a solution of 4 (4.7 g, 16.4 mmol) in anhydrous MeOH (10 mL), during which time a precipitate formed and the temperature
was held to <15°C. The resulting mixture was stirred for 15 min, diluted with H O (300 mL), and extracted with Et O
2
2
(3 ꢅ 100 mL). The combined extract was washed with H O and saturated NaCl solution and dried over anhydrous MgSO .
2
4
The solvent was vacuum distilled to afford a mixture of two diastereomers 5 (4.43 g, 96%) as a yellow oil that was used
without further purification, C H O .
16 26
4
(1S,2R,3S,5S)-Methyl 3-hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclopentanecarboxylate (6). A solution of 5
(4.43 g, 15.7 mmol) in MeOH (35 mL) was treated with a catalytic amount of pyridinium p-toluenesulfonate (PPTS, 10 mol%)
and held at 50°C for 2 h. When the reaction was finished (TLC monitoring), the solvent was vacuum distilled. The residue
was percolated through a layer of SiO to afford pure (by TLC) oily 6 (2.77 g, 90%) that was used without further purification,
2
19
C H O , [ꢃ] –4.65° (c 0.096, CHCl ).
11 18
3
D
3
1
Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 1.06 (3Í, d, J = 7, Í-7), 1.72 (3H, s, Í-10), 1.87–1.80 (2H, m,
Í-5, OH-6ꢀ), 2.0–2.08 (1H, m, Í-5), 2.52–2.47 (1H, m, H-1), 2.84 (1H, dd, J = 9.6, 12, Í-3), 3.28–3.17 (1H, m, Í-4), 3.60
(3H, s, Í-11), 4.25 (1H, t, J = 4.3, Í-6), 4.7–4.79 (2H, m, Í-9). C NMR spectrum (100.6 MHz, CDCl , ꢂ, ppm): 13.59 (s,
Ñ-7), 22.49 (s, Ñ-10), 39.39 (s, Ñ-5), 42.46 (s, Ñ-4), 46.63 (s, Ñ-3), 51.28 (s, Ñ-1), 53.19 (s, Ñ-11), 75.06 (s, Ñ-6), 111.42 (s,
Ñ-9), 145.24 (s, Ñ-8), 174.99 (s, Ñ-2).
3
13
3
(1S,2R,3S,5S)-Methyl 2-methyl-3-(3-oxobutanoyloxy)-5-(prop-1-en-2-yl)cyclopentanecarboxylate (7). Asolution
of 6 (2.77 g, 14 mmol) in C H (20 mL) was treated with anhydrous Py (two drops) and diketene (2.5 g, 29.7 mmol) and heated
6
6
for 2 h at 50°C. The solvent was vacuum distilled. The residue was percolated through a layer of SiO (3 g) to afford a yellow
2
16
oil of 7 (3.62 g, 92%), C H O , [ꢃ] –21.3° (c 0.097, CHCl ).
15 22
5
D
3
1
Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 1.02 (3Í, d, J = 6.9, Í-7), 1.74 (3H, s, Í-15), 1.97–1.91 (1H,
3
m, Í-5ꢀ), 2.18–2.13 (1H, m, Í-5ꢀꢀ), 2.29 (3H, s, H-10), 2.75–2.66 (1H, m, Í-3), 2.86–2.82 (1H, m, Í-1), 3.16–3.09 (1H, m,
13
Í-4), 3.48 (2Í, s, Í-13), 3.63 (3H, s, Í-11), 4.65–4.98 (2H, m, Í-9), 5.39 (1H, t, J = 4.7, Í-6). C NMR spectrum
(100.6 MHz, CDCl , ꢂ, ppm): 13.91 (s, Ñ-7), 25.48 (s, Ñ-15), 30.25 (s, Ñ-10), 36.95 (s, Ñ-5), 41.12 (s, Ñ-4), 46.69 (s, Ñ-1),
3
50.24 (s, Ñ-13), 51.46 (s, Ñ-13), 53.73 (s, Ñ-11), 79.15 (s, Ñ-6), 111.89 (s, Ñ-9), 144.41 (s, Ñ-8), 166.66 (s, Ñ-12), 174.27 (s,
Ñ-2), 200.54 (s, Ñ-14).
(1S)-1-{(1S,3S,6R)-4,7-Dimethylbicyclo[4.1.0]hept-4-en-3-yl}ethyl-3-oxobutanoate (14) was prepared analogously
16
–1
to 7. Colorless oil, 97% yield, C H O , [ꢃ] +92.55° (c 0.1426, CHCl ). IR spectrum (ÑÑI , , cm ): 1735, 1720, 1670,
15 22
3
D
3
4
1
1375. Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 0.84–0.80 (1Í, m, H-6), 0.87 (3Í, s, H-9), 0.93–0.89 (1Í, m, Í-5ꢀ),
3
1.05 (3Í, s, H-8), 1.24 (3Í, d, J = 6.2, Í-12), 1.45–1.39 (1Í, m, H-5ꢀꢀ), 1.72 (3Í, s, Í-10), 1.88–1.85 (1Í, m, H-1), 2.03–1.97
13
(1Í, m, Í-4), 2.28 (3Í, s, Í-16), 3.46 (2Í, s, Í-14), 5.23–5.16 (1Í, m, Í-11), 5.48 (1Í, s, Í-2).
