Total synthesis of (-)· and (+)-balanol

Article abstract of DOI:10.1021/jo952280k

Two total syntheses of the potent protein kinase C inhibitory fungal metabolite balanol are described. In the first approach, the core aminohydroxyazepane subunit was prepared in racemic form by stereospecific functionalization of N-benzyl-∈-caprolactam.

Full text of DOI:10.1021/jo952280k

4572
J . Org. Chem. 1996, 61, 4572-4581
Tota l Syn th esis of (-)- a n d (+)-Ba la n ol1
J ohn W. Lampe,* Philip F. Hughes,* Christopher K. Biggers, Shelley H. Smith, and Hong Hu
Department of Chemical Research, Sphinx Pharmaceuticals, A Division of Eli Lilly and Company,
4615 University Drive, Durham, North Carolina 27707
Received December 28, 1995X
Two total syntheses of the potent protein kinase C inhibitory fungal metabolite balanol are described.
In the first approach, the core aminohydroxyazepane subunit was prepared in racemic form by
stereospecific functionalization of N-benzyl-ꢀ-caprolactam. Resolution prior to coupling to the
benzophenone subunit provided access to both enantiomers of balanol. In the second approach, an
efficient silicon-mediated cyclization of (2S,3R)-3-hydroxylysine followed by reduction provided the
azepane subunit in enantiomerically pure form. The sterically congested benzophenone subunit
was assembled from two highly substituted aromatic precursors by way of an anionic homo-Fries
rearrangement.
In tr od u ction
to the PKC inhibitor area,6 and the combined structural
novelty and low availability of the compound has gener-
ated substantial interest in the development of synthetic
approaches to the natural material7-9 and related struc-
tures.10,11 As part of an ongoing program directed toward
the discovery of novel therapeutic agents for the treat-
ment of PKC-mediated disorders, we required a synthesis
of (-)-balanol which would provide access to large
quantities of the compound for detailed pharmacological
characterization and which would be sufficiently flexible
to provide ready access to synthetic analogs with in-
creased enzyme selectivity and improved pharmaco-
kinetic properties. In this paper we present the full
account of two synthetic approaches to either enantiomer
of balanol.
Protein kinase C (PKC) is a family of phospholipid-
dependent serine/threonine-specific protein kinases which
play an important role in cellular growth control, regula-
tion, and differentiation.2 Activation of PKC is a critical
step in the signal transduction pathways controlling
processes such as cellular proliferation and gene expres-
sion,3 and the enzyme has been implicated in the
progression of a wide variety of diseases, facts which have
rendered PKC inhibitors attractive therapeutic targets.4
Recently, the isolation and structural elucidation of (-)-
balanol, (-)-1, a metabolite which is produced in trace
Resu lts a n d Discu ssion
Ben zop h en on e Syn th esis. Our synthetic approach
began with the obvious disconnection of balanol at its
ester linkage to yield the hydroxyazepane and the benzo-
phenone carboxylic acid subunits. We anticipated as-
sembling the sterically congested benzophenone subunit
by forming one of the two bonds to the benzophenone
(6) Previous work in this area has been focused primarily on the
staurosporine family, for example, see Link, J . T.; Raghavan, S.;
Danishefsky, S. J . J . Am. Chem. Soc. 1995, 117, 552-553, and
references therein.
(7) (a) Lampe, J . W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.;
Hu, H. J . Org. Chem. 1994, 59, 5147-5148. (b) Hughes, P. F.; Smith,
S. H.; Olson, J . T. J . Org. Chem. 1994, 59, 5799-5802. (c) Hollinshead,
S. E.; Nichols, J . B.; Wilson, J . W. J . Org. Chem. 1994, 59, 6703-6709.
(d) Hu, H.; J agdmann, G. E., J r.; Hughes, P. F.; Nichols, J . B.
Tetrahedron Lett. 1995, 36, 3659-3662.
(8) (a) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J . Am. Chem. Soc.
1994, 116, 8402-8403. (b) Nicolaou, K. C.; Koide, K.; Bunnage, M. E.
Chem. Eur. J . 1995, 1, 454-466.
(9) 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, 2355-2362.
amounts by the fungus Verticillium balanoides and which
has been shown to inhibit PKC at low nanomolar
concentrations, was reported from our laboratories.5 The
discovery of balanol has provided a new structural motif
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
(2) (a) Nishizuka, Y. Science 1986, 233, 305-312. (b) Nishizuka, Y.
Nature 1984, 308, 693-698. (c) Farago, A.; Nishizuka, Y. FEBS Lett.
1990, 268, 350-354.
(3) (a) Castagna, M.; Takai, Y.; Kaibuchi, K.; Sano, K.; Kikkawa,
U.; Nishizuka, Y. J . Biol. Chem. 1982, 257, 7847-7851. (b) J akobovits,
A.; Rosenthal, A.; Capon, D. J . EMBO J . 1990, 9, 1165-1170.
(4) (a) Bradshaw, D.; Hill, C. H.; Nixon, J . S.; Wilkinson, S. E. Agents
Actions 1993, 38, 135-147. (b) Tritton, T. R.; Hickman, J . A. Cancer
Cells 1990, 2, 95-105.
(5) (a) Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.;
J anzen, W. P.; Ballas, L. M.; Loomis, C. R.; J iang, J . B.; Katz, B.;
Steiner, J . R.; Clardy, J . J . Am. Chem. Soc. 1993, 115, 6452-6453. (b)
This compound was subsequently isolated from Fusarium merismoides
Corda and termed “azepinostatin”: 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.
(10) (a) Heerding, J . M.; Lampe, J . W.; Darges, J . W.; Stamper, M.
L. Bioorg. Med. Chem. Lett. 1995, 5, 1839-1842. (b) J agdmann, G. E.,
J r.; Defauw, J . M.; Lai, Y.-S.; Crane, H. M.; Hall, S. E.; Buben, J . A.;
Hu, H.; Gosnell, P. A. Bioorg. Med. Chem. Lett. 1995, 5, 2015-2020.
(c) Crane, H. M.; Menaldino, D. S.; J agdmann, G. E., J r.; Darges, J .
W.; Buben, J . A. Bioorg. Med. Chem. Lett. 1995, 5, 2133-2138. (d) Lai,
Y.-S.; Stamper, M. Bioorg. Med. Chem. Lett. 1995, 5, 2147-2150. (e)
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. (f) Lai, Y.-S.; Mendoza, J . S.; Hubbard, F.; Kalter, K. Bioorg.
Med. Chem. Lett. 1995, 5, 2155-2160. (g) Mendoza, J . S.; J agdmann,
G. E., J r.; Gosnell, P. A. Bioorg. Med. Chem. Lett. 1995, 5, 2211-2216.
(11) Koide, K.; Bunnage, M. E.; Paloma, L. G.; Kanter, J . R.; Taylor,
S. S.; Brunton, L. L.; Nicolaou, K. C. Chem. Biol. 1995, 2, 601-608.
S0022-3263(95)02280-8 CCC: $12.00 © 1996 American Chemical Society

Total Synthesis of (-)- and (+)-Balanol
J . Org. Chem., Vol. 61, No. 14, 1996 4573
Sch em e 1
Sch em e 3
Sch em e 2
carbonyl carbon by addition of a metalated precursor for
one of the two aromatic rings to a suitably activated
benzoic acid precursor for the second ring. A model for
such a transformation is shown in Scheme 1. Regio-
specific metalation of benzyl alcohol 2 in analogy to the
method of Trost12 followed by trapping of the resulting
aryllithium with 4-carbomethoxybenzoyl chloride yields
the benzophenone 3, albeit in modest yield. Compound
3 contains the necessary functionality for elaboration into
an analog of the balanol benzophenone in which two of
the hydroxy substituents have been deleted.
Scheme 2 details the preparation of the acid chloride
component for a coupling reaction which would provide
a fully functionalized benzophenone. Differentially pro-
tected aryl bromide 5 was prepared in 71% overall yield
from acid 4 by way of a three-step sequence in which 4
was perbenzylated, the benzyl ester was hydrolyzed, and
the acid was reesterified after activation with 1,1′-
carbonyldiimidazole. Bromide 5 undergoes rapid trans-
metalation with n-butyllithium at -78 °C to yield the
aryllithium, which on trapping with carbon dioxide gives
carboxylic acid 6 in 48% yield. Treatment of 6 with oxalyl
chloride gives the acid chloride in quantitative yield.
Alternatively, the aryllithium may be reacted with DMF
to give in 53% yield aldehyde 8, another potential
intermediate for benzophenone synthesis.
Unfortunately, as shown in Scheme 3, acid chloride 7
proved to be inadequate as a substrate for coupling
reactions aimed at providing the required benzophenone.
Metalation of alcohol 2 and attempted coupling with 7
under the same conditions which yielded 3 provided in
this case none of the desired benzophenone 9. The poor
reactivity of this acid chloride extended to a variety of
other aryl nucleophiles. For example, oxazoline 10,
prepared from the corresponding carboxylic acid by the
method of Meyers and co-workers,13 afforded none of the
benzophenone 11 after metalation and subsequent reac-
tion with 7. Similar behavior of 10 toward other acid
chloride electrophiles has recently been reported by
Nicolaou and co-workers,8b although the reaction of
aryloxazolines related to 10 with acid chlorides to give
benzophenones is precedented.14 In contrast, metalation
of 10 and addition to aldehyde 8 was successful, affording
a 50% yield of diarylmethanol 12. This result showed
that 10 was metalated successfully and suggested that
it might serve as a suitable precursor to highly substi-
tuted benzophenones; however, we were unable to elabo-
rate 12 into the benzophenone needed for balanol, as
numerous attempts at oxidation of 12 to give a benzophe-
none led only to decomposition of the starting material.
