Chiral derivatives

The interest in chiral derivatives of pyrazoles is increasing partly due to the demand of chiral ligands in coordination chemistry. Some of these compounds have already been described (111), 

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Inclusions of Other Grown Analogues. A variety of crown analogues and hybrid modifications (24—28) with other topological features (lariat ethers (31,32), octopus molecules (33), spherands (eg, (12) (34), torands (35)) including chiral derivatives (36) have been prepared and demonstrated to show particular inclusion properties such as chiroselective inclusion (Fig. 4) (37) or formation of extremely stable complexes (K ">(LR) for (12)... 

There are a number of important kinds of stereogenic centers besides asymmetric carbon atoms. One example is furnished by sulfoxides with nonidentical substituents on sulfur. Sulfoxides are pyramidal and maintain dieir configuration at room temperature. Unsymmetrical sulfoxides are therefore chiral and exist as enantiomers. Sulfonium salts with three nonidentical ligands are also chiral as a result of their pyramidal shape. Some examples of chiral derivatives of sulfur are given in Scheme 2.1. 

The use of chiral ketones for the protection of diols serves two purposes first, diol protection is accomplished, and second, symmetrical intermediates are converted to chiral derivatives that can be elaborated further, so that when the diol is deprotected, the molecule retains chirality. ... 

Incorporation of chiral units into polymers generates optically active polymers.27 Two types of optically active polymers could be obtained according to where the chiral units reside optically active polymers with chirality derived from chiral side chains and optically active polymers with chirality derived from tire chiral main chain. The circular dichroism (CD) measurement of 32, an optically active polymer with chiral side chains, showed that the chiral substituents have induced main-chain chirality. The induced main-chain chirality disappeared at higher temperature and appeared upon cooling. This type of chiral conjugated polymer is potentially useful in reversing optical recording28 ... 

Alternative routes to -amino acids have also been explored and involve, stereoselective alkylation of chiral derivatives of y9-alanine [136-140], Curtius rearrangement of enantiomerically pure and regioselectively protected substituted-succinic acids [134, 141, 142] (the approach is also suitable for the synthesis of y9 -amino acids [143]), or the formation of chiral isoxazolidinone intermediates [144]. 

Wurz RP, Lee EC, Ruble JC, Fu GC (2007) Synthesis and resolution of planar-chiral derivatives of 4-(dimethylamino)pyridine. Adv Synth Catal 349 2345-2352... 

Hodous BL, Fu GC (2002) Enantioselective addition of amines to ketenes catalyzed by a planar-chiral derivative of PPY possible intervention of chiral Bronsted-acid catalysis. J Am Chem Soc 124 10006-10007... 

Ruble JC, Tweddell J, Fu GC (1998) Kinetic resolution of arylalkylcarbinols catalyzed by a planar-chiral derivative of DMAP a new benchmark for nonenzymatic acylation. J Org Chem 63 2794-2795... 

Ruble JC, Fu GC (1998) Enantioselective construction of quaternary stereocenters rearrangements of 0-acylated azlactones catalyzed by a planar-chiral derivative of 4-(pyrrolidino) pyridine. J Am Chem Soc 120 11532-11533... 

Bappert E, Mueller P, Fu GC (2006) Asymmetric [3 -i- 2] annulations catalyzed by a planar-chiral derivative of DMAP. Chem Commun 2604—2606... 

Subsequently, Paquette and Johnson used LAH reductions to convert strained thietane or thiolane derivatives to their respective sulphides, generally in good yields. Whitney and Cram described the LAH reduction of a chiral derivative of benzothiophene sulphone, as outlined in equation (24). The authors also noted the formation of hydrogen gas and suggested that their results were consistent with those of Bordwell as outlined in equation (22), namely that reduction takes place by the formation of an aluminium oxide and hydrogen gas. In this case, the reduction clearly cannot involve the formation of an a-sulphonyl carbanion and it is unlikely that any C—S bond cleavage and reformation could have occurred. 

Scheme 6.7 shows some other examples of enantioselective catalysts. Entry 1 illustrates the use of a Co(III) complex, with the chirality derived from the diamine ligand. Entry 2 is a silver-catalyzed cycloaddition involving generation of an azome-thine ylide. The ferrocenylphosphine groups provide a chiral environment by coordination of the catalytic Ag+ ion. Entries 3 and 4 show typical Lewis acid catalysts in reactions in which nitrones are the electrophilic component. 

The procedure described has advantages over previously published methods. The starting material is easily obtained on a large scale at low cost. The ozonolysis can be conducted even on a large scale (150 g) and the workup is simple since the benzoic acid that is also formed can be removed by distillation, chromatography, or crystallization. The method is general and can be applied to different esters including chiral derivatives such as dimenthyl mesoxalate (see Table). 

