3610 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10
Dominguez et al.
was purified by HPLC (10% EtOAc/hexanes to 50% EtOAc/
hexanes), affording 6 (38.22 g, 230 mmol, 92% yield). Mp )
75-77 °C. FDMS: M+ ) 166. 1H NMR (CDCl3) δ: 7.61 (dd, J
) 5.5 and 2.4 Hz, 1H), 5.73 (d, J ) 5.5 Hz, 1H), 4.15 (q, J )
7.1 Hz, 2H), 2.97-2.94 (m, 1H), 2.64-2.61 (m, 1H), 2.27 (t, J
) 2.7 Hz, 1H), 1.27 (t, J ) 7.1 Hz, 3H). 13C NMR (CDCl3) δ:
203.24, 167.92, 159.66, 129.60, 61.32, 45.82, 30.01, 28.91,
14.11. Anal. (C9H10O3) C, H.
(1SR,4SR,5RS,6SR)-Ethyl-2-oxo-4-methylbicyclo[3.1.0]-
hexane 6-Carboxylate (7). Methyllithium (71 mL of a 1.4
M solution in Et2O, 100 mmol) was added to a mixture of
copper(I) iodide (9.5 g, 50 mmol) in anhydrous Et2O (10 mL)
at 0 °C. The solution was stirred for 30 min at 0 °C and cooled
to -78 °C. Compound 6 (1.6 g, 10 mmol) in Et2O (25 mL) was
added dropwise. Upon complete addition, the mixture was
stirred for another hour at -20 °C for 1 h and then was
quenched with saturated ammonium chloride solution and
extracted with Et2O. The combined organic phases were dried
over MgSO4, filtered, and evaporated to dryness. Purification
of the crude product by flash chromatography (hexane/ethyl
acetate 4:1) gave 7 (1.52 g, 8.3 mmol, 83% yield). FDMS: M+
) 182. 1H NMR (CDCL3), δ: 4.1 (q, 2H, J ) 7.15 Hz), 2.5 (m,
1H), 2.35-2.19 (m, 3H), 2.1 (t, 1H, J ) 2.60 Hz), 1.65 (d, 1H,
J ) 18.60 Hz), 1.19 (t, 3H, J ) 7.15 Hz), 1.10 (d, 3H, J ) 6.90
Hz). 13C NMR (CDCl3), δ: 211.13, 170.16, 61.13, 40.45, 36.09,
34.96, 29.93, 26.92, 21.80, 14.03. Anal. (C10H14O3) C, H.
Cl. The organic phase was dried (MgSO4) and concentrated to
dryness. The residue was dissolved in CH3CN, cooled to 5 °C,
and treated with Pd(OAc)2 (11.0 g, 49 mmol) in one portion.
The reaction was allowed to continue at room temperature
overnight, then was diluted with Et2O, filtered through a pad
of silica gel and Celite, and concentrated to dryness yielding
10 (7.1 g, 35.4 mmol, 88% yield). The product solidified to a
low-melting solid on standing, mp ) 50-52 °C. FDMS: M+
)
1
180. H NMR (CDCl3) δ: 5.41 (s, 1H), 4.15 (q, J ) 7 Hz, 2H),
2.80-2.75 (m, 1H), 2.60-2.55 (m, 1H), 2.22 (t, J ) 2.5 Hz, 1H),
2.18 (s, 3H), 1.25 (t, J ) 7 Hz, 3H). Anal. (C10H12O3.0.05CH2-
Cl2) C, H.
(1SR,4RS,5RS,6SR)-Ethyl-2-oxo-4-methylbicyclo[3.1.0]-
hexane 6-Carboxylate (11). To a solution of 10 (5.55 g, 30.8
mmol) in EtOH (100 mL) was added 5% Pd-C (0.6 g). The
mixture was subjected to H2(g) at 40 psi for 1 h. The mixture
was diluted with Et2O and filtered through Celite. The solvent
was evaporated, and the crude product was purified by HPLC
(hexanes-ethyl acetate 3:1), providing 11 (5.08 g, 28 mmol,
1
91%). FDMS: M+ ) 182. H NMR (CDCl3) δ: 4.18-4.08 (m,
2H), 2.70-2.60 (m, 1H), 2.51-2.48 (m, 1H), 2.28-2.25 (m, 1H),
2.18 (ddd, J ) 18.4, 8.8, and 1.0 Hz, 1H), 2.03 (dd, J ) 3.3
and 2.5 Hz), 1.61 (ddd, J ) 18.4, 9.5, and 1.0 Hz, 1H), 1.26 (t,
J ) 7 Hz, 3 H), 1.15 (d, J ) 7 Hz, 3H). 13C NMR (CDCl3) δ:
210.8, 170.47, 61.22, 39.56, 37.17, 34.79, 29.56, 23.76, 18.07,
14.09. Anal. (C10H14O3) C, H.
(1SR,2SR,4RS,5RS,6SR)-Ethyl-2-spiro-5-hydantoin-4-
methylbicyclo[3.1.0]hexane 6-Carboxylate (12). To a solu-
tion of 11 (1.82 g, 10 mmol) in ethanol (20 mL) and water (10
mL) was added KCN (1.0 g, 15 mmol) and (NH4)2CO3 (2.0 g,
25 mmol) and the mixture was heated at 50 °C for 48 h. The
reaction mixture was diluted with H2O (30 mL) and cooled in
an ice bath, and the resulting solids were filtered to yield 0.5
g of crude product. This was recrystallized from EtOH to yield
a single diastereomer 12 (0.18 g, 0.71 mmol, 7.1%). Mp ) 222-
224 °C. FDMS: M+ ) 252. 1H NMR (pyridine-d5), δ: 12.47 (s,
1H), 9.58 (s, 1H), 4.08 (q, 2H, J ) 7.1 Hz), 2.97 (ddd, J ) 10.5,
6.8, and 3.8 Hz, 1H), 2.45 (dd, J ) 6.3 and 3.2 Hz, 1H), 2.25
(ddd, J ) 6.3, 3.2, and 3.2 Hz, 1H), 2.16 (dd, J ) 3.2 and 3.2
Hz, 1H), 2.11 (dd, J ) 13.7 and 7.9 Hz, 1H), 1.23 (dd, J ) 13.7
and 10.5 Hz, 1H), 1.08 (t, J ) 7.1 Hz, 3H), 0.89 (d, J ) 6.8 Hz,
3H). 13C NMR (pyridine-d5), δ: 178.65, 172.33, 157.97, 70.17,
60.74, 38.43, 34.56, 33.85, 33.39, 18.92, 18.92, 14.20. Anal.
(C12H16N2O4) C, H, N.
(1SR,2SR,4RS,5RS,6SR)-2-Amino-4-methylbicyclo[3.1.0]-
hexane 2,6-Dicarboxylic Acid (13). A mixture of 12 (0.15
g, 0.6 mmol) and 1 N NaOH solution (15 mL) was heated under
reflux for 5 days. The pH was adjusted to 1 by addition of 1 N
HCl, and the resulting solution was evaporated to dryness,
yielding a white solid. The solids were redissolved at pH 12,
the solids were removed by filtration, and the filtrate was
applied to an anion exchange column (AG1-X8, acetate form).
Amino acid 13 (0.067 g, 0.34 mmol, 56%) was isolated following
elution with 3 N AcOH. Mp >270 °C (dec). FDMS: M+ (+H)
) 200. 1H NMR (D2O, KOD), δ: 2.25-2.10 (m, 1H), 1.70-1.43
(m, 3H), 1.22 (br.s, 1H), 0.7-0.67 (m, 3H), 0.52-0.43 (m, 1H).
13C NMR (D2O, KOD) δ: 180.97, 180.16, 64.26, 40.17, 34.39,
31.46, 31.33, 19.04, 14.47. Anal. (C9H13NO4) C, H, N.
Separation of the Enantiomers of rac-11. The individual
enantiomers of rac-11 were obtained by chiral column chro-
matography (Chiralpak AD 8 cm × 28 cm column; 500 mg of
racemate loaded each run; elution with 100% CH3OH at 300
mL/min; detection at 220 nm). Retention times for (+)-11 and
(-)-11 were 6.22 and 10.07 min, respectively. From 8.5 g (46.6
mmol) of rac-11 was obtained 3.56 g (19.5 mmol, 42% yield,
>98.8% ee) of (+)-11 and 3.66 g (20.0 mmol, 43% yield, 98.8%
ee) of (-)-11. Optical rotations: (+)-11, RD 78.5 (c 1.07, CH3-
OH); (-)-11, Rd -83.3 (c 1.08, CH3OH).