Thus, 7 proved to be poorly suited to the direct coupling
with aryl nucleophiles to provide highly substituted
benzophenones. A number of related approaches involv-
ing metalation of bromide 5 and addition to activated
benzoic acid precursors to the carboxylic acid bearing ring
of the benzophenone were similarly unsuccessful. We
attributed the failure of these carbonyl additions to the
severely crowded transition states encountered along the
addition reaction pathways. The chlorocarbonyl sub-
stituent of 7 is presumably forced by the two neighboring
benzyloxy substituents to lie out of the plane of the
aromatic ring. As a result, the benzyloxy substituents
effectively block access to either face of the carbonyl by
large incoming nucleophiles. Consistent with this view,
a related system in which the benzyloxy substituents
have been replaced by smaller but less labile methoxy
groups has recently been reported to couple successfully
to give a benzophenone.9 In contrast to the behavior
exhibited by 7, the comparatively small aldehyde unit of
8 can assume an orientation coplanar with the aromatic
ring of the molecule, such that large nucleophiles can
approach the carbonyl relatively unimpeded by the
adjacent substituents. This observation regarding the
superior accessibility of 2,6-disubstituted aldehydes such
as 8 was ultimately exploited in the development of two
highly efficient syntheses of differentially protected ben-
(12) (a) Trost, B. M.; Rivers, G. T.; Gold, J . M. J . Org. Chem. 1980,
45, 1835-1838. (b) Uemura, M.; Tokuyama, S.; Sakan, T. Chem. Lett.
1975, 1195-1198.
(13) Meyers, A. I.; Temple, D. L.; Haidukewych, D.; Mihelich, E. D.
J . Org. Chem. 1974, 39, 2787-2793.
(14) Edgar, K. E.; Bradsher, C. K. J . Org. Chem. 1982, 47, 1585-
1587.

4574 J . Org. Chem., Vol. 61, No. 14, 1996
Lampe et al.
Sch em e 4
Sch em e 5
zophenones suited for use for the synthesis of balanol and
The final elaboration of 9 into the fully-protected
balanol benzophenone is shown in Scheme 5. Oxidation
of 9 with pyridinium dichromate in DMF20 afforded
aldehyde 15, which was curiously resistant to further
oxidation. The difficulty in the oxidation of 15 is pre-
sumably a result of the crowded environment which the
tetrahedral intermediate formed in the course of the
oxidation experiences due to the many substituents ortho
to the benzophenone carbonyl; in contrast to the behavior
of 15, alcohol 3, which lacks two of the ortho substituents,
is oxidized smoothly by pyridinium dichromate to the
corresponding carboxylic acid in 72% yield. Screening
of a series of oxidants showed that permanganate re-
agents were capable of effecting the desired transforma-
tion to acid 16, with tetrabutylammonium permangan-
ate21 proving to be particularly efficacious; sodium
chlorite22 was also effective in bringing about the oxida-
tion. Standard benzylation afforded benzyl ester 17 in
71% overall yield from alcohol 9.
Diester 17 proved to be particularly sensitive to the
acid conditions normally used for the hydrolysis of tert-
butyl esters. Treatment of 17 with trifluoroacetic acid
or formic acid afforded the desired acid 18 along with
substantial quantities of a debenzylated side-product.
Thermolysis of 17 either neat or in neutral solvents also
led to the formation of unacceptable levels of this de-
benzylated product, presumably due to acid catalysis by
the product carboxylic acid; however, thermolysis in
quinoline at 205 °C led cleanly to the desired benzo-
phenone carboxylic acid 18, which was isolated as a
crystalline solid in 68% yield.
analogs, which has been detailed in
a separate
communication.7c
The initial difficulties which we encountered in the
oxidation of diarylmethanol 12 and our desire to avoid
as much as possible the protecting group manipulations
involved in the use of such an intermediate led us to
consider other approaches in which the benzophenone
unit could be generated directly. We reasoned that the
steric obstacles encountered in the use of electrophiles
such as 7 might be overcome if the addition to the
carbonyl could be accomplished in an intramolecular
fashion.15 One approach suited to such an intramolecular
generation of a benzophenone is the Fries rearrange-
ment.16 The anionic homologous variant of the Fries
rearrangement17 appeared to be particularly well suited
to our needs, although it had not previously been applied
to such a hindered and complex system.
The preparation and use of the required precursor for
the homo-Fries rearrangement is detailed in Scheme 4.
Metalation of 2 as described above followed by trapping
of the aryllithium with 1,2-dibromo-1,1,2,2-tetrafluoro-
ethane18 regiospecifically afforded bromide 13 in 51%
yield. Acid chloride 7 smoothly acylates the benzyl
alcohol of 13, a relatively sterically undemanding nucleo-
phile, to give an 81% yield of ester 14. We were gratified
to find that treatment of 14 with n-butyllithium at -78
°C led to a rapid transmetalation and rearrangement of
the intermediate aryllithium to afford the desired tetra-
ortho-substituted benzophenone 9 in 51% yield.19
(15) The use of intramolecular approaches in the synthesis of
sterically congested compounds is well known; for example, see
Overman, L. E. Pure Appl. Chem. 1994, 66, 1423-1430.
(16) (a) Blatt, A. H. Org. React. 1942, 1, 343-369. (b) Martin, R.
Org. Prep. Proc. Int. 1992, 24, 369-435.
(17) Horne, S.; Rodrigo, R. J . Chem. Soc., Chem. Commun. 1992,
164-166.
(18) (a) Finkelstein, B. L. J . Org. Chem. 1992, 57, 5538-5540. (b)
Paquette, L. A.; Ross, R. J .; Shi, Y.-J . J . Org. Chem. 1990, 55, 1589-
1598.
(19) Compound 9 and the related benzophenone 3 proved to be
photolabile in solution, although they could be stored for prolonged
periods when kept as solids in the dark. Photoreactivity of 2-(alkoxy-
methyl)benzophenones is well known; for example, see: (a) Oka, M.;
Konishi, M.; Oki, T. Tetrahedron Lett. 1990, 31, 7473-7474. (b) Kraus,
G. A.; Wu, Y. J . Org. Chem. 1992, 57, 2922-2925. (c) Coll, G.; Costa,
A.; Deya´, P. M.; Flexas, F.; Rotger, C.; Saa´, J . M. J . Org. Chem. 1992,
57, 6222-6231.
Ra cem ic Azep a n e Syn th esis a n d Resolu tion . Our
approach to the synthesis of the azepane ring proceeded
along two lines. Although an enantioselective synthesis
of the azepane was ultimately desired for the synthesis
of analogs, we felt that it would be prudent to pursue a
racemic synthesis as well, since a simple racemic syn-
thesis would allow quicker assembly of balanol and
analogs and might be more amenable to scale-up. Reso-
(20) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399-402.
(21) Sala, T.; Sargent, M. V. J . Chem. Soc., Chem. Commun. 1978,
253-254.
(22) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888-
890.

Total Synthesis of (-)- and (+)-Balanol
J . Org. Chem., Vol. 61, No. 14, 1996 4575
Sch em e 6
Sch em e 7
Ta ble 1. P KC In h ibitor y Activity of Syn th etic Ba la n ol
En a n tiom er s
IC50 values for inhibition of human PKC isozymes, nMa
compd
PKC-R
PKC-âII
PKC-γ
PKC-δ
PKC-ꢀ
(()-1
(-)-1
(+)-1
67
30
3000
30
10
880
30
10
400
23
4
420
38
10
1000
a
IC50 values were calculated from four-point curves of tenfold
dilutions; the assays were carried out using partially purified
recombinant human PKC isozymes as described previously.30
lution of the racemate would also provide access to both
enantiomers of the natural product. Our strategy was
to assemble the azepane via elaboration of ꢀ-caprolactam
19.7d We envisioned that the trans amino alcohol would
be introduced via olefin formation, epoxidation of the
olefin, and epoxide opening with a suitable nitrogen
nucleophile. Hydride reduction would then give the
desired differentially protected azepane.
25, which on acylation with 4-(benzyloxy)benzoyl chloride
afforded the desired amide alcohol 26 (55% from 24), the
planned intermediate for coupling with the properly
functionalized benzophenone.
The synthesis of racemic balanol (()-1 was completed
in two steps as shown in Scheme 7. Conversion of the
benzophenone 18 to its acid chloride with oxalyl chloride
followed by reaction with alcohol 26 afforded the desired
ester 27. Hexabenzylbalanol 27 was then converted by
exhaustive hydrogenolysis (H2, 20% Pd(OH)2/C) to race-
mic balanol (()-1. This compound was identical to
natural balanol by HPLC and NMR and showed PKC
inhibitory potencies remarkably close to half that of
natural balanol (Table 1).
At this point, an enantioselective synthesis of the
azepane had not yet been completed, and thus the
question of the relative protein kinase inhibitory poten-
cies of the two enantiomers of balanol loomed. This was
an important question for two reasons. First, a finding
of comparable activity in both enantiomers would suggest
that the activity is related to nonspecific interactions or
perhaps chemical reactivity, either of which is undesir-
able for drug development. However, a good separation
of activity (>25:1) would suggest a specific interaction
amenable to further optimization. Additionally, a good
separation of activity would simplify the interpretation
of SAR data generated from racemic analogs which are
more easily accessible via synthesis.
To obtain both enantiomers of balanol, we chose to
resolve the azepane alcohol 26 as shown in Scheme 8.
The free alcohol gave a convenient point for attachment
and removal of a suitable chiral auxiliary. The diastereo-
meric Mosher esters24 were made and separated by
repeated silica gel chromatography (3% NEt3 in 7:3
hexanes:ethyl acetate). The esters were then saponified
and the resolved alcohols, 26a and 26b, converted to the
enantiomers of balanol as described above for racemic
balanol. The resolution did not allow for the determi-
nation of the absolute stereochemistry of the enantiomers
Amide alkylation of ꢀ-caprolactam 19 (Scheme 6) gave
N-benzyl derivative 20 (NaH, benzyl bromide, 96%).
Lactam 20 was converted to olefin 21 in 78% yield by
selenation (LiHMDS, 2 equiv, C6H5SeCl) followed by
oxidative elimination of the phenylselenyl group (NaIO4
or H2O2). Unfortunately, repeated attempts at carrying
out the planned epoxidation of the olefin under a variety
of conditions23 proved unsuccessful, so an alternative
approach was taken. Osmium tetraoxide-catalyzed di-
hydroxylation of the olefin gave diol 22 in 78% yield.
