An asymmetric aminohydroxylation approach to the azepine core of (-)-balanol

Article abstract of DOI:10.1021/ol0061034

(equation presented) An efficient formal synthesis of the potent protein kinase C inhibitor (-)-balanol that relies on a modified asymmetric aminohydroxylation of the α,β-unsaturated aryl ester (1) is reported. The aryl ester functionality and the dihydroquinyl alkaloid ligand system (DHQ)₂-AQN are used to control the regio- and enantioselectivity of the process.

Full text of DOI:10.1021/ol0061034

ORGANIC
LETTERS
2000
Vol. 2, No. 17
2571-2573
An Asymmetric Aminohydroxylation
Approach to the Azepine Core of
(−)-Balanol
Craig E. Masse, Adam J. Morgan, and James S. Panek*
Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for
Science and Engineering Boston UniVersity, Boston, Massachusetts 02215
panek@chem.bu.edu
Received May 25, 2000
ABSTRACT
An efficient formal synthesis of the potent protein kinase C inhibitor (−)-balanol that relies on a modified asymmetric aminohydroxylation of
the r,â-unsaturated aryl ester (1) is reported. The aryl ester functionality and the dihydroquinyl alkaloid ligand system (DHQ)2−AQN are used
to control the regio- and enantioselectivity of the process.
(-)-Balanol (1, Figure 1), an unusual metabolite first isolated
from the fungus Verticillium balanoides1 in 1993 and again
in 1994 from another fungus, Fusarium merismoides,2 is a
agents for controlling inflammation, central nervous system
disorders, cardiovascular disorders, and even HIV infection.
Despite the fact that the selectivity of 1 for the known
PKC isoenzymes is low, it has displayed potent activity with
IC50 values in the 5-9 nM range5 for the R, â-I, â-II, γ, δ,
ꢀ, and η PKCs, making (-)-balanol an ideal lead structure.
The structure and absolute configuration of the natural
product were determined by NMR and X-ray crystallographic
analysis.1 These results showed an anti orientation of the
substituents at C3 and C4 and established the absolute
configuration as 3R,4R. A stereoview of an energy-minimized
(-)-balanol conformation illustrating its associated structural
elements is shown in Figure 1. Because of its potent
inhibitory properties, (-)-balanol has been the focus of
numerous synthetic efforts. Recently, Naito and co-workers
reported an approach to the azepine core which centered
(1) Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.; Janzen,
W. P.; Ballas, L. M.; Loomis, C. R.; Jiang, J. B.; Katz, B.; Steiner, J. R.;
Clardy, J. J. Am. Chem. Soc. 1993, 115, 6452-6453.
(2) Ohshima, S.; Yanagisawa, M. Katoh, A.; Fujii, T.; Sano, T.;
Matsukama, S.; Furumai, T.; Fujiu, M.; Watanabe, K.; Yokose, K.; Arisawa,
M.; Okuda, T. J. Antibiot. 1994, 47, 639-641.
Figure 1. Energy-minimized view of (-)-balanol.4
potent inhibitor of human protein kinase C (PKC). This
enzyme class plays a crucial role in signal transduction
pathways that lead to a variety of cellular responses including
gene expression and cellular proliferation.3 Consequently,
this family of enzymes represents a critical biological target
for the development of anticancer agents and therapeutic
(3) Nishizuka, Y. Science 1992, 258, 607-614. (b) Nishizuka, Y. Nature
1988, 334, 661-665.
(4) Three-dimensional modeling was carried out with Chem 3D Pro using
MM2 minimization techniques.
(5) Boros, C.; Hamilton, S. M.; Katz, B.; Kulanthaivel, P. J. Antibiot.
1994, 47, 1010-1016.
10.1021/ol0061034 CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/26/2000

