Recent Advances in The Chemistry of Allenamides · Outline 1.Introduction 2.Preparation of...
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Recent Advances in Recent Advances in The Chemistry of The Chemistry of Allenamides Allenamides Partha Nandi 11/08/2006 Department of Chemistry Michigan State University
Transcript of Recent Advances in The Chemistry of Allenamides · Outline 1.Introduction 2.Preparation of...
Recent Advances in Recent Advances in The Chemistry of The Chemistry of AllenamidesAllenamides
Partha Nandi
11/08/2006Department of ChemistryMichigan State University
Outline
1. Introduction
2. Preparation of Allenamides
3. Recent Advances:(A) Radical Cyclization(B) Cycloadditions(C)Pauson-Khand Reaction(D)Substituted Heterocycles
4. Future Challenges & Conclusion
Introduction•One of the most versatile chiral synthons•Undergoes diverse array of reactions•Poor regioselectivity
•Limited synthetic applications•Difficult to prepare•High reactivity and easy hydrolysis
CR
R1
R3R2allene
Ma, S. Chem. Rev. 2005, 105, 2839.
CX
R1
R3R2
CX
R1
R3R2
X = -NR2 or -OR
Allenamide
•EWG diminishes electron donating ability
•Amide: Ubiquitous functional group
Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773
CN
R1
R3
R2
stabilized allenyl amine
R
EWGC
N
R1
R3R2
X
O
R
Allenamide
Crystal Structure of Unsubstituted Allenamide
•Preferential π-π interaction
•Facial blocking
•2.89 kcalmol-1 rotational barrier
CH H
H
O
NO
Tracey, M.; Tyler, P. G.; Brennessel, W. W.; Hsung, R. P. Acta Cryst. 2004, 60, 830
O
N
HC
H
H
O
CH H
H
ON
O
Rotational BarrierO
N
HC
H
H
O
O
N
HC
H
H
O
2.89
2.72
H3C
O
NCH3
CH3
0.81
kcalmol-1
Wiberg, K. B.; Rush, D. J. J. Org. Chem. 2002, 67, 863
Tracey, M.; Tyler, P. G.; Brennessel, W. W.; Hsung, R. P. Acta Cryst. 2004, 60, 830
Outline
1. Introduction
2. Preparation of Allenamides
3. Recent Advances:
(A) Radical Cyclization(B) Pauson-Khand Reaction(C)Cycloaddition(D)Substituted Heterocycles
4. Future Challenges & Conclusion
Early ExamplesBogentoft’s Isomerization
Overman’s Claisen Rearrangement
Bogentoft et al. Tetrahedron Lett. 1969, 10, 4745
Overman et al. Tetrahedron Lett. 1979, 20, 599
O
NN
O
NN C
NaOEt, heat50%
NaOHO
HNCNHCHO
N
O
NHCHO
Cyclization
CCl3
NHO
R
R1
Xylene
10-20%
Cl3CO
HNR1
C
R
Corbel’s Deprotonation (1st acyclic allenamide)
Corbel et al. Tetrahedron Lett. 1976, 17, 835-38
de Meijere’s Isomerization
de Meijere et al. Eur. J. Org. Chem. 2001, 2283-92
Allenamide Analogues
P
NR
OEtOEtO
P
NR
C
OEtOEtO
NaH, THF
quantitativeR=Me,Et, Bn
NaH, THF
quantitativeR=Me,Et, Bn
P
NR
NEt2
NEt2OP
NR
C
NEt2
NEt2OP
NR
C
NEt2
NEt2O
+
SO O
NH
CH2Br
NaH, THFTs
N
C
19%
No versatile and efficient methodof synthesis yet!
Katritzky, A. R.; Ramer, W. H. J. Org. Chem. 1985, 50, 852Wei, L.; Mulder, J. A.; Xiong, H.; Zificsask, C. A.; Douglas, C. J.; Hsung, R. P. Tetrahedron, 2001, 57, 459
First Efficient Preparation of Allenamides
Allenamide ?Ynamide?
