Matthias Brewer

Synthetic Organic Chemistry

Assistant Professor

Matthias.Brewer@uvm.edu
phone: 802-656-1042
office: Cook Rm A335

Research in our group focuses on the development of new organic reactions and applications of these reactions to the synthesis of complex organic molecules. The overarching objective of our research is to develop synthetic methods that facilitate the efficient preparation of complex nitrogen or oxygen-containing heterocyclic compounds from trivial starting materials. Ultimately, we will apply our synthetic methods to the synthesis of both natural products and non-natural medicinal agents.

Descriptions of three of our ongoing research interests:

A Ring Fragmentation Approach to Tethered Aldehyde Ynoates:

We have discovered that cyclic g-silyloxy-b-hydroxy-a-diazoesters (e.g. 1, Scheme 1) undergo efficient rupture of the C_b-C_g bond when treated with Lewis acids to provide tethered aldehyde ynoate products in excellent yield (e.g. 2, Scheme 1). This discovery is important because there are few synthetically-useful ring fragmentation reactions known, and ring fragmentations can unmask latent functional groups under chemoselective reaction conditions to provide functionalized synthetic intermediates that are otherwise difficult to prepare. Tethered aldehyde ynoates are versatile synthetic intermediates and this functional group combination is unique to the fragmentation reaction we discovered. We are currently exploring the use of these bi-functional compounds as precursors to structurally complex heterocyclic products.

The Reaction of Sulfonium Salts with Hydrazones: New Synthetic Routes to Nitrogen-Containing Heterocycles:

We recently discovered that the hydrazone functional group reacts with chlorodimethylsulfonium chloride to give a variety of products depending on the reaction conditions and the hydrazone substitution pattern. For example, N-unsubstituted hydrazones easily and cleanly react with chlorodimethylsulfonium chloride to provide alkyl chlorides in high yield (Scheme 1). Changing the reaction conditions to include two equivalents of Et₃N inhibits alkyl chloride formation and instead provides diazo compounds in high yield. The dehydrogenation of hydrazones to provide diazo compounds is well precedented, but has most often been achieved by treatment with toxic and environmentally deleterious heavy metals (e.g. mercury(II) oxide, lead(IV) acetate). Our method represents a significantly more green route to diazo compounds under mild conditions at low temperature (-78 °C).

The reaction of sulfonium ions with hydrazones is providing us new ways to access a variety of other reactive intermediates as well, and we are studying these reactive intermediates for their ability to participate in unprecedented transformations. This research will provide new methods to convert trivial starting materials into structurally-complex polycyclic heterocycles in a single transformation. From a synthetic chemistry standpoint, these transformations are important because they provide new carbon-carbon bonds under mildly oxidative conditions, while at the same time providing a large increase in a system's molecular complexity.

Carbon to Oxygen Rearrangements: Methodology for the Synthesis of Oxygen-Containing Heterocycles.

We are also exploring the use of electron deficient oxygen species to initiate polar rearrangements to oxygen. Currently this reactivity profile is limited to the use of peroxides (Hock rearrangement; Scheme 2; LG = OH), peroxyesters (Criegee rearrangement; LG = OCOR) and peracids (Baeyer-Villiger rearrangement). Although the Hock and Criegee reactions are potentially powerful transformations, they have found limited use because they require peroxide starting materials. The goal of our research in this area is to develop a rearrangement similar to the peroxide rearrangements, but applicable to tertiary alcohols and allylic or benzylic secondary alcohols. We are currently investigating the use of alternative electron-deficient oxygen sources as polar rearrangement initiators (Scheme 2; LG ≠ OR).

We predict that the reaction intermediates in these transformations will be vinylic oxocarbenium ions (e.g. 3, Scheme 3), and use of these reactive intermediates in inter- and intra-molecular tandem reactions will be investigated. This methodology will be directly applicable to the synthesis of a wide variety of natural products and non-natural oxygen-containing heterocycles.

Selected Publications

Javed, M.I., Brewer, M. "Diphenyldiazomethane." Org. Synth. 2008, 85, 189-195.

Draghici, C., Brewer, M."Lewis Acid Promoted Carbon-Carbon Bond Cleavage of -Silyloxy--hydroxy--diazoesters." J. Am. Chem. Soc. 2008, 130 3766-7.

Javed, M.I., Brewer, M. "Diazo Preparation via Dehydrogenation of Hydrazones with 'Activated' DMSO." Org. Lett. 2007, 9, 1789-92.

Brewer, M. "Conversion of hydrazones to alkyl chlorides under Swern oxidation conditions." Tetrahedron Lett. 2006, 47, 7731-3.

Haug, B.E., Brewer, M., Rich, D.H. "Facile Degradative Lactonization of Gln-Arg and Gln-Phe Hydroxyethylene Dipeptide Derivatives." J. Pept. Res., 2005, 65, 77-83.

Brewer, M., James, C.A., Rich, D.H. "Synthesis of a Tripeptide Derivative Containing the Phe-Arg Hydroxyethylene Dipeptide Isostere." Org. Lett., 2004, 6, 4779.

Oost, T., Sukonpan, C., Brewer, M., Goodnough, M., Tepp, W., Johnson, E.A., Rich, D.H. "Design and Synthesis of Substrate-Based Inhibitors of Botulinum Neurotoxin Type B Metalloprotease" Biopolymers, 2003, 71, 602-19.

Brewer, M., Oost, T., Sukonpan, C., Pereckas, M., Rich, D.H. "Sequencing Hydroxyethylamine Containing Peptides via Edman Degradation." Org. Lett., 2002, 4, 3469-72.

Brewer, M., Rich, D.H. "Synthesis of a Tripeptide Derivative Containing the Phe-Arg Hydroxyethylene Dipeptide Isostere." Org. Lett., 2001, 3, 945-8.