Three-component assembly of amines, boronic acids, and a polyfunctionalized furanose: A concise entry to furanose-based carbohydrate templates

Article abstract of DOI:10.1021/jo9012817

(Chemical Equation Presented) A highly functionalyzed furanose derivative, accessible in five steps from D-mannose, comprising a halo-alkenyl allylic-oxirane system, undergoes a palladium catalyzed one-pot, three component, assembly with boronic acids (or

Full text of DOI:10.1021/jo9012817

pubs.acs.org/joc
reaction sites may serve as a powerful synthetic strategy that
Three-Component Assembly of Amines, Boronic
Acids, and a Polyfunctionalized Furanose: A Concise
Entry to Furanose-Based Carbohydrate Templates
should provide enormous opportunity for diversity-oriented
synthesis as well as target-oriented synthesis.2 In this sense,
the design of novel molecular platforms that allow a stereo-
determined, three-dimensional orientation of pharmaco-
phores remains an important goal in drug discovery.3 In
this context, the successful use of carbohydrates as scaffolds
in the area of peptidomimetics4 has triggered a considerable
research effort on the use of sugar derivatives as templates in
bioactive compound discovery.5 Thus, carbohydrate tem-
plates have been generated from pyranoses, furanoses, dis-
accharides, and bicyclic derivatives, and most of these
strategies have relied on the stepwise derivatization of ortho-
gonally protected carbohydrate derivatives.6-8
ꢀ
Ana M. Gomez,* Aitor Barrio, Ana Pedregosa,
ꢀ
Serafın Valverde, and J. Cristobal Lopez*
ꢀ
´
ꢀ
Instituto de Quımica Organica General, CSIC, Juan de la
Cierva 3, 28006 Madrid, Spain
anagomez@iqog.csic.es; clopez@iqog.csic.es
Received June 15, 2009
Recently, we inititated a research project aimed at building
small libraries of functionalized carbohydrates.9 In
this context, we have became interested in developing syn-
thetic strategies in which the incorporation of some of
the appendages on the carbohydrate templates could be
effected by means of palladium-catalyzed reactions on ortho-
gonally functionalized carbohydrate derivatives. We reported
the preparation of epoxy exo-glycal 1 (four steps from
D-mannose) and its transformation into allylic amines,
e.g., 2, via an intermediate π-allyl palladium complex
(Scheme 1a).10 We also reported the Suzuki cross-coupling
reaction11 of halo-exo-glycals, e.g., 3,12 leading to substi-
tuted exo-glycals, e.g., 4 (Scheme 1b).13 We envisioned that
A highly functionalyzed furanose derivative, accessible in
five steps from D-mannose, comprising a halo-alkenyl
allylic-oxirane system, undergoes a palladium catalyzed
one-pot, three component, assembly with boronic acids
(or alkyl boranes) and amines to give, in a complete regio-
and stereocontrolled manner, a sugar based derivative
with two sites of molecular diversity.
(5) Recent reviews on the preparation of carbohydrate derived templates:
(a) Murphy, P. V. Eur. J. Org. Chem. 2007, 4177–4180. (b) Velter, I.; LaFerla,
B.; Nicotra, F. J. Carbohydr. Chem. 2006, 25, 97–138. (c) Becker, B.; Condie,
G. C.; Le, G. T.; Meutermans, W. Mini-Rev. Med. Chem. 2006, 1, 1164–1194.
(d) Meutermans, W.; Le, G. T.; Becker, B. Chem. Med. Chem. 2006, 1, 1164–
1194. (e) Murphy, P. V.; Dunne, J. L. Curr. Org. Synth. 2006, 3, 403–437.
(f) Cipolla, L.; Peri, F.; LaFerla, B.; Redaelli, C.; Nicotra, F. Curr. Org.
Synth. 2005, 2, 153–173. (g) Le, G. T.; Abbenante, G.; Becker, B.; Grathwohl,
M.; Halliday, J.; Tometzki, G.; Zuegg, J.; Meutermans, W. Drug Discovery
Today 2003, 8, 701–709. (h) Kanemitsu, T.; Kanie, O. Trends Glycosci.
Glycotechnol. 1999, 11, 267–276. (i) Sofia, J. J.; Silva, D. J. Curr. Opin. Drug
Discovery Dev. 1999, 2, 365–376.
