Facile domino access to chiral mono-, bi-, and tricyclic 2,3-dihydrofurans

Article abstract of DOI:10.1021/jo101935k

The asymmetric domino Michael-S_N2 reaction of various 1,3-dicarbonyl compounds to α-bromonitroalkenes is described for the first time, employing readily available cinchona-derived bifunctional thioureas as organocatalysts. The novel transformat

Full text of DOI:10.1021/jo101935k

pubs.acs.org/joc
construction of pharmacologically important furanoid lig-
Facile Domino Access to Chiral Mono-, Bi-, and
Tricyclic 2,3-Dihydrofurans
nans (Figure 1).2 The asymmetric synthesis of chiral dihy-
drofuran derivatives has thus attracted much attention in the
past few decades.3 Ozawa and co-workers obtained enantio-
enriched 2,3-dihydrofurans from 2,3-dihydrofurans through
a palladium-catalyzed asymmetric arylation of 2,3-dihydro-
furans involving a kinetic resolution process.3a Recently,
Tang et al. employed stereoselective formal [4 þ 1] ylide an-
nulation to generate 2,3-dihydrofuran derivatives, in which
camphor-derived sulfur ylides were treated with R-ylidene-β-
diketones in the presence of Cs2CO3.3b Gais et al. also re-
ported the stereoselective synthesis of 2,3-dihydrofuran de-
rivatives from chiral sulfoximine in more than eight steps.3c
Li-Ping Fan, Ping Li, Xin-Sheng Li, Dong-Cheng Xu,
Meng-Meng Ge, Wei-Dong Zhu, and Jian-Wu Xie*
Key Laboratory of the Ministry of Education for Advanced
Catalysis Materials, Department of Chemistry
and Life Science, Zhejiang Normal University,
321004 Jinhua, P. R. China
xiejw@zjnu.cn
Received October 6, 2010
FIGURE 1. Some representative examples of biologically active
compounds derived from 2,3-dihydrofurans.
However, these methods usually needed rather specific sub-
strates (e.g., R-ylidene-β-diketones and ylide auxiliaries),
most of which were not readily available and had inevitably
lowered the overall atomic efficiency. As such, the applica-
tion of chiral 2,3-dihyrofurans in natural product synthesis
has been hampered by the lack of general methods for their
asymmetric synthesis.4,5 Therefore, there is an eager desire
for a new synthetic method that allows the easy preparation
of chiral mono-, bi-, and tricyclic dihydrofurans with high
atomic efficiency and, more importantly, good feasibility to
assemble various substitution patterns.
The asymmetric domino Michael-SN2 reaction of various
1,3-dicarbonyl compounds to R-bromonitroalkenes is
described for the first time, employing readily available
cinchona-derived bifunctional thioureas as organocatalysts.
The novel transformations were highly regio-, chemo-,
diastereo-, and enantioselective, which simultaneously
gave the chiral tricyclic 2,3-dihydrofurans, bicyclic 2,3-
dihydrofurans, and tetrasubstituted 2,3-dihydrofurans with
two vicinal chiral carbon centers.
Organocatalytic asymmetric reactions have been used as
an efficient tool for the synthesis of enantiopure molecules
under mild, environmentally benign conditions over the past
decades.6 Meanwhile, domino reactions have been served as
(3) (a) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T. Organometal-
lics 1993, 12, 4188. (b) Zheng, J.-C.; Zhu, Y.-C.; Sun, X.-L.; Tang, Y.; Dai,
L.-X. J. Org. Chem. 2008, 73, 6909. (c) Gais, H.-J.; Reddy, L. R.; Babu, G. S.;
Raabe, G. J. Am. Chem. Soc. 2004, 126, 4859. (d) Hagiwara, H.; Sato, K.;
Suzuki, T.; Ando, M. Tetrahedron Lett. 1997, 38, 2103. (e) Chuang, C.-P.;
Chen, K.-P.; Hsu, Y.-L.; Tsai, A.-I.; Liu, S.-T. Tetrahedron 2008, 64, 7511.
(4) (a) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113,
1417. (b) Davies, H. M. L.; Ahmed, G.; Calvo, R. L.; Churchill, M. R.;
Churchill, D. G. J. Org. Chem. 1998, 63, 2641. (c) Garrido, J. L.; Alonso, I.;
The highly functionalized 2,3-dihydrofurans are very im-
portant compounds that are recognized for their importance
as precursors for the asymmetric synthesis of tetrahydro-
furans.1 For example, they could serve as precursors for the
ꢀ
Carretero, J. C. J. Org. Chem. 1998, 63, 9406. (d) Garzino, F.; Meou, A.;
Brun, P. Tetrahedron Lett. 2000, 41, 9803. (e) Evans, D. A.; Sweeney, Z. K.;
Rovis, T.; Tedrow, J. S. J. Am. Chem. Soc. 2001, 123, 12095.
