Hydrogen-Bond Structure and Dynamics of TADDOL Asymmetric Organocatalysts Correlate with Catalytic Activity

The catalytic efficiency of diol-based organocatalysts has been shown to strongly depend on the diols molecular structure including hydrogen-bonding, yet, the underlying molecular-level origins have remained elusive. Herein a study on the inter- and intramolecular hydrogen-bonding of two isomeric diol-based catalysts (TADDOLs) in solution is presented: 1-Naphthyl substituted TADDOL (1nTADDOL), which exhibits high catalytic efficiency, and 2-naphthyl substituted TADDOL (2nTADDOL), which is a poor catalyst. Using nuclear magnetic resonance and infrared spectroscopy, comparable hydrogen-bond strengths for both TADDOLs in solution were found, however, significantly slower bonding dynamics for 1nTADDOL. In aromatic solvents, 1nTADDOL forms less, but longer-lived, intermolecular OH⋅⋅⋅π bonds to solvent molecules, as compared to 2nTADDOL. Thus, rather than previously suggested differences in intermolecular hydrogen-bonding strengths, the results suggest that the hydrogen-bonding kinetics and entropies differ for both TADDOLs, which also explains their vastly different catalytic activities.     

TADDOLs, Their Derivatives, and TADDOL Analogues: Versatile Chiral Auxiliaries

TADDOLs, which contain two adjacent diarylhydroxymethyl groups in a trans relationship on a 1,3-dioxolane ring, can be prepared from acetals or ketals of tartrate esters by reaction of the latter with aromatic Grignard reagents. They are extraordinarily versatile chiral auxiliaries. Here, a historical review of the subject is followed by discussion of the preparation of TADDOLs and analogous systems, including TADDOLs with N-, P-, O-, and S-heteroatom ligands appropriate for metals. Crystal structure analysis reveals that the heteroatoms on the diarylmethyl groups are almost always in close proximity to each other, joined together by H-bonds, and predisposed to form chelate complexes in which the metallic centers reside in propeller-like chiral environments. Applications of TADDOL derivatives in enantioselective synthesis extend from utilization as stoichiometric chiral reagents or in Lewis acid mediated reactions, to roles in catalytic hydrogenation and stereoregular metathesis polymerization. Derivatives and complexes based on the following metals have so far been investigated: Li, B, Mg, Al, Si, Cu, Zn, Ce, Ti, Zr, Mo, Rh, Ir, Pd, Pt. The number of stereoselective reactions already accomplished with TADDOLs is correspondingly large. It is also easy to prepare TADDOL derivatives that are readily polymerizable and graftable, and to transform them into immobilized solid-phase catalysts. The result is catalysts, simply or dendritically immobilized in polystyrene or on silica gel and characterized by unexpected stability even after multiple use in titanium TADDOLate mediated reactions. TADDOLs show further unusual characteristics that make them useful for applications in material science and supramolecular chemistry: they are the most effective doping agents known for phase transformations of achiral (nematic) into chiral (cholesteric) liquid crystals. The TADDOL OH group that is not involved in intramolecular H-bonding shows a strong tendency to associate intermolecularly with H-bond acceptors. In the process of crystallization this leads, enantioselectively, to the formation of inclusion compounds that lend themselves to the separation of racemic mixtures not otherwise suited to the classical method of crystallization through diastereomeric salts. The high melting points of TADDOLs even make possible the resolution of racemates by distillation! Host-guest compounds formed between TADDOLs and achiral partners can serve as platforms for enantioselective photoreactions. It seems safe to predict that many more applications will be discovered for the TADDOLs and their derivatives. Supporting information for this article is available on the WWW under http://www.angewandte.com or from the author.     

