Asymmetric aldol approach to dibenzylbutyrolactone lignans: Synthesis of (-)-(7′S)-hydroxymatairesinol and (-)-(7′S)-hydroxyarctigenin

Article abstract of DOI:10.1016/j.tetlet.2013.02.044

A competent and general asymmetric synthesis of 7′- hydroxydibenzylbutyrolactone lignans such as (7′S)-hydroxymatairesinol and (7′S)-hydroxyarctigenin has been reported from N-succinyl-2-oxazolidinone in six steps where diastereoselective aldol reaction and stereoselective alkylation serve as the key steps.

Full text of DOI:10.1016/j.tetlet.2013.02.044

Tetrahedron Letters 54 (2013) 2171–2173
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric aldol approach to dibenzylbutyrolactone lignans: synthesis
of (ꢀ)-(70S)-hydroxymatairesinol and (ꢀ)-(70S)-hydroxyarctigenin
⇑
Saumen Hajra , Abhisek Mandal, Sunit Hazra
Department of Chemistry, Indian Institute of Technology Kharagpur, W. B. 721302, India
a r t i c l e i n f o
a b s t r a c t
A competent and general asymmetric synthesis of 70-hydroxydibenzylbutyrolactone lignans such as
(70S)-hydroxymatairesinol and (70S)-hydroxyarctigenin has been reported from N-succinyl-2-oxazolidi-
none in six steps where diastereoselective aldol reaction and stereoselective alkylation serve as the
key steps.
Article history:
Received 19 December 2012
Revised 12 February 2013
Accepted 14 February 2013
Available online 28 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Aldol reaction
(70S)-Hydroxydibenzylbutyrolactone lignans
(70S)-Hydroxymatairesinol
(70S)-Hydroxyarctigenin
Dibenzylbutyrolactone lignans constitute an important subclass
of the lignan1 family and show a broad range of biological activities
such as immunoregulatory,2 neuroprotective,3 anticancer,4 antitu-
mor,5 and anti-HIV6 properties. In this subclass of lignans, only six
compounds having hydroxyl functionality at the C-70 position are
known. Among these, (70S)- and (70R)-hydroxymatairesinols 3 and
4, (70R)-hydroxyarctigenin 5 and (ꢀ)-(70R)-parabenzlactone 6 are
plant lignans,7 whereas (70R)- and (70S)-hydroxyenterolactones 7
and 8 are mammalian lignans.8 The C-70-epimer of compounds 5
and 6 that is, (70S)-hydroxyarctigenin 9 and (70S)-parabenzlactone
10, respectively, are non-natural compounds. Among the
(70-deoxy)dibenzylbutyrolactone lignans, matairesinol 1 and arc-
tigenin 2 (Fig. 1) are reported to be potent cytostatic agents against
human leukemic HL-60 cells, with IC50 values of less than 100 ng/
mL. In recent studies, 70-hydroxymatairesinols are found to be the
precursors to mammalian lignans, enterolactone, and hydroxyente-
rolactones, which display antiestrogenic and anticarcinogenic activ-
ities among other biological profiles.9,10 Hydroxymatairesinols are
also the dominant lignans in many daily cereals. Compounds 3–10,
in particular hydroxymatairesinols, have been under extensive bio-
logical and clinical studies10,11 due to their pharmaceutical
importance.
the reports of the synthesis of (70-deoxy)dibenzylbutyrolactone
lignans abound in the literature,13 the synthesis of 70-hydrox-
ydibenzylbutyrolactone lignans has received less effort.14 The Sher-
burn group developed an elegant and general convergent synthesis
of 70-hydroxydibenzylbutyrolactone lignans via a domino radical
cyclization though the synthesis of the key intermediate itself takes
seven steps and uses thiophosgene.14a Wähälä et al. reported a gen-
eral synthesis of 70-hydroxydibenzylbutyrolactone lignans utilizing
a Michael addition of lithiated dithiane to Feringa’s chiral 5-men-
thyloxybutenolide15 as the key step.14b Recently, we developed effi-
cient methods for the asymmetric synthesis of butyrolactones16,17
and applied these methods to synthesize a choice of butyrolactone
natural products.18 In a further application of our method,16a here-
in, we report an efficient and general synthetic protocol for the
synthesis of 70-hydroxydibenzylbutyrolactone lignans via an asym-
metric aldol reaction of chiral N-succinyl-2-oxazolidinone and a
stereoselective alkylation as the key steps
Biogenetically lignans are derived from two cinnamyl (ArC3)
units coupled by a b–b0 (8–80) linkage. From a synthetic point, this
Ar2C6 unit can be raised from two Ar-C and one C4 units. Thus chi-
ral succinyl substrate 11 was chosen as the C4 precursor, where the
first Ar-C could be introduced by an asymmetric aldol reaction
with ArCHO to provide stereoselectively the C70-hydroxy function-
ality and the desired stereochemistry of the lactone ring. The sec-
ond Ar-C unit can be attached by a stereoselective alkylation with
Ar0CH2X of the lactone obtained from the aldol product by chemo-
selective reduction of COXc and lactonization (Scheme 1).
Besides their significant biological activities, these compounds
have also been recognized as intermediates in the synthesis of other
classes of lignans.12 Consequently, they have been acknowledged as
interesting targets by synthetic and medicinal chemists. Although
To start with the synthesis of target molecules 3 and 9, dial-
kylboron-triflate-mediated syn-aldol reactions of N-succinyl-
⇑
Corresponding author. Tel.: +91 3222 283340; fax: +91 3222 255303.
E-mail address: shajra@chem.iitkgp.ernet.in (S. Hajra).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.044

