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. 2023 Jul 7;88(13):9136-9156.
doi: 10.1021/acs.joc.3c00763. Epub 2023 May 30.

Ring Opening of Aziridines by Pendant Silanols Allows for Stereospecific Preparations of 1'-Amino-tetrahydrofurans

Appasaheb K Nirpal  1 , Someshwar Nagamalla  1 , Joel T Mague  2 , Shyam Sathyamoorthi  1
Affiliations

Ring Opening of Aziridines by Pendant Silanols Allows for Stereospecific Preparations of 1'-Amino-tetrahydrofurans

Appasaheb K Nirpal et al. J Org Chem. .

Abstract

We have developed a highly stereospecific cyclization of aziridine silanols into 1'-amino-tetrahydrofurans. Our protocol of stirring a substrate with 10 mol % Sc (OTf)3 and 1 equivalent of NaHCO3 in CH2Cl2 is mild and compatible with a range of activating aziridine N-substituents (including tosylates, mesylates, and carbamates) and functional groups on the alkyl chains (including substituted aryl rings, alkyl bromides, and alkyl ethers). In all cases examined, trans di-substituted aziridine silanols give products with an erythro configuration; conversely, cis di-substituted aziridine silanols give products with a threo configuration. While literature syntheses of 1'-amino-tetrahydrofurans exist, only one example, contemporaneous with our work, uses a similar cyclization for their construction. Control experiments demonstrate that, for this transformation, the silanol is not particularly privileged, and a variety of protecting groups on the alcohol (including other silicon protecting groups, benzyl ethers, and MOM ethers) are compatible with product formation.

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Figures

Scheme 1.
Scheme 1.. Our previous work with silanol cyclizations suggests that multiple modes of nucleophllic attack are possible with aziridine silanols.
Scheme 2.
Scheme 2.. A. Lewis acid catalyzed cleavage of aziridines by pendant silanols allows for stereospecific syntheses of 1’-amino-tetrahydrofurans. B. Analysis of the literature shows that this reaction type is underexplored for the construction of such heterocycles.
Scheme 3.
Scheme 3.. Effect of the Aziridine N-Substituent
aYield estimated from 1H NMR integration against an internal standard.
Scheme 4.
Scheme 4.. Substrate Scope (trans aziridines).
asubstrate number, product number; Note: all compounds shown are racemic, and relative stereochemistry is depicted. bPhth = Phthallmide
Scheme 5.
Scheme 5.. Substrate Scope (cis aziridines).
asubstrate number, product number; Note: all compounds shown are racemic, and relative stereochemistry is depicted. bPhth = Phthalimide
Scheme 6.
Scheme 6.. A. Scale-up reactions B. Removal of alcohol or amine protecting groups C. Tetrahydropyridlne formation during alcohol oxidation with Dess-Martin periodinane.
Scheme 7.
Scheme 7.. A. Two mechanistic scenarios. B. Control experiments suggest that Pathway 2 Is more likely.
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