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Dynamic KineticTransformations

How to isolate 1 out of 4 diastereomersi h i ldwith 100 % yield

The isolation of single stereoisomers from a racemic (orThe isolation of single stereoisomers from a racemic (ordiastereomeric) mixture by enzymatic or chemical resolutiontechniques goes in hand with the disposal of 50% (racemate) ortechniques goes in hand with the disposal of 50% (racemate) ormore (diastereomeric mixtures) of the “undesired” substrateisomer(s). In order to circumvent this drawback, dynamicsystems have been developed for the de-racemization ofenantiomers and the de-epimerizations of diastereomers

dynamic kinetic resolution (DKR)

Key strategies

y ( )

dynamic kinetic asymmetricdynamic kinetic asymmetric transformations (DYKAT)

Dr. J. Steinreiber, Prof. Dr. H. GrienglResearch Center Applied BiocatalysisPetersgasse 14, 8010 Graz, (Austria)Fax: (+43) 316-873-9302E il j h t i ib @ tE-mail: johannessteinreiber@gmx.net

Dr. J. SteinreiberCurrent address: Mitterhoferstrasse 17Current address: Mitterhoferstrasse 1780687 Munchen (Germany)

Prof. Dr. K. FaberInstitute of Chemistry, University of GrazHeinrichstrasse 28, 8010 Graz (Austria)P f D H G i lProf. Dr. H. GrienglInstitute of Organic Chemistry, Graz University of TechnologyStremayrgasse 16, 8010 Graz, (Austria)Stremayrgasse 16, 8010 Graz, (Austria)

i i l ii i l iI. Kinetic ResolutionI. Kinetic Resolution

A PKA

fast

B QKB

B Qslow

efficient resolution KA >> KB

i th ti d

ee values are only comparable at the same degree of conversion

ees, eep - varies as the reaction proceeds

y p g

a conversion-independent parameter:

the ratio of the (apparent first-order) reaction rates of enantiomers

- describes the ability of a (bio)catalyst to distinguish between enantiomers under defined reaction conditions

for biocatalyzed reactions: "enantiomeric ratio" (E)enantiomeric ratio (E)

f h t l tfor chemocatalyst: “stereoselectivity factor" (s)

th ti l t t t f KRmathematical treatment of KR:‐ G. Bredig, K. Fajans, Ber. Dtsch. Chem. Ges. 1908, 41, 752 –763.‐ V. S. Martin, S. S. Woodard, T. Katsuki, Y. Yamada, M. Ikeda, K. B. Sharpless, J.   Am. Chem. Soc. 1981, 103, 6237 –6240.‐ C. S. Chen, Y. Fujimoto, G. Girdaukas, C. J. Sih, J. Am. Chem. Soc. 1982, 104, 7294 –7299.

P ll l Ki tiP ll l Ki tiVedejs and Chen Parallel Kinetic Resolution

Parallel Kinetic Resolution

A

B

E. Vedejs, M. Jure, Angew. Chem. 2005, 117, 4040 – 4069; Angew.Chem. Int. Ed. 2005, 44, 3974 – 4001.

KR PKR - maximum yield 50%KR, PKR maximum yield 50%

protocols for the complete transformation of aracemate into a single stereisomeric productprotocols for the complete transformation of aracemate into a single stereisomeric productracemate into a single stereisomeric productracemate into a single stereisomeric product

« De-racemization"« De-racemization"

Kback

dynamic kineticresolution

enantio-convergentprocess

cyclicderacemization

KA

fastK K

KAfast

back

KBslow

Krac KBslow

Kback

Dynamic Kinetic ResolutionDynamic Kinetic Resolution

KA

fast

KB

fastKrac

slow

Krac ≥ KA

KA > Krac >> KB

ΔG0= - T ΔS0 = -RTln2 = -0,41kcal/mol

mathematical treatment of DKR:

M. Kitamura, M. Tokunaga, R. Noyori, J. Am. Chem. Soc. 1993,115, 144 –152., g , y , , ,M. Kitamura, M. Tokunaga, R. Noyori, Tetrahedron 1993, 49,1853 – 1860.J. Andraos, J. Phys. Chem. A 2003, 107, 2374 –2387.

Dynamic Kinetic ResolutionDynamic Kinetic Resolution

KA

fast

KB

fastKrac

slow

RacemizationRacemization- thermal- acid- or base-catalyzed compatibilityy- by Schiff bases - redox reactions

di l ti

chiral catalyst

- radical reactions- enzyme-catalyzed

J. V. Allen, J. M. J. Williams, Tetrahedron Lett. 1996, 37, 1859 –1862.

A. L. E. Larsson, B. A. Persson, J.‐E. Backvall, Angew. Chem.1997, 109, 1256 – 1258; Angew. Chem. Int. Ed. Engl. 1997, 36, 1211 –1212

Prediction of Which Enantiomer Reacts Faster

P l ' l di t th t th tPrelog's rule predicts that the yeastCulvarin lunata preferentially addsH2 to the front side of ketones havingthe shape indicated.

