Enantiomerically pure catalyst

Another interesting issue is the possibility of creating optically active compounds with racemic catalysts. The term chiral poisoning has been coined for the situation where a chiral substance deactivates one enantiomer of a racemic catalyst. Enantiomerically pure (R,R)-chiraphos rhodium complex affords the (iS )-methylsuccinate in more than 98% ee when applied in the asymmetric hydrogenation of a substrate itaconate.109 An economical and convenient method... 

When partially resolved samples of 5-hydroxymethylpyrrolidin-2-one are allowed to react with benzaldehyde in the presence of an acid catalyst, two products, A (C12H13NO2) and B (C24H26N2O4), are formed. The ration A B depends on the enantiomeric purity of the starting material. When the starting material is optically pure, only A is formed. When it is racemic, only B is formed. Partially resolved material gives both A and B. The more nearly it is enantiomerically pure, the less B is formed. The products A is optically active but B is achiral. Develop an explanation for these observations, including structures for A and B. 

A versatile synthetic route to enantiomeric ally pure Diels-Alder adducts was deduced and found dependent on the application of enantiomerically pure 5-methoxy-174a (R=Me) and 5-(l-menthyloxy)-2(5//)-furanones 174b (R = menthyl), which were expected to undergo tt-face-selective cycloaddition with dienes. The reaction was effected by heating no Lewis acid catalysts were required (Scheme 55) (88JOC1127). 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

Two methods are used in practice to obtain enantiomerically pure amino acids. One way is to resolve the racemic mixture into its pure enantiomers (Section 9.8). A more direct approach, however, is to use an enantioselective synthesis to prepare only the desired 5 enantiomer directly. As discussed in the Chapter 19 Focus Oil, the idea behind enantioselective synthesis is to find a chiral reaction catalyst that will temporarily hold a substrate molecule in an unsymmetrical environment. While in that chiral environment, the substrate may be more... 

In light of the previous discussions, it would be instructive to compare the behavior of enantiomerically pure allylic alcohol 12 in epoxidation reactions without and with the asymmetric titanium-tartrate catalyst (see Scheme 2). When 12 is exposed to the combined action of titanium tetraisopropoxide and tert-butyl hydroperoxide in the absence of the enantiomerically pure tartrate ligand, a 2.3 1 mixture of a- and /(-epoxy alcohol diastereoisomers is produced in favor of a-13. This ratio reflects the inherent diasteieo-facial preference of 12 (substrate-control) for a-attack. In a different experiment, it was found that SAE of achiral allylic alcohol 15 with the (+)-diethyl tartrate [(+)-DET] ligand produces a 99 1 mixture of /(- and a-epoxy alcohol enantiomers in favor of / -16 (98% ee). 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

D. Hoppe, Synthesis of Enantiomerically Pure Unnutural Compounds via Nonhiomimetic Ho-moaldol Reactions in Enzymes as Catalysts in Organic Synthesis, M. P. Schneider, Ed., pp 177-198, D. Reidcl, Dordrecht 1986. 

Ar R Enantiomerically Pure Catalyst (equiv) Time (h) ggil.C.tl (%) Yield (%)... 

For a chiral molybdenum-based catalyst available in situ from commercial components, see (a) Aeilts SL, Cefalo DR, Bonitatebus PJ, Houser JH, Hoveyda AH, Schrock RR (2001) Angew Chem Int Ed 40 1452 (b) For the first enantiomerically pure solid-sup-ported Mo catalyst, see Hultzsch KC, Jernelius JA, Hoveyda AH, Schrock RR (2002) Angew Chem Int Ed 41 589 (c) For a chiral Mo catalyst, allowing RCM to small- and medium-ring cyclic amines, see Dolman SJ, Sattely ES, Hoveyda AH, Schrock RR (2002) J Am Chem Soc 124 6991 (d) For a novel adamantyl imido-molybdenum complex with advanced selectivity profiles, see Tsang WCP, Jernelius JA, Cortez GA, Weatherhead GS, Schrock RR, Hoveyda AH (2003) J Am Chem Soc 125 2591... 

In recent years, a great variety of primary chiral amines have been obtained in enantiomerically pure form through this methodology. A representative example is the KR of some 2-phenylcycloalkanamines that has been performed by means of aminolysis reactions catalyzed by lipases (Scheme 7.17) [34]. Kazlauskas rule has been followed in all cases. The size of the cycle and the stereochemistry of the chiral centers of the amines had a strong influence on both the enantiomeric ratio and the reaction rate of these aminolysis processes. CALB showed excellent enantioselec-tivities toward frans-2-phenylcyclohexanamine in a variety of reaction conditions ( >150), but the reaction was markedly slower and occurred with very poor enantioselectivity with the cis-isomer, whereas Candida antarctica lipase A (GALA) was the best catalyst for the acylation of cis-2-phenylcyclohexanamine ( = 34) and frans-2-phenylcyclopropanamine ( =7). Resolution of both cis- and frans-2-phenyl-cyclopentanamine was efficiently catalyzed by CALB obtaining all stereoisomers with high enantiomeric excess. 

These catalysts were first tested as resin-bound derivatives via HTS, first with metals and then without. Three libraries of chiral molecules, based on three different enantiomerically pure diamines, bulky salicylidene moities and optically active ii-amino acids were used for structure optimisation (Scheme 37 TBSCN = fBuMe2SiCN) [152]. 

Asymmetric catalysts these are still relatively rare in industrial processes but they are playing an increasingly important role in the development of pharmaceuticals. This is because they offer one of the most efficient, low-waste methods for producing enantiomerically pure compounds. 

---