First Enantioselective Synthesis of Surinamensinol B and a Non-Natural Polysphorin Analogue by a Two-Stereocentered Hydrolytic Kinetic Resolution

Article abstract of DOI:10.1002/ejoc.201501009

An efficient and economical approach to the synthesis of antitumor and anti-inflammatory surinamensinol B (1) and antimalarial polysphorin analogue 2 has been achieved with high enantiomeric purity (96 % ee) by starting from commercially available 3,4,5-trimethoxybenzaldehyde. The key steps of the strategy include a Co-catalyzed two-stereocentered hydrolytic kinetic resolution (HKR) of racemic 2-[(methoxymethoxy)(3,4,5-trimethoxyphenyl)methyl]oxirane (13) as the chiral inducing step followed by a Mitsunobu reaction. Chiral epoxide 14 and chiral diol 15 were utilized in the syntheses of both compounds.

Full text of DOI:10.1002/ejoc.201501009

FULL PAPER
DOI: 10.1002/ejoc.201501009
First Enantioselective Synthesis of Surinamensinol B and a Non-Natural
Polysphorin Analogue by a Two-Stereocentered Hydrolytic Kinetic Resolution
Komal G. Lalwani[a] and Arumugam Sudalai*[a]
Keywords: Total synthesis / Kinetic resolution / Natural products / Biological activity / Enantioselectivity
An efficient and economical approach to the synthesis of
antitumor and anti-inflammatory surinamensinol B (1) and
antimalarial polysphorin analogue 2 has been achieved with
high enantiomeric purity (96% ee) by starting from commer-
cially available 3,4,5-trimethoxybenzaldehyde. The key
steps of the strategy include a Co-catalyzed two-stereocen-
tered hydrolytic kinetic resolution (HKR) of racemic 2-
[(methoxymethoxy)(3,4,5-trimethoxyphenyl)methyl]oxirane
(13) as the chiral inducing step followed by a Mitsunobu re-
action. Chiral epoxide 14 and chiral diol 15 were utilized in
the syntheses of both compounds.
lish that the syn and anti diastereomers were highly active
at hepatic stages against Plasmodium falciparum and Plas-
modium yoeii, the parasites responsible for malaria.
Introduction
Lignans and neolignans, a class of natural products
found in plants, are produced by the oxidative coupling of
two propanoid units, the attachment site of which deter-
mines their classification as lignans (8,8Ј-linkages), neolig-
nans (all other C,CЈ-linkages), or oxyneolignans (C–O–CЈ-
linkages).[1,2] Many have served as lead compounds in the
development of new drugs such as podophyllotoxin, an an-
tibiotic compound that binds to tubulin.[3] Among the 8,4Ј-
oxyneolignan subgroup, various naturally occurring mem-
bers such as surinamensinol B (1),[4] virolin (3),[5] and ra-
phidecursinol B (4)[6] have been isolated from Myristicaceae
and other primitive plant families in neotropical regions,
whereas polysphorin analogue 2[7] was prepared syntheti-
cally (Figure 1). Currently, neolignans have attracted con-
siderable attention because of their reported biological po-
tential against parasites[8] and fungal[9] infections. However,
the secondary plant metabolites (8-O-4Ј-type oxyneolig-
nans) have also exhibited a plethora of other biological
properties, including antimalarial,[8] antitumor,[4] antifun-
gal,[9] and anti-inflammatory[4] activity. Additionally, the
oxidative coupling reactions of coniferyl alcohol and
sinapyl alcohol constitute the biogenetic pathways of lig-
nans and neolignans.[10] Recently, surinamensinol B (1),
which was first isolated from the rhizome extracts of Acorus
gramineus Soland (Araceae), an aquatic perennial her-
baceous plant widely found in Korea, Japan, and China,
showed both antitumor and anti-inflammatory properties.[4]
New polysphorin analogue 2 has been synthesized, and its
antimalarial activity has been evaluated[7] to further estab-
Figure 1. Some members of the bioactive 8-O-4Ј-type oxyneolig-
nans.
Results and Discussion
We recently reported a flexible method that employed the
(salen)CoIII (salen = N,NЈ-bis(salicylidene)ethylenediamine
catalyst in a two-stereocentered hydrolytic kinetic resolu-
tion (HKR) of racemic alkoxy and azido epoxides. This ap-
proach successfully afforded the enantiopure syn and anti
isomers of these epoxides along with the corresponding 1,2-
diols in a single step (Scheme 1).[11] Herein, we describe the
application of this Co-catalyzed HKR strategy to the enan-
tioselective synthesis of the two important bioactive mol-
ecules 1 and 2. This was achieved in high overall yields and
96% ee by starting from commercially available starting
materials.
[a] Chemical Engineering & Process Development Division,
CSIR-National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India
E-mail: a.sudalai@ncl.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501009.
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Enantioselective Synthesis of Surinamensinol B and a Polysphorin Analogue
under basic conditions into syn-epoxy alcohol 12 as the sole
product (91% yield). The free secondary OH group of 12
was readily protected as its methoxymethyl (MOM) ether
to give racemic epoxide 13 (92% yield), which is the precur-
sor to the HKR.[15] Compound 13 was then subjected to
the two-stereocentered hydrolytic kinetic resolution by
using the cobalt catalyst [(R,R)(salen)CoIIIOAc complex
(0.5 mol-%), H2O (0.5 equiv.), 0 °C, 14 h] to give the corre-
sponding enantiopure syn-epoxide 14 (48% yield, 96% ee)
and diol 15 (47% yield, 96% ee). A regioselective reductive
ring-opening reaction of syn-epoxide 14 by treatment with
LiAlH4 furnished secondary alcohol 16 (96% yield),[16]
which is the main fragment for the preparation of surina-
mensinol B (1; Scheme 2).
For the synthesis of fragment 22, vanillin (17) was chosen
as the starting material and then protected as benzyl ether
18 quantitatively. A Wittig olefination of 18 by treatment
with Ph3P=CHCO2Et produced unsaturated ester 19 in
99% yield. A Co-catalyzed complete and simultaneous re-
duction of both the C=C bond and ester functions[17] was
achieved [NaBH4, CoCl2·2H2O (5 mol-%), iPr2NH,
(10 mol-%), EtOH, 60 °C, 12 h] to produce saturated
alcohol 20 (90% yield), which was then protected as MOM
Scheme 1. CoIII-catalyzed hydrolytic kinetic resolution (HKR) to
give syn-alkoxy epoxide.
Our synthesis began with 3,4,5-trimethoxybenzaldehyde
(5), which was subjected to a two-carbon Wittig olefination
by using Ph3P=CHCO2Et to give cinnamate ester 6 in 98%
yield. The osmium-catalyzed dihydroxylation[12] [K2OsO4,
N-methylmorpholine N-oxide (NMO), acetone/H2O (4:1),
0–25 °C, 12 h] of 6 gave syn-diol (Ϯ)-7 in 95% yield, which
was subsequently protected [2,2-dimethoxypropane, cam-
phorsulfonic acid (CSA), CH2Cl2, 25 °C, 6 h] to afford acet-
onide 8 (98% yield).[13] The LiAlH4 reduction of ester 8
produced the corresponding alcohol 9 (93% yield), which
was protected as its tosylate [TsCl (Ts = p-tolylsulfonyl),
Et3N, CH2Cl2, room temp., 3 h] to give 10. The CSA-cata-
lyzed selective removal of the acetonide group[14] of 10 was
achieved to afford diol 11 (99% yield), which was converted
Scheme 2. Reagents and conditions: (i) Ph3P=CHCO2Et, dry CH2Cl2, 25 °C, 6 h, 98%; (ii) K2OsO4·2H2O (2 mol-%), NMO, acetone/
H2O (4:1), 0–25 °C, 20 h, 95%; (iii) 2,2-dimethoxypropane, camphorsulfonic acid (10 mol-%), CH2Cl2, 25 °C, 6 h, 98%; (iv) LiAlH4,
tetrahydrofuran (THF), 0–25 °C, 1 h, 93%; (v) pTsCl, Et3N, 4-(dimethylamino)pyridine (DMAP, 10 mol-%), CH2Cl2, 25 °C, 3 h, 94%;
(vi) camphorsulfonic acid (10 mol-%), CH3OH, 40 °C, 1 h, quant.; (vii) K2CO3, CH3OH, 25 °C, 2 h, 91%; (viii) MOMCl, N,N-diisoprop-
ylethylamine (DIPEA), CH2Cl2, 0 °C, 3 h, 92%; (ix) (R,R)(salen)CoIIIOAc (0.5 mol-%), H2O (0.5 equiv.), 0 °C, 14 h; (x) LiAlH4, THF,
0–25 °C, 1 h, 96%.
