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![Page 1: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/1.jpg)
Utilization of Ring Closing Metathesis in Alkaloid Synthesis
I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines A-C
Suvi T. M. Simila
Martin Group, University of Texas at AustinGroup Meeting, Research
September 17, 2007
N
H2O3PO
OH
(-)-FR901483 (1)
MeHN
OMe
N
MeO
CO2Me
N
O
14
15
lundurine A = amide (2)
lundurine B = 14,15 (3)
lundurine C = amine (4)
![Page 2: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/2.jpg)
Utilization of Ring Closing Metathesis in Alkaloid Synthesis
I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines A-C
Suvi T. M. Simila
Martin Group, University of Texas at AustinGroup Meeting, Research
September 17, 2007
N
H2O3PO
OH
(-)-FR901483 (1)
MeHN
OMe
N
MeO
CO2Me
N
O
14
15
lundurine A = amide (2)
lundurine B = 14,15 (3)
lundurine C = amine (4)
![Page 3: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/3.jpg)
Retrosynthetic Analysis
N N
CO2R3
O
BrMg
+
3
9
7
CO2R3
N
H2O3PO
OH
MeHN
OMe
N
R1OO
R2O
R2O
MeO2CR2O
TMS CO2Me
3 3
7
3
lactone-lactamrearrangement
RCM
stereoselective
addition to an N-acyl iminium ion
9
N
R3O2C
CO2MeR2O
NO
O
R3O2C
R2O
9
7
3
lactonization
![Page 4: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/4.jpg)
Addition of the Allylzinc to the Chiral Imine
N
TBDPSOPd(PPh3)4 benzotriazole
CH2Cl2TrocCl, THF
-78 °C - 25 °C
37% (dr = 45:55)
NHO
TBDPSO
OO
N
TBDPSO
Troc
TBSO
IZnOTBS
HON
HOO
TBDPSO3
11
N
RO
TBDPSO3
11 PhOMe
Simila, S. T. M.; Martin, S. F. J. Org. Chem. 2007, 72, 5342.
Grubbs II
CH2Cl2, 20 h
90% (dr = 45:55)
N
TBDPSO
Troc
OTBS
H N
TBDPSO
Troc
H
OTBS
+
H HnOE
nOEH H
33
1112
Model studies: Simila, S. T. M.; Reichelt, A.; Martin, S. F. Tetrahedron Lett. 2006, 47, 2933.
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Weinreb’s ResultsOvershadowing Our Endgame
Weinreb. et al. J. Org. Chem. 2006, 71, 2046.
HON
TIPSOO
N
TIPSOO
Ph Ph
LDA
Davisoxaziridine
60% useless intermediate;cannot remove N-Bn efficiently
HON
Boc
O
N
Boc
ONaHMDS
Davisoxaziridine
98%
OTIPS OTIPS
BnON
Boc
OMe
OTIPS1) LAH2) Sc(OTf)3
MeOH
3) BnBr, NaH
73%
BnON
Boc
OTIPS
PhOMeArMgCl
TiCl4
87% (dr 5:4)
N
TIPSO
Boc
O
N
TIPSO
Boc
ONaHMDS
Davisoxaziridine
53%
OH
N
TIPSO
Boc
OOBn
N
TIPSO
Boc
OBn
PhOMeArMgCl
then NaCNBH3
62% (dr ~3:1)
BnBr
NaH
69%
incorrect stereoisomer
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SummaryPart I
• A new route to azaspirane core structure of FR901483 was developed via a nucleophilic addition to an acyl iminium ion followed by a ring-closing metathesis
• Lactone-lactam rearrangement gave the azatricyclic core structure of FR901483 • 1-Ethylallylcarbamate protecting group and its cleavage was developed
• Allylzinc reagent was developed and it was successfully added to the chiral imine, however with lack of diastereoselectivity that persuaded us to divert our initial studies toward (-)-FR901483
![Page 7: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/7.jpg)
N
NMeO
CO2Me
O
lundurine A
14
1516
N
NMeO
CO2Me
N
NMeO
CO2Me
lundurine B lundurine C
II. Toward the Total Synthesis of Lundurines A-CIsolation and Biological Activity
- Isolated in 1995 from the leaf extract of the Borneo species Kopsia tenuis - Biological studies were reported in 2004 - Lundurine B is cytotoxic against B16 melanoma cells (in vitro); 2.8 µg/mL
- Unique hexacyclic core containing dihydroindole-cyclopropane moiety
- No reported total syntheses to date
Kam, T. S.; Yoganathan, K.; Chuah, C. H. Tetrahedron Lett. 1995, 36, 759.Kam, T. S.; Lim, K.; Yoganathan, K.; Hayashi, M.; Komiyama, K. Tetrahedron 2004, 60, 10739.
