Highly diastereoselective and enantioselective formal [4 + 1] ylide annulation for the synthesis of optically active dihydrofurans

Article abstract of DOI:10.1021/jo801135j

(Chemical Equation Presented) On the basis of the reactions of camphor-derived sulfur ylide with α-ylidene-β-diketones, highly efficient and selective synthesis of optically active dihydrofurans has been achieved.

Full text of DOI:10.1021/jo801135j

SCHEME 1. Regio- and Chemoselectivities of Ylide
Cycloaddition
Highly Diastereoselective and Enantioselective
Formal [4 + 1] Ylide Annulation for the
Synthesis of Optically Active Dihydrofurans
Jun-Cheng Zheng, Chun-Yin Zhu, Xiu-Li Sun, Yong Tang,*
and Li-Xin Dai
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Orangic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, China
metric reactions probably due to the difficulty associated with
the regioselectivity, chemoselectivity, diastereoselectivity (cis/
trans), and enantioselectivity.6 As our ongoing research project
on ylide reaction and its applications in organic synthesis,7 we
recently developed a highly diastereoselective and enantiose-
lective formal [4 + 1] annulation reaction8 of R-ylidene-ꢀ-
diketones with sulfur ylide. This annulation leads to optically
active dihydrofurans,9 molecular skeletons frequently occurring
in biologically active compounds10 and extremely useful
synthetic intermediates11 since they can be readily converted
to highly functionalized tetrahydrofuran. In this paper, we wish
to report the results.
tangy@mail.sioc.ac.cn
ReceiVed May 23, 2008
On the basis of the reactions of camphor-derived sulfur ylide
with R-ylidene-ꢀ-diketones, highly efficient and selective
synthesis of optically active dihydrofurans has been achieved.
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Angew. Chem., Int. Ed. 1997, 36, 1317. (b) Li, A.-H.; Zhou, Y.-G.; Dai, L.-X.;
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Gooch, A.; Graham, P.; Holy, N.; Mains, B.; Strunk, J. J. Org. Chem. 1976, 41,
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A.; Piras, P. P.; Secci, F.; Spiga, M. Org. Lett. 2005, 7, 4565.
The formal [2 + 1] ylide cycloaddition1 of R,ꢀ-unsaturated
compounds has been widely applied in the enantioselective
construction of small ring compounds such as epoxides,1,2
cyclopropanes,1,3 and aziridines1,4 (types A and B in Scheme
1). However, as a potential tool for the creation of 5-membered
heterocyclic compounds, the formal [4 + 1] ylide annulation
(type C in Scheme 1) has less been explored.5 Of the
investigations, few have explored the possibility of the asym-
(1) Reviews for ylide cyclization. (a) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K.
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(7) For a review, please see: Sun, X. L.; Tang, Y. Acc. Chem. Res. 2008,
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Liao, W. W.; Deng, X. M.; Tang, Y. Chem. Commun. 2004, 1516. (c) Zheng,
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Int. Ed. 2007, 46, 5951. (e) Cao, P.; Li, C.-Y.; Kang, Y.-B.; Xie, Z.; Sun, X.-L.;
Tang, Y. J. Org. Chem. 2007, 72, 6628. (f) Li, C.-Y.; Wang, X.-B.; Sun, X.-L.;
Tang, Y.; Zheng, J.-C.; Xu, Z.-H.; Zhou, Y.-G.; Dai, L.-X. J. Am. Chem. Soc.
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42, 828. (f) Liao, W. W.; Li, K.; Tang, Y. J. Am. Chem. Soc. 2003, 125, 13030.
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(8) Leading references for the enantioselective synthesis of 5- or 6-membered
rings via ylide route other than formal [4 + 1] annulation: (a) Koep, S.; Gais,
H.-J.; Raabe, G. J. Am. Chem. Soc. 2003, 125, 13243. (b) Gais, H.-J.; Reddy,
L. R.; Babu, G. S.; Raabe, G. J. Am. Chem. Soc. 2004, 126, 4859. (c) Schomaker,
J. M.; Pulgam, V. R.; Borhan, B. J. Am. Chem. Soc. 2004, 126, 13600. (d)
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4189. (e) Kumarn, S.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2006, 3211. (f)
Tiwari, S. K.; Gais, H.-J.; Lindenmaier, A.; Babu, G. S.; Raabe, G.; Reddy,
L. R.; Ko¨hler, F.; Gu¨nter, M.; Koep, S.; Iska, V. B. R. J. Am. Chem. Soc. 2006,
128, 7360. (g) Kokotos, C. G.; Aggarwal, V. K. Chem. Commun. 2006, 2156.
