Perhydropyrido oxazines

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

Molecular mechanics calculations with the molecular mechanics force field program were performed to compare thermodynamic stability among araguspongine B (17) (containing two cw-fused perhydropyrido[2,l-Z>] [l,3]oxazine bicycles), araguspongine D (18) (containing two tran -fused perhydropyrido[2,l-Z)][l,3]oxazine bicycles), and araguspongine E (19)... 

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. 

Reductive N-O bond cleavage of perhydropyrido[l,2-6][l,2]oxazine 10 with Zn dust furnished 2-(3-hydroxypentyl)piperidine 11 (96JCS(P1)1113). Similarly, 2/S,4u S,5Q ,7/0,8yS-H-5-benzyloxy-7-(tert-butyldiphenylsilyloxy)-2-[2-(methoxymethoxy)ethyl]-8-methylperhydropyrido[l,2-6][l,2]oxazine gave the respective ring-opened piperidine (OOOL2955, 01JOC3338). 

Hydroxy group of perhydropyrido[l,2-A][l,2]oxazin-8-one 23 (R = H) was protected with t-BuPh SiCl in the presence of imidazole in DMF (OOOL2955, 01JOC3338). 

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). 

Treatment of perhydropyrido[l,2-c][l,3]oxazin-l-ones 83, 85, and 87 with 2M ethanolic KOH afforded 2-(2-hydroxyalkyl)piperidines 84, 86, and 88 (96CJC2434). (4-)-9-Epi-6-epipinidinol (90) was obtained similarly from 3,8-dimethylperhydropyrido[l,2-c][l,3]oxazin-l-one 89 (98T13505). 

Di-(2-propyl)]perhydropyrido[l, 2-c][l, 3]oxazin-l -one was lithiated with 5-BuLi in the presence of TMEDA 200 times less efficiently, than the five-membered lower homolog 3,3-[di(2-propyl)]perhydropyrido[l,2-c][l,3] oxazolin-l-one, and approximately five times more efficiently than -(tert-butoxycarbonyl)piperidine (01JA315). 

Methyl-3-(tosyloxymethyl)perhydropyrido[l,2-c][l,3]oxazin-l-one 103 was detosylated by treatment with LiBEt3H (Super-Hydride ) (98T13505). 

Substituted perhydropyrido[l,2-c][l,3]oxazines 83 were obtained by the cyclization of l-(/er/-butoxycarbonyl)-2-(2-hydroxyalkyl)piperidines 104 in pyridine on the action of MeS02Cl at room temperature (96CJC2434). Cyclization of c/5-2,6-H- l-(methoxycarbonyl)-2-(2-acetoxyhexyl)-9-methox-ypiperidines 105 and 106 in THF in the presence of KO/-Bu yielded 3-butyl-9-methoxyperhydropyrido[l,2-6 ][l,3]oxazin-l-ones 94. Treatment of l-(/erc-butoxycarbonyl)-2-[2-hydroxy-2,2-di(2-propyl)ethyl]piperidine with NaH in boiling THF yielded 3,3-di(2-propyl)perhydropyrido[l,2-c][l,3] oxazin-l-one (01JA315). 

Reaction of (25,55)- and (2i ,55)-2-[5-(terc-butyldimethylsilyloxy)piper-idin-2-yl]ethanols with phenylglyoxal monohydrate in the presence of 4 A molecular sieves in boiling CH2CI2 overnight gave (15,4n5,7i )- and (2i ,4ni ,7i )-l-benzoyl-7-(terc-butyldimethylsilyloxy)perhydropyrido[l,2-c][l,3]oxazines 97 and 100, respectively, in good yield (99MI19). Both products were accompanied by unidentified minor isomers. 

Treatment of 2-methoxy-l-tert-butoxycarbonylpiperidine (127) with allyltrimethylsilane and TiCU gave a mixture of 2-allyl-l-rerr-butoxycarbo-nylpiperidine (128) and 3-[(trimethylsilyl)methyl]perhydropyrido[l,2-c][l,3] oxazin-l-one (129) (97JCS(P1)2163). 

Treatment of perhydropyrido[2,l-c][l,4]oxazine-3,6-dione 232 with B2H6 yielded (—)-(2i )-[(2S)-hydroxymethyl)piperldin-1 -yl]-2-phenylethanol (233) (00T233). Reduction of ( )-(3i ,4i ,9aS)-4-methyl-3-phenylperhydropyr-ido[2,l-c][l,4]oxazin-3-ol (234) with NaBH4 yielded ring-opened product 235 (97JHC1813). 