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N
NMeO
CO2MeO OtBu
O
N
NMeO
CO2MeO
O
N2N
NMeO
CO2Me
O
RCM
N
N
MeO
MeO2C
O
O
OtBu
lundurine A (1)lundurine B = 14,15 (2)
lundurine C (3)
amide reduction
olefin reduction
2
316
16
14
1516
RCM
cyclopropanation
Retrosynthetic Analysis
![Page 9: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/9.jpg)
N
NH2MeO O
HO
O
Ugi 4CC
NC
N
N
MeO
MeO2C
O
O
OtBu
R R
R = masked divinyl moiety
16
+ +
+
CO2Me
Retrosynthetic Analysis
N
H2N
MeO
CO2MeO
OtBu
O
+
reductive amination
thenCl
O
![Page 10: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/10.jpg)
Synthesis of the Ugi Components:2-Vinyltryptamine
N
MeO HNO
A, Pd(PPh3)4
LiCl, Na2CO3 (aq)
PhCH3/EtOH, 80 °C
87%
N
MeO HN
O
NH
MeO HNO
1) Py·HBr3, THF/CHCl32) Boc2O, DMAP
90% (2 steps)
BO
B
OB
O
NH
MeO NH2
requisite Ugi component
KOH, EtOHNa2S2O4,
A
Br
Boc
Boc
·pyr
Trivinylboroxane: O’Shea, et. al. J. Org. Chem. 2002, 67, 4968.
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Synthesis of the Ugi Components:Masked Divinylketone
PhSH, PhMe70 °C, 24 h
79%
O+ HNMe2·HCl + (CH2O)n
AcOH, 90 °C
40%
O O
Me2N NMe2
NMe
OTsCl, PhCH3
100 °C
then DIPEA 100 °C
30%
NMe
O
Ts
PhSK, PhCH3
20%
O
PhS SPh
S
MeO2C CO2Me
NaOMe, Et2O
>99% S
O
CO2Me
S
O
H2SO4,
70%
TMS
i) n-BuLi, 0 °Cii) HCO2Me, THF
0 °C
87%
OH
TMSTMS
10% H2CrO4
Acetone
0 °C to 25 °C
80%
O
TMSTMS S
ONaSH·H2ONaHCO3, EtOH
25 °C
79%
MeO2C NRCOR'
R R
MeO2C NRCOR'
·2 HCl
Blicke, F.; McCarty, F. et. al. J. Org. Chem. 1959, 24, 1376.Sapi, J. et. al. Synthesis 1988, 619.Ward, D. E. et. al. J. Org. Chem. 2002, 67, 1618.Detty, M. L. et. al. Organometallics 1992, 11, 2157.Angiolini, L. et al. Polymer 1989, 30, 564.
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Successful Ugi Reactions
NH
NH2+CO2H
NH
N
O
HN
ONMe
O
NMe
tBuNC, MeOH
99%
NH
NH2+CO2H
NH
N
O
NHO
MeOH
83%
NMe
O
NMe
NC
NH
N
O
OMe
O
NMe
AcCl, MeOH55 °C
50%
NC
O
a) NaCN, NH4Cl, Et2O; 61%
b) HCOOH, Ac2O; 44%
NC NHCHOc) tBuOK, THF; 60%
b) triphosgene, DABCO; 35%
Convertible isocyanide: Armstrong, R. W.; Keating, T. A. J. Am. Chem. Soc. 1999, 118, 2574.