NH
O
NaH, DMF
Br
rt, 24h, 94%N
O
KOH (0.2 equiv)DMSO, rt, 16 h90%
N
O
C
KOH (0.2 equiv)
DMSO, rt, 16 hN
O
Arrest of the Isomerization
Wei, L.; Mulder, J. A.; Xiong, H.; Zificsask, C. A.; Douglas, C. J.; Hsung, R. P. Tetrahedron, 2001, 57, 459
NaH, DMF
Brrt, 24h
KOH (0.2 equiv)
DMSO, rt, 16 hX
NH
O
XN
O
XN
O
Cn n n
XN
O
n
X=O, CH2, NMe
52
80
77
N N
O
C
N
O
C
O N
O
CN
C
O
75
74N
C
O
NC
O
80
Yield Yield
Suitable methods to makeSubsituted allenamides?
XN
O
Cn
XN
O
n
M ?
Seebach’s Method
Gaul, C.; Seebach, D. Helv. Chim. Acta 2002, 85, 963
9764Ph
9860Methacryl
9766Pr
9767i-Pr
deYield [%]R
N
O
TMS
OPh
Ph
iPrn-BuLi, THF
TiCl(i-PrO)3,RCHO, -78oC
N
O
C
TMS
H
OPh
Ph
iPr
R
HO
H
(R)
γ, γ-Disubstituted Allenamides
TMS
Ti
H R
N
OOPh
Ph
i-PrO
TMS
TiH
RN
O
O
Ph Ph
i-Pr
O
Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2005, 70, 8628-30
•MeO-9-BBN improved de
Hegedus’ Method
HNO
PhPh
O
TMS
O
R H
B
H
TMS
1. nBuLi, THF, TMEDA, -78oC2. Et2BOMe, 0oC
3. BF3.OEt2, 0oC4. RCHO, -45oC, 2h,
H
C
TMS
H
C
TMS
R H
OH OH
R
Ph 87% 83/17
n-pentyl 65% 88/12
72% 81/19
OBn
OBn
78% 88/12
81% 88/12
A B
A+B (A/B)
(S)
N
R
O
O
Ph Ph
NO
O
PhPh
N
O
O
Ph
Ph
Coupling of Allenyl Halide with Amides
Stiles, D. T.; Trost, B. M. Org. Lett. 2005, 7, 2117
X NHR
O
CI
K3PO4 (2 equiv)
7% CuTC, 15 % 1
(1.7 equiv)
X NR
O
C
NHMe
NHMe1
reactant yield (%)
O NH
O
Bn
95
BnN NH
O
100
O
HN
94
reactant yield (%)
NH
O
46
NH
O
28
NH
OAc
O
HHOTBS
36
TC = 2-thiophenecarboxylate
Scope of Allenyl Halide
X NHR
O K3PO4 (2 equiv)
7% CuTC, 15 % 1toluene, 85 °C
X NR
O
C
R2
R1
NHMe
NHMe1
reactant allenyl halide yield (%)
O NH
O
100
NH
O 100
reactant allenyl halide yield (%)
Allenyl halide
CI
CI
O NH
O
Bn
CBr
96
NH
O CBr
71
Stiles, D. T.; Trost, B. M. Org. Lett. 2005, 7, 2117
Cu-Catalyzed N-Allenylations ofAmides
Hsung et al. Org. Lett. 2005, 7, 3081
Optically enriched50% ee
Optically enriched75%ee
CH
IMe
H NH
MeN
O
10 mol % CuCN20 % DMEDA
Cs2CO3 (2 equiv)toluene, 50 °C
63%
NMeN
O
C
MeH
47% ee
CH
IH
Me NH
MeN
O
10 mol % CuCN20 % DMEDA
Cs2CO3 (2 equiv)toluene, 50 °C
79%
NMeN
O
C
MeH
75% ee
Proposed Mechanism
Hsung et al. Org. Lett. 2005, 7, 3081
CI
H
Me
H
CI
H
H
Me
CCu
H
Me
H
INC
CCu
H
H
Me
INC
CuCN
CuCN
N
MeN
O
CsC
Cu
H
Me
H
CNN
MeN
O
CsN
MeN
ON
MeN
O
CCu
H
H
Me
CN
NNMe
OCH
Me
H
NNMe
OCH
H
Me
Summary of Allenamide PreparationsNaH, DMF
Br
KOH
DMSO,X
NH
O
XN
O
XN
O
Cn n n
X=O, CH2, NMe
Unsubstituted
γ, γ-disubstituted
Tri-substituted CR3
IR1
R2NH
MeN
O10 mol % CuCN20 % DMEDA
Cs2CO3
NMeN
O
C
R1
R2
R3
N
OO
Ph
Ph
TMS
1. n-BuLi, THF, TMEDA, 2. Et2BOMe,
3. BF3.OEt2,4. RCHO,
N
OOPh
PhC
TMSR
OH
HH
(S)
N
O
TMS
OPhPh
iPr
n-BuLi, THF
TiCl(i-PrO)3,RCHO,
N
O
C
TMS
H
OPhPh
iPr
R
HO (R)
H
Some Synthetic Opportunities
Possibly Many More!!!
