The furan approach to carbocyclic systems. Synthesis of cyclohexane derivatives from butenolides through an intramolecular Michael addition

Article abstract of DOI:10.1016/j.tetlet.2005.06.137

We describe an efficient new approach for the synthesis of highly substituted cyclohexane derivatives that is based on the oxidation of a furan ring with singlet oxygen followed by an intramolecular Michael addition of the resulting butenolide containing an acidic methine group.

Full text of DOI:10.1016/j.tetlet.2005.06.137

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5819–5822
The furan approach to carbocyclic systems.
Synthesis of cyclohexane derivatives from butenolides
through an intramolecular Michael addition
*
´
´
´
Generosa Gomez, Hilda Rivera, Isela Garcıa, Laura Estevez and Yagamare Fall
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de Vigo, 36200 Vigo, Spain
Received 31 May 2005; revised 22 June 2005; accepted 27 June 2005
Available online 14 July 2005
Abstract—We describe an efficient new approach for the synthesis of highly substituted cyclohexane derivatives that is based on the
oxidation of a furan ring with singlet oxygen followed by an intramolecular Michael addition of the resulting butenolide containing
an acidic methine group.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The construction of carbocyclic systems is of paramount
importance in organic synthesis. Intramolecular
Michael-type conjugate addition of carbanionic species
to activated alkenes and alkynes with an electron-with-
drawing group is one of the most frequently used meth-
ods.1 Radical cyclizations have also proved to be a
powerful and versatile method for the construction of
mono and polycyclic systems.2 We recently described a
new methodology for the synthesis of oxacyclic com-
pounds using either methoxyallene3a,e or furan3b–d as
starting material. Both routes lead to a common inter-
mediate: butenolide 8, which affords bicyclic lactone 9
on removal of its silyl protecting group through an
intramolecular hetero Michael addition (Scheme 1).
The scope and limitations of this very powerful method-
ology are being determined and its application to the
synthesis of cyclic as well as polycyclic natural products
is currently underway in our laboratories.
We now decided to further enlarge the scope of our
methodology by targeting carbocyclic compounds. It
was anticipated that butenolide 7 possessing an acidic
methine group would lead to carbocyclic compound 2
on reaction with a base (Scheme 1).
The synthesis of butenolide 7 can be accomplished
according to the reaction sequence shown in Scheme 2.
Commercially available furan 3 reacted with LAH in
ether to give alcohol 44 in 96% yield. Alcohol 4 was
O
TBAF
O
OTBS
O
O
O
OMe
OMe
8
9
EWG1 EWG2
EWG1
Base
O
O
EWG2
O
OMe
O
OMe
2
7
Scheme 1.
Keywords: Butenolide; Furan; Singlet oxygen; Michael addition; Carbocyclization.
*
Corresponding author. Fax: +34 986 81 22 62; e-mail: yagamare@uvigo.es
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.137

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G. Go´mez et al. / Tetrahedron Letters 46 (2005) 5819–5822
LiAlH4 / Et2O
96%
PPh3, I2, Imid, THF, 0 ºC
OH
CO2Et
O
O
O
77%
4
3
EWG1
EWG2
,
NaH, DMF, THF
EWG2
EWG1
O
6
I
90%
74%
43%
1a
1b
1c
a EWG1 = EWG2 = CO2Me
b EWG1 = EWG2 = CN
c EWG1 = CN; EWG2 = CO2Me
5
1O2, hν, MeOH
Rose Bengal
1)
EWG1
DBU, DMF, rt
O
EWG2
O
OMe
Ac2O, pyr
DMAP
2)
55%
80%
92%
7a
7b
7c
EWG1
EWG2
H
O
O
OMe
63%
35%
60%
2a
2b
2c
2
Scheme 2.
PPh3, DEAD, THF, rt
SO2Ph
SO2Ph
OH
O
O
SO2Ph
PhO2S
4
1d
6d
72%
1O2, hν, MeOH
Rose Bengal
1)
2)
SO2Ph
SO2Ph
DBU, DMF, rt
75%
O
O
OMe
Ac2O, pyr
DMAP
7d
61%
PhO2S
H
SO2Ph
O
O
OMe
2d
Scheme 3.
easily converted into iodide 54,5 in 77% yield. The con-
densation of a methylene active compound 6 with iodide
5 afforded furan 1a–c.4 Oxidation of 1 with singlet oxy-
gen followed by treatment with acetic anhydride in pyr-
idine, afforded butenolide 7.4 We were delighted to see
that treatment of 7 with 0.5 equiv of DBU in DMF at
room temperature,1d afforded bicyclic compounds 2a–
c4,6 through an intramolecular Michael addition. The
synthesis of bicyclic lactone 2d4,6 was carried out
according to Scheme 3. Noteworthy is the straightfor-
ward synthesis of furan 1d from alcohol 4 using the
Mitsunobu conditions.7
x
0.3%
NC
H
CO2Me
CN
1.4%
H
CN
O
O
O
O
MeO
MeO
1.6%
2b
2c
Figure 1. NOE correlations for 2b and 2c.

