Concise enantiodivergent synthesis of (+)- and (-)-trans-quercus lactones

Article abstract of DOI:10.1016/S0957-4166(01)00500-6

A concise enantiodivergent total synthesis of (+)- and (-)-quercus lactones from the known tricyclic lactone (+)-1 as a single chiral template was achieved using the diastereoselective nucleophilic addition of organometallic reagents as the key step.

Full text of DOI:10.1016/S0957-4166(01)00500-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2789–2792
Concise enantiodivergent synthesis of (+)- and (−)-trans-quercus
lactones
Katsufumi Suzuki, Muneo Shoji, Eriko Kobayashi and Kohei Inomata*
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
Received 25 September 2001; accepted 30 October 2001
Abstract—A concise enantiodivergent total synthesis of (+)- and (−)-quercus lactones from the known tricyclic lactone (+)-1 as a
single chiral template was achieved using the diastereoselective nucleophilic addition of organometallic reagents as the key step.
© 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
as the key intermediate (Scheme 1). (+)-trans-Quercus
lactone 4 was isolated together with a cis-(−)-isomer
from oak woods and aged spirits.4 The trans-configura-
tion of the methyl and butyl groups has been deter-
mined by 1H NMR spectroscopy, and its absolute
configuration has been assigned on the basis of an
empirical correlation.5 Many syntheses of 4, including
enantiodivergent routes, have been reported.6,7
g-Butyrolactones can be found as important con-
stituents in many natural products.1 Therefore, the
asymmetric synthesis of g-butyrolactone has been an
ongoing challenge for researchers attempting the
organic synthesis of certain substances.2 We recently
determined that the nucleophilic addition of hydride
and organometallic reagents to racemic tricyclic lactone
( )-1 could be highly diastereoselective and yield
diastereomeric diols 2 and 3,3 respectively, depending
on reaction conditions. We report herein an application
of this methodology to synthesize chiral g-butyrolac-
tones and to effect the enantiodivergent synthesis of
(+)- and (−)-trans-quercus lactones (also known as
whisky lactone) 4 using chiral g-substituted butenolide
2. Results and discussion
Chiral bicyclic lactone (+)-1,8 which was prepared in
enantiomerically pure form from
D
-mannitol,8b was
partially reduced with diisobutylaluminum hydride
(DIBAL) in tetrahydrofuran (THF) to give the lactol
i) H
i) R M
O
R
R
ii) H
ii) R M
OH
HO
O
OH
HO
Me
(+) - 1
3
2
Me
H
H
H
H
O
O
O
O
(-)-trans-Quercus lactone : (-)-4
(+)-trans-Quercus lactone : (+)-4
Scheme 1.
* Corresponding author. Tel.: +81(22)234-4181; fax: +81(22)275-2013; e-mail: inomata@tohoku-pharm.ac.jp
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00500-6

2790
K. Suzuki et al. / Tetrahedron: Asymmetry 12 (2001) 2789–2792
We believe that the diastereoselectivity in the case of
continuous nucleophilic addition can be explained as
follows. First, nucleophilic addition to (+)-1 gives the
corresponding acetal derivative 10, which equilibrates
to the metal-chelated intermediate 11. A second nucle-
ophile then approaches from the outside of the chelate-
ring to give the single diastereomer. Thus, the
configuration of the newly generated stereocenter was
controlled by the order in which the nucleophilic
reagents were added (Scheme 3).
intermediate, followed by the addition of n-butylmag-
nesium chloride in the same flask, resulting in diol 5 in
82% yield with >99% d.e. On the other hand, a stoi-
chiometric amount of n-butyllithium was added to
(+)-1 in toluene to give the ketone, followed by the
addition of L-Selectride™, in one pot, which furnished
1
diol 6 in 78% yield with >99% d.e. as determined by H
NMR, on the basis of the chemical shifts of the oxy-
methine proton of 5 (l 3.65) and 6 (l 3.69). In the latter
case, when THF and DIBAL were used as the solvent
and hydride source, respectively, we observed a lower
yield and diastereoselectivity of 6 (38% yield, 4% d.e.).9
Oxidation with a catalytic amount of tetra-n-propylam-
monium perruthenate (TPAP) in the presence of 4-
3. Conclusion
In conclusion, we have achieved a concise enantiodiver-
gent total synthesis of (+)- and (−)-quercus lactones
from (+)-1. This synthesis suggests that (+)-1 was the
synthetic equivalent of a chiral g-substituted butyrolac-
tone in both enantiomeric forms. On the basis of this
concept, we have begun to investigate the chiral synthe-
ses of versatile g-substituted butyrolactone in enantiodi-
vergent ways.
