4
M. Morkunas, M.E. Maier / Tetrahedron xxx (2015) 1e5
(180 mL) was refluxed for 3 h. Thereafter, the resulting dark-red
solution was cooled down to room temperature, partitioned be-
tween water (500 mL) and Et2O (500 mL). The aqueous layer was
extracted with Et2O (3ꢂ500 mL). The combined organic layers were
washed with satd. NaCl solution (1ꢂ400 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification of
the residue by flash chromatography (petroleum ether/EtOAc, 15:1)
provided xanthenedione 25 (3.22 g, 40%) as a yellowish oil. Rf¼0.34
ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3):
d
¼1.03 (d, J¼6.7 Hz,
6H, 4-H), 1.05 (d, J¼6.7 Hz, 6H, 4-H), 2.20 (qqt, J¼6.8, 6.8, 6.8 Hz, 1H,
3-H), 2.23 (qqt, J¼6.8, 6.8, 6.8 Hz, 1H, 3-H), 2.42 (d, J¼7.1 Hz, 2H, 2-
H), 2.49 (d, J¼7.1 Hz, 2H, 2-H), 6.56 (d, J¼2.0 Hz, 1H, Ar), 6.63 (d,
J¼2.0 Hz, 1H, Ar), 10.02 (s, 1H, CHO), 11.76 (s, 1H, OH); 13C NMR
(100 MHz, CDCl3):
d
¼22.3 (2ꢂC-4), 22.4 (2ꢂC-4), 25.7 (2ꢂC-3), 43.0
(C-2), 43.2 (C-2), 107.7 (C-20), 108.2 (C-60), 111.2 (C-40), 153.8 (C-30),
157.5 (C-10), 164.1 (C-50), 170.0 (C-1), 170.4 (C-1), 191.9 (CHO); HRMS
(ESI/TOF): [MþNa]þ calcd for C17H22O6Na 345.13086, found
345.13110.
(petroleum ether/EtOAc, 10:1); 1H NMR (400 MHz, CDCl3):
d¼0.82
(d, J¼6.2 Hz, 6H, 30-H), 1.34 (s, 3H, 2-CH3), w1.35 (obscured, 1H, 20-
H), w1.35 (obscured, 2H, 10-H), 1.38 (s, 3H, 2-CH3), 1.44 (s, 3H, 4-
CH3), 1.54 (s, 3H, 4-CH3), 3.80 (s, 6H, OCH3), 4.22 (dd, J¼6.4,
5.4 Hz, 1H, 9-H), 6.24 (d, J¼2.3 Hz, 1H, Ar), 6.26 (d, J¼2.3 Hz, 1H, Ar);
4.1.6. 4a-Hydroxy-2,2,4,4-tetramethyl-1,3-dioxo-2,3,4,4a-tetrahy-
dro-1H-xanthene-6,8-diyl bis(3-methylbutanoate) (29). To a 0 ꢁC
cooled suspension of aldehyde 28 (7.0 g, 21.7 mmol) and syncarpic
acid (10) (4.15 g, 22.77 mmol) in EtOH (200 mL), piperidine (0.1 mL,
1.01 mmol) was added. The ice-bath was removed and stirring was
continued for 10 h at room temperature until the reaction mixture
turned to a clear-yellow solution. All volatiles were removed using
a rotavapor. Purification of the resulting yellow oil by flash chro-
matography (petroleum ether/EtOAc, 6:1) provided of xanthene
derivative 29 (7.86 g, 74%) as a yellowish solid. Rf¼0.51 (petroleum
13C NMR (100 MHz, CDCl3):
d
¼22.8 (C-30), 23.6 (C-30), 24.3 (CH3),
24.5 (CH3), 24.6 (CH3), 24.8 (CH3), 25.1 (C-20), 25.4 (C-9), 46.6 (C-10),
47.2 (C-4), 55.4 (OCH3), 55.5 (OCH3), 55.9 (C-2), 92.9, 95.1 (C-5, C-7),
107.8 (C-8a),113.8 (C-9a),152.3 (C-10a),157.9, 159.5 (C-6, C-8), 167.7
(C-4a), 197.5 (C-1), 212.7 (C-3); HRMS (ESI/TOF): [MþNa]þ calcd for
C
23H30O5Na 409.19854, found 409.19848.
