Enantioselective total synthesis of ligraminol d and ligraminol e

Article abstract of DOI:10.1055/s-0039-1690249

As a part of our ongoing research on the synthesis of bioactive constituents or molecules by using an organocatalytic approach, enantioselective total syntheses of ligraminol D and ligraminol E were achieved starting from a commercially available nonchiral aldehyde. Key steps in this synthesis were an asymmetric α-aminoxylation of an aldehyde and a Mitsunobu reaction.

Full text of DOI:10.1055/s-0039-1690249

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
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B. B. Mane et al.
Letter
Synlett
Enantioselective Total Synthesis of Ligraminol D and Ligraminol E
Baliram B. Mane
MeO
OH
D. D. Kumbhar
D-proline
OR2
HO
MeO
R1O
CHO asymmetric
aminoxylation
Suresh B. Waghmode*
0
0
0
0-
0
0
0
1-7
9
6
8-9
9
6
0
R2
=
ligraminol E
OH
O
MeO
MeO
Department of Chemistry, Savitribai Phule, Pune
University (Formerly University of Pune), Ganeshkhind,
Pune 411007, India
OH
R
R
1 = OBn
1 = Me
L-proline
OR2
ligraminol D
suresh@chem.unipune.ac.in
Received: 13.09.2019
Accepted after revision: 21.10.2019
Published online: 30.10.2019
workers isolated the lignans ligraminol A–E (Figure 1) from
A. gramineus; these compounds showed antiproliferative
activities toward human normal and cancer cell lines and
inhibitory effects on nitric oxide (NO) production in lipo-
polysaccharide-activated BV-2 cells, a microglial cell line.10
DOI: 10.1055/s-0039-1690249; Art ID: st-2019-b0488-l
Abstract As a part of our ongoing research on the synthesis of bioac-
tive constituents or molecules by using an organocatalytic approach,
enantioselective total syntheses of ligraminol D and ligraminol E were
achieved starting from a commercially available nonchiral aldehyde. Key
steps in this synthesis were an asymmetric -aminoxylation of an alde-
hyde and a Mitsunobu reaction.
OMe
MeO
MeO
OMe
O
Key words asymmetric synthesis, total synthesis, aminoxylation,
ligraminols, Mitsunobu reaction, asymmetric catalysis
ligraminol A
(1)
OMe
OH
OMe
OH
OMe
GlcO
Lignans and neolignans are a diverse class of pharmaco-
logically active phenylpropanoid oligomers that occur natu-
rally in various plants.1 Lignans act as antioxidants and phy-
toestrogens with estrogenic and antiestrogenic activities.2,3
The action of lignans on the human body can reduce the
risk of breast or prostate cancer.4 Researchers have focused
their attention on syntheses of natural products, which has
led to the discovery of various important anticancer drugs,
such as vinblastine, vincristine, paclitaxel, and the lignin-
derived etoposide, etopophos, and teniposide.
Lignans are the main bioactive constituent of Acorus
gramineus, commonly known as Japanese sweet flag, which
usually grows in wetlands or shallow water in Japan, the
Korean peninsula, and eastern Asia. The plant spreads ag-
gressively by rhizomes, which have been used in traditional
Chinese medicine as a remedy for cognitive problems and
for sedation, enhancing brain function, and analgesia.5 Phy-
tochemical investigations on species of this genus led to the
isolation of various compounds of biological importance.6
Phytochemical studies on A. gramineus have identified sev-
eral active phenolics, such as -asarone, -asarone, and
phenylpropenes that exhibit antibacterial, antifungal, an-
thelmintic, and pesticidal activities.7–9 On 2011, Lee and co-
MeO
HO
O
ligraminol B
OMe
(2)
MeO
MeO
O
O
OMe
ligraminol C
(3)
MeO
OH
O
MeO
OH
MeO
ligraminol D
(4)
MeO
OH
O
HO
OH
MeO
ligraminol E
(5)
