M.W. Kanan/MC. white. Chem 153 Hydrogenation -171 Week of october 21. 2002 Dynamic Kinetic Resolution of 2-substituted-B-keto esters RuBra(R)-BINAP] 9917an,98%ee OMe 100% conversion CH2C215°C,50h NHAc NoyoriJACS1989(111),9134 Scenario 1: There are at least two possibilities for the mechanism of stereoselectivity. One is Scenario 2: Both starting enantiomers are converted to a single that the B-keto-ester enantiomers can interconvert under the reaction conditions and the intermediate species(a prochiral enol formed via deprotonation catalyst reacts with one isomer much more rapidly than the other and with high of the a-proton)and the catalyst reacts stereoselectively with stereoselectivity to produce a single product lis species to produce a single stereoisomer RuBra(r)-BINAP, H2 OMe NHAc NHAc NHAc NHAc NHAc RuBr (R)-BINAPI OMe NHAc NHAc OMe ki>k The following observations support the interconversion mechanism [RuCI(C6H6((R)-BINAP)ICI 99 syn: anti, 93%ee reacts to give p-hydroxy ester in e solvent OMe CH2Cl250°C,7h stion:why does the result with the cyclic strate support the interconversion mechanism?
M.W. Kanan/M.C. White, Chem 153 Hydrogenation -171- Week of October 21, 2002 Dynamic Kinetic Resolution of 2-substituted-ß-keto esters O OMe O NHAc O OMe OH NHAc 99:1 syn:anti, 98% ee, 100% conversion Noyori JACS1989 (111), 9134 RuBr2[(R)-BINAP] H2 (100 atm) CH2Cl2 15°C, 50h O OMe O NHAc O OMe O NHAc O OMe OH NHAc O OMe OH NHAc O OMe OH NHAc O OMe OH NHAc + + k1 k2 k1>k2 major product RuBr2[(R)-BINAP], H2 Scenario 1: There are at least two possibilities for the mechanism of stereoselectivity. One is that the β-keto-ester enantiomers can interconvert under the reaction conditions and the catalyst reacts with one isomer much more rapidly than the other and with high stereoselectivity to produce a single product. O OMe O NHAc O OMe OH NHAc O OMe OH NHAc major product RuBr2[(R)-BINAP], H2 Scenario 2: Both starting enantiomers are converted to a single intermediate species (a prochiral enol formed via deprotonation of the α-proton) and the catalyst reacts stereoselectively with this species to produce a single stereoisomer. O OMe O The following observations support the interconversion mechanism: reacts to give β-hydroxy ester in 88-96% ee depending on the solvent O OMe O OH OMe O [RuCl(C6H6)((R)-BINAP)]Cl 1:99 syn: anti, 93% ee H2 (100 atm) CH2Cl2 50°C, 70h Question: why does the result with the cyclic substrate support the interconversion mechanism?
M.C. White/M.W. Kanan Chem 153 Hydrogenation-172 Week of october 21. 2002 Diastereoselectivity in the noyori dynamic kinetic resolution oH O oH O RuBr2l(R)-BINAPI syn.anti 99: 1 in CH, Cl OMe H, CH,CI Me DMe (R)OMe syn. 71: 29 NHAc NHAc NHAc Excellent enantioselectivity and syn diastereoselectivity is seen in the dynamic kinetic resolution of Recall that in this system hydrogenation is thought to racemic a-acetamido-B-keto-esters when the reaction is carried out in CH, CL. The observed syn proceed through a Ru-monohydride species, capable of selectivity with these substrates can be rationalized by considering the Felkin-Anh model for the ordinating the adjacent ester moiety. The transition state Dunitz trajectory of the incoming hydride and the best acceptor(acetamido group)i s% transition state of hydride addition in which the small substituent(H) is adjacent to the Bur with the acetamido group anti to the incoming hydride may additionally be stabilized via hydrogen bonding between the preferentially oriented anti to the incoming hydride Nh of the acetamido group and the or of the ester competetive binding to solvent may account for the CO,Me COmE COrM diminished syn selectivity seen in MeOH OH NHAc NHAc NHAc P P-Ru---0 terconversion Note that ester position is fixed b/c under reaction conditions of chelate formation w/the catalyst NHAc (H) achn cO,Me AchN COrMe AcH COMe OH O 0 OMe
