Synthesis of arieianal, a prenylated benzoic acid from Piper arieianum

Article abstract of DOI:10.1021/np050237e

Arieianal (1) is a complex prenylated benzoic acid that was isolated from Piper arieianum. It has been synthesized through a convergent sequence that joins a functionalized diterpenoid chain to a protected aromatic core. Key steps include use of a copper enolate for selective displacement of an allylic bromide in the presence of an allylic acetate and a stereoselective Horner-Wadsworth-Emmons condensation to afford the desired E olefin of the isoprenoid side chain. After the diterpenoid chain was joined to the aromatic ring, use of sodium metal in hot sBuOH allowed selective cleavage of two benzyl ether protecting groups, and a sequence of oxidations gave the target compound. This synthesis confirms the structure assigned to the natural product and establishes a route that may be used to prepare more active analogues.

Full text of DOI:10.1021/np050237e

J. Nat. Prod. 2005, 68, 1375-1379
1375
Synthesis of Arieianal, a Prenylated Benzoic Acid from Piper arieianum
Sina I. Odejinmi† and David F. Wiemer*†,‡
Departments of Chemistry and Pharmacology, University of Iowa, Iowa City, Iowa 52242-1294
Received July 4, 2005
Arieianal (1) is a complex prenylated benzoic acid that was isolated from Piper arieianum. It has been
synthesized through a convergent sequence that joins a functionalized diterpenoid chain to a protected
aromatic core. Key steps include use of a copper enolate for selective displacement of an allylic bromide
in the presence of an allylic acetate and a stereoselective Horner-Wadsworth-Emmons condensation to
afford the desired E olefin of the isoprenoid side chain. After the diterpenoid chain was joined to the
aromatic ring, use of sodium metal in hot sBuOH allowed selective cleavage of two benzyl ether protecting
groups, and a sequence of oxidations gave the target compound. This synthesis confirms the structure
assigned to the natural product and establishes a route that may be used to prepare more active analogues.
Scheme 1. Retrosythetic Analysis of Arieianal (1)
Leafcutter ants display fascinating behaviors that attract
interest simply from the standpoint of scientific curiosity.
At the same time, they inflict enormous damage on
agricultural endeavors from the southern United States to
northern Argentina, so they also attract attention on
economic grounds. For a number of years, we investigated
native plants that coexist with leafcutters, looking for
natural chemical defenses against this pest.1 Our studies
uncovered a variety of natural products, including sesquit-
erpenoids (e.g., lasidiol angelate2a and caryophyllene
epoxide2b), diterpenoids (including kolovanes3a,b and clero-
danes3c), triterpenoids,4 flavanones,5 and alkaloids.6 Inves-
tigations of several plant species have yielded compounds
that can be grouped as prenylated derivatives of benzoic
acids.7 One of the more interesting compounds in this last
class is arieianal (1), which was isolated from an ant-
repellent extract of Piper arieianum that showed significant
activity.8 A total synthesis of arieianal was undertaken
because it was isolated in amounts too small for a full set
of bioassays with leafcutter ants and their mutualistic
fungus, because it has an interesting structure, and
because we have developed an interest in the synthesis of
prenylated aromatic compounds.9
Results and Discussion
Arieianal (1) is characterized by the presence of an
oxidized diterpenoid side chain attached to a 3,4-dihy-
droxybenzoic acid. One of the common ways of preparing
prenylated aromatics is through halogen-metal exchange
on a suitably protected aromatic halide followed by coupling
of the resulting anion with the desired isoprenoid electro-
phile.10 In this particular case, choice of protecting groups
is particularly important given the array of functionality
present and the risk of cyclization under common depro-
tection conditions.11 With this caveat, we envisioned prepa-
ration of compound 1 through a convergent coupling of
bromide 2 with the anion derived from a protected aryl unit
(3, Scheme 1). To prepare the desired bromide 2, we
planned to use a Horner-Wadsworth-Emmons (HWE)
condensation to install the C10′-C11′ double bond stereo-
selectively from aldehyde 4 and the known phosphonoester
5.12 Aldehyde 4 in turn could be traced to the geraniol
derivative 6 and ultimately to geranyl acetate (7).
Scheme 2. Selective Extension of the Geranyl Chain
Synthesis of arieianal began with a SeO2 oxidation of
geranyl acetate (7) to afford the known hydroxy ester 813
(Scheme 2). Conversion of alcohol 8 to the bromide 9
occurred smoothly upon standard treatment with NBS and
DMS.14 A two-carbon chain extension was necessary to
* Corresponding author. Tel: 319-335-1365. Fax: 319-335-1270.
E-mail: david-wiemer@uiowa.edu.
† Department of Chemistry.
‡ Department of Pharmacology.
10.1021/np050237e CCC: $30.25
© 2005 American Chemical Society and American Society of Pharmacognosy
Published on Web 09/08/2005

1376 Journal of Natural Products, 2005, Vol. 68, No. 9
Odejinmi and Wiemer
Scheme 3. Assembly of the Arieianal Skeleton
convert compound 9 to ester 10. Kuwajima and Doi15 have
reported preparation of γ,δ-unsaturated esters by reaction
of monofunctional allylic halides, including geranyl bro-
mide, with a copper reagent prepared from ethyl acetate,
LDA, and CuI at -30 °C. Application of this procedure to
compound 9 could give the desired product 10 if selective
displacement of the bromide could be accomplished in the
presence of the acetate moiety. However, treatment of
compound 9 with the lithium enolate of ethyl acetate under
these conditions did not give the desired product, and use
of LDA with CuBr‚DMS at that temperature gave a
complex mixture based on TLC analysis. Fortunately, when
the reaction was conducted at -78 °C, ester 10 was
obtained in good yield through selective displacement of
the allylic bromide in the presence of the allylic acetate.
