In 2006, 31 new chemical entities were introduced to the world pharmaceutical market and 2,075 molecules were in phase I or II of clinical development¹. The majority of these were small-molecule (relative molecular mass <1,000) organic compounds². 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, because 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, making available new targets and materials that would have been previously out of range. For example, new methodologies such as metal-catalysed cross-coupling³ and olefin metathesis^{4, 5, 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 Fig. 1.

Figure 1: Synthesis by functional group modification compared to C–H functionalization.

Traditional sites for modification of organic molecules (indicated by blue arrows) rely on reactive (polarizable) functional groups. Such modes of reactivity include oxidation/reduction, aromatic substitution, and nucleophilic/electrophilic attack. Sites for direct functionalization of C–H bonds (red arrows) often have adjacent 'activating' groups, but can also occur at isolated positions.

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The many opportunities associated with C–H functionalization has made this field 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, 8, 9}. One of the major challenges associated with this chemistry has been to render it catalytic in the metal complex¹⁰. A partial solution to this problem has been to use neighbouring 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, 12, 13, 14, 15, 16, 17}. Here, however, we highlight another approach, in which a divalent carbon (carbene)¹⁸ or a monovalent nitrogen (nitrene)¹⁹, coordinated to a metal complex, inserts into a C–H bond²⁰. 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 (Fig. 2).

Figure 2: Metal carbenoid C–H functionalization versus the 'traditional' C–H activation.

In a traditional C–H activation manifold, the highly reactive metal complex (M = metal, L = ligand) inserts into a C–H bond. Regeneration of the active metal complex to form the C–H activation product has proved difficult. In contrast, C–H functionalization via a metal carbenoid approach typically uses a high-energy diazo compound and loss of nitrogen provides the driving force for the energetically unfavourable formation of the carbenoid. The highly reactive carbenoid species then inserts into a C–H bond to form the C–H activation product and liberates the metal catalyst for another cycle.

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C–H functionalization by metal carbenoids

The standard method for generating the transient metal carbenes is by metal-induced extrusion of nitrogen from diazo compounds²¹. The challenges of regioselectivity associated with the carbene-induced C–H functionalization meant that most of the early advances in this field were achieved in systems capable of intramolecular reactions^{21, 22, 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 favourable regioselective transformation. By using a chiral catalyst, the C–H insertion can be made enantioselective, favouring 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) (Fig. 3).

Figure 3: Intramolecular C–H insertions.

a, The intramolecular C–H insertion of an acceptor substituted carbenoid catalysed by the chiral rhodium carboxamidate catalyst Rh₂(4S-MPPIM)₄ is the key step in an enantioselective synthesis of the GABA_B receptor agonist (R)-(–)-baclofen (ref. 24). b, The intramolecular C–H insertion of an acceptor/acceptor-substituted carbenoid catalysed by the chiral rhodium carboxylate catalyst Rh₂(S-BPTTL)₄ results in a concise synthesis of the phosphodiesterase type IV inhibitor (R)-(-)-rolipram (ref. 25).

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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, 28, 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 Fig. 4^{18, 32, 33}.

Figure 4: Controlling factors of carbenoid reactivity.

The substituents attached to the carbenoid help to modulate its reactivity. The presence of both an electron-donating group (EDG) and an electron-withdrawing group (EWG) is necessary to reduce carbene dimerization pathways and increase selectivity for intermolecular reactions. During the C–H activation event, a partial positive charge build-up occurs at the carbon undergoing C–H functionalization. Sites adjacent to functionality that can stabilize this polarization are considered to be electronically 'activated' towards carbenoid reactions (1°, 2° and 3° represent primary, secondary or tertiary sites, indicating the number of substituents at a particular carbon site).

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The synthetic potential of the donor/acceptor carbenoids is illustrated in a direct enantioselective synthesis of the most active enantiomer of threo-methylphenidate (Ritalin) (compound 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 agent³⁴. 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 catalysed reaction of N-protected piperidine (compound 7) with methyl phenyldiazoacetate (compound 8) followed by removal of the protecting group leads to the rapid synthesis of (R,R')-(+)-methylphenidate (compound 9) in 86% enantiomeric excess (Fig. 5)³⁸.

