Chiral preparation of polyoxygenated cyclopentanoids

Article abstract of DOI:10.1055/s-2000-6271

A series of polyoxygenated cyclopentanoids, including 2,2-dimethyl- 3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one, has been prepared in both enantiomeric forms from cyclopentadiene by employing lipase-mediated kinetic resolution as the key step. Thus, cyclopentadiene is first transformed into racemic cis-4-cumyloxycyclopent-2-en-1-ol which is resolved under transesterification conditions in the presence of lipase PS. After transformation into the corresponding tert-butyldimethylsilyl (TBS) ethers, each of the enantiomers is cis-dihydroxylated diastereoselectively from the less hindered face which is transformed into the 2,3-O-isopropylidene-1,4-di- O-protected (trans-1,2:cis-2,3:trans-3,4)-1,2,3,4-cyclopentanetetraol. Selective removal of the 1,4-protecting group gives the corresponding 2,3,4- O-protected cyclopentanols which are further transformed into the 2,3,4-O- protected cyclopentanones on oxidation without suffering β-elimination. Exposure of the cyclopentanones to warm acetic acid allows β-elimination to give rise to the dehydration product 2,2,-dimethyl-3a,6a-dihydro-4H- cyclopenta[d][1,3]dioxol-4-one having the corresponding chirality without losing their original chiral integrity.

Full text of DOI:10.1055/s-2000-6271

PAPER
817
Chiral Preparation of Polyoxygenated Cyclopentanoids
Hiromi Nakashima, Masayuki Sato, Takahiko Taniguchi, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81(22)2176845; E-mail: konol@mail.cc.tohoku.ac.jp
Received 27 January 2000; revised 28 February 2000
Abstract: A series of polyoxygenated cyclopentanoids, including
2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one,
has been prepared in both enantiomeric forms from cyclopentadiene
by employing lipase-mediated kinetic resolution as the key step.
Thus, cyclopentadiene is first transformed into racemic cis-4-cum-
yloxycyclopent-2-en-1-ol which is resolved under transesterifica-
tion conditions in the presence of lipase PS. After transformation
into the corresponding tert-butyldimethylsilyl (TBS) ethers, each of
the enantiomers is cis-dihydroxylated diastereoselectively from the
less hindered face which is transformed into the 2,3-O-isopropy-
lidene-1,4-di-O-protected (trans-1,2:cis-2,3:trans-3,4)-1,2,3,4-cy-
clopentanetetraol. Selective removal of the 1,4-protecting group
gives the corresponding 2,3,4-O-protected cyclopentanols which
are further transformed into the 2,3,4-O-protected cyclopentanones
on oxidation without suffering b-elimination. Exposure of the cy-
clopentanones to warm acetic acid allows b-elimination to give rise
to the dehydration product 2,2,-dimethyl-3a,6a-dihydro-4H-cyclo-
penta[d][1,3]dioxol-4-one having the corresponding chirality with-
out losing their original chiral integrity.
Figure Structures of (+)- and (-)-2,2-dimethyl-3a,6a-dihydro-4H-
cyclopenta[d][1,3]dioxol-4-ones
Cyclopentadiene was first transformed into racemic 4-
cumyloxycyclopent-2-enone3 [(±)-4] in three steps via the
diastereomeric acetate 24,5 and alcohol 3. Although the
overall yield of (±)-4 was moderate (47% in 3 steps), the
preparation may be carried out in a more than two-molar
scale. Reduction of (±)-4 with sodium borohydride and
cerium(III) chloride6 proceeded chemo- and diastereose-
lectively to give 1,4-cis-4-cumyloxycyclopent-2-en-1-ol
[(±)-5] in 92% yield (Scheme 1).
Key words: lipase-mediated kinetic resolution, enantiodivergent
synthesis, enantioconvergent synthesis, chiral building block, poly-
oxygenated cyclopentanoids, oxidations, osmium
Kinetic resolution was carried out at this stage by treating
the racemic alcohol (±)-5 with an excess vinyl acetate in
tert-butyl methyl ether in the presence of immobilized li-
pase (lipase PS, Pseudomonas sp., Amano) which afford-
ed the enantiopure acetate (-)-6 in 43% yield, leaving the
enantiopure alcohol (+)-5 in 50% recovery yield. The ac-
etate (-)-6 afforded the enantiopure alcohol (-)-5, quan-
titatively, on alkaline methanolysis. Enantiomeric purity
of the products was determined by HPLC using a column
with chiral stationary phase (CHIRALCEL OD). The re-
action rate of the lipase-mediated reaction was mostly de-
pendent on the amount of the lipase used, the amount of
which, however, did not affect the optical purities of the
products. Since the tert-butoxy analogue of 5 failed to car-
ry out the kinetic resolution in complete selectivity,7
namely, 97% ee for the acetate and 91% ee for the remain-
ing alcohol, the present result exhibiting complete resolu-
tion may be noteworthy from the practical viewpoint
(Scheme 2).
Polyoxygenated chiral cyclopentane derivatives, in par-
ticular
2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta
[d][1,3]dioxol-4-one (1),1 serve as important precursors
for the enantiocontrolled construction of a variety of bio-
logically active natural and unnatural compounds (Fig-
ure).
Although several chiral syntheses of polyoxygenated cy-
clopentane derivatives leading to 1 have been established
by using either chiral or achiral precursors,1 a new proce-
dure capable of producing these cyclopentanoids more ef-
ficiently is still required because of their high potential in
chiral synthesis. We wish to report here an efficient prep-
aration of a series of chiral polyoxygenated cyclopen-
tanoids leading to 1 in both enantiomeric forms starting
from cyclopentadiene by employing lipase-mediated ki-
netic transesterification2 as the key step.
