A facile, expeditious route to the benzooxabicyclo[3.2.1]octane system. Application to a short, high-yield synthesis of filiformin

Article abstract of DOI:10.1021/jo952184j

A facile and efficacious route to the benzooxabicyclo[3.2.1]octane system has been developed and applied to a synthesis of filiformin (1). The cycloaddition of ethylene to the methoxychromone 13 furnished the oxetanol 14 through a tandem cycloaddition and

Full text of DOI:10.1021/jo952184j

J . Org. Chem. 1996, 61, 4391-4394
4391
A F a cile, Exp ed itiou s Rou te to th e Ben zooxa bicyclo[3.2.1]octa n e
System . Ap p lica tion to a Sh or t, High -Yield Syn th esis of F ilifor m in
†
Asok Nath, J ayati Mal, and Ramanathapuram V. Venkateswaran*
Department of Organic Chemistry, Indian Association for the Cultivation of Science,
J adavpur, Calcutta-700 032, India
Received December 8, 1995X
A facile and efficacious route to the benzooxabicyclo[3.2.1]octane system has been developed and
applied to a synthesis of filiformin (1). The cycloaddition of ethylene to the methoxychromone 13
furnished the oxetanol 14 through a tandem cycloaddition and γ-hydrogen abstraction sequence.
Lithium aluminum hydride reduction to the diol 15 followed by acid-catalyzed rearrangement
produced benzooxabicyclooctanone (16), arising from exclusive external bond migration. Similarly,
ethoxychromone (17) under the same sequence of reactions afforded the homologous bridged ketone
2
0. For the synthesis of filiformin (1), methoxychromone 24 on ethylene cycloaddition followed by
reduction of resultant oxetanol 25 with lithium aluminum hydride furnished diol 10. Acid-catalyzed
rearrangement of 10 provided the bridged ketone 11 which was brominated to give 26. This bromo
ketone had previously been converted to filiformin (1), and also aplysin 9, and hence, the present
work represents a short, high-yield formal synthesis of these sequiterpenes from a single starting
material.
In tr od u ction
Sch em e 1
The marine sesquiterpene filiformin and congeners
constitute the only examples of naturally occurring
compounds featuring a benzooxabicyclo[3.2.1]octane sys-
tem.1 The oxabicyclo[3.2.1]octane unit is, however, present
in the more widely distributed sesquiterpene antibiotics,
the trichothecenes.2 The isolation of filiformin (1) and
1
a
filiforminol (2) was first reported by Wells et al. from
the alga Laurencia filiformis, which also contained the
uncyclized compound, allolaurinterol (3). It has been
suggested that 1 must be regarded as an artifact formed
by spontaneous in vitro cyclization of 3. Additional
observation on cyclization of 3 to 1 during NMR mea-
surements by addition of a trace of trifluoroacetic acid
3
to a solution of 3 in CDCl also supported this conjecture.
Subsequently, several brominated analogs 4-6 have also
also stems from the fact that some of the A-ring aromatic
trichothecene analogs incorporating this basic unit dis-
play significant biological activity.4 In this paper, we
present the full details of our expeditious and convenient
approach to the benzooxabicyclo[3.2.1]octane system and
its application to a short, high-yield synthesis of filiformin
been isolated.1b
5
(1).
Our strategy for the development of the ring system
present in 1 relied on a cyclobutyl carbinol rearrange-
6
ment. Previously, we had reported the acid-catalyzed
rearrangement of the cyclobutyl carbinol 7 involving a
primary external bond migration followed by a 1,2-oxygen
shift to lead to the key intermediate 8 in a highly
economical synthesis of the marine sesquiterpene aplysin
There have been very few successful efforts at the
synthesis of the ring system of 1.3 These have involved
multistep transformations and attendant poor yields. The
importance of the benzooxabicyclo[3.2.1]octane system
(9, Scheme 1). If a suitable modification were introduced
into the carbinol such that the rearrangement were
terminated with the migration of the external bond, then
the benzooxabicyclo[3.2.1]octane ring system would be
formed. Replacing an angular methyl group with a
hydroxy group so that rapid ketonization after the initial
external bond migration would result in the desired ring
system (Scheme 1, 10 f 11). Since we had already
†
In part.
X
Abstract published in Advance ACS Abstracts, J une 1, 1996.
1) (a) Kazlauskas, R.; Murphy, P. T.; Quinn, R. J .; Wells, R. J .; Aust.
