Prolinol Ether Research Articles

Recent Advances in the Application of Vibrational Circular Dichroism Spectroscopy for the Characterization of Asymmetric Catalysts

In this Minireview, we summarize our recent efforts to use vibrational circular dichroism (VCD) spectroscopy, the chiroptical version of IR spectroscopy, for the characterization of conformational preferences of asymmetric catalysts and complexes, formed upon the respective interactions or reactions of catalysts with substrates. After giving a brief overview of the general aspects of the technique, we showcase how VCD spectra of a chiral ion‐pairing catalyst could be used to confirm a conformational shifting mechanism that determines the enantioselectivity of the catalyst. Chiral thioureas serve as examples for hydrogen bonding organocatalysts for which we demonstrate that both conformational preferences of the catalysts as well as of the hydrogen‐bonded complexes with substrates can be obtained from a detailed computational spectra analysis. Jørgensen–Hayashi‐type prolinol ether catalysts serve as examples to introduce experimental challenges associated with catalysts that operate by covalent activation of reactants.

Stereochemistry of the Reaction Intermediates of Prolinol Ether Catalyzed Reactions Characterized by Vibrational Circular Dichroism Spectroscopy.

Spectroscopic characterizations of key reaction intermediates are often considered the final confirmation of a reaction mechanism. This proof‐of‐principle study showcases the application of vibrational circular dichroism (VCD) spectroscopy for the characterization of in situ generated reaction intermediates using the key intermediates of enamine catalysis of Jørgensen–Hayashi‐type prolinol ether catalysts as model system. By comparison of experimental and computed spectra, the enamines are shown to preferentially adopt an anti‐conformation with E‐configured C=C bond. For the parent prolinol catalyst, the structure and stereochemistry of the oxazolidine side product is determined as well. This study thus demonstrates that VCD spectra can provide insights into structural preferences of organocatalysts that utilize a covalent activation mechanism. Thereby it outlines new fields of applications for VCD spectroscopy and finally adds the technique to the toolbox of physical organic chemistry for in‐depth mechanistic studies.

Enamine/Dienamine and Brønsted Acid Catalysis: Elusive Intermediates, Reaction Mechanisms, and Stereoinduction Modes Based on in Situ NMR Spectroscopy and Computational Studies.

ConspectusOver the years, the field of enantioselective organocatalysis has seen unparalleled growth in the development of novel synthetic applications with respect to mechanistic investigations. Reaction optimization appeared to be rather empirical than rational. This offset between synthetic development and mechanistic understanding was and is generally due to the difficulties in detecting reactive intermediates and the inability to experimentally evaluate transition states. Thus, the first key point for mechanistic studies is detecting elusive intermediates and characterizing them in terms of their structure, stability, formation pathways, and kinetic properties. The second key point is evaluating the importance of these intermediates and their properties in the transition state.In the past 7 years, our group has addressed the problems with detecting elusive intermediates in organocatalysis by means of NMR spectroscopy and eventually theoretical calculations. Two main activation modes were extensively investigated: secondary amine catalysis and, very recently, Brønsted acid catalysis. Using these examples, we discuss potential methods to stabilize intermediates via intermolecular interactions; to elucidate their structures, formation pathways and kinetics; to change the kinetics of the reactions; and to address their relevance in transition states. The elusive enamine in proline-catalyzed aldol reactions is used as an example of the stabilization of intermediates via inter- and intramolecular interactions; the determination of kinetics on its formation pathway is discussed. Classical structural characterization of intermediates is described using prolinol and prolinol ether enamines and dienamines. The Z/E dilemma for the second double bond of the dienamines shows how the kinetics of a reaction can be changed to allow for the detection of reaction intermediates. We recently started to investigate substrate–catalyst complexes in the field of Brønsted acid catalysis. These studies on imine/chiral phosphoric acid complexes show that an appropriate combination of highly developed NMR and theoretical methods can provide detailed insights into the complicated structures, exchange kinetics, and H-bonding properties of chiral ion pairs. Furthermore, the merging of these structural investigations and photoisomerization even allowed the active transition state combinations to be determined for the first time on the basis of experimental data only, which is the gold standard in mechanistic investigations and was previously thought to be exclusively the domain of theoretical calculations.Thus, this Account summarizes our recent mechanistic work in the field of organocatalysis and explains the potential methods for addressing the central questions in mechanistic studies: stabilization of intermediates, elucidation of structures and formation pathways, and addressing transition state combinations experimentally.

Intramolecular Aminoalkoxylation of Unfunctionalized Olefins via Intramolecular Iodoamination and Aziridinium Ion Ring-Opening Sequence.

The preparation of prolinol ether type compounds was realized via MnI2-catalyzed intramolecular iodoamination of unfunctionalized olefins and subsequent ring opening of an aziridinium ion intermediate with alcohols/phenols. In the presence of a catalytic amount of MnI2 and 2 equiv of NaI, intramolecular aminoalkoxylation of different N-benzyl-5-methylhex-4-en-1-amine substrates proceeded readily in alcoholic solvents, leading to 2-(alkoxyalkyl)pyrrolidine products in up to 90% isolated yields.

