Total synthesis of (+)-rutamarin

Article abstract of DOI:10.1002/adsc.200800396

The first enantioselective total synthesis of (+)-rutamarin (1) is described. The synthetic route features the highlyenantiose lective construction of the stereogenic center via the Sharpless asymmetric dihydroxylation (99% ee), the facile assemblyof quat

Full text of DOI:10.1002/adsc.200800396

FULL PAPERS
DOI: 10.1002/adsc.200800396
Total Synthesis of (+)-Rutamarin
Yi-Nan Zhang,a Shi-Lei Zhang,b Lei Ma,b Yu Zhang,a Xu Shen,a,* Wei Wang,b,c,*
and Li-Hong Hua,*
a
Shanghai Institute of Materia Medica, Chinese Academyof Science, Zhang-Jiang Hi-Tech Park, Shanghai, 201203,
Peopleꢀs Republic of China
E-mail: xshen@mail.shcnc.ac.cn, simmhulh@mail.shcnc.ac.cn
School of Pharmacy, East China University of Science & Technology, Shanghai, 200237, Peopleꢀs Republic of China
Department of Chemistry& Chemical Biology, Universityof New Mexico, MSC03 2060, Albuquerque, NM 87131-0001,
b
c
USA
Fax : (+1) 505-277-2609; e-mail: wwang@unm.edu
Received: June 25, 2008; Revised: August 31, 2008; Published online: October 1, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800396.
Abstract: The first enantioselective total synthesis of ing materials. Furthermore, the synthetic strategy
(+)-rutamarin (1) is described. The synthetic route could be readilyadopted for the synthesis of ( +)-ru-
features the highlyenantioselective construction of
the stereogenic center via the Sharpless asymmetric
dihydroxylation (99% ee), the facile assemblyof qua-
ternarycarbon-centered 3-substituted side chain and
tamarin analogues.
Keywords: asymmetric synthesis; furanocoumarins;
high synthetic efficiency from readily available start- rutamarin; Sharpless asymmetric dihydroxylation
Introduction
tamarin had not previouslybeen submitted to asym-
metric synthesis. Inspired by the intriguing anti-dia-
Given their structural diversity, complexity, and nov- betic activityof ( +)-rutamarin, we devised a strategy
elty, natural products continue to serve as a rich toward its first asymmetric synthesis. Notably, the syn-
source in the discoveryof biologicallyinteresting mol-
thetic route features the highlyenantioselective con-
ecules.[1] In the recent past, furanocoumarins have re- struction of the stereogenic center via the Sharpless
ceived considerable attention as results of their broad asymmetric dihydroxylation (99% ee), the facile as-
spectrum of intriguing bioactivities. (+)-Rutamarin, 3- semblyof the quaternarycarbon-centered 3-substitut-
substituted 6,7-furanocoumarin (1) (Figure 1), isolated ed side chain and high synthetic efficiency from readi-
from the Ruta graveolens L.[2] exhibited an inhibitory lyavailable starting materials. Furthermore, the gen-
spasmogenic effect on isolated smooth muscle eral synthetic strategy can be readily elaborated for
organs.[3] Recently, (+)-rutamarin (1) was found to the synthesis of (+)-rutamarin analogues.
possess anti-cancer activities against a varietyof
tumor cell lines at micromolecular concentrations.[4]
Importantly, more recently, we found that (+)-ruta- Results and Discussion
marin (1) possesses new biological implications. It
stronglysensitized insulin in the GLUT4 translocating
Despite the fact that (+)-rutamarin (1) has a relative-
[5]
assay, indicating its promising anti-diabetic activity. lysimple structure, the development of an efficient
These results underline the significant potential of approach to this molecule and a general route for the
(+)-rutamatrin (1) as a lead compound for the devel- preparation of its analogues faces several challenges
opment of novel therapeutic agents. Unfortunately, a (Figure 1). First, the versatile and facile construction
major obstacle to further development has been its of the 3-substituted coumarin moietyis a difficult
limited availability. To date, surprisingly, since its re- task. The widelyused approach relies on the Claisen
ported isolation, onlyone synthesis of rutamarin has
or Ireland–Claisen rearrangement.[7] We hypothesized
How- that the coumarin motif could be constructed via an
ever, the Massanet synthesis was racemic, and that ru- aldol condensation between 2 and 3. Such a strategy
[6]
been described byMassanet and co-workers.
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route.[8c] Enders and co-workers developed an asym-
metric organocatalytic strategy to get dihydrobenzo-
furanols with a high ee after necessaryrecrystalliza-
tion.[8d] With the realization of the drawbacks of these
methods, we proposed to employthe reliable and
highly enantioselective Sharpless dihydroxylation re-
action to install the chiral center in 4, which could be
efficientlyconverted to the furan system through an
intramolecular Mitsunobu reaction[9] and meanwhile
[10]
building the quaternarycarbon.
