Novel synthesis of naturally occurring pulvinones: A heck coupling, transesterification, and Dieckmann condensation strategy

Article abstract of DOI:10.1055/s-2007-983803

Phosphine-free Heck alkenylations of iodoarenes with trifluoroethyl 2-acetoxyacrylate (19) led stereoselectively to trifluoroethyl (Z)-2-acetoxycinnamates 31-34, 42, 44, and 51. Deacetylation followed by acylation with N,N′-dicyclohexylcarbodiimide activa

Full text of DOI:10.1055/s-2007-983803

PAPER
2249
Novel Synthesis of Naturally Occurring Pulvinones: A Heck Coupling,
Transesterification, and Dieckmann Condensation Strategy
N
ovel Synthesis of
a
N
aturally
v
O
ccurring Pu
i
lvinon
d
es Bernier, Reinhard Brückner*
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität, Albertstr. 21, 79104 Freiburg, Germany
Fax +49(761)2036100; E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
Received 14 May 2007
This paper is dedicated to Prof. Paul A. Wender on the occasion of his 60th birthday.
Table 1 Selected Naturally Occurring Pulvinones
Abstract: Phosphine-free Heck alkenylations of iodoarenes with
trifluoroethyl 2-acetoxyacrylate (19) led stereoselectively to trifluo-
roethyl (Z)-2-acetoxycinnamates 31–34, 42, 44, and 51. Deacetyla-
tion followed by acylation with N,N¢-dicyclohexylcarbodiimide
activated arylacetic acids yielded the isomerically pure trifluoro-
ethyl (Z)-2-(arylacetoxy)cinnamates 38a–o. These were excellent
substrates of potassium tert-butoxide mediated Dieckmann conden-
sations, and distinctly superior to fluorine-free analogues, furnish-
ing Z-configured pulvinones 1a–o (1i = aspulvinone A). Cleavage
of the aryl ether moieties of pulvinones 1d,e,h,n,o provided aspul-
vinone E (1r), aspulvinone G (1s), 3¢,4,4¢-trihydroxypulvinone (1v),
and aspulvinones B (1x) and H (1y), respectively. The conversion
of the 2,4-diiodophenyl ethers 48 and 49 into the 4-iodo-2-pre-
nylphenyl ethers 46 and 50, respectively, was effected by unprece-
dented ortho-selective iodine–magnesium exchange reactions
followed by prenylation.
R2
CO H
R2
OH
OH
2
R1
R1
O
O
O
O
2
1
R2
1
aspulvinone
R1
(3¢,4,4¢-trihy-
droxypulvi-
none)
OH
HO
HO
1v
X
X
X
OH
O
1r
1s
X = H: E
X = OH: G
Key words: 2-(acyloxy)acrylates, b-arylpyruvates, Heck reaction,
magnesium–iodine exchange, stereoselective synthesis
HO
1i
1z
X = H: A
X = OH: C
Pulvinones1 1 are bioactive compounds2 from fungi of
genera Suillus grevillei3 and Aspergillus terreus4,5 or from
laboratory syntheses (Table 1). They may contain a car-
boxy group at position C1¢ in which case such pulvinones
are more particularly called pulvinic acids 2.1a,b Different
from most pulvinic acids,6 many natural pulvinones pos-
sess fairly simple structures. This is illustrated in Table 1
by 3¢,4,4¢-trihydroxypulvinone (1v),3 aspulvinone E
(1r),4,5 and the biosynthetically derived5,7 aspulvinones G
(1s),4,8,9a A (1i),4,8 C (1z),4,8,9c B (1x),4,8,9a D (1aa),4,8,9c,d
and H (1y).5 In addition, there are structurally more com-
plex pulvinones, for example the kodaistatins A (3a) and
C (3b)10 or aurantricholon (4).11
O
O
1x
1aa
X = H: B
X = OH: D
HO
HO
OH
1y
H
OH
OH
OH
In the preceding communication, we presented a straight-
forward approach to pulvinones and exemplified it by a
three-step synthesis of pulvinone (Z)-6 (Scheme 1).12 Its
key step was the base-induced Dieckmann cyclization of
trifluoroethyl [(4-methoxyphenyl)acetoxy]cinnamate (Z)-
5 (88%). Although the access to this precursor comprised
only two transformations, its overall yield was quite low
(12%). In order to make this type of pulvinones synthesis
more versatile, the entry steps had to be altered. This mod-
ified route is described in the following along with the
synthesis of a variety of pulvinones based thereupon. The
X
OH
O
HO
O
3a (X = H)
O
OH
O
3b (X = OH)
O
O
O
Ca2
O
O
O
O
4
HO
O
SYNTHESIS 2007, No. 15, pp 2249–2272
x
x.
x
x
.
2
0
0
7
Advanced online publication: 26.07.2007
DOI: 10.1055/s-2007-983803; Art ID: C03007SS
© Georg Thieme Verlag Stuttgart · New York
HO
OH

2250
D. Bernier, R. Brückner
PAPER
O
OH
e.g. ref.14
Ar
M
An
O
Cl
An
An
c
a, b
ORF
An
9
O
O
An
M = MgX, Li
O
(Z)-5 (12%)
(Z)-6 (88%)
O
Ar
Ar
O
R
N
e.g. ref.16
e.g. ref.16
O
10
HO
RFO
An
ORF
O
O
O
RF = CH2CF3 An = p-anisyl
7
8
NH
O
HN
e.g. ref.17
e.g. ref.17
Scheme 1 Proof-of-principle preparation of a pulvinone on a con-
ceptually novel route.12 Reagents and conditions: (a) Mg (3.0 equiv),
THF, 0 °C to r.t., 1 h; addition of 7 (2.0 equiv), Et3N (2.0 equiv), THF,
-78 °C to r.t., 2 h; (b) 8 (>1.0 equiv), DCC (>1.1 equiv), DMAP (>2
mol%), CH2Cl2, r.t., 6 h; (c) t-BuOK (3.0 equiv), DMF, r.t., 90 min.
11
O
Ar
O
Ar
OR
12
OH
13
O
pulvinones we reached include the naturally occurring
3¢,4,4¢-trihydroxypulvinone (1v) and aspulvinones A (1i),
B (1x), E (1r), G (1s), and H (1y).
Ar
Ar
OR
OR
O
e.g. ref.18
e.g. ref.18
14
O
Synthesis of Fluorine-Containing and Fluorine-Free
2-Acetoxycinnamates
OY
e.g. ref.20
e.g. ref.21
15 (Y = alkyl)
16 (Y = acyl)
Our synthesis of all trifluoroethyl ester analogues of the
prototypical ester (Z)-5 (Scheme 1) was different from
previously known chain-extending routes to related com-
pounds like the fluorine-free enol esters 16 or the corre-
sponding enols 13 (Scheme 2). The inefficiency of the
acylation of benzylmagnesium13 halides by bis(trifluoro-
ethyl) oxalate (as opposed to dialkyl oxalates14) and the
scarcity of related acylations by activated monoalkyl
oxalates15 were the origin of our quest. Using aromatic al-
dehydes 12 as an arene source suggested several three-
step and two-step approaches, but none is entirely without
drawbacks: Condensation with in situ formed azlactone in
the presence of sodium acetate16 or with hydantoin/sodi-
um acetate17 gives the corresponding benzylideneoxazo-
lones 1016 and benzylidenehydantoins 11,17 respectively.
Hydrolysis16,17 followed by esterification16 furnishes hy-
droxycinnamates 13 after a total of three steps. A two-step
conversion of arenecarbaldehydes 12 into hydroxycin-
namates 13 consists of a Darzen glycidic ester synthesis to
give 14 and a semi-pinacol rearrangement.18 In the ab-
sence of a general approach to glycidic trifluoroethyl es-
ters in the literature19 this approach did not lend itself
immediately for reaching compounds 13 with
R = CH2CF3.
e.g. ref.21
e.g. ref.24
O
I
Ar
18 (R = Et)
OR
O
19 (R = CH2CF3)
17
this work
O
O
O
O
21 (R = Et)
O−CH2CF3
OR
20
22 (R = CH2CF3)
O
O
SiMe3
An
An = p-anisyl
Scheme 2 C–C Bond-forming syntheses of 2-hydroxycinnamates
13 and the corresponding 2-alkoxycinnamates 15 or 2-(acyloxy)cin-
namates 16.
(benzoyloxy)cinnamates 16.21 However, hydrolysis or al-
coholysis of the enol ester moiety of these compounds fur-
nishing 2-hydroxycinnamates 13 were unknown.22
Moreover, the mentioned fluorine-free 2-(acyloxy)cin-
namates 16 arose as 3:121a and 10:121b E/Z mixtures from
the Horner–Wadsworth–Emmons synthesis. This indicat-
ed that a similar lack of stereocontrol might be faced if we
attempted to access our fluorine-containing 2-(acyl-
oxy)cinnamates 16 likewise by a Horner–Wadsworth–
Emmons reaction. Rather, we attempted to find out
whether such trifluoroethyl 2-(acyloxy)cinnamates can be
obtained isomerically pure by the hitherto unknown
Heck–Mirozoki coupling23 of iodoarenes 17 with trifluo-
roethyl 2-(acyloxy)acrylates 19 or 20. This approach
Arenecarbaldehydes 12 undergo Horner–Wadsworth–
Emmons reactions with phosphonato ester anions, which
contain an O-alkyl substituent at their carbanionic center;
this delivers 2-alkoxycinnamates 15 (Scheme 2).20 How-
ever, we were unaware of a method for the hydrolysis of
15 giving 2-hydroxycinnamates 13 without affecting the
OR group, and therefore skeptical that this approach
would be feasible if OR were OCH2CF3. Horner–Wads-
worth–Emmons reactions have also been known to con-
vert aromatic aldehydes 12 into 2-acetoxy- or 2-
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2251
would be akin to the known Heck couplings of iodoarenes Ethyl 2-acetoxyacrylate (18), for the model Heck cou-
17 with 2-(alkoxy)acrylates, which give Z-selectively plings described below, was prepared as described26 by
alkyl 2-alkoxycinnamates 15.24 Since iodoarenes are dis- the acetylation of ethyl pyruvate (23) with acetic anhy-
tinctly higher-yielding than bromoarenes in the closely re- dride (Scheme 3). An analogous acetylation of trifluoro-
lated Heck couplings of haloarenes with 2- ethyl pyruvate (25) provided 69% trifluoroethyl 2-
(acylamino)acrylates,25 we tested 4-bromoanisole only acetoxyacrylate (19). Pyruvate 25 was obtained by the es-
briefly. It was discarded as a substrate when it delivered terification of pyruvic acid (24) with N,N¢-dicyclohexyl-
coupling product 27 in only 11% yield after 24 hours ap- carbodiimide and 2,2,2-trifluoroethanol in 52% yield.
plying the conditions given in Table 2, entry 6.
This procedure was superior to the 35% yield resulting
from a Fischer esterification.27
O
O
O
Among the conditions tested for the first Heck arylation of
ethyl 2-acetoxyacrylate (18), employing 4-iodoanisole
(Table 2), the best yields were obtained in the absence of
a phosphine and by not heating unduly but rather by rely-
ing on the accelerating effect of an added phase-transfer
catalyst. The adverse effect of too much heating is proba-
bly due to acrylate polymerization (cf. ref 25). The bene-
ficial effect of the presence of phase-transfer catalysts was
gleaned from Jeffery’s observations of the rate of standard
Heck couplings.28 The three ammonium salts as well as
tetrabutylphosphonium bromide that we tested for this
purpose were comparably active. Our optimum yield of
89% cinnamate (Z)-27 (Table 2, entries 5, 7) underline the
compatibility of our coupling conditions with the pres-
ence of the enol acetate functionality. Satisfyingly, cin-
namate (Z)-27 was formed as a pure isomer. The Z-
configuration of its C2–C3 double bond follows unequiv-
b
OEt
OH
ORF
(52%)
O
O
O
23
24
25
c
(69%)
a
(71%, ref.26: 60%)
O
O
OEt
ORF
O
O
R
F = CH2CF3
O
O
18
19
Scheme 3 Preparation of 2-(acyloxy)acrylates. Reagents and condi-
tions: (a) Ac2O (2.0 equiv), TsOH (2 mol%), 140 °C, 20 h;26 (b)
CF3CH2OH (1.5 equiv), DCC (1.1 equiv), –15 °C, 12 h; (c) Ac2O (15
equiv), TsOH (2 mol%), hydroquinone (as a polymerization inhibitor,
1 mol%), 140 °C, 30 h).
3
ocally from the relatively small J(13C1,1H3) heterocou-
pling constant29 of 3.9 Hz. This outcome agrees with the
Table 2 First Heck Synthesis of a 2-(Acyloxy)cinnamate
O
O
3
Pd(OAc)2 (cat.),
NaOAc (3.0 equiv),
I
2
1
OEt
OEt
+
O
O
MeO
MeO
DMF
O
O
26
18
(Z)-27
(2.0 equiv)
Entry
Conditions
Pd(OAc)2
Yield (%)
Additive
Temp (°C)
Time (h)
1
2
3
4a
5
6
7
8
5 mol%
10 mol% Cy3P
70
70
17
17
60
60
24
24
12
18
36
39
47
59
89
84
89
83
–
–
90
–
120
120
95
Bu4NCl (1.0 equiv)
Me4NCl (1.0 equiv)
BnMe3NCl (1.0 equiv)
Bu4PBr (0.5 equiv)
3 mol%
95
95
a Used 18 (1.5 equiv).
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2252
D. Bernier, R. Brückner
PAPER
Z-selectivities of the related Heck arylations of 2- The Z-configuration of the C2=C3 double bond of trifluo-
alkoxyacrylates24 and 2-(acylamino)acrylates.25
roethyl cinnamates (Z)-31, (Z)-33, and (Z)-34 was as-
signed in analogy to that of trifluoroethyl cinnamate (Z)-
32. The latter was proved by determining the relatively
It should be noted that 2-(hydroxy)cinnamates 13 and 2-
(acyloxy)cinnamates 16, particularly their Z-isomers,21a
are excellent precursors of enantiomerically pure 2-oxy-
genated dihydrocinnamates if reduced asymmetrically
microbially14 or using transition metal catalysis.21 Ac-
cordingly, the Heck syntheses of the 2-(acyloxy)cinnama-
tes presented in this study, i.e., of ethyl cinnamate (Z)-27
(Table 2) and of the trifluoroethyl cinnamates shown in
Table 3, Scheme 4, and Scheme 5, also provides a novel
entry into this kind of chemistry.
3
small value 4.2 Hz for the J(13C1,1H3) heterocoupling
constant.29
Syntheses of Model Pulvinones and Aspulvinone E
Trifluoroethyl 2-acetoxycinnamates (Z)-31–(Z)-34 were
transesterified and gave 2-(arylacetoxy)cinnamates (Z)-
38a–h in a one-pot two-step procedure (Table 4). To this
end, trifluoroethanolysis of (Z)-31–(Z)-34 was performed
at 0 °C using a stoichiometric amount of lithium 2,2,2-tri-
fluoroethoxide in tetrahydrofuran. Neutralization by the
H+ form of cation-exchange resin, filtration, and evapora-
tion of residual 2,2,2-trifluoroethanol (from incomplete
conversion of the starting materials) liberated the respec-
tive 2-hydroxycinnamates. As these compounds are high-
ly air-sensitive,32 they were neither isolated nor purified
but immediately esterified with arylacetic acids 8 or 35–
37 activated by N,N¢-dicyclohexylcarbodiimide, using 4-
(dimethylamino)pyridine catalysis.33 This furnished the 2-
(arylacetoxy)cinnamates (Z)-38a–h in 60–92% yield after
separation by flash chromatography on silica gel.34 The
only complication in obtaining (Z)-38a–h pure occurred
when residual 2,2,2-trifluoroethanol consumed some of
the arylacetic acid giving the respective trifluoroethyl es-
ter as a side product.
Next, we turned to the Heck arylation of trifluoroethyl 2-
acetoxyacrylate (19) (Table 3). Disappointingly, coupling
this compound (2.0 equiv) with 4-iodoanisole (26) in N,N-
dimethyformamide solution in the presence of sodium ac-
etate (3.0 equiv) and tetramethylammonium chloride (1.0
equiv) at 95 °C for 24 hours furnished trifluoroethyl cin-
namate (Z)-33 in only 47% yield. The analogous coupling
with ethyl 2-acetoxyacrylate (18) was almost twice as ef-
ficient (84% yield; Table 2, entry 6). We assumed that this
discrepancy reflected the increased inclination of trifluo-
roethyl vs. ethyl 2-acetoxyacrylate for polymerization. By
reducing the reaction temperature, we could increase the
yield of alkenylation product, yet at the cost of a greatly
increased reaction time (method A: 60 °C, 5 d; method B:
80 °C, 60 h). The mildest procedure emerged from the use
of N,N-dicyclohexylmethylamine as a base (method C:
70–75 °C, 40–45 h).30 In this manner we gained access to
trifluoroethyl cinnamates (Z)-31–(Z)-34 from commer-
cially available iodoarenes in 75–81% yields.31 These cin-
namates were off-white solids; in contrast to the
corresponding 2-hydroxycinnamates,32 they are air-stable
and can be stored for months in air without degradation.
We showed that the C2=C3 bond remained Z-configured
throughout the procedure by determining the coupling
3
constants J(13C1,1H3) of four selected trifluoroethyl 2-
(arylacetoxy)cinnamates 38d,e,g,h from their selectively
F3C–C(1H2)-decoupled 126 MHz 13C NMR spectra; the
values were 3.9 Hz, 3.9 Hz, 4.2 Hz, and 3.8 Hz, respec-
tively, which are small as required if the Z-configuration
persists.29 By analogy we also attributed the Z-configura-
tion to 2-(arylacetoxy)cinnamates 38a,f.
Table 3 Heck Syntheses of Trifluoroethyl 2-Acetoxycinnamates
O
O
3
I
2
1
ORF
ORF
+
(MeO)n
(MeO)n
O
O
Pulvinone formation under the previously established
conditions12 for ring-closure through Dieckmann conden-
sation followed (Table 4). This meant treatment of 2-
(arylacetoxy)cinnamates (Z)-38a–h with excess potassi-
um tert-butoxide in N,N-dimethylformamide at 0 °C for
0.5–1.5 h. Pulvinones 1a–h resulted in 75–88% yield after
aqueous acidic workup and precipitation from methanol
(1a–d,f) or diethyl ether (1e,g,h). The Z-configuration of
their C2=C3 bond was deduced from the magnitude of the
3J(13C1,1H3) coupling constant in pulvinones 1f,g (3.7 Hz
in both cases), i.e., by the same criterion as earlier,29 and
assumed by analogy for their congeners 1a–e,h.
O
O
26, 28–30
19
(Z)-31–34
RF = CH2CF3
(MeO)n
–
Iodoarene Methoda Product
Yield (%)
28
26
29
30
A
B
C
A
(Z)-31
(Z)-32
(Z)-33
(Z)-34
81
78
76
75
4-MeO
2,4-(MeO)2
3,4-(MeO)2
a Method A: 19 (2.0 equiv), Pd(OAc)2 (5 mol%), NaOAc (2.0 equiv),
Bu4PBr (1.0 equiv), DMF, 60 °C, 5 d. Method B: 19 (2.0 equiv),
Pd(OAc)2 (3 mol%), NaHCO3 (2.0 equiv), Bu4PBr (0.5 equiv), DMF,
80 °C, 60 h. Method C: 19 (1.2–1.3 equiv), Pd(OAc)2 (3 mol%),
Cy2NMe (1.2 equiv), Et4NBr (0.5 equiv), DMF, 70–75 °C, 40–45 h.
While pulvinone 1a of Table 4 is unsubstituted, pulvino-
nes 1b–h contain one to three methoxy groups. These
were demethylated under established conditions,38 i.e., by
treatment with boron tribromide (1.3 equiv) in refluxing
dichloromethane (Table 5). This yielded the (poly)hy-
droxylated pulvinones 1p–v in 69–89% yield as brightly
yellow amorphous solids that upon exposure to air slowly
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2253
Table 4 Preparation of Pulvinones 1a–h from Trifluoroethyl 2-(Arylacetoxy)cinnamatesa,b
O
O
OH
4
O
3
3
1'
(OMe)m
2
2
5
3
a
b
1
ORF
ORF
(MeO)n
(MeO)n
(MeO)n
(OMe)m
O
O
O
HO
O
(OMe)m
O
O
1a–h
(Z)-31–34
8, 35–37
(Z)-38a–h
RF = CH2CF3
(MeO)n
Cinna- (OMe)m
mate
Arylace- 2-(Arylacetoxy)cinnamate
Pulvinones
tic acid
(Z)-38 Yield 3J(C1,
d(H3)
d(C1)
1
Yield 3J(C4,
d(H1¢) d(C4)
(%)
60
87
92
72
82
84
82
78
H3) (Hz)
(%)
83
81
82
88
78
75
79
81
H1¢) (Hz)
–
(Z)-31
(Z)-31
(Z)-32
(Z)-32
(Z)-32
(Z)-32
–
35
8
a
b
c
–
–
129.7
a
–
6.62
6.49
6.49
6.49
6.32
6.54
6.84
6.34
–
c
–
4-MeO
–
–
7.26
7.29
7.29
7.27
7.30
7.78
7.31
–
b
c
–
107.5
108.6
107.4
107.7
107.5
101.5
107.5
4-MeO
4-MeO
4-MeO
4-MeO
35
8
–
129.5
129.5
129.1
129.6
123.8
129.7
–
4-MeO
dd
e
3.9
3.9
–
de,f
e
–
2,4-(MeO)2
3,4-(MeO)2
4-MeO
36g
37
8
–
f
ff
g
3.7
3.7
–
2,4-(MeO)2 (Z)-33
3,4-(MeO)2 (Z)-34
g
h
4.2
3.8
4-MeO
8
h
a Reagents and conditions: (a) (i) 1.0 M CF3CH2OLi in THF (1.5 equiv), THF, 0 °C, 60–90 min; DOWEX XW-50; filtration under N2 atmo-
sphere followed by removal of THF and CF3CH2OH under reduced pressure; (ii) arylacetic acid (1.05 equiv), DCC (1.1 equiv), DMAP (2
mol%), CH2Cl2, r.t., 5 h; (b) t-BuOK (3.0 equiv), DMF, 0 °C, 30–90 min.
b Stereochemically significant 1H NMR (300, 400, or 500 MHz) and 13C NMR (75, 100, or 126 MHz) parameters in CDCl3 (38), acetone-d6
(1a,b,e,g,h), DMSO-d6 (1c,f) or 98:2 CDCl3/CD3OD (1d) solns.
c The respective resonance could not be attributed unambiguously.
d (Z)-38d is identical to (Z)-5 (Scheme 1).
e 1d is identical to (Z)-6 (Scheme 1).
f This compound has been previously prepared by a different procedure.35
g Compound 36 was prepared from 1-iodo-2,4-dimethoxybenzene and dimethyl malonate using copper catalysis [i.e., analogously to the pro-
cedure published for the corresponding functionalization of diethyl malonate,36 yet in THF–DMF (4:1) as solvent rather than in THF in order
to solubilize the less soluble Cu/dimethyl malonate complex], saponification to the corresponding arylmalonic acid, and finally copper cata-
lyzed decarboxylation to give the arylacetic acid.37
turned blue-green. These pulvinones include synthetic methyllithium (2 equiv) to dihydrocoumarin and cyclode-
specimens of the natural products aspulvinone E (1r; pre- hydration in refluxing toluene gave chromane 40 in 76%
vious synthesis38), aspulvinone G (1s; synthesis of per-O- yield (cf. 62%39). Iodination with benzyltrimethylammo-
methylated aspulvinone G: ref.9b), and 3¢,4,4¢-trihydroxy- nium dichloroiodate and zinc chloride40 was para-selec-
pulvinone (1v; previous synthesis3,38).
tive, giving iodochromane 41 in 89% yield. On one hand,
Heck coupling with trifluoroethyl 2-acetoxyacrylate (19)
converted iodochromane 41 into trifluoroethyl 2-(aryl-
acetoxy)cinnamate 42 (81% yield of a single isomer). On
the other hand, iodochromane 41 and dimethyl malonate
Synthesis of Aspulvinones A, B, and H
In the first part of this paper, we described a new synthesis were coupled under modified Buchwald conditions
of a variety of hydroxylated pulvinones, including aspul- (Table 4, footnote g).36 The resulting arylmalonate was
vinones E and G. We then applied our methodology to the saponified, whereafter copper-catalyzed decarboxyl-
first syntheses of aspulvinone A, aspulvinone B (synthesis ation37 furnished the chromane-containing arylacetic acid
of per-O-methylated aspulvinone B: ref.9d), and aspulvi- 43.
none H as detailed in the following.
Additionally, our natural product syntheses required the
First, making these natural products required the prepara- preparation of the prenylated building blocks trifluoroeth-
tion of the chromane-containing building blocks trifluoro- yl 2-(arylacetoxy)cinnamates 44 or 51 and arylacetic
ethyl 2-(arylacetoxy)cinnamate 42 and arylacetic acid 43 acids 45 or 52 (Scheme 5); these pairs of products differ
(Scheme 4). Following the literature39 the addition of by whether the hydroxy group of the target aspulvinones
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2254
D. Bernier, R. Brückner
PAPER
O
O
Table 5 Preparation of Pulvinones 1p–v by Demethylation of Pul-
vinones 1b–h
HO
ORF
OH
O
O
OMe
MeO
(OMe)m
44
45
(MeO)n
O
a
O
b
(64% over
the 3 steps)
1b–h
OH
a
(69%)
(OR)m
(RO)n
I
I
O
O
1p–v
MeO
OMe
46
(RO)n
–
(OR)m
R = Me R = H
Yield (%)
I
I
I
I
4-OR
–
1b
1c
1d
1p
1q
1r
78
82
81
4-RO
4-RO
RO
RO
c
(88%)
47
48: R = Me
49: R = Bn
4-OR
d
(aspulvinone E)
(98%)
e
(71%)
I
4-RO
2,4-(OR)2
1e
1s
79
(aspulvinone G)
I
4-RO
3,4-(OR)2
4-OR
1f
1t
69
78
BnO
O
OBn
2,4-(RO)2
3,4-(RO)2
1g
1h
1u
50
4-OR
1v (3¢,4,4¢-trihy- 89
droxypulvinone)
g
(45% over
the 3 steps)
f
(78%)
a Reagents and conditions: (a) 1 M BBr3 in heptanes (3 equiv per MeO
group), CH2Cl2, 0 °C, 10 min; 1b–e,g,h: reflux, 1–5 h; 1f: r.t., 8 h.
