カテゴリー: Publication

β,γ-trans-selective γ-butyrolactone formation via homoenolate cross-annulation of enals and aldehydes catalyzed by sterically hindered N-heterocyclic carbene

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β,γ-trans-selective γ-butyrolactone formation via homoenolate cross-annulation of enals and aldehydes catalyzed by sterically hindered N-heterocyclic carbene

Ryuji Kyan, Yuya Kitagawa, Ryuji Ide, Kohei Sato, Nobuyuki Mase, Tetsuo Narumi

Tetrahedron, 2021, 91, 1321

Highly sterically hindered N-heterocyclic carbenes (NHCs), can be readily prepared from the corresponding anilines, and serve as organocatalysts in NHC-catalyzed homoenolate cross-annulation of α,β-enals and aryl aldehydes. This catalysis enables the convergent construction of β,γ-trans-disubstituted γ-butyrolactones that are an important class of molecules in synthetic and medicinal chemistry. The steric features of N-aryl substituents contribute to the selectivity and electronic ones affected the efficiency of this reaction, which proceeds with high diastereoselectivity and affords a variety of β,γ-diaryl-γ-butyrolactones in up to 91% yield with up to 1:99 dr.

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

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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

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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.

Gly-Gly-type Alkene Isosteres for Beta-turn Peptidomimetics

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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 Drive the Efficiency of NHC Catalyst

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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 Catalyzed by NHC

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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.

Methodology: Chloroalkene’s Powerful Potentials

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Improvement of chemical stability of conjugated dienes by chlorine substitution

T. Narumi*, T. Nishizawa, T. Imai, R. Kyan, H. Taniguchi, K. Sato, N. Mase

Tetrahedron, 2018, 74 (45) 6527-6533.

Conjugated systems have versatile utilities in various fields including organic synthesis, pharmaceutical development, and material science. Such systems take advantage of their properties, which include their unique reactivity, relatively rigid structures, and low HOMO-LUMO gap energies. Their utility and the handling of conjugated systems however are both limited by excessively high photosensitivity and reactivity. We now report a novel molecular approach to the improvement of the chemical stability of the acyclic conjugated system against the photolysis and oxidation reactions simply by the introduction of a chlorine atom into the conjugated system. Systematic studies of substrates with various substituents reveal that the improved chemical stability is based on the additive effects of the steric and electronic properties of the chlorine atom substituent.