lewis acid activated synthesis of highly substituted cyclopentanes by the n- heterocyclic carbene...
TRANSCRIPT
Lewis Acid Activated Synthesis of Highly Substituted Cyclopentanes by the N-Heterocyclic Carbene Catalyzed Addition of Homoenolate Equivalents to Unsaturated
Ketoesters
Article by Karl A. Scheidt. Angewandte Chemie. 2011, 50, 1678-1682.
Review by Benjamin Roembke, Department of Chemistry and Biochemistry, University of Maryland, College Park 20740
Karl A. Scheidt
B.S.: University of Notre Dame 1994Ph.D: Indiana University 1999
Research Statement:“Our research focuses on two complementary areas: the
discovery of new organic reactions and bioorganic chemistry. We are particularly interested in designing novel methods and strategies for the construction of complex natural products with important biological attributes. Our methodology programs encompass assembling molecules and introducing stereogenic centers using new catalytic reactions.”
Faculty profiles, Northwestern University: http://www.chemistry.northwestern.edu/faculty/karl-scheidt.html
Goal of the Study
Use enals and -unsaturated -ketoesters to form highly substituted cyclopentanes
Karl A. Scheidt. Angewandte Chemie. 2011, 50, 1678-1682
Carbene Catalysts
Used in organic chemistry to cause polarity reversal also know as Umpolung.
Umpolung is the German name for ‘inverse polarity’. It is given to synthons with d1, a2, d3, a4… reactivity.
Clayden, J.; Greeves, N.; Warren S.; Wothers, P. Organic Chemistry, 1st ed.; Oxford University Press: New York, 2001; pp 798-799
Synthons
R
OH
R
O
R
O
a1 (equivalentto aldehdyde orketone)
d2 (equivalent to enolate of ester or ketone)
a3 (equivalent to -unsaturated carbonyl compounds)
Natural Reactivity Synthons
Unnatural Reactivity Synthons
CN
d1 (cyanide anion)
OH
a2 (equivalentto epoxide)
Clayden, J.; Greeves, N.; Warren S.; Wothers, P. Organic Chemistry, 1st ed.; Oxford University Press: New York, 2001; pp 798-799
Homoenolates: An Umpolung synthon
In this study, an enal is converted into a homoenolate by reaction with a carbene catalyst
Homoenolate (d3 synthon) is a compound containing an anionic carbon to a carbonyl or a moeity that can be transformed into a carbonyl
M
O OM
Enolate
O M O M
Homoenolate
V. Nair, S. Vellalath, B. P. Babu. Chem. Soc. Rev. 2008, 37, 2691
Discovery of the Homoenolate Ion
Proof of the homoenolate ion Optical activity was reduced to zero
A. Nickon and J. L. Lambert. J. Am. Chem. Soc., 1962, 84, 4604
O
KOtBu, HOtBu
250oC, 4 hr.O
=
O
O
+O
ab
Early Example of Homoenolate Equivalents Used in C-C formation
Silyl ethers in the form of cyclopropyl ketals were used as homoenolate equivalents
TiCl4 problematic
H
OOSiMe3
EtO+
TiCl4 (1 eq.), CH2Cl2-78oC, 77% O
O
E. Nakamura and I. Kuwajima, J. Am. Chem. Soc., 1977, 99, 7360
OSiMe3EtOH
O
+TiCl4 (1 eq.), CH2Cl2
0oC, 77%COOEt
OH
COOEt
Cl
Reaction of Enals and Chalcones
V. Nair, S. Vellalath, M. Poonoth, E. Suresh. J. Am. Chem. Soc. 2006, 128, 8736
Proposed Catalytic Cycle
V. Nair, S. Vellalath, M. Poonoth, E. Suresh. J. Am. Chem. Soc. 2006, 128, 8736
Optimization Reaction
Karl A. Scheidt. Angewandte Chemie. 2011, 50, 1678-1682.
NN Mes
Mes Cl-
A
O
NN
N
R
R Mes
ArB: R= Me, Ar= PhC: R= H, Ar= PhD: R= Ph, Ar= 3-indolyl
O
NN
NAr
BF4-
BF4-
Ar= 2,6-Et2C6H4
Varying -Subtitution on the Ketoester
Karl A. Scheidt. Angewandte Chemie. 2011, 50, 1678-1682.
Varying Substitution of the Enal
Karl A. Scheidt. Angewandte Chemie. 2011, 50, 1678-1682.
Catalytic Cycle
N N
N
Ar
Ph H
O
Ph
O
N N
N
[Ti]
Ar
HPh
O
N N
N
[Ti]
ArPh
O
MeO
O
Ph
N N
N
Ar
O
[Ti]
H+
Ph
O
MeO
O
Ph
N N
N
Ar
O
[Ti]
Ph
O
MeO
O
Ph
N N
N
Ar
O
[Ti]
Karl A. Scheidt. Angewandte Chemie. 2011, 50, 1678-1682.
Ph
O
MeO
O
Ph
N N
N
Ar
O
[Ti]
Ph
O
MeO
O
Ph
N N
N
Ar
O
[Ti]
Synthetic Utility of Products
Karl A. Scheidt. Angewandte Chemie. 2011, 50, 1678-1682.
Acknowledgements
Dr. Davis The class