Ester 10 was transformed to the intermediate aldehyde
14 through a short sequence of functional group manipula-
tions. Treatment of ester 10 with K2CO3 furnished alcohol
11,16 through transesterification of the acetate and ethyl
ester groups, which was protected as the silyl ether 12.
Compound 12 was reduced immediately with LiAlH4 to
furnish alcohol 13 in 85% yield from compound 11. A Swern
protocol17 then was used to oxidize the resulting alcohol
13 to the desired aldehyde 14.
Elaboration of aldehyde 14 to the complete diterpenoid
chain was anticipated through an HWE condensation with
phosphonate 5, and this intermediate was prepared by a
variation on the procedure of Kodama et al.12 After some
experimentation, it was found that use of a limited amount
of homoprenyl bromide (15) relative to the triethyl phosphon-
oacetate (16) made it possible to obtain the monoalkylated
product 5 in 91% yield instead of the 42% previously
reported. The coupling of aldehyde 14 and phosphonoester
5 was accomplished through an HWE18 reaction under
thermodynamic control in a 9:1 E/Z ratio. While the
isomers could be isolated at this point, the separation is
more facile at the stage of the alcohol 19. To obtain this
alcohol, ester 17 was treated with DIBAL at -78 °C.17 The
resulting alcohol 18 was protected as a THP ether and then
treated with TBAF to afford the key intermediate 19 in
excellent yield. Because this compound was readily purified
and reasonably stable, the olefin isomers could be sepa-
rated and material could be stored at this stage and then
converted to the allylic bromide 2 through a standard NBS/
DMS protocol14 just prior to the coupling reaction. A
halogen-metal exchange strategy was explored to couple
the protected aryl unit 2019a and bromide 2. Unfortunately,
attempts to couple the lithium anion derived from com-
pound 20 by a halogen-metal exchange with nBuLi and
bromide 2 went unrewarded. In sharp contrast, upon
addition of CuBr‚DMS to the reaction mixture, the desired
reaction proceeded smoothly to afford the desired product
21 in high yield (Scheme 3).
Because compound 21 represents the carbon skeleton of
arieianal, a series of functional group manipulations was
required to complete the synthesis. Hydrogenolysis of the
benzyl ethers may be problematic in the presence of the
isoprenoid olefins, but cleavage with sodium in hot sBuOH
proved straightforward,19 as it was during the synthesis
of montadial A and isopiperoic acid.19a During the acidic
workup the dioxolane was cleaved to afford aldehyde 22
(Scheme 4). This was followed by removal of the THP ether
with pTsOH in MeOH to provide the corresponding alcohol
23. Treatment of the aromatic aldehyde 23 with NaClO2
resulted in smooth oxidation to the carboxylic acid 24 in
the presence of the phenolic groups and the isoprenoid
allylic alcohol with no obvious overoxidation or cyclization
Scheme 4. Total Synthesis of Arieianal
of the isoprenoid chain. Unfortunately, the final oxidation
of the isoprenoid allylic alcohol 24 to the aldehyde arieianal
proved more problematic. Treatment with MnO2, a mild
reagent for oxidation of allylic alcohols, did not give the
desired aldehyde, and attempted oxidation with PDC, the
Dess-Martin periodinane, and Swern conditions went
unrewarded. Because the catechol functionality may be
sensitive to these oxidants, or cyclization with the prenyl
chain may occur under the reaction conditions, it appeared
necessary to protect the phenols of catechol 22 prior to
oxidation of the allylic alcohol.
Treatment of catechol 22 with acetic anhydride and
DMAP afforded diacetate 25 in 72% yield. Oxidation of this
aromatic aldehyde with NaClO2/NaH2PO4 furnished the
carboxylic acid-THP ether 26. An attempt to cleave the

Synthesis of Arieianal from Piper arieianum
Journal of Natural Products, 2005, Vol. 68, No. 9 1377
dried (MgSO4), and filtered. The filtrate was concentrated in
vacuo to give alcohol 11 as a clear oil (3.57 g, 94%) with
spectral data identical to that previously reported for material
prepared by a different route.16 This compound was used
directly in the next step without further purification.
