Niaviolides, new macrocyclic sesquiterpenes secreted by males of the African butterfly Amauris niavius

Article abstract of DOI:10.1002/ejoc.200390189

The abdominal androconial organs ("hairpencils") of the African butterfly Amauris niavius (Danainae) emit a complex scent bouquet consisting of previously described aromatic compounds, terpenoids, fatty acids, and hydrocarbons. This work reports the identification of two major sesquiterpenes, each possessing a unique 13-membered macrolide ring, originating from an α,ω-oxidation pattern of the sesquiterpene backbone. To the best of our knowledge, sesquiterpene macrolides have not been found before in nature. The structure elucidation of the two compounds, which we propose to call niaviolide (3) and epoxyniaviolide (4), by NMR and GC/MS experiments is presented, together with their subsequent synthesis. Finally, the absolute configuration of natural 4 was determined to be (S,S) by stereoselective synthesis and chiral gas chromatography. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390189

FULL PAPER
Niaviolides, New Macrocyclic Sesquiterpenes Secreted by Males of the African
Butterfly Amauris niavius
[a]
[a]
[b]
´
Katja Stritzke, Stefan Schulz,* and Michael Boppre
Keywords: Configuration determination / Macrolides / Natural products / Pheromones / Terpenoids
The abdominal androconial organs (‘‘hairpencils’’) of the
African butterfly Amauris niavius (Danainae) emit a complex
scent bouquet consisting of previously described aromatic
compounds, terpenoids, fatty acids, and hydrocarbons. This
work reports the identification of two major sesquiterpenes,
elucidation of the two compounds, which we propose to call
niaviolide (3) and epoxyniaviolide (4), by NMR and GC/MS
experiments is presented, together with their subsequent
synthesis. Finally, the absolute configuration of natural 4 was
determined to be (S,S) by stereoselective synthesis and chiral
each possessing a unique 13-membered macrolide ring, ori- gas chromatography.
ginating from an α,ω-oxidation pattern of the sesquiterpene
backbone. To the best of our knowledge, sesquiterpene mac- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
rolides have not been found before in nature. The structure
Germany, 2003)
Introduction
and N11 in ref.[3]), of the hairpencil secretion. Additionally,
the absolute configuration of the natural chiral compound
II was determined by its asymmetric synthesis, followed by
GC experiments with a chiral stationary phase.
The milkweed butterfly Amauris niavius (Lepidoptera,
Danainae) lives in African forest habitats. Like other
danaines, males possess dual androconial organs (male-
specific glandular structures generally producing courtship
pheromones): hindwing scent patches and protrudable ab-
dominal hairpencils, the latter being employed in close-
range courtship behavior.[1,2] The hairpencil chemicals com-
prise a complex bouquet,[3] probably necessary to overcome
the difficulty of visual intraspecific recognition caused by
the involvement of A. niavius in complex mimicry rings.[1Ϫ3]
The hairpencil volatiles of A. niavius have been investi-
gated repeatedly. The scent bouquet consists predominately
of aromatic compounds, terpenoids, hydrocarbons, and
fatty acids. Meinwald et al. identified the dihydropyrrolizine
danaidone and 3,4-dimethoxyacetophenone as the major
hairpencil components and reported the presence of further
unidentified components.[4] A reinvestigation showed that
part of this mixture consists of straight-chain alkanes, 2,5-
dialkyltetrahydrofurans, and some other minor compo-
nents.[3]
Results and Discussion
Hairpencils and wing glands of field-collected A. niavius
were extracted with pentane, as described in the Exp. Sect.
The obtained extracts were investigated by GC-MS (Fig-
ure 1), revealing the presence of two unknown compounds,
I and II.
Here we report the identification and synthesis of two
additional major compounds, I and II (compounds N10
[a]
Institut für Organische Chemie, Technische Universität
Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
Fax: (internat.) ϩ 49-(0)531/391-5272
E-mail: Stefan.Schulz@tu-bs.de
[b]
Forstzoologisches Institut, Albert-Ludwigs-Universität,
79085 Freiburg i. Br., Germany
Fax: (internat.) ϩ 49-(0)761/203-3661
E-mail: boppre@fzi.uni-freiburg.de
Figure 1. Mass spectra of the natural components: A) I; B) II
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Eur. J. Org. Chem. 2003, 1337Ϫ1342  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0407Ϫ1337 $ 20.00ϩ.50/0

´
K. Stritzke, S. Schulz, M. Boppre
FULL PAPER
The mass spectra of the two compounds, shown in Fig-
ure 1, exhibit molecular ions at m/z ϭ 234 and 250, respec-
tively. High-resolution mass spectrometry revealed their
molecular compositions to be C15H22O2 and C15H22O3.
