Formal total synthesis of the PKC inhibitor, balanol: Preparation of the fully protected benzophenone fragment

Article abstract of DOI:10.1016/S0040-4020(02)00096-0

The synthesis of a perbenzylated derivative of balanol's highly functionalized benzophenone fragment is reported employing a regioselective Heck reaction as the key step for the connection of the two aromatic rings. The intermediate 7-membered lactone obt

Full text of DOI:10.1016/S0040-4020(02)00096-0

TETRAHEDRON
Pergamon
Tetrahedron 58 72002) 2231±2238
Formal total synthesis of the PKC inhibitor, balanol: preparation
of the fully protected benzophenone fragment
Bolette Laursen, Marie-Pierre Denieul and Troels Skrydstrupp
Department of Chemistry, University of Aarhus, Langelandsgade 140, 8000 Aarhus C, Denmark
Received 15 October 2001; revised 19 December 2001; accepted 17 January 2002
AbstractÐThe synthesis of a perbenzylated derivative of balanol's highly functionalized benzophenone fragment is reported employing a
regioselective Heck reaction as the key step for the connection of the two aromatic rings. The intermediate 7-membered lactone obtained, is
subsequently opened and then subjected to an oxidative degradation, resulting in a short synthesis of the benzophenone unit. As the
benzophenone has previously been successfully carried through to the synthesis of balanol, our work constitutes a formal total synthesis
of this natural product. Attempts were also made to provide other direct entries to this fragment via a Heck-like coupling onto an aryl
aldehyde or a SmI2-promoted ketyl radical cyclization. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
inhibitors, namely balanol 7Scheme 1).1 This natural
product of fungal origin was isolated and reported inde-
pendently by Kulanthaivel et al. at Sphinx Pharmaceuticals
in 1993,2 and by Ohshima et al. at Nippon Roche Research
We have recently been interested in the total synthesis of
one of the newest examples of protein kinase C 7PKC)
OBn
HO2C
O
OH
H
N
OH
HO
O
OH
NPG
OH
O
O
H
N
OBn O
CO2Bn
O
6'
NH
Balanol
BnO2C
BnO OR
1 R = Me
2 R = Bn
Heck Reaction
OR
BnO
BnO
OR
(Ph3P)2PdCl2 (26 mol%)
NaOAc, CH3CN/DMF
I
90˚C, 48 h
55% for R = Me
BnO2C
O
BnO2C
O
O
O
Scheme 1.
Keywords: natural products; benzophenone; Heck reactions; total synthesis.
Corresponding author. Tel.: 145-89-42-39-32; fax: 145-86-19-61-99; e-mail: ts@chem.au.dk
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020702)00096-0

2232
B. Laursen et al. / Tetrahedron 58 %2002) 2231±2238
Center in 1994.3 PKC is a large subclass of the protein
kinases responsible for phosphate transfer from ATP to
protein substrates involved in intracellular signalling path-
ways. Because activation of PKC enzymes has been
implicated in a number of diseases, including AIDS, cancer,
cardiovascular disorders, asthma, diabetes and central
nervous system dysfunction, the identi®cation of a suitable
and speci®c inhibitor of this enzyme class would be of
medicinal interest.4 The structural difference of balanol
compared to other known PKC inhibitors, makes balanol a
new lead compound in the pursuit of more active and
speci®c inhibitors of this enzyme.
1) BnBr, K2CO3, DMF
2) LiOH, H2O/THF
CO2H
OH
CO2H
OBn
96% (2 steps)
OH
OBn
4
see Table 1
1) CH2=CHMgBr, THF
2) MeI, then NaOH,
MeOH, reflux
O
N
CO2H
In a recent paper, we reported a convergent route to the
benzophenone fragment of balanol employing an intra-
molecular Heck reaction as the key step for connecting
the two aromatic subunits 7Scheme 1).1a,c Unlike the
previously reported syntheses,5,6 both aromatic coupling
partners are fully functionalized with substituents in their
correct oxidation state as in the benzophenone unit, making
this route quite convergent. Unfortunately, the C60-hydroxyl
group of 1 was protected as its methyl ether, which did not
make this compound suitable for the total synthesis of
balanol. In support of this, attempted simultaneous
debenzylation and demethylation under conditions reported
by the Rhone±Poulenc Rorer group for a similar compound
were unrewarding leading to multiple product formation.5d
Hence, it was deemed necessary to replace the methyl group
at the C60-hydroxyl group with a benzyl group instead.
OBn
90% (2 steps)
OBn
3
OBn
5
Scheme 2.
the o-methoxy group, was prepared in two steps by amide
formation with 2-amino-3-methylpropanol followed by
cyclization promoted by thionyl chloride, according to the
procedure described by Meyers et al.8 However, this proto-
col proved incompatible with the benzoic acid 4 leading to
signi®cant cleavage of the etheral linkages 7Table 1, entry
1).
Hence, the corresponding amide was prepared in quantita-
tive yield via the acid chloride generated from oxalyl
chloride and DMF. Cyclization was thereafter attempted
by activation of the primary alcohol with tosyl chloride in
the presence of triethylamine and DMAP. Reaction times of
11 days were needed to give a 60% yield of the oxazoline 5
7entry 2).9 Whereas the procedure reported by VorbruÈggen
et al. for the one step cyclization of a carboxylic acid and an
aminoalcohol to an oxazoline employing the PPh3/C2Cl6/
NEt3 combination proved disappointing 7entry 3),10 apply-
ing the same protocol to the above amide in acetonitrile led
to a rapid ring closure 715±30min) affording an 86% overall
yield of the desired oxazoline 5 from the carboxylic acid 4
7entry 4). If the solvent of this reaction was replaced with
dichloromethane simple exchange of the primary alcohol to
its chloride was the major event. Substitution of the
o-benzyloxy group in 5 proved highly effective with vinyl
magnesium bromide8 at 258C affording after a two step
hydrolysis sequence the desired carboxylic acid 3 in a
high overall yield of 90%.
