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Catalytic Enantioselective Formation of All-Carbon Quaternary Stereocenters
Justin T. Malinowski University of North Carolina at Chapel Hill
March 5, 2010
Introduction
2
• Challenges of quaternary center formation: • Steric repulsion in C–C bond forming event • Facial selectivity is difficult (lack of differentiation) • Relative lack of reactions
• “Classic” Methods: • Cycloadditions • Heck reactions • Cyclopropanations
Introduction
3
• Why catalytic enantioselective? • Large quantities of chiral material generated by small
amount of chiral catalyst • Atom economy – no removal of chiral auxiliaries • Improves scope
• Enzymatic catalysis – one enantiomer • Changing chirality of catalyst provides both
enantiomers
Trost, B. M.; Jiang, C. Synthesis 2006, 369. Corey, E. J.; Guzman-Perez, A.; Angew. Chem. Int. Ed. 1998, 37, 388.
Outline
• Conjugate additions to α,β -unsaturated carbonyls
• Alkylations
• Aldol and Mannich reactions
• Cascades
4
Outline
5
• Conjugate additions to α,β -unsaturated carbonyls
• Alkylations
• Aldol and Mannich reactions
• Cascades
Modes of Enantioinduction in Conjugate Additions
1. Coordination of chiral group to carbonyl
2. Chiral group attached to nucleophile
6
Organocatalytic Activation of Carbonyls
7
R1 = alkyl, aryl R2 = aryl 75-99% >95/5 Z/E
76-98% ee
• Phase transfer reaction • Chiral counterion • Elimination gives Z alkene
(electronics)
Organocatalyst
Bell, M.; Poulsen, T. B.; Jorgensen, K. A. J. Org. Chem. 2007, 72, 3053.
Organocatalytic Activation of Carbonyls
8 Bell, M.; Poulsen, T. B.; Jorgensen, K. A. J. Org. Chem. 2007, 72, 3053.
• Isomerization to E geometry:
No loss of optical purity
R1 = alkyl, aryl R2 = aryl 75-99% >95/5 Z/E
76-98% ee
Organocatalyst
Organocatalytic Addition to Allenic Esters and Ketones
9
• β-ketoester scope general – Must be cyclic
• Further elaborated to Hexahydrobenzopyranones
2:1 dr >98% ee
R = OEt, Me 59-95% R1 = alkyl, aryl, H 9:1 dr
76-99% ee Organocatalyst
(R = 1-adamantoyl)
Elsner, P.; Bernardi, L.; Dela Salla, G.; Overgaard, J.; Jorgensen, K. A. J. Am. Chem. Soc. 2008, 130, 4897.
Organocatalytic Addition to Allenic Esters and Ketones
10 Elsner, P.; Bernardi, L.; Dela Salla, G.; Overgaard, J.; Jorgensen, K. A. J. Am. Chem. Soc. 2008, 130, 4897.
R = OEt, Me 59-95% R1 = alkyl, aryl, H 9:1 dr
76-99% ee Organocatalyst
(R = 1-adamantoyl)
Asymmetric Conjugate Addition by NHCs
11
ImH+
Entry R Yield (%) ee (%)
1 Bu 100 77
2 iPr 77 77
3 Cy 79 74
4 tBu 0 -
5 Ph 61 66
Alexakis, A.; et. al. J. Am. Chem. Soc. 2006, 128, 8416.
• Considerations: • Regioselectivity • Enantioselectivity
• Solvent critical • THF gives no ee
• Active catalyst structure:
• First use of Cu-NHC complexes in conjugate additions
Possible Mechanism of Stereoinduction
12 Harutyunyan, S. R.; Feringa, B. L.; et. al. J. Am. Chem. Soc. 2006, 128, 9103.
π-complex σ-complex
ImH+
NHC-Catalyzed Addition of Organoaluminums
13
Entry R (alkyl)3Al Yield (%) ee (%)
1 CH2CH2Ph Me3Al 71 89
2 CH2CH2Ph Et3Al 97 92
3 CH2CH2Ph iBu3Al 74 87
4 nBu Me3Al 80 88
5 Ph Et3Al 87 96
May, T. L.; Brown, M. K.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2008, 47, 7358.
