A chemoenzymatic synthesis of both enantiomers of a cis-lignan lactone

Article abstract of DOI:10.1016/S0957-4166(98)00299-7

The stereoselective acetylation of meso-2,3-bis(3,4- dimethoxybenzyl)butanediol by vinyl acetate in the presence of Candida antarctica lipase in benzene gave the corresponding (+)-(2S,3R) monoester (ee ≥98%). Transesterification of meso-2,3-bis(3,4-dimethoxybenzyl)butyl diacetate, in the presence of the same enzyme, by ethanol in benzene/isopropyl ether gave the corresponding (-)-(2R,3S) monoester (ee ≥98%). Both enantiomers of the known cis-2,3-bis(3,4- dimethoxybenzyl)butyrolactone were synthesized from these monoesters.

Full text of DOI:10.1016/S0957-4166(98)00299-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2827–2831
A chemoenzymatic synthesis of both enantiomers of a cis-lignan
lactone
Robert Chênevert ∗ and Yannick Stéphane Rose
Département de Chimie, Faculté des Sciences et de Génie, Université Laval, Québec, Canada, G1K 7P4
Received 2 June 1998; accepted 13 July 1998
Abstract
The stereoselective acetylation of meso-2,3-bis(3,4-dimethoxybenzyl)butanediolby vinyl acetate in the presence
of Candida antarctica lipase in benzene gave the corresponding (+)-(2S,3R) monoester (ee ≥98%). Transesteri-
fication of meso-2,3-bis(3,4-dimethoxybenzyl)butyl diacetate, in the presence of the same enzyme, by ethanol in
benzene/isopropyl ether gave the corresponding (−)-(2R,3S)monoester (ee ≥98%). Both enantiomers of the known
cis-2,3-bis(3,4-dimethoxybenzyl)butyrolactone were synthesized from these monoesters. © 1998 Elsevier Science
Ltd. All rights reserved.
1. Introduction
Lignans are natural products of widespread occurrence in plants, their structures containing two
characteristic phenylpropanoid units.1–3 Lignans are known to exhibit a wide range of biological
activity1–5 (anti-tumor, antiviral, diuretic, platelet-activating factor antagonism, antioxidant, etc.) and
have attracted great interest on account of their cancer-protective properties.6,7 Also, the biological
significance of these secondary metabolites remains to be established. Considerable interest has been
focussed on the synthesis of lignans and analogues because of their intriguing biological activities.
Several methods for the asymmetric synthesis of trans-dibenzylbutyrolactones have been developed8–18
but very few methods for the asymmetric synthesis of the corresponding cis-lactones8 have been pre-
viously reported. Recently, Ward et al.19,20 reported the enantioselective synthesis of cis-2,3-bis(3,4-
dimethoxybenzyl)butyrolactone 6 via desymmetrization of meso-2,3-dibenzylbutanedioic acid anhydride
by reaction with (+)-α-methylbenzylamine (d.e. 86%). We report here the synthesis of both enantiomers
of cis-2,3-bis(3,4-dimethoxybenzyl)butyrolactone 6 via enzymatic desymmetrization (transesterifica-
tions) of meso-2,3-bis(3,4-dimethoxybenzyl)butanediol 2 and the corresponding diacetate 4.
∗
Corresponding author. E-mail: robert.chenevert@chm.ulaval.ca
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00299-7

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R. Chênevert, Y. S. Rose / Tetrahedron: Asymmetry 9 (1998) 2827–2831
2. Results and discussion
Diester 1 was prepared according to the method of Ward et al.19 Reduction of diester 1 with lithium
aluminum hydride gave the meso-diol 2 in 98% yield (Scheme 1). Diol 2 was subjected to the enzyme
catalyzed esterification by treatment with Candida antarctica lipase (CAL) in benzene using vinyl acetate
as acyl donor to give the optically active monoester (+)-(2S,3R)-3 in 74% yield. The enantiomeric
composition of 3 was measured by 19F NMR (282 MHz) analysis of the corresponding (+)-α-methoxy-
α-trifluoromethyl-α-phenyl acetate (MTPA, Mosher’s ester). The enantiomeric excess was determined
to be higher than 98%. The absolute configuration of monoester 3 (2S,3R; [α]23=+2.88 (c 2.3, CHCl3))
D
was determined by correlation with lactone 6 of known absolute configuration.
