Short Total Synthesis of (±)-Galbulin and (±)-Isogalbulin Using Zirconium Chemistry

Full text of DOI:10.1021/jo9919512

3236
J . Org. Chem. 2000, 65, 3236-3238
Sch em e 1a
Sh or t Tota l Syn th esis of (()-Ga lbu lin a n d
(()-Isoga lbu lin Usin g Zir con iu m Ch em istr y
Alexander N. Kasatkin, Graham Checksfield, and
Richard J . Whitby*
Department of Chemistry, Southampton University,
Southampton, HANTS, SO17 1BJ , U.K.
Received December 21, 1999
In tr od u ction
Galbulin (1) and isogalbulin (2) are natural lignans
first isolated from Himantandra baccata and Himantan-
dra belgraveana.1 Excluding the synthesis of 1 and 2 by
interconversion of other natural compounds (mostly
lignans),2-7 they have been previously prepared by cat-
ionic cyclization of 4,4-diveratryl-2,3-dimethylbutanoic
acid8 or 1,4-diveratryl-2,3-dimethyl-1-butanol,9 and by
oxidative coupling of 1,4-diveratryl-2,3-dimethylbutane.10,11
However, all these methods suffered from low total yield
and were accompanied by formation of complex mixtures
of stereoisomers. We describe here a short, stereoselec-
tive, and experimentally simple route to both (()-galbulin
and (()-isogalbulin using zirconium-promoted cyclization
of 1,7-dienes12 as a key step.
a
Reagents and conditions: (a) CH2dCHMgBr, CuI/2,2′-bipyr-
idyl (10 mol %), THF/benzene, 20 °C, 3 h; (b) tert-BuLi (2.2 equiv),
THF, -78 °C, 30 min; (c) acrolein, -78 to -50 °C, 1 h; (d) H2O; (e)
Cp2ZrBu2, BuLi (1.3 equiv), -78 to 20 °C, then 20 °C, 1.5 h.
1). Lithium-bromine exchange by treatment of 4 with
2.2 equiv of t-BuLi followed by reaction of the resulting
aryllithium with acrolein and hydrolysis gave the alcohol
5 containing a 1,7-dienic system. The reaction between
the lithium alcoholate of 5 and dibutylzirconocene (Negishi
reagent, prepared in situ from Cp2ZrCl2 and 2 equiv of
BuLi)15 at 20 °C for 1.5 h led to the cis-fused zirconacycle
6. Hydrolysis of 6 furnished the substituted tetrahy-
dronaphthol 716 as ∼1:1 mixture of diastereoisomers, both
having the cis-stereochemistry of the â- and γ-methyl
groups. The exclusive formation of the cis-fused zircona-
cycle is in accord with Takahashi’s observations on
cocyclizations of 1,4,7-octatrienes.17 Our attempts to
isomerize 6 to the corresponding trans-fused zirconacycle
by heating in THF (50 °C, 6 h)18 failed, probably because
of elimination of the alcoholate group from an intermedi-
ate zirconocene-alkene complex (eq 1).19 The poor rela-
tive diastereocontrol between the alcoholate group and
the adjacent ring junction stereocenter in the zirconacycle
6 is surprising. Cyclization of the lithium alkoxide of 1,7-
octadien-3-ol is reported to give >94% diastereoisomeric
excess between the analogous centers.20
Resu lts
Copper-catalyzed reaction of the readily available
dibromide 313 with vinylmagnesium bromide14 afforded
the unsaturated monobromide 4 in high yield (Scheme
(1) Hughes, G. K.; Ritchie, E. Aust. J . Chem. 1954, 7, 104.
(2) Garnmalm, B. Acta Chem. Scand. 1954, 8, 1827.
(3) Schrecker, A. W.; Hartwell, J . L. J . Am. Chem. Soc. 1955, 77,
432.
(4) Birch, A. J .; Milligan, B.; Smith, E.; Speake, R. N. J . Chem. Soc.
1958, 4471.
(5) Crossley, N. S.; Djerassi, C. J . Chem. Soc. 1962, 1459.
(6) Liu, J .-S.; Huang, M.-F.; Gao, Y.-L. Can. J . Chem. 1981, 59, 1680.
