3938
J . Org. Chem. 1996, 61, 3938-3939
Ch a r t 1
Alter n a tive Syn th esis of th e
Cycloisod ityr osin e Su bu n it of
Deoxybou va r d in , RA-VII, a n d Rela ted
Agen ts: Rea ssign m en t of th e
Ster eoch em istr y of P r ior In ter m ed ia tes
Dale L. Boger* and J iacheng Zhou
Department of Chemistry, The Scripps Research Institute,
10666 North Torrey Pines Road, La J olla, California 92037
Received February 29, 1996
Deoxybouvardin and RA-VII constitute representative
members of a growing class of naturally occurring
antitumor agents (Chart 1).1-3 In the course of our and
Inoue’s efforts on their total synthesis,4,5 a discrepancy
in the properties of an intermediate cycloisodityrosine
derivative was observed. Given that both efforts provided
synthetic materials identical to the natural products,
investigations into its origin were initiated. Independent
of these efforts, we were investigating6 an alternative
synthesis of the cycloisodityrosine subunit of the natural
products based on an intramolecular aromatic nucleo-
philic substitution reaction7 for formation of the key
biaryl ether and considered this an opportunity to ad-
dress the structural assignments of past intermediates.
Herein, we report this alternative synthesis of the
cycloisodityrosine subunit of deoxybouvardin and related
agents, the extension of the studies to the preparation
of its unnatural diastereomer, the comparison with prior
synthetic intermediates, and the resulting reassignment
of their stereochemistry. The studies also led to docu-
mentation of a remarkably facile epimerization that went
undetected in our prior efforts.
F igu r e 1.
(S,R)- or (R,S)-diastereomer and the use of excess amounts
of optically enriched but impure active ester10 preferen-
tially provided the mixed (S,R)- or (R,S)-diastereomer.
Consistent with prior observations,6,7 treatment of the
dipeptides with K2CO3 (5 equiv, 0.008 M DMF, 45-50
°C, 2-4 h) or NaH (2.2 equiv, 0.004 M THF, 2-6 h) led
to smooth 14-membered ring closure (Scheme 1). In the
case of 2, both conditions provided a single product 3 in
superb conversions (76-78%), and the relative stereo-
chemistry was unambiguously established upon N-BOC
deprotection (2.2 N HCl-EtOAc, 25 °C, 30 min, 100%)
and subsequent X-ray analysis (Figure 1).11
In contrast, 1 only provided the expected diastereomer
4 under carefully defined reaction conditions where
potential epimerization is minimized (2.2 equiv of NaH,
0.004 M THF, 0-25 °C, 2-6 h, 50-61%). Moreover,
increasing amounts of the diastereomer 3 were obtained
if this reaction was extended to longer reaction times or
conducted with excess NaH. Conducting this reaction
under the apparently milder conditions of K2CO3-DMF
(5.0 equiv, 45-50 °C, 0.008 M, 3-4 h) provided the
epimerized diastereomer 3 nearly exclusively (45-55%)
with only a trace of the expected product 4 (5-10%) being
detected at any time during the reaction. Equilibration
studies conducted on (9S,12S)-4 confirmed the unusually
facile epimerization that could be effected by treatment
with K2CO3, K2CO3/18-crown-6, or KF in DMF as well
as DBU or Et3N in THF. The studies also established
an equilibrium ratio of g97:3 in favor of the unnatural
diastereomer 3 and that this epimerization occurs at the
C9 center adjacent to the methyl ester (Figure 1). The
Both (S)- and (R)-3-fluoro-4-nitrophenylalanine methyl
ester, [R]25D +12 (c 1.2, CHCl3) and -11.6 (c 1.2, CHCl3),
were prepared7,8 and coupled with L- and D-BOC-NMe-
Tyr-OC6F5,9 [R]25 -93 (c 1.0, CHCl3) and [R]25 +93 (c
D
D
1.0, CHCl3), in THF (25 °C, 4 h, 80-90%). This coupling
reaction exhibits a kinetic preference for formation of the
(1) 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.
(2) Itokawa, H.; Takeya, K. Heterocycles 1993, 35, 1467.
(3) Itokawa, H.; Takeya, K.; Mori, N.; Sonobe, T.; Mihashi, S.;
Hamanaka, T. Chem. Pharm. Bull. 1986, 34, 3762. Itokawa, H.;
Takeya, K.; Mihara, K.; Mori, N.; Hamanaka, T.; Sonobe, T.; Iitaka,
Y. Chem. Pharm. Bull. 1983, 31, 1424.
(4) Inaba, T.; Umezawa, I.; Yuasa, M.; Inoue, T.; Mihashi, S.;
Itokawa, H.; Ogura, K. J . Org. Chem. 1987, 52, 2957. Inoue, T.; Inabe,
T.; Umezawa, I.; Yuasa, M.; Itokawa, H.; Ogura, K.; Komatsu, K.; Hara,
H.; Hoshino, O. Chem. Pharm. Bull. 1995, 43, 1325.
(5) Boger, D. L.; Yohannes, D.; Zhou, J .; Patane, M. A. J . Am. Chem.
Soc. 1993, 115, 3420. Boger, D. L.; Yohannes, D. J . Am. Chem. Soc.
1991, 113, 1427.
(6) Boger, D. L.; Borzilleri, R. M. Bioorg. Med. Chem. Lett. 1995, 5,
1187. Boger, D. L.; Borzilleri, R. M.; Nukui, S. Bioorg. Med. Chem.
Lett. 1995, 5, 3091.
(7) Beugelmans, R.; Bigot, A.; Zhu, J . Tetrahedron Lett. 1994, 35,
7391. Beugelmans, R.; Zhu, J .; Husson, N.; Bois-Choussy, M.; Singh,
G. P. J . Chem. Soc., Chem. Commun. 1994, 439. Beugelmans, R.;
Singh, G. P.; Bois-Choussy, M.; Chastanet, J .; Zhu, J . J . Org. Chem.
1994, 59, 5535. Rama Rao, A. V.; Reddy, K. L.; Rao, A. S. Tetrahedron
Lett. 1994, 35, 8465. Beugelmans, R.; Bourdet, S.; Zhu, J . Tetrahedron
Lett. 1995, 36, 1279.
(8) Prepared by coupling 4-(bromomethyl)-2-fluoronitrobenzene with
the higher order cuprate of (2R)-(-)- and (2S)-(+)-2,5-dihydro-3,6-
dimethoxy-2-isopropylpyrazine, respectively, followed by hydrolysis
(0.25 N HCl, 25 °C, 8 h; saturated aqueous NaHCO3, 91-92%) of the
intermediate alkylated dihydropyrazines, [R]25D +41 (c 0.9, CHCl3) and
-39 (c 0.5, CHCl3).
(9) Prepared by N-methylation of L- and D-BOC-Tyr(OBn)-OH (2.2
equiv of NaH, 5.0 equiv of CH3I, 20:1 THF-DMF, 0-25 °C, 10 h, 82-
90%), hydrogenolysis of the benzyl ether (H2, 10% Pd-C, CH3OH, 25
°C, 91-97%), and active ester formation (1.1 equiv of C6F5OH, 1.5 equiv
of EDCI, CH2Cl2, 25 °C, 74-83%).
(10) Extensive racemization is observed if the N-methylation of
BOC-Tyr(OBn)-OH is conducted on a corresponding ester or under
conditions where the methyl ester is formed directly especially if excess
NaH is employed.
(11) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
may be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
S0022-3263(96)00414-8 CCC: $12.00 © 1996 American Chemical Society