多组分反应文献

Three-component diastereoselective cascade synthesis ofthiohydantoinsVictor Ceban,Kane Hands,Marta Meazza,Mark E.Light,Ramon Rios ⇑School of Chemistry,University of Southampton,Southampton SO171BJ,UKa r t i c l e i n f o Article history:Received 29August 2013Revised 3October 2013Accepted 23October 2013Available online 1November 2013Keywords:Organocatalysis Cascade reactions Thiohydantoins Edman degradation Diastereoselectivea b s t r a c tA new three-component cascade reaction for the synthesis of thiohydantoins is reported.The reaction between a -amino esters,nitrostyrenes,and aromatic isothiocyanates is efficiently promoted by organic bases to afford highly substituted thiohydantoins in moderate to good yields and diastereoselectivities.Ó2013Elsevier Ltd.All rights reserved.Thiohydantoins 1are very interesting compounds owing to their wide applications,for example,as hypolipidemic,2antithyrodial,3antibacterial,4antiviral 5(e.g.,HIV and tuberculosis),anticarcino-genic,6antimutagenic,7anti-ulcer,and anti-inflammatory agents 8and in pesticides.9However,thiohydantoins have a reputation of being unselective compounds that appear as ‘frequent hitters’in screening campaigns.This behavior has been the subject of contro-versial debate in the medicinal chemistry community:some con-sider that they are promiscuous binders with an insignificant value in drug discovery,while others consider that they are privi-leged scaffolds that could allow quick identification of hits,which could be developed further.10If thiohydantoins are considered to be privileged scaffolds,or-ganic chemists need to develop new methodologies that offer easy access to these structures in order to build large libraries of com-pounds that will lead to more selective hits.Despite the obvious interest in the synthesis of these com-pounds,we have found only a few methods in the literature for their synthesis.11One of the most important methodologies is Ed-man degradation,which was developed by Pehr Edman for sequencing amino acids in a peptide.12In this method,the ami-no-terminal residue is labeled and then cleaved from the peptide without disrupting the peptide bonds between other amino acid residues (Scheme 1).Spurred by our success in the synthesis of similar compounds such as substituted oxazolidinones,13we envisioned an easy entry into disubstituted thiohydantoins based on a multicomponent reaction 14inspired by Edman degradation.The commercially avail-able amino ester 1a was reacted with phenyl isothiocyanate (2a )to afford cyclic intermediate 4a .This highly acidic intermediate was deprotonated and trapped by an appropriate nucleophile 5a to af-ford compound 6a ,that underwent rearrangement to afford the thiohydantoin derivative 7a (Scheme 2).In the preliminary experiments,we investigated the multicom-ponent reaction between phenylglycine methyl ester (1a ),phenyl isocyanate (2a ),and nitrostyrene (5a )in the presence of different bases and solvents.To our delight,the reaction affords the pre-dicted disubstituted thiohydantoins in good yields and moderate to good diastereoselectivities (Table 1).As shown in Table 1,the best reaction conditions are as follows:base,Et 3N;solvent:acetonitrile.The use of DABCO and quinine,as the base,afforded thiohydantoin 7a in lower diastereoselectivities and in a racemic form (1%ee)(Table 1,entries 2and 3).The use of other solvents such as toluene,dichloromethane,chloroform,or ethyl acetate