Synthesis of Racemic cis- and trans-3-Phenylazetidine-2-Carboxylic Acids as Conformationally Restricted Analogs of Phenylalanine

Blythin, David J.; Green, Michael J.; Lauzon, M. J.; Shue, Ho‐Jane

doi:10.1021/jo00099a050

Cited by 17 publications

(16 citation statements)

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“…Earlier syntheses of racemic 2‐azetidine carboxylic acids by resolution and by a series of transformations starting from homoserine have been reviewed (27–29). Aze analogs have been synthesized bearing substituents at the 1‐ (30–37), 2‐ (38–42), 3‐ (21,43–50), and 4‐positions (51), as well as with multiple substitution patterns (52–55).…”

Section: Introductionmentioning

confidence: 99%

Amino acid–azetidine chimeras: synthesis of enantiopure 3‐substituted azetidine‐2‐carboxylic acids

Sajjadi

Lubell

2005

The Journal of Peptide Research

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Azetidine-2-carboxylic acid (Aze) analogs possessing various heteroatomic side chains at the 3-position have been synthesized by modification of 1-9-(9-phenylfluorenyl) (PhF)-3-allyl-Aze tert-butyl ester (2S,3S)-1. 3-Allyl-Aze 1 was synthesized by regioselective allylation of alpha-tert-butyl beta-methyl N-(PhF)aspartate 13, followed by selective omega-carboxylate reduction, tosylation, and intramolecular N-alkylation. Removal of the PhF group and olefin reduction by hydrogenation followed by Fmoc protection produced nor-leucine-Aze chimera 2. Regioselective olefin hydroboration of (2S,3S)-1 produced primary alcohol 23, which was protected as a silyl ether, hydrogenated and N-protected to give 1-Fmoc-3-hydroxypropyl-Aze 26. Enantiopure (2S,3S)-3-(3-azidopropyl)-1-Fmoc-azetidine-2-carboxylic acid tert-butyl ester 3 was prepared as a Lys-Aze chimera by activation of 3-hydroxypropyl-Aze 26 as a methanesulfonate and displacement with sodium azide. Moreover, orthogonally protected azetidine dicarboxylic acid 4 was synthesized as an alpha-aminoadipate-Aze chimera by oxidation of alcohol 26. These orthogonally protected amino acid-Aze chimeras are designed to serve as tools for studying the influence of conformation on peptide activity.

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Section: Introductionmentioning

confidence: 99%

Amino acid–azetidine chimeras: synthesis of enantiopure 3‐substituted azetidine‐2‐carboxylic acids

Sajjadi

Lubell

2005

The Journal of Peptide Research

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“…Intramolecular cyclization can also be observed if the carbon b of the amino group bears a leaving group (Scheme 3.23) [49]. This method has been applied to the preparation of cis and trans 3-phenyl-azetidine-2-carboxylic acids [49], azetidine-2carbonitriles, [50] and diethyl azetidine-2-phosphonates (Scheme 3.24) [51].…”

Section: 1312mentioning

confidence: 99%

“…This method has been applied to the preparation of cis and trans 3-phenyl-azetidine-2-carboxylic acids [49], azetidine-2carbonitriles, [50] and diethyl azetidine-2-phosphonates (Scheme 3.24) [51].…”

Section: 1312mentioning

confidence: 99%

Four‐Membered Heterocycles: Structure and Reactivity

Rousseau

Robin

2011

Modern Heterocyclic Chemistry

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“…12 According to the same strategy, based on the seminal work of Hanessian, 7 we have now synthesized β-lactams 4c and 4d with tert-butyloxycarbonyl and cyano substitu- ents, respectively, at this position (Table 1). Reaction of benzhydrylamine with tert-butyl bromoacetate and bromoacetonitrile, respectively, gave secondary amines 1c 13 and 1d, 14 purified by recrystallization from methanol. Activation of sodium (2R,3R)-cis-2,3-epoxybutanoate (2) 10 with oxalyl chloride in THF at low temperature, followed by addition of pyridine and 1c,d led to the isolation of 3c,d in 40-70% yield, after chromatography on silica gel.…”

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confidence: 99%

“…Compound 6a has been well characterized by 1 H NMR (disappearance of the benzhydryl proton at δ = 5.69 and appearance of the OH proton at δ = 5.12 as a broad signal) and 13 C NMR spectroscopy (NCOH at 87.4 ppm). Moreover, the structure of this intermediate was unambiguously confirmed by X-ray diffraction analysis of a monocrystal.…”

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confidence: 99%

A New Method ofN-Benzhydryl Deprotection in 2-Azetidinone Series

Laurent¹,

Belmans²,

Kemps³

et al. 2003

Synthesis

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A mild and efficient procedure for the selective cleavage of N-benzhydryl protecting group of β-lactams is described. The protected 2-azetidinones 4, precursors of carbapenems, were treated with a stoichiometric amount of N-bromosuccinimide and a catalytic amount of bromine under sun light irradiation in CH 2 Cl 2-H 2 O mixture at 20°C for 3 hours. The N-benzhydrol intermediates 6, which could be isolated, were then hydrolyzed with p-TsOH in aqueous acetone to furnish β-lactams 7 and benzophenone quantitatively.

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Synthesis of Racemic cis- and trans-3-Phenylazetidine-2-Carboxylic Acids as Conformationally Restricted Analogs of Phenylalanine

Cited by 17 publications

References 0 publications

Amino acid–azetidine chimeras: synthesis of enantiopure 3‐substituted azetidine‐2‐carboxylic acids

Amino acid–azetidine chimeras: synthesis of enantiopure 3‐substituted azetidine‐2‐carboxylic acids

Four‐Membered Heterocycles: Structure and Reactivity

A New Method ofN-Benzhydryl Deprotection in 2-Azetidinone Series

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