C O M M U N I C A T I O N S
Scheme 3. Synthesis of Indolecarboxylic Acida
indoline 21, whose regioselective bromination was followed by the
copper-mediated aryl amination to afford the tricyclic skeleton 22.
Finally, through application of a set of transformations essentially
identical to those used for the synthesis of 1, we were able to
complete the total synthesis of 2.
In conclusion, we have achieved a convergent synthesis of 1,
whose flexible strategy also enabled a straightforward synthesis of
2. Furthermore, the novel copper-mediated aryl amination reaction
has been used for forming all of the aryl-nitrogen bonds present
in the duocarmycins, thereby providing a superior alternative to
the existing palladium-catalyzed protocols.
a Reagents and conditions: (a) Br2, AcOH, CH2Cl2, 0 °C, 45 min, 87%;
(b) 16, TMG, CH2Cl2, 23 °C, 3 days, 97%; (c) CuI (1.5 equiv), CsOAc (7
equiv), DMSO, 23 °C, 24 h, 98%; (d) H2, Pd-C, EtOAc-EtOH, 23 °C, 3
h, 99%; (e) KOH, MeOH, reflux, 1 h, 89%; (f) SOCl2, toluene, 60 °C, 20
min.
Acknowledgment. We thank Dr. Yutaka Kanda (Kyowa Hakko
Kogyo) for providing spectral data for the natural duocarmycin A.
This work was financially supported in part by CREST, JST, and
the Ministry of Education, Culture, Sports, Science, and Technol-
ogy, Japan.
Scheme 4. Synthesis of (+)-Duocarmycin SAa
Supporting Information Available: Experimental data and spectra
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) 1: (a) Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano,
K.; Kawamoto, I.; Tomita, F.; Nakano, H. J. Antibiot. 1988, 41, 1915.
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(3) 1: (a) Fukuda, Y.; Nakatani, K.; Ito, Y.; Terashima, S. Tetrahedron Lett.
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Soc. 1992, 114, 10056. (d) Fukuda, Y.; Terashima, S. Tetrahedron Lett.
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Pharm. Bull. 1998, 46, 400. (f) Tietze, L. F.; Haunert, F.; Feuerstein, T.;
Herzig, T. Eur. J. Org. Chem. 2003, 562. For a review, see: (g) Boger,
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(4) Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T. J. Am. Chem. Soc. 1996,
118, 2301.
(5) Ayerbe, M.; Morao, I.; Arrieta, A.; Linden, A.; Cossio, F. P. Tetrahedron
Lett. 1996, 37, 3055.
(6) Prepared from methyl cinnamate: (i) AD-mix-R, MsNH2, t-BuOH-H2O,
23 °C, 24 h, 66% (>99% ee after recrystallization); (ii) 2,2-dimethoxy-
propane, cat. p-TsOH, acetone, 23 °C, 3 h, 97%; (iii) DIBAL, toluene,
-78 °C; MeOH, -78 to 23 °C; Et3N, CH3NO2, 23 °C, 96%; (iv) MsCl,
Et3N, CH2Cl2, 0 °C, 15 min, 88%.
(7) Prepared from p-nitrophenol: (i) MsCl, Et3N, CH2Cl2, 0 to 23 °C, 3 h,
88%; (ii) H2 (900 psi), Ra-Ni, EtOAc, 23 °C, 24 h, quant.; (iii) Br2,
MeOH-CH2Cl2 (1:1), 0 to 23 °C, 30 min, 87%; (iv) NaNO2, H2SO4,
CH3CN-H2O (1:1), 0 °C, 20 min; then KI, 0 to 23 °C, 96%; (v) KOH,
CH2Cl2-MeOH (4:1), 23 °C, 5 min, quant.; (vi) BnBr, K2CO3, DMF, 23
°C, 1 h, 88%.
(8) For generation of benzyne from a similar substrate in THF, see: Du, C.
