Ugi-type four-component reaction for a novel synthesis of 5-oxo-perhydrofuro[3, 2-b]pyran carboxylate derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.10.083

The four-component coupling (4CC) of sugar hydroxyaldehyde, Meldrum's acid, isocyanide, and a secondary alcohol in dichloromethane has been accomplished at room temperature in a highly stereoselective manner to produce a novel class of carbohydrate deriva

Full text of DOI:10.1016/j.tetlet.2010.10.083

Tetrahedron Letters 51 (2010) 6835–6838
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Tetrahedron Letters
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Ugi-type four-component reaction for a novel synthesis of
5-oxo-perhydrofuro[3,2-b]pyran carboxylate derivatives
B. V. Subba Reddy a, , Nilanjan Majumder a, A. V. Hara Gopal a, Deepak Chatterjee b, A. C. Kunwar b
⇑
a Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Center for Nuclear Magnetic Resonance Spectroscopy, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The four-component coupling (4CC) of sugar hydroxyaldehyde, Meldrum’s acid, isocyanide, and a second-
ary alcohol in dichloromethane has been accomplished at room temperature in a highly stereoselective
manner to produce a novel class of carbohydrate derivatives, 5-oxo-perhydrofuro[3,2-b]pyrans in good
yields with trans-selectivity. The stereochemistry of the products was assigned by various NMR
experiments.
Received 16 April 2010
Revised 8 October 2010
Accepted 13 October 2010
Available online 26 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Meldrum’s acid
Sugar hydroxyaldehyde
Isocyanide
Four-component reaction
Furo[3,2-b]pyran-5-one
The multi-component reactions are highly important because of
their wide range of applications in pharmaceutical chemistry for
production of the diversified structural scaffolds and combinatorial
libraries for drug discovery.1 Multi component reactions (MCRs)
are extremely convergent, producing a remarkably high increase
of molecular complexity in just one step.2 Among MCRs, those
based on the peculiar reactivity of isocyanides, such as the Ugi3
and the Passerini reactions,4 have been among the most widely
used, also in an industrial context.5 The ability of isonitriles to un-
dergo facile addition with a nucleophile and an electrophile under
mild conditions makes them useful reactants for the development
of novel MCRs.6,7 Recently, a highly functionalized dihydrocouma-
rin derivatives have been synthesized via a four-component reac-
tion.8 However, to the best of our knowledge, there are no
reports on four-component coupling (4CC) reaction between sugar
hydroxyaldehyde, 2,2-dimethyl-1,3-dioxane-4,6-dione, isocyanide,
and a secondary alcohol to produce sugar annulated 5-oxo-pyran
derivatives.
The structure of 5a was characterized thoroughly with the help
of 2-D rotating frame nuclear Overhauser effect spectroscopy
(ROESY) and double quantum filter correlation spectroscopy
experiments. JH5–H6 = 12.2 Hz suggests that the two protons are
diaxially disposed with respect to each other, which is further con-
firmed by exclusive NOE cross-peaks between H6/H3 and H6/H4.
Hence C5 and C6 have S- and R-configuration, respectively. The
proximity to H3 and H6 is consistent with the flagpole interaction
in the boat conformation of six-membered ring (Figure 1).10
Encouraged by the results obtained with cyclohexyl isocyanide
and cyclododecanol, we turned our attention to various alcohols
and isocyanides. Other isocyanides including 1,1,3,3-tetramethyl-
butyl isocyanide and t-butyl isocyanide participated well in this
reaction (Table 1, entries g–i). Similarly, secondary alcohols such
as cyclohexanol, tetrahydropyran-4-ol, menthol, cyclopentanol,
and isopropanol also gave the desired products in good yields
under identical conditions (Table 1, entries b–i). However, in case
Following our interest on the synthesis of sugar annulated het-
erocycles9 we herein describe a novel multi-component reaction
for the synthesis of 5-oxo-perhydrofuro[3,2-b]pyran derivatives.
Thus, treatment of sugar hydroxyaldehyde (1) with Meldrum’s acid
(2), isocyanide (3), and cyclododecanol (4) in dichloromethane at
room temperature gave the product 5a as a single isomer in 72%
yield (Scheme 1).
NC
NH
H
3
O
O
O
O
OH
O
O
CH2Cl2
O
+
O
O
O
O
16h, 25 º
C
HO
O
O
O
4
O
O
1
5a
2
⇑
Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: basireddy@iict.res.in (B.V. Subba Reddy).