HO
ORF
O
O
OBn
BnO
O
51
52
a
RF = CH2CF3
(76%)
O
O
O
39
40
Scheme 5 Synthesis of the prenylated building blocks. Reagents
and conditions: (a) 19 (1.5 equiv), Pd(OAc)2 (3 mol%), Cy2NMe (1.2
equiv), Et4NBr (0.5 equiv), DMF, 80 °C, 36 h; (b) (i) dimethyl malo-
nate (3 equiv), CuI (5 mol%), Cs2CO3 (1.5 equiv), 2-phenylphenol
(10 mol%), THF–DMF (5:1), 70 °C, 36–48 h; (ii) 2 M NaOH (5
equiv), MeOH, 0 °C, 20 min then 50 °C, 2–3 h; (iii) Cu2O (5 mol%),
MeCN, 80 °C, 3–5 h; (c) i-PrMgCl (1.1 equiv), THF, –40 °C, 30 min;
CuI (5 mol%), THF, –40 °C, 15 min; isoprenyl bromide (1.1 equiv),
THF, –40 °C, 2h; (d) BnBr (1.0 equiv), K2CO3 (3.0 equiv), acetone,
reflux, 4 h; (e) i-PrMgCl (1.1 equiv), THF, –40 °C, 30 min; CuI (5
mol%), THF, –40 °C, 15 min; isoprenyl bromide (1.1 equiv), THF, –
40 °C; (f) 19 (1.5 equiv), Pd(OAc)2 (3 mol%), Cy2NMe (1.2 equiv),
Et4NBr (0.5 equiv), DMF, 80 °C, 36 h; (g) (i), dimethyl malonate (3
equiv), CuI (5 mol%), Cs2CO3 (1.5 equiv), 2-phenylphenol (10
mol%), THF–DMF (5:1), 70 °C, 36–48 h; (ii) 2 M NaOH (5 equiv),
MeOH, 0 °C, 20 min then 50 °C, 2–3 h; (iii) Cu2O (5 mol%), MeCN,
80 °C, 3–5 h.
b
(89%)
I
I
d
(45% over
the 3 steps)
O
O
41
c
(81%)
O
O
HO
ORF
O
O
O
O
42
43
R
F = CH2CF3
Scheme 4 Synthesis of the chromane-containing building blocks.
Reagents and conditions: (a) (i) MeLi (3 equiv), THF, 0 °C, 2 h to r.t.,
2 h; (ii) TsOH (cat.), toluene, Dean–Stark apparatus, reflux, 7 h; (b)
BnMe3N ICl2 (1.0 equiv), ZnCl2 (1.5 equiv), AcOH, 0 °C to r.t., 2 h;
(c) 19 (1.5 equiv), Pd(OAc)2 (3 mol%), Cy2NMe (1.2 equiv), Et4NBr
(0.5 equiv), DMF, 80 °C, 36 h; (d) (i) dimethyl malonate (3 equiv),
CuI (5 mol%), Cs2CO3 (1.5 equiv), 2-phenylphenol (10 mol%), THF–
DMF (5:1), 70 °C, 36–48 h; (ii) 2 M NaOH (5 equiv), MeOH, 0 °C,
20 min then 50 °C, 2–3 h; (iii) Cu2O (5 mol%), MeCN, 80 °C, 3–5 h.
B and H is foreseen as a methyl (44, 45) or a benzyl ether
(51, 52). The prenyl side chains of each of these building
blocks could possibly have been installed by the ortho-
prenylation of an appropriately substituted phenolate.
However, not infrequently this kind of transformation suf-
fers from low yields due to insufficient selectivity for C-
vs. O-allylation.41 We circumvented such problems by an
innovative access to the 2-prenyl-4-iodophenyl ethers 46
and 50. It started from the 2,4-diiodophenyl ethers 48 and
59, respectively. These, in turn, stemmed from the di-
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2255
iododination of anisole42 and the diiododination of ment with a slight excess of isopropylmagnesium chloride
phenol43 followed by benzylation. The conversion of 2,4- at –40 °C.45 At the same temperature the resulting aryl-
diiodoanisole (48) into the ortho-prenylated methyl ether magnesium chloride was alkylated with prenyl bromide in
46 and the conversion of 1-(benzyloxy)-2,4-diiodoben- the presence of a catalytic amount of copper(I) iodide.
zene (49) into the ortho-prenylated benzyl ether 50 both This provided the ortho-prenylated ethers 48 and 50 in
started with a substituent-directed ortho-selective iodine– 88% and 71% yield, respectively.
magnesium exchange reaction44 brought about by treat-
Table 6 Preparation of Pulvinones 1i–o from Trifluoroethyl 2-(Arylacetoxy)cinnamates followed by Demethylation Yielding, inter alia,
a
Aspulvinones
O
O
OH
OH
a
b
c
Ar1
ORF
Ar1
ORF
Ar2
Ar2
O
Ar2
O
Ar1
Ar1
O
O
HO
Ar2
O
O
O
O
O
42, 44, 51
43, 45, 52
(Z)-38i–o
1i–o
1w–y
Cinnamate
Ar1
Arylacetic acid
Ar2
(Arylacetoxy)cinnamate Pulvinone
Yield (%)
Yield (%)
90
Yield (%)
–
O
1ib
(Z)-38i
(Z)-38j
88
80
–
–
43
OMe
1j
73
–
O
42
45
OBn
(Z)-38k
(Z)-38l
(Z)-38m
(Z)-38n
(Z)-38o
74
86
72
71
73
1k
1l
74
69
69
71
64
1w
–
55
–
52
O
43
OMe
MeO
1m
1n
1o
–
–
44
45
O
1xc
1yd
65
45
43
OBn
BnO
51
52
a Reagents and conditions: (a) (i) Trifluoroethyl ester, 1 M CF3CH2OLi in THF (1.5 equiv), THF, 0 °C, 60–90 min; DOWEX XW-50; filtration
under N2 atmosphere followed by removal of THF and CF3CH2OH under reduced pressure; (ii) arylacetic acid (1.05 equiv), DCC (1.1 equiv),
DMAP (2 mol%), CH2Cl2, r.t., 5 h; (b) t-BuOK (3.0 equiv), DMF, 0 °C, 90 min; (c) 1k, 1n or 1o, CH2Cl2, addition of Cy2NMe (2.0 equiv), r.t.,
20 min; addition of 1 M BCl3 in heptanes (3.0 equiv), –78 °C, 2 h; poured into a suspension of CaO (50.0 equiv) in MeOH, –78 °C to r.t.
b Aspulvinone A.
c Aspulvinone B.
d Aspulvinone H.
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2256
D. Bernier, R. Brückner
PAPER
With the required building blocks from the sequences of ulterior chromane formation. As a consequence, aspulvi-
Schemes 4 and 5 in our hands, we combined them to give none B (1x) could be isolated in 65% yield. The same de-
pulvinones 1i–o (Table 6) by applying the exactly same benzylation procedure applied to pulvinone dibenzyl
protocols as in the analogous pulvinone syntheses com- ether 1o rendered 55% of aspulvinone H (1y). The latter
piled in Table 4 and commented in full detail there. That compound was highly air-sensitive in that it decomposed
is, we began with the in situ trifluoroethanolysis of one of rapidly except when handled under an atmosphere of ni-
the trifluoroethyl acetoxycinnamate 42, 44, or 51, contin- trogen.
ued with the N,N¢-dicyclohexylcarbodiimide/4-(dimethyl-
To conclude, we have developed a straightforward access
to Z-configured pulvinones 1a–o. It is terminated with the
Dieckmann cyclization of the respective trifluoroethyl 2-
amino)pyridine mediated esterification of the liberated 2-
hydroxycinnamate intermediate with the arylacetic acids
43, 45, or 52, and effected ring closure by the potassium
(arylacetoxy)cinnamates (Z)-38a–o. A practical synthesis
tert-butoxide induced Dieckmann reaction of the respec-
of the latter was developed, which consists of the Heck
alkenylation of aryl iodides with the readily prepared tri-
tive (arylacetoxy)cinnamate (Z)-38i–o.
Aspulvinone A (1i) resulted, in 79% overall yield, in no fluoroethyl 2-acetoxyacrylate 19, liberation of the under-
more steps than discussed so far (Table 6). However, we lying trifluoroethyl 2-hydroxycinnamates, and their
had not yet made aspulvinones B (1x) and H (1y), because esterification with N,N¢-dicyclohexylcarbodiimide-acti-
we possessed only their methyl ethers (1l and 1m, respec- vated arylacetic acids. The versatility and efficiency of
tively) or their benzyl ethers (1n and 1o, respectively). this methodology are exemplified by syntheses of diverse-
Hence, what remained to be achieved was the cleavage of ly substituted pulvinones. Targets included were aspulvi-
the methyl or benzyl ether.
nones A, E, and G as well as, constituting first-time
syntheses, aspulvinones B and H.
Several attempts to deprotect methyl ether 1j with boron
tribromide at –78 °C in dichloromethane did not lead to
the desired aspulvinone B (1x, Table 6). The prenyl chain
was, rather, attacked by the liberated hydroxy group so
that the compound isolated was aspulvinone A (1i, 89%).
Likewise, attempted demethylation of dimethyl ether 1m
with boron tribromide under the same conditions did not
lead to aspulvinone H (1y) but again to aspulvinone A (1i)
according to thin-layer chromatography. Other groups re-
Products were purified by flash chromatography34 on Macherey-
1
Nagel silica gel 60 (details given in parentheses). H NMR used
TMS (d = 0) as internal standard in CDCl3, acetone-d5 (d = 2.0554)
as internal standard in acetone-d6, CD2HOD (d = 3.3154) as internal
standard in CD3OD, and 13C NMR used CDCl3 (d = 77.1654) as in-
ternal standard in CDCl3, acetone-d6 (d = 29.8454) as internal stan-
dard in acetone-d6 on a Varian Mercury VX 300 or Bruker AM 400
or DRX 500. The assignments of 1H and 13C NMR resonances refer
ported the same kind of cyclization giving chromanes.46 to the IUPAC nomenclature; primed numbers belong to the side
chain (Figures 1). NMR: Dr. M. Keller, Institut für Organische Che-
More reagents known to cleave standard methyl aryl
ethers (LiSEt, DMF, 120 °C;47 LiSPh, NMP, 140–150
mie und Biochemie, Universität Freiburg. Combustion analyses: E.
Hickl, Institut für Organische Chemie und Biochemie, Universität
°C;48 LiI, quinoline, 140–150 °C49) gave complex mix-
Freiburg. MS: Dr. J. Wörth, Institut für Organische Chemie und
Biochemie, Universität Freiburg. IR spectra: FTIR Perkin-Elmer
Spectrum 1000. Melting points: Dr. Tottoli apparatus (Fa. Büchi),
uncorrected. Petroleum ether (PE) used was the fraction boiling in
the range 30–50 °C.
tures when tried for the deprotection of methyl ether 1l.
We suspected that this was due to nucleophilic attack
upon the butenolide moiety.
Unable to deprotect pulvinone methyl ethers 1l and 1m
while leaving the prenyl moieties intact, we next exam-
ined the deprotection of the analogous pulvinone benzyl
ethers 1n and 1o. Hydrogenolysis of benzyl ether 1n of as-
pulvinone B (1x) using hydrogen gas and palladium on
carbon50 or catalytic transfer hydrogenation with sodium
formate or cyclohexene as a hydrogen donor and 5% pal-
ladium on carbon as a catalyst51 invariably resulted in par-
tial hydrogenation of the prenyl double bond. An
aggravating effect was that the over-reduced material
could not be separated from 1x using flash chromatogra-
phy on silica gel.34 Lithium naphthalenide in tetrahydro-
furan at –78 °C52 was also unsuccessful in cleaving the
benzyl ether of 1n giving, instead, a multitude of products.
However, when we deprotonated pulvinone benzyl ether
1n in dichloromethane solution with N,N-dicyclohexyl-
methylamine (2 equiv) and added boron tribromide (3
equiv) at –78 °C thereafter, cleavage of the O–benzyl
bond was complete within two hours. Workup under basic
conditions, by pouring the reaction mixture into a suspen-
sion of excess calcium oxide in methanol, 53 avoided any
The numbering of all compounds used for NMR is shown in
Figure 1.
Heck Coupling I
Ethyl (Z)-2-Acetoxy-3-(4-methoxyphenyl)acrylate [(Z)-27]
A Schlenk tube was charged with 4-iodoanisole (26, 0.234 g, 1.0
mmol), NaOAc (0.246 g, 3.0 mmol, 3.0 equiv), Bu4NCl (0.278 mg,
1.0 mmol, 1.0 equiv), hydroquinone (1.0 mg, 0.01 mmol, 1 mol%),
and Pd(OAc)2 (11.2 mg, 0.05 mmol, 5 mol%), evacuated, and
flushed with N2. DMF (5 mL) and ethyl 2-acetoxyacrylate (18, 0.32
g, 0.29 mL, 2.0 mmol, 2.0 equiv) were added through a rubber sep-
tum. The mixture was degassed. After stirring at 95 °C for 24 h, the
mixture was diluted with Et2O (5 mL). 1 M HCl (5 mL) was added
under ice-cooling and the layers were separated. The aqueous layer
was extracted with Et2O (4 × 10 mL). The combined organic layers
were dried (MgSO4) and the solvent was removed at 50 °C in vacuo.
Purification of the residue by flash chromatography (column diam-
eter 2 cm, cyclohexane–EtOAc, 5:1) furnished 27 as an amber oil;
yield: 0.235 g (89%).
1H NMR (300 MHz, CDCl3): d = 1.34 (t, J = 7.2 Hz, OCH2CH3),
2.33 (s, OCOCH3), 3.83 (s, 4¢-OCH3), 4.29 (t, J = 7.1 Hz,
OCH2CH3), AA¢BB¢ signal centered at 6.90 (H3¢, H5¢) and 7.55
(H2¢, H6¢), 7.26 (s, H3).
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2257
O
2'
2'
5'
2''
HO
2''
4''
2
1
1'
3'
4'
1'
3'
4''
2
1''
1
3''
1''
3''
CF3
3
O
O
O
6'
4'
6'
OR
RO
5'
O
44: R = Me
51: R = Bn
45: R = Me
52: R = Bn
O
CF3
O
CF3
3
2'
5'
2
5'
3
4'
1
3'
4'
O
4a'
8a'
2
3'
2'
1
O
2''
(MeO)n
O
6'
5''
4''
3''
4''
O
7'
4a''
8a''
3''
2''
O
(OMe)m
8'
O
6''
O
7''
5''
O
(Z)-38a–h
(Z)-38i
8''
O
CF3
4'
3
5'
8'
2
4a'
1
3'
2'
O
2''
1'''
2'''
3'''
7'
O
8a'
O
4'''
O
6''
OR
5''
(Z)-38j: R = Me
(Z)-38k: R = Bn
O
CF3
O
CF3
2´
1''
3
2
1''
2´
3
2
3''
3''
1
1
O
O
2''
4''
2''
4''
4'''
2'''
1''''
5'''
3''''
4''''
4a'''
O
6´
O
6´
3'''
2'''
RO
RO
5´
5´
2''''
O
7'''
O
6'''
8a''' O
OR
8'''
(Z)-38l: R = Me
(Z)-38n: R = Bn
5'''
(Z)-38m: R = Me
(Z)-38o: R = Bn
8Ar1
7Ar1
O
5Ar1
OH
6Ar1
4Ar1
R1
3Ar1
2Ar2
1´´
1´
OH
4
3Ar1
2Ar2
1´
3´´
4
5
O
4´´
2´´
RO
3Ar2
R2
4Ar2
2
5Ar1 4Ar1
2Ar1
5
6Ar2
2
O
O
5Ar2
6Ar2
O
(Z)-1a–h,p–v
5Ar2
(Z)-1l: R = Me
(Z)-1n: R = Bn
(Z)-1x: R = H
8Ar1
7Ar1
O
OH
4
4Ar2
5Ar2
5Ar1
OR
1´
3Ar2
6Ar1
3Ar1
OH
4
5
O
5Ar1 4Ar1
2Ar2
1´
2
2´´
4´´
1´´´
3´´
7Ar2
O
O
3´´´
5
O
8Ar2
1´´
4´´´ 2´´´
2Ar1
2
Z-1i
6Ar2
RO
O
5Ar2
5Ar1
OR
(Z)-1m: R = Me
(Z)-1o: R = Bn
(Z)-1y: R = H
6Ar1
OH
4Ar2
5Ar2
2´´
4´´
1´
3´´
3Ar2
4
5
O
1´´
2Ar1
2
7Ar2
O
O
8Ar2
(Z)-1j: R = Me
(Z)-1k: R = Bn
(Z)-1w: R = H
Figure 1
13C NMR (126 MHz, CDCl3): d = 14.3 (OCH2CH3), 20.8
(OCOCH3), 55.4 (4¢-OCH3), 61.7 (OCH2CH3), 114.4 (C3¢, C5¢),
124.9 (half as intense as following peak, C1¢), 127.0 (C3), 132.0
(twice as intense as preceding peak, C2¢, C6¢), 135.6 (C2), 160.9
(C4¢), 162.9 (C1), 168.7 (OCOCH3).
Selected signals from gated-decoupled 13C NMR spectrum (126
MHz, CDCl3): d = 160.9 (mC, C4¢), 162.9 [mC; selective irradiation
at d(OCH2CH3) = 4.29 makes this resonance collapse into d,
J(C1,H3) = 3.9 Hz, C1], 168.7 (q, 2J(CH3) = 7.0 Hz, OCOCH3).
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2258
D. Bernier, R. Brückner
PAPER
2,2,2-Trifluoroethyl (Z)-2-Acetoxy-3-(2,4-dimethoxyphe-
Heck Couplings II
2,2,2-Trifluoroethyl (Z)-2-Acetoxy-3-phenylacrylate [(Z)-31];
Typical Procedure
nyl)acrylate [(Z)-33]
Following the typical procedure for (Z)-31, using 1-iodo-2,4-
dimethoxybenzene (0.792 g, 3.0 mmol), Et4NBr (0.315 g, 1.5
mmol, 0.5 equiv), hydroquinone (3.3 mg, 0.03 mmol, 1 mol%),
Pd(OAc)2 (13.5 mg, 0.06 mmol, 2 mol%), Cy2NMe (0.77 mL, 3.6
mmol, 1.2 equiv), and acrylate 19 (0.827 g, 3.9 mmol, 1.3 equiv) in
DMF (7.5 mL); the mixture was stirred at 70 °C for 45 h. Flash chro-
matography (column diameter 2.5 cm, cyclohexane–EtOAc, 10:1)
and recrystallization [PE–Et2O, 5:1] furnished (Z)-33 as a colorless
solid; yield: 0.792 g (76%); mp 118–121 °C.
A Schlenk tube was charged with iodobenzene (28, 0.612 g, 3.0
mmol), NaOAc (0.492 g, 6.0 mmol, 2.0 equiv), Bu4PBr (1.02 g, 3.0
mmol, 1.0 equiv), activated molecular sieves (3Å, 1.20 g), hydro-
quinone (3.3 mg, 0.03 mmol, 1 mol%), and Pd(OAc)2 (33.7 mg,
0.15 mmol, 5 mol%). It was then evacuated and flushed with N2.
DMF (5 mL) and trifluoroethyl 2-acetoxyacrylate (19, 1.15 g, 5.4
mmol, 1.8 equiv) were added through a rubber septum. The mixture
was degassed. After stirring at 60 °C for 5 d, the mixture was diluted
with Et2O (10 mL). H2O (5 mL) and aq 2 M HCl (4 mL) were added
under ice cooling and the layers were separated. The aqueous layer
was extracted with Et2O (4 × 10 mL). The combined organic layers
were dried (MgSO4) and the solvent was removed at 50 °C in vacuo.
Purification of the residue by flash chromatography (column diam-
eter 3.5 cm, cyclohexane–EtOAc, 12:1) and recrystallization [PE–
Et2O, 6:1) furnished (Z)-31 as a colorless solid; yield: 0.701 g
(81%); mp 68–70 °C.
IR (CDCl3): 3010, 2980, 2945, 1765, 1730, 1640, 1605, 1575, 1500,
1465, 1450, 1435, 1415, 1380, 1310, 1295, 1275, 1250, 1210, 1165,
1120, 1095, 1045, 1035, 970, 840 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.30 (s, OCOCH3), 3.84, 3.85 (2
s, 2¢-OCH3, 4¢-OCH3), 4.58 (q, J(H,F) = 8.4 Hz, CH2CF3), 6.44 (d,
4J(H3¢,H5¢) = 2.5 Hz, H3¢), 6.51 (dd, 4J(H5¢,H3¢) = 2.3 Hz,
J(H5¢,H6¢) = 8.8 Hz, H5¢), 7.70 (d, J(H6¢,H5¢) = 8.8 Hz, H6¢), 7.81
(s, H3).
13C NMR (126 MHz, CDCl3): d = 20.7 (OCOCH3), 55.6, 55.8 (2¢-
OCH3, 4¢-OCH3), 61.1 (q, 2J(C,F) = 36.9 Hz, CH2CF3), 98.3 (C3¢),
105.5 (C5¢), 113.8 (C1¢), 123.1 (q, 1J(C,F) = 277.2 Hz, CF3), 123.9
(C3), 131.3 (C6¢), 133.5 (C2), 159.9, 161.6, 163.1 (C1, C2¢, C4¢),
168.7 (OCOCH3).
IR (CDCl3): 3095, 3065, 3030, 2975, 1770, 1740, 1650, 1495, 1450,
1410, 1375, 1310, 1290, 1255, 1205, 1185, 1105, 1035, 1030, 975,
965, 935, 880 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.33 (s, OCOCH3), 4.60 (q,
J(H,F) = 8.5 Hz, CH2CF3), 7.38 (s, H3), in part overlapped by 7.38–
7.44 (m, H3¢, H4¢, H5¢), 7.57–7.63 (m, H2¢, H6¢).
13C NMR (100 MHz, CDCl3): d = 20.6 (OCOCH3), 61.4 (q,
2J(C,F) = 3.9, 36.8 Hz, CH2CF3), 123.0 (q, 1J(C,F) = 276.6 Hz,
CF3), 129.0, 129.5, 130.5 (C3, C2¢, C3¢, C4¢, C5¢, C6¢), 131.7 (C1¢),
135.6 (C2), 161.2 (C1), 168.5 (OCOCH3).
Anal. Calcd for C15H15F3O6 (348.3): C, 51.73; H, 4.34. Found: C,
51.78; H, 4.13.
2,2,2-Trifluoroethyl (Z)-2-Acetoxy-3-(3,4-dimethoxyphe-
nyl)acrylate [(Z)-34]
Anal. Calcd for C13H11F3O4 (288.2): C, 54.17; H, 3.85. Found: C,
54.30; H, 3.78.
Following the typical procedure for (Z)-31, using 1-iodo-3,4-
dimethoxybenzene (0.792 g, 3.0 mmol), NaOAc (0.738 g, 9.0
mmol, 3.0 equiv), Bu4PBr (1.02 g, 3.0 mmol, 1.0 equiv), activated
molecular sieves (3Å, 1.20 g), hydroquinone (3.3 mg, 0.03 mmol, 1
mol%), Pd(OAc)2 (20.2 mg, 0.09 mmol, 3 mol%), and acrylate 19
(1.15 g, 5.4 mmol, 1.8 equiv) in DMF (10 mL); the mixture was
stirred at 80 °C for 60 h. Flash chromatography (column diameter
3.0 cm, cyclohexane–EtOAc, 10:1) and recrystallization [PE–Et2O,
5:1] furnished (Z)-34 as a colorless solid; yield: 0.785 g (75%); mp
76–78 °C.
2,2,2-Trifluoroethyl (Z)-2-Acetoxy-3-(4-methoxyphenyl)acry-
late [(Z)-32]
Following the typical procedure for (Z)-31, using 4-iodoanisole (26,
0.702 g, 3.0 mmol), NaHCO3 (0.504 g, 6.0 mmol, 2.0 equiv),
Bu4PBr (0.509 mg, 1.5 mmol, 0.5 equiv), activated molecular sieves
(3Å, 0.90 g), hydroquinone (3.3 mg, 0.03 mmol, 1 mol%),
Pd(OAc)2 (20.2 mg, 0.09 mmol, 3 mol%), and acrylate 19 (1.27 g,
6.0 mmol, 2.0 equiv) in DMF (9 mL); that the mixture was stirred
for at 80 °C for 60 h. Flash chromatography (column diameter 3.5
cm, cyclohexane–EtOAc, 10:1) and recrystallization [PE–Et2O,
5:1] furnished (Z)-32 as a colorless solid; yield: 0.742 g (78%); mp
97–99 °C.
IR (CDCl3): 2965, 2940, 2840, 1770, 1735, 1650, 1600, 1515, 1465,
1420, 1330, 1300, 1275, 1250, 1230, 1200, 1175, 1145, 1105, 1025
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.34 (s, OCOCH3), 3.90, 3.92 (2
s, 3¢-OCH3, 4¢-OCH3), 4.59 (q, J(H,F) = 8.4 Hz, CH2CF3), 6.89 (d,
J(H5¢,H6¢) = 8.4 Hz, H5¢), 7.18–7.27 (m, flanked by CHCl3 singlet;
H2¢, H6¢), 7.33 (s, H3).
IR (KBr): 2975, 2940, 1765, 1720, 1645, 1605, 1575, 1515, 1460,
1425, 1370, 1355, 1325, 1290, 1255, 1200, 1180, 1165, 1120, 1105,
1025, 965, 910, 890, 840, 830, 755 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.34 (s, OCOCH3), 3.84 (s, 4¢-
OCH3), 4.58 (q, J(H,F) = 8.4 Hz, CH2CF3), AA¢BB¢ signal centered
at 6.92 (H3¢, H5¢) and 7.58 (H2¢, H6¢), 7.34 (s, H3).
13C NMR (75 MHz, CDCl3): d = 20.6 (OCOCH3), 56.0, 56.1 (3¢-
OCH3, 4¢-OCH3), 61.3 (q, 2J(C,F) = 36.9 Hz, CH2CF3), 111.3,
1
113.0 (C2¢, C5¢), 123.0 (q, J(C,F) = 277.1 Hz, CF3), 124.6 (C1¢),
124.9 (C6¢), 129.6 (C3), 133.9 (C2), 149.1, 151.3 (C3¢, C4¢), 161.3
(C1), 168.4 (OCOCH3).
13C NMR (75 MHz, CDCl3): d = 20.6 (OCOCH3), 55.5 (4¢-OCH3),
2
61.2 (q, J(C,F) = 36.9 Hz, CH2CF3), 114.5 (C3¢, C5¢), 123.0 (q,
Anal. Calcd for C15H15F3O6 (348.3): C, 51.73; H, 4.34. Found: C,
51.80; H, 4.09.
1J(C,F) = 277.2 Hz, CF3), 124.4 (C1¢), 129.4 (half as intense as fol-
lowing peak, C3), 132.4 (C2¢, C6¢), 133.8 (C2), 161.4, 161.5 (C1,
C4¢), 168.6 (OCOCH3).
2,2,2-Trifluoroethyl (Z)-2-Acetoxy-3-(2,2-dimethylchroman-6-
yl)acrylate [(Z)-42]
Selected signals from undecoupled 13C NMR spectrum (126 MHz,
CDCl3) with selective irradiation at d(OCH2CH3) = 4.58: d = 161.4
(d, J(C1,H3) = 4.2 Hz, C1, superimposed by mC, C4¢), 168.6 (q,
2J(CH3) = 7.1 Hz, OCOCH3).
