Stereocontrolled synthesis of fully functionalized D-glucosamine monosaccharides via a domino nitro-Michael/Henry reaction

Article abstract of DOI:10.1039/b805159c

A diastereoselective domino nitro-Michael/Henry reaction involving a β-hydroxyaldehyde and a nitroalkene provides direct access to fully functionalized D-glucosamine monosaccharides. The Royal Society of Chemistry.

Full text of DOI:10.1039/b805159c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Stereocontrolled synthesis of fully functionalized D-glucosamine
monosaccharides via a domino nitro-Michael/Henry reactionw
Alexander Adibekian,a Mattie S. M. Timmer,a Pierre Stallforth,a Jimmy van Rijn,a
Daniel B. Werzab and Peter H. Seeberger*a
Received (in Cambridge, UK) 27th March 2008, Accepted 24th April 2008
First published as an Advance Article on the web 4th June 2008
DOI: 10.1039/b805159c
A diastereoselective domino nitro-Michael/Henry reaction in-
volving a b-hydroxyaldehyde and a nitroalkene provides direct
access to fully functionalized D-glucosamine monosaccharides.
2-Aminosugars constitute the most abundant class of natu-
rally occurring monosaccharides in mammalian carbohy-
drates,1 including glycosaminoglycans, glycoproteins and
GPI anchors.2 Efficient stereoselective preparation of 2-ami-
nosugars has been a major focus in preparative carbohydrate
chemistry.3 Mostly based on modification of glycals by elec-
trophilic reagents, these methodologies, however, suffer from
several drawbacks, such as low stereoselectivity and incompat-
ibility with common protecting groups.
Scheme 1 Proposed domino nitro-Michael/Henry reaction to form
2-nitropyranoside 4.
previously been shown to be a valuable Michael acceptor10
and can easily be prepared in two steps starting from nitro-
methane, DMF and ethyl orthoformate.
In order to investigate the Henry reaction with aldehydes 8
and 9, trials with nitromethane as the nucleophile under
various basic conditions were performed (Scheme 3). Treating
an excess of nitromethane with sodium methoxide in methanol
at room temperature before adding the erythrose 8 resulted in
smooth formation of two diastereomeric addition products 10
and 11 in 2.6 : 1 ratio and a total yield of 82%. A crystal
structure of allo-configured diastereomer 10 simplified the
structural assignment. In contrast, the addition of nitro-
methane to threose 9 delivered an inseparable mixture of both
diastereomers 12 and 13 in only 18% yield.
Nitroalkenes are very useful electrophiles due to their
reactivity towards various nucleophiles and the versatility of
the nitro group as precursor for other functional groups.4
Additionally, nitroolefins are well suited for domino processes,
allowing for one-pot assembly of structurally complex cyclic
molecules from simpler acyclic precursors.5 As a part of our
ongoing studies towards the de novo synthesis of carbohydrate
building blocks6 we report a concise route to D-glucosamines
via a novel domino nitro-Michael/Henry reaction (Scheme 1).7
We anticipated that the base-mediated nucleophilic conju-
gate addition of b-hydroxyaldehyde 1 to nitroalkene 2, fol-
lowed by an intramolecular Henry reaction between the
intermediary formed nitronate 3 and the aldehyde should yield
the nitropyranoside 4. The synthetic utility of 2-nitropyrano-
sides as precursors for b-selective glycosyl donors has been
reported by Schmidt and co-workers.8 In addition, we envi-
saged the subsequent conversion of 2-nitropyranoside 4 into
the corresponding 2-aminosugar building block by reduction
of the nitro group and anomeric substitution.
Our retrosynthetic considerations for selectively protected
D-glucosamine 5 as well as D-galactosamine 6 are depicted in
Scheme 2. Hydroxyaldehydes 8 and 9 can be prepared in one
step from corresponding 4,6-benzylidene-D-glucose and 4,6-
benzylidene-D-galactose by oxidative cleavage with sodium
periodate.9 Push-pull-substituted 2-ethoxy nitroalkene 7 has
a Laboratory for Organic Chemistry, Swiss Federal Institute of
Technology (ETH) Zurich, Wolfgang-Pauli-Str. 10, Zurich 8093,
¨
¨
Switzerland. E-mail: seeberger@org.chem.ethz.ch;
Fax: +41 44 633 12 35; Tel: +41 44 633 21 03
b Institute for Organic and Biomolecular Chemistry, University of
Gottingen, Tammannstr. 2, 37077 Gottingen, Germany
¨
¨
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, 1H and 13C NMR data, analytical data for
new compounds and crystallographic data in CIF format for CCDC
681201 & 681202. See DOI: 10.1039/b805159c
Scheme 2 Retrosynthetic analysis of D-glucosamine and D-galacto-
samine building blocks 5 and 6.
