2:00pm Virtual Poster Session (Even Numbered Presenters)
3:00 Virtual Poster Session (Odd Numbered Presenters)
4:00-4:45 Pharmaceutical Career Panel and Networking
Randolph Escobar, Senior Scientist, Oncology Chemistry, AstraZeneca
Martin Himmelbauer, Scientist II, Medicinal Chemistry, Biogen
Haibo Liu, Principal Scientist, Medicinal Chemistry, Bristol Myers Squibb
Elsie Yu, Sr. Scientist, Medicinal Chemistry, Merck & Co., Inc.
Robert Ziegler, Senior Scientist, Oncology Chemistry, AstraZeneca
8:30am Career Seminar: Developing an Effective Job Search Strategy
Lauren Celano, Founder and CEO, Propel Careers
9:00 Welcome Remarks
Abhishek Chatterjee, Associate Professor of Chemistry, Boston College
9:05 Morning Chair's Remarks
Daniel Smaltz, Senior Principal Scientist, Medicinal Chemistry, Pfizer
9:10-9:30 Graduate Student/Postdoctoral Talk: "Broad-Scoped Enantioselective Transformation of Alkenes by Carbohydrate-Copper Sequential Catalysis"
Elton Kativhu (he/him), Graduate Student, Morken Group, Boston College
Abstract: Alkenes are attractive synthetic building blocks because of their diverse nature and low cost. While there are a number of synthetic reactions that operate on sterically or electronically biased alkenes in a regioselective and enantioselective fashion, there are few catalytic transformations developed that apply to terminal aliphatic olefins. In this seminar, our efforts to address this problem in an easily practicable fashion will be described. To develop practical processes, we have targeted inexpensive readily available catalysts and initiate the process with a carbohydrate-catalyzed alkene diboration. To transform the intermediate diboron, we considered copper-catalysts because of their ready availability and diverse reactivity. A central challenge in this respect is that the efficient coupling of alkyl boronic esters with copper catalysis suffers from sluggish transmetellation. We show that this problem can be overcome and describe an overall process that combines simple aliphatic terminal olefins with a variety of electrophiles under the influence of a carbohydrate and copper catalysts, thereby delivering a broad new array of chiral secondary alkylboronic esters directly from simple alkenes.
9:30-9:50 Graduate Student/Postdoctoral Talk: "Exploiting Short, Unstructured Peptides to Favor Selective Glycation"
Joey McEwen (he/him), Graduate Student, Scheck Group, Tufts University
Abstract: Glycation is a spontaneous, non-enzymatic modification that proceeds via the Maillard reaction and produces numerous stable adducts known collectively as advanced glycation end-products (AGEs). The methylglyoxal-derived hydroimidazolone isomer, MGH-1, is an abundant AGE and is associated with many diseases. As AGE formation occurs spontaneously and without an enzyme, it remains unknown why certain sites on distinct proteins become modified with specific AGEs. In this work, we use a combinatorial peptide library to determine the chemical features that favor MGH-1. When properly positioned, tyrosine was found to play an active mechanistic role that facilitates MGH-1 formation. This work offers new mechanistic insight connecting multiple AGEs, including MGH-1 and carboxyethylarginine (CEA), and reconciles the role of negative charge in influencing glycation outcomes.
