A convenient synthesis of dengibsin

Full text of DOI:10.1021/jo9601369

3920
J . Org. Chem. 1996, 61, 3920-3922
Sch em e 1a
A Con ven ien t Syn th esis of Den gibsin
Winton D. J ones, J r.,* and Fred L. Ciske
Hoechst Marion Roussel, Inc., 2110 East Galbraith Road
Cincinnati, Ohio 45215
Received J anuary 22, 1996
Dengibsin is a natural product isolated from the Indian
orchid Dendrobium gibsonii Lindl.1 A review of the
literature revealed total syntheses by Sargent2 and
Snieckus et al.3 (Scheme 1). Evaluation of these synthe-
ses showed they were unsuitable for the preparation of
gram quantities of 13. Both approaches used fluorenone
7 as a common intermediate. Sargent utilized a Friedel-
Crafts closure of intermediate 1a to give dibenzopyran 2
and fluorenone 3 in 38% and 15% yield, respectively. The
minor product 3 was converted in three steps to fluo-
renone 7 in low overall yield. Snieckus avoided the
problem of dibenzopyran formation4 by the elegant use
of a remote anionic Fries rearrangement of carbamate 4
to give 5.3 Two additional steps gave the amide 6, which
underwent an anionic Friedel-Crafts reaction to give 7.
While an improvement over the previous synthesis, this
process required eight steps to obtain intermediate 7 and
ultimately produced dengibsin 13 in only12% overall
yield.
a
(a) TFAA, rt, 6.5 h; (b) 3 equiv of LDA, THF, recycle; (c) (1)
MeI, K2CO3; (2) TFA, reflux; (d) 2.5 equiv of LDA, THF, 0 °C to
rt.
In this note we describe a new synthesis of dengibsin
in which the conversion of acid 1b to amide 6 is the key
step to prepare 13 in high overall yield (Scheme 2). For
the efficient construction of the biphenyl amide 6, we
chose the coupling of an R-alkoxyoxazoline with a suitably
substituted aryl Grignard reagent.5 Thus, alkylation of
phenol 86 with isopropyl iodide using K2CO3 gave aryl
bromide 9. Reaction of the Grignard reagent derived
from 9 with oxazoline 102,7 at 50 °C in THF gave the
biphenyl derivative 11. This was converted to the
quaternary salt 12 using MeI in DMSO. Hydrolysis of
12 under basic conditions gave acid 1b. We thought that
intermediate amide 6 could be prepared in high yield
from acid 1b by using a reagent that would avoid
dibenzopyran formation.4 (Benzotriazol-1-yloxy)tris(pyr-
rolidino)phosphonium hexafluorophosphate (PyBOP)8,9
when used as the coupling reagent produced the expected
amide with no trace of the unwanted dibenzopyran.
Thus, acid 1b was condensed with diethylamine at
ambient temperature using PyBOP and DIEA to give the
requisite amide 6 in 85% yield. As previously reported,2
ring closure of 6 with LDA in THF gave 7, which was
deprotected to give dengibsin 13.
In conclusion, we have developed a convenient six-step
route to dengibsin in 26% overall yield from readily
prepared intermediates.
Exp er im en ta l Section
Melting points are uncorrected. 1H NMR and 13C NMR
spectra were obtained at 300 and 75 MHz, respectively. Chemi-
cal shifts are reported in δ values relative to Me4Si (δ ) 0.00)
as an internal standard for 1H NMR spectra.
1-Br om o-2-m eth oxy-4-(1-m eth yleth oxy)ben zen e (9). To
a stirred suspension of 86 (2.03 g, 10 mmol) and K2CO3 (1.38 g,
10 mmol) in 2-butanone (70 mL) at ambient temperature under
argon was added dropwise isopropyl iodide (2.21 g, 13.3 mmol).
The resulting mixture was heated and stirred under reflux for
17 h. The mixture was allowed to cool to ambient temperature,
then filtered, and concentrated by evaporation of solvent. The
residue was partitioned between Et2O and H2O. The Et2O layer
was extracted with 5% NaOH (2 × 50 mL), washed with brine,
and dried over MgSO4. The solvent was evaporated and the
resulting residue purified by flash chromatography10 (5% EtOAc/
hexane) to afford the desired compound as a pale yellow oil: 2.13
g (87%); UV (MeOH) λmax ) 283 nm, ꢀ ) 9510; 1H NMR (CDCl3)
δ 7.38 (δ, 1H, J ) 8.6 Hz), 6.47 (1H, d, J ) 2.7 Hz), 6.38 (1H,
dd, J ) 8.5, 2.7 Hz), 4.5 (1H, hept, J ) 6.3 Hz), 3.85 (3H, s),
1.33 (6H, d, J ) 6.3 Hz); 13C NMR (CDCl3) δ 158.4, 156.6, 133.0,
(1) (a) Talapatra, S. K.; Bose, S.; Malik, A. K.; Talapatra, B.
