Synthesis of the benzophenone fragment of balanol via an intramolecular cyclization event

Article abstract of DOI:10.1021/jo000750r

Studies are reported on the use of either a 7-exo radical cyclization or an intramolecular Heck reaction as the key step for the construction of the benzophenone fragment of the PKC inhibitor, balanol. Whereas, the former approach was unsuccessful, the Heck reaction proved to be viable for the coupling of two fully functionalized aryl subunits affording regioselectively a biaryl seven-membered lactone with an exocyclic alkene as the major component, in contrast to the competing eight-membered ring lactone. Hydrolysis of the lactone followed by oxidative cleavage of the alkene with ruthenium tetraoxide completed this short synthesis of the benzophenone unit.

Full text of DOI:10.1021/jo000750r

6052
J . Org. Chem. 2000, 65, 6052-6060
Syn th esis of th e Ben zop h en on e F r a gm en t of Ba la n ol via a n
In tr a m olecu la r Cycliza tion Even t
Marie-Pierre Denieul, Bolette Laursen, Rita Hazell, and Troels Skrydstrup*
Department of Chemistry, University of Aarhus, Langelandsgade 140,8000 Aarhus C, Denmark
ts@kemi.aau.dk
Received May 16, 2000
Studies are reported on the use of either a 7-exo radical cyclization or an intramolecular Heck
reaction as the key step for the construction of the benzophenone fragment of the PKC inhibitor,
balanol. Whereas, the former approach was unsuccessful, the Heck reaction proved to be viable for
the coupling of two fully functionalized aryl subunits affording regioselectively a biaryl seven-
membered lactone with an exocyclic alkene as the major component, in contrast to the competing
eight-membered ring lactone. Hydrolysis of the lactone followed by oxidative cleavage of the alkene
with ruthenium tetraoxide completed this short synthesis of the benzophenone unit.
In tr od u ction
more sensitive structural element necessary for the
inhibitory action of balanol against PKC. Hence, struc-
tural changes of this fragment lead to serious loss of
activity against PKC. It is believed that this fragment
mimics the triphosphate unit of ATP.7m
The structurally unique fungal metabolite, balanol,
isolated from Verticillium balanoides1 and Fusarium
merismoides,2 has attracted much interest owing to its
high inhibitory activity against protein kinase C (PKC)
with IC50 values in the nanomolar range (Figure 1).
Balanol therefore represents a new and potent lead
compound for the deactivation of this important class of
isoenzymes involved in intracellular signaling pathways
and associated with a variety of disorders including
cancer, cardiovascular disorders, asthma, diabetes, cen-
tral nervous system dysfunction, and AIDS.3 To provide
further evaluation of this natural product, as well as
opening up synthetic routes to analogues of balanol,
several groups responded quickly to the synthesis of this
fungal metabolite, with six total syntheses being pub-
lished to date,4 as well as numerous reports on the
prepartion of key fragments.5,6
We have recently provided an approach to the hexahy-
droazepine ring of balanol via a samarium diiodide
promoted 7-exo cyclization of an acyclic carbonylhydra-
(5) For synthetic approaches to the hexahydroazepine fragment,
see: (a) Mu¨ller, A.; Takyar, D. K.; Wit, S.; Ko¨nig, W. A. Liebigs Ann.
Chem. 1993, 651. (b) Hughes, P. F.; Smith, S. H.; Olson, J . T. J . Org.
Chem. 1994, 59, 5799. (c) Hu, H.; J agdmann, G. E.; Hughes, P. F.;
Nichols, J . B. Tetrahedron Lett. 1995, 36, 3659. (d) Albertini, E.; Barco,
A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V. Synlett, 1996,
29. (e) Tuch, A. T.; Sanie`re, M.; Le Merrer, Y.; Depezay, J .-C.
Tetrahedron: Asymmetry 1996, 7, 2901. (f) Albertini, E.; Barco, A.;
Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V. Tetrahedron 1997,
53, 17177. (g) Wu, M. H.; J acobsen, E. N. Tetrahedron Lett. 1997, 38,
1693. (h) Coulon, E.; Can˜o de Andrade, M. C.; Ratovelomanana-Vidal,
V.; Geneˆt, J .-P. Tetrahedron Lett. 1998, 39, 6467. (i) Herdeis, C.;
Mohareb, R. M.; Neder, R. B.; Schwabenla¨nder, F.; Telser, J . Tetra-
hedron: Asymmetry 1999, 10, 4521. (j) Cook, G. R.; Shanker, P. S.;
Peterson, S. L. Org. Lett. 1999, 1, 615.
(6) For synthetic approaches to the benzophenone fragment, see: (a)
Hollinshead, S. P., Nichols, J . B., Wilson, J . W. J . Org. Chem. 1994,
59, 6703. (b) Nilsson, J . P., Andersson, C.-M. Tetrahedron Lett. 1997,
38, 4635. (c) Storm, J . P., Andersson, C.-M. Org. Lett. 1999, 1, 1451.
(7) For the synthesis and study of balanol analogues, see: (a)
Heerding, J . M.; Lampe, J . W.; Darges, J . W.; Stamper, M. L. Bioorg.
Med. Chem. Lett. 1995, 5, 1839. (b) J agdmann, G. E., J r.; Defauw, J .
M.; Lai, Y.-S.; Crane, H. M.; Hall, E. S.; Buben J . A.; Hu, H.; Gosnell,
P. A. Bioorg. Med. Chem. Lett. 1995, 5, 2015. (c) Lai, Y.-S.; Stamper,
M. Bioorg. Med. Chem. Lett. 1995, 5, 2147. (d) Lai, Y.-S.; Menaldino,
D. S.; Nichols, J . B.; J agdmann, G. E., J r.; Mylott, F.; Gillespie, J .;
Hall, S. E. Bioorg. Med. Chem. Lett. 1995, 5, 2151. (e) Lai, Y.-S.;
Mendoza, J . S.; Hubbard, F.; Kalter, K. Bioorg. Med. Chem. Lett. 1995,
5, 2155. (f) Mendoza, J . S.; J agdmann, G. E., J r.; Gosnell, P. A. Bioorg.
Med. Chem. Lett. 1995, 5, 2211. (g) Hu, H.; Hollinshead, S. P.; Hall, S.
E.; Kalter, K.; Ballas, L. M. Bioorg. Med. Chem. Lett. 1996, 6, 973. (h)
J agdmann, G. E., J r.; Defauw, J . M.; Lampe, J . W.; Darges, J . W.;
Kalter, K. Bioorg. Med. Chem. Lett. 1996, 6, 1759. (i) Crane, H. M.;
Menaldino, D. S.; J agdmann, G. E., J r.; Darges, J . W.; Buben, J . A.
Bioorg. Med. Chem. Lett. 1996, 5, 2133. (j) Nielsen, J .; Lyngsø, L. O.
Tetrahedron Lett. 1996, 37, 8439. (k) Defauw, J . M., Murphy, M. M.;
J agdmann, G. E., J r.; Hu, H.; Lampe, J . W.; Hollinshead, S. P.;
Mitchell, T. J .; Crane, H. M.; Heerding, J . M.; Mendoza, J . S.; Davis,
J . E.; Darges, J . W.; Hubbard, F. R.; Hall, S. E. J . Med. Chem. 1996,
39, 521. (l) Lai, Y.-S.; Mendoza, J . S.; J agdmann, G. E., J r.; Menaldino,
D. S.; Biggers, C.; Heerding, J . M.; Wilson, J . W.; Hall, S. E.; J iang, J .
B.; J anzen, W. P.; Ballas, L. M. J . Med. Chem. 1997, 40, 226. (m) Koide,
K.; Bunnage, M. E.; Paloma, L. G.; Kanter, J . R.; Taylor, S. S.; Brunton,
L. L.; Nicolaou, K. C. Chem. Biol. 1995, 2, 601.
Whereas considerable modifications of the hexahy-
droazepine ring of balanol can be tolerated with even in
certain cases such changes resulting in an increase in
biological activity,7 the benzophenone part represents a
(1) Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.;
J anzen, W. P.; Ballas, L. M.; Loomis, C. R.; J iang, J . B. J . Am. Chem.
