Syntheses of D- and L-cyclopentenone derivatives using ring-closing metathesis: Versatile intermediates for the synthesis of D- and L-carbocyclic nucleosides

Full text of DOI:10.1021/jo015733w

6490
J . Org. Chem. 2001, 66, 6490-6494
Syn th eses of D- a n d L-Cyclop en ten on e
Der iva tives Usin g Rin g-Closin g
Meta th esis: Ver sa tile In ter m ed ia tes for th e
Syn th esis of D- a n d L-Ca r bocyclic
Nu cleosid es
Won J un Choi,† J ae Gyu Park,† Su J eong Yoo,†
Hea Ok Kim,‡ Hyung Ryong Moon,† Moon Woo Chun,§
Young Hoon J ung,| and Lak Shin J eong*,†
Laboratory of Medicinal Chemistry, College of Pharmacy,
Ewha Womans University, Seoul 120-750, Korea,
Division of Chemistry and Molecular Engineering and
College of Pharmacy, Seoul National University,
Seoul 151-742, Korea, and College of Pharmacy,
Sungkyunkwan University, Suwon 440-746, Korea
lakjeong@mm.ewha.ac.kr
Received May 7, 2001
In tr od u ction
F igu r e 1. Versatile intermediate, (-)-5, for various carbocy-
clic nucleosides.
Neplanocin A (1)1 and aristeromycin (2)2 are represen-
tatives of naturally occurring carbocyclic nucleosides,
which exhibit interesting biological activity3 (Figure 1).
These compounds act as potent inhibitors of S-adenos-
ylhomocysteine (SAH) hydrolase, which catalyzes the
hydrolysis of S-adenosylhomocysteine into adenosine and
homocysteine.4 Inhibition of the SAH hydrolase ac-
cumulates S-adenosylhomocysteine in the cell, which in
turn inhibits S-adenosylmethionine (SAM) transferase,
resulting in the inhibition of viral mRNA capping.5 Thus,
SAH hydrolase inhibitors such as neplanocin A and
aristeromycin have received great attention in the de-
velopment of broad spectrum antiviral agents.
should be still made to find clinically useful SAH hydro-
lase inhibitor.
On the other hand, since the discovery of (-)-3TC
(lamivudine)9 as a potent anti-HIV and anti-HBV agent,
nucleoside chemists turned their attention to the devel-
opment of L-nucleosides. Several L-nucleosides10 were
found to be less cytotoxic than the corresponding D-
nucleosides while maintaining more potent antiviral
activity such as (-)-3TC. Recently, on the basis of these
findings, L-carbocyclic nucleosides11 such as L-aristero-
mycin and L-carbovir analogues have been synthesized
to search for less toxic and more potent antiviral agents
than the counterpart D-nucleosides. Although most of the
synthesized nucleosides did not exhibit significant anti-
viral activities, systematic structure-activity relation-
ship study of L-carbocyclic nucleosides should be contin-
ued to find novel antiviral agents.
Although neplanocin A and aristeromycin act as good
inhibitors of SAH hydrolase, they were too cytotoxic to
be clinically useful agents.6 Thus, in the search of less
toxic and more potent inhibitors of SAH hydrolase than
these compounds, many D-carbocyclic analogues have
been synthesized and evaluated for SAH hydrolase
inhibitory activity.
Since carbocyclic nucleosides 1-4 could be synthesized
from the same intermediate (-)-512 as shown in Figure
1, a short and efficient synthesis of the key intermediate
(-)-5 is highly demanded for the thorough structure-
activity relationship study of these classes of carbocyclic
As a result, compounds 37 and 48 have been discovered
as potent SAH hydrolase inhibitors, but additional efforts
† College of Pharmacy, Ewha Womans University.
‡ Division of Chemistry and Molecular Engineering, Seoul National
University.
(8) Narayanan, S. R.; Keller, B. T.; Borcherding, D. R.; Scholtz, S.
A.; Borchardt, R. T. J . Med. Chem. 1988, 31, 500.
§ College of Pharmacy, Seoul National University.
| College of Pharmacy, Sungkyunkwan University.
(1) (a) Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi,
M.; Otani, M. J . Antibiot. (Tokyo) 1980, 34, 359. (b) Hayashi, M.;
Yaginuma, S.; Yoshioka, H.; Nakatsu, K. J . Antibiot. (Tokyo) 1981,
34, 675.
(9) (a) Coates, J . A.; Cammack, N.; J enkinson, H. J .; Mutton, I. M.;
Pearson, B. A.; Storer, R.; Cameron, J . M.; Penn, C. R. Antimicrob.
