Isoxazolidine cycloadducts

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. 

Isoxazolidine cycloadducts (491) undergo easy transformation into a-amino-y-lactones (494), which can be readily converted into y- hydroxy-a-amino acids (495) (Scheme 2.240) (Table 2.19). 

Ochiai s landmark paper of 1967, which outlined the basis of the 1,3-APT (Section 1.11.1), also described the reaction of formaldoxime with alkenes and alkynes (284). The oxime 310, behaving as a 1,3-dipole, afforded isoxazolidine cycloadducts 311 through a thermally driven equilibrium (heavily favoring the oxime) in which a proton is transferred from O to N (1,2-prototropy) to afford nitrone 312 (Scheme 1.65). 

Cyclopentyl isoxazolidine cycloadduct 324 was prepared by intramolecular nitrone cycloaddition by Baldwin et al. (280,281,352,353) as part of studies toward a total synthesis of pretazettine (Scheme 1.69). Related adducts have been prepared elsewhere (354—356) including fluorine-substituted carbocycles (357) and the adducts prepared by lOAC by Shipman and co-workers (333,334) who demonstrated their potential as a route to aminocyclopentitols (Scheme 1.66, Section 1.11.2). Such bicyclic structures have been prepared in rather unique intermolecular fashion by Chandrasekhar and co-workers (357a) from the cycloaddition of C,N-diphenyl nitrone to fulvene (325). 

A number of unusual nitrones have been reported from which novel isoxazolidine cycloadducts were prepared. These include the adamantyl dipoles 340,... 

Several years later, Ioffe et al. (16) demonstrated that silyl nitronates also could be engaged in the dipolar cycloaddition with alkenes. These silylated isoxazolidine cycloadducts were then converted to the corresponding isoxazolines by treatment with sodium methoxide (Scheme 2.2). 

The reactions of the vinyl sulfoximines 281 with C./V-diphenylnitrone 282 are highly regioselective and give only 4-sulfonimidoyl-isoxazolidine cycloadducts 283 and 284.104 These reactions proceed with modest n-facial selectivity with respect to the dipolarophiles 281. The stereochemical outcomes of these reactions are consistent with attack on the ground-state conformation 238 of the sulfoximine through an endo -like transition state. 

The Cu(II)-BOX-complex-catalysed 3 + 2-cycloaddition of nitrones with 2-alkenoyl pyridine A -oxide formed isoxazolidines with high diastereo-and enantio-selectivities. ° Microwave catalysis of the 1,3-dipolar cycloaddition of 0 nitrones with tetraethyl l,l-ethenediylbis(phosphonate) produced isoxazolidine (g) bisphosphonates in the absence of solvents. The intennolecular 1,3-dipolar cycloaddition of dimethyl 2-benzylidenecyclopropane-l,l-dicarboxylate with C-aryl or C-amido nitrones formed spiro(cyclopropane-l,4-isoxazolidine) cycloadducts The 1,3-dipolar cycloaddition of nitrones (52) with vinylidenecyclopropanes (53) produced 4-cyclopropylidine-isoxazolidines (54) in moderate yields (Scheme 16). ... 

At equilibrium, all four compounds are present in the exchange pool with some slight selectivity for the two nitrones. Addition of any maleimide species irreversibly transferred the nitrone structmes from the DCL into the product pool by forming the isoxazolidine cycloadduct. In the case of the recognition-disabled methyl ester 57, reaction with the nitrone species was slow and unselective. Both nitrones were converted in the same extent, and the... 

Cu(OTf)2/(49) was also reported to be efficient for exo selective nitrone cycloadditions to a-substituted and a,P-disubstituted dipolarophiles (323) (Scheme 17.71) [102]. In this report, the use of a,P-disubstituted acrylimides proved critical to providing the enhanced reactivity necessary for cycloadditions with a,P-disubstituted substrates. The isoxazolidine cycloadducts (324) and (325) are isolated in moderate to good chemical yields with high enantioselectivity and good to excellent exo endo ratios. 

The copper-catalysed 3 + 2-cycloaddition reactions of nitrones with alkynes leading to / -lactams have been extensively reviewed. The 3+2-cycloaddition reactions of dialkyl-substituted 2-benzylidenecyclopropane-l,l-dicarboxylates (54) and C-carbamoyl nitrones (53) produced simple isomeric spiro[cyclopropane-l,4-isoxazolidine] cycloadducts (55), which are readily transformed into isoxazolidine-fused / -lactams (56) in high yields (Scheme 15). BINOL-derived chiral phosphorami-date Au(l) catalysts have been used to catalyse the 3+2-cycloaddition of A(-allenyl amides with nitrones to produce chiral 4-alkylidenyl isoxazolidines in high yields and excellent enantioselectivity (up to 99% cc). The 3+2-cycloaddition of a-phenylnitroethene and (Z)-CA -diphenylnitrone in polar media (nitromethane and water) yielded 3,4-fra 5 -2,3,5-triphenyl-4-nitroisoxazolidine via a zwitterionic, two-step mechanism. ... 

---