Synthetic Methods in Drug Discovery: Complete Set (Drug Discovery Series) - Hardcover

Hardcover

ISBN 10: 1782627871 ISBN 13: 9781782627876

Publisher: Royal Society of Chemistry, 2016

Synopsis

The number of available synthetic methods can be overwhelming. In order to create novel motifs and templates which confer new and potentially valuable drug-like properties, it is important to know which synthetic methodologies will give the best results. This two-volume set of books provides both academic and industrial perspectives on key reactions giving the reader an excellent overview of the techniques used in modern synthesis. Reaction types are conveniently framed in the context of their value to industry and the challenges and limitations of methodologies are discussed with relevant illustrative examples. Moreover, key opportunities in expanding chemical space are presented, including the increasingly important syntheses that introduce three-dimensional molecular shape. Volume 1 focusses on transition metal mediated methods used in industry and volume 2 covers further valuable methods, such as fluorination, C-N bond formation and asymmetric reactions. Edited and authored by leading scientists from both academia and industry, this set of books will be a valuable reference for all chemists involved in drug discovery as well as postgraduate students in medicinal chemistry.

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The number of available synthetic methods can be overwhelming. In order to create novel motifs and templates which confer new and potentially valuable drug-like properties, it is important to know which synthetic methodologies will give the best results. This two-volume set of books provides both academic and industrial perspectives on key reactions giving the reader an excellent overview of the techniques used in modern synthesis. Reaction types are conveniently framed in the context of their value to industry and the challenges and limitations of methodologies are discussed with relevant illustrative examples. Moreover, key opportunities in expanding chemical space are presented, including the increasingly important syntheses that introduce three-dimensional molecular shape. Volume 1 focusses on transition metal mediated methods used in industry and volume 2 covers further valuable methods, such as fluorination, C-N bond formation and asymmetric reactions. Edited and authored by leading scientists from both academia and industry, this set of books will be a valuable reference for all chemists involved in drug discovery as well as postgraduate students in medicinal chemistry.

Excerpt. © Reprinted by permission. All rights reserved.

Synthetic Methods in Drug Discovery Volume 1

By David Blakemore, Paul Doyle, Yvette Fobian

The Royal Society of Chemistry

Copyright © 2016 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-78262-787-6

Contents

Volume 1, 
Chapter 1 Suzuki–Miyaura Coupling David Blakemore, 1, 
Chapter 2 Negishi Coupling Chris Limberakis, 70, 
Chapter 3 Hiyama Coupling Lee Boulton, 104, 
Chapter 4 Sonogashira Coupling Lee Boulton, 122, 
Chapter 5 Heck Coupling Alpay Dermenci and Jotham W. Coe, 143, 
Chapter 6 Palladium- and Copper-catalysed C–N Cross-coupling in Drug Discovery Kevin D. Hesp and Julien Genovino, 170, 
Chapter 7 Chan–LamCoupling Reaction: Copper-promoted C–Element Bond Oxidative Coupling Reaction with Boronic Acids Patrick Y. S. Lam, 242, 
Chapter 8 C–H Activation Approaches to Molecules Elizabeth M. Beck, Antonia F. Stepan and Damien Webb, 274, 
Chapter 9 Palladium-catalyzed Decarboxylative Couplings Christophe Linder and Nuria Rodríguez, 384, 
Chapter 10 New Frontiers with Transition Metals Brian S. Gerstenberger, 411, 
Subject Index, 443, 
Volume 2, 
Chapter 11 Lithium, Magnesium, and Copper: Contemporary Applications of Organometallic Chemistry in the Pharmaceutical Industry Sajiv K. Nair, Benjamin N. Rocke and Scott Sutton, 1, 
Chapter 12 C–N Bond Formation via Hydrogen Transfer Daniel C. Schmitt and Anne-Marie D. Schmitt, 75, 
Chapter 13 Synthesis of Sulfonamides Anne-Marie D. Schmitt and Daniel C. Schmitt, 123, 
Chapter 14 Asymmetric Methods and Their Use in the Pharmaceutical Industry Peter D. Smith, Mark A. Graham, Rachel H. Munday, Craig S. Donald, Thomas M. McGuire and Robert E. Kyne Jr., 139, 
Chapter 15 Fluorination Approaches Duncan L. Browne and Paul Richardson, 263, 
Chapter 16 The Development of Csp3–Csp2 Coupling Methodology Brian T. O'Neill, 371, 
Chapter 17 Catalytic Amide Bond Forming Methods Benjamin N. Atkinson, A. Rosie Chhatwal and Jonathan M. J. Williams, 413, 
Chapter 18 Accessing Novel Molecular Motifs and Monomers Subramanyam Chakrapani and Joseph S. Warmus, 454, 
Subject Index, 505, 