Compound 4 can
be traced back to commerciallyavailable 2,4-dih-y
droxybenzaldehyde 5.
The total synthesis of (+)-rutamarin (1) is shown in
Scheme 1 and Scheme 2. Chemoselective protection
of the 4-hydroxy group in 5 as the methoxymethyl
ether (MOM) was achieved using MOMCl in the
presence of K2CO3 in 81% yield as a result of the
steric effect and the formation of intramolecular H-
bonding between the 2-OH and CHO groups
(Scheme 1). Horner–Emmons reaction of aldehyde 6
with Wittig reagent Ph3P=CHCOOEt under reflux in
dichloromethane gave rise to the highly E selective
cinnamic ethyl ester, which was then protected as
benzyl ether 7 in 86% yield in a two-step transforma-
tion. It was found that the protection form of the 2-
hydroxy group was critical for the subsequent Sharp-
less dihydroxylation reaction. If the protective group
was acetoxyor benzoyl, no oxidation reaction of the
C=C double bond occurred. The standard Sharpless
dihydroxylation reaction using AD-Mix-a was used to
Figure 1. Retrosynthetic analysis of (+)-rutamarin.
enables us to introduce different side chains at posi- oxidize olefin 7 to the keyintermediate chiral diol 4
tion 3 for the synthesis of analogues to help in the in 81% yield and with an excellent level of enantiose-
evaluation of structure-activityrelationships of the
natural product. Second, the highlyenantioselective
lectivity(99% ee) based on chiral HPLC analysis. Ex-
posure of the resulting diol 4 to triethylsilane and tri-
assemblyof the chiral center (e.g., C-2 ’) in the dihy- fluoroacetic acid led to selective reduction of the ben-
drobenzofuran is a challenging task because of the zylic hydroxy group to afford a-hydroxy ester 8 in
bulkytertiaryalcohol moiety. Several methods for es-
76% yield. It should be noted that, before finding the
tablishing the chiral dihydrobenzofuran related to successful route, we also attempted alternative ap-
coumarins have been described. Hayashi reported a proaches to the asymmetric synthesis of the a-hy-
Pd-catalyzed asymmetric Wacker cyclization.[8a] How- droxyester 8 from the enol oxidation of chiral precur-
ever, low yields and ee were observed for trisubstitut- sors of camphorsulfonyloxazirindine or Evanꢀs chiral
ed olefin precursor. Yamagushi used the Sharpless ki- auxiliaries.[11] However, low enantioselectivitywas
netic resolution to obtain the enantiomer.[8b] Thirdly, seen or a longer synthetic sequence was required in
onlypoor regioselectivitywas observed in Sniderꢀs
the transformations.
Scheme 1. Synthesis of intermediate 8.
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Total Synthesis of (+)-Rutamarin
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Scheme 2. Synthesis of (+)-rutamarin 1.
After deprotection of the benzyl group in 8 byPd-
hindrance. Replacement of the acetoxyester with the
catalyzed hydrogenation, the stage was set for the 1-ethoxy-1-ethyl (EE) ether 2 was achieved in 78%
construction of the chiral benzodihydrofuran via an yield for the 3-step conversion. Treatment of ester 3
intramolecular Mitsunobu reaction (Scheme 2). Grati- with LDA at À788C resulted in an enolate, which re-
fyingly, treatment of 8 with triphenylphosphine and acted with aldehyde 2 and then underwent dehydra-
diisopropyl azodicarboxylate furnished the desired tion of the b-hydroxy under the Bartoliꢀs conditions[12]
product 9 with clean inversion of stereochemistryin
directlyto give Z-selective cinnamic methyl ester 12
87% yield. The resulting tertiary alcohol 10 was ob- owing to the steric hindrance of the isoprene unit in
tained in high yield by reaction of excess Grignard re- 79% yield in two steps. The one-pot process for the
agent (MeMgBr) with ester 9. Notably, this method assemblyof ( +)-rutamarin (1) was accomplished
can allow for the introduction of different side chains through Pd
using a varietyof Grignard reagents, thus providing ether, followed byspontaneous lactonization to form
an opportunityfor making analogues of ( +)-rutamar- the coumarin system and finally acetylation of the ter-
in. tiaryalcohol byacetic anhydride in the presence of
(PPh3)4-mediated cleavage of the allyl
With keyintermediate 10 in hand, we attemped to catalytic amount of p-TsOH in 72% yield in the 3-
construct the final species 3-substituted coumarin step transformation. The spectroscopic and analytical
moiety(Scheme 2). It was necessaryto change the
data for synthetic (+)-rutamrin were in full agree-
acid-labile MOM protecting group to an allyl ether ment with those reported for the natural product iso-
due to the following acidic reaction conditions. Cleav- lated from Ruta graveolens L.
