Inventing Reactions

Table of Contents

1. Frontmatter

2. Catalysis: Unlimited Frontiers – Our Early Personal Journey into the World of Palladium

   Barry M. Trost

   Abstract

   Stimulated by our collaboration in the chemistry of insects, the absence of direct ways to replace allylic C–H bonds by C–C bonds led us to teach ourselves about the organic chemistry of palladium. This journey evolved beyond allylic alkylation and led to the semi-rational development of alkene–alkyne coupling and discovery of palladium complexes of trimethylenemethane as reactive intermediates for cycloadditions to five, seven, and nine membered carbo- and heterocycles. These new synthetic tools enabled facile strategies to complex structures possessing interesting properties, notably of biological relevance.

3. Reinventing Amide Bond Formation

   Jeffrey W. Bode

   Abstract

   The chemical synthesis of peptides and proteins has long relied on innovative inventions of amide-forming reactions. Our group has discovered and developed an amide-forming ligation reaction by the coupling of α-ketoacids and hydroxylamine (KAHA ligation). This reaction does not require reagents or catalysts, proceeds in the presence of unprotected functional groups, and generates no nonvolatile by-products. This chapter recounts our discovery of this reaction, our development of novel methods for the preparation of α-ketoacids and hydroxylamines, and the application of these new methods to the synthesis of peptides and proteins.

4. Catalytic Transformations Involving the Activation of sp2 Carbon–Oxygen Bonds

   Mamoru Tobisu, Naoto Chatani

   Abstract

   This review describes transition metal-catalyzed transformations of conventionally unemployed C(sp²)–O bonds, specifically those of aryl and alkenyl ethers, carboxylates, and carbamates. Nickel-based catalysts are among the most intensively studied in this context, allowing for direct coupling using phenol- and enol-derived electrophiles. Reactions using other metals (Ru, Fe, and Rh) are also presented. The synthetic utility of these C–O bond activation reactions is illustrated in the synthesis of several elaborated molecules, especially through the orthogonal cross-couplings and oxygen-directed functionalization/C–O activation tandem.

5. The Interplay of Invention, Observation, and Discovery in the Development of Lewis Base Activation of Lewis Acids for Catalytic Enantioselective Synthesis

   Gregory L. Beutner, Scott E. Denmark

   Abstract

   This chapter chronicles the evolution of a paradigm shift in the conceptualization and development of chiral Lewis base catalysis of carbonyl addition reactions with organosilicon nucleophiles. Prior to 2000, these reactions were exclusively practiced through the agency of highly electrophilic silicon species such as allyltrichlorosilanes and enoxytrichlorosilanes derived from aldehydes, ketones, and esters. However, a serendipitous discovery made during the development of these processes led to a fundamentally new insight, namely, that silicon tetrachloride could be activated by chiral Lewis bases (primarily phosphoramides) and the resulting chiral silicenium ion could serve as a general and effective catalyst for the addition of many different enoxysilane nucleophiles derived from aldehydes, ketones, esters, nitriles, protected cyanohydrins, conjugated esters and amides, and isocyanides. In addition to providing high generality, high yield, and high stereoselectivity, the new family of Lewis base-catalyzed reactions could be investigated mechanistically, and the foundations of reactivity and selectivity could be revealed. An analysis of how this paradigm shift occurred and the circumstances that led to discovery are described.

6. The Discovery and Development of a Palladium(II)-Catalyzed Oxidative Cross-Coupling of Two Unactivated Arenes

   David R. Stuart, Keith Fagnou

   Abstract

   The process of discovery and development of a palladium(II)-catalyzed oxidative cross-coupling of N-acetyl and N-pivaloylindoles with simple aromatic compounds is described. Within this process our inspiration was primarily derived from the organometallic literature and in particular the recent emergence of new and novel mechanisms for C–H bond cleavage by Pd(II)-complexes. During these studies it was realized that high levels of regio-control for C–H bond cleavage at indole could be obtained and a subsequent investigation has led to the proposal of a C3,C2-palladium migration for the C2-arylation of N-pivaloylindole. The current state of the art in transition-metal catalyzed oxidative cross-coupling is also presented.

7. Decarboxylative Coupling Reactions

   Lukas J. Gooßen, Käthe Gooßen

   Abstract

   Transition metal-catalyzed decarboxylative couplings have recently emerged as a promising concept for C–C and C–heteroatom bond formation. Our contribution to this rapidly evolving field was the development of redox-neutral decarboxylative cross-couplings. In these catalytic transformations, carboxylic acids extrude CO₂ to give organometallic intermediates, which react with aryl electrophiles under regioselective formation of a new C–C bond. This reaction concept compares favorably to traditional cross-couplings involving preformed organometallic reagents, as it draws on stable and broadly available carboxylic acids as the source of carbon nucleophiles. In this chapter, we describe the invention process that resulted in the discovery of the first active catalyst systems and in the stepwise extension of this concept to a broadly applicable synthetic concept. A short overview on recent developments in this field is also provided.

