Asymmetric syntheses of (-)-enterolactone and 7′R)-7′- hydroxyenterolactone via organocatalyzed aldol reaction

Article abstract of DOI:10.1021/jo900810a

(Chemical Equation Presented) Short syntheses of (-)-enterolactone (1a) and (7′R)-7′-hydroxyenterolactone (1b) have been achieved utilizing organocatalyzed asymmetric cross-aldol reaction of aldehydes 2 and 3 and base-mediated alkylation of lactones 5 and 4.

Full text of DOI:10.1021/jo900810a

pubs.acs.org/joc
Asymmetric Syntheses of (-)-Enterolactone and
(70R)-70-Hydroxyenterolactone via Organocatalyzed
Aldol Reaction
Saumen Hajra,* Aswini Kumar Giri, and Sunit Hazra
Department of Chemistry, Indian Institute of Technology,
Kharagpur 721302, India
FIGURE 1. General structure of enterolactone and 70-hydroxyen-
terolactone.
shajra@chem.iitkgp.ernet.in
Received April 20, 2009
other biological profiles.4 Consequently, it has been the
synthetic target of many research groups. The routes to
synthesize enantiomerically pure enterolactone include
(i) kinetic resolution,5 (ii) chiral pool approach,6 (iii) trans-
formation of chiral N-alkyl-unsaturated-γ-lactams,7 (iv)
conjugate addition to chiral butenolides,8 (v) chiral Rh(II)-
catalyzed intramolecular insertion,9 (vi) chemoenzymatic
synthesis,10 (vii) bacterial transformation,11 (viii) chiral
auxiliary directed alkylation,12 (ix) asymmetric radical
reaction,13 (x) chemical conversion of natural lignans,14
and (xi) Pd(0)-catalyzed malonate additions.15 70-Hydro-
xyenterolactone 1b, differing with enterolactone in carrying
a hydroxyl group at the benzylic position of β-benzyl
substitution (Figure 1, Z = OH), was detected and tenta-
tively identified in human urine.16 This mammalian lignan
is also derived from the plant lignan 70-hydroxymatairesi-
nol. 70-Hydroxyenterolactone has been synthesized by the
Short syntheses of (-)-enterolactone (1a) and (70R)-70-
hydroxyenterolactone (1b) have been achieved utilizing
organocatalyzed asymmetric cross-aldol reaction of alde-
hydes 2 and 3 and base-mediated alkylation of lactones 5
and 4.
17
Wahala group. Herein, we describe a short route for the
€ € €
asymmetric syntheses of (-)-enterolactone (1a) and (70R)-
70-hydroxyenterolactone (1b).
(4) Setchell, K. D. R.; Adlercreutz. H. In Role of the Gut Flora Toxicity
and Cancer, Mammalian Lignans and Phytoestrogens: Recent Study on the
Formation, Metabolism and Biological Role in Health and Disease; Rowland,
I. R., Ed.; Academic Press: London, 1988; pp 315-345.
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Lignan natural products have attracted much interest
over the years because of their widespread occurrence in
various plant species, varied biological activities, and use in
folk medicine.1 Among them, enterolactone (Z = H,
Figure 1), unique in lacking para substitution, has been
found in human and animal urine.2 Enterolactone (1a) is
also formed by the metabolism of plant lignans such as
matairesinol, secoisolariciresinol, 7-hydroxymatairesinol,
and lariciresinol by intestinal bacteria.3 Enterolactone dis-
plays antiestrogenic and anticarcinogenic activities among
(1) (a) Cole, J. R.; Wiedhopf, R. M. In Chemistry of Lignans; Rao, C. B. S.,
Ed.; Andhra University Press: Waltair, India, 1978; pp 39-64. (b) Ayres, D. C.;
Loike, J. D. Lignans, Chemical, Biological and Clinical properties; Cambridge
University Press: Cambridge, 1990. (c) Koch, S. S. C.; Chamberlin, A. R. In
Studies in Natural Products Chemistry; Att-ur-Rahman, Ed.; Elsevier Science:
New York, 1995; Vol. 16, pp 687-725. (d) Ward, R. S. Recent Advances in the
Chemistry of Lignans. In Studies in Natural Product Chemistry; Atta-ur Rahman,
Ed.; Elsevier Science: New York, 2000; Vol. 24, pp 739-798.
