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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 bioactive bioactive compounds compounds 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 cysteine cysteine sulfoxide sulfoxide 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 as as proton-pumpproton-pump inhibitor; inhibitor; thethe selective selective NK NK22 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 is is furthermore furthermore used used for for the the treatment treatment of of depression depression [[17]17],, attention-deficitattention-deficit hyperactivity hyperactivity 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 Lafon Lafon [[22]22],, severalseveral methods methods 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-deficient employing 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 approaches approaches is is limited limited to a to 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 need the need for hazardous for hazardous oxidizing oxidizing agents, expensive agents, 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 been in 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 family of ofchiral chiral phosphoric phosphoric acids acids with with results results analogous analogous to to the the best best obtained obtained with with metal catalysts. Having ® already shown a very good performance in a patented,patented, efficient,efficient, and direct route towardstowards SulindacSulindac®

(Figure(Figure1 1))[ [53,54]53,54],, BINOL-derivedBINOL-derived phosphoric acids have surprisingly never been applied for the enantioselectiveenantioselective synthesis of modaﬁnil.modafinil. Following our previous successessuccesses inin applyingapplying LewisLewis base/Brønstedbase/Brønsted acid catalysts for various organicorganic transformations [[5555–5757]],, we decided to test test BINOL-phosphates BINOL-phosphates (chiral(chiral bifunctional bifunctional organocatalysts, Scheme 1) and additional catalytic systems. To the best of our knowledge, we

Symmetry 2017, 9, 88 3 of 9 Symmetry 2017, 9, 88 3 of 9 organocatalysts,present herein Schemethe first1 ) organocatalyzed and additional catalytic synthesis systems. of enantiomerically To the best of our enriched knowledge, modafinil we present via hereinsulfoxidation. the ﬁrst organocatalyzed synthesis of enantiomerically enriched modaﬁnil via sulfoxidation.

Scheme 1.1. ProposedProposed Lewis base/Brønstedbase/Brønsted acid acid catalysis—BINOL-phosphatescatalysis—BINOL-phosphates as bifunctional bifunctional organocatalysts in the oxidationoxidation ofof sulﬁdesulfide withwith hydrogenhydrogen peroxideperoxide asas anan oxidant.oxidant.

2. Materials and Methods Solvents were purifiedpurified byby standardstandard proceduresprocedures andand distilleddistilled priorprior toto use.use. ReagentsReagents obtainedobtained from commercialcommercial sources were usedused withoutwithout further purification.purification. Thin layer chromatography ( (TLC)TLC) chromatography was was performed performed on on pre pre-coated-coated aluminum aluminum silica silica gel ALUGRAM gel ALUGRAM SIL G/UV254 SIL G/UV254 plates plates(Macherey, (Macherey, Nagel & Nagel Co., Düren, & Co., Germany Düren,). Germany).Flash chromatography Flash chromatography was performed was using performed silica gel usingACROS silica 60 gelÅ , ACROS (particle 60 size Å, (particle 0.035–0.070 size 0.035–0.070 mm, Thermofischer mm, Thermofischer ACROS Organics, ACROS Organics,Janssen- 1 Janssen-PharmaceuticalaanPharmaceuticalaan 3a, 2440 3a, Geel, 2440 Belgium) Geel, Belgium).. Proton Proton nuclear nuclear magnetic magnetic resonance resonance spectroscopy spectroscopy ( H- NMR1 ) spectra were recorded in CDCl3 with Bruker Avance 300 or 400 (Bruker, Billerica, MA, USA). ( H-NMR) spectra were recorded in CDCl3 with Bruker Avance 300 or 400 (Bruker, Billerica, MA, USA). Enantioselectivities werewere determined by chiral high pressure liquid chromatography (HPLC)(HPLC) analysis in comparison withwith authenticauthentic racemicracemic material.material.