Dendritic styryl TADDOLs as novel polymer cross-linkers: First application in an enantioselective Et2Zn addition mediated by a polymer-incorporated titanate. Preliminary communication

TADDOLs (α,α,α′,α′,-tetraaryl-1,3-dioxolane-4,5-dimethanols) with dendritic branches attached to the aryl groups and with 8 or 16 peripheral styryl double bonds have been synthesized ( 4 and 5 ). With these compounds, dendritic molecules were employed for the first time as cross-linkers in a polymerization. The resulting polystyrene was loaded with titanate (Ti(OCHMe₂)₄) to generate polymer beads incorporating Ti-TADDOLate centers (Figs. 1 and 2) for enantioselective catalysis (Et₂Zn addition to PhCHO). Compared with conventionally polymer-attached, insoluble Ti-TADDOLates (cf. 3 ), the new materials have a much higher catalytic activity, rather close to that of soluble analogs (Fig. 3).     

Preparation and characterization of TADDOLs immobilized on hydrophobic controlled-pore-glass silica gel and their use in enantioselective heterogeneous catalysis

Highly porous silica gel (controlled-pore glass, CPG, ca. 300 m2 g(-1)) with covalently attached TADDOLs (loading 0.3-0.4 mmol g(-1)) and Me3Si-hydrophobized surface has been prepared: First, mercaptopropyl groups were attached to the silica gel by treatment with (mercaptopropyl)trimethoxysilane; then the SH groups were trityl-protected, and the remaining accessible SiOH groups hydrophobized by silylation (heating with Me3Si-imidazole); after deprotection, the SH groups were used as nucleophiles for benzylation with TADDOLs carrying a 4-bromomethyl-phenyl group in the 2-position of their dioxolane rings; alternatively, the SH groups have been benzylated with the 4-bromomethyl-benzaldehyde acetal of diethyltartrate, and the diarylmethanol moieties of the TADDOLs created on the solid support by addition of excess phenyl, or 1- or 2-naphthyl magnesium bromide. Each step of the immobilizing procedure was carefully monitored and analyzed (Ellman's test, methyl-red test), and resulting materials characterized by electron microscopy, DRIFT spectroscopy (IR), 13C- and 29Si NMR solid-state NMR spectroscopy, and elemental analysis. The immobilized TADDOLs were titanated to give (iPrO)2Ti-, Cl2Ti-, or (TosO)2Ti-TADDOLates which were used for catalyzing the additions of Et2Zn or Bu2Zn to PhCHO and of diphenyl nitrone to 3-crotonoyl-oxazolidinone. The following findings are remarkable: i) The enantioselectivities and conversions of the reactions mediated by the CPG-immobilized Ti-TADDOLates match those observed under standard homogeneous conditions. ii) If and when the rates and/or the enantioselectivities of reactions have dropped after several applications of the same catalyst batch, washing with aqueous HCl/acetone and reloading with titanate leads to full restoration of its performance. iii) There is no detectable loss of the hydrophobizing Me3Si groups after nine acidic washes! iv) There is a seasoning of the catalyst material in the Cl2Ti-TADDOLate-mediated [3+2] cycloaddition of diphenylnitrone: Initially it is necessary to use 0.5 equivalents of the immobilized catalyst to match the performance of the homogeneous catalyst; after three runs the reaction rate, enantio- and diastereoselectivity have dropped considerably; acidic washing after each subsequent run completely restores the performance; after a total of seven runs the amount of catalyst can be reduced to 0.4, 0.3, 0.2, and 0.1 equivalents in the following runs, with identical good results!     

Design, synthesis, and application of tartaric acid derived N-spiro quaternary ammonium salts as chiral phase-transfer catalysts

A novel class of tartaric acid-derived N-spiro quaternary ammonium salts was synthesised starting from known TADDOLs. These compounds were found to catalyse the asymmetric α-alkylation of glycine Schiff bases with high enantioselectivities and in good yields.     