Tetrahedron 1985, 41, 2765-2769. (b) Talapatra, S. K.; Chakraborty,
S.; Bose, S.; Talapatra, B. Ind. J . Chem. 1988, 27B, 250-252.
(2) (a) Sargent, M. V. J . Chem Soc., Perkin Trans. 1 1987, 2553-
2563. (b) To the best of our knowledge, compound 1b has not been
previously reported.
(3) (a) Wang, W.; Snieckus, V. J . Org. Chem. 1992, 57, 424-426.
(b) Fu, J .-M.; Zhao, B.-P.; Sharp, M. J .; Snieckus, V. Can. J . Chem.
1994, 72, 227-236.
(4) Biphenyl carboxylic acids with ether substituents in the 2′
position have been reported to give dibenzopyrans when treated with
TFAA and oxalyl chloride.2
107.7, 102.0, 101.8, 70.3, 56.0, 21.9. Anal. Calcd for C10H13
BrO2: C, 49.00; H, 5.35. Found: C, 48.87; H, 5.12.
-
4,5-Dih ydr o-2-[2,3-bis(1-m eth yleth oxy)-1-ph en yl]-4,4-dim -
eth yloxa zole (10). NaH (8.25 g, 60%, 0.205 mol) was added
portionwise to a stirred solution of 2-amino-2-methylpropanol
(9) PyBOP has the structure shown below and can be purchased
from Nova Biochem, San Diego, CA.
(5) Gant, T. A.; Meyers, A. I. Tetrahedron 1994, 50, 2297-2360.
(6) Bos, M. E.; Wulff, W. D.; Miller, R. A.; Chamberlin, S.; Brandvold,
T. A. J . Am. Chem Soc. 1991, 113, 9293-9319.
(7) (a) The published procedure of Sargent (ref 2) was modified (see
the Experimental Section). (b) Dodd, J . H.; Guan, J .; Schwender C. F.
Synth. Commun. 1993, 23, 1003-1008.
(8) (a) Coste, J .; Le- Nguyen, D.; Castro, B. Tetrahedron Lett. 1990,
31, 205-208. (b) Frerot, E.; Coste, J .; Pantaloni, A.; Dufour, M.-N.;
J ouin, P. Tetrahedron 1991, 47, 259-270.
(10) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
S0022-3263(96)00136-3 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 11, 1996 3921
Sch em e 2a
raphy (40% EtOAc/hexane) to give 11 as a pale yellow oil: 11.34
g (81%); 1H NMR (CDCl3) δ 7.32 (1H, dd, J ) 7.8, 1.3 Hz), 7.28
(1H, dd, J ) 8.0, 7.8 Hz), 7.02 (1H, dd, J ) 8.0, 1.2 Hz), 7.00 (d,
1H J ) 8.8, 2.4 Hz), 6.47 (1H, dd, J ) 7.0, 2.3 Hz), 6.46 (1H, d,
J ) 2.4 Hz), 4.58 (1H, sept, J ) 6.1 Hz), 4.29 (1H, sept, J ) 6.2
Hz), 3.74 (1H, d, J ) 8.0 Hz), 3.69 (3H, s), 3.62 (1H, d, J ) 8.1
Hz), 1.36-1.35 (6H, m), 1.19-1.18 (6H, m), 1.12-1.11 (6H, m);11
13C NMR (CDCl3) δ 163.6, 158.2, 155.9, 131.2, 131.0, 129.3,
127.7, 122.1, 119.0, 117.6, 105.7, 110.1, 79.3, 71.5, 69.9, 67.0,
55.4, 28.0, 22.1, 22.0, 21.9. Anal. Calcd for C24H31NO4: C, 72.52;
H, 7.86; N, 3.52. Found: C, 72.82; H, 8.07; N, 3.52.
