Synthesis of the α,β-unsaturated δ-lactones (+)-anhydrocalopin and (+)-dehydrocalopin

Article abstract of DOI:10.1055/s-2003-36269

During our investigations on the calopin group of mushroom metabolites, a synthesis of 3,4-disubstituted α,β-unsaturated δ-lactones has been developed. It was applied to the synthesis of optically active dehydrocalopin (2) and anhydrocalopin (3).

Full text of DOI:10.1055/s-2003-36269

PAPER
101
Synthesis of the , -Unsaturated -Lactones (+)-Anhydrocalopin and
(+)-Dehydrocalopin
S
ynthesis of (+)-A
e
nhydrocalo
i
pin and
n
(+)-Dehydr
e
ocalopin r Ebel, Kirsten Zeitler, Wolfgang Steglich*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5–13 (F), 81377 München, Germany
Fax +49(89)21807756; E-mail: wos@cup.uni-muenchen.de
Received 15 October 2002
a strategy for the synthesis of unsaturated calopin deriva-
tives.
Abstract: During our investigations on the calopin group of mush-
room metabolites, a synthesis of 3,4-disubstituted , -unsaturated
-lactones has been developed. It was applied to the synthesis of op-
tically active dehydrocalopin (2) and anhydrocalopin (3).
Key step in our retrosynthetic planning is the intramolec-
ular Horner–Emmons reaction of phosphonate ester 5,
Key words: natural products -lactones, cyclizations, epoxides, which should yield the anhydrocalopin system 4
Horner–Emmons reaction
(Scheme 1).
Compounds of the calopin group are responsible for the
bitter taste of the mushrooms Boletus calopus, B. radi-
cans, and B. coniferarum. They represent a new class of
natural products possessing a -lactone moiety and, in the
case of O-acetylcalopin (1a) and calopin (1b) (Figure 1),
a rare methylcatechol residue.1 The absolute configura-
tion of these metabolites has been determined by synthetic Scheme 1 Retrosynthetic analysis of 4
studies2 including the total synthesis of (+)-1b.3
In our first synthesis of the phosphonate ester 5, we started
from commercially available 2,3-dimethoxybenzoic acid
(6) (Scheme 2). Conversion of 6 to the acid chloride fol-
lowed by treatment with N,O-dimethylhydroxylamine/
Et3N afforded the Weinreb amide 7 in 85% yield. Reac-
tion of 7 with 2-propenyllithium, prepared by halogen-
metal exchange from 2-bromopropene, led to ketone 8 in
94% yield.5 Epoxidation of 8 with aqueous NaOH and
H2O2 (95%) followed by regioselective ring cleavage of
the resulting oxirane 9 with tributyltin hydride gave the
racemic -hydroxy ketone 10b in quantitative yield.6,7
Despite its high efficiency, the synthesis of 10b via Wein-
reb amide 7 is not suitable for the synthesis of optically ac-
tive compounds. We therefore developed an alternative
strategy that commences from 3-methylcatechol. The lat-
ter compound was doubly MOM-protected to give 11
(90%),3 ortho-lithiated,3,8 and coupled with the known op-
tically pure Weinreb amide 129 to afford alcohol 10a in
47% yield (Scheme 3).
Figure 1 Structures of calopins and synthetic derivatives 2 and 3
For the synthesis of (+)-anhydrocalopin (3) the optically
pure building block 10a was converted to the phosphonate
ester 5a by treatment with the acyl chloride 1310 under
Our interest in the properties of these and related
-
lactones4 prompted us to synthesize dehydrocalopin (2)
and anhydrocalopin (3), which could not be obtained di-
rectly from calopin (1b) by selective oxidation or dehy-
dration, respectively. In this communication we describe
acidic conditions (91%, Scheme 4). In order to prevent
elimination, the intramolecular Horner–Emmons reaction
had to be performed under mild conditions. In accordance
with the literature,11,12 ring closure of 5a with Et3N in the
presence of LiBr produced the lactone 4a in 38% yield.
The low yield may be caused by the lability of the MOM
groups under the given reaction conditions. This is sup-
ported by the observation that the cyclization of the meth-
yl-protected catechol 5b (Scheme 4) afforded the lactone
Synthesis 2003, No. 1, 30 12 2002. Article Identifier:
1437-210X,E;2003,0,01,0101,0106,ftx,en;Z13402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

102
H. Ebel et al.
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Scheme 2 Synthesis of racemic building block rac-10b
In order to prepare dehydrocalopin (2), the MOM-protect-
ed (+)-anhydrocalopin (4a) was treated with
dimethyldioxirane13,14 to give exclusively the oxirane 14a
in 97% yield (Scheme 5). In the same manner, epoxide
14b was obtained from the racemic analogue 4b. The ster-
ic influence of the -methyl group is responsible for the
selective formation of the anti-diastereomer. The relative
configuration of the products was confirmed by a single-
crystal X-ray diffraction analysis of 14b (Figure 2). A
Scheme 3 Chiral pool synthesis of building block 10a
4b in 63% yield. Deblocking of the optically active lac- comparison of the 1H NMR data as well as NOESY exper-
tone 4a with HCl in EtOAc gave (+)-anhydrocalopin (3) iments proved that both oxiranes 14a,b have the same
in 97% yield. The same sequence of reactions was applied configuration. Treatment of 14a with HCl in EtOAc in-
to the racemic building block 10b to produce racemic duced rearrangement and deprotection to deliver (+)-de-
demethylanhydrocalopin dimethyl ether (4b) (Scheme 4).
hydrocalopin (2) (97%).
