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Summary <strong>of</strong> ResearchKiyoun Lee, Department <strong>of</strong> Chemistry, Duke UniversityDevelopment <strong>of</strong> methods for the synthesis <strong>of</strong> tetrahydropyrans and their application <strong>to</strong> theconcise synthesis <strong>of</strong> structurally and biologically interesting natural productsStructurally complex tetrahydropyrans are found in a wide range <strong>of</strong> biologically interestingnatural products exhibiting significant pharmacological activities, including antitumor, antibiotic,antiviral, and antifungal activities. Since the emergence <strong>of</strong> <strong>this</strong> fact, great emphasis has beenplaced on synthetic approach <strong>to</strong>wards these classes <strong>of</strong> molecules that allows for rapid and easyaccess <strong>to</strong> substrates, proceeds with excellent stereoselectivity and yield, possesses the versatilityfor a wide range <strong>of</strong> tetrahydropyrans, and requires mild reaction conditions compatible withvarious functional groups. Although a number <strong>of</strong> methods have been developed for theconstruction <strong>of</strong> tetrahydropyrans, there is still a great need for a facile synthetic approach forthese molecules. We have recently reported the stereoselective synthesis <strong>of</strong> 2,6-cistetrahydropyransthrough an unprecedented tandem allylic oxidation/oxa-Michael addition <strong>of</strong>alcohol <strong>to</strong> α,β-unsaturated aldehydes promoted by the gem-disubstituent effect. In addition, wealso demonstrated the efficiency <strong>of</strong> the tandem reaction by completing a formal synthesis <strong>of</strong>neopel<strong>to</strong>lide and the first <strong>to</strong>tal synthesis <strong>of</strong> cyanolide A.

Based on the our inspiring preliminary study <strong>of</strong> the oxa-Michael reaction promoted by thegem-disubstituent effect and the dithiane coupling reaction for the rapid and stereoselectiveconstruction <strong>of</strong> substituted tetrahydropyrans, we have further developed the method for thestereoselective synthesis <strong>of</strong> a diverse set <strong>of</strong> structurally more complex 2,3,6-trisubstitutedtetrahydropyrans which are abundant motifs found in structurally and biologically interestingnatural product through the tandem and organocatalytic oxa-Michael reactions (Figure 1).In particular, as shown in Figure 2, we developed the synthetic method for both 2,3-trans-2,6-trans- and 2,3-cis-2,6-cis-tetrahydropyrans, ubiqui<strong>to</strong>us structural motifs found in biologicallyimportant natural product, could be prepared from a common substrate through the oxa-Michaelreaction depending on the reaction temperature, which demonstrates the great versatility <strong>of</strong> thereaction. Through these studies, we expect that it would provide valuable insights on the efficient

activity via inhibition <strong>of</strong> mi<strong>to</strong>chondrial ATP synthesis. As described in Scheme 1, wesuccessfully accomplished 3-methyl-2,3-trans-2,6-trans-THP A and 2,6-cis-THP B through theoxa-Michael reaction promoted by gem-disubstituent effect with excellent stereoselectivities andyields. In particular, the synthesis <strong>of</strong> both the 2,6-cis- and 3-methyl-2,3-trans-2,6-transtetrahydropyrans through the s<strong>am</strong>e type <strong>of</strong> reaction is very rare in the synthesis <strong>of</strong>leucascandrolide A. Moreover, our stereoselective formal synthesis <strong>of</strong> leucascandrolide A is veryunique and efficient compared with the previously reported syntheses <strong>of</strong> the natural product.In summary, we have newly developed the unprecedented tandem and organocatalytic oxa-Michael reaction promoted by the gem-disubstituent effect for the stereoselective synthesis <strong>of</strong>2,3,6-tetrahydropyrans that are more complex and abundant structural motifs found inbiologically interesting natural products. Futhermore, the stereoselective formal synthesis <strong>of</strong>leucascandrolide A was accomplished through the oxa-Michael reaction promoted by gemdisubstituenteffect. Taken <strong>to</strong>gether, we expect that the oxa-Michael reaction promoted by thegem-disubstituent effect in conjunction with the dithiane coupling reaction would establish facileroutes for the stereoselective synthesis <strong>of</strong> a diverse set <strong>of</strong> tetrahydropyrans and be significantlyapplicable <strong>to</strong> the efficient and concise synthesis <strong>of</strong> complex natural products with interestingbiological activities.