(7) Buckleton, J . S.; Cambie, R. C.; Clark, G. R.; Craw, P. A.;
Rickard, C. E. F.; Rutledge, P. S.; Woodgate, P. D. Aust. J . Chem. 1988,
41, 305.
(8) Muller, A.; Vajda, M. J . Org. Chem. 1952, 17, 800.
(9) Perry, C. W.; Kalmins, M. V.; Deitcher, K. H. J . Org. Chem. 1972,
37, 4371.
(10) Biftu, T.; Hazra, G. B.; Stevenson, R.; Williams, J . R. J . Chem.
Soc., Perkin Trans. 1 1978, 1147.
(11) Landais, Y.; Robin, J .-P.; Lebrun, A.; Lenain, V. Tetrahedron
Lett. 1987, 28, 5161.
The trans-â,γ-substituted tetrahydronaphthol 8 was
synthesized as shown in Scheme 2. Oxidation of 7 with
PCC gave the isomerically pure cis-ketone 9 in high yield.
(12) Buchwald, S. L.; Nielsen, R. B. Chem. Rev. 1988, 88, 1047.
Negishi, E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Oxford: Pergamon Press: New York, 1991; Vol. 5, p 1163.
Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124. Taber, D.
F.; Louey, J . P. Tetrahedron 1995, 51, 4495. Bird, A. J .; Taylor, R. J .
K.; Wei, X. D. Synlett 1995, 1237. Mori, M.; Imai, A. E.; Uesaka, N.
Heterocycles 1995, 40, 551. Kemp, M. I.; Whitby, R. J .; Coote, S. J .
Synthesis 1998, 557. Probert, G. D.; Harding, R.; Whitby, R. J .; Coote,
S. J . Synlett 1997, 1371.
(13) Landais, Y.; Robin, J .-P.; Lebrun, A. Tetrahedron 1991, 47,
3787.
(14) Knight, J .; Parsons, P. J . J . Chem. Soc., Perkin Trans. 1 1989,
979.
(15) Rousset, C. J .; Swanson, D. R.; Lamaty, F.; Negishi, E.
Tetrahedron Lett. 1989, 30, 5105.
(16) The alcohols 7, 8 underwent rapid cationic polymerization when
we tried to purify them by distillation or column chromatography on
silica gel. However, the freshly prepared crude products had satisfac-
tory NMR data and were used further without purification.
(17) Takahashi, T.; Kotora, M.; Kasai, K. J . Chem. Soc., Chem.
Commun. 1994, 2693.
(18) Taber, D. F.; Louey, J . P.; Wang, Y.; Nugent, W. A.; Dixon, D.
A.; Harlow, R. L. J . Am. Chem. Soc. 1994, 116, 9457.
(19) Ito, H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y. Tetrahedron
1995, 51, 4507-4518.
(20) Nugent, W. A.; Taber, D. F. J . Am. Chem. Soc. 1989, 111, 6435.
10.1021/jo9919512 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/14/2000

Notes
J . Org. Chem., Vol. 65, No. 10, 2000 3237
Sch em e 2a
Sch em e 3
a
Reagents and conditions: (a) PCC, CH2Cl2, 20 °C, 1 h; (b)
KOH, EtOH, 20 °C, 1.5 h; (c) NaBH4, MeOH, 20 °C, 1 h.
Epimerization of 9 with potassium hydroxide in ethanol
at room-temperature resulted in the precipitation of the
trans-ketone 10 with >98% isomeric purity (72% yield).
Workup of the mother liquor gave a 71:29 (HPLC)
mixture of 10:9 (28% yield). Reduction of 10 with sodium
borohydride in methanol led to 816 as 60:40 mixture of
diastereoisomers.