NMe
O
Hoffmann type elimination trials of the methyl piperidine ring unsuccessful
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Ugi with the Thiopyranone
NH2+
HO2CSPh
S
O
N
OPhS
HN
O
S NaIO4, MeOH
H2O
90%
N
OPhS
HN
O
S O
PhCH3
180-200 °C
(W, 300W)
65%
N
O
HN
O
S O
O
resubjected to
reaction condX
N
O
HN
O
SOH
tBuNC, MeOH
55%
S
O
Sulfoxide eliminations: Rapoport, H. et. al. J. Org. Chem. 1980, 45, 4817. Galons, H. et. al. Synth. Commun, 1991, 21, 1743.
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Ugi with Bisthiophenylpentanone
N
O
NHO
MeO
SPh
SPh
NH2PhMe, Dean-Stark
120 °C
or TiCl4, Et3NCH2Cl2
MeO
N SPh
SPh
tBuNC, MeOH
5 days
30%
MeOO
SPhPhS
mCPBA, CH2Cl2-78 -(-20 °C)
96%N
O
NHO
SOPh
SOPh
MeO
N
O
NHO
MeO
CO2H
p-xylene, pyr, W140 °C, 300W
97%
O
PhS SPh
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Ugi with the 5-Methoxy-2-vinyltryptamine
N
O
NHO
NH
PhS SPh
MeO
O
SPh
SPh
1) PhMe, Dean-Stark
120 °C
2)
tBuNC, MeOH 4 days
NH
NH2MeO
O
O
NHO
SPh
SPh
8%5%
+
+ 55% of A
CO2H
A
Would a protected indole be more soluble?
![Page 16: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/16.jpg)
Protected Tryptamine Piece
NH
OHMeO TBDPS-Cl, imid., DMF
0 - 25 °C
95%NH
OTBDPSMeO NBS, CH2Cl2
71%
NH
OTBDPSMeO
Br
B OBO B O
Pd(PPh3)4, LiClNa2CO3 (aq), EtOH
PhMe, 80 °C
88%
N
OTBDPSMeO
Br
·pyrNaHMDS
MeOCOCl, THF
-78 - 25 °C
79%
N
OTBDPSMeO
CO2Me
TBAF, CH3CO2H
THF, 0 - 25 °C
99%
N
OHMeO
CO2Me
DPPA, DIAD
PPh3, THF 0 - 25 °C
99%
N
N3MeO
CO2Me
PPh3, THF/H2O
55%N
NH2MeO
CO2Me
CO2Me
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Ugi with the 5-Methoxy-2-vinyltryptamine
N
O
NHO
NH
PhS SPh
MeO
O
SPh
SPh
1) PhMe, Dean-Stark
120 °C
2)
tBuNC, MeOH 4 days
NH
NH2MeO
O
O
NHO
SPh
SPh
8%5%
+
+ 55% of A
CO2H
A
N
O
NHO
N
PhS SPh
MeO
O
SPh
SPh
1) PhMe, Dean-Stark
120 °C
2)
tBuNC, MeOH 5 days
N
NH2MeO
CO2H
A
CO2Me
MeO2C
X
the intermediate imine is not soluble in MeOH, CH2Cl2
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Synthesis of the RCM Precursor
N
O
NHO
NH
SPh
MeOSPh
N
O
NHO
N
SPh
MeOSPh
Boc
N
O
NHO
N
SOPh
MeOSOPh
Boc
N
O
NHO
N
MeO
Boc
Boc2O, DMAPEt3N, CH2Cl2
60%
NaIO4, MeOHH2O
0-25 °C 48%
p-xylene, pyr
W, 140 °C300 W
44%
(0.9 mg)
N
N
Boc
MeO
O
NHtBuO
Grubbs II
CH2Cl2
rsm (0.4 mg) + new product by TLC
![Page 19: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/19.jpg)
N
NH2MeO O
HO
O
Ugi 4CC
NC
R R
R = masked divinyl functionality
+ +
+
CO2Me
Execution of the Back-up Plan
N
H2N
MeO
CO2MeO
OtBu
O
+
reductive amination
thenCl
O
N
N
MeO
MeO2C
O
O
OtBu
16
