Synthesis Of

S S symmetry Article ArticleSynthesis of (R)-Modafinil via Organocatalyzed and SynthesisNon-Heme of Iron (R)-Modafinil-Catalyzed viaSulfoxidation Organocatalyzed Using H and2O2 Non-Hemeas an Environmentally Iron-Catalyzed Benign Sulfoxidation Oxidant Using H2O2 as an Environmentally Benign Oxidant Felix E. Held, Kerstin A. Stingl and Svetlana B. Tsogoeva * FelixDepartment E. Held, of Kerstin Chemistry A. and Stingl Pharmacy, and Svetlana Organic B.Chemistry Tsogoeva Chair * I and Interdisciplinary Center for DepartmentMolecular Materials of Chemistry (ICMM), and University Pharmacy, Organicof Erlangen Chemistry-Nuremberg, Chair Henkestraße I and Interdisciplinary 42, 91054 CenterErlangen, for Germany Molecular; [email protected] (ICMM), (F.E.H.); University kerst [email protected] Erlangen-Nuremberg, (K.A.S.) Henkestraße 42, 91054 Erlangen, Germany; [email protected]* Correspondence (F.E.H.);: svetlana. [email protected]@fau.de; Tel.: (K.A.S.) +49-9131-85-22541 *AcademicCorrespondence: Editor: Stephane [email protected]; Béllemin-Laponnaz Tel.: +49-9131-85-22541 AcademicReceived: 11 Editor: May Stephane2017; Accepted: Béllemin-Laponnaz 7 June 2017; Published: 16 June 2017 Received: 11 May 2017; Accepted: 7 June 2017; Published: 16 June 2017 Abstract: The first organocatalyzed sulfoxidation reaction towards enantioenriched (R)-modafinil Abstract:(ArmodafinilThe® first), a drug organocatalyzed against narcolepsy, sulfoxidation is reported reaction here. towards A series enantioenriched of chiral organocatalysts (R)-modafinil, e.g., (Armodafinildifferent chiral®), BINOL a drug-phosphates, against narcolepsy, or a fructose is reported-derived here. N-substituted A series oxazolidinone of chiral organocatalysts, ketone (Shi e.g.,catalyst) different were chiral applied BINOL-phosphates, for the sulfoxidation or a fructose-derived reaction with environmentallyN-substituted oxazolidinone friendly H2O ketone2 as a (Shiconvenient catalyst) oxygen were appliedtransferring for the agent. sulfoxidation Furthermore, reaction the potential with environmentally of a biomimetic friendly catalytic H2 Osystem2 as a convenientconsisting of oxygen FeCl3 transferringand a dipeptide agent.-based Furthermore, chiral ligand the potentialwas demonstrated, of a biomimetic which catalytic constitutes system the consistingmost successful of FeCl asymmetric3 and a dipeptide-based non-heme iron- chiralcatalyzed ligand synthesis was demonstrated, of (R)-modafinil which so far. constitutes the most successful asymmetric non-heme iron-catalyzed synthesis of (R)-modafinil so far. Keywords: sulfoxidation; (R)-modafinil; organocatalysis; non-heme iron catalyst; hydrogen Keywords:peroxide sulfoxidation; (R)-modafinil; organocatalysis; non-heme iron catalyst; hydrogen peroxide 1. Introduction SulfoxidesSulfoxides demonstrate versatile properties and are ubiquitous in bioactivebioactive compoundscompounds and drugs [[1]1].. Being of medicinal interest, chiral sulfoxides serve as building blocks for the generation ofof biologically active compounds [[2]2].. With the discovery of their presence in naturallynaturally chiralchiral sulfoxidesulfoxide metabolites [[3]3],, such as cysteinecysteine sulfoxidesulfoxide derivatives, the demand for new synthetic routes was steadily growing, especiallyespecially sincesince thethe pioneeringpioneering workwork ofof KaganKagan andand ModenaModena [[44––66]].. Optically active sulfoxides are importantimportant representativesrepresentatives ofof therapeuticallytherapeutically usedused drugs.drugs. There are several examples that playing an important role in medicinalmedicinal and pharmaceutical chemistry [2] [2],, includingincluding EsomeprazoleEsomeprazole [[7,8]7,8],, which acts asas proton-pumpproton-pump inhibitor;inhibitor; thethe selectiveselective NKNK22 antagonistantagonist ZD7944 [[9]9];; and the anti-canceranti-cancer agentagent SulindacSulindac®® (Figure1 1))[ [10]10].. Figure 1.1. Examples of chiral biologically active sulfoxides. Symmetry 2017, 9, 88; doi:10.3390/sym9060088 www.mdpi.com/journal/symmetry Symmetry 2017, 9, 88; doi:10.3390/sym9060088 www.mdpi.com/journal/symmetry Symmetry 2017, 9, 88 2 of 9 Symmetry 2017, 9, 88 2 of 9 ModafinilModafinil (also known as Provigil®® [11][11],, Figure 22),), anotheranother importantimportant sulfoxide,sulfoxide, isis administeredadministered as a drug against narcolepsy [[12]12] with significant significant advantages compared to dexamphetamine [[13]13] and several other stimulants [[14]14] because of aa lowerlower abuseabuse potentialpotential [[15,16]15,16].. FigureFigure 2. 