Isoxazolidines

Isoxazolidines continue to play a pivotal role as intermediates in the synthesis of highly functionalized natural compounds and analogues. For example, these versatile heterocycles have been used recently in the stereoselective synthesis of 67, precursor of proteasome inhibitor (-)-omuralide 07JOC10108 , polyhydroxyindolizidines, pentahydroxy perhydroazaazulenes and 

The reaction of 3,4-dihydroisoquinoline A-oxide (74) and methacrylonitrile in the presence of cationic half-sandwich rhodium and iridium complexes containing a chiral diphosphine ligand was analyzed. The cycloadditions occurred with excellent regio- and diastereoselectivity and low-to-moderate enantioselectivity. Analysis of the catalytic system showed the formation of two epimeric complexes 75 containing the dipolarophile methacrylonitrile. The reaction of one of the isolated diastereopure complexes 75 with 74 afforded cycloadduct 76 with high enantioselectivity. A recycling procedure was developed in order to increase the adduct/catalyst ratio 07CEJ9746 . 

The same proline derivative 77 was found to catalyze a highly enantioselective synthesis of 5-hydroxyisoxazolidines 79 hy tandem reaction of -protected hydroxylamines and enals. In situ oxidation of 79 by NaC102 afforded directly /V-protected 5-isoxazolidinones 80 in high yield and ee 

The synthesis of isoxazolidines hy 1,3-DC of nitrones and alkenes in ionic liquid catalyzed by Er(OTf)3 was investigated. Cycloadducts were obtained in good yields and the catalyst and the ionic liquid could he recycled up to five times without loss in activity 07TL7125 . 

Density functional theory (DFT) calculations have been used to investigate and rationahze the regio- and stereochemical outcome of 1,3-DC of (C-hetaryl)nitrones with methyl acrylate and vinyl acetate 07T1448 , diphenyl nitrone with captodative olefins 1-acetylvinyl carboxylates 07EJO2352 and diphenyl nitrone with acrolein in the presence of a Lewis acid catalyst 07T4464 . 

Typically, isoxazolidines are employed as masked (3-amino alcohols which can be released under mild reduction conditions, but other different transformations leading to a variety of useful functionalities are also available as shown by some of the following examples. The 

A-Unsubstituted isoxazolidines such as 65 undergo facile decarboxylative peptide couplings with a-keto acids 06JA1452 . The use of water as solvent or cosolvent was particularly beneficial for the formation of amides in high yields. The methyl a-keto esters obtained could be saponified to the corresponding a-keto acids, and the (i-peptide chain could then be extended by reaction with another isoxazolidine. 

2-Thiazetidine 1,1,-dioxides ((3-sultams) 67 were directly synthesised from pentafluorophenyl (PFP) isoxazolidine-4-sulfonates 66 under mild reducing conditions [Mo(CO)6, MeCN, H20, reflux]. The process is stereoselective and goes through N-O bond cleavage followed by intramolecular displacement of the PFP group by the amine 06OL5513 . 

Nitrone 1,3-DC reactions are still the most general approach to isoxazolidines. The stereocontrol is usually achieved by the use of chiral nitrones and/or dipolarophiles, but new interesting achievements on Lewis acid catalyzed cycloadditions are also frequently reported. Tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanatedionate) europium(III) [Eu(fod)3] selectively activated the Z-isomer of C-alkoxycarbonyl nitrone 75 existing as an E,Z-equilibrium mixture by forming the (Z)-75-Eu(fod)3 complex. (Z)-75-Eu(fod)3 reacted with electron-rich dipolarophiles such as vinyl ethers to give the trans-adducts with excellent diastereoselectivity 06T12227 . 

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 . 

Various reactivities of isoxazolidines have been discussed in detail by Takeuchi and Furusaki (77AHC(21)207). Attention is drawn to the principal reactions below. 

The hydrogenation of (169) with Pd/C produced (170), with Raney Ni (171) was obtained, and with PtOi compound (172) was formed. 

Oxidation of fused isoxazolidine (173) with one equivalent of m-chloroperbenzoic acid produced an oxazine. The mechanism of transformation involves formation of an A/-oxide 

In general,. alkoxy- or silyloxy-isoxazolidines when treated with acid produce 2-isoxazo-lines 77AHC(2i)207, 74MIP41601). Other isoxazolidines are cleaved at the N—O bond with further degradation then following 77AHC(2i)207). The treatment of (182) with HCl generated cinnamic acid and a small amount of benzoic acid, whereas treatment of (182) with 

Strong acid treatment of 2-(trimethylsilyloxy)-5-methoxycarbonylisoxazolidine (183) produced (184) 78ACS(B)118). 

