Synthesis of two osteoclast-forming suppressors, demethylincisterol A 3 and chaxine A

Article abstract of DOI:10.1016/j.tet.2011.12.057

The synthesis of two potent osteoclast-forming suppressing agents isolated from the Chinese mushroom Agrocybe chaxingu, demethylincisterol A₃ and chaxine A, was accomplished using ergocalciferol as the starting material. Our methodology for the synthesis of demethylincisterol A₃ and chaxine A featured the construction of a butenolide moiety by the intramolecular Horner-Wadsworth-Emmons reaction under Masamune-Roush conditions. This is the first reported synthesis of chaxine A.

Full text of DOI:10.1016/j.tet.2011.12.057

Tetrahedron 68 (2012) 1729e1735
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Synthesis of two osteoclast-forming suppressors, demethylincisterol A3
and chaxine A
*
Arata Yajima , Yuuma Kagohara, Keisuke Shikai, Ryo Katsuta, Tomoo Nukada
Department of Fermentation Science, Faculty of Applied Biological Science, Tokyo University of Agriculture (NODAI), Sakuragaoka 1-1-1, Setagaya-ku, Tokyo 156-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of two potent osteoclast-forming suppressing agents isolated from the Chinese mushroom
Agrocybe chaxingu, demethylincisterol A3 and chaxine A, was accomplished using ergocalciferol as the
starting material. Our methodology for the synthesis of demethylincisterol A3 and chaxine A featured the
construction of a butenolide moiety by the intramolecular HornereWadswortheEmmons reaction under
MasamuneeRoush conditions. This is the first reported synthesis of chaxine A.
Received 22 September 2011
Received in revised form 19 December 2011
Accepted 21 December 2011
Available online 23 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Chaxine A
Demethylincisterol A3
Osteoclast
Osteoporosis
1. Introduction
The stereochemistry of chaxine A was elucidated by extensive NMR
analyses and comparison of the NMR data with those of 2, but the
An imbalance between bone formation, which is mediated by
osteoblasts, and resorption, which is mediated by osteoclasts, is
related to metabolic bone diseases, such as osteoporosis and
osteopetrosis. Osteoclasts are multinucleated giant cells developed
from hematopoietic stem cells of the monocyteemacrophage lin-
eage.1,2 The hematopoietic precursor cells differentiate into osteo-
clasts under the control of two critical cytokines, receptor activator
absolute configuration of 1 remained undetermined. These two
were shown to compounds significantly reduce the number of
tartrate-resistant acid phosphatase (TRAP)-(þ) multinucleated cells
in a co-culture of osteoblastic cells and bone marrow cells without
cytotoxicity in the presence of RANKL.4,5 Because bone resorption
can be suppressed by the inhibition of osteoclast formation, this
result indicates that these two compounds might be candidate
chemotherapeutic agents for the treatment of bone diseases, such
postmenopausal osteoporosis. As mentioned above, the availability
of A. chaxingu, from which 1 and 2 can be isolated, is limited, and
of NF
k
B ligand (RANKL) and macrophage colony-stimulating factor
(TNF- ) also accelerates osteo-
(M-CSF). Tumor necrosis factor
a
a
clastogenesis, particularly in states of inflammatory osteolysis
causing rheumatoid arthritis.3 Thus, an inhibitor or a suppressor of
these cytokines that mediates osteoclast differentiation would be
a candidate anti-osteoporosis chemotherapeutic agent. In 2006,
Kawagishi and co-workers isolated the two potent osteoclast for-
mation suppressing compounds from the mushroom Agrocybe
chaxingu, which is found only in mountainous areas in South China
(Fig. 1).4,5 One of the two compounds, demethylincisterol A3 (2),
was first reported as a synthetic intermediate in the synthesis of 17-
methylincisterol6 and has been isolated from various fungi.7 Man-
soor and co-workers reported the isolation of 2 and the (17S)-iso-
mer of 2 from a marine sponge; these compounds have cytotoxic
effects on certain tumor cell lines.8 The second compound was
chaxine A, which is a previously unknown compound (1) (Fig. 1).
* Corresponding author. Tel.: þ81 3 5477 2264; fax: þ81 3 5477 2622; e-mail
address: ayaji@nodai.ac.jp (A. Yajima).
Fig. 1. The structures of demethylincisterol A3, chaxine A, and related natural products.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.12.057

1730
A. Yajima et al. / Tetrahedron 68 (2012) 1729e1735
the contents of the compounds in the mushroom are low, i.e.,
oxidized with OsO4 and NMO to yield the relatively unstable acyloin
7 as a single stereoisomer. The relative stereochemistry of 7 was
confirmed after the construction of a butenolide ring (vide infra).
Unfortunately, we could not obtain the desired butenolide 8 by the
reaction of 7 with the Bestmann ylide15 under various conditions,
probably because of the instability of 7. Next, we investigated the
copper-catalyzed tandem acylation-Wittig reaction under the mild
conditions developed by Matsuo and Shindo.16 Under these condi-
1.4 mg of 1 and 8.1 mg of 2 from 1.5 kg of dried fruiting bodies of A.
chaxingu.5 Furthermore, natural products containing a
g-hydrox-
ybutenolide moiety related to chaxine A have been reported.9 We
were, therefore, interested in synthesizing demethylincisterol A3
and chaxine A to establish a concise method for the synthesis of the
characteristic moiety and also to confirm the stereostructure of
chaxine A. This paper describes the results of our synthetic studies
of demethylincisterol A3 and the first synthesis of chaxine A.
tions, the reaction of
7 with a modified thioester (Ph3P]
CHCOSC6H3Me2) was not observed. With these disappointing re-
sults, we subsequently investigated an alternative approach.
2. Results and discussion
In the total synthesis of dehydrololiolide, Mori and co-workers
reported a simple approach employing an intramolecular Refor-
matsky reaction and a HornereWadswortheEmmons (HWE) re-
action to construct a butenolide moiety.17 First, we applied the
Reformatsky reaction for the construction of the butenolide ring.
The acylation of 7 with bromoacetyl bromide, followed by the
intramolecular Reformatsky reaction with zinc dust under sonica-
tion, gave hydroxylactone 9 in moderate yield. Unfortunately,
however, the dehydration of 9 to obtain 8 was unsuccessful using
various reagents, such as dehydrating reagents, acids, and bases.
