Keywords Surinamensinol A B - anti-inflammatory and antitumour neolignans - stereoselective
total synthesis - Suzuki–Miyaura cross coupling - Mitsunobu reaction
Lignans and neolignans are common, naturally occurring secondary plant metabolites
that are generated via the shikimic acid pathway.[1 ]
[2 ] Large numbers of natural products of these categories have been found in plants.[3,4 ] These plant metabolites exhibit a wide range of biological properties, such as antileishmanial,
platelet activity factor (PAF) antagonism, antiparasitic, trypanocidal, antimalarial
and anticancer activities.[5–8 ] The surinamensinols are recently disclosed examples of these classes of compounds.
Two new diastereomeric 8-O -4′-neolignans, surinamensinols A (1 ) and B (2 ) (Figure [1 ]), along with thirteen other phenolic derivatives, have recently been isolated from
the rhizome extracts of an aquatic perennial herbaceous plant, Acorus gramineus Soland (Araceae ), which is widely distributed in China, Korea and Japan.[9 ]
Surinamensinol A (1 ) possesses the (7R ,8R )-configuration, whereas surinamensinol B (2 ) possesses the (7S ,8R )-configuration (Figure [1 ]). Compounds 1 and 2 exhibit impressive anti-inflammatory and antitumour activities and significant inhibition
of nitric oxide (NO) levels in LPS-stimulated BV-2 cells.[9 ] They also showed potentially useful cytotoxicity towards the A549 cell line and
displayed significant antiproliferative activity against SK-OV-3, SK-MEL-2, and HCT-15
cell lines.[9 ]
Figure 1 Chemical structures of surinamensinols A (1 ) and B (2 )
In a continuation of our work[10 ]
[11 ] on the synthesis of natural products, we herein disclose the stereoselective total
synthesis of surinamensinols A (1 ) and B (2 ). Our present work involves the preparation of both diastereomeric 8-O -4′-oxyneolignans, surinamensinols A (1 ) and B (2 ) simultaneously from easily available allyl alcohol and (S )-ethyl lactate. Previously, surinamensinol A (1 ) was synthesized by Das et al. in 16 steps in an overall yield of 10%.[12 ] On the other hand, surinamensinol B (2 ) was synthesized by Lalwani and Sudalai by following a synthetic sequence that involved
18 steps, with the target molecule 2 being formed in an overall yield of 17%.[13 ]
The retrosynthetic analysis of compounds 1 and 2 indicated that both molecules could be synthesized from the chiral ester 3 , derived from the phenol benzyl ether 4 and (S )-ethyl lactate 5 . Compound 4 can, in turn, be obtained from 4-bromo-2-methoxyphenol 6 and allyl alcohol 7 (Scheme [1 ]).
Scheme 1 Retrosynthetic analysis of surinamensinols A (1 ) and B (2 )
Our synthesis was initiated with allyl alcohol 7 (Scheme [2 ]), which was reacted with benzyl bromide in the presence of NaH in anhydrous THF
when the primary hydroxyl group of the former was protected to furnish the product
8 in high yield (98%). We also attempted the reaction with the TBS protecting group
but due to the low volatility of the product it was difficult to isolate. Compound
8 underwent hydroboration[14 ] with 9-BBN (9-borabicyclo[3.3.1]nonane solution 0.5 M in THF) to form a protected
allyl diorganoborane adduct that was not isolated, but was treated in situ with 4-bromo-2-methoxyphenol
(6 ) in the presence of Pd(PPh3 )4 in anhydrous THF at reflux for 12 h (Suzuki–Miyaura coupling reaction conditions)
to yield the phenol benzyl ether 4 (86%), which was further purified and separated.[15 ] Compound 4 was coupled with (S )-ethyl lactate (5 ) under Mitsunobu reaction conditions using diisopropyl azodicarboxylate (DIAD) and
PPh3 in anhydrous THF to afford the desired chiral ester 3 in high yield (88%).[16 ]
[17 ] The Mitsunobu reaction with similar substrates is well known and previous workers
also obtained products with clean inversion.[18 ] We followed the experimental procedure of these earlier studies to generate compound
3 .
