Triterpenoid total synthesis. Synthesis and absolute configuration of mispyric acid

Article abstract of DOI:10.1039/b406820c

The first synthesis of mispyric acid (1), an inhibitor β DNA polymerase β with a novel triterpene skeleton, was achieved by starting from isoprene (2), geraniol (6) and 1,5-dimethoxy-1,4-cyclohexadiene (14). The absolute configuration of the naturally occ

Full text of DOI:10.1039/b406820c

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A R T I C L E
Triterpenoid total synthesis. Synthesis and absolute configuration
of mispyric acid†
Yusuke Imamura,a Hirosato Takikawa,*a Mitsuru Sasakia and Kenji Mori*b
a
Department of Biosystems Science, Graduate School of Science and Technology,
Kobe University, Rokkodai 1-1, Nada-ku, Kobe 657-8501, Japan.
E-mail: takikawa@kobe-u.ac.jp; Fax: +81 78 803 5958; Tel: +81 78 803 5958
Insect Pheromone and Traps Division, Fuji Flavor Co. Ltd., Midorigaoka 3-5-8, Hamura,
b
Tokyo 205-8503, Japan
Received 6th May 2004, Accepted 9th June 2004
First published as an Advance Article on the web 14th July 2004
The first synthesis of mispyric acid (1), an inhibitor of DNA polymerase  with a novel triterpene skeleton, was achieved
by starting from isoprene (2), geraniol (6) and 1,5-dimethoxy-1,4-cyclohexadiene (14). The absolute configuration of the
naturally occurring 1 was determined as 2S,4S.
Wittig adduct lacking in a hydroxymethyl group (~30%). However,
Introduction
we could obtain geometrically pure 10 without contamination of
the undesired (E)-isomer. Although other methodologies10 might be
applicable for the preparation of 10, this route was adopted due to
its brevity. After protection of the hydroxyl group of 10 as TBDPS
ether (22% based on 9), the resulting bis-silyl ether 11 was con-
verted to the corresponding allylic bromide 13 in 2 steps (80%).
With two alkylating agents, 5 and 13, in hand, we moved to
construct the basic framework of mispyric acid. The lithiated 1,5-
dimethoxy-1,4-cyclohexadiene 1411 was treated with 5 to give the
alkylation product 15 (69%), which was then converted to 16 in
conventional 3 steps (49%) as follows; treatment with acid, enol
ether formation and TBS protection. For the installation of another
side chain, the lithioenolate of 16 was alkylated with an allylic bro-
mide 13 to furnish 17 (93%). This was then exposed to MeMgBr to
afford the key intermediate (±)-18 (91%).
In 1999, Hecht and his co-workers isolated mispyric acid (1), a struc-
turally unique triterpene dicarboxylic acid with a novel skeleton,
from the stem bark ofAustralian plant Mischocarpus pyriformis as a
DNA polymerase  inhibitor.2 This structurally unique monocyclic
triterpene is presumably derived via a new biogenetic pathway in-
cluding direct coupling of two farnesyl units.2 In continuation of our
works on synthesis of DNA polymerase inhibitors3 and biosyntheti-
cally unique triterpenoids,4 we initiated the synthesis of mispyric
acid (1). While we have already reported the first synthesis of (±)-1
as a preliminary communication,5 the enantioselective synthesis of
1 has never been disclosed and the absolute configuration of natural
1 has remained unknown. Herein, we report the first synthesis and
determination of the absolute configuration of 1 in detail.
Our synthetic plan for 1 is shown in Scheme 1, which is based
on our racemate synthesis.5 The target compound 1 was readily
obtainable from A, which was prepared from B by installation of
a methyl group to the enone and subsequent methylenation of the
carbonyl group. For the construction of the key intermediate B, two
alkylations (C with D, and E with F) were chosen as the key steps.
Preparation of the two alkylating agents (D and F), corresponding
to the side chains, was considered to be possible by conventional
methods. However, the remaining problem was how to prepare the
optically active form. There was a need to carry out the asymmetric
reaction or the optical resolution at an appropriate stage, because
our envisioned route could not take in any optically active starting
material.
As mentioned before, there was a need to secure an optically
active intermediate. For this purpose, we first envisioned utiliz-
ing asymmetric reduction. Thus, the key intermediate (±)-18 was
exposed to some chiral reducing reagents such as CBS reagent12
and BINAL-H.13 Unfortunately, however, these trials were unsuc-
cessful. Therefore, we turned to optical resolution (Scheme 3).
For the conventional optical resolution, (±)-18 was reduced with
L-selectride® to give the secondarily allylic alcohols (±)-19a and
(±)-19b (94%; ca. 9:1). The relative configurations of both isomers
1
were elucidated based on the similarity of H-NMR data between
19a/b and the structurally related compounds.14 The minor isomer
(±)-19b could be easily recycled to the parent ketone (±)-18 by oxi-
dation with o-iodoxybenzoic acid (IBX).15 Our attempts to resolve
(±)-19a by enzymatic resolution were not fruitful either, even after
screening of over ten hydrolytic enzymes. The next and remain-
ing method was the classical resolution using a chiral derivatizing
reagent. After examination of some resolving reagents such as O-
methylmandelic acid, camphanic acid and 3-acetoxyetienic acid,16
we eventually found that Harada’s reagent 2017 gave the successful
results as follows. Condensation of (±)-19a and (S)-20 (>99.9% ee)
was performed with DCC in the presence of DMAP to give a
diastereomeric mixture of 21a and 21b. Although this mixture was
chromatographically inseparable, removal of TBS and TBDPS pro-
tecting groups made it possible for us to separate the resulting diols
22a/b by flash chromatography, affording the less polar isomer
(40%) and more polar isomer (36%), respectively. The remaining
problem was determination of the configurations of both diastereo-
mers.Although our trial to apply a modified Mosher’s method18 was
not perfectly successful due to poor resolution of the critical signals,
we tentatively speculated that the less polar isomer was 22a and the
more polar was 22b based on fragmentarily perceived  values at
5′-and 5″-H (vide infra).
Results and discussion
Our synthetic route to the key intermediate B (= 18) is illustrated in
Scheme 2. First, we synthesized the two alkylating agents as follows.
According to the reported procedure, allylic chloride 3 was prepared
from isoprene 2 in 3 steps.6 The chloride 3 was converted into the
corresponding bromide 4, which was immediately exposed to the
homologation reaction developed by Knochel et al.,7 furnishing
homoallylic iodide 5 (42% based on 3). It should be noted that this
homologation was not successful with the allylic chloride 3. Next,
an aldehyde 9 was prepared from geraniol 6 by the following four-
step sequence: TBS protection (98%), regioselective epoxidation
(81%), oxidative cleavage of the epoxide and re-protection (56%;
2 steps). The aldehyde 9 was then subjected to Corey–Yamamoto’s
modified Wittig reaction with concomitant hydroxymethylation.8 In
spite of all our efforts, the reaction of 9 with 5-methyl-4-hexenyli-
denetriphenylphosphorane9 and paraformaldehyde gave the desired
adduct 10 in rather low yield. The major by-product was the usual
† Triterpenoid total synthesis. Part 8. For part 7 see ref. 1
2 2 3 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 3 6 – 2 2 4 4
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Scheme 1 Structure of mispyric acid (1) and its synthetic plan.
Scheme 2 Synthesis of the key intermediate (±)-18. Reagents and conditions: (a) NaBr, DMF, rt; (b) ICH2ZnI, CuI, LiI, THF, −25 °C to rt (42% based on 3);
(c) TBSCl, imidazole, DMF (98%); (d) mCPBA, CHCl3 (81%); (e) HIO4·2H2O, THF–H2O; (f) TBSCl, imidazole, DMF (56% based on 8); (g) 5-methyl-4-
hexenylidenetriphenylphosphorane, THF, −78 °C; s-BuLi, −25 °C; then (CH2O)n, 0 °C to rt; (h) TBDPSCl, imidazole, DMF (22% based on 9); (i) AcOH,
H2O, THF (92%); (j) PBr3, pyridine, Et2O (87%); (k) t-BuLi, THF, −78 °C; then HMPA, 5 (69%); (l) 1 M HCl, THF; (m) CH2N2, Et2O–EtOAc–MeOH, 0 °C;
(n) TBSCl, imidazole, DMF (49% based on 15); (o) LDA, THF, −78 °C; then 13, −90 °C to rt (93%); (p) MeMgBr, THF, 5 °C to rt; then NH4Cl aq. (91%).
Diastereomerically pure diol 22a was converted into the corre-
sponding bis-TBS ether 23a (91%), which was subjected to reduc-
tive cleavage of the resolving auxiliary to furnish allylic alcohol
(−)-24 (87%). This was then exposed to cyclopropanation19 to give
(−)-25 (95%). The bicyclic alcohol (−)-25 was then oxidized with
PDC to afford (+)-26 (91%). Reductive cleavage of the cyclopro-
pane ring20 was carried out under the classical Birch conditions, Li,
NH3, THF and t-BuOH, to yield the desired (−)-27 (66%). Under
these conditions, unexpectedly and delightfully, the resulting 27
was proven to be free from the undesired trans-isomer. The desired
cis-isomer 27 must be not only kinetically but also thermodynami-
cally more preferable than the trans-isomer. Similarly, 22b was also
converted into (+)-27. At this stage, we applied circular dichroism
(CD) spectroscopy for the confirmation of the absolute configura-
tions of (−)- and (+)-27. In their CD spectra, we observed a negative
Cotton effect in the case of (−)-27, while (+)-27 was with a positive
Cotton effect. Applications of the octant rule21 proved the absolute
configurations of (−)- and (+)-27 to be (2R,4S) and (2S,4R), respec-
tively, as shown in Scheme 4. These results are in agreement with
our speculation based on a modified Mosher’s method applied for
22a/b.