We therefore report our work on the synthesis of the fully
benzylated benzophenone unit 72) of balanol. Contrary to
our previous synthesis, the simple replacement of the
C60-methyl ether with a benzyl ether required several
modi®cations in the synthesis in order to obtain the target
molecule. As the fully benzylated benzophenone fragment
has previously been synthesized and effectively carried
through to balanol,5d our work represents a formal total
synthesis of this novel PKC inhibitor. In addition to this
work, we reveal several attempts to shorten the synthesis
via either an intramolecular Heck-like reaction involving an
aldehyde or an intramolecular ketyl radical cyclization
approach.
2. Results and discussion
The synthesis of the highly functionalized aromatic
fragment of balanol began with the preparation of the
disubstituted benzoic acid 3 7Scheme 2). Hence, subsequent
perbenzylation of 2,3-dihydroxy benzoic acid and basic
hydrolysis afforded the dibenzyl ether 4.7 In our previous
work,1a,c the corresponding oxazoline, necessary for carry-
ing out the following nucleophilic aromatic substitution of
Coupling of 3 with the phenol 6 employing Furukawa's
conditions11 as reported in our earlier work led to yields
of the ester 7 no higher than 64% after repeated attempts
7Scheme 3), in contrast to the 95% yield obtained for corre-
sponding compound containing a methoxy substituent. This
Table 1. Conditions attempted for conversion of carboxylic acid 4 to oxazoline 5
Entry
Conditions
Yield 7%)
1
2
3
4
SOCl2 then 2-amino 3-methylpropanol; SOCl2
45
7COCl2), DMF, then 2-amino-3-methylpropanol; TsCl, NEt3, DMAP, CH2Cl2, 508C, 11 days
Ph3P, C2Cl6, NEt3, CH3CN
7COCl2), DMF, then 2-amino-3-methylpropanol; Ph3P, C2Cl6, NEt3, CH3CN, 15 min
60
Mixture of products
86

B. Laursen et al. / Tetrahedron 58 %2002) 2231±2238
2233
1) (COCl)2, DMF
2)
BnO
I
6
OBn
BnO
OBn
BnO2C
OH
I
NEt3, CH2Cl2
83% (2 steps)
HO2C
BnO2C
O
O
3
7
(Ph3P)2PdCl2
(10 mol%)
NaOAc,
52%
CH3CN/DMF (4:1)
(0.6 mmol scale)
OBn
O
BnO
BnO
OBn
BnO2C
BnO2C
O
O
O
8
9
KOH, BnBr,
CH3CN
83%
RuCl3:xH2O (cat.)
NaIO4,
OBn
CO2Bn
OBn O
CO2Bn
CCl4/H2O/CH3CN
BnO2C
42%
RO2C
BnO OBn
BnO OBn
10
2 R = Bn
11 R = H
Ref. 5d
Scheme 3.
could be remedied by transforming 3 ®rst to its acid chloride
and then condensing it with phenol 6 in the presence of
triethylamine affording 7 in 83% yield after recrystallization.
derivative 2, though in a modest yield of 42%. Vicker and
coworkers have previously demonstrated the ability to
selectively hydrolyze the sterically less hindered benzyl
ester in 2 to the carboxylic acid 11 necessary for the comple-
tion of their total synthesis of balanol.5d Therefore, our
synthetic approach to 2 constitutes a formal total synthesis
of this natural product.
It was interesting to examine how the increased steric bulk
on the C6 hydroxyl group in 7 would effect both the yields
and the regioselectivity of the palladium70) catalyzed ring
closing event. In the previous study, best results and regio-
selectivities 77-exo vs 8-endo, 4.2:1) were attained by the
use of 7PPh3)2PdCl2 as the catalyst in a solvent mixture of
CH3CN/DMF.1c Quite pleasingly, when 7 70.6 mmol scale)
was subjected to 10mol% of the catalyst under similar
conditions at 858C, a 52% cyclization yield of the 7-exo
and 8-endo products 8 and 9 as a 6.4:1 mixture was
obtained.12 These isomeric compounds could not be sepa-
rated by column chromatography. Further opening of the
lactone and in situ benzylation then led to a separable
mixture affording alkene 10 in 83% yield. Finally, oxidative
cleavage of 10 with ruthenium tetraoxide gave the desired
benzophenone moiety of balanol as its perbenzylated
In an effort to overcome the ®nal, problematic oxidative
cleavage step encountered with the alkenes such as 10 and
with the methoxy counterpart, an attempt was made to
perform an intramolecular Pd70) catalyzed arylation of a
CvO double bond in order to directly generate the required
benzophenone 7Scheme 4, Approach 1). Precedence for this
unorthodox Heck reaction comes from the work of Satoh et
al. demonstrating the ability of substituted o-hydroxy-
benzaldehydes to undergo an intermolecular Heck-type
arylation with aryl iodides.13 The positioning of the
hydroxyl group is essential for the C±C bond formation as
the coupling reaction becomes intramolecular through the

2234
B. Laursen et al. / Tetrahedron 58 %2002) 2231±2238
Approach 1
OR
O
BnO
O
OR
O
BnO
I
Pd(0)
??