Scheme 5 Synthesis of dehydrocalopin (2)
Figure 2 X-ray structure of 14b
Reductive ring opening of epoxide 14a with palladium on
charcoal and subsequent deprotection of the catechol with
HCl in EtOAc yielded only traces of calopin (1b) that
Scheme 4 Synthesis of anhydrocalopin (3)
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Synthesis of (+)-Anhydrocalopin and (+)-Dehydrocalopin
103
at r.t. The reaction was quenched by the addition of sat. aq NH4Cl
(100 mL), and the aqueous phase was extracted with EtOAc
(3 100 mL). The combined organic layers were dried (MgSO4),
and the solvent was removed under reduced pressure. Flash chro-
matography on silica gel with EtOAc–PE (1:20) yielded 8 (858 mg,
94%) as a colorless liquid.
were detected by mass spectroscopy and HPLC compari-
son with the natural product.
All solvents were distilled before use. Petroleum ether (PE, 40–
60 °C) was used for chromatography. The reactions were monitored
by TLC prior to workup. Solvents were removed from the reaction
mixtures at 40 °C using a rotavapor. TLC was run on silica gel
plates 60 F254 (Merck) and visualized with UV fluorescence (254
and 366 nm). Flash chromatography was performed on silica gel 60
(40–63 m, Merck). Mps were determined with a Büchi SMP 535
apparatus and are uncorrected. Optical rotations were measured
with a Perkin–Elmer 241 spectrometer. UV/Vis spectra were mea-
sured with a Perkin–Elmer Lambda 16 spectrometer. CD spectra
were measured with a S. A. Jobin Yvon CD-6-Dichrograph. All IR
spectra were measured as KBr pellets using a Perkin–Elmer Spec-
trum 1000 spectrophotometer. 1H NMR and 13C NMR spectra were
recorded on Varian Mercury 200, Bruker ARX 300, and AMX 600
instruments. Chemical shifts are given as values from solvent
peak or internal TMS. The mass spectra were recorded at 70 eV on
Finnigan MAT 90 and MAT 95 Q instruments. 3-Methylcatechol
was purchased from Aldrich. Elemental analyses were carried out
by the Microanalytical Laboratory of the Department Chemie, Uni-
versität München.
IR (KBr): 3310 (w), 3088 (w), 2937 (m), 2838 (m), 1666 (s), 1629
(w), 1580 (m), 1477 (s), 1426 (s), 1372 (w), 1333 (s), 1301 (m),
1268 (s), 1230 (s), 1179 (m), 1149 (w), 1086 (m), 1024 (s), 1004 (s),
987 (m), 942 (w), 883 (w), 847 (m), 788 (m), 769 (m), 752 (m), 674
(w), 658 (w), 604 (w) cm–1.
1H NMR (300 MHz, CDCl3, TMS): = 2.03 (s, 3 H), 3.80 (s, 3 H),
3.88 (s, 3 H), 5.62 (s, 1 H), 5.94 (s, 1 H), 6.80 (dd, J = 7.4, 1.7 Hz,
1 H), 6.97 (dd, J = 8.2, 1.7 Hz, 1 H), 7.06 (dd, J = 8.2, 7.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3, TMS): = 17.1, 55.9, 61.6, 113.9,
120.0, 123.7, 129.4, 134.6, 145.1, 146.5, 152.7, 198.2.
EI-MS: m/z (%) = 207 (10, [M+ + H]), 206 (76) [M+], 191 (6), 175
(12), 165 (100), 151 (12), 122 (19).
HRMS: m/z calcd for C12H14O3: 206.0943; found: 206.0953.
UV/Vis (MeCN): max ( ) = 219 (17480), 255 nm (sh, 3030).
Anal. Calcd for C12H14O3: C, 69.88; H, 6.84. Found: C, 69.83; H,
7.12.
2,3,N-Trimethoxy-N-methylbenzamide (7)
(rac)-(2,3-Dimethoxyphenyl) (2-Methyl-2-oxiranyl)methanone
(9)
To a suspension of 2,3-dimethoxybenzoic acid (6; 9.10 g,
50.0 mmol) in toluene (20 mL) were added DMF (5 drops) and
SOCl2 (5.50 mL, 75.4 mmol), and the mixture was heated to 60 °C
for 50 min. The mixture was cooled to r.t. and concentrated under
reduced pressure. The resulting acid chloride was dissolved in
CH2Cl2 (50 mL), and N,O-dimethylhydroxylamine hydrochloride
(4.88 g, 50.0 mmol) was added at 0 °C. Then, a solution of Et3N
(14.6 mL, 104.8 mmol) in CH2Cl2 (10 mL) and a catalytic amount
of 4-dimethylaminopyridine (DMAP) were added, and the reaction
mixture was stirred at r.t. overnight. After dilution with EtOAc
(400 mL), the solution was subsequently washed with aq HCl (2 N,
To a solution of 8 (1.03 g, 5.0 mmol) in MeOH (50 mL) were added
NaOH (2 M, 0.25 mL, 0.5 mmol) and aq H2O2 (30%, 0.66 mL,
6.5 mmol) at 0 °C, and the mixture was stirred overnight. Sat. aq
NH4Cl (5 mL) was added, and the mixture was concentrated under
reduced pressure. After the addition of H2O (50 mL) and extraction
with EtOAc (3 50 mL), the combined organic layers were dried
(Na2SO4), and evaporated. The residue was purified by flash chro-
matography on silica gel with CH2Cl2–acetone (200:1) to yield 9
(1.06 g, 95%) as a colorless liquid.
