New efficient method for the total synthesis of (S,S)-isodityrosine from natural amino acids

Full text of DOI:10.1021/jo9902751

2976
J . Org. Chem. 1999, 64, 2976-2977
Communications
therefore many chemists8 have worked at developing new
methodology to achieve this goal. Several syntheses of
isodityrosine,9 piperazinomycin,10 K-13,11 OF-4949-III,12
bouvardin,13 deoxybouvardin,14 and RA-VII15 have used a
variety of approaches. Several different approaches have
been used to build the diaryl ether moiety,10 e.g., Ullmann-
type couplings,16 nucleophilic displacements of o-nitro-
substituted aryl fluorides17 or bromobenzoquinones,18 oxida-
tive phenol couplings,19 Diels-Alder reactions,20 displacement
of areneruthenium complexes,21 etc. We describe herein a
new method for the synthesis of isodityrosine which involves
a direct coupling of two readily prepared derivatives of the
natural amino acids L-phenylalanine and L-tyrosine. This
convergent synthesis should permit one to easily prepare
the asymmetric isodityrosine derivatives necessary for the
synthesis of the more complex natural products in this
series.
New Efficien t Meth od for th e Tota l Syn th esis
of (S,S)-Isod ityr osin e fr om Na tu r a l Am in o
Acid s
Michael E. J ung* and Tsvetelina I. Lazarova1
Department of Chemistry and Biochemistry, University of
California, Los Angeles, California 90095-1569
Received February 17, 1999
Isodityrosine2 (1), isolated in the early 1980s from ex-
tensin, a plant cell wall glycoprotein, is the key structural
unit which defines a large class of biologically active natural
products. Piperazinomycin3 (2a ) exhibits antimicrobial and
antifungal activity, the cyclic tripeptide K-134 (2b) is a potent
inhibitor of angiotensin I converting enzyme (ACE), and
OF4949-I-OF4949-IV5 (2c-f) are inhibitors of aminopepti-
dase B and exhibit antitumor and immunopotentiating
activity. The bicyclic hexapeptides bouvardin6 and deoxy-
bouvardin7,8 are members of a large class of potent antitumor
antibiotics, including RA-I-RA-IV.7
The first component of this convergent synthesis was
avaiable in five steps and reasonable overall yield from
tyrosine 3 via the selectively monoprotected L-DOPA deriva-
tive 5 prepared by formylation to give 4 followed by ben-
zylation and a Dakin oxidation to give 5.22 Formation of the
ester afforded 6 in good yield (Scheme 1).
The second component was prepared from the com-
mercially available 4-iodophenylalanine 7 (Scheme 2) (which
(9) (a) J ung, M. E.; J achiet, D.; Rohloff, J . C. Tetrahedron Lett. 1989,
30, 4211. (b) Boger, D. L.; Yohannes, D. Tetrahedron Lett. 1989, 30, 2053.
(c) Also K-13, OF4949-III, and OF4949-IV: Boger, D. L.; Yohannes, D. J .
Org. Chem. 1990, 55, 6000. (d) J ung, M. E.; Starkey, L. S. Tetrahedron 1997,
53, 8815; Tetrahedron Lett. 1995, 36, 7363.
(10) (a) Boger, D. L.; Zhou, J . J . Am. Chem. Soc. 1993, 115, 11426. (b)
Boger, D. L.; Zhou, J . J . Am. Chem. Soc. 1994, 116, 1601. (c) Nishiyama,
S.; Nakamura, K.; Suzuki, Y.; Yamamura, S. Tetrahedron Lett. 1986, 27,
4481. (d) Synthetic studies: J ung, M. E.; Rohloff, J . C. J . Org. Chem. 1985,
50, 4909.
(11) (a) Nishiyama, S.; Suzuki, Y.; Yamamura, S. Tetrahedron Lett. 1989,
30, 379. (b) OF4949-III: Evans, D. A.; Ellman, J . A. J . Am. Chem. Soc.
1989, 111, 1063. (c) Boger, D. L.; Yohannes, D. J . Org. Chem. 1989, 54,
2498. (d) Rama Rao, A. V.; Chakraborty, T. K.; Reddy K. L.; Rao, A. S.
Tetrahedron Lett. 1992, 33, 4799. (e) Beugelmans, R.; Bigot, A.; Zhu, J .
Tetrahedron Lett. 1994, 35, 5649. (f) Pearson, A. J .; Lee, K. J . Org. Chem.
1994, 59, 2304. (g) Boger, D. L.; Yohannes, D. J . Org. Chem. 1991, 56, 1763.
(12) OF4949-III: (a) Nishiyama, S.; Suzuki, Y.; Yamamura, S. Tetrahe-
dron Lett. 1988, 29, 559. (b) Schmidt, U.; Weller, D.; Holder, A.; Lie-
berknecht, A. Tetrahedron Lett. 1988, 29, 3227. (c) Evans, D. A.; Ellman,
J . A. J . Am. Chem. Soc. 1989, 111, 1063. (d) OF4949-IV: Boger, D. L.;
Yohannes, D. Tetrahedron Lett. 1989, 30, 5061.
