Enantiospecific Synthesis of (+)-Nemorensic Acid, a Necic Acid Component of the Macropyrrolizidine Alkaloid, Nemorensine

Article abstract of DOI:10.1021/jo990366y

A concise enantiospecific synthesis of nemorensic acid 3, a necic acid component of the macropyrrolizidine alkaloid nemorensine 2, isolated from Senecio nemorensis L., is described. Reaction of an ∈-halo-α,β-unsaturated ester (8), readily accessible from a monoterpene (-)-carvone, with samarium iodide gave a fragmentation product (9), where a carbon-carbon bond cleavage reaction occurred between the γ and δ positions of the carbonyl group, regioselectively. Deprotection of the silyl group of 9 brought about an intramolecular cyclization to provide tetrahydrofuran derivatives (10), which, upon chemical modification of the side chain, gave nemorensic acid.

Full text of DOI:10.1021/jo990366y

5542
J . Org. Chem. 1999, 64, 5542-5546
En a n tiosp ecific Syn th esis of (+)-Nem or en sic Acid , a Necic Acid
Com p on en t of th e Ma cr op yr r olizid in e Alk a loid , Nem or en sin e
Toshio Honda* and Fumihiro Ishikawa
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, J apan
Received March 2, 1999
A concise enantiospecific synthesis of nemorensic acid 3, a necic acid component of the macropyrroli-
zidine alkaloid nemorensine 2, isolated from Senecio nemorensis L., is described. Reaction of an
ꢀ-halo-R,â-unsaturated ester (8), readily accessible from a monoterpene (-)-carvone, with samarium
iodide gave a fragmentation product (9), where a carbon-carbon bond cleavage reaction occurred
between the γ and δ positions of the carbonyl group, regioselectively. Deprotection of the silyl group
of 9 brought about an intramolecular cyclization to provide tetrahydrofuran derivatives (10), which,
upon chemical modification of the side chain, gave nemorensic acid.
In tr od u ction
Samarium iodide has been recognized as a powerful
one-electron reducing agent. Since Kagan and co-workers
first introduced samarium iodide as a useful synthetic
tool in organic synthesis,1 this reagent has rapidly
become an established reagent in a variety of unique and
useful transformations.2
Recently, we developed a novel samarium iodide-
promoted carbon-carbon bond cleavage reaction of γ-halo
carbonyl compounds,3 where fragmentation occurs be-
tween the R and â positions of the carbonyl group
regioselectively. This fragmentation reaction has been
successfully used in the syntheses of natural products
including alkaloids, terpenes, and antibiotics.4 Therefore,
it would be interesting to investigate the further applica-
tion of this fragmentation to an ꢀ-halo-R,â-unsaturated
ester, where carbon-carbon bond cleavage would be
expected to take place between the γ and δ positions of
the carbonyl group, regioselectively.
F igu r e 1.
to exhibit interesting biological activities,7 such as hepato-
toxic activity, and also since necic acid components
contain a wide range of structural and stereochemical
features, considerable effort has been devoted toward
stereoselective syntheses of these alkaloids,8 especially
for the synthesis of necic acids, in optically pure forms.
Resu lts a n d Discu ssion
In this paper, we would like to report an enantiospecific
synthesis of (+)-nemorensic acid 3,5 a necic acid compo-
nent of a macropyrrolizidine alkaloid nemorensine 2,
isolated from Senecio nemorensis L.,6 in which the
regioselective fragmentation reaction of an ꢀ-halo-R,â-
unsaturated ester with samarium iodide plays as a key
role. Since many macropyrrolizidine alkaloids are known
The structure of nemorensic acid was initially assigned
to be 1.9 However, its structure, including its absolute
configuration, was recently revised to be 2 based on its
chiral synthesis starting from (R)-(+)-â-citronellol,10 and
also by X-ray analysis of nemorensine (Figure 1).10
As depicted for the retrosynthetic route in Scheme 1,
the basic feature of our strategy for developing (+)-
(1) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693.
(7) Mattocks, A. R. Chemistry and Toxicology of Pyrrolizidine
Alkaloids; Academic Press: London, 1986.
(2) Reviews: (a) Inanaga, J . J . Org. Synth. Chem. 1989, 47, 200.
(b) Soderquist, J . A. Aldrichim Acta 1991, 24 15. (c) Curran, D. P.;
Fevig, T. L.; J asperse, C. P.; Totleben, M. J . Synlett 1992, 943. (d)
Molander, G. A. Chem. Rev. 1992, 92, 29. (e) Molander, G. A.; Harris,
C. R. Chem. Rev. 1996, 96, 307. (f) Molander, G. A.; Harris, C. R.
Tetrahedron 1998, 54, 3321 and references therein.
(8) For some examples of the syntheses of macrolactonic pyrrolizi-
dine alkaloids, (a) (+)-Dicrotaline: Devlin, J . A.; Robins, D. J . J . Chem.
