Oxidative Carbocation Formation in Macrocycles: Synthesis of the Neopeltolide Macrocycle

Abstract

Processes for the functionalization of carbon-hydrogen bonds are the focus of significant attention in organic synthesis [1] in response to the need to streamline molecular assembly. As a continuation of our efforts to generate carbocations through single-electron oxidation reactions, [2] we recently reported[3] DDQ-mediated cyclization reactions of benzylic and allylic ethers (Scheme 1; DDQ =2,3-dichloro-4,5-dicyanoquinone). Keywordscarbocations; C-H activation; macrocycles; natural products; oxidation These reactions proceed through oxidative cleavage of a carbon-hydrogen bond to form oxocarbenium ions that react with appended nucleophiles.[4] The use of relatively inert ethers as precursors to reactive electrophiles is strategically attractive, because facile substrate preparation makes etherification a useful fragment-coupling process for convergent syntheses. Oxidative carbocation generation enables the inclusion of acid-sensitive functional groups in starting materials and products, and provides an opportunity to incorporate multiple precursors to electrophiles in a synthetic intermediate. These electrophiles can later be revealed through the use of chemically orthogonal conditions. [5] Macrocyclic oxocarbenium ions are interesting synthetic intermediates as a result of their capacity to engage in transannular nucleophilic addition reactions. The viability of these intermediates was demonstrated by the Wender research group in the synthesis of bryostatin analogues.[6] Scheidt and co-workers recently reported [7] carbon-carbon bond formation via a macrocyclic oxocarbenium ion formed in a Lewis acid mediated condensation, and related examples followed.[8] However, the generality of this remarkable protocol is not clear: In the absence of conformational preorganization, the process requires the formation of highly reactive intermediates through kinetically unfavorable pathways. A potentially more general approach to the formation of macrocyclic oxocarbenium ions for carbon-hydrogen-bond functionalization is the oxidation of preformed macrocyclic ethers with DDQ (Scheme 2). Herein, we report cyclization reactions that proceed through oxidatively generated macrocyclic oxocarbenium ions (3→4→5) and demonstrate the applicability of the protocol to the construction of complex molecules through a brief formal synthesis of neopeltolide.

Mechanistic analysis of oxidative C–H cleavages using inter- and intramolecular kinetic isotope effects

“…4a We prepared benzylic ethers that undergo oxidative cyclization quickly ( p -methoxybenzyl ether 1 ), moderately quickly ( p -methylbenzyl ether 2 ), and slowly (benzyl ether 3 ), with reactivity paralleling the ease of substrate oxidation. We also prepared ether 4 in which the cyclization proceeds at a moderate rate despite the low substrate oxidation potential.…”

“…We have been actively pursuing a program that utilizes oxidative carbon–carbon bond cleavage reactions to form oxocarbenium ions in an effort to enhance functional group tolerance 3. Recently we reported4 that cyclization reactions can be initiated by forming oxocarbenium ions through DDQ-mediated oxidative carbon–hydrogen bond activation from benzylic and allylic ethers (Scheme 1). The development of this promising method would be facilitated by a greater understanding of the mechanistic nuances of the individual steps of the process.…”

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone-Catalyzed Reactions Employing MnO2 as a Stoichiometric Oxidant

“…In accord with our efforts8 and those of other groups9 to use DDQ as a reagent for oxidative carbon–carbon bond forming reactions and our interest in developing catalytic oxidative transformations,10 we have initiated an effort to identify an inexpensive, non-acidic, and environmentally benign reagent that can be used as a terminal oxidant in the presence of sub-stoichiometric DDQ loadings. Following the observation that the use of FeCl 3 as a terminal oxidant for DDQ-catalyzed carbon–hydrogen bond functionalization reactions induced substrate decomposition, we directed our initial screen for terminal oxidants toward metal oxides that are known to effect phenol oxidations.…”

Diversity-Oriented Synthesis of a Library of Substituted Tetrahydropyrones Using Oxidative Carbon-Hydrogen Bond Activation and Click Chemistry

“…This versatile methodology is both step [23] and atom [24] efficient, and has been successfully applied to a series of THP-containing natural products [25,26,27,28]. This approach can generate a variety of functionalized THP ring systems and allow for rapid side chain diversification.…”