At the heart of our research interests is the chemistry and biology of natural products. These are unique and often structurally complex molecules that appear designed to interact in highly specific ways with various cellular receptors most importantly those found in humans. Our interest in a particular synthetic target begins by an awe of the structural complexity and/or the presence of β-lactones or functionality derivable from β-lactones in addition to interesting biological activity. Thus, our group is engaged in developing novel synthetic strategies towards these naturally occurring compounds or derivatives that in turn serve are useful leads for inquiries into protein function.
Structural, Synthetic, and Biomechanistic Investigations of Bioactive Marine Natural Products
One focus of our research efforts is the structure elucidation, total synthesis, and determination of the mode of action of marine natural products that display significant physiological activity. Our total synthesis strategies are designed to allow efficient access to the natural product in addition to structural derivatives and conjugates for studies aimed at elucidating their mechanism of action. For example, a project involving the marine sponge isolate, pateamine A, has involved total synthesis, conjugate synthesis, receptor isolation, synthesis of a potent, simplified derivative (DMDAPatA) and collaborations/agreements with pharmaceutical companies to develop this latter lead compound as a potential anticancer therapeutic. Presently, we have total synthesis programs directed towards the total synthesis of several oroidin-derived marine alkaloids including palau'amine/axinellamine, scabrolides, rameswaralide, and building on a recent total synthesis of the novel marine toxin, gymnodimine, we are developing haptens for eventual development of an ELISA assay for ocean monitoring (collaboration with Chris Elliott, U. of Belfast).
Asymmetric Synthesis, Novel Transformations, and Applications of 2-Oxetanones (β-Lactones)
We are interested in developing diastereoselective and enantioselective methods for the preparation of β-lactones, underutilized heterocycles, employing 1) chiral amine catalyzed aldol-lactonization (NCAL) reactions of ketene and carbonyl compounds and 2) tandem Mukaiyama aldol-lactonization (TMAL) reactions. In addition, we are interested in developing new transformations of these strained systems and ultimate application to natural and unnatural product synthesis (e.g. spongiolactone, belactosin C, and Omuralide/salinosporamide derivatives. For example, we have developed methods for conversion of β-lactones to γ- and δ-lactones via a tandem transacylation-debenzylation process, cyclopentanes via intramolecular allylsilane additions to β-lactones, tetrahydropyrans and piperidines via intramolecular addition of esters and imines, respectively, to β-lactones, and a one-pot conversion of β-lactones to β-lactams. Application of a novel cascade process involving the TMAL process coupled to an intramolecular ketone-addition/oxocarbenium trapping has recently been developed for the concise synthesis of highly substituted tetrahydrofurans and -pyrans. Furthermore, application of the NCAL reaction to a highly concise synthesis of potential proteasome inhibitors, Omuralide and the salinosporamide derivatives is being pursued. Additional β-lactone-containing targets being pursued include belactosin C and spongiolactone employing the TMAL and NCAL processes, respectively. Our studies of the TMAL process also led to a collaborative project with Prof. Jeff Smith (Burnham Medical Research Institute) directed towards the synthesis of orlistat derivatives as inhibitors of fatty acid synthase, a recent therapeutic target of interest for cancer,
Development of Novel Strategies for Simultaneous Arming and SAR Studies of Bioactive Natural Products: New Approaches to Forward Chemical Genetics
We are working towards developing a toolbox of reagents and methods for the simultaneous arming and SAR studies of bioactive natural products that will be useful for a variety of life science researchers. The strategy bypasses the usual bottleneck of complete natural product structure determination. Our strategy involves mild reactions that enable simultaneous arming (e.g. with an alkyne for subsequent conjugate to various cellular probes) and SAR studies of bioactive natural products (to determine a suitable site for probe attachment). We recently described our first approach involving Rh(II) catalyzed OH insertions of ubiquitous alcohol-containing natural products. One outcome of these new tools and methodologies will be more rapid coupling of a natural product with its putative cellular target(s) as either a potential inhibitor or activator. In addition, a number of novel natural products will be available for high-throughput screening facilities. Current participants are Coran Watanabe (TAMU), Gyula Vigh (TAMU), Dave Russell (TAMU), Jun Liu (Johns Hopkins), Jeff Smith (Burnham Institute), and numerous natural product isolation and biosynthetic chemists around the world. Our group's involvement includes the development of synthetic methods for natural product derivitization, the synthesis of probes (e.g. biotin and fluorescent) useful for protein receptor isolation by affinity chromatography and capillary electrophoresis followed by identification by mass spectrometry, cellular localization studies, and also development of novel affinity chromatography techniques.
