Dynamic Kinetic Resolution: A Powerful Approach to Asymmetric Synthesis
OH OH Rhizopus arrhizus Ru(II)(R)-BINAP MeO CO2Et MeO CO2Et H2
98% yield O 100% yield 98% de, 99% ee 97% de, 96% ee MeO CO2Et
OH OH
MeO CO2Et Baker's yeast Ru(II)(S)-BINAP MeO CO2Et
H2
70% yield 93% yield 98% de, 95% ee 93% de, 86% ee Erik Alexanian Supergroup Meeting March 30, 2005
For leading references, see: Pellissier, H. Tetrahedron 2003, 59, 8291 Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247 Methods for Asymmetric Synthesis
Synthesis utilizing existing stereogenic centers (chiral substrates or auxiliaries) Catalytic enantioselective organic reactions - Chemocatalysis - metal-mediated, Lewis acid-mediated, organocatalysis - Biocatalysis - enzymes (hydrolases) Resolution - Conventional separation procedures - Kinetic resolution
kR SR PR
kS E = kfast/kslow = 10 SS PS % ee 100 ee S
Problems associated with standard kinetic resolutions:
- Theoretical yield = 50% 50 ee P - Separation of product from remaining substrate required - In the majority of processes, only one stereoisomer is desired
- Drop in enantiomeric purity as process nears 50% conversion 0 0 50 100 % conversion Dynamic Kinetic Resolution
Classic Resolution Dynamic Resolution
kR kR SR PR SR PR
kinv
kS kS SS PS SS PS
kS E = kfast/kslow = 10 % ee 100 kR ∆∆G ee P DKR kinv
50 ee S ee P
SS S 0 R 0 50 100 % conversion P PS R
If racemization can occur concurrently with kinetic resolution, then theoretically 100% of the racemic mixture can be converted to one enantiomer. This process is known as dynamic kinetic resolution (DKR).
DKR is an example of a Curtin-Hammett system in which the composition of products is controlled by the free energies of the transition states and not the composition of the starting materials. Guidelines for Dynamic Kinetic Resolution
Dynamic Resolution
kR SR PR
kinv kS SS PS
In order to design a successful DKR, both the inversion and resolution steps have to be carefully tuned. Here are a few established general guidelines for an efficient DKR:
(1) The kinetic resolution should be irreversible in order to ensure high enantioselectivity.
(2) The enantiomeric ratio (E = kR/kS) should be at least greater than ~20.
(3) To avoid depletion of SR, racemization (kinv) should be at least equal or greater than the reaction rate of the fast enantiomer (kR).
(4) In case the selectivities are only moderate, kinv should be greater than kR by a factor of ~10.
(5) Obviously, any spontaneous reaction involving the substrate enantiomers as well as racemization of the product should be absent.
Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron: Asymmetry 1999, 10, 107 Examples of Racemization
The racemization/inversion step is key to a successful DKR. Following are a number of common techniques used for this step.
1) Acid or base catalyzed racemization
R R
N O CALB HN COOR' O NEt3, R'OH Ph O Ph
up to 96% yield up to 98% ee
2) Enzyme catalyzed racemization
Dehydrogenase Redox-Enzyme OH (reversible) O (irreversible) OH
R1 R2 R1 R2 R1 R2
NAD(P)+ NAD(P)H Examples of Racemization (Cont'd) 3) Schiff base-mediated racemization R R1 Alcalase 1 t-BuOH/H2O (19:1) H N CO H H2N CO2R 2 2 90-98% ee, 87-95% yield pyridoxal 5-phosphate O H O OH CO2R CO2R O P O C N CH2 N O H R R N 1 1 H+ pyridoxal 5-phosphate
4) Racemization via sp2 intermediates (redox, addition/elimination)
O High pH OH Lipase OAc Acyl donor R X R X R X X = SR', OR', NHR', CN X H H R1 R2 [M] H X [M] H X +
R1 R2 H R R [M] 1 2 H Examples of Racemization (Cont'd)