Highly Enantioselective Protonation of the 3,4‐Dihydro‐2‐ methylnaphthalen‐1(2H)‐one Li‐Enolate by TADDOLs

A series of nine TADDOLs (=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanols) 1a – 1i , have been tested as proton sources for the enantioselective protonation of the Li‐enolate of 2‐methyl‐1‐tetralone (=3,4‐dihydro‐2‐methylnaphthalen‐1(2H)‐one). The enolate was generated directly from the ketone (with LiN(i‐Pr)₂ (LDA)/MeLi) or from the enol acetate (with 2 MeLi) or from the silyl enol ether (with MeLi) in CH₂Cl₂ or Et₂O as the solvent (Scheme). The Li‐enolate (associated with LiBr/LDA, or LiBr alone) was combined with 1.5 – 3.0 equiv. of the TADDOL at −78° by addition of the latter or by inverse addition. 2‐Methyl‐1‐tetralone of (S)‐configuration is formed (≤80% yield) with up to 99.5% selectivity if and only if (R,R)‐TADDOLs ( 1d , e , g ) with naphthalen‐1‐yl groups on the diarylmethanol unit are employed (Table). The reactions were carried out on the 0.1‐ to 1.0‐mM scale. The selectivity is subject to non‐linear effects (NLE) when an enantiomerically enriched TADDOL 1d is used (Fig. 1). The performance of TADDOLs bearing naphthalen‐1‐yl groups is discussed in terms of their peculiar structures (Fig. 2).     

On the origin of changes in topicity observed in Diels–Alder reactions catalyzed by Ti–TADDOLates

New C₂ symmetric TADDOLs containing different groups at the 2-position of the dioxolane ring have been prepared. The Ti catalysts derived from these have been studied in the Diels–Alder reaction of cyclopentadiene and (E)-2-butenoyl-1,3-oxazolidin-2-one. Substituents at the C-2 position of the dioxolane ring can play an important role in determining the selectivity as well as the nature of the major isomer. This effect is more important for TADDOLs containing bulky aromatic groups such as 3,5-dimethylphenyl- or 1-naphthyl at the -positions. Experimental evidence supports the hypothesis that π–π interactions between aromatic groups at the C-2 and the ones at the -positions are critical in this respect.     

Structural analysis of sterically hindered 1,4‐diols from the naturally occurring lignan hydroxymatairesinol a quantum chemical study

The structures of TADDOL‐like α‐conidendrin‐based chiral 1,4‐diols (LIGNOLs) have been studied at molecular mechanics, Hartree‐Fock (HF)/6‐31G* and DFT/B3LYP/TZVP level of theory. The molecules included were 1,1‐diphenyl, two diastereomers of 1,1,4‐triphenyl, 1,1,4,4‐tetraphenyl, and 1,1,4,4‐tetramethyl 1,4‐diol. Several conformers of each molecule were studied thorougly also including the entropy contributions. For the triphenyl 1,4‐diols, which can form π ? π interactions between phenyl rings, the DFT optimized structures differed significantly from the HF optimized ones. A property for the most stable structures, in addition to the ability to form π ? π interactions, seemed to be the possibility to have the aliphatic six‐membered ring in a boat conformation. For all of the studied LIGNOLs some conformers were found, where the two OH groups pointed almost to the same direction. By this an intramolecular hydrogen bond can be formed between them. The bridging hydrogen atom falls at the same place as a chelate‐bonded metal ion would be situated, as in the case of the analogous molecules, TADDOLs, but only a few of these molecules would be able to work well as ligands for asymmetric catalysis. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

Preparation and Characterization of New C2‐ and C1‐Symmetric Nitrogen,Oxygen, Phosphorous,and Sulfur Derivatives and Analogs of TADDOL. Part III