around a SmI2-mediated intramolecular radical cyclization
of oxime ethers.6 This methodology afforded the azepine core
as a 6.6:1 mixture of diastereomers; however, the major
isomer required a lipase resolution at a later stage in the
synthesis. A racemic total synthesis of balanol was achieved
by Adams and co-workers in 1995 utilizing a ring expansion
of 3-bromopiperidin-4-ones to access the azepine core.7 The
Tanner group utilized a regio- and stereoselective opening
of a chiral epoxide to control the C3-C4 stereogenic centers
of the heterocycle.8 An asymmetric synthesis of balanol was
reported by Nicolaou and co-workers using D-serine and an
asymmetric allylation with [Ipc]2B-allyl to install the vicinal
amino alcohol functionality as a 12:1 mixture of diastereo-
mers.9 Hughes and Lampe utilized (2S,3R)-hydroxylysine as
a key synthon in their total synthesis of balanol.10 However,
the preparation of the hydroxylysine synthon required eight
steps, which resulted in a somewhat lengthy synthesis.
Additionally, a number of formal syntheses of the hexahy-
droazepine core 2 have been reported.11 It was our intention
to develop a streamlined approach to enantiomerically pure
2 which would make use of a modified aminohydroxylation
methodology to construct the (2R,3S)-hydroxylysine needed
for the rapid assembly of the azepine core.
of 3 to the ꢀ-caprolactam and reduction of the amide would
afford the hexahydroazepine core.
We have previously demonstrated that the asymmetric
aminohydroxylation of p-bromo-substituted aryl esters of
various â-substituted acrylate systems provides access to
unnatural amino acid derivatives including the desired
hydroxylysine derivative for use in the synthesis of the
hexahydroazepine core of (-)-balanol (Scheme 2).12a
Scheme 2
The preparation of substrate 4 and its conversion to the
hydroxylysine synthon starting from commercially available
4-chloro-1-butanol are shown in Scheme 3. Swern oxidation
Our synthetic plans for the construction of the azepine core
of (-)-balanol centered around the use of the modified
asymmetric aminohydroxylation (AA) methodology devel-
oped in our laboratories and recently applied in our synthesis
of (+)-lactacystin.12 This AA methodology is capable of
installing the C3-C4 stereocenters in an efficient one-step
procedure provided the proper regiochemical outcome could
be achieved in the AA process. Our retrosynthetic analysis
is illustrated in Scheme 1. Disconnection of the ester linkage
Scheme 3
Scheme 1
of 4-chloro-1-butanol provided 4-chlorobutanal which was
subjected to a Horner-Emmons olefination with diethyl (p-
bromophenyl)phosphonate 5 to give the requisite olefin 4 in
(6) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito,
T. J. Org. Chem. 1998, 63, 4397-4407.
(7) 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, 2335-2362.
(8) Tanner, D.; Almario, A. Ho¨gberg, T. Tetrahedron 1995, 51, 6061-
6070.
(9) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994,
116, 8402-8403.
(10) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H.
J. Org. Chem. 1996, 61, 4572-4581.
(11) (a) Fu¨rstner, A.; Thiel, O. R. J. Org. Chem. 2000, 65, 1738-1742.
(b) Cook, G. R.; Shanker, P. S.; Peterson, S. L. Org. Lett. 1999, 1, 615-
617. (c) Morie, T.; Kato, S. Heterocycles 1998, 48, 427-431. (d) Wu, M.
H.; Jacobsen, E. N. Tetrahedron Lett. 1997, 38, 1693-1696. (e) Albertini,
E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V.
Tetrahedron 1997, 53, 17177-17182. (f) Tuch, A.; Saniere, M.; Le Merrer,
Y.; Depezay, J.-C. Tetrahedron: Asymmetry 1996, 7, 2901-2905. (g) Mu¨ler,
A.; Takyar, D. K.; Witt, S.; Ko¨nig, W. A. Liebigs Ann. Chem. 1993, 651-
655.
of (-)-balanol affords the azepine and aromatic fragments.
The hexahydroazepine core of (-)-balanol (2) can be further
disconnected to the hydroxylysine synthon (3). Cyclization
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Org. Lett., Vol. 2, No. 17, 2000