Soc., Chem. Commun. 1981, 1272. (b) (+)-Dicrotaline: Niwa, H.;
Okamoto, O.; Ishiwata, H.; Kuroda, A.; Uosaki, Y.; Yamada, K. Bull.
Chem. Soc. J pn. 1988, 61, 3017. (c) (()- Fulvine and (()-crispatine:
Vedejs, E.; Larsen, S. D. J . Am. Chem. Soc. 1984, 106, 3030. (d) (()-
Integerrimine: Narasaka, K.; Sakakura, T.; Uchimaru, T.; Guedin-
Vuong, D. Ibid. 1984, 106, 2954. (e) (-)-Integerrimine and (+)-
usaramine: White, J . D.; Amedio, J . C., J r.; Gut, S.; Ohira, S.;
J ayasinghe, L. R. J . Org. Chem. 1992, 57, 2270. (f) (-)-Integerrimine:
Niwa, H.; Machiya, Y.; Okamoto, O.; Uosaki, Y.; Kuroda, A.; Ishiwata,
H.; Yamada, K. Tetrahedron 1992, 48, 393. (g) Monocrotaline: Vedejs,
E.; Ahmad, S.; Larsen, S. D.; Westwood, S. J . Org. Chem. 1987, 52,
3927. (h) Monocrotaline: Honda, T.; Tomitsuka, K.; Tsubuki, M. J .
Org. Chem. 1993, 58, 4274.
(3) Honda, T.; Naito, K.; Yamane, S.; Suzuki, Y. J . Chem. Soc.,
Chem. Commun. 1992, 1218.
(4) (a) Honda, T.; Yamane, S.; Naito, K.; Suzuki, Y. Heterocycles
1994, 37, 515. (b) Honda, T.; Ishikawa, F.; Yamane, S. J . Chem. Soc.,
Chem. Commun. 1994, 499. (c) Honda, T.; Yamane, S.; Naito, K.;
Suzuki, Y. Heterocycles 1995, 40, 301. (d) Honda, T.; Ishikawa, F.;
Yamane, S. J . Chem. Soc., Perkin Trans. 1 1996, 1125. (e) Honda, T.;
Yamane, S.; Ishikawa, F.; Katoh, M. Tetrahedron 1996, 52, 12177. (f)
Honda, T.; Katoh, M.; Yamane, S. J . Chem. Soc., Perkin Trans. 1 1996,
2219.
(5) Only one synthesis of racemic nemorensic acid was so far
reported: Klein, L. L. J . Am. Chem. Soc. 1985, 107, 2573.
(6) Klasek, A.; Sedmera, P.; Boeva, A.; Santavy, F. Collect. Czech.
Chem. Commun. 1973, 38, 2504.
(9) Nghia, N. T.; Sedmera, P.; Klasek, A.; Boeva, A.; Dvorakova, S.;
Santavy, F. Collect. Czech. Chem. Commun. 1976, 41, 2952.
(10) Dillon, M. P.; Lee, N. C.; Stappenbeck, F.; White, J . D. J . Chem.
Soc., Chem. Commun. 1995, 1645 and references therein. This is the
first and only chiral synthesis of nemorensic acid.
10.1021/jo990366y CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

Enantiospecific Synthesis of (+)-Nemorensic Acid
J . Org. Chem., Vol. 64, No. 15, 1999 5543
Sch em e 1. Retr osyn th etic Rou te for
(+)-Nem or en sic Acid
F igu r e 2.
Sch em e 2
nemorensic acid involved an intramolecular Michael
addition11 of the hydroxy function to R,â-unsaturated
ester (A), which could be derived from ꢀ-halo-R,â-
unsaturated ester (B) by a regioselective fragmentation
reaction, to construct a tetrahydrofuran ring. The desired
ester (B) would be prepared by Wittig olefination of
ketone (C), easily accessible from the known cyclo-
pentanone 4.3
The requisite starting material was prepared as fol-
lows. An optically active cyclopentanone derivative,3
readily derived from (-)-carvone, was treated with
methyllithium to give acetyl compounds (5 and 6), in a
ratio of ca. 2:1, in 91% yield (Scheme 2). The minor
product was assumed to be 6 based on an NMR study,
in which NOE was observed between two methyl groups
at the 1 and 2 positions. After the major compound was
converted to the corresponding triethylsilyl ether with
triethylsilyl triflate, ketone 7 was subjected to a Horner-
Emmons reaction to give the R,â-unsaturated esters 8,
as an inseparable mixture of stereoisomers (E/ Z ) >95
based on NMR analysis), in 96% yield. Since the desired
ester was thus prepared, we applied samarium iodide-
promoted fragmentation to 8, and found that the reaction
proceeded cleanly at room temperature and carbon-
carbon bond cleavage occurred between the γ and δ
positions of the carbonyl group, regioselectively, to pro-
vide olefin-esters 9, as a mixture of stereoisomers (E:Z
) 2:1 based on NMR analysis), in 91% yield. Treatment
of acyclic R,â-unsaturated esters 9 with TBAF brought
about desilylation and subsequent cyclization to give
tetrahydrofuran derivatives 10 as a mixture of cis- and
trans-isomers in quantitative yield. Ozonolysis of the
mixture, followed by reductive treatment with sodium
borohydride gave alcohols 11a and 11b, which could be
separated by HPLC column chromatography on silica gel
to give 2,5-cis-alcohol 11a and 2,5-trans-alcohol 11b in
yields of 17% and 59%, respectively. The stereoselectivity
observed in the formation of 11 can be rationalized by
assuming that the cyclization proceeds via the sterically
favorable transition state TS-1 to predominantly give the
2,5-trans-isomer, whereas, in transition state TS-2, which
leads to the 2,5-cis-isomer, steric repulsion is present
between the methyl groups at the 3 and 6 positions
(Figure 2). A similar cyclization has been previously
reported by White and co-workers, who observed a
similar stereoselectivity.10
(11) Ohrui, H.; J ones, G. H.; Moffatt, J . G.; Maddox, M. L.;
Christensen, A. T.; Byram, S. K. J . Am. Chem. Soc. 1975, 97, 4602.