The muticomponent assembly reaction has emerged as a
powerful means for rapid generation of molecular complex-
ity and diversity.1 In particular, the orthogonal and sequen-
tial functionalization of a simple molecule bearing multiple
€
(6) (a) Hunger, H.; Ohnsmann, J.; Kunz, H. Angew. Chem., Int. Ed. 2004,
43, 1104–1107. (b) Opatz, T.; Kallus, C.; Wunberg, T.; Schmidt, W.; Henke,
S.; Kunz, H. Eur. J. Org. Chem. 2003, 1527–1536. (c) Wunberg, T.; Kallus,
C.; Opatz, T.; Henke, S.; Schmidt, W.; Kunz, H. Angew. Chem., Int. Ed. 1998,
37, 2503–2505.
(7) (a) Jain, R.; Kamau, M.; Wang, C.; Ippolito, R.; Wang, H.; Dulina,
R.; Anderson, J.; Gange, D.; Sofia, M. J. B. Bioorg. Med. Chem. Lett. 2003,
13, 2185–2189. (b) Sofia, M. J.; Hunter, R.; Chan, T. Y.; Vaughan, A.;
Dulina, R.; Wang, H.; Gange, D. J. Org. Chem. 1998, 63, 2802–2803.
(8) (a) Elmouelhi, N.; Aich, U.; Paruchuri, V. D. P.; Meledeo, M. A.;
Campbell, C. T.; Wang, J. J.; Srinivas, R.; Khanna, H. S.; Yarema, K. J.
J. Med. Chem. 2009, 52, 2515–2530. (b) Castoldi, S.; Cravini, M.; Micheli, F.;
Piga, E.; Russo, G.; Seneci, P.; Lay, L. Eur. J. Org. Chem. 2004, 2853–2862.
(1) (a) Dmling, A. Chem. Rev. 2006, 106, 17–89. (b) Multicomponent reac-
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tions; Zhu, J., Bienayme, H., Eds.; Wiley: Weinheim, 2005. (c) Ramon, D. J.; Yus,
M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
(2) (a) Schreiber, S. L. Science 2000, 287, 1964–1969. (b) Burke, M. D.;
Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58. (c) Newman, D. J.;
Gragg, G. M. J. Nat. Prod. 2007, 70, 461–477. (d) Koehn, F. E.; Carter, G. T.
Nature Rev. Drug Discovery 2005, 4, 206–220.
ꢀ ꢀ
(9) (a) Gomez, A. M.; Barrio, A.; Pedregosa, A.; Valverde, S.; Lopez, J. C.
(3) Ariens, E. J.; Beld, A. J.; Rodrigues de Miranda, J. F.; Simonis, A. M.
In The Receptors: A Comprehensive Treatise; O’Brien, R. D., Ed.; Plenum:
New York, 1979; pp 33-91.
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Tetrahedron Lett. 2003, 44, 8433–8435. (b) Gomez, A. M.; Pedregosa, A.;
Barrio, A.; Valverde, S.; Lopez, J. C. Tetrahedron Lett. 2004, 45, 6307–6310.
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(c) Gomez, A. M.; Barrio, A.; Amurrio, I.; Jarosz, S.; Valverde, S.; Lopez, J.
C. Tetrahedron Lett. 2006, 47, 6243–6246.
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(4) (a) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.;
Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B. III; Strader, C. D.;
Cascieri, M. A.; Candelore, M. R.; Donaldson, C.; Vale, W.; Maechler, L.
J. Am. Chem. Soc. 1992, 114, 9217–9218. (b) Hirschmann, R.; Nicolaou, K.
C.; Pietranico, S.; Leahy, E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors,
P. G.; Shakespeare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith, A. B. III;
Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.; Freidinger,
R. M.; Cascieri, M. R.; Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550–
12568.(c) Nicolaou, K. C.; Salvino, J. M.; Raynor, K.; Pietranico, S.; Reisine, T.;
Freidinger, R. M.; Hirschmann, R. In Peptides: Chemical Structure and Biology;
Proceedings of the 11th American Peptide Symposium; Marshall, G. R., Ed.;
Escom: Leiden, 1990; pp 881-884.
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(10) Gomez, A. M.; Pedregosa, A.; Valverde, S.; Lopez, J. C. Chem.
Commun. 2002, 2022–2023.
(11) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; VCH: Weinheim, 1998; pp 49-97. (c) Suzuki, A. J. Organo-
met. Chem. 1999, 576, 147–168.
