| Department of Chemistry University of Utah 315 So. 1400 E. Rm. 4253A Salt Lake City, UT 84112 sigman@chem.utah.edu Office: (801) 585-0774 Seminar Schedule |
||
|
Research Overview |
|
Overview: The discovery and development of versatile synthetic methods for organic synthesis have given chemists the tools to construct virtually any desired target. However, many of the existing methods suffer from practical limitations such as limited substrate scope and functional group tolerance, overall efficiency to the target, harsh conditions, and toxic reagents. The reason for this may stem from a discovery process that involves the rather daunting combination of empirical observations and chemical intuition where optimal systems are easy to miss. We have undertaken a different approach to reaction discovery. Our strategy is to incorporate mechanistic studies of empirical findings with the design of modular catalysts. Using this approach, we believe we can improve both the quality and speed in which new versatile synthetic methods are discovered. |
|
Practical Oxidations in Organic Synthesis. Oxidation reactions are essential for both functional group manipulation and heteroatom incorporation in the synthesis of biologically relevant compounds. Additionally, newly discovered and significantly improved oxidative processes can have a direct effect on the approaches to and execution of targeted syntheses. Therefore, the development of selective practical oxidation reactions is a continuing challenge facing chemists in both academia and industry. A key consideration in developing oxidation reactions is selection of the stoichiometric oxidant where versatility, expense, and environmental impact need to be addressed. An attractive approach is the use of metal-catalyzed oxidations coupled to a practical terminal oxidant such as molecular oxygen or hydrogen peroxide. Based on our success in ligand modulated Pd-catalyzed aerobic alcohol oxidations, our program is now focused on developing new aerobic enantioselective Pd(II)-catalyzed olefin functionalization reactions.
Olefin Difunctionalization Reactions. Developing reactions which add two functional groups across an olefin in an enantiomerically and diastereomerically controlled manner should offer new efficient methods for bond construction. In this regard, we have recently developed an enantioselective direct O2-coupled Pd-catalyzed dialkoxylation reaction of o-propenyl phenols (J. Am. Chem. Soc. 2006, 128, 1460 & J. Am. Chem. Soc 2007, 129, 3076). Isotopic labeling studies and substrate evaluation support a unique mechanism which accounts for the requirement of o-propenyl phenol substrates. In this process, two intimately coupled steps are proposed (Figure 1): (a) regioselective nucleopalladation of A via methanol addition to the β-carbon of the styrene yielding B and (b) subsequent formation of a quinone methide species C with concomitant reduction of Pd (Figure 1). Dialkoxylation is achieved by addition of a second equivalent of methanol to the quinone methide C. Additionally, since propenyl phenol derivatives isomerize rapidly to the E-isomer, we attribute the modest diastereoselection to the chiral center of C directing the second methanol attack. This mechanistic motif is currently inspiring the development on new olefin difunctionalization reactions and the verstatility of the method is promoting us to apply these reactions to synthetic targets.
Olefin Hydrofunctionalization Reactions. While exploring the scope of the dialkoxylation of vinylphenols, we found that Pd[(–)-sparteine]Cl2 catalyzed the transformation in methanol resulting in a 70% yield with a 4.5 to 1 syn to anti ratio in <5% ee. Interestingly, switching the solvent to ethanol led to an unanticipated change in reaction outcome, providing a 64% yield of the hydroalkoxylation product (Figure 2). This process has been optimized to encompass a vast number of alcohol substrates adding to o-vinyl and o-propenyl phenol substrates (J. Am. Chem. Soc. 2006, 128, 2794 & Org. Lett. 2006, 8, 5557). Intrigued by the unique nature of this transformation and potential synthetic applications, we have studied the reaction mechanism. Initially, the reaction was thought to proceed through a nucleopalladation-protonation process similar to that proposed in related metal-catalyzed hydroalkoxylation reactions. Therefore, the use of CH3CH2OD as the solvent should result in a single deuterium atom incorporation at the site of Pd-C protonation. However, submitting X to the hydroalkoxylation conditions in CH3CH2OD resulted in no deuterium incorporation into the product. In contrast, the use of CD3CD2OD produced isotopomers Y and Z in a 2.5 to 1 ratio. The labeling experiments suggest that the Pd-C bond is not protonated by solvent, but rather the incorporated hydrogen originates from the alkyl chain of a separate equivalent of ethanol (Figure 8). Based on these results, we propose a mechanism requiring the oxidation of ethanol to produce a Pd-hydride F. Supported by the isotopic labeling experiments, insertion of vinyl phenol into the hydride is reversible and not regioselective, and the products arise only from palladation at the α-carbon of the styrene. H is proposed to proceed to product via formation of an ortho-quinone methide intermediate I with concomitant reduction of the catalyst. Ethanol would subsequently add into the ortho-quinone methide to form the carbon-oxygen bond.