The construction of the diaryl ether moiety is the foremost
synthetic challenge posed by these target molecules, and
(13) (a) Boger, D. L.; Patane, M. A.; Zhou, J . J . Am. Chem. Soc. 1994,
116, 8544. (b) Bates, R. B.; Cole, J . R.; Hoffmann, T. J .; Kriek, G. R.; Linz,
G. S.; Torrance, S. J . J . Am. Chem. Soc. 1983, 105, 1343.
(14) (a) Boger, D. L.; Yohannes, D. J . Org. Chem. 1988, 53, 487. (b) Inaba,
T.; Umezawa, I.; Yuasa, M.; Inoue, T.; Mihashi, S.; Iitokawa, H.; Ogura, K.
J . Org. Chem. 1987, 52, 2957.
(1) Recipient of the D. J . Cram Award for Excellence in Graduate
Research, UCLA, 1997-8.
(2) (a) Fry, S. C. Biochem. J . 1982, 204, 449. (b) Epstein, L.; Lamport,
D. T. A. Phytochemistry 1984, 23, 1241. (c) Cooper, J . B.; Varner, J . E.
Biochem. Biophys. Res. Commun. 1983, 112, 161.
(3) (a) Tamai, S.; Kaneda, M.; Nakamura, S. J . Antibiot. 1982, 35, 1130.
(b) Kaneda, M.; Tamai, S.; Nakamura, S.; Hirata, T.; Kushi, Y.; Suga, T. J .
Antibiot. 1982, 35, 1137.
(15) (a) Itokawa, H.; Inoue, T.; Umezawa, I.; Yuasa, M.; Inaba, T. J apan
Patent 63 05,0098; Chem. Abstr. 1989, 110, 213344s. Also deoxybouvar-
din: (b) Boger, D. L.; Yohannes, D. J . Am. Chem. Soc. 1991, 113, 1427. (c)
Boger, D. L.; Yohannes, D.; Zhou, J .; Patane, M. A. J . Am. Chem. Soc. 1993,
115, 3420.
(16) (a) See refs 13b, 13g, 14c, and 17c. (b) Bates, R. B.; J anda, K. D. J .
Org. Chem. 1982, 47, 4374. (c) Inoue, T.; Naitoh, K.; Kosemura, S.;
Umezawa, I.; Sonobe, T.; Serizawa, N.; Mori, N. Heterocycles 1983, 20, 397.
(17) (a) Boger, D. L.; Borzilleri, R. M. Bioorg. Med. Chem. Lett. 1995, 5,
1187. (b) Beugelmans, R.; Bigot, A.; Bois-Choussy, M.; Zhu, J . J . Org. Chem.
1996, 61, 771. (c) Rama Rao, A. V.; Reddy, K. L.; Rao, A. S. Tetrahedron
Lett. 1994, 35, 8465.
(4) (a) Kase, M.; Kaneko, M.; Yamada, K. J . Antibiot. 1987, 40, 450. (b)
Yasuzawa, T.; Shirahata, C.; Sano, H. J . Antibiot. 1987, 40, 455.
(5) (a) Sano, S.; Ikai, K.; Katayama, K.; Takesako, K.; Nakamura, T.;
Obayashi, A.; Ezure, Y.; Enomoto, H. J . Antibiot. 1986, 39, 1685. (b) Sano,
S.; Ikai, K.; Kuroda, H.; Nakamura, T.; Obayashi, A.; Ezure, Y.; Enomoto,
H. J . Antibiot. 1986, 39, 1674. (c) Sano, S.; Ikai, K.; Yoshikawa, Y.;
Nakamura, T.; Obayashi, A. J . Antibiot. 1987, 40, 512. (d) Sano, S.; Kuroda,
H.; Ueno, M.; Yoshikawa, Y.; Nakamura, T.; Obayashi, A. J . Antibiot. 1987,
40, 519.
(6) J olad, S. D.; Hoffmann, J . J .; Torrance, S. J .; Wiedhopf, R. M.; Cole,
J . R.; Arora, S. K.; Bates, R. B.; Gargiulo, R. L.; Kriek, G. R. J . Am. Chem.
Soc. 1977, 99, 8040.
(7) (a) Review: Itokawa, H.; Takeya, K. Heterocycles 1993, 35, 1467. (b)
Itokawa, H.; Takeya, K.; Mori, N.; Sonobe, T.; Mihashi, S.; Hamanaka, T.
Chem. Pharm. Bull. 1986, 34, 3762. (c) Itokawa, H.; Takeya, K.; Mihara,
K.; Mori, N.; Hamanaka, T.; Sonobe, T.; Iitaka, Y. Cham. Pharm. Bull. 1983,
31, 1424.
(18) Rama Rao, A. V.; Gurjar, M. K.; Reddy, A. B.; Khare, V. B.
Tetrahedron Lett. 1993, 34, 1657.