methylmorpholine
N-oxide
(NMO)
gave
the
corresponding diastereomeric lactone 7 in 66% yield
from 5, and 8 in 61% yield from 6, respectively.10
Retro-Diels–Alder reaction in refluxing o-dichloroben-
zene (ODCB) yielded the known enantiomeric 4-butyl-
substituted butenolides (−)-9 and (+)-9, which were the
key intermediates in previous quercus lactone synthe-
ses.8c,e,j The enantiomeric excess of 9 was determined by
HPLC with a chiral column, [(−)-9: 90% e.e., and (−)-9:
92% e.e.]. This observed decrease in enantiomeric purity
was probably the result of the partial enolization of 9,
which occurred via retro-Diels−Alder reaction.
Stereoselective 1,4-addition of dimethylcuprate in
diethyl ether, which has been reported previously,8c
gave (+)-4 in 72% yield from (−)-9, and (−)-4 in 61%
yield from (+)-9, respectively (Scheme 2).
4. Experimental
4.1. General procedure
Melting points are uncorrected. IR spectra were
recorded on a JASCO-FT-IR-5000 spectrometer. 1H
NMR spectra were recorded on a JEOL-GSX-270 (270
H
H
v
v
i
i, ii
C4H9
C4H9
O
O
C4H9
OH
5
O
HO
(-)-9
7
O
(+)-
1
C4H9
H
C4H9
H
vi
v
iii, iv
C4H9
O
O
(+)-9
OH
6
O
HO
8
O
vii
vii
(-)-4
(-)-9
(+)-4
(+)-9
ref. 7c
ref. 7c
Scheme 2. Reagents and conditions: (i) DIBAL, THF, −78°C; (ii) n-butylmagnesium chloride, THF, −78°C (82% from 1); (iii) 1.0
,
equiv. n-butyllithium, toluene, −78°C; (iv) L-Selectride, toluene, −78°C; (78% from 1); (v) cat. TPAP, NMO, 4 A molecular sieves,
CH2Cl2 (66% for 7, 61% for 8); (vi) ODCB, reflux [85% for (−)-9, 84% for (+)-9]; (vii) methyllithium, CuI, diethyl ether, −78°C
[72% for (+)-4, 61% for (−)-4].
O M
R1
R2M
R1M
(+) - 1
R2
OH
R1 = H or C4H9
R2 = C4H9 or H
O
R1
11
R1
O
HO
O
10
5 : R1 = H, R2 = C4H9
6 : R1 = C4H9, R2 = H
M
Scheme 3.

K. Suzuki et al. / Tetrahedron: Asymmetry 12 (2001) 2789–2792
2791
MHz) spectrometer. Mass spectra were recorded on a
4.4. (2R,5R,6S)-5-Butyl-4-oxatricyclo[5.2.1.02,6]dec-8-
en-3-one 7
JEOL-DX-303 spectrometer. Enantiomeric excesses
were determined on a Waters-HPLC 600 instrument
equipped with a chiral column. Optical rotations were
measured with a JASCO-DIP-370 digital polarimeter.
To a stirred solution of 5 (95 mg, 0.45 mmol) in
,
anhydrous CH2Cl2 (5 mL) was added 4 A molecular
sieves (crushed and dried, 452 mg), NMO (158 mg, 1.36
mmol), and TPAP (8.0 mg, 0.02 mmol) at 0°C. The
mixture was stirred at rt for 3 h and 10% aq. NaHSO3
(4 mL) was added to quench the reaction. After filtra-
tion on a Celite pad, the filtrate was extracted with
CH2Cl2 (3×15 mL), washed with 10% aq. HCl (10 mL),
satd aq. NaHCO3 (10 mL), and brine (10 mL), dried
(MgSO4), and evaporated under reduced pressure. The
residue was chromatographed on silica gel (hexane/
AcOEt=15: 1) to give 7 as a colorless oil (61 mg, 66%).
Compound 7: [h]1D9=−30.7 (c 0.95, CHCl3). IR (film):
w=2938, 1764, 1183 cm−1. 1H NMR (270 MHz,
CDCl3): l 0.91 (3H, t, J=7.0 Hz), 1.31–1.44 (5H, m),
1.55–1.69 (3H, m), 2.72 (1H, td, J=9.2, 4.0 Hz), 3.08–
3.09 (1H, m), 3.24–3.33 (2H, m), 3.91 (1H, dt, J=6.7,
3.3 Hz), 6.24 (1H, dd, J=5.7, 3.0 Hz), 6.30 (1H, dd,
J=5.7, 3.0 Hz). 13C NMR (270 MHz, CDCl3): l 14.0,
22.5, 27.0, 36.7, 45.6, 46.2, 46.7, 48.5, 51.7, 82.9, 134.9,
136.7, 177.9. EIMS: m/z=206 (M+), 66 (100%).
HRMS: calcd for C13H18O2 206.1307, found 206.1320.
4.2. (1R)-1-[(2%S,3%R)-3-Hydroxymethylbicyclo[2.2.1]-
hept-5-en-2-yl]pentan-1-ol 5
To a stirred solution of (+)-1 (100 mg, 0.67 mmol) in
THF (4 mL) was added a solution of DIBAL (0.94 M
in hexane, 0.80 mL, 0.73 mmol) at −78°C. The mixture
was stirred at the same temperature for 1.5 h, n-butyl-
magnesium chloride (0.90 M in THF, 4.10 mL, 3.67
mmol) was added and the resulting mixture stirred at
the same temperature for 5 h. Saturated aq. NH4Cl (1.5
mL) was added to quench the reaction. The mixture
was extracted with ethyl acetate (AcOEt, 3×15 mL),
washed with satd aq. NaHCO3 (5 mL) and brine (5
mL), dried (MgSO4), and evaporated under reduced
pressure. The residue was chromatographed on silica
gel (benzene/AcOEt=4: 1) to give 5 as a colorless oil
(115 mg, 82%). Compound 5: [h]1D8=+76.2 (c 1.00,
CHCl3). IR (film): w=3254, 2962, 1040, 729 cm−1. H
1
NMR (270 MHz, CDCl3): l 0.94 (3H, t, J=7.1 Hz),
1.30–1.53 (7H, m), 1.62–1.67 (1H, m), 2.27 (1H, ddd,
J=10.3, 8.0, 3.5 Hz), 2.49–2.59 (1H, m), 2.69 (2H, br s,
exchangeable with D2O), 2.78–2.83 (2H, m), 3.35–3.47
(2H, m), 3.65 (1H, dd, J=11.4, 3.1 Hz), 6.01–6.06 (2H,
m). 13C NMR (270 MHz, CDCl3): l 14.1, 22.8, 27.1,
35.8, 45.9, 46.5, 46.9, 49.4, 49.6, 63.7, 71.8, 134.2, 135.3.
EIMS: m/z=210 (M+), 67 (100%). HRMS: calcd for
C13H22O2 210.1620, found 210.1598
4.5. (2R,5S,6S)-5-Butyl-4-oxatricyclo[5.2.1.02,6]dec-8-en-
3-one 8
To a stirred solution of 6 (768 mg, 3.66 mmol) in
,
anhydrous CH2Cl2 (10 mL) was added 4 A molecular
sieves (crushed and dried, 3.65 g), NMO (1.29 g, 10.97
mmol), and TPAP (64 mg, 0.18 mmol) at 0°C. The
mixture was then stirred at rt for 3 h. 10% Aq.