These data suggested that the compounds were sesquiterp-
enes, which was supported by their characteristic terpenoid
fragmentation patterns. The more abundant compound II
was isolated by preparative GC on a packed glass column.
Several microreactions were then performed, both with to-
tal hairpencil extract and with the isolated compound, to
obtain information on the functional groups in both com-
pounds. During hydrogenation of isolated II, 2 equiv. of
hydrogen were taken up. The hydrogenation product con-
sisted of at least three diastereomers, because a GC analysis
showed the presence of three different peaks with very simi-
lar mass spectra. It follows that the hydrogenation product
must have three or more stereocenters, which could be ex-
plained by the presence of two trisubstituted double bonds
and one stereocenter in the original molecule II. Compound
II did not react with N-methyl-N-(trimethylsilyl)trifluo-
roacetamide (MSTFA), but reduction with LAH resulted in
several compounds, which took up three trimethylsilyl
groups after treatment with MSTFA. Transesterification of
II with sodium methoxide in methanol resulted in the for-
mation of a hydroxy methyl ester. These results are consist-
ent with a lactone structure containing either an oxo or an
epoxy group and two double bonds in II.
Compound I took up 3 equiv. of hydrogen, was silylated
twice after reduction, and also formed a hydroxy methyl
ester after transesterification. These derivatives of I were
identified in the derivatized extracts. Compound I therefore
seems to have a structure similar to that of II, lacking the
oxo or epoxy group, but with an additional double bond.
Compound II thus seems to be the oxidized form of I.
NMR experiments were performed with the purified
sample of II. Since the amount of isolated II was less than
1 mg, only one- and two-dimensional 1H NMR experi-
ments were performed (Figure 2). Each of the double bonds
contained one proton. The isolated proton (δ ϭ 5.6 ppm)
seems to be in an α-position next to a carbonyl group, be-
cause of the low-field shift. The signal at δ ϭ 4.8 ppm is a
triplet and the proton appears to be located at a double
bond next to a CH2 group. The diastereotopic oxymethy-
lene hydrogen atoms (δ ഠ 4.2 ppm) are isolated, as no
further coupling to other protons was detected. Finally, a
dd at δ ϭ 2.8 ppm was interpreted as a signal of an oxirane
proton next to another CH2 group.
1
Figure 2. H NMR (400 MHz, C6D6, 25 °C) of II
Scheme 1. Structures of I, II, and III
lylic oxidation with SeO2/tBHP yielded a mixture of methyl
12-hydroxyfarnesoates (2) (54%).[6] The esters 2 were sapon-
ified and the acids were cyclized under Corey/Nicolaou
conditions with PPh3 and dithiodipyridine in boiling tolu-
ene (33%).[7] A mixture of three major macrolides 3 in a
ratio of (Z,E,E)-3/(Z,Z,E)-3/(E,E,E)-3 ϭ 41:33:26 was ob-
tained, accompanied by minor amounts of other regioiso-
mers.
Scheme 2. a) PDC, dichloromethane, 0 °C to 25 °C; b) MnO2,
KCN, HOAc, MeOH; c) SeO2, tBHP, dichloromethane, 0Ϫ25 °C;
d) KOH, MeOH, H2O, 50 °C; e) PPh3, (C5H4NS)2, toluene, 25 °C;
f) toluene, reflux
From these data it was concluded that both I and II are
13-membered macrolides, derived from ω-oxidized farne-
soic acid (Scheme 1). The location of the epoxy group was
Chromatographic purification of the crude mixture of 3
uncertain, so structure III was also consistent with the ob- and subsequent NOESY experiments on the isolated prod-
tained data. ucts allowed the configurations of the isomers to be deter-
To verify the suggested structures and to determine the mined. The presence of coupling between an olefinic proton
configurations of their double bonds, a combinatorial syn- and the neighboring CH3 group showed that double bond
thesis commencing from the isomeric mixture of farnesols to possess (Z) configuration, the absence of coupling
was carried out (Scheme 2). Farnesol was quantitatively ox- characterizing the (E) configuration. Pure (Z,E,E)-3 and a
idized to farnesal with PDC. After MnO2/KCN/MeOH oxi- mixture of inseparable (Z,Z,E)- and (E,E,E)-3 were thus
dation and esterification to methyl farnesoate (75%),[5] al- obtained.
