Stereoselective Oxidation and Reduction Reactions Dr Simon Woodward School of Chemistry, University of Nottingham

Oxidation Reactions Epoxidation –Epoxide opening Dihydroxylation Aminohydroxylation Alcohol oxidation “Click Chemistry: Diverse Chemical Function from a Few Good Reactions” Kolb, Finn, Sharpless, Angew. Chem. Int. Ed. 2001, 40, 2004.

Sharpless Asymmetric Epoxidation of Allylic Alcohols Review: Katsuki and Martin, Org. React., 1996, 48, 1. Sharpless, J. Am. Chem. Soc., 1987, 109, Mechanism: J. Am. Chem. Soc., 1991, 113, 106 and 113. t BuOOH, Ti(O i Pr) 4, DET, CH 2 Cl 2, 4Å MS Hydroxamic acid ligands for Vanadium-catalysed asymmetric epoxidation of allylic alcohols: Yamamoto, J. Am. Chem. Soc. 2000, 122,

Chiral Mn(salen) Catalysts: Overview Stoichiometric co-oxidants: Usually aq. NaOCl, CH 2 Cl 2 mCPBA / NMO (low temperature ) Preparation of catalyst: Organic Syntheses, 1998, 75, 1. Polymer supported catalyst: e.g. Janda, J. Am. Chem. Soc., 2000, 122, Cis-Disubstituted alkenes: J. Am. Chem. Soc. 1991, 113, Trisubstituted alkenes: J. Org. Chem. 1994, 59, Tetrasubstituted alkenes: Tetrahedron Lett. 1995, 36, Cinnamate esters: Tetrahedron 1994, 50, Review: Katsuki Coord. Chem. Rev. 1995, 140, 189. Poor enantioselectivities for trans-disubstituted and terminal alkenes] (but see Katsuki, Synlett, 2000, 1557) Via radical intermediate, so stereospecificity with respect to alkene geometry sometimes eroded. Can use to make trans-epoxides from cis-alkenes: Jacobsen, J. Am. Chem. Soc. 1994, 116, Asymmetric epoxidation of E-alkenes using Cr(salens): Gilheany, Org. Lett. 2001, 3, 663, and refs. therein

Dioxiranes Isolation of dioxiranes: neutral, anhydrous oxidants Preparation of dimethyldioxirane (DMDO) solutions: Adam, Chem. Ber., 1991, 124, More concentrated, “acetone free” solutions: Messeguer, Tetrahedron Lett., 1996, 37, Electrophilic oxidants, but successful for epoxidation of electron poor alkenes: e.g. Baumstark, J. Org. Chem., 1993, 58, In situ dioxirane formation Biphasic, CH 2 Cl 2 / H 2 O: Denmark, J. Org. Chem., 1995, 60, Monophasic, CH 3 CN / H 2 O: Yang, J. Org. Chem., 1995, 60, In situ DMDO prep.: Shi, J. Org. Chem., 1998, 63, Trifluoroacetone + H 2 O 2 : Shi, J. Org. Chem., 2000, 65, 8808.

Chiral Dioxiranes: Asymmetric Epoxidation of trans-Alkenes Shi, J. Am. Chem. Soc. 1997, 119, Review: Shi, Synthesis, 2000, Preparation: 2 steps from D-fructose (enantiomer available in 5 steps from L-sorbose) Excellent enantioselectivities for epoxidation of trisubstituted and trans-disubstituted alkenes Poor ee for cis- and terminal alkenes Ketone decomposes by Baeyer-Villiger reaction - cannot be recycled. High pH conditions required. Other substrate types: Conjugated dienes: J. Org. Chem. 1998, 63, 2948 Enynes: Tetrahedron Lett. 1998, 39, Modified catalyst for cis-alkenes: J. Am. Chem. Soc. 2000, 122, Terminal alkenes: Org. Lett., 2001, 3, Stable catalysts: Armstrong, Chem. Commun. 1998, 625; Tetrahedron: Asymmetry, 2000, 11, Shi, Org. Lett. 2001, 3, 715.

