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. Nozaki’s laboratory at Kyoto, we discovere d t he first exa m ple of asy m metric catalysis usi ng a str uct urally well- de fi ne d c hiral tra n- sitio n metal co mplex[8]. T his fi ndi ng resulted fro m researc h do ne for a n e n- tirely different purpose which was to elucidate the mechanis m of carbene r e a cti o ns. As ill ustr at e d i n Fi g ur e 2, w h e n a s m all a m o u nt ( 1 m ol % ) of a c hi- ral Sc hiff base– Cu(II) co mplex was used as a molecular catalyst i n t he reac-

Fi g ure 2. Discovery of asy m metric reactio n by mea ns of a c hiral orga no metallic molecular catalyst. P hoto: Professor H. Nozaki (1985).

1 8 8 tio n of styre ne a nd et hyl diazoacetate, t he cis - a n d tr a ns -cyclopropa necar- boxylates were obtai ne d i n 10 a n d 6 % e na ntio meric excess (ee), res pectively. We also observed asy m metric induction in carbene insertion to a C– O bond of 2- p he nyloxeta ne givi ng o ptically active 2,3-s ubstit ute d tetra hy drof ura n de- rivatives. At t hat ti me, t he fi n di ng was sy nt hetically pri mitive si nce t he degree of e na nti oselecti o n was mea ni ngless practically. Later, T. Arata ni, a Ky ot o st u- de nt, we nt to Su mito mo C he mical Co., w here he i nve nted a n excelle nt c hiral C u catalyst for asy m metric cyclo pro pa natio n, ac hievi ng t he i n d ustrial sy nt he- sis of c hrysa nt he mates (ef ficie nt i nsecticides) a nd ( S )-2,2-cyclo pro pa necar- b o xyli c a ci d. T h e l att er c o m p o u n d is a b uil di n g bl o c k of cil ast ati n, a n i n viv o stabilizer of the carbapene m antibiotic, i mipene m ( Merck Co.) (Figure 3 ) [ 9 ].

ASY M METRIC HYDR OGENATI ON IN T HE EARLY DAYS At prese nt t he asy m metric cyclopropa natio n is i mporta nt practically, but i n t h e l at e 1 9 6 0s, it w as j ust a s p e ci al r e a cti o n i n or g a ni c sy nt h esis. I d e ci d e d t o pursue hydrogenation, which is a core technology in che mistry. It is the

Fi g ure 3. Su mito mo asy m metric cyclopropanation. a) Useful chiral cyclopropanes and b) reactio n a p parat us.

1 8 9 si mplest but most po werful way to produce a wide array of i mportant co m- pounds in large quantities using inexpensive, clean hydrogen gas without for mi ng a ny waste. Hydroge natio n was i nitiated at t he e nd of t he 19t h ce n- t ury by P. Sabatier (1912 Nobel la ureate) w ho use d fi ne metal particles as he- teroge neous catalysts. So me notable ac hieve me nts t hat attracted me, before doi ng researc h i n t his area, i ncl u de: activatio n of H 2 by a tra nsitio n metal co mplex in the late 1930s ( M. Calvin, 1961 Nobel laureate)[10]; ho mogene- ous hydrogenation of olefinic substrates with Ru Cl 3 i n 1961 (J. Hal per n, J. Harrod, and B. R. Ja mes)[11]; and hydrogenation of olefinic co mpounds using Rh Cl[P( C 6 H 5 ) 3 ] 3 in 1965 ( G. Wilkinson, 1973 Nobel laureate)[12]. Most i mportantly, in 1956, S. Akabori at Osaka reported that metallic Pd dra wn on silk catalyzes asy m metric (heterogeneous) hydrogenation of oxi- mes a nd oxazolo nes[13]. T his pio neeri ng work, t houg h not effective sy nt he- tically, was alrea dy well k no w n t hro ug ho ut Ja pa n. I n 1968, t wo years after o ur asy m metric cyclopropanation in 1966, W. S. Kno wles (fello w Nobel laureate in 2001)[14] and L. Horner[15] reported independently the first ho moge- neously catalyzed asy m metric hydroge natio n of ole fi ns wit h c hiral mo node n- tate tertiary p hosp hi ne– R h co mplexes, albeit i n 3–15 % optical yield[16]. H. B. Kaga n provided a major breakt hroug h i n t his area i n 1971, w he n he devi- s e d DI O P, a C 2 c hiral di p hos p hi ne derive d fro m tartaric aci d. He use d its R h co mplex for asy m metric hydrogenation of dehydro a mino acids leading to phenylalanine in about 80 % ee, then recorded as 72 % ee[17]. The Kno wles group at Monsanto established a method for the industrial synthesis of L- D OP A, a drug for treati ng Parki nso n’s disease, usi ng his DIP A MP– R h cataly- zed asy m metric hydroge natio n as a key step[18]. T hese ac hieve me nts sig ni fi- ca ntly sti m ulate d t he s ubseq ue nt i nvestigatio n of t his i m porta nt s ubject. S hortly after movi ng fro m Kyoto to Nagoya i n 1969–70, I spe nt a postdoc- toral year at Harvard wit h E. J. Corey (1990 Nobel laureate). He asked me to hy droge nate selectively o ne of t he t wo C = C bo n ds i n a prostagla n di n F 2 α d e- rivative t o t he F 1 α for m having only one C = C bond[19]. This research was helped by K. B. S harpless (a not her fello w Nobel laureate i n 2001) w ho was t he n a postdoctoral fello w wit h K. Bloc h (1964 Nobel laureate i n P hysiology or Medicine) and who suggested a convenient T L C technique for analyzing t he structurally very si milar ole fi nic co mpou nds. I n additio n to t his back- grou nd, my perso nal i nteractio n wit h J. A. Osbor n, a for mer Wilki nso n stu- dent and co-inventor of Rh Cl[P( C 6 H 5 ) 3 ] 3 [12] who was then an Assistant Professor at Harvard, greatly e n ha nced my i nterest i n asy m metric hydroge- natio n, w hic h later beca me my life-lo ng researc h i nterest. My desire was to develop a truly ef ficie nt asy m metric hydroge natio n w hic h would have a wide scope of applications. In the early 1970s, chiral phosphine– Rh co mplexes could hydrogenate satisfactorily only dehydro a mino acids but not many other olefins. Asy m metric hydrogenation of ketones was totally unex- pl ore d[20].