(19) (a) References 12c, 16b, 18c, and 18d. (b) Bates, R. B.; Gin, S. L.;
Hassen, M. A.; Hruby, V. J .; J anda, K. D.; Kriek, G. R.; Michaud, J .-P.;
Vine, D. B. Heterocycles 1984, 22, 785.
(20) Olsen, R. K.; Feng, X.; Campbell, M.; Shao, R.; Math, S. K. J . Org.
Chem. 1995, 60, 6025.
(21) Pearson, A. J .; Bignan, G.; Zhang, P.; Chelliah, M. J . Org. Chem.
1996, 61, 3940 and references therein.
(8) Review: Rama Rao, A. V.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S.
Chem. Rev. 1995, 95, 2135.
(22) J ung, M. E.; Lazarova, T. I. J . Org. Chem. 1997, 62, 1553.
10.1021/jo9902751 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/07/1999

Communications
J . Org. Chem., Vol. 64, No. 9, 1999 2977
arylboronate 10 in 82% yield.24 The use of the diphenylphos-
phoferrocene ligand (dppf) was cruical to the success of this
process. Reaction of 10 with diethanolamine gave in 76%
yield the cyclic aminoboronate which was hydrolyzed under
acidic conditions to the arylboronic acid 11. The amino acid
prepared from this compound, L-(4-boronophenyl)alanine (L-
BPA), is used clinically in boron neutron capture therapy
(BNCT) for the tretament of brain tumors.25 Although it has
been made previously,26 this represents the first synthesis
of this system from phenylalanine. The key step of this new
method is the cupric acetate promoted coupling of an
arylboronic acids with phenols developed jointly by Chan,
Evans, and Lam.27 Thus, treatment of the L-DOPA deriva-
tive 6 with 1.5 equiv of the arylboronic acid 11 in the
presence of cupric acetate, 4 Å powdered molecular sieves,
and 5 equiv of pyridine gave the desired aryloxy phenol 12
in 71% crude yield (60% after flash column chromatography).
This compound was identical in all respects with authentic
material prepared by another route.9d Final conversion of
12 to isodityrosine 1 was accomplished in one operation by
catalytic hydrogenation followed by acidic hydrolysis to
afford 1 in 92% yield.
Sch em e 1
Sch em e 2
This ends a very efficient convergent synthesis of 1 in
which all of the chirality in the molecule is derived directly
from the two aromatic amino acids L-tyrosine and L-phenyl-
alanine. This novel approach opens the door to the synthesis
of the many isodityrosine-derived natural products and to
unique analogues as well.28
Ack n ow led gm en t. We thank the National Institutes
of Health (GM 31349) and the Agricultural Division of
American Cyanamid Company for generous financial sup-
port.
Su p p or tin g In for m a tion Ava ila ble: Experimental Section,
1H and 13C NMR spectra of all new compounds, and the 11B NMR
spectrum of the acid derived from 11. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O9902751
(24) Isiyama, T.; Murate, M.; Miyaura, N. J . Org. Chem. 1995, 60, 7508.
(25) (a) Mishima Y.; Honda, C.; Ichihashi, M.; Obara, H.; Hiratsuka, J .;
Fukuda, H.; Karashima, H.; Kobayashi, T.; Kanda, K.; Yoshino, K. Lancet
1989, 388.25. For reviews of BNCT, see: (a) Hawthorne, M. F. Angew.
Chem., Int. Ed. Engl. 1993, 32, 950. (b) Morris, J . H. Chem. Brit. 1991,
331. (c) Hatanaka, H. Borax Rev. 1991, 9, 5. (d) Slatkin, D. N. Brain 1991,
114, 1609. (e) Gabel, D. Adv. Techn. Radiother. 1992, 85.
(26) For a racemic synthesis, see: Snyder, H. R.; Reedy, A. J .; Lennarz,
W. M. J . Am. Chem. Soc. 1958, 80, 835.26. For a chiral synthesis, see:
Malan, C.; Morin, C. Synlett 1996, 167.
(27) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933. (b) Evans, D. A.; Katz, J . L.; West, T. R.
Tetrahedron Lett. 1998, 39, 2937. (c) Lam, P. Y. S.; Clark, C. G.; Saubern,
S.; Adams, J .; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett.
1998, 39, 2941.
(28) Since the completion of this work and the original submission of
this manuscript, two papers on the synthesis of L-(4-boronophenyl)alanine
(L-BPA) have appeared. (a) Nakamura, H.; Fujiwara, M.; Yamamoto, Y. J .
Org. Chem. 1998, 63, 7529. (b) Malan, C.; Morin, C. J . Org. Chem. 1998,
63, 8019.
can be prepared from phenylalanine by iodination in one
step).23 Protection of both the amine and acid gave 8 in 91%
yield. The key process involved the conversion of this iodide
into the corresponding boronic acid 11. This was accom-
plished by palladium-catalyzed coupling of the iodide 8 with
the commercially available bis(boronate) 9 to give the
(23) Lei, H.; Stoakes, M. S.; Herath, K. P. B.; Lee, J .; Schwabacher, A.
W. J . Org. Chem. 1994, 59, 4206.