An Approach to Catalytic Enantioselective Protonation of Prochiral Lithium Enolates[1]

@

Tetrahedron Letters,Vol. 38,No.43,pp.7589-7592, 1997 01997 Elsevier Science Ltd

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An Approach

to Catalytic Enantioselective Protonation of Prochiral Lithium Enolatesl PierreRiviem2andKenjiKoga*

Graduate School of Pharmaceutical Sciences, Universi~ of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan

Abstract: Protonationof prochirallithiumenolates(4), preparedfrom racemic2substituted-1-tetralones(2) via their silyl enol ethers(3), withexcesssuccinimidein the presenceof lithiumbromideand0.2equivalentof a chiraltetmdentateamine((R)1) in tolueneat -78‘Cgaveopticallyactive2 in upto 83%ee. @1997 Elsevier Science Ltd. Enantioselectiveprotonationof prochiralenolatesis a promisingmethodforthepreparationof optically activecarbonylcompoundshavinga chiraltertiarycarbonat the a-positionof thecarbonylgroup,becausethis methodmakesit possibleto convertthe racemiccarbonylcompoundsintothe correspondingopticallyactive ones. Sincethe pioneeringworkby Duhamel,3manyexampleshavebeenreportedto date,4includingcatalytic versionsof this process.5

/-(ph 00 :RS).2..R=M. 05 N

(RS)-2b:R = CH2Ph

HN~o+NMe2

o

(R)-1 I ‘ OSiMe3

o— 03 \R

3a: R= Me 3b: R = CH2Ph

o

OLi

MeLi-LiBr

0\ 05

R+LiBr

4a:R = Me

4b:R= CH2Ph

1)(R}l

D

2) Protonsource in toluene at -78 ‘C

OR 05 (S}2a:R=Me iR)-2b:R = CH2Ph

Scheme 1. Enantioselective Protonation Wehavepreviouslyreportedenantioselectiveprotonationof prochirrdlithiumenolates(4)by aceticacid usinga stoichiometricamountof a chiraltetradentateamine((R)-l)asa chiralsourceas shownin Scheme1.6 Thus,racemic2-substituted-l-tetralones(2) wereconvertedto theircorrespondingsilylenolethers(3), which weretreatedwithmethyllithium-lithium bromide(LiBr)in etherto givethe lithiumenolates(4)containingLiBr. Afteradditionof (R)-1(1 equivalent),protonationby acetic acid was camiedout in tolueneat -78 ‘C to give opticallyactive 2 in up to 91’ZOee (Table 1, run 1). By a similarstrategy,enantioselectivealkylationof the 7589

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lithiumenolate of I-tetralonewas realizedusing alkyl halidesas electrophilesinsteadof acetic acid.7 It is postulatedthatthe reactiveintermediatein theseenantioselectivereactionsshouldbe a ternarycomplexformed froma lithiumenolate,a chiraltetradentateamine,andLiBr.c-8 Catalyticenrrntioselective alkylationwasalso realizedby this strategyusinglessthana stoichiornetricamountof a chiraltetradentateamineas a chirrdsource in thepresenceof an achiralbidentateamine. Thismeansthatthe lithiumenoiatethatis complexedwitha chiral tetradentateaminereactswithalkylhalidesfasterthanthelithiumenolatethatis notcomplexedor is complexed witha bidentsteamine,andthat ligandexchangein situ occurs fasterthanalkylation.7bfJAlthoughprotonation is obviously faster than alkylation,the above data suggest the possibility that catalytic enantioselective protonationby using less than a stoichiometricamountof (R)-1 may be possible,if some devicecould be designedwherebythe protonationof the lithiumenolatesthat are complexedwith(R)-1couldbe madeto take placeslowerthanthe ligandexchange. Table1. Enantioaelective Protonation of 4 to Give 2a

(R)-1 Run

Substrate

lb

3a

2C 3d 4e 5f ~f ~f

ti

8f

9f ,~f

1.03

3a 3a

0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1

3a

0.1

3a 3a 3a 3a 3a

Proton source (eq.)