A brief overview is presented of the field of organocatalysis using chiral H‐bond donors, chiral Brønsted acids, and chiral counter‐anions (Fig. 1). The role of TADDOLs (=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanols) as H‐bond donors and the importance of an intramolecular H‐bond for acidity enhancement are discussed. Crystal structures of TADDOLs and of their N‐, S‐, and P‐analogs (Figs. 2 and 3) point the way to proposals of mechanistic models for the action of TADDOLs as organocatalysts (Scheme 1). Simple experimental two‐step procedures for the preparation of the hitherto strongest known TADDOL‐derived acids, the bicyclic phosphoric acids ( 2 in Scheme 2) and of a phosphoric‐trifluorosulfonic imide ( 9 in Scheme 4), are disclosed. The mechanism of sulfinamide formation in reactions of TADDAMIN with trifluoro‐sulfonylating reagents is discussed (Scheme 3). pK_a Measurements of TADDOLs and analogs in DMSO (reported in the literature; Fig. 5) and in MeO(CH₂)₂OH/H₂O (described herein; Fig. 6) provide information about further possible applications of this type of compounds as strong chiral Brønsted acids in organocatalysis.     

Experimental and theoretical studies on the hydrogen-bond-promoted enantioselective hetero-Diels-Alder reaction of Danishefsky's diene with benzaldehyde

The enantioselective hetero-Diels-Alder (HDA) reaction of Danishefsky's diene with benzaldehyde has been achieved catalytically by a series of alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL) derivatives through hydrogen-bonding activation, affording 2-phenyl-2,3-dihydro-4H-pyran-4-one after trifluoroacetic acid workup in moderate yield and good enantioselectivity. The alpha,alpha'-aryl substituents in the TADDOL molecules are found to exert a significant impact on both the activity and the enantioselectivity of the catalysis. In combination with the experimental investigations, the mechanism of the present reaction has also been studied theoretically using the ONIOM (B3LYP/6-31G:PM3) method with trans-1,3-dimethoxy-1,3-butadiene as the model for Danishefsky's diene. In agreement with the experimental findings, the calculation results indicate that this TADDOL-catalyzed HDA reaction proceeds via a concerted mechanism through an asynchronous and zwitterionic transition structure (TS). The carbonyl group of benzaldehyde is activated by forming an intermolecular hydrogen bond with one of the hydroxy groups of TADDOL. Meanwhile, the intramolecular hydrogen bond between the two hydroxy groups in TADDOL is found to facilitate the intermolecular hydrogen bonding with benzaldehyde. The sense of asymmetric induction is well-rationalized by the analysis of the relative energies of TADDOL-complexed TSs, while the different stereocontrol capabilities exhibited by TADDOLs in the reaction can be qualitatively established on the basis of the structural features of their corresponding TSs.     

Enantioselective photocycloaddition mediated by chiral Brønsted acids: asymmetric synthesis of the rocaglamides

Enantioselective syntheses of methyl rocaglate and the related natural products rocaglamide and rocaglaol are outlined. The approach involves enantioselective [3 + 2] photocycloaddition promoted by chiral Br?nsted acids (TADDOLs) to afford an aglain precursor followed by a ketol shift/reduction sequence to the rocaglate core.     

Total Syntheses of the Isomeric Aglain Natural Products Foveoglin A and Perviridisin B: Selective Excited‐State Intramolecular Proton‐Transfer Photocycloaddition

Selective excited‐state intramolecular proton‐transfer (ESIPT) photocycloaddition of 3‐hydroxyflavones with trans , trans ‐1,4‐diphenyl‐1,3‐butadiene is described. Using this methodology, total syntheses of the natural products (±)‐foveoglin A and (±)‐perviridisin B were accomplished. Enantioselective ESIPT photocycloaddition using TADDOLs as chiral hydrogen‐bonding additives provided access to (+)‐foveoglin A. Mechanistic studies have revealed the possibility for a photoinduced electron‐transfer (PET) pathway.     

