Stereoselective C-H Functionalizations

As aromatic structures are typically planar—and therefore often not the focus of method development in enantioselective synthesis—this chapter contains only few examples of stereoselective arene C-H functionahzations. Despite this restriction, stereoselective syntheses can he performed through chelate-assisted C-H functionalizations of arene moieties in specially designed 

SCHEME 23.51 Rh-catalyzed C-H alkylation inducing axial chirality. 

SCHEME 23.53 Enantioselective Pd-catalyzed C-H alkylation with alkyl boronic acids. 

SCHEME 23.54 Enantioselective hydroarylation generaUng a quaternary stereocenter. 

In conclusion, several approaches have been taken in order to enable stereoselective C-H functionalizations of arene substrates. Most currently known examples take advantage of chiral features in the substrate, but recent developments aim at establishing catalyst-controlled enantioselectivity. 

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The copper-mediated stereoselective C-H functionalization of a prochiral benzyl sp1, as well as an r/>-C-H bonds leads to good enantioselectivities (Equation (45)).so... 

Radical rebound mechanisms are frequently invoked for reactions of metal-oxo catalysts," " bnt also for some functionalizations proceeding throngh metal nitrenoids." Since the formation of radical intermediates (11) is involved, selectivity for the functionalization of weak C—H bonds is typical in such protocols. Stereoselective C—H functionalizations are often difficult to achieve with this mechanistic manifold due to the stereochemical liability of 11," but can be overcome if radical recombination is fast (e.g., in enzymes)." ... 

This research was supported by the National Science Foundation under the Center for Chemical Innovation in Stereoselective C-H Functionalization (CHE-1205646). The authors gratefully acknowledge NSF MRI-R2 grant (CHE-0958205) and the use of the resources of the Cherry L. Emerson Center for Scientific Computation. 

Du Bois has extensively studied and developed the chemistry of carbamates that permit stereoselective C-H functionalization reactions via putative nitrenoid intermediates [22, 93, 101-106]. Thus, in the presence of diacetoxyiodobenzene, MgO, and 5 mol% Rli2(OAc)4, substrates such as 194 were converted into products that arise from C-H insertion (Equation 33) [102]. The amination was observed to proceed stereoselectively to give the corresponding product oxazolidinones (cf. 195) as single regio- and dia-stereomers. 

Yu J-Q, Giri R, ChenX (2006) a-chelation-directed C-H functionalizations using Pd(II) and Cu(II) catalysts regioselectivity, stereoselectivity and catalytic turnover. Org Biomol Chem 4 4041 1047... 

Ruthenium(II)-Catalyzed Regio- and Stereoselective Hydroarylation of Alkynes via Directed C-H Functionalization... 

Direct insertions into C—H bonds have been postnlated for reactions that proceed through metal carbenes and nitrenes (12/13). " In these mechanisms, the unsat-nrated M=X intermediates 12 or 13 directly attack the C—H bond and form the prodnct in one concerted step. Often, a preference for cleaving weak C—H bonds is observed however, C—H functionalizations of alkanes are known that have been proposed to follow this so-called C—H insertion pathway. Stereoselective and even enantioselective methodologies have been developed based on this strategy using snitable enantiomerically pure ancillary ligands." ... 

Oxidative Heck reactions via Pd(II) C—H functionalization of terminal alkenes with pinacol boranes have been described for the preparation of styrenes and derivatives through electrophilic Pd(II) catalysis (Scheme 3.20). ° Treatment of a functionalized allylic precursor with the Pd(II) catalysts listed facilitated an allylic C—H activation. Subsequent transmetallation of the aryl boronic acid and reductive elimination afforded the desired olefin with excellent stereoselectivity. The scope of the transformation allows for a variety of activating and deactivating substituents on the aryl boronic acid as well as numerous functional groups on the starting alkene. A tandem allylic C—H oxidation/vinylic arylation protocol has also been reported. " ... 

Davies HLM, Morton D. Guiding principles for site selective and stereoselective intermolecular C—H functionalization by donor/acceptor rhodium carbenes. Chem. Soc. Rev. 2011 40 1857-1869. 

Functionalization of C-H bonds by metal carbenoid or nitrenoid insertions represents a promising alternative to the more traditional approach of direct activation by a metal center. Carbenoids and nitrenoids show unusual regio- and stereoselectivity in insertions into C-H bonds, and unlike insertions of metal centers, these are intrinsically functionalizations rather than activations, which must be followed by functionalization (although in either case, loss of the functionalized group, to regenerate the active metal complex, is still required for catalysis) [129]. The use of dimeric Rh(n) complexes in this area has been extensively developed [129]. 

At first glance, the requirement for the use of already functionalized alkanes seems to limit the applicability of the directed C-H activation approach. However, the utility of such a method is obvious for chemists familiar with the use of auxiliary groups during stereoselective synthesis (neighboring group participation was also applied in the total synthesis shown in Scheme 6). 

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