Catalytic C-H functionalization by metal carbenoid and nitrenoid insertion

Abstract

Novel reactions that can selectively functionalize carbon-hydrogen bonds are of intense interest to the chemical community because they offer new strategic approaches for synthesis. A very promising 'carbon-hydrogen functionalization' method involves the insertion of metal carbenes and nitrenes into C-H bonds. This area has experienced considerable growth in the past decade, particularly in the area of enantioselective intermolecular reactions. Here we discuss several facets of these kinds of C-H functionalization reactions and provide a perspective on how this methodology has affected the synthesis of complex natural products and potential pharmaceutical agents.

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

Traditional sites for modification of organic molecules (blue) 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) often have adjacent “activating” groups, but also can occur at isolated positions.

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 inserts into a C–H bond. Regeneration of the active metal complex to form the C–H activation product has proven difficult. In contrast, C–H functionalization via a metal carbenoid approach typically utilizes a high-energy diazo compound and loss of nitrogen provides the driving force for the energetically unfavorable 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.

Figure 3. Intramolecular C–H insertions

a) The intramolecular C–H insertion of an acceptor substituted carbenoid catalyzed 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 catalyzed 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).

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 and an electron-withdrawing group is necessary to reduce carbene dimerization pathways and increase selectivity for intermolecular reactions. During the C–H activation event, a partial positive charge buildup occurs at the carbon undergoing C–H functionalization. Sites adjacent to functionality that can stabilize this polarization are considered to be electronically “activated” toward carbenoid reactions.

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).

Figure 6. C–H functionalization as a strategic reaction

a) C–H insertion α 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 a to nitrogen generates the products formally derived from a Mannich reaction, with high levels of enantiocontrol (ref 42).

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).

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).

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 stereocenters shown in red (ref 61). One of the most challenging aspects in synthesizing these molecules is controlling the stereochemistry at these sites because of the lack of neighboring 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 stereocenters in a single step.

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

a–b) Sulfamate 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 illustrates the utility and complementarity of C–H functionalization by metal carbenoids and nitrenoids (ref 76).

Figure 11. Enantioselective C–H amination

Lebel has developed an alternative method for the in-situ generation of metal nitrenoids using N-tosyloxycarbamates as the precursor. This method avoids the generation of a stoichiometric amount of iodobenzene, a drawback to the use of hypervalent iodine reagents which 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).

Figure 12. a) In-situ generation of metal nitrenoid precursor

The bridged, achiral rhodium catalyst Rh₂(esp)₂, developed by Du Bois 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 sulfonamide as the nitrene precursor and a chiral rhodium catalyst (ref 87), c) The anti-Parkinson's agent rasagiline was synthesized in three steps in high enantiomeric excess using the chiral catalyst Rh₂(S-TCPTAD)₄ (ref 82).