Catalytic Asymmetric Addition to Ketones Using Organozinc Reagents Mariam Shamszad February 9, 2006 Literature Seminar 1
Importance of Chiral Tertiary Alcohols in Organic Synthesis 2
Outline Organometallic reagents Organolithium reagents Grignard reagents Organozinc reagents Catalytic asymmetric addition of organozinc reagents to aldehydes Catalytic asymmetric addition of organozinc reagents to ketones Application to organic synthesis Conclusions 3
Enantioselective e Addition of Organolithium Reagents to Ketones Collum, D. B. et al, J. Am. Chem. Soc. 1998, 120, 2028-2038. 4
Enantioselective Addition of Grignard Reagents to Ketones R Ketone Yield er C 2 H 5 C 6 H 5 COCH 3 62% 99:1 C 2 H 5 4-BrC 6 H 4 COCH 3 90% 97:3 C 4 H 9 C 6 H 5 COC 2 H 5 7% 95:5 C 4 H 9 cyclohexyl methyl ketone trace 62:38 C 2 H 5 benzyl methyl ketone 22% 75:25 Seebach, D.; Weber, B. Angew. Chem. Int. Ed. 1992, 31, 84-85. 5
Negative Factors Associated with Use of Organolithium and Grignard Reagents Inherent reactivity Low temperatures (< -100 C) Stoichiometric chiral ligand Expensive Difficult to prepare Functional group incompatibility Limited substrate scope 6
Organozinc Reagents as Candidates for the Enantioselective Addition to Carbonyl Compounds Low nucleophilic character Necessity of activating the carbonyl compound, the organozinc reagent, or both Development of chiral promoters Successful for aldehydes but becomes complicated when the electrophilic ec c substrate of the reaction is a ketone e 7
Addition of Organozinc Reagents to Carbonyl Groups Possible Side Reaction: 8
Catalytic Cycle and Source of Enantioselectivity Coordination of ligands to dialkylzinc converts linear structure into approximate tetrahedral structure, decreasing Zn-C bond order, increasing nucleophilicity of zinc alkyl groups 9
First Success in Enantioselective e Organozinc Addition to Aldehydes Ligand Yield ee (%) (S)-1-phenylethylamine 95% 3.8 (S)-1-phenylpropan-1-ol 1 ol 56% 16 1.6 (S)-alaninol 97% 26.4 (S)-valinol 95% 46.9 (S)-leucinol 96% 48.8 (S)-phenylalaninol 98% 39.2 (S)-prolinol 100% 28.3 Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823-2824. 10
First Highly Enantioselective Addition Proposed Mechanism: Kitamura, M.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-6072. Yamakawa, M.; Noyori, R.; J. Am. Chem. Soc. 1995, 117, 6327-6335. 11
Substrate Scope Aldehyde Yield %ee C 6 H 5 CHO 97% 98 (S) p-clc 6 H 4 CHO 86% 93 (S) p-ch 3 OC 6 H 4 CHO 96% 93 (S) (E)-C 6 H 5 CH=CHCHO 81% 96 (S) C 6 H 5 CH 2 CH 2 CHO 80% 90 (S) n-c 6 H 13 CHO 81% 61 (S) * This reaction failed when the substrate was a ketone Kitamura, M.; Suga, S.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071-6072. 12
Nonlinear Effect and Structure of Catalytic Species 15% ee in DAIB led to 95% ee in product Monomeric species determined to be catalytically active species: Reactions rates of the reaction run with racemic ligand vs. optically pure ligand were studied Racemic ligand produces 3 dimeric structures while optically pure ligand can only product one Reactions rates were found to be the same 13
