Diisopropyl nitrile oxide cycloadditions, chiral

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

Most of the approaches outlined in Figure 15.10 have been successfully realized on insoluble supports, either with the alkene or alkyne linked to the support, or with support-bound 1,3-dipoles (Table 15.16). Nitrile oxides are highly reactive 1,3-dipoles and react smoothly with both electron-poor and electron-rich alkenes, including enol ethers [200]. The addition of resin-bound nitrile oxides to alkenes (Entries 5 and 6, Table 15.16) has also been accomplished enantioselectively under catalysis by diisopropyl tartrate and EtMgBr [201], The diastereoselectivity of the addition of nitrile oxides and nitrones to resin-bound chiral acrylates has been investigated [202], Intramolecular 1,3-dipolar cycloadditions of nitrile oxides and nitrones to alkenes have been used to prepare polycyclic isoxazolidines on solid phase (Entries 7 and 9, Table 15.16). 

A chiral zinc(II) complex derived from Et2Zn and diisopropyl (/ ,/ )-tartrate as a chiral auxiliary is applied to the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to an achiral allylic alcohol, giving the corresponding (R)-2-isoxazolines with high enantioselectivity. Addition of a small amount of ethereal compounds such as DME and 1,4-dioxane is crucial for achieving the high asymmetric induction in a reproducible manner [71] (Eq. 8A.47). 

Dipolar cycloadditions. In the reaction of allylic alcohols with nitrile oxides cocomplexation of the alcohol and diisopropyl tartrate to Zn directs the steric course in the formation of 2-isoxazolines. Bonding of the nitrones that participate in cycloadditions to the boron atom of a chiral oxazaborolidine (4) through their oxygen atoms is important to determine the transition states leading to isoxazolidine products. 

This result prompted us to first apply the strategy to the asymmetric 1,3-dipolar cycloaddition of nitrile oxides, which had not been developed when our research project started. The idea was presented as follows when nitrile oxide is generated in situ from hydroximoyl chloride by treatment with ethylzinc moiety as abase, the stereochemical course of nitrile oxide coordinated to the chiral zinc species 5 was anticipated to be controlled efficiently. In accordance with this hypothesis, the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to allylic alcohols was realized to afford the corresponding 2-isoxazolines 6 with excellent enantioselectivity (Eq. 11.3). Even when a catalytic amount (0.2 equiv) of diisopropyl (R,/f)-tartrate [(R,/ )-DlPT] was employed, the 2-isoxazolines 6 were obtained with the selectivity of up to 93% ee by the addition of a small amount of 1,4-dioxane (Eq. 11.4). This method was the first catalytic enantioselec-tive 1,3-dipolar cycloaddition of nitrile oxides with alkenes. The method was efficiently applied to the total synthesis of (—)-Lasubine 11 (Scheme 11.2) [11]. 

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