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(12) Gomez, A. M.; Danelon, G. O.; Pedregosa, A.; Valverde, S.; Lopez,
J. C. Chem. Commun. 2002, 2024–2026.
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Lett. 2003, 44, 6111–6116.
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(13) Gomez, A. M.; Pedregosa, A.; Valverde, S.; Lopez, J. C. Tetrahedron
DOI: 10.1021/jo9012817
r
Published on Web 07/14/2009
J. Org. Chem. 2009, 74, 6323–6326 6323
2009 American Chemical Society

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Gomez et al.
JOCNote
SCHEME 1. Palladium-Catalyzed Reactions on Functionalized
Furanose Systems 1 and 3
TABLE 1. Reaction of Compound 5 with Piperidine
entry
reaction conditions
T (°C)
yield (%)
i
ii
iii
Pd(OAc)2, PPh3, THF
Pd(OAc)2, PPh3, THF
EtOH
rt
reflux
reflux
0
80
88
TABLE 2. Synthesis of Furanoid Derivatives 8-10 by Suzuki Cross-
Coupling Reaction of Alkenyl Bromide 7 with Boronic Acids
SCHEME 2. Proposed Palladium-Catalyzed, Three-Compo-
nent Assembly of Tetrahydrofuran Template 6 by Reaction of
Polyfunctionalized Furanose Derivative 5, Boronic Acids, and
Amines
these two reactions could be combined in a one-pot opera-
tion on a conveniently functionalized exo-glycal, i.e., 5, and
in this paper, we report on the implementation of such an
approach leading to a variety of furanoid derivatives, e.g., 6
(Scheme 2).
Compound 5 possesses two sites susceptible to activation
with palladium catalysis: (i) the allylic epoxide, by allylic
ionization and (ii) the vinyl bromide through oxidative
addition, and it was uncertain which functionality would
be more reactive.14-16 With that in mind, the success-
ful implementation of our proposed transformation (5 f 6,
Scheme 2) will require a subtle handling of these functional-
ities.
In our hands, the Suzuki cross-coupling reaction of 5, with
different boronic acids, under several reaction conditions,
led to complex reaction mixtures. On the other hand,
attempted palladium-catalyzed amination of compound 5,
under experimental conditions similar to those previously
applied to compound 1 (room temperature, Scheme 1a),
resulted in no incorporation of the amino derivative
(Table 1, entry i). It was found, however, that refluxing of
the above-mentioned solution provided amino alcohol 7 in
80% yield (Table 1, entry ii).
amine 7 in 88% yield (Table 1, entry iii). These observations
seemed to indicate that the reaction was taking place by
uncatalyzed nucleophilic opening of the epoxide and that the
presence of bromine in the vinyl oxirane deactivates the
system toward allylic ionization with palladium14-16
(Scheme 1a vs Table 1, entries i and ii).
We next decided to test the cross-coupling reaction of
amino alcohol 7, with different boronic acids, keeping in
mind the possible deleterious interaction between the amino
group and the boronic acid.17 Our results (Table 2) showed
that aromatic allylic amines17 8-10 could be obtained in
good yields by treatment of vinyl bromide 7 with aryl or vinyl
boronic acids in the presence of Pd(PPh3)4 and NaOH in a
THF/H2O solution at 60 °C.
After having established the viability of the two-step
sequence for the transformation, we next turned our atten-
tion to the one-pot multicomponent assembly of compound
5 with amines and boronic acids. We found that experimen-
tal conditions similar to those applied for the Suzuki cou-
pling of amine 7 with boronic acids (Pd(PPh3)4, NaOH,
THF/H2O, 60 °C, Table 2) allowed the desired one-pot,
three-component reaction furnishing derivatives 8-13 in
good yields (Table 3). In all instances where a comparison
is possible (Table 3, entries i-iii), the one-pot transformation
was found to be more efficient than the alternative stepwise
The fact that the stereochemistry at C-10 was maintained in
compound 7 suggested that no π-allyl palladium intermedi-
ate has been involved in the transformation. This was con-
firmed when a refluxing ethanolic solution containing
piperidine and compound 5 exclusively also furnished allylic
(14) For studies on allylic ionization versus oxidative addtion into vinyl
C-Br bonds, see: (a) Comer, E.; Organ, M. G.; Hynes, S. J. J. Am. Chem.