age of the methoxymethyl ether by concentrated HCl
in warm methanol was followed byselective protec-
tion of the phenol hydroxy group as the allyl ether al- Conclusions
cohol, which was then acylated by Ac2O to give 11 in
72% overall yield from 9. The next step was to intro- In summary, we have reported the first asymmetric
duce an aldehyde group for the subsequent aldol con- total synthesis of (+)-rutamarin, a natural product
densation reaction. The main concern of the formyla- with a varietyof interesting biological activities. The
tion reaction was regioselectivitybecause it could
strategydeveloped is distinguished bythe highly
occur at positions a and b in 11 (Scheme 2). We were enantioselective construction of the chiral dihydro-
delighted to observe that the employment of the Vils- benzofuran framework via intramolecular Mitsunobu
meier formylation method using POCl3 in DMF at reaction, while the chiral center is established by
808C led to the desired product 2 in excellent regiose- Sharpless asymmetric dihydroxylation. The coumarin
lectivity. No angular product (postion a) was detected moietywas efficientlyinstalled byaldol condensation
in the formylation process presumbably due to steric and subsequent intramolecular lactonization in a one-
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pot process. The approach enables one to accomplish (E)-Ethyl 3-[2-(Benzyloxy)-4-(methoxymethoxy)-
the total synthesis of the natural product in an overall phenyl]acrylate (7)
12% yield from readily available substances with high
A solution of ethyl (triphenylphosphoranylidene)acetate
enantioselectivity(99% ee). Moreover, significantly,
(2.3 g, 6.6 mmol) in CH2Cl2 (10 mL) was added to 6 (1.09 g,
the method can be readilyadopted for the prepara-
6 mmol) in CH2Cl2 (20 mL) dropwise. Then the mixture was
tion of the analogues of (+)-rutamarin that could be
used to evaluate structure-activityrelationships of this
natural product in our on-going medicinal chemistry
program.
refluxed overnight and allowed to cool to room tempera-
ture. The resulting mixture was partitioned between CH2Cl2
and water twice. The combined organic layers were washed
with brine, dried over Na2SO4 and concentrated under
vacuum. The crude product was directlyused in the next
step without further purification.
To a solution of (E)-ethyl 3-[2-hydroxy-4-(methoxyme-
thoxy)phenyl]acrylate and K2CO3 (1.24 g, 9 mmol) in anhy-
drous DMF solution (15 mL) was added benzyl bromide
(0.75 mL, 6.6 mmol). The reaction mixture was stirred at
room temperature for 4 h and quenched with water. The
aqueous layer was extracted three times with EtOAc. The
combined organic layers were washed with brine, dried over
Na2SO4 and concentrated under vacuum. Purification by
column chromatography(50:1, petroluem ether: EtOAc)
provided 7 as a colorless oil; yield: 1.76 g (86% for two
Experimental Section
General
1H (300 MHz) and 13C (75 MHz) NMR spectra were record-
ed on a Varian Mercury-VX300 Fourier transform spectrom-
eter. The chemical shifts were reported in d (ppm) using the
d=7.26 signal of CDCl3 (1H NMR) and the d=77.23 signal
of CDCl3 (13C NMR) as internal standards. The following
abbreviations were used to describe the multiplicities: s=
singlet, d=doublet, t=triplet, q=quartet, m=multiplet.
LC-ESI-MS was run on a Bruker Esquire 3000 plus spec-
trometer in MeOH and HR-ESI-MS was run on a Bruker
Atex III spectrometer in MeOH, respectively. Optical rota-
tions were determined on a Perkin–Elmer 341 polarimeter
at room temperature. The enantiomeric excess was deter-
mined byHPLC with a Chiralpak AD-H, OD-H and AS-H
column, 258C compared with the racemic or conformational
isomer.
1
steps). H NMR (CDCl3, 300 MHz): d=8.00 (d, J=16.2 Hz,
1H), 7.47–7.32 (m, 6H), 6.65 (m, 2H), 6.44 (d, J=16.2 Hz,
1H), 5.15 (s, 2H), 5.14 (s, 2H), 4.23 (q, J=7.2 Hz, 2H), 3.45
(s, 3H), 1.31 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d=167.7, 160.1, 158.6, 139.6, 136.4, 129.9, 128.6”
2, 128.0, 127.2”2, 117.7, 116.6, 108.3, 101.4, 94.2, 70.3, 60.1,
56.1, 14.3; ESI-HR-MS: m/z=365.1357, calcd. for
C20H22O5Na [M+Na]+: 365.1365; anal. calcd. for C20H22O5:
C 70.16, H 6.48; found: C 70.31, H 6.60.
All commerciallyavailable reagents were used without
further purification. The solvents used were all AR (a stan-
dard grade of analytical reagents) grade and were redistilled
under a positive pressure of drynitrogen atmosphere in the
presence of a proper desiccant when necessary. The progress
of the reactions was monitored byanalytical thin-layer chro-
matography(TLC) on HSGF 254 precoated silica gel plates.