3
200 mL), sat. aq NaHCO3 (3 200 mL), and brine (200 mL).
IR (KBr): 2982 (m), 2940 (m), 2838 (w), 1696 (s), 1581 (m), 1478
(s), 1443 (m), 1427 (s), 1380 (w), 1322 (m), 1269 (s), 1225 (s), 1178
(m), 1147 (w), 1086 (m), 1020 (s), 1002 (s), 972 (m), 920 (w), 864
(w), 843 (w), 793 (m), 752 (m), 669 (w), 603 (w), 569 (w), 543 (w)
cm–1.
The organic layer was dried (Na2SO4) and concentrated under re-
duced pressure. Flash chromatography on silica gel with EtOAc–PE
(1:5 1:2) yielded 7 (9.62 g, 85% over 2 steps) as a colorless solid;
mp 57 °C.
1H NMR (300 MHz, CDCl3, TMS): = 1.65 (s, 3 H), 2.86 (s, 2 H),
3.88 (s, 3 H), 3.91 (s, 3 H), 6.90 (dd, J = 7.2, 2.0 Hz, 1 H), 7.00 (dd,
J = 8.2, 2.0 Hz, 1 H), 7.06 (dd, J = 8.2, 7.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3, TMS): = 17.2, 52.5, 55.9, 60.1, 61.6,
115.1, 119.8, 123.8, 131.7, 147.1, 152.4, 203.0.
EI-MS: m/z (%) = 223 (5, [M+ + H]), 222 (52, [M+]), 191 (1), 177
(3), 165 (100), 150 (8), 122 (28).
IR (KBr): 2970 (m), 2938 (m), 2837 (w), 1655 (s), 1599 (w), 1582
(m), 1480 (s), 1427 (s), 1381 (s), 1304 (m), 1268 (s), 1230 (s), 1173
(m), 1102 (w), 1085 (m), 1051 (s), 1003 (s), 923 (w), 837 (w), 796
(m), 785 (w), 752 (m), 734 (w), 683 (w), 617 (w), 569 (w), 536 (w),
474 (w) cm–1.
1H NMR (300 MHz, CDCl3, TMS): = 3.33 (br s, 3 H), 3.50 (s, br,
3 H), 3.88 (s, 6 H), 6.87 (dd, J = 7.6, 1.1 Hz, 1 H), 6.95 (dd, J = 8.1,
1.1 Hz, 1 H), 7.08 (dd, J = 8.1, 7.6 Hz, 1 H).
HRMS: m/z calcd for C12H14O4: 222.0892; found: 222.0889.
13C NMR (75 MHz, CDCl3, TMS): = 32.2 (br), 55.9, 61.1, 61.6,
113.4, 119.1, 124.1 (br), 130.7, 145.5, 152.6, 169.0.
EI-MS: m/z (%) = 225 (1, [M+]), 195 (1), 165 (100), 122 (11).
UV/Vis (MeCN):
(1620).
( ) = 218 (14570), 250 (3410), 283 nm
max
Anal. Calcd for C12H14O4: C, 64.85; H, 6.35. Found: C, 64.89; H,
6.36.
HRMS: m/z calcd for C11H15NO4: 225.1001; found: 225.1000.
UV/Vis (MeCN): max ( ) = 201 (33600), 222 (sh, 11470), 278 nm
(2190).
(rac)-3-Hydroxy-1-(2,3-dimethoxyphenyl)-2-methylpropan-1-
one (10b)
Anal. Calcd for C11H15NO4: C, 58.66; H, 6.71; N 6.22. Found: C,
58.49; H, 6.75; N, 6.20.
A mixture of 9 (510 mg, 2.3 mmol), AIBN (37 mg, 225 mol) and
tributyltin hydride (0.72 mL, 2.7 mmol) in anhyd benzene (15 mL)
was refluxed for 45 min. The mixture was cooled to r.t., and the sol-
vent was removed under reduced pressure. Flash chromatography
on silica gel with EtOAc–PE (1:3) gave 10b (510 mg, 99%) as a col-
orless liquid.
1-(2,3-Dimethoxyphenyl)-2-methylprop-2-en-1-one (8)
To a solution of 2-bromopropene (1.97 mL, 22.2 mmol) in anhyd
THF (5 mL) was added t-BuLi (1.7 M in pentane, 13.10 mL,
22.3 mmol) at –78 °C, and the mixture was stirred for 10 min. Then,
this suspension was added to a solution of 7 (1.00 g, 4.44 mmol) in
anhyd THF (5 mL) at 0 °C and stirred for 90 min at 0 °C and for 1 h
IR (KBr): 3437 (br, s), 3079 (w), 2937 (s), 2876 (m), 2838 (m),
1681 (s), 1579 (s), 1475 (s), 1426 (s), 1371 (m), 1307 (s), 1266 (s),
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104
H. Ebel et al.
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1187 (m), 1075 (m), 991 (s), 879 (w), 836 (w), 799 (m), 753 (m),
693 (w), 644 (w), 567 (w) cm–1.
1H NMR (300 MHz, CDCl3, TMS): = 1.16 (d, J = 7.3 Hz, 3 H),
2.31 (t, J = 6.4 Hz, 1 H, OH), 3.47 3.58 (m, 1 H), 3.75 3.86 (m,
2 H), 3.89 (s, 3 H), 3.90 (s, 3 H), 7.02 7.13 (m, 3 H).
13C NMR (75 MHz, CDCl3, TMS): = 13.5, 47.9, 56.0, 61.8, 64.6,
115.4, 120.4, 124.3, 134.0, 147.4, 152.9, 207.9.