An extension of Prelog's rule to hydrolases. Kazlauskas: for esters of secondary alcohols,the enantiomer shown reacts faster with CE, PCL, and CRL than the other enantiomer

CE, bovine cholesterol esterase; , ;CRL, lipase from Candida rugosa;;PCL, Amano P = lipase from Pseudomonas cepacia

R. J. Kazlauskas, A. Weissfloch, A. Rappaport, L. A. Cuccia, J. Org. Chem. 1991, 56, 2656 –2665.

L Boren B Martin Matute Y Xu A Cordova J E BQckvall Chem Eur J 2006 12L. Boren, B. Martin‐Matute, Y. Xu, A. Cordova, J.‐E. BQckvall, Chem. Eur. J. 2006, 12,225 – 232.

M.‐J. Kim, Y. I. Chung, Y. K. Choi, H. K. Lee, D. Kim, J. Park, J. Am. Chem. Soc. 2003, 125, 11494 – 11495.

De-racemization of a-hydroxycarboxylic acids using a sequential two-enzyme (racemase/lipase) protocol.

U. T. Strauss, U. Felfer, K. Faber, Tetrahedron: Asymmetry 1999, 10, 107 –117.

Enantio-convergent processesEnantio-convergent processesECPECP

ti l ti it

prerequisities for the

enantioselectivity - by preferingone enantiomer over other

p qchiral catalyst

stereoselectivity ‐ with respect to retention or inversion of configuration

ECPECP Aspergillus niger

Beauveria bassiana

S. Pedragosa‐Moreau, A. Archelas, R. Furstoss, J. Org. Chem. 1993, 58, 5533 –5536.

ECPECP

P. Gadler, S. M. Glueck, W. Kroutil, B. M. Nestl, B. Larisseggerschnell, B. T.Ueberbacher, S R Wallner K Faber Biochem Soc Trans 2006 34 296 – 300S. R. Wallner, K. Faber, Biochem. Soc. Trans. 2006, 34, 296  300.

Cyclic de-racemizationCyclic de-racemizationCycDCycD

K. Faber, Chem. Eur. J. 2001, 7, 5004 –5010.

N J Turner Curr Opin Biotechnol 2003 14 401 –406N. J. Turner, Curr. Opin. Biotechnol. 2003, 14, 401  406.C. J. Dunsmore, R. Carr, T. Fleming, N. J. Turner, J. Am.Chem.Soc. 2006, 128, 2224 –2225.

II De-epimerization of Diasteromers/II De-epimerization of Diasteromers/II. De-epimerization of Diasteromers/Diastereomeric Intermediates

II. De-epimerization of Diasteromers/Diastereomeric Intermediates

De-epimerization = the transformation of a mixture of diastereomersinto a single stereoisomer*.

For racemization ΔH = 0

F i i i ΔH ≠ 0For epimerization ΔH ≠ 0

h fi f d i i i d l d f hDYKATDYKATThe first concept of de-epimerization was developed for theselective crystallization of diastereomers from in-situequilibrating mixtures of epimers crystallization induced

= the de-symmetrization of racemic or diastereomeric mixtures involvinginterconverting diastereomeric intermediates implying different

DYKATDYKAT

equilibrating mixtures of epimers – crystallization inducedasymmetric transformation CIAT**

interconverting diastereomeric intermediates - implying differentequilibration rates of the stereoisomers.

*K. Faber, Chem. Eur. J. 2001, 7, 5004 –5010**N. G. Anderson, Org. Process Res. Dev. 2005, 9, 800 –813.

DYKATDYKAT

A,B=substrate enantiomers; P,Q=product enantiomers; Cat=catalyst;ACat,BCat=diastereomeric substrate – catalyst complexes; YCat= complexof chiral catalyst with achiral intermediate Y; kA, kB = pre‐equilibriumconstants for ACat and BCat complex formation;B. M. Trost, Chem. Pharm. Bull. 2002, 50, 1– 14.p ;kACat,kBCat = equilibration constants of epimerization of diastereomericfor ACat and BCat complexes with YCat; kP,kQ = rate constant ofirreversible formation of product enantiomers P and Q;

B. M. Trost, D. E. Patterson, E. J. Hembre, J. Am. Chem. Soc. 1999,121, 10834 – 10835

irreversible formation of product enantiomers P and Q;kAYCat, kBYCat = equilibration constants of epimerization of diastereo‐meric substrates A and B.

