Macrocyclisation of 2-(5-(2-hydroxyethyl)furan-2-yl)acetic acid model compounds of nonactic acid

Article abstract of DOI:10.1007/s00706-008-0031-4

The macrocyclisation of hydroxyethylfuranyl acetic acid and of dehydrogenated model compounds of nonactic acid was investigated to develop a facile synthesis of nonactin analogues. By applying the Yamagushi macrocyclisation to our ω-hydroxyacids, we were

Full text of DOI:10.1007/s00706-008-0031-4

Monatsh Chem (2009) 140:349–354
DOI 10.1007/s00706-008-0031-4
ORIGINAL PAPER
Macrocyclisation of 2-(5-(2-hydroxyethyl)furan-2-yl)acetic acid
model compounds of nonactic acid
Carine Eng Æ Jean-Mary Simone Æ Akane Hartenbach Æ
Franc¸ois Loiseau Æ Reinhard Neier
Received: 20 May 2008 / Accepted: 17 June 2008 / Published online: 3 September 2008
Ó Springer-Verlag 2008
Abstract The macrocyclisation of hydroxyethylfuranyl
acetic acid and of dehydrogenated model compounds of
nonactic acid was investigated to develop a facile synthesis
of nonactin analogues. By applying the Yamagushi
macrocyclisation to our x-hydroxyacids, we were able
to isolate a mixture of di-, tri-, tetra- and pentameric
macrocycles.
and carboxylic acid ends have to be achieved. The final
step is the macrocyclisation of the linear tetramer. The
second method consists in the cyclodimerisation of a linear
dimer composed of two nonactic acids. The reported syn-
theses of 1 do not compete successfully with fermentation
[8]. Nonactin (1) is therefore expensive. The major diffi-
culties encountered to date are the making of (+) and
(-)—nonactic acids (2) in enantiopure form and the con-
trolled assembly of the enantiomers to the macrotetralide.
As part of our ongoing studies on macrocycle 1, we have
developed a method for synthesising 2,5-disubstituted
furans and tetrahydrofurans as nonactic acid precursors and
analogues [9–11]. The key steps used to introduce the alkyl
chains to the furan ring are radical couplings. We report
here the O-deprotection of the 2,5-disubstituted furans 3–5,
and the cyclopolymerisation of x-hydroxyacids 9 and 10
under Yamagushi’s conditions (Scheme 2).
Keywords Heterocycles Á Macrocycles Á
Natural product analogues Á Nonactin Á Protecting groups
Introduction
Nonactin (1), a macrotetralide antibiotic, is used as an
ionophore in ammonium ion selective electrodes. First
reported in 1955 [1], 1 is isolated from Streptomyces cul-
tures and is the lowest homologue of the nactin family.
Nonactin (1) consists of four nonactic acids (2) (Scheme 1)
condensed in a (+)(-)(+)(-) atypical fashion, which
confers S4 symmetry (meso compound) to this macrocycle.
To the best of our knowledge, six total syntheses of non-
actin have been reported in the literature [2–7]. Two
methodologies have been used to assemble the four non-
actic acid units to obtain 1. The first methodology consists
in a step-by-step assembly of the four units of nonactic
acids to obtain a linear tetramer. To achieve this stepwise
condensation, selective O-deprotections of both the alcohol
Results and discussion
We studied first the selective O-debenzylation of the 2,5-
disubstituted furans 3–5. Deprotecting the furans 3–5 was
not a trivial undertaking. Neither hydrogenations using
catalysts, such as rhodium over alumina, Pd/C or Raney-Ni
catalysts, nor debenzylation using MeI/TMSCl in MeCN,
Pd(OH)2/Et3SiH/Et3N in CH2Cl2 or SnCl4 in CH2Cl2 gave
O
OH
O
O
O
O
(
)
S
(
R
)
O
(+)
−
( )
O
OH
)
(
R
)
O
O
(
S
(+)
O
H
H
−
( )
O
O
O
2
(+)-
C. Eng Á J.-M. Simone Á A. Hartenbach Á F. Loiseau Á
R. Neier (&)
O
ˆ
Department of Chemistry, University of Neuchatel,
Avenue Bellevaux 51, 2007 Neuchatel, Switzerland
1
ˆ
e-mail: reinhard.neier@unine.ch
Scheme 1
123