NaHSO3 (4 mL) was added to quench the reaction.
After filtration on a Celite pad, the filtrate was
extracted with CH2Cl2 (3×20 mL), washed with 10% aq.
HCl (20 mL), satd aq. NaHCO3 (20 mL), and brine (20
mL), dried (MgSO4), and evaporated under reduced
pressure. The residue was chromatographed on silica
gel (hexane/AcOEt=10: 1) to give 8 (463 mg, 61%) as
a colorless oil. Compound 8: [h]1D9=−104.3 (c 1.04,
4.3. (1S)-1-[(2%S,3%R)-3-Hydroxymethylbicyclo[2.2.1]-
hept-5-en-2-yl]pentan-1-ol 6
To a stirred solution of (+)-1 (700 mg, 4.67 mmol) in
anhydrous toluene (40 mL) was added n-butyllithium
(2.46 M in hexane, 2.00 mL, 5.13 mmol) at −78°C. The
mixture was stirred at the same temperature for 2 h,
and treated with L-Selectride™ (1.00 M in THF, 9.30
mL, 9.33 mmol) to it. The resulting mixture was stirred
at the same temperature for 2.5 h. Then 10% aq. NaOH
(5 mL) and 30% aq. hydrogen peroxide (3.5 mL) were
added to quench the reaction. The mixture was
extracted with AcOEt (3×20 mL), washed with brine
(10 mL), dried (MgSO4), and evaporated under reduced
pressure. The residue was chromatographed on silica
gel (hexane/AcOEt=4: 1) to give 6 as colorless crystals
(768 mg, 78%). Compound 6: mp 97–98°C. [h]2D2=−8.2
(c 0.99, CHCl3). IR (film): w=3288, 2926, 1460, 1023,
1
CHCl3). IR (film): w=2960, 1763, 1187 cm−1. H NMR
(270 MHz, CDCl3): l 0.92 (3H, t, J=7.3 Hz), 1.30–1.77
(8H, m), 2.99–3.08 (2H, m), 3.25–3.29 (1H, m), 3.39
(1H, dd, J=8.8, 4.9 Hz), 4.41–4.49 (1H, m), 6.20–6.21
(2H, m). 13C NMR (270 MHz, CDCl3): l 13.9, 22.5,
28.8, 31.0, 44.7, 44.9, 45.2, 48.6, 52.7, 81.5, 135.0, 135.7,
177.8. EIMS: m/z=206 (M+), 66 (100%). HRMS: calcd
for C13H18O2 206.1307 found 206.1316.
4.6. (R)-5-Butyl-2(5H)-furanone (−)-9
A solution of 7 (340 mg, 1.65 mmol) in ODCB (24 mL)
was sonicated under bubbling of argon gas for 20 min.
The mixture was stirred under reflux for 20 h. After
cooling, the mixture was directly chromatographed on
silica gel (hexane/AcOEt=3: 1) to give (−)-9 (197 mg,
85%) as a colorless oil. Compound (−)-9: [h]2D1=−90.3
(c 0.84, CHCl3), lit.:8c [h]D21=−101.0 (CHCl3). IR (film):
1
1004 cm−1. H NMR (270 MHz, CDCl3): l 0.90 (3H, t,
J=7.3 Hz), 1.26–1.59 (8H, m), 2.24–2.31 (1H, m), 1.71
(2H, brs, exchangeable with D2O), 2.37–2.47 (1H, m),
2.98 (1H, brs), 3.02 (1H, brs), 3.34–3.48 (2H, m), 3.69
(1H, dd, J=10.8, 5.3 Hz), 6.18–6.26 (2H, m). 13C NMR
(270 MHz, CDCl3): l 14.1, 22.7, 28.6, 38.2, 45.1, 45.2,
45.6, 49.0, 49.3, 63.1, 71.5, 135.5. EIMS: m/z=210
(M+), 66 (100%). HRMS: calcd for C13H22O2 210.1620
found 210.1594.
