ThaiREU in Organic Chemistry

Research Project Descriptions

Dr. Somsak Ruchirawat Chulabhorn Research Institute

In medicinal chemistry, we are interested in the synthesis of biologically active compounds, especially nitrogen heterocycles. Current target areas include anti-malarial compounds, isoquinolines and the lamellarin series of natural products. A student might be involved in the synthesis of analogs, using our already developed synthetic route, for subsequent in-house biological screening.

In natural products chemistry, our emphasis is on the extraction of active natural products from indigenous Thai plants. The work involves extraction, isolation, structural elucidation (principally by NMR methods), and biological evaluation.

Dr. Poonsakdi Ploypradith Chulabhorn Research Institute

Marine organisms have emerged as a source of medicinal therapeutically useful agents.   However, ecological concerns and low natural abundance of marine natural products with interesting biological activity are major limitations to extensive investigation and medical application. Through total synthesis, these compounds can be prepared in sufficient quantities to establish structure-activity relationships and to investigate their therapeutic indices. Further incorporation of pharmacologically useful functional groups can be optimized to provide the appropriate biological profile for drug development.   Studies on their mechanisms of action would also aid in the development of more desirable analogues.            

Dr. Poonsakdi Ploypradith's research group has been interested in the lamellarins, a group of marine natural products.   A number of successful synthetic routes have been developed in his group including the use of environmentally friendly solid-supported reagents.   His group's objectives are to fully optimize each synthetic step to prepare both natural and unnatural lamellarins for detailed biological evaluations for screens including anticancer, anti-HIV, and antioxidant activities as well as for studies on the mechanism of action.

            In addition, they have also been interested in the use of solid-supported acids for the deprotection of O - and N -protected functionalities as their respective ethers, esters, amines and amides.   It is expected that successful optimization would represent a key advance in protecting group chemistry essential for the complex syntheses of natural products.

Selected publications:

1.Ploypradith, P.; Petchmanee, T.; Sahakitpichan, P.; Litvinas, N. D.; Ruchirawat, S.   Total Synthesis of Natural and Unnatural Lamellarins with Saturated and Unsaturated D-Rings. J. Org. Chem. 2006 , 71 , 9440-9448.

2. Petchmanee, T.; Ploypradith, P.; Ruchirawat, S.   Solid-Supported Acids for Debenzylation of Aryl Benzyl Ethers.   J. Org. Chem. 2006 , 71 , 2892-2895.

3. Ploypradith, P.; Kagan, R. K.; Ruchirawat, S.   Utility of Solid-supported Reagents in the Total Synthesis of Lamellarins.   J. Org. Chem. 2005 , 70 , 5119-5125.

4. Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.; Wongbundit, S.; Ruchirawat, S.   A Highly Efficient Synthesis of Lamellarins K and L by the Michael Addition/Ring-Closure Reaction of Benzyldihydroisoquinoline Derivatives with Ethoxycarbonyl-beta-nitrostyrenes.   Angew. Chem. Int. Ed. 2004 , 43 , 866-868.

Dr. Thawatchai Tuntulani Chulalongkorn University

Dr. Thawatchai Tuntulani is the coordinator of the Supramolecular Chemistry Laboratory (SML), Department of Chemistry, Faculty of Science, at Chulalongkorn University. Dr. Tuntulani’s research is focused on the synthesis of electrochemical heteroditopic anion sensors containing crown ethers or calix[4]arenes as cation binding sites and amidoferrocene as anion binding sites. The binding and detection abilities of these anion sensors in the absence and presence of alkali metal ions is then investigated by NMR, cyclic voltammetry and square wave voltammetry.

Students will prepare novel anion sensors using the synthetic route developed in this lab, characterize their products by 1H-NMR, 13C-NMR, elemental analysis and X-ray crystallography, and then investigate the anion binding abilities.

Dr. Palangpon Kongsaeree Mahidol University

Dr. Kongsaeree’s lab is interested in developing new effective treatments against malaria by investigating antifolate drugs such as pyrimethamine, which inhibit dihydrofolate reductase enzyme (DHFR) at the cellular level. Structural investigation of dihydrofolate reductase-thymidylate synthase has been explored in this laboratory: the recombinant gene was cloned, the enzyme was expressed and purified to homogeneity, and the enzyme in complex with pyrimethamine was crystallized. The X-ray structure revealed the binding mechanism of the drug with atomic details. Current work is focused on elucidating the drug-resistance mechanism by studying crystal structures of mutant enzymes complexed with antifolates, leading to the development of a new generation of antifolate inhibitors.