BnO2C
O
BnO2C
O
O
Approach 2
I2Sm
O
BnO
O
OR
BnO
O
O
OR
SmI2
BnO2C
O
BnO2C
O
Cyclization
and
??
aromatization
OR
OR
O
HO
BnO
BnO
oxidation
BnO2C
BnO2C
O
O
O
O
Scheme 4.
generation of a Pd±O species. Larock has likewise reported
the intramolecular addition of a vinylpalladium inter-
mediate to a CvO bond resulting in the synthesis of
indenols.14
typical solvent mixture CH2Cl2/MeOH did not lead to the
required aldehyde 13 after treatment with Ph3P, but rather
phenol 6 and the monomethyl acetal of 6-methoxy-2-
carboxybenzaldehyde 14 7RˆMe) 7Table 2, entry 1). This
latter compound most likely arose from the transesterifca-
tion of a hemiacetal intermediate. On the other hand, if
the oxidation reaction was run under strictly anhydrous
To study this route, we prepared the labile aldehyde 13 from
the alkene 12.1c Ozonolysis of the vinyl substituent in a
Table 2. Ozonolysis studies of the alkene 13
BnO
O
OMe
I
BnO2C
O
13
BnO
OMe
O
ozonolysis
I
OMe
RO
BnO2C
O
O
6
O
12
O
14
Entry
Conditions
Yield 7%)
13
14
6
1
O3, CH2Cl2/MeOH, then Ph3P
O3, CH2Cl2, then Ph3P
O3, dry CH2Cl2, then Ph3P
±
67
10
56 7RˆMe)
33 7RˆH)
0
56
33
2a
3a
±
±
a
Yields based on 1H NMR spectrum of crude product mixture.

B. Laursen et al. / Tetrahedron 58 %2002) 2231±2238
2235
1) (COCl)2, DMF
2)
17
OMe
X
OMe
BnO2C
OH
NEt3, CH2Cl2
89% (2 steps)
HO2C
BnO2C
O
O
16
18 X = CH2
O3, dry CH2Cl2,
then Ph3P
100%
15 X = O
SmI2
SmI2
OMe
OMe
17
O
HO
O
BnO2C
O
O
19
Scheme 5.
conditions in dichloromethane, the crude 1H NMR spectrum
in dry C6D6 revealed quantitative conversion to the
aldehyde 13 7entry 3). Use of solvents which were not
dried prior to the ozonolysis led to a considerable amount
of cleavage products such as 6 and in this case the hemi-
acetal 14 7RˆH) 7entry 2). Without further puri®cation this
aldehyde was thus subjected to the conditions reported by
Satoh for Pd70) catalyzed C±C bond formation 7PdCl2,
Na2CO3, LiCl, DMF).13 However, both these conditions as
well as others only led to multiple product mixtures accord-
and cooled to 2788C, after which a 0.1 M solution of
SmI2 in THF was added dropwise. An instantaneous
reaction ensued and the reaction was worked up after
completed addition of the reducing agent and stirring for
30min. Disappointingly, only the product from ester
cleavage, the phenol 17, was identi®ed, possibly originating
from a trans-esteri®cation pathway. The slow cyclization
rate for the 7-exo ring closure and the requirement for a
higher energy rotamer of the ester linkage for cyclization
to take place both possible contribute to the unsuccessful
preparation of the desired alcohol 19.
1
ing to both TLC and H NMR analysis and hence further
investigation in this line were discontinued.
Finally, inspired by a recent report from Dinesh and Reissig
demonstrating the high tendency of alkyl ketones to undergo
SmI2-promoted intramolecular 6-exo radical cyclizations on
to arenes,15 we considered a similar type of reaction as
illustrated in Scheme 4, Approach 2, for the construction
of balanol's aryl fragment. Successful cyclization would
then only require a simple oxidation step of the secondary
benzylic alcohol formed. Although, a slower 7-exo ring
closure of the intermediate ketyl would be implicated in
this case, the correct placement of the electron withdrawing
benzylcarboxy group could make this cyclization step
competitive with the potential, but undesirable trans-
esteri®cation step involving the ketyl oxygen in a similar
process as described above.
3. Conclusion
In conclusion, we have successfully prepared the perbenzyl-
ated derivative of balanol's benzophenone fragment
employing our previously described intramolecular Heck
reaction as the key step. The described work therefore repre-
sents a formal total synthesis of this naturally occurring
PKC inhibitor. Attempts were also made to improve the
synthesis by either an intramolecular Heck-like reaction
with a carbon±oxygen double bond or a SmI2-mediated
radical cyclization event involving
intermediate.
a ketyl radical
4. Experimental
4.1. General
To study this reaction the model compound 15 was synthe-
sized. Preparation of the aldehyde 15 began with the
selective benzylation of m-hydroxybenzoic acid to 17
followed by its esteri®cation in near quantitative yield
with the acid chloride of the previously described 161c
7Scheme 5). Oxidative cleavage of the alkene 18 proceeded
as expected though only if dry dichloromethane was used,
providing the aldehyde 15 in quantitative yield. Without
further puri®cation, the aldehyde was dissolved in THF
Unless otherwise stated, all reactions were carried out
under argon. THF was dried and freshly distilled over
sodium/benzophenone. Dichloromethane and acetonitrile
were freshly distilled over P2O5 and CaH2, respectively.
Reactions were monitored by thin-layer chromatography
7TLC) analysis. Melting points are uncorrected.