(eq.)

w

l-m

o

3a

0.1

3a 3b

0.2

3a

0.1 0.011

NH(l.2)

2

Product E.e. (%)9

(S)-2a (S)-2a (S)-2a (S)-2a (S)-2a (S)-2a (S)-2a (S)-2a (S)-2a

91 28 15 51 59 55 67 69 72

heterogeneous

(S)-2a

74

heterogeneous heterogeneous heterogeneous heterogeneous

(S)-2a (S)-2a (R)-2b (S)-2a .,

73 83 68 54

AcOH (1.02) homogeneous homogeneous AcOH (1.2) homogeneous di-tBu malonate (1.2) 2,4,6-tri-tBu-phenol (1.2) homogeneous homogeneous 2-piperidinone(1.2) phthalimide(1.2) heterogeneous Me2NEt HCI (1.2) heterogeneous succinimide(1.2) heterogeneous polymaleimide (excess) heterogeneous

o

1If 12f 13f 14f

Reaction mixture

0

succinimide(10) succinimide(10) succinimide(1.2) succinimide(3.8)

a Two reaction procedures(for runs 2-13, and for run 14) are described in the text. The products (2) were isolated in over 86’%.yields. b Date taken from ref. 6. c Proton sourcewas added slowly during 45 min. d proton sourcewas addad within 1 min. e Proton soucewas added slowlyduring 150 min. f Proton source was added in one portion. 9 Determinedby HPLC using a chiral column.’4

Protonationexperimentswerecarriedoutas shownin Scheme1 usinglessthana stoichometricamount of (R)-1 in toluene at -78 ‘C. In all cases, the productswere isolated in over 88Y0yield. The results are summarizedin Table 1 (runs2-13). By slowadditionof aceticacid (pKa 4.76in water9)in tolueneduring45 min in the presenceof 0.1 equivalentof (R)-1, (S)-2awas obtainedin 28%ee (run2), indicatingthat (R)-1is actuallyrecycledin situ.. Quickadditionof the less acidicdi-ter-t-butylmalonate(pKa 13.510) gave (S)-2ain loweree (run3), but still showsthe recyclingof (R)-1. Onthe otherhand,veryslowadditionof 2,4,6-tri-ter-t-

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butylphenol(pKa 12.2 in waterll) in tolueneduring 150min gave (S)-2ain 51%ee (run4). Interestingly, quickadditionof 2-piperidinonewasfoundto be effective(run5). Basedon the assumptionthat slowadditionof the protonsourcemaybe realizedby usingacidsthat are solid and are not practicallysolublein toluene,phthalimide(pKa 8.3 in water12),N,N-dimethylethylamine hydrochloride(pKa 9.99 in waterls) and succinimide(pKa 9.6 in waterlO)were powderedand addedin one portion(runs6-8). A heterogeneousmixturewas obtained,whichwas stirredat -78 “Cfor 1 hr. Acidshaving an imidemoiety,suchas polymaleimideandpyromelliticdiimide,werealsoexaminedin a similarway(runs9, 10). It is shownthat ee’sof (S)-2awere foundto be increased. By usinga largeexcessof succinimideand 0.2 equivalentof (R)-1,ee of (S)-2a was furtherincreasedto 83% (run 12). In a similarway, by using 0.1 equivalentof (R)-1,4b wasenantioselectivelyprotonatedto give(R)-2bin 68%ee (mn 13). A typical experimentalprocedure(Table 1, run 12)is as follows. A solutionof MeLi-LiBrin ether (1.03M in MeLi,0.75 mL,0.77mmol)was addedto 3a (171.6mg, 0.72mmol)at roomtemperature,andthe wholewas stirredat this temperaturefor 90 min. Toluene(7 mL) was added,and the resultingmixturewas cooledto -20 “C. A solutionof (R)-1 (46.0 mg,0.144mmol)in toluene(1.5mL)was added,andthe resulting clearsolutionwas stirredat -20 ‘Cfor40 rein,andthen at -78 ‘Cfor 20 min. Powderedsuccinimide(712mg, 7.2 mrnol)was addedin one portion,and the resultingsuspensionwas stirredat -78 ‘C for 1hr. 10%aqueous citricacid(10mL)wasaddedto the reactionmixture,andthe wholewasextractedwithether(20mLx 3). The combinedorganicextractswere washedwith saturatedaqueousNaHC03and brine,and driedover MgS04. Evaporationof the solventto drynessunderreducedpressuregave(S)-2a(103mg,90%)as a colorlessliquid of 83%ee.14 Protonationcan be carriedout in a differentway as follows(run 14). A solutionof 4a and LiBr was preparedfrom 3a (612.3mg, 2.63 mmol)and MeLi-LiBrin ether (1.03M in MeLi, 2.76 mL, 2.84 mmol) followedby dilutionwithtoluene(20 mL)as describedabove,and was addedveryslowlyto a suspensionof (I/)-l (10.0 mg, 0.03 mmol) and powderedsuccinimide(995 mg, 10 mmol) in toluene (18 rnL) at -78 “C during5 hr usinga microfeeder.Work-upas describedabovegave(S)-2a(383mg, 91%)as a colorlessoil of 54%ee.14 The reasonforthe loweree of (S)-2ain this case maybe dueto the amountof (R)-1(0.011equiv. to 4a), or to the partialracemizationof (S)-2abecauseof the longerreactiontime. However,this result may mean the necessity of forming the intermediate complex prior to the protonation. Details are under investigation. In conclusion,it is shownthat, in the presenceof LiBr,catalyticenantioselectiveprotonationof achiral lithiumenolates(4), preparedfrom racemic2-substituted-l-tetralones((RS)-2),was achievedby using less thana stoichiometricamountof (R)-1andexcessamountof protonsourcesthatare solidandare notpractically solublein toluene. Acknowledgment The authors are grateful to the Japan Society for the Promotionof Science for the postdoctoralfellowshipto P. R. andto the Ministryof Education,Science,SportsandCultureof the Japanese Governmentfor financialsupport. REFERENCES AND NOTES 1 Thispaperis dedicatedto ProfessorEkkehardWinterfeldtonthe occasionof his 65thbirthday