afforded the corresponding products with slightly lower diastereoselectivities and as more complex crude mixtures (Table 1,entries 4–7).Takemoto’s catalyst 15afforded a similar dia-stereoselectivity to Et 3N (10:1dr)with almost negligible enanti-oselectivity (10%ee).However,when the reaction was carried out in the absence of a base,a complex mixture was obtained with-out the desired product (Table 1,entry 9).We also tested the reaction with the hydrochloride salt of the a -amino ester 1a using 1.1equiv of Et 3N and obtained a similar result to entry 1(Table 1,entry 10).0040-4039/$-see front matter Ó2013Elsevier Ltd.All rights reserved./10.1016/j.tetlet.2013.10.110Corresponding author.E-mail address:R.Rios-Torres@ (R.Rios).With the optimized reaction conditions in hand,we decided to study the scope of the reaction using several nitrostyrenes,isothio-cyanates,and amino esters (Scheme 3).The thiocyanates containing electron-withdrawing substituents afforded the corresponding thiohydantoins in better yields but poorer diastereoselectivities compared to phenyl isothiocyanateTable 1Catalyst screening aEntry Base Solvent Conv.(4h)b dr c 1Et 3N MeCN 100%10:12DABCO MeCN 100%6:13Quinine MeCN 100%6:14Et 3N Toluene 100%5:15Et 3N CH 2Cl 2100%6:16Et 3N CHCl 3100%7.5:17Et 3NEtOAc 100%3:18Takemoto 15MeCN 100%10:19—MeCN ——10dEt 3NMeCN100%10:1aIn a small vial,1.0equiv of aminoester 1a ,1.1equiv of isothiocyanate 2a ,and 1.1equiv of nitrostyrene 5a were added in 1mL of the corresponding solvent in the presence of base (20mol %).The reaction was stirred at room temperature for 4h.bDetermined by 1H NMR of the crude mixture.cDetermined by 1H NMR of the crude mixture.dReaction carried out with 1.1equiv of Et 3N and 1a as a hydrochloride salt.7184V.Ceban et al./Tetrahedron Letters 54(2013)7183–7187(examples:7b and7g);when bulky isothiocyanates were tested, the reaction did not work(example7c).For the a-aminoesters, those containing aromatic substituents afforded better yields than those containing aliphatic substituents at the a-position,however, with slightly poorer diastereoselectivities(examples:7e and7k). Finally,we tested several nitrostyrenes and those containing electron-donating substituents that afforded poor yields and better diastereoselectivities(examples:7d and7j),while highly reactive p-nitronitrostyrene afforded a complex mixture(example:7f).16 The reaction pathway proposed in Scheme2was confirmed by 1H NMR analysis of the crude reaction mixture andfinal product.In Figure1,the1H NMR spectrum of the crude reaction mixture (upper spectrum)after the nitrostyrene addition is compared to the1H NMR spectrum of7a after purification using column chro-matography(lower spectrum).It is clear that the spectra are differ-ent and this indicates that the intermediate4a is the nucleophile, and the rearrangement that led to thefinal hydantoin product took place after the addition of the nitrostyrene.Moreover,thiohydantoin8a was prepared by following a literature procedure and was reacted with nitrostyrene under the same reaction conditions.After four hours,a complex mixture of several products was observed.These data confirm that intermediate4a,as shown in Scheme2,is the nucleophilic species(Scheme4).In order to establish the stereochemistry of the nitro com-pounds obtained,an X-ray diffraction study of the major isomer of7a was performed.17As shown in Figure2,the crystal structure of this compound confirms the previously