Soc. 1993, 115, 6452.
(2) Ohshima, S.; Yanagisawa, M.; Katoh, A.; Fujii, T.; Sano, T.;
Matsukuma, S.; Furumai, T.; Fujiu, M.; Watanabe, K.; Yokose, K.; M.
Arisawa, M.; Okuda, T. J . Antibiot. 1994, 47, 639.
(3) For a recent review on the application of PKC inhibitors, see:
Bradshaw, D.; Hill, C. H.; Nixon, J . S.; Wilkinson, S. E. Agents Actions
1993, 38, 135. See also, Ishii, H.; J irousek, M. R.; Koya, D.; Takagi,
C.; Xia, P.; Clermont, A.; Bursell, S.-E.; Kern, T. S.; Ballas, L. M.;
Heath, W. F.; Stramm, L. E.; Feener, E. P.; King, G. L. Science 1996,
272, 728.
(4) (a) Nicolaou, K. C.; Bunnage, M. E., Koide, K. J . Am. Chem. Soc.
1994, 116, 8402. (b) Nicolaou, K. C.; Koide, K.; Bunnage, M. E. Chem.
Eur. J . 1995, 1, 454. (c) Lampe, J . W.; Hughes, P. F.; Biggers, C. K.;
Smith, S. H.; Hu, H. J . Org. Chem. 1994, 59, 5147. (d) Lampe, J . W.;
Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H. J . Org. Chem. 1996,
61, 4572. (e) Adams, C. P.; Fairway, S. M.; Hardy, C. J .; Hibbs, D. E.;
Hursthouse, M. B.; Morley, A. D.; Sharp, B. W.; Vicker, N.; Warner, I.
J . Chem. Soc., Perkin Trans. 1 1995, 2355. (f) Barbier, P.; Stadlwieser,
J . Chimia 1996, 50, 530. (g) Tanner, D.; Tadenborg, L.; Almario, A.;
Pettersson, I.; Csoeregh, I.; Kelly, N. M.; Andersson, P. G. Tetrahedron
1997, 53, 4857. (h) Miyabe, H.; Torieda, M.; Kiguchi, T.; Naito, T.
Synlett 1997, 580. (i) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.;
Kiguchi, T.; Naito, T. J . Org. Chem. 1998, 63, 4397.
10.1021/jo000750r CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/19/2000

Synthesis of the Benzophenone Fragment of Balanol
J . Org. Chem., Vol. 65, No. 19, 2000 6053
Sch em e 1
routes for ring closure could then be envisaged. The first
involves a 7-exo-dig radical cyclization with iodide 3
mediated by either SmI2 or tributyltin hydride. Although
7-exo radical cyclizations have been reported to be slow,10
we felt that because of the participation of a reactive aryl
radical in combination with the conformational restric-
tions imparted by the two aryl groups, radical cyclization
could nevertheless be competitive with simple reduction.
In both cases, competing 8-endo ring closure would be a
serious concern; however, a possible remedy in this
respect would be to coax the reaction into favoring the
seven-membered lactone formation via the introduction
of an electron withdrawing group at the terminal position
of the alkyne. Subsequent bond disconnection of the ester
linkage then leads to two readily accessible tri- and tetra-
functionalized aromatic rings.
In the second approach, ring closure could potentially
take place via an intramolecular Heck reaction11,12 in-
volving the participation of the iodide 3 possessing a
vinyl-substituted aryl unit, although some concern was
also made about the regioselectivity in this cyclization
event. Again, two easily available aryl subunits would
allow the preparation of the δ-lactone precursor. Whether
an intramolecular version of Pd-catalyzed C-C bond
forming reaction was indeed necessary to attain the
diaryl core structure of balanol was supported by the
preliminary synthetic studies reported by Nicolaou and
co-workers (Scheme 1). Attempts to promote the Pd-
catalyzed Stille coupling of the stannane 5 with the acid
chloride 4 failed, possibly owing to the sterically con-
gested environment at the carbonyl center of the product
owing to the four ortho substituents.4b This was further
substantiated by the lack of reactivity of the correspond-
ing anion 6 with the acid chloride 4,4b,6a known to perform
well in simpler systems.4e
F igu r e 1. Retrosynthetic scheme for the synthesis of the
benzophenone core structure of balanol.
zone.8 In our continued endeavors for completing the
synthesis of balanol, we now present our work concerning
the preparation of the fully functionalized benzophenone
moiety. Several routes to the benzophenone moiety have
earlier been reported, with approaches involving key
coupling steps of the two aryl units such as an anionic
homo-Fries rearrangement,4a-d intermolecular carbonyl
addition reactions,4e,6a and an iron-assisted SNAr reaction
followed by an intramolecular Friedel-Craft reaction.6b,c
A possible biomimetic approach has also been published
involving an oxidative ring cleavage of the naturally
occurring anthraquinone, chrysophanic acid.4h,i In this
work, we report on an alternative approach involving the
application of an intramolecular Heck reaction as the key
step for the coupling of two fully functionalized and
readily available aryl subunits to the benzophenone
fragment.9
Th e Ra d ica l Cycliza tion Ap p r oa ch . To prepare the
necessary cyclic precursor for the radical cyclization step,
we first required the benzoic acid derivative 8 and the
phenol 11 (Scheme 2). Methyl ester formation and
triflation of commercially available 2-hydroxy-3-meth-
oxybenzoic acid was followed by an efficient Sonogashira-
Resu lts a n d Discu ssion s
Retr osyn th etic Con sid er a tion s. A retrosynthetic
analysis of the benzophenone moiety 1 of balanol is
illustrated in Figure 1. This aryl fragment could arise
from the simple oxidative cleavage of the corresponding
exocyclic alkene 2, incorporated in a seven-membered
lactone involving the C3-hydroxyl group and the C6′-
carboxylic acid, and then lactone hydrolysis. Two possible
(10) Beckwith, A. L. J .; Schiesser, C. H. Tetrahedron 1985, 42, 3925.
(11) For recent reviews on the Heck reaction, see: (a) Bra¨se, S.; de
Meijere, A. In Metal-catalyzed Cross-coupling Reactions; Diederick, F.,
Stang, P. J ., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 3. (b) Link,
J . T.; Overman, L. E. In Metal-catalyzed Cross-coupling Reactions;
Diederick, F., Stang, P. J ., Eds.; Wiley-VCH: Weinheim, 1998; Chapter
6. (c) Gibson, S. E.; Middleton, R. J . Contemp. Org. Synth. 1996, 3,
447.
(12) Only three other 7-exo intramolecular Heck reactions have been
reported before. (a) Trost, B. M.; Fortunak, J . M. D. Organometallics
1982, 1, 7. (b) Sundberg, R. J .; Cherney, R. J . J . Org. Chem. 1990, 55,
6028. (c) Masters, J . J .; J ung, D. K.; Bornmann, W. G., Danishefsky,
S. J .; de Gala, S. Tetrahedron Lett. 1993, 34, 7253.
(8) Riber, D.; Hazell, R.; Skrydstrup, T. J . Org. Chem., in press.