Excellent enantioselectivity and syn diastereoselectivity is seen in the dynamic kinetic resolution of racemic α-acetamido-ß-keto-esters when the reaction is carried out in CH2Cl2. The observed syn selectivity with these substrates can be rationalized by considering the Felkin-Anh model for the transition state of hydride addition in which the small substituent (H) is adjacent to the BurgiDunitz trajectory of the incoming hydride and the best acceptor (acetamido group) is preferentially oriented anti to the incoming hydride. Recall that in this system hydrogenation is thought to proceed through a Ru-monohydride species, capable of coordinating the adjacent ester moiety. The transition state with the acetamido group anti to the incoming hydride may additionally be stabilized via hydrogen bonding between the NH of the acetamido group and the OR of the ester. Interruption of this hydrogen bonding interaction via competetive binding to solvent may account for the diminished syn selectivity seen in MeOH. Me OMe NHAc O O RuBr2[(R)-BINAP] (R) Me OMe NHAc OH O (S) (R) Me OMe NHAc OH O (R) + syn:anti 99:1 in CH2Cl2 syn:anti 71:29 in MeOH H2, CH2Cl2 H O O NHAc R O P Ru P H X N H O O H R O Me O P Ru P H X (S) (R) vs. favored syn anti * * Diastereoselectivity in the Noyori dynamic kinetic resolution M.C. White/M.W. Kanan Chem 153 Hydrogenation -172- Week of October 21, 2002 H CO2Me NHAc AcHN CO2Me H H AcHN (H-) (H-) NHAc H CO2Me CO2Me H AcHN NHAc H CO2Me CO2Me Me OMe NHAc OH O Me OMe NHAc OH O interconversion under reaction conditions ‡ ‡ = = Me O Me O H Me OH Me O O Me H Me OH (S) (R) Note that ester position is fixed b/c of chelate formation w/the catalyst
M.W. Kanan/M C white Chem 153 Hydrogenation-173- Week of october 21. 2002 Stereoselective synthesis of iso-dolaproine: the power and limitations of DKR with a-substituted-B-keto esters As part of an effort to develop a stereocontrolled synthesis of dolaproine, Genet and coworkers carried out the Noyori DKR shown below. Based on the literature precedents for DKR with a-methyl-substituted B-keto esters. the authors were expecting a syn relationship between C2 and C3. Instead that observed very good diastereoselectivity in the formation of the undesired anti isomer. This example highlights a limitation of the Noyori methodology. In DKR of a-substituted-B-keto esters, the ligand on Ru controls the stereochemistry of the ketone being reduced, but the diastereoselectivity is controlled by the substrate. This means OMe o that only one of the syn or anti relationships between the two stereocenters can be accessed reliably and, in this case, prevents access to the desired product. This particular substrate has a y-stereocenter which may be exerting an influence on the selectivity Me 10barH2,EOH,50°C I mol% Ru((S)-MeO-BIPHEP Br2 HCl;H 0 HCLH OH O Boc Ome o oc-2S)-iso-dolaproine MeOY pph2 2S,3R)(2R,3S)92.5:7.5 (S)-MeO-BIPHEP Ru[(s)-MeO-BlPHEP Br2, H OEt Ru[(s)-Meo-BIPHEP Br2, H2 Genet Org. Lett. 2001, (3)1909. HCI, H HCL; H