Other Chiral Ligands Used to Promote Addition of Dialkylzinc Reagents to Aldehydes Amino Alcohols (acyclic, cyclic, pyridyl and iminyl alcohols, axially chiral, carbohydrate-based, ferrocene-based, oxazolines) Amino thiols, disulfides, diselenides Amines Diols (i.e., TADDOL, BINOL) Titanium sulfonamide and phosphoramide complexes Pu, L.; Yu, H. Chem. Rev. 2001, 101, 757-824. 14
Aryl, Vinyl-, and Alkynylzinc y Additions to Aldehydes Arylzinc Additions Huang and Pu Vinylzinc Additions Soai: Alkynylzinc l Additions Carreira: 15
Aldehydes vs. Ketones Proposed Transition States: Aldehydes Ketones Reactivity: Aldehydes > Ketones Ketones have more difficulty in controlling facial selectivity 16
First Catalytic tic Asymmetric Addition of Organozinc Reagent to Ketones With 1.5 equiv MeOH Dosa, P.I.; Fu, G.C. J. Am. Chem. Soc. 1998, 120, 445-446. 17
Success of Dosa and Fu s Reaction Methoxide increases Lewis acidity of zinc Diphenylzinc has high reactivity No hydrogen atoms in α-position of reagent prevents reduction 18
Substrate Scope Dosa, P.I.; Fu, G.C. J. Am. Chem. Soc. 1998, 120, 445-446. 19
Nonlinear Effect Nonlinear Dependence of Product ee on Catalyst ee 100 % ee of Pro oduct 80 60 40 20 0 0 50 100 % ee of Catalyst Dosa, P.I.; Fu, G.C. J. Am. Chem. Soc. 1998, 120, 445-446. 20
Catalytic tic Asymmetric Addition of Dialkylzincs l incs to α-ketoesters Catalyst must accelerate addition faster than uncatalyzed, racemic addition or reduction Catalyst must accelerate addition to a greater degree than reduction Kozlowski, M. C.; DiMauro, E. F. J. Am. Chem. Soc. 2002, 124, 12668-12689 21
Zinc-Salen Complexes as Catalysts Bifunctional Lewis acid-lewis base salen catalysts thought to be more reactive than DAIB-type catalysts due to separation of Lewis acid and Lewis base sites Kozlowski, M. C.; DiMauro, E. F. J. Am. Chem. Soc. 2002, 124, 12668-12689 22
Catalyst Screening reduction addition Catalyst T ( C) t (h) reduction conversion (%) addition conversion (%) addition ee (%) none 0 24 86 11 none -40 2 45 23 Zn(salen) 0 24 6 93 20 Mg(salen) -40 2 0 99 34 Ti(Oi-Pr 2 )(salen) -40 2 0 99 56 Kozlowski, M. C.; DiMauro, E. F. Org. Lett. 2002, 4, 3781-3784. 23
Proposed Transition State and Absence of Nonlinear Effect Absence of Nonlinear Effect %ee produc ct 80 70 60 50 40 30 20 10 0 0 50 100 %ee catalyst Kozlowski, M. C.; DiMauro, E. F. Org. Lett. 2002, 4, 3781-3784. 24
Substrate t Scope Entry R 1 R 2 Addition Conversion (%) Addition ee (%) 1 Ph t-bu 99 30 (R) 2 Ph Et 99 56 (R) 3 p-ch 3 O-C 6 H 4 Et 99 52 (R) 4 p-br-c 6 H 4 Et 96 42 (R) 5 Me Et 92 30 (R) 6 i-pr Et 98 30 (R) 7 t-bu Et 57 47 (R) Kozlowski, M. C.; DiMauro, E. F. Org. Lett. 2002, 4, 3781-3784. 25
Enantioselective Additions of Alkynylzinc y Reagents to Ketones salen: Cozzi, P.G. Angew. Chem. Int. Ed. 2003, 42, 2895-2898. 26