N
H
X
H
HOC
Cycloadditions,EpoxidationRadical Cyclizations
α−metallation-functionalization
Pauson-Khand Reaction
γ−metallation-functionalization
Removal of urea
Outline
1. Introduction
2. Preparation of Allenamides
3. Recent Advances:(A) Radical Cyclization(B) Cycloadditions(C)Pauson-Khand Reaction(D)Substituted Heterocycles
4. Future Challenges & Conclusion
Possible Radical Cyclization Pathways
Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775
ABC
NC
EWG Br
n
NC
EWG
n
c b a
NEWG
n
vinyl radical
Bu3SnH
NEWG
n
a: endo
b. central
NEWG
allyl radicaln
c.exo
NEWGn
HSnBu3
NEWGn
NEWG
n
HSnBu3
SnBu3
Radical Cyclization of Allenamide
Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775
•Highly regioselective
•Only Iodide substituted precursor worked
I
N
C
Boc
0.4 equiv AIBN
1.5 equiv n-Bu3SnH N
Boc91%
NR
O
onto c (exo)
NR
O
+
onto a (endo)
+I
N R
C
O
N R
O
ba
c
onto b (central)
AIBN, n-Bu3SnH
Electronics of Allenamide Nitrogen
R Yield (%)Ester OtBu 75O-(+)-menthyl 80
Urea NMe2 69Me 58
Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775
No Change in regioselectivity
I
N R
C
O
N R
O
AIBN, n-Bu3SnH
Allyl vs Allenyl Groups in Radical Cyclization
Shen, L.; Hsung, R. P. Org. Lett. 2005, 7, 775
N
CI
O
N
O
N
O
O
N
CI
O
N
I
C
O
N C N
OC
O
N
C
N
O
N
O
N
O
+ N
O
major minor34%
17%
3%
H
H
Outline
1. Introduction
2. Method of Preparation of Allenamides
3. Recent Advances:(A) Radical Cyclization(B)Cycloaddition(C)Pauson-Khand Reaction(D)Substituted Heterocycles
4. Future Challenges & Conclusion
Intermolecular [4+3] Cycloaddition in N-Stabilized Oxyallyl Cations
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50
X
N
HC
HH
O
R
X=CH2, O, NR
ON
Ph
OC
HEpoxidation O
ON
Ph
OC
H O
O
O
O N
O
C
Ph
2-3 equiv DMDO
O10 equiv
ONO
O H
PhO
O
O
H
N
OO
Ph
THF, -40 °C endo 1 endo 2
no additive 80% 75 25ZnCl2 77% 94 06
Lewis Acid and Ligand Screening
N
OO
N
N
O
RR
O
N
Ph
R R
Ph
Ph Ph
O N
O
C
Ph
2-3 equiv DMD
O10 equiv
ONO
O H
PhO
O
O
H
N
OO
Ph
THF, -40 °C endo 1 endo 2
no additive 80% 75 25ZnCl2 77% 94 06
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50
blocking endo-2
ZnCl
Cl
O
HO
X
N
Ph
Substituent Effect
NA9991
NA6167
64(89)7186
10(50)9991
Harmata%Yield(%ee)
%ee%YieldSubstrate
O
O
O
O
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindhu, S.; Kirchhoefer, P.