2172
S. Hajra et al. / Tetrahedron Letters 54 (2013) 2171–2173
1 R1 = OMe; R2 = R3 = OH; R4 = R5 = H
2 R1 = R3 = OMe; R2 = OH; ; R4 = R5 = H
matairesinol
arctigenin
(7'S)-hydroxymatairesinol
(7'R)-hydroxymatairesinol
(7'R)-hydroxyarctigenin
R5
8'
R4
1'
6'
9'
R1
5'
3 R1 = OMe; R2 = R3 = OH; R4 = OH; R5 = H
7'
O
1
4
5
6
7
8
2
R
= OMe; R2 = R3 = OH; R4 = H; R5 = OH
= R3 = OMe; R2 = OH; R4 = H; R5 = OH
2'
9
R3
7
1
1
4'
R
3'
O
1
R - R2 = R1- R3 = OCH2O; R4 = H; R5 = OH (7'R)-parabenzlactone
6
5
1
R
= OH; R2 = R3 = R5 = H; R4 = OH
(7'S)-hydroxyenterolactone
(7'R)-hydroxyenterolactone
8 R1 = OH; R2 = R3 = OH; R4 = H; R5 = OH
R1
3
4
9 R1 = R3 = OMe; R2 = OH; R4 = OH; R5 = H (7'S)-hydroxyarctigenin
10 R1- R2 = R1- R3 = OCH2O; R4 = OH; R5 = H (7'S)-parabenzlactone
R2
Figure 1. 70-Hydroxydibenzylbutyrolactone lignans and their 70-deoxy analogues.
2-oxazolidinone16a 11 were carried out with O-silyl vanillin 12a
and veratraldehyde 12b. Costly n-Bu2BOTf, which afforded high
diastereoselectivity (dr >95:5) for both aldehydes 12, was replaced
with cheap and easily accessible (cy-Hex)2BOTf (prepared in the
laboratory19) and provided the corresponding syn-aldol products
13a,b with 92:8 and >95:5 diastereoselectivities, respectively
(Scheme 2). The aldols 13a,b were found to undergo lactonization
with time at rt. Hence, after filter column the compounds 13a,b
were immediately protected with TBSOTf in the presence of 2,6-
lutidine in CH2Cl2 at 5 °C to obtain the corresponding O-silyl aldols
14a and 14b as a single diastereomer after column chromato-
graphic purification in 68% and 75% yields over two steps, respec-
tively. Chemoselective reduction of the COXc unit of 14 either with
NaBH4 or LiBH4 was not successful. This problem was overcome by
a two-step method. At first, the chiral auxiliary of 14a,b was re-
moved via LiOH–H2O2 mediated chemoselective hydrolysis in
THF–H2O (5:1) to provide the corresponding acids 15a,b in 83%
and 88% yields, respectively. Acids 15a,b were then chemoselec-
tively reduced with BH3ꢁDMS in THF which provided a mixture of
alcohol 16 and the lactone 17. Subsequent treatment of the result-
ing mixture with a sub-stoichiometric amount of PPTS in benzene
at 60 °C afforded the pure lactones 17a,b in 81% yields over two
steps.
optical rotation of ½a D26
ꢂ
ꢀ9.6 (c 1.6, THF), [lit.14a
½
a 2D5
ꢂ
ꢀ11.0 (c 4.0,
THF)] and (70S)-hydroxyarctigenin 9 with optical rotation of ½a 2D6
ꢂ
ꢀ22.8 (c 1.1, CHCl3), [lit.14a
½
a 2D1
ꢂ
ꢀ22.4 (c 1.1, CHCl3) were completed
in 28.5% and 31.5% overall yields in six steps from N-succinyl-2-
oxazolidinone 11. Spectral data and optical rotation values were in
good agreement with those in the literature.14a
In conclusion, we have described an efficient route for the syn-
thesis of (70S)-hydroxymatairesinol and (70S)-hydroxyarctigenin
via asymmetric aldol reaction of chiral succinyl substrate followed
by chemoselective hydrolysis, reduction and lactonization, and a
subsequent stereoselective alkylation. Further application of these
O
O
MeO2C
N
O
11
CHO
MeO
RO
a
12a R = TBS
12b R = Me
OR'
O
O
MeO
N
O
To complete the synthesis of C70-hydroxy lignans alkylation of
17a,b with corresponding benzyl bromides was studied with differ-
ent bases. There was no reaction with LDA in THF at different tem-
peratures (ꢀ78 to ꢀ30 °C). The reaction also failed to provide the
desired alkylated products when it was carried out with LiHMDS
and KHMDS in THF and also in the presence of DMPU and TMEDA
as co-solvent/additive. But the alkylation was successful when
HMPA was used as a co-solvent with THF. LiHMDS-mediated alkyl-
ation of 17b in the presence of HMPA afforded the desired product
19b along with non-separable uncharacterized compounds. Under
the same conditions, KHMDS-mediated alkylation of 17 was found
to be very promising. Thus in the presence of HMPA (1.4 equiv),
alkylation of lactones 17a,b using KHMDS (1.3 equiv) with 4-silyl-
oxy-3-methoxybenzyl bromide 18 gave the desired alkylated
products 19a and 19b in 78% and 67% yields, respectively, with high
diastereoselectivity (dr: >95:5; Scheme 3). Silyl deprotection of
19a,b with TBAF at low temperature produced (70S)-hydroxyma-
tairesinol 3 and (70S)-hydroxyarctigenin 9, respectively, in 80% and
88% yields. Thus the synthesis of (70S)-hydroxymatairesinol 3 with
RO
MeO2C
13a R = TBS;R' = H dr: 92:08
13b R = Me;R' = H dr:> 95:5
b
14a R = R' = TBS dr:> 95:05; 68%
14b
R = Me; R' = TBS dr;> 95:05; 75%
c
TBSO
O
MeO
RO
OH
CO2Me
15a
R = TBS; 83%
R = Me; 88%
15b
d
TBSO
TBSO
H
MeO
O +
MeO
RO
OH
CO2Me
RO
O
16a
16b
R = TBS
R = Me
17a
17b
R = TBS
R = Me
e
81% over two steps
OH
Aldol
O
O
MeO
RO
O
O
Xc
CO2Me
ArCH2
Ar
H
Reagents : (a) (cy-Hex)2 BOTf (1.2 equiv), (i-Pr)2NEt (1.3
equiv), OTBS-vanilin 12a or veratraldehyde 12b (1.4 eq),
−45°C, 3 h; (b) TBSOTf (3.0 equiv), lutidine (4.0 equiv),
DMAP (0.2 equiv), CH2Cl2, 5°C, 16 h; 14a 68% (for two
steps) and 14b 75% (for two steps); (c) LiOH (1.5 equiv),
H2O2 (10.0 equiv), THF-H2O (5:1), 0°C to rt 10 h; 15a
83% and 56b 88%; (d) BH3.Me2S (1.5 equiv), THF,0°C
to r.t, 6h; (e) PPTS (0.2 equiv), benzene, 60°C, 6 h; 17a
and 17b 81% (for two steps).
Alkylation
X
O
OMe
HO
3: R = H; (7'S)-hydroxymatairesinol
9:
Xc
=
N
O
R = Me; (7'S)-hydroxyarctigenin
Scheme 1. Retrosynthesis of 70-hydroxydibenzyl-butyrolactone lignans.
Scheme 2. Asymmetric aldol reaction for the synthesis of lactone 17.

