Highly Enantioselective Michael Additions of Indole to Benzylidene Malonate Using Simple Bis(oxazoline) Ligands:  Importance of Metal/Ligand Ratio

Rasappan, Ramesh; Hager, Markus; Gissibl, and Anja; Reiser, Oliver

doi:10.1021/ol062697k

Cited by 127 publications

(31 citation statements)

References 21 publications

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“…(1)], we assumed that an enantioselective FriedelCrafts alkylation of indoles through the noncovalent activation of a-keto esters using N-triflylphosphoramides [Eq. (2)] should also be feasible. Therefore, our investigations started with the examination of the Brønsted acid catalyzed addition of N-methylindole (1 a) to the a-keto ester 2 a.…”

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confidence: 99%

Asymmetric Brønsted Acid Catalysis: Enantioselective Nucleophilic Substitutions and 1,4‐Additions

et al. 2007

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Asymmetric alkylations of electron-rich arenes such as indoles are of great importance for the synthesis of many natural products and pharmaceuticals.[1] Hence, different approaches have been undertaken to develop catalytic enantioselective additions of indoles to a,b-unsaturated carbonyl compounds. To date, these have been based on the application of chiral transition-metal complexes [2] or secondary amines, the latter of which function through covalent activation, forming intermediary iminium ions. [3] In this context the use of b,g-unsaturated a-keto esters is of particular interest since they not only exhibit a higher reactivity but also can be functionalized readily to the corresponding amino acids or a-hydroxy acids.Given the frequent occurrence of the indole core structure in biologically active substances and natural products [4] together with the possibility of activating carbonyl functionalities with chiral Brønsted acids, [5][6] the development of an enantioselective, metal-free, noncovalently catalyzed Friedel-Crafts alkylation of indoles appeared to be of great significance. This would not only be the first example of such an organocatalyzed transformation, but more importantly it would give simple and direct access to optically pure a-keto and a-amino acids. We report here on the development of such a reaction, a highly enantioselective Brønsted acid catalyzed addition of indoles to a,b-unsaturated carbonyl compounds.In continuing studies on the Bønsted acid catalyzed asymmetric Nazarov cyclization of divinyl ketones [5] [Eq. (1)], we assumed that an enantioselective FriedelCrafts alkylation of indoles through the noncovalent activation of a-keto esters using N-triflylphosphoramides [Eq. (2)] should also be feasible. Therefore, our investigations started with the examination of the Brønsted acid catalyzed addition of N-methylindole (1 a) to the a-keto ester 2 a. While no reaction was observed when weak Brønsted acids, such as carbonic acids or diphenyl phosphate, were used, catalytic amounts of N-triflylphosphoramide 5 a resulted in product formation. However, in addition to the desired 1,4-addition product 3 a, the bisindole 4 a was isolated as the main product (Scheme 1).The Lewis or Brønsted acid catalyzed formation of bisindoles starting from aldehydes, ketones, and 1,2-diketones is well known, [7] and several naturally occurring alkaloids contain this structural element.[8] However, the remarkable regioselectivity observed in the reaction of indoles with b,gunsaturated a-keto esters favoring the 1,2-addition with the generation of bisindole 4 a has not previously been reported. Figure 1 shows the X-ray crystal structure of 4 a. In contrast to all previously reported bisindoles, 4 a exhibits atropisomerism as a result of the rotation barrier about the bonds to the quaternary carbon bond. The bisindole atropisomers are not only observed in the X-ray crystal structure but can also be Scheme 1. Brønsted acid catalyzed reaction of N-methylindole (1 a) with a-keto ester 2 a to form bisindole 4 a.

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Asymmetric Brønsted Acid Catalysis: Enantioselective Nucleophilic Substitutions and 1,4‐Additions

et al. 2007

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“…However, we found the stereoelectronic outcome of the asymmetric monobenzolyation of 1,2‐diols to be affected by neither an excess of copper(II) nor bis(oxazoline) ligands,5 which raised the question as to if these catalyses might even be negatively influenced in their optical yields by a ligand surplus. Indeed, we observed such a detrimental effect on the enantioselective Michael addition of indole to benzylidene malonate, which gave rise to selectivities that were not achieved with simple bis(oxazoline) ligands heretofore 6. This unprecedented effect was subsequently validated in the copper(I)‐catalyzed alkynylation of an α‐amino ester with arylacetylenes, which responds to any excess of pybox (pybox=pyridine‐2,6‐bis(oxazoline)) with a significant decrease in enantiofacial selection to the point that even a reversal of enantioselectivity can be achieved 7…”

Section: Introductionmentioning

confidence: 90%

Dependence of Enantioselectivity on the Ligand/Metal Ratio in the Asymmetric Michael Addition of Indole to Benzylidene Malonates: Electronic Influence of Substrates

Schätz

Rasappan

Hager

et al. 2008

Chemistry A European J

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Simple bis(oxazoline) ligands, especially azabis(oxazolines), can promote the copper(II)-catalyzed Michael addition of indoles to benzylidene malonates with up to >99 % ee (ee=enantiomeric excess), provided that the ligand/metal ratio is tuned meticulously with particular regard to the electronic properties of the substrate. Despite a common paradigm followed in many asymmetric catalyses, an excess of chiral ligand is not always beneficial. In fact any excess of ligand has to be avoided to reach excellent enantioselectivities when electron-rich benzylidene malonates are used. On the contrary, malonates carrying an electron-withdrawing group require an excess of ligand for an optimum ee value. A correlation of optical yields versus the sigma(I) values of several para substituents shows a sigmoid trajectory. In the presence of an additive, such as triflate, the significance of the ligand/metal ratio vanishes and very good enantioselectivities are achieved at any rate--no matter whether electron-donating or withdrawing substituents are present.

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“…165 Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyse the addition of indoles to benzylidene malonates in up to 99% ee, provided that excess of the chiral ligand is avoided. 166 The paradigm followed in many asymmetric catalytic ee reactions that an excess of the chiral ligand with respect to the metal should improve enantioselectivity because the background reaction catalysed by a free metal is suppressed, was shown not to be applicable here, 166 which might call for revisiting some of the many copper(II)-bis(oxazoline)-catalysed processes known. Enantioselective ee additions of pyrroles and indoles to α,β-unsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine-scandium(III) triflate complex have been accomplished.…”

Section: Rch=chchomentioning

confidence: 99%

Addition Reactions: Polar Addition

Kočovský

2010

Organic Reaction Mechanisms · 2006

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Highly Enantioselective Michael Additions of Indole to Benzylidene Malonate Using Simple Bis(oxazoline) Ligands: Importance of Metal/Ligand Ratio

Cited by 127 publications

References 21 publications

Asymmetric Brønsted Acid Catalysis: Enantioselective Nucleophilic Substitutions and 1,4‐Additions

Asymmetric Brønsted Acid Catalysis: Enantioselective Nucleophilic Substitutions and 1,4‐Additions

Dependence of Enantioselectivity on the Ligand/Metal Ratio in the Asymmetric Michael Addition of Indole to Benzylidene Malonates: Electronic Influence of Substrates

Addition Reactions: Polar Addition

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