(9) A preliminary communication of part of this work has been
reported. Denieul, M.-P.; Skrydstrup, T. Tetrahedron Lett. 1999, 40,
4901.

6054 J . Org. Chem., Vol. 65, No. 19, 2000
Denieul et al.
Sch em e 2
Sch em e 3
compounds arose according to TLC analysis. On the other
hand, cyclization attempts with Bu3SnH in benzene
under conditions favoring ring closure (high dilution, slow
addition of Bu3SnH) produced a much cleaner reaction,
but nevertheless gave rise to four chromatographically
1
inseparable compounds as observed by H NMR. Proper
identification of these compounds as any of the three
possible isomeric cyclization products (two 7-exo modes
affording 13 and one 8-endo) was complicated by the
1
overlap of the H NMR signals from both the alkene and
aryl protons. In any event, attempted ozonolysis of this
mixture in order to determine its composition, as well
as potentially getting hold of balanol’s benzophenone
fragment were thwarted by the extensive decomposition
observed. This route was therefore abandoned and re-
course was taken to investigate the intramolecular Heck
reaction as an alternative approach for the cyclization
step.
Ap p lica tion of th e Heck Rea ction . As indicated
above with the radical cyclization approach, several
potential problems were also anticipated in the adapta-
tion of a Heck reaction for the formation of the seven-
membered biaryl lactone as illustrated in Scheme 4.
Again, we assumed that applying an intramolecular
version of this Pd-catalyzed reaction would override any
steric problems arising in the C-C bond forming step
due to the four ortho-substituents. However, in the event
of successful cyclization, 8-endo ring closure could also
here become a serious competitor to the 7-exo cyclization
as in the radical approach, and it was difficult to assess
which of the two would be the most dominant. In
addition, a third option involving cyclization onto the
aromatic ring was also a contender leading to a benzopy-
ranone derivative. As this pathway, nevertheless, re-
quires dearomatization in the six-membered ring forming
step, we assumed that the production of this compound
would be less likely.
type coupling with phenylacetylene according to that
reported by Chen and Yang,13 affording the diaryl
substituted alkyne 7 in good yield. Subsequent hydrolysis
of the methyl ester provided the acid 8 with an overall
yield of 63% from the methyl ester of 2-hydroxy-3-
methoxybenzoic acid. The corresponding phenol coupling
partner could be prepared starting with a selective
iodination of 3,5-dihydroxybenzoic acid under aqueous
conditions in analogy to that reported for other systems.14
Whereas some problems were encountered in the isola-
tion of the iodide owing to its solubility in water, better
results were obtained by converting the benzoic acid to
its benzyl ester 9 prior to the iodination step. In this way,
the iodide 10 was secured in 89% yield. Selective benzy-
lation of one of the two alcohols proceeded only in a
modest yield affording the phenol 11 in 44% yield (based
on 36% recovered starting material), but considering the
facility of the combined three steps required to prepare
11, we still considered this a viable approach.15 Subse-
quent ester formation of the two components employing
the mild conditions developed by Furukawa performed
well furnishing the cyclic precursor 12 in a 93% yield.16
Initial cyclization attempts were first performed with
the SmI2/HMPA combination, a well-known system pre-
viously exploited as a substitute to tributyltin hydride
for promoting 5-exo cyclizations of aryl iodides (Scheme
3).17 However, when SmI2/HMPA in THF was slowly
added to a solution of the iodide, a complex mixture of
Synthesis of the cyclic precursor 20 only required
modification of the right-hand fragment with respect to
12, which was easily prepared from a two step procedure
employing the readily available oxazoline 14 (Scheme 5).
Nucleophilic aromatic substitution of 14, as described by
Meyers and co-workers,18 with vinylmagnesium bromide,
followed by a two step hydrolysis procedure (MeI, then
NaOH) readily afforded the vinyl benzoic acid derivative
15 in 70% overall yield.19 This material was then coupled
to the phenol 11 as above, providing the diaryl ester 20
(13) (a) Chen, Q.-Y.; Yang, Z.-Y. Tetrahedron Lett. 1986, 27, 1171.
(b) Evans, K. L.; Prince, P.; Huang, E. T.; Boss, K. R.; Gandour, R. D.
Tetrahedron Lett. 1990, 31, 6753.
(14) Thomsen, I.; Torssel, K. B. G. Acta Chem. Scand. 1991, 45, 539.
(15) (a) Matsumoto, T.; Hosoya, T.; Suzuki, K. J . Am. Chem. Soc.
1992, 114, 3568. (b) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki,
K. J . Am. Chem. Soc. 1994, 116, 1004.
(18) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J . Org. Chem. 1978,
43, 1372.
(16) Hashimoto, S.; Furukawa, I. Bull. J . Chem. Soc. 1981, 54, 2227.
(17) For recent reviews on the application of SmI2 in organic
synthesis, see: (a) Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745.
(b) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307. (c)
Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321. (d)
Skrydstrup, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 345.
(19) Hydrolysis of 2-(3-methoxy-2-vinylphenyl)-4,4-dimethyl-2-ox-
azoline to the benzoic acid 15 was reported in ref 18 to proceed under
acid conditions. However, in our hands hydrolysis of this oxazoline
under identical conditions led to the formation of 4-methoxy-3-
methylphthalide, and hence, the procedure for basic hydrolysis was
employed.

Synthesis of the Benzophenone Fragment of Balanol
J . Org. Chem., Vol. 65, No. 19, 2000 6055
Ta ble 1. In tr a m olecu la r Heck Rea ction of th e Dia r yl Ester 18a
yields (%)
entry
catalyst (equiv)
base (equiv)
NaOAc (3)
NaOAc (3)
NaOAc (3)
solvent
T (°C)
t (h)
21
22
23
1
2
3
4
5
6
7
8
(Ph3P)2PdCl2 (0.26)
(Ph3P)2PdCl2 (0.26)
(Ph3P)2PdCl2 (0.52)
(Ph3P)2PdCl2 (0.52)
Pd(OAc)2 (0.025)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.10), Ph3P (0.26)
Pd(OAc)2 (0.10), Ph3P (0.26)
DMA
DMF
125
85
90
90
95
90
85
85
0.5
0.75
48
58
75
29
58
11
13
6
7
8
2
CH3CN
CH3CN
DMF
CH3CN
CH3CN
CH3CN
47
65
0.25
96
48
25
NaOAc (3)
K2CO3 (4), Bu4NBr (1)
K2CO3 (4), Bu4NCl (1)
Et3N (2)
10
4
decomposition
5
decomposition
65
Ag2CO3 (2)
a
Reaction was performed on the corresponding aryl bromide
Sch em e 4. P ossible Com p etin g Cycliza tion P a th w a ys
Sch em e 5
Sch em e 6
in 95% yield.17 To test the efficiency of the Heck reaction,
two simpler systems 18 and 19 were also prepared
from o-iodophenol (16) and the benzylated 2-iodoresor-
cinol 17, the latter which was obtained as described for
the phenol 11.
The feasibility of the 7-exo ring closure was initially
carried out on the sterically less hindered model 18,
employing several conditions with the readily available
palladium catalysts, Pd(OAc)2 and PdCl2(PPh3)2 (Scheme
6 and Table 1).11 Cyclization with PdCl2(PPh3)2 (26 mol
%)/NaOAc (3 equiv) in a polar medium such as DMA
proceeded fast (<1 h) and led to a 6:1.4:1 mixture of three
isomeric cyclic compounds in 67% yield (entry 1). To our
delight, the major compound did indeed correspond to the
7-exo product 21 as shown by 1H NMR spectroscopy
followed by the 8-endo product 22 and the pyrone 23.