8. Gold-Catalyzed Organic Reactions

   A. Stephen K. Hashmi

   Abstract

   Although homogeneous gold catalysis was known previously, an exponential growth was only induced 12 years ago. The key findings which induce that rise of the field are discussed. This includes early reactions of allenes and furanynes and intermediates of these conversions as well as hydroarylation reactions. Other substrate types addressed are alkynyl epoxides and N-propargyl carboxamides. Important vinylgold intermediates, the transmetalation from gold to other transition metals, the development of new ligands for gold catalysis, and significant contributions from computational chemistry are other crucial points for the field highlighted here.

9. Developing Catalytic Asymmetric Acetalizations

   Ilija Čorić, Sreekumar Vellalath, Steffen Müller, Xu Cheng, Benjamin List

   Abstract

   Acetals are among the most common stereocenters in Nature. They form glycosidic bonds that link together essential molecules of life, carbohydrates, including starch and cellulose, the most abundant organic material on Earth. Stereogenic acetals are also common motifs in other natural products, from small insect pheromones to highly complex spiroacetal polyketides. Although far less common than O,O-acetals, chiral N,N-, N,O-, and N,S-acetals are structural motifs also found in a number of natural products and pharmaceuticals. Here, recent progress towards chiral acetals using asymmetric Brønsted acid catalysis is summarized, with particular emphasis on O,O-acetalizations. In this context the development of novel catalyst classes, namely spirocyclic phosphoric acids and confined Brønsted acids, proved crucial and is also presented.

10. Designing Molecular Catalysts for Selective CH Functionalization

    Steven M. Bischof, Brian G. Hashiguchi, Michael M. Konnick, Roy A. Periana

    Abstract

    The design of molecular catalysts for the selective hydroxylation of hydrocarbons is an important challenge. Designing systems that couple the CH activation reaction with oxy-functionalization of the resulting M–R intermediates has emerged as a promising strategy to meeting this goal. A large number of well-defined CH activation systems have been reported, but relatively few have been utilized as efficient hydroxylation catalysts. The primary reason for this observation is that most efficient CH activation catalysts are incompatible with the conditions required for oxy-functionalization of M–R. Significantly, the reported systems for CH hydroxylation suffer from a combination of challenges related to product protection, poor reaction selectivity, low catalytic activity, stability, and/or expensive product separation which have prevented further development. The design of next generation systems that are more active for both the CH activation and M–R functionalization steps will be directly dependent on improving reaction selectivity and stability of the catalyst systems. Herein, we outline the requirements for meeting these goals in regard to developing new oxy-functionalization catalysts and describe our efforts in this area.

11. Carbene Catalysis: Beyond the Benzoin and Stetter Reactions

    Benoit Cardinal-David, Karl A. Scheidt

    Abstract

    The discovery and development of new N-heterocyclic carbene-catalyzed reaction is described. Based on inspiration from nature, we have taken thiazolium-based approaches to umpolung reactivity and invented a suite of related reactions involving acyl anions, homoenolate, and enolate nucleophiles all generated under catalytic conditions.

12. Asymmetric Autocatalysis of Pyrimidyl Alkanol

    Kenso Soai, Tsuneomi Kawasaki

    Abstract

    We have discovered an asymmetric autocatalysis in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, where the product, 5-pyrimidyl alkanol, acts as highly efficient asymmetric autocatalyst. Asymmetric autocatalysis proceeded quantitatively (>99%), affording itself as a near enantiomerically pure (>99.5% ee) product. An extremely low enantiomeric excess (ca. 0.00005% ee) can automultiply during three consecutive asymmetric autocatalysis to >99.5% ee. Circularly polarized light, quartz, chiral organic crystals, and statistical fluctuation of ee in racemate, which are considered a possible candidate for the origin of chirality, act as the chiral source in asymmetric autocatalysis. Asymmetric autocatalysis has the enormous power to recognize the isotope chirality arising from the small difference between carbon (carbon-13/carbon-12) and hydrogen (D/H) isotopes.

13. Natural Products as Inspiration for Reaction Development: Catalytic Enantioselective Decarboxylative Reactions of Prochiral Enolate Equivalents

    Douglas C. Behenna, Brian M. Stoltz

    Abstract

    This account describes the circumstances leading to our group’s innovations in the area of decarboxylative asymmetric allylic alkylation reactions and the initial discovery of palladium phosphinooxazoline complexes as efficient enantioselective catalysts. This chapter also chronicles the growth of the methodology to include several substrate classes, the expansion of the project into several other reaction manifolds, and the use of these reactions in natural product synthesis. Finally, important contributions from other research groups involving related methods or products similar to the α-quaternary products that are the focus of our studies, as well as future directions for asymmetric alkylation reactions, are discussed.

14. Acid Catalysis in Organic Synthesis

    Hisashi Yamamoto

    Abstract

    New reagents and catalysts have unlimited potential for the future of organic synthesis. We have been interested in Lewis and Brønsted acid catalysis for a number of years. In this chapter, I am going to review on several of these acids and related catalysts from the conceptual aspect of their molecular design and engineering.

15. Backmatter