Isoxazolidines, preparation from

Among the J ,J -DBFOX/Ph-transition(II) metal complex catalysts examined in nitrone cydoadditions, the anhydrous J ,J -DBFOX/Ph complex catalyst prepared from Ni(C104)2 or Fe(C104)2 provided equally excellent results. For example, in the presence of 10 mol% of the anhydrous nickel(II) complex catalyst R,R-DBFOX/Ph-Ni(C104)2, which was prepared in-situ from J ,J -DBFOX/Ph ligand, NiBr2, and 2 equimolar amounts of AgC104 in dichloromethane, the reaction of 3-crotonoyl-2-oxazolidinone with N-benzylidenemethylamine N-oxide at room temperature produced the 3,4-trans-isoxazolidine (63% yield) in near perfect endo selectivity (endo/exo=99 l) and enantioselectivity in favor for the 3S,4J ,5S enantiomer (>99% ee for the endo isomer. Scheme 7.21). The copper(II) perchlorate complex showed no catalytic activity, however, whereas the ytterbium(III) triflate complex led to the formation of racemic cycloadducts. 

We are the first group to succeed with the highly enantioselective 1,3-dipolar cycloadditions of nitronates [75]. Thus, the reaction of 5,6-dihydro-4H-l,2-oxazine N-oxide as a cyclic nitronate to 3-acryloyl-2-oxazilidinone, at -40 °C in dichloro-methane in the presence of MS 4 A and l ,J -DBFOX/Ph-Ni(II) complexes, gave a diastereomeric mixture of perhydroisoxazolo[2,3-fe][l,2]oxazines as the ring-fused isoxazolidines in high yields. The J ,J -DBFOX/Ph aqua complex prepared from... 

Reaction of porphyrins with nitrones has also been studied and the results obtained showed that this is a versatile approach leading to the synthesis of isoxazolidine fused-chlorins (Scheme 26). For instance, chlorin 74 was successfully prepared from the reaction of the jV-methylnitrone, generated in situ from JV-methyl hydroxylamine and paraformaldehyde, with porphyrin Id . It is important to note that bis-addition also took place, yielding exclusively bacteriochlorin type derivatives 76 and 77 (Figure 6). This result contrasts with those obtained in 1,3-DC reactions with azomethinic ylides where isobacteriochlorins were obtained preferentially. 

Nitroisoxazolines were prepared from ALalkoxy-3,3-dinitroisoxazolidines by thermally induced P-elimination. For example, isoxazolidines 42 synthesized by a three-component reaction of tetranitromethane with two equivalents of alkenes 41, were converted into isoxazolines 43 by heating in boiling chlorobenzene <06S706>. 

These authors also showed that the indolizidine skeleton can be prepared from cyclopropyl dipolarophiles (Scheme 1.16). The cycloaddition of alkyhdenecyclo-propanes 67 with various nitrones (e.g., 68) afforded the expected isoxazolidine adducts 69 and 70, commonly forming the C(5) substituted adducts 70 (97,105-108) predominantly but not exclusively (109-111). Thermally induced rearrangement of the spirocyclopropyl isoxazolidine adduct 70 afforded the piperidinones 71 (107,108). These authors propose reaction via initial N—O bond homolysis of 70 to diradical 72 followed by ring expansion through relief of the cyclopropyl ring strain forming the carbonyl of a second diradical intermediate 73, which cyclizes to afford the isolated piperidinone 71. 

This work has since been extended to cyclobutyl isoxazolidine adducts (e.g., 86) from the cycloaddition of 87 to methylenecyclopropane (88) (Scheme 1.18) (124— 127). Thermolysis afforded a mixture of products, of which the bicyclic azepinone (89) predominated. Spirocyclic adducts were also prepared from an intramolecular reaction in the synthesis of cyclic amines (Scheme 1.72, Section 1.11.3). 

The A-silyloxy-isoxazolidine (XIX) provides several opportunities for further elaboration. One of the more common transformations is the elimination of silanol from the isoxazolidine (Scheme 2.9), which results in the formation of isoxazolines (XX), which are also prepared from the [3 + 2] cycloaddition of nitrile oxides... 

Isoxazolidines were prepared from primary nitroalkanes and alkenes in the presence of catalytic amounts of copper acetate and 1-methylpiperidine (NMP). Under these reaction conditions, adduct 49 was obtained in quantitative yield starting from nitropentane and norbomene. 

Vinyl isoxazolidine 84 was prepared by intramolecular 5-exo Pd-catalyzed allylic substitution of hydroxylamine 83. A comparative study on the Pd-based catalytic system proved that Pd(II) in the presence of lithium halides was the most selective catalyst giving the trans isoxazolidine 84 from syn-83 and the czs-84 from the isomeric anti-83 <07SL944>. 

N- A ry I - 3 - (ary lmethy 1 )i soxazol id i nes were prepared from O-homoallylhydroxylamines by a Pd-catalyzed domino A-arylation/carboamination process. Optimized reaction conditions used catalytic amounts of Pd(dba)2 and of the bis(phosphine) ligand Xantphos in the presence of an excess of NaO -Bu as a base in toluene. Generally, the substituted isoxazolidines such as 86 were obtained with complete diastereoselectivity and good yields <07JOC3145>. 

