the baylis –hillman reaction and related modifications
DESCRIPTION
The Baylis –Hillman Reaction and Related Modifications. Literature meeting Presented by Josée Philippe Prof André B. Charette October 4 th , 2005. 2. Content. What is the Baylis – Hillman Reaction? Activation of the Reaction Enantioselective Reaction Intramolecular Reaction - PowerPoint PPT PresentationTRANSCRIPT
Literature meeting Presented by
Josée Philippe
Prof André B. CharetteOctober 4th, 2005
The Baylis–Hillman Reaction and
Related Modifications
Content
What is the Baylis–Hillman Reaction?
Activation of the Reaction
Enantioselective Reaction
Intramolecular Reaction
Aza–Baylis–Hillman Reaction
Application of Baylis–Hillman Reaction in the Synthesis of Natural Products such as Salinosporamide A.
2
About Baylis–Hillman Reaction
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.
DABCO
N
N
Morita, K. et al. Bull. Chem. Soc. Jpn. 1968, 41, 2815Basavaiah, D. et al. Chem. Rev. 2003, 103, 811-891
EWG
H R1 R2
Z R3N or R3P EWG
ZHR1
R2
EWG = CONH2, CONR2, COOR, etc.Z = O, NTs, NCO2R, NSO2ArR1, R2 = Alkyl, Aryl, H
3
What Kind of Substrates Are Used in BH Reaction?
Activated alkenes
Electrophile
Catalyst
Amine (BH Rxn)
Phosphine (MBH Rxn)
RCO2Me
OH
EWG
R1
RCHO
DABCO (cat.)
RSO3Ph
OH
RCN
OH
RCO2R
OH
RCOR
OH
RCHO
OH
RSO2Ph
OHRCONH2
OH
MeCO2Me
OH
MeCN
OH
RSOPh
OH
RPO(OEt)2
OH•
Me
Me
R1 = H
R1 = H
R = R1 = Me R1 = H
R1 =
H
R1 =
H
R1 = H
R1 = H
R 1 = H
R 1 =
H
R = R1 = Me
R 1 =
HBasavaiah, D. et al. Chem. Rev. 2003, 103, 811-891
4
General Mechanism of BH Reaction
N
N
O
CH3
N
N
H3C O
O
H
N
N
H3C O
OH
N
N
H3C O
OH
OHO
H3C
N
N
N
N
H3C O
O
H3C
N
N
H3C O
HO
CH3
N
N
H3C O
OH
CH3
H3C
O O
CH3
N
N
Path I
Path II
MAJOR
MINOR
Basavaiah, D. et al. Chem. Rev. 2003, 103, 811-891
H
O
Me
O OH
Me
O
5
New Interpretation of the Mechanism
• 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
McQuade, D.T. et al. Org. Lett. 2005, 7, 147-150
Aprotic Solvent
Byproduct observed
6
Protic Solvent
New Interpretation of the Mechanism7
Aggarwal, V.K. et al. Angew. Chem. Int. Ed. 2005, 44, 1706-1708
Tertiary Amines and PhosphinesUsed in the BH or MBH Reaction
N
N
N N
OH
N
O
DABCO25g = 26.00$
Quinuclidine10g = 600.50$
3-HQD25g = 112.60$
3-Quinuclidone*25g = 78.50$
* Sold in Aldrich under the HCl salt
N
N
N,N-Dimethylaminopyridine25g = 47.40$
P(n-Bu)3 P(Me)3 P(Et)3
25 g = 361.60 $ 25 g = 233.00 $25 mL = 209.60 $
Drawback of reaction: very slow process: can take many days,
weeks or even months to complete the reaction!!!
8
What Can Be Used to Activate the Reaction?
• 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
9
Activation of the BH Reaction
• Catalysis by Ionic Liquid Immobilized Quinuclidine
N Nn-C4H9
HN
N
R H
O EWG (0.3 equiv.)
MeOH (2 equiv.)1 equiv. 1.5 equiv.
