2250
Z. Wang, R. B. Silverman / Bioorg. Med. Chem. 14 (2006) 2242–2252
+
C H NO F (M ) 321.0807, found 321.0824. Irradia-
The crude product was then dissolved in 1,4-dioxane
5 mL) and added dropwise to a potassium permanga-
1
6
13
4 2
(
tion of H-2 resulted in NOE of 1.7%, 0.2%, and 1.6%
for H-3 (cis to H-2), H-3 (trans to H-2), and H-1, respec-
tively. Irradiation of H-4 resulted in NOE of 0.5%,
2.4%, and 0.7% for H-3 (cis to H-2), H-3 (trans to H-
2), and H-5, respectively. Thus, the gem-difluorocyclo-
propane moiety is trans to the C-4 phthalimide, while
cis to the C-2 methyl ester.
nate solution (0.1 M, 10 mL). The mixture was heated
at 50 ꢁC for 1 h, and it was cooled and extracted with
ethyl acetate (2 · 30 mL). The organics were washed
with saturated sodium carbonate (20 mL), sodium thio-
sulfate (1 M, 10 mL), and brine (20 mL), dried with
sodium sulfate, evaporated under reduced pressure,
and chromatographed (ethyl acetate/hexanes, 1:5) to af-
ford a white powder (0.15 g, 63%; 81% based on con-
3.2.18. (±)-(1S,2R,4S,5S)-6,6-Difluoro-4-phthalimidobi-
cyclo[3.1.0]hexane-2-carboxylic acid (25). The title com-
pound was prepared as a white solid (0.11 g, 92%)
from 23 (0.13 g, 0.4 mmol) using the same conditions
1
verted starting material); mp 173.0–176.0 ꢁC. H NMR
(
CDCl , 500 MHz) d 2.19–2.24 (dd, 1H, J = 8.7 Hz,
3
13.7 Hz, H-5), 2.48–2.55 (m, 1H, H-3, cis to H-2),
2.63–2.66 (dm, 1H, J = 14.2 Hz, H-3, trans to H-2),
3.02–3.06 (dd, 1H, J = 9.5 Hz, 14.2 Hz, H-1), 3.18–3.20
1
as described for 19; mp 195.0–197.0 ꢁC. H NMR
(CD OD, 500 MHz) d 2.12–2.19 (m, 1H, H-3, cis to
3
(
4
d, 1H, J = 10.0 Hz, H-2), 3.83 (s, 3H, COOCH3),
.96–4.98 (d, 1H, J = 8.5 Hz, H-4), 7.72–7.74 (dd, 2H,
J = 3.2 Hz, 5.2 Hz, ArH), 7.82–7.84 (dd, 2H,
H-2), 2.22–2.24 (dm, 1H, J = 14.5 Hz, H-3, trans to H-
2), 2.33–2.38 (dd, 1H, J = 8.0 Hz, 15.0 Hz, H-5), 2.42–
2.46 (dd, 1H, J = 8.0 Hz, 14.5 Hz, H-1), 3.10–3.11 (d,
1 H, J = 8.5 Hz, H-2), 4.55–4.56 (d, 1H, J = 7.0 Hz, H-
4), 7.38–7.39 (d, 1H, J = 7.5 Hz, ArH), 7.45–7.48 (t,
1H, J = 7.2 Hz, ArH), 7.52–7.55 (t, 1H, J = 7.0 Hz,
1
3
J = 3.0 Hz, 5.0 Hz, ArH).
C
NMR (CDCl3,
1
3
4
25 MHz) d 32.10–32.38 (t, J = 10.7 Hz, C-5), 32.36–
2.53 (t, J = 10.7 Hz, C-1), 36.93 (C-3), 44.31 (C-2),
9.94(C-4), 52.82 (COO CH ), 110.82–115.41 (dd,
1
3
ArH), 7.89–7.90 (d, 1H, J = 7.0 Hz, ArH). C NMR
3
J = 281.6 Hz, 294.5 Hz, C-6), 123.66 (Ar), 131.93 (Ar),
1
(CD OD, 125 MHz) d 32.51–32.70 (t, J = 11.8 Hz, C-
3
34.40 (Ar), 166.77 (phthalyl CO), 173.18 (COOMe).
F NMR (CDCl , 376 MHz) d ꢀ149.69 to ꢀ149.25
5), 34.06–34.24 (t, J = 11.9 Hz, C-1), 36.16 (C-3), 44.23
(C-2), 52.64 (C-4), 113.26–117.80 (dd, J = 295.2 Hz,
275.5 Hz, C-6), 128.88 (Ar), 130.87 (Ar), 131.55 (Ar),
1
9
3
(
J = 166.4 Hz, 14.0 Hz). HRMS (EI) calcd for
d, 1F, J = 164.9 Hz), ꢀ127.73 to ꢀ127.22 (dt, 1F,
133.23 (Ar), 139.83 (Ar), 169.18 (phthalyl CO), 171.98
(phthalyl CO), 177.90 (COOH). F NMR (CD OD,
+
C H NO F (M ) 321.0807, found 321.0805. Irradia-
19
1
6
13
4
2
3
tion of H-2 resulted in NOE of 1.9%, 0.7%, and 0.4%
for H-3 (cis to H-2), H-3 (trans to H-2), and H-1, respec-
tively. Irradiation of H-4 resulted in NOE of 2.1%,
376 MHz) d ꢀ148.95 to ꢀ148.51 (d, 1F, J = 167.9 Hz),
ꢀ126.29 to ꢀ125.77 (dt, 1F, J = 167.9 Hz, 14.9 Hz).