Scheme 1. Selective formation of 5a via four-component reaction.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.083

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B. V. Subba Reddy et al. / Tetrahedron Letters 51 (2010) 6835–6838
Table 1
Four-component reaction for the synthesis of sugar fused pyrone derivatives
Entry
Alcohol
Aldehyde
Isonitrile
Medium’s acid
Producta (5/6)
Time
16.0
Yieldb (%)
H
O
NC
O
O
OH
O
O
HN
O
O
O
O
O
HO
72c
O
O
a
O
O
O
O
H
O
NC
NC
NC
NC
NC
O
O
OH
O
O
HN
O
b
c
O
O
17.0
20.0
18.0
19.0
17.0
76 (7:3)d
75 (7:3)d
70 (1:1)d
80 (7:3)d
65 (6:4)d
O
O
HO
O
O
O
O
O
O
OH
H
O
O
O
O
O
O
HN
O
O
O
O
O
HO
O
O
O
O
O
O
O
H
O
O
O
O
HN
O
O
O
O
d
e
O
O
OH
OH
O
HO
O
O
O
O
O
H
O
O
O
O
O
HN
O
O
O
O
O
HO
O
O
O
O
O
O
OH
H
O
O
O
O
f
O
HN
O
O
O
O
O
HO
O
O
O
O
O
O
OH
OH
OH
H
O
NC
O
O
g
h
i
HN
O
O
O
O
23.0
24.0
18.0
77 (6:4)d
75 (6:4)d
79 (6:4)d
O
O
O
O
HO
O
O
O
O
O
O
H
O
NC
O
O
HN
O
O
O
O
O
O
O
HO
O
O
O
O
O
O
H
O
O
O
NC
O
NH
O
O
O
O
O
O
O
HO
O
O
O
O
a
b
c
The products were characterized by NMR, IR and mass spectroscopy.
Yield refers to pure products after chromatography.
100% monoester with trans-stereochemistry.
d
Monoester was obtained as a major product.
of secondary alcohols, except cyclododecanol, the products were
obtained as a mixture of mono- and diesters 5e and 6e, respec-
tively, as depicted in Scheme 2. The structures of mono and dies-
ters were established and confirmed by 1H NMR and HRMS.
In addition to 5a, the structure of 5e was also established by
NOE experiments. The chemical shifts in the coumarin ring of 5e
were very similar to those of 5a, suggesting small perturbation
H5 and H6 are oriented diaxially with respect to each other, which
is further supported by NOE cross-peaks between H6/H3 and H6/
H4, similarly to 5a. Hence C5 and C6 have same configuration as
in 5a.
The mono- and diesters could easily be separated by column
chromatography. It is noteworthy to mention that the ratio of
mono- and diesters was decreased as increasing the steric hin-
drance of the alcohol (Table 1). Notably, secondary alcohols are
3
due to change of the side chain. JH5–H6 = 12.0 Hz suggests that

B. V. Subba Reddy et al. / Tetrahedron Letters 51 (2010) 6835–6838
6837
R
+
-
R'
N
C
R
O
O
N
O
O
H1
OHC
H4
5
O
O
H
O
H
O
O
O
+
O
O
O
O
HO
O
6
O
O
O
H
RO
OH
O
O
O
H3 H2
N
R
N
O
O
O
O
R'-OH
O
O
O
O
O
O
OH
O
O
O
O
O
R2
R
HN
R
O
HN
O
O
O
R'-OH
O
O
O
O
R1
R'O
R'O
O OH
O
O
R'O
O
6
5
Scheme 3. A plausible reaction mechanism.
In case of sterically less hindered alcohols, the product 5 under-
went further alcoholysis to give the diester 6 as a minor product
(Scheme 2). This method doesn’t require any activators or promot-
ers. The scope and generality of the reaction are illustrated with re-
spect to various alcohols and isocyanides and the results are
presented in Table 1.11
R1 = C13H23O2; R2 = C7H12NO
Figure 1. Charteristic NOE’s and energy minimized structure of 5a.
In summary, we have developed a novel four-component reac-
tion for the synthesis of highly functionalized perhydrofuro[3,2-
b]pyran-5-one derivatives from readily available precursors under
neutral conditions. It is entirely a new strategy to produce ester,
amide, and lactone ring system in a single-step operation.
NH
O
O
O
O
O
O
O
NC
O
H
Acknowledgments
O
5e (major product)
OH
O
O
CH2Cl2
O
+
+
O
O
16h, 25 0
C
N.M., A.V.H.G., and D.C. thank CSIR, New Delhi for the award of
fellowships. Authors also thank Dr. J. S. Yadav, Director, IICT for his
kind encouragement and support.
