Abstract
Analogs of the seco-cyclopyrroloindoline (seco-CPI), the DNA alkylation pharmacophore of CC-1065 and the duocarmycins, can be prepared through a 5-exo-trig radical cyclization of a free radical and a 3-chloro-2-allylic moiety. This manuscript reports an unexpected discovery that, depending on the structure and stability of the free radical, the cyclization process leads to the production of an appreciable amount of seco- cyclopropyltetrahydroquinolines 7a-d along with the seco-cyclopropoyltetra- hydroindoline products (6a-e). For instance, free radical reaction of the bromoallylic chloride 5a produced an equal amount of 6-benzyloxy-N-t-butoxycarbonyl-3- (chloromethyl)furano[e]indoline (6a), and 7-benzyloxy-N-t-butoxycarbonyl-3-chloro- 1,2,3,4-tetrahydrofurano[f]quinoline (7a). Three other examples that produced mixtures of indoline and quinoline products are provided. In only one of the examples reported in this manuscript, the 6-benzyloxy-N-t-butoxycarbonyl-3-(chloromethyl)benzo[e]indoline, was a seco-CBI precursor 6e formed exclusively, consistent with literature precedents.
Highlights
CC-1065 (1) and the duocarmycins [such as duocarmycin SA (2), duocarmycin C1 (3) and duocarmycin C2 (4)], whose structures are given in Figure 1, are members of an extremely potent group of anticancer agents that contain an interesting cyclopropylpyrroloindolone (CPI) DNA alkylating functionality
We propose that formation of the quinolines 7a-d is due to the generation of a stabilized radical intermediate, formed via a 5-exo-trig ring closure reaction
Quinoline 7d: Colorless oily residue; TLC (10% EtOAc-Hexane) Rf = 0.51; IR (KBr, cm-1) 2991, 1704, 14062, 1368, 1328, and 1147; 1H-NMR (CDCl3, 500 MHz) 8.56 (d, 2.0, 1H), 8.36 (d, 8.0, 1H), 8.03 (s br, 1H), 7.94 (dd, 2.0, 8.0, 1H), 7.54 (d, 8.0, 7H), 7.48 (t, 8.0, 2H), 7.39 (t, 8.0, 1H), 5.30 (s, 2H), 4.40 (t, 6.0, 2H), 4.21 (t, 6.0, 2H), 3.80 (m, 3H), 1.82 (quintet, 6.0, 2H), 1.60 (s, 9H), 1.50 (quintet, 6.0, 2H), 0.98 (t, 6.0, 3H); EIMS m/z
Summary
CC-1065 (1) and the duocarmycins [such as duocarmycin SA (2), duocarmycin C1 (3) and duocarmycin C2 (4)], whose structures are given in Figure 1, are members of an extremely potent group of anticancer agents that contain an interesting cyclopropylpyrroloindolone (CPI) DNA alkylating functionality.
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