13-Dipolar cycloaddition Enantioselective allylation

The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 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). 

An enantioselective 1,3-dipolar cycloaddition reaction of nitrile oxides RCNO (R = Ph, MeOCgHq, p-ClCqHa, t-Bu or 11-C7H15) to allyl alcohol to give the isoxazolines 16 with ee... 

Pericas et al. prepared polystyrene-supported chiral phosphinooxazoline (PHOX) ligands having a 1,2,3-triazole tether, which was constructed by a 1,3 dipolar cycloaddition. The catalyst (50) gave allylamine from racemic allyl acetate in high yield with excellent enantioselectivity under microwave-assisted continuous-flow conditions (Scheme 7.37) [141]. Although the enantioselectivity was not changed, the catalytic activity of the polymer catalyst was decreased after 3 h. 

As an alternative, iridium complexes show exciting catalytic activities in various organic transformations for C-C bond formation. Iridium complexes have been known to be effective catalysts for hydrogenation [1—5] and hydrogen transfers [6-27], including in enantioselective synthesis [28-47]. The catalytic activity of iridium complexes also covers a wide range for dehydrogenation [48-54], metathesis [55], hydroamination [56-61], hydrosilylation [62], and hydroalkoxylation reactions [63] and has been employed in alkyne-alkyne and alkyne - alkene cyclizations and allylic substitution reactions [64-114]. In addition, Ir-catalyzed asymmetric 1,3-dipolar cycloaddition of a,P-unsaturated nitriles with nitrone was reported [115]. 

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]. 

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]. 

First, the 1,3-dipolar cycloaddition of l-alkylidene-3-oxopyrazolidin-l-ium-2-ide 11 was examined. In this case, a magnesium-mediated system instead of the zinc-mediated system was found to be effective to realize the asymmetric 1,3-dipolar cycloaddition, that is, to a mixture of allyl alcohol (lA) and (R,R)-DIPT were added 3.0 equiv of alkylmagne-sium bromide and azomethine imines 11 successively. The corresponding pyrazolidines 12 were obtained in a good chemical yield with the excellent enantioselectivities as listed in Table 11.1, even in the case of pentyl- and cyclohexyl-substituted ones llg and llh (entries 7 and 8) [14]. 

Asymmetric 1,3-dipolar cycloadditions of azomethine imines with terminal alkynes have been catalysed by 11 chiral ligand (8) coordinated metal amides to form N,N-bicyclic pyrazolidinone derivatives. Mechanistic studies have established the factors that determine the regioselectivity of the stepwise reaction. Novel phosphoramidite ligands (9) coordinated with palladium have been used to effect enantioselective synthesis of pyrrolidines by 3-P 2-cycloaddition of trimethylenemethane (from 2-trimethylsilylmethyl allyl acetate) to a wide range of imine acceptors (Scheme 11). ... 

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