Forming spirocyclohexadienone-oxocarbenium cation species in the biomimetic synthesis of amomols

Article abstract of DOI:10.1021/jo102414s

The oxidation of appropriate 2-(4-hydroxyphenyl)ethyl ketones gives direct access to amomols by means of the formation of a transient spirocyclohexadienone-oxocarbenium ion that is intermolecularly intercepted by an alcohol. Furthermore, homochiral amomols and other new analogues were synthesized for the first time and were biologically evaluated on Plasmodium falciparum.(Figure Presented)

Full text of DOI:10.1021/jo102414s

pubs.acs.org/joc
Forming Spirocyclohexadienone-Oxocarbenium Cation Species
in the Biomimetic Synthesis of Amomols
‡
Mariam Traore, Marjorie Maynadier, Florence Souard, Luc Choisnard, Henri Vial,
†
†
‡
ꢀ †
and Yung-Sing Wong*,†
†
ꢀ
ꢀ
ꢀ
Departement de Pharmacochimie Moleculaire, Universite Joseph Fourier-Grenoble 1, CNRS UMR 5063,
CNRS ICMG FR 2607, ba^timent AndreꢀRassat, 470 rue de la Chimie, F-38041 Grenoble Cedex 9, France, and
‡
ꢀ
Dynamique des Interactions Membranaires Normales et Pathologiques, Universite de Montpellier 2,
CNRS UMR 5235, CP 107, Place E. Bataillon, F-34095 Montpellier Cedex 5, France
yung-sing.wong@ujf-grenoble.fr
Received December 7, 2010
The oxidation of appropriate 2-(4-hydroxyphenyl)ethyl ketones gives direct access to amomols by
means of the formation of a transient spirocyclohexadienone-oxocarbenium ion that is intermole-
cularly intercepted by an alcohol. Furthermore, homochiral amomols and other new analogues were
synthesized for the first time and were biologically evaluated on Plasmodium falciparum.
Introduction
have thus emerged.3 Recently, Kinghorn and co-workers have
isolated two new members of this family, amomols A and B,
from Amomum aculeatum leaves. The new substances show
cytotoxicity against three cancer cell lines (Lu1, LNCaP, and
MCF-7) with ED50 ranging from 0.5 to 0.9 μM.4 The absolute
configuration of the hydroxyl group at C-12 was assigned only
on the basis of an 1H NMR analysis of Mosher ester deriva-
tives (ΔδR-S).5 We became interested in testing the new natural
products against malaria. This prompted us to explore
a biomimetic synthesis of amomols and their deriva-
tives that might also provide new insight into the cascade
mechanism.
Biomimetic cascade reactions have been a source of in-
spiration for chemists due to their ability to generate com-
plex scaffolds in a concise and efficient manner.1 For the past
few years, we have been involved in the synthesis of aculea-
tins, a family of antimalarial natural products extracted from
Amomum aculeatum rhizomes, of which the most bioactive
member is the aculeatin A (Scheme 1).2 Our interest in
optimizing the biological potency of aculeatins has induced
us to develop short synthetic routes that encompass either
stereodivergent, cascade, or tandem reaction strategies.
Practical routes to the natural products and their congeners
Our previous work3e demonstrated the direct production
of aculeatins A and B in only one step through the oxidative
conversion of phenol 1a into a highly electrophilic phenox-
nium cation 2a6 (Scheme 1). It is noteworthy that all syntheses
of aculeatins reported to date use this oxidative strategy,7
which was inspired by a biosynthetic hypothesis.3a,7a Since
(1) (a) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun.
2003, 551–564. (b) de la Torre, M. C.; Sierra, M. A. Angew. Chem., Int. Ed.
2003, 43, 160–181. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem., Int. Ed. 2006, 45, 7134–7186. (d) Bulger, P. G.; Bagal, S. K.; Marquez,
R. Nat. Prod. Rep. 2008, 25, 254–297.
(2) (a) Heilmann, J.; Mayr, S.; Brun, R.; Rali, T.; Sticher, O. Helv. Chim.
Acta 2000, 83, 2939–2945. (b) Heilmann, J.; Brun, R.; Mayr, S.; Rali, T.;
Sticher, O. Phytochemistry 2001, 57, 1281–1285.
(3) (a) Wong, Y.-S. Chem. Commun. 2002, 686–687. (b) Peuchmaur, M.;
Wong, Y.-S. J. Org. Chem. 2007, 72, 5374–5379. (c) Peuchmaur, M.; Wong,
(4) Chin, Y.-W.; Salim, A. A.; Su, B.-N.; Mi, Q.; Chai, H.-B.; Riswan, S.;
Kardono, L. B. S.; Ruskandi, A.; Farnsworth, N. R.; Swanson, S. M.;
Kinghorn, A. D. J. Nat. Prod. 2008, 71, 390–395.
(5) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
(b) Kelly, D. R. Tetrahedron: Asymmetry 1999, 10, 2927–2934. (c) Seco,
J. M.; Quinoa, E.; Riguera, R. Tetrahedron: Asymmetry 2001, 12, 2915–2925.
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dani, N.; Botte, C.;
Marechal, E.; Vial, H.; Wong, Y.-S. J. Med. Chem. 2008, 51, 4870–4873.
Y.-S. Synlett 2007, 2902–2906. (d) Peuchmaur, M.; Saı
¨
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(e) Traore, M.; Ahmed-Ali, S.; Peuchmaur, M.; Wong, Y.-S. Tetrahedron
2010, 66, 5863–5872.
DOI: 10.1021/jo102414s
r
Published on Web 01/21/2011
J. Org. Chem. 2011, 76, 1409–1417 1409
2011 American Chemical Society

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SCHEME 1. Plausible Biomimetic Pathways for the Synthesis of Aculeatins and Amomols
water was necessary to obtain good yields, two pathways, I
and II, can be considered.
the aculeatins A and B. It turns out that phenoxonium cations
display good propensity to be intercepted by other sp2 or sp
heteroatoms and carbon atoms.9 In the context of aculeatin
syntheses, we postulated that pathway II is involved in most
cases,3e given that the cascade sequence usually proceeds at a
fast rate. However, the actual intervention of a cationic species
such as 4 remains to be established.
The foregoing considerations suggest that if pathway II were
to operate, then the oxidation of phenol 1b (X = H) should
afford amomols A and B, through the intermolecular capture
of a transient spirocyclohexadienone-oxocarbenium cation 4b
by a nucleophile such as methanol. By contrast, a mechanism
according to pathway I would produce the p-quinol ether 3b.
On one hand (pathway I), the phenoxonium cation 2a can be
first trapped by intermolecular addition of water, giving rise
to the corresponding p-quinol 3a, which then allows further
ring formations to produce the aculeatins.8 On the other hand
(pathway II), a more straightforward cascade reaction can arise
through the more kinetically favored intramolecular trapping of
the phenoxonium cation 2a by the γ-ketone. As a result, a highly
electrophilic spirocyclohexadienone-oxocarbenium cation 4a is
formed, which then undergoes a final spiro-annulation to yield
(6) For reviews reporting phenoxonium cation as key transient reactant,
see: (a) Tohma, H.; Kita, Y. Topics in Current Chemistry; Wirth, T., Ed.;
Springer-Verlag: Berlin/Heidelberg, Germany, 2003; Vol. 224, p 209.
(b) Rodriguez, S.; Wipf, P. Synthesis 2004, 2767–2783. (c) Ciufolini, M. A.;
Canesi, S.; Ousmer, M.; Braun, N. A. Tetrahedron 2006, 62, 5318–5337.
(d) Quideau, S.; Pouysegu, L.; Deffieux, D. Synlett 2008, 467–495. (e) Sabot,
C.; Commare, B.; Duceppe, M.-A.; Nahi, S.; Guerard, K. C.; Canesi, S.
Synlett 2008, 3226–3230. (f) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetra-
hedron 2010, 66, 2235–2261. (g) Guerard, K. C.; Sabot, C.; Beaulieu, M.-A.;
Giroux, M.-A.; Canesi, S. Tetrahedron 2010, 66, 5893–5901.
Results and Discussion
We selected 4-(4-hydroxyphenyl)-2-butanone 5 as a sim-
pler model to test our hypothesis and to set up the best
(9) (a) Callinan, A.; Chen, Y.; Morrow, G. W.; Swenton, J. S. Tetrahedron
Lett. 1990, 31, 4551–4552. (b) Swenton, J. S.; Carpenter, K.; Chen, Y.; Kerns,
M. L.; Morrow, G. W. J. Org. Chem. 1993, 58, 3308–3316. (c) Swenton, J. S.;
Callinan, A.; Chen, Y.; Rohde, J. J.; Kerns, M. L.; Morrow, G. W. J. Org.
