Asymmetric hetero-Diels-Alder reaction of 1-alkyl-3-silyloxy-1,3-dienes with ethyl glyoxylate catalyzed by a chiral (salen)cobalt(II) complex

Article abstract of DOI:10.1016/S0957-4166(98)00204-3

The hetero-Diels-Alder reactions of 1-alkyl-3-(tert- butyldimethylsilyl)oxy-1,3-butadienes with ethyl glyoxylate catalyzed by chiral salen-metal complexes have been studied. With a cobalt(II) complex as the catalyst, the reaction of 1-(2-benzyloxyethyl)-3-(tert- butyldimethylsilyl)oxy-1,3-butadiene with ethyl glyoxylate gave the Diels- Alder product in 75% isolated yield with the endo:exo ratio >99:1 and the enantiomeric excess ≤52%. The effects of temperature, catalyst and solvent are also discussed.

Full text of DOI:10.1016/S0957-4166(98)00204-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2271–2277
Asymmetric hetero-Diels–Alder reaction of 1-alkyl-3-silyloxy-
1,3-dienes with ethyl glyoxylate catalyzed by a chiral
(salen)cobalt(II) complex
Lian-Sheng Li, Yikang Wu, Yun-Jin Hu, Li-Jun Xia and Yu-Lin Wu ∗
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, 200032 Shanghai, PR China
Received 6 April 1998; accepted 7 May 1998
Abstract
The hetero-Diels–Alder reactions of 1-alkyl-3-(tert-butyldimethylsilyl)oxy-1,3-butadienes with ethyl glyoxylate
catalyzed by chiral salen–metal complexes have been studied. With a cobalt(II) complex as the catalyst, the reaction
of 1-(2-benzyloxyethyl)-3-(tert-butyldimethylsilyl)oxy-1,3-butadiene with ethyl glyoxylate gave the Diels–Alder
product in 75% isolated yield with the endo:exo ratio >99:1 and the enantiomeric excess ≥52%. The effects of
temperature, catalyst and solvent are also discussed. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The asymmetric hetero-Diels–Alder (HDA) reaction is one of the most efficient synthetic methodolo-
gies for the regio- and stereoselective construction of six-membered heterocycles. The last two decades
have witnessed many successful cases of employing asymmetric Diels–Alder reactions1–3 as the key step
in the synthesis of natural products. The selectivities of the HDA reactions, however, are not always
high. It is therefore not surprising that much attention4–10 has been paid to developing new catalysts for
different reaction systems.
∗
Corresponding author. E-mail: ylwu@pub.sioc.ac.cn
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00204-3

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We recently reported a (salen)Co(II) complex-catalysed formal total synthesis11 of KDO (3-deoxy-
D-manno-2-octulosonic acid), where high selectivities were achieved (endo:exo=93:7, d.e.=70) when a
chiral diene was used. As an extension of that work, we next examined some achiral dienes and other
salen-derived catalysts. Disclosed herein are some of the results.
2. Results and discussion
The model system chosen for our study is shown in Scheme 1, with ethyl glyoxylate as the dienophile
and 1a as well as 1b (prepared from propane-1,3-diol or ethylene glycol, respectively, Scheme 2) as the
diene. Several salen–transition metal complexes were then tested under different conditions for catalytic
activity. The main results are summarized in Table 1. Due to the instability and the low polarity of the
silyl enol ethers (which led to difficulties in purification), the ee values for the main isomers 2a,b were
determined (by HPLC on a chiral column) after hydrolysis to the corresponding ketones 3a,b.
Scheme 1.
We first ran the reaction at 0°C in CH2Cl2 using 2 mol% of (salen)Co(II) as the catalyst (entry 1,
Table 1). Under these conditions, the HDA products were obtained in 68% yield with the endo:exo
ratio=90:10. The enantioselectivity, however, was rather poor (13% e.e.). Using larger amounts of the
catalyst (entries 2 and 3) led to moderately improved e.e. values. Lowering the reaction temperature from
0°C to −78°C further raised the e.e. value to 52%, the best result so far obtained. The presence of 4 Å
molecular sieves did not cause any changes in the outcome of the reaction.
Recently both Jacobsen12 and Katsuki13 reported in a different context (not related to Diels–Alder
reactions) that Co(III) species showed better enantioselectivity than the corresponding Co(II). This
persuaded us to examine (salen)Co(III)OAc and (salen)Co(III)Br complexes. The results were rather
disappointing (entries 4 and 5), so we extended the catalyst further to some other salen–M complexes