(
J . Chem. 1976, 29, 2533. (b) Suzuki, M.; Kurosawa, E. Bull. Chem.
Soc. J pn. 1979, 52, 3349.
(
2) Tamm, Ch. Fortschr. Chem. Org. Naturst. 1974, 31, 64. Bam-
berg, J . R.; Strong, F. M. In Microbial Toxins; Kadis, S., Ed.; Academic
Press: New York, 1973; Vol. 3, p 207.
(4) Anderson, W. K.; Lee, G. E. J . Org. Chem. 1980, 45, 501.
(5) Preliminary communication: Nath, A.; Venkateswaran, R. V. J .
Chem. Soc., Chem. Commun. 1993, 281.
(3) (a) Goldsmith, D. J .; J ohn, T. K.; Kwong, C. D.; Painter, G. R.,
III. J . Org. Chem. 1980, 45, 3989. (b) Laronze, J . Y.; Boukili, R. E.;
Patigny, D.; Dridi, S.; Cartier, D.; Levy, J . Tetrahedron 1991, 47, 10003.
(6) Nath, A.; Ghosh, A.; Venkateswaran, R. V. J . Org. Chem. 1992,
57, 1467.
S0022-3263(95)02184-0 CCC: $12.00 © 1996 American Chemical Society

4
392 J . Org. Chem., Vol. 61, No. 13, 1996
Nath et al.
6
developed conditions that favor a primary external bond
migration in these cyclobutyl carbinol rearrangements,
the proposed route appeared viable. We report here a
short synthesis of filiformin (1) following this approach.
Sch em e 2
Resu lts a n d Discu ssion
Generation of the required angular hydroxy substi-
tuted cyclobutyl carbinol for rearrangement studies
entailed a photolytic ethylene addition to a suitably
substituted 3-hydroxychromone followed by a Grignard
reaction. Before synthesizing the requisite chromone, the
course of the proposed strategy was studied using the
7
known 3-hydroxy-2-methylchromone (12). Irradiation
of a benzene solution of 12 subjected to a continuous flow
8
of ethylene gave only recovered 12. Conversion of 12 to
this asymmetric center. Embedded within the oxetanol
structure 14 was the desired angular hydroxy cyclobutyl
carbinol system proposed as the progenitor of a cyclo-
pentanone (bridged or fused) which would be revealed
through an acid-catalyzed rearrangement, in the manner
of the well-known pinacol-pinacolone rearrangement.
Initial external bond migration would eventually provide
the benzooxabicyclo[3.2.1]octane system (Scheme 2). To
our knowledge, the potential of oxetanols has not been
explored.11 Attempted rearrangement of 14 under a few
methyl ether 13 was accomplished through reaction with
methyl iodide in the presence of anhydrous potassium
carbonate. Irradiation of 13 as described for 12 resulted
in a gradual disappearance of 13; after 5 h, no more 13
could be detected by TLC. The benzene was distilled off,
and the viscous residue was purified by preparative TLC
to furnish a solid product in 73% yield which was
characterized as oxetanol 14. Elemental analysis cor-
responded to a molecular formula C13
spectrum showed the absence of a carbonyl group. The
H NMR spectrum revealed the absence of methoxy
protons but showed a two-proton AB quartet at δ 4.43
and 4.56 along with a singlet at δ 2.81 corresponding to
14 3
H O , and the IR
conditions (BF
3
2
‚Et O in benzene, sulfuric acid in petro-
1
leum ether or in nitromethane) led to a complex and
unencouraging product mixture. An alternate pathway
from 14 was then tried. Oxetanol 14 was reduced with
lithium aluminum hydride in refluxing tetrahydrofuran,
furnishing the diol 15 in excellent yield. This diol was
endowed with all the features needed for the acid-
catalyzed rearrangement to the benzooxabicyclo[3.2.1]-
octane system (Scheme 1). The rearrangement was
2
one proton assignable to a hydroxy group based on D O
exchange experiments. The above features fit the
oxetanol structure 14, an assignment which was also
borne out by subsequent transformations.
