Miller hydroxamate, synthesis

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

In a very interesting paper Hu and Miller have described the synthesis of a L-lysine-derived cyclic hydroxamic acid 174 starting by the oxidation of protected Z-L-lysine 171 (formed from 170) with dimethyldioxirane (DMD) in acetone, followed by nitrone... 

M.J. Miller, Synthesis and therapeutic potential of hydroxamic acid based siderophores and analogues, Chem. Rev., 89, 1563, 1989. 

Solid-Phase Synthesis of (3-Lactams by Miller s Hydroxamate Approach. 292... 

It is clear that the hydroxamate approach offers an attractive methodology to the preparation of a variety of optically active P-lactam antibiotics through the development of highly controlled aldol additions [101]. Although this methodology is straightforward in the preparation of valuable P-hydroxyhy-droxamates for subsequent cyclization, recently Miller and Rajendra [102] introduced a new stereoselective synthesis of 3,4-substituted P-lactams by bromine-induced oxidative cyclization of 0-acyl P,y-unsaturated hydroxamic acid derivatives (Scheme 41). 

Miller s hydroxamate method [41], widely used for the preparation of mono-bactams, surprisingly scores a single application useful for penem synthesis [42]. Chiral 0-butyl hydroxamate 91 was prepared by aldol reaction of crotonalde-hyde with synthon 90a (Sn(OTf )2/iV-ethylmorpholine), followed by temporary 0-TBDMS protection of obtained 90b and displacement with butoxyamine. Lactamization of 91 under Mitsunobu conditions (PPh3/DEAD) afforded 92, an equivalent (by alkene oxidative cleavage and deprotection) of enantiomerically pure 4-acetoxyazetidinone. 

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). 

Mattingly, P. G., and M. J. Miller Synthesis of 2-Azetidinones from Serine-hydroxamates Approaches to the Synthesis of 3-Aminonocardicinic Acid. J. Org. Chem. 46, 1557 (1981). 

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