Soc. 2004, 126, 16087–16092. (b) Organ, M. G.; Arvanitis, E. A.; Dixon, C.
E.; Cooper, J. T. J. Am. Chem. Soc. 2002, 124, 1288–1294.
(15) For studies on 1-acetoxy-2-bromo-2-alkenes, see: (a) Nwokogu, G.
C. J. Org. Chem. 1985, 50, 3900–3908. (b) Nwokogu, G. C. Tetrahedron Lett.
1984, 25, 3263–3266. (c) Trost, B. M.; Oslob, J. D. J. Am. Chem. Soc. 1999,
121, 3057–3064.
(16) For studies on R,β-epoxy vinyl triflates: Yamamoto, K.; Heathcock,
C. H. Org. Lett. 2000, 2, 1709–1712.
(17) Organ, M. G.; Mayhew, D.; Cooper, J. T.; Dixon, C. E; Lavorato, D.
J.; Kaldor, S. W.; Siegel, M. G. J. Comb. Chem. 2001, 3, 64–67.
6324 J. Org. Chem. Vol. 74, No. 16, 2009

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Gomez et al.
JOCNote
TABLE 3. One-Pot Multicomponent Assembly of Furanoid Derivatives
8-13 by Reaction of Alkenyl Bromide 5 with Piperidine and Boronic Acids
TABLE 4. One-Pot Multicomponent Assembly of Furanose Derivatives
15-18 by Reaction of Epoxy Alkenyl Bromide 5 with Diethyl(3-pyridyl-
)borane and Amines
SCHEME 3. Pd(0)-Mediated Allylic Ionization of R,β-Epoxy
Vinyl Derivatives 18 and 20
synthesis. This transformation could be applied to a variety
of aryl and heteroaryl boronic acids (Table 3).
Alkyl boranes have also been used in B-alkyl Suzuki cross-
coupling reactions.18 So, we next sought to extend this meth-
odology to the coupling of 5 with alkyl boranes and primary/
secondary amines. In Table 4, we display our results on the
three-component assembly of vinyl bromide 5 with diethyl-
(3-pyridyl)borane and different amines leading to furanose
derivatives 14-17. Good yields of 2-deoxy-2-amino exogly-
cals were obtained, and no appreaciable difference was
observed in terms of yields between primary and secondary
amines.
These studies have revealed the remarkable effect of
bromine at position C-10 in the reactivity of the R,β-epoxy
vinyl systems 1819 versus 20 (Scheme 3). Thus, it appears that
the presence of bromine in 20 deactivates the allylic system
toward Pd-mediated ionization leading to 19, a result in
contrast with that observed for compounds of type 18 (e.g., 1,
Scheme 1a) and also with the behavior in related systems
with nonterminal vinyl bromides.14-16
palladium-catalyzed, one-pot, multicomponent assembly of a
furanose-derived halogenated allyl epoxide with boronic acids
(or alkyl boranes) and amines.20 The reaction takes place with
complete regio- and stereocontrol, by regioselective nucleophi-
lic opening of the oxirane with the amine, followed by Suzuki
(or B-alkyl Suzuki) cross-coupling reaction of the alkenyl
bromide with the boronic acid (or alkyl borane). The latter
takes place with retention of the configuration at the olefin.11,18
This approach could be easily extended to the generation
of carbohydrate libraries with more than two appendages,
since the simultaneous incorporation of the two substituents
(C-10 and C-2) is accompanied by the unveiling of a free
hydroxyl group at O-3, which would still allow the incor-
poration of a third appendage. Further work with the
polyfunctionalized furanose derivative system 5 is currently
underway in our laboratory.
Experimental Section
In summary, we have reported a novel method for the
preparation of furanose-derived templates that relies on the
General Procedure A: Suzuki Cross-Coupling of Alkenyl Bro-
mide 7 with Boronic Acids. To a mixture of alkenyl bromide 7
(18) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2001, 40, 4544–4568.
(19) For compounds related to 18, see: (a) Hirota, K.; Takasu, H.; Tsuji,
Y.; Sajiki, H. Chem. Commun. 1999, 1827–1828. (b) Dalla, V.; Pale, P.
Tetrahedron Lett. 1996, 37, 2777–2780. (c) Chuche, J.; Pale, P. Eur. J. Org.
Chem. 2000, 1019–1025.