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K. G. Lalwani, A. Sudalai
FULL PAPER
ether 21. The debenzylation of 21 was accomplished under which was readily transformed into syn-epoxide 25 (94%
catalytic transfer hydrogenation conditions (10% Pd/C, yield) under basic conditions. The regioselective ring-open-
HCO2NH4, MeOH, 60 °C) to give phenolic derivative 22 ing reaction of epoxide 25 by treatment with LiAlH4 af-
quantitatively. Finally, both fragments 16 and 22 were forded secondary alcohol 26 in 97% yield. Finally, alcohol
coupled under Mitsunobu[18] conditions (Ph3P, iPrO2CN= 26 was coupled with 3,5-dimethoxy-1,1Ј-biphenyl-4-ol
NCO2iPr, THF, 70 °C) to provide MOM ether 23 in 75% (aucuparin, 27)[19] under Mitsunobu conditions to give
yield, which was successfully deprotected under acidic con- MOM ether 28, which underwent deprotection under acidic
ditions to furnish the target molecule surinamensinol B (1) conditions to furnish polysphorin analogue 2 in 90% yield
1
in 90% yield (Scheme 3). Remarkably, the Mitsunobu reac- (Scheme 4). The H and 13C NMR data and other spectro-
tion proceeded smoothly without racemization as con- scopic data of 1 and 2 are in complete agreement with the
firmed by the specific rotation of surinamensinol B (1, reported values.[4,7]
96%ee).
Conclusions
An efficient and straightforward enantioselective synthe-
sis of surinamensinol B (1) and polysphorin analogue 2 has
been described. Our strategy employs the Co-catalyzed two-
stereocentered HKR of racemic epoxide 13 as the key chiral
inducing step. This synthetic approach has significant po-
tential for the preparation of a variety of other biologically
important diastereomers that are part of the 8-O-4Ј-type
neolignan subgroup by suitably employing the (S,S)(salen)-
CoIII(OAc) complex for the HKR step.
Experimental Section
Scheme 3. Reagents and conditions: (i) BnBr, NaH, N,N-dimethyl-
General Methods: Solvents were purified and dried by standard
procedures prior to use. Petroleum ether with a boiling range 60–
80 °C was employed. Optical rotations were measured by using the
sodium D line of a polarimeter. The 1H and 13C NMR spectro-
scopic data were recorded with 200, 400, and 500 MHz spectrome-
ters. HRMS data for new compounds were recorded with an Or-
bitrap mass analyzer associated with an Accela 1250 pump. HPLC
formamide (DMF), room temp., 3 h, quant.; (ii) Ph3P=CHCO2Et,
dry CH2Cl2, 0 °C, 5 h, 99%; (iii) NaBH4, CoCl2·2H2O (5 mol-%),
iPr2NH (10 mol-%), EtOH, 50–60 °C, 12 h, 90%; (iv) MOMCl,
DIPEA, dry CH2Cl2, 0 °C, 1 h, 92%; (v) 10% Pd/C, HCO2NH4,
MeOH, 60 °C, overnight, quant.; (vi) PPh3, iPrO2CN=NCO2iPr,
alcohol fragment 16, THF, 70 °C, 12 h, 75%; (vii) HCl (3 n in
CH3OH), 50 °C, 6 h, 90%.
was performed with
a variable-wavelength detector. Column
Next, chiral diol 15 was employed as the starting material
for the synthesis of polysphorin analogue 2. The selective
protection of the primary alcohol in 15 was achieved in the
presence of Bu2SnO as the catalyst to give tosylate 24,
chromatography was carried out on silica gel (100–200 or 230–
400 mesh). The (R,R)(salen)CoII catalyst and diisopropyl azodicar-
boxylate were purchased from Sigma–Aldrich.
Ethyl (E)-3-(3,4,5-Trimethoxyphenyl)acrylate (6): To a stirred solu-
tion of 3,4,5-trimethoxybenzaldehyde (5; 9.81 g, 50 mmol) in
CH2Cl2 (100 mL) was added Ph3P=CHCO2Et (19.25 g, 55 mmol),
and the resulting mixture was then stirred under N2 for 5 h. Upon
completion of the reaction, the CH2Cl2 was removed by distillation
to give the crude product. Purification by column chromatography
on silica gel (petroleum ether/EtOAc, 90:10) afforded cinnamate 6
(13.32 g, 98% yield) as a colorless solid; m.p. 68–70 °C. Rf = 0.7
(15% ethyl acetate in petroleum ether). IR (CHCl ): ν
= 768,
˜
3
max
980, 1039, 1176, 1203, 1270, 1312, 1367, 1450, 1639, 1705,
1
3063 cm–1. H NMR (200 MHz, CDCl3): δ = 1.34 (t, J = 7.2 Hz,
3 H), 3.86 (s, 3 H), 3.88 (s, 6 H), 4.25 (q, J = 7.2 Hz, 2 H), 6.32 (d,
J = 15.9 Hz, 1 H), 6.73 (s, 2 H), 7.58 (d, J = 15.9 Hz, 1 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 14.2, 55.8, 60.2, 60.6, 105.0,
117.3, 129.7, 139.9, 144.4, 153.2, 166.5 ppm. C14H18O5 (266.29):
calcd. C 63.15, H 6.81; found C 63.02, H 6.71.
Ethyl 2,3-Dihydroxy-3-(3,4,5-trimethoxyphenyl)propanoate (7):
Potassium osmate dihydrate (0.16 g, 0.45 mmol) and N-methyl-
morpholine N-oxide (50% aqueous solution, 10.4 mL, 44.5 mmol)
were added to a solution of cinnamate 6 (6 g, 22.5 mmol) in acet-
one (41.6 mL) at 0 °C. After continuous stirring at 25 °C for 20 h,
the reaction mixture was diluted with CH2Cl2 (40 mL). The mix-
Scheme 4. Reagents and conditions: (i) TsCl, Et3N, Bu2SnO,
CH2Cl2, 0 °C, 2 h, 98%; (ii) K2CO3, MeOH, 0 °C, 1 h, 94%;
(iii) LiAlH4, THF, 0–25 °C, 1 h, 97%; (iv) PPh3, iPrO2CN=
NCO2iPr, aucuparin (27), THF, 70 °C, 12 h, 72%; (v) HCl (3 n in
CH3OH), 50 °C, 6 h, 90%.