5544 J . Org. Chem., Vol. 64, No. 15, 1999
Honda and Ishikawa
Sch em e 3
F igu r e 3.
The stereochemical assignment of these alcohols was
made based on the analysis of their NMR spectra. In the
NMR spectrum of 11a , NOE of 1.3% between the methyl
group at the 5-position and the 4-â-proton was observed
in addition to that between the 4-R-proton and the
methylene protons of the acetate unit. On the other hand,
the 4-â-proton and 4-R-proton were correlated to the
methylene protons of the acetate and methyl group at
the 5-position, respectively, in the NMR spectrum of 11b,
as depicted in Figure 3.
Although the desired tetrahydrofuran derivative hav-
ing the same stereochemistry as the natural compound
was isolated as a minor stereoisomer, we focused our
attention on conversion of the hydroxyethyl moiety to the
one-carbon-reduced carboxylic acid. To determine the
stereochemistry unambiguously, both alcohols 11a and
11b were transformed into olefins 13 and 15 using
Grieco’s procedure12 via 2-nitrophenylselenides (12 and
14), respectively. Ozonolysis of olefin 13, followed by
reductive workup with triphenylphosphine gave an al-
dehyde, which without purification was subjected to
further oxidation with sodium chlorite13 and subsequent
hydrolysis of the ester group to give acid 3 in 72% yield
from olefin 13 (Scheme 3). The spectral properties includ-
ing the specific optical rotation of 3 were identical to those
reported in the literature.10 The major isomer was also
converted into the known acid 16,9 via aldehyde, by using
the same procedure that was used to prepare 3 in 80%
yield from 15. Acid 16 was further esterified with methyl
iodide to give ester 17, in 71% yield, whose spectroscopic
data were also identical to those reported in the litera-
ture.10
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. All melting points
are uncorrected. IR spectra were measured for solutions in
CHCl3. 1H NMR and 13C NMR spectra were obtained for a
solution in CDCl3 unless otherwise stated, and chemical shifts
are reported on the δ scale from TMS as an internal standard.
(1S,2R,3R,4R)- a n d (1R,2R,3R,4R)-3-Acetyl-4-(2-ch lor o-
2-m eth yleth yl)-1,2-d im eth yl-1-cyclop en ta n ol (5 a n d 6).
To a stirred solution of acid (4) (1.0 g, 4.58 mmol) in THF (20
mL) was added dropwise methyllithium (21.6 mL, 1.06M Et2O
solution, low halide) at -78 °C, and the resulting mixture was
stirred for 1 h at the same temperature and then for 12 h at
room temperature. The reaction was quenched by adding
aqueous NH4Cl solution, and the mixture was extracted with
ethyl acetate. The extract was washed with brine and dried
over Na2SO4. Evaporation of the solvent gave a residue, which
was subjected to column chromatography on silica gel. Elution
with hexanes-ethyl acetate (4:1) gave alcohol (5) (0.55 g, 61%)
In summary, we have developed a novel stereospecific
synthetic route for (+)-nemorensic acid by means of
samarium iodide-promoted regioselective carbon-carbon
bond cleavage reaction of an ꢀ-halo-R,â-unsaturated ester.
This type of fragmentation with samarium iodide is
unprecedented, and the strategy developed here should
also be applicable to the synthesis of other types of necic
acid components of macropyrrolizidine alkaloids.
as a colorless oil; [R]25 +20.7 (c 0.9, CHCl3); IR 3420, 2970,
D
1750 cm-1; 1H NMR δ 1.10 (d, 3H, J ) 7.4 Hz, 2-Me), 1.22 (s,
3H, 1-Me), 1.46 (s, 3H, 4-Me), 1.55 (s, 3H, 4-Me), 1.67-1.75
(m, 1H, 4-H), 1.87-1.93 (m, 1H, 2-H), 2.30 (s, 3H, Ac), 2.75-
2.83 (m, 1H, 3-H), 2.90-3.00 (m, 2H, 5-H2); 13C NMR δ 18.43,
19.96, 20.40, 29.93, 33.17, 43.67, 44.90, 49.34, 63.24, 64.03,
111.06; HRMS calcd for C12H20O2 (M+ - HCl) 196.1462, found
(M+ - HCl) 196.1462. Anal. Calcd for C12H21O2Cl: C, 61.91;
H, 9.09. Found: C, 62.13; H, 9.02. Further elution with the
same solvent system gave 1R-isomer (6) (0.27 mg, 30%) as a
(12) Grieco, P. A.; Gilman, S,; Nishizawa, M. J . Org. Chem. 1976,
41, 1485.