EI-MS: m/z (%) = 224 (2, [M+]), 206 (4), 194 (8), 165 (100), 150
1H NMR (300 MHz, CDCl3, TMS): = 1.19 (d, J = 7.2 Hz, 3 H),
1.33 (t, J = 7.0 Hz, 6 H), 2.35 (s, 3 H), 2.91 (d, J = 21.6 Hz, 2 H),
3.45 (s, 3 H), 3.60 (s, 3 H), 3.76 3.88 (m, 1 H), 4.09 4.17 (m, 4 H),
4.20 (dd, J = 11.1, 6.2 Hz, 1 H), 4.47 (dd, J = 11.1, 6.6 Hz, 1 H),
5.06 (d, J = 5.8 Hz, 1 H), 5.09 (d, J = 5.8 Hz, 1 H), 5.12 (s, 2 H),
7.00 (d, J = 8.0 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3, TMS): = 14.0, 16.3 (d, J = 6.2 Hz,
CH3), 17.0, 34.2 (d, J = 134.7 Hz, PCH2), 44.2, 57.7, 58.0, 62.7 (d,
J = 6.2 Hz, CH2), 62.7 (d, J = 6.2 Hz, CH2), 66.7, 99.5, 100.2,
124.5, 126.6, 132.4, 137.6, 148.2, 149.0, 165.7 (d, J = 5.9 Hz,
CO2), 203.1.
(5), 122 (13).
HRMS: m/z calcd for C12H16O4: 224.1049; found: 224.1049.
EI-MS: m/z (%) = 476 (9, [M+]), 431 (10), 400 (36), 399 (100), 385
(27), 371 (6), 285 (15), 204 (55), 197 (67), 191 (28), 183 (21), 179
(77), 163 (83), 151 (24), 137 (15), 123 (16), 45 (99).
UV/Vis (MeCN): max ( ) = 221 (sh, 20900), 264 nm (4050).
Anal. Calcd for C12H16O4: C, 64.27; H, 7.19. Found: C, 64.34; H,
7.33.
HRMS: m/z calcd for C21H33O10P: 476.1811; found: 476.1772.
(2R)-1-[2,3-Bis(methoxymethoxy)-4-methylphenyl]-3-hydroxy-
2-methylpropan-1-one (10a)
UV/Vis (MeCN):
(2300).
( ) = 214 (21190), 251 (8950), 292 nm
max
To a solution of 113 (5.77 g, 27.2 mmol) in anhyd THF (35 mL) was
added BuLi (2.5 M solution in hexanes, 11.1 mL, 27.8 mmol) at 0
°C. The mixture was stirred for 2 h at r.t. and cooled to 0 °C again.
The resulting red suspension was added to a pre-cooled (0 °C) solu-
tion of 129 (1.00 g, 6.8 mmol) in anhyd THF (6.5 mL) and stirred
for 30 min. Then, the mixture was warmed to r.t. and stirred for an-
other 15 h. The reaction was quenched by the addition of aq KHSO4
(1.1 M, 30 mL), diluted with sat. aq NH4Cl (200 mL), and extracted
with EtOAc (3 150 mL). The combined organic layers were
washed with brine (200 mL), dried (Na2SO4), and concentrated un-
der reduced pressure. Flash chromatography on silica gel with
EtOAc–PE (1:8 1:2) gave 10a (0.96 g, 47%) as a colorless liquid,
together with 11 (3.57 g); [ ]D23 +0.1 (c = 0.048, CHCl3).
Anal. Calcd for C21H33O10P: C, 52.94; H, 6.98. Found: C, 52.81; H,
7.03.
(rac)-3-(2,3-Dimethoxyphenyl)-2-methyl-3-oxopropyl
(Diethoxyphosphinyl)acetate (5b)
Prepared as described above from 10b (2.00 g, 8.9 mmol), freshly
prepared (diethylphosphinyl)acetyl chloride (13;10 3.83 g,
17.8 mmol), and a catalytic amount of p-toluenesulfonic acid. Flash
chromatography of the crude product on silica gel with EtOAc–PE
(2:1) afforded 5b (3.30 g, 92%) as a colorless liquid.
IR (KBr): 3471 (w), 2983 (m), 2939 (m), 2840 (w), 1738 (s), 1693
(m), 1579 (m), 1476 (s), 1427 (m), 1392 (w), 1369 (w), 1267 (s),
1164 (w), 1118 (m), 1095 (m), 1051 (s), 1026 (s), 973 (s), 839 (w),
800 (w), 754 (w), 615 (w) cm–1.
1H NMR (300 MHz, CDCl3, TMS): = 1.20 (d, J = 7.1 Hz, 3 H),
1.32 (t, J = 7.1 Hz, 6 H), 2.92 (d, J = 21.6 Hz, 2 H), 3.68 3.79 (m,
1 H), 3.89 (s, 3 H), 3.89 (s, 3 H), 4.09 4.19 (m, 4 H), 4.23 (dd,
J = 10.9, 5.9 Hz, 1 H), 4.46 (dd, J = 10.9, 7.0 Hz, 1 H), 7.02 7.13
(m, 3 H).
13C NMR (75 MHz, CDCl3, TMS): = 13.8, 16.3 (d, J = 6.2 Hz),
34.2 (d, J = 134.4 Hz, PCH2), 44.8, 56.0, 61.7, 62.7 (d, J = 6.1 Hz,
CH2), 62.7 (d, J = 6.4 Hz, CH2), 66.7, 115.6, 120.7, 124.2, 133.7,
147.6, 152.9, 165.7 (d, J = 6.2 Hz, CO2), 204.3.
