《苯环还原.pdf》由会员分享，可在线阅读，更多相关《苯环还原.pdf（12页珍藏版）》请在taowenge.com淘文阁网|工程机械CAD图纸|机械工程制图|CAD装配图下载|SolidWorks_CaTia_CAD_UG_PROE_设计图分享下载上搜索。
1、Organic Process Research& Development 20032003,7,559 570ProcessProcessResearchResearchofof( (R R)-Cyclohexyl)-Cyclohexyl LacticLacticAcidAcidandand RelatedRelatedBuildingBuilding Blocks:Blocks:A A ComparativeComparativeStudyStudyThomas Storz* and Peter DittmarProcess Research and DeVelopment, Chemic
2、al and Analytical DeVelopment; NoVartis Pharma AG,CH-4002 Basel, SwitzerlandPierre Franc ois Fauquex and Philippe MarschalBiotechnology DeVelopment, NoVartis Pharma AG, CH-4002 Basel, SwitzerlandWilly Urs Lottenbach and Heinz SteinerHydrogenation and High-Pressure SerVice, SolVias AG, CH-4002 Basel,
3、 SwitzerlandAbstract:Abstract:( (S S)-Cyclohexyl)-Cyclohexyllacticlactic acidacid is is a a componentcomponentofof thethe selectiveselectiveE-selectinE-selectininhibitorinhibitor2 2 ( (S S)-cHexLact-2-)-cHexLact-2- O O-(3-Gal-(3-Gal(1(1f3)ddGlc-3)ddGlc-(4(4f1)1)rFuc).Fuc).WeWedescribedescribethethe
4、evaluationevaluationofof variousvarioussyntheticsyntheticroutesroutestotothisthisbuildingbuildingblock:block: ( (A A) ) diazotationdiazotation ofofphenylalaninephenylalaninefollowedfollowed byby phenylphenyl ringring hydrogenation;hydrogenation;( (B B) ) phenylphenyl ringringhydrogenationhydrogenati
5、on ofof phenylphenylalaninealaninefollowedfollowedbyby diazotation;diazotation;( (C C) )acidicacidichydrolysishydrolysisofof thethe cyanohydrincyanohydrinderivedderivedfromfromphenylac-phenylac-etaldehyde,etaldehyde,enantiomericenantiomeric resolutionresolutionofof thethe resulting,resulting,racemic
6、racemicphenylphenyllacticlacticacidacidviaviadiasteromericdiasteromeric saltsaltformationformationandandphenylphenylringringhydrogenation;hydrogenation; ( (D D) ) enantioselectiveenantioselective dihydroxylationdihydroxylation ofof a acinnamatecinnamateester,ester, followedfollowedbyby hydrogenation
7、hydrogenationofof thethe benzylicbenzylichydroxyhydroxygroupgroupandandthethearomaticaromaticnucleus;nucleus;( (E E) ) enantioselectiveenantioselectivebiocatalyticbiocatalytic reductionreduction ofofphenylpyruvicphenylpyruvic acid,acid,followedfollowed bybyphenylphenylringringhydrogenation.hydrogena
8、tion. TheThedevelopmentdevelopment ofof(2(2R R)-2-)-2-O O-(4-nitrophe-(4-nitrophe-nyl)sulfonyl-cyclohexylnyl)sulfonyl-cyclohexyl lacticlacticacidacidp p-bromobenzylester-bromobenzylester 2121asasa abuidlingbuidlingblockblockwithwithimprovedimprovedcrystallinitycrystallinity andandstabilitystabilityi
9、s isalsoalsodescribed.described.leukocyte surface via interaction with the common tetrasac-charide epitope sialyl Lewisx(sLex, 1 1).5Analogues of sialylLewisxhavethereforebeenproposedas potentialtherapeuticsfor a host of inflammatory disorders (e.g., ischemia/reper-fusion injury following organ tran
10、splantation).6The sLexanalogue 2 2 (Figure 1) was discovered by Thoma et al. atNovartis Pharmaceuticals Corporation.7Compared to sLex,2 2 showeda 30-foldimprovedaffinityin a cell-freeE-selectin-ligand binding assay.8As a simplified analogue of SLex, 2 2 features the (S)-cyclohexyl lactic acid moiety
11、 as a substitute9for thestructurally more complex N-acetylneuraminic acid residue.The former is introduced into the trisaccharide precursor of2 2 via nucleophilic displacement reaction of a 2-O-sulfonylsubstituted (R)-cyclohexyl lactic acid building block. Enan-tiomerically pure (R)-cyclohexyl lacti
12、c acid10is not com-mercially available. Hence, an efficient synthetic access tothis hydroxy acid needed to be elaborated.ResultsResultsandand DiscussionDiscussion(A)(A) TheThe MedicinalMedicinal ChemistryChemistry Synthesis.Synthesis. The synthesis(Scheme 1)7of the (R)-cyclohexyl lactic acid buildin
13、gblock 6 6 started from commercially available (R)-3-phenyllactic acid10b(3 3). Hydrogenation of the aromatic nucleus,followed by benzyl ester formation with CsCO3/BnBr andO-sulfonylation with triflic anhydride, gave the buildingblock 6 6 in three steps and 60% total yield after twochromatographies.