2236
B. Laursen et al. / Tetrahedron 58 %2002) 2231±2238
3-Benzyloxy-5-hydroxy-4-iodobenzoic acid, benzyl ester
76) was prepared as previously described.1c Samarium
diiodide was prepared according to the literature.16
reduced pressure. The residue afforded 2-%3-benzyloxy-2-
vinylphenyl)-4,4-dimethyl-4,5-dihydrooxazole 71.89 g, 100%)
as a pale yellow solid. Further puri®cation through crystal-
lization from ethyl acetate/pentane gave the pure oxazoline
as colorless crystals. Mp. 68±698C; IR 7KBr) 2970, 1845,
4.1.1. 2-//2,3-Dibenzyloxy)phenyl)-4,4-dimethyl-4,5-di-
hydrooxazole /5). To a solution of 2,3-dibenzyloxybenzoic
acid 4 73.46 g, 10.4 mmol) in CH2Cl2 750mL) was added
oxalyl chloride 712 mL, 137 mmol) and DMF 710 mL,
129 mmol), followed by stirring for 1 h under nitrogen.
The solvent and excess of oxalyl chloride were removed
under reduced pressure yielding the acid chloride. 1H
NMR 7CDCl3, 200 MHz) d 7.57±7.107m, 13H), 5.15 7s,
2H), 5.08 7s, 2H); 13C NMR 7CDCl3, 50MHz) d 164.7,
152.5, 147.7, 136.4, 135.8, 129.4, 128.7 72C), 128.6,
128.3 72C), 128.2, 128.2, 127.5 72C), 124.3, 124.0, 119.7,
75.5, 71.3.
1
1648, 1626, 1570cm 21; H NMR 7CDCl3, 200 MHz) d
7.28±7.43 7m, 5H), 7.23 7dd, Jˆ8.0, 1.6 Hz, 1H), 7.19 7t,
Jˆ8.0, 8.0 Hz, 1H), 7.02 7dd, Jˆ18.0, 11.6 Hz, 1H), 7.00
7dd, Jˆ8.0, 1.6 Hz, 1H), 5.80 7dd, Jˆ18.0, 2.0 Hz, 1H), 5.46
7dd, Jˆ11.6, 2.0Hz, 1H), 5.11 7s, 2H), 4.06 7s, 2H), 1.38 7s,
6H); 13C NMR 7CDCl3, 50MHz) d 163.1, 156.6, 136.7,
130.9, 129.3, 128.5 72C), 127.8, 127.7, 127.2 72C), 127.1,
122.5, 119.7, 114.4, 79.3, 70.5, 67.9, 28.2 72C); HR-MS
7ES) calcd for C20H21NO2Na 308.1650 7M1Na), found
308.1651.
Freshly distilled methyl iodide 72 mL, 32 mmol) was added
to the oxazoline 763 mg, 175 mmol) under nitrogen, and
stirred overnight. After evaporation of the excess of methyl
iodide, the 1H NMR spectrum clearly indicated formation of
The acid chloride was redissolved in CH2Cl2 750mL)
whereafter NEt3 78.7 mL, 62 mmol) and 2-amino-2-methyl-
propanol 71.0mL, 11 mmol) were added. After stirring for
6.5 h under nitrogen, water was added to the solution
followed by extraction with CH2Cl2 73 times). The
combined organic phases were dried over MgSO4, and
evaporated under reduced pressure. The residue which
contains almost pure amide yielded by crystallization
%pentane/ethyl acetate) 2,3-dibenzyloxy-N-%2-hydroxy-1,1-
dimethylethyl)benzamide 74.22 g, 100%) as colorless
crystals. Mp. 111±1148C; IR 7KBr) 3431, 3376, 2928,
1
the methyl salt. H NMR 7CDCl3, 200 MHz) d 7.45±7.26
7m, 5H), 7.21 7t, Jˆ7.9, 7.9 Hz, 1H), 6.84 7dd, Jˆ7.9,
1.0Hz, 1H), 6.84 7dd, Jˆ17.8, 11.8 Hz, 1H), 6.79 7dd,
Jˆ7.9, 1.0Hz, 1H), 5.78 7dd, Jˆ17.8, 1.8 Hz, 1H), 5.42
7dd, Jˆ11.8, 1.8 Hz, 1H), 5.08 7s, 2H), 3.82 7s, 1H), 3.81
7s, 1H), 2.71 7s, 3H), 1.38 7s, 3H), 1.37 7s, 3H).
The pale yellow methyl iodide salt was subjected to 2 M
NaOH7aq) 71 mL) and MeOH 71 mL) and stirred for 4 days
under re¯ux. After cooling the reaction to room tempera-
ture, followed by an etheral wash, the aqueous phase was
acidi®ed to pH 1 with 6 M HCl resulting in a white partici-
pate, which was extracted into the organic phase with ether
74 times). The combined organic phases were washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The product 3 was afforded as colorless crystals
through crystallization in CH2Cl2/pentane 739 mg, 90%).
Mp. 123±123.58C; IR 7KBr) 2873, 1690, 1576, 1453,
2872, 1648, 1572, 1545 cm21
;
1H NMR 7CDCl3,
400 MHz) d 8.14 7bs, 1H), 7.69 7dd, Jˆ5.4, 4.4 Hz, 1H),
7.33±7.85 7m, 10H), 7.15 7d, Jˆ4.4 Hz, 1H), 7.15 7d,
Jˆ5.4 Hz, 1H), 5.15 7s, 2H), 5.09 7s, 2H), 3.52 7s, 2H),
1.08 7s, 6H); 13C NMR 7CDCl3, 50MHz) d 165.7, 151.6,
146.7, 136.3, 136.2, 128.9 72C), 128.8, 128.7 72C), 128.3,
127.7 72C), 127.2, 124.5, 123.2, 117.2, 76.6, 71.4, 71.1,
56.2, 24.5 72C); HR-MS 7ES) calcd for C25H27NO4Na
428.1838 7M1Na), found 428.1839.
