Lecture 6: Transition-Metal Catalysed C-C Bond Formation (a) Asymmetric allylic substitution 1 u - d u (b) Asymmetric eck reaction 2 3 Ar- d (0) Ar 2 3 (c) Asymmetric olefin metathesis
alladium π-allyl mediated alkylation reactions palladium (0) complexes displace allylic leaving groups (with inversion of configuration) to generate cationic π-allyl palladium species; trapping with a suitable soft nucleophile (with inversion) gives substitution with overall inversion schematic mechanism: 2 2 u - 2 + d(0) d(0) d + u Leaving group: = halogen, - 2 C (carboxylate), - 2 C (carbonate) ucleophile: EWG - EWG EWG = C, C 2, S 2-2 - 2 3 egiochemistry: generally, the nucleophile attacks the less hindered end. If both ends are similar, mixtures result: 2 2 2 u - 2 u - u d d u 2 2 General review of palladium-catalysed allylic substitution: Comprehensive rganic Synthesis, ergamon, 1991, vol 4, p585 ecent reviews of asymmetric approaches: Williams, Synlett, 1996, 705; elmchen, faltz, Acc. Chem. es., 2000, 33, 336; Trost, Acc. Chem. es., 1996, 29, 355; Chem. ev., 1996, 96, 395 1 2 u 2 2
alladium π-allyl mediated alkylation reactions - important asymmetric processes Meso-substrates: the absolute stereochemistry is determined by which carbon is attacked: u d u - u - u Substrates which are disubstituted on one terminal carbon: the use of racemic starting materials is generally not a problem since the π-allyl palladium species rapidly isomerise (epimerise); however, it's important that this is a fast process relative to nuc. attack: 2 2 2 2 d d or 2
Asymmetric palladium π-allyl mediated alkylation reactions challenge: control of stereochemistry from ligands on metal when the nucleophile approaches from the outside of the co-ordination sphere - not true for most metal-catalysed processes! L L d u - early solution was the use of ligands with 'extended' reach to guide the nucleophile in to the complex 2.5% d (0), a + - C(C 2 Et) 2 Ac Fe 2 2 Et 2 C C 2 Et = Me = Me 2 62% ee 96% ee d u - ayashi, Tetrahedron Lett., 1986, 27, 191
Asymmetric palladium π-allyl mediated alkylation reactions an alternative approach pioneered by the groups of Williams, faltz and elmchen, was to use electronically distinguished ligands. Thus, in non-symmetrical, ligands such as phosphino oxazolines, the nucleophile always attacks the carbon trans-to the π-accepting phosphine ligand: 2.5% d (0), a + - C(C 2 Et) 2 94% ee Ac TF, r.t. Et 2 C C 2 Et 2 i r via d u - vs. d elmchen, Tetrahedron Lett., 1993, 34, 1769; Williams, Tetrahedron Lett., 1993, 34, 3149; faltz, Angew. Chem., Int. Ed. Engl., 1993, 32, 566 eg 2.5% [d(allyl)cl] 2 i) Cr 3, Ac 2 C Ac 2 Me 2 C C 2 Me 92-98% ee ii) a/me iii) Cl, C 2 i r Williams, Tetrahedron Lett., 1995, 36, 41; Tetrahedron: Asymmetry, 1995, 6, 2535
Asymmetric palladium π-allyl mediated alkylation reactions third ploy is to exploit ligands which enforce a wider than normal bite-angle at phosphorus, thus pushing the phosphine substituents out into the trajectory of the incoming nucleophile: d ϑ LIKE LIKE cf d ϑ CIAL SCAFFLD -d- bite angle ca. 110 o (cf. ca. 90 o ) these Trost ligands are by far the best (most general) ligand type for substitution on cyclic templates, although they work on acyclic templates as well: Bz Bz d 2 (dba) 3, ligand TF, r.t., u - u Bz u - = Me 2C - C 2 Me - BnMe 80% ee 95% ee 95% ee 3 - (TMS 3 ) >98% ee Trost, Chem. Eur. J., 1995, 1, 568; Acc. Chem. es., 1996, 29, 355
Asymmetric palladium π-allyl mediated alkylation reactions the use of meso-substrates with two leaving groups allows for the stepwise introduction of nucleophiles byu palladium catalysis - useful in the synthesis of nucleosides and carbanucleosides: Me + Bz Bz 2% d 2 (dba) 3, 3% ligand Et 3, TF, 0 o C Bz Me 65%, >98% ee ligand: 3% d 2 (dba) 3, 10% 3 Cs 2 C 3, MeC, CbzC(C 2 Bn) 2-2 C constituent of nikkomycin 3 + Bn 2 C Bn 2 C Cbz Me 95% Trost, J. Am. Chem. Soc., 1996, 118, 3037
