A novel approach to the synthesis of N-substituted 1-C-aminomethyl glycofuranosides

Article abstract of DOI:10.1055/s-2005-922762

Reductive amination of formyl C-glycofuranosides, easily available from hexose-derived equatorial-2-OH-glycopyranosides by DAST-promoted ring contraction, afforded N-substituted 1-C-aminomethyl glycofuranosides in most cases in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-922762

LETTER
45
A Novel Approach to the Synthesis of N-Substituted 1-C-Aminomethyl
Glycofuranosides
Synthesis of
N
-Sub
o
stituted 1-
C
l
-Amino
a
methyl
G
ly
n
cofuranosid
d
es a Vera-Ayoso,a Pastora Borrachero,a Francisca Cabrera-Escribano,*a Manuel Gómez-Guillén,a Pierre Vogelb
a
Departamento de Química Orgánica ‘Profesor García González’, Facultad de Química, Universidad de Sevilla,
Apartado de Correos No. 553, 41071 Sevilla, Spain
Fax +34(95)4624960; E-mail: fcabrera@us.es
b
Laboratoire de Glycochimie et Synthèse Asymétrique, Swiss Federal Institute of Technology (EPFL),
BCH-EPFL, 1015 Lausanne, Switzerland
Received 18 October 2005
syl cyanide8 or, (c) by degradation of a C-vinyl glycoside
and subsequent formation of the azidomethyl intermedi-
ate.3b Alternatively, rearrangement involving 5-exo SN2-
opening of a terminal aziridine ring, and transformation of
a primary hydroxyl function into the corresponding azide
gave access to the 2,5-anhydro derivatives 34 and 4,9 re-
spectively. These routes are rather complicated, and for
those involving an anomeric carbon–carbon bond-form-
ing reaction, chemical efficiency and stereocontrol remain
a difficult task. Moreover, for reaching an N-substituted
1-C-aminomethyl glycoside, additional N-alkylation pro-
cess would be still required.
Abstract: Reductive amination of formyl C-glycofuranosides, eas-
ily available from hexose-derived equatorial-2-OH-glycopyrano-
sides by DAST-promoted ring contraction, afforded N-substituted
1-C-aminomethyl glycofuranosides in most cases in high yields.
Key words: 1-C-aminomethyl glycofuranosides, formyl C-glyco-
furanosides, reductive amination, DAST-promoted ring contrac-
tion, sugar diamines
The stereoselective synthesis of functionalized C-glyco-
sides has become an important area of carbohydrate re-
search, as many naturally occurring C-glycosides show
useful antibacterial, antiviral, and antitumoral properties.1
One significant type of C-glycoside derivatives are 1-C-
aminomethyl glycosides. These compounds are key inter-
mediates for glycoconjugate syntheses, and a number of
them have proved to be glycosidase inhibitors.2 Sugar
amino acids 23 and 3,4 which containing the substructure
1 (Figure 1), are dipeptide isosters and have been used as
secondary structure inducing elements for the generation
of peptide-based drugs. This kind of substructure is also
found in the naturally occurring alkaloid muscarine (4), a
rigid muscarinic agonist of acetylcholine,5 for which a
renewed interest is due, in part, to the suggestion that
various subtypes of muscarinic receptors seem to be
implicated6 in Alzheimer’s disease.
Here we introduce a straightforward approach to N-sub-
stituted 1-C-aminomethyl glycofuranosides from hexose-
derived equatorial-2-OH-glycopyranosides (Scheme 1).
The strategy takes advantage of a diethylaminosulfur
trifluoride (DAST)-promoted ring contraction that, under
remarkably mild conditions, leads to formyl C-glyco-
furanosides.10 The use of these compounds in standard
coupling reactions with nucleophiles should provide a
ready access to hydrolytically stable C-glycofuranoside-
based molecules (C-oligosaccharides and C-glycocon-
jugates). With this aim, our first goal has been to explore
their coupling with biologically relevant amines as nitro-
gen-containing nucleophiles.