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10.1021/jo801135j CCC: $40.75
Published on Web 08/01/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6909–6912 6909

TABLE 1. Regio- and Chemoselective Synthesis of Dihydrofuran
with Sulfur Ylidea
TABLE 2. Effects of Reaction Conditions on the Cyclization
entrya temp (°C)
base
t-BuOK MeCN
KOH MeCN
solvent trans/cisb ee (%)c yield (%)d
entry
2/R
2a/C6H5
2a/C6H5
2b/4-ClC6H4
2c/4-BrC6H4
2d/4-NO2C6H4
2e/2,4-Cl2C6H3
2f/4-MeC6H4
2g/2-furyl
base
3/4b
trans/cisb
yield (%)
1
0
6.2/1
7/1
6/1
52
56
51
90
90
82
trace
95
15
8
80
88
25
95
97
15
97
96
92
94
99
1
2
3
4
5
6
7
8
9
Cs2CO3
DBU
Cs2CO3
Cs2CO3
DBU
DBU
DBU
Cs2CO3
Cs2CO3
Cs2CO3
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
5/1
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
>10/1
>50/1
95
96
94
94
94
88
85
90
83
58
2
0
3
0
K2CO3 MeCN
Na2CO3 MeCN
Cs2CO3 MeCN
Cs2CO3 PhMe
Cs2CO3 PhCF3
Cs2CO3 DCM
Cs2CO3 DCE
Cs2CO3 Et2O
Cs2CO3 THF
Cs2CO3 DME
Cs2CO3 PhMe
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
4
0
5
6
0
0
6/1
51
6
0
19
20
20
56
60
6
>99/1
>99/1
7.8/1
7.5/1
12/1
5/1
7
0
8
0
9
0
2h/E-cinnamyl
2i/Et
10
11
12
13
14
15
16
17e
18f
0
0
0
0
10
2/1
a All reactions were carried out at 0 °C, base/1/2 ) 1.3/1.3/1.0 (molar
ratio). Determined by H NMR and trans/cis was for 3.
6/1
b
1
>99/1
0
5/1
73
80
87
87
91
-20
-40
-40
-40
6.5/1
11/1
10/1
10/1
Since Payne documented the first example for the construction
of dihydrofuran using sulfur ylide,5a there have been several
reports5,6a involved in the formation of dihydrofuran via ylide
cyclization. However, few general asymmetric versions have
been developed via a chiral ylide due to the difficult control of
regio- and/or chemoselectivities (type A and/or type B vs type
C in Scheme 1). Gratifyingly, we found that sulfonium salt 1,
after deprotonation by DBU or Cs2CO3, could react with 2a to
afford dihydrofuran with specific regioselectivity (3a/4a >99/
1), chemoselectivity (no epoxide was observed), and excellent
stereoselectivity (trans/cis > 50/1) (entries 1 and 2, Table 1).
Further studies revealed that a variety of R-ylidene-ꢀ-diketones
were suitable substrates for this reaction. As shown in Table 1,
the annulation reaction proceeded well with R being aryl or
2-furyl group, and only a single regio- and stereoisomer was
isolated regardless of the electronic properties of aryl groups
(entries 1-8). However, the regioselectivity decreased greatly
when R was E-cinnamyl or ethyl (entries 9 and 10).
a Molar ratio: 5/base/2a ) 1.3/1.3/1.0, dr (at sulfur atom) of 5 is
8.3/1. b Determined by 1H NMR. c Determined by chiral HPLC for the
trans-isomer. d Yield of 3a. e Dr (at sulfur atom) of 5 is 17.6/1. f Dr (at
sulfur atom) of 5 is >50/1.
could be a potential reagent for the asymmetric formal [4 + 1]
annulation for the synthesis of dihydrofuran derivatives. With
2a as a model substrate, a systematic survey on reaction
conditions revealed that solvent, base, temperature, and the
diastereomeric purity of sulfonium salt 513 strongly influenced
the regioselectivity, chemoselectivity, and diastereoselectivity,
as well as enantioselectivity (entries 1-18, Table 2). For
example, when the reaction was run in CH3CN in the presence
of Na2CO3, only a trace amount of product was observed while
95% yield, 51% ee, and 6/1 trans/cis ratio could be obtained in
the case of Cs2CO3 used as a base (entries 4 and 5). Of the
solvents screened, DMF was found to be the optimal one.