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Kirk, D. N.; Cooley, G.; Farrant, R. D.; Wynn, S.; Axelson, M. Biochem. J.
1981, 197, 447–458. (b) Setchell, K. D. R.; Lawson, A. M.; Mitchell, F. L.;
Adlercreutz, H.; Kirk, D. N.; Axelson, M. Nature 1980, 287, 740–742.
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J.; Vink, J.; Woods, G. F. Nature 1980, 287, 738–740.
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(16) (a) Bannwart, C.; Adlercreutz, H.; Makela, T.; Brunow, G.; Hase, T.
Identification of a new mammalian lignan, 7-hydroxyenterolactone in human
urine by GC/MS. 11th International Congress on Mass Spectrometry, Bordeaux,
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France, 1988. (b) Adlercreutz, H.; Mousavi, Y.; Loukovaara, M.; Hamalainen, E.
Lignans, Isoflavones, Sex Hormone Metabolism and Breast Cancer. In The New
Biology of Steroid Hormones; Hochberg, R. B., Naftolin, F., Eds.; Raven Press:
New York, 1991; pp 145-154.
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(3) Heinonen, S.; Nurmi, T.; Liukkonen, K.; Poutanen, K.; Wahala, K.;
Deyama, T.; Nishibe, S.; Adlercreutz, H. J. Agric. Food. Chem. 2001, 49,
3178–3186.
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2006, 4, 331–341. (b) Makela, T. H.; Kaltia, S. A.; Wahala, K. T.; Hase, T. A.
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7978 J. Org. Chem. 2009, 74, 7978–7981
Published on Web 09/23/2009
DOI: 10.1021/jo900810a
r
2009 American Chemical Society

Hajra et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis for (-)-Enterolactone
and (70R)-70-Hydroxyenterolactone
SCHEME 2. Synthesis of (-)-Enterolactone
SCHEME 3. Synthesis of (70R)-70-Hydroxyenterolactone
Recently, we reported organocatalytic and enantioselec-
tive one-pot syntheses of 4-(hydroxyalkyl)-γ-butyro-
lactones,18 which are important synthons for the asymmetric
synthesis of γ-butyrolactone-containing natural products,19
such as dibenzylbutyrolactone lignans and 70-hydroxybutyro-
lactones. Thus, we planned a short and divergent route for
the asymmetric syntheses of enterolactone 1a and (70R)-70-
hydroxyenterolactone 1b utilizing organocatalyzed asym-
metric cross-aldol reaction and alkylation as the key steps
(Scheme 1).
For this purpose, a cross-aldol reaction was carried out by
slow addition over 22 h of 4-oxobutyrate 2 (1.0 equiv) to
a solution of 3-methoxybenzaldehyde 3 (2.5 equiv) and
L-proline (20 mol %) in dry DMF at 4 °C under an argon
atmosphere. After an additional 4 h of stirring, the resulting
mixture was diluted with methanol at 4 °C. NaBH4 was then
added portion wise. This addition was followed by stirring at
35-40 °C for 10 h. Workup of the reaction mixture afforded
the desired β-substituted-γ-butyrolactone 4 with high dia-
stereo- (dr >24:1) and enantioselectivity (ee = 97%) in 55%
yield (Scheme 2).
-39.2 (c 0.78, CHCl3), [R]25 -38.8 (c 1.06, CHCl3)}, of
D
compound 6 were compared with the literature data. It was
converted to the (-)-enterolactone (1a) by demethylation
using BBr3 (4.0 equiv) in 87% yield.9 The specific rotation
{[R]27D -38.5 (c 0.50, CHCl3)} of compound 1a was compar-
able to reported value.2c,7,8,13,14 The overall yield for the (-)-
enterolactone (1a) was 23% from 2 (Scheme 2).