THP ether in the presence of catalytic pTsOH in MeOH
gave a mixture of mono- and diacetates that was difficult
to separate by flash chromatography. However treatment
of compound 26 with a solution of pTsOH in a 4:1 mixture
of THF and MeOH selectively removed the THP ether in
the presence of the acetate groups, and oxidation of the
allylic alcohol could be conducted with PDC under standard
conditions to afford aldehyde 27 in good yield. Finally,
(4E,8E)-10-(tert-Butyldimethylsilyloxy)-4,8-dimethyl-
deca-4,8-dien-1-ol (13). TBDMSCl (6.7 g, 44.3 mmol) was
added to a solution of ester 11 (6.7 g, 29.5 mmol) in CH2Cl2
(200 mL) followed by imidazole (6.03 g, 88.6 mmol). The
reaction mixture was stirred overnight and then quenched by
addition of H2O (10 mL). The aqueous layer was extracted with
ether, and the combined organic layer was washed with brine
and dried (MgSO4). After filtration and concentration in vacuo,
the oily product 12 was used in the next step without further
purification. Flash chromatography (4:1 hexane/EtOAc) was
used to purify a small sample for elemental analysis: 1H NMR
δ 5.30 (m, 1H), 5.14 (m, 1H), 4.19 (d, J ) 5.7 Hz, 2H), 3.66 (s,
3H), 2.43-2.38 (m, 2H), 2.32-2.27 (m, 2H), 2.14-1.97 (m, 4H),
1.62 (s, 3H), 1.61 (s, 3H); 13C NMR δ 174.1, 136.9, 133.7, 125.1,
124.8, 60.6, 51.7, 39.6, 34.9, 33.3, 26.5, 26.3 (3C) 18.7, 16.6,
16.1, -4.8 (2C); anal. C 67.05%, H 10.78%, calcd for C19H36O3-
Si, C 67.01%, H 10.65%.
Solid LiAlH4 (1.42 g, 37.3 mmol) was added to a solution of
ester 12 in THF (150 mL) at 0 °C, and the reaction mixture
was allowed to warm to room temperature over a period of 3
h. This reaction was quenched by the addition of saturated
Na2SO4 (50 mL) and left overnight. The aqueous layer was
extracted with ether, the combined organic layer was rinsed
with brine and dried (MgSO4), and the filtrate was concen-
trated in vacuo. The initial product was purified by flash
chromatography (4:1 hexane/EtOAc) to give alcohol 13 as a
clear oil (7.84 g, 85% yield for the two steps): 1H NMR δ 5.30
(t, J ) 5.2 Hz, 1H), 5.15 (t, J ) 6.6 Hz, 1H), 4.19 (d, J ) 6.2
Hz, 2H), 3.62 (t, J ) 6.4 Hz, 2H), 2.13-2.00 (m, 6H), 1.71-
1.62 (m, 8H), 0.91 (s, 9H), 0.07 (s, 6H); 13C NMR δ 136.9, 135.0,
124.8 (2C), 62.8, 60.6, 39.7, 36.2, 30.8, 26.4, 26.3 (3C), 18.7,
16.5, 16.1, -4.8 (2C); anal. C 69.12%, H 11.58%, calcd for
C18H36O2Si, C 69.17%, H 11.61%.
(4E,8E)-10-(tert-Butyldimethylsilyloxy)-4,8-dimethyl-
deca-4,8-dienal (14). Oxallyl chloride (3.1 mL, 35.1 mmol)
was added to CH2Cl2 (70 mL) at -78 °C, and after 10 min
DMSO (4.98 mL, 70.2 mmol) was added dropwise and the
solution was stirred for ∼15 min. A solution of alcohol 13 in
CH2Cl2 (30 mL) was transferred via cannula to the reaction
mixture at -78 °C, and this reaction mixture was stirred for
an additional 15 min. After Et3N (17.5 mL, 125.4 mmol) was
added, the temperature was brought to 0 °C. This solution was
diluted with CH2Cl2 (100 mL) and quenched by the addition
of H2O (20 mL). After extraction of the aqueous layer with
ether, the combined organic layer was rinsed with brine, dried
(MgSO4), and concentrated in vacuo. The initial product was
purified by flash chromatography (5:1 hexane/EtOAc) to afford
aldehyde 14 (7.1 g, 92%) as a clear oil: 1H NMR δ 9.75 (t, J )
1.9 Hz, 1H), 5.32-5.26 (m, 1H), 5.17-5.12 (m, 1H), 4.19 (dq,
J ) 6.4 Hz, 0.7 Hz, 2H), 2.54-2.48 (m, 2H), 2.31 (t, J ) 7.6
Hz, 2H), 2.15-1.98 (m, 4H), 1.62 (s, 6H), 0.91 (s, 9H), 0.08 (s,
6H); 13C NMR δ 202.9, 136.8, 133.4, 125.4, 124.9, 60.6, 42.4,
39.6, 32.1, 26.4, 26.3 (3C), 18.7, 16.6, 16.4, -4.8 (2C); anal. C
69.68%, H 11.18%, calcd for C18H34O2Si, C 69.62%, H 11.04%.
Ethyl 2-(Diethoxyphosphoryl)-6-methylhept-5-enoate
(5). Solid tBuOK (6.0 g, 50.6 mmol) was added to a solution of
phosphonoacetate 16 (9.1 mL, 44.6 mmol) in DMF (20.0 mL)
at 0 °C, and the resulting mixture was stirred for 10 min. The
homoallylic bromide 15 (5.0 g, 29.7 mmol) was added to the
reaction mixture, and it was allowed to warm to room
temperature. The reaction mixture was left to stir for 18 h
and then quenched by addition of HCl (3.0 M, 12.0 mL). The
aqueous layer was extracted with ether, and the combined
organic layer was rinsed with brine, dried (MgSO4), and
concentrated in vacuo. The initial product was purified by flash
chromatography (2:1 to 1:1 hexane/EtOAc) to furnish the
desired product 5 (8.29 g, 91%) as a clear oil. The 1H NMR
spectrum was identical to the partial data previously re-
ported12 with additional resonances at 2.13-1.96 (m, 3), 1.93-
1.80 (m, 1H); 31P NMR 23.0.
20
treatment of aldehyde 27 with a solution of NaHCO3
furnished arieianal (1) as a brown oil, with 1H and 13C
NMR spectra identical to those of the natural product, in
∼3% overall yield from compound 8.