Concurrently, new leads for antimalarials are being explored by searching for bioactive compounds from microorganisms, especially fungi from tropical Thailand. Fungi with promising bioactivity profiles in a preliminary screening stage will be cultured and then using bioassay-guided isolation, pure secondary metabolites will be obtained using chromatographic techniques including HPLC. The chemical identity of each compound will be established spectroscopically using NMR, IR, MS, X-ray crystallographic analysis when possible. ThaiREU students can take part in work with mutant enzymes, or in bioassay-guided natural product isolation and structural elucidation.

Dr. Thientong Thongpanchang Mahidol University

Dr. Thongpanchang’s research focus is in three main categories: 1) the development of new synthetic methodologies towards compounds with interesting activities, 2) the design and development of new materials and 3) physical organic chemistry in terms of the relationship between molecular conformations and properties. He is now studying the synthesis of arylsulfides by the addition of nucleophiles to the keto tautomer of phenol in the presence of acid. A variety of arylsulfides can be prepared in large quantity, as well as aryldioxins and aryldithiins, which are important pharmacophores with possible new electro- and optochemical materials. He is also interested in preparing highly conjugated helicenes for new material applications using an acid catalyzed intramolecular cyclization of binaphthols, or by photocyclization of diarylsulfides. A variety of helicenes with key functional groups will be prepared; incorporation into macromolecules by supramolecular assembly or via polymerization will provide materials with interesting properties.
He is also interested in establishing the relationship between the conformation of bonds and the properties of the molecules, especially as it applies to the process of resolution. With camphanate ester derivatives of binaphthols as model compounds, each diastereomerically pure material can be isolated. Conformation analysis by means of CD / ORD and NMR spectroscopy complemented with molecular conformation calculations as well as X-ray analyses provides an insight into chemical bonding leading to the difference in polarity of each diatereomeric pair on TLC. This finding can lead to an efficient yet most straightforward method for the determination of the absolute configuration of binaphthols.

Dr. Tirayut Vilaivan Chulalongkorn University

Dr. Vilaivan's main research interest concerns a new class of DNA mimic with a peptide-like backbone called "Peptide Nucleic Acid" (PNA). During the past ten years, he has designed and synthesized a number of PNA systems based on a conformationally rigid proline skeleton. Some of these PNA structures show unique nucleic acid binding properties such as exceptionally high affinity and specificity towards DNA, high preference for antiparallel binding mode, and selective recognition between DNA and RNA. Work in this area is directed towards better understanding the structural aspects of the binding and designing new PNA systems with enhanced binding properties. Their potential applications in diagnostics and therapeutics are current subjects of intensive research.

Dr. Vilaivan's two other major research areas are 1) development of new catalysts for asymmetric nucleophilic addition to C=N, C=O and C=C bonds, and 2) synthetic Dihydrofolate Reductase Inhibitors to be used as antimalarial drugs effective against mutant strains of maleria.

For more details please visit: http://www.chemistry.sc.chula.ac.th/personnel/details/vilaivan.htm

Representative publications:
1. Vilaivan, T.; Srisuwannaket, C. "Hybridization of pyrrolidinyl peptide nucleic acids and DNA: Selectivity, base-pairing specificity, and direction of binding" Org. Lett. 2006 , 8 , 1897-1900.
2. 2. Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. "Recent advances in catalytic asymmetric addition to imines and related C=N systems" Curr. Org. Chem. 2005 , 9 , 1315-1392.
3. . Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. " Indium-mediated asymmetric Barbier-type allylation of aldimines in alcoholic solvents: Synthesis of optically active homoallylic amines" J. Org. Chem. 2005 , 70 (9), 3464-3471.
4. . Banphavichit, V.; Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T. "A highly enantioselective Strecker reaction catalyzed by titanium- N -salicyl- b-amino alcohol complexes" Tetrahedron 2004 , 60 , 10559-10568 .
5. Vilaivan, T.;   Saesaengseerung, N.; Jarprung, D; Kamchonwongpaisan, S.; Sirawaraporn, W.; Yuthavong, Y. "Synthesis of solution-phase combinatorial library of 4,6-diamino-1,2-dihydro-1,3,5-triazine and identification of new leads against A16V+S108T mutant dihydrofolate reductase of Plasmodium falciparum " Bioorg. Med. Chem. 2003 , 11 , 217-224.