2.The The hippocampalhippocampal activatoractivator inin itsits racemicracemic (modafinil)(modafinil) and optically pure (Armodafinil (Armodafinil®®) )forms. forms. It isis furthermorefurthermore usedused forfor thethe treatmenttreatment ofof depressiondepression [[17]17],, attention-deficitattention-deficit hyperactivityhyperactivity disorder [[18]18],, Parkinson’sParkinson’s disease [[19]19],, and epilepsyepilepsy [[20]20].. Moreover, it is aa memory-improvingmemory-improving andand mood-brighteningmood-brightening psychostimulantpsychostimulant [[21]21].. After the firstfirst synthesissynthesis was developed in 1979 by LafonLafon [[22]22],, severalseveral methodsmethods have been envisioned for its racemic generation using hydrogen peroxide as an abundant,abundant, environmentallyenvironmentally benign oxidant [[2323–2929]].. The fact that there is aa continuedcontinued demanddemand for novelnovel syntheticsynthetic methods to attain modafinilmodafinil is further demonstrated by a recently published one-potone-pot parallel synthetic approach [29] [29] as well as another strategy,strategy, established established by Cibulka by Cibulka and co-workers, and co employing-workers, electron-deficientemploying electron heteroarenium-deficient saltsheteroarenium for the activation salts for of the hydrogen activation peroxide of hydrogen [30]. peroxide [30]. The quantitative potency of the two enantiomers of modafinil, modafinil, however, is indeed influenced influenced by the stereogenic sulfoxide group. (R)-modafinil)-modafinil has a longer half-lifehalf-life in the human body compared to ((S)-modafinil)-modafinil [[31]31],, whichwhich isis metabolizedmetabolized threethree timestimes fasterfaster [[32]32].. An ester, amide,amide, or carboxylic acid moiety close to the sulfidesulfide function, however, can adverselyadversely affect enantioselectivity enantioselectivity [33] [33.]. Given Given that that no nodirecting directing group group is available is available adjacent adjacent to the to sulfur the sulfuratom, atom,compar compared,ed, for instance for instance,, to omeprazole to omeprazole [7], [7most], most known known procedures procedures aim aim to to circumvent circumvent an enantioselective oxidation. As an alternative, race racemicmic resolution of diastereomers [34,35] [34,35],, preferential crystallization or chiral chromatography can be appliedapplied [[36]36].. Thus, the varietyvariety ofof enantioselectiveenantioselective synthetic approachesapproaches is is limited limited to ato small a small selection, selection, namely, na amely, microbial a microbial sulfoxidation sulfoxidation [37], an advanced [37], an Kaganadvanced method Kagan patented method bypatented Cephalon by Cephalon [33], and [33 an] oxygen-transfer, and an oxygen- bytransfer a chiral by oxaziridinea chiral oxaziridine in ionic liquidin ionic [38 liquid]. [38]. These methods,methods, however, however, suffer suffer from from the needthe need for hazardous for hazardous oxidizing oxidizing agents, expensiveagents, expensive solvents, andsolvents metal, and catalysts. metal catalysts. Apart from Apart a vanadium-based from a vanadium catalytic-based catalytic system, system developed, developed in our group, in our whichgroup, waswhich able was to able provide to provide (R)-modafinil (R)-modafinil in excellent in excellent yield and yield moderate and moderate enantiomeric enantiomeric excess excess within within a very shorta very reactionshort reaction time [time39], [39] all other,all other attempts attempts making making use use of of convenient convenient metal metal complexes complexes generally resulted in a drastically decreaseddecreased performanceperformance ofof thethe catalystcatalyst [[38]38].. For the pharmaceutical industry it is a permanentpermanent issue to freefree biologicallybiologically activeactive compoundscompounds from metalmetal traces.traces. Thus, the development of aa metal-freemetal-free sulfoxidationsulfoxidation processprocess isis inin highhigh demand.demand. A class class of of powerful powerful organo organocatalystscatalysts is represented is represented by Brønsted by Brønsted acid catalysts acid catalysts such as suchBINOL as- BINOL-derivedderived phosphoric phosphoric acids, which acids, have which already have been already applied beenin numerous applied highly in numerous enantioselective highly enantioselectivetransformations [40 transformations–49] since the pioneering [40–49] since studies the by pioneering the groups studies of Akiyama by theet al. groups [50] and of AkiyamaUraguchi etand al. Terada [50] and [51] Uraguchi. and Terada [51]. Wang, TaoTao andand co-workersco-workers [[52]52] werewere thethe firstfirst toto developdevelop aa sulfoxidationsulfoxidation reaction catalyzed by BINOL-phosphates,BINOL-phosphates, and and List List et et al al.. [53,54] [53,54 ]impressively impressively demonstrated demonstrated the the potential potential of ofa new a new family

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