The formation of oxetanol 14 by photolytic ethylene
addition to 13 can be explained in terms of a hydrogen
abstraction from the methoxy substituent in the initial
photoadduct by the photoexcited carbonyl group to give
a 1,4-biradical X in a Norish type II process. Radical
recombination then results in the oxetanol 14. Abstrac-
tion of a γ-hydrogen in the photolysis of R-methoxy
initially tried using BF
5 in benzene with a catalytic amount of BF
ambient temperature for 1 h furnished bridged ketone
6 in very good yield as the only islated product, arising
3
‚Et
2
O as catalyst. Treatment of
1
3
‚Et O at
2
1
from exclusive migration of the external bond. The
structural assignment of 16 followed from spectral analy-
sis, particularly IR, which displayed a strong carbonyl
9
ketones to produce oxetanols is well precedented, and
the tandem cycloaddition and γ-hydrogen abstraction in
-
1
absorption at 1765 cm in agreement with the value
alkene addition to R-methoxy enones has also been
reported for this system.3
a,4
Interestingly and indeed
reported.10 The assignement of cis stereochemistry to the
ring juncture in 14 followed from our previous results6
gratifyingly, no isomeric cyclopentanone product from
initial internal bond migration was seen. The rearrange-
ment of 15 was next carried out under different polar
of ethylene addition to chromones, while the configura-
tion of the oxetanol has been assigned by analogy to
cognate systems.10 Similar irradiation of ethoxychromone
conditions, (i) BF
ether at -78 °C, (ii) BF
3
‚Et
2
O or sulfuric acid in petroleum
‚Et O or sulfuric acid in nitro-
3
2
1
7, prepared by alkylation of 12 with ethyl iodide,
ethane at -78 °C, which had remarkably altered the
course of the initial bond migration.6 Even under these
conditions, diol 15 furnished only bridged ketone 16 in
yields ranging from 80 to 85%. Although the reasons for
the exclusive external bond migration under a variety of
conditions are not immediately apparent, the result
provided us with a novel and facile access to the
benzooxabicyclo[3.2.1]octane system. Application of the
sequence of lithium aluminum hydride reduction and
rearrangement to oxetanol 18 afforded bridged ketone
20 exclusively in excellent yield.
furnished oxetanol 18, in 68% yield, as a single epimer
at the secondary methyl group. The homogeneity was
1
evident from H NMR which showed only one doublet at
δ 1.35 for the secondary methyl group and a quartet at
δ 4.58 for the methine hydrogen. It has not been possible
to conclusively assign the configuration of this secondary
methyl group but subsequent transformations remove
(
7) Backet, G. J . P.; Ellis, G. P.; Trindade, M. I. U. J . Chem. Res.,
Miniprint 1978, 0865.
8) The 3-hydroxychromones were sparingly soluble in this solvent.
Other solvents, like acetonitrile and THF, were tried without success.
9) (a) Yates, P.; Szabo, A. G. Tetrahedron Lett. 1965, 485. (b) Lewis,
(
With an efficient and short route to the benzooxabicyclo-
[3.2.1]octane system in hand, we turned to applying this
methodology to a synthesis of filiformin 1. This required
starting from 2,7-dimethyl-3-methoxychromone which
(
F. D.; Turro, N. J . J . Am. Chem. Soc. 1970, 92, 311. (c) Arnould, J .
C.; Pete, J . P. Tetrahedron 1975, 31, 8151. (d) Hancock, K. G.; Wylie,
P. L. J . Org. Chem. 1977, 42, 1850. (e) Wender, P. A.; Rawlins, D. W.
Tetrahedron 1992, 48, 7033.
(10) (a) Anet, F. A. L.; Mullis, D. P. Tetrahedron Lett. 1969, 737.
(
b) Gupta, S. C.; Mukherjee, S. K. Tetrahedron Lett. 1973, 5073. (c)
Ellis, J . V.; J ones, J . E. J . Org. Chem. 1975, 40, 485. (d) Schultz, A.
G.; Plummer, M.; Taveras, A. G.; Kullnig, R. K. J . Am. Chem. Soc.
1
(11) For the possibly only other but unsuccessful attempt see:
Schultz, A. G.; Taveras, A. G.; Kullnig, R. K. Tetrahedron Lett. 1990,
31, 849.
988, 110, 5547.

