Synthesis of challenging 6-functionalized 1-oxaspiro[3.3]heptanes – New scaffolds for drug discovery

Kozyriev, Yevhenii K.; Palchykov, Vitalii A.

doi:10.1016/j.tetlet.2023.154515

Cited by 4 publications

References 31 publications

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1‐Oxa‐2,6‐Diazaspiro[3.3]heptane as a New Potential Piperazine Bioisostere – Flow‐Assisted Preparation and Derivatisation by Strain‐Release of Azabicyclo[1.1.0]butanes

Graziano,

Natho,

Andresini

et al. 2024

Adv Synth Catal

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The development of novel strained spiro heterocycles (SSHs) as bioisosteres for aromatic or non‐strained aliphatic rings is highly sought after for improving drug design. Their high molecular rigidity and predictable vectorization can enhance drug‐likeness, target selectivity and clinical success. Towards this goal, 1‐oxa‐2,6‐diazaspiro[3.3]heptane (ODASE) is reported as a novel potential SSH‐bioisostere. We demonstrate through theoretical studies the potential of this strained spiro heterocycle to act as a bioisostere for piperazine. We have developed its synthesis from the highly strained azabicyclo[1.1.0]butyl intermediate through a robust and mild flow technology‐assisted two‐step protocol. Its tolerance and stability towards medicinally relevant N‐functionalisation protocols are studied, as well as its mild reduction to the C3‐aminoalkylazetidinol motif found in anti‐cancer drug cobimetinib.

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1‐Oxa‐2,6‐Diazaspiro[3.3]heptane as a New Potential Piperazine Bioisostere – Flow‐Assisted Preparation and Derivatisation by Strain‐Release of Azabicyclo[1.1.0]butanes

Graziano,

Natho,

Andresini

et al. 2024

Adv Synth Catal

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Four-membered ring systems

Sánchez,

Anaya

2024

Progress in Heterocyclic Chemistry

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Diastereoselective Construction of Spirocyclic Isobenzofurans via a Tandem Michael Addition/5-Exo-dig Cyclization Reaction

Mehdidoust,

Rajai-Daryasarei,

Hosseini

et al. 2024

J. Org. Chem.

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A practical approach for rapid and efficient access to spirocyclic isobenzofurans is described. The reaction proceeds through the cycloaddition of 1,6-ynenone derivatives and 4-nitro-1,3-diarylbutan-1-ones, promoted by Cs 2 CO 3 in the presence of Lproline as a catalyst. The advantages of this reaction include the formation of two C−C bonds and one C−O bond as well as mild reaction conditions. Extended spirocyclic isobenzofurans are obtained with good efficiency and diastereoselectivity under these mild conditions, and this new protocol avoids the use of any transition-metal reagents.

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Synthesis of challenging 6-functionalized 1-oxaspiro[3.3]heptanes – New scaffolds for drug discovery

Cited by 4 publications

References 31 publications

1‐Oxa‐2,6‐Diazaspiro[3.3]heptane as a New Potential Piperazine Bioisostere – Flow‐Assisted Preparation and Derivatisation by Strain‐Release of Azabicyclo[1.1.0]butanes

1‐Oxa‐2,6‐Diazaspiro[3.3]heptane as a New Potential Piperazine Bioisostere – Flow‐Assisted Preparation and Derivatisation by Strain‐Release of Azabicyclo[1.1.0]butanes

Four-membered ring systems

Diastereoselective Construction of Spirocyclic Isobenzofurans via a Tandem Michael Addition/5-Exo-dig Cyclization Reaction

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