The relative configuration of the cis- and trans-ketones
9, 10 was proven by NMR-spectroscopy. In the carbon-
13 NMR spectrum of the cis-isomer 9 the signals of the
â- and γ-methyl groups are 1.7 and 4.6 ppm higher field
than those in the spectrum of the trans-isomer 10 (γ-
1
gauche effect21). H NMR data of 9 and 10 are also in
Ta ble 1. F r ied el-Cr a fts Rea ction of 7 a n d 8 w ith
Ver a tr olea
good agreement with the data of cis- and trans-2,3-
dimethyl-1-tetralones (demethoxy-analogues of 9, 10),
respectively.22 Noteworthy that in contrast to 9 which is
a viscous oil at 20 °C, the trans-isomer 10 is a light yellow
solid with mp 135 °C.
entry alcohol excess of veratrole T, °C 2:1c yield of 2+1, %
1
2
3
4
7
7
7
8
5 equiv
20 89:11
20 89:11
-30 97:3
26
57
47
76
cosolventb
cosolventb
cosolventb
-30
6:94
The reaction of 7 with 5 equiv of veratrole in the
presence of aluminum chloride under Friedel-Crafts
conditions described for similar systems23 led to (()-
isogalbulin (2) in low yield contaminated with (()-
galbulin (1) (Table 1, entry 1). Simultaneously a large
amount of polymeric material was formed. The presence
of 1 can be explained by isomerization of the initially
formed cis-carbocation 11 to the trans-carbocation 12
through a â-elimination-protonation mechanism fol-
lowed by the attack of veratrole to the less-hindered side
of 12 (Scheme 3). The use of a larger excess of veratrole
(cosolvent) increased the yield but did not change the 9/10
ratio (Table 1, entry 2). However, decreasing the tem-
perature from 20 to -30 °C led to almost exclusive
formation of (()-isogalbulin (2) (entry 3). The reaction
of 8 with veratrole under the same optimized conditions
afforded (()-galbulin (1) in high yield containing only 6%
of 2 probably due to isomerization of the trans-carbocat-
ion 12 as shown in Scheme 3 (entry 4). The spectral data
of both isomers 110,24 and 26,9,25 were in good agreement
with those described in the literature.
a
Slow addition of an alcohol to a solution of veratrole and AlCl3
in dichloroethane was used in all cases. b1:1 mixture of veratrole
and dichloroethane. According to 1H NMR spectroscopy.
c
4,5-dimethoxybenzene (3) was prepared by bromination of
commercial (3,4-dimethoxyphenyl)methanol.13 THF and 1,2-
dichloroethane were dried by refluxing over benzophenone ketyl
and calcium hydride, respectively, followed by distillation. Air
and moisture sensitive reactions were run in oven dried glass-
ware under a positive pressure of argon. Chromatography was
carried out on silica gel (230-400 mesh). NMR spectra (300 MHz
proton, 75 MHz carbon) were recorded as solutions in CDCl3.
Proton spectra were referenced to CHCl3, and carbon spectra to
CDCl3. IR spectra were recorded as films (oils) or solutions in
chloroform.
1-Allyl-2-br om o-4,5-d im eth oxyben zen e (4). The title com-
pound was prepared according to the procedure described for
1-allyl-2-bromobenzene.14 To a stirred mixture of 3 (3.00 g, 9.68
mmol), CuI (0.184 g, 0.97 mmol), 2,2′-bipyridyl (0.151 g, 0.97
mmol), and benzene (3.5 mL) was rapidly added vinylmagnesium
bromide (19.20 mL, 0.78 M in THF, 14.98 mmol) at 5 °C. After
the exothermic reaction was complete, the cooling bath was
removed and the reaction mixture was stirred at 20 °C for 3 h.