O
Syntheses of 1-C-aminomethyl glycosides so far de-
scribed rely on the introduction of a CH2NH2 equivalent
at the anomeric position: (a) as CH3NO2 via nucleophilic
aldol reaction,7 (b) by reducing the corresponding glyco-
R
R
R
HO
O
OMe
NR1R2
H
O
O
O
+
OMe
R
HOOC
HNR1R2
O
R
n
HO
HO
HO
NH2
NH2
O
O
Scheme 1
OH
1 n = 0, 1
2
HO
HO
OH
We describe herein the synthesis of enantiopure orthogo-
nally protected C-glycofuranosyl diamines by reductive
amination of formyl C-glycofuranosides, easily obtained
as their synthetic equivalents 6 and 12 from the methyl
equatorial-2-OH-glycohexopyranosides 5 and 11, respec-
tively, by DAST methodology.10,11
Me
CH2NMe2
CH2NH2
HOOC
O
3
4
Figure 1
Treatment of the crude aldehyde obtained in situ by hy-
drolysis (9:1 TFA–H2O, r.t., 1 h) of the dimethyl acetal 6,
with diverse primary or secondary amines (1.4 mol equiv)
SYNLETT 2006, No. 1, pp 0045–0048
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-922762; Art ID: D32105ST
© Georg Thieme Verlag Stuttgart · New York
0
5.
0
1.
2
0
0
6

46
Y. Vera-Ayoso et al.
LETTER
MeONa,
MeOH
1M
1. 9:1 TFA/H2O,
r.t., 1 h
2. RNH2 or R1R2NH,
NaBH(OAc)3
DCE, 25 °C
1. DAST, MeCN,
reflux, 12 min
HO
N3
AcO
N3
AcO
N3
O
O
Ph
O
r.t., 2 h
2. i. MeOH, PTSA,
r.t., 1 h
ii. Ac2O,
NR1R2
HO
NR1R2
OMe
OMe
AcO
AcO
HO
OMe
O
O
O
N3
pyridine, 0 °C
6
5
8
7
(69%)
(75–95%)
(35–88%)
Scheme 2
in dry 1,2-dichloroethane, and subsequent reduction of the corresponding reductive amination compounds 7a–e as
respective, not isolated, imine using sodium triacetoxy- the sole product. In the case of the other aniline deriva-
borohydride (1.4 mol equiv), afforded the respective com- tives (2-biphenylamino, ethyl 4-aminobenzoate and 4-
pounds 7a–h in moderate to high yields (Scheme 2, aminobenzonitrile, entries 8–10), however, reductive
Table 1).12 Their deprotection with 1 M NaMeO–MeOH amination products 7f–h were obtained together with the
gave the corresponding products 8a–h.13
primary alcohol 10.
As shown in Table 1, primary and secondary aliphatic Starting from N-aminomorpholine as the amine (entry 5),
amines (benzylamine, piperidine, benzyloxycarbonyl pip- the only isolated product was the hydrazone 9, which
erazine, and morpholine, entries 1–4), as well as the aro- could not be reduced by the reagent employed. When us-
matic amine 4-hydroxymethyl aniline (entry 6), gave the ing imidazole as the starting amine (entry 7), the expected
Table 1 Reductive Amination Products 7 of the Formyl Azido-C-glycofuranoside Synthetic Equivalent 6 with Various Amines, and Their
Deacetylated Products 8a
Entry
1
Amines R1R2NH
Reaction time (h)
3
Products 712 (yield after purification, %)
Products 813 (yield, %)
H2N
7a (55)
8a (75)
2
3
4
5
7b (65)
7c (80)
7d (67)
8b (92)
8c (95)
8d (87)
HN
Cbz
N
2.5
6
HN
O
HN
AcO
N3
O
O
b
N
5
6
7
1.5
2
–
N
AcO
N
O
H2N
9 (88)
OH
7e (77)
8e (90)
H2N
AcO
N3
NH
N
20
–
OH
AcO
O
1011 (56)
Ph
8
9
18
18
18
7f (63) + 10 (19)
7g11 (47) + 10 (34)
7h (35) + 10 (48)
8f (85)
8g (86)
8h (89)
H2N
COOEt
CN
H2N
10
H2N
a All products were fully characterized by their IR, 1H NMR, 13C NMR, and HRMS spectral data.14
b Complex mixture of products.
