A synthesis of D,L-N,N-dimethylcycloisodityrosines: A comment on the stereochemistry of previously reported intermediates related to the synthesis of RA-VII and deoxybouvardin

Full text of DOI:10.1021/jo960381s

3936
J . Org. Chem. 1996, 61, 3936-3937
Communications
A Syn th esis of
D,L-N,N-Dim eth ylcycloisod ityr osin es: A
Com m en t on th e Ster eoch em istr y of
P r eviou sly Rep or ted In ter m ed ia tes Rela ted
to th e Syn th esis of RA-VII a n d
Deoxybou va r d in
Tsutomu Inoue,*,† Tomomitsu Sasaki,†
Hiroaki Takayanagi,‡ Yoshihiro Harigaya,‡
Osamu Hoshino,§ Hiroshi Hara,§ and Takashi Inaba
Ohmiya Research Laboratory, Fuji Yakuhin Co., Ltd.,
3936-2 Sashi-ougi, Ohmiya 331, J apan, School of
Pharmaceutical Sciences, Kitasato University,
5-9-1 Shirogane, Minato-ku, Tokyo 108, J apan,
Faculty of Pharmaceutical Sciences, Science University of
Tokyo, 12 Ichigaya Funagawara-machi, Shinjuku-ku,
Tokyo 162, J apan, and Central Pharmaceutical Research
Institute, J apan Tabaco, Inc., 1-1 Murasaki-cho, Takatsuki,
Osaka 569, J apan
L
L
F igu r e 1.
1H NMR spectral data for the free amine 6 and the N-
Boc derivative 7 were not in agreement with those for
the compounds 10 and 9 reported by Boger and co-
workers.4-6 This finding provided the incentive to ad-
dress the discrepancy by the synthesis of the diastere-
omer 20 of 6. The present paper details the synthesis of
the title compounds 20 and 21 for direct comparison with
the stereostructure of 9 and 10 and the X-ray crystal-
lographic analysis of the N-Boc derivative 21.
Received February 23, 1996
A number of bicyclic hexapeptides (bouvardin1 and RA-
I-XIV2), which have an L,L-N,N-dimethylcycloisodity-
rosine subunit, have been isolated from Rubiaceae plants
(Rubia akane in J apan, Rubia cordifolia in China, and
Bouvardia ternifolia). Previously,3 we reported the first
total synthesis of RA-VII (1) and deoxybouvardin (2)
(Figure 1) starting from L,L-N,N-dimethylcycloisodity-
rosine (6), which was synthesized by thallium trinitrate
(TTN) oxidation of the L,L-dibromo dichloro amide 3
followed by the sequential reaction sequences of aroma-
tization, O-methylation, and catalytic hydrogenolysis.
Independently, Boger and co-workers4 have reported a
total synthesis of 1 and 2 via L,L-N,N-dimethylcycloisodi-
tyrosine (10), which was obtained by means of an
Ullmann reaction of the amide 8 followed by N-Boc
deprotection (Chart 1). In addition, they have also
reported the synthesis of N-desmethyl derivatives of RA-
VII and deoxybouvardin by the same method.5
N-Methyl-D-tyrosine (11)7 was converted quantitatively
into N-Cbz-N-methyl-D-tyrosine (12), [R]25D +45.7 (c 2.38,
CHCl3) in a usual manner (2 equiv of CbzCl, K2CO3,
aqueous acetone, 25 °C, 1 h). Coupling (1.1 equiv of DCC,
dioxane, 25 °C, 3 h) of 12 with methyl 3,5-dibromo-N-
methyl-L-tyrosinate (13)3 gave methyl N-methyl-D-ty-
rosyl-3,5-dibromo-L-tyrosinate (14, pale yellow foam,
48%), [R]23 +8.9 (c 0.51, CHCl3).
D
Chlorination (3.3 equiv of Cl2, CHCl3, 15-20 °C, 1 h)3
of 14 afforded the dibromo dichloro amide 15 (pale yellow
25
amorphous solid, 74%), [R]D +24 (c 0.7, CHCl3) (Chart
2).
With the dibromo dichloro amide 15 in hand, conver-
sion into D,L-N,N-dimethylcycloisodityrosine (20) was
carried out in a manner similar to that reported previ-
ously.3 TTN oxidation (3 equiv of TTN, MeOH, 4 °C, 18
h, then pyridine) of 15 gave 16 (pale yellow foam, 11%),
[R]25 +70 (c 0.5, CHCl3) and 17 (yellow oil, 34%), [R]25
As part of our continuing examination of the stereo-
structure of this key intermediate,6 we found that the
† Fuji Yakuhin Co., Ltd.
D
D
‡ Kitasato University.
+113 (c 0.7, CHCl3), respectively, each structure of which
was supported on the basis of the spectral evidence.
Interestingly, the oxidation of 15 was found to proceed
more readily than that of 3. Aromatization (Zn, AcOH,
25 °C, 18 h) of the former 16 gave the phenol 18 (colorless
§ Science University of Tokyo.
J apan Tabaco, Inc.
