Chiral alkyl methanols

Figure 4.28 Plot of CD intensities of poly -hexyl(j -/ -propoxyphenyl)silane (41) aggregates in toluene/series of (S)-primary chiral alkyl alcohols/methanol mixtures at 20°C. [For comparison, CD intensity with (A)-2-butanol is inserted.].

Popova and colleagues47 carried out TLC of oxidation products of 4,4 -dinitrodiphenyl sulphide (the sulphoxide and sulphone) on silica gel + a fluorescent indicator, using hexane-acetone-benzene-methanol(60 36 10 l) as solvent mixture. Morris130 performed GLC and TLC of dimethyl sulphoxide. For the latter, he applied a 6% solution of the sample in methanol to silica gel and developed with methanol-ammonia solution(200 3), visualizing with 2% aqueous Co11 thiocyanate-methanol(2 1). HPLC separations of chiral mixtures of sulphoxides have been carried out. Thus Pirkle and coworkers131-132 reported separations of alkyl 2,4-dinitrophenyl sulphoxides and some others on a silica-gel (Porosil)-bonded chiral fluoroalcoholic stationary phase, with the structure ... 

Stereoselective formation of 3-alkyl-6-methoxy-2,5-piperazine-dione derivatives by the addition of methanol in the presence of NBS to 3-alkyl-6-alkylidene-2,5-piperazinediones was recently reported by Shin et al. 232 The asymmetric induction in this reaction was accomplished by the chiral center of a derivative of the natural proteinogenic chiral amino acid threonine. 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

Several alkyl aryl ketones were reduced with PMHS in the presence of a complex prepared in situ consisting of Sn(0S02CF3)2 and a nitrogen-based ligand Pybox-Ph [5] (substrate Sn ligand= 10 1 1) in methanol at room temperature to give the chiral products in up to 58% ee [38]. 

The industrial production of Crixivan (9 H2S04) took advantage of the chirality of (IS,2R)-aminoindanol to set the two central chiral centers of 9 by an efficient diastereoselective alkylation-epoxidation sequence.17 The lithium enolate of 12 reacted with allyl bromide to give 13 in 94% yield and 96 4 diastereoselective ratio. Treatment of a mixture of olefin 13 and V-chlorosuccinimide in isopropyl acetate-aqueous sodium carbonate with an aqueous solution of sodium iodide led to the desired iodohydrin in 92% yield and 97 3 diastereoselectivity. The resulting compound was converted to the epoxide 14 in quantitative yield. Epoxide opening with piperazine 15 in refluxing methanol followed by Boc-removal gave 16 in 94% yield. Finally, treatment of piperazine derivative 16 with 3-picolyl chloride in sulfuric acid afforded Indinavir sulfate in 75% yield from epoxide 14 and 56% yield for the overall process (Scheme 24.1).17-22... 

Chlorinated alkyl phenoxy-propanoates, etc. Silica gel (Nucleosil, 5 pm) coated with Chirasil-Dex Methanol-20 mM MES buffer, pH 6 (1 1, 2 3 or 7 3) 400 mm x 100 pm i.d. 250 mm effective length, pressure-supported chiral separation 53... 

Phthalocyanines 84 and 85 substituted with six optically active alkyl chains and one chiral diol have been synthesized by mixed cyclization of the two corresponding phthalonitriles [72], The self-organizing properties of these compounds in chloroform solution and thin film have been studied by a range of spectroscopic and physical methods. Both compounds show split Q-band absorptions at 678 and 694 nm in chloroform, and the emission (at 696 nm) is red-shifted compared with that of a non-diol-containing analog. Upon addition of 0.5% methanol, the absorption at 694 nm... 

Oxidation of sulfur-containing azoles quite often leads to the formation of sulfones and sulfoxides. Thus, 3-alkyl-1,2-benzisothiazoles 142 with MCPBA give the oxaziridines 143, and the use of a chiral 3-alkyl substituent leads to pure diastereomers. Reaction of 1,2,3-benzothiadiazole with 30% hydrogen peroxide in a mixture of acetic acid and methanol for 45 days affords 144 in 60% yield. 

A recent example of zeolite-catalyzed esterification involving biochemicals is the reaction of aminoacids with methanol. For instance, L-phenylalanine was converted to its methyl ester over H-USY at 130°C. However, the chiral carbon atom was racemized to a considerable extent, yielding an eventual ee of 52% (27). In the reaction of a, (3-unsaturated acids with phenols, the esterification over H-Beta is followed by an alkylation of the aromatic ring for instance resorcinol and acrylic acid react to form 7-hydroxy-3,4-dihydrocoumarin (28). 

The separation of chiral compounds will be discussed in Chapter 22. However, the separation of diastereomers can be accomplished using achiral stationary phases. Another alternative is the use of chiral columns for the separation of diastereomers in either the reversed-phase or normal-phase mode. The use of achiral bonded phases without chiral additives, such as phenyl and alkyl bonded phases for the separation of diastereomeric pharmaceutical compounds, is acceptable. Different selectivities can be obtained by employing stationary phases containing varying functionalities (phenyl, polar embedded moieties). The effect of aqueous mobile-phase pH, temperature, and type of organic eluent (acetonitrile versus methanol) can also play a dramatic role on the separation selectivity of diastereomeric compounds. 

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