1 9 0 BI NAP, A BEA UTIF UL C HIRAL M OLEC ULE

H 2 is t he si mplest molecule but it has e nor mous pote ntial fro m bot h a scie n- tific and technical point of vie w. To discover high-perfor mance asy m metric c at alysts, d ev el o pi n g a n e x c ell e nt c hir al li g a n d is cr u ci al. Attr a ct e d by its m o- lecular beauty[21], we i nitiated t he sy nt hesis of BI N AP (2,2'-bis(dip he nyl- phosphino)-1,1'-binaphthyl)[22] in 1974 at Nagoya with the help of H. Takaya, my respected lo ng-ter m collaborator. BI N AP was a ne w fully aro matic, a xi ally dissy m m etri c C 2 c hiral di p hos p hi ne t hat wo ul d exert stro ng steric a n d electro nic i n flue nces o n tra nsitio n metal co mplexes. Its properties could be fi ne-t u ne d by s ubstit utio ns o n t he aro matic ri ngs. Ho wever, sy nt hesis of t his o pti c ally p ur e C 2 c hiral dip hosp hi ne was u nexpectedly dif ficult. I n 1976, for t he first ti me, we ma naged to obtai n optically active BI N AP starti ng fro m op- ti c ally p ur e 2, 2'- di a mi n o- 1, 1'- bi n a p ht hyl ( Fi g ur e 4 a ). H o w ev er, t his s e e mi n gly straig htfor ward sy nt hetic pat h way was not reproducible due to t he te nde ncy of t he c hiral i nter me diates to ca use race mizatio n[23]. I n 1978, we fo u n d a re- liable method for resolving race mic BI N AP with an optically active di me- t hyl(1-p he nylet hyl)a mi ne–Pd(II) c hloride co mplex[22], w hile later optically pure BI N AP beca me available more conveniently by resolution of BI N AP dioxide with ca mphorsulfonic acid or 2,3- O - dibe nzoyltartaric aci d (Fig ure 4b)[24,25]. Alt houg h t he elusive BI N AP was available, ac hievi ng our goal was

a) Irreproducible stereospecific synthesis

Fi g ure 4. Access to e na ntio merically pure BI N AP.

1 9 1 still i n t he dista nce. E na ntioselectivity of BI N A P– R h(I) catalyze d asy m metric hydroge natio n of α -(acyla mi no)acrylic aci ds was hig hly variable a n d not sa- tisfactory at t hat ti me, ee of t he c hiral products bei ng at most about 80 %. H o wever, we re mai ne d patie nt. I n 1980, six years after t he start, t ha nks t o t he uns werving efforts of my young associates, we published our first work on asy m metric sy nt hesis of a mi no acids of hig h e na ntio meric purity, up to 100 % ee, toget her wit h t he X-ray crystalli ne str uct ure of a catio nic BI N A P– R h( nor- bornadiene) co mplex[22,26].

BI N AP, a co nfor matio nally flexible atropiso meric C 2 di p h os p hi n e, c a n a c- co m modate a range of transition metals by rotating about the binaphthyl C(1)– C(1') pivot a n d C(2 or 2')– P bo n ds wit ho ut serio usly i ncreasi ng torsio- nal strai n, w hile t he res ulti ng seve n- me mbere d c helate ri ngs co ntai ni ng o nly s p 2 carbo n ato ms are i n tur n skeletally u na mbiguous. T he c hirality of BI N AP is tra ns mitte d to ot her metal coor di natio n sites t hro ug h t he c helate str uct u- re[22,26]. T he δ or λ geo metry is highly ske wed and deter mines the chiral dis p ositi o n of t h e P - p he nyl ri ngs t hat play a key role i n ge nerati ng o utsta n d- i ng c hirality- discri mi nati ng ability at t he reactive coor di natio n sites. T h us BI N AP-based metal co mplexes were expected to ex hibit hig h c hiral recog ni- ti o n a bility i n v ari o us c at alyti c r e a cti o ns i n a d diti o n t o hy dr o g e n ati o n.

ASY M METRIC SYNT HESIS OF MENT H OL The cationic BI N AP– Rh co mplex was best used in asy m metric iso merization of allylic a mi nes[27], realizi ng a n i n d ustrial sy nt hesis of (–)- me nt hol fro m myrce ne (Figure 5)[28]. T his resulted fro m a fruitful acade mic/i ndustrial

Fi g ure 5. Takasago me nt hol sy nt hesis.

1 9 2 collaboration between groups at Osaka University (S. Otsuka and H. Ta ni)[29], Nagoya U niversity ( R. Noyori), I nstit ute for Molec ular Scie nce ( H. Takaya), Sizuoka University (J. Tanaka and K. Takabe)[30], and Takasago I nter natio nal Co.(Figure 6). T he key step was t he asy m metric iso merizatio n of gera nyl diet hyla mi ne catalyze d by a n ( S )-BI N AP– Rh co mplex in T HF for ming ( R )-citro nellal e na mi ne, w hic h upo n hydrolysis gives ( R )- citr o n ell al i n 9 6 – 99 % ee. T his is far s u perior to t he 80 % ee of t he nat urally occ urri ng pro d uct available fro m rose oil. A mo ng various R h a nd ot her catalysts exa mi ned, t he BI N AP-based catio nic R h co mplex was t he most reactive a nd t he most stereo- selective. T he BI N A P– R h catalyst clearly differe ntiates bet wee n t he pro- S a n d pr o- R hydroge ns o n t he flexible allylic a mi ne skeleto n duri ng t he 1,3-supra- facial s hift t hat occurs via a nitroge n-triggered mec ha nis m[31]. T he asy m- metric reactio n is perfor med o n a ni ne-to n scale. T he full tec h nical re fi ne- me nts of t he positio n- a nd stereoselective additio n of diet hyla mi ne to myr- ce ne, givi ng t he starti ng gera nyla mi ne, a nd t he Z n Br 2 -catalyze d i ntra molec u- lar e ne reacti o n of ( R )-citro nellal, for mi ng iso p ulegol wit h t he t hree correct stereoge nic ce nters, allo we d for t he pro d uctio n of ter pe nic s ubstrates totali ng abo ut 1500 to ns per year at Takasago I nter natio nal Co. Most of t he ( R )- citr o- nellal is co nverted to 1000 to ns per year of (–)- me nt hol, o ne-t hird of t he w orl d d e m a n d. ( R )-7- Hydroxydi hydrocitro nellal t hus prepared is a perfu me- r y a g e nt t h at s m ells li k e lily of t h e v all ey. Its m et hyl et h er is a n i nt er m e di at e i n the synthesis of methoprene, a gro wth regulator of the yello w fever mos- q uit o[28,29].