(1) (a) 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. (b) Bates, R. B.; Cole, J . R.;
Hoffmann, J . J .; Kriek, G. R.; Linz, G. S.; Torrance, S. J . J . Am. Chem.
Soc. 1983, 105, 1343.
foam, 73%), [R]25 +79.8 (c 0.87, CHCl3), followed by
D
O-methylation (CH2N2-Et2O, MeOH) and catalytic hy-
drogenolysis (5% Pd-C/H2, AcOK, MeOH, 25 °C) pro-
duced D,L-N,N-dimethylcycloisodityrosine (20), [R]21D +17
(c 0.21, MeOH) in 50% overall yield from 18. The 1H
NMR spectral data of 20 were in agreement with those
for 10.8
(2) (a) For a review on oligopeptides related to RA: Itokawa, H.;
Takeya, K. Heterocycles 1993, 35, 1482-1501 and references cited
therein. (b) Itokawa, H.; Saitou, K.; Morita, H.; Takeya, K.; Yamada,
K. Chem. Pharm. Bull. 1992, 40, 2984. (c) Hitotsuyanagi, Y.; Suzuki,
J .; Takeya, K.; Itokawa, H. Bioorg. Med. Chem. Lett. 1994, 4, 1633.
(d) Itokawa, H.; Kondo, K.; Hitotsuyanagi, Y.; Isomura, M.; Takeya,
K. Chem. Pharm. Bull. 1993, 42, 1402.
(3) (a) Inaba, T.; Umezawa, I.; Yuasa, M.; Inoue, T.; Mihashi, S.;
Itokawa, H.; Ogura, K. J . Org. Chem. 1987, 52, 2957. (b) Inoue, T.;
Inaba, T.; Umezawa, I.; Yuasa, M.; Komatsu, K.; Itokawa, H.; Ogura,
K.; Hara, H.; Hoshino, O. Chem. Pharm. Bull. 1995, 43, 1325.
(4) (a) Boger, D. L.; Yohannes, D. J . Am. Chem. Soc. 1991, 113, 14.
(b) Boger, D. L.; Yohannes, D.; Zhou, J .; Patane, M. A. J . Am. Chem.
Soc. 1993, 115, 3420.
Finally, tert-butoxycarbonylation [5.4 equiv of (Boc)2O,
THF, 25 °C, 2.5 h, 99%] of 20 furnished D,L-N-Boc-N-
methylcycloisodityrosine (21) (mp 137-138 °C), [R]21
D
+168 (c 0.21, MeOH), the 1H NMR spectral data of which
were also in agreement with those for 9.8 In contrast to
(5) Boger, D. L.; Zhou, J . J . Am. Chem. Soc. 1995, 117, 7364.
(6) The observation that the spectral data of 9 are not identical with
those for our synthetic compound 73 has been described in the
literature.5 However, the origin of this discrepancy in the spectral
properties had not been addressed.
(7) Izumiya, N.; Nagamatsu, A. Bull. Chem. Soc. J pn. 1952, 25, 265.
(8) Specific rotation and mp are not coincident with those for 10
described in the literature.5
S0022-3263(96)00381-7 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 12, 1996 3937
Ch a r t 1
Ch a r t 2
Ch a r t 3
F igu r e 2. ORTEP drawing.
9 and 1011 described in the literature.4,5 to be 21 and 20
or their enantiomers.
Ack n ow led gm en t. We gratefully acknowledge Prof.
Katsuyuki Ogura of Chiba University and Prof. Hideji
Itokawa of Tokyo University of Pharmacy & Life Sci-
ence, School of Pharmacy, for their valuable discussion
and would like to express our thanks to Prof. D. L. Boger
of The Scripps Research Institute for accepting our
comment on the stereochemistry of his prior intermedi-
ate leading to RA-VII and deoxybouvardin. Thanks are
also due to Dr. Isao Umezawa of Fuji Yakuhin Co., Ltd.,
and Mr. Masayuki Yuasa of POLA R & D Laboratory
for their technical assistance.
L,L-N,N-dimethylcycloisodityrosines,3,9 all cyclized prod-
ucts (16-21) were found to be single conformational
isomers (Chart 3).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
15-21 and their full experimental data and X-ray crystal-
lographic data of 21 are provided (13 pages).
The stereostructure of 21 was confirmed by X-ray
crystallographic analysis of crystals grown from ether-
hexane. An ORTEP drawing of 21 is shown in Figure
2.10
In conclusion, D,L-N,N-dimethylcycloisodityrosines 20
and 21 were synthesized, proving the stereostructure of
J O960381S
(10) Atomic coordinates for this structure have been deposited with
the Cambridge Crystallographic Data Center. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge, CB2 1EZ, UK.
(11) For RA-VII (1) and deoxybouvardin (2) to be synthesized from
the enantiomer of D,L-N,N-dimethylcycloisodityrosine (20), epimeriza-
tion of 20 or its enantiomer to 10 must occur. Boger and Zhou address
this in an accompanying paper.12
(9) The conformational isomers are separable. However, when each
separated compound was allowed to stand in CHCl3, it reverted to an
equilibrium mixture.3
(12) Boger, D. L.; Zhou, J . J . Org. Chem. 1996, 61, XXXX.