Published on Web 05/03/2008
Asymmetric Total Synthesis of (-)-Quinocarcin
Yan-Chao Wu, Me´lanie Liron, and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France
Received January 27, 2008; E-mail: zhu@icsn.cnrs-gif.fr
Abstract: (-)-Quinocarcin (1) has been synthesized in a longest linear sequence of 22 steps from
3-hydroxybenzaldehyde in 16% overall yield. The Pictet-Spengler reaction of L-tert-butyl-2-bromo-5-hydroxy
phenylalanate (17), synthesized according to Corey-Lygo’s enantioselective alkylation process, with
benzoxyacetaldehyde (12) under mild acidic conditions afforded 1,3-cis tetrahydroisoquinoline 20 as an
only isolable stereomer in 91% yield. The diazabicycle[3,2,1]-octane ring system of 28 was constructed by
a silver tetrafluoroborate-promoted intramolecular Mannich reaction using amino thioether as a latent
N-acyliminium species and tethered silyl enol ether as a nucleophile. Using amino thioether instead of
aminal as a precursor of N-acyliminium was of high importance to the success of this otherwise disfavored
5-endo-Trig cyclization. A Hf(OTf)4-catalyzed (0.1 equiv) transformation of aminal to amino thioether was
uncovered in the course of this study, allowing the conversion of tricyclic aminal 24 to amino thioether 25
to be realized in high yield. From the bridged tetracyclic compound 28, a sequence of oxidation of aldehyde
to acid, global deprotection under hydrogenolysis conditions, and one-pot partial reduction of lactam to
aminal/oxazolidine formation completed the total synthesis of the pentacyclic (-)-quinocarcine.
Introduction
(-)-Quinocarcin (1) is a pentacyclic tetrahydroisoquinoline
alkaloid1 that was isolated by Takahashi and Tomita in 1983
from the culture broth of Streptomyces melunoVinuceus.2 It
exhibited potent antitumor activities against a variety of tumor
cell lines and its citrate salt (KW2152) had been in clinic trials
in Japan.3,4 The DX-52-1 (2), a more stable compound resulting
from the ring opening of oxazolidine by cyanide, also has
significant antitumor activities.4 Quinocarcin underwent self-
redox disproportionation under anaerobic conditions leading to
inactive quinocarcinol (3) and quinocarcinamide (4).3d The
structurally related (-)-tetrazomine (5) displayed similar anti-
tumor antibiotic activity (see Figure 1).5 The antiproliferative
effect of (-)-quinocarcin was partly accounted for by its ability
Figure 1. Structures of (-)-quinocarcin (1) and related alkaloids.
(1) For a comprehensive review of the chemistry and biology of
tetrahydroisoquinoline alkaloids, see: Scott, J. D.; Williams, R. M.
Chem. ReV. 2002, 102, 1669–1730.
to inhibit RNA and/or DNA synthesis.3a However, it has been
suggested that (-)-quinocarcin and (-)-tetrazomine exerted their
cytotoxic activity through the expression of multiple mechanisms
including the mediation of oxidative damage to DNA via the
reduction of molecular oxygen to superoxide by the autoredox
disproportionation of the fused oxazolidine.6
The fascinating molecular architecture and important biologi-
cal profile of quinocarcin have attracted significant attention
from the synthetic community, culminating in one racemic7 and
three asymmetric synthesis of (-)-quinocarcine.8–10 Total
syntheses of more stable quinocarcinol methyl ester11 and
(2) (a) Takahashi, K.; Shimizu, K. J. Antibiot. 1983, 463–467. (b)
Takahashi, K.; Tomita, F. J. Antibiot. 1983, 468–470. (c) Tomita, F.;
Takahashi, K.; Tamaoki, T. J. Antibiot. 1984, 1268–1272.
(3) (a) Fujimoto, K.; Oka, T.; Morimoto, M. Cancer Res. 1987, 47, 1516–
1522. (b) Kanamaru, R.; Konishi, Y.; Ishioka, C.; Kakuta, H.; Sato,
T.; Ishikawa, A.; Asamura, M.; Wakui, A. Cancer Chemother.
Pharmacol. 1988, 22, 197–200. (c) Saito, H.; Hirata, T.; Kasai, M.;
Fujimoto, K.; Ashizawa, T.; Morimoto, M.; Sato, A. J. Med. Chem.
1991, 34, 1959–1966. (d) Kahsai, A. W.; Zhu, S. T.; Wardrop, D. J.;
Lane, W. S.; Fenteany, G. Chem. Biol. 2006, 13, 973–983.
(4) (a) Plowman, J.; Dykers, D. J.; Narayanan, V. L.; Abbott, B. J.; Saito,
H.; Hirata, T.; Grever, M. R. Cancer Res. 1995, 55, 862–867. (b)
Bunnell, C. A.; Supko, J. G.; Eder, J. P.; Clark, J. W.; Lynch, T. J.;
Kufe, D. W.; Shulman, L. N. Cancer Chemother. Pharmacol. 2001,
48, 347–355.
(6) (a) Williams, R. M.; Flanagan, M. E.; Tippie, T. N. Biochemistry 1994,
33, 4086–4092. (b) Williams, R. M.; Glinka, T.; Flanagan, M. E.;
Gallegos, R.; Coffman, H.; Pei, D. H. J. Am. Chem. Soc. 1992, 110,
733–740.
(5) (a) Suzuki, K.; Sato, T.; Morioka, M.; Nagai, K.; Abe, K.; Yamaguchi,
H.; Saito, T. J. Antibiot. 1991, 44, 479–485. (b) Ponzo, V. L.;
Kaufman, T. S. J. Chem. Soc., Perkin Trans. 1 1997, 3131–3133. (c)
Wipf, P.; Hopkins, C. R. J. Org. Chem. 2001, 66, 3133–3139. (d)
Scott, J. D.; Williams, R. M. Angew. Chem., Int. Ed. 2001, 40, 1463–
1465. (e) Scott, J. D.; Williams, R. M. J. Am. Chem. Soc. 2002, 124,
2951–2956.
(7) Fukuyama, T.; Nunes, J. J. J. Am. Chem. Soc. 1988, 110, 5196–5198.
(8) (a) Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1992, 114,
2767–2768. (b) Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc.
1993, 115, 10742–10753.
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7148 J. AM. CHEM. SOC. 2008, 130, 7148–7152
10.1021/ja800662q CCC: $40.75
2008 American Chemical Society