An Enantiomerically Pure Building Block for Hydroporphyrins
FULL PAPER
Methoxyphenyl)ethyl]-1,5-dimethyl-2-oxa-8-azabicyclo[3.3.0]octane-
3,7-dione (8b): Procedure A. Treatment of bislactone 5 (1.02 g,
82 (54), 57 (7), 56 (7), 55 (12), 54 (5), 53 (4), 44 (2) [CO2], 43 (42)
[CHNO]+, 42 (32), 41 (10), 40 (4).39 (12), 29 (8). HRMS (CI):
5.99 mmol) with (S)-(–)-(4-methoxyphenyl)ethylamine (906 mg, C8H10NO3 calcd.168.06607; found 168.06571.
6.02 mmol) gave the N-alkylated lactam-lactone pair 8a/8b. The
Compound ent-7: Yield: 100 mg (0.59 mmol, 59%). TLC [silica gel,
diastereomeric mixture was separated by MPLC.
CH2Cl2/EtOAc (99:1)]: Rf = 0.55. M.p. 183.5 °C. [α]2D0 = +101.9 (c
= 1 in CH2Cl2). 1H NMR (200 MHz, CDCl3): δ = 1.35 [s, 3 H,
C(5)-CH3], 1.63[s, 3 H, C(1)-CH3], 2.36–2.82 (m, 4 H, –CH2–), 6.20
Mixture 8a/8b: Yield: 1.27 g (4.19 mmol, 70%). IR (KBr): ν = 3005,
˜
2990, 2945, 2910, 2875, 1780, 1710, 1540, 1495, 1460, 1420, 1395,
1375, 1350, 1305, 1290, 1235, 1195, 1145, 1105, 1080, 1055, 1010,
950, 900, 850, 830, 795, 780, 760, 725, 700 cm–1. UV/Vis (MeOH):
λmax (rel. intensity) = 275 (0.12), 227 (1), 203 (0.99) nm. MS (EI,
70 eV, direct inlet): m/z (%) = 304 (16) [M + H]+, 303 (98) [M]+,
288 (12), 191 (12), 190 (24), 177 (10), 176 (100), 160 (32), 149 (9),
136 (18), 135 (68), 134 (20). MS (DCI negative, NH3, direct inlet):
m/z (%) = 605 (16) [2M + H]+, 338 (20) [M + Cl]–, 303 (26) [M]–,
302 (100) [M – H]+, 275 (15), 231 (14), 168 (56), 127 (5), 120 (71),
109 (11). MS (DCI positive, NH3, direct inlet): m/z (%) = 305 (21)
[M + 2H]+, 304 (100) [M + H]+, 303 (18) [M]+, 176 (13), 170 (9),
160 (6), 136 (6), 135 (32), 134 (4). HRMS (DCI–) C17H20NO4:
calcd. 302.13923, found 302.13922.
(s, 1 H, NH) ppm. IR (KBr): ν = 3212, 3070, 3010, 2990, 2926,
˜
1769, 1703, 1495, 1442, 1417, 1347, 1309, 1300, 1280, 1240, 1231,
1213, 1176, 1145, 1105, 1054, 1023, 951, 914, 850, 824, 760,
725, 700 cm–1. MS (EI, 70 eV, direct inlet): m/z (%) = 170 (2)
[M + H]+, 126 (4) [M – CHNO]+, 125 (46) [M – CO2]+, 124 (3),
111 (8) [M – C2H4NO]+, 110 (100) [M – C2H3O2]+, 96 (6), 83 (10),
82 (54), 57 (7), 56 (7), 55 (12), 54 (5), 53 (4), 44 (2) [CO2], 43 (42)
[CHNO]+, 42 (32), 41 (10), 40 (4).39 (12), 29 (8). HRMS (DCI):
C8H10NO3 calcd. 168.06607; found 168.06571.
