Transcript Stereoselective Claisen and Related Rearrangements

Stereoselective Claisen and Related
Rearrangements: Fundamental Methodology and
Synthetic Applications
David Mountford and Prof. Donald Craig
Centre for Chemical Synthesis,
Department of Chemistry,
Imperial College London.
SW7 2AZ
Industrial Supervisor: Dr Paul King, GSK
13th September 2005
The Claisen Rearrangement
•
The Claisen rearrangement is the [3,3] sigmatropic rearrangement
of an allyl-vinyl ether.
heat
O
•
O
Many variants exist…
Johnson-Claisen
Eschenmoser-Claisen
OR
NR2
O
•
Ireland-Claisen
OH
O
O
Ireland-Claisen Rearrangement.
O
O
R
1. LDA
R' 2.TMSCl
O
OTMS
R
R'
O
OTMS
R
R'
O
3. H3O+
HO
R
R'
Felkin-Anh Model in Pericyclic Reactions
•
The Felkin-Anh model can be applied to a wide range of pericyclic
processes by the replacement of C=O by C=CH-EWG'.
Nu
Nu
H
H
O
H
EWG'
R
H
R
EWG
•
EWG
In the Claisen rearrangement.
Felkin
O
O
O
OMe 1. LDA
CO2H
2.TMSCl
O
O
O
O
X O
O
Felkin
O
O
O
CO2H
O
O
:
OMe
O H
X
H
59% Yield
78
O
MeO
H
H
+
OMe
22
Li
anti-Felkin
anti-Felkin
O
O
O
MeO
Li
O
Belluš−Claisen Rearrangement
(Aza-Claisen, Zwitterionic Claisen Rearrangement)
• in situ generation of a ketene.
• Activation with a suitable Lewis acid.
• Addition to a tertiary allyllic amine.
O
O
R
LA
NR2
R
LA
NR2
O
R
R'
O
NR3
Cl
R'
O
R
NR2
R'
NR2
R
R'
O
LA
(Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121, 9726).
R
Aim of Project
•
1,2-Asymmetric Induction.
OLA
NR'2
R*
R
Lewis acid
iPr2NEt
RCH2COCl
O
R
NR'2
R*
NR'2
R*
O
H
H
H
L
R
S
H
S
N
L
O
Lewis acid
iPr2NEt
RCH2COCl
N
L
O
R
Major
Diastereoisomer
O
H
N
R
L
OLA
H
S
OLA
H
S
O
N
O
S
N
L
R
Minor
Diastereoisomer
O
Initial Studies
O
N
Ph
TiCl4
iPr2NEt
PhCH2COCl
O
CH2Cl2
79% Yield
•
•
•
Cyclic amines have a
greater nucleophilicity
compared to acyclic
amines.
Diagnostic morpholine
protons in 1H NMR
would aid analysis of
diastereomeric mixtures.
anti diastereomer
formed exclusively.
N
TiCl4
iPr2NEt
MeCH2COCl
O
CH2Cl2
O
N
Me
58% Yield
O
Synthesis of Chiral Allylic Amine Substrate
O
OMe
BocNBn
O
EtO P
EtO
O
DIBAL-H
H
Et2O
-78ºC
BocNBn
O
CO2Et
NaH
THF
PPh3, NBS
N
90% Yield
•
•
BocNBn
O
87% Yield
BF3·OEt2
DIBAL-H
CH2Cl2
-78ºC
86% Yield
BocNBn
CO2Et
morpholine
THF, 70ºC
OH
BocNBn
70% Yield
Neighbouring group effects gave selective reduction to the aldehyde.
The presence of BF3∙OEt2 prevented 1,4-reduction.
Chiral Allylic Amine Claisen Rearrangement
N
O PhCH2COCl
CH2Cl2
BocNBn
O
TiCl4
iPr2NEt
O
N
O
BocNBn Ph
N
+
BocNBn Ph
4.5% Yield
•
O
O
N
+
O
HNBn Ph
4.5% Yield
17% Yield
Deprotected allylic alcohol generated by the hydrolysis of an
intermediate vinyl aziridine.
N
BocNBn
N
O
NBn
N
O
BnN
O
O
t-Bu
O
TiCl4
:OH2
OH
HNBn
OH2
NBn
N
Bn
(Ohno, H.; Toda, A.; Fujii, N.; Ibuka, T. Tetrahedron: Asymmetry 1998, 9, 3929).
