Enantioselective Catalytic Transformations of Barbituric Acid Derivatives
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catalysts Review Enantioselective Catalytic Transformations of Barbituric Acid Derivatives Claire Segovia, Arthur Lebrêne , Vincent Levacher , Sylvain Oudeyer and Jean-François Brière * Normandie University, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France; [email protected] (C.S.); [email protected] (A.L.); [email protected] (V.L.); [email protected] (S.O.) * Correspondence: [email protected]; Tel.: +33-235-522-464 Received: 20 December 2018; Accepted: 15 January 2019; Published: 1 February 2019 Abstract: Since the beginning of the 20th century, numerous research efforts made elegant use of barbituric acid derivatives as building blocks for the elaboration of more complex and useful molecules in the field of pharmaceutical chemistry and material sciences. However, the construction of chiral scaffolds by the catalytic enantioselective transformation of barbituric acid and derivatives has only emerged recently. The specific properties of these rather planar scaffolds, which also encompass either a high Brønsted acidity concerning the native barbituric acid or the marked electrophilic character of alkylidene barbituric acids, required specific developments to achieve efficient asymmetric processes. This review covers the enantioselective catalytic reactions developed for barbituric acid platforms using an organocatalytic and metal-based enantioselective sequences. These achievements currently allow several unique addition and annulation reactions towards the construction of high valued chiral heterocycles from barbituric acid derivatives along with innovative enantioselective developments. Keywords: organocatalysis; asymmetric synthesis; barbituric acid; alkylidene barbituric acid; metal based-catalysis; cycloaddition; annulation reaction 1. Introduction 1.1. Context Barbituric acid 1, namely 2,4,6-(lH,3H,5H)-pyrimidinetrione, and derivatives are fascinating building blocks in organic synthesis (Figure1). This story dates back to 1894 when von Baeyer reported on the preparation of barbituric acid [1]. Later, in 1903, Fisher and von Mering highlighted the pharmacological properties of 5,5-diethyl barbituric acid, the so-called barbital, as a potent hypnotic agent [2]. Ever since, barbituric acid derivatives served as starting materials for the elaboration of thousands of complex architectures useful in medicinal chemistry, a field of research covered by several exhaustive reviews [3–6]. Selected examples of bioactive compounds in this series are depicted in Figure1, which highlights scaffolds that possess, at least, one stereogenic center or a tetrasubstituted carbon as a source of chemical diversity and structural complexity. Phenobarbital, involved in the treatment of certain types of epilepsy, derived from the original barbital but displays two different substituents at C-5 position (Figure1a) [ 7]. The opportunity afforded by the double functionalization of the C-5 position of barbituric acid allowed the construction of several spiro-compounds and, thus, more rigid architectures highlighted by the development of nucleotide mimics [8], inhibitor of matrix metalloproteinases (MMP) [9] and anticancer agents [10], for example (Figure1b–d) [ 11,12]. On the other hand, the synthesis of fused-bicycle derivatives led to ingredients possessing either Catalysts 2019, 9, 131; doi:10.3390/catal9020131 www.mdpi.com/journal/catalysts Catalysts 2019, 9, 131 2 of 27 antidiabetic [13] or antituberculosis properties (Figure1e–f) [ 14]. Besides medicinal chemistry, theCatalysts photophysical 2018, 8, x FOR properties PEER REVIEW of barbituric acid derivatives were exploited in colorimetric or heat2 of 30 detection [15], and provided promising dyes or fluorogenic probes to name a few [16,17]. 45 46 47 FigureFigure 1. Barbituric 1. Barbituric acid acid scaffolds scaffolds within within bioactive bioactive architectures. architectures. 48 TheThe versatile versatile properties properties of productsof products obtained obtained from from barbituric barbituric acid acid elicited elicited the the motivation motivation of of 49 organicorganic chemists chemists to to explore explore its its chemistry chemistry [3 ,4[3,4,6],,6], and and more more recent recent evolutions evolutions have have met met the the 50 developmentdevelopment of efficientof efficient multicomponent multicomponent reactions reactions (MCR) (MCR) [16,18 [16,18].]