The ketone (−)-27 was exposed to Wittig methylenation to give
(2S,4S)-28 (80%). After removal of the two TBS groups (97%), the
resulting diol (2S,4S)-29 was oxidized stepwise with Dess–Mar-
tin periodinane (DMP)22,23 followed by NaClO2 to give the target
compound (2S,4S)-1 (68%, 2 steps), []D27 +9.2 (c 0.22 in MeOH),
{lit.,2 []D20 +12.5 (c 0.05 in MeOH)}. The various spectral data
of synthetic (2S,4S)-1 are in good accord with those of the natural
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 3 6 – 2 2 4 4
2 2 3 7

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Scheme 3 Optical resolution of the intermediate (±)-19a. Reagents and conditions: (a) L-selectride, THF (84.6% for 19a, 9.4% for 19b, respectively);
(b) IBX, DMSO–THF (93%); (c) (S)-20, DCC, DMAP, CH2Cl2; (d) TBAF, THF (40% for 22a, 36% for 22b, based on 19a, respectively).
product.2 Similarly, (2S,4R)-27 was also converted into (2R,4R)-1,
the internal standard. Chemical shifts are reported in ppm on the 
[]D26 −10.7 (c 0.232 in MeOH). It was noted that absolute values
of specific rotation of the synthesized enantiomers fluctuated con-
siderably, especially at low concentration. Although the reason for
fluctuation of specific rotation was unclear, fortunately, the reversal
of the sign has never been observed. Thus, the absolute configura-
tion of the natural mispyric acid was determined as 2S,4S, because
synthetic (2S,4S)-1 and natural 1 were both dextrorotatory.
scale and J-values are given in Hz. 13C-NMR spectra were recorded
at 75 MHz on a JEOL JNM-AL300 spectrometer, at 100 MHz on a
JEOL JNM-LA400 spectrometer and at 126 MHz on a JEOL JNM-
LA500 spectrometer. The peak for CDCl3 (at  77.0) was used for
the internal standard. Optical rotations were taken with a JASCO
P-1010 polarimeter or a HORIBA SEPA-300 polarimeter. Mass
spectra were measured with a JEOL JMS-SX102A spectrometer.
CD spectra were measured with a JASCO J-720 spectrometer.
Column chromatography was carried out on Merck Kieselgel 60
Art 1.07734 or Kanto Chemical Co., Inc. Silica Gel 60 N (spheri-
cal, neutral, 63–210 m). Flash chromatography was carried out
on Kanto Chemical Co., Inc. Silica Gel 60 N (spherical, neutral,
40–50 m). TLC analyses were performed on Merck silica gel
plates 60F–254.
Conclusion
In conclusion, the first synthesis of mispyric acid (1), a triterpene
inhibitor of DNA polymerase , was accomplished by starting from
isoprene (2), geraniol (6) and 1,5-dimethoxy-1,4-cyclohexadiene
(14). The absolute configuration of naturally occurring mispyric
acid 1 was established as 2S,4S. Detailed studies on DNA poly-
merase inhibitory activities of 1 employing our synthetic samples
are now in progress.
(E)-1-Bromo-4-tert-butyldimethylsilyloxy-2-methylbut-2-ene
4. To a stirred solution of 3 (13.0 g, 55.4 mmol) in DMF (200 cm3)
was added NaBr (28.3 g, 275 mmol) at 0 °C, and the reaction mix-
ture was stirred for 23 h at room temperature. After cooling to 0 °C,
Et2O and water were added to the resulting mixture. This mixture
was extracted with Et2O, and the extract was washed with water
and brine, dried over MgSO4, and concentrated under reduced pres-
sure. The resulting allylic bromide 4 (14.4 g) was used for the next
reaction without purification. 4: H(500 MHz; CDCl3) 0.07 (6 H, s,
SiMe2), 0.90 (9 H, s, SiBut), 1.77 (3 H, s, 2-Me), 3.95 (2 H, s, 1-H2),
4.21 (2 H, d, J 6.7, 4-H2), 5.71 (1 H, t, J 6.7, 3-H).
Experimental
General
Mps were uncorrected. IR spectra were measured on a JASCO FT/
IR-460 spectrometer. 1H-NMR spectra were recorded at 300 MHz
on a JEOL JNM-AL300 spectrometer, at 400 MHz on a JEOL
JNM-LA400 spectrometer and at 500 MHz on a JEOL JNM-LA500
spectrometer. The peak for CHCl3 in CDCl3 (at  7.26) was used for
2 2 3 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 3 6 – 2 2 4 4

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Scheme 4 Synthesis of mispyric acid (1). Reagents and conditions: (a) TBSCl, imidazole, DMF (91%); (b) LiAlH4, Et2O (87%); (c) CH2I2, Et2Zn, Et2O
(95%); (d) PDC, MS 4A, CH2Cl2 (91%); (e) Li, NH3, THF, t-BuOH, −78 °C (66%); (f) Ph3PCH3Br, NaHMDS, THF, 0 °C to rt (80%); (g) TBAF, THF (97%);
(h) DMP, CH2Cl2; NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O (68% based on 29).
(E)-1-tert-Butyldimethylsilyloxy-5-iodo-3-methylpent-2-ene
5. To a stirred solution of crude 4 (14.4 g, ca. 52 mmol), CuI (13.3 g,
69.8 mmol) and LiI (20.1 g, 150 mmol) in THF (250 cm3) was added
a solution of ICH2ZnI7b (ca. 270 mmol) in THF (135 cm3) at −25 °C
under Ar. After having been stirred at room temperature overnight,
the reaction mixture was cooled to 0 °C, quenched with water, and
extracted with Et2O. The extract was washed with saturated aque-
ous Na2S2O3, water and brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was chromatographed on SiO2
to give 5 (8.0 g, 42%, 2 steps) as a slightly pink oil. This homoallylic
iodide 5 was immediately used in the next reaction. 5: H(500 MHz;
CDCl3) 0.07 (6 H, s, SiMe2), 0.90 (9 H, s, SiBut), 1.64 (3 H, s,
3-Me), 2.56 (2 H, t, J 7.6, 4-H2), 3.23 (2 H, t, J 7.6, 5-H2), 4.19 (2 H,
d, J 6.1, 1-H2), 5.37 (1 H, t, J 6.1, 2-H).
(E)-6-tert-Butyldimethylsilyloxy-4-methylhex-4-enal 9.
A
solution of periodic acid dihydrate (31.9 g, 140 mmol) in water
(130 cm3) was added to a solution of epoxide 8 (35.7 g, 125 mmol)
in THF (230 cm3) at 0 °C. After stirring for 30 min, NaHCO3 was
added, and stirring was continued for 1 h. The resulting mixture was
filtered through a pad of Celite, and the filtrate was extracted with
Et2O. The extract was washed with saturated aqueous NaHCO3 and
brine. The combined aqueous layers were further extracted with
CHCl3. The extract was washed with saturated aqueous NaHCO3
and brine. The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was dissolved in
DMF (250 cm3) and cooled to 0 °C. Imidazole (21.6 g, 316 mmol)
and TBSCl (24.7 g, 164 mmol) were added to this solution. The
reaction mixture was stirred for 30 min at room temperature, then
quenched with water at 0 °C and extracted with Et2O. The extract
was washed with water, saturated aqueous NaHCO3 and brine,
dried over MgSO4, and concentrated under reduced pressure. After
removal of a silanol under reduced pressure (ca. 30 °C, 2 mmHg),
the residue was chromatographed on SiO2 to give 9 (17.1 g, 56%) as
a colourless oil, nD25 1.4549 (Found: C, 64.24; H, 11.01. C13H26O2Si
requires C, 64.41; H, 10.81%); max(film)/cm−1 2715w (H–CO),
1730s (CO), 1670w (CC), 1255m (Si–Me), 1115s (Si–O);
H(400 MHz; CDCl3) 0.06 (6 H, s, SiMe2), 0.90 (9 H, s, SiBut), 1.64
(3 H, s, 4-Me), 2.33 (2 H, t, J 7.6, 3-H2), 2.56 (2 H, td, J 7.6 and 1.7,
2-H2), 4.19 (2 H, d, J 6.3, 6-H2), 5.32 (1 H, td, J 6.3 and 1.2, 5-H),
9.77 (1 H, t, J 1.7, 1-H); C(100 MHz; CDCl3) −5.3, 16.3, 18.2, 25.8,
31.3, 41.7, 60.0, 125.2, 134.6, 201.9.
(E)-1-tert-Butyldimethylsilyloxy-6,7-epoxy-3,7-dimethyloct-
2-ene 8. A solution of m-chloroperbenzoic acid (70%; 15.2 g,
62 mmol) in CHCl3 (150 cm3) was added to a solution of 7 (14.7 g,
54.7 mmol) in CHCl3 (230 cm3) at 0 °C and the reaction mixture
was stirred for 1 h at this temperature. The reaction mixture was
diluted with saturated aqueous NaHCO3 and extracted with CHCl3.
The extract was washed with water, saturated aqueous NaHCO3
and brine, dried over MgSO4, and concentrated under reduced pres-
sure. The residue was chromatographed on SiO2 to give 8 (12.6 g,
25
81%) as a colourless oil, nD 1.4534 (Found: C, 67.43; H, 11.60.
C16H32O2Si requires C, 67.54; H, 11.34%); max(film)/cm−1 1670w
(CC), 1255m (Si–Me), 1120s (Si–O); H(400 MHz; CDCl3) 0.07
(6 H, s, SiMe2), 0.90 (9 H, s, SiBut), 1.26 (3 H, s, Me), 1.30 (3 H, s,
Me), 1.58–1.74 (2 H, m, 5-H2), 1.64 (3 H, s, MeCC), 2.07–2.22
(2 H, m, 4-H2), 2.71 (1 H, t, J 6.1, 6-H), 4.19 (2 H, d, J 6.3, 1-H2),
5.34 (1 H, t, J 6.3, 2-H); C(100 MHz; CDCl3) −5.3, 16.2, 18.2, 18.6,
24.7, 25.8, 27.0, 35.9, 58.1, 60.0, 63.8, 124.8, 135.7.
