Synthesis of a core carbon framework of cyanosporasides A and B

Article abstract of DOI:10.1021/jo901141t

(Chemical Equation Presented) Treatment of 3-(2-ethynylphenyl)prop-2-ynyl benzenesulfinate with 2.5 mol % of [RhCl(CO)₂]₂ at 40°C under an atmosphere of CO effected the successive 2,3-sigmatropic rearrangement and carbonylative [2 +

Full text of DOI:10.1021/jo901141t

pubs.acs.org/joc
Synthesis of a Core Carbon Framework of Cyanosporasides A and B
Daisuke Aburano, Fuyuhiko Inagaki, Shoichirou Tomonaga, and Chisato Mukai*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa
University, Kakuma-machi, Kanazawa 920-1192, Japan
cmukai@kenroku.kanazawa-u.ac.jp
Received May 28, 2009
Treatment of 3-(2-ethynylphenyl)prop-2-ynyl benzenesulfinate with 2.5 mol % of [RhCl(CO)2]2 at
40 °C under an atmosphere of CO effected the successive 2,3-sigmatropic rearrangement and
carbonylative [2 þ 2 þ 1] ring-closing reaction to afford the 8-(phenylsulfonyl)-1H-cyclopent[a]-
inden-2-one in a high yield. Chemical modification of the ring-closed product via lipase-mediated
optical resolution produced the optically active 3-acetoxy-3a-cyclohexyloxy-3,3a-dihydrocyclopent-
[a]indene skeleton, the core carbon framework of cyanosporasides A and B.
Introduction
In 2006, Fenical and co-workers1 reported the isolation of
two structurally novel cyclopent[a]indene glycosides, cya-
nosporasides A (1) and B (2), from Salinispora pacifica
collected at a depth of 500 m in Palau. Cyanosporides A
(1) and B (2) have an intriguing novel common structural
feature with the 3,3a-dihydrocyclopent[a]indene carbon fra-
mework as the aglycon moiety as well as a novel 30-oxo-40-
methyl-β-fucopyranose as the sugar part. Their biological
activity is still uncertain except for the weak cytotoxicity of
1 against human colon carcinoma HCT-116.
FIGURE 1. Structure of cyanosporasides.
leading to the efficient formation of bicyclo[m.3.0] skeletons
(m=4-6) (Scheme 1). As an extension of our work in this field,
we have focused on the synthesis of the carbon framework 3 of
cyanosporasides A (1) and B (2) by taking advantage of the
Rh(I)-catalyzed carbonylative [2 þ 2 þ 1] ring-closing reaction
of phenylsulfonylallenynes.
We have recently been involved in the investigation of the
[RhCl(CO)2]2- or [RhCl(CO)dppp]2-catalyzed intramolecu-
lar carbonylative [2 þ 2 þ 1] ring-closing reaction (Pauson-
Khand-type reaction) of phenylsulfonylallenynes,2 phenylsul-
fonylallenenes,3 and bis(phenylsulfonylallene) derivatives4
*To whom correspondence should be addressed. Tel: þ81-76-234-4411.
Fax: þ81-76-234-4410.
Results and Discussion
(1) Oh, D.-C.; Williams, P. G.; Kauffman, C. A.; Jensen, P. R.; Fenical,
W. Org. Lett. 2006, 8, 1021–1024.
A year before the isolation of 1 and 2, Liu and Datta5
developed the efficient synthesis (82%) of 1H-cyclopent[a]-
inden-2-one (5) from 1-ethynyl-2-(1,2-propadienyl)benzene
(4) through the Mo(CO)3(MeCN)3-mediated carbonylative
[2þ2þ1] ring-closing reaction at 25 °C in a stoichiometric
manner. They also reported the catalytic version of that
transformation in the presence of 5 mol % of [RhCl(CO)2]2
(2) (a) Mukai, C.; Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett.
2002, 4, 1755–1758. (b) Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem.
2003, 68, 1376–1385. (c) Mukai, C.; Inagaki, F.; Yoshida, T.; Kitagaki, S.
Tetrahedron Lett. 2004, 45, 4117–4121. (d) Mukai, C.; Inagaki, F.; Yoshida,
T.; Yoshitani, K.; Hara, Y.; Kitagaki, S. J. Org. Chem. 2005, 70, 7159–7171.
(e) Mukai, C.; Hirose, T.; Teramoto, S.; Kitagaki, S. Tetrahedron 2005, 61,
10983–10994. (f) Inagaki, F.; Kawamura, T.; Mukai, C. Tetrahedron 2007,
63, 5154–5160.
(3) Inagaki, F.; Mukai, C. Org. Lett. 2006, 8, 1217–1220.
(4) Inagaki, F.; Narita, S.; Hasegawa, T.; Kitagaki, S.; Mukai, C. Angew.