Differentiation of the two hydroxyl groups by selective
protection of the â-hydroxyl was initially elusive. Acyl-
ation with benzoyl chloride gave primarily the R-ben-
zoate, along with some â-benzoate, bisbenzoate, and diol.
However, treatment of 22 with trimethyl orthobenzoate
in refluxing toluene gave only the â-benzoate, along with
some starting diol. On the basis of these findings, it
seemed reasonable to suspect that the â-benzoate is the
more thermodynamically stable product and that it
therefore might be most cleanly prepared by selective
monobenzoylation of the diol followed by equilibration of
the R,â-benzoate mixture to the â-benzoate. Treatment
of the diol 22 with trimethyl orthobenzoate in the
presence of boron trifluoride etherate gave the mixed
ortho ester which was decomposed with water to a
mixture of R and â monobenzoate esters. Extractive
workup followed by treatment with DBU gave exclusively
the â-benzoate 23 in 72% yield. Nitrogen was then
introduced at the R position with inversion of configura-
tion by conversion of the R-hydroxyl to the triflate (Tf2O,
2,6-lutidine) followed by displacement with sodium azide
to give the desired trans-R-azido-â-(benzoyloxy)caprolac-
tam 24 in 87% yield. Concomitant reduction of the
lactam, azide, and benzoate with LiAlH4 gave azepane
(24) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549.
(23) Li, B.; Smith, M. B. Synth. Commun. 1995, 25, 1265-1275.

4576 J . Org. Chem., Vol. 61, No. 14, 1996
Lampe et al.
Sch em e 8
Sch em e 9
exchange chromatography (AG-50, H+-form, 1 N HCl) to
remove the epimeric byproduct. Borane reduction fol-
lowed by decomposition of the resulting borane complex
by sequential additions of methanol, alkali (1 N NaOH),
and acid (1 N HCl) afforded the desired azepane 29,
which was isolated as a crystalline solid in 67% yield after
ion exchange chromatography (AG-50, H+-form, 3 N HCl).
The addition of alkali was an unanticipated requirement
to break up the borane-complexed products. If the alkali
step was omitted, a substantial amount (20-40%) of a
crystalline byproduct was obtained which eluted from the
ion-exchange column with 2 N HCl. The 1H-NMR of this
material was similar to that of the desired product but
showed slight chemical shift differences. Treatment of
the 1H-NMR sample with 1 N NaOH led to a rapid
and the assignment of absolute configuration was based
on optical rotation and confirmed by biochemical testing.
Evaluation of the two enantiomers as PKC inhibitors
(Table 1) indicated that the natural enantiomer was at
least 40-100 times as potent as the unnatural enanti-
omer.25
En a n tioselective Azep a n e Syn th esis. Develop-
ment of a balanol synthesis which avoids a resolution
required an enantioselective synthesis of the azepane. We
envisioned that the chiral balanol azepane could be
obtained via cyclization and reduction of (2S,3R)-3-
hydroxylysine 28. Two complimentary enantioselective
syntheses of 3-hydroxylysine were developed in our
laboratories and have been previously reported.7b Syn-
thesis of azepane 29 from hydroxylysine 28 is shown in
Scheme 9. As an initial attempt, the methyl ester of 28
was formed (HCl, MeOH) and cyclized with potassium
carbonate in refluxing methanol. Unfortunately, com-
plete epimerization of the 3-amino stereocenter was seen.
However, drawing from a recent Soviet patent,26 addition
of powdered hydroxylysine 28 to hexamethyldisilazane
in refluxing xylenes gave a homogeneous solution. Slow
addition of 2-propanol27 then led to the desired lactam
and only 7% of the epimeric byproduct. Caprolactam 30
was obtained as a crystalline solid in 79% yield after ion
1
release of gas, presumably hydrogen, and H-NMR and
TLC analysis indicated conversion to the desired azepane.
Mass spectral analysis (FAB) gave the base peak at m/z
143 (M + 1), which together with elemental analysis
suggested a molecular formula of C6H15N2OB as a
hydrochloride salt.28 Further structural investigation of
this interesting and very water stable boron hydride is
ongoing.
The synthesis of (-)-balanol was completed as shown
in Scheme 9. Selective protection of the azepane nitrogen
was accomplished by reaction of 29 with di-tert-butyl
(27) Although product often formed without 2-propanol addition,
progress of the reaction was highly variable from run to run and
possibly depended on adventitious introduction of moisture. We believe
the 2-propanol served to partially desilylate the initially formed and
unreactive persilylated compound.
(28) The spectral data are consistent with structure:
(25) This figure represents a lower limit on the selectivity, since our
limits on determining the enantiomeric purity of 26b leave open the
possibility that (+)-1 is contaminated by as much as 2% of the potent
inhibitor (-)-1.
(26) Belyaev, A. A.; Konyukhova, E. V.; Radina, L. B. SU Patent
1708812-A1 J anuary, 30, 1994.
though a dimeric or oligomeric structure might be more accurate.

Total Synthesis of (-)- and (+)-Balanol
J . Org. Chem., Vol. 61, No. 14, 1996 4577
(CDCl3) δ 5.20 (s, 4H), 5.34 (s, 2H), 7.33-7.40 (m, 13H), 7.47-
7.49 (m, 4H). Anal. Calcd for C28H23BrO4: C, 66.81; H, 4.61.
Found: C, 66.68; H, 4.60.
dicarbonate. Acylation of this mono-protected compound
with 4-(benzyloxy)benzoyl chloride provided amide 31 in
66% yield from 29. Further acylation of 31 with the acid
chloride derived from benzophenone acid 18 led to ester
32. Deprotection by hydrogenolysis followed by treat-
ment with trifluoroacetic acid afforded (-)-balanol (-)-1
in 63% yield from 31 after isolation by reversed phase
HPLC. This synthetic material was found to be identical
with naturally occurring balanol by 1H NMR, TLC,
HPLC, and optical rotation. The natural and synthetic
materials were also found to be indistinguishable in their
inhibitory potencies as determined in protein kinase C
enzyme assays.
4-Br om o-3,5-bis(ben zyloxy)ben zoic Acid . A solution of
NaOH (216 g, 5.4 mol) in water (2.5 L) was added to benzyl
4-bromo-3,5-bis(benzyloxy)benzoate (503.4 g, 1.1 mol). The
resulting suspension was heated to 100 °C and stirred for 12
h. The mixture was poured into ice water (2 L) and adjusted
to pH 1-2 by addition of 6 N HCl. The pale yellow solids were
filtered, washed with water and dried to give the title
compound (422.9 g, 95%), mp 230-232 °C dec. 1H NMR
(DMSO-d6) δ 5.28 (s, 4H), 7.34-7.44 (m, 8H), 7.49-7.51 (m,
4H). Anal. Calcd for C21H17BrO4: C, 61.03; H, 4.15. Found:
C, 61.03; H, 4.19.
1,1-Dim eth yleth yl 3,5-Bis(ben zyloxy)-4-br om oben zoate
(5). 1,1′-Carbonyldiimidazole (264.14 g, 1.63 mol) was added
in portions to a solution of 3,5-bis(benzyloxy)-4-bromobenzoic
acid (448.85 g, 1.09 mol) in DMF (1.5 L). The resulting
solution was heated to 40 °C and stirred for 1 h. tert-Butyl
alcohol (204.82 mL, 2.17 mol) was then added dropwise
followed by the dropwise addition of DBU (162.41 mL, 1.09
mol). The resulting solution was stirred at 40 °C for 60 h.
The reaction was cooled to rt and poured into ice-water (2
L). The mixture was adjusted to pH 5 by addition of concd
aqueous HCl and the mixture stirred for 1 h. The tan solids
were filtered, washed with water, and dried to give the title
compound (499.4 g, 99%), mp 90-92 °C. 1H NMR (CDCl3) δ
1.57 (s, 9H), 5.20 (s, 4H), 7.32-7.42 (m, 8H), 7.49-7.51 (d, 4H,
J ) 6.8). Anal. Calcd for C25H25BrO4: C, 63.97; H, 5.37.
Found: C, 64.19; H, 5.34.
In summary, we have described two total syntheses of
(-)-balanol (-)-1. The convergent syntheses have pro-
vided ready access to racemic balanol as well as its two
enantiomers. The direct synthesis of the enantiomeri-
cally pure material was accomplished in eighteen total
operations and proceeds in 22% yield for six linear steps
from 28 and 4.3% yield for fourteen linear steps from 4,
proving it to be a particularly efficient route to this
material. These synthetic routes have allowed the
preparation of gram quantities of synthetic (-)-balanol
as well as a diverse set of over 400 synthetic analogs.
Exp er im en ta l Section
2,6-Bis(ben zyloxy)-4-[(1,1-d im eth yleth oxy)ca r bon yl]-
ben zoic Acid (6). To a solution of 10.00 g (21.3 mmol) of 1,1-
dimethylethyl 3,5-bis(benzyloxy)-4-bromobenzoate (5) in 150
mL of freshly distilled THF at -70 °C under nitrogen was
added 10.5 mL (23.4 mmol) of a 2.23 M solution of butyllithium
in hexanes over 10 min. The solution was stirred at -70 °C
for 10 min, after which CO2 was bubbled through the mixture
for 10 min. The mixture was stirred for an additional 20 min
at -78 °C and then was allowed to warm to rt. After 45 min
the reaction mixture was poured onto 500 mL of ether and
250 mL of saturated aqueous NH4Cl, and this mixture was
stirred for 15 min. The layers were separated, and the organic
phase was washed with 0.2 M HCl and brine, dried over
MgSO4, and evaporated to give 9.55 g of the crude product.