J. Am. Chem. Soc. 2003, 125, 2058
CHO
OTMS O+
O
OCHO
Harmata’s [4+3] cycloaddition
X N
O
C
25mol% Cu(OTf)2, Ligand9 equiv diene, -78oC2-5 equiv DMDO, syringe pumpacetone/CH2Cl2Mol sieves, 8-10h
WH
RO N
XO
Syn
WH
O N
XO
+
R
anti
W+
R
Intramolecular [4+3] Cycloaddition
Rameshkumar, C.; Hsung, R. P. Angew. Chem. Int. Ed. 2004, 43, 615
N
O
O
R
O
O
O
O
N*
α tethered
N
O
O
R
O
O
O
O
*N
γ tethered
H
Two Approaches:
CN
O
O
R
O
2-5 equivDMDO
CH2Cl2, -78 °C
O
O
N
O
OPh
t yield d.r.
10 min 45% 95:530 min (syr) 75% 95:5
N
O
C
O
Ph
H
H
O
TESO
O
O
H OTESN
OO
PhDMDO
10-15 min
61% (9:1)
Conformations of Oxyallyl Cation
Rameshkumar, C.; Hsung, R. P. Angew. Chem. Int. Ed. 2004, 43, 615
N
O
O
RO
O
O
O
N*
α tethered
endo compact TS
N
O
C
O
Ph
H
H
O
PGO
O
O
H OPGN
OO
Ph N
O
O
R
O
O
γ tethered
H
H
OPGH
Sickle conformation
N
O
O
R
O
O
tethered
H
H OPGH
W conformation
γ
R2R1N R3
H H
R2R1N H
H R3
H R3
NR1R2 H
H H
NR1R2 R3
O O O O
SickleSevere A1,3 strain
SickleW U
R2R1N R3
H H
R2R1N H
H R3
H R3
NR1R2 H
H H
NR1R2 R3
O O O O
Sickle SickleW U
Lewis Acid Mediated Removal of Anomeric Urea
Berry, C. R.; Rameshkumar, C.; Tracey, M. R.; Wei, L.; Hsung, R. P. Synlett, 2003, 791
N
N
H
C Ph
O
+R O
ORH
N
N
Ph
O
MeCN, 85oCYields: 60-70%
de: 70-90%
Lewis acid
NN
Ph
OLA
OR
H
OH
H
Nu:O Nu
HO
R
HO
OH
C-glycosides
H+
[3+2] Cycloaddition of Fischer Carbene and Allenamide
Barluenga, J.; Vicente, R.; Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2006, 128, 7050
OMe
R1
(OC)5Cr C
N+
[Rh(cod)Cl]2CO, CH2Cl2, rt
NR1
O
OMe
O
63-80%
OMe
R1(OC)5Cr+ CO
Cr(CO)6
LnM
OMe
R1LnMC
N
O
NR1
O
OMe
Possible [4+2] and Regioselectivity
Barluenga, J.; Vicente, R.; Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2006, 128, 7050
CN
O
MLn
R1
MeO MLn
OMe
R1NO
-MLn
NR1
O
OMe
C
E
LnMMeO
R1
E -MLn
OMe
E
R1E=COOEt
Outline
1. Introduction
2. Preparation of Allenamides
3. Recent Advances:(A) Radical Cyclization(B) Cycloadditions(C)Pauson-Khand Reaction(D)Substituted Heterocycles
4. Future Challenges & Conclusion
Pauson-Khand Reactions of Allenamides
Anorbe, L.; Poblador, A.; Dominguez, G.; Perez-Castells, J. Tetrahedron Lett., 2004, 45, 4441
Xiong, H.; Hsung, R. P.; Wei, L. L.; Berry, C. R.; Mulder, J. A.; Stockwell, B. Org. Lett. 2000, 2, 2869
N
O
C+
N
O
OCo2(CO)8
CH3CNNMO
CH
N
O
R1On-BuLi
R2I
CN
OR1
O
R2
Mo(CO)6 NO
O
R1
R2
85%
65%
Outline