2.1. (Methylsulﬁnyl)Benzene(Methylsulfinyl)Benzene (1a):):

The corresponding BINOL-phosphateBINOL-phosphate catalystcatalyst (0.048(0.048 mmol)mmol) waswas dissolveddissolved inin CHCH22ClCl22 (0.5 mL)mL) at ◦ −1010 °C.C. After After the the addition addition of of t thehe sulfide sulﬁde (0.24 (0.24 mmol mmol,, 29.8 29.8 mg mg)) aqueous aqueous 30% H 2OO22 (1.2(1.2 equiv equiv,, 0. 0.2929 mmol, mmol, 29.4 µL)L) was added in one portion. The reaction mixture was stirred stirred at at room temperature for for 24 24 h. h. The productproduct waswas obtainedobtained viavia directdirect puriﬁcationpurification byby columncolumn chromatographychromatography (SiO(SiO22,, EtOAc/PEEtOAc/PE 4:1). 4:1). The enantiomeric excessexcess ofof the product was determined byby chiral HPLC analysis. 1HH-NMR-NMR (300 MHz, MHz, CDCl3): δδ = 2.70 2.70 (s, (s, 3H), 3H), 7.47 7.47–7.54–7.54 (m, (m, 3H), 3H), 7.60 7.60–7.64–7.64 (m, (m, 2H). 2H).

2.2. 1-(Methylsulﬁnyl)-4-Nitrobenzene1-(Methylsulfinyl)-4-Nitrobenzene ((1b1b):):

The corresponding BINOL-phosphateBINOL-phosphate catalystcatalyst (0.048(0.048 mmol)mmol) waswas dissolveddissolved inin CHCH22ClCl22 (0.5 mL)mL) at ◦ −1010 °C.C. The The sulfide sulﬁde (0.24 (0.24 mmol, mmol, 40.6 40.6 mg) was added, followed by thethe additionaddition ofof aqueousaqueous 30%30% HH22OO22 (1.2(1.2 equiv,equiv, 0.290.29 mmol,mmol, 29.429.4 µµLL)) inin oneone portion.portion. The reaction mixture was stirred at room temperature for 2424 h.h. TheThe productproduct waswas directlydirectly puriﬁedpurified byby column column chromatography chromatography (SiO (SiO2,2, EtOAc/PEEtOAc/PE 4:1).4:1). The enantiomeric excess of the productproduct waswas determineddetermined byby chiralchiral HPLCHPLC analysis.analysis. 1HH-NMR-NMR (300 MHz, CDCl3): δδ = 2.77 2.77 (s, (s, 3H), 3H), 7.82 7.82 (d, (d, JJ == 8.9 8.9 Hz, Hz, 2H), 2H), 8.38 8.38 (d, (d, JJ == 8.9 8.9 Hz, Hz, 2H). 2H).

2.3. 2-(Benzhydrylsulfinyl)Acetamide2-(Benzhydrylsulfinyl)Acetamide (2):): ◦ BINOL-phosphateBINOL-phosphate VV (0.048(0.048 mmol,mmol, 3636 mg)mg) was was dissolved dissolved in in CH CH2Cl2Cl22 (0.5(0.5 mL)mL) at at− −10 °C,C, followed µ by the addition of aqueous 30% H22O2 (1.2(1.2 equiv equiv,, 0.29 mmol, 29 29.4.4 µL)L) in one portion. Then, the sulfide sulfide ◦ (0.24(0.24 mmol,mmol, 61.861.8 mg) mg) was was added added to to the the reaction reaction mixture, mixture, which which was was stirred stirred at − at10 −10C. The°C. The product product was directlywas directly purified purified by column by column chromatography chromatography (SiO2, EtOAc). (SiO2, EtOAc). The isolated The enantiomerically isolated enantiomerically enriched 1 (R)-enrichedmodafinil (R)-modafinil was identified was identified through comparison through comparison of H-NMR of spectra1H-NMR with spectra literature with literature data [38]. data The enantiomeric[38]. The enantiomeric excess of the excess product of the was product determined was by determined chiral HPLC by analysis chiral HPLC (Daicel analysis Chiralpak (Daicel AS, ◦ 1 nChiralpak-hexane/ iAS,-PrOH n-hexane/ (60:40),i- flowPrOH 0.9 (60:40), mL/min, flow 25 0.9C, mL/min, 31 bar). 25H-NMR °C, 31 bar). (300 MHz,1H-NMR DMSO-d (300 MHz,6): δ = DMSO 3.21 (d,- Jd=6): 13.5 δ = 3.21 Hz, 1H),(d, J 3.36= 13.5 (d, Hz,J = 1H), 13.5 Hz,3.36 1H),(d, J 5.34= 13.5 (s, Hz, 1H), 1H), 7.32–7.43 5.34 (s, (m, 1H), 7H), 7.32 7.50–7.52–7.43 (m, (m, 7H), 4H), 7.50 7.68–7.52 (s, 1H).(m, 4H), 7.68 (s, 1H).