Synthesis of Methyl [(2ЈR,3ЈR)-2Ј-Cyano-2Ј,3Ј-dimethyl-5Ј-oxopyr-
rolidin-3Ј-yl]acetate (9): Potassium cyanide (130.2 mg, 2.00 mmol)
was added to a solution of lactam-lactone 7 (169 mg, 1.0 mmol)
and dry methanol (20 mL). The reaction was stirred at room tem-
perature under argon for 20 h, after which about three quarters of
the solvent was removed in vacuo. A solution of NaH2PO4 (2 ,
15 mL) was added to the remaining reaction mixture and it was
cooled in an ice bath, concentrated H3PO4 was carefully added to
the cooled reaction mixture until pH 2 was reached (caution: evol-
ution of hydrogen cyanide gas!), and saturated NaCl solution was
then added to the reaction mixture, after which the product was
extracted three times with ethyl acetate. The combined organic ex-
tracts were dried with anhydrous Na2SO4, filtered and concentrated
in vacuo, and the colourless, oily residue was dried in vacuo (oil
pump) and dissolved in methanol (5 mL). This solution was cooled
in an ice bath, after which a solution of ethereal diazomethane
(0.5 , 10 mL) was added, the ice bath was removed, and the reac-
tion mixture was stirred at room temperature for 15 min. The mix-
ture was concentrated in vacuo (a small amount of acetic acid was
added to the receiver flask during the concentration to neutralize
the excess diazomethane) and the residue was chromatographed on
silica gel with elution with CH2Cl2/MeOH (95:5). A mixture of
colourless cis-, trans-cyano lactam crystals 9 was obtained. Yield:
168 mg (0.80 mmol, 80%). M.p. 127 °C. TLC: [silica gel, CH2Cl2/
Compound 8a: Yield: 764 mg (2.52 mmol, 60 %). M.p. 135 °C.
[α]2D0 = –3.4 (c = 1 in CH2Cl2). TLC [silica gel, CH2Cl2/EtOAc
(99:1)]: Rf = 0.45. HPLC: Nucleosil 50–10 Si, PE/EtOAc (1:1),
2 . 0 m L m i n – 1 , 2 5 4 n m , t R = 1 1 m i n . C D ( M e O H , c =
0.062 mgmL–1): Θ (λ) = 29300 (205 nm), 27400 (218 nm). 1H NMR
(200 MHz, CDCl3): δ = 1.28 [s, 3 H, C(1)-CH3], 1.53 [s, 3 H, C(5)-
CH3], 1.79 [d, 3J = 6.9 Hz, 3 H, C(8Ј)-CH3], 2.32–2.76 [2ϫAB
system, 4 H, C(4)-H2, C(6)-H2], 4.63–4.73 [q, 3J = 6.9 Hz, 1 H,
C(8Ј)-H], 6.85, 7.36 (2ϫd, 4 H, C6H4) ppm.
Compound 8b: Yield: 509 mg (1.68 mmol, 40 %). M.p. 149 °C.
[α]2D0 = –11.2 (c = 1 in CH2Cl2). TLC [silica gel, CH2Cl2/EtOAc
(99:1)]: Rf = 0.44. HPLC: Nucleosil 50–10 Si, PE/EtOAc (1:1),
1.5 mLmin–1, detector UV 254 nm, tR = 12 min. CD (MeOH, c =
0.060 mg mL–1): Θ (λ) = –5900 (204 nm), –11100 (231 nm). 1H
NMR (200 MHz, CDCl3): δ = 1.21 [s, 3 H, C(1)-CH3], 1.32 [s, 3
3
H, C(5)-CH3], 1.75 [d, J = 6.4 Hz, 3 H, C(8Ј)-CH3], 2.35–2.66 [m,
3
4 H, C(4)-H2, C(6)-H2], 5.20 [q, J = 6.4 Hz, 1 H, C(8Ј)-H], 6.85,
7.34 (2ϫd, 4 H, C6H4) ppm.
(1R,5S)-1,5-Dimethyl-2-oxa-8-azabicyclo[3.3.0]octane-3,7-dione (7)
and (1S,5R)-1,5-Dimethyl-2-oxa-8-azabicyclo[3.3.0]octane-3,7-dione
(ent-7): A solution of ammonium cerium(IV) nitrate (1.14 g,
2.08 mmol) in water (30 mL) was added in portions to a stirred
mixture of the N-alkylated lactam-lactone 8a (300 mg, 0.99 mmol)
in a solution of MeCN and water (4:1, 25 mL). The mixture was
allowed to react at room temperature for 17 h, quenched by the
addition of saturated aqueous NaHCO3 solution and stirred vigor-
ously for 15 min. The solution was then extracted three times with
CH2Cl2 and the combined organic extracts were dried with anhy-
drous Na2SO4, filtered and concentrated in vacuo. The residue was
chromatographed on silica gel with elution with CH2Cl2/MeOH
(95:5), giving the lactam-lactone 7 as colourless crystals after re-
moval of the eluent. The same procedure was used with 8b to yield
ent-7.