Following the typical procedure for (Z)-31, using 6-iodo-2,2-di-
methylchromane (41, 0.864 g, 3.0 mmol), Et4NBr (0.315 g, 1.5
mmol, 0.5 equiv), hydroquinone (3.3 mg, 0.03 mmol, 1 mol%),
Pd(OAc)2 (13.5 mg, 0.06 mmol, 2 mol%), Cy2NMe (0.77 mL, 3.6
mmol, 1.2 equiv), and acrylate 19 (0.827 g, 3.9 mmol, 1.3 equiv) in
DMF (7.5 mL); the mixture was stirred at 70 °C for 42 h. Flash chro-
matography (column diameter 3.0 cm, cyclohexane–EtOAc, 12:1)
Anal. Calcd for C14H13F3O5 (318.2): C, 52.84; H, 4.12. Found: C,
53.00; H, 3.91.
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2259
and recrystallization [PE–t-BuOMe, 5:1] furnished (Z)-42 as a col-
orless solid; yield: 0.908 g (81%); mp 108–110 °C.
IR (KBr): 2980 2920, 1765, 1730, 1645, 1600, 1500, 1450, 1415,
1375, 1325, 1310, 1295, 1265, 1245, 1200, 1180, 1165, 1125, 1095,
1030, 980, 725 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.66 (s, 3¢¢-CH3), 1.76 (s, 3 H4¢¢),
2.32 (s, OCOCH3), 3.38 (d, J(H1¢¢,H2¢¢) = 7.3 Hz, 2 H1¢¢), 4.58 (q,
J(H,F) = 8.4 Hz, CH2CF3), 5.13 (s, CH2Ph), 5.30 (not entirely re-
solved tqq, J(H2¢¢,H1¢¢) = 7.3 Hz, 4J(H2¢¢,H4¢¢) ≈ 4J(H2¢¢,CH3) = 1.4
Hz, H2¢¢), 6.90 (d, J(H5¢,H6¢) = 8.5 Hz, H5¢), 7.32 (s, H3), over-
lapped by 7.30–7.45 (mc, H6¢, Ph), 7.48 (d, J(H2¢,H6¢) = 2.2 Hz,
H2¢).
IR (KBr): 2980, 1770, 1725, 1650, 1610, 1575, 1500, 1450, 1420,
1370, 1360, 1335, 1295, 1275, 1235, 1205, 1180, 1155, 1120, 1110,
1030, 950, 835, 655 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.34 [s, 2¢-(CH3)2], 1.82 (t,
J(H3¢,H4¢) = 6.8 Hz,
2 H3¢), 2.33 (s, OCOCH3), 2.77 (t,
J(H4¢,H3¢) = 6.7 Hz, 2 H4¢), 4.58 (q, J(H,F) = 8.4 Hz, CH2CF3),
6.78 (d, J(H8¢,H7¢) = 8.6 Hz, H8¢), 7.30 (s, H3), 7.32 (d,
4J(H5¢,H7¢) = 2.1 Hz, H5¢), 7.40 (dd, J(H7¢,H8¢) = 8.6 Hz,
4J(H7¢,H5¢) = 2.3 Hz, H7¢).
13C NMR (100 MHz, CDCl3): d = 17.9 (3¢¢-CH3), 20.6 (OCOCH3),
2
26.0 (C4¢¢), 28.6 (C1¢¢), 61.2 (q, J(C,F) = 36.9 Hz, CH2CF3), 70.1
13C NMR (100 MHz, CDCl3): d = 20.7 (OCOCH3), 22.5 (C4¢), 27.0
[most intense signal, 2¢-(CH3)2], 32.6 (C3¢), 61.2 (q, 2J(C,F) = 36.9
Hz, CH2CF3), 75.4 (C2¢), 118.2 (C8¢), 121.4 (C4a¢), 123.0 (q,
1J(C,F) = 277.2 Hz, CF3), 123.4 (C6¢), 129.9 (C7¢), 130.0 (C3),
132.8 (C5¢), 133.2 (C2), 156.6 (C8a¢), 161.5 (C1), 168.6
(OCOCH3).
(OCH2Ph), 111.7 (C5¢), 121.8 (C2¢¢), 123.0 (q, 1J(C,F) = 277.2 Hz,
CF3), 124.3 (C1¢), 127.3 (CBn2¢, CBn6¢), 128.2 (CBn4¢), 128.8 (CBn3¢,
CBn5¢), 129.9 (C3), 130.43 (C6¢), 131.69 (C2¢), 131.2, 133.5 (C3¢,
C2, C3¢¢), 136.8 (CBn1¢), 158.4 (C4¢), 161.5 (C1), 168.6 (OCOCH3).
HRMS: m/z [M+] calcd for C25H25F3O5: 462.1654; found: 462.1647.
Anal. Calcd for C18H19F3O5 (372.3): C, 58.06; H, 5.14. Found: C,
58.28; H, 4.96.
Preparation of Arylacetic Acids
(2,4-Dimethoxyphenyl)acetic Acid (36)
Following the three-step sequence typical procedure for 43, using
CuI (0.081 mg, 0.43 mmol, 5 mol%), 2-phenylphenol (0.145 g, 0.85
mmol, 10 mol%), Cs2CO3 (8.33 g, 25.6 mmol, 3.0 equiv), 1-iodo-
2,4-dimethoxybenzene (29, 2.25 g, 8.52 mmol), dimethyl malonate
(2.92 mL, 3.38 g, 25.6 mmol, 3.0 equiv), THF (15 mL), and DMF
(3.8 mL). Flash chromatography (column diameter 4.0 cm, cyclo-
hexane–EtOAc, 3:1) yielded the dimethyl ester of the arylmalonic
acid (1.94 g). After saponification of the dimethyl ester (1.48 g, 5.50
mmol) with aq 2 M NaOH (13.8 mL, 27.5 mmol, 5 equiv) in MeOH
(40 mL) and decarboxylation with Cu2O (0.039 g, 0.28 mmol,
5 mol%) in refluxing MeCN (140 mL) for 4 h, purification of the
residue by flash chromatography (column diameter 4.0 cm, cyclo-
hexane–EtOAc, 3:1 with 1 vol% HCO2H) furnished 36 as a color-
less solid; yield: 0.906 g (71% based on starting iodoarene); mp 99–
102 °C (Lit.55 102–105 °C).
1H NMR (300 MHz, CDCl3): d = 3.60 (s, 2 H2), 3.80, 3.81 (2 s, 2¢-
OCH3, 4¢-OCH3), 6.45 (d, presumably the high field part of an in-
completely resolved dd at d = 6.46, J(H5¢,H6¢) invisible,
4J(H5¢,H3¢) = 2.5 Hz, H5¢), partially overlapped by 6.47 [s (!), H3¢],
7.09 (br d, J(H6¢,H5¢) = 8.0 Hz, H6¢).
13C NMR (101 MHz, CDCl3): d = 35.2 (C2), 55.5, 55.6 (2¢-OCH3,
4¢-OCH3), 98.9 (C3¢), 104.4 (C5¢), 115.0 (C1¢), 131.4 (C6¢), 158.6,
160.6 (C2¢, C4¢), 178.2 (C1).
2,2,2-Trifluoroethyl (Z)-2-Acetoxy-3-[4-methoxy-3-(3-methyl-
but-2-enyl)phenyl]acrylate [(Z)-44]
Following the typical procedure for (Z)-31, using aryl iodide 46
(0.906 g, 3.0 mmol), NaHCO3 (0.630 g, 7.5 mmol, 2.5 equiv),
Bu4PBr (1.02 g, 3.0 mmol, 1.0 equiv), activated molecular sieves
(3Å, 1.20 g), hydroquinone (3.3 mg, 0.03 mmol, 1 mol%),
Pd(OAc)2 (33.7 mg, 0.15 mmol, 5 mol%), and acrylate 19 (1.15 g,
5.4 mmol, 1.8 equiv) in DMF (8 mL); the mixture was stirred at 75
°C for 36 h. Flash chromatography (column diameter 3.0 cm, cyclo-
hexane–EtOAc, 12:1) and recrystallization [PE–t-BuOMe, 10:1,
overnight at –30 °C] furnished (Z)-44 as a colorless solid; yield:
0.800 g (69%); mp 66–68 °C.
IR (KBr): 2965, 1775, 1730, 1645, 1600, 1500, 1465, 1445, 1420,
1355, 1325, 1285, 1260, 1245, 1200, 1165, 1110, 1040, 1025, 960,
915, 885, 815, 645 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.70 (s, 3¢¢-CH3), 1.77 (s, 3 H4¢¢),
2.32 (s, OCOCH3), 3.31 (d, J(H1¢¢,H2¢¢) = 7.3 Hz, 2 H1¢¢), 3.87 (s,
OMe), 4.58 (q, J(H,F) = 8.4 Hz, CH2CF3), 5.30 (not entirely re-
solved tqq, J(H2¢¢,H1¢¢) = 7.4 Hz, 4J(H2¢¢,H4¢¢) ≈ 4J(H2¢¢,CH3) = 1.4
Hz, H2¢¢), 6.85 (d, J(H5¢,H6¢) = 8.4 Hz, H5¢), 7.33 (s, H3), 7.44 (dd,
J(H6¢,H5¢) = 8.5 Hz, 4J(H6¢,H2¢) = 2.0 Hz, H6¢), overlapped by
7.45 [s (!), H2¢].
13C NMR (126 MHz, CDCl3): d = 17.9 (3¢¢-CH3), 20.6 (OCOCH3),
2
26.1 (C4¢¢), 28.2 (C1¢¢), 55.6 (OMe), 61.2 (q, J(C,F) = 36.8 Hz,
(2,2-Dimethylchroman-6-yl)acetic Acid (43); Typical Proce-
dure
1
CH2CF3), 110.3 (C5¢), 121.7 (C2¢¢), 123.0 (q, J(C,F) = 277.0 Hz,
CF3), 124.1 (C1¢), 130.0 (C3), 130.5 (C6¢), 131.4 (C2¢), 130.8,
133.4, 133. 6 (C3¢, C2, C3¢¢), 159.3 (C4¢), 161.5 (C1), 168.6
(OCOCH3).
A Schlenk tube was charged with CuI (0.043 g, 0.23 mmol, 5
mol%), 2-phenylphenol (0.077 g, 0.45 mmol, 10 mol%), and
Cs2CO3 (4.40 g, 13.5 mmol, 3.0 equiv) evacuated and flushed with
N2. The iodoarene 41 (1.30 g, 4.5 mmol), dimethyl malonate (1.54
mL, 1.78 g, 13.5 mmol, 3.0 equiv), THF (9 mL), and DMF (2.25
mL) were added through a rubber septum. The mixture was de-
gassed. After stirring at 70 °C for 48 h, the mixture was diluted with
t-BuOMe (20 mL), then washed successively with ice-water (15
mL), sat. aq NH4Cl (2 × 10 mL), and brine (10 mL). The organic
layer was dried (MgSO4) and the solvent was removed in vacuo.
Most of the excess dimethyl malonate was removed at 50 °C/0.133
mbar (overnight). Purification of the residue by flash chromatogra-
phy (column diameter 3.0 cm, cyclohexane–EtOAc, 5:1) yielded
the dimethyl arylmalonate (0.941 g) in an 81:19 mixture with di-
methyl malonate.
Anal. Calcd for C19H21F3O5 (386.4): C, 59.06; H, 5.48. Found: C,
59.35; H, 5.13.
2,2,2-Trifluoroethyl (Z)-2-Acetoxy-3-[4-(benzyloxy)-3-(3-meth-
ylbut-2-enyl)phenyl]acrylate [(Z)-51]
Following the typical procedure for (Z)-31, using aryl iodide 50
(1.51 g, 4.0 mmol), Et4NBr (0.420 g, 2.0 mmol, 0.5 equiv), hydro-
quinone (4.4 mg, 0.04 mmol, 1 mol%), Pd(OAc)2 (26.9 mg, 0.12
mmol, 3 mol%), Cy2NMe (1.03 mL, 4.8 mmol, 1.2 equiv), and acry-
late 19 (1.10 g, 5.2 mmol, 1.3 equiv) in DMF (10 mL); the mixture
was stirred at 70 °C for 36 h. Flash chromatography (column diam-
eter 3.0 cm, cyclohexane–EtOAc, 15:1) and recrystallization [PE–
Et2O, 10:1] furnished (Z)-51 as a colorless solid; yield: 1.44 g
(78%); mp 81–84 °C.
To a soln of this mixture (0.917 g, corresponding to 0.825 g of di-
ester, 2.82 mmol) in MeOH (25 mL) was added aq 2 M NaOH (7.05
mL, 14.1 mmol, 5 equiv) dropwise. After the addition, the mixture
was stirred at r.t. for 30 min and at reflux for 2 h. The mixture was
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2260
D. Bernier, R. Brückner
PAPER
diluted with H2O (35 mL), acidified under ice cooling first with aq
1 M HCl (14 mL) and subsequently with aq 0.1 M HCl to pH 3–4,
and extracted with CH2Cl2 (5 × 30 mL). The combined organic lay-
ers were dried (Na2SO4) and the solvent was removed in vacuo. The
crude arylacetic acid was dissolved in anhyd MeCN (75 mL). Cu2O
(20.2 mg, 0.141 mmol, 5 mol%) was added and the mixture was re-
fluxed 5 h under inert atmosphere. The solvent was removed in vac-
uo. The residue was dissolved in CH2Cl2 (25 mL) and washed with
aq 0.5 M HCl (2 × 10 mL). The organic layer was dried (Na2SO4)
and the solvent was removed in vacuo. Purification of the residue
by flash chromatography (column diameter 2.0 cm, cyclohexane–
EtOAc, 4:1 with 1 vol% HCO2H) furnished 43 as a colorless solid;
yield: 0.441 g (45% based on starting iodoarene); mp 88–90 °C.
yielded the dimethyl arylmalonate (1.59 g). After saponification of
the dimethyl ester (0.956 g) with aq 2 M NaOH (6.25 mL, 12.5
mmol, 5 equiv) in MeOH (15 mL) and decarboxylation with Cu2O
(18 mg, 0.12 mmol, 5 mol%) in refluxing MeCN (50 mL) for 7 h,
purification of the residue by flash chromatography (column diam-
eter 2.0 cm, cyclohexane–EtOAc, 3:1) furnished 52 as a colorless
solid; yield: 0.615 g (43% based on starting iodoarene); mp 95–98
°C.
IR (film): 2965, 2915, 2850, 1705, 1605, 1500, 1450, 1410, 1380,
1255, 1210, 1175, 1115, 1095, 1025, 795, 725, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.65, 1.73 (2 br s, 3¢¢-CH3, 3 H4¢¢),
3.36 (d, J(H1¢¢,H2¢¢) = 7.3 Hz, 2 H1¢¢), 3.56 (s, 2 H2), 5.06 (s,
OCH2Ph), 5.30 (incompletely resolved tqq, J(H2¢¢,H1¢¢) = 7.3 Hz,
4J(H2¢¢,3 H4¢¢) ≈ 4J(H2¢¢,3¢¢-CH3) = 1.2 Hz, H2¢¢), 6.84 (d,
J(H5¢,H6¢) = 8.9 Hz, H5¢), 7.26–7.45 (m, HBn, H2¢, H6¢), 10.86 (br
s, COOH).
13C NMR (75 MHz, CDCl3): d = 17.9 (3¢¢-CH3), 25.9 (C4¢¢), 28.9
(C1¢¢), 40.4 (C2), 70.2 (OCH2Ph), 111.9 (C5¢), 122.5 (C2¢¢), 125.5,
131.0, 132.7 (C1¢, C3¢, C3¢¢), 127.3, 128.6 (CBn2/CBn6, CBn3/CBn5),
127.8, 127.9 (C2¢, CBn4), 130.74 (C6¢), 137.5 (CBn1), 155.9 (C4¢),
177.9 (C1).
IR (film): 2975, 2930, 2850, 1705, 1610, 1580, 1495, 1435, 1410,
1385, 1345, 1295, 1265, 1235, 1205, 1185, 1155, 1120, 945, 895,
885 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.32 [s, 2¢-(CH3)2], 1.78 (t,
J(H3¢,H4¢) = 6.7 Hz, 2 H3¢), 2.75 (t, J(H4¢,H3¢) = 6.7 Hz, 2 H4¢),
3.53 (s, 2 H2), 6.73 (d, J(H8¢,H7¢) = 7.9 Hz, H8¢), 6.97 (s, H5¢),
overlapped in part by 6.98 (dd, J(H7¢,H8¢) = 7.9 Hz,
J(H7¢,H5¢) = 2.3 Hz, H7¢).
13C NMR (101 MHz, CDCl3): d = 22.57 (C4¢), 27.03 [s, 2¢-(CH3)2],
32.87 (C3¢), 40.35 (C2), 74.42 (C2¢), 117.60 (C8¢), 121.20 (C4a¢),
124.33 (C6¢), 128.39 (C7¢), 130.44 (C5¢), 153.50 (C8a¢), 178.11
(C1).
HRMS: m/z [M+] calcd for C20H22O3: 310.1569; found: 310.1572.
Transesterification
2,2,2-Trifluoroethyl (Z)-3-Phenyl-2-(phenylacetoxy)acrylate
[(Z)-38a]
HRMS: m/z [M+] calcd for C13H16O3: 220.1099; found: 220.1107
Following the typical procedure for (Z)-38i, using 1.0 M lithium
2,2,2-trifluoroethoxide in THF (3.00 mL, 3.00 mmol, 1.5 equiv),
(Z)-31 (0.576 g, 2.00 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-
methylphenol (8.8 mg, 0.04 mmol, 2 mol%) in THF (20 mL) and
workup with Dowex 50WX8-100 (1.50 g, corresponding to 0.5 g/
mmol of substrate). After esterification of the resulting enol with
phenylacetic acid (35, 0.30 g, 2.2 mmol, 1.1 equiv), DCC (0.45 g,
2.2 mmol, 1.1 equiv), and DMAP (4.9 mg, 0.04 mmol, 2 mol%) in
CH2Cl2 (30 mL), purification of the residue by flash chromatogra-
phy (column diameter 3.5 cm, cyclohexane–EtOAc, 10:1) and re-
crystallization [PE–Et2O, 10:1] furnished (Z)-38a as a colorless
solid; yield: 0.434 g (60%); mp 41–44 °C.
[(4-Methoxy-3-(3-methylbut-2-enyl)phenyl]acetic Acid (45)
Following the three-step sequence typical procedure for 43, using
CuI (0.095 g, 0.5 mmol, 5 mol%), 2-phenylphenol (0.17 g, 1.0
mmol, 10 mol%), Cs2CO3 (9.77 g, 30.0 mmol, 3.0 equiv), the io-
doarene 46 (3.02 g, 10.0 mmol), dimethyl malonate (3.43 mL, 3.96
g, 30.0 mmol, 3.0 equiv), THF (20 mL), and DMF (5 mL). Flash
chromatography (column diameter 5.0 cm, cyclohexane–EtOAc,
7:1) yielded the dimethyl arylmalonate (2.97 g) as a 64:36 mixture
with dimethyl malonate. After saponification of this mixture (2.45
g) with aq 2 M NaOH (20.0 mL, 40.0 mmol, 5 equiv) in MeOH (60
mL) and decarboxylation with Cu2O (57.2 mg, 0.40 mmol, 5 mol%)
in refluxing MeCN (200 mL) for 5 h, purification of the residue by
flash chromatography (column diameter 4.0 cm, cyclohexane–
EtOAc, 4:1 with 1 vol% HCO2H) furnished 45 as a colorless oil;
yield: 1.53 g (64% based on starting iodoarene).
IR (CDCl3): 3065, 3035, 2970, 1765, 1740, 1650, 1600, 1495, 1450,
1410, 1310, 1290, 1255, 1230, 1200, 1175, 1105, 1025, 975 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.89 (s, OCOCH2Ar), 4.58 (q,
J(H,F) = 8.3 Hz, CH2CF3), 7.18–7.40 (H3, 2 × 5 Ph-H).
IR (film): 2980, 2915, 2835, 1755, 1710, 1500, 1440, 1410, 1375,
1295, 1250, 1120, 1035 cm–1.
13C NMR (75 MHz, CDCl3): d = 41.2 (OCOCH2Ar), 61.4 (q,
1
2J(C,F) = 37.0 Hz, CH2CF3), 123.0 (q, J(C,F) = 277.1 Hz, CF3),
1H NMR (400 MHz, CDCl3): d = 1.69 (br s, 3¢¢-CH3), 1.73 (d,
4J(H4¢¢,H2¢¢) = 1.4 Hz, 3 H4¢¢), 3.29 (d, J(H1¢¢,H2¢¢) = 7.3 Hz, 2
H1¢¢), 3.55 (s, 2 H2), 3.80 (s, OCH3), 5.28 (incompletely resolved
127.8 (C4¢¢), 128.9, 129.0, 129.8, 130.6 (C3¢, C5¢, C3¢¢, C5¢¢, C2¢¢,
C6¢¢, C2¢, C6¢), 129.7 (C3), 130.42 (C4¢), 131.5 (C1¢), 132.7 (C1¢¢),
135.5 (C2), 161.2 (C1), 168.9 (OCOCH2Ar).
4
4
tqq, J(H2¢¢,H1¢¢) = 7.3 Hz, J(H2¢¢,H4¢¢) ≈ J(H2¢¢,3¢¢-CH3) = 1.4
Hz, H2¢¢), 6.79 (d, J(H5¢,H6¢) = 8.3 Hz, H5¢), 7.02 (d,
4J(H2¢,H6¢) = 2.0 Hz, H2¢), 7.07 (dd, J(H6¢,H5¢) = 8.2 Hz,
4J(H6¢,H2¢) = 2.4 Hz, H6¢).
Anal. Calcd for C19H15F3O4 (364.3): C, 62.64; H, 4.15. Found: C,
62.81; H, 3.97.
2,2,2-Trifluoroethyl (Z)-2-[(4-Methoxyphenyl)acetoxy)]-3-phe-
nylacrylate [(Z)-38b]
13C NMR (101 MHz, CDCl3): d = 17.9 (3¢¢-CH3), 25.9 (C4¢¢), 28.5
(C1¢¢), 40.4 (C2), 55.6 (MeO), 110.5 (C5¢), 122.4 (C2¢¢), 125.1,
130.5, 132.7 (C1¢, C3¢, C3¢¢), 127.8 (C6¢), 130.5 (C2¢), 156.8 (C4¢),
178.5 (C1).
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (2.25 mL, 2.25 mmol, 1.5 equiv),
(Z)-31 (0.432 g, 1.5 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (5.3 mg, 0.02 mmol, 1.6 mol%) in THF (15 mL) and work-
up with Dowex 50WX8-100 (2.25 g, corresponding to 1.0 g/mmol
of substrate). After esterification of the resulting enol with (4-meth-
oxyphenyl)acetic acid (8, 0.26 g, 1.58 mmol, 1.05 equiv), DCC
(0.34 g, 1.65 mmol, 1.1 equiv), and DMAP (5.5 mg, 0.045 mmol, 3
mol%) in CH2Cl2 (20 mL), purification of the residue by flash chro-
matography (column diameter 3.5 cm, cyclohexane–EtOAc, 10:1)
and recrystallization [PE–Et2O, 8:1] furnished (Z)-38b as a color-
less solid; yield: 0.516 g (87%); mp 48–50 °C.
HRMS: m/z [M+] calcd for C14H18O3: 234.1256; found: 234.1262.
2-[4-(Benzyloxy)-3-(3-methylbut-2-enyl)phenyl]acetic Acid (52)
Following the three-step sequence typical procedure for 43, using
CuI (72 mg, 0.38 mmol, 5 mol%), 2-phenylphenol (0.13 g, 0.76
mmol, 10 mol%), Cs2CO3 (7.43 g, 22.8 mmol, 3.0 equiv), the io-
doarene 50 (2.87 g, 7.60 mmol), dimethyl malonate (2.61 mL, 22.8
mmol, 3.0 equiv), THF (15 mL), and DMF (4 mL). Flash chroma-
tography (column diameter 5.0 cm, cyclohexane–EtOAc, 9:1)
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2261
IR (CDCl3): 3005, 2965, 2935, 2910, 2840, 1765, 1740, 1650, 1615,
1585, 1515, 1495, 1465, 1450, 1410, 1290, 1250, 1180, 1105, 1035,
975 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.82 (s, 4¢¢-OCH3), 3.83 (s,
OCOCH2Ar), 4.58 (q, J(H,F) = 8.4 Hz, CH2CF3), AA¢BB¢ signal
centered at 6.91 (H3¢¢, H5¢¢) and 7.29 (H2¢¢, H6¢¢), overlapped by
7.29 (s, H3), 7.20–7.40 (m, 5 Ph-H).
1H NMR (300 MHz, CDCl3): d = 3.80, 3.83 (2 s, 4¢-OCH3, 4¢¢-
OCH3), 3.83 (s, OCOCH2Ar), 4.57 (q, J(H,F) = 8.4 Hz, CH2CF3),
AA¢BB¢ signal centered at 6.73 (H3¢, H5¢)* and 7.29 (H2¢, H6¢),
AA¢BB¢ signal centered at 6.92 (H3¢¢, H5¢¢)* and 7.30 (H2¢¢, H6¢¢),
overlaps partially 7.29 (s, H3); *assignment interchangeable.
13C NMR (126 MHz, CDCl3): d = 40.4 (OCOCH2Ar), 55.4, 55.5 (2
s, 4¢-OCH3, 4¢¢-OCH3), 61.2 (q, 2J(C,F) = 36.9 Hz, CH2CF3), 114.3,
1
114.4 (C3¢, C5¢, C3¢¢, C5¢¢), 123.0 (q, J(C,F) = 277.2 Hz, CF3),
13C NMR (75 MHz, CDCl3): d = 40.3 (OCOCH2Ar), 55.5 (4¢¢-
124.2, 124.9 (C1¢, C1¢¢), 129.5 (C3), 130.9 (C2¢¢, C6¢¢), 132.5 (C2¢,
C6¢), 133.7 (C2), 159.2, 161.3, (C4¢, C4¢¢), 161.4 (C1), 169.3
(OCOCH2Ar).
2
OCH3), 61.4 (q, J(C,F) = 36.9 Hz, CH2CF3), 114.4 (C3¢¢, C5¢¢),
123.0 (q, 1J(C,F) = 277.2 Hz, CF3), 124.7 (C1¢¢), 129.6, 130.4 (each
signal half as intense as both following peaks, C3, C4¢), 128.8,
130.6,, 130.8 (C3¢, C5¢, C2¢, C6¢, C2¢¢, C6¢¢), 131.5 (C1¢), 133.5
(C2), 159.3 (C4¢¢), 161.2 (C1), 169.2 (OCOCH2Ar).
Selected signal from gated-decoupled 13C NMR (126 MHz,
CDCl3): d = 161.4 (d, 3J(C1,H3) = 3.9 Hz, C1).
Anal. Calcd for C20H17F3O5 (394.3): C, 60.92; H, 4.35. Found: C,
60.82; H, 4.13.