Figure 5: Ritalin synthesis.

A concise, stereoselective synthesis of the biologically active enantiomer of the pharmaceutical agent Ritalin (threo-methylphenidate) was achieved using the bridged, chiral rhodium catalyst Rh₂(S-biDOSP)₂ (ref. 38). Boc, tert-butoxycarbonyl.

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C–H functionalization can provide complementary approaches to achieve transformations equivalent to some of the classic reactions of organic synthesis^{40, 41, 42, 43, 44, 45}. For example, C–H functionalization adjacent to oxygen can lead to products that would be commonly derived from an aldol reaction (Fig. 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, compound 11 is formed in 92% yield, >94% diastereomeric excess and 72% enantiomeric excess⁴⁴.

Figure 6: C–H functionalization as a strategic reaction.

a, C–H insertion to oxygen generates products that would classically be formed via an aldol reaction. The insertion occurs preferentially at the site adjacent to the more electron-rich siloxy-protected oxygen (ref. 44) b, C–H insertion to nitrogen generates the products formally derived from a Mannich reaction, with high levels of enantiocontrol (ref. 42). TBSO, tert-butyldimethylsiloxy.

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C–H functionalization adjacent to nitrogen can lead to products that would be typically formed from a Mannich reaction, as illustrated in the direct synthesis of -amino ester 13 (ref. 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 of the C-H insertion step initiating a cascade sequence. A spectacular example of such an event is termed the 'combined C–H activation/Cope rearrangement'^{51, 52, 53, 54, 55, 56}. One of the earliest examples of this reaction is shown between the vinyldiazoacetate 15 and 1,3-cyclohexadiene in Fig. 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, Fig. 7)⁵¹.

Figure 7: Combined C–H activation/Cope rearrangement.

The C–H functionalization with a vinyldiazoacetate begins at the allylic C–H bond, but is interrupted when a Cope rearrangement occurs (see blue intermediate) to give the combined C–H activation/Cope rearrangement product with exceptionally high enantioselectivity (ref. 51).

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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, 59, 60}. In contrast, the C–H functionalization strategy results in a very efficient method for generating 4-substituted indoles with high enantioselectivity (Fig. 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.

Figure 8: Tris-indole synthesis.

The product of the combined C–H activation/Cope rearrangement between the vinyldiazoacetate 18 and the 4-acetoxy-6,7-dihydroindole 19 undergoes loss of acetic acid to generate the aromatized tris-indole compound 20 in good yield and in high enantiomeric excess (ref. 56).

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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 (Fig. 9)⁶¹. Previous syntheses have struggled with controlling the stereochemistry at the three stereocentres indicated in red, primarily because the natural products lack suitable functional groups as handles in the synthetic transformations^{62, 63, 64, 65, 66, 67}. In contrast, an enantiodivergent C–H functionalization of racemic dihydronaphthalenes 21 generates the core structures 23 with high stereoselectivity at all three stereocentres. In the presence of the chiral catalyst Rh₂(R-DOSP)₄ (ref. 68), the other enantiomer of the dihydronaphthalene 21 reacts in an entirely different manner to form cyclopropanation products⁶⁹. 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 (compound 24), colombiasin A⁷⁰ (compound 25), elisabethadione⁷¹ (compound 26), the p-benzoquinone 27⁷¹ and erogorgiaene (compound 28)⁶⁹.

Figure 9: Application of C–H functionalization to natural product synthesis.

A series of diterpene natural products have been isolated from the gorgonian coral Pseudopterogorgia elisabethae. All are derived biosynthetically from (+)-elisabethatriene and share the same configuration at the three stereocentres shown by red arrows (ref. 61). One of the most challenging aspects in synthesizing these molecules is controlling the stereochemistry at these sites because of the lack of neighbouring functional groups. A powerful feature of the combined C–H activation/Cope rearrangement is the ability of the chiral catalyst Rh₂(R-DOSP)₄ to differentiate between the enantiomers of a racemic substrate to generate all three stereocentres in a single step.

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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 and colleagues for the synthesis of complex natural products such as manzacidin A⁷⁴ (compound 32), (+)-saxitoxin⁷⁵ (compound 35) and (-)-tetrodotoxin⁷⁶ (compound 40) (Fig. 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 complex⁷⁷. In the syntheses described here, the aryliminoiodinanes are produced in situ from the corresponding amine, which makes the overall transformations even more attractive^{78, 79}.

