Tricyclic isoxazolidine

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]. 

Similar oxidative ring opening occurs in other bi- and tricyclic isoxazolidines upon treatment with m-CPBA (126, 127). 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

Nitrones can be generated by Michael reaction of oximes with appropriate conjugated substrates.25 If a generated nitrone has a built-in dipolarophile, cyclization can ensue (Scheme 15). There are three synthetic variations on this theme.25a,b First, the oxime may contain the dipolarophile as in (56). Reaction of (56) with phenyl vinyl sulfone provided a quantitative yield of the tandem product as one stereoisomer. Alternatively, die dipolarophile can reside in the Michael substrate as in (57). Reaction of (57) with cyclohexanone oxime produced two isoxazolidines from competitive cyclization of the intermediate nitrone through six- and seven-membered carbocyclic transition states. It is also possible to carry out an intramolecular Michael addition followed by an intramolecular nitrone cyclization as in thermolysis of (58) to produce a tricyclic isoxazolidine. Very recently several examples of a tandem Diels-Alder, Michael addition, nitrone cyclization sequence have been reported.250... 

Scheme 21 Access to tricyclic isoxazolidines by an inter-intramolecular cross-coupling-cydoaddition cascade [81]...

Insoluble polymer-supported dipolarophiles such as 92 were used to mask the nitrone moiety of the chiral pyrroline A-oxide 91 to prevent racemization at the vicinal stereogenic center by temporary formation of the resin linked isoxazolidines 93. A thermally induced 1,3-dipolar cycloreversion was used to cleave the product from the resin and restore the 1,3-dipole functionality which underwent intramolecolar 1,3-DC to afford the enantiomerically pure tricyclic isoxazolidine 95 <03SL1889>. 

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>. 

Under analogous reaction conditions, tricyclic isoxazolidines 85c afforded the p-homoprolines 87, probably by ring opening and A-acylation of the primary carbapenam intermediates 86c <04EJ02205>. The chemistry of spirocyclopropane isoxazolidines 85 as versatile precursors of different azaheterocycles has been reviewed <04M649>. 

Tricyclic isoxazolidines. The possibility exists for an intramolecular reaction following oximation of certain ketones that contain double bonds at proper distances. Based on this concept, a potential precursor of histrionicotoxin has been assembled. 

The masked p-benzoquinone 50 reacted with the nitrone 51 to give solely the tricyclic isoxazolidine 52 with complete regio- and stereospecificity. The product was converted into compound 53 by ba.se-promoted elimination of thiophenol <97JOC7781>. 

Peracetic acid added dropwise at 0-5° with stirring to the startg. tricyclic isoxazolidine, stirring continued 2 hrs. at 0°, neutralized with NaHGOg, ether... 

The intramolecular [2+3] cycloaddition of the nitrone derivative 31 followed by hydrogenolysis in methanol-hydrochloric acid of the N-O bond in the intermediate tricyclic isoxazolidine with concomitant removal of the benzylidene group, furnished compound 32. ... 

---