Direct functionalization of C–H bonds represents a powerful strategy for the synthesis of complex organic compounds due to its inherent efficiency. Among various approaches, transition metal catalyzed direct activation of unreactive C–H bonds is particularly effective for this purpose. However, the development of practical methods for transition metal catalyzed direct C–H functionalization has been challenging. Apart from identifying the reaction conditions that allow the activation of relatively unreactive C–H bonds, these reactions need to be selective, allowing one C–H bond to be differentiated from the rest of the ubiquitous C–H bonds of the compound. Whereas directing group guided, transition metal catalyzed ortho-C–H functionalization of aromatic compounds has seen significant growth in the past few decades, methods for meta-C–H functionalization of arenes have also emerged. This review summarizes approaches for directing group guided, transition metal catalyzed meta-C–H functionalization of aromatic compounds. Some steric-controlled, transition metal catalyzed formal meta-C–H functionalization reactions without coordinating directing groups are also discussed.

A synthetic method has been developed for diastereoselective de novo synthesis of pyrroloindolines using readily available α,β-unsaturated N-aryl ketonitrones and amino acid derived activated alkynes. The reaction likely proceeded by initial formation of C3-quaternary indolenines followed by N-cyclization of the pendent nitrogen atom to give the complex heterocyclic system from simple starting materials in one step. Pyrroloindolines with substituents that may be difficult to introduce via other approaches have been prepared using this method.

A precatalyst of FeCl2 and iminopyridine was activated in situ by a combination of diethylzinc and magnesium bromide etherate; it catalyzed the reductive cyclization of 1,6-enynes to give pyrrolidine and tetrahydrofuran derivatives from N- and O-tethered 1,6-enynes. The scope of the transformation was explored.

An iron-catalyzed formal hydroamination of alkenes has been developed. It features O-benzoyl-N,N-dialkylhydroxylamines as the electrophilic nitrogen source and cyclopentylmagnesium bromide as the reducing agent for intermolecular hydroamination of styrene and derivatives with good yield and excellent Markovnikov regioselectivity. The reaction presumably proceeds through the iron-catalyzed hydrometalation of styrene followed by electrophilic amination with the electrophilic O-benzoylhydroxylamine.

We developed a six-step synthesis of the polycyclic core of vincorine using two cascades of reactions. A cascade of Michael–Mannich reactions was employed for one-pot preparation of a polycyclic intermediate, which was transformed into the desired polycyclic pyrroloindoline ring system using a cascade of methanolysis-N-imine cyclization reactions.

Methyl ketone oxime esters have been found to be excellent coupling partners for C(sp2)–C(sp3) bond formation via Pd-catalyzed aromatic C–H activation. This transformation forms the basis of an approach to regioselectively synthesize substituted isoquinolines via coupling with aryloxime esters. Our mechanistic studies suggested that the reaction proceeded through Pd(II)-catalyzed aromatic C–H activation, tautomerization, and a 1,3-shift of the palladacycle-ligated methyl ketone oxime ester to enable the C–C bond formation by reductive elimination, and intramolecular condensation of an imido-Pd(II) intermediate to form the heterocycle. The aryloxime group not only was used as a directing group for Pd-catalyzed aromatic C–H activation but also functioned as an internal oxidant to allow the reaction to be redox-neutral. Our study illuminated the scope and limitations of this C–H alkylation process, which may serve as the point of departure for developing other C–H functionalization reactions using oxime esters and potentially other carbonyl derivatives as the nucleophilic coupling partners.

N-Indolyltriethylborate was found to be a useful reagent for dearomatizing C3-alkylation of 3-substituted indoles with both activated and nonactivated alkyl halides to give C3-quaternary indolenines, pyrroloindolines, furoindoline, and hexahydropyridoindoline under mild reaction conditions. The utility of these reagents was demonstrated in the syntheses of a pyrroloindoline-4-cholestene hybrid and debromoflustramine B.

A detailed account of the first total synthesis of alotaketal A, a tricyclic spiroketal sesterterpenoid that potently activates the cAMP signaling pathway, is provided. The synthesis employs both intra- and intermolecular reductive allylation of esters for assembling one of the fragments and their coupling. A Hg(OAc)2-mediated allylic mercuration is used to introduce the C22-hydroxyl group. The subtle influence of substituents over the course of the spiroketalization process is revealed. The synthesis confirms the relative and absolute stereochemistry of (−)-alotaketal A and allows verification of alotaketal A's effect over cAMP signaling using reporter-based FRET imaging assays with HEK 293T cells. Our studies also revealed alotaketal A's unique activity in selectively targeting nuclear PKA signaling in living cells.

We have developed a convergent synthetic route to an all-carbon, 14-membered Z,E-macrocyclic bis-enone during our synthetic study of celastrol. The 1,3-dipolar cycloaddition of nitrile oxide and alkyne was employed for fragment coupling and introducing the 1,3-diketone moiety masked in the form of an isoxazole. We discovered that cycloaddition of the nitrile oxide and the enyne gave the rare 3,4-disubstituted isoxazole adduct under kinetic reaction conditions. The cycloaddition was found to be reversible, and the thermodynamic 3,5-disubstituted isoxazole could be obtained by isomerization of its 3,4-disubstituted isomer under elevated temperature. Our mechanistic studies support the role of hydrogen bonding in accelerating the isomerization. Consistent with our previous studies, the Z,E-macrocyclic bis-enone was found to be inactive toward the transannular bis-Michael reaction under the conditions evaluated.

