Organometallic Enantiomeric Scaffolding. Enantiomerically-pure Heterocycle Molybdenum π-Complexes as Scaffolds for the Construction of Biologically-active Natural Products.
Nature gives us chiral, non-racemic and plentiful natural products that can be used as chiral synthons or "chirons" from which diverse molecular architectures can be constructed or that can be used as chiral auxiliaries or chiral ligands. We are exploring another approach to enantiocontrolled bond construction that uses single enantiomers of organometallic complexes as "enantiomeric scaffolds" from which single enantiomers of complex organic structures are elaborated. This strategy entails the production, in quantity, of a single enantiomer of a metal π-complex of an unsaturated organic ligand, and the subsequent synthetic elaboration of the scaffold over a number of steps to generate, after demetalation, an advanced compound possessing multiple stereocenters. In this strategy the stoichiometric nature of the chemistry is mitigated by the use of a single metal moiety either to activate the organic ligand for multiple enantiocontrolled functionalizations or to open pathways for unique bond constructions not easily achieved by traditional synthetic manipulations. We have developed particularly versatile organometallic enantiomeric scaffolds that are conceptually simple yet allow the construction of widely differing families of structures (Figure 1).
Figure 1. Organometallic Enantiomeric Scaffolds in Enantiocontrolled Synthesis
Figure 2. Organometallic Enantiomeric Scaffolds in Enantiocontrolled Synthesis
(Click to enlarge)
Bioinspired Organometallic Chemistry
Nature has evolved significant metalloenzymatic and non-enzymatic processes that rely on key interactions of thiols and thiolates with redox-active metals such as Co, Cu, Fe, Ni, and Mo, and with non-redox active metals such as Zn. How can these metals function as robust catalysts in vivo even though the bond between a mercaptide ligand and the late transition metals is often quite strong? How is a metal thiolate bond selectively labilized in an aqueous, aerobic environment at ambient temperatures and near neutral pH?
Scheme 2. Thiol Ester – To a new ketone synthesis?
· Can Nature be mimicked and highly efficient metal-mediated catalysis of thioorganics be achieved at ambient temperature under mild conditions in the laboratory?
· How can these metals function as robust catalysts in vivo even though the bond between a mercaptide ligand and the late transition metals is often quite strong?
· How is a metal thiolate bond selectively labilized in an aqueous, aerobic environment at ambient temperatures and near neutral pH?
By probing answers to these questions, we have uncovered a series of synthetically useful, metal-mediated transformations of organosulfur compounds that occur under mild conditions. The most recent variants of these reactions take place under biologically relevant, aerobic conditions without the introduction of stoichiometric activators.
From a synthetic perspective, the coupling of stable organosulfur compounds with boronic acids would be a boon to the synthetic chemist, since both reaction partners are readily available and are stable molecules of low toxicity. The low thiophilicity of boron or tin combined with the low nucleophilic reactivity of organoboron derivatives render this transmetallation problematic.
1. One solution to this problem was found in the unusual efficacity of tetrahydrothiophene-based sulfonium salts as partners in palladium-catalyzed cross-coupling reactions.
2. A dual thiophilic/borophilic activation was conceived using an additive reagent M-X (M has a high affinity for thiolate and does not interfere with the catalyst, while X has a high affinity for boron) as shown in Scheme 3.
Scheme 3. Thiol Ester – Boronic Acid Coupling under Non-Basic Conditions
Scheme 4. Application to the Synthesis of Amino Acid, di-, tri- and Polypeptidyl Ketones
Heteroaromatic compounds are important in the chemical, agricultural, and pharmaceutical industries. Accordingly, the development of new, mild, and general methods to functionalize heteroaromatics is an important synthetic goal. Heteroaromatic thioethers and aryl, heteroaryl, and alkenylstannanes are able to participate in a palladium-catalyzed, copper(I)-mediated cross-coupling reaction at 50 °C in THF (Scheme 5)
Scheme 5. Heteroaromatic Thioethers – Boronic Acid Coupling under Non-Basic Conditions
In recent years, heterocycles have been successfully utilized as scaffold systems for lead discovery and prospecting for biological activities via the combinatorial and parallel medicinal chemistry formats. As heterocycles can often be considered “condensed, conformationally constrained” derivatives of amino acids, they are ideal central platforms for the generation of peptide surrogates. These systems can be designed to spatially display remnants of peptide secondary structure and side-chain functionality to enable the preferred ligand-receptor conformational ensemble in concordance with the strategic movement from peptides to peptidomimetics possessing the required pharmacokinetic characteristics. Liebeskind's team reported a modular synthesis of highly functionalized pyrimidinone heterocycles that has proven efficient for traditional analogue synthesis and may have application to parallel methodologies. This strategy can be envisioned as a combination of “graded functionality” and “orthogonal reactivity”. For selectivity, it relies upon the mechanistic differences between the Suzuki-Miyaura and Stille cross-coupling of halides compared to the Liebeskind-Srogl protocol for thioorganics (Scheme 6).
Scheme 6. Application to Parallel Methodologies?