4-Phenylperhydropyrido

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. 

Treatment of 3-phenylperhydro[l, 3]oxazolo[3,2-a]pyridine-5-carboxylates 303 and 304 with BF3 Et20 in THE, followed by reduction with NaBD4 afforded 6-deutero-4-phenylperhydropyrido[2,1 -c][l, 4]oxazin-1 -ones 220 and 222 (97JA6446). 

Reaction of 40% glioxal with silylated compounds 308 (97SL799, 99SL1094, OOJOC4435) and 310 (97SL799) gave a diastereomeric mixture of l-hydroxy-4-phenylperhydropyrido[2,l-c][l,4]oxazines 309 and 311, respectively. Similarly, diastereomeric mixtures of 8-substituted l-hydroxy-4-phenylperhydropyrido[2,l-c][l,4]oxazines were prepared (01EJOC2385). 

A single isomer of 4-phenylperhydropyrido[2,l-c][l,4]oxazin-l-one 319 was isolated from a reaction mixture of 2-bromocyclohexane and 2-azido-2-phenylethanol. The formation of 319 was deduced from azepino[l,2-i]... 

Mild acidic hydrolysis of amino nitrile 369 gave m-4,9a-/7-rra r-9-7/-9-benzyloxy-4-phenyl-3,4,9,9a-tetrahydro-17/,67/-pyrido[2,l-d[l,4]oxazin-l-one <1996TL4001>. (2A)-2-Cyano-l-[(lR)-2-hydroxy-l-phenylethyl]piperidin-6-one, on standing for 20 days in ethanol saturated with HC1 gas, afforded (4/ ,9aA)-4-phenylperhydropyrido[l,2-4[l,4]oxazine-l,6-dione, which was sometimes accompanied by the unstable (26 )-l-[(l/ )-2-hydroxy-l-phenylethyl]-... 

Reduction of 6,8-diazabicyclo[3,2,l]oct-6-enes 411, prepared from 410 with alkyl- or phenyllithium, with NaBH3CN gave 1-amino-l-substituted 4-phenylperhydropyrido[2,l-f][l,4]oxazines 412 (Equation 76) <1996JOC6700>. The 1-methyl derivative of 412 (R1 = Me) was accompanied by 10% of the C-l epimer. A 3 7 mixture of 4-phenylperhy-dropyrido[2,l-r ][l,4]oxazin-l-one was obtained from 410 by treatment with HC1 in the presence of Si02, then with Zn(BH4)2 <2003JOC1401>. 

X-Ray diffraction determination revealed that in solid state the asymmetric unit cell of (4R,9flR)-4-phenylperhydropyrido[l,2-fl]pyrazine-l,3-dione contains two distinct invertomers 150 and 151, and they formed a head-to-head dimer (09TA1759). The invertomer 150 adopts trans-chair/ sofa conformation with a frans-diaxial arrangement of the N5 lone pair and the H-C9a. The invertomer of 151 adopts cis-chair/sofa conformation with a cis-axial/equatorial arrangement of the N5 lone pair and the H-C9a, with respect to the piperidine ring. 

Optically active pipecolic acids, and their 2-substituted derivatives were prepared by the catalytic hydrogenation of the respective optically active 4-phenylperhydropyrido[2,l-c][l,4]oxazin-l-ones and their 9a-substituted derivatives over Pearlman s catalyst in good yields (05TA3858). 

The epimerization of (4R,9aR)-4-phenylperhydropyrido[2,l-c][l,4]oxazin-1-one at C9a carbon could be achieved by treatment with KN(SiMe3)2 in THF at 78 °C for 30 min to yield effectively the (4R,9aS) epimer (05TA3858). NaN(SiMe3)2 and LiN Pr2 proved to be less appropriate than KN(SiMe3)2, as they gave only 10% and 50% conversion, respectively. 9a-Substituted derivatives were obtained by alkylation of (4R,9flR)-4-phenyl-perhydropyrido[2,l-c][l,4]oxazin-l-one with alkyl iodides, allyl and benzyl bromides in THF in the presence of KN(SiMe3)2/ and HMPA at —78 °C for 1.5 h in 61-83% yields. 

THF at room temperature for 220 min to give 4-phenylperhydropyrido [2,1 -c][1,4Joxazin-6-one (07USA2007/0117839). Reduction of ethyl 1-[1-aryl-2-hydroxyethyl]-6-oxopipeperidine-2-carboxylates with NaBH4 in MeOH at 0 °C for 80-100-min-yielded l-hydroxy-4-arylperhydropyrido [2,1 -c] [ 1,4] oxazin-6-ones. 

Cyclocondensation of optically active (S)-pipecolinamide 389 and enantiomers of methyl 2-(4-methylphenylsulfonyloxy)phenylacetates 390 in the presence of an excess of K2CO3 in MeCN led to 67-81 33-19 mixture of (4R,9aS)- and (4S,9aS)-4-phenylperhydropyrido[l,2-a]pyra-zine-l,3-diones 391, regardless of whether (S)-390, (R)-390, or rac-390 was used as starting material (09TA1759). 

Cyclization of methyl 4-(c/s-3,5-H-2-oxomorpholin-5-yl)butyrate in boiling toluene provided c/s-4,9a-H-4-phenylperhydropyrido[2,l-c][l,4]ox-azine-3,6-dione [95H(41)1931], Heating l,4-oxazin-2-one 163 afforded [l,4]oxazino[4,3-a]quinoline-4,6-dione 164 (94IZV299, 94JFC119). The reaction of carboxylic acid 165 with l.l -carbonyldiimidazole in the presence of 4-methylmorpholine afforded pyrido[2,l-c][l,4]oxazin-4-one (61)... 

The 1-imine derivatives of 4-phenylperhydropyrido[l,2-c][l,3]oxazines were prepared from erythro- and t/ireo-2-(2-piperidyl)-2-phenylethanols with cyanogen bromide followed by treatment with hydrogen chloride in boiling ethanol (73AP284). 

---