Recrystallization of the crude material from EtOAc-hexane
afforded 4.44 g (48%) of the title compound as a white solid,
Gen er a l. Melting points are uncorrected. Starting materi-
als were obtained from Aldrich and used without further
purification unless otherwise noted. THF was distilled from
sodium/benzophenone under nitrogen. Baker silica gel (40 µM)
was used for flash chromatography. 1H NMR and 13C NMR
spectra were recorded at 300 and 75 MHz, respectively;
coupling constants are in Hz. Microanalyses were obtained
on crystalline intermediates and were determined either in
our laboratories or by Atlantic Microlab, Inc. of Norcross, GA.
HPLC chromatography was monitored by UV absorbance at
254 nm.
Meth yl 4-[6-(Ben zyloxy)-2-(h yd r oxym eth yl)ben zoyl]-
ben zoa te (3). To a solution of 1.07 g (5.00 mmol) of 3-(benzyl-
oxy)benzyl alcohol in 15 mL of toluene at -5 °C under nitrogen
was added 5.8 mL (12.2 mmol) of a 2.1 M solution of
butyllithium in hexanes over 15 min. The solution was stirred
at -5 °C for 6 h, after which it was cooled to -78 °C, and a
solution of 1.00 g (5.03 mmol) of 4-(methoxycarbonyl)benzoyl
chloride in 5 mL of THF was added. The mixture was stirred
for 1 h, after which it was poured onto 200 mL of ether and
100 mL of saturated aqueous NH4Cl, and this mixture was
stirred for 10 min. The layers were separated, and the organic
phase was washed with saturated aqueous NaHCO3 and brine,
dried over MgSO4, and evaporated to give the crude product.
Flash chromatography on silica gel eluting with 3/1 EtOAc-
hexane afforded 0.68 g (36%) of the title compound as a white
solid, mp 90-96 °C. The proton NMR for this material showed
a 60/40 mixture of ketone and hemiketal forms. For the
ketone: 1H NMR (CDCl3) δ 2.66 (t, 1H, J ) 6), 3.98 (s, 3H),
4.54 (d, 2H, J ) 6), 4.95 (s, 2H), 6.88 (m, 2H), 7.01 (d, 2H, J )
8), 7.16-7.21 (m, 3H), 7.48 (t, 1H, J ) 8), 7.86 (d, 2H, J ) 8),
8.10 (d, 2H, J ) 8). Anal. Calcd for C23H20O5: C, 73.39; H,
5.35. Found: C, 73.35; H, 5.65.
mp 140-146 °C dec. IR (KBr) 1709, 1589, 1423 cm-1
.
1H
NMR (CDCl3) δ 1.62 (s, 9H), 5.23 (s, 4H), 7.30 (s, 2H), 7.34-
7.43 (m, 6H), 7.46-7.48 (m, 4H). Anal. Calcd for C26H26O6:
C, 71.87; H, 6.03. Found: C, 71.76; H, 6.12.
1,1-Dim eth yleth yl 3,5-Bis(ben zyloxy)-4-for m ylben zoate
(8). To a solution of 0.510 g (1.09 mmol) of 1,1-dimethylethyl
3,5-bis(benzyloxy)-4-bromobenzoate (5) in 11 mL of freshly
distilled THF at -78 °C under nitrogen was added 478 µL (1.20
mmol) of a 2.5 M solution of butyllithium in hexanes over 3
min. The solution was stirred at -78 °C for 20 min, after
which DMF (168 µL, 2.17 mmol) was added dropwise. The
mixture was stirred for an additional 20 min at -78 °C and
then was allowed to warm to rt. After 3 h the reaction mixture
was poured onto 25 mL of EtOAc and 2 mL of 0.1 N HCl, and
this mixture was stirred for 10 min. The layers were sepa-
rated, and the organic phase was washed with brine, dried
over MgSO4, and evaporated to give the crude product.
Chromatography of the crude material on silica gel eluting
with 3-6% EtOAc-hexanes afforded 0.239 g (53%) of the title
compound as an off white foam. 1H NMR (CDCl3) δ 1.60 (s,
9H), 5.24 (s, 4H), 7.27-7.28 (d, 1H, J ) 2.3), 7.34-7.44 (m,
9H), 7.49-7.50 (d, 2H, J ) 6.7), 10.65 (s, 1H). HRMS: calcd
for C26H27O5: 419.1858, found 419.1859.
Ben zyl 4-Br om o-3,5-bis(ben zyloxy)ben zoa te. Potas-
sium carbonate (8.96 g, 64.4 mmol) and benzyl bromide (8.42
mL, 70.81 mmol) were added to a stirred solution of 4-bromo-
3,5-dihydroxybenzoic acid (4) (5.00 g, 21.5 mmol) in dry DMF
(200 mL) at rt under nitrogen. The resulting solution was
stirred for 20 h. The reaction mixture was then filtered and
the filtrate partitioned between EtOAc (750 mL) and water
(500 mL). The organic portion was washed with water (250
mL), 1 N NaOH (250 mL), and brine (250 mL) and then dried
over MgSO4 and concentrated. The resulting residue was
recrystallized from CH2Cl2-hexanes to afford the title com-
pound (8.10 g, 75%) as a white solid, mp 127-128 °C. 1H NMR
2-[2-[[2,6-Bis(b en zyloxy)-4-[(1,1-d im et h ylet h oxy)ca r -
bon yl]p h en yl]h yd r oxym eth yl]-3-(ben zyloxy)p h en yl]-4,4-
d im eth yl-2-oxa zolin e (12). To a solution of 0.653 g (2.32
mmol) of 2-[3-(benzyloxy)phenyl]-4,4-dimethyl-2-oxazoline (10)29
(29) This material was prepared in a fashion identical to that used
in reference 13 to prepare a closely related compound.

4578 J . Org. Chem., Vol. 61, No. 14, 1996
Lampe et al.
in 22 mL of freshly distilled THF at -50 °C under nitrogen
was added 1 mL (2.48 mmol) of a 2.5 M solution of butyllithium
in hexanes over 5 min. The solution was stirred at -50 °C
for 6 h, after which a solution of 1,1-dimethylethyl 3,5-bis-
(benzyloxy)-4-formylbenzoate (8) (0.648 g, 1.55 mmol) in 10
mL THF was added dropwise. The mixture was stirred for
an additional 1 h at -50 °C and then was allowed to warm to
rt. After 16 h the reaction mixture was poured onto 50 mL of
EtOAc and 20 mL of water, and this mixture was stirred for
10 min. The layers were separated, and the organic phase
was washed with brine, dried over MgSO4, and evaporated to
give the crude product. Chromatography of the crude material
on silica gel eluting with 15-30% EtOAc-hexanes afforded
0.408 g (38%) of the title compound as a white foam. 1H NMR
(CDCl3) δ 1.20 (s, 3H), 1.27 (br s, 3H), 1.63 (s, 9H), 3.26-3.29
(d, 1H, J ) 7.9), 3.33-3.37 (d, 1H, J ) 12.6), 4.67-5.01 (m,
6H), 6.72-6.75 (d, 2H, J ) 8.2), 6.87-6.89 (d, 2H, 8.4), 6.92-
6.95 (d, 1H, 7.9), 7.11-7.33 (m, 17H). HRMS: calcd for
C44H46NO7: 700.3274, found 700.3273. Anal. Calcd for
C44H45NO7‚0.5H2O: C, 74.55; H, 6.54; N, 1.98. Found: C,
74.44; H, 6.55; N, 2.27.
9.2 mL (23 mmol) of a 2.5 M solution of n-butyllithium in
hexanes over 10 min. The solution was stirred at -72 °C for
15 min, after which TLC analysis still showed the presence of
some starting material. An additional 0.45 mL of n-butyl-
lithium was added, and the mixture was stirred at -72 °C for
45 min. The reaction was quenched at low temperature by
the addition of 50 mL of saturated NH4Cl, and the mixture
was allowed to warm to rt. The reaction mixture was poured
onto 500 mL of ether and washed with water and brine, dried
over MgSO4, and evaporated to give 15.28 g of the crude
product. Chromatography of the crude material on silica gel
eluting with 3/1 hexane-EtOAc afforded 6.32 g (51%) of the
title compound as a white solid. An analytical sample was
obtained by recrystallization from EtOAc-hexane, mp 113-
116 °C. IR (KBr) 1709, 1644, 1583, 1421 cm-1
.
1H NMR
(CDCl3) δ 1.66 (s, 9H), 3.30 (t, 1H, J ) 8), 4.26 (d, 2H, J ) 8),
4.73 (s, 6H), 6.82 (d, 2H, J ) 7), 6.93 (d, 1H, J ) 8), 6.97 (d,
1H, J ) 8), 7.06-7.09 (m, 6H), 7.17 (t, 2H, J ) 7), 7.27-7.29
(m, 7H), 7.40 (t, 1H, J ) 8). Anal. Calcd for C40H38O7: C,
76.17; H, 6.07. Found: C, 75.97; H, 6.26.
1,1-Dim eth yleth yl 3,5-Bis(ben zyloxy)-4-[6-(ben zyloxy)-
2-for m ylben zoyl]ben zoa te (15). To a solution of 6.21 g (9.85
mmol) of 1,1-dimethylethyl 3,5-bis(benzyloxy)-4-[6-(benzyloxy)-
2-(hydroxymethyl)benzoyl]benzoate (9) in 100 mL of DMF was
added 11.11 g (29.5 mmol) of PDC. The solution was stirred
at rt under a nitrogen atmosphere for 8 h, after which it was
poured onto 1 L of ether and washed with 500 mL each of
water, 0.2 M HCl, and brine and dried over MgSO4. Evapora-
tion of the solvent afforded 6.03 g (97%) of the crude product.