Scheme 1
Synthesis 2000, No. 6, 817–823 ISSN 0039-7881 © Thieme Stuttgart · New York

818
H. Nakashima et al.
PAPER
tions. In the Eschenmoser reaction under the same
conditions as above, (-)-10 gave the amide (-)-11 which
afforded the same lactone (-)-8 on exposure to dilute acid
to complete the enantioconvergent synthesis (Scheme 3).
Having determined the stereochemistry of the resolved
products, we next examined the conversion of the re-
solved products into the corresponding (cis-4,5)-4,5-O-
isopropylidene-4,5-dihydroxycyclopent-2-enone (1) in a
diastereocontrolled manner via cis-dihydroxylation.1g,13
Thus, osmium-catalyzed dihydroxylation of the TBS
ether (-)-9 proceeded diastereoselectively from the oppo-
site face of the 1,4-substituents to give the single diol (-)-
12 which was transformed into the acetonide (+)-13. By
the same treatment, the enantiomeric TBS ether (+)-9, ob-
tained from (+)-5, furnished the enantiomeric acetonide
(-)-13 via the enantiomeric diol (+)-12 (Scheme 4).
Scheme 2
In order to determine the absolute configuration of the re-
solved products as well as to demonstrate the synthetic
potential of the resolved products as chiral building
blocks, we examined their enantioconvergent transforma-
tion into a single enantiomeric oxabicyclo[3.3.0]oct-6-en-
3-one8,9 (-)-8, used for an important prostaglandin inter-
mediate, on the basis of our originally established proce-
dure.10
To establish enantiodivergent and, at the same time, enan-
tioconvergent synthesis of the cyclopentenone 1 from
each enantiomer of the acetonide 13, (-)-13 was first sub-
jected to catalytic hydrogenolysis to remove the cumyl
functionality to give the 4-TBS-oxy alcohol (-)-14. Oxi-
dation of (-)-14 under Dess-Martin conditions14 afforded
the cyclopentanone (+)-15 excellently, but other oxidation
conditions induced considerable decomposition. Rather
surprisingly, the ketone (+)-15 was found to be fairly sta-
ble under ordinary conditions which gave the cyclopen-
tenone (+)-1 in satisfactory yield when it was stirred with
warm acetic acid (60 °C) for 4 days (Scheme 5).
Thus, the alcohol (+)-5 was heated with a 2.5-fold excess
of dimethylacetamide dimethyl acetal11 in refluxing
diphenyl ether to give the cyclopenteneacetamide (-)-7,
neatly, through a [3.3]-sigmatropic rearrangement. The
Eschenmoser conditions employed were found to proceed
in a much cleaner way than the Johnson conditions9,12 as
the latter required an acid catalyst which induced consid-
erable decomposition. Upon exposure to diluted hydro-
chloric acid, the amide (-)-7 furnished the target lactone
(-)-8 facilely with concurrent decumylation and lacton-
ization. The absolute configuration of the starting alcohol
(+)-5, thus, was determined as 1R,4S and, consequently,
the enantiomeric alcohol (-)-5 as 1S,4R.
On the other hand, the same acetonide (-)-13 was ex-
posed to tetrabutylammonium fluoride (TBAF) to remove
the TBS functionality to give the 4-cumyloxy alcohol
(-)-16 which afforded the cyclopentanone (-)-17 in ex-
cellent overall yield under Dess-Martin conditions. Sim-
ilarly to the siloxy counterpart (+)-15, (-)-17 was found
to be fairly stable under ordinary conditions though it
gave the enantiomeric cyclopentenone (-)-1 on warming
in acetic acid for 4 days (Scheme 5). Thus, an enantiodi-
vergent route to the enone 1 from the same (-)-13 has
been established.
On the other hand, the enantiomeric alcohol (-)-5 was
first transformed into the tert-butyldimethylsilyl (TBS)
ether (-)-9 whose cumyl functionality was next removed
under Birch conditions to give the siloxy alcohol 10. It
was interesting to note that reductive cleavage did not take
place at the allylic carbon-oxygen bond but selectively at
the desired benzylic carbon-oxygen bond to give the cy-
clopentenol (-)-10 in satisfactory yield under these condi-
Scheme 3
Synthesis 2000, No. 6, 817–823 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Chiral Preparation of Polyoxygenated Cyclopentanoids
819
determined on a Gilson Model-307 instrument equipped with a
chiral column. Optical rotations were measured with a JASCO-DIP-
370 digital polarimeter.
(±)-4-Cumyloxycyclopent-2-enone (±)-4
(a) Oxidation by MnO2: A solution of 3 (51 mg, 0.234 mmol) in hex-
ane/CH2Cl2 (1.0 mL:0.2 mL) was stirred with MnO2 (400 mg, 4.60
mmol) at r.t. for 2 h. After filtration through a Celile pad, the mix-
ture was evaporated and chromatographed (silica gel, 4 g, elution
with hexane/EtOAc, 4:1 v/v) to give the ketone (±)-4 (45 mg, 89%).
(b) Oxidation by Pyridinium Dichromate (PDC): To a stirred solu-
tion of 3 (15.6 g, 71.6 mmol) in CH2Cl2 (300 mL) was added PDC
(32.3 g, 85.9 mmol) portionwise at r.t. After stirring at the same
temperature for overnight, the mixture was filtered through a Celite
pad and evaporated under reduced pressure. The residue was chro-
matographed (silica gel, 300 g, elution with hexane/EtOAc, 4:1 v/v)
to give the ketone (±)-4 (14.7 g, 95%).