(1) (a) Gottlieb, O. R. New Natural Products and Plant Drugs with
Pharmacological, Biological, or Therapeutical Activity; Springer-Verlag:
Berlin-Heidelberg, Germany, 1987; p 227. (b) Ward, R. S. Tetrahedron 1990,
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S. V. Nat. Prod. Rep. 1992, 9, 243. (e) Moody, C. J.; Davies, M.
Stud. Nat. Prod. Chem. 1992, 10, 201. (f) Koert, U. Synthesis 1995, 115.
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A. R., Rees, C. W., Scrivan, E. F. V., Bird, C. W., Eds.; Elsevier: Oxford,
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chemistry 1997, 45, 991.
(5) For recent syntheses and applications of racemic 2,3-dihydrofurans,
see: (a) Bottex, M.; Caviccholi, M.; Hartmann, B.; Monteiro, N.; Balme, G.
J. Org. Chem. 2001, 66, 175. (b) Ma, S.; Gao, W. Synlett 2002, 65. (c) Calo, V.;
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Chem. 2003, 68, 4406.
(6) Recent general reviews, see: (a) Sohtome, Y.; Nagasawa, K. Synlett
2010, 1. (b) Xu, L.-W.; Luo, J.; Lu, Y.x. Chem. Commun. 2009, 1807.
(c) MacMillan, D. W. C. Nature 2008, 455, 304. (d) Mohr, J. T.; Krout,
M. R.; Stoltz, B. M. Nature 2008, 455, 323. (e) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (f) List, B. Chem.
€
Commun. 2006, 819. (g) Berkessel, A. Groger, H. In Asymmetric Organoca-
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8716 J. Org. Chem. 2010, 75, 8716–8719
Published on Web 11/23/2010
DOI: 10.1021/jo101935k
r
2010 American Chemical Society

Fan et al.
JOCNote
TABLE 1. Screening Studies of Organocatalytic Domino Reaction of
4-Hydroxylcoumarin 2a to R-Bromonitroalkene 3aa
entry
catalyst
base
solvent
yieldb (%)
eec (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1c
1c
1c
1c
1c
1c
1c
1c
1c
DCM
DCM
DCM
DCM
toluene
THF
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
35
52
58
64
54
42
62
quant
quant
quant
90
78
quant
21
51
64
53
64
60
71
70
73
69
92
83
78
FIGURE 2. Structures of bifunctional organocatalysts 1a-1d.
8d
9d
10d
11e
12f
13g
DABCO
DIPEA
DBU
DIPEA
DIPEA
DIPEA
a powerful tool for the rapid and efficient assembly of com-
plex structures from simple starting materials with mini-
mized waste production.7 Herein we present such an advance
and its direct application in an atom-economical synthesis of
chiral mono-, bi-, and tricyclic 2,3-dihydrofurans based on
the development of a new organocatalytic enantioselective
domino Michael-SN2 reaction of 1,3-dicarbonyl compounds
to R-bromonitroalkenes. Notably, the designed reactions are
highly regio-, chemo-, diastereo-, and enantioselective and
simultaneously give the desired multifunctional products
with two vicinal chiral carbon centers.
aUnless otherwise noted, reactions performed with 0.1 mmol of 2a,
0.12 mmol of 3a, 30 mol % of1 in 1 mL of solvent at 0 °C under N2 for48 h.
bIsolated yield. cDetermined by the chiral HPLC analysis. dAdding
e
f
30 mol % base. At -40 °C under N2 for 96 h. 20 mol % of 1c and
20 mol % of DIPEA. g50 mol % DIPEA.
organic synthesis, the R-bromonitroalkenes turned out to
be highly reactive and versatile.12,13 Especially, the bromo or
nitro group could behave as a better leaving group in the
reaction in comparison with bromoalkenes or nitroalkenes.