Synlett 2006, No. 1, 45–48 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Substituted 1-C-Aminomethyl Glycofuranosides
47
DAST, CH2Cl2,
reflux, 1.5 h
9:1 TFA/H2O,
F
OBn
H
BnO
HO
BnO
r.t., 1 h
O
(65–79%)
(92%)
OMe
OMe
BnO
HO
O
F
11
12
O
O
Boc
F
OBn
NH2
6'
N
F
OBn
1'
N
14
2
1
5'
4'
NH
Boc
2'
3'
BnO
O
BnO
H
NaBH(OAc)3
DCE, r.t., 1.5 h
O
O
O
15
O
13
(70% from 12)
Scheme 3
2,5-anhydro-1-(imidazol-1-yl)-D-altritol derivative was References and Notes
not obtained, only 10 was obtained. The reason of this be-
(1) (a) Fischer, C.; Lipata, F.; Rohr, J. J. Am. Chem. Soc. 2003,
125, 7818. (b) Faizi, S.; Ali, H. Planta Med. 1999, 65, 383.
(2) (a) Gremyachinskiy, D. E.; Samoshin, V. V.; Gross, P. H.
Tetrahedron Lett. 2003, 44, 6587. (b) Bhat, A. S.; Gervay-
Hague, J. Org. Lett. 2001, 3, 2081. (c) BeMiller, J. N.;
Gilson, R. J.; Myers, R. W.; Santoro, M. M.; Yadav, M. P.
Carbohydr. Res. 1993, 250, 93. (d) Lai, W.; Martin, O. R.
Carbohydr. Res. 1993, 250, 185. (e) Maity, S. K.; Dutta, S.
K.; Banerjee, A. K.; Achari, B.; Singh, M. Tetrahedron
1994, 50, 6965. For 2-(aminomethyl)pyrrolidine-3,4-diol
derivatives, see: (f) Saotome, C.; Wong, C.-H.; Kanie, O.
Chem. Biol. 2001, 8, 1061. (g) Popowycz, F.; Gerber-
Lemaire, S.; Schütz, C.; Vogel, P. Helv. Chim. Acta 2004,
87, 800. (h) Fiaux, H.; Popowycz, F.; Favre, S.; Schütz, C.;
Vogel, P.; Gerber-Lemaire, S.; Juillerat-Jeanneret, L. J.
Med. Chem. 2005, 48, 4237. (i) Popowycz, F.; Gerber-
Lemaire, S.; Rodriguez-García, E.; Schütz, C.; Vogel, P.
Helv. Chim. Acta 2003, 86, 1914.
havior of imidazole may be its weak nucleophilic charac-
ter, much lower than those of the remainder amines used.
In the same way, formation of the primary alcohol 10 as
accompanying product of 7f–h, arise from the lack of
nucleophilicity provoked by the electron-withdrawing
substituent at the para position of the anilines.
A shorter experimental protocol, in which a 2,5-anhydro-
1-fluoro-1-O-methylhexitol (a formyl C-glycofuranoside
synthetic equivalent directly formed in the ring-contrac-
tion reaction promoted by DAST) is subjected to hydro-
lysis and subsequent in situ reductive amination process,
can be applied. Adopting this one-pot procedure, fluoro
aldehyde 13 obtained in situ by hydrolysis (9:1 TFA–
H2O, r.t., 1 h) of (1R,1S)-2,5-anhydro-3,6-di-O-benzyl-4-
deoxy-1,4-difluoro-1-O-methyl-D-talitol (12),10a was
made react with diamine 14,15 furnishing fluoro-C-glyco-
furanosyl aminomethylpyrrolidine derivative 15 in good
yield (Scheme 3).16
(3) (a) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H.
Chem. Rev. 2002, 102, 491. (b) Durrat, F.; Xie, J.; Valéry,
J.-M. Tetrahedron Lett. 2004, 45, 1477.
