Fields: Organic, Bioorganic
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Organic Chemistry is ...
"The study of the world’s best element, carbon, and how it interacts with its best friends, hydrogen, nitrogen and the halogens and other compounds that have carbon."
"The study of our extremely versatile friend carbon and its many adventures in displaying the unique and divine in the universe through order, geometry and in forming a myriad of new possibilities."
"Extremely colorful with a wide assortment of ingredients containing carbon, oxygen, and hydrogen (nitrogen too!) and many different recipes that will make desired goods."
from the final exam for Chem 221 (spring 2007)
Phosphates are a ubiquitous functional group within biological systems that are incorporated in critical molecules such as DNA, RNA, proteins and small molecule messengers such as ATP and inositol phosphates. The development of new and more efficient methods for forming phosphorylated compounds can impact the treatment of diseases where phosphorylation is aberrant (such as cancer), initiate the use of phosphorylated small molecules in disease treatment and answer fundamental questions about the nature of this chemical structure.
Research in my group focuses on the development of new methods to phosphorylate alcohols utilizing both phosphorous (III) and phosphorous (V) reagents. Current limitations in these reactions include non-catalyzed pathways, poor protecting groups on phosphorous and harsh reaction conditions.
Typically, phosphorous (III) reactions require an excess of tetrazole (the catalyst). This is most likely the result of deactivation of the catalyst from the amine by-product formed during the reaction. We hypothesized that addition of amine scavengers should sequester the by-product and allow the catalyst to regenerate.
We have successfully demonstrated that addition of isocyante additives facilitates efficient turnover of the tetrazole catalyst. This process was validated with primary, secondary and tertiary alcohols as well as a variety of phosphoramidites (see: P.B. Brady, E.M. Morris, O.S. Fenton and B.R. Sculimbrene Tetrahedron Lett. 2009, 50, 975-978.)
Many phosphorous (v) reagents are unreactive towards alcohols unless the alcohol is first deprotonated. We hypothesized that the use of catalysts could overcome this lower reactivity and provide a robust method to phosphorylate alcohols. Pyrophosphates are an ideal P(V) phosphorylating agent due to the multiple methods available for their synthesis, allowing the incorporation of multiple protecting group.
We have successfully demonstrated that Lewis acids are efficient catalysts for the phosphorylation of primary and secondary alcohols with pyrophosphates. This reaction was validated by the phosphorylation of ten uniquely functionalized alcohols and five different pyrophosphates (see: O.S. Fenton, E.E. Allen. K.P. Pedretty, S.D. Till, J.E. Todaro and B.R. Sculimbrene Tetrahedron, 2012, 68, 9023-9028.) The method was amendable for the synthesis of phosphates using benzyl, methyl, ethyl, allyl and o-nitrobenzyl protecting groups.
The Lewis acid catalyzed phosphorylation can also be used to selectively mono-phosphorylate diols. Thirteen diols of varying chain lengths and substituents were examined to study the factors that influence selectivity. It was discovered that 2-alkyl-2-amino-1,3-propanediols can be selectively mono-phosphorylated in up to 97% yield. (see: K.A. Coppola, J.W. Testa, E.E. Allen and B.R. Sculimbrene Tetrahedron Lett. 2014, 55, 4203-4206. This structural core is mono-phosphorylated in numerous immunomodulating compounds including the FDA-approved drug, FTY720.
Our goal is to generate a convergent synthetic approach to alkene-peptide isosteres. Isosteres are molecules that mimic the size and geometry of the targeted molecule but lack an electronic component (such as a H-Bond donor or acceptor). A useful isostere of the amide bond is a trans-alkene. In emulating the convergent method in which peptides are generated in the lab and in nature, our retrosynthesis would involve formation of the alkene carbon-carbon bond. As a powerful reaction for alkene synthesis, olefin cross-metathesis was chosen to investigate the formation of peptide isosteres.
Our initial target is the peptide sequence D-Ala-D-Ala, (present on bacterial cell walls). This peptide sequence is implicated in the recognition of Vancomycin (a potent antibiotic) to the bacteria. By replacing the amide bond with a trans-olefin, information about the nature of this interaction can be probed by asking, "How much is an H-bond worth?"
(16) ""Synthesis of alpha-chiral-beta,gamma-unsaturated carboxylic acid derivatives using chiral auxiliaries" K.E. Poremba, V.A. Lee, B.R. Sculimbrene Tetrahedron, 2014, 70, 5463-5467.
(15) "Selelctive Phosphorylation of Diols with a Lewis Acid Catalyst" K.A. Coppola, J.W. Testa, E.E. Allen, and B.R. Sculimbrene Tetrahedron Lett. 2014, 55, 4203-4206.
(14) "Catalytic Lewis Acid Phosphorlyation with Pyrophosphates" O.S. Fenton, E.E. Allen, K.P. Pedretty, S.D. Till, J.E. Todaro and B.R. Sculimbrene Tetrahedron, 2012, 68, 9023-9028.
(13) "A Wet-lab Approach to Stereochemistry Using 31P NMR Spectroscopy" O.S. Fenton and B.R. Sculimbrene J. Chem. Ed. 2011, 88, 662-664 .
(12) "Synthesis of a D-Ala-D-Ala Peptide Isostere via Olefin Cross-metathesis and Evaluation of Vancomycin Binding" R.K. Quinn, A.L. Cianci, J.A. Beaudoin and B.R. Sculimbrene Bioorg. Med. Chem. Lett. 2010, 20, 4382-4385.
