Given the emerging demand to “escape from flatland” for drug discovery, synthetic methods that can efficiently construct complex three-dimensional structures with multi-stereocenters become ...increasingly valuable. Here, we describe the development of Rh(I)-catalyzed intramolecular annulations between cyclobutanones and 1,5-enyne groups to construct complex C(sp3)-rich scaffolds. Divergent reactivities are realized with different catalysts, and excellent diastereo- and enantioselectivity have been achieved. The use of (R)-H8-binap as the ligand favors forming the bis-bicyclic scaffolds with multiple quaternary stereocenters, while the (R)-segphos ligand prefers to generate the tetrahydro-azapinone products. Owing to the versatile reactivity of ketone moieties, these C(sp3)-rich scaffolds can be further functionalized. Experimental and computational mechanistic studies support a reaction pathway involving enyne-cyclometallation, 1,2-carbonyl addition, and then β-carbon elimination; the divergent reactivities are dictated by a product-determining Rh-alkyl migratory insertion step.
Keywords: amidation; desymmetrization; rhodium; alpha-methyl stereocenter; beta-amino alcohol Desymmetrization of gem-dimethyl groups en route to the rhodium(III)-catalyzed enantioselective sp.sup.3 ...C-H amidation is reported. Synthetically important beta-amino alcohol derivatives were accessed in moderate to good yields and high enantioselectivity. The high enantioselectivity is enabled by an appropriate oxime directing group, sterically biased gem-groups in the C-H substrate, and high reactivity of the amidating reagent. Article Note: Dedicated to the 100.sup.th anniversary of Chemistry at Nankai University Supporting information: Additional Supporting Information may be found in the online version of this article As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. CAPTION(S): Supplementary Byline: Bingxian Liu, Pengfei Xie, Jie Zhao, Juanjuan Wang, Manman Wang, Yuqin Jiang, Junbiao Chang, Xingwei Li
The synthesis of complex organic compounds usually relies on controlling the reactions of the functional groups. In recent years, it has become possible to carry out reactions directly on the C-H ...bonds, previously considered to be unreactive. One of the major challenges is to control the site-selectivity because most organic compounds have many similar C-H bonds. The most well developed procedures so far rely on the use of substrate control, in which the substrate has one inherently more reactive C-H bond or contains a directing group or the reaction is conducted intramolecularly so that a specific C-H bond is favoured. A more versatile but more challenging approach is to use catalysts to control which site in the substrate is functionalized. p450 enzymes exhibit C-H oxidation site-selectivity, in which the enzyme scaffold causes a specific C-H bond to be functionalized by placing it close to the iron-oxo haem complex. Several studies have aimed to emulate this enzymatic site-selectivity with designed transition-metal catalysts but it is difficult to achieve exceptionally high levels of site-selectivity. Recently, we reported a dirhodium catalyst for the site-selective functionalization of the most accessible non-activated (that is, not next to a functional group) secondary C-H bonds by means of rhodium-carbene-induced C-H insertion. Here we describe another dirhodium catalyst that has a very different reactivity profile. Instead of the secondary C-H bond, the new catalyst is capable of precise site-selectivity at the most accessible tertiary C-H bonds. Using this catalyst, we modify several natural products, including steroids and a vitamin E derivative, indicating the applicability of this method of synthesis to the late-stage functionalization of complex molecules. These studies show it is possible to achieve site-selectivity at different positions within a substrate simply by selecting the appropriate catalyst. We hope that this work will inspire the design of even more sophisticated catalysts, such that catalyst-controlled C-H functionalization becomes a broadly applied strategy for the synthesis of complex molecules.
Rh(III)-Catalyzed 1 : 2 coupling of 3-aryl-2
-benzo
1,4oxazines with α-diazo-β-ketoesters has been realized for the mild synthesis of spiropyrans. The reaction proceeded
twofold C-H activation ...followed by unusual 3+3 and 4+2 annulation with decent functional group tolerance. Moreover, a pyranoid-skeleton intermediate was isolated as a key intermediate as a result of monoalkylation and enol oxygen annulation, which offers direct mechanistic insight.
Unique structure, characteristic reactivity, and facile synthesis of metal complexes have made them efficient ligands in drug development research. Among them, rhodium complexes have a limited ...history and there are a few discussions about their biological activities documented in the literature. However, investigation of kinetically inert rhodium complexes has recently attracted lots of attention and especially there are various evidences on their anti-cancer activity. It seems that they can be investigated as a versatile surrogates or candidates for the existing drugs which do not affect selectively or suffer from various side effects. In recent years, there has been an increasing interest in the use of mononuclear rhodium (III) organometallo drugs due to its versatile structurally important aspects to inhibit various enzymes. It has been demonstrated that organometallic Rh complexes profiting from both organic and inorganic aspects have shown more potent biological activities than classical inorganic compartments. In this respect, smart design, use of the appropriate organic ligands, and efficient and user-friendly synthesis of organometallic Rh complexes have played crucial roles in the inducing desirable biological activities. In this review, we focused on the recent advances published on the bioactivity of Rh (III/II/I) complexes especially inhibitory activity, from 2013 till now. Accordingly, considering the structure-activity relationship (SAR), the effect of oxidation state (+1, +2, and +3) and geometry (dimer or monomer complexes with coordination number of 4 and 6) of Rh complexes as well as various ligands on in vitro and in vivo studies was comprehensively discussed.
