[2+2] Photoadditions with chiral 2,5-cyclohexadienone synthons

Article abstract of DOI:10.1016/S0957-4166(02)00339-7

Three chiral 2,5-cyclohexadienone synthons bearing different chiral auxiliaries were examined in [2+2] photoadditions with cyclopentene. Regeneration of the 'masked' double bond in the adducts resulted in the preparation of optically active 5-4-6 adducts. The enantiomeric purity of each adduct was found to be >95% using comparative ¹³C NMR analysis of the appropriate ketals. The asymmetry induced in the cycloaddition step of our methodology indicated that the facial selectivity was directly correlated to the degree of steric bulk of the chiral auxiliary on the synthon.

Full text of DOI:10.1016/S0957-4166(02)00339-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1355–1362
[
2+2] Photoadditions with chiral 2,5-cyclohexadienone synthons
Gordon L. Lange,* Craig C. Humber and Jeffrey M. Manthorpe
Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry and Biochemistry, University of Guelph,
Guelph, Ontario, Canada N1G 2W1
Received 5 March 2001; revised 17 June 2002; accepted 17 June 2002
Abstract—Three chiral 2,5-cyclohexadienone synthons bearing different chiral auxiliaries were examined in [2+2] photoadditions
with cyclopentene. Regeneration of the ‘masked’ double bond in the adducts resulted in the preparation of optically active 5-4-6
13
adducts. The enantiomeric purity of each adduct was found to be >95% using comparative C NMR analysis of the appropriate
ketals. The asymmetry induced in the cycloaddition step of our methodology indicated that the facial selectivity was directly
correlated to the degree of steric bulk of the chiral auxiliary on the synthon. © 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
series of (−)-quinic acid-derived 2-cyclohexenones con-
taining ketal moieties. Previously we have reported the
transformation of photoadduct derivatives into racemic
Chiral 2,5-cyclohexadienone synthons have received
1,2
5–7
only limited attention in natural product synthesis. In
this methodology, a diastereomerically pure substrate 1
undergoes 1,4-addition or cycloaddition with diastereo-
facial selectivity to give primarily 2. Removal of the
chiral auxiliary in 2 gives enantiomerically enriched 3
terpenoid natural products. Use of the ketal auxiliary
to induce high diastereofacial selectivity in the photoad-
dition step followed by facile removal of the auxiliary
would provide an effective method for the preparation
2
,6
of optically active 5-4-6 adducts (bicyclo[5.4.0.0 ]-
undecanes) and then natural products.
(
Scheme 1). In previous examples, optically active 5-
trimethylsilyl-2-cyclohexenone was shown to undergo
cuprate addition with high diastereoselectivity.
Removal of the TMS group followed by a further
sequence of reactions ultimately yielded (+)-a-curcum-
2. Results and discussion
1
ene. Similarly, cuprate addition to homochiral 5-t-
2.1. Preparation of chiral 2,5-cyclohexadienone
synthons 7
butyldimethylsilyloxy-2-cyclohexenone followed by
elimination of the TBDMSO group gave 5-alkylated-2-
2
cyclohexenones with high enantiomeric excesses. Tri-
The desired synthons 7 were prepared from relatively
inexpensive, commercially available (−)-quinic acid 4
(Scheme 2). The use of quinic acid as an effective
‘chiron store’ for natural product synthesis has been
reviewed. Three different ketals, 7a–c, were prepared
so that the facial selectivities of the photoaddition step
cyclic
Diels–Alder
adducts
containing
a
2
-cyclohexenone moiety have been shown to be effec-
3
,4
tive chiral 2,5-cyclohexadienone synthons. To date
there have been no reports of [2+2] photoadditions with
this type of chiral synthon. Herein we wish to report
our studies on the photoaddition of cyclopentene with a
8
could be compared. The synthesis of ketal 7c has not
Scheme 1.
*
0
Corresponding author. Tel.: (519)-824-4120, ext. 3850; fax: (519)-766-1499; e-mail: lange@chembio.uoguelph.ca
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00339-7

1
356
G. L. Lange et al. / Tetrahedron: Asymmetry 13 (2002) 1355–1362
Scheme 2. Reagents and conditions: : (a) cyclohexanone, p-TsOH, toluene, reflux, 5a (80%); (CH ) C(OCH ) , p-TsOH, rt, 5b
3
2
3 2
(
84%); (C H ) CO, p-TsOH, toluene, reflux, 5c (75%) (b) NaOCH , CH OH, rt, 5 h: 6a (96%), 6b (94%), 6c (72%). (c) PCC, 5%
2
5
2
3
3
pyr. in CH Cl , 3 A
,
mol. sieves, rt, 24 h: 7a (43%), 7b (55%), 7c (50%).
2
2
been reported previously but its synthesis was similar to would be expected to have H –H coupling constants of
6
7
9
10
those reported for 7a and 7b. In these preparations 4
was converted to the ketal lactone 5. For environmental
reasons we used toluene rather than benzene as solvent
in the preparation of 5a and 5c and in the preparation
of 5b 2,2-dimethoxypropane was used as reagent and
solvent. Lactones 5 were then converted to esters 6,
which upon oxidation/dehydration with PCC/pyridine
gave the three desired chiral synthons 7a–c. The yield in
this step was optimized by filtering the crude reaction
mixture through a pad of Celite© and washing the pad
with CH Cl to efficiently extract the product from the
10–11 Hz and both C and C would resonate at about
3 5
12
28 ppm.
The relative configurations of the adducts 8 and 9 were
determined by NOE experiments. The NOESY spec-
trum of 9b (Scheme 3), but not 8b, showed a positive
correlation between H and H , confirming that the
7
9
minor photoadduct 9b resulted from addition of
cyclopentene to the more hindered face of 7b. Similar
results were observed with the adducts from 7a and 7c.
Also diagnostic was H , which resonated at ꢀ3.4 ppm
2
2
7
chromium tars. An alternative two-step procedure has
also been reported for the conversion of 6a to 7a.
in adducts 8a–c because of deshielding by the ketal
oxygens, but was found at ꢀ3.0 ppm in adducts 9a–c
and 14. Thus, the major adducts 8a–c must possess the
cis–anti–cis configuration and result from attack of
cyclopentene on the less hindered face of 7a–c.
11
2
.2. Investigation of chiral synthons 7a–c in [2+2]
photoadditions
The cycloaddition of excess cyclopentene with each of
the three chiral synthons 7a–c bearing different ketal
auxiliaries was investigated. CH Cl was found to be
the most effective solvent for the irradiations and a
canary glass filter (hw >320 nm) was employed to mini-
mize decomposition of the products by a Norrish type
Table 1 indicates significant differences in the facial
selectivity of the three chiral synthons 7a–c. The methyl
groups of acetonide 7b appear to provide more steric
hindrance than the cyclohexane ring in 7a where the
carbons are ‘tied back’ in the cyclic structure. Ketal 7c
exhibits the highest degree of facial selectivity because
of the greater hindrance provided by the ethyl groups
as compared with the methyls in 7b. Thus, the new
chiral synthon 7c provides the highest degree of
stereoselectivity (6:1) in the photoaddition step.
