Chapter 1: Introduction

Sustainable Catalysis: With Non-endangered Metals, Parts 1 and 2 were concerned with catalysis brought about with the aid of Earth crust abundant metals as represented by those coloured green or orange in Figure 1.1. However, a number of nonmetals are also relatively abundant in the Earth's crust, biosphere or atmosphere and these include hydrogen, carbon, nitrogen, oxygen, silicon, sulfur and chlorine. Therefore, Sustainable Catalysis: Without Metals or Other Endangered Elements, Parts 1 and 2 will focus on catalysts comprised of these elements that function without the need for any metal.

The focus of Sustainable Catalysis: Without Metals or Other Endangered Elements is largely on a topic that has become known as “organocatalysis”, i.e. catalysis by organic molecules and in particular, asymmetric catalysis by organic molecules. However, the scope is broader than that as, for example, protons are widely used to catalyse many chemical reactions, such as ester hydrolysis (Scheme 1.1). Thus, the next three chapters of this volume provide an overview of acid and base catalysis, before the subsequent 20 chapters of these two volumes cover asymmetric organocatalysis by various classes of organocatalyst. These latter chapters will focus predominantly on relatively recent work and may give the impression that asymmetric organocatalysis is a new topic. The term organocatalysis was certainly only coined in the 1990s, but the use of metal-free catalysts has a history dating back over 100 years. Therefore, the remainder of this introductory chapter will provide a historical perspective to asymmetric organocatalysis. Enzymatic catalysis has not been included within this work as the focus is on synthetic catalysts derived from abundant elements. However, many enzymes function without the need for a metal (abundant or otherwise) within their active site and hence could be classified as organocatalysts.

Asymmetric organocatalysis can be traced back over one hundred years and early work was largely concerned with catalysis of a single reaction: the asymmetric addition of hydrogen cyanide to aldehydes to form a nonracemic cyanohydrin (Scheme 1.2). In 1912, Bredig and Fiske reported the use of alkaloids to catalyse this reaction.¹  Forty two years later, Prelog and Wilhelm carried out a mechanistic analysis of this reaction, suggesting that the Cinchona alkaloid is protonated by the hydrogen cyanide to form a chiral cyanide salt that then adds to the aldehyde.²  They screened 33 alkaloid derivatives, but never obtained a cyanohydrin with greater than 10% enantiomeric excess. Much later, Danda et al. used alkaloid-containing polymers to catalyse the asymmetric addition of HCN to 3-phenoxybenzaldehyde.³  It was found that a polymer containing quinidine gave the (S)-isomer of the cyanohydrin with 46% ee, whilst a polymer containing quinine gave the (R)-isomer of the cyanohydrin with 20% ee. Matsumoto and coworkers showed that Cinchona alkaloids could also be used to catalyse the asymmetric addition of trimethylsilyl cyanide to acetophenone, though only very low enantiomeric excesses (up to 10%) were obtained.⁴ 

In 1962, Tsuboyama reported that poly-(S)-isobutylethylenimine 1 (prepared by ring-opening polymerisation of (S)-leucine derived aziridine 2 as shown in Scheme 1.3) would catalyse the asymmetric addition of hydrogen cyanide to benzaldehyde, giving the (−)-isomer of the cyanohydrin with 19.6% enantiomeric excess.⁵  The catalytic activity of the poly-(S)-isobutylethylenimine was suggested to be due to the helical conformation adopted by this polymer. Tsuboyama subsequently reported that crosslinking poly-(S)-isobutylethylenimine with diisocyanates gave a polymer that catalysed formation of the (+)-isomer of mandelonitrile, but with only 5.5% ee.⁶  N-alkylation of the polymers was found to destroy their catalytic activity, and ORD spectra suggested that this was due to the polymers no longer adopting a helical conformation.⁷ 

Starting in 1979, the group of Inoue pioneered the use of peptides as catalysts for asymmetric cyanohydrin synthesis. Whilst linear peptides gave disappointing results, some cyclic dipeptides (diketopiperazines) were found to be much more effective catalysts.⁸  In 1981 the group reported that cyclic dipeptide 3 (Figure 1.2) derived from phenylalanine and histidine would catalyse the asymmetric addition of hydrogen cyanide to benzaldehyde to form (R)-mandelonitrile in 97% chemical yield and with 97% enantioselectivity.⁹  Catalyst 3 was also shown to catalyse the asymmetric addition of hydrogen cyanide to other aromatic aldehydes.¹⁰  Aliphatic aldehydes are also accepted as substrates, but with much lower enantioselectivity. Inoue subsequently reported diketopiperazine 4 that, like catalyst 1, is derived from (S)-amino acids, but which catalyses the formation of (S)-cyanohydrins and gives higher enantioselectivities with aliphatic than aromatic aldehydes.¹¹ 

Asymmetric cyanohydrin synthesis remains an important reaction for organocatalysis and many of the catalyst classes discussed in subsequent chapters give highly effective catalysts for this reaction. These include: Cinchona alkaloid derivatives, thioureas, guanidines, amine-oxides, diols and diamines.¹² 

Other organocatalysed reactions also have a long history, though not as long as asymmetric cyanohydrin synthesis. The first (S)-proline (5) catalysed asymmetric transformation was the Hajos–Parrish–Eder–Sauer–Wiechert reaction (Scheme 1.4), first reported in 1971.¹³  This is an unusual intramolecular aldol reaction that relies on discrimination of enantiotopic carbonyl groups rather than the enantiotopic faces of a single carbonyl group. It took over 25 years for this reaction to be generalised into proline catalysed intermolecular aldol reactions, the transformation that, more than any other, convinced organic chemists used to using metal-based catalysts that asymmetric organocatalysis was more than just a curiosity.

Asymmetric phase-transfer catalysis usually stands somewhat separate from the rest of asymmetric organocatalysis and has always been dominated by metal-free catalysts. The earliest report in asymmetric phase-transfer catalysis dates back 30 years to 1984 when Dolling and coworkers first reported the use of a quaternised Cinchona alkaloid (6) as a phase-transfer catalyst for the asymmetric alkylation of ketone 7 during an asymmetric synthesis of (+)-Indacrinone (Scheme 1.5).¹⁴  Quaternised Cinchona alkaloids dominated the area of asymmetric phase-transfer catalysis for the rest of the 20th century, and were especially used as catalysts for asymmetric amino acid synthesis through alkylation or Michael additions of glycine enolates. More recently, purely synthetic, asymmetric phase-transfer catalysts have been developed based on quaternary ammonium salts of binaphthyl derivatives.¹⁵ 

This brief overview of the history of asymmetric organocatalysis should have given a flavour of the content of the latter chapters of Sustainable Catalysis: Without Metals or Other Endangered Elements. One interesting fact is that the initial breakthroughs in both proline-catalysed reactions (Scheme 1.4) and asymmetric phase-transfer catalysis (Scheme 1.5) came not from academic research groups, but from industrial laboratories. This may reflect the industrial importance of developing highly effective and sustainable catalysts for important transformations.