IR (KBr): 3469 (br, w), 2936 (m), 1683 (s), 1601 (m), 1455 (m),
1426 (m), 1389 (m), 1251 (s), 1207 (m), 1159 (s), 1083 (s), 964 (s),
924 (s), 824 (w), 787 (w), 756 (w) cm–1.
1H NMR (300 MHz, CDCl3, TMS): = 1.14 (d, J = 7.2 Hz, 3 H),
2.35 (s, 3 H), 2.49–2.56 (m, 1 H), 3.46 (s, 3 H), 3.60 (s, 3 H), 3.73–
3.79 (m, 1 H), 3.82–3.89 (m, 1 H), 5.08 (s, 2 H), 5.12 (s, 2 H), 7.00
(d, J = 8.0 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3, TMS): = 13.8, 16.9, 47.2, 57.7, 58.0,
64.7, 99.4, 100.2, 124.3, 126.6, 132.8, 137.4, 148.2, 149.1, 206.6.
EI-MS: m/z (%) = 298 (2, [M+]), 222 (1), 192 (37), 163 (38), 150
(16), 45 (100).
EI-MS: m/z (%) = 402 (3, [M+]), 206 (10), 165 (100), 151 (5), 122
(5).
HRMS: m/z calcd for C15H22O6: 298.1416; found: 298.1417.
UV/Vis (MeCN):
(970).
( ) = 214 (18460), 250 (6690), 291 nm
max
HRMS: m/z calcd for C18H27O8P: 402.1444; found: 402.1432.
UV/Vis (MeCN):
(2230).
( ) = 216 (19880), 247 (5320), 298 nm
max
Anal. Calcd for C15H22O6: C, 60.39; H, 7.43. Found: C, 60.60; H,
7.57.
Anal. Calcd for C18H27O8P: C, 53.73; H, 6.76. Found: C, 53.70; H,
6.84.
(2R)-3-[2,3-Bis(methoxymethoxy)-4-methylphenyl]-2-methyl-
3-oxopropyl (Diethoxyphosphinyl)acetate (5a); Typical
Procedure
(4S)-3-[2,3-Bis(methoxymethoxy-4-methylphenyl]-4-methyl-
2,3-didehydro- -valerolactone (4a)
To a solution of 10a (940 mg, 3.14 mmol) in anhyd THF (13 mL)
were added a solution of freshly prepared (diethylphosphinyl)acetyl
chloride (13;10 1.35 g, 6.28 mmol) in anhyd THF (5 mL) and a cat-
alytic amount of p-toluenesulfonic acid at 0 °C. After stirring for 2 h
at 0 °C followed by the addition of sat. aq NH4Cl (100 mL), the
mixture was extracted with EtOAc (3 100 mL). The combined or-
ganic layers were dried (Na2SO4) and evaporated. Flash chromatog-
raphy on silica gel with EtOAc–PE (10:1) yielded 5a (1.37 g, 91%)
as a colorless liquid; [ ]D23 +9.5 (c = 0.051, CHCl3).
Et3N (0.42 mL, 3.00 mmol) was added to a stirred solution of 5a
(1.30 g, 2.73 mmol) and LiBr (710 mg, 8.18 mmol) in anhyd MeCN
(50 mL) at 0 °C, and the stirring was continued for 9 h. After the ad-
dition of Et3N (0.21 mL, 1.50 mmol), the mixture was warmed to
r.t. overnight. Sat. aq NH4Cl (200 mL) was then added followed by
extraction of the mixture with EtOAc (3 250 mL). The combined
organic layers were dried (Na2SO4) and concentrated under reduced
pressure. Flash chromatography on silica gel with EtOAc–PE (1:2)
yielded 4a (336 mg, 38%) as a colorless liquid together with elimi-
nation product (200 mg, 26%) and alcohol 10a (117 mg, 14%);
[ ]D29 +280.2 (c = 0.003, CHCl3).
IR (KBr): 3470 (br, w), 2982 (m), 2936 (m), 1739 (s), 1687 (m),
1600 (w), 1456 (m), 1427 (m), 1390 (m), 1265 (s), 1208 (m), 1160
(s), 1054 (s), 1025 (s), 965 (s), 827 (w), 786 (w), 614 (w) cm–1.
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Synthesis of (+)-Anhydrocalopin and (+)-Dehydrocalopin
105
IR (KBr): 3522 (w), 2966 (m), 2933 (m), 2829 (w), 1715 (s), 1620
(w), 1454 (m), 1427 (m), 1391 (m), 1348 (w), 1306 (w), 1286 (m),
1265 (s), 1223 (s), 1159 (s), 1083 (s), 1062 (s), 1014 (m), 966 (s),
925 (s), 826 (w), 813 (w), 784 (w) cm–1.
1H NMR (300 MHz, CDCl3, TMS): = 1.08 (d, J = 7.1 Hz, 3 H),
2.34 (s, 3 H), 3.14 3.27 (m, 1 H), 3.46 (s, 3 H), 3.60 (s, 3 H), 4.23
(dd, J = 11.1, 5.0 Hz, 1 H), 4.54 (dd, J = 11.1, 4.2 Hz, 1 H), 5.04 (s,
2 H), 5.10 (s, 2 H), 6.09 (s, 1 H), 6.88 (d, J = 7.9 Hz, 1 H), 6.98 (d,
J = 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3, TMS): = 15.5, 16.7, 32.1, 57.7, 57.9,
72.0, 99.3, 99.5, 117.9, 124.2, 126.7, 130.3, 135.0, 147.3, 149.1,
161.7, 164.7.
