Lecture 1c

1. Lecture 1c Asymmetric Synthesis

2. Assigned reading • Hanson, J. J. Chem. Educ.2001, 78(9), 1266 (including supplemental material). • Larrow, J.F.; Jacobsen, E.N. Org. Synth.1998, 75, 1. • Cepanec, I. et al. Synth. Commun. 2001, 31(19), 2913. • Flessner, T.; Doye, S. J. Prakt. Chem.1999, 341, 436. • McGarrigle, E.M.; Gilheany, D.G. Chem. Rev.2005, 105(5), 1563. • Schurig, V.; Nowotny, H.P. Angew. Chem. Int. Ed. Engl. 1990, 29(9), 939. • Sharpless, B. Angew. Chem. Int. Ed. Engl. 2002, 41, 2024. • Katsuki, T. Coord. Chem. Rev.1995, 140, 189. • Kunkely, H.; Vogler, A. Inorg. Chem. Comm.2001, 4, 692. • Trost, B. PNAS2004, 101, 5348 • Yoon, J.W.; Soon, W.L.; Shin, W. Acta Cryst .1997, C53, 1685. • Yoon, J.W.; Yoon, T.; Soon, W.L.; Shin, W. Acta Cryst.1999, C55, 1766.

3. Why asymmetric synthesis? • Chirality plays a key role in many biological systems i.e., DNA, amino acids, sugars, terpenes, etc. • Many commercial drugs are sold as single enantiomer drugs because often only one enantiomer (eutomer) exhibits the desired pharmaceutical activity while the other enantiomer is inactive or in many cases even harmful (distomer) • (*) These drugs are isomerized in vivo

4. History of Asymmetric Synthesis I • 1848: Louis Pasteur discovers the chirality of sodium ammonium tartrate • 1894: Hermann Emil Fischer outlined the concept of asymmetric induction • 1912: G. Bredig and P.S. Fiske conducted one of the first well documented enantioselective reactions (addition of hydrogen cyanide to benzaldehyde in the presence of quinine with 10% e.e.) • 1960ties: Monsanto uses transition metal complexes for catalytic hydrogenations i.e., Rh-DIPAMPforL-dopa(Parkinson disease, 95% e.e.) • 1980ties : R. Noyori developed hydrogenation catalyst using rhodium or ruthenium complexes of the BINAPligand

5. History of Asymmetric Synthesis II • 1980: T. Katsukiand K.B. Sharpless develop chiral epoxidation of allylic alcohols (90% e.e., but moderate yields!) • They attribute the high selectivity to the in-situ formation of a chiral, dinuclear Ti-complexes • The alkene is tied to the reaction center by the allylic hydroxyl function • This places the peroxide function in close proximity to the alkene function • The reaction is usually carried out at low temperatures (-23 oC) and is very sensitive towards water

6. History of Asymmetric Synthesis III • Example: Sharpless epoxidation is used to prepare (+)-disparlure, a sex pheromone, that has been used to fight Gypsy moths through mating disruption (note that the (-) enantiomer is a deterrent and reduces trap captures) • The Sharpless epoxidation is also used to obtain intermediates in the preparation of methymycin and erythromycin(both macrolide antibiotic) • The Nobel Prize in Chemistry in 2001was awarded to three pioneers in the field: K. B. Sharpless, R. Noyori, W. S. Knowles

7. How do chemists control chirality? • Chiral pool: optically active compounds that can be isolated from natural sources (i.e., amino acids, monosaccharides, terpenes, etc.) and can be used as reactants or as part of a chiral catalyst or a chiral auxiliary • The TADDOL and DIOP ligand have tartaric acid as chiral backbone • Enzymatic process: very high selectivity, but it needs suitable substrates and well controlled conditions • The Lipitor synthesis requires halohydrindehalogenase, nitrilase, aldolase • Chiral reagent: it exploits differences in activation energies for alternative pathways • Chiral auxiliary: it is a chiral fragment that is temporarily added to the molecule to provide control during the key step of the reaction and is later removed from product

8. How do chemists control chirality? • Energy differences in transition states (DDG‡) • Bottom line • The higher the energy difference in the transition states is the higher the selectivity will be at a given temperature • The lower the temperature, the more selective the reaction will be at a given difference in transition energy

9. Chiral Reagent • Example: Enantioselective reduction of aromatic ketones using BINAL-H • The enantioselectivity for the reaction increases from R=Me (95 %) to R=n-Bu (100 %), but decreases for R=iso-Pr (71 %) and R=tert.-Bu (44 %) due to increased 1,3-diaxial interactions in the six-membered transition state

10. Chiral Auxiliary I Front view • Evans (1982): Oxazolidinones for chiral alkylations • The oxazolidinoneis obtained from L-valine (via a reduction to formL-valinol, which is reacted with either urea or diethyl carbonate under MW conditions) • The iso-propyl group in the auxiliary generates steric hindrance for the approach from the same side in the enolate (the high-lighted atom is the one which is deprotonated) • Chiral auxiliaries • The auxiliary has to be close to reaction center, but not slow down the reaction significantly or change the structure in the transition state • The auxiliary should be easily removed without loss of chirality • It should be readily available for both enantiomers Side view

11. Chiral Auxiliary II • In 1976, E. J. Corey and D. Enders developed the SAMPand RAMP approach that uses cyclic amino acid derivatives ((S)-proline for SAMP, (R)-glutamic acid for RAMP) and hydrazones to control the stereochemistry of the product. • Below is an example for the use of SAMP in an asymmetric alkylation reaction. • The condensation of SAMP with a ketone affords an E-hydrazone • The deprotonation with LDA leads to the enolate ion that undergoes alkylation from the backside • The chiral auxiliary is removed by ozonolysis