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

被引：1
|
作者：
Graziano, Elena [1 ]
Natho, Philipp [1 ]
Andresini, Michael [1 ]
Mastrolorito, Fabrizio [1 ]
Mahdi, Iktedar [1 ]
Mesto, Ernesto [2 ]
Colella, Marco [1 ]
Degennaro, Leonardo [1 ]
Nicolotti, Orazio [1 ]
Luisi, Renzo [1 ]
机构：
[1] Univ Bari Aldo Moro, Dept Pharm Drug Sci, Via E Orabona 4, I-70125 Bari, Italy
[2] Univ Bari Aldo Moro, Dept Earth & Geoenvironm Sci, Via E Orabona 4, I-70125 Bari, Italy
来源：
ADVANCED SYNTHESIS & CATALYSIS | 2024年 / 366卷 / 18期
关键词：
Azabicyclo[1.1.0]butane; Flow chemistry; Bioisostere; Strained spiro heterocycle; Azetidine; MULTIFUNCTIONAL MODULES; STRUCTURAL-ANALYSIS; DRUG; ANALOGS; DESIGN;
D O I：
10.1002/adsc.202400781
中图分类号：
O69 [应用化学];
学科分类号：
081704 ;
摘要：
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 the anti-cancer drug cobimetinib. image
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页码：3894 / 3902
页数：9
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