With 21, two doublets were found at 5.61 and 5.49 ppm
with a small coupling constant (J ) 1.2 Hz) conforming
with the exocyclic methylene protons. On the other hand,
in 22 the CdC protons, being bound to two different
vicinal carbon atoms, and adjacent to an aromatic ring,
are downfield shifted to 6.85 and 6.91 ppm and display
a cis coupling of 11.2 Hz. The isomeric 6-exo product 23
is likewise easily identified by the presence in the 1H
NMR spectrum of the complete vinyl group, whereas only
six aromatic protons could be identified.
Attempted cyclization in DMF was also rapid but did
not improve greatly the ratio in favor of the 7-exo product
(entry 2). In contrast, switching to acetonitrile dramati-

6056 J . Org. Chem., Vol. 65, No. 19, 2000
Ta ble 2. In tr a m olecu la r Heck Rea ction of th e Dia r yl Ester 19 a n d 20
Denieul et al.
yields (%)
26, 27
traces
entry
catalyst (equiv)
(Ph3P)2PdCl2 (0.26)
Pd(OAc)2 (0.10)
(Ph3P)2PdCl2 (0.26)
(Ph3P)2PdCl2 (0.52)
(Ph3P)2PdCl2 (0.26)
Pd(OAc)2 (0.10), Ph3P (0.26)
Pd(OAc)2 (0.10), (o-Tol)3P (0.26)
base (equiv)
NaOAc (3)
K2CO3 (4), Bu4NCl (1)
NaOAc (3)
NaOAc (3)
NaOAc (3)
solvent
CH3CN
DMF
CH3CN
CH3CN
CH3CN/DMF (4:1)
CH3CN
T (°C)
t (h)
24, 25
28, 29
1 (19)
2 (19)
3 (20)
4 (20)
5 (20)
6 (20)
7 (20)
90
100
90
90
90
68
2
53
13
decomposition
144
79
48
10
42
32
70
55
44
37
11
13
13
20
5
19
5
4
(iPr)2NEt (2)
Et3N (2)
90
90
CH3CN
Sch em e 7
with 20 had dropped somewhat (entry 6) compared to
18 (Table 1, entry 7). Confirmation of the structure of
the 7-exo and 8-endo compounds, 25 and 27, were made
by single-crystal X-ray (see Figures S1 and S2, Support-
ing Information). It is interesting to note the approxi-
mately 60° torsional angle of the exocyclic CdC bond in
25 with respect to the planes of the aromatic rings,
suggesting little conjugation between these chromophores.
Although, no sign of the pyrone derivative were de-
tected in the reaction mixtures of these cyclizations as
previously observed with 18, we did detect a second minor
component which was identified in the reaction of 25 as
the primary iodide 29 by X-ray analysis (Scheme 7 and
Figure S3, Supporting Information). As these products
are themselves the result of an initial 7-exo cyclization
event, implies that the ratio 7-exo/8-endo ring closures
are even greater than initially observed. Nevertheless,
this was of little use as attempts to convert the iodides
28 and 29 by simple elimination to either 24 or 25 with
sterically hindered bases (DBU, KO-t-Bu) failed leading
mainly to decomposition. Examination of the X-ray
structure of 29 suggests an explanation for this observa-
tion. The C11-C12 bond is also approximately 60° to the
planes of the aryl rings placing the C11 proton directly
between the OMe and OBn substituents in the ortho-
position. Hence, access by a base to this sterically
encumbered proton becomes difficult.
cally reduced the rate of cyclization being completed only
after approximately 90 h (entry 3). Although the catalyst
had to be replenished during the course of the reaction
with a total of up to 52 mol % added in the end, the
reaction was much cleaner affording 21 in 75% yield with
only 6% of 22 and no traces of the pyrone product. The
corresponding bromide was less reactive as expected but
could not be forced to completion and only led to a low
cyclization yield. Substituting the palladium catalyst
with Pd(OAc)2 did not improve the selectivity under
various conditions (entries 5-8), although in one case,
Pd(OAc)2/PPh3/Et3N, a cyclization yield of 70% was
obtained with a 21:22 ratio of 13:1, and with only 10%
catalyst loading (entry 7).
With these encouraging results, the more encumbered
substrates 19 and 20 were then tested as shown in
Scheme 7 and Table 2. As with the model compound 18,
best cyclization yields and regioselectivities were ob-
tained with PdCl2(PPh3)2 (entries 1,3-5). Again, high
catalyst loading was necessary to bring about the comple-
tion of the reaction (26-52 mol %) particularly in the case
of correct substrate 20. Although a good yield (70%) of
the 7-exo product 25 was obtained in one instance (entry
4), it was not reproducible and in general the yields were
in the order of 50%. To try to reduce the reaction times,
solvent mixtures of acetonitrile and DMF were also tested
of which a 4:1 mixture, respectively, proved to give the
best results (entry 5). Quite pleasing was it that the
regioselectivity in the cyclization step was still in favor
of the 7-exo product, implying that the sterical influence
from the new ortho-substitutent was not a problem. On
the other hand, employing Pd(OAc)2 the regioselectivity
Although no mechanistic investigation was undertaken
to examine the pathways leading to these iodides, the
observation that a similar compound was not formed in
the cyclization of 18, suggests that these compounds do
not originate from simple nucleophilic addition of iodide
to the activated double bond. Instead, another mecha-
nism is proposed as illustrated in Scheme 8. Oxidative
addition of Pd(0) to the aryl iodides 19 and 20 and
subsequent insertion of the adjacent alkene leads to the
σ-alkyl Pd intermediate 30. For the â-elimination step
to the alkenes 24 and 25, a rotation of the adjacent C-C
bond is required in order to place the Pd and the â-H in
a syn orientation. However, the sterical hindrance from
the flanking alkoxy groups may prevent this step, result-
ing in reductive elimination and formation of the corre-
sponding alkyl iodides 28 and 29.
Oxid a tive Clea va ge a n d Rin g Op en in g. The final
steps to balanol’s benzophenone fragment now only
required an oxidative cleavage step of the exocyclic alkene
in 25 and a ring opening of the seven-membered lactone.
However, these steps proved not to be so facile as first
anticipated. In the model compound 21, ozonolysis led
only to degradation and cleavage of the two aryl units,
while OsO4 failed to react at all, even under stoichiomet-
ric conditions (Scheme 9). Epoxidation with m-CPBA did
proceed to afford the labile epoxide 31, however several
attempts to hydrolyze this compound and then subjecting

Synthesis of the Benzophenone Fragment of Balanol
J . Org. Chem., Vol. 65, No. 19, 2000 6057
Sch em e 8
Sch em e 10
Sch em e 11
Sch em e 9
in this oxidation step were obtained with the opened
substrate, whereas yields of less than 10% were charac-
teristic of the same reaction performed with lactone 21.
Finally, it was gratifying to observe that the same
sequence of reactions (ring opening and oxidative cleav-
age) could be carried out on the correct substrate 25
affording the protected benzophenone moiety 36 of bal-
anol (Scheme 11).
Con clu sion s
The benzophenone fragment of the PKC inhibitor
balanol has been synthesized using an intramolecular
Heck reaction as the key step for assembling the two aryl
units. In contrast to previous syntheses of the benzophe-
none moiety, the mild conditions of this approach allows
the use of fully functionalized and readily available aryl
units in the coupling step, though further studies are still
required to improve the problematic alkene cleaving step.
