Oxazine alkaloid

Hyperaspine (1), a perhydropyrido[l,2-c][l,3]oxazine alkaloid was isolated from the ladybird beetle H. campestris (01TL4621). 9-Epi-6-epipinidinol (90), a piperidine alkaloid, was prepared from a perhydropyrido[l,2-c][l,3]oxazin-l-one derivative (98T13505). Perhydropyrido[l,2-c][l,3]oxa-zin-l-ones were used to prepare 2,6-disubstituted piperidines (96CJC2434). 

A range of alkaloids including isoquinoline, indolizidine, benzazepine, oxazine, quinoline and indole alkaloids were examined as potential inhibitors of eukaryote protein kinases such as PKC, MLCK and PKA. Only three oxazine alkaloids and four isoquinoline-based alkaloids and inhibitors of the protein kinases tested. A narrow structural and protein kinase target specificity, was observed. (+)-Boldine (39) and bulbocapnine (40) are specific for MLCK, while apomorphine (41) and sanguinarine (42) are for PKA. 

Dibenz[h,e]azepine-6,11-diones ent-Morphinan nomenclature, 1, 29 Morphinan, 1,2,3,4-tetrahydro-nomenclature, 1, 29 14-a-Morphinan, N-methyl-synthesis, 1, 480 Morphinans nomenclature, 1, 29 as pharmaceuticals, 1, 148 synthesis, 2, 377 Morphine, 2, 512 as analgesic, 1, 167 as metabolite of normorphine, 1, 235 as pharmaceutical, 1, 146, 147, 148 synthesis, 1, 480 Morphine alkaloids structure, 4, 534 Morphin-7-en nomenclature, 1, 29 Morphinone, dihydro-as pharmaceutical, 1, 147 Morpholine — see also 1,4-Oxazine, tetrahydrocarcinogenicity, 1, 229 corrosion inhibitor, 1, 409 metabolism, 1, 226 nomenclature, 3, 996 structure, 2, 5 synthesis, 2, 89 Morpholine, 4-aciyloyl-polymers, 1, 291 Morpholine, alkenyl-polymers, 1, 291... 

The perhydropyrido[2,l-Z)][l,3]oxazine skeleton is a constituent part of macrocyclic xestospongine/araguspongine and aragupetrosine alkaloids... 

Karrer thought that the dihydro-1,3-oxazine skeleton can possibly be formed in proteins during their transformation to polypeptides. Fodor - and Fiescr explained the stereospecific migration of acyl groups from N to 0 and vice versa in tropine alkaloids by an intermediate formation of a 1,3-oxazine ring. 

Perhydro derivatives of pyrido[l,2-7)][l,2]oxazines are frequently applied in the total synthesis of various alkaloids to control the stereochemistry, and pyrido[l,2-c][l,3]oxazines and [l,3]oxazino[3,4-u]quinolines were also used in the stereoselective syntheses of different alkaloids. Perhydropyrido[l,2-c][l,3]oxazines and their benzologs are formed form 2-(2-hydroxyethyl) piperidines and from their benzologs to justify the stereochemistry of 2-(2-hydroxyethyl) derivatives. Different optically active pipecolic acids can be prepared via 4-phenylperhydropyrido[2,l-c][l,4]oxazin-l-ones. 

Perhydropyrido[l,2-A][l,2]oxazines are applied as key intermediates in a stereospecific total syntheses of (-)-pumiliotoxin C and 5-e/ /-pumiliotoxin C(96JCS(P1)1113), and the marine alkaloid)—)-lepadins A, B, C (OOOL2955). (2-Pyridyl)propionic acids 13 can be regioselectively prepared via 2,3,4, 4fl,7,8-hexahydropyrido[l,2-A][l,2]oxazin-2-ones 12 (00OL4007). 

Reaction of (+)-sedridine (118) and a 37% aqueous solution of CH2O in MeOH at room temperature gave 3-methylperhydropyrido[l,2-c][l,3]oxa-zine (81) (97TA109). Similarly, reaction of andrachcinidine alkaloid, cis-2,6-H-2-(2-oxopropyl)-6-(2-hydroxypentyl)piperidine with 1.5% methanolic formaldehyde solution afforded cw-3,4n,9-H-9-(2-oxopropyl)-3-propylper-hydropyrido[l, 2-c][ 1,3]oxazine (00MI71). 

Functionalized 5,6-dihydro-4// -oxazines are direct precursors of a series of useful products, for example, of proline derivatives (539), unnatural amino acids (540), and some alkaloids (541). 

An intermediate 5-hydroxy-5,6-dihydro-2/7-pyrrolo[l,2- ][l,2]oxazin-7(4a//)-one 142 has been described in the total synthesis of (—)-loline, a pyrrolizidine alkaloid extracted from rye grass Lolium cuneatum. The key step of the synthesis was an intramolecular cycloaddition of acylnitrosodienes (obtained by in situ oxidation of the corresponding hydroxamic acids 143). This reaction generated predominantly the rro/o-stereoisomer that was further cleaved at the N-O bond with Na(Hg) and further elaborated in several steps to reach the target compound (Scheme 19) <2001J(P 1)1831 >. 

The perhydropyrido[2,l-b][l,3]oxazine skeleton is a constituent part of macrocyclic xestospongine/araguspongine and aragupetrosine alkaloids isolated from different marine sponges. Pyrido[2,l-fo][l,3]oxazines, pyrido[2,l-fc][l,3]thiazines, and [l,3]oxazino[3,4-a]quinolines are also applied as key intermediates in the total syntheses of different alkaloids. Other examples of these ring systems have aroused much interest owing to their valuable pharmacological properties. 

Perhydropyridol[2,l-h][l,3]oxazines are used in the synthesis of in-dolizidines (gephyrotoxins and monomorine-I) [88H(27)1575 91SL44, 91SL878] and histrionicotoxin (91SL44) alkaloids. 

Hydrogenated derivatives of the monocyclic and bicyclic oxazines and thiazines are also very well established compounds and a number are so familiar that they too have trivial names. Tetrahydro-l,4-oxazine, for example, is better known as morpholine, a name first allocated to it because of a supposed, but erroneous, relationship to the alkaloid morphine. By analogy the corresponding thiazine is called thiomorpholine or sometimes thiazane. 

Perhydropyrido[l,2-fr][l,2]oxazine 10 was applied in the total synthesis of (-)-monomorine I, an indolizidine alkaloid, to control the stereoselectivity (09S655). 

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