Chem. 1996, 61, 1267–1274. (d) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki,
M.; Yakura, T. J. Org. Chem. 1991, 56, 435–438. (e) Kita, Y.; Takada, T.;
Gyoten, M.; Tohma, H.; Zenk, M. H.; Eichhorn, J. J. Org. Chem. 1996, 61,
5857–5864. (f) Braun, N. A.; Ciufolini, M. A.; Peters, K.; Peters, E.-M.
Tetrahedron Lett. 1998, 39, 4667–4670. (g) Braun, N. A.; Ousmer, M.; Bray,
J. D.; Bouchu, D.; Peters, K.; Peters, E.-M.; Ciufolini, M. A. J. Org. Chem.
2000, 65, 4397–4408. (h) Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.;
Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534–7538. (i) Canesi, S.;
Bouchu, D.; Ciufolini, M. A. Org. Lett. 2005, 7, 175–177. (j) Liang, H.;
Ciufolini, M. A. J. Org. Chem. 2008, 73, 4299–4301. (k) Mendelsohn, B. A.;
Ciufolini, M. A. Org. Lett. 2009, 11, 4736–4739. (l) Andrez, J.-C.; Giroux,
M.-A.; Lucien, J.; Canesi, S. Org. Lett. 2010, 12, 4368–4371. (m) Beaulieu,
(7) For other synthetic approaches to aculeatins, see: (a) Baldwin, J. E.;
ꢀ
Adlington, R. M.; Sham, V. W.-W.; Marquez, R.; Bulger, P. G. Tetrahedron
2005, 61, 2353–2363. (b) Falomir, E.; Alvarez-Bercedo, P.; Carda, M.;
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Marco, J. A. Tetrahedron Lett. 2005, 46, 8407–8410. (c) Alvarez-Bercedo,
P.; Falomir, E.; Carda, M.; Marco, J. A. Tetrahedron 2006, 62, 9641–9649.
(d) Chandrasekhar, S.; Rambabu, Ch.; Shyamsunder, T. Tetrahedron Lett.
2007, 48, 4683–4685. (e) Ramana, C. V.; Srinivas, B. J. Org. Chem. 2008, 73,
3915–3918. (f) Suresh, V.; Selvam, J. J. P.; Rajesh, K.; Venkateswarlu, Y.
Tetrahedron: Asymmetry 2008, 19, 1509–1513. (g) Zhen, Z.-B.; Gao, J.; Wu,
Y. J. Org. Chem. 2008, 73, 7310–7316. (h) Kamal, A.; Reddy, P. V.;
Prabhakar, S.; Balakrishna, M. Tetrahedron: Asymmetry 2009, 20, 2861–
2865. (i) Malathong, V.; Rychnovsky, S. D. Org. Lett. 2009, 11, 4220–4223.
(j) Harbindu, A.; Kumar, P. Synthesis 2010, 1479–1484. (k) Ramana, C. V.;
Pandey, S. K. Tetrahedron 2010, 66, 390–399. (l) Yadav, J. S.; Rao, K. V. R.;
Ravindar, K.; Subba Reddy, B. V. Synlett 2010, 51–54. (m) Yadav, J. S.;
Thrimurtulu, N.; Venkatesh, M.; Prasad, A. R. Synthesis 2010, 431–436.
(8) For a representative example, see ref 3c
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;
2010, 16, 11224–11228.
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conditions to obtain the amomol-like product 6 (Table 1). To
our delight, when 5 was treated with PhI(OAc)2 (PIDA) or
PhI(OCOCF3)2 (PIFA) in methanol at 0 °C (entries 1 and 2),
we observed the direct formation of the product 6, albeit with
the unwanted p-quinol ether 7 in about the same propor-
tions. We postulated that a high concentration of the nu-
cleophilic adduct (MeOH as solvent) may increase the
competitive outcome for pathway I. Thus, we examined
reactions with only 10 equiv of methanol using different
solvents (entries 3-6). CH2Cl2 and 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP)10 are among the best solvents (entries 3 and
6). Using PIDA as oxidant in CH2Cl2 (entry 3), we managed
to isolate 6 in a yield of 68% along with a small amount of the
p-quinol ether 7 (8%). Use of HFIP as a solvent gave a better
yield of 6 (75%) with no trace of 7 (entry 6). Unexpectedly,
when PIFA was used as oxidant (entries 7 and 8) in CH2Cl2
or HFIP, the reaction failed to yield any product, resulting
mainly in the formation of complex mixtures.
To extend the study with other phenolic precursors, we
synthesized (()-1b in three steps and the phenolic analogue
12 in one step11 from 5 and hexadecanal 1012 (Scheme 2). The
product 12 aims at proving that oxocarbenium cation species
can also be generated through the bonding of the phenox-
enium cation with the more electron rich carbonyl oxygen of
an enone (vide infra).
TABLE 1. Conditions for the Preparation of Amomol-like Product 6
entry
reagent
conditions
6 (%)a
7 (%)a
1
2
3
4
PIDA
PIFA
PIDA
PIDA
PIDA
PIDA
PIFA
PIFA
MeOH
MeOH
35
39
68
34
64
75
25
44
8
8
13
0
10 equiv of MeOH in CH2Cl2
10 equiv of MeOH in acetone
10 equiv of MeOH in CH3CN
10 equiv of MeOH in HFIP
10 equiv of MeOH in CH2Cl2
10 equiv of MeOH in HFIP
5
6
7b
8b
5
aIsolated yield. bComplex mixture.
SCHEME 2. Synthesis of Phenolic Precursors (()-1b and 12
SCHEME 3. One-Step Synthesis of Amomols and New Derivatives from Phenol (()-1b
aRatio determined by 1H NMR of the crude products.
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SCHEME 4. 1,2-Selective Addition of Alcohols to Vinyl Oxo-
carbenium Cation 16 in CH2Cl2
species can also behave as excellent dienophiles.14 Thus, we
examined the PIDA oxidation of 12 in CH2Cl2 containing 10
equiv of (2E,4E)-hexa-2,4-dien-1-ol 18. The amomol-like
structure (()-19 was obtained in a yield of 38%, indicating
that the 1,2-addition of the alcohol to cation 16 proceeds
faster than the [4 þ 2] cycloaddition.
We also undertook the enantioselective synthesis of amo-
mols A and B and their non-natural enantiomers to study the
influence of their configurations on the antimalarial activity
(Scheme 5). According to Nokami’s procedure,15 the reac-
tion of (þ)-20 with hexadecanal (10) under acid catalysis
provided the crotyl alcohol (-)-21 in good yield (81%) and in
high enantioselectivity (er >95:5).3b Next, the hydroxyl
group was converted into the tripropyl silyl ether to yield
(þ)-22 (95%). This easily removable protecting group was
amenable to clean TBAF deprotection without formation of
the elimination product 12 during the later conversion of
(-)-28 into (-)-1b. The oxidative cleavage of (þ)-22 by the
OsO4/NMO/NaIO4 procedure gave the aldehyde (-)-23 in a
moderate yield of 41%. Use of ozone in CH2Cl2 at -78 °C as
an alternative procedure did not improve the yield. Treat-
ment of (-)-23 with the lithium salt of dimethyl methyl-
phosphonate provided a β-hydroxyphosphonate 24 that
was oxidized with Dess-Martin periodinane16 to give the
β-ketophosphonate (-)-25 in an overall yield of 61%.
The Horner-Wadsworth-Emmons coupling of β-ketopho-
sphonate (-)-25 and aldehyde 26 mediated by K2CO3 in
ethanol gave enone (-)-27 (79%). Hydrogenation of (-)-27
induced simultaneous phenol debenzylation and enone re-
duction to afford product (-)-28 (67%), from which the
phenolic key intermediate (-)-1b was selectively obtained in
a yield of 83% upon TBAF deprotection in THF at 25 °C
over 30 min. Finally, (-)-1b was oxidized with PIDA in
CH2Cl2 to give (-)-amomol A (15%) and (þ)-amomol B
(21%). Starting from the Nokami’s reagent (-)-20, the non-
natural enantiomers of (þ)-amomol A and (-)-amomol B
were similarly synthesized.
