Catalytic C–H Functionalization by Metal Carbenoid and Nitrenoid Insertion

Introduction

In 2006, 31 new chemical entities were introduced to the world pharmaceutical market and 2,075 molecules were in Phase I/II clinical development.¹ The majority of these were small-molecule (molecular weight <1000) organic compounds.² As knowledge about the specific interactions of drugs in-vivo increases, often so does the structural complexity of new drug targets. A major obstacle to the development of such drugs is the difficulty associated with synthesizing large quantities in an economical fashion, as complex multi-step syntheses are usually required. In the general media, it is often overlooked that the accessibility of the components required for these new treatments will often govern their eventual success or failure. Likewise, a design element of any pharmaceutical agent is the expectation that the target compounds can be made economically. Therefore, new strategies for synthesis can become enabling technologies, opening up new vistas of targets and materials that would have been previously out of range. For example, new methodologies such as metal catalyzed cross-coupling³ and olefin metathesis^4–6 have rapidly become central transformations in the synthesis of new pharmaceutical agents. Selective C–H functionalization is a class of reactions that could lead to a paradigm shift in organic synthesis, relying on selective modification of ubiquitous C–H bonds of organic compounds instead of the standard approach of conducting transformations on pre-existing functional groups. The reactive sites in each type of transformation are very different, as illustrated in Figure 1.

Due to the many opportunities associated with C–H functionalization, this field has become an active area of research. Organometallic chemists have focused much attention on developing “C–H activation” strategies, whereby a highly reactive metal complex inserts into a C–H bond, activating the system for subsequent transformations.^7–9 One of the major challenges associated with this chemistry has been to render it catalytic in the metal complex.¹⁰ A partial solution to this problem has been to use neighboring functionality to direct less reactive metal complexes to the site for functionalization. Numerous reviews have been written about this method for C–H functionalization.^11–17 This review, however, will highlight an alternative approach, in which a divalent carbon (carbene)¹⁸ or a monovalent nitrogen (nitrene),¹⁹ coordinated to a metal complex, inserts into a C–H bond.²⁰ This alternative approach offers many advantages over the metal-induced C–H insertion because the reactions exhibit high turnover numbers and can lead to high levels of selectivity, both in terms of regioselectivity and stereoselectivity (Figure 2).

C–H Functionalization by Metal Carbenoids

The standard method for generating the transient metal carbenes is by metal-induced extrusion of nitrogen from diazo compounds.²¹ On account of the challenges of regioselectivity associated with the carbene-induced C–H functionalization, most of the early advances in this field were achieved in systems capable of intramolecular reactions.^21–23 Because the rhodium carbenoid and the reacting C–H bond are connected by a suitable tether, they are brought into close proximity, leading to a favorable regioselective transformation. By using a chiral catalyst, the C–H insertion can be made enantioselective, favoring the formation of one mirror image of the product over the other. This type of approach has been used in the synthesis of various pharmaceutical agents, such as (R)-(−)-baclofen²⁴ (3) and (R)-(−)-rolipram²⁵ (6) (Figure 3).

In terms of strategic reactions, controllable intermolecular transformations would be much more powerful because the sequence of steps required to make the substrate for an intramolecular reaction would no longer be needed. Controlling the regioselectivity of intermolecular C–H insertions, however, has been challenging, particularly in the case of the most commonly used metal carbenoids derived from acceptor-only substituted diazoacetates.^{22, 26} The metal carbenoids behave as very electrophilic species and the electron-withdrawing ester group reinforces the high reactivity, generating a system characterized by poor regioselectivity between different C–H bonds.^27–29 In recent years, extensive efforts have been made to attenuate the carbenoid reactivity by altering the nature of the catalysts with some improvements having been made by using very bulky ligands with copper³⁰ and silver³¹ complexes. The major breakthrough in this field, however, was the discovery that carbenoids functionalized with both donor and acceptor groups were much more chemoselective than the traditional carbenoids as shown in Figure 4.^{18, 32, 33}

