An improved and scalable process for 3,8-diazabicyclo[3.2.1]octane analogues

Huang, Longjiang; Teng, Da

doi:10.1016/j.cclet.2010.11.030

Cited by 6 publications

(2 citation statements)

References 15 publications

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“…We were faced with the need to prepare large quantities of a building block containing the 3,8-diazabicyclo[3.2.1]octane system ( 3 ) to support a program with ongoing clinical trials . Although multiple strategies exist for preparing this ring system, the most commonly utilized precursor is meso -diethyl-2,5-dibromohexanedioate ( 1 ) . In addition to the 3,8-diazabicyclo[3.2.1]octane system, dibromide 1 has been demonstrated as a precursor to a variety of unique ring systems (Scheme , 1 → 2 , 1 → 4 ) .…”

Section: Introductionmentioning

confidence: 99%

Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form

Brown

Caporello

Goetz

et al. 2021

Org. Process Res. Dev.

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We describe a series of improvements to the synthesis of a 3,8-diazabicyclo[3.2.1]octane derivative that result in a reduced step count and higher overall efficiency compared to previously published syntheses. Our method includes optimization and mechanistic understanding of a key diastereoselective cyclization to achieve a >95:5 diastereomeric ratio, as well as demonstration of a unique enzyme-catalyzed amidation reaction using hexamethyldisilazane as both an ammonia source and scavenger. Finally, we identify a novel cocrystal solid form of the target compound that provides improved purity and material properties. Demonstration of the new chemistry to prepare >100 kg of the target compound serves to illustrate the robustness of the new process.

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Section: Introductionmentioning

confidence: 99%

Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form

Brown

Caporello

Goetz

et al. 2021

Org. Process Res. Dev.

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“…It is well known that macrocycle size is carried out prior to the synthesis of macrocycles—large enough not to be strained and small enough to avoid clashes with the protein. As part of our previous efforts on exploring biologically important heterocyclic compounds and natural products [33,34,35], we herein report the successful synthesis of a collection of 13- to 15-member macrocyclic scaffolds, which incorporate 1,3-benzene rings and hydroxyproline, and evaluate their anti-tumor activities toward human tumor cell lines A549, MDA-MB-231 and Hep G2.…”

Section: Introductionmentioning

confidence: 99%

Synthetic Strategy and Anti-Tumor Activities of Macrocyclic Scaffolds Based on 4-Hydroxyproline

Cao

Yang

et al. 2016

Molecules

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Abstract:A series of novel 13-to 15-member hydroxyproline-based macrocycles, which contain alkyl-alkyl ether and alkyl-aryl ether moieties, have been synthesized by the strategy of macrocyclization utilising azide-alkyne cycloaddition, Mitsunobu protocol and amide formation. Their anti-tumor activities towards A549, MDA-MB-231 and Hep G2 cells were screened in vitro by an MTT assay. The results indicated that 13-member macrocycle 33 containing alkene chain showed the best results, exhibiting the highest inhibitory effects towards lung cancer cell line A549, which was higher than that of the reference cisplatin (IC 50 value = 2.55 µmol/L).

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Diastereoselective Phosphonylation of Chiral Cyclic Imines for the Synthesis of Phosphoproline Derivatives

et al. 2022

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We report here the first diastereoselective synthesis of (2S,5R)-5methyl-5-(phosphono)-proline, a phosphoproline derivative from L-pyroglutamic acid. The main feature of this methodology is the transformation of L-pyroglutamic acid into chiral cyclic imines as a versatile intermediate followed by diastereoselective nucleophilic addition of trialkyl phosphites or diethyl phosphite in the presence of PhB(OH) 2 , Ph 2 P(O)OH, (PhO) 2 P(O)OH, Ph(H)P-(O)OH and TiCl 4 . N-Cbz Cleavage with simultaneous hydrolysis of phosphonate and carboxylate esters in the quaternary cyclic α-aminophosphonate, gave the target compound.

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An improved and scalable process for 3,8-diazabicyclo[3.2.1]octane analogues

Cited by 6 publications

References 15 publications

Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form

Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form

Synthetic Strategy and Anti-Tumor Activities of Macrocyclic Scaffolds Based on 4-Hydroxyproline

Diastereoselective Phosphonylation of Chiral Cyclic Imines for the Synthesis of Phosphoproline Derivatives

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