Small-scale one-pot reductive alkylation of unprotected aminocyclitols with supported reagents

Article abstract of DOI:10.1055/s-2008-1067258

A protocol for the reductive alkylation of unprotected aminocyclitols with supported reagents and scavengers is described. The method is operatively simple and provides the corresponding secondary amines in high yields and purities. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067258

SPECIAL TOPIC
3167
Small-Scale One-Pot Reductive Alkylation of Unprotected Aminocyclitols with
Supported Reagents
Reductive Alkylation
o
i
f
U
npr
r
otected
A
o
minocyclito
s
ls lav Sisa,a,b,1 Ana Trapero,a Amadeu Llebaria,a Antonio Delgado*a,b
a
Research Unit on BioActive Molecules (RUBAM), Departament de Química Orgànica Biològica,
Institut d’Investigacions Químiques i Ambientals de Barcelona (IIQAB-C.S.I.C), Jordi Girona 18–26, 08034 Barcelona, Spain
Fax +34(93)2045904; E-mail: adelgado@cid.csic.es
Facultat de Farmàcia, Unitat de Química Farmacèutica (Unitat Associada al CSIC), Universitat de Barcelona,
Avgda. Juan XXIII, s/n, 08028 Barcelona, Spain
b
Received 6 May 2008
nocyclitol libraries for its preliminary evaluation as gluco-
cerebrosidase inhibitors.17 An inherent limitation of the
method was the need to carry out the N-alkylation step on
a fully protected penta-O-benzylaminocyclitol scaffold.
This required a subsequent ‘on-bench’ massive deprotec-
tion of the library members, since the required reaction
conditions were not compatible with the technical restric-
tions imposed by the robotic automated system used. For
this reason, the possibility to carry out the N-alkylation
step from a fully unprotected aminocyclitol scaffold
seemed attractive to us. As an additional value, the design
of a simple and efficient workup and purification proto-
cols would enable the construction and in situ screening of
large aminocyclitol libraries.
Abstract: A protocol for the reductive alkylation of unprotected
aminocyclitols with supported reagents and scavengers is de-
scribed. The method is operatively simple and provides the corre-
sponding secondary amines in high yields and purities.
Key words: alkylations, aldehydes, supported reagents, aminocy-
clitols
Aminocyclitols are a group of aminocycloalkane polyols
found in a variety of natural products2 and synthetic com-
pounds. They have multiple applications in medicinal
chemistry as antibiotics,3 glycosidase inhibitors,4–7 modu-
lators of sphingolipid metabolism,8,9 and are used as phar-
macological tools for the study of inositol-related cellular
processes.10 In addition, some of them are advanced key
synthetic intermediates in the total synthesis of several
Amarilladaceae alkaloids.11
Initial experiments were addressed at the direct reductive
alkylation of unprotected 1-amino-1-deoxy-scyllo-inosi-
tol (1) and aldehyde 2a (1.5:1 ratio) with NaBH3CN (2.8
equiv/mol) in MeOH–H2O (5:1) in the presence of a cata-
lytic amount of AcOH.18 This afforded a mixture of
amines (the expected secondary amine, together with mi-
nor amounts of the corresponding tertiary amine and some
unreacted starting amine) after reaction workup.19 The use
of an alternative water-compatible reducing agent, such as
a-picoline-borane20 afforded complex reaction mixtures
under otherwise similar reaction conditions. As an alter-
native strategy, we considered the use of polymer support-
ed cyanoborohydride (PSCBH)21 and the decrease of the
water content of the system by using DMSO as a solvent,
which would presumably drive the equilibrium towards
imine formation. Interestingly, the choice of the solvent
system was critical for the efficiency of the process, since
only DMSO afforded a good balance between solubility
of the starting aminocyclitol and reaction rates in the pres-
ence of excess PSCBH.22 The molar ratio of aldehyde ver-
sus aminocyclitol was also important in this reaction
system, since an excess aldehyde (3:1 ratio) led to a non-
negligible percentage of overalkylation to the correspond-
