Under prior NSF support, the Romo Group at Texas A&M University developed practical, catalytic asymmetric routes to both bicyclic and tricyclic beta-lactones from ketoacid substrates employing a nucleophile-catalyzed aldol lactonization process (NCAL). Building on a growing understanding of the NCAL process, novel transformations of these beta-lactones and new variants of the NCAL process including dynamic kinetic resolution are being pursued with the support from the Chemical Synthesis Program of the Division of Chemistry. The utility and practicality of these methods will be demonstrated in the context of natural product total synthesis targeting the completion of spongiolactone and curcumalactone/curcumanolide A. In addition, specific cellular probes based on these bioactive natural products will be prepared to serve as basic proteomics tools in collaborative studies. Mechanistic studies of ammonium enolates directed toward development of new reaction manifolds involving these versatile intermediates are being pursued in collaboration with Prof. Dean Tantillo (UC Davis).
The practice of organic synthesis continues to be instrumental in propelling significant advances in the areas of human and animal health among other fields. Successful development of the proposed methods for beta-lactones will impact the field of organic synthesis pertinent to the pharmaceutical and agricultural industries as the methods being developed are robust and "user friendly". In addition, synthesis of the targeted biologically active natural products by synthetic methods being developed will have broader impacts in enabling the further understanding of fundamental cellular processes and enabling collaborations with computational chemists and biochemists/cell biologists. The Romo Group has initiated a number of outreach initiatives including a Natural Products Discovery Lab during the Annual Chemistry Open House, combining NSF-funded research and teaching by importing new experiments into the chemistry major's laboratory, and developing multimedia presentations to demonstrate the societal relevance of organic synthesis.
Intellectual Merit. Toward our primary goal of developing practical asymmetric syntheses of b-lactones (2-oxetanones) in the last grant period, we discovered the great utility of unsaturated acylammonium species derived from commodity acid chlorides for organocatalysis and organocascade processes, which significantly expand the synthetic methodology and bioactive natural products we are now undertaking. This initial discovery was made in the context of developing the arguably most concise route to bicyclic b-lactones involving a Michael aldol-b-lactonization. We have utilized these versatile unsaturated acylammonium salts in nucleophile-catalyzed, Michael-proton transfer-lactamization (NCMPL) to access g-lactams and enol lactones and we also recently exploited these for tandem Diels-Alder lactonization (TDAL) and a multicomponent Michael-Michael-aldol-b-lactonization processes. The TAMU Undergraduate MiniPharma continues to grow. The first manuscript resulting from this team-based approach in collaboration with scientists in the Natural Products LINCHPIN Laboratory is close to submission. In the past grant period, 8 NSF-supported manuscripts were published or recently accepted. Broader Impacts. The synthetic methods we propose to develop are highly practical and scalable and can be applied to address problems in biology, in particular for the synthesis of medicinally important compounds including natural products thus impacting public health. Furthermore, our continued studies of beta-lactones will include the study of this promising class of proteomics tools for analyzing various cell proteomes for the presence of reactive enzyme families toward these electrophilic agents (i.e. spongiolactone and derivatives). As a prelude to activity based-profiling experiments with Prof. Stephan Sieber (Technische Universität München), spongiolactone itself, several simpler precursors, and unnatural diastereomers were sent to the Sieber Lab for whole cell cytotoxicity assays. Initial SAR data obtained is guiding proteome-profiling experiments to identify cellular target(s) of spongiolactone contributing to the Broader Impacts of this research. Intellectual property was generated based on research supported by NSF and two patents were recently issued. One involves synthesis of bicyclic beta-lactones including salinosporamide derivatives via the NCAL process, a reaction developed during the previous grant periods. A second patent involves the synthesis of novel dual inhibitors of the proteasome and fatty acid synthase, two targets for cancer chemotherapy, and is pertinent to one of the projects being undertaken by the TAMU Undergraduate MiniPharma group (vide infra). This project is giving undergraduate students a taste of intellectual property issues since some of the derivatives synthesized and assayed by MiniPharma will be added to a Continuation-In-Part patent. TAMU Natural Products LINCHPIN Laboratory. A collaboration center was established in Fall 2010, an outgrowth of a previous NIH Natural Product methodologies grant. This center has enabled productive national and international collaborations significantly impacting the broader impacts of our research including that funded by NSF. For example, the synthesis of novel FAS/proteasome dual inhibitors and serum stability studies is a collaborative effort between TAMU MiniPharmers and LINCHPIN scientists. This new laboratory adds a new dimension to broader impacts and integration of research with educational goals of this project. Highlights of the Previous Grant Period: Towards Methods Development 1) In the last grant period, we discovered the broad utility of a,b-unsaturated acylammonium catalysis with the discovery of several novel organocascade processes that proceed with excellent yields, diastereoselectivity and enantioselectivity from commodity acid chlorides. We completed a full study of the nucleophile-catalyzed, Michael-Aldol-b-Lactonization (NCMAL) process, which delivers up to 4 contiguous stereocenters and generates 2 rings, 2 C-C bonds, and 1 C-O bond in a single pot from readily available starting materials. This provides an expeditious assembly of highly substituted, optically active cyclopentanes. In addition, we developed NCMPL that again delivers in one step from commodity acid chlorides, optically pure N-heterocycles including pyrrolidinones and related processes leading to piperidinones, dihydropyridinones, and enol lactones. We developed practical, diastereoselective routes to optically active b-lactones and isothiourea catalysts. Applications of Developed Methods to Natural Product Synthesis 2) The NCAL process in conjunction with the dyotropic rearrangement enabled a concise, enantioselective synthetic strategy to both curcumanolide A and curcumalactone. These unique dyotropic rearrangements were studied both experimentally and computationally in collaboration with Prof. Dean Tantillo (UC Davis). 3) We demonstrated the utility of the NCMAL for construction of steroid skeletons and the NCMPL process for the one-step, synthesis of a key pyrrolidinone and dihydropyridone intermediate for the synthesis of an FDA-approved drug and several clinical candidates. 4) In this past grant period, we completed an enantioselective 11-stepsynthesis of spongiolactone from 1,3-cylclohexanedione! Key features of the synthesis include the first use of the NCAL process in a kinetic resolution on a highly ad vanced substrate leading to the desired b-lactone in 94% ee. As a prelude to activity based-profiling experiments with Prof. Stephan Sieber (Technische Universität München), the natural product, several simpler precursors, and diastereomers were sent to the Sieber Lab for initial whole cell cytotoxicity assays. Initial SAR data obtained is guiding proteome-profiling experiments to identify cellular target(s) contributing to the Broader Impacts of this research.