(2R,3S)-Ethyl 3-[2-(Benzyloxy)-4-(methoxymethoxy)-
phenyl]-2,3-dihydroxypropanoate (4)
To a mixed solution (t-BuOH/H2O, 25 mL/25 mL) of 7
(1.76 g, 5.14 mmol) and methanesulfonamide (513 mg,
5.4 mmol), AD-mix-a (Aldrich-Sigma, 7.56 g, 5.4 mmol) was
added byportions over 1 h under an ice bath. Then, the re-
action mixture was allowed to warm to room temperature
and stirred for 3 d. After quenching with saturated NaHSO3
aqueous solution, the resulting mixture was extracted by
EtOAc for three times. The combined organic layers were
washed with water, brine, dried over Na2SO4 and concen-
trated under vacuum. Purification bycolumn chromatogra-
phy(3:1, petroluem ether: EtOAc) provided 4 as a colorless
2-Hydroxy-4-(methoxymethoxy)benzaldehyde (6)
To
a mixture of 2,4-dihydroxybenzaldehyde 5 (8.28 g,
60 mmol) and K2CO3 in acetone (60 mL) was added the
MOMCl (4.8 mL, 63 mmol) dropwise. After addition, the re-
action mixture was warmed to reflux for 3 h. After removal
of the solvent, the resulting mixture was partitioned be-
tween EtOAc and water twice. The combined organic layers
were washed with brine, dried over Na2SO4 and concentrat-
ed under vacuum. Purification bycolumn chromatography
[50:1, petroluem ether (60~908C) : EtOAc] provided 6 as a
colorless solid; yield: 8.87 g (81%). 1H NMR (CDCl3,
300 MHz): d=11.35 (s, 1H), 9.71 (s, 1H), 7.42 (d, J=8.4 Hz,
1H), 6.63 (dd, J=2.1, 8.4 Hz, 1H), 6.58 (d, J=2.1 Hz , 1H),
5.20 (s, 2H), 3.46 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=
194.8, 164.4, 164.2, 135.5, 116.0, 109.2, 103.5, 94.2, 56.6; ESI-
HR-MS: m/z=205.0480, calcd. for C9H10O4Na [M+Na]+:
205.0477; anal. calcd. for C9H10O4: C 59.34, H 5.53; found: C
59.30, H, 5.57.
1
solid; yield: 1.57 g (81%). H NMR (CDCl3, 300 MHz): d=
7.45–7.34 (m, 6H), 6.67 (m, 2H), 5.38 (d, J=7.5 Hz, 1H),
5.13 (s, 2H), 5.04 (d, J=3.3 Hz, 2H), 4.47 (dd, J=2.4,
6.6 Hz, 1H), 4.20 (m, 2H), 3.45 (s, 3H), 1.21 (t, J=7.2 Hz,
3H); 13C NMR (CDCl3, 75 MHz): d=173.2, 157.9, 155.8,
136.6, 128.5”2, 127.9, 127.8, 127.0”2, 122.2, 107.6, 100.8,
94.4, 73.4, 69.9, 69.8, 61.7, 55.9, 14.1; ESI-HR-MS: m/z=
375.1427, calcd. for C20H23O7 [M-H]+: 375.1444; anal. calcd.
for C20H24O7: C 63.82, H 6.43; found: C 64.15, H 6.39; [a]2D0:
0.0 (c 0.90, CHCl3). The enantiomeric excess was deter-
mined byHPLC with a Chiralpak AS-H column (hexane:
2-propanol 70:30), 258C, l=254 nm, 1.0 mLminÀ1, ee value:
99%, major enantiomer t2R,3S =17.47 min, minor enantiomer
t
2S,3R =13.26 min.
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Total Synthesis of (+)-Rutamarin
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with TLC monitoring at 08C and quenched with saturated
aqueous NH4Cl solution. The resulting mixture was parti-
tioned between EtOAc and water twice. The combined or-
ganic layers were washed with brine, dried over Na2SO4 and
concentrated under vacuum. The ee value of the crude prod-
uct 10 was found to be 97%. The enantiomeric excess was
determined byHPLC with a Chiralpak OD-H column
(hexane:2-propanol 95:5), 258C, l =254 nm, 0.6 mLminÀ1,
major enantiomer tS =16.45 min, minor enantiomer tR =
18.68 min.
Crude (S)-2-[6-(methoxymethoxy)-2,3-dihydrobenzofuran-
2-yl]propan-2-ol 10 was dissolved in MeOH (25 mL) with
concentrated HCl (0.2 mL) added. Then, the mixture was al-
lowed to warm to 458C with stirring for 1 h. After evapora-
tion of the superfluous solution, the resulting mixture was
partitioned between EtOAc and water twice. The combined
organic layers were washed with brine, dried over Na2SO4
and concentrated under vacuum. The product was directly
used in the next step without purification.