350
C. Eng et al.
Scheme 2
R
n(
O
O
O
O
O
R'
R'
O
O
O
Et
HO
O
Bn
OH
O
O
O
R'
R
R
(
R
3, = H, '= H
R
R
11a-11d, = H, n= 1-4
9, = H
R
10, =
R Bn
R
4,
=
, '= H
R
Bn R
= H, '=
12a-12d,
=
, n=1-4
R
Bn
5
,
R
R
Me
the deprotected products in good selectivity and high
yields. Applying Hanessian’s transfer hydrogenation
conditions [12]—Pd(OH)2 and cyclohexene in refluxing
EtOH—to our substrates resulted in a high selectivity of
the expected O-debenzylated products 6–8 in 71–90%
yields (Table 1).
conditions, we obtained a mixture of di-, tri-, tetra- and pen-
tamer 11a– in almost a 77% overall yield. As 1 is known to
effectively complex potassium cations, we hoped that the
tetramer of our furan analogue would also be stabilized by
complexation to potassium cations. We attempted to take
advantage of a template effect using K2CO3 [16] in order to
increase the proportion of the tetramer. The application of
Yamagushi conditions to monomer 10 in the presence of
added K2CO3 did not favour the amount of tetramer formed.
Under these modified conditions, the overall yield of macro-
cycles 12a–d decreased drastically. The use of the potassium
cation has been reported to increase the yield of calix [9–11]
furan formation [16], while chelation can be used for the
assembly of furan rings into a macrocycle. In our case,
the rigid furan rings reduce the flexibility needed for the
assembly into macrocycles. This may explain why chelation
with potassium decreased the yield of macrocycle formation.
Using the conditions reported by Schmidt et al. [13], we
were able to saponify the ethylesters of alcohols 6 and 7
using KOH in EtOH at room temperature. To avoid poly-
merisation of the x-hydroxyacids 9 and 10 that formed,
substrates 6 and 7 had to be submitted only for a short time
to the reaction conditions (Table 2).
With the unstable x-hydroxyacids 9 and 10 in hand,
we studied the Yamagushi macrocyclisation conditions
[14], which are known to give good yields of macrocy-
cles, minimizing the amount of linear polymers formed
[15]. Treating monomer 9 under these macrocyclisation
Table 1 O-debenzylation under Hanessian’s conditions
O
O
R'
R'
Pd(OH)2 /C
O
O
HO
O
Et
Bn
Et
O
O
OH, cyclohexene
reflux, t (h)
Et
R
R
3
4
6
,
,
= H, '= H
,
,
= H, '= H
R R
R
R
R
7
=
,
'= H
=
,
'= H
Bn R
R Bn R
5, = H, '=
8, = H, '=
R
R
Me
R
R
Me
Reagent
t/h
4a
Product and yield
O
O
O
O
6, 90%
7, 71%
3
4
HO
HO
OEt
O
O
O
O
BnO
Et
O
4
O
Et
Et
BnO
BnO
Et
O
Bn
Bn
2.5
O
O
8, 90%
5
HO
O
O
O
Et
O
a
Decreasing the reaction time to 1 h 40 afforded 87% yield
123

Macrocyclisation of 2-(5-(2-hydroxyethyl)furan-2-yl)acetic acid model compounds of nonactic acid
351
Table 2 Saponification of the ethyl ester function
O
O
KOH,
OH
Et
HO
O
HO
OH
Et
O
O
RT,t (min)
R
R
6, = H
R= Bn
9, = H
R
R
7,
10,
=
R
Bn
Reagent
t/min
Product and yield
30
O
O
9, 95%
6
7
HO
HO
OH
O
HO
OEt
OEt
O
30
O
O
10, 98%
OH
O
HO
O
Bn
Bn
To reduce the amount of the di- and trimer formed, we worked
at higher dilutions—unfortunately, also without success
(Scheme 3).