CHAPTER 1

Suzuki–Miyaura Coupling

DAVID BLAKEMORE

Pfizer World Wide Medicinal Chemistry, The Portway Building, Granta Park, Cambridge CB21 6GS, UK Email: david.blakemore@pfizer.com

1.1 Introduction

In this book, we will focus on reactions that are of importance to the pharmaceutical industry and the synthesis of drug-like molecules or motifs. It therefore seems highly appropriate to start this book and our coupling section with a true work-horse of the pharmaceutical industry. The Suzuki–Miyaura coupling (SMC) is the most frequently used carbon–carbon bond forming reaction in drug discovery; more specifically, it is the most frequently used reaction for carrying out C(sp2)–C(sp2) couplings and, in the context of drug synthesis, this translates to the synthesis of biaryl motifs (Scheme 1.1).

At its simplest, the biaryl SMC is the reaction of an aryl boronic acid, boronate ester (also referred to as boronic esters) or other boronate species (for simplicity we will refer to all these species as aryl boronates) with an aryl halide in the presence of a palladium(0) catalyst (which may have been generated from a palladium(II) source and is likely partnered with a ligand that stabilises the species and facilitates reaction) and aqueous base in a suitable solvent. The success of the reaction is due to the fact that it works across a wide range of aryl and heteroaryl substrates and has a high degree of functional group tolerance. A large number of boronic acids and boronate esters are now commercially available and the majority of aryl halides, including the traditionally challenging aryl chlorides, can be coupled with aryl boronates by the appropriate choice of palladium species and accompanying ligand. From a pharmaceutical industry perspective, in comparison with other common coupling protocols, the SMC reaction has a number of advantages including (1) the reagents used in SMC reactions are typically non-toxic (unlike the Stille coupling where the toxic tin reagents and residues left at the end of the reaction pose a huge issue for any scale-up work), and (2) the fact that boronic acids or esters are generally relatively stable intermediates (although, as we will see in the protodeboronation section, this is not always the case) means that they can be isolated rather than having to be generated and used in situ (in comparison, organozinc species or Grignard species need to be generated in situ in the reaction as they are highly reactive species).

The impact of the SMC reaction on the pharmaceutical industry has been profound: an analysis of the types of molecules synthesised within the pharmaceutical industry noted that there had been an increase in the "flatness" of molecules since the 1970s and that this correlates with the availability of chemistry facilitating sp2–sp2 couplings. Indeed, one of the key challenges currently for carbon–carbon coupling reactions is to access motifs with increased three-dimensional shape. With the success of the SMC reaction in generating biaryl motifs, it is clear that a variant of the SMC allowing aryl–alkyl couplings in a chiral manner is both highly desirable and could fundamentally change the motifs being generated. This topic will be discussed further in Volume 2, Chapter 16.

This issue of the ubiquity of biaryl motifs has cast the SMC reaction in a negative light in recent years but there can be little doubt that the reaction is a key work-horse in drug discovery programs. Ultimately, the importance of the reaction and coupling chemistry itself is evidenced in the award of the 2010 Nobel Prize in Chemistry to Heck, Negishi and Suzuki.

In this chapter, we will look in detail at the SMC highlighting optimal conditions but also, and very importantly, detailing the limitations of the reaction. For a reaction that is used routinely in a drug discovery environment, typically attaching elaborated fragments to one another, and that results in a significant increase in molecular complexity, it is important to know which reactions will work and which are likely to be challenging. For example, we could envisage a situation where we are coupling one aryl bromide with a range of aryl boronic acids to make a library of molecules to be screened for biological activity against a target. If a number of the boronic acids used fail to give desired product, it is important to understand why they have failed to react and whether there is a subset of the chemical space we defined at the outset that we have failed to screen against our target.

