Kinetic Resolutions Material outline: General References: For the Scientist in you: Vedejs, ACIEE, 2005, 3974 Definitions Jacobsen, Adv. Syn. Cat. 2001, 5 Theoretical treatment Kagan, Topics in Stereochemistry, 1988, 18, 249 For the technician in you: Practical considerations Useful KR’s Oxidative KR of allylic alcohols An extreme example Acylation/deacylation Hydrogenation olefins ketones Dynamic kinetic resolution Epoxide ring opening A very extreme example Parallel kinetic resolution Ready; Catalysis Kinetic Resolution Some definitions and examples Resolution: A process leading to the separation of enantiomers, or derivatives thereof Simplest examples: Resolution by making diastereomeric derivatives O O O O CO2H CO2H OH (+)-Menthol + + enantiomers diastereomers (identical mp, mobilitiy on silica gel, bp, etc) (different mp, mobility on silica gel, bp, etc) Resolution via salt formation: NH2 HO2C CO2H NH + - + 2 (0.5 equiv) NH3 O C OH NH3 + HO OH 2 + -OAc H O/HOAc 2 NH2 2 + - + NH3 O2C OH NH3 (solid) (soluble) NH2 Larrow, Jacobsen, OS, 1998, 75, 1 1 Ready; Catalysis Kinetic Resolution Kinetic Resolution: One enantiomer reacts faster than the other: k OAc fast OH Bu Bu + H2O, Lipase high ee product 50% yield max OAc OAc kslow Bu Bu high ee unreacted sm racemic mixture 50% yield max slow reacting enantiomer ‡ ‡ ‡ ΔΔG (slow - fast) = ΔG (slow) - ΔG (fast) Potential fast reacting enantiomer Energy (S) + (R)- SM ‡ krel = s = kfast/kslow = exp(ΔΔG /RT) minor product major product Ready; Catalysis Kinetic Resolution Relationships between krel, ee and conversion (1) Calculated from eq 1 Important Points 1. KR can give any arbitrarily high ee recovered sm with any krel >1 if you sacrifice yield 2. KR can give high ee product only if very high krel (needs to be more selective than ‘normal’ asymmetric reaction (Jacobsen, 2001) 2 Ready; Catalysis Kinetic Resolution Some thoughts: -Sharpless, JACS, 1981, 6237 Ready; Catalysis Kinetic Resolution Note that eq 1 may not always hold: Ln[(1-c)(1-ee)] k = (1) rel Ln[(1-c)(1+ee)] It assumes rxn is first order in substrate, but consider simple enzyme kinetics: k1 Reagent Sub + Cat Sub-Cat Product k k-1 2 k2(R)[Reagent][Cat]t[Sub] K = (k + k )/k ~ dissociation constant Rate = M -1 2 1 (R-sub) Sub = substrate KM + [Sub] For [sub]>>Km, rxn is 0 order in [sub]; equation 1 does not hold For [sub]<<Km, rxn is 1st order, equation 1 needs modification: k K Ln[(1-c)(1-ee)] Relative rate = E = cat(R) M(S) = (2) kcat(S)KM(R) Ln[(1-c)(1+ee)] Eq. 2 is eq 1 normalized to binding affinity Many (most?) KR’s would likely show enzyme kinetics if anyone looked. Therefore they may start out zero order, then change. Also, one enantiomer could be 1st order, while the other is 0th order! Hallmark of trouble is if krel (as calculated by eq 1) changes as a function of conversion The real question is: what yield of what ee? 3 Ready; Catalysis Kinetic Resolution O OH OH DIPT, Ti(OiPr)4 tBuOOH 47% recovered sm O 94% ee + M Drawbacks to KR’s KR’s may be useful if the following are true: Max 50% yield 1. Very high ee needed Poor ‘atom economy’ 2. Racemate cheap; optically active hard to make Viewed by some as inelegant 3. Resolving agent cheap 4. Products easily separable 5. Catalyst cheap and works well Ready; Catalysis Kinetic Resolution with D-(-)-DET HO OH EtO2C CO2Et (cat) R R' (-)-diethyl tartrate (DET) R R' (unnatural isomer) O OH OH Ti(OiPr)4 (cat), 3AMS OH R' tBuOOH (TBHP) R' Katsuki, Sharpless, with L-(+)-DET JACS, 1980, 6237 General trend: asymmetric catalytic reaction disclosed; soon after KR disclosed OH + OH Sharpless, JACS, 1981, 6237 improved (addn MS3A): JOC, 1986, 1922 (recovered, relative rates: JACS, 1988, 2978 c-C6H11 H c-C6H11 H 48% y, 94%ee) kfast kslow krel = 104 Epoxidation is enantiomer-selective and dr = 2:98 dr = 38:62 diastereoselective O O O O OH OH OH OH c-C6H11 H c-C6H11 H c-C6H11 H c-C6H11 H major product 4 Ready; Catalysis Kinetic Resolution Ready; Catalysis Kinetic Resolution Examples: isolated products shown (for a large list, see Adv. Syn Cat, 2001, 5, supporting info) OH TMS C5H11 ~40%y, Bu3Sn 99%ee OPh + OH OH 47% y, TMS C5H11 ~40%y >98% ee 99% ee 40% y, 99% ee O big trans