The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho/meta-substituted arenes is described. The synthesis of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles has been achieved from a simple common intermediate. Several ortho and/or meta-substituted benzene analogues as well as simple molecular matched pairs have also been prepared using this platform. In-depth biological and computational studies are currently in progress to validate the ortho and/or meta-character of these new bioisosteres. Results of these investigations will be reported in due course.

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.

The synthesis of E-macrocycles is achieved using stereoretentive, Ru-based olefin metathesis catalysts supported by dithiolate ligands. Kinetic studies elucidate marked differences in activity among the catalysts tested, with catalyst 4 providing meaningful yields of products in much shorter reaction times than stereoretentive catalysts 2 and 3. Macrocycles were generated with excellent selectivity (>99% E) and in moderate to high yields (47–80% yield) from diene starting materials bearing two E-configured olefins. A variety of rings were constructed, ranging from 12to 18-membered macrocycles, including the antibiotic recifeiolide.

The synthesis of E-macrocycles is achieved using stereoretentive, Ru-based olefin metathesis catalysts supported by dithiolate ligands. Kinetic studies elucidate marked differences in activity among the catalysts tested, with catalyst 4 providing meaningful yields of products in much shorter reaction times than stereoretentive catalysts 2 and 3. Macrocycles were generated with excellent selectivity (>99% E) and in moderate to high yields (47-80% yield) from diene starting materials bearing two E-configured olefins. A variety of rings were constructed, ranging from 12- to 18-membered macrocycles, including the antibiotic recifeiolide.

Olefin metathesis is an incredibly valuable transformation that has gained widespread use in both academic and industrial settings. Lately, stereoretentive olefin metathesis has garnered much attention as a method for the selective generation of both E- and Z-olefins. Early studies employing ill-defined catalysts showed evidence for retention of the stereochemistry of the starting olefins at low conversion. However, thermodynamic ratios E/Z were reached as the reaction proceeded to equilibrium. Recent studies in olefin metathesis have focused on the synthesis of catalysts that can overcome the inherent thermodynamic preference of an olefin, providing synthetically useful quantities of a kinetically favored olefin isomer. These reports have led to the development of stereoretentive catalysts that not only generate Z-olefins selectively, but also kinetically produce E-olefins, a previously unmet challenge in olefin metathesis. Advancements in stereoretentive olefin metathesis using tungsten, ruthenium, and molybdenum catalysts are presented.

AbstractDie Olefinmetathese ist ein wertvolles Verfahren für Wissenschaft und Industrie. In letzter Zeit rückte die stereoretentive Olefinmetathese als eine Methode für die selektive Erzeugung von sowohl E‐ als auch Z‐Olefinen in den Fokus. In früheren Untersuchungen wurde nachgewiesen, dass die stereochemische Konfiguration der Ausgangsolefine zu Anfang der Umwandlung beibehalten wird. Als sich die Reaktion dem Gleichgewichtszustand näherte, wurden jedoch thermodynamische E/Z‐Verhältnisse erreicht. Bei neueren Untersuchungen lag das Hauptaugenmerk auf der Synthese von Katalysatoren, mit denen die inhärente thermodynamische Präferenz eines Olefins überwunden und ein kinetisch begünstigtes Olefinisomer erzeugt werden kann. Diese Berichte führten zur Entwicklung von stereoretentiven Katalysatoren, mit denen nicht nur selektiv Z‐Olefine erhalten werden, sondern auch E‐Olefine. Fortschritte bei der stereoretentiven Olefinmetathese unter Verwendung von Wolfram‐, Ruthenium‐ und Molybdänkatalysatoren werden hier dargelegt.

Olefin metathesis is a prevailing method for the construction of organic molecules. Recent advancements in olefin metathesis have focused on stereoselective transformations. Ruthenium olefin metathesis catalysts have had a particularly pronounced impact in the area of stereoselective olefin metathesis. The development of three categories of Z-selective olefin metathesis catalysts has made Z-olefins easily accessible to both laboratory and industrial chemists. Further design enhancements to asymmetric olefin metathesis catalysts have streamlined the construction of complex molecules. The understanding gained in these areas has extended to the employment of ruthenium catalysts to stereoretentive olefin metathesis, the first example of a kinetically E-selective process. These advancements, as well as synthetic applications of the newly developed catalysts, are discussed.

Dithiolate ligands have recently been used in ruthenium-catalyzed olefin metathesis and have provided access to a kinetically E selective pathway through stereoretentive olefin metathesis. The typical dithiolate used is relatively simple with low steric demands imparted on the catalyst. We have developed a synthetic route that allows access to sterically demanding dithiolate ligands. The catalysts generated provided a pathway to study the intricate structure–activity relationships in olefin metathesis. It was found that DFT calculations can predict the ligand arrangement around the ruthenium center with remarkable accuracy. These dithiolate catalysts proved resistant to ligand isomerization and were stable even under forcing conditions. Additionally, catalyst initiation and olefin metathesis studies delivered a better understanding to the interplay between dithiolate ligand structure and catalyst activity and selectivity.

“The ideal synthesis creates a complex skeleton… in a sequence only of successive construction reactions involving no intermediary refunctionalizations, and leading directly to the structure of the target, not only its skeleton but also its correctly placed functionality.”1 The Hendricksonian view of synthetic efficiency1 tacitly recognizes the importance of merged redox-construction events (“redox-economy”);2 regio-, chemo- (site-), and stereoselectivity;3 protecting-group-free chemical synthesis;4 and the minimization of pre-activation: the degree of separation between reagent and feedstock.5 Guided by these principles, it can be posited that stereo- and site-selective methods for the assembly of organic molecules that occur with the addition, acceptorless removal or redistribution of hydrogen are natural endpoints in the advancement of methods for process-relevant chemical synthesis.6,7 Hydrogenation and hydroformylation represent two of the largest-volume applications of homogeneous metal catalysis. Merging the chemistry of hydrogenation and carbonyl addition, we have developed a broad new family of “C–C bond forming hydrogenations”—processes wherein two or more reactants are hydrogenated to form a single, more complex product in the absence of stoichiometric byproducts (Scheme 1).7a,b,8 Unlike classical carbonyl additions, such transformations bypass the use of premetallated reagents and cryogenic conditions, and are completely atom-efficient. Scheme 1 Byproduct-Free Carbonyl and Imine Addition via C–C Bond-Forming Hydrogenation. (Ref. 8) By folding hydrogen into the carbonyl reactant, one can exploit the native reducing ability of alcohols in the related “C–C bond forming transfer hydrogenations.” Here, redox-triggered carbonyl addition is achieved upon hydrogen exchange between alcohols and π-unsaturated reactants to generate transient aldehyde–organometal pairs that combine to form products of alcohol C–H functionalization.7c,d Remarkably, certain chiral iridium catalysts display a pronounced kinetic preference for primary alcohol dehydrogenation, enabling enantio- and site-selective C–C coupling of diols and triols (Scheme 2).9 Such site-selectivity streamlines chemical synthesis, as it precludes protecting group installation and removal, as well as discrete alcohol-to-aldehyde redox manipulations. Scheme 2 Catalyst-Directed Diastereo- and Site-Selectivity Ir-Catalyzed Alcohol C–H Functionalization. (Ref. 9) As illustrated in the total syntheses of diverse polyketide natural products (Figure 1),7c the ability to engage polyfunctional molecules in a site-selective manner has induced a shift in retrosynthetic paradigm and a step-function change in synthetic efficiency. More broadly, the hydrogen-mediated C–C couplings we have developed suggest other processes that traditionally employ premetallated reagents can now be conducted catalytically in the absence of stoichiometric metals. Figure 1 Polyketide Natural Products Prepared via Direct Alcohol C–H Functionalization. (Ref. 7c)

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Ruthenium-catalyzed hydrogen transfer from 4-aminobutanol to butadiene results in the pairwise generation of 3,4-dihydro-2H-pyrrole and an allylruthenium complex, which combine to form products of imine anti-crotylation. In couplings of 1-substituted-1,3-dienes, novel C2 regioselectivity is observed. As corroborated by deuterium labeling studies, kinetically preferred hydrometalation of the terminal olefin of the 1-substituted-1,3-diene delivers a 1,1-disubstituted π-allylruthenium complex that isomerizes to a thermodynamically more stable monosubstituted π-allylruthenium complex, which undergoes imine addition with allylic inversion through a closed transition structure. Direct ruthenium-catalyzed diene hydroaminoalkylations with pyrrolidine also are described.

4‐Aminobutanol (II) and some related amino alcohols such as (X) can be used in the title reaction.

The use of alcohols and unsaturated reactants for the redox-triggered generation of nucleophile-electrophile pairs represents a broad, new approach to carbonyl addition chemistry. Discrete redox manipulations that are often required for the generation of carbonyl electrophiles and premetalated carbon-centered nucleophiles are thus avoided. Based on this concept, a broad, new family of enantioselective C-C coupling reactions that are catalyzed by iridium or ruthenium complexes have been developed, which are summarized in this Minireview.

AbstractDie Verwendung von Alkoholen und ungesättigten Reaktanten zur redoxvermittelten Bildung von Nucleophil‐Elektrophil‐Paaren stellt einen breiten, neuartigen Ansatz in der Chemie der Carbonyl‐Addition dar. Mit dieser Vorgehensweise lassen sich diskrete Redoxmanipulationen, die oftmals für die Erzeugung von Carbonyl‐Elektrophilen und vormetallierten Kohlenstoff‐zentrierten Nucleophilen benötigt werden, vermeiden. Die Methode begründet eine neue Klasse von enantioselektiven C‐C‐Kupplungen, die durch Iridium‐ oder Rutheniumkomplexe katalysiert werden.

A new benzannulation protocol is described and applied to the synthesis of polycyclic aromatic hydrocarbons. Ruthenium(0)-catalyzed diol-diene [4+2] cycloaddition delivers cyclohex-1-ene-4,5-diols, which are subject to aromatization upon dehydration or Nicholas diol deoxydehydration. Employing diol and tetraol reactants, benzannulation can be conducted efficiently in one- and two-directional modes, respectively, as illustrated in the construction of substituted fluoranthenes and acenes.

Heteroaromatic secondary alcohols react with isoprene to form products of hydrohydroxyalkylation in the presence of ruthenium(0) catalysts generated from Ru3(CO)12 and tricyclohexylphosphine, enabling direct conversion of secondary to tertiary alcohols in the absence of premetalated reagents or stoichiometric byproducts. The putative oxaruthenacycle intermediate has been isolated and characterized, and reversible metallacycle formation has been demonstrated.

A new benzannulation protocol is developed consisting of Ru-catalyzed diol-diene [4 + 2] cycloaddition and subsequent aromatization upon dehydration or deoxydehydration is developed to allow the synthesis of a diverse range of polycyclic arenes.