Mitsunobu reactions hydroxylamine synthesis

Intermolecular reactions of hydroxylamines with secondary alkyl halides and mesylates proceed slower than with alkyl triflates and may not provide sufficiently good yield and/or stereoselectivity. A nseful alternative for these reactions is application of more reactive anions of 0-alkylhydroxamic acids or 0-alkoxysulfonamides ° like 12 (equation 8) as nucleophiles. The resulting Af,0-disubstituted hydroxamic acids or their sulfamide analogs of type 13 can be readily hydrolyzed to the corresponding hydroxylamines. The same strategy is also helpful for synthesis of hydroxylamines from sterically hindered triflates and from chiral alcohols (e.g. 14) through a Mitsunobu reaction (equation 9). 

The strategy was chosen to (1) link the amino acid derivative to a polystyrene-supported hydroxylamine, (2) carry out the cyclization under Mitsunobu conditions, and (3) assemble a short peptide on the free amino group present in the ring. This approach has been shown to be suitable particularly for solid-phase synthesis, as the supported (3-lactam could be easily separated from the by-products of the Mitsunobu reaction. The linker employed was a polystyrene resin carrying 0-trityl-hydroxylamine linker, prepared according to the literature procedure [151]. After the deprotection of Fmoc group carried out with 20% piperidine in DMF, the L-cbz-serine (or L-cbz-threonine) was coupled using (4,6-Dimethoxy-[l, 3, 5]-triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM) [152] in M-methylpyrrolidone (NMP) in the presence of M,M-diisopropylethylamine (DIPEA) (Schemes 42 45). 

Based on the Amaryllidaceae alkaloid galanthamine, a biomimetic solid-phase synthesis of 2527 compounds was reported by Shair and coworkers (Figure 11.13) The core scaffold, initially prepared in several steps, was diversified by means of four successive reactions Mitsunobu reaction of the phenolic moiety with five primary alcohols, Michael addition of the a, 3-unsatnrated cyclohexenone with thiols, iV-acylation or A -alkylation of the cyclic secondary amine, and treatment of the ketone with hydrazines and hydroxylamines. Further evaluation of library constituents for their ability to block protein trafficking in the secretory pathway of mammalian cells led to the discovery of sercramine as a potent inhibitor of the VSVG-GFP protein movement from the Golgi apparatus to the plasma m brane. 

Two different N-protected hydroxylamines have been used to accomplish the synthesis of these novel hydroxylamine-functionalized resins. fV-Hydroxy-phthalimide has been employed in two ways first, as a nucleophile to splace either a resin-bound chloride ion (30) or a resin-bound mesylate ion (31) Figure 8a) and second, to generate the active phosphonium species required to perform a Mitsunobu reaction on a hydroxyl-functionalized resin (32) (Figure 8b). In both cases, the resin-bound iV-hydroxyphthalimide ester that is generated is subsequently treated with hydrazine to afford resin-bound hydroxylamine. 

Figures. Synthesis of a resin-bound /V-hydroxyphthaiimide ester via (a) dispiacement of a mesyiate or chloride ion or (b) a Mitsunobu reaction, foilowed by hydrazinolysis to generate a resin-bound hydroxylamine.

It has been shown that during the synthesis of the nitrile 124 by free radical chemistry (Vol. 22, p. 214), some of the C-3 epimer is also formed. 156 Nitrile 124 was used in an alternative route to 3 -deoxy-3 -C-hydroxymethylthymidine 125 (see Vol. 25, p. 257) Mitsunobu reaction with N-hydroxyphthalimide at the branched hydroxymethyl group gave an (9-alkyl hydroxylamine used to make the dinucleotide analogue 91 (see Section 6). 126 The 3 -aldehyde formed as an intermediate in... 

The strategy of releasing amides (Scheme 43) can be applied to the synthesis of lactams by immobilization of acids containing a /3-hydroxy functionality 284. Ring closure can be carried out under Mitsunobu conditions as shown in a publication of Taddei et al. in 2001 [219]. The authors chose an 0-trityl-hydroxylamine resin for the reaction sequence because other linker types as for example a Wang-type resin carrying a hydroxylamine functionality failed. 

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