The Application of Molecular Rearrangements to the Concise Synthesis of Natural Products

Prof. Leo A. Paquette
Universidad Estatal de Ohio

As synthetic methodology advances, pressure increases to arrive at targeted structures in highly stereoselective fashion, with good atom economy, and in as few steps as possible. These goals can be realized in notable fashion by the proper deployment of molecular rearrangements. In this lecture, attention will be given to specific examples where the superb scaffolding power of the so-called 'squarate ester cascade' and anionic sigmatropy are shown to be instrumental in delivering complex natural products in a highly efficient manner.

Prof. Antonio M. Echavarren Pablos
Universidad Autónoma de Madrid

Electrophilic metal complexes promote the anti attack of alkenes onto the (?2-alkyne)metal complexes to give cyclopropyl metal carbenes as intermediates, which react with alcohols or water to give cyclized derivatives. A similar type of reaction was found in the intramolecular reaction of allylsilanes and allylstannanes with alkynes. Furans can also be used instead of alkenes to finally afford substituted phenol derivatives. The scope, mechanistic aspects, and new developments will be presented.

Prof. Erick M. Carreira
Instituto Tecnológico de Zurich

A novel concept for the development of asymmetric catalytic C-C bond forming reactions will be presented involving the in situ activation of terminal acetylenes under mild conditions. In this regard, we have recently documented the addition of terminal acetylenes to nitrones and aldehydes under mild conditions utilizing catalytic Zn(II) and amine base. In the coupling reactions of acetylenes, the use of the inexpensive commercially available amino alcohol ligands was observed to furnish optically active propargylic alcohols and hydroxylamines in excellent enantioselectiviy and yields. We have also recently documented the use of [Ir(COD)Cl]2 as a catalyst for the addition reaction of Me3SiCCH to simple N-benzyl and N-allyl imines. Both the Zn(II) and Ir(I) chemistry are notable for their convenience, as these can be run in the absence of solvent without rigorous exclusion of moisture or air.

Prof. José Barluenga
Universidad de Oviedo

In this lecture, several transformations using group 6 Fischer carbene complexes, of interest in selective organic synthesis, will be presented. In this sense, pentacarbonyl(alkoxy)carbene-chromium and -tungsten complexes have proven as highly useful intermediates in the synthesis of acyclic and cyclic molecules. The marked p-acceptor behavior of metal pentacarbonyl moiety makes these complexes appropriate substrates for reactions with different nucleophiles.Processes involving pentacarbonyl complexes bearing alkenylcarbene and alkynylcarbene ligands will be reported. Asymmetric transformations using either optically active complexes or nonracemic, chiral substrates, will receive special attention

Prof. William R. Roush
Universidad de Michigan

Recent studies in the total synthesis of structurally complex, biologically active natural products will be presented. Studies on the development of new synthetic methodology involving the aldol reaction or the reactions of carbonyl compounds with novel allylmetal reagents (of the allylboron or allylsilane families) also will be presented.

Prof. Paul A. Wender
Universidad de Stanford

Studies in our laboratory focus on the synthesis and investigation of molecules of structural, biological, and medicinal significance. Representative of this program are natural products such as taxol, phorbol, and bryostatin. This lecture will focus on the interplay of chemistry, biology and medicine leading to the design of a fascinating cancer therapeutic lead moving toward clinical trials (background: Proc. Natl. Acad. Sci. USA 1998, 95, 6624; J. Am. Chem. Soc. 1998, 120, 4534) and a series of fundamentally new transition metal catalyzed reactions (e.g., J. Am. Chem. Soc. 1998, 120, 10976; 2000, 122, 7815; 2002, 124, in press). A further product of this multidisciplinary program is the identification of compounds that solubilize and facilitate cellular and tissue uptake of a variety of drug and probe cargoes, findings that have led to a new biotech company, CellGate Inc. (recent references include: Nature Medicine 2000, 6, 1253-1257; Proc. Natl. Acad. Sci. USA , 2000, 97, 13003).

Prof. Joan Bosch
Universidad de Barcelona

The following syntheses will be discussed: a) a straightforward synthesis of indole alkaloids of the ervitsine-ervatamine group, via a dihydropyridinium cation that can be envisaged as a synthetic equivalent of the key intermediate in the biosynthesis of these alkaloids; b) an enantioselective synthesis of pentacyclic Strychnos indole alkaloids involving a biomimetic transannular cyclization as the key step; and c) a general entry to Strychnos alkaloids via a common advanced intermediate, which has culminated in the synthesis of (-)-Strychnine.

Prof. Steven Ley
Universidad de Cambridge

With the ever increasing demand for new compounds, synthetic chemists have been expected to accelerate greatly their rate of production of new chemical entities. The preparation of biologically active and many other functional material from small, commercially available building blocks inevitably involves more that one synthetic step. For most modern drugs and other complex molecules, it is not uncommon to require at least 10 steps and sometimes many more. In order to address these goals we believe a much better practical solution for the preparation of large chemical libraries rather than use solid phase organic synthesis would be to use solid-supported reagents in a designed sequential and multi-step fashion. In combination with advances in the use of scavenging agents and catch and release techniques even greater opportunities for organic synthesis become apparent. This lecture will present results from our laboratories towards this goal.

Prof. Peter Wipf
Universidad de Pittsburgh

The hydrozirconation of alkenes and alkynes is one of the most versatile and direct pathways for the formation of organometallic intermediates organic synthesis. Due to the steric shielding of the C-Zr bond by the cyclopentadienyl ligands, however, many applications of organozirconocenes been limited to oxidative cleavage with halogens. In addition to chloride abstractions with silver(I) salts and subsequent cascade processes initiated by formally cationic zirconocenes, transmetalation of the C-Zr bond to other metal salts is an effective way to utilize the potential of the organozirconocene intermediate for carbon-carbon bond formation. We have previously developed protocol for Zr–>Zn which allows in situ addition to aldehydes, and, in the presence of chiral ligand, the enantioselective preparation of allylic alcohols. In this lecture, I will report recent developments of our methodology studies with zirconocenes as well as applications of catalytic asymmetric carboaluminations and water-accelerated Claisen rearrangements.