Moreover, it was notably difficult to convert the hydroxyl group of 9
into the corresponding ester or sulfonate, which might have been
the result of the steric hindrance caused by the angular methyl
group shielding the hydroxyl group. The only transformation that
occurred was the dehydration of 9 with SOCl2 under reflux condi-
tions in pyridine to give undesired tetrasubstituted olefin 10. This
compound might be formed from 8 by isomerization because 10
would be thermodynamically favored over 8 (vide infra). Next, we
examined the HWE approach, i.e., phosphonate 11 was subjected to
the intramolecular HWE reaction under the optimized conditions,
MasamuneeRoush conditions,18 to produce the desired butenolide
8 in 82% yield. However, the conversion of butenolide 8 into the
corresponding furan was unsuccessful using DIBAL as a reducing
agent.19 The major products that we could isolate were the starting
material and diol 13 together with hydroxyaldehyde 12 instead of
a lactol. The favored conformation of hydroxyaldehyde 12 pos-
sesses an axially oriented hydroxyl group that would prevent the
formation of the furan ring through a lactol. Furthermore, we ob-
served an epimerization at C-4 of 8 to afford 14 under basic con-
ditions, such as those of the intramolecular HWE reaction or the
silyloxyfuran formation reaction conditions, that is, in the presence
of TBSOTf and a base. The epimerized butenolide 14 was formed at
first, and 14 was subsequently isomerized to yield the corre-
A wide variety of the synthetic approaches for
g-hydrox-
ybutenolide derivatives have been reported. For example, Sodano
and co-workers reported the synthesis of demethylincisterol A3 (2)
as a synthetic intermediate in the synthesis of 17-methylincisterol,
employing the hetero DielseAlder reaction of a diene with singlet
oxygen as the key step.6 Although the chemical yield was low
(approximately 0.14%), Sakaguchi and co-workers directly prepared
2 using the photo-oxidative degradation of ergosterol.10 These ap-
proaches require the use of photo-reaction equipment. Takikawa
and co-workers synthesized a cytotoxic sesquiterpene, glaucesce-
nolide (3), via a g
-ketoacid derivative as a precursor of butenolide.11
The butenolide was oxidized via a furan derivative to give glau-
cescenolide in high yield.12 This approach cannot be used for the
synthesis of 1 or 2 because the appropriate starting material cannot
be obtained easily. Our retrosynthetic analysis is summarized in
Scheme 1. The
troduced by oxidation of butenolide A constructed by an intra-
molecular cyclization reaction of B. The -acyloxy ketone B was
g-hydroxybutenolide moiety of 1 and 2 was in-
a
obtained from C, which can be derived from ergocalciferol.
sponding
g,d-unsaturated lactone 10 after a prolonged reaction
time. These results indicate that both of the ring systems of bute-
nolides 8 and 14 are highly strained, which made it to difficult to
form the furan derivatives. Because the obtained diol 13 was the
synthetic intermediate of Sodano’s synthesis of demethylincisterol
A3,6 the stereochemistry of 13 was confirmed by a comparison of
the 1H NMR spectra. Finally, 13 was oxidized with the Jones reagent
according to Sodano’s method to afford demethylincisterol A3 in
a low yield. The overall yield of demethylincisterol A3, based on
ergocalciferol, was 11.4% after eight steps. This compound’s prop-
erties, such as the NMR spectra, were identical to those of the re-
ported data.4 Although the overall chemical yield of our synthesis
of demethylincisterol A3 was lower than that of Sodano’s synthesis,
our synthesis is convenient and scalable.
Using the developed methodology, we synthesized chaxine A by
starting from 6 (Scheme 3). The reduction of the double bond of 6
was found to be quite difficult. Namely, under standard catalytic
hydrogenation conditions, epimerization at C-3a adjacent to the
carbonyl group occurred. As in the case of the intramolecular HWE
reaction described above, the ring system of 8 is highly strained,
probably because of the repulsion between the angular methyl
group and the bulky side chain. Therefore, we tentatively reduced
Scheme 1. Retrosynthetic analysis of demethylincisterol A3 and chaxine A.
Weinreb
and
co-workers
synthesized
(þ)-14,15-
dihydronorsecurinine (4) and related alkaloids that contain fused
butenolide ring systems via a tandem acylation-Wittig reaction of
acyloin derivatives with the Bestmann ylide.13 Because the buteno-
lide can be converted into the corresponding g-hydroxybutenolide
via furan oxidation, we therefore employed these simple and suc-
cessive approaches for the synthesis of demethylincisterol A3.
According to the literature,14 ketone 6 was prepared from ergo-
calciferol (5) (Scheme 2). The corresponding silyl enol ether of 6 was

A. Yajima et al. / Tetrahedron 68 (2012) 1729e1735
1731
Scheme 2. Synthesis of demethylincisterol A3. Reagents, conditions, and yields: (a) Ref. 14: (i) KMnO4, EtOH, H2O, ꢀ15 ꢁC; (ii) Pb(OAc)4, pyridine, CH2Cl2, ꢀ15 ꢁC, 80% in two steps;
(b) LDA or LiHMDS, TMSCl, THF, ꢀ78 ꢁC; (b) OsO4, NMO, THF, H2O, t-BuOH; (c) BrCH2COBr, pyridine, DMAP, CH2Cl2, 59% in three steps; (d) Zn, HMPA, THF, sonication, 66%; (e) SOCl2,
pyridine, reflux, 82%; (f) (EtO)2POCH2COOH, EDC, DMAP, CH2Cl2, 53% in three steps; (g) LiCl, DBU, THF, 0 ꢁC, 82%; (h) DIBAL (4 equiv), CH2Cl2, ꢀ78 ꢁC, 50e60% of 13, and 30e40% of
12; (i) DIBAL (7 equiv), CH2Cl2, toluene, ꢀ78 ꢁC, 84%; (j) Jones reagent, acetone, 0 ꢁC, 39%.
Scheme 3. Synthesis of chaxine A. Reagents, conditions, and yields: (a) NaBH4, MeOH; (b) H2, PtO2, AcOH, 89% in two steps; (c) DesseMartin periodinane, NaHCO3, CH2Cl2, 0 ꢁC,
93%; (d) LiHMDS, TMSCl, THF, ꢀ78 ꢁC; (e) OsO4, NMO, THF, H2O, t-BuOH; (f) (EtO)2POCH2COCl, pyridine, DMAP, CH2Cl2, 52% in three steps; (g) LiCl, DBU, THF, 0 ꢁC, 86%; (h) DIBAL
(7 equiv), CH2Cl2, toluene, ꢀ78 ꢁC, 95%; (i) 1-Me-AZADO, NaOCl, KBr, TBAB, NaHCO3, CH2Cl2, H2O; (j) Jones reagent, acetone, 0 ꢁC, 67% in two steps.

1732
A. Yajima et al. / Tetrahedron 68 (2012) 1729e1735
the carbonyl group of 6 with NaBH4 to avoid the undesired epi-
merization. The resulting alcohol whose stereochemistry was de-
duced by its 1H NMR spectrum20 was subjected to catalytic
hydrogenation with Adams’ catalyst in acetic acid under a hydrogen
atmosphere to give 15 (89%). Oxidation of the hydroxyl group with
DesseMartin periodinane gave 16 (93%). Phosphonate 17 was
prepared by the developed method via an acyloin (52% in three
steps), and the intramolecular HWE reaction under carefully con-
trolled conditions gave butenolide 18 in 86%. The stereochemistry
of 18 was confirmed by NOE experiments. Diol 19 was obtained by
the reduction of 18 with an excess amount of DIBAL, and the sub-
sequent Jones oxidation of 19 gave chaxine A in 38% yield. Although
the synthesis of chaxine A was achieved, we further investigated
the final oxidation reaction to improve the yield. Under the Jones
oxidation conditions, we observed multiple products using TLC
analysis. To avoid the side reactions, we investigated the step-wise
oxidation processes. Namely, we assumed that the mild oxidation
of diol 19 into the corresponding ketoaldehyde 20 without refor-
mation of lactone 18 would be possible because we obtained
hydroxyaldehyde 12 in the previous reaction shown in Scheme 2.