4.1.3. 6,8-Dihydroxy-9-isobutyl-2,2,4,4-tetramethyl-4,9-dihydro-1H-
xanthene-1,3(2H)-dione (16). To a solution of dimethyl ether 25
(400 mg, 1.03 mmol) in CH2Cl2 (15 mL) was added dropwise a so-
lution of BBr3 in CH2Cl2 (1 M, 5.2 mL, 5.2 mmol) at ꢀ78 ꢁC. After
complete addition, the dark-red reaction mixture was left to reach
room temperature overnight while stirring. It was quenched with
water (50 mL) and extracted with EtOAc (4ꢂ50 mL). The combined
organic layers were dried over Na2SO4, filtered and concentrated in
vacuo. The crude product was purified by flash chromatography
(petroleum ether/EtOAc, 2:1) to give the dihydroxy-xanthene-
1,3(2H)-dione 16 (260 mg, 70%) as a brownish solid. Its spectral data
matched with the reported ones.13
ether/EtOAc, 4:1); 1H NMR (400 MHz, CDCl3):
d
¼1.04 (d, J¼6.7 Hz,
6H, 4-H), 1.08 (d, J¼6.7 Hz, 6H, 4-H), 1.10 (s, 3H, 40-CH3), 1.37 (s, 3H,
20-CH3), 1.40 (s, 3H, 20-CH3), 1.46 (s, 3H, 40-CH3), 2.23 (qqdd, J¼6.8,
6.8, 6.8, 6.8 Hz, 1H, 3-H), 2.24 (qqdd, J¼6.8, 6.8, 6.8, 6.8 Hz, 1H, 3-H),
2.42 (d, J¼7.1 Hz, 2H, 2-H), 2.53 (d, J¼7.1 Hz, 2H, 2-H), 3.70 (br s, 1H,
OH), 6.69 (d, J¼2.1 Hz, 1H, Ar), 6.80 (d, J¼2.0 Hz, 1H, Ar), 7.78 (s, 1H,
90-H); 13C NMR (100 MHz, CDCl3):
d
¼22.3 (2ꢂC-4), 22.4 (2ꢂC-4),
23.2 (40-CH3), 24.0 (20-CH3), 25.8 (20-CH3), 25.8 (2ꢂC-3), 26.7 (40-
CH3), 43.1 (C-2), 43.2 (C-2), 53.8 (C-40), 54.6 (C-20), 97.8 (C-4a’),
108.6, 110.1 (C-50, C-70), 110.6 (C-8a’), 125.8 (C-90), 126.1 (C-9a’),
149.2 (C-80), 153.3 (C-60), 153.5 (C-10a’), 170.7 (C-1), 171.0 (C-1),
198.2 (C-10), 211.5 (C-30); HRMS (ESI/TOF): [MþNa]þ calcd for
4.1.4. 2,4,6-Trihydroxybenzaldehyde (26). To a cooled (0 ꢁC) solu-
tion of phloroglucinol (13) (20.0 g, 0.159 mol) and DMF (12.2 mL,
0.159 mol) in EtOAc (300 mL), POCl3 (14.83 mL, 0.159 mol) was
added dropwise within 60 min. After complete addition the
resulting suspension was left to stir at room temperature for 6 h.
When full consumption was achieved, the yellow suspension was
poured on ice-water (500 mL), and the two-phase mixture was
stirred vigorously while adding satd. NaOAc solution to it until a pH
of 5e6 was reached. During the addition the solution became dark-
red, then it was extracted with EtOAc (4ꢂ600 mL). The combined
organic layers were washed with satd. NaCl solution (1ꢂ500 mL),
dried over Na2SO4, filtered, and evaporated to dryness. The residue
was recrystallized from water (200 mL) to provide benzaldehyde 26
C27H34O8Na 509.21459, found 509.21506.
4.1.7. 4a-Methoxy-2,2,4,4-tetramethyl-1,3-dioxo-2,3,4,4a-tetrahy-
dro-1H-xanthene-6,8-diyl bis(3-methylbutanoate) (30). To a 0 ꢁC
cooled solution of hemiacetal 29 (50 mg, 0.1 mmol) in MeOH (3 mL)
perchloric acid (60%, one drop, catalytic amount) was added. The
ice-bath was removed and stirring was continued for 4 h at room
temperature until full conversion was observed (TLC control). The
mixture was partitioned between water (10 mL) and Et2O (10 mL).