Chem., Int. Ed. 2009, 48, 2007–2011.
(5) Datta, S.; Liu, R.-S. Tetrahedron Lett. 2005, 46, 7985–7988.
5590 J. Org. Chem. 2009, 74, 5590–5594
Published on Web 06/26/2009
DOI: 10.1021/jo901141t
r
2009 American Chemical Society

Aburano et al.
JOCArticle
SCHEME 1. Rh(I)-Catalyzed Pauson-Khand-Type Reaction
of Allenes
SCHEME 3. Preparation of 9
SCHEME 2. Carbonylative Ring-Closing Reaction of Allenyne
4
SCHEME 4. Attempt at Conversion of 5 into 13
at 90 °C to furnish 5 in 62% yield along with the byproduc-
tion of 2-methylnaphthalene (8%), the latter of which should
arise from the Myers-Saito cycloaromatization6 of 4. They
claimed that a low reaction temperature is required to avoid the
formation of the undesired 2-methylnaphthalene (Scheme 2).
Thus, this investigation began in order to develop the
catalytic procedure for the preparation of the 1H-cyclopent
[a]inden-2-one derivatives without production of 2-methyl-
naphthalene. According to the previously established met
hod,2e the propargyl alcohol derivative 6 was treated with
benzenesulfinyl chloride at -78 °C to afford the correspond-
ing sulfinate 7 in a quantitative yield, subsequent exposure of
which to 2.5 mol % of [RhCl(CO)2]2 in toluene at 40 °C
under an atmosphere of CO for 10 h effected the successive
2,3-sigmatropic rearrangement and carbonylative [2 þ 2 þ 1]
ring-closing reaction of the resulting allenyne species 8 to
provide 8-(phenylsulfonyl)-1H-cyclopent[a]inden-2-one (9)
in 81% yield. The formation of 2-methylnaphthalene could
not be detected in the reaction mixture (Scheme 3).
The catalytic preparation of the 1H-cyclopent[a]inden-2-
one skeleton was realized, but the phenylsulfonyl group of 9
might not be essential for the synthesis of the target com-
pound 3. The simpler 1H-cyclopent[a]inden-2-one (5)5
seemed to be the better substrate for conversion into the 3.
Therefore, the chemical modification of compound 5 was
first examined. Reduction of 5 with NaBH4 in the presence of
CeCl3 afforded the allyl alcohol 10 in 78% yield, which was
then oxidized with m-CPBA to produce the epoxy derivative
11 in 49% yield. The two trisubstituted olefin moieties of
10 with a similar reactivity might contribute to the moderate
chemical yield of 11. The Lewis acid-catalyzed ring-opening
of an epoxy group7 of 11 in the presence of cyclohexanol
unexpectedly furnished 2-hydroxy-1,2,3,8-tetrahydrocyclo-
pent[a]inden-3-one (12) in 83% yield. Although various
conditions were screened, the desired cis-diol derivative 13
could not be obtained. The formation of 12 can tentatively be
rationalized in terms of the intermediacy of the benzylic
cation species 14a (R = H) followed by hydride transfer8 as
shown in Scheme 4.
We assumed that the two olefin parts of 8-(phenylsulfo-
nyl)-1H-cyclopent[a]inden-2-one (9) might be differentiated
during epoxidation reaction, because one of them has an
electron-withdrawing group, whereas the other does not. In
addition, the phenylsulfonyl group of 9 would be expected to
indirectly suppress the generation of the benzylic cation
species (e.g., 14b). As a result, the stereoselective SN2-type
ring-opening of the epoxy group at the benzylic position may
dominate over the hydride transfer reaction via the benzylic
cation species 14b. Based on these expectations, we tried to
convert 9 into the cis-diol derivatives 17 (Scheme 5). Treat-
ment of 9 with NaBH4 provided the allyl alcohol derivative
15, which was exposed to m-CPBA to give the desired 16 in
83% yield in a highly stereoselctive manner. The highly
stereo- and regioselective ring-opening of the epoxy group7
of 16 was realized by the reaction of cyclohexanol in the
presence of BF3 OEt2 in methylene chloride at 0 °C to
3
furnish 17a in 70% yield. Other alcohols such as allyl
alcohol, propargyl alcohol, and methanol also served as
good nucleophiles to produce the corresponding diol deri-
vatives 17b-d in satisfactory yields, the RO groups of which
(6) Myers, A. G. Tetrahedron Lett. 1987, 28, 4493–4496. (b) Myers, A. G.;
Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989, 111, 8057–8059. (c)