We envisioned that the bifunctional organocatalysts 1a-c
would be efficient catalysts for the domino Michael-SN2
reaction of 1,3-dicarbonyl compounds to R-bromonitroalk-
enes. Table 1 shows some screening results for the reaction of
2a with 3a. Initially, bifunctional thiourea 1a was investi-
gated as the organocatalyst, but only 21% ee was obtained
(Table 1, entry 1). To our delight, when the reaction was
catalyzed by Takemoto’s catalyst 1b, chiral 4aa was formed
in moderate yields and 51% ee (Table 1, entry 2). Subse-
quently, organocatalyst 1c, derived from quinine, was
proved to be superior to 1a, 1b, and 1d, and product 4aa
was obtained with up to 64% ee (Table 1, entry 3). Various
solvents were screened, and chloroform turned out to be
optimal to give the product in higher enantioselectivities and
yields (Table 1, entries 5-7). Interestingly, clean and quan-
titative product 4aa was obtained without affecting the ee
when achiral 1,4-diazabicyclo[2.2.2]octane (DABCO) was
used as additive (entry 8). Among the additives examined,
the use of N,N-diisopropylethylamine (DIPEA) as additive
gave the best result (entry 9). By lowing the temperature to
-40 °C, we got an excellent enantioselectivity (92% ee) and
yield (90%) in the presence of 1c (30 mol %) and N,N-
diisopropylethylamine (DIPEA, 30 mol %) while the reac-
tion time should be extended (entry 11). The ee was drama-
tically decreased when the catalyst loadings were reduced to
20 mol %, as well as when 50 mol % of DIPEA was added
(entries 12 and 13).
Recently, bifunctional thioureas 1a-c have appeared to
be efficient organocatalysts for asymmetric additions of
nucleophiles to nitroolefins (Figure 2).8-11 In the course of
our investigations on the use of R-bromonitroalkenes in
(7) (a) Wasilke, J. C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev.
2005, 105, 1001. (b) Tietze, L. F. Chem. Rev. 1996, 96, 115. (c) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134.
(8) For 1,2-diaminohexane-derived bifunctional thioureas, see: (a) Oki-
no, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672.
(b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem.
Soc. 2005, 127, 119. (c) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.; Ding, L.- S.;
Wu, Y. Synlett 2005, 603. (d) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org.
Lett. 2005, 7, 4293. (e) Fuerst, D. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2005,
127, 8964. (f) Dove, A. P.; Pratt, R. C.; Lohmeijer, B. G. G.; Waymouth,
R. M.; Hedrick, J. L. J. Am. Chem. Soc. 2005, 127, 13798. (g) Xu, X.; Yabuta,
T.; Yuan, P.; Takemoto, Y. Synlett 2006, 137. (h) Wang, J.; Li, H.; Zu, L.;
Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652.
(9) (a) Xie, J.-W.; Fan, L.-P.; Su, H.; Li, X.-S.; Xu, D.-C. Org. Biomol.
Chem. 2010, 2117. (b) Xie, J.-W.; Yoshida, K.; Takasu, K.; Takemoto, Y.
Tetrahedron Lett. 2008, 49, 6910.
(10) For cinchona-derived bifunctional thioureas, see: (a) Tian, S.; Chen,
Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621.
(b) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967.
(c) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191.
(d) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am.
Chem. Soc. 2006, 128, 4932. (e) McCooey, S. H.; Connon, S. J. Angew.
Chem., Int. Ed. 2005, 44, 6367. (f) France, S.; Shah, M. H.; Weatherwax, A.;
Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem. Soc. 2005, 127, 1206.
(g) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831. (h) Marcelli, T.; van der Haas,
R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2006,
45, 929. (i) Tan, B.; Chua, P. J.; Li, Y.; Zhong, G. Org. Lett. 2008, 10, 2437.
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2682–2685.
(11) For pyrrolidine-thiourea, see: Cao, C.-L.; Ye, M.-C.; Sun, X.-L.;
Tang, Y. Org. Lett. 2006, 8, 2901–2904.
(12) Xie, J.-W.; Wang, Z.; Yang, W.-J.; Kong, L.-C.; Xu, D.-C. Org.
Biomol. Chem. 2009, 7, 4352.
(13) (a) Itoh, K.; Kishimoto, S.; Sagi, K. Can. J. Chem. 2009, 87, 760.
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(c) Muruganantham, R.; Mobin, S. M.; Namboothiri, I. N. N. Org. Lett.
2007, 9, 1125. (d) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org. Chem.
2006, 71, 7494. (e) O’Neil; Cleator, I. A.; Southern, J. M.; Bickley, J. F.;
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E. V.; Berestovitskaya, V. M. Russ. J. Org. Chem. 2004, 40, 594.
With the optimal reaction conditions in hand, the scope of
the present organocatalytic asymmetric domino Michael-
SN2 reaction using catalyst 1c-DIPEA was extended to
various cyclic 1,3-dicarbonyl compounds (Figure 3) and R-
bromonitroalkenes. Only the anti-products were detected for
all the reactions. As illustrated in Table 2, for the reactions of
J. Org. Chem. Vol. 75, No. 24, 2010 8717

Fan et al.