1
The amide 72.57 g, 6.33 mmol), Ph3P 72.50g, 9.53 mmol),
C2Cl6 72.25 g, 9.50mmol), and Et 3N 78.8 mL, 63 mmol) in
CH3CN 7100 mL) were stirred for 25 min under nitrogen.
As amide was still present after this time according to TLC
analysis, additional Ph3P 71.0g, 3.8 mmol) and C 2Cl6 71.0g,
4.2 mmol) were added, and the reaction was completed after
an additional 20min. The reaction mixture was concen-
trated under reduced pressure. Flash-chromatography
7EtOAc/petane 1:4) gave the oxazoline 5 72.10g, 86%) as
colorless crystals. Mp. 67.2±67.68C; IR 7KBr) 3064, 3032,
3966, 1952, 1812, 1648 cm21; 1H NMR 7CDCl3, 200 MHz)
d 7.00±7.43 7m, 13H), 5.13 7s, 2H), 5.10 7s, 2H), 4.05 7s,
2H), 1.36 7s, 6H); 13C NMR 7CDCl3, 50MHz) d 161.3,
152.7, 148.1, 137.8, 136.9, 128.7, 128.6, 128.3, 128.1,
127.9, 127.6, 124.3, 124.1, 123.2, 117.5, 79.2, 75.7, 71.5,
67.5, 28.5 72C); HR-MS 7ES) calcd for C25H25NO3Na
410.1732 7M1Na), found 410.1732.
1413, 1263 cm21; H NMR 7CDCl3, 200 MHz) d 11.22
7bs, 1H), 7.49 7dd, Jˆ8.0, 1.1 Hz, 1H), 7.31±7.45 7m,
5H), 7.26 7t, Jˆ8.0, 8.0 Hz, 1H), 7.12 7dd, Jˆ8.0, 1.1 Hz,
1H), 7.107dd, Jˆ17.8, 11.6 Hz, 1H), 5.76 7dd, Jˆ17.8,
1.8 Hz, 1H), 5.55 7dd, Jˆ11.6, 1.8 Hz, 1H), 5.13 7s, 2H);
13C NMR 7CDCl3, 50MHz) d 174.3, 156.8, 136.7, 131.2,
131.1, 128.7 72C), 128.7, 128.2, 127.4 72C), 122.9, 120.9 72C),
116.6, 71.0; MS 7ES) calcd for C16H13O3 253.1, found 253.1.
4.1.3. 3-Benzyloxy-2-vinylbenzoic acid, 5-benzylcar-
boxyl-3-benzyloxy-2-iodophenyl ester /7). To a solution
of the benzoic acid 3 7208 mg, 0.82 mmol) in CH2Cl2
710mL) was added oxalyl chloride 71.1 mL, 12 mmol)
and DMF 710 mL, 0.13 mmol). The reaction mixture was
stirred for 1 h under nitrogen. Solvent and excess of the
oxalyl chloride were removed under reduced pressure,
1
leaving the acid chloride as a pale yellow solid. H NMR
7CDCl3, 200 MHz) d 7.48±7.27 7m, 7H), 7.13 7dd, Jˆ8.2,
1.0Hz, 1H), 6.91 7dd, Jˆ17.8, 11.6 Hz, 1H), 5.71 7dd,
Jˆ17.8, 1.6 Hz, 1H), 5.59 7dd, Jˆ11.6, 1.6 Hz, 1H), 5.13
7s, 2H); 13C NMR 7CDCl3, 50MHz) d 168.5, 156.6, 136.3,
135.9, 129.9, 128.7 72C), 128.2, 128.1, 127.7, 127.2 72C),
122.8, 122.3, 116.9, 70.9.
4.1.2. 3-Benzyloxy-2-vinylbenzoic acid /3). To a solution
of the oxazoline 5 72.04 g, 5.26 mmol) in THF 720 mL) was
added a 0.1 M solution of vinylmagnesiumbromide 717 mL,
17 mmol). After being stirred under nitrogen for 18.5 h,
saturated aqueous NH4Cl was added. The aqueous phase
was extracted 5 times with ether, and the combined organic
phases were dried over MgSO4, and concentrated under
A solution of the acid chloride 70.82 mmol), Et3N 7150 mL,

B. Laursen et al. / Tetrahedron 58 %2002) 2231±2238
2237
1.08 mmol) and the phenol 6 7377 mg, 0.82 mmol) in
CH2Cl2 710mL) was stirred under nitrogen for 17 h. After
addition of water 75 mL), and extraction with ether 73
times), the combined organic phases were dried over
MgSO4 and evaporated to dryness. The solid residue
137.072C), 136.6, 136.3, 136.0, 134.3, 133.8, 132.3, 129.2,
128.7 72C), 128.4 73C), 128.3 75C), 128.2 76C), 128.0,
127.7, 127.6 72C), 127.5 72C), 127.4 74C), 127.2 72C),
125.4, 121.6, 114.5, 107.1 72C), 70.4 72C), 66.8 72C); HR-
MS 7ES) calcd for C51H42O7Na 789.2828 7M1Na), found
789.2871.