Symmetry 2017, 9, 88 4 of 9

3. Results and Discussion Our initial work started with the screening of different BINOL-phosphates for the synthesis of thioanisole via sulfoxidation as a model reaction. The required organocatalysts I–VII for the reaction were prepared by conventional means [58]. SymmetryInitially,2017, 9 ,the 88 reaction was performed in dichloromethane using 20 mol % of the organocatalyst4 of 9 at −10 °C within 24 h. In case of BINOL-phosphate II, only moderate yield was observed (44% yield, entry 1, Table 1) and the enantiomeric excess was rather low (10% ee). A further reduction of the 3.amount Results of andcatalyst Discussion from 20 mol % to 10 mol % resulted in a decreased yield, but the enantiomeric ratioOur remained initial work constant started (26% with yield, the 10%screening ee, entry of different 2, Table BINOL-phosphates 1). Surprisingly, BINOL for the-phosphate sulfoxidation III ofprovided thioanisole the corresponding as a model reaction. sulfoxide The in required high yield organocatalysts (98%) with anI– VIIenantiomericfor the reaction excess were of 20% prepared (entry by3, Tableconventional 1) and means we continued [58]. to investigate catalyst I. To our delight, the enantiomeric excess increasedInitially, to the36% reaction ee, but was the yieldperformed was lowered in dichloromethane to 68% (entry using 4, 20 Table mol 1). % of In the the organocatalyst case of BINOL at- −phosphate10 ◦C within with 24 a h.more In casesterically of BINOL-phosphate hindered moietyII, a, onlycomplete moderate loss of yield activity was was observed the consequence (44% yield, entry(entry 1,5, TableTable1 )1). and With the catalyst enantiomeric V, on the excess other was hand, rather the lowproduct (10% couldee). Abe furtherisolated reduction with 73% of yield the amountand an enantiomeric of catalyst from excess 20 mol of 30% % to (entry 10 mol 6, %Table resulted 1). Furthermore, in a decreased carrying yield, but out the one enantiomeric reaction without ratio remainedan external constant catalyst, (26% we could yield, preclude 10% ee, entry a background 2, Table1). reaction Surprisingly, (entry BINOL-phosphate 7, Table 1). III provided the correspondingWe investigated sulfoxide the oxidation in high yieldof a thioanisole (98%) with derivative an enantiomeric bearing excess a nitro of 20%moiety (entry in 4 3,-position Table1) and(entries we continued 8–11, Table to 1). investigate We applied catalyst BINOLI. To-phosphate our delight, VI the, and enantiomeric found that excess the product increased could to 36% be eeisolated, but the with yield a was low lowered yield of to 11% 68% and (entry a moderate 4, Table1 ). enantiomeric In the case of excess BINOL-phosphate of 33% (entry with 8, Table a more 1). stericallyCarrying hindered out the reaction moiety, a with complete a lower loss amount of activity of was hydrogen the consequence peroxide (0.27 (entry equiv 5, Tablealent1).) under With catalystotherwiseV, identical on the other conditions, hand, the the product isolated could product be isolated had a significantly with 73% yield higher and anenantiomeric enantiomeric excess excess of of59% 30% (entry (entry 9, 6,Table Table 1).1). With Furthermore, catalyst VII carrying, bearing out an one electron reaction withdrawing without an external substituent catalyst, on the we phenyl could precludemoiety in a para background position, reactionthe desired (entry product 7, Table was1). generated only in traces (entry 10, Table 1).

Table 1.1. BINOL-phosphateBINOL-phosphate catalyzedcatalyzed oxidationoxidation ofof thioanisolethioanisole derivatives.derivatives.

