PAPER
Carlosic Acid and Other 5-Carboxymethyltetronates
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gel to yield 5 (1.61 g, 50%) as a colorless oil; Rf 0.31 (hexane–
EtOAc, 4:1); [a]D25 –15.9 (c = 1, CHCl3).
(5S)-3-Butanoyl-5-trimethylsilylethylcarboxymethyldihydrofu-
ran-2,4-dione (8)
Et3N (0.15 mL, 1.1 mmol) was added at 0 °C to a stirred suspension
of tetronic acid 7 (258 mg, 1.0 mmol) in anhyd CH2Cl2 (10 mL). To
the resulting homogeneous solution was added in succession
DMAP (36 mg, 0.3 mmol), butyric acid (97 mg, 1.1 mmol) and
DCC (2.47 mg, 1.2 mmol) in three portions. The mixture was stirred
for 10 min at 0 °C, the cooling bath was removed, and stirring con-
tinued for 15 h at r.t. The precipitate N,N¢-dicyclohexylurea was fil-
tered off over a short plug of celite which was washed with EtOAc.
The combined filtrates were washed with 5% HCl, dried over
Na2SO4 and concentrated on a rotary evaporator. The crude product
was purified by chromatography on silica gel to leave 8 (300 mg,
IR (ATR): 3451, 1738, 1248, 858, 832 cm–1.
1H NMR (CDCl3): d = 0.0 (s, 9 H, SiMe3), 0.90–0.96 (m, 2 H,
CH2Si), 2.73 (dd, J = 16.3, 5.8 Hz, 1 H, CH2), 2.83 (dd, J = 16.3, 4.7
Hz, 1 H, CH2), 4.09–4.17 (m, 2 H, CH2CH2Si), 4.50 (dd, J = 5.8, 4.7
Hz, 1 H, H-5), 5.20 (s, 2 H, OCH2), 7.30–7.37 (m, 5 H, ar-H).
13C NMR (75.5 MHz, CDCl3): d = –1.6 (SiMe3), 17.2 (CH2Si), 38.7
(C3), 63.3 (CH2CH2Si), 67.3 (C2), 67.6 (OCH2), 128.3, 128.5,
128.6 (ar-CH), 135.0 (ar-Cq), 170.5 (C4), 173.2 (C1).
Anal. Calcd for C16H24O5Si: C, 59.23; H, 7.46. Found: C, 59.36; H,
7.37.
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91%) as orange crystals; mp 86–88 °C; [a]D –28.0 (c = 0.5,
MeOH).
(5S)-4-Benzyloxy-5-trimethylsilylethylcarboxymethyl[5H]fu-
ran-2-one (6)
IR (ATR): 3380, 1726, 1633, 1465, 1249, 1167, 858, 832 cm–1.
1H NMR (CD3OD): d = 0.05 (s, 9 H, SiMe3), 0.94 (t, J = 7.55 Hz, 3
H, CCH3), 0.99 (t, J = 8.4 Hz, 2 H, CH2Si), 1.50–1.59 (m, 2 H,
CH2CH3), 2.54 (dd, J = 16.2, 7.0 Hz, 1 H, CH2), 2.76 (t, J = 7.0 Hz,
2 H, COCH2), 2.92 (d, J = 16.2 Hz, 1 H, CH2), 4.19 (t, J = 8.4 Hz,
2 H, OCH2), 4.73 (s, 1 H, H-5), 9.52 (br, 1 H, OH).
MS: m/z (%) = 328 (5) [M+], 313 (15), 285 (50), 257 (20), 239 (30),
167 (20), 151 (10), 123 (20), 101 (15), 84 (15), 73 (100).
Compound 5 (650 mg, 2.0 mmol), Ph3PCCO (786 mg, 2.6 mmol),
and catalytic amounts of benzoic acid were dissolved in benzene
(15 mL) and heated under reflux for 16 h or irradiated for 1 h at 100
°C in a microwave oven. The solvent was evaporated and the crude
product was purified by column chromatography to leave 6 (591
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mg, 85%) as a colorless oil; Rf 0.37 (hexane–EtOAc, 2:1); [a]D
–15.1 (c = 1, CHCl3).
IR (ATR): 3120, 3066, 1760, 1730, 1628, 1248, 1166, 1152, 858,
832 cm–1.
Anal. Calcd for C15H24O6Si: C, 54.85; H, 7.37. Found: C, 54.69; H,
7.30.
1H NMR (CDCl3): d = 0.0 (s, 9 H, SiMe3), 0.90–0.96 (m, 2 H,
CH2Si), 2.59 (dd, J = 16.1, 8.1 Hz, 1 H, CH2), 2.83 (dd, J = 16.2,
4.3, 1 H, CH2), 4.10–4.17 (m, 2 H, CH2CSi), 5.04 (s, 2 H, OCH2),
5.13 (s, 1 H, H-3), 5.20 (dd, J = 8.1, 4.3 Hz, 1 H, H-5), 7.31–7.39
(m, 5 H, ar-H).
13C NMR (75.5 MHz, CDCl3): d = –1.6 (SiMe3), 17.2 (CH2Si), 37.2
(CH2CO2), 63.5 (CCSi), 74.6 (CH2Ph), 75.1 (C5), 89.9 (C3), 127.9,
128.8, 129.1 (ar-CH), 133.6 (ar-Cq), 168.8 (CO2TMSE), 171.7
(C2), 179.7 (C4).