Scheme 1. Reagents: (i) LiAlH4, CH2Cl2:ether (3:2), r.t., 98%; (ii) Candida antartica lipase, vinyl acetate, benzene, r.t., 74%,
ee>98%
The synthesis of the opposite enantiomer, (−)-(2R,3S)-3, is reported in Scheme 2. Diol 2 was
acetylated by acetic anhydride in pyridine in the presence of DMAP to give meso-diacetate 4 in 96%
yield. Transesterification of diacetate 4 by treatment with ethanol in the presence of CAL in diisopropyl
ether/benzene provided (−)-(2R,3S)-3 in 80% yield ([α]25=−2.95 (c 2.7, CHCl3)). The enantiomeric
D
excess was determined to be higher than 98% (Mosher’s ester as above).
Scheme 2. Reagents: (i) Acetic anhydride, 4-DMAP, pyridine, r.t., 96%; (ii) Candida antartica lipase, EtOH, isopropyl
ether:benzene (5:2), 80%, ee>98%
Both enantiomers of cis-2,3-bis(3,4-dimethoxybenzyl)butyrolactone 6 were synthesized from mono-
esters (−)-(3) and (+)-(3). Alcohol (+)-(2S,3R)-3 was oxidized with pyridinium dichromate in DMF to
yield acid (+)-(2R,3S)-5 in 60% yield which upon treatment with 5 N HCl and p-toluenesulfonic acid
in benzene gave lactone (+)-(2R,3S)-6 of known absolute configuration in 80% yield ([α]25=+75.33 (c
D
1.16, CH2Cl2); lit.19 [α]21=+32.3 (c 1.434, CH2Cl2). The same reaction sequence applied to alcohol (−)-
D
(2R,3S)-3 provided lactone (−)-(2S,3R)-6 ([α]21=−75.22 (c 1.01, CH2Cl2)) (Scheme 3). The enantio-
D
meric composition of acid 5 was measured by reaction with (S)-(+)-1-(1-naphthyl)ethyl amine in the
presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) followed by 1H NMR
(300 MHz) analysis of the resulting diastereoisomeric amides (ee ≥98%).

R. Chênevert, Y. S. Rose / Tetrahedron: Asymmetry 9 (1998) 2827–2831
2829
Scheme 3. Reagents: (i) PDC, DMF, r.t., 60%; (ii) p-TsOH, 5 N HCl, toluene, reflux, 80%
3. Experimental section
NMR spectra were recorded in CDCl3 solutions at 300 MHz (1H), 282 MHz (19F), 75 MHz (13C) on
a Bruker AC-300 instrument. Optical rotation values were obtained from a JASCO DIP-300 polarimeter.
Infrared spectra were recorded on Perkin–Elmer 781 spectrometer. Melting points were recorded on a
Thomas Hoover 6427-H10 melting point apparatus, and are uncorrected. Candida antarctica lipase was
a gift from Novo Nordisk. Column purifications were conducted by flash chromatography in silica gel 60
(230–400 mesh, adsorbant to compound ratio ∼50).
