Iridium complex-catalyzed highly enantio- and diastereoselective [2+2+2] cycloaddition for the synthesis of axially chiral teraryl compounds

An asymmetric [2+2+2] cycloaddition of an alpha,omega-diyne, possessing ortho-substituted aryl groups on its terminus, and a monoalkyne with oxygen functionalities gave various axially chiral teraryl compounds. The coupling proceeded with extremely high enantio- (>99.5% ee) and diastereoselectivities (dl/meso = >95/5) when catalyzed by an iridium-chiral phosphine complex. As the products were readily transformed into diol compounds by deprotection without racemization, the present procedure provides access to a new chiral pool of diol compounds with C2 symmetry.     

Regioselective acylation of aminoresorcinarenes

The acid catalyzed hydrolytic cleavage of the oxazine rings in the readily available tetraoxazine derivatives of resorcinarenes results in tetraaminoresorcinarenes. A similar process applied to C₂-symmetrical bisoxazine resorcinarene tetratosylates affords C_2v-symmetrical resorcinarenediamines. The mild acylation of these resorcinareneamines with BOC-anhydride or para-nitrophenyl ester proceeds selectively at the nitrogen atoms without affecting the hydroxyl groups. Most of the resulting resorcinareneamides are thus obtained in preparative yields and can be easily purified by simple crystallizations. In the crystalline state the compounds obtained are found to bind chloride anions through hydrogen bonds and electrostatic interactions and to display a chiral arrangement of hydrogen bonded functional groups at the wide rim of the macrocycle.     

Enantioselective intramolecular [2+2+2] cycloaddition of triynes for the synthesis of atropisomeric chiral ortho-diarylbenzene derivatives

An iridium-chiral diphosphine complex was used to catalyze an enantioselective [2+2+2] cycloaddition of oxygen- and nitrogen-bridged triynes with ortho-substituted aryl groups on their termini. ortho-Diarylbenzenes with atropisomeric chiralities were obtained in high yield and enantiomeric excess.     

Asymmetric synthesis of α-substituted alkylphosphonates based on symmetrical dialkyl phosphites

Chiral C₂-symmetrical dialkyl phosphites and C₃-symmetrical trialkyl phosphites, derived from (−)-borneol, (−)-menthol, and 1,2∶5,6-di-O-isopropylidene-α-d-glucofuranose, were studied as the starting reagents for the preparation of chiral organophosphorus compounds. The reactions of C₂-symmetrical dialkyl phosphites and C₃-symmetrical trialkyl phosphites with aldehydes and amines or aldehydes are accompanied by asymmetrical induction at the α-carbon atom to yield optically active α-aminoalkylphosphanates or α-hydroxyalkylphosphonates, respectively. The stereoselectivity of the reaction depends on the structure of the starting compounds and the reaction conditions. Translated fromIzvestiya Akademii, Nauk, Seriya Khimicheskaya, No. 8, pp. 1588–1593, August, 1999.     

Efficient One-Step Synthesis of C 3-Symmetrical Benzenoid Compounds Mediated by SOCl2/EtOH

Abstract

An efficient one-step synthesis of branched functionalized benzenoid compounds from aryl methyl ketones mediated by SOCl₂/EtOH is described; some novel C ₃-symmetrical molecules were prepared with satisfactory yields. The method enjoys short reaction time and simple operation, and avoids use of organometallic reagents.     

Addition of lithium ethyl fluoroacetate to cis and trans α,β-epoxyaldehydes. Access to C2 fluorinated butyrolactones

The aldolisation reaction of lithium ethyl fluoroacetate with cis and trans α,β-epoxyaldehydes in their racemic forms proceeds with good C₃-OH diastereoselectivity and much less at the C₂-F carbon atom. A two-step reaction on the major aldol compounds (iodination, lactonisation) led to racemic functionalised C₂ fluorinated lactones, possessing a C₂/C₃cis relationship between the fluorine and hydroxyl groups.     

Highly enantioselective construction of a chiral spirocyclic structure by the [2 + 2 + 2] cycloaddition of diynes and exo-methylene cyclic compounds

The enantioselective [2 + 2 + 2] cycloaddition of 1,6-diynes with alpha-methylene lactones and cyclic ketones gave various chiral spirocyclic compounds. The reaction proceeded with high enantioselectivity when the rhodium-xylylBINAP complex was used as a chiral catalyst. Not only exo-methylene cyclic compounds but also exo-methylene acyclic compounds could be used as coupling partners for diynes. The present protocol provides access to a new chiral library possessing a quaternary carbon center, including a spirocyclic system.     

Asymmetric synthesis of dimethyl-1,2-bis-(diphenylphosphino)-1,2-ethanedicarboxylate by means of a chiral palladium template promoted hydrophosphination reaction

An optically pure C₂-symmetrical diphosphine ligand containing two ester functional groups at the two chiral carbon stereogenic centres was prepared efficiently from the asymmetric hydrophosphination reaction between diphenylphosphine and dimethyl acetylenedicarboxylate in the presence of an organopalladium(II) complex derived from (S)-N,N-dimethyl-1-(1-naphthyl)ethylamine.     