Previous reports have already shown that selective
hydrolysis of the least encumbered ester of compounds
analogous to 35 is a viable process,4e making it possible
to couple this compound onto the hexahydroazepine unit
of balanol and hence completing the synthesis of this
natural product. This work is currently ongoing and will
be reported in due course.
this material to a sodium periodate promoted cleavage
were not successful.
To examine whether the undesired reactivity of 21 was
a result of the lactone ring, this compound was hydro-
lyzed and simulaneously benzylated to give 32 in 85%
yield (Scheme 10).20 Again, similar results as with 21
were obtained upon attempted ozonolysis or dihydroxy-
lation with OsO4 of this alkene. Treatment of 32 with
m-CPBA did not lead to the corresponding epoxide in this
case but instead led to the five-membered lactone 33 in
low yield.
Efforts to hydrolyze this compound also proved futile
and only led to migration and formation of the six-
membered lactone. At last, treatment of alkene 32 with
in situ generated ruthenium tetraoxide (RuCl3:xH2O/
NaIO4) did provide the desired benzophenone 34 in
modest yield.21 It is interesting to note, that best results
Exp er im en ta l P r oced u r e
Gen er a l Con sid er a tion s. THF was dried and freshly
distilled over sodium/benzophenone. Dichloromethane was
freshly distilled over P2O5, and acetonitrile from calcium
hydride. Reactions were monitored by thin-layer chromatog-
raphy (TLC) analysis. The following compounds were prepared
according to literature procedures: 2-hydroxy-3-methoxyben-
zoic acid, methyl ester,22 and oxazoline 14.18
(20) Suau, R.; Lo´pez-Romero, J . M.; Rico, R.; Alonso, F. J .; Lobo, C.
Tetrahedron 1996, 52, 11307.
(21) Ghosh, S.; Karpha, A.; Saha, G.; Patra, D. Tetrahedron Lett.
1992, 33, 2363.
(22) Paulis, T.; Hewlett, W. A.; Schmidt, D. E.; Mason, N. S.; Trivedi,
B. L.; Ebert, M. H. Eur. J . Med. Chem. 1997, 32, 385.

6058 J . Org. Chem., Vol. 65, No. 19, 2000
Denieul et al.
3,5-Dih yd r oxyben zoic Acid , Ben zyl Ester (9). Benzyl
bromide (3.9 mL, 32.8 mmol) was added to a solution of 3,5-
dihydroxybenzoic acid (5.00 g, 32.4 mmol) and dry sodium
carbonate (3.44 g, 32.5 mmol) in DMF (50 mL). The reaction
was stirred overnight at room temperature under nitrogen.
After addition of water, the solution was extracted five times
with ether, and the combined organic phases were then
washed three times with water and once with brine, dried over
MgSO4, and concentrated in vacuo. The solid residue was
purified by crystallization in CH2Cl2/pentane affording the
benzyl ester 9 as colorless crystals (6.03 g, 76% yield): mp
A solution of this oxazoline (5.23 g, 22.6 mmol) in an excess
of methyl iodide (7 mL, 5 equiv) was stirred overnight at 20
°C. After removal of the methyl iodide under vacuum, 100 mL
of a 1:1 solution MeOH/NaOH (20% aq) was added to the
residue and the mixture was heated for 2 days to reflux.
Cooling was followed by an etheral extraction. The aqueous
phase was then acidified to pH 2 with 1 N HCl resulting in
the formation of a white precipitate. The aqueous phase was
extracted three times with Et2O and the combined organic
phases were then dried over MgSO4 and concentrated under
vacuum. The residue was purified by column chromatography
(CH2Cl2) to give 15 as a solid (2.79 g, 69% yield) which was
recrystallized from EtOAc/pentane: mp 123 °C; 1H NMR
(CDCl3, 200 MHz) δ ) 7.48 (dd, 1H, J ) 1.0, 7.8 Hz), 7.26 (t,
1H, J ) 8.0 Hz), 7.08 (dd, J ) 1.0, 8.3 Hz), 7.06 (dd, 1H, J )
11.6 and 17.8 Hz), 5.71 (dd, 1H, J ) 1.8, 17.7 Hz), 5.55 (dd,
1H, J ) 1.8, 11.6 Hz), 3.68 (s, 1H); 13C NMR (CDCl3, 50 MHz)
δ ) 173.6, 157.0, 130.1, 127.5, 127.2, 121.7, 119.8, 114.1, 55.3;
IR (KBr) ν 3003, 1683, 1590, 1457 cm-1; HR-MS (ES) calcd
for C10H10O3 201.0527 (M + Na), found 201.0525.
3-Meth oxy-2-vin ylben zoic Acid 2-Iod op h en yl Ester
(18). Gen er a l P r oced u r e for t h e P r ep a r a t ion of t h e
Ar ylben zoa tes. A solution of 2-iodophenol (660 mg, 3.0
mmol), 3-methoxy-2-vinylbenzoic acid (15) (641 mg, 3.0 mmol),
triphenylphosphine (944 mg, 3.6 mmol), Et3N (502 µL, 3.6
mmol), and CCl4 (347 µL, 3.6 mmol) in acetonitrile (12 mL)
was heated overnight at 60 °C. After evaporation of the solvent,
the residue was purified by silica gel column chromatography
(pentane/EtOAc, 7:3) affording 18 as a colorless oil (1.11 g,
97% yield): 1H NMR (200 MHz, CDCl3) δ 7.86 (dd, 1H, J )
1.6, 7.8 Hz), 7.72 (dd, 1H, 1.7, 10.0 Hz), 7.36 (t, J ) 8.3 Hz),
7.11 (dd, 1H, J ) 1.4, 9.3 Hz), 7.10 (dd, 1H, J ) 11.6, 17.8
Hz), 7.01 (dt, J ) 1.7, 7.8 Hz), 5.76 (dd, 1H, J ) 1.8, 17.8 Hz),
5.57 (dd, 1H, J ) 1,8, 11.6 Hz), 3.89 (s, 3H); 13C NMR (50 MHz,
CDCl3) δ 165.0, 157.1, 150.7, 138.9, 130.2, 130.0, 128.9, 127.7,
127.4, 127.1, 122.4, 121.7, 120.0, 113.9, 89.9, 55.3; IR (film) ν
1590, 1465 cm-1; HR-MS (ES) calcd for C29H24O5 402.9809 (M
+ Na), found 402.9816.
3-Meth oxy-2-vin ylben zoic Acid, 3-Ben zyloxy-2-iodoph e-
n yl Ester (19). The aryl benzoic ester 19 was prepared
according to the general procedure outlined for 18, with the
following quantities: 3-benzyloxy-2-iodophenol (326 mg, 1.00
mmol), benzoic acid 15 (214 mg, 1.20 mmol), PPh3 (315 mg,
1.20 mmol), Et3N (170 µL, 1.2 mmol), distilled CCl4 (110 µL,
1.2 mmol) in acetonitrile (12 mL). Purification by column
chromatography (pentane/Et2O, 1:1) afforded 19 (480 mg, 99%
yield) as a solid. Recrystallization frome EtOAc/pentane gave
colorless crystals: mp 107-109 °C; 1H NMR (200 MHz, CDCl3)
δ 7.76 (dd, 1H, J ) 1.0, 7.7 Hz), 7.54-7.02 (m, 8H), 6.85 (dd,
1H, J ) 1.0, 8.1 Hz), 6.76 (dd, 1H, J ) 1.0, 8.1 Hz), 5.77 (dd,
1H, J ) 1.8, 17.2 Hz), 5.56 (dd, 1H, J ) 1.8, 11.8 Hz), 5.17 (s,
2H), 3.88 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 165.0, 158.2,
157.0, 152.1, 135.6, 130.2, 129.1, 127.9, 127.3, 126.4, 121.7,
120.0, 115.0, 113.8, 109.3, 70.6, 55.3; IR (KBr) ν 1732, 1587,
1469, 1449 cm-1; HR-MS (ES) calcd for C23H19IO4 509.0227
(M + Na), found 509.0221.