R
OH
EWG
Reaction time between 30 minutes and 12 hours
Works well when EWG = CO2Alkyl and CN (yields > 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
10
Activation of the BH Reaction
• Use of TiCl4 in combination with proazaphosphatranes
Verkade J. G. et al. Angew. Chem. Int. Ed, 2003, 42, 5054-5056
PNN
N
N
RRR
P
S
NN
N
NP
S
NNN
P
O
NN
N
NP
S
NN
N
N
RRR
P
S
NNN
R = Me, iBu, iPr R = Me, iBu, iPr
11
Activation of the BH Reaction
CHOO2N O
O
O
CHOCl O
H
O
O
OOH
OOH
OOH
O2N
O2N
O2N
OOH
Cl
OH O
10
10
10
10
10
94
92
91
94
88
Entry Aldehyde enone Product t (min) Yield (%)
CHOO2N
CHOO2N
1
2
3
4
5
R
O
H
O OOH
RTiCl4 (1 equiv)
Cat (5 mol%)DCMr.t.
P
S
NN
N
N
catalyst
12
Activation of the BH Reaction
CHO
CHO
CHO
OMe
CHOH3C
CHO
O
O
O
O
OH O
OOH
OOH
OMeOOH
30
30
10
10
H3COOH
10
81
89
88
91
90O
6
7
8
9
10
Entry Aldehyde enone Product t (min) Yield (%)
R
O
H
O OOH
RTiCl4 (1 equiv)
Cat (5 mol%)DCMr.t.
P
S
NN
N
N
catalyst
13
CHO
R
EWG EWG
OH
R
1 equiv 3 equiv
cat (5 mol%)
TiCl4 (1 equiv)DCMr.t.
Activation of the BH Reaction
Entry R EWG t (min) Yield (%)
1 NO2 COCH3 5 92
2 H COCH3 5 85
3 NO2 CO2Et 10 92
4 NO2 CO2CH3 10 92
5 Cl CO2CH3 10 92
6 H CO2CH3 10 88
7 OCH3 CO2CH3 10 87
8 H CN 20 95
9 NO2 CN 10 88
P
S
NN
N
N
catalyst
14
• Few work has been done on the intramolecular MBH reaction compared to the acyclic one
• Can lead to interesting multifunctionalized cycles
R
O
n
OH
Intramolecular Morita–BH Reaction
O
O
OH
O
OO
15
Intramolecular Morita–BH Reaction
Murphy, P. J. et al. Tetrahedron, 2001, 57, 7771-7784
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 20.3 equiv. piperidine, CDCl3, 14 to 28
days24-30
4 Ph 2 0.2 equiv. n-Bu3P, CDCl3, 2 h 75
5 OEt 2 0.2 equiv. n-Bu3P, CDCl3, 24 h 50
R
O
O
n
R
O
n
OH
r.t.R
O
n
OH
X
2 3
X
X = HN
P(n-Bu)3
When an excessof piperidine is
used, the reaction stops at the
intramolecular aldol reaction to give
mainly product 2.
16
Vinylogous Intramolecular Morita–BH Reaction
Roush, W. R et al. J. Am. Chem. Soc. 2002, 124, 2404-2405
Entry R R’ Cat (%) Solvent [M] t (h) Yield (%)Ratio (A/B)
1 Me OMe PBu3 (10) CH3CN 0.05 24 80 95:5
2 Me OMe PBu3 (10) CH3CN 0.10 8 61 95:5
3 Me OMe PBu3 (10) t-amyl-OH 0.10 11 88 96:4
4 Me OMe PMe3 (10) t-amyl-OH 0.05 3 91 97:3
5 Me OMe PMe3 (10) t-amyl-OH 1.00 0.75 81 96:4
6 H OMe PMe3 (20) t-amyl-OH 0.10 0.25 43 100:0
7 H OMe PMe3 (20) t-amyl-OH 0.01 4 90 100:0
COR
COR'
CORConditions
COR'
A B
COR'
COR
17
Vinylogous Intramolecular Morita–BH Reaction
Roush, W. R et al. J. Am. Chem. Soc. 2002, 124, 2404-2405
Entry R R’ Cat (%) Solvent [M] t (h) Yield (%)Ratio(A/B)
8 Me OMe PMe3 (25) t-amyl-OH 0.10 8 83 92:8
9 H Me PBu3 (50) CH3CN 0.06 0.5 55 90:10
10 H Me PMe3 (50) t-amyl-OH 0.01 0.75 45 95:5
COR
COR'
COR
COR'
Condition
COR'
COR
A B
Conclusion: 5 membered cycloalkenes are easier to synthesise by a vinologous intramolecular MBH reaction. Lower concentration reduces the yield due to self-condensation.