77% overall yield. The asymmetric aminohydroxylation of
4 proceeded as expected to afford the R-amino-â-hydroxy
ester 6 with good levels of enantioselection (82% ee). The
ratio of regioisomers was >20:1 as determined by 1H NMR
analysis of the crude product, and it was expected that the
initial ee of 82%13 could be enhanced at a later stage by
recrystallization of the hydroxylysine bis-hydrochloride salt.
This AA reaction resulted in the installation of the C3-C4
stereogenic centers in a single step with high levels of
regioselectivity and useful levels of enantioselectivity. The
high levels of enantioselection with these aryl ester substrates
offset their susceptibility to saponification under the standard
conditions of the AA reaction.14 The degree of saponification
can be attenuated by careful monitoring of the reaction by
TLC; however, yields could be significantly improved by
limiting the competing hydrolytic pathway. Attempts to
reduce saponification by using the analogous p-bromobenzyl
esters were less successful as these substrates proved less
reactive in terms of the rate of the reaction and afforded
generally lower levels of regio- and enantioselection.
Transformation of 6 to the hydroxylysine synthon is
illustrated in Scheme 4 and commenced with a displacement
application in the Hughes and Lampe synthesis.10 As such,
addition of 3 to hexamethyldisilazane in refluxing xylenes
followed by treatment of the persilylated material with
2-propanol, to effect desilylation, afforded the ꢀ-caprolactam
(Scheme 5). Reduction of lactam 8 with excess borane (5.5
Scheme 5
equiv) furnished the hexahydroazepine core 2 in eight steps
(from 4-chloro-1-butanol) with an overall yield of 16%.
Azepine 2 proved identical in all respects to the correspond-
ing compound obtained by Lampe and co-workers10 (1H and
13C NMR, IR, HRMS, and optical rotation). The virtues of
this approach are apparent from the concise nature of the
synthetic route leading to the critical hydroxylysine synthon
(2), the availability of starting materials, the mild reaction
conditions employed, and the fact that either enantiomer of
2 can be accessed by proper choice of the alkaloid ligand in
the AA reaction. Additionally, structural modifications to the
azepine core can be addressed by selection of the olefinic
substrate utilized in the AA protocol, allowing for the
preparation of substituted azepine rings for SAR studies.
A formal total synthesis of (-)-balanol has been ac-
complished in a highly concise manner. The synthesis of
the azpeine ring of (-)-balanol has been achieved in eight
steps in an overall yield of 16%. In this synthesis, the target’s
two stereogenic centers are established using a Sharpless AA
protocol with modified olefin substrates. The synthetic
strategy should provide access to sufficient quantities of the
azepine ring system for further biological evaluation and use
as probes of protein kinase C activity.
Scheme 4
of the primary chloride with an azide (NaN3/DMF) to afford
7. The terminal azido group served as the masked amino
functionality of the hydroxylysine derivative. Hydrogenation
of azide 7 resulted in deprotection of the Cbz group with
simultaneous reduction of the azide moiety to give hydroxy-
lysine p-bromophenyl ester which was immediately saponi-
fied to afford, after an acidic workup, (2S,3R)-hydroxylysine
as its bis-hydrochloride salt (3).
Acknowledgment. This work has been financially sup-
ported by the National Institutes of Health (RO1GM55740).
Support by a Pfizer PREPARE summer fellowship for A.J.M.
is gratefully acknowledged.
Completion of the synthesis of the azepine core involved
cyclization of 3 using a procedure from a recent patent.15
The choice of these conditions stemmed from their successful
(12) (a) Morgan, A. J.; Masse, C. E.; Panek, J. S. Org. Lett. 1999, 1,
1949-1952. (b) Panek, J. S.; Masse, C. E. Angew. Chem., Int. Ed. 1999,
38, 1093-1095.
Supporting Information Available: General experimen-
tal procedures and full characterization of compunds 2-6.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) Determined by Mosher Analysis: see Dale, J. A.; Mosher, H. S. J.
Am. Chem. Soc. 1973, 95, 512-513 and Supporting Information.
(14) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 35, 2813-2816.
(15) Belyaev, A. A. U.S. Patent 1708812-A1, January 30, 1994.
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