Research Statement 05

7/27/2019 Research Statement 05

1/4

Student Research Projects

William Dasher Department of ChemistryUniversity of Puget Sound

Quaternary amines have been used as phase-transfer catalysts (PTC) allowing many reactions tooccur under milder conditions and greater yields than other techniques. The pharmaceuticalindustry has pioneered and continues to use phase-transfer reactions extensively. Recentapplications involve use of a chiral PTC reagent (APTC) to induce asymmetry in a reaction. Oneof the most successful series of asymmetric PTC reagents are those derived from quinine, analkaloid found in the bark of the cinchona tree. Quinine is best known historically for use intreating malaria.

Several groups, most notably from Merck Pharmaceuticals and the labs E. J. Corey at Harvardand B. Lygo at University of Nottingham, have developed highly efficient quinine derived PTCreagents for the production of chiral amino acids and other medicinally useful molecules. To date,modifications on quinine have been to quarternize the 3 amine group with large, flat,substituents such as the anthracene derivative, shown below, and possibly adding a substituentto the 2 hydroxy group.

BrN

OH

N

OMe

Figure 1. A modified cinchonium salt - third generation.

Our focus on the use of quinine in asymmetric reactions is on modifications of the secondaryalcohol rather than the tertiary nitrogen. Currently we have three related projects which utilizequinine (or related molecules) which have been esterified to form new reagents for use as a chiralcatalyst or chiral ancillary.


2/4

The first project derives from earlier work in our lab which explored the use of underivatizedquinine as a catalyst for the Michael reaction between malonates and cyclic enones. The yieldswere high with modest stereoenhancement. By esterifying with 4-hydroxy phenyl acetic acid we

hope to change the nonbonding interactions responsible for creating a tighter chiral environmentfor the reaction to occur in. This is illustrated in Scheme 1.

HO

CO 2

R =

O

CO 2 R

CO 2 R

+

O

RO 2 C CO 2 R

RedAl

N

MeO

RO N

N

MeO

HO N

Scheme 1. Chiral Michael Reaction and modified quinine

The second project is to explore the use of a quinine-borohydride complex to effect chiralreduction of ketones. To this end we are making sodiumborohydride complexes withunderivatized quinine and evaluating the degree of stereoselectivity in the reduction of bulkyketones. We have also esterified with several anhydrides to give a free acid which we hope will,once again, create a tighter chiral complex and thus lead to greater asymmetric induction. (see

scheme 2).


3/4

R =

COOH

CO2

CO 2 H

CO 2

or

NaBH 4

"ComplexNaBH 4NOH

N

OMe

NOR

N

OMe

Scheme 2. Quinine - sodium borohydride complex and modified quinine.

And lastly, we have synthesized the crotyl ester of quinine and are exploring its use in the Diels-Alder reaction. Here quinine is being used as a chiral auxiliary rather than a catalyst. Much of

the early work on this project is focusing on finding an appropriate diene and conditions to effecta thermal reaction. Later we hope to look at a Lewis acid catalyzed DA reaction as well. (SeeScheme 3).

N

O

O

N

OMe

RO CO 2

+

RO

Scheme 3. Quinine as an ancillary agent in the chiral Diels-Alder reaction


4/4

All of these projects have generated some preliminary results but much remains to be done.These projects involve performing reactions, including purification and complete spectralcharacterization. You will be expected to research reaction conditions and background material inthe library (or with an on-line database) and to run and maintain a research laboratory includingany purification of reagents. Expertise in spectral methods and in handling (sometimes) complex

mixtures will be part of your legacy.

General References

The Quest for Quinine, T.S. Kaufman adn E.A. Ruveda, Angewandte Chemie Int. Ed, 2005 ,44, 845-885

Dolling, Ulf-H; Davis, Paul; Grabowski, Edward J. J. JACS. 1984, 106, 446. Lygo, Barry; Andrews, Benjamin I. Acc. Chem. Res. 2004 , 37, 518-525.ODonnel, M. J. Acc. Chem. Res. 2004, 37, 506-517.Jah, S.C.; Joshi, N.N. Tetrahedron: Asymmetry, 2001 , 12.

Hanson, Kelsey. Sr. Thesis, University of Puget Sound, 2004 .Gang, Zhao; Jian-Bing, Hu. Chinese Journal of Chemistry, 2003 , 21, 819-823.Aldriciica Acta, M.J. ODonnel, 2001 , 44, 3-15.

Documents

Research Statement 05