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.     

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.     

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.     

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 .     

Total Synthesis with a Chirogenic Opening Move Demonstrated on Steroids with Estrane or 18a-Homoestrane Skeleton

A concept of first choice for the synthesis of the title compounds had been proposed by Dane in the late 1930s. It was soon turned down, because the opening move–a chirogenic Diels-Alder reaction – did not work. With Lewis acids as mediators, however, a successful start has been achieved now. With Ti complexes of chelating ligands (Seebach's TADDOLs (= α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanols)), enantioselective formation of the desired adducts does occur. Efficient total syntheses of 2 and 3a have been accomplished.     

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.     

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).     

Enantioselective 1,4-Addition of Aliphatic Grignard Reagents to Enones Catalyzed by Readily Available Copper(I) thiolates derived from TADDOL. Preliminary communication

Two simple thiols derived from the parent TADDOL, α,α,α′,α′ tetraphenyl-2,2-dimethyl-1,3-clioxolan-4,5-dimethanol, are used to prepare Cu¹ complexes C and D to catalyze (0.05 equiv.) 1,4-additions of Grignard reagents RMgCl to cyclic enones with enantioselectivities which are comparable to or better than previously reported (enantiomer ratios up to 92:8).     

Enzymatic synthesis of novel quercetin sialyllactoside derivatives

Quercetin and its derivatives are important flavonols that show diverse biological activity, such as antioxidant, anticarcinogenic, anti-inflammatory, and antiviral activities. Adding different substituents to quercetin may change the biochemical activity and bioavailability of molecules, when compared to the aglycone. Here, we have synthesised two novel derivatives of quercetin, quercetin-3-O-β-d-glucopyranosyl, 4′′-O-d-galactopyranosyl 3′′′-O-α-N-acetyl neuraminic acid i.e. 3′-sialyllactosyl quercetin (3′SL-Q) and quercetin-3-O-β-d-glucopyranosyl, 4′′-O-β-d-galactopyranosyl 6′′′-O-α-N-acetyl neuraminic acid i.e. 6′-sialyllactosyl quercetin (6′SL-Q) with the use of glycosyltransferases and sialyltransferases enzymes. These derivatives of quercetin were characterised by high-resolution quadrupole-time-of-flight electrospray ionisation mass spectrometry (HR-QTOF-ESI/MS) and ¹H and ¹³C nuclear magnetic resonance (NMR) analyses.     

Synthetic Studies on Sialoglycoconjugates 60: α-Stereocontrolled,Glycoside Synthesis of Trimeric Sialic Acid with Galactose and Lactose Derivatives

Abstract

α-Stereocontrolled, glycoside synthesis of trimeric sialic acid is described toward a systematic approach to the synthesis of sialoglycoconjugates containing an α-sialyl-(2→8)-α-sialyl-(2→8)-sialic acid unit α-glycosidically linked to O-3 of a galactose residue in their oligosaccharide chains. Glycosylation of 2-(trimethylsilyl)ethyl 6-O-benzoyl-β-d-galactopyranoside (4) or 2-(trimethylsilyl)ethyl 2,3,6,2′,6′-penta-O-benzyl-β-lactoside (5), with methyl [phenyl 5-acetamido-8-O-[5-acetamido-8-O-(5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-d-glycero-α-d-galacto-2-nonulopyranosylono-1”, 9′-lactone)-4,7-di-O-acetyl-3,5-dideoxy-d-glycero-α-d-galacto-2-nonulopyranosylono-1′, 9-lactone]-4,7-di-O-acetyl-3,5-dideoxy-2-thio-d-glycero-d-galacto-2-nonulopyranosid]onate (3), using N-iodosuccinimide-trifluoromethanesulfonic acid as a promoter, gave the corresponding α-glycosides 6 and 8, respectively. The glycosyl donor 3 was prepared from trimeric sialic acid by treatment with Amberlite IR-120 (H⁺) resin in methanol, O-acetylation, and subsequent replacement of the anomeric acetoxy group with phenylthio. Compounds 6 and 8 were converted into the per-O-acyl derivatives 7 and 9, respectively.     

Asymmetric PTC C-alkylation mediated by TADDOL—novel route to enantiomerically enriched α-alkyl-α-amino acids

Compound (4R,5R)- or (4S,5S)-2,2-dimethyl-α,α,α′,α′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (TADDOL) was shown to catalyze C-alkylation of aldimine Schiff's bases of alanine esters under phase-transfer catalysis conditions (solid NaOH, toluene, ambient temperature, 10% TADDOL) with the e.e. of the final α-methylphenylalanine or α-allylalanine reaching 82%.     