18
Explanation of Regioselectivity
O
CH3
O
OMe
Path A
Path B
PBu3 O
CH3
O
OMe
Bu3P
O
CH3
O
OMe
Bu3P
HO
CH3
Major
O
CH3
O
OMe
Bu3P
O
OMeBu3P
H
OMeO
Minor
O
Me
O
Me
OMe
O
Roush, W. R et al. J. Am. Chem. Soc. 2002, 124, 2404-2405
The most electrophilic carbon will react first: aldehyde>ketone>ester
19
Combination of MBH Reaction and Trost–Tsuji Reaction
Krische M.J. et al. J. Am. Chem. Soc. 2003, 125, 7758-7759
OH
R
O
R2R1
LG
R2R1
Nuc
PBu3
Pd (0)
O
O
R
Soft Nuc: Retention configurationHard Nuc: Inversion of configuration
MBH Reaction
Trost-Tsuji Reaction
R
OPBu3
Pd (0)
ORO
RCombination
of both
20
Combination of MBH Reaction and Trost–Tsuji Reaction
Entry R n yield (%)
1
2
3
4
Ph 1 92
Ph 2 64
furyl 1 83
cyclopropyl 1 76
PBu3 (100 mol%)Pd(PPh3)4 (1 mol%)
tert-BuOH60oC
Reaction Conditions
21
New MBH Cyclization Reactions
Entry R R1 yield (%)
1
2
3
4
5
6
Ph H
Me Me
Ph Me
PhCH2CH2 Me
Ph H
Ph Me
n
1
1
1
1
2
2
82
78
94
74
75
80
ClO
R
n
R
O
n
PBu3 or PMe3 (100 mol%)
tert-BuOH 0.5 Mthen, KOH (200 mol%),
DCM/H2O (1:1)BnEt3NCl (10 mol%)
R1
R1
2 possible sites of attack
ClO
R
n
R1
ClO
R
n
R1
R3P
PR3
PR3 O
R
n
R1
R3P
Does not occur
Favorable attack
Krafft, M. E. et al. J. Am. Chem. Soc. 2005, 127, 10168-10169
22
• Have been a challenge in organic synthesis
• Enantioselectivity can come from:
– Chiral Lewis acid
– Chiral amine
– Bifunctional organocatalyst
– Kinetic Resolution
23
Enantioselective MBH Reactions
Enantioselective MBH Reactions
R H
O
CH3
O NH
CO2H
N
N
CH3
BocHN O
Peptide
CH3
O
R
OH
(R) configuration
Entry Aldehyde Yield (%) ee
1
2
3
4
CHO
NO2
CHOO2N
OCHO
CHO
NO2MeO
81 78
81 69
95 63
88 81
Conditions: CHCl3/THF 0.5M, 25oC
H2N
HN
O
NH
OHN
O
NHtrtO
N
O
Ph
HNO
NH
O
OMe
O
Miller, S. J. et al. Org. Lett. 2003, 5, 3741-3743
Proposed Intermediate
N
Me
N
N
RHNO
NH R
O
O
OHN
Me
R
n
24
Enantioselective MBH Reactions
Entry Ar Yield (%) ee (%)
1
2
3
4
Cl
Br
S
5
82 (51)
92 (56)
88 (66)
94 (46)
83 (50)
80
79
79
51
74
O O
Ar
OH
Ar
ONH
CO2H
NN
(20 mol%)
(10 mol%) R configuration
OHO OHO
90 10
5 mol% catAc2O (3 equiv.)
Toluener.t.
24 hOHO OAcO
50% yield98% ee
Miller, S. J. et al. Org. Lett. 2005, 7, 3849-3851Conditions: THF/H2O 3:1, 0.6M, 48 h at r.t.