4,5-Dih yd r o-2-[2′-m eth oxy-4′,6-bis(1-m eth yleth oxy)[1,1′-
bip h en yl]-2-yl]-3,4,4-tr im eth yloxa zoliu m Iod id e (12). To a
stirred solution of 11 (5.80 g, 14.6 mmol) in dry DMSO12 (30
mL) was added MeI (12.42 g, 87.5 mmol) at ambient tempera-
ture. The resulting mixture was stirred overnight and diluted
with dry Et2O. The precipitate was removed by filtration. The
solid was triturated with CHCl3 (400 mL) and filtered. Evapo-
ration of the filtrate followed by recrystallization from MeOH/
EtOAc gave 12 as a white solid: 7.40 g (94%); mp 213-214 °C;
1H NMR (CDCl3) δ 7.8 (1H, dd, J ) 8.0, 1.1 Hz), 7.47 (1H, dd, J
) 8.0, 8.0 Hz), 7.18 (1H, br d, J ) 8.2 Hz), 6.94 (1H, d, J ) 8.4
Hz), 6.52 (1H, dd, J ) 8.4, 2.3 Hz), 6.47 (1H, d, J ) 2.3 Hz),
5.09 (1H, d, J ) 9.5 Hz), 4.85 (1H, d, J ) 9.4 Hz), 4.57 (1H,
sept, J ) 6.2 Hz), 4.44 (1H, sept, J ) 6.0 Hz), 3.68 (3H, s), 2.87
(3H, s), 1.63 (3H, s), 1.33-1.31 (6H, m), 1.28 (3H, s), 1.16-1.15
(6H, m);11 13C (CDCl3) δ 172.8, 159.8, 157.6, 155.9, 131.9, 128.1,
122.5, 122.4, 120.5, 118.9, 114.9, 106.4, 100.5, 82.3, 71.2, 70.0,
67.57, 55.7, 30.36, 24.2, 23.4, 21.9, 21.8, 21.7, 21.6. Anal. Calcd
for C25H34NO4: C, 55.66; H, 6.35; N, 2.60. Found: C, 55.82; H,
6.42; N, 2.55.
2′-Meth oxy-4′,6-bis(1-m eth yleth oxy)[1,1′-biph en yl]-2-car -
boxylic Acid (1b). Compound 12 (13.2 g, 24.5 mmol) was
heated and stirred under reflux overnight in a mixture of 20%
aqueous NaOH /MeOH (1/1, 280 mL). The reaction was evapo-
rated until turbid and diluted with H2O (300 mL). The solution
was acidified with concentrated HCl, and the precipitated acid
was extracted into CH2Cl2. Evaporation of the solvent gave a
glass. Crystallization of the glass from cyclohexane gave 1b as
a white solid: 7.10 g (84%); mp 118-120 °C; IR (KBr) 1697
a
(a) K2CO3, i-PrI, 2-butanone; (b) Mg, THF, 9, 50 °C; (c) MeI,
DMSO, rt, 20 h; (d) (1) 20% NaOH, MeOH, ∆; (2) 12 M HCl; (e)
PyBOP, CH2Cl2, Et2NH, DIEA; (f) 4.1 equiv of LDA, THF, -50 °C
to rt, 48 h; (g) BCl3, CH2Cl2, 0 °C to rt.
1
(CdO), 1674 (CdO); H NMR (CDCl3) δ 7.52 (1H, dd, J ) 7.7,
(17.52 g, 0.196 mol) in dry THF (200 mL). The mixture was
stirred at ambient temperature for 1 h. To this solution was
added methyl 2,3-diisopropoxybenzoate2 (24.82 g, 0.098 mol)
dissolved in THF (50 mL). The mixture was stirred overnight
under argon, quenched with H2O (4 mL), and concentrated by
evaporation of solvent. The residue was dissolved in CH2Cl2,
extracted with H2O, washed with brine, and dried over MgSO4.
Filtration and evaporation of solvent gave 33.3 g of a yellow
liquid. To this crude product dissolved in CH2Cl2 (30 mL) was
added dropwise SOCl2 (19 mL, 0.37 mol) at 0-5 °C. Following
the addition the reaction mixture was allowed to warm to
ambient temperature and stirred for 1.5 h. The mixture was
diluted with EtOAc (300 mL) and poured into ice water (500
mL), and the aqueous layer was separated and neutralized with
solid K2CO3 to pH 9, and then the oily precipitate was extracted
into EtOAc. The EtOAc was washed with brine, dried with
MgSO4, and filtered. The solvent was evaporated, and final
traces of solvent were removed under high vacuum to give 102
as a yellow liquid: 23.6 g (83%) overall; 1H NMR (CDCl3) δ 7.29-
7.27 (1H, m), 6.99-6.98 (2H, m), 4.55 (1H, sept, J ) 6.1 Hz),
4.44 (1H, sept, J ) 6.1 Hz), 4.09 (2H, s), 1.38 (6H, s), 1.31 (3H,
d, J ) 6.1 Hz), 1.27 (6H, d, J ) 6.1 Hz).