Experimental
All moisture-sensitive reactions were carried out under Ar
and N2 using oven-dried glassware. All reagents were of
commercial quality if not specifically mentioned. Solvents
were freshly distilled prior to use. Flash chromatography
(FC): Brunschwig silica gel 60, 0.032–0.063 mm; positive
pressure. Thin-lay chromatography (TLC): Merck precoated
silica gel thin-layer sheets 60 F 254; detection by UV and
treatment with basic KMnO4 solvent. Mp: Gallenkamp
MFB–595. IR spectra: Perkin Elmer Spectrum One FT-IR,
in cm-1. NMR spectra: Bruker Avance-400 [400 MHz
In conclusion, we have achieved the macrocyclisation of
x-hydroxyacids 9 and 10. This direct macrocyclisation
represents a very short method to producing furan-contain-
ing macrotetralides. These furan-containing macrotetralides
represent interesting precursors for the synthesis of nonactin
and analogues of nonactin. To study the ionophore properties
of these macrocycles, which can be obtained by reduction
from our products, we are currently investigating methods
for the catalytic hydrogenation of the furan rings.
O
Scheme 3
OH
HO
O
R
a
9, = H
R
10
,
=
R
Bn
Cl
O
DMAP, sieve 4A,
CH2Cl2, RT
Cl
Cl
O
O
O
O
O
O
O
O
O
O
O
O
R
O
O
R
O
R
R
O
R
O
O
R
O
R
O
O
O
R
O
O
O
O
R
O
R
O
O
O
O
R
O
O
R
O
O
R
O
11a
12a
,
,
= H: 33%
R
R
R
=
: 4%
Bn
11b, = H: 25%
R
R
O
O
O
O
12b,
=
: 5%
Bn
O
11c
12c
,
,
= H: 13%
R
R
O
=
: 4%
Bn
a K2CO3 added
11da, = H: 4%
R
12d
,
=
: <1%
Bn
R
123

352
C. Eng et al.
701 cm-1; H NMR (400 MHz, CDCl3): d = 7.29–7.14
(m, Ph), 6.14 (d, J = 3.2, H-4), 6.04 (d, J = 3.2, H-5),
4.10-4.16 (m, J = 7.2, Ha-11), 4.105 (dq, J = 10.9, J = 7.2,
Hb-11), 3.96 (t, J = 7.9, H-2), 3.85 (t, J = 6.2, H-8), 3.31
(dd, J = 13.7, J = 8.3, Ha-21), 3.19 (dd, J = 13.7, J = 7.6,
Hb-21), 2.88 (t, J & 6.0, H-7), 1.78 (br, OH), 1.18 (t,
J = 7.1, H-12) ppm; 13C NMR (100 MHz, CDCl3):
d = 171.8 (C-1), 152.5 (C-3), 150.9 (C-6), 138.9, 129.3,
128.7, 127.0, 108.2 (C-4), 107.9 (C-5), 61.6 (C-8, C-11),
37.6 (C-21), 32.0 (C-7), 14.5 (C-12) ppm; ESI-MS: m/
z = 312 (30), 311 (100, [M + Na]+).
1
(1H) and 100 MHz (13C)], at room temperature (rt),
chemical shifts
d
in ppm relative to CDCl3
(1H = 7.264 ppm, 13C = 77.0 ppm) as internal reference,
coupling constants J in Hz. ESI-MS Finnigan LCQ. HR-
ESI-MS analyses of novel compounds agreed favourably
with calculated values (Fig. 1).
General procedure for O-debenzylation under
Hanessian’s conditions
Palladium hydroxide over charcoal (10%) was added to
the benzylether and freshly distilled cyclohexene in EtOH,
and the mixture was refluxed. After several hours, the
mixture was filtered on celite and the volatiles removed by
evaporation in vacuo. The residue was purified by chro-
matography on a silica gel column using n-hexane/AcOEt
as an eluent.
