Macrocycle Formation by Catalytic Cyclopropanation
1S,10R)-5,6-Benzo-3,8-dioxa-11,11-dimethylbicyclo[8.1.0]undecan-
J. Am. Chem. Soc., Vol. 122, No. 24, 2000 5727
(
(1R,20S)-5,6,10,11,15,16-trisbenzo-3,8,13,18-tetroxa-20-methylbicyclo-
[18.1.0]henicosan-2-one (20a) and (1S*,20S*)-5,6,10,11,15,16-tris-
benzo-3,8,13,18-tetroxa-20-methylbicyclo[18.1.0]henicosan-2-one (20b)
as an inseparable mixture by column or radial chromatography (94.3
mg, 0.20 mmol, 46%). Enantiomeric excess and absolute configuration
were determined for the (1S*,20R*) compound by hydrogenolysis [Pd-
1
2
5
1
1
(
(
3
-one (8e): H NMR (250 MHz, CDCl ) δ 7.38-7.25 (comp, 4H),
.31 (d, J ) 12.1 Hz, 1H), 5.10 (d, J ) 12.1 Hz, 1H), 4.78 (d, J )
1.3 Hz, 1H), 4.27 (d, J ) 11.3 Hz, 1H), 4.05 (dd, J ) 11.0, 6.4 Hz,
H), 3.38 (dd, J ) 11.0, 9.5 Hz, 1H), 1.64 (d, J ) 9.3 Hz, 1H), 1.58
ddd, J ) 9.5, 9.3, 6.4 Hz, 1H), 1.32 (s, 3H), 1.11 (s, 3H); 13C NMR
75 MHz, CDCl
3.0, 66.5, 66.0, 33.3, 32.1, 29.2, 26.8, 15.8. Anal. Calcd for
: C, 73.15; H, 7.37 Found: C, 73.14; H, 7.38.
Enantiomeric separation was achieved on a 30 m Chiraldex B-DM
column operated at 145 °C: 87.6 min for the (1S,10R)-enantiomer,
3
) δ 172.8, 136.9, 136.0, 131.1, 130.7, 128.8, 128.5,
2 2
(OH) , H (1 atm) in EtOH, 24 h] to give (1R,5S)-5-methyl-3-
7
oxabicyclo-[3.1.0]hexan-2-one. Absolute configuration was determined
by comparison of the elution order on a 30 m Chiraldex G-TA column
[120 °C, 12.2 min for (1R,5S), 12.5 min for (1S,5R)] versus a sample
of known absolute stereochemistry10 prepared directly from 2-methyl-
15 18 3
C H O
2
3
8
9.4 min for the (1R,10S)-enantiomer. [R]
D
) +1.54° (c ) 3.6,
]. A small sample of 8e (from
, H (1
2
2-propenyl diazoacetate catalyzed by Rh (4S-MPPIM)4.
CHCl
3
) for 63% ee [from Rh
2
(4S-IBAZ)
4
General Procedure for Diazo Decomposition of 21. The procedure
-
1
, X ) PF
6
) was then subjected to hydrogenolysis [Pd(OH)
2
2
-
6
) is representative. Diazo-
for diazo decomposition with 1 (X ) PF
acetate 21 (87 mg, 0.28 mmol) was dissolved in 3 mL of freshly distilled
CH Cl and added via syringe pump over 3 h to a solution of Cu-
MeCN) PF (1 mg, 1.0 mol %) and the bisoxazoline corresponding to
(1 mg, 1.2 mol %) in 3 mL of refluxing CH Cl . After the addition
atm) in EtOH, 24 h] to give (1S,5R)-6,6-dimethyl-3-oxabicyclo[3.1.0]-
hexan-2-one whose absolute configuration was determined by com-
parison of its elution order on a 30 m Chiraldex G-TA column [110
2
2
(
1
4
6
°
C: 18.9 min for (1R,5S), 23.3 min for (1S,5R)] versus a sample of
2
2
1
0
known absolute stereochemistry prepared directly from 3-methyl-2-
butenyl diazoacetate catalyzed by Rh (5S-MEPY)
1R*,10S*,11R*)-5,6-Benzo-3,8-dioxa-11,11-dimethylbicyclo[8.1.0]-
was complete, the solution was passed through a plug of silica gel to
remove the catalyst, and the silica was washed with 50 mL of 30%
ethyl acetate in hexanes. The solvent was removed under reduced
pressure. GC and NMR analysis revealed the presence of a single major
compound. Purification by column chromatography (8:2 hexanes/ethyl
acetate) gave cyclopropane 22 (75 mg, 0.27 mmol, 95% yield) as a
white solid (mp 88-90 °C).
2
4
.