JOCNote
TABLE 3. Synthesis of Chiral Monocyclic 2,3-Dihydrofurans 4a
entry
R (2)
3
4
yieldb (%)
eec (%)
1
2
3
4
OMe (2i)
OMe (2i)
CH3 (2j)
CH3 (2j)
3a
3d
3a
3d
4ia
4id
4ja
4jd
86
88
89
86
87
87
77
76
FIGURE 3. Structures cyclic 1,3-dicarbonyl compounds.
aUnless otherwise noted, reactions performed with 0.1 mmol of 2,
0.12 mmol of 3, 30 mol % of 1c, and 30 mol % of DIPEA in 1 mL
ofCHCl3 at -50 °C under N2 for 96 h. bIsolated yield. cDetermined by
the chiral HPLC analysis.
TABLE 2. Asymmetric Domino Reaction of 1,3-Dicarbonyl Com-
pounds 2 to R-Bromonitroalkenes 3a
when cyclohexane-1,3-dione (2g) and 5,5-dimethylcyclohex-
ane-1,3-dione (2h) (Table 2, entries 13-19) were used, as
well as when 4-hydroxythiocoumarins were used as Michael
donors.
To extend the scope of the domino reaction further, acyclic
1,3-dicarbonyl compounds 2h-2i were utilized as Michael
donors in the reaction with R-bromonitroalkenes in the
presence of 1c-DIPEA (Table 3). As demonstratedinTable 3,
the domino Michael-SN2 process takes place with R-bromo-
nitroalkene Michael acceptors, which possess electron-do-
nating, electron-withdrawing groups in the phenyl ring at
-50 °C. It appeared that substituents’ electronics have a
minimal impact on efficiencies, enantioselectivities, and diaster-
eoselectivities of the domino Michael-SN2 reactions when ethyl
acetoacetate 2i was used as Michael donor (Table 3, entries 1
and 2). The ee was decreased when acetylacetone 2j was used as
Michael donor (Table 3, entries 3 and 4).
In summary, we have developed the first organocatalytic
asymmetric domino Michael-SN2 reaction of various 1,3-
dicarbonyl compounds to R-bromonitroalkenes with excel-
lent chemo- and stereoselectivities, employing an easily
available organic catalyst. This novel, versatile, and efficient
domino reaction affords chiral tricyclic 2,3-dihydrofurans,
bicyclic 2,3-dihydrofurans, and tetrasubstituted 2,3-dihydro-
furans in high yields and enantioselectivities that, to date, have
not been reported in the literature. This novel methodology
should be of great potential for natural product synthesis due to
the mild reaction conditions.
entry
sub. (2)
Ar (3)
yieldb (%)
eec (%)
4
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2b
2c
2d
2d
2d
2e
2f
2g
2g
2g
2g
2g
2h
2h
p-MeO-Ph (3a)
p-Me-Ph (3b)
Ph (3c)
90
94
96
89
89
89
87
92
98
96
86
89
96
98
97
99
98
97
98
92
86
85
92
90
82
79
89
92
84
82
90
82
84
84
87
85
84
88d
4aa
4ab
4ac
4ad
4ae
4ba
4ca
4da
4dd
4df
4ea
4fa
4ga
4gb
4gc
4gd
4ge
4ha
4hd
p-Cl-Ph (3d)
p-Br-Ph (3e)
p-MeO-Ph (3a)
p-MeO-Ph (3a)
p-MeO-Ph (3a)
p-Cl-Ph (3d)
2-furanyl (3f)
p-MeO-Ph (3a)
p-MeO-Ph (3a)
p-MeO-Ph (3a)
p-Me-Ph (3b)
Ph (3c)
9
10
11
12
13
14
15
16
17
18
19
p-Cl-Ph (3d)
p-Br-Ph (3e)
p-MeO-Ph (3a)
p-Cl-Ph (3d)
aUnless otherwise noted, reactions performed with 0.1 mmol of 2,
0.12 mmol of 3, 30 mol % of 1c, and 30 mol % of DIPEA in 1 mL of
CHCl3 at -40 °C under N2 for 96 h. bIsolated yield. cDetermined by the
chiral HPLC analysis. dThe absolute configuration was determined to be
(C9R,C10R), see Supporting Information.