This material was sufficiently pure for further use. An
analytical sample was obtained by recrystallization from
EtOAc-hexane to give the title compound as a white solid,
3-Ben zyloxy-2-br om oben zyl Alcoh ol (13). To a solution
of 10.24 g (47.1 mmol) of 3-(benzyloxy)benzyl alcohol (2) in 150
mL of toluene at -10 °C under nitrogen was added 46 mL
(115 mmol) of a 2.5 M solution of butyllithium in hexanes over
15 min. The solution was stirred at -5 °C for 6 h, after which
it was cooled to -78 °C, and 11.5 mL (25.0 g, 96.3 mmol) of
1,2-dibromo-1,1,2,2-tetrafluoroethane was added. The mixture
was allowed to warm to rt. After 16 h the reaction mixture
was poured onto 500 mL of ether and 250 mL of saturated
aqueous NH4Cl, and this mixture was stirred for 1 h. The
layers were separated, and the organic phase was washed with
brine, dried over MgSO4, and evaporated to give the crude
product. Recrystallization of the crude material from EtOAc-
hexane afforded 7.05 g (51%) of the title compound as a white
mp 138-139 °C. IR (KBr) 1700, 1652, 1581 cm-1 1H NMR
.
(CDCl3) δ 1.65 (s, 9H), 4.77 (s, 2H), 4.80 (s, 4H), 6.85 (d, 2H,
J ) 7.5), 7.07-7.13 (m, 7H), 7.17 (t, 2H, J ) 7.5), 7.25-7.28
(m, 7H), 7.41-7.48 (m, 2H), 9.89 (s, 1H). Anal. Calcd for
C40H36O7: C, 76.42; H, 5.77. Found: C, 76.42; H, 5.70.
Meth yl 4-[6-(Ben zyloxy)-2-ca r boxyben zoyl]ben zoa te.
To a solution of 0.63 g (1.7 mmol) of methyl 4-[6-(benzyloxy)-
2-(hydroxymethyl)benzoyl]benzoate (3) in 20 mL of DMF was
added 4.41 g (11.7 mmol) of PDC. The solution was stirred at
rt under a nitrogen atmosphere for 4 days, after which it was
poured onto 300 mL of ether, washed with 200 mL of water,
150 mL of 2 M HCl, and 150 mL of brine, and dried over
MgSO4. Evaporation of the solvent afforded 0.47 g (72%) of
the title compound as a glass. 1H NMR (CDCl3) δ 3.96 (s, 3H),
5.04 (s, 2H), 7.02-7.06 (m, 2H), 7.21-7.27 (m, 4H), 7.47 (t,
1H, J ) 8), 7.72 (d, 1H, J ) 8), 7.83 (d, 2H, J ) 8), 8.08 (d, 2H,
J ) 8). HRMS: calcd for C23H19O6: 391.1182, found 391.1184.
3-(Ben zyloxy)-2-[2,6-b is(b en zyloxy)-4-[(1,1-d im et h yl-
eth oxy)ca r bon yl]ben zoyl]ben zoic Acid (16). To a solution
of 5.98 g (9.51 mmol) of 1,1-dimethylethyl 3,5-bis(benzyloxy)-
4-[6-(benzyloxy)-2-formylbenzoyl]benzoate (15) in 75 mL of dry
pyridine was added 5.17 g (14.3 mmol) of tetrabutylammonium
permanganate. The solution was stirred at rt under a nitrogen
atmosphere for 24 h. An additional 2.60 g of tetrabutyl-
ammonium permanganate was added, and the mixture was
stirred for 20 h more. The mixture was then poured onto 1 L
of ether, washed with 500 mL of cold half-saturated NaHSO3,
two 500 mL portions of cold 2 M HCl, and brine, and dried
over MgSO4. Evaporation of the solvent afforded 6.11 g (100%)
of the crude product. This material was sufficiently pure for
further use. An analytical sample was obtained by recrystal-
lization from 2-propanol to give the title compound as a tan
solid, mp 123-124 °C. IR (KBr) 1699, 1660, 1458 cm-1 1H
.
NMR (CDCl3) δ 2.06 (t, 1H, J ) 7), 4.79 (d, 2H, J ) 7), 5.19 (s,
2H), 6.91 (dd, 1H, J ) 1.5, 7.5), 7.13 (dd, 1H, J ) 1.5, 7.5),
7.27 (t, 1H, J ) 7.5), 7.34-7.44 (m, 3H), 7.48-7.51 (m, 2H).
Anal. Calcd for C14H13BrO2: C, 57.36; H, 4.47. Found: C,
57.11; H, 4.42.
1,1-Dim eth yleth yl 2-Br om o-3-(ben zyloxy)ben zyl 2,5-
Bis(ben zyloxy)-1,4-d iben zoa te (14). To a solution of 10.37
g (23.6 mmol) of 2,6-bis(benzyloxy)-4-[(1,1-dimethylethoxy)-
carbonyl]benzoic acid (6) in 100 mL of CH2Cl2 at 0 °C under
nitrogen was added 0.05 mL of DMF and 14.5 mL (29.0 mmol)
of a 2.0 M solution of oxalyl chloride in CH2Cl2. The solution
was stirred at rt for 3 h, after which the solvent was
evaporated, and the residue was evaporated twice from 30 mL
of CH2Cl2 to afford crude acid chloride 7 as a tan solid.
A solution of 6.96 g (23.7 mmol) of 3-(benzyloxy)-2-bromo-
benzyl alcohol (13) in 100 mL of THF at 0 °C under nitrogen
was treated with 28.8 mL (28.8 mmol) of a 1.0 M solution of
potassium tert-butoxide in THF. To this mixture was added
a solution of the above acid chloride in 50 mL of THF. After
45 min the reaction mixture was poured onto 500 mL of ether
and washed with 250 mL each of saturated aqueous NH4Cl
and brine. The organic phase was dried over MgSO4, stirred
with 10 g each of silica gel and alumina, and evaporated to
give 13.63 g (81%) of the title compound as a white solid, mp
116-118 °C. IR (KBr) 1744, 1709, 1580, 1423 cm-1 1H NMR
.
(CDCl3) δ 1.58 (s, 9H), 5.15 (s, 2H), 5.17 (s, 4H), 5.48 (s, 2H),
6.83 (dd, 1H, J ) 1.6, 8), 6.93 (t, 1H, J ) 8), 7.04 (dd, 1H, J )
1.6, 8), 7.27 (s, 2H), 7.30-7.42 (m, 13H), 7.46-7.48 (m, 2H).
Anal. Calcd for C40H37BrO7: C, 67.70; H, 5.26. Found: C,
67.71; H, 5.31.
solid, mp 165-167 °C. IR (KBr) 3470, 1709, 1664, 1578 cm-1
.
1H NMR (CDCl3) δ 1.62 (s, 9H), 4.46-5.23 (m, 6H), 6.79 (m,
1H), 6.93-7.03 (m, 4H), 7.11-7.32 (m, 10H), 7.33-7.41 (m,
5H), 8.42 (s, 1H). Anal. Calcd for C40H36O8: C, 74.52; H, 5.63.
Found: C, 74.74; H, 5.64.
1,1-Dim eth yleth yl 3,5-Bis(ben zyloxy)-4-[6-(ben zyloxy)-
2-(h yd r oxym eth yl)ben zoyl]ben zoa te (9). To a solution of
13.53 g (19.1 mmol) of 1,1-dimethylethyl 2-bromo-3-(benzyl-
oxy)benzyl 2,5-bis(benzyloxy)-1,4-dibenzoate (14) in 150 mL
of freshly distilled THF at -72 °C under nitrogen was added
1,1-Dim eth yleth yl 4-[6-(Ben zyloxy)-2-[(ben zyloxy)ca r -
bon yl]ben zoyl]-3,5-bis(ben zyloxy)ben zoa te (17). To a
solution of 5.98 g (9.28 mmol) of 3-(benzyloxy)-2-[2,6-bis-
(benzyloxy)-4-[(1,1-dimethylethoxy)carbonyl]benzoyl]benzoic acid
(16) in 75 mL of dry DMF were added 3.85 g (27.9 mmol) of
K2CO3 and 1.21 mL (1.74 g, 10.2 mmol) of benzyl bromide.
The solution was stirred at rt under a nitrogen atmosphere
(30) (a) Kulanthaivel, P.; J anzen, W. P.; Ballas, L. M.; J iang, J .; Hu,
C.; Darges, J . W.; Seldin, J .; Cofield, D.; Adams, L. Planta Medica 1995,
61, 41-44. (b) Kashiwada, Y.; Huang, L.; Ballas, L. M.; J iang, J . B.;
J anzen, W. P.; Lee, K.-H. J . Med. Chem. 1994, 37, 195-200.

Total Synthesis of (-)- and (+)-Balanol
J . Org. Chem., Vol. 61, No. 14, 1996 4579
for 13 h. The mixture was then poured onto 800 mL of water
and extracted with three 400 mL portions of ether. The
organic extracts were washed twice with water and then with
brine and dried over MgSO4. Evaporation of the solvent
afforded 6.76 g of the crude product, which was chromato-
graphed on silica gel, eluting with 4/1 hexane-EtOAc to give
4.98 g (73%) of the title compound as a colorless oil. IR (KBr)
Met h od B: To a solution of N-benzyl-2-oxo-3-(phenyl-
selenyl)azepane (6.0 g, 16.74 mmol) in THF (100 mL) was
added a solution of NaIO4 (13.6 g, 63.62 mmol) in MeOH:H2O
(7:3, 350 mL). The resulting mixture was stirred at rt for 72
h. Upon removal of volatiles, the crude material was flash
chromatographed (silica gel, 80% hexane/EtOAc) to afford the
product as a light brown oil (3.25 g, 97%).
1716, 1668, 1580, 1456 cm-1 1H NMR (CDCl3) δ 1.64 (s, 9H),
.