. Despite Despite great great synthetic synthetic advances advances in 51 thisin field this of research,field of theresearch, use of diastereoselectivethe use of diastere sequencesoselective or separation sequences techniques or separation (crystallization techniques or 52 chromatography)(crystallization of or racemic chromatography) mixtures were of required racemic for mixtures the elaboration were required of enantiopure for the architectures elaboration of of 53 chiralenantiopure bioactive architectures compounds asof chiral depicted bioactive in Figure compounds1[ 19]. At as thedepicted end of in the Figure 1990s, 1 [19]. the pioneeringAt the end of 54 researchthe 1990s, of Brunner’s the pioneering group, onresearch the palladium-catalyzed of Brunner’s group, enantioselective on the palladium-catalyzed alkylation of barbituric enantioselective acid 55 derivativesalkylation have of barbituric shed light acid on thederiva potentialtives have of this shed starting light on material the potential in asymmetric of this starting synthesis material while in 56 pointingasymmetric out challenges, synthesis which while have pointing to be out overcome challenges, with thiswhich unique have architecture to be overcome [20–23 with]. This this review unique 57 intendsarchitecture to cover [20–23]. the literature This review dealing intends with the to enantioselective cover the literature catalytic dealing transformations with the enantioselective of barbituric 58 acidcatalytic derivatives, transformations an exercise of which barbituric is unprecedented acid derivatives, to the an best exercise of our which knowledge. is unprecedented The literature to the 59 concerningbest of our the knowledge. enantioselective The literature transformations concerning of barbituricthe enantioselective acid and alkylidenetransformations barbituric of barbituric acid 60 derivativesacid and willalkylidene be discussed barbituric separately, acid derivatives to focus on specificwill be typesdiscussed of reactions separately, developed to focus for on a givenspecific 61 barbituratetypes of reactions structure. developed To give a flavor for a given of the barbiturate uniqueness structure. of barbituric To acidgive compounds,a flavor of the its uniqueness properties of 62 willbarbituric first be introduced. acid compounds, its properties will first be introduced. 63 1.2.1.2. Properties Properties of Barbituricof barbituric Acid acid Derivatives derivatives 64 To gainTo gain insight insight into into the reactivitythe reactivity of barbituric of barbituric acid acid derivatives, derivatives, the unique the unique chemical chemical properties properties of 65 theseof these molecules molecules have have to be to taken be taken into account.into account. As shownAs shown in Figure in Figure2a, barbituric2a, barbituric acid acid1 displays 1 displays a a 66 ratherrather low low pK apKvaluea value (pK (pa K=a 8.4= 8.4 in in DMSO) DMSO) [24 [24]] lying lying just just above above Meldrum’s Meldrum’s acid acid2 well-known 2 well-known for for its its 67 remarkableremarkable acidity acidity (pK (pa =Ka 7.03 = 7.03 in DMSO)in DMSO) [25 [25,26].,26]. Consequently, Consequently, barbituric barbituric acid acid1 and 1 and derivatives derivatives will will 68 be much more prone to deprotonation by soft bases than dimedone 3 or non-cyclic homologues, 69 such as malonate 4, for instance. However, direct correlation between the pKa value and the 70 nucleophilic behavior is not always feasible [27]. 71 Catalysts 2019, 9, 131 3 of 27 Catalystsbe much 2018, more 8, x FOR prone PEER to REVIEW deprotonation by soft bases than dimedone 3 or non-cyclic homologues,3 suchof 30 as malonate 4, for instance. However, direct correlation between the pKa value and the nucleophilic behavior is not always feasible [27]. 72 73 74 FigureFigure 2. 2.PropertiesProperties of ofbarbituric barbituric acid acid derivatives. derivatives. (a) (Aciditya) Acidity given given in inDMSO. DMSO. (b) ( bNucleophilic) Nucleophilic 75 reactivityreactivity parameters parameters of ofanions. anions. 76 In In2017, 2017, Spange Spange and and co-workers co-workers embarked embarked on on the the insightful insightful evaluation evaluation of ofthe the kinetics kinetics of of 77 derivativesderivatives of ofbarbiturate barbiturate acid acid anions anions thanks thanks to tothe the reaction reaction with with specific specific electrophiles, electrophiles, such such as as 78 benzhydryliumbenzhydrylium cations cations and and Michael Michael acceptors acceptors [28]. [28 Then,]. Then, the the so-called so-called nucleophilicity nucleophilicity parameter parameter N N 79 andand the the corresponding corresponding nucleophile-sp nucleophile-specificecific susceptibility susceptibility parameter parameter sNs ofN ofbarbiturate barbiturate anions anions 1’ 1’couldcould 80 bebe determined determined and and compared compared to torelated related 1,3-dicarbonyl 1,3-dicarbonyl anions anions 2’-2’4’- 4(Figure’ (Figure 2b)2b) [27]. [ 27 ].Barbituric Barbituric acid acid 81 anionanion 1’ 1’featuresfeatures a nucleophilic a nucleophilic character character