4-hydroxycoumarins 2a and 2d, excellent results were
achieved with R-bromonitroalkenes 3a-3e bearing various
β-aryl substitutions or heteroaryl substitutions (Table 2,
entries 1-5, 8-10). Subsequently, a few 4-hydroxycoumarin
derivatives 2b-2d with different substitutions were investi-
gated. The electronic effect was very marginal, and remark-
able enantioselectivity was achieved (entries 6-10). 4-Hyd-
roxythiocoumarin 2e also exhibited a good reactivity, and a
good ee (82%, entry 11) was still obtained. Although a very
low solubility of 2f was observed in chloroform, gratifyingly,
the domino reaction proceeded very well at -40 °C due to the
very high solubility of product 4fa in chloroform, and an
excellent ee (90%) was achieved in a yield of 89% after 96 h
(entry 12). Having succeeded in synthesizing chiral tricyclic
2,3-dihydrofurans 4aa-4fa, we then turned our attention to
the synthesis of chiral bicyclic 2,3-dihydrofurans. The domino
reactions proceeded in good yields with high enantioselectivities
Experimental Section
General Procedure for Asymmetric Domino Reaction of 1,3-
Dicarbonyl Compounds 2 to R-Bromonitroalkenes 3. Compounds 2a
16.2 mg (0.1 mmol), 3a 30.7 mg (1.2 mmol), 1c 17.8 mg (0.03 mol),
and DIPEA 5.0 μL (0.03 mol) were stirred in CHCl3 (1 mL)
at -40 °C under N2 for 96 h. Then flash chromatography on silica
gel (10% ethyl acetate/petroleum ether) gave 4aa as a white solid
(30 mg, 90% yield).
3-(4-Methoxyphenyl)-2-nitro-2H-furo[3,2-c]chromen-4(3H)-
one (4aa). 90% yield. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.87
(d, J=8.6 Hz, 1H), 7.70-7.68 (m, 1H), 7.47-7.41 (m, 2H), 7.19
(d, J=8.6 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 6.22 (d, J=1.6 Hz,
1H), 4.91 (d, J=2.0 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 193.8, 175.9, 159.6, 128.8, 128.1, 116.3, 114.6,
111.1, 55.3, 52.4, 36.8, 23.4, 21.6; IR (KBr) cm-1 2957, 2925,
1726, 1659, 1576, 1498, 1367, 1082, 820, 761; ESI-HRMS calcd
for C18H13NO6 þ Na 362.0635, found 362.0635; [R]25D=-24.0
8718 J. Org. Chem. Vol. 75, No. 24, 2010

Fan et al.
JOCNote
(c 0.32, CH2Cl2), 92% ee. The enantiomeric ratio was deter-
mined by HPLC on a Chiralpak OD column (30% 2-propanol/
hexane, 1 mL/min), tmajor=10.68 min, tminor=15.45 min.
Crystal data for 4hd:C16H16ClNO4 (321.75), orthorhombic, space
coefficient 0.102 mm-1, reflections collected 21781, independent
reflections 3315 [R(int) = 0.0258], refinement by full-matrix
least-squares on F2, data/restraints/parameters 3315/0/190, good-
ness-of-fit on F2=1.039, final R indices [I > 2σ(I)] R1=0.0431,
wR2=0.1166, R indices (all data) R1=0.0561, wR2=0.1283,
˚
group P2(1)2(1)2(1), a=6.5771(2), b=7.3843(2), c=32.6590(8) A,
3
3
-3
˚
˚
U=1586.16(8) A , Z=4, specimen 0.371 ꢀ 0.230 ꢀ 0.128 mm , T=
296(2) K, SIEMENS P4 diffractometer, absorption coefficient
0.258 mm-1, reflections collected 25743, independent reflections
3683 [R(int) = 0.0312], refinement by full-matrix least-squares on
F2, data/restraints/parameters 3683/1/199, goodness-of-fit on F2 =
1.032, final R indices [I > 2σ(I)] R1 = 0.0399, wR2 = 0.1034, R
indices (all data) R1=0.0505, wR2=0.1104, largest diff. peak and
largest diff. peak and hole 0.219 and -0.249 e A
.
Acknowledgment. We are grateful for the financial sup-
port from the National Natural Science Foundation of China
(20902083) and the Natural Science Foundation of Zhejiang
Province, China (Y4090082).
-3
˚
hole 0.202 and -0.302 e A
Crystal data for 4ga: C5H15NO5 (289.28), monoclinic, space
.
Supporting Information Available: Detailed experimental
procedures and spectral data for all new compounds and X-ray
structural data for 4hd and 4ga in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
˚
group C2/c, a=22.0833(10), b=7.0950(3), c=20.9180(10) A,
3
3
˚
U=2856.5(2) A , Z=8, specimen 0.653 ꢀ 0.263 ꢀ 0.248 mm ,
T = 296(2) K, SIEMENS P4 diffractometer, absorption
J. Org. Chem. Vol. 75, No. 24, 2010 8719