Synthesis of Filiformin
J . Org. Chem., Vol. 61, No. 13, 1996 4393
Sch em e 3
Exp er im en ta l Section
Gen er a l P r oced u r es. All the compounds described herein
possessing asymmetric centers are racemates. All reactions
were performed under a N atmosphere. Compounds isolated
2
by the reported purification procedures were sufficiently pure
for the next reaction. However, for analytical purposes, solid
compounds were crystallized from suitable solvents, and
melting points of such crystallized samples have been reported
and are uncorrected. Liquid products were subjected to bulb
to bulb distillations, and the oven temperature is designated
as ot. Solvents and reagents were reagent grade materials
and were further purified by conventional methods. The
petroleum ether that was used is that fraction of bp 60-80 °C
and light petroleum ether of bp 40-60 °C. Et
2
O refers to
was prepared as follows. 2-Hydroxy-4-methylacetophe-
none (21) was brominated12 to furnish bromo ketone 22
which was then transformed to 2,7-dimethyl-3-hydroxy-
diethyl ether. Preparative TLC was performed with silica gel
60 HF254 plates of 1-mm thickness. Na
organic extracts.
2 4
SO was used to dry
7
1H NMR spectra of CDCl
3
solutions were recorded at 100,
00, or 300 MHz and that of CCl solutions at 60 MHz. The
IR spectra are of CHCl solutions.
-Meth yl-3-m eth oxych r om on e (13). A mixture of 2-hy-
chromone (23) following the procedure of Ellis et al. and
2
4
then methylated with methyl iodide to desired methoxy-
chromone 24 (Scheme 3). Irradiation of a benzene
solution of 24 with continuous passage of ethylene
through the solution produced oxetanol 25 in 75% yield.
Reduction of this oxetanol with lithium aluminum hy-
dride in refluxing tetrahydrofuran furnished diol 10 in
3
2
7
droxy-3-methylchromone (12) (810 mg, 4.6 mmol), MeI (710
mg, 5 mmol), and anhydrous K CO (691 mg, 5 mmol) in dry
2
3
acetone (25 mL) was heated under reflux with stirring for 4
h. It was then concentrated, diluted with water, and extracted
with Et O. The ether extracts were washed with water, dried,
2
9
5% yield as a crystalline solid. The rearrangement of
and concentrated to afford methoxychromone 13 as a solid (740
mg, 85%): crystallized from ether-light petroleum ether; mp
diol 10, under all the previously described conditions,
followed the already established pathway to give bridged
ketone 11 in yields ranging between 85 and 90%. The
-
1 1
1
(
02-103 °C; IR 1640 cm ; H NMR (CCl ) δ 2.40 (s, 3H), 3.89
4
s, 3H), 7.17-7.76 (m, 3H), 8.10-8.30 (m, 1H). Anal. Calcd
for C11 : C, 69.46; H, 5.30. Found: C, 69.63; H, 5.46.
-Meth yl-3-eth oxych r om on e (17). Alkylation of 2-hy-
droxy-3-methylchromone (12) (540 mg, 3.07 mmol) with EtI
(624 mg, 4 mmol) in the presence of anhydrous K CO (553
-1
1
IR absorption at 1765 cm , in combination with H NMR
and 13C NMR spectral features, confirmed the structural
assignment. Controlled bromination of 11 following our
previous procedure13 afforded bromo ketone 26 in good
10 3
H O
2
2
3
1
mg, 4 mmol) in dry acetone (20 mL) was carried out as per
the procedure for 13 to furnish ethoxychromone 17 as an oil
yield. The melting point and H NMR spectrum of 26
were in agreement with those of an authentic sample
synthesized previously by Goldsmith et al.3 Since this
bromo ketone had served as an advanced intermediate
in their synthesis of filiformin (1) and aplysin (9), our
synthesis of 26 concluded a formal total synthesis of both
sesquiterpenes from a single precursor. The attractive
features of the synthesis are the use of readily available
and inexpensive reagents and simple reaction conditions
which make it a viable process.
-
1 1
(
490 mg, 78%): ot 95-100 °C (0.05 mmHg); IR 1640 cm ; H
NMR (CCl ) δ 1.33 (t, J ) 7 Hz, 3H), 2.40 (s, 3H), 4.17 (q, J )
Hz, 3H), 2.40 (s, 3H), 4.17 (q, J ) 7 Hz, 2H), 7.10-7.74 (m,
H), 8.06-8.26 (m, 1H). Anal. Calcd for C12 : C, 70.57;
a
4
7
3
12 3
H O
H, 5.92. Found: C, 70.46; H, 5.96.
