Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities

Carreira, Erick M.; Fessard, Thomas C.

doi:10.1021/cr500127b

Cited by 489 publications

(307 citation statements)

References 274 publications

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“…Considering the specific properties of the strained spiro oxetanylazetidinyl moiety in AZD1979 and the increasing interest in incorporating spirocycles as scaffolds in drug design (Wuitschik et al, 2008;Stepan et al, 2011;Carreira and Fessard, 2014;Zheng et al, 2014), it was of particular interest to characterize the metabolic pathways of this compound and the enzymology contributing to its clearance. In this study, we describe the non-P450-mediated formation of a metabolite M1 of AZD1979 and its structural characterization.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Hayes

Grönberg

et al. 2016

Drug Metabolism and Disposition

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Oxetane moieties are increasingly being used by the pharmaceutical industry as building blocks in drug candidates because of their pronounced ability to improve physicochemical parameters and metabolic stability of drug candidates. The enzymes that catalyze the biotransformation of the oxetane moiety are, however, not well studied. The in vitro metabolism of a spiro oxetane-containing compound AZD1979 [(3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-ethoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone] was studied and one of its metabolites, M1, attracted our interest because its formation was NAD(P)H independent. The focus of this work was to elucidate the structure of M1 and to understand the mechanism(s) of its formation. We established that M1 was formed via hydration and ring opening of the oxetanyl moiety of AZD1979. Incubations of AZD1979 using various human liver subcellular fractions revealed that the hydration reaction leading to M1 occurred mainly in the microsomal fraction. The underlying mechanism as a hydration, rather than an oxidation reaction, was supported by the incorporation of 18 O from H 2 18O into M1. Enzyme kinetics were performed probing the formation of M1 in human liver microsomes. The formation of M1 was substantially inhibited by progabide, a microsomal epoxide hydrolase inhibitor, but not by trans-4-[4-(1-adamantylcarbamoylamino)cyclohexyloxy]-benzoic acid, a soluble epoxide hydrolase inhibitor. On the basis of these results, we propose that microsomal epoxide hydrolase catalyzes the formation of M1. The substrate specificity of microsomal epoxide hydrolase should therefore be expanded to include not only epoxides but also the oxetanyl ring system present in AZD1979.

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Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Hayes

Grönberg

et al. 2016

Drug Metabolism and Disposition

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“…The oxetane motif is also ubiquitous in many natural products (e.g., taxol, oxetanocin, mitrophorone) [2][3][4] and is widely used in the medicinal chemistry for fine-tuning the physicochemical and hydrophilic properties of (biological active) organic compounds; it is also used as an isosteric replacement of both the carbonyl and the gem-dimethyl groups [5]. In addition, oxetanes are versatile templates for the construction of valuable heterocyclic compounds and several chiral synthons by ring expansion, ring opening, rearrangement and desymmetrization reactions [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

2-(tert-Butyl)-4-phenyloxetane

Perna

Vitale

Summa

et al. 2017

Molbank

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Abstract:The two geometric isomers of 2-(tert-butyl)-4-phenyloxetane have, for the first time, been prepared starting from the commercially available 4,4-dimethyl-1-phenylpentane-1,3-dione. The latter was reduced with NaBH 4 to give a mixture of diastereomeric syn and anti diols which were then stereospecifically cyclized into the corresponding oxetanes with an overall yield for the two steps of 69.6%. The newly synthesized stereoisomeric four-membered oxygenated heterocycles were separated by column chromatography on silica gel and fully spectroscopically characterized.

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“…To our knowledge, these compounds are the first and only examples of oxetane acetal with a 1,5-dioxaspiro[3.4]octane ring system synthesized to date. 4 The unusual stability of the strained oxetane acetal can be attributed to the strong electron-withdrawing characteristics of the bromo substitutions.Scheme 1. Formation of spiro-oxetane acetal by Br + -triggered cascade reaction…”

mentioning

confidence: 99%

Synthesis of Dibromo Compounds Containing 2,6-Dioxabicyclo[3.1.1]heptane Similar to Core Moiety of Thromboxane A2

Nishikawa¹,

Nakazaki²,

Nokura³

2018

HETEROCYCLES

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-Thromboxane A 2 , a potent platelet aggregation factor, contains a labile 2,6-dioxabicyclo[3.1.1]heptane as the core moiety. Dibromo compounds with a similar core structure were synthesized by the cyclization of tribromides derived from D-glucal. While investigating the synthesis of crambescine B, a guanidine-containing marine alkaloid, 1 we accidentally observed the formation of spiro-oxetane acetal 2 when intermediate 1 was treated with PyHBr 3 and K 2 CO 3 in CH 2 Cl 2 -H 2 O, 2 a condition of cascade cyclization developed in our laboratory (Scheme 1). 3 Although the yield was low, to our surprise, the product was stable enough to allow for purification by column chromatography using a neutralized silica gel. A similar reaction was also observed in the case of a simpler substrate 3, indicating that the guanidine group was not responsible for this cyclization. To our knowledge, these compounds are the first and only examples of oxetane acetal with a 1,5-dioxaspiro[3.4]octane ring system synthesized to date. 4 The unusual stability of the strained oxetane acetal can be attributed to the strong electron-withdrawing characteristics of the bromo substitutions.Scheme 1. Formation of spiro-oxetane acetal by Br + -triggered cascade reaction

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Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities

Cited by 489 publications

References 274 publications

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

Discovery of a Novel Microsomal Epoxide Hydrolase-Catalyzed Hydration of a Spiro Oxetane

2-(tert-Butyl)-4-phenyloxetane

Synthesis of Dibromo Compounds Containing 2,6-Dioxabicyclo[3.1.1]heptane Similar to Core Moiety of Thromboxane A2

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