Nitrones isoxazolidines, 4-amino

The mechanism of 1,3-dipolar cycloaddition can be found in Ref. 63 and the references within. The reaction of nitrone with 1,2-disubstituted alkenes creates three contiguous asymmetric centers, in which the geometric relationship of the substituents of alkenes is retained. The synthetic utility of nitrone adducts is mainly due to their conversion into various important compounds. For instance, P-amino alcohols can be obtained from isoxazolidines by reduction with H2-Pd or Raney Ni with retention of configuration at the chiral center (Eq. 8.44). 

Alkenylboronic esters undergo regio- and stereoselective 1,3-dipolar cycloadditions with nitrones. These reactions lead to boronic ester-substituted isoxazolidines, which can be converted by oxidation with H202 to the corresponding 4-hydroxy derivatives (Eq. 8.48).69 The high selectivity could be the result of a favorable interaction between the boronic ester and the amino group. 

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

Bis(oxazolinyl)pyridine-Ce(IV) triflate complex 78 catalyzed the enantioselective 1,3-DC of acyclic nitrones with a, 3-unsaturated 2-acyl imidazoles. For example, C-phenyl 7V-benzyl nitrone reacted with 77 in the presence of 78 to give the adduct 79 with excellent diastereo-and enantioselectivity. Isoxazolidine 79 was then converted into P -hydroxy-P-amino acid derivatives by hydrogenation of the N-0 bond in the presence of Pd(OH)2/C and cleavage of the 2-acyl imidazole with MeOTf in MeCN <06OL3351>. 

Related to the nitrile oxide cycloadditions presented in Scheme 6.206 are 1,3-dipolar cycloaddition reactions of nitrones with alkenes leading to isoxazolidines. The group of Comes-Franchini has described cycloadditions of (Z)-a-phenyl-N-methylnitrone with allylic fluorides leading to enantiopure fluorine-containing isoxazolidines, and ultimately to amino polyols (Scheme 6.207) [374]. The reactions were carried out under solvent-free conditions in the presence of 5 mol% of either scandium(III) or indium(III) triflate. In the racemic series, an optimized 74% yield of an exo/endo mixture of cycloadducts was obtained within 15 min at 100 °C. In the case of the enantiopure allyl fluoride, a similar product distribution was achieved after 25 min at 100 °C. Reduction of the isoxazolidine cycloadducts with lithium aluminum hydride provided fluorinated enantiopure polyols of pharmaceutical interest possessing four stereocenters. 

Over the last years, one of the most studied DCR has been the asymmetric version of the cycloaddition of nitrones with alkenes. This reaction leads to the construction of up to three contiguous asymmetric carbon centers (Scheme 4). The resulting five-membered isoxazolidine derivatives may be converted into amino alcohols, alkaloids, or p-lactams. Several chiral metal complexes have been used as catalysts for this process [13-15, 18-22]. However, the employment of iridium derivatives is very scarce. 

Cycloaddition to endocyclic unsaturation has been used by many researchers for the preparation of isoxazoUdinyl adducts with y-lactams derived from pyrogluta-minol and is discussed later in this chapter as a synthesis of unusual amino acids (Scheme 1.20, Section 1.6) (79,80). A related a,p-unsaturated lactam has been prepared by a nitrone cycloaddition route in the total synthesis of the fungal metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting materials is given in the work of Chiacchio et al. (82) who prepared isoxazolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11). 

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. 

These cyclic nitrones 91 react with electron-rich olefins in 1,3-cycloaddition reactions to afford fused isoxazolidines 92-94 from which several unusual amino acids 95-97 have been obtained (Scheme 7.22). ... 

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. 

INOC reactions are occasionally synthetic alternatives to nitrone cyclizations. The isoxazolines produced can substitute for isoxazolidines in a number of further transformations. Thus, isoxazolines, like isoxazolidines, can be converted to 7-amino alcohols.31 Isoxazolines can be converted to isoxazolidines and vice versa.32... 

Several isoxazolidines or their quaternary salts derived from the 1,3-dipolar cycloaddition of rr/i-hcxcnolidcs (6,7-dihydrooxepin-2(5//)-ones) to cyclic nitrones, were converted into the corresponding piperidyl- and pyrrolidyloxepi-nones by reduction of the nitrogen-oxygen bond (Equation 4). These amino alcohols provide a new access to the l-azabicyclo[5.3.0]decane core of the Stemona alkaloids <2004EJ04215>. 

The intramolecular nitrone cycloaddition (INC) has been used particularly for the synthesis of amino carbasugars [60, 61]. The following scheme illustrates this strategy (Scheme 16) [60], The cycloaddition of nitrone derived from lactol 49 and an excess of N-methylhydroxylamine occurs from the least hindered face affording the isoxazolidine 51 (85% yield). The amino carbasugar 52 was obtained after the cleavage of the N-0 bond. 

Isoxazolidines are useful and versatile intermediates in the synthesis of highly functionalized compoimds. Frequently, they are prepared by 1,3-DC of enantiomerically pure nitrones derived from compounds belonging to the chiral pool such as carbohydrates, amino acids, and hydroxy acids. 

The asymmetric 1,3-dipolar cycloaddition of nitrones to 3-(( )-2-butenoyl)-2-oxazoli-dinone [214] is catalyzed by nickel(II) [215] and palladium(II) [216] complexes (Sch. 66). The resulting isoxazolidines are of interest because they are readily converted into y-amino alcohols, precursors to alkaloids and /3-lactam antibiotics. 

The 1,3-dipolar cycloaddition of nitrones to alkenes is a useful route to isoxazolidine derivatives, the reductive cleavage of which furnishes a range of compounds such as fi-hydroxy ketones, /S-amino alcohols, etc. [29]. Although Lewis acids are known to promote the cycloaddition [29,30], some nitrones, especially aliphatic nitrones, are unstable under these conditions and lower yields are sometimes obtained. The three-component coupling reaction of benzaldehyde, A/-benzylhydroxylamine, and A-phe-nylmaleimide proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, to afford the corresponding isoxazolidine derivative in a good yield with high diaster-eoselectivity (Eq. 12) [31]. 

Under catalytic hydrogenation conditions, the adducts of nitrones and acrylates, 5-alkoxycarbonyl and 5-aminocarbo-nyl isoxazolidines, give 3-hydroxypyrrolidin-2-ones by intramolecular N-acylation of the amino group. 3,5-Dicarboxylic... 

Isoxazolidines, Isoxazolines, Oxazolines, and Oxazines isoxazoiidines, easily obtained by cycloaddition of nitrones to olefins, are reduced to 1,3-amino alcohols by reaction with LAH in ether media. The synthesis of racemic sedridine from 3.256 is illustrative [TA2] (Figure 3.100). 

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