Agents Chemother. 1992, 36, 202. (b) Schinazi, R. F.; Chu, C. K.; Peck,
A.; McMillan, A.; Mathis, R.; Cannon, D.; J eong, L. S.; Beach, J . W.;
Choi, W.-B.; Yeola, S.; Liotta, D. C. Antimicrob. Agents Chemother.
1992, 36, 672. (c) Beach, J . W.; J eong, L. S.; Alves, A. J .; Pohl, D.;
Kim, H. O.; Chang, C. N.; Doong, S. L.; Schinazi, R. F.; Cheng, Y.-C.;
Chu, C. K. J . Org. Chem. 1992, 57, 2217. (d) J eong, L. S.; Schinazi, R.
F.; Beach; Kim, H. O.; Nampalli, S.; Shanmuganathan, K.; Alves, A.
J .; McMillan, A.; Chu, C. K. J . Med. Chem. 1993, 36, 181.
(10) (a) Chu, C. K.; Ma, T.; Shanmuganathan, K.; Wang, C.; Xiang,
Y.; Pai, S. B.; Tao, G.-Q.; Sommadossi, J .-P.; Cheng, Y.-C. Antimicrob.
Agents Chemother. 1995, 39, 979. (b) Lin, T.-S.; Luo, M.-Z.; Liu, M.-
C.; Zhu, Y.-L.; Gullen, E.; Dutschman, G. E.; Cheng, Y.-C. J . Med.
Chem. 1996, 39, 1757.
(2) (a) Kusaka, T.; Yamamoto, H.; Shibata, M.; Murio, M.; Kishi,
T.; Mizuno, K. J . Antibiot. (Tokyo) 1968, 21, 255. (b) Kishi, T.; Muroi,
M.; Kusaka, T.; Nishikawa, M.; Kamiya, K.; Mizuno, K. Chem. Pharm.
Bull. 1972, 20, 940.
(3) De Clerq. E. Biochem. Pharmacol. 1987, 36, 2567.
(4) Ueland, P. M. Pharmacol. Rev. 1982, 34, 223.
(5) (a) Borchardt, R. T.; Keller, B. T.; Patel-Thrombre, U. J . Biol.
Chem. 1984, 259, 4353. (b) Cools, M.; De Clerq, E. Biochem. Pharmacol.
1989, 38, 1061.
(6) (a) Glazer, R. I.; Knode, M. C.; Tseng, C. K. H.; Haines, D. R.;
Marquez, V. E. Biochem. Pharmacol. 1986, 35, 4523. (b) Hill, D. L.;
Straight, S.; Allan, P. W.; Bennett, L. L., J r. Mol. Pharmacol. 1971, 7,
375. (c) Bennett, L. L., J r.; Brockman, R. W.; Rose, L. M.; Allan, P.
W.; Shaddix, S. C.; Shealy, Y. F.; Clayton, J . D. Mol. Pharmacol. 1985,
27, 666.
(11) (a) Wang, P.; Agrofoglio, L. A.; Newton, M. G.; Chu, C. K. J .
Org. Chem. 1999, 64, 4173. (b) Chong, Y.; Gumina, G.; Chu, C. K.
Tetrahedron: Asymmetry 2000, 11, 4853. (c) Wang, P.; Gullen, B.;
Newton, M. G.; Cheng, Y.-C.; Schinazi, R. F.; Chu, C. K. J . Med. Chem.
1999, 42, 3390.
(7) Patil, S. D.; Schneller, S. W.; Hosoya, M.; Snoeck, R.; Andrei,
G.; Balzarini, J .; De Clerq, E. J . Med. Chem. 1992, 35, 3372.
(12) (a) Bestmann, H. J .; Roth, D. Synlett 1991, 751. (b) Borcherding,
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10.1021/jo015733w CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/23/2001

Notes
J . Org. Chem., Vol. 66, No. 19, 2001 6491
Sch em e 1
Sch em e 2
nucleosides as well as for the synthesis of compounds
1-4. Therefore, it was of great interest to develop new
and efficient methodology for the common intermediate
(-)-5. In addition, an efficient synthesis of its enantiomer,
(+)-5,13 is also highly required for the synthesis of
L-carbocyclic nucleosides. In this paper, we wish to report
syntheses of D- and L-cyclopentenone derivatives (-)-5
and (+)-5 through the ring-closing metathesis (RCM)14,15
reaction using Grubbs catalyst as a key step starting from
the cheap and commercially available D-isoascorbic acid.