DYKATDYKAT

“Match”/“mismatch” situations of DYKAT type I.

D i Ki ti A t i T f tiD i Ki ti A t i T f tiDynamic Kinetic Asymmetric Transformation (DYKAT)

Dynamic Kinetic Asymmetric Transformation (DYKAT)

Comparison of the eep ofKR, DKR and DYKAT (matchand mismatch) as functionand mismatch) as functionof the conversion with anenantiomeric ratio of E=9.1

Y M Ostrovskii N S Nemerya B I Gorenshtein T N Pyzhik D Y Gerashchenko VestsiY. M. Ostrovskii, N. S. Nemerya, B. I. Gorenshtein, T. N. Pyzhik, D. Y. Gerashchenko, VestsiNats. Akad. Navuk Belarusi, Ser. Biyal. Navuk 1994, 60 –63.

DYKATDYKATT l h f t i ll li lk l ti (AAA)Trost et al. – new approach for asymmetric allylic alkylation (AAA)

B. M. Trost, Chem. Pharm. Bull. 2002, 50, 1– 14.B. M. Trost, D. L. Van Vranken, C. Bingel, J. Am. Chem. Soc. 1992,114, 9327 – 9343.B. M. Trost, J. Org. Chem. 2004, 69, 5813 – 5837.

DYKATDYKATDTR*

Y. S. Park, E. K. Yum, A. Basu, P. Beak, Org. Lett. 2006, 8, 2667 –2670.

DYKAT (II) DYKAT (II)

DYKAT type II (L*: enantiopure ligand, Nu: nucleophile).

B. M. Trost, D. E. Patterson, E. J. Hembre, J. Am. Chem. Soc. 1999,121, 10834 – 10835.B. M. Trost, D. E. Patterson, E. J. Hembre, Chem. Eur. J. 2001, 7, 3768 – 3775.

DYKAT type I and IIDYKAT type I and II allenesa

Asymmetric synthesis of

vinyl epoxidesb,c

y y fBaylis-Hillman adductsd

natural productse-k

a. B. M. Trost, D. R. Fandrick, D. C. Dinh, J. Am. Chem. Soc. 2005, 127, 14186 – 14187.a. B. M. Trost, D. R. Fandrick, D. C. Dinh, J. Am. Chem. Soc. 2005, 127, 14186  14187.b. B. M. Trost, R. C. Bunt, R. C. Lemoine, T. L. Calkins, J. Am. Chem. Soc. 2000, 122, 5968 –5976.c. B. M. Trost, D. B. Horne, M. J. Woltering, Angew. Chem. 2003, 115, 6169 – 6172; , , g, g , , ;Angew. Chem. Int. Ed. 2003, 42, 5987 –5990.d. B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 1999, 121, 3543 –3544.e. B. M. Trost, D. E. Patterson, E. J. Hembre, J. Am. Chem. Soc. 1999,121, 10834 – 10835.f. B. M. Trost, D. E. Patterson, E. J. Hembre, Chem. Eur. J. 2001, 7, 3768 – 3775.g. B. M. Trost, M. L. Crawley, J. Am. Chem. Soc. 2002, 124, 9328 – 9329.h. B. M. Trost, N. G. Andersen, J. Am. Chem. Soc. 2002, 124, 14320 – 14321.i. B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 2003, 125, 3090 –3100.j. B. M. Trost, D. B. Horne, M. J. Woltering, Chem. Eur. J. 2006, 12, 6607 – 6620.

De-epimerization of diastereomers via diastereomersDe-epimerization of diastereomers via diastereomers

DYKAT type IIIDYKAT type III(type III and IV)(type III and IV)

ypyp

DYKAT type III with simplifiedepimerization rates. ERS/ESR & ERR/ESS = enantiomeric pairs of diastereomericinitial products; p ;FRS/FSR & FRR/FSS = enantiomeric pairs of diastereo-meric final products;meric final products;kSS/ kSR through kRS/ kSS =equilibration rates of formationESS/ESR/ERR/ERS;ESS/ESR/ERR/ERS; kRR through kSS = rates of irreversible formation of FRS/FSR & FRR/FSS/FSR & FRR/FSS.

DYKAT type IIIDYKAT type III

DYKAT of symmetric 1,4- and 1,3-diols via lipase-catalyzed acyl-transfer in bi ti ith R t l d i i ti f h d lcombination with Ru-catalyzed epimerization of hydroxyl groups.

H=chiral carbon, convertable for equilibration and for the irreversible step; I=chiral carbon, stable chirality; n=1,2.