L.-S. Li et al. / Tetrahedron: Asymmetry 9 (1998) 2271–2277
2273
Scheme 2.
Table 1
The results of the HDA reaction of 1a with ethyl glyoxylate (1.5 equiv.) in CH2Cl2
(M=Mn(III)Cl, Ni(II), V(IV)=O); all prepared by known methods.14,15 We found that with the nickel(II)
complex as the catalyst the e.e. was only 8%, whereas with the manganese(III) and the vanadium(IV)
complexes almost no enantioselectivity was observed, even at low temperature (entries 7, 8, and 9).
We have also explored the solvent effects on the stereochemical outcome (Table 2) in the (salen)Co(II)-
catalyzed reaction of 1a with ethyl glyoxylate. CH2Cl2 seems to be the most suitable solvent for this
reaction. When using ether solvents (diethyl ether or THF) to replace CH2Cl2, not only the e.e. value

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Table 2
HDA reactiona of 1a with ethyl glyoxylate catalyzed by (salen)Co(II) complex (10 mol%) in different
solvents at 0°C
decreases, but also the endo:exo ratio. In hexanes the endo:exo selectivity is the same as in CH2Cl2 but
the enantioselectivity is significantly reduced.
Considering the tendency of ethyl glyoxylate to polymerize or hydrate, we normally used an excess
of ethyl glyoxylate (1.5 equiv. with respect to the diene) in the reaction. Reducing the amount of ethyl
glyoxylate to 1 equiv. lowered the yield to 62% (compared with entry 6 in Table 1) but did not lead to
any improvement in the selectivities (endo:exo>99:1, 41% e.e. for the endo isomer).
The diene 1a used in the present work does not bear any oxygen atom at the carbon α to the C–C double
bond. This might be a reason for the relatively lower enantioselectivity in comparison with our earlier
work.11 To look into this, we synthesized 1b and tested it in place of 1a. It turned out that no changes
(endo:exo>99:1, 45% e.e. for the endo isomer) could be detected, except that the yield was lowered to
45% (presumably due to the increased steric hindrance associated with the bulky benzyl group). In other
words, the better selectivities11 recorded with the chiral diene do stem from the matched interactions
between the substrate and the chiral catalyst as suggested earlier.
3. Experimental
1
IR spectra were recorded on a Shimadzu IR-440 spectrometer. H and 13C NMR were recorded
on an EM-360A, an FX 90q, or an AMX-300 spectrometer with TMS as the internal standard. Mass
spectra were taken on a VG Quattro MS/MS or an HP 5989A instrument. The HRMS (EI) spectrum was
obtained on a Finnigan Mat 8430 mass spectrometer. Optical rotations were measured on a Perkin–Elmer
241 MC polarimeter. The CD spectrum was recorded on a J-715 spectropolarimeter. Flash column
chromatography was performed on silica gel H (10–40 µm) with a petroleum ether–ethyl acetate system
as eluant. Microanalyses were carried out in the Microanalytical Laboratory at Shanghai Institute of
Organic Chemistry.
3.1. 3-Benzyloxypropanol16 4a
To a solution of NaH (5.0 g, 125 mmol) in a 10:7 mixture of THF:DMF (85 mL) stirred at 0°C was
added dropwise a solution of propane-1,3-diol (8.5 g, 112 mmol) in THF (25 mL). After stirring at
room temperature for 3 h, benzyl bromide (13.3 mL, 112 mmol) was introduced dropwise. The stirring
was continued at room temperature for another 12 h before the reaction was quenched with water. The
reaction mixture was extracted three times with ether. The combined organic layers were dried over