cis-1,2,2a ,7c-Tetr a h yd r o-2a -m eth yl-7c-oxeto-9H-ben zo-
[b]cyclobu ta [e]p yr a n -7b-ol (14). A solution of chromone 13
(440 mg) in dry thiophene-free benzene (260 mL) was irradi-
ated through a Pyrex filter with a Hanovia 450 W mercury
lamp for 5 h, during which time ethylene was bubbled through
the solution. Then the solvent was evaporated under reduced
pressure. The residual viscous oil was purified by preparative
TLC [petroleum ether/EtOAc (9:1)] to afford 14 as a colorless
In conclusion, an expeditious route to the benzo-
oxabicyclo[3.2.1]octane system has been developed and
applied to a short, high-yield formal synthesis of fili-
formin and aplysin. The synthesis revealed for the first
time the potential of oxetanols as intermediates in
synthesis and additionally underscored the versatility of
the cyclobutyl carbinol rearrangements in providing
convenient access to polycyclic frameworks of complex
natural products under simple reaction conditions. This
versatility forms the basis of the current, continued
crystalline solid (370 mg, 73%): crystallized from ether-light
1
petroleum ether; mp 110-111 °C; H NMR (CDCl
3
) δ 1.40-
1
1
6
.52 (m, 1H), 1.58 (s, 3H), 1.68-1.86 (m, 2H), 2.34-2.48 (m,
H), 2.81 (s, 1H, OH), 4.43 and 4.56 (ABq, J ) 6.7 Hz, 2H),
.90-7.10 (m, 2H), 7.24-7.34 (m, 1H), 7.49 (dd, J ) 7.7, 1.7
Hz, 1H). Anal. Calcd for C13
Found: C, 71.72; H, 6.51.
14 3
H O : C, 71.54; H, 6.47.
cis-1,2,2a ,7c-Tet r a h yd r o-2a ,9-d im et h yl-7c-oxet o-9H -
ben zo[b]cyclobu ta [e]p yr a n -7b-ol (18). Photolytic ethylene
addition to chromone 17 (480 mg) in dry thiophene-free
benzene (260 mL) was carried out as for 14 to furnish 18 as a
interest in the application of this rearrangement to
natural product synthesis.14
solid (370 mg, 68%): crystallized from ether-light petroleum
(
(
12) King, L. C.; Ostrum, G. K. J . Org. Chem. 1964, 29, 3459.
13) Biswas, S.; Ghosh, A.; Venkateswaran, R. V. J . Org. Chem.
ether; mp 75-77 °C; H NMR (CDCl
1
) δ 1.39 (d, J ) 6 Hz,
3
3
H), 1.58 (s, 3H), 1.68-1.84 (m, 2H), 2.20-2.48 (m, 2H), 4.58
1
990, 55, 3498.
14) (a) Corey, E. J .; Nozoe, S. J . Am. Chem. Soc. 1964, 86, 1652.
b) Do Khac Manh, D.; Fetizon, M.; Kone, M. Tetrahedron 1978, 34,
513. (c) Pirrung, M. C. J . Am. Chem. Soc. 1981, 103, 82. (d) Hayano,
K.; Ohfune, Y.; Shirahama, H.; Matsumoto, T. Helv. Chim. Acta 1981,
(q, J ) 6 Hz, 1H), 6.88-7.52 (m, 4H).
(
(
3
Analytical data (C, H) for the oxetanol 18 could not be
obtained. However, isobutane chemical ionization (IBCI)
+
showed MH at 233 corresponding to the desired molecular
6
1
4, 1347. (e) White, J . D.; Matsui, T.; Thomas, J . A. J . Org. Chem.
981, 46, 3376. (f) Ikeda, M.; Takahashi, M.; Uchino, T.; Ohno, K.;
weight.
cis-1,2,2a ,8a -Tetr a h yd r o-2a ,8-d im eth yl-8H-ben zo[b]cy-
clobu ta [e]p yr a n -8,8a -d iol (15). To a magnetically stirred
solution of oxetanol 14 (200 mg, 0.92 mmol) in dry THF (15
mL) was added LAH (35 mg, 0.92 mmol). The mixture was
then vigorously refluxed for 5 h. Upon cooling, the reaction
Tamura, Y. Ibid. 1983, 48, 4241. (g) Takeda, K.; Shimono, Y.; Yoshii,
E. J . Am. Chem. Soc. 1983, 105, 563. (h) Smith, A. B., III; Wexler, B.
A.; Tu, C-Y.; Konopelski, J . P. Ibid. 1985, 107, 1308. (i) Fetizon, M.;
Do Khac, D.; Dinh Tho, N. Tetrahedron Lett. 1986, 26, 1777. (j)
Paquette, L. A.; Lin, H.-S.; Gunn, B. P.; Coghlan, M. J . J . Am. Chem.
