Short, Highly Efficient Syntheses of Protected 3-Azido- and 4-Azidoproline and Their Precursors

Gómez-Vidal, José A.; Silverman, Richard B.

doi:10.1021/ol0161054

Cited by 62 publications

(44 citation statements)

References 37 publications

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“…The Pd(OH) 2 catalyst also is much cheaper than PtO 2 , propitious for a large scale reaction. After filtration of the catalyst and evaporation of the solvent, Boc-L-MeOrn-OH (19) directly underwent nitroguanidination using 2-methyl-1-nitro-2-thiopseudourea (20), which was prepared by nitration of commercially available S-methylisothiourea hemisulfate salt (Scheme 2). 19…”

Section: N α -Methylated Inhibitorsmentioning

confidence: 99%

Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors

Seo

Martásek

Roman

et al. 2007

Bioorganic & Medicinal Chemistry

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Selective inhibition of the localized excess production of NO by neuronal nitric oxide synthase (nNOS) has been targeted as a potential means of treating various neurological disorders. Based on observations from the X-ray crystal structures of complexes of nNOS with two nNOS-selective, a series of descarboxamide analogues was designed and synthesized (3-7). The most potent compound was aminopyrrolidine analogue 3, which exhibited better potency and selectivity for nNOS than parent compound 2. In addition, 3 provided higher lipophilicity and a lower molecular weight than 2, therefore having better physicochemical properties. N α -Methylated analogues (8-11) also were prepared for increased lipophilicity of the inhibitors, but they had 4-5 fold weaker binding affinity compared to their parent compounds.

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Section: N α -Methylated Inhibitorsmentioning

confidence: 99%

Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors

Seo

Martásek

Roman

et al. 2007

Bioorganic & Medicinal Chemistry

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“…Because a side chain amino group was important, we prepared a family of conformationally-rigid analogues of 1 by replacing the diaminobutyramide group with 4-aminoprolinamides ( 9 ) xiv. The syntheses of these compounds required the development of new synthetic methodologies xv. These analogues have three stereogenic centers; therefore, we synthesized all eight stereoisomers.…”

Section: Introductionmentioning

confidence: 99%

Design of Selective Neuronal Nitric Oxide Synthase Inhibitors for the Prevention and Treatment of Neurodegenerative Diseases

2009

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Nitric oxide (NO), which is produced from l-arginine by the nitric oxide synthase (NOS) family of enzymes, is an important second-messenger molecule that regulates several physiological functions. In endothelial cells, it relaxes smooth muscle, which decreases blood pressure. Macrophage cells produce NO as an immune defense system to destroy pathogens and microorganisms. In neuronal cells, NO controls the release of neurotransmitters and is involved in synaptogenesis, synaptic plasticity, memory function, and neuroendocrine secretion. NO is a free radical that is commonly thought to contribute to oxidative damage and molecule and tissue destruction, and thus it is somewhat surprising that it has so many significant beneficial physiological effects. However, the cell is generally protected from NO’s toxic effects, except under certain pathological conditions in which excessive NO is produced. In that case, tissue damage and oxidative stress can result, leading to a wide variety of diseases, including rheumatoid arthritis, Alzheimer’s disease, and Parkinson’s disease, among others. In this Account, we describe research aimed at identifying small molecules that can selectively inhibit only the neuronal isozyme of NOS, nNOS. By targeting only nNOS, we attained the beneficial effects of lowering excess NO in the brain without the detrimental effects of inhibition of the two isozymes found elsewhere in the body (eNOS and iNOS). Initially, in pursuit of this goal, we sought to identify differences in the second sphere of amino acids in the active site of the isozymes. From this study, the first class of dual nNOS-selective inhibitors was identified. The moieties important for selectivity in the best lead compound were determined by structure modification. Enhancement provided highly potent, nNOS-selective dipeptide amides and peptidomimetics, which were active in a rabbit model for fetal neurodegeneration. Crystal structures of these compounds bound to NOS isozymes showed a one-amino-acid difference between nNOS and eNOS in the second sphere of amino acids; this was the difference that we were searching for from the beginning of this project. With the aid of these crystal structures, we developed a new fragment-based de novo design method called “fragment hopping”, which allowed the design of a new class of nonpeptide nNOS-selective inhibitors. These compounds were modified to give low nanomolar, highly dual-selective nNOS inhibitors, which we recently showed are active in a rabbit model for the prevention of neurobehavioral symptoms of cerebral palsy. These compounds could also have general application in other neurodegenerative diseases for which excess NO is responsible.

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“…Alcohol 3 was converted to the protected 4-methylamino derivative 7a through a four-step sequence involving a Mitsunobu process 11 to give azide 4, 12 which was reduced to the primary amine 5, 13 undergoing subsequent methoxycarbonylation and methylation to give carbamate 7a (Scheme 2). The methoxycarbonyl group at C-2 of proline 7a was transformed into the required 3-oxobutyl side chain by an initial conversion to aldehyde 9a (TEMPO, NaOCl, NaBr) 14 through alcohol 8a, followed by a Wittig olefination and hydrogenation of the resulting enone 10a (Scheme 3).…”

Section: Resultsmentioning

confidence: 99%

“…11 After chromatography (hexane-hexane/EtOAc 60:40), 4 12 was obtained as a viscous yellow oil in a quantitative yield. and Pd/C (0.53 g, 10%) in MeOH (60 mL) was stirred overnight at rt under hydrogen pressure (500 psi).…”

Section: Methodsmentioning

confidence: 99%

Synthesis of enantiopure 1-azaspiro[4.5]dec-6-en-8-ones from l-proline derivatives

Diaba

Ricou

Bonjoch

2006

Tetrahedron: Asymmetry

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Short, Highly Efficient Syntheses of Protected 3-Azido- and 4-Azidoproline and Their Precursors

Cited by 62 publications

References 37 publications

Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors

Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors

Design of Selective Neuronal Nitric Oxide Synthase Inhibitors for the Prevention and Treatment of Neurodegenerative Diseases

Synthesis of enantiopure 1-azaspiro[4.5]dec-6-en-8-ones from l-proline derivatives

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