Nagata, R.; Yamanaka, H.; Okazaki, E.; Saito, I. Tetrahedron Lett. 1989, 30,
4995–4998. (d) Nagata, R.; Yamanaka, H.; Murahashi, E.; Saito, I. Tetra-
hedron Lett. 1990, 31, 2907–2910. (e) Myers, A. G.; Dragovich, P. S.; Kuo,
E. Y. J. Am. Chem. Soc. 1992, 114, 9369–9386.
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438. (b) Costantino, P.;Crotti, P.;Ferretti, M.; Macchia, F.J. Org. Chem. 1982,
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2191–2194. (d) Demyttenaere, J.; Vervisch, S.; Debenedetti, S.; Coussio, J.;
(8) (a) Kita, Y.; Yoshida, Y.; Kitagaki, S.; Mihara, S.; Fang, D.-F.;
Furukawa, A.; Higuchi, K.; Fujioka, H. Tetrahedron 1999, 55, 4979–4998.
(b) Fehr, C.; Galindo, J. Angew. Chem., Int. Ed. 2000, 39, 569–573. (c) Kasal,
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A. Tetrahedron 2000, 56, 3559–3565. (d) Kasal, A.; Matyas, L.; Budesı
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ꢁꢁ
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J. Org. Chem. Vol. 74, No. 15, 2009 5591

Aburano et al.
JOCArticle
SCHEME 5. Synthesis of Diol Derivatives 17 from 9
SCHEME 6. Synthesis of 3,3a-Dihydrocyclopent[a]indene 20
from 17a
would be converted to a hydroxyl functionality in a later
manipulation.
With the required diol derivatives 17 in hand, a further
elaboration was carried out using the cyclohexyloxy deriva-
tive 17a (Scheme 6). Acetylation of the diol group under the
standard conditions afforded the diacetoxy derivative 18 in
84% yield. The phenylsulfonyl group of 18 was removed by
exposure to radical conditions9 with nBu3SnH in the presence
of AIBN, followed by acid treatment to provide 19 in 66%
yield. The introduction of a double bond between C1and C2
remains prior to completion of the preparation of the target
structure. Upon treatment with DBU in DMF at 140 °C,
compound 19 underwent an E2-type elimination to produce
the desired 20, but the chemical yield was rather low (24%).
A more powerful leaving group instead of an acetoxy group
would improve the chemical yield. Thus, a multistep con-
version of 19 into 20 with a higher overall yield was devel-
oped. Compound 19 was treated with K2CO3, and the
resulting diol derivative was subsequently monotosylated
with TsCl and nBu2SnO10 to provide 21 in 86% yield. DBU
treatment of an acetyl derivative, derived from 21, effected
E2-type elimination resulting in the easy formation of 20 in
78% yield.
SCHEME 7. Synthesis of (-)-16
As the carbon framework 20 of 1 and 2 could be synthe-
sized in a racemic form, the next objective was the prepara-
tion of the optically active 20 (Scheme 7). Although the
asymmetric reduction of 9 was examined under several con-
ditions such as CBS reduction,11 Noyori’s asymmetric hydro-
gen transfer reaction,12 BINAL reduction,13 and Baker’s yeast
reduction,14 and so on, all efforts led to fruitless results. We
next attempted the lipase-mediated optical resolution of the
alcohol derivative 15. After screening various conditions,
treatment of the racemic 15 with lipase AK Amano (Pseudo-
monas fluorescens)15 in isobutyl methyl ketone in the presence
of vinyl acetate as an acetyl donor at 60 °C provided the best
result by producing the chiral acetoxy derivative 2216 in 43%
yield (67% ee) together with recovery of the chiral1516 in 31%
yield (82% ee). In addition to the unsatisfied ee values of both
compounds 15 and 22, a fairly easy racemization of the chiral
15 (83% ee to 50% ee) was observed during its storage for a
short time, although the mechanism for the racemization is
still uncertain (Scheme 7).
Finally the epoxy alcohol derivative 16 was found to be a
suitable substrate for the optical resolution method
(Scheme 7). Indeed, the racemic 16 was exposed to lipase
AK Amano (P. fluorescens)15 in toluene at 60 °C in the
presence of vinyl acetate to afford (-)-23 in 43% yield (95%
ee) together with (þ)-16 in 44% yield (g99% ee). The
absolute stereochemistry of (þ)-16 was determined by ap-
plication of the modified Mosher method.17 Calculation of
(9) (a) Watanabe, Y.; Ueno, Y.; Araki, T.; Endo, T.; Okawara, M.
Tetrahedon Lett. 1986, 27, 215–218. (b) Bew, S. P.; Sweeney, J. B. Synthesis
1994, 698. (c) Aboutayab, K.; Caddick, S.; Jenkins, K.; Joshi, S.; Khan, S.
Tetrahedron 1996, 52, 11329–11340.
(10) (a) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447–450. (b) Martinelli,
M. J.; Vaidyanathan, R.; Khau, V. V. Tetrahedron Lett. 2000, 41, 3773–3776.
(11) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986–2012.