5) Anionic interconversion
O N N O N O N O s-BuLi Li L Li L E E Et (-)-sparteine
6) Racemization via π-allyl intermediates
R R 1 2 [ M ] R1 R2 Nu R1 R2 Nu M Nu
7) Racemization via SN2 processes
Br Br C. rugosa
CO2Me CO2H PPh3 Br
79% ee, 78% yield The "Catalytic Triad" - Reaction Mechanism of CALB
Asp187 Asp187 O O R1 O O R O O O 1 R2 O R2 H H O H H O N N Ser105 N N Ser105
His224 His224
R3 O
R4 O R2
187 Asp187 R3 Asp O O R R1 O O 4 O O O O R2 R2 H H O H H O 105 N N Ser105 N N Ser R1OH OH His224 His224 R3 R4
Pamies, O; Backvall, J-E. Chem. Rev. 2003, 103, 3247 Enzymatic Methods - Reductions of β-Ketoesters
OH O OH O OH OH OH CO2Et CO2Et CO2Et H3C OEt H3C OEt
1 2 OMe 345
OH O O OH O O OH O CO2Et O MeO OMe CO Et OH BocN 2 S OH 67 8910
Product Microorganism Yield (%) de (%) ee (%)
1 G. candidum 80 98 98 2 Baker's yeast 94 92 99 3 M. racemosus 75 98 99 4 Saccharomyces sp. 95 98 98 5 Baker's yeast 72-85 99 99 6 K. magna 80 100 94 7 Y. lipolytica 95 - 95 8 Dipodascus sp. 80 - 99 9 Baker's yeast 74 - 98 10 Baker's yeast 71 98 85 Pellissier, H. Tetrahedron 2003, 59, 8291 Ward, R. S. Tetrahedron: Asymmetry 1995, 6,1475 Enzymatic Methods - Other Selected Reductions OH OH OH O OH OH CO2Et CN SEt C5H11 S OH 12 3 4
OH OH OH O OH O MeO CN SO2Ph NH2 NHBn
5 678
Product Microorganism Yield (%) de (%) ee (%)
1 Baker's yeast 88 100 96
2 Baker's yeast 82 76 99
3 Baker's yeast 76 - 80
4 S. montanus 89 - 97
5 Baker's yeast 95 96 98
6 R. arrhizus 97 98 99
7 M. isabellina 92 72:28 dr 99
8 M. isabellina 100 92 99
Pellissier, H. Tetrahedron 2003, 59, 8291 Enzymatic Methods - Hydrolysis
Amino acid synthesis O H R Alcalase R1 O 1 OH pyridoxal 5-phosphate H N CO H O P O H2N CO2R 2 2 t-BuOH/H2O (19:1) O 90-98% ee, 87-95% yield N H+ CO2H pyridoxal 5-phosphate P. thiasolinophilum CO2H S N HS NH2 NH2 100% ee, 100% yield
O Lipozyme O N O Et3N/BuOH Toluene Ph N CO2Bu H H2N CO2H Ph 99.5% ee, 94% yield L-(S)-tert leucine
Many other useful hydrolysis systems
S. griseus CO2Et CO2H N buffer pH 9.7 N O O (S) - keterolac 85% ee, 92% yield
Stecher, H.; Faber, K. Synthesis 1997,1 Enzymatic Methods - Esterifications
DKR of Hemiacetals, cyanohydrins, and derivatives
O High pH OH Lipase OAc Acyl donor R H R X R X X = SR', OR', NHR', CN
OH OAc P. cepacia MeO MeO SBu SBu SiO2 O O OAc, TBME > 95% ee, 63% yield
Many other esterifications
O OH OH H HO H slow OH O fast
Conditions: Lipase, vinyl acetate, Et3N OAc O H 97% ee, 75% yield AcO H O
Taniguchi, T.; Ogasawara, K. Chem. Commun. 1997, 1399 Other Enzymatic Methods via DKR
DKR applied to microbiological Baeyer-Villiger oxidation O recombinant O O E.coli, pH 9 O slow fast O OBn OBn O OBn OBn
96% ee, 85% yield
Chemoenzymatic DKR of Phenylglycine Methyl Ester
NH NH2 2 CALB (Candida antarctica lipase B) OMe NH2 NH3, tert-butanol O N O O or HO 88% ee, 85% yield OH OH O
DKR combining enzyme and racemization via SN2 displacement
O O C. cylindracea lipase OEt NHR' R'NH2, PPh3 Cl Cl Cl up to 86% ee, up to 92% yield
Berezina, N.; Alphand, V.; Furstoss, R. Tetrahedron: Asymmetry 2002, 13, 1953 Wegman, M. A.; Hacking, A. P. J.; Rops, J.; Pereira, P.; van Rantwijk, F.; Sheldon, R. A. Tetrahedron: Asymmetry 1999, 10, 1739 Badjic, J. D.; Kadnikova, E. N.; Kostic, N. M. Org. Lett. 2001, 3, 2025. Combination of Enzymes and Transition Metals in DKR
Question: Why use anything other than simple enzymes and nonmetallic racemization methods? Answer: These DKR approaches are mainly limited to substrates that possess a stereogenic center with an acidic proton.