To a solution of 2-(2-hydroxypropan-2-yl)-2,3-dihydroben-
zofuran-6-ol and K2CO3 (414 mg, 3 mmol) in anhydrous
DMF solution (5 mL) was added allyl bromide (0.26 mL,
3 mmol). The reaction mixture was stirred at room tempera-
ture overnight and quenched with water. The aqueous layer
was extracted three times with EtOAc. The combined or-
ganic layers were washed with brine, dried over Na2SO4 and
concentrated under vacuum. Then, the crude product was
dissolved in acetic anhydride (2 mL) with a catalytic amount
of p-toluenesulfonic acid (21 mg, 0.12 mmol). The mixture
was stirred for 1 h at room temperature and water was
added followed byadditional stirring for 0.5 h. The aqueous
layer was extracted with Et2O twice. The combined organic
layer was washed with saturated NaHCO3, brine, dried over
Na2SO4 and concentrated under vacuum. Purification by
column chromatography(70:1, petroluem ether: EtOAc) af-
forded 11 as a colorless oil; yield: 500 mg (72% from 9).
1H NMR (CDCl3, 300 MHz): d=6.93 (d, J=8.7 Hz, 1H),
6.34 (m, 2H), 5.99–5.92 (m, 1H), 5.33 (dd, J=1.5, 17.1 Hz,
1H), 5.21–5.17 (m, 1H), 4.90 (t, J=8.7 Hz, 1H), 4.41 (dd,
J=1.5, 3.9 Hz, 2H), 3.10–2.92 (m, 2H), 1.92 (s, 3H), 1.48 (s,
3H), 1.42 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=170.4,
161.0, 159.3, 133.4, 124.7, 118.6, 117.6, 106.9, 96.8, 87.6, 82.7,
69.1, 30.2, 22.5, 21.9, 21.0; ESI-HR-MS: m/z=299.1239,
calcd. for C16H20O4Na [M+Na]+: 299.1259; [a]20: +43.2 (c
0.60, CHCl3); anal. calcd. for C16H20O4: C 69.D54, H 7.30;
found: C 69.71, H 7.56.
(R)-Ethyl 3-[2-(Benzyloxy)-4-(methoxymethoxy)-
phenyl]-2-hydroxypropanoate (8)
To a solution of 4 (1.5 g 4 mmol) in anhydrous CH2Cl2
(40 mL) under argon, triethylsilane (1.96 mL, 12 mmol) and
trifluoroacetic acid (3 mL, 40 mmol) were added in se-
quence under ice bath conditions. The reaction mixture was
stirred for about 1 h with TLC monitoring at 08C and
quenched with saturated aqueous NaHCO3 solution careful-
ly. After that, the resulting mixture was extracted by EtOAc
for three times. The combined organic layers were washed
with water, brine, dried over Na2SO4 and concentrated
under vacuum. Purification bycolumn chromatography
(10:1, petroluem ether: EtOAc) provided 8 as a colorless
oil; yield: 1.09 g (76%). 1H NMR (CDCl3, 300 MHz): d=
7.43–7.32 (m, 5H), 7.08 (d, J=8.1 Hz, 1H), 6.66 (s, 1H),
6.61 (dd, J=2.1, 8.1 Hz, 1H), 5.14 (s, 2H), 5.07 (s, 2H), 4.45
(m, 1H), 4.10 (m, 2H), 3.47 (s, 3H), 3.20 (dd, J=4.2,
13.5 Hz, 1H), 2.91 (m, 1H), 1.19 (t, J=7.2 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d=174.8, 157.7, 157.6, 136.9,
132.1, 128.8”2, 128.1, 127.3”2, 118.9, 107.8, 101.5, 94.7,
70.8, 70.2, 61.6, 56.2, 35.7, 14.3; ESI-HR-MS: m/z=
383.1472, calcd. for C20H24O6Na [M+Na]+: 383.1471; anal.
calcd. for C20H26O4: C 66.65, H 6.71; found: C 66.79, H 6.80;
[a]2D0: À6.7 (c 0.90, CHCl3).
(S)-Ethyl 6-(Methoxymethoxy)-2,3-dihydrobenzo-
furan-2-carboxylate (9)
A mixture of 8 (1.08 g, 3 mmol), 10% Pd/C (0.5 g) in EtOAc
(15 mL) was stirred under an atmosphere of H2 overnight.
After that, the mixture was filtered through a fritted funnel
and the filtrate was concentrated under vacuum. The prod-
uct was directlyused in the next step without purification.
To a solution of (R)-ethyl 3-[4-(methoxymethoxy)phenyl]-
2-hydroxypropanoate and triphenylphosphine (865 mg,
3.3 mmol) in anhydrous THF was added diisopropyl azodi-
carboxylate (0.7 mL, 3.6 mmol) under ice bath conditions.
