Asymmetric synthesis and in vivo biological inactivity of the right-hand terpenoid fragment of terpendole e

Article abstract of DOI:10.1002/ejoc.201001104

Synthesis of the DEF-ring terpenoid fragment of terpendole E, an Eg5 inhibitor, is described. The DE-ring was constructed by a modification of Barrero's radical cyclization. The F-ring tetrahydropyran was then constructed by acid-induced cyclization of an epoxy alcohol, which was prepared by cross-metathesis followed by Shi's epoxidation. Cell-based assays indicated that the DEF-ring fragment is not capable of inhibiting cell growth and cell cycle progression of human cancer cell lines, indicating that the DEF-ring fragment alone is not sufficient for the biological activity. The DEF-ring terpenoid fragment of terpendole E, has been synthesized in 15 steps starting from farnesyl acetate, employing radical cyclization (DE-ring formation) and stereoselective cyclization of an epoxyalcohol (F-ring formation). Cell-based assays showed that the right-hand DEF-ring fragment is inactive in cell growth and cell cycle progression of human cancer cell lines.

Full text of DOI:10.1002/ejoc.201001104

FULL PAPER
DOI: 10.1002/ejoc.201001104
Asymmetric Synthesis and in vivo Biological Inactivity of the Right-Hand
Terpenoid Fragment of Terpendole E
Masato Oikawa,*[a,b] Ryo Hashimoto,[b] and Makoto Sasaki[b]
Dedicated to the memory of Professor Mugio Nishizawa
Keywords: Natural products / Terpenoids / Radical reactions / Reduction / Metathesis / Cyclization / Inhibitors
Synthesis of the DEF-ring terpenoid fragment of terpendole
E, an Eg5 inhibitor, is described. The DE-ring was con-
structed by a modification of Barrero’s radical cyclization.
The F-ring tetrahydropyran was then constructed by acid-
induced cyclization of an epoxy alcohol, which was prepared
by cross-metathesis followed by Shi’s epoxidation. Cell-
based assays indicated that the DEF-ring fragment is not
capable of inhibiting cell growth and cell cycle progression
of human cancer cell lines, indicating that the DEF-ring frag-
ment alone is not sufficient for the biological activity.
indolinoditerpenes such as paspaline.[8] In spite of the intri-
guing biological activity, no synthetic study has been re-
ported except for a recent study of an analog synthesis by
the Giannis group.[9] This could be attributed to several syn-
thetic difficulties in the selective construction of a hexacy-
clic molecular skeleton with eight asymmetric carbons, as
can be anticipated from other indoloditerpene synthe-
ses.[8c,10] The synthetically challenging structure, as well as
the interesting biological activity, prompted us to study the
chemical synthesis. Here, we report our studies on the syn-
thesis and in vivo biological activity of the DEF-ring terpe-
noid fragment 2 of terpendole E (1).
Introduction
Eg5, also known as kinesin spindle protein (KSP), is a
member of a kinesin-5 family, and is an extraordinary
active protein in mitosis, the process involved in all cells
that are undergoing cell division.[1] Inhibition of Eg5 results
in cell cycle arrest and apoptotic cell death, without affect-
ing microtuble integrity in the interphase.[2] Eg5 has, there-
fore, recently been recognized as an attractive molecular
target for treatment of malignant tumors, since Eg5 plays
an important role in the assembly and stabilization of the
mitotic spindle.[3] Inhibitors of Eg5 have been explored
from synthetic and natural[4] resources in this context[5] and,
in 2003, the microbial metabolite terpendole E (1) was iden-
tified by Osada’s group as a novel Eg5 inhibitor that in-
hibits M phase progression by inducing formation of a
monastrol spindle in the M phase.[6] Terpendole E (1) at a
concentration of 50 μm caused cell cycle arrest of tsFT210
cells at the boundary of the G2/M phase.
Terpendole E (1), an indoloditerpene that possesses an
indole fragment fused to a tetracyclic diterpene system, was
originally isolated from the fungal strain FO-2546 by-
Tomoda and Omura in 1995.[7] They established the relative
stereostructure of terpendole E (1) by X-ray crystallo-
graphic analysis as shown in Scheme 1, and the absolute
configuration has been assigned by analogy with other
Results and Discussion
As shown in Scheme 1, terpendole E (1) was retrosyn-
thetically disconnected first by Wittig reaction[11] at the C2–
C18 bond to generate the advanced intermediate A. The
intermediate was envisaged to be synthesized from the
DEF-ring terpenoid fragment 2, which includes the right-
hand carbon framework with correct stereochemistry, by
employing a modified Barrero radical cyclization[12–14] and
acidic cyclization of an epoxy alcohol for the DE- and F-
rings, respectively.
The synthesis of the optically active DE-ring fragment 9
is shown in Scheme 2. Oxidation of farnesyl acetate (3) with
SeO2, in the presence of tert-butyl hydroperoxide (TBHP),
selectively provided alcohol 4 in 38% yield.[15,16] Sharpless
asymmetric epoxidation using diethyl (+)-tartrate [(+)-
DET] gave the epoxide 5 after silylation in 80% yield.[17]
The enantioselectivity in the epoxidation was determined to
be 91% ee by analysis of the Mosher ester derivative.
[a] Graduate School of Nanobioscience and University-Industry
Cooperative Research Center, Yokohama City University,
Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
Fax: +81-45-787-2403
E-mail: moikawa@yokohama-cu.ac.jp
[b] Graduate School of Life Sciences, Tohoku University,
Aoba-ku, Sendai 980-8577, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001104.
538
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The Terpenoid Fragment of Terpendole E
Scheme 1. Our retrosynthetic plan for terpendole E generates the DEF-ring terpenoid fragment 2.
Scheme 2. Construction of the DE-ring and synthesis of aldehyde 9.
The construction of the DE-ring moiety was next at-
Introduction of a carbon chain corresponding to the F-
tempted using the radical reaction procedure originally re- ring was next attempted. Appropriate reaction conditions
ported by Barrero et al.[13] It was found, however, that the were initially investigated with model aldehyde 10, which
original procedure (0.2 equiv. of Cp2TiCl2, Mn, TMSCl, was prepared in six steps from cyclohexanone (see the Sup-
2,4,6-collidine, THF, r.t.) was not capable of providing porting Information). Although prenyl addition is known
the desired bicycle 6 in our hands, and only unreacted 5 to proceed at the γ-position,[23] we initially expected that
was recovered. Although the use of a combination of the reaction with neopentylic aldehyde 10 might provide the
stoichiometric amounts (2 equiv.) of Cp2TiCl2 and Mn α-addition product for steric reasons.[24] The results are
(8 equiv.)[13,14] at room temperature was also unsuccessful, shown in Table 1. Addition of a prenyl group was first at-
the desired bicycle 6 was obtained in 41% yield by changing tempted with prenylmagnesium bromide (Table 1, entry 1).
the metal to Zn (8 equiv.).[18–20] Spectroscopic data of 6 However, γ-addition product 11 was found to be generated
were identical with those reported for racemic 6.[14] Protec- solely in 62% yield. After several experiments, the desired
tion of the secondary hydroxyl group as the p-meth- α-addition product 12 was found to be produced with pre-
oxybenzyl (PMB) ether, which was carried out via the cor- nylzinc bromide,[25] but in only 14% yield, with the major
responding trichloroacetimidate,[21] and desilylation (tetra- product still being the γ-addition product 11 (Table 1,
butylammonium fluoride, TBAF, in THF) followed by entry 2, 55% yield). As shown in Table 1, entry 3, prenyl-
Swern oxidation,[22] gave the DE-ring aldehyde 9 in 61% barium bromide,[23] which is an excellent α-addition
yield for the three steps.
reagent, caused only decomposition even at –78 °C.
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M. Oikawa et al.
FULL PAPER
Table 1. Model study for the introduction of an alkenyl group at entry 6). We thus decided to further explore the two-step
the C11 position.
procedure with aldehyde 9 to generate the DE-ring frag-
ment of terpendole E.
Introduction of an allyl side chain and establishing the
required C11–hydroxy stereochemistry were accomplished
as shown in Scheme 3. Here, we employed allylzinc bromide
for reaction with aldehyde 9 because it did not cause de-
composition of the acetyl protecting group. As expected
from Table 1 (entry 5), the reaction proceeded quite
smoothly in THF to give alcohol 15 with unfavorable dia-
stereoselectivity (α/β = 1:1.4). Enrichment of the desired α-
alcohol was next studied. We anticipated that an oxidation–
reduction sequence should facilitate the process by giving
an identical diastereoselectivity to that observed in the ad-
dition of allylzinc bromide (9Ǟ15). Indeed, oxidation of
alcohol 15 with 2-iodoxybenzoic acid (IBX) and dimethyl
sulfoxide (DMSO),[26] followed by reduction of the resulting
carbonyl group in 16 with lithium aluminum hydride
(LAH), successfully delivered diol 17 (75%, three steps
from 9) with acceptable diastereoselectivity (α/β = 4.2:1).
The major product 17α was separated and subjected to cy-
clic acetal formation to confirm the stereochemistry at C-
11. Thus, when 17α was treated with 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (DDQ) and molecular sieves
(4 Å),[27] 4-methoxybenzylidene acetal 18α was cleanly ob-
tained in 83% yield. NOESY spectra of 18α showed that
the stereochemistry at C-11 position was identical with that
of the natural product, as shown in Scheme 3. The minor
diol 17β was also converted into the diastereomer 18β for
characterization (see the Exp. Section).
Considering the difficulties described above, we then ex-
plored a two-step procedure for prenylation; namely, allyl
group addition followed by cross-metathesis. Thus, treat-
ment of 10 with allylmagnesium bromide at 0 °C gave the
adduct 13 in 91% yield as an inseparable, diastereomeric
mixture (Table 1, entry 4). By extensive structural analysis
of p-methoxybenzylidene acetal derivatives (see the Sup-
porting Information), the desired α-alcohol was shown to
be generated in preference to the β-alcohol (α/β = 1.4:1) in
Scheme 3. Stereoselective introduction of an allyl group in the C11
position; Ar = p-methoxyphenyl.
this reaction. Other allylation reagents were also examined
as follows. When allylzinc bromide was employed, the α-
diastereoselectivity was decreased (Table 1, entry 5, α/β =
Synthesis of the desired DEF-ring terpenoid fragment of
1:2.2). Reaction with allyltrimethylsilane in the presence of terpendole E from 17α was further studied as shown in
SnCl4 completely controlled the diastereoselectivity, giving Scheme 4. Diol 17α was first protected by acetyl groups
rise to the undesired β-alcohol in 67% yield (Table 1, [Ac2O, pyridine, 4-(dimethylamino)pyridine (DMAP)] to
540
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The Terpenoid Fragment of Terpendole E
Scheme 4. Synthesis of the DEF-ring fragment 2.
give diacetate 19 in 100% yield, which, in turn, was sub-
In vivo biological activity of the DEF-ring terpenoid
jected to a cross-metathesis reaction with 2-methyl-2-butene fragment 2 was then investigated by evaluation of inhibitory
in the presence of the Grubbs’ catalyst 20 (second genera- activity on (1) the growth of five human cancer cell lines
tion)[28] to introduce 28,29-dimethyl groups successfully in (HL-60, K562, tsFT210, HT1080, HeLa), and (2) the cell
98% yield.[29] Deprotection of the PMB ether was then ef- cycle progression of K562 cells.[6] In all assay systems, how-
fected by DDQ in H2O and CH2Cl2,[30] and the trisubsti- ever, 2 was biologically inactive. The result indicates that
tuted C9–C27 olefin was selectively epoxidized by Shi’s attachment of the left-hand moiety (the A-, B-, or C-ring)
asymmetric reaction[31,32] to generate monoepoxide 24 in to 2 is necessary for the Eg5 inhibitory activity.
good yield (90%).[33] Epoxide 24 was obtained as an insepa-
rable mixture of two diastereomers (4:1 ratio), and the
Conclusions
major product was tentatively assigned as the desired α-
We have developed a stereoselective synthetic route to
isomer on the basis of Shi’s empirical rule.[32] The F-ring
the DEF-ring fragment of the Eg5 antagonist terpendole E
tetrahydropyran was next constructed by pyridinium p-tolu-
(1). The overall yield from farnesyl acetate (3) was 2.3%
enesulfonate (PPTS) catalyzed epoxide ring opening in
over 15 steps. Several cell-based assays, performed using 2,
CH2Cl2 at 0 °C to give 25 in 61% yield. From NOESY as
indicated that the DEF-ring fragment is not capable of in-
n
well as JH,H analyses, 25 was shown to have the desired
hibiting cell growth and cell cycle progression. Further syn-
stereochemistry, which was identical with that of the natural
thetic studies toward the total synthesis of terpendole E as
product, thus validating the stereochemical assignment of
well as studies on structure–activity relationships are un-
24 based on Shi’s empirical rule. The β-isomer of 24, which
derway in these laboratories.
is expected to give the thermodynamically disfavored C9-
epi-25 upon cyclization, was recovered intact (14%) in this
reaction. Finally, the two acetyl groups were removed by
Experimental Section
alkaline methanolysis to furnish the desired DEF-ring ter-
penoid fragment 2 (95%).
General Methods: Details of the experimental techniques and the
apparatus are summarized in our previous paper.[34] The purity of
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M. Oikawa et al.
FULL PAPER
1
all purified products was assessed to be Ͼ95% by inspection of H
(dd, J = 13.0, 3.5 Hz, 1 H), 1.78 (d, J = 13.0 Hz, 1 H), 1.65–1.48
(m, 2 H), 1.42–1.22 (m, 4 H), 0.78 (s, 3 H), 0.74 (s, 3 H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 171.3, 159.2, 146.1, 130.6, 129.5
(ϫ2), 113.9 (ϫ2), 107.5, 79.6, 69.8, 67.3, 61.4, 47.1, 42.6, 38.4,
37.0, 36.5, 23.0, 22.2, 21.1, 15.6, 12.4 ppm. HRMS (FAB): calcd.
for C25H36O5Na [M + Na]+ 439.2460; found 439.2468.
and 13C NMR spectra, unless specified otherwise.
Bicyclic Alcohol 6: A mixture of Cp2TiCl2 (205 mg, 0.500 mmol)
and Zn dust (262 mg, 4.00 mmol) in strictly deoxygenated THF
(3.0 mL) was stirred at r.t. for 15 min, at which point the red solu-
tion turned green. The green TiIII solution was slowly added by
using a cannula to a solution of the epoxide 5 (205.3 mg,
0.500 mmol) in THF (10 mL). The reaction mixture was stirred at
r.t. for 1 h before it was quenched with hydrochloric acid (1 m,
5 mL). The mixture was extracted with Et2O (3ϫ30 mL), and the
combined organic layers were washed with brine (5 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash column chromatography (silica gel;
EtOAc/hexanes) gave the bicyclic alcohol 6 (84.5 mg, 41%) as a
colorless oil. Chromatographic and spectroscopic data were iden-
tical with those of racemic compound reported previously.[14] [α]2D4
= +5.2 (c = 0.115, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 4.85
(br. s, 1 H), 4.52 (br. s, 1 H), 4.30 (dd, J = 11.5, 4.0 Hz, 1 H), 4.17
(dd, J = 11.5, 9.5 Hz, 1 H), 3.65–3.61 (m, 2 H), 3.41 (br. s, 1 H),
3.33 (d, J = 9.0 Hz, 1 H), 2.37 (m, 1 H), 2.03–1.96 (m, 2 H), 2.00
(s, 3 H), 1.76–1.66 (m, 2 H), 1.50–1.31 (m, 3 H), 1.25 (dd, J = 12.0,
3.0 Hz, 1 H), 0.89 (s, 9 H), 0.83 (s, 3 H), 0.78 (s, 3 H), 0.06 (s, 3
H), 0.05 (s, 3 H) ppm.
Aldehyde 9: To a solution of (COCl)2 (0.0432 mL, 0.504 mmol) in
CH2Cl2 (2.0 mL) at –78 °C, was added a solution of DMSO
(0.447 mL, 0.672 mmol) in CH2Cl2 (1.0 mL). The resultant mixture
was stirred at the same temperature for 1 h. To the mixture was
added a solution of the alcohol 8 (70.2 mg, 0.168 mmol) in CH2Cl2
(1.5 mL) at –78 °C. After being stirred for 30 min, Et3N (0.141 mL,
1.01 mmol) was added to the mixture, which was stirred for 30 min
before the reaction was quenched with saturated aqueous NaHCO3
(5 mL). The mixture was extracted with Et2O (3ϫ15 mL), and the
combined organic layers were washed with brine (10 mL), dried
with MgSO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash column chromatography (silica
gel, EtOAc/hexanes, 1:5Ǟ1:4) gave the aldehyde 9 (62.4 mg, 88%)
as a colorless oil. [α]2D0 = +55.0 (c 0.83, CHCl ). IR (film): ν = 2932,
˜
3
2805, 1733, 1513, 1247, 1033 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 9.21 (s, 1 H), 7.14 (d, J = 8.5 Hz, 2 H), 6.83 (d, J = 8.5 Hz, 2
H), 4.86 (s, 1 H), 4.55 (s, 1 H), 4.47 (d, J = 11.5 Hz, 1 H), 4.32 (dd,
J = 11.5, 4.0 Hz, 1 H), 4.28 (d, J = 11.5 Hz, 1 H), 4.16 (dd, J =
11.5, 8.0 Hz, 1 H), 3.78 (s, 3 H), 3.50 (dd, J = 11.5, 4.5 Hz, 1 H),
2.32 (br. d, J = 13.0 Hz, 1 H), 2.05 (br. d, J = 6.0 Hz, 1 H), 2.02–
1.94 (m, 2 H), 2.00 (s, 3 H), 1.83 (br. d, J = 14.0 Hz, 1 H), 1.62–
1.50 (m, 2 H), 1.45 (ddd, J = 13.0, 13.0, 4.5 Hz, 1 H), 1.36 (ddd, J
= 13.0, 13.0, 3.0 Hz, 1 H), 1.13–1.05 (m, 1 H), 1.09 (s, 3 H), 0.79
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 206.4, 171.2,
159.1, 145.2, 130.2, 129.1 (ϫ2), 113.7 (ϫ2), 108.5, 78.6, 70.0, 61.1,
55.2, 55.0, 54.2, 46.9, 37.8, 36.7, 36.3, 24.9, 22.1, 21.0, 15.3,
9.9 ppm. HRMS (FAB): calcd. for C25H34O5Na [M + Na]+
437.2299; found 437.2304.
PMB Ether 7: To a solution of the bicyclic alcohol 6 (476 mg,
1.16 mmol) and p-methoxybenzyl trichloroacetimidate (89.4 mg,
2.50 mmol) in toluene (6.0 mL) at r.t., was added La(OTf)3
(34.0 mg, 0.0580 mmol). The reaction mixture was stirred at r.t. for
45 min before it was concentrated under reduced pressure. Purifica-
tion of the residue by flash column chromatography (silica gel;
EtOAc/hexanes, 1:15Ǟ1:10) gave the PMB ether 7 as a colorless
oil. [α]2D5 = +12.0 (c = 0.125, CHCl ). IR (film): ν = 2934, 2856,
˜
3
1
1735, 1513, 1249 cm–1. H NMR (600 MHz, CDCl3): δ = 7.26 (d,
J = 7.9 Hz, 2 H), 6.84 (d, J = 7.9 Hz, 2 H), 4.85 (br. s, 1 H), 4.52
(d, J = 10.7 Hz, 1 H), 4.50 (br. s, 1 H), 4.34 (d, J = 10.7 Hz, 1 H),
4.31 (dd, J = 11.6, 3.2 Hz, 1 H), 4.18 (dd, J = 10.7, 10.4 Hz, 1 H),
3.79 (s, 3 H), 3.52 (d, J = 9.7 Hz, 1 H), 3.46 (dd, J = 11.9, 4.3 Hz,
1 H), 3.18 (d, J = 9.7 Hz, 1 H), 2.37 (br. d, J = 12.9 Hz, 1 H),
2.03–1.99 (m, 2 H), 2.02 (s, 3 H), 1.84 (m, 1 H), 1.74 (br. d, J =
12.9 Hz, 1 H), 1.68 (br. d, J = 11.9 Hz, 1 H), 1.57–1.52 (m, 2 H),
1.35–1.22 (m, 2 H), 0.89 (s, 9 H), 0.76 (s, 3 H), 0.64 (s, 3 H), 0.02
Aldehyde 10: Synthesized from cyclohexanone in six steps includ-
ing: (1) formylation,[35] (2) methylation, (3) LAH-mediated re-
duction, (4) p-methoxybenzylidene acetal formation, (5) DIBA-H
mediated reduction of the acetal, and (6) Parikh–Doering oxi-
dation.[36] Aldehyde 10 was obtained as a colorless oil. IR (film): ν
˜
= 2936, 2861, 1725, 1513, 1247, 1087 cm–1. 1H NMR (500 MHz,
(s, 6 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 171.4, 159.1, CDCl3): δ = 9.40 (s, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 6.84 (d, J =
146.4, 130.4, 128.8 (ϫ2), 113.6 (ϫ2), 107.4, 78.8, 71.3, 64.0, 61.5,
55.2, 54.6, 45.8, 43.3, 38.3, 37.2, 36.8, 25.9 (ϫ2), 23.1, 22.8, 21.1,
18.1, 15.5, 13.0, –5.4 (ϫ2) ppm. HRMS (ESI): calcd. for
C31H51O5Si [M + H]+ 531.3500; found 531.3503.
8.0 Hz, 2 H), 4.51 (d, J = 11.5 Hz, 1 H), 4.32 (d, J = 11.5 Hz, 1
H), 3.78 (s, 3 H), 3.59 (dd, J = 9.5, 4.0 Hz, 1 H), 1.84 (m, 1 H),
1.72 (m, 1 H), 1.58–1.35 (m, 5 H), 1.11 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 206.4, 159.0, 130.6, 129.0 (ϫ2), 113.6
(ϫ2), 77.5, 70.1, 55.2, 51.2, 30.8, 25.6, 23.1, 20.6, 13.7 ppm. HRMS
(FAB): calcd. for C16H22O3Na [M + Na]+ 285.1461; found
285.1467.
Alcohol 8: To a solution of the PMB ether 7 obtained above, in
THF (8.0 mL) at r.t., was added TBAF (1.0 m in THF, 1.51 mL,
1.51 mmol). The reaction mixture was warmed to 50 °C and stirred
at the same temperature overnight before it was quenched with
hydrochloric acid (1 m, 5 mL). The mixture was extracted with
CH2Cl2 (3ϫ30 mL), and the combined organic layers were washed
with brine, dried with Na2SO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash column
chromatography (silica gel, EtOAc/hexanes, 1:4Ǟ1:2) gave the
alcohol 8 (333 mg, 69% over two steps from 6) as a colorless oil.
Reaction of Aldehyde 10 with Prenylzinc Bromide: (Table 1, entry 2).
To a stirred solution of the aldehyde 10 (37.5 mg, 0.143 mmol) in
THF (1.0 mL) at –78 °C, was added prenylzinc bromide[25] (0.4 m
in THF, 0.72 mL, 0.286 mmol). After stirring for 30 min, the mix-
ture was warmed to r.t. over 75 min. The reaction was quenched
with saturated aqueous NH4Cl (2 mL) and the mixture was ex-
tracted with EtOAc (3ϫ3 mL). The combined organic extracts
were washed with brine (2 mL), dried with Na2SO4, and concen-
trated under reduced pressure. Purification of the residue by flash
column chromatography (silica gel, EtOAc/hexanes, 1:3) gave an
inseparable mixture of the adducts 11 and 12 (4:1, 33.0 mg, 69%)
as a colorless oil. Data for γ adduct 11: IR (film, as a 4:1 mixture
[α]2D0 = +66.3 (c = 0.66, CHCl ). IR (film): ν = 3456 (br), 2936,
˜
3
1735, 1513, 1248, 1035 cm–1. 1H NMR (500 MHz, CDCl3): δ =
7.25 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.0 Hz, 2 H), 4.84 (s, 1 H),
4.61 (d, J = 11.5 Hz, 1 H), 4.51 (s, 1 H), 4.35–4.29 (m, 1 H), 4.15
(dd, J = 11.0, 9.0 Hz, 1 H), 3.78 (s, 3 H), 3.45 (d, J = 10.5 Hz, 1
H), 3.32 (dd, J = 11.5, 4.5 Hz, 1 H), 3.22 (d, J = 10.5 Hz, 1 H),
2.86 (d, J = 13.5 Hz, 1 H), 2.05–1.97 (m, 2 H), 2.00 (s, 3 H), 1.94
of 11 and 12): ν = 3450, 2933, 2863, 1610, 1513, 1245, 1036 cm–1.
˜
1H NMR (400 MHz, CDCl3, selected): δ = 7.24 (d, J = 8.3 Hz, 2
542
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The Terpenoid Fragment of Terpendole E
H), 6.86 (d, J = 8.3 Hz, 2 H), 6.01 (dd, J = 17.6, 10.9 Hz, 1 H),
4.94 (dd, J = 17.6, 1.3 Hz, 1 H), 4.90 (dd, J = 10.9, 1.3 Hz, 1 H),
4.54 (d, J = 11.4 Hz, 1 H), 4.29 (d, J = 11.4 Hz, 1 H), 3.79 (s, 3
H), 3.75 (dd, J = 11.4, 4.5 Hz, 1 H), 3.25 (d, J = 6.4 Hz, 1 H), 2.69
(d, J = 7.1 Hz, 1 H), 1.91 (m, 1 H), 1.71–1.65 (m, 2 H), 1.55 (m, 1
as a colorless solid. IR (KBr): ν = 3292, 2935, 2862, 1432,
˜
1
1250 cm–1. H NMR (400 MHz, CDCl3): δ = 5.79 (m, 1 H), 5.18
(br. s, 1 H), 5.13 (d, J = 9.6 Hz, 1 H), 3.58 (dd, J = 11.2, 4.3 Hz,
1 H), 3.49 (dd, J = 10.6, 2.1 Hz, 1 H), 2.35 (m, 1 H), 2.00 (m, 1
H), 1.72–1.66 (m, 2 H), 1.49–1.13 (m, 5 H), 0.92 (s, 3 H), 0.92 (m,
H), 1.46–1.26 (m, 4 H), 1.10 (s, 3 H), 1.09 (s, 3 H), 1.07 (s, 3 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 135.5, 118.7, 81.5,
H) ppm. 13C NMR (100 MHz, CDCl3, selected): δ = 159.0, 147.6,
78.8, 41.1, 35.7, 34.1, 30.1, 24.6, 20.9, 9.6 ppm. HRMS (ESI):
131.0, 129.1 (ϫ2), 113.7 (ϫ2), 109.8, 83.3, 80.3, 69.3, 55.2, 43.4, calcd. for C11H21O2 [M + H]+ 185.1536; found 185.1540.
41.9, 33.0, 28.1, 25.7, 25.0, 24.3, 21.0, 17.9 ppm. HRMS (ESI, as
β,γ-Unsaturated Ketone 16: To a solution of the aldehyde 9
a 4:1 mixture of 11 and 12): calcd. for C21H33O3 [M + H]+
(30.3 mg, 0.0731 mmol) in THF (1.5 mL) at –20 °C, was added al-
lylzinc bromide (0.50 m in THF, 0.292 mL, 0.146 mmol). After stir-
333.2424; found 333.2418. Data for α adduct 12: IR (film, as a 4:1
mixture of 11 and 12): ν = 3450, 2933, 2863, 1610, 1513, 1245,
˜
ring at –20 °C for 2 h, the reaction was quenched with saturated
aqueous NH4Cl (5 mL), and the mixture was extracted with Et2O
(2ϫ10 mL). The combined organic layers were washed with brine
(5 mL), dried with MgSO4, filtered, and concentrated under re-
duced pressure. Purification of the residue by flash column
chromatography (silica gel, EtOAc/hexanes, 1:10Ǟ1:5) gave the
homoallylic alcohol 15 (31.4 mg, 94%, dr = 1:1.4) as a colorless
oil. 1H NMR (500 MHz, CDCl3): δ = 7.24–7.20 (m, 2 H), 6.88–
6.84 (m, 2 H), 5.94 (m, ca. 0.4 H, α-isomer), 5.70 (m, ca. 0.6 H, β-
isomer), 5.09–4.99 (m, 2 H), 4.84–4.83 (m, 1 H), 4.60–4.12 (m, 5
H), 3.79 (s, ca. 1.2 H, α-isomer), 3.78 (s, ca. 1.8 H, β-isomer), 3.67–
3.30 (m, 2 H), 2.36–1.74 (m, 7 H), 2.03 (s, ca. 1.2 H, α-isomer),
2.00 (s, ca. 1.8 H, β-isomer), 1.60–1.50 (m, 1 H), 1.44–1.24 (m, 3
H), 1.11 (s, ca. 1.2 H, α-isomer), 0.94 (s, ca. 1.8 H, β-isomer), 0.81
(s, ca. 1.2 H, α-isomer), 0.80 (s, ca. 1.8 H, β-isomer) ppm. HRMS
(ESI): calcd. for C28H41O5 [M + H]+ 457.2949; found 457.2948.
1036 cm–1. 1H NMR (400 MHz, CDCl3, selected): δ = 7.24 (d, J =
8.3 Hz, 2 H), 6.86 (d, J = 8.3 Hz, 2 H), 5.23 (br. t, J = 6.4 Hz, 1
H), 4.54 (d, J = 11.4 Hz, 1 H), 4.34 (d, J = 11.4 Hz, 1 H), 3.78 (s,
3 H), 3.57 (dd, J = 11.4, 4.3 Hz, 1 H), 3.40 (br. d, J = 10.0 Hz, 1
H), 2.15 (m, 1 H), 2.01–1.87 (m, 2 H), 1.71 (s, 3 H), 1.71–1.65 (m,
2 H), 1.59 (s, 3 H), 1.46–1.26 (m, 6 H), 0.97 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3, selected): δ = 159.0, 133.6, 131.0, 129.2
(ϫ2), 122.4, 113.8 (ϫ2), 79.2, 77.2, 69.9, 55.2, 44.8, 31.3, 30.1,
25.9, 25.9, 24.5, 21.1, 17.9, 15.6 ppm. HRMS (ESI, as a 4:1 mixture
of 11 and 12): calcd. for C21H33O3 [M + H]+ 333.2424; found
333.2418.
Alcohol 13: (Table 1, entry 4). To a stirred solution of the aldehyde
10 (19.0 mg, 0.0724 mmol) in THF (0.72 mL) at 0 °C, was added
allylmagnesium bromide (1.0 m in Et2O, 0.145 mL, 0.145 mmol).
After stirring for 30 min, saturated aqueous NH4Cl (3 mL) was in-
troduced and the mixture was extracted with Et2O (2ϫ10 mL).
The combined organic extracts were washed with brine (3 mL),
dried with Na2SO4, and concentrated under reduced pressure. Puri-
fication of the residue by flash column chromatography (silica gel,
EtOAc/hexanes, 1:3) gave the alcohol 13 (α/β = 1.4:1, 20.1 mg,
To a solution of the alcohol 15 (50.2 mg, 0.110 mmol) in DMSO
(1.0 mL) at r.t., was added IBX (62.9 mg, 0.220 mmol). The reac-
tion mixture was stirred at r.t. overnight before being diluted with
EtOAc (5 mL). The mixture was quenched with saturated aqueous
Na2SO3 (3 mL), the mixture was extracted with EtOAc
(2ϫ15 mL), and the combined organic layers were washed success-
ively with saturated aqueous NaHCO3 (5 mL) and brine (5 mL),
dried with Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash column chromatography
(silica gel, EtOAc/hexanes, 1:10) gave the ketone 16 (44.6 mg, 89%)
91%) as a colorless oil. IR (film): ν = 3435, 2936, 2862, 1613, 1514,
˜
1249 cm–1. 1H NMR (400 MHz, CDCl3, selected for the major iso-
mer): δ = 7.21 (d, J = 10.3 Hz, 2 H), 6.83 (d, J = 10.3 Hz, 2 H),
5.89 (m, 1 H), 5.08–5.02 (m, 2 H), 4.57 (d, J = 11.0 Hz, 1 H), 4.33
(d, J = 11.0 Hz, 1 H), 3.77 (s, 3 H), 3.56 (m, 1 H), 3.37 (dd, J =
11.0, 4.9 Hz, 1 H), 2.21 (dd, J = 12.2, 5.6 Hz, 1 H), 2.07–1.98 (m,
2 H), 1.79–1.69 (m, 2 H), 1.49–1.36 (m, 3 H), 1.20–1.10 (m, 1 H),
1.01–0.94 (m, 1 H), 0.97 (s, 3 H) ppm. 1H NMR (400 MHz, CDCl3,
selected for the minor isomer): δ = 7.24 (d, J = 10.3 Hz, 2 H), 6.86
(d, J = 10.3 Hz, 2 H), 5.89 (m, 1 H), 5.08–5.02 (m, 2 H), 4.56 (d,
J = 11.0 Hz, 1 H), 4.33 (d, J = 11.0 Hz, 1 H), 3.78 (s, 3 H), 3.56
(m, 1 H), 3.44 (br. d, J = 10.4 Hz, 1 H), 2.30 (dd, J = 14.0, 6.2 Hz,
1 H), 2.03–1.91 (m, 2 H), 1.79–1.69 (m, 2 H), 1.49–1.36 (m, 3 H),
1.20–1.10 (m, 1 H), 1.01–0.94 (m, 1 H), 0.97 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3, selected for the major isomer): δ = 159.1,
137.0, 129.8, 129.3 (ϫ2), 116.0, 113.8 (ϫ2), 86.8, 79.0, 69.5, 55.2,
41.4, 35.5, 34.1, 25.5, 24.4, 21.0, 10.7 ppm. 13C NMR (100 MHz,
CDCl3, selected for the minor isomer): δ = 159.1, 137.2, 130.8,
129.4 (ϫ2), 116.6, 113.7 (ϫ2), 81.4, 76.5, 69.7, 55.2, 41.9, 36.0,
34.1, 25.7, 24.4, 21.0, 15.6 ppm. HRMS (ESI): calcd. for C19H29O3
[M + H]+ 305.2111; found 305.2109.
as a colorless oil. [α]2D5 = +33.5 (c = 0.1, CHCl ). IR (film): ν =
˜
3
2936, 2862, 1732, 1644, 1265 cm–1. 1H NMR (500 MHz, CDCl3):
δ = 7.12 (d, J = 9.0 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 5.95–5.85
(m, 1 H), 5.11 (dd, J = 10.0, 1.0 Hz, 1 H), 5.00 (dd, J = 17.0,
1.0 Hz, 1 H), 4.83 (s, 1 H), 4.52 (s, 1 H), 4.44 (d, J = 11.0 Hz, 1
H), 4.31 (dd, J = 11.0, 4.0 Hz, 1 H), 4.19 (d, J = 11.0 Hz, 1 H),
4.16 (dd, J = 11.0, 9.0 Hz, 1 H), 3.77 (s, 3 H), 3.63 (dd, J = 11.5,
4.0 Hz, 1 H), 3.31 (dd, J = 18.0, 6.5 Hz, 1 H), 3.11 (dd, J = 18.0,
6.5 Hz, 1 H), 2.28 (br. d, J = 13.0 Hz, 1 H), 2.07 (br. d, J = 5.5 Hz,
1 H), 2.03–1.85 (m, 3 H), 2.01 (s, 3 H), 1.78 (d, J = 13.5 Hz, 1 H),
1.56–1.37 (m, 3 H), 1.22 (s, 3 H), 1.04–0.97 (m, 1 H), 0.77 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 215.3, 171.3, 159.0,
145.5, 131.7, 130.5, 129.0 (ϫ2), 117.7, 113.6 (ϫ2), 108.0, 83.1, 70.4,
61.2, 57.3, 55.2, 54.4, 50.0, 45.0, 38.1, 36.8, 36.3, 25.3, 22.7, 21.0,
15.5, 11.6 ppm. HRMS (FAB): calcd. for C28H36O5Na [M + Na]+
477.2612; found 477.2617.
Diol 14: (Table 1, entry 6). To a stirred solution of the aldehyde 10
(15.4 mg, 0.0582 mmol) in CH2Cl2 at –78 °C, was added SnCl4 Diols 17α and 17β: To a solution of LAH (3.5 mg, 0.092 mmol) in
(1.0 m in CH2Cl2, 0.058 mL, 0.0582 mmol). After 5 min, allyltri-
methylsilane (0.0139 mL, 0.0873 mmol) was added and stirring was
continued for 2 h. The mixture was poured into saturated aqueous
THF (1.0 mL) at –78 °C, was added a solution of the ketone 16
(13.9 mg, 0.0306 mmol) in THF (1.0 mL). The reaction mixture
was stirred at –40 °C for 6 h then quenched with H2O (1 mL). The
NaHCO3 (3 mL) and extracted with Et2O (2ϫ10 mL). The com- mixture was extracted with Et2O (2ϫ10 mL), and the combined
bined organic extracts were washed with brine (3 mL), dried with
MgSO4, and concentrated under reduced pressure. Purification of
the residue by flash column chromatography (silica gel, EtOAc/
hexanes, 1:3) gave the diastereomerically pure diol 14 (7.2 mg, 67%)
organic layers were washed with brine (3 mL), dried with Na2SO4,
filtered, and concentrated under reduced pressure. Purification of
the residue by flash column chromatography (silica gel, EtOAc/
hexanes, 1:15Ǟ1:10) gave the desired diol 17α (9.3 mg, 73%) and
Eur. J. Org. Chem. 2011, 538–546
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
543

M. Oikawa et al.
FULL PAPER
the undesired diastereomer 17β (2.2 mg, 17%) as colorless oils.
(3ϫ10 mL) and the combined organic layers were dried with
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
Data for 17α: [α]2D0 = +35.5 (c = 0.62, CHCl ). IR (film): ν = 3428,
˜
3
2938, 1613, 1513, 1249, 1065, 1033 cm–1. 1H NMR (500 MHz, cation of the residue by flash column chromatography (silica gel,
CDCl3): δ = 7.21 (d, J = 9.0 Hz, 2 H), 6.85 (d, J = 8.5 Hz, 2 H),
EtOAc/hexanes, 1:3) gave the p-methoxybenzylidene acetal 18β
5.75–5.65 (m, 1 H), 5.11–5.04 (m, 2 H), 4.92 (s, 1 H), 4.62 (s, 1 H), (3.0 mg, 30%) as a colorless solid. No side product was detected in
4.54 (d, J = 11.5 Hz, 1 H), 4.29 (d, J = 11.5 Hz, 1 H), 3.84–3.73 the reaction, and only unreacted diol 17β (3.2 mg, 32%) was reco-
(m, 2 H), 3.78 (s, 3 H), 3.65 (d, J = 11.0 Hz, 1 H), 3.32 (dd, J =
11.5, 4.5 Hz, 1 H), 2.41–2.33 (m, 2 H), 2.10–1.93 (m, 4 H), 1.70 (d,
J = 13.5 Hz, 1 H), 1.62–1.48 (m, 3 H), 1.46–1.36 (m, 2 H), 1.32–
vered. Data for 18β: [α]2D4 = –15.5 (c = 0.165, CHCl ). IR (KBr): ν
˜
3
= 3489, 2937, 2879, 1518, 1250 cm–1. H NMR (500 MHz, C6D6):
1
δ = 7.67 (d, J = 8.5 Hz, 2 H), 6.85 (d, J = 9.0 Hz 2 H), 5.93 (m, 1
1.20 (m, 2 H), 0.93 (s, 3 H), 0.77 (s, 3 H) ppm. 13C NMR H), 5.76 (s, 1 H), 5.13 (d, J = 17.0 Hz, 1 H), 5.10 (d, J = 10.0 Hz,
(125 MHz, CDCl3): δ = 159.0, 147.3, 137.4, 130.9, 129.1 (ϫ2),
117.6, 113.7 (ϫ2), 106.4, 78.6, 74.7, 69.7, 59.0, 58.7, 55.2, 48.0,
45.3, 38.8, 37.4, 37.1, 36.3, 24.3, 22.9, 15.8, 13.2 ppm. HRMS
(FAB): calcd. for C26H38O4Na [M + Na]+ 437.2668; found
437.2672.
1 H), 4.83 (s, 1 H), 4.58 (s, 1 H), 3.72 (dd, J = 12.0, 4.0 Hz, 1 H),
3.66–3.54 (m, 2 H), 3.57 (dd, J = 11.5, 5.0 Hz, 1 H), 3.26 (s, 3 H),
2.75 (m, 1 H), 2.12 (dd, J = 13.0, 2.0 Hz 1 H), 1.97 (m, 1 H), 1.78–
1.62 (m, 4 H), 1.41 (m, 1 H), 1.29 (s, 3 H), 1.24–1.02 (m, 2 H),
1.00–0.88 (m, 3 H), 0.61 (s, 3 H) ppm. 13C NMR (125 MHz, C6D6):
δ = 160.3, 146.9, 135.9, 132.4, 128.2 (ϫ2), 116.2, 113.7 (ϫ2), 107.3,
95.3, 80.6, 78.3, 59.2, 58.5, 54.7, 48.0, 39.5, 38.9, 37.1, 36.8, 30.2,
24.6, 22.8, 16.3, 16.1 ppm. HRMS (FAB): calcd. for C26H36O4Na
[M + Na]+ 435.2506; found 435.2512.
Data for Undesired 17β: [α]2D5 = +22.9 (c = 0.15, CHCl3). IR (film):
ν = 3433, 3054, 2942, 1514, 1265 cm–1. 1H NMR (500 MHz,
˜
CDCl3): δ = 7.22 (d, J = 8.0 Hz, 2 H), 6.86 (d, J = 8.0 Hz, 2 H),
5.99–5.89 (m, 1 H), 5.02 (d, J = 9.5 Hz, 1 H), 5.01 (d, J = 18.0 Hz,
1 H), 4.63 (s, 1 H), 4.59 (d, J = 11.0 Hz, 1 H), 4.35 (d, J = 11.0 Hz,
1 H), 4.21 (d, J = 8.5 Hz, 1 H), 3.83–3.72 (m, 2 H), 3.78 (s, 3 H),
3.61 (dd, J = 11.5, 4.0 Hz, 1 H), 3.51 (dd, J = 8.5, 7.5 Hz, 1 H),
2.30 (d, J = 13.5 Hz, 1 H), 2.24 (dd, J = 14.0, 7.5 Hz, 1 H), 2.04–
1.87 (m, 4 H), 1.74 (d, J = 13.0 Hz, 1 H), 1.63–1.49 (m, 2 H), 1.48–
1.22 (m, 4 H), 1.11 (s, 3 H), 0.79 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 159.4, 146.5, 137.2, 129.8 (ϫ2), 129.3,
115.7, 113.9 (ϫ2), 106.8, 81.2, 77.9, 69.1, 59.2, 58.6, 55.2, 49.3,
44.4, 38.8, 37.1, 36.5, 36.4, 22.9, 22.0, 16.1, 13.3 ppm. HRMS
(FAB): calcd. for C26H38O4Na [M + Na]+ 437.2668; found
437.2672.
Diacetate 19: To a solution of the diol 17α (28.7 mg, 0.0692 mmol)
in CH2Cl2 (1.0 mL) at r.t., were added pyridine (0.0448 mL,
0.554 mmol), Ac2O (0.0262 mL, 0.277 mmol), and DMAP
(0.84 mg, 0.069 mmol). After stirring at 40 °C overnight, the reac-
tion mixture was concentrated under reduced pressure. Purification
of the residue by flash column chromatography (silica gel, EtOAc/
hexanes, 1:5) gave the acetate 19 (34.5 mg, 100%) as a colorless oil.
[α]2D0 = +42.6 (c = 0.72, CHCl ). IR (film): ν = 2933, 2873, 1612,
˜
3
1513, 1248, 1032 cm–1. H NMR (500 MHz, CDCl3): δ = 7.29 (d,
1
J = 8.5 Hz, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 5.58–5.48 (m, 1 H),
5.31 (d, J = 10.0 Hz, 1 H), 4.94 (d, J = 17.0 Hz, 1 H), 4.92 (d, J =
8.5 Hz, 1 H), 4.84 (s, 1 H), 4.57 (d, J = 11.5 Hz, 1 H), 4.52 (s, 1
H), 4.36–4.30 (m, 2 H), 4.14 (dd, J = 11.0, 9.0 Hz, 1 H), 3.78 (s, 3
H), 3.21 (dd, J = 11.5, 4.5 Hz, 1 H), 2.37 (dd, J = 11.0, 4.0 Hz, 1
H), 2.29–2.22 (m, 1 H), 2.16–2.06 (m, 1 H), 2.03–1.92 (m, 3 H),
2.00 (s, 3 H), 1.99 (s, 3 H), 1.77 (d, J = 11.5 Hz, 1 H), 1.60–1.48
(m, 3 H), 1.43–1.36 (m, 1 H), 1.30–1.18 (m, 2 H), 0.86 (s, 3 H),
0.78 (s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.3, 170.6,
159.0, 145.9, 135.8, 130.5, 129.4 (ϫ2), 129.1, 116.7, 113.7 (ϫ2),
107.5, 78.5, 69.9, 61.3, 55.2, 54.8, 48.3, 45.7, 38.8, 37.0, 36.3, 35.0,
24.2, 22.6, 21.1 (ϫ2), 15.6, 13.1 ppm. HRMS (FAB): calcd. for
C30H42O6Na [M + Na]+ 521.2879; found 521.2876.
p-Methoxybenzylidene Acetal 18α: To a solution of the diol 17α
(14.9 mg, 0.0326 mmol) in CH2Cl2 (1.0 mL), was added powdered
4 Å MS (45 mg). After stirring at r.t. for 30 min, the mixture was
cooled to 0 °C, and DDQ (8.9 mg, 0.039 mmol) was added. The
resultant mixture was stirred at 0 °C for 1.5 h then quenched with
saturated aqueous NaHCO3 (2 mL). The mixture was extracted
with CH2Cl2 (3ϫ10 mL), and the combined organic layers were
dried with Na2SO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash column chromatography
(silica gel, EtOAc/hexanes, 1:3) gave the acetal 18α (12.4 mg, 83%)
as a colorless oil. NOE experiments indicated that the stereochem-
istry at C-11 was identical to that of the natural product. Data for
Metathesis Product 21: To a solution of the diene 19 (35.4 mg,
0.0701 mmol) in 2-methyl-2-butene (1.0 mL), was added the second
generation Grubbs’ catalyst 20 (3.0 mg, 3.5 μmol). After stirring at
r.t. overnight, the mixture was concentrated under reduced pres-
sure. Purification of the residue by flash column chromatography
(silica gel, EtOAc/hexanes, 1:5) gave the metathesis product 21
(36.1 mg, 98%) as a colorless oil. [α]2D4 = +38.8 (c = 0.1, CHCl3).
p-methoxybenzylidene acetal 18α: [α]2D0 = +22.6 (c = 1.00, CHCl3).
1
IR (film): ν = 3434, 2940, 2852, 1615, 1517, 1249 cm–1. H NMR
˜
(500 MHz, CDCl3): δ = 7.40 (d, J = 7.5 Hz, 2 H), 6.86 (d, J =
8.0 Hz, 2 H), 6.05–5.85 (m, 1 H), 5.51 (s, 1 H), 5.03 (d, J = 17.5 Hz,
1 H), 4.98 (d, J = 10.0 Hz, 1 H), 4.94 (s, 1 H), 4.65 (s, 1 H), 3.86–
3.72 (m, 2 H), 3.77 (s, 3 H), 3.51 (dd, J = 8.0, 2.5 Hz, 1 H), 3.46
(dd, J = 11.5, 3.5 Hz, 1 H), 2.53 (dd, J = 13.5, 8.0 Hz, 1 H), 2.40
(d, J = 13.0 Hz, 1 H), 2.31–2.23 (m, 1 H), 1.88–165 (m, 4 H), 1.60–
1.43 (m, 2 H), 1.39 (br. s, 1 H), 1.28 (dd, J = 11.5, 3.0 Hz, 1 H),
1.05 (s, 3 H), 0.79 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ
= 159.8, 146.5, 136.4, 131.3, 127.4 (ϫ2), 115.6, 113.5 (ϫ2), 106.7,
101.3, 87.2, 86.1, 58.9, 58.6, 55.2, 50.7, 41.5, 39.8, 38.1, 37.2, 37.1,
25.9, 24.1, 16.9, 10.4 ppm. HRMS (FAB): calcd. for C26H36O4Na
[M + Na]+ 435.2506; found 435.2511.
IR (film): ν = 2933, 1735, 1513, 1246, 1030, 821 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 7.29 (d, J = 9.0 Hz, 2 H), 6.86 (d, J =
8.5 Hz, 2 H), 5.28 (dd, J = 10.5, 2.0 Hz, 1 H), 4.90–4.82 (m, 1 H),
4.84 (s, 1 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.52 (s, 1 H), 4.37–4.31
(m, 2 H), 4.14 (dd, J = 11.0, 9.0 Hz, 1 H), 3.77 (s, 3 H), 3.22 (dd,
J = 12.0, 4.5 Hz, 1 H), 2.37 (dd, J = 13.0, 1.5 Hz, 1 H), 2.24–2.15
(m, 1 H), 2.11–2.04 (m, 1 H), 2.04–1.91 (m, 3 H), 2.00 (s, 3 H),
1.98 (s, 3 H), 1.77 (d, J = 13.0 Hz, 1 H), 1.62 (s, 3 H), 1.60–1.47
(m, 3 H), 1.52 (s, 3 H), 1.46–1.18 (m, 4 H), 0.86 (s, 3 H), 0.78 (s, 3
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 171.3, 170.5, 159.0,
146.0, 133.2, 131.8, 130.7, 129.2 (ϫ2), 121.2, 113.7 (ϫ2), 107.5,
78.9, 77.8, 70.1, 61.4, 55.2, 54.8, 48.4, 45.7, 38.8, 37.0, 36.4, 28.8,
25.7, 24.4, 21.1, 21.0, 17.7, 15.6, 13.1 ppm. HRMS (FAB): calcd.
p-Methoxybenzylidene Acetal 18β: To a solution of the diol 17β
(9.9 mg, 0.019 mmol) in CH2Cl2 (1.0 mL), was added 4 Å MS
(30 mg). The mixture was stirred at r.t. for 30 min and then treated
with DDQ (5.5 mg, 0.024 mmol) at 0 °C. The resultant mixture was
stirred at 0 °C for 1.5 h then quenched with saturated aqueous
NaHCO3 (2 mL). The mixture was extracted with CH2Cl2 for C32H46O6Na [M + Na]+ 549.3187; found 549.3192.
544 Eur. J. Org. Chem. 2011, 538–546
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

The Terpenoid Fragment of Terpendole E
Alcohol 22: To a solution of the PMB ether 21 (24.9 mg,
0.0473 mmol) in CH2Cl2 and H2O (10:1, 1.1 mL) at 0 °C, was
added DDQ (14.0 mg, 0.0615 mmol). After stirring at r.t. for 1 h,
the reaction was quenched with saturated aqueous NaHCO3
(2 mL). The resultant mixture was extracted with CH2Cl2
(2ϫ10 mL), the combined organic layers were washed with brine
(5 mL), dried with Na2SO4, filtered, and concentrated under re-
duced pressure. Purification of the residue by flash column
chromatography (silica gel, EtOAc/hexanes, 1:4) gave the alcohol
22 (18.8 mg, 98%) as a colorless oil. [α]2D0 = +26.7 (c = 0.80,
4.18 (dd, J = 11.0, 9.0 Hz, 1 H), 3.54 (dd, J = 11.5, 4.5 Hz, 1 H),
3.40 (dd, J = 12.0, 2.5 Hz, 1 H), 2.46 (br. s, 1 H), 2.37 (br. d, J =
13.0 Hz, 1 H), 2.10 (s, 3 H), 2.08–2.02 (m, 1 H), 2.01 (s, 3 H), 1.92
(ddd, J = 14.0, 12.0, 3.5 Hz, 1 H), 1.86 (ddd, J = 13.0, 13.0, 4.5 Hz,
1 H), 1.75 (d, J = 13.0 Hz, 1 H), 1.68–1.56 (m, 2 H), 1.55–1.38 (m,
4 H), 1.34 (ddd, J = 13.0, 13.0, 4.5 Hz, 1 H), 1.15 (s, 3 H), 1.10 (s,
3 H), 0.86 (s, 3 H), 0.79 (s, 3 H) ppm. 13C NMR (150 MHz,
CDCl3): δ = 171.3, 170.2, 145.5, 107.9, 79.3, 78.0, 71.9, 71.6, 61.2,
54.9, 46.7, 39.8, 37.1, 36.6, 26.9, 26.1, 24.3, 23.6, 22.1, 21.1, 16.2,
13.3 ppm. HRMS (FAB): calcd. for C24H38O6Na [M + Na]+
445.2566; found 445.2565.
CHCl ). IR (film): ν = 3502, 2931, 2360, 1705, 1645, 1241,
˜
3
1028 cm–1. H NMR (500 MHz, CDCl3): δ = 5.23 (t, J = 6.5 Hz,
1
DEF-Ring Terpenoid Fragment 2: To a solution of the diacetate 25
(5.9 mg, 0.014 mmol) in MeOH (1.0 mL) at r.t., was added KOH
(7.8 mg, 0.14 mmol). After stirring for 1 d, the reaction mixture
was concentrated under reduced pressure. The mixture was diluted
with CH2Cl2 (2 mL) and saturated aqueous NH4Cl (2 mL) was
added. The mixture was extracted with CH2Cl2 (2ϫ5 mL), and the
combined organic layers were washed with brine (3 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure. Purifi-
cation of the residue by flash column chromatography (silica gel,
MeOH/CHCl3, 1:20Ǟ1:10) gave the DEF-ring terpenoid fragment
2 (4.5 mg, 95%) as a white solid. The purity of 2 was assessed to
1 H), 5.03 (t, J = 7.0 Hz, 1 H), 4.85 (s, 1 H), 4.52 (s, 1 H), 4.31
(dd, J = 11.5, 3.5 Hz, 1 H), 4.16 (dd, J = 11.5, 9.0 Hz, 1 H), 3.64–
3.56 (m, 1 H), 2.38 (dd, J = 13.5, 3.0 Hz, 1 H), 2.31 (dd, J = 7.0,
6.5 Hz, 2 H), 2.04–1.95 (m, 2 H), 2.00 (s, 3 H), 1.99 (s, 3 H), 1.78–
1.70 (m, 2 H), 1.68–1.48 (m, 2 H), 1.65 (s, 3 H), 1.60 (s, 3 H), 1.47–
1.26 (m, 4 H), 0.83 (s, 3 H), 0.78 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 171.3, 170.5, 145.8, 133.8, 120.8, 107.6,
77.9, 72.4, 61.3, 54.7, 48.1, 45.8, 38.8, 37.0, 36.5, 28.7, 28.2, 25.7,
24.4, 21.1, 21.0, 17.8, 15.6, 12.1 ppm. HRMS (FAB): calcd. for
C24H38O5Na [M + Na]+ 407.2797; found 407.2799.
1
be Ͼ98% by inspection of the H and 13C NMR spectra (see the
Epoxide 24: To a mixture of the diene 22 (23.5 mg, 0.0578 mmol),
sodium tetraborate buffer (0.05 m solution in 4ϫ10–4 m aqueous
Na2EDTA, 0.58 mL), tetrabutylammonium hydrogen sulfate
(0.98 mg, 2.9 μmol), and ketone 23 (14.9 mg, 0.0578 mmol)[31,32] in
CH3CN (1.0 mL) at 0 °C were added a solution of Oxone (35.5 mg,
0.0578 mmol) in aqueous Na2EDTA (4ϫ10–4 m, 1.0 mL) and a
solution of K2CO3 (143.6 mg, 1.04 mmol) in H2O (1.0 mL) over
2 h. When the addition was complete, the reaction mixture was
diluted with CH2Cl2 (5 mL) and washed with H2O (5 mL). The
aqueous layer was extracted with CH2Cl2 (3ϫ10 mL) and the com-
bined organic layers were dried with Na2SO4, filtered, and concen-
trated under reduced pressure. Purification of the residue by flash
column chromatography (silica gel, EtOAc/hexanes, 1:3Ǟ1:1) gave
the epoxide 24 as an inseparable mixture of diastereomers (22.0 mg,
90%, α/β = 4:1). Epoxide 24 was obtained as a colorless oil. Data
Supporting Information), and 2 was used for biological assays
without further purification. Data for 2: [α]2D0 = –32.2 (c = 0.85,
1
CHCl ). IR (film): ν = 3396 (br.), 2935, 1385, 1075, 1054 cm–1. H
˜
3
NMR (500 MHz, CDCl3, 20 °C): δ = 4.88 (s, 1 H, 17a-H), 4.66 (s,
1 H, 17b-H), 3.80 (dd, J = 11.0, 4.0 Hz, 1 H, 2a-H), 3.75–3.69 (m,
2 H, 2b-H and 11-H), 3.57–3.49 (m, 2 H, 7-H and 9-H), 2.39 (dd,
J = 12.5, 3.0 Hz, 1 H, 15-Heq), 2.11 (ddd, J = 13.0, 12.5, 4.5 Hz, 1
H, 15-Hax), 1.98–1.88 (m, 2 H, 3-H and 10-Hax), 1.77 (m, 2 H, 5-
Heq and 13-H), 1.65 (m, 1 H, 14-Heq), 1.53 (m, 2 H, 6-H2), 1.51
(ddd, J = 14.0, 3.0, 2.5 Hz, 1 H, 10-Heq), 1.35 (m, 2 H, 5-Hax and
14-Hax), 1.16 (s, 3 H, 28-H3 or 29-H3), 1.15 (s, 3 H, 28-H3 or 29-
H3), 0.84 (s, 3 H, 30-H3), 0.78 (s, 3 H, 26-H3) ppm. 13C NMR
(125 MHz, CD3OD, 20 °C): δ = 149.1 (16-C), 108.1 (17-C), 81.1
(9-C), 79.4 (7-C), 73.5 (27-C), 71.3 (11-C), 60.8 (3-C), 59.7 (2-C),
48.1 (13-C), 42.5 (12-C), 40.6 (4-C), 39.1 (15-C), 38.9 (5-C), 31.5
(10-C), 26.5 (28-C or 29-C), 26.4 (28-C or 29-C), 26.2 (6-C), 24.0
(14-C), 17.6 (26-C), 15.1 (30-C) ppm. HRMS (FAB): calcd. for
C20H34O4Na [M + Na]+ 361.2355; found 361.2350.
for 24: [α]2D5 = –6.0 (c = 0.125, CHCl ). IR (film): ν = 3428, 2938,
˜
3
1613, 1513, 1249, 1065, 1033 cm–1. 1H NMR (500 MHz, CDCl3,
selected for the major isomer): δ = 5.41 (dd, J = 10.5, 3.0 Hz, 1 H),
4.84 (s, 1 H), 4.52 (s, 1 H), 4.30 (dd, J = 11.0, 4.0 Hz, 1 H), 4.15
(dd, J = 11.0, 7.5 Hz, 1 H), 3.64–3.56 (m, 1 H), 2.77 (dd, J = 7.5,
4.5 Hz, 1 H), 2.37 (dd, J = 13.5, 4.0 Hz, 1 H), 2.14–2.04 (m, 1 H),
2.06 (s, 3 H), 2.02–1.86 (m, 2 H), 2.00 (s, 3 H), 1.78–1.54 (m, 4 H),
1.50–1.18 (m, 4 H), 1.25 (s, 3 H), 1.22 (s, 3 H), 0.84 (s, 3 H), 0.78
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3, selected for the major
isomer): δ = 171.3, 170.2, 14.5.6, 107.7, 75.4, 72.1, 62.6, 61.2, 58.9,
54.7, 48.0, 45.7, 38.8, 36.9, 36.5, 29.9, 24.6, 24.3, 21.1, 21.0, 18.9,
15.5, 12.0 ppm. HRMS (ESI): calcd. for C24H39O6 [M + H]+
423.2741; found 423.2746.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for com-
pounds 3–5, 10, and other synthetic intermediates, in vivo bio-
1
logical assay data of 2, and copies of H and 13C NMR spectra of
new compounds.
Acknowledgments
The authors are grateful to Dr. Tamio Saito and Dr. Hiroyuki Os-
ada (RIKEN NPDepo) for biological assays. Mr. Yuya Oikawa and
Mr. Shin’ichiro Oba (Yokohama City University) are also gratefully
acknowledged for experimental assistance. M. O. thanks the refer-
ees of this article for valuable suggestions with regard to Barrero’s
radical cyclization and biological activity of biosynthetic intermedi-
ates.
Tetrahydro-2H-pyran 25: To a solution of the epoxide 24 (α/β =
4:1, 15.0 mg, 0.0355 mmol) in CH2Cl2 (1.0 mL) at r.t., was added
PPTS (1.8 mg, 7.1 μmol). The resultant solution was stirred for
2.5 h then quenched with saturated aqueous NaHCO3 (1 mL). The
mixture was extracted with CH2Cl2 (3ϫ10 mL) and the combined
organic layers were washed with brine (5 mL), dried with Na2SO4,
filtered, and concentrated under reduced pressure. Purification of
the residue by flash column chromatography (silica gel, EtOAc/
hexanes, 1:3Ǟ1:1) gave the tetrahydro-2H-pyran 25 (9.2 mg, 61%)
and unreacted β-epoxide 24β (2.1 mg, 14%) as colorless oils. Data
[1] a) K. E. Sawin, K. LeGuellec, M. Philippe, T. J. Mitchison, Na-
ture 1992, 359, 540–543; b) M. T. Valentine, P. M. Fordyce,
S. M. Block, Cell Div. 2006, 1, 31.
[2] a) A. I. Marcus, U. Peters, S. L. Thomas, S. Garrett, A. Zelnak,
T. M. Kapoor, P. Giannakakou, J. Biol. Chem. 2005, 280,
for 25: [α]2D5 = –10.6 (c = 0.035, CHCl ). IR (film): ν = 2935, 2878,
˜
3
1698, 1247, 1040 cm–1. H NMR (500 MHz, CDCl3): δ = 4.90 (s,
1
1 H), 4.84 (s, 1 H), 4.52 (s, 1 H), 4.32 (dd, J = 11.0, 3.5 Hz, 1 H),
Eur. J. Org. Chem. 2011, 538–546
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
545

M. Oikawa et al.
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Received: August 6, 2010
Published Online: December 6, 2010
546
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 538–546