3-(2-alkenoyl)-2-thiazolidinethiones 74 with high enantio- and eM(/o(alkyl)-selectivity 05OL1431 . 

The reaction of 77 and a,P-disubstituted acrylamides 78 mediated by Cu(OTl)2-79 afforded C-4 disubstituted isoxazolidines 80 with good diastereo- and enantioselectivity. In this case, the N-H imide template was chosen to accomplish rotamer control and improve 

High levels of regio- and stereoselectivity were observed in metal-catalyzed 1,3-DC of acyclic nitrones with a -hydroxy enones. The reaction probably occurs through the formation of reactive 1,4-metal-chelated intermediates. The remarkable diastereo- and enantiocontrol could be obtained through two complementary approaches by using a camphor-derived a -hydroxy enone in combination with Cu(OTf)2 or an achiral enone such as 81 in combination with the bis(oxazoline)-Cu(II) catalyst 83. At the end, the hydroxylated auxiUaiy could be easily removed. For example, treatment with periodic acid released a carboxylic moiety as in 86 and 87 05AG(E)6187 . 

R = Ph, 4-MeCeH4, 4-MeOCeH4, 4-CIC0H4, 2-naphthyl, t-Bu, 2-methyl-1,3-dithian-2-yl 

The asymmetric 1,3-DC between nitrones 88 and acrolein catalyzed by the chiral bis-Ti(IV) oxide 89 afforded adducts 90 with complete ewcfo-selectivity and good enantioselectivity (88-97% ee) 05JA11926 . 

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A"-Octadienylatiori, rather than 0-octadienylation, of aldehyde oximes takes place to give the nitrone 37 as an intermediate, which undergoes 1.3-dipolar addition to butadiene, yielding the isoxazolidine 38[39],... 

Isoxazolidines sometimes undergo retro 1,3-dipolar cycloaddition to give back alkenes and nitrones (77AHC(2D207). 

The preparation of isoxazolidine derivatives was first reported by Bodforss in 1918 (18CB192). The major synthesis of isoxazolidines involves the cycloaddition of nitrones with alkenes, and isoxazolidines have also enjoyed an increasing use as key intermediates in the synthesis of natural products and other heterocycles (79ACR396, 1892CB1498, 1892CB3291, 1882CB2105). 

The review by Takeuchi and Ferusaki is quite encompassing and, in addition to synthesis and reactivity, the physical and spectroscopic properties of isoxazolidines are discussed in detail. Additional spectral studies on the parent and derivatives include H NMR (68MI41600, 77H(7)201, 78IZV850). 

Isoxazoles, isoxazolines, isoxazolidines and benzisoxazoles are all thermally stable, distilling without decomposition, but the stability of the system depends on the substitution pattern. For example, aminoisoxazoles distill unchanged but the isoxazole carboxylic acids usually decompose at or above their melting points without giving the corresponding isoxazole. 

The isoxazolidine ring exists primarily as an envelope (77AHQ2l)207) and the nitrogen lone pair can occupy an axial or equatorial position. Photoelectronic spectroscopy is a useful tool to determine conformational analysis of molecules possessing vicinal electron lone-pairs. Rademiacher and Frickmann (78TL841) studied isoxazolidine and 2-methyl- and 2-t-butyl-isoxazolidine and found mixtures of equatorial and axial (e/a) compounds. The ratios of H, Me and Bu in the efa position were 1 3, 4 1 and 10 1, respectively. 

Sodium borohydride and 3-isoxazolium salts with a 3-unsubstituted position also give isoxazolines, as do the 3-substituted 5-unsubstituted derivatives. With the latter group, further reduction occurs to the isoxazolidines (74CPB70). 

The photooxygenation of (175) produced a ring ruptured compound (176) (Scheme 57) B-78MI41612) while similar treatment of steroidal isoxazolidine (177) resulted in the formation of two major nitro compounds also shown in Scheme 57 <77CC749). 

Mild base does not effect isoxazolidine ring cleavage by fission of the N—O bond rather, C—O bond cleavage takes place <77AHC(2l)207). The reaction of iV-trimethyl-silylisoxazolidine (185) with KOH produced a /3-hydroxyketone oxime (Scheme 59) (74DOK109). 

Isoxazolidine reacted with acetone and perchloric acid to produce the iminium salt (189) <80JA1649). 

