π-Facial Selectivities in Hydride Reductions of Hindered Endocyclic Iminium Ions

Chen, Shuming; Chan, Amy Y.; Walker, Morgan M.; Ellman, Jonathan A.; Houk, K. N.

doi:10.1021/acs.joc.8b02603

Cited by 2 publications

(6 citation statements)

References 27 publications

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“…Addition of an organometallic reagent then occurred with high diastereoselectivity, likely by minimizing torsional strain in the first-formed products. 544 The allylcerium reagent derived from the allylmagnesium halide was employed to favor addition over proton transfer. 543 Fused bicyclic iminium ions also undergo stereoselective allylations (Scheme 389).…”

Section: Additions Of Allylmagnesium Reagents To Iminium Ionsmentioning

confidence: 98%

“… , The iminium ion was generated by alkylating the enamine. Addition of an organometallic reagent then occurred with high diastereoselectivity, likely by minimizing torsional strain in the first-formed products . The allylcerium reagent derived from the allylmagnesium halide was employed to favor addition over proton transfer …”

Section: Additions Of Allylmagnesium Reagents To Imines and Related S...mentioning

confidence: 99%

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Reactions of Allylmagnesium Reagents with Carbonyl Compounds and Compounds with C═N Double Bonds: Their Diastereoselectivities Generally Cannot Be Analyzed Using the Felkin–Anh and Chelation-Control Models

et al. 2020

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This review describes the additions of allylmagnesium reagents to carbonyl compounds and to imines, focusing on the differences in reactivity between allylmagnesium halides and other Grignard reagents. In many cases, allylmagnesium reagents either react with low stereoselectivity when other Grignard reagents react with high selectivity, or allylmagnesium reagents react with the opposite stereoselectivity. This review collects hundreds of examples, discusses the origins of stereoselectivities or the lack of stereoselectivity, and evaluates why selectivity may not occur and when it will likely occur. CONTENTS 4.2.5. Additions to β-Substituted Aldehydes 4.2.6. Additions to Aldehydes with Distant Chelating Groups 4.3. Additions to Cyclic Ketones 4.3.1. Alkoxy-Substituted Cyclic Ketones 4.3.2. Additions to Alkoxy-Substituted Five-Membered-Ring Ketones 4.3.3. Additions to Alkoxy-Substituted Four-Membered-Ring Ketones 4.4. Additions of Allylmagnesium Halides to Cyclic Hemiacetals 5. Diastereoselectivity of Reactions of Allylmagnesium Reagents with Carbonyl Compounds by Felkin−Anh Control 5.1. Felkin−Anh Stereoselectivity 5.2. Additions to α-Chiral Acyclic Ketones 5.3. Additions to Chiral Exocyclic Ketones and Aldehydes 5.4. Additions of Allylmagnesium Halides to Chiral Cyclic Ketones Controlled by Felkin−Anh Selectivity 5.5. Additions of Allylmagnesium Halides to Chiral Acyclic Aldehydes 6. Diastereoselectivity of Reactions with Carbonyl Compounds by Steric Approach Control 6.1. Steric Approach Control and Stereoselectivity

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Section: Additions Of Allylmagnesium Reagents To Iminium Ionsmentioning

confidence: 98%

Section: Additions Of Allylmagnesium Reagents To Imines and Related S...mentioning

confidence: 99%

Reactions of Allylmagnesium Reagents with Carbonyl Compounds and Compounds with C═N Double Bonds: Their Diastereoselectivities Generally Cannot Be Analyzed Using the Felkin–Anh and Chelation-Control Models

et al. 2020

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“…Protonation occurs on the face opposite to the R 6 substituent, which is disposed directly above the six-membered ring because of A(1,2) allylic strain between R 6 and the R 1 nitrogen substituent. , When R 5 is a carbon substituent, A(1,2) allylic strain with the R 6 substituent further reinforces this conformation. Similarly, the face selectivity for hydride addition was also found to be controlled by steric hindrance, as supported by computational studies carried out in collaboration with the Houk lab …”

Section: Diastereoselective Synthesis Of Highly Substituted Tetrahydr...mentioning

confidence: 99%

“…It is notable that tetrahydropyridines 9 provide a differential spatial display of substituents relative to previously described tetrahydropyridines 6 (Table ). In collaboration with the Houk lab, the π-facial preference of the hydride attack to give 9 was found to be controlled by torsional steering, in which the favored attack leads to a lower-energy “half-chair”-like conformation of 9 , with attack at the other π face resulting in an unfavorable “twist-boat” conformation …”

Section: Diastereoselective Synthesis Of Highly Substituted Tetrahydr...mentioning

confidence: 99%

“…Similarly, the face selectivity for hydride addition was also found to be controlled by steric hindrance, as supported by computational studies carried out in collaboration with the Houk lab. 21 In practice, dihydropyridines 4 are reduced without workup or isolation to enable the efficient one-pot preparation of tetrahydropyridines 6 from imines 1 and alkynes 2 (Table 1). 18 Both the precatalyst [RhCl(coe) 2 ] 2 and the optimal ligand 4-Me 2 NPhPEt 2 are commercially available, which adds to the utility of this one-pot sequence.…”

Section: Diastereoselective Synthesis Of Highlymentioning

confidence: 99%

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Rhodium-Catalyzed C–H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles

2021

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Metrics & MoreArticle Recommendations CONSPECTUS: Nitrogen heterocycles are present in approximately 60% of drugs, with nonplanar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C−H bond alkenylation/electrocyclization cascade from readily available α,β-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with density functional theory (DFT) calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective ring opening furnishes hydroxysubstituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yields with high face selectivity.When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C−H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group and the formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, [3 + 2] cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. When different types of conditions are employed, loss of the silyl group can result in either rearrangement to cyclopropyl-fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements.The transformations described in this Account are amenable to natural product synthesis and drug discovery applications because of the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric s...

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π-Facial Selectivities in Hydride Reductions of Hindered Endocyclic Iminium Ions

Cited by 2 publications

References 27 publications

Reactions of Allylmagnesium Reagents with Carbonyl Compounds and Compounds with C═N Double Bonds: Their Diastereoselectivities Generally Cannot Be Analyzed Using the Felkin–Anh and Chelation-Control Models

Reactions of Allylmagnesium Reagents with Carbonyl Compounds and Compounds with C═N Double Bonds: Their Diastereoselectivities Generally Cannot Be Analyzed Using the Felkin–Anh and Chelation-Control Models

Rhodium-Catalyzed C–H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles

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