M.W. Kanan/M.C.White Chem 153 Hydrogenation -173- Week of October 21, 2002 As part of an effort to develop a stereocontrolled synthesis of dolaproine, Genet and coworkers carried out the Noyori DKR shown below. Based on the literature precedents for DKR with α-methyl-substituted ß-keto esters. the authors were expecting a syn relationship between C2 and C3. Instead that observed very good diastereoselectivity in the formation of the undesired anti isomer. This example highlights a lilmitation of the Noyori methodology. In DKR of α-substituted-β-keto esters, the ligand on Ru controls the stereochemistry of the ketone being reduced, but the diastereoselectivity is controlled by the substrate. This means that only one of the syn or anti relationships between the two stereocenters can be accessed reliably and, in this case, prevents access to the desired product. This particular substrate has a γ-stereocenter which may be exerting an influence on the selectivity. N H O OH Me OMe 2R 3R 4S Dolaproine N O OEt Me H O PPh2 PPh2 MeO MeO 4S 3R N O OEt Me H OH 2S 4S 3R N O OH Me Boc OMe 2S HCl; HCl; 10 bar H2, EtOH, 50°C 1 mol% Ru[(S)-MeO-BIPHEP]Br2 (S)-MeO-BIPHEP Boc-(2S)-iso-dolaproine quant. yield (2S,3R):(2R,3S) 92.5:7.5 N O OEt Me H O N O OEt Me H O 4S 4S 3S 3R N O OEt Me H OH N O OEt Me H OH 2S 2R HCl; HCl; Ru[(S)-MeO-BIPHEP]Br2, H2 kfast Ru[(S)-MeO-BIPHEP]Br2, H2 kslow HCl; HCl; Stereoselective synthesis of iso-dolaproine: the power and limitations of DKR with α-substituted-β-keto esters Genet Org. Lett. 2001, (3) 1909
M C. White, Chem 153 Hydrogenation -174- Week of october 21. 2002 Non-directed carbonyl hydrogenations a reversal in chemoselectivity H2(10 atm), benzene 70oC under these conditions, ketones are not hydrogenated Suzuki Chem Lett. 19771085 RuCl(PPh3)3 0.5 me H,(29 atm), ethanol/benzene,rt strong preference for sterically unhindered olefins Suzuki Chem. Lett. 1977 1083 Hydrogenation conditions B Hydrogenation conditions a ICh(PPh3h, 0.2 mol% 250 x RuCl(PPh3h, 0.2 mol% faster H2(4 atm), 2-propanol/toluene, rtl 1500XNH2CH2N2(05m09%, KOH (1.0 mol%) H,(4 atm), 2-propanol/toluene, rt Bases have been used in conjunction with Ru(ll) catalysts to effect olefin hydrogenations. Recall that base is thought to promote NoyoriJACS 1995(117)10417 heterolytic cleavage of H2 to form the catalytically active Ru monohydride species. Therefore, the observed reversal in chemoselectivity must be primarily due to the added 1, 2 diamine Selective hydrogenation of carbonyl vS. olefinic functionality using hydrogenation conditions B 95% isolated yield 88% isolated yie 97% isolated yield 98.6: 1.4(unsat alcohol: sat alcohol) 100: 0(unsat alcohol: sat alcohol)98. 2: 1.8(unsat. alcohol: sat alcohol) OH isolated yie uantitative isolated yield 99.6: 0.4(unsat 70: 30(unsat alcohol:sat. 98% isolated yield alcohol: sat alcohol) alcohol) 100: 0(unsat alcohol: sat alcohol)
M.C. White, Chem 153 Hydrogenation -174- Week of October 21, 2002 Non-directed carbonyl hydrogenations: a reversal in chemoselectivity 0.5 mol% H2 (10 atm), benzene, 70oC 83% yield O OH The Original Report: under these conditions, ketones are not hydrogenated. Suzuki Chem. Lett. 1977 1085. 