A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison...
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A Cyclopropane Fragmentation Approach to Heterocycle Assembly Kevin Minbiole James Madison University August 11, 2005
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A Cyclopropane Fragmentation Approach to Heterocycle Assembly
Kevin MinbioleJames Madison University
August 11, 2005
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
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
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
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.
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
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
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
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
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.
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.
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
Initial Attempts at Oxepane Formation
OH
OH O
O
Ph
PhCHO, Na2SO4
CH2Cl2, 0.1M
M(OTf)3,-78 oC
M = Al, Bi, In
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
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
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%
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
Zimmerman-Traxler Cyclization
O
OR R OR
O LA
R OR
O
RO
MO
R R
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
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
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.
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%
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
Inclusion of Sidechain Functionality
O
O
O
OCH3
O
H OBn
O
O
OBn
O
OCH3H
O
47% 15%
Certain chelating groups are tolerated…
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
Reaction Optimization
Alternate Lewis acids
Zirconium tetrachloride
Alternate drying agents
Molecular sieves
Alternate solvent systems
More or less polar solvents
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
Nitrogen Analogs: Azepines
NH
OHN
O
R N
O
R
RCHO, Na2SO4
Lewis Acid(s)
R
R R
Analogous reaction in nitrogenous heterocycles?
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
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%
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
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
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
Radical Cyclization
OM
O
O M
O
Heterolytic
Homolytic
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+).
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.
Radical Cyclization Towards Heterocycles
OH
N3 N3
O
HN
O
Mn(pic)3
orFeCl3
- N2
solvent
pic =N
O
O
Radical Cyclization Towards Functionalized Heterocycle
OH
N3 N3
O
HN
O
Mn(pic)3
orFeCl3
RR R
- N2
solvent
pic =N
O
O
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
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
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.
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
Alternative Ring Size
OHOHR
OO
R
R
RCHOO
R
MO
HR
O
O
R R
Lewis AcidLewis Acid
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
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.
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
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
Epilogue on Undergraduate Teaching and Research
Quality of Life
Opportunities for Funding
Satisfaction
Direction of research
Students
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
Where’s James Madison University?
Funding
Acknowledgements
NMR: Tom Gallaher and Jeff Molloy
Nebraska Center for Mass Spectrometry
Drs. Kevin Caran and Scott Lewis
James Madison University
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
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
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
Aza Cope Possibility
NR
Ph
OLA
NR
O
Ph
LA
NR
O
Ph
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
Precedent For Acyliminium Formation
Hsung Precedent
NHBocO
OTBS
R
NBoc
OTBS
R
NBoc
OTBS
R
OHCO
HCO2H
THFToluene
R = hexyl
61%Hsung, 2004