L.-S. Li et al. / Tetrahedron: Asymmetry 9 (1998) 2271–2277
2275
MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on
silica gel (eluting with 5:1 petroleum ether:ethyl acetate) to afford 4a (12.0 g, 65% yield). 1H NMR (90
MHz, CCl4): δ 7.32 (s, 5H), 4.49 (s, 2H), 3.45–3.72 (m, 4H), 1.73 (m, 2H); IR (film): 3385, 2929, 2866,
1603, 1495, 1451, 748 cm−1; EI MS (m/z): 167 (M++1), 107 (90.08), 91 (100), 79 (30.38).
3.2. 2-Benzyloxyethanol17 4b
This compound was obtained using the procedure for 4a (except for utilizing ethylene glycol instead
1
of 1,3-propanediol). H NMR (90 MHz, CDCl3): δ 7.38 (s, 5H), 4.51 (s, 2H), 3.72–3.45 (m, 4H), 2.65
(s, 1H); IR (film): 3389, 3029, 2942, 1635, 1495, 1452, 742 cm−1; EI MS (m/z): 152 (M+, 42.95), 107
(67.07), 91 (100, PhCH2).
3.3. (3E)-6-Benzyloxyhex-3-en-2-one18 E-5a
To a solution of oxalyl chloride (3.32 mL, 33.2 mmol) in CH2Cl2 (75 ml) stirred at −78°C was added
DMSO (5.10 mL, 73 mmol) in CH2Cl2 (15 mL). The mixture was stirred at −78°C for 30 min. A solution
of compound 4a (5.4 g, 33.2 mmol) in CH2Cl2 (15 mL) was added, and the stirring was continued at
−78°C for 30 min before NEt3 (23.4 mL, 166 mmol) was added at the same temperature. After stirring
at 0°C for 30 min and then at room temperature for 1 h, water (80 mL) was added. The organic layer was
washed with 2 M aq. HCl, saturated aq. NaHCO3 and brine, dried over MgSO4. Removal of the drying
agent and the solvent in vacuo gave the crude product, which was dissolved in dry benzene (80 mL) and
treated with Ph3P_CHCOCH3 (10.8 g, 34.1 mmol). The mixture was heated at reflux for 5 h, then was
cooled and concentrated. The residue was extracted with hexane several times. The organic layers were
combined and concentrated to give the crude mixture of the Z/E isomers, which were separated by flash
chromatography (10:1 petroleum ether:ethyl acetate) to afford Z-5a (500 mg) and E-5a (4.1 g) in a total
yield of 64% (over two steps). Data for E-5a: 1H NMR (90 MHz, CDCl3): δ 7.20 (m, 5H), 6.75 (m, 1H),
5.96 (d, 1H, J=15.5 Hz), 4.43 (s, 2H), 3.46 (t, 2H, J=6 Hz), 2.42 (m, 2H), 2.10 (s, 3H); IR (film): 3040,
2870, 1680, 1500, 1460, 1100, 740, 700 cm−1; EI MS (m/z): 204 (M+), 91 (100, PhCH2).
3.4. (3E)-5-Benzyloxypent-3-en-2-one19 E-5b
1
This compound was obtained using the procedure for 5a (except for utilizing 4b instead of 4a). H
NMR (300 MHz, CDCl3): δ 7.34 (m, 5H), 6.80 (dt, 1H, J=16.1, 4.5 Hz), 6.35 (dt, 1H, J=16.1, 3.9 Hz),
4.57 (s, 2H), 4.20 (dd, 2H, J=4.5, 2.0 Hz), 2.26 (s, 3H); IR (film): 3032, 2857, 1677, 1635, 1497, 1454,
1121, 740, 699 cm−1; EI MS (m/z): 189 (M+−1), 91 (100, PhCH2).
3.5. (3E)-2-(tert-Butyldimethylsilyl)oxy-6-benzyloxy-hexa-1,3-diene E-1a
To a cooled ether solution (0°C) of enone 5a (1.02 g, 5 mmol in 30 mL of dry ether) was added drop-
wise tert-butyldimethylsilyl trifluoromethanesulfonate (1.26 mL, 5.5 mmol) followed by triethylamine
(0.83 mL, 6 mmol). The mixture was stirred for 10 min before the cooling bath was removed. The
stirring was continued at room temperature for another 30 min, when TLC showed the consumption of
the starting material. The solvent was removed in vacuo and the residue was chromatographed on neutral
alumina (eluting with petroleum ether) to afford 1a (1.84 g, 99% yield) as a colorless oil. 1H NMR (300
MHz, CD3COCD3): δ 7.33 (m, 5H), 6.04 (m, 2H), 4.49 (s, 2H), 4.24 (d, 2H, J=3.1 Hz), 3.52 (t, 2H,