Optimisation of Lewis Acid and Reaction Conditions
O
N
Lewis Acid
iPr2NEt
O
Ph
N
O
PhCH2COCl
CH2Cl2
•
AlCl3, BF3·OEt2, Sc(OTf)3, SnCl4 and ZnCl2 gave very low yields of
rearranged product.
•
What about a milder titanium Lewis acid?
TiCl4 + n Ti(OiPr)4
TiCl4 + n AgOTf
(n+1) TiCl4/(n+1)(OiPr)4n/(n+1)
TiCl4-n(OTf)n + nAgCl
Optimisation of Titanium Lewis Acid
•
Lewis Acid
Yield of Product
TiCl4
79%
Ti(OiPr)4
No product isolated
TiCl(OiPr)3
No product isolated
TiCl2(OiPr)2
44%
TiCl3(OiPr)
61%
TiCl2(OTf)2
73%
TiCl(OTf)3
84%
“Ti(OTf)4”
68%
Optimum conditions found were 0.1 equiv. TiCl(OTf)3, with a 0.17M
solution of the acid chloride added dropwise over 5 hours.
O
O
Ph
N
O
TiCl(OTf)3
iPr2NEt
PhCH2COCl
CH2Cl2
84% Yield
(cf. 79% with TiCl4)
N
TiCl(OTf)3
iPr2NEt
O
Me
N
O
CH3CH2COCl
CH2Cl2
96% Yield
(cf. 58% with TiCl4)
Application of Optimised Conditions to Chiral Substrate
N
BocNBn
O
TiCl(OTf)3
iPr2NEt
O
PhCH2COCl
CH2Cl2
N
BocNBn Ph
O
•
•
•
•
0.1 equiv. TiCl(OTf)3 – Starting material.
1.2 equiv. TiCl(OTf)3 – 13% deprotected rearranged product.
Lewis acid coordinating with Boc group.
Lowering the temperature reduced decomposition but inhibited
rearrangement.
•
Solution: Use a less Lewis basic tosyl group…
Synthesis of New Chiral Allylic Amine Substrate
O
OMe
TsNBn
O
EtO P
EtO
O
DIBAL-H
H
Et2O
-78ºC
TsNBn
O
CO2Et
NaH
THF
CO2Et
TsNBn
71% Yield
(Over 2 Steps)
BF3·OEt2
DIBAL-H
CH2Cl2
-78ºC
PPh3, NBS
N
TsNBn
88% Yield
•
•
•
O
morpholine
THF, 70ºC
OH
TsNBn
76% Yield
0.2, 1.5 and 2.5 equiv. TiCl(OTf)3 – Starting material.
Steric hindrance may also be contributing to the lack of reactivity.
Due to lack of reactivity and the large quantities of AgOTf being
used a new method was required…
Belluš−Claisen Modification
OLA
R
OTMS
R
NR2
R'
OTMS
R
O
R'
Belluš-Claisen
N
TMSOTf
iPr2NEt
R'
Ireland-Claisen
O
?
OTMS
Ph
O
N
N
OTMS
O
Ph
N
O
PhCH2COCl
CH2Cl2
O
74% Yield
(cf. 79% TiCl4)
(cf. 84% TiCl(OTf)3)
Ph
N
O
Extension of Modification to Other Ketenes and
Silylating Agents
O
O
Cl
Cl
N
O
57% Yield
(cf. 44% TiCl4)
(cf. 64% TiCl(OTf)3)
TMSOTf
iPr2NEt
Cl2CHCOCl
CH2Cl2
R3SiOTf
iPr2NEt
PhCH2COCl
CH2Cl2
•
•
TMSOTf
iPr2NEt
N
CH3CH2COCl
CH2Cl2
O
N
O
O
Ph
N
O
Me
N
O
83% Yield
(cf. 58% TiCl4)
(cf. 96% TiCl(OTf)3)
Silylating Agent Yield
___________________
Me3SiOTf
74%
tBuMe2SiOTf
30%
iPr3SiOTf
0%
Me3SiCl
0%
Catalytic TMSOTf gave a lower yield of rearranged product (44%)
and recovery of starting material (48%).