Acylation Kinetic Resolution
NN
BocHN
HN
O
NH
OHN
O
NH
OHN
O
NH
O
O
HN
O
OMe
H3C Oi-Bu
i-Pr
NNTrt
Ph
H3C
CH3i-BuO
H3C
H3CCatalyst
25
R
O
H
O OH
R
10 mol% catPEt3 (2 equiv.)
THF, –10oC48 h
O
S Configuration
Enantioselective MBH Reactions
Mechanism
Schaus, S. E. et al. J. Am. Chem. Soc. 2003, 125, 12095-12096
B-H = Chiral Bronsted Acid
OH
OH
CR3
CR3
CR3
CR3
R = F or H
26
R
O
H
O OH
R
10 mol% catPEt3 (2 equiv.)
THF, –10oC48 h
O Entry Aldehyde Cat Yield (%) ee (%)
1
2
3
4
5
6
7
8
Ph
O
H
BnO
O
HO
HO
H
O
H
O
O
O
H
O
H
Ph
O
H
2f
2f
2f
2e
2e
2e
2e
2e
88
74
72
71
82
70
40
39
90
82
96
96
95
92
67
81
Enantioselective MBH Reactions
Schaus, S. E. et al. J. Am. Chem. Soc. 2003, 125, 12095-12096
Catalyst :
OH
OH
CR3
CR3
CR3
CR3
2e R = H 2f R = F
27
R
O
H
O OH
R10 mol% cat
CH3CN, 0oC48 h
O
R configuration Entry Aldehyde Yield (%) ee (%)
1
2
3
4
5
Ph
O
H
O
H
O
H
O
H
O
Hn
80 83
82 81
75 81
67 92
63 94
Enantioselective MBH Reactions Via a Bifunctional Organocatalyst
Wang, W. et al. Org. Lett. 2005, 7, 4293-4296
N
N
N
S
CF3
F3C
O
H H
HR
O
Catalyst and Transition State:
28
Aza-BH Reaction: General
• Use of imines instead of aldehydes
• General reaction:
R
NTs
H
EWGEWG
NTs
R
R1 R2
R1 R2
Conditions
29
Enantioselective Aza-BH Reaction
Shi, M. et al. Angew. Chem. Int. Ed. 2002, 69, 4507-4510
Ar
NTs
H
EWGEWG
NHTs
RDMF/CH3CN–30oC
Cat 10 mol%
N
O
O
N
O
H
NAr
H
TsH
Proposed Transition State
30
Enantioselective Aza-BH Reaction
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-CH=CH 54 46
Shi, M. et al. Angew. Chem. Int. Ed. 2002, 69, 4507-4510
•Only works when directly attached to Ph ring•With aliphatic imines, no product obtained
•Best results obtained with EDG•Configuration is R
ORTEP of 4
Ar
NTs
H
NHTs
ArDMF/CH3CN–30oC
Cat 10 mol%CH3
OO
CH3
31
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
Ar
NTs
H
NHTs
ArCat 10 mol%
R
OO
R
(S) Configuration
Shi, M. et al. Chem. Eur. J. 2005, 11, 1794-1802
N
O
O
N
H
Enantioselective Aza-BH Reaction
ORTEP of 3
Catalyst
32
N
O
O
N
O
H
N
Ar
H
TsH
H
H
H
S Adduct
N
O
O
N
O
H
N
H
Ar
TsH
H
H
H
R Adduct
N
O
O
N
O
O
H
N
Ar
H
TsH
S Adduct
H
H H
N
O
O
N
O
H
N
H
Ar
TsH
R Adduct
O
H
H H
Change of Configuration: Explanation
Shi, M. et al. Chem. Eur. J. 2005, 11, 1794-1802
33
Enantioselective Aza-BH Reaction
Ar
NTs
H
TsHN
ArTHF
–30oCMS 4A
Cat 10 mol%O
CH3 CH3
O
S Configurationo
PPh2
OH
Catalyst
Shi, M. et al. J. Am. Chem. Soc. 2005, 127, 3790
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 C6H5CH=CH 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!