![Page 20: Utilization of Ring Closing Metathesis in Alkaloid Synthesis I. Synthetic Studies on the Immunosuppressant FR901483 II. Toward the Total Synthesis of Lundurines.](https://reader035.fdocuments.us/reader035/viewer/2022062409/5697bf991a28abf838c91706/html5/thumbnails/20.jpg)
Preparation of the Divinylglycine Piece
N
Ph Ph
CO2Me
SOPh
Et3BnN+Cl-, K2CO3
60 °C, 4 h
N
Ph Ph
CO2Me
SOPh
SOPhN
Ph Ph
CO2Me
SOPh
NH
Ph Ph
H2N CO2Me
CH2Cl2, rt24 h
78%0%
82%
subjected to rxn cond
+
N
Ph Ph
CO2tBu
Br CO2tBuDIEA, MeCNreflux, 12 h
83%
2 x
X
SOPh
Et3BnN+Cl-, K2CO3
60 °C, 4 h
2 x
N
Ph Ph
CO2tBu
SOPh
SOPhN
Ph Ph
CO2tBu
SOPh
0% 30%
+
Bis-conjugate addition: Galons, H. et. al. Synth. Commun, 1991, 21, 1743.
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Preparation of the Divinylglycine Piece
N
Ph Ph
CO2Me
SOPh
Et3BnN+Cl- K2CO3, 60 °C
N
Ph Ph
CO2Me
SOPh
SOPhN
Ph Ph
CO2Me
SOPh
0%0%0%
82%45%57%
+
N
Ph Ph
CO2Me
SOPh
SOPh
Conditions1) LDA, THF, -78 °C 0%2) K2CO3, Et3BnN+Cl- H2O (cat) , 60 °C 19% 3) KOtBu, Et3BnN+Cl-
H2O (1 eq), 60 °C 23%
SOPh
2 x
Conditions18 h W, 4 hW, 4 h (H2O)
Bis-conjugate addition: Galons, H. et. al. Synth. Commun, 1991, 21, 1743.
N
Ph Ph
CO2tBu
SOPh
SOPh
N
Ph Ph
CO2tBu
KOtBuEt3BnN+Cl-
60 °C, 1 h
61%
SOPh
2 x
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Successful Formation of the RCM Precursors
N
OMeO
N
OHMeO
IBX, EtOAc80 °C
>99%
N
NH
MeOCO2tBu
CO2Me CO2MeCO2Me
N
Ph Ph
CO2tBu
SOPh
SOPh
N
Ph Ph
CO2tBu
KOtBuEt3BnN+Cl-
60 °C
61%
SOPh
2 x
p-xylene, pyr140 °C
66%
H2N
CO2tBuN
Ph Ph
CO2tBu
citric acid (aq)THF
71%
citric acid (aq)THF
89%
H2N
CO2tBu
SOPh
SOPh
H2N
CO2tBu
Na(OAC)3BHCH2Cl2
81%
H2N
CO2tBu
i) Na(OAC)3BHCH2Cl2, 89%
ii) p-xylene, pyr W, 140 °C
69%
SOPh
SOPh
Et3N, CH2Cl2 94%
N
NMeO
CO2Me
O
CO2tBu
COCl
N
NMeO
CO2MeCO2tBu
Br
K2CO3, TBAI, CH3CN W, 80 °C
72%
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Tandem-RCM Attempts
catalyst
C6H6, N
N
MeO
MeO2C
O
CO2tBuN
N
MeO
MeO2CCO2tBu
O
A B
CatalystGrubbs II 26 % A 0% B (39% RSM)Schrock 0% A 0% B (99% RSM)Lance 0% A 0% B (99% RSM)
Grubbs II or SchrockC6H6,
N
NMeO
CO2Me
O
CO2tBu
Grubbs II
CH2Cl2, W150 W, 50 °C
orPhMe, 100 °C
N
N
MeO
MeO2CCO2tBu
40% 0%
N
NMeO
CO2MeCO2tBu
N
N
MeO
MeO2CCO2tBu
+
Grubbs IIPhMe, 100 °C
RuPh
PCy3
NMesMesN
ClCl Ru
NN
ClCl
Oi-Pr
Grubbs 2nd Generation catalyst
"Lance"
i-Pr i-Pr
N
Mo
Ph(F3C)2MeCO
(F3C)2MeCO
Schrock catalystGrubbs catalysts: Grubbs, R. H. Angew. Chem. Int. Ed, 2006, 45, 3760.Lance: Grubbs, R. H. et. al. Org. Lett. 2007, 9, 1589.Schrock catalysts: Schrock, R. R. Angew. Chem. Int. Ed. 2006, 45, 3748.