Scheme 2
Reagents and conditions : (a) NaH, BnBr, anhydrous THF, 0 °C to room temperature, 4 h, 98%; (b) (i) 9-BBN,
anhydrous THF, 0 °C to room temperature, 2 h (ii) 4-bromo-2-methoxyphenol 6 , Pd(PPh3 ), anhydrous THF, reflux, 12 h, 86% (2 steps); (c) PPh3 , DIAD, anhydrous THF, reflux, 24 h, 88%; (d) DIBAL-H, anhydrous DCM, –78 °C, 30 min
(e) (3,4,5-trimethoxyphenyl) magnesium bromide, anhydrous THF, 0 °C to room temperature,
19 h; (f) 10% Pd/C, H2 , EtOAc, room temperature, 2 h, 49% (combined 1 and 2 from compound 3 ).
Reduction of compound 3 with DIBAL-H at –78 °C to 0 °C gave the corresponding aldehyde in good yield, which
was then treated with 3,4,5-trimethoxyphenyl magnesium bromide in anhydrous THF.[18 ] A mixture of products was formed. We presumed this mixture might contain the syn - and anti -diastereomers of compound 9 (as evident from the next step and also from the HRMS, which showed m /z 519.2347 [M+Na+. ]) along with a similar amount of starting materials. TLC and HPLC examination did
not result in clean resolution of the constitutes of the mixture. We were also unable
to obtain a meaningful 1 H NMR spectrum of the mixture due to solubility problems with the product mixture.
Finally, we attempted the removal of the benzyl ether from the mixture 9 by hydrogenation in the presence of 10% Pd-C.[19 ] We were pleased to observe that this conversion yielded a separable mixture of surinamensinol
A (1 ) and surinamensinol B (2 ), which could be separated and purified by column chromatography. The physical and
spectroscopic properties of these compounds were found to be identical to those reported
for the natural products.[9 ]
In conclusion, an efficient approach to the total synthesis of anti-inflammatory and
antitumour 8-O -4′-neolignans, surinamensinols A (1 ) and B (2 ), has been described. The key steps in the synthetic sequence include a Pd-catalysed
Suzuki–Miyaura cross-coupling reaction and a chiral Mitsunobu protocol as key steps.
This approach resulted in the preparation of 1 and 2 , which were subsequently separated by column chromatography. The overall yields of
1 and 2 starting from 7 were 14 and 22%, respectively, from only six synthetic steps. This is the first report
of the total synthesis of surinamensinols A and B by a common approach.
All experiments were carried out in dry reaction vessels under dry nitrogen atmosphere.
All reagents were purchased from Sigma–Aldrich, Germany. Solvents were purified and
dried according to standard procedures. Analytical data were recorded with the following
instruments: Specific rotations were measured using the sodium D line with a Kruss
Optronic polarimeter. IR spectra were recorded with a Perkin Elmer RX FT-IR spectrophotometer,
wave numbers (ν) being reported in cm−1 . High-resolution electrospray ionization mass spectra (HR-ESI-MS) were recorded with
an Agilent 6530 LC Q-TOF. 1 H and 13 C NMR spectra were recorded with a Bruker NMR spectrometer operating at 600 MHz (150
MHz for 13 C) and 200 MHz (50 MHz for 13 C) using the solvent peak as the internal reference (CDCl3 , δH = 7.26 ppm; δC = 77.0 ppm). Data are reported in the following order: chemical shift (δ, ppm), multiplicities
and coupling constants (J , Hz). Column chromatography was carried out by using 100–200 mesh particle size silica
gel. All reactions were monitored by thin-layer chromatography (TLC) using silica
gel F254 pre-coated plates. Visualization was accomplished with UV-light and I2 staining. Solvents for column chromatography (EtOAc, n -hexane) were technical grade and distilled prior to use. Organic extracts were dried
over anhydrous MgSO4 .
Allyl Benzyl Ether 8
To a suspension of NaH (0.155 g, 6.48 mmol) in anhydrous THF (25 mL) a solution of
7 (0.250 g, 4.31 mmol) in anhydrous THF (10 mL) was added dropwise at 0 °C under nitrogen.