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

TADDOL (=α,α,α′,α′‐Tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol) and the corresponding dichloride are converted to TADDAMINs (=(4S,5S)‐2,2,N,N′‐tetramethyl‐α,α,α′,α′‐tetraphenyl‐1,3‐dioxolan‐4,5‐dimethanamines) (Scheme 2) and ureas, 12 – 15 , and to TADDOP derivatives with seven‐membered O? P? O ester rings (Schemes 3 and 4). Cl/P‐Replacement via the Michaelis? Arbuzov reaction (Scheme 7) on mono‐ and dichlorides, derived from TADDOL, are described. It was not possible to obtain phosphines with the P‐atom attached to the benzhydrylic C‐atom of the TADDOL skeleton (Schemes 6 and 7). The X‐ray crystal structures (Figs. 1 and 2) of ten of the more than 30 new TADDOL derivatives are discussed. Full experimental details are presented.     

A new and efficient chemoenzymatic route to both enantiomers of α′-acetoxy and α′-hydroxy-α-methoxy cyclic enones

A chemoenzymatic synthesis of both enantiomers of the pharmacologically interesting α′-acetoxy and α′-hydroxy-α-methoxy cyclic enones starting from α-hydroxy cyclic enones is described. Protection of 1,2-diketones, manganese(III) acetate-mediated acetoxylation followed by enzyme-mediated hydrolysis of α′-acetoxy enones gives acetoxy enones 3a–d and hydroxy enones 4a–d with high enantiomeric excesses (up to 99%) and good yields. The transesterification of rac-4b in the presence of DMAP afforded (+)-4b and (−)-3b in high enantiomeric excesses (91–94%) and good chemical yields.     

A Case Study on the Resolution of the 1‐i‐Butyl‐3‐methyl‐3‐phospholene 1‐Oxide via Diastereomeric Complex Formation Using TADDOL Derivatives and via Diastereomeric Coordination Complexes Formed from the Calcium Salts of O,O′‐Diaroyl‐(2R,3R)‐tartaric Acids

The resolution of 1‐i‐butyl‐3‐methyl‐3‐phospholene 1‐oxide was studied applying TADDOL [(−)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane], spiro‐TADDOL [(−)‐(2R,3R)‐α,α,α′,α′‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol], or the acidic and neutral Ca²⁺ salts of (−)‐O,O′‐dibenzoyl‐ and (−)‐O,O′‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid as the resolving agent. The absolute configuration of the P‐asymmetric center was determined by circular dichroism spectroscopy and related quantum chemical calculations. In one instance, the single crystal of the diastereomeric complex incorporating i‐butyl‐3‐phospholene oxide and spiro‐TADDOL was subjected to X‐ray analysis, which suggested a feasible hypothesis for the efficiency of the resolution process under discussion that may be an example for the “solvent‐inhibited” resolution.     

Nitration of dithieno[3,2-b:3′,2′-d]pyridine and dithieno[3,2-b:3′,4′-d]pyridine

Nitration of dithieno[3,2-b:3′,2′-d]pyridine ( 4 ) and dithieno[3,2-b:3′,4′-d]pyridine ( 5 ) has been studied. Nitration of 4 occurred in both positions of the C ring, while 5 was predominantly substituted on the 3,4-fused ring. The structures of the nitro derivatives were proven by extensive use of ¹H and ¹³C nmr spectroscopy.     

Synthesis of optically active 4,4,4-trifluoro-3-{4-(4-methoxyphenyl)phenyl}butanoic acid and its application to chiral dopant for nematic liquid crystals

We synthesized an optically active 4,4,4-trifluoro-3-{4-(4-methoxyphenyl)phenyl}butanoic acid (5^*). New chiral dopants for nematic liquid crystals were derived from (R)-(−)-5^*, and their helical twisting power (HTP) values were measured. Their HTP values were largely influenced by the linkage between the asymmetric frame and the core moiety. The chiral dopant, (R)-(+)-4,4,4-trifluoro-1-(4-hexyloxyphenyl)-3-{4-(4-methoxyphenyl)phenyl}-1-butanone ((R)-(+)-7^*) showed the largest HTP value (−21.7 μm⁻¹).     

