Asymmetric reaction nitrile oxide addition

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]. 

The [2 + 3] cycloaddition reaction of nitrile oxides, easily accessible from corresponding aldoximes, with different alkenes is known as an excellent route to isoxazohne derivatives . The reactions of asymmetric addition ° or addition of unsaturated ger-manes and stannanes to nitrile oxides were reviewed in recent years. In this subsection only the main directions of the synthesis of isoxazole derivatives are briefly reported. 

Another impressive example of the transition metal-catalyzed Michael reaction was reported by Sawamura and Ito in 1992 (Scheme 6) [7]. a-Methylcyanoacetate was treated with enones using 1 mol% Rh-TRAP (12) complex, and the corresponding adduct 13 was formed in up to 93 % ee. For this reaction, the trans-coordination mode of the chiral diphosphine 12 was essential for high asymmetric induction. It was proposed that coordination of the nitrile group to Rh, then oxidative addition of the active methine C-H bond gave not the a-C-bound enolate, but the nitrile-coordinating enolate 14, which was considered to be a reactive intermediate. The unique structure of this enolate was supported by X-ray analysis of a similar achiral Ru-cyanoacetate complex [8]. 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

New asymmetric reactions utilizing tartaric acid esters as chiral auxiliaries (formation of N- and A,0-heteroeyeles by nucleophilic addition of iminoderivatives or 1,3-dipolar cycloaddition of nitrile oxides and nitrones) 03SL1075. 

The mechanism of the related palladium-catalyzed asymmetric hydrocyanation of alkenes has also been examined in detail using [Pd(RR-diop)(C2H4)] and related chiral species as precursor complexes. These additions gave the exo nitrile product with up to 40% enantiomeric excess, indicating stereoselective complexa-tion of norbornene to the Pd(0) via the exo face. The plausible reaction intermediates [Pd(diop)(norbornene)] and the hydrido cyanide (60) were characterized by and P NMR spectroscopy. Oxidative addition of HCN to Pd(0) is believed to precede rate-determining alkene binding. 

Another [3+2]-cycloaddition process that has proven value in the construction of macrocyclic natural products, but has been underexplored to date for medicinal chemistry purposes, is the intramolecular addition of nitrile oxides (typically generated in situ from the corresponding oxime) with alkenes (Scheme 11.23). For example, this reaction has been employed for the conversion of oxime-acrylate 172 into 173, an intermediate for the synthesis of the macrosphelide skeleton, and for the construction of macrocycles useful in studies directed towards an asymmetric synthesis of brefeldin... 

Enantiopure sulfinimines (thiooxime-S-oxides) 44 have been reported to facilitate the asymmetric Strecker reaction.28 Davis found that typical cyanide sources, such as potassium cyanide and TMSCN, did not possess sufficient reactivity for addition to the sulfinimines. Product 46, however, could be obtained using the more Lewis acidic Et2AlCN. Not only did the coordination of the aluminum to the oxygen of the sulfinimine activate the imine toward nucleophilic addition, this complexation also facilitated the delivery of the nitrile (see 45), These results triggered numerous modifications and variations that have enhanced this approach to chiral a-amino acids. 

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