Lecture 1c

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), Flessner, T.; Doye, S. J. Prakt. Chem. 1999, 341, 436. McGarrigle, E.M.; Gilheany, D.G. Chem. Rev. 2005, 105(5), Schurig, V.; Nowotny, H.P. Angew. Chem. Int. Ed. Engl. 1990, 29(9), 939. Sharpless, B. Angew. Chem. Int. Ed. Engl. 2002, 41, Katsuki, T. Coord. Chem. Rev. 1995, 140, 189. Kunkely, H.; Vogler, A. Inorg. Chem. Comm. 2001, 4, 692. Trost, B. PNAS 2004, 101, 5348 Yoon, J.W.; Soon, W.L.; Shin, W. Acta Cryst.1997, C53, Yoon, J.W.; Yoon, T.; Soon, W.L.; Shin, W. Acta Cryst. 1999, C55, 1766.

Chirality When we talk about chirality, we usually refer to asymmetrically substituted carbon atoms However, other atoms can also act as chiral centers i.e., nitrogen, phosphorus, sulfur, etc. Chirality is not limited to the presence of stereogenic atoms but also can be caused by hindered rotations (atropisomerism) CyclanolineVX (nerve agent)Esomeprazole (Nexium)

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 DrugR-enantiomerS-enantiomer ThalidomideMorning sicknessTeratogenic* IbuprofenSlow actingFast acting* ProzacAnti-depressantHelps against migraine NaproxenLiver poisonArthritis treatment MethadoneOpioid analgesicNMDA antagonist DopaBiologically inactiveParkinson’s disease

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-DIPAMP for L-dopa (Parkinson disease, 95 % e.e.) 1980ties : R. Noyori developed hydrogenation catalyst using rhodium or ruthenium complexes of the BINAP ligand

History of Asymmetric Synthesis II 1980: T. Katsuki and 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 (-20 o C), is very sensitive towards water and require up to 18 hours to complete The yields are moderate (77 % for the reaction above) due to the increased water solubility of the products

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 2001 was awarded to three of the pioneers in the field: K. B. Sharpless, R. Noyori, W. S. Knowles

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, DIOP and the Chiraphos 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 halohydrin dehalogenase, nitrilase, aldolase The reduction of benzil using cryptococcus macerans leads to the formation of (R,R)-hydrobenzoin (dl:meso=95:5, 99 % e.e.) 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

How do Chemists control Chirality? By manipulating the energy differences in transition states (  G ‡ ) 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 T\  G ‡ 4000 J

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

Chiral Auxiliary I Evans (1982): Oxazolidinones for chiral alkylations The oxazolidinone is obtained from L-valine (via a reduction to form L-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) Front view Side view

Chiral Auxiliary II In 1976, E. J. Corey and D. Enders developed the SAMP and 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

Chiral Auxiliary III Chiral Auxiliaries (Summary) The desired enantiomer should be obtained in high purity and high chemical yield, preferably without extended purification required. It should ideally be available in both enantiomeric forms. The chiral auxiliary should be close to the reacting center, but not adversely affect the rate of reaction. If the directing group is too large, it will slow down the reaction too much or even can cause changes in conformation in the substrate, which is highly undesirable. The final product must be readily separable from any chiral auxiliary. The incorporation and removal of any chiral auxiliary should be chemically efficient and achieved without loss of optical activity of the product and the auxiliary (recovery). For catalytic processes, the turnover number has to be high.

Chiral Catalyst In Chem 30CL, a chiral catalyst is used to form a specific enantiomer of an epoxide