34
Enantioselective Aza-BH Reaction: Proposed TS35
RS
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
Ar
NTs
H
NHTs
RToluene: CPME (9:1)–15oC
Cat 10 mol%O
R Ar
O
R Configuration
Enantioselective Aza-BH Reaction
OH
OH
N
N
(S)-CatalystLewis Base
Lewis Acid
Sasai, H. et al. J. Am. Chem. Soc. 2005, 127, 3680-3681
36
NH
O
O
OMe
Cl
OH
H
Application of BH Reaction in Total Synthesis
Salinosporamide A
Corey, E.J. et al. J. Am. Chem. Soc. 2004, 126, 6230-6231
NH
OHCO2Me
O
MeHO
OH
H
H
N
OHCO2Me
O
Me
OPG
PG
O
NMeO
Me
MeO2C
OPG
1
CO2MeH2N
HO Me
(S)–Threonine
1
Retrosynthetic Analysis
37
Corey, E.J. et al. J. Am. Chem. Soc. 2004, 126, 6230-6231
Application of BH Reaction in Total Synthesis
NH
O
O
OMe
Cl
OH
H
CO2MeH2N
HO Me(S)–Threonine
MeO
O
Cl1)
DCM, r.t71%
2) p-TsOH, TolueneReflux, 12 h
80%
CO2Me
Me
N
O
MeO
–78oCClCH2OBn, 4 h,
69%
LDA, THF/HMPA
Me
N
O
MeOOBn
CO2MeNaCNBH3, AcOH
40oC, 12 h90% Me
HN
HO
OBn
CO2Me
1) TMSCl, Et2O23oC, 12 h
2) Acryloyl chloridei-PrNEt, DCM, 1 h
then H+, Et2O, r.t. 1 h96%
PMB
Me
N
HO
OBn
CO2MePMB
O Dess–Martin Oxidation
r.t.1 h
96%Me
N
O
OBn
CO2MePMB
O
38
Me
N
O
OBn
CO2MePMB
O N
OHCO2Me
O
Me
OBn
PMB
N
ORCO2Me
O
Me
OBn
PMB1) Quinuclidine, DME0oC, 7 days, 90%
2) BrCH2Si(CH3)2ClDMAP, DCM, 0oC
0.5 h, 95%
1 : 9
NH
O
O
OMe
Cl
OH
H
N
NO
OOCH3
O
O
HH
HN
NO
OOCH3
O
OH3C
O
CH3
O
H3C
A lot of interactionbetween the tertiary
amine and the methylof the ketone
BH Reaction as Key Step
Explanation
39
NO
OOCH3
O
OH
H
HN
NO
OOCH3
O
CH3
O
OH3C
OH3C
N
BH Reaction as Key Step
Explanation
Less interaction because the methyl is more far from the quinuclidine moiety
40
NO
OOCH3
O
O
CH3
Si
OH3C
Br
NO
OOCH3
O
CH3
O
Si
Br
OH3C
Why One is Silylated and Not the Other One?
Big interaction between the chain and benzyl group
The methyl groups on the silicon aremore far from the methyl of the ester
41
N
OCO2Me
O
Me
OBn
PMB
Bu3SnH, AIBN
BenzeneReflux, 8 h
89%
N
CO2MeO
OBnPMB
Si
OMe
Me
Me
H
1) Pd-C/EtOH
H2 (1 atm)18 h, 95%
2) Dess–Martinr. t. 1 h
95%
N
CO2MeO
OPMB
Si
OMe
Me
Me
H
ZnClTHF, -78oC
5 h, 88%
NCO2Me
O
PMB
Si
OMe
Me
Me
H
H
OH
KF, KHCO3
H2O2
THF/MeOH 1:1r.t. 18 h,
92%
NCO2Me
O
PMB
OHMeH
H
OH
HO
1) CAN, MeCN/H2O, 1 h, 83%2) 3N LiOH/THF, 5oC, 4d
3) BOPCl, pyr, DCM, r.t. 4) Ph3PCl2, MeCN, pyr, r.t. 1 h, 65%
NH
O
O
OMe
Cl
OH
H
1
dr 20:1
Si
Br
End of the Synthesis of Salinosporamide A42
• 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 α-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
Conclusion43