Activated hydroxamate

Metal alkoxides undergo alkoxide exchange with alcoholic compounds such as alcohols, hydro-xamic acids, and alkyl hydroperoxides. Alkyl hydroperoxides themselves do not epoxidize olefins. However, hydroperoxides coordinated to a metal ion are activated by coordination of the distal oxygen (O2) and undergo epoxidation (Scheme 1). When the olefin is an allylic alcohol, both hydroperoxide and olefin are coordinated to the metal ion and the epoxidation occurs swiftly in an intramolecular manner.22 Thus, the epoxidation of an allylic alcohol proceeds selectively in the presence of an isolated olefin.23,24 In this metal-mediated epoxidation of allylic alcohols, some alkoxide(s) (—OR) do not participate in the epoxidation. Therefore, if such bystander alkoxide(s) are replaced with optically active ones, the epoxidation is expected to be enantioselective. Indeed, Yamada et al.25 and Sharp less et al.26 independently reported the epoxidation of allylic alcohols using Mo02(acac)2 modified with V-methyl-ephedrine and VO (acac)2 modified with an optically active hydroxamic acid as the catalyst, respectively, albeit with modest enantioselectivity. 

Acylnitroso compounds 197 (R = Me, Ph or Bn) react in situ with 1-methoxycarbonyl-1,2-dihydropyridine to yield solely the bridged adducts 198 quantitatively. On the other hand, 1 1 mixtures of the regioisomers 199 and 200 were formed from the nitroso-formates 187 (R = Me or Bn) (equation 110)103. The chiral acylnitroso compounds 201 and 202, which are of opposite helicity, add to cyclohexadiene to give optically active dihydrooxazines in greater than 98% diastereomeric excess (equations 111 and 112)104. Similarly, periodate oxidation of the optically active hydroxamic acid 203 in the presence of cyclopentadiene, cyclohexa-1,3-diene and cyclohepta-1,3-diene affords chiral products 204 (n = 1, 2 and 3, respectively) in 70-88% yields and 87-98% de (equation 113)105. 

SCHEME 60. Optically active hydroxamic acid ligands for the vanadium-catalyzed asymmetric epoxidation of allylic alcohols,... 

N-methyl derivative resulted in oxidation of the ligand with concomitant reduction of Co (III) to Co (II). The preparation of tris (benzohydroxa-mato) chromium (III), Cr(benz)3, was successful and resulted in the separation and characterization of its two geometric isomers (2). The half-lives for isomerization of these complexes near physiological conditions is on the order of hours. To facilitate the separation of all four optical isomers of a simple model tris (hydroxamate) chromium (III) complex, we prepared (using Z-menthol as a substituent) the optically active hydroxamic acid, N-methyl-Z-menthoxyacethydroxamic acid (men). This resulted in the separation of the two cis diastereoisomers of tris(N-methyl-Z-menthoxyacethydroxamato) chromium (III) from the trans diastereoisomers and their characterization by electronic absorption and circular dichroism spectra. 

To enhance the separation of the optical isomers of Cr(hy-droxamate)3 complexes, the optically active hydroxamic acid, -menthoxyacethydroxamic acid (men), was prepared as well as its iron(III) and chromium(III) complexes, Fe(men)3 and Cr(men)3. While four diastereomers (A-cis, A-cis, A-trans, and A-trans) are expected for Cr(men)3, only three fractions were separated by chromatographic techniques. Two fractions were assigned to be A-cis and A-cis while the partially resolved A- and A-trans mixture separate as one fraction. The geometries of these were assigned based upon the criteria mentioned above. The iron(III) complex gave only one band under the same conditions. 

The Lossen rearrangement, discovered in 1872, is the transformation of a hydroxamic acid derivative to an isocyanate by using an activated hydroxamic acid 71 as the key intermediate tScheme 4.27)Z This activation can be achieved by O-acylation, O-arylation, or O-sulfonylation. From a mechanistic point of view, a base or a thermal treatment can initiate the reaction, giving a rearrangement of the corresponding anion 72 via a three-membered ring transition state 73. 

Early attempts to further facilitate this rearrangement via generation of more highly activated hydroxamates through O-phosphorylation or O-sulfonylation were not successful as these systems preferentially underwent spontaneous dimerization. In later studies, the problem of spontaneous dimerization could be mitigated through the use of intramoleeular nucleophiles to generate JV-hydroxyimides (see 1.1.6.4 for further discussion). iV-Hydroxyimides were found to yield stable precursors via O-phosphorylation and 0-sulfonyloxylation. ... 

Hydroxamic acid 3 can be converted to activated hydroxamate 2 via reaction with a variety of electrophilic reagents. The Lossen rearrangement is then initiated by exposure of 2 to base or heat resulting in anion 10. Through a fast subsequent transformation via cyclic intermediate 12, isocyanate 1 is generated. This isocyanate 1 can be further converted to urea 13 or amine 15. 

In the scale up effort of 5,6-disubstituted benz[cc/]indolones 42, a precursor for inhibitors of thymidylate synthase, the Lessen rearrangement was utilized as the key step. A-hydroxylnaphthalimide 38 was converted to activated hydroxamate 40 through aromatic nucleophilic substitution reaction with 39. The Lessen precursor 40 then xmderwent conversion to amino acid intermediate 41, which was subsequently transformed to lactam 42 under acidic conditions. ... 

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