(12) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 7562–7563. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521–
2522.
(13) Noyori, R. Pure Appl. Chem. 1981, 53, 2315–2322.
€
(14) Csuk, R.; Glanzer, B. I. Chem. Rev. 1991, 91, 49–97.
(15) (a) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T. J. Org. Chem.
(16) The absolute stereochemistry was not determined. The stereochem-
istry described in Scheme 7 was deduced on the basis of the precedents.15
(17) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
(b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092–4096.
ꢀ
1999, 64, 4914–4919. (b) Arrayas, R. G.; Alcudia, A.; Liebeskind, L. S. Org.
Lett. 2001, 3, 3381–3383. (c) Taber, D. F.; Reddy, P. G.; Arneson, K. O.
J. Org. Chem. 2008, 73, 3467–3474.
5592 J. Org. Chem. Vol. 74, No. 15, 2009

Aburano et al.
JOCArticle
the value [Δδ = δ(S) - δ(R)] of the (S)- and (R)-MTPA
esters,18 derived from (þ)-16, in their 1H NMR spectra,
confirmed its absolute stereochemistry as shown in Scheme 7.
Thus, compound (-)-23 possessing the required absolute
stereochemistry was then hydrolyzed with lipase PS Amano
SD (Burkholderia cepacia)19 in a mixed solution of acetone
and pH 7.0 buffer at 45 °C to furnish (-)-16 in 90% yield.
According to the procedures described in Schemes 5 and 6, the
optically active alcohol (-)-16 was converted into (þ)-17a,
which was subsequently transformed into the final target
molecule (þ)-20 through (þ)-18, (þ)-19, and (þ)-21, in turn.
In summary, we have synthesized a 3,3a-dioxygenated-
3,3a-dihydrocyclopent[a]indene skeleton, the core carbon
framework of cyanosporasides A and B, in an optically
active form. The most significant feature of this synthesis
involves the previously developed Rh(I)-catalyzed carbony-
lative ring-closing reaction of an allenyne as the key step.
Further studies regarding the total synthesis of cyanospora-
sides A and B are now in progress.
3.66 (dd, 1H, J=19.9, 5.7 Hz), 2.87 (dd, 1H, J = 19.9, 1.3 Hz),
2.14 (d, 1H, J=7.8 Hz); 13C NMR δ 159.5, 148.3, 143.8, 141.7,
140.8, 133.4, 129.6, 129.3, 128.9, 128.8, 127.1, 125.5, 123.4, 120.8,
81.4, 36.1; MS m/z 310 (Mþ, 29.3); HRMS calcd for C18H14O3S
310.0664, found 310.0666.
(2R*,3R*,3aS*)-3,3a-Epoxy-8-(phenylsulfonyl)-1,2,3,3a-tet-
rahydorocyclopent[a]inden-2-ol (16). To a solutionof 15 (220 mg,
0.710 mmol) in CH2Cl2 (7 mL) was added m-CPBA (244 mg,
1.42 mmol) at 0 °C. After being stirred for 3 h at the same
temperature, the reaction mixture was warmed to room tempera-
ture and then stirred for 10 h. The mixture was quenched by
addition of saturated aqueous NaHCO3 and Na2S2O3 and ex-
tracted with CH2Cl2. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was
chromatographed with hexane-Et2O (2:1) to afford 16 (192 mg,
83%) as a pale yellow foam: IR3587, 1321, 1151 cm-1; 1H NMR δ
8.02-8.00 (m, 2H), 7.72 (d, 1H, J=7.8 Hz), 7.64-7.60 (m, 1H),
7.56-7.53 (m, 2H), 7.40-7.36 (m, 1H) 7.27-7.26 (m, 1H), 7.24-
7.21 (m, 1H), 4.60-4.54 (m, 1H), 4.34 (d, 1H, J=1.7 Hz), 3.65 (dd,
1H, J=17.2, 7.4 Hz), 2.49 (dd, 1H, J=17.2, 6.8 Hz), 2.43 (d, 1H,
J=9.8 Hz); 13C NMR δ 157.4, 140.7, 140.3, 134.7, 134.0, 133.8,
130.0, 129.4, 127.4, 126.5, 122.7, 122.2, 75.6, 73.1, 64.8, 30.4; MS
m/z 326 (Mþ, 16.6); HRMS calcd for C18H14O4S 326.0613, found
326.0615.
