Metal catalysed asymmetric epoxidation of olefins

Metal catalysed asymmetric epoxidation of olefins First report: chiral molybdenum peroxo complexes squalene Mo 2 (acac) 2, di-isopropyl tartrate 14% ee S tsuka et al, Tetrahedron Lett. 1979, 3017 Iron porphyrin complexes act as mimics for cytochrome P450 enzymes Cl Fe 1 Cl 1, Ar I toluene, 0 o C Cl 51% ee = C C 2 Me J T Groves et al, J. Am. Chem. Soc. 1983, 105, 5791

Metal salen complexes as catalysts for AE reactions * * 1 1 M vs. 2 M 2 * * 3 3 (E Jacobsen, T Katsuki) Advantages of metal salen catalysed AE: Chiral centres close to metal centre Simple to prepare - substituted salicylaldehyde plus chiral diamine elatively stable to oxidation: range of co-oxidants extended Achiral metal salen catalysed epoxidations: J K Kochi et al, J. Am. Chem. Soc. 1985, 107, 7606

Manganese salen catalysed asymmetric epoxidation of unfunctionalised olefins di-t-butyl substituted chiral manganese salen complexes catalyse the efficient asymmetric epoxidation of Z-olefins with good selectivities; the reaction is poor for terminal (low selectivity), E- or trisubstituted olefins (low reactivity). ote that the co-oxidant is bleach! 3rd generation: Et 34% ee L S 3-10% catalyst L S 92% ee acl, C 2 Cl 2 catalyst: Ac Mn + C 2 Et 97% ee 4 : 1 C 2 Et 78% ee 86% ee Jacobsen, J. Am. Chem. Soc., 1991, 113, 7063

Manganese salen catalysed asymmetric epoxidation - mechanism and stereochemistry as seen on the previous slide, dialkyl substituted olefins react with retention of configuration (concerted), whereas acyclic aryl substituted olefins react with loss of geometric purity, suggesting a stepwise radical mechanism L S 1 2 Ac Mn Mn Mn Mn 1 2 2 1 alkyl substituents: concerted Mn Ar 2 Ar 2 aryl substituents: radical 1 Mn 2 model explains why trans/trisubstituted olefins are poorly reactive (steric hindrance in side-on approach) Mn electron rich olefins are most selective, because their transition state is further along the reaction coordinate Jacobsen, J. Am. Chem. Soc., 1998, 120, 948; Tetrahedron, 1994, 50, 4323

Process-scale application of manganese salen catalysed asymmetric epoxidation C 2 F 5 x mol% cat., acl additive o additive, x = 1: Isoquinoline--oxide, x = 0.2: C 2 F 5 90% ee, 12 h, quant. 95% ee, 2 h, quant. 2-piperidone K C 2 F 5 SB potassium channel activator Tetrahedron Lett., 1996, 37, 3895; increase in rate/selectivity of epoxidations with -oxide additives: Jacobsen,Tetrahedron, 1994, 50, 4223

Dioxirane-Mediated Asymmetric Epoxidation 3 4 1 2 S 4 - - S 3 Baeyer-Villiger 1 2 1 2 3 4 1 2 S 5 - (from xone TM ) C 3 30 mol% ketone xone, K 2 C 3 C 3 C, 0ºC p 10.5 buffer C 3 93% yield; 92% ee 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. igh p conditions required. Stable ketones: Armstrong, Chem. Commun., 1998, 621; Tetrahedron: Asymmetry, 2000, 11, 2057.

Asymmetric Epoxide ing pening Asymmetric ring opening of racemic terminal epoxides kinetic resolution + u Desymmetrization of meso-epoxides u