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Eur. J. Org. Chem. 2015, 7344–7351

Enantioselective Synthesis of Surinamensinol B and a Polysphorin Analogue
ture was dried with anhydrous Na2SO4 and then concentrated to
give the crude diol, which was purified by column chromatography
on silica gel (petroleum ether/EtOAc, 40:60) to afford diol 7 (6.76 g,
95% yield) as a colorless liquid; Rf = 0.2 (50% ethyl acetate in
(200 MHz, CDCl3): δ = 1.45 (s, 3 H), 1.52 (s, 3 H), 2.46 (s, 3 H),
3.83 (s, 3 H), 3.86 (s, 6 H), 4.09–4.19 (m, 3 H), 4.85 (d, J = 8.3 Hz,
1 H), 6.59 (s, 2 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.76 (d, J = 8.3 Hz,
2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 21.6, 26.7, 27.0, 56.0,
petroleum ether). IR (CHCl ): ν
= 670, 762, 1039, 1182, 1217, 60.6, 67.2, 79.0, 80.4, 103.2, 109.7, 127.9, 129.8, 132.6, 132.9, 138.0,
˜
3
max
1326, 1732, 2362, 3020, 3451 cm–1. 1H NMR (200 MHz, CDCl3): 144.8, 153.5 ppm. HRMS (ESI): calcd. for C22H28O8SNa [M +
δ = 1.30 (t, J = 7.3 Hz, 3 H), 2.84 (d, J = 6.9 Hz, 1 H), 3.19 (d, J
= 6.0 Hz, 1 H), 3.83 (s, 3 H), 3.87 (s, 6 H), 4.29 (q, J = 7.3 Hz, 2
H), 4.35 (dd, J = 2.8, 6.0 Hz, 1 H), 4.94 (dd, J = 2.8, 6.9 Hz, 1 H),
6.64 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.0, 56.0,
60.7, 62.0, 74.5, 74.8, 103.1, 135.8, 137.3, 153.0, 172.6 ppm. HRMS
(ESI): calcd. for C14H20O7Na [M + Na]+ 323.1101; found 323.1102.
Na]+ 475.1397; found 475.1398.
2,3-Dihydroxy-3-(3,4,5-trimethoxyphenyl)propyl 4-Methylbenz-
enesulfonate (11): To a solution of tosylate 10 (2.84 g, 6.27 mmol)
in CH3OH (40 mL) was added camphorsulfonic acid (0.317 g,
0.62 mmol), and the resulting mixture was stirred at 40 °C for 1 h.
The solvent was evaporated, and the residue was extracted with
EtOAc (3ϫ 30 mL). The combined organic phases were dried with
anhydrous Na2SO4 and concentrated to give the crude product,
which was purified by column chromatography on silica gel (petro-
leum ether/EtOAc, 50:50) to give diol 11 (2.57 g, 99% yield) as a
colorless gum. Rf = 0.3 (50% ethyl acetate in petroleum ether).
Ethyl
2,2-Dimethyl-5-(3,4,5-trimethoxyphenyl)-1,3-dioxolane-4-
carboxylate (8): To a solution of diol 7 (2 g, 6.6 mmol) in dry
CH2Cl2 (30 mL) were added 2,2-dimethoxypropane (8 mL) and
camphorsulfonic acid (0.152 g, 0.3 mmol). The reaction mixture
was stirred at 25 °C for 6 h and then diluted with water. The re-
sulting mixture was extracted with CH2Cl2 (3ϫ 50 mL), and the
combined organic phases were dried with anhydrous Na2SO4 and
concentrated under reduced pressure. The crude product was puri-
fied by column chromatography on silica gel (petroleum ether/
EtOAc, 85:15) to furnish 8 (2.3 g, 98% yield) as a colorless solid;
m.p. 57–59 °C. Rf = 0.8 (10% ethyl acetate in petroleum ether). IR
IR (CHCl ): ν
= 688, 771, 1130, 1216, 1470, 1631, 2368, 3028,
˜
3
max
3432 cm–1. 1H NMR (200 MHz, CDCl3): δ = 2.45 (s, 3 H), 3.11
(br. s, 2 H), 3.81 (s, 3 H), 3.83 (s, 6 H), 3.89–3.99 (m, 3 H); 4.62
(d, J = 6.1 Hz, 1 H), 6.54 (s, 2 H), 7.33 (d, J = 8.1 Hz, 2 H), 7.75
(d, J = 8.3 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.5,
55.8, 60.5, 70.4, 73.4, 73.5, 103.3, 127.8, 129.7, 132.2, 135.6, 137.1,
144.8, 152.9 ppm. HRMS (ESI): calcd. for C19H24O8SNa [M +
Na]+ 435.1084; found 435.1085.
(CHCl ): ν
= 682, 721, 834, 1006, 1132, 1235, 1381, 1462, 1595,
˜
3
max
1753, 2990 cm–1. 1H NMR (200 MHz, CDCl3): δ = 1.31 (t, J =
7.2 Hz, 3 H), 1.54 (s, 3 H), 1.61 (s, 3 H), 3.83 (s, 3 H), 3.87 (s, 6
H), 4.27 (q, J = 7.1 Hz, 3 H), 5.11 (d, J = 7.5 Hz, 1 H), 6.64 (s, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2, 25.7, 26.9, 52.3,
55.9, 60.6, 80.5, 81.0, 103.2, 111.4, 133.2, 138.0, 153.3, 170.7 ppm.
HRMS (ESI): calcd. for C17H24O7Na [M + Na]+ 363.1210; found
363.1211.
(Oxiran-2-yl)(3,4,5-trimethoxyphenyl)methanol (12): To a stirred
solution of 11 (2.48 g, 6.02 mmol) in CH3OH (30 mL) was added
anhydrous K2CO3 (1.62 g, 12.04 mmol) at 0 °C. The mixture was
then warmed and stirred at 25 °C. Upon completion of the reaction
(monitored by TLC), an aqueous solution of NaHCO3 (50 mL)
was added, and the mixture was extracted with EtOAc (3ϫ 60 mL).
The combined organic phases were dried with anhydrous Na2SO4
and concentrated to give the crude product, which was purified by
flash column chromatography on silica gel (petroleum ether/
EtOAc, 65:35) to give epoxy alcohol 12 (1.36 g, 91% yield) as a
colorless oil. Rf = 0.4 (30% ethyl acetate in petroleum ether). IR
[2,2-Dimethyl-5-(3,4,5-trimethoxyphenyl)-1,3-dioxolan-4-yl]methan-
ol (9): A solution of ester 8 (2 g, 5.8 mmol) in THF (10 mL) was
added to a stirred slurry of lithium aluminum hydride (0.23 g,
5.8 mmol) in THF (30 mL). After the mixture had been stirred at
25 °C for 1 h, the reaction was carefully quenched with EtOAc and
water. The mixture was then extracted with EtOAc (2ϫ 100 mL),
and the combined organic phases were dried with anhydrous
Na2SO4 and concentrated. The crude product was purified by col-
umn chromatography on silica gel (petroleum ether/EtOAc, 70:30)
to give alcohol 9 (1.64 g, 93% yield) as a colorless gum. Rf = 0.4
(CHCl ): νmax = 690, 748, 1109, 1690, 2408, 2945, 3040, 3420 cm–1.
˜
3
1H NMR (200 MHz, CHCl3): δ = 2.57 (d, J = 4.9 Hz, 1 H), 2.80–
2.89 (m, 2 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 3.88 (s, 3 H); 4.40 (t, J
= 4.9 Hz, 1 H), 6.62 (s, 2 H) ppm. 13C NMR (50 MHz, CHCl3): δ
= 45.1, 55.9, 60.5, 74.3, 103.2, 135.9, 137.5, 153.2 ppm. HRMS
(ESI): calcd. for C12H16O5Na [M + Na]+ 263.0890; found 263.0890.
