Design of P-Chirogenic Aminophosphine–Phosphinite Ligands at Both Phosphorus Centers: Origin of Enantioselectivities in Pd-Catalyzed Allylic Reactions

Jaillet, Antonin; Darcel, Christophe; Bayardon, Jérôme; Schlachter, Adrien; Salomon, Christine; Rousselin, Yoann; Harvey, Pierre D.; Jugé, Sylvain

doi:10.1021/acs.joc.0c00536

“…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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“…In all cases, the aminophosphine-boranes 7a−t were obtained with retention of the configuration at the P-center, due to the nucleophilic attack in the anti position of the P−N bond of the oxazaphospholidine ring (Scheme 2). 3d,4e, 12,13 This stereochemistry has been previously well established by X-ray structures of reagents and products. 4e,12−14, 16 It is noteworthy that the reaction of the dilithioferrocenyl-TMEDA reagent with two equivalents of the oxazaphospholidine-borane complex 10a afforded the bis-1,1′-(aminophosphinoborane)ferrocene 7l with 52% yield (entry 12).…”

Section: Resultsmentioning

confidence: 99%

“…A large series of modified P-chirogenic aminophosphine-boranes 7 were synthesized from the oxazaphospholidine-boranes 10a – f , which were previously prepared from (+)- or (−)-ephedrine 6a , ( S )-prolinol 6b or (+)- cis -1-amino-2-indanol 6c according to well-established methodologies, respectively (Scheme ). − The starting complexes 10a , c , e , f were obtained by heating the bis(dialkylamino)phenylphosphine with the corresponding amino alcohols in toluene at 105 °C for 4–6 h and then complexation with BH 3 ·DMS (Scheme a–d). In these conditions, the oxazaphospholidine-borane complexes 10a , c , f were isolated diastereomerically pure as crystallized compounds.…”

Section: Resultsmentioning

confidence: 99%

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P(III)-Chirogenic Phosphinite Building Blocks by Stereospecific N→O Phosphinyl Migration

Jaillet,

Bayardon,

Rousselin

et al. 2023

J. Org. Chem.

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In the recent past, the chirality borne by a phosphorus center has aroused growing interest in many fields, and the development of new methodologies, notably using inexpensive reagents and simple experimental conditions, has become topical. An efficient stereoselective synthesis of P-chirogenic phosphinites useful as chiral phosphorus building blocks is herein described thanks to a new intramolecular phosphorus rearrangement based on P*(III)-phosphinyl N→O migration. This rearrangement was performed by heating at 50 °C aminophosphine-boranes, easily prepared from chiral amino alcohols, with DABCO in toluene overnight. Twenty-seven P-chirogenic phosphinites and borane complexes were thus prepared in yields up to 89%. The crude P*(III)-phosphinites were in situ used in stereoselective synthesis of P-chirogenic aminophosphine-phosphinites, phosphinothioates, sec-and tert-phosphine-oxides, and mono-and diphosphines in overall yields ranging from 28 to 89% and with e.e. up to 99%. Twenty-one X-ray structures of P-chirogenic compounds were established, allowing us to attribute undoubtedly their absolute configuration and the stereochemistry of the reactions. Finally, new ferrocenyl-bridged diphosphine ligands synthesized from P*(III)-chirogenic diphosphinites were tested in asymmetric metal-catalyzed reactions, providing enantioselectivities up to 95% e.e. in allylation of α-naphthylmethylamine at room temperature. To conclude, this rearrangement opens up an efficient new way for the stereoselective synthesis of numerous classes of P-chirogenic phosphorus compounds, notably bearing bulky substituents.

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“…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.

show abstract

Design of P-Chirogenic Aminophosphine–Phosphinite Ligands at Both Phosphorus Centers: Origin of Enantioselectivities in Pd-Catalyzed Allylic Reactions

Cited by 12 publications

References 103 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

P(III)-Chirogenic Phosphinite Building Blocks by Stereospecific N→O Phosphinyl Migration

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

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