Figure 10: Application of C–H amination to natural product synthesis.

a, b, Sulphamate esters provide excellent precursors to nitrenes that can undergo highly diastereoselective intramolecular insertions into tertiary C–H bonds. Du Bois has shown the potential of this methodology with syntheses of the marine alkaloid manzacidin A (ref. 74) and the natural product (+)-saxitoxin, an ion channel blocker (ref. 75). c, An elegant synthesis of the potent marine poison ()-tetrodotoxin by Du Bois and colleagues illustrates the utility and complementarity of C–H functionalization by metal carbenoids and nitrenoids (ref. 76). Ph₂^tBuSiO, diphenyl-tert-butylsiloxy; Piv, pivalate.

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Lebel and colleagues have shown that N-tosyloxyamides such as compound 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 Fig. 11⁸². The site for C–H amination is governed by the length of the tether and in general five-membered rings are preferred.

Figure 11: Enantioselective C–H amination.

Lebel and colleagues have developed an alternative method for the in situ generation of metal nitrenoids using N-tosyloxycarbamates as the precursors. This method avoids the generation of a stoichiometric amount of iodobenzene, a drawback to the use of hypervalent iodine reagents that are commonly used to generate nitrene precursors in situ. Lebel's method proceeds with high efficiency (ref. 80), and when the chiral catalyst Rh₂(S-TCPTAD)₄ is used, good levels of enantioselectivity can be achieved (ref. 82).

High resolution image and legend (110K)

Du Bois and colleagues have developed a bridged achiral rhodium catalyst Rh₂(esp)₂ that has performed well at low catalyst loadings in both intra- and intermolecular C-H amination reactions (Fig. 12)^{83, 84, 85}. Enantioselective intermolecular reactions of metal nitrenes are less developed than the parallel reactions 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 sulphonamide (compound 48) as the amine source in the reactions. Exceptionally high diastereoselectivity can be obtained in matched reactions between the appropriate enantiomers of a chiral sulphonamide and a chiral rhodium catalyst⁸⁷. Given the ubiquity of nitrogen atoms in biologically active compounds, C-H amination as an enabling technology in pharmaceutical synthesis has broad potential. A number of efficient transformations have been achieved at benzylic positions, but broad application of this chemistry is still relatively limited.

Figure 12: In situ generation of metal nitrenoid precursor.

a, The bridged, achiral rhodium catalyst Rh₂(esp)₂, developed by Du Bois and co-workers specifically for nitrenoid reactions, has demonstrated remarkable efficiency in both intra- and intermolecular reactions with catalyst loadings as low as 2 mol.% (ref. 84). b, Exceptionally high diastereoselectivity can be achieved in intermolecular C–H amination reactions when a 'matched' reaction is carried out using a chiral sulphonamide as the nitrene precursor and a chiral rhodium catalyst (ref. 87). 'esp' is a trivial name for the catalyst (structure shown). Tces, 2,2,2-trichloroethoxysulphonyl.

