Morpholinones

The morpholinone analogs 108 have been prepared from the reaction of sodium glyphosate with epoxides. Upon acidifrcation and heating, the resulting Al-hydroxyalkyl intermediates 107 produced the morpholinone monosodium salts 108 (66). 

A ring enlargement process was used effectively to access the enantiopure pyrrolo [ 1,4]oxazepine-9a(7//)-carboxylate derivatives 142 and 143. The sequence involved copper (Il)-catalysed decomposition of an a-diazocarbonyl derivative attached to a chiral morpholinone, and a carbenoid, spiro-[5,6]-ammonium ylide, Stevens [1,2] rearrangement sequence. The Stevens and related rearrangements have considerable further potential for novel heterocyclic syntheses <00TA3449>. 

Morpholinone 177, derived from allyl glycine, cyclized stereoselectively under UV irradiation (A > 342 nm) in the presence of 9,10-anthracene dicarbonitrile (ADC) and biphenyl (PB) to give compound 176 as a single diastereo-isomer <2001JOC6896> (Scheme 26). 

A series of analogous py rrolo[ 2,1 -c [ 1,4]oxazine-8-carboxy latcs 188 and 189 (Scheme 28) were obtained by cycloaddition of azomethine ylide 187 with dipolarophiles. The ylide was formed by /(-toluene sulfonic acid-mediated reaction of the benzotriazolyl chiral morpholinone 186, which can be considered as a stable crystalline azomethine ylide precursor <2001SL1841>. This procedure was applied also to morpholinone 190 that generated ylide 191 by reaction with... 

Chloriminovanadium trichloride, 4165 A-Chloroacetamide, 0789 A-Chloroallylamine, 1202 A -Chloro-3 -aminopropyne, 1129 A -Chloro-3 -aminopropyne, 1129 1-Chloroaziridine, 0786 1-Chlorobenzotriazole, 2150 A -Chloro-bis(2-chloroethyl)amine, 1590 A-Chlorobis(trilluoromethanesulfonyl)imide, 0596 A-Chlorocinnamaldimine, 3126 A -Chlorodimethylamine, 0895 A -Chloro-4,5-dimethyltriazole, 1490 A -Chloro-4-methyl-2-imidazolinone, 1554 A -Chloro-5-methyl-2-oxazolidinone, 1488 A -Chloro-3 -morpholinone, 1489 A-Chloro-4-nitroaniline, 2231 A-Chloro-5-phenyltetrazole, 2674 A-Chloropiperidine, 1948 A -Chloropy rrolidine, 1584... 

Synthesis of hindered morpholinones or piperazinones from ketones (such as acetone) and 2-amino-2-methyl-l-propanol or 1,2-diaminopropanes. 

The stereochemical outcome of the reaction was rationalized by invoking axial approach of the alkene lowest occupied molecular orbital (LUMO) to the least hindered lower face of the highest occupied molecular orbital (HOMO) of the dipole, in which the morpholinone ring was held in a quasi-chair conformation with the C(5) phenyl substiment in an equatorial environment (Fig. 3.13). 

Moloney and co-workers (64) also made use of the morpholinone template in the synthesis of analogues of the kainoid group of amino acids. Treatment of the template under the conditions reported by Harwood furnished the expected adducts. In keeping with earlier observations, the reaction proceeded with complete facial selectivity generating the new C(3) stereogenic center with complete control. 

An inverse y-turn mimetic, containing a 3-morpholinone ring 23 (Scheme 14) as the key structural feature was prepared enantiospecifically.[43] Molecular mechanics calculations revealed that the torsional angles of the second residue of the mimetic were effectively constrained in an inverse y-turn-like conformation. 

Scheme 14 An Inverse y-Turn Mimetic Containing a 3-Morpholinone Ring 431...

Chloromethylphenyl acetate, (4-Acetoxyphenyl)methyl chloride, see 4-Acetoxybenzyl chloride, 3132b 2-Chloro-5-methylphenylhydroxylamine, 2792 Chloromethylphenylsilane, 2806 f 3-Chloro-2-methyl-l-propene, 1548 2-Chloromethylthiophene, 1836 A-Chloro-3-morpholinone, 1485 /V- C h I o ro -4 - n i t ro a n i I i n e, 2224 2-Chloro-5-nitrobenzaldehyde, 2645 2-Chloro-6-nitrobenzaldehyde, 2646... 

An alternative multistep approach to the synthesis of a-amino acids, using the boronic acid as the precursor of the carboxylic acid group, was reported by Harwood et al. [56]. Thus, reaction of a chiral morpholinone derivative with furyl boronic acid and various aldehydes gave, in a diastereocontrolled manner, the corresponding adducts which were converted in several steps to the a-amino acids [56],... 

The methyleneoxy peptide isostere was also used to replace the aj-aj amide bond. The requisite ether isostere dipeptides were synthesized according to Scheme 2.42 High levels of 1,4-asymmetric induction were observed in the alkylation of morpholinone 14 pseudo-allylic A, 3 strain in acylmorpholinone 14 caused the... 

A series of 2-siIa-5-morpholinones have been prepared and their biological activity evaluated. They are found to exhibit certain antihypoxic property in animals tested against chlorphos-poisoning.504,505 2,2,4-Trimethyl-6-phenyl-2-sila-5-morpholinone (A R = Ph) displays a cold-resistant activity.504... 

The initial synthesis of aprepitant (1), which relies on a Tebbe olefination and reduction to install a methyl group on the benzyl ether side chain, is shown in Scheme 3.8,19 The initial steps are from a literature-precedented synthesis of p-fluorophenyl glycine based on conversion of chiral oxazolidinone 33 to azide 34. Formation of morpholinone intermediate 36 proceeds via benzylation and reaction with 1,2-dibromoethane. 

To prepare aprepitant in optically active form, this group reported a resolution-based scheme using di-p-toluoyl-tartaric acid (D-(+)-DPTTA) to afford the key morpholinone intermediate 36.24... 

To build up the desired cyclic key precursors, containing an amide bond as an anchor to connect the triazole moiety, different strategies can be pursued. Cyclization of y-amino acids directly yields pyrroli-dones, whereas P-amino alcohols allow access to two different chiral bicyclic frameworks. They can form either oxazolidin-2-ones (Enders and Kallfass 2001) or morpholinones upon treatment with phosgene or chloro acetylchloride, respectively (Scheme 3). 

Stereoselective synthesis of the pseudo 2-epibotcinolide 323, which contains a nine-membered lactone has been reported <2006OL5279>. Functionalized oxonine 324 can be synthesized by RCM of the corresponding spin morpholinone precursor <2006OL5897>. 

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