Scheme 4
IR (film): n = 1719 cm-1.
On exactly the same treatment as for (-)-13, the enantio-
meric (+)-13 furnished enantiodivergently (-)-1, via (+)-
14 and (-)-15, and (+)-1, via (+)-16 and (+)-17, both in
comparable overall yields. Thus, (-)- and (+)-13 pro-
duced the enone 1 in both enantiomeric forms enantio-
1H NMR (300 MHz, CDCl3): d = 1.61 (3 H, s), 1.63 (3 H, s), 2.33
(1 H, dd, J = 18.3, 2.4 Hz), 2.54 (1 H, dd, J = 18.3, 6.0 Hz), 4.46 (1
H, ddd, J = 6.0, 3.9, 2.4 Hz), 6.14 (1 H, dd, J = 5.7, 1.2 Hz), 7.27-
7.50 (6 H, m).
13C NMR (75 MHz, CDCl3): d = 27.88, 29.66, 44.29, 71.77, 78.50,
126.11, 127.60, 128.54, 134.79, 145.88, 163.41, 206.74.
complementarily
in
enantioconvergent
and
enantiodivergent manners via the polyoxygenated chiral
cyclopentane intermediates, 14-17. Among these inter-
mediates obtained, the isolation of the b-oxy-ketones 15
and 17 in stable form may be of particular interest from
the synthetic viewpoint as they allow stereoselective mod-
ification of the ketone functionality with keeping the b-
oxy functionality intact (Scheme 5).
MS: m/z = 216 (M+).
HRMS: m/z calcd for C14H16O2 (M+) 216.1150. Found 216.1105.
Anal. calcd for C14H16O2 (216.3): C 77.75; H 7.64. Found: C 77.60;
H 7.41.
(±)-(cis-1,4)-4-Cumyloxycyclopent-2-en-1-ol (±)-5
To a stirred solution of (±)-4 (7.71 g, 35.6 mmol) and CeCl3•7H2O
(14.6 g, 39.2 mmol) in MeOH (100 mL) was added NaBH4 (1.01 g,
26.7 mmol) portionwise at -78 °C. After stirring at the same tem-
In conclusion, we have established an efficient diastereo-
controlled preparation of a series of polyoxygenated
chiral cyclopentane derivatives starting from cyclopenta- perature for 30 min, the reaction was quenched by addition of ace-
diene by employing lipase-mediated kinetic transesterifi-
cation as the key step. On the basis of the latent meso
symmetry in the key intermediates, the chiral products in-
volved in the present synthesis may be used in both enan-
tiodivergent and enantioconvergent ways. Exploitation of
the prepared chiral products as chiral building blocks is
tone (10 mL) and the mixture was extracted with EtOAc (4 î 50
mL). The extract was washed with brine (20 mL), dried (MgSO4),
evaporated under reduced pressure, and chromatographed (silica
gel, 380 g, elution with hexane/EtOAc, 2:1 v/v) to give the alcohol
(±)-5 (7.18 g, 92%).
IR (film): n = 3410 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.56 (3 H, s), 1.58 (3 H, s), 1.61
(1 H, ddd, J = 13.8, 7.2, 7.2 Hz), 2.57 (1 H, ddd, J = 13.8, 4.8, 4.8
presently under investigation.
Melting points are uncorrected. IR spectra were recorded on a
Hz), 4.05-4.12 (1 H, m), 4.43-4.52 (1 H, m), 5.83 (1 H, ddd,
JASCO-IR-700 spectrometer. 1H NMR spectra were recorded on a
J = 5.7, 1.5, 1.5 Hz), 5.91 (1 H, ddd, J = 5.7, 1.5, 1.5 Hz), 7.23-
Gemini 2000 (300 MHz) spectrometer. Enantiomeric excess was
7.48 (5 H, m).
Scheme 5
Synthesis 2000, No. 6, 817–823 ISSN 0039-7881 © Thieme Stuttgart · New York

820
H. Nakashima et al.
PAPER
13C NMR (75 MHz, CDCl3): d = 28.64, 29.60, 43.94, 74.98, 76.20,
for diphenyl ether and 1:1 v/v for (-)-7] to give the acetamide (-)-
28
77.84, 126.18, 127.17, 128.32, 136.07, 136.17, 146.82.
7 (2.44 g, 84%), [a]D -140.57 (c = 1.08, CHCl3); mp 50-51 °C
(hexane) as colorless prisms.
IR (film): n = 1651 cm-1.
MS: m/z = 203 (M+ - CH3).
HRMS: m/z calcd for C13H15O2 (M+ - CH3) 203.1072. Found
203.1054.
1H NMR (300 MHz, CDCl3): d = 1.52 (3 H, s), 1.53 (3 H, s), 2.21
(1 H, dd, J = 15.6, 8.5 Hz), 2.26-2.29 (2 H, m), 2.77 (1 H, dd,
J = 15.6, 2.7 Hz), 2.95 (3 H, s), 3.04 (3 H, s), 3.04-3.07 (1 H, m),
4.04 (1 H, dd, J = 8.5, 8.5 Hz), 5.58 (1 H, br d, J = 6.6 Hz), 5.75 (1
H, ddd, J = 6.6, 2.7, 1.8 Hz), 7.21-7.45 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 28.17, 29.35, 32.47, 35.41, 37.46,
38.67, 44.32, 78.85, 77.42, 126.00, 127.00, 128.19, 128.42, 134.49,
147.23, 173.13.
Anal. calcd for C14H18O2 (218.3): C 77.03; H 8.31. Found: C 76.59;
H 8.04.