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References

1. Longwell, L. IMS Health Reports Global Pharmaceutical Market Grew 7.0 Percent in 2006 to $643Billion. Press release. http://www.imshealth.com/ims/portal/front/articleC/0,2777,6599_3665_80560241,00.html (IMS, 2007)
2. Lipinski, C. & Hopkins, A. Navigating chemical space for biology and medicine. Nature 432, 855–861 (2004) | Article | PubMed | ISI | ChemPort |
3. King, A. O. & Yasuda, N. Palladium-catalyzed cross-coupling reactions in the synthesis of pharmaceuticals. Top. Organometallic Chem. 6, 205–245 (2004) | ChemPort |
4. Nicolaou, K. C. et al. Synthesis of epothilones A and B in solid and solution phase. Nature 387, 268–272 (1997) | Article | PubMed | ISI | ChemPort |
5. Crabtree, R. H. A catalytic knight's move. Nature 441, 165–166 (2006) | Article | PubMed | ChemPort |
6. Grubbs, R. H. Handbook of Metathesis (Wiley-VCH, New York, 2003)
7. Waltz, K. M. & Hartwig, J. F. Selective functionalization of alkanes by transition-metal boryl complexes. Science 277, 211–213 (1997) | Article | ISI | ChemPort |
8. Saaby, S., Bayon, P., Aburel, P. S. & Jorgensen, K. A. Optically active aromatic and heteroaromatic -amino acids by a one-pot catalytic enantioselective addition of aromatic and heteroaromatic C–H bonds to -imino esters. J. Org. Chem. 67, 4352–4361 (2002) | Article | PubMed | ChemPort |
9. Bergman, R. G. Organometallic chemistry: C-H activation. Nature 446, 391–393 (2007) | Article | PubMed | ChemPort |
10. Arndtsen, B. A., Bergman, R. G., Mobley, T. A. & Peterson, T. H. Selective intermolecular carbon-hydrogen bond activation by synthetic metal complexes in homogeneous solution. Acc. Chem. Res. 28, 154–162 (1995) | Article | ChemPort |
11. Dyker, G. Transition metal catalyzed coupling reactions under C–H activation. Angew. Chem. Int. Edn Engl. 38, 1698–1712 (1999) | Article |
12. Shilov, A. E. & Shul'pin, G. B. Activation of C–H bonds by metal complexes. Chem. Rev. 97, 2879–2932 (1997) | Article | PubMed | ChemPort |
13. Labinger, J. A. & Bercaw, J. E. Understanding and exploiting C–H bond activation. Nature 417, 507–514 (2002) | Article | PubMed | ChemPort |
14. Dick, A. R. & Sanford, M. S. Transition metal catalyzed oxidative functionalization of carbon-hydrogen bonds. Tetrahedron 62, 2439–2463 (2006) | Article | ChemPort |
15. Godula, K. & Sames, D. C–H bond functionalization in complex organic synthesis. Science 312, 67–72 (2006) | Article | PubMed | ChemPort |
16. Dyker, G. (ed.) Handbook of C–H Transformations Vols 1 2 (Wiley-VCH, Weinheim, 2005)
17. Yu, J.-Q., Giri, R. & Chen, X. Sigma-chelation-directed C–H functionalizations using Pd(II) and Cu(II) catalysts: regioselectivity, stereoselectivity and catalytic turnover. Org. Biomol. Chem. 4, 4041–4047 (2006) | Article | PubMed | ChemPort |
18. Davies, H. M. L. & Beckwith, R. E. J. Enantioselective C–H activation by means of metal-carbenoid-induced C–H insertion. Chem. Rev. 103, 2861–2903 (2003) | Article | PubMed | ChemPort |
19. Espino, C. G. & DuBois, J. Rhodium(II)-catalyzed oxidative amination. In Modern Rhodium-Catalyzed Organic Reactions (Evans, P. A., ed.) (Wiley-VCH, Weinheim, 2005)
20. Davies, H. M. L. Recent advances in catalytic enantioselective intermolecular C–H functionalization. Angew. Chem. Int. Edn Engl. 45, 6422–6425 (2006) | Article | ChemPort |
21. Doyle, M. P., McKervey, M. & Ye, T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides (Wiley, New York, 1998)
22. Ye, T. & McKervey, M. A. Organic synthesis with -diazocarbonyl compounds. Chem. Rev. 94, 1091–1160 (1994) | Article | ChemPort |