1. Introduction
2. Method of Preparation of Allenamides
3. Recent Advances:
(A) Radical Cyclization(B) Cycloadditions(C)Pauson-Khand Reaction(D)Substituted Heterocycles
5. Future Challenges & Conclusion
Dimerization of Allenyl Ketone andAllenamide
Ma, S.; Gu, Z.; Yu, Z. J. Org. Chem. 2005, 70, 6291
•One pot reaction
•Pd+2 is regenerated using Benzoquinone (BQ) in AcOH
C
CONHTs
C
COR
+Pd(MeCN)2Cl2
MeCN
O
ON
Ts
4-(furan-3’-yl)-2(5H)-furanimines
Proposed Mechanism
Ma, S.; Gu, Z.; Yu, Z. J. Org. Chem. 2005, 70, 6291
PdCl2Ln
OR4
OR2R3
NR1
CNHR1
O
R2
R3
CR4
O
+
Pd
Pd(0)Ln
OR4
OR2R3
NR1
O
O
+ 2H
OH
OH
CR1HN
O
R2
R3
CR4
O
Pd+2
O R4
H
H
Pd+2
OH
R4
H
H
Pd+2
AcO
O R4
Pd+2
AcO
O R4
O R3
R2
R1HN
Pd
O R4
O R3
R2R1N
Pd
Side Reactions and Limitations
•Homodimerization-monohydrolysis product
•Steric inhibition of dimerization approach
Ma, S.; Gu, Z.; Yu, Z. J. Org. Chem. 2005, 70, 6291
CH
CONHC
COBu
+
OBu
ONH
+H
O
O
O
NH
H
76% 15%
2
Pd(MeCN)2Cl2BQ+AcOH
CC10H21
CONHBnC
COBu+
CPh Me
CONHBn+ C
COBu
Ma, S.; Gu, Z.; Yu, Z. J. Org. Chem. 2005, 70, 6291
Iminolactones and γ-Hydroxy- γ-Lactams
CR1
R2
R3
ONHR4
R3
R5
R1
R2
OR4HN
Pd
NO
R1
H
R5 R3
R4
ONH
R1
R2
R5 R3
R4
R2=H
N attack
R1/R2=H
O-attack
R5PdI
+N
OR1
HO
R5 R3
R4
ON
R1
R2
R5 R3
R4
Pd(0) Catalyzed Synthesis of Iminolactones
Ma, S.; Gu, Z.; Yu, Z. J. Org. Chem. 2005, 70, 6291
C
R1
R2
R3
O
NHR4
R5I+
O
R3R5
N
R4
R1
R2
1 mol% Pd(PPh3)45 mol% TBAB
2 equiv. K2CO370oC, toluene
ONBn
Prn
ONBn
Prn
(95%)MeO
(95%)
NO
HO
Ph Me
Bn
ON
Ph nPr
NO
Bun
HO
Ph Me
Bn(45%)
(48%)
(99%)
Bn
ONBn
(75%)
O NucleophileN Nucleophile
2,5-Disubstituted Furans from γ-Substituted Chiral Allenamide
Berry, C. R.; Hsung, R. P.; Antoline, J. A.; Petersen, M. A.; Challeppan, R.; Neilson, J. A. J. Org. Chem. 2005, 70, 4038
TMS
C
OH
H N
N
Ph
Ph
O
0.1 equiv. PPTS, CH2Cl2
Or: 1.2 equiv TBAF, THFH
O N
N
Ph
PhOH
dihydroxylationor allylation
HO N
N
Ph
PhO
HHO N
N
Ph
PhO
H
HO OHOHHO
HO
H
Proposed MechanismAcid catalyzed mechanism
Fluoride mediated mechanism
N
N
C
O
Ph
H
TMSR
OH
H
S
N N
O
Ph
HR
TMS
OH
O N
NO
Ph
R
TMS
HH
N
N
C
O
Ph
Ph
H
TMSR
OH
S
O N
NO
Ph
PhR HH
F
H2ON
N
C
O
Ph
Ph
H
F
H2O
R
O
H
Berry, C. R.; Hsung, R. P.; Antoline, J. A.; Petersen, M. A.; Challeppan, R.; Neilson, J. A. J. Org. Chem. 2005, 70, 4038
Oxazolidinone vs Imidazolidinone
Imidazolidinone Oxazolidinone
N
N
C
O
Ph
H
HOH2O
More Reactive
