Literature meeting

1
The BaylisHillman Reaction and Related
Modifications

• Literature meeting
• Presented by
• Josée Philippe
• Prof André B. Charette
• October 4th, 2005

2
Content
2

• What is the BaylisHillman Reaction?
• Activation of the Reaction
• Enantioselective Reaction
• Intramolecular Reaction
• AzaBaylisHillman Reaction
• Application of BaylisHillman Reaction in the
  Synthesis of Natural Products such as
  Salinosporamide A.

3
About BaylisHillman Reaction
3

• In 1968, Morita reported the reaction between
  acetaldehyde and ethyl acrylate in the presence
  of a tertiary phosphine.
• Four years later, Baylis and Hillman developed
  the same transformation, but in the presence of a
  tertiary amine, DABCO, which is less toxic and
  cheaper.
• Reaction works with aliphatic as well as aromatic
  aldehydes.
• Carbon-carbon bond formation involving
  Michael-type addition.

Morita, K. et al. Bull. Chem. Soc. Jpn. 1968, 41,
2815 Basavaiah, D. et al. Chem. Rev. 2003, 103,
811-891
4
What Kind of Substrates Are Used in BH Reaction?
4

• Activated alkenes
• Electrophile
• Catalyst
• Amine (BH Rxn)
• Phosphine (MBH Rxn)

Basavaiah, D. et al. Chem. Rev. 2003, 103, 811-891
5
General Mechanism of BH Reaction
5
Basavaiah, D. et al. Chem. Rev. 2003, 103, 811-891
6
New Interpretation of the Mechanism
6

• RDS is the elimination product and not the
  1,2-Addition
• The rate law is second order in aldehyde and
  first order in catalyst and in methyl acrylate

Aprotic Solvent
Byproduct observed
McQuade, D.T. et al. Org. Lett. 2005, 7, 147-150
7
New Interpretation of the Mechanism
7
Protic Solvent
Aggarwal, V.K. et al. Angew. Chem. Int. Ed.
2005, 44, 1706-1708
8
Tertiary Amines and PhosphinesUsed in the BH or
MBH Reaction
8
Drawback of reaction very slow process can take
many days, weeks or even months to complete the
reaction!!!
9
What Can Be Used to Activate the Reaction?
9

• Different methods have been used so far to
  enhance the rate of the reaction.
• Use of DBU as catalyst or DMAP
• Mixture of water and organic solvent has been
  shown to increase the rate of reaction
• Solvent dependant Dioxane and methanol are also
  used
• Use of stoichiometric amount of catalyst
• Use of co-catalyst in the reaction LiClO4 with
  DABCO, proline with imidazole, DABCO with CaH2
• These modifications are often substrate dependant
  and vary in yield and in time usually between
  0.5 h and 6 days or more!!!
• Question Are there more efficient conditions for
  the BH-reaction?

Basavaiah, D et al. Chem. Rev. 2003, 103, 811-891
10
Activation of the BH Reaction
10

• Catalysis by Ionic Liquid Immobilized Quinuclidine

• Reaction time between 30 minutes and 12 hours
• Works well when EWG CO2Alkyl and CN (yields gt
  62)
• Good yield obtained with R alkyl, aromatic
  subtituted either by EDG or EWG and hetero
  aromatic ring
• The catalyst can be reused after extraction with
  ether up to 6 time without losing significant
  activity

Cheng, J.P. et al. J. Org. Chem. 2005, 70,
2338-2341
11
Activation of the BH Reaction
11

• Use of TiCl4 in combination with
  proazaphosphatranes

Verkade J. G. et al. Angew. Chem. Int. Ed, 2003,
42, 5054-5056
12
Activation of the BH Reaction
12
catalyst
13
Activation of the BH Reaction
13
catalyst
14
Activation of the BH Reaction
14
Entry R R EWG t (min) Yield ()
1 1 NO2 COCH3 5 92
2 2 H COCH3 5 85
3 3 NO2 CO2Et 10 92
4 4 NO2 CO2CH3 10 92
5 5 Cl CO2CH3 10 92
6 6 H CO2CH3 10 88
7 7 OCH3 CO2CH3 10 87
8 8 H CN 20 95
9 9 NO2 CN 10 88
catalyst
15
Intramolecular MoritaBH Reaction
15