Screening of Reaction Conditions Entry Salen [mol%] Additive Yield (%) ee (%) 1 10 40 62 2 20 72 61 3 20 (in ether) n.d. 51 4 20 (in methylene chloride) n.d. 50 5 20 (in hexane) n.d. 53 6 20 at 50 C for 48 h 85 31 7 10 (R,R)-indanolR) n.d. 39 8 10 (R,R)-binol n.d. 30 9 10 DABCO n.d. 53 10 10 2,6-lutidine n.d. 44 11 20 at -15 C for 96 h 0 - Cozzi, P.G. Angew. Chem. Int. Ed. 2003, 42, 2895-2898. 27
Substrate Scope Cozzi, P.G. Angew. Chem. Int. Ed. 2003, 42, 2895-2898. 28
Absence of Nonlinear Effect Absence of Nonlinear Effect ee (product) )/% 90 80 70 60 50 40 e30 20 10 0 0 20 40 60 80 100 ee (salen)/% Proposed Transition State Cozzi, P.G. Angew. Chem. Int. Ed. 2003, 42, 2895-2898. 29
Enantioselective Alkynylation of α-ketoesters Use differentially substituted acetylenes as nucleophile source and simultaneously as the solvent Addition of terminal alkynes through in situ formation of alkynlzinc Jiang, B.; Chen, Z.; Tang, Z. Org. Lett. 2002, 4, 3451-3453. 30
Substrate Scope Jiang, B.; Chen, Z.; Tang, Z. Org. Lett. 2002, 4, 3451-3453. 31
Hydroxysulfonamides as Chiral Ligands Promoted by Titanium Tetraalkoxides Chiral Ligands: 20 mol% used Yield: 25-95% ee: 50-79% 10 mol% used Yield: 89-95% ee: 70-92% Yus, M.; Ramón, D.J. Tetrahedron 1998, 54, 5651-5666. Yus, M.; Ramón, D.J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14, 1103-1104. 32
Role of Titanium(IV) Alkoxide 1. Alkyltitanium(IV) alkoxides add smoothly to ketones at room temperature 2. Mixtures of diethylzinc and titanium tetraalkoxide form ethyltitanium(iv) alkoxide derivatives to some extent 3. Titanium(IV) alkoxides derived from chiral diols act as Lewis acids in the catalytic reduction of ketones 33
Possible Structures of Catalytic Species Catalytic species and catalytic cycle are not clearly defined Role of dialkylzinc reagent is to transfer alkyl moiety to titanium center: Enantioselectivity found when methyltitanium triisopropoxide used as nucleophilic source was zero Yus, M.; Ramón, D.J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14, 1103-1104. 34
Substrate Scope ligand: Entry Ketone Time (days) Yield (%) ee (%) 1 4-MeC 6 H 4 COMe 2 >95 92 2 4-CF 3 C 6 H 4 COMe 2 >95 92 3 α-tetralone 6 42 16 4 2-acetylnaphthalene 2 85 58 5 2-acetylthiophene 2 95 40 Yus, M.; Ramón, D.J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14, 1103-1104. 35
Evolution of the HOCSAC Ligand Yus Ligand: HOCSAC Ligand: Possible Catalytic Species: (trans-1,2-bis(hydroxycamphorsulfonamido)cyclohexane) Linker has less conformational freedom Improved enantioselectivity it Higher catalyst activity Walsh, P.J.; García, C.; LaRochelle, L.K. J. Am. Chem. Soc. 2002, 124, 10970-10971. 36
Preparation and Reactivity of HOCSAC Ligand HOCSAC Slow: 5-20% conversion after 24 h Walsh, P.J.; García, C.; LaRochelle, L.K. J. Am. Chem. Soc. 2002, 124, 10970-10971. 37
Alkyl Addition to Ketones Using HOCSAC Entry Ketone mol% time (h) yield (%) ee (%) O X 1 X= H 2 29 71 96 (S) 2 X= 3-Me 10 12 82 99 (S) 3 X= 3-CF 3 2 14 55 96 (S) 3 4 X= 2-Me 10 48 24 96 (S) 5 O Cl 10 44 82 89 (S) 6 7 O O 2 26 80 90 (S) 10 68 68 70 (S) Walsh, P.J.; García, C.; LaRochelle, L.K. J. Am. Chem. Soc. 2002, 124, 10970-10971. 38