Oxidation of silyl enol ethers Other methods for asymmetric oxidation of silyl enol ethers: Chiral Mn(salens): Thornton, Chem. Commun. 1992, 172; Adam, Tetrahedron Lett. 1996, 37, 6531, and refs. therein. Chiral oxaziridines: Review: Davis, Chem. Rev., 1992, 92, 919. Asymmetric dihydroxylation: J. Org. Chem. 1992, 57, Shi, Tetrahedron Lett. 1998, 39, 7819:

Hydrolytic Kinetic Resolution Jacobsen, Science 1997, 277, 936. Acc. Chem. Res. 2000, 33, 421. Catalyst can be recycled (AcOH, air) Easily-synthesised oligomeric Co(salen) catalysts are highly active for epoxide opening by water, alcohols and phenols: J. Am. Chem. Soc. 2001, 123, 2687.

Asymmetric Epoxidation of Electron-Deficient Alkenes Review: M.J. Porter and J. Skidmore, Chem. Commun., 2000, Polyleucine, H 2 O 2, base: e.g. Tetrahedron Lett., 2001, 42, Reviews: Tetrahedron: Asymmetry 1997, 8, 3163; 1998, 9, Catalytic Mg peroxides ( t BuOOH, cat. Bu 2 Mg, cat. diethyl tartrate): R 1, R 2 =Ph Jackson, Angew. Chem., Int. Ed. Engl. 1997, 36, 410. Chiral phase-transfer catalysts (R 2 can be alkyl): Lygo, Tetrahedron, 1999, 55, 6289; Tetrahedron Lett. 2001, 42, Lanthanide catalysis (BINOL, La(O i Pr) 3 or Yb(O i Pr) 3, 4Å MS, t BuOOH): R 1 =Ph, i Pr or Me; R 2 =Ph, i Pr, Ph(CH 2 ) 2 or Me. La-BINOL-Ph 3 AsO -mechanistic studies: J. Am. Chem. Soc., 2001, 123, Chiral hydroperoxides, KOH, CH 3 CN: Adam, J. Am. Chem. Soc., 2000, 122, Stoichiometric zinc alkylperoxides (O 2, Et 2 Zn, R*OH): R 1 =Ph or t Bu, R 2 =alkyl or aryl Enders, Angew. Chem. Int. Ed. Engl. 1996, 35, 1725; Liebigs Ann. Chem. 1997, 1101 Chiral dioxiranes: e.g. Tetrahedron: Asymmetry, 2001, 12, 1113.

Alkene Dihydroxylation Catalytic systems: NMO / acetone / H 2 O (Upjohn procedure): Tetrahedron Lett. 1976, 23, Cat. Me 3 NO2H 2 O, CH 2 Cl 2 : Poli, Tetrahedron Lett. 1989, 30, K 3 Fe(CN) 6, K 2 CO 3, t BuOH / H 2 O: Minato, Yamamoto, Tsuji, J. Org. Chem. 1990, 55, 766. NMO, PhB(OH) 2, CH 2 Cl 2 : Narasaka, Chem. Lett. 1988, Diol trapped as boronate ester - useful if diol is unstable or highly water soluble Selenoxides as co-oxidants: Krief, Synlett, 2001, 501. H 2 O 2, cat. flavin, cat. N-methylmorpholine: Backvall, J. Am. Chem. Soc. 1999, 121, 10424; J. Am. Chem. Soc. 2001, 123, H 2 O 2, cat. V(O)(acac) 2, NMM, acetone/water: Backvall, Tetrahedron Lett., 2001, 42, O 2, K 2 [OsO 2 (OH) 4 ], t BuOH / H 2 O: Beller, Angew. Chem. Int. Ed. 1999, 38, 3026; J. Am. Chem. Soc. 2000, 122, Wirth, Angew. Chem. Int. Ed. 2000, 39, 334. Fe-catalysed asymmetric dihydroxylation: Que, J. Am. Chem. Soc. 2001, 123, 6722.