Saturated aq NH4Cl (40 mL) and 35% aq NH3 (10 mL) were
added, and the mixture was stirred for 30 min and extracted
with ether. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The crude
product was purified by column chromatography on silica gel
(40-60 petroleum ether-EtOAc, 4:1) followed by Kugelrohr
distillation (bp 105-108 °C/0.5 mmHg) to afford the title
compound (1.741 g, 70% yield). 1H NMR δ 3.35 (d, J ) 6.0 Hz,
2 H), 3.76 (s, 6 H), 4.95-5.05 (m, 2 H), 5.80-5.95 (m, 1 H), 6.65
(s, 1 H), 6.95 (s, 1 H). 13C NMR δ 38.20, 54.34, 54.57, 111.44,
112.57, 113.94, 114.67, 129.68, 134.30, 146.44, 146.86. IR 1637,
1602 cm-1. Anal. Calcd for C11H13BrO2: C, 51.38; H, 5.09; Br,
31.07. Found: C, 51.77; H, 5.24; Br, 31.21.
Exp er im en ta l Section
Gen er a l Meth od s a n d Ma ter ia ls. Cp2ZrCl2 and anhydrous
AlCl3 were purchased from Aldrich. 1-Bromo-2-(bromomethyl)-
(21) Whitesell, J . K.; Minton, M. A. Stereochemical Analysis of
Alicyclic Compounds by C-13 NMR Spectroscopy; Chapman and Hall:
New York, 1987, pp 37-55.
(22) Dozen, Y.; Hatta, M. Bull. Chem. Soc. J pn. 1975, 48, 2842.
(23) Bencze, W. L.; Barsky, L. I.; Carney, R. W. J .; Renzi, A. A.;
deStevens, G. J . Med. Chem. 1967, 10, 138. Bijoy, P.; SubbaRao, G. S.
R. Synth. Commun. 1993, 23, 2999.
(24) McAlpine, J . B.; Riggs, N. V. Aust. J . Chem. 1975, 28, 831.
(25) Dhal, R.; Landais, Y.; Lebrun, A.; Lenain, V.; Robin, J .-P.
Tetrahedron 1994, 50, 1153.
1-(2-Allyl-4,5-d im eth oxyp h en yl)-2-p r op en -1-ol (5). To a
solution of 4 (2.99 g, 11.62 mmol) in THF (60 mL) was added

3238 J . Org. Chem., Vol. 65, No. 10, 2000
Notes
t-BuLi (15.0 mL, 1.7 M in pentane, 25.6 mmol) at -78 °C. The
reaction mixture was stirred at -78 °C for 30 min, and then
freshly distilled acrolein (0.847 g, 15.1 mmol) was added. The
resulting solution was slowly warmed to -50 °C over 1 h and
hydrolyzed by addition of water (40 mL). After extraction with
ether the organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (40-60
petroleum ether-EtOAc, 2:1) to give the title alcohol (1.822 g,
washed with cooled ethanol (2 × 5.0 mL), and dried at 0.5 mmHg
for 1 h to afford the title trans-ketone (0.763 g, 72% yield) of
more than 98% isomeric purity. Mp 135 °C (ethanol). H NMR
δ 1.13 (d, J ) 6.3 Hz, 3 H), 1.27 (d, J ) 7.0 Hz, 3 H), 1.99 (m, 1
H), 2.20 (m, 1 H), 2.68 (dd, J 1 ) 16.5 Hz, J 2 ) 10.3 Hz, 1 H),
2.91 (dd, J 1 ) 16.5 Hz, J 2 ) 4.0 Hz, 1 H), 3.90 (s, 3 H), 3.93 (s,
3 H), 6.65 (s, 1 H), 7.50 (s, 1 H). 13C NMR δ 13.05, 20.43, 36.80,
37.32, 48.89, 56.13, 56.17, 108.83, 110.14, 125.21, 137.91, 148.02,
153.50, 199.58. IR 1655, 1601 cm-1. Anal. Calcd for C14H18O3:
C, 71.77; H, 7.74. Found: C, 71.60; H, 7.68.
1
1
67% yield). H NMR δ 2.04 (d, J ) 3.3 Hz, OH), 3.42 (d, J ) 5.9
Hz, 2 H), 3.88 (s, 6 H), 5.00 (d, J ) 16.9 Hz, 1 H), 5.07 (d, J )
9.9 Hz, 1 H), 5.19 (d, J ) 9.9 Hz, 1 H), 5.32 (d, J ) 16.9 Hz, 1
H), 5.41 (m, 1 H), 5.90-6.10 (m, 2 H), 6.67 (s, 1 H), 6.99 (s, 1 H).