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 3549–3551 | 3549

View Article Online
Fig. 1 ORTEP plot (50% ellipsoid probability) of ethyl 4,6-O-
benzylidene-2-deoxy-2-nitro-a-D-glucopyranoside (a-14). Hydrogen
atoms are omitted for the sake of clarity.
Scheme 3 Henry reaction between b-8 and 9 and nitromethane.
transformation did neither result in improved selectivity
nor yield.
Next, the domino nitro-Michael/Henry reaction between
hydroxyaldehyde 8 and nitroalkene 7 was investigated. The
results of a series of reactions using different bases are
summarized in Table 1.
According to frontier orbital considerations we assume that
the most reactive conformation of the acyclic nitronate inter-
mediate is that of the C–O bond adjacent to the carbonyl
group adopting an almost perpendicular position. Such a
conformation would lower the LUMO by efficient overlap of
the p* orbital of the aldehyde with the low-lying s* orbital of
the adjacent C–O bond. Keeping in mind that coordinating
lithium cations are present in the reaction mixture, chair-like
transition states are plausible as shown in Fig. 2. We suppose
that the energetically most favorable transition state is TS1
with the substituents of the six-membered structure in an
almost equatorial arrangement (Fig. 2). TS1 leads to the
observed product. The other two possible transition states
TS2 and TS3 leading to non-observed diastereomers show a
less favorable axial-equatorial arrangement of the substitu-
ents. A fourth transition structure (not shown) would have
both substituents in an axial position; chelation with lithium
would thus not be possible.
Applying the same reaction conditions (entry 1) used in the
Henry reaction with nitromethane, even after prolonged reac-
tion times no conversion was observed. Only the starting
material was isolated after testing tertiary amine bases in
THF (entries 2 and 3). Considering that every step of this
domino process is in principle reversible, we next tried to trap
the potentially formed nitronate intermediate 3 with TBSCl.11
In this case, only silylation of alcohol 8 was observed. Stronger
bases were explored next. With NaH, 2-nitropyranoside 14
was isolated as an a/b-mixture (entry 5). Even though the
product was obtained only in moderate yield (32%), only the
gluco-configured isomer out of four possible stereoisomers was
formed. The crystal structure of a-14 is shown in Fig. 1. While
NaHMDS as base furnished the same product in slightly
higher yield, reaction with KHMDS resulted in the formation
of a complex and inseparable mixture of diastereomers. Grat-
ifyingly, when LiHMDS was employed as base, only a-14 was
isolated in a very good yield of 83% (Entry 8). Thus, only one
of eight possible stereoisomers was formed under these
reaction conditions.
A comparable transition state to TS1, leading from threose
to the D-galactosamine motif, would force the aldehyde moiety
in line with the adjacent C–O bond. In such a case, the LUMO
energy cannot be decreased, thus, the reactivity of the carbonyl
is not increased. This unfavorable stereoelectronic effect may
account for the poor selectivity and the low yield observed in
the case of galactosamine.
With the optimized protocol in hand, this reaction was also
applied to threose 9. Again an inseparable mixture of different
diastereomers was formed. Further attempts to optimize this
Table 1 Domino nitro-Michael/Henry reaction to afford 2-nitropyr-
anoside 14
Entry Reagent
Solvent T/1C
r.t./h Yield
1
2
3
4
5
6
7
8
NaOMe
Et3N
NEt(iPr2)
Et3N, TBSCl THF
NaH
NaHMDS
KHMDS
LiHMDS
MeOH rt
THF
THF
—
—
—
—
72
n.r.
n.r.
n.r.
n.r.
rt
rt
rt
0 to rt
THF
THF
THF
THF
32% of 14 (a : b, 1 : 1)
41% of 14 (a : b, 1 : 1)
Complex mixture
83% of 14 (only a)
À78 to 0 3
À78 to 0 3
À78 to 0 3
Fig. 2 Potential transition states TS1–TS3 for the reaction of nitro-
nate with the carbonyl.