Asymmetric eck reactions eck reactions can create new asymmetric centres in systems where syn-elimination of d- is forced to occur away from the newly formed C-C bond, ie on formation of quaternary centres or in cyclic systems Ar- 2 3 d(0) Ar-d- Ar 2 3 d - -d- if, 2 is not Ar 2 3 Ar-d- Ar d - -d- only syn-hydrogen Ar chiral ligands at palladium allow for control of absolute stereochemistry: eview of asymmetric eck reactions: Shibasaki, Tetrahedron, 1997, 53, 7371 First examples: Shibasaki, J. rg. Chem., 1989, 54, 4738; verman, J. rg. Chem., 1989, 54, 5846
Asymmetric intramolecular eck reactions care needs to be exercised as to the conditions (base, additives, halogen/triflate): 65%, 66% ee Me 5% d 2 (dba) 3 11% ()-BIA M, 80 o C pentamethylpiperidine Me I 5% d 2 (dba) 3 11% ()-BIA M, 80 o C Ag 3 4 Me 86%, 70% ee via: d Ar I d Ar I via: + + d Ar d Ar insertion insertion + d I - Ar verman, J. Am.Chem. Soc., 1998, 120, 6477; J. Am. Chem. Soc., 1998, 120, 6488
Asymmetric intermolecular eck reactions although BIA and modified BIA's have given moderate to acceptable ee's, a better ligand class for intermolecular eck reactions are the phosphinoxazolines: + Tf 6% ligand 3% d (0) i r 2 Et, TF + Tf 6% ligand 3% d (0) i r 2 Et, TF 70 o C, 4 days 95%, 88% ee 70 o C, 5 days 91%, 85% ee (BIA - 36% ee) ligand = 2 t Bu phosphinooxazalines: faltz, Angew. Chem., Int. Ed. Engl., 1996, 35, 200 BIA: Shibasaki, Tetrahedron Lett., 1994, 35, 1227
Alkene Metathesis Y catalyst + + Y Y Y ecent reviews: T.M. Trnka and.. Grubbs, Acc. Chem. es. 2001, 34, 18. A. Furstner, Angew. Chem. Int. Ed. 2000, 39, 3012.
Stable, Structurally Defined Catalysts Mo 2 Schrock catalysts.. Schrock, Acc. Chem. es. 1990, 23, 158. ften more active than Grubbs catalysts, allowing reaction with sterically demanding alkenes. 1a = C 3 1b = CF 3 Cl Cl u 3 3 2 = 3 =Cy Cl Cl u Cy 3 Cy 3 4 Grubbs catalysts.. Grubbs, S.J. Miller, and G.C. Fu, Acc. Chem. es. 1995, 28, 446 T.M. Trnka and.. Grubbs, Acc. Chem. es. 2001, 34, 18.. Tolerate a wide range of polar functional groups and are less sensitive to air and water Mes Cl Cl u Cy 3 Mes Catalysts 1, 3 and 4 are commercially available
Important Metathesis rocesses n CM ring-closing metathesis -C 2 4 n M +C 2 4 M ring-opening metathesis polymerisation ADMET Acyclic diene metathesis n + 2 CM cross-metathesis 2 +
Chauvin mechanism CM 2 C C 2 [M] C 2 2 C [M] [M] C 2 C 2 2 C [M]
Chiral Metathesis Catalysts lefin metathesis commences with addition of a metal carbene to an olefin - potentially a symmetry breaking operation. Thus, chiral olefin metathesis catalysts have been prepared which can be exploited in resolution or desymmetrisation reactions. Mo catalysts have been most widely studied, e.g. i r i r Mo i r Mo i r 1 2 i r i r catalyst 1 is superior for 5-ring formation, catalyst 2 better for 6-ring formation Chiral Mo catalyst that can be made in situ, and does not require glove box: oveya, Schrock, Angew. Chem. Int. Ed. 2001, 40, 1452. Chiral u system: Grubbs, rg. Lett. 2001, 3, 3225. Air-stable, recyclable chiral u catalyst: oveyda, J. Am. Chem. Soc. 2002, 124, 4954.
Asymmetric Metathesis Kinetic resolution: t BuMe 2 Si t BuMe 2 Si t BuMe 2 Si 5 mol% [Mo]cat. C 6 6, 25 C + k rel up to 56 J. Am.Chem. Soc., 1999, 121, 8251 Desymmetrisation: 5 mol% [Mo]cat. C 6 6, 22 C 6 hr 83% 99% ee J. Am.Chem. Soc., 1999, 121, 8251
Asymmetric Metathesis ing opening/ring closing metathesis t BuMe 2 Si 5 mol% [Mo]cat. 10 eq TF t BuMe 2 Si C 6 6, 4 C 24 hr 94% 96% ee J. Am.Chem. Soc., 2002, 124, 10779. 5 mol% cat. C 6 6, 50 C 2.5 hr Schrock, oveyda, J. Am.Chem. Soc., 2000, 122, 1828 ing opening/cross metathesis Bn Bn + 5 mol% cat. C 6 6, 22 C 2.5 hr 86% >98% ee Schrock, oveyda, J. Am.Chem. Soc., 2001, 123, 7767