Lowering temperature benefited both the enantioselectivity and
the trans/cis ratio of the reaction. For example, decreasing the
reaction temperature from 0 to -40 °C increased the ee value
from 73% ee to 87% ee with a slight loss of yields (entries
14-16). The enantioselectivity of the reaction is also dependent
upon the diastereoisomeric purity of salt 5. For example, salt 5
with a dr ratio of 8.3/1 reacted with 3-benzylidenepentane-2,4-
dione (2a) in the presence of Cs2CO3 afforded the desired 3a
in 92% yield with 87% ee while a nearly diasteromeric pure
salt 5 (dr >50/1) favored to give dihydrofurans product 3a with
high diastereoselectivities in 99% yield and up to 91% ee could
be achieved (entries 16-18, Table 2) at -40 °C in DMF.
Having established the optimal conditions for the synthesis
of optically active dihydrofurans, we investigated the scope and
limitation of the substrates by employing various alkylidene and
3-arylidene-2,4-pentanediones. As summarized in Table 3,
various R-ylidene-ꢀ-diketones prove to be good substrates for
this annulation reaction. Both aliphatic and aromatic diketones
were favored to give dihydrofurans over the competing cyclo-
propanes. For example, various ꢀ-aryl- and heteroaryl-substi-
tuted diketones 2a-g all worked well to afford the desired
products with excellent selectivities (3/4 >99/1, trans/cis up to
In view of the successful application of camphor-derived
sulfide4a,b,7a,12 in enantioselective ylide epoxidation, cyclopro-
panation, and aziridination, we envisaged that sulfonium salt 5
(9) Leading references for the enantioselective synthesis of dihydrofurans:
(a) Daivs, H. M.L.; Ahmed, G.; Calvo, R. L.; Churchill, M. R.; Churchill, D. G.
J. Org. Chem. 1998, 63, 2641. (b) Evans, D. A.; Sweeney, Z. K.; Rovis, T.;
Tedrow, J. S. J. Am. Chem. Soc. 2001, 123, 12095. (c) Garzino, F.; Me´ou, A.;
Brun, P. Eur. J. Org. Chem. 2003, 1410. (d) Xia, W.; Yang, C.; Patrick, B. O.;
Scheffer, J. R.; Scott, C. J. Am. Chem. Soc. 2005, 127, 2725. (e) Calter, M. A.;
Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc. 2005, 127, 14566. (f)
Bowman, R. K.; Johnson, J. S. Org. Lett. 2006, 8, 573. (g) Son, S.; Fu, G. C.
J. Am. Chem. Soc. 2007, 129, 1046.
(10) (a) Fraga, B. M. Nat. Prod. Rep. 1992, 9, 217. (b) Merrit, A. T.; Ley,
S. V. Nat. Prod. Rep. 1992, 9, 243. (c) Mortensen, D. S.; Rodriguez, A. L.;
Carlson, K. E.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med.
Chem. 2001, 44, 3838. (d) Kilroy, T. G.; O’Sullivan, T. P.; Guiry, P. J. Eur. J.
Org. Chem. 2005, 4929.
(11) (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795. (b) Faul, M. M.; Huff,
B. E. Chem. ReV. 2000, 100, 2407. (c) Garzino, F.; Meou, A.; Brun, P. Synthesis
2003, 598. (d) Pettigrew, J. D.; Wilson, P. D. Org. Lett. 2006, 8, 1427.
(12) For applications of camphor-derived sulfonium salts in organic synthesis,
please see: (a) Li, A.-H.; Dai, L.-X.; Hou, X.-L.; Huang, Y.-Z.; Li, F.-W. J.