(13) Bal, B. S.; Childers, W. E., J r.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
colorless oil: [R]25 -16.3 (c 0.05, CHCl3); IR 3450, 1710
D

Enantiospecific Synthesis of (+)-Nemorensic Acid
J . Org. Chem., Vol. 64, No. 15, 1999 5545
1
cm-1; H NMR δ 0.95 (d, 3H, J ) 6.7 Hz, 2-Me), 1.24 (s, 3H,
3H, 3-Me), 2.18 (d, 1H, J ) 7.4 Hz, 4-H), 2.42 (d, 1H, J ) 7.4
Hz, 4-H), 4.09-4.18 (m, 2H, CO2CH2Me), 5.16-5.22 (m, 1H,
8-H), 5.64 (s, 0.7 H, 2-H), 5.73 (s, 0.3 H, 2-H); 13C NMR δ 6.99,
7.25, 7.26, 14.13, 14.35, 18.09, 18.47, 22.71, 29.38, 29.68, 29.72,
31.95, 40.26, 59.43, 77.96, 116.87, 117.69, 120.41; HRMS calcd
for C22H42O3Si (M+) 353.2511, found (M+) 353.2508. Anal.
Calcd for C22H42O3Si: C, 69.05; H, 11.06. Found: C, 69.18; H,
10.65.
1-Me), 1.44 (s, 3H, 4-Me), 1.53 (s, 3H, 4-Me), 1.85-1.95 (m,
2H, 3-H and 5-H), 2.11-2.20 (m, 1H, 2-H), 2.19 (s, 3H, Ac),
2.69-2.76 (m, 2H, 4-H and 5-H); HRMS calcd for C12H20O2
(M+ - HCl) 196.1462, found (M+ - HCl) 196.1458.
(1S,2R,3R,4R)-3-Acet yl-4-(2-ch lor o-2-m et h ylet h yl)-1-
(tr ieth ylsiloxy)-1,2-d im eth ylcyclop en ta n e (7). A solution
of alcohol (5) (10.8 g, 55.1 mmol), 2,6-lutidine (23.6 g, 220.2
mmol), and triethylsilyl trifluoromethanesulfonate (26.0 g,
110.2 mmol) in CH2Cl2 (200 mL) was stirred at -30 °C for 2
h under argon. After adding aqueous NH4Cl solution, the
mixture was treated with CH2Cl2, and the organic layer that
separated was washed with brine and dried over Na2SO4.
Removal of the solvent left a residue, which was purified by
column chromatography on silica gel using hexanes-ethyl
acetate (9:1) as an eluent to give triethylsilyl ether (7) (16.7
g, 88%) as a colorless oil: [R]25D -54.4 (c 0.01, CHCl3); IR 2960,
A Mixt u r e of (2S,3R,5R)- a n d (2S,3R,5S)-5-(E t h oxy-
ca r bon ylm eth yl)-2,3,5-tr im eth yl-2-(3′-m eth yl-2-bu ten yl)-
tetr a h yd r ofu r a n s (10). To a stirred solution of triethylsilyl
ether (9) (0.86 g, 2.44 mmol) in THF (30 mL) was added TBAF
(1.0 M THF solution, 4.87 mL, 4.87 mmol) at ambient tem-
perature, and the resulting solution was heated at reflux for
2 h. The mixture was treated with water (30 mL) and extracted
with ethyl acetate. The organic layer was washed with brine
and dried over Na2SO4. Evaporation of the solvent gave a
residue, which was purified by column chromatography on
silica gel using hexanes-ethyl acetate (12:1) as an eluent to
give an inseparable diastereomeric mixture of tetrahydrofuran
derivatives (10) (5S:5R ) 3:1) (0.65 g, 100%) as a colorless oil:
1715 cm-1; H NMR δ 0.55 (q, 6H, J ) 7.6 Hz, TES), 0.93 (t,
1
9H, J ) 7.9 Hz, TES), 1.06 (d, 3H, J ) 7.3 Hz, 2-Me), 1.23 (s,
3H, 1-Me), 1.41 (s, 3H, 4-Me), 1.53 (s, 3H, 4-Me), 1.75-2.18
(m, 3H, 2-H and 5-H2), 2.20 (s, 3H, Ac), 2.53 (dd, 1H, J ) 7.3
and 7.6 Hz, 3-H), 3.01 (dt, 1H, J ) 7.6 and 9.8 Hz, 4-H); 13C
NMR δ 3.92, 4.39, 12.73, 18.63, 21.97, 30.32, 41.85, 43.09,
44.03, 48.38, 61.52, 107.75, 143.52; HRMS calcd for C18H35O2-
SiCl (M+) 346.2095, found (M+) 346.2088.