• Cu catalyst is necessary for conversion
• Aluminum reagents: • Higher reactivity • Low cost
• Applied to 6, 7-membered rings
(Ar = 2,6-(Et)2Ph) NHC-Ag
NHC-Catalyzed Addition of Organoaluminums
14
Entry Ar Yield (%) ee (%)
1 Ph 66 72
2 o-MePh 85 98
3 p-MePh 67 71
4 o-MeOPh 55 95
• Applied to arylations • Triaryl aluminum reagents:
• Not commercially available
• Poor atom economy • More substitution on NHC for
asymmetric induction
NHC-Ag
May, T. L.; Brown, M. K.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2008, 47, 7358.
Enantioselectivity Description
15 Lee, K.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182.
(Ar = 2,6-(Et)2Ph) NHC-Ag
Alkylations:
Arylations:
Rh-Cat. Conjugate Addition of Aryl Borates
16
Entry Ar Yield (%) ee (%)
1 Ph 83 98
2 4-MeC6H4 73 91
3 4-FC6H4 62 91
4 3-MeC6H4 84 95
5 3-ClC6H4 65 97
Shintani, R.; Hayashi, T.; et. al. J. Am. Chem. Soc. 2009, 131, 13588.
• Diene ligands necessary, phosphines failed
• Tetraarylborates: • Easy to handle • Air stable
• BAr3 acts as Lewis acid after transmetalation
• Na borates successful, K failed
Ligand
Rh-Cat. Conjugate Addition of Aryl Borates
17 Shintani, R.; Hayashi, T.; et. al. J. Am. Chem. Soc. 2009, 131, 13588.
Ligand
Assistance from Meldrum’s Acid: α-Quaternary Centers
18
Ligand
Entry Ar R Yield (%) ee (%)
1 C6H5 Et 100 88
2 4-ClC6H5 Et 91 94
3 4-tBuC6H5 Et 82 92
4 4-MeOC6H5 Et 100 92
5 3-ClC6H5 Et 92 83
6 4-ClC6H5 Me 100 60
7 4-MeOC6H5 iPr 86 88
• Goal: carbonyl compounds with α- quaternary centers
• Highly activated Meldrum’s acid Michael acceptor
• Renders α position of methyl ester electrophilic
Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801.
Assistance from Meldrum’s Acid: α-Quaternary Centers
19
Ligand
Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801.
Elaboration of Addition Products
20 Wilsily, A.; Fillion, E. Org. Lett. 2008, 10, 2801.
• Products elaborated to γ-butyrolactones, β-amino acid derivatives, and succinimides
Outline
21
• Conjugate additions to α,β -unsaturated carbonyls
• Alkylations
• Aldol and Mannich reactions
• Cascades
Tsuji-Trost Allylation
22 Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron. Lett. 1965, 4387.. Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292.
Chiral Counterions in α-Allylations
23
(R)-TRIP
Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336.
• Tsuji Trost allylation - stereocontrol by counterion
• Chiral phosphoric acid serves three purposes:
– H+ source (enamine formation)
– Anionic ligand for Pd – Chiral induction
• Counterion bound to both reactants during allylation
• First Tsuji-Trost to form quaternary centers using chiral counterions
‡
Chiral Counterions in α-Allylations
24
Entry R1 R2 Yield (%) ee (%)
1 C6H5 H 85 97
2 4-MeC6H5 H 89 94
3 3-FC6H5 H 85 96
4 2-naph H 71 94
5 Cy Et 65 70
6 C6H5 Me 40 92
7 C6H5 C6H5 82 82
Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336.
‡
(R)-TRIP
Mo-Catalyzed Allylic Alkylation
25
Ligand
• Electronics and sterics present
divergent reaction modes: – C-bound Mo: red. elim. favors linear
substituted – O-bound Mo: forms preferred branched
product through “Claisen-like” TS
Ar = e- rich, e- poor 83-95% R = aryl, vinyl up to 19:1 dr
89-97% ee
Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548.
