Asymmetric Catalysis by Lewis Acids and Amines Asymmetric Lewis acid catalysis - Chiral (bisooxazoline) copper (II) complexes - Monodentate Lewis acids: the formyl -bond Amine catalysed reactions
Asymmetric Lewis acid catalysis of organic reactions complexation of a Lewis acid to a π-system (localised or extended) places an increased partial positive charge in the system, lowers the energy of the LUM and facilitates attack by nucleophiles or cycloaddition to electron rich dienes/dienophiles/dipoles/dipolarophiles: X =, " X ' or ' X X =, " X δ LA - ' δ ' X LA - aldol/ Mannich allylation ene hetero- Diels-Alder Michael addition cycloaddition
rganising principles: Bidentate Coordination M M Chiral (bisooxazoline) copper (II) complexes as versatile Lewis acid catalysts Evans, Acc. Chem. es. 2000, 33, 325. 2 conformationally restricted; high selectivity Cu 2 X - (Distorted) square planar geometry at Cu
C 2 -symmetrical bis-oxazoline-metal complexes as catalysts: Diels-Alder copper-box catalysts promote asymmetric Diels-Alder reactions with oxazolidinone-substituted dienophiles catalyst: Cu 2 2 X - 10% catalyst DCM, 25 o C X = Tf: 90% ee X = SbF 6 : 96% ee SbF 6 - gives faster reaction and higher ee's than Tf - - attributed to detrimental competitive co-ordination of Tf - ; SbF 6 - catalyst also works as hydrated form. conformationally restricted; high selectivity Cu 2 2 X - Cu X X - conformationally free; low selectivity Evans, J. Am. Chem. Soc., 1993, 115, 6460; Angew. Chem., Int. Ed. Engl., 1995, 34, 798; J. Am. Chem. Soc., 1999, 121, 7582 Acc. Chem. es. 2000, 33, 325.
Catalytic asymmetric Diels-Alder reactions of 2-azadienes Synthesis of 2-pyridones: TMS 8% Tf Cu Tf DCM, 4Å sieves, then Me (B in this case, the TMS-group makes the diene electron rich) 96% 99:1 exo:endo 94% ee L. Ghosez, J. Am. Chem. Soc., 1999, 121, 2617
xo Diels-Alders: carbonyls as dienophile and diene aldehydes bearing an additional co-ordinating group undergo asymmetric hetero-diels-alder reactions: Bn Me TMS 5% Cu Tf Tf -78 o C, C 2 Cl 2 76% 85% ee Bn Ghosh, Tetrahedron Lett., 1997, 38, 2427 α,β-unsaturated ketones act as electron-poor dienes with electron-rich dienophiles: Et 10% 2 Cu 2 Tf - TF, -78 o C Et 96% >99:1 endo:exo 99.5% ee diene portion Jørgensen, Angew. Chem., Int. Ed. Engl., 1998, 37, 2404 For a (very!) closely related study, see: Evans, Angew. Chem., Int. Ed. Engl., 1998, 37, 3372
Asymmetric ene reaction ethyl glyoxalate undergoes ready ene reaction with a range of alkenes to generate homoallylic alcohols TBDPS Et 10% catalyst TF, 0 o C TBDPS C 2 Et 96% ee catalyst: Cu 2-2 SbF 6 Evans, J. Am.Chem. Soc., 1998, 120, 5824
Bidentate coordination: M rganising principles M But levels of asymmetric induction are often surprisingly high even for monodentate substrates (e.g. aldehydes)... Corey has recently put forward an explanation... Formyl -bond: eview: Corey, Chem. Commun., 2001, 1321. B - F F F B X - Y - attractive interaction controls conformation. Evidence: X-ray crystal structures. Calculations suggest the interaction may be due to a combination of electrostatic attraction and an anomeric effect (donation from aldehyde lone-pair into C-F σ*).
Amino acid based B and Al catalysts for monodentate dienophiles - the formyl C- bond Br C 5 mol% catalyst DCM, -78 o C Br >99% ee C Catalyst: Ts B Bu E. J. Corey, J. Am. Chem. Soc., 1991, 113, 8966 For catalyst structure studies, see: E. J. Corey, J. Am. Chem. Soc., 1992, 114, 8290 For an example with a related aluminium-based catalyst, see: E. J. Corey, J. Am. Chem. Soc., 1996, 118, 5502 levels of asymmetric induction with monodentate dienophiles are surprisingly high, given that rotation around the -M bond exposes enantiotopic faces of the dienophile: M * M * Explanation: formyl -bond (see earlier!) Br 2 S B Bu E. J. Corey, Tetrahedron Lett., 1997, 38, 33, 37, 1699 and 4351 tol
rganic catalysis of the Diels-Alder reaction: a new paradigm? problems with Lewis acid catalysis of Diels-Alder reactions: generally need reactive dienes (eg siloxydienes, cyclopentadiene), anhydrous conditions and moderate to low temperatures. A new approach based upon organic catalysis circumvents all of these problems: Iminium ion formation for dienophile activation: 2 2 2 LUM activated cf. LA - Diels-Alder 2 2 catalyst = Ac 20 mol% cat. 23 o C, Me/ 2 Ac 72% 11:1 endo:exo 85% ee 20 mol% cat. 23 o C, Me/ 2 75% 90% ee C this approach is, in theory, general to any class of reactions involving Lewis acid activation of extended conjugated systems (eg other cycloadditions, Michael additions etc) MacMillan, J. Am. Chem. Soc., 2000, 122, 4243
Stereocontrol elements (i) (ii) (iii) E-iminium formed selectively to avoid non-bonding interactions with geminal-dimethyl group s-cis conformation of single bond between iminium and alkene preferred Benzyl group shields top (re) face, leading to approach of diene from bottom (si) face C First general enantioselective catalytic Diels-Alder reactions of simple α,β-unsaturated ketones: J. Am. Chem. Soc. 2002, 124, 2458.
Asymmetric 1,3-Dipolar Cycloaddition MacMillan, J. Am. Chem. Soc., 2000, 122, 9874. Bn - Lewis acid (LA) 2 Cl Bn LA Bn - 2 Inhibition of [32] Activation of [32] 20 mol% Bn - Cl C 3 2-2 Bn Bn via: C endo endo:exo 96:4 98% yield 94% ee (exo) C exo - Bn
Enantioselective Friedel-Crafts Alkylation MacMillan, J. Am. Chem. Soc., 2001, 123, 4370. 20 mol% C TF- 2 CF 3 C 2 C = alkyl,, C 2 Me Yields 72-90% 87-93% ee via: Sterics of catalyst prevent 1,2-attack on iminium Also indole alkylation (modified catalyst): J. Am. Chem. Soc., 2002, 124, 1172.
2 X Enantioselective 1,4-Addition of Anilines to α,β-unsaturated Aldehydes MacMillan, J. Am. Chem. Soc., 2002, 124, 7894. C 20 mol% t Bu C 2 Cl 2 Cl 2 X C X = Alkyl, aryl, C 2 Me; = Me, pyrrolidinyl 70-90% yield 84-99% ee - Common natural product subunit (>5000 examples) - Privileged structural motif in medicinal chemistry via: t Bu
emoval of amino group 10 mol% Me 2 Me C t Bu C 2 Cl 2 Cl Me 2 Me C Me Si t BuMe 2 MeI a/ 3, -78 C 96% yield Me 2 Me Si t BuMe 2