Total Synthesis of the Diterpenes (+)-Randainin D and (+)-Barekoxide via Photoredox-Catalyzed Deoxygenative Allylation.

We report the first enantioselective total synthesis of diterpenoid randainin D, which possesses a hydroazulenone core with a ß-substituted butenolide moiety on the cycloheptane ring. The trans-5/7 ring system was formed via a highly challenging ring-closing metathesis delivering the tetrasubstituted cycloheptenone. The butenolide moiety was installed via a novel deoxygenative allylation under Ir-photoredox catalysis, employing methyl oxalate as a red/ox tag. Moreover, the developed allylation was successfully utilized in the 7-step total synthesis of (+)-barekoxide. This study suggests that this deoxygenative allylation method is a promising strategy for the formation of Cq-C(sp3) bonds (Cq = quaternary center) in the context of natural product synthesis.

1,4-Pd Migration-Enabled Synthesis of Fused 4-Membered Rings.

1,4-Palladium migration has been widely used for the functionalization of remote C-H bonds. However, this mechanism has been limited to aryl halide precursors. This work reports an unprecedented Pd0-catalyzed cyclobutanation protocol producing valuable fused cyclobutanes starting from cycloalkenyl (pseudo)halides. This reaction takes place via alkenyl-to-alkyl 1,4-Pd migration, followed by intramolecular Heck coupling. The method performs best with cyclohexenyl precursors, giving access to a variety of substituted bicyclo[4,2,0]octenes. Reactants containing an N-methyl or methoxy group give rise to fused azetidines or oxetanes, respectively, via the same mechanism. Kinetic and deuterium-labeling studies point to a rate-limiting C(sp3)-H activation step.

Methylene C(sp3 )-H Arylation Enables the Stereoselective Synthesis and Structure Revision of Indidene Natural Products.

The divergent synthesis of two indane polyketides of the indidene family, namely (±)-indidene A (11 steps, 1.7 %) and (+)-indidene C (13 steps, 1.3 %), is reported. The synthesis of the trans-configured common indane intermediate was enabled by palladium(0)-catalyzed methylene C(sp3 )-H arylation, which was performed in both racemic and enantioselective (e.r. 99 : 1) modes. Further elaboration of this common intermediate by nickel-catalyzed dehydrogenative coupling allowed the rapid installation of the aroyl moiety of (±)-indidene A. In parallel, the biphenyl system of (±)- and (+)-indidene C was constructed by Suzuki-Miyaura coupling. These investigations led us to revise the structures of indidenes B and C.

Iridium(III)-Catalyzed Intermolecular C(sp3 )-H Amidation for the Synthesis of Chiral 1,2-Diamines.

Chiral 1,2-diamines are privileged scaffolds among bioactive natural products, active pharmaceutical ingredients, ligands for transition-metal-based asymmetric catalysis and organocatalysts. Despite this interest, the construction of chiral 1,2-diamine motifs still remains a challenge. To address this, an iridium(III)-catalyzed intermolecular C(sp3 )-H amidation reaction was developed. This method relies on the design of a new, cheap and cleavable exo-protecting/directing group derived from camphorsulfonic acid, which is directly installed from easily accessible precursors, and furnishes scalemic free 1,2-diamines upon cleavage of both nitrogen substituents. It was found applicable to both α-secondary and α-tertiary-1,2-diamines, for which a two-step protocol involving intermolecular olefin hydroamination and C(sp3 )-H amidation was developed. Kinetic and computational studies provided insights into the observed reactivity difference between pairs of diastereoisomeric substrates.

Remote Construction of N-Heterocycles via 1,4-Palladium Shift-Mediated Double C-H Activation.

In the past years, Pd0 -catalyzed C(sp3 )-H activation provided efficient and step-economical methods to synthesize carbo- and heterocycles via direct C(sp2 )-C(sp3 ) bond formation. We report herein that a 1,4-Pd shift allows access to N-heterocycles which are difficult to build via a direct reaction. It is shown that o-bromo-N-methylanilines undergo a 1,4-Pd shift at the N-methyl group, followed by intramolecular trapping by C(sp2 )-H or C(sp3 )-H activation at another nitrogen substituent and remote C-C bond formation to generate biologically relevant isoindolines and ß-lactams. The product selectivity is influenced by the employed ligand, with NHCs favoring the product of remote C-C coupling against products arising from direct C-C coupling and N-demethylation.