Experimental Section
3-(2-Ethynylphenyl)prop-2-ynyl Benzenesulfinate (7). To a
solution of 6 (500 mg, 3.20 mmol) and Pr2NEt (1.67 mL, 9.90
i
General Procedure for Ring-Opening of Epoxide with Alco-
hols. To a solution of epoxide 16 (16.3 mg, 0.0500 mmol) and
alcohol (0.50 mmol) in CH2Cl2 (0.5 mL) was added BF3 OEt2
mmol) in THF (25 mL) was added PhS(O)Cl(566mg, 3.52mmol)
in THF (5 mL) at -78 °C. The reaction mixture was stirred for
1 h, quenched by addition of water, and extracted with AcOEt.
The extract was washed with water and brine, dried, and con-
centrated to dryness. The residue was chromatographed with
hexane-AcOEt (5:1) to afford 7 (905 mg, quant) as a pale yellow
3
(0.019 mL, 0.15 mmol) at 0 °C. The reaction mixture was stirred
at room temperature until the complete disappearance of the
starting material (monitored by TLC), quenched by addition of
saturated aqueous NaHCO3, and extracted with CH2Cl2. The
extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was chromatographed with
hexane-AcOEt to afford diol 17. Chemical yields of 17 are
summarized in Scheme 5.
1
oil: IR 3308, 1479, 1445 cm-1; H NMR δ 7.81-7.79 (m, 2H),
7.56-7.48 (m, 4H), 7.40 (dt, 1H, J=9.4, 3.8 Hz), 7.31-7.27 (m,
2H), 4.91 (d, 1H, J=15.8 Hz), 4.64 (d, 1H, J=15.8 Hz), 3.28 (s,
1H); 13C NMR δ 144.3, 132.6, 132.4, 132.2, 129.1, 128.5, 128.4,
125.4, 124.9, 124.8, 86.8, 86.1, 81.7, 81.3, 52.8; MS m/z 280 (Mþ,
48.5); HRMS calcd for C17H12O2S 280.0558, found 280.0557.
8-(Phenylsulfonyl)-1H-cyclopent[a]inden-2-one (9). To a solu-
tion of 7 (905 mg, 3.23 mmol) in toluene (30 mL) was added
[RhCl(CO)2]2 (31.4 mg, 8.08ꢀ10-3 mmol) at room temperature.
The reaction mixture was stirred at room temperature under CO
atmosphere for 4 h. The reaction mixture was concentrated and
chromatographed with hexane-AcOEt (8:1) to afford 9 (810
mg, 81%) as yellow needles: mp 186-187 °C (AcOEt); IR 1720,
1607, 1323 cm-1; 1H NMR δ 8.04 (d, 2H, J=8.3 Hz), 7.68-7.55
(m, 5H), 7.43 (t, 1H, J=7.7 Hz), 7.26-7.25 (m, 1H), 6.76 (s, 1H),
3.45 (s, 2H); 13C NMR δ 203.9, 167.4, 150.1, 141.9, 140.6, 134.0.
133.6, 132.8, 129.6, 129.5, 129.3, 127.5, 126.9, 126.0, 121.9, 35.8;
MS m/z 308 (Mþ, 57.9). Anal. Calcd for C18H12O3S: C, 70.11; H,
3.92. Found: C, 69.99, H, 3.97.
(2R*,3R*,3aR*)-3a-Cyclohexyloxy-8-(phenylsulfonyl)-1,2,3,3a-
tetrahydrocyclopent[a]indene-2,3-diol (17a): pale yellow foam; IR
1
3568, 3367, 1319, 1150 cm-1; H NMR δ 7.98-7.96 (m, 2H),
7.58-7.54 (m, 2H), 7.50-7.47 (m, 2H), 7.40 (d, 1H, J=7.3 Hz),
7.31-7.28(m, 1H), 7.23-7.19(m, 1H), 5.13-5.08 (m, 1H), 4.21 (d,
1H, J=2.9 Hz), 3.34 (dd, 1H, J=19.0, 9.8 Hz), 2.91 (dd, 1H, J=
19.0, 5.6 Hz), 2.83-2.77 (m, 1H), 2.74 (d, 1H, J=8.5 Hz), 1.87 (s,
1H), 1.60-1.53 (m, 3H), 1.33-0.90 (m, 7H); 13C NMR δ 164.4,
141.1, 140.8, 139.8, 136.3, 133.6, 129.8, 129.2, 127.0, 126.8,
124.5, 121.6, 96.8, 77.2, 75.3, 73.8, 34.2, 34.1, 33.2, 25.2, 24.0,
23.9; MS m/z 426 (Mþ, 2.7); HRMS calcd for C24H26O5S
426.1501, found 426.1504. (þ)-(2S,3S,3aS)-17a: [R]22Dþ24.2 (c=
0.47, CHCl3).