C NMR spectrum
(100.6 MHz, CDCl , ꢂ, ppm): 15.11 (s, C-12), 18.10 (s, C-9), 18.58 (s, C-8), 22.26 (s, C-16), 23.59 (s, C-10), 24.03 (s, C-7),
3
24.24 (s, C-6), 27.65 (s, C-5), 30.15 (s, C-1), 43.29 (s, C-4), 50.59 (s, C-14), 73.95 (s, C-11), 123.31 (s, C-2), 136.67 (s, C-3),
166.74 (s, C-13), 200.79 (s, C-15).
Method for Preparing 10a and b and 15a and b. A suspension of isatin (8, 0.13 g, 0.89 mmol, 1 eq) in anhydrous
CH Cl (4 mL) was stirred, treated with malononitrile (9, 0.06 g, 0.89 mmol, 1 eq), DABCO (0.01 g, 10 mol%), and freshly
2
2
°
calcined molecular sieves (4 A), cooled to 0°C, treated with the appropriate acetoacetate (0.94 mmol, 1.05 eq), and stirred for
3–6 h until starting 8 disappeared (TLC monitoring). The solvent was vacuum distilled (water aspirator). The residue was
chromatographed over SiO with elution by CH Cl :MeOH (0–2%).
2
2
2
(R)-[(1S,2R,3S,4S)-3-(Methoxycarbonyl)-2-methyl-4-(prop-1-en-2-yl)cyclopentyl] 2ꢀ-amino-3ꢀ-cyano-6ꢀ-methyl-
16
2-oxospiro[indoline-3,4ꢀ-pyran]-5ꢀ-carboxylate (10a). Yellow oil, 33% yield, C H N O , [ꢃ] +47.55° (c 0.02, CHCl ).
26 27
3
6
D
3
1
Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Ãö): 0.37 (3Í, d, J = 7.2, Í-7), 1.38 (3H, s, Í-15), 1.76–1.70 (1H, m, Í-5ꢀ),
3
2.00–1.93 (1H, m, Í-5ꢀꢀ), 2.23 (1H, t, J = 9.6, Í-3), 2.45 (3H, s, Í-10), 2.49–2.43 (1H, m, Í-1), 2.90 (1H, m, Í-4), 3.58 (3H, s,
Í-11), 4.71 (2H, d, J = 50, Í-9), 5.02 (2Í, s, NÍ ), 5.36 (1H, t, J = 4.9, Í-6), 6.92 (1Í, d, J = 7.8, Í-22), 7.06 (1H, t, J = 7.6,
2
13
H-23), 7.20 (1Í, d, J = 7.6, Í-25), 7.23 (1H, t, J = 7.8, H-24), 8.44 (1Í, s, NÍ). C NMR spectrum (100.6 MHz, CDCl , ꢂ,
3
ppm): 13.24 (s, Ñ-7), 19.53 (s, Ñ-15), 22.17 (s, Ñ-10), 36.42 (s, Ñ-5), 41.04 (s, Ñ-4), 46.66 (s, Ñ-1), 48.94 (s, Ñ-19), 49.27 (s,
Ñ-3), 51.36 (s, Ñ-17), 53.68 (s, Ñ-11), 79.53 (s, Ñ-6), 104.38 (s, Ñ-13), 110.39 (s, Ñ-9), 112.06 (s, Ñ-22), 116.57 (s, Ñ-18),
123.32 (s, Ñ-24), 123.95 (s, Ñ-23), 129.31 (s, Ñ-26), 134.37 (s, Ñ-25), 144.25 (s, Ñ-21), 144.68 (s, Ñ-8), 158.44 (s, Ñ-14),
160.33 (s, Ñ-16), 164.49 (s, Ñ-20), 174.05 (s, Ñ-12), 178.77 (s, Ñ-2).
(S)-[(1S,2R,3S,4S)-3-(Methoxycarbonyl)-2-methyl-4-(prop-1-en-2-yl)cyclopentyl] 2ꢀ-amino-3ꢀ-cyano-6ꢀ-methyl-
16
2-oxospiro[indoline-3,4ꢀ-pyran]-5ꢀ-carboxylate (10b). Colorless oil, 33% yield, C H N O , [ꢃ] –75.06° (c 0.01, CHCl ).
26 27
3
6
D
3
1
Í NMR spectrum (400 MHz, CDCl , ꢂ, ppm, J/Hz): 0.87 (3Í, d, J = 7.2, Í-7), 1.02–1.09 (1H, m, Í-5ꢀ), 1.63 (3H, s, Í-15),
3
1.87–1.78 (1H, m, Í-5ꢀꢀ), 2.44 (3H, s, Í-10), 2.54–2.45 (2H, m, Í-3 + H-1), 2.61 (1H, t, J = 9.8, Í-4), 3.59 (3H, s, Í-11),
4.65 (2H, d, J = 6.8, Í-9), 4.96 (2H, s, NH ), 5.20 (1H, t, J = 5.0, Í-6), 6.86 (1Í, d, J = 7.7, Í-22), 7.08 (1H, t, J = 7.5,
2
106