"The interplay of target-oriented synthesis and new reaction development is critical
for the intellectual development of the field of organic synthesis."
"Frontiers of organic synthesis defined by one's ability to successfully handle
the challenges of escalating architectural & dynamic molecular complexity."
As the above graphic illustrates, our research group is committed to the development of new reactions that are relevant to the synthesis of complex organic structures. It is my conviction that new reaction discovery is the most important research activity in the area of organic chemistry, and that targetdirected reaction discovery is one of the best strategies for identifying important transformations to be developed. Our group’s research activities are nearly equally apportioned between target-oriented synthesis and new reaction discovery, and students will frequently gain experience in both of these areas during their Ph. D. thesis research. Several case studies of target-driven reaction development are provided below. This discussion is followed by a summary of some of our studies in the design of chiral metal complexes and their applications as Lewis acid catalysts in important C–C bond forming reactions such as Diels-Alder, Michael, and aldol addition reactions.
Case Study: Ionomycin
Some years ago, while contemplating the synthesis of the calcium-selective ionophore ionomycin it became obvious that major portions of this structure could be assembled through a series of iterative chiral enolate alkylation reactions. Thus, ionomycin provided the stimulus to develop practical enolates derived from chiral amides (pub 54, 55, 60
) and imides (pub 58, 59, 66
) that functioned well in highly diastereoselective alkylation and aldol addition reactions. In turn, these new methods were applied to the synthesis of ionomycin (pub 128
Ionomycin synthesis resulted in design of iterative asymmetric alkylation reactions
Such methodology, if refined, reduces the synthesis to a series of interative bond constructions
Case Study: Vancomycin
A more recent study from our laboratory has been concerned with the the development of a general approach to the synthesis vancomycin and teicoplanin, antibiotics of last resort that have been effective in the treatment of methicillin-resistant staphylococcal infections. It is evident from the graphic provided below that the peptide based architectural complexity is exceptionally high. Some of the problems that we addressed in this project are outlined below.
Complex molecular targets quickly identify the current limitations of the field!
Antibiotics of choice for treatment of Methicillin-resistant Staphylococcal infections
The Atropisomer Problem.
The high barrier to rotation about the biaryl bond in vancomycin introduces an element of axial chirality into the structure, while hindered rotation about the axes defined by the para-oriented CH(OH) and OAryl substituents in ring-2 and ring-6 incorporates two examples of planar chirality. Collectively, these three features of the aglycon architecture present the significant challenge of controlling atropisomerism in the construction of each of the three macrocyclic tripeptide subunits designated as M(2-4), M(4-6), M(5-7). Hence, even with asymmetric syntheses of the amino acid constituents and an assemblage strategy in hand, one is still faced with the problem of producing the vancomycin aglycon skeleton as only one of eight possible atropdiastereomers. For a solution of these stereochemical challenges see pub 232
The Amino Acid Constituents.
Complex arylglycines and b-hydroxy-a-amino acids comprise the principle amino acid constituents in this family of antibiotics. Chiral enolate methodology was used to develop a range of electrophilic amination (pub 91, 101, 110, 126
), oxygenation (pub 81
), and bromination (pub 98
) reactions that afforded efficient approaches to the arylglycine residues. The synthesis of b-hydroxy-a-amino acids, was again addressed using chiral enolate methodology (pub 97, 99, 119
). Our interest in methods that deliver enantiomerically pure amino acids continues. Over the last several years we have development catalytic enantioselective approaches to these important building blocks using chiral metal complexes (pub 168, 217, 250, 267
Diaryl Ether Synthesis.
Mild approaches to the synthesis of diaryl ethers, under conditions that avoid amino acid racemization, were needed. The use of arylboronic acids to “arylate” phenols under the influence of copper(II) salts (pub 225
) successfully addressed this problem. In effect, this reaction is a mild version of the Ullmann diaryl ether synthesis. Our application of this transformation in a highly complex setting may be found in our recently reported synthesis of the teicoplanin aglycon (pub 273
The preceding methodologies have been recently integrated into the syntheses of the aglycons of vancomycin, eremomycin, orienticin C (pub 231
) and teicoplanin (pub 273
Case Study: Altohyrtin and Phorboxazole
The phorboxazoles and spongistatins (altohyrtins) are among the most cytostatic marine natural products known inhibiting the growth of tumor cells at nanomolar to sub-nanomolar concentrations. Over the last few years our laboratory has addressed the syntheses of both of these targets. Our studies relevant to the synthesis and stereochemical proof of altohyrtin C (spongistatin 2) may be found in the following publications (pub 222, 223, 244
) while our studies culmination in the synthesis of phorboxazole B have also appeared in the literature (pub 243, 261, 262, 264
). These syntheses illustrate the growing role that asymmetric catalysis has played on the reactions that we now have at our disposal. In the graphic below the indicated catalytic processes and their color-coded applications to the construction of each of the indicated structures is highlighted.
Catalytic Processes Incorporated into the Altohyrtin & Phorboxazole Syntheses
Chiral Metal Complexes as Lewis Acid Catalysts
Chiral bis(oxazoline)-Cu(II) complexes were introduced in 1993 as chiral Lewis acid catalysts for imidebased enantioselective Diels-Alder reactions (pub 171, 175, 189
). These complexes were designed to have two open coordination sites to facilitate chelate association with substrates possessing suitably positioned donor heteroatoms. In the graphic below are illustrated a series of hydrated cationic Cu(2+)–Box complexes. The bound waters locate the binding sites for chelating substrates. These structures highlight the effect of the ligand substituents on the orientation of the open coordination sites.
Bis(oxazoline)Cu(SbF6–)2•2H2O X-ray Structures: Steric & Electronic Induced Distortions
These reactions were followed by further studies that improved catalyst performance through the introduction of the cationic Cu(II)-based catalyst variants illustrated above. These modified catalysts perform at ambient temperatures with a broad range of reactants in both bimolecular and intramolecular processes and deliver asymmetric induction above 90% ee (pub 189, 205, 208, 216, 245. 246
). Chiral bis(oxazoline)-Cu(II) complexes were then introduced as chiral catalysts for the enantioselective glyoxylate ene reaction (pub 229, 260
) and as chiral catalysts for two important classes of hetero Diels-Alder Reactions (pub 235, 251
). These same complexes are also highly effective aldol (pub 199, 202, 218, 233, 234
) and Michael addition catalysts (pub 236, 253, 263
).This family of cationic copper(II) Lewis acid catalysed reactions has recently been reviewed (pub 249, 252
). A selection of reactions developed by our group is summarized below.
Recent Lewis Acid Catalyzed Transformations Developed by the Evans Group
We have also introduced a new family of chiral Sn(II) complexes that exhibit levels of stereocontrol comparable to the previously described Cu(II) complexes but with complementary diastereoselection (pub 222
). In as yet unpublished research, we have been able to obtain X-ray structures of the stannous triflate box and pybox complexes. The influence of the stereochemically active nonbonding lone pair on the metal center is evident in the illustrated structures.
X-ray Structures of Sn(II)-Pybox & Sn(II)-Box Complexes