Mechanism Problem 1. NaH allyl bromide, THF N 2. 9-BBN (1.2 equiv), THF, rt; N H NaOMe (1.2 equiv); t-BuLi (2.4 equiv), TMEDA (2.4 equiv) –30 to rt; allyl bromide; 30% H2O2, aq. NaOH, 0 °C (58% yield) Mechanism Problem 9-BBN OMe N N N H BR2 t-Bu H Li N OMe N OMe B B HR2 HR2 Br OOH BR BHR 2 2 BHR2 alkyl N N migration N OH H + R2B O O BR2 -H N N N N Terashima, TL 1992, 33, 6849-6852. Enantioselection by C1-Symmetric Ligands Design and Applications in Asymmetric Catalysis Boram Hong Stoltz Group January 10, 2011 Privileged Ligand Structures Prevalence of C2-symmetry R Ph Ph R P O O R O OH R R N N P O OH R R R Ph Ph BOX BINOL (R = OH) TADDOL DuPhos BINAP (R = PPh2) N Et N N Et O O N N N MeO OMe R OH HO R N N R R Cinchona alkaloid SALEN Diverse applications: Diels-Alder, hydrogenation, Mukaiyama aldol, conjugate additions, cyclopropanation, epoxidation Jacbosen, Science 2003, 299, 1691–1693. First C2-symmetric ligands DIOP & DIPAMP Kagan's DIOP – Ligand conformations must have maximum rigidity O O – Ligands must stay firmly bonded to the metal Ph2P PPh2 – Avoid competing, diastereomeric transition states via C2-symmetry DIOP Ph NHCOMe Ph NHCOMe [RhCl(cyclooctene)2]2 H DIOP, H2 COOH EtOH/PhH COOH (95% yield) 72% ee Knowles' DIPAMP OMe MeO COOH Rh(I) MeO COOH DIPAMP * P P NHAc H2 NHAc AcO AcO MeO 95% ee DIPAMP Kagan, J. Am. Chem. Soc. 1972, 94, 6429-6433. Knowles, Adv. Synth. Catal. 2003, 345, 3-13. Rational Design of C1-symmetric Bisphosphine Ligand Electronic and Steric Asymmetry – Mechanism of asymmetric hydrogenation of dehydroamino acids reported by Halpern – Oxidative addition of H2 is rate-determining step – Important interactions: occupied dyz of Rh and σ* of hydrogen d-π* back-donation from Rh to olefin R1 Pcis NH * Rh RO2C Ptrans O Pcis : steric control (enantioselection) Ptrans : electronic control – Distinct roles; need to optimize each phosphine group individually Achiwa, Synlett 1992, 169-178. Electronic Desymmetrization Controlling Regioselectivity – Faller studied nucleophilic addition reactions on unsaturated ligands bound to Mo Mo Mo ON CO ON CO endo isomer exo isomer preferred HO OH– Mo Mo 95% regioselectivity ON CO ON CO - H+ - H+ Mo Mo Mo ON CO ON CO ON CO not observed Faller, J. Am. Chem. Soc. 1984, 3, 1231-1240. Rational Design of C1-Symmetric Bisphosphine Ligand Electronic and Steric Asymmetry Ph2P Cy2P PPh2 PPh2 N N CO2t-Bu CO2t-Bu BPPM BCPM (2S, 4S)-N-butoxycarbonyl-4-diphenylphosphino-2- diphenylphosphinomethylpyrrolidine Ph NHCOMe Rh(I), BPPM Ph NHCOMe * Et3N, H2 COOH EtOH COOH Ph2 O 91% ee P O Rh N P Ph2 t-BuO2C HOOC COOH COOH Rh(I), BCPM * Et N, H COOH 3 2 COOH MeOH 92% ee Achiwa, J. Am. Chem. Soc. 1976, 98, 8265. Achiwa, Synlett 1992, 169-178. Rational Design of C1-Symmetric Bisphosphine Ligand Electronic and Steric Asymmetry Cy2P PPh Ph NHCOMe Rh(I), BCPM Ph NHCOMe 2 * N H2 COOH EtOH COOH CO2t-Bu 37% ee BCPM Ph NHCOMe Rh(I), MOD-BPPM Ph NHCOMe * H2 COOH EtOH COOH 99% ee cis (enantioselecting function) Ar2P OMe steric effect of m-methyl groups PAr2 N Ar= OMe CO t-Bu 2 trans (rate-acceleration) OMe MOD-BPPM electron-donating effect Achiwa, Synlett 1992, 169-178. Rational Design of C1-Symmetric Bisphosphine Ligand Development of Modified DIOP ligand O O O O Ph2P PPh2 Ph2P PCy2 DIOP DIOCP Rh(I), DIOP O O O H2 HO THF * O O 52% ee – activity and enantioselectivity of catalyst enhanced by desymmetrization of DIOP Rh(I), DIOCP O O O H2 HO THF * O O 75% ee Achiwa, Synlett 1992, 169-178. From C2-Symmetric to Nonsymmetrical Ligands BOX to PHOX CN O O N N N N H R R R R Semicorrins BOX MeO2C CO2Me OAc [Pd(C H )Cl] (1 mol%) 3 5 2 * L* (2.5 mol%) O O O O Ligand Conditions % yield % ee N N N N 1 NaCH(CO2Me)2, THF, 50 °C 86 77 Ph Ph Ph Ph CH (CO Me) , BSA, KOAc 1 2 2 2 2 2 97 88 CH2Cl2, 23 °C N O O 3 99 95 Ph Ph " N N N N 4 " 97 97 OR RO OR RO 3 4 R= SiMe2t-Bu Pfaltz, Acc. Chem. Res. 