Nitrones or aci-nitro esters react with alkenes to give in some cases A/-substituted isoxazolidines and in others 2-isoxazolines. When the intermediate isoxazolidines were observed, a number of procedures transformed them into the 2-isoxazolines. Acrylonitrile and phenyl rzcf-nitrone esters produced an A/-methoxyisoxazolidine. Treatment with acid generated a 2-isoxazole while treatment with base generated an oxazine (Scheme 118) (68ZOR236). When an ethoxycarbonyl nitrone ester was reacted with alkenes, no intermediate isoxazolidine was observed, only A -isoxazolines. Other aci-mtro methyl esters used are shown in Scheme 118 and these generate IV-methoxyisoxazolidines or A -isoxazolines which can be further transformed (72MI41605). 

The trimethylsilyl group has been used to prepare stable aci-nitro esters and these react with alkenes to produce intermediate isoxazolidines which were readily converted into 2-isoxazolines (Scheme 119) (73ZOB1715, 74DOK109, 78ACS(B)ll8>. 

This small class of compounds is characterized by an N-alkyl moiety, and they are synthesized from isoxazolium salts by isomerization or by the dehydration of 2-alkyl-isoxazolidin-3-ols (Scheme 128) (74BSF1025). The reaction of isoxazolium salts that are unsubstituted in the 5-position with phenylmagnesium halides was reported to give 3-isoxazolines by 1,4-conjugate addition, and this reaction is also shown in Scheme 128 (74CPB70). 

Isoxazolidines and isoxazolidinones are a small class of compounds which has received only limited attention. Reviews have appeared dealing with isoxazolidines in 1962 (62HC(17)l,p.7) and 1977 (77AHC(21)207>. 

Chiral nitrones react with alkenes to produce 3,5-disubstituted isoxazolidines that are nonracemic diastereomeric mixtures and are oriented predominantly cis (equation 53) (77CC303, 79JOC1212). 

The reaction of nitrones with allenes produced three main products an azepine, a pyrrolidinone and an isoxazolidine (Scheme 155) (79JOC4213). The intramolecular cycloaddition of nitrones (529) produced different products depending on the length of n (Scheme 156) (78H(10)257). 

Nitrone (530) exists in thermal equilibrium with vinylamine (531) and isoxazolidine (532), with (532) (a dimer of 530 and 531) being predominant. The equilibrium in DMSO was studied by and NMR spectra (80TL3447). 

A newer method for the preparation of nitronic esters, namely utilizing the (9-trimethyl-silyl ester, has been reported and these are prepared by the reaction of alkylnitro compounds and (V,(V-bis(trimethylsilyl)acetamide. These nitronic esters also undergo cycloaddition with alkenes to produce isoxazolidines (equation 54) (74MIP41601, 74DOK109, 78ACS(B)ll8). 

Steroidal alkene (531a) reacted with a nitronic ester at 14 000 atmospheres to produce an isoxazolidine (532a) (80IZV1893). 

Tetranitromethane was decomposed in the presence of alkenes to generate isoxazolidines (equation 55) (72ZOR1419). 

A number of other syntheses were discussed by Takeuchi and Furusaki and the most common involved reaction of hydroxylamine with selected a,/3-unsaturated ketones to give isoxazolidine-3- or -5-ols, which exist in equilibrium with an open-chain counterpart (77AHC(21)207). A similar equilibrium was observed in the reaction of a,/3-unsaturated ketones with N-hydroxyurea. The geometric orientation of the ring substituents was studied as a dynamic process (Scheme 158) (75TL2337). 

Azetidine N-oxides produce isoxazolidines by a thermal ring expansion (77AHC(21)207, 75GEP2365391), and nitrosobenzenes react with alkenes to provide isoxazolidines (77AHC(21)207, 79IZV1059). 

The reduction of 3,5-diphenylisoxazoline with sodium cyanoborohydride produced a mixture of isomeric 3,5-diphenylisoxazolidines. The H and NMR spectra were utilized to distinguish the isomers SOLAIOI). Sodium borohydride reductions likewise reduce isoxazolines to isoxazolidines (equation 56) (80JA4265). 

Treatment of (537) with acid chloride (538) in the presence of triethylamine produced isoxazolidine (539) in 45% yield (80IZV1694). 

Three isoxazolidinones are possible, the 3-, 4- and 5-isoxazolidinones, with 3-isoxazolidinones being the group containing the most members. Only one synthesis of 4-isoxazolidinones has been reported, although a number of 4-arylmethylene compounds exist. A number of isoxazolidine-3,5-diones have been synthesized. A review by Quilico with nine references appeared in 1962 (62HC(17)l,p. 7> and since then the number of references has slightly more than tripled. 

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