Aminoalkyl-phosphine (P,N) ligands with pentane-2,4-diyl backbone in asymmetric allylic substitution reactions

Császár, Zsófia; Imre, Patrik; Balogh, Szabolcs; Bényei, Attila; Farkas, Gergely; Bakos, József

doi:10.1007/s00706-017-2029-2

“…There has been interest in using P,N ligands because they can discriminate between the two terminal allylic carbons based on their electronic differentiation, directing the nucleophile towards the allylic carbons trans to the phosphorus atom. Some common ligands used for this reaction include the PHOX ligands, phosphite-oxazoline ligands, and aminoalkyl-phosphine ligands 7,[18][19][20][21][22] . These ligands can control exo-endo preference through the chiral oxazoline/amine moiety which, thanks to the trans phosphorus, is in close proximity to the reacting allyl terminus (Fig.…”

mentioning

confidence: 99%

Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations

Wahlers

¹

,

Margalef

²

,

Hansen

³

et al. 2021

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The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome.

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“…A validation dataset containing 77 structures (Figs. S3 and S4, Table S3 in Supporting Information) assembled from the literature 18,20,[37][38][39][40][41][42][43][44] was used to test the performance of the TSFF for systems different than the training set (Figure 2A). 1,3-Diphenyl propenyl was used as the allyl component reacting with 16 different amines, catalyzed by the Pd-complexes of 53 different P,N ligands.…”

Section: Resultsmentioning

confidence: 99%

“…Some common ligands used for this reaction include the PHOX ligands, phosphite-oxazoline ligands, and aminoalkyl-phosphine ligands. 6,[17][18][19][20][21] These ligands can control exo-endo preference through the chiral oxazoline/amine moiety which, thanks to the trans phosphorus, is in close proximity to the reacting allyl terminus (Figure 1C). 16 There have been a few methods developed to predict stereoselectivity in asymmetric catalysis.…”

mentioning

confidence: 99%

Proofreading Experimentally Assigned Stereochemistry Through Q2MM Predictions in Pd-Catalyzed Allylic Aminations

Wahlers

¹

,

Margalef

²

,

Hansen

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome.

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“…Solvents were purified, dried and deoxygenated by standard methods. Compounds [Pd (COD)Cl 2 ], [Pd(η 3 ‐PhCHCHCHPh)(COD)]BF 4 ,[5i] 3a , b and 3c were prepared according to literature methods. All other starting materials were purchased from Sigma Aldrich and used without further purification.…”

Section: Methodsmentioning

confidence: 99%

Double stereoselective coordination of chiral N,S ligands: Synthesis, coordination chemistry and utilization in Pd‐catalyzed allylic alkylation

Major

¹

,

Rövid

²

,

Balogh

³

et al. 2018

Applied Organom Chemis

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A series of chiral pentane‐2,4‐diyl‐based thioether‐amine ligands [4 and 5; (R,S)‐ and (S,S)‐R1SCH(CH3)CH2CH(CH3)NHR2, respectively, where 4a R1 = iPr, R2 = Ph; 4b R1 = tBu, R2 = Ph; 4c R1 = 1‐Ad, R2 = Ph; 5a R1 = iPr, R2 = Ph; 5b R1 = tBu, R2 = Ph; 5c R1 = 1‐Ad, R2 = Ph; 5d R1 = iPr, R2 = 4‐MeOC6H4; 5e R1 = iPr, R2 = 4‐MeC6H4; 5f R1 = iPr, R2 = 3,5‐Me2C6H3] with stereogenic S‐ and N‐donor atoms has been prepared starting from cyclic sulfates via optically pure γ‐aminoalcohol or 2,4‐dimethylazetidine intermediates. The synthesis of the novel diastereomerically related ligand sets 4 and 5 was accomplished starting from the same source of chirality. The modular ligand structure and the novel synthetic strategies developed for their synthesis allowed the easy modification of the ligands’ (i) S‐ and (ii) N‐substituents, as well as (iii) the relative stereochemistry within the ligand backbone. Six‐membered [Pd(N,S)Cl2]‐type chelate complexes of the diastereomerically related ligands 4a and 5a were synthesized and characterized by X‐ray crystallography in the solid phase, by density functional theory calculations and in solution by NMR spectroscopy. The coordination of 5a resulted in the formation of a single chair conformation by the stereospecific locking of both stereolabile (N and S) donor atoms. In contrast, compound 4a forms rapidly equilibrating palladium species due to the fast inversion of the sulfur donor. Ligands with stereochemically fixed donor atoms provided robust and efficient catalytic systems that can be effectively applied in alkylene carbonates as green reaction media. Remarkably, the phosphine‐free catalysts are air‐stable, and at room temperature in the presence of moisture gave excellent ee’s (up to 93%) in asymmetric allylation processes thanks to the double stereoselective coordination.

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Aminoalkyl-phosphine (P,N) ligands with pentane-2,4-diyl backbone in asymmetric allylic substitution reactions

Cited by 11 publications

References 53 publications

Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations

Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations

Proofreading Experimentally Assigned Stereochemistry Through Q2MM Predictions in Pd-Catalyzed Allylic Aminations

Double stereoselective coordination of chiral N,S ligands: Synthesis, coordination chemistry and utilization in Pd‐catalyzed allylic alkylation

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