This proposal outlines the synthesis of biological active natural products of varying stereochemical complexity through the efficient assembly of chiral building blocks. Several targets are accessed in a convergent manner by taking advantage of the dramatically expanded """"""""chiral pool"""""""" made readily available through modern asymmetric catalytic methods. Three of the four stereocenters of the cytotoxic agent longanin (1) are displayed along an extended hydrocarbon chain. A straightforward synthesis plan is described involving condensation of four optically active epoxides obtained by a catalytic hydrolytic kinetic resolution recently discovered in our labs. Taurospongin A (2) displays dual activity against DNA polymerase beta and HIV reverse transcriptase. All three stereocenters in 2 can be accessed by efficient asymmetric catalytic methods, thereby allowing the straight-forward preparation of stereochemical analogs of the natural product. Fostriecin (3) is a promising cytoxic agent currently undergoing clinical trials in Europe. New methodology is proposed to access its monophosphorylated vicinal diol core involving hydrolytic kinetic resolution and diastereoselective alkylation of epoxyketones. Synthesis of the delta-unsaturated lactone of 33 will be investigated by elaboration of butadiene monoxide, recently made readily available through heterogeneous and homogenous catalytic technology. The resulting route to the natural products sets three of four stereocenters by chiral catalysis and is highly adaptable to the preparation of stereoisomeric and structural analogs. The synthesis of FR901464 (4) is intended to illustrate our synthetic approach on a more elaborate target through assembly of relatively complex chiral building blocks. The development of a useful synthetic route will serve as the basis for a collaboration directed toward elucidation of the mode of action of this transcription regulator. This study will also serve to show how a target structure can define the need and guide the development of new asymmetric catalytic methods.
| Rajapaksa, Naomi S; McGowan, Meredeth A; Rienzo, Matthew et al. (2013) Enantioselective total synthesis of (+)-reserpine. Org Lett 15:706-9 |
| McGowan, Meredeth A; Stevenson, Christian P; Schiffler, Matthew A et al. (2010) An enantioselective total synthesis of (+)-peloruside A. Angew Chem Int Ed Engl 49:6147-50 |
| Groll, Michael; Balskus, Emily P; Jacobsen, Eric N (2008) Structural analysis of spiro beta-lactone proteasome inhibitors. J Am Chem Soc 130:14981-3 |
| Grachan, Melissa L; Tudge, Matthew T; Jacobsen, Eric N (2008) Enantioselective catalytic carbonyl-ene cyclization reactions. Angew Chem Int Ed Engl 47:1469-72 |
| Mergott, Dustin J; Zuend, Stephan J; Jacobsen, Eric N (2008) Catalytic asymmetric total synthesis of (+)-yohimbine. Org Lett 10:745-8 |
| Balskus, Emily P; Jacobsen, Eric N (2007) Asymmetric catalysis of the transannular Diels-Alder reaction. Science 317:1736-40 |
| Balskus, Emily P; Jacobsen, Eric N (2006) Alpha,beta-unsaturated beta-silyl imide substrates for catalytic, enantioselective conjugate additions: a total synthesis of (+)-lactacystin and the discovery of a new proteasome inhibitor. J Am Chem Soc 128:6810-2 |
| Boezio, Alessandro A; Jarvo, Elizabeth R; Lawrence, Brian M et al. (2005) Efficient total syntheses of (-)-colombiasin A and (-)-elisapterosin B: application of the Cr-catalyzed asymmetric quinone Diels-Alder reaction. Angew Chem Int Ed Engl 44:6046-50 |
| Jarvo, Elizabeth R; Lawrence, Brian M; Jacobsen, Eric N (2005) Highly enantio- and regioselective quinone Diels-Alder reactions catalyzed by a tridentate [(Schiff Base)Cr(III)] complex. Angew Chem Int Ed Engl 44:6043-6 |
| Raheem, Izzat T; Goodman, Steven N; Jacobsen, Eric N (2004) Catalytic asymmetric total syntheses of quinine and quinidine. J Am Chem Soc 126:706-7 |
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