Mechanistic Insight
26
• Electronics and sterics present
divergent reaction modes: – C-bound Mo: red. elim. favors linear
substituted – O-bound Mo: forms preferred branched
product through “Claisen-like” TS
Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548.
Ar = e- rich, e- poor 83-95% R = aryl, vinyl up to 19:1 dr
89-97% ee
Ligand
Mechanistic Insight
27
• Electronics and sterics present
divergent reaction modes: – C-bound Mo: red. elim. favors linear
substituted – O-bound Mo: forms preferred branched
product through “Claisen-like” TS
Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548.
Ar = e- rich, e- poor 83-95% R = aryl, vinyl up to 19:1 dr
89-97% ee
Ligand
‡
Structural Consequences
28
• Large Ar = O-bound • Small Ar = C-bound • Electron rich Mo disfavors red. elim.
– Branched product observed
Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548.
Ar = e- rich, e- poor 83-95% R = aryl, vinyl up to 19:1 dr
89-97% ee
Ligand
Vicinal Quaternary Centers
29 Du, C.; Li, L.; Li, Y.; Xie, Z. Angew. Chem. Int. Ed. 2009, 48, 7853.
• Initial experiments gave mix of undesired products
• Quenched after 10 min
Ligand
Vicinal Quaternary Centers
30
Entry R R1 Yield (%) dr ee (%)
1 Me Ph 59 26:1 99
2 Et p-OMeC6H4 57 32:1 99
3 Et p-ClC6H4 68 53:1 99
4 Me iPr 55 8.3:1 99
• Protection to stop lactonization • Yields reported for desired branched
product
Du, C.; Li, L.; Li, Y.; Xie, Z. Angew. Chem. Int. Ed. 2009, 48, 7853.
Ligand
Modes of Catalysis in Allylic Alkylations
31
X = P, N
Transition Metal Organocatalytic
Organocatalytic Allylic Alkylation
32
Organocatalyst
V.C. van Steenis, D. J.; Hiemstra, H.; et. al. Adv. Synth. Catal. 2007, 349, 281.
• Racemic Morita-Baylis-Hillman carbonates • Two stereocenters • Enantioenriched starting material recovered • Without –OH on catalyst, reaction shuts down
R1 = e- rich, e- poor aryl R2 = Ph, Me 94-95% 1.1:1 – 4:1 dr
79-85% ee
Mechanism and Selectivity
33
• Kinetic resolution in second step • Used 2:1 mol ratio carbonate:Nu
• Rate enhancement (KR)
V.C. van Steenis, D. J.; Hiemstra, H.; et. al. Adv. Synth. Catal. 2007, 349, 281.
Cr-Catalyzed Alkylation of Sn Enolates
34
Catalyst Th = thexyl = 1,2,2-‐trimethylpropyl
• Dynamic system with interconversion of enolate geometry
• ~1.8:1 E:Z ratio used • One isomer selectively reacts
Doyle, A. G.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2007, 46, 3701.
Cr-Catalyzed Alkylation of Sn Enolates
35
Entry R-X Yield (%) (Et=nBu) ee (%) (Et=nBu)
1 Allyl-Br 80 79
2 Allyl-I 83 (92) 82 (87)
3 Bn-Br 86 (83) 81 (86)
4 I-CH2CO2Et 73 76
• Electrophile scope is general
• Substitution on enolate: – Branched, aryl decreased
yield and enantioselectivity
• nBu substitution for Et improved results
Doyle, A. G.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2007, 46, 3701.
Catalyst Th = thexyl = 1,2,2-‐trimethylpropyl
Mechanistic Possibilities
36 Doyle, A. G.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2007, 46, 3701.
• Activation of Sn enolate by halide addition (ate complex)
• Mech. 1: Ion pairing – Non polar solvents give better selectivity
• Mech. 2: Activation of electrophile for SN2
1 2
‡
‡
Catalyst Th = thexyl = 1,2,2-‐trimethylpropyl
Phase Transfer Catalyzed α-Alkylations
37 Nagata, K.; Itoh, T.; et. al. Tetrahedron: Asymmetry. 2009, 20, 2530.
Catalyst Ar = 3,4,5-trifluorophenyl
Elaboration of α-Alkylation Adducts
38
β-lactams: 2-oxindoles:
Nagata, K.; Itoh, T.; et. al. Tetrahedron: Asymmetry. 2009, 20, 2530.
