Asymmetric synthesis of the balanol heterocycle via a palladium-mediated epimerization and olefin metathesis.

Article abstract of DOI:10.1021/ol990705+

[formula: see text] The enantioselective formal synthesis of balanol, a potent protein kinase C inhibitor, was accomplished from D-serine utilizing a Pd-catalyzed equilibration of diastereomeric 5-vinyloxazolines to set the stereochemistry of the vicinal

Full text of DOI:10.1021/ol990705+

ORGANIC
LETTERS
1999
Vol. 1, No. 4
615-617
Asymmetric Synthesis of the Balanol
Heterocycle via a Palladium-Mediated
Epimerization and Olefin Metathesis
Gregory R. Cook,* P. Sathya Shanker, and Scott L. Peterson
Department of Chemistry, North Dakota State UniVersity,
Fargo, North Dakota 58105-5516
grcook@plains.nodak.edu
Received June 2, 1999
ABSTRACT
The enantioselective formal synthesis of balanol, a potent protein kinase C inhibitor, was accomplished from D-serine utilizing a Pd-catalyzed
equilibration of diastereomeric 5-vinyloxazolines to set the stereochemistry of the vicinal amino and hydroxyl groups. A ruthenium-catalyzed
ring-closing metathesis was employed to form the seven-membered nitrogen heterocyle.
Balanol (1, Figure 1) was first isolated in 1993 from the
fungus Verticillium balanoides1 and again in 1994 from a
species of Fusarium.2 It is a potent inhibitor of human protein
kinase C displaying IC50 values of 4-9 nM.3 Due to its high
inhibitory activity, balanol has been the target of a number
of synthetic efforts. Most recently, a samarium-mediated
radical cyclization of an oxime ether afforded the nitrogen
heterocycle in racemic form as a 6.6:1 mixture of diastere-
omers, and the major isomer was subsequently resolved at a
later stage.4 The Nicolaou group has reported an asymmetric
synthesis of balanol beginning with D-serine. Key to the
synthesis was a chiral allylation of a protected serinal with
(Ipc)2B-allyl to afford a 12:1 mixture of diastereomers.5 The
Tanner group utilized regio- and stereoselective opening of
chiral epoxides and aziridines to control the vicinal amino
alcohol stereochemistry.6 Preparation of (2S,3R)-3-hydroxy-
lysine in enantiomerically pure form7 was key to the total
synthesis of balanol reported by Lampe and Hughes.8 Other
total syntheses relying on chiral resolution of racemates have
(1) Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. M.; Janzen,
W. P.; Ballas, L. M.; Loomis, C. R.; Jiang, J. B. J. Am. Chem. Soc. 1993,
115, 6452.
(2) 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.
(3) Boros, C.; Hamilton, S. M.; Katz, B.; Kulanthaivel, P. J. Antiobiot.
1994, 47, 1010.
(4) (a) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito,
T. J. Org. Chem. 1998, 63, 4397. (b) Miyabe, H.; Torieda, M.; Kiguchi,
T.; Naito, T. Synlett 1997, 580. (c) Naito, T.; Torieda, M.; Tajiri, K.;
Ninomiya, I.; Kiguchi, T. Chem. Pharm. Bull. 1996, 44, 624.
(5) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994,
116, 8402.
(6) (a) Tanner, D.; Almario, A.; Ho¨gberg, T. Tetrahedron 1995, 51, 6061.
(b) Tanner, D.; Tedenborg, L.; Almario, A.; Pettersson, I.; Cso¨regh, I.; Kelly,
N. M.; Andersson, P. G.; Ho¨gberg, T. Tetrahedron 1997, 53, 4857.
(7) (a) Hughes, P. F.; Smith, S. H.; Olson, J. T. J. Org. Chem. 1994, 59,
5799. (b) Coulon, E.; Can˜o de Andrade, M. C.; Ratovelomanana-Vidal,
V.; Geneˆt, J.-P. Tetrahedron Lett. 1998, 39, 6467.
(8) (a) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu,
H. J. Org. Chem. 1994, 59, 5147. (b) Lampe, J. W.; Hughes, P. F.; Biggers,
C. K.; Smith, S. H.; Hu, H. J. Org. Chem. 1996, 61, 4572.
Figure 1.
10.1021/ol990705+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/21/1999

appeared.8a,9 The hexahydroazepine 2 (Figure 1) has been
alcohol 813,14 in 58% yield (two steps) as a 67:33 mixture of
syn and anti diastereomers, respectively.15,16 Oxazolidinone
formation was achieved by treatment with sodium hydride
in THF, and acylation gave the required 5-vinyloxazolidinone
9 in high yield. The palladium-catalyzed oxazoline formation/
epimerization provided 10 as a 94:6 (trans:cis) mixture of
diastereomers.15 The isolated yield of the purified major
diastereomer was 79% (cis isomer, 3%). The optimal
epimerization conditions were 35 °C in THF. When toluene
was employed as the solvent, a slightly lower selectivity was
obtained. Higher temperatures resulted in the formation of
trace amounts of elimination products with no improvement
in the diastereomer ratio.
targeted in several formal syntheses of balanol.10
We have recently shown11 that chiral 5-vinyloxazolidino-
nes (3) derived from R-amino acids react with palladium(0)
catalysts to afford 5-vinyloxazolines (6) via oxidative inser-
tion, loss of CO2, and subsequent cyclization of the amide
oxygen (Scheme 1). The oxazoline products were obtained
Scheme 1
Removal of the tert-butyldimethylsilyl protecting group
from 10 with tetrabutylammonium fluoride afforded the free
alcohol in 83% yield (Scheme 3). Mitsunobu reaction with
Scheme 3a
with enhanced diastereomeric ratios, which suggested that
the intermediate π-allyl palladium complexes 4 and 5 were
undergoing equilibration. Oxazolines 6 were also ionized by
the palladium catalyst and were in equilibrium with 4 and
5, thus giving rise to thermodynamic product ratios.12 We
envisioned that this equilibration could be utilized to set the
vicinal amino alcohol stereochemistry of the balanol het-
erocycle. The pendant vinyl group could be employed in a
transition metal catalyzed ring-closing metathesis to generate
the hexahydroazepine ring. This approach to the synthesis
of 2 is presented in this Letter.
The synthesis of 2 began with the protected D-serine
derivative 7 as shown in Scheme 2. Diisobutylaluminum
hydride reduction of the ester and addition of vinylmagne-
sium bromide to the crude aldehyde afforded the allylic
a (a) TBAF, THF, 83%; (b) DPPA, Ph3P, DEAD, 88%; (c) Ph3P,
THF-H2O; then BnOCOCl, Et3N, 70%; (d) NaH, allyl bromide,
87% (11% recovered starting material); (e) Cl2(PCy3)2RudCHPh
(2 × 5 mol %), 45 °C, CH2Cl2, 77%; (f) KO2CNNCO2K, AcOH,
50%; g) 1 N HCl, EtOH, 60 °C; then excess Et3N, MeOH, rt, 63%;
(h) 2 N HCl, THF, rt; then excess Et3N, MeOH, rt, 72%; (i)
(Ph3P)3RhCl (5 mol %) H2 (25 psi), benzene, 94%.
Scheme 2a
diphenylphosphoryl azide17 was employed to introduce the
nitrogen in 88% yield (11). Reduction with triphenylphos-
(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.
(10) For asymmetric syntheses of protected (3R,4R)-3-amino-4-hydroxy-
hexahydroazepines, see: (a) Mu¨ller, A.; Takyar, D. K.; Witt, S.; Ko¨nig,
W. A. Liebigs Ann. Chem. 1993, 651. (b) Tuch, A.; Saniere, M.; Le Merrer,
Y.; Depezay, J.-C. Tetrahedron: Asymmetry 1996, 7, 2901. (c) Wu, M.
H.; Jacobsen, E. N. Tetrahedron Lett. 1997, 38, 1693. (d) Albertini, E.;
Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V. Tetrahedron
1997, 53, 17177. (e) Morie, T.; Kato, S. Heterocycles 1998, 48, 427.
(11) Cook, G. R.; Shanker, P. S. Tetrahedron Lett. 1998, 39, 3405.
(12) A similar Pd-mediated thermodynamic equilibration of vinyl aziri-
dines has been reported: (a) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji,
M.; Ohno, H.; Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N.;
Yamamoto, Y. J. Org. Chem. 1997, 62, 999. (b) Ibuka, T.; Mimura, N.;
Aoyama, H.; Ohno, H.; Nakai, K.; Akaji, M.; Habashita, H.; Tamamura,
H.; Miwa, Y.; Taga, T.; Fujii, N.; Yamamoto, Y. J. Org. Chem. 1997, 62,
2982.
a (a) DIBAL-H, Tol, -78 °C; (b) vinylmagnesium bromide, THF,
58% for two steps; (c) NaH, THF, 91%; (d) 4-BnO-C6H4COCl,
NaH, 90%; (e) Pd2(dba)3CHCl3 (1 mol %), dppp (4 mol %), THF,
35 °C, 79% isolated pure trans diastereomer.
616
Org. Lett., Vol. 1, No. 4, 1999

phine and water, protection with benzyl chloroformate, and
allylation with allyl bromide gave the diene 12. The olefin
metathesis reaction with 10 mol % of the Grubbs ruthenium
alkylidene catalyst18 provided the desired seven-membered
nitrogen heterocycle 13 in a respectable yield (77%). The
experimental conditions for the olefin metathesis reaction
are worthy of comment. Optimal results were obtained when
5 mol % of the catalyst was used followed by the addition
of another 5 mol % after 4 h. The reaction would not proceed
to completion with a single loading of the catalyst, even up
to 20 mol %. Presumably, the catalyst decomposed and an
additional loading was required to obtain complete conver-
sion.
Diimide reduction of the olefin was accomplished with
potassium azodicarboxylate in acetic acid to afford the
saturated nitrogen heterocycle 14 in a moderate yield.
Hydrolysis of the oxazoline was carried out with 1 N HCl
in ethanol at 60 °C. The formation of 2 required subsequent
treatment with base. Under simple aqueous workup condi-
tions, the benzoate derivative was isolated as the amine
hydrochloride salt. Stirring with triethylamine in methanol
for 36 h was necessary to effect the benzoyl transfer to the
amine. A higher overall yield from 13 to 2 was realized by
reversing the hydrolysis and reduction steps. Acidic hydroly-
sis and base treatment afforded 15 in 72% yield, and
hydrogenation with Wilkinson’s catalyst gave 2 with no
observed cleavage of the protecting groups.
We have described an asymmetric synthesis of the balanol
heterocycle from D-serine which incorporated a palladium-
mediated equilibration to set the relative stereochemistry.
Seven-membered ring formation was accomplished with a
ruthenium-catalyzed olefin metathesis reaction in high yield.
The utility of intermediate 13 for the synthesis of balanol
analogues19 and novel azasugar derivatives is currently under
investigation and will be reported in due course.
Acknowledgment. We thank NSF (OSR-9452892, CHE-
9875013), NIH (GM58470-01), and North Dakota State
University for support of our programs. We are grateful to
Boulder Scientific, Inc. for a generous gift of Grubbs’
catalyst. We thank Dr. Peter Wuts for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 2 and 9-15
and unnumbered intermediates isolated. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL990705+
(19) For studies on analogues of balanol, see: (a) Heerding, J. M.; Lampe,
J. W.; Darges, J. W.; Stamper, M. L. Biorg. Med. Chem. Lett. 1995, 5,
1839. (b) Jagdmann, G. E., Jr.; Defauw, J. M.; Lai, Y.-S.; Crane, H. M.;
Hall, S. E.; Buben, J. A.; Hu, H.; Gosnell, P. A. Biorg. Med. Chem. Lett.
1995, 5, 2015. (c) Lai, Y.-S.; Menaldino, D. S.; Nichols, J. B.; Jagdmann,
G. E., Jr.; Mylott, F.; Gillespie, J.; Hall, S. E. Biorg. Med. Chem. Lett.
1995, 5, 2151. (d) Lai, Y.-S.; Mendoza, J. S.; Hubbard, F.; Kalter, K. Biorg.
Med. Chem. Lett. 1995, 5, 2155. (e) Mendoza, J. S.; Jagdmann, G. E., Jr.;
Gosnell, P. A. Biorg. Med. Chem. Lett. 1995, 5, 2211. (f) Hu, H.;
Hollinshead, S. P.; Hall, S. E.; Kalter, K.; Ballas, L. M. Biorg. Med. Chem.
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M.; Jagdmann, G. E., Jr.; Hu, H.; Lampe, J. W.; Hollinshead, S. P.; Mitchell,
T. J.; Crane, H. M.; Heerding, J. M.; Mendoza, J. S.; Davis, J. E.; Dargess,
J. W.; Hubbard, F. R.; Hall, S. E. J. Med. Chem. 1996, 39, 5215. (i) Nielsen,
J.; Lyngsø, L. O. Tetrahedron Lett. 1996, 37, 8439. (j) Lai, Y.-S.; Mendoza,
J. S.; Jagdmann, G. E., Jr.; Menaldino, D. S.; Biggers, C. K.; Heerding, J.
M.; Wilson, J. W.; Hall, S. E.; Jiang, J. B.; Janzen, W. P.; Ballas, L. W. J.
Med. Chem. 1997, 40, 226.
(13) The alcohol 8 is a known compound. See ref 12a and references
therein.
(14) All compounds displayed satisfactory spectroscopic (NMR, IR) data
consistent with their structures.
1
(15) Diastereomer ratios were determined by H NMR (400 MHz).
(16) Careful chelation controlled addition of vinyllithium reagents to
aminoaldehydes generated in situ from DIBAL/TRIBAL in non-ether
solvents have been reported to proceed with high (>20:1) selectivity. (a)
Sames, D.; Polt, R. J. Org. Chem. 1994, 59, 4596. See also: (b) Angle, S.
R.; Henry, R. H. J. Org. Chem. 1997, 62, 8549. (c) Ibuka, T.; Habashita,
H.; Otaka, A.; Fujii, N.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. J. Org.
Chem. 1991, 56, 4370.
(17) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahedron
Lett. 1977, 1977.
(18) For recent reviews on ring-closing metathesis, see: (a) Schuster,
M.; Blechert, S. Angew. Chem. 1997, 109, 2144; Angew. Chem., Int. Ed.
Engl. 1997, 36, 2036. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413. (c) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
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