Total synthesis of (-)-balanol

Article abstract of DOI:10.1021/jo980208r

The efficient total synthesis of (-)-balanol, a potent inhibitor of the protein kinase C, is described (-)-Balanol consists of a chiral hexahydroazepine-containing fragment and a benzophenone fragment, both of which were prepared via novel synthetic routes. The hxahydroazepine fragment was prepared in racemic form through either Bu₃SnH- or SmI₂-promoted radical cyclization of oxime ethers 2ab intramolecularly connected with the formyl group. SmI₂-promoted radical cyclization of 2b was found to be particularly successful in the selective synthesis of the seven-membered trans-amino alcohol 8b. Preparation of the enantiomerically pure hexahydroazepine-containing fragment was achieved through the enantioselective enzymatic acetylation of racemic alcohol 9, employing the immobilized lipase from Pseudomonas sp. The benzophenone fragment was prepared in short steps through a biomimetic oxidative anthraquinone ring cleavage starting from commercially available natural chrysophanic acid 15c. This reaction proceeded via [4 + 2]-cycloaddition of single of oxygen to anthracene derivative 17c, followed by Baeyer-Villiger-type rearrangement of the resulting hydroperoxide to afford the benzophenone derivatives 22 and 23.

Full text of DOI:10.1021/jo980208r

J . Org. Chem. 1998, 63, 4397-4407
4397
Tota l Syn th esis of (-)-Ba la n ol
Hideto Miyabe, Mayumi Torieda, Kyoko Inoue, Kazumi Tajiri, Toshiko Kiguchi, and
Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, J apan
Received February 5, 1998
The efficient total synthesis of (-)-balanol, a potent inhibitor of the protein kinase C, is described.
(-)-Balanol consists of a chiral hexahydroazepine-containing fragment and a benzophenone
fragment, both of which were prepared via novel synthetic routes. The hexahydroazepine fragment
was prepared in racemic form through either Bu3SnH- or SmI2-promoted radical cyclization of oxime
ethers 2a b intramolecularly connected with the formyl group. SmI2-promoted radical cyclization
of 2b was found to be particularly successful in the selective synthesis of the seven-membered
trans-amino alcohol 8b. Preparation of the enantiomerically pure hexahydroazepine-containing
fragment was achieved through the enantioselective enzymatic acetylation of racemic alcohol 9,
employing the immobilized lipase from Pseudomonas sp. The benzophenone fragment was prepared
in short steps through a biomimetic oxidative anthraquinone ring cleavage starting from
commercially available natural chrysophanic acid 15c. This reaction proceeded via [4 + 2]-cy-
cloaddition of singlet oxygen to anthracene derivative 17c, followed by Baeyer-Villiger-type
rearrangement of the resulting hydroperoxide to afford the benzophenone derivatives 22 and 23.
In tr od u ction
Roche Research, who called it azepinostatin instead of
balanol.4 Its remarkable inhibitory activity and its
structural novelty have attracted significant attention as
a new lead compound of potent drugs against diseases
associated with PKC activation. Thus, balanol and its
analogues have been the recent new subject of synthetic
studies, and independently, three total syntheses of
balanol were achieved by Nicolaou’s group and by re-
searchers at Sphinx and at Rhone-Poulenc Rorer.5-9 We
have also started synthetic studies involving sufficiently
flexible synthetic routes to allow ready access to a variety
of balanol analogues for the improvement of enzyme
selectivity and pharmacokinetic properties.10 In this
paper, we describe full details of our total synthesis of
(-)-balanol via novel synthetic routes.
Protein kinase C (PKC) is a family of phospholipid-
dependent serine/threonine specific protein kinases that
mediate a wide range of signal transduction processes
in cells.1 Human PKC enzyme consists of at least eight
isoforms R, â-I, â-II, δ, ꢀ, γ, η, and ú, which play important
roles in cellular growth control, regulation, and dif-
ferentiation. Since activation of PKC enzymes has been
implicated in a number of diseases such as cancer,
cardiovascular disorders, central nervous system dys-
function, HIV infection, and so on, a selective inhibitor
against PKC isozyme may have wide-ranging therapeutic
potential.2
Balanol (1), initially isolated from the fungus Verticil-
lium balanoides by Kulanthaivel and co-workers at
Sphinx Pharmaceuticals, has been shown to inhibit
human PKC isozymes at low nanomolar concentrations
(IC50 ranges 4-9 nM).3 It was also more recently isolated
from a species of Fusarium by researchers at Nippon
Balanol consists of two distinct structural domains, a
chiral hexahydroazepine-containing fragment and a ben-
(4) Isolation from Fusarium merismoides Corda, see: 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, 639-647.
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E., J r.; Hughes, P. F.; Nichols, J . B. Tetrahedron Lett. 1995, 36, 3659-
3662. (c) Hollinshead, S. P.; Nichols, J . B.; Wilson, J . W. J . Org. Chem.
1994, 59, 6703-6709. (d) Lampe, J . W.; Hughes, P. F.; Biggers, C. K.;
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P. F. Private communication.
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fragment, see the following. (a) Recently, total syntheses of balanol
were also achieved by Tanner’s group. See: Tanner, D.; Tedenborg,
L.; Almario, A.; Pettersson, I.; Co¨sregh, I.; Kelly, N. M.; Andersson, P.
G.; Ho¨gberg, T. Tetrahedron 1997, 53, 4857-4868. (b) Tanner, D.;
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S0022-3263(98)00208-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/05/1998

4398 J . Org. Chem., Vol. 63, No. 13, 1998
Miyabe et al.
F igu r e 2. Substrates 2a b, (E)-2b, and (Z)-2b.
become useful tools in organic synthesis.11 Particularly,
free radical-mediated cyclization has been an important
method for the construction of various types of cyclic
compounds. While there have been extensive investiga-
tions into radical-mediated five- or six-membered ring
formation,12 the difficulty in achieving radical-mediated
construction of the seven-membered ring has remained
unresolved.13 Thus, the radical-promoted intramolecular
construction of seven-membered compounds and its ste-
reocontrol are subjects of considerable interest. Previ-
ously, we reported the first example of the synthesis of
cyclic amino alcohols via a route involving the tributyltin
hydride-induced radical cyclization of oxime ethers, which
were intramolecularly connected with an aldehyde or a
ketocarbonyl group.13 This approach was particularly
successful for the synthesis of not only five- and six-
membered compounds but also seven-membered cyclic
amino alcohols. Thus, this procedure would provide a
convenient method for preparing natural balanol and its
analogues with readily accessible replacement of the
hexahydroazepine moiety.
Since trans relative stereochemistry of the two aro-
matic side chains of balanol are indispensable for optimal
potency,9a we explored the selective synthesis of trans
cyclic amino alcohols. To investigate the substituent
effects of the O-alkyl groups R and the geometry of the
oxime ether group on the trans/cis selectivity of radical
cyclizations, we selected the substrates 2a b, (E)-2b, and
(Z)-2b (Figure 2), which were prepared as shown in
Scheme 1. R-Chloroacetaldoxime ethers 4a b were readily
prepared from chloroacetaldehyde and the corresponding
O-alkylhydroxyamine hydrochloride.14 Alkylation of com-
mercially available 4-aminobutanol 3 with 4a b gave the
secondary amines 5a b in 69 and 82% yields, respectively,
as an E/Z mixture in a 3:2 ratio. The E/Z ratios were
F igu r e 1. Retrosynthesis of (-)-balanol.
zophenone fragment. Our synthetic approach includes
the preparation of the enantiomerically pure hexahy-
droazepine-containing fragment through either the Bu3-
SnH- or SmI2-promoted radical cyclization of the oxime
ether intramolecularly connected with the formyl group,
followed by the lipase-catalyzed optical resolution of the
resulting racemic alcohols. Preparation of a benzophe-
none fragment was achieved through a biomimetic oxida-
tive anthraquinone ring cleavage starting from natural
chrysophanic acid (Figure 1).
Resu lts a n d Discu ssion
Ra d ica l Cycliza tion a n d Ra cem ic Hyd r oa zep in e
Syn th esis. Strategies involving radical reactions have
(9) For some recent studies on balanol analogues, see: (a) Lai, Y.-
S.; Mendoza, J . S.; J agdmann, G. E., J r.; Menaldino, D. S.; Biggers, C.
K.; 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, 226-235. (b) 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, 5215-5227. (c) Lai, Y.-S.; Stamper, M. Bioorg.
Med. Chem. Lett. 1995, 5, 2147-2150. (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, 2151-2154. (e) Lai, Y.-S.;
Mendoza, J . S.; Hubbard, F.; Kalter, K. Bioorg. Med. Chem. Lett. 1995,
5, 2155-2160. (f) Mendoza, J . S.; J agdmann, G. E., J r.; Gosnell, P. A.
Bioorg. Med. Chem. Lett. 1995, 5, 2211-2216. (g) Hu, H.; Hollinshead,
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1996, 6, 973-978. (h) J agdmann, G. E., J r.; Defauw, J . M.; Lampe, J .
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(10) For our total synthesis of (-)-balanol, see: (a) Miyabe, H.;
Torieda, M.; Kiguchi, T.; Naito, T. Synlett 1997, 580-582. (b) Naito,
T.; Torieda, M.; Tajiri, K.; Ninomiya, I.; Kiguchi, T. Chem. Pharm. Bull.
1996, 44, 624-626.
(11) For recent reviews, see: (a) Ryu, I.; Sonoda, N.; Curran, D. P.
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Chemistry; Translated by Lomas, J .; J ohn Wiley & Sons Inc.: New
York, 1995; pp 151-158, 243-255.
(13) We reported the first example of the synthesis of five- to seven-
membered cyclic amino alcohols in the tributyltin hydride-induced
radical cyclization of oxime ethers. See: (a) Naito, T.; Tajiri, K.;
Harimoto, T.; Ninomiya, I.; Kiguchi, T. Tetrahedron Lett. 1994, 35,
2205-2206. (b) Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T.; Hira-
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of the radical-mediated formation of seven-membered ring were
reported. For recent examples, see: (d) Giese, B.; Kopping, B.; Go¨bel,
T.; Dickhaut, J .; Thoma, G.; Kulicke, K. J .; Trach, F. Org. React. (N.Y.)
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89603d.

Total Synthesis of (-)-Balanol
Sch em e 1
J . Org. Chem., Vol. 63, No. 13, 1998 4399
Sch em e 2
be trans by converting it into an authentic compound
9.5-7 In the case of the radical cyclization employing an
E/Z mixture of O-benzyl oxime ether 2b, similar selectiv-
ity and chemical yield were obtained (Table 1, entry 2).
