A convenient synthesis of monocyclic .BETA.-lactams by means of solid-liquid phase transfer reactions.

Takahata, Hiroki; Ohnishi, Yoshinori N.; Takehara, Hiroyuki; Tsuritani, K.; Yamazaki, Takao

doi:10.1248/cpb.29.1063

Cited by 36 publications

(3 citation statements)

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“…Fisher esterification of 4 gave the benzyl ester 5 as its crystalline tosylate salt (Zervas et al, 1957), which was condensed with 2-bromopropionyl chloride to afford the amide 6. Closure to the glycyl /3-lactam 7 was achieved with potassium hydroxide under phase-transfer conditions (Takahata et al, 1981). Treatment of 7 with lithium bis(trimethylsilyl)amide at low temperature and reaction with Ox-protected 3-aminopropanal [Ox = 4,5diphenyl-4-oxazolidin-2-one, see Sheehan and Guziec (1972)] gave a kinetic mixture of erythro and threo products 8 and 9, respectively (each as racemates), in a 3:1 ratio.…”

Section: Resultsmentioning

confidence: 99%

Elucidation of the order of oxidations and identification of an intermediate in the multistep clavaminate synthase reaction

Salowe

Krol²,

Iwata‐Reuyl³

et al. 1991

Biochemistry

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The enzyme clavaminate synthase (CS) catalyzes the formation of the first bicyclic intermediate in the biosynthetic pathway to the potent beta-lactamase inhibitor clavulanic acid. Our previous work has led to the proposal that the cyclization/desaturation of the substrate proclavaminate proceeds in two oxidative steps, each coupled to a decarboxylation of alpha-ketoglutarate and a reduction of dioxygen to water [Salowe, S. P., Marsh, E. N., & Townsend, C. A. (1990) Biochemistry 29, 6499-6508]. We have now employed kinetic isotope effect studies to determine the order of oxidations for CS purified from Streptomyces clavuligerus. By using (4'RS)-[4'-3H,1-14C]-rac-proclavaminate, a primary T(V/K) = 8.3 +/- 0.2 was measured from [3H]water release data, while an alpha-secondary T(V/K) = 1.06 +/- 0.01 was determined from the changing 3H/14C ratio of the product clavaminate. Values for the primary and alpha-secondary effects of 11.9 +/- 1.7 and 1.12 +/- 0.07, respectively, were obtained from the changing 3H/14C ratio of the residual proclavaminate by using new equations derived for a racemic substrate bearing isotopic label at both primary and alpha-secondary positions. Since only the first step of consecutive irreversible reactions will exhibit a V/K isotope effect, we conclude that C-4' is the initial site of oxidation in proclavaminate. As expected, no significant changes in the 3H/14C ratio of residual substrate were observed with [3-3H,1-14C]-rac-proclavaminate. However, two new tritiated compounds were produced in this incubation, apparently the result of isotope-induced branching brought about by the presence of tritium at the site of the second oxidation. One of these compounds was identified by comparison to authentic material as dihydroclavaminate, a stable intermediate that normally remains enzyme-bound. On the basis of the body of information available and the similarities to alpha-ketoglutarate-dependent dioxygenases, a comprehensive mechanistic scheme for CS is proposed to account for this unusual enzymatic transformation.

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Section: Resultsmentioning

confidence: 99%

Elucidation of the order of oxidations and identification of an intermediate in the multistep clavaminate synthase reaction

Salowe

Krol²,

Iwata‐Reuyl³

et al. 1991

Biochemistry

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“…14 Similarly, 2b reacted with 6-methyl-1,2,3,4tetrahydroquinoline (3a) or 6-bromo-1,2,3,4-tetrahydroquinoline (3b) in the presence of HCl to yield 4b and 4c, respectively, in 75−80% yields. 6-Methoxy-2,3-dihydroquinolin-4(1H)-one (3c) 15,16 and 7-methoxy-3,4-dihydro-2H-benzo-[b] [1,4]oxazine (3d) 17,18 were prepared according to literature methods and then coupled individually with 2a and 2b to afford 5a,b and 5d,e, respectively. Next, the ketone in 5b was converted to the hydroxyl in 5c by reduction with NaBH 4 .…”

Section: ■ Chemistrymentioning

confidence: 99%

Optimization of 4-(N-Cycloamino)phenylquinazolines as a Novel Class of Tubulin-Polymerization Inhibitors Targeting the Colchicine Site

Wang

Guan²,

Ohkoshi

et al. 2014

J. Med. Chem.

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The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a–c and 5a–m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI50 1.9–3.2 nM), significant potency against tubulin assembly (IC50 0.77 μM), and substantial inhibition of colchicine binding (99% at 5 μM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.

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“…In order to favour one or the other deprotonation site, many factors can be varied. Yamazaki used pulverized KOH in CH 2 Cl 2 (or in a mixture of CH 2 Cl 2 and CH 3 CN) in the presence of a phase transfer catalyst (Bu 4 NBr) and reported that both high concentration (> 0.05 M) and rapid addition of amide to the basic solution resulted in low yields of β‐lactams, with substantial formation of acrylamides. The scope of this communication is the determination of simple conditions to obtain selectively and in high yields, either β‐lactam 3 or acrylanilide 2 using the same starting material 1 , by chemical or electrochemical means.…”

Section: Deprotonation Of 3‐bromo‐n‐(p‐bromophenyl)propanamide 1 a Tomentioning

confidence: 91%

Two Different Selective Ways in the Deprotonation of β‐Bromopropionanilides: β‐Lactams or Acrylanilides Formation.

et al. 2019

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The reactivity of 3‐bromo‐N‐(p‐bromophenyl)propanamide with different bases in an ionic liquid (BMImBF4) and in acetonitrile (ACN) was studied. Two possible deprotonation sites are present in this molecule, leading to different products. When the NH group is deprotonated, a β‐lactam is obtained after internal halide displacement; when the CH2 in alpha to the carbonyl is deprotonated, the corresponding acrylanilide is formed. This study allowed determining the experimental conditions to obtain selectively and in high yields both products starting from the same molecule. In particular, to obtain the acrylanilide Et3N in ACN is to be used, while to obtain selectively the β‐lactam ring the base must be generated by cathodic reduction of a DMF or ACN‐Et4NBF4 solution. These reactions were extended to other β‐bromopropionanilides, allowing to easily synthesize both β‐lactams and acrylanilides, molecules having noteworthy biological activities.

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A convenient synthesis of monocyclic .BETA.-lactams by means of solid-liquid phase transfer reactions.

Cited by 36 publications

References 0 publications

Elucidation of the order of oxidations and identification of an intermediate in the multistep clavaminate synthase reaction

Elucidation of the order of oxidations and identification of an intermediate in the multistep clavaminate synthase reaction

Optimization of 4-(N-Cycloamino)phenylquinazolines as a Novel Class of Tubulin-Polymerization Inhibitors Targeting the Colchicine Site

Two Different Selective Ways in the Deprotonation of β‐Bromopropionanilides: β‐Lactams or Acrylanilides Formation.

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