2
2
1
process. As indicated in Table 1, the three irradiations
proceeded in high yield (>90%) to give mixtures of
diastereomers 8 and 9 (Scheme 3). H NMR analysis
1
was used to measure the ratio of diastereomers. The
two diastereomers from each irradiation process were
1
separated by flash chromatography and shown by H
2.3. Removal of the ketal auxiliary from the photo-
adducts 8a–c
1
3
and C NMR spectroscopy to both be cis–anti–cis
adducts. Our previous NMR study of less highly substi-
12
tuted 5-4-6 photoadducts was particularly helpful in
We now wished to remove the ketal chiral auxiliary
from the major photoadducts 8a–c and replace it with a
double bond. The ketal functions in 8a–c, particularly
8a, were surprisingly resistant to hydrolysis but treat-
ment with 10% aqueous H SO /MeOH (1:2) gave diol
confirming these structures. For example, the H –H7
6
coupling constants of 6–7 Hz for 8b and 9b and the
1
3
different C chemical shifts for C and C (ꢀ27 and
3
5
ꢀ
33 ppm, respectively) in both adducts are consistent
with the proposed anti configurations. syn-Adducts
2
4
10. Similarly minor adduct 9 could be hydrolyzed to
diol 11, which was not investigated further (Scheme 3).
For the deoxygenation of 10, neither the Corey–Winter
13
Table 1. [2+2] Photoadditions of 7a–c with cyclopentene
method (via a thiocarbonate) nor the Garegg proce-
a
(
10 equiv.)
14
dure (¥ P, I , imidazole) was effective. However, the
3
2
15,16
two-step Eastwood procedure
proved to be an
Entry
Synthon
Yield (%)
Stereoselectivity (8:9)
efficient means for converting the diol 10 to the alkene
3. Thus, reaction of diol 10 with triethyl orthoformate
yielded a stereoisomeric mixture of cyclic orthoformates
1
1
2
3
7a
7b
7c
90
96
93
2:1
3:1
6:1
12 in high yield. Pyrolysis of 12 in a sealed tube at
200°C gave the optically active enone 13 in an overall
a
Irradiation time 6 h with a 450 W Hanovia lamp, canary glass filter,
yield from 10 of 85%. Preparation of enone 13 from
enone 4 completed the desired chiral 2,5-cyclohexa-
CH Cl2 solvent.
2

G. L. Lange et al. / Tetrahedron: Asymmetry 13 (2002) 1355–1362
1357
Scheme 3. Reagents and conditions: : (a) hw, cyclopentene, CH Cl , see Table 1. (b) 10% aq. H SO /MeOH (1:2), yield of 10 from:
2
2
2
4
8
a (74%), 8b (70%), 8c (82%). (c) HC(OEt) , HCl (94%). (d) 200°C, cat. HOAc, toluene (85%). (e) H , 10% Pd/C, EtOAc (68%).
3
2
(
f) (R,R)-2,3-butanediol, p-TsOH, toluene, D (88%).
dienone methodology but we also wished to confirm the
diastereomeric purity of 13.
adducts such as 14 which can then be converted into
optically active natural products using transformations
5–7
reported previously.
2
.3.1. Determination of enantiomeric purity of 13.
Hydrogenation of enone 13 using Pd on carbon gave
the saturated optically active adduct 14. As mentioned
earlier, the racemic form of adducts such as 14 has been
4. Experimental
5
–7
converted into terpenoid natural products. The opti-
4
.1. General
cally active adduct 14 was permitted to react with
1
7
(
R,R)-2,3-butanediol to give ketal 15. The racemic
1
13
The 400-MHz H NMR and 100-MHz C NMR spec-
tra were recorded on a Bruker Aspect 400 NMR spec-
trometer with tetramethylsilane as an internal standard.
The multiplicities of the C spectra were determined by
either DEPT or J-MOD experiments. The 200-MHz H
NMR and 50-MHz C NMR spectra were recorded on
a Varian Gemini NMR spectrometer. The solvent used
in all NMR experiments was CDCl . Infrared (IR)
18
form of 14 was prepared as previously described and
was reacted with the same butanediol to give a 1:1
mixture of diastereomeric ketals. Comparison of the
13
1
3
C NMR spectra of the diastereomeric mixture with
1
the sample of 14 derived from this study, established
that the latter enone had enantiomeric purity of >95%
13
(
NMR error limits ꢀ5%).
3
spectra were obtained on a Bomem MB-100 FTIR
spectrometer using NaCl liquid cells and the indicated
solvent. Mass spectral analyses were performed either
on a Kratos MS 890 or an Autospec Ultima mass
spectrometer using electron ionization (EI). All UV–vis
spectra were obtained on a Shimadzu UV 160U UV–vis
recording spectrophotometer. Optical rotation measure-
ments were recorded on a Rudolph Research Autopol
III Automatic Polarimeter, and the values are reported
3
. Conclusions
We have developed methodology for employing chiral
,5-cyclohexadienone synthons 7 in [2+2] photoaddi-
tions. The new synthon 7c has been prepared and
shows markedly enhanced diastereofacial selectivity in
the photoaddition with cyclopentene. This methodolo-
gy allows the synthesis of enantiomerically pure photo-
2
25
as [h] , (c concentration in g/100 ml of solvent). The
D

1
358
G. L. Lange et al. / Tetrahedron: Asymmetry 13 (2002) 1355–1362
melting points were determined on a Mel-Temp
apparatus and were uncorrected.
CDCl ): l 4.71 (dd, J=6.4, 2.8 Hz, 1H, H-4), 4.42 (dt,
J=3.2 Hz, 1H, H-5), 4.24 (m, 1H, H-3), 3.20 (bs, 1H,
3
-
OH
2.10 (dd, J=14.4, 3.2 Hz, 1H, H-5a), 1.69 (q, J=7.6
Hz, 2H, -CH -CH ), 1.53 (q, J=7.6 Hz, 2H, -CH6 -
2
6 ), 2.55 (d, J=12 Hz, 1H, H-5b), 2.32 (m, 2H, H-2),
All moisture- and oxygen-sensitive experiments were
run under a positive pressure of argon in flasks which
were flame- or oven-dried. All air- and moisture-sensi-
tive reagents were transferred via syringe and intro-
duced into the reaction flasks through rubber septa.
6
2
3
CH ), 0.91 (t, J=7.2 Hz, 3H, -CH -CH6 ), 0.81 (t,
3
3
2
1
3
J=7.6 Hz, 3H, -CH -CH
6
3); C NMR (100 MHz,
2
CDCl ): l 178.9 (-C
71.8 (C-4), 71.5 (C-1), 71.1 (C-3), 38.8 (C-6), 34.6 (C-2),
28.7 (-CH -CH ), 27.6 (-CH -CH ), 8.5 (-CH -CH ), 8.0
6
O -), 113.9 (O CMe ), 75.9 (C-5),
6
3
2
2
2
Toluene, THF and CH Cl were dried over 4 A
,
molec-
2
2
ular sieves (activated). All other solvents were used
without purification. All crude reaction mixtures were
dried with anhydrous MgSO4.
