Hydroxylamines configurations

One of the most important routes to isoxazole and isoxazoline rings involving the formation of the 1—5 and 2—3 bonds involves the condensation of hydroxylamine with a,/8-unsaturated carbonyl compounds. This method was previously widely used, but it is now of no preparative value, though it has been recently applied to determine the configuration of oximes. " The only new modification of this synthesis is the use of the acetals (27) of a,/8-acetylenic aldehydes for preparation of 5-substituted isoxazoles (28)... 

The ( + )-(/ )-methyl 4-tolyl sulfoxide anion from 1 reacts with nitrones 2 to afford optically active hydroxylamines with very high fi stereoselectivity5. The diastereomeric ratio of the products 3 a, b varies from d.r. 75 25-100 0, the highest being for R = t-Bu. The configuration of the diastereomers 3 a, b has not been determined. 

W-benzyl-TV-hydroxylamine)phenylmethyl]-3-hydroxybutanoate (398) (637). The absolute configuration (398) was determined as (aRfiS,yR) thus, diastere-oselective addition of ketene silyl acetals (397) to nitrone proceeds as anti-a, p-anti-p, y (Scheme 2.176). 

Alkylation of hydroxylamines with secondary alkyl halides and alkyl sulfonates like 10 (equation 7) is one of the most frequently used synthetic approaches, especially to enantiomerically pure hydroxylamines such as 11 (equation 7). The reaction proceeds with inversion of configuration and does not produce appreciable amounts of diaUcyla-tion products. Both hydroxylamine as well as N- and O-alkylhydroxylamines have been successfully used. Alkyl trillates are probably the most useful substrates for these transformations since they can be prepared from a large pool of commercially available enantiomerically pure chiral secondary alcohols. 

Stereoselectivity in reductions of acyclic oximes depends on the configuration of C=N bond. ( )-Isomer of oxime 89 produced syn-hydroxylamine 90 in excellent stereoselectivity in reaction with phenyldimethylsilane-trifluroacetic acid while giving anti-product in the reaction with lithium aluminium hydride. Stereoselectivity in reductions of (Z)-isomers of 89 was substantially lower in both cases (equation 62) . It can be assumed that the rules of stereoselectivity established in diastereoselective reduction of ketones can be applied to reduction of oximes as well. 

The Beckmann rearrangement is known to occur with retention of configuration at the migrating carbon . Treatment of 329 with hydroxylamine-0-sulfonic acid enabled a Beckmann rearrangement with complete retention of configuration at the migrating carbon and enantiopure cyclobutane amino acid 330 could be obtained (equation 122). 

Harger has studied the rearrangement of A-substituted N-phosphinoylhydroxylamines in the presence of base . He proposed a concerted mechanism based on the observed retention of the configuration at the phosphorous center during the transposition , and on studies with 0-labelled compounds . Similar cyclic transition states 572 were proposed in the base-induced rearrangement of A,0-bis(diphenylphosphinoyl)hydroxylamines (571) (equation 254). However, in the rearrangement of O-benzoyl-A-(diphenylphosphino-thiol)hydroxylamine where a transposition of O and S atoms occurs, the proposed cyclic transition state has sulfur participation . 

In all cases, the free a-substituted benzylamines with R configuration were obtained by transimination with hydroxylamine acetate41,42. 

Mukund Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2004,126,718) a powerful three-component coupling, combining an a,(5-unsaturated amide 9, a hydroxylamine 10, and an aldehyde 11. The hydroxylamine condenses with the aldehyde to give the nitrone, which then adds in a dipolar sense to the unsaturated ester. The reaction proceeds with high diastereocontrol, and the absolute configuration is set by the chiral Cu catalyst. As the amide 9 can be prepared by condensation of a phosphonacetate with another aldehyde, the product 12 can be seen as the product of a four-component coupling, chirally-controlled aldol addition and Mannich condensation on a starting acetamide. 

Oximation of the jS-diketone (3) gave the H-bonded enol form of the monooxime (4).8 Its Z-configuration and resistance to further attack by hydroxylamine were attributed to chelation, which is also regarded as responsible for the forced regiospecificity. Cyclization was effected by heating with acetyl chloride, a procedure also claimed for the cyclization of the oxime (5).9... 

The configuration at a-C in 8 (R-C6H5) was assigned by its conversion to (-)-norephedrine (11, R = C6H5). After hydrolysis of crude 8 (R = C6H5) evaporation of the aqueous phase, erythro-selective reduction of the /J-keto-Ar-hydroxylamine hydrochloride 9 with sodium boro-hydride in methanol to 10 followed by reductive cleavage of the N-O bond afforded (-)-norephedrine (11, R = C6H5) in 68% overall yield (erythro/threo 95 5 ee 96%). 

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