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Possible Explanations for Unsuccessful RCM
N
NMeO
[Ru]N
N
MeO
MeO2COO OO
N
N
MeO
MeO2C
O
CO2tBu[Ru]
O
O
Modes of catalyst inhibition: Grubbs, R. H. Acc. Chem. Res, 1995, 28, 446.
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Troubleshooting the Functional Group Problems
NH
NMeO
CO2tBu
NH
N
MeO
CO2tBu
Grubbs II
PhMe, W150W, 80 °C, 6 h
~10%
(sm consumed)
Grubbs IIPhMe, W150 W, 80 °C, 3h
N
NMeO
CO2tBuCO2Me
KOH, MeOH
reflux, 18 h
>99%
new spot, sm consumed>>not the desired pdt by MS
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Troubleshooting the Functional Group Problems
N
NH
MeOCO2tBu
CO2Me
N
NMeO
CO2tBu
CO2Me
Grubbs IIPhMe
W, 80 °C, 3 hthen 70 °C, 2 d
XN
NMeO
CO2Me
CO2tBu
PhOMe
MeO
Cl
TBAI, K2CO3
CH3CN, W150 W, 80 °C, 3 h
26%
PhOMe
KOH(aq), MeOHreflux, 18 h
84%
NH
NMeO
CO2tBu
PhOMe
Grubbs IIPhMe
W, 80 °C, 3 hthen 70 °C, 24 h N
H
MeON PhOMe
CO2tBu
X
Examples of 8-membered RCM: Martin, S. F. et. al. Tetrahedron Lett. 1994, 35, 691.Lubell, W. D. et. al. J. Org. Chem. 2005, 70, 3838.Rodriguez, J. Angew. Chem. Int. Ed. 2006, 45, 5740.Bennasar, M.-L. Tetrahedron, 2007, 63, 861.
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Ts-indole and Cyanide in Place of the t-Butyl Ester
N
OMeO
N
NH
MeOCN
Ts Ts
H2N
CN
Na(OAC)3BHCH2Cl2
45%
H2N
CN
i) Na(OAC)3BHCH2Cl2, 58%
ii) p-xylene, pyr, 140 °C
SOPh
SOPh
N
NMeO
TsCN
Br
K2CO3, TBAI CH3CN, 80 °C
DECOMPOSITION
N
NMeO
TsCN
Br
NaH, TBAI DMF
~50%
//
N
N
MeO
TsCN
Grubbs II2 x 25 mol%C6D6
LRMS shows correct mass;however not enough material to verify the structure by NMR
Scale-up attempts unsuccessful
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Methyl Ester in Place of the t-Butyl Ester
N
OMeO
N
NH
MeOCO2Me
Ts Ts
H2N
CO2Me
i) Na(OAC)3BHCH2Cl2, 58%
ii) p-xylene, pyr W, 140 °C, 50%
SOPh
SOPh
N
NMeO
TsCO2Me
Br
K2CO3, TBAI CH3CN, W 80 °C
79%
N
NMeO
TsCO2Me
Grubbs II2 x 25 mol%
PhMe, rt, 48 h
49%
+ a product that looks like8-membered ring closure; however, mass doesn't match
NH
NMeO
CO2MeNH
NMeO
CO2Me
a) Na, naphthalene (decomp)b) K2CO3, MeOH (saponification)c) Mg, MeOH: (the amine not soluble)
Mg, MeOH
30%
NH
NMeO
CO2Me
Grubbs II
PhMeX
TLC looks terrible...
