First synthesis and structural elucidation of (-)-presphaerene

Article abstract of DOI:10.1021/jo049351c

The first total synthesis of (-)-presphaerene (1) was achieved from (R)-glyceraldehyde 9 in 19 steps, demonstrating the novel "folding and allylic strain-controlled" intramolecular ester enolate S _N2′ alkylation strategy could be extended to the stereoselective synthesis of cyclopentanoid natural products. The present study also established the relative and absolute stereochemistry of 1, and the absolute structures of co-occurring sphaeroanes from the red alga Sphaerococcus coronopifolius.

Full text of DOI:10.1021/jo049351c

F ir st Syn th esis a n d Str u ctu r a l Elu cid a tion of (-)-P r esp h a er en e1
J ongkook Lee* and J iyong Hong
College of Pharmacy, Seoul National University, San 56-1, Shillim-Dong,
Kwanak-Ku, Seoul 151-742, Korea
jongkook91@hanmail.net
Received April 17, 2004
The first total synthesis of (-)-presphaerene (1) was achieved from (R)-glyceraldehyde 9 in 19 steps,
demonstrating the novel “folding and allylic strain-controlled” intramolecular ester enolate SN2′
alkylation strategy could be extended to the stereoselective synthesis of cyclopentanoid natural
products. The present study also established the relative and absolute stereochemistry of 1, and
the absolute structures of co-occurring sphaeroanes from the red alga Sphaerococcus coronopifolius.
In tr od u ction
The sphaeroanes with a skeleton of 2,7-cycloneodola-
bellane such as (-)-presphaerene (1), (+)-presphaerol (2),
(+)-isosphaerodiene 1 (3), and (+)-isosphaerodiene 2 (4)
were isolated from the red alga Sphaerococcus coronopi-
folius by Fattorusso and co-workers (Figure 1).2 The
structures of these natural products were determined by
a combination of chemical correlation, NMR spectroscopy,
and X-ray crystallography except for their absolute
configurations and the C-7 stereochemistry of 1. In detail,
the relative configuration of 3 was resolved by X-ray
crystallography. The chemical transformation of 2 into
a mixture of 3 and 4 by treatment with acetyl chloride
in refluxing xylene, coupled with NMR spectroscopy, led
to the tentative assignment of 2. Aromatization of 2 with
SeO2 also produced 1.
Previously, we reported the application of the novel and
highly stereoselective “folding and allylic strain-con-
trolled” intramolecular enolate SN2′ alkylation methodol-
ogy to the synthesis of cyclohexanoid natural products.3
Encouraged by the report that some of the sphaeroanes
are biologically active,4 we set out to examine the
feasibility of the internal SN2′ alkylation for the construc-
tion of highly functionalized cyclopentane systems with
a particular emphasis on the stereochemical outcome.
Described herein is the first total synthesis and complete
structural elucidation of 1 utilizing a folding and allylic
F IGURE 1. Structures of 1-4.
* To whom correspondence should be addressed. Phone: +82-2-880-
7850. Fax: +82-2-888-0649.
strain-controlled5 intramolecular ester enolate SN2′ alky-
lation and an intramolecular Friedel-Crafts acylation as
key steps.
(1) Taken in part from the doctoral thesis of J . Lee, Seoul National
University, 2001.
(2) (a) Cafieri, F.; Napoli, L. D.; Fattorusso, E.; Piattelli, M.; Sciuto,
S. Tetrahedron Lett. 1979, 20, 963. (b) Cafieri, F.; Fattorusso, E.; Blasio,
B. D.; Pedone, C. Tetrahedron Lett. 1981, 22, 4123. (c) Cafieri, F.;
Ciminiello, P.; Santacroce, C.; Fattorusso, E. Phytochemistry 1983, 22,
1824. (d) Cafieri, F.; Napoli, L. D.; Fattorusso, E.; Santacroce, C.
Phytochemistry 1987, 26, 471.
(3) (a) Kim, D.; Choi, W. J .; Hong, J . Y.; Park, I. Y.; Kim, Y. B.
Tetrahedron Lett. 1996, 37, 1433. (b) Kim, D.; Lim, J . I.; Shin, K. J .;
Kim, H. S. Tetrahedron Lett. 1993, 34, 6557. (c) Kim, D.; Kim, H. S.;
Yoo, J . Y. Tetrahedron Lett. 1991, 32, 1577. (d) J o, H.; Lee, J .; Kim,
H.; Kim, S.; Kim, D. Tetrahedron Lett. 2003, 44, 7043. (e) For a review
of the SN2′ reaction, see: Paquette, L. A.; Stirling, C. J . M. Tetrahedron
1992, 48, 7383.
Resu lts a n d Discu ssion
Our retrosynthetic analysis for 1 (Scheme 1) called for
the intermediacy of tricyclic ketone 5 and highly func-
tionalized cyclopentanecarboxylate 7 as key intermedi-
ates, which could be constructed by intramolecular
(5) (a) Tokoroyama, T.; Okada, K.; Iio, H. J . Chem. Soc., Chem.
Commun. 1989, 1572. (b) Asao, K.; Iio, H.; Tokoroyama, T. Tetrahedron
Lett. 1989, 30, 6397.
(4) Engler, M.; Anke, T.; Sterner, O. Phytochemistry 1998, 49, 2591.
10.1021/jo049351c CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/24/2004
J . Org. Chem. 2004, 69, 6433-6440
6433

Lee and Hong
SCHEME 1. Retr osyn th etic An a lysis of 1
SCHEME 2 a
Friedel-Crafts acylation and SN2′ alkylation from acyclic
precursors 6 and 8, respectively.
The requisite intramolecular SN2′ alkylation substrate
8 was prepared from readily available (R)-glyceraldehyde
96 by a straightforward manner as depicted in Scheme
2. (R)-Glyceraldehyde 9 was transformed to an easily
separable mixture of Z-olefin 11 and E-olefin 12 (11:1)
by a Wittig reaction with m-tolylphosphonium bromide
107 in a total 90% yield. Z-Olefin 11 could be cleanly
isomerized to E-olefin 12 by treatment with thiophenol
in the presence of AIBN in refluxing benzene according
to the protocol described by Schwarz8 in 76% yield. It is
worthwhile to mention the stereoselective access to both
Z- and E-olefin is an important factor for the determi-
nation of the absolute stereochemistry of 1 in our syn-
thetic scheme. Removal of the acetonide group of olefin
12, followed by a selective monobenzoylation9 of the
resulting diol 13 (>95% ee),10 furnished monobenzoate
14 in 88% yield for the two steps. Subjection of allylic
alcohol 14 to J ohnson ortho ester Claisen rearrangement
conditions11 and subsequent deprotection of the benzoyl
protecting group of the resulting diester 15 by a trans-
esterification led to the formation of hydroxy ester 16 in
85% overall yield. Catalytic hydrogenation of olefin 16
using PtO2 and PCC oxidation of the resulting alcohol
17 produced the corresponding aldehyde 18 in 74% yield
for the two steps. The aldehyde 18 was elaborated to the
cyclization precursor 8 by a convenient three-step se-
a
Reagents and conditions: (i) t-BuOK, THF, -78 to -30 °C,
90%; (ii) PhSH, AIBN, benzene, reflux, 3 h, 76%; (iii) 60% aqueous
AcOH, rt, 6 h, 97%; (iv) BzCl, Et3N, CH2Cl2, -40 °C, 4 h, 91%; (v)
CH3CH2CH(OEt) 3, phenol, toluene, reflux, 20 h, 87%; (vi) NaOEt,
EtOH, rt, 7 h, 98%; (vii) PtO2, H2, EtOH, rt, 7 h, 88%; (viii) PCC,
NaOAc, CH2Cl2, 0 °C, 2 h, 84%; (ix) Ph3PdC(CH3)CHO, toluene,
reflux, 8 h; (x) NaBH4, EtOH, 0 °C, 0.5 h, 78% for two steps; (xi)
CBr4, Ph3P, CH2Cl2, 0 °C, 2 h, 89%.
quence. Wittig reaction of aldehyde 18 with 2-(triphenyl-
phosphoranylidene)propionaldehyde, NaBH4 reduction of
the corresponding R,â-unsaturated aldehyde 19, and
finally bromination of the resulting allylic alcohol 20 by
the protocol described by Hooz12 afforded the desired
allylic bromide 8 in 69% overall yield over the three steps.