(2R*,3R*,3aR*)-3a-Cyclohexyloxy-8-(phenysulfonyl)-1,2,3,3a-
tetrahydrocyclopent[a]indene-2,3-diylDiacetate(18).Toasolution
of 17a (44.0 mg, 0.103 mmol), pyridine (0.1 mL), and DMAP
(1.3 mg, 0.010 mmol) in CH2Cl2 (1 mL) was added Ac2O (0.032
mL, 0.31 mmol)at 0 °C. The reactionmixturewas stirred for1 hat
room temperature, quenched by addition of 10% aqueous HCl,
and extracted with CH2Cl2. The extract was washed with water
and brine, dried, and concentrated to dryness. The residue was
chromatographed with hexane-AcOEt (4:1) to afford 18 (43.9
mg, 84%) as colorless needles: mp 145-145.5 °C (hexane-
CH2Cl2); IR 1749, 1321, 1147 cm-1; 1H NMR δ 8.03-8.01 (m,
2H), 7.62-7.51 (m, 4H), 7.34-7.27 (m, 2H), 7.17 (t, 1H, J=7.6
Hz), 6.03-5.99 (m, 1H), 5.63 (d, 1H, J=4.4 Hz), 3.47 (dd, 1H, J=
19.1, 10.0 Hz), 3.09 (dd, 1H, J=19.1, 6.5 Hz), 2.81-2.77 (m, 1H),
2.05 (s, 3H), 1.62-1.51 (m, 3H), 1.35 (s, 3H), 1.33-1.22 (m, 4H),
1.15-0.89 (m, 3H); 13C NMR δ 169.6, 169.0, 162.1, 140.8, 140.2,
139.2, 136.9, 133.7, 129.8, 129.2, 127.2, 126.9, 125.5, 121.3, 95.4,
76.8, 74.2, 74.1, 34.2, 33.9, 30.2, 25.1, 23.9, 23.8, 20.6, 19.9; MS m/z
510 (Mþ, 8.3); HRMS calcd for C28H30O7S 510.1712, found
510.1708. (þ)-(2S,3S,3aS)-18: [R]23Dþ3.5 (c=0.68, CHCl3).
8-(Phenylsulfonyl)-1,2-dihydrocyclopent[a]inden-2-ol (15). To
a solution of 9 (120 mg, 0.390 mmol) in THF (4 mL) was added
a mixture of NaBH4 (37.1 mg, 0.975 mmol) and CeCl3 7H2O
3
(400 mg, 1.05 mmol) in MeOH (2 mL) at 0 °C. The reaction
mixture was stirred for 3 h, quenched by addition of water, and
extracted with AcOEt. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was
chromatographed with hexane-Et2O (1:2) to afford 15 (77.7
mg, 64%) as yellow plates: mp 190-191 °C (CH2Cl2); IR 3587,
1317, 1151 cm-1; 1H NMR δ 8.03-8.01 (m, 2H), 7.65 (d, 1H, J=
7.8 Hz), 7.60-7.56 (m, 2H), 7.53-7.50 (m, 2H), 7.34-7.31 (m, 1H),
7.21-7.18 (m, 1H), 6.97 (d, 1H, J=2.4 Hz), 5.48-5.45 (m, 1H),
(18) See the Supporting Information.
(19) (a) Bonomi, P.; Cairoli, P.; Ubiali, D.; Morelli, C. F.; Filice, M.;
Nieto, I.; Pregnolato, M.; Manitto, P.; Terreni, M.; Speranza, G. Tetrahe-
dron: Asymmetry 2009, 20, 467–472. (b) Brem, J.; Paizs, C.; Tos-a, M. I.; Vass,
E.; Irimie, F. D. Tetrahedron: Asymmetry 2009, 20, 489–496.
J. Org. Chem. Vol. 74, No. 15, 2009 5593

Aburano et al.
JOCArticle
(2R*,3R*,3aS*)-3a-Cyclohexyloxy-1,2,3,3a-tetrahydrocyclo-
pent[a]indene-2,3-diyl Diacetate (19). To a solution of 18 (30.0 mg,
0.0588 mmol) in benzene (1 mL) were successively added nBu3SnH
(51 mg, 0.18 mmol) and AIBN (2.2 mg, 0.018 mmol) at room
temperature. After being refluxed for 10 h, the reaction mixture was
allowed to cool to room temperature, and 10% aqueous HCl was
added. The reaction mixture was stirred for 14 h, quenched by
addition of saturated aqueous NaHCO3, and extracted with AcOEt.