En route to the synthesis of (70R)-70-hydroxyenterolactone
1b (Scheme 3), the dihydrofuran-2-one 4 was silylated by
treating with TIPSOTf and 2,6-lutidine in dichloromethane
at 0 °C for 1 h.20 However, the reaction delivered the rear-
ranged lactone 8a exclusively in 95% yield, as suggested by
spectral data. NMR data of compound 8a were seen to be
comparable with those of the similar type of compounds.21
In 1H NMR of lactone 4, H-70 appeared as a doublet at δ 4.6
(J = 7.5 Hz), whereas for silylated lactone 8a, it was found as
a doublet at δ 5.63 (J = 6.4 Hz) and two H-90 of 4 appeared
as a multiplet at δ 4.4, but those of compound 8a came as a
doublet at δ 3.36 (J = 5.2 Hz). cis-Stereochemistry of rear-
ranged lactone 8a was suggested by assuming that there was
To complete the synthesis of (-)-enterolactone (1a)
(Scheme 2), dihydrofuran-2-one 4 was subjected to hydro-
genolysis at atmospheric pressure of hydrogen over 10% Pd/
C in dichloroethane at 50-60 °C for 20 h to produce the
compound 5.14 The specific rotation {[R]27 +6.4 (c 1.00,
D
CHCl3)}5,7,12 of compound 5 supported, in part, our pre-
viously established stereochemistry for β-(hydroxyalkyl)-
γ-butyrolactones.18 Alkylation9,13 of 5 on successive treat-
ment with LiHMDS and 3-methoxybenzyl bromide afforded
lactone 6 with >95:5 trans-selectivity. Spectral data and
optical rotation, [R]27D -41.1 (c 1.00, CHCl3) {lit.9b,13 [R]25
D
(20) Yamauchi, S.; Uno, H. Org. Biomol. Chem. 2003, 1, 1323–1329.
(21) Yamauchi, S.; Kinoshita, Y. Biosci. Biotechnol. Biochem. 2001, 65,
1559–1567.
(18) Hajra, S.; Giri, A. K. J. Org. Chem. 2008, 73, 3935–3937.
(19) Seitz, M.; Reiser, O. Curr. Opin. Chem. Biol. 2005, 9, 285–292.
J. Org. Chem. Vol. 74, No. 20, 2009 7979

Hajra et al.
JOCNote
SCHEME 4. Plausible Pathways for Translactonization
In conclusion, we have developed an efficient, short, and
divergent route for the asymmetric syntheses of (-)-entero-
lactone 1a and (70R)-70-hydroxyenterolactone 1b via organo-
catalytic asymmetric cross-aldol reaction and alkylation as
the key steps.
Experimental Section
(4R,40R)-4-[40-Hydroxyl-(3-methoxyphenyl)methyl]dihydrofuran-
2-one (4). 3-Methoxybenzaldehyde 3 (0.88 g, 6.46 mmol, 2.5 equiv)
was taken in dry DMF (3.5 mL) under argon atmosphere and
cooled to 4 °C. L-Proline (0.058 g, 0.52 mmol, 0.2 equiv) was added
and stirred for 2 min. Methyl 4-oxobutyrate (2) (0.30 g, 2.58 mmol,
1.0 equiv) dissolved in dry DMF (1.5 mL) was added slowly over
22 h through a syringe pump. After an additional 4 h, dry methanol
(1.5 mL) was added to the reaction mixture followed by portion wise
addition of sodium borohydride (0.152 g, 4.01 mmol). Low-tem-
perature bath was removed, and the reaction mixture was stirred at
35-40 °C for 10 h. It was quenched with saturated ammonium
chloride solution (30 mL) and extracted with dichloromethane (3 ꢀ
75 mL). The combined extracts were washed with water and brine,
dried over Na2SO4, and concentrated under vacuum. HPLC ana-
lysis revealed the enantiomeric ratios, where enantiomers were
identified on comparing with HPLC analysis of the same reaction
catalyzed by D-proline. Diastereomeric ratios were measured from
1H NMR spectrum analysis. Purification by flash column chromato-
graphy of the crude using petroleum ether and EtOAc as an eluent
afforded 0.316 g (55%) of β-(hydroxyphenylmethyl)-γ-butyro-
lactone 4:[R]27D þ46.9 (c1.00, CHCl3);1H NMR (200 MHz, CDCl3)
δ 7.30-7.22 (m, 1H), 6.95-6.85 (m, 3H), 4.6 (d, J = 7.5 Hz, 1H),
no epimerization during rearrangement. This idea was sup-