1
IR 2970, 1735 cm-1; H NMR δ 0.97 (d, 0.75 H, J ) 6.8 Hz,
3-Me), 0.99 (d, 2.25 H, J ) 6.8 Hz, 3-Me), 1.14 (s, 0.75H, 2-Me),
1.16 (s, 2.25H, 2-Me), 1.25 (s, 0.75H, 5-Me), 1.31 (s, 2.25H,
5-Me), 1.26 (t, 3H, J ) 7.3 Hz, CO2CH2Me), 1.59 (s, 3H, 3′-
Me), 1.73 (s, 3H, 3′-Me), 1.93-2.50 (m, 5H, 3-H, CH2CO2, and
1′-H2), 2.61 (t, 2H, J ) 14.2 Hz, 4-H2), 4.06-4.20 (m, 2H,
CO2CH2Me), 5.24-5.35 (m, 1H, 2′-H); 13C NMR for 5S-isomer
δ 5.74, 13.39, 14.12, 17.93, 25.82, 25.96, 28.28, 33.90, 43.28,
44.55, 47.88, 60.14, 78.97, 84.97, 120.33, 171.19; 13C NMR for
5R-isomer δ 6.52, 13.44, 14.15, 17.93, 25.43, 25.98, 28.80,
34.18, 43.48, 44.16, 47.06, 60.14, 79.32, 85.04, 120.33. 171.19;
HRMS calcd for C16H28O3 (M+) 268.2038, found (M+) 268.2048.
(2S,3R,5S)- a n d (2S,3R,5R)-5-(Eth oxyca r bon ylm eth yl)-
2-(2-h yd r oxyeth yl)-2,3,5-tr im eth yltetr a h yd r ofu r a n s (11).
A solution of olefin (10) (3.2 g, 11.9 mmol) in EtOH (60 mL)
was saturated with ozone at -78 °C. The solution was stirred
for 15 min at the same temperature, and the ozone was
removed by exchange with argon. Sodium borohydride (0.45
g, 12.0 mmol) was added portionwise to the solution, and the
mixture was then warmed to 0 °C. After the mixture was
stirred for an additional 1 h at the same temperature, the
reaction was quenched by adding acetone (2 mL). The solvent
was removed by evaporation, and the residue was dissolved
in Et2O. The insoluble material was filtered off through a pad
of Celite, and the filtrate was concentrated to leave a residue,
which was subjected to column chromatography on silica gel.
Elution with hexanes-ethyl acetate (4:1) gave a mixture of
alcohols (11) (2.18 g, 75%) as a colorless oil. This mixture was
separated by HPLC using a silica gel column (Waters 5SL:
250 mm × 4.6 mm i.d.; flow rate: 3.0 mL/min; column temp.
25 °C; UV detection at 210 nm) with hexanes-Et2O (16:1) to
give a 5S-compound (0.48 g, 17%) and 5R-compound (1.70 g,
(E)-Eth yl 3-[1′-(1′R,2′R,3′S,5′R)-5′-(2′′-Ch lor o-2′′-m eth yl-
et h yl)-3′-(t r iet h ylsiloxy)-2′,3′-d im et h ylcyclop en t yl]-2-
bu ten oa te (8). To a stirred solution of triethyl phosphono-
acetate (2.76 g, 13.0 mmol) in THF (20 mL) was added
n-butyllithium (8.76 mL, 1.0M THF solution) at -15 °C under
argon, and the resulting mixture was stirred for an additional
30 min at the same temperature. A solution of ketone (7) (1.5
g, 4.33 mmol) in THF (10 mL) was added to the above solution,
and the mixture was heated at reflux for 12 h. After cooling
to 0 °C, the reaction was quenched by adding aqueous NH4Cl
solution, and extracted with ethyl acetate. The extract was
washed with brine and dried over Na2SO4. Evaporation of the
solvent gave a residue, which was purified by column chro-
matography on silica gel using hexanes-ethyl acetate (9:1) as
an eluent to give (E)-R,â-unsaturated ester (8) (1.72 g, 96%)
as a colorless oil: [R]25 -16.0 (c 0.2, CHCl3); IR 2960, 1730
D
cm-1; 1H NMR δ 0.65 (q, 6H, J ) 7.9 Hz, TES), 0.83 (d, 3H, J
) 6.3 Hz, 2′-Me), 0.95 (t, 9H, J ) 7.9 Hz, TES), 0.86-0.95 (m,
1H, 2′-H), 1.26 (t, 3H, J ) 7.3 Hz, CO2CH2Me), 1.19 (s, 3H,
5′-Me), 1.28 (s, 3H, 5′-Me), 1.64 (s, 3H, 3′-Me), 1.95-2.09 (m,
3H, 5′-H and 4′-H2), 2.13 (s, 3H, 3-Me), 4.13 (q, 2H, J ) 7.3
Hz, CO2CH2Me), 4.68 (br s, 1H, olefinic proton); 13C NMR δ
6.65, 7.10, 14.30, 14.66, 19.93, 25.52, 29.69, 46.77, 47.29, 50.58,
59.47, 61.28, 81.26, 110.68, 117.24, 145.83, 166.63; HRMS
calcd for C22H41O3SiCl (M+) 416.2513, found (M+) 416.2493.