(30% ethyl acetate in petroleum ether). IR (CHCl ): ν
= 670,
˜
3
max
2-[(Methoxymethoxy)(3,4,5-trimethoxyphenyl)methyl]oxirane (13):
To a solution of epoxy alcohol 12 (1.00 g, 4.1 mmol) and N,N-
diisopropylethylamine (3.60 mL, 20.8 mmol) in dry CH2Cl2
(20 mL) was added methoxymethyl chloride (0.80 mL, 10.2 mmol)
at 0 °C under nitrogen over 5 min. The resulting mixture was
warmed to 25 °C and then stirred for 8 h. After cooling to 0 °C,
the reaction was quenched with water, and the mixture was ex-
tracted with CH2Cl2 (3ϫ 20 mL). The combined organic extracts
were washed with water (3 ϫ 50 mL) and brine, dried with an-
hydrous Na2SO4, and concentrated under reduced pressure. Purifi-
cation of the crude product by column chromatography on silica
gel (petroleum ether/EtOAc, 70:30) gave racemic syn-epoxide 13
(1.15 g, 92% yield) as a colorless oil. Rf = 0.5 (30% ethyl acetate
763, 1128, 1217, 1461, 1595, 2362, 3019, 3422 cm–1. 1H NMR
(200 MHz, CDCl3): δ = 1.52 (s, 3 H), 1.58 (s, 3 H), 1.95 (dd, J =
4.2, 9.0 Hz, 1 H), 3.59–3.69 (m, 1 H), 3.80 (d, J = 2.8 Hz, 1 H),
3.83 (s, 3 H), 3.87 (s, 6 H), 3.92 (d, J = 2.9 Hz, 1 H), 4.85 (d, J =
8.5 Hz, 1 H), 6.59 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 27.0, 27.1, 55.9, 60.2, 60.6, 78.5, 83.3, 103.2, 109.0, 133.3, 137.8,
153.4 ppm. HRMS (ESI): calcd. for C15H22O6Na [M + Na]+
321.1309; found 321.1310.
[2,2-Dimethyl-5-(3,4,5-trimethoxyphenyl)-1,3-dioxolan-4-yl]methyl
4-Methylbenzenesulfonate (10): A solution of alcohol 9 (2 g,
6.7 mmol) in dry CH2Cl2 (50 mL) was treated with p-toluenesulf-
onyl chloride (1.39 g, 7.3 mmol), DMAP (0.081 g, 0.67 mmol), and
Et3N (2.3 mL, 16.7 mmol) at 25 °C. The mixture was stirred for 4 h
and extracted with CH2Cl2 (3ϫ 50 mL). The combined organic
extracts were washed with water, dried with anhydrous Na2SO4,
and concentrated. The crude tosylate was purified by column
in petroleum ether). IR (CHCl ): νmax = 672, 760, 1102, 1209, 1677,
˜
3
2361, 2930, 3026, 3633 cm–1. 1H NMR (200 MHz, CHCl3): δ =
2.64 (dd, J = 2.7, 4.9 Hz, 1 H), 2.77 (t, J = 4.2 Hz, 1 H), 3.16–3.23
(m, 1 H), 3.40 (s, 3 H), 3.84 (s, 3 H), 3.86 (s, 3 H), 3.87 (s, 3 H),
chromatography on silica gel (petroleum ether/EtOAc, 80:20) to 4.25 (d, J = 6.3 Hz, 1 H), 4.52–4.72 (m, 2 H), 6.57 (s, 2 H) ppm.
give tosylate 10 (2.84 g, 94% yield) as a colorless solid; m.p. 45–
47 °C. Rf = 0.5 (20% ethyl acetate in petroleum ether). IR (CHCl3):
13C NMR (50 MHz, CHCl3): δ = 44.4, 55.0, 56.0, 60.6, 78.6, 93.9,
104.1, 133.4, 138.0, 153.4 ppm. C14H20O6 (284.31): calcd. C 59.15,
H 7.09; found C 59.04, H 7.16.
ν
= 690, 762, 1129, 1224, 1631, 2371, 3019 cm–1 1H NMR
.
˜
max
Eur. J. Org. Chem. 2015, 7344–7351
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FULL PAPER
(2S,3S)-3-(Methoxymethoxy)-3-(3,4,5-trimethoxyphenyl)-1,2-epoxy-
propane (14) and (2S,3S)-3-(Methoxymethoxy)-3-(3,4,5-trimethoxy-
at 0 °C, and the resulting mixture was stirred for 15 min. Benzyl
bromide (0.98 mL, 7.887 mmol) was then slowly added, and the
phenyl)propane-1,2-diol (15): To a solution of (R,R)(salen)CoII reaction mixture was stirred at the same temperature for 2 h. A
complex (0.043 g, 0.07 mmol) in toluene (2.0 mL) was added glacial
AcOH (0.04 g, 7.3 mmol). The resulting mixture was stirred at
25 °C in the air for 30 min, over which time the color changed
from orange-red to dark brown. The reaction mixture was then
concentrated in vacuo to obtain the (R,R)(salen)CoIII(OAc) com-
saturated aqueous ammonium chloride solution (20 mL) was
added, and the mixture was extracted with Et2O (3ϫ 50 mL). The
combined organic extracts were washed with brine (50 mL) and
dried with Na2SO4. The solvent was removed under reduced pres-
sure, and the residue was purified by column chromatography on
plex as a brown solid. To a stirred solution of (R,R)(salen)- silica gel (EtOAc/hexane, 1:10) to give benzyl-protected vanillin 18
CoIII(OAc) complex (0.004 g, 0.5 mol-%) and racemic syn-epoxide
(1.57 g, 96% yield) as a colorless solid; m.p. 67–69 °C. Rf = 0.9
13 (400 mg,1.41 mmol) in THF (0.5 mL) at 0 °C was added H2O (10 % ethyl acetate in petroleum ether). 1H NMR (200 MHz,
(0.012 g, 0.7 mmol) dropwise over 5 min. The reaction mixture was CDCl3): δ = 1.84 (quint, J = 6.4 Hz, 2 H), 2.62 (t, J = 8.1 Hz, 2
warmed to 25 °C and then stirred for 14 h. Upon completion of
the reaction (monitored by TLC), the solvent was removed in
vacuo. The crude product was purified by column chromatography
on silica gel (petroleum ether/EtOAc, 70:30) to afford (2S,3S)-3-
(methoxymethoxy)-3-(3,4,5-trimethoxyphenyl)-1,2-epoxypropane
(14; 192 mg, 48% yield) and (petroleum ether/EtOAc, 55:45) the
diol (2R,3R)-3-(methoxymethoxy)-3-(3,4,5-trimethoxyphenyl)prop-
ane-1,2-diol (15; 197 mg, 47% yield) in high enantiomeric excess.
Data for 14: [α]2D5 = +63.5 (c = 0.3, CH3OH); 96% ee. HPLC [Chir-
acel AD-H, 250ϫ4.6 mm; n-hexane/iPrOH, 90:10; 0.5 mLmin–1;
220 nm]: tR = 10.157 (major) and 11.353 min (minor). Rf = 0.5
H), 3.63 (t, J = 6.4 Hz, 2 H), 3.86 (s, 3 H), 5.09 (s, 2 H), 6.61–6.79
(m, 3 H), 7.26–7.43 (m, 5 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 55.9, 70.7, 109.2, 112.3, 126.5, 127.1, 128.1, 128.6, 130.2, 135.9,
149.9, 153.5, 190.8 ppm. MS (ESI): m/z = 265.1 [M + Na]+.