(4) For recent reviews see: (a) Chakraborty, T. K.; Srinivasu,
P.; Tapadar, S.; Mohan, B. K. Glycoconjugate J. 2005, 22,
83. (b) Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.;
Mohan, B. J. Chem. Sci. 2004, 116, 187. See also:
(c) Prasad, S.; Mathur, A.; Jaggi, M.; Sharma, R.; Gupta, N.;
Reddy, V. R.; Sudhakar, G.; Kumar, S. U.; Kumar, S. K.;
Kunwar, A. C.; Chakraborty, T. K. J. Pept. Res. 2005, 66,
75. (d) Chakraborty, T. K.; Jayaprakash, S.; Diwan, P. V.;
Nagaraj, R.; Jampani, S. R. B.; Kunwar, A. C. J. Am. Chem.
Soc. 1998, 120, 12962. (e) Chakraborty, T. K.; Ghosh, S.;
Jayaprakash, S.; Sarma, J. A. R. P.; Ravikanth, V.; Diwan, P.
V.; Nagaraj, R.; Kunwar, A. C. J. Org. Chem. 2000, 65,
6441.
(5) Patrick, G. L. An Introduction to Medicinal Chemistry, 2nd
ed.; Oxford University Press: Oxford, 2002, 446.
(6) (a) Broadley, K. J.; Kelly, D. R. Molecules 2001, 6, 142.
(b) Liu, J.-K. Chem. Rev. 2005, 105, 2723.
(7) (a) Locardi, E.; Stöke, M.; Gruner, S.; Kessler, H. J. Am.
Chem. Soc. 2001, 123, 8189. (b) Graf von Roedern, E.;
Kessler, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 687.
(c) Graf von Roedern, E.; Kessler, H. Angew. Chem., Int. Ed.
Engl. 1994, 33, 684.
In conclusion, this work provides a simple approach to the
synthesis of functionalized N-substituted aminomethyl C-
glycofuranosides by reductive amination of formyl C-gly-
cofuranosides, readily available by DAST methodology
from hexose-derived equatorial-2-OH-glycopyranosides.
The method works well with good nucleophilic amines
and allows complete stereocontrol at the anomeric center.
Stereo- and functional diversity on the furanoid ring could
be achieved on starting from different equatorial-2-OH-
glycohexopyranosides. Extension of this work to other
substrates as well as studies with other nucleophiles is
currently under investigation.
Acknowledgment
We thank the European Commission, Directorate General for
Science and Development (FP6-508430), the Spanish ‘Ministerio
de Ciencia y Tecnología’ (predoctoral fellowship to Y.V.-A.), and
the ‘Junta de Andalucía’ (FQM142) for financial support.
(8) Benksim, A.; Beaupère, D.; Wadouahi, A. Org. Lett. 2004,
6, 3913.
(9) Mantell, S. J.; Fleet, G. W. J.; Brown, D. J. Chem. Soc.,
Perkin Trans. 1 1992, 3023.
Synlett 2006, No. 1, 45–48 © Thieme Stuttgart · New York

48
Y. Vera-Ayoso et al.
LETTER
(14) In comparison with the NMR spectra of each direct
(10) (a) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.;
Carmona, A. T.; Gómez-Guillén, M. Tetrahedron:
Asymmetry 2004, 15, 429. (b) Borrachero, P.; Cabrera-
Escribano, F.; Carmona, A. T.; Gómez-Guillén, M.
Tetrahedron: Asymmetry 2000, 11, 2927. (c) Borrachero-
Moya, P.; Cabrera-Escribano, F.; Gómez-Guillén, M.;
Madrid-Díaz, F. Tetrahedron Lett. 1997, 38, 1231.
(11) Vera-Ayoso, Y.; Borrachero, P.; Cabrera-Escribano, F.;
Gómez-Guillén, M. Tetrahedron: Asymmetry 2005, 16, 889.
