A-protected hydroxylamines

O-Tetrahydropyran-2-ylhydroxylamine (35)46 shows considerable promise as a protected hydroxylamine for use in hydroxamic acid synthesis, as exemplified by the synthesis46 of l-hydroxy-2-thiouracil (36). 

A milder alternative to the classical Gabriel synthesis, which allows the appendage of a protected primary amine to a secondary alkyl group, exploits the Mit-sunobu inversion as illustrated in Scheme 8.15. The method can also be adapted to the synthesis of A/-protected hydroxylamines [Scheme 8.16]. ... 

Next came the challenging task of introducing the hydroxylamine moiety in an asymmetric fashion. To acconplish this we fbrst needed access to enantiomerically enriched/pure 3-iodocyclopent-2-enol (24), then we needed to establish that this allylic alcohol would undergo Sk2 reaction with a protected hydroxylamine nucleophile without loss of stereochemical integrity. We found that racemic 3-iodo-cyclopent-3-enol 23 could be prepared in high yield by Luche reduction (17) of enone 22. After screening a number of lipases we found... 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

Figure 27.8 SATA may be used to modify a 5 -amine derivative of an oligonucleotide, forming a protected sulf-hydryl. Deprotection with hydroxylamine results in generation of a free thiol.

The organosilane reduction of hydrazones to hydrazines is readily accomplished in good yields with Et3SiH/TFA (Eq. 336).560,561 (V-Tosylimines294 are reduced to their A-Boc tosylamino counterparts,294 and are also reduced with (MeO)3SiH/LiOMe in good yields.294 Benzyl-protected hydroxylamines are reduced with PhMe2SiH/TFA.551... 

Nucleophilic addition of metallated heterocyclic derivatives to AMetrahydro-pyranyl (THP) protected nitrones (361) makes it possible to synthesize a-branched hydroxylamines (362) (Table 2.13) (597). 

The analogous transformation of 125, also realized by flash vacuum pyrolysis, gave rise to allenic oximes 126 [165], which are not directly accessible by the classical route starting from allenyl ketones and hydroxylamine (see Section 7.3.2) [122], Because compounds 125 are prepared from allenyl ketones and furan by [4 + 2]-cycloaddition followed by treatment with hydroxylamine, the retro-Diels-Alder reaction 125 —> 126 is in principle the removal of a protecting group (see also Scheme 7.46). 

Aziridines represent an important class of building block within synthesis. This structural motif is also embedded within a number of biologically significant natural products, and thus robust and efficient methods for their construction represent an important contribution to the synthetic toolkit. Cordova reported an enantiose-lective aziridination of a,P-unsaturated aldehydes catalysed by diarylprolinol ether 30 using protected hydroxylamine 91 as the nitrogen source (Scheme 38) [150]. The reaction was proposed to proceed via iminium ion formation followed by... 

The transformation of endocyclic nitrone 56 (made from N,0-bis-protected hydroxylamine 55) to lactam 20 can be carried out by photochemical activation or by a two-step modification of Barton s protocol, that is, by trapping the nitrone oxygen followed by an alkali-promoted, semi-pinacol-like rearrangement (03JOC8065). 

Due to a much lower danger of dialkylation, alkylation of iV-alkyl- and Ai-alkyl-O-protected hydroxylamines (e.g. 8, equation 6) with primary alkyl halides proceeds substantially more selectively giving high yields of Al,Al-disubstituted products " of type 9. 

Multicomponent reactions have recently become one of the favored methods to prepare pharmacologically important compounds. Ugi condensations with O-protected hydroxylamines have been successfully performed in THE using ZnCl2 as activating agent (Scheme 56). This synthetic strategy opens up the route to a very convergent assembly of internal hydroxamic acid derivatives (A-acyl-A-hydroxypeptides 109)" . 

The direct solution-phase hydroxyamination of esters is commonly accomplished by a two-step preparation of the potassium salt of hydroxylamine followed by the addition of the ester in alcohol". Alternatively, the stepwise saponification of the ester to the acid is followed by activation of the acid as acyl chloride or mixed anhydride and then by quenching with an O-protected hydroxylamine analogue". In special cases, the hydrox-yamination of ester substrates has been achieved via enzymatic methods" or, for more reactive esters, by treatment with excess hydroxylamine in alcohol". ... 

Concentrated nitric acid passivates many metals, such as, iron, cobalt, nickel, aluminum and chromium, forming a protective film of oxides on their surfaces, thus preventing any further reaction. Very dilute nitric acid is reduced by a strong reducing agents, such as metallic zinc, to form ammonia and hydroxylamine, NH2OH. 

J. L. Romine, Bis-Protected Hydroxylamines as Reagents in Organic Synthesis. A Review Org. Prep. Proced. Int. 1996, 28, 249-288. 

The same proline derivative 77 was found to catalyze a highly enantioselective synthesis of 5-hydroxyisoxazolidines 79 hy tandem reaction of -protected hydroxylamines and enals. In situ oxidation of 79 by NaC102 afforded directly /V-protected 5-isoxazolidinones 80 in high yield and ee... 

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