As expected, the 1-Me-AZADO-mediated oxidation developed by
Iwabuchi21 of diol 19 proceeded smoothly to give ketoaldehyde 20,
and, subsequently, the resulting ketoaldehyde was directly oxidized
under LindgreneKrausePinnick condition22 in one pot to afford 1
in moderate yield (57%). Finally, we obtained 1 by the step-wise
oxidation of 19 using Iwabuchi oxidation and Jones oxidation
with a 67% yield. The overall yield of chaxine A, based on ergo-
calciferol, was 18.8% after ten steps. The 1H and 13C NMR spectra of
the synthetic 1 were identical with those of the reported data, and
the optical rotation value of the synthetic 1 was in good accord with
that of the natural product.4 The absolute stereochemistry of
chaxine A was confirmed to be that proposed by Kawagishi.
4.1.1. (1R,3aR,5R,7aR,10R,20E,40R)-5,6,7,7a-Tetrahydro-5-bromoacetoxy-
7a-methyl-1-(10,40,50-trimethyl-20-hexenyl)-3aH-indan-4-one. To
stirred solution of LDA [prepared from 87.6 l (624 mol) of diiso-
a
m
m
propylamine and n-BuLi (378 ml, 624 mmol, 1.65 M solution in
hexane)] in THF (1 ml) at ꢀ78 ꢁC was added 614 (143 mg, 520
mmol)
and HMPA (66 ml) in THF (2 ml) was added dropwise, and the
mixture was stirred for 45 min. After addition of TMSCl (107
ml,
624 mol), the reaction mixture was stirred for 1.5 h at the same
m
temperature. Next, the mixture was poured into water. The aqueous
phase was extracted with ether. The combined organic layers were
washed with water and brine and dried with Na2SO4. Removal of
the solvent in vacuo yielded the crude silyl enol ether. A stirred
solution of the silyl enol ether and N-methylmorpholine-N-oxide
(216
was treated with 264
(10 mol). The resulting yellow solution was stirred at room tem-
ml, 1.04 mmol, 4.8 M solution in water) in THF/H2O (3/1, 14 ml)
ml of 1% (w/v) t-BuOH solution of OsO4
m
perature overnight, followed by the addition of 100 mg of NaHSO3,
filtration, and the removal of the THF in vacuo. The aqueous phase
was extracted with CH2Cl2, and the combined organic extracts were
washed with brine and dried over MgSO4. Removal of the solvent in
vacuo afforded a dark brown oil. This oil was dissolved in CH2Cl2
(2.5 ml), and DMAP (ca. 4 mg), pyridine (84
ml, 1.04 mmol), and
bromoacetyl bromide (90 l, 1.04 mmol) were successively added
m
to the resulting solution at 0 ꢁC. After stirring for 1.5 h, the mixture
was diluted with water and extracted with CH2Cl2. The combined
organic extracts were washed with brine and were dried over
MgSO4. After concentration in vacuo, the residue was purified
by column chromatography (hexane/ethyl acetate¼80/1) to give
the titled compound (126 mg, 59% in three steps) as a yellow oil;
½
a 2D5
1385, 1267, 1159, 1108, 995, 971, 886, 870 cmꢀ1
ꢂ
ꢀ36.1 (c 1.0, CHCl3); nmax (liquid film) 2958, 2871, 1749, 1458,
;
dH (400 MHz,
CDCl3) 0.66 (s, 3H), 0.82 (d, J¼6.8 Hz, 3H), 0.83 (d, J¼6.8 Hz, 3H),
0.91 (d, J¼6.4 Hz, 3H), 1.04 (d, J¼6.9 Hz, 3H), 1.2e2.2 (m, 12H), 3.16
(dd, J¼7.3, 11.4 Hz, 1H), 3.85 (s, 2H), 4.95 (dd, J¼3.0, 3.0 Hz, 1H), 5.17
(dd, J¼8.5, 15.5 Hz, 1H), 5.24 (dd, J¼7.8, 15.5 Hz, 1H); dC (100 MHz,
CDCl3) 12.5, 17.6, 18.5, 19.6, 20.0, 21.0, 25.4, 27.7, 29.5, 33.0, 34.3,
39.9, 42.8, 50.9, 56.7, 58.4, 78.2, 132.8, 134.6, 165.9, 205.7. HRMS
(ESI): MþNaþ, observed 435.1499; expected for C21H33O3NaBr:
435.1511.
3. Conclusion
We achieved the synthesis of demethylincisterol A3 and the first
synthesis of chaxine A employing the intramolecular HWE reaction
as a key step to construct the tricyclic ring systems of these com-
pounds. The proposed stereochemistry of natural chaxine A was
confirmed by direct comparison of the physical properties between
the synthetic and the natural 1. Because the developed method to
4.1.2. (3aR,3bR,5aR,6R,8aR,10R,20E,40R)-3a,3b,4,5,5a,7,8,8a-Octahy-
dro-3a-hydroxy-5a-methyl-6-(10,40,50-trimethyl-20-hexenyl)-2H-in-
deno[5,4-b]dihydrofuran-2-one (9). The suspension of the above
construct
a fused g-hydroxybutenolide structure, specifically,
butenolide formation by the intramolecular HWE reaction under
MasamuneeRoush conditions followed by reduction and oxidation
by the combination of Iwabuchi and Jones oxidations, is versatile
and practical, it is applicable to the synthesis of related natural
products and may be useful for the syntheses of the analogues of
compound (50.0 mg, 121
mmol), zinc powder (2.76 g, 42.2 mmol),
and HMPA (20.9 l, 121
m
mmol) in THF (1 ml) was sonicated for 2 h.
Next, the mixture was poured into 2 N HCl solution and filtered. The
aqueous phase was extracted with ether. The combined organic
extracts were washed with saturated aqueous NaHCO3 solution and
brine and were dried over MgSO4. After concentration in vacuo, the
residue was purified by column chromatography (hexane/ethyl
acetate¼10/1) to give the titled compound 9 (26.6 mg, 66%) as
chaxine
A
including chaxines BeE23 to develop an anti-
osteoporosis chemotherapeutic agent.
4. Experimental
4.1. General
a white powder; ½a D25
ꢂ
þ15.9 (c 0.67, CHCl3); nmax (KBr) 3538, 2959,
dH
2930, 2871, 1744, 1459, 1369, 1206, 1190, 1107, 1004, 969 cmꢀ1
;
(400 MHz, CDCl3) 0.82 (d, J¼6.8 Hz, 3H), 0.85 (d, J¼6.9 Hz, 3H), 0.89
(s, 3H), 0.92 (d, J¼6.8 Hz, 3H), 1.01 (d, J¼6.9 Hz, 3H), 1.15e1.86 (m,
14H), 2.03 (m, 3H), 2.58 (d, J¼16.5 Hz, 1H), 2.61 (d, J¼16.5 Hz, 1H),
4.38 (dd, J¼3.0, 3.0 Hz, 1H), 5.14 (dd, J¼7.8, 15.5 Hz, 1H), 5.22 (dd,
J¼7.8, 15.5 Hz, 1H); dC (100 MHz, CDCl3) 12.3, 17.6, 18.9, 19.6, 20.0,
20.8, 22.0, 27.0, 33.1, 33.7, 39.8, 40.9, 42.8, 44.8, 50.9, 55.9, 76.0, 82.1,
132.5, 134.9, 174.3. HRMS (ESI): MþNaþ, observed 357.2397; ex-
pected for C21H34O3Na: 357.2406.