The rationale of the reaction pathway of this 7-exo-trig
radical cyclization is that the stannyl radical initially
reacted with the oxygen atom of the formyl group to form
the ketyl radical, which attacked intramolecularly the
oxime ether moiety (Scheme 2). In this reaction, the
oxime ether group acts as an excellent radical acceptor
because of the extra stabilization of the intermediate
aminyl radical provided by the lone pair on the adjacent
oxygen atom.16,17 Interestingly, we have also observed
no remarkable effect of the geometry of the starting oxime
ether group on either the chemical yield or trans/cis
selectivity by employing geometrically pure (E)-2b and
(Z)-2b (Table 1, entries 3 and 4). A similar trend has
been recently reported by Bartlett in a tributyltin hy-
dride-induced reductive coupling of phenyl thionocarbon-
ates with oxime ethers.18
In recent years, samarium diiodide (SmI2) has evolved
as a unique single-electron reducing agent that is well
suited for highly chemo- and stereoselective radical
reactions.19,20 Next, we examined the intramolecular
reductive coupling of O-benzyl oxime ether 2b by SmI2
for the selective synthesis of the seven-membered trans-
amino alcohol. Cyclizations were performed in the pres-
ence of 2.2 equiv of t-BuOH as a proton donor in THF
from -78 °C to room temperature by the use of a 0.1 M
solution of SmI2 in THF (4.0 equiv). In the absence of
HMPA, the cyclization of an E/Z mixture of 2b did not
proceed at all and resulted in the recovery of the starting
Ta ble 1. Ra d ica l Cycliza tion of Oxim e Eth er 2a b
ratio
entry strate E:Z
conditions
reagent T (°C)
reflux
ratiod
(%) 7a b:8a b
sub-
yieldc
1
2
3
4
5
6
2a 3:2 Bu3SnHa
2b 3:2 Bu3SnHa
48
50
51
43
1:2.0
1:2.6
1:2.9
1:2.6
reflux
reflux
reflux
rt
(E)-2b 1:0 Bu3SnHa
(Z)-2b 0:1 Bu3SnHa
b
2b 3:2 SmI2
no reaction
53 1:6.6
2b 3:2 SmI2, HMPAb -78 to rt
a
Reaction was carried out in the presence of AIBN in boiling
b
benzene. Reaction was carried out in the presence of t-BuOH in
d
THF. c Combined yield of cis and trans cyclic products. Ratio is
based on respective isolated yields of cis and trans cyclic products.
determined by 1H NMR spectroscopy. In general, the
signals due to the imino hydrogen of the E-oxime ether
are shifted downfield by the influence of the alkoxy group
of the oxime ether moiety.15 In the case of 5a , the triplet
signal due to the imino hydrogen of the E-isomer (δ 7.42
ppm) was shifted downfield with respect to that of the
Z-isomer (δ 6.76 ppm). These amines 5a b were protected
as the N-Boc derivatives 6a b in good yields by treatment
with di-tert-butyl dicarbonate under the Schotten-Bau-
mann-type conditions. Mild oxidation of 6a b with chro-
mium(VI) oxide-pyridine afforded the unstable alde-
hydes 2a b in 69 and 78% yields, respectively, in favor of
the E isomer in a 3:2 ratio. After careful separation of
(E)-2b and (Z)-2b by medium-pressure column chroma-
tography, these isomers were subjected to the following
radical cyclization.
At first, we examined stannyl radical-promoted cy-
clization of the O-methyl oxime ether 2a (Table 1).
Treatment of an E/Z mixture of 2a with tributyltin
hydride (2 equiv) in the presence of AIBN (1 equiv) in
boiling benzene gave a 1:2 mixture of two cyclized
products 7a and 8a in 48% combined yield in favor of
trans-amino alcohol 8a (Table 1, entry 1). We were able
to separate and purify each isomer by either flash or
medium-pressure column chromatography. Relative ster-
eochemistry of the major product 8a was determined to
(16) For our recent work in radical addition to oxime ethers, see:
(a) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun. 1997, 1789-
1790. (b) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. Tetrahedron
Lett. 1998, 39, 631-634.
(17) For selected examples of the radical reaction of oxime ethers,
see: (a) Bhat, B.; Swayze, E. E.; Wheeler, P.; Dimock, S.; Perbost, M.;
Sanghvi, Y. S. J . Org. Chem. 1996, 61, 8186-8199. (b) Kim, S.; Lee, I.
Y.; Yoon, J .-Y.; Oh, D. H. J . Am. Chem. Soc. 1996, 118, 5138-5139.
(c) Hart, D. J .; Seely, F. L. J . Am. Chem. Soc. 1988, 110, 1631-1633.
(d) Clive, D. L. J .; Zhang, J . Chem. Commun. 1997, 549-550. (e) Marco-
Contelles, J .; Balme, G.; Bouyssi, D.; Destabel, C.; Henriet-Bernard,
C. D.; Grimaldi, J .; Hatem, J . M. J . Org. Chem. 1997, 62, 1202-1209.
(f) Keck, G. E.; Wager, T. T. J . Org. Chem. 1996, 61, 8366-8367. (g)
Hollingworth, G. J .; Pattenden, G.; Schulz, D. J . Aust. J . Chem. 1995,
48, 381-399. (h) Chiara, J . L.; Marco-Contelles, J .; Khiar, N.; Gallego,
P.; Destabel, C.; Bernabe´, M. J . Org. Chem. 1995, 60, 6010-6011. (i)
Santagostino, M.; Kilburn, J . D. Tetrahedron Lett. 1995, 36, 1365-
1368. (j) Grissom, J . W.; Klingberg, D.; Meyenburg, S.; Stallman, B.
L. J . Org. Chem. 1994, 59, 7876-7888. (k) Parker, K. A.; Fokas, D. J .
Org. Chem. 1994, 59, 3927-3932. (l) Della, E. W.; Knill, A. M. Aust.
J . Chem. 1994, 47, 1833-1841.
(18) Bartlett, P. A.; McLaren, K. L.; Ting, P. C. J . Am. Chem. Soc.
1988, 110, 1633-1634.
(19) For reviews, see: (a) Skrydstrup, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 345-347. (b) Molander, G. A.; Harris, C. R. Chem. Rev.
1996, 96, 307-338.
(20) For selected examples of the reductive coupling of oxime ether
and carbonyl compound by use of SmI2, see: (a) Marco-Contelles, J .;
Gallego, P.; Rodr´ıguez-Ferna´ndez, M.; Khiar, N.; Destabel, C.; Bernabe´,
M.; Mart´ınez-Grau, A.; Chiara, J . L. J . Org. Chem. 1997, 62, 7397-
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3556.
(15) McCarty, C. G. In The Chemistry of Functional Groups; The
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Wiley & Sons, Inc.: New York, 1970; pp 383-392.

4400 J . Org. Chem., Vol. 63, No. 13, 1998
Miyabe et al.
Sch em e 3
Sch em e 4
in MeOH followed by N-acylation of the resulting crude
amine with p-(benzyloxy)benzoyl chloride afforded the
desired racemic hydroazepine 9 in 55 and 58% yields,
respectively (Scheme 3). This compound 9 was identical
with an authentic sample upon comparison of their
spectral data.6 Thus, we have succeeded in the six-step
preparation of a racemic hexahydroazepine-containing
fragment.
F igu r e 3. Proposed radical intermediate favoring trans
cyclization.
material 2b (Table 1, entry 5). The addition of HMPA
(10 equiv), which was recognized to increase the reaction
rate by SmI2, was found to be essential for successful
cyclization of 2b to afford trans cyclized product 8b in
46% yield accompanied with a minor amount of cis
product 7b in 7% yield (Table 1, entry 6).21 This one-
electron reducing agent has been recently used for the
intramolecular coupling of aldehydes and ketones with
oxime ethers for the synthesis of five-membered amino-
cyclopentitols.20a In these cases, the coupling reaction
proceeded even in the absence of HMPA, in contrast to
our seven-membered ring formation. Probably, this
reductive coupling reaction was initiated by single-
electron transfer to the formyl group with generation of
a ketyl radical, which then attacked the oxime ether
moiety. The preferential formation of the trans isomer
8b could be explained by chelation of the ketyl radical
and the oxime ether group to a Sm(III)(HMPA)n cation
as shown in Figure 3.22 There are less steric and
electronic repulsions in the chelated radical 1A ) 1B
leading to the trans isomer 8b than in the chelated
radical 1C ) 1D leading to the cis isomer 7b.
Op tica l Resolu tion . To prepare the enantiomerically
pure hexahydroazepine-containing fragment, racemic
hydroazepine 9 was then subjected to chemical optical
resolution by forming the corresponding diastereomeric
esters and enzymatic optical resolution using lipase.
Among the diastereomeric esters 10a -c and 11a -c
derived from N-Z-L-alanine, (S)-camphanic acid chloride,
and (R)-2-methoxy-2-(trifluoromethyl)phenylacetyl (MTPA)
chloride, the esters (3R,4R)-10c and (3S,4S)-11c were
found to be readily separable by medium-pressure column
chromatography eluting with pentane-ethyl acetate (4:
7, v/v) (Scheme 4). Alkaline hydrolysis of esters (3R,4R)-
10c and (3S,4S)-11c gave the desired hydroazepine
(3R,4R)-9 and its isomer (3S,4S)-9, respectively, in 95%
overall yield from racemic hydroazepine 9. The enan-
tiomeric purity of (3R,4R)-9 and (3S,4S)-9 was found to
be not less than 99% ee using chiral chromatography
(Chiral Pack AD column) eluting with ethanol-heptane
(15:85, v/v). The absolute configuration of (3R,4R)-9 was
determined by comparison with the literature value of
the optical rotation.6
Subsequent hydrogenolysis of the alkoxyamino group
of trans product 8a b in the presence of platinum dioxide
(21) Although the cleavage of the N-O bond of a hydroxyamine by
excess SmI2 was reported, the N-O bond cleavage of 8b could not be
observed. See: (a) Keck, G. E.; Wager, T. T. J . Org. Chem. 1996, 61,
8366-8367. (b) Chiara, J . L.; Destabel, C.; Gallego, P.; Marco-Contelles,
J . J . Org. Chem. 1996, 61, 359-360.
(22) In the reactions of the ketyl radical induced by SmI2, the
chelated intermediates were proposed. See: (a) Molander, G. A.;
McWilliams, J . C.; Noll, B. C. J . Am. Chem. Soc. 1997, 119, 1265-
1276. (b) Taniguchi, N.; Uemura, M. Synlett 1997, 51-53. (c) Tanigu-
chi, N.; Kaneta, N.; Uemura, M. J . Org. Chem. 1996, 61, 6088-6089.
(d) Kawatsura, M.; Dekura, F.; Shirahama, H.; Matsuda, F. Synlett
1996, 373-376.
Enzymes have become increasingly popular as a chiral
catalyst in organic synthesis.23 Lipases are especially
attractive for this purpose because they are relatively
inexpensive, effective in both organic and aqueous solu-
tions, and useful under mild reaction conditions. For the
(23) Santaniello, E.; Ferraboschi, P.; Paride, G.; Manzocchi, A. Chem.
Rev. 1992, 92, 1071-1140.

Total Synthesis of (-)-Balanol
J . Org. Chem., Vol. 63, No. 13, 1998 4401
Ta ble 2. Lip a se-Ca ta lyzed Op tica l Resolu tion of 9
Sch em e 6
12
(3S,4S)-9
yieldd eee yieldd eee
Baeyer-Villiger-type reaction has been recognized as a
key reaction in biosynthesis of fungal metabolites,24 we
planned to explore the biomimetic route for the synthesis
of the benzophenone fragment of balanol (Scheme 6).