Site-Selective Pd-Catalyzed C(sp3 )-H Arylation of Heteroaromatic Ketones.

A ligand-controlled site-selective C(sp3 )-H arylation of heteroaromatic ketones has been developed using Pd catalysis. The reaction occurred selectively at the α- or ß-position of the ketone side-chain. The switch from α- to ß-arylation was realized by addition of a pyridone ligand. The α-arylation process showed broad scope and high site- and chemoselectivity, whereas the ß-arylation was more limited. Mechanistic investigations suggested that α-arylation occurs through C-H activation/oxidative addition/reductive elimination whereas ß-arylation involves desaturation and aryl insertion.

Chiral Catalysts for Pd0 -Catalyzed Enantioselective C-H Activation.

In the past few decades, processes that involve transition-metal catalysis have represented a major part of the synthetic chemist's toolbox. Recently, the interest has shifted from the well-established cross-coupling reactions to C-H bond functionalization, thus making it a current frontier of transition-metal-catalyzed reactions. Constant progress in this field has led to the discovery of enantioselective methods to generate and control various types of stereogenic elements, thereby demonstrating its high value to generate scalemic chiral molecules. The present review is dedicated to enantioselective Pd0 -catalyzed C-H activation, which may be considered as an evolution of Pd0 -catalyzed cross-couplings, with a focus on the different chiral ligands and catalysts that enable these transformations.

A Personal Account on Industrial Collaborations in the Field of C-H Activation.

In recent years, transition-metal-catalyzed C-H functionalization has emerged as a potentially greener alternative to classic cross-couplings and as a powerful tool to access complex functional molecules with improved step-economy. This short account relates our experience of industrial collaborations in C(sp³)-H bond activation, which were key to the development of this topic in our group. The synthesis of the antianginal drug Ivabradine led us to develop a general approach to benzocyclobutenes, which were further employed in peri cyclic reactions. A follow-up study led us to discover a new method to construct arylcyclopropanes via double C-H activation and the coupling of two alkyl groups. Finally, targeting the herbicide Indaziflam contributed to develop C(sp³)-H activation as a powerful tool to access a variety of relevant indane motifs. We hope that these successful stories will help to stimulate further fruitful Industry-Academia collaborations in the field of synthetic chemistry.

Enantioselective Pd0 -Catalyzed C(sp2 )-H Arylation for the Synthesis of Chiral Warped Molecules.

C-H activation-based ring-forming methods are a powerful approach for the construction of complex molecular architectures, especially those containing a congested stereocenter. Therefore, this strategy seems perfectly suited to address the synthesis of chiral polycyclic aromatic hydrocarbons (PAHs) and bowl-shaped molecules, which are important target molecules in the field of organic electronic materials. Herein, we describe an enantioselective Pd0 -catalyzed C(sp2 )-H arylation protocol for the synthesis of chiral fluoradenes and other warped molecules, which could serve to the bottom-up construction of chiral PAHs. The current approach relies on the use of chiral bifunctional phosphine-carboxylate ligands and delivers diverse polycyclic compounds in high yield and with good to excellent enantioselectivity. The chiroptical properties of the obtained products were investigated, and some of them were found to have a strong ellipticity and an emission band located in the visible region.

A New Dioxazolone for the Synthesis of 1,2-Aminoalcohols via Iridium(III)-Catalyzed C(sp3 )-H Amidation.

Vicinal aminoalcohols are widespread structural motifs in bioactive molecules. We report the development of a new dioxazolone reagent containing a p-nitrophenyldifluoromethyl group, which 1. displays a good safety profile; 2. shows a remarkably high reactivity in the oxime-directed iridium(III)-catalyzed amidation of unactivated C(sp3 )-H bonds; 3. leads to amide products which can be hydrolyzed under mild conditions. The amidation reaction is mild, general and compatible with both primary C-H bonds of tertiary and secondary alcohols, as well as secondary C-H bonds of cyclic secondary alcohols. This method provides an easy access to free 1,2-aminoalcohols after efficient and mild cleavage of the oxime directing group and activated amide.

Palladium(0)-Catalyzed Enantioselective Intramolecular Arylation of Enantiotopic Secondary C-H Bonds.

