Synthesis of (−)‐Hebelophyllene E: An Entry to Geminal Dimethyl‐Cyclobutanes by [2+2] Cycloaddition of Alkenes and Allenoates

Wiest, Johannes; Conner, Michael L.; Brown, M. Kevin

doi:10.1002/anie.201801110

Cited by 36 publications

(6 citation statements)

References 50 publications

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“…We later found that a more accessible thiobenzyl allenoate also exhibited comparable reactivity and enantioselectivity and, in some cases, higher E/Z selectivity (compare 3.13 to 3.14 ) . Oxazaborolidine 3.15 with a 3,5-(CF 3 ) 2 –C 6 H 3 backbone instead of Ph was found to be more selective when reacting with trisubstituted alkenes and activated alkenes. , γ-Dimethyl-substituted allenoates were also tolerated in reactions with unactivated alkenes (products 3.19 and 3.20 ).…”

Section: Enantioselective [2 + 2] Cycloadditions Of Allenoatesmentioning

confidence: 99%

“…31 The synthesis commenced with trisubstituted alkene 4.1 that was prepared on decagram scale from t-Bu-acetoacetate. 28 Key to the synthesis of 4.3 were a kinetic resolution of 4.2 and diastereoselective addition of vinylMgBr (Scheme 4A). Alkene 4.3 was well tolerated in the enantioselective [2 + 2] cycloaddition to give 4.4 in 52% yield after separation of the Z/E mixture.…”

Section: Of Ketenesmentioning

confidence: 99%

“…The synthesis commenced with trisubstituted alkene 4.1 that was prepared on decagram scale from t -Bu-acetoacetate . Key to the synthesis of 4.3 were a kinetic resolution of 4.2 and diastereoselective addition of vinylMgBr (Scheme A).…”

Section: Enantioselective [2 + 2] Cycloadditions Of Allenoatesmentioning

confidence: 99%

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Lewis Acid-Promoted [2 + 2] Cycloadditions of Allenes and Ketenes: Versatile Methods for Natural Product Synthesis

Guo

Brown

2023

Acc. Chem. Res.

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Conspectus Cycloaddition reactions are an effective method to quickly build molecular complexity. As predicted by the Woodward–Hoffmann rules, concerted cycloadditions with alkenes allow for the constructions of all possible stereoisomers of product by use of either the Z or E geometry. While this feature of cycloadditions is widely used in, for example, [4 + 2] cycloadditions, translation to [2 + 2] cycloadditions is challenging because of the often stepwise and therefore stereoconvergent nature of these processes. Over the past decade, our lab has explored Lewis acid-promoted [2 + 2] cycloadditions of electron-deficient allenes or ketenes with alkenes. The concerted, asynchronous cycloadditions allow for the synthesis of various cyclobutanes with control of stereochemistry. Our lab developed the first examples of Lewis acid-promoted ketene–alkene [2 + 2] cycloadditions. Compared with traditional thermal conditions, Lewis acid-promoted conditions have several advantages, such as increased reactivity, increased yield, improved diastereoselectivity, and, for certain cases, inverse diastereoselectivity. Detailed mechanistic studies revealed that the diastereoselectivity was controlled by the size of the substituent and the barrier of a deconjugation event. However, these reactions required the use of stoichiometric amounts of EtAlCl2 because of the product inhibition, which led us to investigate catalytic enantioselective [2 + 2] cycloadditions of allenoates with alkenes. Through the use of chiral oxazaborolidines, a broad range of cyclobutanes can be prepared with the control of enantioselectivity. Mechanistic experiments, including 2D-labled alkenes and Hammett analysis, illuminate likely transition state models for the cycloadditions. Additional studies led to the development of Lewis acid-catalyzed intramolecular stereoselective [2 + 2] cycloadditions of chiral allenic ketones/esters with alkenes. The methods we developed have been instrumental in the synthesis of several families of natural products. Specifically, one key lactone motif in (±)-gracilioether F was constructed by a ketene–alkene [2 + 2] cycloaddition and subsequent regioselective Baeyer–Villiger oxidation sequence. Enantioselective allenoate–alkene [2 + 2] cycloadditions allowed for the synthesis of (−)-hebelophyllene E. Another attempt of applying this method in the synthesis of (+)-[5]-ladderanoic acid failed to deliver the desired cyclobutane because of an unexpected rearrangement. The key cyclobutane was later assembled by a stepwise carboboration/Zweifel olefination process. Finally, the stereoselective [2 + 2] cycloadditions of allenic ketones and alkenes was applied in the syntheses of (−)-[3]-ladderanol, (+)-hippolide J, and (−)-cajanusine.