Aryl Addition to Ketones Using HOCSAC Walsh, P.J.; García, C. Org. Lett. 2003, 5, 3641-3644. 39
Alkyl Addition to Cyclic α,β-unsaturated Ketones Walsh, P.J.; Jeon, S. J. Am. Chem. Soc. 2003, 125, 9544-9545. 40
Tandem Enantioselective Addition/Diastereoselective Epoxidation Walsh, P.J.; Jeon, S. J. Am. Chem. Soc. 2003, 125, 9544-9545. 41
Vinylation of Ketones Using HOCSAC Walsh, P.J.; Li, H. J. Am. Chem. Soc. 2005, 127, 8355-8361. 42
Vinylation of Enones and Ynones Walsh, P.J.; Li, H. J. Am. Chem. Soc. 2005, 127, 8355-8361. 43
Dienylation of Acyclic Ketones Limitations: dialkyl ketones result in lower ee (~ 40%) enones do not provide addition products Walsh, P.J.; Li, H. J. Am. Chem. Soc. 2005, 127, 8355-8361. 44
Vinylation of Ketones with Divinylzinc Reagents Limitations: works with bis(2-methyl-1-propenyl)zinc but not with bis(1-methylvinyl)zinc Walsh, P.J.; Li, H. J. Am. Chem. Soc. 2005, 127, 8355-8361. 45
A Green Chemistry Approach Challenge: lower ratio of weight waste to weight product (E factor) lower ratio of volume of reaction medium to grams product (volume productivity) Results: 051 0.5-1 mol% catalyst loading under solvent-free conditions Similar yields and enantiomeric excess obtained under-solvent free conditions compared to standard conditions for the additions of diethylzinc, dimethylzinc, functionalized dialkylzinc reagents to ketones, as well as tandem asymmetric addition/diastereoselective epoxidation of ketones Scalability: Walsh, P.J.; Jeon, S.; Li, H. J. Am. Chem. Soc. 2005, 127, 16416-16425. 46
Application to the Synthesis of (-)-Frontalin Isolated from pine beetles of the Dendroctonus family Used to control progression of harmful insect infestations Key asymmetric step is construction of one oxygen-substituted quaternary carbon stereocenter t Previous syntheses restricted to construction of the stereocenter by formation of carbon-oxygen bond Previous Synthesis: Soderquist, J.A.; Santiago, B. J. Org. Chem. 1992, 5844-5847. 47
Synthesis of (-)-Frontalin Yus, M.; Ramón, D.J.; Prieto, O. Eur. J. Org. Chem. 2003, 2745-2748 48
Summary and Conclusions The catalytic asymmetric addition of organozinc reagents to ketones has improved considerably since Dosa and Fu published the first example of this reaction in 1998. A variety of chiral ligands have been synthesized by various laboratories over the past decade that have made this possible. In particular, the HOCSAC ligand has made this type of reaction suitable for asymmetric synthesis. Future directions: Expansion of substrate scope, lower catalyst loading, higher catalytic reactivity, further investigation into mechanism. 49
Acknowledgements Dr. Michael T. Crimmins The Crimmins Group: Dr. Hamish S. Christie Amran A. Gowani Aaron C. Smith Dr. Mark A. Hatcher Matthew W. Haley Yan Zhang Dr. Matthew M. Kreilein Danielle L. Jacobs J. Lucas Zuccarello Dr. Theodore Martinot Patrick J. McDougall Adam Azman Dr. Gregory M. Schaaf Erin E. Milner Amanda Jones J. Michael Ellis Todd B. Showalter Jay Stevens 50
Possible Transition States for HOCSAC Ligand 51