Figure 1 Ligraminols A–E isolated from Acorus gramineus; Glc = glucosyl
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
B. B. Mane et al.
Letter
Synlett
The natural-product synthetic approach and the develop-
ment of new lignan derivatives as anticancer drugs is an at-
tractive and promising avenue. Two total syntheses of li-
graminol E and one of ligraminol D have previously been
reported in the literature.11 The synthesis of ligraminol E (5)
reported by Gangar et al. was accomplished by using a chi-
ral auxiliary and gave an overall yields of 23.9% over eight
steps.11a A recent approach by Muthukrishnan and co-
workers relied on a regioselective ring opening of a chiral
epoxide with a Grignard reagent.11b
Over the past few years, the field of asymmetric organo-
catalysis has become an emerging area of research in the
synthesis of chiral compounds with high optical purity.12
Among various organocatalysts, proline is readily available
in both its D- and L-forms, and is a bifunctional amino ac-
id.12a,13 Asymmetric aminoxylation is an attractive method
for introducing chirality from nonchiral aldehydes.14 As part
of our research program on the development of new strate-
gies for the enantioselective syntheses of biologically active
compounds and their key chiral intermediates based on
proline-catalyzed asymmetric -aminoxylation of alde-
hydes,15 we have developed enantioselective syntheses of
ligraminol D (4) and ligraminol E (5) involving an organo-
catalytic asymmetric -aminoxylation of an aldehyde and a
Mitsunobu reaction as key steps.
methoxyphenyl)propanoate (6). To obtain enantiomerically
pure sec-alcohols 7 and 8, the nonchiral aldehydes 9 and 10
could be subjected to L- or D-proline-catalyzed asymmetric
-aminooxylation, respectively, followed by protection
with benzoyl chloride.
Our synthesis of ligraminol E (5) started from commer-
cially available vanillin (11), which was subjected to Wittig
olefination followed by double-bond reduction through cat-
alytic hydrogenation in methanol to give ester 6 in 94%
yield over the two steps (Scheme 2). The phenolic group of
ester 6 was protected by treatment with BnBr in anhydrous
DMF to afford the O-benzylated ester 13 in 90% yield. Ester
13 was reduced with DIBAL-H in CH2Cl2 to deliver the corre-
sponding aldehyde 10 in 91% yield.16
Aldehyde 10 was treated with nitrosobenzene in the
presence of ecofriendly D-proline, which catalyzed an -
aminooxylation reaction15 in MeCN at –10 °C. This was fol-
lowed by in situ reduction of the aldehyde group with
NaBH4 in MeOH to afford the aminooxy alcohol 14 (Scheme
3). This crude aminooxy alcohol intermediate 14 was treat-
ed with 30 mol% of Cu(OAc)2·H2O in MeOH to cleave the O–
20
N bond and give the chiral diol 15 {[]D –16.4 (c 0.55,
MeOH)} in 72% yield over the two steps. The enantiomeric
excess was 97.3%, as determined by HPLC on a Chiralpak IA
column. Selective benzoylation of the primary hydroxy
functionality of diol 15 was carried out by using benzoyl
chloride and triethylamine in CH2Cl2 at –10 °C to give the
secondary alcohol 8 in 90% yield. Secondary alcohol 8 was
subjected to a Mitsunobu reaction17 with ester 6 in the
presence of DEAD and PPh3 in refluxing dry THF to give
Our retrosynthetic analysis for ligraminol D (4) and li-
graminol E (5) is outlined in Scheme 1. We envisaged short
and efficient syntheses of ligraminol D (4) and ligraminol E
(5) from the chiral sec-alcohols 7 and 8, respectively,
through Mitsunobu reaction with ethyl 3-(4-hydroxy-3-
MeO
MeO
OH
OH
O
O
MeO
HO
OH
OH
MeO
MeO
ligraminol D (4)
ligraminol E (5)
Mitsunobu reaction
MeO
MeO
OBz
OBz
OH
OH
BnO
MeO
7
8
D-proline-catalysed
α-aminooxylation
L-proline-catalysed
α-aminooxylation
MeO
MeO
CHO
MeO
CHO
BnO
9
10
Scheme 1 Retrosynthetic analysis for ligraminol D and ligraminol E
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

C
B. B. Mane et al.
Letter
Synlett
Pd/C (10%)
H2 (150 psi)
MeO
HO
CO2Et
MeO
HO
CO2Et
MeO
HO
CHO
Ph3P=CH-CO2Et
toluene, 110 °C, 3 h
MeOH, 12 h
(94% over 2 steps)
6
11
12
DIBAL-H
anhyd CH2Cl2, –78 °C, 1 h
MeO
CO2Et
MeO
CHO
BnBr, K2CO3
anhyd DMF
0 °C to rt, 12 h
90%
then Rochelle salt
91%
BnO
BnO
10
13
Scheme 2 Synthesis of the key intermediate aldehyde 10
ether 16 in 88% yield. Debenzylation of ether 16 by hydro-
genation in the presence of 10% Pd/C in MeOH, followed by
global reduction with LiAlH4 in dry THF gave ligraminol E (5).