Fi g ure 6. At t he Takasago pla nt for (–)- me nt hol sy nt hesis (Febr uary, 1984). Fro m t he left, K. Ta ni, H. Ta k ay a, R. N oy ori, S. Ots u k a, S. A k ut a g a w a, a n d H. K u m o b ay as hi.

1 9 3 ASY M METRIC HYDR OGENATI ON OF OLEFINS BY BINAP–R UT HENI U M C O MPLEXES Returning to the topic of asy m metric hydrogenation, our success resulted fro m t he i nve ntio n of t he BI N AP liga nd[32] a nd also fro m t he use of Ru ele- ment that behaves differently fro m conventional Rh[33,34]. The cationic BI N AP– Rh co mplexes catalyze hydrogenation of α -(acyla mi no)acrylic aci ds or esters to give t he corres po n di ng a mi no aci d derivatives of hig h ee (Fig ure 7)[22,23]. H o wever, t he reacti o n is relatively sl o w, a n d hig h e na nti oselectivity is obtai ned o nly u nder special co nditio ns probably due to operatio n of t he unsaturate/dihydride mechanis m. J. Halpern[35] and J. M. Bro wn[36] sho w- e d t hat hy droge natio n of e na mi des i n t he prese nce of a C 2 c hir al di p h os p hi n e – Rh co mplex proceeds via oxidative addition of H 2 to diastereo meric Rh– s ubstrate c helate co m plexes, follo we d by ste p wise tra nsfer of t he t wo hy dri des to t he coordi nated ole fi n. Most sig ni fica ntly, t he mi nor diastereo mer of t hese co mplexes is t he more reactive o ne[37]. Because of t he excelle nt c hiral re- cog nitio n ability of BI N A P, t he reactive s pecies, lea di ng to t he desire d hy dro- ge natio n product, is prese nt i n a very s mall qua ntity a nd is eve n N M R-i nvis- ible i n t he equilibriu m mixture[23a]. T herefore, co nditio ns suc h as hydro- gen pressure, te mperature, and concentration must be chosen carefully to obtai n hig h e na ntioselectivity. Furt her more, asy m metric hydroge natio n was li mite d to t he sy nt hesis of a mi no aci ds. A major breakthrough occurred when we devised the BI N AP– Ru(II) dicar- boxylate co mplexes in 1986 (Figure 8)[38,39]. The Ru co mplexes are excel- le nt catalysts for asy m metric hy droge natio n of vario us f u nctio nalize d ole fi ns, as su m marized in Figure 9. The reaction proceeds via a Ru monohydride in- ter mediate for med by heterolysis of H 2 by t he Ru co mplex. T he Ru ce nter re- mai ns i n t he +2 oxi datio n state t hro ug ho ut t he catalytic cycle[40] i n co ntrast to t he R h co mplex w hic h i nvolves a +1/+3 redox process. Heteroato ms i n t he fu nctio nal groups serve as a bi ndi ng tet her to t he catalytic Ru ce nter. T his hydroge natio n has a very wide scope. Hydroge natio n of α ,β - a n d β ,γ- u nsat u- rate d carboxylic aci ds takes place i n alco holic me dia, w here t he se nse a n d de-

Fi g ure 7. Asy m metric hydrogenation of α -(acyla mino)acrylic acids catalyzed by BI N AP– Rh co mplexes.

1 9 4 Fi g ure 8. Structures of BI N AP– Ru diacetate co mplexes.

gree of t he e na ntioselectio n are hig hly de pe n de nt o n t he s ubstit utio n patter n a nd hydroge n pressure[41]. Allylic a nd ho moallylic alco hols are also hydro- ge nated wit h hig h e na ntioselectio n[42]. Certai n race mic allylic alco hols ca n be resolved by the BI N AP– Ru catalyzed hydrogenation[43]. The chiral Ru co mplexes effect hig hly e na ntioselective hydroge natio n of ( Z )- 2- a cyl- 1- b e nzy- lidene-1,2,3,4-tetrahydroisoquinolines[38,44]. In a si milar manner, enan- ti o- e nri c h e d α - and β -a mino acids[45] as well as α -a mino phosphonic aci ds[46] are obtai nable fro m s uitably a mi do-s ubstit ute d ole fi ns. Notably, t he Ru(II) a nd R h(I) co mplexes possessi ng t he sa me BI N AP c hirality for m a nti- podal a mino acids as the predo minant products[47]. Figure 10 illustrates so me chiral co mpounds that can be obtained by t his asy m metric hydroge natio n. A n i mporta nt applicatio n is t he sy nt hesis of the anti-infla m matory drug, naproxen, in 97 % ee fro m an α - ar yl- a cr yli c acid[41,46]. Natural a nd u n natural citro nellol wit h up to 99 % ee are obtai n- able fro m gera niol or nerol wit hout saturatio n of t he C(6)– C(7) double bo nd wit h a hig h substrate to catalyst (S/ C) ratio. T he hydroge natio n of ( R ,E )-

1 9 5 Fi g ure 9. Asy m metric hydroge natio n of fu nctio nalized ole fi ns catalyzed by ( S )- BI N A P – R u di- car b oxylates.

1b- methylcarbapene m inter mediate

Fi g ure 1 0. Applicatio ns of BI N AP– Ru catalyzed hydroge natio n of ole fi ns.