6
6
6
2
3
2
3
2
3
+
(-CH -C6 H ); EIMS m/z (rel. int.): 243 ([M+H] , 34),
2
3
213 (100), 111 (33), 95 (33), 87 (59), 83 (46), 57 (97);
HRMS calcd for C H O 243.123, found 243.122.
12
19
5
4
4
.2. Preparation of lactones 5 from (−)-quinic acid
4
.3. General procedure for the preparation of diol
.2.1. 3,4-O-Cyclohexylidenequinic acid-1,5-lactone, 5a.
esters, 6a–c
A solution of (−)-quinic acid 4 (4.97 g, 25.9 mmol),
p-toluenesulfonic acid monohydrate (0.061 g, 0.32
mmol) and cyclohexanone (13.5 mL, 130 mmol) in
toluene (38 mL) was heated under reflux for 5 h using
a Dean–Stark apparatus. The reaction mixture was
cooled to rt and quenched with cold saturated aqueous
A general procedure was used for the preparation of all
diol esters: a solution of sodium methoxide and lac-
tones 5a–c was stirred in dry MeOH at rt until comple-
tion as indicated by TLC. The reaction mixture was
neutralized by the dropwise addition of 1 equiv. of
glacial acetic acid at 0°C, followed by the addition of
NaHCO (25 mL). The aqueous layer was extracted
3
with CH Cl (3×), the organic layers were combined
saturated aqueous NH Cl. The aqueous layer was
2
2
4
and washed with brine, dried with MgSO and concen-
extracted with CH Cl (3×), the organic layers were
4
2
2
trated in vacuo. The residue was washed with 5%
ether/hexanes (100 mL). The white crystals were dried
in a vacuum oven for 24 h, yielding 3,4-O-cyclohexyli-
denequinic acid-1,5-lactone 5a (5.28 g, 80%). TLC (50%
then combined, washed with brine (1×) and dried with
MgSO . Evaporation of the solvent in vacuo followed
4
by FC (60–100% EtOAc/hexanes) yielded the desired
dihydroxy methyl esters 6.
EtOAc/hexanes) R =0.24. All spectral data for this
f
9
compound are similar to those previously reported.
4.3.1. Methyl 3,4-O-cyclohexylidenequinate, 6a. Sodium
methoxide (0.505 g, 9.52 mmol) was added to solution
of lactone 5a (1.99 g, 7.82 mmol) in dry MeOH (40 mL)
and the reaction was stirred for 5 h at rt. After workup
as described in the general procedure, FC (60–100%
EtOAc/hexanes) of the crude product yielded the dihy-
droxy methyl ester 6a as a brownish oil (2.16 g, 96%).
4.2.2. 3,4-O-Isopropylidenequinic acid-1,5-lactone, 5b. A
solution of (−)-quinic acid 4 (1.99 g, 10.4 mmol), p-
toluenesulfonic acid monohydrate (0.206 g, 1.08 mmol)
in 2,2-dimethoxypropane (15.0 mL) was stirred for 24 h
at rt. The reaction mixture was quenched with cold
saturated aqueous NaHCO (5 mL). The aqueous layer
TLC (60% EtOAc/hexanes) R =0.18. Complete spec-
3
f
was extracted with EtOAc (3×), the organic layers were
combined and washed with brine, dried with MgSO4
and concentrated in vacuo. The residue was washed
with 5% ether/hexanes (100 mL). The white crystals
were dried in a vacuum oven for 24 h yielding 3,4-O-
isopropylidenequinic acid-1,5-lactone 5b (1.85 g, 84%).
tral data for this compound have been previously
reported.
9
4.3.2. Methyl 3,4-O-isopropylidenequinate, 6b. Sodium
methoxide (1.22 g, 23.0 mmol) was added to a solution
of lactone 5b (4.11 g, 19.2 mmol) in dry MeOH (100
mL). The solution was reacted and worked up as
described above. FC (60–100% EtOAc/hexanes) of the
crude product yielded the dihydroxy ester 6b as a
tan-brown oil (4.44 g, 94%). TLC (50% EtOAc/hex-
TLC (5% EtOAc/hexanes) R =0.59. Complete spectral
f
10
data for this compound has been reported previously.
4.2.3. 3,4-O-isopentylidenequinic acid-1,5-lactone, 5c. A
solution of (−)-quinic acid 4 (4.97 g, 26.1 mmol), p-
toluenesulfonic acid monohydrate (0.500 g, 2.63 mmol)
and 3-pentanone (13.2 mL, 124 mmol) in toluene (30
mL) was heated under reflux for 5 h using a Dean–
Stark apparatus. The reaction mixture was cooled to rt
and quenched with cold saturated aqueous NaHCO3
anes) R =0.14. Complete spectral data for this com-
f
10
pound have previously been reported.
4.3.3. Methyl 3,4-O-isopentylidenequinate, 6c. Sodium
methoxide (0.350 g, 6.60 mmol) was added to solution
of lactone 5c (1.29 g, 5.31 mmol) in dry MeOH (30 mL)
and the reaction was stirred for 6 h at rt. After workup
as described in the general procedure, FC (50–100%
EtOAc/hexanes) yielded the dihydroxy methyl ester 6c
as a brownish oil (0.990 g, 68%). TLC (50% EtOAc/
(
(
25 mL). The aqueous layer was extracted with CH Cl2
3×), the organic layers were combined and washed
2
with brine, dried with MgSO4 and concentrated in
vacuo. The residue was washed with 5% ether/hexanes
2
5
−5
(
100 mL) and the white crystals were dried in a vacuum
oven for 24 h yielding 3,4-O-isopentylidenequinic acid-
,5-lactone 5c (4.30 g, 68%). TLC (50% EtOAc/hex-
hexanes) R =0.19; [h] =−42.2 (c 9.36×10 , CH Cl );
f
D
2
2
−
1
1
IR (CHCl ): 3450, 1730 cm ; H NMR (400 MHz,
3
1
CDCl ): l 4.40 (m, 1H, H-4), 4.08 (m, 1H, H-5), 3.94
3
25
−4
anes) R =0.46; [h] =−19.7 (c 1.69×10 , CH Cl ); IR
(m, 1H, H-3), 3.74 (s, 3H, -CO CH
-OH6 ), 2.14 (m, 2H, H-2), 1.98 (m, 1H, H-5b), 1.79 (m,
6
3), 3.30 (bs, 2H,
f
D
2
2
2
−
1
1
(CHCl ): 3430, 1785 cm ; H NMR (400 MHz,
3

G. L. Lange et al. / Tetrahedron: Asymmetry 13 (2002) 1355–1362
1359
1
H, H-5a), 1.69 (q, J=7.6 Hz, 2H, -CH
6
-CH ), 1.57 (q,
(-OCH C
6
H ), 7.80 (-OCH C
6
H ); EIMS m/z (rel. int.):
2
3
2
3
2
3
+
J=7.2 Hz, 2H, -CH
6
-CH ), 0.90 (t, J=7.6 Hz, 3H,
255 ([M+H] , 35), 225 (48), 57 (100); HRMS calcd for
2
3
1
3
-
CH -CH
6
), 0.83 (t, J=7.6 Hz, 3H, -CH -CH
6
3);
C
C H O 255.123, found 255.122.