• Few work has been done on the intramolecular MBH
  reaction compared to the acyclic one
• Can lead to interesting multifunctionalized
  cycles

16
Intramolecular MoritaBH Reaction
16
Entry R n Method Yield ()
1 Ph 1 0.3 equiv. piperidine, CDCl3, 144 h 50
2 OEt 1 0.4 equiv. n-Bu3P, CDCl3, 28 days 40
3 Ph 2 0.3 equiv. piperidine, CDCl3, 14 to 28 days 24-30
4 Ph 2 0.2 equiv. n-Bu3P, CDCl3, 2 h 75
5 OEt 2 0.2 equiv. n-Bu3P, CDCl3, 24 h 50
When an excess of piperidine is used, the
reaction stops at the intramolecular aldol
reaction to give mainly product 2.
Murphy, P. J. et al. Tetrahedron, 2001, 57,
7771-7784
17
Vinylogous Intramolecular MoritaBH Reaction
17
Entry R R Cat () Solvent M t (h) Yield () Ratio (A/B)
1 Me OMe PBu3 (10) CH3CN 0.05 24 80 955
2 Me OMe PBu3 (10) CH3CN 0.10 8 61 955
3 Me OMe PBu3 (10) t-amyl-OH 0.10 11 88 964
4 Me OMe PMe3 (10) t-amyl-OH 0.05 3 91 973
5 Me OMe PMe3 (10) t-amyl-OH 1.00 0.75 81 964
6 H OMe PMe3 (20) t-amyl-OH 0.10 0.25 43 1000
7 H OMe PMe3 (20) t-amyl-OH 0.01 4 90 1000
Roush, W. R et al. J. Am. Chem. Soc. 2002, 124,
2404-2405
18
Vinylogous Intramolecular MoritaBH Reaction
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Entry R R Cat () Solvent M t (h) Yield () Ratio (A/B)
8 Me OMe PMe3 (25) t-amyl-OH 0.10 8 83 928
9 H Me PBu3 (50) CH3CN 0.06 0.5 55 9010
10 H Me PMe3 (50) t-amyl-OH 0.01 0.75 45 955
Conclusion 5 membered cycloalkenes are easier to
synthesise by a vinologous
intramolecular MBH reaction. Lower concentration
reduces the yield due to
self-condensation.
Roush, W. R et al. J. Am. Chem. Soc. 2002, 124,
2404-2405
19
Explanation of Regioselectivity
19
The most electrophilic carbon will react first
aldehydegtketonegtester
Roush, W. R et al. J. Am. Chem. Soc. 2002, 124,
2404-2405
20
20
Combination of MBH Reaction and TrostTsuji
Reaction
Krische M.J. et al. J. Am. Chem. Soc. 2003, 125,
7758-7759
21
Combination of MBH Reaction and TrostTsuji
Reaction
21
22
New MBH Cyclization Reactions
22
Krafft, M. E. et al. J. Am. Chem. Soc. 2005, 127,
10168-10169
23
Enantioselective MBH Reactions
23

• Have been a challenge in organic synthesis
• Enantioselectivity can come from
• Chiral Lewis acid
• Chiral amine
• Bifunctional organocatalyst
• Kinetic Resolution

24
Enantioselective MBH Reactions
24
Proposed Intermediate
Miller, S. J. et al. Org. Lett. 2003, 5, 3741-3743
25
Enantioselective MBH Reactions
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Acylation Kinetic Resolution
Conditions THF/H2O 31, 0.6M, 48 h at r.t.
Miller, S. J. et al. Org. Lett. 2005, 7, 3849-3851
26
Enantioselective MBH Reactions
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B-H Chiral Bronsted Acid
Mechanism
Schaus, S. E. et al. J. Am. Chem. Soc. 2003, 125,
12095-12096
27
Enantioselective MBH Reactions
27
Catalyst
Schaus, S. E. et al. J. Am. Chem. Soc. 2003, 125,
12095-12096
28
Enantioselective MBH Reactions Via a Bifunctional
Organocatalyst
28
Catalyst and Transition State
Wang, W. et al. Org. Lett. 2005, 7, 4293-4296
29
29
Aza-BH Reaction General