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•Rh complexes have shown significant anti-cancer activity.•Biological activity of the Rh complexes is comparable to those of organic small molecules.•The biological activity of organometallic rhodium (III) complexes is more potent than those of (II) and (I) complexes.•The biological activity of Rh complexes is more significant than those of neighboring metal complexes.
The use of enaminones as effective synthons for a directed C-H functionalization is reported. Proof-of-concept protocols have been developed for the Rh(III) -catalyzed synthesis of naphthalenes, ...based on the coupling of enaminones with either alkynes or α-diazo-β-ketoesters. Two inherently reactive functionalities (hydroxy and aldehyde groups) are integrated into the newly formed cyclic framework and a broad range of substituents are tolerated, rendering target products readily available for further elaboration.
A change in reaction pathway was achieved for the first time by tuning the cyclopentadienyl (Cp) ligand used for the rhodium‐catalyzed cyclization of benzamides with conjugated enynones. Depending on ...the Cp ligand, the reaction pathway switched between 4+2 and 4+1 annulation. Electronic effects turned out to be crucial for the product distribution. The dichotomy was attributed to the alteration of the Lewis acidity of the resultant Cp‐bound rhodium species.
The choice is yours: A change in reaction pathway was achieved by tuning the cyclopentadienyl (Cp) ligand used for the rhodium‐catalyzed cyclization of benzamides with conjugated enynones. Depending on the Cp ligand, the reaction pathway switched between 4+2 and 4+1 annulation. Electronic effects turned out to be crucial for the product distribution.
Over the last several decades, researchers have achieved remarkable progress in the field of organometallic chemistry. The development of metal-catalyzed cross-coupling reactions represents a ...paradigm shift in chemical synthesis, and today synthetic chemists can readily access carbon–carbon and carbon–heteroatom bonds from a vast array of starting compounds. Although we cannot understate the importance of these methods, the required prefunctionalization to carry out these reactions adds cost and reduces the availability of the starting reagents. The use of C–H bond activation in lieu of prefunctionalization has presented a tantalizing alternative to classical cross-coupling reactions. Researchers have met the challenges of selectivity and reactivity associated with the development of C–H bond functionalization reactions with an explosion of creative advances in substrate and catalyst design. Literature reports on selectivity based on steric effects, acidity, and electronic and directing group effects are now numerous. Our group has developed an array of C–H bond functionalization reactions that take advantage of a chelating directing group, and this Account surveys our progress in this area. The use of chelation control in C–H bond functionalization offers several advantages with respect to substrate scope and application to total synthesis. The predictability and decreased dependence on the inherent stereoelectronics of the substrate generally result in selective and high yielding transformations with broad applicability. The nature of the chelating moiety can be chosen to serve as a functional handle in subsequent elaborations. Our work began with the use of Rh(I) catalysts in intramolecular aromatic C–H annulations, which we further developed to include enantioselective transformations. The application of this chemistry to the simple olefinic C–H bonds found in α,β-unsaturated imines allowed access to highly substituted olefins, pyridines, and piperidines. We observed complementary reactivity with Rh(III) catalysts and developed an oxidative coupling with unactivated alkenes. Further studies on the Rh(III) catalysts led us to develop methods for the coupling of C–H bonds to polarized π bonds such as those in imines and isocyanates. In several cases the methods that we have developed for chelation-controlled C–H bond functionalization have been applied to the total synthesis of complex molecules such as natural products, highlighting the utility of these methods in organic synthesis.
Abstract
Die selektive Aktivierung von C‐F‐Bindungen unter milden Reaktionsbedingungen ist nach wie vor eine Herausforderung im Bereich der Bindungsaktivierung. Hier stellen wir ein kooperatives ...Rh/P(O)
n
Bu
2
‐Template für die katalytische Hydrodefluorierung (HDF) von Perfluorarenen vor. Zusätzlich zu Substraten mit elektronenziehenden funktionellen Gruppen zeigte das System eine äußerst seltene Toleranz gegenüber elektronenschiebenden funktionellen Gruppen und Heterozyklen. Die hohe Chemoselektivität des Katalysators und die Möglichkeit, ihn im präparativen Maßstab einzusetzen, verdeutlichen seine Praxistauglichkeit. Empirische mechanistische Studien und eine Dichtefunktionaltheorie (DFT)‐Studie haben einen Rhodium(I)‐Dihydrid‐Komplex als katalytisch relevante Spezies identifiziert und die entscheidende Rolle von Phosphinoxid als kooperatives Fragment ermittelt. Insgesamt zeigen wir, dass molekulare Templates, welche auf diesen Designelementen basieren, zusammengesetzt werden können, um Katalysatoren mit erhöhter Reaktivität für anspruchsvolle Bindungsaktivierungen zu schaffen.
The first formal intramolecular 1,3-insertion into OSi bond of rhodium(II) azavinyl carbene have been developed, and valuable phthalan derivatives could be synthesized efficiently. In addition, ...various functional groups could be introduced to the product conveniently in the assistant of TBAF.
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The first formal intramolecular 1,3-insertion into OSi bond of rhodium(II) azavinyl carbene have been developed, and valuable phthalan derivatives could be synthesized efficiently. In addition, various functional groups could be introduced to the product conveniently in the assistant of TBAF.
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