2
3
2
13 19
5
NMR (100 MHz, CDCl ): l 175.6 (-C
6 O Me), 113.2
3
2
(
5
O C
3.1 (-OC
6
Me ), 79.6 (C-5), 73.6 (C-1), 72.9 (C-4), 68.3 (C-3),
2
2
6
H ), 38.9 (C-6), 34.9 (C-2), 29.7 (-C
6
H -CH ),
3
2
3
4
.5. General irradiation procedure for preparation of
2
8.3 (-C
6
H -CH ), 8.6 (-CH -C
6
H ), 8.1 (-CH -C
3
6
H3);
2
3
2
2
photoadducts
+
EIMS m/z (rel. int.): 275 ([M+H] , 22), 245 (50), 171
(
41), 57 (100); HRMS calcd for C H O 275.149,
13 23 6
The appropriate amounts of the enone and cycloalkene
were dissolved in the indicated solvent and placed in
Pyrex irradiation tubes (15×1.2 cm o.d.) within a
canary glass (Corning no. 3320) sleeve. The solutions
were deoxygenated with argon (1 min) and the tubes
were sealed with rubber septa. The irradiations were
performed using a Hanovia 450 W light source. The
light source was placed in a water-cooled immersion
well. The irradiation tubes were attached to the outside
of this well and cooled in ice. The disappearance of
enone 7 was monitored by TLC (60% EtOAc/hexanes).
found 275.151.
4
4
.4. Preparation of the enone esters, 7
.4.1. Methyl 4,5-O-cyclohexylidene-3-dehydro-4-epi-
shikimate 7a. Pyridinium chlorochromate (1.35 g, 6.28
mmol) was added to a mixture of dihydroxy ester 6a
(
0.402 g, 1.40 mmol) and 3 A
,
powdered molecular
sieves (0.9 g) in 5% pyridine/CH Cl (6.0 mL) and
2
2
stirred for 24 h at rt. The reaction mixture was diluted
with EtOAc (5 mL) and Celite© (1 g) and stirred for 10
min, then filtered through a pad of Celite© and washed
with EtOAc (50 mL). The combined filtrate was washed
with a saturated CuSO4 solution and dried with
4.5.1. Methyl (1R,2R,6S,7R,9R,10R)-9,10-O-cyclo-
2,6
MgSO . The solution was concentrated in vacuo and
hexylidene-8-oxotricyclo[5.4.0.0 ]undecane-1-carboxyl-
4
purified using FC (17–25% EtOAc/hexanes) to yield
enone 7a as white crystals (0.160 g, 43%). TLC (60%
EtOAc/hexanes) R =0.48. Complete spectral data for
ate, 8a and methyl (1S,2S,6R,7S,9R,10R)-9,10-O-cyclo-
2,6
hexylidene-8-oxotricyclo[5.4.0.0 ]undecane-1-carboxyl-
ate, 9a. A solution of methyl 4,5-O-cyclohexylidene-3-
dehydro-4-epi-shikimate 7a (0.104 g, 0.391 mmol) and
cyclopentene (0.34 mL, 3.8 mmol) in CH Cl (7.0 mL)
f
9
this compound have been previously reported.
2
2
4
.4.2. Methyl 4,5-O-isopropylidene-3-dehydro-4-epi-
was irradiated following the general procedure. Upon
completion of the irradiation (6 h), the solvent was
removed in vacuo. The crude product was purified
using FC (5–15% EtOAc/hexanes) to give a mixture of
photoadducts 8a and 9a (0.119 g, 90%) in a 2:1 ratio as
shikimate, 7b. Pyridinium chlorochromate (1.13 g, 5.24
mmol), dihydroxy ester 6b (0.311 g, 1.26 mmol) and 3
A
,
powdered molecular sieves (activated) (0.8 g) in 5%
pyridine/CH Cl (6.0 mL) was reacted and worked up
2
2
1
as described for 7a. The solution of the crude reaction
mixture was concentrated in vacuo and purified using
FC (17–25% EtOAc/hexanes) to yield enone 7b as white
crystals (0.148 g, 55%). TLC (50% EtOAc/hexanes)
R =0.41. Complete spectral data for this compound
has previously been reported.
indicated by H NMR.
Compound 8a: TLC (60% EtOAc/hexanes) R =0.66;
f
white crystals, mp=110–112°C; IR (CHCl ): 2943,
3
−
1 1
1724, 1712 cm ; H NMR (400 MHz, CDCl ): l 4.64
f
3
10
(m, 1H, H-10), 4.10 (d, J=8.0 Hz, 1H, H-9), 3.66 (s,
3
H, -OCH3
6 ), 3.41 (d, J=6.0 Hz, 1H, H-7), 3.01 (q,
4
.4.3. Methyl 4,5-O-isopentylidene-3-dehydro-4-epi-
J=6.4 Hz, 1H, H-6), 2.67 (m, 1H, H-11b), 2.43 (m, 1H,
13
shikimate, 7c. Pyridinium chlorochromate (3.11 g, 14.4
H-2), 1.68–1.18 (m, 17H); C NMR (100 MHz,
CDCl3): 210.4 (C-8), 173.3 (-CO Me), 112.3
(O CMe ), 76.6 (C-10), 76.2 (C-9), 51.5 (-OC
mmol), dihydroxy ester 6c (0.990 g, 3.61 mmol) and 3 A
powdered molecular sieves (1.5 g) in 5% pyridine/
CH Cl (20 mL) was reacted and worked up as
,
l
6
2
6
6 H ), 48.8
3
2
2
(C-1), 47.3 (C-2), 45.2 (C-7), 39.5 (C-6), 33.7, 33.3, 32.1,
2
2
described above except the pad of Celite© was washed
32.1, 29.2, 25.8, 25.1, 23.8, 23.5; EIMS m/z (rel. int.):
334 (M , 15), 291 (20), 67 (18), 55 (100), 42 (15), 41
+
with CH Cl . The combined filtrate was washed with
2
2
saturated CuSO and dried with MgSO . The solution
(29); HRMS calcd for C H O 334.178, found
334.178.
