Dicobalt Hexacarbonyl Complexes of AlkynylImines in a Sequential Staudinger/Pauson-Khand
Process. A Route to New Fused Tricyclic β-Lactams
Clarisse Olier, Nadia Azzi, Gérard Gil, Stéphane Gastaldi,and Michèle P. Bertrand
J. Org. Chem. 2008, 73, 8469–8473.
(CO)3Co Co(CO)3
EtO
OEtR
1. TMSOTf, ArNH2CH2Cl2
2. DIPEA, CH2Cl2
NClOCTs
3. PKR
NTsN
O
R
ArO
H
H
H + NTs
O
RH
HNO
HAr
Presented by Melissa Sprachman, December 20, 2008
Melissa Sprachman @ Wipf Group Page 1 of 15 12/27/2008
The Pauson-Khand Reaction
R1 R2
R6 R5
R3R4
+Co2(CO)8
solvent, heatR1 > R2
O
R1
R2
R5
R6
R3
R4
R1 R2
R6 R5
R3R4
+
Co2(CO)8 (≤ 1 equiv)
promoter/solventCO atmosphere
Mechanism:
Other metal complexes used: Fe(CO)5, Ru2(CO)12, Cp2TiR2, Ni(COD)2, W(CO)6, Mo(CO)6, [RhCl(CO)2]2
Common promoters: NMO, high-intensity light/photolysis, “hard” Lewis bases
Kürti, L.; Czakó, B. Strategic Applications of Named Reactions inOrganic Synthesis; Elsevier: New York, 2005.
Co(CO)3(CO)3CoCO
CO
R1 R2 R2
R1
Co(CO)3Co(CO)3
- 2 CO - CO
R3
R2
R1
Co(CO)3Co
R3
COCO
+ CO
(alkene insertion)
R2
R1
Co(CO)3Co
R3
+ COR2
R1
Co(CO)3Co(CO)3
O
O
Co(CO)3Co(CO)3
R2R1
- [Co(CO)6] O
R1R2
Melissa Sprachman @ Wipf Group Page 2 of 15 12/27/2008
The Pauson Khand Reaction: CO Labilization is Rate-Determining
Pure Appl. Chem. 2002, 74, 167-174.
DFT (VWN/PW91xc)
Melissa Sprachman @ Wipf Group Page 3 of 15 12/27/2008
The Pauson-Khand Reaction in Natural Product Synthesis
J. Am. Chem. Soc. 1997, 119, 4353–4363.
Me H
HMe3Si
OEt
OH 1. CO2(CO)8, ether
2. TMSOTf, ether-78 oC
Me H
H
OH
(CO)3Co
Co(CO)3
> 20:1 d.r.(1:1 mixture of diastereomers)
91% (2 steps)
(91:9 site selectivityfor Lewis acid activation)
CH3CN, airreflux, 15 min
NMO, CH2Cl2rt, 12 h
85% (5:1 d.r.)
70% (11:1 d.r.)
Me H
HO
O
H
H
-or-
Key intermediate in thesynthesis of (+)-Epoxydictymene
Schreiber’s synthesis of (+)-epoxydictymene:
OTBSTBSOCo2(CO)8, CH2Cl2then Me2S. 45 oC, 12 h
89%
TBSO
TBSO
O
H TBSOSEMO
H
TMS
Co2(CO)8, CH2Cl2then Me2S, 18 oC, 4 d
79%OMOM
TBSOSEMO
H
O
HH
H
OMOM
Lycopodium Alkaloids
MeN
HHH
O
HMe
HO
(+)-paniculatine + otherJ. Org. Chem. 2007, 72, 10147–10154.
Melissa Sprachman @ Wipf Group Page 4 of 15 12/27/2008
Advances in Pauson-Khand Reaction Methodology
Catalytic Pauson-Khand Reactions:
OTBS
n-PrCo2(Co)8 (35 mol%)
CyNH2, 60 mol%
DME, 70 oC, N2
15 h, 95%OTBS
n-Pr
O
Asymmetry by use of chiral auxiliaries orchiral metal complexes:
S*Co2(CO)8
80 oC O
H S*Zn, NH4Cl
O
H
96% ee60-65%92-95%
O O
Chem. Soc. Rev. 2004, 33, 32-42.
J. Org. Chem. 2001, 66, 3004-3020.
Tetrahedron: Asymmetry, 2000, 11, 797-808
Eur. J. Org. Chem. 2002, 2881-2889.
