Isoxazolidine synthesis

Isoxazolines and isoxazolidines, synthesis from aliphatic nitro compounds... 

A recent example of isoxazolidine synthesis that involves generation of an allylpalladium complex via allylic C—H activation was reported by the White group [90]. As shown below (Eq. (1.52)), treatment of homoallylic carbamate 128 with Pd(OAc)2 in the presence of sulfoxide ligand 130 and phenylbenzoquinone (PhBQ) provided 129 in 72% yield with 6 1 dr. A related transformation that affords indohne products has been described by Larock [17a]. 

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). 

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. 

IsoxazoIidine-3,3-dicarboxylic acid, 2-methoxy-dimethyl ester reaction with bases, 6, 47 Isoxazolidine-3,5-diones synthesis, 6, 112, 113 Isoxazoli dines conformation, 6, 10 3,5-disubstituted synthesis, 6, 109 oxidation, 6, 45-46 PE spectra, 6, 5 photolysis, 6, 46 pyrolysis, 6, 46 reactions, 6, 45-47 with acetone, 6, 47 with bases, 6, 47 reduction, 6, 45 ring fission, S, 80 spectroscopy, 6, 6 synthesis, 6, 3, 108-112 thermochemistry, 6, 10 Isoxazolidin-3-ol synthesis, 6, 111 Isoxazolidin-5-oI synthesis, 6, 111... 

Isoxazolidin-5-one, 2-methyl-3-phenyl-synthesis, 6, 113 Isoxazolidinones synthesis, 6, 112-114 IsoxazoIidin-3-ones synthesis, 6, 112 Isoxazolidin-4-ones synthesis, 6, 113 Isoxazolidin-5-ones synthesis, 6, 113... 

The high enantioselectivity of the exo product opens up a new and readily accessible route to an enantioselective synthesis of interesting isoquinoline alkaloids (Scheme 6.15) [35]. The tricyclic isoxazolidine exo-15b was obtained from the 1,3-dipolar cydoaddition reaction as the pure exo isomer and with 58% ee [34]. As shown in Scheme 6.15 the exo product from the 1,3-dipolar cydoaddition was converted into 17 in two steps without racemization at the chiral center. In addition to the illustrated synthesis, the 6,7-dimethoxy-derived isoxazolidine exo-15b is a very useful precursor for the synthesis of naturally occurring isoquinoline alkaloids [36-40]. 

The key step in the synthesis of 4-354 is the retro-1,3-dipolar cycloaddition of the isoxazolidine 4-351 to give the nitronate 4-352, which underwent an intramolecular 1,3-dipolar cycloaddition. The obtained cycloadduct 4-353 can be transformed in a few steps into the desired target 4-354 (Scheme 4.78). 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

In the overall cycloaddition-rearrangement process [64], the C-3 - C-8a relative stereochemistry of the indolizidinone obtained by rearrangement of the isoxazolidine derives from the cycloaddition step and is not affected during the rearrangement. This allowed the control of two out of three chiral centers in a synthetic protocol for a synthesis of the amphibian alkaloid ( + )-Gephyro-toxin 223AB (Scheme 46) [65c]. 

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. 

The reaction of silyl ketene acetal addition to nitrones has been used for the synthesis of optically active (2S,3S)-benzoyl- and /V- oc-phenyl isoserine (636a) of isoxazolidine nucleoside-analog of thymine polyoxine C(636b) and of... 

The reaction of O-methyl-O-tert-butyldimethylsilyl ketene acetal with N-benzyl- and A-methyl-2,3-O-Mopropylidene D-glyceraldehyde nitrones (292), in the presence of boron trifluoride etherate, affords the corresponding isoxazolidine-5-ones in high yields. These compounds were successfully applied as key intermediates in the synthesis of isoxazolidinyl nucleosides of the L-series (Scheme 2.177) (638). 

The tricyclic compound (441) is a key compound in the synthesis of enan-tiomerically pure indolizidine (442). It was obtained in an intramolecular 1,3-cycloaddition of nitrone (440), by retro-cycloaddition from isoxazolidine (439) (Scheme 2.215) (708). 

Cycloaddition of nitrone (26) to allylamine (538) leads to the synthesis of chiral tetracyclic isoxazolidine (539) which is used in the preparation of compound R107500. This compound has been found to be active as an antiolytic and antidepressant. It also has the potential to inhibit drug abuse (Scheme 2.252) (80). 

Dipolar cycloaddition reactions between three A-benzyl-C-glycosyl nitrones and methyl acrylate afforded key intermediates for the synthesis of glyco-syl pyrrolidines. It was found that furanosyl nitrones (574) and (575) reacted with methyl acrylate to give mixtures of all possible 3,5-disubstituted isoxazolidines (577) and (578). On the other hand, the reaction with pyranosyl nitrone (576) was much more selective and cycloaddition at ambient temperatures afforded only one of the possible Re-endo adducts (579a). The obtained isoxazolidines were transformed into the corresponding (V-benzyl-3-hydroxy-2-pyrrolidinones (580—582) on treatment with Zn in acetic acid (Scheme 2.264) (773). 

Recently, dipolarophile 1)13 (fumaronitrile) (777) has been used in the synthesis of indolizine lactone (677). Both, intermolecular and intramolecular cycloadditions were studied. Intermolecular 1,3-cycloaddition of nitrone (671) to D13 led to the formation of isoxazolidine (672). Subsequent deprotection and esterification of the obtained alcohol (673) with (674) gave isoxazolidine (675) in 65% yield. Ester (675), when refluxed in xylene for 10 min, after elimination of fumaronitrile by cyclo-reversion, underwent spontaneously intramolecular cycloaddition to give the tricyclic cycloadduct (676) in 84% yield (Scheme 2.291). 

As a result, diastereo- and enantiomerically pure functionalized nitro derivative (205) was synthesized in satisfactory yield. This compound was used in the ISOC procedure, which gave diastereo- and enantiomerically pure isoxazolidine (206) in good yield. The latter compound can be considered as a possible reagent for asymmetric synthesis. It should be noted that silylation in this procedure, like that described above (Scheme 3.145), was performed with the use of BSA as the silylating agent in the presence of a small amount of Hunig s base, the latter being evidently added for acceleration of silylation and stabilization of intermediate silyl nitronate. 

Hinzen B, Ley SV (1998) Synthesis of isoxazolidines using polymer supported perruthenate (PSP). J Chem Soc Perkin Trans 11-2... 

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