When compound (()-1b was treated with PIDA in metha-
nol (Scheme 3), the p-quinol ether (()-3b was obtained as the
major product (36%), along with a mixture of amomols A
and B (18%). These products were difficult to separate,
necessitating multiple chromatographies that led to consid-
erable material loss. Therefore, the final yields do not
accurately reflect the true proportion of the various reaction
products. A better indication of the product distribution was
1
garnered through H NMR analysis of the crude reaction
mixtures, which indicated that amomols A and B and
compound (()-3b have formed in a ratio of ca. 1:1:2. Using
CH2Cl2 as solvent with 10 equiv of methanol, (()-amomols
A and B were isolated in yields of 14% and 19%, respec-
tively. The ratio of amomols A/B/3b analyzed by 1H NMR
was 46:47:7. Interestingly, with HFIP as solvent and with
10 equiv of methanol, a slight diastereoselectivity between
amomols A and B was observed. The ratio of amomols A
and B, evaluated by 1H NMR, was found to be around 2:3
with no trace of p-quinol ether (()-3b. Amomols A and B
were isolated in yields of 12% and 27%, respectively. Like-
wise in the oxidation of 5 (see Table 1), the use of HFIP as
solvent slightly improves the yields. However, because of the
high cost of HFIP and because fighting malaria requires
inexpensive syntheses of bioactive molecules, CH2Cl2 arises
as a suitable solvent that performs well enough in the key
oxidation reaction. Finally, to access two novel amomol
analogues having an additional lipophilic side chain, (()-
1b was oxidized in CH2Cl2 with PIDA in the presence of 10
equiv of decanol 13 yielding (()-amomols-like A 14 (21%)
and B 15 (23%).
We have already reported that the cyclohexadienone
moiety of aculeatins is required for antimalarial activity,
given that the reduced analogue (()-29 of aculeatin A
(Figure 1) is inactive. Furthermore, we have shown that
products displaying two cyclohexadienone units, like (()-31
and 32, show improved potency.3d The compounds thus
synthesized were tested against the parasite Plasmodium
falciparum, the causative agent of malaria, on a chloroquine
sensitive strain 3D7.
In Figure 1, products are classified according to their
efficiency, from least to most potent. Formerly synthesized
molecules (()-30,3e (()-29, (()-31, 32,3d and homochiral
natural and non-natural aculeatins A and B3b are repre-
sented with gray coloration. Amomols A and B proved to be
potent antimalarial products, with IC50 ranging from 0.48 to
0.64 μM, very close to those of aculeatins. Similarly to
aculeatins, the configuration of amomols does not have a
strong impact on antimalarial efficiency, the configuration
of natural (-)-amomol A being a little more efficient (0.48
μM). With amonol analogues, addition of a second lipophilic
side chain like (()-14 and (()-15 or loss of spirocyclic
We also tested the ability of a carbonyl group of enone 12
to intercept the presumed phenoxonium cation obtained
upon oxidation of the phenol. When compound 12 was
oxidized with PIDA in CH2Cl2 containing 10 equiv of
methanol, the amomol-like product (()-17 was indeed iso-
lated in a yield of 41% (Scheme 4). This is consistent with the
documented 1,2 regioselectivity in the addition of alcohols to
vinyl oxocarbenium cations such as 16.13 However, these
(10) Trifluoroethanol (TFE) was also examined as solvent in the oxida-
tion of 5 with PIDA in the presence of 10 equiv of methanol. Amomols-like
products including 6 were isolated as an inseparable mixture making
characterization difficult.
(11) Mase, N.; Kitagawa, N.; Takabe, K. Synlett 2010, 93–96.
(12) Gung, B. W.; Dickson, H. D.; Seggerson, S.; Bluhm, K. Synth.
Commun. 2002, 32, 2733–2740.
(13) Lin, H.-C.; Yang, W.-B.; Gu, Y.-F.; Chen, C.-Y.; Wu, C.-Y.; Lin,
C.-H. Org. Lett. 2003, 5, 1087–1089.
(14) Marmata, M.; Rashatasakhon, P. Tetrahedron 2003, 59, 2371–2395.
(15) Nokami, J.; Ohga, M.; Nakamoto, H.; Matsubara, T.; Hussain, I.;
Kataoka, K. J. Am. Chem. Soc. 2001, 123, 9168–9169.
(16) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
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FIGURE 1. In vitro evaluation of amomols and their new analogues on Plasmodium falciparum.
SCHEME 5. Enantioselective Syntheses of Natural and Non-natural Amomols A and B
structure like (()-3b are detrimental to the antimalarial activ-
ity. As a result, maximum antimalarial activity is observed in
products having spirocyclohexadienone moieties and one
lipophilic side chain.
J. Org. Chem. Vol. 76, No. 5, 2011 1413

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Conclusions
J=10.2, Hz, 2H), 6.71 (d, J=10.2, Hz, 2H);13C NMR(100 MHz,
CDCl3) δ 30.5 (CH3), 32.8 (CH2), 37.6 (CH2), 53.5 (CH3), 75.3
(C), 131.9 (2 ꢀ CH), 150.7 (2 ꢀ CH), 185.1 (C), 207.3 (C); LRMS
(ESIþ) m/z (%) 217 [M þ Na]þ (100), 213 (25), 137 (49); HRMS
(ESIþ) m/z found 217.0835, C11H14O3Na requires 217.0835.
4-(4-(Tetrahydro-2H-pyran-2-yloxy)phenyl)butan-2-one (9). To
a stirred solution of 4-(4-hydroxyphenyl)butan-2-one (5) (4 g,
24.39 mmol) in CH2Cl2 (50 mL) were added PPTS (612 mg, 2.44
mmol) and 3,4-dihydro-2H-pyran (8) (2.5 g, 29.76 mmol). The
mixture was stirred for 16 h at room temperature. Then an
aqueous solution of NaHCO3 (30 mL) was added, followed by
extraction with EtOAc (3 ꢀ 40 mL). The combined organic
layers were dried over MgSO4, filtered, and evaporated. The
residue was subjected to silica gel column chromatography,
eluting with cyclohexane/EtOAc (90/10), to give 9 (5.7 g, 22.98
mmol, 94%). Rf 0.18 (90/10 cyclohexane/EtOAc); IR νmax (film,
We have shown that phenolic oxidation of the precursor
1b yields amomols in only one step, presumably through to
the formation of a transient spiro-oxocarbenium cation that
subsequently reacts with methanol. This efficient biomimetic
reaction allows two new bonds to be made with the trapping
of an intermolecular alcohol. Moreover, we showed that this
cascade sequence works equally well in combination with a
more electron rich carbonyl oxygen of an enone. We made
use of this straightforward process to obtain homochiral
amomols and their new analogues in a modular manner. The
resultant set of molecules has enabled us to get new insights
on structure-activity relationships and has established amo-
mols as potent antimalarial products. Taken together with
our actual knowledge on aculeatins, the recent discovery of
amomols constitutes indeed the “missing link” to an under-
standing of their biomimetic synthesis and to the identifica-
tion of important functional groups involved in the anti-
malarial property.
1
cm-1) 2950, 1713, 1613, 1502; UV (MeOH) 274, 222 nm; H
NMR (400 MHz, CDCl3) δ 1.55-1.72 (m, 3H), 1.80-1.87 (m,
2H), 1.99 (m, 1H), 2.12 (s, 3H), 2.72 (m, 2H), 2.82 (m, 2H), 3.58
(m, 1H), 3.89 (m, 1H), 5.36 (t, J=3.2 Hz, 1H), 6.96 (d, J=8.7
Hz, 2H), 7.08 (d, J=8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 18.9 (CH2), 25.3 (CH2,), 29.0 (CH3), 30.2 (CH2), 30.5 (CH2),
45.5 (CH2), 62.1 (CH2), 96.5 (CH), 116.6 (2 ꢀ CH), 129.2 (2 ꢀ
CH), 134.1 (C), 155.5 (C), 208.2 (C); HRMS (ESIþ) m/z found
271.1310, C15H20O3Na requires 271.1310.
Experimental Section
General Procedure for Phenolic Oxidation. Method A. To a
stirred ice-cold solution of phenol (0.1 M) in the appropriate
solvent was added alcohol (10 equiv) and PIDA (1.5 equiv). The
mixture was stirred at 0 °C for 5 min and at room temperature
for 30 min, after which time solid NaHCO3 was added. The solid
was removed by filtration and the solution was concentrated in
vacuo to give a mixture that was purified by flash chromatog-
raphy.
Method B. To a stirred ice-cold solution of phenol (0.1 M) in
anhydrous methanol was added hypervalent iodine(III) reagent
(1.5 equiv). The mixture was stirred at 0 °C for 5 min and at
room temperature for 30 min, after which time solid NaHCO3
was added. The solid was removed by filtration and the solution
was concentrated in vacuo to give a mixture that was purified by
flash chromatography.