4,5-Dih yd r o-2-[2′-m eth oxy-4′,6-bis(1-m eth yleth oxy)[1,1′-
bip h en yl]-2-yl]-4,4-d im eth yloxa zole (11). To a stirred sus-
pension of Mg (0.917 g, 37.7 mmol), a crystal of I2, and 3 drops
of ethylene dibromide was added dropwise 10 mL of a solution
of 9 (8.51 g, 34.7 mmol) dissolved in THF (30 mL). The mixture
was warmed to 40 °C, and the remainder of the solution of 9
was added. After the reaction moderated, the mixture was
heated at 50 °C for 40 min. To this solution was added oxazoline
102 (11.27 g, 38.0 mmol) in THF (30 mL) dropwise at ambient
temperature. The reaction mixture warmed 10 °C during the
addition. The reaction mixture was heated and stirred at 50
°C overnight. The mixture was chilled in an ice bath and
quenched with saturated NH4Cl. The THF layer was washed
with brine, dried over MgSO4, and filtered. The solvent was
evaporated, and the residue was purified by flash chromatog-
1.2 Hz), 7.30 (1H, dd, J ) 8.0, 8.0 Hz), 7.13 (1H, dd, J ) 8.3, 1.2
Hz), 7.06 (1H, d, J ) 8.3 Hz), 6.56 (1H, dd, J ) 8.4, 2.4 Hz),
6.46 (1H, J ) 2.3 Hz), 4.59 (1H, sept, J ) 6.1 Hz), 4.26 (1H,
sept, J ) 6.3 Hz), 3.66 (3H, s), 1.37 (6H, J ) 6.2 Hz), 1.15 (3H,
d, J ) 6.1 Hz), 1.08 (3H, d, J ) 6.0 Hz); 13C NMR (CDCl3) δ
171.8, 158.7, 157.7, 156.1, 132.4, 131.6, 129.6, 127.8, 122.6, 119.9,
117.4, 105.9, 100.2, 71.9, 69.9, 55.3, 22.2, 22.1, 21.9, 21.9. Anal.
Calcd for C20H24O5: C, 69.75; H, 7.02. Found: C, 69.83; H, 6.90.
N,N-Dieth yl-2′-m eth oxy-4′,6-bis(1-m eth yleth oxy)[1,1′-bi-
p h en yl]-2-ca r boxa m id e (6). To a mixture of 1b (3.40 g, 9.9
mmol), PyBOP9 (5.15 g, 9.9 mmol), and Et2NH (0.88 g, 12.1
mmol) in CH2Cl2 (30 mL) was added N,N-diisopropylethylamine
(2.82 g, 21.8 mmol). The resulting mixture was stirred overnight
under argon. The solvent was evaporated, and the residue was
dissolved in EtOAc (250 mL). The EtOAc solution was extracted
with 5% HCl (3 × 70 mL), washed with brine, extracted with
NaHCO3 (3 × 70 mL), and dried over MgSO4. Filtration and
evaporation of solvent gave a light brown oil. The oil was
purified by flash chromatography (40% EtOAc/hexane), affording
the desired amide as a solid. The solid was recrystallized from
hexane (50 mL), giving 6 as a white solid: 3.35 g (85%); mp 73-
74 °C; IR (neat) 1629 cm-1 (C dO); 1H NMR (CDCl3) δ 7.28 (1H,
dd, J ) 8.0, 8.0 Hz), 7.15 (1H, d, J ) 8.2 Hz), 6.92 (1H, d, J )
8.0 Hz), 6.92 (1H, d, J ) 8.0 Hz), 6.46 (1H, dd, J ) 8.2, 2.3 Hz),
6.43 (1H, d, J ) 2.1 Hz), 4.55 (1H, sept, J ) 6.1 Hz), 4.32 (1H,
sept, J ) 6.1 Hz), 3.77 (1H, m), 3.68 (3H, s), 3.19 (1H, m), 2.76
(1H, m), 2.63 (1H, m), 1.3-1.31 (6H, m), 1.18 (3H, d, J ) 6.1
Hz), 1.09 (3H, d, J ) 6.0 Hz), 0.84 (3H, t, J ) 7.1 Hz), 0.67 (3H,
t, J ) 7.2 Hz); 13C NMR (CDCl3) δ 170.0, 158.5, 156.0, 139.4,
132.3, 128.4, 126.0, 118.2, 117.5, 114.7, 105.5, 100.0, 71.1, 69.8,
55.1, 41.6, 37.6, 22.2, 22.1, 21.9, 21.7, 13.7, 11.8. Anal. Calcd
(11) (a) A number of these compounds may exist as mixtures of
atropisomers. (b) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 977-991.