6. . Vilaivan, T.; Lowe, G. "A novel pyrrolidinyl PNA showing high sequence specificity and preferential binding to DNA over RNA" J. Am. Chem. Soc. 2002 , 124 , 9326-9327 .

Dr. Prasat Kittakoop Chulabhorn Research Institute

Dr. Nopporn Thasana Chulabhorn Research Institute

Dr. Thasana's work encompasses both natural products and organic synthesis. Natural product research involves structure elucidation of Thai medicinal plants such as Derris malaccensis and Derris scandens, which contained isoflavonoid derivatives.  The synthetic work involves the development of new methodologies in heterocyclic chemistry. This work has encompassed new cyclization chemistries based on metal-mediated reactions of a lactone synthon in the synthesis of isolamellarin 1 and coumestan 2 , the synthesis of pyrroloisoquinoline 3 (Telisatin A and B), imidazoloisoquinolin-3-ones 4 , benzo[ a ]quinolizin-4-ones 5 using arylpyruvate derivatives.

The oxygen-containing natural product wrightiadione 6 and its synthetic isomer, isowrigthiadione 7 were synthesized using directed ortho metalation and directed remote metalation (D o M&DreM). This methodology is being extended in ongoing work using D o M/Transmetalation and Double Allylation/Cyclization to synthesize the dimeric naphthalene diospyrol 8 (R = R' = H), isolated from Diospyros mollis , a tree distributed throughout Thailand.

Recent efforts have been directed towards a new efficient synthesis of dibenzo[ b,d ]pyran-6-ones and phenanthridin-6-ones based on a Cu(I)-mediated and microwave-assisted intramolecular Caryl -Ocarboxylate lactone and Caryl -Namide lactam bond formation under mild, ligand- and base-free conditions. Various Cu(I) salts including CuI, CuBr, CuCl, and CuTC have been utilized in this project.

International Publications (2005-present)

1. Thasana, N. ; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young, L.; Ruchirawat, S. Copper(I)-mediated and microwave-assisted C aryl -O carboxylic coupling: Synthesis of benzopyaranones and isolamellarin alkaloids. J. Org. Chem. 2007 , in press.

2.  Worayuthakarn, R.; Thasana, N. ; Ruchirawat, S. Three distinct reactions of 3,4-dihydroisoquinolines with azlactones: Novel synthesis of imidazoloisoquinolin-3-ones, benzo[ a ]quinolizin-4-ones, and benzo[ d ]azocin-4-ones. Org. Lett. 2006 , 8 , 5845-5848.

3.  Thasana, N. ; Pisutjaroenpong, S.; Ruchirawat, S. Two protocols for the conversion of biphenol to binaphthol: Synthesis of diospyrol. Synlett 2006 , 1080-1084.

4. Athikomkulchai, S.; Prawat, H.; Thasana, N. ; Ruangrungsi, N.; Ruchirawat, S. COX-1, COX-2 Inhibitors and antifungal agents from Croton hutchinsonianus. Chem. Pharm. Bull. 2006 , 54 , 262-264.

5. Sahakitpichan, P.; Thasana, N. ; Ruchirawat, S. Efficient synthesis of diospyrol via Suzuki-Miyaura and modified in situ cross-coupling. Synthesis 2005 , 2934-2938.

6. Tempeam, A.; Thasana, N. ; Pavaro, C.; Chuakul, W.; Siripong, P.; Ruchirawat, S. A new cytotoxic daphnane diterpenoid, rediocide G, from Trigonostermon reidioides . Chem. Pharm. Bull. 2005 , 53 , 1321-1323.

7.  Kondo, N.; Kuse, M.; Mutarapat, T.; Thasana, N. ; Isobe, M. Novel synthetic route of coelenterazines-2-: Synthesis of various dehydrocoelenterazine analogs. Heterocycles 2005 , 65 , 843-856.