1
131-133 °C; H NMR (200 MHz, acetone-d6) δ 8.57 (s, 2H),
7.30-7.51 (m, 5H), 7.04 (d, 2H, J ) 2.3 Hz), 6.59 (t, 1H, J )
2.3 Hz), 5.32 (s, 2H); 13C NMR (50 MHz, acetone-d6) δ 166.4,
159.4, 137.3, 132.9, 129.3, 128.8, 108.6, 108.0, 66.9; IR (KBr)
ν 3380, 1696, 1611, 1337 cm-1; HR-MS (ES) calcd for C14H12O4
267.0633 (M + Na), found 267.0622.
3,5-Dih yd r oxy-4-iod oben zoic Acid , Ben zyl Ester (10).
Iodine (1.44 g, 5.68 mmol) and NaHCO3 (479 mg, 5.70 mmol)
were added in small portions to a solution of the dihydroxy-
benzoate 9 (1.32 g, 5.40 mmol) in a 1:1 mixture of THF and
H2O (25 mL) at 0 °C. The reaction was stirred for 90 h at 20
°C. As 9 was still present, an additional 0.2 eq. of both NaHCO3
and iodine were added and reaction mixture was left to react
for an additional 50 h. After filtration through Celite, and
extraction with ether (4 times), the combined organic phases
were washed with a saturated solution of potassium thiosul-
fate, dried over MgSO4, and finally evaporated to dryness in
vacuo. The solid residue, consisting of predominantly 10, was
purified by crystallization in methanol to give 10 (1.78 g, 89%
1
yield) as colorless crystals: mp 164 °C; H NMR (200 MHz,
acetone-d6) δ 9.38 (s, 2H), 7.30-7.50 (m, 5H), 7.13 (s, 2H), 5.31
(s, 2H); 13C NMR (50 MHz, acetone-d6) δ 164.5, 157.5, 135.7,
131.0, 127.8, 127.5, 105.9, 80.1, 65.8; IR (KBr) ν 3474, 3392,
1698, 1584, 1498 cm-1; HR-MS (ES) calcd for C14H11IO4
392.9600 (M + Na), found 392.9601.
3-Ben zyloxy-5-h yd r oxy-4-iod oben zoic Acid , Ben zyl Es-
ter (11). Benzyl bromide (450 µL, 3.78 mmol) in DMF (5 mL)
was slowly added to a solution of 10 (1.40 g, 3.78 mmol) and
dry potassium carbonate (524 mg, 3.79 mmol) in DMF (20 mL).
The reaction was stirred for 2 days at 20 °C under nitrogen.
After addition of water, the solution was extracted six times
with CH2Cl2 and once with ether. The combined organic phases
were then washed five times with water, dried over MgSO4,
and concentrated in vacuo. The solid residue was purified by
flash chromatography (CH2Cl2/pentane 1:1, 3:2, 9:1), affording
compound 11 as a colorless solid (486 mg, 28% yield) along
with the monobenzylated product 9 (733 mg, 36% yield) and
the tribenzylated product 576 mg, 28% yield): mp 131-133
°C; 1H NMR (200 MHz, CDCl3) δ 7.30-7.60 (m, 11H), 7.01 (d,
1H, J ) 1.8 Hz), 5.61 (s, 1H), 5.35 (s, 2H), 5.20 (s, 2H); 13C
NMR (50 MHz, CDCl3) δ 165.0, 158.0, 156.5, 136.0, 135.6,
132.0, 128.7, 128.6, 128.4, 128.2, 128.0, 127.1, 109.2, 105.0,
84.9, 71.2, 67.2; IR (KBr) ν 3392, 1692, 1592, 1423 cm-1; HR-
MS (ES) calcd for
483.0072.
C29H24O5 483.0071 (M + Na), found
3-Meth oxy-2-vin ylben zoic Acid (15). To a solution of
oxazoline 14 (6.0 g, 25.5 mmol) in dry THF (50 mL) was added
a 1.0 M solution of vinylmagnesiumbromide in THF (38 mL,
38 mmol). After being stirred overnight at room temperature
under nitrogen, the reaction mixture was treated by addition
of a solution of saturated aqueous NH4Cl, and the aqueous
phase was then extracted three times with ether. The com-
bined organic phases were dried over MgSO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography (pentane:EtOAc, 1:1) affording 2-(3-methoxy-
2-vinylphenyl)-4,4-dimethyl-2-oxazoline as a pale yellow solid
(5.35 g, 91% yield): 1H NMR (CDCl3, 200 MHz) δ ) 7.23 (m,
2H), 6.97 (dd, 1H, J ) 11.5, 17.8 Hz), 6.95 (m, 1H), 5.75 (dd,
1H, J ) 2.0, 17.8 Hz), 5.46 (dd, 1H, J ) 2.0, 11.5 Hz), 3.85 (s,
2H), 1.38 (s, 6H); 13C NMR (CDCl3, 50 MHz) δ ) 162.4, 156.9,
130.4, 128.6, 127.1, 125.9, 121.4, 118.8, 112.0, 78.5, 67.3, 55.0,
27.5; HR-MS (ES) calcd for C14H17NO 254.1157 (M + Na),
found 254.1158.
3-Meth oxy-2-vin ylben zoic Acid , 4-Ben zylca r boxyl-3-
ben zyloxy-2-iod op h en yl Ester (20). The aryl benzoic ester
20 was prepared according to the general procedure outlined
for 18, with the following quantities: 3-benzyloxy-3-hydroxy-
2-iodobenzoic acid, benzyl ester 11 (1.93 g, 4.18 mmol), benzoic
acid 15 (896 mg, 5.02 mmol), PPh3 (1.32 g, 5.02 mmol), distilled
NEt3 (700 µL, 5.0 mmol), distilled CCl4 (485 µL, 5.0 mmol) in
acetonitrile (50 mL). Purification by column chromatography
(pentane:Et2O, 3:2) followed by recrystallization (pentane/CH2-
Cl2) afforded compound 20 as colorless crystals (2.46 g, 95%
yield): mp 149-150 °C; 1H NMR (200 MHz, CDCl3) δ 7.62 (dd,
1H, J ) 1.2, 8.0 Hz), 7.19-7.40 (m, 12H), 7.00 (dd, 1H, J )
0.6, 8.0 Hz), 6.98 (dd, 1H, J ) 11.4, 17.8 Hz), 5.65 (dd, 1H, J
) 2.2, 17.8 Hz), 5.45 (dd, 1H, J ) 2.2, 11.4 Hz), 5.23 (s, 2H),
5.09 (s, 2H), 3.74 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 164.7,
164.5, 158.2, 152.3, 135.1, 135.0, 131.4, 130.1, 129.7, 128.0,
127.8, 127.7, 127.5, 127.4, 126.5, 121.8, 120.2, 116.1, 114.1,

Synthesis of the Benzophenone Fragment of Balanol
J . Org. Chem., Vol. 65, No. 19, 2000 6059
90.1, 70.9, 66.7, 55.3; IR (KBr) ν 1745, 1723, 1414 cm-1; HR-
MS (ES) calcd for C31H25IO6 643.0594 (M + Na), found
643.0594.
1H, J ) 11.5 Hz), 5.23 (s, 2H), 5.03 (s, 2H), 3.73 (s, 3H); HR-
MS (ES) calcd for C31H24O6 515.1470 (M + Na), found
515.1442.