Optical rotations were measured on a Jasco P-2100 polarimeter.
IR spectra were measured on a Jasco IR-4100 spectrometer. 1H NMR
spectra were recorded on a Jeol ECS400 (400 MHz) spectrometer
using CDCl3 at
13C NMR spectra were recorded on a Jeol ECS400 (100 MHz) spec-
trometer using CDCl3 at
d¼7.26 or CD3OD at
d¼3.30 as an internal standard.
d¼77.0 or CD3OD at
d¼49.0 as an internal
standard. Elemental compositions were analyzed on a J-Science
MICROCORDER JM10 apparatus. High-resolution EI-MS and ESI-MS
data were recorded on Jeol JMS-HX110 and Waters SYNAPT G2
spectrometers. Column chromatography was performed with
Wakogel-C200 silica gel.
4.1.3. (3bRS,5aR,6R,10R,20E,40R)-3b,4,5,5a,7,8-Hexahydro-5a-methyl-
6-(10,40,50-trimethyl-20-hexenyl)-2H-indeno[5,4-b]dihydrofuran-2-
one (10). To a stirred solution of 9 (10 mg, 30
mmol) in pyridine
(1 ml) was added SOCl2 (11 l, 150 mol), and the mixture was
m
m

A. Yajima et al. / Tetrahedron 68 (2012) 1729e1735
1733
stirred for 30 min at room temperature. After addition of an addi-
tional SOCl2 (11 l, 150 mol), the reaction mixture was stirred for
508
(32.3 mg, 761
m
mol) in THF (3 ml) under an Ar atmosphere were added LiCl
m
m
m
mol) and DBU (83.4 l, 558 mol). The mixture was
m
m
30 min at 110 ꢁC. Next, the mixture was cooled and poured into
water. The aqueous phase was extracted with ether. The combined
organic layers were washed with water, saturated aqueous NaHCO3
solution, and brine and were dried with Na2SO4. After concentra-
tion in vacuo, the residue was purified by column chromatography
(hexane/ethyl acetate¼80/1) to give the titled compound 10
stirred for 1 h at 0 ꢁC and subsequently quenched with water. The
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with brine, dried with Na2SO4, and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy (hexane/ethyl acetate¼20/1) to give the titled compound 8
(132 mg, 82%) as a colorless oil; [found: C, 79.52; H, 9.92. C21H32O2
(8.2 mg, 86%) as a yellow oil; ½a D25
ꢂ
þ17.5 (c 0.10, CHCl3); nmax (liquid
requires C, 79.70; H, 10.19%]; ½a D26
ꢀ91.3 (c¼1.0, CHCl3); nmax (liquid
ꢂ
film) 2958, 2929, 2871, 1784, 1465, 1370, 1260, 1174, 1138, 1010, 973,
film) 2958, 2873, 1754, 1641, 1460, 1384, 1329, 1156, 1084, 1018, 972,
803 cmꢀ1
;
dH (400 MHz, CDCl3) 0.82e0.86 (m, 6H), 0.89 (s, 3H),
941, 897, 849, 805 cmꢀ1
;
dH (400 MHz, CDCl3) 0.82 (d, J¼6.8 Hz, 3H),
0.92, 0.93 (each d, J¼6.8 Hz, total 3H), 1.01, 1.06 (each d, J¼6.4 Hz,
total 3H), 1.25e1.90 (m, H), 2.05e2.25 (m, 4H), 2.99 (d, J¼20.6 Hz,
1H), 3.08 (m, 1H), 4.82 (m, 1H), 5.21 (dd, J¼7.8, 15.5 Hz, 1H), 5.26
(dd, J¼7.8, 15.5 Hz, 1H); dC (100 MHz, CDCl3) 14.1, 17.6, 19.7, 20.0,
20.5, 21.5, 25.9, 26.6, 28.1, 29.7, 31.9, 32.0, 32.7, 33.1, 39.2, 42.8, 42.9,
43.7, 53.8, 68.5, 78.8, 121.9, 132.8, 134.7, 146.9, 175.6. HRMS (ESI):
MþHþ, observed 317.2479; expected for C21H33O2: 317.2481.
0.83 (d, J¼6.8 Hz, 3H), 0.91 (s, 3H), 0.92 (d, J¼6.8 Hz, 3H), 1.01 (d,
J¼6.4 Hz, 3H), 1.25e1.60 (m, 5H), 1.83e2.13 (m, 6H), 2.31 (m, 1H),
2.69 (m, 1H), 5.15 (dd, J¼7.8, 15.5 Hz, 1H), 5.26 (dd, J¼7.8, 15.5 Hz,
1H), 5.30 (m, 1H), 5.70 (dd, J¼2.2, 2.2 Hz, 1H); dC (100 MHz, CDCl3)
17.6, 19.0, 19.6, 19.9, 20.6, 22.3, 26.1, 29.2, 33.0, 34.2, 40.1, 41.5, 42.8,
49.5, 56.8, 80.6, 113.3, 133.0, 134.4, 174.1, 174.8. HRMS (ESI): MþHþ,
observed 317.2478; expected for C21H33O2: 317.2481. The prolonged
reaction time resulted in isomerization of C-4 to give 14. Properties
4.1.4. (1R,3aR,5R,7aR,10R,20E,40R)-5,6,7,7a-Tetrahydro-5-(dieth-
ylphosphonoacetoxy)-7a-methyl-1-(10,40,50-trimethyl-20-hexenyl)-
of 14: ½a 2D5
ꢂ
þ233.2 (c¼0.485, CHCl3); nmax (liquid film) 2956, 2872,
1749, 1654, 1457, 1383, 1153, 1129, 1060, 1003, 889, 851 cmꢀ1
;
dH
3aH-indan-4-one (11). To
a
stirred solution of 614 (15.8 mg,
(400 MHz, CDCl3) 0.60 (s, 3H), 0.83 (d, J¼6.8 Hz, 3H), 0.84 (d,
J¼6.8 Hz, 3H), 0.92 (d, J¼6.8 Hz, 3H), 1.04 (d, J¼6.8 Hz, 3H),
1.22e1.64 (m, 6H), 1.74 (m, 1H), 1.88 (m, 2H), 2.05 (m, 2H),
2.29e2.43 (m, 2H), 4.65 (ddd, J¼0.9, 7.3, 10.5 Hz, 1H), 5.16 (dd,
J¼8.2, 15.5 Hz, 1H), 5.25 (dd, J¼7.8, 15.5 Hz, 1H), 5.63 (br dd, J¼1.9,
1.9 Hz, 1H); dC (100 MHz, CDCl3) 12.2, 17.6, 19.6, 19.9, 21.0, 28.9, 29.7,
30.8, 33.0, 35.6, 40.1, 42.8, 48.0, 52.2, 55.4, 81.8, 111.1, 132.9, 134.6,
172.7, 173.9. HRMS (ESI): MþHþ, observed 317.2475; expected for
C21H33O2: 317.2481.