ported when lactone 8a was desilylated with n-Bu4NF to give
lactone 4. It is also worth mentioning that a minor amount of
lactone 8 (P = H) was detected in the 1H NMR of the crude
reaction mixture during the synthesis of lactone 4, in parti-
cular, prior to stirring of the reaction mixture at 40 °C
(Scheme 2). When the silylating reagent was changed from
TIPSOTf to TBDMSOTf, both the lactone 7b and rearranged
lactone 8b were obtained as an inseparable mixture in 1:3.4
4.45-4.3 (m, 2H), 3.8 (s, 3H), 3.0-2.8 (m, 1H), 2.5-2.3 (m, 3H); 13
C
NMR (50 MHz, CDCl3) δ 176.8, 159.5, 143.1, 129.5, 117.6, 113.1,
111.3, 74.53, 69.8, 54.8, 41.9, 30.9; HPLC analysis, Chiralpak AD-H
(hexane/i-PrOH = 93/7, flow rate = 1.0 mL/min, 230 nm, 25 °C); tR
26.7 min and tR 41.2 min (ee 97%); HRMS found m/z 245.0786
[M þ Na]þ, calcd for C12H14O4Na 245.0790; FTIR (CHCl3) υmax
1
ratio as depicted from H NMR. Protection of 4 with non-
silylating agent, such as 3,4-dihydropyran (DHP), provided
an inseparable and uncharacterized mixture of compounds.
There was no reaction of 4 with MOMCl. To circumvent the
lactone rearrangement, a direct alkylation of the unprotected
4 was performed with 2.1 equiv of LiHMDS at -78 °C
followed by treatment with 1.1 equiv of 3-methoxybenzyl
bromide. It provided the desired alkylated product 9 in 45%
yield along with recovery of 30% of lactone 4. Stereochemis-
try of compound 9 was assigned by analogy9,22 and spectral
analysis. Itis knownintheliterature17a thatthe H-70S signal of
1H NMR for 70-hydroxybutyrolactone lignans appears at
δ 4.6, while that of H-70R is at δ 4.4, irrespective of the
3445, 1763, 1655, 1610, 1491, 1459, 1260, 1188, 1020, 789, 705 cm-1
.
(40R,4R,3R)-4-[Hydroxy-(3-methoxyphenyl)methyl]-3-(3-meth-
oxybenzyl)dihydrofuran-2-one (9). To a cold (-78 °C) solution of
lactone 4 (0.20 g, 0.9 mmol, 1.0 equiv) in 4 mL of THF under
argon atmosphere was added dropwise LiHMDS (1.9 mL, 1.0 M
in THF, 1.89 mmol, 2.1 equiv) over a period of 5 min. After
stirring at that temperature for 1 h, a solution of 3-methoxybenzyl
bromide (0.99 mmol, 0.20 g, 1.1 equiv) in THF (2 mL) was added
dropwise over a period of 5 min. The reaction mixture was then
slowly warmed to -54 °C and stirred at this temperature for
20 h. The reaction was then quenched with saturated aqueous
NaHCO3 and extracted with diethyl ether. The organic layers were
combined, washed with brine, dried over Na2SO4, and concen-
trated. The crude product was purified by flash chromatography
using ethyl acetate/petroleum ether as eluent to afford 0.14 g of the
alkylated product 9 as a light yellow oil in 45% yield along with
1
aromatic substitutions. In the H NMR spectrum of 9, the
H-70R signal appeared at δ 4.39 as a doublet (J = 6.0 Hz),
which is in good agreement with literature data for similar
compounds.17a Formation of corresponding cis-alkylated
product and rearranged lactone17a was not observed. De-
methylation of 9 using BBr3 afforded (70R)-70-hydroxyentero-
lactone 1b in 82% yield. The specific rotation of 1b was found
recovery of 0.06 g of starting lactone 4 (30%): [R]25 -13.98
D
1
(c 3.00, CHCl3); H NMR (200 MHz, CDCl3) δ 7.27-7.14 (m,
2H), 6.84-6.63 (m, 6H), 4.39 (d, J = 5.8 Hz, 1H), 4.32 (dd, J =
9.4 Hz, 7.4 Hz, 1H), 4.0 (dd, J = 9.2 Hz, 8.0 Hz, 1H), 3.77 (s, 3H),
3.76 (s, 3H), 2.92-2.78 (m, 3H), 2.59-2.52 (m, 1H); 13C NMR
(50 MHz, CDCl3) δ 178.6, 159.9, 159.8, 143.3, 139.2, 129.8, 129.6,
121.5, 117.9, 114.7, 113.6, 112.4, 111.2, 73.3, 67.3, 55.2 (2C), 46.4,
42.9, 35.3. Anal. Calcd for C20H22O5: C, 70.16; H, 6.48. Found: C,
69.85; H, 6.62.
