ID. Aldol Reaction III. Basic PrinciplesDr. P. WipfPage 1 of 281/21/2008The Ivanov Reactionrationalization: Zimmerman-Traxler, JACS 1 957, 79, 1920.OMgOHPhHPhcyclic TSOMgBrBrSfavoredvs.OMgOPhHHPhOMgBrBrSweak pseudo-1,3-diaxial interactionPhOMgBrOMgBrPhCHOPhCO2HOHPh+PhCO2HOHPhsynanti24% 76%(rac!)Dr. P. WipfPage 2 of 281/21/2008To achieve high diastereo- and enantioselectivity, it is necessaryto:- control the enolization step- use an auxiliary with a large diastereofacial bias- control competing transition states, e.g.- half-chair vs. twist boat- closed vs. open- use metal-derivatives that have clearly defined coordination geometries.Dr. P. WipfPage 3 of 281/21/2008The stereochemical implications of the Zimmerman-Traxlertransition state model for the aldol reaction can be summarized asfollows:ORcMeOMetRcMeOMetRcMeRCHORCHOre - sisi - resi - sire - reOMetORcMeRsireOMetOHRMeRcsireOMetOHRRcsisiOMetOHRRcrereORc ROHMesynORc ROHMesynORc ROHMeantiORc ROHMeantiDr. P. WipfPage 4 of 281/21/2008Zimmerman-Traxler transition states represent the mostfrequently used models, but other possibilities have always to beconsidered as well:Chair vs. boatOMetORcHMeRRcROOHMesyn-diastereomerhalf-chairRcOMetRCHORcRO OHMeanti-diastereomertwist boatRcHOMetOHRMeDr. P. WipfPage 5 of 281/21/2008Closed vs. Open Transition StatesRcOMetOMeHRHRcOMetL.A.OMeHRHMetO RcL.A.OMetRcRcROMeOHanti-diastereomerDr. P. WipfPage 6 of 281/21/2008Evans’ Chiral Oxazolidinone AuxiliaryNOOOLDAONOLiOZ-enolateBu2BOTf, NEt3ONOOZ-enolateBBuBuD. A. Evans, JACS 1981, 103, 2127ONOOBBuBuPhCHO>99% deOBOPhNOOBuBuresiONOPhOH ODr. P. WipfPage 7 of 281/21/2008Smith, A. B.; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011. PMBO NOOH O1. DDQ, CH2Cl2, 78%2. LAH, THF, 80%HO OOPMPNOBnOOn-Bu2BOTf, Et3N,CH2Cl2, 80%O OHOPMPNOOOBnNOBnOOBOBuBuR1. TBSOTf, 2,6-lutidine, CH2Cl22. LiBH4, EtOH, THF, 81%3. Ph3P, I2, imid., PhH/Et2O (1:2), 95%O OTBSOPMPIDr. P. WipfPage 8 of 281/21/2008Crimmins, M. T.; King, B. W.; Tabet, E. A., "Asymmetric aldol additions with titaniumenolates of acyloxazolidinethiones: Dependence of selectivity on amine base andLewis acid stoichiometry." J. Am. Chem. Soc. 1997, 119, 7883.ONXBnOLxMONXBnROH OOLxMONROXBn"Evans" synX=O, SONXBnROH OOTiONROXBnsire"non-Evans" syn- Cl-ClClClsireRCHODr. P. WipfPage 9 of 281/21/2008TiOOClClMeHHRNOSBnLLOTiOMeHHRNOSBnClClClN OSPhORMeOHN OSPhORMeOH"Non-Chelated""Chelated"S1 "Evans' Syn"S2 "Non-Evans' Syn"(–)–sparteineorNMPTiOOClClMeHHRNOSBnLLchlorideremovalTiCl4or AgSbF6OTiOMeHHRNOSBnClClClLigand additionDr. P. WipfPage 10 of 281/21/2008Experiments employing N-acyloxazolidinethione auxiliaries (sulfur has a higheraffinity to titanium than oxygen), 2 equiv of TiCl4 and 1 equiv of Hünig’s base gaveexcellent selectivity for the “non-Evans” syn aldol product. Crimmins believes thatthe second equivalent of Lewis acid abstracts the chlorine ion and leads to achelated transition state (in contrast to the acyclic transition state postulated byHeathcock). In addition, very high (>98:2) “Evans” syn aldol selectivities could beobtained by using 1 equiv of TiCl4 in combination with sparteine (2.5 equiv). The roleof sparteine is presently unknown.An added advantage of oxazolidinethiones is that they are easily