Glutarimides, synthesis

Meng X, Maggs JL, Pryde DC, Planken S, Jenkins RE, Peak-man TM, Beaumont K, Kohl C, Park BK, Stachulski AV. Cyclization of the acyl glucuronide metabolite of a neutral endopeptidase inhibitor to an electrophilic glutarimide synthesis, reactivity, and mechanistic analysis. J. Med. Chem. 2007 50 6165-6176. 

That the methyl group in the less substituted isomer of the enamine (20) is axial was borne out by the work of Johnson et al. (18) in the total synthesis of the glutarimide antibiotic //-dehydrocycloheximide (24). The acylation of the morpholine enamine of 2,4-dimethylcyclohexanone (25) with 3-glutarimidylacetylchloride (26), followed by the hydrolysis of the intermediate product (27) with an acid buffer, led to the desired product in 35 % yield. The formation of the product in a rather low yield could most probably be ascribed to the relatively low enamine-type aetivity exhibited by the tetrasubstituted isomer, which fails to undergo the acylation reaction, and also because in trisubstituted isomer one of the CHj groups is axial. Since the methyl groups in the product are trans to each other, the allylic methyl group in the less substituted isomer of the enamine should then be in the axial orientation. 

Obrig, T. G., Culp, W. J., McKeehan, W. L., and Hardesty, B. (1971). The mechanism by which cycloheximide and related glutarimide antibiotics inhibit peptide synthesis on reticulocyte ribosomes. J. Biol. Chem. 246, 174-181. 

These methods parallel the synthesis just described for the five-membered rings. As indicated in structures (42)—(49), standard reactions of aliphatic chemistry can be extended to the preparation of piperidines, tetrahydropyrans and pentamethylene sulfides (44 Z = N, O, S) glutarimides, glutaric anhydrides and glutaric thioanhydrides (46 Z = N, O, S) and 8-lactams, 8-lactones and 8-thiolactones (49 Z = N, O, S). 

Reaction of the nitrile oxide (498) with the enone (499) gave after chromatography the expected isoxazoline (500) plus some of its dehydro derivative (76TL3983). Hydrogenation of (500) using 30% Pd/SrC03 as catalyst yielded an enaminoketone (501) which was further hydrolyzed to the diketone (502 Scheme 110). This compound is a gem-dimethyl isomer of dehydrocycloheximide, a key intermediate in a previously reported synthesis of the glutarimide antibiotic cycloheximide. 

The disadvantage of the intermolecular dipolar cycloaddition strategy is nonstereoselectivity. A recent stereoselective synthesis of lasubine 1 (2) utilizes the intramolecular tt cyclization of an /V-acyliminium ion as a key step (Scheme 4) (16). The reaction of carbinol 38, prepared from 3,4-dimethoxybenzaldehyde (33) and allylmagnesium bromide, with glutarimide under Mitsunobu conditions... 

Martin and Neipp developed a flexible and efficient synthesis of azabicyclo[n.3.1]alkenes starting from either glutarimide or 4-methoxypyridine (Scheme 35) <02T1779>. These reactions proceed in higher yield and at lower temperature with the MC2. 

The use of chiral lithium amides in the preparation of biologically potent piperidines from highly enriched glutarimides is illustrated in the synthesis of the antidepressant drug substance (—)-paroxetine (Figure 7)107. 

Cyclization of aspartic acid and asparagine to form aspartimides, and to a lesser extent of glutamic acid and glutamine to form glutarimide is an acid- and base-catalyzed common side reaction in peptide synthesis (see also Section 2.2.2). In SPPS it is particularly troublesome when Asp-Gly, Asp-Ala, and Asp-Ser sequences are present,but also with Asp-Asn.P P Piperidine-catalyzed aspartimide formation can be very rapid,and in this context DBU is even worse than piperidine.P The formation of aspartimide is reduced by the addition of HOBt or 2,4-dinitrophenol, but more efficiently it is reduced by protecting the aspartyl amide bond with the 2-hydroxy-4-methoxybenzyl (Hmb) group (see Section 2.3.2).P 1... 

The GLUTARIMIDE antibiotic streptimidone is formed from seven malonate units and is in itself unusual by having the polyketide synthesis initiated by a malonate unit which is retained intact in the final structure. The derivitive, 9-methylstreptimidone (12) is reported to be made similarly, with a double decarboxylation of the terminal malonate unit. This is... 

The following discussion of hydroxamic acids includes saturated systems, e.g., 2, compounds such as 3, derived from aromatic systems, N-hydroxyimides such as N-by droxy glutarimide (78), and certain of their derivatives including thiohydroxamic acids. Naturally occurring cyclic hydroxamic acids are discussed to show the range of structural types that has been found, but macrocyclic polyhydroxamic acids are mentioned very briefly, because several comprehensive reviews of these compounds are already available.7,8 9 The main purpose of this review is to summarize the methods available for the synthesis of cyclic hydroxamic acids, to outline their characteristic reactions, and to present some useful physical data. Their synthesis and some biological properties have previously been reviewed by Coutts.° ... 

Coe, J.W. Total synthesis of (+/)-cytisine via the intramolecular heck cychzation of activated n-aUcyl glutarimides. Org. Lett. 2000, 2, 4205 208. 

Oxo-3a,4,5,6,7,7a-hexahydroindoxazenes (92) are oxidized by chloranil to the 4,5,6,7-tetrahydro derivatives and are useful precursors for the synthesis of 2-acylcyclohexane-l,3-diones and for glutarimide antibiotic analogs.105... 

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