Org. Chem. 1996, 61, 489. (b) Zhou, Y.-G.; Hou, X.-L.; Dai, L.-X.; Xia, L.-J.;
Tang, M.-H. J. Chem. Soc., Perkin Trans. I 1999, 77. (c) Aggarwal, V. K.; Hynd,
G.; Picoul, W.; Vasse, J. L.; Winn, C. L. J. Am. Chem. Soc. 2002, 124, 9964.
(d) Huang, K.; Huang, Z.-Z. Synlett 2005, 1621. (e) Aggarwal, V. K.; Charmant,
J. P. H.; Fuentes, D.; Harvey, J. N.; Hynd, G.; Ohara, D.; Picoul, W.; Robiette,
R.; Smith, C.; Vasse, J. L.; Winn, C. L. J. Am. Chem. Soc. 2006, 128, 2105. (f)
Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu,
Y.-D.; Dai, L.-X. J. Am. Chem. Soc. 2006, 128, 9730. (g) Wang, Q.-G.; Deng,
X.-M.; Zhu, B.-H.; Ye, L.-W.; Sun, X.-L.; Li, C.-Y.; Zhu, C.-Y.; Shen, Q.; Tang,
Y. J. Am. Chem. Soc. 2008, 130, 5408.
(13) For details, please see the Supporting Information.
6910 J. Org. Chem. Vol. 73, No. 17, 2008

287.2 (M + Br-). Anal. Calcd for C15H27BrO3S: C, 49.04; H, 7.41.
TABLE 3. Stereoselective Synthesis of Dihydrofurans via
Camphor-Derived Sulfur Ylidea
Found: C, 49.00; H, 7.37. [R]20 +88.0 (c 0.6, MeOH).
D
General Procedure for the Enantioselective Synthesis of
Dihydrofurans (3b as an example). To a solution of sulfur salt 5
(100 mg, 0.27 mmol) and Cs2CO3 (86 mg, 0.26 mmol) in DMF
(1.5 mL), which had been stirred for 45 min at -60 °C, was added
a solution of compound 2b (44 mg, 0.2 mmol) in DMF (1.5 mL).
The reaction mixture was stirred until the starting material disap-
peared (determined by TLC), and then passed through a short silica
gel column (eluted with ethyl acetate). After removal of the solvent
under reduced pressure, the crude mixture was directly purified by
flash chromatography on silica gel to give the pure product. Yield
54 mg (88%). For trans-isomer: IR (film) ν/cm-1 3062 (w), 2925
(w), 2853 (w), 1757 (s), 1676 (m), 1629 (m), 1602 (s), 1491 (m);
1H NMR (300 MHz, CDCl3/TMS) δ 7.32 (dd, J ) 6.3, 1.8 Hz,
2H), 7.18 (dd, J ) 6.3, 2.1 Hz, 2H), 4.72 (d, J ) 5.1 Hz, 1H), 4.47
(dd, J ) 4.8, 1.5 Hz, 1H), 4.34-4.25 (m, 2H), 2.43 (d, J ) 1.5
Hz, 3H), 1.99 (s, 3H), 1.33 (t, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 193.8, 169.5, 168.7, 140.6, 133.3, 129.1, 128.4,
115.1, 85.5, 61.9, 52.5, 29.5, 14.9, 14.0; MS (EI) m/z (% rel
intensity) 308 (2.1) M+, 43 (100); HRMS (MALDI/DHB) calcd
for C16H18O4Cl + 1 (M+ + H) 309.0885, found 308.0888. HPLC
analysis (Chiralcel AD-H, 2/100 iPrOH/hexanes, 0.8 mL/min, 238
nm; tr(minor) ) 32.10 min, tr(major) ) 22.32 min) gave the
entry
2/R
2a/C6H5
3/4b
trans/cisb
yield (%)c
eed
1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
10/1
10/1
9/1
15/1
9/1
14/1
9/1
12/1
9/1
10/1
6.5/1
14/1
12/1
99
97
88
93
90
96
95
99
80f
94
89
86
91
90
93
89
94
89
92
81
88
89
94
95
2
2b/4-ClC6H4
2b/4-ClC6H4
2c/4-BrC6H4
2c/4-BrC6H4
2d/4-NO2C6H4
2d/4-NO2C6H4
2e/2,4-Cl2C6H3
2f (4-MeC6H4)
2g (2-furyl)
3e
4
5e
6
7e
8
9
10
11
12
2h (E-cinnamyl)
2i (Et)
7/1
a -40 °C, dr (at sulfur atom) of 5 is >50/1, molar ratio: Cs2CO3/5/2
) 1.3/1.3/1.0. b Determined by 1H NMR. c Yield of 3. d Determined by
chiral HPLC for the trans-isomer of compound 3. e Reaction was carried
out at -60 °C. f -45 °C, 17% of 2f was recovered.