(12) General Procedure for the One-Pot Preparation of
Compounds 7.
precursor, each acetylated compound 7a–h lacked any signal
of aldehyde proton and carbon, but showed instead the
signals corresponding to the two new diastereotopic protons
at C(1). For the compounds obtained from some primary
amines (7e,f–h), the amine proton gave rise to the typical
broad signal in the 1H NMR spectrum at d = 4.41 (7e), 4.44–
4.38 (7f), 5.81 (7g), and 6.00 ppm (7h), values that can be
correlated with the electron-withdrawing or electron-
donating character of the substituent at the para position of
the aromatic group. However, the amine proton signal of 7a
was not observed, probably because it is overlapped. The
molecular weight found for 9 in its HRMS agreed with the
aldimine structure assigned, while its NMR spectra showed
the sp2 (C)H signal at d = 6.86 ppm and the imine carbon at
d = 134.1 ppm, thus corroborating the assignation. For the
deacetylated compounds 8a–h, their respective calculated
molecular weights were in agreement with those found by
HRMS. Furthermore, the 1H NMR and 13C NMR spectra of
these compounds showed no signal corresponding to the O-
acetyl groups present in the precursors 7a–h, as expected.
(15) Popowycz, F.; Gerber-Lemarie, S.; Demange, R.;
Rodriguez-García, E.; Asenjo, A. T. C.; Robina, I.; Vogel, P.
Bioorg. Med. Chem. Lett. 2001, 11, 2489.
Compound 6 (100 mg, 0.315 mmol) was dissolved in a 9:1
TFA–H2O mixture (2.7 mL) and the solution was kept at r.t.
for 1 h. The reaction mixture was poured into ice-water (100
mL) and extracted with CH2Cl2 (4 × 20 mL). The combined
organic layers were successively washed with sat. aq
NaHCO3 and brine, then dried (Na2SO4), and concentrated.
The residue (crude aldehyde) was dissolved in 1,2-
dicloroethane (3.1 mL) and treated with the amine (0.437
mmol) and sodium triacetoxyborohydride (93.0 mg, 0.441
mmol). The reaction was stirred at r.t. for the appropriate
time (Table 1). The mixture was then diluted with sat. aq
NaHCO3 (25 mL) and the aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic layers were
dried (Na2SO4), and concentrated under reduced pressure to
give the crude product, which was purified by column
chromatography using EtOAc–hexane, Et2O–hexane or
Et2O–acetone as eluent.
(16) Compound 15 was obtained from 12 (100 mg, 0.265 mmol)
and diamine 14 (78 mg, 0.287 mmol) in the presence of
NaBH(OAc)3 (60.2 mg, 0.287 mmol) by a similar one-pot
procedure to that described above for the preparation of
compounds 7 from 6.
Compound 7a: Rf = 0.37 (5:1 Et2O–acetone); [a]D26 +19.3 (c
0.56, CH2Cl2). IR: nmax = 3324 (NH), 2106 (N3), 1746 (CO),
1231 and 1119 (CO) cm–1. 1H NMR (300 MHz, acetone-d6):
d = 7.25–7.08 (m, 5 H, Ph), 5.31 (dd, 1 H, J4,5 = 7.8 Hz,
3,4 = 5.1 Hz, H-4), 4.48 (dd, 1 H, J2,3 = 3.9 Hz, H-3), 4.32
(ddd, 1 H, J1,2 = J1¢,2 = 6.6 Hz, H-2), 4.23 (dd, 1 H,
6,6¢ = 10.8 Hz, J5,6 = 2.4 Hz, H-6), 4.07–3.95 (m, 2 H, H-5
More relevant data of 15: Rf = 0.45 (Et2O); [a]D24 +14.6 (c
0.63, acetone). IR: nmax = 3295 (NH), 1692 (CO), 1370
(NCO), 1157, 1059 (COC), and 991 (CF) cm–1. 1H NMR
(500 MHz, DMSO-d6, 363 K): d = 7.41–7.25 (m, 5 H, Ph),
5.27 (dt, 1 H, 2J4,F = 54.9 Hz, J3,4 = J4,5 = 3.0 Hz, H-4), 4.79,
4.63 (2 d, 1 H each, JH,H¢ = 11.5 Hz, CH2Ph), 4.69 (dd, 1 H,
J
J
and H-6′), 3.83 (d, 1 H, JH,H¢ = 13.5 Hz, CHaPh), 3.78 (d, 1
H, JH,H¢ = 13.8 Hz, CHbPh), 2.82 (d, 2 H, H-1 and H-1′), 2.11
and 2.02 (each 2 s, 3 H, 2 COMe) ppm. 13C NMR (75.4 MHz,
acetone-d6): d = 170.8, 170.7 (2 CO), 141.8–127.5 (Ph), 80.0
(C-2), 78.1 (C-5), 75.8 (C-4), 64.6 (C-6), 64.4 (C-3), 54.4
(CH2Ph), 49.4 (C-1), 20.7 and 20.4 (2 COMe) ppm. HRMS
(CI): m/z calcd for C17H22N4O5 + H: 363.1668; found
363.1671.