In conclusion, the total synthesis of arieianal (1) has been
completed by a highly convergent strategy. The key reac-
tions used to assemble the terpenoid side chain were a
selective alkylation of a copper enolate with an allylic
bromide in the presence of an allylic acetate, and an HWE
condensation that favored the desired E olefin. Once this
chain was joined to a protected aromatic core through
halogen-metal exchange, use of Na in hot sBuOH allowed
selective cleavage of the benzyl protecting groups without
side reactions. After the resulting catechol proved sensitive
to even mild oxidation conditions, incorporation of acetate
protecting groups on the catechol allowed oxidation to the
desired aldehyde in high yield. This synthesis confirms the
structure originally assigned to arieianal and provides a
route that can be modified to prepare analogues of the
natural product for further biological studies.
Experimental Section
General Experimental Procedures. Tetrahydrofuran
(THF) and diethyl ether were distilled from sodium and
benzophenone and used immediately. Dichloromethane, EtOAc,
sBuOH, diisopropylamine, benzene, and toluene were distilled
freshly from CaH2. DMF was used directly without further
purification. All nonaqueous reactions were done under an
argon atmosphere, in oven-dried or flame-dried glassware and
with magnetic stirring. Flash chromatography was done on
silica gel with an average 40-63 µm particle size. The 1H and
13C NMR spectra were recorded at 300 or 400 MHz with CDCl3
as solvent and (CH3)4Si as internal standard. High-resolution
and electrospray (ES) mass spectra were obtained at the
University of Iowa Mass Spectrometry Facility. The elemental
analyses were executed by Atlantic Microlab, Inc. (Norcross,
GA).
(4E,8E)-Ethyl 10-Acetoxy-4,8-dimethyldeca-4,8-dienoate
(10). A solution of LDA [prepared from nBuLi (60.2 mL, 139
mmol) and diisopropylamine (20.3 mL, 145 mmol) at -78 °C]
in THF (120 mL) was transferred by cannula to a solution of
CuBr‚DMS (13.1 g, 63.7 mmol) and anhydrous EtOAc (14.7
mL, 150 mmol) in THF (100 mL) at -78 °C. The reaction
mixture was allowed to stir for 30 min, and then bromide 914
in THF (50 mL) at -78 °C was added via cannula. The reaction
was allowed to stir for another 80 min and then quenched by
addition of saturated NH4Cl (50 mL). The aqueous layer was
extracted with ether, and the combined organic layer was
washed with 10% NH4OH solution. The aqueous layer was
extracted with ether, and the total organic layer was washed
with brine, dried (MgSO4), and concentrated in vacuo. After
final purification by flash chromatography (4:1 hexane/EtOAc),
the desired product 10 was obtained as a clear oil (11.4 g, 70%
from alcohol 8) with 1H and 13C NMR spectra identical to that
reported for material prepared by a different route.21
(4E,8E)-Methyl 10-Hydroxy-4,8-dimethyldeca-4,8-di-
enoate (11).16,22 Solid K2CO3 (3.0 g, 21.8 mmol) was added to
a solution of acetate 10 (4.8 g, 16.8 mmol) in MeOH (30 mL),
and the reaction mixture was stirred for 85 min. After the
reaction was quenched by addition of HCl (3.0 M, 9.0 mL),
the aqueous layer was extracted with EtOAc, the solvent
volume was reduced, and the aqueous layer was extracted with
ether. The combined organic extract was rinsed with brine,

1378 Journal of Natural Products, 2005, Vol. 68, No. 9
Odejinmi and Wiemer
(2E,6E,10E)-Ethyl 12-(tert-Butyldimethylsilyloxy)-6,10-
dimethyl-2-(4-methylpent-3-enyl)dodeca-2,6,10-tri-
enoate (17). Solid tBuOK (1.36 g, 12.02 mmol) was added to
a solution of phosphono ester 5 (3.17 g, 10.35 mmol) in toluene
(50 mL), and the mixture was stirred at room temperature
until most of the tBuOK was dissolved. The reaction mixture
was brought to -78 °C, and a solution of aldehyde 14 (2.72 g,
8.77 mmol) in toluene (60 mL) was transferred via cannula
within 40 min. After 3 h, the reaction mixture was quenched
by addition of saturated NH4Cl (20 mL). The aqueous layer
was extracted with ether, and the combined organic layer was
washed with brine, dried (MgSO4), filtered, and concentrated
in vacuo to give the initial product 17 as a 9:1 E/Z mixture.
This oil was purified by flash chromatography (95:5 hexane/
EtOAc) to afford the E-isomer (2.6 g, 64%). For the E-isomer:
1H NMR δ 6.73 (t, J ) 7.2 Hz, 1H), 5.33-5.29 (m, 1H), 5.17-
5.12 (m, 2H), 4.22-4.15 (m, 4H), 2.34-2.23 (m, 4H), 2.15-
1.99 (m, 8H), 1.68 (s, 3 H), 1.63 (s, 3 H), 1.62 (s, 3 H), 1.60 (s,
3 H), 1.29 (t, J ) 7.2 Hz, 3 H), 0.91 (s, 9H), 0.07 (s, 6H); 13C
NMR δ 168.0, 142.3, 136.8, 134.1, 132.2, 132.1, 124.9, 124.5,
123.8, 60.3, 60.3, 39.5, 38.6, 27.8, 27.3, 27.0, 26.4, 26.0 (3C),
25.7, 18.4, 17.6, 16.4, 16.0, 14.3, -5.0 (2C); anal. C 72.46%, H
11.11%, calcd for C28H50O3Si, C 72.67%, H 10.89%.