23. Doyle, M. P. & Forbes, D. C. Recent advances in asymmetric catalytic metal carbene transformations. Chem. Rev. 98, 911–935 (1998) | Article | PubMed | ChemPort |
24. Doyle, M. P. & Hu, W. Enantioselective carbon-hydrogen insertion is an effective and efficient methodology for the synthesis of (R)-(-)-baclofen. Chirality 14, 169–172 (2002) | Article | PubMed | ChemPort |
25. Anada, M., Mita, O., Watanabe, H., Kitagaki, S. & Hashimoto, S. Catalytic enantioselective synthesis of the phosphodiesterase type IV inhibitor (R)-(-)-rolipram via intramolecular C–H insertion process. Synlett 1775–1777 (1999)
26. Demonceau, A., Noels, A. F., Hubert, A. J. & Teyssie, P. Transition metal-catalyzed reactions of diazo esters. Insertion into carbon-hydrogen bonds of paraffins catalyzed by bulky rhodium(II) carboxylates: enhanced attack on primary carbon-hydrogen bonds. Bull. Soc. Chim. Belg. 93, 945–948 (1984) | ChemPort |
27. Wee, A. G. H. & Yu, Q. Rh(II)-catalyzed reaction of some ', '- and '-branched-O-alkyl -(alkoxycarbonyl)--diazoacetates. J. Org. Chem. 62, 3324–3331 (1997) | Article | PubMed | ChemPort |
28. Wang, J., Liang, F. & Chen, B. Investigation of electronic effects of Rh(II)-mediated -methyl-substituted carbenoid intramolecular C–H insertion. J. Org. Chem. 63, 8589–8594 (1998) | Article | ChemPort |
29. Davies, H. M. L. & Antoulinakis, E. G. Recent progress in asymmetric intermolecular C–H activation by rhodium carbenoid intermediates. J. Organomet. Chem. 617–618, 47–55 (2001)
30. Diaz-Requejo, M. M., Belderrain, T. R., Nicasio, M. C., Trofimenko, S. & Perez, P. J. Intermolecular copper-catalyzed carbon-hydrogen bond activation via carbene insertion. J. Am. Chem. Soc. 124, 896–897 (2002) | Article | PubMed | ChemPort |
31. Urbano, J. et al. Functionalization of primary carbon-hydrogen bonds of alkanes by carbene insertion with a silver-based catalyst. Organometallics 24, 1528–1532 (2005) | Article | ChemPort |
32. Davies, H. M. L. Catalytic asymmetric C–H activation of sp³ hybridized C–H bonds by means of carbenoid C–H insertions: applications in organic synthesis. J. Molec. Catal. A 189, 125–135 (2002) | Article | ChemPort |
33. Davies, H. M. L., Hansen, T. & Churchill, M. R. Catalytic asymmetric C–H activation of alkanes and tetrahydrofuran. J. Am. Chem. Soc. 122, 3063–3070 (2000) | Article | ChemPort |
34. Keating, G. M. & Figgitt, D. P. Dexmethylphenidate. Drugs 62, 1899–1904 (2002) | Article | PubMed | ChemPort |
35. Panizzon, L. La preparazione di piridil-e piperidil-arilacetonitrili e di alcuni prodotti di trasformazione (Parte 1a). Helv. Chim. Acta 27, 1748–1756 (1944) | Article | ChemPort |
36. Deutsch, H. M., Shi, Q., Gruszecka-Kowalik, E. & Schweri, M. M. Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs. J. Med. Chem. 39, 1201–1209 (1996) | Article | PubMed | ChemPort |
37. Axten, J. M., Krim, L., Kung, H. F. & Winkler, J. D. A Stereoselective synthesis of dl-threo-methylphenidate: preparation and biological evaluation of novel analogues. J. Org. Chem. 63, 9628–9629 (1998) | Article | ChemPort |
38. Davies, H. M. L., Hansen, T., Hopper, D. W. & Panaro, S. A. Highly regio-, diastereo-, and enantioselective C–H insertions of methyl aryldiazoacetates into cyclic N-boc-protected amines. asymmetric synthesis of novel C₂-symmetric amines and threo-methylphenidate. J. Am. Chem. Soc. 121, 6509–6510 (1999) | Article | ChemPort |
39. Davies, H. M. L. & Panaro, S. A. Novel dirhodium tetraprolinate catalysts containing bridging prolinate ligands for asymmetric carbenoid reactions. Tetrahedr. Lett. 40, 5287–5290 (1999) | Article | ChemPort |
