A simple and efficient approach to the synthesis of 4H-furo[3,4-b]pyrans via a three-component reaction of isocyanides

Article abstract of DOI:10.1016/j.bmcl.2008.06.014

A three-component reaction of an isocyanide, a dialkyl acetylenedicarboxylate, and tetronic acid in dichloromethane at room temperature afforded 4H-furo[3,4-b]pyran derivatives. These compounds are closely related with ring systems, TAN-2483B, TAN-2483A, and FD-211 which have a broad spectrum of biological activity.

Full text of DOI:10.1016/j.bmcl.2008.06.014

Bioorganic & Medicinal Chemistry Letters 18 (2008) 3968–3970
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A simple and efficient approach to the synthesis of 4H-furo[3,4-b]pyrans
via a three-component reaction of isocyanides
*
Ahmad Shaabani , Ebrahim Soleimani, Afshin Sarvary, Ali Hossein Rezayan
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran 19839-4716, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-component reaction of an isocyanide, a dialkyl acetylenedicarboxylate, and tetronic acid in
dichloromethane at room temperature afforded 4H-furo[3,4-b]pyran derivatives. These compounds are
closely related with ring systems, TAN-2483B, TAN-2483A, and FD-211 which have a broad spectrum
of biological activity.
Received 5 March 2008
Revised 28 May 2008
Accepted 5 June 2008
Available online 10 June 2008
Ó 2008 Published by Elsevier Ltd.
Keywords:
Multi-component reaction
Isocyanide
Tetronic acid
4H-furo[3,4-b]pyran
Me
Multi-component reactions (MCRs) have been frequently used
by synthetic chemists as a facile means to generate molecular
diversity from bifunctional substrates that react sequentially in
an intramolecular fashion.1–4 Devising such types of MCRs that
achieve the formation of multiple bonds in a single operation is
one of the major challenges in modern organic synthesis.5–9 As
such processes avoid time-consuming and costly purification pro-
cesses, as well as protection–deprotection steps, they are inher-
ently more environmentally benign and atom-economic.10,11
They provide a powerful tool toward the one-pot synthesis of di-
verse and complex compounds as well as small and drug-like het-
erocycles.12 MCRs that involve isocyanides are by far the most
versatile reactions in terms of scaffolds and number of accessible
compounds.1–5,13
Me
Me
Me
Me
O
Me
O
H
H
H
H
H
H
O
H
O
H
O
H
O
HO
HO
HO
H
H
H
O
O
O
TAN-2483B
FD-211
TAN-2483A
Et
Et
Me
Me
OH
Me
Me
Me
O
Me
Me
Me
O
H
O
O
O
O
HO
HO
HO
H
O
O
O
OH
OH
OH
Mizoue and co-workers reported the isolation of waol A (FD-
211), which has a broad spectrum of activity against cultured tu-
mor cell lines, including adriamycin-resistant HL-60 cells, from
the fermentation broth of Myceliophthora lutea TF-0409.14 TAN-
2483B and TAN-2483A which have closely related compounds
with this ring system (FD-211) show strong c-src kinase inhibitory
action and inhibit PTH-induced bone resorption of a mouse fe-
mur.15 Other related compounds include the antibacterial massar-
ilactone B, which was isolated by Gloer from the freshwater
aquatic fungus Massarina tunicata in 2001.16 Fusidilactones A and
B isolated by Krohn from an endophytic Fusidium sp. in 200217
show good antifungal activity against Eurotium repens and
Fusarium oxysporum (Fig. 1).
massarilactone B
massarilactone A
fusidilactone B
Figure 1. Structures of TAN-2483B, TAN-2483A, FD-211, massarilactone B, mas-
sarilactone A, and fusidilactone B.
Very recently, Snider and co-workers reported the synthesis of
TAN-2483A, massarilactone B, fusidilactone B, and waol A (FD-
211) via multi-step approach under very hard reaction
conditions.18,19
As part of our continuing interest in the development of new
synthetic methods in heterocyclic chemistry and our interest in
isocyanide-based multi-component reactions,20–27 herein we de-
scribe an efficient synthesis of 4H-furo[3,4-b]pyrans 4 via the reac-
tion of an isocyanide 1 with an dialkyl acetylenedicarboxylate 2
and tetronic acid 3 in high yields without using any catalyst at
ambient temperature28 (Scheme 1).
* Corresponding author. Tel.: +98 21 29902800; fax: +98 21 22403041.
E-mail address: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
0960-894X/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2008.06.014