1 9 6 6,7,10,11-tetra hy drofar nesol pro d uces (3 R , 7 R )- hexa hydrofar nesol, a C 1 5 si d e c h ai n of α -tocop herol (vita mi n E) a nd a part of vita mi n K 1 . The hydrogena- tio n of a n allylic alco hol possessi ng a c hiral azeti di no ne u nit gives a 1 β - m e- t hylcarbape ne m sy nt hetic i nter mediate diastereoselectively[48]. T he discove- ry of this asy m metric hydrogenation made possible the general asy m metric sy nt hesis of isoqui noli ne alkaloids i ncludi ng morp hi ne, be nzo morp ha ns, a nd morp hi na ns suc h as t he a ntitussive dextro met horp ha n[43,49]. I m porta ntly, t he list of s ubstrates ca n be exte n de d to i ncl u de vario us keto- nes, as ge neralized i n Figure 11. T he haloge n-co ntai ni ng BI N AP– Ru(II) co m- plexes (oligo mers)[50], but not t he diacetate co mplexes, are ef ficie nt cata-

Fi g ure 1 1. Asy m metric hydroge natio n of fu nctio nalized keto nes catalyzed by ( S )-BI N AP– Ru di halide co mplexes ( X = haloge n). P hoto: major co ntributors (fro m t he left, H. Takaya, M. Kita mura, and T. Ohku ma).

1 9 7 lysts for t he asy m metric hydroge natio n of a ra nge of fu nctio nalized keto nes, wherein coordinative nitrogen, oxygen, and halogen ato ms near C= O func- tio ns direct t he reactivity a nd stereoc he mical outco me i n a n absolute se n- se[51]. A wi de variety of ac hiral keto nes are hy droge nate d e na ntioselectively to t he correspo ndi ng c hiral alco hols i n 90–100 % ee i n a predictable ma n ner. T he reactio n ca n be perfor med nor mally i n alco hols wit h up to 50 % substra- te concentration under 4–100 at m at roo m te mperature with an S/ C ratio of u p to 10 000 o n a ny scale eve n usi ng >100 kg of t he s ubstrate. Fig ure 12 s ho ws so me synthetic applications of this asy m metric hydrogenation. ( R )- 1, 2- Propa nediol t hus obtai ned fro m hydroxyaceto ne is used for i ndustrial sy n- t hesis of t he a ntibacterial levo floxaci n ( Takasago Co./ Daiic hi P har maceutical C o. ). I n a d diti o n, γ- a mi n o- β -hydroxybutyric acid ( G A B O B) and a co mpactin i nter mediate ca n be prepared wit h hig h e na ntio meric purity[49,52]. Pre-ex- isti ng stere oge nic ce nters i n t he ket o nic s u bstrate sig ni fica ntly affect t he steric co urse. Stati nes ca n be obtai ne d wit h a hig h diastereo- a n d e na ntioselectivi- ty[53]. The double hydrogenation of 1,3-diones via chiral hydroxy ketones l e a ds t o t h e a nti 1, 3- di ols i n cl os e t o 1 0 0 % e e [ 5 1 a ].

Fi g ure 1 2 . Applicatio ns of BI N AP– Ru catalyzed hydroge natio n of keto nes.

R a c e mi c β -keto esters wit h a co n fig uratio nally labile α -stereoge nic ce nter, u ndergoi ng i n sit u stereoi nversio n, ca n be tra nsfor me d i nto a si ngle stereo- is o mer, o ut of t he f o ur stere ois o mers, wit h hig h stere oselectivity, as ill ustrate d i n Figure 13[54]. T his dy na mic ki netic resolutio n[55] has bee n used for t he sy nt hesis of various biologically i mporta nt co mpou nds suc h as t hreo ni ne, L- D OPS[52], p hosp hot hreo ni ne[56], a nd fosfo myci n[57]. Its utility was hig h- lighted by the industrial synthesis of carbapene m antibiotics at Takasago I nter natio nal Co. (Figure 14). T he requisite c hiral 4-acetoxyazetidi no ne is pre pare d by t he ( R )- BI N AP– Ru catalyzed hydrogenation of race mic methyl α -(benza mido methyl)acetoacetate in dichloro methane giving the 2 S , 3 R hy- droxy ester wit h 94:6 eryt hro:t hreo diastereoselectivity[58] a n d 99.5:0.5 e na n- ti oselectivity[54a]. Q ua ntitative a nalysis[54] i n dicates t hat t he 2 S s u bstrate is hy droge nate d 15 ti mes faster t ha n t he R e na ntio mer, a n d t he slo w-reacti ng R iso mer is i nverte d to t he 2 S e na ntio mer 92 ti mes easier t ha n it is hydroge- nate d. T he exte nt of t he BI N A P catalyst-base d asy m metric i n d uctio n is calc u-

1 9 8 Fi g ure 1 3. Asy m metric hydroge natio n via dy na mic ki netic resolutio n.

Fi g ure 1 4. Stereoselective sy nt hesis of carba pe ne m a ntibiotics.

late d to be 104 i n favor of t he 3 R iso mer, w hereas t he substrate-based asy m- metric i n d uctio n is 9 i n favor of t he C(2) / C(3) eryt hro stereoc he mistry. T he volu me of t he hydroge natio n reactor s ho w n i n Figure 15 is 13 m 3 . β - Keto esters are t he best substrates for t he Ru catalyzed asy m metric hy- droge natio n leadi ng to t he β - hydroxy esters i n >98 % ee[59]. Figure 16 illu- strates t he mec ha nistic model. T he halide liga nd i n t he Ru co mplex, ge nerat- ing a strong acid and a Ru H Cl species by the action of H 2 , is i m p orta nt t o facilitate t he hydride tra nsfer fro m Ru to t he carbo nyl carbo n[55]. I n addi- ti o n, t he prese nce of t he ester m oiety i nteracti ng wit h t he R u ce nter is cr ucial f or b ot h hig h reactivity a n d e na nti oselectivity. Beca use of t he excelle nt c hiral recog nitio n ability of BI N AP, t he t wo stereo-deter mi ni ng diastereo meric TSs are well differe ntiate d wit h t he assista nce of t he oxyge n– R u i nteractio n. T he R -directi ng TS is hig hly favored over t he S -generating diastereo mer, which s uffers fro m s ubsta ntial R / P -p he nyl repulsive i nteractio n. T he oxyge n– Ru da- tive bo n d (a n d relate d i nteractio n i n t he reactio ns i n Fig ure 11) exerts a pi- votal function in the acceleration of hydrogenation as well. Thus, β -ket o

1 9 9 Fig ure 15. A large-scale BI N AP– Ru catalyzed hydroge natio n at Takasago I nter natio nal Co.

Fi g ure 1 6. Mec ha nis m of ( R )- BI N AP– Ru catalyzed hydrogenation of β - ket o esters.

