Syntheses of retipolide E and ornatipolide, 14-membered biaryl-ether macrolactones from mushrooms

Article abstract of DOI:10.1016/j.tet.2007.03.022

Two approaches for the total synthesis of the spiromacrolide retipolide E (5) are described, the first using a modified Mitsunobu reaction as key step for the formation of the strained 14-membered macrolactone, the second a nucleophilic aromatic substitution (S_NAr). In the first approach an α-oxomacrolactone 15 was obtained, which could either be converted into ornatipolide (6) or further transformed into racemic retipolide E [(R,S)-5] by directed aldol condensation with a methyl arylpyruvate. The second approach allowed the synthesis of either racemic or enantiomerically pure retipolide E (5). In the latter case Evans' methodology was used for the introduction of stereogenic center via stereoselective alkylation. The oxazolidinone auxiliary was removed under mild conditions by exchange for 2-arylethanol 22 with Otera's distannoxane catalyst. Synthetic retipolide E allowed the identification of this biosynthetic intermediate in the fruit bodies of the North American mushroom Retiboletus retipes.

Full text of DOI:10.1016/j.tet.2007.03.022

Tetrahedron 63 (2007) 6548–6557
Syntheses of retipolide E and ornatipolide, 14-membered
biaryl-ether macrolactones from mushrooms
Andrea Ingerl,a Karl Justus,b Veronika Hellwiga and Wolfgang Steglicha,
*
aDepartment Chemie, Universita€t Mu€nchen, Butenandtstrasse 5-13, D-81377 Mu€nchen, Germany
Kekule-Institut fu€r Organische Chemie und Biochemie der Universita€t Bonn, Gerhard-Domagk-Strasse 1, D-53121 Bonn 1, Germany
b
´
Received 21 January 2007; revised 1 March 2007; accepted 2 March 2007
Available online 7 March 2007
Abstract—Two approaches for the total synthesis of the spiromacrolide retipolide E (5) are described, the first using a modified Mitsunobu
reaction as key step for the formation of the strained 14-membered macrolactone, the second a nucleophilic aromatic substitution (SNAr). In
the first approach an a-oxomacrolactone 15 was obtained, which could either be converted into ornatipolide (6) or further transformed into
racemic retipolide E [(R,S)-5] by directed aldol condensation with a methyl arylpyruvate. The second approach allowed the synthesis of either
racemic or enantiomerically pure retipolide E (5). In the latter case Evans’ methodology was used for the introduction of stereogenic center via
stereoselective alkylation. The oxazolidinone auxiliary was removed under mild conditions by exchange for 2-arylethanol 22 with Otera’s
distannoxane catalyst. Synthetic retipolide E allowed the identification of this biosynthetic intermediate in the fruit bodies of the North Amer-
ican mushroom Retiboletus retipes.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
2.1. Retrosynthetic considerations
Fruit bodies of the North American mushrooms Retiboletus
retipes (Berk. & Curtis) Binder and Bresinsky and Retibole-
tus ornatipes (Peck) Binder and Bresinsky1 contain several
closely related macrolactones, named retipolides A–D (1–
4).2,3 The major compound, retipolide A, is responsible for
the yellow color and bitter taste of these mushrooms. Its ab-
solute (R)-configuration has been unambiguously assigned
by X-ray analysis of a suitable derivative.2 The structures
of the retipolides suggest a common origin from a hitherto
hypothetical 4-hydroxyphenyl analog, retipolide E (5),
which could undergo oxidativering enlargement to retipolide
C (3), followed by rearrangement into retipolide A (1).3 For
the identification of the proposed precursor 5 in the fungal
extract, we decided to synthesize racemic retipolide E as
a reference compound for chromatographic comparison.
Our first synthetic approach is based on the idea that the
spiro system of retipolide E (5) could be obtained by aldol
condensation of a suitably protected 14-membered a-oxo-
macrolide A with an O-protected methyl 3-(4-hydroxyphe-
nyl)pyruvate B (Scheme 1). A possible pathway for the
synthesis of oxomacrolide A is the cyclization of a suitable
hydroxy acid C.4 Alternatively, the macrocyclic ring could
be closed at the diaryl ether linkage by intramolecular nucleo-
philic aromatic substitution of an adequate precursor D,
which is accessible by transesterification of methyl ester E
with a suitable 2-arylethanol derivative. This approach could
be adapted for the synthesis of (R)-retipolide E (5), if enan-
tiomerically pure butenolide E is used as starting material.
O
OH
OH
2
OH
OH
9'
4
O
1 16
R
3
O
O
R
O
O
8'
7'
15
14
5
6
17
19
6'
3'
18
11
13
12
OH
7
4' OH
5'
O
8
O
O
O
OH
O
9
O
O
O
O
1'
O
O
O
O
retipolide E (5)
retipolide A (1): R = H
retipolide B (2): R = OH
retipolide C (3): R = H
retipolide D (4): R = OH
* Corresponding author. Tel.: +49 89 565147; fax: +49 89 2180 77756; e-mail: wos@cup.uni-muenchen.de
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.022

A. Ingerl et al. / Tetrahedron 63 (2007) 6548–6557
OPG OMe
6549
OMe
OPG
OMe
OPG
O
OBn
OH
O
O
c
d, e, f
CHO
a, b
+
OH
CO2Me
O
HO2C
OPG
O
OH
OH
OAc
OAc
O
O
8
9
10
B
A
C
5
OMe
OMe
OPG
OPG
O
OPG
X
OH
X
i
g, h
MeO2C
OAc
11
OH
HO2C
12
OTBDPS
MeO2C
O
OPG
OPG
OH
O
O
O
O
O
OMe
OMe
D
E
O
O
Scheme 1. Retrosynthesis of retipolide E (5).
j
k
O
O
Interestingly, the free phenol corresponding to macrolide A,
named ornatipolide (6), has been isolated from a Japanese
collection of R. ornatipes,5 and secoretipolide E (7), a com-
pound resembling ester D, has been detected in the methanol
extract of R. retipes.2 The biosynthetic relevance of these
findings remains to be investigated.
OH
OTBDPS
O
O
14
13
OMe
OMe
OMe
O
O
m
l
OH
(R,S)-5
OH
HO
OH
3
O
OH
O
4
16
O
O
1
O
5
6
15
14
O
16
O
15
O
17
19
13
12
18
m
7
8
6
O
OH
O
O
O
O11
9
O
Scheme 2. Synthesis of (R,S)-retipolide E [(R,S)-5] by macrolactonization.
Reagents and conditions: (a) Ac2O, pyridine; (b) H2, Pd/C, 77% (2 steps); (c)
4-bromobenzaldehyde, CuO, 82%; (d) ClCH2CO2Me, NaOMe, MeOH; (e)
Ac2O, pyridine; (f) H2, Pd/C, 41% (3 steps); (g) TBDPS-Cl, imidazole,
DMAP; (h) LiOH, THF, H2O, 85% (2 steps); (i) DEAD, PPh3, 73%; (j)
n-Bu4NF (97%); (k) PCC (94%); (l) methyl 3-(4-methoxyphenyl)pyruvate,
NEt3, EtOAc, 90%; (m) BI3, CH2Cl2, 0 ꢀC (47%). Bn¼benzyl, TBDPS-
Cl¼tert-butyldiphenylchlorosilane, DMAP¼4-(dimethylamino)pyridine,
DEAD¼diethyl azodicarboxylate, PCC¼pyridinium chlorochromate.
O
ornatipolide (6)
secoretipolide E (7)
2.2. Synthesis of ornatipolide (6) and (R,S)-retipolide E
[(R,S)-5] via macrolactonization
Our first approach started from the known 2-(3-benzyloxy-4-
methoxyphenyl)ethanol (8),6 which was converted in two
steps into acetate 9 (Scheme 2). Copper-catalyzed coupling
of the latter with 4-bromobenzaldehyde yielded the biphenyl
ether aldehyde 10, which was used for the introduction of the
hydroxy acid side chain by Darzens’ methodology. Reaction
of aldehyde 10 with methyl chloroacetate under basic con-
ditions gave the corresponding glycidic ester, which was
acetylated to reintroduce the O-protecting group and subse-
quently hydrogenolyzed at the benzylic position to afford
hydroxy ester 11 in 41% yield without isolation of the inter-
mediates. After protection of the hydroxy group with tert-
butyldiphenylchlorosilane (TBDPS-Cl) and hydrolysis of
the ester groups, the resulting hydroxy acid 12 was obtained
ready for macrocyclization.
and an end concentration of 0.0079 M, a decrease in the yield
of lactone 13 to 53% was observed.
Treatment of macrolide 13 with tetra-n-butylammonium
fluoride furnished the free hydroxylactone 14, which could
be oxidized to the desired oxolactone 15 in excellent yield.
According to the NMR spectra, compound 15 in CDCl3 is
completely present in the keto form, which is unusual for
phenylpyruvate moieties.7 Removal of the O-methyl group
with boron triiodide yielded phenol 6, in all respects identi-
cal with ornatipolide from R. ornatipes.5
Condensation of ketone 15 with methyl 3-(4-methoxyphe-
nyl)pyruvate in the presence of triethylamine afforded
(R,S)-retipolide E dimethyl ether (16) in nearly quantitative
yield. The exclusive formation of the desired condensation
product can be explained by the absence of the enol form
of the oxomacrolide and the high reactivity due to ring strain.
Treatment of 16 with BI3 yielded (R,S)-retipolide E [(R,S)-
5]. The compound was obtained from 8 in 13 steps with
6.2% overall yield.
As has already been observed with a simpler analog,4 most of
the popular methods for the macrocyclization to the 14-mem-
bered lactone failed and delivered only the corresponding
diolide. In contrast, our modified Mitsunobu procedure4 af-
forded the desired macrolide 13 in 55% yield. This could be
furtherimprovedto73%bysimultaneouslyaddingallthecon-
stituents (DEAD, PPh3, and hydroxy acid 12) as toluene solu-
tions within 6 h to a toluene solution of DEAD in PPh3. In this
case the reaction was performed on a 2.14 mmol scale reach-
ing a 0.0015 M end concentration. On scaling up to 10 mmol
The synthetic sample enabled us to detect retipolide E in the
crude extract of R. retipes by chromatographic comparison.