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Eur. J. Org. Chem. 2003, 1337Ϫ1342

Niaviolides, New Macrocyclic Sesquiterpenes
FULL PAPER
Because of the moderate yield of the cyclization by the
CoreyϪNicolaou procedure, other macrolactonization
methods were tried. Mukaiyama[8] prepared macrolides di-
rectly from their ω-hydroxycarboxylic acids by the use of a
combination of 4-(trifluoromethyl)benzoic anhydride, a
catalytic amount of active titanium() salts, and chlorotri-
methylsilane. These milder conditions furnished only a low
yield (12%) of the same macrolides. Kitagawa and co-work-
ers used NaH in toluene.[9] They also synthesized macrol-
ides derived from (E,E)-farnesol, but with the carbonyl
group at C-12 rather than at the C-1 position as in our
work. Again, the yield of 3 was low (9%). All three methods
showed different compositions of the three isomers. In es-
sence, in comparison with the Corey/Nicolaou method,
only minor amounts of the desired (E,E,E)-3 could be ob-
tained by the other methods [(Z,E,E)-3/(Z,Z,E)-3/(E,E,E)-
3: CoreyϪNicolaou: 41:33:26; Kitagawa: 62:27:11; Mukai-
yama: 15:62:23].
Scheme 4. Enantioselective synthesis of (S,S)-4: A) Ti(OiPr)4, ()-
(ϩ)-diisopropyl tartrate, tBHP, dichloromethane, Ϫ20 °C; b) KOH,
MeOH, H2O; c) PPh3, (C5H4NS)2, toluene, 25 °C; d) toluene, reflux
Gas chromatographic analysis of the synthetic epoxy-
macrolide (S,S)-4 and the natural androconial extract on a
chiral cyclodextrin phase showed that the natural epoxynia-
violide (4) possesses the (S,S) configuration. The natural
compound is enantiomerically pure, while the synthetic
compound had an ee of 91% (Figure 3).
Comparison of the fragmentation patterns and the reten-
tion times of the synthetic products with those of the natu-
ral compound showed I to be identical with (E,E,E)-3, for
which we propose the name niaviolide. Pure niaviolide
[(E,E,E)-3] was then obtained by the described synthetic
route by starting from (E,E)-farnesol instead of an iso-
meric mixture.
Scheme 3. Conversion of niaviolide [(E,E,E)-3] into epoxyniaviol-
ides [(2E,6E,10R/S,11R/S)-4] and [(2E,6R/S,7R/S,10E)-4] by use of
mCPBA in dichloromethane, 0 °C
The proposed structures II or III were synthesized by
epoxidation of (E,E,E)-3 with mCPBA. Because of steric
hindrance and electronic effects, the 10,11-double bond was
attacked preferentially, forming II as the main product
(75%), while the 6,7-epoxide III was formed only in minor
amounts. No product containing an epoxy group in the 2,3-
position was obtained. This is in agreement with previous
findings on the epoxidation of methyl farnesoate.[10] Com-
parison of the analytical data for the synthetic and natural
products confirmed our initial considerations and showed
compound II to be the (2E,6E,10R/S,11R/S)-macrolide 4,
which we propose to call epoxyniaviolide.
Figure 3. Gas chromatographic investigation of natural and syn-
thetic 4 on a chiral Hydrodex-6-TBDMS stationary phase, T ϭ 125
°C isotherm; A) isolated natural 4, B) co-injection of natural and
rac-4, C) rac-4, D) (S,S)-4
To the best of our knowledge, the niaviolides are the first
sesquiterpenoid α,ω-macrolides to be found in nature.
