The Nobel Prize in Chemistry 2001 William S. Knowles Ryoji Noyori K. Barry Sharpless Prize share: 1/4. Prize share: 1/4 Prize share: 1/2 The Nobel Prize in Chemistry 2001 was divided, one half jointly to William S. Knowles and Ryoji Noyori "for their work on chirally catalysed hydrogenation reactions” and the other half to K. Barry Sharpless “for his work on chirally catalysed oxidation reactions".ENANTIOSELECTIVE ADDITION OF H2 TO C Backgroun: — me hycrogenstes poauct cra) The discovery by G. Wilkinson that the solution of the moaium complex 1, catalyzes the reduction of unhindered alkenes by Hz gas at 1 atmosphere pressure’ paved the way for W.S. Knowles’ and co-workers 1o show that the use of the chiral monodentate phosphorous ligand (S)-CAMP (2) resulted in good. enantioselectvity in the Wilkinson hydrogenation of dehydroamino acids. Studies by H. Kagan? revealed that Cesymmetric bidentate phosphine ligands such ‘as 3 gave comparable results to xoce (SOM (Ig) (8.5}-010P (1971) Pray oP pm Nor Wiese’ cat (1965) nantioselective Homogeneous Hydrogenation An even more effective bidentate phosphine ligand-h complex, (S,S)DIPAMP-Rh (5), that was developed by Knowles was used in the commercial production at Monsanto ef L-DOPA 7, an anti-Parkinson's drug” This section is organized according 1© the type of unsaturated substrate and the transition metal (Fh, Fu, I, ‘tc.) used for reduction by He.HN Acyt rerides ° Most Common Substrate Types 1 isbstinted ‘sence "6 Figure 1 12dmsutes v“OQ ms “H Mena oP t 4 x Cos GD FS Me ay ff Pen " a we a) ed tou fou (ssc SSiekonm See (SSRI % a ‘s we 2 « nf ‘0: Me PPh af Pm af PP Oy PPh op em on PPh PPh PPh 9. PPI foo" < a "Ph ene Gane (ome (ssegenos vorygeree os aremnseros s s ‘2 3 8 3 figure2 Chiral Monodentate Phosphorus, 2 ae moe R pom eal YQ wd, J d 7 x ef Ros=nd ae (crete ergex ena — = 3 st 2 FiguresEnantioselective Hydrogenation of a- and [-Dehydroamino Acid Derivatives™* ores (RmELOUMAFO ors come ISSR-Tegpreey poste ‘n2ra%) Oar fh, 0 Cae ES f onan ce wade Eten tise 0 283%600 Aree 0% >aace ¥ ” > 2 moje 2020 voertferoate ing weerwercooe “y ° & trguncrerer ‘acim les et mye EE Gye a te washer Soe Srey MOE en " 529% 0 6 4 ae wee os « “ « “ on Fr os (7)/S)osPhoslent So(orsrat) ” Ee te eden F 0, Behe r * Reteronce Key tr Equations)", 09" a)” Feterance Koy for Equations: (¥"(Enantioselective Hydrogenation of Enamid USS) EeDuProsR 38002 mF, ete >Ph00 Nike [RSRSMePemPteeR 374m) “ aa Meo Bh wHcooMe 4 os {o?hneatteoHSIPHEPIRNT Seon) Ee, orc, 20°C % o “ Reteronce Key for Equations: a= ‘Scheme 2 ike (SE. uProse 98002 et), (Op, Medi En w 0% 00 RSRSMg Perron Pn -APHEP = Serraine et, ~ = Fetorence Key for Equations: (yawEnantioselective Hydrogenation of Enol Esters‘***"* Ae (SSRRM=raPhosAN” Gk eR MeoR FO Wypre » eran Sater i" ar an ae BERR eottierore * 00% 7608 0% O00 " weawone a we RR ELOUPoaR v5 5 ° 73102 rahe) Me o 0 '38 (0.005 mor) o xy wer om sacri, Hi, ora ® Cyc, 50°C Aco Ne (MSUH, 20°C Aco? Me a 100%, 98%.00 83 oy pee Hes one Hone ° we. ISRS Me PanbronkO Is. sea-cmarneon* » Seared toi oN a, re BT neat BG now Son 6 100%, 220% 00 99%, 87H 0 Retorance Key tor Equations: (7 ans (wy ‘Scheme 4 Roterence Key for Equations: (1¥)°*; (77: (Wi)tEnantioselective Hydrogenation of a,-Unsaturated Carboxylic Acids and Derivatives*** coon SP HeBINAP FU . Veneto —— apHeujru™ 22.05 mos) isco " (8510.25 mor) ‘ Ban. . rc oF on 100% 7% 80 ie (erbwwten 