Unsaturated amino alcohols

Bortolussi described the synthesis of unsaturated amino alcohols 83 by thermolysis of furan adducts 82 use of microwaves resulted in a significant reduction in reaction time (Scheme 9.24) [75],... 

Neat amino alcohols la-e (10 mmol) were placed in a Pyrex open flask allowing the removal of furan. After microwave irradiation or conventional heating, the products were removed with methylene dichloride and analyzed by ll NMR spectroscopy. Unsaturated amino alcohols 2 obtained under microwaves were highly pure and did not need further purification. 

The mixed electrolytic reduction of pyridines substituted at position 4 leads exclusively to the unsaturated amino alcohols (e.g., 75).71... 

This modification resulted in a yield improvement for the pentacyclization process from 47 % to 66 %. Treatment of the amino ether 192 with diisobutylaluminum hydride in refluxing toluene accomplished Eschenmoser-Grob fragmentation and reduction of the initially formed immonium ion, to give the unsaturated amino alcohol 193 in 86% yield. It was gratifying to find that 193 was the only product formed in this reaction. In the tetrahydropyran derivative, reduction of 192 to 193 is accompanied by about 15 % simple elimination. Displacement of the tosyl group in 196 gives sulfide 197, which is oxidized to sulfone 198. This material is metallated and coupled with enantiomerically pure aldehyde to secure the codaphniphylline skelton [74]. 

Retro-Diels-Alder reactions often require drastic conditions, high temperature and sometimes even flash-vacuum thermolysis (FVT). Such thermolytic procedures have been used to prepare unsaturated amino alcohols from a variety of amino alcohols. Several reactions were performed for a variety of neat liquid adducts and submitted to MW irradiation or to classical heating at the same temperature. The improvements obtained by coupling MW and the solvent-free technique are remarkable if we consider that both classical thermolysis and FVT (leading to decomposition) are poorly productive (Scheme 31). 

Apart from the chemistry of these pyrrolizidine alkaloids, their physiological effects, in particular their hepatotoxicity, have been investigated in depth by the CSIRO Division of Animal Health, as a result of which it has been possible to establish correlations between activity and structure liver damage is caused by alkaloids such as 90 or 91 because unsaturated amino alcohols of this type, which are esterified on one or both hydroxyl groups, undergo metabolism in the liver to form the toxin 93 this substance is immediately responsible for the mutagenic and carcinogenic effects observed [106, 107], which include... 

Bp3-OEt2 followed hy DiisobutyUduminum Hydride is used for the 1,2-reduction of y-aimno-Q, -unsaturated esters to give unsaturated amino alcohols, which are chiral building blocks for a -amino acids. Q , -Unsaturated nitroalkenes can be reduced to hydroxylamines by Sodium Borohydride and BF3-OEt2 in THF extended reaction times result in the reduction of the hydroxylamines to alkylamines. Diphenylamine-borane is prepared from sodium borohydride, BF3-OEt2, and diphenylamine in THF at 0 °C. This solid is more stable in air than BF3-THF and is almost as reactive in the reduction of aldehydes, ketones, carboxyhc acids, esters, and anhydrides, as well as in the hydrob-oration of alkenes. 

Garrido, L., Zubia, E., Ortega, M.J., Naranjo, S., and Salva, J. (2001) Obscuraminols, new unsaturated amino alcohols from the tunicate Pseudodistoma obscurum structure and absolute configuration. Tetrahedron, 57, 4579-4588. 

The stereochemical course of reduction of imonium salts by Grignard reagents was found to depend on the structure of the reagent 714). Hydro-boration of enamines and oxidation with hydrogen peroxide led to amino-alcohols (7/5). While aluminum hydrogen dichloride reacted with enamines to yield mostly saturated amines and some olefins on hydrolysis, aluminum hydride gave predominantly the unsaturated products 716). 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

Phospholipids are important constituents of cell membranes and are of two kinds. Glycerophospholipids, such as phosphatidylcholine and phos-phatidylethanolamine, are closely related to fats in that they have a glycerol backbone esterified to two fatty acids (one saturated and one unsaturaled) and to one phosphate ester. Sphingomyelins have the amino alcohol sphingo-sine for their backbone. 