The reaction mixture was allowed to warm to room temper-
ature and stirred for 4 h. After evaporating the superfluous
solution, the resulting mixture was partitioned between
EtOAc and water twice. The combined organic layers were
washed with brine, dried over Na2SO4 and concentrated
under vacuum. Purification bycolumn chromatography
(50:1, petroluem ether: EtOAc) afforded 9 as a colorless
oil; yield: 0.66 g (87% for two steps). 1H NMR (CDCl3,
300 MHz): d=7.02 (d, J=8.1 Hz, 1H), 6.62 (d, J=2.1 Hz,
1H), 6.55 (dd, J=2.1, 8.1 Hz, 1H), 5.18 (dd, J=6.9, 10.5 Hz,
1H), 5.10 (s, 2H), 4.24 (q, J=7.2 Hz, 2H), 3.51–3.45 (m,
1H), 3.44 (s, 3H), 3.27 (dd, J=6.9, 15.3 Hz, 1H), 1.19 (t, J=
7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d=171.3, 160.3,
158.1, 124.8, 118.1, 109.1, 99.1, 94.7, 79.9, 61.7, 56.0, 33.4,
14.3; ESI-HR-MS: m/z=275.0907, calcd. for C13H16O5Na
[M+Na]+: 275.0895; anal. calcd. for C13H16O5: C 61.90, H
6.39; found: C 62.13, H 6.42; [a]2D0: À42.7 (c 1.80, CHCl3).
(S)-6-(Allyloxy)-2-[2-(1-ethoxyethoxy)propan-2-yl]-
2,3-dihydrobenzofuran-5-carbaldehyde (2)
To a solution of 11 (442 mg, 1.6 mmol) in anhydrous DMF,
phosphoryl trichloride (0.3 mL, 3.2 mmol) was added drop-
wiselyat room temperature. The reaction mixture was
stirred at 808C for 1 h and then allowed to cool to room
temperature. After quenching with water, the resulting mix-
ture was extracted byEt 2O twice. The combined organic
layer was washed with saturated NaHCO3, brine, dried over
Na2SO4 and concentrated under vacuum. The product was
directlyused in the next step without purification.
(S)-2-[6-(Allyloxy)-2,3-dihydrobenzofuran-2-
yl]propan-2-yl Acetate (11)
To a solution of 9 (630 mg, 2.5 mmol) in anhydrous THF
(20 mL) under argon was added slowlya solution of methyl-
magnesium bromide (2.5 mL, 3M in THF) under ice bath
conditions. The reaction mixture was stirred for about 1 h
The crude product from above was hydrolyzed in a solu-
tion of 5N NaOH (1 mL), MeOH (1 mL) and THF (2 mL)
at room temperarure overnight. After neutralizing the su-
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Yi-Nan Zhang et al.
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perfluous base with 2N HCl, the mixture was partitioned
between EtOAc and water twice, dried over Na2SO4, and
evaporated under vacuum. Without further purification, the
residue was directlydissolved in anhydrous CH 2Cl2 with a
catalytic amount of pyridinium p-toluenesulfonate (10 mg,
0.03 mmol). Ethyl vinyl ether (0.19 mL, 2 mmol) was added
to the mixture and the reaction was stirred for 4 h. The re-
sulting mixture was participated between CH2Cl2 and water
twice. The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated under vacuum. Purifi-
cation bycolumn chromatography(20:1, petroluem ether:
EtOAc) afforded 2 as a colorless oil; yield: 420 mg (78% for
160.6, 156.7, 145.9, 139.8, 133.2, 124.8, 123.8, 118.6, 118.2,
116.8, 111.9, 94.8, 90.5, 71.8, 69.1, 51.5, 41.5, 30.1, 26.7”2,
26.0, 24.1; ESI-HR-MS: m/z=409.2008, calcd. for
C23H30O5Na [M+Na]+: 409.1991; anal. calcd. for C23H30O5:
C 71.48, H 7.82; found: C 71.59, H 7.88; [a]2D0: +35.4 (c 0.35,
CHCl3).
(+)-Rutamarin (1)
To a stirred solution of 12 (347 mg, 0.9 mmol) in MeOH was
added catalytic amounts of tetrakis(triphenylphosphine)pal-
ladium (20 mg, 0.018 mmol) under argon at room tempera-
ture. The slightlyyellow solution was stirred for 5 min, and
K2CO3 (373 mg, 2.7 mmol) was added with replacement of
argon once again. The reaction mixture was stirred for 3 h
and then quenched when open to fresh air. The resulting
mixture was partitioned between CH2Cl2 and water twice.