consisting of
7 predominantly 7556 mg, 99%) was
recrystallized from CH2Cl2/pentane to give the product 7
as colorless crystals 7462 mg, 83%). Mp. 848C; IR 7KBr)
4.1.6. 6-Benzyloxy-2-benzyloxycarbonylphenyl-2,6-di-
benzyloxy-4-benzyloxycarbonylphenylketone /2). The
alkene 10 721.9 mg, 0.029 mmol), NaIO4 7205 mg,
0.285 mmol) and a catalytic amount of RuCl3´xH2O in a
solvent mixture of CH3CN, CCl4 and water
70.5:0.5:0.75 mL, respectively) was rigorously stirred for
18 h at 208C. An additional amount of NaIO4 760mg) and
a catalytic amount RuCl3´xH2O were added and TLC analy-
sis indicated that the reaction was complete after another
18 h of stirring. Water was added and the reaction mixture
was extracted with DCM 74 times). The combined organic
phases were ®ltered through Celite and washed with brine
and dried over MgSO4, and then concentrated under reduced
pressure. Flash chromatography 7CH2Cl2/pentane 9:1) gave
the benzophenone 2 78.0mg, 42%) as a colorless foam. 1H
NMR 7d6-Acetone, 200 MHz) d 7.01±7.48 7m, 27H), 6.95
7d, Jˆ8 Hz, 1H), 6.82 7m, 2H), 5.38 7s, 2H), 5.12 7s, 2H),
4.78 7s, 4H), 4.7072, 2H); HR-MS 7ES) calcd for
C50H40O8Na 791.2621 7M1Na), found 791.2620.
1
3422, 2927, 1718, 1577, 1453, 1416, 1234 cm21; H NMR
7CDCl3, 200 MHz) d 7.77 7dd, Jˆ4.0, 0.2 Hz, 1H), 7.30±
7.52 7m, 18H), 7.17 7d, Jˆ8.4 Hz, 1H), 7.14 7dd, Jˆ18.0,
12.0Hz, 1H), 5.84 7dd, Jˆ18.0, 0.8 Hz, 1H), 5.57 7dd,
Jˆ12.0, 0.8 Hz, 1H), 5.36 7s, 2H), 5.24 7s, 2H), 5.16 7s,
2H); 13C NMR 7CDCl3, 50MHz) d 165.5, 165.3, 159.0,
159.0, 156.9, 153.0, 136.7, 135.9, 135.7, 132.1, 130.8,
130.5, 129.2, 128.8 73C), 128.6, 128.4, 128.3, 128.1 75C),
127.3 74C), 123.0, 121.2, 116.8, 116.6, 110.3, 91.3, 71.6,
70.9, 67.4; HR-MS 7ES) calcd for C37H29IO5Na 719.0908
7M1Na), found 719.0917.
4.1.4.
1,10-Dibenzyloxy-11-methylene-11-H-dibenzo-
[b,e]oxepin-6-one-3-carboxylic acid, benzyl ester /8). A
solution of the substrate 7 7380mg, 0.55 mmol) with
7Ph3P)2PdCl2 719.6 mg, 0.028 mmol) and anhydrous
NaOAc 7146 mg, 1.78 mmol) in freshly distilled CH3CN
712 mL) and distilled DMF 73 mL) was stirred in a sealed
tube at 858C. After 21 h, an additional 5 mol% of
7Ph3P)2PdCl2 719.6 mg, 0.028 mmol) was added and the
reaction was continued for a further 22 h. 1 M AcOH
72 mL) was added and the mixture was extracted with
ether 75 times). The combined organic phases were washed
once with brine and dried over MgSO4 and concentrated
under reduced pressure. Flash chromatography 7CH2Cl2/
pentane, 3:2) gave a an inseparable mixture 7165 mg) of
the 7-exo and 8-endo products 8 and 9 in the yields of 45
and 7%, respectively, the ratio of which was determined by
1H NMR. For compound 8: 1H NMR 7CDCl3, 200 MHz) d
7.57 7d, Jˆ1.4 Hz, 1H), 7.53 7d, Jˆ1.4 Hz, 1H), 7.507dd,
Jˆ7.8, 1.0Hz, 1H), 7.17±7.43 7m, 16H), 7.12 7dd, Jˆ8.2,
1.0Hz, 1H), 5.99 7d, Jˆ1.2 Hz, 1H), 5.93 7d, Jˆ1.2 Hz,
1H), 5.32 7s, 2H), 5.14 7d, Jˆ2.4 Hz, 2H), 5.107s, 2H);
13C NMR 7CDCl3, 50MHz) d 165.1 72C), 155.4, 153.9,
150.3, 136.6, 136.4, 135.6, 132.6, 130.6, 129.0, 128.6,
128.6, 128.5 74C), 128.4, 128.1 72C), 127.8 72C), 126.8,
126.6, 124.4, 118.0, 114.6, 111.0, 70.7, 70.6, 67.1;
HR-MS 7ES) calcd for C37H28O6Na 591.1792 7M1Na),
found 591.1784.
4.1.7. 3-Methoxy-2-formylbenzoic acid, 5-benzylcar-
boxyl-3-benzyloxy-2-iodophenyl ester /13). Ozone was
bubbled through a solution of the alkene 12 710mg,
0.016 mmol) dissolved in dry CH2Cl2 72 mL) at 2788C
until a blue color was obtained. After removal of the excess
ozone by bubbling nitrogen through the solution for 5±10
minutes
at
2788C,
triphenylphosphine
710mg,
0.040 mmol) was added, and the reaction mixture was
warmed to 208C over a period of 15 min. Stirring was
continued for an additional 30min, and the solvents were
removed by evaporation to dryness in vacuo to give the
crude aldehyde 13 with excess triphenylphosphine, which
was immediately used in the palladium-catalyzed coupling
1
step. H NMR 7C6D6, 200 MHz) d 10.28 7s, 1H), 8.35 7d,
Jˆ1.6 Hz, 1H), 6.73±7.28 7m, 14H), 4.95 7s, 2H), 4.31 7s,
2H), 2.95 7s, 3H).
