A Stereoselective [3+1] Ring Expansion for the Synthesis of Highly Substituted Methylene Azetidines

Schmid, Steven M.; Guzei, Ilia A.; Schomaker, Jennifer M.

doi:10.1002/ange.201705202

Cited by 23 publications

(26 citation statements)

References 68 publications

(15 reference statements)

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“…With the goal of ascertaining the most likely mechanistic pathway, detailing the factors responsible for successful ring expansion, and increasing the reactivity profile of our methylene aziridines, we initiated a more rigorous mechanistic study of this unusual reaction. 2 …”

Section: Resultsmentioning

confidence: 99%

“…2 Control reactions demonstrated the necessity of forming the rhodium-bound carbene prior to ring expansion. Due to the constraints associated with carrying out kinetic analyses on reactions that require slow addition, we felt that density functional theory (DFT) calculations would be an excellent tool to help elucidate the reaction pathway, with experimental evidence serving as a control on the calculations.…”

Section: Resultsmentioning

confidence: 99%

“…The Schomaker group recently reported an efficient ring expansion of carbamate-derived bicyclic methylene aziridines (MAs) to methylene azetidines using substituted α -diazoacetates under dirhodium catalysis (Scheme 1B). 2 This transformation was synthetically impressive in its ability to efficiently set adjacent functionalized stereocenters, as well as forge new C−C and C− N bonds. The transformation displayed an unexpected ability to transfer chirality from the initial allene substrate to the azetidine products and represents a rare example of a successful catalytic, intermolecular one-carbon ring expansion reaction involving a three-membered nitrogen heterocycle and a metal-supported carbene.…”

Section: Introductionmentioning

confidence: 99%

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Ring Expansion of Bicyclic Methyleneaziridines via Concerted, Near-Barrierless [2,3]-Stevens Rearrangements of Aziridinium Ylides

et al. 2018

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The synthesis of densely functionalized azetidinesin a highly stereocontrolled manner is challenging, but interest in the bioactivities of these small heterocycles has stimulated methods for their preparation. We recently reported a one-carbon ring expansion of bicyclic methylene aziridines under dirhodium catalysis capable of delivering enantioenriched azetidines. This work explores this ring expansion using computational and experimental studies. DFT computations indicate that the reaction proceeds through formation of an aziridinium ylide, which is precisely poised for concerted, asynchronous ring-opening/closing to deliver the azetidines in a [2,3]-Stevens-type rearrangement. The concerted nature of this rearrangement is responsible for the stereospecificity of the reaction, where axial chirality from the initial allene substrate is transferred to the azetidine product with complete fidelity. The computed mechanistic pathway highlights the key roles of the olefin and the rigid structure of the methylene aziridine in differentiating our observed ring expansion from competing cheletropic elimination pathways noted with ylides derived from typical aziridines.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ring Expansion of Bicyclic Methyleneaziridines via Concerted, Near-Barrierless [2,3]-Stevens Rearrangements of Aziridinium Ylides

et al. 2018

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“…We previously leveraged the unusual strain (~42 kcal/mol) in methyleneaziridine 1a to achieve a formal [3+1] reaction to furnish methyleneazetidine 1d upon exposure to rhodium-supported carbene 1b ( Fig. 2a) [55][56][57][58][59][60][61][62] . Mechanistic studies support initial formation of the aziridinium ylide 1c, which subsequently undergoes a highly asynchronous, concerted [2,3]-Stevens rearrangement to form 1d 63 .…”

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Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides

et al. 2020

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The importance of N-heterocycles in drugs has stimulated diverse methods for their efficient syntheses. Methods that introduce significant stereochemical complexity are attractive for identifying new bioactive amine chemical space. Here, we report a [3 + 3] ring expansion of bicyclic aziridines and rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate that the reaction proceeds through formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a pseudo-[1,4]-sigmatropic rearrangement to directly furnish heterocyclic products with net retention at the new CC bond. In combination with asymmetric silver-catalyzed aziridination, enantioenriched scaffolds with up to three contiguous stereocenters are rapidly delivered. The mild reaction conditions, functional group tolerance, and high stereospecificity of this method are well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates for converting small, strained rings to larger N-heterocycles.

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“…[7] In addition, Schomaker and co-workers reported an elegant stereoselective [3+ +1] ring expansion for the synthesis of highly substituted methyl azetidines from methylene aziridines (Scheme 1a,r ight). [8] Each transformation is initiated by nitrogen ylide formation followed by C À N bond cleavage and migration or rearrangement.…”

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confidence: 99%

Catalytic Desymmetric Cycloaddition of Diaziridines with Metalloenolcarbenes: The Role of Donor–Acceptor Cyclopropenes

Zheng

Doyle

2019

Angewandte Chemie

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Ac hiral copper(I) complex catalyzesr eactions of symmetric diaziridines with enol diazoc ompounds,w hich react through NÀNb ond ring opening in af ormal [3+ +3] cycloaddition to form four chiral centers with high stereocontrol. Abroad spectrum of bridged dinitrogen heterocycles were obtained in high yields and excellent diastereo-and enantioselectivities from g-substituted enol diazoacetates,w hile their geometrical isomers gave different enantioselectivities.Donoracceptor cyclopropenes formed from the geometrical isomers of the g-substituted enol diazoacetates underwent catalytic ring opening to give only the Zisomer of the metalloenolcarbene intermediate,provided excellent yields and selectivities for the 1,5-diazabicyclo[n.3.1]non-2-ene derivatives. Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201906754. Scheme 1. Backgrounda nd this work. Angewandte Chemie Communications [a] Reactionswere performed with 1a (0.24 mmol) and 2a (0.2 mmol) in the indicated solvent (4 mL). [b] Yields of isolated product. Scheme 2. Scope of the copper(I)-promoted [3+ +3] annulation reaction. Scheme 3. Catalytic enantioselective [3+ +3] cycloadditionr eaction.

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A Stereoselective [3+1] Ring Expansion for the Synthesis of Highly Substituted Methylene Azetidines

Cited by 23 publications

References 68 publications

Ring Expansion of Bicyclic Methyleneaziridines via Concerted, Near-Barrierless [2,3]-Stevens Rearrangements of Aziridinium Ylides

Ring Expansion of Bicyclic Methyleneaziridines via Concerted, Near-Barrierless [2,3]-Stevens Rearrangements of Aziridinium Ylides

Intermolecular [3+3] ring expansion of aziridines to dehydropiperi-dines through the intermediacy of aziridinium ylides

Catalytic Desymmetric Cycloaddition of Diaziridines with Metalloenolcarbenes: The Role of Donor–Acceptor Cyclopropenes

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