A Possible Solution: Transition Metal-Catalyzed Racemizations
X H H R1 R2 [M] H X [M] H X +
R1 R2 H R R [M] 1 2 H
R R 1 2 [ M ] R1 R2 Nu R1 R2 Nu M Nu
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247 Shvo's Catalyst - Mechanism of Action
O O Ph Ph Ph H Ph Ph OH Ph O Ph Ph + Ph Ph Ph Ph Ru H Ru Ph Ph Ph Ph OC CO Ru Ru OC CO OC H OC OC Shvo's Catalyst OC
Ph Ph Ph Ph O Ph OH Ph O OH O OH Ph Ph + Ph Ph + Ph Ph + R H* R R' Ru R' Ru R R' Ru H* OC OC H* OC OC OC OC
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247 Combination Enzyme-Metal Catalysis - DKR of Alcohols/Diols CALB OAc OH p-Cl-C6H4-OAc (3 equiv) Shvo's Ru Cat. (2 mol%) R1 R2 R1 R2 PhCH3 78-92% yield 91- >99% ee OAc OAc OAc OAc OAc OAc O OAc
5
80%, >99% ee 80%, 98% ee 77%, >99% ee 88%, >99% ee 79%, >99% ee 65%, >99% ee 90%, >97% ee
OH CALB OH OH p-Cl-C6H4-OAc (3 equiv) + Shvo's Ru Cat. (4 mol%) OH PhCH3 OH OH 63%, >99% ee (R,R)-product meso-product 86 14 OAc : OAc OAc 90%, >99% ee AcO (R,R:meso) 43%, >99% ee OAc 77%, >99% ee (38:62) (74:26) (98:2) OAc
OAc OAc OAc OAc 63%, >97% ee 78%, >99% ee OAc Bn OAc 64%, >96% ee (90:10) N (100:0) (89:11) N
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247 Enzyme-Metal Catalysis - DKR of Hydroxy Acid Derivatives Tandem Aldol Reaction/DKR 1) LDA/THF OAc O O O 2) NH4Cl sat. 2 equiv. + 3) P. cepacia lipase R OEt R H OEt Shvo Cat. (6 mol%) up to 82% yield p-Cl-C6H4-OAc up to 99% ee TBME, 60 oC, 6d
Enzyme OH O Acyl donor OAc O Fast R OEt R OEt Major Ru - catalyzed O OLi C-C bond + racemization formation R H OEt OH O Slow OAc O R OEt Acyl donor R OEt Enzyme Minor
DKR of Racemic α-Hydroxy Esters
OH P. cepacia lipase OAc Shvo Cat. (2 mol%) R CO2R' p-Cl-C6H4-OAc (3 equiv) R CO2R' Cyclohexane R = alkyl, aryl 60-80% yield R' = Me, Et 30-98% ee
Huerta, F. F.; Backvall, J.-E. Org. Lett. 2001, 3, 1209 Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103,3247 Enzyme-Metal Catalysis - Other Alcohol DKRs
Azido Alcohols
OH CALB OAc
N3 Shvo's catalyst (4 mol%) N3 p-Cl-C6H4-OAc (3 equiv) PhCH3 86%, >99% ee
Hydroxy Nitriles CALB OH Shvo's catalyst (4 mol%) OAc CN p-Cl-C6H4-OAc (3 equiv) CN 7 7 PhCH3 93%, 92% ee
Halo Alcohols CALB OH Shvo's catalyst (4 mol%) OAc Cl p-Cl-C6H4-OAc (3 equiv) Cl PhCH3 74%, 91% ee Allylic Alcohols
P. cepacia lipase Cl OH OAc Cl Ru catalyst (4 mol%) Ru Ru H Pr p-Cl-C6H4-OAc, Et3N Pr Cl CH2Cl2 83%, 95% ee
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247 Enzyme-Metal Catalysis Utilizing Palladium
DKR of Allylic Acetates
Ph Ph PF lipase OAc 37-40 oC, pH 7.0 OH 0.1M phosphate buffer PdCl2(MeCN)2 (5 mol%) 19 days 81%, 96% ee
DKR of Amines
NH2 NHAc Pd/C CALB Et3N, EtOAc
64%, 99% ee
NH NH 2 NH + + Pd Ph PdH2 Ph Ph HPdH
Ph PdH - NH3 Pd + Ph NH 2 Ph N HN NH2 Ph Ph Ph
Pamies, O.; Backvall, J.-E. Chem. Rev. 2003, 103, 3247 Challenges w/Enzymatic DKR
Question: Why use anything other than enzymatic systems with DKR? Answer: There are currently a number of serious drawbacks towards applications of this technology.