4.1.8. 3-Hydroxybenzoic acid, benzyl ester /17). Benzyl
bromide 7861 mL, 7.24 mmol) was added to a mixture of
3-hydroxybenzoic acid 71.00 g, 7.24 mmol) and sodium car-
bonate 7767 mg, 7.24 mmol) in dry DMF 710mL). After
stirring for 12 h at 208C, water was added and the mixture
was extracted 5 times with ether. The combined organic
phases were ®rst washed with water 75 times) and once
with brine, and then dried over MgSO4, and concentrated
under reduced pressure, affording the benzyl ester 17 as a
colorless solid 71.54 g, 93%). Mp. 68±698C 7lit.17 708C); 1H
NMR 7CDCl3, 200 MHz) d 7.65 7dt, Jˆ7.8, 1.0Hz, 1H),
7.59 7d, Jˆ1.0, 0.9 Hz, 1H), 7.46±7.25 7m, 5H), 7.30 7t,
Jˆ7.8 Hz, 1H), 7.05 7ddt, Jˆ7.8, 2.6, 0.9 Hz, 1H), 5.68
7broad s, 1H), 5.35 7s, 2H).
4.1.5. Diarylalkene /10). A mixture of the 7-exo and 8-endo
products 8 and 9 in the ratio 6.4:1 7165 mg, 0.29 mmol),
KOH 758 mg, 1.2 mmol) and benzyl bromide 7400 mL,
2.89 mmol) in CH3CN 76 mL) was stirred for 16.5 h under
nitrogen. The reaction mixture was evaporated to dryness,
and water was added, followed by extraction with CH2Cl2 73
times). The combined organic phases were washed with
brine and dried over MgSO4 and concentrated in vacuo.
Flash-chromatography afforded the diarylalkene 11
7152 mg, 83%) as well as the diarylalkene arising from
the 8-endo cyclization product 723 mg, 78%). For
1
compound 11: H NMR 7CDCl3, 200 MHz) d 6.80±7.46
4.1.9. 3-Methoxy-2-vinylbenzoic acid, 3-benzylcarboxyl-
phenyl ester /18). Oxalyl chloride 7700 mL, 8.02 mmol)
was added to a solution of the benzoic acid 16 7128 mg,
0.56 mmol) in CH2Cl2 710mL) and DMF 710 mL,
7m, 30H), 5.83 7d, Jˆ1.6 Hz, 1H), 5.74 7d, Jˆ1.6 Hz, 1H),
5.35 7s, 2H), 5.00 7s, 2H), 4.71 7s, 4H), 4.62 7s, 2H); 13C
NMR 7CDCl3, 50MHz) d 169.0, 166.3, 157.0 72C), 156.2,

2238
B. Laursen et al. / Tetrahedron 58 %2002) 2231±2238
2000, 65, 5382. 7c) Denieul, M.-P.; Laursen, B.; Hazell, R.;
Skrydstrup, T. J. Org. Chem. 2000, 65, 6052.
0.13 mmol). The reaction mixture was stirred for 1.5 h
under nitrogen. Solvent and excess of the oxalyl chloride
were removed under reduced pressure, leaving the acid
chloride as a pale yellow solid.
2. Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.;
Janzen, W. P.; Ballas, L. M.; Loomis, C. R.; Jiang, J. B. J. Am.
Chem. Soc. 1993, 115, 6452.
3. Ohshima, S.; Yanagisawa, M.; Katoh, A.; Fujii, T.; Sano, T.;
Matsukuma, S.; Furumai, T.; Fujiu, M.; Watanabe, K.;
Yokose, K.; Arisawa, M.; Okuda, T. J. Antibiot. 1994, 47, 639.
4. 7a) Bradshaw, D.; Hill, C. H.; Nixon, J. S.; Wilkinson, S. E.
Agents Actions 1993, 38, 135. 7b) Ishii, H.; Jirousek, 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.
5. For previous total syntheses of balanol, see 7a) Lampe, J. W.;
Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H. J. Org.
Chem. 1994, 59, 5147. 7b) Nicolaou, K. C.; Bunnage, M. E.;
Koide, K. J. Am. Chem. Soc. 1994, 116, 8402. 7c) Nicolaou,
K. C.; Koide, K.; Bunnage, M. E. Chem. Eur. J. 1995, 1, 454.
7d) 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.
7e) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.; Smith,
S. H.; Hu, H. J. J. Org. Chem. 1996, 61, 4572. 7f) Barbier,
P.; Stadlwieser, J. J. Chim. 1996, 50, 530. 7g) Tanner, D.;
Tadenborg, L.; Almario, A.; Pettersson, I.; Csoeregh, I.;
Kelly, N. M.; Andersson, P. G. Tetrahedron 1997, 53, 4857.
7h) Miyabe, H.; Torieda, M.; Kiguchi, T.; Naito, T. Synlett
1997, 580. 7i) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.;
Kiguchi, T.; Naito, T. J. Org. Chem. 1998, 63, 4397.
6. For previous work on the benzophenone fragment, see
7a) Hollinshead, S. P.; Nichols, J. B.; Wilson, J. W. J. Org.