(+)-Ethyl-2-spiro-5-hydantoin-4-methylbicyclo[3.1.0]-
hexane 6-Carboxylate ((+)-12). To a solution of (+)-11 (3.20
g, 17.6 mmol) in ethanol (15 mL) and water (15 mL) was added
KCN (1.71 g, 26.3 mmol) and (NH4)2CO3 (4.12 g, 52.8 mmol),
and the mixture was heated at 50 °C overnight and then at
room temperature for an additional 24 h. The resulting solids
(1SR,2SR,4SR,5RS,6SR)-Ethyl-2-acetamido-2-cyano-4-
methylbicyclo[3.1.0]hexane 6-Carboxylate (8). A hetero-
geneous mixture of alumina (14 g, Merck, type 90 for column
chromatography, neutral, activity I) and ammonium chloride
(26 mmol) in acetonitrile (50 mL) was ultrasonically irradiated
for 30 min. Then, a solution of 7 (2.19 mmol) in acetonitrile (5
mL) was added, and after sonication for an addition 2 h, 2.19
mmol of KCN was added. The mixture was sonicated over-
night, and then the alumina was filtered off and the filtrate
was concentrated to dryness to give a mixture of diastereo-
meric aminonitriles. To a solution of this mixture (1.25 mmol)
in dry CH2Cl2 at 0 °C was added ethyl diisopropylamine (1.37
mmol), and the resultant mixture was stirred for 15 min.
Acetyl chloride (1.37 mmol) was added, and the mixture was
stirred at ambient temperature for 5 h. The reaction was
quenched with water and extracted with CH2Cl2. The com-
bined organic extracts were dried over MgSO4 and evaporated
to dryness. Desired diastereomer 8 (0.16 g, 0.66 mmol) was
isolated in 30% yield from the mixture by column chromatog-
raphy (hexane/ethyl acetate 1:1), using 230-400 mesh silica
1
gel (Merck). FDMS: M+ ) 250. H NMR (CDCl3), δ: 6.15 (s,
1H), 4.1 (q, 2H, J ) 7.1 Hz), 2.7 (dd, 1H, J ) 2.8 and 6.2 Hz),
2.55 (d, 1H, J ) 15 Hz), 2.45 (m, 1H), 2.15-1.95 (m, 5H), 1.62
(t, 1H, J ) 3.5 Hz), 1.55 (dd, 1H, J ) 7.8 and 15 Hz), 1.25 (m,
6H). 13C NMR (CDCl3), δ: 171.16, 169.97, 121.09, 61.28, 55.05,
42.26, 34.94, 34.62, 34.29, 23.03, 22.04, 21.15, 14.25. Anal.
(C13H18N2O3) C, H,N.
(1SR,2SR,4SR,5RS,6SR)-2-Amino-4-methylbicyclo[3.1.0]-
hexane 2,6-Dicarboxylic Acid (rac-9). A mixture of 8 (0.8
mmol) and 5 N HCl solution (10 mL) was heated under reflux
overnight. The resulting solution was evaporated to dryness,
yielding a white solid. Amino acid 9 (0.05 g, 0.25 mmol) was
isolated in 31% yield as a zwitterion after ion exchange
chromatography on Dowex 50X8 50-100 mesh using 10%
pyridine-water as eluent. Mp > 300 °C. FDMS: M+ ) 199.
1H NMR (D2O, Pyr-d5), δ: 2.2 (dd, 1H, J ) 3.1 and 6.2 Hz),
1.94 (m, 1H), 1.8-1.6 (m, 3H), 1.52 (t, 1H, J ) 3.1 Hz), 0.9 (d,
3H, J ) 7.2 Hz). 13C NMR (D2O, KOD) δ: 181.32, 179.68, 67.05,
41.58, 35.02, 34.77, 33.61, 25.56, 20.24. Anal. (C9H13NO4) C,
H, N.
(1SR,5RS,6SR)-Ethyl-2-oxo-4-methylbicyclo[3.1.0]hex-
3-ene 6-Carboxylate (10). A solution of 7 (8.15 g, 44.7 mmol)
and Et3N (10.86 g, 107 mmol) in CH2Cl2 at 0 °C was treated
dropwise with TMSI (10.74 g, 53.7 mmol) at a rate that
maintained the internal temperature below 5 °C. Upon
complete addition, the mixture was allowed to stir at this
temperature for 2 h. The reaction mixture was diluted with
Et2O and washed with a saturated aqueous solution of NH4-