• Use of imines instead of aldehydes
• General reaction

30
30
Enantioselective Aza-BH Reaction
Proposed Transition State
Shi, M. et al. Angew. Chem. Int. Ed. 2002, 69,
4507-4510
31
Enantioselective Aza-BH Reaction
31
Entry Ar Yield () ee ()
1 C6H5 80 97
2 p-MeC6H4 76 96
3 p-MeOC6H4 64 99
4 p-ClC6H4 68 93
5 p-NO2C6H4 60 74
6 C6H5-CHCH 54 46
ORTEP of 4

• Only works when directly attached to Ph ring
• With aliphatic imines, no product obtained
• Best results obtained with EDG
• Configuration is R

Shi, M. et al. Angew. Chem. Int. Ed. 2002, 69,
4507-4510
32
Enantioselective Aza-BH Reaction
32
Catalyst
Entry Ar R Conditions Yield () ee ()
1 C6H5 H THF, -25oC 80 85
2 C6H5 OMe DCM, 0oC 76 83
3 p-MeOC6H5 OMe DCM, 0oC 64 70
4 C6H5 OPh CH3CN, -20oC 64 74
5 p-MeC6H4 H THF, -25oC 68 83
6 p-MeC6H4 OMe DCM, 0oC 60 80
7 p-MeC6H4 OPh CH3CN, -20oC 54 69
ORTEP of 3
Shi, M. et al. Chem. Eur. J. 2005, 11, 1794-1802
33
Change of Configuration Explanation
33
Shi, M. et al. Chem. Eur. J. 2005, 11, 1794-1802
34
Enantioselective Aza-BH Reaction
34
Entry Ar Yield () ee ()
1 C6H5 83 83
2 p-MeC6H5 82 81
3 p-FC6H5 84 81
4 m-FC6H5 96 85
5 p-BrC6H5 85 83
6 p-ClC6H5 90 87
7 m-ClC6H5 88 88
8 o-ClC6H5 85 61
9 p-NO2C6H5 86 92
10 o-NO2C6H5 88 84
11 C6H5CHCH 94 95

• The use of phenyl acrylate or acrolein worked
• well, but showed a decrease in
  enantioselectivity
• Reaction time between 18 and 36 h
• By changing CH3 by H or OPh, the same
• configuration was obtained!

Shi, M. et al. J. Am. Chem. Soc. 2005, 127, 3790
35
Enantioselective Aza-BH Reaction Proposed TS
35
R
S
36
Enantioselective Aza-BH Reaction
36
Entry Ar R Yield () ee ()
1 C6H5 Me 93 87
2 p-ClC6H4 Me 96 95
3 m-ClC6H4 Me 93 93
4 p-BrC6H4 Me 93 94
5 p-MeOC6H4 Me 93 94
6 2-furyl Me 100 88
7 2-naphtyl Me 94 91
8 p-NO2C6H4 Me 91 91
9 p-NO2C6H4 Et 88 88
10 p-NO2C6H4 H 95 94
Lewis Base
Lewis Acid
Sasai, H. et al. J. Am. Chem. Soc. 2005, 127,
3680-3681
37
Application of BH Reaction in Total Synthesis
37
Salinosporamide A
1
Retrosynthetic Analysis
Corey, E.J. et al. J. Am. Chem. Soc. 2004, 126,
6230-6231
38
Application of BH Reaction in Total Synthesis
38
Corey, E.J. et al. J. Am. Chem. Soc. 2004, 126,
6230-6231
39
BH Reaction as Key Step
39
Explanation
40
BH Reaction as Key Step
40
Explanation
Less interaction because the methyl is more far
from the quinuclidine moiety
41
Why One is Silylated and Not the Other One?
41
Big interaction between the chain and benzyl
group
The methyl groups on the silicon are more far
from the methyl of the ester
42
End of the Synthesis of Salinosporamide A
42
43
Conclusion
43

• Activation of BH reaction by reusable Ionic
  Liquid Immobilized Quinuclidine and use of TiCl4
  in combination with proazaphosphatranes can
  provide adduct in less than 10 minutes!
• Development of new methods of intramolecular
  cyclization
• Enantioselective MBH reaction providing ee up to
  99
• Synthesis of aromatic a-substituted chiral tosyl
  amines by Aza-BH reaction. Very few BH adducts
  with alkyl imines
• Total synthesis of Salinosporamide A by Corey
  using BH reaction as a key step with a 10
  overall yield for 18 steps