Alcohols aminoalcohol synthesis

More recently a rhodium-catalyzed enantioselective synthesis of duloxetine (3) has been reported (Scheme 14.17). In this work, readily available amino ketone 51 was converted to (6)-aminoalcohol 36 in 75% yield and greater than 99% ee. The intermediate alcohol was subsequently converted into duloxetine (3) in a single step via standard etherification. 

Enantiomerically pure aminoalcohols, which are readily available by reduction of a-amino acids, can be converted into alkoxycarbonylating reagents suitable for the solid-phase synthesis of oligocarbamates (Figure 16.26). Particularly convenient alkoxycarbonylating reagents are 4-nitrophenyl carbonates, which can be prepared from alcohols and 4-nitrophenyl chloroformate, and which react smoothly with aliphatic primary or secondary amines to yield the corresponding carbamates. 

Intramolecular nucleophilic displacement of an activated alcohol by amines using -aminoalcohols constitutes a very powerful method for the synthesis of azetidines . Particularly useful is the cyclization of... 

To develop a method of obtaining comparatively pure styryl compounds in a less cumbersome way, a solid phase synthesis route was also designed and performed.21 Briefly, 2-chlorotrityl resin was functionalized with two different aminoalcohols, and the alcohol groups were sequentially mesylated and treatment with picoline or quinoline moieties (seven diversities). Subsequently, 64 aldehydes were condensed with the solid-supported pyridinium salts, and finally compounds were cleaved off from the resin. On the basis of the purity, 320 compounds were selected for further screening (Fig. 17.14). 

Acetylcholine is synthesized by the transfer of the acetyl group from its activated acetyl coenzyme A form to the aminoalcohol choline (Eq. 8.1). The enzyme, ChAT, is not actually highly substrate-specific and can acetylate other basic alcohols or transfer acyl groups other than acetyl. The rate of synthesis can be as high as 4,000 (ig/g of tissue per hour. 

This chapter focuses on the metal-catalyzed amination of alcohols and related compounds such as aminoalcohols, phenols and di- and polyhydroxy compounds. Details of the synthesis of amines with acidic catalysts, including zeolites, mixed oxides and metal phosphates, can be found elsewhere [3,5-7]. 

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56). Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated P-aminoalcohols stereoselectively. Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57). Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58). Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

The reduction of carbonyl compounds by hydrosilylation is one of the most effective methods for the synthesis of alcohols [150]. The reactivity of organosil-icon reagents, such as trialkoxysilanes and trihalogenated silanes, in these reactions is enhanced by coordination with Lewis bases such as fluoride or DMF. Upon reaction with diols or aminoalcohols, these reagents can form pentacoor-... 

The synthesis of the enantiopure AB segment 184 [68] by Shibasaki et al. [178] relied on the enantioselective opening of the oxirane ring of the readily available meso-epoxide 177 with p-anisidine [179,180], followed by two steps with 1,3-chiraUty transfer. After extensive experimentation the best enantiomeric excess was obtained with a catalyst prepared from Pr(0-f-Pr)3-(Jl)-BINAP in the ratio 1 1.5 with three equivalents of triph-enylphosphine oxide as an additive. Thus, reaction of 177 with p-anisidine in the presence of 10 mol% of the chiral catalyst provided fraws-aminoalcohol 178 in 80% yield with a moderate enantiomeric excess (65% ee), which was raised to 95% ee by one recrystaUization in 40% yield (Scheme 36). Methy-lation of 178 and Hofmann degradation of the resulting quaternary salt with butyllithium at -78 °C gave aUyhc alcohol 179. Oxymercuration of alcohol 179 with Hg(OAc)2 in methanol, followed by sodium borohydride reduction [181]... 

Aminohydroxylation of Alkenes. Sharpless asymmetric aminohydroxylation (AA) allows for the catalytic and enantios-elective symthesis of protected vicinal aminoalcohols in a single step. This reaction is significant as it applies to the synthesis of a wide variety of biologically active agents and natural products. For example, new monoterpene /3-amino alcohols can effectively be synthesized from (+)-2-carene, (+)-3-carene, (—)-/3-pinene, and... 

Commercial hexythiazox is a racemic mixture of the two trans enantiomers Scheme 26.2.2 shows the main synthetic pathways [11, 17, 19]. Starting from 4-chloro propiophenone the key intermediate erythro amino alcohol may be obtained by stereoselective catalytic reduction of the corresponding hydroxy imi-noketone or by sodium borohydride reduction of the aminoketones obtained via Gabriel synthesis. Different routes lead from this aminoalcohol to the trans-thiazolidinone system the basis of all routes is activation of the hydroxy group, e.g., in form of the sulfonate and a ring forming reaction with carbon disulfide or carbonyl sulfide. The final acylation of the NH group with cyclohexyl isocyanate leads to hexythiazox. 

Toward this end, a Fischer indole synthesis employing 4-carbethoxycyclo-hexanone (212) and phenyl hydrazine in warm acetic acid was followed by reduction of the resulting indole with lithium aluminum hydride to fomish hydroxymethyltetrahydrocarbazole 213. Alcohol activation with tosyl chloride and subsequent displacement of the tosylate with cyanide yielded nitrile 214. Oxidation with periodic add in methanol then formed ketone 215. Reduction of both the nitrile and carbonyl moieties was next achieved using lithium aluminum hydride in a mixture of THF and glyme at reflux to furnish aminoalcohol 216. A thermal dehydrative cyclization via heating this product in o-dichlorobenzene at reflux then led to 1,3-(iminoethano)carbazole 83. 

A single case of thiophene synthesis by gold-catalyzed dehydrative cyclization of a thiolated propargyl alcohol has been reported. Compared with the corresponding transformation of propargyl diols or aminoalcohols (Sections 4.1 and... 

For the last two decades, the use of the platinum- or rhodium-catalyzed intramolecular hydrosilylation/Tamao-Fleming oxidation sequence has been well recognized as a powerful method for the stereoselective synthesis of various structurally diverse alcohols (1,3-diols, 2-alkoxy-l,3-diols, and 2-aminoalcohols) and ketone derivatives (/3-hydroxyketones, y-hydroxyketones, o, /3-dihydroxyketones, and a,y-dihydroxyketones) from simple and readily available starting materials such as substituted allyl or propargyl alcohols and their homologues (4,177). Selected applications are presented in equations (24-26). 

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