Catalytic asymmetric ring-opening of meso-epoxides Asymmetrically substituted cis-epoxides are achiral compounds with a meso-plane of symmetry: opening at either carbon produces enantiomeric products. A range of catalysts have been applied to this problem: azide as nucleophile 1 halide as nucleophile 2 2% cat-1a, TMS- 3 Et 2, r.t. 3 80% 98% ee E E = C 2 Et 5% cat-2, TMS- 3 allyl bromide (B allyl azide by-product!) E TMS Br 83%, 95% ee thiol as nucleophile 3 benzoate as nucleophile 4 TBS 10% cat-3, S 4 Å sieves, toluene, r.t. TBS S 90%, 91% ee 5% cat-ent-1b, r.t. C 92%, 92% ee phenolate as nucleophile 5 20% cat-3, Ar 4 Å sieves, toluene, r.t. Ar = 4-Me- 70% 87% ee Ar cyanide as nucleophile 6 CCF 3 CCF 3 10% cat 4, TMSC CCl 3, -10 o C, 7 days! C TMS 80% 98% ee see next slide for catalyst structures and references

Appendix 1: catalysts for asymmetric ring-opening of meso-epoxides Catalyst 1: Catalyst 2: a: M= CrCl b: M = Co(Ac) M Catalyst 4: Zr( ) 4 / 3 Catalyst 3: YbCl 3 Catalyst 5: Ga Li Cr 3 Si 2 Me eferences from slide 1) Jacobsen, J. Am. Chem. Soc., 1995, 117, 5897; see also Zr catalysis: ugent, J. Am. Chem. Soc., 1992, 114, 2768; 2) ugent, J. Am. Chem. Soc., 1998, 120, 7139; see also Lewis base catalysis: Denmark, J. rg. Chem., 1998, 63, 2428; 3) Shibasaki, J. Am. Chem. Soc., 1997, 119, 4783; see also Cr catalysis: Jacobsen, J. rg. Chem., 1998, 63, 5252; 4) Jacobsen, Tetrahedron Lett., 1997, 38, 773; 5) Shibasaki, Angew. Chem., Int. Ed. Engl., 1998, 37, 223; 6) Jacobsen, rg. Lett., 2000, 2, 1001; see also Ti catalysis: Snapper, oveyda, Angew. Chem., Int. Ed. Engl., 1997, 36, 1704

Kinetic resolution of racemic epoxides by catalytic asymmetric ring-opening Meso-epoxides are necessarily a small subset of all possible epoxides. Broader applicability needs a wider range of substrates - but these will all be chiral. Since terminal epoxides are very cheap, a resolution process is viable: + - Cl 0.25 mol% cat-1b 0.7 eq. 2, DCM, r.t Cl volatile - distilled + Cl water soluble >99% ee 92-95% ee Jacobsen, Science, 1997, 277, 936; J. rg. Chem., 1998, 63, 6776; Tetrahedron Lett., 1999, 40, 7303 polymer-supported catalyst: J. Am. Chem. Soc., 1999, 121, 4147 reactions can be run neat; now 1000kg process (Chirex) other nucleophiles can also be used: Boc + + - C 4 9 2.2 eq. 4% cat-1b TBME, r.t. Boc C 4 9 86%, 99% ee Jacobsen, J. Am. Chem. Soc., 1999, 121, 6086 also with azide: J. Am. Chem. Soc., 1996, 118, 7420 eviews of asymmetric epoxide ring opening (meso- and resolution modes): Acc. Chem. es., 2000, 33, 421; Tetrahedron, 1996, 52, 14361

Mechanism Jacobsen J. Am. Chem. Soc. 1996, 118, 10924 Catalyst activates both nucleophile and electrophile 3 Cr Cl Cr 3 Cr Cr 3 Cr 3 Cr 3 Tethered dimeric salens give increased rates: J. Am. Chem. Soc. 1998, 120, 10780.

Alkene Dihydroxylation 1 2 s 4 s 1 2 1 2 3 4 3 4 3 4 Catalytic systems: M / acetone / 2 (Upjohn procedure): Tetrahedron Lett. 1976, 23, 1973. K 3 Fe(C) 6, K 2 C 3, / 2 : Minato, Yamamoto, Tsuji, J. rg. Chem. 1990, 55, 766. ecent catalytic systems: 2 2, cat. flavin, cat. -methylmorpholine: Backvall, J. Am. Chem. Soc. 1999, 121, 10424; J. Am. Chem. Soc. 2001, 123, 1365. 2 2, cat. V()(acac) 2, MM, acetone/water: Backvall, Tetrahedron Lett., 2001, 42, 2569. 2, K 2 [s 2 () 4 ], / 2 : Beller, Angew. Chem. Int. Ed. 1999, 38, 3026; J. Am. Chem. Soc. 2000, 122, 10289. Wirth, Angew. Chem. Int. Ed. 2000, 39, 334.