The synthetic potential of the donor/acceptor carbenoids is illustrated in a direct enantioselective synthesis of the most active enantiomer of threo-methylphenidate (Ritalin) (9). Ritalin is an important drug for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and, as an old drug, is sold as a racemate. The most active enantiomer of Ritalin has been marketed as an independent therapeutic agent.³⁴ Its synthesis using conventional functional group manipulations requires multiple steps.^{35, 36} The C–H functionalization approach to Ritalin, conversely, is direct.^{37, 38} The Rh₂(S-biDOSP)₂³⁹ catalyzed reaction of N-protected piperidine (7) with methyl phenyldiazoacetate (8) followed by removal of the protecting group leads to the rapid synthesis of (R,R')-(+)-methylphenidate (9) in 86% ee (Figure 5).³⁸

C–H Functionalization can provide complementary approaches to achieve transformations equivalent to some of the classic reactions of organic synthesis.^40–45 For example, C–H functionalization adjacent to oxygen can lead to products that would be commonly derived from an aldol reaction (Figure 6).^{44, 46} In the specific example used to illustrate this concept, other key elements that control the selectivity of this chemistry are demonstrated. The carbenoid has an electronic preference to functionalize C–H bonds in which the carbon can stabilize positive charge build-up because the C–H insertion has the partial characteristic of a hydride abstraction event.^{47, 48} In this case, selective functionalization occurs adjacent to the siloxy group rather than the more electron-withdrawing acetoxy group in compound 10. Additionally, if there is good steric differentiation at the C–H insertion site, high levels of diastereoselectivity can be achieved. Thus, 11 is formed in 88% yield, >94% de and 82% ee.⁴⁴

C–H Functinalization adjacent to nitrogen can lead to products that would be typically formed from a Mannich reaction, as illustrated in the direct synthesis of β-amino ester 13.⁴² This example illustrates the important controlling influences in steric factors, because the electronically most activated site in compound 12, the benzylic carbon, is sterically inaccessible and selective functionalization occurs at the N-methyl group.^{42, 49, 50}

A further advantage of the carbenoid-induced C–H functionalization is the possibility for the C–H insertion step to initiate a cascade sequence. A spectacular example of such an event is termed the combined C–H activation/Cope rearrangement.^51–56 One of the earliest examples of this reaction is shown between the vinyldiazoacetate 15 and 1,3-cyclohexadiene in Figure 7. Before the C–H functionalization is complete a rearrangement occurs to form a 1,4-cyclohexadiene derivative 16 with exceptional enantiocontrol. The entire process is believed to occur via a concerted, ordered transition state that leads to higher stereoselectivity than is normally observed in a direct C–H insertion. This transformation has been used in a very concise enantioselective formal synthesis of the antidepressant sertraline (Zoloft, Figure 7).⁵¹

An even more elaborate sequence of events has been developed for the enantioselective synthesis of 4-substituted indoles. Indoles are present in a number of pharmaceutical agents⁵⁷ and there has been much interest in the enantioselective synthesis of 1-aryl-1-indolylalkyl derivatives. Normally the indole is functionalized at the 2- or 3-position because these are the most reactive sites using conventional chemistry.^58–60 In contrast, the C–H functionalization strategy results in a very efficient method for generating 4-substituted indoles with high enantioselectivity (Figure 8).⁵⁶ These types of compounds and related structures have not been extensively studied as potential therapeutic agents, presumably because they were not readily accessible.

