Concise Synthesis of a Pateamine A Analogue with In Vivo Anticancer Activity Based on an Iron-Catalyzed Pyrone Ring Opening/Cross-Coupling

The marine macrolide pateamine A and its non-natural sibling DMDA-Pat A are potent translation inhibitors targeting the eukaryotic initiation factor 4A (eIF4A), an enzyme with RNA helicase activity. Although essential for every living cell, this protein target seems “drugable” since DMDA-Pat A has previously been shown to exhibit remarkable in vivo activity against two different melanoma mouse models. The novel entry into this promising compound presented herein is shorter and significantly more productive than the literature route. Key to success was the masking of the signature Z,E-configured dienoate subunit of DMDA-Pat A in the form of a 2-pyrone ring, which was best crafted by a gold-catalyzed cyclization. While the robustness of the heterocycle facilitated the entire assembly stage, the highly isomerization-prone seco-Z,E-dienoic acid could be unlocked in due time for macrolactonization by an unconventional iron-catalyzed ring opening/cross coupling. Moreover, the crystal structure analysis of an advanced intermediate gave first insights into the conformation of the macrodilactone framework of the pateamine family, which is thought to be critical for eliciting the desired biological response

Total synthesis of aspercyclide C

The first total synthesis of (+)-aspercyclide C (1) is reported using a kinetically controlled RCM reaction to form the 11-membered, unsaturated lactone ring of this bioactive diaryl ether macrolide

PtCl₂-Catalyzed Rearrangement of Methylenecyclopropanes

Alkylidenecyclopropanes readily convert into cyclobutene derivatives on treatment with catalytic amounts of PtCl2. The reaction is strongly accelerated when performed under an atmosphere of CO (1 atm). The resulting cyclobutenes are isolated in good to excellent yields for substrates bearing aliphatic as well as aromatic substituents R on their olefinic site. If the substituent R, however, is a very electron-rich arene, the cyclobutenes initially formed react further to give dimeric products with a previously unknown 1,2,2a,7a-tetrahydrospiro[cyclobuta[a]indene-7,1‘-cyclobutane skeleton. A mechanism accounting for these experimental observations as well as for a deuterium-labeling experiment is proposed which implies reactive intermediates at the nonclassical cation/carbene interface. Furthermore it is shown that the PtCl2-catalyzed cyclobutene formation can be geared with subsequent ring-opening/ring-closing metathesis (ROM/RCM) events. Finally, a convenient “one pot” method for the preparation of the alkylidenecyclopropane substrates used in this study is presented, which is based on a modified Julia−Kocienski olefination of aldehydes with readily available 1-tert-butyl-1H-tetrazol-5-yl-cyclopropyl sulfone under Barbier conditions

Alkyne Cross Metathesis Reactions of Extended Scope

A catalyst formed in situ from Mo[N(t-Bu)(Ar)]3 1 (Ar = 3,5-dimethylphenyl) and CH2Cl2 in toluene effects cross metathesis reactions of functionalized alkynes that are beyond reach of more traditional promotors. An application to the synthesis of prostaglandin E2 (PGE2) 19 and the acetylated PGE derivative 18b shows the compatibility of this method with sensitive substrates

Two Manifolds for Metal-Catalyzed Intramolecular Diels-Alder Reactions of Unactivated Alkynes

Being unconventional: Although conventional metal-catalyzed [4+2] cycloadditions of inactivated dienynes are known to proceed by an oxidative cyclization/insertion mechanism, two entirely different pathways also result in formal Diels–Alder reactions (see scheme). These alternative mechanisms open new vistas for further functionalization of the products, as exemplified by an unprecedented cycloaddition/alkylation cascade

Formal Ring-Opening/Cross-Coupling Reactions of 2-Pyrones: Iron-Catalyzed Entry into Stereodefined Dienyl Carboxylates

Open access: Despite the exceptional level of sophistication in cross-coupling chemistry, reactions of substrates that incorporate the leaving group as an integral part into a heterocyclic scaffold are scarce. The title reaction outlines the utility of this reaction format (see scheme; acac=acetylacetonate), provides a convenient entry into stereodefined diene carboxylates, and adds a new chapter to the field of iron catalysis