This is due to the generation of TMSCl, which is less active than
TMSOTf.
Catalytic Belluš−Claisen Modification
•
Carboxylic Acid Activation Approach.
O
Ph
N
O
O
DCC
PhCH2CO2H
TMSOTf
iPr2NEt
CH2Cl2
Tf2O
PhCH2CO2H
TMSOTf
iPr2NEt
CH2Cl2
N
52% Yield
(12% cat. TMSOTf)
•
O
Ph
N
53% Yield
(15% cat. TMSOTf)
Pentafluorophenol Ester Approach.
OH
F
F
F
F
PhCH2CO2H
DCC
F
DMAP
CH2Cl2
O
Ph
O
N
PFP ester
TMSOTf
iPr2NEt
CH2Cl2
OPFP
76% Yield
O
Ph
N
O
O
64% Yield
(13% cat. TMSOTf)
Wolff−Belluš−Claisen Rearrangement
•
Wolff Rearrangement Approach.
O
R
•
O
CH2N2
Cl
R
N2
Wolff
R
O
In the presence of a tertiary amine and silver salts, α-diazoketones
undergo the Wolff rearrangement.
O
N
PhCO2Ag
NEt3
TMSOTf
PhCOCHN2
CH2Cl2
O
Ph
N
O
43% Yield
Wolff−Belluš−Claisen Rearrangement
•
Wolff Rearrangement Approach.
O
R
•
O
CH2N2
Cl
N2
R
Wolff
R
O
In the presence of a tertiary amine and silver salts, α-diazoketones
undergo the Wolff rearrangement.
O
N
O
Rh2(octanoate)4
TMSOTf
PhCOCHN2
CH2Cl2
Ph
O
Via
Ph
N2
TMS
N
O
52% Yield
(46% cat. TMSOTf)
(Steer, J. T. Ph.D. Thesis,
University of London, 2002).
Extension of Modification to Other Substrates
O
OH
N
amination
Ph
O
Claisen
Ph
Ph
90% Yield
N
Ph
O
88% Yield
O
OH
amination
O
Claisen
N
N
H
Ph
76% Yield
O
76% Yield
O
OH
amination
Ph
Claisen
N
O
N
73% Yield
H O
77% Yield
O
OH
amination
Claisen
89% Yield
N
N
Ph
O
79% Yield
O
N
BocNBn
Claisen
O
16% Yield
N
HNBn Ph
O
O
Return to Chiral Nitrogen Substrates
•
New protecting group strategy.
HCl
N
O
BocNBn
EtOAc
NaBH(OAc)3
HCHO
N
O
HNBn
CH2Cl2
92% Yield
•
N
O
MeNBn
75% Yield
Direct reduction using DIBAL-H or lithium aluminium hydride led only to
decomposition.
O
TMSOTf
iPr2NEt
N
MeNBn Ph
O
PhCH2COCl
CH2Cl2
TMSOTf
iPr2NEt
N
MeNBn
O
CH3CH2COCl
CH2Cl2
O
N
MeNBn Me
71% Yield
49% Yield
55 : 45 Mixture of
Diastereomers
86 : 14 Mixture of
Diastereomers
O
Synthesis of Chiral Oxygen Substrates
•
Substrate synthesis.
H
OH
•
1) TBSCl
imidazole
CH2Cl2
2) BuLi
ClCO2Me
THF, -78ºC
CO2Me
OTBS
Red-Al®
Et2O, -30 ºC
76% Yield
(Over 2 steps)
The analogous methyl ether failed to
undergo rearrangement due to the ether
oxygen sequestering the silylating agent.
OH
OTBS
PPh3, NBS
morpholine
THF, 70ºC
N
OTBS
62% Yield
N
OMe
O
78% Yield
O
Rearrangement of Chiral Oxygen Substrates
•
O
Claisen rearrangement.
96% Yield
(R = Ph)
N
N
OTBS
TMSOTf
iPr2NEt
TBSO
Ph
O RCH2COCl
CH2Cl2
O
Single
Diastereomers
O
66% Yield
(R = Me)
N
TBSO
Me
O
OTMS
O
OR
*
*
X
(Mulzer, J.; Shanyoor, M. Tetrahedron Lett.
1993, 34, 6545).