14、 The triflate 6 6 proved to be an unstableoil at room temperature and resisted all attempts to crystal-lization.(5) Kansas, G. S. Blood 19961996, 88, 3259.(6) For a review, see: Simanek, E. E.; McGarvey, G. J.; Jablonowsky, J. A.;Wong, C.-H. Chem. ReV. 19981998, 98, 833.(7) Thoma, G.; Kinzy, W.; Bru
15、ns, C.; Patton, J. T.; Magnani, J. L.; Ba nteli, R.J. Med. Chem. 19991999, 42, 4909.(8) Ba nteli, R.; Herold, P.; Bruns, C.; Patton, J. T.; Magnani, J. L.; Thoma, G.HelV. Chim. Acta 20002000, 83, 2893.(9) Kolb, H. C.; Ernst, B. Chem. Eur. J. 19971997, 1571.(10) (a) v. Braun, J.; Nelles, J. Chem. Ber
16、. 19331933, 66, 1464 (racemate).(b) Bajusz,S.; Baraba s, E.; Fauszt, I.; Fehe r, A.; Horva th, Gy.; Juha sz, A.; Szabo , A.G.; Sze ll, E. Bioorg. Med. Chem. 19951995, 3, 1079 (R-enantiomer).Vol. 7,No.4,2003/Organic Process Research& Development559559IntroductionIntroductionExcessive leukocyte influx
17、 from blood vessels into thesurrounding tissues has been linked to acute or chronicreactionsas observedin reperfusioninjuries,psoriasis,stroke,rheumatoid arthritis or respiratory diseases.1-3Selectin-dependent leukocyte adhesion is the first step in the cascadeof events that leads to the extravasati
18、on of leukocytes.4Inparticular, E-Selectin on the surface of the endothelial bloodvessel walls recognizes complex glycoprotein ligands on theDedicated to Professor Andrea Vasella on the occasion of his 60th birthday.* To whom correspondence should be addressed. Current address: AmgenInc., One Amgen
19、Center Drive, Thousand Oaks, CA 91320-1799, U.S.A.E-mail: .(1) Mousa, S. A. Drugs Fut. 19961996, 21, 283.(2) Mousa, S. A.; Cheresh, D. A. Drug DiscoVery Today 19971997, 2, 187.(3) Cines, D. B.; Pollak, E. S.; Buck, C. A.; Loscalzo, J.; Zimmermann, G. A.;McEver, R. P.; Pober, J. S.; Wick, T. M.; Konk
20、le, B. A.; Schwartz, B. S.;Barnathan, E. S.; McCrae, K. R.; Hug, B. A.; Schmidt, A.-M.; Stern, D.M. Blood 19981998, 91, 3527.(4) Spertini, O.; Luscinskas, F. W.; Gimbrone, M. A.; Tedder, T. F. J. Exp.Med. 19921992, 175, 1789.10.1021/op030202qCCC: $25.002003American Chemical SocietyPublished on Web 0
21、6/27/2003FigureFigure 1.1.TableTable 1.1.AromaticAromatic ringring hydrogenationhydrogenation ofof phenylphenyl lacticlactic acid:acid: catalystcatalyst screeningscreeningentry12345(concentration, mmol)batch size (%)12.0(5)300.9(5)12.0(5)12.0(14.3)12.0(13.5)catalyst,H2pressure5% Rh/C(10 wt %/wt)15 b
22、ar5% Rh/C(10 wt %/wt)15 bar10% Ru/C(15 wt %/wt)15 bar5% Rh/C(10 wt %/wt)15 bar10% Ru/C(10 wt %/wt)30 barsolvent (%),temperature ( C)EtOH (94)50EtOH (94)50AcOH50-70-100AcOH/H2O(8:6) 50-801 M NaOH60reaction time, hyield (%)/purity (%)2592.9 (GLC)conversion: 99.899.6, crude59 h89.4% (GLC)conversion: 99
23、.9%10870.6 (GLC)conversion: 99.9167.0 (GLC)conversion: 13.2SchemeScheme 1.1.MedicinalMedicinal chemistrychemistry synthesissynthesis(B)(B) ProcessProcess R&D.R&D. Surprisingly, there is only oneliterature report for the production of (R)-cyclohexyl lacticacid (4 4): aromatic ring hydrogenation ofD-(
24、+)-3-phenyllactic acid (3 3) over a platinum oxide catalyst.10bDue to thehigh price and limited availability of 3 3, and the unfavorablephysicochemical properties combined with the instability ofthe triflate 6 6, we aimed to find a more economic access to4 4 and,ultimately,alsoto replacethe triflate
25、6 6 by a crystalline,more stable activated building block.In our first strategy, (R)-phenyl alanine (7 7) was chosenas starting material. Two variants were investigated:(A A) diazotation of phenylalanine under retention ofconfiguration,11followed by hydrogenation of the aromatic(11) Cohen, S. G.; We
