Catalytic Enantioselective Formation of All-Carbon ... Malinowski/Malinowski.pdfCatalytic Enantioselective Formation of All-Carbon Quaternary Stereocenters Justin T. Malinowski University

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


•  Alkylations


•  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


•  Alkylations


•  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







89-97% ee

Ligand

Mechanistic Insight

27







89-97% ee

Ligand

‡

Structural Consequences

28

•  Large Ar = O-bound •  Small Ar = C-bound •  Electron rich Mo disfavors red. elim.

–  Branched product observed



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.


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

‡

‡


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


•  Alkylations


•  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-trifluorophenyl

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.


Possible Diastereoselectivity Explanation

51

Acyclic = anti

Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010, 132, 56.

Cyclic = syn


Outline

52


•  Alkylations


•  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

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Catalytic Enantioselective Formation of All-Carbon ... Malinowski/Malinowski.pdfCatalytic Enantioselective Formation of All-Carbon Quaternary Stereocenters Justin T. Malinowski University