Research

Expanding Chemical Space in Heterocyclic and Carbocyclic Chemistry

The recent chemistry performed in the Doyle Group has created convenient access to a vast array of new chemical structures that are otherwise difficult to prepare. They fall into the category of heterocyclic compounds that constitute the majority of pharmaceutically important drugs and drug candidates, and they are adaptable to highly stereoselective syntheses and further elaboration. New chemical space is accessed catalytically from stable diazo compounds and affords structurally complex products with high efficiencies and selectivities. Our research is being developed in stages in order to assess biological effectiveness: (1) development of unique libraries that explore new chemical space, (2) biological assays of representative compounds, and (3) structural modifications that enhance biological activities.

Enoldiazoacetates are a subclass of vinyldiazoacetates that are directly accessed from diazoacetoacetates in high yield. These compounds are exceptionally stable, having no tendency to undergo intramolecular dipolar cycloaddition to form 3H-pyrazoles, and they have shown remarkable versatility in catalytic cycloaddition reactions. Their intermolecular cycloaddition reactions have made possible facile synthesis of heterocyclic compounds containing one or more nitrogen and/or oxygen atoms (Scheme 1). With enoldiazoacetates we have shown that stepwise highly enantioselective [3+3]-cycloaddition is a viable synthetic transformation for the construction of six-membered ring heterocyclic compounds, and a variety of [3+2]-cycloaddition processes give five-membered ring heterocycles. The key to the rapid development of this methodology has been recognition that catalytically generated metallo-enolcarbenes are effective dipolar adducts for [3+3]-cycloaddition. One or more heteroatoms is introduced and, with high levels of enantioselectivity obtained via asymmetric catalysis, this methodology has the potential to be the catalytic method of choice for the synthesis of many classes of heterocyclic compounds.

Scheme 1 
Expanding Chemical Space for Heterocyclic Compounds through Applications of Enol-diazoacetates. Asymmetric catalytic syntheses of 1,2-Oxazines, 1,2,3,6-Tetrahydropyridazines, Dihydro-quinolines, and Quinolizidines. Catalytic Selective Syntheses of Pyrazolidinones, Pyrazoles, Pyrazolidin-ones, Tetrahydroquinolines, Benzazepines, Aminofuranones, Aziridines, and Oxazoles, among others.

Selective Chemical Oxidations
Oxidation reactions of organic compounds are critically important throughout the chemical sciences, and they are particularly relevant in biological systems and for industrial processes. The search for precise control over the oxidation state of functional groups in target molecules and for chemo- and regioselectivity of oxidation has led to the development of a large variety of oxidative protocols. Variation of selectivity and improvement of efficiency has inspired progress in catalytic approaches, and efforts to decrease cost have drawn investigators to chemical catalysis and towards dioxygen as the optimal oxidant. Peroxides, especially hydroperoxides, have been useful for the development of selective oxidations and for understanding how to eventually engage dioxygen. We have made substantial progress in developing and understanding radical oxidations in their investigations using dirhodium caprolactamate [Rh2(cap)4] as a catalyst and tert-butyl hydroperoxide (TBHP) as a terminal oxidant (Scheme 1). Recent research on dirhodium caprolactamate catalyzed chemical oxidations with hydroperoxides has not only produced highly selective processes (for example, allylic oxidation – the Umera-Doyle reaction, oxidative Mannich reactions, and phenolic peroxidation), but recently we have also uncovered a synthetically applicable iron(III) chloride catalyzed oxidative Mannich reaction in which molecular oxygen is the oxidant.

Scheme 1 The Rh2(cap)4–TBHP system has provided multiple synthetically-valuable oxidative transformations and continues to be a source for fruitful discoveries.
 
A wide range of oxidative processes employs tert-butyl hydroperoxide (TBHP) as a terminal oxidant. With a half-life of over 520 hours in refluxing benzene, TBHP has fewer handling risks than does H2O2 in water or peracetic acid. The low acidity of TBHP (pKa = 12.8) contributes to the versatility of its uses, and volatile reaction products derived from TBHP (tert-butyl alcohol, water, molecular oxygen, and di-tert-butyl peroxide) simplify purification. Anhydrous solutions of TBHP are commercially available or can be easily prepared due to the high solubility of TBHP in organic solvents. Furthermore, TBHP is available as a 70% aqueous solution (T-HYDRO) that offers fewer handling risks and is less expensive than solutions of TBHP decane or benzene.

Sulfoxides with catalytic dirhodium(II) is a highly chemoselective reagent for the quantitative conversion of diazocarbonyl compounds to dicarbonyl compounds without also oxidizing other unsaturated centers. This oxidative procedure will be elaborated for the conversion of diazoacetoacetates to 2,3-diketoesters that have shown remarkable reactivity and selectivity in asymmetric ene reactions41 and show promise for other condensation reactions.
Novel Transformations of Diazo Compounds

In the long history of Diels-Alder reactions there has not been a reported example of [4+2]-cycloaddition between a diene and a diazo compound. Their isoelectronic allene and ketene counterparts, however, do undergo these reactions and have received considerable attention (Scheme 3). Concerted thermal [4+2]-cycloaddition reactions of dienes with highly polarized allenes have been extensively investigated, but favorable competing stepwise [2+2]-cycloaddition reactions diminish their synthetic importance. Transition-metal-catalyzed allene-diene cycloaddition reactions, although recent in their discovery, have circumvented this competition and become a mainstay of new process developments. Ketenes readily undergo [2+2]-cycloaddition5 and, recently, [4+2]-cycloaddition reactions, but for the latter only with highly activated diene equivalents6 or with the aid of suitable catalysts. In contrast, diazo compounds commonly react with one double bond of dienes by dipolar cycloaddition or, following dinitrogen extrusion, by cyclopropanation (Scheme 1), but not by [4+2]-cycloaddition.

 
The diene is formed by gold(I) catalysed rearrangement of propargyl phenyldiazoacetates in the presence of a pyridine-N-oxide. Isolation of the diene product allows examination of the cycloaddition reaction that occurs at room temperature. This process is favored over [3+2]-cycloaddition only for this system, and this has been confirmed by computational methods. The heterocyclic product is a stable dipole that itself undergoes cycloaddition with activated alkenes.