Material outline: For the Scientist in you: Definitions Theoretical treatment Kinetic esolutions General eferences: Vedejs, ACIEE, 2005, 3974 Jacobsen, Adv. Syn. Cat. 2001, 5 Kagan, Topics in Stereochemistry, 1988, 18, 249 For the technician in you: Practical considerations Useful K s xidative K of allylic alcohols An extreme example Acylation/deacylation Hydrogenation olefins ketones Dynamic kinetic resolution Epoxide ring opening A very extreme example Parallel kinetic resolution eady; Catalysis Kinetic esolution Some definitions and examples esolution: A process leading to the separation of enantiomers, or derivatives thereof Simplest examples: esolution by making diastereomeric derivatives C 2 H C 2 H ()-Menthol enantiomers (identical mp, mobilitiy on silica gel, bp, etc) diastereomers (different mp, mobility on silica gel, bp, etc) esolution via salt formation: H 2 C C 2 H H H H 2 2 /HAc (0.5 equiv) H 3-2 C H 3 -Ac 2 H - 3 2 C H 3 (solid) (soluble) Larrow, Jacobsen, S, 1998, 75, 1 1
eady; Catalysis Kinetic esolution Kinetic esolution: ne enantiomer reacts faster than the other: Ac k fast Bu Ac H 2, Lipase k slow Bu high ee product 50% yield max Ac Bu racemic mixture Bu high ee unreacted sm 50% yield max slow reacting enantiomer ΔΔG (slow - fast) = ΔG (slow) - ΔG (fast) Potential Energy fast reacting enantiomer (S) ()- SM k rel = s = k fast /k slow = exp(δδg /T) minor product major product eady; Catalysis Kinetic esolution elationships between k rel, ee and conversion (1) Calculated from eq 1 Important Points 1. K can give any arbitrarily high ee recovered sm with any k rel >1 if you sacrifice yield 2. K can give high ee product only if very high krel (needs to be more selective than normal asymmetric reaction (Jacobsen, 2001) 2
eady; Catalysis Kinetic esolution Some thoughts: -Sharpless, JACS, 1981, 6237 eady; Catalysis Kinetic esolution ote that eq 1 may not always hold: Ln[(1-c)(1-ee)] k rel = (1) Ln[(1-c)(1ee)] It assumes rxn is first order in substrate, but consider simple enzyme kinetics: Sub Cat k 1 k- 1 Sub-Cat eagent k 2 Product ate (-sub) = k 2() [eagent][cat] t [Sub] K M [Sub] K M = (k -1 k 2 )/k 1 ~ dissociation constant Sub = substrate For [sub]>>km, rxn is 0 order in [sub]; equation 1 does not hold For [sub]<<km, rxn is 1 st order, equation 1 needs modification: elative rate = E = k cat() K M(S) k cat(s) K M() = Eq. 2 is eq 1 normalized to binding affinity Ln[(1-c)(1-ee)] Ln[(1-c)(1ee)] Many (most?) K s would likely show enzyme kinetics if anyone looked. Therefore they may start out zero order, then change. Also, one enantiomer could be 1 st order, while the other is 0 th order! Hallmark of trouble is if k rel (as calculated by eq 1) changes as a function of conversion The real question is: what yield of what ee? (2) 3