Directed Dihydroxylations “Kishi rule” - dihydroxylation occurs anti- to oxygen functionality. Review: Cha, Chem. Rev. 1995, 95, Hydroxyl-directed dihydroxylation: Donohoe, Tetrahedron Lett. 1997, 38, Bidentate ligand required Dihydroxylation directed by trichloroacetamides: Donohoe, J. Org. Chem. 1999, 64, Catalytic directed dihydroxylation of cyclic trichloroacetamides: Donohoe, Tetrahedron Lett. 2000, 41, Syn-selective dihydroxylation of acyclic allylic alcohols: Donohoe, Tetrahedron Lett. 1999, 40, 6881.

Sharpless Asymmetric Dihydroxylation Review: Sharpless, Chem. Rev. 1994, 94, DHQD= dihydroquinidine DHQ= dihydroquinine "pseudoenantiomers" DHQ series DHQD series

Sharpless AD: Recent Developments Improved ligands: Pyrimidine (PYR) spacer for sterically congested / terminal alkenes: J.Org. Chem. 1993, 58, Anthraquinone (AQN) spacer gives better results for almost all alkenes having only aliphatic substituents: Angew. Chem. Int. Ed. Engl. 1996, 35, 448. Mechanism: Comparison of theoretical and experimental kinetic isotope effects supports [3+2]-mechanism Sharpless, Houk et al. J. Am. Chem. Soc. 1997, 119, Origins of asymmetric induction: Sharpless: J. Am. Chem. Soc. 1997, 119, Corey (“enzyme like” binding pocket): J. Am. Chem. Soc. 1996, 118, 319; Polymer supported chiral ligands: Review: Synlett, 1999, Crudden, Org. Lett. 2001, 3, Bolm, Synlett, 2001, 93 (AQN-ligands). Polymer supported Os-catalyst: Kobayashi, J. Am. Chem. Soc. 1999, 121, Org. Lett. 2001, 3, Importance of pH control: improved rates for internal olefins at pH 12 (no MeSO 2 NH 2 ); higher ee for terminal olefins at pH 10: Beller, Tetrahedron Lett. 2000, 41, 8083.

Aminohydroxylation Review: O’Brien, Angew. Chem., Int. Ed. Engl. 1999, 38, 326. DHQD-ligand series generally provide opposite enantiomer. Effect of substrate structure on regioselectivity: Janda, Chem. Eur. J. 1999, 5, Cinnamates: Styrenes, Aryl alkenes (X=Ts, CBz, Boc, Teoc): Altering ligand spacer, solvent can reverse regioselectivity without decreasing ee! Aryl esters (and AQN-ligands) give opposite regioselectivity! Panek, Org. Lett. 1999, 1, Can be run at higher concentration in presence of acetamide to suppress diol formation: Wuts, Org. Lett. 2000, 2, 2667.

Recent Developments in Asymmetric Aminohydroxylation Amino-substituted heterocycles as nitrogen sources: Sharpless, Angew. Chem. Int. Ed. Engl. 1999, 38, Adenine derivatives as N-source: Sharpless, Tetrahedron Lett. 1998, 39, N-bromo-N-lithio salts of primary carboxamides as N-source: Sharpless, Org. Lett. 2000, 2, Unsaturated phosphonates as substrates: Sharpless, J. Org. Chem., 1999, 64, 8379.

Pd-Catalysed Oxidative Kinetic Resolution of Secondary Alcohols with O 2 Sigman, J. Am. Chem. Soc. 2001, 123, Stoltz, J. Am. Chem. Soc. 2001, 123, 7725.