A variety of chiral amides as well as oxazolidones388 and imidazolidones389,390 may easily be prepared from amino alcohols that are derived from amino acids391 392. The addition of the lithium enolates of these amides under kinetically controlled conditions to a,/i-unsaturated esters yields optically active pentanedioates. Both syn- and //-5-amino-5-oxopcntanoates may be obtained with good diastereomeric ratios192. 

Nitrile oxides are usually prepared via halogenation and dehydrohalogenation of aldoximes [11] or via dehydration of primary nitro alkanes (Scheme 1) [12]. However, it is important to note that nitrile oxides are relatively unstable and are prone to dimerization or polymerization, especially upon heating. 1,3-Dipolar cycioaddition of a nitrile oxide with a suitable olefin generates an isoxazoline ring which is a versatile synthetic intermediate in that it provides easy access to y-amino alcohols, )5-hydroxy ketones, -hydroxy nitriles, unsaturated oximes, and a host of other multifunctional molecules (Scheme 1) [5a]. Particularly for the formation of )5-hydroxy ketones, nitrile oxide-olefin cycioaddition serve as an alternative to the Aldol reaction. 

Amino alcohols (33) were transformed to ketones on copper.360 361 The transformation involves the dehydrogenation of the hydroxyl group, the elimination of dimethylamine, and the hydrogenation of the unsaturated ketone (Scheme 4.111). 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

The hydroformylation of unsaturated nitriles such as crotonitrile and allyl cyanide is a potential route towards chiral amino alcohols, which are building blocks in the synthesis of pharmaceuticals. The hydroformylation of acrylonitrile was studied in the early years [5], but lately the hydroformylation of allyl cyanide and crotonitrile have also been investigated [25,81]. 

Figure 12.11 Phosphoglyceride structure. The members of this group are derivatives of the parent compound, l,2-diacyl-src-glycerol-3-phosphate (phosphatidic acid) in which X is a hydrogen atom. This is replaced by either an amino alcohol or a polyhydroxy residue. In phosphoglycerides derived from animal tissues R1 is usually a saturated acyl chain of between 16 and 20 carbon atoms and R2 is usually unsaturated. Polyunsaturated acyl chains containing 16 or 18 carbon atoms predominate in leaf phosphoglycerides and those of bacterial origin are often more complex.

More recently, Menendez et al. reported a closely related four-component access to tetrahydropyridines, the amino alcohol being replaced by a primary amine and an alcohol. Thus, the cerium(IV) ammonium nitrate (CAN)-catalyzed reaction between primary aliphatic amines, 1,3-dicarbonyls, cx,p-unsaturated aldehydes, and alcohols resulted in the formation of 6-aUcoxy-2-methyl-l,4,5,6-tetrahydropyridines with... 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Dipolar cycloaddition reactions between nitrile oxides and aUcenes produce 2-isoxazolines. Through reductive cleavage of the N—O bond of the 2-isoxazohnes, the resulting heterocycles can be readily transformed into a variety of important synthetic intermediates such as p-hydroxy ketones (aldols), p-hydroxy esters, a,p-unsaturated carbonyl compounds, y-amino alcohols, imino ketones and so forth (7-12). 

Other alcohols ring-open unsaturated oxazolones including glycerol that was used to prepare monoglycerides of acylamino acids.In addition, alcoholysis with 3,4,4-trifluorobut-3-enol leads to amino acid fluorobutenyl esters that are used as pesticides.Finally, (dimethylamino)ethanol and other amino alcohols have also been used to obtain the corresponding aminoalkyl esters. 

Catalytic hydrogenation of the exocychc double bond of several oxazolones 611, in the presence of acetic acid, gives a-acylamino alcohols 613 via the saturated derivatives 612 (Scheme 7.196). Selected examples of amino acid derivatives and amino alcohols available from reduction of unsaturated oxazolones are shown in Table 7.45 (Fig. 7.56). 

TABLE 7.45. AMINO ACID, AMINO ESTER AND AMINO ALCOHOL DERIVATIVES FROM HYDROGENATION OF UNSATURATED 5(4//)-OXAZOLONES... 

During an investigatior of the utihty of epoxide 240 as an intermediate in the synthesis of the HIV protease inhibitor Indinavir 241, it was found that the amino alcohol 237 must first be protected prior to iodination. Without protection, the iodination of the unsaturated amide 237 gave the unstable oxazoline 239 in 83% yield (Scheme 8.65). 

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