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Methyl Ester in Place of the t-Butyl Ester
N
NMeO
TsCO2Me
Grubbs I2 x 25 mol%
CH2Cl2, uW150W, 50 oC
2 x 3 h
N
NMeO
CO2Me
TsLCMS matches!!!
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Reduction of the Ester
N
NMeO
TsCO2tBu
LiAlH4, THF
-20 C to rt
93%
N
NMeO
TsOH
Ac2O, DMAP
Et3N, CH2Cl2
63%
N
NMeO
TsOAc
N
NMeOGrubbs II
PhMe
TsAcO
N
NMeO
TsAcO
N
NMeO
TsAcO
25 mol% cat, 7 h, rt only A50 mol% cat, 24 h, rt about 1:1 ratio of A and B
A B C
75 mol% cat, 48 h, rt only B; no A nor C
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Substrate for 8-Membered Ring Closure
N
NH
MeOCO2Me
Ts
Mg, MeOH
Grubbs II
NH
NH
MeOCO2Me
MOMCl, LHMDS
THF
N
NMeO
CO2Me
MOM
MOM N
N
MeO
MOM
MOM CO2Me
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End Game
NH
N
MeO
CO2Me
Pd/C, H2
MeOCOCl N
N
MeO
MeO2CCO2Me
i) H+
ii) iPrCOCl
iii) CH2N2
N
N
MeO
MeO2CO N2
i) CuOTfii) TsNHNH2
NaCNBH2N
N
MeO
MeO2Clundurine C
NH
N
MeO
CO2Me
Rh, H2
MeOCOCl N
N
MeO
MeO2CCO2Me
i) H+
ii) iPrCOCl
iii) CH2N2
N
N
MeO
MeO2CO N2
i) CuOTfii) TsNHNH2
NaCNBH2N
N
MeO
MeO2Clundurine A
O O
OO
MeOBF4
N
N
MeO
MeO2Clundurine B
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SummaryPart II
• Ugi reactions with cyclic ketones appeared to give better results than acyclic
• Successful route to the RCM precursor via Ugi was developed; however, the low yielding Ugi step steered us to develop another route
• Bisalkylation of an imine, reductive amination and acylation/alkylation provided an efficient route to the RCM precursors
• Preliminary experiments to cyclize 5- and 8-membered rings have been accomplished and further studies are in progress
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Acknowledgements
University of Texas at AustinProf. Stephen F. Martin
Martin GroupLab 1
$$$$$$Robert A. Welch Foundation
NIH (GM 25439)RochePfizerMerck
Materia Inc. for catalyst supportProf. Robert H. Grubbs for catalyst support
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Woerpel: Inside Addition
Me
inside attack
O
Nu
Nu
O
BnO
MeO
NuMe
OBn
inside attack
Nu
O
Me
BnOOBn
OBnO
Nu
inside attack
Nu
O
OBn
BnOOBn
1,3-cis product
1,3-cis product
1,3-trans product
Woerpel K. A. et al. J. Am. Chem. Soc. 1999, 121, 12208.