isomeric composition of the product: 93% ee. [R]20 +176.6 (c
D
1.00, CHCl3).
15/1 and ee up to 94%) in good yields (entries 1-10). Although
cyclopropanes were observed in the cases of substrates 2h and
2i, the dihydrofurans were isolated in 89% and 86% yields,
respectively (entries 11 and 12, Table 3). Thus, the current
formal [4 + 1] ylide annulation reaction provides an easy access
to the optically active functionalized dihydrofurans.
(2S,3S)-Ethyl Acetyl-5-methyl-3-phenyl-2,3-dihydrofuran-2-car-
boxylate (3a). Yield 99%. Trans-isomer: mp 57-59 °C; IR (film)
ν/cm-1 3029 (w), 2982 (w), 2926 (w), 1756 (s), 1675 (m), 1629
(m), 1603 (s); 1H NMR (300 MHz, CDCl3/TMS) δ 7.39-7.21 (m,
5H), 4.78 (d, J ) 5.1 Hz, 1H), 4.48 (dd, J ) 4.8, 1.5 Hz, 1H),
4.35-4.24 (m, 2H), 2.43 (d, J ) 1.5 Hz, 3H), 1.99 (s, 3H), 1.33 (t,
J ) 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 194.1, 169.6, 168.4,
142.0, 128.9, 127.4, 127.0, 114.9, 85.8, 61.7, 53.0, 29.5, 14.7, 14.0;
MS (EI) m/z (% rel intensity) 275 (10.4) M+ + H, 274 (2.6) M+.
Anal. Calcd for C16H18O4: C, 70.06; H, 6.61. Found: C, 70.05; H,
6.63. HPLC analysis (Chiralcel OJ, iPrOH/hexanes, 10/100, 0.8 mL/
min, 238 nm; tr(minor) ) 13.18 min, tr(major) ) 16.04 min) gave
1
Products 3a-i were characterized by H NMR, 13C NMR,
IR, and mass spectra. The absolute configuration of 3c was
determined by X-ray analysis and was assigned as 2S,3S.13
In summary, we have developed an efficient protocol for the
preparation of optically active dihydrofurans in high to excellent
yields with high selectivities via the reaction between chiral
sulfur ylide and R-ylidene-ꢀ-diketones. The protocol further
expanded the synthetic potential of ylide chemistry. The chiral
sulfide is readily available from cheap D-camphor in two-steps
in 10-g scale and is recoverable.14 The high chemoselectivity,
good diastereoselectivity, high enantioselectivity, and the easily
accessible starting material make this reaction potentially useful
in organic synthesis.
the isomeric composition of the product: 91% ee. [R]20 +142.1
D
(c 1.40, CHCl3).