assigned regiochemistry and shows that the relative configuration is(R⁄,S⁄).In summary,we developed a new three-component cascade reaction for the synthesis of thiohydantoins.The reaction is pro-moted using a base,affording thefinal products with moderate to good yields and diastereoselectivities.The mechanistic studies, synthetic applications,appropriate chiral version of this new methodology,and the discovery of new reactions based on this concept are currently under investigation in our laboratory.V.Ceban et al./Tetrahedron Letters54(2013)7183–718771857186V.Ceban et al./Tetrahedron Letters54(2013)7183–7187X-ray structure(ORTEP)of compound7a.The displacement ellipsoidsthe35%probability level,selected hydrogens omitted for clarity.2.Tomkins,J.E.J.Med.Chem.1986,29,855–859.3.Marx,J.V.;Richert,D.A.;Westerfeld,W.W.J.Med.Chem.1970,13,1179.4.Marton,J.;Enisz,J.;Hosztafi,S.;Timar,T.J.Agric.Food Chem.1993,41,148–152.5.El-Barbary,A.A.;Khodair,A.I.;Pedersen,E.B.;Nielsen,C.J.Med.Chem.1994,37,73–77.6.Al-Obaid,A.M.;El-Subbagh,H.I.;Khodair,A.I.;Elmazar,M.M.AnticancerDrugs1996,7,873–880.7.Takahashi,A.;Matsuoka,H.;Ozawa,Y.;Uda,Y.Agric.Food Chem.1998,46,5037–5042.8.Curran, Patent3,984,430,1976;Chem.Abstr.1977,86,55444.9.Nagpal, Patent4,473,393,1984;Chem.Abstr.1984,101,224844.10.Mendgen,T.;Steuer,C.;Klein,C.D.J.Med.Chem.2012,55,743–753.11.For recent work on the synthesis of thiohydantoins,see:(a)Kumar,V.;Rana,H.;Sankolli,R.;Kaushik,M.P.Tetrahedron Lett.2012,53,2377–2379;For areview regarding thiohydantoins,see:(b)Metwally,M.A.;Abdel-Latif,E.J.Sulfur.Chem.2012,33,229–257.12.Edman,P.;Högfeldt,E.;Sillén,L.G.;Kinell,P.-O.Acta Chem.Scand.1950,4,283–293.13.(a)Alba,A.-N.R.;Valero,G.;Calvet,T.;Font-Bardia,M.;Moyano,A.;Rios,R.Chem.Eur.J.2010,16,9884–9889;(b)Balaguer,A.-N.;Companyó,X.;Calvet,T.;Font-Bardía,M.;Moyano,A.;Rios,.Chem.2009,199;(c)Alba,A.-N.R.;Rios,R.Chem.-Asian.J.2011,16,720–734.14.For selected reviews on multicomponent organocatalytic reactions see:(a)Moyano, A.;Rios,R.Chem.Rev.2011,111,4703–4832;(b)Alba, A.-N.;Companyo,X.;Viciano,M.;Rios,.Chem.2009,13,1432–1474;(c) Enders,D.;Grondal,C.;Huettl,M.R.M.Angew.Chem.,Int.Ed.2007,46,1570–1581.15.Okino,T.;Hoashi,Y.;Takemoto,Y.J.Am.Chem.Soc.2003,125,12672.16.General procedure for the preparation of quaternary a-amino acids via Edmandegradation:To a solution of amino ester(1equiv)in MeCN were added isothiocyanate(1.2equiv),a b-nitrostyrene(1.2equiv),and triethylamine(0.2 equiv).The solution was stirred for the indicated time and subsequently the solvent was removed by rotary evaporation.The reaction mixture was purified by column chromatography(hexane/acetone).Compound7a:Reaction time is 4h.Purified by column chromatography(hexane/acetone9:1).Yield:75%.Dr: 10:1.MS(ESI-)m/z:416.4(M-1).1H NMR(CDCl3,300MHz):9.60(s,1H,NH),7.73(d,2H,J=8.05Hz),7.2–7.5(m,11H,),6.43(d,2H,J=8.05Hz),4.80(ddd,1H,J=2.56Hz,3J=11.71Hz,3J=12.81Hz), 4.56(dd,1H,2J=3.66Hz, 3J=11.71Hz), 4.31(dd,1H,2J=3.66Hz,3J=12.81Hz).13C NMR(CDCl3, 75MHz):183.4,171.9,133.3,129.8,129.1,127.9,125.7,125.5,74.8,71.9,52.2.17.Crystallographic data(excluding structure factors)for the structure7a havebeen deposited with the Cambridge Crystallographic Data Centre with CCDC number963585.Copies of the data can be obtained,free of charge,on application to the Cambridge Crystallographic Data Centre,12Union Road, Cambridge,CB21EZ,UK,(fax:+44(0)1223336033or e-mail: deposit@).V.Ceban et al./Tetrahedron Letters54(2013)7183–71877187。