Kinetic Transesterification of (±)-5
A solution of (±)-5 (1.07 g, 4.91 mmol) and vinyl acetate (2.53 mL,
27.4 mmol) in t-BuOMe (30 ml) was suspended with immobilized
lipase (Lipase PS, pseudomonas sp. AMANO) (1.07 g) and the sus-
pension was stirred at r.t. for 2 h. After filtration through a Celite
pad, the filtrate was evaporated under reduced pressure and chro-
matographed (silica gel, 70 g, elution with hexane/EtOAc, 4:1 v/v
for (-)-6 and hexane/EtOAc, 2:1 for (+)-5) to give the acetate (-)-
6 (543 mg, 43%) and the alcohol (+)-5 (538.9 mg, 50%).
MS: m/z = 287 (M+).
HRMS: m/z calcd for C18H25O2N (M+) 287.1885. Found 287.1905.
Anal. calcd for C18H25O2N(287.4): C 75.22; H 8.77; N 4.87. Found:
C 75.38; H 8.69; N 4.75.
(-)-6
Silylation of the (-)-Alcohol (-)-5
[a]D29 -62.02 (c = 0.98, CHCl3).
The alcohol (-)-5 (4.02 g, 8.42 mmol), tert-butyldimethylsilyl chlo-
ride (3.92 g, 26.1 mmol) in DMF (40 mL) was mixed with imida-
zole (2.04 g, 29.96 mmol) at 0 °C and the mixture was stirred at r.t.
for 3 h. The mixture was diluted with H2O (20 mL) and was extract-
ed with Et2O (2 î 30 mL). The extract was washed with brine (10
mL), dried (MgSO4), evaporated under reduced pressure, and chro-
matographed (silica gel, 200 g, elution with hexane/EtOAc, 8:1 v/v)
to give the silyl ether (-)-9 (6.07 g, 99%); [a]D31 -47.01 (c = 1.01,
CHCl3) as a colorless oil.
IR (film): n = 1738 cm-1.
1H NMR (300 MHz, CDCl3): d = 1.56 (3 H, s), 1.57 (3 H, s), 1.71
(1 H, ddd, J = 14.1, 4.8, 4.8 Hz), 2.04 (3 H, s), 2.66 (1 H, ddd,
J = 14.1, 7.5, 7.5 Hz), 4.00-4.17 (1 H, m), 5.32-5.38 (1 H, m), 5.86
(1 H, ddd, J = 6.0, 1.5, 1.5 Hz), 5.94 (1 H, ddd, J = 6.0, 1.5, 1.5 Hz),
7.23-7.48 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 21.09, 28.61, 29.49, 40.36, 75.92,
76.96, 77.78, 126.12, 127.17, 128.31, 131.65, 138.15, 146.76,
171.06.
1H NMR (300 MHz, CDCl3): d = 0.061 (6 H, s), 0.896 (9 H, s), 1.57
(6 H, s), 1.64 (1 H, ddd, J = 13.8, 6.3, 6.3 Hz), 2.53 (1 H, ddd,
J = 13.8, 7.0, 7.0 Hz), 4.05 (1 H, dd, J = 7.0, 6.3 Hz), 4.50 (1 H, dd,
J = 7.0, 6.3 Hz), 5.77 (1 H, s), 5.78 (1 H, s), 7.23-7.50 (5 H, m).
13C NMR (75 MHz, CDCl3): d = -4.72, -4.64, 18.07, 25.86, 29.05,
29.40, 44.58, 74.81, 76.07, 77.48, 126.23, 127.03, 128.28, 135.00,
136.54, 147.27.
MS: m/z = 260 (M+).
HRMS: m/z calcd for C16H20O3 (M+) 260.1412. Found 260.1401.
Anal. calcd for C16H20O3 (260.3): C 73.82; H 7.74. Found: C 73.56;
H 7.79.
Optical purity was determined to be >99% ee by HPLC using a
chiral column with chiral stationary phase (CHIRALCEL OD, elu-
tion: hexane/i-PrOH, 200:1 v/v).
MS: m/z = 275 (M+ - t-C4H9).
HRMS: m/z calcd for C16H23O2Si (M+ - t-C4H9) 275.1468. Found:
275.1456.
(+)-5
Anal. calcd for C20H32O2Si (332.6): C 72.23; H 9.70. Found: C
72.27; H 9.74.
[a]D31 +27.52 (c = 1.11, CHCl3).
The enantiomeric silyl ether (+)-9; [a]D28 +48.90 (c = 1.61, CHCl3),
was obtained quantitatively from the (+)-alcohol (+)-5 by the same
treatment.
Spectroscopic data were identical with those of (±)-5. Optical purity
was determined to be >99% ee by HPLC using a chiral column with
chiral stationary phase (CHIRALCEL OD, elution: hexane/i-PrOH,
200:1 v/v) after transformation into the acetate (+)-6.
Birch Reduction of the Silyl Ether (-)-9
Conversion of (-)-Acetate (-)-6 into (-)-Alcohol (-)-5
To a stirred solution of (-)-9 (3.01 g, 9.05 mmol) in THF (20 mL)
was introduced liq. NH3 (ca. 30 mL) at -78 °C. Then, Na (ca. 1.0 g)
was added to the mixture, piece by piece, until blue color was main-
tained and NH4Cl (200 mg) was added to quench the reaction. After
evaporation of ammonia by stirring at room temperature, the mix-
ture, after dilution with water (20 mL), was extracted with Et2O (2
î 50 mL), washed with brine (10 ml), dried (MgSO4), evaporated
under reduced pressure, and chromatographed (silica gel, 150 g,
elution with hexane/EtOAc, 6:1 v/v) to give the silyl alcohol (-)-10
A solution of (-)-6 (10.11 g, 38.84 mmol) in MeOH (150 ml) was
stirred with K2CO3 (16.10 g, 116.5 mmol) at r.t. for 1.5 h. The mix-
ture was diluted with H2O (70 mL) and extracted with EtOAc (4 î
70 mL). The extract was washed with brine (30 mL), dried
(MgSO4), evaporated under reduced pressure, and chromato-
graphed (silica gel, 500 g, elution with hexane/EtOAc, 2:1 v/v to
31
give the alcohol (-)-5 (8.09 g, 95%), [a]D -27.43 (c = 1.01,
CHCl3). Spectroscopic data were identical with those of the enanti-
omer. Optical purity was determined to be >99% ee by HPLC using
a chiral column as above.