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2. Presentaddress:LeadOptimizationResearchLaboratory,TanabeSeiyakuCo., Ltd., 2-2-50,Kawagishi, Toda,Saitama335,Japan. 3. a) Duhamel,L. C. R. Acad. Sci 1976, 282c, 125-127. b) Duhamel,L.; Plaquevent,J.-C. Tetrahedron Left. 1977, 2285-2288. 4. For reviews, see: a) Duhamel,L.; Duhamel,P.; Launey,J.-C.; Plaquevent,J.-C. Bull. Soc. Chirn. Fr.

1984, II, 421-430. b) Sebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624-1654. c) Waldman, H. Nachr. Chem. Tech. Lab. 1991,39, 413-418. d) Fehr, C. Chimia 1991, 45, 253-261. e) Hunig, S. In Houben-Weyl, Methods of Organic Chemistry, Vol. E21d, Helmchen,G.; Hoffmann,R. W.; Mulzer, J.; Schaumann,E. Eds., Georg Thieme Verlag, Stuttgart, 1995,pp. 3851-3911. e) Fehr, C. Angew. Chem. Int. Ed. Engl. 1996,35, 2566-2587. 5. For recent examples,see: a) Kumar,A.; Salunkhe,R. V.; Rane, R. A.; Dike, S. Y. J Chem. Soc., Chem. Commun. 1991, 485-486. b) Fehr, C.; Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. Engl. 1993,32, 1044-1046.c) Fehr, C.; Galindo,J. Angew. Chem., Int. Ed. Engl. 1994,33, 1888-1889. d) Yanagisawa,A.; Kikuchi,T.; Watanabe,T.; Kuribayashi,T.; Yamamoto,H. Syrdett 1995, 372-374. e) Nakamura,Y.; Takeuchi,S.; Ohira, A.; Ohgo, Y. Tetrahedron Lett. 1996, 37, 2805-2808. f) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1996, lf8, 12854-12855. g) Muzart,J.; H6nin,F.; Aboulhoda,S. J. Tetrahedron: Asymmetry 1997, 8, 381-389. 6. Yasukata,T.; Koga,K. Tetrahedron: Asymmetry 1993,4, 35-38. 7. a) Murakata,M.; Kawasaki,H.; Koga, K. J. Chem. Soc., Chem.Commun.1990, 1657-1658.b) Imai, M.; Hagihara,A.; Kawasaki,H.; Manabe,K.; Koga, K. J. Am. Chem.Soc. 1994,116, 8829-8830. 8. a) Koga,K. Pure Appl. Chem.1994, 66, 1487-1492.b) Koga, K.; Shindo,M. J. Synth. Org. Chem., Jpn. 1995, 52, 1021-1032. 9. Guthrie,J. P. Can. J. Chem. 1978, 56, 2342-2345. 10. Pine,S. H. Organic Chemistry, 5thEd.; McGraw-Hill,NewYork, 1987;pp. 99-101.

11. Cohen,L. A.; Jones, W. M. J. Am. Chem.Soc. 1963,85, 3397-3402. 12. Bell, R. P.; Higginson,W. C. E. Proc. Royal Soc. (London) 1949, 197A, 141-159. 13. Hrdl,H. K., Jr. J. Am. Chem.Soc. 1957, 79, 5441-5444. 14. Ee’sof the productswere determinedby HPLC with a chiral column (Daicel Chiralcel OD-H@)and hexane-isopropanol (600:1)as an ehrent.

(Received in Japan 30 July 1997; revised 27 August 1997;accepted 29 August 1997)