TsN
Co2(CO)8 (20 mol%)(S)-BINAP (20 mol%)
80 oC, 1 atm COTsN O
H
54% 94% ee
J. Am. Chem. Soc. 2000, 122,10242-10243.
Melissa Sprachman @ Wipf Group Page 5 of 15 12/27/2008
β-Lactam Antibiotics
Eur. J. Org. Chem. 1999, 3223-3235
“The biologically active principle of all β-lactam antibiotics is the β-lactam ring, the reactivity and selectivity ofwhich towards biological substrates can be decisively influenced by substituents or fused rings.”
Angew. Chem. Int. Ed. Engl. 1985, 24, 180-202.
-->Motivation to diversify β-lactam scaffolds?
Melissa Sprachman @ Wipf Group Page 6 of 15 12/27/2008
Construction of Polycyclic β-Lactams
Cycloadditions:
NO
OOMs
PMP
DBU, toluene
190 oC, 24 h88%
NO PMP
OH
HH
80 :10 :10 (mixture of diastereomers)
Tetrahedron Lett. 1999, 40, 1015-1018.
NO
HTBSO
H OO
CO2Bn
LiHMDS/THF
-78 oC to rt N
O
O
HTBSO H
CO2BnH
O
76%
Reaction of substituents on the azetidinone:
Tetrahedron Lett. 1997, 38, 5913-5916.
Precedence: Pauson-Khand Reactions:
NO
BnO 1. Co2(CO)8, toluene, rt2. toluene, reflux
95%N
O
BnO H
H
O
NPMPO
1. Co2(CO)8CH2Cl2, rt
2. TMNO, 0 oC to rtN
O PMP
O
HHH
80%
J. Org. Chem. 1998, 63, 6786-6796.
Melissa Sprachman @ Wipf Group Page 7 of 15 12/27/2008
The Staudinger Reaction
The Staudinger Reaction:
Suggested mechanism and explanation of stereochemistry in the case of imines:
O
R1 R2O
R4 R5
R1 R2
R3
N
R1 R2
R3
Lewis Acidsolvent solvent
solvent
OO
R2
R1R4
R5
O
R2
R1R4
R5
R3
NO
R2
R1R4
R5
R3
Kürti, L.; Czakó, B. Strategic Applications of Named Reactions inOrganic Synthesis; Elsevier: New York, 2005.
J. Am. Chem. Soc. 2006, 128, 6060-6069.
Melissa Sprachman @ Wipf Group Page 8 of 15 12/27/2008
Tandem Imine Formation-Staudinger Reaction
R1 CH(OEt)2
Co2(CO)6
+ArNH2
TMSOTf, CH2Cl2 rt, N2
O
ClAcO
DIPEA, CH2Cl2 rt, N2
R1
Co2(CO)6
N Ar
N
O
Ar
OAc
R1
Co2(CO)6
Entry R1 Ar Yield (%) Ratio cis:trans
1 H Ph 19 100:0
2 Me Ph 81 100:0
3 Me p-MeOC6H4 47 100:0
4 Me p-NO2C6H4 36 79:21
5 SiMe3 Ph 42 100:0
The observed stereoselectivities are consistent with the electronic effects of the zwitterionic model.
Melissa Sprachman @ Wipf Group Page 9 of 15 12/27/2008
Tandem Staudinger-Pauson Khand Reactions
Me CH(OEt)2Co2(CO)6
1. TMSOTf, PhNH2CH2Cl2 rt, N2
2. DIPEA, CH2Cl2OClOC
N
O
Ar
O
R1
Co2(CO)6 PKR condnsNo Tricyclic ProductObserved
N
O
Ar
O
R1
CAN43%
Allyl ethers were not reactive toward the Pauson Khand Conditions
Only thiazolidin-3-ones formed when trying to replaceoxygen with sulfur:
Me
CH(OEt)2
(CO)6Co2
1. TMSOTf, PhNH2CH2Cl2 rt, N2
2. DIPEA, CH2Cl2SClOC
NS
O
Me
(85:15 mixture of diastereomers)3. CAN
48%
SClOC
C
S
O
Cl
Me
NAr
(CO)6Co2
[2,3]
NS
O
Me
Co2(CO)6
Melissa Sprachman @ Wipf Group Page 10 of 15 12/27/2008
Pauson Khand Reactions with the Nitrogen Analog
Entry Conditions T (oC) Yield (%)(3 steps)
Ratio A : B
1 SiO2, Ar, 18 h 40 53 65:35
2 SiO2, Ar 18 h 60 54 35:65