Catalyst Ar = 3,4,5-trifluorophenyl
Pd-Catalyzed Arylations and Vinylations
39 Taylor, A. M.; Altman, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900.
Ligand
Pd-Catalyzed Arylations and Vinylations
40
Ligand
Taylor, A. M.; Altman, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900.
Outline
41
• Conjugate additions to α,β -unsaturated carbonyls
• Alkylations
• Aldol and Mannich reactions
• Cascades
Lithium BINOLate-Catalyzed Aldol
42
Catalyst
Ichibakase, T.; Orito, Y.; Najajima, M. Tetrahedron. Lett. 2008, 49, 4427.
syn anti
• Mild conditions prevent retro-aldol • Quenching/purification conditions
important • KF/HCO2H quench • Benzoylation before silica
• Chair TS provides anti adduct
‡
Lithium BINOLate-Catalyzed Aldol
43
Entry R1 R2 Yield (%) syn:anti ee (%)
1 Me Ph 94 1:49 87
2 Me 4-MeOC6H5 98 1:14 81
3 Me 4-CF3C6H5 62 1:10 52
4 Me 2-Naphthyl 97 1:50 87
5 Me (E)-PhCH=CH 98 1:20 90
6 Et Ph 98 1:10 79
Ichibakase, T.; Orito, Y.; Najajima, M. Tetrahedron Lett. 2008, 49, 4427.
Catalyst
syn anti
‡
Lewis Acid/Base Catalysis
44
Lewis base
• Use of silyl ketene imine nucleophile controls geometry of R groups
• LA/LB catalyst system directs addition to re face of RCHO
• Aliphatic aldehydes unreactive:
R = aryl R1, R2 = aryl, alkyl 73-93% 6:4 - >99:1 dr
57-99% ee
Denmark, S. E.; Wilson, T. W.; Burk, M. T.; Heemstra, J. R. J. Am. Chem. Soc. 2007, 129, 14864. Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem. Soc. 2005, 127, 3774.
Lewis Acid/Base Catalysis
45 Denmark, S. E.; Wilson, T. W.; Burk, M. T.; Heemstra, J. R. J. Am. Chem. Soc. 2007, 129, 14864. Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem. Soc. 2005, 127, 3774.
Lewis base
R = aryl R1, R2 = aryl, alkyl 73-93% 6:4 - >99:1 dr
57-99% ee
“Conglomerate” Catalyzed Mannich-Type Reaction
46 Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 5630.
anti
• Complicated structural data • Oligomeric
conglomerate of Substrate/Ligand/Sc
• Dynamic system • Forms ordered TS
• Sc–O and H bonding • Solvent effect
• THF gives no ee
Ligand
Entry R Yield (%) Anti:Syn ee (%)
1 Ph 90 94:6 94
2 4-MeOC6H5 97 85:15 77
3 4-FC6H5 88 90:10 96
4 2-Naphthyl 97 90:10 94
5 2-Furyl 94 75:25 82
6 Ph(CH2)2 89 64:36 50
Applied to Michael Additions
47 Kawato, Y.; Takahashi, N.; Kumagai, N.; Shibasaki, M. Org. Lett. ASAP
• Sc – low conversion and racemic product
• Solvent effect: • CH2Cl2 gives best ee
Ligand R = aryl 48-98%
69-98% ee
Cu cat. Decarboxylative Mannich-Type Reaction
48 Yin, L.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9610.
Entry R1 Yield (%)
dr ee (%)
1 Ph 94 7.1:1 87
2 4-MeOC6H5 93 7.4:1 97
3 4-MeCOC6H5 95 7.4:1 80
4 1-Naphthyl 63 4:1 90
5 Cy 82 2.1:1 95
6 Ph(CH2)2 83 2.5:1 85
7 Furyl 94 8.9:1 85
• Occurs under mild conditions
• Imine scope is general • Includes acidic α-
protons
Ligand
Lithium BINOLate Catalyzed Mannich-Type Reaction
49 Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010, 132, 56.