(2Z,6E)-8-tert-Butyldimethylsilyloxy-6-methyl-2-(4-methyl-
3-pentenyl)-2,6-octadien-1-ol 10. To a suspension of 5-methyl-4-
hexenyltriphenylphosphonium iodide (15.0 g, 30.8 mmol) in THF
(200 cm3) was added n-BuLi (1.59 mol dm−3 in n-hexane; 19.4 cm3,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 3 6 – 2 2 4 4
2 2 3 9

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30.8 mmol) at 0 °C underAr.After stirring for 30 min at this temper-
ature, the mixture was cooled to −78 °C and a solution of aldehyde
9 (7.5 g, 31 mmol) in THF (50 cm3) was added. After stirring for
5 min at this temperature, the reaction mixture was allowed to warm
to −25 °C and treated with sec-BuLi (0.99 mol dm−3 in cyclohex-
ane–n-hexane; 62.4 cm3, 61.8 mmol). The resulting solution was al-
lowed to warm to 0 °C and treated with paraformaldehyde (92.0%;
5.00 g, 153 mmol). After having been stirred at room temperature
for 1 h, the reaction mixture was quenched with water and extracted
with Et2O. The extract was washed with water and brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
chromatographed on SiO2 to give 10 (2.65 g). This was used in the
next reaction without further purification. An analytical sample was
obtained by careful re-chromatography to give pure 10 as a colour-
less oil, nD25 1.4876 (Found: C, 71.28; H, 11.67. C21H40O2Si requires
C, 71.53; H, 11.43%); max(film)/cm−1 3550s (O–H), 1670w (CC),
1255m (Si–CH3), 1110s (Si–O); H(400 MHz; CDCl3) 0.06 (6 H, s,
SiMe2), 0.90 (9 H, s, SiBut), 1.60 (3 H, s, MeCC), 1.64 (3 H, s,
MeCC), 1.68 (3 H, s, MeCC), 2.03 (2 H, t, J 7.3, CH2CC),
2.12 (4 H, br s, 2 × CH2CC), 2.20 (2 H, q, J 7.3, CH2CC),
4.09 (2 H, d, J 5.4, CH2OH), 4.17 (2 H, d, J 6.3, CH2OH), 5.11
(1 H, m, CHC), 5.24–5.31 (2 H, m, 2 × CHC); C(100 MHz;
CDCl3) −5.2, 16.4, 17.7, 18.4, 25.66, 25.70, 26.0, 26.9, 34.9, 39.4,
60.0, 60.1, 124.1, 124.8, 127.6, 131.6, 136.5, 138.8.
pyridine and PBr3 (90%; 49 mm3, 0.46 mmol) at −40 °C under Ar.
After having been stirred at this temperature for 20 min and −20 °C
for 40 min, the reaction mixture was quenched with MeOH, poured
into saturated aqueous NaHCO3 and pentane, and extracted with
pentane. The extract was washed with saturated aqueous NaHCO3,
water and brine, dried over MgSO4, filtered through neutral SiO2
and Celite, and concentrated under reduced pressure to give crude
13 (543 mg, 87%) as a light brown oil. This was immediately used
in the next reaction.
2-[(E)-5′-tert-Butyldimethylsilyloxy-3′-methyl-3′-pentenyl]-
1,5-dimethoxycyclohexa-1,4-diene 15. To a stirred solution of
t-BuLi (1.64 mol dm−3 in pentane; 18.7 cm3, 30.7 mmol) in THF
(200 cm3) was added a solution of 1,5-dimethoxy-1,4-cyclohexadi-
ene 14 (4.3 g, 31 mmol) in THF (5 cm3) at −78 °C and the resulting
solution was stirred at this temperature for 1 h. To this solution
HMPA (5.4 cm3, 31 mmol) was added, and stirring was continued
for additional 10 min. Then a solution of 5 (8.0 g, 24 mmol) in THF
(4 cm3) was added, and the reaction mixture was allowed to warm to
room temperature. The resulting solution was quenched with brine
and extracted with Et2O. The extract was washed with saturated
aqueous Na2S2O3, water and brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was chromatographed
on SiO2 to give 15 (5.70 g, 69%) as a colourless oil. This compound
contained inseparable impurities and was not so stable, thus we im-
mediately used it for the next reaction.
(6Z,10E)-12-tert-Butyldimethylsilyloxy-6-tert-butyldiphenyl-
silyloxymethyl-2,10-dimethyl-2,6,10-dodecatriene 11. To
a
2-[(E)-5′-tert-Butyldimethylsilyloxy-3′-methyl-3′-pentenyl]-
3-methoxy-2-cyclohexen-1-one 16. To a stirred solution of 15
(5.70 g, ca. 16 mmol) in THF (57 cm3) was added aqueous HCl
(1.0 mol dm−3; 37 cm3, 37 mmol) at 0 °C. After having been stirred
at room temperature for 1 h, EtOAc and NaCl were added to the
resulting solution. The organic layer was separated, and the aqueous
layer was extracted with CHCl3. The combined organic layers were
dried over MgSO4, and concentrated under reduced pressure to give
the crude hydroxy ketone.
This was dissolved in MeOH (15 cm3) and EtOAc (45 cm3),
and cooled to 0 °C. Then a solution of CH2N2 (0.1 mol) in Et2O
(100 cm3) was added to this solution. After having been stirred
for 30 min, excess CH2N2 was destroyed by adding a few drops of
AcOH, and the resulting solution was diluted with EtOAc, washed
with saturated aqueous NaHCO3 and brine, dried over MgSO4, and
concentrated under reduced pressure.
stirred solution of 10 (inseparable mixture; 2.65 g, ca. 7.5 mmol)
in DMF (27 cm3) were added imidazole (1.28 g, 18.8 mmol) and
TBDPSCl (98%; 2.21 cm3, 8.27 mmol) at 0 °C. After having been
stirred at room temperature for 40 min, the reaction mixture was
quenched with water at 0 °C and extracted with Et2O. The extract
was washed with water, saturated aqueous NaHCO3 and brine,
dried over MgSO4, and concentrated under reduced pressure. The
residue was chromatographed on SiO2 to give 11 (4.11 g, 22%
from 9) as a colourless oil, nD25 1.5170 (Found: C, 75.29; H, 10.14.
C37H58O2Si2 requires C, 75.19; H, 9.89%); max(film)/cm−1 1670w
(CC), 1255m (Si–CH3), 1110s (Si–O); H(400 MHz; CDCl3) 0.05
(6 H, s, SiMe2), 0.89 (9 H, s, SiBut), 1.04 (9 H, s, SiBut), 1.51 (3 H,
s, MeCC), 1.59 (3 H, s, MeCC), 1.68 (3 H, s, MeCC), 1.91
(4 H, br s, 2 × CH2CC), 2.11 (2 H, q-like, J 7.6, CH2CC), 2.20
(2 H, t-like, J 7.6, CH2CC), 4.14 (2 H, d, J 6.4, 1-H2), 4.17 (2 H,
s, CH2OTBDPS), 5.12 (1 H, t, J 7.6, CHC), 5.15–5.25 (2 H, m,
2 × CHC), 7.33–7.45 (6 H, m, m-, p-Ar), 7.68 (4 H, dd, J 8.0 and
1.7, o-Ar); C(100 MHz; CDCl3) −5.1, 16.2, 17.7, 18.4, 19.2, 25.6,
25.7, 26.0, 26.8, 27.0, 34.7, 39.7, 60.2, 61.1, 124.50, 124.55, 126.1,
127.6, 129.5, 131.2, 133.8, 135.6, 136.4, 138.3.
The residue was dissolved in DMF (100 cm3) and cooled to
0 °C. Imidazole (3.4 g, 50 mmol) and TBSCl (3.8 g, 25 mmol)
were added to this solution. After having been stirred at room
temperature for 1 h, the resulting mixture was quenched with water
and extracted with Et2O. The extract was washed with saturated
aqueous NaHCO3, water and brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was chromatographed
(2E,6Z)-7-tert-Butyldiphenylsilyloxymethyl-3,11-dimethyl-
2,6,10-dodecatrien-1-ol 12. To a stirred mixture of 11 (1.52 g,
2.57 mmol) in THF (3 cm3) and water (3 cm3) was added AcOH
(9 cm3) at 0 °C. After having been stirred at room temperature for
19 h, the resulting solution was extracted with Et2O. The extract
was washed with water, saturated aqueous NaHCO3 and brine, dried
over MgSO4, and concentrated under reduced pressure. The residue
was chromatographed on SiO2 to give 12 (1.13 g, 92%) as a colour-
less oil, nD25 1.5169 (Found: C, 78.12; H, 9.39. C31H44O2Si requires
C, 78.10; H, 9.30%); max(film)/cm−1 3330w (O–H), 1670w (CC),
1110s (Si–O); H(500 MHz; CDCl3) 1.04 (9 H, s, SiBut), 1.57 (3 H,
s, MeCC), 1.59 (3 H, s, MeCC), 1.67 (3 H, s, MeCC), 1.91–
1.94 (4 H, m, 2 × CH2CC), 2.11 (2 H, q-like, J 7.3, CH2CC),
2.21 (2 H, t-like, J 7.3, CH2CC), 4.10 (2 H, t, J 6.4, 1-H2), 4.18
(2 H, s, CH2OTBDPS), 5.12 (1 H, t, J 7.3, CHC), 5.18 (1 H, br s,
CHC), 5.31 (1 H, t, J 6.4, 2-H), 7.35–7.45 (6 H, m, m-, p-Ar), 7.68
(4 H, dd, J 6.8 and 1.5, o-Ar); C(100 MHz; CDCl3) 16.1, 17.7, 19.2,
25.6, 25.7, 26.8, 26.9, 34.7, 39.6, 59.2, 61.1, 123.5, 124.5, 125.9,
127.6, 129.5, 131.2, 133.7, 135.6, 138.4, 139.2.