1
MeOH (9:1)]: Rf = 0.62. H NMR (200 MHz, CDCl3): δ = 1.22 [s,
3 H, C(3Ј)-CH3], 1.63 [s, 3 H, C(2Ј)-CH3], 2.38–2.90 [2ϫAB sys-
tem, 4 H, C(4)-H2, C(3)-CH2], 3.74 (s, 3 H, CO2CH3), 5.94 (s, 1 H,
NH) ppm. IR (KBr): ν = 3172, 3115, 3001, 2976, 2955, 2915, 2848,
˜
2230, 1732, 1725, 1668, 1450, 1440, 1389, 1351, 1329, 1297, 1280,
1236, 1214, 1185, 1159, 1150, 1091, 1000, 925, 900, 885, 865, 840,
780, 760, 720 cm–1. MS (EI, 70 eV, direct inlet): m/z (%) = 210 (18)
[M]+, 179 (37) [M – OCH3]+, 178 (5) [M – CH4O]+, 168 (7), 152
(7), 142 (22), 141 (13), 137 (23), 136 (3), 137 (23), 124 (10), 115 (8),
114 (100),113 (10), 110 (28), 109 (6), 108 (9), 99 (8), 86 (26), 83
(15), 82 (86), 81 (7), 72 (11), 71 (28), 69 (23), 68 (5), 67 (12), 59
(36), 56 (6), 55 (50), 54 (15), 53 (15), 43 (24), 42 (19), 41 (6), 40 (7),
39 (26), 29 (9), 28 (19), 27(16). HRMS (EI): C10H14N2O3 calcd.
210.10044; found 210.09981.
Compound 7: Yield: 108 mg (0.64 mmol, 65 %). M.p. 188 °C.
[α]2D0 = –104.5 (c = 1 in CH2Cl2). TLC [silica gel, CH2Cl2/EtOAc
1
(9+1)]: Rf = 0.61. H NMR (200 MHz, CDCl3): δ = 1.35 [s, 3 H, Methyl [(2ЈR,3ЈS)-2Ј-Cyano-2Ј,3Ј-dimethyl-5Ј-thioxopyrrolidin-3Ј-
C(5)-CH3], 1.62 [s, 3 H, C(1)-CH3], 2.36–2.82 (m, 4 H, –CH2–),
yl]acetate (10a) and Methyl [(2ЈS,3ЈS)-2Ј-Cyano-2Ј,3Ј-dimethyl-5Ј-
thioxopyrrolidin-3Ј-yl]acetate (10b): Lawesson’s reagent (247 mg,
0.62 mmol) was added to a solution of lactam 9 (106 mg,
6.19 (s, 1 H, NH) ppm. IR (KBr): ν = 3212, 3070, 3010, 2990, 2926,
˜
1769, 1703, 1495, 1442, 1417, 1347, 1309, 1300, 1280, 1240, 1231,
1213, 1176, 1145, 1105, 1054, 1023, 951, 914, 850, 824, 760, 0.51 mmol) in THF (10 mL) under argon, and the reaction mixture
725, 700 cm–1. MS (EI, 70 eV, direct inlet): m/z (%) = 170 (2)
[M + H]+, 126 (4) [M – CHNO]+, 125 (46) [M – CO2]+, 124 (3),
111 (8) [M – C2H4NO]+, 110 (100) [M – C2H3O2]+, 96 (6), 83 (10),
was heated at 40 °C with stirring for 30 min and then at room tem-
perature for 3½ h. The reaction mixture was concentrated in vacuo
and the residue was chromatographed on silica gel laminated with
Eur. J. Org. Chem. 2007, 249–257
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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