Curriculum VitaeKIYOUN LEEDepartment <strong>of</strong> Chemistry, Duke University3206 French F<strong>am</strong>ily Science CenterScience DriveDurh<strong>am</strong>, NC 27708, USA(Tel) 919-451-0714, (Fax) 919-660-1605, (E-mail) kiyoun.lee@duke.eduEducation09/2007-PresentDuke University (Durh<strong>am</strong>, NC, USA)-Ph.D Course in Chemistry (Advisor: Pr<strong>of</strong>. Jiyong Hong)09/2003-02/2006 Chungn<strong>am</strong> National University (Daejeon, Korea)-MS in Chemistry ( Advisor : Pr<strong>of</strong>. Guncheol Kim)03/1997-08/2003 Chungn<strong>am</strong> National University (Daejeon, Korea)-BS in Chemistry09/1998-11/2000 Military ServiceExperience09/2007-05/2009 -Teaching Assistant (Duke University)-Taught Organic, General chemistry experiments09/2003-02/2006 -Teaching Assistant (Chungn<strong>am</strong> National University)-Taught Organic, General chemistry experiments-International Chemistry Olympiad TAHonors and Awards2010 C.R. Hauser Memorial Fellowship

Conference- K. Y. Lee, C. H. Yoo, Guncheol Kim*, “ Synthetic Study <strong>of</strong> Lennox<strong>am</strong>ine andChilenine via Oxidative Cyclization”, 11 th Asian Chemical Congress, 13 th GeneralAssembly in Seoul, Republic <strong>of</strong> Korea.- K. Y. Lee, C. H. Yoo, Guncheol Kim*, “Synthetic Study <strong>of</strong> Lennox<strong>am</strong>ine andChilenine via Oxidative Cyclization”, 2005 Asian Chemical Congress inSingapore.Publication- Lee, Kiyoun; Kim, Hyoungsu; Park, Yongho; Hong, Jiyong*. “StereoselectiveSynthesis <strong>of</strong> Tetrahydropyrans through Tandem and Organocatalytic oxa-MichaelReactions Promoted by the Gem-Disubstituent Effect: Formal Synthesis <strong>of</strong>Neopel<strong>to</strong>lide and Leucascandrolide A”, J. Am. Chem. Soc., Submitted, ja-2010-08354y)- Lee, Kiyoun; Kim, Hyoungsu; Hong, Jiyong*. “A Facile and Efficient Synthesis<strong>of</strong> 4-Hydroxy-2,6-cis-tetrahydropyrans via Tandem Cross-Metathesis/ThermalS N 2' Reaction: Protecting-Group-Free Synthesis <strong>of</strong> Diospongin A” Org. Lett. 2009,11(22), 5202−5205.- Kim, Guncheol*, Lee, Ki Youn, Yoo, Chul-Hwan, “ Synthetic Study <strong>of</strong>Lennox<strong>am</strong>ine and Chilenine via Oxidative Cyclization”, Syn. Commun., 2008,38(19), 3251−3259.- M. J. Seo, K. Y. Lee, S. N. Jung and S. S. Kim*, “Preparation <strong>of</strong> a-TricalciumPhospate Bone Cement : Effect <strong>of</strong> Citric Acid”, Key Eng.Mater. 2007, 342−343.- Kim, Guncheol*; Kim, Jin Hee; Lee, Ki Youn, “New palladium-CatalyzedReaction Pathway <strong>to</strong> Erythrina Skele<strong>to</strong>n”, J. Org. Chem. 2006, 71(5), 2185−2187.