1.2 The Catalytic Cycle of the SMC

To understand the SMC, we need to start by examining the catalytic cycle (Figure 1.1). The cycle starts with the active catalytic LnPd(0) species where L represents the ligand stabilising the Pd(0) species. The Pd(0) species can be added directly to the reaction with examples being Pd(PPh3)4, Pd(dba)2 and Pd(tBu3P)2. An alternative to the use of a Pd(0) species is to use a Pd(II) species which is then reduced in situ. The advantage here is that the Pd(II) species is more stable than the Pd(0) species but typically it is also less reactive as it does require the reduction to generate the active species. Representative examples of Pd(II) species are Pd(OAc)2, Pd(dppf)Cl2 and PdCl2(PPh3)2. Reduction of the Pd(II) species is typically effected by the phosphine or excess boronic acid/boronate ester in the reaction.

Once Pd(0) has been generated, the next step to occur is oxidative addition of the Pd(0) into the C–X bond of the aryl halide to give R1Pd(II)X. The ease of oxidative addition is influenced by the strength of the C–X bond and generally goes in the order Ar–I>Ar–Br [greater than or equal to] Ar–OTf≥>>Ar–Cl ≈ ArOTs. The order is not absolute and can be influenced by the ligand on the Pd(0), but in general aryl chlorides are the most challenging species to react and the less readily available and less atom efficient aryl iodides are the most reactive. In addition, electron withdrawing groups on the aryl halide facilitate oxidative addition while electron donating groups make it more challenging.

Following oxidative addition, transmetallation of the aryl boronate with R1Pd(II)X then occurs. In a SMC, oxidative addition or transmetallation can be the turnover limiting step. For the electron-deficient heterocyclic boronates that are often used, it is more common for transmetallation to be the turnover limiting step. Typically, reaction occurs in the presence of aqueous base (we will discuss exceptions such as the use of fluoride under anhydrous conditions later), and this is critical to the reaction as aryl boronates fail to undergo transmetallation in the absence of base. The exact details of what occurs in this step is still somewhat controversial, but it seems that the RPd(II)X and aryl boronate require a bridging hydroxyl (or alkoxyl) group to react (Figure 1.2). Originally, it was supposed that the hydroxide reacted with the aryl boronate to form a four-coordinate boron ate-complex and this reacted with RPd(II)X, but recent evidence suggests that, at least in some circumstances, RPd(II)OH is generated and then reacts with the aryl boronate. It is worth noting that transmetallation is facilitated by having an electron-rich aryl boronate species.

The final step of the catalytic cycle is reductive elimination of the Pd(II) species to regenerate Pd(0) while generating the desired biaryl system.

1.3 The Impact of the Ligand

A wide range of ligands can be utilised in SMC couplings. The nature of the ligand is important as it has a significant impact on reactivity: the ease of oxidative addition, transmetallation, and reductive elimination can all be influenced by the ligand.

A number of different ligand classes have been investigated; for example, sterically hindered, electron-rich ligands have become very popular recently. Examples of these systems include Fu's P(tBu)3, Beller's CataCXium A, Buchwald's XPhos and SPhos, and Hartwig's Q-Phos. The popularity of these ligands is due to the challenges seen in palladium couplings of electron-rich aryl halides (particularly aryl chlorides), which are primarily caused by the difficulty of oxidative addition into the C–X bond. The trend towards these electron-rich, sterically encumbered ligands has significantly improved the success in such reactions. It seems counter-intuitive that the steric and electronic properties of the ligand could accelerate both oxidative addition and reductive elimination, but this is exactly what happens with this ligand class. Other important classes of ligand include the bidentate ferrocene ligands such as dppf and the N-heterocyclic carbene variants championed by Herrmann, Nolan and Organ.

Examples of highly effective ligands for the SMC are shown in Figure 1.3.

