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. 2025 Aug 1;27(30):8332-8337.
doi: 10.1021/acs.orglett.5c02601. Epub 2025 Jul 22.

Stereospecific Synthesis of Cyclobutanones and Spirohexanones via Formal [3 + 1] Cycloaddition of Cyclopropanones with Sulfur Ylides

Joanna E Muir  1 , Brandon M Sulc  1 , Danh T Tran  1 , Christopher M Poteat  1 , Allen K MacMillan  1 , Vincent N G Lindsay  1
Affiliations

Stereospecific Synthesis of Cyclobutanones and Spirohexanones via Formal [3 + 1] Cycloaddition of Cyclopropanones with Sulfur Ylides

Joanna E Muir et al. Org Lett. .

Abstract

A concise synthetic route to enantioenriched cyclobutanones is reported via ring expansion of cyclopropanone surrogates with unstabilized sulfoxonium ylides. The reaction is shown to proceed with complete regio- and stereospecificity with chiral substrates, leading to optically active 2,3-disubstituted cyclobutanones where reversible enamine formation allowed for controlled equilibration to the thermodynamic trans diastereomer. Alternatively, employing Trost's cyclopropylsulfonium reagent provided the first synthesis of enantioenriched spiro[2.3]hexan-4-ones via a unique semipinacol rearrangement of a dicyclopropyl betaine intermediate.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1.
Scheme 1.
Formal [3+1] Cycloaddition of 1-Sulfonylcyclopropanols as Cyclopropanone surrogates
Scheme 2.
Scheme 2.
Preparation of Cyclopropanone Surrogates 1a-1f, Optimized Conditions and Effect of Piperidine Additive aNMR yield from 1a determined by 1H NMR of the crude mixture using 1,3,5-trimethoxybenzene as internal standard (>20:1 rr observed for 3a in all cases).
Scheme 3.
Scheme 3.
Scope of Accessible Cyclobutanones via Addition of Sulfoxonium Ylides to Cyclopropanone Equivalentsa,b aAll yields correspond to yields of isolated products 3a-3l on a 0.3 mmol scale of 1a-1f unless otherwise noted (>20:1 rr in all cases unless otherwise noted). bEnantiomeric excesses were determined by HPLC analysis using a chiral stationary phase (% ee of 1a-1b in parentheses). cIsolated yield on 1 mmol scale of 1a in parentheses. dThe reactions were quenched after the first stage.
Scheme 4.
Scheme 4.
Synthesis of Spirohexanones and Mechanistic Insighta aEnantiomeric excesses were determined by HPLC analysis using a chiral stationary phase (% ee of 1a-1b in parentheses). bIsolated yield from 1a, 1b or 1e on 0.5–1.7 mmol scale (gram scale in parentheses). cIsolated yield from 1f on 6.3 mmol scale (1.36 g). dIsolated yield from 1f (1 mmol) of the corresponding tosylhydrazone (volatile ketone).
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