Anal. Calcd for C21H19F3O6 (424.4): C, 59.44; H, 4.51. Found: C,
59.40; H, 4.31.
2,2,2-Trifluoroethyl (Z)-3-(4-Methoxyphenyl)-2-(phenylacet-
oxy)acrylate [(Z)-38c]
2,2,2-Trifluoroethyl (Z)-2-[(2,4-Dimethoxyphenyl)acetoxy]-3-
(4-methoxyphenyl)acrylate [(Z)-38e]
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (2.25 mL, 2.25 mmol, 1.5 equiv),
(Z)-32 (0.477 g, 1.5 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (5.3 mg, 0.02 mmol, 1.6 mol%) in THF (15 mL) and work-
up with Dowex 50WX8-100 (2.25 g, corresponding to 1.0 g/mmol
of substrate). After esterification of the resulting enol with pheny-
lacetic acid (35, 0.21 g, 1.58 mmol, 1.05 equiv), DCC (0.34 g, 1.65
mmol, 1.1 equiv), and DMAP (5.5 mg, 0.045 mmol, 3 mol%) in
CH2Cl2 (20 mL), purification of the residue by flash chromatogra-
phy (column diameter 3.5 cm, cyclohexane–EtOAc, 10:1) and re-
crystallization [PE–Et2O, 8:1] furnished (Z)-38c as a colorless solid;
yield: 0.542 g (92%); mp 81–83 °C.
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (1.95 mL, 1.95 mmol, 1.3 equiv),
(Z)-32 (0.477 g, 1.5 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (5.3 mg, 0.02 mmol, 1.6 mol%) in THF (15 mL) and work-
up with Dowex 50WX8-100 (0.75 g, corresponding to 0.5 g/mmol
of substrate). After esterification of the resulting enol with (2,4-
dimethoxyphenyl)acetic acid (36, 0.32 g, 1.65 mmol, 1.1 equiv),
DCC (0.34 g, 1.65 mmol, 1.1 equiv), and DMAP (3.7 mg, 0.03
mmol, 2 mol%) in CH2Cl2 (20 mL), purification of the residue by
flash chromatography (column diameter 3.5 cm, cyclohexane–
EtOAc, 7:1) and recrystallization [PE–t-BuOMe, 6:1] furnished
(Z)-38e as a colorless solid; yield: 0.559 g (82%); mp 87–89 °C.
IR (KBr): 3000, 2960, 2940, 2845, 1760, 1720, 1645, 1600, 1510,
1495, 1460, 1420, 1360, 1325, 1290, 1250, 1230, 1175, 1165, 1135,
1120, 1110, 1030, 965, 835, 715 cm–1.
IR (KBr): 2970, 2935, 2840, 1770, 1730, 1650, 1620, 1605, 1515,
1465, 1445, 1420, 1405, 1350, 1330, 1315, 1305, 1255, 1210, 1180,
1160, 1130, 1110, 1040, 975, 830 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.80 (s, 4¢-OCH3), 3.90 (s,
OCOCH2Ar), 4.57 (q, J(H,F) = 8.8 Hz, CH2CF3), AA¢BB¢ signal
centered at 6.72 (H3¢, H5¢) and 7.29 (H2¢, H6¢), overlapped by 7.29
(s, H3), 7.33–7.42 (mC, 5 Ph-H).
13C NMR (126 MHz, CDCl3): d = 41.3 (OCOCH2Ar), 55.4 (4¢-
OCH3), 61.2 (q, 2J(C,F) = 36.9 Hz, CH2CF3), 114.3 (C3¢, C5¢),
123.0 (q, 1J(C,F) = 277.2 Hz, CF3), 124.2 (C1¢), 127.7 (half as in-
tense as the following peak, C4¢¢), 129.0, 129.8 (C2¢¢, C6¢¢, C3¢¢,
C5¢¢), 129.5 (C3), 132.5 (C2¢, C6¢), 132.8, 133.6 (C2, C1¢¢), 161.31,
161.35 (C1, C4¢), 168.9 (OCOCH2Ar).
1H NMR (300 MHz, CDCl3): d = 3.75, 3.82, 3.83 (3 s, 2¢¢-OCH3, 4¢-
OCH3, 4¢¢-OCH3), 3.84 (s, OCOCH2Ar), 4.57 (q, J(H,F) = 8.4 Hz,
4
CH2CF3), 6.49 (dd, J(H5¢¢,H6¢¢) = 9.0 Hz, J(H5¢¢,H3¢¢) = 2.4 Hz,
H5¢¢), overlaps 6.50 (d, 4J(H3¢¢,H5¢¢) = 2.2 Hz, H3¢¢), AA¢BB¢ signal
centered at 6.81 (H3¢, H5¢) and 7.44 (H2¢, H6¢), 7.19 (d,
J(H6¢¢,H5¢¢) = 9.1 Hz, H6¢¢), 7.27 (s, H3).
13C NMR (75 MHz, CDCl3): d = 35.3 (OCOCH2Ar), 55.4, 55.56,
2
55.59 (2¢¢-OCH3, 4¢-OCH3, 4¢¢-OCH3), 61.2 (q, J(C,F) = 36.9 Hz,
CH2CF3), 98.8 (C3¢¢), 104.4 (C5¢¢), 114.3 (C3¢, C5¢), 114.4 (C1¢¢),
1
123.1 (q, J(C,F) = 277.2 Hz, CH2CF3), 124.5 (C1¢), 129.1 (C3),
131.7 (C6¢¢), 132.7 (C2¢, C6¢), 133.9 (C2), 158.7, 160.7, 161.2 (C4¢,
Anal. Calcd for C20H17F3O5 (394.3): C, 60.92; H, 4.35. Found: C,
61.03; H, 4.24.
C3¢¢, C4¢¢), 161.5 (C1), 169.6 (OCOCH2Ar).
Selected signals from undecoupled 13C NMR spectrum (126 MHz,
CDCl3) with selective irradiation at d(OCH2CH3) = 4.57: d = 161.5
(d, J(C1,H3) = 3.9 Hz, C1), overlapped by 158.7, 160.7, and 161.2
(3 mC, C4¢, C3¢¢, C4¢¢), 169.6 (t, 2J(CH2) = 8.0 Hz, OCOCH2Ar).
2,2,2-Trifluoroethyl (Z)-3-(4-Methoxyphenyl)-2-[(4-methoxy-
phenyl)acetoxy]acrylate [(Z)-38d = (Z)-5]
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (2.25 mL, 2.25 mmol, 1.5 equiv),
(Z)-32 (0.477 g, 1.5 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (5.3 mg, 0.02 mmol, 1.6 mol%) in THF (15 mL) and work-
up with Dowex 50WX8-100 (2.25 g, corresponding to 1.0 g/mmol
of substrate). After esterification of the resulting enol with (4-meth-
oxyphenyl)acetic acid (8, 0.26 g, 1.58 mmol, 1.05 equiv), DCC
(0.34 g, 1.65 mmol, 1.1 equiv), and DMAP (5.5 mg, 0.045 mmol,
3 mol%) in CH2Cl2 (20 mL), purification of the residue by flash
chromatography (column diameter 3.5 cm, cyclohexane–EtOAc,
10:1) and recrystallization [PE–Et2O, 5:1] furnished (Z)-38d as a
colorless solid; yield: 0.458 g (72%); mp 100–101 °C.
HRMS: m/z [M+] calcd for C22H21F3O7: 454.1239; found: 454.1229.
2,2,2-Trifluoroethyl (Z)-2-[(3,4-Dimethoxyphenyl)acetoxy]-3-
(4-methoxyphenyl)acrylate [(Z)-38f]
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (1.95 mL, 1.95 mmol, 1.3 equiv),
(Z)-32 (0.477 g, 1.5 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (5.3 mg, 0.02 mmol, 1.6 mol%) in THF (15 mL) and work-
up with Dowex 50WX8-100 (0.75 g, corresponding to 0.5 g/mmol
of substrate). After esterification of the resulting enol with (3,4-
dimethoxyphenyl)acetic acid (37, 0.32 g, 1.65 mmol, 1.1 equiv),
DCC (0.34 g, 1.65 mmol, 1.1 equiv), and DMAP (3.7 mg, 0.03
mmol, 2 mol%) in CH2Cl2 (20 mL), purification of the residue by
flash chromatography (column diameter 3.5 cm, cyclohexane–
IR (KBr): 2985, 2965, 2935, 2840, 1770, 1725, 1645, 1605, 1570,
1515, 1425, 1405, 1345, 1315, 1305, 1295, 1255, 1205, 1180, 1170,
1115, 1035, 1015, 975, 830, 775 cm–1.
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2262
D. Bernier, R. Brückner
PAPER
EtOAc, 5:1) and recrystallization [PE–t-BuOMe, 6:1] furnished
(Z)-38f as a colorless solid; yield: 0.573 g (84%); mp 79–81 °C.
in CH2Cl2 (20 mL), purification of the residue by flash chromatog-
raphy (column diameter 3.5 cm, cyclohexane–EtOAc, 5:1) and re-
crystallization [PE–t-BuOMe, 5:1] furnished (Z)-38h as a colorless
solid; yield: 0.532 g (78%); mp 78–81 °C.
IR (CDCl3): 2965, 2940, 2840, 1760, 1740, 1650, 1605, 1515, 1465,
1420, 1290, 1260, 1170, 1115, 1100, 1030, 975, 960 cm–1.
IR (KBr): 2960, 2930, 2910, 2840, 1760, 1740, 1645, 1595, 1520,
1465, 1410, 1345, 1325, 1270, 1250, 1235, 1185, 1170, 1140, 1120,
1100, 1025, 965, 805, 650 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.78, 3.81, 3.89 (3 s, 3¢-OCH3, 4¢-
OCH3, 4¢¢-OCH3), 3.85 (s, OCOCH2Ar), 4.57 (q, J(H,F) = 8.4 Hz,
CH2CF3), AA¢BB¢ signal centered at 6.90 (H3¢¢, H5¢¢) and 7.28
(H2¢¢, H6¢¢), 6.71 (d, J(H5¢,H6¢) = 8.5 Hz, H5¢), 7.00 (d,
J(H6¢,H5¢) = 8.5 Hz, H6¢), 7.04 [s (!), H2¢], 7.31 (s, H3).
13C NMR (126 MHz, CDCl3): d = 40.3 (OCOCH2Ar), 55.4, 55.9,
56.0 (3¢-OCH3, 4¢-OCH3, 4¢¢-OCH3), 61.3 (q, 2J(C,F) = 37.3,
CH2CF3), 111.1 (C5¢), 113.3 (C2¢), 114.3 (C3¢¢, C5¢¢), 123.0 (q,
1J(C,F) = 277.2, CF3), 124.1, 124.7 (C1¢, C1¢¢), 124.7 (C6¢), 129.7
(C3), 130.7 (C2¢¢, C6¢¢), 134.0 (C2), 148.9, 151.1, 159.2 (C3¢, C4¢,
C4¢¢), 161.3 (C1), 169.3 (OCOCH2Ar).
1H NMR (300 MHz, CDCl3): d = 3.80, 3.85, 3.90 (3 s, 3¢¢-OCH3, 4¢-
OCH3, 4¢¢-OCH3), 3.84 (s, OCOCH2Ar), 4.57 (q, J(H,F) = 8.3 Hz,
CH2CF3), 6.84–6.96 (m, H2¢¢, H5¢¢, H6¢¢), 7.30 (s, H3), overlapped
by low-field part of AA¢BB¢ signal centered at 6.73 (H3¢, H5¢) and
7.30 (H2¢, H6¢).
13C NMR (75 MHz, CDCl3): d = 40.9 (OCOCH2Ar), 55.4, 56.0,
2
56.1 (3¢¢-OCH3, 4¢-OCH3, 4¢¢-OCH3), 61.2 (q, J(C,F) = 36.9 Hz,
CH2CF3), 111.6 (C2¢¢), 112.8 (C5¢¢), 114.3 (C3¢, C5¢), 122.1 (C6¢¢),
123.0 (q, 1J(C,F) = 277.1 Hz, CF3), 124.2, 125.3 (C1¢, C1¢¢), 129.6
(C3), 132.6 (C2¢, C6¢), 133.7 (C2), 148.7, 149.4 (C3¢¢, C4¢¢), 161.4
(C1, C4¢), 169.2 (OCOCH2Ar).
Anal. Calcd for C22H21F3O7 (454.4): C, 58.15; H, 4.66. Found: C,
58.16; H, 4.55.
2,2,2-Trifluoroethyl (Z)-3-(2,4-Dimethoxyphenyl)-2-[(4-meth-
oxyphenyl)acetoxy]acrylate [(Z)-38g]
Selected signals from undecoupled 13C NMR spectrum (126 MHz,
CDCl3) with selective irradiation at d(OCH2CH3) = 4.57: d = 148.9,
151.1, 159.2 (3 mC, C3¢, C4¢, C4¢¢), 161.3 (d, J(C1,H3) = 3.8 Hz,
C1), 169.3 (t, 2J(CH2) = 8.0 Hz, OCOCH2Ar).
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (1.95 mL, 1.95 mmol, 1.3 equiv),
(Z)-33 (0.522 g, 1.5 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (5.3 mg, 0.02 mmol, 1.6 mol%) in THF (15 mL) and work-
up with Dowex 50WX8-100 (0.75 g, corresponding to 0.5 g/mmol
of substrate). After esterification of the resulting enol with (4-meth-
oxyphenyl)acetic acid (8, 0.27 g, 1.65 mmol, 1.1 equiv), DCC (0.34
g, 1.65 mmol, 1.1 equiv), and DMAP (3.7 mg, 0.03 mmol, 2 mol%)
in CH2Cl2 (20 mL), purification of the residue by flash chromatog-
raphy (column diameter 3.5 cm, cyclohexane–EtOAc, 5:1) and re-
crystallization [PE–Et2O, 5:1] furnished (Z)-38f as a colorless solid;
yield: 0.559 g (82%); mp 83–86 °C.
HRMS: m/z [M+] calcd for C22H21F3O7: 454.1239; found: 454.1252.
2,2,2-Trifluoroethyl (Z)-3-(2,2-Dimethylchroman-6-yl)-2-[(2,2-
dimethylchroman-6-yl)acetoxy]acrylate [(Z)-38i]; Typical
Procedure
A soln of 1 M lithium 2,2,2-trifluoroethoxide in THF (0.40 mL,
0.40 mmol, 1.5 equiv) was added dropwise over 5 min to an ice-
cooled soln of (Z)-42 (0.10 mg, 0.27 mmol, 1.0 equiv), and 2,6-di-
tert-butyl-4-methylphenol (1.2 mg, 5.5 mmol, 2 mol%) in THF (5
mL). After 90 min at this temperature, Dowex 50WX8-100 (0.27 g,
corresponding to 1 g/mmol of substrate) was added. The suspension
was stirred at r.t. for 15 min. The resin was removed quickly by fil-
tration, and the solvent was removed in vacuo. The intermediate
should not be exposed to air since this provides some of the corre-
sponding aldehyde by oxidative cleavage of the C=C bond. Under
N2, the residue was dissolved in CH2Cl2 and the arylacetic acid 43
(0.055 g, 0.27 mmol, 1.0 equiv), DCC (0.061 g, 0.30 mmol, 1.1
equiv), and DMAP (3.3 mg, 0.03 mmol, 10 mol%) were added. Af-
ter stirring at r.t. for 6 h, the mixture was diluted with PE (15 mL).
The precipitated N,N¢-dicyclohexylurea was filtered off and the sol-
vent was removed in vacuo. Purification of the residue by flash
chromatography (column diameter 2.0 cm, cyclohexane–EtOAc,
12:1) and recrystallization [PE–Et2O, 5:1] furnished (Z)-38h as a
colorless solid; yield: 0.126 g (88%); mp 128–131 °C.
IR (CDCl3): 2980, 2935, 2875, 1760, 1735, 1655, 1610, 1575, 1560,
1540, 1515, 1460, 1385, 1350, 1295, 1250, 1215, 1170, 1120, 1075,
1035, 940, 910, 895, 885, 845, 775 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.80, 3.81, 3.82 (3 s, 2¢-OCH3, 4¢-
OCH3, 4¢¢-OCH3), 3.81 (s, OCOCH2Ar), 4.57 (q, J(H,F) = 8.4 Hz,
CH2CF3), 6.19 (dd, J(H5¢,H6¢) = 8.7 Hz, 4J(H5¢,H3¢) = 2.4 Hz,
H5¢), 6.38 (d, 4J(H3¢,H5¢) = 2.2 Hz, H3¢), AA¢BB¢ signal centered at
6.90 (H3¢¢, H5¢¢) and 7.28 (H2¢¢, H6¢¢), 7.26 (d, J(H6¢,H5¢) = 8.2 Hz,
H6¢), 7.78 (s, H3).
13C NMR (126 MHz, CDCl3): d = 40.4 (OCOCH2Ar), 55.4, 55.5,
2
55.8 (2¢-OCH3, 4¢-OCH3, 4¢¢-OCH3), 61.1 (q, J(C,F) = 36.9 Hz,
CH2CF3), 98.1 (C3¢), 105.2 (C5¢), 113.6 (C1¢), 114.3 (C3¢¢, C5¢¢),
123.1 (q, 1J(C,F) = 277.2 Hz, CF3), 123.8 (C3), 125.0 (C1¢¢), 130.8
(C2¢¢, C6¢¢), 131.6 (C6¢), 133.4 (C2), 159.1, 159.8, 162.9 (C2¢, C4¢,
C4¢¢), 161.6 (C1), 169.3 (OCOCH2Ar).
IR (CDCl3): 2980, 2935, 2855, 1760, 1735, 1645, 1605, 1575, 1495,
1470, 1450, 1420, 1370, 1335, 1310, 1285, 1260, 1225, 1205, 1170,
1155, 1120, 1030, 980, 950 cm–1.
Selected signals from undecoupled 13C NMR spectrum (126 MHz,
CDCl3) with selective irradiation at d(OCH2CH3) = 4.57: d = 159.1,
159.8, 162.9 (3 mC, C2¢, C4¢, C4¢¢), 161.6 (d, J(C1,H3) = 4.2 Hz,
C1), 169.3 (t, 2J(CH2) = 7.8 Hz, OCOCH2Ar).
1H NMR (500 MHz, CDCl3): d = 1.32, 1.34 [2 s, 2¢-(CH3)2, 2¢¢-
(CH3)2], 1.77, 1.79 (2 t, J(H3¢,H4¢) = J(H3¢¢,H4¢¢) = 6.8 Hz, 2 H3¢,
2 H3¢¢), 2.63, 2.75 (2 t, J(H4¢,H3¢) = J(H4¢¢,H3¢¢) = 6.8 Hz, 2 H4¢, 2
H4¢¢), 3.79 (s, OCOCH2Ar), 4.56 (q, J(H,F) = 8.4 Hz, CH2CF3),
6.61 (d, J = 8.5 Hz), 6.78 (d, J = 8.3 Hz) [H8¢, H8¢¢], 7.09 (dd,
Anal. Calcd for C22H21F3O7 (454.4): C, 58.15; H, 4.66. Found: C,
58.07; H, 4.49.
4
4
J = 8.2 Hz, J = 2.2 Hz), 7.15 (dd, J = 8.5 Hz, J = 2.2 Hz) [H7¢,
H7¢¢], 7.06 (d, 4J = 2.0 Hz), 7.17 (d, 4J = 2.0 Hz) [H5¢, H5¢¢], 7.27 (s,
H3).
2,2,2-Trifluoroethyl (Z)-3-(3,4-Dimethoxyphenyl)-2-[(4-meth-
oxyphenyl)acetoxy]acrylate [(Z)-38h]
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (1.95 mL, 1.95 mmol, 1.3 equiv),
(Z)-34 (0.522 g, 1.5 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (5.3 mg, 0.02 mmol, 1.6 mol%) in THF (15 mL) and work-
up with Dowex 50WX8-100 (0.75 g, corresponding to 0.5 g/mmol
of substrate). After esterification of the resulting enol with (4-meth-
oxyphenyl)acetic acid (8, 0.27 g, 1.65 mmol, 1.1 equiv), DCC (0.34
g, 1.65 mmol, 1.1 equiv), and DMAP (3.7 mg, 0.03 mmol, 2 mol%)
13C NMR (126 MHz, CDCl3): d = 22.4, 22.6 (C4¢, C4¢¢), 27.04,
27.05 [2¢-(CH3)2, 2¢¢-(CH3)2], 32.7, 32.9 (C3¢, C3¢¢), 40.4
(OCOCH2Ar), 61.2 (q, 2J(C,F) = 36.8 Hz, CH2CF3), 74.5, 75.3
(C2¢, C2¢¢), 117. 7, 117.9 (C8¢, C8¢¢), 123.1 (q, 1J(C,F) = 277.2 Hz,
CH2CF3), 121.31, 121.34, 123.3, 123.7 (C6¢, C6¢¢, C4a¢, C4a¢¢),
130.0 (C3), 128.6, 130.3 (C7¢, C7¢¢), 130.7, 132.9 (C5¢, C5¢¢), 133.2
(C2), 153.7, 156.5 (C8a¢, C8a¢¢), 161.5 (C1), 169.6 (OCOCH2Ar).
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2263
Anal. Calcd for C29H31F3O6 (532.55): C, 65.40; H, 5.87. Found: C,
65.40; H, 5.78.
preted as an incompletely resolved tqq, J(H2¢¢¢,H1¢¢¢) = 7.3 Hz,
4J(H2¢¢¢,H4¢¢¢) ≈ 4J(H2¢¢¢,3¢¢¢-CH3) = 1.4 Hz, H2¢¢¢), 6.59 (d,
J(H8¢,H7¢) = 8.5 Hz, H8¢), 6.88 (mc, interpreted as d,
J(H5¢¢,H6¢¢) = 9.1 Hz, H5¢¢), 7.12 (dd, J(H7¢,H8¢) = 8.5 Hz,
4J(H7¢,H5¢) = 2.2 Hz, H7¢), 7.13–7.17 (m, H5¢, H2¢¢, H6¢¢), 7.27 (s,
H3), 7.32 (mC, HBn4), 7.39 (mC, HBn3, HBn5), 7.45 (mC, HBn2, HBn6).
2,2,2-Trifluoroethyl (Z)-3-(2,2-Dimethylchroman-6-yl)-2-
{[4-methoxy-3-(3-methylbut-2-enyl)phenyl]acetoxy}acrylate
[(Z)-38j]
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (0.40 mL, 0.40 mmol, 1.5 equiv),
(Z)-42 (0.10 g, 0.27 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (1.2 mg, 5.5 mmol, 2 mol%) in THF (5 mL) and workup
with Dowex 50WX8-100 (0.27 g, corresponding to 1.0 g/mmol of
substrate). After esterification of the resulting enol with the arylace-
tic acid 45 (0.063 g, 0.27 mmol, 1.0 equiv), DCC (0.061 g, 0.30
mmol, 1.1 equiv), and DMAP (3.3 mg, 0.03 mmol, 10 mol%) in
CH2Cl2 (10 mL), purification of the residue by flash chromatogra-
phy (column diameter 2.0 cm, cyclohexane–EtOAc, 12:1) furnished
(Z)-38j as a colorless oil; yield: 0.115 g (80%).
13C NMR (126 MHz, CDCl3): d = 17.9 (3¢¢¢-CH3), 22.4 (C4¢), 25.9
(C4¢¢¢), 27.0 [2¢-(CH3)2], 28.9 (C1¢¢¢), 32.6 (C3¢), 40.5
(OCOCH2Ar), 61.2 (q, 2J(C,F) = 36.9 Hz, CH2CF3), 70.2
(OCH2Ph), 75.3 (C2¢), 111.9 (C5¢¢), 118.0 (C8¢), 121.3, 123.3,
124.9, 131.1, 132.7, 133.2, 137.5 (7 Cq: C4a¢, C6¢, C1¢¢, C3¢¢, C3¢¢¢,
C2, CBn1), 122.4 (C2¢¢¢), 123.05 (q, 1J(C,F) = 277.6 Hz, CF3),
127.37 (CBn2, CBn6), 127.95, 128.06 (CBn4, C6¢¢), 128.7 (CBn3,
CBn5), 130.0 (C3), 130.2 (C7¢), 131.0 (C2¢¢), 133.0 (C5¢), 156.1,
156.4 (C8a¢, C4¢¢), 161.5 (C1), 169.5 (OCOCH2Ar).
HRMS: m/z [M+] calcd for C36H37F3O6: 622.2542; found: 622.2537.
IR (CDCl3): 2980, 2935, 2915, 1760, 1735, 1685, 1650, 1605, 1575,
1560, 1500, 1450, 1335, 1315, 1285, 1255, 1225, 1175, 1155, 1120,
1105, 1035, 980 cm–1.
2,2,2-Trifluoroethyl (Z)-2-[(2,2-Dimethylchroman-6-yl)acet-
oxy]-3-[4-methoxy-3-(3-methylbut-2-enyl)phenyl]acrylate
[(Z)-38l]
1H NMR (500 MHz, CDCl3): d = 1.32 [s, 2¢-(CH3)2], 1.68 (br s, 3¢¢¢-
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (0.39 mL, 0.39 mmol, 1.5 equiv),
(Z)-44 (0.10 g, 0.26 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (1.2 mg, 5.5 mmol, 2 mol%) in THF (5 mL) and workup
with Dowex 50WX8-100 (0.26 g, corresponding to 1.0 g/mmol of
substrate). After esterification of the resulting enol with the arylace-
tic acid 43 (0.057 g, 0.26 mmol, 1.0 equiv), DCC (0.059 g, 0.29
mmol, 1.1 equiv), and DMAP (3.3 mg, 0.03 mmol, 10 mol%) in
CH2Cl2 (10 mL), purification of the residue by flash chromatogra-
phy (column diameter 2.0 cm, cyclohexane–EtOAc, 12:1) furnished
(Z)-38l as a colorless oil; yield: 0.122 g (86%).
CH3), 1.71 (d, 4J(H4¢¢¢,H2¢¢¢) = 0.9 Hz,
3 H4¢¢¢), 1.77 (t,
J(H3¢,H4¢) = 6.7 Hz, 2 H3¢), 2.59 (br t, J(H4¢,H3¢) = 6.8 Hz, 2 H4¢),
3.31 (d, J(H1¢¢¢,H2¢¢¢) = 7.2 Hz, 2 H1¢¢¢), 3.81 (s, OCOCH2Ar), 3.84
(s, OMe), 4.56 (q, J(H,F) = 8.4 Hz, CH2CF3), 5.28 (incompletely re-
solved tqq, J(H2¢¢¢,H1¢¢¢) = 7.3 Hz, 4J(H2¢¢¢,4¢¢¢) ≈ 4J(H2¢¢¢,3¢¢¢-
CH3) = 1.4 Hz, H2¢¢¢), 6.59 (mc, interpreted as a d, J(H8¢,H7¢) = 9.2
Hz, H8¢), 6.83 (d, J(H5¢¢,H6¢¢) = 8.5 Hz, H5¢¢), 7.12 (d, 4J(H2¢¢,H6¢¢)
or 4J(H5¢,H7¢) = 2.3 Hz), 7.14 [br s (!)] (H2¢¢ or H5¢), overlapped by
7.13 (tentatively interpreted as dd, J(H7¢,H8¢) not readable due to
overlapping,
4J(H7¢,H5¢) = 2.3
Hz,
H7¢),
7.17
(dd,
J(H6¢¢,H5¢¢) = 8.3 Hz, 4J(H6¢¢,H2¢¢) = 2.3 Hz, H6¢¢), 7.27 (s, H3).