6550
A. Ingerl et al. / Tetrahedron 63 (2007) 6548–6557
Optically active retipolide E (5) was subsequently isolated in
larger quantity and its spectroscopic data matched those of
the synthetic racemate.2
orthogonal 1,4-disubstituted benzene ring shields this pro-
ton, an effect typically observed for all retipolides.2 Reduc-
tion of the nitro group by catalytic hydrogenation yielded
amino compound 25, which could be deaminated to (R,S)-re-
tipolide E trimethyl ether (26) by treatment with tert-butyl
nitrite.14 Removal of the O-methyl groups with BI3 at
ꢁ78 ꢀC15 afforded racemic retipolide E [(R,S)-5], identical
with the compound obtained with our first synthesis. The
SNAr strategy yielded retipolide E in eight steps from methyl
glyoxylate (17) with 5.7% overall yield.
2.3. Synthesis of (R,S)-retipolide E by intramolecular
aromatic nucleophilic substitution
Our second synthesis started from methyl glyoxylate (17),
which was obtained by ozonolysis of dimethyl fumarate
and reductive workup with dimethyl sulfide. Treatment of
the crude solution with methyl 3-(4-methoxyphenyl)pyru-
vate (18) and triethylamine yielded hydroxylactone 19,8
which afforded enol methyl ether 20 on treatment with
diazomethane (Scheme 3). Alkylation of ester 20 with 4-
fluoro-3-nitrobenzyl bromide9 was carried out with 1 equiv
of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile
at room temperature to yield the substitution product 21. The
transesterification of methyl ester 21 with 2-(3-hydroxy-4-
methoxyphenyl)ethanol (22)10,11 to ester 23 was easily
achieved with Otera’s catalyst 1,3-dichlorotetrabutyldistan-
noxane.12 Due to the steric hindrance of the ester group in
23, alternative procedures based on base or acid catalysis
were unsuccessful.
2.4. Stereoselective synthesis of (R)-retipolide E (5) via
intramolecular aromatic nucleophilic substitution
The second approach to retipolide E could be easily adapted
for the synthesis of the optically active compound. For this
purpose, the enantiomerically pure 4-fluoro-3-nitrobenzyl
compound 31 was prepared using Evans’ methodology16
(Scheme 4). The (ꢁ)-norephedrine-derived auxiliary was in-
troduced by condensation of N-glyoxyloyloxazolidinone 28,
prepared in situ by ozonolysis of the corresponding prope-
noyl compound 27,17 with methyl 3-(4-methoxyphenyl)pyr-
uvate (18). The resulting hydroxybutenolide 29 was obtained
as a mixture of two diastereomers, which was transformed
into enol ether 30 by treatment with diazomethane. Alkyl-
ation of 30 with 4-fluoro-3-nitrobenzyl bromide in aceto-
nitrile in the presence of DBU yielded a 4:1 mixture of the
4R and 4S diastereomers, from which the pure 4R compound
31 could be separated by fractional crystallization in 44%
yield. Interestingly, treatment of the imide 31 with 2-aryl-
ethanol 22 in the presence of distannoxane as catalyst yielded
the desired ester (R)-23 in 66% yield. To our knowledge this
is the first example for the direct conversion of an Evans
imide into a carboxylic ester under exceptionally mild condi-
tions. Ester (R)-23 could be transformed into (R)-retipolide
(5) by the same sequence of reactions that were applied to
the racemic compound. The CD spectrum of the synthetic
material was also in agreement with that of the natural sam-
ple,2 thus proving the (R)-configuration of retipolide E.
OMe
OMe
b
OMe
MeO2C
MeO2C
H
MeO2C
H
c
CHO
+
a
17
O
O
OMe
OH
19
OH
MeO2C
F
O
O
20
18
NO2
HO
MeO
F
OMe
NO2
OMe
OH
O
OMe
e
OH
22
MeO2C
d
O
OMe
O
O
OMe
O
O
23
21
OMe
OMe
OMe
OMe
OMe
O
O
O
O
CHO
O
R
O
O
d
b
H
a
2'
O
N
O
N
O
N
g
O
4
h
O 5
2
3 OR
(R,S)-5
5' 4'
Ph
Me
Ph
Me
Ph
Me
O
OMe
O
OMe
O
O
O
O
28
O
29, R = H
30, R = Me
27
O
c
O
24, R = NO2
25, R = NH2
26
f
F
F
NO2
MeO
NO2
OH
Scheme 3. Synthesis of (R,S)-retipolide E [(R,S)-5] via intramolecular aro-
matic nucleophilic substitution. Reagents and conditions: (a) NEt3, EtOAc,
RT, 72%; (b) CH2N2, Et2O, 80%; (c) 4-fluoro-3-nitrobenzyl bromide, DBU,
MeCN, rt, 83%; (d) 22, 1,3-dichlorotetrabutyldistannoxane (cat.), toluene,
reflux, 90%; (e) K2CO3, MeCN, 61% (1:1 mixture of atropdiastereomers);
(f) H2, Pd/C, 86% (1:1 mixture of atropdiastereomers); (g) tert-butyl nitrite,
DMF, 62%; (h) BI3, CH2Cl2, 41%. DBU¼1,8-diazabicyclo[5.4.0]undec-7-
ene.
OMe
OMe
O
O
O
g,h,i,j
f
e
5
O
O
N
O
O
OMe
OMe
Ph
Me
O
O
(R)-23
31
Scheme 4. Synthesis of (R)-retipolide E (5) via intramolecular aromatic nu-
cleophilic substitution. Reagents and conditions: (a) O3, EtOAc, ꢁ78 ꢀC,
then Me2S, 59%; (b) 18, NEt3, EtOAc, rt, 59%; (c) CH2N2, Et2O, 73%;
(d) 4-fluoro-3-nitrobenzyl bromide, DBU, MeCN, rt, R/S¼4:1; (e) separa-
tion of (R)-diastereomer by crystallization, 44% (two steps); (f) 2-(3-hy-
droxy-4-methoxyphenyl)ethanol (22), 1,3-dichlorotetrabutyldistannoxane
(cat.), toluene, reflux, 66%; the experimental conditions for steps (g)–(j)
correspond to those given for steps (e)–(h) in Scheme 3.
The 14-membered lactone 24 was produced from the acti-
vated fluoride 23 by treatment with K2CO3 in DMF.9,13
The intramolecular SNAr reaction afforded 24 in 61% yield
as a 1:1 mixture of the two atropdiastereomers.13c The ring
closure is indicated by the strong up-field NMR shift of
the 19-H proton from d w6.6 in 23 to d w4.8 in 24. The

A. Ingerl et al. / Tetrahedron 63 (2007) 6548–6557
6551
In conclusion, we have synthesized the highly strained 14-
membered lactone system of the fungal metabolite retipolide
E by two different strategies. In the course of these investi-
gations, the Mitsunobu technique for the formation of such
macrolactones from the corresponding hydroxy acids was
further improved and a mild method for the direct exchange
of Evans oxazolidinone auxiliaries against alcohols was de-
veloped. The synthesis of retipolide E allowed us the detec-
tion and isolation of this elusive biosynthetic precursor from
the fungal extract.
(90 MHz, CDCl3): d 1.99 (s, 3H), 2.76 (t, J¼7 Hz, 2H), 3.78
(s, 3H), 4.16 (t, J¼7 Hz, 2H), 5.77(s, 1H), 6.50–6.83(m, 3H);
13C NMR (22.6 MHz, CDCl3): d 21.1, 34.5, 56.0, 65.2,
110.8, 115.2, 120.3, 131.2, 145.4, 145.7, 171.2; MS (EI)
m/z (rel int.): 210 (8, M+), 151 (12), 150 (100), 137 (43),
135 (49), 122 (10), 107 (6), 94 (6), 91 (10), 43 (28). Anal.
Calcd for C11H14O4: C 62.85; H 6.71; found: C 62.98; H 6.60.
3.2.2. 2-[3-(4-Formylphenoxy)-4-methoxyphenyl]ethyl
acetate (10). A mixture of 9 (49.0 g, 233 mmol), 4-bromo-
benzaldehyde (47.4 g, 256 mmol), anhydrous K2CO3
(64.4 g, 466 mmol), and dry pyridine (250 mL) was stirred
under an argon atmosphere at 90 ꢀC (bath temperature). After
addition of CuO (46.3 g, 582 mmol), the bath temperature
was raised to 135 ꢀC and the stirring continued for 18 h.
The suspension was cooled to rt, diluted with EtOAc (2 L),
and filtered over Celite. The filtrate was washed with 1 M
aq NaHSO4 (1.5 L, 3ꢂ), water (500 mL), 0.1 M aq NaOH
(500 mL), water (500 mL), and brine (500 mL), dried
(MgSO4), and concentrated under reduced pressure. Purifi-
cation by flash chromatography (hexanes/EtOAc, 3:1,
Rf¼0.34) afforded 10 (60 g, 82%) as a colorless, highly vis-
cous oil. 1H NMR (90 MHz, CDCl3): d 2.00 (s, 3H), 2.85 (t,
J¼7 Hz, 2H), 3.70 (s, 3H), 4.22 (t, J¼7 Hz, 2H), 6.80–7.17
(m, 5H), 7.67–7.90 (m, 2H), 9.89 (s, 1H); 13C NMR
(22.6 MHz, CDCl3): d 20.9, 34.2, 56.0, 64.8, 113.2, 116.3
(2C), 123.1, 126.6, 131.0, 131.3, 131.9 (2C), 142.8, 150.4,
163.6, 171.0, 190.8; MS (EI) m/z (rel int.): 314.1 (6, M+),
255 (20), 254 (100), 242 (7), 241 (13), 211 (16), 77 (9), 43
(29). Anal. Calcd for C18H18O5: C 68.78; H 5.77; found: C
68.86; H 5.81.
3. Experimental
3.1. General
UV–vis: Varian Cary 17; NMR: Bruker AC 200, Bruker
ARX 300, Bruker WM 400, Varian EM 390, Varian VXR
400S, Bruker WH 90, and Bruker AMX 600 instruments
with chemical shifts in parts per million d units relative to
TMS as internal standard. For retipolide E (5) and its deriv-
atives 16 and 24–26, the assignments of the H-atoms are
given in Figure 1; MS (EI) and HRMS (EI) were recorded
on a Finnigan MAT 90, MAT 95, or A.M.E. Kratos MS 50
mass spectrometer, equipped with an EI ion source operated
at 70 eV; TLC: silica gel 60 F TLC plates 0.2 mm (Merck);
flash column chromatography (FC): silica gel 60 (40–63 mm,
230–400 mash, Merck); hexanes refers to the fraction of pe-
troleum ether with bp 40–60 ꢀC; C, H, N analyses were per-
formed by the Microanalytical Laboratory of the Chemistry
€
Department, LMU, Munchen or of the Institute for Organic
Chemistry and Biochemistry, University of Bonn.