We then turned our attention to the synthesis of ligram-
inol D (4) (Scheme 4). We realized that our previously re-
ported (R)-diol 1815i might serve as a suitable precursor
with the required C-3 stereocenter of ligraminol D (4). Se-
PhNO, D-proline
MeCN, –10 °C, 24 h;
MeO
BnO
MeO
BnO
Cu(OAc)2·H2O
MeOH, rt, 12 h
OH
OH
ONHPh
10
in situ NaBH4
MeOH, 0 °C, 45 min
OH
(72% over 2 steps)
15
14
MeO
OBz
MeO
BnO
6, DEAD, PPh3
BzCl, Et3N
OBz
O
BnO
anhyd THF, reflux, 6 h
88%
OH
CH2Cl2, –10 °C, 3 h
90%
MeO
CO2Et
8
16
1) H2 (150 psi), Pd/C (10%),
MeOH, rt, 12 h
2) LiAlH4, anhyd THF, rt, 3 h
MeO
OH
O
HO
(93% over 2 steps)
OH
MeO
ligraminol E (5)
Scheme 3 Synthesis of ligraminol E (5) from intermediate aldehyde 10
MeO
MeO
CHO
MeO
MeO
MeO
ref. 15i
PhCOCl, Et3N
OH
OBz
OH
OH
58%, 98% ee
over 4 steps
CH2Cl2, –10 °C, 3 h
91%
MeO
18
17
7
MeO
MeO
MeO
MeO
OBz
OH
6, DEAD, PPh3
LiAlH4
O
O
anhyd THF, reflux, 6 h
87%
anhyd THF, rt, 3 h
93%
OH
MeO
CO2Et
MeO
ligraminol D (4)
19
Scheme 4 Synthesis of ligraminol D (4) from diol 18
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

D
B. B. Mane et al.
Letter
Synlett
lective benzoylation of the primary hydroxy group of diol
18 was carried out by using benzoyl chloride and triethyl-
amine in CH2Cl2 at –10 °C. Finally both fragments, the diol
18 and the ester 6, were coupled under Mitsunobu condi-
tions17 to afford ether 19 in 87% yield. This was successfully
reduced by LiAlH4 in dry THF to afford ligraminol D (4) in
93% yield. The spectral data were in good agreement with
those reported in the literature.11b
In conclusion, we have achieved a concise enantioselec-
tive total synthesis of ligraminol D in seven steps with
42.6% overall yield and that of ligraminol E in ten steps with
40.8% overall yield through proline-catalyzed asymmetric
-aminoxylation of aldehydes.18 High yields, the ready
availability of the starting material, and high enantioselec-
tivity are among the salient features of our synthetic ap-
proach. The reported procedure provides the shortest
known route to the synthesis of the title compound from
nonchiral starting materials.
(13) For reviews of proline-catalyzed asymmetric reactions, see:
(a) List, B. Synlett 2001, 1675. (b) Movassaghi, M.; Jacobsen, E. N.
Science 2002, 298, 1904. (c) List, B. Tetrahedron 2002, 58, 5573.
(d) List, B. Acc. Chem. Res. 2004, 37, 548.
(14) (a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2003, 125, 10808. (b) Janey, J. M. Angew. Chem.
Int. Ed. 2005, 44, 4292. (c) Merino, P.; Tejero, T. Angew. Chem.
Int. Ed. 2004, 43, 2995. (d) Zhong, G. Angew. Chem. Int. Ed. 2003,
42, 4247. (e) Lu, M.; Zhu, D.; Lu, Y.; Hou, Y.; Tan, B.; Zhong, G.
Angew. Chem. Int. Ed. 2008, 47, 10013; corrigendum; Angew.
Chem. Int. Ed. 2008, 47, 10187. (f) Ramachary, D. B.; Barbas, C. F.
Org. Lett. 2005, 7, 1577. (g) Hayashi, Y.; Yamaguchi, J.; Hibino, K.;
Shoji, M. Tetrahedron Lett. 2003, 44, 8293. (h) Bøgevig, A.;
Sundén, H.; Córdova, A. Angew. Chem. Int. Ed. 2004, 43, 1109.
(i) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M. Angew. Chem.