The extract was washed with water and brine dried and concentrated
to dryness. The residue was chromatographed with hexane-AcOEt
(6:1) to afford 19 (14.4 mg, 66%) as a colorless oil: IR 1741 cm-1; 1H
NMR δ 7.31 (d, 1H, J=7.3 Hz), 7.23-7.20 (m, 1H), 7.11 (d, 1H,
J=7.3 Hz), 7.10-7.06 (m, 1H), 6.46 (s, 1H), 5.94 (ddd, 1H, J=10.3,
5.7, 4.6 Hz), 5.60 (d, 1H, J=4.6 Hz), 3.19 (ddd, 1H, J=17.0, 10.3, 2.4
Hz), 2.95-2.90 (m, 1H), 2.41 (dd, 1H, J=17.0, 5.7 Hz), 2.02 (s, 3H),
1.64-1.61 (m, 2H), 1.60 (s, 3H), 1.58-1.53 (m, 1H), 1.37-1.29 (m,
3H), 1.17-1.09 (m, 3H), 1.01-0.93 (m, 1H); 13C NMR δ 169.8,
169.7, 150.1, 146.7, 141.0, 128.9, 127.4, 125.1, 124.9, 120.8, 95.7, 77.8,
74.0, 73.0, 34.2, 34.1, 29.4, 25.4, 24.1, 24.0, 20.7, 20.3; MS m/z 370
(Mþ, 16.9); HRMS calcd for C22H26O5 370.1780, found 370.1780.
(þ)-(2S,3S,3aR)-19: [R]23Dþ43.7 (c=0.26, CHCl3).
The residue was chromatographed with hexane-AcOEt (6:1) to
afford 20 (2.9 mg, 78%) as colorless needles: mp 95-97 °C
1
(hexane); IR 1736 cm-1; H NMR δ 7.38 (d, 1H, J=7.3 Hz),
7.28-7.20 (m, 2H), 7.12 (t, 1H, J=7.3 Hz), 6.79 (d, 1H, J=5.6
Hz), 6.54 (dd, 1H, J=5.6, 2.5Hz), 6.51 (s, 1H), 5.71(d, 1H, J=2.5
Hz), 2.88-2.82 (m, 1H), 1.69 (s, 3H), 1.52-1.50 (m, 2H), 1.33-
1.26 (m, 3H), 1.12-0.94 (m, 5H); 13C NMR δ 170.4, 154.9, 148.0,
142.0, 140.4, 131.6, 129.1, 125.5, 125.4, 123.2, 121.9, 94.5, 77.2,
72.0, 34.3, 34.2, 25.4, 24.3, 24.2, 20.8; MS m/z 310 (Mþ, 25.4);
HRMS calcd for C20H22O3 310.1569, found 310.1569. (þ)-
(3S,3aS)-20: [R]20D þ431.9 (c=0.11, CHCl3).
Optical Resolution of (()-16. To a solution of (()-16 (60.0 mg,
0.184 mmol) and vinyl acetate (0.5 mL) in toluene (2.5 mL) was
added lipase AK Amano (120 mg) at room temperature. The
reaction mixture was stirred at 60 °C for 24 h, passed through a
filter paper, and concentrated to dryness. The residue was
chromatograhed with hexane-AcOEt (4:1 to 2:1) to afford
(þ)-16 (26.5 mg, 44%, 99% ee) and (-)-23 (33.0 mg, 49%,
95% ee).
(2R,3R,3aS)-3,3a-Epoxy-8-(phenylsulfonyl)-1,2,3,3a-tetrahy-
dorocyclopent[a]inden-2-ol ((þ)-16): pale yellow foam; [R]23
D
(2R*,3R*,3aS*)-3a-Cyclohexyloxy-3-hydroxy-1,2,3,3a-tetra-
hydrocyclopent[a]inden-2-yl Benzenesulfonate (21). K2CO3 (17
mg, 0.12 mmol) was added to a solution of 19 (15.0 mg, 0.0405
mmol) in MeOH (0.5 mL) at room temperature. The reaction
mixture was stirred for 10 min, quenched by addition of water,
and extracted with AcOEt. The extract was washed with water
and brine, dried, and concentrated to leave the crude diol. To a
þ28.1 (c=0.39, CHCl3) for 99% ee. The enantiomeric excess
of (þ)-16 was determined to be 99% by chiral HPLC using
Daicel Chiralpak IA; hexane/iPrOH= 4:1 as an eluent; flow rate
=1.0 mL/min; detector ultraviolet absorption at 254 nm; tR=
12.4 min (major), 15.3 min (minor). The other analytical data for
(þ)-16 were found to be identical with those of the racemic 16.