eady; Catalysis Kinetic esolution DIPT, Ti(iPr) 4 tbu 47% recovered sm 94% ee M Drawbacks to K s Max 50% yield Poor atom economy Viewed by some as inelegant K s may be useful if the following are true: 1. Very high ee needed 2. acemate cheap; optically active hard to make 3. esolving agent cheap 4. Products easily separable 5. Catalyst cheap and works well eady; Catalysis Kinetic esolution H with D-(-)-DET Et 2 C C 2 Et (cat) ' (-)-diethyl tartrate (DET) ' (unnatural isomer) Ti(iPr) 4 (cat), 3AMS ' t Bu (TBHP) ' Katsuki, Sharpless, JACS, 1980, 6237 General trend: asymmetric catalytic reaction disclosed; soon after K disclosed with L-()-DET c-c 6 H 11 H c-c 6 H 11 H (recovered, 48% y, 94%ee) Sharpless, JACS, 1981, 6237 improved (addn MS3A): JC, 1986, 1922 relative rates: JACS, 1988, 2978 k fast k rel = 104 k slow dr = 2:98 dr = 38:62 Epoxidation is enantiomer-selective and diastereoselective c-c 6 H 11 H c-c 6 H 11 H major product c-c 6 H 11 H c-c 6 H 11 H 4
eady; Catalysis Kinetic esolution eady; Catalysis Kinetic esolution Examples: isolated products shown (for a large list, see Adv. Syn Cat, 2001, 5, supporting info) 47% y, >98% ee big trans group helps TMS C 5 H 11 TMS C 5 H 11 ~40%y, 99%ee ~40%y 99% ee Bu 3 Sn 40% y, 99% ee H H ~40 y 30% ee 18%y, 98%ee 2 P Bu 43% y 94% ee 37% y >95% ee 2 P 36% y 95% ee Bu 46% y 32% y 99% ee 45% y?? ee H 46% y HTs 47%y 95% ee (rxn not general for amines) 5
eady; Catalysis Kinetic esolution 2 o K ()-DIPT, Ti(iPr) 4, TBHP k rel *: 0.36 0.62 100 fast 2.04 slow ent-1 ent-epi-1 1 epi-1 k rel *: fast ~102 ~102 ~0.98 slow ~0.98 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 conversion yield 1 (%) ee 1 (%) 50 48 99.4 99 93 (max) 99.96 99.9 91 99.664 99.999 85 99.99999 *krel calc using c-hex Schreiber, JACS, 1987, 1525 eady; Catalysis Kinetic esolution Experimental validation ()-DIPT, Ti(iPr) 4, TBHP -25 o C time ee de 3 h 84 92 24 h 93 99.7 140 h >97.7 Bn Bn ()-DIPT, Ti(iPr) 4, TBHP -25 o C Bn Bn time ee de 1 h 3 h 44 h 93 95 >97 >97 >97 >97 6
eady; Catalysis Kinetic esolution ext-generation epoxidation?? 1 mol% 1 TBHP (70% aq) CH 2 Cl 2 51% conversion 95% ee 93% ee potential advantages: aqueous conditions substrate classes inaccessible with Sharpless: 1 = V ipr demonstrated with = H K with not H?? ' obvious disadvantage: hard to beat tartrate Yamamoto, ACIEE, 2005, 4389 eady; Catalysis Kinetic esolution Enzymatic acylation/deacylation of amines and alcohols review: Chem ev. 1992, 1071 H 3 HC C (rac)- HAc C 2 H H 2 porcine kidney acylase ( = straight chain) H 2 acylase from mold Aspergillus oryzae ( = branched) HAc AA's produced by Degusa on commercial scale C 2 H Me C 2 H C 2 H Bn C 2 H BnS C 2 H Me CH 3 C 2 H F 3 C C 2 H C 2 H C 2 H 7
eady; Catalysis Kinetic esolution Enzymatic acylation/deacylation of amines and alcohols review: Chem ev. 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 xns 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!!: Some examples from ester hydrolysis (for details, see tables 8-12 in review): 89% ee 90% Et Ts S H >97% ee ent ester >97% ee Cl >95% ee ent ester >95%ee Cl Et >98% ee S 99% ee ent ester 93% ee 99% ee ent ester 99%ee eady; Catalysis Kinetic esolution Some products from acylation: ote cleavage of ester or acylation of alcohol gives enantiomeric product Ac CH 3 Et 2 C 48%y, 98% ee ent alcohol: 49% y, >98%ee Ac TBDPS 38% y, >98% ee Ac 36%, >98% ee ent alcohol 32%, 98%ee Ac extension to desymmetrization (often with 2 o K) 46%y, >95% ee ent alcohol, 43%y, >95% ee Bn Bn Ac H Ac C 2 Me Bn 70%, >95% ee 98% ee Ac 43% y, 92% ee 35% y, 99.4% ee 8
