Petri M. Pihko

Hydrogen bonding in organic synthesis

Preface INTRODUCTION Introduction Hydrogen Bonding in Organic Synthesis HYDROGEN-BOND CATALYSIS OR BRONSTED-ACID CATALYSIS? GENERAL CONSIDERATIONS Introduction What is the Hydrogen Bond? Hydrogen-Bond Catalysis or Bronsted-Acid Catalysis Bronsted-Acid Catalysis Hydrogen-Bond Catalysis COMPUTATIONAL STUDIES OF ORGANOCATALYTIC PROCESSED BASED ON HYDROGEN BONDING Introduction Dynamic Kinetic Resolution (DKR) of Azlactones-Thioureas Can Act as Oxyanion Holes Comparable to Serine Hydrolases On the Bifunctionality of Chiral Thiourea-Tert-Amine-Based Organocatalysts: Competing Routes to C-C Bond Formation in a Michael Addition Dramatic Acceleration of Olefin Epoxidation in Fluorinated Alcohols: Activation of Hydrogen Peroxide by Multiple Hydrogen Bond Networks TADDOL-Promoted Enantioselective Hetero-Diels-Alder Reaction of Danishefskys Diene with Benzaldehyde - Another Example for Catalysis by Cooperative Hydrogen Bonding Epilog OXYANION HOLES AND THEIR MIMICS Introduction What are Oxyanion Holes? A More Detailed Description of the Two Classes of Oxyanion Holes in Enzymes Oxyanion Hole Mimics Concluding Remarks BRONSTED ACIDS, H-BOND DONORS, AND COMBINED ACID SYSTEMS IN ASYMMETRIC CATALYSIS Introduction Bronsted Acid (Phosphoric Acid and Derivatives) N-H Hydrogen Bond Catalysts Combined Acid Catalysis (THIO)UREA ORGANOCATALYSTS Introduction and Background Synthetic Applications of Hydrogen-Bonding (Thio)urea Organocatalysts Summary and Outlook HIGHLIGHTS OF HYDROGEN BONDING IN TOTAL SYNTHESIS Introduction Intramolecular Hydrogen Bonding in Total Syntheses Intermolecular Hydrogen Bondings in Total Syntheses Conclusions

Palladium-Catalyzed Dehydrogenative β′-Functionalization of β-Keto Esters with Indoles at Room Temperature

The dehydrogenative β-functionalization of α-substituted β-keto esters with indoles proceeds with high regioselectivities (C3-selective for the indole partner and β-selective for the β-keto ester) and good yields under mild palladium catalysis at room temperature with a variety of oxidants. Two possible mechanisms involving either late or early involvement of indole are presented.

Asymmetric Organocatalytic Diels-Alder Reactions on Solid Support

Asymmetric organocatalysis on solid support combines the environmental advantages of metal-free catalysts and the ease of operation of solid-supported reagents. Enantioselective organocatalytic DielsAlder reactions have been demonstrated by two different solid-supported chiral organocatalysts. The catalysts are easy to recover and they can be reused. The reactivity of the catalyst can be tuned by changing the solid support.

Dihydrooxazine Oxides as Key Intermediates in Organocatalytic Michael Additions of Aldehydes to Nitroalkenes

Pause and play: dihydrooxazine oxides are stable intermediates that are protonated directly, without the intermediacy of the zwitterions, in organocatalytic Michael additions of aldehydes and nitroalkenes (see scheme, R=alkyl). Protonation of these species explains both the role of the acid co-catalyst in these reactions, and the observed stereochemistry when the reaction is conducted with α-alkylnitroalkenes.

Cooperative Assistance in Bifunctional Organocatalysis: Enantioselective Mannich Reactions with Aliphatic and Aromatic Imines

Hold them tight: Guided by X-ray structures, bifunctional thiourea catalysts containing an activating intramolecular hydrogen bond were redesigned. The new catalysts were used to effect a highly enantioselective Mannich reaction between malonates and both aliphatic and aromatic imines (see scheme; Boc=tert-butoxycarbonyl).

Synthesis of the FGHI Ring System of Azaspiracid

Previously attempted spirocyclizations to form the ABCD ring system of azaspiracid (1) have proven unsuccessful owing to the anomeric effects that favor the formation of the undesired 13S diastereomer. By the use of a hydrogen bond donor as an auxiliary group, such anomeric effects were successfully overcome. Thus, the first synthesis of the ABCD ring system of azaspiracid with the proper 13R configuration of the C13 stereocenter was achieved.