Entry Product BINOL-Phosphate Yield, a % ee,% (S) Entry Product BINOL-Phosphate Yield, a % ee, % (S) 1 1 1a 1aII II 4444 1010b b d b 2 2 1a 1a II IId 2626 1010 b b 3 3 1a 1aIII III 9898 2020 b b 4 4 1a 1aI I 6868 3636 b 5 5 1a 1aIV IV TracesTraces n.d.n.d. 6 1a V 73 30 b 6 1a V 73 30 b 7 1a – Traces n.d. 7 1a – Traces n.d. 8 1b VI 11 33 c c 8 9 1b 1bVI VI e 1411 5933c e 9 10 1b 1bVI VII Traces14 1859c c 10 1b VII Traces 18 c a b c a Yield of of isolated isolated product; product;determined b determined by HPLC by HPLC (OD, n -hexanes/(OD, n-hexanes/iPrOH (93:7),iPrOH flow (93:7), 1.0 mL/min); flow 1.0 mdeterminedL/min); c d e by HPLC (IA, n-hexanes/iPrOH (90:10), flow 1.0 mL/min); 10 mol % catalyst loading;d c (educt) = 0.8 mol/l; H2O2 =determined 0.27 equiv. For by detailsHPLC of (IA, the reactionn-hexanes/ proceduresiPrOH and(90:10), product flow characterizations, 1.0 mL/min); see 10 Supplementary mol % catalyst Information. loading; e c (educt) = 0.8 mol/l; H2O2 = 0.27 equiv. For details of the reaction procedures and product characterizations, see Supplementary Information. We investigated the oxidation of a thioanisole derivative bearing a nitro moiety in 4-position (entries 8–11, Table1). We applied BINOL-phosphate VI, and found that the product could be isolated with a low yield of 11% and a moderate enantiomeric excess of 33% (entry 8, Table1). Carrying out the reaction with a lower amount of hydrogen peroxide (0.27 equivalent) under otherwise identical conditions, the isolated product had a significantly higher enantiomeric excess of 59% (entry 9, Table1). Symmetry 2017, 9, 88 5 of 9

Subsequently, we studied the sulfoxidation of the prochiral sulfide in the presence of 20 mol % of BINOL-phosphate V, which had previously performed best. The reaction proceeded at −10 °C, in Symmetry 2017, 9, 88 5 of 9 CH2Cl2 as a solvent (Table 2). Initially, we applied the optimized reaction conditions, and the product could be isolated after 24 h in quantitative yield with an enantiomeric excess of 10% (entry 1, Table 2) WithIn order catalyst to examineVII, bearing the temperature an electron withdrawingeffect on the reaction substituent, we on carried the phenyl out the moiety sulfoxidation in para position, at 0 °C. theThe desired product product was obtained was generated quantitatively only in but traces with (entry a slightly 10, Table lower1). ee value of 7% (entry 2, Table 2). A shorterSubsequently, reaction time we of studied 12 h resulted the sulfoxidation in a lower of yield the prochiral of 61%, and sulfide no inenantioselectivity the presence of 20could mol be % ofdetected BINOL-phosphate (entry 3, TableV, which2). A higher had previously initial concentration performed best.of the The sulfide reaction had proceeded a positive atinfluence−10 ◦C, on in CHthe 2stereoselectivityCl2 as a solvent (Tableof the2 oxidation.). Initially, Thus, we applied following the optimizedthe previous reaction trend conditions,concerning and the theoxidation product of couldthioanisol be isolatede (entry after 9, Table 24 h in 1) quantitative, we observed yield this with supporting an enantiomeric effect excess on the of reaction 10% (entry outcome 1, Table for2) Inmodafinil order to as examine well. Due thetemperature to an accelerated effect on reaction the reaction,, the desired we carried compound out the sulfoxidation could be isolated at 0 ◦C. in Thequantitative product yield was obtainedalready after quantitatively 12 h and the but eewith value a slightly slightly incre lowerasedee value to 13% of (entry 7% (entry 4, Table 2, Table 2). 2). A shorterThe Shi’s reaction N-substituted time of 12 hoxazolidinone resulted in a ketone lower yieldVIII ofbelongs 61%, andto the no enantioselectivityattractive class of couldfructose be- detectedderived asymmetric (entry 3, Table organocatalysts,2). A higher initial generally concentration employed of for the the sulfide epoxidation had a positive of unfunctionali influencez oned theterminal stereoselectivity alkenes [59,60] of the. Having oxidation. successfull Thus, followingy applied the it previous to the one trend-pot concerning, two-step the synthesis oxidation of ofβ- thioanisoleadrenergic (entryblockers 9, Tablevia epoxidation1), we observed as a this key supporting enantiosele effectctive on step the [60] reaction, we decided outcome to for evaluate modafinil its asactivity well. Duefor the to ansulfoxidation accelerated reaction reaction, as the well desired. Modafinil compound was generated could be isolated with a inyield quantitative of 38% and yield an alreadyenantioselectivity after 12 h andof 26 the% eeee (entryvalue slightly5, Table increased2). to 13% (entry 4, Table2).