30
(1.39 g, 72%), [a]D -24.53 (c = 1.59, CH2Cl2) [Lit15 for 1S,4R
enantiomer, [a]D20 +24.29 (c = 2.47, CH2Cl2)], as a colorless oil.
IR (film): n = 3307 cm-1.
Reaction of the (+)-Alcohol (+)-5 with N,N-Dimethylacetamide
Dimethyl Acetal
A mixture of (+)-5 (2.20 g, 10.08 mmol) and N,N-dimethylaceta-
mide dimethyl Acetal (3.69 ml, 25.2 mmol) in diphenyl ether (53
mL) was refluxed for 30 min. After cooling, the mixture was chro-
matographed [silica gel, 150 g, elution with hexane/EtOAc, 4:1 v/v
1H NMR (300 MHz, CDCl3): d = 0.079 (6 H, s), 0.889 (9 H, s), 1.50
(1 H, ddd, J = 13.8, 4.5, 4.5 Hz), 2.00 (1 H, br s), 2.68 (1 H, ddd,
J = 13.8, 6.9, 6.9 Hz), 4.57-4.59 (1 H, m), 4.63-4.67 (1 H, m), 5.87
(1 H, d, J = 6.0 Hz), 5.94 (1 H, d, J = 6.0 Hz).
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PAPER
Chiral Preparation of Polyoxygenated Cyclopentanoids
821
13C NMR (75 MHz, CDCl3): d = -4.72, 18.15, 25.88, 44.69, 75.23,
1H NMR (300 MHz, CDCl3): d = 0.034 (3 H, s), 0.042 (3 H, s),
0.881 (9 H, s), 1.48 (1 H, ddd, J = 13.5, 7.2, 7.2 Hz), 1.54 (3 H, s),
1.58 (3 H, s), 2.19 (1 H, ddd, J = 13.5, 8.0, 6.7 Hz), 2.29 (1 H, br s),
2.50 (1 H, br s), 3.55 (1 H, ddd, J = 8.0, 7.2, 6.7 Hz), 3.80 (1 H, dd,
J = 4.7, 4.7 Hz), 3.83 (1 H, ddd, J = 7.2, 6.7, 4.7 Hz), 3.98 (1 H, dd,
J = 4.7, 4.7 Hz), 7.23-7.48 (5 H, m).
135.82, 137.10.
MS: m/z = 157 (M+ - t-C4H9).
HRMS: m/z calcd for C7H13O2 (M+- t-C4H9) 175.0685. Found
175.0666.
13C NMR (75 MHz, CDCl3): d = -4.89, 17.90, 25.65, 28.71, 28.78,
39.24, 74.89, 76.33, 76.89, 77.38, 77.50, 126.08, 127.21, 128.27,
146.85.
MS: m/z = 351 (M+ - CH3), 309 (M+ - t-C4H9), 229 (M+ - C9H13O).
HRMS: m/z calcd for C11H21O3Si(M+ - C9H13O) 229.1260. Found:
229.1278.
Reaction of the Silyl Alcohol (-)-10 with N,N-Dimethylaceta-
mide Dimethyl Acetal
A mixture of (-)-10 (1.00 g, 4.68 mmol) and N,N-dimethylaceta-
mide dimethyl acetal (1.71 ml, 11.7 mmol) in diphenyl ether (20
mL) was refluxed for 30 min. After cooling, the mixture was chro-
matographed (silica gel, 70 g, elution with hexane/EtOAc, 4:1 v/v
for diphenyl ether and 1:1 v/v for (-)-11) to give the acetamide
(-)-11 (1.03 g, 78%); [a]D27 -56.55 (c = 1.01, CHCl3), as a colorless
oil.
Anal. calcd for C20H34O4Si (366.6): C 65.53; H 9.35. Found: C
65.64; H 9.35.
The enantiomeric cis-diol (-)-12 was obtained in 90% yield from
the enantiomeric bis-ether (-)-9 by the same treatment; mp 48-
49 °C (hexane); [a]D30 -10.25 (c = 0.752, CHCl3)
IR (film): n = 1655 cm-1.
1H NMR (300 MHz, CDCl3): d = -0.002 (3 H, s), 0.030 (3 H, s),
0.850 (9 H, s), 2.18-2.23 (2 H, m), 2.52 (1 H, dd, J = 16.8, 6.6 Hz),
2.64 (1 H, dd, J = 15.9, 7.5 Hz), 2.92 (3 H, s), 2.98 (3 H, s), 3.15 (1
H, dd, J = 13.8, 6.6 Hz), 4.51 (1 H, ddd, J = 6.6, 6.6, 4.2 Hz), 5.66
(2 H, s).
13C NMR (75 MHz, CDCl3): d = -5.43, -4.99, 18.06, 25.79, 31.92,
35.30, 37.11, 41.59, 45.83, 73.18, 128.16, 133.76, 172.82.