Further analysis showed that 3 and 4 occur in both andro-
conial organs, the hindwing patches as well as in the hair-
pencils.
Finally, the absolute configuration of II was determined.
Enantiomers of 4 were synthesized by Sharpless epoxid-
ation (Scheme 4).[11] The (S,S)-oxirane 5 was obtained from
Conclusion
The structure of two previously unknown terpenoid mac-
the already synthesized methyl 12-hydroxyfarnesoate (2) in rolides present in the androconial extract of the African
96% yield by use of ()-(ϩ)-diisopropyl tartrate, Ti(OiPr)4, danaine butterfly Amauris niavius was elucidated by the use
and tBHP in the presence of molecular sieves, according to of microreactions and NMR and GC/MS experiments and
the Sharpless mnemonic scheme.[11] Saponification confirmed by synthesis. Niaviolide (3) is derived from ω-
and further cyclization of the (S,S)-acid
6 under oxidized (E,E,E)-farnesoic acid, whereas the more highly
CoreyϪNicolaou conditions furnished the macrolide (S,S)- oxidized macrolide 4 (epoxyniaviolide) has the same carbon
4 in 25% yield.
skeleton, but contains an epoxide in the 10,11-positions.
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Eur. J. Org. Chem. 2003, 1337Ϫ1342

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K. Stritzke, S. Schulz, M. Boppre
FULL PAPER
Methyl (2E,6E)-Farnesoate:[5] (E,E)-Farnesal (2.62 g, 11.8 mmol)
was added dropwise to a suspension of KCN (3.4 g, 51.8 mmol),
acetic acid (0.8 mL, 15.8 mmol), activated MnO2 (19.5 g,
224 mmol), and methanol (45 mL). The reaction mixture was
stirred at room temperature for 24 h. This mixture was then filtered
through a short silica plug and the solvent was removed. The resi-
due was diluted with water (50 mL) and extracted three times with
diethyl ether. The combined organic extracts were dried with
MgSO4 and the solvent was evaporated. The crude product (2.24 g,
8.9 mmol, 75%) was sufficiently pure for characterization and
further work. NMR data are identical to the reported data.[16] MS
(70 eV): m/z (%) ϭ 41 (43), 69 (100), 79 (10), 81 (27), 114 (43),
121 (33).
The absolute configuration of the naturally occurring mac-
rolide 4 was determined as (S,S). Interestingly, epoxidation
of terpenoids is also used by other danaines to produce
scent compounds.[12] While the function of the compounds
remains to be elucidated, their uniqueness and occurrence
in the androconia indicate a prominent role in the complex
courtship communication of A. niavius.
Experimental Section
Methyl (2E,6E,10E)-12-Hydroxyfarnesoate [(E,E,E)-2]:[6] A solu-
tion of methyl (E,E)-farnesoate (1.75 g, 6.9 mmol) in dry dichloro-
methane (4 mL) was added dropwise to an ice-cold mixture of SeO2
(420 mg, 3.5 mmol), anhydrous tert-butyl hydroperoxide solution
(4 mL, 22 mmol, 5.5  in nonane), and dry dichloromethane
(100 mL). The mixture was stirred in the dark overnight while being
allowed to warm to room temperature. It was then diluted with
dichloromethane (50 mL) and washed with saturated NaHCO3
solution, followed by brine. The organic layer was dried with
MgSO4 and filtered, and the dichloromethane was removed. Etha-
nol (20 mL) and NaBH4 (26 mg, 0.8 mmol) were added to the resi-
due at 0 °C, and the mixture was stirred for 45 min. It was then
concentrated in vacuo, and water (50 mL) was added to the residue.
The aqueous phase was extracted three times with diethyl ether.
The combined ethereal extracts were dried with MgSO4 and the
solvent was removed. The crude product was purified by flash chro-
matography on silica, with pentane/diethyl ether (4:1) as eluent.
