Stereodivergence in asymmetric catalysis: towards selecting the configuration of consecutively formed stereogenic centers in a single pot catalytic process

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Optimization for BTA-P(DTF)2 ligand: Cu(OAc)2∙H2O versus Cu(II)-i-butyrate as a metal precursor.

Further investigations were performed in order to determine the effect of the copper precursor on the performance of the best performing ligand. For this purpose, Cu(II)-i-butyrate was selected to be tested with the BTA-P(DTF)2/BTA Leu mixture. For the reaction scheme and conditions, and plots of reactant consumption and product formation, see Scheme III-13. For catalytic results see Table III-2. For NMR spectra (See Annex, subsection III.4.b.ii, Figure S.III-11).
Scheme III-13 Conditions: Styrene (0.15 mmol, 1 equiv.), Cu(II)-i-butyrate (5 mol%), BTA ligand (10 mol%), BTA (R)-Leu (10 mol%), DMMS (0.6 mmol, 4.0 eq), amine-DM (0.18 mmol, 1.2 eq), toluene-d8 (600 μL). Evolution was tracked by 1H NMR in presence of IS: 1,3,5- trimethoxybenzene (0.15 mmol, 1 equiv.).
We were pleased to see that changing the copper source form Cu(OAc)2.xH2O to Cu(II)-ibutyrate increases the chemoselectivity of the reaction without altering the rate of conversion of styrene and the enantioselectivity. In addition, the overall rate with Cu(II)-i-butyrate is increased 2-fold relative to Cu(OAc)2.xH2O. It is assumed that in presence of Cu(II)-i-butyrate, the oligo/polymerization of styrene is reduced at the expense of the formation of the amine product-1. Reasonable yield (65%) and enantioselectivity (67%) were reached under these conditions (Table III-2).
Table III-2 Comparison of reactivity, chemoselectivity, and enantioselectivity between both systems [a] Chemoselectivity= Yield product-1/conversion of styrene, [b] Relative rate (rate/rateCu(II)-i-butyrate). [c]. % ee determined by HPLC analysis.

Hydrosilylation/hydroamination cascade process on “enone” substrates.

Hydrosilylation of benzylideneacetone, and cascade of (E)-3-methyl-4-phenylbut-3-en-2-one.