(()-2-Methoxy-2-methyl-1-oxaspiro[4.5]deca-6,9-dien-8-one
(6). According to method A, and starting from 4-(4-
hydroxyphenyl)butan-2-one (5) (115 mg, 0.70 mmol) and anhy-
drous MeOH (224 mg, 7.0 mmol) in CH2Cl2 (5 mL), the
products were purified by flash chromatography on silica gel
column chromatography, eluting with cyclohexane/EtOAc
(75/25), to give (()-6 (94.0 mg, 0.48 mmol, 69%) along with 7
(11 mg, 0.057 mmol, 8%). Rf 0.23 (75/25 cyclohexane/EtOAc);
IR νmax (film, cm-1) 3428, 2900, 1714, 1396, 1126; UV (MeOH)
220 nm; 1H NMR (400 MHz, CDCl3) δ 1.48 (s, 3H), 1.94-2.04
(m, 2H), 2.21 (m, 1H), 2.36 (m, 1H), 3.26 (s, 3H), 6.05 (dd, J=
10.0, 1.8 Hz, 1H), 6.08 (dd, J=10.0, 1.8 Hz, 1H), 6.75 (dd, J=
10.0, 3.0 Hz, 1H), 6.82 (dd, J=10.0, 3.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 21.4 (CH3), 35.4 (CH2), 39.1 (CH2), 48.9 (CH3),
78.7 (C), 109.7 (C), 126.9 (CH), 127.4 (CH), 149.2 (CH), 151.5
(CH), 185.5 (C); LMRS (ESIþ) m/z (%) 217 [M þ Na]þ (38),
203 (100), 163 (75); HRMS (ESIþ) m/z found 217.0838,
C11H14O3Na requires 217.0835.
4-Methoxy-4-(3-oxobutyl)cyclohexa-2,5-dienone (7). Accord-
ing to method B with PIFA as oxidant (220 mg, 0.51 mmol) and
starting from 4-(4-hydroxyphenyl)butan-2-one (5) (56 mg, 0.34
mmol) in anhydrous MeOH (2 mL), the products were purified
by flash chromatography [silica gel eluting with cyclohexane/
EtOAc (75/25)] to give 7 (30 mg, 0.15 mmol, 44%) and (()-6
(25.2 mg, 0.13 mmol, 39%). Rf 0.20 (75/25 cyclohexane/EtOAc);
IR νmax (film, cm-1) 3500, 2900, 1750, 1110, 775; UV (MeOH)
227 nm; 1H NMR (400 MHz, CDCl3) δ 2.04 (t, J=7.6 Hz, 2H),
2.12 (s, 3H), 2.43 (t, J = 7.6 Hz, 2H), 3.21 (s, 3H), 6.38 (d,
(()-5-Hydroxy-1-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)-
icosan-3-one (11). To a stirred ice-cold solution of diisopropy-
lamine (918 mg, 9.09 mmol) in THF (10 mL) was added
dropwise 2.5 M n-BuLi in hexane (9.09 mmol, 3.63 mL). The
mixture was stirred at 0 °C for 15 min, and then cooled at
-78 °C. Ketone 9 (1.88 g, 7.58 mmol) in THF (10 mL) was added
dropwise, then the mixture was stirred for 15 min at -78 °C.
Hexadecanal (10) (1.80 g, 7.58 mmol) was injected dropwise,
then the mixture was stirred for 30 min and allowed to warm to
room temperature over 1 h, after which time an aqueous
solution of NH4Cl (10 mL) was added, followed by extraction
with EtOAc (3 ꢀ 20 mL). The combined organic layers were
dried over MgSO4, filtered, and evaporated. The residue was
subjected to silica gel column chromatography, eluting with
cyclohexane/EtOAc (90/10), to give (()-11 (1.45 g, 2.97 mmol,
39%). Rf 0.15 (90/10 cyclohexane/EtOAc); IR νmax (film, cm-1
)
1
3346, 2909, 1707, 1514, 1351; UV (MeOH) 222 nm; H NMR
(400 MHz, CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.19-1.33 (m,
26H), 1.54-1.73 (m, 2H), 1.79-1.88 (m, 3H), 1.87-1.90 (m,
2H), 1.99 (m, 1H), 2.47 (dd, J=17.5, 8.8 Hz, 1H), 2.56 (dd, J=
17.5, 3.0 Hz, 1H), 2.69-2.75 (m, 2H), 2.80-2.87 (m, 2H), 3.59
(m, 1H), 3.90 (m, 1H), 4.01 (m, 1H), 5.37 (t, J=3.2 Hz, 1H), 6.96
(d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 14.3 (CH3), 19.0 (CH2), 22.9 (CH2), 25.4 (CH2),
25.6 (CH2), 28.9 (CH2), 29.5 (CH2), 29.8 (CH2), 29.9 (8 ꢀ CH2),
30.6 (CH2), 32.1 (CH2), 36.6 (CH2), 45.5 (CH2), 49.5 (CH2), 62.3
(CH2), 67.8 (CH2), 96.6 (CH), 116.7 (2 ꢀ CH), 129.3 (2 ꢀ CH),
133.9 (C), 155.7 (C), 211.6 (C); HRMS (ESIþ) m/z found
511.3763, C31H52O4Na requires 511.3763.
(()-5-Hydroxy-1-(4-hydroxyphenyl)icosan-3-one (1b). To a
stirred solution of (()-11 (650 mg, 1.29 mmol) in MeOH
(20 mL) was added PPTS (80 mg, 0.26 mmol). The mixture
was stirred overnight at room temperature. The solvent was
removed in vaccuo and the residue was subjected to silica gel col-
umn chromatography, eluting with cyclohexane/EtOAc (80/20),
to give (()-1b (469.6 mg, 1.12 mmol, 99%). Rf 0.2 (75/25
cyclohexane/EtOAc); IR νmax (film, cm-1) 3375, 2915, 1689,
1
1516, 1459, 1260; UV (MeOH) 224 nm; H NMR (400 MHz,
CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.23-1.28 (m, 24H),
1.33-1.41 (m, 2H), 1.44-1.53 (m, 2H), 2.48 (dd, J=17.5, 8.9
Hz, 1H), 2.57 (dd, J=17.5, 2.9, 1H), 2.72 (m, 2H), 2.83 (m, 2H),
4.03 (m, 1H), 6.74 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 14.3 (CH3), 22.9 (CH2), 25.7
1414 J. Org. Chem. Vol. 76, No. 5, 2011

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JOCArticle
(CH2), 28.9 (CH2), 29.6 (CH2), 29.7 (CH2), 29.8 (CH2), 29.9 (7 ꢀ
CH2), 32.1 (CH2), 36.4 (CH2), 45.5 (CH2), 49.4 (CH2), 68.1
(CH), 115.6 (2 ꢀ CH), 129.6 (2 ꢀ CH), 133.0 (C), 154.6 (C),
212.1 (C); HRMS (ESIþ) m/z found 427.3182, C26H44O3Na
requires 427.3182.
(m, 40H), 1.42 (m, 2H), 1.48-1.62 (m, 2H), 1.92-2.00 (m, 2H),
2.04 (m, 1H), 2.20-2.27 (m, 2H), 2.42 (m, 1H), 3.43 (m, 1H),
3.56 (m, 1H), 3.80 (m, 1H), 6.13 (dd, J=10.0, 2.0 Hz, 1H), 6.16
(dd, J=10.0, 2.0 Hz, 1H), 6.80 (dd, J=10.0, 3.0 Hz, 1H), 6.85
(dd, J=10.0, 3.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.3
(2 ꢀ CH3), 22.9 (2 ꢀ CH2), 25.8 (CH2), 26.5 (CH2), 29.5 (CH2),
29.6 (CH2), 29.7 (CH2), 29.8 (2 ꢀ CH2), 29.9 (8 ꢀ CH2), 30.3 (2 ꢀ
CH2), 32.1 (2 ꢀ CH2), 35.5 (CH2), 36.9 (CH2), 38.0 (CH2), 41.3
(CH2), 61.3 (CH2), 68.5 (CH), 78.9 (C), 111.8 (C), 127.6 (CH),
127.8 (CH), 148.5 (CH), 150.9 (CH), 185.5 (C); HRMS (ESIþ)
m/z found 583.4697, C36H64O4Na requires 583.4697.