Allylic bromide 8 underwent a smooth SN2′ cyclization
upon treatment with LHMDS in THF for 22 h at room
temperature to afford a highly functionalized cyclopen-
tanecarboxylate, 7, as a major component along with
diastereomeric 7-iso and 7-cis in a 9.9:3.3:1 ratio (capil-
lary GLC analysis) in a total 86% yield. These stereo-
isomers could be separated by preparative HPLC, and
the relative stereochemistry of the cyclized products was
established by NOE experiments as shown in Scheme 3.
In addition, the second major isomer, 7-iso, could be
converted to the desired isomer 7 by a straightforward
three-step sequence (ozonolysis, epimerization, Wittig
reaction) as described in Scheme 3, which reinforces our
structural assignment.
(6) (a) Schmid, C. R.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J .
L.; Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org.
Chem. 1991, 56, 4056. (b) (R)-Glyceraldehyde 9 prepared according to
the protocol described by Schmid5a is commercially available now.
(7) Friedrich, K.; Henning, H. G. Chem. Ber. 1959, 92, 2756.
(8) Schwarz, M.; Graminski, G. F.; Waters, R. M. J . Org. Chem.
1986, 51, 260.
(9) Schlessinger, R. H.; Lopes, A. C. J . Org. Chem. 1981, 46, 5252.
(10) The ee of dio1 13 was calculated by the analysis of the 1H 500
MHz NMR spectrum of the corresponding (S)-MTPA ester, which was
prepared from diol 13 by a two-step sequence [(i) NaH, BnBr, DMF,
rt, 5 h, 58%; (ii) (S)-(+)-MTPC, DMAP, CH2Cl2, rt, 4 h, >95% ee, 100%].
Anderson, R. J .; Adams, K. G.; Chinn, H. R.; Henrick, C. A. J . Org.
Chem. 1980, 45, 2229.
The observed stereoselectivity can best be rationalized
by considering that the reaction proceeds via chairlike
“double H-eclipsed” transition-state geometry 21 where
the nucleophilic ester enolate moiety and electrophilic
allylic bromide assume a “H-eclipsed” conformation with
(11) (a) J ohnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J .; Li, T.; Faulkner, J .; Petersen, M. R. J . Am. Chem. Soc. 1970, 92,
741. (b) Takano, S.; Sugihara, T.; Samizu, K. Chem. Lett. 1989, 1781.
(12) Hooz, J .; Gilani, S. S. H. Can. J . Chem. 1968, 46, 86.
6434 J . Org. Chem., Vol. 69, No. 19, 2004

Synthesis of (-)-Presphaerene
SCHEME 3
SCHEME 4 a
tion of endo-olefin 26, which was generated by a system-
atic Monte Carlo conformational search and subsequent
energy minimization using MM2 calculation, revealed the
â-face of the olefin is distinctively less hindered as shown
in Figure 2.17 As we expected, catalytic hydrogenation of
endo-olefin 26 with 10% Pd/C produced exclusively a
quantitative yield of the 7-R-methyl isomer, which turned
out to be 7-epi-presphaerene (1′). However, use of PtO2
as catalyst instead of Pd/C for the hydrogenation of endo-
olefin 26 yielded a small amount (10%) of 1, the desired
7-â-methyl isomer, in addition to 1′ as a major product
(90%). These two isomeric compounds could be separated
by column chromatography on AgNO3-impregnated silica
gel, and their structure was fully determined by the
analyses of their NOE, DEPT, 1H-1H COSY, and
1H-13C COSY spectra. Moreover, the spectrum of the
minor 7-â-methyl isomer was in agreement with the
spectral data of natural 1 reported in the literature.2c,e
Since it was not so obvious from the inspection of the
most stable conformation of exo-olefin 27 (Figure 2) which
side of the exo-methylene double bond is more hindered,17
we hoped that we had a better chance of obtaining the
desired 7-â-methyl isomer from exo-olefin 27 as a major
product. The catalytic hydrogenation of exo-olefin 27, also
prepared from tricyclic ketone 5 by a Wittig reaction in
high yield, with 10% Pd/C produced only 1′ in almost
quantitative yield. We reasoned that the reduction with
Pd catalyst might proceed through endo-olefin 26 via in
situ isomerization.18
a
Reagents and conditions: (i) DIBALH, toluene, -78 to -30
°C, 93%; (ii) PCC, NaOAc, 0 °C, 2.5 h, 77%; (iii) TMSCH2CO2Bn,
LDA, THF, -25 °C, 2 h; (iv) PtO2, H2, EtOAc, rt, overnight, 92%
for two steps; (v) PPA, 90 °C, overnight, 89%.
the bulky m-tolyl appendage in an equatorial position,
affording a cyclopentanecarboxylate with three contigu-
ous stereogenic centers.3
Treatment of the desired cyclopentanecarboxylate 7
with DIBALH led to the formation of primary alcohol 23
(Scheme 4), which was further oxidized with PCC to the
corresponding aldehyde 24 (72% overall yield). Peterson
olefination13 of aldehyde 24 with benzyl (trimethylsilyl)-
acetate14 yielded R,â-unsaturated benzyl ester 25, and
then simultaneous catalytic hydrogenation of olefin and
hydrogenolysis of benzyl ester with PtO2 afforded car-
boxylic acid 6 in 92% overall yield. It is quite interesting
to note that the Peterson olefination yielded E-olefinic
ester in an exclusive manner. Intramolecular Friedel-
Crafts acylation13a,15 of carboxylic acid 6 with PPA gave
the desired seven-membered tricyclic ketone 5 in high
yield (89%).
Taking advantage of these experimental findings, exo-
olefin 27 was hydrogenated in ethanol using PtO2 as
(14) (a) Benzyl (trimethylsilyl)acetate was prepared from ethyl
(trimethylsilyl)acetate by titanate-mediated transesterification in 80%
yield. See: Seebach, D.; Hungerbu¨hler, E.; Naef, R.; Schnurrenberger,
P.; Weidmann, B.; Zu¨ger, M. Synthesis 1982, 138. (b) For other
preparations of benzyl (trimethylsilyl)acetate, see: Emde, H.; Simchen,
G. Synthesis 1977, 867. Emde, H.; Simchen, G. Liebigs Ann. Chem.
1983, 816. Maruoka, K.; Banno, H.; Yamamoto, H. Synlett 1991, 253.
Soderberg, B. C.; Bowden, B. A. Organometallics 1992, 11, 2220.
(15) (a) Anderson, C. L.; Horton, W. J .; Walker, F. E.; Weiler, M. R.
J . Am. Chem. Soc. 1955, 77, 598. (b) Corey, E. J .; Behforouz, M.;
Ishiguro, M. J . Am. Chem. Soc. 1979, 101, 1608.
To establish unambiguously the configuration of the
secondary methyl group at C-7, tricyclic ketone 5 was
first treated with methyllithium and SOCl2 to provide a
5:1 mixture of endo-olefin 26 and exo-olefin 27 as depicted
in Scheme 5 .16 Examination of the most stable conforma-
(13) (a) Budhram, R. S.; Palaniswamy, V. A.; Eisenbraun, E. J . J .
Org. Chem. 1986, 51, 1402. (b) For a review of Peterson olefination,
see: Ager, D. J . Org. React. 1990, 38, 1. (c) For a review of alkene
synthesis, see: Kelly, S. E. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon Press: Seoul, 1991; Vol. 1, pp 729-817.
(16) Olah, G. A.; Wu, A.; Farooq, O. J . Org. Chem. 1989, 54, 1375.
(17) All calculations were performed on MacroModel/BATCHMIN
(version 6.0).
J . Org. Chem, Vol. 69, No. 19, 2004 6435

Lee and Hong
SCHEME 5
F IGURE 2. The most stable conformations of endo-olefin 26
and exo-olefin 27 by a systematic Monte Carlo conformational
search and subsequent energy minimization using MM2
calculation.17
hydrogenation. Currently, efforts are being made to apply
this internal SN2′ alkylation strategy to the syntheses of
various biologically active natural products in our labo-
ratories.
