1
Enantioselective X–H insertion reactions based on carbenoids
Speaker: Shaolong ZhangSupervisor: David Zhigang WangDate: Jan. 3nd, 2014
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Outline
• Background• Construction of C-X bond via metal carbene
N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions
• Application in synthesis• Summary&Acknowlegement
3
Outline
• Background• Construction of C-X bond via metal carbene
N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions
• Application in synthesis• Summary&Acknowlegement
4
BackgroundConstruction of C-X bonds:
Transition-metal-catalyzed insertion of carbenes or carbenoids:
2)Transition-metal-catalyzed C-X coupling reactions
Advantages:a)mild reaction conditions;b)high efficiency;c)diverse ligand sources render highenantioselectivily X-H insertion results.
palladium-catalyzed C-N and C-O couplings;Buchwald-Hartwig cross-coupling;stoichiometric amounts of strong base;coulpling partners are limited to aryl iodides or aryl bromides.
Traditional strategy to construct C-X bonds:
1)Uncatalysed nucleophilic displacement reactionsto achieve the substitution of polar X-H bonds.
O
R1 R2
N2
O
R1 R2
MLn
O
R1 R2
H XR3
metal-carbenoid
via:
R3X-H
LnMN2
XY NR2
HR1
amine
+
[L2PdCl2](catalytic)base
NYR1
R1
S. Zhu, Q. Zhou, Acc. Chem. Res. 2012, 1365.
R1X-H Leaving Group-R2+ R1X-R2base
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Background
Carbenoid based X-H insertions remain underdeveloped:
1) The predominant focus in the carbenoid field was insteadcyclopropanation and C-H insertion;
2) There are good ways to achieve the substitution of polarX-H bonds through classical uncatalysed nucleophilicdisplacement reactions.
synthetic chemistry
bond destruction bond construction
Functional group transformationC-H bond activation
task 1 task 2
To achieve this goal:
Carbene chemistry
Key learning points1)X-H insertion is an underexploited process with great potential for further development.2) Metal carbenoids are less reactive than is typically believed and are compatible with a var iety of common functional groups.3)The availability of diverse ligand classes has reinvigorated the study of X-H insertion. Many metals behave poorly or are completely inactive without the right ligand.4)Recent breakthroughs in copper- and iron-catalysed X-H insertion should stimulatefurther development with these metals.5)X-H insertion can be carr ied out in water , opening the door to applications in chemicalbiology.
packed destruction-consructionstrategy
direct destruction-consructionstrategy
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NHN2
OH
O
O
CO2pNB
H
N
OH
O
H0.1 mol%Rh2(OAc)4
80 oCO
CO2pNB
HH
NO
SCHH
H
F3CHO
OOH
OH
NO
SC
HH
H
F3CHO
OOH
HNNH
Faropenem
NO
SC
HH
H
F3CHO
OOH
N
H
CH3HN
NO
SC
HH
H
F3CHO
OO
NN
NN
O
SC
HH
H
F3CHO
OOH
H CH3
NHH
HNH
CH3
H OH
Tmipenem Paniperem
Biapenem Lenapenem
Used industrially by MeckIn synthesis of (+)-Thienamycin
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AcO
Me
H
H
Me
H
O N2
CuO
MeOH
AcO
Me
H
H
Me
H
O OMe
Seminal observations f rom Reichstein in 1950
ON2 Cu, RX-H
OXR
Yates in 1952
R. Casanova, T. Reichstein, Helv. Chim. Acta, 1950, 33, 417.
P. Yates, J. Am. Chem. Soc. , 1952, 74, 5376.
representative products:
O
PhOEt
O
PhXPh
O
PhN
X = N, O, S
P. Teyssie, Tetrahedron Lett., 1973, 14, 2233.
O
OEtN2
Rh2(OAc)4
R-OH
O
OEtOR
R = Me, Et, iPr, tBu
Tetssie in 1973
Background
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General mechanistic study
N2cat. [M]
MR H
[M]
[M]
R H
A concerted mechanism for carbenoids with non-polar bonds(cyclopropanation,
C-H insertion, or Si-H insertion)
MLnNN
R COOR
LnMR
COORN N
LnMCOOR
RXH R
LnMX R
COOR
H R
R COOR
H XR
A
BC
D
prefered stepwise ylide machanisim with polar bonds
(X = N, O, or S)
S. Zhu, Q. Zhou, Acc. Chem. Res. 2012, 1365.
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Metals for carbenoid-transfer reactions. (The font scaling is meant to qualitatively convey the effectiveness of each metal)
Conclution:
elements in the smallest font(Co, Ni, Pd, Pt, Os, Ir) have applied in carbenoidchemistry but have seen little or no use in X-H insertion;It is copper(I) and rhodium(II) that have proven, as yet, most versatile.
