A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison...
-
date post
22-Dec-2015 -
Category
Documents
-
view
231 -
download
2
Transcript of A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison...
![Page 1: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/1.jpg)
A Cyclopropane Fragmentation Approach to Heterocycle Assembly
Kevin MinbioleJames Madison University
August 11, 2005
![Page 2: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/2.jpg)
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
II. Proof of Concept: Oxepane Synthesis
III. Progress Towards Nitrogenous Heterocycles
IV. Radical Strategies
V. Future Directions
![Page 3: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/3.jpg)
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
II. Proof of Concept: Oxepane Synthesis
III. Progress Towards Nitrogenous Heterocycles
IV. Radical Strategies
V. Future Directions
![Page 4: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/4.jpg)
Cyclopropane Strain and Reactivity
Cyclopropane has significant ring strain.
Cyclopropanes have pi character.
Coulson-Moffitt ModelBent Bonds
Walsh Model
Ring Strain ~ 27.5 kcal/mol
![Page 5: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/5.jpg)
Alkenes and Cyclopropanes
“Virtually every reaction that an alkene undergoes has its counterpart in the repertoire of transformations possible with cyclopropanes.”
OH
E+
OH
E+O
E
O
E
O
O
Nu
Nu
Nu O
ONu
Reactivity towards nucleophiles Reactivity towards electrophiles
Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 5, p 901.
![Page 6: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/6.jpg)
Alkenes and Cyclopropanes
Carreira’s approach to spirotryprostatin B
Cossy’s approach to zincophorin
NBn
OMgI2
NR
R
NBn
OMgI
I
NBn
O
I
R
NR
N
Bn
O
NR
R
N
H
O
N
N
O
O H
spirotryprostatin B
Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, ASAP.Cossy, J.; Blanchard, N.; Defosseux, M.; Meyer, C. Angew. Chem. Int. Ed. 2002, 41, 2144.
OH
O
OHBzO
O
O
OHBzO
H H
HgBr
OH3CO
O
OHHH
Hg(OTf)2;
KBr
85% zincophorinH
![Page 7: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/7.jpg)
Alkenes and Cyclopropanes
OH
E+
OH
E+O
E
O
E
OH
E+
O
E
Could this be used to generate heterocycles?
Reactivity towards electrophiles
![Page 8: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/8.jpg)
Oxocarbenium-Based Heterocycle Syntheses
OH RCHO
O
O
O
O
O
O
O
O
LA
O
O LA
O
O
O LA
O
OLA
O
O
O
O
O
O
O
H
O
X
Petasis
This work
Prins
Prins-Pinacol
Analogous modes of cyclization
LA
LA
LA
LA
X
![Page 9: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/9.jpg)
Zimmerman-Traxler Cyclization
O
OR R
O
OR R
OR
O LA
R
OR
O LA
R
OR
O
R
OR
O
R
Petasis
This workOMO
H
R R
OMO
H
R R
OH
OHOH
OHInitial target
LA
LA
![Page 10: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/10.jpg)
The Kulinkovich Cyclopropanation
R1 OR2
O
H3C CH3
TiRO
ROTi
RO
RO
XMgO RTi
RO
RO
ROO
TiRO
RO
ROR
O
ORR
R1 OH
TiRO
RO
R
TiRO
RO
XMgOR
R
R
Kulinkovich Reaction
Ti(O-iPr)4 (0.1 eq)EtMgBr (3 eq)THF/Et2O (4:1)
Ti(OR)4
+2 EtMgBr
EtMgBr EtMgBr
Kulinkovich, O. G. Chem. Rev. 2003, 103, 2597.
![Page 11: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/11.jpg)
Cyclopropanation Yields
OH
OEt
O
OH
OEt
O
OH
OH
OH
OH
OH
TiCl(O-iPr)3 (1 eq)EtMgBr (4 eq)THF/Et2O (4:1)
51%
Ti(O-iPr)4 (0.1 eq)EtMgBr (3 eq)THF/Et2O (4:1)
80%
TiCl(O-iPr)3 (1 eq)EtMgBr (4 eq)THF/Et2O (4:1)
51%
OO OH
OH
Ti(O-iPr)4 (0.1 eq)EtMgBr (3 eq)THF/Et2O (4:1)
<30%
OH
O
O
Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337-1339.