Ethyl (E)-3-[4-(Benzyloxy)-3-methoxyphenyl]acrylate (19): To a
stirred solution of 18 (800 mg, 3.302 mmol) in dichloromethane
(10 mL) was added ethyl (triphenylphosphoranylidene)acetate
(1.733 g, 4.953 mmol), and the mixture was stirred at room tem-
perature for 6 h. Upon completion of the reaction (monitored by
the TLC), the mixture was concentrated in vacuo to give the crude
residue, which was purified by column chromatography on silica
gel (petroleum ether/EtOAc, 1:9) to afford pure 19 (1.03 g, 99%
yield) as a colorless solid; m.p. 64–66 °C. Rf = 0.7 (10% ethyl acet-
(30% ethyl acetate in petroleum ether). IR (CHCl ): ν
= 672,
˜
3
max
760, 1102, 1209, 1677, 2361, 2930, 3026, 3633 cm–1 1H NMR
.
(200 MHz, CHCl3): δ = 2.64 (dd, J = 2.7, 4.9 Hz, 1 H), 2.77 (t, J
= 4.2 Hz, 1 H), 3.16–3.23 (m, 1 H), 3.40 (s, 3 H), 3.84 (s, 3 H), 3.86
(s, 3 H), 3.87 (s, 3 H), 4.25 (d, J = 6.3 Hz, 1 H), 4.52–4.72 (m, 2
H), 6.57 (s, 2 H) ppm. 13C NMR (50 MHz, CHCl3): δ = 44.4, 55.0,
56.0, 60.6, 78.6, 93.9, 104.1, 133.4, 138.0, 153.4 ppm. HRMS (ESI):
calcd. for C14H20O6Na [M + Na]+ 307.1152; found 307.1153. Data
for 15: [α]2D5 = –15.1 (c = 0.65, CH3OH); 96% ee HPLC [Chiracel
1
ate in petroleum ether). H NMR (200 MHz, CDCl3): δ = 1.33 (t,
J = 7.1 Hz, 3 H), 3.91 (s, 3 H), 4.25 (q, J = 7.1 Hz, 2 H), 5.19 (s,
2 H), 6.3 (d, J = 15.9 Hz, 1 H), 6.86 (d, J = 8.1 Hz, 1 H), 7.01–
7.07 (dd, J = 1.8, 12.1 Hz, 2 H), 7.33–7.41 (m, 5 H), 7.60 (d, J =
15.9 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.3, 55.8,
60.2, 70.7, 110.1, 113.3, 116.0, 122.2, 127.1, 127.9, 128.5, 136.5,
144.4, 149.7, 150.1, 167.0 ppm. MS (ESI): m/z = 312.1 [M + H]+.
AD-H, 250 ϫ 4.6 mm; n-hexane/iPrOH, 90:10; 0.5 mL min–1
;
220 nm]: tR = 23.547 (major) and 27.613 min (minor). Rf = 0.7
(15% ethyl acetate in petroleum ether); Rf = 0.1 (30% ethyl acetate
3-[4-(Benzyloxy)-3-methoxyphenyl]propan-1-ol (20): To a stirred
solution of ester 19 (900 mg, 2.881 mmol), CoCl2·6H2O (34.3 mg,
5 mol-%), and diisopropylamine (0.04 mL, 10 mol-%) in 95% eth-
anol (10 mL) was slowly added NaBH4 (218 mg, 5.762 mmol) at
0 °C. The resulting mixture was then stirred at 25 °C for 12 h. Upon
completion (monitored by TLC), the reaction was quenched by the
addition of water (20 mL) and ethyl acetate (20 mL) to form a
black mixture, which was passed through Celite. The organic layer
was separated, and the aqueous layer was extracted with ethyl acet-
ate (2 ϫ 20 mL). The combined organic layers were washed with
brine (2ϫ 20 mL), dried with anhydrous Na2SO4, and concentrated
under reduced pressure to give the crude product. Purification by
column chromatography on silica gel (230–400 mesh; petroleum
ether/ethyl acetate, 70:30) afforded pure alcohol 20 (867 mg, 90%
yield) as a colorless gum. Rf = 0.4 (30% ethyl acetate in petroleum
in petroleum ether). IR (CHCl ): νmax = 670, 748, 840, 1075, 1275,
˜
3
1278, 1385, 1494, 1644, 2920, 3018, 3088, 3458 cm–1 1H NMR
.
(200 MHz, CHCl3): δ = 2.33 (s, 1 H), 3.10 (s, 2 H), 3.42 (s, 3 H),
3.79 (br. s, 1 H), 3.85 (s, 3 H), 3.87 (s, 6 H), 4.55–4.61 (m, 3 H),
4.91 (s, 1 H), 6.58 (s, 2 H) ppm. 13C NMR (50 MHz, CHCl3): δ =
55.9, 56.1, 60.8, 63.2, 74.5, 79.2, 94.6, 104.3 ppm. HRMS (ESI):
calcd. for C14H22O7Na [M + Na]+ 325.1205; found 325.1206.
(1R,2R)-1-(Methoxymethoxy)-1-(3,4,5-trimethoxyphenyl)propan-2-
ol (16): A solution of epoxide 15 (400 mg, 1.406 mmol) in THF
(10 mL) was added to a stirred slurry of lithium aluminum hydride
(81 mg, 2.110 mmol). The resulting mixture was stirred at 25 °C
for 4 h and then carefully quenched with water. The mixture was
extracted with EtOAc (3 ϫ 50 mL), and the combined organic
phases were dried with anhydrous Na2SO4 and concentrated to give
the crude product. Purification by flash column chromatography
on silica gel (petroleum ether/EtOAc, 60:40) gave alcohol 16
(190 mg, 96% yield) as a colorless oil. [α]2D5 = +108.1 (c = 0.64,
CH3OH). Rf = 0.3 (30 % ethyl acetate in petroleum ether). IR
1
ether). H NMR (200 MHz, CDCl3): δ = 1.84 (quint, J = 6.4 Hz,
2 H), 2.62 (t, J = 8.1 Hz, 2 H), 3.63 (t, J = 6.4 Hz, 2 H), 3.86 (s, 3
H), 5.09 (s, 2 H), 6.61–6.79 (m, 3 H), 7.26–7.43 (m, 5 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 31.6, 34.2, 35.9, 62.1, 71.1, 112.3,
114.2, 120.2, 127.2, 128.4, 135.1, 137.3, 146.3, 149.5 ppm. MS
(ESI): m/z = 295.1 [M + Na]+.
(CHCl ): νmax = 690, 762, 1031, 1129, 1217, 1461, 1593, 2363, 3019,
˜
3
1
3452 cm–1. H NMR (200 MHz, CDCl3): δ = 1.02 (d, J = 6.3 Hz,
1-(Benzyloxy)-2-methoxy-4-[3-(methoxymethoxy)propyl]benzene
(21): To an ice-cooled solution of compound 20 (600 mg,
2.201 mmol) in dry CH2Cl2 (10 mL) was added DIPEA (1.1 mL,
3.305 mmol) at 0 °C under N2. After 2 min, MOMCl (0.6 mL,
4.407 mmol) was added, and the reaction mixture was stirred at
room temperature for 2 h. Upon completion of the reaction, water
was added, and the organic layer was separated. The aqueous phase
was extracted with CH2Cl2 (50 mL), and the combined organic lay-
ers were washed with brine (50 mL), dried with anhydrous Na2SO4,
3 H), 2.83 (br. s, 1 H), 3.26–3.38 (m, 1 H), 3.40 (s, 3 H), 3.84 (s, 3
H), 3.86 (s, 6 H), 4.22 (d, J = 7.7 Hz, 1 H), 4.57 (s, 2 H), 6.50 (s,
2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 18.4, 55.8, 56.1, 60.8,
71.1, 83.7, 94.2, 104.7, 134.0, 138.0, 153.4 ppm. HRMS (ESI):
calcd. for C14H22O6Na [M + Na]+ 309.1201; found 309.1202.