Conversion of the Diol (+)-12 into the Acetonide (-)-13
A solution of the diol (+)-12 (11.16 g, 30.44 mmol) and 2,2-
dimethoxypropane (37 mL, 300 mmol) in CH2Cl2 (115 mL) con-
taining a catalytic amount of pyridinium p-toluenesulfonate (PPTS)
(76 mg, 0.3 mmol) was stirred at r.t. for 24 h. To the mixture was
added sat. aq NaHCO3 (100 mL) and extracted with Et2O (2 î 150
mL). The combined Et2O extracts were dried (MgSO4), evaporated
under reduced pressure, and the residue chromatographed (silica
gel, 500 g, elution with hexane/EtOAc, 20:1 v/v) to give the ace-
tonide (-)-13 (12.04 g, 97%); [a]D32 -20.76 (c = 1.01, CHCl3) as a
colorless oil.
MS: m/z = 283 (M+).
HRMS: m/z calcd for C15H29O2NSi (M+) 283.1968. Found
283.1950.
Anal. calcd for C15H29O2NSi (283.5): C 63.55; H 10.31; N 4.94.
Found: C 63.33; H 10.09; N 4.81.
1H NMR (300 MHz, CDCl3): d = 0.060 (3 H, s), 0.071 (3 H, s),
0.897 (3 H, s), 1.24 (3 H, s), 1.33 (3 H, s), 1.50 (3 H, s), 1.61 (3 H,
s), 1.71 (1 H, ddd, J = 13.5, 6.6, 6.6 Hz), 2.07 (1 H, ddd, J = 13.5,
6.6, 6.6 Hz), 3.66 (1 H, ddd, J = 6.5, 6.5, 2.9 Hz), 3.98 (1 H, ddd,
J = 6.5, 6.5, 2.7 Hz), 4.37 (1 H, dd, J = 6.9, 2.7 Hz), 4.51 (1 H, dd,
J = 6.9, 2.0 Hz), 7.21-7.47 (5 H, m). 13C NMR (75 MHz, CDCl3):
d = -4.88, 17.91, 24.55, 25.70, 26.73, 27.32, 30.42, 40.52, 76.62,
77.14, 77.67, 86.49, 86.78, 110.87, 126.08, 126.86, 128.09, 147.16.
MS: m/z = 391 (M+ - CH3), 287 (M+ - C9H11).
HRMS: m/z calcd for C14H27O4Si (M+ - C9H11) 287.1679. Found:
287.1678.
Conversion of the Acetamide (-)-7 into Oxabicyclo[3.3.0]oct-6-
en-3-one [(-)-8]
A solution of the acetamide (-)-7 (2.41 g, 8.38 mmol) in a solution
of 10% HCl (20 mL) and dioxane (20 mL) was stirred at r.t. for 10
h. The mixture was extracted with Et2O (3 î 30 mL), washed with
brine (10 mL), dried (MgSO4), evaporated under reduced pressure,
and chromatographed (silica gel, 140 g, elution with hexane/Et2O,
1:1 v/v) to give the lactone (-)-8 (909 mg, 87%); mp 43-44 °C;
[a]D29 -103.21 (c = 1.02, MeOH) [Lit.9 mp 42 °C; [a]D26 -102.3 (c
= 0.7, MeOH)], as colorless crystals. Spectroscopic data were iden-
tical with those of an authentic material.
Anal. calcd for C23H38O4Si (406.6): C 67.94; H 9.42. Found: C
67.85; H 9.51.
Conversion of the Acetamide (-)-11 into Oxabicyclo[3.3.0]oct-
6-en-3-one [(-)-8]
The enantiomeric acetonide (+)-13 was obtained in 97% yield from
the enantiomeric diol (-)-12 by the same treatment; [a]D30 +20.76 (c
= 0.95, CHCl3).
A solution of the acetamide (-)-11 (857 mg, 3.02 mmol) in a solu-
tion of 10% HCl (10 mL) and dioxane (10 mL) was stirred at r.t. for
15 h. The mixture was extracted with Et2O (3 î 20 mL), washed
with brine (5 mL), dried (MgSO4), evaporated under reduced pres-
sure, and chromatographed (silica gel, 60 g, elution with hexane/
Et2O, 1:1 v/v) to give the lactone (-)-8 (286 mg, 76%); mp 44 °C,
Hydrogenolysis of the Bis-Ether (-)-13 to the Cyclopentanol
(-)-14
The cumyl ether (-)-13 (10.00 g, 24.62 mmol) was stirred under an
hydrogen atmosphere in EtOAc (100 mL) containing 3 drops of
CHCl3 in the presence of 10% Pd-C (756 mg) at r.t. for 17 h. After
filtration through a Celite pad, the filtrate was evaporated under re-
duced pressure and chromatographed (silica gel, 500 g, elution with
hexane/EtOAc, 8:1 v/v) to give the alcohol (-)-14 (6.80 g, 96%);
[a]D28 -5.42 (c = 1.11, CHCl3), as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 0.124 (3 H, s), 0.134 (3 H, s),
0.892 (9 H, s), 1.29 (3 H, s), 1.39 (3 H, s), 1.76 (1 H, d, J = 14.4 Hz),
2.09 (1 H, ddd, J = 14.4, 4.2, 4.2 Hz), 3.21 (1 H, d, J = 11.3 Hz),
4.09 (1 H, dd, J = 11.3, 4.2 Hz), 4.25 (1 H, d, J = 4.2 Hz), 4.51 (1
H, dd, J = 5.7, 1.5 Hz), 4.66 (1 H, dd, J = 5.7, 1.5 Hz).
30
[a]D -103.11 (c = 1.02, MeOH), as colorless crystals. Spectro-
scopic data were identical with those of an authentic material.
