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Organic Chemistry in TPCB

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Facts:

fume-hood126 fume hoods

nmrspectrometer10 NMR spectrometers

mas-spectrometericon15 mass spectrometers

software10 major software packages

chemistry-journals1530 chemistry journal subscriptions

Organic Synthesis Plays a Central Role in TPCB Research

Synthetic organic chemistry enables the construction of biologically active molecules and provides powerful tools for chemical biology research. Organic synthesis plays a central role in TPCB research and our students have access to comprehensive resources and facilities to support these efforts across all three institutions.

Three complete laboratory floors on our campuses are dedicated to organic synthesis and are fully-equipped with chemical fume hoods, chemistry benches, equipment rooms, and chemical storage rooms. Our state-of-the-art instrumentation, housed in our analytical chemistry core facilities and maintained by professional support staff, includes high-field NMR spectrometers (500 and 600 MHz, including four with cryoprobes), mass spectrometers (LC-MS, LC-TOF-MS, LC-MS/MS, GC-MS), spectrophotometers (FTIR, UV-Vis, CD, polarimetry), and analytical and preparative chromatography instruments (UPLC, HPLC, SFC, AutoPurification, CombiFlash) with various combinations of MS, PDA, and ELSD detectors.

Our research libraries provide online access to all major chemistry journals through institutional subscriptions. Our students have access to a full suite of major chemistry software packages, including SciFinder, Reaxys, Schrödinger Drug Discovery Suite, ChemDraw, PyMOL, MacSpartan, Pipeline Pilot, MestReNova, ACD/NMR Predictor, and Prism. The  Tri-Institutional Therapeutics Discovery Institute (http://triitdi.org/) provides a unique and outstanding resource for students interested in translational research, collaborating with TPCB laboratories to support efforts in molecular modeling, virtual screening, high-throughput screening, medicinal chemistry, and preclinical pharmacology and toxicology.
Finally, TPCB students receive advanced training in organic chemistry through graduate level coursework offered at Rockefeller University, Weill Cornell Medicine, Columbia University, and the City University of New York.
 

TPCB Synthetic Chemistry Research Highlights

Total Synthesis of Oridamycins A and B

Oridamycins A and B belong to the xiamycin family of indolosesquiterpene natural products that exhibit antiviral and antibacterial properties. TPCB student Adam Trotta completed the total syntheses of both oridamycins A and B from a common synthetic intermediate that was readily prepared from geranyl acetate. The sequence features an oxidative radical cyclization to construct the trans-decalin ring system, setting three of four contiguous stereocenters in one synthetic operation. The carbazole was forged through a one-pot process entailing acid-promoted dehydration followed by 6p-electrocyclization/aromatization.

Trotta, A. H. Org. Lett. 2015, 17, 3358–3361.
DOI: 10.1021/acs.orglett.5b01629  PMID: 26069989

 

Total Synthesis of Aspeverin via an Iodine(III)-Mediated Oxidative Cyclization

Aspeverine is an unusual prenylated indole alkaloid that was isolated from the fungus Aspergillus versicolor in 2013. TPCB student Adam Levinson reported the first total synthesis of aspeverine, leveraging a highly diastereoselective Diels–Alder reaction and a Curtius rearrangement to access the core structure. A unique strategy involving formation of a temporary carbamate bridge was developed to install the geminal dimethyl group. Finally, a novel iodine(III)-initiated cyclization was used to install the bicyclic urethane linkage that is distinctive to the natural product.

Levinson, A. M. Org. Lett. 2014, 16, 4904–4907.
DOI: 10.1021/ol5024163 PMID: 25171639

 

Large-Scale, Protection-Free Synthesis of Se-Adenosyl-L-selenomethionine Analogues and Their Application as Cofactor Surrogates of Methyltransferases

S-Adenosyl-L-methionine (SAM) analogues have demonstrated utility as chemical reporters of protein methyltransferase enzymes. To investigate such analogues, TPCB student Ian Bothwell developed a facile, large-scale synthesis of Se-alkyl Se-adenosyl-L-selenomethionine (SeAM) analogues and their precursor, Se-adenosyl-L-selenohomocysteine (SeAH). Comparison of SeAM analogues with their equivalent SAM analogues suggests that the S-to-Se substitution enhances their compatibility with certain protein methyltransferases, boosting the reactivity of otherwise less-reactive analogues. This facile access to SeAH enables further application of SeAM analogues as chemical reporters of diverse methyltransferases.