25
on SiO2 to give 16 (2.66 g, 49% from 15) as a colourless oil, nD
1.4978 (Found: C, 67.13; H, 10.28. C19H34O3Si requires C, 67.40;
H, 10.12%); max(film)/cm−1 1650s (CO), 1615s (CC), 1255m
(Si–CH3), 1110s (Si–O); H(500 MHz; CDCl3) 0.06 (6 H, s, SiMe2),
0.90 (9 H, s, SiBut), 1.65 (3 H, s, MeCC), 1.94–1.99 (4 H, m, 5-
and 2′-H2), 2.32 (2 H, t, J 6.4, 4-H2), 2.38 (2 H, t, J 7.4, 6-H2), 2.54
(2 H, t, J 6.4, 1′-H2), 3.78 (3 H, s, MeO), 4.17 (2 H, d, J 6.4, 5′-H2),
5.23 (1 H, t, J 6.4, 4′-H); C(100 MHz; CDCl3) −5.3, 16.0, 18.2,
20.1, 20.7, 24.6, 25.8, 36.2, 38.1, 54.8, 60.1, 118.8, 123.9, 137.1,
171.9, 197.9.
2-[(E)-5′-tert-Butyldimethylsilyloxy-3′-methyl-3′-pentenyl]-
6-[(2″E,6″Z)-7″-tert-butyldiphenylsilyloxymethyl-3″,11″-di-
methyl-2″,6″,10″-dodecatrienyl]-3-methoxy-2-cyclohexen-1-one
17. To a stirred solution of diisopropylamine (0.185 cm3, 1.31 mmol)
in THF (3 cm3) was added n-BuLi (1.59 mol dm−3 in n-hexane;
0.79 cm3, 1.26 mmol) at 0 °C. After having been stirred at this
temperature for 30 min, the resulting LDA solution was cooled
to −78 °C. Then a solution of 16 (329 mg, 0.972 mmol) in THF
(1 cm3) was added. After having been stirred at this temperature
for 30 min, the mixture was cooled to −90 °C, and the solution of
(6Z,10E)-12-Bromo-6-tert-butyldiphenylsilyloxymethyl-
2,10-dimethyl-2,6,10-dodecatriene 13. To a stirred solution of 12
(551 mg, 1.16 mmol) in Et2O (5.5 cm3) was added a few drops of
2 2 4 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 3 6 – 2 2 4 4

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13 (543 mg, 1.01 mmol) in THF (1 cm3) was quickly added. The
mixture was allowed to warm to room temperature and stirred
for 1 h. The resulting solution was quenched with water and ex-
tracted with Et2O. The extract was washed with saturated aqueous
Na2S2O3, water and brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was chromatographed on SiO2
to give 17 (628 mg, 93% based on the consumed 16) and recovered
16 (41 mg, 12%). 17: colourless oil, nD25 1.5172 (Found: C, 75.27;
H, 9.73. C50H76O4Si2 requires C, 75.32; H, 9.61%); max(film)/cm−1
1650s (CO), 1620s (CC), 1250m (Si–Me), 1110s (Si–O);
H(400 MHz; CDCl3) 0.06 (6 H, s, SiMe2), 0.90 (9 H, s, SiBut),
1.04 (9 H, s, SiBut), 1.50 (3 H, s, MeCC), 1.59 (3 H, s, MeCC),
1.65 (3 H, s, MeCC), 1.68 (3 H, s, MeCC) 1.89–2.16 (12 H, m,
4 × CH2CC, 5- and 2′-H2), 2.20 (2 H, t, J 6.8, CH2CC), 2.36
(2 H, br t, J 6.9, 4-H2), 2.41–2.46 (1 H, m, 6-H), 2.47–2.59 (2 H,
m, 1′-H2), 3.75 (3 H, s, MeO), 4.17 (2 H, d, J 6.4, 5′-H2), 4.17 (2 H,
s, CH2OTBDPS), 5.02 (1 H, t, J 6.9, CHC), 5.12 (1 H, t, J 6.8,
CHC), 5.17 (1 H, m, CHC), 5.24 (1 H, t, J 6.4, 4′-H), 7.35–7.44
(6 H, m, m-, p-Ar), 7.68 (4 H, dd, J 8.0 and 1.7, o-Ar); C(100 MHz;
CDCl3) −5.1, 16.0, 16.1, 17.7, 18.4, 19.2, 20.7, 23.7, 25.2, 25.7,
25.9, 26.0, 26.7, 27.0, 28.0, 34.7, 38.3, 39.9, 44.8, 54.7, 60.3, 61.2,
118.5, 122.3, 124.0, 124.5, 126.2, 127.6, 129.5, 131.1, 133.7, 135.5,
136.3, 137.5, 138.1, 170.8, 199.5.
4.02 (1 H, br s, 1-H), 4.18 (2 H, s, CH2OTBDPS), 4.19 (2 H, d, J 6.4,
5′-H2), 5.01 (1 H, m, CHC), 5.13 (1 H, t, J 6.4, CHC), 5.19 (1 H,
br s, CHC), 5.33 (1 H, t, J 6.4, 4′-H), 7.35–7.45 (6 H, m, m-, p-Ar),
7.69(4H, d, J6.8, o-Ar);C(126MHz;CDCl3) −5.1, 16.1, 16.4, 17.0,
17.7, 18.4, 19.2, 23.5, 25.7, 26.0, 26.8, 27.0, 28.9, 30.1, 31.2, 34.7,
38.5, 39.9, 40.8, 60.2, 61.2, 68.4, 123.2, 124.3, 124.6, 126.3, 127.6,
129.5, 131.1, 133.7, 133.8, 134.7, 135.6, 135.7, 137.4, 138.1.
19b: nD26 1.5166 (Found: C, 76.41; H, 9.79. C50H78O3Si2 requires
C, 76.67; H, 10.04%); max(film)/cm−1 3330w (O–H), 1665w (CC),
1255m (Si–Me), 1110s (Si–O); H(400 MHz; CDCl3) 0.07 (6 H, s,
SiMe2), 0.91 (9 H, s, SiBut), 1.04 (9 H, s, SiBut), 1.28–1.39 (1 H, m),
1.40–1.46 (1 H, m), 1.49 (3 H, s, MeCC), 1.56 (1 H, m), 1.59 (3 H,
s, MeCC), 1.61–1.75 (2 H, m), 1.66 (3 H, s, MeCC), 1.68 (6 H,
s, 2 × MeCC), 1.81–1.87 (2 H, m, CH2CC), 1.92 (4 H, m), 2.01–
2.16 (5 H, m), 2.16–2.32 (4 H, m), 3.93 (1 H, br s, 1-H), 4.18 (2 H,
s, CH2OTBDPS), 4.19 (2 H, d, J 6.3, 5′-H2), 5.01 (1 H, m, CHC),
5.13 (1 H, t, J 6.6, CHC), 5.19 (1 H, br s, CHC), 5.31 (1 H, t,
J 6.3, 4′-H), 7.34–7.42 (6 H, m, m-, p-Ar), 7.69 (4 H, dd, J 7.8 and
1.5, o-Ar); C(126 MHz; CDCl3) −5.1, 16.0, 16.5, 17.7, 17.8, 18.4,
19.2, 20.7, 25.7, 25.95, 26.01, 26.8, 27.0, 27.8, 29.2, 29.7, 34.8,
38.7, 39.9, 40.7, 60.3, 61.3, 67.1, 123.9, 124.4, 124.6, 126.3, 127.6,
129.5, 131.1, 132.5, 133.9, 135.2, 135.6, 137.1, 138.2.
Oxidation of 19b. To a solution of 19b (33.6 mg, 43 mol) in
DMSO (1 cm3) and THF (0.2 cm3) was added IBX (24 mg, 86 mol)
at room temperature, and the mixture was stirred at this tempera-
ture for 2 h. The reaction mixture was diluted with water, and the
resulting mixture was stirred at 0 °C for 20 min. The mixture was
filtered through a pad of Celite and the precipitate was washed
with Et2O. The filtrate was extracted with Et2O. The extract was
washed with water and brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was chromatographed on SiO2
to give 18 (31.3 mg, 93%). This was identical with 18, which was
prepared from 17.
2-[(E)-5′-tert-Butyldimethylsilyloxy-3′-methyl-3′-pentenyl]-
4-[(2″E,6″Z)-7″-tert-butyldiphenylsilyloxymethyl-3″,11″-di-
methyl-2″,6″,10″-dodecatrienyl]-3-methyl-2-cyclohexen-1-one
18. To a stirred solution of 17 (2.97 g, 3.73 mmol) in THF (50 cm3)
was added MeMgBr (0.93 mol dm−3 in THF; 12.0 cm3, 11.2 mmol)
at 5 °C under Ar. After having been stirred at room temperature
for 3 h, the resulting solution was quenched with ice and saturated
aqueous NH4Cl, and extracted with Et2O. The extract was washed
with water and brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was chromatographed on SiO2 to give
18 (2.64 g, 91%) as a colourless oil, nD25 1.5171 (Found: C, 76.58;
H, 9.99. C50H76O3Si2 requires C, 76.86; H, 9.80%); max(film)/cm−1
1670s (CO), 1625w (CC), 1255m (Si–Me), 1110s (Si–O);
H(500 MHz; CDCl3) 0.06 (6 H, s, SiMe2), 0.90 (9 H, s, SiBut),
1.04 (9 H, s, SiBut), 1.51 (3 H, s, MeCC), 1.59 (3 H, s, MeCC),
1.66 (3 H, s, MeCC), 1.69 (3 H, s, MeCC), 1.73–1.80 (1 H, m),
1.93 (11 H, m), 2.11 (2 H, q-like, J 6.7, CH2CC), 2.16–2.23 (4 H,
m), 2.26 (1 H, dt, J 17.1 and 4.9, 6-H), 2.31–2.47 (3 H, m), 4.17
(4 H, m, 2 × CH2O), 5.02 (1 H, t, J 7.1, CHC), 5.12 (1 H, t, J 6.7,
CHC), 5.18 (1 H, m, CHC), 5.28 (1 H, t, J 6.1, 4′-H), 7.34–7.44
(6 H, m, m-, p-Ar), 7.68 (4 H, dd, J 7.9 and 1.2, o-Ar); C(100 MHz;
CDCl3) −5.1, 16.1, 16.4, 17.7, 18.4, 19.2, 19.8, 24.0, 25.4, 25.7,
25.9, 26.0, 26.8, 27.0, 29.5, 33.6, 34.7, 38.5, 39.9, 41.5, 60.3, 61.2,
122.5, 124.50, 124.51, 126.0, 127.6, 129.5, 131.2, 133.8, 135.1,
135.6, 136.8, 136.9, 138.3, 158.6, 198.1.