Some of the methyl (E,E)-farnesoate starting material (320 mg,
1.3 mmol, 18%) could also be reisolated. Yield: 1.0 g (3.7 mmol,
54%; 66% excluding recovered starting material). NMR data ident-
ical to reported data.[6]
General Remarks: 1H and 13C NMR spectra were obtained with
Bruker AC 200 and AMX 400 instruments. CDCl3 was used in
NMR experiments if not mentioned otherwise; the internal stand-
ard was tetramethylsilane or solvent (CD2Cl2, δ ϭ 5.32 and
53.7 ppm). GC-MS was carried out with a HewlettϪPackard mo-
del 5973 mass-selective detector connected to a HewlettϪPackard
model 6890 gas chromatograph. Analytical GLC analyses were per-
formed with a CE instruments GC 8000 gas chromatograph
equipped with a flame ionization detector and split/splitless injec-
tion. The optical rotatory power was measured with a Dr Kernchen
Propol Digital Automatic polarimeter. Chiral GC separations were
performed on a hydrodex-6-TBDMS phase (50 m, 0.25 mm i.d.,
Macherey & Nagel). All reactions were carried out under nitrogen
in oven-dried glassware. Dry solvents: dry toluene was distilled
from Na, dichloromethane from CaH2, THF from K and Na. All
other chemicals were commercially available (Fluka, Aldrich) and
were used without further treatment. All reactions were monitored
by thin layer chromatography (TLC) carried out on
MachereyϪNagel Polygram SIL G/UV254 silica plates and viewed
by use of heat gun treatment with 10% molybdatophosphoric acid
in ethanol. Column chromatography was performed on Merck sil-
ica gel 60 (70Ϫ200 mesh). Preparative GC was performed with a
CarloϪErba Fractovap gas chromatograph equipped with a 2-m
glass column (2 mm i.d.) filled with Carbowax 20 M. Nitrogen was
used as carrier gas. Butterflies were collected in Kenya, mostly near
Kwale (Coast Province). Additional butterflies were bought from
Kipepo Project, Kenya. The hairpencils were protruded by manual
pressure, removed with forceps, touched on absorbent paper to re-
move excess hemolymph and stored under pentane (Merck, Supra-
solv) in vials. In Germany, samples were stored at Ϫ70 °C until
workup. Wing patches were cut out with scissors and treated in the
same way.
(2E,6E,10E)-12-Hydroxyfarnesenic Acid: Methyl hydroxyfarneso-
ate (2, 300 mg, 1.1 mmol) was dissolved in methanol (20 mL), and
KOH solution (3 mL, 2 ) was added. The mixture was stirred at
50 °C for 3 d. After concentration in vacuo, brine (25 mL) was
added. The mixture was extracted once with diethyl ether, and the
aqueous layer was then acidified with HCl (1 ). After extraction
with diethyl ether (three times), the combined organic phases were
dried with MgSO4 and the solvent was evaporated to yield the
hydroxy acid, sufficiently pure for the next step (186 mg, 0.7 mmol,
64%). 1H NMR: δ ϭ 1.61 (s, 3 H, CH3), 1.66 (s, 3 H, CH3),
2.01Ϫ2.23 (m, 8 H), 2.17 (s, 3 H, CH3), 3.99 (s, 2 H, CH2),
5.08Ϫ5.14 (m, 1 H, CH), 5.35Ϫ5.39 (m, 1 H, CH), 5.68 (s, 1 H,
CH) ppm. 13C NMR: δ ϭ 13.7 (q), 16.0 (q), 19.1 (q), 25.8 (t), 26.0
(t), 39.2 (t), 41.1 (t), 68.8 (t), 115.1 (d), 123.0 (d), 125.8 (d), 134.7
(s), 135.9 (s), 162.8 (s), 171.4 (s) ppm. C15H24O3 (252.4): calcd. C
71.39, H 9.59; found C 71.42, H 9.42.
Microreactions: Silylations were performed by addition of MSTFA
(20 µL) to a CD2Cl2 solution of II (about 20 µL) in a closed-cap
vial. After the mixture had been heated at 50 °C for 30 min, the
solvent and excess MSTFA were removed with a gentle stream of
nitrogen. The residue was taken up in CH2Cl2 and analyzed by GC-
MS. Reduction with LAH[13] and transesterification with sodium
methoxide[14] were performed as described earlier.