After stirring for 30 min, benzyl bromide (0.62 mL, 5.17 mmol) was added slowly dropwise
and the reaction mixture was stirred at r.t. for 4 h. After completion of the reaction,
the reaction was quenched with saturated aq. NH4 Cl at 0 °C and the mixture was extracted with Et2 O (3 × 20 mL). The combined organic extracts were washed with water (2 × 20 mL) and
brine solution (10 mL), and dried over anhydrous MgSO4 . After filtration, the solvent was removed under reduced pressure. The crude product
was purified by column chromatography to afford compound 8 .
Yield: 0.624 g (98%); pale-yellow liquid; Rf
= 0.78 (hexane/EtOAc, 9:1).
IR (KBr): 2854, 1495, 1453, 1227, 1067, 1027, 919, 735, 694 cm–1 .
1 H NMR (600 MHz, CDCl3 ): δ = 7.35–7.32 (m, 4 H), 7.29–7.25 (m, 1 H), 5.94 (ddt, J = 17.2, 10.4, 5.6 Hz, 1 H), 5.29 (dq, J = 17.2, 1.7 Hz, 1 H), 5.19 (dq, J = 10.4, 1.4 Hz, 1 H), 4.51 (s, 2 H), 4.02 (dt, J = 5.6, 1.5 Hz, 2 H).
13 C NMR (150 MHz, CDCl3 ): δ = 138.3, 134.7, 128.4, 127.7, 127.6, 117.1, 72.1, 71.1.
HRMS (ESI+ ): m /z [M+· ] calcd for C10 H12 O: 148.1139; found: 148.1137; m /z [M + H+ ] calcd for C10 H13 O: 149.1156; found: 149.1158.
4-(3-Benzyloxypropyl)-2-methoxyphenol (4)
4-(3-Benzyloxypropyl)-2-methoxyphenol (4)
To compound 8 (0.300 g, 2.02 mmol) in anhydrous THF (10 mL) at 0 °C under nitrogen was added 9-BBN
(0.5 M in THF, 4.85 mL, 2.42 mmol) dropwise. The reaction mixture was warmed to r.t.
and stirred for 2 h. The flask was covered with foil and aq. NaOH (3 M, 2.02 mL) was
slowly added at 0 °C (CARE : H2 evolution) and then flushed for 10–15 min with nitrogen. A solution of Pd (PPh3 )4 (0.040 g, 0.034 mmol) in anhydrous THF (15 mL) was added, and then a solution of
4-bromo-2-methoxyphenol (6 ; 0.451 g, 2.22 mmol) in anhydrous THF was added dropwise to the reaction mixture
at 0 °C under nitrogen. The reaction mixture was heated to reflux for 12 h. After
completion of the reaction, as monitored by TLC, the reaction was quenched with sat.
aq. NH4 Cl at 0 °C. The crude reaction product was dissolved in THF (3 mL, 0.2 mmol of alkene)
and aqueous NaOH (1 M, 1 mL, 0.2 mmol of alkene) was added, followed by aqueous H2 O2 (60 % w/v, 0.2 mmol: 0.2 mmol of alkene) and the mixture was stirred vigorously for
10–15 minutes at 0 °C. The residue was filtered and extracted with ether (3 × 10 mL).
The combined organic extracts were washed with water (2 × 20 mL) and brine (10 mL),
filtered, dried over anhydrous MgSO4 , and concentrated under reduced pressure. The crude product, was purified by column
chromatography to afford compound 4 .
Yield: 0.473 g (86%); pale-brown liquid; Rf
= 0.56 (hexane/EtOAc, 9:1).
IR (KBr): 3332, 2940, 2830, 1495, 1446, 1397, 1250, 1220, 1181, 1132, 840, 769 cm–1 .
1 H NMR (600 MHz, CDCl3 ): δ = 7.33 (d, J = 4.4 Hz, 4 H), 7.27 (ddd, J = 8.8, 4.9, 3.9 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.68–6.64 (m, 2 H), 5.43 (brs, 1 H), 4.49 (s, 2 H), 3.83 (s, 3 H),
3.47 (t, J = 6.3 Hz, 2 H), 2.63 (dd, J = 8.6, 6.8 Hz, 2 H), 1.91–1.87 (m, 2 H).