(E)-1-(4-Hydroxyphenyl)icos-4-en-3-one (12). To a solution of
4-(4-hydroxyphenyl)butan-2-one (5) (1 g, 6.09 mmol) in DIM-
CARB (ration carbone dioxide/dimethylamine <0.2/1, 6 mL)
was added portionwise hexadecanal (10) (4.4 g, 18.33 mmol)
(3 ꢀ 1 equiv, every 3 h) at room temperature. Stirring was
continued for 48 h. The solvent mixture was acidified with 1 N
HCl (10 mL) and extracted with CH2Cl2 (3 ꢀ 10 mL). The
combined organic fraction was dried with MgSO4 then filtrated,
and the solvent was removed in vacuo. The residue was sub-
jected to silica gel column chromatography, eluting with cyclo-
hexane/EtOAc (90/10), to give 12 (1.2 g, 3.11 mmol, 51%). Rf
0.23 (85/15 cyclohexane/EtOAc); IR νmax (film, cm-1) 3407,
2621, 1691, 1623, 1086; UV (MeOH) 278, 224 nm; 1H NMR (400
MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 3H), 1.25-1.30 (m, 24H),
1.42 (m, 2H), 2.18 (m, 2H), 2.82-2.88 (m, 4H), 6.10 (d, J=15.9
Hz, 1H), 6.75 (d, J=8.5 Hz, 2H), 6.84 (dt, J=15.9, 6.9 Hz, 1H),
7.03 (d, J=8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 14.3
(CH3), 22.9 (CH2), 28.2 (CH2), 29.4 (CH2), 29.6 (2 ꢀ CH2), 29.7
(CH2), 29.9 (7 ꢀ CH2), 31.1 (CH2), 32.8 (CH2), 42.1 (CH2), 115.6
(2 ꢀ CH), 129.5 (2 ꢀ CH), 130.3 (CH), 133.0 (C), 148.9 (CH),
154.4 (C), 201.0 (C); HRMS (ESIþ) m/z found 409.3078,
C26H42O2Na requires 409.3087.
(()-4-(5-Hydroxy-3-oxoicosyl)-4-methoxycyclohexa-2,5-die-
none (3b). According to method B using PIDA as oxidant (64.4
mg, 0.17 mmol) and starting from (()-1b (43.6 mg, 0.11 mmol)
in MeOH (1.5 mL), the product (()-3b (19.1 mg, 0.05 mmol,
36%) and a mixture of (() amomols A and B (10.2 mg, 0.02
mmol, 18%) were obtained after flash chromatography [silica
gel eluting with cyclohexane/EtOAc (90/10)]. Rf 0.19 (75/25
cyclohexane/EtOAc); IR νmax (film, cm-1) 3407, 2925, 1712,
1668, 1270; UV (MeOH) 225 nm; 1H NMR (400 MHz, CDCl3) δ
0.88 (t, J=6.8 Hz, 3H), 1.23-1.28 (m, 24H), 1.29-1.52 (m, 3H),
1.67 (m, 1H), 2.04 (t, J=7.6 Hz, 2H), 2.44 (t, J=7.6 Hz, 2H),
2.51 (dd, J=15.0, 6.0 Hz, 1H), 3.21 (s, 3H), 3.36 (m, 1H), 4.01
(m, 1H), 6.37 (d, J=10.2 Hz, 2H), 6.71 (d, J=10.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 14.3 (CH3), 22.9 (CH2), 25.6 (CH2),
29.6 (CH2), 29.7 (CH2), 29.8 (CH2), 29.9 (7 ꢀ CH2), 32.1 (CH2),
32.6 (CH2), 36.7 (CH2), 37.8 (CH2), 49.5 (CH3), 53.4 (CH2), 67.9
(CH), 75.2 (C), 132.0 (2 ꢀ CH), 150.6 (2 ꢀ CH), 185.3 (C), 210.3
(C); HRMS (ESIþ) m/z found 457.3288, C27H46O4Na requires
457.3288.
(()-[(E)-Heptadec-1-enyl]-2-methoxy-1-oxaspiro[4.5]deca-6,9-
dien-8-one (17). According to method A and starting from 12
(105 mg, 0.27 mmol) and methanol (86 mg, 2.7 mmol) in CH2Cl2
(2.5 mL), the product (()-17 (46.8 mg, 0.11 mmol, 41%) was
obtained after flash chromatography [silica gel eluting with
cyclohexane/EtOAc (90/10)]. Rf 0.31 (85/15 cyclohexane/
EtOAc); IR νmax (film, cm-1) 2920, 1680, 1631, 1463; UV
1
(MeOH) 225 nm; H NMR (400 MHz, CDCl3) δ 0.88 (t, J =
6.8 Hz, 3H), 1.23-1.32 (m, 24H), 1.40 (m, 2H), 2.00-2.14 (m,
4H), 2.29 (m, 1H), 2.40 (m, 1H), 3.24 (s, 3H), 5.51 (dt, J=15.6,
1.1 Hz, 1H), 5.93 (dt, J=15.6, 6.7 Hz, 1H), 6.13 (dd, J=10.0, 2.0
Hz, 1H), 6.16 (dd, J=10.0, 2.0 Hz, 1H), 6.88 (dd, J=10.0, 3.0
Hz, 1H), 6.91 (dd, J=10.0, 3.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.3 (CH3), 22.9 (CH2), 29.1 (CH2), 29.4 (CH2), 29.6
(2 ꢀ CH2), 29.9 (6 ꢀ CH2), 32.1 (2 ꢀ CH2), 32.2 (CH2), 35.3
(CH2), 39.5 (CH2), 49.8 (CH3), 78.9 (C), 110.2 (C), 127.2 (CH),
127.5 (CH), 128.0 (CH), 134.5 (CH), 149.2 (CH), 151.5 (CH),
185.7 (C); HRMS (ESIþ) m/z found 439.3179, C27H44O3Na
requires 439.3183.
(()-[(E)-Heptadec-1-enyl]-2-[(2E,4E)-hexa-2,4-dienyloxy]-1-
oxaspiro[4.5]deca-6,9-dien-8-one (19). According to method A
and starting from 12 (50 mg, 0.13 mmol) and (2E,4E)-hexa-2,4-
dien-1-ol (18) (63.8 mg, 0.65 mmol) in CH2Cl2 (1.5 mL), the
product (()-19 (21.5 mg, 0.05 mmol, 38%) was obtained after
flash chromatography [silica gel, eluting with cyclohexane/
EtOAc (90/10)]. Rf 0.17 (90/10 cyclohexane/EtOAc); IR νmax
1
(film, cm-1) 2924, 1671, 1631, 1463; UV (MeOH) 226 nm; H
NMR (400 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 3H), 1.22-1.33
(m, 24H), 1.39 (m, 2H), 1.76 (d, J=6.6 Hz, 3H), 2.00-2.12 (m,
4H), 2.33-2.47 (m, 2H), 3.98 (dd, J=12.6, 6.0 Hz, 1H), 4.05 (dd,
J=12.6, 6.3 Hz, 1H), 5.55 (d, J=15.6 Hz, 1H), 5.63 (dt, J=15.0,
6.3 Hz, 1H), 5.72 (dq, J=14.8, 6.7 Hz, 1H), 5.93 (dt, J=15.6, 6.8
Hz, 1H), 6.07 (m, 1H), 6.11-6.12 (m, 1H), 6.15 (m, 1H), 6.21 (m,
1H), 6.82 (dd, J=10.0, 3. 0 Hz, 1H), 6.89 (dd, J=10.0, 3.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 14.3 (CH3), 18.3 (CH2),
22.9 (CH2), 29.1 (CH2), 29.4 (CH2), 29.6 (2 ꢀ CH2), 29.7 (CH2),
29.8 (CH2), 29.9 (5 ꢀ CH2), 32.1 (CH2), 32.2 (CH2), 35.4 (CH2),
39.6 (CH2), 62.9 (CH2), 79.0 (C), 110.1 (C), 127.1 (CH), 127.2
(CH), 127.6 (CH), 128.5 (CH), 130.1 (CH), 131.1 (CH), 132.6
(CH), 134.3 (CH), 149.2 (CH), 151.6 (CH), 185.8 (C); HRMS
(ESIþ) m/z found 505.3653, C32H50O3Na requires 505.3652.