General points on catalysts
G. Dennis *, F. Na, Chem. Soc. Rev., 2013, 42, 4918.
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Outline
• Background• Construction of C-X bond via metal carbene
N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions
• Application in synthesis• Summary&Acknowlegement
11
Outline
• Background• Construction of C-X bond via metal carbene
N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions
• Application in synthesis• Summary&Acknowlegement
12
N-H bond insertions
N2
MeOEt
O
PhNH2+
5 mol% CuCl6 mol% (Sa,S,S)-SpiroBox
6 mol% NaBArF4CH2Cl2, 25 oC, 2 h
94 %, 98 % ee
NHPh
MeOEt
O
N
O
O
N Ph
Ph
SpiroBox
NHPhMe OBn
On
NHPhPh OBn
On
NHPhOBn
OMe
Me
NHPhOBn
O
NHPhTBSO OBn
On
OEt
O
NHPhEtO
O
95 %, 88% een = 4, 83 %, 98 % een = 6, 75 %, 98 % ee84 %, 95 % ee
72 %, 91 % een = 1, 62 %, 96 % een = 2, 87 %, 96 % ee
n = 1, 83 %, 98 % een = 2, 87 %, 98 % een = 3, 75 %, 98 % een = 4, 77 %, 97 % ee
B. Liu, S. Zhu, W. Zhang, C. Chen, Q. Zhou, J. Am. Chem. Soc. 2007, 5834.
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BocHN COOMe
N25 mol% (S)- COOH
OH
Rh2(OAc)4, 0 oC, DCM45 % ee
NBoc
COOMe
NBoc
COOMe
HCO2Me
HNHBoc BocHN
COOMe
2.6 1.31: :C. F. Garci, M. A. McKervey, T. Ye, Chem. Commun. 1996 , 1465.
S. Bachmann, D. Fielenbach, K. A. Jorgensen, Org. Biomol. Chem. 2004, 3044.
NH2 N2
CO2EtNH
CO2Et
+
10 mol% CuPF6Ligand
N
OPR2
R =
Me
Me
75%, 26% ee.
N-H bond insertions
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N-H bond insertions
N2
MeOBn
O
+
1 mol% CuCl1.2 mol% (Sa,S,S)-SpiroBox
1.2 mol% NaBArF4CH2Cl2, 25 oC, 2 h
92 %, 98 % eeNH
MeOBn
O
N
O
O
N Ph
Ph
SpiroBox
OMeNH2
OMe
NH2
MeOBn
O
TCCAMeCN, H3O
70 %, 97 % ee
N
N
N
O
O O
Cl
Cl
Cl
TCCATrichloroisocyanuric acid
This copper-catalyzed asymmetric N-H insertion shows a high potential for wide applications in the preparation of optically active -amino acid derivatives.
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Outline
• Background• Construction of C-X bond via metal carbene
N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions
• Application in synthesis• Summary&Acknowlegement
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O-H bond insertions
N2
OMe
O+ nBuOH
OnBuOMe
O
5 mol% FeCl2.4H2O6 mol% (Sa,S,S)-SpiroBox
6 mol% NaBArFCHCl3, 40 oC, 15 h
93%, 98% ee
N
O
O
N iPr
iPr
SpiroBox
OOMe
O
OOMe
O
MeO
OMe
O
Ph
OOMe
O
Me
Me
Me
OOMe
O
Me
Me
Me
24 h, 88%, 95% ee 24 h, 91%, 95% ee
12 h, 90%, 95% ee3 h, 92%, 93% ee48 h, 86%, 89% ee
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O-H bond insertions
P
N2
OMe
OOMeX n-BuOH+
5 mol% CuOTf6 mol% (Sa,S,S)-SpiroBox
6 mol% NaBArFCH2Cl2, 25 oC P
OOMe
OOMeX
nBu
X = F, Cl, Me, MeO, etc. 45-89% yield84-98% ee
P
OOMe
OOMe
TMS BF3.OEt2CH2Cl2, rt.