Ethyl [5-(2-hydroxypropyl)-furan-2-yl]acetate (8, C11H16O4)
General procedure with 705 mg of 5 (2.33 mmol), 12 cm3
of cyclohexene and 0.14 g of palladium hydroxide over
charcoal in 25 cm3 of EtOH over a 2.5-h period. Thus,
445 mg of product 8 (2.10 mmol, 90%) was obtained. Oil;
Rf = 0.09 (n-hexane/AcOEt 75/25 + 1% MeOH); IR
(film): vꢀ = 3,432, 2,975, 2,932, 1,740, 1,614, 1,565,
1,447, 1,402, 1,370, 1,338, 1,268, 1,233, 1,182, 1,082,
1,031, 1,015 cm-1; 1H NMR (400 MHz, CDCl3): d = 6.14
(d, J = 3.1, H-4), 6.06 (d, J = 3.1, H-5), 4.19 (q, J = 7.1,
H-11), 4.12–4.04 (m, H-8), 3.65 (s, H-2), 2.79 (dd,
J = 14.9, J = 4.6, Ha-7), 2.71 (dd, J = 14.9, J = 7.6, Hb-
7), 1.96 (br, OH), 1.28 (t, J = 7.1, H-12), 1.24 (d, J = 6.2,
H-9) ppm; 13C NMR (100 MHz, CDCl3): d = 170.0 (C-1),
152.8 (C-3), 147.2 (C-6), 109.1 (C-4), 108.4 (C-5), 67.1
(C-8), 61.6 (C-11), 38.3 (C-7), 34.6 (C-2), 23.0 (C-9), 14.5
(C-12) ppm; ESI-MS: m/z = 236 (12), 235 (100,
[M + Na]+).
Ethyl [5-(2-hydroxyethyl)-furan-2-yl]acetate (6, C10H14O4)
General procedure with 1.22 g of 3 (4.24 mmol), 24 cm3 of
cyclohexene and 0.23 g of palladium hydroxide over
charcoal in 48 cm3 of EtOH over a 4-h period. Thus,
0.75 g of product 6 (3.80 mmol, 90%) was obtained. Oil;
Rf = 0.06 (n-hexane/AcOEt 75/25 + 1% MeOH); IR
(film): vꢀ = 3,440, 2,982, 1,740, 1,644, 1,614, 1,566,
1,467, 1,446, 1,397, 1,371, 1,338, 1,266, 1,228, 1,186,
1,097, 1,031, 790 cm-1 1H NMR (400 MHz, CDCl3):
;
d = 6.14 (d, J = 3.1, H-4), 6.06 (dd, J = 3.1, H-5), 4.19 (q,
J = 7.1, H-11), 3.86 (t, J = 6.2, H-8), 3.65 (s, H-2), 2.88 (t,
J = 6.2, H-7), 1.93 (br, OH), 1.29 (t, J = 7.1, H-12) ppm;
13C NMR (100 MHz, CDCl3): d = 170.1 (C-1), 152.8 (C-
3), 147.1 (C-6), 109.1 (C-4), 107.9 (C-5), 61.6 (C-11), 61.5
(C-8), 34.6 (C-2), 32.0 (C-7), 14.5 (C-12) ppm; ESI-MS: m/
z = 221 (100, [M + Na]+).
General procedure for ethyl ester deprotection
A 2 M solution of KOH in EtOH was added to the ethyl
ester at room temperature. After 30 min, the mixture was
acidified with 32% HCl and the product extracted twice
with AcOEt. The combined organic layers were washed
with brine and dried (MgSO4). Evaporation in vacuo of the
volatiles resulted in the product, which contained traces of
AcOH.