4-Acetyl-3-(4-bromophenyl)-5-methyl-2,3-dihydrofuran-2-car-
boxylate (3c). Yield 90%. Trans-isomer: IR (film) ν/cm-1 3062 (w),
1
2981 (w), 2925 (w), 1757 (s), 1676 (m), 1629 (m), 1602 (s); H
NMR (300 MHz, CDCl3/TMS) δ 7.47 (d, J ) 8.4 Hz, 2H), 7.12
(d, J ) 8.4 Hz, 2H), 4.72 (d, J ) 4.8 Hz, 1H), 4.46 (dd, J ) 4.5,
0.9 Hz, 1H), 4.33-4.25 (m, 2H), 2.43 (d, J ) 0.9 Hz, 3H), 2.00 (s,
3H), 1.33 (t, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.7,
169.5, 168.6, 141.1, 132.1, 128.8, 121.4, 115.1, 85.5, 61.9, 52.6,
29.5, 14.9, 14.1; MS (EI) m/z (% rel intensity) 352 (1.3) M+, 43
Experimental Section
(100); HRMS (MALDI/DHB) calcd for C16H18O4Br + 1 (M+
+
Synthesis of Sulfonium Salt 5. Camphor-derived sulfide 615
(3.44 g, 17.2 mmol) was mixed with ethyl R-bromoacetate (2.87
g, 17.2 mmol) in ether and the resulting mixture was stirred at -20
°C for 96 h. The product 5 was obtained as a white solid by washing
with n-hexane. Yield: 5.74 g (91%, dr 17.6/1). It can be recrystal-
lized from CH2Cl2/MeOH to give the 5 with a dr ratio >50/1. Mp
168-170 °C; IR (film) ν/cm-1 3153 (br), 2964 (m), 1737 (s), 1455
(w), 1210 (m), 1080 (m); 1H NMR (300 MHz, DMSO-d6/DMSO)
δ 6.49 (d, J ) 6.0 Hz, 1H), 4.75 (d, JAB ) 15.9 Hz, 1H), 4.64 (d,
JAB ) 15.9 Hz, 1H), 4.34 (d, J ) 7.5 Hz, 1H), 4.27 (q, J ) 6.9 Hz,
2H), 3.92 (dd, J ) 6.9, 6.3 Hz, 1H), 3.16 (s, 3H), 2.35 (d, J ) 4.5
Hz, 1H), 1.91-1.82 (m, 1H), 1.56-1.47 (m, 1H), 1.28 (t, J ) 7.3
Hz, 3H), 1.24-1.05 (m, 5H), 0.90 (s, 3H), 0.84 (s, 3H); 13C NMR
(75 MHz, DMSO-d6/ DMSO) δ 165.1, 77.7, 65.0, 63.7, 50.9, 48.1,
47.3, 46.0, 32.4, 28.3, 23.2, 21.9, 21.1, 14.8, 12.2; MS (ESI) m/z
H) 353.0385, found 353.0383. HPLC analysis (Chiralcel AD-H,
2/100 iPrOH/hexanes, 0.8 mL/min, 238 nm; tr(minor) ) 44.80 min,
tr(major) ) 30.46 min) gave the isomeric composition of the
product: 94% ee. [R]20 +177.1 (c 1.00, CHCl3).
D
(2S,3S)-Ethyl 4-Acetyl-5-methyl-3-(4-nitrophenyl)-2,3-dihydro-
furan-2-carboxylate (3d). Yield 95%. Trans-isomer: liquid, IR (film)
ν/cm-1 3062 (w), 2983 (w), 2925 (w), 2854 (w), 1757 (s), 1676
1
(m), 1628 (m), 1599 (m), 1521 (s); H NMR (300 MHz, CDCl3/
TMS) δ 8.23 (d, J ) 8.7 Hz, 2H), 7.42 (d, J ) 8.7 Hz, 2H), 4.76
(d, J ) 5.1 Hz, 1H), 4.61 (d, J ) 4.5 Hz, 1H), 4.35-4.26 (m, 2H),
2.46 (s, 3H), 2.09 (s, 3H), 1.34 (t, J ) 7.5 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 192.9, 169.1, 168.8, 149.4, 147.2, 128.1, 124.1,
115.7, 84.8, 62.1, 52.8, 29.4, 15.1, 14.0; MS (EI) m/z (% rel
intensity) 319 (1.5) M+, 43 (100); HRMS (MALDI/DHB) calcd
for C16H18O6N + 1 (M+ + H) 320.1137, found 320.1129. HPLC
analysis (Chiralcel AD-H, 20/100 iPrOH/hexanes, 0.5 mL/min, 254
nm; tr(minor) ) 24.82 min, tr(major) ) 36.17 min) gave the
isomeric composition of the product: 92% ee. [R]D +286.7 (c 1.00,
CHCl3).
(14) 60-70% sulfide 6 was recovered.
(15) For the synthesis of sulfide 6 see: Li, A.-H.; Dai, L.-X.; Hou, X.-L.;
Huang, Y.-Z.; Li, F.-W. J. Org. Chem. 1996, 61, 489.