57.4
m
mol) in THF (0.5 ml) at ꢀ78 ꢁC was added dropwise
LiHMDS (68.8 ml, 68.8 mmol, 1.0 M solution in THF), and the
mixture was stirred for 45 min. After addition of TMSCl (6
ml,
69 mol), the reaction mixture was stirred for 2 h at the same
m
temperature. Next, the mixture was poured into a saturated
aqueous NaHCO3 solution. The aqueous phase was extracted
with ether. The combined organic layers were washed with brine
and dried with MgSO4. Removal of the solvent in vacuo yielded
the crude silyl enol ether. A stirred solution of the silyl enol ether
and N-methylmorpholine-N-oxide (29
tion in water) in THF/H2O (3/1, 2 ml) was treated with 32
a 1% (w/v) t-BuOH solution of OsO4 (1 mol). The resulting yel-
m
l, 143
m
mol, 4.8 M solu-
4.1.6. (1R,3aR,4Z,5R,7aR,10R,20E,40R)-5,6,7,7a-Tetrahydro-4-(2-
hydroxyethylidene)-7a-methyl-1-(10,40,50-trimethyl-20-hexenyl)-3aH-
indan-5-ol (13). To a stirred and cooled (ꢀ78 ꢁC) solution of 8
m
l of
m
low solution was stirred at room temperature overnight, fol-
lowed by the addition of 5 mg of NaHSO3, filtration, and the
removal of the THF in vacuo. The aqueous phase was extracted
with CH2Cl2, and the combined organic extracts were dried over
MgSO4. Removal of the solvent in vacuo afforded a dark brown
oil. This oil was dissolved in CH2Cl2 (0.5 ml), and DMAP (ca.
(106 mg, 333 mmol) in CH2Cl2 (3 ml) was added DIBAL (1.55 ml,
2.33 mmol, 1.5 M solution in toluene). The mixture was stirred for
1.5 h at ꢀ78 ꢁC and was quenched by the careful addition of MeOH.
The mixture was then warmed to room temperature and diluted
with aqueous Rochelle’s salt solution and ether. The mixture was
stirred vigorously for 2 h. Next, the aqueous phase was extracted
with EtOAc, and the combined organic extracts were dried over
MgSO4. After concentration of the solvent in vacuo, the residue was
purified by column chromatography (hexane/ethyl acetate¼1/1) to
give the titled compound 13 (89.7 mg, 84%) as a white powder;
[found: C, 78.95; H, 11.13. C21H36O2 requires C, 78.69; H, 11.32%];
5 mg), diethylphosphonoacetic acid (18
ml, 110 mmol), and EDC
(19.8 mg, 115 mol) were successively added to the resulting
m
solution at 0 ꢁC. After stirring for 48 h at room temperature, the
mixture was diluted with water and extracted with EtOAc. The
combined organic extracts were washed with water, saturated
aqueous NH4Cl solution, and brine and were dried over MgSO4.
After concentration in vacuo, the residue was purified by column
chromatography (hexane/ethyl acetate¼2/1) to give the titled
compound 11 (14.4 mg, 53% in three steps) as a colorless oil;
[found: C, 63.58; H, 9.07. C25H43O6P requires C, 63.81; H, 9.21%];
½
a 2D5
1462, 1371, 1262, 1075, 1013, 973, 804, 739 cmꢀ1
ꢂ
þ1.7 (c 1.0, CHCl3); nmax (KBr) 3403 (br), 2957, 2927, 2872,
;
dH (400 MHz,
CDCl3) 0.55 (s, 3H), 0.83 (d, J¼6.4 Hz, 3H), 0.84 (d, J¼6.4 Hz, 3H),
0.92 (d, J¼6.8 Hz, 3H), 1.03 (d, J¼6.3 Hz, 3H), 1.25e1.55 (m, 7H),
1.75e1.90 (m, 6H), 2.02 (m, 1H), 2.52 (m, 1H), 4.20 (ddd, J¼0.9, 6.8,
12.4 Hz,1H), 4.33 (ddd, J¼1.4, 7.8, 12.4 Hz,1H), 4.73 (t, J¼1.5 Hz, 1H),
5.18 (dd, J¼7.8, 15.5 Hz, 1H), 5.21 (dd, J¼7.8, 15.5 Hz, 1H), 5.35 (dt,
J¼2.0, 7.3 Hz, 1H); dC (100 MHz, CDCl3) 11.4, 17.6, 19.6, 20.0, 21.1,
22.1, 27.7, 30.2, 33.1, 34.5, 40.4, 42.8, 44.9, 49.7, 56.2, 57.8, 64.4,
122.5, 132.1, 135.5, 144.8. HRMS (ESI): MþNaþ, observed 343.2592;
expected for C21H36O2Na: 343.2613. By using less amount of DIBAL,
the corresponding aldehyde 12 was obtained in 30e40% yield.
½
a 2D6
1746, 1461, 1386, 1268, 1114, 1025, 973, 905, 869, 836 cmꢀ1
ꢂ
ꢀ17.8 (c 1.0, CHCl3); nmax (liquid film) 3470, 2960, 2872,
;
dH
(400 MHz, CDCl3) 0.65 (s, 3H), 0.82 (d, J¼7.3 Hz, 3H), 0.83 (d,
J¼6.8 Hz, 3H), 0.91 (d, J¼6.4 Hz, 3H), 1.03 (d, J¼6.9 Hz, 3H),
1.4e1.9 (m, 9H), 1.34 (t, J¼6.9 Hz, 6H), 2.04 (m, 2H), 2.13 (m, 1H),
3.00 (d, J¼21.5 Hz, 2H), 3.03 (dd, J¼7.3, 11.5 Hz, 1H), 4.16 (m, 4H),
4.91 (t, J¼3.4 Hz, 1H), 5.16 (dd, J¼7.8, 15.5 Hz, 1H), 5.23 (dd, J¼7.8,
15.5 Hz, 1H); dC (100 MHz, CDCl3) 12.5, 16.3, 16.4, 17.6, 18.5, 19.6,
20.0, 21.0, 27.8, 29.6, 33.0, 33.8, 34.3, 35.1, 39.8, 42.9, 51.1, 56.7,
58.1, 62.71, 62.76, 62.83, 77.9, 132.8, 134.6, 164.5, 164.6, 205.7.
HRMS (ESI): MþNaþ, observed 493.2674; expected for
C25H43O6NaP: 493.2695.