(2E,6E,10E)-Niaviolide [(E,E,E)-3]: (2E,6E,10E)-12-Hydroxyfarne-
soic acid (150 mg, 0.6 mmol) was added at room temperature to a
solution of 2,2Ј-dithiodipyridine (230 mg, 1 mmol) and tri-
phenylphosphane (270 mg, 1 mmol) in dry toluene (1 mL). The
mixture was stirred for 5 h and was then diluted with dry toluene
(10 mL). This solution was added by syringe pump over 15 h to
(2E,6E)-Farnesal: (2E,6E)-Farnesol (1, 4 mL, 16 mmol) was dis-
solved in dichloromethane (140 mL) and cooled to 0 °C. Pyridin-
ium dichromate (9 g, 24 mmol) was then added in portions and the
mixture was stirred for 24 h. Afterwards, diethyl ether (100 mL) boiling toluene (150 mL) and the mixture was then boiled for ad-
was added and the reaction mixture was filtered through a short ditional 10 h. The toluene was removed in vacuo and the crude
silica plug. The solvent was removed and the product was obtained
quantitatively and sufficiently pure for the next step. NMR data
are consistent with reported data.[15] MS (70 eV): m/z (%) ϭ 41
(53), 69 (100), 81 (22), 84 (56), 93 (10), 136 (10), 220 (3).
product was purified by silica flash chromatography (pentane/di-
ethyl ether, 19:1). Yield: 43 mg (0.2 mmol, 33%). 1H NMR
(CD2Cl2): δ ϭ 1.35 (s, 3 H, CH3), 1.47 (s, 3 H, CH3), 1.95 (d, J ϭ
1 Hz, 3 H, CH3,), 2.00Ϫ2.42 (m, 8 H), 4.46 (d, J ϭ 1 Hz, 2 H,
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Niaviolides, New Macrocyclic Sesquiterpenes
FULL PAPER
˚
CH2), 4.91 (t, J ϭ 7 Hz, 1 H, CH), 5.14 (m, 1 H, CH), 5.67 (m, vated molecular sieves (50 mg, 4 A) and dry dichloromethane
1 H, CH) ppm. 13C NMR: δ ϭ 13.7 (q), 14.4 (q), 17.9 (q), 22.6 (t), (5 mL). The mixture was cooled to Ϫ20 °C, and tert-butyl hydro-
26.1 (t), 39.5 (t), 40.9 (t), 68.5 (t), 118.2 (d), 123.1 (d), 125.6 (d), peroxide solution (0.38 mL, 2.2 mmol, 5.5  anhydrous in nonane)
129.9 (s), 135.4 (s), 159.6 (s), 166.9 (s) ppm. MS (70 eV): m/z (%) ϭ
was added. After the mixture had been stirred for 20 min, (E,E,E)-
39 (25), 41 (24), 67 (23), 82 (100), 83 (14), 93 (27), 107 (33), 121 2 (280 mg, 1.0 mmol) in dry dichloromethane (0.5 mL) was added.
(42). HRMS: calcd. for C15H22O2 234.1620; found 234.1612.
The solution was stirred at Ϫ20 °C for 3 h. Water (0.5 mL) was
then added at 0 °C and the mixture was stirred at room temperature
for 45 min. An NaOH solution (0.8 mL, 30%) saturated with NaCl
was added, and the phases separated. The aqueous phase was ex-
tracted three times with dichloromethane and the combined or-
ganic layers were dried with MgSO4. After removal of the solvent,
the crude product was purified by flash chromatography (pentane/
diethyl ether, 1:1), providing pure epoxyfarnesoate (S,S)-5. Yield:
270 mg (0.96 mmol, 96%). 1H NMR: δ ϭ 1.28 (s, 3 H, CH3),
1.61Ϫ1.73 (m, 2 H, CH2), 1.63 (d, J ϭ 1 Hz, 3 H, CH3), 2.07Ϫ2.21
(m, 6 H), 2.16 (d, J ϭ 1 Hz, 3 H, CH3), 3.01 (t, J ϭ 6 Hz, 1 H,
CH), 3.55 (d, J ϭ 12 Hz, 1 H, CH2), 3.57 (d, J ϭ 12 Hz, 1 H, CH2),
3.69 (s, 3 H, CH3), 5.13Ϫ5.14 (m, 1 H, CH), 5.67 (d, J ϭ 1 Hz,
1 H, CH) ppm. 13C NMR: δ ϭ 14.2 (q), 16.0 (q), 18.8 (q), 25.8 (t),
26.7 (t), 36.2 (t), 40.7 (t), 50.8 (q), 59.7 (d), 60.8 (s), 65.4 (t), 115.3
(d), 123.7 (d), 135.1 (s), 159.8 (s), 167.2 (s) ppm. [α]2D0 ϭ Ϫ11.4 (c ϭ
2.2, diethyl ether). C16H26O4 (282.4): calcd. C 68.06, H 9.28; found
C 67.84, H 9.29.