ing tertiary amine, whereas an excess aminocyclitol might
avoid the above problem at the expense of the reaction
yield.23 In both scenarios, the presence of significant
amounts of residual starting amine or tertiary amine
would complicate the purification of the required second-
ary amine. After some experimentation, a molar ratio of
1.5:1 (aminocyclitol/aldehyde) was considered optimal
and it was used in all experiments. Reductive alkylation of
The use of combinatorial chemistry to generate libraries
of compounds is a common approach in medicinal chem-
istry to explore the chemical space in search of new enti-
ties with defined biological profiles. Along this line,
nitrogen functionalization of aminocyclitol systems offers
the opportunity to explore the influence of side chain vari-
ations in structure–activity studies. A common structural
modification is N-alkylation. Classical approaches to N-
alkylaminocyclitols include, inter alia, the regio and ste-
reoselective nucleophilic attack of suitable amines upon
appropriate cyclitol epoxides,12 sulfites13 or sulfates,14 and
the reductive amination of polyhydroxy cyclohex-
anones.15 Although reductive alkylation of amines with
aldehydes or ketones is a common approach to secondary
and, to a lesser extent, tertiary amines, this method has
been scarcely used in the aminocyclitol arena. In some
cases,16 the method requires elaborated and cumbersome
purification protocols that make the process unsuitable for
combinatorial chemistry, where the simultaneous manip-
ulation and workup of a large number of reactions, some-
times in a microtiter plate format, is required for library
production. In this context, we recently reported on a
combinatorial approach leading to N-substituted ami-
SYNTHESIS 2008, No. 19, pp 3167–3170
x
x.
x
x
.
2
0
0
8
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067258; Art ID: C13208SS
© Georg Thieme Verlag Stuttgart · New York

3168
M. Sisa et al.
SPECIAL TOPIC
amines with cyanoborohydride requires the use of acidic resin (Wang resin), which played the role of reaction scav-
conditions to ensure the protonation and activation of the enger in this process.
intermediate imine for the subsequent borohydride reduc-
The above optimized procedure was tested with a set of
tion.23 In our case, the use of excess AcOH afforded good
aromatic and aliphatic aldehydes 2a–i with different steric
results.24 The resulting aminocyclitol acetates could be
easily freed at the end of the process by treatment with the
basic carbonate resin IRA900, as described in the experi-
and/or electronic demands (Table 1).25 In all cases, puri-
ties and yields of the resulting aminocyclitols 3a–i were
good to excellent, as determined by HPLC(LS) and
mental section. Finally, in order to design a methodology
HPLC-MS of the crude material. No trace of the corre-
amenable to combinatorial protocols, the excess of start-
sponding tertiary amine was detected in any of the above
examples, which proves the versatility and reproducibility
ing aminocyclitol 1 was removed with PS-benzaldehyde
Table 1 One-Pot Reductive Alkylation of Aminocyclitols with Supported Reagents and Scavengers
NMe3 NaCO3
OH
OH
H
N
HO
HO
NH2
HO
HO
R
NMe3 BH3CN
DMSO, AcOH
O
R
+
+ excess 1
(3a–i) (AcOH )
OH
H
OH
OH
OH
CHO
(removal from mixture)
1
2a–i
3a–i
Entry
1
Aldehyde R
Yield (%) (purity, %)a
96 (100)
2a
2
3
95 (100)
90 (94)
O
F
2b
Cl
2c
4
5
77 (80)
73 (76)
2d
2e
6
7
8
90 (96)
83 (95)
85 (95)
2f
2g
2h
9
84 (97)
N
2i
a Yields based on purities estimated from HPLC using a light scattering detector.
Synthesis 2008, No. 19, 3167–3170 © Thieme Stuttgart · New York

SPECIAL TOPIC
Reductive Alkylation of Unprotected Aminocyclitols
3169
( )-1-Amino-1-deoxy-chiro-inositol (4)
of our protocol. Interestingly, this process has also been
successfully applied to the reductive alkylation of the iso-
meric ( )-1-amino-1-deoxy-chiro-inositol (4) with alde-
hydes 2c and 2j with similar results (Scheme 1).