Properties of 12: white powder, ½a D25
þ130.8 (c 0.68, CHCl3); nmax
ꢂ
(KBr) 3399 (br), 2956, 2872, 1664, 1458, 1372, 1136, 1028, 971 cmꢀ1
;
dH (400 MHz, CD3OD) 0.63 (s, 3H), 0.84 (d, J¼7.3 Hz, 3H), 0.85 (d,
J¼6.8 Hz, 3H), 0.93 (d, J¼6.9 Hz, 3H), 1.05 (d, J¼6.4 Hz, 3H),
1.25e1.55 (m, 6H), 1.76e1.95 (m, 6H), 2.05 (m, 1H), 2.86 (m, 1H),
5.21 (dd, J¼7.8, 15.5 Hz, 1H), 5.25 (dd, J¼7.8, 15.5 Hz, 1H), 5.33 (m,
1H), 5.67 (dd. J¼1.3, 8.3 Hz, 1H), 10.08 (d, J¼8.3 Hz, 1H); dC
(100 MHz, CD3OD) 12.1, 18.2, 20.1, 20.5, 21.6, 22.6, 28.8, 32.0, 34.4,
35.6, 41.7, 44.4, 51.8, 58.0, 64.1, 125.9, 133.6, 136.7, 169.0, 191.9.
4.1.5. (3bR,5aR,6R,8aR,10R,20E,40R)-3a,3b,4,5,5a,7,8,8a-Octahydro-
5a-methyl-6-(10,40,50-trimethyl-20-hexenyl)-2H-indeno[5,4-b]furan-
2-one (8). To a stirred and cooled (0 ꢁC) solution of 11 (240 mg,

1734
A. Yajima et al. / Tetrahedron 68 (2012) 1729e1735
HRMS (ESI): MþNaþ, observed 341.2445; expected for C21H34O2Na:
1226, 1056, 942, 874, 836 cmꢀ1
; dH (400 MHz, CDCl3) 0.63 (s, 3H),
341.2456.
0.78 (d, J¼6.9 Hz, 3H), 0.79 (d, J¼6.9 Hz, 3H), 0.85 (d, J¼6.6 Hz, 3H),
0.90e1.20 (m, 2H), 0.95 (d, J¼6.4 Hz, 3H), 1.10e2.30 (m, 16H), 2.44
(dd, J¼7.5, 11.6 Hz, 1H); dC (100 MHz, CDCl3) 12.5, 15.4, 17.6, 18.9,
19.1, 20.5, 24.1, 27.5, 30.5, 31.5, 33.5, 35.9, 38.98, 39.01, 41.0, 49.9,
56.6, 62.0, 212.1. HRMS (ESI): MþNaþ, observed 301.2498; ex-
pected for C19H34ONa: 301.2507.
4.1.7. Demethylincisterol A3 (2). To a solution of 13 (5 mg, 16 mmol)
in acetone (0.5 ml), Jones reagent was added dropwise until an
orange-brown color persisted. Thereafter, the reaction mixture was
poured into water, the aqueous mixture was extracted with three
portions of EtOAc, and the organic phases were washed succes-
sively with water and brine and dried over MgSO4. The solvent was
evaporated and the residue was purified by column chromatogra-
phy (hexane/EtOAc¼5/1) to give the titled compound 2 (2 mg, 39%)
4.1.10. (1R,3aR,5R,7aR,10R,40S)-5,6,7,7a-Tetrahydro-5-(dieth-
ylphosphonoacetoxy)-7a-methyl-1-(10,40,50-trimethylhexyl)-3aH-in-
dan-4-one (17). To a stirred solution of 16 (100 mg, 359 mmol) in
as a colorless oil; ½a D25
ꢂ
þ130.0 (c 0.35, MeOH), lit.4 [
D þ130 (c 0.69,
a
]
THF (2 ml) at ꢀ78 ꢁC was added dropwise LiHMDS (430
ml,
MeOH); nmax (liquid film) 3266 (br), 2953, 2871, 1759, 1730, 1667,
430 mmol, 1.0 M solution in THF), and the mixture was stirred for
1465, 1378, 1342, 1131, 1115, 1054, 970, 948, 904, 852 cmꢀ1
; dH
45 min. After addition of TMSCl (37 ml, 430 mmol), the reaction
(400 MHz, CDCl3) 0.61 (s, 3H), 0.83 (d, J¼6.9 Hz, 3H), 0.84 (d,
J¼6.8 Hz, 3H), 0.92 (d, J¼6.8 Hz, 3H), 1.04 (d, J¼6.4 Hz, 3H),
0.93e1.00 (m, 2H), 1.10e2.10 (m, 14H), 2.27 (ddd, J¼2.3, 3.6, 13.7 Hz,
1H), 2.65 (m, 1H), 2.76 (br s, 1H), 5.17 (dd, J¼8.2, 15.2 Hz, 1H), 5.25
(dd, J¼7.8, 15.2 Hz, 1H), 5.64 (d, J¼1.8 Hz, 1H); dC (100 MHz, CDCl3)
11.7, 17.6, 19.6, 20.0, 21.0, 21.4, 28.8, 33.0, 35.0, 35.3, 40.1, 42.8, 48.8,
50.3, 55.3, 104.7, 112.3, 132.9, 134.6, 170.5, 170.7. HRMS (EI): Mþ,
observed 332.2351; expected for C21H32O3: 332.2354. The 1H and
13C NMR spectra of the synthetic 2 are identical with those of the
natural product. The purity of the synthetic 2 is >98% as judged by
the NMR spectra.
mixture was stirred for 2 h at the same temperature. Next, the
mixture was poured into a saturated aqueous NaHCO3 solution. The
aqueous phase was extracted with ether. The combined organic
layers were washed with brine and dried with MgSO4. Removal of
the solvent in vacuo yielded the crude silyl enol ether. A stirred
solution of the silyl enol ether and N-methylmorpholine-N-oxide
(150
was treated with 181
(7 mol). The resulting yellow solution was stirred at room tem-
ml, 718
mmol, 4.8 M solution in water) in THF/H2O (3/1, 10 ml)
ml of a 1% (w/v) t-BuOH solution of OsO4
m
perature overnight, followed by the addition of 25 mg of NaHSO3,
filtration, and the removal of the THF in vacuo. The aqueous phase
was extracted with CH2Cl2, and the combined organic extracts were
dried over MgSO4. Removal of the solvent in vacuo afforded a dark
brown oil. This oil was dissolved in CH2Cl2 (1 ml), and pyridine
4.1.8. (1R,3aR,4S,7aR,10R,40S)-Hexahydro-7a-methyl-1-(10,40,50-tri-
methylhexyl)-indan-4-ol (15). To a stirred and cooled (ꢀ7 ꢁC) so-
lution of 614 (766 mg, 2.77 mmol) in MeOH (8 ml) was added NaBH4
(146 mg, 3.86 mmol). After stirring for 1 h at room temperature, the
reaction was quenched with water. The aqueous phase was
extracted with EtOAc, and the organic extract was washed with
saturated aqueous NaHCO3 solution, water, and brine and was dried
with MgSO4. Removal of the solvent in vacuo gave the crude alco-
hol. The obtained crude alcohol was dissolved in acetic acid (10 ml),
(43.5
(153 mg, 716
m
l, 538
m
mol), and diethylphosphonoacetyl chloride24
mol) were added to the resulting solution at 0 ꢁC.