40. Davies, H. M. L. & Ren, P. Catalytic asymmetric C–H activation of silyl enol ethers as an equivalent of an asymmetric Michael reaction. J. Am. Chem. Soc. 123, 2070–2071 (2001) | Article | PubMed | ChemPort |
41. Davies, H. M. L., Ren, P. & Jin, Q. Catalytic asymmetric allylic C–H activation as a surrogate of the asymmetric Claisen rearrangement. Org. Lett. 3, 3587–3590 (2001) | Article | PubMed | ChemPort |
42. Davies, H. M. L. & Venkataramani, C. Catalytic enantioselective synthesis of ²-amino acids. Angew. Chem. Int. Edn Engl. 41, 2197–2199 (2002) | Article | ChemPort |
43. Davies, H. M. L., Venkataramani, C., Hansen, T. & Hopper, D. W. New strategic reactions for organic synthesis: catalytic asymmetric C–H activation alpha to nitrogen as a surrogate for the Mannich reaction. J. Am. Chem. Soc. 125, 6462–6468 (2003) | Article | PubMed | ChemPort |
44. Davies, H. M. L., Beckwith, R. E. J., Antoulinakis, E. G. & Jin, Q. New strategic reactions for organic synthesis: catalytic asymmetric C–H activation to oxygen as a surrogate to the aldol reaction. J. Org. Chem. 68, 6126–6132 (2003) | Article | PubMed | ChemPort |
45. Davies, H. M. L., Yang, J. & Nikolai, J. Asymmetric C–H insertion of Rh(II) stabilized carbenoids into acetals: A C–H activation protocol as a Claisen condensation equivalent. J. Organomet. Chem. 690, 6111–6124 (2005) | Article | ChemPort |
46. Davies, H. M. L. & Antoulinakis, E. G. Asymmetric catalytic C–H activation applied to the synthesis of Syn-aldol products. Org. Lett. 2, 4153–4156 (2000) | Article | PubMed | ChemPort |
47. Doyle, M. P. et al. Electronic and steric control in carbon-hydrogen insertion reactions of diazoacetoacetates catalyzed by dirhodium(II) carboxylates and carboxamides. J. Am. Chem. Soc. 115, 958–964 (1993) | Article | ChemPort |
48. Wang, P. & Adams, J. Model studies of the stereoelectronic effect in Rh(II) mediated carbenoid C–H insertion reactions. J. Am. Chem. Soc. 116, 3296–3305 (1994) | Article | ChemPort |
49. Davies, H. M. L. & Jin, Q. Double C–H activation strategy for the asymmetric synthesis of C₂-symmetric anilines. Org. Lett. 6, 1769–1772 (2004) | Article | PubMed | ChemPort |
50. Davies, H. M. L. & Ni, A. Enantioselective synthesis of -amino esters and its application to the synthesis of the enantiomers of the antidepressant Venlafaxine. Chem. Commun. 3110–3112 (2006)
51. Davies, H. M. L., Stafford, D. G. & Hansen, T. Catalytic asymmetric synthesis of diarylacetates and 4,4-diarylbutanoates. a formal asymmetric synthesis of (+)-sertraline. Org. Lett. 1, 233–236 (1999) | Article | PubMed | ChemPort |
52. Davies, H. M. L. & Jin, Q. Highly diastereoselective and enantioselective C–H functionalization of 1,2-dihydronaphthalenes: a combined C–H activation/Cope rearrangement followed by a retro-Cope rearrangement. J. Am. Chem. Soc. 126, 10862–10863 (2004) | Article | PubMed | ChemPort |
53. Davies, H. M. L. & Jin, Q. Catalytic asymmetric reactions for organic synthesis: the combined C–H activation/Cope rearrangement. Proc. Natl Acad. Sci. USA 101, 5472–5475 (2004) | Article | PubMed | ChemPort |
54. Davies, H. M. L. & Jin, Q. Enantioselective double C–H activation of dihydronaphthalenes. Org. Lett. 7, 2293–2296 (2005) | Article | PubMed | ChemPort |
55. Davies, H. M. L., Yang, J. & Manning, J. R. Direct synthesis of methyl 2-diazo-4-aryl-3-butenoates and their application to the enantioselective synthesis of 4-aryl-4-(1-naphthyl)-2-butenoates. Tetrahedron Asymmetry 17, 665–673 (2006) | Article | ChemPort |