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Addition to the Acyl Iminium IonWoerpel’s Model
N
OR2 R3
outside attack
Nu
N
OR2 R3
NuH
H
eclipsed product
N
R3
R2ONu
Stereoselective additions to oxonium ions: Woerpel, K. A. et al. J. Am. Chem. Soc. 1999, 121, 12208.Stereoselective additions to iminium ions: Martin, S. F.; Bur, S. K. Org. Lett. 2000, 2, 3445; Tetrahedron Lett. 1997, 38, 7641.
inside attack
Nu
N
OR2
R3
Nu
H
H
staggered product
N
R3
R2ONu
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Hydroboration of the Azaspirane
borane fromthe top
borane from the bottom
N
OO
MeO2C
HO N
OO
MeO2C
OH
A B
NN
MeO2C OO
O
O
CO2Me
Predicted selectivity:
N
Cbz
CO2R
OHN
Cbz
CO2R
BHR2
[O]
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Development of a New Protecting GroupSubstituted Alloc
NO
HN
O
TMEDA, THF-78 °C, 1 h
MgBr
NH
O
OCOCl
R
O O
R
O
O
R
Et3N, DMAPCH3CN, 24 h
R = Me 42%R = Pr 48%R = i-Bu 41%
R = Me 73%R = Pr 87%R = i-Bu 74%
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Development of the Deprotection Conditions
HN
O
O
O N
Pd(PPh3)4 (20-mol%)nucleophile (5 equiv)
solvent, [0.08 M], 25 °C
Entry Nucleophile Solvent Time (25 °C) Yield
1 Morpholine CH2Cl2/EtOAc 4 h >99%
2 Morpholine CH2Cl2 3 h >99%
3 Pyrrolidine CH2Cl2 1 h >99%
4 Phthalimide CH2Cl2 >18 h N/A
5 Phthalimide K-salt CH2Cl2 >18 h N/A
6 HoBt/DIEA CH2Cl2 >18 h N/A
7 Benzotriazole CH2Cl2 45 min >99%
8* Benzotriazole (1 equiv) CH2Cl2/[0.45 M] 45 min >99%
*) 10-mol% Pd(PPh3)4
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Allylsilane Addition
Allylsilane acid synthesis: Weiler, L. Can. J. Chem. 1983, 61, 2530.
CO2MeTMS
TMS MgClO
O CO2HTMSNiCl2, THF
0 °C - 25 °C, 6 h
80%
CH3I, K2CO3, DMF
0 °C - 25 °C,1 h
85%
+
N
R
CO2MeR-Cl, AgOTfCH2Cl2
-78 °C - 25 °C, 18 h
R = Cbz 42%R = Troc 56%
N
Troc = O
O
Cl
ClCl
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Staudinger/Aza-Wittig/Ugi
N
O
NHO
N
N
NH
PhS
MeO
CO2H
SPh
MeO
NC
O
SPh
SPh
MeOH
CO2Me
NN :PPh3, MeOH
N
NMeO
CO2Me
PPh3
N
NMeO
CO2Me
NN PPh3
N
NMeO
CO2Me
N
Ph3P N
Staudinger
Aza-Wittig
N
NMeO
CO2Me
SPh
SPh
Ugi
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Towards the Divinyl Functionality
O
OOH
OH
OH
HO
TBS-Cl, imidazole
DMF, 0 oC, 30 min
94%
O
OTBSTBSO
NH
N
O
NHO
OH
O
mono-oxidized pdt
NH
NH2+HO
O
NH
N
O
NHO
MeOH, 25 °C, 20 h
83%
TBSO OTBS
O
OTBS
OTBS
NC
NH
N
O
NHO
OH
OH
TBAF, THF
0 °C, 30 min
94%NH
N
O
NHO
O
O[O], cond
Conditions:1) Dess-Martin, CH2Cl2, 18 h, 18% mono-ox, 40% rsm 2) Dess-Martin, 2,6-lutidine, CH2Cl2, 17% mono-ox, 45% rsm3) IBX, EtOAc, 80 C, 3 h: mono-ox only; 6 h: unidentified pdt 4) Pyr-SO3, Et3N, DMSO, 18 h, mono-ox & rsm (NMR)
R1
N
OR2
NHR3
OOR
ORO
ORRO
R1NH2 + R2CO2H+ R3NC
R1
N
OR2
NHR3
OO
O
R1
N
OR2
NHR3
O
[O] PPh3