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

Abstract

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...

Organocatalyzed Cyclopropanation of α‐Substituted α,β‐Unsaturated Aldehydes: Enantioselective Synthesis of Cyclopropanes Bearing a Chiral Quaternary Center

“…[12] Moving to the Et 3 N/I catalytic system, previously reported for the cyclopropanation of a,b-unsaturated aldehydes, proved to be poorly effective in our case. [5] This combination dramatically decreases the enantioselection of the reaction even under slow addition techniques (syringe pump) ( Table 1, entries 2-3). These observations prompted us to surmise that, under the presence of this base, the cyclopropanation might occur via another mechanism which is not driven by the organocatalyst (Scheme 2).…”

“…Over the years, cyclopropanes have gained many synthetic groups interest and inspired new asymmetric routes allowing to their stereocontrolled construction. [3] Nevertheless, in the field of organocatalysis, [4,5] none of such studies have yet been able to establish the synthesis of cyclopropanes in which the stereogenic carbon at the a-position of the aldehydes involves a chiral quaternary center. [6] Although syntheses of these unique strained rings which are useful targets for further elaboration into more complex structures are well documented, [7] the a,b-difunctionalization of a-substituted a,b-unsaturated enals by chiral aminocatalysis is still unexplored.…”

1,3-Dicarbonyl compounds in stereoselective domino and multicomponent reactions

“…Three different groups have developed independently a sequence involving a Michael addition followed by intramolecular alkylation for the synthesis of densely functionalized chiral cyclopropanes 112 (Scheme 42). 93,94,95 This reaction is rather difficult to realize since the catalyst (a secondary amine) can be easily be poisoned by alkylation of its nitrogen atom by the substrate, hence stopping the reaction. These domino reactions generally use an α-halogenated malonate 111 and an α,β-unsaturated aldehyde to give the corresponding cyclopropanes 112 in very good yields and excellent enantioselectivities.…”

Organocatalytic Asymmetric Synthesis and Use of Organoselenium Compounds

“…19 To date only a limited number of diastereo-and enantioselective protocols for the organocatalyzed formation of cyclopropanes are available in the literature, typically Michael-initiated ringclosure reactions (MIRC) in which the cyclization of the adduct occurs by nucleophilic substitution of an halide initially positioned on the Michael donor. 24 The optimization of the addition step, which governs the enantioselectivity of the sequence, revealed the efficiency of the ureidic catalyst 17a, which gave the best results in terms of yield, diastereoselectivity, and enantioselectivity. The addition of 18a to the β-phenyl-substituted vinyl selenone 25A with 20 mol% of 17a in toluene at room temperature gave a diastereomeric mixture of 26aA and 27aA in a 85:15 diastereomeric ratio and 80% enantiomeric excess for the major isomer.…”