N
O
C
O
Ph
H
HOH2O
More electronegetivemore delocalizedtowards C=O
More stable
C
H N
NO
Ph
R
OH
H2O
HN
NO
Ph
RO
H
OH
No diastereoselectivityBerry, C. R.; Hsung, R. P.; Antoline, J. A.; Petersen, M. A.; Challeppan, R.; Neilson, J. A. J. Org. Chem. 2005, 70, 4038
Hegedus’ Approach
Hyland, C. J. T.; Hegedus, L. J. Org. Chem. 2006, 71, 8658
•Can tolerate oxazolidinone substitution
•Single diastereomer in 5 minutes
•High yielding
N
O
C
O
H
TMS
R
OH
Ph
Ph
AuAu catalysis
O N O
Ph Ph
OTMS Au
R O N O
Ph Ph
OTMS
RProtonolysis
Additional Flexibility
N
O
C
O
H
TMS
R
OH
Ph
PhAu(PPh3)Cl/AgBF4
CH2Cl2, rt, <5mins O N O
Ph Ph
OTMS
R
NIS, acetone
10 mins, rtO N O
Ph Ph
OTMS
R
I
Hyland, C. J. T.; Hegedus, L. J. Org. Chem. 2006, 71, 8658
O N O
Ph Ph
OTMS
RO N O
Ph Ph
OTMS
R
I
Pd(PPh3)4 (10mol%)
PhB(OH)2, Na2CO3,DMFMicrowave
Ph
89%
Scope
O NN
O
Ph
PhH HH2/Pd
O NN
O
Ph
PhH H OsO4
TMEDAO N
NO
Ph
PhH H
HO OH
O NN
O
Ph
PhH H
HO OH
OH H
HO OH
TMS
SnBr4
O NN
O
Ph
PhH HH2/Pd
O NN
O
Ph
PhH H OsO4
TMEDAO N
NO
Ph
PhH H
HO OH
Berry, C. R.; Hsung, R. P.; Antoline, J. A.; Petersen, M. A.; Challeppan, R.; Neilson, J. A. J. Org. Chem. 2005, 70, 4038
Stereoselectivity of Oxidation Step
O
N H
R
N
OPh
Ph
HOs
O
O
O
O
OR
HH
N
N
O
Ph
Ph
Os
O
O
O
O
O NN
O
Ph
PhH H OsO4
TMEDAO N
NO
Ph
PhH H
HO OH
O NN
O
Ph
PhH H OsO4
TMEDAO N
NO
Ph
PhH H
HO OH
Berry, C. R.; Hsung, R. P.; Antoline, J. A.; Petersen, M. A.; Challeppan, R.; Neilson, J. A. J. Org. Chem. 2005, 70, 4038
Outline
1. Introduction
2. Preparation of Allenamides
3. Recent Advances:(A) Radical Cyclization(B) Cycloaddition(C)Pauson-Khand Reaction(D)Substituted Heterocycles
4. Future Challenges & Conclusions
Future Challanges
1. Applications of allenamides in natural product synthesis
(+) Zincophorin Hsung et al, 2006 Fall ACS National Meeting
OTBDPSO
C
N
N
Ph
O
TBDPSO O N
N
Ph
O54% (95:5)
HO O
OH OH OHO
OH
H H
Future Challenges2. Application in olefin metathesis
3. Cyclic allenamide
4. Applications in Multi-component reactions (MCRs)
Kinderman, S. S.; Marseveen, J . H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. Org. Lett. 2001, 3, 2045
R
C
N
Ts
C
N
Ts
Ru
NPhMesMes
PCy3ClCl
Conclusions
O
X
N
HC
HH
O
W
R
W
O
N
N
Ph
O
H
ON
Ph
OC
O
O
O PhR
X=CH2, O, NR
ON
Ph
OC
H
Epoxidation
O
ON
Ph
OC
H O
O
[4+3]
W=O
chiral template O
OHHO
H H
N
O
RN
O
R
radical cyclization