1993, 26, 339-345. From C2-Symmetric to Nonsymmetrical Ligands BOX to PHOX Nu O O Nu N N Ph Ph Ph Ph R Pd R Ph Ph R = benzyl Nu- H Ph H Ph H H R Nu R Nu R Ph Ph R Ph R Ph R – steric repulsion between allylic phenyl group and benzyl substituent – nucleophile attacks the longer, more strained Pd–C bond: strain release Pfaltz, Acc. Chem. Res. 1993, 26, 339-345. Controlling Regioselectivity via Electronic Differentiation PHOX O O O N N Ph P N R R 2 R BOX PHOX – Desymmetrize N,N-ligand to mixed donor P,N-ligand – "soft" P-ligand (π−acceptor) and "hard" N-ligand (σ−donor) – exploit trans influence of P atom MeO2C CO2Me OAc [Pd(C H )Cl] (1 mol%) 3 5 2 * L* (2.5 mol%) NaCH(CO2Me)2 98.5% ee MeO2C CO2Me OAc [Pd(C H )Cl] (1 mol%) 3 5 2 * L* (2.5 mol%) NaCH(CO Me) 2 2 94% ee Pfaltz, Proc. Natl. Acad. Sci. 2004, 101, 5723-5726. Pfaltz, Acc. Chem. Res. 2000, 33, 336-345. Controlling Regioselectivity via Electronic Differentiation PHOX H H O O N exo N P P endo Pd Pd 9 : 1 Ph Ph Ph Ph Nu- – high exo/endo selectivity through sterics – enantioselectivity controlled by electronics (trans influence guides regioselectivity) H O N P Ph Ph Pd Ph E E Ph E E Pfaltz, Acc. Chem. Res. 2000, 33, 336-345. Controlling Regioselectivity via Electronic Differentiation PHOX Cyclic substrates OC H3COOC COOCH3 OC CO O Mn - N Nu Pd P 95% ee Nonsymmetrical substrates O A O A B B N P X N P X Pd X Pd X R R Nu- R R O O Ts - L = N OAc Nu Nu Nu N P [PdL*] : N R * R R t-Bu Ts - 84 : 16 94% ee (R = phenyl) Nu = NaCH(CO2Me)2 98 : 2 98% ee (R = 1-naphthyl) – Usually Pd complexes favor linear products – More cationic Pd and bulky phosphine favors branched products Pfaltz, Acc. Chem. Res. 2000, 33, 336-345. C2-Symmetric N,N-ligands Sulfoximines Pd dba (4 mol%) 2 3 Me Br O rac-BINAP (8 mol%) O Me O 5 equiv S NH S N N S Ph NaOt-Bu, toluene Br Me 135 °C, 10 h (70% yield) (S,S)-1 BiSOX O (S,S)-1 (5 mol%) Cu(OTf) (5 mol%) H OEt 2 98% ee endo:exo 99:1 MS 4 Å, CH2Cl2 O O CO2Et (81% yield) O O (S,S)-1 (5 mol%) Cu(OTf) (5 mol%) CO Et EtO OEt 2 2 98% ee MS 4 Å, CH2Cl2 O O CO2Et –40 °C (92% yield) Bolm, J. Am. Chem. Soc. 2001, 123, 3830-3831. From C2- to C1-Symmetric Sulfoximines – Spectroscopic investigations of BiSOX Cu(II) complexes revealed distorted, nonsymmetric square pyramidal geometry – Two coordinating sulfoximine nitrogens occupy non-equivalent positions O NH Pd2dba3 (5 mol%) rac-BINAP (10 mol%) O S R R 1 2 Cs2CO3, toluene R1 S N N N R3 110 °C, 20 h R Br R2 3 O Ligand Cu(OTf) H OEt 2 CH2Cl2, rt O O CO2Et entry ligand % yield %ee endo:exo 1 1 62 99 99:1 O Me O Me O S N N S Me S N N 2 2 98 91 98:2 OMe H 3* 2 65 96 99:1 (S,S)-1 (R)-2 *with Cu(ClO4)2, –10 °C BiSOX Bolm, J. Am. Chem. Soc. 2003, 125, 6222-62227. Bolm, Chem. Commun. 2003, 2826-2827. From C2- to C1-Symmetric Sulfoximines Mechanistic Model O O N S O N Cu O vs N Me O S N Cu O O O Me O O A B favored – Enantioselectivity of the reaction is determined by the coordination mode of substrate O O Me S N N t-Bu S N N H OMe H 75% ee 0% ee Bolm, Chem. Commun. 2003, 2826-2827. C1-Symmetric P,N-ligand in Enyne Cyclization E [(MeCN)4Pd](BF4)2 (5 mol%) Ligand (10 mol%) E HCOOH (1 equiv) DMSO, 80 °C X X X = C(CO2Et)2, E = CONMe2 O O O PAr 2 N ligand time % yield % ee config. PAr t-Bu O 2 PPh2 1 3 >99 6 S O 1 2 2 24 42 81 S 3 9 >99 86 S O O N N 4 t-Bu PPh 24 9 50 R PPh2 2 3 4 – C1 symmetry yields better enantioselectivities than C2 symmetry – Sense of chirality does does not matter Mikami, Eur. J. Org. Chem. 2003, 2552-2555. C1-Symmetric P,N-ligand in Enyne Cyclization Rational Design of Optimized Ligand X-ray analyses reveals: IV I less hindered * O O little P N N difference Pd PPh2 X X R R hindered III II 5 E [(MeCN)4Pd](BF4)2 (5 mol%) Ligand 5 (10 mol%) E HCOOH (1 equiv) DMSO, 80 °C X X X = C(CO2Et)2, E = CONMe2 (>99% yield) 95% ee previous best 86% ee (with t-Bu ligand) Mikami, Eur.