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Section: Enantioselective [2 + 2] Cycloadditions Of Allenoatesmentioning

confidence: 99%

Section: Of Ketenesmentioning

confidence: 99%

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Lewis Acid-Promoted [2 + 2] Cycloadditions of Allenes and Ketenes: Versatile Methods for Natural Product Synthesis

Guo

Brown

2023

Acc. Chem. Res.

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“…We envisioned that a highly reactive cyclobutenone with better stability would provide a practical approach to access enantioenriched bicyclo[4.2.0]octane derivatives. Herein we report our work on unique reactivity of 3-methoxycarbonylcyclobutenone 2 as dienophile in enantioselective Diels-Alder reaction under the catalysis of chiral oxazaborolidinium ion [12,13] (Scheme 1 b).…”

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confidence: 99%

3‐(Methoxycarbonyl)Cyclobutenone as a Reactive Dienophile in Enantioselective Diels–Alder Reactions Catalyzed by Chiral Oxazaborolidinium Ions

et al. 2021

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Cyclobutenone has been used as a highly reactive dienophile in Diels–Alder reactions, however, no enantioselective example has been reported. We disclose herein a chiral oxazaborolidine‐aluminum bromide catalyzed enantioselective Diels–Alder reaction of 3‐alkoxycarbonyl cyclobutenone with a variety of dienes. Furthermore, a total synthesis of (−)‐kingianin F was completed for the first time via enantioenriched cycloadduct bicyclo[4.2.0]octane derivative.

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“…The 3.2.0 bicyclic unit is found in a myriad of natural products and functional bioactive molecules. 1 Several of these examples feature an alkene motif that suggests sealing the four-membered ring via an intramolecular [2 + 2] cycloaddition from an enallene. 2 However, the allene functionalization presents regiochemical challenges ( Scheme 1 ).…”

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confidence: 99%

Orthogonal Syntheses of 3.2.0 Bicycles from Enallenes Promoted by Visible Light

et al. 2020

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Enallenes can be readily converted into two families of 3.2.0 (hetero)bicycles with high diastereoselectivities through the combination of visible light with a suitable Ir(III) complex (1 mol %). Two complementary pathways, namely, a photocycloaddition versus a radical chain, can then take place. Both manifolds grant complete regiocontrol of the allene difunctionalization. This is accompanied by an original 1,3-group shift using sulfonyl allenamides that deliver a congested tetrasubstituted headbridging carbon in the corresponding product.

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Synthesis of (−)‐Hebelophyllene E: An Entry to Geminal Dimethyl‐Cyclobutanes by [2+2] Cycloaddition of Alkenes and Allenoates

Cited by 36 publications

References 50 publications

Lewis Acid-Promoted [2 + 2] Cycloadditions of Allenes and Ketenes: Versatile Methods for Natural Product Synthesis

Lewis Acid-Promoted [2 + 2] Cycloadditions of Allenes and Ketenes: Versatile Methods for Natural Product Synthesis

3‐(Methoxycarbonyl)Cyclobutenone as a Reactive Dienophile in Enantioselective Diels–Alder Reactions Catalyzed by Chiral Oxazaborolidinium Ions

Orthogonal Syntheses of 3.2.0 Bicycles from Enallenes Promoted by Visible Light

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