Int. Ed. 2004, 43, 1112. (j) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.;
Hibino, K.; Shoji, M. J. Org. Chem. 2004, 69, 5966. (k) Font, D.;
Bastero, A.; Sayalero, S.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2007,
9, 1943. (l) Cambeiro, X. C.; Martín-Rapún, R.; Miranda, P. O.;
Sayalero, S.; Alza, E.; Llanes, P.; Pericàs, M. A. Beilstein J. Org.
Chem. 2011, 7, 1486.
(15) (a) Markad, S. B.; Bhosale, V. A.; Bokale, S. R.; Waghmode, S. B.
ChemistrySelect 2019, 4, 502. (b) Bhosale, V. A.; Waghmode, S. B.
Org. Chem. Front. 2018, 5, 2442. (c) Bhosale, V. A.; Markad, S. B.;
Waghmode, S. B. Tetrahedron 2017, 73, 5344. (d) Bhosale, V. A.;
Waghmode, S. B. Tetrahedron 2017, 73, 2342. (e) Bhosale, V. A.;
Waghmode, S. B. ChemistrySelect 2017, 2, 1262. (f) Sawant, R. T.;
Waghmode, S. B. Tetrahedron 2009, 65, 1599. (g) Sawant, R. T.;
Waghmode, S. B. Tetrahedron 2010, 66, 2010. (h) Sawant, R. T.;
Jadhav, S. G.; Waghmode, S. B. Eur. J. Org. Chem. 2010, 4442.
(i) Sawant, R. T.; Waghmode, S. B. Synth. Commun. 2010, 40,
2269. (j) Sawant, R. T.; Waghmode, S. B. Synth. Commun. 2011,
41, 2385. (k) Patil, V. P.; Ghosh, A.; Sonavane, R.; Joshi, U. R.;
Sawant, R. T.; Jadhav, S. G.; Waghmode, S. B. Tetrahedron: Asym-
metry 2014, 25, 489.
Funding Information
Savitribai Phule Pune University (Ref. No. O.S.D./B.C.U.D./83); Council
of Scientific and Industrial Research [09/137(0560)/2016-EMR-I to
B.B.M.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690249.
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(16) Yadav, J. S.; Singh, V. K.; Thirupathaiah, B.; Reddy, A. B. Tetrahe-
dron Lett. 2014, 55, 4427.
(17) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
(18) 4-{(2R)-3-Hydroxy-2-[4-(3-hydroxypropyl)-2-methoxyphe-
noxy]propyl}-2-methoxyphenol (Ligraminol E) (5)
References and Notes
(1) Teponno, R. B.; Kusari, S.; Spiteller, M. Nat. Prod. Rep. 2016, 33,
1044.
(2) Kitts, D. D.; Yuan, Y. V.; Wijewickreme, A. N.; Thompson, L. U.
Mol. Cell. Biochem. 1999, 202, 91.
(3) Cornwell, T.; Cohick, W.; Raskin, I. Phytochemistry 2004, 65, 995.
(4) Magee, P. J.; Rowland, I. R. Br. J. Nutr. 2004, 91, 513.
(5) Liao, J.-F.; Huang, S.-Y.; Jan, Y.-M.; Yu, L.-L.; Chen, C.-F. J. Ethno-
pharmacol. 1998, 61, 185.
(6) Della Greca, M.; Monaco, P.; Previtera, L.; Aliotta, G.; Pinto, G.;
Pollio, A. Phytochemistry 1989, 28, 2319.
(7) Lee, J. Y.; Lee, J. Y.; Yun, B.-S.; Hwang, B. K. J. Agric. Food Chem.
2004, 52, 776.
(8) Perrett, S.; Whitfield, P. J. Phytother. Res. 1995, 9, 405.
(9) McGaw, L. J.; Jäger, A. K.; van Staden, J.; Eloff, J. N. S. Afr. J. Bot.
2002, 68, 31.
To a solution of ether 16 (0.190 g) in MeOH (10 mL) was added
10% Pd/C (0.05 g), and the mixture was stirred for 12 h under H2
(150 psi; 1.03 MPa). The catalyst was filtered off and the filtrate
was concentrated under reduced pressure. A solution of the
resulting crude ether (0.154 g, 0.30 mmol) in anhyd THF (5 mL)
was added dropwise to a cold (0 °C) suspension of LiAlH4 (0.025
g, 0.66 mmol) in anhyd THF (5 mL), and the suspension as
stirred for 3 h at rt, then cooled to 0 °C. The reaction as
quenched with sat. aq NH4Cl (2 mL), and mixture was diluted
with EtOAc (10 mL), filtered through a Celite pad under vacuum,
and concentrated under reduced pressure. The crude product
was purified by column chromatography [silica gel, EtOAc–
hexane (3:7)] to give a sticky colourless liquid; yield: 0.119 g
(10) Kim, K. H.; Kim, H. K.; Choi, S. U.; Moon, E.; Kim, S. Y.; Lee, K. R.