3.1. Preparation of meso-2,3-bis(3,4-dimethoxybenzyl) butanediol (2)
The diester 1 (2.16 g, 4.84 mmol) was dissolved in CH2Cl2 (30 mL) and diethyl ether (20 mL). The
solution was cooled to 0°C and LiAlH4 (809 mg, 2.32 mmol) was added slowly. The mixture was allowed
to warm to room temperature and stirred overnight. The reaction mixture was quenched with a 3 N HCl
solution, diluted with water and extracted with CH2Cl2 (3×100 mL). The combined extracts were dried
(Na2CO3) and the solvent was evaporated to give a crude product purified by flash chromatography
(EtOAc) to give a white solid (1.854 mg, 98%) (m.p.: 90–92°C). IR (neat): 3250 (OH), 1590 and 1520
(C_C), 1260 (Ar–O), 1030 (C–OH), 860 (_C–H); 1H NMR (CDCl3): 2.02 (m, 2H, H-2 and H-3), 2.53
(dd, J=6.27, J=13.75, 2H, H-5 and H-6), 2.67 (dd, J=9.23, J=13.75, 2H, H-5 and H-6), 3.50 (dd, J=2.77,
J=11.00, 2H, H-1 and H-4), 3.59 (dd, J=6.83, J=11.00, 2H, H-1 and H-4), 3.82 and 3.83 (s, 12H, OCH3),
6.67 (s, 2H, H-2N and H-2O), 6.71 (dd, J=1.71, J=9.00, 2H, H-6N and H-6O), 6.77 (d, J=9.00, 2H, H-
5N and H-5O); 13C NMR (CDCl3): 33.2 (C-2, C-3), 44.9 (C-5, C-6), 55.7 and 55.8 (OCH3), 63.1 (C-1,
C-4), 111.1 (C-5N, C-5O), 12.1 (C-2N, C-2O), 120.9 (C-6N, C-6O), 132.9 (C-1N, C-1O), 147.3 (C-3N,
C-3O), 148.8 (C-4N, C-4O). HRMS (EI) calcd for C22H30O6 (M+) 390.2042, found 390.2048.
3.2. Preparation of meso-2,3-bis(3,4-dimethoxybenzyl)butyl diacetate (4)
The diol 2 (244 mg, 625 µmol) was dissolved in pyridine (20 mL) under nitrogen. Acetic anhydride
(1.00 mL, 10.6 mmol) and 4-dimethylaminopyridine (9 mg) were added and the mixture was stirred
overnight. The mixture was diluted with AcOEt (100 mL) and successively washed with 3 N HCl (3×40
mL), aq. NaHCO3 (3×40 mL) and brine (3×4 mL). The organic extract was dried (MgSO4), filtered
and concentrated under reduced pressure. The crude product was purified by flash chromatography
(AcOEt:hexanes, 11:9) to give a white solid (284 mg, 96%) (m.p.: 95–96°C). IR (neat): 1740 (C_O),
1
1590 and 1520 (C_C), 1250 (Ar–O), 1150 (C–O–C), 850 (_C–H); H NMR: 2.02 (s, 3H, CH3COO),
2.21 (m, 2H, H-2 and H-3), 2.56 (dd, J=8.65, J=13.90, 2H, H-5 and H-6), 2.72 (dd, J=6.10, J=13.90,
2H, H-5 and H-6), 3.82 and 3.83 (s, 12H, OCH3), 4.06 (m, 4H, H-1 and H-4), 6.59 (s, 2H, H-2N and
H-2O), 6.66 (d, J=8.14, 2H, H-6N and H-6O), 6.76 (d, J=8.14, 2H, H-5N and H-5O); 13C NMR: 20.8
(CH3COO), 33.8 (C-2 and C-3), 39.5 (C-5 and C-6), 55.7 and 55.8 (OCH3), 64.8 (C-1 and C-4), 111.1

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R. Chênevert, Y. S. Rose / Tetrahedron: Asymmetry 9 (1998) 2827–2831
(C-5N and C-5O), 111.8 (C-2N and C-2O), 120.8 (C-6N and C-6O), 132.1 (C-1N and C-1O), 147.4
(C-3N and C-3O), 148.8 (C-4N and C-4O), 170.8 (CH3COO). HRMS (EI) calcd for C26H34O8 (M+)
474.2253, found 474.2259.