(-)-(2E,5R)-Icos-2-en-5-ol [(-)-21]. To a stirred solution of
hexadecanal (10) (2 g, 8.33 mmol) and (þ)-(1S,2S,5R)-1-(1-
methylallyl)-menthol (20) (3.5 g, 16.66 mmol) in CH2Cl2 (140
mL) was added p-TsOH (158 mg, 0.83 mmol). The mixture was
stirred at room temperature overnight, after which time satu-
rated aqueous NaHCO3 (70 mL) was added, and the mixture
was extracted with CH2Cl2 (3 ꢀ 70 mL). The combined organic
layers were dried over MgSO4, filtered, and evaporated. The
residue was subjected to silica gel column chromatography,
eluting with cyclohexane/EtOAc (2/98), to give (-)-21 (2 g,
(()-(Hydroxyheptadecyl)-2-nonyloxy-1-oxaspiro[4.5]deca-6,9-
dien-8-on (14 and 15). According to method A and starting from
(()-1b (37 mg, 0.091 mmol) and decanol (13) (71 mg, 0.45 mmol)
in CH2Cl2 (1.5 mL), the products (()-14 (10.6 mg, 0.019 mmol,
21%) and (()-15 (11.7 mg, 0.021 mmol, 23%) were obtained
after flash chromatography [silica gel eluting with CH2Cl2/Et2O
(94/06)]. (()-14: Rf 0.32 (96/4 CH2Cl2/Et2O); IR νmax (film,
cm-1) 3497, 2929, 1679, 1625; UV (MeOH) 225 nm; 1H NMR
(400 MHz, CDCl3) δ 0.88 (t, J = 6.8 Hz, 6H), 1.23-1.40 (m,
40H), 1.41-1.54 (m, 4H), 1.69 (m, 1H), 2.05 (m, 1H), 2.10-2.20
(m, 2H), 2.32-2.44 (m, 2H), 3.56 (m, 2H), 3.83 (m, 1H), 6.12
(dd, J=10.0, 2.0 Hz, 1H), 6.17 (dd, J=10.0, 2.0 Hz, 1H), 6.78
(dd, J=10.0, 3.0 Hz, 1H), 6.82 (dd, J=10.0, 3.0 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 14.3 (2 ꢀ CH3), 22.9 (2 ꢀ CH2), 25.7
(CH2), 26.5 (CH2), 29.5 (CH2), 29.6 (CH2), 29.8 (CH2), 29.9
(10 ꢀ CH2), 32.0 (2 ꢀ CH2), 32.1 (2 ꢀ CH2), 35.3 (CH2), 37.0
(CH2), 37.9 (CH2), 41.8 (CH2), 61.6 (CH2), 69.3 (CH), 79.2 (C),
111.7 (C), 127.3 (CH), 128.0 (CH), 148.7 (CH), 150.6 (CH),
185.5 (C); HRMS (ESIþ) m/z found 583.4697, C36H64O4Na
requires 583.4697. (()-15: Rf 0.30 (96/4 CH2Cl2/Et2O); IR νmax
6.76 mmol, 81%). [R]20 -0.6 (c 1.0, CH3Cl); Rf 0.29 (95/5
D
cyclohexane/EtOAc); IR νmax (film, cm-1) 3442, 2956, 1645,
1130, 1094, 1020, 960; UV (MeOH) 276, 225, 208 nm; 1H NMR
(400 MHz, CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.24-1.31
(m, 24H), 1.40-1.47 (m, 4H), 1.69 (dd, J = 6.2, 0.6 Hz, 3H),
2.05 (m, 1H), 2.22 (m, 1H), 3.57 (m, 1H), 5.43 (m, 1H), 5.55 (dq,
1
(film, cm-1) 3497, 2929, 1679, 1625; UV (MeOH) 225 nm; H
NMR (400 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz, 6H), 1.24-1.36
J. Org. Chem. Vol. 76, No. 5, 2011 1415

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J = 15.2, 6.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.3
(CH3), 18.2 (CH3), 22.9 (CH2), 25.9 (CH2), 29.6 (CH2),
29.8 (CH2), 29.9 (8 ꢀ CH2), 32.1 (CH2), 37.0 (CH2), 40.9
(CH2), 71.2 (CH), 127.4 (CH), 129.0 (CH); HRMS (ESIþ)
m/z found 319.2972, C20H40ONa requires 319.2971. (þ)-
(2E,5S)-Icos-2-en-5-ol [(þ)-21]: Starting from hexadecanal (10)
and (-)-(1R,2R,5S)-1-(1-methylallyl)-menthol (20), the product
for 10 min, after which time a solution of (-)-23 (710 mg, 1.61
mmol) in dry THF (4 mL) was added dropwise. The reaction
mixture was stirred at -78 °C for 1 h, and then allowed to warm
to room temperature over 1 h, before hydrolysis with aqueous
NH4Cl (10 mL), followed by extraction with Et2O (3 ꢀ 10 mL).
The combined organic layers were dried over MgSO4, filtered,
and evaporated. The residue was subjected to silica gel column
chromatography, eluting with cyclohexane/EtOAc (60/40), to
give 24 (570.6 mg, 1.01 mmol, 63%). Rf 0.14 (50/50 cyclohexane/
EtOAc); IR νmax (film, cm-1) 3389, 2950, 1468, 1330, 1224, 106;
UV (MeOH) 227 nm; 1H NMR (400 MHz, CDCl3) δ 0.56-0.66
(m, 6H), 0.88 (t, J = 6.8 Hz, 3H), 0.96 (t, J = 7.2 Hz, 9H),
1.21-1.33 (m, 26H), 1.33-1.45 (m, 6H), 1.45-1.55 (m, 2H),
1.60-1.75 (m, 2H), 1.90-2.05 (m, 2H), 3.74 (s, 3H), 3.77 (s, 3H),
3.98 (m, 1H), 4.10-4.32 (m, 1H); 13C NMR (100 MHz, CDCl3,
an asterisk (*) indicates the diastereomer pick) δ 14.2 (CH3),
16.9 (3 ꢀ CH2), 17.0, 17.2* (3 ꢀ CH2), 18.6 (3 ꢀ CH3), 22.8
(CH2), 24.9, 25.5* (CH2), 29.5 (CH2), 29.7 (CH2), 29.8 (6 ꢀ
CH2), 32.0 (CH2), 32.7, 32.9* (CH2), 34.0, 34.2* (CH2), 36.9,
37.7* (CH2), 43.2, 43.3* (CH2), 44.0, 44.1* (CH2), 52.2, 52.3*
(CH3), 52.4, 52.5* (CH3), 63.6, 65.8* (CH), 70.8, 72.3* (CH);
HRMS (ESIþ) m/z found 587.4227, C30H65O5NaSiP requires
587.4231. (4S)-Dimethyl (2-hydroxy-4-tripropylsilyloxy)non-
adecylphosphonate (24): HRMS (ESIþ) m/z found 587.4229,
(þ)-21 was similarly prepared. [R]20 þ0.8 (c 1.0, CH3Cl);
D
HRMS (ESIþ) m/z found 319.2974, C20H40ONa requires
319.2971.
(þ)-(2E,5R)-(Icos-2-en-5-yloxy)tripropylsilane [(þ)-22]. To a
stirred solution of (-)-21 (2 g, 6.76 mmol) in DMF (40 mL) were
successively added imidazole (2.8 g, 40.56 mmol) and chloro-
tripropylsilane (3.9 g, 20.28 mmol). The mixture was stirred at
room temperature overnight, after which time saturated aque-
ous NH4Cl (20 mL) was added, and the mixture was extracted
with Et2O (3 ꢀ 20 mL). The combined organic layers were dried
over MgSO4, filtered, and evaporated. The residue was sub-
jected to silica gel column chromatography, eluting with cyclo-
hexane, to give (þ)-22 (2.9 g, 6.41 mmol, 95%). [R]20D þ5 (c 1.0,
CH3Cl); Rf 0.28 (cyclohexane); IR νmax (film, cm-1) 2950, 1202,
1052, 963; UV (MeOH) 226 nm; 1H NMR (400 MHz, CDCl3) δ
0.54-0.61 (m, 6H), 0.88 (t, J=6.8 Hz, 3H), 0.96 (t, J=7.2 Hz,
9H), 1.24-1.30 (m, 24H), 1.31-1.43 (m, 10H), 1.64 (dd, J=6.2,
0.6 Hz, 3H), 2.05-2.17 (m, 2H), 3.62 (m, 1H), 5.35-5.48 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 14.4 (CH3), 17.1 (3 ꢀ CH2),
17.5 (3 ꢀ CH2), 18.2 (CH3), 18.9 (3 ꢀ CH3), 23.0 (CH2), 25.7
(CH2), 29.7 (CH2), 30.1 (9 ꢀ CH2), 32.3 (CH2), 37.2 (CH2), 41.1
(CH2), 72.8 (CH), 127.1 (CH), 128.3 (CH); HRMS (ESIþ) m/z
found 475.4306. C29H60ONaSi requires 475.4306. (-)-(2E,5S)-
(Icos-2-en-5-yloxy)tripropylsilane [(-)-22]: Starting from (þ)-
21, the product (-)-22 was similarly prepared. [R]20D -4 (c 1.0,
CH3Cl); HRMS (ESIþ) m/z found 475.4306, C29H60ONaSi
requires 475.4306.
C
30H65O5NaSiP requires 587.4231.
(-)-(R)-Dimethyl 2-Oxo-4-(tripropylsilyloxy)nonadecylphos-
phonate [(-)-25]. To a stirred ice-cold solution of (-)-24 (215
mg, 0.38 mmol) in dry CH2Cl2 (6 mL) was added Dess-Martin’s
reagent (242 mg, 0.57 mmol). The reaction mixture was allowed
to warm to room temperature and further stirred for 30 min,
before hydrolysis with 1 N NaOH (5 mL), followed by extrac-
tion with Et2O (3 ꢀ 5 mL). The combined organic layers were
dried over MgSO4, filtered, and evaporated. The residue was
subjected to silica gel column chromatography, eluting with
cyclohexane/EtOAc (40/60), to give (-)-25 (210 mg, 0.37 mmol,
97%). [R]20D -18.1 (c 1.0, CH3Cl); Rf 0.28 (50/50 cyclohexane/
EtOAc); IR νmax (film, cm-1) 2924, 1698, 1216; UV (MeOH) 227
nm; 1H NMR (400 MHz, CDCl3) δ 0.57 (m, 6H), 0.88 (t, J=6.8
Hz, 3H), 0.95 (t, J=7.2 Hz, 9H), 1.24-1.30 (s, 26H), 1.30-1.40
(m, 6H), 1.40-1.48 (m, 2H), 2.69 (dd, J=15.8, 5.3 Hz, 1H), 2.75
(dd, J=15.8, 6.7 Hz, 1H), 3.10 (m, 1H), 3.16 (m, 1H), 3.77 (d, J=
2.5 Hz, 3H), 3.80 (d, J=2.5 Hz, 3H), 4.14 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.1 (CH3), 16.8 (3 ꢀ CH2), 16.9 (3 ꢀ CH2),
18.4 (3 ꢀ CH3), 22.7 (CH2), 24.9 (CH2), 29.3 (CH2), 29.5 (CH2),
29.7 (8 ꢀ CH2), 31.9 (CH2), 37.6 (CH2), 41.9, 43.2 (CH2), 51.2
(CH2), 52.7, 52.8 (CH3), 52.8, 52.9 (CH3), 68.8 (CH), 200.9,
201.0 (C); HRMS (ESIþ) m/z found 585.4074, C30H63O5NaSiP
requires 585.4075. (þ)-(S)-dimethyl 2-oxo-4-(tripropylsilyloxy)-
(-)-(R)-3-(Tripropylsilyloxy)octadecanal [(-)-23]. To a stir-
red solution of (þ)-22 (1.1 g, 2.43 mmol) and NMO (569 mg,
4.86 mmol) in THF (12 mL) was added a solution of OsO4 (4 wt
% in H2O, 1.3 g, 0.24 mmol). The mixture was stirred for 2 h at
room temperature, after which time saturated aqueous NaHSO3
(10 mL) was added and the mixture was extracted with EtOAc
(3 ꢀ 10 mL). The combined organic layers were dried over
MgSO4, filtered, and evaporated. The resulting colorless oil was
diluted in EtOAc/MeOH/THF/H2O (2/2/1/1) (30 mL), the
NaIO4 (3.1 g, 14.6 mmol) was added, and the mixture was
stirred for 30 min, after which time saturated aqueous NaHCO3
(15 mL) was added and the mixture was extracted with Et2O (3 ꢀ
15 mL). The combined organic layers were dried over MgSO4,
filtered, and evaporated. The residue was subjected to silica gel
column chromatography, eluting with cyclohexane/EtOAc
nonadecylphosphonate [(þ)-25]: [R]20 þ17.8 (c 1.0, CH3Cl);
D
(95/5), to give (-)-23 (439.4 mg, 1.0 mmol, 41%). [R]20 -5.2
HRMS (ESIþ) m/z found 585.4075, C30H63O5NaSiP requires
D
(c 1.0, CH3Cl); Rf 0.36 (95/5 cyclohexane/EtOAc); IR νmax (film,
585.4075.
1
cm-1) 2955, 1733; UV (MeOH) 209 nm; H NMR (400 MHz,
(-)-(1E,5R)-1-[4-(Benzyloxy)phenyl]-5-(tripropylsilyloxy)isos-
1-en-3-one [(-)-27]. To a stirred solution of (-)-25 (323 mg, 0.57
mmol) in EtOH (5 mL) were added successively 4-(benzyloxy)-
benzaldehyde (26) (121 mg, 0.57 mmol) and K2CO3 (157 mg,
1.14 mmol). The reaction mixture was stirred at room tempera-
ture for 3 h, after which time aqueous NH4Cl (5 mL) was added,
and the mixture was extracted with EtOAc (3 ꢀ 15 mL). The
combined organic layers were dried over MgSO4, filtered, and
evaporated. The residue was subjected to silica gel column
chromatography, eluting with cyclohexane/EtOAc (90/10), to
CDCl3) δ 0.54-0.65 (m, 6H), 0.88 (t, J=6.8 Hz, 3H), 0.96 (t, J=
7.2 Hz, 9H), 1.22-1.36 (m, 24H), 1.36-1.50 (m, 10H), 2.50 (dd,
J=5.9, 2.5 Hz, 2H), 4.18 (m, 1H), 9.80 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 14.3 (CH3), 17.0 (3 ꢀ CH2), 17.2 (3 ꢀ CH2), 18.7
(3 ꢀ CH3), 22.9 (CH2), 25.4 (CH2), 29.6 (CH2), 29.8 (CH2), 29.9
(8 ꢀ CH2), 32.2 (CH2), 38.2 (CH2), 51.1 (CH2), 68.4 (CH), 202.6
(C); HRMS (ESIþ) m/z found 463.3941, C27H56O2NaSi re-
quires 463.3942. (þ)-(S)-3-(Tripropylsilyloxy)octadecanal [(-)-
23]: Starting from (þ)-22, the product (-)-23 was similarly
prepared. [R]20D þ4.7 (c 1.0, CH3Cl); HRMS (ESIþ) m/z found
463.3942, C27H56O2NaSi requires 463.3942.
(4R)-Dimethyl (2-Hydroxy-4-tripropylsilyloxy)nonadecylpho-
sphonate (24). A stirred solution of dimethyl methylphospho-
nate (599 mg, 4.83 mmol) in dry THF (8 mL) was cooled at
-78 °C and treated dropwise with n-BuLi 2.5 M in hexane
(1.9 mL, 4.83 mmol). The reaction mixture was stirred at -78 °C
give (-)-27 (292 mg, 0.46 mmol, 79%). [R]20 -8.2 (c 1.0,
D
CH3Cl); Rf 0.67 (90/10 cyclohexane/EtOAc); IR νmax (film,
cm-1) 2929, 1685, 1654, 1605, 1512, 1171; UV (MeOH) 323,
278 nm; 1H NMR (400 MHz, CDCl3) δ 0.57 (m, 6H), 0.88 (t, J=
6.8 Hz, 3H), 0.92 (t, J = 7.2 Hz, 9H), 1.23-1.30 (m, 26H),
1.30-1.38 (m, 6H), 1.46-1.52 (m, 2H), 2.64 (dd, J=14.7, 5.2
Hz, 1H), 2.84 (dd, J = 14.7, 7.0 Hz, 1H), 4.25 (m, 1H), 5.07
1416 J. Org. Chem. Vol. 76, No. 5, 2011

ꢀ
Traore et al.