26、instein, S. Y. J. Am. Chem. Soc. 19641964, 86, 5326.560560Vol. 7,No.4,2003/Organic Process Research& Developmentnucleus of the resulting phenyl lactic acid over a moreeconomic catalyst:Although literature reports11-14hadclaimed that diazotation of (R)-phenyl alanine to (R)-phenyllactic acid 3 3 proc
27、eeds under complete retention of config-uration (only optical rotation values were cited as proof ofenantiomeric purity), we invariably observed a loss ofenantiomeric purity as unequivocally determined by HPLCanalysis on a chiral column (2-5%, see ExperimentalSection). The hydrogenation of the aroma
28、tic nucleus in 3 3was investigated under various conditions (Table 1). Ingeneral, none, or only insignificant loss (99%7 h100% crude7 h91.5% (GLC)conversion: 99.9%SchemeScheme 2.2.DiazotizationDiazotization strategies:strategies: approachapproach A ASchemeScheme 3.3.DiazotizationDiazotization strate
29、gies:strategies: approachapproach B Bously difficult substrates and, in general, tend to give loweree16f,17,18thantheiraromaticcounterparts.A kineticresolutionof racemic phenylacetaldehyde-cyanohydrinon an analyticalscale (no product isolated, no yields given) with a mutantPseudomonas strain to give
30、 enantiomerically enriched (ca.75% ee) (S)-(-)-phenyl lactic acid has been reported.19Onestudy reporting the synthesis of enantiomerically enriched(88% ee) (R)-phenylacetaldehyde-cyanohydrinin 83% yieldon a millimolar scale via oxynitrilase-catalyzed transcyana-tion with acetone cyanohydrinhas appea
31、red.20However,dueto the high substratedilution,high enzymeconcentration(ca.1000 units/mmolsubstrate)and the requirementfor a specialenzyme purification of the commercial enzyme prior to use,this method appeared not practical for preparative scalesynthesis.On the other hand, we obtainedracemicphenyll
32、acticacid(-PLA)1111 withoutneedfor the isolationof the intermediate101021via cyanohydrin reaction of the bisulfite adduct22of 9 9(16) For reviews, see: (a) Groger, H. AdV. Synth. Catal. 20012001, 343, 547. (b)Van Der Gen, A.; Brussee, J. NATO Sci. Ser. 1: Disarm. Technol. 20002000,33, 365. (c) Grego
33、ry, R. J. H. Chem. ReV. 19991999, 99, 3649. (d) Effenberger,F. Chimia 19991999, 53, 3. (e) Johnson, D. V.; Griengl, H. Chim. Oggi 19971997,15, 9. (f) North, M. Synlett 19931993, 807. (g) Kruse, C. G. In Chirality inIndustry; Collins, A. N., Sheldrake, G. N., Crosby, J., Eds.; Wiley: NewYork, 1992; C
34、hapter 14, p 279.(17) Zandbergen, P.; Van Der Linden, J.; Brussee, J.; Van Der Gen, A. Synth.Commun. 19911991, 21, 1387.(18) Ziegler, T.; Ho rsch, B.; Effenberger, F. Synthesis 19901990, 575.(19) Hashimoto, Y.; Kobayashi, E.; Endo, T.; Nishiyama, M.; Horinouchi, S.Biosci. Biotechnol. Biochem. 199619
35、96, 60, 1279.(20) Ognyanov, V. I.; Datcheva, V. K.; Kyler, K. S. J. Am. Chem. Soc. 19911991,113, 6992.Vol. 7,No.4,2003/Organic Process Research& Development561561However, the subsequent diazotation of 8 8 proceeded onlyin very poor yields. Hence, approach B B, as summarized inScheme 3, was quickly a
36、bandoned.(C C) Cyanohydrinreactionof phenylacetaldehyde,followedby acidic hydrolysis to (R/S)-phenyl lactic acid, resolutionof the racemic acid via diastereomeric salt formation andhydrogenolytic reduction of the phenyl ring as in approach(A A):Although much progress has recently been achieved withe
37、nantioselective cyanohydrin reactions,16R-methylene-alde-hydes, such as arylacetaldehydes, have proved to be notori-SchemeScheme 4.4.ApproachApproach C C: : resolutionresolution ofof racemicracemic PLAPLAfollowed by acid-catalyzed hydrolysis in 71% yield afterrecrystallization of the crude product f
38、rom toluene (Scheme4). A variety of readily available optically pure bases werethenscreenedfor theirpotentialto formdiastereomericsalts23(Table 3).Resolution with the most promising bases, (+)-dehydro-abietylamine,(S)-phenylglycinoland (S)-phenylalaninolwasoptimized (data not shown); typical results
