Stereoselective Synthesis of β‐Proline Derivatives from Allylamines <i>via</i> Domino Hydroformylation/Wittig Olefination and Aza‐Michael Addition

Farwick, Andreas; Helmchen, Günter

doi:10.1002/adsc.201000016

Cited by 27 publications

(5 citation statements)

References 28 publications

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“…Although highly desirable, no single catalytic protocol for the selective synthesis of β-proline has been reported to date. We anticipated that the asymmetric hydroformylation of pyrrolines, followed by subsequent transformation of the aldehyde into the free carboxylic acid (Scheme ), would provide an atom-efficient, catalytic route for the synthesis of enantioenriched β-proline, with the added potential to perform selective, stereospecific isotope labeling of of β-proline …”

Section: Resultsmentioning

confidence: 99%

Highly Selective Asymmetric Rh-Catalyzed Hydroformylation of Heterocyclic Olefins

et al. 2012

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A small family of new chiral hybrid, diphosphorus ligands, consisting of phosphine-phosphoramidites L1 and L2 and phosphine-phosphonites L3a−c, was synthesized for the application in Rh-catalyzed asymmetric hydroformylation of heterocyclic olefins. High-pressure (HP)-NMR and HP-IR spectroscopy under 5−10 bar of syngas has been employed to characterize the corresponding catalyst resting state with each ligand. Indole-based ligands L1 and L2 led to selective ea coordination, while the xanthene derived system L3c gave predominant ee coordination. Application of the small bite-angle ligands L1 and L2 in the highly selective asymmetric hydroformylation (AHF) of the challenging substrate 2,3-dihydrofuran (1) yielded the 2-carbaldehyde (3) as the major regioisomer in up to 68% yield (with ligand L2) along with good ee's of up to 62%. This is the first example in which the asymmetric hydroformylation of 1 is both regio-and enantioselective for isomer 3. Interestingly, use of ligand L3c in the same reaction completely changed the regioselectivity to 3-carbaldehyde (4) with a remarkably high enantioselectivity of 91%. Ligand L3c also performs very well in the Rh-catalyzed asymmetric hydroformylation of other heterocyclic olefins. Highly enantioselective conversion of the notoriously difficult substrate 2,5-dihydrofuran (2) is achieved using the same catalyst, with up to 91% ee, concomitant with complete regioselectivity to the 3-carbaldehyde product (4) under mild reaction conditions. Interestingly, the Rh-catalyst derived from L3c is thus able to produce both enantiomers of 3-carbaldehyde 4, simply by changing the substrate from 1 to 2. Furthermore, 85% ee was obtained in the hydroformylation of N-acetyl-3-pyrroline (5) with exceptionally high regioselectivities for 3-carbaldehyde 8Ac (>99%). Similarly, an ee of 86% for derivative 8Boc was accomplished using the same catalyst system in the AHF of N-(tert-butoxycarbonyl)-3-pyrroline (6). These results represent the highest ee's reported to date in the AHF of dihydrofurans (1, 2) and 3-pyrrolines (5, 6).

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Section: Resultsmentioning

confidence: 99%

Highly Selective Asymmetric Rh-Catalyzed Hydroformylation of Heterocyclic Olefins

et al. 2012

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“…66 In earlier work, the same group had shown that the synthesis of α,β-unsaturated esters 71 and cyclisation to afford β-proline derivatives can also be achieved via domino hydroformylation/Wittig olefination of protected amines deriving from Ir-catalysed AAS. 67 The sequence of hydroboration and subsequent Suzuki-Miyaura coupling has also been exploited for products deriving from the Ir-catalysed asymmetric allylic amination of carbonates with o-haloanilines. Unfortunately, the reactions of these nucleophiles were characterised by lower yields than those typically observed for Ir-catalysed AAS.…”

Section: Nitrogen Nucleophilesmentioning

confidence: 99%

Recent advances and applications of iridium-catalysed asymmetric allylic substitution

2012

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Since their discovery in 1997, iridium-catalysed asymmetric allylic substitutions have been developed into a broadly applicable tool for the synthesis of chiral building blocks via C-C and C-heteroatom bond formation. The remarkable generality of these reactions and the high levels of regio- and enantioselectivity that are usually obtained in favour of the branched products have been made possible by a thorough investigation of the catalyst system and its mode of action. Therefore, today the Ir-catalysed asymmetric allylic substitution is a powerful reaction in the organic chemist's repertoire and has been used extensively for several applications. This article aims to provide an overview of the development of iridium catalysts derived from an Ir salt and a chiral phosphoramidite and their application to the enantioselective synthesis of natural products and biologically relevant compounds.

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“…Initially,w et ried diverse aza-Michaelc onditions on an acrylate derivative. [33] This unprecedented approach on ap yrazolew as unsuccessful, possibly because of the limited electrophilicity of the electron rich carbon beta to the carbonyl. We attempted to circumvent this synthetic problem by an intramolecular Heck reactiono raradical cyclisation, [34,35] however,b oth approaches failed to deliver the desired product after exploring a range of reaction conditions.…”

Section: Resultsmentioning

confidence: 99%

Generation of Polar Semi‐Saturated Bicyclic Pyrazoles for Fragment‐Based Drug‐Discovery Campaigns.

Luise

Wyatt

2018

Chemistry A European J

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Synthesising polar semi-saturated bicyclic heterocycles can lead to better starting points for fragment-based drug discovery (FBDD) programs. We report the application of diverse chemistry to construct bicyclic systems from a common intermediate, where pyrazole, a privileged heteroaromatic able to bind effectively to biological targets, is fused to diverse saturated counterparts. The generated fragments can be further developed either after confirmation of their binding pose or early in the process, as their synthetic intermediates. Essential quality control (QC) for selection of small molecules to add to a fragment library is discussed.

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Stereoselective Synthesis of β‐Proline Derivatives from Allylamines via Domino Hydroformylation/Wittig Olefination and Aza‐Michael Addition

Cited by 27 publications

References 28 publications

Highly Selective Asymmetric Rh-Catalyzed Hydroformylation of Heterocyclic Olefins

Highly Selective Asymmetric Rh-Catalyzed Hydroformylation of Heterocyclic Olefins

Recent advances and applications of iridium-catalysed asymmetric allylic substitution

Generation of Polar Semi‐Saturated Bicyclic Pyrazoles for Fragment‐Based Drug‐Discovery Campaigns.

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