56. Davies, H. M. L. & Manning, J. R. C–H activation as a strategic reaction: enantioselective synthesis of 4-substituted indoles. J. Am. Chem. Soc. 128, 1060–1061 (2006) | Article | PubMed | ChemPort |
57. Kleeman, A., Engel, J., Kutscher, B. & Reichert, D. Pharmaceutical Substances 4th edn (Thieme, New York, 2001)
58. Austin, J. F. & MacMillan, D. W. C. Enantioselective organocatalytic indole alkylations. Design of a new and highly effective chiral amine for iminium catalysis. J. Am. Chem. Soc. 124, 1172–1173 (2002) | Article | PubMed | ChemPort |
59. Ferreira, E. M. & Stoltz, B. M. Catalytic C–H bond functionalization with palladium(II): aerobic oxidative annulations of indoles. J. Am. Chem. Soc. 125, 9578–9579 (2003) | Article | PubMed | ChemPort |
60. Evans, D. A., Scheidt, K. A., Fandrick, K. R., Lam, H. W. & Wu, J. Enantioselective indole Friedel-Crafts alkylations catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes. J. Am. Chem. Soc. 125, 10780–10781 (2003) | Article | PubMed | ChemPort |
61. Heckrodt, T. J. & Mulzer, J. Marine natural products from Pseudopterogorgia elisabethae: structures, biosynthesis, pharmacology, and total synthesis. Top. Curr. Chem. 244, 1–41 (2005) | ChemPort |
62. Nicolaou, K. C., Vassilikogiannakis, G., Magerlein, W. & Kranich, R. Total synthesis of colombiasin A. Angew. Chem. Int. Edn Engl. 40, 2482–2486 (2001) | Article | ChemPort |
63. Kim, A. I. & Rychnovsky, S. D. Unified strategy for the synthesis of (–)-elisapterosin B and (–)-colombiasin A. Angew. Chem. Int. Edn Engl. 42, 1267–1270 (2003) | Article | ChemPort |
64. Harrowven, D. C., Pascoe, D. D., Demurtas, D. & Bourne, H. O. Total synthesis of (–)-colombiasin A and (–)-elisapterosin B. Angew. Chem. Int. Edn Engl. 44, 1221–1222 (2005) | Article | ChemPort |
65. Boezio, A. A., Jarvo, E. R., Lawrence, B. M. & Jacobsen, E. N. Efficient total syntheses of (–)-colombiasin A and (–)-elisapterosin B: application of the Cr-catalyzed asymmetric quinone Diels-Alder reaction. Angew. Chem. Int. Edn Engl. 44, 6046–6050 (2005) | Article | ChemPort |
66. Waizumi, N., Stankovic, A. R. & Rawal, V. H. A general strategy to elisabethane diterpenes: stereocontrolled synthesis of elisapterosin B via oxidative cyclization of an elisabethin precursor. J. Am. Chem. Soc. 125, 13022–13023 (2003) | Article | PubMed | ChemPort |
67. Cesati, I. R. R., de Armas, J. & Hoveyda, A. H. Enantioselective total synthesis of erogorgiaene: applications of asymmetric Cu-catalyzed conjugate additions of alkylzincs to acyclic enones. J. Am. Chem. Soc. 126, 96–101 (2004) | Article | PubMed | ChemPort |
68. Davies, H. M. L., Bruzinski, P. R., Lake, D. H., Kong, N. & Fall, M. J. Asymmetric cyclopropanations by rhodium(II) N-(arylsulfonyl)prolinate catalyzed decomposition of vinyldiazomethanes in the presence of alkenes. practical enantioselective synthesis of the four stereoisomers of 2-phenylcyclopropan-1-amino acid. J. Am. Chem. Soc. 118, 6897–6907 (1996) | Article | ChemPort |
69. Davies, H. M. L. & Walji, A. M. Direct synthesis of (+)-erogorgiaene through a kinetic enantiodifferentiating step. Angew. Chem. Int. Edn Engl. 44, 1733–1735 (2005) | Article | ChemPort |
70. Davies, H. M. L., Dai, X. & Long, M. S. Combined C–H activation/Cope rearrangement as a strategic reaction in organic synthesis: total synthesis of (–)-colombiasin A and (–)-elisapterosin B. J. Am. Chem. Soc. 128, 2485–2490 (2006) | Article | PubMed | ChemPort |