It is worth considering the impact of the ligand on the catalytic cycle in more detail at this point. The choice of ligand influences the nature of LnPd(0) at the start of the catalytic cycle: for sterically demanding phosphine ligands such as P(tBu)3, the active species is a LPd(0) species, (tBu3P)Pd(0), while for less sterically demanding ligands such as PPh3, the active species is the L2Pd(0), (Ph3P)2Pd(0). The LPd(0) species are unsaturated and very reactive twelve electron complexes, and it is the steric bulk of the ligand that drives their formation and subsequent reaction with aryl halides. At the same time, the steric bulk of the ligand accelerates reductive elimination as the ligand is removed from the system alleviating the strain. In terms of the electronics of the ligand, oxidative addition is typically facilitated by electron-rich metal complexes (and thus by electron-rich ligands) while reductive elimination is facilitated by more electron-poor metal complexes. However, it would appear that steric factors are more significant for reductive elimination than electronic properties. Thus, electron-rich, sterically demanding phosphines are typically favoured in these reactions. Phosphines are good σ-donors, but they can also function as π-acceptors (through back-donation into the P–C σ*-orbital); as aryl phosphines aremuch better π-acceptors than alkyl phosphines, they are typically viewed as less electron-rich ligands.

For bidentate phosphine ligands such as dppf, the active species is still LPd(0) but both phosphines on the ligand are co-ordinated to the palladium; while the ligand is not sterically hindered or electron-rich, its bidentate nature is significant in driving very effective reductive elimination in the catalytic cycle (Figure 1.4). The reason that bidentate ligands such as dppf are so effective in increasing the rate of reductive elimination is ascribed to their wide bite-angle in palladium complexes; the bite-angle for bidentate phosphine ligands is the P–Pd–P angle and for Pd(dppf)Cl2 it is 96°; this wide bite-angle reduces the angle between the two aryl groups (R1 and R2) increasing the orbital overlap between the two groups and accelerating reductive elimination.

N-heterocyclic carbene ligands (NHCs) are powerful electron donors (with π-back donation from Pd to the NHC being negligible); they typically function as electron-rich, sterically demanding ligands with the active species likely to be LPd(0), and as with the electron-rich, sterically demanding phosphines, these properties favour both oxidative addition and reductive elimination.

1.4 Electron-rich, Sterically Hindered Phosphine Ligands

The effectiveness of sterically hindered, electron-rich ligands can be seen in the fact that highly electron-rich aryl chlorides can now be made to couple with boronic acids in good yield. For example, Fu showed that 4-methoxychlorobenzene can be reacted with phenyl boronic acid using P(tBu)3 and Pd2(dba) 3 in excellent yield (Scheme 1.2). Both cesium carbonate and potassium phosphate proved to be effective bases under these conditions.

Subsequently, Fu went on to show that fluoride bases were highly effective in these couplings. Aryl chlorides were typically coupled at reflux temperatures in THF or dioxane while even sterically demanding aryl bromides could be coupled at room temperature (Scheme 1.3). Buchwald also developed conditions utilising potassium fluoride as base.

The use of a fluoride base in the reaction is worthy of further comment. Generally, aqueous bases such as potassium carbonate, sodium hydrogen carbonate, cesium carbonate, or potassium phosphate are used in SMC reactions. It was Wright and co-workers at Pfizer who first demonstrated that the aqueous base could be replaced by a fluoride source (cesium fluoride typically working best) and the reaction carried out under anhydrous conditions. The advantage of this approach is that groups sensitive to hydrolysis in the coupling partners are left intact. This is particularly relevant for coupling partners containing ester groups (Scheme 1.4) where hydrolysis typically occurs when using aqueous bases.

We have discussed the key role that hydroxide (or alkoxide) plays in the transmetallation step in the SMC. Given that the hydroxide can be replaced by fluoride, it is possible that an alternative mechanism for transmetallation occurs with fluoride functioning as a bridging ligand. However, DFT (density functional theory) calculations suggest that fluoride bridges the palladium and boron much less effectively than hydroxide. The simpler explanation here may be that the conditions used are not truly anhydrous: boronic acids are prone to trimerisation generating cyclic boroxines with the concomitant liberation of water (such species react effectively in SMC reactions themselves so this is not typically a major issue; we will return to these species in the boronate section); similarly, solvents and bases are rarely completely free of moisture. As suggested by Lloyd-Jones, the role of the fluoride may therefore be to deliver hydroxide to the palladium through hydrogen bonding interactions between the fluoride and water in the medium.