J4¢,3¢ = J4¢,5¢b = 5.7 Hz, H-4′), 4.62 (d, 1 H, H-3′), 4.55 (s, 2 H,
CH2Ph), 4.38 (dddd, 1 H, 3J5,F = 30.5 Hz, J5,6a = J5,6b = 6.0
Hz, H-5), 4.33–4.21 (m, 2 H, H-2 and H-2′), 4.17 (dt, 1 H,
3J3,F = 23.5 Hz, J2,3 = 8.5 Hz, H-3), 3.75 (dd, 1 H,
J6a,6b = 10.2 Hz, H-6a), 3.75 (d, 1 H, J5¢a,5¢b = 14.0 Hz, H-5′a),
3.60 (ddd, 1 H, 4J6b,F = 1.8 Hz, H-6b), 3.32 (dd, 1 H, H-5′b),
3.20–2.91 (m, 4 H, H-1a, H-1b, H-6′a, H-6′b), 1.41 (s, 9 H,
CMe3), 1.34 and 1.25 (each 2 s, 3 H, CMe2) ppm. 13C NMR
(125.7 MHz, DMSO-d6, 363 K): d = 152 (CO), 137.7–126.8
(Ph), 110.6 (CMe2), 89.1 (d, 1J4,F = 188.2 Hz, C-4), 81.6 (C-
3′), 80.1 (d, 2J3,F = 16.2 Hz, C-3), 79.5 (C-4′), 78.4 (d,
2J5,F = 17.1 Hz, C-5), 78.3 (CMe3), 74.7 (C-2), 72.2 and 71.2
(CH2Ph), 67.0 (d, 3J6,F = 11.6 Hz, C-6), 59.8 (C-2′), 50.4 (C-
5′), 49.0, 46.6 (C-1, C-6′), 27.6 (CMe3), 26.3 and 26.2
(CMe2). HRMS (CI): m/z calcd for C33H45N2O7F + H:
601.3289; found: 601.3281.
(13) General Procedure for Deacetylation of 7 and
Preparation of Compounds 8.
The corresponding reductive amination product 7 (0.070
mmol) was dissolved in: (i) (2 mL of 1:1 MeOH–CHCl3), (ii)
(2 mL of MeOH), or (iii) (2 mL of EtOH abs.), and 5 drops
of 1 M MeONa–MeOH were added to the solution [for the
deprotection of 7g was used EtONa–EtOH abs. (1 M)]. The
reaction mixture was kept at r.t. for 2 h. Work-up was done
by one of the following procedures.
Procedure 1 (8b–d,f): the reaction mixture was cooled and
600 mL TFA was added. The residue was purified by a
Dowex 50 × 8 W column, using MeOH (50 mL), H2O (50
mL) and NH4OH (10% aq soln; 100 mL) as eluents.
Procedure 2 (8a,e,g,h): the reaction mixture was neutralized
with Amberlyst 15, the resin was removed by filtration and
the solvent under reduced pressure.
Synlett 2006, No. 1, 45–48 © Thieme Stuttgart · New York