4
4
19 26
5
was concentrated in vacuo and purified using FC (20–
5% EtOAc/hexanes) to yield enone 7c as yellow crys-
tals (0.440 g, 50%). TLC (50% EtOAc/hexanes)
3
Compound 9a: TLC (60% EtOAc/hexanes) R =0.64;
f
2
5
R =0.48; mp=84–86°C; [h] =−28 (c 0.018, CH Cl );
white crystals, mp=112–114°C; IR (CHCl ): 2944,
f
D
2
2
3
−
1
1
−1 1
IR (CHCl ): 1726, 1686 cm ; H NMR (400 MHz,
1728, 1710 cm ; H NMR (400 MHz, CDCl ): l 4.50
3
3
CDCl ): l 6.76 (s, 1H, H-2), 4.67 (t, J=4.8 Hz, 1H,
H-6), 4.24 (d, J=5.2 Hz, 1H, H-5), 3.79 (s, 3H, -
(d, J=8.8 Hz, 1H, H-9), 4.41 (m, 1H, H-10), 3.77 (s,
3
3H, -OCH6 3), 3.05 (q, J=6.4 Hz, 1H, H-6), 2.97 (d,
OCH
6
3), 3.18 (d, J=20.4 Hz, 1H, H-4), 2.77 (m, 1H,
CH ), 1.45 (m, 2H,
J=5.6 Hz, 1H, H-7), 2.73 (dd, J=13.2, 4.4 Hz, 1H,
H-11b), 2.51 (t, J=7.4 Hz, 1H, H-2), 1.76–1.23 (m,
H-4), 1.60 (q, J=7.2 Hz, 2H, -OCH
6
2
3
13
-
-
(
(
(
OCH
OCH CH
C-1), 166.1 (-C
6
CH ), 0.86 (m, 3H, -OCH CH
6
3), 0.73 (m, 3H,
17H); C NMR (100 MHz, CDCl ): l 208.7 (C-8),
3
2
3
2
1
3
6
3); C NMR (100 MHz, CDCl ): l 197.1
174.0 (- C6 O Me), 111.0 (O C6 Me ), 77.6 (C-10), 75.0
2 2 2
2
3
6
O Me), 144.3 (C-3), 131.3 (C-2), 113.3
2
(C-9), 52.2 (-OC6 H ), 49.1 (C-1), 47.3 (C-2), 46.7 (C-7),
3
O C
6
Et ), 74.7 (C-6), 72.2 (C-5), 52.7 (-OC
6
H ), 29.6
3
38.1 (C-11), 37.1 (C-6), 36.3, 34.0, 32.2 (C-5), 29.0
2
2
-OC
6
H CH ), 29.0 (-OC
6
H CH ), 26.5 (C-4), 8.36
(C-3), 25.6 (C-4), 25.0, 23.9, 23.6; EIMS m/z (rel. int.):
2
3
2
3

1
360
G. L. Lange et al. / Tetrahedron: Asymmetry 13 (2002) 1355–1362
+
3
34 (M , 15), 291 (56), 69 (31), 55 (100), 41 (58);
Compound 8c: TLC (30% EtOAc/hexanes) R =0.54;
25
f
HRMS calcd for C H O 334.178, found 334.178.
white crystals, mp=110–112°C; [h] =− 67 (c 0.023,
19
26
5
D
−
1 1
CH Cl ); IR (CHCl ): 1731, 1718 cm ; H NMR (400
2
2
3
4
.5.2. Methyl (1R,2R,6S,7R,9R,10R)-9,10-O-isopropyli-
MHz, CDCl
3
): l 4.68 (m, 1H, H-10), 4.14 (d, J=8.0
2,6
dene-8-oxotricyclo[5.4.0.0 ]undecane-1-carboxylate, 8b
Hz, 1H, H-9), 3.69 (s, 3H, -OCH6 ), 3.39 (d, J=6.0 Hz,
3
and methyl (1S,2S,6R,7S,9R,10R)-9,10-O-isopropyli-
1H, H-7), 3.01 (m, 1H, H-6), 2.65 (m, 1H, H-11b), 2.49
(m, 1H, H-2), 1.78–1.64 (m, 8H), 1.52–1.40 (m, 3H),
2,6
dene-8-oxotricyclo[5.4.0.0 ]undecane-1-carboxylate, 9b.
A solution of methyl 4,5-O-isopropylidene-3-dehydro-
0.85 (t, J=7.6 Hz, 3H, -OCH
CH
); C NMR (100 MHz, CDCl
10.0 (C-8), 173.2 (-CO Me), 115.9 (O CEt ), 75.4 (C-
6
), 0.80 (t, J=7.6 Hz,
2
3
13
4
-epi-shikimate 7b (0.104 g, 0.459 mmol) and cyclopen-
tene (0.40 mL, 4.5 mmol) in CH Cl (7.0 mL) was
irradiated following the general procedure. Upon com-
pletion of the irradiation (5 h) the solvent was removed
in vacuo. The crude product was purified using FC
5–15% EtOAc/hexanes) to give a mixture of photoad-
ducts 8b and 9b (0.130 g, 96%) in a 3:1 ratio as
indicated by H NMR.
3H, -OCH
2
CH
6
3
3
): l
2
1
4
6
6
2
2
2
2
2
0), 75.2 (C-9), 51.5 (-O C6 H ), 48.6 (C-1), 47.2 (C-2),
3
5.5 (C-7), 39.4 (C-6), 33.7 (C-11), 32.1 (C-5), 29.2
H CH ), 25.7 (C-4), 24.7 (-OCH CH ),
(
C-3), 26.2 (-OC
6
6
2
3
2
3
8
.50 (-OCH C6 H ), 8.50 (-OCH C6 H ); EIMS m/z (rel.
2 3 2 3
+
(
int.): 323 ([M+H] , 4), 293 (12), 91 (7), 67 (14), 57 (100);
1
HRMS calcd for C H O 323.186, found 323.185.
