Alcohols y-amino

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. 

The 10 OC route was followed for the synthesis of tetrahydrofurans possessing a y-amino alcohol moiety 247 (Eq. 29) 118]. Aldoximes 21a-f (see also Eq. 3 and Table 2), when heated in benzene in a sealed tube at 110 -120 °C for 6 h, underwent smooth intramolecular cycloaddition to the tetrahydrofuranoisoxazo-lidines 246a-f in 70-83% yield (Eq. 29). This ring closure proceeded stereo-specifically to generate three adjacent stereogenic centers. LAH reduction of 246 b resulted in isolation of stereospecifically functionalized tetrahydrofuran derivative 247b in 75% yield. 

Optically active 5-(hydroxymethyl)-3-phenyl-2-isoxazoline 13 is a versatile key intermediate for the syntheses of /3-hydroxy ketones, y-amino alcohols,and y-amino acids. However, the Upase-catalyzed kinetic resolution of isoxazoline ( )-13 has not been reported so far probably because of the low enantioselectivity expected for primary alcohols (Scheme 3). The enantioselectivity was found to be very low E value = 4-5 in /-Pr20) at room temperature however, it could be markedly improved up to an value of 249 at —60°C by using lipase PS-C 11 in acetone, which was the best solvent among those tested (THF, /-Pt20) 1 )-... 

A typical second step after the insertion of CO into aryl or alkenyl-Pd(II) compounds is the addition to alkenes [148]. However, allenes can also be used (as shown in the following examples) where a it-allyl-r 3-Pd-complex is formed as an intermediate which undergoes a nucleophilic substitution. Thus, Alper and coworkers [148], as well as Grigg and coworkers [149], described a Pd-catalyzed transformation of o-iodophenols and o-iodoanilines with allenes in the presence of CO. Reaction of 6/1-310 or 6/1-311 with 6/1-312 in the presence of Pd° under a CO atmosphere (1 atm) led to the chromanones 6/1-314 and quinolones 6/1-315, respectively, via the Jt-allyl-r 3-Pd-complex 6/1-313 (Scheme 6/1.82). The enones obtained can be transformed by a Michael addition with amines, followed by reduction to give y-amino alcohols. Quinolones and chromanones are of interest due to their pronounced biological activity as antibacterials [150], antifungals [151] and neurotrophic factors [152]. 

Isoxazolines are valuable substrates in organic synthesis as they can be transformed into useful building blocks such as y-amino alcohols, 3-hydroxy ketones,... 

Thus, isoxazolines are converted into y-amino alcohols and (3-hydroxy ketones stereoselec-tively. However, the intermolecular cycloaddition involving 1,2-unsymmetrically substituted alkenes such as trans-cinnamyl alcohol proceeds nonregioselectively to give a mixture of the two regioisomers (Eq. 8.63).98... 

The optically active isoxazolidines obtained in these cycloaddition reactions can be easily transformed into biologically active 3 -amino acids, into j3-lactams and into important chiral building blocks such as y-amino alcohols. The multitude of synthetic results in these reactions is of course expected by the wide variety... 

Selective reduction of the oximino fragment in products (224) or (225) gives rise to poorly studied y-amino alcohols (226). In addition, desoximation of (225) can produce the corresponding p-hydroxycarbonyl derivatives (227). In addition, oximino alcohols (225) can be oxidized to y-nitro alcohols (228). 

Condensation of [3- or "y-amino alcohols with aldehydes or ketones RR CO gives the product 27. In solution the position of the equilibrium varies with R and R, and with the solvent (73). When the carbonyl reactant is a substituted benzaldehyde, the solid is found (IR, KBr) to comprise molecules of the open-chain structure 27a, whereas aliphatic aldehydes and ketones give crystals of dihydro- 1,3-benzoxazines, 27b. An interesting case is that of the condensation product of o-hydroxybenzylamine with cyclopentanone, for which McDonagh and Smith (73) suggest that ring and chain tautomers coexist in the solid. 

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). 