2 0 0 esters are hydroge nated s moot hly eve n i n t he si mplest keto ne, aceto ne, co n- tai ni ng a s mall a mou nt of water. T hus, alt houg h BI N AP– Ru di halide catalysts have a very wi de sco pe, t hey are u nable to hy droge nate si m ple u nf u nctio nali- ze d keto nes.

ASY M METRIC HYDR OGENATI ON OF SI MPLE KET ONES BY BINAP/ DIA MINE R UT HENI U M C O MPLEXES For more t ha n half a ce ntury, selective reductio n of si mple keto nes relied heavily on the metal hydride che mistry developed largely by H. C. Bro wn (1979 Nobel laureate). Che moselective reduction of a C= O function in the prese nce of a C= C group has bee n best effected by t he stoic hio metric Na B H 4 reagent[60]. Diastereoselective reduction of ketones has frequently been ac hieve d by Selectri des[61]. E na ntioselective re d uctio n of ac hiral keto nes are effected by c hiral stoic hio metric reage nts i ncludi ng BI N A L- H[62], DIP c hlo- ride[63], and Alpine-borane[64] or by the Corey– Bakshi–Shibata ( C BS) me- thod co mbining B 2 H 6 or catec holbora ne a nd a c hiral oxazaborolidi ne cata- lyst[65]. U ntil very rece ntly, t hese ty pes of selective C= O re d uctio ns were not ge nerally ac hievable by catalytic hy droge natio n[49 d,66]. I n 1995 w he n I was t he director of t he E R A T O Molecular Catalysis Project, we found that hydrogenation catalyzed by a Ru Cl 2 (phosphine) 2 ( di a mi n e ) co mplex a nd a n alkali ne base provided a ge neral solutio n to t his lo ng-sta n- ding proble m[67]. The use of appropriate chiral diphosphines and chiral dia mi nes allo ws asy m metric hydroge natio n of si mple keto nes w hic h lack a ny Le wis-basic fu nctio nality capable of i nteracti ng wit h t he metal ce nter. T he reactivity a n d stereoselectivity are fi ne-t u ne d by c ha ngi ng t he steric (b ulki ness a n d c hirality) a n d electro nic pro perties of t he a uxiliaries. As ge neralize d i n Figure 17, the ne wly devised BI N AP/dia mine co mplex catalyzes rapid, pro- d uctive a n d hig hly e na ntioselective hy droge natio n of a ra nge of aro matic, he- tero-aro matic, and olefinic ketones in 2-propanol containing K O- t- C 4 H 9 or K O H[68–70]. A mong various co mplexes, Ru Cl 2 (xylbi nap)(daipe n)[71] is partic ularly effective. For exa m ple, aceto p he no ne a n d its derivatives are hy- droge nated wit h S/ C of up to 100 000 givi ng t he seco ndary alco hols qua nti- tatively in 99 % ee[72], although the dia mine free BI N AP– Ru co mplexes are totally i neffective. Nor mally C= C bo nds are muc h more reactive t ha n C= O i n catalytic hy droge natio n, b ut t his syste m allo ws for t he prefere ntial sat uratio n of a C= O f u nctio n over a coexisti ng C= C li nkage[73,74]. Ole fi nic keto nes, eit- her co njugated or no nco njugated, ca n be co nverted to ole fi nic alco hols se- lectively. T he hy droge natio n tolerates vario us f u nctio nalities i ncl u di ng F, Cl,

Br, I, C F 3 , O C H 3 , O C H 2 C 6 H 5 , C O OC H(C H 3 ) 2 , N O 2 , N H 2 , and N R C O R. Both electro n-ric h (f ura n, t hio p he ne, t hiazole, etc.) a n d - de ficie nt ri ngs ( pyri di ne a nd pyri midi ne) are left i ntact[75]. T he si mple Ru Cl 2 ( P Ar 3 ) 2 ( N H 2 C H 2 C H 2 - N H 2 ) co mplex hydroge nates various substituted cyclic a nd acyclic keto nes wit h hig h diastereoselectivity, w here t he Ru H i nter mediate acts as a bulky hydride species[76]. Because of t he basic a nd protic nature of t he reactio n e nviro n me nt, hydroge natio n of co n figuratio nally labile keto nes allo ws for t he

2 0 1 Fig ure 1 7. Ge neral asy m metric hydroge natio n of si mple keto nes. Ar = aryl, Het = hetero- ar yl, U n = al k e nyl.

dyna mic kinetic discri mination of diastereo mers, epi mers, and enantio- mers[76–78], effecti ng a ne w type of stereoselective reductio ns of keto nes w hic h are not possible wit h stoic hio metric hy dri de reage nts. T his asy m metric hydroge natio n s ho ws pro mise for t he practical sy nt hesis of a wide variety of chiral alcohols. The chiral diphosphine/dia mine Ru co m- plexes effect e na ntioselective hy droge natio n of certai n a mi no or a mi do keto- nes via a no n-c helate mec ha nis m wit hout i nteractio n bet wee n Ru a nd nitro- gen or oxygen[78]. This method has been applied to the asy m metric syn- t hesis of vario us i m porta nt p har mace uticals, i ncl u di ng ( R )- d e n o p a mi n e, a β 1 - receptor ago nist, t he a ntidepressa nt ( R )- fluoxetine, the antipsychotic B MS 1 8 1 1 0 0, a n d ( S )- d ul o x eti n e w hi c h is a p ot e nt i n hi bit or of s er ot o ni n a n d n o- repinephrine uptake carriers (Figure 18). Benzophenones can be hydroge- nated to be nz hydrols wit h a n S/ C ratio of up to 20 000 wit hout over-reduc- tion[79]. Enantioselective hydrogenation of certain ort ho -s ubstit ute d be n- zophenones leads to the unsy m metrically substituted benzhydrols with high ee, allo wi ng co nve nie nt sy nt hesis of t he a ntic holi nergic a nd a nti hista mi nic ( S )-orp he nadri ne. T he a nti hista mi nic ( R )-neobenodine can be synthesized by usi ng asy m metric hydroge natio n of o-bro mo- p' - methylbenzophenone. T his approac h is t he first exa mple of ge neral a nd ef ficie nt asy m metric hy- droge natio n of α ,β -u nsaturated keto nes to c hiral allylic alco hols of hig h