Although the biosynthetic features of balanol have not
been confirmed, the oxidative ring cleavage of natural
anthraquinones such as chrysophanic acid, aloe-emodine,
and rhein could be one of the possible pathways for the
benzophenone fragment. Our synthesis of the benzophe-
none fragment of balanol started from natural chrysophan-
ic acid as the commercially available natural anthraquino-
ne. In general, chemical Baeyer-Villiger reactions of
anthraquinones are known to proceed slowly because
they give the unstable seven-membered lactones as an
intermediate.25 The only two successful examples of
anthraquinone ring cleavage are the experiments using
an enzyme or singlet oxygen.24,26,27
entry
1
immobilized lipasea
(%)
11
(%)
97
(%)
72
(%)
3
Pseudomonas sp.b
(320 g/mol)
2
3
Pseudomonas sp.b
(1600 g/mol)
42
96
49
82
Pseudomonas fluorescencec
(500 g/mol)
no reaction
a
Reactions were carried out in t-BuOMe at 20 °C for 48 h (run
1), 20-45 °C for 20 h (run 2), and 20 °C for 52 h (run 3),
b
d
respectively. 0.5 unit/mg. c 4.0 unit/mg. Isolated yield. e Enan-
tiomeric excess was determined by chiral HPLC analysis.
Sch em e 5
Despite its importance from a synthetic point of view,
a detailed survey of the latter method mentioned above
has not been reported yet. To learn about the substituent
effects of anthraquinone structure on both the regiose-
lectivity of the ketal hydrolysis step and the migratory
aptitude of the following rearrangement step, we carried
out extensive studies of this process by employing three
methoxy-substituted derivatives 17a -c.
Hydroxyanthraquinone 15c was first protected by
methylation using dimethyl sulfate and K2CO3 in acetone
to give methyl ether 16c (Scheme 7). Quinone derivative
16c was then reductively methylated to the correspond-
ing anthracene derivative 17c by treatment with sodium
hydrosulfite in the presence of tetrabutylammonium
bromide as a phase-transfer catalyst followed by meth-
ylation employing dimethyl sulfate and KOH.28 Accord-
ing to the literature,27 an etheral solution of anthracenes
17a -c, which also served as a sensitizer, was irradiated
with a halogen lamp through a Pyrex filter under oxygen
bubbling. After the solvent was evaporated in vacuo, the
resulting oxygen adducts were treated with a catalytic
amount of sulfuric acid in acetone to give the benzophe-
none derivatives 18-23.29 The reaction pathway from
17 to 18-23 can be rationalized by a [4 + 2]-cycloaddition
of anthracene 17 to singlet oxygen, regioselective hy-
convenient preparation of enantiomerically pure hexahy-
droazepine, we next investigated the lipase-catalyzed
optical resolution such as the enzymatic esterification of
racemic alcohol 9 and the enzymatic hydrolysis of racemic
acetate (()-12. The screening of several enzymes showed
that the lipase from Pseudomonas sp. was the enzyme
of choice to perform the esterification of 9 in high yields
and enantiomeric purity. These enzymatic esterifications
of 9 were carried out by use of vinyl acetate as an
acylating agent in tert-butyl methyl ether as a solvent.
The acetylation of 9 employing the immobilized lipase
(1600 g/mol, 0.5 unit/mg) from Pseudomonas sp. (Wako
Pure Chemical Industries, Ltd.) at 20-45 °C for 20 h was
found to be most effective and the optimum reaction
conditions. Chromatographic separation of the products
afforded the desired acetate 12 in 42% yield (96% ee) with
the recovered (3S,4S)-9 in 49% yield (82% ee) (Table 2,
entry 2). The enantiomeric purity of 12 and (3S,4S)-9
was checked by chiral column chromatography (Chiral
Pack AD column) eluting with ethanol-heptane (15:85,
v/v). The absolute configuration of 12 was determined
by converting it into (3R,4R)-9 mentioned above. Alter-
native enantioselective enzymatic hydrolysis of racemic
acetate (()-12 was unsuccessful, and the starting acetate
(()-12 was completely recovered when the immobilized
lipase from Pseudomonas sp. was employed. Treatment
of acetate 12 with trifluoroacetic acid in CH2Cl2 gave the
deprotected product, which without further purification,
was reprotected with benzyloxycarbonyl chloride in ac-
etone to afford N-Z acetate 13 in 87% from 12 (Scheme
5). Alkaline hydrolysis of N-Z acetate 13 gave enantio-
merically pure alcohol 14, which was found to be identical
with an authentic sample upon comparison of their
spectral data, including optical rotation.5-7
(24) Frank, B. In The Biosynthesis of Mycotoxins, Steyn, P. S., Ed.;
Academic Press: New York, 1980; pp 151-191.
(25) Svensson, L.-A° . Acta Chem. Scand. 1972, 26, 2372-2384.
(26) Fujii, I.; Ebizuka, Y.; Sankawa, U. J . Biochem. 1988, 103, 878-
883.
(27) Frank, B.; Berger-Lohr, B. Angew. Chem., Int. Ed. Engl. 1975,
14, 818-819.
(28) (a) Blankespoor, R. L.; Schutt, D. L.; Tubergen, M. B.; De J ong,
R. L. J . Org. Chem. 1987, 52, 2059-2064. (b) Hydroxyanthraquinones
15a b could be directly converted into the corresponding methylated
anthracene derivatives 17a b by treatment with sodium hydrosulfite
in the presence of tetrabutylammonium bromide as a PTC followed
by methylation employing dimethyl sulfate and KOH. See: Kraus, G.
A.; Man, T. O. Synth. Commun. 1986, 16, 1037-1042.
(29) The reason trimethoxy-substituted benzophenone 20 was ob-
tained from 17b even in the absence of methanol and/or other
methylating agents is not clear at the moment.
Ben zop h en on e Syn th esis. From the fact that the
conversion of anthraquinones to benzophenones via the

4402 J . Org. Chem., Vol. 63, No. 13, 1998
Miyabe et al.
Sch em e 7
Sch em e 9
and 1,4-dimethoxy groups of 17b dramatically affected
the migratory aptitude on the Baeyer-Villiger-type rear-
rangement of 2B. Therefore, in the case of 17c possess-
ing 1,8-dimethoxy groups and a 3-methyl group, an
inseparable mixture of two regioisomeric benzophenones
22 and 23 was obtained in 57% combined yield in a 1:1
ratio among four possible regioisomers via the regiose-
lective ketal hydrolysis process and a nonselective migra-
tion process in addition to 30% yield of the starting
anthraquinone 16c, which could be recycled.30
Sch em e 8
A mixture of benzophenones 22 and 23 was converted
into a mixture of the corresponding methyl ethers 24 and
25 that was separated by medium-pressure column
chromatography (Scheme 9). Fortunately, benzophe-
nones 24 and 25 were fully characterized by their spectral
data including NOESY spectral analysis. Bromination
of 24 with NBS in the presence of a catalytic amount of
AIBN proceeded smoothly to give bromide 26 in 57%
(67%)31 yield. Bromide 26 was treated with boron tri-
bromide in CH2Cl2 to give the crude deprotected triph-
enolic acid, which was then reprotected by benzylation
using benzyl bromide and K2CO3 to afford the tetrabenzyl
derivative 27 in 28% yield. Hydrolysis of 27 under mild
conditions using CaCO3 provided the desired alcohol 28
drolysis of the resulting ketal moiety at the 9-position of
2A, and the Baeyer-Villiger type of acid-catalyzed rear-
rangement of the resulting hydroperoxide 2B, in which
the migrating group can be placed antiperiplanar to the
O-O bond (Scheme 8). The reaction of anthracene 17a
having 1,8-dimethoxy groups took place smoothly to
afford the benzophenone derivative 18 as a single isomer
in 67% yield via a completely regioselective ketal hy-
drolysis process. In the case of 17b having 1,4-dimethoxy
groups, trimethoxy-substituted benzophenone derivative
20 was obtained in 27% yield with no detection of another
product 21 via a regioselective migration process. These
results indicate that the electron-donating property of
1,8-dimethoxy groups of 17a was sufficient for the
formation and stabilization of the cation at C-9 of 2B,
(30) The formation of this peroxide intermediate was also confirmed
by EI and high-resolution mass spectra. A peroxide intermediate: MS
(EI) m/z 330 (M+); high-resolution MS calcd for C18H18O6 330.1102,
found 330.1115.
(31) Yield in parentheses is based on the consumed starting mate-
rial.

Total Synthesis of (-)-Balanol
Sch em e 10
J . Org. Chem., Vol. 63, No. 13, 1998 4403
4-[[2-(Meth oxyim in o)eth yl]a m in o]-1-bu ta n ol (5a ). To
4-amino-1-butanol (3) (12 g, 135 mmol) was added chloro-
acetaldehyde O-methyloxime (4a )14 (6.0 g, 56 mmol) under a
nitrogen atmosphere at 0 °C. After being stirred at room
temperature for 48 h, the reaction mixture was added to
saturated aqueous NaHCO3 and CH2Cl2. The layers were
separated, and the aqueous phase was extracted with CH2-
Cl2. The combined organic phase was dried over Na2SO4 and
concentrated at reduced pressure. Purification of the residue
by flash chromatography (AcOEt to CH2Cl2/MeOH 10:1) af-
forded 5a (6.2 g, 69%) as a yellow oil and a 3:2 mixture of E/Z-
oxime: IR (CHCl3) 3670-3200 (OH) cm-1; 1H NMR (CDCl3) δ
7.42 (3/5H, t, J ) 5.5 Hz), 6.76 (2/5H, t, J ) 4.5 Hz), 3.88 (6/
5H, s), 3.84 (9/5H, s), 3.59 (2H, t, J ) 6 Hz), 3.50 (4/5H, d, J
) 4.5 Hz), 3.37 (6/5H, d, J ) 5.5 Hz), 2.67 (2H, m), 1.73-1.48
(4H, m); HRMS calcd for C7H16N2O2 (M+) 160.1211, found
160.1220.
4-[[2-[(P h e n y lm e t h o x y )im in o ]e t h y l]a m in o ]-1-b u -
ta n ol (5b). To a solution of chloroacetaldehyde O-(phenylm-
ethyl)oxime (4b)14 (7.0 g, 38 mmol) in MeOH (150 mL) was
added 4-amino-1-butanol (3) (6.8 g, 76 mmol) under a nitrogen
atmosphere at 0 °C. The reaction mixture was heated at reflux
for 2 h. After the solvent was evaporated at reduced pressure,
the resulting residue was added to saturated aqueous NaHCO3
and CH2Cl2. The layers were separated, and the aqueous
phase was extracted with CH2Cl2. The combined organic
phase was dried over Na2SO4 and concentrated at reduced
pressure. Purification of the residue by flash chromatography
(AcOEt/hexane 1:9 to AcOEt/MeOH 5:1) afforded 5b (7.4 g,
82%) as a yellow oil and a 3:2 mixture of E/Z-oxime: IR
in 79% yield, which was found to be identical with an
authentic sample upon direct comparison of their spec-
tra.5 According to Nicolaou’s conditions, alcohol 28 was
oxidized into acid 30 by use of TPAP-NMO followed by
sodium chlorite.5 Thus, we succeeded in the biomimetic
synthesis of the desired benzophenone 30, which was the
known key intermediate for the synthesis of balanol.