13 C NMR (150 MHz, CDCl3 ): δ = 146.3, 143.6, 138.6, 133.9, 128.4, 127.7, 127.5, 121.0, 114.1, 111.0, 73.0,
69.5, 55.8, 32.1, 31.7.
HRMS (ESI+ ): m /z [M + H+ ] calcd for C17 H21 O3 : 273.1506; found: 273.1508.
(R )-Ethyl 2-(4-(3-(Benzyloxy)propyl)-2-methoxyphenoxy)propanoate (3)
(R )-Ethyl 2-(4-(3-(Benzyloxy)propyl)-2-methoxyphenoxy)propanoate (3)
A mixture of 5 (0.150 g, 1.27 mmol), 4 (0.415 g, 1.52 mmol), triphenylphosphine (0.432 g, 1.65 mmol), and DIAD (0.33 mL,
1.65 mmol) in anhydrous THF (15 mL) was heated to reflux for 24 h under nitrogen.
After completion of the reaction, as monitored by TLC, the mixture was cooled to 0
°C, the reaction was quenched with sat. aq. NH4 Cl and the mixture was extracted with Et2 O (3 × 10 mL). The combined organic extracts were washed with water (2 × 20 mL), brine
(10 mL), dried over anhydrous MgSO4 , filtered and concentrated in vacuo. The crude product was purified by column chromatography
to afford compound 3 .
Yield: 0.415 g (88%); pale-brown liquid; Rf
= 0.60 (hexane/EtOAc, 9:1); [α]D
22 = +0.94 (c = 0.016, CHCl3 ).
IR (KBr): 2984, 1734, 1589, 1493, 1444, 1396, 1250, 1195, 1179, 1046, 849, 783 cm–1 .
1 H NMR (600 MHz, CDCl3 ): δ = 7.33 (d, J = 4.4 Hz, 4 H), 7.29–7.25 (m, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 6.70 (d, J = 2.0 Hz, 1 H), 6.63 (dd, J = 8.1, 2.0 Hz, 1 H), 4.68 (q, J = 6.8 Hz, 1 H), 4.49 (d, J = 3.4 Hz, 2 H), 4.19 (qd, J = 7.1, 4.4 Hz, 2 H), 3.81 (s, 3 H), 3.46 (t, J = 6.4 Hz, 2 H), 2.65–2.62 (m, 2 H), 1.91–1.87 (m, 2 H), 1.60 (d, J = 6.8 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
13 C NMR (150 MHz, CDCl3 ): δ = 172.4, 149.9, 145.1, 138.6, 136.6, 128.4, 127.6, 127.5, 120.3, 116.4, 112.7,
74.4, 73.0, 69.5, 61.0, 55.9, 32.0, 31.5, 18.6, 14.1.
HRMS (ESI+ ): m /z [M + H+ ] calcd for C22 H29 O5 : 373.1314; found: 373.1312.
(2R )-2-(4-(3-(Benzyloxy)propyl)-2-methoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)propan-1-ol
(9)
(2R )-2-(4-(3-(Benzyloxy)propyl)-2-methoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)propan-1-ol
(9)
To a stirred solution of ester 3 (0.160 g, 0.43 mmol) in anhydrous CH2 Cl2 (10 mL), DIBAL-H (1 M in THF, 0.64 mL, 0.64 mmol) was added dropwise at –78 °C under
nitrogen and the reaction mixture was stirred for 30 min. The reaction was quenched
with 2 M HCl (8 mL) and the mixture was extracted with CH2 Cl2 (2 × 50 mL). The combined organic extracts were washed with water (2 × 20 mL), and
brine (10 mL), dried over anhydrous MgSO4 , filtered, and concentrated under reduced pressure. The aldehyde (0.128 g, 0.38 mmol)
thus obtained as a colourless oil was immediately used after flash column chromatography
for the subsequent reaction.