(2S,1′S,4′S)-2-[(E)-5″-Hydroxy-3″-methyl-3″-pentenyl]-
4-[(2E,6Z)-7-hydroxymethyl-3,11-dimethyl-2,6,10-
dodecatrienyl]-3-methyl-2-cyclohexen-1-yl
2-methoxy-2-(1-
naphthyl)propionate 22a and its (2S,1′R,4′R)-diastereoisomer
22b. To a mixture of 19a (2.504 g, 3.197 mmol), (S)-2-methoxy-
2-(1-naphthyl)propionic acid (20) (3.72 g, 16.2 mmol) and DMAP
(391 mg, 3.20 mmol) in CH2Cl2 (100 cm3) was added DCC
(5.65 g, 27.4 mmol) at 0 °C under Ar, and the mixture was stirred
at room temperature for 26 h. Further addition of DMAP (185 mg,
1.51 mmol) and stirring for 20 h completed the reaction. The result-
ing mixture was diluted with Et2O and filtered through a pad of
Celite. The filtrate was washed with saturated aqueous NaHCO3 and
brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was chromatographed on SiO2 to give the inseparable
mixture of 21a and 21b (2.648 g, 83%) as a colourless oil.
(1R*,4R*)-2-[(E)-5′-tert-Butyldimethylsilyloxy-3′-methyl-3′-
pentenyl]-4-[(2″E,6″Z)-7″-tert-butyldiphenylsilyloxymethyl-3″,11″-
dimethyl-2″,6″,10″-dodecatrienyl]-3-methyl-2-cyclohexen-1-ol
19aandits(1S*,4R*)-isomer19b.Toastirredsolutionof18(122 mg,
156 mol) in THF (2 cm3) was added L-Selectride® (1.0 mol dm−3
in THF; 234 mm3, 234 mol) dropwise at −78 °C under Ar. After
having been stirred at −60 °C for 4 h, the reaction mixture was al-
lowed to warm up to 5 °C, quenched with MeOH, and diluted with
Et2O. This mixture was washed with water and brine, dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by flash chromatography to afford 19a (103.2 mg, 84.6%)
as a colourless oil (less polar) and 19b (11.5 mg, 9.4%) also as a
colourless oil (more polar). 19a: nD25 1.5165 (Found: C, 76.42; H,
10.14. C50H78O3Si2 requires C, 76.67; H, 10.04%); max(film)/cm−1
3430w (O–H), 1670w (CC), 1255m (Si–Me), 1110s (Si–O);
H(500 MHz; CDCl3) 0.07 (6 H, s, SiMe2), 0.91 (9 H, s, SiBut), 1.04
(9 H, s, SiBut), 1.28–1.38 (1 H, m), 1.39–1.47 (1 H, m), 1.51 (3 H,
s, MeCC), 1.53–1.74 (3 H, m), 1.59 (3 H, s, MeCC), 1.66 (3 H,
s, MeCC), 1.69 (3 H, s, MeCC), 1.92 (6 H, m), 2.07 (2 H, t, J
8.0, CH2CC), 2.12 (2 H, t, J 7.7, CH2CC), 2.16–2.32 (5 H, m),
To a mixture of 21a and 21b (2.648 g, 2.660 mmol) in THF
(40 cm3) was added TBAF (1.0 mol dm−3 in THF; 10.7 cm3,
10.7 mmol), and the solution was stirred at room temperature for
3 h. The resulting mixture was diluted with EtOAc, washed with
brine, dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography to afford 22a
(825 mg, 40% from 19a) as a colourless oil (less polar) and 22b
(749 mg, 36% from 19a) also as a colourless oil (more polar).
24
22a: nD 1.5172; []D24 −92 (c 0.10 in CHCl3); max(film)/cm−1
3420m (O–H), 1725s (CO); H(500 MHz; CDCl3) 1.23–1.76
(11 H, m), 1.33 (3 H, s, MeCC), 1.49 (3 H, s, MeCC), 1.57 (3 H,
s, MeCC), 1.60 (3 H, s, MeCC), 1.68 (3 H, s, MeCC), 1.84–
1.95 (2 H, m), 1.98 (3 H, s, 3-H3), 1.96–2.06 (1 H, m), 2.06–2.23
(7 H, m), 3.06 (3 H, s, MeO), 4.02 (2 H, d, J 6.8, 5″-H2), 4.11 (2 H, br
s, 7-CH2OH), 4.97 (2 H, m, 1′- and 4″-H), 5.11 (1 H, br s, CHC),
5.18 (1 H, br s, CHC), 5.30 (1 H, t, J 7.1, CHC), 7.37–7.50 (3 H,
m, Ar), 7.58 (1 H, d, J 7.4, Ar), 7.75–7.85 (2 H, m, Ar), 8.48 (1 H, d,
J 7.7, Ar); C(126 MHz; CDCl3) 16.1, 16.2, 17.0, 17.7, 21.8, 23.5,
25.6, 26.1, 26.2, 27.0, 28.2, 30.7, 35.2, 37.3, 40.0, 40.3, 50.8, 59.2,
60.2, 72.7, 81.5, 122.7, 123.1, 124.1, 124.6, 125.4, 125.6, 125.7,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 3 6 – 2 2 4 4
2 2 4 1

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126.4, 128.3, 128.5, 129.32, 129.35, 131.3, 131.7, 134.0, 135.0,
135.6, 137.2, 138.4, 139.5, 173.9; m/z (FAB) 665.4177 ([M + Na]+.
C42H58O5Na requires 665.4182), 665 (3%), 435 (78), 395 (3), 309
(3), 275 (15), 221 (35), 185 (100), 105 (68), 69 (87).
5.13 (2 H, m, 2 × CHC), 5.19 (1 H, t, J 7.1, CHC), 5.32 (1 H, t,
J 6.4, 4′-H); C(126 MHz; CDCl3) −5.3, −5.1, 16.2, 16.5, 17.0, 17.7,
18.3, 18.4, 23.5, 25.7, 25.95, 26.02, 26.2, 27.0, 29.0, 30.2, 31.2,
34.7, 38.5, 40.1, 40.8, 60.2, 60.5, 68.4, 123.2, 124.3, 124.5, 126.1,
133.70, 133.72, 134.7, 135.9, 137.4, 138.5.
24
22b; nD 1.5170; []D25 +5.9 (c 0.16 in CHCl3); max(film)/cm−1
3450s (O–H), 1740s (CO); H(500 MHz; CDCl3) 0.40–0.53
(1 H, m, 5′-H), 1.00–1.09 (1 H, m, 5′-H), 1.12–1.22 (1 H, m, 6′-H),
1.27–1.36 (1 H, m, 6′-H), 1.42 (3 H, s, MeCC), 1.51 (3 H, s,
MeCC), 1.58 (3 H, s, MeCC), 1.62 (3 H, s, MeCC), 1.67 (3 H,
s, MeCC), 1.41–1.80 (5 H, m), 1.90–2.06 (6 H, m), 1.98 (3 H,
s, 3-H3), 2.06–2.23 (6 H, m, 3 × CH2CC), 3.09 (3 H, s, MeO),
4.15–4.20 (4 H, m, 2 × CH2OH), 4.75 (1 H, t, J 6.7, CHC), 5.11
(1 H, m, CHC), 5.21 (1 H, br s, 1′-H), 5.26 (1 H, t, J 7.2, CHC),
5.33 (1 H, t, J 6.6, 4″-H), 7.38–7.45 (3 H, m, Ar), 7.56 (1 H, d, J 7.4,
Ar), 7.75–7.86 (2 H, m, Ar), 8.39–8.46 (1 H, m, Ar); C(126 MHz;
CDCl3) 16.1, 16.3, 16.9, 17.7, 21.4, 22.8, 25.6, 26.1, 26.2, 27.0,
29.1, 30.8, 35.1, 38.0, 39.9, 40.1, 50.8, 59.2, 60.2, 72.4, 81.5,
122.9, 123.3, 124.1, 124.5, 125.2, 125.56, 125.61, 126.3, 128.3,
128.5, 129.0, 129.2, 131.4, 131.7, 133.9, 135.1, 135.3, 137.6, 138.3,
139.4, 174.2; m/z (FAB) 665.4178 ([M + Na]+. C42H58O5Na requires
665.4182), 665 (1%), 435 (38), 395 (3), 309 (4), 275 (5), 199 (25),
185 (100), 153 (45), 105 (76), 69 (94).
The enantiomeric allylic alcohol (+)-24 (568 mg, 81%, 2 steps)
was prepared from diastereomeric ester 22b (688 mg, 1.07 mmol).
This was identical with its enantiomer in all respects except the sign
of optical rotation. (+)-24: nD24 1.4940 (Found: C, 73.03; H, 11.51.