HO
O
O
NH
O
O
O
O
Supplementary data
O
O
O
OH
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.083.
6e (minor product)
References and notes
Scheme 2. Formation of both mono-5e and diesters 6e via four-component
reaction.
1. (a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A.
Acc. Chem. Res. 1996, 29, 123; (b) Terret, N. K.; Gardner, M.; Gordon, D. W.;
Kobylecki, R. J.; Steel, J. Tetrahedron 1995, 51, 8135.
2. (a) Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley: Weinheim, 2005; (b)
Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G. J. Am. Chem. Soc. 2009, 131, 11660.
3. (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810; (b) Ugi, I.; Lohberger, S.;
Karl, R. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon press: Oxford, 1991; Vol. 2, p 1083.
4. Banfi, L.; Riva, R. Org. React. 2005, 65, 1.
5. (a) Dömling, A. Chem. Rev. 2006, 106, 17; (b) Bienayme, H.; Hulme, C.; Oddon,
G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321.
6. (a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169; (b) Nair, V.; Rajesh,
C.; Vinod, A. U.; Bindu, S.; Sreekanth, A. R.; Mathess, J. S.; Balagopal, L. Acc.
Chem. Res. 2003, 36, 899.
7. (a) Ramazani, A.; Mahyari, A. T.; Rouhani, M.; Rezaei, A. Tetrahedron Lett. 2009,
50, 5625; (b) Sanudo, M.; Garcia-Valverde, M.; Marcaccini, S.; Delgado, J. J.;
Rojo, J.; Torroba, T. J. Org. Chem. 2009, 74, 2189.
more effective than primary ones for this reaction. The reactions
are so sluggish with primary alcohols such as methanol, ethanol,
and benzyl alcohol. Furthermore, phenols also failed to give the de-
sired product under these conditions. As a solvent, dichlorometh-
ane appeared to give the best results. In all cases, the reactions
proceeded at room temperature in dichloromethane and the corre-
sponding products were obtained in good yields. A variety of func-
tional groups such as cyclic acetal, ester, amide, and lactone are
well-tolerated. Mechanistically, we assume that a conjugated elec-
tron-deficient alkylidene derivative may be formed from sugar
hydroxyaldehyde and Meldrum’s acid by means of Knoevenagel
reaction. Then a Michael addition of isocyanide would take place
diastereoselectively as a result of the adjacent stereogenic centers
to give iminolactone. This adduct simultaneously undergo intra-
molecular cyclization with hydroxyl group of sugar to give bis-lac-
tone with concomitant loss of acetone. Eventual alcoholysis of
iminolactone with a secondary alcohol gave the desired product
5 as depicted in Scheme 3.
8. Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi, H. R. Org. Lett.
2008, 10, 2581.
9. (a) Yadav, J. S.; Reddy, B. V. S.; Narsimhaswamy, D.; Lakshmi, P. N.; Narsimulu,
K.; Srinivasulu, G.; Kunwar, A. C. Tetrahedron Lett. 2004, 45, 3493; (b) Yadav, J.
S.; Reddy, B. V. S.; Singh, A. P.; Chaya, D. N.; Chatterjee, D.; Kunwar, A. C.
Tetrahedron Lett. 2010, 50, 1478; (c) Yadav, J. S.; Reddy, B. V. S.; Chandraiah, L.;
Jagannadh, B.; Kiran Kumar, S.; Kunwar, A. C. Tetrahedron Lett. 2002, 43, 4527.
10. Bogatskii, A. V.; Gren, A. I.; Samitov, Yu. Yu.; Bogatskaya, E. D.
Ekspermental’nayakhimiya 1970, 6, 530–537.
11. Typical procedure: A mixture of sugar hydroxyaldehyde (188 mg, 1 mmol) and
Meldrums’ acid (144 mg, 1 mmol) was stirred in dichloromethane (5 mL) for

6838
B. V. Subba Reddy et al. / Tetrahedron Letters 51 (2010) 6835–6838
30 min at room temperature and then cyclohexylisocyanide (109 mg, 1 mmol)
(dd, J = 4.5, 12.8 Hz, 1H), 2.00–1.50 (m, 18H), 1.49 (s, 3H), 1.33 (s, 3H). 13C NMR
(75 MHz, CDCl3): d 168.7, 167.1, 166.8, 112.7, 104.7, 82.7, 81.8, 76.1, 48.8, 47.2,
45.3, 32.6, 32.4, 32.4, 31.9, 29.7, 29.3, 26.6, 26.1, 25.3, 24.6, 23.6, 22.7. LC–MS:
m/z: 490 (M+Na). HRMS calcd for C23H33NO9Na (M+Na): 490.2053. Found:
490.2068. 5e: liquid, IR (KBr): mmax 3329, 2928, 2855, 1739, 1660, 1542, 1454,
followed by cyclopentanol (86 mg, 1 mmol) was added at room temperature.