Anal. Calcd for C22H41O3SiCl: C, 63.35; H, 9.91. Found: C,
63.73; H, 10.04.
Eth yl (5R,6S)-6-(Tr ieth ylsiloxy)-3,5,6,9-tetr am eth yldeca-
2,8-d ien oa te (9). To a stirred suspension of samarium metal
(6.91 g, 45 mmol) in THF (50 mL) was added a solution of 1,2-
diiodoethane (11.8 g, 41.8 mmol) in THF (30 mL) under argon
at ambient temperature, and the solution was stirred for 30
min. After adding HMPA (6.0 mL), the resulting solution was
stirred for 10 min at the same temperature. To this mixture
was added a solution of ester (8) (5.8 g, 13.9 mmol) in THF
(30 mL). After stirring for 15 min, the mixture was treated
with saturated sodium hydrogen carbonate solution, an excess
of ether (400 mL), and Celite (100 g). Insoluble materials were
filtered off, and the filtrate was treated with water (100 mL).
The organic layer was separated, and the aqueous layer was
extracted with ether. The combined ethereal layer was washed
with brine and dried over Na2SO4. Evaporation of the solvent
gave a residue, which was purified by column chromatography
on silica gel using hexanes-ethyl acetate (15:1) as an eluent
to give a mixture of (E)- and (Z)-R,â-unsaturated esters (9)
59%), respectively. (2S,3R,5S)-Compound (11a ): [R]25 +65.2
D
(c 0.1, CHCl3); IR 3430, 2980, 1725 cm-1; H NMR δ 0.94 (d,
1
H, J ) 6.9 Hz, 3-Me), 1.28 (t, 3H, J ) 7.2 Hz, CO2CH2Me),
1.29 (s, 3H, 2-Me), 1.31 (s, 3H, 5-Me), 1.62 (t, 1H, J ) 12.5
Hz, 4-H), 1.72-1.82 (m, 2H, 1′-H2), 2.25 (dd, 1H, J ) 6.9 and
12.5 Hz, 4-H), 2.28-2.35 (m, 1H, 3-H), 2.47 (br s, 2H, CH2-
COO), 4.01 (t, 2H, J ) 11.4 Hz, 2′-H2), 4.13 (q, 2H, J ) 7.2
Hz, OCH2Me); 13C NMR δ 13.18, 14.08, 24.74, 28.30, 35.98,
43.88, 44.45, 46.83, 59.57, 60.18, 80.13, 86.08, 170.75; HRMS
calcd for
C
13H24O4 (M+) 244.3263, found (M+) 244.3259.
(2S,3R,5R)-Compound (11b): [R]25 +49.1 (c 0.1, CHCl3); IR
D
3430, 2980, 1730 cm-1; 1H NMR δ 0.96 (d, H, J ) 6.9 Hz, 3-Me),
1.26 (t, 3H, J ) 7.1 Hz, CO2CH2Me), 1.28 (s, 3H, 2-Me), 1.31
(s, 3H, 5-Me), 1.73-1.90 (m, 2H, 1′-H2), 1.83 (t, 1H, J ) 12.5
Hz, 4-H), 2.01 (dd, 1H, J ) 6.6 and 12.5 Hz, 4-H), 2.17-2.36
(m, 1H, 3-H), 2.57 and 2.64 (each d, each 1H, J ) 13.7 Hz,
CH2COO), 4.03 (t, 2H, J ) 10.6 Hz, 2′-H2), 4.14 (q, 2H, J )
7.1 Hz, OCH2Me); 13C NMR δ 13.18, 14.04, 25.31, 27.54, 36.19,
43.62, 45.37, 47.78, 59.30, 60.33, 79.55, 85.91, 170.84; HRMS
calcd for C13H24O4 (M+) 244.3263, found (M+) 244.3266.