The enantioselective functionalization of nonactivated enantiotopic secondary C-H bonds is one of the greatest challenges in transition-metal-catalyzed C-H activation proceeding by an inner-sphere mechanism. Such reactions have remained elusive within the realm of Pd0 catalysis. Reported here is the unique reactivity profile of the IBiox ligand family in the Pd0 -catalyzed intramolecular arylation of such nonactivated secondary C-H bonds. Chiral C2 -symmetric IBiox ligands led to high enantioselectivities for a broad range of valuable indane products containing a tertiary stereocenter, as well as the arylation of secondary C-H bonds adjacent to amides. Depending on the amide substituents and upon control of reaction time, indanes containing labile tertiary stereocenters were also obtained with high enantioselectivities. Analysis of the steric maps of the IBiox ligands indicated that the level of enantioselectivity correlates with the difference between the two most occupied and the two less occupied space quadrants, and provided a blueprint for the design of even more efficient ligands.

Direct Synthesis of Cyclopropanes from gem-Dialkyl Groups through Double C-H Activation.

Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C-H bonds on gem-dialkyl groups has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C(sp3)-H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.

Intermolecular Palladium(0)-Catalyzed Atropo-enantioselective C-H Arylation of Heteroarenes.

Atropisomeric (hetero)biaryls are motifs with increasing significance in ligands, natural products, and biologically active molecules. The straightforward construction of the stereogenic axis by efficient C-H functionalization methods is extremely rare and challenging. An intermolecular and highly enantioselective C-H arylation of relevant heteroarenes providing an efficient access to atropisomeric (hetero)biaryls is reported. The use of a Pd(0) complex equipped with H8-BINAPO as a chiral ligand enables the direct functionalization of a broad range of 1,2,3-triazoles and pyrazoles in excellent yields and selectivities of up to 97.5:2.5 er. The method also allows for an atroposelective double C-H arylation for the construction of two stereogenic axes with >99.5:0.5 er.

Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp3 )-H Activation Strategy.

This article provides a detailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (-)-epicoccin G and (-)-rostratin A using a double C(sp3 )-H activation strategy. The strategy's viability was first established on a model system lacking the C8/C8' alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access a key bis-triflate substrate. This bis-triflate served as the functional handles for the key transformation of the synthesis: a double C(sp3 )-H activation. The successful double activation opened access to a common intermediate for both natural products in high overall yield and on a multigram scale. After several unsuccessful attempts, this intermediate was efficiently converted to (-)-epicoccin G and to the more challenging (-)-rostratin A via suitable oxidation/reduction and protecting group sequences, and via a final sulfuration that occurred in good yield and high diastereoselectivity. These efforts culminated in the synthesis of (-)-epicoccin G and (-)-rostratin A in high overall yields (19.6 % over 14 steps and 12.7 % over 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin A as a 20x more potent analogue.

Multiple Catalytic C-H Bond Functionalization for Natural Product Synthesis.

In the past decade, multiple catalytic C-H bond functionalization has been successfully applied in natural product synthesis as a strategy to reduce the number of steps, increase overall yield and employ more easily available starting materials. This minireview presents selected examples making use of multiple C-H bond functionalization in conceptually different ways. First, linear syntheses are discussed, wherein multiple C-H functionalization is employed either from simple (hetero)cyclic cores, at a late stage, or to build polycyclic systems. Second, the use of multiple C-H functionalization as a strategic tool in convergent synthesis to access and couple complex fragments is discussed. Information on the scalability of the employed methods is provided when available. The presented cases indicate that multiple C-H functionalization strategies should play a great role to shape the future synthesis of functional complex molecules with improved sustainability.

Synthesis of Amides and Esters by Palladium(0)-Catalyzed Carbonylative C(sp3 )-H Activation.

The 1,4-palladium shift strategy allows the functionalization of remote C-H bonds that are difficult to reach directly. Reported here is a domino reaction proceeding by C(sp3 )-H activation, 1,4-palladium shift, and amino- or alkoxycarbonylation, which generates a variety of amides and esters bearing a quaternary ß-carbon atom. Mechanistic studies showed that the aminocarbonylation of the σ-alkylpalladium intermediate arising from the palladium shift is fast using PPh3 as the ligand, and leads to the amide rather than the previously reported indanone product.

