Bruce Ganem

Strategies for Innovation in Multicomponent Reaction Design

By generating structural complexity in a single step from three or more reactants, multicomponent reactions (MCRs) make it possible to synthesize target compounds with greater efficiency and atom economy. The history of such reactions can be traced to the mid-19th century when Strecker first produced alpha-aminonitriles from the condensation of aldehydes with ammonia and hydrogen cyanide. Recently, academic chemists have renewed their interest in MCRs. In part, the pharmaceutical industry has fueled this resurgence because of the growing need to assemble libraries of structurally complex substances for evaluation as lead compounds in drug discovery and development programs. The application of MCRs to that increasingly important objective remains limited by the relatively small number of such reactions that can be broadly applied to prepare biologically relevant or natural-product-like molecular frameworks. We were interested in applying logic-based approaches, such as our single reactant replacement (SRR) approach, as a way both to improve known MCRs and to design new multiple-component routes to bioactive structures. This Account provides several examples that illustrate the use of SRR with known MCRs as starting points for synthetic innovation in this area. As part of our working hypothesis, we initially explored strategies for engineering improvements into known MCRs, either by increasing the dimensionality--that is, changing an n-component to an (n + 1)-component reaction--or broadening the scope of useful input structures, or both. By exhaustively applying retrosynthetic analysis to the cognate MCR to identify and exploit alternative entry points into the overall reaction manifold, we have devised several such re-engineered MCRs. Serendipitous findings have also augmented the yield of useful developments from our logic-inspired approach. In some cases, we have identified surprising links between different compound families that provide useful new entry points for chemical library synthesis. In other cases, the same re-engineering logic made it possible (sometimes in unexpected ways) to transform certain nonelementary two-component reactions into higher order MCRs. While logic may also inspire the search for new MCRs, the design process requires added chemical creativity, which cannot be reduced to a simple formula. The long-term goal of our research is to expand the useful repertoire of such reactions, which are important as complexity-generating tools in both combinatorial and diversity-oriented synthesis.

An exceptionally mild deprotection of phthalimides

Abstract Phthalimides are converted to primary amines in an efficient, two-stage, one-flask operation using NaBH4/2-propanol, then acetic acid.

Detection of oligonucleotide duplex forms by ion-spray mass spectrometry

Abstract Three representative examples of duplex DNA, each eight base pairs in lenght, have been examined by ion-spray mass spectrometry. The ability to detect base-paired duplex ions in each case further indicates the use of this technique for monotoring noncovalent instructions in biological systems.

Efficient preparation of enantiomerically pure cyclic aminoalditols, total synthesis of 1-deoxynojirimycin and 1-deoxymannojirimycyn

Abstract Expeditious new syntheses of the title compounds, which are potent glycosidase inhibitors, have been developed based on a high-yield, ring-forming aminomecuration.

Studies on heme binding in myoglobin, hemoglobin, and cytochrome c by ion spray mass spectrometry

The ion spray mass spectra of three representative heme-containing proteins were studied, with an emphasis on results obtained under neutral (pH 7) aqueous conditions. The noncovalently bound heme in myoglobin and hemoglobin may be readily distinguished from the covalently bound heme prosthetic group attached to cytochrome c by using collisioninduced dissociation in the free-jet expansion region of the mass spectrometer as well as in the collision quadrupole with premass selection. The charge state of iron in the expelled heme from myoglobin and hemoglobin appears to be 3+ but 2f for heme expelled from cytochrome c.

A NEW APPROACH TO PORPHOBILINOGEN AND ITS ANALOGS

Abstract The van Leusen pyrrole synthesis was used to assemble three potential precursors of porphobilinogen, one of which was converted to the natural product using a new method for the direct alkylation of β-hydroxymethylpyrroles.

Epoxides as alkene protecting groups. A mild and efficient deoxygenation

Abstract Dimethyl diazomalonate smoothly deoxygenates epoxides to alkenes with rhodium(II) acetate catalysis.

New insight into the catalytic mechanism of chorismate mutases from structural studies

Chorismate mutase catalyzes the rearrangement of chorismic acid to prephenic acid, which is the first committed step in the biosynthesis of aromatic amino acids. Its catalytic mechanism has been much studied, but is poorly understood. Recent structural information on enzymes from two species, and on an antibody that catalyzes the same reaction, has shed new light on this topic.

Rapid and efficient reduction of aliphatic nitro compounds to amines

Abstract The combination of NaBH4 with catalytic quantities of NiCl2 smoothly reduces aliphatic nitro compounds to amines in methanol; Ni2B formed in situ is the active catalyst.

Catalyzed insertion reactions of substituted α-diazoesters. A new synthesis of cis-enoates☆

Abstract The decomposition of α-diazoesters is notably catalyst-dependent; with rhodium (II) carboxylates a stereoselective insertion reaction leads to the title structures in high yield.