Chem. 1994, 59, 6703. 7b) Nilsson, J. P.; Andersson, C.-M.
Tetrahedron Lett. 1997, 38, 4635. 7c) Storm, J. P.; Andersson,
C.-M. Org. Lett. 1999, 1, 1451±1453. 7d) Storm, J. P.;
Andersson, C.-M. J. Org. Chem. 2000, 65, 5264.
A solution of the above acid chloride 70.56 mmol), Et3N
7100 mL, 0.71 mmol) and the phenol 17 7100 mg,
0.56 mmol) in CH2Cl2 710mL) was stirred under nitrogen
for 2 h. After addition of water, and extraction with CH2Cl2
73 times), the combined organic phases were dried over
MgSO4 and evaporated to dryness. Flash chromatography
7CH2Cl2/pentane, 1:1 to 3:2) gave the ester 18 7198 mg,
1
89%) as a colorless oil. H NMR 7CDCl3, 200 MHz) d
8.02 7dt, Jˆ7.4, 1.6 Hz, 1H), 7.92 7dt, Jˆ1.6, 0.6 Hz, 1H),
7.32±7.56 7m, 9H), 7.107dd, Jˆ15.8, 11.6 Hz, 1H), 5.70
7dd, Jˆ15.8, 1.8 Hz, 1H), 5.59 7dd, Jˆ11.6, 1.8 Hz, 1H),
5.407s, 2H), 3.907s, 3H); 13C NMR 7CDCl3, 50MHz) d
166.8, 165.5, 157.6, 150.9, 135.8, 131.7, 131.0, 129.5, 128.7
72C), 128.4, 128.3 72C), 128.2, 127.3, 126.4, 122.9, 121.9,
120.4, 114.3, 67.0, 55.9; HR-MS 7ES) calcd for C24H20O5Na
411.1207 7M1Na), found 411.1211.
4.1.10. Attempted cyclization of 3-methoxy-2-formyl-
benzoic acid, 3-benzylcarboxylphenyl ester /15) with
samarium diiodide. Ozone was bubbled through a solution
of the alkene 18 759 mg, 0.15 mmol) dissolved in dry
CH2Cl2 75 mL) at 2788C until a blue color was obtained.
After removal of the excess ozone by bubbling nitrogen
through the solution for 5±10minutes at 2788C, triphenyl-
phosphine 7100 mg, 0.38 mmol) was added, and the reaction
mixture was warmed to 208C over a period of 15 min. Stir-
ring was continued for an additional 30min, and the
solvents were removed by evaporation to dryness in vacuo
to give the crude aldehyde 15 with excess triphenyl-
phosphine which was immediately used in the subsequent
reaction with samarium diiodide. 1H NMR 7C6D6,
200 MHz) d 10.16 7s, 1H), 8.20 7t, Jˆ2.0Hz, 1H), 7.74
7dt, Jˆ7.8, 1.0Hz, 1H), 6.77±7.25 7m, 9H), 6.19 7dt,
Jˆ9.4, 3.6 Hz, 1H), 4.94 7s, 2H), 2.95 7s, 3H).
7. Deng, J.; Hamada, Y.; Shioiry, T. Synthesis 1998, 627.
8. Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem. 1978,
43, 1372.
9. 7a) Boyd, R. N.; Hansen, R. H. J. Am. Chem. Soc. 1953, 75,
5896. 7b) Meyers, A. I.; Haidukkewych, D.; Mihelich, E. D.
J. Org. Chem. 1974, 39, 2787. 7c) Giordano, C.; Cavicchioli,
S.; Levi, S.; Villa, M. Tetrahedron Lett. 1988, 29, 5561.
7d) Peer, M.; de Jong, J. C.; Kiefer, M.; Langer, T.; Rieck,
H.; Schell, H.; Sennhenn, P.; Sprinz, J.; Steinhagen, H.;
Wiese, B.; Helmchen, G. Tetrahedron 1996, 52, 7547.
10. 7a) VorbruÈggen, H.; Krolikiewicz, K. Tetrahedron Lett. 1981,
22, 4471. 7b) VorbruÈggen, H.; Krolikiewicz, K. Tetrahedron
1981, 49, 9353.
The aldehyde was redissolved in THF 71 mL) under argon
and then cooled to 2788C. A 0.1 M solution of SmI2 in THF
73.4 mL, 0.34 mmol) was slowly added dropwise and the
solution was stirred for 30min and then quenched with
saturated aqueous NH4Cl. CH2Cl2 was added and the
mixture was ®ltered through celite, whereafter the organic
phase was dried over Na2SO4 and concentrated in vacuo.
The residue was subjected to ¯ash chromatography
7CH2Cl2/pentane, 3:1 to 1:0) affording the phenol 17
720mg, 60% yield).
11. Hashimoto, S.; Furukawa, I. Bull. J. Chem. Soc. 1981, 54,
2227.
12. In our previous work 7Ref. 1c), it was necessary to employ a
catalytic loading of 26 mol% in order to effect the desired
cyclization reaction in reasonable yields. We ascribe the
possibility for reducing the catalyst loading in the reaction
with 7 to the larger scale used in this work.
Acknowledgements
We are grateful to the Danish National Science Foundation
7THOR Program), the University of Aarhus and the
Carlsberg Foundation for ®nancial support.
13. Satoh, T.; Itaya, T.; Miura, M.; Nomura, M. Chem. Lett. 1996,
823.
14. Larock, R. C.; Doty, M. J. J. Org. Chem. 1993, 58, 4579.
15. Dinesh, C. U.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl.
1999, 38, 789.
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