Synthesis and Structural Characterization of β-Turn Mimics Containing (Z)-Chloroalkene Dipeptide Isosteres

Yuki Kodama, Sayuri Takeo, Junko Fujimoto, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi

J. Org. Chem. 2022, 87 (5), 2167–2177.

Described here is the synthetic, spectroscopic, crystallographic, and computational analysis of a series of peptidomimetics containing L-Xaa-D-Yaa-type (Z)-chloroalkene dipeptide isosteres (CADIs) that were measured in an investigation of the β-turn mimicry of this peptide bond surrogate. We found that the 1,3-allylic strain across the chloroalkene moiety engenders the hyperconjugative interactions between the chloroalkene moiety and the C–H bonding or antibonding orbitals of the C–H bonds in allylic positions. These effects contribute significantly to the stabilization of β-turn structures.

Fine-Bubble–Slug-Flow Hydrogenation of Multiple Bonds and Phenols

Takuya Iio, Kohei Nagai, Tomoki Kozuka, Akhtar Mst Sammi, Kohei Sato, Tetsuo Narumi, Nobuyuki Mase∗

Synlett, 2020, 31, 1919-1924

We describe a promising method for the continuous hydrogenation of alkenes or alkynes by using a newly developed fine-bubble generator. The fine-bubble-containing slug-flow system was up to 1.4 times more efficient than a conventional slug-flow method. When applied in the hydrogenation of phenols to the corresponding cyclohexanones, the fine bubble–slug-flow method suppressed over-reduction. As this method does not require the use of excess gas, it is expected to be widely applicable in improving the efficiency of gas-mediated flow reactions.

Late-​stage solubilization of poorly soluble peptides using hydrazide chemistry

Kohei Sato*, Shoko Tanaka, Junzhen Wang, Kenya Ishikawa, Shugo Tsuda, Tetsuo Narumi, Taku YoshiyaTaku Yoshiya

Org. Lett. 2021, 23, 1653–1658. 

A novel late-stage solubilization of peptides using hydrazides is described. A solubilizing tag was attached through a selective N-alkylation at a hydrazide moiety with the aid of a 2-picoline–borane complex in 50% acetic acid–hexafluoro-2-propanol. The tag, which tolerates ligation and desulfurization conditions, can be detached by a Cu-mediated selective oxidative hydrolysis of the N-alkyl hydrazide. This new method was validated through the synthesis of HIV-1 protease.

Stereoselective synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres and their application to 14-mer RGG peptidomimetics

H. Okita, Y. Kato, T. Masuzawa, K. Arai, S. Takeo, K. Sato, N. Mase T. Oyoshi and T. Narumi*

RSC Adv., 2020, 10, 29373-29377.

Stereoselective and efficient synthesis of Gly-Gly-type (E)-methylalkene and (Z)-chloroalkene dipeptide isosteres is realized by organocuprate-mediated single electron transfer reduction. The synthetic isosteres can be used in Fmoc-based solid phase peptide synthesis, resulting in the preparation of the 14-mer RGG peptidomimetics containing an (E)-methylalkene or a (Z)-chloroalkene unit.

Pendant Alkoxy Groups on N-Aryl Substitutions Drive the Efficiency of Imidazolylidene Catalysts for Homoenolate Annulation from Enal and Aldehyde

R. Kyan, K. Sato, N. Mase and T. Narumi*

Angew. Chem. Int. Ed. 2020, 59, 19031–19036.

The formation of conjugated Breslow intermediate is a turnover-limiting step in the NHC-catalyzed γ-butyrolactone formation via homoenolate addition. Structural and mechanistic studies including deuterium exchange experiments revealed that the formation of conjugated Breslow intermediate is facilitated by the proximity effects of pendant alkoxy groups on ortho-N-aryl groups of imidazolylidene catalyst.

Chemoselective Umpolung of Enals for Asymmetric Homoenolate Cross-Annulation of Enals and Aldehydes Catalyzed by N-Heterocyclic Carbene

R. Ide, R. Kyan, T. P. Le, Y. Kitagawa, K. Sato, N. Mase and T. Narumi*

Org. Lett. 2019, 21, 22, 9119–9123.

An asymmetric homoenolate cross-annulation of enals and aldehydes with high enantioselectivity is realized by NHC-catalyzed chemoselective umpolung of enals. The reaction proceeds in a highly chemoselective manner, selectively generating the conjugated Breslow intermediates from enals rather than aldehydes, enabling the homoenolate addition of enals to aldehydes in preference to competing acyl anion-mediated reactions. Enantioenriched substituted γ-butyrolactones are formed in good yields with high enantioselectivities.