The combined organic layers were washed with brine, dried
over Na2SO4 and concentrated under vacuum. Then, the
crude product was dissolved in acetic anhydride (2 mL) with
catalytic amount of p-toluenesulfonic acid (8 mg,
0.045 mmol). The mixture was stirred for 1 h at rrom tem-
perature and water was added followed byadditional stir-
ring for 0.5 h. The aqueous layer was extracted with Et2O
twice. The combined organic layer was washed with saturat-
ed NaHCO3, brine, dried over Na2SO4 and concentrated
under vacuum. Purification bycolumn chromatography
(20:1, petroluem ether: EtOAc) afforded 1 as a colorless
1
three steps). H NMR (CDCl3, 300 MHz): d=10.27 (s, 1H),
7.61 (s, 1H), 6.33 (s, 1H), 6.06–5.96 (m, 1H), 5.40 (dd, J=
1.5, 17.1 Hz, 1H), 5.28 (dd, J=1.5, 10.5 Hz, 1H), 4.97 (t, J=
8.4 Hz, 1H), 4.74–4.66 (m, 1H), 4.55 (dd, J=1.5, 3.9 Hz,
2H), 3.51–3.39 (m, 2H), 3.16–3.06 (m, 2H), 1.29–0.76 (m,
12H); 13C NMR (CDCl3, 75 MHz): d=188.2, 167.0 (166.9),
163.3, 132.4, 124.5 (124.5), 120.5, 120.4, 119.0, 118.1, 94.5
(94.2, 94.2, 94.1), 91.0 (90.9), 76.6 (76.4), 69.4, 58.7 (58.5),
29.5 (29.3), 24.0, 22.8 (22.6), 21.7 (21.7, 21.3, 21.2), 15.6
(15.5); ESI-HR-MS: m/z=357.1684, calcd. for C19H26O5Na
[M+Na]+: 357.1678; anal. calcd. for C19H26O5: C 68.24, H
7.84; found: C 68.44, H 7.94.
(S,Z)-Methyl 2-{[6-(Allyloxy)-2-(2-hydroxypropan-2-
yl)-2,3-dihydrobenzofuran-5-yl]ethylene}-3,3-
dimethylpent-4-enoate (12)
1
solid; yield: 500 mg (72% for two steps). H NMR (CDCl3,
300 MHz): d=7.44 (s, 1H), 7.17 (s, 1H), 6.63, (s, 1H), 6.11
(dd, J=10.5, 18.0 Hz, 1H), 5.05–5.00 (m, 3H), 3.22–3.13 (m,
2H), 1.94 (s, 3H), 1.51 (s, 3H), 1.47 (s, 3H), 1.41 (s, 6H);
13C NMR (CDCl3, 75 MHz): d=170.3, 162.5, 160.2, 154.7,
145.6, 138.2, 130.8, 124.0, 123.2, 113.1, 112.1, 97.1, 88.4, 82.2,
40.3, 29.7, 26.2”2, 22.4, 22.0, 21.1; ESI-HR-MS: m/z=
357.1710, calcd. for C21H25O5 [M+H]+: 357.1702; anal.
calcd. for C21H25O5: C 70.77, H 6.79; found: C 70.90, H 6.91;
[a]20: +24.6 (c 0.35, CHCl3). The enantiomeric excess was
detDermined byHPLC with a Chiralpak AD-H column
(hexane:2-propanol 70:30), 258C, l =210 nm, 1.0 mLminÀ1,
ee value: 99%, major enantiomer tS =6.92 min, minor enan-
tiomer tR =11.65 min.
Anhydrous THF (2 mL) and diisopropylamine (0.24 mL,
1.7 mmol) were placed in a flask under argon in an ice bath.
n-Butyllithium (0.65 mL, 2.2M in hexane) was added drop-
wise over 5 min. The reaction mixture was stirred for addi-
tional 10 min to complete LDA formation and cooled to
À788C with an dryice-acetone bath. The 3,3-dimethylpenta-
noic methyl ester (200 mg, 1.44 mmol) in 2 mL of THF was
then added to the LDA solution over a period of 5 min and
then the mixture was stirred for another 90 min to afford
the lithium ester enolate. To this solution maintained at
À788C, 2 (400 mg, 1.2 mmol) in 2 mL of THF was added
during 5 min. After stirring for 2 h, the reaction mixture was
quenched byadding 1 mL of saturated NH Cl solution, fol-
4
lowed bywater and EtOAc. The aqueous layer was extract
with EtOAc twice. The combined organic layer was washed
with water, brine, dried over Na2SO4 and concentrated
under vacuum. Without further purification, the residue was
dissolved in 12 mL of CH3CN with cerium chloride heptahy-
drate (670 mg, 1.8 mmol) and sodium iodide (270 mg,
1.8 mmol). The resulting mixture was stirred for 4 h at re-
fluxing temperature. After quenching with saturated
NaHSO3 solution, the resulting mixture was extracted by
Et2O twice. The combined organic layer was washed with
saturated NaHCO3, brine, dried over Na2SO4 and concen-
trated under vacuum. Purification bycolumn chromatogra-
phy(10:1, petroluem ether: EtOAc) afforded 12 as a color-
less oil; yield: 230 mg (78.8% for two steps). 1H NMR
(CDCl3, 300 MHz): d=6.96 (s, 1H), 6.78 (s, 1H), 6.31 (s,
1H), 6.00–5.91 (m, 2H), 5.40 (d, J=16.8 Hz, 1H), 5.23 (d,
J=10.8 Hz, 1H), 5.08 (d, J=17.1 Hz, 1H), 5.03 (d, J=
9.6 Hz, 1H), 4.57 (t, J=9 Hz, 1H), 4.42 (d, J=3.3 Hz, 2H),
3.57 (s, 3H), 3.00 (d, J=8.7 Hz, 2H), 1.30 (s, 6H), 1.24 (s,
3H), 1.16 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=171.2,
GLUT4 Membrane Translocation Assay
The CHO-K1/GLUT4 cells were grown in a 96-well plate at
a densityof 10,000 cells/well before compound incubation.