• Wet or alcoholic Li BINOLate salts show improved catalytic activity • Break up oligomeric species
• Products elaborated to spiro β-lactams:
BINOL Ar = 3,4,5-tri- fluorophenyl
Lithium BINOLate Catalyzed Mannich-Type Reaction
50
• Switch in diastereoselectivity when using acyclic β-ketoesters
Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010, 132, 56.
BINOL Ar = 3,4,5-tri- fluorophenyl
Possible Diastereoselectivity Explanation
51
Acyclic = anti
Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010, 132, 56.
Cyclic = syn
BINOL Ar = 3,4,5-tri- fluorophenyl
Outline
52
• Conjugate additions to α,β -unsaturated carbonyls
• Alkylations
• Aldol and Mannich reactions
• Cascades
Michael Addition, α-Alkylation Cascade
53
Organocatalyst
Enders, D.; Wang, C.; Bats, J. W. Angew. Chem. Int. Ed. 2008, 47, 7539.
• H+ additive increases rate and yield • Solvent effect observed
– Less polar – stopped at Michael addition – More polar – completion
• Conversion to γ-amino acids • Pharmaceutically relevant
R = alkyl 73-93% 2:1 - 99:1 dr
93-97% ee
Michael Addition, α-Alkylation Cascade
54 Enders, D.; Wang, C.; Bats, J. W. Angew. Chem. Int. Ed. 2008, 47, 7539.
Organocatalytic Cascade Cyclization
55 Penon, O.; Melchiorre, P.; et. al. Chem. Eur. J. 2008, 14, 4788.
• Enamine, iminium, enamine catalytic sequence
• Challenges: – Cyanoacrylate (3) must be attacked by 1
preferentially – Adduct must attack Michael acceptor – Intramolecular cyclization
R1 = alkyl R2 = Ph, Me 32-52% 2:1 - >20:1 dr
98 - >99% ee
Organocatalyst
Organocatalytic Cascade Cyclization
56 Penon, O.; Melchiorre, P.; et. al. Chem. Eur. J. 2008, 14, 4788.
R1 = alkyl R2 = Ph, Me 32-52% 2:1 - >20:1 dr
98 - >99% ee
Organocatalyst
Primary Amine Catalyzed Cyclization
57
Organocatalyst
Wu, L.; Melchiorre, P.; et. al. Angew. Chem. Int. Ed. 2009, 48, 7196.
• Primary amine catalyzed • Formal Diels-Alder reaction • Enamine, iminium catalytic
sequence
Proposed:
R1 = aryl, CO2Et 53-86% R2 = H, Me 9:1 - >19:1 dr 94-98% ee
Evidence for Double Michael Mechanism
58
• Catalytic activity is shut down in polar solvents (MeOH, H2O)
– Concerted reaction generally accelerated
• Rate and selectivity depend on co-catalyst
– Imine/enamine formation
• Isolated intermediate after first addition, resubjected to conditions to give product
Proposed:
Wu, L.; Melchiorre, P.; et. al. Angew. Chem. Int. Ed. 2009, 48, 7196.
Organocatalyst R1 = aryl, CO2Et 53-86% R2 = H, Me 9:1 - >19:1 dr 94-98% ee
Conclusion
59
• Construction of all-carbon quaternary stereocenters is a key challenge in modern organic synthesis
– Catalytic, enantioselective methodology is currently an exciting topic
• Modern methods: – Asymmetric conjugate additions – Enantioselective alkylations – Aldol + Mannich reactions – Cascade cyclizations
• Organocatalytic and transition metal catalyzed reactions • Most reactions still require development:
– Substrate scopes rarely general (alkyl, aryl) – Specific functionality required