(
1
undecan-2-one (9e): H NMR (250 MHz, CDCl ) δ 7.54 (d, J ) 7.2
3
Hz, 1H), 7.42-7.24 (comp, 3H), 5.95 (d, J ) 13.2 Hz, 1H), 5.31 (d,
J ) 13.2 Hz, 1H), 4.88 (d, J ) 12.8 Hz, 1H), 4.51 (d, J ) 12.8 Hz,
1
1
6
1
H), 3.95 (dd, J ) 13.0, 5.8 Hz, 1H), 3.39 (dd, J ) 13.0, 9.5 Hz, 1H),
.51 (d, J ) 6.0 Hz, 1H), 1.16 (s, 3H), 1.05 (s, 3H), 0.70 (dt, J ) 9.5,
When diazo decomposition was performed using 79 mg (0.25 mmol)
of diazoacetate 21 catalyzed by Rh (4R-MEOX) , GC and NMR
2 4
13
.0 Hz, 1H); C NMR (75 MHz, CDCl
3
) δ 172.5, 137.4, 135.5, 130.5,
29.5, 129.1, 128.3, 72.2, 67.4, 65.8, 30.5, 25.8, 22.7, 21.0, 18.1; mass
analysis of the reaction mixture revealed the presence of a second
compound, 23, in a 3:7 ratio with cyclopropane 22, Purification by
radial chromatography gave 43 mg (0.15 mmol, 60% yield) of the
cyclopropane 22, and 17 mg (0.06 mmol, 24% yield) of aromatic
cycloaddition product 23.
spectrum, m/z (rel intens) 246 (M, 1), 163 (42), 162 (81), 119 (55),
17 (37), 104 (78), 92 (100), 91 (73). Enantiomeric separation was
1
achieved on a 30 m Chiraldex B-DM column operated at 145 °C: 91.4
min for the (1R*,10S*)-enantiomer, 93.4 min for the (1S*,10R*)-
2
3
enantiomer. [R]
D
3
) +28.9° (c ) 2.62, CHCl ) for 30% ee (from 1,
(
1R,11S)-11-Methyl-5,6,7[i,j]naphthobicyclo[9.1.0]dodecan-2-one
22): 1H NMR (500 MHz, CDCl
) δ 7.90 (dd, J ) 8.1, 1.3 Hz, 1H),
.89 (dd, J ) 8.1, 1.3 Hz, 1H), 7.62 (dd, J ) 7.0, 1.4 Hz, 1H), 7.52
dd, J ) 7.0, 1.4 Hz, 1H), 7.47 (dd, J ) 8.1, 7.0 Hz, 1H), 7.41 (dd, J
-
X ) PF
6
).
(
7
(
)
)
1
1
1
2
7
3
General Procedure for Diazo Decomposition of 17. The procedure
-
for diazo decomposition with 1 (X ) PF
6
) is representative. Diazo-
acetate 7 (390 mg, 1 mmol) was dissolved in 10 mL of freshly distilled
CH Cl and added via syringe pump over 5 h to a solution of Cu-
MeCN) PF (4.0 mg, 1.0 mol %) and the bisoxazoline corresponding
to 1 (4.2 mg, 1.3 mol %) in 10 mL of refluxing CH Cl . After the
8.1, 7.0 Hz, 1H), 5.50 (br s, 2H), 4.86-4.76 (comp, 2H), 3.79 (d, J
11.0 Hz, 1H), 3.38 (d, J ) 11.0 Hz, 1H) 1.65 (dd, J ) 7.8, 5.6 Hz,
2
2
(
4
6
H), 1.35 (t, J ) 5.4 Hz, 1H), 1.22 (s, 3H), 0.81 (dd, J ) 7.8, 5.0 Hz,
H); 13C NMR (75 MHz, CDCl
) δ 173.1, 135.8, 133.8, 133.0, 131.8,
31.7, 131.6, 131.5, 131.0, 130.7, 125.3, 124.7, 73.3, 72.3, 69.9, 26.1,
3.2, 18.7. Anal. Calcd for C18 : C, 76.58; H, 6.42. Found: C,
6.69; H, 6.45. Enantiomer separation was achieved on a 30 m
2
2
3
addition was complete, the solution was passed through a plug of silica
gel to remove the catalyst, and the silica was washed with 50 mL of
18 3
H O
30% ethyl acetate in hexanes. The solvent was removed under reduced
pressure. GC and NMR analysis revealed the presence of two
diastereomeric cyclopropanes, 18a and 18b, in a 69:31 ratio. Purification
by column chromatography (10:1 hexanes/ethyl acetate) gave 156 mg
of (1R,15S)-5,6,10,11-bisbenzo-3,8,3-trioxa-15-methylbicyclo[13.1.0]-
hexadecan-2-one (18a; 0.44 mmol, 44%) followed by 69 mg of
Chiraldex B-DM column operated at 160 °C for 60 min and then heated
at 0.2 °C/min to 220 °C: 186.8 min for the (1R,11S)-enantiomer, 188.8