Compound 2 and rutamarin were dissolved in DMSO and
stored at À208C. Before experiment, the compounds were
diluted in the F-12 culture medium for cell incubation. An
equal concentration of DMSO was used as the vehicle con-
trol. The cells were starved and pre-incubated with com-
pounds for 8 h, and then were stimulated with insulin
(80 nM) for 5 min. Immediatelyafter stimulation, the cells
were fixed with 3.7% formaldehyde. The plasma membrane-
bound GLUT4 was determined byimmunoctyochemistr.y
Briefly, the fixed cells were incubated with anti-c-myc pri-
maryantibodyand subsequentlythe Cy5-conjugated secon-
daryantibod.y The whole procedure was detergent-free, so
onlymembrane GLUT4 could be stained. Membrane-asso-
ciated GLUT4 was quantified bycalculating the intensityof
Cy5 fluorescence. Similarly, the total GLUT4 was evaluated
through calculating the intensityof GFP fluorescence. The
2378
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ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2373 – 2379

Total Synthesis of (+)-Rutamarin
FULL PAPERS
relative membrane translocation ratio was therefore deter-
mined byevaluating the fluorescence ratio of membrane/
total GLUT4. Data from the IN Cell Analyzer 1000 were
analyzed by using the IN Cell Analyzer workstation version
3.2. Paired Studentꢀs t test was performed to determine the
statistical significance, and unless otherwise indicated, n=6.
A P value <0.05 was thought to be statisticallysignificant.
[5] See Supporting Information for details.
[6] G. M. Massanet, E. Pando, F. Rodriguez-Luiz, J. Salva,
Heterocycles 1987, 26, 1541–1548.
[7] a) V. K. Ahluwalia, R. P. Singh, S. Bala, Tetradedron
Lett. 1982, 23, 2049–2050; b) R. Hernandez-Galan, J.
Salva, G. M. Massanet, I. G. Collado, Tetrahedron 1993,
49, 1701–1710.
[8] a) Y. Uozumi, K. Kato, T. Hayashi, J. Am. Chem. Soc.
1997, 119, 5063–5064; b) S. Yamaguchi, S. Muro, M.
Kobayashi, M. Miyazawa, Y. Hirai, J. Org. Chem. 2003,
68, 6274–6278; c) Y. Zou, M. Lobera, B. B. Snider, J.
Org. Chem. 2005, 70, 1761–1770; d) D. Enders, O. Nie-
meier, L. Strawer, Synlett 2006, 20, 3399–3402.
[9] C. Ahn, R. Correia, P. DeShong, J. Org. Chem. 2002,
67, 1751–1753.
Acknowledgements
Financial support for this work was provided by the key pro-
gram of the Chinese NSFC (90713046) and the Chinese Na-
tional High-tech R&D Program (2007AA02Z147).
[10] a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A.
Crispino, J. Hartung, K. S. Jeong, H. L. Kwong, K. Mor-
ikawa, Z. M. Wang, D. Xu, X. L. Zhang, J. Org. Chem.
1992, 57, 2768–2771; b) H. C. Kolb, M. S. VanNieu-
wenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 6274–
6278.
[11] F. A. Davis, B. C. Chen, Chem. Rev. 1992, 92, 919–934.
[12] G. Bartoli, M. C. Bullucei, M. Petrini, E. Marcantoni,
L. Sambri, E. Torregiani, Org. Lett. 2000, 2, 1791–1793.
References
[1] M. S. Butler, Nat. Prod. Rep. 2005, 22, 162–195.
[2] J. Reisch, I. Novak, K. Szendrei, E. Minker, Acta.
Pharm. Suec. 1967, 4, 179–181.
[3] E. Minker, C. Batha, Z. Rozsa, K. Szendrei, J. Reisch,
Plant Med. 1979, 37, 156–160.
[4] Q. Y. Yang, X. Y. Tian, W. S. Fang, J. Asian Nat. Prod.
Res. 2007, 9, 59–65.
Adv. Synth. Catal. 2008, 350, 2373 – 2379
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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