3.3. Preparation of (+)-(2S,3R)-2,3-bis(3,4-dimethoxybenzyl)-4-hydroxybutyl acetate (3)
A solution of diol 2 (197.1 mg, 505.1 µmol) in benzene (50 mL) containing Candida antarctica
lipase (30.3 mg) and vinyl acetate (240 µL, 2.53 mmol) was stirred for 23 h at room temperature. The
mixture was filtered and the solvent was evaporated. The residue was purified by flash chromatography
(EtOAc:hexanes, 7:3) to yield the monoacetate (+)-3 (162 mg, 74%) as a viscous colorless oil.
[α]23=+2.88 (2.3, CHCl3); IR (film): 3500 (OH), 1740 (C_O), 1590–1510 (C_C), 1260 (Ar–O), 1240
D
(C(_O)–O–C), 1160–1140 (C–O–C), 1030 (C–OH); 1H NMR (CDCl3): 1.83 (s, 1H, OH), 1.99 (s, 3H,
CH3COO), 2.01 (m, 1H, H-3), 2.27 (m, 1H, H-2), 2.47–2.74 (m, 4H, H-5 and H-6), 3.57 (m, 2H, H-4),
3.78, 3.79, 3.81 (s, 12H, OCH3), 3.98 (dd, J=11.19, J=5.82, 1H, H-1), 4.19 (dd, J=11.19, J=6.25, 1H,
H-1), 6.60–6.76 (m, 6H, aromatics); 13C NMR (CDCl3): 20.9 (CH3COO), 33.4 (C-3), 34.3 (C-2), 39.6
(C-5), 42.8 (C-6), 55.7, 55.8 (O–CH3), 63.2 (C-4), 65.1 (C-1), 111.1 (C-5N, C-5O), 111.9 (C-2N, C-2O),
120.7, 120.8 (C-6N, C-6O), 132.5, 132.9 (C-1N, C-1O), 147.3 (C-3N, C-3O), 148.8 (C-4N, C-4O), 171.1
(CH3COO). HRMS (EI) calcd for C24H32O7 (M+) 432.2148, found 432.2141.
3.4. Preparation of (−)-(2R,3S)-2,3-bis(3,4-dimethoxybenzyl)-4-hydroxybutyl acetate (3)
A solution of diacetate 4 (56 mg, 129 µmol) in isopropylether (5 mL) and benzene (2 mL) containing
Candida antarctica lipase (50 mg) and ethanol 95% (30 µL, 511 µmol) was stirred for 23 h at room
temperature. The mixture was filtered and the solvent was evaporated. The residue was purified by flash
chromatography (EtOAc:hexanes, 7:3) to yield the hydroxyacetate (−)-3 (46.9 mg, 80%) as a viscous
colorless oil. [α]25=−2.95 (2.7, CHCl3).
D
3.5. Preparation of (−)-(2S,3R)- and (+)-(2R,3S)-4-acetyloxy-2,3-bis(3,4-dimethoxybenzyl)butanoic
acid (5)
A solution of monoacetate (−)-3 (143 mg, 331 µmol in N,N-dimethylformamide (1.2 mL) and
pyridinium dichromate (435 mg, 1.16 mmol) was stirred for 18 h under dry nitrogen. Then one equivalent
of PDC was added 3 times at 18 h intervals. The reaction mixture was diluted with water (pH=3) (12 mL)
and extracted with EtOAc (3×50 mL). The combined extracts were dried (Na2CO3) and concentrated
under reduced pressure. The residue was purified by flash chromatography (EtOAc:hexanes:AcOH,
50:49:1) to give an oil (85.5 mg, 58%). (−)-5 [α]23=−8.99 (1.1, CH2Cl2); (+)-5 [α]23=+8.22 (3.16,
D
D
CH2Cl2); IR (neat): 3100 (OH), 1740 (C_O), 1590–1510 (C_C), 1260 (Ar–O), 1240 (C(_O)–O–C),
1
1160–1140 (C–O–C), 1030 (C–OH); H NMR (CDCl3): 1.99 (s, 3H, CH3COO), 2.40 (m, 1H, H-3),
2.61 (dd, J=14.15, J=9.09, 1H, H-6), 2.76 (dd, J=14.15, J=6.06, 1H, H-6), 2.84–2.98 (m, 3H, H-2 and
H-5), 3.81, 3.82, 3.83, 3.84 (s, 12H, OCH3), 4.08 (d, J=5.64, 2H, H-4), 6.64–6.79 (m, 6H, aromatics);
13C NMR (CDCl3): 20.6 (CH3COO), 33.4 (C-3), 34.2 (C-2), 41.0 (C-6), 47.6 (C-5), 55.6, 55.7, 55.8
(O–CH3), 63.6 (C-4), 111.1 (C-5N, C-5O), 111.9 (C-2N, C-2O), 120.7, 120.9 (C-6N, C-6O), 131.3 (C-
1N, C-1O), 147.5 (C-3N, C-3O), 148.8 (C-4N, C-4O), 170.7 (CH3COO), 179.9 (C-1). HRMS (EI) calcd
for C24H26O6 (M+) 446.1941, found 446.1951.