S. Hajra et al. / Tetrahedron Letters 54 (2013) 2171–2173
2173
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a
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3 R = H, 80%
9 R = Me, 88%
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´
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two lignans to their 70-deoxy analogues and the synthesis of other
natural and unnatural members of this lignan family are in
progress.
Acknowledgments
CSIR (New Delhi) is gratefully acknowledged for the financial
support. A. Mandal thanks CSIR (New Delhi) and S. Hazra thanks
UGC (New Delhi) for their fellowships. The authors are thankful
to the referees for constructive scientific comments and
suggestions.
Supplementary data
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1345–1348; (b) Raffaelli, B.; Wähälä, K.; Hase, T. Org. Biomol. Chem. 2006, 4,
331–341.
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16. (a) Hajra, S.; Giri, A. K.; Karmakar, A.; Khatua, S. Chem. Commun. 2007, 2408–
Supplementary data (the detailed experimental procedures,
characterization data of the compounds and 1H and 13C NMR spec-
tra) associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2013.02.044.
2410; (b) Hajra, S.; Giri, A. K. J. Org. Chem. 2008, 73, 3935–3937.
16a
17. Our organocatalytic method (Ref.
aldehydes like O-protected
)
is not successful for electron-rich
veratraldehyde and 3,4,5-
vanillin,
trimethoxybenzaldehyde. Also to note that there is no organocatalytic
asymmetric cross-aldol reaction of electron-rich aromatic aldehydes.
18. (a) Hajra, S.; Karmakar, A.; Giri, A. K.; Hazra, S. Tetrahedron Lett. 2008, 49, 3625–
3627; (b) Hajra, S.; Giri, A. K.; Hazra, S. J. Org. Chem. 2009, 74, 7978–7981.
19. Abiko, A. Org. Synth. 2004, 10, 273.
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