As we have already noted, SMC of heterocyclic systems is of particular importance in the pharmaceutical industry as heterocyclic biaryl scaffolds are common motifs. There is often the potential for such systems to act as palladium ligands themselves and therefore for the reaction to work poorly. Fortunately, electron-rich, sterically hindered phosphine ligands prove highly effective in the SMC reaction of such systems. Fu has shown that tricyclohexylphosphine is an effective ligand in such couplings. For example, 3-pyridyl boronic acid can be coupled with 2-chloropyridine in excellent yield using a combination of Pd2(dba)3 and PCy3 with potassium phosphate as base and dioxane/water as solvent (Scheme 1.5). Pyrimidine, pyrazole and indazole boronic acids were also coupled successfully under these conditions.

As we have seen, Fu has demonstrated that both PCy3 and P(tBu)3 are highly effective ligands in SMC couplings. However, both of these ligands are prone to oxidation to the phosphine oxide in air, requiring their careful handling and storage. Fu has shown that the tetrafluoroborate salts of these phosphines are stable in air and can be readily transformed into the desired phosphine in situ under the basic conditions utilised in the SMC reaction thus avoiding this issue (Scheme 1.6).

The Buchwald ligands such as XPhos and SPhos are also highly effective in SMC reactions including those of heterocyclic systems. Buchwald has shown that a combination of XPhos or SPhos as ligand together with Pd(OAc)2 or Pd2(dba)3 as the Pd source and potassium phosphate as base proves highly effective for a wide range of heterocyclic couplings. For example, 3-pyridyl boronic acid couples effectively with the electron-rich aryl halide, 2-amino-5-chloro pyridine under the XPhos conditions (Scheme 1.7).

Similarly, 5-indole boronic acid can be coupled in excellent yield with a 2-chloropyrazine under SPhos conditions (Scheme 1.8).

Buchwald has further developed these ligands by developing palladacycle pre-catalysts which can generate active Pd(0) species under mild conditions. Typically, mild base deprotonates the pre-catalyst which then undergoes reductive elimination to give LPd(0). This is illustrated in Scheme 1.9 for the XPhos second generation pre-catalyst.

By generating the highly active LPd(0) species under mild conditions, challenging Suzuki couplings can be carried out under mild conditions (Scheme 1.10). Indeed, both the XPhos and SPhos pre-catalysts have also been found to be effective in coupling halo-azoles with unprotected acidic NH groups.

1.5 N-Heterocyclic Carbene Ligands

While a significant amount of work has gone into developing effective phosphine ligands for challenging SMC reactions, N-heterocyclic carbenes can also prove effective in these reactions. As we have already noted, N-heterocyclic carbenes are electron-rich, sterically hindered ligands and can prove very effective in SMC reactions of heterocyclic systems. For example, the PEPPSI (Pyridine Enhanced Precatalyst Preparation Stabilisation and Initiation) set of catalysts developed by Organ have proven effective in SMC reactions of heterocycles. These catalysts are Pd(II) pre-catalysts with the N-heterocyclic carbene being both a strong electron donator and providing the steric bulk courtesy of the two substituted phenyl groups (the different PEPPSI catalysts vary according to the nature of the alkyl substituents on these phenyl rings). During reaction, the Pd(II) species is reduced to the Pd(0) species by two equivalents of the boronate followed by loss of the 3-chloropyridine ligand to give the active catalytic species.

(Continues...)

Excerpted from Synthetic Methods in Drug Discovery Volume 1 by David Blakemore, Paul Doyle, Yvette Fobian. Copyright © 2016 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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Edition details

• Publisher: Royal Society of Chemistry
• Publication date: 2016
• Language: English
• ISBN 10: 1782627871
• ISBN 13: 9781782627876
• Binding: Hardcover
• Number of pages: 1010
• Editor: Blakemore David C, Fobian Yvette M, Doyle Paul M