(20) In this sense, this protocol could be regarded as reminiscent of the
Petasis reaction, since it permits the three-component coupling of boronic
acids and amines with our substrate: (a) Petasis, N. A.; Zavialov, I. A. J. Am.
Chem. Soc. 1997, 119, 445–446. (b) Petasis, N. A.; Akritopoulou, I. Tetra-
hedron Lett. 1993, 34, 583–586.
J. Org. Chem. Vol. 74, No. 16, 2009 6325

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Gomez et al.
JOCNote
(1.0 mmol) and the corresponding arylboronic acid (1.3 mmol)
in THF (5 mL) was added aqueous NaOH (2 N, 3 mmol). The
resulting mixture was degassed under argon and cooled to
-40 °C. The ensuing suspension was heated to 60 °C and stirred
at that temperature under argon. After the starting materials
were consumed (TLC: petroleum ether/EtOAc 2:8), the mixture
was diluted with EtOAc and washed with brine. The organic
layer was dried, concentrated, and subjected to silica gel column
chromatography.
General Procedure B: One-Pot Multicomponent Asembly. To
a mixture of compound 5 (1.0 mmol), the corresponding amine
(3.0 mmol), and the appropriate boronic acid (1.3 mmol) in
THF (5 mL) was added aqueous NaOH (2 N, 3 mmol). The
solution was degassed under argon during 10 min, and then
Pd(PPh3)4 (0.05 mmol) was added. The resulting suspension was
heated to 60 °C and stirred at that temperature under argon.
After the starting materials were consumed (TLC), the mixture
was diluted with EtOAc and washed with brine. The organic
layer was dried, concentrated, and subjected to silica gel column
chromatography.
8.9 Hz,), 6.85 (d, 2 H, J = 8.9 Hz), 5.40 (s, 1 H), 4.49 (b s, 1 H),
4.43 (m, 2 H), 4.24 (m, 1 H), 4.13 (dd, 1 H, J = 8.6, 3.8 Hz), 3.81
(s, 3 H), 3.51 (s, 1 H), 2.58 (m, 4 H), 1.58 (m, 4 H), 1.50 (s, 3 H),
1.44 (m, 2 H), 1.40 (s, 3 H). 13C NMR δ (CDCl3, 75 MHz) 157.5,
152.4, 129.1, 128.9, 113.8, 109.7, 102.8, 85.0, 76.6, 73.7, 71.5, 67.6,
55.4, 51.7 (ꢀ2), 27.0, 26.3 (ꢀ2), 25.4, 24.5; API-ES positive 390.0
(Mþ1)þ. Anal. Calcd for C22H31NO5 (389.22): C, 67.84; H, 8.02;
N 3.60. Found: C, 67.63; H, 7.96, N 3.55.
From 5. The same compound was obtained following method
B for the one-pot multicomponent assembly procedure using
epoxide 5 (100 mg, 0.36 mmol), piperidine (107 µL, 1.1 mmol),
and p-methoxyphenylboronic acid (71 mg, 0.47 mmol). Silica
gel chromatography (EtOAc/hexane 70%) provided pure 8
(88 mg, 63%).
Acknowledgment. Generous financial support from
Janssen-Cilag is gratefully acknowledged. This research
ꢀ
was supported with funds from the Direccion General
de Ensenanza Superior (Grants PPQ2003-00396 and
~
CTQ2006-15279-C03-02). A.P. and A.B. thank Janssen-
Cilag and the Ministerio de Educacion y Ciencia, respec-
tively, for predoctoral scholarships.
(2S,3R,4R,Z)-2-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-5-(4-
methoxybenzylidene)-4-(piperidin-1-yl)tetrahydrofuran-3-ol,
8. From 7. Following general procedure A, cross-coupling of 7
(50 mg, 0.14 mmol) with p-methoxyphenylboronic acid (26 mg,
0.18 mmol) afforded after flash chromatography (EtOAc/hexane
70%) compound 8 (31.4 mg, 73%) as a colorless oil: [R]25D þ75.3
(c 1.5, CHCl3); 1H NMR δ (CDCl3, 300 MHz) 7.49 (d, 2 H, J =
Supporting Information Available: Preparation and physi-
cal data for compounds 7-17. This material is available free of
charge via the Internet at http://pubs.acs.org
6326 J. Org. Chem. Vol. 74, No. 16, 2009