α,β enones have been selected by Buchwald for the synthesis of amino alcohols via a cascade copper-catalyzed hydrosilylation/hydroamination[102]. Buchwald was able to obtain the analogous amino alcohols from a variety of different α,β enones in yields ranging from 60% to 80%. It was thus appealing to test these substrates with the BTA helical catalysts. Some of these experiments were performed before establishing that BTA-P(DTF)2/BTA Leu mixture as the best performing mixture for HA of styrene, and thus other ligand/BTA Leu mixtures were employed.
We first evaluated the BTA helical catalyst in the hydrosilylation (HS) of benzylidenacetone. For this purpose, different conditions have been probed: 1) the nature of the ligand, 2) the temperature, and 3) the nature of the silane reagent used. For reaction scheme, and catalytic results, see Table III-3. For selected 1H NMR data (see Annex, subsection III.4.b.iii, Figure S.III-12).
We first tested the fate of the reaction with commercial ligand, DTBM-(R)-SEGPHOS. At room temperature, the yield of the desired allyl alcohol A was low (18%), relatively to the fully reduced B (55%) (entry 1, Table III-3).
This result is somewhat in agreement with the literature for which a yield of 76% was reported after the cascade reaction (the difference might come from the different silane source). With BTA-pPPh2, the desired allylic alcohol A was obtained in 22% yield at room temperature, concomitantly with a huge amount of fully reduced B (70%) (entry 3, Table III-3). Lowering the temperature has no positive influence on the chemoselectivity of the reaction (entries 4, Table III-3). The effect of the silane reagent was also evaluated and it was found that the yield in allylic alcohol A dropped to 5% with DEMS instead of PhSiH3 (entry 5, Table III-3). Since both DEMS and PhSiH3 show high consumption of benzylidenacetone, this result indicates that the reaction with DEMS generated more by-products. The effect of BTA ligand was also evaluated by replacing BTA-pPPh2 with BTA-P(Xylyl)2, in presence of two different silanes (DEMS, and PhSiH3) at -60°C (entries 6, and 7, Table III-3). The yield in allylic alcohol A was increased to 30% when BTA-P(Xylyl)2 and PhSiH3 were used, but again the fully reduced B was the major product (70%).
The propensity of the BTA helical catalysts to reduce both functions is a severe limitation towards engaging this substrate into the second hydroamination step. Accordingly, the cascade reaction was not attempted on that substrate. However, further investigations will be carried out notably by testing the influence of BTA-P(DTF)2/BTA Leu mixture and the amount of silane on the fate of this catalytic reaction.
It was shown above (subsection III.1.b, Scheme III-6) that methyl substituents on  position of the keto group could prevent the 1,4-reduction pathway. For this purpose, (E)-3-methyl-4- phenylbut-3-en-2-one was selected to be probed in the cascade process using a catalytic system composed of Cu(OAc)2.xH2O/BTA-P(DTF)2/BTA Leu in presence of DMMS as silane reagent, and amine-DM as amine electrophile. The reaction was carried out at RT for 1h, then temperature was elevated to 55°C for overnight. For reaction scheme and catalytic results see Scheme III-14.
Scheme III-14 Conditions: (E)-3-methyl-4-phenylbut-3-en-2-one (0.25 mmole, 1.0 eq), Cu(OAc)2.xH2O (5 mol%), BTA-P(DTF)2 (10 mol%), BTA (R)-Leu (10 mol%), DMMS (4.0 eq), amine-DM (1.2 equiv.), toluene (800 μL). Yield estimated by 1H NMR according to an internal standard: 1,3,5-trimethoxybenzene.
The allyl alcohol C was detected in 65% yield, while no traces of the fully reduced D were detected under these conditions. Although the 1,4 reduction appears to be completely suppressed by methylation, no traces of the amino alcohol E were detected by 1H NMR analysis. Further investigations will be carried out for probing different copper sources, solvents, and HA reaction temperature for the cascade on (E)-3-methyl-4-phenylbut-3-en-2- one.

Evaluation of hydrosilylation and cascade reaction on (E)-1,4- diphenylbut-3-en-1-one and derivatives.

To suppress the undesired reduction of the vinyl function, we envisaged to add a carbon atom between both functionalities to break down the conjugation. For this purpose, α,γ-enone substrates were selected.
Two different BTA ligands (BTA-pPPh2 and BTA-P(Xylyl)2) were selected for evaluating the hydrosilylation reaction on (E)-1,4-diphenylbut-3-en-1-one at RT in presence of DMMS as silane reagent. For reaction conditions and catalytic results see Scheme III-15. For selected 1H NMR data (see Annex, subsection III.4.b.iii, Figure S.III-13)
The conversions were high but yields in the desired α,γ-alcohol F were very low, ca. 4%, in both cases. This low yield could be attributed to unidentified side reactions, since no peaks for the fully reduced were detected.
Scheme III-15 Conditions: (E)-1,4-diphenylbut-3-en-1-one (0.17 mmole, 1eq), Cu(OAc)2.H2O (3 mol%), BTA ligand (6 mol%), DMMS (2.0 eq), toluene (590 μL). Yields were estimated by 1H NMR according to an IS (DMA).
A combination of BTA-P(DTF)2 and BTA (R)-Leu was evaluated in the cascade hydrosilylation/hydroamination reaction of unaltered and substituted α,γ-enone substrates.
The latter compounds contain a fluorine atom or a phenyl moiety at the para position of the benzyl ring. The hydrosilylation step was carried out at room temperature for 3 hours, followed by hydroamination which was expected to take place after the addition of amine-TB at elevated temperature (55° C) for 2 days. The reaction outcome was analyzed by 1H NMR analysis. For reaction scheme catalytic results see Table III-4. For selected 1H NMR data (see Annex, subsection III.4.b.iii, Figure S.III-14) Only the α,γ-alcohol G was detected in the crude 1H NMR mixture. The reason why the hydroamination did not occur for this substrate is unclear. It can be due to the inherent reactivity of the double bond (-methyl substituted styrenes are expected to be less reactive than non-substituted styrene), but additional control experiments are required notably to control whether the silane was consumed totally or not during the HS step.


Table of contents :

Chapter I : Stereodivergence in asymmetric catalysis: towards selecting the configuration of consecutively formed stereogenic centers in a single pot catalytic process.
I.1. General introduction:
I.2. Examples of stereodivergent strategies.
I.2.a. Stereodivergency in concerted reactions.
I.2.a.i. By tuning the substrate structure.
I.2.a.ii. By catalyst redesign.
I.2.a.iii. By changing the reaction conditions.
I.2.a.iv. By changing the ligand
I.2.a.v. By changing the metal cation
I.2.b. Case of stereodivergent dual catalysis
I.2.c. Case of cascade (sequential) catalysis
I.2.d. Conclusion.
I.3. Enantiodivergency by means of switchable asymmetric catalysts.
I.3.a. Light.
I.3.b. Redox potential.
I.3.c. Temperature.
I.3.d. Combined heat and light stimuli.
I.3.e. Helical polymers as scaffolds for switchable catalysis.
I.3.e.i. Switchable helical covalent catalysts.
I.3.e.ii. Switchable helical supramolecular catalyst.
I.4. In situ control of product configuration by means of switchable asymmetric catalysts
I.4.a. With two (pseudo) enantiomeric catalysts.
I.4.b. By two catalysts anchored on the rotating arm of a substrate.
I.4.c. With a single asymmetric catalyst.
I.5. Description and objectives of the project.
I.6. References.
Chapter II : Phosphine-containing BTA ligands with various aryl groups on the phosphorous atom: Synthesis, characterization, assembly behavior, and implementation in asymmetric copper catalyzed hydrosylilation of 1-(4-nitrophenyl)ethanone.
II.1. Introduction:
II.1.a. Synthesis and importance of BTAs.
II.1.b. Helical BTA ligands for asymmetric reactions
II.1.c. Role of the ligand structure in catalyst design.
II.1.d. Designing a new set of phosphine-containing BTA ligands.
II.2. Synthesis of a new set of phosphine-containing BTA ligands
II.2.a. General retrosynthetic route.
II.2.b. Synthesis of 4-P(Mesityl)2-aniline, 4-P(Ph)2-aniline, and 4-P(Xylyl)2-aniline via protocol I
II.2.c. Synthesis of new 4-P(Ar)2-aniline derivatives via protocol II.
II.2.c.i. Issues with the purity and stability of some PAr2Cl precursors:
II.2.c.ii. Attempted synthesis of some PAr2Cl precursors.
II.2.c.iii. Synthesis of new phosphinoaniline derivatives via protocol II.
II.2.d. Synthesis of the BTA ligands.
II.2.e. Table of comparison between protocol I and II for the synthesis of BTA-pPPh2.
II.3. Structural characterization of the (S&S) co-assemblies by SANS and FT-IR analyses
II.4. Implementation in copper-catalyzed hydrosilylation of 1-(4-nitrophenyl)ethenone .
II.5. Conclusion.
II.6. Annex.
II.6.a. Experimental procedures.
II.6.b. Synthesis of the BTA ligands.
II.6.c. NMR data.
II.6.d. Selected chiral GC analyses:
II.7. References.
Chapter III Copper-catalyzed hydro-functionalization reactions with sergeants-and-soldiers type helical BTA catalysts : Hydroamination of styrene and cascade hydrosilylation/hydroamination of enone derivatives.
III.1. Introduction
III.1.a. Hydrosilylation of unsaturated substrates by phosphine copper hydride catalysts
III.1.b. Regioselectivity issues in hydrosilylation reactions.
III.1.c. Asymmetric copper catalyzed hydroamination for the preparation of chiral amines
III.1.d. Content of this chapter.
III.2. Copper-catalyzed hydroamination of styrene with sergeants-and-soldiers type helical BTA catalysts.