Viewed in a much broader context, C-aldopentofuranosyl derivatives may also be regarded as highly functionalized, chiral derivatives of substituted tetrahydrofuran. As such, they may be useful intermediates in the synthesis of a variety of compounds that contain a chiral, substituted tetrahydrofuran ring. 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

Figure 6.8 Phthalocyanine 63 self-assembles in chloroform to give bundles of micrometer length fibers. Single fibers have diameter of 50 A (highlighted between arrows) and can be envisaged as nanowires (top left). Chiral derivative 64 forms left-handed super helices (top right) due to chirality within side chains. This chiral expression can be turned-off by addition of K+ ions, which bind within the crown-ether part of the molecule, forcing the phthalocyanines to be stacked directly on top of each other, resulting in straight wires (bottom left).

Hydrogenation is not limited to the use of (EBTHI)MX2-type catalysts. In polymerization, linked amido-cyclopentadienyl ligands have emerged as very important systems, and the corresponding chiral derivatives have been prepared (Scheme 6.9) [113-116]. Nonetheless, whilst high TON can be achieved (500-1000), the ee-values are quite low (<25%). 

In this reaction, complex 35 has to be regarded as an intermediate, since a direct conversion of 35 into 42 is also possible. Further functionalizations of these complexes with simple reagents such as hydrogen chloride, bromine, or dihydrogen afford the novel and easily applicable chiral derivatives 43—46 [34],... 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

Tolman and co-workers (67) investigated a series of pyrazolyl-derived ligands for this reaction. Initial investigations centered on the use of tris(pyrazolyl) phosphine oxide (95) as a ligand with chirality derived from camphor. Diastereoselectivities with ethyl diazoacetate are poor, slightly favoring the cis isomer, and enantioselectivities are modest, Eq. 50. The BHT esters greatly increase the diastereoselectivity of this process (96 4) at the expense of enantioselectivity (10% ee for trans isomer). 

It is expedient in the case of chiral derivatives of [2.2]paracyclophane to number the atoms independently of absolute configuration and in such a way that substituents have the lowest possible numbers. Absolute configuration is then indicated by adding the prefix R or S. Cf. 

In 1966 Landor and co-workers reported the preparation of chiral derivatives of LAH by its reaction with monosaccharide derivatives (46,61). These studies have been reviewed by Inch (62). Landor and co-workers planned to construct... 

In the fourth and final chapter, Howard Haubenstock discusses asymmetric reduction of organic molecules. Within this general topic of wide and continuing interest, Haubenstock s chapter deals with chiral derivatives of lithium aluminum hydride, their preparation from suitable amino or hydroxy compounds, and their use in reducing carbonyl groups. Related reactions of the Meerwein-Ponndorf-Verley type or involving tri-alkylaluminum reagents are also presented. 

Ondansetron (17) is a racemic compound not easy to resolve by chemical means because the carbonyl function is poorly reactive so it is difficult to form chiral derivatives. However, a resolution was achieved by the classical method of forming diastereomeric salts with an optically active acid and then separating the salts by recrystallisation. A number of acids were tried, but only the salts prepared from (-f)- and (—)-di-p-toluoyltartaric acid could be separated in this way. Each isomer was obtained in greater than 95 %ee. The absolute stereochemistry of the isomer from the (-E)-acid was determined by X-ray crystallography (Williams, D., personal communication) and shown to possess the 5-configuration (18). 

Chiral butyrolactones of type 27 and 28 have substantial value in asymmetric synthesis because they contain readily differentiable difunctional group relationships e.g. 1,5-di-carboxylic acid, 1,4-hydroxy carboxylic acid, 1,6-hydroxy-carboxylic acid, 1,6-diol etc.) that would be difficult to assemble by existing asymmetric condensation and pericyclic processes. Applications of these chiral derivatives of glutaric acid to syntheses of indole, indoline and quinolinone alkaloids are illustrated in Schemes 16-18. 

In order to obtain stereoselective formation of the chiral centers C-3, C-7, and C-14, we explored the use of chiral derivatives of our indoloaze-pine 153. Earlier, we had already found that the A(-benzylindoloazepine ester 215 rearranged on heating to an a-methylene lactam 216, indicating the possibility of thermal generation of an intermediate secondary amine indoloacrylate 217. It was also found that this intermediate could be trapped with a variety of aldehydes. Thus, D-seco D-E-trans vincadiffor-mine congeners (218) could be obtained by condensation of the indoloaze-pine 215 with aldehydes at 100°C (Scheme 54) (132). Consequently, introduction of a chiral substituent onto N of the indoloazepine 153 prior to condensation with our 4-ethyl-4,5-dihydroxypentanal acetonides 186 and 187 appeared to be an option for chiral induction in the formation of cen-... 