Compounds (-)-5 and (+)-5 represent versatile synthons
for the syntheses of D- and L-carbocyclic nucleosides,
respectively.
under Swern conditions also gave a mixture of 9a and
9b (1.2:1 ratio) in very poor yield. However, oxidation
with tetrapropylammonium perruthenate (TPAP)17 and
N-methylmorpholine N-oxide (NMO) afforded the desired
lactone 9a over 9b in 20 to 1 ratio after isolation by silica
gel column chromatography. During TPAP oxidation, an
inseparable mixture of lactone 9a and lactol 10 was
obtained depending on reaction time and amounts of
oxidizing agents. Short reaction time always gave an
inseparable mixture of 9a and 10 with unreacted starting
material, while longer reaction time (15 h) and use of
excess oxidizing agents resulted in the sole formation of
lactone 9a in 67% yield. Reduction of 9a with DIBALH
in toluene gave a lactol 10, which is ready for Wittig
reaction.
As illustrated in Scheme 3, Wittig reaction of 10 with
methyl triphenylphosphonium bromide was greatly af-
fected by bases used in view of yield and epimerization.
Use of n-BuLi gave the desired diene 11a almost exclu-
sively in 40% yield, while use of bulky LDA afforded 11a
as a sole product, but the yield was only 50% even after
recovery of starting materials. To improve the yield, we
used another bulky base, KO-t-Bu, but the yield was low
(42% yield after recovering starting materials) and
extensive epimerization occurred, giving the desired
diene 11a and its epimer 11b in a 1:1 ratio. However,
use of DMSO anion as a base only produced the desired
diene 11a in 88% yield without forming its epimerized
product 11b.
Resu lts a n d Discu ssion
As shown in Scheme 1, retrosynthetic analysis shows
that the target intermediates, (-)-5 and (+)-5, can be
synthesized via dienes I and II, respectively.
The key intermediates I and II can be derived from
the lactol, which is easily obtained from the cheap and
commercially available D-isoascorbic acid.
For the synthesis of D-cyclopentenone, (-)-5, D-isoascor-
bic acid was converted to the lactol 10 as illustrated in
Scheme 2.
D-Isoascorbic acid was converted to the commercially
available lactone 6 according to the known procedure.16
Reduction of 6 with DIBALH at -78 °C to room temper-
ature for 2 h gave the lactol 7 in 81% yield. Ring opening
of 7 with vinylmagnesium bromide at -78 to 0 °C gave
the diol 8 as a single stereoisomer in quantitative yield.
Selective oxidation of the primary alcohol over allylic
alcohol in 8 was greatly affected by oxidizing agents used.
Oxidation with pyridinium chlorochromate (PCC) as an
oxidizing agent yielded a mixture of the desired 9a and
undesired 9b in 0.9 to 1 ratio in 21% yield. Oxidation
(13) (a) Ali, S. M.; Ramesh, K.; Borchardt, R. T. Tetrahedron Lett.
1990, 31, 1509. (b) Deardorff, D. R.; Shambayati, S.; Myles, D. C.;
Heerding, D. J . Org. Chem. 1988, 53, 3614. (c) J ohnson, C. R.; Penning,
T. D. J . Am. Chem. Soc. 1986, 108, 5655.
(14) (a) Nguyen, S. T.; J ohnson, L. K.; Grubbs, R. H.; Ziller, J . W.
J . Am. Chem. Soc. 1992, 114, 3974. (b) Grubbs, R. H.; Miller, S. J .
Acc. Chem. Res. 1995, 28, 446. (c) Grubbs, R. H.; Chang, S. Tetrahedron
1988, 54, 4413.
(15) Similar approaches using RCM reaction have recently been
published in (a) Seepersaud, M.; Al-Abed, Y. Tetrahedron Lett. 2000,
41, 7801. (b) Lee, K.; Cass, C.; J acobson, K. A. Org. Lett. 2001, 3, 597.
(16) Cohen, N.; Banner, B. L.; Laurenzano, A. J .; Carozza, L. Org.
Synth. 1985, 63, 127.
Ring-closure metathesis (RCM) of 11a with Grubbs
catalyst14 smoothly proceeded to give cyclopentenol 12
as a single stereoisomer. However, the epimer 11b was
remained intact under the RCM conditions. Oxidation of
allylic alcohol 12 with activated MnO2 afforded the key
intermediate (-)-5, which serves as a versatile interme-
diate for the synthesis of D-carbocyclic nucleosides. To
(17) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. Chem.
Commun. 1987, 1625.

6492 J . Org. Chem., Vol. 66, No. 19, 2001
Notes
Sch em e 3
is a versatile synthon for the synthesis of L-carbocyclic
nucleosides. The physical and spectroscopic data of the
synthesized (-)-5 and (+)-5, including optical rotations,
were identical to those of the authentic samples,12,13
respectively.