2 0 2 Fi g ure 1 8. Applicatio n of asy m metric hydroge natio n of si mple keto nes. e na ntio meric p urity[72–74]. T he selectivity pro file is i n s har p co ntrast to t hat observed with the dia mine-free BI N AP– Ru co mplex, efficiently catalyzing asy m metric hy droge natio n of allylic alco hols (Fig ure 9). Its utility has bee n de mo nstrate d by t he sy nt hesis of i nter me diates of a n α -toco p herol si de c hai n a n d a nt hr a cy cli n es as w ell as β -io nol (Figure 18)[72,73]. T he asy m metric hy- droge natio n s ho w n i n Figure 17 is ge nerally ac hieved by t he co mbi ned use of a n ( S )- BI N AP ligand and an ( S )- 1, 2- di a mi n e ( or R a n d R ). T his is als o t he case f or t he reacti o n of s-cis ex ocyclic e n o nes, s uc h as ( R )-pulego ne. Ho wever, asy m metric hydrogenation of 2,4,4-tri methyl-2-cyclohexenone was effected best wit h Ru Cl 2 [ ( S )-t ol bi na p][( R ,R )-dpe n][74,80]. T he cyclic allyl alco hol obtai ne d i n 96 % ee (Fig ure 18) ca n be co nverte d to a series of carote noi d- de- rive d o dora nts a n d bioactive ter pe nes, s uc h as α -da mascone. The R or S al c o- hols wit h ee as hig h as 95 % ca n be obtai ned eve n wit h a race mic Tol BI N AP–

R u Cl 2 co mplex i n t he prese nce of ( R ,R )- or ( S ,S )- D P E N vi a asy m m etri c a cti- vatio n[80–82]. I n t his case, t he hig hly e na ntioselective hydroge natio n cata-

2 0 3 lyzed by t he ( S )-diphosphine/( R ,R )-dia mine co mplex (or R / S ,S c o m bi n a- tio n) t ur ns over 121 ti mes faster t ha n t he less stereoselective reactio n pro mo- te d by t he diastereo meric S / S ,S ( or R / R ,R ) co mplex[83]. T he reactio n is rapid a nd hig hly productive. For exa mple, w he n a mixture of acetophenone (601 g), the ( S )- Tol BI N AP/( S ,S )- DPE N Ru co mplex (2.2 mg), a nd K O- t- C 4 H 9 (5.6 g) i n 2-propa nol (1.5 L) (30 % w/v substrate co n- ce ntratio n) was stirred u nder 45 at m H 2 at 3 0 ° C f or 4 8 h, t h e R al c o h ol w as obtained with 80 % ee and 100 % yield[71,84]. Under such conditions, the tur nover nu mber was greater t ha n 2 400 000, w hile t he tur nover freque ncy at 30 % conversion was 228 000 h – 1 or 6 3 s – 1 . T his hig h rate a nd c he moselectivity for t he C= O fu nctio n are due to t he nonclassical metal–ligand bifunctional mechanis m (Figure 19)[68,70]. The hydroge natio n i nvolves a metal hydride i nter mediate. Hydride tra nsfer fro m t he metal to t he carbo nyl carbo n has bee n co nsi dere d to occ ur via a 2 + 2 me- chanis m. This reaction involves a Ru hydride species possessing an N H 2 li-

Fi g ure 1 9. a) No nclassical metal–liga nd bifu nctio nal mec ha nis m a nd co nve ntio nal 2 + 2 me- c ha nis m. b) Catalytic cycle of hydroge natio n of keto nes wit h a Ru Cl 2 ( P R 3 ) 2 ( N H 2 C H 2 C H 2 - N H 2 )/stro ng base co mbi ned syste m i n 2-propa nol. X = H, O R, etc.

2 0 4 ga nd, w hose hydridic Ru– H a nd protic N– H are si multa neously tra nsferred to t h e C = O li n k a g e vi a a si x- m e m b er e d p eri cy cli c T S, t h er e by f or mi n g a n al c o- holic pro d uct directly, wit ho ut for mi ng a metal alkoxi de (Fig ure 19a). I n t his hydrogenation, the metal and the ligand participate cooperatively in the bo nd-for mi ng a nd -breaki ng processes. A more detailed mec ha nistic model is given in Figure 19b. The 18e Ru H species reduces the ketone substrate via the pericyclic mechanis m and the for mal 16e Ru a mide reacts directly with

H 2 i n a 2 + 2 ma n ner or by a step wise mec ha nis m assisted by a n alco hol a nd a base, giving back the reducing Ru H co mplex[85]. The reducing activity of the Ru H species is generated by the hydrogen-bonding N H 2 e n d i n t he dia- mi n e li g a n d t h at f or ms a f ac r el ati o ns hi p wit h t h e hy dri d e li g a n d i n t h e o ct a- hedral geo metry. Neit her keto ne substrate nor alco holic product i nteracts wit h t he metallic ce nter t hroug hout t he hydroge natio n. T he e na ntiofaces of proc hiral keto nes are differe ntiate d o n t he molec ular s urface of t he coor di- natively saturated Ru H i nter mediate. T his notio n is i n co ntrast to t he co n- ventional mechanis m for hydrogenation of unsaturated bonds that requires t he metal–s ubstrate π co mplexatio n. T his N H eff e ct is c o m m o n t o t h e m e c h a nis m of R u – c at alyz e d asy m m etri c transfer hydrogenation[86]. Recently we found that Ru Cl[( S, S )- Y C H- 6 ( C 6 H 5 )C H(C 6 H 5 ) N H 2 ] ( η -arene) (Y = O, N Ts) or their analogues catalyze asy m metric tra nsfer hydroge natio n of aro matic a nd acetyle nic carbo nyl co m- pou nds usi ng a 2-propa nol/alkali ne base syste m to give t he correspo ndi ng S chiral alcohols of high enantio meric purity, as generalized in Figure 20[87,88]. A for mic acid/triet hyla mi ne mixture ofte n serves as a better re- d uci ng age nt. Certai n i mi nes are also re d uce d e na ntioselectively by t his me- thod. The detailed experi mental[89] and theoretical analyses[90] revealed t hat t he tra nsfer hydroge natio n of carbo nyl co mpou nds wit h 2-propa nol pro- ceeds via a coordi natively saturated 18e co mplex, Ru H[( S, S )-Y C H( C 6 H 5 ) C H- 6 ( C 6 H 5 ) N H 2 ] ( η - ar e n e ), as ill ustr at e d i n Fi g ur e 2 1. T h e m et al –li g a n d bif u n c- tional mechanis m allo ws for si multaneous delivery of the Ru– H and N– H to t he C= O fu nctio n via a six- me mbered pericyclic TS, givi ng a n S alco hol a n d 6 R u[( S, S )-Y C H( C 6 H 5 )C H(C 6 H 5 ) N H]( η -arene). The latter 16e Ru a mide co mplex dehydrogenates 2-propanol to regenerate the Ru hydride spe- ci es [ 8 6, 9 1 ].