α-metallation
N
O
PhC
MRCHOO NR
O
Ph
O
O
N
XO
H
R
XR3 R4
R2 R1
R5
X=O, NRR4= =O, NR
Acknowledgement1. Parents: Asim K Nandi & Parbati Nandi
2. Prof. Dye, Prof. Jackson, Prof. Walker, Prof. Wulff, Prof. Smith, Prof. Namboothiri
3. Labmates- Jennifer, Karrie, Misha, Simona
4. Friends- Kapil, Sampa, Supriyo, Aparajita, Nilanjana,Vishal, Kim, Sanjukta
5. Roommate- Manish
Isomerization Mechanism of Allenamides
Stiles, D. T.; Trost, B. M. Org. Lett. 2005, 7, 2117
R NH
C
O
R N C
OH HOR
R
O
N
H
R
O
NR
R NR
C
O
R NR
OH
OR
Dienamides
Cycloadducts: New Molecular Architechture
ONO
O H
O
(1) H2-Pd-C, EtOAc(2) Dibal-H, CH2Cl2
(3)Na/NH3, THF-tBuOH71% over 3 steps
O
H
OH
H2N
R
L=
Huang, J.; Ianni, J. C.; Antoline, J. E.; Hsung, R. P.; Kozlowski, M. C. Org. Lett. 2006, 8, 1565
•High in Yield& Enantioselectivity
H
O
2.2 equiv. ZnEt2, toluene
5-10mol% L, -45 oC-rt81-93% yield
Et
OH
96% ee
O
H
OH
N O
H
OH
N O
H
OH
N
O
H
OH
N
H
OTBDPS
N
H
OH
N
O
O
R3
R6
R4
R5
N
R2
R1
OH
Et2Zn
R3
R6
R4
R5
NR2 R1
O
ZnEt
R3
R6
R4
R5
NR2R1
OZn
EtAmino alcohol Dimer
R3
R6
R4
R5
NR2 R1
OZn R1
Monomer/Catalyst
Proposed Mechanism
Huang, J.; Ianni, J. C.; Antoline, J. E.; Hsung, R. P.; Kozlowski, M. C. Org. Lett. 2006, 8, 1565
Substrate Scope
•Allenamides with furan tethershowed better selectivity & yield
•Medium sized tether better in yields & selectivity
•Stereoselectivity drops for longer(n>3) tethers
•Acyclic diene was least stereoselective
Hsung et al. J. Am. Chem. Soc. 2003, 125, 12695
BocN C
O
BocN C
O N
O
C
On
N
O
C
On
O N
O
C
N
O
O
Boc
ON
BocH
47 (60:40)
65 (53:47)
NO O
O
H76 (62:38)
O
O
N
H
O
OH
O
O
N
H
OH
82 (96:4)
n=2 75 (96:4)n=3 57(70:30)n
% Yield (ratio)
N
OW
R
M
TS Geometry: Oxyallyl Ion, Lewis Acid & Ligand
Huang, J.; Hsung, R. P. J. Am. Chem. Soc. 2005, 127, 50
OH
H
endo-2
OH
H endo-1
O
NCu
Ph
Ph
N
O
Ph
Ph
O
N
OORR
O
O
NCu
Ph
Ph
N
O
Ph
Ph
O
N
OO
O
R
R
H
"sliding over"
furtheraway
top views
2,5-disubstituted
3,4-disubstituted
ON
CuN
OO
ON
O
in the backtop
front-bottom
SIDE
VIE
W
![Enantioselective gold (SI-revision-last) · Enantioselective Gold Catalyzed Dearomative [2+2]-Cycloadditions between Indoles and Allenamides Minqiang Jia, Magda Monari, Qing-Qing](https://static.fdocuments.net/doc/165x107/5ec63ef4993ba67f5c362ce1/enantioselective-gold-si-revision-last-enantioselective-gold-catalyzed-dearomative.jpg)
