(3S)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one → tert-Butyl (3R,9aS)-3-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

HRID 1501948Notes

Reaction equation

[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:12]3[O:17][CH2:16][C@@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1.[CH3:30][C@@H:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C@@H:41]3[O:46][CH2:45][C@@H:44]4[CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50][N:43]4[CH2:42]3)[CH:38]=2)[C:33](=[O:58])[O:32]1.BrC1C=C2C(=CC=1)C(=O)O[C@@H](C)C2>>[CH3:1][C@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:12]3[O:17][CH2:16][C@@H:15]4[CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][N:14]4[CH2:13]3)[CH:9]=2)[C:4](=[O:29])[O:3]1.[CH3:30][C@H:31]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C@@H:41]3[O:46][CH2:45][C@@H:44]4[CH2:47][N:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49][CH2:50][N:43]4[CH2:42]3)[CH:38]=2)[C:33](=[O:58])[O:32]1

Participants

Reactant 3

HCID 67517728(3S)-6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one

HCID 71273516tert-Butyl (3R,9aS)-3-[(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

HCID 71273517tert-Butyl (3S,9aS)-3-[(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

Product 2

HCID 71273547tert-Butyl (3R,9aS)-3-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

HCID 86727030tert-Butyl (3S,9aS)-3-[(3S)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

Procedure

8C and 8D were prepared in a similar manner as Intermediates 8A and 8B except (3S)-6-Bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one was used as the starting material. The cis/trans mixture was purified via chiral HPLC (30% 2:1 MeOH:MeCN/CO2) on an AD column. The faster eluting diastereomer was the trans isomer. 8C: 1H NMR (500 MHz; CDCl3): 8.07 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 4.72 (dd, J=1.8, 10.5 Hz, 1H), 4.68 (m, 1H), 4.1-3.8 (bs, 2H), 3.96 (dd, J=3.0, 11.3 Hz, 2H), 3.48 (t, J=10.7 Hz, 1H), 2.95 (m, 4H), 2.74 (d, J=10.5 Hz, 1H), 2.2 (m, 3H), 1.54 (d, J=6.2 Hz, 3H), 1.49 (s, 9H); LC-MS: (M+1)+403; 8D: 1H NMR (500 MHz; CDCl3): 8.10 (d, J=8.2 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 4.81 (bt, 1H), 4.71 (m, 1H), 3.62 (dd, J=2.8, 11.5 Hz, 1H), 3.41 (m, 1H), 3.25 (dd, J=3.7, 12.1 Hz, 1H), 2.95 (m, 4H), 2.76 (m, 3H), 2.50 (m, 2H), 2.28 (m, 1H), 1.54 (d, J=6.2 Hz, 3H), 1.48 (s, 9H); LC-MS: (M+1)+403.

Workup

customThe cis/trans mixture was purified via chiral HPLC (30% 2:1 MeOH:MeCN/CO2) on an AD column
washThe faster eluting diastereomer

Sources & evidence

ORD record: ord-35008768d6604ccf8770aeea74a04bf4
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09206199B2

Reaction notes

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