IR (CDCl3): 3155, 2980, 2935, 2360, 2340, 1825, 1795, 1760, 1735,
1720, 1655, 1600, 1560, 1540, 1500, 1470, 1460, 1385, 1305, 1290,
1250, 1210, 1170, 1100 cm–1.
13C NMR (126 MHz, CDCl3): d = 17.9 (3¢¢¢-CH3), 22.4 (C4¢), 25.9
(C4¢¢¢), 27.0 [2¢-(CH3)2], 28.6 (C1¢¢¢), 32.7 (C3¢), 40.5
2
(OCOCH2Ar), 55.6 (OMe), 61.2 (q, J(C,F) = 36.8 Hz, CH2CF3),
1H NMR (500 MHz, CDCl3): d = 1.33 [s, 2¢¢¢-(CH3)2], 1.69 (br s, 3¢¢-
75.3 (C2¢), 110.6 (C5¢¢), 117.9 (C8¢), 121.3, 123.3, 124.5, 130.7,
132.8, 133.2 (6 Cq: C4a¢, C6¢, C1¢¢, C3¢¢, C3¢¢¢, C2), 122.4 (C2¢¢¢),
123.1 (q, 1J(C,F) = 277.1 Hz, CF3), 128.1 (C6¢¢), 130.0 (C3), 130.3
(C7¢), 130.8 (C2¢¢), 132.9 (C5¢), 156. 4, 156.9 (C8a¢, C4¢¢), 161.5
(C1), 169.5 (OCOCH2Ar).
CH3), 1.74 (d, 4J(H4¢¢,H2¢¢) = 0.7 Hz,
3 H4¢¢), 1.79 (t,
J(H3¢¢¢,H4¢¢¢) = 6.7 Hz, 2 H3¢¢¢), 2.76 (br t, J(H4¢¢¢,H3¢¢¢) = 6.8 Hz, 2
H4¢¢¢), 3.25 (d, J(H1¢¢,H2¢¢) = 7.3 Hz, 2 H1¢¢), 3.79 (s, OCOCH2Ar),
3.84 (s, OMe), 4.55 (q, J(H,F) = 8.4 Hz, CH2CF3), 5.25 (incom-
pletely resolved tqq, J(H2¢¢,H1¢¢) = 7.3 Hz, 4J(H2¢¢,H4¢¢)
≈
HRMS: m/z [M+] calcd for C30H33F3O6: 546.2229; found: 546.2233.
4J(H2¢¢,3¢¢-CH3) = 1.4 Hz, H2¢¢), 6.66 (d, J(H5¢,H6¢) = 8.5 Hz, H5¢),
6.77 (mc, interpreted as d, J(H8¢¢¢,H7¢¢¢) = 9.1 Hz, H8¢¢¢), 7.05 (br s,
H5¢¢¢), overlaps with high field part of 7.06 (dd, J(H7¢¢¢,H8¢¢¢) invis-
2,2,2-Trifluoroethyl (Z)-2-{[4-Benzyloxy-3-(3-methylbut-2-
enyl)phenyl]acetoxy}-3-(2,2-dimethylchroman-6-yl)acrylate
[(Z)-38k]
4
ible due to overlapping, J(H7¢¢¢,H5¢¢¢) = 2.3 Hz, H7¢¢¢), 7.23 (dd,
J(H6¢,H5¢) = 8.9 Hz, 4J(H6¢,H2¢) = 2.6 Hz, H6¢), overlaps with 7.27
(s, H3), 7.33 (d, 4J(H2¢,H6¢) = 2.1 Hz, H2¢).
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (1.50 mL, 1.50 mmol, 1.5 equiv),
(Z)-42 (0.372 g, 1.0 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (2.2 mg, 0.01 mmol, 1 mol%) in THF (20 mL) and workup
with Dowex 50WX8-100 (0.50 g, corresponding to 0.5 g/mmol of
substrate). After esterification of the resulting enol with the arylace-
tic acid 52 (0.341 g, 1.1 mmol, 1.1 equiv), DCC (0.227 g, 1.10
mmol, 1.1 equiv), and DMAP (2.4 mg, 0.02 mmol, 2 mol%) in
CH2Cl2 (20 mL), purification of the residue by flash chromatogra-
phy (column diameter 3.0 cm, cyclohexane–EtOAc, 15:1) and re-
crystallization (pentane–Et2O, 20:1) furnished (Z)-38k as a
colorless solid; yield: 0.459 g (74%); mp 68–71 °C.
13C NMR (126 MHz, CDCl3): d = 17.9 (3¢¢-CH3), 22.6 (C4¢¢¢), 26.0
(C4¢¢), 27.0 [2¢¢¢-(CH3)2], 28.4 (C1¢¢), 32.9 (C3¢¢¢), 40.3
2
(OCOCH2Ar), 55.6 (OMe), 61.2 (q, J(C,F) = 36.9 Hz, CH2CF3),
74.4 (C2¢¢¢), 110.3, 117.7 (C5¢, C8¢¢¢), 121.3, 123.7, 124.0, 130.7,
133.3, 133.5 (6 Cq: C2, C1¢, C3¢, C3¢¢, C4a¢¢¢, C6¢¢¢), 121.9 (C2¢¢),
123.0 (q, 1J(C,F) = 277.3 Hz, CF3), 128.6, 130.2 (C6¢, C7¢¢¢), 130.0
(C3), 130.7 (C5¢¢¢), 132.2 (C2¢), 153.6 (C8a¢¢¢), 159.2 (C4¢), 161.5
(C1), 169.6 (OCOCH2Ar).
Anal. Calcd for C30H33F3O6 (546.6): C, 65.92; H, 6.09. Found: C,
65.72; H, 5.98.
IR (KBr): 2975, 2945, 2925, 1755, 1730, 1645, 1605, 1575, 1500,
1445, 1420, 1380, 1335, 1310, 1285, 1265, 1235, 1160, 1120, 1110,
1015 cm–1.
2,2,2-Trifluoroethyl (Z)-3-[4-Methoxy-3-(3-methylbut-2-
enyl)phenyl]-2-{[4-methoxy-3-(3-methylbut-2-enyl)phe-
nyl]acetoxy}acrylate [(Z)-38m]
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (0.39 mL, 0.39 mmol, 1.5 equiv),
(Z)-44 (0.10 g, 0.26 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (1.2 mg, 5.5 mmol, 2 mol%) in THF (5 mL) and workup
with Dowex 50WX8-100 (0.26 g, corresponding to 1.0 g/mmol of
1H NMR (500 MHz, CDCl3): d = 1.31 [s, 2¢-(CH3)2], 1.63 (br s, 3¢¢¢-
CH3), 1.70 (d, 4J(H4¢¢¢,H2¢¢¢) = 0.9 Hz,
3 H4¢¢¢), 1.76 (t,
J(H3¢,H4¢) = 6.7 Hz, 2 H3¢), 2.61 (br t, J(H4¢,H3¢) = 6.6 Hz, 2 H4¢),
3.38 (d, J(H1¢¢¢,H2¢¢¢) = 7.3 Hz, 2 H1¢¢¢), 3.82 (s, OCOCH2Ar), 4.56
(q, J(H,F) = 8.4 Hz, CH2CF3), 5.08 (s, OCH2Ph), 5.30 (mc, inter-
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2264
D. Bernier, R. Brückner
PAPER
substrate). After esterification of the resulting enol with the arylace-
tic acid 45 (0.067 g, 0.29 mmol, 1.0 equiv), DCC (0.059 g, 0.29
mmol, 1.1 equiv), and DMAP (3.3 mg, 0.03 mmol, 10 mol%) in
CH2Cl2 (10 mL), purification of the residue by flash chromatogra-
phy (column diameter 2.0 cm, cyclohexane–EtOAc, 14:1) furnished
(Z)-38m as a colorless oil; yield: 0.105 g (72%).
131.0 (C3¢), 132.4 (C2¢), 133.3 (C3¢¢), 133.6 (C2), 136.8 (CBn1),
153.6 (C8a¢¢¢), 158.3 (C4¢), 161.5 (C1), 169.6 (OCOCH2Ar).
Selected signals from undecoupled 13C NMR spectrum (126 MHz,
CDCl3) with selective irradiation at d(OCH2CH3) = 4.55: d = 153.6
(mC, C8a¢¢¢), 158.3 (mC, C4¢), 161.5 (d, J(C1,H3) = 3.8 Hz, C1),
169.6 (t, 2JCH2 = 7.9 Hz, OCOCH2Ar).
IR (CDCl3): 2970, 2930, 2855, 2840, 1760, 1735, 1645, 1600, 1500,
1465, 1440, 1415, 1375, 1325, 1290, 1250, 1210, 1175, 1100, 1035,
980 cm–1.
HRMS: m/z [M+] calcd for C36H37F3O6: 622.2542; found: 622.2539.
2,2,2-Trifluoroethyl (Z)-3-(3-Methylbut-2-enyl)phenyl]-2-{[4-
benzyloxy-3-(3-methylbut-2-enyl)phenyl]acetoxy}-3-[4-benzyl-
oxyacrylate [(Z)-38o]
1H NMR (500 MHz, CDCl3): d = 1.67, 1.69 (2 s, 3¢¢-CH3, 3¢¢¢¢-CH3),
4
1.70, 1.74 (2 d, J(H4¢¢,H2¢¢) = 4J(H4¢¢¢¢,H2¢¢¢¢ = 1.1 Hz, 3 H4¢¢, 3
H4¢¢¢¢), 3.24 (d, J = 7.2 Hz), 3.31 (d, J = 7.4 Hz) (2 H1¢¢, 2 H1¢¢¢¢),
3.81 (s, OCOCH2Ar), 3.83 (s, 4¢-OCH3, 4¢¢¢-OCH3), 4.56 (q,
J(H,F) = 8.4 Hz, CH2CF3), 5.24 (incompletely resolved tqq, J = 7.4
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (1.11 mL, 1.11 mmol, 1.5 equiv),
(Z)-51 (0.342 g, 0.74 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-
methylphenol (1.7 mg, 7.4 mmol, 1 mol%) in THF (15 mL) and
workup with Dowex 50WX8-100 (0.37 g, corresponding to 0.5 g/
mmol of substrate). After esterification of the resulting enol with the
arylacetic acid 52 (0.253 g, 0.82 mmol, 1.0 equiv), DCC (0.168 g,
0.82 mmol, 1.1 equiv), and DMAP (1.8 mg, 0.015 mmol, 2 mol%)
in CH2Cl2 (20 mL), purification of the residue by flash chromatog-
raphy (column diameter 3.0 cm, cyclohexane–EtOAc, 18:1) and re-
4
Hz, J = 1.4 Hz) and 5.26 (incompletely resolved tqq, J = 7.3 Hz,
4J = 1.5 Hz), (H2¢¢, H2¢¢¢¢), 6.61 (d, J(H5¢,H6¢) = 8.6 Hz, H5¢), 6.83
4
(d, J(H5¢¢¢,H6¢¢¢) = 8.3 Hz, H5¢¢¢), 7.10 (d, J(H2¢¢¢,H6¢¢¢) = 2.3 Hz,
4
H2¢¢¢), 7.16 (dd, J(H6¢¢¢,H5¢¢¢) = 8.2 Hz, J(H6¢¢¢,H2¢¢¢) = 2.4 Hz,
4
H6¢¢¢), 7.17 (dd, J(H6¢,H5¢) = 8.5 Hz, J(H6¢,H2¢) = 2.5 Hz, H6¢),
7.29 (s, H3), 7.31 (d, 4J(H2¢,H6¢) = 2.3 Hz, H2¢).
13C NMR (126 MHz, CDCl3): d = 17.86, 17.92 (3¢¢-CH3, 3¢¢¢¢-CH3),
crystallization (pentane–Et2O, 20:1) furnished (Z)-38o as
a
25.9, 26.0 (C4¢¢, C4¢¢¢¢), 28.4, 28.6 (C1¢¢, C1¢¢¢¢), 40.4 (OCOCH2Ar),
colorless solid; yield: 0.385 g (73%); mp 86–90 °C.
2
55.5, 55.6 (2 OCH3), 61.2 (q, J(C,F) = 36.9 Hz, CH2CF3), 110.3,
110.6 (C5¢, C5¢¢¢), 121.9, 122.4 (C2¢¢, C2¢¢¢¢), 123.0 (q,
1J(C,F) = 277.3 Hz, CF3), 124.0, 124.6, 130.60, 130.63, 132.8,
133.3, 133.5 (7 Cq: C1¢, C1¢¢¢, C3¢, C3¢¢¢, C2, C3¢¢, C3¢¢¢¢), 130.7
(C2¢¢¢), 130.0 (C3), 132.2 (C2¢), 156.9, 159.2 (C4¢, C4¢¢¢), 161.5
(C1), 169.5 (OCOCH2Ar).
IR (KBr): 2970, 2915, 2855, 1755, 1725, 1650, 1600, 1500, 1450,
1425, 1405, 1380, 1320, 1285, 1255, 1205, 1175, 1160, 1115, 1100,
1050, 1025, 960, 735 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.62, 1.63 (2 overlapping s, 3¢¢-
CH3, 3¢¢¢¢-CH3), 1.69, 1.73 (2 unresolved d, 3 H4¢¢, 3 H4¢¢¢¢), 3.30,
3.37 (2 d, J(H1¢¢,H2¢¢) = J(H1¢¢¢¢,H2¢¢¢¢) = 7.3 Hz, 2 H1¢¢, 2 H1¢¢¢¢),
3.82 (s, OCOCH2Ar), 4.55 (q, J(H,F) = 8.4 Hz, CH2CF3), 5.05, 5.08
(2 s, 2 OCH2Ph), 5.26, 5.29 (2 mc, each interpreted as an incom-
pletely resolved tqq, J(H2¢¢,H1¢¢) = J(H2¢¢¢¢,H1¢¢¢¢) = 7.3 Hz,
Anal. Calcd for C31H35F3O6 (560.6): C, 66.42; H, 6.29. Found: C,
66.68; H, 5.99.
2,2,2-Trifluoroethyl (Z)-3-[4-Benzyloxy-3-(3-methylbut-2-
enyl)phenyl]-2-[(2,2-dimethylchroman-6-yl)acetoxy]acrylate
[(Z)-38n]
4
4
4
4J(H2¢¢,H4¢¢) ≈ J(H2¢¢,3¢¢-CH3) ≈ J(H2¢¢¢¢,H4¢¢¢¢) ≈ J(H2¢¢¢¢,3¢¢¢¢-
CH3) = 1.3 Hz, H2¢¢, H2¢¢¢¢), 6.68 (d, J(H5¢,H6¢) = 8.8 Hz, H5¢), 6.89
(mc, interpreted as an incompletely resolved d, J(H5¢¢¢,H6¢¢¢) = 8.8
Hz, H5¢¢¢), 7.13–7.18 (m, H6¢, H6¢¢¢, H2¢¢¢), 7.28–7.44 (m, 2 Ph, H3,
H2¢).
Following the typical procedure for (Z)-38i, using 1 M lithium
2,2,2-trifluoroethoxide in THF (1.50 mL, 1.50 mmol, 1.5 equiv),
(Z)-51 (0.462 g, 1.0 mmol, 1.0 equiv), and 2,6-di-tert-butyl-4-meth-
ylphenol (2.2 mg, 0.01 mmol, 1 mol%) in THF (20 mL) and workup
with Dowex 50WX8-100 (0.50 g, corresponding to 0.5 g/mmol of
substrate). After esterification of the resulting enol with the arylace-
tic acid 43 (0.242 g, 1.1 mmol, 1.1 equiv), DCC (0.227 g, 1.1 mmol,
1.1 equiv), and DMAP (2.4 mg, 0.02 mmol, 2 mol%) in CH2Cl2 (20
mL), purification of the residue by flash chromatography (column
diameter 3.0 cm, cyclohexane–EtOAc, 18:1) and recrystallization
(pentane–Et2O, 20:1) furnished (Z)-38n as a colorless solid; yield:
0.443 g (71%); mp 76–78 °C.
13C NMR (126 MHz, CDCl3): d = 17.91, 17.94 (3¢¢-CH3, 3¢¢¢¢-CH3),
25.9, 26.0 (C4¢¢, C4¢¢¢¢), 28.7, 28.9 (C1¢¢, C1¢¢¢¢), 40.4 (OCOCH2Ar),
61.2 (q, 2J(C,F) = 36.9 Hz, CH2CF3), 70.0, 70.2 (2 OCH2Ph), 111.5
(C5¢), 111.9 (C5¢¢¢), 122.0, 122.4 (C2¢¢, C2¢¢¢¢), 123.0 (q,
1J(C,F) = 277.2 Hz, CF3), 124.2, 124.9, 130.96, 131.05, 132.8,
133.2, 133.6 (7 Cq: C1¢, C1¢¢¢, C3¢, C3¢¢¢, C2, C3¢¢, C3¢¢¢¢), 127.2,
127.3 (CBn12/CBn16, CBn22/CBn26), 127.9, 128.1 (C2¢¢¢, CBn14,
CBn24), 128.65, 128.69 (CBn13/CBn15, CBn23/CBn25), 129.9 (C3),
130.1, 130.96 (C6¢, C6¢¢¢), 132.4 (C2¢), 136.7, 137.4 (2 Cq: CBn11,
CBn21), 156.0, 158.3 (C4¢, C4¢¢¢), 161.5 (C1), 169.5 (OCOCH2Ar).
Selected signals from undecoupled 13C NMR spectrum (126 MHz,
CDCl3) with selective irradiation at d(OCH2CH3) = 4.55: d = 156.0,
156.3 (2 mC, C4¢, C4¢¢¢), 161.5 (d, J(C1,H3) = 4.0 Hz, C1), 169.5 [t,
2JCH2 = 7.8 Hz, ArCH2C(=O)O].
IR (KBr): 2980, 2930, 1765, 1730, 1645, 1600, 1500, 1455, 1430,
1325, 1285, 1240, 1205, 1165, 1105, 1000, 955 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.33 [s, 2¢¢¢-(CH3)2], 1.64 (br s, 3¢¢-
CH3), 1.74 (s, 3 H4¢¢), 1.79 (t, J(H3¢¢¢,H4¢¢¢) = 6.6 Hz, 2 H3¢¢¢), 2.76
(br t, J(H4¢¢¢,H3¢¢¢) = 6.6 Hz, 2 H4¢¢¢), 3.32 (d, J(H1¢¢,H2¢¢) = 7.3 Hz,
2 H1¢¢), 3.82 (s, OCOCH2Ar), 4.55 (q, J(H,F) = 8.3 Hz, CH2CF3),
5.09 (s, OCH2Ph), 5.27 (mc, interpreted as an incompletely resolved
tqq, J(H2¢¢,H1¢¢) = 7.3 Hz, 4J(H2¢¢,H4¢¢) ≈ 4J(H2¢¢,3¢¢-CH3) = 1.3
Hz, H2¢¢), 6.73 (d, J(H5¢,H6¢) = 8.8 Hz, H5¢), 6.76 (mc, interpreted
as d, J(H8¢¢¢,H7¢¢¢) = 9.1 Hz, H8¢¢¢), 7.05 [br s. (!), H5¢¢¢], overlaps
with 7.06 (mC, probably the low-field part of a dd, J(H7¢¢¢,H8¢¢¢) and
J(H7¢¢¢,H5¢¢¢) invisible, H7¢¢¢), 7.21 (dd, J(H6¢,H5¢) = 8.5 Hz,
J(H6¢,H2¢) = 2.2 Hz, H6¢), 7.30 (s, H3), 7.31–7.44 (m, PhBn, H2¢).
HRMS: m/z calcd for C36H36F3O6 [M+ – Bn]: 621.2464; found:
621.2464.
Dieckmann Condensations
(Z)-5-Benzylidene-4-hydroxy-3-phenylfuran-2(5H)-one (Pulvi-
none, 1a);3a Typical Procedure
To an ice-cooled soln of (Z)-38a (291 mg, 0.80 mmol) in DMF (10
mL) was added over 5 min t-BuOK (269 mg, 2.40 mmol, 3.0 equiv)
and the mixture was stirred at 0 °C for 45 min. After TLC had
showed disappearance of the starting material, H2O (25 mL) was
added at 0 °C. The mixture was washed with t-BuOMe (3 × 10 mL).
The aqueous phase was acidified with aq 1 M HCl, until a yellow
solid precipitated. The mixture was extracted with t-BuOMe (10
mL each) until the aqueous phase was no longer yellow. The com-
13C NMR (126 MHz, CDCl3): d = 17.9 (3¢¢-CH3), 22.6 (C4¢¢¢), 26.0
(C4¢¢), 27.0 [2¢¢¢-(CH3)2], 28.7 (C1¢¢), 32.9 (C3¢¢¢), 40.3
2
(OCOCH2Ar), 61.2 (q, J(C,F) = 36.9, CH2CF3), 70.1 (OCH2Ph),
74.4 (C2¢¢¢), 111.6 (C5¢), 117.7 (C8¢¢¢), 121.3 (C4a¢¢¢), 122.0 (C2¢¢),
123.7 (C6¢¢¢), 124.2 (C1¢), 127.4 (CBn2, CBn6), 128.2 (CBn4), 128.6
(C5¢¢¢), 128.7 (CBn3, CBn5), 129.9 (C3), 130.1 (C6¢), 130.7 (C7¢¢¢),
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2265
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure at 60 °C. The crude product was taken up in
MeOH (5 mL). The precipitate of 1a, which formed upon standing
at r.t. for 1 h, was isolated as a yellow solid by filtration; yield: 175
mg (83%); mp 238–242 °C (Lit.3a 243–247 °C).
(Z)-3-(2,4-Dimethoxyphenyl)-4-hydroxy-5-(4-methoxyben-
zylidene)furan-2(5H)-one (1e)
Following the typical procedure for 1a using (Z)-38e (0.364 g, 0.80
mmol) and t-BuOK (269 mg, 2.40 mmol, 3.0 equiv) in DMF (10
mL); yellow solid (Et2O); yield: 0.221 g (78%); mp 180–183 °C.
1H NMR (300 MHz, acetone-d6): d = 6.62 (s, H1¢), 7.29–7.52 (m,
IR (KBr): 3200, 3010, 2980, 2940, 1720, 1665, 1595, 1510, 1465,
1435, 1415, 1305, 1255, 1210, 1180, 1160, 1125, 1115, 1105, 1030,
990, 930, 875, 830 cm–1.
H3Ar1, H5Ar1, H3Ar2, H5Ar2, H4Ar1, H4Ar2), 7.82, 7.95 (2 mC, H2Ar1
H6Ar1, H2Ar2, H6Ar2).
,
1H NMR (400 MHz, 98% CDCl3/2% CD3OD): d = 3.85, 3.85, 3.99
(Z)-5-Benzylidene-4-hydroxy-3-(4-methoxyphenyl)furan-
2(5H)-one (1b)
Following the typical procedure for 1a using (Z)-38b (316 mg, 0.80
mmol), and t-BuOK (269 mg, 2.40 mmol, 3.0 equiv) in DMF (10
mL) gave the product as a yellow solid (MeOH); yield: 0.191 g
(81%); mp 223–226 °C.
4
(3 s, 3 OCH3), 6.32 (s, H1¢), 6.60 (d, J(H3Ar1,H5Ar1) = 2.5 Hz,
H3Ar1), 6.70 (dd, J(H5Ar1,H6Ar1) = 8.8 Hz, 4J(H5Ar1, H3Ar1) = 2.5
Hz, H5Ar1), AA¢BB¢ signal centered at 6.93 (H3Ar2, H5Ar2) and 7.76
(H2Ar2, H6Ar2), 7.96 (d, J(H6Ar1,H5Ar1) = 8.8 Hz, H6Ar1); 4-OH was
not detected.
13C NMR (100 MHz, 98% CDCl3/2% CD3OD ): d = 55.4, 55.7, 57.3
(3 OCH3), 99.1 (C3), 100.3 (C3Ar1), 107.0 (C5Ar1), 107.7 (C1¢),
111.7 (C1Ar1), 114.4 (C3Ar2, C5Ar2), 125.8 (C1Ar2), 130.9 (C6Ar1),
132.2 (C2Ar2, C6Ar2), 140.4 (C5), 156.1, 160.2, 160.8, 161.4 (C4,
C2Ar1, C4Ar1, C4Ar2), 168.9 (C2).
IR (KBr): 3420, 3000, 2830, 2620, 1700, 1630, 1605, 1575, 1515,
1495, 1450, 1425, 1400, 1345, 1330, 1310, 1290, 1255, 1180, 1155,
1130, 1100, 995, 830, 745, 690 cm–1.
1H NMR (400 MHz, 98% CDCl3/2% CD3OD): d = 3.76 (s, 4Ar1
OMe), 6.49 (s, H1¢), AA¢BB¢ signal centered at 6.89 (H3Ar1, H5Ar1
-
)
HRMS: m/z [M+] calcd for C20H18O6: 354.1103; found: 354.1096.
and 7.86 (H2Ar1, H6Ar1), 7.23 (mC, H4Ar2), 7.31 (mC, H3Ar2, H5Ar2),
7.72 (mC, H2Ar2, H6Ar2), 10.97 (br s, tentatively assigned as 4-OH).
(Z)-3-(3,4-Dimethoxyphenyl)-4-hydroxy-5-(4-methoxyben-
zylidene)furan-2(5H)-one (1f)
Following the typical procedure for 1a using (Z)-38f (0.364 g, 0.80
mmol) and t-BuOK (269 mg, 2.40 mmol, 3.0 equiv) in DMF (10
mL) gave the product as a yellow solid (MeOH); yield: 0.212 g
(75%); mp 208–210 °C. This compound was prepared previously
using a different route.35
13C NMR (100 MHz, 98% CDCl3/2% CD3OD ): d = 55.3 (4Ar1
-
OCH3), 102.0 (C3), 107.5 (C1¢), 113.8 (C3Ar1, C5Ar1), 122.4 (C1Ar1),
128.5 (C4Ar2), 128.7 (C3Ar2, C5Ar2), 129.3 (C2Ar1, C6Ar1), 130.4
(C2Ar2, C6Ar2), 133.2 (C1Ar2), 142.9 (C5), 158.8, 161.8 (C4, C4Ar1),
169.1 (C2).
HRMS: m/z [M+] calcd for C18H14O4: 294.0892; found: 294.0889.