3 SiO2, Ar, 18 h 80 48 38:62
4 Basic Al2O3, Ar, 18 h 40 15 47:53
5 SiO2, H2O (10 equiv), Ar, 18 h 40 44 54:46
6 SiO2, O2, Ar, 18 h 40 44 58:42
7 DMSO (6 equiv), CH2Cl2, 18 h, rt 61 44:56
8 NMO•H2O (1.8 equiv), CH2Cl2,18 h
-20 53 52:48
9 NMO•H2O (1.8 equiv), DIPEA(2.7 equiv) CH2Cl2, 18 h
rt 49 35:65
10 NMO•H2O (1.8 equiv), DIPEA(2.7 equiv) CH2Cl2, 18 h
rt 32 30:70
11 Toluene, 18 h 110 33 71:29
Me
CH(OEt)2
(CO)6Co2
1. TMSOTf, PhNH2CH2Cl2 rt, N2
2. DIPEA, CH2Cl2
NClOCTs
N
O
Ar
N
Me
Ts
Co2(CO)6PKRcondns
NTs
N HH
PhO
OH
+ NTs
HO
OH
NH
Ph
A B
Melissa Sprachman @ Wipf Group Page 11 of 15 12/27/2008
Mechanism for Formation of the Tricycle and Open Amide
Co
NPh O
NTs
Me
Co
Co
(CO)3
(CO)2
N
O
PhNTs
Me
Co
H
(CO)3
(CO)3
Co
NPhNTs
Me
Co
H
(CO)3
(CO)3O
migratoryinsertion
CO insertion
NPhNTs
Me
Co
H
(CO)3
OCo(CO)3
N
O O
O
Ph NTsH
O
MeCo
(CO)3(CO)3CoNTs
N HH
PhO
OH
HHH
H
H
H HH
H
H
Co
NOPh
NTsMe
Co
H
(CO)3
(CO)3
H
Co
NOPh
NTsMe
Co
H
(CO)3
(CO)3
H
[Co-H]
(CO insertion)Co
NTsMe
Co
H
(CO)3
(CO)3O
HNOPh
NTs
HO
OH
NH
Ph
Melissa Sprachman @ Wipf Group Page 12 of 15 12/27/2008
Tandem Staudinger-Pauson Khand Scope
NTs
N HH
RO
O
Me
H
+ NTs
HO
O
Me
H
NH
R
Me
CH(OEt)2
(CO)6Co2
1. TMSOTf, RNH2CH2Cl2 rt, N2
2. DIPEA, CH2Cl2TsNClOC
A: SiO2, Ar, 40 oC
B: NMO•H2O, rt, 18 h
3.
A B
R = Ph, 53%, ratio A:B = 65:35; R = PMP, 15%, ratio A:B = 52:48
R = Ph, 49%, ratio A:B = 35:65; R = PMP, 49%, ratio A:B = 48:52
NTs
N HH
RO
O
TMS
H
+ NTs
HO
O
TMS
H
NH
R
TMS
CH(OEt)2
(CO)6Co2
1. TMSOTf, RNH2CH2Cl2 rt, N2
2. DIPEA, CH2Cl2TsNClOC
A: SiO2, Ar, 40 oC
B: NMO•H2O, rt, 18 h
3.
A B
R = Ph, 39%, ratio A:B = 77:23; R = PMP, 55%, ratio A:B = 60:40
R = Ph, 33%, only A isolated; R = PMP, 49%, ratio A:B = 55:45
Melissa Sprachman @ Wipf Group Page 13 of 15 12/27/2008
Tandem Staudinger-Pauson Khand Scope
Me
CH(OEt)2
(CO)6Co2
1. TMSOTf, PhNH2CH2Cl2 rt, N2
2. DIPEA, CH2Cl2TsNClOC
A: SiO2, Ar, 40 oC
B: NMO•H2O, rt, 18 h
3.
NTsNPh
O
HH
O
H
30%
30%
NTs
N HH
PhO
O
H
H
+ NTs
HO
O
H
H
NH
Ph
H
CH(OEt)2
(CO)6Co2
1. TMSOTf, PhNH2CH2Cl2 rt, N2
2. DIPEA, CH2Cl2TsNClOC
A: SiO2, Ar, 40 oC
B: NMO•H2O, rt, 18 h
3.
A B
23%, ratio A:B = 29:71
14%, ratio A:B = 29:71
Melissa Sprachman @ Wipf Group Page 14 of 15 12/27/2008
Summary
Novel tricyclic scaffolds were synthesized via a tandem Staudinger/Pauson-Khand process
Although overall yields are low, the methodology provides a route for rapid formation of complexsubstrates with possible utility in medicinal applications
The approach is limited to stoichiometric use of Co(CO)8, and cleavage of the β-lactam is an unsolvedproblem in this methodology. Suppression of N-C cleavage has been achieved, but the precedence isfor amines:
C DC D
J. Organomet. Chem. 2001, 624, 316-326.
Melissa Sprachman @ Wipf Group Page 15 of 15 12/27/2008
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