To a stirred solution of the aldehyde (0.128 g, 0.38 mmol) from the preceding step
in anhydrous THF (10 mL), 3,4,5-trimethoxyphenyl magnesium bromide (0.5 M in THF,
1.80 mL, 0.90 mmol) was added dropwise at 0 °C under nitrogen and the reaction mixture
was stirred at r.t. for 19 h. After completion of the reaction, as monitored by TLC,
the mixture was cooled to 0 °C, the reaction was quenched with sat. aq. NH4 Cl, and the mixture was extracted with Et2 O (2 × 25 mL). The combined organic extracts were washed with water (2 × 20 mL), brine
(10 mL), dried over anhydrous MgSO4 , filtered and concentrated in vacuo to obtain a brown gum (0.164 g) that was presumed
to be a mixture of syn - and anti -diastereomers of 9 (as evident from the next reaction) along with starting materials. We proceeded with
the next step with this crude material.
Surinamensinols A (1) and B (2)
Surinamensinols A (1) and B (2)
To a stirred solution of crude compound 9 (0.082 g) in anhydrous EtOAc (5 mL) was added a catalytic amount of Pd/C (10%) and
the reaction mixture was stirred at r.t. under hydrogen for 2 h. After completion
of the reaction, as monitored by TLC, the mixture was filtered, washed with EtOAc
(3 × 10 mL) and the filtrate was concentrated under reduced pressure to furnish a
gum. This was purified by silica gel column chromatography, using hexane and EtOAc
as eluent, to afford 1 (0.018 g) and 2 (0.027 g). The combined yields of 1 and 2 were 49% from compound 3 and the overall yield from the whole sequence of 1 was 14% and that of 2 was 22%.
Surinamensinol A (1)
Rf
= 0.30 (hexane/EtOAc, 3:2); [α]D
22 = –60.5 (c = 1.0, CHCl3 ; 95% ee ).
IR (KBr): 3432, 2927, 2845, 1459, 1233, 1125 cm–1 .
1 H NMR (200 MHz, CDCl3 ): δ = 6.92 (d, J = 8.0 Hz, 1 H), 6.78 (d, J = 2.0 Hz, 1 H), 6.73 (dd, J = 8.0, 2.0 Hz, 1 H), 6.60 (s, 2 H), 4.62 (d, J = 7.0 Hz, 1 H), 4.06 (m, 1 H), 3.88 (s, 9 H), 3.85 (s, 3 H), 3.69 (t, J = 7.0 Hz, 2 H), 2.63 (t, J = 7.0 Hz, 2 H), 1.91–1.82 (m, 2 H), 1.21 (d, J = 7.0 Hz, 3 H).
13 C NMR (50 MHz, CDCl3 ): δ = 153.3, 150.7, 146.2, 145.3, 138.2, 137.3, 135.2, 121.1, 119.3, 112.2, 104.7,
83.3, 77.5, 62.2, 56.2, 34.3, 32.1, 17.0.
HRMS (ESI+ ): m /z [M + Na+ ] calcd for C22 H30 O7 Na: 429.1994; found: 429.1992.
Surinamensinol B (2)
Rf
= 0.24 (hexane/EtOAc, 3:2); [α]D
25 = –11.4 (c = 0.2, CH3 OH; 96% ee ).
IR (KBr): 3389, 2952, 1601, 1510, 1278, 1036 cm–1 .
1 H NMR (200 MHz, CDCl3 ): δ = 6.95 (d, J = 8.0 Hz, 1 H), 6.78 (d, J = 2.0 Hz, 1 H), 6.76 (dd, J = 8.0, 2.0 Hz, 1 H), 6.57 (s, 2 H), 4.80 (d, J = 3.5 Hz, 1 H), 4.35 (dq, J = 6.5, 3.5 Hz, 1 H), 3.88 (s, 3 H), 3.85 (s, 6 H), 3.83 (s, 3 H), 3.68 (t, J = 6.5 Hz, 2 H), 2.70 (t, J = 7.5 Hz, 2 H), 1.89 (m, 2 H), 1.17 (d, J = 6.5 Hz, 3 H).
13 C NMR (50 MHz, CDCl3 ): δ = 153.1, 151.0, 144.5, 137.3, 135.9, 121.0, 119.3, 112.5, 103.4, 82.1, 73.8,
62.0, 60.8, 56.1, 55.8, 34.4, 31.6, 13.2.
HRMS: m /z [M + Na+ ] calcd for C22 H30 O7 Na: 429.1990; found: 429.1992.