Table 2.2. Organocatalytic synthesissynthesis ofof modaﬁnil.modafinil.

Entry Catalyst Time, h Yield, a % ee, b % (R) Entry Catalyst Time, h Yield, a % ee, b % (R) 1 1 V V 2424 >99 >99 10 2 V c 24 >99 7 2 V c 24 >99 7 3 V 12 61 rac 3 V 12 61 rac 4 d V 12 >99 13 d 4 5 VVIII 1224 >99 38 2613 5 6 VIIIIX e 2496 38 66 1626 6 IX e 96 66 16 a b a Yield of of isolated isolated product; product;determined b determined by chiral by chiral HPLC HPLC (AS, n -hexanes/ (AS, n-hexanes/iPrOH (60:40),iPrOH flow(60:40), 0.9 mL/min,flow 0.9 ◦ c ◦ d e o 25 C, 31 bar); T = 0 C; c (sulfide) = 0.8 mol/l; without H2O2, 1.5 equiv of IX, T = −30 C > room mL/min, 25 °C, 31 bar); c T = 0 °C; d c (sulfide) = 0.8 mol/l; e without H2O2, 1.5 equiv of IX, T = −30 oC > temperature (RT), tetrahydrofuran (THF). For details of the reaction procedures and product characterizations, see Supplementaryroom temperature Information. (RT), tetrahydrofuran (THF). For details of the reaction procedures and product characterizations, see Supplementary Information. TheIn order Shi’s to minimizeN-substituted the number oxazolidinone of reactants, ketone we nextVIII intendedbelongs to combine to the attractivethe oxidizing class agent of fructose-derivedand the chiral source. asymmetric Therefore, organocatalysts, we applied the generallysynthesized employed chiral hydroperoxide for the epoxidation TADOOH IX of, unfunctionalizedwhich is generally terminal known for alkenes its high [59 efficie,60]. Havingncy for sulfoxidation successfully appliedreactions it [61] to the. A one-pot,striking feature two-step of synthesisthis method of βis-adrenergic that no further blockers external via epoxidation catalyst is needed. as a key With enantioselective an amount stepof 1.5 [60 equiv], wealent decided of the to evaluateoxidant in its tetrahydrofuran activity for the sulfoxidation (THF), the product reaction was as well.generated Modafinil in 66% was yield generated with an with enantioselectivity a yield of 38% andof 16% an enantioselectivity(entry 6, Table 2). of 26% ee (entry 5, Table2). In order to minimize the number of reactants, we next intended to combine the oxidizing agent and the chiral source. Therefore, we applied the synthesized chiral hydroperoxide TADOOH IX, which Symmetry 2017, 9, 88 6 of 9 is generally known for its high efficiency for sulfoxidation reactions [61]. A striking feature of this method is that no further external catalyst is needed. With an amount of 1.5 equivalent of the oxidant inSymmetry tetrahydrofuran 2017, 9, 88 (THF), the product was generated in 66% yield with an enantioselectivity of6 16% of 9 (entry 6, Table2). Following our previous interest in the application of the non-hemenon-heme iron-catalyzediron-catalyzed sulfoxidation reaction, which exhibited high activity in the oxidation of the thioanisol but, up to now now,, showedshowed unsatisfactoryunsatisfactory results for the modafinilmodafinil precursor [[39]39],, we decideddecided to investigateinvestigate a dipeptide-baseddipeptide-based chiral ligand as an alternative chiral source (Scheme(Scheme2 2).).