4-(Benzyloxy)-3-methoxybenzaldehyde (18): Vanillin (17; 1 g,
6.572 mmol) was added to a suspension of sodium hydride (60%
suspension in mineral oil, 315 mg, 7.887 mmol) in DMF (20 mL)
7348
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 7344–7351

Enantioselective Synthesis of Surinamensinol B and a Polysphorin Analogue
1
and filtered. The filtrate was then concentrated under reduced pres-
sure to obtain a crude product, which was purified by column
chromatography on silica gel (EtOAc/hexane, 10:90) to furnish pure
3389 cm–1. H NMR (200 MHz, CDCl3): δ = 1.16 (d, J = 6.4 Hz,
3 H), 1.88 (quint, J = 6.4 Hz, 2 H), 2.69 (t, J = 8.1 Hz, 2 H), 3.68
(t, J = 6.3 Hz, 2 H), 3.82 (s, 3 H), 3.85 (s, 6 H), 4.33 (dq, J = 3.2,
6.3 Hz, 1 H), 4.80 (d, J = 3.1 Hz, 1 H), 6.56 (s, 2 H), 6.75 (d, J =
compound 21 (1.0 g, 92% yield) as a colorless gum. Rf = 0.6 (10%
ethyl acetate in petroleum ether). H NMR (200 MHz, CDCl3): δ 6.7 Hz, 2 H), 6.93 (d, J = 8.6 Hz, 1 H) ppm. 13C NMR (50 MHz,
= 1.87 (quint, J = 6.4 Hz, 2 H), 2.63 (t, J = 7.2 Hz, 2 H), 3.36 (s, CDCl3): δ = 13.3, 31.8, 34.2, 55.7, 56.0, 60.7, 61.9, 73.8, 81.9, 103.2,
3 H), 3.52 (t, J = 6.4 Hz, 2 H), 3.87 (s, 3 H), 4.6 (s, 2 H), 5.1 (s, 2 112.4, 119.2, 120.9, 135.7, 137.1, 144.6, 151.0, 153.0 ppm. HRMS
1
H), 6.62–6.80 (m, 3 H), 7.30–7.43 (m, 5 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 31.5, 32.0, 55.1, 55.9, 67.0, 71.1, 96.4, 112.3,
114.2, 120.2, 127.2, 127.6, 128.4, 135.1, 137.3, 146.3, 149.5 ppm.
MS (ESI): m/z = 316.2 [M + H]+.
(ESI): calcd. for C22H30O7Na [M + Na]+ 429.1884; found 429.1885.
(2R,3R)-2-Hydroxy-3-(methoxymethoxy)-3-(3,4,5-trimethoxyphen-
yl)propyl 4-Methylbenzenesulfonate (24): A solution of diol 15
(500 mg, 1.654 mmol) in dry CH2Cl2 (20 mL) was treated with p-
toluenesulfonyl chloride (346 mg, 1.819 mmol), dibutyltin(IV) ox-
ide (9.1 mg, 2 mol-%), DMAP (20.2 mg, 0.165 mmol), and Et3N
(0.3 mL, 1.819 mmol) at 25 °C. The reaction mixture was stirred
for 2 h and then extracted with CH2Cl2 (3ϫ 50 mL). The combined
organic extracts were washed with water, dried with anhydrous
Na2SO4, and concentrated to give the crude tosylate, which was
purified by column chromatography on silica gel (petroleum ether/
EtOAc, 80:20) to give tosylate 24 (740 mg, 98% yield) as a colorless
solid; m.p. 72–74 °C. [α]2D5 = –81.3 (c = 0.5, CH3OH). Rf = 0.5
2-Methoxy-4-[3-(methoxymethoxy)propyl]phenol (22): To a solution
of 21 (550 mg, 1.738 mmol) in MeOH (10 mL) were added the cata-
lyst Pd/C (10 % w/w, 55 mg) and ammonium formate (1.096 g,
17.38 mmol). The mixture was heated at reflux for 6 h until the
debenzylation was complete. After cooling, the mixture was fil-
tered, and the solvent was evaporated under reduced pressure. To
the residue was added CHCl3 (5 mL) to precipitate the excess
amount of ammonium formate. The mixture was filtered, and the
solvent was evaporated to give the crude product, which was puri-
fied by column chromatography on silica gel (EtOAc/petroleum
ether, 20:80) to furnish pure product 22 (380 mg, quantitative yield)
as a colorless liquid. Rf = 0.5 (20 % ethyl acetate in petroleum
(20% ethyl acetate in petroleum ether). IR (CHCl ): ν
= 768,
˜
3
max
980, 1039, 1176, 1203, 1270, 1312, 1367, 1450, 1639, 1705, 3063,
3430 cm–1. 1H NMR (200 MHz, CDCl3): δ = 2.45 (s, 3 H), 3.36 (d,
J = 4.7 Hz, 3 H), 3.84 (s, 6 H), 3.85 (s, 3 H), 3.91–4.14 (m, 2 H),
4.18–4.21 (dd, J = 3.3, 5.3 Hz, 1 H), 4.54–4.62 (m, 3 H), 6.54 (s, 2
H), 7.31–7.36 (dd, J = 2.7, 8.5 Hz, 2 H), 7.74–7.81 (dd, J = 3.6,
8.2 Hz, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 21.4, 55.8,
55.9, 60.6, 70.5, 72.2, 78.0, 94.4, 104.2, 127.8, 129.7, 132.6, 132.7,
137.5, 144.8, 153.2 ppm. HRMS (ESI): calcd. for C21H28SO9Na [M
+ Na]+ 479.1309; found 479.1310.
1
ether). H NMR (200 MHz, CDCl3): δ = 1.87 (quint, J = 6.4 Hz,
2 H), 2.63 (t, J = 7.2 Hz, 2 H), 3.37 (s, 3 H), 3.53 (t, J = 6.3 Hz, 2
H), 3.87 (s, 3 H), 4.62 (s, 2 H), 5.47 (s, 1 H), 6.68 (s, 2 H), 6.80 (d,
J = 8.6 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 31.8, 32.1,
55.1, 67.0, 96.4, 111.0, 114.4, 121.0, 133.6, 143.8, 146.4 ppm. MS
(ESI): m/z = 248.1 [M + Na]+.
1,2,3-Trimethoxy-5-[(1S,2R)-2-{2-methoxy-4-[3-(methoxymethoxy)-
propyl]phenoxy}-1-(methoxymethoxy)propyl]benzene (23): To a
stirred solution of chiral alcohol 16 (100 mg, 0.35 mmol), PPh3
(91.49 mg, 0.35 mmol), and diisopropyl azodicarboxylate (70.9 mg,
0.35 mmol) in THF (5 mL) at 0 °C was added 2-methoxy-4-[3-
(methoxymethoxy)propyl]phenol (22; 78.54 mg, 0.35 mmol). The
resulting solution was stirred at 70 °C for 12 h and then concen-
trated in vacuo. The crude compound was purified by column
chromatography on silica gel (petroleum ether/EtOAc, 80:20) to af-
ford aryloxy ether 23 (129 mg, 75 % yield) as a colorless gum.