3.2.3. Methyl 3-{4-[5-(2-acetoxyethyl)-2-methoxyphen-
oxy]phenyl}-2-hydroxypropionate (11). A solution of 10
(56.2 g, 179 mmol) in methyl chloroacetate (26.5 mL,
268 mmol) was added under an argon atmosphere to a stirred
solution of NaOMe (14.5 g, 268 mmol) in dry MeOH
(250 mL), maintained at ꢁ10 ꢀC. The mixture was warmed
to rt and stirred for 18 h. After addition of acetic acid
(5.1 mL, 89.0 mmol), the solution was poured into ice water
(900 mL) and extracted with EtOAc (2ꢂ300 mL). The com-
bined organic phases were washed with water (200 mL) and
brine (200 mL), dried (MgSO4), and concentrated under
reduced pressure. The resulting orange oil (68.1 g) was
purified by flash chromatography (hexanes/EtOAc, 1:1),
whereby all fractions with Rf¼0.39 (hexanes/EtOAc, 1:1)
were combined to afford a colorless oil (49.7 g), which
was dissolved in dry pyridine (70 mL) and treated with
Ac2O (54.4 mL, 576 mmol) at 0 ꢀC under an argon atmo-
sphere. The solution was stirred for 18 h at rt, then poured
into ice water (500 mL), and extracted with EtOAc
(2ꢂ200 mL). The combined organic phases were washed
with 20% aq citric acid (1 L, then 500 mL), satd aq NaHCO3
(2ꢂ500 mL), and brine (500 mL), dried (MgSO4), and con-
centrated under reduced pressure to yield a brown oil
(51.8 g), which was dissolved in a mixture of EtOAc
(15 mL) and MeOH (150 mL). The solution was transferred
to a shaking apparatus and hydrogenated with 10% Pd on
charcoal (5.00 g) and Na2CO3 (1.00 g) at 3 atmH2 pressure.
After removal of the catalyst by filtration over a Celite pad
and evaporation of the solvent under reduced pressure, the
oily residue was diluted with Et2O (500 mL), filtered, and
concentrated again. The resulting yellowish oil (51.6 g)
16
H
O
HO
H17
H
15
H
19H
5
6
H18
Ha
13 Hb
8
H
O
Hb
O
Ha
Ha
9
O
O
Hb
Ar
OH
Figure 1. Conformation of retipolide E (5) with numbering of the H atoms
used in the 1H NMR spectra of compounds 5, 16, and 24–26 (Ar¼C6H4OH
or C6H4OMe).
3.2. Synthesis of ornatipolide and (R,S)-retipolide A via
macrolactonization
3.2.1. 2-(3-Hydroxy-4-methoxyphenyl)ethyl acetate (9).
A mixture of 2-(3-benzyloxy-4-methoxyphenyl)ethanol
(8)6 (80.0 g, 310 mmol), Ac2O (59.0 mL, 620 mmol), and
pyridine (50.0 mL, 620 mmol) was refluxed under an argon
atmosphere for 1.5 h. After cooling to rt, the solution was
poured into ice-cold aq HCl (5%, 720 mL) and extracted
with Et2O (2ꢂ500 mL). The combined organic phases were
washed with water (500 mL), satd aq NaHCO3 (3ꢂ500 mL),
and brine (500 mL), dried (MgSO4), and concentrated under
reduced pressure to yield a yellowish solid (89 g), which was
dissolved in EtOAc (200 mL). After addition of 10% Pd on
charcoal (5.0 g), the mixture was shaken at rt for 3 h under
H2 (3 atm). The catalyst was removed by filtration over Celite
and the solution concentrated under reduced pressure. Re-
crystallization of the residue from Et2O/hexanes yielded 9
1
(49.0 g, 77%) as colorless crystals. Mp 40 ꢀC; H NMR

6552
A. Ingerl et al. / Tetrahedron 63 (2007) 6548–6557
was purified by flash chromatography, first on a column with
hexanes/EtOAc (3:2, Rf¼0.31), then on a second column
with CHCl3/acetone (20:1, Rf¼0.41) to yield 11 (28.7 g,
41%) as a colorless solid. Mp 63–64 ꢀC; 1H NMR
(90 MHz, CDCl3): d 1.92 (s, 3H), 2.76 (t, J¼7 Hz, 2H),
2.81–3.16 (m, 3H), 3.64 (s, 3H), 3.74 (s, 3H), 4.17 (t,
J¼7 Hz, 2H), 4.27–4.50 (m, 1H), 6.49–7.47 (m, 7H); 13C
NMR (22.6 MHz, CDCl3): d 20.9, 34.2, 39.8, 52.4, 56.1,
64.9, 71.3, 112.9, 117.1 (2C), 121.6, 124.9, 130.4, 130.6
(2C), 130.9, 144.9, 150.1, 156.9, 171.0, 174.6; MS (EI) m/z
(rel int.): 389 (6), 388 (29, M+), 329 (12), 328 (53), 310
(6), 300 (33), 299 (98), 259 (15), 240 (35), 239 (100), 224
(10), 211 (16), 120 (10), 91 (10), 90 (13), 43 (23). Anal. Calcd
for C21H24O7: C 64.94; H 6.23; found: C 64.90; H 6.40.
oil. UV–vis (acetonitrile): lmax (log 3) 218 (4.36), 272 nm
(3.36); H NMR (90 MHz, CDCl3): d 1.14 (s, 9H), 2.37 (t,
1
J¼5 Hz, 2H), 3.18 (d, J¼6 Hz, 2H), 3.44, 3.61 (each dt,
J¼11, 5 Hz, 1H), 3.88 (s, 3H), 4.43 (t, J¼6 Hz, 1H), 4.80
(d, J¼2 Hz, 1H), 6.49 (dd, J¼8, 2 Hz, 1H), 6.68 (d, J¼
8 Hz, 1 H), 6.85–7.81 (m, 14 H); 13C NMR (100.6 MHz,
CDCl3): d 19.0, 26.6 (3C), 31.0, 40.0, 55.7, 66.5, 75.0,
110.8, 115.5, 120.4, 124.0, 124.4, 127.2 (2C), 127.6
(2C), 129.5, 129.8, 131.0, 132.0, 132.4, 132.6, 132.7,
133.2, 135.4 (2C), 135.5 (2C), 145.9, 152.4, 157.7, 171.9;
MS (EI) m/z (rel int.): 552 (1.8, M+), 496 (5), 495 (15),
468 (7), 467 (20), 389 (8), 371 (7), 329 (19), 240 (12),
239 (55), 225 (12), 200 (14), 199 (100), 197 (19), 195
(34), 183 (6), 135 (52), 134 (6), 104 (12), 91 (7);
HRMS (EI) calcd for C34H36O5Si [M+]: 552.2332, found:
552.2341.
3.2.4. 2-tert-Butyldiphenylsilanyloxy-3-{4-[5-(2-hydroxy-
ethyl)-2-methoxyphenoxy]phenyl}propionic acid (12).
Imidazole (3.21 g, 47.2 mmol), tert-butyldiphenylchloro-
silane (11.0 mL, 42.8 mmol), and DMAP (0.22 g, 1.8 mmol)
were added under an argon atmosphere to a stirred solution
of 11 (14.1 g, 36.3 mmol) in dry CH2Cl2 (150 mL) and the
stirring was continued for 20 h at rt. The mixture was diluted
with Et2O (1 L) and washed with 0.5 M aq NaHSO4
(400 mL), satd aq NaHCO3 (300 mL), and water (300 mL).
Concentration under reduced pressure yielded the silyl de-
rivative as a colorless oil, which was dissolved in THF/water
(1 L, 2:1) and treated dropwise with stirring over 2 h with
a solution of LiOH$H2O (4.57 g, 109 mmol) in THF/water
(550 mL, 1:1). The stirring was continued for 3 d at rt. After
reduction of the volume under vacuum to 500 mL, the solu-
tion was acidified with 1 N aq NaHSO4 to pH 1–2, saturated
with NaCl, and extracted with EtOAc (2ꢂ600 mL). The or-
ganic phases were washed with water (3ꢂ400 mL), dried
(MgSO4), and concentrated under reduced pressure. Purifi-
cation by flash chromatography (hexanes/EtOAc/AcOH,
60:40:1, Rf¼0.28) yielded 12 (17.5 g, 85%) as a colorless
3.2.6. 12-Hydroxy-4-methoxy-2,10-dioxatricyclo-
[12.2.2.13,7]nonadeca-1(17),3,5,7(19),14(18),15-hexaene-
11-one (14). A 1.1 M solution of Et4NF in THF (17.2 mL,
18.9 mmol) was added at 0 ꢀC over 2 min to a stirred solu-
tion of 13 (9.51 g, 17.2 mmol) in THF (150 mL) and the stir-
ring was continued for a further 20 min. After treatment with
acetic acid (1.20 g, 20.0 mmol), the solution was concen-
trated under reduced pressure. The residue was purified
twice by flash chromatography (CHCl3/acetone, 20:1,
Rf¼0.50) to yield 14 (5.22 g, 97%) as a colorless solid.
Mp 218–220 ꢀC; UV–vis (acetonitrile): lmax (log 3) 216
(4.23), 276 nm (3.33); IR (KBr, cmꢁ1): 3520s, 1740s,
1
1715m; H NMR (200 MHz, CDCl3): d 2.61 (d, J¼9.3 Hz,
1H), 2.75 (t, J¼4.6 Hz, 2H), 3.00 (dd, J¼13.0, 7.6 Hz,
1H), 3.31 (dd, J¼13.0, 4.4 Hz, 1H), 3.93 (s, 3H), 3.96,
4.13 (each dt, J¼11.5, 4.6 Hz, 1H), 4.41 (ddd, J¼9.3, 7.6,
4.4 Hz, 1H), 4.79 (d, J¼2.2 Hz, 1H), 6.57 (dd, J¼8.1,
2.2 Hz, 1H), 6.73 (d, J¼8.1 Hz, 1H), 7.06, 7.10 (each dd,
J¼6.8, 2.0 Hz, 1H), 7.26, 7.30 (each dd, J¼6.8, 2.0 Hz,
1H); 13C NMR (100.6 MHz, CDCl3): d 31.5, 41.4, 56.0,
67.8, 74.0, 111.2, 115.5, 120.8, 124.7, 125.4, 131.1, 131.2,
132.1, 133.1, 146.3, 152.6, 158.0, 173.2; MS (EI) m/z
(rel int.): 315 (6), 314 (48, M+), 257 (11), 240 (28), 239
(100), 225 (13), 104 (16), 91 (22); HRMS (EI) calcd
for C18H18O5 [M+]: 314.1154, found: 314.1155. Anal.
