Enzymes in Functional Group Transformation: Lipases in Asymmetric Synthesis, Slides of Biochemistry

Download Enzymes in Functional Group Transformation: Lipases in Asymmetric Synthesis and more Slides Biochemistry in PDF only on Docsity! Module 9: Enzymes in Functional G T f tiroup rans orma on Lecture23: Enzymes in Functional Group Transformation 1 Docsity.com Lipases in asymmetric synthesis 1. EKR (enzymatic kinetic resolution) A B + C racemic fast reacting enantiomer slow reacting enantiomer E 2. EED (enantioseletive enzymatic desymmetrization) Maximum 50% yield can be obtianed for individual enantiomers XH XH XY XH XH XH XY XH hi l E E X = O, NH, SH pro-c ra enantiopure meso enantiopure Maximum 100% yield can be obtained for individual enantiomers 3. Dynamic kinetic resolution (DKR) A (+)-product E *A and A' are enantiomers; racemization can be done enzymatically or by means of other methods. A' (-)-productX * Maximum 100% yield can be obtained for individual enantiomers Docsity.com Enantioselectivity factor in EKR * The enantioselectivity named as enantiomeric ratio (E) measures the ability of a enzyme to distinguish between enantiomers. * A non selective reaction has an E 1, while resolutions with E's above 20 are useful for synthetic purpose. * To calculate E one measures two of the three variables: enantiomeric purity of product (eep) , , enantiomeric purity of substrtae (ees) and extent of conversion (c) and then follows any of the following three equations developed by Sih. E = ln[1- ees/1 + (ees/eep)] ln[1+ ees/1 + (ees/eep)]E = ln [1-c (1+eep)] l [1 (1 )] eq 1 eq 3 n -c -eep ln [(1-c) (1-ees)] /( + ) E = ln [(1-c) (1+ees)] eq 2c = ees ees eep Often enantiomeric purities (ees and eep) are more correctly measured than conversion; in these cases the eq 3 is more accurate Docsity.com Survey of enantioselective lipase catalyzed reactions * In the next few slides we will try to cover a detailed literature survey on different substrates which have been synthesized by lipase catalyzed EKR or EED strategy. Secondary alcohols OH secondary alcohols are the most common substrates for lipases. M L Kazlauskas emperical rule to predict which enantiomer of a secondary alcohol reacts faster in lipase catalysed EKR. M= medium sized substutuents; L = Large substituents There must be enough steric differences between M and L to have efficient resolution. CAL-B and PCL are the most enantioselective lipases towards secondary alcohols. Docsity.com Selected examples of 2-alkanols resolved by CAL-B OH OH OH n OH OH N OH OH OH E >150, S-ethyl thiooctanoate E >100, vinylacetate n = 6, E >100 S-methyl thioacetate R OH OH OH OH OH OH OH R E Bn 2 Ph 35 1-naphthyl 57 N N N Br OH 2-naphthyl 66 Diketene E >100, S-ethyl thiooctanoate 73-99% ee for diacylated products N OH R N OH N R OH X OH RR = H, Br, CH2OTBS, CH2OTr, Ph E >100; vinyl acetate R = H, Br, CH2OTBS R = H, E = 1.3 R = TMS, E > 100 X = Cl, Br E >100 Docsity.com OH N HOH OH Selected examples of cyclic 2-alkanols resolved by CRL R MeO2C R = Et, C6H13, Ph E >50 hydrolysis of acetate E = 10 vinyl acetate OH O OH S S R OH OHOH Ph OBn OH OH OH OH E = 24 vinyl acetate E = 20-100; R = n-alkyl CRL, E > 100 vinyl acetate CF3n OH Ph Ph C5H11 SPh SPh O2N E >100, vinyl acetate E >50 vinyl acetate E >100h d l i f t t E = 11 isopropenyl acetate CCl OAc MeO y ro ys s o ace a e substituents with similar sizes3 E > 50 hydrolysis of acetate Docsity.com OH OH H OH H OH Br OH Selected examples of cyclic secondary alcohols resolved by CRL H H O Ph Ph N HO R E = 50, hydrolysis of butyrate E = 27, hydrolysis of acetate E = 125 vinyl acetate E = 61-64 hydrolysis of butyrate R iP Ph OH OH Ar OH OtBu N N3 OAc Br OAc Br = r, E 10 t 50 E = 50 3 Br OAc Br OAc OH O O OH N OH = o transesterification or hydrolysis of acetate Ar = Ph, 4tBuPh transesterification E > 100 hydrolysis of butyrate regioselective hydrolysis of diacetate O N F O 3 CO2Me R OH E = 20 E = 39 hydrolysis of acetate CRL E 8 24 OH OAc OH OMe OTBS OH Ph E >50, hydrolysis of formate , = - R = OM e, Cl, Br, I, SM e hydrolysis of butanoate OAc OMe O98% ee hydrolysis of diacetate (EED) ee = 98% hydrolysis of diacetate (EED) E = 36-76 vinyl acetate Docsity.com OH OH Selected examples of 2-alkanols resolved by PPL R OH E = 26, vinyl acetate E = 90, trifluoroethyl laurate E = 100, trifluoroethyl laurate R = Et, E = 2.5 R = Pr, E = 52 OH n OH OH R = Bu, E > 100 R = C5H11, E = 92 R = C8H18, E >100 CO2Et On = 0, E = 41 n = 1, E > 100 n = 2, E > 100 n = 3, E >80 trifluoroethyl laurate E = 70, trifluoroethyl butyrate E = 20, methyl propanoate E = 100, vinyl acetate OH OH OH E = 60 trifluoroethyl butyrate OH OH OH , E = 65, trifluoroethyl laurate E = 15-29, trifluoroethyl laurate Ph SnMe3E > 100, vinyl butyrate E = 50, Vinyl acetate E = 100, trifluoroethyl pentanoate Docsity.com