Con clu sion s
We developed a new synthetic methodology to the key
intermediates (-)-5 and (+)-5 using ring-closing metath-
esis (RCM) reaction as a key step starting from the cheap
and commercially available D-isoascorbic acid. These
intermediates represent convenient synthons for the
synthesis of D- and L-carbocyclic nucleosides, respectively.
Finally, our procedure highlights mild reaction condi-
tions, no epimerization, no enzymatic resolution, and
improved overall yields when compared to the previously
published procedures.12,13
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were measured in
CDCl3, and chemical shifts are reported in parts per million (δ)
downfield from tetramethylsilane as internal standard. Elemen-
tal analyses were performed at the general instrument labora-
tory of Ewha Womans University, Korea. TLC was performed
on Merck precoated 60F254 plates. Column chromatography was
performed using silica gel 60 (230-400 mesh, Merck). All
anhydrous solvents were distilled over CaH2 or P2O5 or Na/
benzophenone immediately prior to use.
Sch em e 4
(4R,5R)-2,2-Dim eth yltetr a h yd r ofu r o[3,4-d ][1,3]d ioxol-4-
ol (7). To a cooled (-78 °C) solution of lactone 6 (4.5 g, 28.45
mmol) in dry toluene (93 mL) was added dropwise diisobutyla-
luminum hydride (1.0 M solution in toluene, 31.3 mL, 31.3
mmol), and the reaction mixture was stirred at - 78 °C for 1 h
and allowed to stir at room temperature for 30 min. The reaction
mixture was cooled to 0 °C and diluted with methanol (31.3 mL)
and 50% ethyl acetate/hexanes. The mixture was warmed to
room temperature and stirred for 2 h, and the white precipitate
was removed by filtration through a pad of Celite and washed
with ethyl acetate. The filtrates were concentrated in vacuo and
purified by silica gel column chromatography (hexanes/ethyl
acetate ) 2:1) to give 7 (3.68 g, 81%) as a white crystal: 1H NMR
(CDCl3) δ 5.43 (d, J ) 2.0 Hz, 1 H), 4.85 (dd, J ) 4.0, 5.6 Hz, 1
H), 4.59 (d, J ) 5.6 Hz, 1 H), 4.10-4.02 (m, 2 H), 2.55 (br s, 1
H), 1.48 (s, 3 H), 1.33 (s, 3 H). Anal. Calcd for C7H12O4: C, 52.49;
H, 7.55. Found: C, 52.48; H, 7.54.
(4S,5R)-1-(5-Hyd r oxym eth yl-2,2-d im eth yl[1,3]d ioxola n -
4-yl)-(S)-p r op en ol (8). To a cooled solution of 7 (3.68 g, 22.97
mmol) in dry tetrahydrofuran (46 mL) was added vinylmagne-
sium bromide (1 M solution in tetrahydrofuran, 68.9 mL, 68.9
mmol) at -78 °C. After the addition was completed, the mixture
was stirred at -78 °C for 1 h and allowed to stir at 0 °C for 1 h.
The reaction mixture was quenched by saturated ammonium
chloride solution and brine. The mixture was extracted with
ethyl acetate, and the extracts were dried over anhydrous
magnesium sulfate, filtered, and concentrated to dryness. The
resulting oil was purified by silica gel column chromatography
(hexanes/ethyl acetate ) 2:1) to afford 8 (4.32 g, 100%) as a single
stereoisomer: [R]D -42.2° (c 1.83, CHCl3); IR (neat) 3370, 1645
a
Reagents and conditions: (a) Ph3PCH3Br, NaH, DMSO, THF,
rt, overnight; (b) Swern oxidation; (c) CH2dCHMgBr, THF, -78
°C, 1 h; (d) Grubbs catalyst, CHCl3, rt, 2 h; (e) MnO2, CH2Cl2, rt,
15 h.
confirm the stereochemistry of the hydroxyl group of 12,
(-)-5 was reduced with sodium borohydride and cerium
chloride to give the same cyclopentenol 12, indicating ring
opening of 7 with vinylmagnesium bromide to give 8 was
totally proceeded stereospecifically.
For the synthesis of another key intermediate, (+)-5,
compound 7 was treated with methyl triphenylphospho-
nium bromide and DMSO anion to give ring-opened
product 13 in 72% yield (Scheme 4). Oxidation of the
primary alcohol with PCC followed by the treatment of
the resulting aldehyde with vinylmagnesium bromide
yielded the diene 14 as an inseparable diastereomeric
mixture (R/â ) 1/2) in 40% yield, but the production (63%)
of 14 was greatly increased by the use of Swern oxidation
instead of PCC oxidation. RCM of 14 with Grubbs
catalyst14 gave the cyclopentenol 15, which was oxidized
with MnO2 to furnish the key intermediate, (+)-5, which
1
cm-1; H NMR (CDCl3) δ 6.03 (m, 1 H), 5.36 (m, 2 H), 4.34 (m,
2 H), 4.06 (dd, J ) 6.4, 8.8 Hz, 1 H), 3.87 (m, 2 H), 2.73 (m, 2
H), 1.45 (s, 3 H), 1.37 (s, 3 H); 13C NMR (CDCl3) δ 137.68, 116.98,
108.74, 79.75, 77.47, 70.87, 60.94, 27.92, 25.44. Anal. Calcd for
C9H16O4: C, 57.43; H, 8.57. Found: C, 57.45; H, 8.59.