Following the same protocol described for 1, ( )-1-azido-1-deoxy-
2,3,4,5-tetra-O-benzyl-chiro-inositol12 afforded the aminocyclitol 4
in 97% isolated yield.
1H NMR (500 MHz, D2O): d = 3.28 (t, J = J¢ = 4.0 Hz, 1 H), 3.50
(m, 2 H), 3.73 (dd, J = 9.6, 3.8 Hz, 1 H), 3.80 (dd, J = 9.6, 4.4 Hz,
1 H), 3.85 (t, J = J¢= 3.3 Hz. 1 H).
OH
OH
HO
HO
OH
HO
HO
OH
O
R
HRMS: m/z calcd for C6H14NO5: 180.0872; found: 180.0865.
see Table 1
+
NH2
R
N
H
H
Reductive Alkylation of 1 and 4 with Aldehydes 2a–j; General
Procedure
OH
OH
4
To a screw cap glass vial was added a solution of 1 or 4 (15 mg, 83
mmol) in DMSO (3.5 mL), followed by AcOH (70 mL) and the ap-
propriate aldehyde 2a–j (55 mmol) at r.t. After shaking for 1 h, sup-
ported cyanoborohydride (150 mg, equiv to 300 mmol) was added
portionwise and the mixture was shaken for additional 16 h. Wang
resin (15 mg, equiv to 45 mmol) was added and the resulting slurry
was shaken for 12 h. The resins were filtered and thoroughly
washed with MeOH–H2O (9:1). The combined filtrates were evap-
orated to dryness and the residue was taken up in 9:1 MeOH–H2O
(3 mL). This solution was treated with carbonate resin (500 mg,
equiv to 1.75 mmol) and Wang resin (15 mg, equiv to 45 mmol) and
stirred for 4 h. The resins were filtered, washed with MeOH–H2O
(9:1), and evaporated to dryness to give compounds 3a–i, 5c, and 5j
(Table 1).
5c: R = 2-Cl-5-FC6H3; 81% (88%)
5j: R = 2-MeOC6H4; 85% (93%)
2c (see Table 1)
2j R = 2-MeOC6H4
Scheme 1 Reaction of inositol 4 with aldehydes 2c and 2j; yields
are based on isolated compounds and purities are shown in brackets
In summary, a solution-phase procedure for the reductive
alkylation of unprotected aminocyclitols 1 and 4 with a set
of aldehydes with different structural and electronic re-
quirements has been developed with the aid of supported
reagents and scavengers. The corresponding secondary
amines are obtained in generally high yields and purities
with no trace of the undesired tertiary amines. The method
is operatively simple and easily adaptable to combinatori-
al protocols
1-(4-Phenylbenzyl)amino-1-deoxy-scyllo-inositol (3a)
1H NMR (500 MHz, MeOD): d = 2.60 (t, J = 10.0 Hz, 1 H), 3.25–
3.41 (m, not integrated, overlapped with MeOD), 4.04 (s, 2 H),
7.36–7.41 (m, 1 H), 7.46–7.50 (m, 4 H), 7.63–7.67 (m, 4 H).
All the materials were obtained commercially and used without fur-
ther purification. Solvents were distilled prior to use and dried by
standard methods.26 Analytical samples were homogeneous as con-
firmed by TLC and afforded spectroscopic results consistent with
the assigned structures. NMR spectra were recorded on a 500 MHz
instrument. Chemical shifts are reported in delta units (d), parts per
million (ppm) relative to the central signal of the quintuplet cen-
tered at 3.31 ppm for MeOD. TLC was performed on silica gel (Alu-
gram Sil G/UV). HPLC conditions for aminocyclitol analysis:
RPC18 column (5 m, 110 Å); solvent A (H2O + 1% TFA); solvent B
(MeCN + 1% TFA); conditions 1 (for compounds 3c, 3f, 3g, 3h, 3i,
5c): t = 0 min (80% A; 20% B); t = 9 min (56% A; 44% B); t = 14
min (56% A; 44% B); conditions 2 (compounds 3a, 3b, 3d, 3e, 5j):
t = 0 min (90% A; 10% B); t = 10 min (90% A; 10% B); t = 15 min
(0% A; 100% B); t = 20 min (0% A; 100% B). The following resins
HRMS: m/z calcd for C19H23NO5 (M + H+): 346.1646; found:
346.1654.
