1996
DOI: 10.1021/jo9605298
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Synthesis, Chemical Properties, and Preliminary Evaluation of Substituted CBI Analogs of CC-1065 and the Duocarmycins Incorporating the 7-Cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one Alkylation Subunit:  Hammett Quantitation of the Magnitude of Electronic Effects on Functional Reactivity

Abstract: The synthesis of 7-cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CCBI), a substituted CBI derivative bearing a C7 cyano group, is described in efforts that establish the magnitude of potential electronic effects on the functional reactivity of the agents. The CCBI alkylation subunit was prepared by a modified Stobbe condensation/Friedel−Crafts acylation for generation of the appropriately functionalized naphthalene precursors followed by 5-exo-trig aryl radical−alkene cyclization for synthesis of t… Show more

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Cited by 54 publications
(42 citation statements)
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“…Nevertheless, 6 had to be used in the carbonylation reaction as the Curtius rearrangement of the corresponding acid to the protected naphtholamine could not be achieved after the introduction of the TMSE ester moiety. Iodination of 7 employing NIS [ 20 , 21 ] with TsOH·H 2 O as catalyst followed by N -alkylation of the formed 8 with 1,3-dichloropropene and subsequent radical cyclization [ 22 ] using the untoxic tris-(trimethylsilyl)-silan (TTMSS) [ 23 ] as hydride source and AIBN as radical starter provided seco -CBI derivative 10 in 65 % yield over three steps.…”
Section: Resultsmentioning
confidence: 99%
“…Nevertheless, 6 had to be used in the carbonylation reaction as the Curtius rearrangement of the corresponding acid to the protected naphtholamine could not be achieved after the introduction of the TMSE ester moiety. Iodination of 7 employing NIS [ 20 , 21 ] with TsOH·H 2 O as catalyst followed by N -alkylation of the formed 8 with 1,3-dichloropropene and subsequent radical cyclization [ 22 ] using the untoxic tris-(trimethylsilyl)-silan (TTMSS) [ 23 ] as hydride source and AIBN as radical starter provided seco -CBI derivative 10 in 65 % yield over three steps.…”
Section: Resultsmentioning
confidence: 99%
“…[9] Radical cyclisation of 19a and 19b, mediated by tris(trimethylsilyl)silane and azobisisobutyronitrile in toluene, worked well to afford the cyclised products 22a-c (Scheme 7) in 85-92 % yields as racemic mixtures, and in the case of 19b in a nearly 1:1 ratio of the two possible diastereomers 22b/22c. [10] Similarly, metal-induced cyclisation of (2R,3R)-21b in the presence of ZnCl 2, MeLi and TMS-SCN led to the benzindole derivative (1S,10R)-23b in 53 % yield, in this case as a pure enantiomer (Ͼ99 % ee) and a pure diastereomer. In comparison, (2R)-21a gave the Scheme 8.…”
Section: Introductionmentioning
confidence: 91%
“…Treatment of (1S)-23a under Appel conditions afforded enantiopure (1S)-22a, [10] whereas treatment of (1S,10R)-23b with SOCl 2 in the presence of pyridine led to enantiopure (1S,10R)-22b. Alternatively, the enantiomeric mixture of rac-22a obtained from 19a could be resolved by preparative HPLC on a chiral stationary support (Chiralpak IA), with ee values of 99.7 % for (+)-(1R)-22a and 99.2 % for (-)-(1S)-22a.…”
Section: Introductionmentioning
confidence: 98%
“…Prodrug (+)- 6 was synthesized 16 in 11 steps from known intermediate 7 17 as shown in Scheme 1. The phenol of 7 was protected as its benzyl ether and 8 was hydrolyzed using LiOH to provide the carboxylic acid 9 in good overall yield.…”
Section: Chemistrymentioning
confidence: 99%