Mixture of Niaviolide Isomers: The reaction was performed as de-
scribed for (E,E,E)-3, ω-hydroxyfarnesoic acid derived from the
isomeric mixture of farnesol being used as starting material. Yield:
116 mg [0.31 mmol, 31%; mixture of (E,E,E)-3/(Z,Z,E)-3/(Z,E,E)-
3 ϭ 26:33:41].
(2Z,6Z,10E)-Niaviolide [(Z,Z,E)-3]: Compound (Z,Z,E)-3 was ob-
tained as an inseparable mixture with (E,E,E)-3. 1H NMR
(CD2Cl2): δ ϭ 1.62 (s, 3 H, CH3), 1.62 (d, J ϭ 1 Hz, 3 H, CH3),
1.81 (d, J ϭ 1 Hz, 3 H, CH3), 2.00Ϫ2.42 (m, 8 H), 4.42 (s, 2 H,
CH2), 5.04 (t, J ϭ 7 Hz, 1 H, CH), 5.46 (dt, J ϭ 2, J ϭ 7 Hz, 1 H,
CH), 5.51 (d, J ϭ 1 Hz, 1 H, CH) ppm. 13C NMR: δ ϭ 15.4 (q),
23.3 (q), 25.6 (q), 27.2 (t), 28.2 (t), 31.7 (t), 35.1 (t), 67.8 (t), 117.9
(d), 126.2 (d), 129.1 (d), 130.8 (s), 134.2 (s), 156.4 (s), 166.9 (s)
ppm. MS (70 eV): m/z (%) ϭ 39 (49), 41 (49), 53 (33), 54 (29), 55
(24), 67 (46), 68 (32), 77 (27), 79 (37), 80 (32), 81 (24), 82 (100), 83
(22), 91 (33), 93 (68), 94 (26), 105 (28), 107 (51), 111 (40), 121
(95), 135 (60), 166 (21) ppm. HRMS: calcd. for C15H22O2 234.1620;
found 234.1606.
(2E,6E,10S,11S)-10,11-Epoxy-12-hydroxyfarnesoic Acid [(S,S)-6]:
Methyl epoxyfarnesoate [(S,S)-5, 100 mg, 0.36 mmol] was dissolved
(2Z,6E,10E)-Niaviolide [(Z,E,E)-3]: 1H NMR (CD2Cl2): δ ϭ 1.41 in methanol (7 mL), and KOH solution (1 mL, 2 ) was added.
(s, 3 H), 1.52 (s, 3 H), 1.81 (d, J ϭ 1 Hz, 3 H, CH3), 1.90Ϫ2.13 (m, The mixture was stirred at 60 °C overnight and concentrated in
8 H), 4.35 (s, 2 H, CH2), 4.85Ϫ4.92 (m, 1 H, CH), 5.03Ϫ5.06 (m, vacuo, and brine (4 mL) was added to the residue. The mixture was
1 H, CH), 5.69 (s, 1 H, CH) ppm. 13C NMR (CD2Cl2): δ ϭ 14.2 extracted once with diethyl ether, and the aqueous layer was then
(q), 14.2 (q), 22.9 (t), 23.9 (q), 25.6 (t), 31.8 (t), 39.6 (t), 66.5 (t), acidified with HCl (1 ). After extraction with diethyl ether (three
118.0 (d), 123.5 (d), 125.0 (d), 129.1 (s), 130.2 (s), 156.7 (s), 166.6 times) the combined organic phases were dried with MgSO4 and
(s) ppm. MS (70 eV): m/z (%) ϭ 39 (36), 41 (33), 53 (34), 54 (18),
the solvent was evaporated to yield the crude hydroxy acid (S,S)-6
55 (21), 67 (36), 68 (31), 79 (26), 80 (35), 82 (88), 91 (22), 93 (43),
(91 mg, 0.34 mmol, 94%), which was directly used in the next step.
