Organocatalytic Conjugate Addition of Malonates to α,β‐Unsaturated Aldehydes: Asymmetric Formal Synthesis of (−)‐Paroxetine, Chiral Lactams, and Lactones

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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“…[16] }. Hence, the reactions with catalysts (S)-8 and (S)-9 give access to (2R,3R)-2-formylcyclopropanes 3.…”

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confidence: 97%

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

et al. 2007

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“…26,27 When these conditions were applied to α,ß-unsaturated aldehydes, complex mixtures of peroxides were observed that could not be separated. We expected the formation of dieneamines, as described in the work by Jørgensen et al 28,29 Obviously, we were not able to trap these dienes with singlet oxygen. Thus, the reaction conditions were modified and the photooxygenation was designed as a delayed step.…”

Section: Resultsmentioning

confidence: 85%

Singlet oxygen addition to cyclo-1,3-hexadienes from natural sources and from organocatalytic enal dimerization

Griesbeck¹,

Kiff²,

Neudörfl³

et al. 2015

Arkivoc

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The photoxygenation reactions of the natural monoterpene aldehyde safranal (1) and its reduction product safranol (4) were studied and the endoperoxide 5 from safranol was isolated and characterized by single crystal X-ray analysis. A dyade synthesis using DCC coupling of safranol with artesunic acid delivered the reactive substrate 7 for 1,3-diene photooxygenation. Singlet oxygen reaction of the substrate 7 enabled the synthesis of the trioxane-endoperoxide dyade 8. The diastereoisomeric 1,3-cyclohexadienes 10 were obtained from the proline-catalyzed Diels-Alder dimerization of the Michael aldehyde 9. From the singlet oxygen addition with the diastereoisomeric substrates 10, only the kinetically preferred cis-endoperoxide 11 was formed.

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“…The enantioselectivity achieved in the catalytic cyclopropanation step was not affected by the ring-opening step. Moreover, the alcohol used in the ring-opening step can be readily changed and b-malonate esters are valuable chiral syn- [29] ). Hence, the reactions with catalysts (S)-9 and (S)-10 give access to (2R,3R)-2-formyl-cyclopropanes 3.…”

Section: Solvent and Base Screenmentioning

confidence: 99%

“…(R)-1,1-diethyl 3-ethyl 2-phenylpropane-1,1,3-tricarboxylate 18 a: [32] [a] (R)-1,1-diethyl 3-methyl 2-phenylpropane-1,1,3-tricarboxylate 18 b: [29] [a] To a stirred solution of (S)-11 (16 mg, 20 mol %) in CHCl 3 (1 mL) at 4 8C, was added aldehyde 1 h (0.3 mmol), BrCHA C H T U N G T R E N N U N G (CO 2 Et) 2 2 a (0.25 mmol), NEt 3 (0.25 mmol) and MeOH (30 mL, 3.0 equiv). The reaction was vigorously stirred at 4 8C for 6 h. To this mixture was added DIPEA (40 mol %) and thiazolium precatalyst 17 (20 mol %).…”

mentioning

confidence: 99%

One‐Pot Organocatalytic Domino Michael/α‐Alkylation Reactions: Direct Catalytic Enantioselective Cyclopropanation and Cyclopentanation Reactions

Ibrahem

Zhao

Rios

et al. 2008

Chemistry A European J

158

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The development of one-pot organocatalytic domino Michael/alpha-alkylation reactions between bromomalonates or bromoacetoacetate esters and alpha,beta-unsaturated aldehydes is presented. The chiral-amine-catalyzed reactions with bromomalonates as substrates give access to the corresponding 2-formylcyclopropane derivatives in high yields with excellent diastereoselectivity and up to 99 % ee. The catalytic domino Michael/alpha-alkylation reactions between 4-bromo-acetoacetate and enals provide a route for the synthesis of functionalized cyclopentanones in good to high yields with 93-99 % ee. The products from the organocatalytic reactions were also reduced with high diastereoselectivity to the corresponding cyclopropanols and cyclopentanols, respectively. Moreover, one-pot combinations of amine and heterocyclic carbene catalysis (AHCC) enabled the highly enantioselective synthesis of beta-malonate esters (91-97 % ee) from the reaction between bromomalonates and enals. The tandem catalysis included the catalytic domino reaction followed by catalytic in situ chemoselective ring-opening of the 2-formylcyclopropane intermediates.

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Organocatalytic Conjugate Addition of Malonates to α,β‐Unsaturated Aldehydes: Asymmetric Formal Synthesis of (−)‐Paroxetine, Chiral Lactams, and Lactones

Abstract: In addition: The scope of the title reaction is demonstrated by the synthesis of chiral lactones and lactams. The latter class of compounds is very important for the preparation of the pharmaceutical compounds such as (−)‐paroxetine and (+)‐femoxetine.

Cited by 319 publications

References 62 publications

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

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

Singlet oxygen addition to cyclo-1,3-hexadienes from natural sources and from organocatalytic enal dimerization

One‐Pot Organocatalytic Domino Michael/α‐Alkylation Reactions: Direct Catalytic Enantioselective Cyclopropanation and Cyclopentanation Reactions

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