3456 J . Org. Chem., Vol. 61, No. 10, 1996
Charlton et al.
Gen er a l P r oced u r e for th e Syn th esis of Ar yln a p h th a -
len es. Glacial acetic acid was added to a mixture of hydroxy-
acetal 16, 17, or 18 and dienophile in a minimum amount of
solvent and the temperature of the mixture quickly brought
up to 140 °C. The mixture was heated for 1-20 h, depending
on the type of dienophile used. The cooled mixture was diluted
with CH2Cl2 (10 mL), washed with 5% sodium bicarbonate
solution (3 × 10 mL), dried (MgSO4), and concentrated under
vacuum.
Sch em e 6
Lign a n An a logu e 6. Acetal 16 (0.16 g, 0.41 mmol),
DLADC (0.10 g, 0.35 mmol),2 CH2Cl2 (0.3 mL), and acetic acid
(0.2 mL) were heated at 140 °C for 1 h and worked up as above.
Chromatography of the crude product using 25-35% EtOAc/
hexanes afforded a colorless solid (0.18 g, 85%): mp 69-72
°C, identical to that previously reported.2
kcal/mol barrier for 24 with those in Table 3 would
indicate that the 8-methoxy substituent alone is insuf-
ficient to give rise to stable atropisomers. The calculated
barrier for prostalidin B (23) is higher than any of the
calculated barriers found in Table 3 and may indicate
the possibility of it forming stable atropisomers at room
temperature. Investigation of this compound and others
is ongoing.
Lign a n An a logu e 13. Acetal 17 (0.247 g, 0.69 mmol),
DEADC (0.119 g, 0.70 mmol), CH2Cl2 (0.3 mL), and acetic acid
(0.2 mL) were heated at 140 °C for 1 h. After work-up as
above, the crude product was recrystallized from CH2Cl2/
hexanes to afford a colorless solid (0.28 g, 80%): mp 152-153
°C; IR (CH2Cl2) 3303 (OH), 1730, 1658 cm-1; 1H NMR (DMSO-
d6) δ 0.95 (t, 3H, J ) 7.09), 1.26 (t, 3H, J ) 7.09), 3.65 (s, 3H),
3.93 (s, 3H), 3.95 (q, 2H, J ) 7.09), 4.34 (q, 2H, J ) 7.09), 6.09
(AB, 2H, ∆δ ) 10.17), 6.68 (dd, 1H, J ) 7.9, 1.63), 6.72 (s,
1H), 6.78 (d, 1H, J ) 1.52), 7.00 (d, 1H, J ) 7.91), 7.64 (s,
1H), 11.95 (s, 1H); 13C NMR (CDCl3) δ 13.8 (CH3), 13.9 (CH3),
55.8 (CH3) 56.1 (CH3), 60.8 (CH2), 61.9 (CH2), 101.0 (CH2),
101.1 (C), 102.8 (CH), 105.7 (CH), 107.9 (CH), 111.4 (CH),
119.8 (C), 124.3 (CH), 127.4 (C), 129.0 (C), 130.6 (C), 132.2
(C), 147.0 (C), 147.2 (C), 149.6 (C), 152.3 (C), 159.6 (C), 168.7
(CO), 170.2 (CO); mass spectrum m/ z (relative intensity) 468
(M+, 23), 422 (19), 394 (88), 149 (75); HRMS calcd for C25H24O9
468.1420, found 468.1409.
An h yd r id e 19. Acetal 17 (0.30 g, 0.83 mmol), maleic
anhydride (83 mg, 0.85 mmol), acetic anhydride (0.3 mL), CH2-
Cl2 (0.3 mL), and glacial acetic acid (0.2 mL) were heated at
140 °C for 20 h and worked up as above to give a yellow oily
solid (0.35 g) which was used directly in the next reduction
reaction without purification. 1H NMR (CDCl3) δ 3.86 (s, 3H),
4.09 (s, 3H), 6.10 (AB, 2H, ∆δ ) 10.69, J ) 1.36), 6.86 (m,
1H), 6.88 (s, 1H), 7.00 (dd, 1H, J ) 7.71, 0.58), 7.21 (s, 1H),
7.36 (s, 1H), 8.33 (s, 1H).
Exp er im en ta l Section
Gen er a l Meth od s. The general experimental procedures
and instrumentation have been described previously.17 The
instrument used to perform the dynamic NMR studies was a
Bruker AM 300 FT spectrometer. Temperature was refer-
enced to the known temperature dependent spectra of metha-
nol (at low temperature) and ethylene glycol (at high temper-
ature) and was accurate to (1 °C.
Hyd r oxya ceta ls 16 a n d 17. 2-Bromo-5,6-dimethoxyben-
zaldehyde (1.32 g, 5.40 mmol), ethylene glycol (0.493 g, 7.95
mmol), and p-TsOH.5H2O (90 mg) were refluxed in benzene
(75 mL) under a Dean-Stark trap. After water ceased to
distill (ca. 3 h), the solution was reduced to 10 mL by
evaporation, cooled to room temperature, and then filtered
through a short column of anhydrous silica gel, eluting with
50% EtOAc/hexanes (ca. 50 mL). Evaporation of the solvents
gave a solid (1.56 g, 100% yield) which was very susceptible
to hydrolysis. The crude acetal, 14, was redissolved in dry
THF (40 mL) under nitrogen, and cooled to -78 °C, and n-BuLi
(2.45 M in hexanes, 2.30 mL, 5.6 mmol) was added dropwise
over 5 min. The mixture was stirred for another 15 min,
followed by the dropwise addition of 3,4-dimethoxybenzalde-
hyde (0.85 g, 5.11 mmol) or 3,4-(methylenedioxy)benzaldehyde
(0.77 g, 5.11 mmol), in THF (10 mL). After stirring for 30 min,
the solution was gradually warmed to room temperature and
was stirred for another 2.5 h, followed by the addition of H2O
(30 mL). The resulting mixture was extracted with Et2O (3 ×
30 mL), dried (MgSO4), and concentrated to give a colorless
solid (1.90 g and 1.80 g, respectively, 100% and 98%) which
turned green upon standing at room temperature. These crude
products were not further purified or characterized, but were
used immediately in the following Diels-Alder reactions.