Ethyl [5-(2-hydroxyethyl)-furan-2-yl]-3-phenyl propionate
(7, C17H20O4)
General procedure with 842 mg of 4 (2.23 mmol), 12 cm3
of cyclohexene and 0.13 g of palladium hydroxide over
charcoal in 24 cm3 of EtOH over a 4-h period. Thus,
458 mg of product 7 (1.59 mmol, 71%) was obtained. Oil;
Rf = 0.07 (n-hexane/AcOEt 75/25 + 1% MeOH); IR
(film): vꢀ = 3,446, 3,087, 3,063, 3,030, 2,980, 2,959,
2,935, 1,736, 1,605, 1,560, 1,496, 1,455, 1,370, 1,334,
1,277, 1,217, 1,153, 1,096, 1,078, 1,034, 790, 749,
2-(5-(2-hydroxyethyl)furan-2-yl)acetic acid (9, C8H10O4)
General procedure with 683 mg of ester 6 (3.44 mmol) in
10 cm3 of 2 M solution of KOH in EtOH. Two extractions
with 80 cm3 of AcOEt each time afforded 559 mg 9
(3.28 mmol, 95%) with approximately 63 mg of AcOH.
Oil; IR (film): vꢀ = 3,600–3,300, 2,962, 2,338, 1,718,
9
5
4
O
1
1,644, 1,617, 1,567, 1,400, 1,376, 1,236, 1,046 cm-1; H
11
8
3
6
2
12
NMR (400 MHz, CDCl3): d = 6.38–6.20 (br, OH, CO2H),
6.16 (d, J = 3.1, H-4), 6.06 (d, J = 3.1, H-5), 3.87 (t,
RO
O
1
O
7
J = 6.2, H-8), 3.69 (s, H-2), 2.87 (t, J = 6.2, H-7) ppm; 13
C
21
NMR (100 MHz, CDCl3): d = 175.0 (C-1), 153.0 (C-3),
146.4 (C-6), 109.6 (C-4), 108.0 (C-5), 61.4 (C-8), 34.2
Fig. 1 Labeling used for nuclear magnetic resonance assignment
123

Macrocyclisation of 2-(5-(2-hydroxyethyl)furan-2-yl)acetic acid model compounds of nonactic acid
353
(C-2), 31.8 (C-7) ppm; ESI-MS: m/z = 194 (10), 193 (100,
[M + Na]+), 143 (11).
4,13,22,28,28,30-Hexaaoxatetracyclo
[23.2.1.17,10.116,19]triaconta-1(27)7,9,16,18,25-hexaene-3,
12,21-trione 11b
Oil; Rf = 0.34 (after three elutions in n-hexane/AcOEt 75/
2-(5-(2-hydroxyethyl)furan-2-yl)-3-phenylpropanoic acid
(10, C15H16O4)
1
25 + 1% MeOH); H NMR (400 MHz, CDCl3): d = 6.06
General procedure with 253 mg of ester 7 (0.88 mmol) in
5 cm3 of 2 M solution of KOH in EtOH. Two extractions
with 25 cm3 of AcOEt each time afforded 224 mg 10
(0.86 mmol, 98%) with approximately 10 mg of AcOH.
Oil; IR (film): vꢀ = 3,600–3,000, 3,063, 3,030, 2,959,
2,632, 1,713, 1,605, 1,584, 1,560, 1,496, 1,455, 1,393,
(d, J = 3.1, H-4), 5.94 (d, J = 3.1, H-5), 4.35 (t, J = 6.1,
H-8), 3.63 (s, H-2), 2.92 (t, J = 6.1, H-7) ppm; 13C NMR
(100 MHz, CDCl3): d = 169.7 (C-1), 151.8 (C-3), 146.8
(C-6), 109.1 (C-4), 107.8 (C-5), 63.4 (C-8), 34.8 (C-2),
28.0 (C-7) ppm; ESI-MS: m/z = 480 (24), 479 (100,
[M + Na]+).