Extension to new olefin functionalization reactions coupled to aerobic alcohol oxidation. Considering these results, we questioned whether other Pd(II)-catalyzed processes, such as transmetallation with an organometallic reagent, could be integrated into the olefin functionalization sequence to form new C-C bonds (Figure 3). If this is indeed possible, a substantial number of unique synthetically attractive transformations can be envisioned. Specifically, oxidation of the alcohol solvent (in this case 2-propanol) with a Pd-catalyst J will lead to the formation of a Pd(II)-hydride K. Insertion of the alkene into the Pd(II)-hydride yields a Pd(II)-alkyl intermediate M similar to that formed via oxidative addition of an organic electrophile in a traditional cross-coupling reaction. Transmetallation to form N and subsequent reductive elimination generates the reductive coupling product as well as the reduced catalyst O. Aerobic oxidation of Pd(0) to Pd(II) completes the catalytic cycle. In the overall reaction, the sp2-hybridized carbon atoms of the alkene will be reduced to sp3-hybridized carbon atoms. Incorporation of sp3-hybridized carbon atoms in traditional cross-coupling reactions is significantly more challenging than sp or sp2-hybridized carbons (J. Am. Chem. Soc. 2007, 129, 14193). An exciting aspect of this type of alkene reductive coupling with an organostannane is expansion to reaction types not accessible using reported hydroarylation methods. To this end, several vinyl stannanes were tested under the optimized conditions with a slight increase of catalyst loading (3h-k). Stannanes containing enol ethers were good coupling agents for the reductive coupling as is highlighted by the ability to perform an overall hydroacylation reaction (3k). Current efforts are focused on exploiting this unique approach to alkene functionalization by expanding the scope of these processes to other cross-coupling partners and asymmetric catalysis. We have also extended this approach to hydrohalogenation/hydroalkoxylation of styrenes (Organometallics 2007, 26, 5680). |
|
Modular Ligands in Asymmetric Catalysis and Physical Organic Chemistry. There has been remarkable progress in asymmetric catalysis since the inception of the field three decades ago and, chiefly, over the last decade. Because of this, asymmetric catalysis now provides chemical researchers in both academia and industry with the means to directly access useful enantiomerically enriched compounds. With advances in technology (i.e. high throughput screening), the identification of an asymmetric catalyst that promotes a transformation in high enantiomeric excess has been expedited. However, the approach to catalyst identification remains mainly empirical, wherein evaluation of a significant number of ligands, often structurally unrelated, is required to develop a mature chiral catalyst. This leads to a fundamental question: why does the use of a particular ligand or catalyst structure prove effective for a specific reaction? Addressing this question should provide insight into the guiding principles of asymmetric catalyst design, thereby significantly accelerating the development of new catalysts via enhanced predictability. Thus, our program is focused on developing a greater understanding of chiral catalyst design by using modular ligand templates in the context of identifying new asymmetric catalysts for synthetically useful transformations.
Enantioselective Addition of Activated Halides to Carbonyl Compounds. Nozaki-Hiyama-Kishi (NHK) and related reactions are being investigated due to the plethora of Cr(II)-mediated carbon-carbon bond forming reactions to produce diverse chiral building blocks. Although there have been several recent examples of successful catalytic enantioselective NHK reactions, discovery of catalysts for these reactions has been primarily focused on allylation of aldehydes (including in our laboratory – Org. Lett. 2005, 7, 1837). Therefore, by having a modular ligand template and understanding the relationship between structure and selectivity, we hope to facilitate the rapid development of new asymmetric NHK reactions. In this regard, we have recently developed an enantioselective ketone allylation reaction using allylic bromides (Figure 4, J. Am. Chem. Soc. 2007, 129, 2752). We are currently exploring diverse reactions types with this motif as well as elucidating the factors that control enantioselectivity using the modular nature of the ligand.
Exploring Electronic Effects in Hydrogen Bond Catalysis.The development of enantioselective hydrogen bond catalyzed reactions has seen amazing growth over the last several years. However, very few mechanistic investigations have been performed to elucidate the features that lead to effective catalysis. A hydrogen bond catalyst has been developed in our laboratory with a unique design featuring an oxazoline core with a pendant amine and alcohol (Org. Lett. 2005, 7, 5473). This design provides two sites capable of hydrogen bond donation, which can be independently tuned (see above). Catalysts of this type have been shown to be effective in the asymmetric hetero Diels-Alder reaction between Rawal’s diene (D) and benzaldehyde (A). The modular nature of the catalyst makes it suitable for mechanistic studies as rapid synthesis of analogs allows one to probe the relationship between catalyst structure and activity. We hypothesized that a more acidic catalyst would be a better hydrogen bond donor and thus would lead to enhanced substrate activation. We recently have investigated this assertion by synthesizing and evaluating a series of hydrogen bond catalysts in the hetero Diels-Alder reaction (Angew. Chem. Int. Ed. 2007, 46, 4748). In this study, we found that both rate and enantioselectivity could be correlated to the relative pKa of the catalyst. |
|
|
|