R. Chênevert, Y. S. Rose / Tetrahedron: Asymmetry 9 (1998) 2827–2831
2831
3.6. Preparation of (−)-(2S,3R)- and (+)-(2R,3S)-2,3-bis(3,4-dimethoxybenzyl)butyrolactone (6)
The acid (−)-5 (80 mg, 179 µmol) was dissolved in toluene (10 mL) containing p-toluenesulfonic acid
(20 mg) in the presence of 5 N HCl (2.5 mL). The mixture was heated under reflux for 6 h. The reaction
mixture was diluted in EtOAc, washed successively with aq. NaHCO3 (3×50 mL) and brine (3×50
mL). The organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash
chromatography (CH2Cl2:acetone, 49:1) and recrystallization in diethyl ether gave a white solid (55.8
mg, 80%). (−)-6 [α]23=−75.22 (1.01, CH2Cl2), m.p.: 108–109°C; (+)-6 [α]25=+75.33 (1.16, CH2Cl2),
D
D
m.p.=111–112°C; lit.19 [α]21=+32.3 (c 1.434, CH2Cl2), oil. IR (neat): 1770 (C_O), 1590–1510 (C_C),
D
1260 (Ar–O), 1230 (C(_O)–O–C), 1160–1140 (C–O–C); 1H NMR (CDCl3): 2.26 (dd, J=13.07, J=12.80,
1H, H-6), 2.56–2.63 (m, 1H, H-3), 2.71 (dd, J=14.74, J=10.43, 1H, H-5), 2.89 (dd, J=12.80, J=4.05, 1H,
H-6), 3.01 (ddd, J=10.43, J=6.99, J=4.72, 1H, H-2), 3.19 (dd, J=14.79, J=4.72, 1H, H-5), 3.74, 3.77,
3.81, 3.82 (s, 12H, OCH3), 3.97 (dd, J=13.12, J=8.92, 2H, H-4), 6.41–6.78 (m, 6H aromatics); 13C NMR
(CDCl3): 30.4 (C-6), 32.5 (C-5), 40.0 (C-3), 45.3 (C-2), 55.8 (O–CH3), 69.4 (C-4), 111.3, 111.4 (C-5N,
C-5O), 111.7, 111.9 (C-2N, C-2O), 120.3, 120.7 (C-6N, C-6O), 130.7, 131.0 (C-1N, C-1O), 147.7 (C-
3N, C-3O), 149.0 (C-4N, C-4O), 177.8 (C-1). HRMS (CI, NH3) calcd for C22H26O6 (M+) 386.1729,
found 386.1722.
Acknowledgements
The authors would like to thank the Natural Sciences and Engineering Research Council of Canada
(NSERC) for financial support and ‘le Fonds pour la Formation de Chercheurs et l’Aide à la Recherche,
Québec’ (FCAR) for a postgraduate scholarship to Y.S.R.
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