13C NMR δ 36.48, 56.03, 71.11, 109.90, 113.04, 114.88, 115.95,
129.43, 132.70, 137.80, 140.02, 147.81, 148.45. IR 3500, 1637,
1608 cm-1. Anal. Calc. for C14H18O3: C, 71.77; H, 7.74. Found:
C, 71.50; H, 7.66.
r a c-(1RS,2S,3R)-6,7-Dim eth oxy-2,3-d im eth yl-1,2,3,4-tet-
r a h yd r o-1-n a p h th a len ol (8). To a solution of 10 (0.763 g, 3.26
mmol) in methanol (25 mL) was added sodium borohydride
(0.223 g, 5.87 mmol) at 20 °C. The reaction mixture was stirred
for 1 h at room temperature, methanol was removed under
reduced pressure, and saturated aq NaHCO3 (5 mL) was added.
After extraction with ether, the organic layer was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The crude product (0.739 g, 96% yield, ∼60:40 mixture
of two diastereoisomers) had satisfactory NMR data and was
used further without purification. 1H NMR δ 0.90 (d, J ) 7.0
Hz, 3 H major), 0.97 (d, J ) 6.6 Hz, 6 H minor), 1.09 (d, J ) 6.3
Hz, 3 H major), 1.22 (m, 1 H major + 1 H minor), 1.51 (m, 1 H
major), 1.80 (br. s, 1 H major + 1 H minor), 2.20 (m, 1 H minor),
2.30-2.43 (m, 1 H major + 1 H minor), 2.61 (dd, J 1 ) 16.2 Hz,
J 2 ) 4.8 Hz, 1 H major), 2.88 (dd, J 1 ) 15.1 Hz, J 2 ) 7.0 Hz, 1
H minor), 3.77 and 3.80 (two s, 6 H major + 6 H minor), 4.16 (d,
J ) 9.2 Hz, 1 H major), 6.45 (s, 1 H major + 1 H minor), 6.57 (s,
1 H minor), 6.98 (s, 1 H major). 13C NMR δ 15.87, 17.36, 19.69,
21.73, 33.29, 34.24, 35.82, 38.35, 45.15, 56.00, 56.06, 56.13, 75.72,
76.79, 109.03, 109.93, 110.65, 112.01, 125.42, 127.44, 128.93,
131.51, 147.25, 147.31, 147.63, 148.21.
(()-Isoga lbu lin (2) (Table 1, entry 3). To a mixture of
veratrole (4.0 mL), 1,2-dichloroethane (4.0 mL), and aluminum
chloride (0.100 g, 0.75 mmol) was added dropwise during 30 min
a solution of 7 (0.146 g, 0.62 mmol) in 1,2-dichloroethane (4.0
mL) at -30 °C. After addition was complete, the mixture was
stirred at -30 °C for 30 min and hydrolyzed with 2 M aq HCl
(10 mL). The organic layer was separated, washed with satu-
rated aq NaHCO3 and brine, dried over MgSO4, and concen-
trated under reduced pressure. The excess of veratrole was
removed by Kugelrohr distillation (50-60 °C, 5 mmHg). The
residue was purified by column chromatography on silica gel
(40-60 petroleum ether-EtOAc, 3:1) to give the title compound
(0.104 g, 47% yield). 13C NMR δ 15.53, 16.70, 28.72, 34.88, 40.95,
51.03, 55.87, 55.91, 55.95, 56.00, 110.69, 111.28, 112.29, 113.35,
121.45, 128.58, 129.64, 139.95, 147.22, 147.37, 148.70. 1H NMR
and IR spectral data were in good agreement with those
described in the literature.6,9,25
r a c-(1RS,2R,3R)-6,7-Dim eth oxy-2,3-d im eth yl-1,2,3,4-tet-
r a h yd r o-1-n a p h th a len ol (7). To a solution of Cp2ZrCl2 (2.035
g, 6.97 mmol) in THF (60 mL) was added BuLi (9.20 mL, 2.5 M
in hexanes, 23.0 mmol) at -78 °C. The reaction mixture was
stirred at -78 °C for 1 h, and then a solution of 5 (1.631 g, 6.97