Exp er im en ta l Section
(Z /E ,4S )-2,2-D i m e t h y l-4-(2-m -t o ly lv i n y l)[1,3]d i -
oxola n e (11 a n d 12). To a mixture of m-tolylphosphonium
bromide 10 (1374 mg, 3.07 mmol) and anhydrous THF (5.1
mL) was added a 1.0 M solution of t-BuOK (2.76 mL) in THF
at 0 °C. After 1 h at ambient temperature, the mixture was
cooled to -78 °C, and a solution of (R)-glyceraldehyde 9 (180.0
mg, 1.38 mmol) in THF (1.5 mL) was added. The mixture was
stirred and slowly warmed to -30 °C over 3 h. The reaction
mixture was quenched with a few drops of saturated aqueous
NH4Cl solution and filtered through a pad of silica gel. The
filtrate was concentrated in vacuo, and the resulting residue
was purified by column chromatography on silica gel (hexane/
EtOAc, 15:1) to afford Z-olefin 11 (247.0 mg) and E-olefin 12
(22.5 mg) in a total 90% yield. Data for Z-olefin 11: 1H NMR
(500 MHz, CDCl3) δ 7.23 (t, J ) 7.5 Hz, 1H), 7.09 (d, J ) 7.5
Hz, 1H), 7.07 (s, 1H), 7.06 (d, J ) 7.8 Hz, 1H), 6.68 (d, J )
11.6 Hz, 1H), 5.68 (dd, J ) 11.5, 8.9 Hz, 1H), 4.91 (dddd, J )
8.8, 7.6, 6.3, 1.2 Hz, 1H), 4.14 (dd, J ) 8.1, 6.1 Hz), 3.66 (t, J
) 7.9 Hz, 1H), 2.35 (s, 3H), 1.47 (s, 3H), 1.38 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 137.9, 136.1, 134.1, 129.4, 128.9, 128.2,
128.1, 125.7, 109.3, 72.4, 69.7, 26.8, 25.9, 21.4; IR (neat) 1604,
catalyst, which is known to be less prone to isomeriza-
tion,18 to give rise to a 3:1 mixture of 1 and 1′, to our
delight (Scheme 5). Use of other solvents such as MeOH,
EtOAc, and n-hexane exhibited somewhat decreased
stereoselectivity than ethanol. It is interesting to note
that use of Pt/C or Pt/Al2O3 for the hydrogenation of exo-
olefin 27 afforded a 1:1 mixture of 1 and 1′.
1454, 1060 cm-1; [R]20 ) -37.3 (c 3.04, CHCl3); HRMS (EI)
D
m/z calcd for C14H18O2 (M+) 218.1307, found 218.1313. Data
for E-olefin 12: 1H NMR (500 MHz, CDCl3) δ 7.20-7.18 (m,
3H), 7.06 (br d, J ) 6.6 Hz, 1H), 6.63 (dd, J ) 15.8, 0.6 Hz,
1H), 6.14 (dd, J ) 15.8, 7.6 Hz, 1H), 4.67 (dddd, J ) 8.5, 7.6,
6.4, 1.1 Hz, 1H), 4.15 (dd, J ) 8.1, 6.2 Hz, 1H), 3.67 (t, J ) 8.0
Hz, 1H), 2.33 (s, 3H), 1.47 (d, J ) 0.5 Hz, 3H), 1.43 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 138.1, 136.2, 133.4, 128.7, 128.4,
127.3, 126.5, 123.8, 109.4, 77.2, 69.5, 26.7, 25.9, 21.3; IR (neat)
In summary, the first total synthesis and structure
determination of 1 have been accomplished from (R)-
glyceraldehyde 9 employing a folding and doubly allylic
strain-controlled intramolecular ester enolate SN2′ alky-
lation and an intramolecular Friedel-Crafts acylation as
key steps. The present synthesis also established the
absolute structures of co-occurring sphaeroanes from the
red alga S. coronopifolius such as 2-4 as a result. More
importantly, we have demonstrated that the internal SN2′
methodology is a viable method for the stereoselective
construction of highly functionalized cyclopentanoid natu-
ral products, though the observed stereoselectivity seems
to be slightly inferior to that of the corresponding six-
membered cases. During the course of the study we
introduced benzyl (trimethylsilyl)acetate14 for the pur-
pose of introducing a two-carbon acetic acid unit to a very
hindered position and observed a very interesting inter-
play of catalyst and molecular geometry in the catalytic
1604, 1454, 1059 cm-1; [R]20 ) +58.5 (c 2.02, CHCl3); HRMS
D
(EI) m/z calcd for C14H18O2 (M+) 218.1307, found 218.1305.
E-Olefin 12 fr om Z-Olefin 11. To a solution of Z-olefin 11
(2094 mg, 9.59 mmol) in benzene (9.6 mL) were added
thiophenol (0.49 mL, 4.77 mmol) and AIBN (236 mg, 1.44
mmol). The reaction mixture was refluxed for 3 h. Removal of
the solvent and column chromatography of the resulting
residue on silica gel (hexane/EtOAc, 30:1) gave E-olefin 12
(1582 mg) in 76% yield.
(2S)-4-m -Tolylbu t-3-en e-1,2-d iol (13). A mixture of E-
olefin 12 (645.7 mg, 2.96 mmol) and 60% aqueous acetic acid
(5.9 mL) was stirred for 6 h at room temperature. After
neutralization with saturated aqueous NaOH solution, the
mixture was extracted with EtOAc (30 mL × 5). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (hexane/EtOAc/MeOH,
8:16:1) to give diol 13 (510.0 mg) in 97% yield: 1H NMR (500
MHz, CDCl3) δ 7.22-7.17 (m, 3H), 7.07 (d, J ) 7.1 Hz, 1H),
(18) (a) Nishimura, S.; Sakamoto, H.; Ozawa, T. Chem. Lett. 1973,
855. (b) For a review for heterogeneous catalytic hydrogenation, see:
Siegel, S. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Seoul, 1991; Vol. 8, pp 417-442.
6436 J . Org. Chem., Vol. 69, No. 19, 2004

Synthesis of (-)-Presphaerene
6.65 (d, J ) 16.0 Hz, 1H), 6.18 (dd, J ) 16.0, 6.4 Hz, 1H), 4.41
(dt, J ) 6.5, 3.5 Hz, 1H), 3.74 (dd, J ) 11.2, 3.5 Hz, 1H), 3.59
(dd, J ) 11.2, 7.4 Hz, 1H), 2.45 (br s, 1H), 2.34 (s, 3H), 2.23
(br s, 1H); 13C NMR (75 MHz, CDCl3) δ 137.9, 136.2, 131.7,
128.4, 128.3, 127.4, 127.2, 123.5, 73.2, 66.4, 21.2; IR (neat)
and 3.93-3.86 (m), 2H], [4.12 (t, J ) 5.7 Hz) and 4.05 (t, J )
5.4 Hz, 2H], [3.46 (t, J ) 9.5 Hz) and 3.40 (t, J ) 9.7 Hz), 1H],
2.82-2.75 (m, 1H), [2.34 (s) and 2.31 (s), 3H], [1.34 (t, J ) 6.0
Hz) and 1.28 (t, J ) 6.1 Hz), 1H], [1.26 (t, J ) 7.2 Hz) and
0.98 (t, J ) 7.1 Hz), 3H], [1.21 (d, J ) 6.9 Hz) and 0.96 (d, J
) 6.9 Hz), 3H]; 13C NMR (75 MHz, CDCl3) δ 175.7, 175.3,
142.1, 141.2, 138.2, 137.8, 133.3, 132.1, 131.3, 130.1, 128.7,
128.5, 128.4, 128.2, 127.4, 127.3, 124.9, 124.6, 63.13, 63.08,
60.3, 60.0, 52.3, 52.2, 45.4, 45.0, 21.4, 21.3, 15.8, 15.5, 14.2,
3389, 1074 cm-1; [R]20 ) +29.5 (c 1.91, CHCl3); HRMS (EI)
D
m/z calcd for C11H14O2 (M+) 178.0994, found 178.0993.
Ben zoic Acid (E,2S)-2-H yd r oxy-4-m -t olylb u t -3-en yl
Ester (14). To a solution of diol 13 (245.0 mg, 1.38 mmol) in
CH2Cl2 (6.9 mL) were added Et3N (0.57 mL, 4.09 mmol) and
benzoyl chloride (0.24 mL, 2.07 mmol) at -78 °C. The mixture
was stirred for 4 h at -40 °C and cooled to -78 °C. A 3%
aqueous HCl solution (1.0 mL) was added to the mixture at
-78 °C with vigorous agitation. After 1 h, the mixture was
poured into brine and extracted with EtOAc (30 mL × 4). The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated at reduced pressure. The
resulting residue was purified by column chromatography on
silica gel (hexane/EtOAc, 2:1) to produce benzoate 14 (352.5
mg) in 91% yield: 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J )
8.1 Hz, 1H), 8.06 (d, J ) 8.6 Hz, 1H), 7.59-7.55 (m, 1H), 7.45
(dd, J ) 8.1, 7.5 Hz, 2H), 7.23-7.19 (m, 3H), 7.08 (dd, J ) 6.9,
1.3 Hz, 1H), 6.74 (dd, J ) 16.0, 1.2 Hz, 1H), 6.25 (dd, J ) 15.9,
6.2 Hz, 1H), 4.72-4.68 (m, 1H), 4.50 (dd, J ) 11.4, 3.7 Hz,
1H), 4.37 (dd, J ) 11.4, 7.4 Hz, 1H), 2.34 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 166.7, 138.2, 136.2, 133.2, 132.6, 129.8, 129.7,
128.8, 128.5, 128.4, 127.3, 126.9, 123.8, 71.1, 68.5, 21.3; IR
13.8; IR (neat) 3444, 1732 cm-1; HRMS (EI) m/z calcd for
-
C
16H20O2 (M+ H2O) 244.1463, found 244.1464.