A. Shaabani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3968–3970
3969
R1
HN
methoxy groups (d = 3.67 ppm and d = 3.72 ppm,), a singlet for
the CH–CO2Me (d = 4.30 ppm), an AB-q for CH2–O protons
CO2R2
O
O
2
CH2Cl2
r.t., 12 h
C
(d = 4.78, 4.83 ppm, JAB = 16.4 Hz), and a doublet for NH (d =
O
R1
N
C
O
+
+
3
8.89 ppm, JHH = 7.8 Hz) protons. The 1H decoupled 13C NMR spec-
R2O2C
C
CO2R2
O
CO2R2
trum of 4a showed 17 distinct resonances, and partial assignment
of these resonances is given in Experimental section.
O
3
1
2
4a-h
The reaction proceeds under mild conditions and is compatible
with a wide range of functional groups. Two constituents in the
products can be varied independently of each other. Representa-
tive examples of this reaction are shown in Table 1.
Although the mechanism of this reaction has not been estab-
lished experimentally, the formation of these heterocycles can be
rationalized by initial Michael-type vinylisonitrilium cation
5.29–33 Then, the positively charged ion might be attacked by
the anion of the tetronic acid leading to the keteneimine 6.
Such an addition product may isomerize under the reaction
conditions employed to produce the fused heterocyclic system
4 (Scheme 2).
Scheme 1. Synthesis of 4H-furo[3,4-b]pyrans via three-component reaction.
As indicated in Table 1, isocyanides 1 with dialkyl acetylenedi-
carboxylate 2 and tetronic acid 3 undergo a smooth 1:1:1 addition
reaction in dichloromethane at ambient temperature to produce
4H-furo[3,4-b]pyrans 4. The structures of the products were de-
duced from their IR, mass, 1H NMR and 13C NMR spectra. The mass
spectra of these compounds displayed molecular ion peaks at the
appropriate m/z values. The 1H NMR spectrum of 4a consisted of
a multiplet for the cyclohexyl ring (d = 1.25–1.91 ppm), a multiplet
for the NH–CH cyclohexyl proton (d = 3.60 ppm), two singlet for
Table 1
Synthesis of furo[3,4-b]pyran derivatives
HN
O
O
HN
O
O
HN
O
O
HN
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Me
O
O
Me
O
O
Et
O
O
Et
O
O
Me
Me
Et
Et
4c
4a
4b
4d
Me
Me
O
Me
Me
O
Me
Me
O
HN
O
O
HN
O
HN
O
HN
O
O
O
O
O
O
O
O
O
O
O
O
O
Me
O
O
Me
O
O
Et
O
O
O
4h
O
Me
Me
Et
4f
4e
4g
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
Cyclohexyl
Cyclohexyl
tert-Butyl
tert-Butyl
1,1,3,3-Tetramethyl-butyl
2,6-Dimethyl-phenyl
2,6-Dimethyl-phenyl
2,6-Dimethyl-phenyl
Me
Et
Me
Et
4a
4b
4c
4d
4e
4f
71
73
80
79
70
75
75
68
Me
Me
Et
4g
4h
tBu
O
O
CO2R2
R1
R1
H
O
N
N
C
C
C
O
O
R1
N C
CO2R2
CO2R2
+
O
C
CO2R2
CO2R2
CO2R2
5
1
2
R1
N
R1
HN
R1
O
HO
N
O
C
O
C
O
O
O
R2O2C
R2O2C
R2O2C
O
CO2R2
O
CO2R2
CO2R2
4
6
Scheme 2. Proposed mechanism.