B. Martin‐Matute, M. Edin, J.‐E. BQckvall, Chem. Eur. J. 2006, 12, 6053 – 6061.

DYKAT of 1,3-diols via lipase-catalyzed acyl-transfer in combination with Ru-catalyzed epimerization of hydroxyl groups. G = chiral carbon, convertible for

ilib ti d l i ti b t t f th i ibl t H hi l bequilibration and acyl migration, but not for the irreversible step, H = chiral carbon, convertible for equilibration, acyl migration and irreversible step, I = chiral carbon, convertible for acyl migration, stable chirality.

DYKAT (or pseudo-DKR) of asymmetric 1,4-diols via lipase catalyzed acyl-transfer in combination with Ru-catalyzed epimerization of hydroxyl groups. y p y y g pW=achiral carbon, accessible for reduction.B. Martin‐Matute, J.‐E. BQckvall, J. Org. Chem. 2004, 69, 9191 – 9195.

A.‐B. L. Fransson, Y. Xu, K. Leijondahl, J.‐E. BQckvall, J. Org. Chem. 2006, 71, 6309 –6316.

DYKAT type IVDYKAT type IV

C+D=achiral substrates; ERS/ESR & ERR/ ESS=enantiomeric pairs of diastereomericinitial products; FRS/FSR & FRR/FSS = enantiomeric pairs of diastereomeric final products; kRR’ through kSS’=equilibration rates of formation ERS/ESR & ERR/ ESS;products; kRR through kSS equilibration rates of formation ERS/ESR & ERR/ ESS; kRR’’ through kSS’’=rates of irreversible formation of FRS/FSR & FRR/FSS.

DYKAT type IVDYKAT type IV

One-pot synthesis of polyketide sugars from racemicp y p y gβ-hydroxy aldehydes using an organo - catalyzedDYKAT type IV.E. Reyes, A. Cordova, Tetrahedron Lett. 2005, 46, 6605 –6609

The ability of amino acids to catalyze the asymmetric formation of sugarsmay have prebiotic significance. Extraterrestrial amino acids with up to 9%y p g pee have been isolated from the Murchison meteorite.The presence ofextraterrestrial and prebiotic amino acids with a minor amount ofenantiomeric excess suggests, plausibly, that amino acids catalyzedenantiomeric excess suggests, plausibly, that amino acids catalyzedasymmetric aldol reactions according to the routes presented, andtransferred their chiral information to tetroses and hexoses,which are thebuilding blocks of prebiotic RNA and most common polysaccarides Inbuilding blocks of prebiotic RNA and most common polysaccarides. Inaddition, the intrinsic catalytic activity of amino acids when reacting withaldehydes in water to give carbohydrates, according to the mechanismpresented gives rise to the possibility that this reaction may be occurringpresented, gives rise to the possibility that this reaction may be occurringcurrently, either on earth, or elsewhere in universe.

A. Cordova, I. Ibrahem, J. Casas, H. Sunden, M. Engqvist, E. Reyes, Chem. Eur. J. 2005, 11, 4772 –4784.

DYKAT type IVDYKAT type IV

Bi-enzymatic dynamic kinetic asymmetric transformation based on reversible J. Steinreiber, M. Schurmann, M.  Wolberg,  F. van Assema, C. Reisinger, K. Fesko, D. Mink,  H. aldol reaction followed by irreversible decarboxylation.Griengl, Angew. Chem. 2007, 119, 1648 – 1651; Angew. Chem. Int. Ed. 2007, 46, 1624 –1626.

J. Steinreiber, M. SchGrmann, F. van  Assema, M.  Wolberg, K. Fesko, C. Reisinger, D. Mink, H. Griengl, Adv. Synth. Catal. 2007, 349, 1379 – 1386.

L TA D TA d t i l d i i id t b li / t b liL-TA, D-TA, and most enzymes involved in amino acid metabolism/catabolismare highly Cα selective (l/d), while the Cβ selectivity is disappointingly low forboth L-TA and D-TA (kinetic limitation, syn/anti).

L-Amino acid decarboxylases are known to be highly substrate specific. OnlyL-tyrosine decarboxylase (L-TyrDC, PLP-dependent) was shown to tolerate any y ( y p )additional hydroxy group in the β position and to be tolerant towards aromaticsubstituents.L-TyrDC is highly selective with respect to the NH2-bound carbonatom, and only the L enantiomer is transformed.

J. Steinreiber, M. Schurmann, M. Wolberg, F. van Assema, C. Reisinger, K. Fesko, D. Mink, 

atom, and only the L enantiomer is transformed.

, , g, , g , , ,H. Griengl, Angew. Chem. 2007, 119,1648 – 1651; Angew. Chem. Int. Ed. 2007, 46, 1624 –1626.

Combined KR/DYKAT strategy: