Lewis Acid Activated Synthesis of Highly Substituted Cyclopentanes by the N- Heterocyclic Carbene Catalyzed Addition of Homoenolate Equivalents to Unsaturated.

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