2,6,10-trienyloxy)tetrahydro-2H-pyran (21). Neat DMS
(0.29 mL, 3.95 mmol) was added dropwise to a solution of NBS
(699 mg, 3.93 mmol) in CH2Cl2 (20 mL) at 0 °C. After the
resulting yellow mixture was stirred for 10 min, a solution of
alcohol 19 (1.0 g, 2.6 mmol) at 0 °C was transferred into the
reaction mixture by cannula. The resulting mixture was stirred
for 3 h at 0 °C and then quenched by addition of saturated
NH4Cl. The aqueous layer was extracted with CH2Cl2, and the
combined organic extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The resulting oil, bromide
2, was used in the next reaction without further purification.
Bromide 20 (3.5 g, 7.9 mmol) was added to a mixture of
benzene (10 mL) and ether (5 mL), followed by the dropwise
addition of nBuLi (3.6 mL, 8.4 mmol). CuBr‚DMS (807 mg,
3.9 mmol) was added to the reaction mixture, and it was
allowed to stir for 1 h. The solution of bromide 2 in ether (15
mL) was transferred into this reaction mixture, and after 10.5
h, it was quenched by addition of saturated NH4Cl. The
aqueous layer was extracted with ether, and the combined
organic extract was washed with 10% NH4OH followed by
brine, dried (MgSO4), and concentrated in vacuo. After final
purification by flash chromatography (6:1, 5:1 hexane/EtOAc),
the desired product 21 was obtained as a brown oil (1.6 g,
83%): 1H NMR δ 7.48-7.25 (m, 10H), 7.07 (d, J ) 2.0 Hz,
1H), 6.92 (d, J ) 1.7 Hz, 1H), 5.73 (s, 1H), 5.42 (t, J ) 6.9 Hz,
1H), 5.26 (m, 1H), 5.13 (br s, 4 H), 4.99 (s, 2H), 4.60 (t, J ) 3.4
Hz, 1H), 4.18-4.01 (m, 5H), 3.87-3.83 (m, 2H), 3.53-3.47 (m,
1H), 3.34 (d, J ) 7.1 Hz, 2H), 2.17-1.97 (m, 12H), 1.71-1.47
(m, 18H); anal. C 75.81%, H 8.23%, calcd for C48H62O6‚1.5H2O,
C 75.66%, H 8.60%.
3,4-Dihydroxy-5-((2E,6E,10E)-3,7,15-trimethyl-11-((tet-
rahydro-2H-pyran-2-yloxy)methyl)hexadeca-2,6,10,14-
tetraenyl)benzaldehyde (22). Metallic sodium (2.0 g, 85
mmol) was added to a solution of compound 21 (1.4 g, 1.9
mmol) in distilled sBuOH (20 mL) at 80 °C. The resulting
solution was stirred for 130 min between 75 and 80 °C and
then quenched by addition of a mixture of AcOH (6.0 mL), H2O
(10 mL), and Na2S2O4 (350 mg). The aqueous layer was
extracted with EtOAc, and the combined organic extract was
washed with brine, dried (MgSO4), and concentrated in vacuo.
The initial product was purified by flash chromatography (2:1
hexane/EtOAc) to afford catechol 22 (649 mg, 81%) as a dark
brown oil: 1H NMR δ 9.72 (s, 1H), 7.31 (d, J ) 1.8 Hz, 1H),
7.24 (d, J ) 1.9 Hz, 1H), 5.40-5.31 (m, 2H), 5.10-5.03 (m,
2H), 4.67 (t, J ) 3.3 Hz, 1H), 4.19-3.85 (m, 3H), 3.59-3.55
(m, 1H), 3.41 (d, J ) 7.2 Hz, 2H), 2.13-1.43 (m, 30H); 13C NMR
δ 191.9, 149.3, 144.1, 137.3, 135.2, 134.9, 131.7, 129.7, 129.0,
128.1, 126.7, 124.2, 124.0, 121.6, 112.1, 97.5, 71.6, 62.3, 39.6,
39.5, 30.6, 28.5, 28.4, 27.0, 26.2, 26.0, 25.7, 25.4, 19.4, 17.6,
16.0 (2C); HREIMS m/z 533.3226 [M + Na]+ (calcd for
C32H46O5Na, 533.3243).
For the Z-isomer: 1H NMR δ 5.83 (t, J ) 7.3 Hz, 1H), 5.33-
5.29 (m, 1H), 5.16-5.08 (m, 2H), 4.24-4.17 (m, 4H), 2.52 (m,
2H), 2.25 (t, J ) 7.14 Hz, 2H), 2.16-1.98 (m, 8H), 1.68 (s, 3H),
1.63 (s, 3H), 1.60 (s, 3H), 1.59 (s, 3H), 1.31 (t, J ) 7.2 Hz, 3H),
0.91 (s, 9H), 0.06 (s, 6H); 13C NMR δ 168.1, 141.6, 136.9, 134.4,
132.0, 131.7, 124.6, 124.3, 123.6, 60.3, 59.9, 39.5, 39.2, 34.7,
28.0, 27.9, 26.3, 26.0 (3C), 25.7, 18.4, 17.6, 16.3, 15.8, 14.3,
-5.1(2C).