2
3
min for the (1S,10R)-enantiomer. [R]
D
3
) +25.1° (c ) 10.4, CHCl )
-
for 80% ee (from 1, X ) PF
6
). A small sample of 22 (from 1) was
, H (1 atm) in EtOH, 24 h]
then subjected to hydrogenolysis [Pd(OH)
2
2
(1S*,15S*)-5,6,10,11-bisbenzo-3,8,13-trioxa-15-methylbicyclo[13.1.0]-
to give (1R,5S)-5-methyl-3-oxabicyclo[3.1.0]hexan-2-one whose ab-
solute configuration was determined by comparison of the elution order
on a 30 m Chiraldex G-TA column [(120 °C, 12.2 min for (1R,5S),
hexadecan-2-one (18b; 0.20 mmol, 20%). Enantiomeric separation was
achieved for 18a on a 30 m Chiraldex B-DM column operated at 200
°
C: 119.3 min for the (1R,15S)-enantiomer, 121.6 min for the (1S,15R)-
enantiomer. A small sample of 18a (from Rh (4S-IBAZ) ) was then
subjected to hydrogenolysis [Pd(OH) , H (1 atm) in EtOH, 24 h] to
1
2.5 min for (1S,5R)] versus a sample of known absolute stereochem-
2
4
10
istry prepared directly from 2-methyl-2-propenyl diazoacetate cata-
lyzed by Rh (4S-MPPIM)
,7-[2-(2-Methyl-2-propen-1-yloxymethyl)benzo]-3-oxatricyclo-
2
2
2
4
.
give (1S,5R)-5-methyl-3-oxabicyclo[3.1.0]hexan-2-one whose absolute
configuration was determined by comparison of its elution order on a
6
4,3,01 .0 ]-(Z)-8-decene-2-one (23): 1H NMR (500 MHz, CDCl
,5
5,10
[
3
)
3
0 m Chiraldex G-TA column [120 °C, 12.2 min for (1R,5S), 12.5
10
δ 7.27-7.20 (comp, 2H), 7.12 (dd, J ) 6.9, 2.0 Hz, 1H), 6.48 (d, J )
min for (1S,5R)] versus a sample of known absolute stereochemistry
9
4
.6 Hz, 1H), 6.26 (dd, J ) 9.6, 4.5 Hz, 1H), 5.23 (d, J ) 9.6 Hz, 1H),
.97 (s, 1H), 4.93 (s, 1H), 4.67 (d, J ) 11.9 Hz, 1H), 4.59 (d, J ) 11.9
prepared directly from 2-methyl-2-propenyl diazoacetate catalyzed by
Rh (4S-MPPIM)4.
General Procedure for Diazo Decomposition of 19. The procedure
for diazo decomposition with Rh (4S-MEOX) is representative.
Diazoacetate 19 (215 mg, 0.43 mmol) was dissolved in 5 mL of freshly
distilled CH Cl and added via syringe pump over 5 h to a solution of
Rh (4S-MEOX) (3.4 mg, 1.0 mol %) in 5 mL of refluxing CH Cl
2
Hz, 1H), 4.22 (d, J ) 9.6 Hz, 1H), 3.93 (s, 2H), 2.27 (dd, J ) 4.5, 3.4
Hz, 1H), 1.76 (s, 3H), 1.18 (d, J ) 3.4 Hz, 1H); 13C NMR (125 MHz,
2
4
CDCl
3
δ 177.2, 141.3, 136.7, 131.8, 129.4, 128.7, 127.5, 125.1, 123.2,
13.1, 112.5, 74.3, 73.4, 71.5, 32.8, 32.6, 19.6, 19.2. Enantiomeric
separation was achieved on a 30 m Chiraldex B-DM column operated
at 160 °C for 60 min and then heated at 0.2 °C/min to 220 °C: 201.9
min for the (1R*,5S*)-enantiomer, 203.0 min for the (1S*,5R*)-
enantiomer.
1
2
2
2
4
2
2
.
After the addition was complete, the solution was passed through a
plug of silica gel to remove the catalyst, and the silica was washed
with 50 mL of 30% ethyl acetate in hexanes. The solvent was removed
under reduced pressure. GC and NMR analysis revealed the presence
of two diastereomeric cyclopropanes, 20a and 20b, in a 75:25 ratio.
Purification by column chromatography (8:2 hexanes/ethyl acetate) gave
Acknowledgment. We are grateful to the National Science
Foundation, to the National Institutes of Health (Grant GM