JOCArticle
(s, 2H), 6.64 (d, J=16.1 Hz, 1H), 6.97 (d, J=8.7 Hz, 2H), 7.32
(m, 1H), 7.35-7.43 (m, 4H), 7.45-7.52 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 14.3 (CH3), 17.1 (3 ꢀ CH2), 17.2 (3 ꢀ CH2), 18.7
(3 ꢀ CH3), 22.9 (CH2), 25.4 (CH2), 29.6 (CH2), 29.8 (CH2), 29.9
(8 ꢀ CH2), 32.1 (CH2), 38.3 (CH2), 48.6 (CH2), 69.8 (CH), 70.2
(CH2), 115.4 (2 ꢀ CH), 125.4 (CH), 127.6 (2 ꢀ CH), 127.7 (C),
128.3 (CH), 128.8 (2 ꢀ CH), 130.2 (2 ꢀ CH), 136.6 (C), 142.7
(CH), 160.9 (C, C33), 199.4 (C, C3); HRMS (ESIþ) m/z found
671.4823, C42H68O3NaSi requires 671.4830. (þ)-(1E,5S)-
1-[4-(benzyloxy)phenyl]-5-(tripropylsilyloxy)isos-1-en-3-one [(þ)-
(natural) (7.8 mg, 0.018 mmol, 15%) and (þ)-amomol B =
(natural) (10.8 mg, 0.025 mmol, 21%) were isolated by
flash chromatography (elution with CH2Cl2/Et2O). Amomol A:
[R]20D -11.1 (c 0.6, CH3Cl); Rf 0.36 (75/25 cyclohexane/EtOAc);
IR νmax (film, cm-1) 2915, 1671, 1636, 1560, 1167; UV (MeOH)
230 nm; 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=6.8 Hz, 3H),
1.22-1.34 (m, 24H), 1.35-1.47 (m, 3H), 1.52 (m, 1H), 1.69 (dd,
J=14.7, 1.8 Hz, 1H), 2.07 (m, 1H), 2.13 (m, 1H), 2.15 (m, 1H),
2.34 (m, 1H), 2.39 (m, 1H), 3.35 (s, 3H), 3.85 (m, 1H), 6.12 (dd,
J=10.0, 2.0 Hz, 1H), 6.17 (dd, J=10.0, 2.0 Hz, 1H), 6.78 (dd,
J=10.0, 3.0 Hz, 1H), 6.84 (dd, J=10.0, 3.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 14.3 (CH3), 22.9 (CH2), 25.7 (CH2), 29.6
(CH2), 29.9 (9 ꢀ CH2), 32.1 (CH2), 35.1 (CH2), 37.0 (CH2), 38.0
(CH2), 40.9 (CH2), 49.2 (CH3), 69.3 (CH), 79.3 (C), 111.8 (C),
127.3 (CH), 127.9 (CH), 148.6 (CH), 150.6 (CH), 185.5 (C);
HRMS (ESIþ) m/z found 457.3285, C27H46O4Na requires
27]: [R]20 þ7.4 (c 1.0, CH3Cl); HRMS (ESIþ) m/z found
D
671.4823, C42H68O3NaSi requires 671.4830.
(-)-(R)-1-(4-Hydroxyphenyl)-5-(tripropylsilyloxy)isocan-3-one
[(-)-28]. To a stirred solution of (-)-27 (393.4 mg, 0.61 mmol) in
EtOAc (8 mL) was added 10% Pd/C (55.2 mg, 0.06 mmol). The
reaction mixture was stirred at room temperature under H2
atmosphere for 3 h, after which time the reaction mixture was
filtrated on Celite and the solution was concentrated in vacuo.
The residue was subjected to silica gel column chromatography,
eluting with cyclohexane/EtOAc (90/10), to give (-)-28 (230.4
mg, 0.41 mmol, 67%). [R]20D -12.8 (c 1.0, CH3Cl); Rf 0.25 (90/
10 cyclohexane/EtOAc); IR νmax (film, cm-1) 3993, 2924, 1702,
1605, 1512, 1047; UV (MeOH) 224, 278 nm; 1H NMR (400
MHz, CDCl3) δ 0.56 (m, 6H), 0.88 (t, J=6.8 Hz, 3H), 0.95 (t, J=
7.2 Hz, 9H), 1.23-1.28 (m, 22H), 1.29-1.37 (m, 10H),
1.38-1.44 (m, 2H), 2.44 (dd, J = 15.1, 4.9 Hz, 1H), 2.58 (dd,
J=15.1, 7.2 Hz, 1H), 2.73 (m, 2H), 2.79 (m, 2H), 4.16 (m, 1H),
6.75 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 14.3 (CH3), 17.0 (3 ꢀ CH2), 17.2 (3 ꢀ CH2), 18.7
(3 ꢀ CH3), 22.9 (CH2), 25.3 (CH2), 28.8 (CH2), 29.6 (CH2), 29.8
(CH2), 29.9 (8 ꢀ CH2), 32.1 (CH2), 38.0 (CH2), 46.7 (CH2), 50.5
(CH2), 69.4 (CH), 115.6 (2 ꢀ CH), 129.5 (2 ꢀ CH), 132.9 (C),
154.4 (C), 210.6 (C); HRMS (ESIþ) m/z found 583.4515,
C35H64O3SiNa requires 583.4522. (þ)-(S)-1-(4-hydroxyphenyl-
)-5-(tripropylsilyloxy)isocan-3-one [(þ)-28]: [R]20D þ11.7 (c 1.0,
CH3Cl); HRMS (ESIþ) m/z found 583.4516, C35H64O3SiNa
requires 583.4522.
457.3288. (þ)-Amomol B: [R]20 þ8.9 (c 0.6, CH3Cl); Rf 0.36
D
(75/25 cyclohexane/EtOAc); IR νmax (film, cm-1) 2915, 1671,
1636, 1560, 1167; UV (MeOH) 230 nm; H NMR (400 MHz,
1
CDCl3) δ 0.88 (t, J=6.8 Hz, 3H), 1.22-1.35 (m, 25H), 1.43 (m,
2H), 1.53 (m, 1H), 1.96 (m, 2H), 2.06 (m, 1H), 2.24 (m, 2H), 2.42
(m, 1H), 3.31 (s, 3H), 3.79 (m, 1H), 6.13 (dd, J=10.0, 2.0 Hz,
1H), 6.17 (dd, J=10.0, 2.0 Hz, 1H), 6.81 (dd, J=10.0, 3.0 Hz,
1H), 6.85 (dd, J=10.0, 3.0Hz, 1H);13C NMR (100 MHz, CDCl3)
δ 14.3 (CH3), 22.9 (CH2), 25.8 (CH2), 29.6 (CH2), 29.8 (CH2),
29.9 (8 ꢀ CH2), 32.1 (CH2), 35.3 (CH2), 36.9 (CH2), 38.0 (CH2),
40.3 (CH2), 48.8 (CH3), 68.4 (CH), 78.9 (C), 111.8 (C), 127.6
(CH), 127.7 (CH), 148.4 (CH), 150.8 (CH), 185.5 (C); HRMS
(ESIþ) m/z found 457.3286, C27H46O4Na requires 457.3288.
(þ)-Amomol A and (-)-Amomol B (non-natural). According to
method A and starting from (þ)-1b (53.6 mg, 0.133 mmol), (þ)-
amomol A (6.0 mg, 0.014 mmol, 11%) and (-)-amomol B (14.2
mg, 0.033 mmol, 25%) were isolated after flash chromatography
(elution with CH2Cl2/Et2O). (þ)-Amomol A: [R]20D þ10.9 (c 0.4,
CH3Cl);HRMS(ESIþ) m/zfound 457.3288, C27H46O4Na requires
457.3288. (-)-Amomol B: [R]20 -8.2 (c 0.5, CH3Cl); HRMS
D
(ESIþ) m/z found 457.3286, C27H46O4Na requires 457.3288.
(-)-(R)-5-hydroxy-1-(4-hydroxyphenyl)icosan-3-one [(-)-1b].
To a stirred solution of (-)-9 (102.8 mg, 0.18 mmol) in THF
(3 mL) was added a solution of 1 M TBAF in THF (0.2 mL). The
reaction mixture was stirred at room temperature for 30 min,
after which time the mixture was concentrated in vacuo. The
residue was subjected to silica gel column chromatography,
eluting with cyclohexane/EtOAc (25/75), to give (-)-1b (59.5
Acknowledgment. We thank the University of Grenoble,
ꢀ
the Institut de Chimie Moleculaire de Grenoble (ICMG), the
Cluster Chimie Rhone-Alpes, the Agence Nationale de la
^
Recherche (ANR), and the CNRS for financial support and
the MENRT for a doctoral fellowship (M.T.). Y.-S.W.
mg, 0.15 mmol, 83%). [R]20 -18.8 (c 1.0, CH3Cl); HRMS
ꢀ
thanks Dr. Alice Kanazawa for helpful discussions, Stepha-
D
nie Boullanger for masse spectrometry analyses, and Alberto
Medina for proof reading.
(ESIþ) m/z found 427.3181, C26H44O3Na requires 427.3182.
(þ)-(S)-5-hydroxy-1-(4-hydroxyphenyl)icosan-3-one [(þ)-1b]:
[R]20 þ19.2 (c 1.0, CH3Cl); HRMS (ESIþ) m/z found
D
Supporting Information Available: NMR spectra of all new
compounds and details on biological assay. This material is
available free of charge via the Internet at http://pubs.acs.org.
427.3184, C26H44O3Na requires 427.3182.
(-)-Amomol A and (þ)-Amomol B. According to method A,
and starting from (-)-1b (48.4 mg, 0.12 mmol), (-)-amomol A
J. Org. Chem. Vol. 76, No. 5, 2011 1417