Organocatalytic Enantioselective Aziridination of α,β‐Unsaturated Aldehydes

Veselý, Ján; Ibrahem, Ismail; Zhao, Gui‐Ling; Rios, Ramón; Córdova, Armando

doi:10.1002/anie.200603810

Cited by 228 publications

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“…[25] This has led to the development of aminocatalytic aziridinations of a,bunsaturated aldehydes and ketones. [26][27] Herein, we report the development, the substrate scope, and one-pot applications of the amine-catalyzed enantioselective aziridination of a,b-unsaturated aldehydes.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Asymmetric Aziridination of α,β‐Unsaturated Aldehydes

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Dziedzic

Zhao

et al. 2011

Chemistry A European J

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The development, scope, and application of the highly enantioselective organocatalytic aziridination of α,β-unsaturated aldehydes is presented. The aminocatalytic azirdination of α,β-unsaturated aldehydes enables the asymmetric formation of β-formyl aziridines with up to >19:1 d.r. and 99% ee. The aminocatalytic aziridination of α-monosubstituted enals gives access to terminal α-substituted-α-formyl aziridines in high yields and up to 99% ee. In the case of the organocatalytic aziridination of disubstituted α,β-unsaturated aldehydes, the transformations were highly diastereo- and enantioselective and give nearly enantiomerically pure β-formyl-functionalized aziridine products (99% ee). A highly enantioselective one-pot cascade sequence based on the combination of asymmetric amine and N-heterocyclic carbene catalysis (AHCC) is also disclosed. This one-pot three-component co-catalytic transformation between α,β-unsaturated aldehydes, hydroxylamine derivatives, and alcohols gives the corresponding N-tert-butoxycarbonyl and N-carbobenzyloxy-protected β-amino acid esters with ee values ranging from 92-99%. The mechanisms and stereochemistry of all these catalytic transformations are also discussed.

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Section: Introductionmentioning

confidence: 99%

Catalytic Asymmetric Aziridination of α,β‐Unsaturated Aldehydes

Deiana

Dziedzic

Zhao

et al. 2011

Chemistry A European J

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“…The same type of reaction mechanism has also been observed in the organocatalytic asymmetric epoxidation of enals [12l,o] and asymmetric aziridination of enals. [17] In summary, we report a new example of a highly chemo-and enantioselective organocatalytic cyclopropanation of a,b-unsaturated aldehydes. The reaction was efficiently catalyzed by simple chiral pyrrolidine derivatives and gives the corresponding 2-formylcyclopropanes in high yields with 9:1 to > 25:1 dr and 93-99 % ee.…”

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confidence: 98%

A Simple Organocatalytic Enantioselective Cyclopropanation of α,β‐Unsaturated Aldehydes

et al. 2007

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A highly chemo-and enantioselective organocatalytic cyclopropanation of a,b-unsaturated aldehydes with bromomalonate and 2-bromoacetoacetate esters is presented. The reaction is catalyzed by chiral amines and gives access to 2-formylcyclopropanes in high yields and up to 99 % ee.Keywords: asymmetric catalysis; cyclopropanes; domino reactions; halomalonates; organocatalysis; a,b-unsaturated aldehydesThe cyclopropane motif has long been an interesting target for organic chemists. The cyclopropane ring is a constituent in more than 4000 natural isolated [1] and 100 biologically active agents. In addition, cyclopropyl derivatives are attractive as intermediates in complex molecule synthesis, [2] as synthetic building blocks, [3] and as templates for the construction of conformationally restricted amino acids and peptides. [4] Hence, the importance of cyclopropyl derivatives has inspired chemists to develop asymmetric methods for their synthesis.[5] For example, in the last few years high levels of asymmetric induction have been achieved involving metal-catalyzed intermolecular cyclopropanations of electron-rich olefins.[6] In the realm of organocatalysis, there are a few examples of enantioselective cyclopropanations. [7][8][9][10][11] For instance, Aggarwal and Gaunt pioneered the use of catalyst-bound ylides in enantioselective intermolecular cyclopropanation reactions.[7b] Moreover, Gaunt developed a very elegant catalytic intramolecular cyclopropanation using modified Cinchona alkaloids as organocatalysts.[10] Cinchona alkaloid derivatives have also been used by Connon and co-workers as catalysts for the asymmetric cyclopropanation of nitroalkenes.[8] Most recently, MacMillan and co-workers disclosed a novel enantioselective cyclopropanation rection between stabilized ylides and a,b-unsaturated aldehydes using a 2-carboxylic acid dihydroindole as the catalyst.[11] Encouraged by these studies and our previous experience on the combination of enamine and iminium catalysis, [12] we envisioned a chiral amine-catalyzed domino reaction between halomalonates or 2-halo-b-keto esters and enals would be a simple asymmetric entry to 2-formylcyclopropanes [Eq. (1)].[13]Herein, we report the highly enantioselective catalytic asymmetric reaction between bromomalonates or 2-bromoacetoacetate esters and a,b-unsaturated aldehydes that gives the corresponding 2-formylcyclopropanes in high yields and diasteromeric ratios and excellent asymmetric induction (93-99 % ee).After an extensive screening of catalysts and different solvents for the asymmetric cyclopropanation of cinnamic aldehyde 1a, we found that that the addition of 1 equivalent of Et 3 N was crucial in order to obtain high yields. In Table 1, selected results from the screening of reaction conditions for the enantioselective transformation between enal 1a and diethyl bromomalonate 2a are shown.We found that chiral amines 4-9 catalyzed the asymmetric formation of the corresponding 2-formylcyclopropanes 3a with up to > 25:1 dr (trans/cis) and ee values ranging fr...

