Isoxazolidines, enantioselective synthesi

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]. 

Recently, analogous nitrones have been used by others in the synthesis of (2S)-4-oxopipecolic acid [45] and (-l-)-negamycin [46]. Chiacchio et al. [47] applied the Vasella-type nitrone 53 in an enantioselective synthesis of isoxazolidinyl thymine 55 (Scheme 10.18). As illustrated, the A-furanosyl nitrone 53 reacted with vinyl acetate to give a 1 1 mixture of two isoxazolidines 54 epimeric at C-5. In contrast to the poor cw/tran -diastereoselectivity, the diastereofacial selectivity... 

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). 

Asymmetric and enantioselective olefination reactions continue to be of interest. Wadsworth-Emmons reactions of 4-substituted cyclohexanones with the phosphonate (147), which carries a chiral benzopyrano-isoxazolidine substituent, proceed with diastereomeric excesses of 80-90% and hence provide another example of such an approach to enantiomerically pure, axially dissymmetric cyclohexylidene derivatives. A further example of trapping of in situ generated ketenes by Wadsworth-Emmons reactions to give allene carboxylates has been reported and the reaction has been extended to enantioselective synthesis by use of the optically active phosphonates (148) (Scheme 14). Moderate to good chemical yields and e.e. values up to 84% were obtained depending on the nature of (148) and the reactions conditions. 

Dipolar cycloadditions between nitrones and alkenes are most useful and convenient for the preparation of isoxazolidine derivatives, which are readily converted to 1,3-amino alcohol equivalents under mild reducing conditions (Tufariello 1984, Torssell 1988). In spite of the importance of chiral amino alcohol units for the synthesis of biologically important alkaloids, amino acids, 3-lactams, and amino sugars, etc. (for a review see Frederickson 1997), catalytic enantioselective 1,3-dipolar cycloadditions remain relatively unexplored (Seerden et al. 1994, 1995, Gothelf and Jorgensen 1994, Gothelf et al. 1996, Hori et al. 1996, Seebach et al. 1996, Jensen et al. 1997). Catalytic enantioselective... 

Recently, the scope of gold-catalyzed intramolecular exo-selective hydroaminations was expanded to allenic hydrazines and hydroxylaminesJ The former substrates afforded pyrazolidines in the presence of DTBM-SEGPHOS-Au complex J, whereas [Au2 (R)-xylyl-BINAP (OPNB)2] gave the best results in the cyclization of hydroxylamine derivatives to isoxazolidines. Excellent chemical yields and enantioselectivities were obtained in most cases, and the method was also applied to the synthesis of chiral tetrahydrooxazines. 

Cordova and co-workers developed a highly enantioselective three-component synthesis of isoxazolidines 266. The reactions were carried out between A -arylhydroxylamines, aldehydes and o,(i-unsaturated aldehydes, Scheme 3.84 [106],... 

Very recently, Maruoka reported an alternative catalytic asymmetric [3 + 2] cycloaddition reaction between various nitrones and acrolein catalyzed by the x-oxo-type chiral bis-Ti(IV) oxide, giving rise to the corresponding isoxazolidine derivatives in good yields and high enantioselectivities [177]. This type of titanium Lewis acid has also been used in enantioselective 1,3-dipolar cycloaddition of diazoacetates to various substituted acroleins, affording 2-pyrazolines with a chiral quarternary carbon center (Scheme 14.78) [178]. The products obtained with these methodologies have been applied to the synthesis of natural product and biologically important molecules. 

The asymmetric 1,3-dipolar cycloaddition of nitrones instead of nitrile oxides was also realized The nitrones 7 possessing an amide moiety were reacted with allylic alcohols 1 (R, R = H) by the use of a catalytic amount of (R,R)-DIPT as a chiral auxiliary to afford the corresponding 3,5-cw-isoxazolidines 8 with high regio-, diastereo-, and enantioselectivity up to over 99% ee (Eq. 11.5). This asymmetric 1,3-dipolar cycloaddition was applied to the synthesis for the (25,4R)-4,5-dihydroxynorvaline derivative 10, which is a key component of polyoxin E, via amino alcohol intermediate 9 (Scheme 11.3) [12]. 

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