After complete conversion, as monitored by TLC, the mixture was concentrated
in vacuo and purified by column chromatography using ethyl acetate–hexane
(1:9) as eluent to afford pure product. Spectral data for the selected compounds:
5a: solid, mp 184–190 °C. IR (KBr): mmax 3342, 2932, 2858, 1769, 1668, 1542,
1378, 1225, 1163, 1025, 865 cmꢀ1 1H NMR (300 MHz, CDCl3): d 5.94 (d,
.
1329, 1290, 1164, 1078, 1011 cmꢀ1
.
1H NMR (600 MHz, CDCl3): d 5.92 (d,
J = 8.3 Hz, NH), 5.91 (d, J = 3.8 Hz, 1H), 5.27–5.23 (m, 1H), 4.75 (d, J = 3.7 Hz,
1H), 4.68 (d, J = 3.0 Hz, 1H), 4.56 (t, J = 3.0 Hz, 1H), 3.77–3.70 (m, 1H), 3.68 (d,
J = 12.0 Hz, 1H), 3.04 (dd, J = 3.8, 12.0 Hz, 1H), 2.00–1.58 (m, 18H), 1.49 (s, 3H),
1.33 (s, 3H). 13C NMR (75 MHz, CDCl3): d 168.6, 167.1, 166.4, 112.7, 104.7, 82.7,
81.8, 76.3, 64.9, 48.8, 47.1, 45.2, 32.7, 32.6, 31.9, 31.2, 31.1, 29.6, 29.3, 26.6,
26.1, 25.2, 24.6. LC–MS: m/z: (M+H) 452. HRMS calcd for C23H33NO8 (M+H):
452.2284. Found: 452.2296. 6e: 1H NMR (CDCl3, 600 MHz): d 6.30 (d, J = 8.1 Hz,
NH), 5.90 (d, 1H, J = 3.7 Hz, C1H), 5.23–5.15 (m, 2H), 4.49 (d, 1H, J = 3.7 Hz,
C2H), 4.30 (dd, 1H, J = 2.3, 8.3 Hz, C4H), 4.21 (d, 1H, J = 8.3 Hz, C6H), 3.90 (d, 1H,
J = 2.3 Hz, C3H), 3.75–3.65 (m, 1H, OH), 3.35 (t, 1H, J = 8.3 Hz, C5H), 2.00–1.00
(m, 26H), 1.45 (s, 3H, CH3), 1.35 (s, 3H, CH30). HRMS calcd for C28H43NO9
(M+H): 538.2998. Found: 538.3086.
J = 3.7 Hz, 1H), 5.71 (d, J = 8.3 Hz, NH), 5.12–5.07 (m, 1H), 4.77 (d, J = 3.7 Hz,
1H), 4.67 (d, J = 3.3 Hz, 1H), 4.63 (t, J = 3.4 Hz, 1H), 3.75–3.68 (m, 1H), 3.63 (d,
J = 12.2 Hz, 1H), 3.04 (dd, J = 3.4, 12.2 Hz, 1H), 2.00–1.00 (m, 32H), 1.54 (s, 3H),
1.33 (s, 3H). 13C NMR (75 MHz, CDCl3): d 168.7, 167.1, 166.7, 112.7, 104.6, 96.0,
82.7, 81.8, 76.1, 74.7, 48.8, 47.5, 45.3, 32.6, 32.5, 29.7, 28.7, 26.6, 26.1 25.3,
24.6, 23.8, 23.6, 23.2, 23.1, 23.0, 22.9, 20.6, 20.6. LC–MS: m/z: 550 (M+H).
HRMS calcd for C30H47NO8Na (M+Na): 572.3199. Found: 572.3223. 5c: liquid,
IR (KBr): mmax 3340, 2925, 2855, 1767, 1667, 1542, 1454, 1376, 1207, 1029,
891 cmꢀ1 1H NMR (300 MHz, CDCl3):
. d 5.90 (d, J = 3.7 Hz, 1H), 5.81 (d,
J = 7.5 Hz, NH), 5.08–4.97 (m, 1H), 4.74 (d, J = 3.7 Hz, 1H), 4.65 (d, J = 3.0 Hz,
1H), 4.58 (t, J = 3.7 Hz, 1H), 3.95–3.82 (m, 1H), 3.68 (d, J = 12.0 Hz, 1H), 3.04