Past Research Area

Our major research interests are in the area of organometallic chemistry with the emphasis on developing and applying new uses of these reagents to organic synthetic chemistry. A particular interest is the development of new methods for introducing chirality into molecules. The chirality of a molecule often plays a key role in the biological activity of the molecule. For example, there are cases where as little as 1% of the “wrong” enantiomer will block biological response to the “correct” enantiomer.

Asymmetric Reductions:

We have found that chiral trialkyl-boranes are highly selective reducing agents. These chiral reagents have been used to reduce a variety of ketones to alcohols of high optical purity. For example, alkynyl ketones are reduced by the reagent to propargyl alcohols with enantiomeric purities approaching 100%.

Conformational Analysis:

We are also interested in how the shape of a molecule effects its biological activity. We are particularly interested in simple sugars and carbohydrates related to the anti-coagulant compound heparin. Heparin also shows a number of other biological properties including involvement in the cancer problem. Heparin is composed of alternating sulfated glucosamine (A-Ring) and iduronic acid (I-Ring) sugars. The iduronic acid is a particularly interesting section since the ring is conformationally flexible. Contrary to expectations, the most stable conformation places most of the groups in the axial position.

We are investigating the factors which control this very unusual equilibrium. This work involves synthesis of the sugars, and NMR and molecular modeling analysis of the conformations. We plan to synthesize small models of the heparin molecule and study how these bind to biologically important molecules. Ultimately this should lead to a better understanding of how heparin works and to the development of therapeutic agents.

Synthesis of Heparin:

The synthesis of heparin requires a ready source of iduronic acid. This material is not comercially available and literature methods for its synthesis are unreliable or provide low yields. We are currently working on a synthesis starting from readily available diacetone glucose. A key step is an asymmetric reduction using a chiral trialkylborane. The goal is to produce large quantities of an iduronic acid which is suitably protected for further incorporation into heparin.

Selected Publications

Midland, M.M.; Morell, L.A. “Enantio-selective Reductions,” in Houben-Weyl Methods of Organic Chemistry. Stereoselective Synthesis; Helmchen, G.; Hoffmann, R.W.; Mulzer, J.; Schaumann, E., eds., Verlog, E21d, pp. 4049-4066 (1995).

Midland, M.M.; Morell, L.A. “Formation of C-H Bonds by Reduction of Carbonyl Groups with C-H Hydride Donors. Boron Reagents,” in Houben-Weyl Methods of Organic Chemistry. Stereoselective Synthesis; Helmchen, G.; Hoffmann, R.W.; Mulzer, J.; Schaumann, E., eds., Verlog, E21d, pp. 4082-4098 (1995).

Tobiason, F.L.; Kelley, S.S.; Midland, M.M.; Hemingway, R.W. “Temperature Depend-ence of (+)-Catechin Pyran Ring Proton Coupling Constants as Measured by NMR and Modeled Using GMMX Search Methodology,” Tetrahedron Lett. 1997, 38, 985-988.

Midland, M.M. “An Ab Initio Investigation of the Transition State for Asymmetric Synthesis with Boronic Esters,” J. Org. Chem. 1998, 63, 914-915.