Catalytic, Asymmetric, Intramolecular Carbon–Hydrogen Insertion

Abstract

The insertion of a chiral‐ligated metal carbene into an aliphatic C‐H bond to construct a carbon‐carbon bond imparts asymmetry into the resultant molecule to form enantiomerically enriched lactones, lactams, and cycloalkane derivatives and returns the chiral‐ligated metal to its catalytically active state. Insertion is favored by electron‐donating groups adjacent to the C‐H bond that undergoes insertion, and is disfavored by electron‐withdrawing groups. Chiral dirhodium(II) carboxamidates have proven to have the greatest breadth of high selectivities, but other classes of catalysts are selective in specific cases. Although there are examples of iodonium ylides as reactants, diazo compounds are the reactants of choice for these reactions. Diazocarbonyl compounds, especially diazoacetates and diazoacetamides, have reactivities and selectivities that are most suitable for high product yields and high stereoselectivities. This reaction is optimally designed for the formation of five‐membered ring compounds using diazoacetates and diazoacetamides and of four‐membered ring products with constrained diazoacetamides. Access to lignan lactones, baclofen, deoxyxylolactone, and rolipram, among others, exemplify the efficiencies of this methodology relative to other synthetic approaches.

Enantioselective cis-β-lactam synthesis by intramolecular C–H functionalization from enoldiazoacetamides and derivative donor–acceptor cyclopropenes

“…That donor–acceptor cyclopropene 6 can serve as a precursor to an intermediate metal carbene of dirhodium( ii ) which undergoes C–H insertion prompted us to investigate if other transition metals, particularly those of copper( i ) and silver( i ), could undergo the same transformation. Although both of these catalytically active metal ions are known to form metal carbenes directly from diazo compounds, 7 , 8 , 20 they undergo Lewis acid catalyzed reactions with enoldiazoacetates, 15 and they are distinctly different from dirhodium( ii ) carboxylates in cycloaddition reactions with nitrones. 18 c Since C–H insertion is notably unique to metal carbenes, reactions of metal catalysts with enoldiazoacetamides or their derivative cyclopropenes would be a demonstration of metal carbene involvement with these catalysts.…”

“… 4 Considerable effort has been focused on chemical catalysis for the construction of β-lactams, including those through catalytic intramolecular amide N–H insertion reactions of diazo compounds, 5 and asymmetric synthesis has been a primary focus. 2 , 6 However, the same C–H functionalization methodology of diazo compounds that has provided exceptional selectivities in intermolecular reactions 7 and intramolecular syntheses of γ-lactones and γ-lactams 8 has been limited in efforts to synthesize β-lactams. …”

Catalytic Intermolecular C(sp3)–H Amination: Selective Functionalization of Tertiary C–H Bonds vs Activated Benzylic C–H Bonds

“…[1][2][3] A first general approach to meet this goal is based on directed functionalization reactions that include the use of coordinating groups or intramolecular reactions. [4][5][6][7][8][9] These processes convert proximal C-H bonds with high levels of selectivity but substrates devoid of such directing effect remain out of their scope. Thus, undirected C-H functionalization has emerged as a conceptually different strategy.…”

Asymmetric Rh(I)-Catalyzed Functionalization of the 3-C(sp3)–H Bond of Benzofuranones with α-Diazoesters

“…Herein, we report a highly stereoselective functionalization of the 3-C­(sp 3 )–H bond of benzofuranones with α-diazoesters catalyzed by a chiral diene-Rh­(I) catalyst. It might be worth noting the following: (1) Although great advances have been achieved in the asymmetric functionalization of C–H bonds with diazo compounds, no example deals with α-C­( sp 3 )–H bonds of carbonyl compounds. Even the corresponding nonasymmetric variants are extremely rare (e.g., gold catalysis by Shi et al and scandium catalysis by Bi et al with 1,3-dicarbonyl compounds as substrates).…”