1
1,235, 1,180, 1,078, 1,033, 789, 738, 701 cm-1; H NMR
(400 MHz, CDCl3): d = 7.36–7.13 (m, Ph), 7.13–6.12 (br,
OH, CO2H), 6.12 (d, J = 3.2, H-4), 6.04 (d, J = 3.2, H-5),
4.00 (t, J = 7.8, H-2), 3.85 (t, J = 6.2, H-8), 3.34 (dd,
J = 13.8, J = 7.6, Ha-21), 3.20 (dd, J = 13.8, J = 8.0, Hb-
21), 2.88 (t, J = 6.2, H-7) ppm; 13C NMR (100 MHz,
CDCl3): d = 176.9 (C-1), 152.8 (C-3), 149.9 (C-6), 138.5
(C-22), 129.2, 128.8, 127.1, 108.9 (C-4), 108.0 (C-5), 61.4
(C-8), 47.4 (C-2), 37.2 (C-21), 31.9 (C-7) ppm; APCI-MS:
m/z = 279 (20), 278 (28, [M + H2O]+), 277 (24),.262
(19), 261 (100, [M + H]+), 257 (15), 143 (32), 216 (15),
215 (91), 197 (33).
4,13,22,31,37,39,40-Octaaoxapentacyclo
[32.2.1.17,10.116,19.125,28]tetraconta-1(36)7,
9,16,18,25,27,34-octaene-3,12,21,30-tetrone 11c
Oil; Rf = 0.11 (after three elutions in n-hexane/AcOEt 75/
1
25 + 1% MeOH); H NMR (400 MHz, CDCl3): d = 6.08
(d, J = 3.1, H-4), 5.96 (d, J = 3.1, H-5), 4.34 (t, J = 6.5,
H-8), 3.63 (s, H-2), 2.93 (t, J = 6.5, H-7) ppm; 13C NMR
(100 MHz, CDCl3): d = 169.7 (C-1), 151.7 (C-3), 146.8
(C-6), 109.1 (C-4), 107.8 (C-5), 63.4 (C-8), 34.6 (C-2),
28.0 (C-7) ppm; ESI-MS: m/z = 632 (28), 631 (100,
[M + Na]+).
4,13,22,31,40,46,47,48,49,50-Decaaoxahexacyclo
[41.2.1.17,10.116,19.125,28.134,37]pentaconta-1(45)
7,9,16,18,25,27,34,36,43-decaene-3,12,21,30,
39-pentone 11d
Synthesis of macrocycles 11a–11d from acid 9
Acid 9 (73 mg, 85% purity, 362 lmol) and 168 mg DMAP
(1.38 mmol) were dissolved in 30 cm3 of CH2Cl2 under an
argon atmosphere in the presence of 2 g molecular sieve
Oil; Rf = 0.04 (after three elutions in n-hexane/AcOEt 75/
1
25 + 1% MeOH); H NMR (400 MHz, CDCl3): d = 6.09
3
˚
(4 A). At RT, 2, 0.08 cm , 113 mg 6-dichlorobenzoyl
(d, J = 3.1, H-4), 5.97 (d, J = 3.1, H-5), 4.34 (t, J = 6.6,
H-8), 3.63 (s, H-2), 2.94 (t, J = 6.6, H-7) ppm; 13C NMR
(100 MHz, CDCl3): d = 169.7 (C-1), 151.7 (C-3), 146.8
(C-6), 109.1 (C-4), 107.8 (C-5), 63.4 (C-8), 34.6 (C-2),
28.0 (C-7) ppm; ESI-MS: m/z = 785 (11), 784 (36), 783
(100, [M + Na]+), 632 (23), 631 (100).
chloride (539 lmol) was added. After 23 h, the molecular
sieve was filtered off, and the organic layer was washed with
three times with 0.3 M HCl. The combined aqueous layers
were extracted with CH2Cl2 and the combined organic layers
dried (MgSO4). The volatiles were removed by evaporation
in vacuo. The residue was purified by chromatography on a
silica gel column using n-hexane/AcOEt as an eluent, and
four macrocycles were isolated. These are, in order of
decreasing polarity: 184 mg dimer 11a (60.5 lmol, 33.4 %),
137 mg trimer 11b (30.0 lmol, 24.9%), 1.2 mg tetramer 11c
(2.0 lmol, 2.2%), 7.0 mg of a second isomer of the tetramer
11c (11.5 lmol, 12.7%) and 1.9 mg pentamer 11d
(2.5 lmol, 3.5%). The overall yield is 76.7%.