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“…[14] We have applied diphenylprolinol silyl ether to the reaction of a,b-unsaturated aldehydes with enecarbamates and found that a formal aza [3+3] cycloaddition reaction proceeds in a highly enantioselective manner as reported herein (Figure 1). …”

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confidence: 62%

Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective, Catalytic, Formal Aza [3+3] Cycloaddition Reaction for the Formation of Enantioenriched Piperidines

et al. 2008

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The piperidine ring system is one of the most common structural subunits in natural products and biologically significant compounds.[1] The aza Diels-Alder reaction [2] and the aza [3+3] cycloaddition reaction [3] are straightforward synthetic methods for making piperidine ring systems. Several methods have been developed for formal aza [3+3] cycloaddition reactions, such as reactions of 1,3-cyclic sulfonates with C/N dianions, [4] vinylogous amides with a,b-unsaturated iminium ions, [5] and aziridines with Pd-trimethylenemethane complexes.[6] In spite of these formal aza [3+3] cycloaddition methods, and to the best of our knowledge, an enantioselective catalytic version has not been reported.Asymmetric catalytic reactions promoted by organocatalysts is a rapidly growing area of research.[7] Our group developed diarylprolinol silyl ether as an effective catalyst in the Michael reaction, [8] the ene reaction, [9] the Diels-Alder reaction, [10] the tandem Michael/Henry reaction, [11] and the Michael reaction of nitroalkanes.[12] At the time of our first report, the group of Jørgensen also developed the same type of catalyst; [13] the diarylprolinol silyl ether catalyst has been widely used in enantioselective reactions. [14] We have applied diphenylprolinol silyl ether to the reaction of a,b-unsaturated aldehydes with enecarbamates and found that a formal aza [3+3] cycloaddition reaction proceeds in a highly enantioselective manner as reported herein (Figure 1).Enecarbamates and enamides have been successfully utilized as reactive nucleophiles by the group of Kobayashi, [15] and Terada et al. recently used them in an aza-ene-type reaction.[16] Having reported the asymmetric ene reaction of cyclopentadiene, [9] we employed an enamide and an a,bunsaturated aldehyde with the expectation that an ene reaction would occur. Notably, the asymmetric, catalytic intermolecular ene reaction of a,b-enals as enophiles is rare.[9]The reaction of cinnamaldehyde and N-(1-phenylvinyl)acetamide 9 was selected as a model reaction and we expected that an amine catalyst and cinnamaldehyde would afford an iminium ion, which would react with enamide 9 to generate 7 by an ene reaction, to afford ketoaldehyde 5[17] after hydration (Scheme 1). When cinnamaldehyde and enamide 9 were treated with a catalytic amount of diphenylprolinol trimethylsilyl ether (1), ketoaldehyde 5 was obtained in 18 % yield in nearly optically pure form along with an unexpected piperidine derivative (6) in 47 % yield as a mixture of a and b isomers (44:56). The a and b isomers were separated and their optical purities were found to be the same (87 % ee, Table 1, entry 1). A pure sample of the a isomer resulted in a Figure 1. Organocatalysts examined in the present study. Scheme 1. The reaction mechanism of 5 and 6.

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Organocatalytic Enantioselective Aziridination of α,β‐Unsaturated Aldehydes

Cited by 228 publications

References 76 publications

Catalytic Asymmetric Aziridination of α,β‐Unsaturated Aldehydes

Catalytic Asymmetric Aziridination of α,β‐Unsaturated Aldehydes

A Simple Organocatalytic Enantioselective Cyclopropanation of α,β‐Unsaturated Aldehydes

Diphenylprolinol Silyl Ether as a Catalyst in an Enantioselective, Catalytic, Formal Aza [3+3] Cycloaddition Reaction for the Formation of Enantioenriched Piperidines

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