1-(3-Benzyloxyphenyl)amino-1-deoxy-scyllo-inositol (3b)
1H NMR (500 MHz, MeOD): d = 2.47 (t, J = 9.5 Hz, 1 H), 3.12–
3.30 (m, 5 H), 4.00 (s, 2 H), 6.87–6.91 (m, 1 H), 6.99 (s, 1 H), 7.00
(s, 1 H), 7.05 (s, 1 H), 7.09–7.16 (m, 2 H), 7.30–7.38 (m, 3 H).
HRMS: m/z calcd for C19H23NO6 (M + H+): 362.1598; found:
362.1604.
1-(2-Chloro-4-fluorobenzyl)amino-1-deoxy-scyllo-inositol (3c)
1H NMR (500 MHz, MeOD): d = 2.40–2.46 (m, 1 H), 3.12–3.39 (m,
not integrated, overlapped with MeOD), 4.16 (s, 2 H), 7.05–7.10
(m, 1 H), 7.21–7.26 (m, 1 H), 7.52–7.57 (m, 1 H).
HRMS: m/z calcd for C13H17ClFNO5 (M + H+): 322.0858; found:
322.0862.
–
were used in this study: IRA 900 (NaCO3 form, Fluka, Cat. #
21850, 3.5 mmol/g loading), Wang resin (Aldrich, Cat. # 547409,
3.0 mmol/g loading), IRA 900 (BH3CN– form, Aldrich, Cat. #
526304, 2.0 mmol/g loading).
1-Butylamino-1-deoxy-scyllo-inositol (3d)
1H NMR (500 MHz, MeOD): d = 0.90–1.00 (m, 3 H), 1.29–1.56 (m,
4 H), 2.33–2.39 (m, 1 H), 2.85 (t, J = 7.5 Hz, 2 H), 3.14–3.28 (m, 5
H).
HRMS: m/z calcd for C10H21NO5 (M + H+): 236.1498; found:
236.1496.
1-Amino-1-deoxy-scyllo-inositol (1)
A
solution of 1-azido-1-deoxy-2,3,4,5-tetra-O-benzyl-scyllo-
inositol12 (1 g, 1.8 mmol) in a 1:1 mixture of THF–MeOH (30 mL)
containing aq 35% HCl (0.5 mL) was treated with 10% Pd/C (100
mg) and stirred at r.t. for 24 h under H2 (3 atm). The mixture was
filtered and the solid residue washed with MeOH–H2O mixture (5
mL). The combined filtrates were evaporated to dryness to give
1·HCl as a solid in quantitative yield. The above hydrochloride was
taken up in a 9:1 MeOH–H2O mixture (50 mL) and stirred for 3 h at
r.t. in the presence of IRA 900 resin (NaCO3– form, 2 g, equivalent
to 7 mmol). The resin was next filtered and washed with an addi-
tional 9:1 MeOH–H2O mixture (10 mL) and the combined filtrates
were evaporated to dryness to give 1; yield: 315 mg (98%).
1-(2,2-Dimethylpropyl)amino-1-deoxy-scyllo-inositol (3e)
1H NMR (500 MHz, MeOD): d = 0.96 (s, 9 H), 2.32 (t, J = 10.0 Hz,
1 H), 3.15–3.31 (m, not integrated, overlapped with MeOD).
HRMS: m/z calcd for C11H23NO5 (M + H+): 250.1654; found:
250.1660.
1-(2-Methylpropyl)amino-1-deoxy-scyllo-inositol (3f)
1H NMR (500 MHz, MeOD): d = 0.95 (d, J = 6.5 Hz, 6 H), 1.73–
1.82 (m, 1 H), 2.31–2.37 (m, 1 H), 2.67 (d, J = 9.0 Hz, 2 H), 3.10–
3.27 (m, 5 H).
1H NMR (500 MHz, D2O): d = 2.62 (t, J = J¢ = 10.0 Hz, 1 H), 3.18
(t, J = J¢ = 9.3 Hz, 2 H), 3.27–3.34 (m, 3 H).