39、 are shown inTable 4.Especially the resolution via the diastereomeric (S)-saltseparationwith (+)dehydroabietylaminelookedvery promis-ing, due to the very low cost of the chiral amine. Resolutionswith (S)-phenylglycinol and (S)-phenylalaninol also workedvery well, but required recycling of the (expen
40、sive) chiralbase.(D D) Enantioselectivedihydroxylationof methylcinnamate,followedby selectivehydrogenolyticremovalof the benzylichydroxy group and hydrogenation of the aromatic nucleus.24Cinnamate esters are very cheap starting materials (Me,Et, Bn: $8-15/kg), and readily scaleable protocols for the
41、irenantioselective dihydroxylation to R,-dihydroxy-phenyl-propionates in good yield and enantiomeric purity are wellestablished.25We aimed at an efficientand selectiveone pot-reductionprocess,employingonly a noble metal catalystandhydrogen as the sole reducing agent (Scheme 5).The methyl and benzyl
42、esters of the corresponding (2R,-3S)-3-phenyl-2,3-dihydroxypropionate26were synthesizedasstarting materials. The methyl ester is easily purified byrecrystallization and can be obtained in very high enantio-meric purity, whereas the benzyl ester has to be purified bychromatography and, in our hands,
43、was routinely obtainedin inferior optical purity (Scheme 6).The subsequent hydrogenolytic removal of the benzylichydroxy group proceeded in good yield and without signifi-cant loss in optical purity, but the benzyl ester apparently(21) (a) Erlenmeyer, E.; Lipp, A. Ann. Chem. 18831883, 219, 187. (b)
44、Ruggli, P.;Hegedues, B. HelV. Chim. Acta 19421942, 25, 1285.(22)(a) Biquard,D. Ann.Chim.(Paris)19331933, 10, 97. (b) Meerpoel,L.; Hoornaert,G. Synthesis 19901990, 905. (c) Chesters, N. C. J. E.; OHagan, D.; Robins, R.J. J. Chem. Soc., Perkin Trans. 1 19941994, 1159.(23) The only diastereomeric salt
45、resolution for (D)-(+)-3-phenyl lactic acid weare aware of (base: morphine!) was reported by A. McKenzie and H. Wren(J. Chem. Soc. 19101910, 97, 1358), who later also described the resolution ofracemic PLA via its diastereomeric(-)-menthol esters (J. Chem. Soc. 19211921,119, 801).(24) To the best of
46、 our knowledge, only two selective reductions of R,-dihydroxy-dihydro-cinnnamic esters to 3-aryl lactic acid esters have beenreported: (a) Nakajima, M.; Tomioka, K. and Koga, K. Tetrahedron 19931993,49, 10807 (Et3SiH/TFA); (b) Rho, H. S.; Ko, B.-S. Synth. Commun. 20012001,31, 283 (Mg-reduction of th
47、e corresponding thionocarbonate derivative).A Mn-catalyzed oxidation of cinnamates in the presence of triphenyl silanealso leads to 3-aryl lactic acid esters:Tanaka, M.; Mukaiyama, C.;Mitsuhashi, H.; Maruno, M.; Wakamatsu, T. J. Org. Chem. 19951995, 60, 4339.(25) For a review, see: Kolb, H. C.; VanN
48、ieuwenhze, M. S.; Sharpless, K. B.Chem. ReV. 19941994, 94, 2483.(26) Wang, Z. M.; Kolb, H. C.; Sharpless, K. B. J. Org. Chem. 19941994, 59, 5104.562562Vol. 7,No.4,2003/Organic Process Research& Developmentwas prone to acid-catalyzed transesterification, as theintermediate 3-phenyl lactic acid was is
49、olated as the methylester after the reaction (Scheme 7).Because of this finding and the unfavorable physicalproperties of the benzyl ester 13B13B in combination with theloweree in the dihydroxylationreactionof benzylcinnamate,it was decided to focus on the crystalline methyl ester 13A13A.Initially,
50、we isolated the intermediate phenyl lactic ester 1414before starting a fresh hydrogenolysis experiment in aseparate vessel with the second catalyst. It was thendiscovered that equivalent results were also obtained bysequentialadditionof the two catalystsin one pot in the samesolvent (Scheme 8). This