A Rhodium-Catalyzed C−H Activation/Cycloisomerization Tandem

A reaction cascade comprising a rhodium-catalyzed C−H activation, a subsequent hydrometalation of an alkylidene cyclopropane in vicinity, regioselective C−C bond activation of the flanking cyclopropane ring, followed by reductive elimination of the resulting metallacycle, opens a new entry into functionalized cycloheptene derivatives. This crossover of C−H activation and higher order cycloaddition has been performed in two different formats, either using alkylidenecyclopropanes with a lateral vinylpyridine moiety or with a pending aldehyde group as the trigger. The reaction tolerates various functional groups, leaves chiral centers α to the reacting sites unaffected, and proceeds with excellent stereoselectivity. Labeling experiments support the proposed mechanism explaining the observed net cycloisomerization process

Toward the total synthesis of spirastrellolide A. Part 3: Intelligence gathering and preparation of a ring-expanded analogue

Different methods for the formation of the C.25–C.26 bond of spirastrellolide A (1) are evaluated that might qualify for the end game of the projected total synthesis, with emphasis on metathetic ways to forge the macrocyclic frame

Preparation, Structure, and Reactivity of Nonstabilized Organoiron Compounds. Implications for Iron-Catalyzed Cross Coupling Reactions

A series of unprecedented organoiron complexes of the formal oxidation states −2, 0, +1, +2, and +3 is presented, which are largely devoid of stabilizing ligands and, in part, also electronically unsaturated (14-, 16-, 17- and 18-electron counts). Specifically, it is shown that nucleophiles unable to undergo β-hydride elimination, such as MeLi, PhLi, or PhMgBr, rapidly reduce Fe(3+) to Fe(2+) and then exhaustively alkylate the metal center. The resulting homoleptic organoferrate complexes [(Me4Fe)(MeLi)][Li(OEt2)]2 (3) and [Ph4Fe][Li(Et2O)2][Li(1,4-dioxane)] (5) could be characterized by X-ray crystal structure analysis. However, these exceptionally sensitive compounds turned out to be only moderately nucleophilic, transferring their organic ligands to activated electrophiles only, while being unable to alkylate (hetero)aryl halides unless they are very electron deficient. In striking contrast, Grignard reagents bearing alkyl residues amenable to β-hydride elimination reduce FeXn (n = 2, 3) to clusters of the formal composition [Fe(MgX)2]n. The behavior of these intermetallic species can be emulated by structurally well-defined lithium ferrate complexes of the type [Fe(C2H4)4][Li(tmeda)]2 (8), [Fe(cod)2][Li(dme)]2 (9), [CpFe(C2H4)2][Li(tmeda)] (7), [CpFe(cod)][Li(dme)] (11), or [Cp*Fe(C2H4)2][Li(tmeda)] (14). Such electron-rich complexes, which are distinguished by short intermetallic Fe−Li bonds, were shown to react with aryl chlorides and allyl halides; the structures and reactivity patterns of the resulting organoiron compounds provide first insights into the elementary steps of low valent iron-catalyzed cross coupling reactions of aryl, alkyl, allyl, benzyl, and propargyl halides with organomagnesium reagents. However, the acquired data suggest that such C−C bond formations can occur, a priori, along different catalytic cycles shuttling between metal centers of the formal oxidation states Fe(+1)/Fe(+3), Fe(0)/Fe(+2), and Fe(−2)/Fe(0). Since these different manifolds are likely interconnected, an unambiguous decision as to which redox cycle dominates in solution remains difficult, even though iron complexes of the lowest accessible formal oxidation states promote the reactions most effectively

Elementary Steps in Gold Catalysis: The Significance of gem-Diauration

Disturbing neighbors: Alkenylgold species with a heteroatom substituent are thought to be key intermediates in gold-catalyzed trans additions of protic nucleophiles to alkynes. One reason for the scarcity of such compounds lies in the non-innocence of the neighboring heteroatom, which may enforce the uptake of a second gold fragment with formation of surprisingly robust species with a gem-digold unit adjacent to a largely cationic center