Reduction Reactions Hydrogenation Transfer hydrogenation Boranes Hydride reagents Hydrosilylation Asymmetric reduction of alkenes, ketones, imines…….

Monsanto synthesis of L-DOPA

Rh(I)-BINAP Complexes Noyori, J. Am. Chem. Soc. 1980, 102, Ru BINAP complexes are more general; work for e.g. simple acrylic acids. Mechanistically distinct: Tetrahedron Lett. 1990, 31, 7189.

Rh(I)-diphosphole Complexes Review: Burk, Acc. Chem. Res. 2000, 33, 363 sense of enantioselectivity independent of acrylamide geometry

Monodentate ligands MonoPhos: deVries, Feringa, J. Am. Chem. Soc. 2000, 122, Ligand A: Reetz, Angew. Chem. Int. Ed. 2000, 39, Review: Angew. Chem. Int. Ed. 2001, 40, 1197.

Asymmetric Hydrogenation of Functionalised Ketones Ru BINAP: J. Am. Chem. Soc. 1987, 109, 5856; J. Am. Chem. Soc. 1988, 110, 629. Ru BPE: J. Am. Chem. Soc. 1995, 115, Review: Ager, Tetrahedron Asymm. 1997, 8, 3327.

Mixed Ru bisphosphine/diamine complexes afford much improved turnover numbers: Basic conditions allow dynamic kinetic resolution: Noyori, J. Am. Chem. Soc. 2000, 122, Also for reduction of unfunctionalised ketones. Review: Noyori, Angew. Chem., Int. Ed., 2001, 40, 40. Catalytic asymmetric hydrogenation of aminoketones

Asymmetric Transfer Hydrogenation of Ketones Reduction with the aid of a hydrogen donor in the presence of a catalyst Reviews: Wills, Tetrahedron Asymmetry, 1999, 10, 2045; Noyori, Acc. Chem. Res. 1997, 30, 97. Aminoalcohols as ligands: Arylalkylketones with electron rich aryl groups and benzocycloalkanones suffer from reversibility and give lower ee…but aminoalcohols are generally not compatible with the irreversible hydride donor formic acid

Monotosylated diamines: formic acid-tolerant ligands for transfer hydrogenation - monotosylated diamines give slightly less reactive catalysts than the amino alcohols but have proven to be a more useful ligand system for ruthenium based transfer hydrogenations since compatibility with the formic acid system allows efficient reduction even in readily reversible systems:

Ketone Reduction Catalyzed by Oxazaborolidines Review: Angew Chem. Int. Ed. 1998, 37, 1986

Polymer-supported amino alcohol and in situ generation of borane Angew. Chem. Int. Ed., 2001, 40,1109

Asymmetric reduction of ketones: stoichiometric aluminium hydrides Noyori, J. Am. Chem. Soc., 1984, 106, 6709, 6717

A catalytic binapthyl-substituted hydride source based on hard-soft principles Woodward, Angew. Chem., Int. Ed. Engl., 1999, 38, 335; Chem. Eur. J. 2000, 6, replacing 'hard' aluminium by 'soft' gallium, the intermediate 'hard' alkoxide can be transferred to the 'hard' borane stoichiometric co-reductant, allowing catalytic turnover:

Organometallics, 1991, 10, 560;Tetrahedron:Asymm., 1991, 2, 919 Hydrosilylation of imines/ketones: an alternative to hydrogenative reduction

Asymmetric hydrosilylation of ketones and imines using cheap siloxanes PMHS = poly(methylhydrosiloxane) J. Am. Chem. Soc., 1999, 121, 5640 (ketone); Angew. Chem., Int. Ed. Engl., 1998, 37, 1103, Org. Lett., 2000, 2, 713 (imine)

Catalytic asymmetric hydrosilylation of enones/enoates Buchwald, J. Am. Chem. Soc., 1999, 121, 9473; J. Am. Chem. Soc., 2000, 122, 6797