Mukaiyama–Michael Reactions with Acrolein and Methacrolein: A Catalytic Enantioselective Synthesis of the C17–C28 Fragment of Pectenotoxins

Enantioselective iminium-catalyzed reactions with acrolein and methacrolein are rare. A catalytic enantioselective Mukaiyama-Michael reaction that readily accepts acrolein or methacrolein as substrates, affording the products in good yields and 91-97% ee, is presented. As an application of the methodology, an enantioselective route to the key C17-C28 segment of the pectenotoxin using the Mukaiyama-Michael reaction as the key step is described.

Dual Hydrogen‐Bond/Enamine Catalysis Enables a Direct Enantioselective Three‐Component Domino Reaction

The nitro group enjoys a privileged position among the functional groups that can be activated through hydrogenbond catalysis. However, the hydrogen-bond-acceptor capacity of the nitro group is lower than that of the carbonyl or the imine group. To increase reactivity, the use of catalysts bearing multiple-hydrogen-bond donor (MHBD) groups to increase the catalytic activity through possible formation of several hydrogen bonds represents an attractive option for enantioselective catalysis. 4] Although this approach has been successfully used in multifunctional catalysts where all the necessary functionalities are incorporated in the same catalyst molecule, the use of separate catalysts for electrophile and nucleophile activation might allow more opportunities for catalyst and reaction screening because both catalysts could be optimized separately. As an example, enantioselective enamine catalysts typically incorporate a hydrogen-bond-donor site (Scheme 1, Type A) or rely on steric control alone (Type B). Herein we demonstrate that the use of a dual catalyst system can lead to significant rate enhancements in enamine catalysis and describe the successful use of a dual MHBD/ enamine catalyst system for a highly enantioselective domino three-component reaction sequence (Scheme 2). Both steps are catalyzed by the MHBD catalyst as well as the amine catalyst, and two different aldehydes can also be used in a cross-domino sequence, thus providing the products in excellent enantioselectivity, diastereoselectivity, and high yield.

Palladium-Catalyzed Dehydrogenative β′-Arylation of β-Keto Esters under Aerobic Conditions: Interplay of Metal and Brønsted Acids

The Brønsted aids: The first dehydrogenative arylation of β-keto esters with arenes under ambient aerobic conditions is described. Under a Pd(II)/Brønsted acid co-catalytic system, regioselective arylations with alkoxylated arenes and phenols were achieved in good yields, even in gram-scale conditions.

Cross-Dehydrogenative Couplings between Indoles and β-Keto Esters : Ligand-Assisted Ligand Tautomerization and Dehydrogenation via a Proton-Assisted Electron Transfer to Pd(II)

Cross-dehydrogenative coupling reactions between β-ketoesters and electron-rich arenes, such as indoles, proceed with high regiochemical fidelity with a range of β-ketoesters and indoles. The mechanism of the reaction between a prototypical β-ketoester, ethyl 2-oxocyclopentanonecarboxylate, and N-methylindole has been studied experimentally by monitoring the temporal course of the reaction by (1)H NMR, kinetic isotope effect studies, and control experiments. DFT calculations have been carried out using a dispersion-corrected range-separated hybrid functional (ωB97X-D) to explore the basic elementary steps of the catalytic cycle. The experimental results indicate that the reaction proceeds via two catalytic cycles. Cycle A, the dehydrogenation cycle, produces an enone intermediate. The dehydrogenation is assisted by N-methylindole, which acts as a ligand for Pd(II). The computational studies agree with this conclusion, and identify the turnover-limiting step of the dehydrogenation step, which involves a change in the coordination mode of the β-keto ester ligand from an O,O-chelate to an α-C-bound Pd enolate. This ligand tautomerization event is assisted by the π-bound indole ligand. Subsequent scission of the β-C-H bond takes place via a proton-assisted electron transfer mechanism, where Pd(II) acts as an electron sink and the trifluoroacetate ligand acts as a proton acceptor, to produce the Pd(0) complex of the enone intermediate. The coupling is completed in cycle B, where the enone is coupled with indole. Pd(TFA)2 and TFA-catalyzed pathways were examined experimentally and computationally for this cycle, and both were found to be viable routes for the coupling step.