Isoxazoles and their dihydro and tetrahydro analogues serve as immensely flexible building blocks in synthesis through their ability to function as masked forms of /3-diketones, /3-hydroxyketones (and thus enones) and y-amino alcohols. All of these interrelationships are possible because of the relatively labile nature of the nitrogen-oxygen bond. 

Elaboration of 2-isoxazolines via their 4-endo-anions has been studied as a method to synthesize y-amino alcohols (78TL3129,3133,81AG(E)601,603). When the 5-methyl-3-phenyl-2-isoxazoline (527) was deprotonated with LDA/HMPA and methylated with methyl iodide, the tra 5-4,5-substituted isoxazoline (528) was formed predominantly (trans-.cis = 12 1). Reduction of this isoxazoline with lithium aluminum hydride proceeded with steric approach control to provide a diastereomeric mixture of y-amino alcohols (529, 530 Scheme 116). The 5-substituent was found to exhibit a greater steric influence on this reaction than the 4-substituent. 

Cleavage of oxetanes.2 In the presence of Znl2, oxetanes are opened by cyanotrimethylsilane regioselectively to y-hydroxy isocyanides, which undergo acid-catalyzed hydrolysis to y-amino alcohols. 

Intramolecular cycloaddition of jV-(cycloalkenyl)nitrones has also been extensively investigated. Thus, stepwise oxidation of the amine (35) and cyclization of the ensuing nitrone provided isoxazolidine (36) in 64% overall yield as the only observed regioisomer (Scheme 8).16 Isoxazolidine (36) was then desul-fonated with buffered sodium amalgam and further reduced with zinc-acetic acid to provide the corresponding y-amino alcohol subsequent dehydration provided (-)-hobartine. 

Reduction of chiral /3-enamino ketones with sodium borohydride in acetic acid is convenient, stereoselective, and high yielding and allowed the preparation of enan- (g) tiopure y-amino alcohols with syn diastereoselectivity. A mechanistic hypothesis (Scheme 15) has been presented.321... 

Primary, secondary, and tertiary y-amino alcohols (27-30) have been used as chiral catalysts in the enantioselective addition of diethylzinc to aromatic aldehydes.109 The first evidence of the substituent-dependent enantioselectivity of 1,3-amino alcohol catalysts has been observed, and the phenomenon interpreted by using molecular modeling at the ab initio level. 

In conclusion, this new organocatalytic direct asymmetric Mannich reaction is an efficient means of obtaining optically active //-amino carbonyl compounds. It is worthy of note that besides the enantioselective process, enantio- and diastereose-lective Mannich reactions can also be performed, which makes synthesis of products bearing one or two stereogenic centers possible. Depending on the type of acceptor or donor, a broad range of products with a completely different substitution pattern can be obtained. The range of these Mannich products comprises classic / -amino ketones and esters as well as carbonyl-functionalized a-amino acids, and -after reduction-y-amino alcohols. 

Fluorinated y -amino alcohols have been prepared in moderate yield, but high de and very high ee, using a proline-catalysed cross-Mannich reaction of fluorinated aldimines with aliphatic aldehydes, followed by NaBH4 reduction.35... 

The Mannich adducts are reduced to the more stabile y-amino alcohols prior to isolation and ee determination due to their lower risk of decomposition, epi-merization and racemization. 

These diastereomerically and enantiomerically enriched compounds are useful as intermediates for a variety of interesting building blocks such as 1-aminobutanes, nonprotected homoallylamines, [3-amino acids, and y-amino alcohols (Figure 25.5). The conversion to 1-aminobutanes and homoallylamines will be described. 

The N—O bond of isoxazolines can easily be cleaved via reduction. It is for this reason that isoxazolines are interesting synthetic intermediates. y-Amino alcohols are formed by reduction with LiAlH4 (for an example, see Figure 15.46, left). Hydrogenolysis of isoxazolines catalyzed by Raney nickel yields /j-hydroxy imines, which undergo hydrolysis to / -hydroxy-carbonyl compounds in the presence of boric acid (Figure 15.46, right). 

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