Dihydroxylation of the Bis-Ether (+)-9
A solution of (+)-9 (11.25 g, 33.83 mmol) in 50% aq THF (150 mL)
was stirred with NMO (5.95 g, 50.8 mmol) and a solution of OsO4
(0.196 M in THF, 4.3 mL, 0.85 mmol) at r.t. for 3 d. After treatment
with sat. aq Na2SO3 (5 mL), the mixture was extracted with EtOAc
(3 î 200 mL). The extract was washed with brine (50 mL), dried
(MgSO4), evaporated under reduced pressure, and chromato-
graphed (silica gel, 500 g, elution with hexane/EtOAc, 4:1 v/v) to
give the cis-diol (+)-12 (11.16 g, 90%); mp 48-49 °C (hexane);
[a]D30 +10.16 (c = 0.734, CHCl3) as colorless needles.
13C NMR (75 MHz, CDCl3): d = -5.27, -5.15, 17.74, 23.68, 25.58,
26.02, 37.24, 77.53, 78.40, 85.82, 86.43, 110.10.
IR (film): n = 3390 cm-1.
Synthesis 2000, No. 6, 817–823 ISSN 0039-7881 © Thieme Stuttgart · New York

822
H. Nakashima et al.
PAPER
MS: m/z = 289 (M+ + H), 273 (M+ – Me).
HRMS: m/z calcd for C13H25O4Si (M+ - CH3) 273.1522. Found:
273.1524.
less oil; mp 110-111 °C (EtOAc/hexane); [a]D31 -19.53 (c = 1.08,
CHCl3).
IR (film): n = 3500 cm-1.
Anal. calcd for C14H28O4Si (288.5): C 58.29; H 9.78. Found: C
58.31; H 9.60.
1H NMR (300 MHz, CDCl3): d = 1.25 (3 H, s), 1.31 (3 H, s), 1.56
(3 H, s), 1.63 (3 H, s), 1.74 (1 H, d, J = 14.4 Hz), 1.96 (1 H, ddd,
J = 14.4, 4.5, 4.5 Hz), 3.33 (1 H, d, J = 11.0 Hz), 3.87 (1 H, d,
J = 4.5 Hz), 4.05 (1 H, dd, J = 11.0, 4.5 Hz), 4.60 (1 H, dd, J = 5.7,
1.5 Hz), 4.61 (1 H, dd, J = 5.7, 1.5 Hz), 7.25-7.45 (5 H, m).
13C NMR (75 MHz, CDCl3): d = 23.67, 25.96, 27.37, 29.60, 36.45,
77.26, 78.67, 79.17, 85.32, 86.37, 109.98, 126.02, 127.50, 128.38,
145.20.
The enantiomeric cyclopentanol (+)-14 was obtained in 96% yield
from the enantiomeric cumyl ether (+)-13 by the same treatment;
25
[a]D +5.52 (c = 1.02, CHCl3).
Oxidation of the Cyclopentanol (-)-14 into the Cyclopentanone
(+)-15
MS: m/z = 292 (M+).
To a stirred solution of the alcohol (-)-14 (6.14 g, 21.29 mmol) in
CH2Cl2 (100 mL) was added the Dess-Martin reagent (14.60 g,
35.00 mmol) portionwise at r.t. After stirring at the same tempera-
ture for 30 min, the mixture was treated with 0.5 N NaOH (100 mL),
extracted with EtOAc (2 î 100 mL), and the organic layer was sep-
arated. The organic layer was washed with brine (20 mL), dried
(MgSO4), evaporated under pressure, and chromatographed (silica
gel, 420 g, elution with hexane/EtOAc, 8:1 v/v) to give the cyclo-
pentanone (+)-15 (5.94 g, 97%); [a]D31 +133.48 (c = 1.16, CHCl3),
as a colorless oil.
HRMS: m/z calcd for C17H24O4 292.1675. Found 292.1695.
Anal. calcd for C17H24O4 (292.4): C 69.84; H 8.27. Found: C 69.89;
H 8.24.
The enantiomeric alcohol (+)-16 was obtained in 98% yield from
the enantiomeric ether (+)-13 by the same treatment; mp 110-
111 °C (EtOAc/hexane); [a]D29 +19.75 (c = 0.75, CHCl3).
Oxidation of Cyclopentanol (-)-16 into Cyclopentanone (-)-17
To a stirred solution of the alcohol (-)-16 (2.98 g, 10.19 mmol) in
CH2Cl2 (50 mL) was added the Dess-Martin reagent (6.39 g, 15.29
mmol) portionwise at r.t. After stirring at the same temperature for
30 min, the mixture was treated with 0.5 N NaOH (50 mL), extract-
ed with EtOAc (3 î 50 mL), and the organic layer was separated.
The organic layer was washed with brine (10 mL), dried (MgSO4),
evaporated under reduced pressure, and chromatographed (silica
gel, 150 g, elution with hexane/EtOAc, 4:1 v/v) to give the cyclo-
pentanone (-)-17 (2.85 g, 96%) as colorless needles; mp 98-99 °C
(hexane); [a]D31 -142.81 (c = 1.13, CHCl3).
IR (film): n = 1764 cm-1.
1H NMR (300 MHz, CDCl3): d = 0.085 (3 H, s), 0.11 (3 H, s), 0.87
(9 H, s), 1.35 (3 H, s), 1.42 (3 H, s), 2.17 (1 H, d, J = 18.0 Hz), 2.28
(1 H, dd, J = 18.0, 5.0 Hz), 4.30 (1 H, d, J = 5.4 Hz), 4.42 (1 H, d,
J = 5.0 Hz), 4.54 (1 H, d, J = 5.4 Hz).