N-Ben zyl-cis-3,4-d ih yd r oxy-2-oxoa zep a n e (22). N-Ben-
zyl-2-oxoazep-3-ene (21) (6.9 g, 34.3 mmol) was added in
acetone (10 mL) to a mixture of osmium tetraoxide (95 mg,
0.38 mmol) and N-methylmorpholine N-oxide (6.02 g, 51.4
mmol, 8.9 mL of 60% aqueous solution) in tert-butyl alcohol
(20 mL) and acetone (20 mL). After 4 h, TLC showed almost
complete reaction (starting material Rf ) 0.57, product Rf )
0.47 in 100% EtOAc). After 1.5 d, more N-methylmorpholine
N-oxide (2 mL of 60% solution) was added but no further
reaction appeared to take place by TLC. The reaction mixture
was concentrated and the residue chromatographed (7 × 12
cm, 100% EtOAc) to give the product (7.8 g, 97%). The product
was recrystallized from EtOAc/hexanes to give white crystals
(6.3 g, 78%), mp 87-88 °C. 1H-NMR (CDCl3) δ 1.45-1.56 (1H,
m), 1.6-1.8 (2H, m), 2.03-2.08 (1H, m), 2.63 (1H, br s), 3.17-
3.36 (2H, m), 4.14 (1H, br s), 4.46 (1H, d, J ) 4), 4.63 (1H, d,
J ) 15), 4.72 (1H, d, J ) 15), 4.76 (1H, d, J ) 4), 7.21-7.35
4.74 (s, 2H), 4.80 (s, 4H), 5.15 (s, 2H), 6.89 (d, 2H, J ) 7), 6.96
(dd, 1H, J ) 1.7, 7.6), 7.07-7.16 (m, 8H), 7.20-7.32 (m, 14H).
Anal. Calcd for C47H42O8‚0.5H2O: C, 75.89; H, 5.83. Found:
C, 75.97; H, 5.76.
4-[6-(Ben zyloxy)-2-[(ben zyloxy)ca r bon yl]ben zoyl]-3,5-
bis(ben zyloxy)ben zoic Acid (18). A solution of 0.428 g
(0.582 mmol) of 1,1-dimethylethyl 4-[6-(benzyloxy)-2-[(benzyl-
oxy)carbonyl]benzoyl]-3,5-bis(benzyloxy)benzoate (17) in 5 mL
of distilled quinoline was heated at 200 °C under nitrogen for
3 h. The mixture was then cooled, poured onto 75 mL of ether,
and washed three times with 2 N HCl and once with brine.
The organic extracts were dried over MgSO4 and evaporated
to give 0.42 g of the crude product, which was recrystallized
from 2-propanol to give 0.270 g (68%) of the title compound
as a tan solid, mp 151-156 °C. IR (KBr) 3433, 1718, 1654,
1582, 1425 cm-1 1H NMR (CDCl3) δ 4.72 (s, 2H), 4.80 (s, 4H),
.
5.14 (s, 2H), 6.85 (d, 2H, J ) 7), 6.97 (d, 1H, J ) 8), 7.05-7.08
(m, 4H), 7.13 (t, 2H, J ) 8), 7.18-7.34 (m, 16H). Anal. Calcd
for C43H34O8‚H2O: C, 74.12; H, 5.21. Found: C, 73.74; H, 5.24.
(5H, m). IR (KBr) 3438, 3387, 1623 cm-1
. Anal. Calcd for
C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.37; H,
7.40; N, 5.89.
N -B e n zy l-ci s-4-(b e n zo y lo x y )-3-h y d r o x y -2-o x o a ze -
p a n e (23). N-Benzyl-cis-3,4-dihydroxy-2-oxoazepane (22, 4.17
g, 17.7 mmol) was dissolved in CH2Cl2 (20 mL) and treated
with trimethyl orthobenzoate (4.84 g, 26.6 mmol) followed by
BF3 etherate (110 µL, 886 µmol). The mixture was stirred at
rt for 2 h and then treated with water (20 mL) and stirred for
30 min. The mixture was partitioned between EtOAc and
brine (50 mL each). The organic layer was removed, dried
(MgSO4), and concentrated to an oil. The oil was dissolved in
CH2Cl2 (10 mL) and treated with DBU (132 µL, 886 µmol).
The mixture was then poured onto a silica gel column (7 × 14
cm, packed in and eluted with 40% EtOAc in hexanes) and
chromatographed to give, after concentration, the product as
a white solid. The product was recrystallized from EtOAc/
hexanes to give white crystals (4.32 g, 72%), mp 113-114 °C.
1H-NMR (CDCl3) δ 1.4-1.65 (2H, m), 1.8-1.95 (1H, m), 2.36-
2.42 (1H, m), 3.36-3.51 (2H, m), 4.58-4.65 (3H, m), 4.93 (1H,
d, J ) 15), 5.46 (1H, m), 7.2-7.3 (3H, m), 7.31-7.39 (2H, m),
7.45 (2H, pseudo t, J ) ≈7), 7.58 (1H, t, J ) 7), 8.00 (2H, d, J
N-Ben zyl-2-oxoa zep a n e (20). To a 0 °C suspension of
NaH (80% in mineral oil, 10.1 g, 0.34 mol, prewashed with
hexane (30 mL × 2)) in THF (100 mL) was added a solution of
2-oxoazepane (34.7 g, 0.3 mol) in THF (450 mL) through an
addition funnel at such a rate that H2 generation remained
gentle. The reaction mixture was allowed to warm up to rt
for 2 h prior to the addition of benzyl bromide (55 g, 35 mL,
0.32 mol). The resulting mixture was stirred at rt for ad-
ditional 2 h. The sodium bromide was filtered and rinsed with
EtOAc. The combined filtrate was concentrated and crystal-
lized in EtOAc/hexane to afford a white solid (60 g, 96%), mp
54-56 °C. IR (KBr) 1625, 1493, 1453 cm-1 1H NMR (CDCl3)
.
δ 1.46 (m, 2H), 1.68 (m, 4H), 2.59 (dd, J ) 4.3, 6.3, 2H), 3.28
(t, J ) 5, 2H), 4.57 (s, 2H), 7.27 (m, 5H). Anal. Calcd for
C13H17NO: C, 76.81; H, 8.43; N, 6.88. Found: C, 76.78; H,
8.45; N, 6.86.
N-Ben zyl-2-oxoa zep -3-en e (21). To a cooled solution (-45
°C) of N-benzyl-2-oxoazepane (20, 101.6 g, 0.5 mol) in THF
(350 mL) was added LHMDS (1.0 M solution in THF, 1 L, 1.0
mol). The mixture was allowed to warm up to 0 °C for 30 min
and cooled to -45 °C while a solution of PhSeCl (96 g, 0.501
mol) in THF (150 mL) was added. The resulting mixture was
warmed up to rt over 5 h and then poured into 1 N HCl (400
mL). The THF layer was separated. The aqueous was
extracted with EtOAc (200 mL × 2). The combined organic
layer was washed with brine, dried (MgSO4), concentrated, and
diluted with hexane to precipitate N-benzyl-2-oxo-3-(phenyl-
selenyl)azepane as a while solid (142.7 g, 80%), mp 97-98 °C.
) 7). IR (KBr) 3386, 1707, 1642 cm-1. Anal. Calcd for C20H21
-
NO4: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.70; H, 6.27; N,
4.00.
N-Ben zyl-tr a n s-4-(ben zoyloxy)-3-a zid o-2-oxoa zep a n e
(24). N-Benzyl-cis-4-(benzoyloxy)-3-hydroxy-2-oxoazepane (23,
2.0 g, 5.89 mmol) and 2,6-lutidine (757 mg, 840 µL, 7.07 mmol)
were dissolved in CH2Cl2 (20 mL), cooled in an ice bath, and
treated with triflic anhydride (1.83 g, 1.09 mL, 6.48 mmol).
TLC analysis (silica gel, 1/4 EtOAc/hexanes-eluted twice)
showed instantaneous, though incomplete, formation of the
desired triflate (starting material Rf ) 0.06, triflate Rf ) 0.29).
After stirring for 16 h, with no further reaction, the mixture
was recooled and treated with 2,6-lutidine (380 mg, 420 µL,
3.5 mmol) followed by triflic anhydride (0.91 g, 0.54 mL, 3.2
mmol). TLC immediately showed complete reaction. Sodium
azide (3.8 g, 58.9 mmol), slurried in methanol (50 mL), was
added followed by benzyltrimethylammonium bromide (40
mg). TLC analysis (as above) showed very slow formation of
the azide product (azide Rf ) 0.32), so the mixture was treated
with DMF (5 mL), concentrated to ≈20 mL, and stirred for 3
d. TLC analysis showed complete reaction. The mixture was
partitioned between ether and water (50 mL each). The
aqueous layer was washed with ether (50 mL), and the
combined organic layers were washed with brine (30 mL),
dried (MgSO4), and concentrated. The residue was chromato-
graphed (silica gel, 7 × 13 cm, 1/4 EtOAc/hexanes) to give clean
azide as an oil (1.86 g, 87%). 1H-NMR (CDCl3) δ 1.4-1.65 (2H,
m), 1.45-1.70 (2H, m), 1.91-2.12 (2H, m), 3.29-3.38 (1H, m),
3.61-3.68 (1H, m), 4.49 (1H, d, J ) 14), 4.65 (1H, d, J ) 8),
4.82 (1H, d J ) 14), 5.33 (1H, m), 7.26-7.32 (5H, m), 7.45 (2H,
IR (KBr) 1634, 1476 cm-1 1H NMR (CDCl3) δ 1.48-1.62 (m,
.
2H), 1.80 (m, 1H), 1.99-2.19 (m, 3H), 3.33 and 3.48 (m and
m, 1H and 1H), 4.35 (m, 1H), 4.60 (m, 2H), 7.29 (m, 8H), 7.59
(m, 2H). Anal. Calcd for C19H21NOSe: C, 63.37; H, 5.91; N,
3.91. Found: C, 63.40; H, 5.90; N, 3.87.
Met h od A: To a solution of N-benzyl-2-oxo-3-(phenyl-
selenyl)azepane (142.7 g, 0.398 mol) in CH2Cl2 (500 mL) was
added pyridine (65 mL, 0.804 mol), followed by H2O2 (10%, 50
mL) dropwise. The mixture was heated to reflux at which time
additional H2O2 (10%, 100 mL) was added dropwise. After
cooling to rt, the CH2Cl2 layer was separated, washed with
saturated NaHCO3 (300 mL × 3), 1 N HCl (300 mL × 3), and
brine, dried (MgSO4), and concentrated. The crude material
was flash chromatographed (silica gel, 80% hexane/EtOAc) to
afford the product as a light brown oil (78.4 g, 98%). IR (neat)
1650, 1602 cm-1
.