EI-MS: m/z (%) = 322 (17, [M+]), 307 (11), 291 (1), 277 (19), 246
(35).
13C NMR (150 MHz, CDCl3, TMS): = 15.7, 16.0, 31.8, 72.1,
116.9, 120.1, 121.3, 122.2, 125.9, 142.0, 142.2, 160.9, 165.4.
EI-MS: m/z (%) = 234 (25, [M+]), 216 (48), 201 (22), 190 (61), 175
(100).
HRMS: m/z calcd for C13H14O4: 234.0892; found: 234.0885.
UV/Vis (MeCN): max ( ) = 219 (14880), 283 nm (11720).
CD (MeCN):
(
) = 218 (–1.1), 220 (–1.1), 226 (0), 227
max
(+0.1), 235 (+0.4), 259 (+1.3), 273 (sh, +0.2), 277 (0), 280 (–0.2),
283 (0), 287 (+0.3), 308 nm (+2.0).
(2S,3R,4R)-3-[2,3-Bis(methoxymethoxy-4-methylphenyl]-2,3-
epoxy-4-methyl- -valerolactone (14a)
Compound 4a (238 mg, 740 mol) was dissolved in
dimethyldioxirane14 (0.1 M solution in acetone, 22.0 mL,
2.2 mmol) and stirred for 18 h at r.t. Then, the solution was concen-
trated under reduced pressure and the residue purified by flash chro-
matography on silica gel with EtOAc–PE (1:4) to yield 14a
(242 mg, 97%) as a colorless liquid; [ ]D29 –6.2 (c = 0.003, CHCl3).
HRMS: m/z calcd for C17H22O6: 322.1416; found: 322.1419.
UV/Vis (MeCN): max ( ) = 214 (19320), 271 nm (9550).
CD (MeCN):
(
) = 217 (–2.6), 224 (–2.0), 230 (–0.2), 232
max
(0), 234 (+0.5), 257 (+3.1), 292 nm (+4.7).
IR (KBr): 3624 (w), 3470 (w), 2971 (m), 2830 (w), 1747 (s), 1607
(w), 1455 (s), 1429 (m), 1392 (s), 1318 (w), 1266 (s), 1232 (m),
1210 (m), 1160 (s), 1061 (s), 1005 (m), 964 (s), 927 (s), 869 (m),
811 (m), 782 (w), 718 (w), 570 (w) cm–1.
1H NMR (300 MHz, CDCl3, TMS): = 1.06 (d, J = 7.2 Hz, 3 H),
2.33 (s, 3 H), 2.84 2.96 (m, 1 H), 3.60 (s, 3 H), 3.61 (s, 3 H), 3.83
(s, 1 H), 4.01 (d, J = 10.8 Hz, 1 H), 4.77 (dd, J = 10.8, 3.1 Hz, 1 H),
5.08 (d, J = 6.0 Hz, 1 H), 5.11 (d, J = 6.0 Hz, 1 H), 5.12 (d,
J = 5.1 Hz, 1 H), 5.18 (d, J = 5.1 Hz, 1 H), 6.91 (d, J = 7.9 Hz, 1 H),
6.95 (d, J = 7.9 Hz, 1 H).
Anal. Calcd for C17H22O6: C, 63.34; H, 6.88. Found: C, 63.52; H,
6.75.
(rac)-3-(2,3-Dimethoxyphenyl)-4-methyl-2,3-didehydro- -
valerolactone (4b)
Prepared as described above from 5b (990 mg, 2.46 mmol), LiBr
(432 mg, 4.97 mmol), and Et3N (0.55 mL, 3.96 mmol). Flash chro-
matography on silica gel with EtOAc–PE (1:2) yielded 4b (388 mg,
63%) as a colorless solid; mp 53 54 °C, together with elimination
product 8 (151 mg, 29%) and alcohol 10b (17 mg, 3%).
13C NMR (75 MHz, CDCl3, TMS): = 13.8, 16.7, 33.0, 54.4, 57.7,
58.0, 66.3, 69.6, 99.2, 99.8, 124.9, 126.2, 126.9, 135.0, 149.1,
149.1, 167.8.
IR (KBr): 3430 (m), 2968 (m), 2934 (m), 2839 (w), 1718 (s), 1617
(w), 1575 (m), 1471 (s), 1426 (m), 1401 (m), 1375 (w), 1349 (w),
1306 (m), 1262 (s), 1229 (s), 1170 (w), 1135 (w), 1095 (s), 1063
(m), 1001 (s), 959 (w), 898 (w), 882 (w), 794 (m), 753 (m) cm–1.
EI-MS: m/z (%) = 338 (1, [M+]), 322 (1), 262 (3), 246 (5), 234 (9),
232 (12), 219 (7), 218 (6), 188 (20), 45 (100).
1H NMR (300 MHz, CDCl3, TMS): = 1.08 (d, J = 7.1 Hz, 3 H),
3.11 3.21 (m, 1 H), 3.79 (s, 3 H), 3.90 (s, 3 H), 4.24 (dd, J = 11.1,
5.0 Hz, 1 H), 4.56 (dd, J = 11.1, 4.2 Hz, 1 H), 6.04 (s, 1 H), 6.77
(dd, J = 7.7, 1.2 Hz, 1 H), 6.98 (dd, J = 8.1, 1.2 Hz, 1 H), 7.09 (dd,
J = 8.1, 7.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3, TMS): = 15.5, 32.3, 55.9, 61.1, 72.2,
113.6, 117.8, 120.9, 124.5, 131.8, 146.3, 152.9, 162.3, 164.7.