0) [1S.S,A,AV-TangPhosfRn* Hee aa [(S,5)-£-DuPhosFin* Hogi Pr iy wos ream w wo Neteceemm “ (13 atmp eons Meo" He (5 5 am), e doate He el boone Voye BSR boats ° 100% 0% 08 e 7 102% 0% 08 we WrpA13)1600) Fu Me o ama Oo con bebe Flotehy wr pions th 8 em OL, . oe et ye Us.eurenctaneput a wy — Oe, (erFieres cevatne (osjegaerme MONS EAN,.GS coor . nce Kay tr Equations: (9°, 05" Scheme 5 Aetoronce Key for Equatons: (vy: cy: evn?.ctive Hydrogenation of Unsaturated Ketones and Alcohols" come Hyyrooate oH spi fr, tiara ® a nat er ¥ oe Be Y Me 109 hee oe ee + 2%, 20h moe Soar we he Ks .802%R" me SONAR he ‘ec08 ra) G » cersoonany Mle Tey, mom So Son Lon ER on 99% oe we 80%, 92% e8 ance Key for Equations: (y%°2™ ay” Scheme 6 Reference Key for Equation: (l)™ QV)Background: Highly Enantioselective Homogeneous Hydrogenation of Ketones roca The st Wansiion metal-catalyzed righiy enantioselective homogeneous hydrogenation of functionalized ketones to form enanliopure secondary alcohols was reported by R. Noyor! ot al. in me late 1980s. Using either (F- or (S-SINAP-Rulll) complexes (2 of 3), f= elo esters such as 1 were converted to the corresponding (B)- oF (S)--hydroxy esters (4 or 5) in high yield and enantiomeric puriy, Catalysis 2 and 3 were also highly etiectve for the enantioselective hydrogenation of a wide variety of a- and functionalized ketones (2g., camino ketones and fihydroxy ketones) * Later it was discovered that Ru-cataysis having both chiral bisphosphine and chiral diamine ligands catalyzed the enantioselective reduction of Unfunctionalized Ketones (e.g., dialkyl Ketones, aryalkyl ketones)? Iepanuerrac, He ono (008m) on Te wove we BE . ho 1 Kspear uci, ‘stcor mom) EE, 57%; 220%600 no, 2 oA om Iwas also demonstrated that hydrogen donors, such as ‘small ethanol, 2-propanol and triethylammonium formate, can replace hydregen gas (H:) as the hydrogen source in the enantioselective reduction of ketones, a process called asymmetric transfer hydrogenation. A significant advantage fof this version is that i does not requice the use of Pressurized reaction vesselsCommon Ketonic Substrates if 3g Af so, emeasee gman ; whe why, eRe “meee ister Metres 8 ae we 8 peer a patorerenden was ns eS retSome Bisphosphine Ligands. (ener (Tae mene (syseaeHos (awo.geree (SrRaLpasres m ‘2 2 on roe Me Ry be ok Co Be A TR (syvereeeeHos ASRS MePeNEh wsoccem (525,01C0»,Co.cpnaeNoP (ocrzoPnee F ‘3 = es ea Figure 2 Chiral 1,2. and 1,4-Diamine Ancillary Ligands wsaigren «sagen soyren ecagAan Figure 3Enantioselective Hydrogenation of a-, - and -Keto Acid Derivatives*#*™™ ECE wn o ,yss5sieoncote HOLE) on 4, SESS ® ae eo OY ae abe CY Le EE en Gene . ‘ome . yr SOF! [@s.35-NORPHOSN* Gco.et a {1S} TetraMe-BIMANPIRG?* ° ¥ meme OK Se - SP 0 aK one astare woe =o ‘ame « - seo eee “ » wowers ot mee oe issue cy, zs Sem oo wo, 9 Am —ascam ~ LT, Ava Se orn eter . Ste a ™ 0%; 99.5% 08 a 2 78%; 9% ee CT ° (BINARIES HOH ° (s)-6aR s ‘monet DReaxco, 88,1 mo! oye cm mt loa ye I SEER ya ae (255 795%; % ee 6-86 7 100%; 8% Co oo me mpseommcop? Sere ~ tc He (109 atm) i PERn Y See Peelers Baterance Key for Equations: (ai a’ who Aeloronce Key for Equations: (vn ¢vn"® i"! 