Hyd r oxya ceta l 18. The general procedure for preparation
of this compound has been published by Rodrigo.13 The
ethylene glycol acetal of 3,4-dimethoxybenzaldehyde was
prepared as described above for acetal 14, by treating 3,4-
dimethoxybenzaldehyde (0.81 g, 5.4 mmol) with ethylene glycol
and p-TsOH in benzene. The unstable crude acetal 15 was
immediately dissolved in dry THF (40 mL), followed by
dropwise addition of n-BuLi (2.45 M in hexanes, 2.30 mL, 5.6
mmol) under nitrogen. The mixture was stirred for 15 min
and then at ice temperature for 20 min. The mixture was
again cooled to -78 °C, followed by dropwise addition of 3,4-
(methylenedioxy)benzaldehyde (0.77 g, 5.11 mmol) in THF (10
mL). The resulting orange solution was stirred at that
temperature for 20 min and then at room temperature for 1.5
h. The workup procedure was similar to that described for
the preparation of hydroxyacetals 16 and 17, and the brown-
green residue (1.75 g, 94%) isolated was also employed in the
following reactions without further purification or character-
ization.
Lign a n An a logu e 12. Acetal 18 (0.500 g, 1.45 mmol),
DLADC (0.411 g, 1.44 mmol), CH2Cl2 (0.5 mL) and acetic acid
(0.6 mL) were heated at 140 °C for 1.5 h. The foamy brown
solid obtained after workup was recrystallized from methanol
to afford light yellow crystals (0.72 g, 88%): mp 150-151 °C;
[R]20 +34.1° (c 0.47, CHCl3); IR (CH2Cl2) 3370 (OH), 1746,
D
1660 cm-1; 1H NMR (DMSO-d6) δ 1.01 (d, 3H, J ) 6.81), 1.06
(d, 3H, J ) 6.81), 1.45 (d, 3H, J ) 6.98), 1.46 (d, 3H, J ) 6.98),
3.59 (s, 6H), 3.69 (s, 3H), 3.70 (s, 3H), 4.99 (q, 2H, J ) 6.89),
5.35 (q, 1H, J ) 6.98), 5.37 (q, 1H, J ) 6.98), 5.91-6.07 (m,
8H), 6.62-6.89 (m, 6H), 7.46 (d, 2H, J ) 8.82), 8.08 (d, 2H, J
) 8.82), 11.78 (br s, 2H); 13C NMR (CDCl3) δ 16.4 (CH3), 16.5
(CH3), 16.8 (CH3), 17.1 (CH3), 52.2 (2 × CH3), 52.5 (2 × CH3),
69.5 (CH), 69.6 (CH), 70.2 (2 × CH), 99.6 (C), 99.7 (C), 100.9
(2 × CH2), 101.6 (2 × CH2), 107.0 (2 × CH), 110.7 (3 × CH),
111.6 (CH), 111.8 (CH), 119.8 (CH), 120.9 (2 × C), 121.67 (C),
121.74 (C), 124.3 (CH), 124.5 (CH), 125.0 (C), 125.1 (C), 129.88
(C), 129.90 (C), 130.8 (2 × C), 130.9 (2 × C), 142.56 (C), 142.60
(C), 146.4 (2 × C), 147.0 (2 × C), 148.8 (2 × C), 161.9 (CO),
162.0 (CO), 166.78 (CO), 166.80 (CO), 168.83 (CO), 168.9 (CO),
170.2 (CO), 170.4 (CO); mass spectrum m/ z (relative intensity)
568 (M+, 10), 464 (10), 378 (91), 306 (17); HRMS calcd for
C28H24O13 568.1216, found 568.1241.
An h yd r id e 20. Acetal 18 (0.50 g, 1.45 mmol), maleic
anhydride (0.142 g, 1.45 mmol), acetic anhydride (0.5 mL),
CH2Cl2 (0.5 mL), and acetic acid (0.2 mL) were heated at 140
°C for 24 h. A yellow solid (0.44 g, 85%) was obtained after
workup and was used in the next reaction without further
purification. 1H NMR (CDCl3) δ 6.00 (AB, 2H, ∆δ ) 6.26, J )
1.24), 6.07 (AB, 2H, ∆δ ) 10.55, J ) 1.36), 6.82 (m, 1H), 6.84
(s, 1H), 6.89 (dd, 1H, J ) 7.46, 0.9), 7.44 (d, 1H, J ) 8.56),
7.75 (d, 1H, J ) 8.56), 8.43 (s, 1H).
J u sticid in A (7). This compound was synthesized by
methylation of diphyllin (4-O-demethyljusticidn A). Diphyllin
(17) Maddaford, S. P.; Charlton, J . L. J . Org. Chem. 1993, 58, 4132-
4138.