eady; Catalysis Kinetic esolution chemical methods for K of alcohols achiral σ plane Me 2 σ plane Me 2 Fe 5 'planar chiral' version of DMAP Fu, Accts, 2000, 412; Accts, 2004, 542 Ac ' Ac 2 ' Advantage: clever design Idea extended to other asymmetric reactions ne of most selective small molecule cat s Disadvantages: $3000/mmol Fighting lipases and oyori hydrogenation eady; Catalysis Kinetic esolution Kinetic resolution via asymmetric hydrogenation (much more on asymmetric hydrogenation to come) 2 P H 2 u P 2 (<0.5 mol%) ecovered allylic alcohols: only useful when complementary to Sharpless Pretty tough to separate products 48%, 96% ee 46%, % ee 44%, 82% ee 32%, 98% ee oyori, JC, 1988, 708 9
eady; Catalysis Kinetic esolution 1st (best?) example of dynamic kinetic resolution: racemization faster than reaction CH 3 ux 2 (()-BIAP) H 2, CH 2 Cl 2 fast CH 3 CH 3 really fast CH 3 slow CH 3 Products: CH 3 HAc d.r. 99:1, 98% ee P CH 3 CH 3 98% ee, 9:1 d.r. HAc CH 3 d.r. 99:1, 94% ee P() 2 HAc d.r. 94:6, 98% ee CH 3 d.r. 1:99, 93% ee CH 3 oyori, JACS, 1989, 9134; 1993, 144; 1995, 2931 eady; Catalysis Kinetic esolution Jacobsen Hydrolytic kinetic resolution: background ' ' u - Mn M proposed TS for asymmetric epoxidation Lewis-acid catalyzed epoxide opening? Asymmetric ring-opening of meso epoxides (salen)crcl t-bu Cr Cl t-bu t-bu t-bu (cat) 3 TMS TMS 3 3 3 3 3 3 TMS TMS TMS TMS TMS ee(%) 97 93 82 85 92 Jacobsen, Accts, 2000, 421 10
eady; Catalysis Kinetic esolution catalyst activation: Co (salen)co(ii) Aldrich: $93/5g 1/4 2 /Ac -1/2 H 2 Ac Co (salen)co(iii)ac hydrolytic kinetic resolution H 2 (,)-(salen)co(ac) (0.5-2 mol%) Unreacted epox (0.55 equiv H 2 ) yield ee Product diol (0.45 equiv H 2 ) yield ee k rel CH 3 CH 2 t-bu CH 2 Cl CH 2 TBS C 2 Me C CTBS 46 46 41 43 47 43 44 41 45 40 40 40 42 37 42 41 99 95 95 95 98 97 98 99 500 96 79 190 250 130 130 420 Procedure: JACS, 2002, 1307 Mechanism and improved procedure (CoTs): JACS, 2004, 1360 eady; Catalysis Kinetic esolution Terminal epoxides undergo simple K with enols; epibromohydrin is a special case: (,)-SalenCo(III) (4mol%) MS3A, Li (1 equiv) (1.05 equiv) 74%, >%ee (,)-SalenCo(III) major minor - - dyanmic kinetic resolution major slow minor fast secondary kinetic resolution JACS, 1999, 6086 11
eady; Catalysis Kinetic esolution Parallel kinetic resolution: Theory fast P 1 S SM s slow P 1 called 'parallel' because SM --> P1 is an (S)-selective K, SM --> P2 is an ()-selective K slow P 2 S SM fast P 2 Parallel kinetic resolution: example ften make great exam questions; rarely make useful synthetic methods Hoveyda, Tet, 1995, 4383 1 (cat) EtMg n-c 6 H 13 slow fast n-c 6 H 13 Et H 48% y 98% ee ZrCl 2 n-c 6 H 13 1 (cat) EtMg fast H n-c 6 H 13 H Et 48% y 98% ee 1 12