Efficient and Divergent Total Synthesis of (-)-Epicoccin G and (-)-Rostratin A Enabled by Double C(sp3)-H Activation.

Dithiodiketopiperazines are complex polycyclic natural products possessing a variety of interesting biological activities. Despite their interest, relatively few total syntheses have been completed. We herein report the enantioselective, scalable, and divergent total synthesis of two symmetrical pentacyclic dithiodiketopiperazines, (-)-epicoccin G and (-)-rostratin A. A common intermediate was synthesized on a multigram scale from inexpensive, commercially available starting materials using an enantioselective organocatalytic epoxidation and a double C(sp3)-H activation as key steps, with the latter allowing the efficient simultaneous construction of the two five-membered rings. In addition to the cis,cis-fused target (-)-epiccocin G, the more challenging (-)-rostratin A, possessing two trans ring junctions, was obtained for the first time on a 500 mg scale through the optimization of each step and validation on multigram quantities. Both natural products were synthesized with high overall yields (13-20%). This study should facilitate access to this fascinating and yet understudied family of biologically active natural products.

Total Synthesis of (Nor)illudalane Sesquiterpenes Based on a C(sp3)-H Activation Strategy.

Three (nor)illudalane sesquiterpenes were synthesized from a common intermediate in racemic and enantioenriched forms using Pd0-catalyzed C(sp3)-H arylation as a key step. The configuration of the isolated, highly symmetric quaternary stereocenter of the target molecules was controlled through a matched combination of chiral substrate and catalyst. Moreover, the recently developed Ir-catalyzed C-H borylation/Cu-catalyzed methylation method was employed to install the methyl group on the benzene ring. This strategy allowed the efficient synthesis of both racemic and (S)-configured puraquinonic acid, deliquinone, and russujaponol F.

Redox-Neutral Coupling between Two C(sp3 )-H Bonds Enabled by 1,4-Palladium Shift for the Synthesis of Fused Heterocycles.

The intramolecular coupling of two C(sp3 )-H bonds to forge a C(sp3 )-C(sp3 ) bond is enabled by 1,4-Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp3 )-C(sp3 ) cross-dehydrogenative couplings, this reaction operates under redox-neutral conditions, with the C-Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C-H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho-bromophenol and aniline precursors. The second C-H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp3 )-C(sp3 ) bonds.

Ring Construction by Palladium(0)-Catalyzed C(sp3)-H Activation.

The catalytic activation and functionalization of unactivated C(sp3)-H bonds of alkyl groups has undergone intense development in recent years. In particular, a variety of directing groups as well as native functional groups have been employed in combination with palladium(II) catalysis in order to perform a variety of intermolecular, and to some extent intramolecular reactions. In parallel, inspired by precedents in C(sp2)-H arylation, our group and others have developed a different approach, which is the focus of this Account. This strategy relies on the use of oxidative addition of a carbon-leaving group bond to palladium(0) to induce intramolecular C(sp3)-H activation and the subsequent formation of a C(sp2)-C(sp3) or C(sp3)-C(sp3) bond. Since our first publication in 2003, the construction of olefins and, more interestingly, of an array of valuable monocyclic and polycyclic systems has been reported according to this principle. (Hetero)aryl bromides were initially employed as reactants, but the scope was later expanded to include (hetero)aryl chlorides and triflates, alkenyl bromides, carbamoyl chlorides and α-chloroamides. Mechanistic studies enabled a better understanding of the C-H activation step, which was proposed to occur through ambiphilic metal-ligand activation-6 (AMLA-6), also known as concerted metalation deprotonation (CMD), and a better rationalization of the observed selectivity patterns. Moreover, the wealth of accumulated experimental data indicate that the number of atoms separating the C-H bond from Pd and the type of C-H bond are the main factors controlling the site-selectivity of the C-H bond cleavage. Recent efforts have been devoted to the development of enantioselective reactions. To this purpose, two different strategies have been employed: a chiral ancillary ligand in combination with an achiral base, and a chiral base in combination with an achiral ligand, and allowed for the achievement of high enantioselectivities in the construction of both tri- and tetrasubstituted stereocenters. On the other hand, the current C-H activation-based ring-forming method was applied to the synthesis of pharmacologically active substances and agrochemicals, as well as complex natural products such as the aeruginosins, thereby demonstrating its great potential for step-economical organic synthesis.