Opportunity Knocks: Organic Chemistry for Fragment‐Based Drug Discovery (FBDD)

Murray, Christopher W.; Rees, David C.

doi:10.1002/anie.201506783

Cited by 163 publications

(184 citation statements)

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“…[21] Our synthetic approach yields small, polar molecules that may have value in drug discovery applications.T ounderstand this value,w ed etermined the molecular properties of the afluoro b-hydroxy esters 3a-n;t he intermediate carboxylic acids 6a-n;a nd the corresponding 2-fluoro 1,3-diols 8a-n (see Supporting Information for the synthesis of an exemplar 1,3-diol) (Figure 3). Most of these compounds meet guidelines that have been established both for high-quality fragments [22] and building blocks [17] for drug discovery. In conclusion, we have developed ar obust chemoenzymatic synthesis of a-fluoro b-hydroxy esters.The scope of the approach is broad, enabling the conversion of many aromatic and heteroaromatic aldehydes into chiral products with > 98 % ee and high diastereoselectivity.C rucially,t he syn diasteroselectivity of the process complements the anti selectivity of ar ecent organocatalysed synthesis of a-fluoro thioesters.…”

Section: Zuschriftenmentioning

confidence: 99%

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

et al. 2016

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The trans-o-hydroxybenzylidene pyruvate aldolasecatalysed reactions between fluoropyruvate and many (hetero)aromatic aldehydes yield aldol adducts without subsequent dehydration. Treatment of the reaction products with hydrogen peroxide yields the corresponding syn-configured afluoro b-hydroxy carboxylic acids which have > 98 %ee. The overall chemoenzymatic approach,i nw hich fluoropyruvate serves as af luoroacetate equivalent, may be exploited in the synthesis of polar building blocks and fragments with potential value in drug discovery.Fluorination can profoundly affect the conformation, bioavailability,m etabolism, pharmacokinetics and pharmacodynamics of bioactive small molecules.[1] Thei ntroduction of fluorine is therefore widely used to tune biological function, and around 20 %ofleading drugs contain at least one fluorine atom [2] (10 of the top 50 drugs in 2013 by US prescription [3] ). Examples of leading fluorinated pharmaceuticals include the cholesterol-lowering drug Rosuvastatin [4] and the antidiabetic drug Sitagliptin. [4] Thec ontrolled formation of fluorine-substituted stereocentres,h owever, presents as ignificant challenge.M ost usually,t he challenge is addressed by stereoselective CÀF bond formation. Fore xample,t he fluorination of allylic silanes is often diastereoselective, [5] and organo- [6] and Pd- [7] catalysed methods enable the enantioselective a-fluorination of carbonyl compounds. Stereoselective CÀCbond formation could provide acomplementary approach for controlling fluorine-bearing stereocentres (Scheme 1). However,aldol (and related) reactions of esters of fluoroacetic acid generally exhibit poor diastereoselectivity (e.g.r eactions of lithium enolates, [8] Reformatsky reactions [9] and Mukayama aldol reactions [10]

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Section: Zuschriftenmentioning

confidence: 99%

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

et al. 2016

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“…We expect that this method can be used to rapidly generate diverse libraries of C3-arylated, N-alkylated indolyl compounds for use in fragment-based drug discovery programs. [41] …”

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Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Chen

2017

Angew Chem Int Ed

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“…We expect that this method can be used to rapidly generate diverse libraries of C3-arylated, N-alkylated indolyl compounds for use in fragment-based drug discovery programs. [41] Performing the reaction in deuterated DMSO provided some insight into the mechanism. As shown in Scheme 2, the use of degassed DMSO-D 6 as solvent resulted in approximately 76% deuterium incorporation at the position indicated in 19.…”

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Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Chen

2017

Angewandte Chemie

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Herein, we report an unprecedented transition metal-free, coupling of indoles with aryl halides. The reaction is promoted by KOtBu and is regioselective for C3 over nitrogen. The use of degassed solvents devoid of oxygen is necessary for the success of the transformation. Preliminary studies implicate a hybrid mechanism that involves both aryne intermediates and non-propagative radical processes. Electron transfer is also a distinct possibility. These conclusions were substantiated by EPR data, isotopic labeling studies, and the use of radical scavengers and electron transfer inhibitors. Graphical AbstractMetals? What metals? Regioselective transition metal-free cross-coupling of aryl halides with indoles at C3 has been reported. The reaction proceeds through an unusual hybrid radical/aryne mechanism. Keywordsindole; transition metal-free; cross-coupling; radical; aryne Indoles with aromatic substituents at C3 are an important class of compounds, many of which possess potent biological activity. For instance, fluvastatin is an FDA-approved HMG-CoA reductase inhibitor that is used in the clinic for lowering LDL cholesterol. [1] Other C3 arylated indoles exhibit pico-to nanomolar inhibitory actions against a wide range of biological targets and processes such as the progesterone receptor, [2] COX-II enzyme, [3] carbonic anhydrase I and II, [4] and tubulin polymerization, [5] etc.The direct introduction of aromatic groups onto an extant indole nucleus at C3 is typically carried out by transition metal-catalyzed cross-coupling reactions (Figure 1). [2,[6][7][8][9][10][11][12][13][14] Methods utilizing C-H activation have also been reported. [15][16][17][18] While transition metal-free Correspondence to: Jimmy Wu. Supporting information for this article is given via a link at the end of the document. processes are rare, they have been accomplished through the use of hypervalent iodine reagents, [19][20][21] diazonium salts, [22] or by means of electrochemistry. [23][24][25] Our group has a longstanding interest in the reaction of indoles and related heterocycles. [26][27][28][29] Herein, we disclose a new approach for the intermolecular C3 arylation of unprotected indoles with simple aryl halides. The reaction is promoted by KOtBu and does not require the use of transition metal catalysts. Preliminary mechanistic investigations point towards an unusual hybrid reaction pathway that exhibits features of both radical and aryne intermediates. Although Daugulis and Tu have reported a limited number of basepromoted C2-and N-selective arylation reactions of indoles, [30][31][32] there appear to be very few precedents for C3-selective variants [32,33] and none that proceed by the proposed hybrid radical/aryne mechanism. HHS Public AccessOptimization studies were carried out on the reaction between indole (1a) and iodobenzene (Table 1). A brief solvent survey identified DMF and DMSO as the only effective solvents (entries 1-5). A reaction performed in the dark resulted in similar yield and selectivity (entry 7 vs 5). ...

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Opportunity Knocks: Organic Chemistry for Fragment‐Based Drug Discovery (FBDD)

Abstract: biological chemistry ·d rug design ·d rug discovery · fragment-based drug discovery

Cited by 163 publications

References 50 publications

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

An Enantio‐ and Diastereoselective Chemoenzymatic Synthesis of α‐Fluoro β‐Hydroxy Carboxylic Esters

Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

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