Calcd for C18H18O5: C 68.78; H 5.77; found: C 68.68;
H 5.86.
1
oil. H NMR (90 MHz, CDCl3): d 1.03 (s, 9H), 2.63 (t,
J¼7 Hz, 2H), 2.86 (d, J¼6 Hz, 2H), 3.64 (t, J¼7 Hz, 2H),
3.68 (s, 3H), 4.39 (t, J¼6 Hz, 1H), 6.12 (br s, 2H), 6.60–
7.70 (m, 17H); 13C NMR (22.6 MHz, CDCl3): d 19.1, 26.7
(3C), 37.7, 40.4, 55.7, 63.1, 73.5, 112.7, 116.8 (2C), 121.3,
124.9, 127.4 (4C), 129.6, 129.7, 130.5, 130.9 (2C), 131.3,
132.6, 132.7, 135.6 (2C), 135.8 (2C), 144.7, 149.7, 156.7,
176.6; MS (EI) m/z (rel int.): 570 (1.3, M+), 347 (13), 329
(14), 269 (22), 258 (14), 257 (100), 239 (10), 199 (67),
135 (24), 78 (18). Anal. Calcd for C34H38O6Si: C 71.55; H
6.71; found: C 71.61; H 6.87.
3.2.7. 4-Methoxy-2,10-dioxatricyclo[12.2.2.13,7]nona-
deca-1(17),3,5,7(19),14(18),15-hexaene-11,12-dione (15).
Pyridinium chlorochromate (10.5 g, 48.6 mmol) was added
to a stirred solution of 14 (5.10 g, 16.2 mmol) in dry
CH2Cl2 at rt under an argon atmosphere and the stirring
was continued for 48 h. The reaction mixture was filtered
over a Celite pad, rinsed with CHCl3 (300 mL), and concen-
trated under reduced pressure to a volume of 20 mL. Flash
chromatography of the dark-brown solution (CHCl3/ace-
tone, 50:1) yielded a brown oil that was flash chromato-
graphed again to yield 15 (4.77 g, 94%) as a colorless
solid. Mp 123 ꢀC; Rf¼0.23 (CHCl3/acetone, 50:1); UV–vis
(acetonitrile): lmax (log 3) 214 (4.28), 276 nm (3.48); IR
(KBr, cmꢁ1): 1730s (sh), 1720s; 1H NMR (200 MHz,
CDCl3): d 2.83 (m, 2H), 3.94 (s, 3H), 4.04 (s, 2H), 4.19
(m, 2H), 4.92 (d, J¼2.1 Hz, 1H), 6.61 (dd, J¼8.2, 2.1 Hz,
1H), 6.77 (d, J¼8.2 Hz, 1H), 7.11–7.21 (m, 2H), 7.33–
7.43 (m, 2H); 13C NMR (100.6 MHz, CDCl3): d 31.4,
3.2.5. 12-(tert-Butyldiphenylsilanyloxy)-4-methoxy-2,10-
dioxatricyclo[12.2.2.13,7]nonadeca-1(17),3,5,7(19),14(18),
15-hexaene-11-one (13). Three precision dropping funnels
were charged with a solution of 12 (1.22 g, 2.14 mmol) in
dry toluene/THF (100 mL, 9:1), a solution of diethyl azodi-
carboxylate (1.18 mL, 7.48 mmol) in dry toluene (100 mL),
and a solution of PPh3 (1.68 g, 6.41 mmol) in dry toluene
(100 mL), respectively. Then, the three solutions were added
simultaneously over 6 h at rt under an argon atmosphere to
a vigorously stirred solution of diethyl azodicarboxylate
(1.18 mL, 7.48 mmol) and PPh3 (1.68 g, 6.41 mmol) in dry
toluene (1.1 L). The reaction mixture was concentrated un-
der reduced pressure and purified by flash chromatography,
first with hexanes/EtOAc (5:1), then with hexanes/EtOAc
(7:1, Rf¼0.29), to afford 13 (866 mg, 73%) as a colorless

A. Ingerl et al. / Tetrahedron 63 (2007) 6548–6557
6553
47.3, 56.1, 67.9, 111.4, 115.2, 121.3, 126.0 (2C), 127.3,
132.0, 132.9 (2C), 146.6, 152.1, 158.6, 164.3, 191.7; MS
(EI) m/z (rel int.): 313 (20), 312 (100, M+), 259 (7), 240
(40), 239 (62), 226 (7), 225 (32), 211 (10), 105 (16), 104
(37), 103 (7), 91 (16), 90 (11); HRMS (EI) calcd for
C18H16O5: [M+] 312.0998, found: 312.0999.
2.2 Hz, 1H, 15-H), 8.10–8.19 (m, 2H); 13C NMR
(100.6 MHz, acetone-d6/CDCl3, 1:1): d 31.1, 43.7, 54.7,
55.5, 67.7, 88.0, 110.8, 113.4 (2C), 114.7, 120.6, 121.7,
123.6, 123.8, 128.5, 130.6 (2C), 131.1, 132.3, 132.4,
133.3, 138.5, 146.0, 152.2, 157.9, 159.5, 167.1, 167.5; MS
(EI) m/z (rel int.): 488 (0.6), 445 (26), 444 (100, M+), 414
(13), 354 (6), 240 (25), 226 (12), 221 (11), 135 (84), 121
(12), 91 (14), 90 (11), 57 (12), 44 (44); HRMS (EI) calcd
for C28H24O8 [M+]: 488.1471, found: 488.1458. Anal. Calcd
for C28H24O8$CH3COCH3: C 68.12; H 5.53; found: C
68.08; H 5.58.
3.2.8. Ornatipolide, 4-hydroxy-2,10-dioxatricyclo-
[12.2.2.13,7]nonadeca-1(17),3,5,7(19),14(18),15-hexaene-
11,12-dione (6). A solution of BI3 (540 mg, 1.4 mmol) in
dry CH2Cl2 (9 mL) was slowly added to a solution of 15
(87 mg, 0.28 mmol) in dry CH2Cl2 (10 mL), maintained
under an argon atmosphere in the dark at ꢁ78 ꢀC. The solu-
tion was stirred for 10 min at ꢁ78 ꢀC, then warmed to rt,
treated with 1 N aq NaHSO3 (20 mL), and extracted with
CH2Cl2 (3ꢂ). The combined extracts were washed with
H2O, dried (MgSO4), and concentrated under reduced pres-
sure. Purification of the residue by TLC on silica gel (tolu-
ene/EtOAc/HCO2H, 10:5:3, Rf¼0.62) yielded 6 (20 mg,
25%) as a colorless oil. UV–vis (acetonitrile): lmax (log 3)
276 nm (4.46); 1H NMR (300 MHz, acetone-d6): d 2.68 (ob-
scured by H2O signal, 2H, 8-H), 4.07 (s, 2H, 13-H), 4.14 (dd,
J¼4.7, 4.7 Hz, 2H, 9-H), 4.93 (d, J¼2.0 Hz, 1H, 19-H), 6.55
(dd, J¼8.1, 2.0 Hz, 1H, 6-H), 6.73 (d, J¼8.1 Hz, 1H, 5-H),
7.16 (d, J¼8.5 Hz, 2H, 16-H, 17-H), 7.44 (d, J¼8.5 Hz,
3.2.10. (R,S)-Retipolide E, 4,40-dihydroxy-30-(4-hydroxy-
phenyl)spiro{2.10-dioxatricyclo[12.2.2.13,7]nonadeca-
1(17),3,5,7(19),14(18),15-hexaene-12,20(50H)-furan}-
11,50-dione [(R,S)-5]. A 0.23 M solution of BI3 in CH2Cl2
(7.2 mL, 1.65 mmol) was added to a stirred solution of
16$acetone (90 mg) in dry CH2Cl2 (5 mL), maintained un-
der an argon atmosphere at 0 ꢀC. The mixture was stirred for
10 min at 0 ꢀC and then concentrated under reduced pres-
sure. The solid residue was triturated with ice water
(10 mL), filtered off, and rinsed with water (50 mL). Purifi-
cation by flash chromatography (CHCl3/acetone, 4:1,
Rf¼0.33) afforded (R,S)-5 (36 mg, 47%) as a colorless solid.
Mp 245–247 ꢀC; UV–vis (acetonitrile): lmax (log 3) 212
(4.02), 2.24 (sh, 3.90), 290 (sh, 3.58), 304 (3.59), 350 nm
(2.84); IR (KBr, cmꢁ1): 3410s, 3300s, 1730s, 1715s,
1585m, 1510m, 1495m, 1430m, 1260s, 1110m, 970m,
915m, 870m, 840m; 1H NMR (400 MHz, acetone-d6):
d 2.59 (dd, J¼17.1, 5.2 Hz, 1H, 8-Ha), 2.84 (dddd, J¼17.1,
11.2, 1.2, 0.9 Hz, 1H, 8-Hb), 3.17 (d, J¼13.8 Hz, 13-Hb),
3.90 (ddd, J¼11.3, 5.2, 1.2 Hz, 1H, 9-Hb), 3.95 (d,
J¼13.8 Hz, 1H, 13-Ha), 4.21 (dd, J¼11.3, 11.2 Hz, 1H, 9-
Ha), 4.79 (dd, J¼2.1, 0.9 Hz, 1H, 19-H), 6.50 (dd, J¼8.0,
2.1 Hz, 1H, 6-H), 6.70 (d, J¼8.0 Hz, 1H, 5-H), 6.95
(AA0BB0-d, J¼8.9 Hz, 2H, 80-H), 6.96 (dd, J¼8.5, 2.5 Hz,
1H, 17-H), 7.20 (dd, J¼8.5, 2.5 Hz, 1H, 16-H), 7.35 (dd,
J¼8.5, 2.5 Hz, 1H, 18-H), 7.65 (dd, J¼8.5, 2.5 Hz, 1H,
15-H), 7.90 (s, 1H, OH), 8.00 (AA0BB0-d, J¼8.9 Hz, 2H,
70-H), 8.72 (s, 1H, OH), 9.24 (br s, 1H, OH); 13C NMR
(100.6 MHz, acetone-d6): d 32.2 (C8), 44.3 (C13), 68.8
(C9), 89.1 (C12), 115.9 (C19), 115.9 (2ꢂC80), 116.3 (C5),
122.2 (C60), 122.3 (C6), 124.65 (C16), 124.72 (C17),
129.9 (C30), 132.1 (2ꢂC70), 132.5 (C7), 133.1 (C14),
133.9 (C18), 134.6 (C15), 139.8 (C40), 144.6 (C4), 152.4
(C3), 158.8 (C-90), 159.3 (C1), 167.8 (C50), 168.7 (C11);
MS (EI) m/z (rel int.): 460 (1.5, M+), 417 (15), 416 (84),
226 (29), 225 (16), 207 (14), 198 (14), 188 (17), 121 (8),
120 (11), 91 (30), 44 (100); HRMS (EI) calcd for
C26H20O8 [M+]: 460.1158, found: 460.1152.