J. Nat. Prod. 2011, 74, 2187.
25
(93%; two steps); []D +17.5 (c 0.103, MeOH) [Lit.11b +18.3 (c
(11) (a) Gangar, M.; Goyal, S.; Hathiram, V.; Ramdas, W. A.; Rao, V.
K.; Nair, V. A. ChemistrySelect 2017, 2, 257. (b) Ghotekar, G. S.;
Mujahid, M.; Muthukrishnan, M. Synthesis 2019, in press; DOI:
10.1055/s-0037-1611919.
(12) (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726.
(b) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138.
(c) Houk, K. N.; List, B. Acc. Chem. Res. 2004, 37, 487. (d) List, B.
Adv. Synth. Catal. 2004, 346, 1021. (e) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719.
0.10, MeOH)].
IR (neat): 3387, 2923, 2852, 1602, 1509, 1261, 1026, 798 cm–1
.
1H NMR (400 MHz, CDCl3):  = 6.87–6.83 (m, 1 H), 6.81–6.76 (m,
3 H), 6.74–6.69 (m, 2 H), 4.24–4.18 (m, 1 H), 3.87 (s, 3 H), 3.86
(s, 3 H), 3.71–3.63 (m, 4 H), 3.06 (dd, J = 13.9, 6.7 Hz, 1 H), 2.90
(dd, J = 13.9, 6.9 Hz, 1 H), 2.66 (t, J = 6.9 Hz, 2 H), 1.91–1.84 (m, 2
H). 13C NMR (101 MHz, CDCl3):  = 150.9, 146.5, 145.6, 144.3,
137.3, 129.7, 122.1, 121.0, 119.8, 114.4, 112.4, 112.2, 85.14,
63.4, 62.1, 55.9, 55.8, 37.3, 34.2, 31.8. HRMS (ESI, +): m/z [M +
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E

E
B. B. Mane et al.
Letter
Synlett
Na]+ calcd for C20H26NaO6: 385.1627; found: 385.1628.
(c 0.154, MeOH); {Lit.11b –29.0 (c 0.1, MeOH); Lit.11a +9.5 (c 0.1,
(2S)-3-(3,4-Dimethoxyphenyl)-2-[4-(3-hydroxypropyl)-2-
methoxyphenoxy]propan-1-ol (Ligraminol D) (4)
MeOH)}
IR (neat): 3402, 2945, 1605, 1510, 1036 cm–1 1H NMR (400
.
A solution of ether 19 (0.115 g, 0.23 mmol) in anhyd THF (5 mL)
was added dropwise to a cold (0 °C) suspension of LiAlH4 (0.018
g, 0.48 mmol) in dry THF (5 mL) and the suspension was stirred
for 3 h at r.t, then cooled to 0 °C. The reaction was quenched
with sat. aq NH4Cl (3 mL), and the mixture was diluted with
EtOAc (10 mL), filtered through a Celite pad under vacuum, and
concentrated under reduced pressure. The crude product was
purified by column chromatography (silica gel, 25% EtOAc–
hexane) to give a sticky liquid; yield: 0.077 g (93%), []D25 –24.3
MHz, CDCl3):  = 6.82 (br s, 3 H), 6.76 (br s, 1 H), 6.68 (d, J = 0.9
Hz, 2 H), 4.25–4.19 (m, 1 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.86 (s, 3
H), 3.69–3.67 (m, 4 H), 3.08 (dd, J = 13.9, 6.7 Hz, 1 H), 3.01–2.88
(m, 2 H), 2.66 (t, J = 6.7 Hz, 2 H), 1.91–1.84 (m, 2 H). 13C NMR
(101 MHz, CDCl3):  = 150.9, 148.9, 147.7, 145.5, 137.3, 130.5,
121.5, 121.0, 119.8, 112.8, 112.4, 111.3, 85.1, 63.5, 62.1, 55.9,
55.9, 55.9, 37.3, 34.2, 31.8. HRMS (ESI, +): m/z [M + Na]+ calcd
for C21H28NaO6: 399.1784; found: 399.1781.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–E