1H NMR (300 MHz, acetone-d6): d = 3.84, 3.84, 3.85 (3 s, 3 OCH3),
6.68 (s, H1¢), 7.00 (d, J(5Ar1,6Ar1) = 8.5 Hz, H5Ar1), AA¢BB¢ signal
centered at 7.02 (H3Ar2, H5Ar2) and 7.76 (H2Ar2, H6Ar2), 7.64 (dd,
J(H6Ar1,H5Ar1) = 8.4 Hz, 4J(H6Ar1,H2Ar1) = 2.0 Hz, H6Ar1), 7.70 (d,
4J(H2Ar1,H6Ar1) = 2.2 Hz, H2Ar1), 11.75 (br s, tentatively assigned as
4-OH).
13C NMR (126 MHz, acetone-d6): d = 55.7 (twice as intense as fol-
lowing peak) and 56.0 (3 OCH3), 101.4 (C3), 107.9 (C1¢), 112.4
(C2Ar1), 112.5 (C5Ar1), 115.2 (C3Ar2, C5Ar2), 121.4 (C6Ar1), 124.0
(C1Ar1), 126.9 (C1Ar2), 132.7 (C2Ar2, C6Ar2), 142.0 (C5), 149.6,
149.8 (C4Ar1, C3Ar1), 161.0 (C4Ar2), 162.9 (C4), 168.9 (C2).
(Z)-4-Hydroxy-5-(4-methoxybenzylidene)-3-phenylfuran-
2(5H)-one (1c)
Following the typical procedure for 1a using (Z)-38c (316 mg, 0.80
mmol), and t-BuOK (269 mg, 2.40 mmol, 3.0 equiv) in DMF (10
mL) gave the product as a yellow solid (MeOH); yield: 0.193 g
(82%); mp 230–232 °C [Lit.56 239–242 °C (from a synthesis by a
different approach)].
1H NMR (400 MHz, acetone-d6): d = 3.86 (s, 4Ar2-OCH3), 6.73 (s,
H1¢), AA¢BB¢ signal centered at 7.03 (H3Ar2, H5Ar2) and 7.77
(H2Ar2, H6Ar2), 7.29 (mC, H4Ar1), 7.42 (mC, H3Ar1, H5Ar1), 8.03 (mC,
H2Ar1, H6Ar1), 4-OH was not detected.
13C NMR (100 MHz, acetone-d6): d = 55.7 (4Ar2-OCH3), 101.3
(C3), 108.6 (C1¢), 115.2 (C3Ar2, C5Ar2), 126.7 (C1Ar2), 127.8 (C4Ar1),
128.4 (C2Ar1, C6Ar1), 128.9 (C3Ar1, C5Ar1), 131.3 (C1Ar1), 132.8
(C2Ar2, C6Ar2), 141.8 (C5), 161.1, 164.2 (C4, C4Ar2), 168.7 (C2).
Selected signals from gated-decoupled 13C NMR spectrum (126
MHz, CDCl3): d = 142.0 (d, 2J(C5,H1¢) = 4.6 Hz, C5), 149.6, 149.8
(2 mC, C4Ar1, C3Ar1), 161.0 (mC, C4Ar2), 162.9 (d, J(C4,H1¢) = 3.7
Hz, C4), 168.9 (s, C2).
HRMS: m/z [M+] calcd for C20H18O6: 354.1103; found: 354.1110.
(Z)-4-Hydroxy-5-(4-methoxybenzylidene)-3-(4-methoxyphe-
nyl)furan-2(5H)-one [1d = (Z)-6]
Following the typical procedure for 1a using (Z)-38d (424 mg, 1.00
mmol), and t-BuOK (337 mg, 3.00 mmol, 3.0 equiv) in DMF (10
mL) gave the product as a yellow solid (MeOH); yield: 0.286 g
(88%); mp 244–247 °C (Lit.56 250–253 °C). This compound was
previously obtained by different routes.35,56
1H NMR (500 MHz, 95% CDCl3/5% DMSO-d6/CHCl3): d = 3.76,
3.77 (2 s, 2 OCH3), 6.46 (s, H1¢), AA¢BB¢ signal centered at 6.84
(H3Ar2, H5Ar2)* and 7.67 (H2Ar2, H6Ar2), AA¢BB¢ signal centered at
6.87 (H3Ar1, H5Ar1)* and 7.85 (H2Ar1, H6Ar1); 4-OH was not detect-
ed; *assignment interchangeable.
(Z)-5-(2,4-Dimethoxybenzylidene)-4-hydroxy-3-(4-methoxy-
phenyl)furan-2(5H)-one (1g)
Following the typical procedure for 1a using (Z)-38g (0.364 g, 0.80
mmol) and t-BuOK (269 mg, 2.40 mmol, 3.0 equiv) in DMF (10
mL) gave the product as a yellow solid (Et2O); yield: 0.224 g (79%);
mp 194–196 °C.
IR (KBr): 3420, 3070, 3000, 2940, 2840, 1705, 1605, 1570, 1515,
1470, 1455, 1440, 1420, 1310, 1275, 1250, 1210, 1160, 1130, 1110,
1025, 985, 925, 840, 825 cm–1.
1H NMR (400 MHz, 98% CDCl3/2% CD3OD ): d = 3.82, 3.83, 3.85
(3 s, 3 OCH3), 6.43 (d, 4J(H3Ar2,H5Ar2) = 2.4 Hz, H3Ar2), 6.54 (dd,
4
J(H5Ar2,H6Ar2) = 8.7 Hz, J(H5Ar2,H3Ar2) = 2.4 Hz, H5Ar2), 6.84 (s,
13C NMR (126 MHz, 95% CDCl3/5% DMSO-d6): d = 55.1, 55.2 (2
H1¢), AA¢BB¢ signal centered at 6.95 (H3Ar1, H5Ar1) and 7.86
(H2Ar1, H6Ar1), 8.16 (d, J(H6Ar2,H5Ar2) = 8.7 Hz, H6Ar2); 4-OH was
not detected.
OCH3), 101.1 (C3), 107.4 (C1¢), 113.6, 114.1 (C3Ar1, C5Ar1, C3Ar2
,
,
C5Ar2), 122.5, 125.8 (C1Ar1, C1Ar2), 129.0, 131.9 (C2Ar1, C6Ar1
C2Ar2, C6Ar2), 141.1 (C5), 158.5, 159.8 (C4Ar1, C4Ar2), 161.9 (C4),
169.0 (C2).
13C NMR (100 MHz, 98% CDCl3/2% CD3OD): d = 55.3, 55.5, 55.7
(3 OCH3), 98.3 (C3Ar2), 101.5 (C1¢), 101.5 (C3), 105.5 (C5Ar2),
113.9 (C3Ar1, C5Ar1), 115.1 (C1Ar2), 122.4 (C1Ar1), 129.2 (C2Ar1
,
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2266
D. Bernier, R. Brückner
PAPER
C6Ar1), 132.7 (C6Ar2), 140.8 (C5), 158.78, 158.83, 161.6 (C4Ar1
C2Ar2, C4Ar2), 162.1 (C4), 169.8 (C2).
,
H2Ar1 or H5Ar2], 7.80 (d, presumably the low-field part of a dd at
7.79 overlapped by s at d = 7.78, 4J = 2.3 Hz, H6Ar1 or H7Ar2).
Selected signals from gated-decoupled 13C NMR spectrum (126
13C NMR (126 MHz, acetone-d6): d = 17.9 (3¢¢-CH3), 23.0 (C4Ar2),
25.9 (C4¢¢), 27.1 [2Ar2-(CH3)2], 29.3 (C1¢¢), 33.2 (C3Ar2), 55.8
(OMe), 75.6 (C2Ar2), 102.3 (C3), 107.7 (C1¢), 111.1 (C5Ar1), 118.5
(C8Ar2), 122.4, 123.0, 125.9 (3 Cq: C4aAr2, C6Ar2, C1Ar1), 123.5
(C2¢¢), 127.7, 130.7 (C6Ar1, C7Ar2), 129.8, 132.7 (C2Ar1, C5Ar2),
141.6 (C5), 155.9, 157.6 (C4Ar1, C8aAr2), 162.1 (C4), 168.8 (C2).
MHz, CDCl3): d = 140.8 (d, 2J(C5,H1¢) = 4.6 Hz, C5), 158.78,
, ,
158.83, 161.65 (3 mC, C4Ar1 C2Ar2 C4Ar2), 162.1 (d,
J(C4,H1¢) = 3.7 Hz, C4), 169.8 (s, C2).
HRMS: m/z [M+] calcd for C20H18O6: 354.1103; found: 354.1106.
(Z)-5-(3,4-Dimethoxybenzylidene)-4-hydroxy-3-(4-methoxy-
phenyl)furan-2(5H)-one (1h)
Following the typical procedure for 1a using (Z)-38h (0.364 g, 0.80
mmol) and t-BuOK (269 mg, 2.40 mmol, 3.0 equiv) in DMF (10
mL) gave the product as a yellow solid (Et2O); yield: 0.230 g (81%);
mp 219–222 °C [Lit.3b 224–225 °C (AcOH); as a mixture with 1f).
HRMS: m/z [M+] calcd for C28H30O5: 446.2093; found: 446.2096.
(Z)-3-[4-Benzyloxy-3-(3-methylbut-2-enyl)phenyl]-5-[(2,2-di-
methylchroman-6-yl)methylene]-4-hydroxyfuran-2(5H)-one
(1k)
Following the typical procedure for 1a using (Z)-38k (0.467 g,
0.750 mmol) and t-BuOK (0.253 g, 2.25 mmol, 3.0 equiv) in DMF
(15 mL) gave the product as a yellow solid (acetone–pentane, 1:1);
yield: 0.289 g (74%); mp 183–185 °C.
1H NMR (300 MHz, 97% CDCl3/3% CD3OD ): d = 3.84, 3.91, 3.95
(3 s, 3 OCH3), 6.34 (s, H1¢), 6.88 (d, J(H5Ar2,H6Ar2) = 8.4 Hz,
H5Ar2), AA¢BB¢ signal centered at 6.96 (H3Ar1, H5Ar1) and 7.83
(H2Ar1, H6Ar1), 7.30 (dd, low-field part overlapped by CHCl3 signal,
IR (KBr): 3170, 2975, 2930, 1690, 1655, 1620, 1605, 1575, 1500,
1450, 1430, 1410, 1385, 1335, 1300, 1285, 1265, 1250, 1230, 1160,
1115, 1025, 995 cm–1.
4
J(H6Ar2,H5Ar2) ≈ 8.1 Hz, J(H6Ar2,H2Ar2) = 2.1 Hz, H6Ar2), 7.46 (d,
4J(H2Ar2,H6Ar2) = 1.8 Hz, H2Ar2); 4-OH was not detected.
13C NMR (300 MHz, DMSO-d6): d = 55.1, 55.5, 55.6 (3 OCH3),
1H NMR (400 MHz, 95% acetone-d6/5% DMSO-d6): d = 1.33 [s,
4
99.7 (C3), 107.5 (C1¢), 112.0, 113.1 (C2Ar2, C5Ar2), 113.8 (C3Ar1
,
,
2Ar2-(CH3)2], 1.69 (d, J(3¢¢-CH3,H2¢¢) = 0.6 Hz, 3¢¢-CH3), 1.72 (d,
C5Ar1), 122.3, 125.5 (C1Ar1, C1Ar2), 123.9 (C6Ar2), 128.5 (C2Ar1
4J(H4¢¢,H2¢¢) = 1.0 Hz, 3 H4¢¢), 1.85 (t, J(H3Ar2,H4Ar2) = 6.8 Hz, 2
H3Ar2), 2.83 (br t, J(H4Ar2,H3Ar2) = 6.8 Hz, 2 H4Ar2), 3.40 (d,
J(H1¢¢,H2¢¢) = 7.3 Hz, 2 H1¢¢), 5.19 (s, OCH2Ph), 5.35 (mc, inter-
preted as an incompletely resolved tqq, J(H2¢¢,H1¢¢) = 7.3 Hz,
4J(H2¢¢,H4¢¢) ≈ 4J(H2¢¢,3¢¢-CH3) = 1.4 Hz, H2¢¢), 6.60 (s, H1¢), 6.77
(d, J(H8Ar2,H7Ar2) = 8.3 Hz, H8Ar2), 7.08 (d, J(H5Ar1,H6Ar1) = 8.6
Hz, H5Ar1), 7.30–7.36 (m, HBn4), 7.37–7.44 (m, HBn3, HBn5), 7.49–
7.56 (m, HBn2, HBn6, H7Ar2, H5Ar2), 7.84 (dd, J(H6Ar1,H5Ar1) = 8.5
Hz, 4J(H6Ar1,H2Ar1) = 2.3 Hz, H6Ar1), 7.88 (d, 4J(H2Ar1,H6Ar1) = 2.1
Hz, H2Ar1).
13C NMR (100 MHz, 95% acetone-d6/5% DMSO-d6): d = 17.9 (3¢¢-
CH3), 22.9 (C4Ar2), 25.9 (C4¢¢), 27.1 [2Ar2-(CH3)2], 33.2 (C3Ar2),
70.5 (OCH2Ph), 75.6 (C2Ar2), 101.4 (C3), 108.1 (C1¢), 112.4
(C5Ar1), 118.4 (C8Ar2), 122.3, 123.8, 126.0 (C4aAr2, C6Ar2, C1Ar1),
123.7 (C2¢¢), 127.4 (C6Ar1), 128.3 (CBn2, CBn6), 128.5 (CBn4), 129.3
(CBn3, CBn5), 129.9 (C2Ar1), 130.6, 132.5 (C7Ar2, C3Ar1, C3¢¢), 132.6
(C5Ar2), 138.6 (CBn1), 141.8 (C5), 155.8, 156.4 (C4Ar1, C8aAr2),
162.9 (C4), 169.0 (C2).
C6Ar1), 140.9 (C5), 148.8, 149.7, 158.2 (C4Ar1, C3Ar2, C4Ar2), 162.4
(C4), 168.1 (C2).
HRMS: m/z [M+] calcd for C20H18O6: 354.1103; found: 354.1105.
(Z)-3-(2,2-Dimethylchroman-6-yl)-5-[(2,2-dimethylchroman-6-
yl)methylene]-4-hydroxyfuran-2(5H)-one (Aspulvinone A, 1i)
To an ice-cooled soln of (Z)-38i (105 mg, 0.197 mmol, 1.0 equiv)
in DMF (10 mL), t-BuOK (88 mg, 0.79 mmol, 4.0 equiv) was added
over 15 min and the resulting mixture was stirred at 0 °C for 30 min.
After TLC showed disappearance of the starting material, 10% aq
HCl (4 mL) was added at 0 °C. The title compound was filtered off
and dried in vacuo for 5 d to give yellow crystals (MeOH); yield:
77.0 mg (90%); mp 241–243 °C (Lit.4a,8 243–245 °C).
1H NMR (400 MHz, 95% CDCl3/5% DMSO-d6): d = 1.34, 1.35 [2
s, 2Ar1-(CH3)2, 2Ar2-(CH3)2], 1.80, 1.83 (2 overlapping t,
J(H3Ar2,H4Ar2) = J(H3Ar1,H4Ar1) = 6.7 Hz, 2 H3Ar1, 2 H3Ar2), 2.81,
2.82 (2 overlapping t, J(H4Ar1,H3Ar1) and J(H4Ar2,H3Ar2) invisible, 2
H4Ar1, 2 H4Ar2), 6.45 (s, H1¢), 6.77 (d, J = 8.6 Hz), 6.81 (d, J = 8.6
Hz) (H8Ar1, H8Ar2), 7.48 (dd, J = 8.5 Hz, 4J = 2.1 Hz), 7.68 (dd, larg-
est coupling constant invisible because of overlapping, 4J = 2.2 Hz)
(H7Ar1, H7Ar2), 7.58 (d, 4J = 1.3 Hz), 7.69 (s, overlaps with low-field
part of the dd at d = 7.68) (H5Ar1, H5Ar2); 4-OH was not detected.
HRMS: m/z [M+] calcd for C34H34O5: 522.2406; found: 522.2412.
(Z)-3-(2,2-Dimethylchroman-6-yl)-4-hydroxy-5-[4-methoxy-3-
(3-methylbut-2-enyl)benzylidene]furan-2(5H)-one (1l)
Following the typical procedure for 1a using (Z)-38l (0.180 g, 0.330
mmol) and t-BuOK (0.111 g, 0.99 mmol, 3.0 equiv) in DMF (8 mL)
gave the product as a yellow solid [Et2O–PE, 2:1]; yield: 0.102 g
(69%); mp 152–155 °C.
(Z)-5-[(2,2-Dimethylchroman-6-yl)methylene]-4-hydroxy-3-[4-
methoxy-3-(3-methylbut-2-enyl)phenyl]furan-2(5H)-one (1j)
Following the typical procedure for 1a using (Z)-38j (0.191 g, 0.350
mmol) and t-BuOK (0.118 g, 1.05 mmol, 3.0 equiv) in DMF (9 mL)
gave the product as a yellow solid [CH2Cl2–PE, 2:1]; yield: 0.114 g
(73%); mp 176–179 °C.
IR (KBr): 3425, 3160, 2970, 2925, 1695, 1655, 1625, 1600, 1575,
1500, 1440, 1395, 1325, 1295, 1260, 1225, 1185, 1160, 1120, 1035,
1000, 810 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.32 [s, 2Ar1-(CH3)2], 1.71, 1.74 (2
s, 3¢¢-CH3, 3 H4¢¢), 1.78 (t, J(H3Ar1,H4Ar1) = 6.7 Hz, 2 H3Ar1), 2.78
(br t, J(H4Ar1,H3Ar1) = 6.7 Hz, 2 H4Ar1), 3.30 (d, J(H1¢¢,H2¢¢) = 7.2
Hz, 2 H1¢¢), 3.84 (s, OMe), 5.27 (mc, interpreted as an incompletely
IR (KBr): 3425, 3145, 2975, 2930, 2850, 1695, 1660, 1625, 1605,
1570, 1495, 1440, 1390, 1340, 1300, 1285, 1250, 1155, 1120, 1000,
945, 895, 820, 660 cm–1.
1H NMR (500 MHz, acetone-d6): d = 1.33 [s, 2Ar2-(CH3)2], 1.71 (d,
4J = 1.1 Hz), 1.72 (d, 4J = 0.6 Hz) (3¢¢-CH3, 3 H4¢¢), 1.85 (t,
J(H3Ar2,H4Ar2) = 6.8 Hz, 2 H3Ar2), 2.83 (br t, J(H4Ar2,H3Ar2) = 6.7
Hz, 2 H4Ar2), 3.32 (d, J(H1¢¢, H2¢¢) = 7.2 Hz, 2 H1¢¢), 3.87 (s, OMe),
5.31 (mc, interpreted as an incompletely resolved tqq,
J(H2¢¢,H1¢¢) = 7.3 Hz, 4J(H2¢¢,H4¢¢) ≈ 4J(H2¢¢,3¢¢-CH3) = 1.4 Hz,
H2¢¢), 6.48 (s, H1¢), 6.78 (d, J(H8Ar2,H7Ar2) = 8.5 Hz, H8Ar2), 6.99
resolved tqq, J(2¢¢,1¢¢) = 7.3 Hz, 4J(H2¢¢,H4¢¢) 4J(H2¢¢,3¢¢-
≈
CH3) = 1.4 Hz, H2¢¢), 6.30 (s, H1¢), 6.81 (d, J = 8.6 Hz) overlaps
with 6.83 (d, J = 8.4 Hz) (H8Ar1, H5Ar2), 7.36 (br d, J = 8.9 Hz,
H6Ar2 or H7Ar1), 6.93 (br s), 7.40 (br s) (H5Ar1 or H2Ar2, 4-OH), 7.46
(d, 4J = 2.1 Hz, H5Ar1 or H2Ar2), 7.71 (dd, J = 8.6 Hz, 4J = 2.2 Hz,
H6Ar2 or H7Ar1).
13C NMR (126 MHz, acetone-d6): d = 17.8 (3¢¢-CH3), 22.8 (C4Ar1),
25.8 (C4¢& prime;), 27.0 [2Ar1-(CH3)2], 28.7 (C1¢¢), 33.1 (C3Ar1),
55.7 (OMe), 74.7 (C2Ar1), 102.2 (C3), 107.4 (C1¢), 111.1 (C5Ar2),
4
(d, J(H5Ar1,H6Ar1) = 8.5 Hz, H5Ar1), 7.53 (dd, J = 8.5 Hz, J = 2.3
Hz, H6Ar1 or H7Ar2), 7.55 [br s (!), H2Ar1 or H5Ar2], 7.78 [br s (!),
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2267
117.4 (C8Ar1), 121.2, 121.7, 126.1 (C4aAr1, C6Ar1, C1Ar2), 122.7
(C2¢¢), 127.6, 129.6, 130.1 (C7Ar1, C6Ar2, C5Ar1 or C2Ar2), 129.9
(C3Ar2), 132.0 (C5Ar1 or C2Ar2), 132.9 (C3¢¢), 141.4 (C5), 154.1,
158.4 (C8aAr1, C4Ar2), 161.4 (C4), 168.7 (C2).
HRMS: m/z [M+] calcd for C34H34O5: 522.2406; found: 522.2405.
(Z)-5-[4-Benzyloxy-3-(3-methylbut-2-enyl)benzylidene]-3-[4-
benzyloxy-3-(3-methylbut-2-enyl)phenyl]-4-hydroxyfuran-
2(5H)-one (1o)
Following the typical procedure for 1a using (Z)-38o (0.535 g,
0.750 mmol) and t-BuOK (0.253 g, 2.25 mmol, 3.0 equiv) in DMF
(10 mL) gave the product as a yellow solid (Et2O–pentane, 3:1);
yield: 0.295 g (64%); mp 142–144 °C.
HRMS: m/z [M+] calcd for C28H30O5: 446.2093; found: 446.2099.
(Z)-4-Hydroxy-5-[4-methoxy-3-(3-methylbut-2-enyl)ben-
zylidene]-3-[4-methoxy-3-(3-methylbut-2-enyl)phenyl]furan-
2(5H)-one (1m)
Following the typical procedure for 1a using (Z)-38m (0.168 g, 0.30
mmol) and t-BuOK (0.101 g, 0.90 mmol, 3.0 equiv) in DMF (7 mL)
gave the product as a yellow solid [CH2Cl2–PE, 2:1]; yield: 0.095 g
(69%); mp 149–151 °C.
IR (KBr): 3060, 3035, 2970, 2910, 1710, 1660, 1625, 1600, 1570,
1500, 1455, 1415, 1380, 1320, 1295, 1250, 1115, 1000, 900, 810,
735, 695 cm–1.
1H NMR (500 MHz, acetone-d6, 280 K): d = 1.67 (br s, 3¢¢-CH3, 3¢¢¢-
CH3), 1.70, 1.73 (2 br s, 3 H4¢¢, 3 H4¢¢¢), 3.38 (br d,
J(H1¢¢,H2¢¢) = J(H1¢¢¢,H2¢¢¢) = 7.3 Hz, 2 H1¢¢, 2 H1¢¢¢), 5.19, 5.21 (2
s, 2 OCH2Ph), 5.33 (mc, H2¢¢, H2¢¢¢), 6.52 (s, H1¢), 7.08 (d, J = 8.5
Hz), 7.12 (d, J = 8.5 Hz) (H5Ar1, H5Ar2), 7.34 (mC, 2 HBn4), 7.41
(mC, 2 HBn3, HBn5), 7.52 (mC, 2 HBn2, HBn6), 7.63 [br s (!), H2Ar1 or
H2Ar2], 7.65 [presumably the low-field part of a dd, couplings invis-
ible due to insufficient resolution, H6Ar1 or H6Ar2], 7.79 (incom-
IR (KBr): 3240, 2965, 2910, 2840, 1695, 1660, 1625, 1600, 1500,
1460, 1440, 1395, 1320, 1295, 1255, 1185, 1165, 1115, 1030, 1000,
900, 865, 815, 730 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.69, 1.70 (2 s, 3¢¢-CH3, 3¢¢¢-CH3),
4
1.70, 1.73 (2 d, J(H4¢¢,H2¢¢) = 4J(H4¢¢¢,H2¢¢¢) = 0.9 Hz, 3 H4¢¢, 3
H4¢¢¢), 3.28, 3.29 (2 overlapping d, J(H1¢¢,H2¢¢) =
J(H1¢¢¢,H2¢¢¢) = 7.4 Hz, 2 H1¢¢, 2 H1¢¢¢), 3.78, 3.81 (2 s, 2 OMe),
5.25, 5.26 (mc, interpreted as 2 overlapping and incompletely re-
solved tqq, J(H2¢¢,H1¢¢) = J(H2¢¢¢,H1¢¢¢) = 7.2 Hz, 4J(H2¢¢,H4¢¢) ≈
4J(H2¢¢¢,H4¢¢¢) ≈ 4J(H2¢¢,3¢¢-CH3) ≈ 4J(H2¢¢¢,3¢¢¢-CH3) ≈ 1.4 Hz, H2¢¢,
4
pletely resolved dd, J = 8.5 Hz, J = 1.9 Hz, H6Ar1 or H6Ar2), 7.82
[br s(!), H2Ar1].
13C NMR (126 MHz, acetone-d6): d = 17.9 (3¢¢-CH3, 3¢¢¢-CH3), 25.9
(C4¢¢, C4¢¢¢), 70.2, 70.4 (2 OCH2Ph), 102.0 (C3), 107.6 (C1¢), 112.2,
112.8 (C5Ar1, C5Ar2), 123.0, 123.5 (C2¢¢, C2¢¢¢), 123.15, 126.62,
H2¢¢¢), 6.33 (s, H1¢), 6.77 (d, J = 8.4 Hz), 6.84 (d, J = 9.2 Hz) (H5Ar1
,
4
H5Ar2), 7.43 (d, J = 2.2 Hz), overlaps in part with 7.44 [br s (!)],
(H2Ar1, H2Ar2), 7.48 [br d (!), J = 8.2 Hz], 7.68 (dd, J = 8.6 Hz,
4J = 2.2 Hz) (H6Ar1, H6Ar2).
130.53, 131.22 132.58, 133.18 (6 Cq: C1Ar1, C1Ar2, C3Ar1, C3Ar2
,
C3¢¢, C3¢¢¢), 127.5, 130.5 (C6Ar1, C6Ar2), 128.2, 128.3 (2 CBn2, CBn6),
128.5, 128.6 (2 CBn4), 129.25, 129.28 (2 CBn3, 2 CBn5), 129.9, 132.4
(C2Ar1, C2Ar2), 138.1, 138.4 (2 CBn1), 141.8 (C5), 156.5, 157.8
(C4Ar1, C4Ar2), 162.1 (C4), 168.7 (C2); C1¢¢, C1¢¢¢ were not detected
(presumably overlapped by the signal of acetone-d6).
13C NMR (126 MHz, CDCl3): d = 17.92, 17.93 (3¢¢-CH3, 3¢¢¢-CH3),
25.90, 25.91 (C4¢¢, C4¢¢¢), 28.6, 28.7 (C1¢¢, C1¢¢¢), 55.52, 55.55 (2
OMe), 102.9 (C3), 108.9 (C1¢), 110.65, 110.72 (C5Ar1, C5Ar2),
120.8, 125.2, 130.6, 130.9, 132.9, 133.0 (6 Cq: C1Ar1, C1Ar2, C3Ar1
,
C3Ar2, C3¢¢, C3¢¢¢), 122.2, 122.3 (C2¢¢, C2¢¢¢), 126.9, 128.9, 130.0,
Selected signals from gated-decoupled 13C NMR spectrum (126
132.2 (C6Ar1, C6Ar2, C2Ar1, C2Ar2), 140.2 (C5), 157.2, 158.3 (C4Ar1
C4Ar2), 161.1 (C4), 169.6 (C2).