G. Go´mez et al. / Tetrahedron Letters 46 (2005) 5819–5822
5821
PhO2S
H
SO2Ph
PhO2S
SO2Ph
TBDPSCl, DMF, rt
77%
LAH, BF3.OEt2
O
HO
O
HO
OMe
86%
2d
10
PhO2S
SO2Ph
LiDBB, THF, -78º C
TBDPSO
TBDPSO
HO
HO
75%
12
11
Scheme 4.
Res., Synop. 1984, 2, 44–45; (c) Pelter, A.; Ward, R. S.;
Storer, N. P. Tetrahedron 1994, 50, 10829–10838; (d)
Geertsema, E. M.; Leung, C. W.; van Oeveren, A.;
Meetsma, A.; Feringa, B. L. Tetrahedron Lett. 1995, 36,
7315–7318; (e) Little, R. D.; Masjedizadeh, M. R.; Wall-
quist, O.; Mcloughlin, J. I. Org. React. 1995, 47, 315–552;
(f) JP patent 89-300747; (g) Kang, F.-A.; Yu, Z.-Q.; Yin,
H.-Y.; Yin, C.-L. Tetrahedron: Asymmetry 1997, 8, 3591–
3596; (h) Jousse-Karinthi, C.; Zouhiri, F.; Mahuteau, J.;
Desmae¨le, D. Tetrahedron 2003, 59, 2093–2099; (i) Mukai,
C.; Ukon, R.; Kuroda, N. Tetrahedron Lett. 2003, 44,
1583–1586.
Bicyclic lactones 2a–d were obtained as a single diaste-
reoisomer as confirmed by their 1H and 13C NMR data.
Presumably the cyclization of 7a–d occurs to give 2a–d
with the thermodynamically preferred cis ring-junction.
This hypothesis was confirmed in the cases of 2b and 2c
where carrying out NOE correlations was possible (Fig.
1).
Surprisingly, 2c with two different EWG (CO2Me and
CN) was formed as a single diastereoisomer.
2. (a) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma,
G.; Kulicke, K. J.; Trach, F. Org. React. 1996, 48, 301–856;
(b) Briggs, M. E.; El Qacemi, M.; kala¨ı, C.; Zard, S. Z.
Tetrahedron Lett. 2004, 45, 6017–6020.
The transformations in Scheme 4 illustrate, in part, the
potential utility of bicyclic lactone 2d. The latter was
opened with LAH.3b–d leading to diol 10 in good yield.
Selective protection of the primary alcohol of 10 affor-
ded 11 in 77% yield. Alcohol 11 may be desulfonylated8
to afford 2-substituted cyclohexanol 12 in 75% yield.
Compounds 10, 11, and 12 are diastereoisomeric mix-
tures, which can be stereoselectively transformed into
the cis derivatives.3d
´
´
3. (a) Fall, Y.; Gomez, G.; Fernandez, C. Tetrahedron Lett.
1999, 40, 8307–8308; (b) Fall, Y.; Vidal, B.; Alonso, D.;
´
Gomez, G. Tetrahedron Lett. 2003, 44, 4467–4469; (c)
´
´
´
Perez, M.; Canoa, P.; Gomez, G.; Teran, C.; Fall, Y.
´
Tetrahedron Lett. 2004, 45, 5207–5209; (d) Perez, M.;
´
Canoa, P.; Gomez, G.; Teijeira, M.; Fall, Y. Synthesis 2005,
´
´
411–414; (e) Alonso, D.; Perez, M.; Gomez, G.; Covelo, B.;
Fall, Y. Tetrahedron 2005, 61, 2021–2026.
4. All new compounds exhibited satisfactory 1H and 13C
NMR, analytical, and/or high resolution mass spectral
data.
In conclusion, a new and efficient method for the synthe-
sis of highly substituted cyclohexanes from commer-
cially available furan has been developed. Work is
now in progress toward the optimization of the yields
and large scale synthesis of bicyclic lactones 2 and their
use as building blocks for the synthesis of biologically
interesting natural products. The application of this
new methodology to the synthesis of smaller and larger
carbocyclic systems is also currently underway in our
laboratories.
´
5. Perez-Sestelo, J.; Mascarenas, J. L.; Castedo, L.; Mourino,
˜
˜
A. J. Org. Chem. 1993, 58, 118–123.
6. General procedure for the cyclization of 7a–d to 2a–d: To a
solution of 7a–d (0.38 mmol) in DMF (3 mL) was added
DBU (0.19 mol, 0.5 equiv) and the mixture was stirred at rt.
At the end of the reaction (TLC), EtOAc (20 mL) was
added and the organic layers washed with water
(3 · 20 mL), dried (Na2SO4), filtered, and concentrated to
afford a residue, which was chromatographed on silica gel
1
giving 2a–d. Compound 2a: H NMR (300 MHz, CDCl3),
Acknowledgments
d: 3.75 (3H, s, CO2Me), 3.70 (3H, s, CO2Me), 3.39 (3H, s,
OMe), 2.74 (1H, dd, J = 8.73, 17.53), 2.57 (1H, dd,
J = 10.68, 17.53), 2.35–2.29 (1H, m), 2.10–2.06 (1H, m),
1.83–1.90 (1H, m), 1.70–1.51 (3H, m); 13C NMR (CDCl3),
d: 172.67 (CO), 169.99 (CO), 169.96 (CO), 109.00 (C), 55.84
(C), 53.68 (OCH3), 53.00 (OCH3), 50.28 (OCH3), 40.96
(CH), 33.24 (CH2), 31.11 (CH2), 26.17 (CH2), 17.8 (CH2);
HRMS: calcd for C13H19O7 [M+1H]+ 287.1131, found
287.1088. Compound 2b: mp 175–177 ꢁC; IR (neat): 2248,
1800, 1744 cmÀ1; 1H NMR (300 MHz, CDCl3), d: 3.38 (3H,
s, OMe), 3.21 (1H, dd, J = 7.60, 17.78), 2.86 (1H, dd,
J = 3.53, 7.60), 2.70 (1H, dd, J = 3.53, 17.78), 2.39–2.33
(2H, m), 2.16–1.80 (4H, m); 13C NMR (CDCl3), d: 171.69
(CO), 114.67 (CN), 112.89 (CN), 105.51 (C), 50.05 (OCH3),
This work was supported by a grant from the Xunta de
Galicia (PGIDIT04BTF301031PR). We also thank the
NMR service of the CACTI, University of Vigo, for
NMR studies.
References and notes
1. (a) Perlmutter, P. In Conjugate Addition Reactions in
Organic Synthesis; Tetrahedron Organic Chemistry Series;
Pergamon: Oxford, 1992; Vol. 9; (b) Farina, F.; Maestro,
M. C.; Martin, M. R.; Martin, M. V.; Sanchez, F. J. Chem.