Bothwell, I. R.; Luo, M. Org. Lett. 2014, 16, 3056–3059.
DOI: 10.1021/ol501169y PMID: 24852128

 

Total Synthesis, Relay Synthesis, and Structural Confirmation of the C18-Norditerpenoid Alkaloid Neofinaconitine

The aconitine family of alkaloids originate in Aconitum and Delphinium plants that have been used in traditional folk medicines as antiarrhythmics and analgesics. TPCB student Yuan Shi reported the first total synthesis of the C18-norditerpenoid aconitine alkaloid neofinaconitine, as well as the relay syntheses of neofinaconitine and 9-deoxylappaconitine from condelphine. A modular, convergent synthetic approach involves initial Diels–Alder cycloaddition between two unstable components, a cyclopropene and cyclopentadiene. A second Diels–Alder reaction features the first use of an azepinone dienophile, with high diastereofacial selectivity achieved via rational design of the siloxydiene component with a sterically demanding bromine substituent. Subsequent Mannich-type N-acyliminium and radical cyclizations provide complete hexacyclic skeleton of the aconitine alkaloids. Key endgame transformations include the installation of the C8-hydroxyl group via conjugate addition of water to a putative strained bridgehead enone intermediate and one-carbon oxidative truncation of the C4 side chain to afford racemic neofinaconitine. Complete structural confirmation was provided by a concise relay synthesis of (+)-neofinaconitine and (+)-9-deoxylappaconitine from condelphine, with X-ray crystallographic analysis of the former clarifying the NMR spectral discrepancy between neofinaconitine and delphicrispuline, which were previously assigned identical structures.

Shi, Y.; Wilmot, J. T.; Nordstrøm, L. U.; Tan, D. S.; Gin, D. Y. J. Am. Chem. Soc. 2013, 135, 14313–14320.
DOI: 10.1021/ja4064958 PMID: 24040959

 

Stereoselective Synthesis of Acortatarins A and B

The acortatarins are the lead members of a recently discovered family of pyrrolomorpholine spiroketal natural products isolated from plant and fungi used in traditional herbal medicines. TPCB student Jacqueline Wurst developed an efficient synthesis of the antioxidants acortatarins A and B via stereoselective spirocyclizations of glycals. Mercury-mediated spirocyclization of a pyrrole monoalcohol side chain leads to acortatarin A. Glycal epoxidation and reductive spirocyclization of a pyrrole dialdehyde side chain leads to acortatarin B. Acid equilibration and crystallographic analysis indicate that acortatarin B is a contrathermodynamic spiroketal with distinct ring conformations compared to acortatarin A.

Wurst, J. M.; Verano, A. L.; Tan, D. S. Org. Lett. 2012, 14, 4442–4445.
DOI: 10.1021/ol3019456 PMID: 22924668

 

Biomimetic Diversity-Oriented Synthesis of Benzannulated Medium Rings via Ring Expansion

Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, owing to the limitations of conventional cyclization-based approaches to medium-ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts. To address this problem, TPCB student Renato Bauer established a biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries. Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products. The ring expansion reaction can be induced using three complementary reagents that avoid competing dienone-phenol rearrangements and is driven by rearomatization of a phenol ring adjacent to the scissile bond. Cheminformatic analysis of the resulting first-generation library confirms that these molecules occupy chemical space overlapping with medium-ring natural products and distinct from that of synthetic drugs and drug-like libraries.

Bauer, R. A.; Wenderski, T. A.; Tan, D. S. Nat. Chem. Biol. 2012, 9, 21–29.
DOI: 10.1038/nchembio.1130 PMID: 23160003

 

 

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