1
2H, 15-H, 18-H), 8.04 (s, 1H, 4-OH); H NMR (600 MHz,
CDCl3): d 2.79 (m, 2H, 8-H), 4.03 (s, 2H, 13-H), 4.17 (m,
2H, 9-H), 4.89 (br s, 1H, 19-H), 5.49 (br s, 1H, 4-OH),
6.53 (d, J¼7.5 Hz, 1H, 6-H), 6.77 (d, J¼7.5 Hz, 1H, 5-H),
7.12 (d, J¼7.5 Hz, 2H, 16-H, 17-H), 7.36 (d, J¼7.5 Hz,
2H, 15-H, 18-H); 13C NMR (150 MHz, CDCl3): d 31.5 (C-
8), 47.3 (C-13), 67.9 (C-9), 114.8 (C-19), 115.0 (C-5),
122.0 (C-6), 125.9 (C-16, C-17), 127.7 (C-14), 131.6 (C-
7), 133.0 (C-15, C-18), 143.0 (C-4), 150.2 (C-3), 158.3 (C-
1), 164.2 (C-11), 191.6 (C-12); MS (EI) m/z (rel int.): 299
(17, M++H), 298 (100, M+), 226 (32), 225 (42), 211 (6),
197 (4), 120 (34), 107 (23), 77 (6).
3.2.9. (R,S)-Retipolide E dimethyl ether (16). A solution of
15 (1.00 g, 3.20 mmol), methyl 3-(4-methoxyphenyl)pyru-
vate (1.67 g, 8.00 mmol), and NEt3 (2.23 mL, 16.0 mmol) in
dry EtOAc (25 mL) was stirred for 5 h under an argon atmo-
sphere at rt. The solution was diluted with EtOAc (200 mL),
washed with 1 N aq NaHCO3 (100 mL), water (2ꢂ100 mL),
and brine (100 mL), dried (MgSO4), and concentrated under
reduced pressure. Flash chromatography (CHCl3/acetone,
gradient 50:1–10:1) yielded a yellowish solid, which on
crystallization from acetone afforded 16 (1.57 g, 90%) as
colorless crystals, containing 1 mol of acetone per mol.
Mp 252–254 ꢀC; Rf¼0.25 (CHCl3/acetone, 50:1), 0.45
(CHCl3/acetone, 20:1); UV–vis (acetonitrile): lmax (log 3)
214 (4.29), 2.26 (sh, 4.21), 290 (sh, 3.92), 304 nm (3.94);
IR (KBr, cmꢁ1): 3360s (br), 1755s, 1720s, 1600m, 1255s;
1H NMR (200 MHz, CDCl3): d 2.54 (dd, J¼17.3, 5.3 Hz,
1H, 8-Ha), 3.00 (dddd, J¼17.3, 11.0, 1.8, 0.5 Hz, 1H, 8-
Hb), 3.03 (d, J¼13.8 Hz, 1H, 13-Hb), 3.50 (br s, 1H, OH),
3.86 (ddd, J¼11.1, 5.3, 1.8 Hz, 1H, 9-Hb), 3.87, 3.94 (each
s, 3H, OMe), 3.98 (d, J¼13.8 Hz, 1H, 13-Ha), 4.28 (dd,
J¼11.1, 11.0 Hz, 1H, 9-Ha), 4.76 (dd, J¼2.2, 0.5 Hz, 1H,
19-H), 6.55 (dd, J¼8.2, 2.2 Hz, 1H, 6-H), 6.73 (d,
J¼8.2 Hz, 1H, 5-H), 6.97–7.06 (m, 2H), 7.01 (dd, J¼8.4,
2.4 Hz, 1H, 17-H), 7.25 (dd, J¼8.4, 2.4 Hz, 1H, 16-H),
7.32 (dd, J¼8.4, 2.2 Hz, 1H, 18-H), 7.62 (dd, J¼8.4,
3.3. Synthesis of (R,S)-retipolide E via intramolecular
nucleophilic aromatic substitution
3.3.1. Methyl 4-hydroxy-3-(4-methoxyphenyl)-5-oxo-2,5-
dihydrofuran-2-carboxylate (19). A solution of dimethyl
fumarate (4.32 g, 30.0 mmol) in EtOAc (200 mL) was
cooled to ꢁ78 ꢀC and treated with ozone until the solution
remained light blue. The excess of ozone was then removed
by bubbling argon through the solution. Dimethyl sulfide
(6.60 mL, 90.0 mmol) was added and the solution warmed
to rt. The mixture was treated with methyl 3-(4-methoxyphe-
nyl)pyruvate (18) (13.5 g, 65.0 mmol) and NEt3 (9.10 mL,

6554
A. Ingerl et al. / Tetrahedron 63 (2007) 6548–6557
65.0 mmol) and stirred for 4 h. After dilution with EtOAc
(150 mL), the solution was washed with 1 M aq NaHSO4
(3ꢂ), water, and brine. The organic layer was dried
(MgSO4) and concentrated under reduced pressure. The resi-
due was purified by recrystallization from EtOAc/hexanes
to yield 19 (11.4 g, 72%) as colorless needles. Mp 161 ꢀC;
1H NMR (400 MHz, CDCl3): d 3.75, 3.85 (each s, 3H,
OMe), 5.73 (s, 1H, 5-H), 6.12 (s, 1H, OH), 6.97 (m, 2H,
Ar]H), 7.73 (m, 2H, Ar]H); 13C NMR (100 MHz,
CDCl3): d 53.2, 55.5, 76.8, 115.0 (2C), 123.0, 126.2, 129.5
(2C), 137.7, 161.0, 169.0, 169.5; MS (EI) m/z (rel int.):
265 (6), 264 (44, M+), 220 (19), 193 (10), 192 (100), 191
(77), 162 (7), 161 (65), 149 (14), 135 (13), 134 (12), 133
(22), 132 (17), 117 (69), 91 (8), 89 (10). Anal. Calcd for
C13H12O6: C 59.09; H 4.58; found: C 59.21; H 4.55.
10 min, a solution of 2-(4-methoxyphenyl)ethanol (2.97 g,
19.5 mmol) in dry THF (50 mL) was added dropwise over
a period of 1 h. The mixture was stirred for 10 min and
then treated dropwise with trimethyl borate (21.7 mL,
195 mmol). After 15 min, the mixture was allowed to
warm to 0 ꢀC and the stirring continued for 1 h at this tem-
perature. Acetic acid (15 mL) was then added in one portion,
followed by dropwise addition of hydrogen peroxide (30%,
10 mL). The mixture was slowly warmed to rt and diluted
with Et2O (200 mL) and water (150 mL). The two phases
were separated and the aqueous layer extracted with Et2O
(2ꢂ). The combined organic layers were washed with 10%
aq ammonium ferrous(II) sulfate and saturated with
(NH4)2SO4 (4ꢂ). After washing with diluted aq NaHSO3,
water, and brine, the organic phases were dried (MgSO4)
and concentrated under reduced pressure. Purification by
flash chromatography (hexanes/EtOAc, 3:2, Rf¼0.21)
yielded 22 (2.04 g, 62%) as a colorless oil, which was crys-
tallized from t-BuOMe/n-hexane. Mp 77 ꢀC; 1H NMR
(300 MHz, CDCl3): d 1.61 (s, 1H, OH), 2.76 (t, J¼6.5 Hz,
2H), 3.80 (t, J¼6.5 Hz, 2H), 3.85 (s, 3H), 5.62 (s, 1H,
OH), 6.63 (dd, J¼8.2, 2.0 Hz, 1H), 6.72 (d, J¼8.2 Hz,
1H), 6.73 (d, J¼2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d 38.5, 56.0, 63.7, 110.8, 115.1, 120.5, 131.6, 145.2,
145.7; MS (EI) m/z (rel int.): 168 (28, M+), 138 (9), 137
(100), 122 (11). Anal. Calcd for C9H12O3: C 64.27; H
7.19; found: C 64.76; H 7.19.
3.3.2. Methyl 4-methoxy-3-(4-methoxyphenyl)-5-oxo-
2,5-dihydrofuran-2-carboxylate (20). A freshly prepared
solution of diazomethane in Et2O (250 mL) was added to
a solution of 19 (6.61 g, 25 mmol) in acetone (40 mL).
The mixture was stirred for 1 h, then treated with acetic
acid (1 mL), and concentrated. Purification by flash chroma-
tography (hexanes/Et2O, 2:1, Rf¼0.53) afforded 20 (5.54 g,
80%) as a colorless powder. Mp 96 ꢀC; 1H NMR (300 MHz,
acetone-d6): d 3.71, 3.83, 4.13 (each s, 3H, OMe), 5.68 (s,
1H, 5-H), 6.94 (m, 2H, Ar]H), 7.71 (m, 2H, Ar]H); 13C
NMR (75 MHz, CDCl3): d 53.4, 55.7, 58.8, 76.7, 115.0
(2C), 122.3, 130.1 (2C), 134.6, 140.0, 161.9, 167.5, 168.4;
MS (EI) m/z (rel int.): 279 (15), 278 (100, M+), 220 (6),
219 (47), 191 (33), 176 (31), 148 (10), 135 (6), 120 (7).
Anal. Calcd for C14H14O6: C 60.43; H 5.07; found: C
60.56; H 5.12.
3.3.5. 2-(3-Hydroxy-4-methoxyphenyl)ethyl 2-(4-fluoro-
3-nitrobenzyl)-4-methoxy-3-(4-methoxyphenyl)-5-oxo-
2,5-dihydrofuran-2-carboxylate (23). 1,3-Dichlorotetra-
butyldistannoxane12 (552 mg, 1.00 mmol) was added to a
solution of 21 (863 mg, 2.0 mmol) and 22 (1.01 g,
6.01 mmol) in dry toluene (80 mL). The mixture was re-
fluxed for 20 h and then concentrated under reduced pres-
sure. The residue was purified by flash chromatography
(CHCl3/acetone, 70:1, Rf¼0.40) to yield 23 (1.05 g, 90%)
as a light yellow oil in addition to recovered 21 (44 mg)
and 22 (650 mg, Rf¼0.25).
Ester 23. 1H NMR (300 MHz, CDCl3): d 2.81 (t, J¼6.6 Hz,
2H, CH2CH2OH), 3.40, 3.61 (each d, J¼14.6 Hz, 1H, benz.
CH2), 3.82, 3.86, 3.90 (each s, 3H, OMe), 4.37–4.41 (m, 2H,
CH2OH), 5.56 (s, 1H, OH), 6.54 (dd, J¼8.2, 2.0 Hz, 1H,
Ar]H), 6.64 (d, J¼8.2 Hz, 1H, Ar]H), 6.67 (d,
J¼2.0 Hz, 1H, Ar]H), 6.94 (m, 2H, Ar]H), 7.10 (dd,
J¼10.3, 8.5 Hz, 1H, Ar]H), 7.21–7.25 (m, 1H, Ar]H),
7.38–7.41 (m, 3H, Ar]H); 13C NMR (75 MHz, CDCl3):
d 34.2, 38.2, 55.4, 55.9, 58.7, 67.5, 84.1, 110.7, 114.6 (2C)
115.0, 118.0, 120.4, 121.2, 127.7, 129.4 (2C), 130.0,
130.3, 135.0, 137.2, 137.5, 141.1, 145.5, 145.6, 154.7,
160.8, 166.4, 168.3; MS (EI) m/z (rel int.): 569 (7), 568
(35), 567 (100, M+), 537 (7), 417 (7), 372 (5), 284 (6), 154
(9), 150 (72), 137 (10), 136 (5), 135 (10), 119 (15), 108
(7), 107 (5), 91 (18). Anal. Calcd for C29H26FNO10: C
61.37; H 4.62; N 2.47; found: C 61.44; H 4.83; N 2.20.
3.3.3. Methyl 2-(4-fluoro-3-nitrobenzyl)-4-methoxy-3-(4-
methoxyphenyl)-5-oxo-2,5-dihydrofuran-2-carboxylate
(21). DBU (1.10 g, 7.20 mmol) was slowly added to a solu-
tion of 20 (2.00 g, 7.19 mmol) and 4-fluoro-3-nitrobenzyl
bromide9 (1.99 g, 8.50 mmol) in dry acetonitrile (150 mL).
The solution was stirred for 1 h, diluted with Et2O, and
washed with 2 M HCl, satd aq NaHCO3, and brine. The
organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by flash chroma-
tography (hexanes/EtOAc, 3:2, Rf¼0.53) and recrystallized
from CH2Cl2/n-hexane (3:2) to give 21 (2.59 g, 83%) as col-
1
orless needles, Mp 104 ꢀC; H NMR (300 MHz, CDCl3):
d 3.47, 3.66 (each d, J¼14.7 Hz, 1H, benz. CH2), 3.83,
3.88, 3.92 (each s, 3H, OMe), 7.00 (m, 2H, Ar]H), 7.12
(dd, J¼10.5, 8.6 Hz, 1H, Ar]H), 7.25–7.29 (m, 1H,
Ar]H), 7.44–7.48 (m, 1H, Ar]H), 7.54 (m, 2H, Ar]H);
13C NMR (75 MHz, CDCl3): d 38.4, 53.9, 55.5, 58.6, 84.0,
114.8 (2C), 118.1, 121.2, 127.7, 129.4 (2C), 130.3, 134.7,
136.7, 137.6, 141.1, 154.8, 160.9, 166.2, 169.1; MS (EI)
m/z (rel int.): 432 (23), 431 (100, M+), 373 (5), 372 (24),
344 (7), 284 (14), 277 (16), 249 (39), 221 (21), 206 (10),
154 (13), 148 (12), 147 (11), 135 (10), 119 (16), 108 (17).
Anal. Calcd for C21H18FNO8: C 58.47; H 4.21; N 3.25;
found: C 58.72; H 4.29; N 3.35.
3.3.6. (R,S)-Nitroretipolide (24, 1:1 mixture of atropdia-
stereomers). A solution of 23 (289 mg, 0.51 mmol) in dry
DMF (4 mL) was added dropwise to a vigorously stirred sus-
pension of anhydrous K2CO3 (280 mg, 2.00 mmol) in dry
DMF (130 mL) under an argon atmosphere over a period
of 1 h. The stirring was continued for 3 h at rt. The mixture
3.3.4. 2-(3-Hydroxy-4-methoxyphenyl)ethanol (22). A so-
lution of TMEDA (9.06 g, 78 mmol) in dry THF (150 mL),
maintained at ꢁ78 ꢀC under an argon atmosphere, was
treated dropwise with 60 mL (78.0 mmol) of a 1.3 M solu-
tion of s-BuLi in cyclohexane/n-heptane (1:1). After

A. Ingerl et al. / Tetrahedron 63 (2007) 6548–6557
6555
was then diluted with CH2Cl2 (150 mL), washed with 2 M
HCl (3ꢂ), water, and brine, dried (MgSO4), and concen-
trated under reduced pressure. Purification by flash chroma-
tography (CHCl3/acetone, 100:1, Rf¼0.41 and 0.35)
afforded 24 (170 mg, 61%) as a yellow oil, which was crys-
tallized from CH2Cl2/n-hexane as a yellow powder. Mp
(MgSO4), and concentrated under reduced pressure. The
residue was dried for 16 h in vacuo and then flash chromato-
graphed (CHCl3/acetone, 100:1) to afford a yellow oil,
which was further purified by a second flash chromato-
graphy (hexanes/EtOAc, 2:1, Rf¼0.35) to yield 26
(155 mg, 62%) as a colorless solid. Recrystallization from
CH2Cl2/n-hexane gave colorless prisms. Mp 210 ꢀC; 1H
NMR (300 MHz, CDCl3): d 2.54 (dd, J¼17.3, 5.4 Hz, 1H,
8-Ha), 3.00 (ddd, J¼17.3, 11.0, 1.1 Hz, 1H, 8-Hb), 3.02 (d,
J¼13.6 Hz, 1H, 13-Hb), 3.69 (d, J¼13.6 Hz, 1H, 13-Ha),
3.84, 3.85 (each s, 3H, OMe), 3.89 (ddd, J¼11.1, 5.4,
1.1 Hz, 1H, 9-Hb), 3.92 (s, 3H, OMe), 4.22 (dd, J¼11.1,
11.0 Hz, 1H, 9-Ha), 4.73 (d, J¼1.5 Hz, 1H, 19-H), 6.54
(dd, J¼8.2. 1.5 Hz, 1H, 6-H), 6.72 (d, J¼8.2 Hz, 1H, 5-H),
6.94 (dd, J¼8.4, 2.4 Hz, 1H, 17-H), 6.98 (m, 2H, 80-H),
7.16 (dd, J¼8.4, 2.2 Hz, 1H, 18-H), 7.22 (dd, J¼8.4,
2.4 Hz, 1H, 16-H), 7.61 (m, 2H, 70-H), 7.62 (dd, J¼8.4,
2.2 Hz, 1H, 15-H); 13C NMR (75 MHz, CDCl3): d 31.6
(C8), 43.9 (C13), 55.3 (OMe), 56.1 (OMe), 59.1 (OMe),
68.4 (C9), 87.9 (C12), 111.2 (C5), 113.8 (2ꢂC80), 115.2
(C19), 120.9 (C6), 121.6 (C60), 124.2 (C16), 124.6 (C17),
131.0 (C30), 131.2 (2ꢂC70), 132.5 (C18), 132.6 (C7),
133.7 (C15), 134.9 (C14), 141.9 (C40), 146.4 (C4), 152.7
(C3), 158.4 (C1), 160.4 (C90), 166.2 (C50), 167.4 (C11);
MS (EI) m/z (rel int.): 504 (6), 503 (31), 502 (100, M+),
359 (14), 276 (24), 255 (5), 253 (5), 251 (6), 240 (19), 239
(48), 226 (6), 225 (18), 211 (6), 206 (5), 205 (11), 147 (6),
134 (5), 120 (5), 119 (7), 105 (7), 104 (17). Anal. Calcd
for C29H26O8$½CH2Cl2: C 65.02; H 4.99; found: C 65.42;
H 4.98.
1
208 ꢀC; H NMR (300 MHz, CDCl3): d 2.54/2.55* (each
dd, J¼17.3, 5.2 Hz, together 1H, 8-Ha), 3.01 (dd, J¼17.3,
10.4 Hz, 1H, 8-Hb), 3.05/3.06* (each d, J¼13.5 Hz, together
1H, 13-Hb), 3.76*/3.77 (each d, J¼13.5 Hz, together 1H, 13-
Ha), 3.85, 3.86 (each s, 3H, OMe), 3.86–3.92 (m, 1H, 9-Hb),
3.93 (s, 3H, OMe), 4.23/4.24* (each dd, J¼11.1, 10.4 Hz, to-
gether 1H, 9-Ha), 4.82*/4.86 (each d, J¼1.5 Hz, together
1H, 19-H), 6.59 (dd, J¼8.2, 1.5 Hz, 1H, 6-H), 6.76 (d,
J¼8.2 Hz, 1H, 5-H), 6.99 (m, 2H, 80-H), 7.44 (d,
J¼8.4 Hz, 1H, 17-H), 7.61 (m, 2H, 70-H), 7.82 (dd, J¼8.4,
2.2 Hz, 1H, 18-H), 7.89/8.25* (each d, J¼2.2 Hz, together
1H, 15-H), * signals belong to the same atropdiastereomer;
13C NMR (75 MHz, CDCl3): d 32.0, 43.8, 55.7, 56.8, 59.6,
69.1, 87.8, 112.7, 114.4 (2C), 114.5, 121.5, 123.1, 128.0,
129.0, 131.6 (2C), 132.8, 133.1, 134.7, 138.8, 142.2,
144.2, 147.7, 151.5, 152.9, 161.0, 166.3, 167.5; MS (EI)
m/z (rel int.): 549 (7), 548 (31), 547 (100, M+), 487 (7),
285 (18), 284 (56), 235 (9), 207 (6), 151 (5), 150 (6), 149
(8), 147 (8), 135 (9), 134 (7), 121 (7), 119 (14), 105 (10),
104 (24), 103 (6), 91 (9). Anal. Calcd for C29H25NO10: C
63.62; H 4.60; N 2.56; found: C 63.80; H 4.72; N 2.65.