Since enzymes and chemical catalysts usually work in different environments, their combination in a one-pot transformation in far from straightforward.
For instance, with lipase catalyzed DKRs with transition-metal catalysts, solvents, metal, acyl donor, and temperature all need to be optimized.
The necessary chiral recognition by enzymes can place significant constraints on substrate scope.
H OH M L
Finally, the achilles' heel: in many cases only one enantiomer is accessible.
Potential Solution: Enzyme-free DKR! Using Chiral Auxiliaries in DKR
O O O O Nu O H slow O H3CN N O R* R* O N Me X Nu CO2tBu addition-induced Durst Nunami Devine epimerization R* = O O O Nu R* R* H3CN N Fast N X Nu S O2 Me Ph major Ward Caddick & Jenkins
k R + SR PRR PRS
kinv k S + SS PSR PSS
O O O O O O NaCH(CO Me) Me Me 2 2 Me BnNH2 Me N N Me N N Me N N TBAI TBAI CH(CO Me) Br NHBn 2 2 THF Et3N / THF Me Ph Me Ph Me Ph 78%, 40-60% de 100%, 74% de
Caddick, S.; Afonso, C. A. M.; Candeias, S. X.; Hitchcock, P. B.; Jenkins, K.; Murtagh, L.; Pardoe, D.; Gil Santos, A.; Treweeke, N.; Weaving, R. Tetrahedron 2001, 57, 6589 DKR Utilizing Configurationally Labile Anions Ph Ph n-BuLi / (-)-sparteine H PhCH Br N 2 N Boc Ar Ph Ar Boc 84%, 96% ee asymmetric R deprotonation E RLi / L* L* Li N Boc Ar H enantioenriched R R H H N Ar Boc R E N Ar Boc L* Li N Boc Ar RLi / L* E asymmetric R substitution L* Li N Boc Ar
NBn NBn NBn NBn NBn Li 2 2 2 2 2 + H Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Me O OH OH OH OH 60% 21% 13% 6%
Ratio of products identical with racemic or enatiomerically pure electrophile Weisenburger, G. A.; Faibish, N. C.; Pippel, D. J.; Beak, P. J. Am. Chem. Soc. 1999, 121, 9522 Hoffmann, R. W.; Ruhl, T.; Chemla, F.; Zahneisen, T. Liebigs Ann. Chem. 1992, 719 DKR with Boron Electrophiles
O Cy i PrOB Cy OH O O ClMg Cy PhCHO B Cy Ph O
89%, 94% de 71%, 94% ee
O O B O O O O O OLi O O B Br O N LDA ON O N NaI (cat), 18-Crown-6
100%, >97% de
Sturmer, R. Angew. Chem. Int. Ed. Engl. 1990, 29, 59 Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475 Ruthenium-Catalyzed Hydrogenation of β-Ketoesters Ru-catalyzed DKR has been developed into a powerful transformation of very broad scope
O O OH O X O O [RuCl((R)-BINAP)(C6H6)]Cl [(R)-binap]Ru O O H , 100 atm O 2 H H H C H 96% de, 94% ee 3 OH O OH O O [RuCl2((R)-BINAP)]2Et3N OMe OMe H , 100 atm SR 2 NHBz N NHBz 100% conv. O CO H syn:anti = 94:6 2 98% ee carbapenems Cl Cl Cl BnO BnO BnO (R)-MeO-BIPHEPRuBr O 2 OH H2 , 140 bar CO2H AcHN CO2Me AcHN CO2Me 100% yield, 95% de, 80% ee (enantiomerically pure after O O OH O two recrystallizations) [(R)-BINAP]Ru(II) Ph OEt diltiazem (a potent channel blocker) H2 , 80 bar Ph OEt Cl Cl 90% de, 88% ee