![Page 12: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/12.jpg)
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
II. Proof of Concept: Oxepane Synthesis
III. Progress Towards Nitrogenous Heterocycles
IV. Radical Strategies
V. Future Directions
![Page 13: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/13.jpg)
Initial Attempts at Oxepane Formation
OH
OH O
O
Ph
PhCHO, Na2SO4
CH2Cl2, 0.1M
M(OTf)3,-78 oC
M = Al, Bi, In
![Page 14: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/14.jpg)
Initial Attempts at Oxepane Formation
OH
OHO
O
Ph O
O
Ph
PhCHO, Na2SO4
CH2Cl2, 0.1M
30-50%
M(OTf)3,-78 oC
warm to
0 oC
M = Al, Bi, In
Softer Lewis acids (CuSO4, ZnCl2, SnCl2) stop at acetal
![Page 15: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/15.jpg)
Mechanism of Oxepane Formation
OH
OHO
O
Ph O
O
Ph
LA
O Ph
OLA
O
O
Ph
PhCHO, Na2SO4
CH2Cl2, 0.1M
Al(OTf)30 oC
![Page 16: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/16.jpg)
Mechanism of Oxepane Formation
OH
OH
OH
OH
O
O
Ph
O
O
Ph Ph
O
O
Ph
LA
OPh Ph
OLA
O Ph
OLA
Ph
OLA
O
O
Ph
OPh
PhCHO, Na2SO4
CH2Cl2, 0.1M
Al(OTf)30 oC
PhCHO, Na2SO4
CH2Cl2, 0.1M
Al(OTf)3
0 oC
- PhCHO
69%
![Page 17: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/17.jpg)
Stereochemistry of Oxepane Formation
OH
OH
O
O
PhH H
O
O
Ph
H HO
O
Ph
O
O
Ph
PhCHO, Na2SO4
CH2Cl2, 0.1M
30-50%
M(OTf)3,-78 oC
warm to
0 oC
10% nOe 10% nOe
M = Al, Bi, In
![Page 18: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/18.jpg)
Zimmerman-Traxler Cyclization
O
OR R OR
O LA
R OR
O
RO
MO
R R
![Page 19: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/19.jpg)
Initial Limitations of Oxepane Formation
OH
OH
O
O
PhH H
OH
OH
O
O
Ph
O
O
Ph
H HO
O
Ph
X
O
O
Ph
O
O
Ph
PhCHO, Na2SO4
CH2Cl2, 0.1M
30-50%
M(OTf)3,-78 oC
warm to
0 oC
10% nOe 10% nOe
M = Al, Bi, In
PhCH2CH2CHO, Na2SO4
CH2Cl2, 0.1M
M(OTf)3,-78 oC
M = Al, Bi, In
![Page 20: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/20.jpg)
Two-Lewis Acid System
R1
OH
OH O
O
R1 R2
R2CHO, Na2SO4
Al(OTf)3, -10 oC, 1 h;
50-70%
then TiCl4, 45 min
No problems associated with coexistence of two Lewis acids
![Page 21: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/21.jpg)
Yields and Scope of Oxepane Formation
RCHO
OH
OH
OH
OH
OH
OH
O
H Ph
O
H
O
O
PhO
O
O
O
O
O
Ph
O
O
O
O
Ph
O
H
O Ph
O
O Ph
O
O Ph
O
diol
51% 55%
71%71%
70%62%
55%
66%
69%
O'Neil, K. E.; Kingree, S. V.; Minbiole, K. P. C. Org. Lett. 2005, 7, 515-517.
![Page 22: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/22.jpg)
Appearance of Trans Oxepane
R
OH
OH
O
O
R
O
O
RM
O
O
R
O
O
R
PhCHO, Na2SO4
Yb(OTf)3 (1.0 eq);
then TiCl4(1.1 eq)
TiCl4
0 oC, 45 min
~1:1
R YieldPr 61%Me 70%iPr 55%
![Page 23: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/23.jpg)
Inclusion of Sidechain Functionality
O
H
O
H
NO2
RCHO
OH
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
O
O
diol
34%
30%
30%
26%
36%
36%
NO2
NO2
NO2
![Page 24: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/24.jpg)
Inclusion of Sidechain Functionality
O
O
O
OCH3
O
H OBn
O
O
OBn
O
OCH3H
O
47% 15%
Certain chelating groups are tolerated…
![Page 25: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/25.jpg)
Inclusion of Sidechain Functionality
O
O
R O
O
R
O
HOCH3
O
O
HOBn
ProductiveChelation
No rearrangement No rearrangementNo rearrangement
Non-ProductiveChelation
O
HN
OM
R M O
R
Certain chelating groups are tolerated…but others fail to rearrange to oxepane
![Page 26: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/26.jpg)
Reaction Optimization
Alternate Lewis acids
Zirconium tetrachloride
Alternate drying agents
Molecular sieves
Alternate solvent systems
More or less polar solvents
![Page 27: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/27.jpg)
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
II. Proof of Concept: Oxepane Synthesis
III. Progress Towards Nitrogenous Heterocycles
IV. Radical Strategies
V. Future Directions
![Page 28: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/28.jpg)
Nitrogen Analogs: Azepines
NH
OHN
O
R N
O
R
RCHO, Na2SO4
Lewis Acid(s)
R
R R
Analogous reaction in nitrogenous heterocycles?
![Page 29: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/29.jpg)
Nature of Protecting Group on Nitrogen
NH2
OH
NH
OH
Boc
NH
O
Ph
N
O
Ph
Boc
NH
O
Ph
LA
N
O
Ph
LA
Boc
NH
Ph
OLA
N Ph
OLA
Boc
NH
O
Ph
N
O
PhBoc
PhCHO, Na2SO4
Lewis Acid(s)
PhCHO, Na2SO4
Lewis Acid(s)
Boc =
O
O
![Page 30: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/30.jpg)
Assembly of Azepine Precursor
OEt
NH2 O
OEt
NHBoc
O
OH
NHBoc
Boc2O;
KulinkovichCyclopropanation
>99%
Ti(O-iPr)4 (1 eq)EtMgBr (4 eq)THF/Et2O (4:1)
72%
![Page 31: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/31.jpg)
Cyclization attempts
OH
NHBoc
N OH
O
O
H
ZrCl4LaCl3TiCl4BBr3
PhCHO, LANo Reaction
Brönsted Acids employed:HCOOHTFApTSA
Lewis Acids employed:Al(OTf)3Yb(OTf)3
In(OTf)3
Bi(OTf)3
![Page 32: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/32.jpg)
Cyclization Attempts with Free Amine
OH
OH
OH
NH2
OH
N3
NH
O
Ph
PhCHO, LA
PPh3, DIAD,Zn(N3)3-pyr2
60% OH
NH2LAH or NaBH4
or PPh3/H2O
Amino alcohol not yet isolated
![Page 33: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/33.jpg)
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
II. Proof of Concept: Oxepane Synthesis
III. Progress Towards Nitrogenous Heterocycles
IV. Radical Strategies
V. Future Directions
![Page 34: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/34.jpg)
Radical Cyclization
OM
O
O M
O
Heterolytic
Homolytic
![Page 35: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/35.jpg)
Radical Cyclization
OM
O
O M
O
Heterolytic
Homolytic
OH [O]
Heterolysis is known for cyclopropanols with mild single electron oxidants (e.g., Mn3+ and Fe3+).
![Page 36: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/36.jpg)
Radical Cyclization Utilizing Azide
IN3
IN3
NH
H
N
Ts
N N N
N
N
N2
1. Bu3SnH, AIBN
PhH, , 2h
2. TsCln
n n = 1, 88%n = 2, 50%
Kim, 1994
n
- N2
Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1994, 116, 5521-5522.
![Page 37: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/37.jpg)
Radical Cyclization Towards Heterocycles
OH
N3 N3
O
HN
O
Mn(pic)3
orFeCl3
- N2
solvent
pic =N
O
O
![Page 38: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/38.jpg)
Radical Cyclization Towards Functionalized Heterocycle
OH
N3 N3
O
HN
O
Mn(pic)3
orFeCl3
RR R
- N2
solvent
pic =N
O
O
![Page 39: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/39.jpg)
Progress Towards Piperidine
N3 O
X
OH
N3 N3
O
HN
O
Not observed
X = H, OH, OOH, Cl
Oxidant
DMF or benzene
Oxidants Used:FeCl3Fe(NO3)3Mn(OAc)3Mn(pic)3
![Page 40: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/40.jpg)
Recourse for Piperidine
OO
PhMgBr
OH
N3Ph
OH
OH Ph
N3
O
Ph
HN
O
Ph
Ti(O-iPr)4 (0.1 eq)THF/Et2O (4:1)
Oxidant
![Page 41: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/41.jpg)
Towards the Pyrrolidine
R3N
R3
R1 R2
O[O]
R
O
OR'
OH
R
O
OR'
NH2
R
O
OR'
N3
R
ROH
N3
R
Tf2O, NaN3;
Cu(II)SO4
Kulinkovich Reaction
Ti(Oi-Pr)4 (0.1 eq),EtMgBr, THF/Et2O
Tf2O, pyr;
NaN3, DMF, 24h
Alper, P. B.; Hung, S.-C.; Wong, C.-H. Tetrahedron Lett. 1996, 6029-6032.
![Page 42: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/42.jpg)
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
II. Proof of Concept: Oxepane Synthesis
III. Progress Towards Nitrogenous Heterocycles
IV. Radical Strategies
V. Future Directions
![Page 43: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/43.jpg)
Alternative Ring Size
OHOHR
OO
R
R
RCHOO
R
MO
HR
O
O
R R
Lewis AcidLewis Acid
![Page 44: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/44.jpg)
Sites of Functionalization on Oxepane Ring
OH
OHO
O
O
O
R
RR
OH
OH O
O
O
OR
R
4 diastereomers 4 diastereomers
O
OR
R+
Aldehyde, LA
Aldehyde, LA
![Page 45: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/45.jpg)
Cyclopropane Functionalization via Cyclopropene
OH
R
OH
OH
OH
R
F
OTIPS
R
OTIPS
OR R
R
OM
OTIPS
M
OTIPS
R
OR R
RO
OTIPS
N2
R
Chiral Rh(II)
RCHO, LA
O
O
R
Doyle, M. P.; Protopopova, M.; Müller, P.; Ene, D.; Shapiro, E. A. J. Am. Chem. Soc. 1994, 116, 8492.Müller, P.; Granicher, C. Helv. Chim. Acta 1995, 78, 129.
Fox, J. M.; Yan, N. Curr. Org. Chem. 2005, 9, 719.
![Page 46: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/46.jpg)
Natural Product Total Synthesis
NH
O
H3CO OHO
N
O H
O
O
HH3C
Piperidines Azepines
TetrahydropyransOxepanes (7) and Oxocanes (8)
Coniine Spectalinine
Stemoamide
Centrolobine Lauthisan
NH
H3C
OH
OH
11
O
Cl BrH H
Isolaurepinnacin
![Page 47: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/47.jpg)
Conclusions
Cyclopropanes can be utilized as homo-alkenes to prepare heterocycles
A facile two-step procedure has been developed to prepare oxepanes with excellent stereoselectivity
Further substitution and alternate heterocycles are being explored
Radical cyclization promises another method to deliver heterocycles from cyclopropanols
![Page 48: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/48.jpg)
Epilogue on Undergraduate Teaching and Research
Quality of Life
Opportunities for Funding
Satisfaction
Direction of research
Students
![Page 49: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/49.jpg)
The Group
Kerry O’Neil, JMU ’05 Seth Kingree, JMU ’06 Cambria Baylor, JMU ’06
Andrew Blanchard, JMU ’07 Steve Andrews, JMU ’07 Erik Stang, JMU ’06
![Page 50: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/50.jpg)
Where’s James Madison University?
![Page 51: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/51.jpg)
Funding
![Page 52: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/52.jpg)
Acknowledgements
NMR: Tom Gallaher and Jeff Molloy
Nebraska Center for Mass Spectrometry
Drs. Kevin Caran and Scott Lewis
James Madison University
![Page 53: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/53.jpg)
![Page 54: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/54.jpg)
Future Direction: Cyclopropane Functionalization
OTIPSTIPSO
N2
CO2R
O
CHOR
CO2R
OTIPS
CO2R
TIPSO
O R R
OH
CO2R
HO
O
R
OHRO2C
Chiral Rh Cat
RCHO, LA
TBAF, -78 oC
R
![Page 55: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/55.jpg)
Other Backups: Discrete Homoenolate
X
OTMS
R
R
X
O
R
R
M
X RR
O M
X
R
R
O
R
Metals
Employed:
AgI, AuI, CuII,
HgII, PdII,
PtII, SnIV
![Page 56: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/56.jpg)
Other Backups: Radical
N
HO
R
RN
O
R
R
N
R
R
O
R
CO2RO
HO
R R
CO2RO
O
O
CO2R
R
O
![Page 57: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/57.jpg)
Aza Cope Possibility
NR
Ph
OLA
NR
O
Ph
LA
NR
O
Ph
![Page 58: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/58.jpg)
Modified Point of Attachment
R
OH
O
OR2R1
R
OH OHR1
OMO
H
H
H
R RO
H
H
H
R R
R1 OR
O OLA
R R1
R3
R
O Ti(Oi-Pr)n
O
R1
O
R
R3
R
OH OHR1Ti(Oi-Pr)4, PhCH3, rt;then c-C5H9MgCl, THF
15 examples42-68% yield3.5-12.2:1 ds
Cha, 2002
R3CHO, LA
Previous Modified Connectivity
H
H
![Page 59: A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005.](https://reader035.fdocuments.net/reader035/viewer/2022062314/56649d795503460f94a5be92/html5/thumbnails/59.jpg)
Precedent For Acyliminium Formation
Hsung Precedent
NHBocO
OTBS
R
NBoc
OTBS
R
NBoc
OTBS
R
OHCO
HCO2H
THFToluene
R = hexyl
61%Hsung, 2004