(12) Meyers, A. I.; Slade, J . J . Org. Chem. 1980, 45, 2785-2791.

3922 J . Org. Chem., Vol. 61, No. 11, 1996
Notes
for C24H33NO4: C, 72.15; H, 8.33; N, 3.51. Found: C, 72.20; H,
8.56; N, 3.56.
mL) was added BCl3 (7.2 mL, 7.2 mmol) (1.0 M) at 0 °C. The
green mixture was allowed to warm to ambient temperature and
stirred for 2 h under argon. The mixture was cooled to 0 °C
and quenched with H2O (20 mL). The precipitated red solid was
removed by filtration and recrystallized from MeOH/H2O, af-
fording 0.331 g (76%)13 of 13 as a red solid: mp 235-237 °C
(lit,2 mp 238-240 °C); IR (KBr) 1697, 1614, 1597 cm-1; UV
(EtOH) λmax ) 265, 274, and 338 nm (ꢀ ) 32 576, 36 000, and
3406 nm); 1H NMR (CD3COCD3) δ 9.22 (1H, broad s), 9.92 (1H,
s), 7.16-7.09 (2H, m), 6.96 (1H, dd, J ) 7.02, 2.1 Hz), 6.81 (1H,
d, J ) 2.0 Hz), 6.78 (1H, d, J ) 2.1 Hz). Anal. Calcd for
4-Meth oxy-2,5-bis(1-m eth yleth oxy)-9H-flu or en -9-on e (7).
To a stirred solution of LDA (15.0 mmol) in THF (30 mL) was
added 6 (1.28 g, 3.2 mmol) in THF (15.0 mL) at -50 °C. The
resulting yellow solution was allowed to warm to ambient
temperature and stirred for 48 h under argon. During this
period the solution turned a brilliant red color. The red solution
was quenched with saturated NH4Cl (30 mL). The mixture was
diluted with THF (150 mL) and separated. The NH4Cl layer
was extracted with THF (50 mL), and the combined organic
extracts were dried over MgSO4. The THF was evaporated and
the resulting red oil purified by flash chromatography (15%
EtOAc/hexane), affording a red solid. Recrystallization from
hexane afforded 7 as red flakes: 0.65 g (62%); mp 74-75 °C; IR
(KBr) 1712 cm-1 (CdO); UV (MeOH) λmax ) 476 nm, ꢀ ) 1570,
λmax ) 339 nm, ꢀ ) 3489, λmax ) 276, ꢀ ) 40 200; 1H NMR (CDCl3)
δ 7.27 (1H, dd, J ) 6.9 Hz, J ) 1.2 Hz), 7.1 (1H, dd, J ) 8.3, 6.8
Hz), 7.04 (1H, dd, J ) 8.2, 1.2 Hz), 6.86 (1H, d, J ) 2.2 Hz),
6.57 (1H, d, J ) 2.2 Hz), 4.59 (1H, m), 3.88 (3H, s), 1.38 (6H, d,
C
14H10O4: C, 69.42; H, 4.16. Found: C, 69.03; H, 4.26.
Ack n ow led gm en t. The authors wish to acknowl-
edge Drs. V. Snieckus, J im Fu, Braulio Santiago, and
Alan Warshawsky for helpful discussions. The authors
also wish to acknowledge Drs. Dirk Friedrich and Ed
Huber for the NMR data and interpretations.
J O9601369
J
C
) 6.1 Hz), 1.35 (6H, d, J ) 6.1 Hz). Anal. Calcd for
20H22O4: C, 73.60; H, 6.79. Found: C, 73.46; H, 6.83.
2,5-Dih yd r oxy-4-m eth oxy-9H-flu or en -9-on e (Den gibsin ,
(13) In a later experiment, 2.03 g of 7 was converted into 1.40 g of
dengibsin 13.
13). To a stirred solution of 7 (0.58 g, 1.8 mmol) in CH2Cl2 (15.0