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995 68, 36 Ruthenium-Catalyzed Hydrogenations (Cont'd)
O O O H2 OH O [(S)-BINAP]Ru(II) OH P(OCH ) H3C P P(OCH3)2 3 2 OH MeOH H H Br Br O 80% de, 98% ee fosfomycin
Ts Ph N O Ru OH Ph N Cl Ph Ts Ph Ph Ph H2, HCO2H, Et3N O OH 100%, 97% de, >99% ee
O O OH O
OMe OMe O PPh2 Ru(S-C3-Tunephos) N N n MeOH, 50oC 100 bar O PPh2
(S)-Tunephos >99% ee, anti:syn >97:3
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995 68, 36 Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004 126, 1626 DKR via Cross-Coupling
R H MgCl Br L* = Me N PPh Ph cat. NiCl2 / L* Ph 2 2 >95%, >80% ee (R = iPr, sBu, tBu)
MgCl MgCl H Ph Ph CH3 CH3 H MgBrCl MgBrCl
L L L L Ni (L2)(Br)Ni Ni
Ph H Ph CH3 CH3 H
Br Br
Ph H Ph CH3 CH3 H
Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475 DKR via Pd-Catalyzed Allylic Substitution
2.5 mol% Pd2dba3 7.5 mol% L* + ROH 30 mol% Bu NCl RO O O BocO O O 4 H 89%, >95% ee
O EtO O 6 steps O O O R = NH HN I L* = O O
PPh O 2 Ph2P H H3CO OH O O H H3CO Aflatoxin B
O L L L L Pd Pd Pd R Nu O O L* OPdL O O 2 Nu O O O O O O
racemization via η3-η1 complexes
Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543 DKR via Asymmetric Conjugate Reduction
O 10 mol% CuCl/(S)-p-tol-BINAP O R NaOt-Bu (1.7 equiv) R tBuOH (5.0 equiv), PMHS (2.2 equiv) PhCH3, 26 h, then TBAF R' R' R = alkyl R' = alkyl, aryl de = 82-93%, ee=91-94%
O OTMS O R [H] R F R fast
R' R' R'
NaOR, ROH very fast
O OTMS O R [H] R F R slow
R' R' R'
Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 2892 DKR Utilizing Organocatalysts DKR of azlactones using urea-based bifunctional organocatalysts
H-bond donor H-bond donor O O R R N N * chiral spacer N N * chiral spacer H H H H Bronsted base NR2 Bronsted base O NR2 H H O O O 3 H R2 N R O R1 R2 N R1
CF3 R catalyst (5 mol%) O R H O N O allyl alcohol (1.5 equiv) O PhCH3, RT, 48 h Ph N allyl O H F3C N N O H H Ph NMe2 R = PhCH , Me, iPr, iBu, tBu, Ph 43-96% conversion, 72-87% ee 2 urea-based catalyst
Berkessel, A.; Cleemann, F.; Mukherjee, S.; Muller, T. N.; Lex, J. Angew. Chem. Int. Ed. Engl. 2005, 44, 807 DKR Utilizing Organocatalysts Asymmetric Synthesis of α-Hydroxy Carboxylic Acids
O O R (DHQD)2AQN (10 mol%) R O EtOH (1.5 equiv), Et O OEt O 2 OH O 61-85% yield R = aryl 60-96% ee
H O R O R'OH, NR3* O R O fast OR' O OH O R + HNR3* O O O
H O O R R'OH, NR * R O 3 OR' O slow OH O
Racemization rate with R=alkyl was too slow to allow for efficient DKR
Tang, L.; Deng, L. J. Am. Chem. Soc. 2002, 124, 2870