Synthesis of (1R,4R)-2,5-diazabicyclo[2.2.1]heptane derivatives by an epimerization–lactamization cascade reaction

Cui, Benqiang; Yu, Jie; Yu, Fuchao; Li, Yamin; Chang, Kwen‐Jen; Shen, Yuehai

doi:10.1039/c4ra13611j

Cited by 9 publications

(4 citation statements)

References 35 publications

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“…A second reductive amination with either 4-methoxybenzaldehyde or 4-(methylthio)benzaldehyde provided intermediates 7a and 7b , respectively. This three-step conversion from the tosylate 4 to amines 7a , b gave higher yields (overall three-step yield 32%) than the direct displacement with 4-methoxybenzylamine or 4-(methylthio)benzylamine (<10%) . While the low yields of this direct conversion could be slightly improved by the employment of a large excess of the amines under elevated reaction temperatures in a polar solvent, the unreacted amines greatly complicated the purification of the product.…”

Section: Resultsmentioning

confidence: 94%

“…This three-step conversion from the tosylate 4 to amines 7a-b gave higher yields (overall three-step yield 32%) than the direct displacement with 4-methoxybenzylamine or 4-(methylthio)benzylamine (<10%). 45 While the low yields of this direct conversion could be slightly improved by the employment of a large excess of the amines under elevated reaction temperatures in a polar solvent, the unreacted amines greatly complicated the purification of the product. Furthermore, the use of excess amines is not amenable to scale-up synthesis of this common intermediate.…”

Section: Resultsmentioning

confidence: 99%

“…Since the initial hit 1 has a 4-methylthio at the 4-benzyl group on the proline scaffold, after exploring various substituents at the Throughout the course of these studies, most of the compounds we tested displayed competitive antagonism in the curve-shift assays; however, several compounds (23,32,33,41,42,45) showed evidence of insurmountable antagonism by shifting the curve to the right and also depressing the maximal NPFF signal. While allosteric modulators commonly produce such a response, this type of antagonism can also be observed with competitive orthosteric antagonists with slow dissociation rates.…”

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of Novel Proline-Based Neuropeptide FF Receptor Antagonists

Nguyễn

Decker

Langston

et al. 2017

ACS Chem. Neurosci.

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The neuropeptide FF (NPFF) system has been implicated in a number of physiological processes including modulating the pharmacological activity of opioid analgesics and several other classes of drugs of abuse. In this study, we report the discovery of a novel proline scaffold with antagonistic activity at the NPFF receptors through a high throughput screening campaign using a functional calcium mobilization assay. Focused structure-activity relationship studies on the initial hit 1 have resulted in several analogs with calcium mobilization potencies in the submicromolar range and modest selectivity for the NPFF1 receptor. Affinities and potencies of these compounds were confirmed in radioligand binding and functional cAMP assays. Two compounds, 16 and 33, had good solubility and blood-brain barrier permeability that fall within the range of CNS permeant candidates without the liability of being a P-glycoprotein substrate. Finally, both compounds reversed fentanyl-induced hyperalgesia in rats when administered intraperitoneally. Together, these results point to the potential of these proline analogs as promising NPFF receptor antagonists.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of Novel Proline-Based Neuropeptide FF Receptor Antagonists

Nguyễn

Decker

Langston

et al. 2017

ACS Chem. Neurosci.

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“…The diamine system of 2,5-diazabicyclo[2.2.1]heptane is traditionally included in screening libraries as a rigid counterpart of the flexible piperazine ring (Siebeneicher et al, 2016;Dam et al, 2016;Cernak et al, 2017;Llona-Minguez et al, 2017;Wei et al, 2017). As a consequence, numerous synthetic routes for the preparation of 2,5-diazabicyclo[2.2.1]heptane derivatives have been introduced (see: Portoghese & Mikhail, 1966;Jordis et al, 1990;Yakovlev et al, 2000;Fiorelli et al, 2005;Beinat et al, 2013;Cui et al, 2015;Choi et al, 2016 and the references cited therein). At the same time, the reported structural data on 2,5diazabicyclo[2.2.1]heptane derivatives are surprisingly scarce (see the Database survey).…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

Britvin

Rumyantsev

2017

Acta Cryst E

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The cage of 2,5-diazabicyclo[2.2.1]heptane is frequently employed in synthetic chemistry as a rigid bicyclic counterpart of the piperazine ring. The 2,5-diazabicyclo[2.2.1]heptane scaffold is incorporated into a variety of compounds having pharmacological and catalytic applications. The unsubstituted parent ring of the system, 2,5-diazabicyclo[2.2.1]heptane itself, has not been structurally characterized. We herein report on the molecular structure of the parent ring in (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide, C 5 H 12 N 2 2+ Á2Br À . The asymmetric unit contains two crystallographically independent cages of 2,5-diazabicyclo[2.2.1]heptane. Each cage is protonated at the two nitrogen sites. The overall charge balance is maintained by four crystallographically independent bromide ions. In the crystal, the components of the structure are linked via a complex three-dimensional network of N-HÁ Á ÁBr hydrogen bonds.

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Syntheses of Lactams by Tandem Reactions

2018

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Tandem reactions form two or more new bonds, sequentially and in only one step, avoiding the purification of each step and the use of protecting groups, thus making them greener procedures. Lactams are cyclic amides present in numerous natural products and pharmaceuticals, therefore the development of new methodologies for their synthesis attracted the attention of synthetic chemists. The aim of this review is to summarize the last advances, since 2012, in the synthesis of lactams through tandem reactions.

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Synthesis of (1R,4R)-2,5-diazabicyclo[2.2.1]heptane derivatives by an epimerization–lactamization cascade reaction

Abstract: An epimerization–lactamization cascade of functionalized (2S,4R)-4-aminoproline methyl esters is developed and applied in synthesizing (1R,4R)-2,5-diazabicyclo[2.2.1]heptane (DBH) derivatives.

Cited by 9 publications

References 35 publications

Discovery of Novel Proline-Based Neuropeptide FF Receptor Antagonists

Discovery of Novel Proline-Based Neuropeptide FF Receptor Antagonists

Crystal structure of (1S,4S)-2,5-diazoniabicyclo[2.2.1]heptane dibromide

Syntheses of Lactams by Tandem Reactions

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