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J=6.5 Hz), 2.39 (m, 2H), 0.96 (s, 9H), 0.17 (s, 6H); IR (film): 3020, 2940, 1600, 1500, 1460, 1030, 700
cm−1; EIMS (m/z): 319 (M++1, 4.11), 91 (100, PhCH2).
3.6. (3E)-2-(tert-Butyldimethylsilyl)oxy-5-benzyloxy-penta-1,3-diene E-1b
This compound was obtained using the procedure for 1a (except for utilizing E-5b instead of E-5a). 1H
NMR (300 MHz, CD3COCD3): δ 7.33 (m, 5H), 6.18 (dt, 1H, J=15.08, 1.25 Hz), 6.07 (dt, 1H, J=15.08,
5.6 Hz), 4.51 (s, 2H), 4.36 (d, 2H, J=7.54 Hz), 4.10 (d, 2H, J=4.79 Hz), 0.97 (s, 9H), 0.19 (s, 6H);
IR (film): 3032, 2958, 2859, 1661, 1595, 1497, 1455, 1318, 1255, 1025, 697 cm−1; EI MS (m/z): 305
(M++1, 2.01), 91 (100, PhCH2 ).
3.7. (2R,6R)-2-(2-Benzyloxyethyl)-3-(tert-butyldimethylsilyl)oxy-6-ethoxycarbonyl-5,6-dihydro-2H-
pyran 2a
To a solution of ethyl glyoxylate (78.5 mg, 0.75 mmol) in anhydrous CH2Cl2 (5 mL) stirred at −78°C
(or 0°C) under nitrogen, was added the catalyst (salen–M, M=Co(II), Co(III), Mn(III), Ni(II), V(IV)_O)
(10 mol%) in dry CH2Cl2 (5 ml). The mixture was stirred for 30 min then the diene E-1a (159 mg,
0.5 mmol) was added. The stirring was continued at the same temperature until TLC (4:1 petroleum
ether:ethyl acetate) showed the disappearance of the starting material. After removal of the solvent, the
1
residue was chromatographed on silica gel (20:1 petroleum ether:ethyl acetate) to afford 2a. H NMR
(300 MHz, CD3COCD3): δ 7.34 (m, 5H), 4.91 (s, 1H), 4.49 (s, 2H), 4.34 (m, 1H), 4.21 (dd, 1H, J=10.7,
4.0 Hz), 4.17 (q, 2H, J=7.0 Hz), 3.61 (m, 2H), 2.29 (m, 1H), 2.15 (m, 1H), 1.82 (m, 2H), 1.24 (t, 3H,
J=7.0 Hz), 0.92 (s, 9H), 0.16 (s, 6H); IR (film): 2931, 2859, 1747, 1676, 1497, 1455, 1207, 1184, 840,
698 cm−1; EI MS (m/z): 419 (M+−1, 1.84), 329 (45.64), 285 (61.77), 91 (100), 73 (84.37).
3.8. (2S,6R)-2-(2-Benzyloxymethyl)-3-(tert-butyldimethylsilyl)oxy-6-ethoxycarbonyl-5,6-dihydro-2H-
pyran 2b
This compound was obtained using the procedure for 2a (except for utilizing E-1b instead of E-1a).
1H NMR (300 MHz, CD3COCD3): δ 7.40–7.32 (m, 5H), 4.92 (m, 1H), 4.56 (m, 2H), 4.40 (m, 1H), 4.26
(dd, 1H, J=10.9, 4.0 Hz), 4.18 (q, 2H, J=7.0 Hz), 3.58–3.44 (m, 2H), 2.40–2.32 (m, 2H), 1.24 (t, 3H,
J=7.0 Hz), 0.92 (s, 9H), 0.16 (s, 6H); IR (film): 2932, 2860, 1739, 1674, 1497, 1455, 1203, 1184, 840,
698 cm−1; EI MS (m/z): 405 (M+−1), 285 (100), 91 (62.35), 73 (50.08).
3.9. (2R,6R)-2-Ethoxycarbonyl-6-(2-benzyloxyethyl)-tetrahydro-1,4-pyrone 3a
To a solution of compound 2a (120 mg, 0.3 mmol) in dry THF (4 mL) stirred at room temperature
under nitrogen, was added tetrabutylammonium fluoride (1 N, 0.4 mL). The mixture was stirred for 15
min when TLC (4:1 petroleum ether:ethyl acetate) showed the completion of the reaction. The mixture
was then diluted with ether (10 mL), washed with water and brine. The organic layer was dried over
MgSO4. After removal of the drying agent and the solvent, the residue was chromatographed on silica gel
(4:1 petroleum ether:ethyl acetate) to afford product 3a as a clear oil (75 mg, 87% yield). [α]D18=+20.5
(c 1.53, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 7.48–7.35 (m, 5H), 4.50 (s, 2H), 4.25 (q, 2H, J=7.08
Hz), 4.21 (dd, 1H, J=11.66, 3.28 Hz), 3.92–3.83 (m, 1H), 3.73–3.65 (m, 1H), 3.63–3.58 (m, 1H), 2.61
(m, 2H), 2.40 (m, 2H), 2.10–2.01 (m, 1H), 1.93–1.84 (m, 1H), 1.30 (t, 3H, J=7.0 Hz); IR (film): 2982,

