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Complementary to studies that provided the first yatakemycin total synthesis resulting in its structure revision and absolute stereochemistry assignment, a second-generation asymmetric total synthesis is disclosed herein. Since the individual yatakemycin subunits are identical to those of duocarmycin SA (alkylation subunit) or CC-1065 (central and right-hand subunits), the studies also provide an improvement in our earlier total synthesis of CC-1065 and, as detailed herein, have been extended to an asymmetric total synthesis of (+)-duocarmycin SA. Further extensions of the studies provided key yatakemycin partial structures and analogues for comparative assessments. This included the definition of the DNA selectivity (adenine central to a five-base-pair AT sequence, e.g., 5'-AAAAA), efficiency, relative rate, and reversibility of ent-(-)-yatakemycin and its comparison with the natural enantiomer (identical selectivity and efficiency), structural characterization of the adenine N3 adduct confirming the nature of the DNA reaction, and comparisons of the cytotoxic activity of the natural product (L1210, IC50 = 5 pM) with those of its unnatural enantiomer (IC50 = 5 pM) and a series of key partial structures including those that probe the role of the C-terminus thiomethyl ester. The only distinguishing features between the enantiomers is that ent-(-)-yatakemycin alkylates DNA at a slower rate (krel = 0.13) and is reversible, whereas (+)-yatakemycin is not. Nonetheless, even ent-(-)-yatakemycin alkylates DNA at a faster rate and with a greater thermodynamic stability than (+)-duocarmycin SA, illustrating the unique characteristics of such "sandwiched" agents.

We describe the design, synthesis, and physicochemical and biological properties of a novel series of 7-heterocycle-6-trifluoromethyl-3-oxoquinoxaline-2-carboxylic acids bearing a substituted phenyl group joined through a urethane or urea linkage to the heterocycle at the 7 position. Introduction of the trifluoromethyl group at the 6 position conferred good biological activity, including neuroprotective effects, as well as good physicochemical properties. In terms of α-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) affinity, a urea linkage was equivalent to a urethane linkage and a pyrrole ring at the 7 position reduced affinity in comparison with an imidazole ring. Among this series, compound 14h ( KRP - 199 ), which has a 4-carboxyphenyl group joined through a urethane linkage to a 7-imidazolyl heterocycle, was found to possess high potency and selectivity for the AMPA-R in vitro and to exhibit good neuroprotective effects in vivo. Furthermore, the compound showed good physicochemical properties, including stability to light and good solubility in aqueous solutions.

We describe the synthesis, physicochemical, and biological properties of a novel series of 7-imidazolyl-6-trifluoromethyl quinoxalinecarboxylic acids with a substituted phenyl group attached through a urethane linkage at the C-7 position. We found that the introduction of trifluoromethyl group at the C-6 position brought about good biological activity and physicochemical properties. Among them, compound 9k (KRP-199), which has a 4-carboxyphenyl group, was found to possess high potency and selectivity for the AMPA-R in vitro and to exhibit good neuroprotective effects in vivo. Furthermore, the compound showed good physicochemical properties such as stability to light and good solubility in aqueous solutions.

The title synthesis was achieved by employing oxidative cyclization of the enaminoester as a key step. Some of these novel 3-methoxycarbonyl-2-trifluoromethylcyclopropapyrroloindole (MCTFCPI) derivatives, dl- 10c,d , (+)-10d, and (S)- 21b were found to exhibit antitumor activity against murine leukemia and murine solid tumors more prominent than that of the known CPI derivatives dl- 4 and the clinical trial candidates 5 and 7.

The palladium-catalyzed reaction of 2-alkynylanilines and 2-alkynylphenols in the presence of carbon monoxide and methanol under basic conditions gave the sequential cyclization / carbonylation products, methyl 2-substituted indole and benzo[b]-furan-3-carboxylates. Similar reaction of 2-alkynylbenzamides gave 3-alkylidenisoindole derivatives.

The palladium-catalyzed cross-coupling reaction of aryl iodides with 3,3,3-triethoxy-1-propyne gave 1-aryl-3,3,3-triethoxy-1-propynes which were converted to the corresponding ethyl arylpropiolates. The arylpropiolates were also synthesized from the cross-coupling reactions of aryl iodides with 2-ethoxycarbonyl-1-ethynylzinc chloride or ethyl (tributylstannyl)propiolate, but the reactions were not generally applicable

1,3-Dipolar cycloaddition reaction of diazomethane and ethyl diazoacetate with tributylstannyl-acetylenes occurred regioselectively to afford the corresponding 3(5)-tributylstannylpyrazoles. The cycloaddition reaction of 3-phenylsydnone with the stannylacetylenes proceeded also regioselectively, and 3-tributylstannyl-1-phenylpyrazoles were isolated. 4-Tributylstannyl- and 5-tributylstannyl-1-phenylpyrazole were prepared by the stannylation of 4-lithio- and 5-lithio-1-phenylpyrazoles with tributylstannyl chloride. Iodination, benzoylation, and phenylation of the stannylpyrazoles were examined

The title synthesis was achieved by employing oxidative cyclization of the enaminoester as a key step. Some of these novel 3-methoxycarbonyl-2-trifluoromethylcyclopropapyrroloindole (MCTFCPI) derivatives, dl- 10c,d , (+)-10d, and (S)- 21b were found to exhibit antitumor activity against murine leukemia and murine solid tumors more prominent than that of the known CPI derivatives dl- 4 and the clinical trial candidates 5 and 7.

We describe the design, synthesis, and biological properties of a novel series of 7-substituted 6-nitro-3-oxoquinoxaline-2-carboxylic acids. After designing, studying the structure–activity relationships, and evaluating the properties of various compounds, we found that 7-heterocyclic-6-nitro-3-oxoquinoxaline-2-carboxylic acids that contain a substituted phenyl group linked through urethane at the 7 position possess good α-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) antagonistic activity. Among the compounds tested, compound 29p (GRA-293), which has a 4-carboxy group on the terminal phenyl moiety, exhibited high potency and selectivity for the AMPA-R in vitro and good neuroprotective efficacy in vivo. It also showed good aqueous solubility.

The synthesis and biological properties of a novel class of 7-heterocycle-substituted quinoxalinecarboxylic acids, which bear a substituted phenyl group through a urethane linkage at the C-7 position, are described. One of the synthesized compounds, 15l, which has a 4-carboxyphenyl carbamoyloxymethyl imidazole group at the C-7 position and is water-soluble, was found to possess high potency in vitro and showed excellent neuroprotective efficacy in vivo.

The palladium-catalyzed cross-coupling reaction of aryl iodides with 3,3,3-triethoxy-1-propyne gave 1-aryl-3,3,3-triethoxy-1-propynes which were converted to the corresponding ethyl arylpropiolates. The arylpropiolates were also synthesized from the cross-coupling reactions of aryl iodides with 2-ethoxycarbonyl-1-ethynylzinc chloride or ethyl (tributylstannyl)propiolate, but the reactions were not generally applicable

1,3-Dipolar cycloaddition reaction of diazomethane and ethyl diazoacetate with tributylstannyl-acetylenes occurred regioselectively to afford the corresponding 3(5)-tributylstannylpyrazoles. The cycloaddition reaction of 3-phenylsydnone with the stannylacetylenes proceeded also regioselectively, and 3-tributylstannyl-1-phenylpyrazoles were isolated. 4-Tributylstannyl- and 5-tributylstannyl-1-phenylpyrazole were prepared by the stannylation of 4-lithio- and 5-lithio-1-phenylpyrazoles with tributylstannyl chloride. Iodination, benzoylation, and phenylation of the stannylpyrazoles were examined