HRMS: m/z calcd for C17H22O7: 338.1366; found: 338.1364.
UV/Vis (MeCN):
271 nm (1090).
( ) = 202 (4511090), 220 (sh, 10260),
max
CD (MeCN):
(
) = 218 (0), 221 (+4.1), 224 (sh, +2.9), 228
max
(0), 233 (–3.9), 266 (0), 274 nm (+0.2).
Anal. Calcd for C17H22O7: C, 60.35; H, 6.55. Found: C, 60.49; H,
6.63.
EI-MS: m/z (%) = 248 (100) [M+], 230 (7), 217 (13), 203 (9), 189
(19).
HRMS: m/z calcd for C14H16O4: 248.1049; found: 248.1043.
(rac-2S,3R,4R)-3-(2,3-Dimethoxyphenyl)-2,3-epoxy-4-methyl-
-valerolactone (14b)
UV/Vis (MeCN): max ( ) = 222 (53290), 263 nm (26330).
Prepared as described above from 4b (300 mg, 1.21 mmol) and
dimethyldioxirane14 (0.1 M solution in acetone, 36.0 mL,
3.6 mmol). Purification by flash chromatography on silica gel with
EtOAc–PE (1:4) yielded 14b (300 mg, 94%, 98% related to recov-
ered 4b) as a colorless solid; mp 82 83 °C, together with recovered
starting material 4b (13 mg, 4%).
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C, 67.68; H,
6.42.
(4S)-3-[2,3-Dihydroxy-4-methylphenyl]-4-methyl-2,3-
didehydro- -valerolactone (Anhydrocalopin, 3)
Compound 4a (4.5 mg, 13.9 mol) was dissolved in a sat. solution
of HCl in EtOAc (0.7 mL) and stirred for 30 min at r.t. Removal of
the solvent under reduced pressure afforded spectroscopically pure
3 (3.2 mg, 97%) as a colorless solid; mp 152 153 °C (dec.);
[ ]D30 +88.5 (c = 0.002, CHCl3).
IR (KBr): 3462 (m), 2972 (m), 2942 (m), 1741 (s), 1584 (w), 1479
(s), 1412 (m), 1378 (w), 1320 (m), 1304 (m), 1282 (m), 1264 (s),
1229 (m), 1185 (w), 1106 (m), 1076 (m), 1062 (s), 1005 (s), 956
(w), 867 (w), 823 (m), 792 (m), 755 (m) cm–1.
1H NMR (600 MHz, CDCl3, TMS): = 1.04 (d, J = 7.3 Hz, 3 H),
2.81 2.85 (m, 1 H), 3.77 (s, 1 H), 3.89 (s, 3 H), 3.92 (s, 3 H), 4.00
(d, J = 10.7 Hz, 1 H), 4.80 (dd, J = 10.7, 3.0 Hz, 1 H), 6.82 (d,
J = 7.5 Hz, 1 H), 6.97 (d, J = 8.2 Hz, 1 H), 7.06 (dd, J = 8.2, 7.5 Hz,
1 H).
IR (KBr): 3454 (m), 3194 (m), 2970 (m), 2930 (w), 2560 (w), 2373
(w), 1667 (s), 1614 (s), 1595 (s), 1466 (s), 1409 (m), 1376 (m), 1354
(m), 1309 (m), 1296 (m), 1269 (s), 1219 (s), 1132 (m), 1088 (m),
1061 (m), 1006 (m), 889 (m), 804 (m), 760 (w), 735 (w), 707
(w) cm–1.
1H NMR (600 MHz, CDCl3, TMS): = 1.17 (d, J = 7.1 Hz, 3 H),
2.29 (s, 3 H), 3.14 3.20 (m, 1 H), 4.27 (dd, J = 10.6, 3.1 Hz, 1 H),
4.57 (dd, J = 10.6, 2.7 Hz, 1 H), 5.25 (s, 1 OH), 6.10 (s, 1 OH), 6.22
(s, 1 H), 6.73 (‘s’, 2 H).
13C NMR (150 MHz, CDCl3, TMS): = 13.8, 33.0, 54.4, 55.8, 61.3,
66.4, 69.7, 113.6, 121.3, 124.1, 128.7, 148.5, 153.0, 167.9.
EI-MS: m/z (%) = 264 (40, [M+]), 207 (100), 165 (40).
Synthesis 2003, No. 1, 101–106 ISSN 0039-7881 © Thieme Stuttgart · New York

106
H. Ebel et al.
PAPER
HRMS: m/z calcd for C14H16O5: 264.0998; found: 264.0997.
wR2 = 0.1315 for all data and 175 variables. Goodness-of-fit:
1.126.17
UV/Vis (MeCN):
(1010).
( ) = 201 (41110), 220 (sh, 5590), 279 nm
max
Anal. Calcd for C14H16O5: C, 63.63; H, 6.10. Found: C, 63.68; H,
6.12.
Acknowledgments
The crystal structure determination was carried out by Dr. Kirsten
Zeitler. This work was supported by the Fonds der Chemischen In-
dustrie through a Ph.D. fellowship to H. E. We thank Priv.-Doz. Dr.
Johann Jauch (TU München) for valuable discussions.