The synthesis of (-)-balanol was completed as shown
in Scheme 10. The coupling of benzophenone fragment
30 with hydroazepine fragments (3R,4R)-9 or 14 was
accomplished by the Mukaiyama procedure32 to afford the
protected balanols 31a b in 77 and 77% yields, respec-
tively. These two products 31a b were found to be
identical with the respective authentic chiral samples
upon comparison of their spectral data.5-7 Finally,
palladium black-catalyzed hydrogenolysis of 31b in for-
mic acid gave (-)-balanol (1) under the same conditions
as the Nicolaou method.5 Purification of the resulting
crude balanol (1) was accomplished by a combination of
normal-phase preparative TLC and reversed-phase pre-
parative TLC. The synthetic (-)-balanol (1) exhibited
characterization data consistent with authentic spectral
data.5,6
(CHCl3) 3600-3200 (OH) cm-1 1H NMR (CDCl3) δ 7.49 (3/
;
5H, t, J ) 5.5 Hz), 7.42-7.22 (5H, m), 6.80 (2/5H, t, J ) 4.5
Hz), 5.10 (4/5H, s), 5.06 (6/5H, s), 3.62-3.49 (14/5H, m), 3.35
(6/5H, d, J ) 5.5 Hz), 2.63 (2H, t, J ) 6 Hz), 1.71-1.48 (4H,
m); HRMS calcd for C13H20N2O2 (M+) 236.1524, found 236.1541.
1,1-Dim et h ylet h yl (4-H yd r oxyb u t yl)[2-(m et h oxyim i-
n o)eth yl]ca r ba m a te (6a ). To a solution of 5a (6.2 g, 38.8
mmol) in acetone (93 mL) was added a solution of Na2CO3 (3.4
g, 32.0 mmol) in H2O (15.5 mL) under a nitrogen atmosphere
at room temperature. After di-tert-butyl dicarbonate (12.7 g,
58.3 mmol) was added dropwise at 0 °C, the reaction mixture
was heated at reflux for 5 h. After the reaction mixture was
filtered through a pad of Celite, the filtrate was concentrated
at reduced pressure. The resulting residue was quenched with
5% HCl at 0 °C and then extracted with CHCl3. The organic
phase was washed with brine, dried over Na2SO4, and con-
centrated at reduced pressure. Purification of the residue by
medium-pressure column chromatography (AcOEt/hexane 2:1)
afforded 6a (8.92 g, 88%) as a colorless oil and a 3:2 mixture
of E/Z-oxime. The presence of rotamers precluded a compre-
hensive assignment of all proton resonances: IR (CHCl3)
3600-3400 (OH), 1685 (NCOO) cm-1; 1H NMR (CDCl3) δ 7.32
(3/5H, br m), 6.64 (2/5H, br m), 4.03 (4/5H, br m), 3.90 (6/5H,
br m), 3.88 (6/5H, s), 3.84 (9/5H, s), 3.67 (2H, td, J ) 6, 2 Hz),
3.25 (2H, br m), 1.77-1.48 (4H, m), 1.46 (9H, s); HRMS calcd
for C12H24N2O4 (M+) 260.1735, found 260.1717.
Con clu sion s
We succeeded in the total synthesis of (-)-balanol by
the preparation of the chiral hexahydroazepine fragment
through the SmI2-promoted radical cyclization followed
by enzymatic esterification using the immobilized lipase
from Pseudomonas sp. and by the facile preparation of
the benzophenone fragment through a biomimetic oxida-
tive anthraquinone ring cleavage starting from natural
chrysophanic acid.
1,1-Dim eth yleth yl (4-Hydr oxybu tyl)[2-[(ph en ylm eth ox-
y)im in o]eth yl]ca r ba m a te (6b). Following the same proce-
dure as for 6a , compound 6b was obtained from 5b in almost
quantitative yield as a colorless oil and a 3:2 mixture of E/Z-
oxime. The presence of rotamers precluded a comprehensive
assignment of all proton resonances: IR (CHCl3) 3600-3400
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H
and 13C NMR spectra were recorded at 200, 300, or 500 MHz
and at 50 or 125 MHz, respectively. IR spectra were recorded
using FTIR apparatus. Mass spectra were obtained by EI, CI,
or SIMS methods. Preparative TLC separations were carried
out on precoated silica gel plates (E. Merck 60F254 or E. Merck
reversed-phase plates RP-18WF254S). Medium-pressure col-
umn chromatography was performed using Lobar gro¨sse B (E.
Merck 310-25, Lichroprep Si60). Flash column chromatogra-
phy was performed using E. Merck Kieselgel 60 (230-400
mesh).
1
(OH), 1686 (NCOO) cm-1; H NMR (CDCl3) δ 7.40 (3/5H, t, J
) 5.5 Hz), 7.39-7.25 (5H, m), 6.70 (2/5H, br t, J ) 4 Hz), 5.11
(4/5H, s), 5.07 (6/5H, s), 4.15-4.00 (4/5H, br m), 3.89 (6/5H,
br d, J ) 4 Hz), 3.69-3.55 (2H, m), 3.30-3.10 (2H, m), 1.64-
1.40 (4H, m), 1.44 (9H, s); HRMS calcd for C18H28N2O4 (M+)
336.2047, found 336.2049.
1,1-Dim eth yleth yl [2-(Meth oxyim in o)eth yl](4-oxobu -
tyl)ca r ba m a te (2a ). To a solution of pyridine (14.6 g, 185
mmol) in CH2Cl2 (240 mL) was portionwise added CrO3 (9.23
g, 92.3 mmol) under a nitrogen atmosphere at room temper-
ature. After the solution was stirred at room temperature for
15 min, a solution of 6a (4.0 g, 15.4 mmol) in CH2Cl2 (54 mL)
was added to the reaction mixture. The reaction mixture was
(32) Mukaiyama T. Angew. Chem., Int. Ed. Engl. 1979, 18, 707-
721.

4404 J . Org. Chem., Vol. 63, No. 13, 1998
Miyabe et al.
stirred at the same temperature for 2 h, and then the solvent
was evaporated at reduced pressure. The resulting residue
was diluted with Et2O and filtered through a pad of Celite,
and the filtrate was concentrated at reduced pressure. Puri-
fication of the residue by medium-pressure column chroma-
tography (AcOEt/hexane 1:2) afforded 2a (2.76 g, 69%) as a
colorless oil and a 3:2 mixture of E/Z-oxime. The presence of
rotamers precluded a comprehensive assignment of all proton
resonances. After characterization by IR and NMR spectra,
unstable 2a was immediately subjected to radical cyclization:
IR (CHCl3) 1723 (CHO), 1688 (NCOO) cm-1; 1H NMR (CDCl3)
δ 9.78 (1H, br s), 7.32 (3/5H, br m), 6.64 (2/5H, br m), 4.03
(4/5H, br m), 3.89 (6/5H, br m), 3.88 (6/5H, s), 3.84 (9/5H, s),
3.27 (2H, t, J ) 7 Hz), 2.47 (2H, br t, J ) 7 Hz), 1.84 (2H,
quint, J ) 7 Hz), 1.46 (9H, s).
Ra d ica l Cycliza tion Usin g Sm I2. To a solution of HMPA
(3.0 mL, 17.2 mmol), t-BuOH (0.2 mL, 2.15 mmol), and SmI2
(0.1 M in THF) (43.1 mL, 4.31 mmol) was added dropwise a
solution of 2b (300 mg, 0.862 mmol) in THF (10 mL) under an
argon atmosphere at -78 °C. After being stirred at the same
temperature for 2 h, the reaction mixture was slowly allowed
to warm to room temperature over 10 h. After the solvent
was evaporated at reduced pressure, the resulting residue was
diluted with Et2O and filtered through a pad of Celite. After
the filtrate was concentrated at reduced pressure, purification
of the residue by medium-pressure column chromatography
(AcOEt/hexane 3:2) afforded 7b (133 mg, 46%) and 8b (20 mg,
7%) as colorless oils.
1,1-Dim eth yleth yl tr a n s-(()-Hexa h yd r o-4-h yd r oxy-3-
[[4-(p h en ylm et h oxy)b en zoyl]a m in o]-1H -a zep in e-1-ca r -
boxyla te (9). F r om 8a . A suspension of PtO2 (25 mg, 0.11
1,1-Dim eth yleth yl [2-[(P h en ylm eth oxy)im in o]eth yl](4-
oxobu tyl)ca r ba m a te (2b). Following the same procedure as
for 2a , compound 2b was obtained from 6b in 78% yield as a
colorless oil and a 3:2 mixture of E/Z-oxime. Subsequent
separation of E/Z-isomers by medium-pressure column chro-
matography (AcOEt/hexane 1:4) afforded (E)-2b and (Z)-2b.
The presence of rotamers precluded a comprehensive assign-
ment of all proton resonances. After characterization by IR,
NMR, and MS spectra, unstable (E)-2b and (Z)-2b were
immediately subjected to the following radical cyclization: IR
mmol) in MeOH (1 mL) was stirred under
a hydrogen
atmosphere at room temperature for 1 h. To this suspension
was added a solution of 8a (50 mg, 0.19 mmol) in MeOH (6
mL). After being stirred under a hydrogen atmosphere at
room temperature for 5 h, the reaction mixture was filtered
and the filtrate was concentrated at reduced pressure to afford
the crude amine. To a solution of the resulting crude amine
in CH2Cl2 (3 mL) were added a solution of NaHCO3 (18 mg,
0.21 mmol) in H2O (0.5 mL) and a solution of p-(benzyloxy)-
benzoyl chloride (52 mg, 0.21 mmol) in CH2Cl2 (1 mL) under
a nitrogen atmosphere at room temperature. After being
stirred at the same temperature for 2.5 h, the reaction mixture
was extracted with CH2Cl2. The organic phase was dried over
Na2SO4 and concentrated at reduced pressure. Purification
of the residue by medium-pressure column chromatography
(AcOEt/hexane 2:1) afforded 9 (46 mg, 55%) as a white powder.
F r om 8b. Following the same procedure as above, compound
9 was obtained from 8b in 58% yield as a white powder. The
presence of rotamers precluded a comprehensive assignment
of all proton and carbon resonances: IR (CHCl3) 1666, 1630
(NCOO, NHCO) cm-1; 1H NMR (CDCl3) δ 8.95 (1H, br d, J )
5 Hz), 7.86 (2H, br d, J ) 9 Hz), 7.46-7.32 (5H, m), 7.02 (2H,
br d, J ) 9 Hz), 5.12 (2H, s), 4.12-4.02 (3H, m), 3.78 (1H, m),
3.28 (1H, dd, J ) 15, 5.5 Hz), 2.73 (1H, td, J ) 13, 3.5 Hz),
1.98-1.59 (4H, m), 1.49 (9H, s); 13C NMR (CDCl3) δ 168.5,
161.6, 157.3, 136.4, 129.1, 128.7, 128.1, 127.5, 125.9, 114.7,
80.8, 79.8, 70.1, 60.8, 50.6, 49.9, 32.8, 28.4, 27.3; HRMS calcd
for C25H32N2O5 (M+) 440.2309, found 440.2298.
(CHCl3) 1723 (CHO), 1688 (NCOO) cm-1
.
(E)-2b: 1H NMR
(CDCl3) δ 9.71 (1H, t, J ) 1 Hz), 7.41-7.20 (5H, m), 7.39 (1H,
t, J ) 5.5 Hz), 5.06 (2H, s), 3.98-3.82 (2H, m), 3.31-3.08 (2H,
m), 2.45-2.30 (2H, br t, J ) 7 Hz), 1.90-1.70 (2H, quint, J )
7 Hz), 1.44 (9H, s). (Z)-2b: 1H NMR (CDCl3) δ 9.74 (1H, t, J
) 1 Hz), 7.41-7.20 (5H, m), 6.69 (1H, t, J ) 4.5 Hz), 5.11 (2H,
s), 4.15-4.00 (2H, m), 3.33-3.12 (2H, m), 2.47-2.35 (2H, br
t, J ) 7 Hz), 1.90-1.70 (2H, quint, J ) 7 Hz), 1.44 (9H, s).