(2S,3R,5S)-2-Eth en yl-5-(eth oxyca r bon ylm eth yl)-2,3,5-
t r im et h ylt et r a h yd r ofu r a n (13). To a stirred solution of
(4.48 g, 91%) as a colorless oil: IR 2960, 1720 cm-1; H NMR
1
δ 0.59 (q, 6H, J ) 7.9 Hz, TES), 0.78 (d, 3H, J ) 6.3 Hz, 5-Me),
0.96 (t, 9H, J ) 7.9 Hz, TES), 0.82-0.89 (m, 2H, 7-H2), 1.18
(s, 3H, 6-Me), 1.28 (t, 3H, J ) 7.3 Hz, CO2CH2Me), 1.61 (s,
3H, 9-Me), 1.72 (s, 3H, 9-Me), 1.73-1.84 (m, 1H, 5-H), 2.11 (s,

5546 J . Org. Chem., Vol. 64, No. 15, 1999
Honda and Ishikawa
alcohol (11a ) (1.7 g, 6.96 mmol) and o-nitrophenyl selenenyl
cyanide (2.4 g, 10.4 mmol) in THF (35 mL) was added
portionwise tributylphosphine (2.1 g, 10.4 mmol) at 0 °C, and
the resulting mixture was allowed to warm to room temper-
ature and then stirred for an additional 5 h. After evaporation
of the solvent, the residue was taken up with CH2Cl2 (50 mL).
To this solution was added m-CPBA (7.7 g, 45.0 mmol)
portionwise at 0 °C, and the mixture was again allowed to
warm to room temperature and then stirred for 30 min at the
same temperature. The mixture was diluted with CH2Cl2,
washed successively with 10% sodium thiosulfate solution,
saturated sodium hydrogen carbonate solution, and brine, and
dried over Na2SO4. Evaporation of the solvent gave a residue,
which was purified by column chromatography on silica gel
using hexanes-ethyl acetate (6:1) as an eluent to give olefin
hydrochloric acid and extracted with CH2Cl2. The organic layer
was washed with brine and dried over Na2SO4. Evaporation
of the solvent gave a residue, which was dissolved in methanol
(2 mL). After adding 2 N NaOH solution (1 mL), the mixture
was heated at reflux for 5 h and then cooled to 0 °C. The
aqueous layer was washed with CH2Cl2 and then treated with
1 N hydrochloric acid to adjust the pH to 1-2. Removal of the
solvent gave a residue, which was taken up with methanol.
The insoluble material was filtered off, and the filtrate was
concentrated to leave a residue, which was purified by
reversed-phase column chromatography using Sep pak C18
with water to give acid (3) (29.6 mg, 72%) as a colorless
powder: mp 174-176.5 °C [lit.,9 174-178 °C; lit.,10 174-175
°C]; [R]25D +88.1 (c 0.06, EtOH) [lit.,9 [R]24D +87 (c 0.84, EtOH);
lit.,10 [R]23D +87.2 (c 0.24, EtOH)]; IR 2970, 1705 cm-1; 1H NMR
(D2O) δ 1.00 (d, 3H, J ) 6.9 Hz, 3-Me), 1.34 (s, 3H, 2-Me),
1.42 (s, 3H, 5-Me), 1.83 (t, 1H, J ) 12.5 Hz, 4-H), 2.09 (dd,
1H, J ) 6.8 and 12.5 Hz, 4-H), 2.30-2.44 (m, 1H, 3-H), 2.64
(dd, 2H, J ) 14.5 and 14.5 Hz, CH2COO); HRMS calcd for
C10H16O5 (M+) 216.0998, found (M+) 216.0998. The spectro-
scopic data were identical to those reported in the literature.9,10
tr a n s-Nem or en sic Acid (16). Ozonolysis of olefin (15) (50
mg, 0.22 mmol), followed by oxidation of the aldehyde with
sodium chlorite and hydrolysis of the ester group was carried
out using essentially the same procedure that was used to
prepare cis-nemorensic acid to give trans-nemorensic acid (16)