After separation of the layers, the aqueous layer was extracted with
Et2O (3ꢂ10 mL). The combined organic layers were washed with
satd. NaCl solution (1ꢂ20 mL), dried over MgSO4, filtered and
concentrated in vacuo. On this scale purification was done by
preparative TLC (petroleum ether/EtOAc, 6:1) giving methyl acetal
30 (37 mg, 72%) as an amorphous solid. Rf¼0.61 (petroleum ether/
(17.18 g, 70%) as red crystals. 1H NMR (400 MHz, DMSO-d6):
(s, 2H, 3-H), 9.92 (s,1H, CHO),10.64 (s,1H, OH),11.45 (s, 2H, OH); 13
d
¼5.78
C
NMR (100 MHz, DMSO-d6):
167.2 (C-4), 190.9 (CHO).
d¼94.1 (C-3), 104.5 (C-1), 164.1 (C-2),
EtOAc, 6:1); 1H NMR (400 MHz, CDCl3):
d
¼1.03 (d, J¼6.7 Hz, 6H, 4-
H), 1.04 (s, 3H, 40-CH3), 1.08 (d, J¼6.7 Hz, 6H, 4-H), 1.30, 1.36 (2 s, 3H,
20-CH3), 1.40 (s, 3H, 40-CH3), 2.20 (qqdd, J¼6.8, 6.8, 6.7, 6.7 Hz,1H, 3-
H), 2.27 (qqdd, J¼6.8, 6.8, 6.7, 6.7 Hz, 1H, 3-H), 2.41 (d, J¼7.1 Hz, 2H,
2-H), 2.53 (d, J¼7.1 Hz, 2H, 2-H), 3.03 (s, 3H, OCH3), 6.65 (d,
J¼2.1 Hz, 1H, Ar), 6.77 (dd, J¼2.1, 0.8 Hz, 1H, Ar), 8.00 (d, J¼0.8 Hz,
4.1.5. 4-Formyl-5-hydroxy-1,3-phenylene
bis(3-methylbutanoate)
(28). To a cooled solution (0 ꢁC) of isovaleric acid (27) (11.75 mL,
0.106 mol) in CH2Cl2 (500 mL) was added DMAP (650 mg,
5.32 mmol), followed by the addition of aldehyde 26 (8.2 g,
0.053 mol) in one portion. Subsequently, a solution of DCC (22.5 g,
0.109 mol) in CH2Cl2 (150 mL) was added dropwise over 30 min at
1H, 90-H); 13C NMR (100 MHz, CDCl3):
d
¼22.3 (2ꢂC-4), 22.4 (2ꢂC-
4), 22.5 (40-CH3), 24.5 (20-CH3), 25.8 (20-CH3), 25.8 (2ꢂC-3), 26.4 (40-
CH3), 43.1 (C-2), 43.2 (C-2), 50.9 (OCH3), 54.3 (C-40), 54.8 (C-20),
101.9 (C-4a0), 106.5 (C-70), 109.5 (C-8a0), 109.7 (C-50), 121.6 (C-9a0),
128.0 (C-90), 149.3 (C-80), 153.8 (C-60), 155.9 (C-10a0), 170.5 (C-1),
170.6 (C-1), 198.6 (C-10), 211.0 (C-30); HRMS (ESI/TOF): [MþNa]þ
calcd for C28H36O8Na 523.23024, found 523.23083.
0
ꢁC. The resulting suspension was allowed to stir at room tem-
perature for 6 h. All precipitates were filtered-off and the filtrate
was transferred to a separation funnel together with water
(650 mL). After separation of the layers, the aqueous layer was
extracted with CH2Cl2 (3ꢂ500 mL). The combined organic layers
were washed with satd. NaCl solution (1ꢂ500 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (petroleum ether/EtOAc, 18:1) to
give bis-ester 28 (8.22 g, 48%) as a white solid. Rf¼0.5 (petroleum
4.1.8. 9-Isobutyl-2,2,4,4-tetramethyl-1,3-dioxo-2,3,4,9-tetrahydro-
1H-xanthene-6,8-diyl bis(3-methylbutanoate) (32). A solution of
compound 30 (222 mg, 0.44 mmol) in Et2O (2 mL) and CH2Cl2
(2 mL) was treated with CuI (8 mg, 0.04 mmol) at ꢀ78 ꢁC. The