group helps OH H3C O OH Ph P 2 + O 18%y, 37% y 98%ee O >95% ee OH + H OH OH Ph2P HO 32% y 45% y O 99% ee ?? ee 36% y 95% ee OH OH OH NH O + Bu + O O 46% y Bu NHTs 47%y ~40 y 43% y OH 46% y 95% ee O 30% ee 94% ee O (rxn not general for amines) 5 Ready; Catalysis Kinetic Resolution OH 2o KR (+)-DIPT, Ti(OiPr)4, TBHP krel*: 0.36 0.62 100 fast 2.04 slow OH OH OH OH O O ent-1 ent-epi-1 1 O epi-1 O fast krel*: ~102 ~102 ~0.98 slow ~0.98 OH OH OH OH O O O O O O O O ee = %1 - % ent-1 de = %(1 + ent-1) - %(epi-1 + ent-epi-1) predict ee and de will increase with conversion because of a secondary kinetic resolution predicted *krel calc using conversion yield 1 (%) ee 1 (%) OH 50 48 99.4 99 93 (max) 99.96 c-Hex 99.9 99.664 91 Schreiber, JACS, 1987, 1525 99.999 85 99.99999 Ready; Catalysis Kinetic Resolution Experimental validation OH (+)-DIPT, Ti(OiPr)4, TBHP OH -25 oC O time ee de 3 h 84 92 24 h 93 99.7 140 h >97 >99.7 OH (+)-DIPT, Ti(OiPr)4, TBHP OH -25 oC BnO OBn BnO OBn O time ee de 1 h 93 >97 3 h 95 >97 44 h >97 >97 6 Ready; Catalysis Kinetic Resolution Next-generation epoxidation?? 1 mol% 1 TBHP (70% aq) O OH CH2Cl2 OH OH 51% conversion Ph Ph Ph 95% ee 93% ee Ph potential advantages: O Ph aqueous conditions substrate classes inaccessible with Sharpless: N O OH O 1 = V demonstrated with R = H OiPr R N O KR with R not H?? R' O Ph obvious disadvantage: hard to beat tartrate Ph Yamamoto, ACIEE, 2005, 4389 Ready; Catalysis Kinetic Resolution Enzymatic acylation/deacylation of amines and alcohols review: Chem Rev. 1992, 1071 O NH2 NHAc (rac)- + NH3 + HCN R R CN R CO2H H2O H2O porcine kidney acylase acylase from mold (R = straight chain) Aspergillus oryzae (R = branched) NHAc R CO H AA's produced by Degusa on commercial scale 2 MeO CO H CO2H CO2H CO2H 2 BnO BnS NH NH2 NH NH2 2 2 OMe CH3 CO H CO2H Ph CO H F3C CO2H 2 2 H3C H3C NH NH2 NH2 NH2 2 7 Ready; Catalysis Kinetic Resolution Enzymatic acylation/deacylation of amines and alcohols review: Chem Rev. 1992, 1071 enzymes can be used to put Ac on or take Ac off. Isopropenyl acetate or vinyl acetate common acylating agents Enzyme 'kits' are available for screening purposes from SigmaAldrich and Biocatalytics Rxns can be performed in water or organic solvents (hexane common); need exclude water from esterification reactions General rule: an enzyme will work for almost any substrate!!: Cl Some examples from ester hydrolysis (for details, see tables 8 - 12 in review): OH HO Ph O OH H3C 89% ee >95% ee ent ester >95%ee OH N H3CO OTs 90% Ph OH >97% ee OH OEt S ent ester >97% ee S 99% ee Cl OEt 99% ee ent ester 99%ee ent ester 93% ee >98% ee OH Ready; Catalysis Kinetic Resolution Some products from acylation: Note cleavage of ester or acylation of alcohol gives enantiomeric product OAc CH3 EtO2C Ph OAc 48%y, 98% ee OAc OTBDPS H C ent alcohol: 49% y, >98%ee 3 36%, >98% ee 38% y, >98% ee ent alcohol 32%, 98%ee OAc extension to desymmetrization (often with 2o KR) Ph 46%y, >95% ee OAc ent alcohol, 43%y, >95% ee OBn OBn HO OAc O OBn 70%, >95% ee OH CO2Me 98% ee 43% y, 92% ee AcO 35% y, 99.4% ee 8 Ready; Catalysis Kinetic Resolution chemical methods for KR of alcohols Fu, Accts, 2000, 412; NMe σ−plane 2 Accts, 2004, 542 N Fe NMe2 Ph σ−plane 5 N 'planar chiral' version of DMAP achiral OAc N R R' Ac2O OH R R' N + Advantage: clever design O Idea extended to other asymmetric reactions One of most selective small molecule cat’s Disadvantages: $3000/mmol Fighting lipases and Noyori hydrogenation Ready; Catalysis Kinetic Resolution Kinetic resolution via asymmetric hydrogenation (much more on asymmetric hydrogenation to come) Ph2 P O O Ru O OH P O OH OH Ph R 2 R R R (<0.5 mol%) R R + H2 R R R R R R only useful when complementary to Sharpless Recovered allylic alcohols: Pretty tough to separate products OH OH OH OH O 48%, 96% ee 46%, >99% ee 44%, 82% ee 32%, 98% ee Noyori, JOC, 1988, 708 9 Ready; Catalysis Kinetic Resolution 1st (best?) example of dynamic kinetic resolution: racemization faster than reaction O O OH O OH O RuX2((R)-BINAP) H2, CH2Cl2 R OCH3 R OCH R OCH fast 3 3 R R R really fast O O OH O slow R OCH3 R OCH3 R R Products: OH OH O OH O OH O O H C OCH H3C OCH3 3 3 OCH3 OCH3 NHAc NHAc d.r.