T O WARD CEREBRAL M OLECULAR SCIENCE T he major goals of sy nt hetic c he mists a nd t he c he mical i ndustry have bee n the efficient synthesis of kno wn valuable co mpounds. Another and perhaps more i mporta nt pursuit is t he creatio n of ne w valuable substa nces a nd mate- rials t hroug h c he mical sy nt hesis. To ward t his e nd, mere c he mical k no wledge or tec h nology is ofte n i ns uf ficie nt a n d basic researc h t hro ug h i nter disci pli- nary collaboratio n wit h scie ntists i n ot her fiel ds is nee de d. T he rece nt pro- gr ess i n asy m m etri c sy nt h esis h as, i n f a ct, s p urr e d s u c h e n d e av ors w hi c h ar e directed to ward t he creatio n of molecularly e ngi neered novel fu nctio ns. In the mid-1980s, we established the long-sought after three-co mponent

2 0 5 Fi g ure 2 0. Asy m metric transfer hydrogenation of carbonyl co mpounds and i mines catalyzed by c hir al R u c o m pl e x es.

Fi g ure 2 1. Metal–liga nd bifu nctio nal mec ha nis m i n asy m metric tra nsfer hydroge natio n ca- 6 talyzed by Ru H[( S ,S )-Y C H( C 6 H 5 )C H(C 6 H 5 ) N H 2 ] ( η - ar e n e ). R = al kyl or D; Y = O or N Ts.

2 0 6 coupli ng sy nt hesis of prostagla ndi ns (P Gs) illustrated i n Figure 22[92]. T he

five- me mbered unit could be co mbined with the t wo C 7 a nd C 8 si de c hai n units by organo metallic methodologies. Our asy m metric methods play a key role i n co ntrolli ng t he C(11) a nd C(15) O H-beari ng stereoge nic ce nters. T he r e q uisit e ( R )-4- hydroxy-2-cyclope nte no ne is co nve nie ntly prepared o n a multi- kilogra m scale by ki netic resolutio n of t he race mate by BI N AP– Ru catalyzed hydroge natio n[43]. T he BI N A L– H reage nt is useful for asy m metric sy nt hesis of t he lo wer si de-c hai n block[93,94]. T his straig htfor war d proce d ure is usef ul for t he sy nt hesis of not o nly nat urally occ urri ng P Gs b ut also t heir arti ficial a nalogues[95]. To ex plore a p plicatio ns to t he scie nce of t he h u ma n brai n, we collaborate d with the research groups led by M. Suzuki ( my long-ter m collaborator at Nagoya a nd no w at Gifu U niversity), Y. Wata nabe ( Osaka City U niversity), a nd B. Lå ngströ m ( U p psala U niversity)[96,97]. After a lo ng i nvestigatio n, (15 R )-

TI C, a P GI 2 -ty pe carboxylic aci d, was fo u n d to s ho w stro ng, selective bi n di ng in the central nervous syste m, thereby identifying the novel IP 2 rece ptor (Figure 23). I nteresti ngly, t his co mpou nd has t he u n natural 15 R co n figura- tio n, alt houg h most biologically active P G derivatives have t he natural 15 S co n figuratio n. T his discovery was made by a n i n vitro study usi ng froze n sec- ti o ns of rat brai n a n d (15 R )- [ 3 H] TI C as a probe[98]. Ho wever, t his ra dioacti- ve probe is not a p pro priate for st u dies o n livi ng mo nkey or h u ma n brai n, si n- c e β – particles e mitte d fro m 3 H ca n not pe netrate tiss ues. I ncor poratio n of 1 1 C, a p ositr o n e mitt er h avi n g a s h ort h alf-lif e of a b o ut 2 0 mi n a n d a hi g h s p e- ci fic ra di oactivity, as a ra di oactive n ucli de is esse ntial f or n o ni nvasive st u dies usi ng positro n e missio n to mograp hy (P E T). Positro ns ( β + ) i nteract wit h free electro ns i n biological materials pro d uci ng γ rays t hat ca n pe netrate tiss ues

Fig ure 2 2. Three-co mponent synthesis of prostaglandins. α chain = I C H 2 C ≡ C( C H 2 ) 3 - C O OC H 3 ; ω c h ai n = ( E ,S )-LiC H=C HC H( OR')(C H 2 ) 4 C H 3 .

2 0 7 Fi g ure 2 3. ( 1 5 R )- TI C ( R = H) a nd t he met hyl esters ( R = C H 3 ) l a b el e d by r a di o a ctiv e n u cli- des a nd a n i nterdiscipli nary collaborative tea m (fro m t he left, M. Suzuki, R. Noyori, Y. Wata nabe, a nd B. Lå ngströ m). and are detectable outside the hu man body. Ho wever, this presents a ne w 1 1 c h e mi c al pr o bl e m. T h e C H 3 group must be i ncorporated i n t he fi nal step of t he sy nt hesis of (15 R )- TI C met hyl ester, a n d t he t otal ti me f or sy nt hesis, w ork- u p, p uri ficatio n, a n d sterilizatio n s ho ul d be less t ha n 40 mi n beca use of t he s h ort h alf-lif e ti m e of 1 1 C. A stude nt i n my group at Nagoya made a co ncerted effort to achieve this and, eventually succeeded with a rapid Pd- mediated co u pli ng of met hyl io di de a n d trib utyl(aryl)sta n na ne (excess) w hic h is a p pli- ca ble t o t he sy nt hesis of (15 R )- [ 1 1 C] TI C met hyl ester[99]. T his tec h nology was t he n tra nsferred to t he P E T Ce nter at Uppsala. A very de dicate d colleag ue i n o ur tea m, S uz uki, vol u nteere d to test t his ne w arti fici- al co mpound on hi mself. After being carefully exa mined, (15 R )- [ 1 1 C] TI C met hyl ester was i njected i nto his rig ht ar m. T he met hyl ester was carried through his blood strea m, passed through the blood-brain barrier, reached his brai n, a n d was hy drolyze d to t he free carboxylic aci d, w hic h was bo u n d to