Soc. 1988, 110, 5818. (k) Ranu, B. C.; Sarkar, D. C.; Basu, M. K.
Tetrahedron 1989, 45, 3107. (l) Ghosh, S.; Patra, D.; Saha, G. J . Chem.
Soc., Chem. Commun. 1993, 783. (m) Patra, D.; Ghosh, S. Synth.
Commun. 1994, 24, 1663.
mixture was treated with saturated aqueous Na
ether layer was separated, and the aqueous layer was ex-
tracted with Et O. The combined ether extracts were washed
2 4
SO . The
2

4
394 J . Org. Chem., Vol. 61, No. 13, 1996
Nath et al.
with saturated brine, dried, and concentrated to afford diol
5 as a crystalline solid (190 mg, 94%): crystallized from light
methylated with MeI (2.84 g) as for 13 to furnish 2,7-dimethyl-
3-methoxychromone (24) as a solid [2.98 g, 84% (based on
hydroxychromone)]: crystallized from ether; mp 91-92 °C; IR
1
1
petroleum ether; mp 92-93 °C; H NMR (CDCl
H), 1.55 (s, 3H), 1.60-1.74 (m, 2H), 1.86-2.06 (m, 2H), 2.13
s, 1H, OH), 2.21 (s, 1H, OH), 6.91 (dd, J ) 7.8, 1.3 Hz, 1H),
3
) δ 1.39 (s,
3
-1 1
1
3
640 cm ; H NMR (CCl
H), 7.0-7.23 (m, 2H), 8.02 (d, J ) 8 Hz, 1H). Anal. Calcd
: C, 70.57; H, 5.92. Found: C, 70.41; H, 5.93.
4
) δ 2.36 (s, 3H), 2.46 (s, 3H), 3.87 (s,
(
7
.06-7.17 (m, 1H), 7.21-7.32 (m, 1H), 7.55 (dd, J ) 7.5, 1.8
for C12
12 3
H O
Hz, 1H). Anal. Calcd for C13
Found: C, 70.86; H, 7.38.
16 3
H O : C, 70.89; H, 7.32.
cis-1,2,2a ,7c-Tet r a h yd r o-2a ,5-d im et h yl-7c-oxet o-9H -
ben zo[b]cyclobu ta [e]p yr a n -7b-ol (25). Photolytic ethylene
addition to chromone 24 (730 mg) in dry thiophene-free
benzene (260 mL) was carried out as per procedure for 14 to
2
,3,4,5-Tetr a h ydr o-2,5-dim eth yl-2,5-m eth a n o-1-ben zox-
ep in -10-on e (16). Meth od A. To a magnetically stirred
solution of diol 5 (90 mg) in benzene (10 mL) at rt was added
1
a drop of freshly distilled BF
for 1 h and then treated with saturated aqueous NaHCO
two liquid layers were separated. The aqueous layer was
extracted with Et O. The combined organic layers were
3
‚Et
2
O. The mixture was stirred
furnish oxetanol 25 as a viscous oil (620 mg, 75%): H NMR
3
. The
(CDCl ) δ 1.40-1.50 (m, 1H), 1.58 (s, 3H), 1.70-1.78 (m, 2H),
3
2.32 (s, 3H), 2.37-2.44 (m, 1H), 4.42 and 4.58 (ABq, J ) 7 Hz,
2
2
7
7
1
H), 6.75 (br s, 1H), 6.84 (br d, J ) 7.8 Hz, 1H), 7.38 (d, J )
washed with water, dried, and concentrated. The residual oil
was purified by preparative TLC [petroleum ether/EtOAc (98:
13
.8 Hz, 1H); CMR (CDCl ) δ 19.78, 21.13, 21.77, 24.05, 69.92,
3
8.42, 80.41, 92.05, 118.30, 120.23, 122.55, 125.62, 139.96,
2
)] to afford the ketone 16 (70 mg, 85%): ot 78-83 °C (0.05
+
51.15; HRMS calcd for C14
H
16
O
3
(M ) 232.1099, found 232.1096.
-
1 1
mmHg); IR 1765 cm ; H NMR (CDCl ) δ 1.43 (s, 3H), 1.44
3
cis-1,2,2a ,8a -Tetr a h yd r o-2a ,5,8-tr im eth yl-8H-ben zo[b]-
(
4
7
s, 3H), 1.78-2.08 (m, 2H), 2.20-2.66 (m, 2H), 6.74-7.26 (m,
H). Anal. Calcd for C13
6.85; H, 7.03.
