Alex Radosevich - Associate Professor of Chemistry at MIT
Alexander Radosevich is originally from Waukegan, IL. He received his B.S. degree from the University of Notre Dame (2002) where he pursued computational chemistry research with Prof. Olaf Wiest. He obtained his Ph.D. degree from the University of California at Berkeley (2007) with Prof. F. Dean Toste in the area of organic reaction development and oxometal catalysis. After completing an NIH postdoctoral fellowship at MIT with Prof. Daniel G. Nocera, he joined the faculty at the Pennsylvania State University in 2010. In August of 2016, he returned to the Department of Chemistry at MIT as an Associate Professor. He works at the interface of inorganic and organic chemistry to design new chemical reactions. In particular, his interests concern the invention of compositionally new classes of molecular catalysts based on inexpensive and earth-abundant elements of the p-block. This research explores the connection between molecular structure and reactivity in an effort to discover new efficient and sustainable approaches to chemical synthesis. He has been the recipient of the Amgen Young Investigator’s Award (2015), a Sloan Research Fellowship (2014), and an NSF CAREER Award (2014).
Subha Raghavan - Executive Director in Discovery Chemistry at Merck
Dr. Subharekha Raghavan joined Merck Research Laboratories in 1995 as a Senior Research Chemist after receiving her Ph.D. at Princeton University and completing post-doctoral studies at Columbia University. An accomplished drug hunter she has worked in several therapeutic areas including Diabetes, Infectious Disease, Cardiovascular Disease and Neuroscience. Her scientific contributions at Merck have spanned all phases of drug discovery from target validation through early clinical development. She has led several cross-functional program teams and identified multiple high-quality molecules that have advanced to the clinic.
Subha is currently an Executive Director in Discovery Chemistry, at Kenilworth, New Jersey, leading the High Throughput Experimentation and Lead Discovery capabilities group. Her team builds innovative chemistry platforms and workflows across all modalities. The team applies these capabilities to impact Merck’s Discovery programs by enabling rapid access to the best molecules through data rich high-throughput experimentation and design.
Matthew Mailloux (he/him) - Boston University - Beeler Group
Photochemical Ring Expansion of Pyridines: Development and Applications in Molecular Editing
In this presentation, we recount the discovery and development of the photochemical dearomative ring expansion of pyridines – a reaction which permits unprecedented access to functionalized azepines from abundant feedstocks. We also cover our ongoing research in the molecular editing of natural products and active pharmaceutical ingredients through late stage ring expansion.
John Mark Awad (he/him) - University of Massachusetts Boston - Zhang Group
GBB reaction-initiated pot-economy synthesis of two new heterocyclic scaffolds
Three-component Groebke–Blackburn–Bienaymé (GBB) reaction followed by the Pictet-Spengler (PS) or Diels-Alder (DA) reactions is developed. Imidazo[1,2-a]pyridines generated from Yb(OTf)3-catalized GBB reaction of 2-aminopyridines, aldehydes and isocyanides are used for sequential one-pot PS reaction with aldehydes or for intramolecular DA reaction to afford two highly condensed heterocyclic scaffolds. The combination of multicomponent reactions with cycloaddition reactions has good pot, atom, and step economy (PASE) and green chemistry advantages of reducing waste generated from intermediate purification.
Ryan P. Conger (he/him) - Boston College - Hoveyda Group
A Divergent Synthesis Strategy for Navigating Chemical Space
A key factor in drug discovery is that the three-dimensional space corresponding to a particular class of lead compounds can be properly and expeditiously navigated. We have designed a strategy for efficient, programmable, and divergent synthesis of bridged bicyclic amine scaffolds by which the spatial relationship between three alterable moieties can be explored. The heart of the approach is a catalytic process that delivers multifunctional unprotected -secondary NH2-amines which contain a versatile stereochemically defined trisubstituted alkenyl boronate. Thus, each core molecule can be modified through a variety of routes to afford analogs that possess an assortment of stereochemical, skeletal, and peripheral alterations.
Beverly Fu (she/her) - Harvard University - Balskus Group
Mechanistic studies of a skatole-forming glycyl radical enzyme
Gut microbial decarboxylation of amino acid-derived arylacetates is a challenging enzymatic transformation with strong repercussions on host physiology. For instance, indoleacetate decarboxylase from the microbe Olsenella uli (Ou IAD) is responsible for the non-oxidative radical decarboxylation of indole-3-acetate into skatole, a disease-associated metabolite produced in the guts of swine and ruminants. IAD is part of the larger glycyl radical enzyme (GRE) family, which uses a protein-based glycyl radical to catalyze diverse C–C, C–O, C–N, and C–S bond cleavage and formation reactions. In addition, GREs are prominent members of the anaerobic gut environment. Here, we mechanistically characterize Ou IAD to determine if IAD uses a Kolbe-type decarboxylation reaction involving a 1-electron oxidation of the carboxylate or a hydrogen atom transfer from the α-carbon to generate a substrate-based radical. Retention of activity with a point variant (H514A), kinetic isotope effect of 1.1–1.7 with deuterated substrate, incorporation of two deuteria into product in D2O, and computational modeling are consistent with a key hydrogen atom abstraction step. This finding expands the types of radical mechanisms employed by GRE decarboxylases and non-oxidative decarboxylases, more broadly. Elucidation of the mechanistic underpinnings of IAD decarboxylation can inform downstream therapeutic development.