(1S,2R,3S)-2,2-Dim eth yl-6-vin yld ih yd r ofu r o[3,4-d ][1,3]-
d ioxol-4-on e (9a ) a n d Its Regioisom er 9b. To a stirred
solution of 8 (2.207 g, 11.73 mmol) in dry methylene chloride
(23 mL) were added 4 Å molecular sieves (5.86 g, 0.5 g/mmol),
4-methylmorpholine N-oxide (4.12 g, 35.19 mmol), and tetra-
propylammonium perruthenate (206 mg, 0.587 mmol) at 0 °C,
and the reaction mixture was stirred overnight at room tem-
perature and then diluted with methylene chloride. The result-

Notes
J . Org. Chem., Vol. 66, No. 19, 2001 6493
ing suspension was filtered through a short pad packed with
Celite and silica gel and repeatedly washed with methylene
chloride. The filtrates were concentrated, and the residue was
purified by silica gel column chromatography (hexanes/ethyl
acetate ) 8:1) to give 9a (1.421 g, 66%) and 9b (72.7 mg, 3.3%).
Compound 9a : [R]D +42.9° (c 2.38, CHCl3); IR (neat) 2993,
1792 cm-1; 1H NMR (CDCl3) δ 5.87 (m, 1 H), 5.39 (m, 2 H), 5.06
(m, 1 H), 4.74 (d, J ) 5.6 Hz, 1 H), 4.62 (d, J ) 5.6 Hz, 1 H),
1.50 (s, 3 H), 1.39 (s, 3 H); 13C NMR (CDCl3) δ 174.05, 132.78,
118.59, 114.31, 81.89, 79.51, 74.41, 27.00, 25.91. Anal. Calcd for
C9H12O4: C, 58.69; H, 6.57. Found: C, 58.67; H, 6.59. Compound
9b: 1H NMR (CDCl3) δ 6.11 (dd, J ) 10.8, 17.6 Hz, 1 H), 5.59
(dd, J ) 1.6, 17.6 Hz, 1 H), 5.39 (dd, J ) 1.6, 10.8 Hz, 1 H), 4.91
(dd, J ) 3.6, 6.0 Hz, 1 H), 4.47 (d, J ) 5.2 Hz, 1 H), 4.11-4.01
(m, 2 H), 1.48 (s, 3 H), 1.32 (s, 3 H). Anal. Calcd for C9H12O4: C,
58.69; H, 6.57. Found: C, 59.08; H, 6.76.
(1S,2R,3S)-2,2-Dim eth yl-6-vin yltetr ah ydr ofu r o[3,4-d][1,3]-
d ioxol-4-ol (10). To a stirred solution of 9a (2.35 g, 12.76 mmol)
in dry toluene (49 mL) was added diisobutylaluminum hydride
(1.0 M solution in toluene, 15.3 mL, 15.3 mmol) dropwise at -78
°C. After the addition was completed, the reaction mixture was
allowed to warm to -20 °C, stirred for 2 h, and diluted with
methanol (15.3 mL) and 50% ethyl acetate/hexanes. After the
mixture was warmed to room temperature and stirred for 2 h,
the white precipitate was removed by filtration through a pad
of Celite and washed with ethyl acetate. The filtrates were
concentrated in vacuo, and the residue was purified by silica
gel column chromatography (hexanes/ethyl acetate ) 4:1) to give
10 (1.99 g, 84%): 1H NMR (CDCl3) δ 6.01 (m, 0.8 H), 5.79 (m,
0.2 H), 5.50 (d, J ) 2.8 Hz, 0.8 H), 5.43-5.16 (m, 2.2 H), 4.70-
4.56 (m, 3 H), 3.93 (d, J ) 10.4 Hz, 0.2 H), 2.66 (d, J ) 2.8 Hz,
0.8 H), 1.59 (s, 0.6 H), 1.51 (s, 2.4 H), 1.39 (s, 0.6 H), 1.33 (s, 2.4
H). Anal. Calcd for C9H14O4: C, 58.05; H, 7.58. Found: C, 58.47;
H, 7.89.