+
HRMS (CI) calcd for C H NO F
4 2
(M+H)
1
5
12
0
.7%, and 0.8% for H-3 (cis to H-2), H-3 (trans to
308.0729, found 308.0725.
H-2), and H-5, respectively. Thus, the gem-difluorocy-
clopropane moiety is trans to both the ester and phthal-
imide groups.
3.2.19. (±)-(1S,2S,4S,5S)-6,6-Difluoro-4-phthalimidobi-
cyclo[3.1.0]hexane-2-carboxylic acid (26). The title com-
pound was prepared as a white solid (0.28 g, 99%)
from 24 (0.29 g, 0.9 mmol) using the same conditions
3
.2.17. (±)-(1S,2S,4S,5S)-Methyl 6,6-difluoro-4-phthali-
1
midobicyclo[3.1.0]hexane-2-carboxylate (24). Starting
from trans-22 (0.21 g, 0.8 mmol), the above procedures
for the preparation of 23 before oxidation were fol-
lowed. NMR analysis indicated a 1:1 ratio of the desired
product to the starting alkene. So the same procedures
were repeated twice on the mixed product, and the same
ratio increased to 1:0.36 after the second round and to
as described for 19; mp 174.0–176.3 ꢁC. H NMR
(CD OD, 500 MHz) d 1.98–2.08 (m, 2H, H-3), 2.17–
3
2.28 (m, 2H, H-1 and H-5), 3.44–3.50 (m, 1H, H-2),
4.50–4.52 (d, 1H, J = 6.5 Hz, H-4), 7.32–7.33 (d, 1H,
J = 7.5 Hz, ArH), 7.41–7.44 (t, 1H, J = 7.5 Hz, ArH),
7.49–7.52 (t, 1H, J = 7.5 Hz, ArH), 7.87–7.89 (d, 1H,
1
3
J = 8.0 Hz, ArH). C NMR (CD OD, 125 MHz) d
3
1
was then treated with potassium permanganate as de-
:0.13 after the third round of reaction. The mixture
30.56–30.74 (t, J = 11.4 Hz, C-5), 33.87–34.06 (t,
J = 11.8 Hz, C-1), 34.30–34.37 (d, J = 8.4 Hz, C-3),
44.60 (C-2), 52.66 (C-4), 114.11–118.66 (dd,
J = 273.9 Hz, 297.5 Hz, C-6), 128.98 (Ar), 130.69 (Ar),
131.57 (Ar), 133.39 (Ar), 140.10 (Ar), 169.09 (phthalyl
scribed above to give a white solid (0.16 g, 62%); mp
9
1
2.0–95.5 ꢁC. H NMR (CDCl , 500 MHz) d 2.08–2.12
3
(
dd, 1H, J = 8.0 Hz, 14.0 Hz, H-5), 2.21–2.26 (t, 1H,
19
J = 12.0 Hz, H-3, cis to H-2), 2.47–2.55 (m, 1H, H-3,
trans to H-2), 2.63–2.68 (m, 1H, H-1), 3.75 (s, 3H,
COOCH ), 4.11–4.17 (m, 1H, H-2), 5.05–5.07 (d, 1H,
CO), 172.51 (phthalyl CO), 176.40 (COOH). F NMR
(CD OD, 376 MHz) d ꢀ146.64 to ꢀ146.19 (d, 1F,
3
J = 169.4 Hz), ꢀ125.15 to ꢀ124.63 (dt, 1F,
J = 169.4 Hz, 13.6 Hz). HRMS (EI) calcd for
C H NO F (M ) 307.0656, found 307.0652.
3
J = 9.0 Hz, H-4), 7.74–7.76 (dd, 2H, J = 3.0 Hz,
5
+
.5 Hz, ArH), 7.84–7.86 (dd, 2 H, J = 3.0 Hz, 5.5 Hz,
1
5
11
4
2
1
3
ArH). C NMR (CDCl , 125 MHz) d 31.72–31.89 (t,
3
J = 10.7 Hz, C-5), 32.71–32.89 (t, J = 10.8 Hz, C-1),
3.2.20.
(±)-(1S,2R,4S,5S)-4-Amino-6,6-difluorobicy-
3
4
2
1
4.85–34.90 (d, J = 6.0 Hz, C-3), 44.98 (C-2), 50.56 (C-
), 52.38 (COOCH ), 111.14–115.73 (dd, J = 279.3 Hz,
clo[3.1.0]hexane-2-carboxylic acid (5). Sodium borohy-
dride (19 mg, 0.5 mmol) was added to a mixture of 25
(15.6 mg, 0.05 mmol) in 2-propanol (3.0 mL) and water
(0.5 mL), and the solution was stirred at room tempera-
ture for 24 h. Acetic acid (0.2 mL) was then carefully
added dropwise, and the solution was heated at 80 ꢁC
for 2 h after the foam had subsided. The crude reaction
3
96.8 Hz, C-6), 123.63 (Ar), 131.87 (Ar), 134.54 (Ar),
67.86 (phthalyl CO), 173.26 (COOMe). F NMR
1
9
(
CDCl , 376 MHz) d ꢀ147.39 to ꢀ146.92 (dt, 1F,
3
J = 169.4 Hz, 4.5 Hz), ꢀ126.37 to ꢀ125.86 (dt, 1F,
J = 167.9 Hz, 13.7 Hz). HRMS (EI) calcd for