71. Davies, H. M. L. & Dai, X. Application of the combined C–H activation/Cope rearrangement as a key step in the total syntheses of the assigned structure of (+)-elisabethadione and a (+)-p-benzoquinone natural product. Tetrahedron 62, 10477–10484 (2006) | Article | ChemPort |
72. Muller, P. & Fruit, C. Enantioselective catalytic aziridinations and asymmetric nitrene insertions into CH bonds. Chem. Rev. 103, 2905–2919 (2003) | Article | PubMed | ChemPort |
73. Davies, H. M. L. & Long, M. S. Recent advances in catalytic intramolecular C–H aminations. Angew. Chem. Int. Edn Engl. 44, 3518–3520 (2005) | Article | ChemPort |
74. Wehn, P. M. & DuBois, J. Enantioselective synthesis of the bromopyrrole alkaloids manzacidin A and C by stereospecific C–H bond oxidation. J. Am. Chem. Soc. 124, 12950–12951 (2002) | Article | PubMed | ChemPort |
75. Fleming, J. J. & DuBois, J. A synthesis of (+)-saxitoxin. J. Am. Chem. Soc. 128, 3926–3927 (2006) | Article | PubMed | ChemPort |
76. Hinman, A. & DuBois, J. A stereoselective synthesis of (–)-tetrodotoxin. J. Am. Chem. Soc. 125, 11510–11511 (2003) | Article | PubMed | ISI | ChemPort |
77. Dauban, P. & Dodd, R. H. Iminoiodanes and C–N bond formation in organic synthesis. Synlett 1571–1586 (2003)
78. Yu, X.-Q., Huang, J.-S., Zhou, X.-G. & Che, C.-M. Amidation of saturated C–H bonds catalyzed by electron-deficient ruthenium and manganese porphyrins. a highly catalytic nitrogen atom transfer process. Org. Lett. 2, 2233–2236 (2000) | Article | PubMed | ChemPort |
79. Espino, C. G. & DuBois, J. A. Rh-catalyzed C–H insertion reaction for the oxidative conversion of carbamates to oxazolidinones. Angew. Chem. Int. Edn Engl. 40, 598–600 (2001) | Article | ChemPort |
80. Lebel, H., Huard, K. & Lectard, S. N-Tosyloxycarbamates as a source of metal nitrenes: rhodium-catalyzed C–H insertion and aziridination reactions. J. Am. Chem. Soc. 127, 14198–14199 (2005) | Article | PubMed | ChemPort |
81. Lebel, H. & Huard, K. De novo synthesis of troc-protected amines: intermolecular rhodium-catalyzed C–H amination with N-tosyloxycarbamates. Org. Lett. 9, 639–642 (2007) | Article | PubMed | ChemPort |
82. Reddy, R. P. & Davies, H. M. L. Dirhodium tetracarboxylates derived from adamantylglycine as chiral catalysts for enantioselective C–H aminations. Org. Lett. 8, 5013–5016 (2006) | Article | PubMed | ChemPort |
83. Espino, C. G., Fiori, K. W., Kim, M. & DuBois, J. Expanding the scope of C–H amination through catalyst design. J. Am. Chem. Soc. 1267, 15378–15379 (2004) | Article | ChemPort |
84. Fiori, K. W. & DuBois, J. Catalytic intermolecular amination of C–H bonds: method development and mechanistic insights. J. Am. Chem. Soc. 129, 562–568 (2007) | Article | PubMed | ChemPort |
85. Kim, M., Mulcahy, J. V., Espino, C. G. & DuBois, J. Expanding the substrate scope for C–H amination reactions: oxidative cyclization of urea and guanidine derivatives. Org. Lett. 8, 1073–1076 (2006) | Article | PubMed | ChemPort |
86. Yamawaki, M., Tsutsui, H., Kitagaki, S., Anada, M. & Hashimoto, S. Dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate]: a new chiral Rh(II) catalyst for enantioselective amidation of C–H bonds. Tetrahedr. Lett. 43, 9561–9564 (2002) | Article | ChemPort |
87. Liang, C. et al. Efficient diastereoselective intermolecular rhodium-catalyzed C–H amination. Angew. Chem. Int. Edn Engl. 45, 4641–4644 (2006) | Article | ChemPort |

Acknowledgements

The research conducted in the Davies laboratories was supported by the National Institutes of Health and the National Science Foundation.

Author Contributions This was a collaborative writing project between H.M.L.D. and J.R.M., in which both contributed equally.