C40H74O3Si2 requires C, 72.88; H, 11.32%); []D25 +37 (c 0.12 in
CHCl3).
(1R,2S,5S,6R)-1-[(E)-5′-tert-Butyldimethylsilyloxy-3′-
methyl-3′-pentenyl]-5-[(2″E,6″Z)-7″-tert-butyldimethyl-
silyloxymethyl-3″,11″-dimethyl-2″,6″,10″-dodecatrienyl]-
6-methylbicyclo[4.1.0]heptan-2-ol (−)-25 and its enantiomer
(+)-25. To a solution of (−)-24 (465 mg, 705 mol) were added
CH2I2 (114 mm3, 1.43 mmol) and Et2Zn (0.99 mol cm−3 in n-hexane;
1.45 cm3, 1.44 mmol) at room temperature under Ar. The mixture
was stirred at room temperature for 3.5 h. It was then quenched
with saturated aqueous NH4Cl at 0 °C and extracted with Et2O. The
extract was washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The residue was chromatographed on
SiO2 to give (−)-25 (450 mg, 95%) as a colourless oil, nD24 1.4902;
[]D24 −11 (c 0.10 in CHCl3); max(film)/cm−1 3360w (O–H), 3055w
(cyclopropyl C–H), 1670w (CC), 1255m (Si–Me), 1070s (Si–O);
H(500 MHz; CDCl3) −0.08 (1 H, d, J 4.6, 7-H), 0.06 (12 H, s,
2 × SiMe2), 0.69 (1 H, d, J 4.6, 7-H), 0.90 (18 H, s, 2 × SiBut), 0.95–
1.05 (1 H, m), 1.17 (3 H, s, 6-Me), 1.23–1.40 (4 H, m), 1.46–1.53
(1 H, m), 1.59 (6 H, s, 2 × MeCC), 1.63 (3 H, s, MeCC), 1.67
(3 H, s, MeCC), 1.64–1.72 (1 H, m), 1.79 (1 H, dt, J 14.1 and 9.2),
1.86 (1 H, dq, J 13.8 and 5.5), 1.97–2.18 (10 H, m), 2.18–2.26 (1 H,
m), 4.03 (1 H, br s, 2-H), 4.14 (2 H, s, 7″-CH2OTBS), 4.18 (2 H, d, J
6.4, 5′-H2), 5.10 (1 H, br s, CHC), 5.13–5.24 (2 H, m, 2 × CHC),
5.31 (1 H, t, J 6.4, 4′-H); C(126 MHz; CDCl3) −5.3, −5.1, 16.1,
16.3, 16.5, 17.7, 18.3, 18.4, 21.0, 22.3, 25.7, 25.9, 26.0, 26.1, 27.0,
27.7, 29.6, 31.3, 32.1, 33.2, 34.7, 37.0, 39.9, 40.1, 60.3, 60.5, 69.0,
123.8, 124.2, 124.5, 126.2, 131.1, 135.3, 137.2, 138.5; m/z (EI)
672.5318 (M+. C41H76O3Si2 requires 672.5333).
Determination of the diastereomeric purities of 22a and 22b.
(S)-2-Methoxy-2-(1-naphthyl)propionic acid (20) was prepared ac-
cording to the reported procedure17 and its enantiomeric purity was
estimated by HPLC analysis of the corresponding methyl ester 20′.
HPLC analysis [column, Chiralcel® OD (4.6 mm × 25 cm); solvent,
hexane:propan-2-ol = 9:1; flow rate, 0.5 cm3 min−1; detection at
254 nm]: 20′ tR/min 10.9 [0%, (R)-20′], 12.1 [99.9%, (S)-20′]. The
enantiomeric purity of (S)-20 was estimated to be >99.9% ee.
The diastereomeric purities of 22a and 22b were estimated
by HPLC analysis. HPLC analysis [column, Senshu Pak Pegasil
Silica 60–5 (4.6 mm × 25 cm); solvent, hexane :propan-2-ol = 9:1;
flow rate, 0.5 cm3 min−1; detection at 254 nm]: 22a tR/min 16.7
[99.9%, 22a], 21.3 [0%, 22b]. The diastereomeric purity of 22a
was estimated to be >99.9% de. 22b tR/min 16.7 [0.25%, 22a], 21.3
[99.75%, 22b]. The diastereomeric purity of 22b was estimated to
be 99.5% de.
The enantiomeric cyclopropyl alcohol (+)-25 (556 mg, 96%) was
prepared from (+)-24 (567 mg, 860 mol). This was identical with
its enantiomer in all respects except the sign of optical rotation.
(+)-25: nD24 1.4906; []D23 +12 (c 0.11 in CHCl3); m/z (EI) 672.5344
(M+. C41H76O3Si2 requires 672.5333).
(1S,4S)-2-[(E)-5′-tert-Butyldimethylsilyloxy-3′-methyl-3′-
pentenyl]-4-[(2″E,6″Z)-7″-tert-butyldimethylsilyloxymethyl-3″,11″-
dimethyl-2″,6″,10″-dodecatrienyl]-3-methyl-2-cyclohexen-1-ol
(−)-24 and its enantiomer (+)-24. To a solution of 22a (801 mg,
1.25 mmol)inDMF(10cm3)wereaddedimidazole(470mg,6.9mmol)
and TBSCl (770 mg, 5.1 mmol) at 0 °C, and the mixture was stirred
at room temperature for 30 min. The reaction mixture was cooled to
0 °C, diluted with Et2O, quenched with saturated aqueous NaHCO3
and extracted with Et2O. The extract was washed with saturated
aqueous NaHCO3, water and brine, dried over MgSO4 and concen-
trated under reduced pressure. The residue was chromatographed on
SiO2 to give 23a (990 mg, 91%) as a colourless oil.
To a suspension of LiAlH4 (92 mg, 2.4 mmol) in Et2O (15 cm3)
at −78 °C was added a solution of 23a (990 mg, 1.14 mmol) in Et2O
(10 cm3) dropwise under Ar. The mixture was allowed to warm to
0 °C over 2.5 h, stirred at 0 °C for 30 min and quenched with MeOH
at −20 °C. To the resulting mixture was added saturated aqueous po-
tassiumsodiumtartrate(5cm3).Themixturewasstirredfor10 minat
room temperature, and extracted with Et2O. The extract was washed
with brine, dried over MgSO4 and concentrated under reduced
pressure. The residue was chromatographed on SiO2 to give (−)-24
(664 mg, 87%) as a colourless oil, nD24 1.4933 (Found: C, 73.10; H,
11.49. C40H74O3Si2 requires C, 72.88; H, 11.32%); []D24 −38 (c 0.13
in CHCl3); max(film)/cm−1 3340w (O–H), 1670w (CC), 1255m
(Si–Me), 1070s (Si–O); H(500 MHz; CDCl3) 0.06 (6 H, s, SiMe2),
0.07 (6 H, s, SiMe2), 0.901 (9 H, s, SiBut), 0.905 (9 H, s, SiBut),
1.44–1.51 (1 H, m), 1.52–1.74 (3 H, m), 1.60 (3 H, s, MeCC),
1.61 (3 H, s, MeCC), 1.67 (6 H, s, 2 × MeCC), 1.68 (3 H, s,
MeCC), 1.92–2.17 (13 H, m), 2.20–2.32 (3 H, m), 4.02 (1 H, m,
1-H), 4.15 (2 H, s, 7″-CH2OTBS), 4.18 (2 H, d, J 6.4, 5′-H2), 5.06–
(1R,5S,6R)-1-[(E)-5′-tert-Butyldimethylsilyloxy-3′-
methyl-3′-pentenyl]-5-[(2″E,6″Z)-7″-tert-butyldimethyl-
silyloxymethyl-3″,11″-dimethyl-2″,6″,10″-dodecatrienyl]-6-
methylbicyclo[4.1.0]heptan-2-one (+)-26 and its enantiomer
(−)-26. To a suspension of PDC (132 mg, 351 mol) and powdered
MS 4A (126 mg) in CH2Cl2 (2 cm3) was added a solution of (−)-25
(150 mg, 233 mol) in CH2Cl2 (2 cm3). The reaction mixture was
stirred at room temperature for 3 h, and then filtered through a pad
of Celite. The filtrate was concentrated under reduced pressure.
The residue was chromatographed on SiO2 to give (+)-26 (136 mg,
91%) as a colourless oil, nD27 1.4883; []D23 +5.7 (c 0.11 in CHCl3);

max(film)/cm−1 3060w (cyclopropyl C–H), 1690s (CO), 1255m
(Si–Me), 1070s (Si–O); H(500 MHz; CDCl3) 0.06 (12 H, s,
2 × SiMe2), 0.54 (1 H, d, J 5.2, 7-H), 0.89 (18 H, s, 2 × SiBut), 1.13–
1.27 (2 H, m), 1.30 (3 H, s, 6-Me), 1.32 (1 H, d, J 5.2, 7-H), 1.59
(3 H, s, MeCC), 1.61 (3 H, s, MeCC), 1.62 (3 H, s, MeCC),
1.67 (3 H, s, MeCC), 1.58–1.75 (2 H, m), 1.82–1.89 (1 H, m),
1.90–2.12 (9 H, m), 2.14 (2 H, q-like, J 7.4, CH2CC), 2.31 (1 H,
dt, J 17.7 and 4.6, 3-H), 2.35–2.43 (1 H, m), 2.50 (1 H, dq, J 13.7
and 5.5), 4.14 (2 H, s, 7″-CH2OTBS), 4.16 (2 H, d, J 6.1, 5′-H2), 5.10
(1 H, br s, CHC), 5.14–5.22 (2 H, m, 2 × CHC), 5.26 (1 H, t, J
6.1, 4′-H); C(126 MHz; CDCl3) −5.3, −5.1, 16.1, 16.3, 17.7, 18.3,
18.4, 19.0, 21.7, 23.8, 25.7, 25.9, 25.99, 26.03, 27.0, 29.1, 30.4,
31.3, 34.7, 37.3, 37.4, 38.6, 38.9, 40.1, 60.3, 60.5, 122.3, 124.3,
124.4, 126.0, 131.2, 136.1, 137.1, 138.6, 209.3; m/z (EI) 670.5173
2 2 4 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 3 6 – 2 2 4 4

View Article Online
(M+. C41H74O3Si2 requires 670.5176), 670 (2%), 613 (10), 538 (10),
481 (6), 469 (2), 406 (5), 389 (5), 377 (2), 335 (6), 281 (5), 253 (12),
203 (18), 175 (16), 135 (32), 81 (38), 75 (100).