For 29: 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 3H), 7.51
(m, 2H), 7.32-7.46 (m, 9H), 7.08 (dd, 1H, J ) 0.8, 8.2 Hz),
5.98 (dd, 1H, J ) 7.4, 10.1 Hz), 5.34 (s, 2H), 5.20 (d, 1H, J )
11.7 Hz), 5.16 (d, 1H, J ) 11.7 Hz), 3.82 (s, 3H), 3.74 (dd, 1H,
J ) 9.7, 10.1 Hz), 3.52 (dd, 1H, J ) 7.4, 9.7 Hz); 13C NMR (50
MHz, CDCl3) δ 165.2, 164.6, 156.2, 151.8, 136.4, 135.7, 132.9,
131.0, 130.8, 128.7, 128.6, 128.5, 128.3, 128.2, 128.0, 127.8,
127.2, 125.3, 115.7, 115.5, 110.3, 71.0, 67.2, 56.4, 32.8; IR (KBr)
1732, 1716, 1584, 1422 cm-1; mp 147-149 °C; HR-MS (ES)
calcd for C31H25IO6 643.0595 (M + Na), found 643.0596.
2-[1-(3-Ben zyloxyph en yl)vin yl]-3-m eth oxyben zoic Acid,
Ben zyl Ester (32). To a solution of seven-membered ring
lactone 21 (237 mg, 0.94 mmol) in CH3CN (12 mL) was added
powdered KOH (232 mg, 4.13 mmol) and benzylbromide (1.12
mL, 9.39 mmol). The reaction mixture was then stirred
overnight at 20 °C. After evaporation of the solvent, water was
added to the residue and the mixture was extracted two times
with chloroform. The organic phase was then washed with
brine, dried over MgSO4 and concentrated under vacuum.
Purification by column chromatography (pentane/CH2Cl2, 3:2)
afforded compound 32 as a colorless oil (361 mg, 85% yield):
1H NMR (200 MHz, CDCl3) δ 7.10-7.28 (m, 14H), 6.79-6.91
(m, 3H), 5.94 (d, 1H, J ) 1.6 Hz), 5.34 (d, 1H, J ) 1.6 Hz),
5.05 (s, 2H), 4.91 (s, 2H), 3.57 (s, 3H); 13C NMR (50 MHz,
CDCl3) δ 167.8, 156.5, 155.5, 140.2, 136.5, 135.1, 132.4, 131.8,
130.3, 129.5, 128.4, 127.9, 127.8, 127.6, 127.4, 127.2, 127.1,
126.9, 126.8, 126.6, 126.1, 123.5, 121.5, 120.4, 119.9, 119.5,
113.3, 112.2, 66.6, 66.1, 55.3; IR (film) ν 3032, 2937, 1725, 1595,
1576, 1489 cm-1; HR-MS (ES) calcd for C30H26O4 473.1729 (M
+ Na), found 473.1750.
10-Met h oxy-11-m et h ylen e-11H -d ib en zo[b,e]oxep in -6-
on e (21). Gen er a l P r oced u r e for th e In tr a m olecu la r
Heck Rea ction . A solution of iodide 18 (152 mg, 0.40 mmol),
anhydrous NaOAc (98 mg, 1.2 mmol), and 0.26 equiv of bis-
(triphenylphosphine)palladium(II) dichloride (73 mg, 0.10
mmol) in fresh distilled CH3CN (12 mL) was heated at 85-90
°C under argon in a sealed tube. After 20 h, another portion
of the catalyst (73 mg, 0.10 mmol) was added, and the reaction
mixture was left stirring for another 26 h at 90 °C. CH2Cl2
was then added, and the reaction mixture was washed once
with 1 N AcOH, two times with water, and then brine. The
organic phase was dried over MgSO4 and then concentrated
under vacuum. Purification by flash chromatography afforded
the lactone 21 (76 mg, 75% yield) together with 22 (6 mg, 6%
yield) and the starting iodide 18 (18 mg, 12% yield) was also
recovered. For 21: 1H NMR (200 MHz, CDCl3) δ 7.36 (dd, 1H,
J ) 1.6, 7.6 Hz), 7.10-7.24 (m, 3H), 6.93-7.06 (m, 3H), 5.61
(d, 1H, J ) 1.2 Hz), 5.49 (d, 1H, J ) 1.2 Hz), 3.69 (s, 3H); 13
C
NMR (50 MHz, CDCl3) δ 153.8, 148.3, 136.0, 134.3, 128.5,
128.1, 125.0, 123.4, 121.9, 119.4, 115.0, 55.6; HR-MS (ES) calcd
for C16H12O3 275.0684 (M + Na), found 275.0684.
For 22: 7.40-7.02 (m, 7H), 6.91 (d, 1H, J ) 11.2 Hz), 6.85
(d, 1H, J ) 11.2 Hz), 3.79 (3H, s).
1-Ben zyloxy-10-m et h oxy-11-m et h ylen e-11H -d ib en zo-
[b,e]oxep in -6-on e (24). The biaryl lactone 24 was prepared
according to the general procedure outlined for 21, starting
from 19 (95 mg, 0.19 mmol), bis(triphenylphosphine)palla-
dium(II) dichloride (36 mg, 0.049 mmol), NaOAc (48 mg, 0.58
mmol) in CH3CN (6 mL). Another 18 mg (0.13 eq) of the
catalyst was added after 45 h and the reaction was stopped
after 68 h. Purification by chromatography (pentane/CH2Cl2,
2:3 to 3:2) afforded the alkene 24 (37 mg, 53% yield), iodide
28 (13 mg, 13% yield) and 19 (17 mg, 18% yield). For 24: 1H
NMR (200 MHz, CDCl3) δ 7.08-7.55 (m, 9H), 6.85 (dt, 2H, J
) 1.2, 8.4 Hz), 5.86 (d, 1H, J ) 1.4 Hz), 5.85 (d, 1H, J ) 1.4
Hz), 5.08 (s, 2H), 3.78 (s, 3H); 13C NMR (50 MHz, CDCl3) δ
154.8, 136.5, 128.9, 127.9, 127.7, 127.0, 125.9, 124.7, 123.2,
Dia r yla lk en e 35. To a solution of 25 (22 mg, 0.045 mmol)
in CH3CN (3 mL) was added powdered KOH (11 mg, 0.20
mmol) and benzylbromide (53 µL, 0.44 mmol). The reaction
mixture was then stirred for 4 h at 20 °C. After evaporation
of the solvent, water was added to the residue and the mixture
was extracted three times with CH2Cl2. The organic phase was
then washed with brine, dried over MgSO4 and concentrated
under vacuum. Purification by column chromatography (pen-
tane:EtOAc, 19:1) afforded compound 35 as a colorless oil (19
mg, 63% yield): 1H NMR (200 MHz, CDCl3) δ 7.33-7.41 (m,
6H), 7.09-7.26 (m, 18H), 6.78 (dd, J ) 1.6, 7.8 Hz), 5.93 (d,
1H, J ) 1.7 Hz), 5.80 (d, 1H, J ) 1.7 Hz), 5.30 (s, 2H), 5.24 (s,
4H), 4.93 (s, 2H), 3.42 (s, 3H); 13C NMR (50 MHz, CDCl3) δ
168.5, 166.2, 157.3, 157.1, 136.9, 136.1, 136.0, 133.1, 133.0,
132.0, 129.5, 128.7, 128.3, 128.2, 128.1, 127.9, 127.6, 127.5,
127.2, 126.1, 121.0, 113.8, 106.9, 70.6, 66.8, 66.6, 55.9; IR (film)
ν 3064, 3032, 2936, 1715, 1574, 1454 cm-1; HR-MS (ES) calcd
for C45H38O7 713.2515 (M + Na), found 713.2501.