as [R]25 -13.0 (c 1.5, acetone), and overall yield for the
D
hydroxyenterolactone was 20% from 2. It is to be noted that
1
the H NMR data of compound 1b did not match with the
€ € €
spectral data of the racemic compound reported by Wahala
et al.,17a but the 13C NMR matched perfectly.
Formation of the rearranged lactone 8a may be explained
via the pathways as shown in Scheme 4, where chelation of
carbonyl oxygen with R3SiOTf activates it toward translac-
tonization via either stepwise or a concerted mechanism.
(3R,40R,4R)-3-(3-Hydroxybenzyl)-4-[hydroxyl-(3-hydroxy-
phenyl)methyl]dihydrofuran-2-one (1b). To a rapidly stirred
solution of lactone 9 (0.20 g, 0.58 mmol, 1.0 equiv) in 15 mL of
anhydrous CH2Cl2 at 0 °C was added BBr3 (2.90 mL, 1.0 M
solution in CH2Cl2, 2.90 mmol, 5.0 equiv) dropwise during 5 min.
Stirring was continued at 0 °C for 1 h and then at -18 °C. After
10 h, the reaction mixture was quenched with water (10 mL),
(22) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, Part B,
4th ed.; Kluwer Academic: New York, 2001; p 29.
7980 J. Org. Chem. Vol. 74, No. 20, 2009

Hajra et al.
JOCNote
DCM layer was separated, and the aqueous layer was extracted
three times with diethyl ether. DCM layer and ether layers were
separately washed with brine, combined, dried over anhydrous
Na2SO4, and the solvent was evaporated under reduced pressure.
The crude product was purified by flash chromatography using
diethyl ether/dichloromethane as eluent to provide 0.15 g of 1b as
a colorless semisolid in 82% yield: [R]25D -13.04 (c 1.50, acetone);
1H NMR (200 MHz, acetone-d6) δ 8.28 (br s, 1.6H), 7.64 (br s,
0.4H), 7.12 (m, 2H), 6.8-6.65 (m, 6H), 4.69 (d, J = 4.2 Hz, 1H),
4.51 (t, J = 4.2 Hz, 1H), 4.19 (t, J = 8.6 Hz, 1H), 3.87 (t, J =
8.6 Hz, 1H), 3.05-2.85 (m, 2H), 2.79 (t, J = 6.2 Hz, 1H),
2.66-2.57 (m, 1H); 13C NMR (50 MHz, acetone-d6) δ 179.1,
158.4 (2C), 146.0, 140.7, 130.3 (2C), 121.6, 117.8, 117.2, 115.2
114.5, 113.7, 73.0, 67.6, 47.3, 43.5, 35.6.
Acknowledgment. We thank CSIR, New Delhi, for pro-
viding financial support. A.K.G. thanks CSIR, New Delhi,
and S.H. thanks UGC, New Delhi, for their fellowships. The
authors are thankful to the reviewers for constructive scien-
tific comments and suggestions. We are also thankful to
Prof. Dipakranjan Mal for his valuable suggestions.
Supporting Information Available: Synthetic details and
characterization data for compounds 1a, 1b, 4, 5, 6, 8a, and 9 as
well as copies of 1H NMR and 13C NMR spectra for compounds
1b, 4, 5, 8a, and 9 and HPLC chromatogram for compound 4
and its enantiomer. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 20, 2009 7981