09"Enantioselective Hydrogenation of «and y-Functionalized Ketones te ", eiEnantioselective Hydrogenation of Simple Ketones***#*** sense ° loke Ea gv (SPBINAPII(ALA) OPENRU ener a ue 1941006 mab) ees Oo Se "spa ae “ tle Ag @ atm), FBLOK : erie eo mane sgt aay om Set ots nave Tis (8am), £0608 HOR) eh 199 rence Key or Equations (3 (0 P,P torte 6 (is s)punp-eaayst jo, yu SE Vs om ssw et woe ae ote mom , ve —Hegaarn, FBR Bre <0 so 08 A“ FS gue wn saye hogy CH eet mone) “ wr > Tear, rs Ce Fe ico Vbron aa Can em 10% 6% 98 Feleronee Key for Equations (07, cv, cn; cy?Background: Gatalytic Enantios ctive Reduction of Prochiral Ketones by Borane: a ketone (sonra Chiral B-substituted oxazaborolidines such as 1, derived from diphenylprolinol (2, 1,1-diphenyipytrolidinomethanol), are very useful as catalysts for the enantioselective synthesis of chiral secondary alcohols from ketones using various oranes as the sloichiometric reductant.’ - ie : The reduction of acetophenone (3) by the borane- tetrahydrofuran complex (BHsTHF, 0.6 equiv) in the presence of 10 mol% of 1 in THF at 2 °C to form (A}1- pphenylethanol (4) in 99% yield and 96.5% enantiomeric purty represents a simple and typical example of the general method.® sae 009 x me oes Es 3 “Pn“oo.Background: Highly Enantioselective Homogeneous Hydrogenation of Imines tira estat Tho enantioselective catalytic hydrogenation of imines to chiral amines provides a route to many Useful intermediates, pharmaceuticals and agrochemicals.” There are fewer fllecive catalysts for this. ansformation than for the ‘enantioselective reduction of C=O because of the following problems: (a) stronger coordination of the transition metal to the unshared electron than to the GeN x-bond resulting in low catalticacvivtumover: (6) ‘fequent problems. in preparing pure (E) and (2) imines: (e) hydrolytic instability of {he imine substrate and (4) requicement for Hy at elevated pressure An early and modestly snantoselectve catalytic reduction of an imine by hydrosiylation, using a chiral hil) complex was reported by H. Kagah in 1973.* Common Imine Subst: “ i Pay My) & ws! Roos shy ehas ee ae re pee pithae Ane ruins — wii walt stones ‘Subsequent to Kagar's report, a large number of Fu; Ir land Rih-chiral bisphosphine complexes have been examined {or imine hydrogenation. Various additives (e.g., TBA, KI, la) have been found to influence enantioselectvty [RRNEDICA 1 re) a 223 more) 7a soon betta 1. 25°C 0%: 72400 An effective catalytic homogeneous hydrogenation of imines (@.9., 1-93) was. demonsirated by Markd et However, it was not uni the late 1980s that highly effective chiral calalysts emerged for this transformation using either hydrogen gas_or various hydrogen donore such as 2- propanol or Wriethylammoniam formate." perp phe aoe acyl cle re ores rytores Marini inns Figure +tn 1990, 7, Kalu and KB Shepless made ne sumery, tecoery tal eas dee uniogs ‘nionlocive eprkdaton Inte presence of TIOFP Ne ‘Sat tarvae (1) or corny Taree. (2) ane. te Sciynyeropore pure)" Lar tay roparieg Pak ‘he inser of 4 8 meloouar sever alae eae ot Eubeochonese amount THO°Phs an late slot ‘thon dy f2cOON sed Ths pronees (seu Sharpes “poudaten) © now one ele ot wel ues ease ‘Symmomneonatore m eins atess! The 2p ‘ifels potieed by Ue valuta chal tung Boeke “na have eon nd. enone tie pearaton of ‘ompioe natural procuct.