HRMS: m/z calcd for C6H14NO5: 180.0872; found: 180.0867.
Synthesis 2008, No. 19, 3167–3170 © Thieme Stuttgart · New York

3170
M. Sisa et al.
SPECIAL TOPIC
HRMS: m/z calcd for C10H21NO5 (M + H+): 236.1498; found:
236.1498.
(4) El Ashry, E. S.; Rashed, N.; Shobier, A. H. Pharmazie 2000,
55, 403.
(5) El Ashry, E. S.; Rashed, N.; Shobier, A. H. Pharmazie 2000,
55, 331.
(6) El Ashry, E. S.; Rashed, N.; Shobier, A. H. Pharmazie 2000,
55, 251.
1-(3-Methylbutyl)amino-1-deoxy-scyllo-inositol (3g)
1H NMR (500 MHz, MeOD): d = 0.94 (d, J = 6 Hz, 6 H), 1.40–1.46
(m, 2 H), 1.57–1.73 (m, 1 H), 2.36–2.44 (m, 1 H), 2.89 (t, J = 8 Hz,
2 H), 3.13–3.28 (m, 5 H).
HRMS: m/z calcd for C11H23NO5 (M + H+): 250.1654; found:
250.1638.
(7) Lysek, R.; Schutz, C.; Favre, S.; O’Sullivan, A. C.; Pillonel,
C.; Krulle, T.; Jung, P. M.; Clotet-Codina, I.; Este, J. A.;
Vogel, P. Bioorg. Med. Chem. 2006, 14, 6255.
(8) Delgado, A.; Casas, J.; Llebaria, A.; Abad, J. L.; Fabrias, G.
Biochim. Biophys. Acta, Biomembr. 2006, 1758, 1957.
(9) Delgado, A.; Casas, J.; Llebaria, A.; Abad, J. L.; Fabrias, G.
ChemMedChem 2007, 2, 580.
(10) Clarke, J. H. Curr. Biol. 2003, 13, R815.
(11) Hudlicky, T.; Abboud, K. A.; Entwistle, D. A.; Fan, R.;
Maurya, R.; Thorpe, A. J.; Bolonick, J.; Myers, B. Synthesis
1996, 897.
1-Phenethylamino-1-deoxy-scyllo-inositol (3h)
1H NMR (500 MHz, MeOD): d = 2.58 (t, J = 10.5 Hz, 2 H), 2.79–
2.84 (m, 1 H), 3.10–3.26 (m, 7 H), 7.15–7.68 (m, 5 H).
HRMS: m/z calcd for C19H23NO5 (M + H+): 284.1498; found:
284.1500.
1-(2-Pyridylmethyl)amino-1-deoxy-scyllo-inositol (3i)
1H NMR (500 MHz, MeOD): d = 2.57–2.65 (m, 1 H), 3.11–3.31 (m,
not integrated, overlapped with MeOD), 4.18 (s, 2 H), 7.28–7.34
(m, 1 H), 7.44–7.52 (m, 1 H), 7.77–7.84 (m, 1 H), 8.49–8.55 (m, 1
H).
HRMS: m/z calcd for C12H18N2O5 (M + H+): 271.1294; found:
271.1285.
(12) Serrano, P.; Llebaria, A.; Delgado, A. J. Org. Chem. 2005,
70, 7829.
(13) Shing, T. K. M.; Li, T. Y.; Kok, S. H. L. J. Org. Chem. 1999,
64, 1941.
(14) Shing, T. K. M.; Tai, V. W. J. Org. Chem. 1995, 60, 5335.
(15) Fukase, H.; Horii, S. J. Org. Chem. 1992, 57, 3651.
(16) Horii, S.; Fukase, H.; Matsuo, T.; Kameda, Y.; Asano, N.;
Matsui, K. J. Med. Chem. 1986, 29, 1038.
(17) Serrano, P.; Casas, J.; Zucco, M.; Emeric, G.; Egido-Gabas,
M.; Llebaria, A.; Delgado, A. J. Comb. Chem. 2007, 9, 43.