H
14
O
2
: C, 77.20; H, 6.98. Found: C,
cyclobu ta [e]p yr a n -8,8a -d iol (10). Reduction of oxetanol 25
(480 mg, 2.07 mmol) with LAH via the procedure for 15
afforded diol 10 as a crystalline solid (460 mg, 95%): crystal-
Meth od B. To a magnetically stirred solution of diol 15
90 mg) in dry petroleum ether (10 mL) at -78 °C was added
a drop of concentrated H SO or BF ‚Et O. The mixture was
stirred at -78 °C for 1 h and then was allowed to warm to rt
and then treated with saturated aqueous NaHCO . Et O was
added. The two liquid layers were separated, and the aqueous
layer was extracted with Et O. The combined organic layers
1
(
lized from light petroleum ether; mp 100-101 °C; H NMR
2
4
3
2
(CDCl ) δ 1.38 (s, 3H), 1.55 (s, 3H), 1.62-1.66 (m, 2H), 1.92-
3
1
.97 (m, 4H), 2.34 (s, 3H), 6.75 (br s, 1H), 6.90 (br d, J ) 7.8
3
2
13
Hz, 1H), 7.43 (d, J ) 7.8 Hz, 1H); CMR (CDCl
3
) δ 20.99,
2
1
2
1.11, 24.53, 26.33, 27.91, 72.80, 82.46, 83.28, 119.18, 123.10,
2
+
23.79, 130.48, 138.19, 152.07; HRMS calcd for C14 (M )
H
18
O
3
were washed with water, dried, and concentrated. The
residual oil was purified by preparative TLC as before to afford
bridged ketone 16 (68 mg, 83%). This was identical with a
sample prepared by method A.
34.1255, found 234.1259. Anal. Calcd for C14H O : C, 71.77;
18 3
H, 7.74. Found: C, 71.43; H, 7.59.
2,3,4,5-T e t r a h y d r o -2,5,8-t r im e t h y l-2,5-m e t h a n o -1-
ben zoxep in -10-on e (11). Rearrangement of diol 10 (120 mg)
was carried out as for 16 to furnish bridged ketone 11 as a
colorless oil (100 mg, 90%): ot 88-93 °C (0.3 mmHg); IR 1765
Meth od C. To a magnetically stirred solution of the diol
1
5 (90 mg) in dry EtNO
of concentrated H SO
0 min, the reaction mixture was allowed to warm to 0 °C and
neutralized by adding saturated aqueous NaHCO . Et O was
added, and the layers were separated. The aqueous layer was
extracted with Et O. The combined organic layers were
2
(10 mL) at -78 °C was added a drop
2
4
or BF ‚Et O. After being stirred for
3
2
3
-1 1
cm ; H NMR (CDCl
3
) δ 1.41 (s, 3H), 1.43 (s, 3H), 1.81-1.97
3
2
(m, 2H), 2.26 (s, 3H), 2.29-2.35 (m, 1H), 2.46-2.57 (m, 1H),
6
.58 (br s, 1H), 6.71 (br d, J ) 7.8 Hz, 1H), 6.91 (d, J ) 7.8
13
2
Hz, 1H); CMR (CDCl
3
) δ 14.63, 17.87, 20.94, 32.31, 36.38,
washed with water, dried, and concentrated. Preparative TLC
purification of the residual oil furnished ketone 16 (70 mg,
4
8.60, 80.10, 116.37, 122.04, 123.94, 138.87, 151.99, 213.98;
+
HRMS calcd for C14
H
16
O
2
(M ) 216.1150, found 216.1152. Anal.
8
5%), identical with a sample prepared by previous methods.
Calcd for C14
.50.
