Oxetanes as Promising Modules in Drug Discovery

Wuitschik, Georg; Rogers‐Evans, Mark; Müller, Klaus; Fischer, Holger; Wagner, Björn; Schuler, Franz; Polonchuk, Liudmila; Carreira, Erick M.

doi:10.1002/anie.200602343

Cited by 225 publications

(164 citation statements)

References 14 publications

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“…[27] In this reaction, [(2-biphenyl)Cy 2 PAu]NTf 2 turns out to be the most effective catalyst and Tf 2 NH proves to be superior to MsOH as an acid additive. Various functionalized propargylic alcohols 50 (Scheme 14) can be tolerated.…”

Section: Oxygen-atom Transfer From Pyridine N-oxidesmentioning

confidence: 97%

Gold α‐Oxo Carbenoids in Catalysis: Catalytic Oxygen‐Atom Transfer to Alkynes

2011

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An overview of reactive gold α-oxo carbenoid intermediates in the gold-catalyzed functionalization of alkynes is presented. Such intermediates can be generated from inter- and intramolecular oxidation of alkynes by nucleophilic oxygen-atom donor groups, such as amine N-oxides, pyridine N-oxides, nitrones, nitro compounds, sulfoxides, and epoxides. These O-atom transfer processes occur by gold-mediated addition-elimination reactions. In catalytic systems, α-oxo carbenoids can undergo nucleophilic attack by imine, arene, and migrating hydride as well as alkyl groups, leading to cascade reactions and the construction of new skeletons. The facile construction of C-E (E=C, N, S, or O) bonds makes it an attractive step-economic approach to value-added molecules from readily available starting materials. The scope, mechanisms, and reactivity of such α-oxo carbenoid species are discussed. The remarkable diversity of structures accessible is demonstrated with various recent examples.

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Section: Oxygen-atom Transfer From Pyridine N-oxidesmentioning

confidence: 97%

Gold α‐Oxo Carbenoids in Catalysis: Catalytic Oxygen‐Atom Transfer to Alkynes

2011

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“…In contrast, the spiro-oxetanes occupy the "rod-like" area of molecular space (see Figure S2). Since the original report highlighting the potential of oxetanes in medicinal chemistry, [7] this small ring system has attracted considerable attention, not only due to its low steric bulk, but also because of the advantageous effect on physicochemical parameters. [8] Originally conceived as polar replacements for lipophilic gem-dimethyl groups, oxetanes also act as surrogates for carbonyl groups, [9] and in bioisosteres for morpholine.…”

Section: Introductionmentioning

confidence: 99%

C−H Insertion as a Key Step to Spiro‐Oxetanes, Scaffolds for Drug Discovery

Nicolle

Nortcliffe

Bartrum

et al. 2017

Chemistry A European J

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Abstract:A new route to spiro-oxetanes, potential scaffolds for drug discovery, is described. The route is based on the selective 1,4-C-H insertion reactions of metallocarbenes, generated from simple carbonyl precursors in flow or batch mode, to give spiro-β-lactones that are rapidly converted into spiro-oxetanes. The three-dimensional and lead like-properties of spiro-oxetanes is illustrated by the conversion of the 1-oxa-7-azaspiro [3,5]nonane scaffold into a range of functionalized derivatives.Modern drug discovery programs drive an appetite for new, low molecular weight bioactive molecules. In support of the wellestablished drug discovery process, strategies such as diversity-oriented synthesis (DOS), lead-oriented synthesis (LOS), biologyoriented synthesis (BOS), and fragment based drug discovery (FBDD) have recently emerged as tools to accelerate the search for new drug candidates.[1] Nevertheless, access to compounds with desirable properties by chemical synthesis remains challenging. For example, the power of transition metal-catalyzed sp 2 -sp 2 cross coupling reactions has inadvertently led to large numbers of (hetero)aromatic-rich fragments, despite evidence that such compounds are susceptible to attrition in the later stages of drug development due to inappropriate physicochemical properties.[2] As a result, there is now a desire to develop robust synthetic methods that will provide ready access to diverse collections of lead-like, sp 3 -atom rich, low molecular weight and often densely functionalized molecules, ideally creating molecular complexity from simple starting materials in a few steps.One contemporary initiative, the European Lead Factory (ELF), [3] was established with the precise goal of identifying compound libraries that fulfil the above criteria. As part of our work under the ELF programme, [4] we were intrigued by the recent interest in spirooxetanes, [5] and identified the little known 1-oxa-7-azaspiro[3,5]nonane ring system (Figure 1) as an ideal scaffold for drug discovery.Spirocycles incorporating a small ring, such as an oxetane, have relatively rigid structures, and can be densely functionalized, with the substituent vectors clearly defined in their three-dimensional arrangement. Evidence that the 1-oxa-7-azaspiro[3,5]nonane scaffold does indeed allow access to lead-like properties came from analysis of a virtual library generated using the open access LLAMA tool (see Supporting Information for details).[ 6] When one functionalization was considered, 42% of the molecules in the virtual library fell within lead-like space (MW < 350, logP < 3) ( Figure S1), and all were compliant to Lipinski's 'rule of five'. In addition, current medicinal chemistry space is well populated with "disc-like" molecules. In contrast, the spiro-oxetanes occupy the "rod-like" area of molecular space (see Figure S2). Since the original report highlighting the potential of oxetanes in medicinal chemistry, [7] this small ring system has attracted considerable attention, not only due to its low steric bul...

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“…As an important building block, an oxetane can trigger profound changes in aqueous solubility, lipophilicity, metabolic stability, and conformational preference when replacing commonly employed functionalities such as gem-dimethyl or carbonyl groups [1,2]. Therefore, as the important source of oxetane unit, oxetan-3-ol plays an important role in the drug development.…”

Section: Introductionmentioning

confidence: 99%