ꢀc
This journal is The Royal Society of Chemistry 2008
3550 | Chem. Commun., 2008, 3549–3551

View Article Online
2. (a) R. A. Dwek, Chem. Rev., 1996, 96, 683–720; (b) C. R. Bertozzi
and L. L. Kiessling, Science, 2001, 291, 2357–2364; (c) A. Helenius
and M. Aebi, Science, 2001, 291, 2364–2369; (d) P. H. Seeberger
and D. B. Werz, Nature, 2007, 446, 1046–1051.
3. (a) R. U. Lemieux and R. M. Ratcliffe, Can. J. Chem., 1979, 57,
1244–1251; (b) E. Kozlowska-Gramsz and G. Descotes, Tetrahe-
dron Lett., 1981, 22, 563–566; (c) Y. Leblanc, B. J. Fitzsimmons,
J. P. Springer and J. Rokach, J. Am. Chem. Soc., 1989, 111,
2995–3000; (d) D. A. Griffith and S. J. Danishefsky, J. Am. Chem.
Soc., 1990, 112, 5811–5819; (e) J. Du Bois, C. S. Tomooka,
J. Hong and E. M. Carreira, J. Am. Chem. Soc., 1997, 119,
3179–3180; (f) T. J. Donohoe, K. Blades and M. Helliwell, Chem.
Commun., 1999, 1733–1734; (g) K. C. Nicolaou, P. S. Baran,
Y.-L. Zhong and J. A. Vega, Angew. Chem., Int. Ed., 2000, 39,
2525–2529; (h) V. Di Bussolo, J. Liu, L. G. Huffman, Jr and
D. Y. Gin, Angew. Chem., Int. Ed., 2000, 39, 204–207;
(i) G. A. Winterfeld and R. R. Schmidt, Angew. Chem., Int. Ed.,
2001, 40, 2654–2657; (j) J. Liu and D. Y. Gin, J. Am. Chem. Soc.,
2002, 124, 9789–9797; (k) E. Levites-Agababa, E. Menhaji,
L. N. Perlson and C. M. Rojas, Org. Lett., 2002, 4, 863–865;
(l) S. D. Russell and S. F. Nathaniel, J. Am. Chem. Soc., 2004, 126,
8356–8357; (m) R. Lorpitthaya, Z.-Z. Xie, J.-L. Kuo and
X.-W. Liu, Chem.–Eur. J., 2008, 14, 1561–1570.
Scheme 4 Conversion of ethyl 2-nitropyranoside 14 into thioglyco-
side 16.
In order to demonstrate the utility of 2-nitropyranoside a-14
as a valuable intermediate for the preparation of glycosylating
agents (Scheme 4), the 2-nitro group was reduced with zinc
dust/HCl and the amine was chemoselectively protected as a
trichloroacetamide in 81% yield after 2 steps. The free hydro-
xyl was masked as a benzyl ether to provide the fully protected
D-glucosamine 15. After considerable screening, the ethyl
glycoside was efficiently converted into the corresponding
ethyl thioglycoside 16 in 74% yield using thioethyl-trimethyl-
silane and ZnI2 in dichloroethane.12 Benzaldehyde was added
during the reaction to replace the partially cleaved benzylidene
acetal.13
4. For recent review, see S. Sulzer-Mosse and A. Alexakis, Chem.
Commun., 2007, 3123–3137.
5. (a) L. F. Tietze, G. Brasche and K. Gericke, Domino Reactions in
Organic
Synthesis,
Wiley-VCH,
Weinheim,
2006;
(b) K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew.
Chem., Int. Ed., 2006, 45, 7134–7186; (c) D. Enders, C. Grondal
and M. R. M. Huttl, Angew. Chem., Int. Ed., 2007, 46, 1570–1581.
¨
6. (a) M. S. M. Timmer, A. Adibekian and P. H. Seeberger, Angew.