Treatment of perhydropyrido[2,l-c][l,4]oxazin-l-ones 236 with vinyl and 1 -chloroethyl chloroformate in the presence of 4A molecular sieves afforded ring-opened (2i )-pipecolic acid derivatives 237 (97SL799, 98EJOC2461, 98T10309). Similarly, perhydropyrido[l,2-c][l,4]oxazin-l-one 238 yielded (2S)-pipecolic acid derivative 239 (98T10309). 

Reduction of a perhydropyrido[l,2-c][l,4]oxazin-l-one with BH3 in anhydrous THF at room temperature yielded a perhydropyrido[l,2-c] [l,4]oxazine (OOMIPl). 

Treatment of an epimeric mixture of l-hydroxy-8-methylene-4-phenyl-perhydropyrido[2,l-c][l,4]oxazines with 4% aqueous solution of OSO4 in aqueous THE in the presence of NaI04 at room temperature gave an epimeric mixture of l-hydroxyl-8-oxo derivatives (OOJOC4435, 01EJOC2385). 

Alkoxy-3-(4-biphenyl)perhydropyrido[], 2-c][], 4]oxazines were obtained from 3-hydroxy derivative with PrOH and Br(CH2)30H in a boiling acidified medium (00JMC609, 00MIP13). Spontaneous dehydration of b-hydroxy-1,3,4,6,7,1 lZ -hexahydro[l,4]oxazino[3,4-n]isoquinolin-4-one 258 in CHCI3 gave 3,4,6,7-tetrahydro derivative 259 (97JOC2080). 

Reaction of 3-(3-bromopropy])-3-(4-biphenyl)perhydropyrido[l,2-c][l,4]oxazine with AgN03 in a boiling solvent yielded 3-[(4-biphenyl)per-hydropyrido[l,2-c][],4]oxazin-3-yl]propyl nitrate (00MI9). 

Phenyl-9-(2-propoxycarbonylamino)perhydropyrido[2,l-c][l,4]oxazin-1-one was prepared from methyl 4 phenyl-l-oxoperhydropyrido[2, l-c][l,4]oxazine-9-carboxylate (98MIP12). First, the methyl ester was hydrolyzed into 9-carboxylic acid by heating in 6N HCl, then the carboxylic acid was reacted with (Ph0)2P(0)N3 in benzene in the presence of NEt3 at 22 °C for 45 min, then at reflux for 50 min. After addition of -PrOH the reaction mixture was boiled for 20 h to yield a 9-(iso-propoxycarbonylamino) derivative. 

Treatment of an epimeric mixture of 4-substituted 2-(trimethylsilyloxy)-5-phenyl-3-phenylthio-l,4-oxazine 264 with ZnBr2 led to the stereoselective formation of perhydropyrido[2,l-c][l,4]oxazine 266 via the iminium ion 265 by the phenyl bearing stereocenter directed addition of the olefinic double bond from the /S-face of the cyclic moiety (97SL799, 98T10309). Similarly, an epimeric mixture of (45,9aS)-l-trimethylsilyloxy-4-phenyl-3,4,6,7-tetra-hydropyrido[2,l-c][l,4]oxazine was prepared by cyclization of (Z)-5(S)-phenyl-3-phenvlsulfanyl-2-trimethylsilyloxy-4-[4-(trimethylsilyl)but-3-enyll morpholine (OOSC2565). 

Treatment of l-(2-hydroxyethyl)-2-cyanopiperidines 282 with HCl gas in the presence of Si02 afforded perhydropyrido[2,l-c][l,4]oxazin-l-ones 283-285 (00TA3913). 

The presence or the lack of the Bohlmann bands in the infrared (IR) spectra of perhydropyrido[l,2-c][l,3]oxazines was used to identify /ram-fused <1997TA109, 2003TL8609> orm-fused <2005EJ01378> conformations of the bicycle. 

Flash vacuum thermolysis (FVP) at 600°C or microwave excitation of 1-substituted perhydropyrido[l,2-f][l,3]oxa-zines afforded 1-substituted 1,4,5,6-tetrahydropyridines <2005TL5451>. Perhydropyrido[l,2-f][l,3]oxazin-l-ones were hydrolyzed with 2M ethanolic KOH to 2-(2-hydroxyalkyl)piperidines <1996CJC2434, 2005EJ01378>. (+)-9- />z -6-Epipinidinol 102 was similarly obtained from 3,8-dimethylperhydropyrido[l,2-f][l,3]oxazin-l-one 101 (Equation 16) <1998T13505>. 

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