(E)-2b + (Z)-2b: HRMS calcd for C18H26N2O4 (M+) 334.1891,
found 334.1889.
Gen er a l P r oced u r e for R a d ica l Cycliza t ion Usin g
Bu 3Sn H. To a boiling solution of 2 (10 mmol) in benzene (76
mL) was added portionwise (17 mL/h) a solution of Bu3SnH
(20 mmol) and AIBN (10 mmol) in benzene (46 mL) under a
nitrogen atmosphere. The reaction mixture was heated at
reflux for 6-8 h, and then the solvent was evaporated at
reduced pressure. The resulting residue was diluted with
acetonitrile, and the acetonitrile phase was washed with
hexane and concentrated at reduced pressure. Purification of
the residue by medium-pressure column chromatography
(AcOEt/hexane 2:1) afforded 7 and 8 as colorless oils. The
presence of rotamers precluded a comprehensive assignment
of all proton resonances.
1,1-Dim et h ylet h yl [3R-[3r,4â(S*)])-H exa h yd r o-3-[[4-
(ph en yl m eth oxy)ben zoyl]am in o]-4-[2-[[(ph en ylm eth oxy)-
ca r bon yl]a m in o]-1-oxop r op oxy]-1H-a zep in e-1-ca r boxy-
la te (10a ) a n d 1,1-Dim eth yleth yl [3S-[3r,4â(R*)])-Hexa -
h ydr o-3-[[4-(ph en ylm eth oxy)ben zoyl]am in o]-4- [2-[[(ph en -
ylm eth oxy)ca r bon yl]a m in o]-1-oxop r op oxy]-1H-a zep in e-
1- ca r boxyla te (11a ). To a solution of 2-chloro-1-methylpy-
ridinium iodide (12.3 mg, 0.047 mmol), Et3N (15.3 mg, 0.15
mmol), and a catalytic amount of DMAP in CH2Cl2 (0.34 mL)
were added 9 (15 mg, 0.034 mmol) and N-Z-L-alanine (7.6 mg,
0.034 mmol) under a nitrogen atmosphere at room tempera-
ture. After the reaction mixture was heated at reflux for 10
h, the reaction mixture was diluted with H2O and extracted
with CH2Cl2. The organic phase was dried over Na2SO4 and
concentrated at reduced pressure. Purification of the residue
by medium-pressure column chromatography (AcOEt/hexane
2:1) afforded a mixture of 10a and 11a (11.2 mg, 51%) as a
white powder and 9 (3.4 mg, 23%). The presence of rotamers
precluded a comprehensive assignment of all proton reso-
1,1-Dim et h ylet h yl cis-(()-h exa h yd r o-4-h yd r oxy-3-
(m et h oxya m in o)-1H -a zep in e-1-ca r b oxyla t e (7a ): IR
1
(CHCl3) 3600-3300 (OH, NH), 1682 (NCOO) cm-1; H NMR
(CDCl3) δ 4.07 (1H, br m), 3.72-3.40 (2H, m), 3.56 (3H, s),
3.30-3.06 (3H, m), 2.05-1.91 (2H, m), 1.71-1.48 (2H, m), 1.46
(9H, s); HRMS calcd for C12H24N2O4 (M+) 260.1735, found
260.1735.
1,1-Dim et h ylet h yl tr a n s-(()-h exa h yd r o-4-h yd r oxy-3-
(m et h oxya m in o)-1H -a zep in e-1-ca r b oxyla t e (8a ): IR
1
(CHCl3) 3600-3200 (OH, NH), 1680 (NCOO) cm-1; H NMR
(CDCl3) δ 3.66 (1H, ddd, J ) 4, 1.5, 0.5 Hz), 3.54 (3H, s), 3.55-
3.03 (4H, m), 2.85 (1H, m), 2.05-1.70 (2H, m), 1.70-1.40 (2H,
m), 1.48 (9H, s); HRMS calcd for C12H24N2O4 (M+) 260.1735,
found 260.1741.
1
nances: IR (CHCl3) 1720 (COO), 1705 (NCO) cm-1; H NMR
1,1-Dim et h ylet h yl
cis-(()-h exa h yd r o-4-h yd r oxy-3-
[(p h e n y lm e t h o x y )a m in o ]-1H -a ze p in e -1-c a r b o x y la t e
(CDCl3) δ 8.00 (1/2H, d, J ) 8 Hz), 7.93 (1/2H, br d, J ) 8 Hz)
7.75 (2H, br d, J ) 9 Hz), 7.46-7.28 (10H, m), 6.97 (2H, br d,
J ) 9 Hz), 5.75 (1/2H, br m) 5.45 (1/2H, br m), 5.05 (1H, m),
5.09 (4H, s), 4.52-4.24 (2H, m), 4.04-3.86 (2H, m), 3.29 (1H,
br m), 2.82 (1H, br m), 2.00-1.20 (7H, m), 1.52 (9H, s); HRMS
calcd for C36H43N3O8 (M+) 645.3047, found 645.3029.
1,1-Dim et h ylet h yl [3R-[3r,4â(S*)])-H exa h yd r o-3-[[4-
(p h en ylm et h oxy)b en zoyl]a m in o]-4-[[(4,7,7-t r im et h yl-3-
o x o -2-o x a b ic y c lo [2.2.1]h e p t -1-y l)c a r b o n y l]o x y ]-1H -
a zep in e-1-ca r boxyla te (10b) a n d 1,1-Dim eth yleth yl [3S-
[3r,4â(R *)])-H e xa h yd r o-3-[[4-(p h e n ylm e t h oxy)b e n zo-
(7b): IR (CHCl3) 3600-3300 (OH, NH), 1682 (NCOO) cm-1
1H NMR (CDCl3) δ 7.42-7.28 (5H, m), 4.70 (2H, s), 4.05 (1H,
m), 3.66-3.07 (5H, m), 2.08-1.55 (4H, m), 1.44 (9H, s); HRMS
calcd for C18H28N2O4 (M+) 336.2047, found 336.2036.
;
1,1-Dim et h ylet h yl tr a n s-(()-h exa h yd r o-4-h yd r oxy-3-
[(p h e n y lm e t h o x y )a m in o ]-1H -a ze p in e -1-c a r b o x y la t e
(8b): IR (CHCl3) 3600-3300 (OH, NH), 1681 (NCOO) cm-1
;
1H NMR (CDCl3) δ 7.42-7.25 (5H, m), 4.70 and 4.68 (2H, ABq,
J ) 14 Hz), 3.71-2.83 (6H, m), 2.00-1.40 (4H, m), 1.44 (9H,
s); HRMS calcd for C18H28N2O4 (M+) 336.2047, found 336.2032.

Total Synthesis of (-)-Balanol
J . Org. Chem., Vol. 63, No. 13, 1998 4405
yl]a m in o]-4-[[(4,7,7-tr im eth yl-3-oxo-2-oxa bicyclo[2.2.1]-
h ep t-1- yl)ca r bon yl]oxy]-1H-a zep in e-1-ca r boxyla te (11b).
To a solution of 9 (9.8 mg, 0.023 mmol), Et3N (2.4 mg, 0.024
mmol), and a catalytic amount of DMAP in CH2Cl2 (2 mL) was
added S-camphanic acid chloride (26.5 mg, 0.12 mmol) under
a nitrogen atmosphere at room temperature. After being
stirred at 50 °C for 30 min, the reaction mixture was diluted
with 3% HCl and extracted with CH2Cl2. The organic phase
was washed with H2O, dried over Na2SO4, and concentrated
at reduced pressure. Purification of the residue by medium-
pressure column chromatography (AcOEt/hexane 3:2) afforded
a mixture of 10b and 11b (13.8 mg, quantitative) as a white
powder. The presence of rotamers precluded a comprehensive
assignment of all proton resonances: IR (CHCl3) 1740 (COO),
N2O52/3H2O: C, 66.35; H, 7.43; N, 6.19. Found: C, 66.38; H,
7.24; N, 6.03.
En zym a tic Op tica l Resolu tion Usin g Lip a se. To a
solution of 9 (435 mg, 0.99 mmol) and vinyl acetate (2.57 g,
0.030 mol) in t-BuOMe (10 mL) was added immobilized lipase
from Pseudomonas sp. (0.5 unit/mg) (1.58 g) under a nitrogen
atmosphere at room temperature. The reaction mixture was
stirred at 20 °C for 12 h and then at 45 °C for 8 h. After
dilution with CH2Cl2, the reaction mixture was filtered and
the filtrate was concentrated at reduced pressure. Purification
of the residue by medium-pressure column chromatography
(AcOEt/hexane 2:1) afforded 12 (200 mg, 42%) as a white
powder and recovered (3S,4S)-9 (213 mg, 49%) as a white
powder.
1
1660 (NCO) cm-1; H NMR (CDCl3) δ 7.88 (1H, br d, J ) 5.5
1,1-Dim eth yleth yl (3S-tr a n s)-4-(Acetyloxy)h exa h yd r o-
3-[[4-(p h en ylm eth oxy)ben zoyl]a m in o]-1H-a zep in e-1-ca r -
boxyla te (12). The presence of rotamers precluded a com-
prehensive assignment of all proton and carbon resonances:
Hz), 7.79, 7.76 (each 1H, br d, J ) 9 Hz), 7.45-7.31 (5H, m),
6.99, 6.98 (each 1H, br d, J ) 9 Hz), 5.34 (1/2H, br t, J ) 7
Hz), 5.23 (1/2H, br t, J ) 7 Hz), 5.11 (2H, s), 4.39 (1H, m),
4.04 (1H, br m), 3.90 (1H, m), 3.34 (1H, dd, J ) 15, 4 Hz), 2.95
(1H, m), 2.50-0.80 (17H, m), 1.53 (9H, s); HRMS calcd for
[R]20 +5.5 (c 1.27, MeOH); IR (CHCl3) 1727 (COO), 1660
D
(NCO) cm-1; H NMR (CDCl3) δ 7.78 (2H, br d, J ) 8.5 Hz),
1
C
35H44N2O8 (M+) 620.3095, found 620.3080.
7.73 (1H, br s), 7.50-7.29 (5H, m), 6.98 (2H, br d, J ) 8.5 Hz),
5.10 (2H, s), 5.07 (1H, br m), 4.38 (1H, br m), 3.93 (1H, m),
3.59 (1H, br m), 3.32 (1H, dd, J ) 15, 3 Hz), 2.91 (1H, br m),
2.02 (3H, s), 2.13-1.34 (4H, m), 1.52 (9H, s); 13C NMR (CDCl3)
δ 172.6, 166.1, 136.3, 128.7, 128.5, 128.0, 127.3, 126.7, 114.4,
80.5, 74.9, 69.9, 53.9, 49.1, 48.7, 28.2, 27.6, 23.5, 21.0; HRMS
calcd for C27H34N2O6 (M+) 482.2415, found 482.2422.
1,1-Dim et h ylet h yl [3R-[3r,4â(S*)]]-H exa h yd r o-3-[[4-
(ph en ylm eth oxy)ben zoyl]am in o]-4-(3,3,3-tr iflu or o-2-m eth -
oxy-1-oxo-2-p h en ylp r op oxy)-1H -a zep in e-1-ca r b oxyla t e
(10c) a n d 1,1-Dim eth yleth yl [3S-[3r,4â(R*)]]-Hexa h yd r o-
3-[[4-(p h en ylm eth oxy)ben zoyl]a m in o]-4-(3,3,3-tr iflu or o-
2-m eth oxy-1-oxo-2-ph en ylpr opoxy)-1H-azepin e-1-car box-
yla te (11c). To a solution of 9 (144 mg, 0.33 mmol), Et3N (66
mg, 0.65 mmol), and DMAP (37 mg, 0.3 mmol) in CH2Cl2 (1.7
mL) was added dropwise a solution of (R)-R-methoxy-R-
(trifluoromethyl)phenylacetyl chloride (96 mg, 0.38 mmol) in
CH2Cl2 (1.7 mL) under a nitrogen atmosphere at room tem-
perature. After being stirred at the same temperature for 7.5
h, the reaction mixture was concentrated at reduced pressure.
Purification of the residue by medium-pressure column chro-
matography (AcOEt/hexane 7:4) afforded 10c (101 mg, 47%)
and 11c (95 mg, 44%) as white powders. The presence of
rotamers precluded a comprehensive assignment of all proton
resonances. 10c: [R]20D -53.3 (c 0.77, MeOH); IR (CHCl3) 1750
P h en ylm eth yl (3R-tr a n s)-4-(Acetyloxy)h exa h yd r o-3-
[[4-(p h en ylm et h oxy)b en zoyl]a m in o]-1H -a zep in e-1-ca r -
boxyla te (13). To a solution of 12 (174 mg, 0.36 mmol) in
CH2Cl2 (4.0 mL) was added dropwise TFA (0.5 mL, 6.5 mmol)
under a nitrogen atmosphere at room temperature. After
being stirred at the same temperature for 4 h, the reaction
mixture was neutralized with saturated aqueous NaHCO3 and
extracted with CH2Cl2. The organic phase was dried over Na2-
SO4 and concentrated at reduced pressure to afford the crude
amine. To the resulting crude amine in acetone (4.0 mL) were
successively added a solution of Na2CO3 (31.7 mg, 0.30 mmol)
in H2O (0.14 mL) and a solution of benzyloxycarbonyl chloride
(90 mg, 0.53 mmol) in acetone (1.0 mL) under a nitrogen
atmosphere at room temperature. After being stirred at the
same temperature for 14 h, the reaction mixture was concen-
trated at reduced pressure. After dilution with H2O, the
mixture was extracted with CH2Cl2. The organic phase was
dried over Na2SO4 and concentrated at reduced pressure.
Purification of the residue by medium-pressure column chro-
matography (AcOEt/hexane 2:1) afforded 13 (162 mg, 87%) as
1
(COO), 1661 (NCO) cm-1; H NMR (CDCl3) δ 7.83 (1H, br s),
7.75 (2H, br d, J ) 9 Hz), 7.56-7.18 (10H, m), 6.98 (2H, br d,
J ) 9 Hz), 5.56 (1H, br m), 5.12 (2H, s), 4.27 (1H, br m), 4.10
(1H, br d, J ) 15 Hz), 3.72 (1H, br m), 3.50 (3H, s), 3.16 (1H,
d, J ) 15 Hz), 2.86 (1H, br m), 2.14-1.10 (4H, m), 1.51 (9H,
s); HRMS calcd for
C
35H39N2O7F3 (M+) 656.2706, found
656.2697. 11c: [R]20 -2.6 (c 2.43, MeOH); IR (CHCl3) 1750
D
(COO), 1660 (NCO) cm-1; 1H NMR (CDCl3) δ 7.91 (1H, br d, J
) 4.5 Hz), 7.80 (2H, br d, J ) 8.5 Hz), 7.60-7.22 (10H, m),
6.99 (2H, br d, J ) 8.5 Hz), 5.50 (1H, br m), 5.11 (2H, s), 4.33
(1H, br m), 4.05 (1H, br d, J ) 15 Hz), 3.72 (1H, br m), 3.50
(3H, s), 3.19 (1H, br d, J ) 15 Hz), 2.81 (1H, br m), 2.17-1.17
(4H, m), 1.51 (9H, s); HRMS calcd for C35H39N2O7F3 (M+)
656.2706, found 656.2698.
a
white powder. The presence of rotamers precluded a
comprehensive assignment of all proton and carbon reso-
nances: mp 129-131 °C (AcOEt/hexane); [R]20 +9.3 (c 1.10,
D
MeOH); IR (CHCl3) 1729 (COO), 1684, 1656 (NCOO, NHCO)
cm-1; 1H NMR (CDCl3) δ 7.73 (2H, br d, J ) 8 Hz), 7.63-6.81
(11H, m), 6.98 (2H, br d, J ) 8 Hz), 5.25-4.94 (5H, m), 4.40
(1H, br m), 4.02 (1H, br m), 3.69 (1H, br m), 3.40 (1H, dd, J )
15.5, 4.5 Hz), 2.88 (1H, m), 2.02 (3H, s), 2.06-1.70 (4H, m);
13C NMR (CDCl3) δ 170.1, 166.1, 161.1, 157.6, 136.3, 136.2,
128.7, 128.44, 128.39, 128.0, 127.9, 127.6, 127.2, 126.6, 114.4,
75.0, 69.8, 67.5, 53.7, 49.6, 48.4, 27.9, 23.7, 20.9; HRMS calcd
for C30H32N2O6 (M+) 516.2258, found 516.2268.
1,1-Dim eth yleth yl (3R-tr a n s)-Hexa h yd r o-4-h yd r oxy-3-
[[4-(p h en ylm et h oxy)b en zoyl]a m in o]-1H -a zep in e-1-ca r -
boxyla te ((3R,4R)-9). To a solution of 10c (89 mg, 0.14 mmol)
in MeOH (3.7 mL) was added a methanolic solution of KOH
(1M, 1.5 mL) at room temperature. After being stirred at the
same temperature for 5 h, the reaction mixture was concen-
trated at reduced pressure. Purification of the residue by
medium-pressure column chromatography (AcOEt/hexane 4:1)
afforded (3R,4R)-9 (59.3 mg, quantitative) as colorless crystals.
This compound was identical with an authentic sample upon
comparison of their spectral data.6 The presence of rotamers
precluded a comprehensive assignment of all proton reso-
nances: mp 136-138 °C (Et2O/petroleum ether) [lit.6 mp 115-
P h en ylm eth yl (3R-tr a n s)-Hexa h yd r o-4-h yd r oxy-3-[[4-
(p h en ylm eth oxy)ben zoyl]a m in o]-1H-a zep in e-1-ca r boxy-
la te (14). To a solution of 13 (130 mg, 0.25 mmol) in MeOH
(7.0 mL) was added a methanolic solution of KOH (1 M, 3.0
mL) at room temperature. After being stirred at the same
temperature for 2 h, the reaction mixture was concentrated
under reduced pressure. Purification of the residue by medium-
pressure column chromatography (AcOEt/hexane 4:1) afforded
14 (121 mg, quantitative) as colorless crystals. The presence
of rotamers precluded a comprehensive assignment of all
proton and carbon resonances. This compound was identical
with an authentic sample upon comparison of their spectral
data:5,7 mp 101-103 °C (AcOEt) [lit.5 mp 123-124.5 °C (lit.7
117 °C]; [R]20 -2.9 (c 1.30, MeOH) [lit.6 [R]D -8.9 (c 1.98,
D
MeOH)]. Anal. Calcd for C25H32N2O5: C, 68.16; H, 7.32; N,
6.36. Found: C, 67.89; H, 7.34; N, 6.20.
1,1-Dim eth yleth yl (3S-tr a n s)-Hexa h yd r o-4-h yd r oxy-3-
[[4-(p h en ylm et h oxy)b en zoyl]a m in o]-1H -a zep in e-1-ca r -
boxyla te ((3S,4S)-9). Following the same procedure as for
(3R,4R)-9, compound (3S,4S)-9 was obtained from 11c in
almost quantitative yield: mp 136-138 °C (Et2O/petroleum
mp 132-134 °C)]; [R]20 -6.5 (c 1.09, MeOH); IR (CHCl3)
D
3500-3200 (OH), 1671, 1630 (NCOO, NHCO) cm-1; 1H NMR
ether); [R]20 +2.5 (c 1.26, MeOH). Anal. Calcd for C25H32
-
(CDCl3) δ 8.68 (1H, br d, J ) 3.5 Hz), 7.82 (2H, br d, J ) 8.5
D

4406 J . Org. Chem., Vol. 63, No. 13, 1998
Miyabe et al.
Hz), 7.53-7.18 (10H, m), 7.00 (2H, br d, J ) 8.5 Hz), 5.19,
5.10 (each 2H, s), 4.29-3.93 (3H, m), 3.78 (1H, br m), 3.33
(1H, dd, J ) 15, 3 Hz), 2.80 (1H, m), 2.14-1.50 (4H, m); 13C
NMR (CDCl3) δ 167.9, 161.2, 157.4, 136.0, 135.9, 128.7, 128.3,
128.2, 127.8, 127.7, 127.3, 127.1, 125.4, 114.3, 78.0, 69.6, 67.3,
59.8, 49.5, 49.4, 31.7, 26.0; HRMS calcd for C28H30N2O5 (M+)
474.2153, found 474.2155.
reduced pressure. Purification of the residue by medium-
pressure column chromatography (AcOEt/hexane 1:1) afforded
24 (409 mg, 39%) and 25 (431 mg, 41%) both as colorless
crystals. 24: mp 118-119 °C (AcOEt/hexane); IR (CHCl3)
1721 (ArCOO), 1665 (ArCOAr) cm-1; 1H NMR (CDCl3) δ 7.47
(1H, dd, J ) 8, 1 Hz), 7.32 (1H, t, J ) 8 Hz), 7.04 (1H, dd, J
) 8, 1 Hz), 6.35 (2H, s), 3.71 (3H, s), 3.68 (3H, s), 3.64 (6H, s),
2.33 (3H, s); 13C NMR (CDCl3) δ 192.0, 167.5, 160.1, 156.9,
143.9, 135.3, 129.6, 128.9, 121.7, 116.3, 115.2, 105.7, 56.6, 56.1,
52.0, 22.4; HRMS calcd for C19H20O6 (M+) 344.1258, found
344.1229. Anal. Calcd for C19H20O6: C, 66.27; H, 5.85.
Found: C, 66.00; H, 5.84. 25: mp 161-162 °C (AcOEt/
Meth yl 2-(2-Hyd r oxy-6-m eth oxy-4-m eth ylben zoyl)-3-
m eth oxyben zoa te (22) a n d Meth yl 2-(2-Hyd r oxy-6-m eth -
oxyben zoyl)-3-m eth oxy-5-m eth ylben zoa te (23). A solu-
tion of 17c (231 mg, 0.74 mmol) in Et2O (200 mL) was
irradiated with a halogen lamp through a Pyrex filter under
oxygen bubbling at 30 °C for 1.5 h. The solvent was evapo-
rated at reduced pressure to afford the crude oxygen adduct.
To a solution of the crude oxygen adduct in acetone (100 mL)
was added a catalytic amount of concentrated H2SO4 under a
nitrogen atmosphere at room temperature. After the mixture
was stirred at the same temperature for 12 h, the solvent was
evaporated at reduced pressure. After dilution with H2O, the
mixture was extracted with CH2Cl2. The organic phase was
dried over MgSO4 and concentrated at reduced pressure.