18 27 5
Compound 9c: TLC (30% EtOAc/hexanes) R =0.47; IR
Compound 8b: TLC (50% EtOAc/hexanes) R =0.61;
f
f
−
1
1
25
(CHCl ): 1735, 1711 cm ; H NMR (400 MHz,
white crystals, mp=106–108°C; [h] =−71.3 (c 0.0202,
3
D
−
1
1
CDCl ): l 4.48 (d, J=9.2 Hz, 1H, H-9), 4.42 (m, 1H,
CH Cl ); IR (CHCl ): 2950, 1733, 1716 cm ; H NMR
3
2
2
3
H-10), 3.78 (s, 3H, -OCH6 3), 3.05 (q, J=6.8 Hz, 1H,
(
400 MHz, CDCl ): l 4.65 (m, 1H, H-10), 4.12 (d,
3
H-6), 2.97 (d, J=5.6 Hz, 1H, H-7), 2.71 (dd, J=13.2,
J=8.0 Hz, 1H, H-9), 3.68 (s, 3H, -OCH6 3), 3.40 (d,
5
1
.2 Hz, 1H, H-11b), 2.50 (t, J=7.6 Hz, 1H, H-2),
J=6.0 Hz, 1H, H-7), 3.01 (m, 1H, H-6), 2.65 (m, 1H,
H-11b), 2.45 (m, 1H, H-2), 1.69–1.64 (m, 4H), 1.44 (m,
.75–1.70 (m, 4H), 1.58–1.49 (m, 7H), 0.91 (t, J=7.2
13
Hz, 3H, -OCH
2
CH
OCH CH6 3); C NMR (100 MHz, CDCl ): l 208.5
2
6
3
), 0.86 (t, J=7.2 Hz, 3H,
3
H), 1.38 (s, 3H, -OCCH
6
), 1.22 (s, 3H, -OCCH
6
);
3
C
3
13
-
(
3
NMR (100 MHz, CDCl ): l 210.1 (C-8), 173.3
3
C-8), 174.0 (-C6 O Me), 114.3 (O C6 Me ), 78.1 (C-9),
2 2 2
(-C6 O Me), 111.4 (O C6 Me ), 77.1 (C-10), 76.6 (C-9),
2 2 2
7
5.4 (C-10), 52.2 (-OC6 H ), 48.9 (C-1), 47.1 (C-7), 46.6
3
1.5 (-OC6 H ), 48.9 (C-1), 47.4 (C-2), 45.3 (C-7), 39.4
3
(
(
C-2), 37.9 (C-11), 37.1 (C-6), 32.2 (C-5), 29.1
-OCH CH ), 29.0 (C-3), 28.5 (-OCH CH ), 25.6 (C-4),
.50 (-OCH C6 H ), 7.30 (-OCH C6 H ); EIMS m/z (rel.
2 3 2 3
+
6
6
2
3
2
3
2
2
3.8 (-OC C6 H ), 23.0 (-OC C6 H ); EIMS m/z (rel. int.):
3 3
+ +
8
94 (M , 37), 279 (M−CH , 100), 177 (54), 149 (52), 91
3
int.): 323 ([M+H] , 1), 293 (11), 57 (100), 36 (13);
(
52), 67 (58); HRMS calcd for C H O 294.1467,
16 22 5
HRMS calcd for C H O 323.186, found 323.187.
18
27
5
found 294.1467.
4
.5.4. Methyl (1R,2R,6S,7R,9R,10R)-9,10-dihydroxy-8-
2,6
Compound 9b: TLC (50% EtOAc/hexanes) R =0.53; IR
f
oxotricyclo[5.4.0.0 ]undecane-1-carboxylate, 10 and
−
1 1
(
CHCl ): 2953, 1735, 1719 cm ; H NMR (400 MHz,
3
methyl (1S,2S,6R,7S,9R,10R)-9,10-dihydroxy-8-oxotri-
CDCl ): l 4.49 (d, J=8.8 Hz, 1H, H-9), 4.42 (m, 1H,
2,6
3
cyclo[5.4.0.0 ]undecane-1-carboxylate, 11. A solution
H-10), 3.78 (s, 3H, -OCH6 3), 3.06 (m, 1H, H-6), 2.99 (d,
of photoadduct 8b (containing trace amounts of 9b)
J=6.0 Hz, 1H, H-7), 2.72 (dd, J=13.2, 5.4 Hz, 1H,
H-11b), 2.51 (t, J=7.4 Hz, 1H, H-2), 1.77–1.67 (m,
(
0.152 g, 0.517 mmol) and methanol (3 mL) was stirred
at rt for 10 min, then 10% H SO (1.0 mL) was added
2
4
2
1
H), 1.59–1.53 (m, 4H), 1.51 (s, 3H, -OCCH6 ), 1.45 (m,
3
13
dropwise to the solution. The reaction was monitored
by TLC (60% EtOAc/hexanes) and was complete after
stirring for 2 h at rt. The reaction mixture was
quenched with saturated aqueous NaHCO (3 mL) and
extracted with CH Cl (3×). The organic layers were the
combined, washed with brine and dried with MgSO4.
The solvent was removed in vacuo and the crude
product was purified using FC (50–60% EtOAc/hex-
anes) to yield 10 as a yellow oil (0.091 g, 70%). A
collection of many fractions from different trials, all
containing trace amounts of 11 was accumulated and
re-purified.
H), 1.31 (s, 3H, -OCCH
6
3); C NMR (100 MHz,
O Me), 110.1
CDCl3):
l
208.6 (C-8), 174.0 (-C
6
2
(
(
3
O C6 Me ), 77.9 (C-9), 76.3 (C-10), 52.2 (-OC6 H ), 49.1
2 2 3
3
C-1), 47.3 (C-7), 46.7 (C-2), 37.9 (C-11), 37.1 (C-6),
2.2 (C-5), 29.0 (C-3), 26.7 (-OCCH ), 25.6 (C-4), 24.5
2
2
6
3
+
(
-OCC6 H ); EIMS m/z (rel. int.): 294 (M , 27), 279
3
+
(
M−CH , 100), 177 (28), 149 (46), 91 (57), 59 (87);
3
HRMS calcd for C H O 294.1467, found 294.1460.
1
6
22
5
4
.5.3. Methyl (1R,2R,6S,7R,9R,10R)-9,10-O-isopentyli-
2,6
dene-8-oxotricyclo[5.4.0.0 ]undecane-1-carboxylate, 8c
and methyl (1S,2S,6R,7S,9R,10R)-9,10-O-isopentyli-
2,6
dene-8-oxotricyclo[5.4.0.0 ]undecane-1-carboxylate, 9c.
A solution of methyl 4,5-O-isopentylidene-3-dehydro-4-
epi-shikimate, 7c (0.104 g, 0.391 mmol) and cyclopen-
Compound 10: TLC (60% EtOAc/hexanes) R =0.24; IR
f
−
1 1
(CHCl ): 3451, 1734, 1701 cm ; H NMR (400 MHz,
3
CDCl ): l 4.30 (m, 1H, H-10), 4.28 (m, 1H, H-9),
3
tene (0.34 mL, 3.8 mmol) in CH Cl2 (7.0 mL) was
4.00–3.80 (bs, 1H, -OH), 3.69 (s, 3H, -OCH6 3), 3.41 (d,
2
irradiated following the general procedure. Upon com-
pletion of the irradiation (6 h), the solvent was removed
in vacuo. The crude product was purified using FC
J=7.6 Hz, 1H, H-7), 3.09 (m, 1H, H-11b), 2.98 (q,
J=6.8 Hz, 1H, H-6), 2.63 (m, 1H, H-2), 2.50–2.25 (bs,
1H, -OH), 2.19 (d, J=14.8 Hz, 1H, H-11a), 1.88–1.72
13
(
5–15% EtOAc/hexanes) to give a mixture of photoad-
(m, 3H), 1.58–1.44 (m, 3H); C NMR (100 MHz,
ducts 8c and 9c (0.119 g, 90%) in a 6:1 ratio, respec-
tively, as indicated by H NMR.