9:50-10:10 Graduate Student/Postdoctoral Talk: "Enantioselective, multicomponent synthesis of homoallylic amines enabled by hydrogen bonding and dispersive interactions"
Elisabetta Ronchi (she/her), Graduate Student, Jacobsen Group, Harvard University
Abstract: Homoallylic amines are common intermediates in the synthesis of a wide variety of chiral, nitrogen-containing compounds, and imine allylation represents an attractiv approach for their construction. We have developed a one-pot, catalytic, enantioselective method for the preparation of homoallylic N-Boc amines directly from acetals, circumventing the requirement for imine synthesis in a separate step. The combination of chiral thioureas, trialkylsilyl triflates and N-Boc carbamate enables the in situ generation of iminium ions, which undergo nantioselective trapping by allylsilane nucleophiles with superb selectivity for iminium allylation over oxocarbenium allylation. Aromatic aldehyde derivatives possessing a variety of functionalities and substitution patterns were found to yield homoallylic amines in excellent levels of enantiomeric enrichment. The method can also be extended to a cyclohexenyl-derived acetal, showing promise for expanding the scope beyond aromatic substrates Experimental and computational investigations suggest an anchoring hydrogenbonding interaction between the aldiminium and the amide of the catalyst, and a key, enantiodifferentiating interaction between the R substituent of the iminium and the pyrenyl moiety of 1a. Both experimental and computational evidence indicate that this key interaction is primarily dispersive, highlighting the versatility of these catalytic scaffolds.
10:10-10:30 Graduate Student/Postdoctoral Talk: "Stereochemical Control Yields Mucin Mimetic Polymers"
Austin Kruger, Graduate Student, Kiessling Group, Massachusetts Institute of Technology
Abstract: Mucins are high molecular weight O-glycoproteins that constitute mucus barriers. These macromolecules adopt linear conformations that display multiple glycans —a key to their ability to block microbial virulence phenotypes. Glycosylation is critical to mucin function, yet the precise characteristics of mucins that give rise to their advantageous biological activities are unknown. To probe the basis of mucin activity, we sought to mimic the morphology, glycosylation, and virulence inhibition of mucin with a glycopolymer. We generated a series of polymers using ring-opening metathesis polymerization (ROMP), exploiting its functional group tolerance and its exquisite control over polymer structure. Depending on the catalyst, we generated substituted norbornene-derived polymers containing either cis or trans alkenes predominantly. A conformational analysis of the polymers based on allylic strain suggested that cis- rather than trans-poly(norbornene) glycopolymers would adopt linear structures that mimic mucins. Atomic force microscopy analysis of our polymers and natively purified Muc2, Muc5AC, and Muc5B mucins revealed that cispolymers adopt extended, mucin-like structure. The cis-polymers retained this structure in solution. Consistent with mucin’s linear morphology, cisglycopolymers were more potent binders of a bacterial virulence factor, cholera toxin, than were trans-polymers. Our findings highlight the importance of the polymer backbone in the design of mucin surrogates, and underscore the significance of the extended mucin backbone for inhibiting virulence.
10:45 Academic Keynote Seminar: "Shining light on the dark matter of natural products: Structure and function of colibactin"
Seth Herzon, Professor of Chemistry, Yale University
12:45pm Afternoon Chair’s Remarks
Alison Wendlandt, Assistant Professor, MIT
12:50-1:10 Graduate Student/Postdoctoral Talk: "Labeling Preferences of Diazirines used in Photoaffinity Labeling"
Alexander West (he/him), Graduate Student, Woo Group, Harvard University
Abstract: Diazirines are a common functional group used in photoaffinity labeling to visualize non-covalent interactions between small molecule probes and their protein binding partners. However, interpretation of these data is challenging without a full understanding of the reactivity and labeling preferences of the diazirine. We show that stereoelectronic substitution on the diazirine alters the reactive intermediates on photolysis and thus affects the protein binding partners that are ultimately captured. During photolysis, the diazirine isomerizes to a linear diazo intermediate en route to a reactive carbene. While aryl trifluoro diazirines primarily react through the carbene, we show that alkyl diazirines possess reactive diazo intermediates that react preferentially with acidic amino acids and regions of proteins in a pH-dependent manner in vitro. Using an array of 32 diazirine probes, we show that alkyl diazirine chemistry preferentially labels membrane proteins and binding sites with acidic residues in cells. These results suggest that alkyl diazirine chemistry is an effective tool poised for discovering binding interactions with membrane proteins in cells. We hope to expand this understanding of diazirine reactivity to better understand photoaffinity labeling results, and use it to develop new photochemistries with different amino acid labeling preferences.