m
After stirring for 1 h at 0 ꢁC, the mixture was diluted with water and
extracted with EtOAc. The combined organic extracts were dried
over MgSO4 and concentrated in vacuo. The residue was purified by
column chromatography (hexane/ethyl acetate¼2/1) to give the
titled compound 17 (88.2 mg, 52% in three steps) as a white solid;
mp 100e102 ꢁC; [found: C, 63.55; H, 9.90. C25H45O6P requires C,
and PtO2 (6.3 mg, 28 mmol) was added to the solution. The mixture
63.54; H, 9.60%]; ½a D25
ꢀ7.9 (c 1.0, CHCl3); nmax (KBr) 3471, 2958,
ꢂ
was stirred under H2 (balloon) for 24 h at room temperature. The
mixture was subsequently diluted with EtOAc and filtered through
a Celite pad. After evaporation of the solvents, the residue was
purified by column chromatography (hexane/ethyl acetate¼90/1)
to give the titled compound 15 (692 mg, 89% in two steps) as
a colorless oil; [found: C, 81.05; H, 13.01. C19H36O requires C, 81.36;
2872, 1746, 1601, 1465, 1387, 1324, 1263, 1162, 1112, 1018, 973, 904,
869, 835 cmꢀ1
;
dH (400 MHz, CDCl3) 0.64 (s, 3H), 0.78 (d, J¼6.8 Hz,
6H), 0.79 (d, J¼6.8 Hz, 3H), 0.86 (d, J¼6.8 Hz, 3H), 0.94 (d, J¼6.4 Hz,
3H), 0.94e1.25 (m, 3H), 1.30e1.62 (m, 4H), 1.34 (t, J¼6.9 Hz, 6H),
1.82e2.13 (m, 6H), 2.98 (s, 1H), 3.01 (dd, J¼7.3, 12.0 Hz, 1H), 3.03 (s,
1H), 4.16 (m, 4H), 4.91 (t, J¼3.4 Hz, 1H); dC (100 MHz, CDCl3) 12.3,
15.4, 16.3, 16.4, 17.6, 18.5, 18.9, 20.5, 27.5, 29.6, 30.4, 31.5, 33.5, 33.8,
34.4, 35.1, 35.9, 39.0, 51.2, 56.7, 58.0, 62.68, 62.74, 62.76, 62.82, 77.9,
164.5, 164.6, 205.8. HRMS (ESI): MþNaþ, observed 495.2842; ex-
pected for C25H45O6NaP: 495.2851.
H, 12.94%]; ½a 2D5
ꢂ
þ23.6 (c 1.0, CHCl3). nmax (liquid film): 3431 (br),
2957, 2873, 1465, 1377, 1242, 1166, 1066, 990, 942, 887 cmꢀ1
;
dH
(400 MHz, CDCl3) 0.78 (d, J¼6.8 Hz, 3H), 0.79 (d, J¼6.9 Hz, 3H), 0.86
(d, J¼6.8 Hz, 3H), 0.87e0.98 (m, 3H), 0.90 (d, J¼6.4 Hz, 3H), 0.93 (s,
3H), 1.00e1.92 (m, 16H), 2.00 (m, 1H), 4.07 (br s, 1H); dC (400 MHz,
CDCl3) 13.5, 15.4, 17.4, 17.6, 18.7, 20.5, 22.5, 27.1, 30.6, 31.5, 33.5, 33.6,
35.7, 39.1, 40.4, 41.8, 52.6, 56.6, 69.5. HRMS (EI): Mþ, observed
280.2761; expected for C19H36O: 280.2766.
4.1.11. (3bR,5aR,6R,8aR,10R,40S)-3a,3b,4,5,5a,7,8,8a-Octahydro-5a-
methyl-6-(10,40,50-trimethylhexyl)-2H-indeno[5,4-b]furan-2-one
(18). To a stirred and cooled (0 ꢁC) solution of 17 (88 mg, 186
m
mol)
in THF (1 ml) under an Ar atmosphere were added LiCl (11.8 mg,
278 mol) and DBU (30.5 l, 204 mol). The mixture was stirred for
4.1.9. (1R,3aR,7aR,10R,40S)-5,6,7,7a-Tetrahydro-7a-methyl-1-(10,40,50-
trimethylhexyl)-3aH-indan-4-one (16). To
(0 ꢁC) solution of 15 (8.7 mg, 31.1
mol) in CH2Cl2 (0.5 ml) was
added NaHCO3 (13.0 mg, 155 mol) and DesseMartin periodinane
(20.0 mg, 62.2 mol). After stirring for 1 h at room temperature,
a stirred and cooled
m
m
m
1 h at 0 ꢁC and subsequently quenched with water. The aqueous
layer was extracted with EtOAc. The combined organic layers were
washed with brine, dried with Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography (hexane/ethyl
acetate¼20/1) to give the titled compound 18 (50.9 mg, 86%) as
m
m
m
the reaction was quenched with saturated aqueous NaHCO3 so-
lution. The aqueous phase was extracted with EtOAc, and the or-
ganic extract was washed with saturated aqueous NaHCO3
solution, water, and brine and was dried with MgSO4. After con-
centration in vacuo, the residue was purified by column chroma-
tography (hexane/ethyl acetate¼60/1) to afford the titled
compound 16 (8.2 mg, 95%) as a colorless oil; [found: C, 81.81; H,
a colorless oil; ½a D25
ꢀ71.6 (c¼1.0, CHCl3); nmax (liquid film) 2957,
ꢂ
2872, 1755, 1643, 1467, 1378, 1329, 1284, 1153, 1087, 1021, 977, 941,
898, 847, 805 cmꢀ1
;
dH (400 MHz, CDCl3) 0.79 (d, J¼6.8 Hz, 3H),
0.79 (d, J¼6.8 Hz, 3H), 0.86 (d, J¼6.8 Hz, 3H), 0.90 (s, 3H), 0.92 (d,
J¼6.4 Hz, 3H), 0.94e1.00 (m, 2H), 1.16e1.62 (m, 9H), 1.82e2.13 (m,
4H), 2.31 (m, 1H), 2.69 (m, 1H), 5.30 (dddd, J¼1.8, 1.8, 5.7, 13.2 Hz,
1H), 5.70 (dd, J¼2.2, 2.2 Hz, 1H); dC (100 MHz, CDCl3) 15.4, 17.6, 18.5,
12.48. C19H34O requires C, 81.95; H, 12.31%]; ½a D25
ꢀ3.6 (c 1.0,
ꢂ
CHCl3); nmax (liquid film) 2956, 2872, 1715, 1465, 1378, 1307, 1241,

A. Yajima et al. / Tetrahedron 68 (2012) 1729e1735
1735
18.9, 20.5, 22.4, 26.2, 28.8, 30.6, 31.5, 33.2, 34.4, 36.1, 39.0, 41.7, 49.3,
56.8, 80.7, 113.2, 174.1, 174.9. HRMS (EI): Mþ, observed 318.2528.
C21H34O2 requires 318.2559.
are identical with those of the natural product. The purity of the
synthetic 1 is >98% as judged by the NMR spectra.
Acknowledgements
4.1.12. (1R,3aR,4Z,5R,7aR,10R,40S)-5,6,7,7a-Tetrahydro-4-(2-
hydroxyethylidene)-7a-methyl-1-(10,40,50-trimethylhexyl)-3aH-in-
dan-5-ol (19). To a stirred and cooled (ꢀ78 ꢁC) solution of 18
We thank Professor H. Kawagishi (Shizuoka University) for the
copies of NMR spectra of chaxine A and demethylincisterol A3. We
thank Dr. T. Tashiro (RIKEN) for the collection of the MS spectra.
This work was supported by a grant from Advanced Research Pro-
ject of Tokyo University of Agriculture.
(10.0 mg, 31.4
219
mmol) in CH2Cl2 (1 ml) was added DIBAL (219 ml,
mmol, 1.0 M solution in toluene). The mixture was stirred for
1.5 h at ꢀ78 ꢁC and was quenched by the careful addition of MeOH.
The mixture was then warmed to room temperature and diluted
with aqueous Rochelle’s salt solution and ether. The mixture was
stirred vigorously for 2 h. Next, the aqueous phase was extracted
with EtOAc, and the combined organic extracts were dried over
MgSO4. After concentration of the solvent in vacuo, the residue was
purified by column chromatography (hexane/ethyl acetate¼1/1) to
give the titled compound 19 (9.5 mg, 95%) as a white solid; mp
80e82 ꢁC; [found: C, 77.90; H, 11.84. C21H38O2 requires C, 78.20; H,
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.12.057.
References and notes
11.18%]; ½a 2D5
þ16.6 (c 1.0, CHCl3); nmax (KBr) 3255, 2959, 2871, 1467,
ꢂ
1. Suda, T. Proc. Jpn. Acad., Ser. B 2004, 80, 407e421.
1377, 1337, 1252, 1214, 1155, 1100, 1054, 1007, 960, 922, 893,
853 cmꢀ1 dH (400 MHz, CDCl3) 0.54 (s, 3H), 0.78 (d, J¼6.6 Hz, 3H),
0.79 (d, J¼6.8 Hz, 3H), 0.86 (d, J¼6.8 Hz, 3H), 0.88e1.02 (m, 2H),
0.93 (d, J¼6.0 Hz, 3H), 1.10e2.30 (m, 17H), 2.51 (dd, J¼7.3, 10.9 Hz,
1H), 4.18 (dd, J¼6.1, 12.0 Hz, 1H), 4.33 (ddd, J¼1.1, 8.2, 12.0 Hz, 1H),
4.73 (br s, 1H), 5.35 (dt, J¼1.6, 7.3 Hz, 1H); dC (100 MHz, CDCl3) 11.1,
15.5, 17.6, 19.0, 20.5, 22.2, 27.5, 30.3, 30.6, 31.5, 33.6, 34.6, 36.5, 39.1,
45.1, 49.6, 56.2, 57.8, 64.4, 122.6, 144.9. HRMS (ESI): MþNaþ, ob-
served 345.2757; C21H38O2Na requires: 345.2770.
2. Udagawa, N.; Takahashi, N.; Akatsu, T.; Tanaka, H.; Sasaki, T.; Nishihara, T.;
Koga, T.; Martin, J.; Suda, T. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 7260e7264.
3. Teitelbaum, S. L. Am. J. Pathol. 2007, 170, 427e435.
4. Kawagishi, H.; Akachi, T.; Ogawa, T.; Masuda, K.; Yamaguchi, K.; Yazawa, K.;
Takahashi, M. Heterocycles 2006, 69, 253e258.
5. Kawagishi, H.; Takahashi, M.; Yamaguchi, K.; Yazawa, K. Jpn. Kokai Tokkyo Koho
JP 2008019223, 2008.
6. De Riccardis, F.; Spinella, A.; Izzo, I.; Giordano, A.; Sodano, G. Tetrahedron Lett.
1995, 36, 4303e4306.
7. (a) Ohta, K.; Yaoita, Y.; Matsuda, N.; Kikuchi, M. Natural Med. 1996, 50, 179e181;
(b) Akihisa, T.; Nakamura, Y.; Tagata, M.; Tokuda, H.; Yasukawa, K.; Uchiyama,
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4.1.13. Chaxine A (1). A 10 ml flask was charged with a solution of
19 (10.0 mg, 31.0
AZADO, 52 g, 0.31
aqueous solution of NaHCO3 (42.0
3.09 mol) and n-Bu4NBr (TBAB, 238
(0 ꢁC) and stirred mixture, a pre-mixed solution of aqueous NaOCl
and a saturated aqueous solution of NaHCO3 (304 l, 1:1.4 v/v) was
m
mol), 1-methyl-2-azaadamantane N-oxyl (1-Me-
mol) in CH2Cl2 (0.2 ml) and a saturated
l) containing KBr (368 g,
g, 1.54 mol). To this cooled
m
m
m
m
m
m
m
m
added dropwise over 6 min. The mixture was stirred for 1 h at 0 ꢁC
and was quenched with a saturated aqueous solution of Na2S2O3
(0.2 ml). The aqueous layer was separated and extracted with ether.
The combined organic layers were washed with brine, dried with
MgSO4, and concentrated under reduced pressure to afford the
crude ketoaldehyde. To a stirred solution of the resulting ketoal-
dehyde in acetone (0.2 ml), the Jones reagent (2.67 M, 161
ml,
4.29
m
mol) was added dropwise at 0 ꢁC. The mixture was stirred for
1 h at 0 ꢁC and then poured into water. The aqueous phase was
extracted with EtOAc. The combined organic extracts were washed
successively with water and brine and dried with MgSO4. After
evaporation of the solvents, the residue was purified by column
chromatography (hexane/ethyl acetate¼4/1) to give the titled
compound 1 (6.6 mg, 67%) as a colorless oil; ½a D24
þ136.8 (c 0.37,
ꢂ
MeOH), lit.4
[
a
]Dþ133 (c 0.1, MeOH); nmax (liquid film) 3359 (br),
€
2959, 1746, 1663, 1465, 1378, 1338, 1214, 1177, 1127, 1048, 960, 905,
854 cmꢀ1
;
dH (400 MHz, CDCl3) 0.59 (s, 3H), 0.78 (d, J¼6.9 Hz, 6H),
0.86 (d, J¼6.9 Hz, 3H), 0.95 (d, J¼6.4 Hz, 3H), 0.93e1.00 (m, 2H),
1.10e1.65 (m, 9H), 1.75 (m, 1H), 1.86 (ddd, J¼4.5, 14.2, 18.8 Hz, 1H),
2.00 (ddd, J¼2.3, 4.6,13.3 Hz,1H), 2.08 (m,1H), 2.27 (ddd, J¼2.3, 4.2,
14.3 Hz, 1H), 2.64 (ddd, J¼1.8, 6.5, 11.6 Hz, 1H), 3.04 (br s, 1H), 5.63
(d, J¼1.8 Hz, 1H); dC (100 MHz, CDCl3) 11.5, 15.4, 17.6, 18.9, 20.5, 21.4,
28.6, 30.5, 31.5, 33.5, 35.2, 35.3, 36.2, 39.0, 49.0, 50.3, 55.4, 104.9,
112.2, 170.8, 171.1. HRMS (EI): Mþ, observed 334.2515; expected for
C21H34O3: 334.2508. The 1H and 13C NMR spectra of the synthetic 1
24. Choi, J.-H.; Ogawa, A.; Abe, N.; Masuda, K.; Koyama, T.; Yazawa, K.; Kawagishi,
H. Tetrahedron 2009, 65, 9850e9853.