Evolution of Asymmetric Dihydroxylation Pyridine, tertiary amines accelerates dihydroxylation by s 4. Chiral pyridines (Sharpless 1979): poor affinity for s 4 Chiral diamines: bind too tightly to s 4, forming stable chelates - so cannot be used catalytically (but can give excellent enantioselectivities) Corey Snyder Me 2 Me 2 ( = neohexyl) irama Ar Ar Ar Tomioka Ar Quinidine / quinuclidine derivatives... Sharpless: Et DQ Me DQD Et Me CLB = Cl =, CLB =, CLB Good ee obtained using M co-oxidant (Upjohn) system. But..ee often lower for catalytic reaction than stoichiometric. Mechanistic studies showed this to be due to a two-cycle catalytic mechanism

Catalytic Cycles for Cis-Dihydroxylation s co-oxidant 3 s 3 s 3 2 co-oxidant - 3 s s 2 co-oxidant s 3 + + s first cycle highly enantioselective second cycle low enantioselectivity To avoid second cycle: With M acetone/water system, add alkene slowly (inconvenient) Better: use biphasic ( / 2 ), ferricyanide co-oxidant system: co-oxidant is in different phase to osmate ester, thus preventing second cycle

AD-Mix: K 2 s 2 () 4 (non-volatile s source): 0.2 mol% (DQD) 2 PAL or (DQ) 2 PAL: 1 mol% K 3 Fe(C) 6 : 3 eq K 2 C 3 : 3 eq Sharpless Catalytic Asymmetric Dihydroxylation eview: Sharpless, Chem. ev. 1994, 94, 2483 Add 1:1 tbu: water, alkene, 0 C; ften supplement K 2 s 2 () 4 to make 1% MeS 2 (1 eq) to accelerate hydrolysis of intermediate osmate ester (unless alkene is terminal) Me Et Et (DQD) 2 -PAL (in β-mix) Me Importance of p control: improved rates for internal olefins at p 12 (no MeS 2 2 ); higher ee for terminal olefins at p 10: Beller, Tetrahedron Lett. 2000, 41, 8083. slightly hindered β-face "" "" DQD-series S L M attractive area - good for aromatic and alkyl substituents "" "" α-face very!!!!! hindered DQ-series

Structural effects in asymmetric dihydroxylation reactions (all reactions shown carried out with (DQD) 2 -PAL; figure in parentheses is ee) terminal olefins* trans-disubstituted olefins 1,1-disubstituted olefins (84) (97) (99.8) C 2 Me (97) TBDPS (91) (69)* C 6 17 (84) C 4 9 Cl (94) Me (97) trisubstituted olefins (98) cis-disubstituted olefins (72) tetrasubstituted olefins (75) * - an alternative anthraquinone-derived spacer offers superior ee's for terminal olefins and those bearing only alkyl substituents. See Angew. Chem., Int. Ed. Engl., 1996, 35, 448

Epoxides via catalytic asymmetric dihydroxylation ' AD-mix α or β ' 59-100% ee MeC(Me) 3 TMSCl or TMSBr ' Me X + ' Yield 83-98% over 2 steps (no chromatography) ' K 2 C 3, Me X Ac ' + Br Ac ' K B Sharpless et al, Tetrahedron, 1992, 48, 10515

Cyclic sulfates as epoxide equivalents ' i) SCl 2, Et 3 ii) ucl 3, ai 4 ' S - i) u (eg - 3 or C - 2 ) ii) 2, cat. 2 S 4 u ' Sharpless,Tetrahedron Lett., 1989, 30, 655 S 2 Bn Me 2 Me Me Me Me Me Bn Me Me Bn neat, Me Bn 65% from diol Me Me Me reticuline irsenkorn, Tetrahedron Lett., 1990, 31, 7591