Scheme 2. Application of a dipeptide-baseddipeptide-based ligand X to thethe biomimeticbiomimetic iron-catalyzediron-catalyzed synthesis of (R)(R)-modaﬁnil.-modafinil.

Under these conditions, modafinil could be isolated in good yield of 75% and with an ee value Under these conditions, modaﬁnil could be isolated in good yield of 75% and with an ee of 24%. This represents the most successful asymmetric non-heme iron-catalyzed synthesis of (R)- value of 24%. This represents the most successful asymmetric non-heme iron-catalyzed synthesis of modafinil so far. (R)-modaﬁnil so far.

4.4. Conclusions We report report here here the the first first organocatalytic organocatalytic synthesis synthesis of of enantiomerically enantiomerically enriched enriched (R)-(R)-modafinilmodafinil (Armodafinil(Armodafinil®®),), accomplished accomplished with with the the chiral chiral bifunctional bifunctional BINOL BINOL-phosphate-phosphate V, Va ,fructose a fructose-derived-derived N- N-substitutedsubstituted oxazolidinone oxazolidinone ketone ketone VIIIVIII,, oror the the chiral chiral peroxide peroxide TA TADOOHDOOH IXIX, ,respectively. respectively. The The desired compound could be obtained via sulfoxidation using H2O2 with excellent yield up to >99% and ee values compound could be obtained via sulfoxidation using H2O2 with excellent yield up to >99% and ee valuesup to 23%. up toThis 23%. protocol This protocol includes includes all the advantages all the advantages of metal of-free metal-free asymmetric asymmetric organocatalysis. organocatalysis. We additionally showedshowed thethe successful application of a dipeptide dipeptide-based-based ligand in the biomimetic non-hemenon-heme iron-catalyzediron-catalyzed sulfoxidationsulfoxidation towardstowards enantiomericallyenantiomerically enriched entioenriched(R)-modafinil, (R)-modafinil, which which could becould isolated be isolated in good in good yield yield of 75% of 75% with with an enantioselectivityan enantioselectivity of of 24% 24%ee ee.. The The sulfoxidation sulfoxidation reported here makes use of mild reaction conditions using aqueous hydrogen peroxide as an environmentally friendly oxidant.

Supplementary Materials: Materials: TheThe following following are available are available online online at www.mdpi.com/link at www.mdpi.com/2073-8994/9/6/88/s1: Experimental Procedures,: ExperimentalAnalytical and Procedures, Spectroscopic Analytical Data of andProducts. Spectroscopic Data of Products.

Acknowledgments: We gratefullygratefully acknowledgeacknowledge thethe financialfinancial supportsupport fromfrom DeutscheDeutsche ForschungsgemeinschaftForschungsgemeinschaft (DFG) by grant TS 87/16-3. We also thank the Interdisciplinary Center for Molecular Materials (ICMM), the (DFG) by grant TS 87/16-3. We also thank the Interdisciplinary Center for Molecular Materials (ICMM), the Graduate School Molecular Science (GSMS) for research support, as well as the Wilhelm Sander-Stiftung (Grant No.Graduate 2014.019.1) School for Molecular funding. Science (GSMS) for research support, as well as the Wilhelm Sander-Stiftung (Grant No. 2014.019.1) for funding. Author Contributions: Felix E. Held conducted the sulfoxidation reactions. Kerstin A. Stingl contributed to the catalystAuthor screeningContributions: of the Felix model E. reaction. Held conducted Svetlana the B. Tsogoeva sulfoxidation conceived reactions and. directedKerstin A. the Stingl research, contributed supervised to the syntheticcatalyst screening experiments. of the The model manuscript reaction. was Svetlana written B. through Tsogoeva contribution conceived ofand all directed authors. the research, supervised Conflictsthe synthetic of Interest: experimentsThe. authors The manuscript declare no was conflict written of interest.through contribution of all authors. Conflicts of Interest: The authors declare no conflict of interest. References

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