2,3,4,5-Tetr ah ydr o-2,5,8-tr im eth yl-7-br om o-2,5-m eth an o-
H O : C, 77.75; H, 7.46. Found: C, 77.49; H,
16 2
cis-1,2,2a ,8a -Tetr a h yd r o-2a -m eth yl-8-eth yl-8H-ben zo-
7
[
b]cyclobu ta [e]p yr a n -8,8a -d iol (19). Reduction with LAH
of oxetanol 18 (140 mg, 0.56 mmol) via the procedure for 15
for 10 h afforded the diol 19 as a crystalline solid (120 mg,
1-ben zoxep in -10-on e (20). To a magnetically stirred solution
of ketone 11 (120 mg, 0.56 mmol) in dry petroleum ether (5
mL) containing suspended anhydrous Na CO (110 mg) was
2 3
added bromine (28.9 µL) slowly until the color of bromine just
persisted. After the completion of bromine addition, the
reaction mixture was filtered through a short column of silica
9
2%): crystallized from light petroleum ether; mp 79-80 °C;
1
H NMR (CDCl
.04 (m, 6H), 2.12 (br, 2H, OH), 6.86-7.34 (m, 3H), 7.50 (dd,
J ) 7.2, 2 Hz, 1H). Anal. Calcd for C14 : C, 71.77; H,
.74. Found: C, 71.75; H, 7.79.
,3,4,5-Te t r a h yd r o-2-m e t h yl-5-e t h yl-2,5-m e t h a n o-1-
3
) δ 0.62 (t, J ) 7.5 Hz, 3H), 1.54 (s, 3H), 1.58-
2
18 3
H O
7
2
gel [petroleum ether/Et
2
O (9:1)] to afford 20 as a solid (130
ben zoxep in -10-on e (20). Rearrangement of diol 19 (80 mg)
was carried out as for 16 to furnish 20 as a colorless oil (60
mg, 79%): crystallized from ether-light petroleum ether; mp
121-122 °C (lit.3a mp 122-123 °C); IR 1765 cm ; H NMR
-1
1
-
1
1
mg, 81%): ot 85-90 °C (0.06 mmHg); IR 1763 cm ; H NMR
CDCl ) δ 1.06 (t, J ) 7.5 Hz, 3H), 1.41 (s, 3H), 1.84-2.64 (m,
H), 6.70-7.24 (m, 4H). Anal. Calcd for C14 : C, 77.75;
H, 7.46. Found: C, 77.79; H, 7.70.
,7-Dim eth yl-3-m eth oxych r om on e (24). To a magneti-
cally stirred suspension of CuBr (11.84 g, 53 mmol) in dry
EtOAc (25 mL) was added 2-hydroxy-4-methylacetophenone
21) (5.25 g, 35 mmol) in dry CHCl (25 mL). The mixture
was then refluxed until the color changed from green to amber
about 8 h). Upon cooling, it was filtered and concentrated to
(CDCl
3
) δ 1.39 (s, 3H), 1.42 (s, 3H), 1.82-1.98 (m, 2H), 2.29
(
3
(
s, 3H), 2.31-2.36 (m, 1H), 2.45-2.52 (m, 1H), 6.63 (s, 1H),
6
16 2
H O
1
3
7.13 (s, 1H); CMR (CDCl ) δ 14.56, 17.80, 22.58, 32.25, 36.31,
3
2
48.57, 80.32, 116.07, 118.09, 127.58, 131.64, 138.31, 151.42,
+
2
213.03; HRMS calcd for C15
294.0252.
H
14
O
2
Br(M ) 294.0255, found
(
3
Ack n ow led gm en t. We graciously thank Professor
Frank M. Hauser, Department of Chemistry, State
University of New York at Albany, for the high-resolu-
(
1
afford bromo ketone 22 (6.58 g, 82%): H NMR (CCl
4
) δ 2.34
(
1
s, 3H), 4.26 (s, 2H), 6.53-6.83 (m, 2H), 7.56 (d, J ) 7.5 Hz,
H).
A mixture of the above bromo ketone 22 (6.58 g, 28.7 mmol),
O (20 mL), and anhydrous NaOAc (5 g) was heated under
1
13
tion H NMR and C NMR spectra of some of the
compounds reported here and Professor David J . Gold-
smith, Department of Chemistry, Emory University, for
Ac
2
reflux for 2 h. Then it was cooled, diluted with water, and
extracted with Et O. The ether extracts were washed with
water, dried, and concentrated. The crude product was stirred
with concentrated H SO (10 mL) at 50 °C for 1 h. It was then
1
the comparison H NMR spectra of our synthetic 26 with
2
that of an authentic sample. The Department of Science
and Technology, Govt. of India is sincerely thanked for
financial support.
2
4
cooled and diluted with water when hydroxychromone 23
precipitated out. This crude hydroxychromone (3.31 g) was
filtered, dried, and directly taken in acetone (60 mL) and
J O952184J