1H NMR (CDCl3) δ 1.79 (m, 2H), 2.29 (m,
2H), 3.31 (m, 2H), 4.67 (s, 2H), 6.05 (d, 1H, J ) 13.6), 6.21 (m,
1H), 7.31 (m, 5H). Anal. Calcd for C13H15NO‚0.1H2O: C,
76.89; H, 7.54; N, 6.89. Found: C, 76.76; H, 7.56; N, 6.96.

4580 J . Org. Chem., Vol. 61, No. 14, 1996
Lampe et al.
pseudo t, J ) ≈7), 7.59 (1H, t, J ) 7), 8.02 (2H, d, J ) 7). IR
fractions were each again chromatographed on a silica column
(41.4 mm ID × 30 cm length) using a linear gradient from
20% to 60% B (A ) hexanes, B ) 10% triethylamine in EtOAc)
over 60 m at 25 mL/min. The clean upper HPLC fractions
from the upper and mixed runs were combined (490 mg) for
hydrolysis. 1H-NMR (CDCl3) δ 1.6-1.8 (2H, m), 1.94 (2H, m),
2.48 (1H, m), 2.77 (1H, m), 2.9-3.0 (2H, m), 3.50 (1H, d, J )
13), 3.54 (3H, s), 3.72 (1H, d, J ) 13), 4.1-4.2 (1H, m), 5.14
(2H, s), 5.28 (1H, m), 6.84-7.65 (14H, m).
The clean lower HPLC fractions from the lower run were
combined (260 mg) for hydrolysis. 1H-NMR (CDCl3) δ 1.64-
1.8 (2H, m), 1.8-1.94 (2H, m), 2.53 (1H, m), 2.77 (1H, m), 2.9-
3.0 (2H, m), 3.50 (1H, d, J ) 13), 3.52 (3H, s), 3.72 (1H, d, J )
13), 4.1 (1H, m), 5.13 (2H, s), 5.28 (1H, m), 6.84-7.54 (14H,
m).
The upper ester (490 mg, 0.76 mmol) was dissolved in
methanol (5 mL) and treated with 85% KOH (97 mg, 1.52
mmol) dissolved in methanol (5 mL) and stirred for 16 h. The
mixture was treated with water (15 mL) and extracted with
CH2Cl2 (2 × 25 mL). The organic layer was concentrated and
chromatographed (2.5 × 10 cm, EtOAc) to give the chiral
alcohol 26a (266 mg) as an oil.
The lower ester (260 mg, 0.40 mmol) was dissolved in
methanol (5 mL) and treated with 85% KOH (53 mg, 0.8 mmol)
dissolved in methanol (5 mL) and stirred for 48 h. The mixture
was treated with water (15 mL) and extracted with CH2Cl2 (2
× 25 mL). The organic layer was concentrated and chromato-
graphed (2.5 × 10 cm, EtOAc) to give the chiral alcohol 26b
(154 mg) as an oil.
(KBr) 3063, 2941, 1719, 1655 cm-1
.
Anal. Calcd for
C20H20N4O3: C, 65.92; H, 5.53; N, 15.37. Found: C, 66.07; H,
5.62; N, 15.51.
N-Ben zyl-tr a n s-4-h ydr oxy-3-[4-(ben zyloxy)ben zam ido]-
a zep a n e (26). N-Benzyl-trans-4-(benzoyloxy)-3-azido-2-oxo-
azepane (24, 1.7 g, 4.6 mmol) was dissolved in THF (20 mL)
in a flask equipped with an overhead stirrer. LiAlH4 (14.9
mL of a 1 M solution in THF, 14.9 mmol) was added dropwise
and the mixture heated to reflux for 1 h. The mixture was
cooled to rt and treated with water (566 µL), 15% NaOH (566
µL), and water (1.7 mL) with stirring for 30 m after the first
two additions and for 16 h after the third. The solid was
filtered off and the solution treated with 12 N HCl (870 µL) in
methanol and concentrated to give azepane 25 as an amber
oil. The oil was treated with CH2Cl2 (20 mL), 1 N NaOH (5
mL), Na2CO3 (1.96 g, 23.3 mmol), water (20 mL), and p-
(benzyloxy)benzoyl chloride (1.72 g, 7.0 mmol) in CH2Cl2 (15
mL) and stirred vigorously for 16 h. The mixture was then
extracted with EtOAc (2 × 50 mL), and the combined organic
layers were washed with brine, dried (MgSO4), and concen-
trated to an oil. The oil was chromatographed (silica gel, 4.1
× 15 cm, 19/1 CH2Cl2/methanol) to give the product as a glass
(1.1 g, 55% from 24). The product was triturated in ether to
give white crystals, mp 119-120 °C. 1H NMR (CDCl3) δ 1.60-
1.95 (m, 4H), 2.50 (td, J ) 3.8, 9.4, 1H), 2.73 (dd, J ) 2.0,
14.4, 1H), 2.93 (dd, J ) 2.6, 14.4, 1H), 3.02 (m, 1H), 3.41 (d, J
) 12.9, 1H), 3.74 (d, J ) 12.9, 1H), 3.78 (dddd, J ) 8.7, 2.9,
2.6, and 2.0, 1H), 3.87 (m, 1H), 5.13 (s, 2H), 6.54 (d, J ) 8.7,
1H), 6.94 (d, J ) 6.6, 2H), 7.30-7.47 (m, 12H); IR (KBr) 3419,
3356, 1623 cm-1. Anal. Calcd for C27H30N2O3: C, 75.32; H,
7.02; N, 6.50. Found: C, 75.52; H, 7.20; N, 6.43.
(()-Ba la n ol ((()-1). A solution of 84 mg (0.12 mmol) of
4-[6-(benzyloxy)-2-[(benzyloxy)carbonyl]benzoyl]-3,5-bis(ben-
zyloxy)benzoic acid (18) in 2 mL of CH2Cl2 containing a trace
(approximately 0.5 µL) of DMF was cooled to 0 °C. Oxalyl
chloride (11.9 µL, 0.136 mmol) was added, and the mixture
was stirred under a nitrogen atmosphere for 1.5 h. An
additional 11.9 µL of oxalyl chloride was added, and the
mixture was stirred for an additional 1.5 h. The reaction
mixture was evaporated, and the residue was evaporated twice
from 15 mL of CH2Cl2. The residue was dissolved in 2 mL of
CH2Cl2, and was added to a solution of 59.1 mg (0.137 mmol)
of trans-N-benzyl-3-[4-(benzyloxy)benzamido]-4-hydroxyazepane
(26), 19.0 µL (0.136 mmol) of triethylamine, and 3 mg of DMAP
in 1.5 mL of CH2Cl2 at 0 °C. The mixture was stirred at rt
under a nitrogen atmosphere for 22 h, after which it was
diluted with 30 mL of CH2Cl2, washed with saturated NaHCO3
and brine, dried over MgSO4, and evaporated to give 139 mg
of the crude product. Chromatography on silica gel eluting
with 6/4 hexane-EtOAc gave 89.4 mg (66%) of the ester as a
yellow oil, which was used directly in the deprotection step.
A solution of 65 mg (0.060 mmol) of the ester in 30 mL of
1/2/2 methanol-ethanol-CH2Cl2 was treated with 17 µL of
TFA and evaporated. The residue was dissolved in 12 mL of
3/1 ethanol-methanol, 15.6 mg of moist 10% palladium
hydroxide on carbon was added, and the mixture was shaken
on a Parr apparatus under 50 psi of hydrogen for 5 h. The
mixture was filtered and evaporated, and the residue was
chromatographed on a 21 × 250 mm C18 column (solvent A:
95:5 water/acetonitrile + 0.1% TFA; solvent B: 100% aceto-
nitrile; gradient: 0-100% B over 60 min, flow: 15 mL/min).
The pure fraction was evaporated and then lyophilized from
water to give 11.2 mg (33%) of the title compound as a yellow
fluffy solid, which was identical with natural balanol by IR,
1H NMR, 13C NMR, FABMS, and HPLC.
(-)-Ba la n ol ((-)-1). This material was prepared in 37%
overall yield as a pale yellow powder from benzophenone 18
and amido alcohol 26a in an identical fashion to that described
for (()-1, with the exception that the hydrogenolysis was
carried out at atmospheric pressure. This compound was
identical with natural balanol by IR, 1H NMR, and TLC. [R]25
) -104° (c ) 0.111, methanol).
D
(+)-Ba la n ol ((+)-1). This material was prepared in 22%
overall yield as a pale yellow powder from benzophenone 18
and amido alcohol 26b in an identical fashion to that described
for (()-1, with the exception that the hydrogenolysis was
carried out at atmospheric pressure. This compound was
identical with natural balanol by IR, 1H NMR, and TLC. [R]25
) +97.8° (c ) 0.319, methanol).
D
(-)-(R)-3-Am in o-(S)-4-h yd r oxy-2-oxoa zep a n e Hyd r o-
ch lor id e (30). Hydroxylysine dihydrochloride (28) (4 g, 17
mmol) was added as a powder to hexamethyldisilizane (17.9
mL, 13.7 g, 85.1 mmol) in xylenes (200 mL), and the mixture
was heated to reflux. After heating for 2 h, the now homoge-
neous reaction mixture was treated with 2-propanol (5 mL, 4
g, 66 mmol) via syringe pump over 6 h. After 2 days at reflux,
TLC analysis (9:1 MeOH:NH4OH) showed complete reaction
(starting material Rf ) 0.13, product Rf ) 0.43, epimeric
product Rf ) 0.35). The reaction mixture was allowed to cool
and treated with 1 N HCl (50 mL) and stirred for 1 h. The
aqueous layer was removed and the organic layer washed
again with 1 N HCl (50 mL). The combined aqueous layers
were concentrated to a glass. Crude NMR indicated a 13:1
ratio of desired to epimerized product. The glass was added
to a cation exchange resin (AG50-X8, 200-400 mesh, H+ form,
2.5 × 27 cm) and eluted with 1 N HCl. The product eluted in
35 mL fractions 16-26, followed by the epimeric byproduct.