,
MHz, acetone-d6): d = 141.8 (d, J(C5,H1¢) = 4.7 Hz, C5), 156.5,
2
157.8 (2 mC, C4Ar1, C4Ar2), 162.1 (d, J(C4,H1¢) = 3.6 Hz, C4), 168.7
(s, C2).
HRMS: m/z [M+] calcd for C29H32O5: 460.2250; found: 460.2252.
HRMS: m/z [M+] calcd for C41H40O5: 612.2876; found: 612.2862.
(Z)-5-[4-Benzyloxy-3-(3-methylbut-2-enyl)benzylidene]-3-(2,2-
dimethylchroman-6-yl)-4-hydroxyfuran-2(5H)-one (1n)
Following the typical procedure for 1a using (Z)-38n (0.300 g,
0.482 mmol) and t-BuOK (0.162 g, 1.45 mmol, 3.0 equiv) in DMF
(10 mL) gave the product as a yellow solid (acetone–pentane, 2:3);
yield: 0.179 g (71%); mp 108–111 °C.
Demethylation
(Z)-5-Benzylidene-4-hydroxy-3-(4-hydroxyphenyl)furan-
2(5H)-one (1p)3a
Following the typical procedure for 1v, using 1b (17.2 mg, 0.058
mmol) and 1 M BBr3 in hexanes (0.18 mL, 0.18 mmol, 3.0 equiv)
in CH2Cl2 (5 mL); the mixture was stirred at reflux for 5 h. Prepar-
ative TLC (cyclohexane–EtOAc, 3:2 with 1 vol% HCO2H) fur-
nished the title compound as a yellow solid; yield: 12.8 mg (78%);
mp 244–248 °C (dec.) (Lit.3a 258–263 °C).
IR (KBr): 3060, 3030, 2975, 2910, 1750, 1690, 1655, 1600, 1575,
1500, 1455, 1435, 1385, 1320, 1295, 1255, 1160, 1120, 1020, 1005,
945, 840, 735, 695 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.31 [s, 2Ar1-(CH3)2], 1.65 (d,
4J(3¢¢-CH3,H2¢¢) = 0.8 Hz, 3¢¢-CH3), 1.73 (d, 4J(H4¢¢,H2¢¢) = 1.0 Hz,
3 H4¢¢), 1.77 (t, J(H3Ar1,H4Ar1) = 6.8 Hz, 2 H3Ar1), 2.77 (br t,
J(H4Ar1,H3Ar1) = 6.7 Hz, 2 H4Ar1), 3.36 (d, J(H1¢¢,H2¢¢) = 7.2 Hz, 2
H1¢¢), 5.06 (s, OCH2Ph), 5.29 (mc, interpreted as an incompletely re-
solved tqq, J(H2¢¢,H1¢¢) = 7.3 Hz, 4J(H2¢¢,H4¢¢) ≈ 4J(H2¢¢,3¢¢-
CH3) = 1.4 Hz, H2¢¢), 6.31 (s, H1¢), 6.83 (d, J(H8Ar1,H7Ar1) = 8.5
Hz, H8Ar1), 6.86 (d, J(H5Ar2,H6Ar2) = 8.7 Hz, H5Ar2), 7.28–7.45 (m,
in total 7 H, PhBn, H7Ar1, H5Ar1), 7.48 (d, 4J(H2Ar2,H6Ar2) = 2.1 Hz,
H2Ar2), 7.70 (dd, J(H6Ar2,H5Ar2) = 8.7 Hz, 4J(H6Ar2,H2Ar2) = 2.3 Hz,
H6Ar2); 4-OH was not detected.
13C NMR (100 MHz, CDCl3): d = 18.0 (3¢¢-CH3), 22.6 (C4Ar1), 25.9
(C4¢¢), 27.0 [2Ar1-(CH3)2], 28.9 (C1¢¢), 32.8 (C3Ar1), 70.1 (OCH2Ph),
74.9 (C2Ar1), 103.1 (C3), 108.6 (C1¢), 112.0 (C5Ar2), 118.1 (C8Ar1),
120.0, 122.0 (C4aAr1, C6Ar1), 122.3 (C2¢¢), 125.5 (C1Ar2), 126.9,
129.2 (2 br s, C7Ar1, C5Ar1), 127.4 (CBn2, CBn6), 128.0 (CBn4), 128.7
(CBn3, CBn5), 130.0 (C6Ar2), 131.0 (C3Ar2), 132.4 (C2Ar2), 133.0
(C3¢¢), 137.07 (CBn1), 140.21 (C5), 154.3, 157.4 (C8aAr1, C4Ar2),
160.6 (C4), 169.2 (C2).
1H NMR (300 MHz, CD3OD ): d = 6.46 (s, H1¢), 7.32 (mC, H4Ar2),
7.41 (mC, H3Ar2, H5Ar2), AA¢BB¢ signal centered at 6.84 (H3Ar1
,
H5Ar1) and 7.78 (H2Ar1, H6Ar1), overlapped by high-field part of 7.78
(mC, H2Ar2, H6Ar2); 4-OH and 4Ar1-OH were not detected.
(Z)-4-Hydroxy-5-(4-hydroxybenzylidene)-3-phenylfuran-
2(5H)-one (1q)
Following the typical procedure for 1v, using 1c (13.8 mg, 0.047
mmol) and 1 M BBr3 in hexanes (0.14 mL, 0.14 mmol, 3.0 equiv)
in CH2Cl2 (4 mL); the mixture was stirred at reflux for 3 h. Prepar-
ative TLC (cyclohexane–EtOAc, 3:2 with 1 vol% HCO2H) fur-
nished the title compound as a yellow solid; yield: 10.8 mg (82%).
IR (KBr): 3405, 3220, 1700, 1625, 1605, 1510, 1495, 1450, 1410,
1340, 1305, 1250, 1210, 1175, 1155, 1125, 1005, 785, 735 cm–1.
1H NMR (300 MHz, CD3OD ): d = 6.45 (s, H1¢), AA¢BB¢ signal
centered at 6.84 (H3Ar2, H5Ar2) and 7.67 (H2Ar2, H6Ar2), 7.27 (mC,
H4Ar1), 7.39 (mC, H3Ar1, H5Ar1), 7.90 (mC, H2Ar1, H6Ar1); 4-OH and
4Ar2-OH were not detected.
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2268
D. Bernier, R. Brückner
PAPER
13C NMR (126 MHz, CD3OD ): d = 101.3 (C3), 107.1 (C1¢), 115.2
H6Ar2); 8.45, 8.68, 8.89 (br s, tentatively assigned to 4Ar1-OH, 2Ar2
OH, 4Ar2-OH, 4-OH).
-
(C3Ar2, C5Ar2), 116.6, 131.3 (C1Ar1, C1Ar2), 129.4 (C4Ar1), 129.7
(C3Ar1, C5Ar1), 129.9 (C3Ar1, C5Ar1, C2Ar1, C6Ar1), 131.3 (C2Ar2
C6Ar2), 145.4 (C5), 157.5, 166.6, 172.1 (C4, C4Ar2, C2).
,
13C NMR (100 MHz, acetone-d6): d = 101.8 (C3), 102.1 (C1¢),
103.1 (C3Ar2), 109.1 (C5Ar2), 115.9 (C3Ar1, C5Ar1), 122.4 (C1Ar1
,
HRMS: m/z [M+] calcd for C17H12O4: 280.0736; found: 280.0742.
C1Ar2), 130.0 (C2Ar1, C6Ar1), 133.0 (C6Ar2), 140.7 (C5), 157.6,
158.2, 160.5, 162.0 (C4, C4Ar1, C2Ar2, C4Ar2), 169.0 (C2).
(Z)-4-Hydroxy-5-(4-hydroxybenzylidene)-3-(4-hydroxyphe-
nyl)furan-2(5H)-one (Aspulvinone E, 1r)38
HRMS: m/z [M+] calcd for C17H12O6: 312.0634; found: 312.0625.
Following the typical procedure for 1v, using 1d (19.5 mg, 0.06
mmol) and 1 M BBr3 in hexanes (0.36 mL, 0.36 mmol, 6.0 equiv)
in CH2Cl2 (4 mL); the mixture was stirred at reflux for 1 h. Prepar-
ative TLC (cyclohexane–EtOAc, 1:1 with 1 vol% HCO2H) fur-
nished the title compound as a yellow solid; yield: 14.4 mg (81%);
mp >250 °C (Lit.4a mp 282–284 °C).
(Z)-5-(3,4-Dihydroxybenzylidene)-4-hydroxy-3-(4-hydroxy-
phenyl)furan-2(5H)-one (3¢,4,4¢-Trihydroxypulvinone, 1v);3b
Typical Procedure
To an ice-cooled soln of 3¢,4,4¢-trimethoxypulvinone (1h, 10.0 mg,
0.028 mmol) in CH2Cl2 (3 mL) was added 1 M BBr3 in hexanes
(0.28 mL, 0.28 mmol, 10.0 equiv) over 5 min. The mixture was
stirred at r.t. for 30 min and at reflux for 4 h. The mixture was al-
lowed to cool to r.t., and ice-water (10 mL) was added. The layers
were separated. The aqueous layer was extracted with EtOAc (3 ×
5 mL). The combined organic layers were dried (Na2SO4) and then
evaporated in vacuo. Purification of the residue by preparative TLC
(cyclohexane–EtOAc, 1:2 with 1 vol% HCO2H) furnished 1v as a
yellow solid; yield: 7.8 mg (89%); mp >250 °C [Lit.3b 291 °C
(dec.)].
1H NMR (300 MHz, CD3OD ): d = 6.39 (s, H1¢), AA¢BB¢ signal
centered at 6.82 (H3Ar1, H5Ar1)* and 7.65 (H2Ar1, H6Ar1), AA¢BB¢
signal centered at d = 6.83 (H3Ar2, H5Ar2)* and d = 7.75 (H2Ar2
,
H6Ar2); 4-OH, 4Ar1-OH and 4Ar2-OH were not detected. *assignment
interchangeable.
(Z)-3-(2,4-Dihydroxyphenyl)-4-hydroxy-5-(4-hydroxyben-
zylidene)furan-2(5H)-one (Aspulvinone G, 1s)8
Following the typical procedure for 1v, using 1e (10.0 mg, 0.03
mmol) and 1 M BBr3 in hexanes (0.25 mL, 0.25 mmol, 9.0 equiv)
in CH2Cl2 (3 mL); the mixture was stirred at reflux for 2 h. Prepar-
ative TLC (cyclohexane–EtOAc, 1:1 with 1 vol% HCO2H) fur-
nished 1s as a yellow solid; yield: 7.0 mg (79%); mp >250 °C [Lit.8
263–265 °C (dec.)].
1H NMR (300 MHz, CD3OD ): d = 6.14 (s, H1¢), 6.74 (d,
J(H5Ar2,H6Ar2) = 8.5 Hz, H5Ar2), overlapped by high-field part of
AA¢BB¢ signal centered at 6.74 (H3Ar1, H5Ar1) and 7.92 (H2Ar1
,
H6Ar1), 7.04 (dd, J(H6Ar2,H5Ar2) = 8.1 Hz, 4J(H6Ar2,H2Ar2) = 1.8 Hz,
4
H6Ar2), 7.38 (d, J(H2Ar2,H6Ar2) = 1.8 Hz, H2Ar2); 4-OH, 4Ar1-OH,
3Ar2-OH, and 4Ar2-OH were not detected.
1H NMR (300 MHz, CD3OD ): d = 6.19 (s, H1¢), 6.29 (d,
4J(H3Ar1,H5Ar1) = 2.3 Hz, H3Ar1), 6.33 (dd, J(H5Ar1,H6Ar1) = 8.5 Hz,
4J(H5Ar1,H3Ar1) = 2.5 Hz, H5Ar1), AA¢BB¢ signal centered at
d = 6.79 (H3Ar2, H5Ar2) and d = 7.63 (H2Ar2, H6Ar2), 7.71 (d,
Debenzylation
(Z)-5-[(2,2-Dimethylchroman-6-yl)methylene]-4-hydroxy-3-
[4-hydroxy-3-(3-methylbut-2-enyl)phenyl]furan-2(5H)-one
(Aspulvinone B¢, 1w)
J(H6Ar1,H5Ar1) = 8.5 Hz, H6Ar1); 4-OH, 2Ar1-OH, 4Ar1-OH, and 4Ar2
-
OH were not detected.
Following the typical procedure for 1x, using 1k (52.3 mg, 0.10
mmol), CH2Cl2 (5 mL), 1.0 M Cy2NMe in toluene (0.40 mL, 0.40
mmol, 4.0 equiv), 1 M BCl3 in hexanes (1.00 mL, 1.00 mmol, 10.0
equiv), and CaO (280 mg, 5.00 mmol, 50 equiv) in MeOH (5 mL).
Purification by flash chromatography [column diameter 1 cm, PE–
EtOAc (3:1)/1 vol% AcOH] furnished the title compound as a raw
mixture. By dropwise addition of a soln of this material in CH2Cl2
(1 ml) into vigorously stirred pentane (25 mL), 1w precipitated;
yield: 24 mg (55%); mp 123–127 °C.
(Z)-3-(3,4-Dihydroxyphenyl)-4-hydroxy-5-(4-hydroxyben-
zylidene)furan-2(5H)-one (1t)38
Following the typical procedure for 1v, using 1f (62.0 mg, 0.175
mmol) and 1 M BBr3 in hexanes (1.58 mL, 0.16 mmol, 9.0 equiv)
in CH2Cl2 (7 mL); the mixture was stirred at r.t. for 8 h. Preparative
TLC (cyclohexane–EtOAc, 1:2 with 1 vol% HCO2H) furnished 1t
as a yellow solid; yield: 38.0 mg (69%); mp >250 °C [Lit.38 295 °C
(dec.)].
1H NMR (300 MHz, CD3OD, slightly contaminated): d = 6.35 (s,
H1¢), 6.79 (d, J(H5Ar1,H6Ar1) = 8.9 Hz, H5Ar1), AA¢BB¢ signal cen-
tered at 6.82 (H3Ar2, H5Ar2) and 7.65 (H2Ar2, H6Ar2), 7.33 (d,
J(H6Ar1,H5Ar1) = 8.4 Hz, H6Ar1), 7.48 (s, H2Ar1); 4-OH, 3Ar1-OH,
4Ar1-OH, and 4Ar2-OH were not detected.
IR (KBr): 3415, 3260, 2975, 2930, 1725, 1620, 1605, 1575, 1495,
1425, 1370, 1335, 1310, 1265, 1155, 1120, 1015, 945, 895, 865,
825, 805, 660 cm–1.
1H NMR (400 MHz, DMSO-d6, contaminated): d = 1.30 [s, 2Ar2
-
(CH3)2], 1.69 (br s, 3¢¢-CH3, 3 H4¢¢), 1.79 (t, J(H3Ar2,H4Ar2) = 6.5
Hz, 2 H3Ar2), 2.79 (br t, J(H4Ar2,H3Ar2) = 6.4 Hz, 2 H4Ar2), 3.24 (d,
J(H1¢¢,H2¢¢) = 7.2 Hz, 2 H1¢¢), 5.29 (br t, J(H2¢¢,H1¢¢) = 7.1 Hz,
(Z)-5-(2,4-Dihydroxybenzylidene)-3-(4-hydroxyphenyl)-4-hy-
droxyfuran-2(5H)-one (1u)
H2¢¢), 6.55 (s, H1¢), 6.79 (d, J = 8.2 Hz), 6.83 (d, J = 8.3 Hz) (H5Ar1
,
H8Ar2), 7.44 (br s, presumably the high-field part of a br d at 7.45,
coupling constant invisible because of overlapping, H6Ar1 or H7Ar2),
overlaps with 7.47 [br s (!), H2Ar1 or H5Ar2], 7.59 (br d, J = 8.3 Hz,
H6Ar1 or H7Ar2), 7.66 [br s (!), H2Ar1 or H5Ar2].
Following the typical procedure for 1v, using 1g (62.0 mg, 0.18
mmol) and 1 M BBr3 in hexanes (1.58 mL, 0.16 mmol, 9.0 equiv)
in CH2Cl2 (4 mL); the mixture was stirred at reflux for 4 h. Prepar-
ative TLC (cyclohexane–EtOAc, 1:2 with 1 vol% HCO2H) fur-
nished the title compound as a yellow solid; yield: 42.5 mg (78%);
mp >250 °C.
13C NMR (100 MHz, DMSO-d6): d = 17.7 (3¢¢-CH3), 21.8 (C4Ar2),
25.5 (C4¢¢), 26.6 [2Ar2-(CH3)2], 28.1 (C1¢¢), 31.9 (C3Ar2), 74.9
(C2Ar2), 100.2 (C3), 107.1 (C1¢), 114.7, 117.4 (C5Ar1, C8Ar2), 120.7,
121.5, 124.5 (3 Cq: C1Ar1, C4aAr2, C6Ar2), 122.8 (C2¢¢), 125.9, 129.5
IR (KBr): 3260, 1730, 1610, 1515, 1470, 1415, 1320, 1270, 1250,
1235, 1175, 1150, 1135, 1105, 990, 920, 835, 750, 660, 590, 515
cm–1.
(C6Ar1, C7Ar2), 127.2, 131.3 (2 Cq: C3Ar1, C3¢¢), 128.6, 131.5 (C2Ar1
,
C5Ar2), 140.5 (C5), 154.2, 154.4 (C4Ar1, C8aAr2), 161.6 (C4), 168.2
(C2).
1H NMR (300 MHz, acetone-d6): d = 6.47 (d, 4J(H3Ar2,H5Ar2) = 2.2
Hz, H3Ar2), 6.50 (dd, J(H5Ar2,H6Ar2) = 8.5 Hz, 4J(H5Ar2,H3Ar2) = 2.5
HRMS: m/z [M+] calcd for C27H28O5: 432.1937; found: 432.1931.
Hz, H5Ar2), 6.88 (s, H1¢), AA¢BB¢ signal centered at 6.89 (H3Ar1
,
H5Ar1) and 7.87 (H2Ar1, H6Ar1), 7.97 (d, J(H6Ar2,H5Ar2) = 8.5 Hz,
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Naturally Occurring Pulvinones
2269
(Z)-3-(2,2-Dimethylchroman-6-yl)-4-hydroxy-5-[4-hydroxy-3-
(3-methylbut-2-enyl)benzylidene]furan-2(5H)-one (Aspulvino-
ne B, 1x); Typical Procedure
Further Compounds
Ethyl 2-(Acetoxy)acrylate (18)
A soln of ethyl pyruvate (11.6 g, 100 mmol) and TsOH·H2O (134
mg, 0.71 mmol, 2 mol%) in Ac2O (18.9 mL, 200 mmol, 2.0 equiv)
was degassed and stirred under a N2 atmosphere at 140 °C for 20 h.
Distillation (80–85 °C/35 mbar; Lit.26 78–79 °C/13.3 mbar) fur-
nished 18 as a colorless liquid; yield: 11.2 g (71%) (Lit.26 60%).
To an ice-cooled soln of 1n (52.3 mg, 0.10 mmol) in CH2Cl2 (5 mL)
was added 1.0 M Cy2NMe in toluene (0.40 mL, 0.40 mmol, 4.0
equiv). The mixture was cooled to –78 °C and 1 M BCl3 in hexanes
(1.00 mL, 1.00 mmol, 10.0 equiv) was added dropwise within
5 min. After 90 min the mixture was transferred into a suspension
of CaO (280 mg, 5.00 mmol, 50 equiv) in MeOH (5 mL) at –78 °C,
and warmed to r.t. within 45 min. CH2Cl2 (20 mL) was added. The
mixture was washed with aq 0.05 M HCl (3 × 5 mL). The organic
layers were washed with aq phosphate buffer (2 × 10 mL). The
combined organic layers were dried (Na2SO4) and evaporated in
vacuo. Purification of the residue by flash chromatography [column
diameter 1 cm, PE–EtOAc, 3:1 with 1 vol% AcOH] furnished the
crude title compound. By dropwise addition of a soln of this mate-
rial in CH2Cl2 (2 ml) to vigorously stirred pentane (40 mL),
1x precipitated; yield: 28 mg (65%); mp 146–149 °C (Lit.8 187–
189 °C).
2,2,2-Trifluoroethyl 2-(Acetoxy)acrylate (19)
A soln of trifluoroethyl pyruvate (25, 6.00 g, 35.3 mmol),
TsOH·H2O (134 mg, 0.71 mmol, 2 mol%), and hydroquinone in
Ac2O (50 mL, 0.530 mol, 15 equiv) was degassed and stirred under
a N2 atmosphere at 140 °C for 30 h. Distillation (84–88 °C/35 mbar)
furnished 19 as a colorless liquid; yield: 5.15 g (69%); nD18 1.3845.
IR (film): 1825, 1775, 1765, 1755, 1650, 1450, 1440, 1415, 1375,
1315, 1275, 1215, 1170, 1140, 1035, 1020, 975, 930, 870, 840, 790,
730, 670 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.24 (s, OCOCH3), 4.56 (q,
J(H,F) = 8.3 Hz, CH2CF3), 5.60, 6.15 (2 d, Jgem(H3a,H3b) = 2.1
2
IR (KBr): 3420, 2975, 2930, 1715, 1630, 1600, 1500, 1435, 1385,
1370, 1330, 1265, 1225, 1160, 1120, 995, 945, 895, 840, 825 cm–1.
Hz, 2 H3).
13C NMR (75 MHz, CDCl3): d = 20.3 (OCOCH3), 61.3 (q,
2J(C,F) = 37.1 Hz, CH2CF3), 116.0 (C3), 122.8 (q, 1J(C,F) = 277.0
Hz, CF3), 143.4 (C2), 160.0 (C1), 168.9 (OCOCH3).
1H NMR (400 MHz, DMSO-d6, contaminated): d = 1.29 [s, 2Ar1
(CH3)2], 1.70, 1.72 (2 br s, 3¢¢-CH3, H4¢¢), 1.78 (t,
-
3
J(H3Ar1,H4Ar1) = 6.7 Hz, 2 H3Ar1), 2.76 (br t, J(H4Ar1,H3Ar1) = 6.8
Hz, 2 H4Ar1), 3.24 (d, J(H1¢¢,H2¢¢) = 7.3 Hz, 2 H1¢¢), 5.29 (mc, ap-
proximately interpretable as tqq, J(H2¢¢,H1¢¢) = 7.3 Hz,
4J(H2¢¢,H4¢¢) ≈ 4J(H2¢¢,3¢¢-CH3) = 1.2 Hz, H2¢¢), 6.57 (s, H1¢), 6.75
(d, J = 8.5 Hz), 6.87 (d, J = 8.1 Hz) (H8Ar1, H5Ar2), 7.43 [br s (!),
H5Ar1 or H2Ar2], 7.46 (d, presumably low-field part of a dd at 7.45
and overlapped by br s at 7.43, large coupling constant invisible be-
cause of overlap, 4J = 1.8 Hz, H7Ar1 or H6Ar2), 7.65 (dd, J = 8.7 Hz,
4J = 2.1 Hz, H7Ar1 or H6Ar2), 7.67 (br s, H5Ar1 or H2Ar2), 9.89 (s,
4Ar2-OH), 11.97 (br s, 4-OH).
HRMS: m/z [M+] calcd for C7H7F3O4: 212.0296; found: 212.0299.
2,2,2-Trifluoroethyl Pyruvate (25)
To a soln of pyruvic acid (8.81 g, 6.96 mL, 0.100 mol) and 2,2,2-
trifluoroethanol (15.0 g, 10.9 mL, 0.150 mol, 1.5 equiv) in CH2Cl2
(200 mL) a soln of DCC (22.7 g, 0.110 mol, 1.1 equiv) in CH2Cl2
(120 mL) was added dropwise at –10 °C and in the dark within 1 h.
Stirring was continued for an additional 3 h at –10 °C and overnight
at r.t. Dicyclohexylurea was removed by filtration over a short plug
of silica gel (6 cm, diameter = 6 cm, CH2Cl2–PE, 1:1, 400 mL). The
filtrate was concentrated under reduced pressure. The residual oil
was distilled under reduced pressure (72–78 °C/80 mbar) to give 25
as a colorless oil; yield: 8.91 g (52%); nD18 1.3576.
13C NMR (100 MHz, DMSO-d6): d = 17.7 (3¢¢-CH3), 21.9 (C4Ar1),
25.5 (C4¢¢), 26.6 [2Ar1-(CH3)2], 27.8 (C1¢¢), 32.1 (C3Ar1), 74.3
(C2Ar1), 99.6 (C3), 107.9 (C1¢), 115.4, 116.6 (C8Ar1, C5Ar2), 120.5,
121.4, 123.8 (3 Cq: C4aAr1, C6Ar1, C1Ar2), 122.3 (C2¢¢), 126.4, 129.3
(C7Ar1, C6Ar2), 128.3, 131.7 (C5Ar1, C2Ar2), 128.1, 131.9 (2 Cq:
C3Ar2, C3¢¢), 139.9 (C5), 152.7, 156.1 (C8aAr1, C4Ar2), 162.0 (C4),
168.1 (C2).
IR (film): 2985, 1760, 1745, 1450, 1415, 1365, 1305, 1290, 1265,
1250, 1180, 1130, 1035, 970, 660, 615 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.52 (s, 3 H3), 4.62 (q,
J(H,F) = 8.2 Hz, CH2CF3).
HRMS: m/z [M+] calcd for C27H28O5: 432.1937; found: 432.1934.
13C NMR (75 MHz, CDCl3): d = 26.9 (C3), 61.6 (q, 2J(C,F) = 37.5
Hz, CH2CF3), 122.5 (q, 1J(C,F) = 277.2 Hz, CF3), 159.0 (C1), 189.5
(C2).
(Z)-4-Hydroxy-5-[4-hydroxy-3-(3-methylbut-2-enyl)ben-
zylidene]-3-[4-hydroxy-3-(3-methylbut-2-enyl)phenyl]furan-
2(5H)-one (Aspulvinone H, 1y)
HRMS: m/z [M+] calcd for C5H5F3O3: 170.0191; found: 170.0196.
Following the typical procedure for 1x, using 1o (30.7 mg, 0.05
mmol), CH2Cl2 (5 mL), 1.0 M Cy2NMe in toluene (0.20 mL, 0.20
mmol, 2.0 equiv), 1 M BCl3 in hexanes (1.00 mL, 1.00 mmol, 20.0
equiv) and CaO (280 mg, 5.00 mmol, 50 equiv) in MeOH (5 mL).
Purification by flash chromatography [column diameter 1 cm, PE–
EtOAc, 3:1 with 1 vol% AcOH] furnished the title compound as a
raw mixture. By dropwise addition of a soln of this material in
CH2Cl2 (1 mL) to vigorously stirred pentane (35 mL), 1y precipitat-
ed; yield: 9.8 mg (45%); mp 115–121 °C.