J. Org. Chem. Vol. 73, No. 17, 2008 6911

(2S,3R)-Ethyl 4-Acetyl-3-(2,4-dichlorophenyl)-5-methyl-2,3-di-
hydrofuran-2-carboxylate (3e). Yield 99%. Trans-isomer: liquid,
IR (film) ν/cm-1 3023 (w), 2981 (m), 2926 (m), 1755 (s), 1678
(m), 1631 (m), 1603 (m); 1H NMR (300 MHz, CDCl3/TMS) δ 7.44
(d, J ) 1.8 Hz, 1H), 7.27-7.23 (m, 1H), 7.09 (d, J ) 8.7 Hz, 1H),
5.01 (dd, J ) 4.8, 1.5 Hz, 1H), 4.69 (d, J ) 4.8 Hz, 1H), 4.35-4.23
(m, 2H), 2.44 (d, J ) 0.9 Hz, 3H), 1.98 (s, 3H), 1.33 (t, J ) 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.4, 169.3, 169.0, 137.7,
134.0, 133.8, 129.6, 129.3, 127.9, 114.5, 85.0, 61.9, 48.7, 29.3,
14.9, 14.0; MS (EI) m/z (% rel intensity) 342 (5.7) M+, 43 (100);
HRMS (MALDI/DHB) calcd for C16H17O4Cl2 + 1 (M+ + H)
343.0482, found 343.0477. HPLC analysis (Chiralcel AD-H, 2/100
iPrOH/hexanes, 0.8 mL/min, 238 nm; tr(minor) ) 24.72 min,
tr(major) ) 21.32 min) gave the isomeric composition of the
the isomeric composition of the product: 89% ee. [R]20 +197.5
D
(c 0.93, CHCl3).
(2S,3S,E)-Ethyl 4-Acetyl-5-methyl-3-styryl-2,3-dihydrofuran-2-
carboxylate (3h). Yield 89%. Trans-isomer: liquid; IR (film) ν/cm-1
3025 (w), 2980 (m), 2932 (w), 1754 (s), 1674 (m), 1625 (m), 1600
(s); 1H NMR (300 MHz, CDCl3/TMS) δ 7.40-7.24 (m, 5H), 6.55
(d, J ) 15.6 Hz, 1H), 6.24 (dd, J ) 15.6, 7.8 Hz, 1H), 4.78 (d, J
) 4.8 Hz, 1H), 4.28 (q, J ) 7.2 Hz, 2H), 4.14-4.09 (m, 1H), 2.36
(d, J ) 0.9 Hz, 3H), 2.19 (s, 3H), 1.33 (t, J ) 7.2 Hz); 13C NMR
(75 MHz, CDCl3) δ 194.1, 169.7, 168.3, 136.2, 132.1, 129.0, 128.5,
127.8, 126.3, 114.1, 83.4, 61.7, 50.6, 29.5, 14.9, 14.0; MS (EI)
m/z (% rel intensity) 300 (0.9) M+, 43 (100); HRMS (MALDI/
DHB) calcd for C18H21O4 + 1 (M+ + H) 301.1422, found 301.1434.
HPLC analysis (Chiralcel OD-H, 5/95 iPrOH/hexanes, 0.8 mL/min,
254 nm; tr(minor) ) 25.65 min, tr(major) ) 18.63 min) gave the
product: 81% ee. [R]20 +127.5 (c 0.95, CHCl3).
D
isomeric composition of the product: 94% ee. [R]20 +242.1 (c
D
(2S,3S)-Ethyl 4-Acetyl-5-methyl-3-p-tolyl-2,3-dihydrofuran-2-
carboxylate (3f). Yield 80%. Trans-isomer: liquid; IR (film) ν/cm-1
3023 (w), 2981 (m), 2924 (m), 2854 (w), 1756 (s), 1767 (m), 1629
(m), 1603 (s); 1H NMR (300 MHz, CDCl3/TMS) δ 7.18-7.11 (m,
4H), 4.76 (d, J ) 4.8 Hz, 1H), 4.45 (dd, J ) 4.8, 0.9 Hz, 1H),
4.33-4.24 (m, 2H), 2.43 (d, J ) 1.2 Hz, 3H), 2.34 (s, 3H), 1.95
(s, 3H), 1.33 (t, J ) 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
194.3, 169.8, 168.4, 139.1, 137.2, 129.6, 126.9, 115.0, 86.0, 61.7,
52.8, 29.6, 21.0, 14.8, 14.0; MS (EI) m/z (% rel intensity) 288 (3.9)
M+, 43 (100); HRMS (MALDI/DHB) calcd for C17H21O4 + 1 (M+
+ H) 289.1427, found 289.1434. HPLC analysis (Chiralcel OJ, 10/
0.85, CHCl3).