A convergent route has been developed to synthesize an antifungal tricyclic o-hydroxy-p-quinone methide diterpenoid and analogues. A Li/naphthalene-mediated reductive alkylation was employed for coupling β-cyclocitral and the corresponding benzyl chloride, while a BBr3-mediated one-pot bis-demethylation and intramolecular Friedel–Crafts alkylation was used to assemble the tricyclic molecular skeleton. The structure–activity relationship of the diterpenoid was assessed on the basis of antiproliferation assays of the natural product and analogues against strains of pathogenic yeasts and filamentous fungi.

We have developed a convergent synthetic route to the potent cAMP signaling agonist (−)-alotaketal A that employs two stages of SmI2-mediated reductive allylation reactions for assembling the polycycle and fragment coupling. Also notable are a Hg(OAc)2-mediated selective alkene oxidation and the subtlety of the formation of the unprecedented spiroketal ring system. The probes AKAR4 and ICUE3 were used to evaluate the cAMP singaling agonistic activity of (−)-alotaketal A and elucidate its structure–activity relationship.

A modular approach to α,β-unsaturated N-aryl ketonitrones has been developed. Specifically, condensation of anilines and enals followed by alkylation of the resulting α,β-unsaturated imines provided N-allyl anilines, which were subjected to oxidation with Oxone® to form α,β-unsaturated N-aryl ketonitrones. This modular approach is general and provides rapid access to diversely substituted α,β-unsaturated N-aryl ketonitrones with a single purification step in good yields.

We systematically explored a transannular Michael reaction cascade for stereoselective synthesis of polycyclic systems. Both E,Z- and E,E-1,7-bis-enones in the form of 14-membered macrocyclic lactones underwent transannular cyclization to give polycyclic products with high efficiency and excellent diastereoselectivity. In contrast, Z,E- and Z,Z-macrocyclic lactones did not cyclize under similar reaction conditions. Our study revealed similarities and subtle stereochemical differences between this transannular cyclization process and transannular Diels–Alder reactions. An acyl ketene approach was developed for efficient synthesis of macrocyclic lactones. This investigation also illuminated the scope and limitation of macrocyclization by intramolecular Reformatsky reaction to prepare macrocyclic lactones.

A 12-step synthesis of the ABC carbocyclic core of norzoanthamine is described. It features an organocatalytic asymmetric intramolecular aldolization to set the stereochemistry of the entire molecule, a fragment coupling by selective alkylation of a bis-enolate, and a transannular Michael reaction cascade for rapid and stereoselective synthesis of the polycyclic core.

An enantioselective approach to a diastereomer of iriomoteolide-1a is described. Highlighted is a SmI2-mediated intramolecular reductive cyclization approach to complex cyclic hemiketals. An acetylide−chloroformate coupling strategy is also featured. Our results show that the structures of iriomoteolide-1a−1c require careful reassessment.

A practical procedure has been developed for γ-oxygenation of α,β-unsaturated esters by a vinylogous O-nitroso Mukaiyama aldol reaction followed by a one-pot N−O bond heterolysis of the in situ generated γ-aminoxy-α,β-unsaturated esters.

A titanium-mediated, hydroxy-directed reductive coupling reaction of propargylic alcohols and aldehydes/ketones is described. Excellent diastereoselectivity and synthetically useful yields have been obtained for a range of substrates. This transformation has enabled a highly convergent three-component approach to syn-1,3-diols using (trimethylsilyl)acetylene as a C1 linchpin.

Direct functionalization of C–H bonds represents a powerful strategy for the synthesis of complex organic compounds due to its inherent efficiency. Among various approaches, transition metal catalyzed direct activation of unreactive C–H bonds is particularly effective for this purpose. However, the development of practical methods for transition metal catalyzed direct C–H functionalization has been challenging. Apart from identifying the reaction conditions that allow the activation of relatively unreactive C–H bonds, these reactions need to be selective, allowing one C–H bond to be differentiated from the rest of the ubiquitous C–H bonds of the compound. Whereas directing group guided, transition metal catalyzed ortho-C–H functionalization of aromatic compounds has seen significant growth in the past few decades, methods for meta-C–H functionalization of arenes have also emerged. This review summarizes approaches for directing group guided, transition metal catalyzed meta-C–H functionalization of aromatic compounds. Some steric-controlled, transition metal catalyzed formal meta-C–H functionalization reactions without coordinating directing groups are also discussed.

A detailed account of the first total synthesis of alotaketal A, a tricyclic spiroketal sesterterpenoid that potently activates the cAMP signaling pathway, is provided. The synthesis employs both intra- and intermolecular reductive allylation of esters for assembling one of the fragments and their coupling. A Hg(OAc)2-mediated allylic mercuration is used to introduce the C22-hydroxyl group. The subtle influence of substituents over the course of the spiroketalization process is revealed. The synthesis confirms the relative and absolute stereochemistry of (−)-alotaketal A and allows verification of alotaketal A's effect over cAMP signaling using reporter-based FRET imaging assays with HEK 293T cells. Our studies also revealed alotaketal A's unique activity in selectively targeting nuclear PKA signaling in living cells.