3.3.7. (R,S)-Aminoretipolide (25, 1:1 mixture of atrop-
diastereomers). A mixture of 24 (295 mg, 0.54 mmol)
and Pd on charcoal (10%, 30 mg) in CHCl3/MeOH (4:1,
125 mL) was hydrogenated under vigorous stirring for
16 h at rt and then filtered through a pad of Celite. The cat-
alyst was rinsed with CHCl3 (150 mL) and the combined
filtrates were concentrated under reduced pressure. Purifica-
tion by flash chromatography (CHCl3/acetone, 100:1, Rf¼
0.25/0.22) afforded 25 (240 mg, 86%) as an oil, which was
crystallized from CH2Cl2/n-hexane. Colorless powder; mp
227 ꢀC; 1H NMR (300 MHz, CDCl3): d 1.58 (br s, H,
NH2), 2.57/2.58* (each dd, J¼17.4, 5.2 Hz, together 1H,
8-Ha), 2.90/2.92* (each d, J¼13.5 Hz, together 1H, 13-
Hb), 3.05/3.06* (each dd, J¼17.4, 10.9 Hz, together 1H, 8-
Hb), 3.55*/3.57 (each d, J¼13.5 Hz, together 1H, 13-Ha),
3.80–3.88 (m, 1H, 9-Hb), 3.83, 3.85, 3.92 (each s, 3H,
OMe), 4.23/4.27* (each dd, J¼11.3, 10.9 Hz, together 1H,
9-Ha), 5.09/5.15* (each d, J¼1.5 Hz, together 1H, 19-H),
6.52–6.77 (m, 3H, Ar]H), 6.94–7.00 (m, 4H, 80-H,
Ar]H), 7.55–7.60 (m, 2H, 70-H), * signals belong the same
atropdiastereomer; 13C NMR (75 MHz, CDCl3): d 34.6,
44.5, 55.7, 56.5, 59.5, 68.8, 88.4, 111.7, 114.2 (2C), 114.3,
119.7, 120.4. 121.8, 122.5, 123.6, 124.8, 129.9, 131.6
(2C), 132.5, 141.9, 144.5, 147.2, 150.5, 152.0, 160.7,
166.5, 167.9; MS (EI) m/z (rel int.): 519 (8), 518 (31), 517
(100, M+), 342 (5), 295 (5), 254 (17), 225 (6), 184 (11),
151 (6), 149 (8), 147 (5), 124 (6), 119 (5), 104 (6).
3.3.9. (R,S)-Retipolide E [(R,S)-5]. A solution of 26
(100 mg, 0.20 mmol) in dry CH2Cl2 (20 mL) was treated
with a solution of boron triiodide (1.17 g, 3.00 mmol) in
dry CH2Cl2 (10 mL) at 0 ꢀC. The mixture was stirred for
30 min and then concentrated under reduced pressure. The
residue was treated with water (50 mL) and extracted with
CH2Cl2 (3ꢂ). The combined organic phases were washed
with water, dried (MgSO4), and concentrated under reduced
pressure. Purification by flash chromatography (CHCl3/
acetone, 4:1, Rf¼0.21) afforded (R,S)-5 (38.0 mg, 41%) as
a colorless solid; mp 245 ꢀC. The spectroscopic data were
identical with those of Section 3.2.10.
3.4. Synthesis of (R)-retipolide E via intramolecular
nucleophilic aromatic substitution
3.4.1. (4S,5R)-4-Methyl-5-phenyl-3-propenoyloxazol-
idin-2-one (27).17 A mixture of (4S,5R)-4-methyl-5-phenyl-
3-trimethylsilyl-2-oxazolidinone (12.0 g, 48.2 mmol),17
CuBr2 (15.1 g, 67.5 mmol), copper powder (217 mg, 3.4
mmol), and propenoyl chloride (21.7 mL, 265 mmol) in
dry toluene (200 mL) was refluxed for 24 h. The suspension
was then cooled to rt, filtered over Celite, and concentrated
under reduced pressure. Purification by flash chromato-
graphy (hexanes/EtOAc, 4:1, Rf¼0.46) afforded 27 (8.02 g,
72%) as a yellow oil. The NMR data agreed with those given
in Ref. 17.
3.3.8. (R,S)-Retipolide E trimethyl ether (26). A solution
of 25 (259 mg, 0.50 mmol) in dry DMF (1 mL) was added
dropwise at 65 ꢀC over 10 min to a solution of freshly dis-
tilled tert-butyl nitrite (83.0 mg, 0.80 mmol) in dry DMF
(33 mL). The mixture was stirred for 20 min, then cooled
to rt, and diluted with CH2Cl2 (150 mL). The solution was
washed with 2 M HCl (3ꢂ), water, and brine, dried
3.4.2. (4S,5R)-3-[(R,S)-4-Hydroxy-3-(4-methoxyphenyl)-
5-oxo-2,5-dihydrofuran-2-carbonyl]-4-methyl-5-phenyl-
oxazolidin-2-one (29, 1:1 mixture of diastereomers). A
solution of 27 (6.94 g, 30 mmol) in EtOAc (200 mL) was

6556
A. Ingerl et al. / Tetrahedron 63 (2007) 6548–6557
cooled to ꢁ78 ꢀC and treated with ozone until the color of
the solution remained light blue. The excess of ozone was
removed by bubbling argon through the solution. After
addition of dimethyl sulfide (6.60 mL, 90.0 mmol), the
solution was warmed to rt and reduced to half its volume
in vacuo. Methyl 3-(4-methoxyphenyl)pyruvate (6.22 g,
30.0 mmol), NEt3 (4.0 mL, 30.0 mmol), and EtOAc
(100 mL) were added and the mixture was stirred for 2 h.
The solution was then diluted with EtOAc (100 mL) and
washed with 1 M aq NaHSO4 (3ꢂ), water, and brine. The
organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by recrystalliza-
tion from EtOAc/hexanes to yield 29 (4.16 g) as colorless
crystals. A second fraction of 29 (3.05 g) was isolated by
flash chromatography of the residue (hexanes/EtOAc, 2:1,
Rf¼0.20 and 0.17). Total yield 7.21 g (59%); mp 84 ꢀC;
1H NMR (CDCl3, 300 MHz) d 0.72/0.91* (d, J¼6.5 Hz,
3H, Me), 3.79*/3.82 (s, 3H, OMe), 4.64*/4.79 (dq, J¼7.3,
6.5 Hz, 1H, CH]Me), 5.62*/5.77 (d, J¼7.3 Hz, 1H,
CH]Ph), 6.31 (br s, 1H, OH), 6.95 (m, 2H, Ar]H),
7.25–7.37 (m, 3H, 2 Ar]H, CO]CH]O), 7.39–7.45 (m,
3H, Ar]H), * signals belong to the same diastereomer;
13C NMR (CDCl3, 75 MHz): d 15.2, 55.4, 55.7, 73.9, 79.7,
114.6 (2C), 121.8, 125.6, 126.5, 128.7 (2C), 128.9 (2C),
129.1 (2C), 132.4, 136.5, 152.7, 160.6, 166.1, 169.8; MS
(EI) m/z (rel int.): 410 (7), 409 (35, M+), 365 (18), 364
(17), 321 (16), 320 (27), 177 (12), 161 (15), 160 (9), 149
(16), 148 (12), 135 (9), 134 (15), 133 (21), 132 (17), 121
(9), 119 (10), 118 (100), 117 (32), 115 (11), 107 (15), 105
(6), 91 (19), 77 (11).
(MgSO4), and concentrated under reduced pressure. Purifi-
cation by flash chromatography (hexanes/EtOAc, 3:1,
Rf¼0.38) yielded 31 as a yellow oil (1.19 g, 69%). The major
diastereomer (S,R,R)-31 was separated by repeated frac-
tional crystallization from EtOAc/hexanes (761 mg, 44%).
25
Mp 244 ꢀC; ½aꢃD +221.4 (c 0.50, acetonitrile); CD: lmax
(D3) 200 (+11.0), 213 (ꢁ26.8), 238 (+3.3), 245 (+2.3), 257
1
(+3.8), 279 (+3.0), 290 (sh, +7.9), 314 (+12.4); H NMR
(300 MHz, CDCl3): d 0.88 (d, J¼6.6 Hz, 3H, Me), 3.52,
3.75 (AB-qu, J¼14.3 Hz, 2H, CH2), 3.87, 4.94 (each s,
3H, OMe), 4.85 (dq, J¼7.3, 6.6 Hz, 1H, CH]Me), 5.54
(d, J¼7.3 Hz, 1H, CH]Ph), 7.00 (m, 2H, Ar]H), 7.11
(ddm, J¼10.5, 8.6 Hz, 1H, Ar]H), 7.20–7.25 (m, 2H,
Ar]H), 7.30 (ddd, J¼8.6, 4.2, 2.2 Hz, Ar]H), 7.37–7.42
(m, 3H, Ar]H), 7.50 (dd, J¼7.1, 2.2 Hz, 1H, Ar]H),
7.63 (m, 2H, Ar]H); 13C NMR (75 MHz, CDCl3): d 14.8,
42.1, 55.8, 57.6, 59.0, 79.8, 85.5, 115.2 (2C), 118.5, 122.2,
126.1, 128.5, 129.2 (2C), 129.4 (2C), 129.5 (2C), 130.4,
131.5, 133.2, 136.7, 138.4, 144.2, 150.9, 153.8, 160.0,
167.2, 169.8; MS (EI) m/z (rel int.): 578 (7), 577 (35), 576
(100, M+), 378 (13), 373 (28), 372 (98), 356 (12), 350
(11), 284 (24), 160 (23), 154 (15), 147 (17), 119 (12), 117
(18), 108 (10), 91 (11).
