Mitsunobu hydroxamic acids

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). 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

A combination of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobu reagent) is useful for the rapid conversion of aromatic hydroxamic acids (211) to 0-(yV-arylcarbamyl)hydroxamates (212), products of the Lossen rearrangement. In some cases, a spontaneous second Lossen rearrangement occurs to give diarylureas (213), as shown in Scheme 33. The yields of (212) and (213) are 70-85%. The intermediacy of the phosphonium salts (214) has been suggested. 

D-Arabinonohydroxamic acid 5-phosphate 58, a potent transition state inhibitor of D-glucose 6-phosphate isomerase, was made from 2,3,4-tri-O-benzyl-D-arabinonic acid 5-(dibenzyl phosphate) by condensation with 0-benzylhydroxyla-mine (using carbonyldiimidazole) followed by hydrogenolysis. o-Arabinono-hydroxamic acid itself and o-threonohydroxamic acid, potent inhibitors of D-xylose isomerase, were obtained similarly. As exemplified in Scheme 11, the addition of AT-benzylhydroxylamine to unsaturated lactones such as 59 provided easy access to precursors of 3-amino-2,3-dideoxy-sugars (e.g. 60). These could be inverted at C-5 by Mitsunobu or sulfonate displacement reactions, or converted to isomeric isoxazolidines, e.g. 62, via epoxide 61. ... 

Alkylation of hydroxamic acids as a method of co-N-hydroxyamino acids (2) synthesis was introduced by Maurer and Miller 196), When N- r -butoxycarbonyl-6-hydroxynorleucine benzylhydroxamate (248) or a homologue was treated with triphenylphosphine and diethylazodi-carboxylate (DEAD) under Mitsunobu conditions 197), intramolecular alkylation took place leading to N-hydroxylactams (249) or (250) as well as lesser amounts of hydroximates Z-(251) and -(252) (Scheme 50). The products were separated and distinguished by NMR spectrometry 196,198,199). Derivatives of the seven-membered N-hydroxylactam (253) were applied for the total synthesis of mycobactin S2 (254) 199) (Scheme 51). 

In the latest of a series of papers Miller and coworkers 202) described the alkylation of hydroxamic acids (263) with alcohol (262) under Mitsunobu conditions 197). In this manner, starting from glutamic acid they obtained several derivatives of N -hydroxyornithine (264-269) which were used subsequently in the synthesis of rhodotorulic acid 202) (Scheme 53). 

Taddei and coworkers [49] also reported an MW-promoted solid-phase synthesis of 3,6-disubstituted perhydro-diazepin-2,5-dione 70 (Scheme 10) involving a Mitsunobu cyclization of a hydroxamic acid derivative anchored to PS-DVB 2-chlorotrityl resin (69). The prepared compound was proved to be useful as constrained peptidomimetics. 

Synthesis of acid 129 starts from the commercially available 6-heptenoic acid (122), which upon reaction with (4S)-benzyloxazolidin-2-one (123) as the chiral auxiliary group yields the intermediate 124, hydroxymethylation of which affords compound 125. Hydrolysis of compound 125 followed by condensation with O-benzylhydroxylamine gives rise to the hydroxamate (126), which is then converted into (Claclam 127 via an intramolecular Mitsunobu reaction. Hydrolysis of the (Claclam 127 affords acid 128, which is subsequently formylated at the benzyloxyamine moiety to give the required intermediate acid (129) in quantitative yield, as depicted in Scheme 26. 

Making use of a O-trityl-hydroxylamine linker, Meloni and Taddei reported the first example of Miller hydroxamate on solid phase (161, Scheme 73). /1-Lactams 162 and 163 were prepared on solid support starting from serine, threonine or other / -hydroxyacids derived from naturally occurring amino acids and a resin bonnd hydroxylamine 159. The ring closure of 160 was carried out under Mitsunobu conditions. 

Carboxylic acids can be attached to these linkers using methods of ester bond formation such as carbodiimide/DMAP [23] and acid chloride/base. For the loading of N-protected-a-amino acids in particular, an array of different methods has been developed to minimize enantiomerizahon and dipeptide formation during the esterification reaction. These include the use of MSNT/N-methylimidazole [24], mixed anhydrides generated with 2,6-dichlorobenzoyl chloride [25], esters of 2,5-diphenyl-2,3-dihydro-3-oxo-4-hydroxythiophene [26] and acid fluorides [27]. Phenols and N-protected hydroxylamines have been immobilized using the Mitsunobu reaction [28, 29], The latter are particularly useful for the preparation of hydroxamates [29, 30],... 

Cyclic sulfite 211 derived from a,/3-dihydroxy hydroxamate 210 underwent stereoselective ring opening at the a position to give azido alcohol 212, which further cyclized to )Q-lactam derivative 213 under Mitsunobu conditions (90TL4317) (Scheme 50). A similar Q-lactam synthesis by the ring opening of cyclic sulfate 214 derived from tartaric acid with azide nucleophile followed by reduction has been reported (90JOC5110) (Scheme 51). 

A similar strategy permits a variety of chiral succinic acid fragments to be generated, which can be further converted to jS-lactam intermediates, useful for natural product synthesis (Scheme 31). The cw-j -lactone 238 is formed as a result of inversion of the hydroxyl-bearing carbon under Mitsunobu conditions. Opening of the lactone with lithium chloride (with inversion of configuration) gives optically pure anti chloride 239. Subsequent hydroxamate formation with O-benzylhydroxylamine and cyclization furnishes the cw-j -lactam 240 [85]. 

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