Self-assembly via ionic interactions of calix[6]arene-based receptors displaying remarkable host-guest properties toward neutral guests

The association of a C_3v-symmetrical calix[6]tris-amine with different concave tris-carboxylic acids of various degrees of flexibility has been explored by ¹H NMR spectroscopy. In all cases, self-assembled structures directed by the selective inclusion of a neutral guest molecule were obtained, the more preorganized being stable in protic solvents. With a rigid C₃-symmetrical cap, chiral guest recognition in the calixarene cavity resulted. A large tris-acidic partner gave a unique molecular ditopic receptor that is able to simultaneously accommodate two neutral molecules in two distinct hydrophobic cavities with different binding processes.     

Diastereoselective Aldol Reaction with an Acetate Enolate: 2,6-Bis(2-isopropylphenyl)-3,5-dimethylphenol as an Extremely Effective Chiral Auxiliary

A C ₂ -symmetrical phenol was used as a chiral auxiliary in the asymmetric aldol reaction of chiral acetates with various aldehydes [Eq. (a)]. The reaction proceeds readily under mild conditions to provide aldol adducts with high enantioselectivity. LDA=lithium diisopropylamide.     

On the Mechanisms of Enantioselective Reactions Using α,α,α′,α′ -Tetraaryl-1,3-dioxolane-4,5-dimethanol(TADDOL)-Derived Titanates: Differences between C2- and C1-symmetrical TADDOLs – facts,implications and generalizations

The titanates derived from α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOLs, prepared from tartrate) act as catalysts for enantioselective additions of dialkylzinc compounds to aldehydes. For the standard reaction chosen for this investigation of the mechanism, the addition of diethylzinc to benzaldehyde, there is very little change of selectivity with different aryl substituents on the TADDOLate ligands (Tables 2–4, examples). With 0.02 to 0.2 equiv. of the chiral titanates, selectivities above 90% are observed only in the presence of excess tetraisopropyl titanate! According to NMR measurements (Fig. 2), the chiral bicyclic titanate and the achiral titanate do not react to give new species under these conditions. From experiments with different stoichiometries of the components, and with different achiral or chiral OR groups on the Ti-atom of the seven-membered ring titanate, it is concluded (i) that a single chiral titanate is involved in the product-forming step, (ii) that the bulky TADDOLate ligand renders the Ti-center catalytically more active than that of (i-PrO)₄Ti, due to fast dynamics of ligand exchange on the sterically hindered Ti-center (Table 5, Fig. 3), and (iii) that the role of excess (i-PrO)₄Ti is to remove – by ligand exchange – the product alkoxides (R*O) from the catalytically active Ti-center (Scheme 4, Table 6). Three new crystal structures of TADDOL derivatives (two clathrates with secondary amines, and a dimethyl ether) have been determined by X-ray diffraction (Figs. 5–7), and are compared with those previously reported. The distances between the C(aryl)₂O oxygen atoms in the C₂- and C₁-symmetrical structures vary from 2.58 to 2.94 Å, depending upon the conformation of their dioxolane rings and the presence or absence of an intramolecular H-bond (Fig. 8). A single-crystal X-ray structure of a spiro-titanate, with two TADDOLate ligands on the Ti-atom, is described (Fig. 9); it contains six different seven-membered titanate-ring conformations in the asymmetric unit (Fig. 10), which suggests a highly flexible solution structure. The structures of Ti TADDOLate complexes are compared with those of C₂-symmetrical Ru, Rh, and Pd disphosphine chelates (Table 7). A common topological model is presented for all nucleophilic additions to aldehydes involving Ti TADDOLates (Si attack with (R,R)-derivatives, relative topicity unlike; Fig. 11). Possible structures of complexes containing bidentate substrates for Ti TADDOLate-mediated ene reactions and cycloadditions are proposed (Fig. 12). A simple six-membered ring chair-type arrangement of the atoms involved can be used to describe the result of TADDOLate-mediated nucleophilic additions to aldehydes and ketones, with Ti, Zr, Mg, or Al bearing the chiral ligand (Scheme 6). A proposal is also made for the geometry of the intermediate responsible for enantioselective hydrogenation of N-(acetylamino)cinnamate catalyzed by Rh complexes containing C₂-symmetrical diphosphines (Fig. 13).     

Synthesis of novel chiral ‘salen-type’ ferrocenyl ligands

Two novel chiral C₂-symmetrical ferrocenyl ‘salen-type’ ligands were prepared via reaction of suitable ferrocenyldiamines with 3,5-di-tert-butylsalicylaldehyde and tested in the asymmetric epoxidation of unfunctionalized alkenes. Although the asymmetric induction was quite low, an unusually high trans/cis-epoxide ratio and high reactivity of a trans-alkene substrate were observed.     