Stereospecific syntheses of both E) and Z)-o -bisabolenes, (73) and (74) respectively, have been carried out (Scheme 9) and the spectral data for each diastereoisomer have been recorded/ The enantiomers of each have also been made starting from (+)- and (-)-limonene and as a result the j8-bisabolene present in the essential oil of Opoponax has been shown to be the (+)-(5,Z)-isomer, thus correcting a previous report. As might be expected the odour characteristics of the ( )- and (Z)-isomers are subtly different. Both dia-stereoisomeric racemic a-bisabolols (75) and (76) (only one enantiomer of each is shown) have been prepared from the two isoxazolidines (77) and (78) which, in turn, were derived from intramolecular cyclization of the nitrones of (6E)- and (6Z)-farnesal respectivelyFrom this work it is suggested that natural (-)-a-bisabolol must be (75) in contradiction to a recent report which held that (76) is the correct structure of the natural isomer. Further work will be needed to resolve this question. 

Isoxazolidines 118, prepared from enantiopure cyclic nitrones 116 and isolevoglucosenone 117, were used as key intermediates in the synthesis of a new class of directly linked (l- 3)-imino-C-disaccharides belonging to D-gulo and D-allo series such as 119 and 120. 

Catalytic asymmetric 1,3-dipolar cycloaddition of a nitrone with a dipolarophile has been performed using a chiral scandium catalyst [31]. The chiral catalyst, which was effective in asymmetric Diels-Alder reactions, was readily prepared from Sc(OTf)3, (7 )-(-i-)-BINOL, and d5 -l,2,6-trimethylpiperidine. The reaction of benzylbenzylide-neamine A-oxide with 3-(2-butenoyl)-l,3-oxazolidin-2-one was performed in the presence of the chiral catalyst to yield the desired isoxazolidine in 69 % ee with perfect diastereoselectivity (endolexo = > 99 1) (Sch. 8) [31,46], It was found that reverse enantioselectivity was observed when a chiral Yb catalyst, prepared from Yb(OTf)3, the same (i )-(-i-)-BINOL, and cd-l,2,6-trimethylpiperidine, was used instead of the Sc catalyst under the same reaction conditions. 

Optically active tricyclic isoxazolidine 105, a precursor to (-)-rosmarinecine, was prepared from racemic hydroxy-nitrone 103 through a hydrolase-catalyzed kinetic resolution (KR). In particular, Candida antarctica lipase, fraction B (CAL-B), effectively catalysed the KR of ( )-103 in the presence of the acyl donor 104 in MeCN at 0-5 °C. The generated (R)-ester underwent a fast intramolecular 1,3-DC to 105 under the reaction conditions <05CC2369>. 

In an analogous manner several other isoxazolidines can be prepared. From the reaction of N,a-diphenylnitrone with... 

Some reactions with morpholinoenamines are anomalous thus with nitrone m and 1-morpholino-l-cyclohexene, a 5-hydroxyamino-isoxazolidine (13c) is formed 60 this, in turn, can be prepared from the same nitrone (lOj) and Af-phenylhydroxyaminocyclohexene. With 1-morpholino-1 -cyclopentene, a mixture of adducts 13d (12.4%) and... 

Some reactive nitrones dimerize to isoxazolidines immediately on formation. Thus, a nitrone 16c, which is prepared from /V-phenylhydroxyl-amine and dimethyl acetylenedicarboxylate, dimerized to isoxazolidine (25).44 A-Phenylhydroxylamine and H-butyraldehyde gives a-(w-propyl)-A-phenylnitrone, which dimerizes in a similar manner.10 ... 

An elegant enantioselective synthesis was described by Konoshu and Oida [62] Nitrone 72, prepared from the chiral aldehyde 71, with (R) absolute configuration, underwent intramolecular cycloaddition and yielded isoxazolidine 73 with high diastereoselectivity (73 74 =15 1). The cycloadduct 73 was transformed into natural cispentacin 5 in four steps (Scheme 11). The reaction conditions were the same as for the synthesis of racemic 2-ACPC (see Scheme 3). 

Allylie and homoallylic secondary amines were prepared by reductive cleavage of isoxazolidines formed by dipolar cycloaddition of nitrones with vinyl- and allyl-silanes, respectively (Scheme 27).65 The approach is useful because the geometry of the alkene can be controlled by choosing the conditions of elimination. Azaphospha macrocycles have been prepared from diethylenetriamine. 

Cycloadditions of chiral nitrones 86 and 87, easily prepared from o-xylose, to vinylated nucleobases 88 derived from uracil and adenine proceeded re-gioselectively and led to the isoxazolidines 89-91 as a mixtiu e of four dia-stereoisomers in aU cases (Fig. 19). In the case of cycloadditions of nitrones 86 and 87 with 9-vmyladenine 88b an inseparable mixture of the adenosine diastereoisomers was obtained. To improve the separation, the free amino group of the adenine moiety was protected. The cycloaddition of nitrone 86 with N,N-dimesylated 9-vinyladenine 88b proceeded with better selectivity in favor of the anti-cis isomer 91a. 

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