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Cinchona Alkaloids in Asymmetric Catalysis

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Cinchona Alkaloids in Asymmetric Catalysis Cinchona Alkaloids in Asymmetric Catalysis Rob Moncure MacMillan Group Meeting August 13, 2003 Introduction Cinchona Alkaloids in Phase Transfer Catalysis Cinchona Alkaloids as Nucleophiles/Bases Sharpless Asymmetric Dihydroxylation Useful Reviews Kacprzak, K. et al. Synthesis, 2001, 7, 961-988. Kwan, B.; MacMillan, D.W.C.; New Strategies for Organocatalysis: Enantioselective Amine Catalysis. 2003, unpublished. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483. H Introduction to Cinchona Alkaloids H H N HO MeO ! Quinine isolated by Pelletier in 1820. N ! First used for a resolution of a racemate in 1853 by Pasteur. Quinine ! Quinine and derivatives were quickly recognized as antimalarial agents. R R2 H 2 H H H HO N N HO pseudoenantiomers H H R R1 1 N N R = OMe R1 = OMe 1 R = vinyl Quinine R2 = vinyl Quinine 2 Dihydroquinine R = Et Dihydroquinine R2 = Et 2 R = H R1= H 1 R = vinyl Cinchonidine R2 = vinyl Cinchonidine 2 R = Et Dihydrocinchonidine R2 = Et Dihydrocinchonidine 2 1 H The First Total Synthesis H H N HO MeO ! Quinine was first synthesized by R.B. Woodward in 1944. N Quinine Me OH OH N H SO N OH 2 4 N EtO OEt Me Me OH OH AcN 1. H CrO , AcOH H2, Pt HN 1. Ac2O, MeOH 2 4 2. EtOH/NaOEt, EtONO HOAc 2. H2, EtOH, Raney Ni + trans CO2Et CO2H Me 1. H2, AcOH Quinine N OH 2. MeI, EtOH, K2CO3 N 3. 60 % NaOH Ac N Woodward, R. B. et al. J. Am. Chem. Soc. 1944, 66, 849. Ac Woodward, R. B. et al J. Am. Chem. Soc. 1945, 67, 860. Cinchona Alkaloids Are Versatile Catalysts ! These are just a few of the reactions that can be performed asymmetrically. C-C Bond Forming C-O Bond Forming C-X Bond Forming Alkylation Epoxidation of Enones Aziridination Aldol Epoxidation of cis-Olefins Azirination Darzens Asymmetric Dihydroxylation Formation of !-Hydroxyphosphonate Esters Michael Addition Asymmetric Aminohydroxylation Addition of Thiols to Cyclic Enones Diels-Alder !-Hydroxylation of Ketones Claisen Rearrangement Miscellaneous Reactions Hydrogenation Desymmetrization Decarboxylation ! Cinchona Alkaloids have been explored in asymmetric synthesis for the last 35 years. H Li H H O N H3Al OH O MeO Me Me N Ether 48% ee Cervinka, O.; Belovsky, O. Coll. Czech. Chem. Commun., 1967, 30, 2487. 2 Br H Cinchona Alkaloids as Phase Transfer Catalysts H H HO N MeO ! Alkylation of Substituted Indanones Ph N Cl O Cl O PTC Cl MeCl Cl Ph Ph 10-50 mol% PTC Me MeO Toluene, aq. NaOH, 20°C MeO 95% yield, 92% ee ! Ion pairing between indanone anion and PTC proposed as reason for selectivity H Cl H O H -face blocked in rigid conformation, opens HO N ! Cl "#face to methylation MeO MeO N Dolling, U. -H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446. O'Donnell: Pioneer in PTC with Cinchona Alkaloids Cl H H H HO N ! Efforts to synthesize chiral !"amino acids MeO Ph O O Ph 10 mol % PTC Ph N N R-Br N t-BuO t-BuO Ph Ph 50% aq. NaOH / CH2Cl2 PTC RT R R Time % Yield % ee Allyl 5 75 66 Bn 9 75 66 Me 24 60 42 n-Bu 14 61 52 C6H4Cl-4 12 81 66 CH2-2-naph 18 82 54 ! Recrystallization procedures were developed to obtain enantiopure compounds, but low yields indicated a need for improvement. O'Donnell, et al. J. Am. Chem. Soc. 1989, 111, 2353. 3 Cl H Mechanism for Phase-Transfer Alkylation H H HO N MeO Ph ! Proposed Mechanism for O'Donnell's PTC Alkylation N * (R4N) O Ph O Ph 2 N R -X Organic Phase R1O N Ph R1O Ph O Ph N R1O Ph Base R2 Base-H Aqueous Phase X O * Ph (R4N) X N R1O Ph Corey Modifications to O'Donnell's Work Br H H N ! By using 9-(chloromethyl)anthracene to quaternize the PTC, approach from the front and right side of the catalyst is blocked. N O ! Corey chose to block ion-pairing from the bottom face of the catalyst by O-allylation. ! Therefore, the top left quadrant is now the only region open to the substrate. PTC O O Ph 10 mol % PTC Ph N R-Br N t-BuO t-BuO Ph Ph Solid CsOH, H2O / CH2Cl2 -60°C or -78°C R R Time / % Yield / % ee / % Me 28 71 97 Et 30 82 98 n-Hexyl 32 79 > 99 CH2c-C3H5 36 75 99 Allyl 22 89 97 Methallyl 20 91 92 CH2C CTBS 18 68 95 Bn 22 73 > 99 ! Enantioselectivity greatly enhanced by Corey's rational approach to catalyst design. Corey arrived at these results while trying to understand the origin of enantioselectivity in the Sharpless Asymmetric Dihydroxylation. For relavent references, see the Kwan review. 