1:10-1:30 Graduate Student/Postdoctoral Talk: "Direct Synthesis of Rare Sugar Isomers Through Site-Selective Epimerization Reactions"
Yong Wang (he/him), Postdoctoral Fellow, Wendlandt Group, Massachusetts Institute of Technology
Abstract: Rare sugars (e.g. D-allose, D-gulose, D-talose, L-glucose) feature prominently in glycosylated natural products and find important applications in the pharmaceutical, cosmetic and food industries. In contrast to abundant biomass-derived carbohydrates (e.g. (D)-glucose, (D)-xylose, (D)-galactose), rare monosaccharides typically cannot be isolated from their natural sources and must instead be prepared through multistep chemical or enzymatic syntheses, which often results in intractable thermodynamic product mixtures. In this regard, we present the preparation of rare sugar isomers directly from biomass carbohydrates through site-selective epimerization reactions. Mechanistic studies establish that these reactions proceed under kinetic control, through sequential hydrogen atom abstraction and hydrogen atom donation steps mediated by two distinct catalysts. This unconventional synthetic strategy provides concise and potentially expansive access to this important class of natural compounds.
1:30-1:50 Graduate Student/Postdoctoral Talk: "What properties make a macrocycle druglike?"
Lauren Viarengo-Baker (she/her), Graduate Student, Whitty Group, Boston University
Abstract: There is a growing interest in chemotypes that violate classic small molecule drug design criteria such as Lipinski’s Rule-of-5, for targeting challenging drug targets such as protein-protein interactions. One class of ‘beyond Rule-of-five’ (bRo5) compounds is macrocyclic compounds (MCs), which are structurally complex molecules that contain a ring of at least 11 atoms. However, discovery of new macrocyclic drugs is hampered by our limited understanding of how MCs achieve oral bioavailability. Using novel MC-specific feature descriptors which we devised, in conjunction with Principal Component Analysis, we show that the oral MC drugs are not distributed widely across MC structure-property space, but instead occupy three adjacent, compact regions. We identify 13 key properties that define the region of chemical space occupied by oral MC drugs, and differentiate them from the other synthetic MCs in our analysis. Several of these properties capture structural features unique to macrocycles that have not previously been considered as design criteria, but that can be considered by the chemist when designing de novo MCs. We show that designing compounds with respect to just these 13 properties results in MC structures that overlap with the regions of structure-property space where oral MC drugs are found, therefore enabling chemists to design MCs that structurally and physicochemical resemble oral MC drugs and clinical candidates.
1:50-2:10 Graduate Student/Postdoctoral Talk: "De novo asymmetric synthesis of diverse array of 2-aminosugars"
Nishikant Satam (he/him), Postdoctoral Fellow, O’Doherty Group, Northeastern University
Abstract: Aminosugars are omnipresent in nature and also plays an important role in a variety of biological activity natural products (e.g., the antibiotics Gentamicin and Purposamine, as well as, the insecticidal natural product Spinosyn A). Herein we describe a de novo asymmetric approach toward 2-aminosugars via a highly efficient isocyanate annulation reaction of the 2-hydroxypyranone product obtained from the Achmatowicz reaction of chiral furan alcohol. In addition to being high yielding, this new annulation reaction occurs with excellent stereoselectivity. A stereo-divergent acid catalyzed glycosylation and highly efficient one pot reductive amination was used to complete the synthesis of 2-aminosugars. This facile synthetic route was employed for the synthesis of -purpurosamine C in seven steps and overall 15% yield starting from achiral furan ketone.
2:30 Industrial Keynote Seminar: "Death in the Afternoon: Discovery of Bcl2 Family Protein Inhibitors for Hematological Malignancies"
Michelle Lamb, Associate Director, Chemistry, AstraZeneca
3:30 Closing Remarks
Jim Sheppeck, Principal Scientist, Chemistry, AstraZeneca