(4S)-3-[2,3-Dihydroxy-4-methylphenyl]-2-hydroxy-4-methyl-
2,3-didehydro- -valerolactone (Dehydrocalopin, 2)
Compound 14a (25 mg, 73.9 mol) was dissolved in a sat. solution
of HCl in EtOAc (1.5 mL) and stirred for 30 min at r.t. After con-
centration of the reaction mixture under reduced pressure, the resi-
due was purified by flash chromatography on reversed phase (RP-
18) with MeOH–H2O (3:2) to afford 2 (18 mg, 97%) as a colorless
foam; [ ]D30 +54.9 (c = 0.003, CHCl3).
References
(1) Hellwig, V.; Dasenbrock, J.; Gräf, C.; Kahner, L.;
Schumann, S.; Steglich, W. Eur. J. Org. Chem. 2002, 2895.
(2) Ebel, H.; Polborn, K.; Steglich, W. Eur. J. Org. Chem. 2002,
2905.
(3) Ebel, H.; Knör, S.; Steglich, W. Tetrahedron 2003, 59, in
press.
IR (KBr): 3418 (s), 2971 (m), 2930 (m), 1713 (s), 1694 (s), 1626
(w), 1574 (w), 1463 (s), 1415 (m), 1353 (s), 1260 (s), 1189 (s),
1112 (w), 1096 (w), 1037 (w), 1020 (w), 1007 (m), 949 (w), 911
(m), 824 (w), 800 (w), 782 (m), 755 (m), 732 (m), 650 (w) cm–1.
1H NMR (300 MHz, CDCl3, TMS): = 1.17 (d, J = 7.0 Hz, 3 H),
2.29 (s, 3 H), 3.02 3.13 (m, 1 H), 4.33 (dd, J = 11.1, 3.0 Hz, 1 H),
4.64 (dd, J = 11.1, 3.6 Hz, 1 H), 6.12 (s, 1 OH), 6.68 (d, J = 8.1 Hz,
1 H), 6.81 (d, J = 8.1 Hz, 1 H), 6.99 (br s, 2 OH).
13C NMR (75 MHz, CDCl3, TMS): = 15.6, 17.0, 33.0, 72.8, 117.8,
119.4, 123.6, 125.8, 128.2, 132.1, 141.2, 145.4, 164.0.
EI-MS: m/z (%) = 250 (100, [M+]), 232 (5), 222 (3), 205 (30), 204
(32), 189 (11), 177 (34), 176 (23), 175 (21), 164 (18), 161 (38), 159
(43).
(4) The numbering of the described -lactones follows that of
the calopins.1
(5) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(6) Bowman, W. R.; Brown, D. S.; Burns, C. A.; Marples, B. A.;
Zaidi, N. A. Tetrahedron 1992, 48, 6883.
(7) Hasegawa, E.; Ishiyama, K.; Kato, T.; Horaguchi, T.;
Shimizu, T.; Tanaka, S.; Yamashita, Y. J. Org. Chem. 1992,
57, 5352.
(8) Snieckus, V. Chem. Rev. 1990, 90, 879.
(9) Luke, G. P.; Morris, J. J. Org. Chem. 1995, 60, 3013.
(10) Cooke, M. P. Jr.; Biciunas, K. P. Synthesis 1981, 283.
(11) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183.
(12) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
(13) Adam, W.; Hadjiarapoglou, L.; Smerz, A. Chem. Ber. 1991,
124, 227.
HRMS: m/z calcd for C13H14O5: 250.0841; found: 250.0833.
UV/Vis (MeCN): max ( ) = 202 (23360), 285 nm (9220).
CD (MeCN):
(
) = 222 (–4.1), 241 (–2.4), 254 (0), 277
max
(+6.8), 294 (+3.3), 339 nm (+0.2).
Crystallographic Data
(14) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991,
124, 2377.
The single-crystal X-ray diffraction experiment was carried out
with a Nonius MACH 3, four-circle, computer-controlled, single-
crystal diffractometer. The structure was solved by direct methods
and refined by full-matrix least squares against F2 of all data, using
SHELXS-86 and SHELXL-93 software.15,16 Crystal data and mea-
surement conditions for compound 14b: Formula: C14H16O5; For-
mula mass: 264.27; Crystal size: 0.13 0.47 0.53 mm; Crystal
system: monoclinic; Space group: P21/n; Lattice parameters:
a = 8.8020(7) Å, b = 8.0244(10) Å, c = 18.903(3) Å,
= 97.142(9)°; V = 1324.8(3) Å3; Z = 4; Dcalcd 1.325 g/cm3; F(000)
560; : 0.101 mm-1; Radiation type: Mo-K , = 0.71073 Å;
(15) Sheldrick, G. M. SHELXS-86, Program for the Solution of
X-ray Structures; Universität Göttingen: Germany, 1986.
(16) Sheldrick, G. M. SHELXL-93, Program for Crystal
Structure Refinement; Universität Göttingen: Germany,
1993.
(17) Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-195296. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [Fax: +44(1223)336-033;
E-mail: deposit@ccdc.cam.ac.uk].
2
max = 48.0°; hmin/hmax = –9/10, kmin/kmax = 0/9, lmin/lmax = –21/0;
No. of measured reflections: 2136, No. of unique reflections: 2071,
No. of observed reflections: 1594 [I > 2 (I)]. Final R-values for
data with I > 2 (I) R1 = 0.0439, wR2 = 0.1169, and R1 = 0.0613,
Synthesis 2003, No. 1, 101–106 ISSN 0039-7881 © Thieme Stuttgart · New York