1
w=2962, 2938, 1752, 1163 cm−1. H NMR (270 MHz,
CDCl3): l 0.92 (3H, t, J=7.1 Hz), 1.33–1.50 (4H, m),
1.61–1.85 (2H, m), 5.01–5.07 (1H, m), 6.11 (1H, dd,

2792
K. Suzuki et al. / Tetrahedron: Asymmetry 12 (2001) 2789–2792
J=5.7, 2.0 Hz), 7.45 (1H, dd, J=5.8, 1.5 Hz). 13C
NMR (270 MHz, CDCl3): l 13.8, 22.4, 27.1, 32.9, 83.4,
121.6, 156.3, 173.2. EIMS: m/z=140 (M+), 84 (100%).
HRMS: calcd for C8H12O2 140.0837, found 140.0862.
References
1. Koch, S. S. C.; Chamberlin, A. R. In Enantiomerically
Pure k-Butyrolactones in Natural Products Synthesis;
Atta-ur-Rahman, Ed.; Elsevier Science: Amsterdam,
1995; pp. 687–725.
2. Ogliaruso, M. A.; Wolfe, J. F. Synthesis of Lactones and
Lactams; John Wiley & Sons: New York, 1993.
The enantiomeric purity was determined to be 90% e.e.
by HPLC using a column with a chiral stationary phase
i
[Chiralcel OD, PrOH/hexane=1/9].
3. (a) Shoji, M.; Kobayashi, E.; Inomata, K.; Numazawa,
M. J. Tohoku Pharm. Univ. 2000, 47, 47; (b) Suzuki, K.;
Kobayashi, E.; Sasaki, T.; Inomata, K., unpublished
results.
4. (a) Suomalainen, H.; Nykanen, L. Naeringsmiddelindus-
trien 1970, 23, 15; (b) Masuda, M.; Nishimura, K. Phyto-
chemistry 1971, 10, 1401; (c) Kepner, A. D.; Webb, A.
D.; Muller, C. J. Am. J. Enol. Viticult. 1972, 23, 103; (d)
Otsuka, K.; Zenibayashi, Y.; Itoh, M.; Totsuka, A.
Agric. Biol. Chem. 1974, 38, 485.
4.7. (S)-5-Butyl-2(5H)-furanone (+)-9
In the same manner as described for (−)-9, 8 gave (+)-9
(159 mg, 84%) as a colorless oil. Compound (+)-9:
[h]2D1=+91.6 (c 1.01, CHCl3). Spectroscopic data were
identical with those of (−)-9. The enantiomeric purity
was determined to be 90% e.e. by HPLC using a chiral
column as above.
5. Masuda, M.; Nishimura, K. Chem. Lett. 1981, 1333.
6. For examples of racemic synthesis of 4, see: (a) Hoppe,
D.; Bronneke, A. Tetrahedron Lett. 1983, 24, 1687; (b)
Moret, E.; Schlosser, M. Tetrahedron Lett. 1984, 25,
4491; (c) Frauenrath, H.; Philipps, T. Liebigs Ann. Chem.
1985, 1951.
4.8. (+)-trans-Quercus lactone (+)-4
To a stirred suspension of copper(I) iodide (1.34 g, 7.05
mmol) in anhydrous diethyl ether (Et2O, 9 mL) was
added methyllithium (1.14 M in Et2O, 12.4 mL, 14.1
mmol) at −30°C. The mixture was stirred at the same
temperature for 0.5 h, a solution of (−)-9 (200 mg, 1.41
mmol) in Et2O (14 mL) was added to the reaction
mixture at −78°C, which was then stirred at the same
temperature for 3.5 h. 10% Aq. HCl (15 mL) was added
to quench the reaction. After filtration on a Celite pad,
the filtrate was extracted with Et2O (3×15 mL), washed
with 28% aq. ammonia (10 mL), dried (MgSO4), and
evaporated under reduced pressure. The residue was
chromatographed on silica gel (hexane/Et2O=3:1) to
give (+)-4 (158 mg, 72%) as a colorless oil. Compound
(+)-4: [h]2D1=79.9 (c 1.01, CH3OH), lit.:6 for the natural
(+) form, [h]1D5=+79 (c 1.04, CH3OH). IR (film): w=
7. For examples of chiral synthesis of 4, see: (a) Marino, J.
P.; Fernades de la Pradilla, R. Tetrahedron Lett. 1985, 26,
5381; (b) Gunther, C.; Mosandl, A. Liebigs. Ann. Chem.