(3S)-6-Hyd r oxy-2-m eth yl-3-m -tolylh exa n oic Acid Eth yl
Ester (17). To a solution of allylic alcohol 16 (264.0 mg, 1.01
mmol) in ethanol (2.0 mL) was added PtO2 (5 mg) at room
temperature. After 7 h at room temperature under a hydrogen
atmosphere, the mixture was filtered through a pad of Celite.
The filtrate was concentrated in vacuo, and the resulting
residue was purified by column chromatography on silica gel
(hexane/EtOAc, 5:1) to afford alcohol 17 (235.1 mg) in 88%
yield: 1H NMR (500 MHz, CDCl3) δ [7.18 (t, J ) 7.7 Hz) and
7.15 (t, J ) 8.1 Hz), 1H], [7.02 (d, J ) 7.4 Hz) and 6.99 (d, J
) 7.6 Hz), 1H], 6.96-6.92 (m, 2H), [4.18 (q, J ) 7.1 Hz) and
3.92-3.86 (m), 2H], [3.57 (t, J ) 6.3 Hz) and 3.54 (t, J ) 6.3
Hz), 2H], [2.79 (ddd, J ) 11.8, 8.4, 3.4 Hz) and 2.73 (dt, J )
10.4, 4.2 Hz), 1H], 2.68-2.60 (m, 1H), [2.33 (s) and 2.31 (s),
3H], [1.89-1.82 (m) and 1.68-1.59 (m), 2H], 1.39-1.25 (m,
3H), 1.29 (t, J ) 7.1 Hz) and 0.99 (t, J ) 7.1 Hz), 3H], [1.21 (d,
J ) 6.9 Hz) and 0.90 (d, J ) 6.9 Hz), 3H]; 13C NMR (75 MHz,
CDCl3) δ 176.7, 175.6, 142.4, 141.9, 137.9, 137.5, 129.00,
128.95, 128.2, 128.0, 127.3, 127.1, 125.2, 125.1, 62.6, 62.4, 60.3,
59.9, 48.6, 48.3, 46.1, 46.0, 30.6, 30.5, 27.8, 21.4, 16.2, 14.8,
14.2, 13.8; IR (neat) 3437, 1731 cm-1; HRMS (EI) m/z calcd
for C16H24O3 (M+) 264.1725, found 264.1725.
(3S)-2-Meth yl-6-oxo-3-m -tolylh exa n oic Acid Eth yl Es-
ter (18). To a solution of alcohol 17 (236.7 mg, 0.90 mmol) in
dry CH2Cl2 (9.0 mL) were added NaOAc (490 mg, 5.97 mmol),
molecular sieves (4 Å, 400 mg), and PCC (429 mg, 1.99 mmol)
at 0 °C. After 2 h at 0 °C, the mixture was diluted with ether.
The mixture was stirred for 0.5 h and filtered through a pad
of Florisil. The filtrate was concentrated at reduced pressure,
and the resulting residue was purified by column chromatog-
raphy on silica gel (hexane/EtOAc, 7:1) to afford aldehyde 18
(198.0 mg) in 84% yield: 1H NMR (500 MHz, CDCl3) δ [9.66
(t, J ) 1.1 Hz) and 9.60 (t, J ) 1.4 Hz), 1H], [7.19 (t, J ) 7.5
Hz) and 7.15 (t, J ) 7.7 Hz), 1H], [7.04 (d, J ) 7.5) and 7.01
(d, J ) 7.5 Hz), 1H], 6.93-6.90 (m, 2H), [4.19 (q, J ) 7.1 Hz)
and 3.93-3.84 (m), 2H], 2.80-2.61 (m, 2H), [2.33 (s) and 2.31
(s), 3H], [2.28-2.13 (m) and 2.00-1.93 (m), 3H], 1.90-1.78 (m,
1H), [1.30 (t, J ) 7.2 Hz) and 0.98 (t, J ) 7.1 Hz), 3H], [1.25
(d, J ) 6.9 Hz) and 0.91 (d, J ) 6.8 Hz), 3H]; 13C NMR (75
MHz, CDCl3) δ 176.1, 175.2, 141.4, 140.8, 138.2, 137.8, 128.9,
128.8, 128.4, 128.2, 127.6, 127.5, 125.2, 125.1, 60.4, 59.9, 48.3,
47.9, 46.0, 45.8, 42.0, 41.9, 26.8, 24.1, 21.4, 21.3, 16.3, 14.9,
14.1, 13.8; IR (neat) 2723, 1730 cm-1; HRMS (EI) m/z calcd
for C16H22O3 (M+) 262.1569, found 262.1569.
(neat) 3443, 1714, 1275 cm-1; [R]20 ) +3.4 (c 0.79, CHCl3);
D
HRMS (EI) m/z calcd for C18H18O3 (M+) 282.1256, found
282.1247.
Ben zoic Acid (E,4S)-5-Eth oxyca r bon yl-4-m -tolylh ex-2-
en yl Ester (15). To a solution of benzoate 14 (352.5 mg, 1.25
mmol) in toluene (6.2 mL) were added triethylorthopropionate
(2.5 mL, 12.4 mmol) and phenol (12 mg, 0.13 mmol) at room
temperature. The reaction mixture was refluxed for 20 h and
cooled to room temperature. The mixture was concentrated
in vacuo, and the resulting residue was purified by column
chromatography on silica gel (hexane/EtOAc, 15:1) to afford
allylic benzoate 15 (399.4 mg) in 87% yield: 1H NMR (500
MHz, CDCl3) δ 8.04-8.00 (m, 2H) 7.57-7.53 (m, 1H), [7.43 (t,
J ) 7.7 Hz) and 7.42 (t, J ) 7.6 Hz), 2 H], [7.21 (t, J ) 7.5 Hz)
and 7.17 (t, J ) 7.8 Hz), 1H], [7.04 (d, J ) 7.2 Hz) and 7.01-
6.98 (m), 3H], [6.03 (dd, J ) 15.4, 8.6 Hz) and 5.96 (dd, J )
15.3, 9.3 Hz), 1H], [5.79 (td, J ) 15.3, 6.2 Hz) and 5.72 (td, J
) 15.3, 6.3 Hz), 1H], [4.82-4.74 (m) and 4.73 (dd, J ) 6.3, 1.0
Hz), 2H], [4.10 (q, J ) 7.1 Hz) and 3.94-3.85 (m), 2H], [3.51
(t, J ) 9.6 Hz) and 3.44 (t, J ) 9.6 Hz), 1H], 2.84-2.77 (m,
1H), [2.34 (s) and 2.31 (s), 3H], [1.21 (t, J ) 6.4 Hz) and 0.98
(t, J ) 7.0 Hz), 3H], [1.22 (d, J ) 5.8 Hz) and 0.97 (d, J ) 7.0
Hz), 3H]; 13C NMR (75 MHz, CDCl3) δ 175.5, 175.0, 166.2,
141.7, 140.8, 138.3, 137.9, 136.7, 135.7, 132.9, 132.8, 130.2,
129.52, 129.50, 128.7, 128.6, 128.5, 128.29, 128.26, 128.23,
127.6, 127.4, 126.1, 125.0, 124.9, 124.6, 65.09, 65.07, 60.3, 60.0,
52.4, 52.3, 45.3, 44.9, 21.38, 21.35, 15.8, 15.6, 14.2, 13.8; IR
(neat) 1725, 1271 cm-1; HRMS (EI) m/z calcd for C23H26O4 (M+)
366.1831, found 366.1845.
(E,3S)-8-Hydr oxy-2,7-dim eth yl-3-m-tolyloct-6-en oic Acid
Eth yl Ester (20). A mixture of 2-(triphenylphosphoranylidene)-
propionaldehyde (226 mg, 0.71 mmol), aldehyde 18 (155.2 mg,
0.59 mmol), and toluene (2.0 mL) was refluxed for 8 h. The
mixture was filtered through a pad of silica gel, and the filtrate
was concentrated to give crude enal 19. The crude product was
dissolved in ethanol (2.0 mL), and NaBH4 (45 mg, 1.19 mmol)
was added at 0 °C. After 0.5 h at the same temperature, the
mixture was quenched with saturated aqueous NH4Cl, and
ethanol was removed at reduced pressure. The resulting
residue was dissolved in EtOAc and washed with brine. The
organic layer was dried over anhydrous Na2SO4 and concen-
trated in vacuo. The resulting residue was purified by column
chromatography on silica gel (hexane/EtOAc, 10:1) to afford
allylic alcohol 20 (140.0 mg) in 78% yield from aldehyde 18:
1H NMR (500 MHz, CDCl3) δ [7.18 (t, J ) 7.5 Hz) and 7.15 (t,
J ) 7.9 Hz), 1H], [7.02 (d, J ) 7.5 Hz) and 6.99 (d, J ) 7.9
(E,3S)-6-Hyd r oxy-2-m eth yl-3-m -tolylh ex-4-en oic Acid
Eth yl Ester (16). Sodium ethoxide (1.82 mL, 1.0 M solution
in ethanol) was added to a solution of allylic benzoate 15 (222
mg, 0.61 mmol) in ethanol (1.2 mL). The mixture was stirred
for 7 h at room temperature under an argon atmosphere and
neutralized with saturated aqueous NH4Cl solution. The
solvent was removed at reduced pressure, and the resulting
residue was dissolved in EtOAc and washed with brine. The
organic layer was dried over anhydrous Na2SO4 and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel (hexane/EtOAc, 4:1) to afford allylic
alcohol 16 (156 mg) in 98% yield: 1H NMR (500 MHz, CDCl3)
δ [7.20 (t, J ) 7.5 Hz) and 7.16 (t, J ) 7.8 Hz), 1H], [7.04 (d,
J ) 7.2 Hz and 7.00-6.97 (m), 3H], [5.87 (dd, J ) 15.2, 8.6
Hz) and 5.81 (dd, J ) 15.4, 9.1 Hz), 1H], [5.73 (td, J ) 15.2,
5.3 Hz) and 5.66 (td, J ) 15.3, 5.6 Hz), 1H], [4.18-4.11 (m)
J . Org. Chem, Vol. 69, No. 19, 2004 6437

Lee and Hong
Hz), 1H], 6.95-6.91 (m, 2H), [5.33 (t, J ) 6.5 Hz) and 5.29 (t,
J ) 6.9 Hz), 1H], [4.17 (q, J ) 6.9 Hz) and 3.95-3.86 (m), 4H],
[2.78 (ddd, J ) 11.3, 8.5, 2.9 Hz) and 2.72 (dt, J ) 10.2, 4.3
Hz), 1H], 2.67-2.58 (m, 1H), [2.33 (s) and 2.31 (s), 3H], [1.87-
1.78 (m) and 1.70-1.62 (m), 4H], [1.50 (s) and 1.48 (s), 3H],
[1.29 (dt, J ) 7.1, 0.5 Hz) and 0.99 (dt, J ) 7.2, 0.5 Hz), 3H],
[1.20 (d, J ) 6.7 Hz) and 0.89 (d, J ) 6.8 Hz), 3H]; 13C NMR
(75 MHz, CDCl3) δ 176.6, 175.6, 142.3, 141.8, 137.7, 137.3,
134.93, 134.91, 129.0, 128.1, 127.8, 127.1, 127.0, 125.4, 125.3,
125.2, 125.1, 68.5, 60.2, 59.8, 48.4, 48.2, 46.1, 45.9, 34.2, 31.4,
25.31, 25.26, 21.32, 21.27, 16.1, 14.7 14.1, 13.8, 13.4; IR (neat)
3443, 1731 cm-1; HRMS (EI) m/z calcd for C19H28O3 (M+)
286.1933, found 286.1937.
11.4, 7.0 Hz, 1H), 2.31 (s, 3H), 2.09 (dq, J ) 11.9, 6.0 Hz, 1H),
2.03-1.98 (m, 1H), 1.96 (dq, J ) 6.0, 1.2 Hz, 1H), 1.79 (dq, J
) 12.2, 6.3 Hz, 1H), 1.63 (s, 3H), 1.18 (s, 3H), 0.84 (t, J ) 7.2
Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 176.0, 145.0, 141.1,
137.1, 129.2, 127.6, 127.3, 125.5, 111.3, 60.1, 59.1, 55.0, 52.8,
30.8, 29.1, 23.5, 21.4, 13.6; IR (neat) 1727 cm-1; [R]20D ) +15.5
(c 0.075, CHCl3); HRMS (EI) m/z calcd for C19H26O2 (M+)
286.1933, found 286.1930.
(1R,2S,5R)-2-Acet yl-1-m et h yl-5-m -t olylcyclop en t a n e-
ca r boxylic Acid Eth yl Ester (22). To a solution of cyclo-
pentanecarboxylate 7 (11.0 mg, 0.038 mmol) in EtOAc (1 mL)
were added a few drops of saturated ozone solution in EtOAc
every 20 min at -78 °C until the starting material disappeared
on TLC. After removal of excess ozone by a stream of nitrogen,
Ph3P (30 mg, 0.11 mmol) was added to the mixture. It was
stirred overnight and filtered through a pad of silica gel. The
filtrate was concentrated, and the resulting residue was
purified by column chromatography on silica gel (hexane/
EtOAc, 10:1) to give ketone 22 (9.4 mg) in 85% yield: 1H NMR
(500 MHz, CDCl3) δ 7.17 (t, J ) 7.5 Hz, 1H), 7.03 (d, J ) 7.6
Hz, 1H), 7.00 (s, 1H), 6.99 (d, J ) 7.5 Hz, 1H), 4.12 (dq, J )
7.1, 1.4 Hz, 2H), 3.68 (dd, J ) 9.8, 6.7 Hz, 1H), 2.85 (t, J ) 8.1
Hz, 1H), 2.33 (s, 3H), 2.17 (s, 3H), 2.20-2.00 (m, 4H), 1.25 (t,
J ) 7.2 Hz, 3H), 1.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
208.8, 176.5, 140.3, 137.4, 129.8, 127.8, 127.3, 125.9, 63.4, 60.7,
54.7, 52.2, 30.0, 29.9, 27.8, 22.5, 21.5, 14.0; IR (neat) 1712,
1233 cm-1; [R]20D ) +56.4 (c 0.70, CHCl3); HRMS (EI) m/z calcd
for C18H24O3 (M+) 288.1725, found 288.1721.
(E,3S)-8-Br om o-2,7-d im eth yl-3-m -tolyloct-6-en oic Acid
Eth yl Ester (8). To a solution of allylic alcohol 20 (105.0 mg,
0.34 mmol) in CH2Cl2 (3.4 mL) were added CBr4 (229 mg, 0.69
mmol) and Ph3P (136 mg, 0.52 mmol) at 0 °C. After 2 h, the
mixture was diluted with hexane and filtered through a pad
of silica gel. The filtrate was concentrated, and the resulting
residue was purified by column chromatography (hexane/
EtOAc, 20:1) to give allylic bromide 8 (112.7 mg) in 89%
yield: 1H NMR (500 MHz, CDCl3) δ [7.18 (t, J ) 7.5 Hz) and
7.15 (t, J ) 7.9 Hz), 1H], [7.02 (d, J ) 7.5 Hz) and 6.99 (d, J
) 8.0 Hz), 1H], 6.94-6.90 (m, 2H), [5.53 (t, J ) 6.7 Hz) and
5.49 (t, J ) 6.9 Hz), 1H], [4.18 (q, J ) 7.1 Hz) and 3.94-3.86
(m), 4H], [2.76 (ddd, J ) 11.7, 8.6, 3.0 Hz) and 2.71 (dt, J )
9.8, 5.0 Hz), 1H], 2.66-2.57 (m, 1H), [2.33 (s) and 2.31 (s), 3H],
1.85-1.75 (m, 3H), 1.70-1.62 (m, 2H], [1.57 (s) and 1.55 (s),
3H], [1.29 (t, J ) 7.1 Hz) and 1.00 (t, J ) 7.1 Hz), 3H], [1.20
(d, J ) 7.0 Hz) and 0.89 (d, J ) 6.8 Hz), 3H]; 13C NMR (75
MHz, CDCl3) δ 176.4, 175.5, 142.1, 141.6, 137.9, 137.5, 132.3,
132.2, 130.9, 129.16, 129.14, 128.3, 128.0, 127.3, 127.2, 125.3,
125.2, 60.3, 59.9, 48.5, 48.2, 46.11, 46.06, 41.8, 41.7, 33.7, 31.0,
26.1, 26.0, 21.44, 21.41, 16.3, 14.8, 14.5, 14.3, 13.9; IR (neat)
1730 cm-1; HRMS (EI) m/z calcd for C19H28BrO2 (MH+)
367.1273, found 367.1268.
(1R,2R,5R)-2-Acet yl-1-m et h yl-5-m -t olylcyclop en t a n e-
ca r boxylic Acid Eth yl Ester (22-iso). To a solution of
cyclopentanecarboxylate 7-iso (24.6 mg, 0.086 mmol) in EtOAc
(1 mL) were added a few drops of saturated ozone solution in
EtOAc every 10 min for 2 h, and 0.5 mL of saturated ozone
solution in EtOAc was added to the mixture every 1 h for 4 h
at -78 °C. After removal of excess ozone by a stream of
nitrogen, Ph3P (68 mg, 0.26 mmol) was added to the mixture.
The mixture was stirred overnight and filtered through a pad
of silica gel. The filtrate was concentrated, and the resulting
residue was purified by column chromatography on silica gel
(hexane/EtOAc, 10:1) to give ketone 22-iso (14.0 mg) in 82%
yield: 1H NMR (500 MHz, CDCl3) δ 7.16 (t, J ) 7.8 Hz, 1H),
7.04 (d, J ) 7.6 Hz, 1H), 6.76 (br s, 2H), 4.21 (q, J ) 7.1 Hz,
2H), 3.71 (t, J ) 9.5 Hz, 1H), 3.66 (dd, J ) 12.1, 8.2 Hz, 1H),
2.38-2.29 (m, 1H), 2.31 (s, 3H), 2.17 (dq, J ) 12.2, 6.3 Hz,
1H), 2.06 (s, 3H), 2.10-2.03 (m, 1H), 1.95 (dtd, J ) 13.2, 9.5,
6.3 Hz, 1H), 1.25 (t, J ) 7.2 Hz, 3H), 0.78 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 207.5, 176.5, 138.2, 137.5, 129.2, 127.9,
127.8, 125.4, 61.1, 61.0, 55.3, 30.1, 26.7, 22.4, 21.4, 14.2, 12.8;
Cycliza tion of Allylic Br om id e 8. To a solution of allylic
bromide 8 (62.0 mg, 0.17 mmol) in THF (17 mL) was added
LHMDS (0.84 mL, 1.0 M solution in THF) at 0 °C. After 22 h
at room temperature, the mixture was cooled to 0 °C and
quenched with saturated aqueous NH4Cl solution. The solvent
was removed at reduced pressure, and the residue was
dissolved in EtOAc. The mixture was washed with brine, dried
over anhydrous Na2SO4, and concentrated in vacuo. The
resulting residue was purified by column chromatography on
silica gel (hexane/EtOAc, 20:1) to give a mixture of 7, 7-iso,
and 7-cis (9.9:3.3:1, by capillary GLC analysis) in a total 86%
yield, and the isomers were separated by NP-preparative
HPLC. Data for cylopentanecarboxylate 7: 1H NMR (500 MHz,
CDCl3) δ 7.15 (t, J ) 7.6 Hz, 1H), 7.00 (d, J ) 7.6, 1H), 6.96
(s, 1H), 6.96 (d, J ) 7.6 Hz), 1H], 4.83 (t, J ) 1.6 Hz, 1H), 4.79
(d, J ) 0.8 Hz, 1H), 4.16-4.04 (m, 2H), 3.96 (dd, J ) 11.5, 6.8
Hz, 1H), 2.48 (t, J ) 8.7 Hz, 1H), 2.31 (s, 3H), 2.11-2.05 (m,
1H), 2.04-1.96 (m, 1H), 1.96-1.90 (m, 2H), 1.77 (s, 3H), 1.25
(t, J ) 7.2 Hz, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
176.4, 145.3, 141.1, 137.4, 129.4, 127.8, 127.0, 125.6, 111.9,
60.4, 59.5, 55.6, 51.8, 30.0, 29.5, 23.3, 22.9, 21.5, 14.2; IR (neat)
1719 cm-1; [R]20D ) +46.5 (c 0.43, CHCl3); HRMS (EI) m/z calcd
for C19H26O2 (M+) 286.1933, found 286.1932. Data for 7-iso:
1H NMR (500 MHz, CDCl3) δ 7.14 (t, J ) 7.9 Hz, 1H), 7.01 (d,
J ) 7.5 Hz, 1H), 6.93 (br s, 2H), 4.87 (q, J ) 1.4 Hz, 1H), 4.77
(d, J ) 0.5 Hz, 1H), 4.15 (q, J ) 7.1 Hz, 2H), 3.73 (t, J ) 10.1
Hz, 1H), 3.27 (t, J ) 9.8 Hz, 1H), 2.30 (s, 3H), 2.13-2.08 (m,
2H), 2.01-1.95 (m, 2H), 1.65 (s, 3H), 1.24 (t, J ) 7.2 Hz, 3H),
0.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.5, 144.4, 139.6,
137.4, 129.2, 127.8, 127.4, 125.3, 111.9, 60.5, 55.6, 55.0, 54.9,
IR (neat) 1712, 1268 cm-1; [R]20 ) -87.3 (c 0.48, CHCl3);
D
HRMS (EI) m/z calcd for C18H24O3 288.1725, found 288.1725.
Ep im er iza tion of Keton e 22 to 22-iso. A mixture of
ketone 22 (7.0 mg, 0.024 mmol) and DBU (0.5 mL) was stirred
for 20 h at room temperature and filtered through a pad of
silica gel to give a mixture of ketone 22 and epimer 22-iso
(6.8 mg, 1:4.2 by 400 MHz 1H NMR analysis) in a total 97%
yield. The mixture was separated by column chromatography
on silica gel (hexane/EtOAc, 10:1).
Ep im er iza tion of Keton e 22-iso to 22. A mixture of
ketone 22-iso (5.5 mg, 0.019 mmol) and DBU (0.5 mL) was
stirred for 36 h at room temperature and then filtered through
a pad of silica gel to give a mixture of ketone 22-iso and epimer
22 (5.5 mg, 4.2:1 by 400 MHz 1H NMR analysis). The mixture
was separated by column chromatography on silica gel (hex-
ane/EtOAc, 10:1).
Cyclop en t a n eca r b oxyla t e
7 fr om 22. A mixture of
methyltriphenylphosphonium iodide (56 mg, 0.14 mmol) and
n-BuLi (0.078 mL, 1.6 M solution in hexane) in THF (1.0 mL)
was stirred for 30 min at -78 °C. To the mixture was added
a solution of ketone 22 (8.1 mg, 0.028 mmol) in THF (0.5 mL)
at -78 °C, and the mixture was stirred for 10 h at room
temperature. The reaction mixture was quenched with a few
drops of saturated aqueous NH4Cl solution and filtered
26.5, 25.6, 23.2, 21.5, 14.2, 11.3; IR (neat) 1726 cm-1; [R]20
)
D
-25.1 (c 0.25, CHCl3); HRMS (EI) m/z calcd for C19H26O2 (M+)
286.1933, found 286.1935. Data for 7-cis: 1H NMR (500 MHz,
CDCl3) δ 7.13 (t, J ) 7.7 Hz, 1H), 7.00 (s, 1H), 6.99 (d, J ) 7.4
Hz, 2H), 4.86 (d, J ) 0.9 Hz, 1H), 4.78 (s, 1H), 3.54 (dq, J )
7.1, 1.6 Hz, 2H), 3.38 (dd, J ) 12.5, 5.9 Hz, 1H), 2.93 (dd, J )
6438 J . Org. Chem., Vol. 69, No. 19, 2004

Synthesis of (-)-Presphaerene
through a pad of silica gel. The filtrate was concentrated in
vacuo, and the resulting residue was purified by column
chromatography on silica gel (hexane/EtOAc, 20:1) to afford
cyclopentanecarboxylate 7 (6.1 mg) in 76% yield.
CHCl3); HRMS (EI) m/z calcd for C19H28O2 (M+) 288.2089,
found 288.2087.
(3R,3a S,10bS)-3-Isop r op yl-3a ,9-d im eth yl-2,3,3a ,4,5,10b-
h exa h yd r o-1H-ben zo[e]a zu len -6-on e (5). A mixture of car-
boxylic acid 6 (25.3 mg, 0.089 mmol) and PPA (1 mL) was
stirred overnight at 90 °C. Crushed ice was added, and the
mixture was extracted with EtOAc (20 mL × 3). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel (hexane/
EtOAc, 20:1) to give ketone 5 (21.0 mg) in 89% yield: 1H NMR
(500 MHz, CDCl3) δ 7.66 (d, J ) 7.7 Hz, 1H), 7.08 (d, J ) 7.7
Hz, 1H), 7.07 (s, 1H), 3.18 (dd, J ) 12.4, 5.5 Hz, 1H), 2.83 (t,
J ) 6.4 Hz, 1H), 2.83 (t, J ) 7.2 Hz, 1H), 2.38 (s, 3H), 2.14 (dt,
J ) 12.8, 6.4 Hz, 1H), 2.09 (dt, J ) 10.9, 5.5 Hz, 1H), 1.98
(ddd, J ) 11.4, 5.7, 5.7 Hz, 1H), 1.85-1.73 (m, 3H), 1.41-1.25
(m, 2H), 0.97 (d, J ) 6.5 Hz, 3H), 0.92 (d, J ) 6.6 Hz, 3H),
0.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 205.6, 142.2, 142.1,
137.2, 127.85, 127.82, 126.9, 59.8, 53.0, 43.7, 41.6, 33.7, 30.1,
((1S,2R,5R)-2-Isop r op en yl-1-m eth yl-5-m -tolylcyclop en -
tyl)m eth a n ol (23). To a solution of cyclopentanecarboxylate
7 (13.0 mg, 0.045 mmol) in dry toluene (0.9 mL) was added
DIBALH (0.27 mL, 1.0 M solution in hexane) at -78 °C. The
reaction mixture was stirred and slowly warmed to -30 °C
over 3 h. The mixture was cooled to -78 °C again, and
methanol (0.5 mL) was added to the mixture. The mixture was
stirred overnight at room temperature and filtered through a
pad of Celite. The filtrate was concentrated at reduced
pressure, and the resulting residue was purified by column
chromatography on silica gel (hexane/EtOAc, 10:1) to afford
alcohol 23 (10.2 mg) in 93% yield: 1H NMR (500 MHz, CDCl3)
δ 7.17 (t, J ) 7.8 Hz, 1H), 7.02-6.99 (m, 3H), 4.98 (t, J ) 1.5
Hz, 1H), 4.96 (s, 1H), 3.45 (br d, J ) 4.1 Hz, 2H), 3.20 (dd, J
) 10.9, 7.7 Hz, 1H), 2.37 (dd, J ) 10.9, 6.9 Hz, 1H), 2.33 (s,
3H), 2.05-1.95 (m, 2H), 1.92 (s, 3H), 1.91-1.86 (m, 1H), 1.85-
1.78 (m, 2H), 0.66 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 148.4,
141.9, 137.4, 129.9, 127.8, 126.9, 126.0, 111.7, 68.4, 56.1, 50.4,
48.7, 29.7, 24.6, 23.0, 21.5; IR (neat) 1040 cm-1; [R]20D ) +15.2
(c 0.35, CHCl3); HRMS (EI) m/z calcd for C17H24O (M+)
244.1827, found 244.1828.
29.4, 28.5, 27.7, 23.5, 22.2, 21.7; IR (neat) 1673 cm-1; [R]20
)
D
-140.9 (c 0.64, CHCl3); HRMS (EI) m/z calcd for C19H26O (M+)
270.1984, found 270.1984.
(3R,3a S,10bS)-3-Isop r op yl-3a ,6,9-tr im eth yl-1,2,3,3a ,4,-
10b-h exa h yd r oben zo[e]a zu len e (26). To a solution of ke-
tone 5 (8.0 mg, 0.030 mmol) in ether (1.0 mL) was added
methyllithium (0.2 mL, 1.5 M solution in ether) at -78 °C,
and the mixture was stirred for 1 h at the same temperature.
SOCl2 (0.04 mL, 0.54 mmol) was then added to the mixture.
After 10 min at -78 °C, the mixture was stirred for 1 h at
room temperature, poured into ice, and extracted with ether
(15 mL × 3). The combined organic layers were washed with
brine, dried over anhydrous MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (hexane) to afford a mixture of endo-olefin 26 and exo-olefin
27 (7.0 mg, 5.3:1 by 500 MHz 1H NMR analysis) in a total
88% yield. The endo-olefin 26 and exo-olefin 27 were separated
by column chromatography on AgNO3-impregnated silica gel
(hexane). Data for endo-olefin 26: 1H NMR (500 MHz, CDCl3)
δ 7.32 (d, J ) 8.0 Hz, 1H), 7.01 (d, J ) 8.1 Hz, 1H), 6.99 (s,
1H), 5.85-5.83 (m, 1H), 2.83 (t, J ) 9.3 Hz, 1H), 2.57 (br d, J
) 15.8 Hz, 1H), 2.35 (s, 3H), 2.20 (t, J ) 1.5 Hz, 3H), 2.21-
2.15 (m, 1H), 1.92-1.88 (m, 1H), 1.84-1.79 (m, 1H), 1.77-
1.68 (m, 1H), 1.30-1.19 (m, 2H), 0.97 (d, J ) 6.4 Hz, 3H), 0.92
(d, J ) 6.6 Hz, 3H), 0.42 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 140.7, 135.8, 135.4, 130.5, 128.4, 126.6, 126.0, 125.9, 59.6,
53.6, 42.3, 41.2, 30.6, 28.3, 27.7, 27.2, 25.7, 23.6, 22.8, 21.3;
(1S,2R,5R)-2-Isop r op en yl-1-m eth yl-5-m -tolylcyclop en -
ta n eca r ba ld eh yd e (24). To a solution of alcohol 23 (12.0 mg,
0.050 mmol) in dry CH2Cl2 (1 mL) were added NaOAc (26 mg,
0.32 mmol), molecular sieves (4 Å, 22 mg), and PCC (24 mg,
1.08 mmol) at 0 °C. After 2.5 h at the same temperature, the
mixture was diluted with ether and filtered through a pad of
Florisil. The filtrate was concentrated, and the resulting
residue was purified by column chromatography on silica gel
(hexane/EtOAc, 15:1) to afford aldehyde 24 (9.2 mg) in 77%
yield: 1H NMR (500 MHz, CDCl3) δ 9.57 (s, 1H), 7.15 (t, J )
7.9 Hz, 1H), 7.00 (d, J ) 7.5 Hz), 6.90 (d, J ) 7.9 Hz, 1H),
6.89 (s, 1H), 4.92 (t, J ) 1.4 Hz, 1H), 4.92 (d, J ) 1.4 Hz, 1H),
3.65 (dd, J ) 11.5, 6.7 Hz, 1H), 2.54 (dd, J ) 11.5, 6.7 Hz,
1H), 2.31 (s, 3H), 2.16 (dtd, J ) 12.3, 6.2, 1.7 Hz, 1H), 2.10
(dq, J ) 11.7, 6.2 Hz, 1H), 1.97 (dtd, J ) 12.7, 6.4, 1.7 Hz,
1H), 1.88 (dq, J ) 11.9, 6.7 Hz, 1H), 1.72 (s, 3H), 0.82 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 205.6, 143.0, 140.2, 137.7, 129.4,
128.0, 127.2, 125.6, 113.1, 58.7, 57.3, 48.9, 30.0, 29.9, 23.4, 21.5,
19.8; IR (neat) 2710, 1721 cm-1; [R]20D ) +39.7 (c 0.22, CHCl3);
HRMS (EI) m/z calcd for
C
17H22O (M+) 242.1671, found
242.1672.