Purification of the residue by medium-pressure column chro-
matography (AcOEt/hexane 1:6) afforded a mixture of 22 and
23 (138 mg, 57%) as colorless crystals and 16c (63 mg, 30%)
1
hexane); IR (CHCl3) 1720 (ArCOO), 1667 (ArCOAr) cm-1; H
NMR (CDCl3) δ 7.29 (1H, t, J ) 8.5 Hz), 7.19 (1H, s), 6.83
(1H, s), 6.54 (2H, d, J ) 8.5 Hz), 3.70 (3H, s), 3.67 (6H, s),
3.64 (3H, s), 2.37 (3H, s); 13C NMR (CDCl3) δ 192.2, 168.4,
159.4, 157.5, 140.5, 132.1, 131.3, 130.6, 122.0, 119.8, 115.8,
104.7, 56.5, 56.2, 52.1, 21.6; HRMS calcd for C19H20O6 (M+)
344.1258, found 344.1264. Anal. Calcd for C19H20O6: C, 66.27;
H, 5.85. Found: C, 66.30; H, 5.87.
Meth yl 2-[4-(Br om om eth yl)-2,6-d im eth oxyben zoyl]-3-
m eth oxyben zoa te (26). To a boiling solution of 24 (35 mg,
0.10 mmol) in CCl4 (1 mL) were added NBS (19 mg, 0.1 mmol)
and AIBN (1.7 mg, 0.01 mmol) under a nitrogen atmosphere.
The reaction mixture was heated at reflux for 30 min. After
dilution with H2O, the layers were separated, and the aqueous
phase was extracted with CH2Cl2. The combined organic
phase was dried over MgSO4 and concentrated at reduced
pressure. Purification of the residue by medium-pressure
column chromatography (AcOEt/hexane 1:1) afforded 26 (24
mg, 57%) and 24 (5.3 mg, 15%) both as colorless crystals: mp
129-130 °C (AcOEt/hexane); IR (CHCl3) 1719 (ArCOO), 1666
(ArCOAr) cm-1; 1H NMR (CDCl3) δ 7.45 (1H, dd, J ) 8, 1 Hz),
7.36 (1H, t, J ) 8 Hz), 7.04 (1H, dd, J ) 8, 1 Hz), 6.57 (2H, s),
4.42 (2H, s), 3.72 (3H, s), 3.69 (3H, s), 3.69 (6H, s); 13C NMR
(CDCl3) δ 191.7, 167.6, 159.9, 157.1, 142.2, 134.0, 130.4, 129.6,
121.7, 118.9, 115.1, 105.5, 56.5, 56.3, 52.2, 33.2; HRMS calcd
for C19H19O679Br (M+) 422.0363, found 422.0374; calcd for
as yellow crystals. 22: IR (CHCl3) 1721 (ArCOO) cm-1 1H
;
NMR (CDCl3) δ 12.95 (1H, s), 7.62 (1H, dd, J ) 8, 1 Hz), 7.37
(1H, t, J ) 8 Hz), 7.11 (1H, dd, J ) 8, 1 Hz), 6.47 (1H, br s),
6.05 (1H, br s), 3.75 (3H, s), 3.72 (3H, s), 3.31 (3H, s), 2.29
(3H, s); 13C NMR (CDCl3) δ 199.5, 166.2, 164.3, 160.9, 155.6,
148.0, 135.1, 128.7, 127.5, 121.8, 115.1, 111.1, 110.2, 102.9,
56.3, 55.6, 52.1, 22.5; HRMS calcd for C18H18O6 (M+) 330.1102,
found 330.1091. 23: IR (CHCl3) 1720 (ArCOO) cm-1; 1H NMR
(CDCl3) δ 12.92 (1H, s), 7.43 (1H, br s), 7.33 (1H, t, J ) 8.5
Hz), 6.93 (1H, br s), 6.63 (1H, dd, J ) 8.5, 1 Hz), 6.25 (1H, dd,
J ) 8.5, 1 Hz), 3.73 (3H, s), 3.70 (3H, s), 3.35 (3H, s), 2.43
(3H, s); 13C NMR (CDCl3) δ 200.5, 166.4, 164.2, 161.1, 155.5,
139.0, 136.1, 132.5, 127.4, 122.2, 116.0, 112.5, 110.7, 101.6,
56.2, 55.7, 52.1, 21.6; HRMS calcd for C18H18O6 (M+) 330.1102,
found 330.1104. 22 + 23. Anal. Calcd for C18H18O6: C, 65.45;
H, 5.49. Found: C, 65.26; H, 5.47.
C
C
19H19O681Br (M+) 424.0343, found 424.0358. Anal. Calcd for
19H19O6Br: C, 53.92; H, 4.52. Found: C, 53.72; H, 4.40.
P h en ylm et h yl 2-[4-(Br om om et h yl)-2,6-b is(p h en yl-
Meth yl 2-(2-Hyd r oxy-6-m eth oxyben zoyl)-3-m eth oxy-
ben zoa te (18). Following the same procedure as for 22 and
23, compounds 18 (67% yield as a colorless solid) and 16a (23%
yield as yellow crystals) were obtained from 17a : IR (CHCl3)
m eth oxy)ben zoyl]-3-(p h en ylm eth oxy)ben zoa te (27). To
a solution of 26 (120 mg, 0.28 mmol) in CH2Cl2 (5 mL) was
added BBr3 (70 mg, 0.28 mmol) under a nitrogen atmosphere
at room temperature. The reaction mixture was stirred at the
same temperature for 5 days. After the mixture was quenched
with 10% HCl saturated with NaCl, the layers were separated
and the aqueous phase was extracted with CH2Cl2. The
combined organic phase was dried over MgSO4 and concen-
trated at reduced pressure to afford the crude triphenolic acid.
To a solution of the crude triphenolic acid in DMF (5.7 mL)
were added K2CO3 (554 mg, 4.0 mmol) and benzyl bromide
(0.33 mL, 2.8 mmol) under a nitrogen atmosphere at room
temperature. The reaction mixture was stirred at the same
temperature for 4.5 h. After dilution with Et2O, the organic
phase was washed with water and brine, dried over MgSO4,
and concentrated at reduced pressure. Purification of the
residue by medium-pressure column chromatography (AcOEt/
hexane 1:3) afforded 27 (57 mg, 28%) as colorless crystals: mp
119-120 °C (AcOEt/hexane); IR (CHCl3) 1720 (ArCOO), 1665
(ArCOAr) cm-1; 1H NMR (CDCl3) δ 7.25-7.11 (16H, m), 7.08-
6.98 (4H, m), 6.96-6.86 (3H, m), 6.52 (2H, s), 5.09, 4.73 (each
2H, s), 4.70 (4H, s), 3.89 (2H, s); 13C NMR (CDCl3) δ 191.6,
166.9, 158.8, 155.8, 141.7, 136.2, 136.1, 135.8, 134.4, 131.8,
129.7, 128.3, 128.2, 127.9, 127.6, 127.5, 127.4, 127.2, 122.3,
115.6, 106.5, 70.4, 66.9, 33.3; SIMS calcd for C43H35O679Br +
H (QM+) 727.1693, found 727.1699; calcd for C43H35O681Br +
H (QM+) 729.1673, found 729.1700. Anal. Calcd for C43H35O6-
Br: C, 70.98; H, 4.85. Found: C, 71.59; H, 4.83.
1721 (ArCOO) cm-1 1H NMR (CDCl3) δ 12.90 (1H, s), 7.62
;
(1H, dd J ) 8.1, 0.9 Hz), 7.38 (1H, t, J ) 8.1 Hz), 7.33 (1H, t,
J ) 8.3 Hz), 7.12 (1H, dd, J ) 8.1, 0.9 Hz), 6.64 (1H, dd, J )
8.3, 1 Hz), 6.24 (1H, dd, J ) 8.3, 1 Hz), 3.74 (3H, s), 3.72 (3H,
s), 3.32 (3H, s); 13C NMR (CDCl3) δ 200.3, 166.2, 164.2, 161.0,
155.6, 136.3, 135.1, 128.8, 127.5, 121.8, 115.2, 112.3, 110.7,
101.6, 56.3, 55.6, 52.1; HRMS calcd for C17H16O6 (M+) 316.0946,
found 316.0962.
Meth yl 2-(2,3,6-Tr im eth oxyben zoyl)ben zoa te (20). Fol-
lowing the same procedure as for 22 and 23, compounds 20
(27% yield as colorless crystals) and 16b (31% yield as yellow
crystals) were obtained from 17b: mp 115.5-117 °C (AcOEt/
1
hexane); IR (CHCl3) 1731 (ArCOO) cm-1; H NMR (CDCl3) δ
9.29 (1H, d, J ) 7.8 Hz), 8.19 (2H, m), 7.66 (2H, m), 5.76 (1H,
d, J ) 7.8 Hz), 4.04 (3H, s), 3.90 (3H, s), 3.88 (3H, s), 3.87
(3H, s); 13C NMR (CDCl3) δ 192.1, 171.6, 166.5, 151.2, 150.9,
129.6, 129.2, 128.2, 123.3, 123.2, 122.7, 120.0, 107.0, 77.1, 63.6,
62.5, 56.7, 52.3; SIMS calcd for C18H18O6 (QM+) 330.1102,
found 330.1126. Anal. Calcd for C18H18O6: C, 65.45; H, 5.49.
Found: C, 65.17; H, 5.39.
Meth yl 2-(2,6-Dim eth oxy-4-m eth ylben zoyl)-3-m eth ox-
yben zoa te (24) a n d Meth yl 2-(2,6-Dim eth oxyben zoyl)-3-
m eth oxy-5-m eth ylben zoa te (25). To a stirred suspension
of NaH (60% oil suspension) (182 mg, 4.55 mmol) in DMF (15
mL) was added a solution of a mixture of 22 and 23 (1.0 g,
3.03 mmol) under a nitrogen atmosphere at room temperature.
After the mixture was stirred at the same temperature for 20
min, MeI (0.26 mL, 4.24 mmol) was added to the reaction
mixture, which was stirred at the same temperature for 30
min. After dilution with Et2O, the organic phase was washed
with water and brine, dried over MgSO4, and concentrated at
P h en ylm et h yl 2-[4-(H yd r oxym et h yl)-2,6-b is(p h en yl-
m et h oxy)b en zoyl]-3-(p h en ylm et h oxy)b en zoa t e (28).