Gmbbs has described a chiral ruthenium-based catalyst and has illustrated its application to enantioselective desymmetrization. The catalyst is a derivative of Grubbs second-generation dihydroimidazolinylidene-containing catalyst with the chirality derived from diphenylethanediamine in the carbene backbone. Substrate 90 undergoes ringclosing metathesis in 90% ee on treatment with this catalyst and Nal ... 

In addition to the planar chiral ferrocenyl catalysts 15-18, 24 developed by Fu, a number of other chiral derivatives of 4-DMAP and 4-PPY [4, 47, 48] have been explored by other groups as organocatalysts for KR of ec-alcohols. Contributions have been made by the groups of Vedejs [104, 105, 110, 111], Fuji and Kawabata... 

In 2004, Birman and coworkers set out to develop an easily accessible and highly effective acylation catalyst based on the 2,3-dihydroimidazo[l,2-a]-pyridine (DHIP) core. The first chiral derivative to be prepared and tested was (R)-2-phenyl-2,3-dihydroimidazo[l,2-fl]-pyridine 44 (H-PIP) [152]. Derived from R)-2-phenylglycinol, this catalyst afforded the KR of ( )-phenylethylcarbinol in 49% ee at 21% conversion s = 3.3). In order to improve the reactivity of the catalyst, the authors decided to introduce an electron-withdrawing substituent on the pyridine ring that would increase the electrophilicity of the acylated intermediate. Hence, three new derivatives (Br-PIP, NO -PIP and CF3-PIP) were synthesised and tested under rigorously identical conditions [152]. One of these easily accessible compounds, 2-phenyl-6-trifluoromethyl-dihydroimidazo[l,2-a]pyridine (45, abbreviated as CF3-PIP), proved to be particularly effective as, when combined with (EtC0)20 and iPr NEt, it resolved a variety of aryl alkyl iec-alcohols with good to excellent selectivities s = 26-85) (Table 7) [152]. 

The synthesis of 9-(l,4-dihydroxybut-2-oxy)purines commenced with 2-butene-l,4-diol (1004) and via 1005 to 1006, which upon reaction with 1007 gave 1011 and then, upon hydrolysis, the racemic alkoxyamine 1012. The chiral derivatives commenced with the enantiomers of malic acid (1009) through 1010 to 1008, as shown in the scheme. Treatment of 1012 with 996 and further transformations followed almost the same sequence as before to give 1013. 

Reduction of 166 with NaBH4/CeCl3 in aqueous MeOH afforded the protected, chiral derivative 169 of Conduritol-D in 73 % yield. Conduritol-D (170) was formed nearly quantitatively upon acid hydrolysis of 169. Treatment with Ac20/pyridine gave the crystalline tetracetate 171. Reduction of 165 with diisobutylaluminium hydride (DIBAL) in toluene (-80 °C, 6 h) gave 172, another chiral derivative of Conduritol-D, in 97 % yield. Alternatively, 167 was reduced with LiAlH4 (THF, -90 °C, 6 h) into 173 (95 %). Deprotection of 167 with tetrabutylammonium fluoride... 

Chirality derived from the readily accessible a-amino acids has been incorporated into the side chains of aza and diaza macrocyclic polyethers. A number of procedures suitable for peptide synthesis have proved (178) to be unsuitable for acylating the relatively unreactive secondary amine groups of aza crown ethers. Eventually, it was discovered that mixed anhydrides of diphenylphos-phinic acid and alkoxycarbonyl-L-alanine derivatives do yield amides, which can be reduced to the corresponding amines, e.g., l-172. By contrast, the corresponding bisamides of diaza-15-crown-S derivatives could not be reduced and so an alternative approach, involving the use of chiral A-chloroacetamido alcohols derived from a-amino acids, has been employed (178) in the synthesis of chiral receptors, such as ll-173 to ll-175, based on this constitution. 

Directed ortho-metalation does not always occur with oxazoline compounds, as was shown by the chiral derivative 185 where competitive chelation of the n-butyllithium with the methoxy group prevented it from approaching close enough to abstract a proton from the benzene ring... 

Chiral derivatives of hemiacetal from fluoral have been prepared by adding an alcohol to fluoral in the presence of (l )-BlNOL— Ti(0—iPr)2 or by HPLC resolution of the racemate. The displacement of the sulfonate moiety from the tosyl derivative, by an alkyl lithium aluminate, affords the trifluoromethyl ether with inversion of configuration and an excellent chirality transfer (Figure 2.49). ° ... 

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