P
OHOMe
OOMe
89.7% ee 93% yield89.2% ee(R)
an efficient approach not only to -alkoxy phosphonates but also to the more useful -hydroxyphosphonates.
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O-H bond insertions
N2
MeOR
O+
OH
X
5 mol% CuCl6 mol% (Sa,S,S)-SpiroBox6 mol% NaBArF, 5A MS
CHCl3, 25 oC, 3 h N
O
O
N Ph
Ph
SpiroBox
O
MeOR
O
X
68-88%95%-99.6% ee
O
MeOEt
O
aq. KOHEtOH, 0 oC
O
MeOH
O99% ee 100%
OH
TMS
N2
OMe
O
2.0 mol% Cu(OTf)23.8 mol% (+)-Fu's Ligand
4.0 mol% H2ODCE, rt.+
94%, 90% ee
PhOMe
O
HOTMS
Me Me
MeMe
Fe
Me
N N
FeMe Me
MeMe
Me
Fu's Ligand
BF3.Et2OCH2Cl2
98%Ph
OMe
O
HHO
T. C. Maier, G. C. Fu, J. Am. Chem. Soc. 2006, 128, 4594.
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O-H bond insertions
N2
ArOMe
O
+ H2O
5 mol% FeCl2.4H2O6 mol% (Sa,S,S)-SpiroBox
6 mol% NaBArFCHCl3, 40 oC
OH
ArO
OMe
OH
O
OMe
87%, 94% ee
OH
O
OMe
90%, 91% ee
S
OHOMe
O
66%, 92% ee
The challenges of asymmetric O-H insertion of water are mainly attributed to two aspects:First , the active transition metal catalysts are generally sensitive to water. Second, the small molecular structure of water makes chiral discrimination quite difficult.
OH
O
OMeCl
95% ee
NsClDMAP, Et3NCH2Cl2, 0oC
90%
ONs
O
OMeCl
S
NCH2
2
Acetone, 20 oC85%, 93% ee
CO2Me
N
Cl
S
Clopidogrel
S. Zhu, Y. Cai, H. Mao, J. Xie, Q. Zhou, Nat. Chem. 2010 , 546.
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OH
N2
CO2Rn
5 mol% CuOTf6 mol%(Sa,S,S)-SpiroBox
6 mol% NaBArFCH2Cl2, 25 oC O
CO2Rn
O
CO2Bn
O
CO2Bn
O
CO2Bn
OCO2Bn
OCO2Bn
OCO2Me
OCO2Bn
80%, 93% ee 89%, 90% ee 77%, 88% ee
81%, 88% ee 80%, 95% ee 79%, 97% ee 14%, 95% ee70%, 83% ee*
N
O
O
N tBu
tBu
SpiroBox
*obtained by using SpiroBox-iPr
double bond is compatible in the chain,no competitive cyclopropanation reaction are abserved.
competitive -H elimination reaction
O-H bond insertions
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Outline
• Background• Construction of C-X bond via metal carbene
N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions
• Application in synthesis• Summary&Acknowlegement
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S-H bond insertions
N2
R1 OR2
O
+ R3 SH
5 mol% CuCl6 mol%(Sa,S,S)-SpiroBox
6 mol% NaBArFCHCl3, 80 oC
SR3
R1 OR2
O*
S
MeOBn
O*
XS
OBn
O*
X
S
MeOBn
O*
X
70-87%68-85% ee
59-88%44-77% ee
76-92%60-72% ee
S
MeOBn
O*
S
MeOBn
O
S
MeOBn
O
S
MeOBn
O
Ph
PhPh
* * *
86%, 17% ee 84%, 32% e 85%, 61% ee 57%, 77% ee
S
MeOBn
O
Ph
PhPh
*
TFA/Et3SiHCH2Cl2, r.t.
SH
MeOBn
O*
81%, 77% ee77% ee
The low level of enantiocontrol maybe partially attr ibuted to:The high coordination ability of the sulfur atom;The relatively high stability of sulfoniumylide may facilitate the degenerationof metal-associated ylide to free ylide.