4 An Interesting Sterics Versus Electronics Argument ! Corey then tried a different experiment using diphenylalkylidene as a substrate, under the same conditions. R R Br H H N CO t-Bu 10 mol % PTC 2 Br CO2t-Bu O CsOH H2O N CH2Cl2 : Et2O (1 : 1) -65 °C R R PTC R !p ee / % Ph 0.00 67 t-Bu -0.15 81 OMe -0.28 91 NMe2 -0.63 96 ! He found that the more electron-donating the subsituent on the phenyl ring, the more enantioselective the reaction. ! He then theorized that the more electron donating, the more negatively the ester oxygen is charged, and therefore the more tightly it can bind to the catalyst, thereby enhancing the selectivity. Corey, E. J. et al. J. Am. Chem. Soc. 1998, 120, 13000. Corey's Catalyst Applied to Epoxidation of Enones Br H ! Corey's catalyst modifications proved successful in the H epoxidation of certain enones. N O O 10 mol % PTC O N O R R KOCl, Toluene, -40°C X 12 h X R X Yield / % ee / % PTC C6H5 H 96 93 C6H5 F 93 98 C6H5 Br 92 93 C6H4NO2-4 H 90 94 C6H4NO2-4 F 97 95 n-C5H11 F 90 91 c-C6H11 H 85 94 c-C6H11 F 87 95 C6H5 OC6H5 89 93 2-naphthyl H 97 93 ! Exocyclic enones were epoxidized, though with extensive erosion in enantioselectivity. Corey, E. J.; Zhang, F. -Y. Org. Lett. 1999, 1, 1287. 5 Aldol Reaction with Cinchona Derivatives ! Shibasaki was the first to report an aldol reaction using a Cl Cinchona-derived catalyst. OMe H H O CHO O NO2 N 10 mol % PTC OH CH3NO2 15 mol % KF N OH Toluene, -20 °C, 19 h 41 % yield, PTC 23 % ee ! At the same time, Shibasaki was developing a lanthanum BINOL catalyst and was achieving better results, so he did not pursue the matter further. ! Corey used a derivative of the epoxidation catalyst to develop this methodology for ester enolate equivalents. OTMS Ph O 10 mol % PTC-2 O OH N t-BuO 3:1 / CH Cl : Hexanes Ph R H 2 2 t-BuO R -78 °C NH2 R Yield / % syn : anti syn ee / % F H i-Pr 70 6 : 1 83 H N c-C6H11 81 13 : 1 46 n-C6H13 79 3 : 1 91 (CH ) Cl 48 1 : 1 86 2 3 N O (CH2)2Ph 64 1 : 1 86 i-Bu 61 3 : 1 70 Ph Corey, E. J. ... Angew. Chem. Int. Ed. 1999, 38, 1931. Corey, E. J. ... Tetrahedron Lett. 1999, 40, 3843. Shibasaki, M. et al. Tetrahedron Lett. 1993, 34, 855. PTC-2 6 PTC with Cinchona Alkaloids in Total Synthesis ! Corey extended this methodology to develop a diastereoselective Henry reaction starting with chiral aldehydes in order to synthesize Amprenavir, an HIV-protease inhibitor. F H H N N O O OH 10 mol % Bn2N Ph Bn2N NO2 H CH3NO2 Ph 12.5 equiv KF Ph THF, -10 °C, 6 h 86 % yield 17 : 1 dr OH ! The key step of Corey's Amprenavir O NH N SO2 synthesis, the Henry reaction of nitroethane O and the chiral aldehyde, proceeded in good Ph yield with excellent selectivity. Amprenavir NH2 ! The same model for selectivity as in the PTC-alkylation can be proposed here. The !- stacking between the aromatic aldehyde and the aromatic rings on the catalyst leave only one face of the aldehyde open to nucleophilic Corey, E. J. et al. Angew. Chem. Int. Ed. 1999, 38, 1931. attack. Cinchona Alkaloids as Nucleophilic Catalysts ! In 1989, Kagan reported the first asymmetric cycloaddition OMe with chiral amines acting as basic catalysts. OH H O O 10 mol % Amine N Me N N Me N CHCl3, -50 °C O H 15 min O O HO Amine 97 % yield 61 % ee (endo) O O Me ! Mechanism 1: N H * NR2 N Me O O O O O O H N Me O ! Mechanism dismissed. Subjection of the conjugate adduct to reaction conditions failed to produce the cycloaddition product. HO ! Mechanism 2: ! In this mechanism, the deprotonated anthrone N forms an ion-contact pair with the quaternized OMe nitrogen of the catalyst. Meanwhile, the H O dienophile is hydrogen-bonded through the H Me N O hydroxyl group of the catalyst. O H N O Kagan, H. B.; Riant, O. Tetrahedron Lett. 1989, 52, 7403. H 7 Catalytic Asymmetric Synthesis of !"Lactones ! In 1982, Wynberg published one of the first truly remarkable OMe results in asymmetric catalysis. H O OH O O 2.5 mol % Amine O N Cl C H Toluene, -50 °C, 1 h N 3 Cl C H H H 3 95 % yield Amine 98 % ee ! Based on this result, he attempted to expand substrate scope to include ketones.
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