π-Nucleophile Traps for Metallonitrene/Alkyne Cascade Reactions: A Versatile Process for the Synthesis of α-Aminocyclopropanes and β-Aminostyrenes

Thornton, Aaron R.; Martin, Véronique I.; Blakey, Simon B.

doi:10.1021/ja809078d

Cited by 100 publications

(41 citation statements)

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“…[4] Implicit in this strategy is the recognition that alkynes can serve as precursors to both a-oxy-and aiminocarbenes and that oxidation of an alkyne under appropriate reaction conditions could serve to reveal the desired reactive intermediate. [8] Despite the inherent attractiveness of this single-step approach, reaction conditions that facilitate efficient intermolecular cascade termination are required for broad applicability and synthetic utility. In intramolecular settings we have demonstrated the feasibility of this direct approach, terminating the cascade in an array of predictable carbene reactions (oxygenylide formation/[2,3] Wittig rearrangement, [7] electrophilic aromatic substitution, and cyclopropanation).…”

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confidence: 99%

“…In intramolecular settings we have demonstrated the feasibility of this direct approach, terminating the cascade in an array of predictable carbene reactions (oxygenylide formation/[2,3] Wittig rearrangement, [7] electrophilic aromatic substitution, and cyclopropanation). [8] Indeed, when a mixture of sulfamate ester 1 and methyl allyl ether (2) were subjected to these established conditions for intramolecular reactions, a complex mixture of products was observed, and only a minor amount (< 5 %) of the desired cascade product 3 was isolated.The report from Guthikonda and Du Bois indicating [Rh 2 (tfacam) 4 ] (tfacam = trifluoroacetamide) promoted metallonitrene interactions with p systems in preference to CÀH bonds led us to explore its activity as a catalyst in the intermolecular cascade reaction. Herein we describe the development of a metallonitrene-initiated alkyne oxidation cascade with intermolecular trapping of the reactive intermediate by a variety of allyl ethers to provide a-oxyimine products in which new C = N, C À O, and C À C bonds have all been generated.…”

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confidence: 99%

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Unveiling Latent α‐Iminocarbene Reactivity for Intermolecular Cascade Reactions through Alkyne Oxidative Amination

2013

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The chemistry of reactive (electrophilic) metallocarbenes, primarily obtained by metal-catalyzed decomposition of adiazocarbonyl compounds, has been extensively developed and offers significant opportunity for strategic CÀC, CÀO, and CÀN bond formation through a variety of well-defined reaction mechanisms. [1] Given the prevalence of nitrogen atoms in biologically and pharmaceutically relevant molecules and the intrinsic electronic similarities between carbonyl and imine functional groups, the development of analogous metallocarbene chemistry with an a imine providing the necessary electrophilic activation represents both an obvious and synthetically important extension of this chemistry. However, the requisite a-diazoimine precursors readily isomerize to 1,2,3-triazoles, and these heterocycles were long believed to represent a thermodynamic sink, thus significantly delaying the development of metallocarbene chemistry associated with such systems. [2] Nonetheless, the perception that reliable methods to access a-iminocarbene chemistry would offer the potential to build structurally complex nitrogen-containing molecules in a remarkably efficient manner has recently resulted in the development of several complementary solutions to the a-diazoimine isomerization problem (Scheme 1).Specifically, Park and co-workers showed that b oximinoesters can be diazotized with minimal rearrangement to the isomeric triazoles, thus providing an entry into a-oximino acceptor-acceptor carbenoid chemistry. [3] More generally, Fokin and co-workers demonstrated that 1,2,3-triazoles can themselves act as precursors to a-iminometallocarbene intermediates, participating predictably in a range of traditional metallocarbene reactions to generate a-functionalized imine products. [4] Implicit in this strategy is the recognition that alkynes can serve as precursors to both a-oxy-and aiminocarbenes and that oxidation of an alkyne under appropriate reaction conditions could serve to reveal the desired reactive intermediate. [5] The approach of Raushel and Fokin separates the alkyne oxidation, which is achieved through copper-catalyzed azide-alkyne cycloaddition, [6] from the rhodium-catalyzed metallocarbene generation.Studies in our laboratory have focused on the direct unveiling of an intermediate with an a-iminometallocarbene reactivity profile by a metallonitrene-initiated oxidative cascade process. In intramolecular settings we have demonstrated the feasibility of this direct approach, terminating the cascade in an array of predictable carbene reactions (oxygenylide formation/[2,3] Wittig rearrangement, [7] electrophilic aromatic substitution, and cyclopropanation). [8] Despite the inherent attractiveness of this single-step approach, reaction conditions that facilitate efficient intermolecular cascade termination are required for broad applicability and synthetic utility. Herein we describe the development of a metallonitrene-initiated alkyne oxidation cascade with intermolecular trapping of the reactive intermediate by a variety of allyl ...

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Unveiling Latent α‐Iminocarbene Reactivity for Intermolecular Cascade Reactions through Alkyne Oxidative Amination

2013

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“…Intermediate 44 was also converted to sulfamoyl derivative 47 in 35% yield by reaction with freshly prepared sulfamoyl chloride in the presence of pyridine. 27 …”

Section: Resultsmentioning

confidence: 99%

Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues

Nicolaou

Ellery

Rivas

et al. 2011

Bioorganic & Medicinal Chemistry

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Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized, including a novel 3′,4′-carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2′,4′-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC50 = 7.0 μM) and HxB2 (IC50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.

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“…30 This intermediate was subjected to Tamao-Fleming oxidation to furnish 65 in 67% yield over the two steps. Boc protection of the amine, followed by NaI-mediated ring contraction, gave 64.…”

Section: Total Synthesis Of (Ae)-detoxinine Methyl Ester and Stereoismentioning

confidence: 99%

Complete stereodivergence in the synthesis of 2-amino-1,3-diols from allenes

2014

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Amine-containing stereotriads ('triads'), where the nitrogen is embedded in an array of three contiguous, heteroatom-bearing chiral carbons, are key motifs in numerous bioactive natural products. Allene aziridination provides convenient access to amine triads where the position of the nitrogen and the identities of the accompanying heteroatoms can be readily manipulated. However, stereochemical flexibility, where a single allene can be selectively transformed into any possible diastereomer of a specific triad, has been elusive. Herein, we describe studies to understand how both reagent and substrate control can be effectively employed in the stereodivergent oxidative amination of allenes, with transfer of the axial chirality of an enantioenriched precursor to point chirality in each possible diastereomeric 2-amino-1,3-diol product. Application of this flexible strategy to the synthesis of all four stereoisomers of the natural product detoxinine is also presented.

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π-Nucleophile Traps for Metallonitrene/Alkyne Cascade Reactions: A Versatile Process for the Synthesis of α-Aminocyclopropanes and β-Aminostyrenes

Cited by 100 publications

References 21 publications

Unveiling Latent α‐Iminocarbene Reactivity for Intermolecular Cascade Reactions through Alkyne Oxidative Amination

Unveiling Latent α‐Iminocarbene Reactivity for Intermolecular Cascade Reactions through Alkyne Oxidative Amination

Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues

Complete stereodivergence in the synthesis of 2-amino-1,3-diols from allenes

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