removed under mild conditions:ONSBnROH ONaBH4,EtOH85%MeNHOMeimidazole90%OHROHONROH ODr. P. WipfPage 11 of 281/21/2008Crimmins, M. T.; King, B. W., "Asymmetric total synthesis of callystatin A: Asymmetricaldol additions with titanium enolates of acyloxazolidinethiones." J. Am. Chem. Soc.1998, 120, 9084.O NSBnOO NSBnOHOTiCl4,(-)-sparteineHOEtEt83%; >98:21. TBSOTf2. LiBH43. Swern83%HOTBSOEtTiCl4,(-)-sparteineO NSBnOO NSBnOHO81%; 98:2EtOTBS1. TMSOTf2. LiBH43. Swern71%HOTMSOEtOTBSPh3P=CMeCO2Et93%OTMSEtOTBSEtO2C1. DIBAl-H2. CBr4, Ph3P3. PBu382%OTMSEtOTBSBu3P+Br-Dr. P. WipfPage 12 of 281/21/2008Oxazolidinethiones can be N-acylated by a variety of standard methods includingacylation of the lithium salt or sodium salt by treatment with an acyl chloride ormixed anhydride or by acylation with an acid chloride in the presence oftriethylamine.Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J. Am. Chem. Soc. 1993, 115, 2613.Yan, T.-H.; Hung, A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J. Org. Chem. 1995, 60, 3301.Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 4, 591.Crimmins, M. T.; She, J., "An improved procedure for asymmetric aldol additions with N-acyloxazolidinones, oxazolidinethiones, and thiazolidinethiones." Synlett 2004, 1371-1374.NHOSBnNOSBnOOn-BuLi, THF, -78 °CCH2=CHCH2OCH2COClNHOSBnNOSBnOEt3N, CH2Cl2, 0 °CCH3CH2COCl85%90%Dr. P. WipfPage 13 of 281/21/2008indirect solution for anti-aldol (D. A. Evans, THL 1986, 27, 4957:ONOO1. Bu2BOTf, NEt32.OHCOBn58%OBnOHRcO1. LAH2. TsCl3. LAHOBnOHJohnson-LemieuxOBnOHODr. P. WipfPage 14 of 281/21/2008For important modern concepts on selective anti-aldol processes, see work byMasamune (Tetrahedron Lett. 1992, 33, 1729)NSO2MesBnOPh O1. (c-C6H11)BOTf, NEt32. EtCHOOOOH PhNSO2MesBn90% yielddr = 96:4Mikami (J. Am. Chem. Soc. 1994, 116, 4077)Denmark (J. Am. Chem. Soc. 1999, 121, 4982)Evans (J. Am. Chem. Soc. 1997, 119, 10859)Kobayashi (Ishitani, H.; Yamashita, Y.; Shimizu, H.; Kobayashi, S., "Highly anti-selectivecatalytic asymmetric aldol reactions." J. Am. Chem. Soc. 2000, 122, 5403-5404)and others:Corey, E. J.; Li, W.; Reichard, G. A. "A new magnesium-catalyzed doubly diastereselective anti-aldol reaction leads to a highly efficient process for the total synthesis of lactacystin in quantity."J. Am. Chem. Soc. 1998, 120, 2330.Gosh, A. K.; Fidanze, S. "Asymmetric synthesis of (-)-tetrahydrolipstatin: An anti-aldol-basedstrategy." Org. Lett. 2000, 2, 2405-2407.Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. "Diastereoselective magnesium halide-catalyzed anti-aldol reactions of chiral N-acyloxyoxazolidinones." J. Am. Chem. Soc. 2002, 124,392-393.Chow, K. Y.-K.; Bode, J. W. "Catalytic generation of activated carboxylates: Direct,stereoselective synthesis of β-hydroxyesters from epoxyaldehydes." J. Am. Chem. Soc. 2004,126, 8126-8127.Dr. P. WipfPage 15 of 281/21/2008Assumed catalytic cycle:PhCHO+OTMSOPhIOOIZrOt-BuOt-Bu10 mol%PrOH (80 mol%), toluene, 0 °CPh OPhOOHsyn:anti = 12:8885% eeIOOIZrORORR'CHOR' HOZrOROROTMSOPhR'CO2PhOZrOROROTMSOROHR'OPhOOHDr. P. WipfPage 16 of 281/21/2008Industrially Relevant Aldol Processes (from Farina et al. “AsymmetricSynthesis of Active Pharmaceutical
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