s, MeCC), 1.71–1.78 (1 H, m), 1.78–1.86 (1 H, m), 1.90 (1 H, td, J
12.5 and 4.3, 6-H), 2.01 (2 H, t, J 7.7, CH2CC), 2.06–2.11 (4 H, m,
2 × CH2CC), 2.11–2.20 (5 H, m, 2 × CH2CC and CHHCC),
2.28 (1 H, dt, J 12.5 and 4.3, 6-H), 4.15 (2 H, s, 7″-CH2OTBS), 4.20
(2 H, d, J 6.4, 5′-H2), 4.54 (1 H, s, CHHC), 4.84 (1 H, s, CHHC),
5.08–5.14 (2 H, m, 2 × CHC), 5.20 (1 H, t, J 7.3, CHC), 5.29
(1 H, t, J 6.4, 4′-H); C(126 MHz; CDCl3) −5.3, −5.0, 15.1, 16.1,
16.4, 17.7, 18.36, 18.43, 23.3, 25.7, 25.97, 26.03, 26.1, 26.6, 27.0,
29.2, 30.2, 34.7, 37.6, 38.6, 39.6, 40.1, 48.8, 53.4, 60.3, 60.5, 106.3,
124.2, 124.6, 125.0, 126.2, 131.1, 134.9, 137.6, 138.5, 149.0; m/z
(EI) 670.5544 (M+. C42H78O2Si2 requires 670.5540), 670 (5%), 613
(23), 601 (5), 538 (8), 523 (2), 481 (13), 469 (2), 406 (6), 391 (2),
337 (4), 277 (5), 266 (44), 203 (17), 201 (12), 135 (21), 81 (24),
75 (100).
The enantiomeric cyclopropyl ketone (−)-26 (120 mg, 90%)
was prepared from (+)-25 (134 mg, 199 mol). This was identical
with its enantiomer in all respects except the sign of optical rota-
27
tion. (−)-26: nD 1.4876; []D25 −5.6 (c 0.10 in CHCl3); m/z (EI)
670.5176 (M+. C41H74O3Si2 requires 670.5176).
(2R,4S)-2-[(E)-5′-tert-Butyldimethylsilyloxy-3′-methyl-3′-
pentenyl]-4-[(2″E,6″Z)-7″-tert-butyldimethylsilyloxymethyl-
3″,11″-dimethyl-2″,6″,10″-dodecatrienyl]-3,3-dimethylcyclohexan-1-one
(−)-27 and its enantiomer (+)-27. To a solution of t-BuOH (81
mg, 1.1 mmol) in THF (1 cm3) were added NH3 (ca. 5 cm3) and Li
(15 mg, 2.2 mmol) at −78 °C under Ar, and the mixture was stirred
at this temperature for 40 min. To the mixture was added a solution
of (+)-26 (106 mg, 158 mol) and t-BuOH (70 mg, 0.9 mmol) in
THF (1 cm3) dropwise.After having been stirred at −78 °C for 1.5 h,
the reaction mixture was quenched with MeOH at this temperature,
and allowed to warm to room temperature.After having been stirred
for 1 h, water and Et2O were added, and the mixture was extracted
with Et2O. The extract was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was purified
by flash chromatography to afford (−)-27 (70 mg, 66%) as a colour-
The enantiomeric pentaene (+)-28 (59 mg, 82%) was prepared
from (+)-27 (72 mg, 107 mol). This was identical with its enan-
tiomer in all respects except the sign of optical rotation. (+)-28:
nD22 1.4926; []D21 +1.0 (c 0.11 in CHCl3); m/z (EI) 670.5538 (M+.
C42H78O2Si2 requires 670.5540).
(2S,4S)-2-[(E)-5′-Hydroxy-3′-methyl-3′-pentenyl]-4-
[(2″E,6″Z)-7″-hydroxymethyl-3″,11″-dimethyl-2″,6″,10″-do-
decatrienyl]-3,3-dimethyl-1-methylenecyclohexane (−)-29 and
its enantiomer (+)-29. To a solution of (−)-28 (57 mg, 85 mol)
in THF (2 cm3) was added TBAF (1.0 mol dm−3 in THF; 0.34 cm3,
0.34 mmol), and the mixture was stirred at room temperature for
2 h. The resulting mixture was diluted with EtOAc, washed with
brine, dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography to afford (−)-29
25
less oil, nD 1.4868; []D25 −12 (c 0.11 in CHCl3); max(film)/cm−1
1715s (CO), 1670w (CC), 1255m (Si–Me), 1070s (Si–O);
H(500 MHz; CDCl3) 0.06 (12 H, s, 2 × SiMe2), 0.60 (3 H, s, 3-
Me), 0.90 (18 H, s, 2 × SiBut), 1.09 (3 H, s, 3-Me), 1.32–1.45 (2 H,
m), 1.56–1.63 (1 H, m, 4-H), 1.59 (3 H, s, MeCC), 1.60 (3 H, s,
MeCC), 1.61 (3 H, s, MeCC), 1.66–1.73 (1 H, m, CHHCC),
1.68 (3 H, s, MeCC), 1.74–1.82 (1 H, m), 1.88–1.97 (1 H, m),
1.99–2.17 (10 H, m), 2.11–2.17 (1 H, m, 2-H), 2.20–2.26 (1 H, m,
CHHCC), 2.27–2.33 (2 H, m, 6-H and CHHCC), 4.15 (2 H,
s, 7″-CH2OTBS), 4.17 (2 H, d, J 6.5, 5′-H2), 5.08–5.16 (2 H, m,
2 × CHC), 5.19 (1 H, t, J 6.7, CHC), 5.25 (1 H, t, J 6.5, 4′-H);
C(126 MHz; CDCl3) −5.3, −5.1, 15.5, 16.10, 16.15, 17.7, 18.3,
18.4, 20.8, 25.7, 25.95, 26.02, 26.05, 26.8, 27.0, 28.5, 29.2, 34.7,
38.9, 40.0, 42.5, 43.4, 48.1, 60.1, 60.2, 60.5, 124.0, 124.5, 124.8,
126.1, 131.2, 135.8, 137.0, 138.6, 212.5; m/z (EI) 672.5335 (M+.
C41H76O3Si2 requires 672.5333), 672 (1%), 657 (1), 615 (4), 603
(2), 540 (4), 523 (2), 483 (6), 415 (4), 391 (9), 339 (2), 293 (2),
253 (16), 185 (12), 135 (35), 81 (48), 75 (100);  −1.3 (296 nm, c
0.0015 mol dm−3 in CHCl3).
23
(36.5 mg, 97%) as a colourless oil, nD 1.5186; []D24 −4 (c 0.07
in CHCl3); max(film)/cm−1 3330s (O–H), 1670w (CC), 1645m
(CC); H(500 MHz; CDCl3) 0.57 (3 H, s, 3-Me), 1.02 (3 H, s,
3-Me), 1.11 (1 H, td, J 12.5 and 4.3, 5-H), 1.14–1.23 (3 H, m),
1.50–1.57 (1 H, m), 1.58 (3 H, s, MeCC), 1.61 (3 H, s, MeCC),
1.58–1.66 (1 H, m), 1.69 (6 H, s, 2 × MeCC), 1.71–1.78 (1 H, m),
1.80–1.87 (1 H, m), 1.90 (1 H, td, J 12.5 and 4.3, 6-H), 2.02 (2 H, t,
J 7.3, CH2CC), 2.08–2.22 (10 H, m, 5 × CH2CC), 2.28 (1 H, dt,
J 12.5 and 4.3, 6-H), 4.11 (2 H, s, 7″-CH2OH), 4.15 (2 H, d, J 7.0,
5′-H2), 4.53 (1 H, s, CHHC), 4.84 (1 H, s, CHHC), 5.08–5.14 (2
H, m, 2 × CHC), 5.30 (1 H, t, J 7.4, CHC), 5.40 (1 H, t, J 7.0,
4′-H); C(126 MHz; CDCl3) 15.0, 16.1, 16.3, 17.7, 23.3, 25.7, 26.2,
26.6, 27.1, 29.2, 30.3, 35.2, 37.6, 38.5, 39.6, 40.0, 48.8, 53.4, 59.4,
60.4, 106.3, 123.1, 124.1, 125.3, 128.6, 131.7, 134.7, 138.3, 140.5,
148.8; m/z (EI) 442.3806 (M+. C30H50O2 requires 442.3811), 442
(1%), 424 (5), 409 (3), 391 (3), 355 (3), 337 (2), 271 (5), 257 (4),
217 (6), 201 (15), 161 (13), 135 (30), 95 (32), 69 (100).
The enantiomeric ketone (+)-27 (60 mg, 60%) was prepared
from (−)-26 (100 mg, 149 mol). This was identical with its en-
antiomer in all respects except the sign of optical rotation and CD
spectrum. (+)-27: nD24 1.4860; []D25 +12 (c 0.12 in CHCl3); m/z (EI)
672.5340 (M+. C41H76O3Si2 requires 672.5333);  +1.3 (293 nm, c
0.0018 mol dm−3 in CHCl3).
