Iridium-catalyzed reductive nucleophilic addition to N-methoxyamides is reported. The reaction took place in high yields in the presence of a variety of sensitive functional groups such as esters and nitro groups. Mechanistic studies revealed that the reaction of N-methoxyamides proceeded without equilibrium to an enamine intermediate in contrast to that with tert-amides.

As the complexity of targeted molecules increases in modern organic synthesis, chemoselectivity is recognized as an important factor in the development of new methodologies. Chemoselective nucleophilic addition to amide carbonyl centers is a challenge because classical methods require harsh reaction conditions to overcome the poor electrophilicity of the amide carbonyl group. We have successfully developed a reductive nucleophilic addition of mild nucleophiles to tertiary amides, secondary amides, and N-methoxyamides that uses the Schwartz reagent [Cp2 ZrHCl]. The reaction took place in a highly chemoselective fashion in the presence of a variety of sensitive functional groups, such as methyl esters, which conventionally require protection prior to nucleophilic addition. The reaction will be applicable to the concise synthesis of complex natural alkaloids from readily available amide groups.

Vasculogenic mimicry (VM) is the formation of microvascular channels by cancer cells. VM requires cellular processes that are regulated by changes in cellular migration and morphology. Cofilin (CFL), a key regulator of actin depolymerization, has been reported to affect malignant phenotypes of cancer. We show that treatment with inhibitors of actin dynamics suppresses VM in MDA-MB-231 human breast cancer cells. We established CFL-knockout (KO) MDA-MB-231 cells and found that VM was attenuated in CFL-KO cells. Although the re-expression of wild-type CFL restored VM in CFL-KO cells, inactive phosphomimetic CFL failed to do so. Collectively, our results demonstrate that CFL is a critical regulator of VM and implicate CFL as a novel therapeutic target for breast cancer.

Chemoselective Reductive Nucleophilic Addition to Tertiary Amides, Secondary Amides, and N-Methoxyamides. -The title transformation consists of (i) reduction of the amide carbonyl group, (ii) formation of an iminium ion with an acid, and (iii) C-C bond formation with a mild nucleophile. The high oxophilicity of the Schwartz reagent, which enables direct reduction of the amide carbonyl group, is crucial for the success of the reaction. -(NAKAJIMA, M.; ODA, Y.; WADA, T.; MINAMIKAWA, R.; SHIROKANE, K.; SATO*, T.; CHIDA, N.; Chem. -Eur. J. 20 (2014) 52, 17565-17571, http://dx.doi.org/10.1002/chem.201404648 ; Dep. Appl. Chem., Fac. Sci. Technol., Keio Univ., Kohoku, Yokohama 223, Japan; Eng.) -M. Paetzel 22-028

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