(1S,2S,3R)-(-)-1-(2,2-Dim eth yl-5-vin yl[1,3]d ioxola n -4-yl)-
p r op -2-en -1-ol (11) a n d Its Ep im er 11b. To a suspension of
sodium hydride (518 mg, 12.96 mmol, 60% dispersion in mineral
oil) in tetrahydrofuran (10 mL) was added dimethyl sulfoxide
(1.64 mL, 23.15 mmol) at 0 °C, and the mixture was stirred for
30 min at room temperature. To this mixture was added a
suspension of methyltriphenylphosphonium bromide (4.96 g,
13.89 mmol) in tetrahydrofuran (20 mL) at 0 °C, and the reaction
mixture was stirred for 1 h at room temperature. To this reaction
mixture was added a solution of 10 (862 mg, 4.63 mmol) in
tetrahydrofuran (16 mL) at 0 °C, and the reaction mixture was
refluxed overnight. Diethyl ether was added to the mixture, and
a white solid was precipitated out. The mixture was filtered
through a short silica gel pad, washed with diethyl ether, and
evaporated. The residue was purified by silica gel column
chromatography (hexanes/ethyl acetate ) 8:1) to give 11 (742
mg, 88%) as a colorless oil.
Compound 11a : MS (FAB) m/z 185 (M + H+); [R]D -50.6° (c
3.15, CHCl3); IR (neat) 3449, 2989, 1219 cm-1; 1H NMR (CDCl3)
δ 6.05 (m, 2 H), 5.36 (m, 4 H), 4.70 (t, J ) 6.8 Hz, 1 H), 4.19 (m,
1 H), 4.04 (dd, J ) 6.8, 7.6 Hz, 1 H), 1.79 (d, J ) 4.4 Hz, 1 H),
1.50 (s, 3 H), 1.38 (s, 3 H); 13C NMR (CDCl3) δ 137.89, 134.24,
118.47, 116.63, 109.06, 80.72 78.88, 71.20, 27.80, 25.46. Anal.
Calcd for C10H16O3: C, 65.19; H, 8.75. Found: C, 65.34; H, 8.43.
Compound 11b: MS (FAB) m/z 185 (M + H+); 1H NMR (CDCl3)
δ 5.84 (m, 2 H), 5.38 (m, 2 H), 5.24 (m, 2 H), 4.40 (m, 2 H), 3.83
(dd, J ) 4.0, 8.4 Hz, 1 H), 2.21 (d, J ) 3.6 Hz, 1 H), 1.46 (s, 3 H),
1.44 (s, 3 H). Anal. Calcd for C10H16O3: C, 65.19; H, 8.75.
Found: C, 65.56; H, 8.35.
(1S,4R,5S)-4,5-O-Isop r op ylid en ecyclop en ten -1-ol (12). A
round-bottomed flask charged with the Grubbs catalyst (49.7
mg, 0.060 mmol) was pumped and filled with nitrogen gas three
times before the addition of a solution of 11 (556 mg, 3.02 mmol)
in degassed chloroform (15 mL). The resulting pink solution was
stirred at room temperature for 2 h. The solvent was removed
in vacuo, and the dark residue was purified by silica gel column
chromatography (hexanes/ethyl acetate ) 4:1) to give 12 (421
mg, 89%) as a single isomer: MS (FAB) m/z 157 (M + H+); [R]D
+15.4° (c 2.36, CHCl3); IR (neat) 3489, 2989, 1058 cm-1; 1H NMR
(CDCl3) δ 5.89 (s, 2 H), 5.02 (d, J ) 5.2 Hz, 1 H), 4.75 (t, J ) 5.2
Hz, 1 H), 4.56 (dd, J ) 5.2, 10.0 Hz, 1 H), 2.72 (d, J ) 10.0 Hz,
1 H), 1.44 (s, 3 H), 1.40 (s, 3 H); 13C NMR (CDCl3) δ 136.63,
132.13, 112.55, 83.81, 77.37, 74.38, 27.85, 26.78. Anal. Calcd for
C8H12O3: C, 61.52; H, 7.74. Found: C, 61.52; H, 7.75.
(4R,5R)-4,5-O-Isop r op ylid en e-2-cyclop en ten on e [(-)-5].