III.2.a. Probing the stability of the co-assemblies.
III.2.b. BTA-pPPh2 as ligand for the copper-catalyzed HA of styrene.
III.2.c. Screening of different BTA ligands with [Cu(OAc)2.xH2O] as metal precursor in the HA of styrene.
III.2.d. Optimization for BTA-P(DTF)2 ligand: Cu(OAc)2∙H2O versus Cu(II)-i-butyrate as a metal precursor.
III.3. Hydrosilylation/hydroamination cascade process on “enone” substrates.
III.3.a. Hydrosilylation of benzylideneacetone, and cascade of (E)-3-methyl-4-phenylbut-3-en-2-one.
III.3.b. Evaluation of hydrosilylation and cascade reaction on (E)-1,4-diphenylbut-3-en-1-one and derivatives.
III.4. Conclusion.
III.5. Annex.
III.5.a. General experimental procedure for catalysis.
III.5.b. Supplementary figures.
III.5.b.i. FT-IR analysis.
III.5.b.ii. 1H NMR analysis of the kinetic study of styrene Hydroamination in toluene-d8
III.5.b.iii. 1H NMR analysis of hydrosilylation and cascade of enone derivatives in CDCl3
III.5.c. Selected HPLC traces.
III.5.d. Synthesis of substrates.
III.5.e. 1H NMR of substrates.
III.5.f. 1H NMR and HRMS of Product-1.
III.6. References.
Chapter IV : Enantio and diastereoselective cascade reaction with supramolecular and chirally amplified helical catalyst: towards stereodivergency.
IV.1. Introduction
IV.2. Hydrosilylation of different vinyl acetophenone derivatives with supramolecular helical BTA catalysts.
IV.2.a. Hydrosilylation of 4-VPnone and 4-E-MeVPnone.
IV.2.b. Hydrosilylation of 3-VPnone and 3-MeVPnone.
IV.2.b.i. Substrate : 3-VPnone
IV.2.b.ii. Substrates : 3-E-MeVPnone and 3-Z-MeVPnone.
IV.2.c. Hydrosilylation of Substrate : 4-VBPnone.
IV.2.d. Conclusion.
IV.3. Preliminary tests for the cascade hydrosilylation/hydroamination reaction of 3-VPnone, 3 MeVPnone and 4-MeVPnone.
IV.3.a. Evaluation of the cascade process for 3-VPnone.
IV.3.b. Evaluation of the cascade process on 3-E-MeVPnone and 3-Z-MeVPnone.
IV.3.c. Evaluation of the cascade process for 4-E-MeVPnone.
IV.4. Cascade hydrosilylation/hydroamination of 3-VPnone : optimization of reaction conditions.
IV.4.a. Order of addition of the amine electrophile and influence of the reaction temperature.
IV.4.b. Screening of different metal precursors.
IV.4.c. Optimization of the conditions with Cu(II)-i-butyrate.
IV.5. Applying the catalytic switch.
IV.6. Probing the chirality amplification properties by Circular Dichroism.
IV.6.a. CD analyses for probing the diluted majority rule effects
IV.6.a.i. In MCH
IV.6.a.ii. In toluene
IV.6.b. Probing chirality amplification effects in catalysis in presence of BTA cyclohex as an additive
IV.6.c. Probing the stereochemical switch capability of the catalyst
IV.6.c.i. Applying the catalytic switch in presence of BTA cyclohex additive
IV.7. Conclusion
IV.8. Annex
IV.8.a. Materials preparation and methods
IV.8.b. General procedures for catalysis
IV.8.c. Preparation of solutions for CD analyses
IV.8.d. Supplementary figures
IV.8.e. Synthesis of substrates
IV.8.f. Analytical chiral HPLC separation for compound 3-APnol
IV.8.g. Formulas for determining ee1, ee2, eetot, and dr
IV.8.h. Selected HPLC spectrums
IV.8.i. Selected crude 1H NMR analyses of some catalytic experiments in CDCl3
IV.8.j. 1H NMR data of substrates
IV.8.k. 1H NMR, 13C NMR, and HRMS of 3-APnol
IV.9. References


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