KemKem--4.4504.450 AsymmetricAsymmetric SynthesisSynthesis Prof. Ari Koskinen Laboratory of Organic Chemistry © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 ChiralityChirality andand DifferingDiffering PropertiesProperties OO Carvone spearmint odor caraway NH NH 2 H 2 H Aspartame HO2C NCO2Me HO2C NCO2Me (Nutrasweet) O O sweet bitter O O Thalidomide N N O O OON OON H H sedative, hypnotic teratogenic © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 PharmaceuticalsPharmaceuticals Growing need for enantiopure compounds Enantiomers/diastereomers may have adverse effects Diastereomers usually easier to separate Enantiomers: FDA required © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 PharmaceuticalsPharmaceuticals Penicillamine: NH2 NH2 CO2H CO2H SH SH antidote for Pb, Au, Hg can cause optic atrophy => blindness Timolol: O OH O OH H H N O N N O N N N N N S S adrenergic blocker ineffective © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 SalesSales ofof EnantiomericEnantiomeric DrugsDrugs andand IntermediatesIntermediates Chem. Eng. News 2001, 79 (40), 79-97. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 AsymmetricAsymmetric InductionInduction -- DefinitionsDefinitions Chirality - handedness Asymmetry - lacking all symmetry (except E) B Dissymmetry - lacking some element of symmery H NB!!! Molecules can be chiral but not asymmetric! e.g. C2 axis Asymmetric Induction (A.I.) - process that breaks (local) mirror symmetry OOHOH + A.I. if not 1:1 AcO AcO Prostaglandin synthesis intermediate Danishefsky, S.J. JACS 1989, 111, 3456. AcO HO © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 SpecificitySpecificity vsvs SelectivitySelectivity SPECIFICITY - non-statistical outcome of reaction - mechanism based SELECTIVITY - product determined by thermodynamics (product stability OR rates) SELECTIVE PROCESS: t O Li, NH3, BuOH H OH SPECIFIC PROCESS: 1) BH3 H 2) H O ; HO- 2 2 HOH ALL specific reactions must be selective, but not necessarily vice versa Two reactions must be carried out to determine if a process is specific 1) BH3 H 2) H O ; HO- 2 2 HO H © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 OpticallyOptically ActiveActive SubstancesSubstances Prochiral substrates Asymmetric synthesis Chemocatalysis Biocatalysis © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 OpticallyOptically ActiveActive SubstancesSubstances Racemates Kinetic resolution Diastereomer crystallisation Chemical Enzymatic © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 EnantioselectiveEnantioselective SynthesisSynthesis Purpose: to create single enantiomer to control stereochemistry at remote sites Methods: resolution z requires separation z loss of material chiral pool z additional operations asymmetric transformations (rare) Asymmetric induction © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 EnantioselectiveEnantioselective SynthesisSynthesis For A.I. to be practical > 99% ee Access both configurations General transformations Speed Control agent readily available Selectivity Stability NO added steps Safety Catalysis: + Sustainability 1 $ © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds Purchase directly from a commercial supplier Isolate from natural sources Resolution direct crystallization diastereomeric derivatives chiral chromatography Asymmetric Transformations Asymmetric Induction (AI) internal a.i. (chiral SM) relayed a.i. (chiral AUX) external a.i. (chiral RGT) Morrison, J.D. Asymmetric Synthesis vol 1, 1983, 1. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds PurchasePurchase directlydirectly fromfrom aa commercialcommercial suppliersupplier Problems: Availability, price, purity, ... A growing number of small companies sell tailor-made specialty chemicals. Applicable also in industry: contractors. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds IsolateIsolate fromfrom naturalnatural sourcessources Ideally a nearly unlimited source of new structures. Tedious!!! Finding the source!!! May require vast amounts of purification, structure identification and labor. Semisynthetic derivatives (e.g. penicillins). NB!!! NOT ALL NATURAL PRODUCTS ARE ENANTIOPURE!!! © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds ResolutionResolution directdirect crystallizationcrystallization distil + OH OH OH OH OH PhCOCl Industrial production of Menthol benzoate esters through fractional crystallization of benzoate ester intermediates crystallize + OH OH OBz OBz Haarmann & Reimer © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 SolubilitySolubility andand meltingmelting pointpoint diagramsdiagrams racemic mixture (conglomerate) racemic compound racemic solid solution (racemate) 0 50 100%(+) 0 50 100%(+) 0 50 100%(+) 100 50 0%(-) 100 50 0%(-) 100 50 0%(-) 0 50 100%(+) 0 50 100%(+) 100 50 0%(-) 100 50 0%(-) © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 OpticalOptical puritypurity duringduring titrationtitration withwith aqaq NaOHNaOH 100 mother liquor N 50 .HCl SN precipitate 0 50 100% starting optical purity © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 FractionalFractional SublimationSublimation ofof L--MandelicMandelic AcidAcid OH * CO2H Sample enantiomeric purity % of L-isomer 134 Stg material 20.7 60.3 Fraction 1 37.2 68.6 122 Fraction 2 31.5 65.7 Fraction 3 25.2 62.6 Fraction 4 16.0 58.0 Fraction 5 4.7 52.3 0 50 0 (L) Stg material 60.2 80.1 100 50 100 (D) Fraction 1 52.5 76.3 Fraction 2 62.0 81.0 Fraction 3 64.1 82.1 Fraction 4 74.3 87.1 Other related examples: H OH S CO2H H 6 %ee 74 %ee 40 %ee 64 %ee racemic non-racemic © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds ResolutionResolution diastereomericdiastereomeric derivativesderivatives NB! Both enantiomers of this half single enantiomer H H H H hydrolyze H O N Me OH Me H Me H OPh O O O O O O Separate 1:1 mixture of diastereomers by column chromatography Corey, E.J. et al. J. Am. Chem. Soc. 1970, 92, 396. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds ResolutionResolution chiralchiral chromatographychromatography Chiral Stationary Phase or Chiral Mobile Phase Additive Several applications, both analytical and preparative. Price! Columns available ‘on request’. Pirkle, W.H.; Finn, J. Asymmetric Synthesis, vol. 1, 1983, 87. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds AsymmetricAsymmetric TransformationsTransformations firstfirst orderorder secondsecond orderorder Thermodynamical control Equilibrium between enantiomers or epimers is set up to favour one or the other of the products. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds AsymmetricAsymmetric TransformationsTransformations firstfirst orderorder Conditions set up so as to favor e.g. crystallisation of one anantiomer. Classical example: spontaneous crystallisation of NaClO4 from aqueous solution. 844 trials, 51.3 % left handed, 48.7 % right handed crystals. Soret, C.H. Z. Krystallogr. Mineral. 1901, 34, 630. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds AsymmetricAsymmetric TransformationsTransformations secondsecond orderorder Me Cl Me O O N CHO N NH2 Cl NH2 N N CSA, i-PrOAc/MeCN Reider, P.J. et al. J. Org. Chem. 1987, 52, 955. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds AsymmetricAsymmetric InductionInduction (AI)(AI) internalinternal a.i.a.i. (chiral(chiral SM)SM) H H2N CO2H N N MeO C HO2C 2 HO Aspartic acid Vincamine Rapoport, H. et al. J. Org. Chem. 1990, 55, 3068. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 InternalInternal AIAI CO2Me CO2Me Ph CO2Me Ph Ph OH OH O H O B AcO OAc O OH Chelation controls selectivity (Saksena, A.K.; Mangiaracina, P. Tetrahedron Lett. 1983, 24, 273.) Turnbull, M.D. et al. Tetrahedron Lett. 1984, 25, 5449. © Helsinki University of Technology, Laboratory of Organic Chemistry © Ari Koskinen, 2007 MethodsMethods forfor ObtainingObtaining EnantiopureEnantiopure CompoundsCompounds AsymmetricAsymmetric