The active fractions were combined and concentrated to a
glass. The glass was slurried in minimal methanol, triturated
with 2-propanol, and stirred overnight. The resulting powder
was filtered off under nitrogen, washed with 2-propanol, and
dried under nitrogen flow to give the title compound (2.7 g,
79% based on 0.4 molar equiv of NH4Cl contamination) as a
white powder. 1H-NMR (D2O) δ 1.5-1.65 (1H, m), 1.75-1.95
(2H, m), 2.25-2.35 (1H, m), 3.25-3.35 (2H, m), 3.77 (1H, dt,
J ) 3.8, 10.5), 4.33 (1H, d, J ) 10.5); 13C-NMR (D2O) δ 26.0,
37.1, 40.9, 57.5, 66.2, 66.5 (dioxane reference), 170.2; IR (KBr)
Resolu tion of N-Ben zyl-tr a n s-4-h yd r oxy-3-[4-(ben zyl-
oxy)ben za m id o]a zep a n e (26a a n d 26b). N-Benzyl-trans-
4-hydroxy-3-[4-(benzyloxy)benzamido]azepane (26, 1.2 g, 2.79
mmol), DMAP (4 mg, 0.3 mmol), and triethylamine (2.25 g,
3.1 mL, 22.3 mmol) were dissolved in CH2Cl2 (10 mL) and
treated with (S)-Mosher’s acid chloride (1.8 g, 1.3 mL, 7 mmol).
When TLC indicated complete reaction, the mixture was
concentrated and chromatographed (7 × 15 cm, 3% triethyl-
amine in 4/1 EtOAc/hexanes). The products were separated
into clean upper, mixed, and clean lower fractions. All three
3428, 1673, 1490 cm-1; [R]25 ) -42° (c ) 0.61 in methanol,
D
corrected for NH4Cl contamination). A sample was obtained
from another reaction by first concentrating the xylenes before
workup to minimize the NH4Cl contamination in the product.

Total Synthesis of (-)- and (+)-Balanol
J . Org. Chem., Vol. 61, No. 14, 1996 4581
Anal. Calcd for C6H12N2O2‚HCl: C, 39.90; H, 7.25; N, 15.51.
Found: C, 39.89; H, 7.11; N, 15.16.
(100%, M+ + 1), 385 (68%, M+ + 1 - C4H8), 341 (35%, M+
+
1 - CO2 - C4H8). Anal. Calcd for C25H32N2O5: C, 68.16; H,
(-)-(R)-3-Am in o-(R)-4-h yd r oxya zep a n e Dih yd r och lo-
r id e (29). (-)-(R)-3-Amino-(S)-4-hydroxy-2-oxoazepane hy-
drochloride (30) (2 g of 89.4% product with NH4Cl, 9.9 mmol)
was slurried in THF (30 mL), treated with borane (1 M in THF,
55 mL, 55 mmol) slowly, and then heated to reflux for 18 h.
TLC analysis (9:1 MeOH:NH4OH) showed complete reaction
(starting material Rf ) 0.43, product Rf ) 0.15). The reaction
mixture was treated with methanol (40 mL) and concentrated
to an oil. The oil was dissolved in water (10 mL) and treated
with 1 N NaOH until pH ) 13 (≈20 mL). The mixture was
then treated with 3 N HCl (20 mL). Both additions elicited
gas evolution. The aqueous solution was added to a cation
exchange resin (AG50-X8, 200-400 mesh, H+ form, 2.5 × 27
cm) and eluted with water and 1 N HCl (≈200 mL ea.), and
the product was eluted with 3 N HCl. The active fractions
were concentrated to a glass. The glass was slurried in
minimal methanol, triturated with 2-propanol, and stirred
overnight. The resulting powder was filtered off under
nitrogen, washed with 2-propanol, and dried under nitrogen
flow to give the title compound (1.34 g, 67%) as a white powder,
mp 175-180 °C. 1H-NMR (D2O) δ 1.70-1.95 (2H, m), 2.00-
2.10 (1H, m), 2.2-2.3 (1H, m), 3.25-3.42 (3H, m), 3.5-3.65
(2H, m), 3.8-3.9 (1H, m); 13C-NMR (D2O) δ 18.4, 31.8, 42.1,
45.9, 53.3, 66.5 (dioxane reference), 71.1; IR (KBr) 3419, 2953,
1619 cm-1; [R]25D ) -19.3° (c ) 0.171 in CH3OH). Anal. Calcd
for C6H14N2O‚2HCl: C, 35.48; H, 7.94; N, 13.79. Found: C,
35.27; H, 8.22; N, 13.43.
N -(t er t -Bu t oxyca r b on yl)-(R )-3-[4-(b e n zyloxy)b e n z-
a m id o]-(R)-4-h yd r oxya zep a n e (31). (-)-(R)-3-Amino-(R)-
4-hydroxyazepane dihydrochloride (29) (150 mg, 738 µmol) was
dissolved in methanol (6 mL) and treated with 1 N NaOH (2.2
mL) and cooled in an ice bath. Di-tert-butyl dicarbonate (187
µL, 177 mg, 812 µmol) was added and the reaction mixture
stirred for 18 h. The mixture was concentrated, partitioned
between 1 N NaOH (5 mL) and CH2Cl2 (5 mL), treated with
p-(benzyloxy)benzoyl chloride (482 mg, 1.9 mmol) in CH2Cl2
(1 mL) and stirred vigorously for 16 h. The organic layer was
removed and chromatographed (2.5 × 15 cm, 1:1 EtOAc:
hexanes) and concentrated to give the product (217 mg, 66%)
as a glass. 1H-NMR (CDCl3) δ 1.47 (9H, s), 1.6-2.0 (4H, m),
2.70 (1H, dt, J ) 3.5, 15.5), 3.25 (1H, dd, J ) 5.2, 15.5), 3.76
(1H, m), 4.1 (3H, m), 5.09 (2H, s), 5.41 (1H, br s), 6.99 (2H, d
J ) 8.8), 7.3-7.42 (5H, m), 7.84 (2H, d, J ) 8.8), 8.91 (1H, d,
J ) 5.4); 13C-NMR (CDCl3) δ 27.9, 29.0, 33.4, 50.5, 51.1, 61.3,
70.6, (77.2, 77.6, 78.1 - CDCl3), 80.4, 81.4, 115.2, 126.4, 128.1,
128.7, 129.2, 129.7, 137.0, 157.9, 162.1, 169.0; IR (KBr) 3374,
2933, 1692, 1624, 1505 cm-1; mass spectrum (FAB) m/z 441
7.32; N, 6.36. Found: C, 68.45; H, 7.36; N, 6.42.
P r otected Ba la n ol 32. Balanol benzophenone 18 (367 mg,
542 mmol) was slurried in CH2Cl2 (2 mL) and treated with
DMF (1 drop) and oxalyl chloride (542 µL of 2 M CH2Cl2
solution, 137 mg, 1.08 mmol). After stirring for 1 h, the
homogeneous solution was concentrated under full vacuum to
give the acid chloride. N-(tert-Butoxycarbonyl)-(R)-3-[4-(ben-
zyloxy)benzamido]-(R)-4-hydroxyazepane (31) (217 mg, 492
µmol) was dissolved in CH2Cl2 (5 mL) and treated with
triethylamine (271 µL, 199 mg, 1.97 mmol) and DMAP (6 mg,
49 µmol) followed by the acid chloride in CH2Cl2 (2 mL). The
mixture was stirred 3 days and then directly chromatographed
(4.1 × 10 cm, 3:2 hexanes:EtOAc) to give the product (283 mg,
52%) as a glass. 1H-NMR (CDCl3) δ occurs as a ≈3:1 rotameric
mixture 1.4-2.1 (4H, m’s), 1.54 and 1.57 (≈1:3 9H, s), 2.8 (1H,
m), 3.31 (1H, m), 3.9-4.1 (2H, m’s), 4.65 (2H, s), 4.8-4.9 (1H,
m), 4.81 (2H, s), 5.03, (2H, s), 5.08 (2H, s), 4.95-5.05 (1H, m),
6.8-7.4 (32H, m’s), 7.7 and 8.0 (2H, d’s).
(-)-Ba la n ol ((-)-1). Protected balanol 32 (280 mg, 254
µmol) was dissolved in EtOAc and ethanol (10 mL each),
treated with 20% palladium hydroxide on carbon (30 mg), and
put under hydrogen (balloon) for 16 h. The balloon was
recharged with hydrogen, additional catalyst (30 mg) was
added, and stirring was continued for 16 h. The reaction
mixture was flushed with nitrogen, filtered, and concentrated
to a solid. The solid was dissolved in TFA (1.5 mL) and stirred
at rt for 1 h. The mixture was concentrated, and the residue
was chromatographed on a C18 column (41 × 300 mm) using
a linear gradient from 100% A (0.1% TFA and 5% acetonitrile
in water) to 50% B (pure acetonitrile) over 60 m at 25 mL/
min. The clean product, which eluted in 37 min, was concen-
trated to remove acetonitrile and freeze-dried to give synthetic
(-)-balanol as a light yellow powder (132 mg, 76%). This
1
sample was identical to balanol by TLC, HPLC, and H-NMR.
mp ≈ 200 °C dec. Anal. Calcd for C28H26N2O10‚2H2O‚
1.25CF3CO2H: C, 50.25; H, 4.32; N, 3.84. Found: C, 50.03;
H, 4.42; N, 3.87. [R]25 ) -107° (c ) 0.252 in CH3OH).
D
Ack n ow led gm en t. We are indebted to Thomas
Mitchell for his assistance in the physical characteriza-
tion of the compounds in this study. We are grateful to
Robert Foglesong, Steve Hall, and our late colleague,
J eff Nichols, for many helpful discussions regarding this
work.
J O952280K