Ring expansion of aziridines to dehydropiperidines

Ring expansion of bicyclic aziridines and rhodium-bound vinyl carbenes to form complex dehydropiperidines.

Go to the profile of Josephine Eshon
Mar 14, 2020
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The importance of N-heterocycles in pharmaceuticals, natural products, and fine chemicals has stimulated continuing interest in new methods for their preparation. Currently, piperidines appear in ~55% of all FDA-approved drugs that contain at least one N-heterocycle. Traditional routes to synthesize dehydropiperidines generally consist of [4+2]-aza-Diels-Alder reactions or ring-closing cyclization via intramolecular SN2-type reactions. Hetero-[4+2] cycloadditions can suffer from issues with regio- and stereoselectivity that result in limited substrate scope, while intramolecular SN2-type reactions often require the installation of pre-functionalized groups. A novel approach towards the synthesis of dehydropiperidines involves a reaction between an aziridine and a vinyl diazoester carbene precursor to generate an unusual aziridinium ylide intermediate. Both the ring strain and the positive charge on the nitrogen were envisaged to provide a driving force for a pseudo-[1,4]-sigmatropic rearrangement to expand the original aziridine to a useful dehydropiperidine scaffold (Scheme 1). 

Scheme 1. Synthesis of dehydropiperidines via ring expansion of aziridines.

We were pleased to find that exposure of a cis-bicyclic aziridine (Scheme 1) to Davies’ vinyl styrenyl diazoacetate and catalytic Rh2(OAc)4 furnished dehydropiperidines in excellent yields and diastereoselectivities. Additionally, silver-catalyzed asymmetric aziridination could be used in tandem with Rh-mediated ring expansion to deliver enantioenriched dehydropiperidines in excellent dr and good er. This reactivity is powerful given that the reaction: (i) forms structurally complex dehydropiperidines in a single step, (ii) highlights the potential of ring expansions of small rings to access stereochemically complex heterocycles, and (iii) illustrates the synthetic utility of previously underexplored aziridinium ylides.

 In terms of scope, a variety of cis-aziridines and vinyl diazoacetates were successful in this chemistry, as halides, protected alcohols, heterocycles, esters, and branched alkyl groups were tolerated (Scheme 2). Our methodology could be employed for late-stage functionalization of biological molecules, including cholesterol and amino acids. Dehydropiperidines derived from these sources demonstrate the potential for the rapid introduction of stereochemical complexity, which is often a challenge associated with N-heterocycle synthesis. 

Scheme 2. Selected substrate scope of dehydropiperidine chemistry.

Finally, dehydropiperidines were shown to be compatible with a variety of post-synthetic functionalization strategies, most notably a photocatalyzed coupling with tryptophan, to furnish a fully substituted piperidine with significant complexity in just two steps. DFT computations to understand the mechanism of this reaction provided insights that we anticipate would open up other fascinating avenues that expand the utility of aziridinium ylides in synthesis.

To read more, check out our article here: https://www.nature.com/articles/s41467-020-15134-x

Go to the profile of Josephine Eshon

Josephine Eshon

Graduate Student , University of Wisconsin-Madison

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