(5S)-Carlosic Acid (2)
A solution of 8 (157 mg, 0.5 mmol) in THF (4 mL) was treated with
TBAF·3H2O (480 mg, 1.5 mmol) in one portion. After stirring of
the mixture at r.t. for 2 h Et2O (5 mL) and water (5 mL) were added
and stirring was continued for 10 min. The layers were separated
and the aqueous one was extracted with Et2O to remove organic im-
purities. Carlosic acid 2 was extracted from the clear aqueous phase
with hot benzene (3 × 50 mL). The combined organic layers were
dried and evaporated to leave yellowish crystals (103 mg, 90%); mp
175 °C (lit.19 176–177 °C); [a]D25 –125.0 (c = 0.25, H2O) {Lit.7e [a]D
–125.0 (c = 0.28, H2O)}.
MS: m/z (%) = 348 (7) [M+], 186 (7), 132 (7), 101 (6), 91 (100), 73
(75), 65 (15), 45 (20).
Anal. Calcd for C18H24O5Si: C, 62.04; H, 6.94. Found: C, 62.16; H,
6.90.
IR (ATR): 3133 (br), 1745, 1707, 1662, 1604, 1016 cm–1.
1H NMR (DMSO-d6): d = 0.88 (t, J = 7.4 Hz, 3 H, CH3), 1.50–1.57
(m, 2 H, CH2CH3), 2.56 (dd, J = 16.7, 7.3 Hz, 1 H, CH2), 2.73 (t,
J = 7.0 Hz, 2 H, COCH2), 2.83 (dd, J = 16.7, 3.5 Hz, 1 H, CH2), 4.83
(dd, J = 7.3, 3.5 Hz, 1 H, H-5), 9.52 (br, 2 H, OH).
13C NMR (75.5 MHz, DMSO-d6): d = 13.7 (Me), 18.3 (CH2Me),
36.2 (CH2CO2), 38.7 (COCH2), 75.8 (C5), 98.2 (C3), 170.5
(CO2H), 170.8 (C2), 192.1 (COCH2), 192.3 (C4).
(5S)-5-Trimethylsilylethylcarboxymethyldihydrofuran-2,4-di-
one (7)
Compound 6 (348 mg, 1.0 mmol) was dissolved in MeOH (20 mL)
and treated with 5% Pd on charcoal (25 mg). The reaction vessel
was repeatedly evacuated and flushed with hydrogen gas and left to
stir at r.t. for 1 h, pressurized with 1 atm of H2. The resulting reac-
tion mixture was filtered through a short plug of celite, which was
washed with MeOH (40 mL). The filtrate was concentrated on an
oil pump to give pure tetronic acid 7 (250 mg, 99%) as a yellowish
solid; mp 80–81 °C; Rf 0.24 (hexane–EtOAc, 1:1); [a]D25 –19.4 (c =
1, MeOH).
MS: m/z (%) = 228 (5) [M+], 210 (35), 192 (25), 183 (15), 167 (50),
151 (30), 139 (20), 97 (40), 84 (100).
Immobilized Malates (9); General Procedure
Under a blanket of anhyd Ar Wang resin (1.0 g, loading 1.2 mmol/
g, 100–200 mesh, 1% DVB) was suspended in anyhd THF (12 mL)
and allowed to swell for 30 min. Malate 4 (2.4 mmol) and Ph3P
(0.65 g, 2.4 mmol) were added, the mixture was chilled to –10 °C
and gently shaken and then treated dropwise with a 2 M solution of
DIAD (0.47 mL, 2.4 mmol) in anhyd THF (1.2 mL). The mixture
was allowed to warm up to r.t. overnight and shaken at this temper-
ature for a further 14 h. The colorless resin was collected on a sin-
tered frit, rinsed in turn with THF (2 × 20 mL), CH2Cl2 (2 × 20 mL),
CH2Cl2 (3 × 20 mL), MeOH (3 × 20 mL) and Et2O (2 × 20 mL), and
dried on an oil pump. Completeness was ascertained by weight in-
crease.
IR (ATR): 3126, 1762, 1726, 1618, 1249, 1168, 858, 832 cm–1.
1H NMR (CDCl3): d = 0.0 (s, 9 H, SiMe3), 0.80–0.92 (m, 2 H,
CH2Si), 3.04 (s, 2 H, H-3), 3.12 (d, J = 22.1 Hz, 1 H, CH2), 3.38 (d,
J = 22.1 Hz, 1 H, CH2), 4.04–4.13 (m, 2 H, CH2CSi), 4.77 (s, 1 H,
H-5).
13C NMR (75.5 MHz, CDCl3): d = –1.6 (SiMe3), 17.2 (CH2Si), 36.4
(CH2CO2), 37.8 (C3), 64.2 (CH2CSi), 81.1 (C5), 169.4
(CO2TMSE), 170.5 (C2), 205.2 (C4).
MS: m/z (%) = 258 (5) [M+], 243 (15), 215 (25), 173 (15), 145 (20),
129 (50), 117 (10), 101 (100), 73 (100).
Anal. Calcd for C11H18O5Si: C, 51.14; H, 7.02. Found: C, 51.28; H,
6.95.
9a
Yield: 1.24 g from 4a (0.54 g = twofold excess).
Synthesis 2005, No. 14, 2421–2425 © Thieme Stuttgart · New York