(2E,6E,10E)-12-(tert-Butyldimethylsilyloxy)-6,10-dimeth-
yl-2-(4-methylpent-3-enyl)dodeca-2,6,10-trien-1-ol (18). A
solution of DIBAL in toluene (19.0 mL, 12.7 mmol) was added
dropwise to a solution of ester 17 (2.5 g, 5.5 mmol) in toluene
(80 mL) at -78 °C over 45 min. The reaction mixture was
stirred for 15 min at -78 °C, diluted with ether (100 mL), and
then quenched with saturated Na2SO4 (30 mL). The organic
layer was separated, and the residue was rinsed with ether.
After the combined organic extract was washed with brine,
dried (MgSO4), and concentrated in vacuo, the initial oil was
purified by flash chromatography (6:1 hexane/EtOAc) to afford
allylic alcohol 18 (1.98 g, 86%) as a clear oil: 1H NMR δ 5.40
(t, J ) 6.7 Hz, 1H), 5.33-3.28 (m, 1H), 5.15-5.10 (m, 2H),
4.19 (dd, J ) 6.3, 0.6 Hz, 2H), 4.03 (d, J ) 4.3 Hz, 2H), 2.19-
1.99 (m, 12H), 1.69 (s, 3H), 1.63 (s, 3H) 1.61(s, 6H), 0.91 (s,
9H), 0.07 (s, 6H); 13C NMR δ 138.8, 136.8, 134.8, 132.0, 126.9,
124.5, 124.4, 124.2, 67.0, 60.4, 39.6, 39.5, 28.3, 27.1, 26.3, 26.1,
26.0 (3C), 25.7, 18.5, 17.7, 16.4, 16.0, -5.0 (2C); HREIMS m/z
420.3431 [M+] (calcd for C26H48O2, 420.3424).
(2E,6E,10E)-3,7,15-Trimethyl-11-((tetrahydro-2H-pyran-
2-yloxy)methyl)hexadeca-2,6,10,14-tetraen-1-ol (19). Neat
DHP (1.1 mL, 4.52 mmol) was added to a solution of alcohol
18 (1.9 g, 4.5 mmol) in CH2Cl2, followed by addition of pTsOH
(4.3 mg, 0.02 mmol). The resulting solution was allowed to stir
for 3 h and then quenched by addition of saturated NaHCO3.
The aqueous layer was extracted with ether, and the combined
organic extract was washed with brine, dried (MgSO4), and
concentrated in vacuo. The resultant oil was dissolved in THF
(40 mL) followed by the addition of TBAF (6.3 mL, 6.3 mmol).
This solution was stirred for 6 h at room temperature and then
quenched by addition of saturated NH4Cl. The aqueous layer
was extracted with ether, and the combined organic extract
was washed with brine, dried (MgSO4), and concentrated in
vacuo. The resultant oil was purified by flash chromatography
(4:1 hexane/EtOAc) to give compound 19 (1.62 g, 92%) as a
clear oil: 1H NMR δ 5.44-5.39 (m, 2H), 5.14-5.10 (m, 2H),
4.61 (t, J ) 3.3 Hz, 1H), 4.19-4.15 (m, 3H), 3.92-3.83 (m, 2H),
3.55-3.48 (m, 1H), 2.19-2.00 (m, 12H), 1.89-1.51 (m, 18H);
13C NMR δ 139.5, 135.8, 135.0, 131.6, 128.6, 124.4, 124.1,
123.5, 97.5, 71.2, 62.1, 59.4, 39.6, 39.5, 30.7, 28.5, 27.1, 26.3,
26.2, 25.7, 25.6, 19.5, 17.7, 16.3, 16.0; anal. C 76.75%, H
10.88%, calcd for C25H42O3, C 76.87%, H 10.84%.
3,4-Dihydroxy-5-((2E,6E,10E)-11-(hydroxymethyl)-3,7,-
15-trimethylhexadeca-2,6,10,14-tetraenyl)benzalde-
hyde (23). A solution of compound 22 (203 mg, 0.398 mmol)
in MeOH (4 mL) was treated with pTsOH (15 mg, 0.089 mmol).
After 3.5 h, the reaction was quenched by addition of saturated
NaHCO3. The solvent volume was reduced in vacuo, and salt
was added. After the aqueous layer was extracted with EtOAc,
the combined organic extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The initial product was
purified by flash chromatography (1:1 hexane/EtOAc) to afford
alcohol 23 (129 mg, 76%) as a dark brown oil: 1H NMR δ 9.71
(s, 1H), 7.35 (d, J ) 1.6 Hz, 1H), 7.22 (d, J ) 1.5 Hz, 1H),
5.40-5.33 (m, 2H), 5.10-5.08 (m, 2H), 4.06 (s, 2H), 3.42 (d, J
) 7.2 Hz, 2H), 2.16-1.95 (m, 12H), 1.75 (s, 3H), 1.67 (s, 3H),
1.58 (s, 6H); 13C NMR δ 192.2, 149.4, 144.6, 138.5, 137.8, 135.2,
132.3, 129.3, 128.3, 128.1, 126.9, 124.3, 124.2, 121.9, 112.3,
67.6, 40.0, 39.8, 28.6, 28.4, 27.3, 26.4, 26.0, 25.8, 17.9, 16.3,
16.2.
3,4-Dihydroxy-5-((2E,6E,10E)-11-(hydroxymethyl)-3,7,-
15-trimethylhexadeca-2,6,10,14-tetraenyl)benzoic Acid
(24). Solid NaH2PO4 (90 mg, 0.735 mmol) was added to a
solution of aldehyde 23 (129 mg, 0.302 mmol) in a mixture of
THF (2.50 mL), H2O (0.5 mL), and 2-methyl-2-butene (0.10
mL), followed by addition of NaClO2 (85 mg, 0.752 mmol). The
2-((2E,6E,10E)-12-(2,3-Bis(benzyloxy)-5-(1,3-dioxolan-
2-yl)phenyl)-6,10-dimethyl-2-(4-methylpent-3-enyl)dode-
ca-

Synthesis of Arieianal from Piper arieianum
Journal of Natural Products, 2005, Vol. 68, No. 9 1379
reaction mixture was stirred overnight and then quenched by
slow addition of HCl (3.0 M) until the solution became slightly
acidic. Salt was added to the aqueous layer, and then it was
extracted with EtOAc. The combined organic extract was
washed with brine, dried (MgSO4), and concentrated in vacuo.
The initial product was purified by flash chromatography (1:1
hexane/EtOAc) to afford carboxylic acid 24 as a clear oil (75
mg, 56%): 1H NMR δ 7.48 (s, 1H), 7.47 (s, 1H), 5.40, (t, J )
6.6 Hz, 1H), 5.31 (t, J ) 6.9 Hz, 1H), 5.09 (m, 2H), 4.06 (s,
2H), 3.37 (d, J ) 7.1 Hz, 2H), 2.27-1.96 (m, 12H), 1.73 (s,
3H), 1.66 (s, 3H), 1.57 (s, 6H); 13C NMR δ 172.0, 148.2, 143.4,
138.0, 137.3, 135.1, 132.3, 128.6, 128.0, 124.8, 124.3 (2C),
122.1, 120.8, 115.0, 67.6, 39.7, 30.6, 30.0, 28.6, 28.4, 27.3, 26.4,
25.9, 17.9, 16.3, 16.2; HREIMS m/z 441.2626 [M - H]- (calcd
for C27H37O5, 441.2641).
3,4-Diacetoxy-5-((2E,6E,10E)-3,7,15-trimethyl-11-((tet-
rahydro-2H-pyran-2-yloxy)methyl)hexadeca-2,6,10,14-
tetraenyl)benzaldehyde (25). Freshly distilled diisopropy-
lamine (0.52 mL, 3.71 mmol) and molecular sieves were added
to a solution of compound 22 (378 mg, 0.74 mmol) in CH2Cl2
(7 mL), followed by addition of DMAP (0.90 mg, 0.01 mmol)
and Ac2O (0.35 mL, 3.70 mmol). The reaction mixture was
allowed to stir overnight at room temperature and then
concentrated in vacuo. The resulting oil was purified by flash
chromatography (3:1 hexane/EtOAc) to afford aldehyde 25 (315
mg, 72%) as a light brown oil: 1H NMR δ 9.92 (s, 1H), 7.65 (d,
J ) 1.8 Hz, 1H), 7.60 (d, J ) 1.9 Hz, 1H), 5.42 (t, J ) 7.0 Hz,
1H), 5.24 (t, J ) 3.3 Hz, 1H), 5.13 (br s, 2H), 4.61 (t, J ) 3.3
Hz, 1H), 4.16 (d, J ) 11.6 Hz, 1H), 3.91-3.83 (m, 2H), 3.52-
3.37 (m, 1H), 3.33 (d, J ) 7.1 Hz, 2H), 2.33 (s, 3H), 2.30 (s,
3H), 2.18-1.99 (m, 12H), 1.88-1.47 (m, 18H); 13C NMR δ
190.3, 167.9, 167.4, 145.6, 143.3, 138.4, 137.0, 135.8, 135.0,
134.5, 131.6, 128.5 (2C), 124.3, 124.1, 122.0, 120.0, 97.5, 71.2,
62.0, 39.6 (2C), 30.7, 28.6, 28.5, 27.1, 26.6, 26.3, 25.7, 25.5,
20.6, 20.3, 19.5, 17.6, 16.3, 16.0; HRESIMS m/z 617.3459 [M
+ Na]+ (calcd for C36H50O7Na, 617.3454).
3,4-Diacetoxy-5-((2E,6E,10E)-3,7,15-trimethyl-11-((tet-
rahydro-2H-pyran-2-yloxy)methyl)hexadeca-2,6,10,14-
tetraenyl)benzoic Acid (26). 2-Methyl-2-butene (0.20 mL)
was added to a solution of compound 25 (314 mg, 0.53 mmol)
in THF (4.00 mL), H2O (1.00 mL), and sBuOH (1.00 mL),
followed by addition of NaH2PO4 (194 mg, 1.59 mmol). After
solid NaClO2 (179 mg, 1.58 mmol) was added, the reaction
mixture was stirred for 3 h at room temperature. The reaction
was then quenched by dropwise addition of saturated NH4Cl.