Synthesis of C2-symmetrical chiral diamines: diastereoselective addition to bis(1,3-oxazolidinyl)alkanes with Grignard reagents

Asymmetric syntheses of C₂-symmetrical chiral 1,4- and 1,5-diamines with stereogenic centers adjacent to the nitrogen atom have been accomplished. Chiral diamines were prepared by diastereoselective alkylations of bisoxazolidine, which was derived from (R)-phenylglycinol. Methyl and phenyl Grignard reagents were employed as alkylating reagents. In addition, tertiary chiral diamines were readily converted to primary diamines in high yield.     

Stereoselective synthesis of 2-C-methylene glycosides and disaccharides via direct allylic substitution of hydroxy group in benzylated glycals

InCl₃ efficiently catalyzes allylic substitution of the hydroxy group of 2-C-hydroxymethyl glycals to afford a diversity of 2-C-methylene alkyl and aryl glycosides as well as disaccharides in high yields. This protocol surpasses the existing methods for the synthesis of 2-C-methylene glycosides as it obviates the need for functionalizing the allylic hydroxy group of glycals. The interest of this methodology relies on the extremely mild conditions required even with a free hydroxyl group at the allylic position of the glycals and that too only with a catalytic amount of InCl₃. The reaction is fast (30 min.), stereoselective and is compatible with a variety of oxygenated nucleophiles including those possessing acid-labile groups. A mechanistic investigation on the direct formation of an α,α-(1→1)linked disaccharide derivative from 2-C-hydroxymethyl galactal reveals that the reaction proceeds through a domino Ferrier rearrangement followed by a facile 1,3-alkoxy migration.     

Facile and efficient synthesis of C2-symmetrical 1,3,5-triazine polycarboxylate ligands under microwave irradiation

A rapid and efficient method for preparation of C₂-symmetrical 1,3,5-triazine polycarboxylate ligands was developed. The reactions included either selective mono- or di-substitution of 2,4,6-trichloro-1,3,5-triazine with various nucleophiles containing carboxyl group(s), followed by nucleophilic displacement of the remained chloride(s) in aqueous media under microwave irradiation. Novel C₂-symmetrical tripodal ligands were afforded in good yields and purities under short reaction time with simple work-up, which are potentially useful as structural directing units in metal-organic frameworks.     

A new C2-symmetric azolium compound for Cu-catalyzed asymmetric conjugate addition of R2Zn to cyclic enone

A new chiral N-heterocyclic carbene (NHC) ligand was designed. Thus, an efficient synthetic route to C₂-symmetric bis(hydroxyamide)-functionalized benzimidazolium salts from chiral β-amino alcohols was developed. The combination of Cu(OTf)₂ and the chiral azolium compound efficiently promoted the conjugate addition reaction of cyclic enone with dialkylzinc to give the corresponding adduct in good yield. Among a series of chiral NHC proligands, the functionalized benzimidazolium chloride possessing a tert-butyl group as a stereodirecting group was found to be the best choice of ligand. Under optimized reaction conditions, an excellent enantioselectivity (96% ee) was realized by allowing 2-cyclohepten-1-one to react with Bu₂Zn at room temperature.     

Development of chiral dinitrones as modular Lewis base catalysts: asymmetric allylation of aldehydes with allyltrichlorosilanes

Chiral dinitrones were synthesized by the condensation of a C₂-symmetrical chiral dihydroxylamine with various aldehydes. The electronic and steric properties of the dinitrones can be modified by changing the aldehyde component. The activity of dinitrones as Lewis base catalysts was examined for the asymmetric allylation of aldehydes with allyltrichlorosilanes. Using DMPU as an additive in chloroform, the reaction proceeded at room temperature to afford allylated products in good yields and good enantioselectivities.     

Use of chiral Ti(IV) complexes in the cycloaddition of C,N-diphenylnitrone to tert-butyl vinyl ether

The 1,3-dipolar cycloaddition of C,N-diphenylnitrone to tert-butyl vinyl ether in the presence of several chiral Ti(IV) species which incorporate different bidentate C₂-symmetrical ligands has been investigated. Several complexes have shown very efficient catalytic activity. The endo/exo selectivity of the process can be dramatically reversed in relation to the uncatalysed reaction, but low enantioselectivities up to 41% ee are found.     

Synthesis of α,β-unsaturated dioxanes, dioxolanes and dioxepanes by trans-acetalisation of dimethylacetals with meso or C2-symmetrical 1,2-, 1,3- and 1,4-diols

Several o-dibenzylic diols were prepared reacting organometallics with o-phthalaldehyde at room temperature in ether. The identity of the meso and C₂-symmetrical (d,l) isomers as well as their ratio were determined by chiral gas chromatography. The meso and C₂ (racemic) stereoisomeric diols were easily separated by flash chromatography on silica gel. A set of 18 α,β-unsaturated acetals were then prepared reacting those, as well as commercially available 1,2, 1,3 and 1,4 diols, with the corresponding methylacetals in acidic medium. A trans-acetalisation procedure adapted to the cases of fragile allylic alcohols or unfavorable 1,6 diols-derived dioxonanes based on a Dean-Stark trapping of methanol was also employed.