CDCl ): l 210.0 (C-8), 173.6 (-C
(C-10), 52.0 (-O
6
O Me), 76.0 (C-9), 71.0
3
2
1
6
CH ), 49.4 (C-2), 47.4 (C-1), 46.9 (C-7),
3

G. L. Lange et al. / Tetrahedron: Asymmetry 13 (2002) 1355–1362
1361
4
0.9 (C-6), 37.2 (C-11), 31.8 (C-5), 28.1 (C-3), 25.8
146.7 (C-10), 129.1 (C-9), 51.9 (-OC
46.4 (C-7), 45.2 (C-1), 41.9 (C-6), 33.1 (C-11), 32.4
6
H ), 50.5 (C-2),
3
+
(
C-4); EIMS m/z (rel. int.): 254 (M , 65), 204 (49), 176
(
82), 165 (70), 91 (74), 67 (100); HRMS calcd for
(C-5), 29.4 (C-3), 25.4 (C-4); EIMS m/z (rel. int.): 220
(M , 10), 161 (31), 153 (100), 109 (47), 68 (68); HRMS
+
C H O 254.1154, found 254.1158.
13
18
5
calcd for C H O 220.1099, found 220.1101.
13
16
3
Compound 11: TLC (60% EtOAc/hexanes) R =0.30; IR
f
−
1 1
(
CHCl ): 3473, 1730, 1716 cm ; H NMR (400 MHz,
3
2,6
4
.5.7. Methyl (1R,2R,6S,7R)-8-oxotricyclo[5.4.0.0 ]-
undecane-1-carboxylate, 14. A solution of enone 13
0.019 g, 0.086 mmol) and 10% palladium on activated
CDCl ): l 4.21 (q, J=4.8 Hz, 1H, H-10), 4.07 (m, 1H,
3
H-9), 3.79 (bs, 1H, -OH), 3.70 (s, 3H, -OCH
J=6.5 Hz, 1H, H-7), 2.92 (q, J=6.4 Hz, 1H, H-6), 2.75
t, J=6.4 Hz, 1H, H-2), 2.67 (bs, 1H, -OH), 2.21 (dq,
J=15.2, 4.2 Hz, 2H, H-11), 1.71–1.65 (m, 2H), 1.59–
6 3), 3.12 (d,
(
carbon (0.020 g) in EtOAc (5 mL) was stirred at rt in
(
an H enriched atmosphere for 2 h. The reaction was
2
monitored by TLC (50% EtOAc/hexanes) until comple-
tion. The suspension was then filtered through a pad of
Celite© and washed with EtOAc (30 mL). The solvent
was removed in vacuo to yield adduct 14 (0.013 g, 68%)
1
3
1
.55 (m, 2H), 1.54–1.39 (m, 2H); C NMR (100 MHz,
CDCl ): l 212.4 (C-8), 175.0 (-C
6
O Me), 75.7 (C-9), 70.8
3
2
(
C-10), 52.0 (-OC
0.5 (C-6), 37.8 (C-11), 32.3 (C-5), 29.5 (C-3), 25.4
6
H ), 48.3 (C-2), 47.1 (C-1), 47.1 (C-7),
3
4
as a colorless oil. TLC (50% EtOAc/hexanes) R =0.57;
f
(
C-4).
2
5
−1
[
h] =−76 (c 0.17, CHCl ); IR (CCl ): 1730, 1705 cm ;
D 3 4
1
H NMR (400 MHz, CDCl ): l 3.73 (s, 3H, -OC H6 3),
3
4
.5.5. Methyl (1R,2R,6S,7R,9R,10R)-9,10-O-ethoxy-
2.94 (d, J=6.4 Hz, 1H, H-7), 2.68 (q, J=6.8 Hz, 1H,
H-6), 2.56 (t, J=7.6 Hz, H-2), 2.38 (t, J=6.2 Hz, 1H,
H-9), 2.22 (dt, J=18.4, 6.8 Hz, 1H, H-9), 2.02–1.42 (m,
2,6
methylene-8-oxotricyclo[5.4.0.0 ]undecane-1-carboxyl-
ate, 12. A solution of diol 10 (0.063 g, 0.25 mmol),
freshly distilled triethyl orthoformate (1.5 mL) and
13
10H); C NMR (100 MHz, CDCl ): l 212.4 (C-8),
3
1
6
saturated methanolic HCl (10 mL) was stirred at rt for
2
174.6 (- C6 O Me), 51.7 (-O C6 H ), 49.1 (C-7), 48.8 (C-1),
2 3
h. The reaction was monitored by TLC (60% EtOAc/
46.8 (C-2), 39.9 (C-6), 38.2 (C-9), 32.5 (C-5), 32.5 (C-3),
29.1 (C-4), 25.3 (C-11), 19.6 (C-10). All spectral data
were similar to those of the corresponding racemic
hexanes) until no starting material was evident. The
reaction mixture was quenched with saturated aqueous
Na CO (1 mL) and was extracted with CH Cl (3×).
1
8
mixture, which has been reported previously.
2
3
2
2
The organic layers were combined, washed with brine
4
4
.6. Preparation of chiral ketals 15 and 16 for
determination of enantiomeric purity of 14
diastereomeric ortho esters 12 (0.073 g, 94%). All
attempts to separate the isomeric mixture of orthofor-
mates 12 were unsuccessful, therefore, only minimal
4.6.1. Ketal 15 from methyl (1R,2R,6S,7R)-8-oxotri-
2,6
cyclo[5.4.0.0 ]undecane-1-carboxylate 14 and (R,R)-
butane-2,3-diol. A solution of optically active adduct 14
(0.038 g, 0.17 mmol), p-toluenesulfonic acid mono-
hydrate (0.004 g, 0.02 mmol) and (R,R)-2,3-butanediol
(0.041 g, 0.46 mmol) in toluene (7.0 mL) was heated
under reflux for 6 h using a Dean–Stark apparatus. The
reaction was monitored using TLC (60% EtOAc/hex-
anes) until completion. The reaction mixture was
cooled to rt, quenched with saturated aqueous Na CO
spectral data were obtained for this mixture. TLC (60%
1
EtOAc/hexanes) R =0.69;
H
NMR (200 MHz,
f
CDCl ): l 5.71 (s, 1H, -O CH
6
OC H ), 4.89 (m, 1H,
3
2
2
5
H-10), 4.30 (d, J=7.4 Hz, 1H, H-9), 3.74 (s, 3H,
OCH ), 3.52 (q, J=7.0 Hz, 2H, -OCH CH ), 3.43 (d,
-
6
6
3
2
3
J=5.2 Hz, 1H, H-7), 3.09 (m, 1H), 2.64 (m, 1H), 2.49
(
m, 1H), 1.74–1.48 (m, 7H), 1.18 (m, 3H, -OCH CH6 3).