3.4.5. 2-(3-Hydroxy-4-methoxyphenyl)ethyl (R)-2-(4-
fluoro-3-nitrobenzyl)-4-methoxy-3-(4-methoxyphenyl)-
5-oxo-2,5-dihydrofuran-2-carboxylate [(R)-23]. 1,3-Di-
chlorotetrabutyldistannoxane12 (168 mg, 0.30 mmol) was
added to a solution of 31 (250 mg, 0.43 mmol) and 22
(723 mg, 4.30 mmol) in dry toluene (30 mL). The mixture
was refluxed for 20 h and then concentrated under reduced
pressure. Purification by flash chromatography (CHCl3/ace-
tone, 70:1) yielded (R)-23 (162 mg, 66%) as a light yellow
3.4.3. (4S,5R)-3-[(R,S)-4-Methoxy-3-(4-methoxyphenyl)-
5-oxo-2,5-dihydrofuran-2-carbonyl]-4-methyl-5-phenyl-
oxazolidin-2-one (30, 1:1 mixture of diastereoisomers). A
freshly prepared solution of diazomethane in Et2O (180 mL)
was added to a solution of 29 (7.21 g, 17.6 mmol) in acetone
(30 mL). The mixture was stirred for 1 h, then treated with
acetic acid (1 mL), and concentrated. Purification by flash
chromatography (hexanes/Et2O, 3:1, Rf¼0.32 and 0.30) af-
forded 30 (5.44 g, 73%) as a colorless powder. Mp 68 ꢀC;
1H NMR (300 MHz, CDCl3): d 0.71/0.94* (d, J¼6.6 Hz,
3H, Me), 3.86, 4.14 (each s, 3H, OMe), 4.70*/4.82 (dq,
J¼7.3, 6.6 Hz, 1H, CH]Me), 5.65*/5.79 (d, J¼7.3 Hz,
1H, CH]Ph), 6.95–7.01 (m, 2H, Ar]H), 7.23–7.33 (m,
3H, 2 Ar]H, CO]CH]O), 7.43–7.46 (m, 3H, Ar]H),
7.63–7.67 (m, 2H, Ar]H), * signals belong to the same
diastereomer; 13C NMR (75 MHz, CDCl3): d 14.0, 55.2,
55.4, 58.4/58.5, 72.9/73.2, 79.4/79.5, 114.1/114.2 (2C),
121.5, 125.5, 128.6/128.7 (2C), 128.8/128.9 (2C), 129.1
(2C), 132.5, 133.4, 139.9, 152.6, 160.7, 166.1, 167.6; MS
(EI) m/z (rel int.): 424 (8), 423 (31, M+), 365 (24), 321
(13), 189 (10), 177 (14), 162 (17), 161 (14), 135 (10), 134
(16), 133 (27), 132 (17), 118 (100), 117 (25), 107 (64),
91 (13).
25
oil. ½aꢃD +71.9 (c 0.99, acetonitrile); CD: lmax (D3) 210
(ꢁ4.8), 216 (ꢁ7.6), 288 (+4.4), 274 (ꢁ1.0), 297 (ꢁ2.4),
314 (ꢁ0.7). For spectroscopic data see Section 3.3.5.
3.4.6. (R)-Nitroretipolide [(R)-24, 1:1 mixture of atrop-
diastereomers]. Same experimental procedure as described
under Section 3.3.6. (R)-23 (108 mg, 0.19 mmol) afforded
(R)-24 (65 mg, 62%) as a yellow oil. CD: lmax (D3) 200
(+7.9), 212 (ꢁ18.8), 247 (+18.5), 278 (sh, +4.0), 322
(ꢁ0.5). For spectroscopic properties see Section 3.3.6.
3.4.7. (R)-Aminoretipolide [(R)-25, 1:1 mixture of atrop-
diastereomers]. Same experimental procedure as described
under Section 3.3.7. (R)-24 (46 mg, 0.08 mmol) afforded
(R)-25 (36 mg, 87%) as a colorless oil. CD: lmax (D3) 200
(+31.5), 213 (ꢁ30.5), 246 (+16.5), 281 (+0.6), 298 (+2.7).
For spectroscopic properties see Section 3.3.7.
3.4.8. (R)-Retipolide E trimethyl ether (R-26). Same ex-
perimental procedure as described under Section 3.3.8.
(R)-25 (35 mg, 0.07 mmol) afforded (R)-26 (20 mg, 58%)
as a colorless oil. CD: lmax (D3) 200 (+3.0), 213 (ꢁ4.8),
224 (sh, ꢁ3.1), 246 (+3.6), 268 (sh, +1.8), 282 (+0.4). For
spectroscopic properties see Section 3.3.8.
3.4.4. (4S,5R)-3-[(R)-2-(4-Fluoro-3-nitrobenzyl)-4-
methoxy-3-(4-methoxyphenyl)-5-oxotetrahydrofuran-2-
carbonyl]-4-methyl-5-phenyl-2-oxazolidinone (31). DBU
(457 mg, 3.00 mmol) was slowly added to a solution of 30
(1.27 g, 3.00 mmol) and 4-fluoro-3-nitrobenzyl bromide
(702 mg, 3.00 mmol) in dry acetonitrile (75 mL). The solu-
tion was stirred for 3 h, diluted with Et2O (250 mL), washed
with 2 N aq HCl, satd aq NaHCO3, and brine, dried
3.4.9. Retipolide E (5). Same experimental procedure as de-
scribed under Section 3.3.9. (R)-26 (16 mg, 0.03 mmol) af-
forded 5 (4 mg, 30%) as a colorless oil. CD: lmax (D3) 200
(+8.8), 213 (ꢁ13.2), 224 (sh, ꢁ9.5), 246 (+10.2), 270 (sh,
+5.0), 288 (+1.2), 297 (+1.8). For spectroscopic data see

A. Ingerl et al. / Tetrahedron 63 (2007) 6548–6557
6557
7. Stock, A. M.; Donahue, W. E.; Amstutz, E. D. J. Org. Chem.
1958, 23, 1840–1848.
8. For dimerization of methyl arylpyruvates to symmetrical but-
Section 3.2.10. The chromatographic, spectroscopic, and
chiroptical properties were identical to those of natural reti-
polide E.
ꢀ
enolides see: Bran˜a, M. F.; Garcıa, M. L.; Lopez, B.;
de Pascual-Teresa, B.; Ramos, A.; Pozuelo, J. M.;
ꢀ
ꢀ
Domınguez, M. T. Org. Biomol. Chem. 2004, 2, 1864–1871
and literature cited therein.
Acknowledgements
9. Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J.;
Zhu, J. J. Org. Chem. 1994, 59, 5535–5542.
10. Castedo, L.; Borges, J. E.; Marcos, C. F.; Tojo, G. Synth.
Commun. 1995, 1717–1727.
We thank the Fonds der Chemischen Industrie for financial
support and Prof. H. Shibata, Shinshu University, for kindly
comparing compound 6 with authentic ornatipolide. We also
thank Dr. Bert Steffan for high field NMR spectra and Drs.
11. Alcohol 22 could be obtained in a three-step one-pot procedure
from 2-(4-methoxyphenyl)ethanol. Treatment of the latter
alcohol with 4 equiv of s-BuLi/TMEDA at ꢁ78 ꢀC resulted
in selective ortho-metallation (cf. Slocum, D. W.; Moon, R.;
Thompson, J.; Coffey, D. S.; Li, J. D.; Slocum, M. G.;
Siegel, A.; Gayton-Garcia, R. Tetrahedron Lett. 1994, 35,
385–388). The resulting anion was trapped with a 10-fold
excess of trimethyl borate to give an intermediate arylboronic
ester, which on oxidative workup with H2O2 in acetic acid
furnished the desired alcohol 22 in 60% overall yield.
12. (a) Otera, J.; Yano, T.; Kawabata, A.; Nozaki, H. Tetrahedron
Lett. 1986, 27, 2383–2386; (b) Otera, J.; Ioka, S.; Nozaki, H.
J. Org. Chem. 1989, 54, 4013–4014; (c) Jousseaume, B.;
Laporte, C.; Rascle, M.-C.; Toupance, T. Chem. Commun.
2003, 1428–1429.
13. (a) Zhu, J. Synlett 1997, 133–144; (b) Gonzalez, G. I.; Zhu, J.
J. Org. Chem. 1997, 62, 7544–7545; (c) Zhu, J.; Laib, T.;
Chastanet, J.; Beugelmans, R. Angew. Chem. 1996, 108,
2664–2666; Angew. Chem., Int. Ed. 1996, 35, 2517–
2519.
14. Doyle, M. P.; Dellaria, J. F.; Siegfried, B.; Bishop, S. W. J. Org.
Chem. 1977, 42, 3494–3498.
15. Lansinger, J. M.; Ronald, R. C. Synth. Commun. 1979, 9, 341–
349.
€
Richard Allen and Jorg-Dieter Klamann for linguistic im-
provements.
References and notes
1. Both species, formerly named Boletus retipes and Boletus
ornatipes, are closely related or may even be synonymous.
See e.g.: Bessette, A. E.; Roody, W. C.; Bessette, A. R. North
American Boletes; Syracuse University Press: Syracuse, NY,
2000; and Both, E. E. The Boletes of North America;
Buffalo Museum of Science: Buffalo, NY, 1993; Binder and
Bresinsky created the new genus Retiboletus on molecular
biological evidence and the presence of retipolides as chemo-
taxonomical markers: Binder, M.; Bresinsky, A. Feddes Repert.
2002, 113, 30–40.
2. Justus, K.; Gruber, G.; Hellwig, V.; Herrmann, R.; Klamann,
J.-D.; Steffan, B.; Steglich, W. Eur. J. Org. Chem., in prepara-
tion.
3. Preliminary publication: Steglich, W. Schering Lecture;
Schering Research Foundation: Berlin, 1994; Vol. 24.
4. Justus, K.; Steglich, W. Tetrahedron Lett. 1991, 32, 5781–5784.
Review on macrolactonization: Parenty, A.; Moreau, X.;
Campagne, J.-M. Chem. Rev. 2006, 106, 911–939.
5. Shibata, H.; Fukuda, T.; Wada, T.; Morita, Y.; Hashimoto, T.;
Asakawa, Y. Biosci. Biotechnol. Biochem. 1998, 62, 1432–
1434.
16. Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737–1739.
17. Thom, C.; Kocienski, P. Synthesis 1992, 582–586. An im-
proved procedure for the preparation of imide 27 using
CuBr2 instead of CuCl2 is given in Section 3.4.1.
6. Fujii, T.; Ohba, M.; Sakaguchi, J. Chem. Pharm. Bull. 1987, 35,
3628–3640.