3970
A. Shaabani et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3968–3970
15. Hayashi, K.; Takizawa, M.; Noguchi, K. Japanese Patent 10287679, 1998; Chem.
In conclusion, we have developed a new and efficient approach to
Abstr. 1999, 130, 3122e.
the synthesis of a wide range of furo[3,4-b]pyran derivatives from
various isocyanides and dialkyl acetylenedicarboxylates in the pres-
ence of tetronic acid. The reaction has been shown to display good
functional group tolerance and is high yielding and product isolation
is very straightforward. We hope that this approach may be of value
to others seeking novel synthetic fragments with unique properties
for medicinal chemistry such as ring system of waol A.
16. Oh, H.; Swenson, D. C.; Gloer, J. B.; Shearer, C. A. Tetrahedron Lett. 2001, 42, 975.
17. Krohn, K.; Biele, C.; Drogies, K.-H.; Steingro¨ ver, K.; Aust, H.-J.; Draeger, S.;
Schulz, B. Eur. J. Org. Chem. 2002, 2331.
18. Gao, X.; Snider, B. B. J. Org. Chem. 2004, 69, 5517.
19. Gao, X.; Nakadai, M.; Snider, B. B. Org. Lett. 2003, 5, 451.
20. Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron Lett. 2007, 48, 2185.
21. Shaabani, A.; Soleimani, E.; Rezayan, A. H. Tetrahedron Lett. 2007, 48, 6137.
22. Shaabani, A.; Soleimani, E.; Khavasi, H. R. Tetrahedron Lett. 2007, 47, 4743.
23. Shaabani, A.; Soleimani, E.; Khavasi, H. R.; Hoffmann, R. D.; Rodewald, U. C.;
Poättgen, R. Tetrahedron Lett. 2006, 47, 5493.
Acknowledgment
24. Shaabani, A.; Soleimani, E.; Maleki, A. Tetrahedron Lett. 2006, 47, 3031.
25. Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem. 2007, 72, 6309.
26. Shaabani, A.; Soleimani, E.; Darvishi, M. Monatsh. Chem. 2007, 138, 43.
27. Shaabani, A.; Rezayan, A. H.; Rahmati, A.; Sarvari, A. Synlett 2007,
1458.
We gratefully acknowledge the financial support from the Re-
search Council of Shahid Beheshti University.
28. Typical procedure for preparation of dimethyl 2-(cyclohexylamino)-5,7-dihydro-5-
oxo-4H-furo[3,4-b]pyran-3,4-dicarboxylate (4a): To
solution of tetronic acid (0.10 g, 1.0 mmol)
acetylenedicarboxylate (0.14 g, 1.0 mmol) in CH2Cl2 (10 mL) was added,
dropwise, solution of cyclohexyl isocyanide (0.11 g, 1 mmol) in CH2Cl2
(2 mL) at À10 °C over 10 min. The mixture was allowed to warm up to room
temperature and was finally stirred for 12 h. The solvent was removed under
vacuum and the residue was crystallized from an n-hexane/dichloromethane
(2:1) mixture and washed with ether (3Â 5 mL) and the product 4a was
a
magnetically stirred
and dimethyl
Supplementary data
a
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2008.06.014.
References and notes
obtained. White crystals (0.25 g, yield 71%). Mp 128–130 °C. IR (KBr) (mmax
/
cmÀ1): 2935, 2857, 1766, 1734, 1715. MS, m/z (%): 352 (M++1, 3), 292 (100),
210 (65), 178 (70), 88 (25), 59 (30), 55 (65), 41 (60). 1H NMR (300 MHz, CDCl3):
dH (ppm) 1.25–1.91 (10H, m, 5CH2 of cyclohexyl), 3.60 (1H, m, CH–NH), 3.67
(3H, s, O–CH3), 3.72 (3H, s, O–CH3), 4.30 (1H, s, CH–CO2Me), 4.78 (1H, d,
1. Dömling, A. Chem. Rev. 2006, 106, 17.
2. Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
3. Zhu, J. Eur. J. Org. Chem. 2003, 1133.
2
2JAB = 16.4 Hz, CH2–O), 4.83 (1H, d, JAB = 16.4 Hz, CH2–O), 8.89 (1H, d,
4. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
5. Zhu, J.; Bienayme’, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
Germany, 2005.
6. Ngouansavanh, T.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46, 5775.
7. Laurent, E. K.; Gizolme, M.; Grimaud, L.; Oble, J. Org. Lett. 2006, 8, 4019.
8. Tempest, P. A. Curr. Opin. Drug Discov. 2005, 8, 776.
9. Lu, K.; Luo, T.; Xiang, Z.; You, Z.; Fathi, R.; Chen, J.; Yang, Z. J. Comb. Chem. 2005,
7, 958.
3JHH = 7.8 Hz, CH–NH). 13C NMR (75 MHz, CDCl3): dC (ppm) 24.29, 24.32,
25.26, 33.53, 33.75 (C–cyclohexyl), 35.53 (CH–CO2Me), 50.14 (CH–NH), 51.31,
52.69 (2O–CH3), 65.47 (CH2–O), 71.46, 102.92, 158.90, 167.30 (C-alkene),
169.11, 169.52, 172.53 (3C@O). Anal. Calcd for C17H21NO7: C, 58.11; H, 6.02; N,
3.99%. Found: C, 58.02; H, 5.96; N, 4.02%.
29. Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon:
Oxford, 1992.
30. Yavari, I.; Zare, H.; Mohtat, B. Mol. Divers. 2006, 10, 247.
31. Yavari, I.; Adib, M.; Sayahi, M. H. J. Chem. Soc., Perkin Trans. 1 2002, 2343.
32. Nair, V.; Vinod, A. U.; Ramesh, R.; Menon, R. S.; Varma, R. L.; Mathew, S.;
Chiaroni, A. Heterocycles 2002, 58, 147.
33. Shaabani, A.; Teimouri, M. B.; Arab-Ameri, S. Tetrahedron Lett. 2004, 45,
8409.
10. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
11. Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765.
12. Weber, L. Curr. Med. Chem. 2002, 9, 2085.
13. Dömling, A. Curr. Opin. Chem. Biol. 2002, 6, 306.
14. Nozawa, O.; Okazaki, T.; Sakai, N.; Komurasaki, T.; Hanada, K.; Morimoto, S.;
Chen, Z.-X.; He, B.-M.; Mizoue, K. J. Antibiot. 1995, 48, 113.