2
2
3
(
3 mL) and washed with H O (2×). The aqueous layer
2
,6
2
4
.5.6. Methyl (1R,2R,6S,7R)-8-oxotricyclo[5.4.0.0 ]-
was extracted (3×) with CH Cl , the organic layers were
2
2
undec-9-ene-1-carboxylate, 13. A solution of ortho ester
2 (0.086 g, 0.28 mmol) and toluene (2.0 mL) was
combined, dried with MgSO4 and concentrated in
vacuo. The residue was purified using FC (10–20%
EtOAc/hexanes) yielding ketal 15 exclusively (0.044 g,
1
transferred to a sealable tube and glacial acetic acid (20
mL) was added dropwise. The mixture was deoxy-
genated with argon for 1 min, the tube was sealed, and
the mixture was heated at 200°C for 24 h. The reaction
was monitored by TLC (60% EtOAc/hexanes) until
completion. The solvent was removed in vacuo to yield
an oily yellow crude product that was purified using FC
8
8%) as a brownish oil. TLC (50% EtOAc/hexanes)
13
R =0.66; C NMR (100 MHz, CDCl ): l 175.4
f
3
(-C6 O Me), 108.2 (C-8), 78.3, 77.5 (O-C6 H(CH )-
2
3
C
6
H(CH )-O), 51.5 (-OC
C-2), 37.6 (C-6), 33.6 (C-9), 32.0 (C-3), 31.5 (C-5), 28.6
6
H ), 47.6 (C-7), 47.5 (C-1), 43.8
3
3
(
(
(
C-4), 26.1 (C-11), 19.5 (C-10), 17.4 (-CCH ), 16.8
6
3
(
8
5–15% EtOAc/hexanes) to give enone 13 (0.052 g,
+
-CC6 H ); EIMS m/z (rel. int.): 294 (M , 17), 235 (6),
3
25
5%). TLC (60% EtOAc/hexanes) R =0.53; [h] =−8.5
f D
−1
1
77 (10), 141 (23), 127 (100); HRMS calcd for
(
c 0.55, CH Cl ); IR (CHCl ): 1733, 1690, 1640 cm ;
2 2 3
C H O 294.1831, found 294.1835.
1
17 26
4
H NMR (400 MHz, CDCl ): l 6.69 (m, 1H, H-10),
3
6
.07 (d, J=10 Hz, 1H, H-9), 3.66 (s, 3H, -OCH3
6 ), 3.10
(
d, J=6.4 Hz, 1H, H-7), 2.81 (ddd, J=19.4, 4.6, 2.0
4.6.2. Diastereomeric ketals 15 and 16 from methyl
2,6
Hz, 1H, H-11b), 2.75 (q, J=6.8 Hz, 1H, H-6), 2.58 (m,
1
1
(1R*,2R*,6S*,7R*)-8-oxotricyclo[5.4.0.0 ]undecane-1-
carboxylate 14* and (R,R)-butane-2,3-diol. A solu-
H, H-2), 2.55 (m, 1H, H-11a), 1.78 (m, 1H, H-5),
.74–1.68 (m, 2H, H-4), 1.57–1.45 (m, 3H); C NMR
O Me),
13
18
tion of a racemic mixture of undecane 14* (0.040 g,
(100 MHz, CDCl ): l 198.4 (C-8), 174.3 (-C
6
0.18 mmol), p-toluenesulfonic acid monohydrate
3
2

1
362
G. L. Lange et al. / Tetrahedron: Asymmetry 13 (2002) 1355–1362
(
0
0.004 g, 0.02 mmol) and R,R-2,3-butanediol (0.040 g,
.44 mmol) in toluene (7.0 mL) was heated under reflux
2. Hikichi, S.; Hareau, G. P.-J.; Sato, F. Tetrahedron Lett.
1997, 38, 8299–8302.
for 6 h using a Dean–Stark apparatus. The reaction
was monitored using TLC (60% EtOAc/hexanes) until
completion. The reaction mixture was cooled to rt and
quenched with saturated aqueous Na CO (3 mL), then
3. Takano, S.; Higashi, Y.; Kamikubo, T.; Moriya, M.;
Ogasawara, K. Synthesis 1993, 948–950.
4. Ogasawara, K. Pure Appl. Chem. 1994, 66, 2119–2122.
5. Lange, G. L.; Gottardo, C. J. Org. Chem. 1995, 60,
2183–2187.
2
3
washed with H O (2×). The aqueous layer was
2
extracted (3×) with CH Cl , the organic layers were
2
2
6. Lange, G. L.; Furlan, L.; MacKinnon, M. C. Tetrahedron
Lett. 1998, 39, 5489–5492.
combined, dried with MgSO4 and concentrated in
vacuo. The residue was purified using FC (10–20%
EtOAc/hexanes) yielding a mixture of diastereomeric
ketals 15 and 16 (0.050 g, 93%). (15) TLC (50% EtOAc/
7
. Lange, G. L.; Gottardo, C.; Merica, A. J. Org. Chem.
999, 64, 6738–6744.
1
8. Barco, A.; Benetti, S.; De Risi, C.; Marchetti, P.; Pollini,
hexanes) R =0.66; spectral data reported above. (16)
f
G. P.; Zanirato, V. Tetrahedron: Asymmetry 1997, 8,
13
TLC (50% EtOAc/hexanes) R =0.64; C NMR (100
f
3
515–3545.
. Shing, T. K. M.; Tang, Y. Tetrahedron 1991, 47, 4571–
578 and references cited therein.
MHz, CDCl ): l 175.3 (-C
6
O Me), 108.5 (C-8), 78.3,
3
2
9
7
8.0 (O-C
6 H(CH )- C6 H(CH )-O), 51.4 (-OC6 H ), 47.2 (C-
3 3 3
4
7
), 47.2 (C-1), 44.7 (C-2), 37.4 (C-6), 32.4 (C-9), 32.2
1
0. Wang, Z.-X.; Miller, S. M.; Anderson, O. P.; Shi, Y. J.
Org. Chem. 1999, 64, 6443–6458 and references cited
therein.
(
1
C-3), 30.9 (C-5), 28.6 (C-4), 26.1 (C-11), 19.1 (C-10),
7.2 (-CC
6
H ), 16.7 (-CC
6
H3).
3
1
1
1
1. Piguel, S.; Ulibarri, G.; Grierson, D. S. Tetrahedron Lett.
1
999, 40, 291–294.
2. Lange, G. L.; Gottardo, C. Magn. Res. Chem. 1996, 34,
60–666.
3. Corey, E. J.; Winter, R. A. E. J. Am. Chem. Soc. 1963,
5, 2677–2678.
Acknowledgements
6
G.L.L. acknowledges the Natural Sciences and Engi-
neering Council of Canada for support in the form of a
research grant and C.C.H. is grateful for an Ontario
Government Scholarship for Science and Technology.
We thank V. Robinson, University of Guelph, for
assistance in acquiring NMR spectra.
8
14. Garegg, P. J. Pure Appl. Chem. 1984, 56, 845–858.
1
5. Crank, G.; Eastwood, F. W. Aust. J. Chem. 1964, 17,
1392–1398.
1
1
1
6. Camps, P.; Cardellach, J.; Font, J.; Ortuno, R. M.;
Ponsati, O. Tetrahedron 1982, 38, 2395–2402.
7. Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 18,
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