2,2-Dimethylchromane (40)39
To an ice-cooled soln of 1 M MeLi in Et2O (200.0 mL, 200.0 mmol,
2.5 equiv) a soln of dihydrocoumarin (10.1 mL, 11.9 g, 80.0 mmol,
1.0 equiv) in THF (20 mL) was added dropwise over 1 h. The mix-
ture was stirred at r.t. for 20 h, recooled in ice bath, and aq 1 M HCl
(100 mL, 100 mmol, 1.25 equiv) was added dropwise. The layers
were separated and the aqueous layer was extracted with Et2O (2 ×
50 mL). The combined ethereal phases were dried (MgSO4) and the
solvent was removed in vacuo. The residue was dissolved in toluene
(100 mL), TsOH·H2O (305 mg, 1.61 mmol, 2 mol%) was added,
and the mixture was refluxed for 6 h in a Dean–Stark apparatus. Af-
ter removal of the solvent in vacuo, purification of the residue by
flash chromatography (column diameter 6.0 cm, cyclohexane) fur-
nished 40 as a colorless oil; yield: 9.90 g (76%).
1H NMR (300 MHz, CDCl3, contaminated): d = 1.69 (br s, 3¢¢-CH3,
3¢¢¢-CH3, 3 H4¢¢, 3 H4¢¢¢), 3.28, 3.30 (2 overlapping d, J = 6.3 Hz,
J = 6.4 Hz, 2 H1¢¢, 2 H1¢¢¢), 5.29 (mc, H2¢¢, H2¢¢¢), 6.26 (s, H1¢),
6.75, 6.76 (2 overlapping d, J = 8.4 Hz, H5Ar1, H5Ar2), 7.37 (d,
4
4J = 1.6 Hz, H2Ar1)*, 7.45 (dd, J = 8.4 Hz, J = 1.9 Hz, H6Ar1)**,
4
4
7.50 (d, J = 1.6 Hz, H2Ar2)*, 7.57 (dd, J = 8.5 Hz, J = 2.1 Hz,
H6Ar2)**); 4-OH, 4Ar1-OH, and 4Ar2-OH were not detected. *assign-
ment interchangeable; **assignment interchangeable.
1H NMR (300 MHz, CDCl3): d = 1.34 [s, 2-(CH3)2], 1.81 (t,
J(H3,H4) = 6.7 Hz, 2 H3), 2.80 (t, J(H4,H3) = 6.7 Hz, 2 H4), 6.75–
6.86, 7.03–7.13 (2 m, H5, H6, H7, H8).
HRMS: m/z [M+] calcd for C27H28O5: 432.1937; found: 432.1936.
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

2270
D. Bernier, R. Brückner
PAPER
6-Iodo-2,2-dimethylchromane (41)57
13C NMR (75 MHz, CDCl3): d = 71.1 (OCH2Ph), 83.9, 88.4 (C2,
C4), 114.6 (C6), 127.1 (CBn2, CBn6), 128.1 (CBn4), 128.7 (CBn3,
CBn5), 136.1 (CBn1), 138.2, 146.8 (C3, C5), 157.3 (C1).
Benzyltrimethylammonium dichloriodate (2.96 g, 8.5 mmol, 1.0
equiv) and ZnCl2 (1.65 g, 12.0 mmol, 1.2 equiv) were added to a
0 °C soln of 2,2-dimethylchromane (40, 1.38 g, 8.5 mmol, 1.0
equiv) in AcOH (50 mL). The ice bath was removed and the mixture
was stirred at r.t. for 4 h. H2O (35 mL) and aq 5% NaHSO3 soln (35
mL) were added successively and the mixture was extracted with
PE (3 × 75 mL). The combined organic layers were dried (Na2SO4)
and the solvent was removed in vacuo. Purification of the residue
by flash chromatography (column diameter 3.0 cm, PE–t-BuOMe,
40:1) furnished 41 as a colorless oil, which solidified upon standing
at +4 °C; yield: 2.18 g (89%).
1H NMR (300 MHz, CDCl3): d = 1.31 [s, 2-(CH3)2], 1.77 (t,
J(H3,H4) = 6.7 Hz, 2 H3), 2.73 (t, J(H4,H3) = 6.7 Hz, 2 H4), 6.54
(d, J(H8,H7) = 8.1 Hz, H8), 7.31–7.38 (m, H5, H7).
13C NMR (126 MHz, CDCl3): d = 22.3 (C4), 26.9 [2-(CH3)2], 32.5
(C3), 74.7 (C2), 81.6 (C6), 119.8 (C8), 123.9 (C4a), 136.1 (C7),
138.1 (C5), 154.1 (C8a).
Anal. Calcd for C13H10I2O (436.0): C, 35.81; H, 2.31. Found: C,
36.07; H, 2.31.
1-(Benzyloxy)-4-iodo-2-(3-methylbut-2-enyl)benzene (50)
Following the typical procedure for 46, starting from 49 (4.36 g,
10.0 mmol) in THF (45 mL), 1.98 M i-PrMgCl in THF (5.30 mL,
10.5 mmol, 1.05 equiv), CuI (0.191 g, 1.0 mmol, 10 mol%), and 1-
bromo-3-methylbut-2-ene (1.28 mL, 1.64 g, 11.0 mmol, 1.1 equiv).
Purification by flash chromatography (column diameter 5.0 cm, cy-
clohexane–EtOAc, 40:1) furnished 50 as a colorless oil; yield: 2.69
g (71%).
IR (film): 3065, 3030, 2965, 2910, 2880, 1585, 1485, 1455, 1395,
1380, 1310, 1280, 1240, 1180, 1120, 1100, 1025, 865, 830, 800,
735, 695, 640 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.64 (d, 4J(3¢-CH3,H2¢) = 1.0 Hz,
3¢-CH3), 1.74 (d, 4J(H4¢,H2¢) = 1.1 Hz,
3 H4¢), 3.31 (d,
4-Iodo-1-methoxy-2-(3-methylbut-2-enyl)benzene (46);
Typical Procedure
J(H1¢,H2¢) = 7.3 Hz, 2 H1¢), 5.04 (s, OCH2Ph), 5.26 (tqq,
4
4
J(H2¢,H1¢) = 7.3 Hz, J(H2¢,H4¢) ≈ J(H2¢,3¢-CH3) ≈ 1.5 Hz, H2¢),
6.64 (d, J(H6,H5) = 9.1 Hz, H6), 7.27–7.44 (m, H3, H5 and 5 HBn).
At –40 °C a soln of 2.30 M i-PrMgCl in THF (14.5 mL, 33.3 mmol,
1.0 equiv) was added to a soln of 2,4-diiodoanisole (12.0 g, 33.3
mmol) in THF (120 mL) at such a rate (within 30 min) that the in-
ternal temperature stayed below –30 °C. The mixture was stirred at
–40 °C for another 30 min. CuI (1.27 g, 6.66 mmol, 20 mol%) was
added and the mixture was allowed to reach –20 °C. After stirring
for 30 min, 1-bromo-3-methylbut-2-ene (3.85 mL, 33.3 mmol, 1.0
equiv) was added. The mixture was stirred at –20 °C for 1 h. The
mixture was quenched with sat. aq NH4Cl (150 mL). The aqueous
layer was extracted with Et2O (3 × 50 mL). The combined organic
13C NMR (100 MHz, CDCl3): d = 17.9 (3¢-CH3), 26.0 (C4¢), 28.5
(C1¢), 70.2 (OCH2Ph), 83.5 (C4), 114.0 (C6), 121.8 (C2¢), 127.3
(CBn2, CBn6), 128.0 (CBn4), 128.7 (CBn3, CBn5), 133.3, 133.5 (C2,
C3¢), 135.7 (C5), 137.0 (CBn1), 138.2 (C3), 156.5 (C1).
Anal. Calcd for C18H19IO (378.2): C, 57.16; H, 5.06. Found: C,
57.09; H, 4.96.
layers were washed with brine (50 mL) and dried (Na2SO4). The Acknowledgment
solvent was removed in vacuo. Purification of the residue by flash
chromatography (column diameter 5.0 cm, PE–t-BuOMe, 40:1) fur-
nished 46 as a colorless oil; yield: 8.88 g (88%).
We thank the Fonds der Chemischen Industrie for continuous finan-
cial support.
IR (film): 2965, 2930, 2910, 2835, 1585, 1485, 1460, 1440, 1395,
1375, 1300, 1280, 1245, 1175, 1125, 1100, 1030, 805 cm–1.
References
1H NMR (300 MHz, CDCl3): d = 1.69, 1.74 (3¢-CH3, 3 H4¢), 3.25
(d, J(H1¢,H2¢) = 7.3 Hz, 2 H1¢), 3.80 (s, MeO), 5.24 (incompletely
(1) Reviews: (a) Pattenden, G. Prog. Chem. Nat. Prod. 1978,
35, 133. (b) Gill, M.; Steglich, W. Prog. Chem. Nat. Prod.
1987, 51, 1. (c) Brückner, R. Curr. Org. Chem. 2001, 5, 679.
(2) (a) Rehse, K.; Lehmke, J. Arch. Pharm. (Weinheim, Ger.)
1985, 318, 11. (b) Caufield, C. E.; Antane, S. A.; Morris, K.
M.; Naughton, S. M.; Quagliato, D. A.; Andrae, P. M.; Enos,
A.; Chiarello, J. F. WO 2005019196, 2005. (c) Antane, S.;
Caufield, C. E.; Hu, W.; Keeney, D.; Labthavikul, P.;
Morris, K.; Naughton, S. M.; Petersen, P. J.; Rasmussen, B.
A.; Singh, G.; Yang, Y. Bioorg. Med. Chem. Lett. 2006, 16,
176.
resolved tqq, J(H2¢,H1¢) = 7.4 Hz, 4J(H2¢,H4¢)
≈
4J(H2¢,3¢-
CH3) = 1.3 Hz, H2¢), 6.59 (d, J(H6,H5) = 8.5 Hz, H6), 7.38 (d,
4J(H3,H5) = 1.9 Hz, H3), 7.38 (dd, J(H5,H6) = 8.3 Hz,
4J(H5,H3) = 2.0 Hz, H5).
13C NMR (75 MHz, CDCl3): d = 17.9 (3¢-CH3), 25.9 (C4¢), 28.2
(C1¢), 55.6 (OMe), 83.1 (C4), 112.6 (C6), 121.7 (C2¢), 133.1, 133.3
(C2, C3¢), 135.7 (C3), 137.9 (C5), 157.4 (C1).
HRMS: m/z calcd for C12H15OI [M+], 302.0168; found, 302.0171.
(3) Structure elucidation (later confirmed through synthesis):
(a) Ramage, R.; Griffiths, G. J.; Shutt, F. E.; Sweeney, J. N.
A. J. Chem. Soc., Perkin Trans. 1 1984, 1539. First
isolation of a naturally occurring pulvinone, namely 3¢,4,4¢-
trihydroxypulvinone (1v), from the higher fungus Suillus
grevillei: (b) Edwards, R. L.; Gill, M. J. Chem. Soc., Perkin
Trans. 1 1973, 1921.
(4) (a) First isolation of 7 naturally occurring pulvinones , later
named5 aspulvinones A–G, from Aspergillus terreus: Ojima,
N.; Takenaka, S.; Seto, S. Phytochemistry 1973, 12, 2527;
this study attributed correctly structure 1r to aspulvinone E
and described the remaining pulvinones as structurally
incompletely defined derivatives thereof. (b) independent
isolation of compound 1r (‘aspergillide B1’ until renamed5
aspulvinone E) from the same source: Golding, B. T.;
Rickards, R. W.; Vanek, Z. J. Chem. Soc., Perkin Trans. 1
1975, 1961.
1-(Benzyloxy)-2,4-diiodobenzene (49)
A mixture of soln of 2,4-diiodophenol (5.19 g, 15.0 mmol), benzyl
bromide (2.64 g, 1.87 mL, 15.5 mmol, 1.03 equiv), and K2CO3 (6.22
g, 45.0 mmol, 3.0 equiv) in acetone (60 mL) was refluxed for 3 h.
The mixture was diluted with PE (40 mL) and insoluble material
was removed by filtration. Removal of the solvents in vacuo fur-
nished 49 as a colorless solid; yield: 6.41 g (98%); mp 38–41 °C.
IR (film): 3060, 3030, 1565, 1555, 1495, 1465, 1455, 1370, 1310,
1275, 1245, 1150, 1030, 1005, 875, 800, 735, 695, 675, 635, 540
cm–1.
1H NMR (300 MHz, CDCl3): d = 5.10 (s, OCH2Ph), 6.58 (d,
J(H6,H5) = 8.8 Hz, H6), 7.25–7.47 (m, 5 HBn), 7.51 (dd,
J(H5,H6) = 8.6 Hz, 4J(H5,H3) = 2.1 Hz, H5), 8.05 (d,
4J(H3,H5) = 2.0 Hz, H3).
Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York

PAPER
(5) Origin of ‘aspulvinone’ terminology: Ojima, N.; Takahashi,
Novel Synthesis of Naturally Occurring Pulvinones
2271
61, 9009; we did not attempt an analogous approach to
fluorine-containing hydroxycinnamates 13 (R = RF).
(16) Representative syntheses of 2-hydroxycinnamates 13 from
arenecarbaldehydes 12 via oxazolones 10: Dalla, V.;
Cotelle, P.; Catteau, J.-P. Tetrahedron Lett. 1997, 38, 1577.
(17) Synthesis of a 2-hydroxycinnamate 13 from an
arenecarbaldehyde 12 via hydantoin 11: Raap, J.;
Nieuwenhuis, S.; Creemers, A.; Hexspoor, S.; Kragl, U.;
Lugtenburg, J. Eur. J. Org. Chem. 1999, 2609.
(18) Synthesis of a 2-hydroxycinnamate 13 from an
arenecarbaldehyde 12 via a glycidic ester 14: Reimann, E.;
Maas, H.-J.; Pflug, T. Monatsh. Chem. 1997, 128, 995.
(19) Trifluoroethyl 2,3-epoxy-2-methylacrylate was obtained by
an epoxidation of trifluoroethyl methacrylate with HOF:
Rozen, S.; Kol, M. J. Org. Chem. 1990, 55, 5155.
(20) Syntheses of cis- and trans-2-methoxycinnamate 15
(Ar = Ph, R = Y = Me) by Horner–Wadsworth–Emmons
reactions of benzaldehyde: Seneci, P.; Leger, I.; Souchet,
M.; Nadler, G. Tetrahedron 1997, 53, 17097.
T.; Ogura, K.; Seto, S. Tetrahedron Lett. 1976, 13, 1013; this
paper also describes the isolation and structure
determination of aspulvinone H(1y).
(6) Example of a structurally complex pulvinic acid: Winner,
M.; Giménez, A.; Schmidt, H.; Sontag, B.; Steffan, B.;
Steglich, W. Angew. Chem. Int. Ed. 2004, 43, 1883; Angew.
Chem. 2004, 116, 1919.
(7) (a) Ojima, N.; Ogura, K.; Seto, S. J. Chem. Soc., Chem.
Commun. 1975, 717. (b) Takahashi, I.; Ojima, N.; Ogura,
K.; Seto, S. Biochemistry 1978, 17, 2696. (c) Kobayashi,
M.; Ojima, N.; Ogura, K.; Seto, S. Chem. Lett. 1979, 579.
(d) Sagami, I.; Ojima, N.; Ogura, K.; Seto, S. Methods
Enzymol. 1985, 110, 320.
(8) The structures of aspulvinone A (1i, correct), aspulvinone B
(later revised to 1x),9d aspulvinone C (later revised to 1z),9c
aspulvinone D (later revised to be 1aa),9c aspulvinone F
(later revised),7b,9c and aspulvinone G (later revised to 1s),9a,b
were first proposed by: Ojima, N.; Takenaka, S.; Seto, S.
Phytochemistry 1975, 14, 573.
(21) (a) Schmidt, U.; Langner, J.; Kirschbaum, B.; Baum, C.
Synthesis 1994, 1138; (12 → 16 for Y = Ac). (b) Burk, M.
J.; Kalberg, C. S.; Pizzano, A. J. Am. Chem. Soc. 1998, 120,
4345; (12 → 16 for Y = Bz).
(9) The structures originally proposed8 for aspulvinones B,4 C,4
D,4 F,4 and G4 were revised by synthetic or biosynthetic
correlations and an X-ray analysis in a series of
communications by Knight and Pattenden, for a summary
see: (a) Begley, M. J.; Gedge, D. R.; Knight, D. W.;
Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1979, 77.
(b) Knight, D. W.; Pattenden, G. J. Chem. Soc., Chem.
Commun. 1975, 876; showed that synthetically per-O-
methylated 2¢,4,4¢-trihydroxypulvinone is different from
per-O-methylated aspulvinone G and deduced that
aspulvinone G equals 1s. (c) Laboratory synthesis of per-O-
methylated aspulvinone G: Knight, D. W.; Pattenden, G. J.
Chem. Soc., Perkin Trans. 1 1979, 70. (d) The identity of
aspulvinone D with 1aa emerged from an X-ray structural
analysis, and biosynthetic considerations led to establishing
the correct structures of aspulvinone C ( = 1z) and
aspulvinone F: Begley, M. J.; Knight, D. W.; Pattenden, G.
Tetrahedron Lett. 1976, 17, 131. (e) The identity of
aspulvinone B as 1x was concluded from a synthesis of per-
O-methylated 1x: Knight, D. W.; Pattenden, G. J. Chem.
Soc., Chem. Commun. 1976, 635.
(22) Horner–Wadsworth–Emmons reactions between
deprotonated phosphonato esters containing an OSiR3
substituent at the carbanionic center and arenecarbaldehydes
12 are also known, yet no ensuing desilylation furnished the
underlying enol: (a) Pujol, B.; Sabatier, R.; Driguez, P.-A.;
Doutheau, A. Tetrahedron Lett. 1992, 33, 1447.
(b) Boehlow, T. R.; Harburn, J. J.; Spilling, C. D. J. Org.
Chem. 2001, 66, 3111. (c) Qin, D.; Ren, R. X.; Siu, T.;
Zheng, C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2001,
40, 4709; Angew. Chem. 2001, 113, 4845. (d) Bailey, K. L.;
Molinski, T. F. Tetrahedron Lett. 2002, 43, 9657.
(e) Ogamino, T.; Ishikawa, Y.; Nishiyama, S. Heterocycles
2003, 61, 73.
(23) (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1987, 28, 3039. (b) Sakamoto, T.; Kondo,
Y.; Kashiwagi, Y.; Yamanaka, H. Heterocycles 1988, 27,
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Heterocycles 1988, 27, 453. (d) Merlic, C. A.; Semmelhack,
M. F. J. Organomet. Chem. 1990, 391, C23. (e) Waters, S.
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1971, 44, 581. (b) Heck, R. F.; Nolley, J. P. Jr. J. Org. Chem.
1972, 37, 2320.
(25) (a) Carlstroem, A.-S.; Frejd, T. Synthesis 1989, 414.
(b) Carlstroem, A.-S.; Frejd, T. J. Org. Chem. 1991, 56,
1289. (c) Carlstroem, A.-S.; Frejd, T. J. Chem. Soc., Chem.
Commun. 1991, 1216. (d) Carlstroem, A.-S.; Frejd, T. Acta
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(26) Monnin, J. Helv. Chim. Acta 1956, 39, 1721.
(27) We could also esterify trifluoroethyl pyruvate (25) to give
trifluoroethyl 2-[(4-methoxyphenyl)acetoxy]acrylate (20),
employing the mixed anhydride obtained from (4-meth-
oxyphenyl)acetic acid, TFAA (2.0 equiv), and TsOH·H2O
(cat., toluene, reflux, 12 h); however, the low yield of 20
(21%) by this route kept us from trying to shortcut our two-
step synthesis of trifluoroethyl 2-(arylacetoxy)cinnamates
by using the one-step alternative of a Heck coupling between
iodoarenes 17 and this reagent.
(10) Vértesy, L.; Burger, H.-J.; Kenja, J.; Knauf, M.; Kogler, H.;
Paulus, E. F.; Ramakrishna, N. V. S.; Swamy, K. H. S.;
Vijayakumar, E. K. S.; Hammann, P. J. Antibiot. 2000, 53,
677.
(11) Klostermeyer, D.; Knops, L.; Sindlinger, T.; Polborn, K.;
Steglich, W. Eur J. Org. Chem. 2000, 4, 603.
(12) Bernier, D.; Moser, F.; Brückner, R. Synthesis 2007, 2240.
(13) Benzylic alkaline metals have been condensed with dialkyl
oxalates only if derived from a two-fold ester-substituted
toluene (M = Li): (a) Julia, M.; Rolando, C.; Vincent, E.;
Xu, J. Z. Heterocycles 1989, 28, 71. Or from nitrotoluenes
(M = Na, K), e.g. (b) Sall, D. J.; Arfsten, A. E.; Bastian, J.
A.; Denney, M. L.; Harms, C. S. J. Med. Chem. 1997, 40,
2843. (c) Suzuki, H.; Gyoutoku, H.; Yokoo, H.; Shinba, M.;
Sato, Y.; Yamada, H.; Murakami, Y. Synlett 2000, 1196.
(d) Hume, W. E.; Tokunaga, T.; Nagata, R. Tetrahedron
2002, 58, 3605.
(14) Synthesis of 13 (R = Et, Ar = Ph) from 9 (M = MgCl,
Ar = Ph) and diethyl oxalate: Dao, D. H.; Okamura, M.;
Akasaka, T.; Kawai, Y.; Hida, K.; Ohno, A. Tetrahedron:
Asymmetry 1998, 9, 2725.
(15) Acylations of Grignard reagents by activated monoalkyl
oxalates are known: (a) Nimitz, J. S.; Mosher, H. S. J. Org.
Chem. 1981, 46, 211. (b) de las Heras, M. A.; Vaquero, J. J.;
García-Navio, J. L.; Alvarez-Builla, J. J. Org. Chem. 1996,
(28) Jeffery, T. Tetrahedron 1996, 52, 10113.
(29) In Z-configured 2-acetoxycinnamates, 3J(13C1,1H3) = 3.0–
4.5 Hz, their E-isomers have 3J(13C1,1H3) = 9.5–10.5 Hz:
Fischer, P.; Schweizer, E.; Langner, J.; Schmidt, U. Magn.
Reson. Chem. 1994, 32, 567.
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PAPER
magnesiation of 2,4-dibromoanisole with i-PrMgCl by:
Nishiyama, H.; Isaka, K.; Itoh, K.; Ohno, K.; Nagase, H.;
Matsumoto, K.; Yoshiwara, H. J. Org. Chem. 1992, 57, 407.
(45) Iodine–magnesium exchange using i-PrMgCl in THF:
Boymond, L.; Rottländer, M.; Cahiez, G.; Knochel, P.
Angew. Chem. Int. Ed. 1998, 37, 1701; Angew. Chem. 1998,
110, 1801.
(46) BBr3-mediated deprotections of ortho-prenylated methyl
phenyl ethers and subsequent in situ cyclizations giving
chromanes: Eicher, T.; Tiefensee, K.; Doenig, R.; Pick, P.
Synthesis 1991, 98; and references therein.
(47) Deprotection of aryl methyl ethers with LiSEt/DMF:
Fentrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970, 11,
1327.
(48) Deprotection of aryl methyl ethers with PhSH/K2CO3/NMP:
Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1997,
38, 8749.
(49) Deprotection of aryl methyl ethers with LiI in quinoline:
Kirschke, K.; Wolff, E. J. Prakt. Chem. 1995, 337, 405.
(50) Precedence for the chemoselective cleavage of a benzyl
ether in the presence of a trisubstituted C=C double bond by
catalytic hydrogenation: Barrero, A. F.; Alvarez-
Manzaneda, E. J.; Chahboun, R. Tetrahedron Lett. 1997, 38,
8101.
(51) Precedence for the chemoselective cleavage of a benzyl
ether in the presence of a trisubstituted C=C double bond by
catalytic transfer hydrogenation: Iikubo, K.; Ishikawa, Y.;
Ando, N.; Umezawa, K.; Nishiyama, S. Tetrahedron Lett.
2002, 43, 291.
(30) (a) This modification was inspired by: Gürtler, C.;
Buchwald, S. L. Chem. Eur. J. 1999, 5, 3107. (b) For a
rationalization of the beneficial effect of Cy2NMe vs.
inorganic bases in Heck couplings cf. also: Hills, I. D.; Fu,
G. C. J. Am. Chem. Soc. 2004, 126, 13178.
(31) Attempts to arylate ethyl 2-(trimethylsiloxy)acrylate (21),
prepared according to: Barton D. H. R., Chern C.-Y.,
Jaszberenyi J. C.; Tetrahedron; 1995, 51: 1867; with 4-
iodoanisole under conditions reasonably effective for ethyl
2-acetoxyacrylate (18, cf. Table 2, entry 3) failed
completely. Therefore, we did not prepare trifluoroethyl 2-
(trimethylsiloxy)acrylate (22) as a potential substrate of
Heck arylation
(32) Facile oxidative degradation of 2-hydroxycinnamates 13 to
the corresponding arenecarbaldehyde, especially in acidic
media, has been observed by ourselves and others (e.g., ref.
16). Detailed study with methyl 2-hydroxy-4¢-methoxy-
cinnamate: Jefford, C. W.; Knöpfel, W.; Cadby, P. A.
Tetrahedron. Lett. 1978, 19, 3585.
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(35) Kaczybura, N.; Brückner, R. Synthesis 2007, 118.
(36) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269.
(37) Method: Toussaint, O.; Capdevielle, P.; Maumy, M.
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(38) Gill, M.; Kiefel, M. J.; Lally, D. A.; Ten, A. Aust. J. Chem.
(52) Cleavage of benzyl ethers with lithium naphthalenide:
Alonso, E.; Ramon, D. J.; Yus, M. Tetrahedron 1997, 53,
14355.
(53) These conditions were inspired by the cleavage of a benzyl
ether within a sensitive, C=C-containing substrate by
treatment with BCl3 (CH2Cl2, –78 °C to 0 °C) and
subsequent methanolysis of the resulting boronic ester
(–78 °C): Williams, D. R.; Brown, D. L.; Benbow, J. W.
J. Am. Chem. Soc. 1989, 111, 1923.
1990, 43, 1497.
(39) Fatope, M. O.; Abraham, D. J. J. Med. Chem. 1987, 30,
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(40) Method: Kajigaeshi, S.; Kakinami, T.; Moriwaki, M.;
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795.
(41) For a recent review see: Hoarau, C.; Pettus, T. R. R. Synlett
2003, 127.
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(44) To the best of our knowledge, there is just one ortho-
selective halogen–metal exchange reaction of an aromatic
compound, which contains a metal-directing substituent at
C1 and halogen atoms both at C2 and C4: the ortho-selective
(54) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem.
1997, 62, 7512.
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Synthesis 2007, No. 15, 2249–2272 © Thieme Stuttgart · New York