Published on Web 02/22/2002
Total Synthesis of (-)-Tetrazomine. Determination of the
Stereochemistry of Tetrazomine and the Synthesis and
Biological Activity of Tetrazomine Analogues
Jack D. Scott and Robert M. Williams*
Contribution from the Department of Chemistry, Colorado State UniVersity,
Fort Collins, Colorado 80523
Received October 26, 2001
Abstract: The first total synthesis of the potent antitumor antibiotic (-)-tetrazomine has been accomplished.
A new method for the formation of the allylic amine precursor to an azomethine ylide has been developed
and exploited in an efficient [1,3]-dipolar cycloaddition to afford the key tetracyclic intermediate used in the
synthesis of (-)-tetrazomine. Several analogues of tetrazomine have been synthesized and tested for
antimicrobial and biochemical activity.
Introduction
The antitumor antibiotic tetrazomine 1 is a natural secondary
metabolite isolated from Saccharothrix mutabilis subsp. chich-
ijimaensis subsp. nov. by Suzuki et al.1 Tetrazomine is a member
of the tetrahydroisoquinoline family of antitumor antibiotics
including ecteinascidin 743 (Et 743)2 (2), bioxalomycin3 (3),
and quinocarcin4 (4). Tetrazomine most closely resembles
quinocarcin with the exception of the amino functionality at
C-10′, the unusual â-hydroxy pipecolic acid moiety, and the
oxidation state of C-5′. Neither the relative nor the absolute
stereochemistry of tetrazomine was determined when the
structure was initially reported.1 The absolute stereochemistry
of the pipecolic acid moiety has since been determined in these
laboratories to be 2(S),3(R) as depicted in Figure 1.5 The relative
stereochemistry at C-5′ then remained as the only stereogenic
center to be in question and was solved through a total synthesis
that we recently communicated.6
Figure 1. Structures of tetrazomine, ecteinascidin 743, bioxalomycin a2,
and quinocarcin.
activity against both Gram-negative and Gram-positive bacteria.1a
Tetrazomine and quinocarcin exert their cytotoxic activity
through the expression of multiple mechanisms that include the
mediation of oxidative damage to DNA via the reduction of
molecular oxygen to superoxide by the auto-redox dispropor-
tionation of the fused oxazolidine and, possibly, DNA alkyla-
tion.7 DNA alkylation has not been observed for tetrazomine
or quinocarcin; however, alkylation has been observed with
Preliminary antitumor and antimicrobial assays of tetrazomine
revealed that this substance possesses potent cytotoxicity with
activity against P388 leukemia in vivo and good antimicrobial
* To whom correspondence should be addressed. E-mail: rmw@chem.
colostate.edu. FAX: (970)-491-3944.
(1) (a) Suzuki, K.; Sato, T.; Morioka, M.; Nagai, K.; Abe, K.; Yamaguchi, H.;
Saito, T. J. Antibiot. 1991, 44, 479-485. (b) Sato, T.; Hirayama, F.; Saito,
T. J. Antibiot. 1991, 44, 1367-1370.
(2) (a) Rinehart, K. L.; Holt, T. G.; Fregeau, N. L.; Keifer, P. A.; Wilson, G.
R.; Perun, T. J.; Sakai, R.; Thompson, A. G.; Stroh, J. G.; Shield, L. S.;
Seigler, D. S. J. Nat. Prod. 1990, 53, 771-792. (b) Rinehart, K. L.; Holt,
T. G.; Fregeau, N. L.; Stroh, J. G.; Keifer, P. A.; Sun, F.; Li, L. H.; Martin,
D. G. J. Org. Chem. 1990, 55, 4512-4515. (c) Wright, A. E.; Forleo, D.
A.; Gunawardana, G. P.; Gunasekera, S. P.; Koehn, F. E.; McConnell, O.
J. J. Org. Chem. 1990, 55, 4508-4512.
bioxalomycin R2 and Et 743.9
8
Prior to our communication,6 the total synthesis of tetrazomine
had not been reported in the literature10 although two syntheses
of the AB ring system of tetrazomine have been reported.11
Ponzo and Kaufman11a reported a racemic synthesis followed
(3) (a) Zaccardi, J.; Alluri, M.; Ashcroft, J.; Bernan, V.; Korshalla, J. D.;
Morton, G. O.; Siegel, M.; Tsao, R.; Williams, D. R.; Maiese, W.; Ellestad,
G. A. J. Org. Chem. 1994, 59, 4045-4047. (b) Bernan, V. S.; Montenegro,
D. A.; Korshalla, J. D.; Maiese, W. M.; Steinberg, D. A.; Greenstein, M.
J. Antibiot. 1994, 47, 1417-1424.
(7) Williams, R. M.; Flanagan, M. E.; Tippie, T. N. Biochemistry 1994, 33,
4086-4092.
(8) Williams, R. M.; Herberich, B. J. Am. Chem. Soc. 1998, 120, 10272-
(4) (a) Tomita, F.; Takahashi, K.; Shimuzu, K. J. Antibiot. 1983, 36, 463-
467. (b) Takahashi, K.; Tomita, F. J. Antibiot. 1983, 36, 468-470.
(5) Scott, J. D.; Tippie, T. N.; Williams, R. M. Tetrahedron Lett. 1998, 39,
3659-3662.
10273.
(9) (a)Pommier, Y.; Kohlhagen, G.; Bailly, C.; Waring, M.; Mazumder, A.;
Kohn, K. W. Biochemistry 1996, 35, 13303-13309. (b) Moore, R. M., II;
Seaman, F. C.; Wheelhouse, R. T.; Hurley, L. H. J. Am. Chem. Soc. 1998,
120, 2490-2491.
(6) Scott, J. D.; Williams, R. M. Angew. Chem. 2001, 40, 1463-1465.
9
10.1021/ja0174027 CCC: $22.00 © 2002 American Chemical Society
J. AM. CHEM. SOC. VOL. 124, NO. 12, 2002 2951