Novel 5-substituted 3-hydroxyphenyl and 3-nitrophenyl ethers of S-prolinol as α4β2-nicotinic acetylcholine receptor ligands

A series of 3-nitrophenyl and 3-hydroxyphenyl ethers of (S)-N-methylprolinol bearing bulky and lipophilic substituents at phenyl C5 were tested for affinity at α4β2 and α3β4 nAChRs. The two phenyl ethers 5-substituted with 6-hydroxy-1-hexynyl showed high α4β2 affinity and significantly increased α4β2/α3β4 selectivity compared to the respective unsubstituted parent compounds. Within the two series of novel phenyl ethers, we observed parallel shifts in affinity and, furthermore, the increase in α4β2/α3β4 selectivity resulting from the hydroxyalkynyl substitution parallels that reported for the same modification at the 3-pyridyl ether of (S)-N-methylprolinol (A-84543), a well-known potent α4β2 agonist. On the basis of these results, our nitrophenyl and hydroxyphenyl prolinol ethers can be considered bioisosteres of the pyridyl ether A-84543 and lead compounds candidable to analogous optimization processes.

Stereodivergent α-Allylation of Linear Aldehydes with Dual Iridium and Amine Catalysis

We describe the fully stereodivergent, dual catalytic α-allylation of linear aldehydes. The reaction proceeds via direct iridium-catalyzed substitution of racemic allylic alcohols with enamines generated in situ. The use of an Ir(P,olefin) complex and a diarylsilyl prolinol ether as catalysts in the presence of dimethylhydrogen phosphate as the promoter proved to be crucial for achieving high enantio- and diastereoselectivity (>99% ee, up to >20:1 dr). The utility of the method is demonstrated in a concise enantioselective synthesis of the antidepressant (-)-paroxetine.

ChemInform Abstract: Efficient Proline and Prolinol Ether Mediated 3‐Component Synthesis of 3‐ and 3,4‐Substituted Chromenone Derivatives.

AbstractReaction of cyclic β‐diketones with aliphatic aldehydes provides an efficient access towards disubstituted chromenones, e.g. (III), (V) and (VII).

Asymmetric synthesis of propargylic alcohols via aldol reaction of aldehydes with ynals promoted by prolinol ether–transition metal–Brønsted acid cooperative catalysis

A catalytic and highly stereoselective entry to propargylic alcohols and products derived thereof is reported based on an unprecedented cross-aldol coupling between unmodified aldehydes and ynals. The method requires an amine–metal salt–Brønsted acid ternary catalyst system and implies synergistic activation of the donor aldehyde via enamine and of the acceptor carbonyl via unique and reversible metal–alkyne complexation. Specifically, by using a combined α,α-dialkylprolinol silyl ether–CuI–PhCO2H catalyst system, remarkably high levels of diastereo- and enantioselectivity (anti/syn up to >20 : 1, ee up to >99%) are achieved.

Assembly of Spirooxindole Derivatives via Organocatalytic Iminium-Enamine Cascade Reactions

The assembly of complex spirocyclopentaneoxindoles via a novel organocatalytic iminium-enamine cascade process is reported. Reactions between 3-substituted oxindoles and α,β-unsaturated aldehydes catalyzed by second generation prolinol ethers provided the desired products in high yield with excellent levels of enantioselectivity in a single step.

ChemInform Abstract: Asymmetric Michael Addition of N‐Boc‐Protected Oxindoles to Nitroalkenes Catalyzed by a Chiral Secondary Amine.

AbstractAmong 14 prolinol ethers tested in the reaction of oxindole (Ig) with nitrostyrene, didodecylprolinol Tms‐ether PRO affords the best result with respect to both yield and diastereo‐ and enantioselectivity of the addition product.

ChemInform Abstract: Unifying Metal‐ and Organocatalysis for Asymmetric Oxidative Iminium Activation: A Relay Catalytic System Enabling the Combined Allylic Oxidation of Alcohols and Prolinol Ether Catalyzed Iminium Reactions.

AbstractThe one‐pot domino reactions are based on the in situ generation of α,β‐unsaturated aldehydes from allylic alcohols in the presence of NMO as an oxidant and TPAP as catalyst, and the subsequent asymmetric transformations such as cyclopropanation, Michael addition, Michael addition/acetalization in the presence of a prolinol‐based catalyst.

Asymmetric Michael Addition of N‐Boc‐Protected Oxindoles to Nitroalkenes Catalyzed by a Chiral Secondary Amine

New mission for prolinol ethers: A secondary-amine-catalyzed Michael addition of N-Boc-protected oxindoles to nitroalkenes through a Brønsted base activation mode has been developed, furnishing the products in excellent yields (88-98 %), diastereoselectivities (d.r.=98:2->99:1) and high to excellent enantioselectivities (82->99 % ee; see scheme).

Unifying Metal‐ and Organocatalysis for Asymmetric Oxidative Iminium Activation: A Relay Catalytic System Enabling the Combined Allylic Oxidation of Alcohols and Prolinol Ether Catalyzed Iminium Reactions

A multicatalytic system consisting of tetrapropylammonium perruthenate/N-methylmorpholine N-oxide (TPAP/NMO) as oxidant, and diarylprolinol TMS-ether as chiral amine catalyst, has been developed and applied in the efficient construction of valuable chiral molecules. The one-pot domino reactions elaborated in the present study are based on the in situ generation of α,β-unsaturated aldehydes from allylic alcohols and their subsequent use in various asymmetric transformations (e.g., cyclopropanation, Michael addition, Michael addition/acetalization). TPAP as a substrate-selective redox catalyst is well tolerated by the amine catalyst and the domino reactions proceed in good yields and high enantioselectivities. The compatibility of metal and organocatalysis presented herein widens the scope of asymmetric iminium catalysis.

Efficient proline and prolinol ether mediated 3-component synthesis of 3- and 3,4-substituted chromenone derivatives

A highly efficient route for the synthesis of valuable 3,4-substituted chromenone derivatives by the reaction of 1,3-diketones with aldehydes in the presence of l-proline was developed. The reactions take advantage of readily available starting materials and follow a Knoevenagel condensation/Michael addition/hemiacetalization domino process. Chiral 3-substituted chromenones are obtained with high enantioselectivities when a chiral diarylprolinol TMS-ether is applied in the reaction.

Solid-Supported Prolinol Ether Catalysts

Solid-Supported Prolinol Ether Catalysts

ChemInform Abstract: Synthesis of 4‐Hydroxy‐4H‐chromenes by Reaction of Salicylic Aldehydes with Alkynals Catalyzed by Silyl Prolinol Ethers.

AbstractOptimized conditions are developed which produce the desired hydroxychromenes as structural motifs of natural compounds either with higher yield and lower e.e.

NMR Studies on Formation and Stability of Prolinol and Prolinol Ether Enamines

NMR Studies on Formation and Stability of Prolinol and Prolinol Ether Enamines

ChemInform Abstract: Catalytic Batch and Continuous Flow Production of Highly Enantioenriched Cyclohexane Derivatives with Polymer‐Supported Diarylprolinol Silyl Ethers.

AbstractThe known prolinol ether (Ia) and the new derivative (Ib) are tested in the enantioselective domino Michael—Knoevenagel reaction of aldehyde (II) with diester (III).

Organocatalyzed Michael Addition of Aldehydes to Nitro Alkenes – Generally Accepted Mechanism Revisited and Revised

AbstractThe amine‐catalyzed enantioselective Michael addition of aldehydes to nitro alkenes (Scheme 1) is known to be acid‐catalyzed (Fig. 1). A mechanistic investigation of this reaction, catalyzed by diphenylprolinol trimethylsilyl ether is described. Of the 13 acids tested, 4‐NO2C6H4OH turned out to be the most effective additive, with which the amount of catalyst could be reduced to 1 mol‐% (Tables 2–5). Fast formation of an amino‐nitro‐cyclobutane 12 was discovered by in situ NMR analysis of a reaction mixture. Enamines, preformed from the prolinol ether and aldehydes (benzene/molecular sieves), and nitroolefins underwent a stoichiometric reaction to give single all‐trans‐isomers of cyclobutanes (Fig. 3) in a [2+2] cycloaddition. This reaction was shown, in one case, to be acid‐catalyzed (Fig. 4) and, in another case, to be thermally reversible (Fig. 5). Treatment of benzene solutions of the isolated amino‐nitro‐cyclobutanes with H2O led to mixtures of 4‐nitro aldehydes (the products 7 of overall Michael addition) and enamines 13 derived thereof (Figs. 6–9). From the results obtained with specific examples, the following tentative, general conclusions are drawn for the mechanism of the reaction (Schemes 2 and 3): enamine and cyclobutane formation are fast, as compared to product formation; the zwitterionic primary product 5 of C,C‐bond formation is in equilibrium with the product of its collapse (the cyclobutane) and with its precursors (enamine and nitro alkene); when protonated at its nitronate anion moiety the zwitterion gives rise to an iminium ion 6, which is hydrolyzed to the desired nitro aldehyde 7 or deprotonated to an enamine 13. While the enantioselectivity of the reaction is generally very high (>97% ee), the diastereoselectivity depends upon the conditions, under which the reaction is carried out (Fig. 10 and Tables 1–5). Various acid‐catalyzed steps have been identified. The cyclobutanes 12 may be considered an off‐cycle ‘reservoir’ of catalyst, and the zwitterions 5 the ‘key players’ of the process (bottom part of Scheme 2 and Scheme 3).

Synthesis of 4-Hydroxy-4H-chromenes by Reaction of Salicylic Aldehydes with Alkynals Catalyzed by Silyl Prolinol Ethers

We report an oxa-Michael/Baylis-Hillman tandem reaction between salicylaldehydes and alk-2-ynals activated by silyl prolinol ethers, affording 2,3-disubstituted 4-hydroxy-4H-chromenes in good yields and enantiomeric ratios (up to 98:2).