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S-H bond insertions
SOMe
O
O
1 mol% [Ir(COD)Cl]2PhNH2, CH2Cl2
NHOMe
O
91%
NBoc
O SO Cl O
SO
NHBoc
1 mol% [Ir(COD)Cl]2CH2Cl2
NBoc
O
I. K. Mangion, I. K. Nwamba, M. Shevlin, M. A. Huffman, Org. Lett. 2009, 3566.
O
OO
F3C
NO2
SO2N3base
O
OO
F3CNN
NSHO2Ar
ONN
NO
ArO2S
F3CO
O
ON
N
ORX
Ocat. Rh2(Oct)4
ArSO3N3base
Rh2(Oct)4RXH
RXH
O
F3C NSHO2Ar
+
B. H. Brodsky, J. D. Bois, Org. Lett. 2004, 2619.
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Outline
• Background• Construction of C-X bond via metal carbene
N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions
• Application in synthesis• Summary&Acknowlegement
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Si-H bond insertionsN2
OMe
- 78oCEt3SiH
NSO2
nC4F9
CO2
H4
Rh2
0.65% mol%
OMeH
Et3Si
94% ee
M. Ge, E. J. Corey, Tetrahedron Lett. 2006, 2319.
R1 R2
R3N2CO2Me
+ TBDMSiH
N
H O
O
Rh
RhSO2Ar 4
pentane, - 78oC
77-95% ee
R1 R2
R3Me2tBuSi
CO2Me
H. M. L. Davies,T. Hansen,J. Rutberg, P. R. Bruzinski, Tetrahedron Lett. 1997, 1741.
CO2Me
N2
Cl N
Cl
N
Cl
Cl
10 mol%, [CuOTf]2C6H6H-SiMe2Ph, CH2Cl2, - 40oC
88%, 83% eeCO2Me
Me2SiH2PhL. A. Dakin, S. E. Schaus, E. N. Jacobsen, J. S. Panek, Tetrahedron Lett.1998, 8947.
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N2
O
OMe+ Me2PhSi-H
5 mol% Cu(OTf)26 mol% SpiroZhou
CH2Cl2, 0 oCSiPhMe2
O
OMe
N
N
SpiroZhou
Cl
Cl
Cl
Cl
95%, 93% ee
SiPhMe2
O
OMeSiPhMe2
O
OEt
SiPhMe2
O
OiPrSinPr3
O
OMe
95%, 97% ee95%, 97% ee
92%, 98% ee92%, 98% ee
Si-H bond insertions
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Outline
• Background• Construction of C-X bond via metal carbene
N-H bond insertions O-H bond insertions S-H bond insertions Si-H bond insertions
• Application in synthesis• Summary&Acknowlegement
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Application in synthesis
NHN2
OH
O
O
CO2pNB
H
N
OH
O
H0.1 mol%Rh2(OAc)4
80 oCO
CO2pNB
Me MeOH
O
OP
N2
O OEtOEt
OMOMMe
Me MeO
O
Me
OMOM
O
P OOEt
EtO
Rh2(OAc)4PhH60 %
Me MeOH
HO
OMOMMe
J. X. Gong, G. A. Lin, W. B. Sun, C. C. Li, Z. Yang, J. Am. Chem. Soc. , 2010, 132 , 16745.
MeMe
O
O O
O
OH Me
Maoecrystal V
NH
OH
O
O
CO2pNB
H
N
OH
O
H
S
CO2H
NH2HHHH
(+)-Thienamycin
T. N. Salzmann, R. W. Ratcliffe, B. G. Christensen, F. A. Bouffard, J. Am. Chem. Soc. , 1980, 102 , 6161.
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Application in selective protein labeling
NH
HN
ONH
Ph
N2
OOMe
3
100 uM Rh2(OAc)480 %H2O/ethylene glycol N
H
HN
ONH
CO2R
Ph
N
HN
ONH
CO2RPh
tryptophan-containingproteins at 100 uM
buffer salt, PH, and temperatureare varied depending on the protein
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Summary
MLnNN
R COOR
LnMR
COORN N
LnMCOOR
RXH R
LnMX R
COOR
H R
R COOR
H XR
A
BC
D
prefered stepwise ylide machanisim with polar bonds
(X = N, O, or S)
preparation of optically active a-amino acid derivatives;an efficient approach not only to a-alkoxy phosphonates
but also to the more useful a-hydroxyphosphonates;introduction of sulfur and silicon atom into certain position.
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Thank you for your attention
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