ASY M METRIC CATALYSIS: SCIE NCE A N D OPP ORT U NITIES Nobel Lecture, Dece mber 8, 2001 by R Y OJI N OY O RI Depart ment of Che mistry, Graduate School of Science, and Research Center of Materials Scie nce, Nagoya U niversity, C hikusa, Nagoya 464-8602, Japa n. PR OL OGUE C hirality ( ha n de d ness; left or rig ht) is a n i ntri nsic u niversal feat ure of vari o us levels of matter[1]. Molec ular c hirality plays a key role i n scie nce a n d tec h- n ol o gy. I n p arti c ul ar, lif e d e p e n ds o n m ol e c ul ar c hir ality, i n t h at m a ny bi ol o- gical functions are inherently dissy m metric. Most physiological pheno mena arise fro m highly precise molecular interactions in which chiral host mo- lecules recog nize t wo e na ntio meric guest molecules i n differe nt ways. T here are nu merous exa mples of e na ntio mer effects w hic h are freque ntly dra matic. Enantio mers often s mell and taste differently. The structural difference bet wee n e na natio mers ca n be serio us wit h res pect to t he actio ns of sy nt hetic drugs. C hiral receptor sites i n t he hu ma n body i nteract o nly wit h drug mo- lecules havi ng t he proper absolute co n figuratio n, resulti ng i n marked diffe- rences in the phar macological activities of enantio mers. A co mpelling ex- a mple of the relationship bet ween phar macological activity and molecular c hirality was provi de d by t he tragic a d mi nistratio n of t hali do mi de to preg na nt wo men in the 1960s. ( R )- Thalido mide has desirable sedative properties, w hil e its S e na ntio mer is teratoge nic a nd i nduces fetal malfor matio ns[2,3]. Such proble ms arising fro m inappropriate molecular recognition should be avoi de d at all costs. Nevert heless, eve n i n t he early 1990s, abo ut 90 % of sy n- t hetic c hiral drugs were still race mic – t hat is, equi molar mixtures of bot h e na ntio mers, re flecti ng t he dif fic ulty i n t he practical sy nt hesis of si ngle e na n- tio meric co mpounds[4]. In 1992, the Food and Drug Ad ministration in the US i ntroduced a guideli ne regardi ng “race mic s witc hes”, i n order to e ncou- rage t he co m mercializatio n of cli nical drugs co nsisti ng of si ngle e na ntio- mers[5]. S uc h marketi ng reg ulatio ns for sy nt hetic dr ugs, co u ple d wit h rece nt pr ogress i n stere oselective orga nic sy nt hesis, res ulte d i n a sig ni fica nt i ncrease i n t he pro portio n of si ngle-e na ntio mer dr ugs. I n 2000, t he worl d wi de sales of si ngle e na ntio mer co mpou nds reac hed 123 billio n US dollars[6]. T hus, gai n- ing access to enantio merically pure co mpounds in the develop ment of phar- mace uticals, agroc he micals, flavors, is a very sig ni fica nt e n deavor. Discovery of tr uly ef ficie nt met ho ds to ac hieve t his has bee n a s ubsta ntial c halle nge for c he mists i n bot h acade mia a nd i ndustry. Earlier, e na ntio meri- 1 8 6 cally pure co mpou nds were obtai ned by t he classical resolutio n of a race mate or tra nsfor matio n of rea dily accessible nat urally occ urri ng c hiral co m po u n ds s uc h as a mi no aci ds, tartaric a n d lactic aci ds, carbo hy drates, ter pe nes, or al- kaloids. Eve n t houg h stereoselective co nversio n of a proc hiral co mpou nd to a c hiral product, na mely, t hroug h a n asy m metric reactio n is t he most attrac- tive a p proac h, practical access to p ure e na ntio mers relie d largely o n bioc he- mical or biological met hods. Ho wever, t he scope of suc h met hods usi ng e n- zy mes, cell cultures, or whole microorganis ms is li mited because of the i n here nt si ngle- ha n de d, lock-a n d-key s peci ficity of biocatalysts. O n t he ot her ha n d, a c he mical a p proac h allo ws for t he flexible sy nt hesis of a wi de array of enantiopure organic substances fro m achiral precursors. The require ments for practical asy m metric sy nt hesis i ncl u de hig h stereoselectivity, hig h rate a n d pro d uctivity, ato m eco no my, cost ef ficie ncy, o peratio nal si m plicity, e nviro n- mental friendliness, and lo w energy consu mption. Traditional asy m metric synthesis using a stoichio metric a mount of a chiral co mpound, though con- ve nie nt for s mall to me di u m scale reactio ns, is practical o nly if t he ex pe nsive c hiral a uxiliary deliberately attac he d to a s ubstrate or reage nt is rea dily re- cycla ble; ot her wise it is a wastef ul pr oce d ure. Fig ure 1 ill ustrates a ge neral pri nci ple of asy m metric catalysis w hic h pro- vi d es a n i d e al w ay f or m ulti plyi n g m ol e c ul ar c hir ality [ 7 ]. A s m all a m o u nt of a well-desig ned c hiral catalyst ca n co mbi ne A a nd B, produci ng t he c hiral A B co m po u n d stereoselectively i n a large q ua ntity. Of vario us possibilities, t he use of c hiral orga no metallic molecular catalysts would be t he most po werful strategy for t his p ur pose. Asy m metric catalysis is a n i ntegrate d c he mical a p- proach where the maxi mu m chiral efficiency can be obtained only by a co m- bination of suitable molecular designing with proper reaction conditions. The reaction must proceed with a high turnover nu mber ( T O N) and a high turnover frequency ( T OF), while the enantioselectivity ranges fro m 50:50 Fi g ure 1. A ge neral pri nciple of asy m metric catalysis wit h c hiral orga no metallic molecular catalysts. M = metal; A, B = reacta nt a n d s u bstrate. 1 8 7 ( no nselective) to 100:0 ( perfectly selective). T he c hiral liga n ds t hat mo dify intrinsically achiral metal ato ms must possess suitable three-di mensional str uct ures a n d f u nctio nality to ge nerate s uf ficie nt reactivity a n d t he desire d stereoselectivity. So meti mes t he pro perties of ac hiral liga n ds are also i m por- ta nt. T he c hiral catalyst ca n per mit ki netic ally precise discri mi natio n a mo ng e n a nti ot o pi c at o ms, gr o u ps, or f a c es i n a c hir al m ol e c ul es. Si mil arly, e n a nti o- m eri c m ol e c ul es c a n als o b e dis cri mi n at e d. C ert ai n w ell- d esi g n e d c hir al m et al catalysts not o nly accelerate t he c he mical reactio ns re peate dly b ut also diffe- re ntiate bet wee n diastereo meric tra nsitio n states ( TSs) wit h a n acc uracy of 10 kJ/ mol. I n t his way suc h co mpact molecular catalysts wit h a molecular weig ht less t ha n 1000, or <20 Å i n le ngt h or dia meter, allo w for a n i deal met ho d for sy nt hesizi ng e na ntio meric co mpou nds. T he diverse catalytic activities of me- t alli c s p e ci es as w ell as t h e virt u ally u nli mit e d str u ct ur al v ari ati o n of t h e or g a- nic liga n d provi des e nor mo us o p port u nities for asy m metric catalysis. DISC OVERY OF ASY M METRIC CATALYSIS VIA C HIRAL ORGAN O METALLIC C O MPLEXES I n 1966, w he n I was i n H.