Stereoselective synthesis of pyrrolo[2,3-d]pyrimidine α- and β-D-ribonucleosides from anomerically pure D-ribofuranosyl chlorides: Solid-Liquid Phase-Transfer Glycosylation and 15N-NMR Spectra

Solid-liquid phase-transfer glycosylation (KOH, tris[2-(2-methoxyethoxy)ethye]amine ( = TDA-1), MeCN) of pyrrolo[2,3-d]pyrimidines such as 3a and 3b with an equimolar amount of 5-O-[(1,1 -dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribofuranosyl chloride (1) [6] gave the protected β-D -nucleosides 4a and 4b , respectively, stereoselectively (Scheme). The β-D -anomer 2 [6] yielded the corresponding α-D -nucleosides 5a and 5b with traces of the β-D -compounds. The 6-substituted 7-deazapurine nucleosides 6a , 7a , and 8 were converted into tubercidin (10) or its α-D -anomer (11) . Spin-lattice relaxation measurements of anomeric ribonucleosides revealed that T₁ values of H? C(8) in the α-D -series are significantly increased compared to H? C(8) in the β-D -series while the opposite is true for T₁ of H? C(1′). ¹⁵N-NMR data of 6-substituted 7-deazapurine D -ribofuranosides were assigned and compared with those of 2′-deoxy compounds. Furthermore, it was shown that 7-deaza-2′deoxyadenosine ( = 2′-deoxytubercidin; 12 ) is protonated at N(1), whereas the protonation site of 7-deaza-2′-deoxyguanosine ( 20 ) is N(3).     

SYNTHESIS OF SIALYL-α-(2→3)-NEOLACTOTETRAOSE DERIVATIVES MODIFIED AT C-2 OF THE N-ACETYLGLUCOSAMINE RESIDUE: PROBES FOR INVESTIGATION OF ACCEPTOR SPECIFICITY OF HUMAN α-1,3-FUCOSYLTRANSFERASES,FUC-TVII,AND FUC-TVI *

A variety of sialyl-α-(2→3)-neolactotetraose (IV³NeuAcnLcOse₄ or IV³NeuGcnLcOse₄) derivatives (23, 31–37, 58–60) modified at C-2 of the GlcNAc residue have been synthesized. The phthalimido group at C-2 of GlcNAc in 2-(trimethylsilyl)ethyl (3,6-di-O-benzyl-2-deoxy-2-phthalimido-β-d-glucopyranosyl)-(1→3)-(2,4,6-tri-O-benzyl-β-d-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-d-glucopyranoside (5) was systematically converted to a series of acylamino groups, to give the per-O-benzylated trisaccharide acceptors (6–11). On the other hand, modification of the hydroxyl group at C-2 of the terminal Glc residue in 2-(trimethylsilyl)ethyl (4,6-O-benzylidene-β-d-glucopyranosyl)-(1→3)-(2,4,6-tri-O-benzyl-β-d-galactopyranosyl)-(1→4)-2,3,6-tri-O-benzyl-β-d-glucopyranoside (42) gave three different kinds of trisaccharide acceptors containing D-glucose (49), N-acetyl-d-mannosamine (50), and D-mannose (51) instead of the GlcNAc residue. Totally ten trisaccharide acceptors (5–11 and 49–51) were each coupled with sialyl-α-(2→3)-galactose donor 12 to afford the corresponding pentasaccharides (14–21 and 52–54) in good yields, respectively, which were then transformed into the target compounds. Acceptor specificity of the synthetic sialyl-α-(2→3)-neolactotetraose probes for the human α-(1→3)-fucosyltransferases, Fuc-TVII and Fuc-TVI, was examined.     

Synthesis of S-5-pyrrolo[2,3-b]pyridinemethyl and S-5- and S-6-pyrrolo[2,3-d]pyridinemethyl derivatives of 5′-deoxy-5′-thioadenosine

Reaction of 5-dimethylaminomethylpyrrolo[2,3-b]pyridine methiodide or 5-dimethylaminomethylpyrrolo[2,3-d]pyrimidin-4-one methiodide with 5′-deoxy-5′-S-thioacetyl-N⁶-formyl-2′,3′-O-isopropylideneadenosine in ethanolic sodium hydroxide solution, followed by deprotection of the resulting thioether in 80% formic acid, afforded 5′-deoxy-5′-(5-pyrrolo[2,3-b]pyridinemethylthio)adenosine or 5′-deoxy-5′-[5-(pyrrolo[2,3-d]pyrimidin-4-one)methylthio]adenosine, respectively. Similarly, the metiodide salt of the iso-gramine analog, 2-amino-6-dimethylaminomethylpyrrolo[2,3-d]pyrimidin-4-one afforded 5′-deoxy-5′-[6-(2-aminopyrrolo[2,3-d]pyrimidin-4-one)methylthio]adenosine.