Ramachandra Reddy Donthiri (he/him) - Northeastern University - O'Doherty Group
De Novo Asymmetric Approach to the Phomopsolidone Natural Products: Via regio- and stereo-selective iterative polyene dihydroxylations.
Over the years we have had success with the regioselective application of the Sharpless asymmetric dihydroxylation of polyenoates (e.g., I/II) for the synthesis of polyketide natural products,1 as well as carbohydrates.2 Key to the success of this approach is the understanding that the high regioselectivity of the Sharpless asymmetric dihydroxylation of di- and tri-enoates redounds from a combination of electronic and steric effects. The regioselectivity for the initial dihydroxylation can be viewed as resulting from the preference for oxidizing the more electron rich double bond.3 The selectivity in the second dihydroxylation is governed by a substrate/reagent mis-match in facial selectivity. In an effort to further explore the selectivity principles that govern this reactivity, we set out to explore the potential for the synthesis of the Phomopsolidone class of natural products4 from the iterative bis-asymmetric dihydroxylation of Z,E,E,E-tetraenoate III. Retrosynthetically this approach can be seen as accessing all four of the Phomopsolidones (A-D) via butanolide V, which in turn could be prepared from a two-step bis-dihydroxylation and protection. Alternatively, butanolide V can be prepared in a step-wise fashion from dienoate IV, which in turn can be prepared from a regioselective dihydroxylation of trienoate II. Our bifurcated efforts to prepare butanolide V and its use in the synthesis of the Phomopsolidones will be discussed.
Daniel Polyak (he/him) - Brandeis University - Krauss Group
Homoallylboration and Cyclopropylcarbinylation of Aldehydes
Cyclopropanated allylboration reagents participate in homoallylation reactions of aliphatic and aromatic aldehydes generating allylic substituted alkenes that are difficult to produce by other methods. In this study, we synthesized cyclopropylcarbinylboronates with a variety of aliphatic and aromatic α- and γ-substituents and explored their reactivity in homoallylation.[1g] Aromatic substituents in either position alter the course of the reaction leading to boronate rearrangement or cyclopropylcarbinylation. The latter was further explored by DFT computation, which suggested a novel mechanism involving ring opening and reclosure, which is supported by experimental evidence.[1f]
Corshai Williams (she/her) - MIT - Jamison Group
Methods for the Continuous Synthesis of Pharmaceuticals
Continuous flow methods provide many opportunities for innovation in organic synthesis. For example, the advantages that microreactors offer in continuous flow systems relative to batch synthesis include reduced reaction times, enhanced temperature control, and generation of small quantities of reactive intermediates. In this lecture we will discuss some of our investigations on the photochemical synthesis of pharmaceuticals using continuous flow technology.
Chuchu Guo (she/her) - MIT - Nolan Group
Heavy-Metal Trojan Horse: Enterobactin-Directed Delivery of Platinum(IV) Prodrugs to Escherichia coli
Although cisplatin is one of the most widely used anticancer agents, it was discovered by its ability to inhibit cell division and induce filamentous morphology in Escherichia coli. In this study, we demonstrate that conjugation of a cisplatin-derived Pt(IV) prodrug to a siderophore (microbial iron chelator) repurposes cisplatin as an antibiotic that specifically targets Gram-negative bacteria via designated siderophore uptake machinery. More specifically, we designed and synthesized a conjugate of the native siderophore enterobactin (Ent) and the Pt(IV) prodrug (L-Ent-Pt(IV)). We demonstrated that L-Ent mediates its delivery into E. coli cytoplasm via Ent transport machinery, where reduction of the Pt(IV) prodrug releases the cisplatin warhead, causing growth inhibition and filamentation of E. coli K12 and the uropathogenic isolate E. coli CFT073. Substitution of L-Ent with its enantiomer affords the D-Ent-Pt(IV) conjugate (D-EP), which displays enhanced antibacterial activity compared to L-EP, presumably because D-Ent is not a substrate for Ent esterases and thus Fe cannot be released from this conjugate for bacterial metabolic use. Pt uptake assays showed that Ent conjugation increases Pt uptake in E. coli treated with L/D-Ent-Pt(IV) as compared to cisplatin treatment, and reduces Pt uptake in human embryonic kidney cells (HEK293T). Overall, this work demonstrates that the siderophore modification can repurpose a Pt anticancer agent as a targeted antibiotic, providing a design strategy for heavy-metal “Trojan-horse” antibiotics and motivating further efforts on leveraging siderophore-directed delivery strategy for repurposing a broad scope of non-antibiotic toxic agents into targeted antibacterials.
Hojong Yoon (he/him) - Broad Institute / Dana-Farber - Fischer and Gray Labs
Small-molecule-induced polymerization triggers degradation of BCL6
Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets, but a substantial subset of proteins are resistant to targeted degradation using existing approaches. Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the BTB domain of the oncogenic transcription factor BCL6 and leads to the proteasomal degradation of BCL6. We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand–protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology.