Total synthesis of 3-hydroxydrimanes mediated by titanocene(III) - Evaluation of their antifeedant activity

Article abstract of DOI:10.1002/ejoc.200400634

We describe the first synthesis of 3β-hydroxydihydroconfertifolin (3) and 3β-hydroxycinnamolide (4), together with improved procedures for the preparation of other 3-hydroxydrimanes (2 and 5) scarce in nature. The key step was the titanocene(III)-promoted

Full text of DOI:10.1002/ejoc.200400634

FULL PAPER
Total Synthesis of 3-Hydroxydrimanes Mediated by Titanocene(III) –
Evaluation of Their Antifeedant Activity
José Justicia,[a] J. Enrique Oltra,[a] Alejandro F. Barrero,[a] Ana Guadaño,[b] and
Azucena González-Coloma,[b]Juan M. Cuerva*
Keywords: Biological activity / Homogeneous catalysis / Radicals / Titanium complexes / Total synthesis
We describe the first synthesis of 3β-hydroxydihydroconferti- the viability of our procedure for the synthesis of drimane
folin (3) and 3β-hydroxycinnamolide (4), together with im-
proved procedures for the preparation of other 3-hydroxydri-
manes (2 and 5) scarce in nature. The key step was the titan-
ocene(III)-promoted cyclization of epoxypolyprenes, readily
prepared from commercial polyenes. In this way, we confirm
sesquiterpenoids with different functionalization patterns.
We also report on the antifeedant activity of 2–5 against four
insect species with different feeding ecologies.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
other 3-hydroxydrimanes (2–5) with different functionali-
zation patterns which are scarce in nature. We also consid-
ered that evaluation of their antifeedant activity might cast
some light on the structure–activity relationships of these
natural products.
Introduction
Among natural sesquiterpenoids,[1] 3-hydroxydrimanes
are intriguing metabolites that occur in organisms such as
plants, fungi, and nudibranchs,[2–12] which are philogenet-
ically very distant but share the common feature of having
an appetizing and apparently vulnerable appearance for
predators. We therefore speculated that, as occurs with
other closely related sesquiterpenoids,[13,14] these metabo-
lites might act as chemical deterrents against insects and
other parasites. Moreover, 3-hydroxydrimanes are consid-
ered to constitute a biochemical linkage between drimanes
and rearranged drimanes,[15] and have proven to be useful
building blocks for the synthesis of higher terpenoids of
pharmacological interest.[16,17] Some of them are also cyto-
toxic, inhibitors of myo-inositol monophosphatase, and
show other interesting biological properties.[18] These com-
pounds have therefore attracted the attention of chemists,
and been synthesized through the degradation of higher ter-
penoids,[19] by microbiologicallyassisted procedures,[20–22]
and by light-induced[23] and acid-induced cyclization of ep-
oxypolyprenes.[24] These procedures, however, are specific
Results and Discussion
As we had previously found, the titanocene(iii)-catalyzed
for only one or a few products and often require numerous cyclization of epoxypolyprene 7,[25] obtained from commer-
steps or give low overall yields. The aim of our present work cially available all-trans-farnesol (6) by van Tamelen’s pro-
has been to confirm the viability of the titanocene(iii)-based cedure,[28] gave a mixture from which the desired exocyclic
[29]
procedure recently developed in our laboratory for the syn- alkene 8
could be isolated in 40% yield (Scheme 1).
thesis of isodrimenediol (1)[25–27] for the production of Apart from 8, we also isolated a minor quantity of the en-
[28]
docyclic regioisomer 9
(7% yield).
[a]
[b]
Once we had the cornerstone intermediate 8 to hand, we
undertook the synthesis of the natural drimane
Department of Organic Chemistry, Faculty of Sciences, Univer-
sity of Granada,
2
18071 Granada, Spain
[4]
(Scheme 2), found in the fungi Marasmius oreades
and
Fax: (internat.) +34-958-248437
Polyporus arcularius,[11] and previously prepared by chemo-
biological and semisynthetic procedures.[3,20,30] Our total
synthesis of 2 began with the protection of the hydroxy
group of 8 as a benzoyl ester, and subsequent treatment
E-mail: jmcuerva@platon.ugr.es
Center of Environmental Sciences, CSIC,
Madrid, Spain
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712
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DOI: 10.1002/ejoc.200400634
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Total Synthesis of 3-Hydroxydrimanes Mediated by Titanocene(iii)
FULL PAPER
in Scheme 3).[37] Under these conditions the reaction pro-
vided the reduced product 13 in an acceptable 65% yield
(from the epimeric mixture), whereas the epimer at C-8 was
not detected.[34] These results might be explained in terms
of a C-8-centered tertiary radical, which would be formed
equally from both epimers 11a and 11b. This radical is then
trapped by a second titanocene(iii) species at the less hin-
dered face to give an alkyl-titanium(iv) complex. In anhy-
drous media this radical evolves towards the alkene 12, pre-
sumably by elimination of Cp2Ti(Cl)H.[36] In the presence
of water, however, the alkyl-TiIV complex would undergo
stereoselective protonolysis to give 13 as an unique stereo-
isomer. The two-step oxidation of 13 with Dess–Martin
periodinane[38] and NaClO2 gave the carboxylic acid 15,
which on basic treatment provided a 99% yield of the de-
sired γ-lactone 3 (direct Jones oxidation of alcohol 13 to
carboxylic acid 15, however, gave a 1:1 mixture of epimers
at C-8). In this way we achieved the first chemical synthesis
of 3, in ten steps and in an overall yield of more than 7%.
The 1H and 13C NMR spectra of synthetic 3 matched those
of natural 3β-hydroxydihydroconfertifolin,[7] confirming the
structure proposed for the fungal metabolite.
Scheme 1. Synthesis of the cornerstone intermediate 8
with MCPBA (Scheme 2), through which we obtained the
epoxides 11a and 11b (roughly 4:1 ratio) in 86% combined
yield. Different assays to open the oxirane ring of these pro-
ducts by treatment with either protic (TsOH) or Lewis
(BF3) acids, gave mixtures in which the desired alkene 12
was not detected.[31,32] On the other hand, titanocene(iii)-
promoted oxirane opening under anhydrous conditions fur-
nished 12 in a moderate yield of 38% (from the epimeric
mixture).[33,34] Finally, saponification of 12 provided a 95%
1
yield of 2. The H and 13C NMR spectra of synthetic 2
matched those of the natural product.[4] In this way, the
stereoselective total synthesis of 2 was completed in eight
steps, providing an overall yield of more than 5%.
Scheme 3. Synthesis of drimanes 3 and 4
Both the (+) and the (–) enantiomers of 3β-hydroxycin-
namolide (4) have been reported as natural products, the
[6]
former from the plant Warburgia stuhlmanii and the lat-
ter from the fungus Peniophora polygonya.[7] Their struc-
tures were established by spectroscopic methods,[6,7] and the
absolute stereochemistry of the (–)-enantiomer (shown in 4)
was assigned on the basis of its CD spectrum.[7] We began
Scheme 2. Synthesis of drimane 2
From our experience of the effects of water on titani- the synthesis of 4 (b in Scheme 3) with a two-step oxidation
um(iii) chemistry,[25,35,36] we deemed that the titanocene(iii)- of 12 via the conjugated aldehyde 16. Subsequent oxidation
promoted reductive opening of epoxides 11a and 11b in of diester 16 and saponification provided the desired lac-
aqueous media might be a convenient procedure for the tone 4 in a 69% yield. The first chemical synthesis of 4 was
synthesis of 3β-hydroxydihydroconfertifolin (3), a drimane thus completed in ten steps and in 3% overall yield. The
lactone isolated from a fungus associated with aspen.[7]
spectroscopic properties of synthetic 4 (except for the op-
We thus started the synthesis of 3 by treating epoxides tical rotation) matched those of the natural product,[6,7]
11a and 11b with Cp2TiCl2/Mn in the presence of water (a thus confirming the structure of 3β-hydroxycinnamolide.
Eur. J. Org. Chem. 2005, 712–718
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713

J. M. Cuerva et al.
FULL PAPER
3β-Acetoxydrimenin (5), found in the leaves of the tree sultsare set out in Table 1. The drimane lactone 3β-hydroxy-
Drimys winteri,[3] showed a β,γЈ-unsaturated nonconjugated dihydroconfertifolin (3) was the strongest antifeedant
γ-lactone group integrated in the drimane skeleton, which against L. decemlineata, followed by 5, but effective anti-
was an interesting synthetic challenge. As epoxy esters have feedant doses (EC values) could only be calculated for 3
50
proven to be excellent precursors for the synthesis of lac- (8.2 µg cm–2, 3.7–18.1 lower-upper 95% confidence limits).
tones,[39,40] we decided to assay this strategy for the chemi- The unsaturated lactone 4 had a moderate-to-strong effect
cal preparation of 5 (see last step in Scheme 4).
on M. persicae, in contrast with the virtually inactive com-
pound 3 (Table 1), possibly due to the presence of a Michael
acceptor group in 4. Finally, we observed no significant
antifeedant or behavioral effect of compounds 2–5 either
on S. littoralis or on R. padi.
Table 1. Antifeedant (%FI) effects of 3-hydroxydrimanes 2–5 on
S. littoralis larvae and adult L. decemlineata; percent settling of ap-
terous M. persicae and R. padi adults on control (%C) and treated
(%T) leaf disks
L. de-
cemline- M. persicae
ata
S. litto-
ralis
R. padi
(%FI)[a]
%C
52
59
72
47
%T
%C
37
%T
63
51
48
53
2
3
4
5
20.0
12.1
48
48.7
16.0
38.8
83.5
49.1
66.5
41[b] 49
28[c] 52
53
47
[a] FI = [1 – (T/C)]×100, where T and C are the consumption on
control and treated leaf disks. [b] Ͻ0.05, [c] Ͻ0.00005. [d] Ͻ0.005,
Mann Whitney W-Test (hypothesis: median %C Ͼ median %T).
These compounds showed molecular and species-de-
pendent selectivity, as previously shown for other dri-
manes.[13,14] Similar species selectivity has been reported for
a neo-clerodane diterpene dialdehyde.[43]
Scheme 4. Synthesis of drimane 5
Table 2 shows the performance parameters of orally in-
jected S. littoralis larvae. A covariance analysis (AN-
COVA1) of food consumption (∆I) and biomass gains (∆B)
with initial larval weight as covariate (covariate p Ͼ 0.05)
was performed to test for any significant effects of the ses-
quiterpenes on these variables.[43] Compounds 2 and 4 sig-
nificantly decreased ∆I and ∆B (ANCOVA1 p Ͻ 0.05 for
∆B and ∆I). Treatment effects on ∆B disappeared with an
additional covariance adjustment with ∆I as covariate, so
we were able to conclude that these compounds had post-
ingestive antifeedant effects with no further toxicity. Post-
ingestive effects have been suggested previously for syn-
thetic analogues (lactones) of polygodial and warbuganal
We began the synthesis of 5 with the acetylation of the
cornerstone intermediate 8 and subsequent selective saponi-
fication of the diacetate 17 to provide the primary alcohol
18. Jones’ oxidation of 18, followed by treatment with diazo-
methane, provided ester 19, which reacted with MCPBA to
give oxiranes 20a and 20b (62% combined yield from 18).
Treatment of these epoxides with titanocene(iii), however,
only gave a discouraging 15% yield of the desired product
5.[41] Fortunately, under acidic conditions the epimeric mix-
ture of 20a and 20b evolved towards the endocyclic alkene
5, providing a substantial yield of 80%. This result con-
firmed that the acid-induced cyclization of epoxy esters,
previously reported by us for the formation of δ-lactones,[39]
can also be used for the synthesis of γ-lactones. The IR,
EIMS, and 1H NMR spectra of synthetic 5 were in accord-
ance with those reported for the metabolite isolated from D
. winteri,[ 3] so the total synthesis of 5 was achieved in nine
steps and in an overall yield of almost 6%.[42]
Table 2. Consumption (∆I) and biomass gain (∆B) of orally in-
jected Spodoptera littoralis larvae and cytotoxic effects on Sf9 and
CHO cells (* treatment p-level Ͻ 0.05, ANCOVA analysis with
initial body weight as covariate)
S. littoralis
(% of control)
ED
50
(µg ml–1)[a]
Sf9
∆I[b]
∆B[c]
CHO
Ͼ100
Ͼ100
Ͼ100
2
3
4
5
51.3*
71.9*
106.7
78.4*
106.5
Ͼ100
Ͼ100
Ͼ100
Evaluation of the Antifeedant Activity
92.9
65.3*
98.7
34.35 (23.43, 50.36)[d] Ͼ100
The antifeedant effects of the 3-hydroxydrimanes 2–5
against several insect species with different feeding ecologies
(Spodoptera littoralis, Leptinotarsa decemlineata, Myzus
[a] D50 = Concentration needed to produce 50% cell viability. [b] I
= mg food consumed (mg of dry weight). [c] B = change in insect
persicae, and Ropalosiphon padi) were tested, and the re- body weight (mg of dry weight). [d] 95 % Confidence limits.
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Eur. J. Org. Chem. 2005, 712–718

Total Synthesis of 3-Hydroxydrimanes Mediated by Titanocene(iii)
FULL PAPER
MS (70 eV, EI): m/z (%): 384 [M]+ (1), 324 (15), 187 (40), 134 (100),
119 (37). HRMS (FAB): calcd. for C24H32O4Na 407.2198, found
407.2198.
on Pieris brassicae and L. decemlineata larvae,[44] but no di-
rect experimental evidence was provided.
Among the structurallyrelated drimanes tested, the least
polar one, acetate 5, showed moderate selective cytotoxicity
against insect-derived Sf9 cells versus the mammalian CHO
Epoxides 11a and 11b: A sample of MCPBA (380 mg, 0.91 mmol)
was added to a solution of 10 (317 mg, 0.82 mmol) in CH2Cl2
cell line, probably due to a combination of polarity and (50 mL) and the mixture was stirred at room temp. for 7.5 h. tBu-
OMe was then added, and the mixture was washed with NaOH
(2 n) and brine. The organic layer was dried over anhyd. Na2SO4
and the solvent was removed. The residue was chromatographed
(hexane/tBuOMe, 3:1) to afford 11b (54 mg, 16%) and 11a (230 mg,
70%). Data for 11b: white solid; m.p. 135–140 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.97 (d, J = 7.5 Hz, 2 H), 7.48 (t, J =
7.5 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 2 H), 4.71 (dd, J = 11.5, 4.6 Hz,
1 H), 4.20 (br. d, J = 11.6 Hz, 1 H), 3.44 (dd, J = 11.6, 8.3 Hz,
1 H), 2.66 (d, J = 4.1 Hz, 1 H), 2.33 (d, J = 3 Hz, 1 H), 1.96 (s,
3 H), 1.94–1.60 (m, 7 H), 1.50–1.25 (m, 2 H), 1.15–1.05 (m, 1 H),
1.00 (s, 3 H), 0.92 (s, 3 H), 0.91 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ = 170.79 (C), 166.25 (C), 132.87 (CH), 130.86 (C),
129.59 (CH), 128.41 (CH), 80.96 (CH), 59.16 (CH2), 56.38 (C),
54.06 (CH), 51.34 (CH), 49.59 (CH2), 38.87 (C), 38.46 (C), 36.82
(CH2), 35.41 (CH2), 28.56 (CH3), 23.64 (CH2), 21.18 (CH3), 19.65
(CH2), 16.90 (CH3), 15.48 (CH3). MS (70 eV, EI): m/z (%): 400 [M]+
(1), 218 (1), 203 (9), 105 (100). HRMS (FAB): calcd. for
C24H32O5Na 423.2147, found 423.2147. Data for 11a: white solid;
m.p. 145–146 °C. 1H NMR (300 MHz, CDCl3): δ = 7.95 (d, J =
7.5 Hz, 2 H), 7.46 (t, J = 7.5 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 2 H),
4.68 (dd, J = 11.5, 4.5 Hz, 1 H), 3.85 (dd, J = 11.6, 6.0 Hz, 1 H),
3.69 (dd, J = 11.6, 3.0 Hz, 1 H), 2.50 (m, 2 H), 1.92 (s, 3 H), 1.90–
1.10 (m, 10 H), 0.96 (s, 3 H), 0.88 (s, 3 H), 0.87 (s, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 170.82 (C), 166.09 (C), 132.82 (CH), 130.68
(C), 129.47 (CH), 128.32 (CH), 80.82 (CH), 58.76 (CH2), 57.22 (C),
53.91 (CH), 52.18 (CH), 51.30 (CH2), 39.02 (C), 38.19 (C), 36.67
(CH2), 35.51 (CH2), 28.33 (CH3), 23.51 (CH2), 21.06 (CH3), 19.41
(CH2), 16.75 (CH3), 15.23 (CH3). MS (70 eV, EI): m/z (%): 400 [M]+
(1), 310 (3), 218 (4), 105 (100). HRMS (FAB): calcd. for
C24H32O5Na 423.2147, found 423.2157.
specific membrane factors. None of the other compounds
affected the cell lines tested (Table 2).
Conclusions
In summary, we confirm the synthetic viability of the ti-
tanocene(iii)-catalyzed cyclization of epoxypolyprenes for
the chemical preparation of natural 3-hydroxydrimanes (2–
5) with different functionalization patterns. We also tested
the antifeedant properties of these drimanes against the in-
sects S. littoralis, L. decemlineata, M. persicae, and R. padi
and observed different activity levels. The antifeedant struc-
ture–activity variation of these compounds (lactones Ͼ al-
cohols) fits with the proposed mode of action for antifeed-
ant drimanes by adduct formation with amino groups on
the insect chemoreceptor.[45] We are currently trying to ex-
tend our synthetic strategy to the chemical preparation of
more complex terpenoids. Additionally, as the asymmetric
synthesis of (10S)-10,11-epoxyfarnesol has recently been
described by Corey’s group,[46] an enantioselective version
of our method might presumably be developed without too
much difficulty.
Experimental Section
General Remarks: In reactions employing titanocene, all solvents
and additives were thoroughly deoxygenated prior to use. The num-
bering used in the NMR assignments corresponds to the drimane
system and not the IUPAC nomenclature. The cornerstone inter-
mediate 8 was prepared by our previously reported procedure.[25]
The following known compounds were isolated as pure samples
and showed NMR spectra identical to those reported: 2,[4] 3,[7]
4,[6,7] and 5.[3,42] Other general experimental details have been re-
ported elsewhere.[29,36]
Allylic Alcohol 12: A mixture of Cp2TiCl2 (95 mg, 0.37 mmol) and
Mn dust (55 mg, 1.00 mmol) in completely deoxygenated THF
(25 mL) was stirred at room temp. until the red solution turned
green. The solvent was then removed and anhydrous benzene
(25 mL) was added. The green suspension of titanocene(iii) was
slowly added to an epimeric mixture of 11a and 11b (4:1 ratio,
48 mg, 0.12 mmol) in benzene (10 mL) and the reaction mixture
was stirred at room temp. for 5 h. The reaction mixture was then
quenched with 5% aqueous NaH2PO4 and extracted with tBuOMe.
The organic layer was washed with brine and dried (anhyd
Na2SO4), and the solvent was removed. The residue was chromato-
graphed (hexane/tBuOMe,1:1) to give 12 (18 mg, 38 %) as a vitre-
ous solid: 1H NMR (300 MHz, CDCl3): δ = 8.05 (d, J = 7.5 Hz,
2 H), 7.57 (t, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 5.85 (m,
1 H), 4.75 (dd, J = 11.4, 4.3, 1 H), 4.34 (dd, J = 11.7, 3.6 Hz, 1 H),
4.27–4.18 (m, 2 H), 3.98 (d, J = 12.8 Hz, 1 H), 2.20–2.15 (m, 1 H),
2.00–1.00 (m, 7 H), 2.05 (s, 3 H), 1.07 (s, 3 H), 0.93 (s, 3 H), 0.87
(s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 170.91 (C), 166.25 (C),
136.09 (C), 132.88 (CH), 130.75 (C), 129.55 (CH), 128.39 (CH),
126.05 (CH), 81.14 (CH), 65.86 (CH2), 62.91 (CH2), 50.42 (CH),
49.27 (CH), 37.97 (C), 37.20 (CH2), 35.56 (C), 28.10 (CH3), 23.86
(CH2), 22.97 (CH2), 21.21 (CH3), 16.79 (CH3), 14.57 (CH3). MS
(70 eV, EI): m/z (%): 340 (7), 173 (10), 105 (100). HRMS (FAB):
calcd. for C24H32O5Na 423.2147, found 423.2144.
Diester 10: A mixture of 8 (190 mg, 0.68 mmol), benzoyl chloride
(0.174 mL, 1.02 mmol), and DMAP (124 mg, 1.02 mmol) in pyri-
dine (7 mL) was stirred at room temp. for 2 h. tBuOMe (15 mL)
was then added and the mixture was washed with HCl (2 n), NaOH
(2 n), and brine. The organic layer was dried (anhyd. Na2SO4), and
the solvent was removed. The residue was subjected to flash chro-
matography (hexane/tBuOMe, 85:15), giving 10 (260 mg, quant):
white solid; m.p. 105–110 °C. 1H NMR (300 MHz, CDCl3): δ =
8.02 (d, J = 7.8 Hz, 2 H), 7.53 (t, J = 7.8 Hz, 1 H), 7.43 (t, J =
7.8 Hz, 2 H), 4.91 (br.s, 1 H), 4.81 (dd, J = 11.6, 4.3 Hz, 1 H), 4.57
(br.s, 1 H), 4.32 (dd, J = 11.3, 4.3 Hz, 1 H), 4.26 (dd, J = 11.3,
8.4 Hz, 1 H), 2.47 (ddd, J = 13.1, 3.8, 2.2 Hz, 1 H), 2.10–2.00 (m,
2 H), 2.06 (s, 3 H), 1.91 (dt, J = 12.5, 3.9 Hz, 1 H), 1.87–1.70 (m,
5 H), 1.56 (td, J = 12.9, 3.6 Hz, 1 H), 1.02 (s, 3 H), 0.95 (s, 3 H),
0.82 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 171.43 (C), 166.30
(C), 146.11 (C), 132.89 (CH), 130.86 (C), 129.60 (CH), 128.54
(CH), 107.81 (CH2), 81.06 (CH), 61.55 (CH2), 54.50 (CH), 54.38
(CH), 38.66 (C), 38.49 (C), 37.36 (CH2), 36.71 (CH2), 28.49 (CH3),
Drimane 2: Compound 12 (10 mg, 0.025 mmol) in ethanolic KOH
24.24 (CH2), 23.40 (CH2), 21.18 (CH3), 16.95 (CH3), 15.20 (CH3). (0.5 m, 4 mL) was stirred at room temp. for 7 h. tBuOMe was then
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J. M. Cuerva et al.
FULL PAPER
added, and the mixture was washed with HCl (2 n) and brine The
organic layer was dried over anhyd. Na2SO4, and the solvent was
removed. Flash chromatography of the residue (tBuOMe) gave 2
(6 mg, 95 %).
166.33 (C), 132.91 (CH), 130.80 (C), 129.62 (CH), 128.44 (CH),
81.01 (CH), 63.64 (CH2), 55.35 (CH), 51.89 (CH), 39.18 (CH),
38.32 (C), 37.88 (C), 36.89 (CH2), 28.49 (CH2), 28.34 (CH3), 23.65
(CH2), 21.20 (CH3), 18.72 (CH2), 16.81 (CH3), 14.77 (CH3). MS
(70 eV, EI): m/z (%): 281 (7), 234 (30), 207, 191 (27), 105 (100).
HRMS (FAB): calcd. for C24H32O6Na 439.2096, found 439. 2101.
Alcohol 13: A mixture of Cp2TiCl2 (360 mg, 1.41 mmol) and Mn
dust (206 mg, 3.76 mmol) in THF (35 mL) was stirred at room
temp. until the red solution turned green, and then a completely
deoxygenated mixture of H2O (0.25 mL) and THF (25 mL) was
added. The deep blue suspension obtained was slowly added to 11
(188 mg, 0.47 mmol) in THF (10 mL), and the system was stirred
at room temp. for 5.5 h. The reaction mixture was then quenched
with aqueous NaH2PO4 (5%) and extracted with tBuOMe. The or-
ganic layer was washed with brine and dried (anhyd Na2SO4), and
the solvent was removed. Flash chromatography of the residue
(hexane/tBuOMe, 3:7) gave 13 (120 mg, 65%): white solid; m.p.
100–105 °C. 1H NMR (300 MHz, CDCl3): δ = 7.97 (d, J = 7.5 Hz,
2 H), 7.48 (t, J = 7.5 Hz, 1 H), 7.37 (t, J = 7.5 Hz, 2 H), 4.65 (dd,
J = 11.5, 4.8 Hz, 1 H), 4.16 (dd, J = 11.3, 5.4 Hz, 1 H), 4.06 (dd,
J = 11.3, 8.5 Hz, 1 H), 3.61 (dd, J = 10.4, 2.9 Hz, 1 H), 3.53 (t, J
= 10.4, 1 H), 1.98 (s, 3 H), 1.75–1.00 (m, 11 H), 0.97 (s, 3 H), 0.87
(s, 3 H), 0.83 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 170.51 (C),
166.25 (C), 132.83 (CH), 130.79 (C), 129.53 (CH), 128.36 (CH),
81.00 (CH), 62.94 (CH2), 61.67 (CH2), 55.41 (CH), 51.68 (CH),
39.26 (CH), 38.23 (C), 37.23 (CH2), 36.88 (C), 28.67 (CH2), 28.22
(CH3), 23.58 (CH2), 21.11 (CH3), 17.33 (CH2), 16.76 (CH3), 16.40
(CH3). MS (70 eV, EI): m/z (%): 220 (10), 165 (10), 105 (100).
HRMS (FAB): calcd. for C24H34O5Na 425.2303, found 425.2306.
3β-Hydroxydihydroconfertifolin (3):
A sample of 15 (30 mg,
0.07 mmol) in ethanolic KOH (0.5 m, 20 mL) was stirred at room
temp. for 4 h. tBuOMe was then added and the mixture was washed
with HCl (2 n) and brine. The organic layer was dried (anhyd
Na2SO4), and the solvent was removed. Flash chromatography
(tBuOMe) of the residue gave 3 (18 mg, 99%).
Conjugated Aldehyde 16: A mixture of 12 (80 mg, 0.2 mmol) and
MnO2 (500 mg, 5.7 mmol) in CH2Cl2 (15 mL) was stirred at room
temp. for 2 h. The mixture was diluted with CH2Cl2 and filtered
through a pad of Celite®, and the solvent was removed from the
filtrate. The residue was chromatographed (hexane/tBuOMe, 4:1)
to give 16 (50 mg, 63%): vitreous solid. 1H NMR (300 MHz,
CDCl3): δ = 9.44 (s, 1 H), 8.03 (d, J = 7.2 Hz, 2 H), 7.56 (t, J =
7.2 Hz, 1 H), 7.44 (t, J = 7.2 Hz, 2 H), 6.93 (m, 1 H), 4.76 (dd, J
= 11.5, 4.4 Hz, 1 H), 4.62 (dd, J = 11.7, 5.7 Hz, 1 H), 4.45 (br. d,
J = 11.7 Hz, 1 H), 2.50–2.40 (m, 2 H), 2.10–1.00 (m, 6 H), 1.95 (s,
3 H), 1.15 (s, 3 H), 0.98 (s, 3 H), 0.90 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ = 193.81 (CH), 170.80 (C), 166.22 (C), 152.26 (CH),
140.07 (C), 133.01 (CH), 130.69 (C), 129.62 (CH), 128.58 (CH),
80.85 (CH), 59.99 (CH2), 48.84 (CH), 48.46 (CH), 37.94 (C), 37.41
(CH2), 35.83 (C), 28.25 (CH3), 24.46 (CH2), 23.72 (CH2), 21.10
(CH3), 16.98 (CH3), 14.76 (CH3). MS (70 eV, EI): m/z (%): 338 (4),
216 (8), 159 (10), 105 (100). HRMS (FAB): calcd. for C24H30O5Na
421.1991, found 421.1994.
Aldehyde 14: Dess–Martin periodinane (172 mg, 0.32 mmol) and
NaHCO3 (30 mg, 0.32 mmol) were added to a solution of 13
(64 mg, 0.16 mmol) in CH2Cl2 (15 mL), and the mixture was stirred
at room temp. for 38 h. tBuOMe was then added, and the solution
was washed with a mixture of aqueous Na2S2O3 (10%) and satu-
rated NaHCO3 (1:1) and with brine. The organic layer was dried
(anhyd Na2SO4) and the solvent was removed. The residue was
chromatographed (hexane/tBuOMe, 55:45) to give 14 (54 mg, 85%):
white solid; m.p. 154–155 °C. 1H NMR (300 MHz, CDCl3): δ =
9.96 (s, 1 H), 8.05 (d, J = 7.5 Hz, 2 H), 7.57 (t, J = 7.5 Hz, 1 H),
7.45 (t, J = 7.5 Hz, 2 H), 4.75 (dd, J = 11.6, 4.4 Hz, 1 H), 4.50–
4.40 (m, 2 H), 2.68 (br. t, J = 5 Hz, 1 H), 2.48 (br. d, J = 12.7 Hz,
1 H), 2.10 (s, 3 H), 2.05–1.00 (m, 9 H), 0.96 (s, 3 H), 0.88 (s, 3 H),
0.82 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 203.76 (C), 171.06
(C), 166.23 (C), 132.92 (CH), 130.72 (C), 129.56 (CH), 128.41
(CH), 80.74 (CH), 61.89 (CH2), 54.78 (CH), 51.80 (CH), 47.08
(CH), 38.21 (C), 37.41 (C), 36.66 (CH2), 28.31 (CH3), 25.63 (CH2),
23.63 (CH2), 21.08 (CH3), 18.52 (CH2), 16.76 (CH3), 15.74 (CH3).
MS (70 eV, EI): m/z (%): 340 (1), 250 (5), 190 (16), 105 (100), 77
(20). HRMS (FAB): calcd. for C24H32O5Na 423.2147, found 423.
2151.
3β-Hydroxycinnamolide (4):
A solution of NaClO2 (189 mg,
1.2 mmol) and NaH2PO4·H2O (141 mg, 0.9 mmol) in water (5 mL)
was slowly added to a mixture of 16 (60 mg, 0.15 mmol) and 2-
methyl-2-butene (2 mL) in tBuOH(10 mL). The reaction mixture
was stirred at room temp. for 5 h, and the solvent was then re-
moved. The obtained mixture was extracted with tBuOMe, the
ethereal solution was washed with brine and dried (anhyd Na2SO4),
and the solvent was removed. The residue was dissolved in meth-
anolic KOH (2 m, 5 mL) and stirred at room temp. for 2 h. tBuOMe
was then added and the mixture was washed with HCl (2 n) and
brine. The organic layer was dried (anhyd Na2SO4), and the solvent
was removed. Flash chromatography (hexane/tBuOMe, 3:2) of the
residue gave 4 (26 mg, 69%).
Diacetate 17: A mixture of 8 (120 mg, 0.43 mmol), Ac2O (0.05 mL,
0.64 mmol), and DMAP (80 mg, 0.64 mmol) in CH2Cl2 (10 mL)
was stirred at room temp. for 1 h. The mixture was then diluted
with tBuOMe and washed with HCl (2 n), saturated NaHCO3, and
brine. The organic layer was dried over anhyd Na2SO4, and the
Carboxylic Acid 15: A mixture of NaClO2 (220 mg, 1.4 mmol) and
NaH2PO4·H2O (163 mg, 1.05 mmol) was added to a solution of 14 solvent was removed. Flash chromatography (hexane/tBuOMe,
(70 mg, 0.17 mmol) in a mixture of tBuOH/H2O/2-methyl-2-butene
(4.5:1.6:1 ratio, 17 mL). The solution was stirred at room temp. for
7 h and was then extracted with tBuOMe. The organic layer was
washed with brine and dried (anhyd Na2SO4), and the solvent was
removed. The residue was chromatographed (hexane/tBuOMe, 3:2)
85:15) of the residue gave 17 (113 mg, 82%): white solid; m.p. 80–
82 °C. 1H NMR (300 MHz, CDCl3): δ = 4.83 (br.s, 1 H), 4.48 (br.s,
1 H), 4.49 (dd, J = 10.2, 4.05 Hz, 1 H), 4.24 (dd, J = 11.3, 4.5 Hz,
1 H), 4.16 (dd, J = 11.3, 8.2 Hz, 1 H), 2.38 (ddd, J = 13.1, 3.9,
2.4 Hz, 1 H), 2.00–1.00 (m, 9 H), 2.01 (s, 3 H), 1.98 m(s, 3 H), 0.84
to give 15 (55 mg, 75%): white solid; m.p. 162–163 °C. 1H NMR (s, 3 H), 0.82 (s, 3 H), 0.74 (s, 3 H). 13C NMR (75 MHz, CDCl3):
(300 MHz, CDCl3): δ = 8.05 (d, J = 7.5 Hz, 2 H), 7.57 (t, J =
7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 2 H), 4.74 (dd, J = 11.2, 4.5 Hz,
1 H), 4.47 (dd, J = 11.4, 8.0 Hz, 1 H), 4.34 (dd, J = 11.4, 5.7 Hz,
1 H), 2.89 (t, J = 4.2 Hz, 1 H), 2.36 (br. d, J = 12.1 Hz, 1 H), 2.07
(s, 3 H), 1.85–1.25 (m, 9 H), 1.03 (s, 3 H), 0.96 (s, 3 H), 0.95 (s,
3 H). 13C NMR (75 MHz, CDCl3): δ = 180.56 (C), 171.28 (C),
δ = 171.25 (C), 170.92 (C), 146.09 (C), 107.73 (CH2), 80.42 (CH),
61.48 (CH2), 54.42 (CH), 54.38 (CH), 38.59 (C), 38.06 (C), 37.33
(CH2), 36.68 (CH2), 28.30 (CH3), 24.15 (CH2), 23.36 (CH2), 21.30
(CH3), 21.12 (CH3), 16.63 (CH3), 15.15 (CH3). MS (70 eV, EI):
m/z (%): 262 (10), 202 (40), 187 (40), 135 (100). HRMS (FAB):
calcd. for C19H30O4Na 345.2041, found 345.2046.
716
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 712–718

Total Synthesis of 3-Hydroxydrimanes Mediated by Titanocene(iii)
FULL PAPER
Alcohol 18: A sample of diacetate 17 (110 mg, 0.34 mmol) was dis-
solved in methanolic K2CO3 (0.5 m, 20 mL) at 0 °C and stirred for
2 h. The mixture was then diluted with tBuOMe and washed with
HCl (2 n) and brine. The organic layer was dried (anhyd Na2SO4),
and the solvent was removed. Flash chromatography (hexane/tBu-
3β-Acetoxydrimenin (5):
A
mixture of epoxides 20 (35 mg,
0.11 mmol) and TsOH·H2O (20 mg, 0.16 mmol) in CHCl3 (10 mL)
was heated under reflux for 2 h. The mixture was then diluted with
CH2Cl2 and washed with brine. The organic layer was dried (anhyd
Na2SO4), and the solvent was removed. Flash chromatography
OMe, 1:1) of the residue provided alcohol 18 (48 mg, 50%) and (hexane/tBuOMe, 7:3) of the residue gave 5 (25 mg, 80%).
starting diacetate 17 (42 mg, 38%). The recovered starting material
Bioassays: Insect rearing, choice feeding assays, and oral can-
was treated under the same conditions, thus increasing the overall
nulations were conducted as described by Reina et al.[47] Cytotoxic-
ity on Sf9 and CHO cell lines were conducted by described pro-
NMR (300 MHz, CDCl3): δ = 4.93 (br.s, 1 H), 4.65 (br.s, 1 H), 4.51
cedures.[48]
1
yield of 18 to 66%. Data for 18: white solid; m.p. 105–107 °C. H
(dd, J = 11.5, 4.3 Hz, 1 H), 3.82–3.71 (m, 2 H), 2.42 (ddd, J = 12.9,
4.0, 2.5 Hz, 1 H), 2.00–1.00 (m, 9 H), 2.02 (s, 3 H), 0.85 (s, 3 H),
0.82 (s, 3 H), 0.73 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 170.95
(C), 147.06 (C), 106.98 (CH2), 80.51 (CH), 58.80 (CH), 58.76
Acknowledgments
(CH2), 54.51 (CH), 38.57 (C), 38.08 (C), 37.60 (CH2), 36.69 (CH2),
This research was supported by the Spanish “Dirección General de
28.31 (CH3), 24.23 (CH2), 23.64 (CH2), 21.30 (CH3), 16.65 (CH3),
Investigación Científica
y
Técnica” (projects PB98–1365,
15.37 (CH3). MS (70 eV, EI): m/z (%): 280 [M]+ (1), 262 (6), 220
(20), 135 (100). HRMS (FAB): calcd. for C17H28O3Na 303.1936,
found 303.1940.
BQU2001–1505, and CYTED IV.13J) and the “Junta de Andalu-
cia” (research group FQM339). J. Justicia thanks the Spanish Min-
istry of Science and Technology for a grant enabling him to pursue
these studies. We thank Juan L. Oller-López for carrying out the
EIMS and A. de Diago and C. González for technical assistance.
We also thank our colleague Dr. J. Trout for revising the English
text.
Methyl Ester 19: A sample of Jones’ reagent (0.2 mL) was added
to a solution of 18 (60 mg, 0.22 mmol) in acetone (10 mL), and the
system was stirred at room temp. for 3 h. The solvent was then
removed, and the residue was dissolved in tBuOMe, washed with
brine, dried over anhyd Na2SO4, and concentrated. The residue was
stirred with a saturated solution of CH2N2 in Et2O (5 mL) for
30 min. The solvent was removed and the residue was subjected to
flash chromatography (hexane/tBuOMe, 85:15) to give 19 (52 mg,
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1
79%): white solid; m.p. 125–127 °C. H NMR (300 MHz, CDCl3):
δ = 4.83 (s, 1 H), 4.65 (s, 1 H), 4.50 (dd, J = 10.5, 5.4 Hz, 1 H),
3.62 (s, 3 H), 2.74 (s, 1 H), 2.41 (ddd, J = 13.5, 4.5, 2.2 Hz, 1 H),
2.10–1.95 (m, 1 H), 2.02 (s, 3 H), 1.80–1.00 (m, 7 H), 1.07 (s, 3 H),
0.86 (s, 6 H). 13C NMR (75 MHz, CDCl3): δ = 171.81 (C), 165.59
(C), 143.12 (C), 108.96 (CH2), 80.51 (CH), 62.53 (CH), 53.88 (CH),
51.04 (CH3), 38.81 (C), 38.03 (C), 36.54 (CH2), 35.84 (CH2), 28.23
(CH3), 23.97 (CH2), 22.77 (CH2), 21.29 (CH3), 16.62 (CH3), 14.27
(CH3). MS (70 eV, EI): m/z (%): 173 (8), 135 (100). HRMS (FAB):
calcd. for C18H28O4Na 331.1885, found 331.1889.
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84, 189–193.
CDCl3): δ = 4.51 (dd, J = 10.5, 4.9 Hz, 1 H), 3.57 (s, 3 H), 3.33
(dd, J = 4.9, 1.5 Hz, 1 H), 2.62 (s, 1 H), 2.57 (d, J = 4.9 Hz, 1 H),
2.03 (s, 3 H), 2.00–1.00 (m, 9 H), 1.16 (s, 3 H), 0.89 (s, 6 H). 13C
NMR (75 MHz, CDCl3): δ = 170.84 (C), 170.73 (C), 80.25 (CH),
59.68 (CH), 56.81 (C), 53.57 (CH), 53.05 (CH2), 51.26 (CH3), 39.63
(C), 37.96 (C), 36.63 (CH2), 34.95 (CH2), 28.33 (CH3), 23.53 (CH2),
21.28 (CH3), 21.17 (CH2), 16.60 (CH3), 14.54 (CH3). HRMS
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1
20b: white solid; m.p. 111–115 °C. H NMR (300 MHz, CDCl3): δ
= 4.51 (dd, J = 9.0, 6.8 Hz, 1 H), 3.60 (s, 3 H), 2.59 (s, 1 H), 2.43
(d, J = 4.1 Hz, 1 H), 2.39 (d, J = 4.1 Hz, 1 H), 2.04 (s, 3 H), 2.00–
1.00 (m, 9 H), 1.38 (s, 3 H), 0.93 (s, 3 H), 0.89 (s, 3 H). 13C NMR
(75 MHz, CDCl3): δ = 170.94 (C), 169.80 (C), 80.44 (CH), 58.16
(CH), 56.22 (C), 53.74 (CH), 51.14 (CH3), 49.15 (CH2), 38.90 (C),
38.03 (C), 36.89 (CH2), 34.70 (CH2), 28.33 (CH3), 23.43 (CH2),
21.31 (CH3), 19.63 (CH2), 16.65 (CH3), 14.54 (CH3). HRMS
(FAB): calcd. for C18H28O5Na 347.1834, found 347.1832.
Eur. J. Org. Chem. 2005, 712–718
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
717

J. M. Cuerva et al.
FULL PAPER
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[31] For experimental details see Supporting Information (see foot-
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[39]
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Besides lactone 5, a mixture of aldehydes, unsaturated alde-
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[42] A previously reported synthesis, using carvone as starting ma-
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Received September 6, 2004
718
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 712–718