(2S,3R,3aR)-3,3a-Epoxy-8-(phenylsulfonyl)-1,2,3,3a-tetrahy-
dorocyclopent[a]inden-2-yl Acetate ((-)-23): pale yellow foam:
[a]23D -78.3 (c=0.51, CHCl3) for 95% ee; IR 1742, 1323, 1153
cm-1; 1H NMR δ 8.02-8.00 (m, 2H), 7.72 (d, 1H, J=7.8 Hz),
7.64-7.61 (m, 1H), 7.57-7.53 (m, 2H), 7.40-7.37 (m, 1H),
7.25-7.21 (m, 2H), 5.34 (ddd, 1H, J=7.7, 7.3, 1.7 Hz), 4.47 (d,
1H, J=1.7 Hz), 3.68 (dd, 1H, J=17.1, 7.7 Hz), 2.67 (dd, 1H, J=
17.1, 7.3 Hz), 2.17 (s, 3H); 13C NMR δ 170.4, 156.2, 140.6, 140.5,
135.8, 133.9, 133.8, 130.1, 129.5, 127.4, 126.7, 122.8, 122.4, 75.7,
72.6, 62.0, 27.1, 20.7; MS m/z 368 (Mþ, 9.3), HRMS calcd for
C20H16O5S 368.0718, found 368.0720.
n
suspension of crude diol, Bu2SnO (3.0 mg, 0.012 mmol), and
Et3N (8.8 μL, 0.061 mmol) in CH2Cl2 (0.5 mL) was added TsCl
(7.8 mg, 0.041 mmol) at room temperature. The reaction
mixture was stirred for 16 h, quenched by addition of water,
and extracted with CH2Cl2. The extract was washed with water
and brine, dried, and concentrated to dryness. The residue was
chromatographed with hexane-AcOEt (6:1) to afford 21 (15.5
mg, 86%) as colorless needles: mp 140.5-141.5 °C (hexane); IR
3589, 1369 cm-1; 1H NMR δ 7.85 (d, 2H, J=8.3 Hz), 7.37-7.33
(m, 3H), 7.26-7.22 (m, 1H), 7.14-7.11 (m, 2H), 6.45 (s, 1H),
5.62-5.58 (m, 1H), 4.26 (t, 1H, J=3.5 Hz), 3.00 (dd, 1H, J=
17.3, 9.8 Hz), 2.89-2.84 (m, 1H), 2.50 (dd, 1H, J=17.3, 6.0 Hz),
2.46 (s, 3H), 1.59-1.58 (m, 3H), 1.51-1.50 (m, 1H), 1.37-1.21
(m, 3H), 1.13-1.07 (m, 3H), 0.96-0.93 (m, 1H); 13C NMR δ
149.1, 146.8, 145.1, 140.9, 133.5, 129.9, 129.2, 128.0, 127.9, 125.4,
124.1, 121.4, 96.4, 85.6, 74.4, 72.9, 34.22, 34.20, 29.0, 25.4, 24.2,
24.0, 21.7; MS m/z 440 (Mþ, 33.3); HRMS calcd for C25H28O5S
440.1657, found 440.1660. Anal. Calcd for C25H28O5S: C,
68.16; H, 6.41. Found: C, 67.79, H, 6.35. (þ)-(2S,3S,3aR)-21:
[R]18D þ48.4 (c=0.22, CHCl3).
(2S,3S,3aR)-3,3a-Epoxy-8-(phenylsulfonyl)-1,2,3,3a-tetrahydor-
ocyclopent[a]inden-2-ol ((-)-16). To a solution of (-)-23 (60.0 mg,
0.163 mmol) in pH 7.0 phosphate buffer (0.3 M, 0.5 mL) and
acetone (1.0 mL) was added lipase PS Amano SD (60.0 mg) at
room temperature. The reaction mixture was stirred at 45 °C for
24 h, quenched by addition of brine, and extracted with AcOEt.
The extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was chromatograhed with hexane-
AcOEt (2:1) to afford (-)-16 (48.1 mg, 90%) as a pale yellow foam:
[R]22D-28.2 (c=1.50, CHCl3).
(3R*,3aR*)-3a-Cyclohexyloxy-3,3a-dihydrocyclopent[a]inden-
3-yl Acetate (20). To a solution of 21 (5.5 mg, 0.012 mmol),
pyridine (0.05 mL), and DMAP (1.0 mg) in CH2Cl2 (0.5 mL) was
added AcCl (10 μL, 0.12 mmol) at room temperature. The
reaction mixture was stirred for 10 min, quenched by addition
of water, and extracted with CH2Cl2. The extract was washed
with water and brine, dried, and concentrated to leave crude
acetate. To a solution of crude acetate in DMF (0.5 mL) was
added DBU (10 μL, 0.065 mmol) at room temperature. The
reaction mixture was stirred at 100 °C for 10 h, quenched by
addition of water, and extracted with AcOEt. The extract was
washed with water and brine, dried, and concentrated to dryness.
Acknowledgment. This work was supported in part by a
Grant-in Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan,
for which we are grateful.
Supporting Information Available: 1H and 13C NMR spec-
tra for compounds 7, 9-12, 15, 16, 17a-d, 18-22, and (-)-23;
characterization data for compounds 10-12, 17b-d, and (-)-
22. This material is available free of charge via the Internet at
http://pubs.acs.org.
5594 J. Org. Chem. Vol. 74, No. 15, 2009