To a stirred solution of 12 (636 mg, 4.08 mmol) in methylene
chloride (20 mL) was added activated manganese oxide (3.55 g,
40.8 mmol), and the mixture was vigorously stirred for 5 h at
room temperature. The resultant mixture was filtered through
a pad of Celite, washed with methylene chloride. The filtrates
were concentrated in vacuo, and the residue was purified by
silica gel column chromatography (hexanes/ethyl acetate ) 4:1)
to afford (-)-5 (520 mg, 83%) as a white crystal: mp 68.6-70.1
°C; MS (FAB) m/z 155 (M + H+); [R]D -70.4° [lit.13c [R]D -70.8°
(c 0.92, CHCl3)]; IR (neat) 2935, 1718, 1585 cm-1 1H NMR
;
(CDCl3) δ 7.61 (dd, J ) 2.4, 6.0 Hz, 1 H), 6.22 (d, J ) 6.0 Hz, 1
H), 5.277 (dd, J ) 2.4, 5.6 Hz, 1 H), 4.47 (d, J ) 5.6 Hz, 1 H),
1.42 (s, 3 H), 1.41 (s, 3 H); 13C NMR (CDCl3) δ 203.17, 159.82,
134.50, 115.70, 78.78, 76.69, 27.60, 26.33. Anal. Calcd for
C10H10O3: C, 62.33; H, 6.54. Found: C, 62.56; H, 6.35.
(4R,5S)-(2,2-Dim et h yl-5-vin yl[1,3]d ioxola n -4-yl)m et h a -
n ol (13). To a suspension of sodium hydride (628 mg, 15.68
mmol, 60% dispersion in mineral oil) in tetrahydrofuran (10 mL)
was added dimethyl sulfoxide (2.0 mL, 28.0 mmol) at 0 °C. After
being stirred for 30 min at room temperature, the mixture was
transferred to a suspension of methyltriphenylphosphonium
bromide (6.00 g, 16.8 mmol) in tetrahydrofuran (35 mL) at 0
°C, and the mixture was stirred for 1 h at room temperature.
To this reaction mixture was added a solution of 6 (897 mg, 5.60
mmol) in tetrahydrofuran (11 mL) at 0 °C, and the reaction
mixture was stirred at room temperature overnight. Diethyl
ether was added to the mixture, and a white solid precipitated
out. The mixture was filtered through a short silica gel pad,
washed with diethyl ether, and evaporated. The residue was
purified by silica gel column chromatography (hexanes/ethyl
acetate ) 8:1) to give alcohol 13 (661 mg, 75%) as a colorless
oil: [R]D +38.0° (c 1.49, CHCl3); IR (neat) 3464, 2989, 1645 cm-1
;
1H NMR (CDCl3) δ 5.88 (m, 1 H), 5.35 (m, 2 H), 4.66 (t, J ) 7.2
Hz, 1 H), 4.27 (q, J ) 6.4 Hz, 1 H), 3.59 (dd, J ) 5.2, 6.4 Hz, 1
H), 1.88 (t, J ) 5.2 Hz, 1 H), 1.52 (s, 3 H), 1.40 (s, 3 H); 13C
NMR (CDCl3) δ 133.21, 119.11, 109.07, 78.50, 78.47, 62.22, 27.97,
25.41. Anal. Calcd for C8H14O3: C, 60.74; H, 8.92. Found: C,
60.90; H, 8.65.
(4R,5S)-1-(2,2-Dim eth yl-5-vin yl[1,3]d ioxola n -4-yl)p r op -
2-en -1-ol (14). To a stirred solution of oxalyl chloride (0.25 mL,
2.88 mmol) in dry methylene chloride (10 mL) was added
dimethyl sulfoxide (0.40 mL, 5.76 mmol) at -78 °C, and the
mixture was stirred at -78 °C for 15 min. To this mixture was
added a solution of 13 (228 mg, 1.44 mmol) in methylene chloride
(4.5 mL), and the reaction mixture was stirred at -78 °C for 1
h. After the addition of triethylamine (1.20 mL, 8.64 mmol), the
mixture was gradually warmed to room temperature. The
reaction mixture was quenched with water and then extracted
with methylene chloride twice. The combined organic layers were
washed with brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated to dryness to give the aldehyde, which
was used in the next step without further purification. To a
stirred solution of crude aldehyde in tetrahydrofuran (11 mL)
was added vinylmagnesium bromide (1 M solution in tetrahy-
drofuran, 2.90 mL, 2.90 mmol) at -78 °C, and the reaction
mixture was stirred at -78 °C for 1 h. After the mixture was
allowed to warm to room temperature, the mixture was quenched
with saturated ammonium chloride solution and brine, extracted
with ethyl acetate, dried over anhydrous magnesium sulfate,
filtered, concentrated to dryness. The resulting oil was purified
by silica gel column chromatography (hexanes/ethyl acetate )
7:1) to give 14 (167 mg, 63%) as an inseparable mixture: MS
1
(FAB) m/z 185 (M + H+); H NMR (CDCl3) δ 6.05 (m, 1.34 H),
5.86 (m, 0.66 H), 5.35 (m, 4 H), 4.70 (t, J ) 6.8 Hz, 0.33 H), 4.61
(dd, J ) 6.8, 7.6 Hz, 0.67 H), 4.11 (m, 2 H), 2.33 (d, J ) 5.6 Hz,
0.67 H), 1.84 (d, J ) 4.4 Hz, 0.33 H), 1.54 (s, 2 H), 1.50 (s, 1 H),
1.40 (s, 2 H), 1.38 (s, 1 H). Anal. Calcd for C10H16O3: C, 65.19;
H, 8.75. Found: C, 64.88; H, 8.94.