(2S,3S)-Ethyl 4-Acetyl-3-ethyl-5-methyl-2,3-dihydrofuran-2-car-
boxylate (3i). Yield 86%. Trans-isomer: liquid; IR (film) ν/cm-1
1
2966 (m), 2931 (m), 1755 (s), 1673 (m), 1627 (s), 1601 (m); H
NMR (300 MHz, CDCl3/TMS) δ 4.64 (d, J ) 4.2 Hz, 1H), 4.24
(q, J ) 6.9 Hz, 2H), 3.31-3.24 (m, 1H), 2.31 (d, J ) 0.9 Hz, 3H),
2.26 (s, 3H), 1.85-1.76 (m, 1H), 1.57-1.47 (m, 1H), 1.29 (t, J )
6.9 Hz, 3H), 0.94 (t, J ) 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 193.6, 170.6, 167.2, 116.2, 82.0, 61.5, 49.2, 29.3, 26.4, 15.2,
14.0, 10.1; MS (EI) m/z (% rel intensity) 226 (2.7) M+, 43 (100);
HRMS (EI) calcd for C12H18O4 (M+) 226.1205, found 226.1211.
i
100 PrOH/hexanes, 0.8 mL/min, 254 nm; tr(minor) ) 10.32 min,
i
HPLC analysis (Chiralcel OD-H, 2/100 PrOH/hexanes, 0.8 mL/
tr(major) ) 14.51 min) gave the isomeric composition of the
min, 254 nm; tr(minor) ) 13.75 min, tr(major) ) 16.01 min) gave
the isomeric composition of the product: 95% ee. [R]20D +52.7 (c
0.85, CHCl3).
product: 88% ee. [R]20 +146.6 (c 0.85, CHCl3).
D
(2S,3S)-Ethyl 4-Acetyl-3-(2-furyl)-5-methyl-2,3-dihydrofuran-
2-carboxylate (3g). Yield 94%. Trans-isomer: liquid; IR (film)
ν/cm-1 2960 (w), 2924 (s), 2854 (w), 1756 (s), 1676 (m), 1603
(s); 1H NMR (300 MHz, CDCl3/TMS) δ 7.37 (t, J ) 0.9 Hz, 1H),
6.33 (q, J ) 1.2 Hz, 1H), 6.17 (d, J ) 3.3 Hz, 1H), 4.94 (d, J )
4.8 Hz, 1H), 4.62 (d, J ) 4.2 Hz, 1H), 4.29 (q, J ) 7.2 Hz, 2H),
2.39 (d, J ) 1.2 Hz, 3H), 2.08 (s, 3H), 1.33 (t, J ) 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 193.7, 169.4, 168.8, 153.6, 142.2,
112.6, 110.5, 106.8, 82.8, 61.9, 46.4, 29.2, 14.9, 14.0; MS (EI)
m/z (% rel intensity) 264 (3.1) M+, 43 (100); HRMS (MALDI/
DHB) calcd for C14H17O5 + 1 (M+ + H) 265.1075, found 265.1071.
Acknowledgment. We are grateful for the financial support
from the National Natural Science Foundation of China, the
Major State Basic Research Development Program (Grant No.
2006CB806105), The Chinese Academy of Sciences, and the
Science and Technology Commission of Shanghai Municipality.
Supporting Information Available: Full experimental de-
tails, CIF file for 3c, and chiral HPLC spectra of 3. This material
is available free of charge via the Internet at http://pubs.acs.org.
i
HPLC analysis (Chiralcel AD-H, 2/100 PrOH/hexanes, 0.8 mL/
min, 238 nm; tr(minor) ) 26.48 min, tr(major) ) 28.37 min) gave
JO801135J
6912 J. Org. Chem. Vol. 73, No. 17, 2008