IR (neat) 1574, 1496 cm-1; [R]20 ) -320.1 (c 0.10, CHCl3);
D
3-((1S,2R,5S)-2-Isop r op yl-1-m eth yl-5-m -tolylcyclop en -
tyl)p r op ion ic Acid (6). To a solution of benzyl (trimethylsi-
lyl)acetate (46 mg, 0.21 mmol) in THF (1.0 mL) was added
LDA (0.21 mL, 0.5 M solution in THF) at -78 °C. After 0.5 h,
a solution of aldehyde 24 (10.0 mg, 0.041 mmol) in THF (0.5
mL) was added to the mixture at the same temperature, and
the mixture was stirred for 2 h at -25 °C. The mixture was
poured into saturated aqueous NH4Cl solution and extracted
with EtOAc (20 mL × 3). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and con-
centrated in vacuo to give crude benzyl ester 25. The crude
product was dissolved in EtOAc (2.0 mL), and PtO2 (1 mg) was
added. The mixture was stirred overnight at ambient temper-
ature under a hydrogen atmosphere. The mixture was filtered
through a pad of Celite, and the filtrate was concentrated in
vacuo. The resulting residue was purified by column chroma-
tography on silica gel (hexane/EtOAc, 2:1) to afford carboxylic
acid 6 (11.0 mg) in 92% overall yield: 1H NMR (500 MHz,
CDCl3) δ 7.15 (t, J ) 8.0 Hz, 1H), 6.99 (d, J ) 7.4 Hz, 1H),
6.94 (d, J ) 8.0 Hz, 1H), 6.94 (s, 1H), 2.91 (t, J ) 7.5 Hz, 1H),
2.49-2.35 (m, 2H), 2.33 (s, 3H), 2.11-1.98 (m, 2H), 1.89-1.73
(m, 3H), 1.72-1.65 (m, 1H), 1.60-1.50 (m, 2H), 0.96 (d, J )
6.7 Hz, 3H), 0.94 (d, J ) 6.7 Hz, 3H), 0.66 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 180.7, 144.4, 137.2, 130.0, 127.7, 126.6,
126.1, 56.3, 53.9, 46.7, 30.9, 30.1, 29.9, 28.6, 27.8, 24.1, 23.5,
HRMS (EI) m/z calcd for C20H28 (M+) 268.2191, found 268.2190.
Red u ction of en d o-Olefin 26 w ith 10% P d /C. A mixture
of endo-olefin 26 (2.3 mg, 0.0086 mmol) and 10% Pd/C (2 mg)
in ethanol (1 mL) was stirred for 1 h at 15 °C under a hydrogen
atmosphere. The mixture was filtered over a pad of Celite to
give only 7-epi-presphaerene (1′) (2.3 mg) in quantitative
yield: 1H NMR (500 MHz, CDCl3) δ 7.10 (d, J ) 7.8 Hz, 1H),
6.97 (d, J ) 7.8 Hz, 1H), 6.95 (s, 1H), 3.14 (dd, J ) 12.6, 5.2
Hz, 1H), 3.05-2.98 (m, 1H), 2.36 (s, 3H), 1.93-1.82 (m, 4H),
1.82-1.72 (m, 2H), 1.65 (td, J ) 14.0, 1.0 Hz, 1H), 1.47-1.30
(m, 3H), 1.34 (d, J ) 7.0 Hz, 3 H), 0.92 (d, J ) 6.5 Hz, 3H),
0.90 (d, J ) 6.6 Hz, 3H), 0.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 142.4, 141.9, 134.4, 126.3, 126.0, 123.8, 59.2, 53.3,
40.3, 38.7, 35.6, 32.3, 30.0, 27.80, 27.75, 25.1, 24.2, 21.9, 21.6,
21.1; IR (neat) 1455 cm-1; [R]20 ) -91.8 (c 0.20, CHCl3);
D
HRMS (EI) m/z calcd for C20H30 (M+) 270.2348, found 270.2348.
Red u ction of en d o-Olefin 26 w ith P tO2. A mixture of
endo-olefin 26 (2.5 mg, 0.0093 mmol) and PtO2 (1 mg) in
ethanol (1 mL) was stirred for 1 h at 15 °C under a hydrogen
atmosphere. The mixture was filtered over a pad of Celite to
give a mixture of (-)-presphaerene (1) and 1′ (2.5 mg, 1:9 by
1
400 MHz H NMR analysis) in quantitative yield.
(3R,3a S,10bS)-3-Isop r op yl-3a ,9-d im eth yl-6-m eth ylen e-
1,2,3,3a ,4,5,6,10b-octa h yd r oben zo[e]a zu len e (27). A mix-
ture of methyltriphenylphosphonium iodide (112 mg, 0.28
22.2, 21.5; IR (neat) 1708, 1297 cm-1; [R]20 ) +38.2 (c 1.03,
D
J . Org. Chem, Vol. 69, No. 19, 2004 6439

Lee and Hong
mmol) and n-BuLi (0.15 mL, 1.6 M solution in hexane) in THF
(2.0 mL) was stirred for 0.5 h at -78 °C. To the mixture was
added ketone 5 (10.7 mg, 0.040 mmol) in THF (1.0 mL) at the
same temperature. After 2 h at room temperature, the mixture
was quenched with saturated aqueous NH4Cl solution and
filtered through a pad of silica gel. The filtrate was concen-
trated in vacuo, and the resulting residue was purified by
column chromatography on silica gel (hexane) to give exo-olefin
27 (9.5 mg) in 89% yield: 1H NMR (500 MHz, CDCl3) δ 7.03
(d, J ) 7.5 Hz, 1H), 6.94 (d, J ) 7.6 Hz, 1H), 6.91 (s, 1H), 5.11
(dd, J ) 2.2, 1.3 Hz, 1H), 4.86 (d, J ) 2.5 Hz, 1H), 2.95 (dd, J
) 12.7, 5.5 Hz, 1H), 2.45 (td, J ) 13.2, 4.1 Hz, 1H), 2.35-2.29
(m, 1H), 2.33 (s, 3H), 1.95 (td, J ) 12.8, 4.0 Hz, 1H), 1.90-
1.81 (m, 3H), 1.80-1.71 (m, 2H), 1.42-1.37 (m, 1H), 1.33-
1.24 (m, 1H), 0.94 (d, J ) 6.4 Hz, 3H), 0.89 (d, J ) 6.6 Hz,
3H), 0.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.3, 141.4,
139.9, 136.3, 127.3, 126.1, 113.7, 59.3, 54.8, 40.8, 39.9, 32.4,
29.7, 27.9, 27.8, 24.7, 24.2, 24.8, 21.4; IR (neat) 1628, 1448
mixture of 1 and 1′ (9.5 mg, 3:1 by 500 MHz 1H NMR analysis)
in quantitative yield. 1 and 1′ were separated by column
chromatography on AgNO3-impregnated silica gel (hexane).
Data for 1: 1H NMR (500 MHz, CDCl3) δ 6.94 (d, J ) 7.5 Hz,
1H), 6.92 (s, 1H), 6.87 (d, J ) 7.4 Hz, 1H), 3.20 (dd, J ) 12.2,
5.6 Hz, 1H), 3.09-3.04 (m, 1H), 2.28 (s, 3H), 2.03-1.93 (m,
2H), 1.90-1.77 (m, 4H), 1.74-1.66 (m, 2H), 1.44-1.33 (m, 2H),
1.31 (d, J ) 7.6 Hz, 3H), 0.93 (d, J ) 6.5 Hz, 3H), 0.90 (d, J )
6.6 Hz, 3H), 0.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.4,
140.9, 135.0, 129.5, 127.6, 126.2, 58.9, 53.3, 41.7, 41.6, 32.9,
28.6, 28.5, 28.2, 27.9, 24.2, 24.0, 21.3, 21.2, 18.3; IR (neat) 1455
cm-1; [R]20 ) -90.2 (c 0.40, CHCl3); HRMS (EI) m/z calcd for
D
C
20H30 (M+) 270.2348, found 270.2347.
Ack n ow led gm en t. This work was supported by a
grant (HMP-00-CD-02-0004) from the Ministry of Health
and Welfare to Professor Deukjoon Kim, whom we
thank for his interest and guidance.
cm-1; [R]20 ) -165.3 (c 0.46, CHCl3); HRMS (EI) m/z calcd
D
for C20H28 (M+) 268.2191, found 268.2193.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR comparison
of natural and synthetic 1 and 1′, the most stable conforma-
tions of endo-olefin 26 and exo-olefin 27, along with copies of
the 1H and 13C NMR spectra for 1, 1′, 5-20, and 22-27,
Red u ction of exo-Olefin 27 w ith 10% P d /C. A mixture
of exo-olefin 27 (2.3 mg, 0.0086 mmol) and 10% Pd/C (2 mg) in
ethanol (1.0 mL) was stirred for 1 h at 15 °C under a hydrogen
atmosphere. The mixture was filtered over a pad of Celite to
give 1′ (2.3 mg) in quantitative yield.
Red u ction of exo-Olefin 27 w ith P tO2. A mixture of exo-
olefin 27 (9.5 mg, 0.035 mmol) and PtO2 (1 mg) in ethanol (2.0
mL) was stirred for 3 h at 15 °C under a hydrogen atmosphere.
The mixture was filtered through a pad of Celite to give a
1
1H-1H COSY, H-13C COSY, and DEPT spectra for 1, 1′, 5,
7, 7-iso, and 7-cis, and NOE spectra for 1, 1′, 7, 7-iso, and
7-cis (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
J O049351C
6440 J . Org. Chem., Vol. 69, No. 19, 2004