3538
J. Am. Chem. Soc. 1998, 120, 3538-3539
free C12 hydroxyl group. We now report the first synthesis of
the fully elaborated aziridino[1,2-a]pyrrolidine substructure of the
azinomycins including a solution to the selectively protected 1,2-
diol of the agents, and we have discovered the potential origin of
the instability of the natural agents.
Synthetic challenges presented by substructure 2 include (1)
diastereocontrolled introduction of the C7-C8 (E)-dehydroamino
acid double bond, (2) incorporation of the differentially acetylated
C12-C13 Vic-diol, and (3) the presence of the electrophilic aziri-
dine ring, particularly as part of the densely functionalized system.
The key transformation in our synthesis was pyrrolidine introduc-
tion by an addition-elimination reaction sequence 3 f 2.7,8
Stereocontrolled Synthesis of the Fully Elaborated
Aziridine Core of the Azinomycins
Robert S. Coleman* and Jian-She Kong
Department of Chemistry and
ComprehensiVe Cancer Center, The Ohio State UniVersity
100 West 18th AVenue, Columbus, Ohio 43210-1185
ReceiVed January 13, 1998
Azinomycins A (1a) and B (1b) are antitumor agents isolated
from cultures of Streptomyces griseofuscus.1 The azinomycins
possess an intricate structure that contains the unprecedented
aziridino[1,2-a]pyrrolidine ring system, which presents the most
significant synthetic challenge of these natural products. The
azinomycins exhibit potent in vitro cytotoxic activity and
significant in ViVo antitumor activity against P388 leukemia in
mice.2 Biological evaluation of these agents has been hampered
by instability and poor availability from natural sources.3
Transformation of 5, prepared as shown in 66% yield (>95%
ee) from 4 according to Brown et al.,9 to the key aldehyde 13
proceeded in over 35% yield for the eight-step conversion. The
two double bonds of 5 were differentiated with a Sharpless
asymmetric epoxidation10 to afford epoxide 6 in 90% yield (g98%
ee). Faced with the choice of the C12-hydroxyl protecting group,
and given our considerable experience from our earlier studies,
we opted for a p-methoxybenzyl (PMB) ether, which can be
removed under neutral, mildly oxidizing conditions. Protection
of the remaining alcohol of 6 as the PMB ether (NaH, 4-MeOC6H4-
CH2Br, 25 °C) afforded 7 (84%) without rearrangement of the
epoxide. Addition of azide to the terminal carbon of the epoxide
7 (NaN3, MeOCH2CH2OH/H2O, NH4Cl(s), 25 °C)11 provided a
good yield of primary azide 8 (74%).
The epoxide and aziridine rings of the agents suggest that the
azinomycins act by covalent alkylation and cross-linking of DNA.
Studies on azinomycin/oligonucleotide interactions by Armstrong
and co-workers4 were interpreted to show cross-link formation
between the agent and DNA within the major groove.
The unprecedented structure, complex molecular mechanism
of action, and effective antitumor activity make the azinomycins
particularly attractive targets for synthetic efforts. While there
has been a significant amount of activity in the area,5-8 no total
synthesis of these agents has been reported,6 largely due to
difficulties surrounding the selectively acylated C12/C13 diol
system. With the exception of our original work, there are no
reports of azabicyclic ring systems containing a differentiated C12/
C13 diol system, nor are there reports of systems containing a
(1) (a) Nagaoka, K.; Matsumoto, M.; Oono, J.; Yokoi, K.; Ishizeki, S.;
Nakashima, T. J. Antibiot. 1986, 39, 1527. (b) Yokoi, K.; Nagaoka, K.;
Nakashima, T. Chem. Pharm. Bull. 1986, 34, 4554.
(2) Ishizeki, S.; Ohtsuka, M.; Irinoda, K.; Kukita, K.; Nagaoka, K.;
Nakashima, T. J. Antibiot. 1987, 40, 60.
(3) Azinomycin B is apparently identical to carzinophilin A, an antitumor
agent isolated in 1954 from Streptomyces sahachiroi: Hata, T.; Koga, F.;
Sano, Y.; Kanamori, K.; Matsumae, A.; Sugawara, R.; Hoshi, T.; Shima, T.;
Ito, S.; Tomizawa, S. J. Antibiot. Ser. A 1954, 7, 107.