The aqueous layer was extracted with ether, washed with
brine, and dried (MgSO4) and then concentrated in vacuo. The
resulting oil was purified by flash chromatography (60:40
hexane/EtOAc) to afford acid 26 (240 mg, 74%): 1H NMR δ
7.87 (s, 1H), 7.79 (d, J ) 1.7 Hz, 1H), 5.43 (t, J ) 6.9 Hz, 1H),
5.23 (t, J ) 6.46, 1H), 5.13 (br s, 2H), 4.66 (t, J ) 3.2 Hz, 1H),
4.17 (d, J ) 11.6 Hz, 1H), 3.86 (m, 2H), 3.54 (m, 1H), 3.31 (d,
J ) 6.9 Hz, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 2.13-2.01 (m, 12H),
1.95-1.46 (m, 18H); 13C NMR δ 169.6. 168.1, 167.6, 145.0,
142.5, 138.0, 136.2, 135.5, 135.0, 131.6, 129.4, 129.1, 127.8,
124.3, 124.1, 123.1, 120.3, 97.1, 71.2, 61.9, 39.6, 30.6, 28.7, 28.4,
27.0, 26.4 (2C), 25.7, 25.5, 20.7, 20.6, 20.3, 17.6, 16.2, 16.0;
HRESIMS m/z 633.3407 [M + Na]+ (calcd for C36H50O8,
633.3403).
EtOAc, washed with brine, dried (MgSO4), and concentrated
in vacuo to afford compound 29 as a clear oil (18 mg, 82%). A
portion of compound 27 was purified by flash chromatography
(9:1:0.01 toluene/hexane/AcOH) for analysis: 1HNMR δ 9.33
(s, 1H), 7.88 (d, J ) 1.8 Hz, 1H), 7.79 (d, 1.9 Hz, 1H), 6.43 (t,
J ) 7.2 Hz, 1H), 5.23-5.09 (m, 3H), 3.31 (d, J ) 7.0 Hz, 1H),
2.47-2.40 (m, 2H), 2.35-2.23 (m, 8H), 2.17-2.00 (m, 8H), 1.70
(s, 3H), 1.66 (s, 3H), 1.63 (s, 3H), 1.56 (s, 3H); HRESMS m/z
547.2670 [M + Na]+ (calcd for C31H40O7Na, 547.2672).
Arieianal (1). Saturated NaHCO3 (0.50 mL) was added to
a solution of carboxylic acid 27 (15 mg, 0.0286 mmol) in MeOH
(1.0 mL) and H2O (0.50 mL), and the solution was stirred for
80 min. The reaction mixture was quenched by dropwise
addition of HCl (3.0 M) until the solution was slightly acidic.
The aqueous layer was extracted with EtOAc, and the com-
bined organic layer was washed with brine, dried (MgSO4),
and concentrated in vacuo to afford arieianal (1) as a brown
oil (∼5 mg, 40%), representing an overall yield of ∼3% from
1
compound 8. Both H and 13C NMR spectra were identical to
those of the natural product.8
Acknowledgment. We thank Dr. E. M. Treadwell for his
initial studies on arieianal. Financial support from the Roy J.
Carver Charitable Trust is gratefully acknowledged.
References and Notes
(1) Hubbell, S. P.; Howard, J. J.; Wiemer, D. F. Ecology 1984, 65, 1067-
1076.
(2) (a) Wiemer, D. F.; Ales, D. C. J. Org. Chem. 1981, 46, 5449-5450.
(b) Hubbell, S. P.; Wiemer, D. F.; Adejare, A. Oecologia (Berlin) 1983,
60, 321-327.
(3) (a) Hubert, T. D.; Wiemer, D. F. Phytochemistry 1985, 24, 1197-
1198. (b) Chen, T.-B.; Wiemer, D. F. J. Nat. Prod. 1991, 54, 1612-
1618. (c) Chen, T.-B.; Galinis, D. L.; Wiemer, D. F. J. Org. Chem.
1992, 57, 862-866.
(4) (a) Chen, T. K.; Ales, D. C.; Baenziger, N. C.; Wiemer, D. F. J. Org.
Chem. 1983, 48, 3525-3531. (b) Okunade, A. L.; Wiemer, D. F.
Phytochemistry 1985, 24, 1203-1205.
(5) Roussis, V.; Ampofo, S. A.; Wiemer, D. F. Phytochemistry 1987, 26,
2371-2375.
(6) Galinis, D. L.; Wiemer, D. F.; Cazin, J., Jr. Tetrahedron 1993, 49,
1337-1342.
(7) (a) Roussis, V.; Ampofo, S. A.; Wiemer, D. F. Phytochemistry 1987,
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Phytochemistry 1990, 29, 1787-1788. (c) Blunt, S. B.; Chen, T. B.;
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3,4-Diacetoxy-5-((2E,6E,10E)-11-formyl-3,7,15-trimeth-
ylhexadeca-2,6,10,14-tetraenyl)benzoic Acid (27). Solid
pTsOH (0.34 mg, 0.0018 mmol) in THF (0.40 mL) was added
to acid 26 (22.0 mg, 0.036 mmol), followed by the addition of
MeOH (0.10 mL). The reaction mixture was stirred for 2 days
and then quenched by dropwise addition of saturated NH4Cl
solution. The aqueous layer was extracted with ether, and the
combined organic layer was washed with brine, dried (MgSO4),
and concentrated in vacuo. The resulting oil was dissolved in
DMF (0.40 mL) followed by addition of PDC (20 mg, 0.053
mmol). After 75 min, the reaction was quenched by addition
of H2O (4.0 mL), and the aqueous layer was extracted with
(16) Colombo, L.; Gennari, C.; Potenza, D.; Scolastico, C.; Aragozzini, F.;
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NP050237E