Lewis acid catalyzed [4+2] annulation of bicyclobutanes with dienol ethers for the synthesis of bicyclo[4.1.1]octanes

Nicolai, Stefano; Waser, Jérôme

doi:10.1039/d4sc02767a

“…43 Besides radical cycloadditions, polar cycloadditions of BCBs have been developed after Leitch's groundbreaking research in Lewis acid catalysis. 44 Currently, the Lewis acid catalyzed (3+n) polar cycloadditions of BCBs can utilize ketenes, 45 aldehydes, 46 heteroarenes, [47][48] dienol ethers, 49 and ynamides 50 as the cycloaddition partners. During the preparation of this manuscript, Deng 29 pioneered the rst Eu(OTf) 3 -catalyzed cycloadditions of BCBs with nitrones.…”

Section: Introductionmentioning

confidence: 99%

Enantioselective formal [4π+2σ] cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

Feng,

Wu,

Yang

et al. 2024

Preprint

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The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of BCB using a chiral Lewis acid catalyst and a bidentate chelating BCB substrate, as exemplified by the current enantioselective formal [4π+2σ] cycloaddition of BCBs with nitrones. In addition to the diverse BCB incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee.

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Lewis Acid‐Catalyzed Unusual (4+3) Annulation of para‐Quinone Methides with Bicyclobutanes: Access to Oxabicyclo[4.1.1]Octanes

Deswal,

Guin,

Biju

2024

Angewandte Chemie

1

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Over the past few years, there has been a surge of interest in the chemistry of bicyclobutanes (BCBs). Although BCBs have been used to synthesize bicyclo[2.1.1]hexanes and bicyclo[3.1.1]heptanes, the synthesis of bicyclo[4.1.1]octanes has remained elusive. Herein, we report the first Lewis acid‐catalyzed unexpected (4+3) annulation of para‐quinonemethides (p‐QMs) with BCBs allowing the synthesis of oxabicyclo[4.1.1]octanes proceeding under mild conditions. With 5 mol % of Bi(OTf)3, the reaction afforded the (4+3) annulated product in high regioselectivity and good functional group compatibility via a simultaneous Lewis acid activation of BCBs and p‐QMs. The reaction is likely initiated by the 1,6‐addition of Lewis acid activated BCBs to p‐QMs followed by the C2‐selective intramolecular addition of the phenol moiety to the generated cyclobutyl cation intermediate. Moreover, detailed mechanistic studies provided insight into the mechanism of the reaction.

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Lewis Acid‐Catalyzed Unusual (4+3) Annulation of para‐Quinone Methides with Bicyclobutanes: Access to Oxabicyclo[4.1.1]Octanes

Deswal,

Guin,

Biju

2024

Angew Chem Int Ed

6

0

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Over the past few years, there has been a surge of interest in the chemistry of bicyclobutanes (BCBs). Although BCBs have been used to synthesize bicyclo[2.1.1]hexanes and bicyclo[3.1.1]heptanes, the synthesis of bicyclo[4.1.1]octanes has remained elusive. Herein, we report the first Lewis acid‐catalyzed unexpected (4+3) annulation of para‐quinonemethides (p‐QMs) with BCBs allowing the synthesis of oxabicyclo[4.1.1]octanes proceeding under mild conditions. With 5 mol % of Bi(OTf)3, the reaction afforded the (4+3) annulated product in high regioselectivity and good functional group compatibility via a simultaneous Lewis acid activation of BCBs and p‐QMs. The reaction is likely initiated by the 1,6‐addition of Lewis acid activated BCBs to p‐QMs followed by the C2‐selective intramolecular addition of the phenol moiety to the generated cyclobutyl cation intermediate. Moreover, detailed mechanistic studies provided insight into the mechanism of the reaction.

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Lewis acid catalyzed [4+2] annulation of bicyclobutanes with dienol ethers for the synthesis of bicyclo[4.1.1]octanes

Abstract: Bicyclic carbocycles containing a high fraction of Csp3 have become highly attractive synthetic targets because of the multiple applications they have found in medicinal chemistry. The formal cycloaddition of bicyclobutanes...

Cited by 18 publications

References 68 publications

Enantioselective formal [4π+2σ] cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

Enantioselective formal [4π+2σ] cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis

Lewis Acid‐Catalyzed Unusual (4+3) Annulation of para‐Quinone Methides with Bicyclobutanes: Access to Oxabicyclo[4.1.1]Octanes

Lewis Acid‐Catalyzed Unusual (4+3) Annulation of para‐Quinone Methides with Bicyclobutanes: Access to Oxabicyclo[4.1.1]Octanes

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