TADDOLs with Unprecedented Helical Twisting Power in Liquid Crystals. Preliminary communication

A large number of TADDOL (α,α,α′, α′-tetraaryl-1,3-dioxolan-4,5-dimethanol) derivatives has been tested as chiral dopants for inducing conversion of nematic to cholesteric phases. With the Merck liquid-crystal materials ZLI-1695 and K15 , it was demonstrated that some TADDOLs have unprecedentedly high helical twisting powers (HTP). Thus, the TADDOL with four 9-phenanthryl α-substituents has a HTP in the achiral mesophase 4-(4-pentylphenyl)benzonitrile of 405 μm^?1 between 24 and 34°. The temperature-dependent HTP measurements have been performed by analyzing Grandjean textures microscopically (Cano method). The structure-dependent HTP of various types of TADDOL dopants is discussed. There are similarities between size and sign of HTP on the one hand, and between degree and relative topicity of enantioselectivity in reactions, on the other hand, as caused by TADDOLs and by 1,1′-binaphthols.     

TADDOLs under closer scrutiny – why bulky substituents make it all different

A systematic investigation of the rotational behavior of aryl substituents in α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOLs) is presented. In the use as chiral ligands for enantioselective metal-catalyzed reactions, a change from phenyl to bulkier substituents, e.g., 1-naphthyl, gives rise to an astounding alteration of the selectivity, The possible existence of preferred rotamers of TADDOLs has so far not been given due attention, which encouraged us to look at the validity of the Knowles model, originally formulated for diaryl substituted bisphosphines. ¹H-NMR Investigations at various temperatures as well as X-ray powder diffraction were employed to study the rotation in the case of tetra(1-naphthyl) TADDOL 1. To support the interpretation of the experimental results, molecular mechanics, semiempirical, and ab initio calculations were performed. For comparison, the energy surface of tetraphenyl TADDOL 2 was calculated as well. Our results lead to the conclusion that for 1 , only one major conformation is present in both solution and solid state, which determines the stereochemical outcome of the catalyzed reactions.     

Thioamides and selenoamides with chirality solely due to hindered rotation about the C–N bond: enantioselective complexation with optically active hosts

Several thioformamides and selenoformamides, with chirality solely due to restricted rotation about the C–N bond, were resolved to enantiomers by inclusion crystallization with optically active diols (TADDOLs). The absolute configuration of the guest molecules was deduced from the X-ray crystal structures of the inclusion complexes. The optical activity of the resolved compounds is manifested by their CD spectra showing relatively strong Cotton effects in the region of thioamide or selenoamide n–π* transition. The optically active thioformamides and selenoformamides are configurationally labile compounds and gradually racemize in solution but are stable in the form of the inclusion complexes. The first-order kinetics of the racemization in solution allowed us to assign the C–N rotation barriers of thioformamides by spectropolarimetric measurements.     

Asymmetric transformation of N-nitrosamines by inclusion crystallization with optically active hosts.

Several N-nitrosopiperidines with chirality solely due to a hindered rotation about the N-N bond were resolved to enantiomers by inclusion crystallization with optically active diols (TADDOLs). The absolute configuration of the guest nitrosamines was deduced from the X-ray crystal structures of the inclusion complexes. The enclathrated nitrosamines were liberated by a competitive complexation of the host diols with piperazine. The optical activity of the resolved nitrosamines is manifested by their CD spectra. A simple chirality rule was proposed for a rationalization of the observed Cotton effect sign corresponding to the n-pi* electronic transition. The optically active nitrosamines are configurationally labile compounds and gradually racemize in solution but they are indefinitely stable in the solid state. The first-order kinetics of the racemization in solution allowed us to assign the N-N rotation barriers by simple polarimetric measurements.     

Polymer- and Dendrimer-Bound Ti-TADDOLates in Catalytic (and Stoichiometric) Enantioselective Reactions: Are pentacoordinate cationic Ti complexes the catalytically active species?