J. F.; Hart, H.; Ng, K. K. D. J. Org. Chem. 1986, 51, 3162.
(9) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301.
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1999, 576, 125.
a Reagents and conditions: (a) n-BuLi, THF, -78 °C; then I2, 97%; (b)
20, Pd(OAc)2, P(o-tolyl)3, Et3N, CH3CN, 90 °C, 4 h, 72%; (c) NBS, DMF,
23 °C, 5 min, 82%; (d) CuI (2 equiv), CsOAc (xs), DMSO, 23 °C, 10 min,
quant.; (e) TrocCl, NaHCO3, CH3CN, 70 °C, 20 min, 77%; (f) Zn, KH2PO4,
H2O-THF (5:1), 23 °C, 1 h, 58%; (g) 12, pyr, CH2Cl2, 0 °C, 10 min,
83%; (h) TBAF, THF, 23 °C, 30 min, 85%; (i) MsCl, pyr, 0 °C, 10 min,
88%; (j) H2, Pd-C, EtOAc-EtOH, 23 °C, 10 min, 81%; (k) Cs2CO3,
CH3CN, 23 °C, 1 h, 92%.
10. Subsequent deprotection of the N-benzyl group afforded the
free indoline 11, which was acylated with acid chloride 12.
Conversion of the TBS ether to the mesylate and subsequent
hydrogenolysis of the benzyl and Cbz groups furnished the substrate
for the final spirocyclization. Upon treatment with excess cesium
carbonate in acetonitrile, the mesylate 13 underwent smooth
cyclization to afford (+)-duocarmycin A (1).
It is noteworthy that preparation of the indolecarboxylic acid
moiety16 involved once again a successful implementation of the
copper-mediated aryl amination (Scheme 3). Thus, the Horner-
Wadsworth-Emmons reaction of aldehyde 15 with phosphonate
16 furnished the requisite amination precursor 17 with excellent
stereocontrol. When treated with excess copper iodide and cesium
acetate at room temperature, the amination reaction proceeded
smoothly to give the desired indole 18 in near-quantitative yield,
which was then converted to the acid chloride 12 in three steps.
For the synthesis of duocarmycin SA (2), the common indoline
intermediate 7 was first converted to the iodide 19 (Scheme 4).
The subsequent Heck reaction with dehydroalanine 2017 gave
(11) The major byproduct was the corresponding debrominated indoline,
obtained in yields of up to 10% (always less in amount than the Pd catalyst
used in the reaction).
(12) (a) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett 2002,
231. For similar copper-catalyzed aminations, see: (b) Klapars, A.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (c) Kwong, F.
Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581.
(13) Prepared from dimethyl malonate: (i) NaNO2, AcOH, 0 to 23 °C, 4 h;
(ii) H2 (1400 psi), Pd-C, EtOH, 23 °C, 12 h, 91% (two steps); (iii) CbzCl,
pyr, CH2Cl2, 0 °C, 5 min, 96%; (iv) MeI, MeONa, MeOH, 50 °C, 2 h,
76%; (v) PLE, acetone-H2O, pH 7.5-8.5, 23 °C, 3 days, quant. (94%
ee, >98% ee after recrystallization); (vi) triphosgene, Et3N, EtOAc, 23
°C, 5 min, quant.
(14) Pines, S. H.; Karady, S.; Sletzinger, M. J. Org. Chem. 1968, 33, 1758.
(15) Mitchell, R. H.; Lai, Y. H.; Williams, R. V. J. Org. Chem. 1979, 44,
4733.
(16) For a standard synthesis, see: Bolton, R. E.; Moody, C. J.; Rees, C. W.;
Tojo, G. J. Chem. Soc., Chem. Commun. 1985, 1775.
(17) Dygos, J. H.; Yonan, E. E.; Scaros, M. G.; Goodmonson, O. J.; Getman,
D. P.; Periana, R. A.; Beck, G. R. Synthesis 1992, 741.
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