Chem., Int. Ed., 2005, 44, 7605–7607; (b) M. S. M. Timmer,
B. L. Stocker and P. H. Seeberger, J. Org. Chem., 2006, 71,
In conclusion, we report the development and first applica-
tion of a new type of domino reactions between a b-hydroxy
aldehyde and 2-ethoxy nitroalkene. The nitro-Michael/Henry
reaction between readily accessible 2-ethoxy nitroalkene 7 and
b-hydroxy aldehyde 8 yielded the ‘‘gluco’’-configured ethyl
2-nitropyranoside 14 upon treatment with LiHMDS in high
yield and excellent diastereoselectivity. We assume that this
transformation proceeds via a cyclic six-membered transition
state, with lithium chelation between nitronate and alkoxide
intermediates as the determining factor for stereoselectivity.
The nitropyranoside was subsequently converted to a differ-
entially protected glucosamine thioglycoside upon reduction
of the nitro group and efficient exchange of the
anomeric group.
8294–8297; (c) A. Adibekian, P. Bindschadler, M. S.
¨
M. Timmer, C. Noti, N. Schutzenmeister and P. H. Seeberger,
¨
Chem.–Eur. J., 2007, 13, 4510–4522; (d) P. Stallforth and
A. Adibekian, Org. Lett., 2008, 10, 1573–1576.
7. Two recent reports describe organocatalyzed nitro-Michael/Henry
reaction for enantioselective preparation of carba- and thiacycles:
(a) Y. Hayashi, T. Okano, S. Aratake and D. Hazelard, Angew.
Chem., Int. Ed., 2007, 46, 4922–4925; (b) R. Dodda,
J. J. Goldman, T. Mandal, C.-G. Zhao, G. A. Broker and E. R.
T. Tiekink, Adv. Synth. Catal., 2008, 350, 537–541.
8. (a) N. Barroca and R. R. Schmidt, Org. Lett., 2004, 6, 1551–1554;
(b) B. G. Reddy and R. R. Schmidt, Nat. Protoc., 2008, 3,
114–121; and references cited therein.
9. (a) R. R. Schmidt and P. Zimmermann, Tetrahedron Lett., 1986,
27, 481–484; (b) S. R. Baker, D. W. Clissold and A. McKillop,
Tetrahedron Lett., 1988, 29, 991–994.
10. T. P. Kogan and F. C. A. Gaeta, Synthesis, 1988, 9, 706–707.
11. (a) E. W. Colvin and D. Seebach, J. Chem. Soc., Chem. Commun.,
1978, 689–691; (b) E. W. Colvin, A. K. Beck and D. Seebach,
Helv. Chim. Acta, 1981, 64, 2264–2271.
12. (a) S. Hanessian and Y. Guindon, Carbohydr. Res., 1980, 86,
C3–C6; (b) K. C. Nicolaou, R. E. Dolle and D. P. Papahatjis,
J. Am. Chem. Soc., 1984, 106, 4189–4192; (c) K. Zegelaar-Jaars-
veld, S. C. van der Plas, G. A. van der Marel and J. H. van Boom,
J. Carbohydr. Chem., 1996, 15, 665–689.
13. Synthesis of a comparable building block based on traditional
carbohydrate chemistry would require temporary protection of all
hydroxyls and the amine prior to introduction of the anomeric
thioethyl group, making such a route rather lengthy and less atom
Current efforts in our group are directed at the expansion of
the substrate scope of this transformation to access further
members of the family of 2-aminosugars as well as its un-
natural analogues.
This research was supported by ETH Zurich (TH Grant 16
06-3), a Kekule Fellowship from the Fonds der Chemischen
´
Industrie (to A. A.), a Niels–Stensen Postdoctoral Fellowship
(to M. T.), a Fellowship from the Studienstiftung des
deutschen Volkes (to P. S.) and an Emmy Noether Fellowship
of the Deutsche Forschungsgemeinschaft (to D. B. W.).
economic. For
a recent example, see A. A. Sherman,
Notes and references
O. N. Yudina, Y. V. Mironov, E. V. Sukhova, A. S. Shashkov,
V. M. Menshov and N. E. Nifantiev, Carbohydr. Res., 2001, 336,
13–46.
1. D. B. Werz, R. Ranzinger, S. Herget, A. Adibekian, C. W. von der
Lieth and P. H. Seeberger, ACS Chem. Biol., 2007, 2, 685–691.
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 3549–3551 | 3551