Synthesis of macrocycles 12a–12d from acid 10
Acid 10 (220 mg, 761 lmol) and 300 mg DMAP (2.46
mmol) were dissolved in 45 cm3 of CH2Cl2 under an argon
˚
atmosphere in the presence of 2.3 g molecular sieve (4 A)
and 0.65 g K2CO3 (4.70 mmol). After 45 min, 0.14 cm3
2,6-dichlorobenzoyl chloride (977 lmol) was added. After
23 h, the molecular sieve was filtered off, and the organic
layer was washed three times with 0.3 M HCl. The com-
bined aqueous layers were extracted with CH2Cl2 and the
combined organic layers dried (MgSO4). The volatiles
were removed by evaporation in vacuo. The residue was
purified by chromatography on a silica gel column using
n-hexane/AcOEt as an eluent, and three macrocycles were
isolated. The products were, in order of decreasing polar-
ity: 6.5 mg dimer 12a (13.4 lmol, 3.5 %), 9.6 mg trimer
12b (13.2 lmol, 5.2%), 7.3 mg tetramer 12c (7.5 lmol,
4,13,19,20-Tetraoxatricyclo[14.2.1.17,10]icosa-1(18)7,9,
16-tetraene-3,12-dione 11a
Oil; Rf = 0.5 (after three elutions in n-hexane/AcOEt 75/
1
25 + 1% MeOH); H NMR (400 MHz, CDCl3): d = 6.00
(d, J = 3.1, H-4), 5.92 (d, J = 3.1, H-5), 4.37 (t, J = 5.6,
H-8), 3.60 (s, H-2), 2.90 (t, J = 5.6, H-7) ppm; 13C NMR
(100 MHz, CDCl3): d = 170.2 (C-1), 151.8 (C-3), 146.7
(C-6), 109.0 (C-4), 108.0 (C-5), 63.3 (C-8), 35.1 (C-2),
27.9 (C-7) ppm; ESI-MS: m/z = 625 (11), 327 (100,
[M + Na]+).
123

354
C. Eng et al.
108.4, 108.3 (C-4), 107.7 (C-5), 63.2 (C-8), 47.7 (C-2),
37.2 (C-21), 28.0, 27.3 (C-7) ppm; ESI-MS: m/z = 993
(22), 992 (65, [M + Na]+), 991 (100), 837 (11), 749 (12).
4.0%); traces of the probable pentamer 12d may be iden-
tified on the TLC. The overall yield is 12.7%.
2,11-Bis(phenylmethyl)-4,13,19,20-tetraoxatricy-
clo[14.2.1.17,10]icosa-1(18)7,9,16-tetraene-3,12-dione
12a
Acknowledgments The NMR spectra (400 MHz) were measured
by Heinz Bursian and Dr. Claude Saturnin, the mass spectra by Dr.
Manuel Tharin and Dr. Bernard Jean-Denis. We thank the University
ˆ
of Neuchatel and the Swiss National Science Foundation for financial
support.
Oil; Rf = 0.29 (n-hexane/AcOEt 75/25 + 1% MeOH);
ESI-MS: m/z = 1,170 (13), 1,169 (16), 992 (13), 991
(19), 508 (34), 507 (100, [M + Na]+).
2,11,20-Tris(phenylmethyl)-4,13,22,28,28,30-hexaaoxatet-
racyclo[23.2.1.17,10.116,19]triaconta-1(27)7,9,16,18,25-
hexaene-3,12,21-trione 12b
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Oil; Rf = 0.19 (n-hexane/AcOEt 75/25 + 1% MeOH); H
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2,11,20,29-Tetrakis(phenylmethyl)-4,13,22,31,37,39,40-
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1(36)7,9,16,18,25,27,34-octaene-3,12,21,30-tetrone 12c
1
Oil; Rf = 0.14 (n-hexane/AcOEt 75/25 + 1% MeOH); H
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150.5, 150.4 (C-6), 138.8 (C-22), 129.3, 128.8, 126.9 (Ph),
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123