0.5 mol% H2 (29 atm), ethanol/benzene, rt 93% yield O O strong preference for hydrogenation of sterically unhindered olefins. Suzuki Chem. Lett. 1977 1083. RuCl2(PPh3)3 RuCl2(PPh3)3 Selective hydrogenation of carbonyl vs. olefinic functionality using hydrogenation conditions B: OH n-C8H17 OH OH OH OH OH 95% isolated yield 98.6:1.4 (unsat. alcohol: sat. alcohol) 88% isolated yield 100:0 (unsat. alcohol: sat. alcohol) 97% isolated yield 98.2:1.8 (unsat. alcohol: sat. alcohol) quantitative isolated yield 70:30 (unsat. alcohol: sat. alcohol) 98% isolated yield 100:0 (unsat. alcohol: sat. alcohol) 90% isolated yield 99.6:0.4 (unsat. alcohol: sat. alcohol) Noyori JACS 1995 (117) 10417. O + Hydrogenation conditions A: RuCl2(PPh3)2 ,0.2 mol% H2 (4 atm), 2-propanol/toluene, rt 250 x faster O + Hydrogenation conditions B: RuCl2(PPh3)2 ,0.2 mol% NH2(CH2)2NH2 (0.5 mol%), KOH (1.0 mol%) H2 (4 atm), 2-propanol/toluene, rt 1500 x faster Bases have been used in conjunction with Ru(II) catalysts to effect olefin hydrogenations. Recall that base is thought to promote heterolytic cleavage of H2 to form the catalytically active Ru monohydride species. Therefore, the observed reversal in chemoselectivity must be primarily due to the added 1,2 diamine
M.C. White, Chem 153 Hydrogenation -175- Week of october 21. 2002 Non-directed carbonyl hydrogenations Rul-H formed acts as a bulky hydride 1, 2-Diamine is a ligand for the Ru Reactive Ru-H species generated acts as a bulky source of hydride Both the chirality of the diphosphine(binap)and the 1, 2-diamineaffectthe stereochemical displaying similar diastereoselectivities observed with other stoichoimetric outcome of the carbonyl hydrogenation. Therefore, the diamine ligand is attached to the Ru large hydride reagents such as KBH(s-Bu)3 center during the catalytic cycle b. torsionally favored axial trajectory generally observed for non-bulky hydride (recall: avoids formation of M-H RuChlsr-binapI(dmf, 0.2 mol% b a sterically favored equatorial Diamine.5 mol%.KoH 1.0 mol% trajectory generally observed H,(4 atm), 28C,6h for bulky h (recall: avoids unfavorable teric interactions with diaxial H Phosphine Diamine %oee 97% H PPh2 H,N (S)- Hydride source atio(cis: trans) 7% H2N NH2 Li in NH3 (non-bulky KBH(s-Bu)3(bulky) RuCl(PPh3) 984:16 PPh(in RuCh(PPh ) 75% NH( CH,)NH,/KOH NoyoriJOC 1996(61)4874 NoyoriJACS 1995(117)2675 D.A. Evans. Chem 206 Notes. October 2000
M.C. White, Chem 153 Hydrogenation -175- Week of October 21, 2002 Non-directed carbonyl hydrogenations Noyori JOC 1996 (61) 4874. D.A. Evans. Chem 206 Notes. October 2000 Ru-H formed acts as a "bulky hydride" Reactive Ru-H species generated acts as a bulky source of hydride displaying similar diastereoselectivities observed with other stoichoimetric large hydride reagents such as KBH(s-Bu)3. O H t-Bu H H M-H M-H a. sterically favored equatorial trajectory generally observed for bulky hydride reagents (recall: avoids unfavorable steric interactions with diaxial H's during approach). b. torsionally favored axial trajectory generally observed for non-bulky hydride sources (recall: avoids formation of eclipsing interactions in TS) a b H t-Bu H t-Bu H OH OH H cis trans a b Hydride source Li in NH3 (non-bulky) KBH(s-Bu)3 (bulky) RuCl2(PPh3)3/ NH2(CH2)2NH2/KOH ratio (cis: trans) 1:99 97:3 98.4:1.6 O OH Ph Ph H2N NH2 Ph Ph H2N NH2 H2N NH2 PPh2 PPh2 Ph Ph H2N NH2 RuCl2[(S)-binap](dmf)n ,0.2 mol% Diamine 0.5 mol%, KOH 1.0 mol% H2 (4 atm), 28 oC, 6h Diamine % ee (S,S)-Diamine 97% 14% 57% 75% (R,R)-Diamine Phosphine (S)-Binap PPh3 (in RuCl2(PPh3)3) (S,S)-Diamine Noyori JACS 1995 (117) 2675. 1,2-Diamine is a ligand for the Ru Both the chiralityof the diphosphine(binap) and the 1,2-diamineaffectthe stereochemical outcome of the carbonyl hydrogenation. Therefore, the diamine ligand is attached to the Ru center during the catalytic cycle