A
mixture of 27 (129 mg, 0.177 mmol) and CaCO3 (86 mg, 0.86
mmol) in dioxane (5.8 mL) and water (3 mL) was heated at
reflux under a nitrogen atmosphere for 15 h. The reaction
mixture was concentrated at reduced pressure. After dilution

Total Synthesis of (-)-Balanol
J . Org. Chem., Vol. 63, No. 13, 1998 4407
with H2O, the aqueous phase was extracted with CH2Cl2. The
organic phase was dried over MgSO4 and concentrated at
reduced pressure. Purification of the residue by medium-
pressure column chromatography (AcOEt/hexane 1:1) afforded
28 (93 mg, 79%) as colorless crystals. This compound was
identical with an authentic sample upon comparison of their
spectral data:5 mp 142-143 °C (AcOEt/hexane) (lit.5 mp
138.5-139.5 °C); IR (CHCl3) 1722 (ArCOO), 1661 (ArCOAr)
cm-1; 1H NMR (CDCl3) δ 7.28-7.16 (14H, m), 7.16-6.86 (8H,
m), 6.90 (1H, dd, J ) 8, 1 Hz), 6.50 (2H, s), 5.13 (2H, s), 4.77
(6H, s), 4.60 (2H, s); 13C NMR (CDCl3) δ 192.2, 166.9, 159.1,
155.8, 146.0, 136.5, 136.3, 135.9, 134.3, 131.7, 129.6, 128.22,
128.16, 127.8, 127.6, 127.5, 127.1, 122.2, 118.7, 115.7, 103.6,
70.4, 66.8, 65.0; HRMS calcd for C43H36O7 (M+) 664.2459, found
664.2437.
assignment of all proton and carbon resonances. This com-
pound was identical with an authentic sample upon compari-
son of their spectral data:6 [R]27 -63.9 (c 0.85, MeOH); IR
D
(CHCl3) 1713 (ArCOO), 1661 (CO) cm-1; H NMR (CDCl3) δ
1
8.03 (1/2H, br d, J ) 8.5 Hz), 7.76 (3/2H, br d, J ) 8.5 Hz),
7.42-6.79 (33H, m), 5.10, 5.05, 4.84, 4.83, 4.67 (each 2H, s),
5.03, 4.81 (each 1H, m), 4.08 (1H, d, J ) 15 Hz), 4.00 (1H, d,
J ) 12 Hz), 3.34 (1H, dd, J ) 15, 4 Hz), 2.83 (1H, br m), 2.12-
1.23 (4H, m), 1.56 (9H, s); 13C NMR (CDCl3) δ 191.6, 167.4,
166.0, 165.6, 161.3, 158.0, 157.5, 156.3, 136.4, 135.8, 132.7,
132.3, 130.4, 128.8, 128.6, 128.3, 128.2, 127.9, 127.8, 127.5,
127.43, 127.38, 127.2, 123.7, 122.0, 115.3, 114.6, 107.0, 93.4,
80.8, 77.8, 70.5, 70.0, 67.0, 53.6, 50.2, 49.6, 31.6, 29.7, 28.8,
28.4, 24.7, 22.6; SIMS calcd for C68H64N2O12 + H (QM+)
1101.4533, found 1101.4563.
P h en ylm et h yl 2-[4-F or m yl-2,6-b is(p h en ylm et h oxy)-
ben zoyl]-3-(p h en ylm eth oxy)ben zoa te (29). To a solution
of 28 (51 mg, 0.077 mmol) in acetonitrile (0.4 mL) were added
NMO (13.5 mg, 0.115 mmol) and TPAP (1.4 mg, 0.004 mmol)
in the presence of 4 Å molecular sieves under a nitrogen
atmosphere at room temperature. The reaction mixture was
stirred at the same temperature for 30 min. After dilution
with AcOEt, the reaction mixture was filtered, and the filtrate
was concentrated at reduced pressure. Purification of the
residue by flash column chromatography (AcOEt/hexane 1:1)
afforded 29 (31 mg, 61%) as colorless crystals. This compound
was identical with an authentic sample upon comparison of
their spectral data:5 1H NMR (CDCl3) δ 9.80 (1H, s), 7.33 (1H,
t, J ) 8 Hz), 7.26-7.15 (13H, m), 7.12-7.04 (6H, m), 6.97 (1H,
dd, J ) 8, 1 Hz), 6.90 (2H, s), 6.83 (1H, dd, J ) 8, 1 Hz), 5.14
(2H, s), 4.81 (4H, s), 4.70 (2H, s); 13C NMR (CDCl3) δ 191.4,
191.3, 167.6, 158.2, 156.6, 138.1, 135.9, 135.7, 135.5, 133.4,
131.3, 131.0, 128.31, 128.26, 128.2, 127.9, 127.7, 127.1, 125.4,
122.0, 115.1, 106.5, 70.6, 70.4, 67.2; HRMS calcd for C43H34O7
(M+) 662.2302, found 662.2287.
P h en ylm eth yl (3R-tr a n s)-4-[[3,5-Bis(p h en ylm eth oxy)-
4-[2-(p h en ylm eth oxy)-6-[(p h en ylm eth oxy)ca r bon yl]ben -
zoyl]ben zoyl]oxy]h exa h yd r o-3-[[4-(p h en ylm eth oxy)ben -
zoyl]a m in o]-1H-a zep in e-1-ca r boxyla te (31b). Following
the same procedure as for 31a , compound 31b was obtained
from 14 and 30 in 77% yield as colorless crystals. This
compound was identical with an authentic sample upon
comparison of their spectral data.5,7 The presence of rotamers
precluded a comprehensive assignment of all proton and
carbon resonances: [R]23 -71.0 (c 1.08, MeOH); IR (CHCl3)
D
1717 (ArCOO), 1660 (CO) cm-1
;
1H NMR (CDCl3) δ 7.78 (1/
2H, br d, J ) 8 Hz), 7.72 (3/2H, br d, J ) 8 Hz), 7.55-6.78
(38H, m), 5.30-4.58 (2H, m), 5.25, 5.04, 4.83, 4.67 (each 2H,
s), 5.10 (4H, s), 4.12 (2H, m), 3.42 (1H, br d, J ) 14 Hz), 2.90
(1H, br m), 2.14-1.50 (4H, m); 13C NMR (CDCl3) δ 191.6, 167.3,
166.0, 165.6, 161.3, 158.0, 156.3, 136.4, 136.3, 135.8, 132.7,
132.4, 130.4, 128.9, 128.6, 128.24, 128.16, 127.9, 127.7, 127.5,
127.4, 127.3, 127.2, 122.0, 115.3, 114.6, 107.0, 77.9, 70.48,
70.46, 70.0, 67.9, 67.0, 53.5, 50.7, 49.3, 28.8, 24.9; SIMS calcd
for C71H62N2O12 + H (QM+) 1135.4377, found 1135.4372.
(-)-Ba la n ol (1). According to Nicolaou’s conditions,5 pal-
ladium black (8 mg) was added to a solution of 31b (30 mg,
0.0265 mmol) in formic acid (1.3 mL) at room temperature.
After the mixture was stirred at the same temperature for 12
h, palladium black (16 mg) was added. After being stirred at
the same temperature for 4.5 h, the reaction mixture was
filtered and the filtrate was concentrated at reduced pressure.
Purification of the residue by preparative TLC on silica gel
(t-BuOH/AcOH/H2O 4:1:1) followed by preparative TLC on C18
reversed-phase silica gel (acetonitrile/H2O 2:3) afforded 1 (11.5
mg, 79%) as a yellow solid. This compound was identical with
3,5-B is (p h e n y lm e t h o x y )-4-[2-(p h e n y lm e t h o x y )-6-
[(p h en ylm eth oxy)ca r bon yl]ben zoyl]ben zoic Acid (30). To
a solution of 29 (31 mg, 0.0467 mmol) in THF (0.2 mL), t-BuOH
(0.2 mL), and H2O (0.07 mL) were added 2-methyl-2-butene
(2.0 M in THF, 0.19 mL), NaH2PO4 (1.0 M in H2O, 0.14 mL)
and 80% NaClO2 (16 mg, 0.14 mmol) under
a nitrogen
atmosphere at room temperature. The reaction mixture was
stirred at the same temperature for 3 h. The reaction mixture
was concentrated at reduced pressure. After dilution with
aqueous KHSO4 (0.5 M), the aqueous phase was extracted with
AcOEt. The organic phase was washed with H2O, saturated
aqueous Na2SO3, and brine, dried over MgSO4, and concen-
trated at reduced pressure. Purification of the residue by flash
column chromatography (MeOH/CH2Cl2 1:20) afforded 30 (26.6
mg, 84%) as colorless crystals. This compound was identical
with an authentic sample upon comparison of their spectral
data:5-7 mp 155-157 °C (AcOEt/hexane) (lit.5 mp 158-160.5
°C; lit.6 mp 151-156 °C; lit.7 mp 132-134 °C); IR (CHCl3) 1720
(ArCOO), 1671 (ArCOAr) cm-1; 1H NMR (CDCl3) δ 7.35-7.00
(22H, m), 6.95 (1H, dd, J ) 8, 1.5 Hz), 6.85 (2H, br m), 5.13
(2H, s), 4.77 (4H, s), 4.69 (2H, s); 13C NMR (CDCl3) δ 191.6,
171.0, 167.5, 157.9, 156.5, 136.1, 135.8, 135.6, 133.0, 131.9,
131.6, 130.7, 128.3, 128.2, 127.9, 127.6, 127.2, 124.6, 122.0,
115.3, 114.4, 107.2, 70.6, 70.4, 67.1; HRMS calcd for C43H34O8
(M+) 678.2251, found 678.2246.
1,1-Dim eth yleth yl (3R-tr a n s)-4-[[3,5-Bis(p h en ylm eth -
oxy)-4-[2-(ph en ylm eth oxy)-6-[(ph en ylm eth oxy)car bon yl]-
ben zoyl]ben zoyl]oxy]h exa h yd r o-3-[[4-(p h en ylm eth oxy)-
ben zoyl]a m in o]-1H-a zep in e-1-ca r boxyla te (31a ). To a
solution of (3R,4R)-9 (8.8 mg, 0.02 mmol) and 30 (13.3 mg,
0.02 mmol) in CH2Cl2 (0.2 mL) were added 2-chloro-1-meth-
ylpyridinium iodide (6.64 mg, 0.026 mmol) and triethylamine
(0.0056 mL, 0.04 mmol) under a nitrogen atmosphere at room
temperature. After the mixture was stirred at the same
temperature for 30 min, DMAP (1.2 mg, 0.01 mmol) was added
to the reaction mixture. After being stirred at the same
temperature for 24 h, the reaction mixture was concentrated
at reduced pressure. Purification of the residue by preparative
TLC (AcOEt/hexane 2:3) afforded 31a (17 mg, 77%) as colorless
crystals. The presence of rotamers precluded a comprehensive
an authentic sample upon comparison of their spectral data:
3,5-7
[R]22 -106.7 (c 0.042, MeOH); IR (film) 1633 (CO) cm-1
;
D
1H NMR (CDCl3) δ 7.61 (2H, d, J ) 8.5 Hz), 7.31 (1H, dd, J )
8, 1 Hz), 7.19 (1H, t, J ) 8 Hz), 6.91 (2H, s), 6.84 (1H, dd, J )
8, 1 Hz), 6.76 (2H, d, J ) 8.5 Hz), 5.22 (1H, m), 4.35 (1H, br
m), 3.4-3.0 (4H, br m), 2.1-1.8 (4H, br m); 13C NMR (CDCl3)
δ 203.8, 174.8, 170.3, 166.5, 162.3, 161.5, 154.5, 138.1, 136.3,
132.4, 130.5, 130.2, 125.7, 120.9, 118.7, 118.3, 116.1, 109.6,
77.0, 54.6, 30.3, 22.2; SIMS calcd for
C28H26N2O10 - H
(negative, M+ - H) 549.1507, found 549.1500.
Ack n ow led gm en t. We wish to thank the Ministry
of Education, Science, Sports and Culture of J apan and
the Science Research Promotion Fund of the J apan
Private School Promotion Foundation for research grants.
Thanks are also extended to Professor Dr. K. C. Nico-
laou, Department of Chemistry, The Scripps Research
Institute, and Dr. P. F. Hughes and Dr. P. Kulanthaivel,
Sphinx Pharmaceuticals, for sending us the valuable
spectral data of authentic samples.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures and characterization of 16c and 17a -c and H NMR
data for all compounds (40 pages). This material is contained
in libraries on microfiche, immediately follows this article in
the microfilm version of the journal, and can be ordered from
the ACS; see any current masthead page for ordering
information.
J O980208R