115.2 112.5, 109.6, 69.8, 55.6; IR (film) ν 1733, 1448 cm-1
;
HR-MS (ES) calcd for C23H18O4 381.1103 (M + Na), found
381.1112.
For 28: 1H NMR (200 MHz, CDCl3) δ 7.68 (, 1H), 7.27-
7.56 (m, 6H), 7.18 (t, 1H, J ) 8.2 Hz), 7.06 (dd, 1H, J ) 1.1,
8.2 Hz), 6.83 (m, 1H), 5.95 (dd, 1H, J ) 7.9, 9.7 Hz), 5.15 (d,
1H, J ) 11.6 Hz), 5.08 (d, 1H, J ) 11.6 Hz), 3.81 (s, 3H), 3.72
(t, 1H, J ) 9.7 Hz), 3.54 (dd, 1H, J ) 7.9, 9.6 Hz); HR-MS
(ES) calcd for C23H19IO4 509.0227, found 509.0231.
1-Ben zyloxy-10-m et h oxy-11-m et h ylen e-11H -d ib en zo-
[b,e]oxep in -6-on e-3-ca r boxylic Acid , Ben zyl Ester (25).
The biaryl lactone 25 was prepared according to the general
procedure outlined for 21, starting from 20 (100 mg, 0.16
mmol), bis(triphenylphosphine)palladium(II) dichloride (29 mg,
0.042 mmol), NaOAc (40 mg, 0.48 mmol) in CH3CN/DMF (4:
1, 8 mL). The reaction was completed after 48 h at 100 °C.
Purification by chromatography (pentane:acetone, 4:1) afforded
the alkene 25 (43 mg, 55% yield), the eight-membered lactone
27 (10 mg, 13% yield) and iodide 29 (4 mg, 4% yield). The three
compounds were recrystallized from pentane:EtOAc. For 25:
2-(2-(Ben zyloxy)ben zoyl)-3-m eth oxyben zoic Acid , Ben -
zyl Ester (34). To a solution of alkene 32 (28 mg, 0.062 mmol)
in a mixture of CH3CN/CCl4/H2O (1.5:1.5:2.3 mL, respectively)
was added NaIO4 (140 mg, 0.65 mmol) and ruthenium(III)
chloride hydrate (approximately 2 mg). After the mixture was
stirred overnight at 20 °C, water was added and the reaction
mixture was extracted three times with CH2Cl2. The combined
organic phases were washed with brine, dried over MgSO4,
and concentrated under vacuum. Purification by column
chromatography (CH2Cl2/pentane, 7:3) afforded the benzophe-
none 32 as a colorless oil (9 mg, 32% yield): 1H NMR (300
MHz, CDCl3) δ 8.03 (dd, 1H, J ) 1.8, 7.8 Hz), 7.37-7.47 (m,
3H), 7.16-7.28 (m, 7H), 7.14 (t, 1H, J ) 8.0 Hz), 7.02 (dt, J )
1.0, 6.6 Hz), 6.87 (m, 4H), 5.12 (s, 2H), 4.70 (s, 2H), 3.63 (s,
3H); 13C NMR (50 MHz, CDCl3) δ 193.8, 191.6, 165.6, 158.6,
155.9, 135.8, 135.5, 135.4, 134.2, 131.4, 129.7, 128.6, 128.4,
128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 127.4, 127.0, 122.1,
120.7, 115.1, 112.8, 70.2, 66.8, 56.0; IR (CHCl3) ν 1717, 1656,
1596, 1468 cm-1; HR-MS (ES) calcd for C29H24O5 475.1521 (M
+ Na), found 475.1514.
1
mp 148-150 °C; H NMR (400 MHz, CDCl3) δ 7.58 (d, 1H, J
) 1.3 Hz); 7.53 (m, 3H), 7.49 (dd, 1H, J ) 0.8, 7.8 Hz), 7.31-
7.43 (m, 9H), 7.12 (dd, 1H, J ) 1.3, 8.0 Hz), 5.90 (d, 1H, J )
0.8 Hz), 5.87 (d, 1H, J ) 0.8 Hz), 5.35 (s, 2H), 5.17 (d, 1H, J
) 12.1 Hz), 5.11 (d, 1H, J ) 12.1 Hz); 13C NMR (50 MHz,
CDCl3) δ 165.3, 155.5, 155.1, 150.3, 136.7, 135.7, 132.2, 130.6,
129.1, 129.0, 128.8, 128.7, 128.5, 128.4, 128.2, 127.8, 126.7,
126.1, 124.0, 116.0, 114.8, 110.9, 70.5, 67.2, 56.3; IR (film) ν
1734, 1718, 1577, 1466 cm-1; HR-MS (ES) calcd for C31H24O6
515.1470 (M + Na), found 515.1480.
4-((2-Ben zyloxycar bon yl-6-m eth oxy)ben zoyl)-3,5-diben -
zyloxyben zoic Acid , Ben zyl Ester (36). To a solution of the
methylene compound 35 (18 mg, 0.026 mmol) in a mixture of
CH3CN/CCl4/H2O (0.5:0.5:0.8 mL, respectively) was added
For 27: 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H, J ) 1.0
Hz), 7.25-7.33 (m, 12 H), 6.98 (dd, 1H, J ) 0.8, 7.8 Hz), 6.89
(d, 1H, J ) 11.5 Hz), 6.80 (dd, 1H, J ) 0.8, 7.6 Hz), 6.77 (d,

6060 J . Org. Chem., Vol. 65, No. 19, 2000
Denieul et al.
NaIO4 (44 mg, 0.21 mmol) and ruthenium(III) chloride hydrate
(approximately 1 mg). After stirring for 2 h at 20 °C, water
was added and the reaction mixture was extracted three times
with CH2Cl2. The combined organic phases were washed with
brine, dried over MgSO4 and concentrated under vacuum.
Purification by column chromatography (ether:pentane, 2:3)
afforded the benzophenone 36 as a colorless oil (5.4 mg, 30%
yield): 1H NMR (400 MHz, CDCl3) δ 7.36-7.42 (m, 6H), 7.26
(m, 4H), 7.23 (m, 6H), 7.17 (m, 4H), 7.13 (m, 4H), 6.82 (m,
1H), 5.35 (s, 2H), 5.09 (s, 2H), 4.94 (s, 4H), 3.45 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 191.6, 167.1, 165.7, 158.2, 157.4,
136.2, 135.8, 132.9, 136.2, 135.8, 132.9, 132.6, 131.7, 130.4,
128.7, 128.5, 128.4, 128.3, 128.0, 127.4, 127.0, 123.7, 121.8,
114.9, 107.0, 79.7, 67.1, 67.0, 56.1; IR (CHCl3) 1718, 1670,
1582, 1455 cm-1; HR-MS (ES) calcd for C44H36O8 715.2308 (M
+ Na), found 715.2310.
Ack n ow led gm en t. We are indebted to the Danish
National Science Foundation, La Ligue Nationale Con-
tre Le Cancer, La Fondation Bettencourt-Schueller, The
University of Aarhus, and the Carlsberg Foundation for
generous financial support. We also thank one of the
referees for comments made on the mechanism of the
alkyl iodide formation.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for all new compounds, ORTEP diagrams and tables
of crystallographic data for the seven-membered lactone 25,
the eight-membered lactone 27 and the iodide 29, and Figures
S1-S3. This material is available free of charge via the
Internet at http//pubs.acs.org.
J O000750R