Rearrangement of Chiral Carbon Substrates
Me
OH
Ph
1) IBX, DMSO
2)
O
EtO P
EtO
O
CO2Et
Ph
CO2Et
NaH, THF
•
Me
77% Yield
(Over 2 steps)
Me
DIBAL-H
CH2Cl2
-78ºC
OH 95% Yield
Ph
PPh3, NBS
morpholine
THF, 70ºC
Will rearrangement proceed with good
1,2-asymmetric induction in the absence
of a heteroatom in the chiral substituent?
Me
N
Ph
O
84% Yield
O
Me
N
Ph
Me
OH
Ph
Me
TMSOTf
iPr2NEt
N
Ph
O
Ph
O
98% Yield
(R = Ph)
83 : 17 Mixture of Diastereomers
RCH2COCl
CH2Cl2
O
Me
N
Ph
Me
O
72% Yield
(R = Me)
Single Diastereomer
Decarboxylative Claisen Rearrangement Reaction
O
Ts
R
O
BSA
KOAc
PhMe
110ºC
O
Ts
Ts
R
Ts
O
R
R
OTMS
+
Me
KOAc
NTMS
•
Reaction catalytic in both
BSA and KOAc.
O
•
•
K
Me
Silylating agent essential,
no reaction with only KOAc
or NaH.
+ TMSOAc
CO2
NTMS
O
If 1 equiv. BSA and no
KOAc used then rearranged
acid formed.
Me
NTMS +
H
KOAc
OTMS
Ts
R
O
OTMS
Ts
R
O
Application and Development of the Decarboxylative Claisen
Ts
O
OH esterification
DCRR
O
Ts
Thermal: 83%
Microwave: 89%
Microwave, n/s: 83%
88% Yield
O
OH esterification
O
Thermal: 89%
Microwave: 67%
Microwave, n/s: 80%
DCRR
Ts
Ts
95% Yield
O
esterification
OH
Ts
O
DCRR
Thermal: 86%
Microwave, n/s: 74%
Ts
61% Yield
O
OH esterification
Ph
Ts
DCRR
O
Ts
Thermal: 88%
Microwave, n/s: 72%
Ph
Ph
88% Yield
O
BnO
OH esterification
BnO
O
96% Yield
Ts
Ts DCRR
BnO
Thermal: 77%
Microwave, n/s: 58%
Asymmetric Induction in the Decarboxylative Claisen
DCRR
O
BocNBn
O
BocNBn
50
DCRR
O
TsNBn
Ts +
Ts
O
OTBS
TsNBn
55
DCRR
:
OTBS
O
DCRR
O
Ph
Ts
O
Me
Ts
:
62% Yield
12
Ts + Me
Ph
60
78% Yield
OTBS
88
Me
Ts
TsNBn
45
Ts +
Ts
74% Yield
BocNBn
50
Ts +
Ts
O
:
Ts
Ts
Ph
:
40
63% Yield
Heteroaromatic Claisen Rearrangements
•
The Claisen rearrangement of heteroaromatic substrates.
O
OH
OEt
O
Hg(OAc)2
NaOAc
100°C
18 h
CHO
O
CHO
O
(Thomas, A. F.; Ozainne, M. J. Chem. Soc. C 1970, 220).
S
OH
MeC(OEt)3
Me(CH2)4CO2H
CO2Et
185°C
18 h
O
CO2Et
2% Yield
CO2Et
61% Yield
S
CO2Et
OR'
S
CHO
21% Yield
OEt
O
S
CO2Et
(Raucher, S.; Lui, A. S.-T.; Macdonald J. E. J. Org. Chem. 1979, 44, 1885).
Heteroaromatic Decarboxylative Claisen
O
Ts
O
Ts
DCRR
O
O
Thermal: 63%
Microwave: 75%
O
Ts
O
DCRR
S
Ts
Thermal: 75%
Microwave: 22%
Thermal, cat: 47%
Ts
Thermal: 67%
Microwave: 77%
Thermal, cat: 48%
Microwave n/s: 70%
S
O
Ts
O
DCRR
N
Ts
•
N
Ts
Ts group on nitrogen essential for synthesis and stability of ester.
Ts
O
O
S
Ts
DCRR
58% Yield
S
Extension of Heteroaromatic Substrates
•
However,
O
O
O
Ts
O
S
Ts
O
Ts
O
O
O
O
Ts
O
No rearrangement.