A powerful enabling synthetic methodology should greatly simplify the total synthesis of complex natural products. Notable examples of this have been illustrated in the synthesis of the natural products derived from the West Indian gorgonian coral pseudopterogorgia elisabethae (Figure 9).⁶¹ Previous syntheses have struggled with controlling the stereochemistry at the three stereocenters indicated in red, primarily because the natural products lack suitable functional groups as handles in the synthetic transformations.^62–67 In contrast, an enantiodivergent C–H functionalization of racemic dihydronaphthalenes 21 generates the core structures 23 with high stereoselectivity at all three stereocenters. In the presence of the chiral catalyst Rh₂(S-DOSP)₄,⁶⁸ the other enantiomer of the dihydronaphthalene 21 reacts in an entirely different manner to form cyclopropanation products.⁶⁹ This reaction can be conducted with a variety of dihydronaphthalene derivatives and has been applied to very efficient syntheses of a range of natural products including elisapterosin B⁷⁰ (24), colombiasin A⁷⁰ (25), elisabethadione⁷¹ (26), the p-benzoquinone 27⁷¹ and erogorgiaene (28).⁶⁹

C–H Functionalization by Metal Nitrenoids

In recent years, metal nitrenoid complexes have also been shown to be capable reagents for C–H functionalization, a reaction that is usually called C–H amination.^{14, 72, 73} Some spectacular intramolecular examples have been reported by Du Bois for the synthesis of complex natural products such as manzacidin A⁷⁴ (32), (+)-saxitoxin⁷⁵ (35) and (−)-tetrodotoxin⁷⁶ (40) (Figure 10). These transformations illustrate how by judicious choice of substrates, the C–H amination can be conducted in the presence of a range of functional groups. Generally, the most broadly used precursors to the transient metal nitrenes have been aryliminoiodinanes, which are decomposed by a suitable metal complex.⁷⁷ In the syntheses described herein, the aryliminoiodinanes are produced in-situ from the corresponding amine, which makes the overall transformations even more attractive.^{78, 79}

Lebel has shown that N-tosyloxyamides such as 41 are also efficient precursors to transient metal nitrenoids.^{80, 81} By conducting this nitrene insertion with chiral dirhodium catalyst Rh₂(S-TCPTAD)₄, enantioselective transformations can be achieved as illustrated in Figure 11.⁸² The site for C–H amination is governed by the length of the tether and in general five-membered rings are preferred.

Du Bois has developed a bridged achiral rhodium catalyst Rh₂(esp)₂ that has performed well at low catalyst loadings in both intra- and inter-molecular C–H amination reactions (Figure 12).^83–85 Enantioselective intermolecular reactions of metal nitrenes are less developed than the parallel reaction of metal carbenes, although some significant examples have been reported.^{81, 82, 86, 87} A conceptually interesting approach to stereoselective intermolecular nitrene chemistry involves the use of a chiral sulfonamide 48 as the amine source in the reactions. Exceptionally high diastereoselectivity can be obtained in matched reactions between the appropriate enantiomers of a chiral sulfonamide and a chiral rhodium catalyst.⁸⁷ Given the ubiquity of nitrogen atoms in biologically active compounds, C–H amination as an enabling technology in pharmaceutical synthesis has broad potential. A concise, highly enantioselective synthesis of the anti-Parkinson's pharmaceutical agent rasagiline (51) was achieved using the Rh₂(S-TCPTAD)₄ catalyst.⁸² A number of efficient transformations have been achieved at benzylic positions, but broad application of this chemistry is still relatively limited.

Future Directions

C–H functionalizations by means of metal carbenoids and metal nitrenoids are rapidly becoming very general strategic reactions for the synthesis of natural products and pharmaceutical targets. The intramolecular C–H insertion of metal carbenoids is now a well-established transformation, while the corresponding intramolecular C–H amination has, in the last few years, been shown to be applicable to the synthesis of highly complex natural product targets. The recognition that donor/acceptor functionalized carbenoids are highly selective intermediates has opened up enantioselective intermolecular C–H insertion as a powerful transformation. Enantioselective intermolecular C–H amination is also developing well and is likely to see broad synthetic application. During the next few years this field is likely to undergo rapid expansion as improved chiral catalysts and even more selective reagents are developed. It has already been shown that these reactions can be considered as complementary to some of the classic reactions of organic synthesis and this will be further underscored as additional ingenious applications of this chemistry to total synthesis are described. As the synthetic utility of C–H functionalization becomes more fully appreciated, its application as an enabling technology for drug discovery and synthesis will become a common practice.