Current Natural Products of Interest in the Romo Group
(fragments in blue will be derived from β-lactones)
"Facile Sythesis of the Trans-Fused Azabicyclo [3.3.0] Octane Core of Palau'amine and the Tricyclic Core of Axinellamine from a Common Intermediate" Zancanella, M. A.; Romo, D. Org. Lett. 2008, ASAP.
"Concise Synthesis of Spirocyclic, Bridged γ-Butrolactones via Stereospecific, Dyotropic Rearrangements of β-Lactones Involving 1,2-Acyl and δ-Lactone Migrations" Purohit, V. C.; Matla, A. S.; Romo, D. J. Am. Chem. Soc. 2008,130, 10478-10479.
"Highly Diastereoselective, Tandem, Three-Component Synthesis of Tetrahydrofurans from Ketoaldehydes via Silylated β-Lactone Intermediates: Application to a Colpsinol B Fragment" Mitchell, T. A.; Zhao, C.; Romo, D. Angew. Chem. Int. Ed. 2008, 47, 5026-5029.
"β-Lactam Congeners of Orlistat as Inhibitors of Fatty Acid Synthase" Zhang, W.; Richardson, R. D.; Chamni, S.: Smith, J. W.; Romo, D. Bioorg. Med. Chem. Lett. 2008, 28, 2491-2494.
(Featured in Chemical & Engineering News, "Fat Chance to Cure Cancer", June 23, 2008)
"Enantioselective Synthesis of (+) Monobromophakellin and (+)-Phakellin: A Concise Phakellin Annulation Strategy Applicable to Palau'amine" Wang, S.; Romo, D. Angew. Chem. Int. Ed. 2008, 47, 1284-1286.
(Highlighted in Synfacts 2008, 7, 678)
"Simultaneous Arming and Structure/Activity Studies of Natural Products Employing O-H Insertions: An Expedient and Versatile Strategy for Natural Products-Based Chemical Genetics" Peddibhotla, S.; Dang, Y.; Liu, J. O.; Romo, D. J. Am. Chem. Soc., 2007, 129, 12222-12231.
(Featured in Chemical & Engineering News, "Tagging Natural Products", October 1, 2007)
"Substrate-Dependent Targeting of Eukaryotic Translation Initiation Factor 4A by Pateamine A: Negation of Domain-Linker Regulation of Activity" Low, W.-K.; Dang, Y.; Bhat, S.; Romo, D.; Liu, J. O. Chem. & Biol. 2007, 14, 1-13.
"Concise Total Synthesis of (+/-)- Salinosporamide A, (+/-)-Cinnabaramide A, and Derivatives via a Bis-Cyclization Process: Implications for a Biosynthetic Pathway?" Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 2143-2146.
(Highlighted in Synfacts 2007, 10, 1014)
"Total Synthesis of Belactosin C and Congeners via the Tandem Mukaiyama Aldol-Lactonization Process" Cho, S. W.; Romo, D. Org. Lett. 2007, 9, 1537-1540.
(Highlighted in Synfacts 2007, 8, 789)
"Isolation and Identification of Eukaryotic Initiation Factor 4A as a Molecular Target for the Marine Natural Product Pateamine A" Low, W.-K.; Dang, Y.; Schneider-Poetsch, T.; Shi, Z.; Choi, N. S.; Rzasa, R. M.; Shea, H. A.; Li, S.; Park, K.; Ma, G.; Romo, D.; Liu, J. O. Methods in Enzymology 2007, 431, 303-0324.
"Eukaryotic Initiation Factor 2α-independent Pathway of Stress Granule Induction by the Natural Product Pateamine A" Dang Y.; Kedersha, N.; Low, W.-K.; Romo, D.; Gorospe, M.; Kaufman, R.; Anderson, P.; Liu, J. O. J. Biol. Chem. 2006, 281, 32870-32878.
"Synthesis, Characterization, and Utility of Thermoresponsive Natural/Unnatural Product Macroligands for Affinity Chromatography" Zhou, M.; Sivaramakrishnan, A.; Ponnamperuma, K.; Low, W.-K.; Li, C.; Zhang, Y.; Liu, J. O.; Bergbreiter, D.; Romo, D. Org. Lett. 2006, 8, 5247-5250.
"Bicyclic and Tricyclic-β-Lactones via an Organonucleophile Bis-cyclization of Keto-Acids: Enantioselective Synthesis of (+)-Dihydroplakevulin" Henry-Riyad, H.; Lee, C. S.; Purohit, V.; Romo, D. Org. Lett. 2006, 8, 4363-4366.
"Practical, Catalytic, Asymmetric Synthesis of β-Lactones via a Sequential Ketene Dimerization/Hydrogenation Process: Inhibitors of the Thioesterase Domain of Fatty Acid Synthase" Purohit, V. C.; Richardson, R. D., Smith, J. W.; Romo, D. J. Org. Chem. 2006, 71, 4549-4558.