[α]2D5 = –9.3 (c = 0.3, CH3OH). Rf = 0.4 (20% ethyl acetate in
(R)-2-[(R)-(Methoxymethoxy)(3,4,5-trimethoxyphenyl)methyl]ox-
irane (25): To a stirred solution of 24 (700 mg, 1.533 mmol) in
CH3OH (10 mL) was added anhydrous K2CO3 (635 mg, 4.6 mmol)
at 0 °C. The mixture was then warmed and stirred at 25 °C. Upon
completion of the reaction (monitored by TLC), an aqueous solu-
tion of NaHCO3 (50 mL) was added, and the resulting mixture was
extracted with EtOAc (3ϫ 60 mL). The combined organic phases
were dried with anhydrous Na2SO4 and concentrated to give the
crude product, which was purified by flash column chromatog-
raphy on silica gel (petroleum ether/EtOAc, 65:35) to give syn-ep-
oxide 25 (408 mg, 94% yield) as a colorless oil. [α]2D5 = –63.4 (c =
0.3, CH3OH). Rf = 0.5 (30% ethyl acetate in petroleum ether). IR
petroleum ether). IR (CHCl ): ν
= 1031, 1275, 1508, 1596,
˜
3
max
2947 cm–1. H NMR (500 MHz, CDCl3): δ = 1.36 (d, J = 6.4 Hz,
3 H), 1.88 (quint, J = 6.7 Hz, 2 H), 2.63 (t, J = 7.9 Hz, 2 H), 3.37
(s, 3 H), 3.43 (s, 3 H), 3.54 (t, J = 6.41 Hz, 2 H), 3.78 (s, 3 H), 3.83
(s, 3 H), 3.85 (s, 6 H), 4.41 (quint, J = 5.8 Hz, 1 H), 4.63 (s, 2 H),
4.67 (q, J = 6.7 Hz, 2 H), 4.76 (d, J = 5.2 Hz, 1 H), 6.63–6.69 (m,
5 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.1, 15.3, 20.9, 29.6,
31.4, 31.9, 55.0, 55.5, 55.6, 55.9, 60.2, 60.6, 66.9, 78.9, 79.6, 94.4,
96.3, 104.7, 112.6, 116.6, 120.2, 134.5, 135.4, 137.3, 145.3, 150.3,
152.8, 170.8 ppm. HRMS (ESI): calcd. for C26H38O9Na [M +
Na]+ 517.2411; found 517.2408.
1
(CHCl ): ν
= 690, 748, 1109, 1690, 2408, 2945, 3040, 3633,
˜
3
max
1
3677 cm–1. H NMR (200 MHz, CHCl3): δ = 2.57 (d, J = 4.9 Hz,
1 H), 2.80–2.89 (m, 2 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 3.88 (s, 3 H);
4.40 (t, J = 4.9 Hz, 1 H), 6.62 (s, 2 H) ppm. 13C NMR (50 MHz,
CHCl3): δ = 45.1, 55.9, 60.5, 74.3, 103.2, 135.9, 137.5, 153.2 ppm.
(1R,2R)-1-(Methoxymethoxy)-1-(3,4,5-trimethoxyphenyl)propan-2-
ol (26): By applying the same procedure as that for the preparation
of alcohol 16, epoxide 25 was employed to give alcohol 26 (97%
yield) as a colorless oil. [α]2D5 = –107.8 (c = 0.64, CH3OH). Rf = 0.3
(30% ethyl acetate in petroleum ether). The 1H and 13C NMR spec-
troscopic data are the same as those previously reported for alcohol
16.
(1S,2R)-2-[4-(3-Hydroxypropyl)-2-methoxyphenoxy]-1-(3,4,5-tri-
methoxyphenyl)propan-1-ol (1): To a stirred solution of the aryloxy
ether 23 (80 mg, 0.161 mmol) in CH3OH (1 mL) was added HCl
(3 n in methanol, 5 mL), and the resulting mixture was stirred for
3,5-Dimethoxy-1,1Ј-biphenyl-4-ol (Aucuparin, 27)
4 h and then extracted with EtOAc (3ϫ 10 mL). The combined Step I. 2,6-Dimethoxyphenol (27-I): To a stirred solution of anhy-
organic extracts were washed with brine, dried with anhydrous
Na2SO4, and concentrated under reduced pressure. Purification by
column chromatographic on silica gel (petroleum ether/EtOAc,
60:40) gave surinamensinol B (1; 59 mg, 90% yield) as a colorless
oil. [α]2D5 = –11.3 (c = 0.2, CH3OH). Rf = 0.2 (40% ethyl acetate in
drous ZnCl2 (1.5 g, 11.0 mmol) in propionic acid (5 mL) was added
dropwise a solution of 1,2,3-trimethoxybenzene (1.25 g, 7.5 mmol)
in propionic acid (10 mL) over 5 min. Then the solution was heated
at reflux under nitrogen for 2 h. The solvent was evaporated in
vacuo, and the residue was dissolved in water. The resulting solu-
petroleum ether). IR (CHCl ): νmax = 1034, 1277, 1510, 1601, 2950, tion was extracted with Et2O (3ϫ 20 mL), and the combined ex-
˜
3
Eur. J. Org. Chem. 2015, 7344–7351
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7349

K. G. Lalwani, A. Sudalai
FULL PAPER
tracts were dried with Na2SO4. The Et2O was removed by distil-
lation, and the resulting residue was purified by flash chromatog-
raphy on silica gel (EtOAc/petroleum ether, 1:10) to afford 2,6-di-
Pd/C (30 mg). The resulting solution was stirred at room tempera-
ture under hydrogen for 12 h until the reaction had reached com-
pletion (monitored by TLC). The reaction mixture was filtered
methoxyphenol (27-I; 0.93 g, 82% yield) as a colorless solid; m.p. through a pad of Celite to remove the catalyst, and the filtrate was
46–47 °C. Rf = 0.8 (10 % ethyl acetate in petroleum ether). 1H concentrated in vacuo to obtain 3,5-dimethoxy-1,1Ј-biphenyl-4-ol
NMR (200 MHz, CDCl3): δ = 3.88 (s, 6 H), 5.50 (s, 1 H), 6.55 (d,
J = 8.0 Hz, 2 H), 6.73–6.81 (dd, J = 6.53, 9.0 Hz, 1 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 55.91, 104.70, 118.75, 134.69,
147.01 ppm.
(27; 211 mg, 98% yield) as a colorless solid; m.p. 80–82 °C. Rf =
0.4 (10% ethyl acetate in petroleum ether). 1H NMR (200 MHz,
CDCl3): δ = 3.95 (s, 6 H), 5.5 (s, 1 H), 6.77 (s, 2 H), 7.30 (t, J =
7.3 Hz, 1 H), 7.4 (t, J = 7.9 Hz, 2 H), 7.51 (d, J = 7.0 Hz, 2 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 56.3, 104.0, 126.9, 128.7,
132.8, 134.4, 141.5, 147.2 ppm. HRMS (ESI): calcd. for
C14H14O3Na [M + Na]+ 253.0835; found 253.0835.
Step II. 4-Bromo-2,6-dimethoxyphenol (27-II): To a solution of 27-
I (900 mg, 5.837 mmol) in CHCl3 (20 mL) was added NaH (60 wt.-
% dispersion in mineral oil, 2.3 mg, 1 mol-%) at ambient tempera-
ture. The solution was cooled to –45 °C, and N-bromosuccinimide
(1.038 g, 5.837 mmol) was added in one portion. The mixture was
stirred at –35 °C for 0.5 h and then warmed to ambient temperature
within 0.5 h. After having reached ambient temperature, the solu-
tion was heated to reflux for an additional 0.5 h. The mixture was
then cooled to ambient temperature, and all volatiles were evapo-
rated in vacuo to dryness. The resulting solid was thoroughly ex-
tracted with diethyl ether (50 mL) and then removed by filtration.
The filter cake was again extracted with diethyl ether, and the com-
bined ethereal extracts were concentrated. The residue was purified
by column chromatography on silica gel (EtOAc/petroleum ether,
1:9) to give 27-II (450 mg, 32% yield) as a colorless solid; m.p. 95–
97 °C. Rf = 0.8 (10% ethyl acetate in petroleum ether). 1H NMR
(200 MHz, CDCl3): δ = 3.88 (s, 6 H), 6.70 (s, 2 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 56.3, 108.4, 110.9, 134.0, 147.5 ppm.
3,5-Dimethoxy-4-{[(1R,2S)-1-(methoxymethoxy)-1-(3,4,5-trimeth-
oxyphenyl)propan-2-yl]oxy}-1,1Ј-biphenyl (28): To a stirred solution
of chiral alcohol 26 (80 mg, 0.281 mmol), PPh3 (91.94 mg,
0.281 mmol), and diisopropyl azodicarboxylate (7.9 mg,
0.281 mmol) in THF (5 mL) at 0 °C was added 3,5-dimethoxy-1,1Ј-
biphenyl-4-ol (27; 64.6 mg, 0.281 mmol). The resulting solution was
stirred at 70 °C for 12 h and then concentrated in vacuo. The crude
compound was purified by column chromatography on silica gel
(petroleum ether/EtOAc, 80:20) to afford aryloxy ether 28 (101 mg,
72% yield) as a gum. [α]2D5 = –40.55 (c = 0.1, CHCl3). Rf = 0.3
(20% ethyl acetate in petroleum ether). IR (CHCl ): ν
= 756,
˜
3
max
891, 1052, 1097, 1130, 1190, 1325, 1374, 1485, 1629, 1765, 2928,
1
3015 cm–1. H NMR (500 MHz, CDCl3): δ = 1.29 (d, J = 6.3 Hz,
3 H), 3.42 (s, 3 H), 3.81 (s, 3 H), 3.82 (s, 6 H), 3.84 (s, 6 H), 4.38–
4.50 (quint, J = 6.2 Hz, 1 H), 4.68–4.82 (dd, J = 6.6, 19.8 Hz, 2
Step III. 2-(Benzyloxy)-5-bromo-1,3-dimethoxybenzene (27-III): 4- H), 4.85 (d, J = 4.5 Hz, 1 H), 6.63 (s, 2 H), 6.71 (s, 2 H), 7.30–7.54
Bromo-2,6-dimethoxyphenol (27-II; 400 mg, 1.716 mmol) was
added to a suspension of sodium hydride (76 mg, 60% suspension
in mineral oil, 1.887 mmol) in DMF (15 mL) at 0 °C, and the re-
sulting mixture was stirred for 15 min. Benzyl bromide (0.2 mL,
1.887 mmol) was added slowly, and the reaction mixture was then
stirred at the same temperature for 2 h. Saturated aqueous ammo-
nium chloride (10 mL) was added, and the mixture was extracted
with Et2O (3 ϫ 15 mL). The combined organic extracts were
washed with brine (200 mL) and dried with Na2SO4. The solvent
was removed under reduced pressure, and the residue was purified
by column chromatography on silica gel (EtOAc/petroleum ether,
1:20) to give compound 27-III (480 mg, 98% yield) as a colorless
solid; m.p. 55–57 °C. Rf = 0.8 (5% ethyl acetate in petroleum ether).
1H NMR (200 MHz, CDCl3): δ = 3.8 (s, 6 H), 4.96 (s, 2 H), 7.26–
7.45 (m, 5 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 56.2, 74.9,
108.9, 116.2, 127.9, 128.1, 128.4, 136.1, 137.5, 154.1 ppm.
(m, 5 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 15.0, 55.6, 55.9,
56.0, 60.6, 80.4, 81.8, 95.0, 104.5, 104.7, 126.9, 128.6, 135.3, 135.8,
136.7, 137.1, 141.3, 152.7, 153.6 ppm. HRMS (ESI): calcd. for
C28H34O8Na [M + Na]+ 521.2122; found 521.2123.
(1R,2S)-2-[(3,5-Dimethoxy-1,1Ј-biphenyl-4-yl)oxy]-1-(3,4,5-trimeth-
oxyphenyl)propan-1-ol (2): To a stirred solution of aryloxy ether
28 (80 mg, 0.16 mmol) in CH3OH (1 mL) was added HCl (3 n in
methanol, 5 mL), and the resulting mixture was stirred for 4 h and
then extracted with EtOAc (3ϫ 10 mL). The combined organic
extracts were washed with brine, dried with anhydrous Na2SO4,
and concentrated under reduced pressure. Purification by column
chromatography on silica gel (petroleum ether/EtOAc, 60:40) gave
polysphorin analogue 2 (53 mg, 90% yield) as a colorless gum.
[α]2D5 = –31.24 (c = 0.1, CHCl3). Rf = 0.5 (40% ethyl acetate in
petroleum ether). IR (CHCl ): ν
= 775, 865, 1019, 1068, 1327,
˜
3
max
1413, 1440, 2957, 3471 cm–1. 1H NMR (200 MHz, CDCl3): δ =
1.15 (d, J = 6.4 Hz, 3 H), 3.82 (s, 3 H), 3.86 (s, 6 H), 3.96 (s, 6 H),
4.07 (br. s, 1 H), 4.33–4.43 (m, 1 H), 4.82 (d, J = 2.5 Hz, 1 H), 6.54
(s, 2 H), 6.82 (s, 2 H), 7.34–7.59 (m, 5 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 12.9, 56.1, 56.2, 60.8, 73.2, 82.5, 103.1,
104.6, 127.1, 127.5, 128.8, 134.5, 135.6, 137.0, 137.6, 141.1, 153.1,
153.9 ppm. HRMS (ESI): calcd. for C26H30O7Na [M + Na]+
477.1884; found 477.1887.
Step IV. 4-(Benzyloxy)-3,5-dimethoxy-1,1Ј-biphenyl (27-IV): A mix-
ture of 27-III (450 mg, 1.389 mmol), phenylboronic acid (338.6 mg,
2.778 mmol), and K3PO4 (1.179 g, 5.554 mmol) in toluene/H2O
(8:2 mL) was degassed in a stream of argon for 15 min. To the
mixture was added tetrakis(triphenylphosphine)palladium(0)
(50 mg, 0.069 mmol), and the reaction mixture was again degassed
for 15 min. The mixture was stirred at 90 °C for 16 h and then
filtered through a pad of Celite. This filter cake was washed with
EtOAc (50 mL), and the filtrate was concentrated under reduced
pressure. The obtained residue was purified by column chromatog-
raphy on silica gel (5% EtOAc in petroleum ether) to give the de-
sired product 27-IV (378 mg, 85% yield) as a colorless gum. Rf =
0.9 (5 % ethyl acetate in petroleum ether). 1H NMR(200 MHz,
CDCl3): δ = 3.89 (s, 6 H), 5.04 (s, 2 H), 6.76 (s, 2 H), 7.31–7.54
(m, 10 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 56.1, 75.1, 104.5,
127.0, 127.2, 127.7, 128.1, 128.4, 128.7, 136.6, 137.2, 137.9, 141.4,
153.7 ppm.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all compounds.
Acknowledgments
We sincerely thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi, India and the Department of Science
and Technology-Science and Engineering Research Board (DST-
SERB) (no. SB/S1/OC-42/2014), for the financial support. K. G. L.
thanks the CSIR, New Delhi, India for providing a senior research
fellowship.
Step V. 3,5-Dimethoxy-[1,1Ј-biphenyl]-4-ol (Aucuparin, 27): To a
solution of 27-IV (300 mg, 6.2 mmol) in methanol was added 10%
7350
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Eur. J. Org. Chem. 2015, 7344–7351

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Received: July 31, 2015
Published Online: October 13, 2015
Eur. J. Org. Chem. 2015, 7344–7351
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7351