1986, 2112; (c) Bloch, R.; Gilbert, L. J. Org. Chem. 1987,
52, 4603; (d) Hoppe, D.; Zschage, O. Angew. Chem., Int.
Ed. Engl. 1989, 28, 69; (e) Beckmann, M.; Hildebrandt,
H.; Winterfeldt, E. Tetrahedron: Asymmetry 1990, 1, 335;
(f) Sharma, G. V. M.; Vepachedu, S. R.; Chandrasekhar,
S. Synth. Commun. 1990, 20, 3403; (g) Miyata, O.;
Shinada, T.; Kawakami, N.; Taji, K.; Ninomiya, I.;
Naito, T.; Date, T.; Okamura, K. Chem. Pharm. Bull.
1992, 40, 2579; (h) Ebata, T.; Matsumoto, K.;
Yoshikoshi, H.; Koseki, K.; Kawakami, H.; Okano, K.;
Matsushita, H. Heterocycles 1993, 36, 1017; (i) Pai, Y.-
C.; Fang, J.-M.; Wu, S.-H. J. Org. Chem. 1994, 59, 6018;
(j) Takahata, H.; Uchida, Y.; Momose, T. J. Org. Chem.
1995, 60, 5628; (k) Brenna, E.; Negri, C. D.; Fuganti, C.;
Serra, S. Tetrahedron: Asymmetry 2001, 12, 1871.
8. For examples of synthesis of (+)-1, see: (a) Lok, K. P.;
Jacovac, I. J.; Jones, J. B. J. Am. Chem. Soc. 1985, 107,
2521; (b) Takano, S.; Kurotaki, A.; Ogasawara, K. Syn-
thesis 1987, 1075; (c) Arai, Y.; Matsui, M.; Koizumi, T.
J. Chem. Soc., Perkin Trans. 1 1990, 1230; (d) Luna, H.;
Prasad, K.; Repic, O. Tetrahedron: Asymmetry 1994, 5,
303; (e) Maruoka, K.; Akakura, M.; Saito, S.; Ooi, T.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 6153; (f)
North, M.; Zagotto, G. Synlett 1995, 639; (g) Seebach,
D.; Jaeschke, G.; Wang, Y. M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2395; (h) Albers, T.; Biagini, S. C. G.;
Hibbs, D. E.; Hursthouse, M. B.; Abdul Malik, K. M.;
North, M.; Uriarte, E.; Zagotto, G. Synthesis 1996, 393.
9. A similar solvent effect of nucleophilic addition to lac-
tone derivatives has been reported. See: Bessieres, B.;
Morin, C. Synlett 2000, 1691.
1
2964, 2938, 1781 cm−1. H NMR (270 MHz, CDCl3): l
0.92 (3H, t, J=6.9 Hz), 1.14 (3H, d, J=6.4Hz), 1.29–
1.73 (6H, m), 2.13–2.27 (2H, m), 2.60–2.75 (1H, m),
4.01 (1H, dt, J=7.6, 4.1 Hz). 13C NMR (270 MHz,
CDCl3): l 13.8, 17.5, 22.4, 22.8, 33.7, 36.0, 37.1, 87.4,
176.6. EIMS: m/z=156 (M+), 99 (100%). HRMS: calcd
for C9H16O2 156.1150, found 156.1176.
4.9. (−)-trans-Quercus lactone (−)-4
In the same manner as described for (+)-4, (+)-9 gave
(−)-4 (28 mg, 61%) as a colorless oil. Compound (−)-4:
[h]2D1=−75.1 (c 1.02, CH3OH). Spectroscopic data were
identical with those of (+)-4.
Acknowledgements
10. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
The authors thank the Japan Association of Chemistry
for financial support (to K.I.).
Synthesis 1994, 639.