* . a gh. myih. ca sage sien a lors Epoxidation Aly leet ae the mou avr o presence ote Fyrom gous fs esseral The reacten Frosseds enatovehcbay wih iuaiy any setter ‘Seamer enaiamere 2 3apon, ston (a) canbe Btaned by wooo the sporoprate aa eer (Ser LA, ‘Fn anaifincs ssetly nao my ei ‘Mfhw_ Kati Sharne opeedaion hee alto. beer sppfed tote neta rsausono rcamibesonday ale ‘Hecho and to Be Geoymmezaion of eso bale ‘Tanstormaton witout elton Theres eo expe 3 ‘cera enantunetveepocatn yt honey Br Femoaipic and rheoyie seco “he ceed maclana Tomar srcarain dese sperma and Mortal eae Two paaye hve fon proposed one an the simene shuns ©. Powe 9) iSite gher invohing @twttaran Maram pees (8 1h Sas ote Kae Sharpless epoxdatn, whch mst be cried st uncer anhysous sanaton bees he ‘Sayac sje forthe aranesectve pcan fae Scone based en varadum eorplones pec? gure‘Asymmetric Epoxidation of Structurally Diverse Allylic AlcoholsRe I choral (senna cataiyst RR ont Kochi’ report” in 1986 that the (salen)Qn(l) complex? 1 catalyzes the. efficient epoxidation of olefins by rodosyl benzene (PhiO) led to Jacobsen's finding in 1990° that this reaction is faily enantioselective (33-93% ee) il the ‘ethylenediamine part of the ligand is replaced by (5,5) oF (F.A}-1.2-diphenyidiaminoethane, and ifthe positions ortho to the phenolic hydroxy cay a bulky group, asin the (FA) complex 2 (Figure 1)" Further improvements included the use of the related catalyst 8, and NaOCl as the terminal ms fap ReHi2)A-oTFS.@) Review iss Figure 1 A similar catalyst system was developed by Katsuki and coworkers (Figure 2)° The most widely used catalysts are 3 ‘and 5 which are commercially avaiable (Figure 1).” Catalyzed Oxidation of Unfunctionalized Olefins ‘The Jacobsen epoxidation has been applied to the enantioselective epoxidation of mono-, dr, tir and tetrasubsttuted olefins. “and to unsymmetrical (2+ ioubstiuled olefins with good results,, However, the epoxidation of (E)-siaubstituted alkenes is usually only poorly enantioselective, ‘The Jacobsen epoxidation takes place with higher yield and enantcselectivily i the olefinic bond is conjugated with a raystem. The rate of the epoxidation, the yield and the enantoselectivity can be affected by the use of vatious fdditves, for example pyridine N-oxide, which may imply that 2 hexacoordinate oxomanganese(V) species is the effective epoxidation reagent, possibly with Cr-symmetic, canted, on-planar six-membered chelate rings.’ The geometric otal of the pre-ransiion state assembly and the basis of tnantioselectivity have been analyzed (ses page 167 for pathway)” Twelve exampes of Wwe Jacobsen eponidalion ae Shown in Schemes 1 and 2. Enties VII-X in Scheme 2 illustrate the formation of a trans epoxide trom a cisdouble bond. These cases show that the Jacobsen epoxidation can occur by a 2elep pathway with intervening C-C bond rolation. The 2-step process is also favored by the use of certain chiral quaternary ammonium halides.""* ge BY scam Re seaman ” Figure 2Otefins R? chiral ligand (catalytic) "K ‘O80, (catalytic) ——— ‘oxidant Re (stoichiometric) Re inlay “HO OF" ADMinB EERE! Ho on ADmixa : LIS emma earn noes ene —— oho AD-mix B: (DHOD),PHAL + K,0s0,(0H), + KgFe(CN)y Figure 1Asymmetric Dihydroxylation of Structurally Diverse Alkenes wesc °C =" EE Cee eo, ganda may Fo; Sem) Koos mab) FON. G ea) OM OUT O'S 704; oTHe8 aw AN essen aCe SoSH 59%: hee. Ses tard 1 (1 ma) Neco en) fect Kousera (th) KFSIGN Soa) velo S(T. ow os eS Reterence Key for Equations: qi vy" vi om an 44 mary IK, (ac). SSG ho, KFe(Gh G my) OHMS TOT a 90%; sK08 gana 81 raPey 1004 (aca) OOH amet Soe LBORHS TROT 90; o7%.00 gan 24 moPiy Feacenn Keone ot Tec equ) war LOH HOO TOT Xe 7H4;>08%00 gan 31 9) 00, ec). SON mat Batre wu. OWNS TOT OG: Bho