Conformationally constrained bis(oxazoline) derived chiral catalyst: A highly effective enantioselective Diels-Alder reaction

Abstract

The reaction of cyclopentadiene with various bidentate dienophiles in the presence of 4-10 mol% of copper(II)-bis(oxazoline) complexes afforded excellent endo/exo selectivity as well as endo enantioselectivity (95-99% ee) and isolated yields. On the other hand, Diels-Alder reaction with Mg(II)-complexes afforded a modest ( 61% ee) reversal in enantioselectivity.The enantioselective Diels-Alder reaction is of paramount interest in organic synthesis. 1 As a consequence, a number of effective enantioselective processes have been developed over the years. 2 Recent discoveries of various catalytic processes have added a new dimension to the enantioselective Diels-Alder reaction. 3,4 Of particular interest, C 2 -symmetric chiral bis(oxazoline)-metal complexes have shown exceptional promise as chiral catalysts for enantioselective Diels-Alder reactions. 5 As part of our interests in various ligand assisted asymmetric syntheses, 6 we have synthesized conformationally constrained chiral bis(oxazoline) ligands and investigated their effectiveness as chiral catalysts in asymmetric Diels-Alder reactions. Recent reports by Merck group 7 on the synthesis and application of (IS, 2R)-1-amino-2-indanol derived other bis(oxazoline) ligands in catalytic Diels-Alder reaction, prompted us to disclose our results in this area. Herein, we report that various metal-ligand complexes of conformationally constrained bis(oxazoline) ligands derived from phenylglycinol surrogates, cisI-amino-2-indanols 8 are indeed highly effective catalysts for the enantioselective Diels-Alder reaction. Among various metal complexes examined, bis(oxazoline)-copper(II) complex is particularly effective. Reaction of cyclopentadiene with various bidentate dienophiles 6 in the presence of 4-10 mol% of bis(oxazoline)-copper(II) complexes afforded excellent endo/exo selectivity as well as endo enantioselectivity and excellent isolated yields. Since either enantiomer of constrained bis(oxazoline) is readily prepared from commercially available 9 optically active cis-1-amino-2-indanols, the current methodology provides a convenient access to either enantiomer of various cyclopentadiene based Diels-Alder adducts in a stereopredictable fashion.Conformationally constrained ligand 4 was readily prepared on a multi gram scale according to the procedure of Lehn. 10 Treatment of malononitrile and ethanol in dioxane in the presence of anhydrous HCI afforded the amide enol ether hydrochloride salt 1 (Scheme I). Reaction of 1 with (IR, 2S)-1-amino-2-indanol 2 in DMF at 23°C provided the bis(oxazoline) 4 as a white solid (m.p.206-208°C; α D 23° + 352, c, 3.7, CHCl 3 ) after

Copper(II)-Bisoxazoline-Catalysed Asymmetric Diels−Alder Reactions of α-Thioacrylates

“…17؊19; largest bite angle was observed with the spirocyclopropyl ligand 17). A similar effect was observed by Ghosh [26] in a related series of reactions in which the methylene bridged ligand 20 gave much improved selectivity compared with its dimethyl-substituted counterpart 7. The bite angle of ligand 20 is larger than that of 7 due to a reduced steric compression [27] effect which, in the latter case, causes an angular contraction.…”

Highly Enantioselective Michael Addition of Pyrazolin‐5‐ones Catalyzed by Chiral Metal/N,N′‐Dioxide Complexes: Metal‐Directed Switch in Enantioselectivity

“…In fact, several metal-based systems, in which the metal and reaction conditions (solvent, pressure, and additive) were tuned, have been developed for this enantiodivergent synthesis. [3] In these systems the unique characteristics of the metal ions, such as the atomic radius and their electronic properties, altered their coordination pattern even with the same chiral ligand. This behavior suggests the existence of different transition states that lead to the switch in enantioselectivity.…”

“…[5] To date, there is only one example of the organocatalytic diastereo-and enantioselective Michael addition of 4-substituted-pyrazolin-5-ones to nitroolefins. [4l] We report herein a highly enantioselective Michael addition of 4-substititued-5-pyrazolones to 1,4-dicarbonyl but-2-enes, [6] using the same ligand with either Sc(OTf) 3 or Y(OTf) 3 to switch the enantioselectivity. [7] We initially investigated the reaction of 4-benzyl-5pyrazolone (1 a) with ethyl (E)-4-oxo-4-phenylbutenoate (2 a) in EtOH at 30 8C catalyzed by scandium(III)/N,N'dioxide complexes, which contain ligands that are derived from (S)-pipecolic acid ( Table 1, entries [1][2][3][4][5].…”

“…We then investigated the Michael addition of 4-substituted pyrazolones and alkyl 4-oxo-4-arylbutenoates in the presence of 5 mol % of Y(OTf) 3 /L3 (Table 3) and the corresponding enantiomers were obtained with excellent diastereoselectivity and enantioselectivity (up to 98 % ee, > 49:1 d.r.). The ester groups of the alkyl 4-oxo-4-arylbutenoates exhibited little effect on the enantioselectivity but they did influence the reactivity of the substrates ( Table 3, entries [1][2][3][4]. The enantioselectivity of the reaction was not sensitive to either the steric or the electronic properties of the substituents on the phenyl ring ( Table 3, entries 5-12), and the corresponding products were isolated in good yields and excellent enantiomeric excess.…”

Diels-Alder reactions in aqueous media

“…The stereochemical aspects of intramolecular Diels-Alder reactions will be discussed separately. Even though asymmetric Diels-Alder reactions using chiral catalysts are known [48], an effective aqueous version of this reaction has not yet been developed.…”