Cyclopropane Strain：环丙烷应变PPT精品文档61页
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Cyclopropane has significant ring strain.
R in g S tra in ~ 2 7 .5 k c a l/m o l
Cyclopropanes have pi character.
Coulson-Moffitt Model Bent Bonds
Walsh Model
ON H NO
O N H spirotryprostatinB
O
B z O
O H H
H g ( O T f) 2 ;
O
B z O O HK B r
O O H HH
8 5 %H g B r
O
H 3 C O
O HH
O H
z in c o p h o r in
Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2019, ASAP. Cossy, J.; Blanchard, N.; Defosseux, M.; Meyer, C. Angew. Chem. Int. Ed. 2019, 41, 2144.
P eta s is
This work
Zimmerman-Traxler Cyclization
LA O ROR
LA O ROR
O LA ROR
O LA ROR
RO R MO H
RO R MO H
O Petasis
ROR
O This work
ROR
OH OH
OH Initial target
OH
The Kulinkovich Cyclopropanation
Reactivitytowardsnucleophiles
O Nu
O Nu
Nu
O
O Nu
Reactivitytowardselectrophiles
H O
E+
O E
H O
E+
O E
Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 5, p 901.
Alkenes and Cyclopropanes
R e a c tiv ity to w a rd s e le c tro p h ile s
H O
E+
O E
H O
E+
O E
C o u ld th is b e u s e d to g e n e ra te h e te ro c y c le s ?
ቤተ መጻሕፍቲ ባይዱ
Alkenes and Cyclopropanes
“Virtually every reaction that an alkene undergoes has its counterpart in the repertoire of transformations possible with cyclopropanes.”
T i(O -iP r)4 (0 .1 e q ) E tM gB r (3 e q) T H F /E t2O (4 :1) 80%
OH OH
OH OH
OH O
T iC l(O -iP r)3 (1 e q )
A Cyclopropane Fragmentation Approach to Heterocycle Assembly
Kevin Minbiole James Madison University
August 11, 2019
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
R EtMgBr RO O Ti RO
R OR
R
RO
Ti
RO
R
R XMgO
R
Kulinkovich, O. G. Chem. Rev. 2019, 103, 2597.
Cyclopropanation Yields
O O
O O
T i(O -iP r)4 (0 .1 e q ) E tM gB r (3 e q) T H F /E t2O (4 :1) <30%
H O
E+
O E
Oxocarbenium-Based Heterocycle Syntheses
LA
OH
RCHO
O
O O
O O
O O
LA LA O O O LA
LA O O LA
LA O
Analogous modes of cyclization
O LA O
O O
O O
O
X X
O O H
O
P rin s P rin s -P ina c o l
II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions
Cyclopropane Strain and Reactivity
II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
O R1 OR2
Kulinkovich Reaction
Ti(O-iPr)4 (0.1 eq) EtMgBr (3 eq) THF/Et2O (4:1)
R1 OH
Ti(OR)4 +
2 EtMgBr
XMgO R
RO Ti
RO
H3C CH3
RO Ti
RO
RO Ti
RO
O
EtMgBr RO O Ti
RO
R OR
Alkenes and Cyclopropanes
Carreira’s approach to spirotryprostatin B
O M gI2
N B n
R N
R
I
O M gI N B n
I R
N
R O N B n
Cossy’s approach to zincophorin
R N
R O N B n
R in g S tra in ~ 2 7 .5 k c a l/m o l
Cyclopropanes have pi character.
Coulson-Moffitt Model Bent Bonds
Walsh Model
ON H NO
O N H spirotryprostatinB
O
B z O
O H H
H g ( O T f) 2 ;
O
B z O O HK B r
O O H HH
8 5 %H g B r
O
H 3 C O
O HH
O H
z in c o p h o r in
Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2019, ASAP. Cossy, J.; Blanchard, N.; Defosseux, M.; Meyer, C. Angew. Chem. Int. Ed. 2019, 41, 2144.
P eta s is
This work
Zimmerman-Traxler Cyclization
LA O ROR
LA O ROR
O LA ROR
O LA ROR
RO R MO H
RO R MO H
O Petasis
ROR
O This work
ROR
OH OH
OH Initial target
OH
The Kulinkovich Cyclopropanation
Reactivitytowardsnucleophiles
O Nu
O Nu
Nu
O
O Nu
Reactivitytowardselectrophiles
H O
E+
O E
H O
E+
O E
Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 5, p 901.
Alkenes and Cyclopropanes
R e a c tiv ity to w a rd s e le c tro p h ile s
H O
E+
O E
H O
E+
O E
C o u ld th is b e u s e d to g e n e ra te h e te ro c y c le s ?
ቤተ መጻሕፍቲ ባይዱ
Alkenes and Cyclopropanes
“Virtually every reaction that an alkene undergoes has its counterpart in the repertoire of transformations possible with cyclopropanes.”
T i(O -iP r)4 (0 .1 e q ) E tM gB r (3 e q) T H F /E t2O (4 :1) 80%
OH OH
OH OH
OH O
T iC l(O -iP r)3 (1 e q )
A Cyclopropane Fragmentation Approach to Heterocycle Assembly
Kevin Minbiole James Madison University
August 11, 2019
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
R EtMgBr RO O Ti RO
R OR
R
RO
Ti
RO
R
R XMgO
R
Kulinkovich, O. G. Chem. Rev. 2019, 103, 2597.
Cyclopropanation Yields
O O
O O
T i(O -iP r)4 (0 .1 e q ) E tM gB r (3 e q) T H F /E t2O (4 :1) <30%
H O
E+
O E
Oxocarbenium-Based Heterocycle Syntheses
LA
OH
RCHO
O
O O
O O
O O
LA LA O O O LA
LA O O LA
LA O
Analogous modes of cyclization
O LA O
O O
O O
O
X X
O O H
O
P rin s P rin s -P ina c o l
II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions
Cyclopropane Strain and Reactivity
II. Proof of Concept: Oxepane Synthesis III. Progress Towards Nitrogenous Heterocycles IV. Radical Strategies V. Future Directions
Outline
I. Introduction to Cyclopropanes and Heterocycle Formation Strategies
O R1 OR2
Kulinkovich Reaction
Ti(O-iPr)4 (0.1 eq) EtMgBr (3 eq) THF/Et2O (4:1)
R1 OH
Ti(OR)4 +
2 EtMgBr
XMgO R
RO Ti
RO
H3C CH3
RO Ti
RO
RO Ti
RO
O
EtMgBr RO O Ti
RO
R OR
Alkenes and Cyclopropanes
Carreira’s approach to spirotryprostatin B
O M gI2
N B n
R N
R
I
O M gI N B n
I R
N
R O N B n
Cossy’s approach to zincophorin
R N
R O N B n