4.
Experimental section
Et2O–hexane); 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 9.1 Hz,
ACCEPTED MANUSCRIPT
1H), 7.13 (d, J = 9.0 Hz, 1H), 6.97 (d, JH,F = 9.1 Hz, 1H), 6.78
(t, JH,F = 10.9 Hz, 1H), 6.27 – 6.13 (m, 2H), 5.23 – 5.16 (m,
3H), 5.04 (d, J = 10.8 Hz, 1H), 1.57 (s, 6H), 1.56 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 174.3, 166.8 (d, JC,F = 15.4 Hz),
164.3 (dd, JC,F = 15.0, 8.1 Hz), 161.7 (d, JC,F = 15.6 Hz), 158.0
(d, JC,F = 15.9 Hz), 157.4, 151.8, 143.7, 143.5, 135.4, 121.3,
117.2, 114.5, 113.4, 101.1 (d, JC,F = 25.1 Hz), 101.0 (t, JC,F =
24.2 Hz), 84.0, 82.6, 27.4, 27.2; HRMS calc. for C23H22F2O4Na
(M + Na)+ 423.1378, found 423.1377.
General information for chemical purification and
compounds characterization. Reactions were monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm E.
Merck silica gel plates (60F-254) and visualized under UV light
and/or by treatment with a solution of CAM or KMnO4 stain
followed by heating. Preparative thin-layer chromatography
separations were carried out on 0.25 or 0.50 mm E. Merck silica
gel plates (60F-254). Flash column chromatography was
performed on silica gel (Merck Kieselgel 60, 230-400 mesh)
using hexane/ethyl acetate or hexane/ethyl ether as standard
eluents. 1H NMR and 13C NMR spectra were recorded on a 400
or 500 MHz Varian or a 500 JEOL instrument. Chemical shifts
(δ) are quoted in parts per million (ppm) referenced to the
appropriate residual undeuterated solvent peak, with the
abbreviations s, bs, d, t, q, dd, m, denoting singlet, broad singlet,
doublet, triplet, quartet, doublet of doublets, multiplet,
respectively. J is a coupling constant given in Hertz (Hz). High
resolution mass spectra (HRMS) were recorded on a VG7070HS
mass spectrometer under chemical ionization (CI) conditions, on
General procedure for Claisen/Diels-Alder reaction. A
solution of allylated compound (1 equiv) in DMF was heated at
120 °C. The onset of a yellow color indicated the formation of
the caged xanthone. The reaction progress was monitored by
TLC. Upon completion, the yellow reaction mixture was cooled
to room temperature and the solvent was removed under vacuum
by rotary evaporation. The crude material was purified by flash
column chromatography (silica, EtOAc or Et2O in hexane) to
yield the caged xanthone.
8-hydroxy-10-(methoxymethoxy)-2,2-dimethyl-3a-(3-
methylbut-2-en-1-yl)-1,2-dihydro-1,5-methanofuro[2,3-
d]xanthene-4,7(3aH,5H)-dione (12): 69%, yellow solid. Rf =
0.24 (25% EtOAc–hexane); 1H NMR (400 MHz, CDCl3) δ 12.38
(s, 1H), 7.43 (d, J = 7.1 Hz, 1H), 6.20 (d, J = 2.1 Hz, 1H), 6.17
(d, J = 2.1 Hz, 1H), 5.19 (s, 2H), 4.45 – 4.41 (m, 1H), 3.51 – 3.48
(m, 1H), 3.47 (s, 3H), 2.61 (d, J = 8.8 Hz, 2H), 2.43 (d, J = 9.6
Hz, 1H), 2.33 (dd, J = 13.6, 4.7 Hz, 1H), 1.68 (s, 3H), 1.38 (s,
3H), 1.32 – 1.31 (m, 1H), 1.29 (s, 3H), 1.09 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 203.2, 179.7, 166.1, 164.9, 161.1, 135.4,
134.2, 133.9, 118.5, 101.8, 97.2, 95.7, 94.1, 90.4, 84.6, 83.7,
56.7, 49.0, 47.0, 30.6, 29.9, 29.3, 25.8, 25.3, 17.0; HRMS calc.
for C25H28O7Na (M + Na)+ 463.1727, found 463.1729.
a
VG ZAB-ZSE mass spectrometer under fast atom
bombardment (FAB) conditions, or on a Bruker microTOF mass
spectrometer under electrospray ionization (ESI) conditions.
Specific information on the synthetic/analytical protocols as well
as copies of the spectroscopic data for all compounds are shown
in the Supporting Information.
General
procedure
for
Pd(0)-catalyzed
reverse
prenylation. A solution of starting xanthone (1 equiv) in
anhydrous THF (approximate 0.2 mM) was degassed by argon
and was placed in an ice bath. To this homogeneous solution was
added tert-butyl 2-methylbut-3-en-2-yl carbonate (9) or bis(2-
methylbut-3-en-2-yl) carbonate (30) (10 equiv) via syringe,
followed by 10% mol Pd(PPh3)4. The mixture was stirred under
argon at 0 to 5 °C and the reaction progress was monitored by
TLC. Upon completion the reaction mixture was quenched with
water and extracted with EtOAc. The combined organic layers
were dried over MgSO4, filtered and concentrated by rotary
evaporation. The crude material was purified through flash
column chromatography (silica, EtOAc in hexane) to yield di-
allylated product.