O
OTMS
Ts
X
•
O
X
Ts
OTMS
Where X=O or S
Secondary alcohol derived ester.
O
O MeMgCl
S
H
THF
OH Esterify
S
Me
92% Yield
O
S
Me
95% Yield
Ts
Ts
DCRR
S
Me
Stoichiometric: 58%
Catalytic: 43%
Mechanistic Details
•
O
Proposed Mechanism,
Ts
Ts
O
X
O
X
OTMS
Ts
Ts
Ts
O
X
X
OTMS
•
What about indoles?
X
NaH
TsCl
H2SO4
N
H
CO2H
Ts
N
Ts
EtOH
N
CO2Et
H
83% Yield
O
DCRR
O
N
Ts
95% Yield
Ts
THF
79% Yield
N
Ts
CO2Et
LiAlH4
THF
Esterify
N
Ts
73% Yield
OH
Indoles as Heteroaromatic Substrates
•
Considering electron density…
N
Ts
•
O
OTMS
Ts
O
N
Ts
Ts
OTMS
Try again
O
O
H
N
H
NaH
TsCl
THF
H LiAlH4
N
Ts
79% Yield
THF
OH
N
Ts
95% Yield
Esterify
Thermal: 28%
Microwave: 16%
Thermal, cat: 61%
Microwave, cat: 29%
DCRR
N
Ts
Ts
O
N
Ts
92% Yield
Ts
O
Mechanistic Studies
•
1H
NMR Studies.
O
N
Ts
O
Ts
O
N
Ts
Ts
OTMS
O
Ts
N
Ts
•
N
Ts
OTMS
Ts
Secondary alcohol derived ester.
Me
Me
O
N
Ts
Ts
O
DCRR
N
Ts
Stoichiometric: 58%
Catalytic: 60%
Ts
Carboaromatic Claisen Rearrangements
•
Allyl phenyl ethers undergo Claisen rearrangement, benzyl vinyl
ethers however, will not generally undergo rearrangement .
O
O
O
•
HO
O
Me
O
An Eschenmoser-Claisen rearrangement.
OH
+
NMe2
OMe
DMF
160ºC
Me
CONMe2
76% Yield
(Felix, D.; Gschwend-Steen, K.; Wick, A. E.; Eschenmoser, A. Helv. Chim. Acta.
1969, 52, 1030).
Carboaromatic Decarboxylative Claisen
O
O
Ts
O
Ts
O
23% Yield
DCRR
O
O
Ts
O
Ts
O
NO2
17% Yield
DCRR
NO2
Me
NO2
Me
Me
O
O
MeO
O
Ts
Ts
DCRR
OMe
MeO
Ts
O
MeO
+
OMe
MeO
MeO
20% Yield
47% Yield
•
No evidence of Claisen rearrangement observed.
OMe
Alkylation of Carboaromatic Substrates
•
Proposed mechanism.
O
O
O
Ts
O
Ts
O
MeO
Ts
O
MeO
MeO
MeO
OMe
OMe
MeO
OMe
Ts
O
Ts
MeO
MeO
OH
O
MeO
+
OMe
•
OMe
OMe
Attempts to facilitate both a radical-induced reaction and a
Lewis acid-catalysed rearrangement led only to decomposition.
Conclusion
Belluš−Claisen Rearrangement
• Refined experimental procedure for Belluš−Claisen rearrangement.
• Developed a novel, metal free variant of the Belluš−Claisen
rearrangement.
• Applied new methodology to a range of ketenes and allylic amines,
substrates with exopericyclic substituents shows good selectivity.
Decarboxylative Claisen Rearrangement Reaction
• Decarboxylative Claisen rearrangement applied to a wide range of
substrates, including heteroaromatics.
• Microwaves greatly increased reaction rate and removed need for
solvent.
Thanks to…
• Prof. Donald Craig
• Dr Paul King (GSK)
• The Craig Group, especially Drs Damien Bourgeois, John Caldwell
and Tanya Wildman
• Ian Campbell (Microwaves)
• Dr Andrew White (Crystal Structures)
• Dick Shepard, Peter Haycock and Sean Lynn (NMR)
• EPSRC
• GSK (CASE Studentship)