mmol) in THF (10 mL) was added and the cooling bath was
removed. After stirring at room temperature for 1.5 h, saturated
aq NaHCO3 (50 mL) was added, and the mixture was stirred
for 1 h and extracted with ether. The organic layer was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. The crude product (1.563 g, 95% yield, ∼1:1 mixture
of two diastereoisomers) had satisfactory NMR data and was
used further without purification. 1H NMR δ 0.75 (d, J ) 7.0
Hz, 3 H), 0.78 (d, J ) 7.4 Hz, 3 H), 0.96 (d, J ) 6.6 Hz, 3 H),
1.00 (d, J ) 7.0 Hz, 3 H), 1.58 (d, J ) 6.3 Hz, 1 H), 1.62 (d, J )
8.5 Hz, 1 H), 1.82-2.10 (m, 2 H + 1 H), 2.23 (m, 1 H), 2.26-
2.47 (m, 1 H + 1 H), 2.52 (dd, J 1 ) 16.5 Hz, J 2 ) 5.5 Hz, 1 H),
2.61 (dd, J 1 ) 16.2 Hz, J 2 ) 4.8 Hz, 1 H), 3.80 and 3.83 (two s,
6 H + 6 H), 4.33 (m, 1 H), 4.74 (m, 1 H), 6.47 (s, 1 H), 6.50 (s, 1
H), 6.80 (s, 1 H), 7.03 (s, 1 H). 13C NMR δ 5.90, 11.18, 17.78,
19.14, 27.54, 31.55, 33.28, 33.39, 39.10, 40.17, 55.48, 55.51, 55.54,
72.84, 74.25, 109.74, 111.03, 111.41, 112.65, 128.07, 128.86,
129.02, 130.18, 147.74, 148.78.
r a c-(2R,3R)-6,7-Dim eth oxy-2,3-d im eth yl-3,4-d ih yd r o-2H-
n a p h th a len -1-on e (9). To a suspension of pyridinium chloro-
chromate (1.569 g, 7.28 mmol) in dichloromethane (100 mL) was
added a solution of 7 (1.321 g, 5.60 mmol) in dichloromethane
(10 mL). The reaction mixture was stirred at 20 °C for 1 h,
diluted with ether (120 mL), and filtered through a short silica
gel column. After concentration under reduced pressure, the
crude product was purified by column chromatography on silica
gel (40-60 petroleum ether-EtOAc, 3:1) to give the title cis-
ketone (1.061 g, 81% yield) of more than 98% isomeric purity.
1H NMR δ 0.98 (d, J ) 7.0 Hz, 3 H), 1.16 (d, J ) 7.0 Hz, 3 H),
2.43 (m, 1 H), 2.67 (m, 1 H), 2.73 (dd, J 1 ) 16.6 Hz, J 2 ) 7.0 Hz,
1 H), 2.98 (dd, J 1 ) 16.6 Hz, J 2 ) 4.8 Hz, 1 H), 3.89 (s, 3 H),
3.93 (s, 3 H), 6.63 (s, 1 H), 7.50 (s, 1 H). 13C NMR δ 11.38, 15.81,
34.20, 35.07, 46.39, 56.12, 56.16, 108.65, 110.62, 125.02, 137.39,
147.97, 153.58, 200.60. IR 1667, 1599 cm-1. Anal. Calcd for
(()-Ga lbu lin (1) (Table 1, entry 4). The title compound was
prepared from 8 in 76% yield as described above. 13C NMR δ
17.33, 20.17, 35.71, 39.17, 43.95, 54.44, 55.94, 56.04, 110.71,
110.79, 112.15, 112.91, 122.09, 129.24, 132.59, 139.17, 147.01,
147.13, 147.42, 148.96. 1H NMR and IR spectral data were in
good agreement with those described in the literature.10,24
C
14H18O3: C, 71.77; H, 7.74. Found: C, 71.56; H, 7.71.
r a c-(2S,3R)-6,7-Dim eth oxy-2,3-d im eth yl-3,4-d ih yd r o-2H-
Ack n ow led gm en t. We thank the EPSRC (GR/
K19907) and the University of Southampton for support
of this work.
n a p h th a len -1-on e (10). A solution of 9 (1.061 g, 4.53 mmol)
and KOH (0.254 g, 4.53 mmol) in ethanol (18.0 mL) was stirred
at 20 °C for 1.5 h. The resulting light yellow solid was filtered,
J O9919512