8,11-dimethoxy-2,2-dimethyl-3a-(3-methylbut-2-en-1-yl)-
1,2-dihydro-1,5-methanofuro[2,3-d]xanthene-4,7(3aH,5H)-
dione (23): 88%, yellow solid. Rf = 0.40 (50% EtOAc–hexane);
1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 6.9 Hz, 1H), 7.04 (d, J
= 9.0 Hz, 1H), 6.47 (d, J = 9.0 Hz, 1H), 4.52 (t, J = 7.9 Hz, 1H),
3.88 (s, 3H), 3.85 (s, 3H), 3.44 (dd, J = 7.0, 4.2 Hz 1H), 2.61 (d, J
= 9.0 Hz, 2H), 2.40 (d, J = 9.6 Hz, 1H), 2.32 (dd, J = 13.5, 4.6
Hz, 1H), 1.78 (s, 3H), 1.39 (s, 3H), 1.30 (s, 3H), 1.30 – 1.27 (m,
1H), 1.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 203.3, 176.1,
154.3, 151.2, 143.0, 136.4, 132.5, 118.7, 118.5, 110.9, 102.8,
90.0, 84.5, 83.6, 57.0, 56.4, 48.5, 46.7, 29.5, 29.1, 29.0, 25.6,
25.4, 16.9; HRMS calc. for C25H28O6Na (M + Na)+, 447.1778
found 447.1776.
1-hydroxy-3-(methoxymethoxy)-5,6-bis((2-methylbut-3-en-
2-yl)oxy)-9H-xanthen-9-one (10): 89%, a colorless oil. Rf =
0.57 (25% EtOAc–hexane); H NMR (400 MHz, CDCl3) δ 7.82
1
(d, J = 9.0 Hz, 1H), 7.11 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 2.2 Hz,
1H), 6.46 (d, J = 2.2 Hz, 1H), 6.29 – 6.14 (m, 2H), 5.25 (s, 2H),
5.21 – 5.15 (m, 3H), 5.03 (d, J = 10.9 Hz, 1H), 3.51 (s, 3H), 1.57
(s, 9H), 1.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 180.9,
164.0, 163.5, 157.5, 152.5, 143.7, 143.5, 120.4, 116.8, 114.4,
113.4, 98.8, 94.9, 94.4, 83.9, 82.5, 56.7, 27.4, 27.1; HRMS calc.
for C25H29O7 (M + H)+ 441.1988, found 441.1907.
8-hydroxy-11-methoxy-2,2-dimethyl-3a-(3-methylbut-2-en-
1-yl)-1,2-dihydro-1,5-methanofuro[2,3-d]xanthene-
4,7(3aH,5H)-dione (24): 72%, yellow solid. Rf = 0.50 (50%
1
EtOAc–hexane); H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H),
7.49 (d, J = 7.0 Hz, 1H), 7.12 (dd, J = 8.9, 1.8 Hz, 1H), 6.47 (dd,
J = 8.9, 1.8 Hz, 1H), 4.43 – 4.39 (m, 1H), 3.84 (s, 3H), 3.55 –
3.52 (m, 1H), 2.64 (d, J = 9.5 Hz, 2H), 2.47 (d, J = 9.6 Hz, 1H),
2.36 (dd, J = 13.6, 4.2 Hz, 1H), 1.78 (s, 3H), 1.36 (s, 3H), 1.31 (s,
4H), 1.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.8, 181.6,
156.2, 149.5, 140.7, 135.4, 135.0, 134.0, 124.1, 119.0, 107.6,
106.5, 90.4, 84.7, 84.0, 57.9, 49.0, 47.1, 29.8, 29.4, 29.3, 25.7,
24.9, 16.8; HRMS calcd for [C24H26O6Na]+ (M + Na)+ 433.1622,
found 433.1623.
1,4-dimethoxy-5,6-bis((2-methylbut-3-en-2-yl)oxy)-9H-
xanthen-9-one (22): 77%, a colorless oil. Rf = 0.43 (50%
1
EtOAc–hexane); H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 9.1
Hz, 1H), 7.15 (d, J = 8.9 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 6.69
(d, J = 9.0 Hz, 1H), 6.41 (dd, J = 10.7, 17.6 Hz, 1H), 6.19 (dd, J =
10.8, 17.6 Hz, 1H), 5.21 – 5.13 (m, 3H), 4.97 (d, J = 10.9 Hz,
1H), 3.96 (s, 3H), 3.95 (s, 3H), 1.61 (s, 6H), 1.55 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 176.4, 156.2, 153.6, 151.2, 148.0,
143.8, 143.7, 142.6, 135.8, 120.8, 117.2, 116.2, 113.9, 113.0,
104.2, 83.9, 82.0, 56.7, 56.5, 27.1, 26.7; HRMS calc. for
C25H28O6Na (M + Na)+, 447.1778 found 447.1777.
8,10-difluoro-2,2-dimethyl-3a-(3-methylbut-2-en-1-yl)-1,2-
dihydro-1,5-methanofuro[2,3-d]xanthene-4,7(3aH,5H)-dione
1
(32): 64% yellow solid; Rf = 0.38 (50% Et2O–hexane); H NMR
1,3-difluoro-5,6-bis((2-methylbut-3-en-2-yl)oxy)-9H-
(400 MHz, CDCl3) δ 7.42 (d, J = 6.9 Hz, 1H), 6.60 (d, JH,F = 9.5
xanthen-9-one (31): 100%, a colorless oil. Rf = 0.56 (33 %
Hz, 1H), 6.53 (t, JH,F = 10.9 Hz, 1H), 4.46 (t, J = 6.9 Hz, 1H),