(4S,5R)-4,5-O-Isop r op ylid en ecyclop en t en -1-ol (15). A
round-bottomed flask charged with the Grubbs catalyst (12.5
mg, 0.015 mmol) was pumped and filled with nitrogen gas three
times before the addition of a solution of 14 (560 mg, 3.04 mmol)
in degassed chloroform (30.4 mL) and the resulting pink solution
was stirred at room temperature for 4 h. The solvent was

6494 J . Org. Chem., Vol. 66, No. 19, 2001
Notes
removed in vacuo and the dark residue was purified by silica
gel column chromatography (hexanes/ethyl acetate ) 4:1) to give
R-alcohol (122.0 mg, 25.7%) and â-alcohol (243.6 mg, 51.3%) of
15.
concentrated in vacuo, and the residue was purified by silica
gel column chromatography (hexanes/ethyl acetate ) 4:1) to
afford (+)-5 (365.0 mg, 81%) as a white crystal: mp 68.7-69.8
°C (lit.13b mp 68-69 °C); MS (FAB) m/z 155 (M + H+); [R]D +69.1°
(c 1.98, CHCl3) [lit.13b [R]D +70.0° (c 0.92, CHCl3)]; IR (neat) 2936,
R-Alcohol of 15: MS (FAB) m/z 157 (M + H+);1H NMR (CDCl3)
δ 5.89 (s, 2 H), 5.02 (d, J ) 5.2 Hz, 1 H), 4.75 (t, J ) 5.2 Hz, 1
H), 4.56 (dd, J ) 5.2, 10.0 Hz, 1 H), 2.72 (d, J ) 10.0 Hz, 1 H),
1.44 (s, 3 H), 1.40 (s, 3 H). Anal. Calcd for C8H12O3: C, 61.52;
H, 7.74. Found: C, 61.65; H, 7.43.
1
1719, 1585 cm-1; H NMR (CDCl3) δ 7.62 (dd, J ) 2.4, 6.0 Hz,
1 H), 6.22 (d, J ) 6.0 Hz, 1 H), 5.28 (dd, J ) 2.4, 5.6 Hz, 1 H),
4.47 (d, J ) 5.6 Hz, 1 H), 1.42 (s, 3 H), 1.41 (s, 3 H); 13C NMR
(CDCl3) δ 203.17, 159.83, 134.49, 115.69, 78.78, 76.69, 27.59,
26.33. Anal. Calcd for C8H10O3: C, 62.33; H, 6.54. Found: C,
62.34; H, 6.54.
â-Alcohol of 15: MS (FAB) m/z 157 (M + H+); IR (neat) 3399,
2989, 1041 cm-1; 1H NMR (CDCl3) δ 6.03 (bd, J ) 5.6 Hz, 1 H),
5.91 (dt, J ) 1.0, 6.0 Hz, 1H), 5.29 (m, 1 H), 4.80 (bd, J ) 4.4
Hz, 1 H), 4.52 (d, J ) 5.6 Hz, 1 H), 1.96 (br s, 1 H), 1.40 (s, 3 H),
1.35 (s, 3 H); 13C NMR (CDCl3) δ 135.88, 134.81, 111.93, 86.12,
84.47, 81.23, 27.53, 25.93. Anal. Calcd for C8H12O3: C, 61.52;
H, 7.74. Found: C, 60.96; H, 7.86.
Ack n ow led gm en t. This research was supported by
a grant from the Korea Science and Engineering Foun-
dation (KOSEF 1999-2-21500-001-3).
(4S,5S)-4,5-O-Isop r op ylid en e-2-cyclop en ten on e [(+)-5].
To a stirred solution of 15 (455 mg, 2.9 mmol) in methylene
chloride (30 mL) was added activated manganese oxide (2.52 g,
29.0 mmol), and the mixture was vigorously stirred at room
temperature overnight. The mixture was filtered through a pad
of Celite and washed with methylene chloride. The filtrates were
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 11a , 12, 14, and 15a . This material is
available free of charge via the Internet at http://pubs.acs.org.
J O015733W