I P 2 receptors i n his ce ntral nervous syste m. Figure 24 s ho ws t he P E T i mages of horizo ntal slices of his brai n, fro m t he lo wer to t he u p per portio ns. Fro m t his tri al, a n e w r e c e pt or, I P 2 , was fo u n d i n vario us i m porta nt str uct ures of t he hu ma n brai n. T hus, (15 R )- TI C a n d its a nalog ues are ex pecte d to have effects

2 0 8 Fi g ure 2 4. T he u ptake of (15 R )- [ 1 1 C ]- TI C i n t h e h u m a n br ai n. T h e P E T i m a g es of 1 8 h ori- zo ntal slices fro m t he lo wer to t he u p per portio ns of t he brai n (vol u nteer: M. S uz uki; J u ne 13, 2000. P E T Ce nter of Uppsala U niversity).

o n t he brai n a n d, i n fact, do s ho w a u niq ue ne uro protective effect, w hic h may be of clinical benefit. Pri mary cultured hippoca mpal neurons exposed to a hig h oxyge n co nce ntratio n display t he morp hological features of apoptotic c ell d e at h a n d ( 1 5 R )- TI C effectively protects t he m agai nst s uc h oxyge n toxi- city[100]. Si milar ne uro protective effects were de mo nstrate d i n ot her i n vitro experi me nts usi ng seru m deprivatio n a nd i n i n vi vo st u di es of is c h e mi c i ns ults wit h gerbils, rats, a n d mo nkeys. T h us, t he I P 2 rece pt or is a n ovel target f or developi ng drugs w hic h may be neuroprotective i n brai n disorders a nd neu- tro dege nerative diseases. St u di es of m ol e c ul ar c hir ality h av e t h e pr o mis e t o yi el d si g ni fi c a nt cli ni c al, scie nti fic, a n d i n d ustrial be ne fits i n t he f ut ure. A str uct urally diverse array of molecular substa nces exist. All molecules possess co m mo n c haracteristics,

2 0 9 viz., fixed ele me ntal co mpositio n, de fi nite ato mic co n nectivity, a de fi ned re- lative a nd absolute stereoc he mistry, a nd so me co nfor matio n. Fro m suc h pre- cise na no meter-scale structures, certai n sig ni fica nt properties a nd fu nctio ns e merge. C he mists ca n desig n a nd sy nt hesize molecules at will, based o n ac- cu mulated scie nti fic k no wledge. T he practical sy nt hesis of e na ntio mers wit h a de fi ned absolute stereoc he mistry is o ne of t he most sig ni fica nt areas of re- searc h. T his e n deavor is not o nly a n i ntellect ual p urs uit b ut is also a fertile area for t he develop me nt of be ne ficial tec h nologies[101]. Its utility is ob- vio us, ra ngi ng fro m basic scie nti fic researc h at a s ub-fe mto mol scale, as i n t he case of brai n researc h describe d above, to t he i n d ustrial pro d uctio n of hig h- value co mpounds in multi-thousand tons per annu m quantities. Louis Pasteur stated i n 1851 t hat, “ Dissy m metry is t he o nly a nd disti nct bou ndary bet wee n biological a nd no nbiological c he mistry. Sy m metrical p hysical or c he- mical force ca n not ge nerate molecular dissy m metry.” T his notio n is no lo ng- er tr ue. T he rece nt revol utio nary develo p me nt i n asy m metric catalysis has to- tally c ha nged t he approac h to c he mical sy nt hesis. T his field is still gro wi ng r a pi dly a n d I a m c ert ai n t h at it will pl ay a piv ot al r ol e i n t h e d ev el o p m e nt of t he life scie nces a n d na no-tec h nology i n t he 21st ce nt ury. The highest honor for me is to be recognized with the prestigious 2001 Nobel Prize i n C he mistry. T his ho nor must be s hared wit h my researc h fa mily at Nagoya a nd wit h ma ny collaborators at ot her i nstitutio ns. Asy m metric hy- droge natio n has bee n t he life-lo ng foc us of my researc h, a n d my st u dies have relied largely o n BI N AP c he mistry w hic h I i nitiated wit h t he late Professor Hide masa Takaya. Subsequently BI N AP che mistry was developed further in our laboratories at Nagoya, where Professors Masato Kita mura and Takeshi Ohku ma made major contributions. Other asy m metric hydrogenation me- thods were discovered during my directorship of the E R AT O Molecular Catalysis Project (1991–1996), w hic h was ma naged by Professor Takao Ikariya (no w Tokyo Institute of Technology) and Dr. Shohei Hashiguchi ( Takeda C h e mi c al I n d ustr y ). O ur l a b or at or y at N a g oy a is s m all. T o r e aliz e t h e utiliz a- tio n of o ur scie nti fic ac hieve me nts, it was i m porta nt to collaborate wit h ot her i nstit utio ns. I n t his regar d, I a p preciate t he coo peratio n of t he gro u ps le d by Professors Sei Otsuka a nd Kazu hide Ta ni ( Osaka U niversity), a nd Professors Masaaki Suzuki ( Gifu University), Yasuyoshi Watanabe ( Osaka City Univer- sity), a nd Be ngt Lå ngströ m ( Uppsala U niversity). T hese are just t he na mes of t he leaders of t he researc h groups, alt houg h ma ny you ng associates a nd stu- de nts als o c o ntri b ute d sig ni fica ntly. I ha d o p p ort u nities t o have fr uitf ul c olla- boratio ns wit h ma ny ot her scie ntists w hose na mes are cite d i n t he refere nces. We have been supported by many co mpanies, particularly Takasago Inter- natio nal Corporatio n a nd Teiji n Co mpa ny. T he ge nerous a nd co nsiste nt sup- port fro m the Ministry of Education, Culture, Sports, Science and Tech- nology was esse ntial for t he s uccess of my researc h. I a m also gratef ul to t he Japan Science and Technology Corporation and many private foundations for t heir s u p port. Last, b ut not least, I ack no wle dge Professor Hitosi Nozaki at Kyoto U niversity, my me ntor w ho first i ntroduced me to t his fasci nati ng a nd re war di ng fiel d of researc h.

2 1 0 REFERE NCES

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