(11) "Efficient Catalyst Turnover in the Phosphitylation of Alcohols with Phosphoramidites" P.B. Brady, E.M. Morris, O.S. Fenton and B.R. Sculimbrene Tetrahedron Lett., 2009, 50, 975-978.
(10) "Lanthanide-Binding Tags with Unnatural Amino Acids: Sensitizing Tb(III) and Eu(III) Luminescnece at Longer Wavelengths." A.M. Reynolds, B.R. Sculimbrene, and B. Imperiali Bioconjugate Chem. 2008, 19, 588-591.
(9) "Lanthanide-Binding Tags as Luminescent Probes for Studying Proteins" B.R. Sculimbrene and B. Imperiali J. Am. Chem. Soc. 2006, 128, 7346-7352.
(8) "Streamlined synthesis of Phosphatidylinositol (PI), PI3P, PI3,5P2 , and Deoxygenated Analogues as Potential Biological Probes" Y.J. Xu, B.R. Sculimbrene, and S.J. Miller J. Org. Chem. 2006, 71, 4919-4928.
(7) "Rapid Combinatorial Screening of Peptide Libraries for the Selection of Lanthanide-Binding Tags (LBTs)" L.J. Martin, B.R. Sculimbrene, M. Nitz, and B. Imperiali QCS Comb. Sci. 2005, 24, 1149-1157.
(6) "Desymmetization of Glycerol Derivatives with Peptide-based Acylation Catalysts" C.A. Lewis, B.R. Sculimbrene, Y.J. Xu, and S.J. Miller Org. Lett. 2005, 7, 3021-3023.
(5) "Asymmetric Synthesis of Phosphatidyl-3-Phosphates with Saturated and Unsaturated Side Chains through Catalytic Asymmetric Phosphorylation." B.R. Sculimbrene, Y.J. Xu and S.J. Miller J. Am. Chem. Soc. 2004, 126, 13182-13183.
(4) "Nonenzymatic Peptide-based Catalytic Asymmetric Phosphorylation of Inositol Derviatives." B.R. Sculimbrene, A.J, Morgan and S.J. Miller Chem. Commun. 2003, 15, 1781-1785.
(3) "Enantiodivergence in Small-Molecule Catalysis of Asymmetric Phosphorylation: Concise Total Syntheses of the Enantiomeric D-myo-Inositol-1-phosphate and D-myo-Inositol-3-phosphate." B.R. Sculimbrene, A.J. Morgan and S.J. Miller J. Am. Chem. Soc. 2002, 124, 11653-11656.
(2) "Discovery of a Catalytic Asymmetric Phosphorylation through Selection of a Minimal Kinase Mimic." B.R. Sculimbrene and S.J. Miller J. Am. Chem. Soc. 2001, 123, 10125-10126.
(1) "Silatranyl-Nucleosides: Transition State Analogues for Phosphoryl Transfer Reactions" B.R. Sculimbrene, R.E. Decanio, B.W. Peterson, E.E. Muntel, and E.E. Fenlon Tetrahedron Lett. , 2001, 30, 4979-4982.
(1) "Peptide as Kinase Mimic Catalysts for Asymmetric Phosphorylation in Synthesis of Phosphorylated Inositols and Cyclo-alkanols" B.R. Sculimbrene, S.J. Miller and A.J. Morgan PCT Int. Appl. WO 2003004141 A3, 2003.
(1) "Catalytic Asymmetric Phosphorylation: Concise Total Syntheses of Inositol Phosphates" B.R. Sculimbrene 2004.
Chemistry 221 - Organic Chemistry I
A study of organic compounds from the points of view of the chemistry of the functional groups, modern structural theory and reaction mechanisms. The chemistry of aliphatic hydrocarbons, alkenes, dienes and alkyl haildes is introduced in a discovery mode. Substitution, addition and elimination mechanisms are studied in detail. Emphasis is placed on stereochemistry. One four-hour "discovery" laboratory session per week is included. Students learn various separation, purification and identification (chemical and spectroscopic) of organic compounds in the laboratory. There is an emphasis on one-step synthetic conversions which introduce the reactions studied in the lecture course.
Prerequisite: Chem 181
Chemistry 222 - Organic Chemistry II
A continuation of Chemistry 221. Aromatic compounds, alcohols, ethers, aldehydes, ketones, amines, carboxylic acids and their deriviatives are studies. Aromatic substitution, acyl transfer and carbonyl condensation reactions are developed. The mechanistic implications and synthetic application of these organic reactions are evaluated. One four-hour "discovery" laboratory session per week is included. Microscale synthetic techniques are included.
Prerequisite: Chem 221
Chemistry 301 - Biochemistry
A detailed study of the chemistry of biological molecules, with a focus on the structure of biological macromolecules and the chemical mechanism of biochemical transformations. Topics may include the structure and synthesis of proteins, nucleic acids, carbohydrates and lipids, enzymatic catalysis, biological thermodynamics, glycolysis and gluconeogenesis, the citric acid cycle, fatty acid oxidation, oxidative phosphorylation, and metabolic regulation. A strong background in thermodynamics and organic chemistry is highly recommended. This course may serve as a prerequisite for Biology 302. Students may not count both Biology 301 and Chemistry 301 for credit.
Prerequisites: Chemistry 222 and 231
Chemistry 305 - Mechanistic Organic Chemistry
There are critical and at times subtle factors that influence organic reactions. These factors will be illustrated through specific case studies. The case studies will demonstrate how experimental data is used to develop mechanistic knowledge about a reaction. The course will aim to develop skills for thinking critically and logically about the mechanism of organic reactions.
Prerequisite: Chem 222