(18) For a related reductive alkylation of an unprotected
aminocyclitol scaffold, see: Ogawa, S.; Mori, M.; Takeuchi,
G.; Doi, F.; Watanabe, M.; Sakata, Y. Bioorg. Med. Chem.
Lett. 2002, 12, 2811.
(19) Although the starting aminocyclitol 1 could be removed
from the reaction mixture by simple precipitation from
MeOH, this was not the case with aminocyclitol 2.
(20) Sato, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y.
Tetrahedron 2004, 60, 7899.
(21) The use of supported reagents and scavengers in
combinatorial chemistry protocols facilitates workup
procedures, allows the use of excess reagents, the reduction
of the reaction scale, and avoids the hazards associated to the
handling of toxic reagents, such as NaBH3CN.
(22) Several reaction systems were tried. Aminocyclitol 1 is only
slightly soluble in MeOH, MeCN, THF, i-PrOH, and
dioxane. In our reductive alkylation protocol with PSCBH,
addition of H2O increases the solubility of 1 at the expense
of the reaction rate, which became too slow for practical
purposes.
1-(2-Chloro-4-fluorobenzyl)amino-1-deoxy-D-chiro-inositol
(5c)
1H NMR (500 MHz, MeOD): d = 3.02–3.06 (m, 1 H), 3.53–3.60 (m,
2 H), 3.80–3.92 (m, 4 H), 4.07–4.11 (m, 1 H), 7.04–7.09 (m, 1 H),
7.19–7.24 (m, 1 H), 7.48–7.53 (m, 1 H).
HRMS: m/z calcd for C13H17ClFNO5 (M + H+): 322.0852; found:
322.0859.
1-(2-Methoxybenzyl)amino-1-deoxy-D-chiro-inositol (5j)
1H NMR (500 MHz, MeOD): d = 3.00 (t, J = 4.5 Hz, 1 H), 3.51–
3.59 (m, 2 H), 3.68 (d, J = 13.5 Hz, 2 H), 3.80–3.88 (m, 3 H), 3.86
(s, 3 H), 4.13 (t, J = 3.0 Hz, 1 H), 6.90 (t, J = 7.5 Hz, 1 H), 6.97 (d,
J = 7.5 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 2 H).
HRMS: m/z calcd for C14H26NO6 (M + H+): 300.1447; found:
300.1436.
Acknowledgment
Partial financial support from the Ministerio de Ciencia y Tecnolo-
gía (Spain) (Project MCYT CTQ2005–00175/BQU), Fondos Feder
(EU), and Generalitat de Catalunya (Project 2005SGR0163) is
acknowledged. M.S. and A.T. are grateful to the Ministerio de Edu-
cación y Ciencia (Spain) for a post- and predoctoral fellowship, re-
spectively.
(23) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem.
Soc. 1971, 93, 2897.
(24) Despite formation of a putative intermediate oxazolidine,
arising from reaction of the initially formed imine with a
vicinal hydroxyl group cannot be ruled out,7 this did not
hamper the reactivity of our DMSO–AcOH system, since
aldehyde consumption was complete after 16 hours reaction
at r.t.
(25) Aldehydes 2a–c and 2j are benzaldehyde derivatives with
different electronic properties; 2e,f are a-branched aliphatic
aldehydes; 2g and 2h are b-branched (aliphatic or aromatic)
aldehydes; and 2i is an example of an heteroaromatic
aldehyde.
References
(1) On leave from IOCB (Institute of Organic Chemistry and
Biochemistry, Prague, Czech Republic).
(2) Mahmud, T. Nat. Prod. Rep. 2003, 20, 137.
(3) Ferrier, R. J.; Blattner, R.; Clinch, K.; Furneaux, R. H.;
Gardiner, J. M.; Tyler, P. C.; Wightman, R. H.; Williams, N.
R. In Specialist Periodical Reports, Carbohydrate
Chemistry, Vol. 28; Ferrier, R. J., Ed.; Royal Society of
Chemistry: Cambridge, 1996, 251.
(26) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon Press: Oxford, 1988, 3rd ed.
Synthesis 2008, No. 19, 3167–3170 © Thieme Stuttgart · New York