(13) (1.42 g, 91%) as a colorless oil: [R]25 +60.1 (c 0.01,
D
CHCl3); IR 2900, 1750 cm-1; 1H NMR δ 0.95 (d, H, J ) 6.9 Hz,
3-Me), 1.26 (t, 3H, J ) 7.3 Hz, CO2CH2Me), 1.31 (s, 3H, 2-Me),
1.35 (s, 3H, 5-Me), 1.71 (t, 1H, J ) 12.4 Hz, 4-H), 1.99 (dd,
1H, J ) 6.3 and 12.4 Hz, 4-H), 2.20-2.33 (m, 1H, 3H), 2.61
and 2.72 (each d, each 1H, J ) 14.0 Hz, CH2COO), 4.14 (q,
2H, J ) 7.3 Hz, OCH2Me), 5.08 (d, 1H, J ) 10.7 Hz, olefinic
proton), 5.27 (d, 1H, J ) 17.2 Hz, olefinic proton), 5.78 (dd,
1H, J ) 10.7 and 17.2 Hz, olefinic proton); 13C NMR δ 14.10,
14.13, 26.38, 27.76, 33.30, 44.38, 46.71, 60.06, 79.86, 85.27,
113.29, 140.75, 170.91; HRMS calcd for C13H22O3 (M+) 226.1596,
found (M+) 226.1578. Anal. Calcd for C13H22O3: C, 68.99; H,
9.80. Found: C, 68.70; H, 9.85.
(38 mg, 80%) as a colorless oil: [R]25 +48.8 (c 0.1, CHCl3)
D
[lit.,10 [R]23 +55.4 (c 0.99, CHCl3)]; IR 2990, 1710 cm-1
;
1H
D
(2S,3R,5R)-2-Eth en yl-5-(eth oxyca r bon ylm eth yl)-2,3,5-
tr im eth yltetr a h yd r ofu r a n (15). Alcohol 11b (3.0 g, 12.3
mmol) was dehydrated by essentially the same procedure that
was used to prepare its stereoisomer using Grieco’s procedure
NMR (D2O) δ 0.95 (d, H, J ) 6.9 Hz, 3-Me), 1.29 (s, 3H, 2-Me),
1.36 (s, 3H, 5-Me), 1.76 (t, 1H, J ) 12.5 Hz, 4-H), 2.03 (dd,
1H, J ) 6.6 and 12.5 Hz, 4-H), 2.24-2.38 (m, 1H, 3-H), 2.53
and 2.54 (each d, each 1H, J ) 13.8 Hz, CH2COO); HRMS calcd
for C10H16O5 (M+) 216.0998, found (M+) 216.0977.
to give olefin (15) (2.38 g, 86%) as a colorless oil: [R]25 +55.3
D
(c 0.02, CHCl3); IR 2980, 1745 cm-1; H NMR δ 0.96 (d, H, J
tr a n s-Nem or en sic Acid Dim eth yl Ester (17). A solution
of acid (16) (24 mg, 0.11 mmol), K2CO3 (62 mg, 0.44 mmol),
and iodomethane (40 mg, 0.28 mmol) in DMF (4 mL) was
stirred at room temperature for 3 h under argon. The mixture
was treated with saturated NH4Cl solution and extracted with
ethyl acetate. The extract was washed with brine and dried
over Na2SO4. Evaporation of the solvent gave a residue, which
was purified by column chromatography on silica gel using
hexanes-ethyl acetate (4:1) as an eluent to give ester (17) (19.2
1
) 6.9 Hz, 3-Me), 1.26 (t, 3H, J ) 7.3 Hz, CO2CH2Me), 1.32 (s,
3H, 2-Me), 1.36 (s, 3H, 5-Me), 1.71 (t, 1H, J ) 12.5 Hz, 4-H),
1.99 (dd, 1H, J ) 6.3 and 12.5 Hz, 4-H), 2.20-2.33 (m, 1H,
3-H), 2.58-2.75 (m, 2H, CH2COO), 4.12 (q, 2H, J ) 7.3 Hz,
OCH2Me), 5.07 (d, 1H, J ) 10.7 Hz, olefinic proton), 5.26 (d,
1H, J ) 17.2 Hz, olefinic proton), 5.79 (dd, 1H, J ) 10.7 and
17.2 Hz, olefinic proton); 13C NMR δ 14.06, 14.10, 26.84, 27.57,
43.35, 44.97, 47.79, 60.06, 79.42, 85.10, 113.19, 140.64, 170.98.
Anal. Calcd for C13H22O3: C, 68.99; H, 9.80. Found: C, 68.69;
H, 9.96.
mg, 71%) as a colorless oil: [R]25 +60.8 (c 0.01, CHCl3); IR
D
2920, 1735 cm-1
;
1H NMR δ 1.08 (d, H, J ) 6.9 Hz, 3-Me),
cis-Nem or en sic Acid (3). A solution of olefin (13) (42 mg,
0.19 mmol) in dichloromethane (15 mL) was saturated with
ozone at -78 °C. The solution was stirred for 30 min at the
same temperature, and ozone was removed by exchange with
argon. To this solution was added triphenylphosphine (75 mg,
29 mmol), and the resulting mixture was allowed to warm to
room temperature. After evaporation of the solvent, the residue
was taken up with Et2O, and the ethereal layer was filtered
through a pad of Celite to remove insoluble materials. The
filtrate was concentrated to leave a residue, which, without
further purification, was used in the next step. To a stirred
solution of the aldehyde obtained above, 2-methyl-2-butene (53
mg, 0.76 mmol), and NaH2PO4 (23 mg, 0.19 mmol) in water
(0.4 mL) and tert-butyl alcohol (1.5 mL) was added portionwise
sodium chlorite (51 mg, 0.57 mmol) at room temperature, and
the resulting mixture was stirred for an additional 1 h at the
same temperature. The solution was acidified with 1 N
1.25 (s, 3H, 2-Me), 1.34 (s, 3H, 5-Me), 1.92 (dd, 1H, J ) 12.3
and 12.5 Hz, 4-H), 2.04 (dd, 1H, J ) 6.8 and 12.5 Hz, 4-H),
2.59-2.79 (m, 3H, 3-H and 1′-H2), 3.66 (s, 3H, Me), 3.74 (s,
3H, Me); HRMS calcd for C12H20O5 (M+) 244.2834, found (M+)
244.2844.
The spectroscopic data of the synthetic compound were
identical to those reported in the literature.10
Ack n ow led gm en t. This work was supported by the
Ministry of Education, Science, Sports and Culture of
J apan.
Su p p or tin g In for m a tion Ava ila ble: IR, 1H and 13C NMR
spectra for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O990366Y