5822
G. Go´mez et al. / Tetrahedron Letters 46 (2005) 5819–5822
45.74 (CH), 35.79 (C), 33.59 (CH2), 31.89 (CH2), 28.56
3.36 (1H, m), 3.34 (3H, s, OMe), 2.80 (1H, dd, J = 1.53,
18.35), 2.57–2.50 (3H, m), 2.44–2.40 (1H, m), 2.03–1.99
(1H, m), 1.81–1.74 (2H, m); 13C NMR (CDCl3), d: 174.83
(CO), 136.51 (C), 135.34 (C), 135.12 (CH), 134.97 (CH),
132.19 (CH), 131.26 (CH), 128.83 (CH), 128.77 (CH),
106.75 (C), 91.33 (C), 49.67 (OCH3), 44.62 (CH), 31.74
(CH2), 29.13 (CH2), 25.57 (CH2), 16.52 (CH2).
7. Yu, J.; Cho, H.-S.; Falck, J. R. J. Org. Chem. 1993, 58,
5892–5894.
8. (a) Yu, J.; Cho, H.-S.; Chandrasekhar, S.; Falck, J. R.
Tetrahedron Lett. 1994, 20, 5437–5440; (b) Rychnovsky, S.
D.; Takaoka, L. R. Angew. Chem., Int. Ed. 2003, 42, 818–
820.
(CH2), 17.68 (CH2); HRMS: calcd for C11H13N2O3
[M+1H]+ 221.0926, found 221.0583. Compound 2c: mp
116–118 ꢁC; IR (neat): 2247, 1786, 1746 cmÀ1 1H NMR
;
(300 MHz, CDCl3), d: 3.86 (3H, s, CO2Me), 3.50 (3H, s,
OMe), 3.17 (1H, t, J = 10.32), 2.59–2.53 (2H, m), 2.49–2.46
(1H, m), 2.40–2.36 (1H, m), 2.25–1.82 (4H, m); 13C NMR
(CDCl3), d: 170.14 (CO), 166.97 (CO), 117.74 (CN), 108.02
(C), 54.11 (CO2Me), 51.00 (OCH3), 44.27 (C), 42.46 (CH),
32.22 (CH2), 30.64 (CH2), 26.85 (CH2), 17.89 (CH2);
HRMS: calcd for C11H15O5 [MÀCN]+ 227.0919, found
1
227.0910. Compound 2d: H NMR (300 MHz, CDCl3), d:
8.16–8.12 (4H, m),7.78–7.70 (2H, m), 7.69–7.58 (4H, m),