L.-S. Li et al. / Tetrahedron: Asymmetry 9 (1998) 2271–2277
2277
2868, 1756, 1725, 1496, 1455, 1098, 740, 699 cm−1; EI MS (m/z): 307 (M++1), 171 (26.42), 91 (100,
PhCH2); anal. calcd for C17H22O5: C, 66.67. H, 7.19. Found: C, 66.57. H, 7.19.
3.10. (2R,6S)-2-Ethoxycarbonyl-6-benzyloxymethyl-tetrahydro-1,4-pyrone 3b
This compound was obtained using the procedure for 3a (except for utilizing 2b instead of 2a).
1
[α]D20=+14.4 (c 1.50, CH2Cl2). H NMR (300 MHz, CDCl3): δ 7.32 (m, 5H), 4.60 (m, 2H), 4.25 (q,
2H, J=7.1 Hz), 4.24 (dd, 1H, J=15.1 and 4.2 Hz), 3.90 (m, 1H), 3.68 (dd, 1H, J=10.5, 5.3 Hz), 3.60 (dd,
1H, J=10.5, 4.3 Hz), 2.72–2.59 (m, 2H), 2.56–2.42 (m, 2H), 1.29 (t, 3H, J=7.1 Hz); IR (film): 2983,
2869, 1726, 1497, 1454, 1107, 740, 700 cm−1; EI MS (m/z): 293 (M++1, 54.52), 185 (65.11), 91 (100,
PhCH2). HRMS (EI): calcd for C16H20O5: 292.1305. Found: 292.1308.
Acknowledgements
This work was supported by the Chinese Academy of Sciences (KJ952-S1-503, LJ95-A1-504), the
Chinese Natural Science Foundation (29790126), and the State Committee of Science and Technology.
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