Probing the Role of the Mycosamine C2'-OH on the Activity of Amphotericin B

A synthetic route to a mycosamine donor was designed and provided access to a set of AmB derivatives targeted to probe the effect of the C2'-OH. It was determined that the configuration of the C2'-position is inconsequential but that O-methylation of this alcohol was deleterious to its mode of action. Additionally, the analog incorporating a mycosamine derivative from the enantiomeric series was devoid of activity

Metal-Catalyzed [2+2+1] Cycloadditions of 1,3-Dienes, Allenes, and CO

Step economy is a preeminent goal of synthesis.[1] It influences the length, efficiency, cost, time, separation, and environmental impact of a synthesis. Step economy is favored by the use of single, serial, or multicomponent reactions that proceed in one operation with a great increase in target revelant complexity. The design or discovery of such reactions is thus critical to extending the practical reach of organic synthesis. Toward this end, we have directed effort at the identification of new metal-catalyzed reactions, especially those which are forbidden or difficult to achieve in the absence of a catalyst. This program has thus far produced several new two-, three-, and four-component reactions, including [4+4],[2] [4+2],[3] [5+2],[4] [6+2],[5] [5+2+1],[6] [2+2+1],[7] [4+2+1],[7a] and [5+1+2+1][8] cycloadditions. Herein, we report the first examples of the [2+2+1] cycloaddition reaction of diene– allenes and CO and preliminary examples of acceleration of this process by Brønsted acids

Rhodium(I)-Catalyzed [2+2+1] Cycloadditions of 1,3-Dienes, Alkenes, and CO

The evolution of organic synthesis relies heavily on the design and discovery of new reactions that generate structural complexity and value with step economy.1 Toward this end, we previously reported studies on new [4+4],2 [4+2],3 [5+2],4 and [6+2]5 cycloadditions and novel three-component [2+2+1],6 [4+2+1],6 and [5+2+1]7 reactions.8 In the course of our studies on the Rh-(I)-catalyzed dienyl Pauson-Khand [2+2+1] reaction, we observed that diene-ynes react significantly faster than alkene-ynes to produce cyclopentenone products. This enhanced reactivity suggests that dienes might be used instead of alkynes to effect a [2+2+1] reaction with simple alkenes and CO. Conventional Pauson-Khand reactions and more recent catalyzed variants have been limited almost exclusively to the use of alkynes as one of the two carbon components.9,10 Bis-alkenes do not undergo this three-component reaction, although useful alternative two-step stoichiometric processes have been reported in which a preformed metallacycle is converted with CO to a cyclopentanone.11 We report herein the first examples of a metal-catalyzed [2+2+1] reaction involving a diene, an alkene, and CO.1

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 °C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates.The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene

The Diene Effect: The Design, Development, and Mechanistic Investigation of Metal-Catalyzed Diene-yne, Diene-ene, and Diene-allene [2+2+1] Cycloaddition Reactions

Metal-catalyzed diene-yne, diene-ene, and diene-allene [2+2+1] cycloaddition reactions provide new methods for the facile construction of highly functionalized five-membered rings. These reactions can be conducted with a variety of substrate substitution patterns and functional groups and often in the absence of solvent. The special reactivity of dienes, a key to enabling or enhancing the effectiveness of the [2+2+1] and other reactions, is significantly different from that of alkynes, alkenes, or allenes. For example, the [2+2+1] reaction of a diene-yne is accelerated compared to that of the corresponding ene-yne. An even more dramatic "diene effect" is found with diene-enes and diene-allenes. While bis-enes and ene-allenes are not reported to yield [2+2+1] cycloadducts, the related diene-enes and diene-allenes undergo efficient [2+2+1] cycloadditions, providing new routes to cyclopentanones and alkylidenecyclopentanones. Mechanistic studies suggest that the unique reactivity observed with dienes arises from their participation in the putative rate-determining reductive elimination step by providing an additional energy-lowering coordination site for the transition metal catalyst

DFT Mechanistic Investigation of an Enantioselective Tsuji–Trost Allylation Reaction

A comprehensive mechanistic examination of an asymmetric palladium-catalyzed Tsuji–Trost allylation reaction that identifies the enantioselective step was completed utilizing DFT computational tools and the nudged elastic band method. Key components of the study include (a) plausible reaction pathways for the full interconversion of a square-planar palladium allyl enolate intermediate with low barriers relative to the subsequent enantioselectivity-determining reductive C–C coupling step, thereby disputing the previously identified mechanism, (b) a detailed analysis of the factors influencing the stereochemical control involved in forming the preferred configuration via the reductive C–C coupling step, (c) a comprehensive examination of the competing outer-sphere mechanism that includes a metal counterion as an escort to the nucleophile in order to modulate the effects of modeling the reaction step of oppositely charged species, and (d) examination of the possible role water plays in stabilizing a keto-coordinated adduct of PdII-?1-allyl, formed early in the catalytic cycle, relative to a carboxylate-coordinated adduct, the known resting state of the reaction. Barrier energies for the enantioselective C–C coupling are investigated with several levels of theory, and together they support a reaction mechanism consistent with the preferred formation of the correct enantiomer on the basis of the enantiomer of the ligand selected

Sequential Pd(0)-, Rh(I)-, and Ru(II)-Catalyzed Reactions in a Nine-Step Synthesis of Clinprost

A step-economical synthesis of clinprost is reported that concludes with 3 different transition metal-catalyzed reactions: Pd-catalyzed decarboxylation with allylic rearrangement, Rh-catalyzed diene-ene [2+2+1] reaction, and Ru-catalyzed cross-metathesis reaction. The complexity bestowed to the molecule from these reactions converts a readily accessible ester to clinprost without using protecting groups in only 9 total steps

New reactions and step economy: the total synthesis of (±)-salsolene oxide based on the type II transition metal-catalyzed intramolecular [4 + 4] cycloaddition

Studies on the viability of the type II nickel-catalyzed intramolecular [4+4] cycloaddition of bis-dienes show that it is influenced by both diene substitution and geometry. Both E- and Z-isomers of 19 and 20 react, albeit at markedly different rates, to afford cycloadducts, whereas only the Z-isomer of 9 (and not the E-isomer) reacts to give 8 and 25. Chemoselective elaboration of 8 to (±)-salsolene oxide (7) was used to confirm the cycloadduct structure while establishing a step economical route to the natural product

Rhodium(I)-Catalyzed [2+2], [2+2+2], and [2+2+2+2] Cycloadditions of Dienes or Alkynes with a Bis-ene

A novel metal-catalyzed, all-alkene [2+2+2] cycloaddition reaction involving a strained and conformationally restricted bis-ene and a diene is reported. Modification of the catalyst leads to competition with a diene-ene [2+2] reaction, and when an alkyne was used in place of the diene, [2+2+2] and [2+2+2+2] cycloaddition reactions occurred involving the bis-ene and 1 or 2 equiv of the alkyne

Rhodium(I)-Catalyzed [2+2+2+2] Cycloaddition of Diynes To Form Cyclooctatetraenes

Unique reactivity of a rhodium catalyst in the presence of many different Lewis basic additives was observed and studied. In the absence of additives, it was observed that a selective [2+2+2] reaction to form benzene products occurred; however, in the presence of an additive, optimally DMSO, the first rhodium(I)-catalyzed [2+2+2+2] reaction of alkynes occurred. A screen of different additives and catalysts was performed. Finally, a brief mechanistic study per-formed by using a ReactIR determined that DMSO coordinates to the catalyst, which affects the energetics of the reaction pathway. This appears primarily to raise the transition-state energy for the reductive elimination to form the benzene products