Highly Diastereo‐ and Enantioselective Mannich Reactions of Synthetically Flexible Ketimines with Secondary Amine Organocatalysts

Kano, Taichi; Song, Sunhwa; Kubota, Yasushi; Maruoka, Keiji

doi:10.1002/anie.201107375

Cited by 85 publications

(29 citation statements)

References 61 publications

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“…The absolute stereochemistry of the product was confirmed through X-ray structure of primary alcohol 9b . It merits note that catalytic enantioselective enolate additions to N -activated ketimines (e.g., N -phosphinoylketimines 36,37 or those derived from α-ketoesters 38 or diethyl ketomalonate 39 ) are limited in scope (see the Supplementary Information for additional references). …”

Section: Resultsmentioning

confidence: 99%

Catalytic diastereo- and enantioselective additions of versatile allyl groups to N–H ketimines

et al. 2017

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There are countless biologically active organic molecules that contain one or more N-containing moieties and broadly applicable and efficient catalytic transformations that deliver them diastereo- and/or enantioselectively are much sought after. Various methods for enantioselective synthesis of α-secondary amines are available (e.g., from additions to protected/activated aldimines), but those involving ketimines are much less common. There are no reported additions of carbon-based nucleophiles to unprotected/unactivated (or N-H) ketimines. Here, we report a catalytic, diastereo- and enantioselective three-component strategy for merging an N-H ketimine, a monosubstituted allene and B2(pin)2, affording products in up to 95% yield, >98% diastereoselectivity and >99:1 enantiomeric ratio. Utility of the approach is highlighted by synthesis of the tricyclic core of a class of compounds that have been shown to possess anti-Alzheimer activity. Stereochemical models, developed with the aid of DFT calculations, which account for the observed trends and levels of enantioselectivity are presented.

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Section: Resultsmentioning

confidence: 99%

Catalytic diastereo- and enantioselective additions of versatile allyl groups to N–H ketimines

et al. 2017

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“…140 Maruoka developed a direct Mannich reaction of aliphatic aldehydes with cyclic ketimines to give g-lactones bearing a quaternary carbon center at the a-position with complete enantioselectivity. 141 Interestingly, whereas use of (S)-proline as a catalyst resulted in the preferential formation of syn-isomer, use of 66 led to the exclusive formation of the anti-isomer (Scheme 115).…”

Section: Proline-catalyzed Mannich Reaction With Amido Sulfonementioning

confidence: 97%

2.16 The Bimolecular and Intramolecular Mannich and Related Reactions

Akiyama

2014

Comprehensive Organic Synthesis II

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“…Obtained aldol product 667 transformed into the corresponding THF 668 in 75% yield, through reduction/lactonization sequence using NaBH 4 in the presence of Et 2 BOMe in THF−MeOH (4/1) at −70°C, followed by treatment with CSA in DCM at 0°C to room temperature. The diastereoselectivity of the THF 668 was determined as 6.4/1 (Scheme 209).317 The obtained THF is a synthetic intermediate for psymberin, a marine cytotoxin.The synthesis of ethyl 3-(2-hydroxyphenylamino)-2-oxotetrahydrofuran-3-carboxylate derivatives 670 was developed by Kano et al318 via diastereo-and enantioselective Mannich reaction of ketimine 669, prepared by cyclocondensation of 2-aminophenol with diethyl oxomalonate in toluene in the presence of 4 Å MS at 70°C for 6 h, with aldehydes using axially chiral aminosulfonamide XIII, or L-proline as organocatalysts. Reactions were performed either using 0.1 mmol 669 and 5 equiv of aldehyde in CH 3 CN in the presence of L-proline (20 mol %) and benzoic acid (10 mol %) for 5 h at 0°C, or using 0.1 mmol 669 and 3 equiv of aldehyde in DMAc in the presence of XIII (5 mol %) for 5 h at 45°C, followed by treatment with NaBH 4 in MeOH at 0°C (Scheme 210).…”

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confidence: 99%