13C NMR (75 MHz, CDCl3): d = -5.11, 17.79, 24.68, 25.49, 26.63,
43.07, 69.18, 77.99, 82.75, 112.80, 212.24.
MS: m/z = 271 (M+ - CH3).
HRMS: m/z calcd for C13H23O4Si (M+ - CH3) 271.1366. Found:
271.1350.
IR (film): n = 1758 cm-1.
Anal. calcd for C14H26O4Si (286.5): C 58.76; H 9.15. Found: C
58.76; H 9.30.
1H NMR (300 MHz, CDCl3): d = 1.30 (3 H, s), 1.34 (3 H, s), 1.55
(3 H, s), 1.62 (3 H, s), 2.23 (1 H, ddd, J = 18.3, 3.0, 1.5 Hz), 2.67 (1
H, dd, J = 18.3, 6.3 Hz), 3.99 (1 H, ddd, J = 6.3, 1.5, 1.5 Hz), 4.36
(1 H, br d, J = 4.36 Hz), 4.58 (1 H, d, J = 5.4 Hz), 7.25-7.44 (5 H,
m).
The enantiomeric ketone (-)-15 was obtained in 97% yield by the
same treatment; [a]D28 -136.59 (c = 1.22, CHCl3).
13C NMR (75 MHz, CDCl3): d = 24.76, 26.63, 27.78, 29.09, 42.63,
69.91, 78.37, 78.64, 82.51, 112.54, 125.95, 127.51, 128.39, 145.58,
212.68.
MS: m/z = 290 (M+).
HRMS: m/z calcd for C17H22O4 (M+) 290.1518. Found 290.1553.
(+)-(3aS,6aS)-2,2-Dimethyl-3a,6a-dihydro-4H-cyclopenta
[d][1,3]dioxol-4-one [(+)-1] from Cyclopentanone (+)-15
A solution of the ketone (+)-15 (5.17 g, 18.05 mmol) in AcOH (100
mL) was stirred at 60 °C for 4 d. After cooling, the mixture was di-
luted with Et2O (300 mL) and the solution was washed successively
with brine (100 mL) and 1 N NaOH (100 mL). The organic layer
was dried (MgSO4), evaporated under reduced pressure, and chro-
matographed (silica gel, 250 g, elution with hexane/Et2O, 3:1 to 1:1
v/v) to give the cyclopentenone (+)-1 (2.18 mg, 78%); mp 68-
Anal. calcd for C17H22O4 (290.4): C 70.32; H 7.64. Found: C 70.19;
H 7.58.
The enantiomeric ketone (+)-17 was obtained in 96% yield from the
enantiomeric alcohol (+)-16 by the same treatment; mp 98-99 °C
(hexane), [a]D29 +144.15 (c = 0.92, CHCl3),
25
69 °C; [a]D32 +69.70 (c = 1.18, CHCl3) [Lit1i mp 68-69 °C [a]D
+70.49 (c 0.95, CHCl3)]. Spectroscopic data were identical with
those of an authentic material.
The enantiomeric enone (-)-1, mp 68-69 °C [a]D31 -69.33 (c 1.22,
CHCl3), was obtained in 78% yield from the enantiomeric ketone
(-)-15 by the same treatment.
(-)-(3aR,6aR)-2,2-Dimethyl-3a,6a-dihydro-4H-cyclopenta-
[d][1,3]dioxol-4-one (-)-1
A solution of the ketone (-)-17 (2.57 g, 8.85 mmol) in AcOH (50
mL) was stirred at 60 °C for 4 d. After cooling, the mixture was di-
luted with Et2O (150 mL) and the solution was washed successively
with brine (50 mL) and 1 N NaOH (50 mL). The organic layer was
dried (MgSO4), evaporated under reduced pressure, and chromato-
graphed (silica gel, 150 g, elution with hexane/Et2O, 1:1 v/v) to give
the cyclopentenone (-)-1 (1.03 g, 76%); mp 68-69 °C (hexane);
[a]D32 -69.88 (c = 1.00, CHCl3).
Desilylation of the Bis-Ether (-)-13 to Cyclopentanol (-)-16
To a stirred solution of the ether (-)-13 (9.18 g, 22.58 mmol) in
THF (50 mL) was added TBAF (1.0 M in THF; 27 mL, 27 mmol)
dropwise at 0 °C. After stirring at r.t. for 2.5 h, the mixture was ex-
tracted with EtOAc (2 î 100 mL), The extract was washed with
brine (20 mL), dried (MgSO4), evaporated under reduced pressure,
and chromatographed (silica gel, 450 g, elution with hexane/EtOAc,
4:1 v/v) to give the cyclopentanol (-)-16 (6.17 g, 93%) as a color-
The enantiomeric cyclopentenone (+)-1, mp 68-69 °C (hexane),
[a]D31 +69.36 (c = 1.05, CHCl3), was obtained in 76% yield from the
enantiomeric cyclopentenone (+)-17 by the same treatment.
Synthesis 2000, No. 6, 817–823 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Chiral Preparation of Polyoxygenated Cyclopentanoids
823
(3) Takano, S.; Iwabuchi, Y.; Takahashi, M.; Ogasawara, K.
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Article Identifier:
1437-210X,E;2000,0,06,0817,0823,ftx,en;F00800SS.pdf
(2) A pertinent monograph, see: Wong, C. H.; Whitesides, G. M.
Enzymes in Synthetic Organic Chemistry, Pergamon: Oxford,
1994.
Synthesis 2000, No. 6, 817–823 ISSN 0039-7881 © Thieme Stuttgart · New York