Reduction of the azide of 8 to the amine 9 (Ph3P, toluene/
H2O, 25 °C)12 and N-acylation (ClCO2Bn, Et3N, CH2Cl2) afforded
carbamate 10 in quantitative yield. Acylation of the secondary
hydroxyl of 10 (CH3SO2Cl, Et3N, 96%), cleavage of the acetal
(anhydrous HCl, MeOH, 25 °C, 74%),13 and introduction of the
azinomycin C13-acetate (Ac2O, pyridine, 99%) afforded 11. Final
closure of 11 to the aziridine 12 (KOt-Bu, THF, -78 °C, 100%)
provided the pivotal intermediate 12 in an overall yield of >35%
from 5. This compound possesses all of the functionality for
elaboration to the azinomycin core, including the essential C13-
acetate ester and a readily removable p-methoxybenzyl ether at
the emergent C12 position.
(4) Armstrong, R. W.; Salvati, M. E.; Nguyen, M. J. Am. Chem. Soc. 1992,
114, 3144. Lown, J. W.; Majumdar, K. C. Can. J. Biochem. 1977, 55, 630.
(5) (a) Bryant, H. J.; Dardonville, C. Y.; Hodgkinson, T. J.; Shipman, M.;
Slawin, A. M. Synlett 1996, 10, 973. Bryant, H. J.; Dardonville, C. Y.;
Hodgkinson, T. J.; Hursthouse, M. B.; Malik, K. M. A.; Shipman, M. J. Chem.
Soc., Perkin Trans. 1 1998, in press. (b) Armstrong, R. W.; Tellew, J. E.;
Moran, E. J. Tetrahedron Lett. 1996, 37, 447. Moran, E. J.; Tellew, J. E.;
Zhao, Z.; Armstrong, R. W. J. Org. Chem. 1993, 58, 7848. Armstrong, R.
W.; Moran, E. J. J. Am. Chem. Soc. 1992, 114, 371. Combs, A. P.; Armstrong,
R. W. Tetrahedron Lett. 1992, 33, 6419. Armstrong, R. W.; Tellew, J. E.;
Moran, E. J. J. Org. Chem. 1992, 57, 2208. Moran, E. J.; Armstrong, R. W.
Tetrahedron Lett. 1991, 32, 3807. England, P.; Chun, K. H.; Moran, E. J.;
Armstrong, R. W. Tetrahedron Lett. 1990, 31, 2669. (c) Hashimoto, M.;
Terashima, S. Heterocycles 1998, 47, 59. Hashimoto, M.; Terashima, S.
Tetrahedron Lett. 1994, 35, 9409. Hashimoto, M.; Terashima, S. Chem. Lett.
1994, 1001. Hashimoto, M.; Matsumoto, M.; Yamada, K.; Terashima, S.
Tetrahedron Lett. 1994, 35, 2207. Hashimoto, M.; Yamada, K.; Terashima,
S. Chem. Lett. 1992, 975. (d) Konda, Y.; Machida, T.; Sasaki, T.; Takeda,
K.; Takayanagi, H.; Harigaya, Y. Chem. Pharm. Bull. 1994, 42, 285. (e) Ando,
K.; Yamada, T.; Shibuya, M. Heterocycles 1989, 29, 2209. Shishido, K.;
Omodani, T.; Shibuya, M. J. Chem. Soc., Perkin Trans. 1 1992, 2053. Shibuya,
M.; Terauchi, H. Tetrahedron Lett. 1987, 28, 2619. Shibuya, M. Tetrahedron
Lett. 1983, 24, 1175.
(6) Recently, Hashimoto and Terashima5c reported the synthesis of the C12/
C13 bis-benzyl ether of the natural products, although these workers were
unsuccessful in effecting either differentiation or deprotection of the diol.
(7) Coleman, R. S.; Carpenter, A. J. J. Org. Chem. 1992, 57, 5813.
(8) Coleman, R. S.; Carpenter, A. J. Tetrahedron 1997, 53, 16313.
(9) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988, 110,
1535.
S0002-7863(98)00138-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/31/1998