α,α,α′,α′-Tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOLs), containing styryl groups either at C(2) of the heterocyclic ring or in the α-position, were prepared in the usual way ( 18–22, 24, 25 ). These compounds were copolymerized with styrene and divinylbenzene in a suspension, yielding polymers ( 33–40 , Scheme 3) as beads with a rather uniform particle-size distribution (150–45 μm), swellable in common organic solvents. HOCH₂- and BrCH₂-substituted TADDOLs were also prepared and used for attachement to Merrifield resin or to dendritic molecules ( 23, 26–32 ). The TADDOL moieties in these materials are accessible to form Ti (and Al) complexes (Scheme 4) which can be used as polymer- or dendrimer-bound reagents (stoichiometric) or Lewis acids (catalytic). The reactions studied with these new chiral auxiliaries are: enantioselective nucleophilic additions to aldehydes (of R₂Zn and RTi(OCHMe₂)₃; Scheme 5, Table 1) and to ketones (of LiAlH₄, Table 2); enantioselective ring opening of meso-anhydrides (Scheme 6); [4+2] and [3+2] cycloadditions of 3-crotonyl-1,3-oxazolidin-2-one to cyclopentadiene and to (Z)-N-benzylidenephenylamine N-oxide ( → 48, 49 , Scheme 7, Tables 3, 4, and Fig. 5). The enantioselectivities reached with most of the polymer-bound or dendritic TADDOL ligands were comparable or identical to those observed with the soluble analogs. The activity of the polymer-bound Lewis acids was only slightly reduced as compared with that encountered under homogeneous conditions. Multiple use of the beads (up to 10 times), without decreased performance, has been demonstrated (Figs. 3 and 4). The poorer selectivity in the Diels-Alder reaction (Scheme 7a), induced by the polymer-bound Cl₂Ti-TADDOLate as compared to the soluble one, is taken as an opportunity to discuss the mechanism of this Lewis-acid catalysis, and to propose a cationic, trigonal-bipyramidal complex as the catalytically active species (Fig. 6). It is suggested that similar cations may be involved in other Ti-TADDOLate-mediated reactions as well.     

Synthesis of C2-symmetric bisamidines: a new type of chiral metal-free Lewis acid analogue interacting with carbonyl groups

The chiral bisamidine 5 has been prepared in just two steps from malonodinitrile. In the monocationic form this compound adopts a planar conformation with an almost convergent orientation of two N-H groups. Ketones, aldehydes, and nitro compounds are assumed to bind to this strongly polar cleft via hydrogen bonds, resulting in a Lewis-acid-like activation of the carbonyl groups. A broad scope of reactions (Diels-Alder, hetero-Diels-Alder, Friedel-Crafts) can be catalyzed. The observed accelerations surpass the rate effects of neutral hydrogen-bond donors such as thioureas or TADDOLs.     

Synthesis,NMR conformational studies and host–guest behaviour of new (+)-tartaric acid derivatives

A series of dimeric α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanol TADDOLs has been prepared and host–guest interactions of these structures have been characterized using a series of ¹H NMR studies. Enantioselective recognition of the chiral alcohols glycidol and menthol was observed for phenyl and 2-naphthyl derivatives. The influence of steric bulk on the dynamic fluxional behaviour of the TADDOL structures was demonstrated by dynamic NMR.     

α,α,α′,α′-Tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOLs) for Resolutions of Alcohols and as Chiral Solvating Agents in NMR Spectroscopy

The use of α,α,α′,α′ -tetraaryl-1,3-dioxolane-4,5-dimethanols ( = TADDOLs;1) as chiral NMR shift reagents (¹H, ¹³C, ¹⁹F) is described. In many cases, the ratio of enantiomeric alcohols and amines can be determined under standard conditions of measurement (CDCl₃ as solvent, room temperature). The preparation and use of a new type of TADDOL, the tetrakis(dimethylamino) derivative 1d , is described. Menthol, octan-2-ol, and oct-1-yn-3-ol are partially resolved by crystallization of clathrates with 1c and 1d .