The enantiomeric diol (+)-29 (37 mg, 95%) was prepared from
(+)-28 (59 mg, 88 mol). This was identical with its enantiomer in
all respects except optical rotation. (+)-29: nD20 1.5174; []D21 +1.6
(c 0.11 in CHCl3); m/z (EI) 442.3816 (M+. C30H50O2 requires
442.3811).
(2S,4S)-2-[(E)-5′-tert-Butyldimethylsilyloxy-3′-methyl-3′-
pentenyl]-4-[(2″E,6″Z)-7″-tert-butyldimethylsilyloxymethyl-
3″,11″-dimethyl-2″,6″,10″-dodecatrienyl]-3,3-dimethyl-1-
methylenecyclohexane (−)-28 and its enantiomer (+)-28. To a
suspension of Ph3PCH3Br (223 mg, 624 mol) in THF (2 cm3) was
added NaHMDS (1.0 mol dm−3 in THF; 530 mm3, 530 mol) at
0 °C under Ar. After having been stirred for 15 min, a solution of
(−)-27 (71 mg, 105 mol) in THF (1.5 cm3) was added dropwise to
the mixture at 0 °C. After having been stirred at room temperature
for 5 h, the resulting mixture was quenched with saturated aque-
ous NH4Cl and extracted with Et2O. The extract was washed with
water and brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was chromatographed on SiO2 to give (−)-28
(2S,4S)-(+)-2-[(E)-4′-Carboxy-3′-methyl-3′-butenyl]-4-
[(2″E,6″Z)-7″-carboxy-3″,11″-dimethyl-2″,6″,10″-dodeca-
trienyl]-3,3-dimethyl-1-methylenecyclohexane (mispyric acid)
1 and its enantiomer (−)-1. To a solution of (−)-29 (14.9 mg,
34 mol) in CH2Cl2 (2 cm3) was added Dess–Martin periodinane
(97%; 50.7 mg, 116 mol) at 0 °C, and the mixture was stirred at
room temperature for 10 min. The reaction mixture was diluted with
Et2O, saturated aqueous NaHCO3 and saturated aqueous Na2S2O3,
and extracted with Et2O. The extract was washed with brine, dried
over MgSO4 and concentrated under reduced pressure. The residue
was used in the next reaction without purification.
To a solution of the crude aldehyde in t-BuOH (1.5 cm3) and
2-methyl-2-butene (0.4 cm3) was added a freshly prepared aque-
ous NaClO2 (NaClO2, 79%, 40 mg, 0.35 mmol; NaH2PO4, 91 mg,
0.76 mmol; H2O, 0.3 cm3), and the reaction mixture was stirred at
room temperature for 1 h. The mixture was diluted with EtOAc,
washed with brine, dried over MgSO4 and concentrated under re-
duced pressure. The residue was purified by flash chromatography
22
(57 mg, 80%) as a colourless oil, nD 1.4922; []D21 −0.8 (c 0.11
in CHCl3); max(film)/cm−1 1670s (CC), 1645w (CC), 1255m
(Si–Me), 1070s (Si–O); H(500 MHz; CDCl3) 0.07 (6 H, s, SiMe2),
0.08 (6 H, s, SiMe2), 0.58 (3 H, s, 3-Me), 0.91 (18 H, s, 2 × SiBut),
1.03 (3 H, s, 3-Me), 1.11 (1 H, td, J 12.5 and 4.3, 5-H), 1.20 (1 H, t,
J 10.7, 4-H), 1.48–1.55 (1 H, m), 1.57 (3 H, s, MeCC), 1.60 (3 H,
s, MeCC), 1.63 (3 H, s, MeCC), 1.62–1.69 (2 H, m), 1.68 (3 H,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 3 6 – 2 2 4 4
2 2 4 3

View Article Online
7 (a) P. Knochel, T.-S. Chou, H. G. Chen, M. C. P. Yeh and M. J. Rozema,
J. Org. Chem., 1989, 54, 5202–5204; (b) for the preparation of ICH2ZnI,
see: D. Seyferth and S. B. Andrews, J. Organomet. Chem., 1971, 30,
151–166.
8 E. J. Corey and H. Yamamoto, J. Am. Chem. Soc., 1970, 92, 6637–
6638.
9 For the preparation of 5-methyl-4-hexenyltriphenylphosphonium
iodide, see: D. E. Cane and M. Tandon, Tetrahedron Lett., 1994, 35,
5355–5358.
10 For example: (a) K. Tago, M. Arai and H. Kogen, J. Chem. Soc., Perkin
Trans. 1, 2000, 2073–2078; (b) H. Takikawa, J. Koizumi, Y. Kato and
K. Mori, J. Chem. Soc., Perkin Trans. 1, 1999, 2271–2276.
11 E. Piers and J. R. Grierson, J. Org. Chem., 1977, 42, 3755–3757.
12 (a) E. J. Corey, R. K. Bakshi and S. Shibata, J. Am. Chem. Soc., 1987,
109, 5551–5553; (b) for a review, see: E. J. Corey and C. J. Helal,
Angew. Chem., Int. Ed., 1998, 37, 1986–2012.
13 (a) R. Noyori, I. Tomino andY. Tanimoto, J. Am. Chem. Soc., 1979, 101,
3129–3131; (b) R. Noyori, I. Tomino, Y. Tanimoto and M. Nishizawa, J.
Am. Chem. Soc., 1984, 106, 6709–6716.
14 F.-J. Gottschalk, H. Marschall-Weyerstahl and P. Weyerstahl, Liebigs
Ann. Chem., 1985, 462–467.
15 (a) M. Frigerio and M. Santagostino, Tetrahedron Lett., 1994, 35, 8019–
8022; (b) for the preparation of IBX, see: M. Frigerio, M. Santagostino
and S. Sputore, J. Org. Chem., 1999, 64, 4537–4538.
16 (a) J. Staunton and E. J. Eisenbraun, Org. Synth. Coll. Vol. 5, 1973,
8–11; (b) K. Mori, Tetrahedron, 1974, 30, 1065–1072.
to afford (+)-1 (10.8 mg, 68% from (−)-29) as a colourless oil,
[]D27 +9.2 (c 0.22 in MeOH); max(film)/cm−1 3500–2500s (car-
boxyl O–H), 1690s (CO), 1645s (CC); H(300 MHz, CDCl3)
0.59 (3 H, s, 3-Me), 1.03 (3 H, s, 3-Me), 1.06–1.25 (2 H, m, 4- and
5-H), 1.59 (6 H, s, 3″- and 11″-Me), 1.59–1.67 (3 H, m, 2-, 1′- and
1″-H), 1.68 (3 H, s, 11″-Me), 1.69–1.80 (2 H, m, 1′- and 5-H), 1.90
(1 H, td, J 12.0 and 4.2, 6-H), 1.97–2.08 (1 H, m, 4″-H), 2.08–2.16
(4 H, m, 2′-H2, 1″- and 4″-H), 2.18 (3 H, s, 3′-Me), 2.23–2.40 (5 H,
m, 6-H, 8″- and 9″-H2), 2.62 (2 H, q, J 7.2, 5″-H2), 4.51 (1 H, s,
CHHC), 4.86 (1 H, s, CHHC), 5.04–5.16 (2 H, m, 2″- and 10″-
H), 5.69 (1 H, s, 4′-H), 6.00 (1 H, t, J 7.2, 6″-H); C(75 MHz, CDCl3)
15.0, 16.0, 17.7, 19.2, 23.0, 25.7, 26.6, 27.9, 28.1, 29.1, 30.2, 34.5,
37.5, 39.2, 39.7, 40.2, 48.6, 53.2, 106.5, 114.8, 123.4, 125.3, 130.6,
132.2, 134.5, 145.6, 148.5, 164.1, 172.0, 173.3; m/z (EI) 470.3414
(M+. C30H46O4 requires 470.3396), 470 (2%), 452 (12), 434 (5), 383
(8), 365 (6), 355 (3), 303 (7), 285 (6), 235 (8), 217 (12), 189 (20),
135 (36), 93 (33), 69 (100).
The enantiomeric mispyric acid (−)-1 (11.6 mg, 69%) was pre-
pared from (+)-29 (15.7 mg, 35 mol). This was identical with its
enantiomer in all respects except optical rotation. (−)-1: []D26 −10.7
(c 0.232 in MeOH); m/z (EI) 470.3412 (M+. C30H46O4 requires
470.3396).
17 (a) A. Ichikawa, S. Hiradate, A. Sugio, S. Kuwahara, M. Watanabe
and N. Harada, Tetrahedron: Asymmetry, 1999, 10, 4075–4078;
(b) N. Harada, M. Watanabe, S. Kuwahara, A. Sugio, Y. Kasai and
A. Ichikawa, Tetrahedron: Asymmetry, 2000, 11, 1249–1253.
18 I. Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa, J. Am. Chem. Soc.,
1991, 113, 4092–4096.
19 (a) J. Nishimura, N. Kawabata and J. Furukawa, Tetrahedron, 1969,
25, 2647–2659; (b) R. Hara, T. Furukawa, H. Kashima, H. Kusama,
Y. Horiguchi and I. Kuwajima, J. Am. Chem. Soc., 1999, 121, 3072–
3082.
20 W. G. Dauben and E. J. Deviny, J. Org. Chem., 1966, 31, 3794–3798.
21 (a) P. Crabbé, Optical Rotatory Dispersion and Circular Dichro-
ism in Organic Chemistry, Holden-Day, San Francisco, 1965, ch. 6;
(b) D. A. Lightner, in Circular Dichroism, Principle and Application,
2nd edn., N. Berova, K. Nakanishi and R. W. Woody, Eds., Wiley-VCH:
,New York, 2000, ch. 10.
Acknowledgements
We thank Dr. T. Tashiro (RIKEN) for his supports of this work.
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2 2 4 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 2 3 6 – 2 2 4 4