Delaunay, T. Poisson, P. Jubault, X. Pannecoucke
SHORT COMMUNICATION
Then, to highlight the versatility of the nitro intermedi-
ate, the transformation of nitro derivative 2a into valuable
N-acetyl glycoside derivative 3a was performed (Scheme 2).
The reduction of the nitro group to an amine was achieved
by using Zn/HCl followed by an acetylation reaction under
standard conditions. The resulting C–N-acetylglycosamine [3]
was isolated in quantitative yield over two steps with a sin-
gle purification step by flash chromatography.
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nitroglucal derivatives, the β stereoisomer was predomi-
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whereas our process gave moderate selectivities with other
2-nitroglycals, for example, 2-nitrogalactal and 2-nitro-
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[8]
Experimental Section
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dissolved in dry THF (2 mL), and the solution was stirred at
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–78 °C. Then, the organometallic derivative (0.24 mmol, 1.5 equiv.)
was added over 5 min at –78 °C, and the reaction mixture was
stirred at this temperature for 1 h. Then, the resulting mixture was
quenched at –78 °C with a solution of NH4Cl (saturated). The solu-
tion was extracted with AcOEt (2ϫ 10 mL). The organic layer was
washed with water (1ϫ 10 mL) and brine (1ϫ 10 mL) and dried
with MgSO4. The solvent was removed under vacuum, and the
residue was purified by preparative TLC (SiO2, petroleum ether/
ethyl acetate).
[11]
Supporting Information (see footnote on the first page of this arti-
cle): Materials and methods, synthesis and characterization, and
1H NMR and13C NMR spectra.
Acknowledgments
This work was partially supported by INSA Rouen, Rouen Univer-
sity, Centre National de la Recherche Scientifique (CNRS), Euro-
pean Fund for Regional Development (EFRD) and Labex SynOrg
(ANR-11-LABX-0029). T. D. thanks the European Fund for Re-
gional Development (EFRD) (grant number 43209) for a postdoc-
toral fellowship.
[12]
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2001–2004; Angew. Chem. 2005, 117, 2037–2040.
During the preparation of this manuscript, Avenoza and Pereg-
rina reported the addition of an α-selective lithium enolate to
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Stereoselective Access to β-C-Glycosamines
nitro galactals, see: C. Aydillo, C. D. Navo, J. H. Busto, F. [16]
Corzana, M. M. Zurbano, A. Avenoza, J. M. Peregrina, J. Org.
A similar observation was made by Schmidt and co-workers,
see ref.[11g]
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[15] For a similar strategy of Michael addition with organocopper
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Synlett 2000, 734–736.
[17] Several unidentified side products, probably degradation prod-
ucts, were obtained in the crude mixture along with the desired
product.
Received: February 1, 2014
Published Online: April 14, 2014
Eur. J. Org. Chem. 2014, 3341–3345
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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