105 (30), 107 (38), 111 (42), 121 (100), 151 (24), 166 (50) ppm. 1H NMR: δ ϭ 1.28 (s, 3 H, CH3), 1.62Ϫ1.72 (m, 2 H), 1.63 (s, 3 H,
HRMS: calcd. for C15H22O2 234.1620; found 234.1603.
CH3), 2.00Ϫ2.29 (m, 6 H), 2.16 (d, J ϭ 1 Hz, 3 H, CH3), 2.91Ϫ3.13
(m, 1 H, CH), 3.57 (d, J ϭ 12 Hz, 1 H, CH2), 3.68 (d, 1 H, CH2),
4.98 (s, 1 H, OH), 4.97Ϫ5.30 (m, 2 H, CH, OH), 5.68 (s, 1 H, CH)
ppm. 13C NMR: δ ϭ 14.1 (q), 19.0 (q), 20.9 (q), 25.7 (t), 26.5 (t),
36.2 (t), 40.9 (t), 60.0 (d), 61.5 (s), 65.3 (t), 115.2 (d), 123.3 (d),
135.1 (s), 162.3 (s), 170.0 (s) ppm.
(2E,6E,10R/S,11R/S)-Epoxyniaviolide [(2E,6E,10R/S,11R/S)-4]: A
solution of (E,E,E)-3 (20 mg, 0.08 mmol) in dichloromethane
(2 mL) was added to a mixture of m-chloroperbenzoic acid (33 mg,
0.1 mmol) in dichloromethane (5 mL) at 0 °C. The reaction was
monitored by TLC. After completion, saturated NaHCO3 solution
(4 mL) was added. The layers were separated and the aqueous one
was extracted three times with dichloromethane. The combined or-
ganic extracts were dried with MgSO4 and the solvent was re-
moved. The crude product was purified by flash chromatography
with pentane/diethyl ether (9:1) as eluent. The minor 6,7-epoxide
could not be isolated. Yield: 16 mg (0.06 mmol, 75%). 1H NMR
(C6D6): δ ϭ 1.11 (s, 3 H, CH3), 1.14Ϫ1.20 (m, 1 H, CH2), 1.32 (s,
3 H, CH3), 1.38Ϫ1.46 (m, 1 H, CH2), 1.77Ϫ1.82 (m, 2 H, CH2),
1.84Ϫ2.17 (m, 4 H), 2.00 (d, J ϭ 1 Hz, 3 H, CH3), 2.86 (dd, J ϭ
2, J ϭ 8 Hz, 1 H, CH), 4.18 (d, J ϭ 12 Hz, 1 H, CH2), 4.29 (d, J ϭ
12 Hz, 1 H, CH2), 4.76 (br. t, J ϭ 3 Hz, 1 H, CH), 5.64 (s, 1 H,
CH) ppm. 13C NMR (C6D6): δ ϭ 14.6 (q), 14.8 (q), 17.5 (q), 24.7
(t), 25.8 (t), 38.1 (t), 40.2 (t), 57.5 (d), 65.0 (t), 118.8 (d), 126.3 (d),
167.1 (s) ppm. MS (70 eV): m/z (%) ϭ 39 (27), 41 (28), 43 (23), 55
(29), 67 (20), 81 (27), 82 (100), 93 (35). HRMS: calcd. for C15H22O3
250.1569; found 250.1585. MS data for the 6,7-epoxide III (70 eV):
m/z (%) ϭ 39 (34), 41 (41), 43 (32), 53 (23), 55 (29), 67 (27), 69
(24), 77 (16), 79 (24), 81 (37), 82 (100), 91 (21), 93 (27), 105 (21),
107 (21), 109 (20), 121 (20), 133 (22), 147 (28).
(؉)-(2E,6E,10S,11S)-Epoxyniaviolide [(S,S)-4]: The preparation
was performed analogously to that of (E,E,E)-1, starting from
(S,S)-epoxyhydroxyfarnesoic acid [(S,S)-6]. Yield: 35 mg
(0.15 mmol, 25%). For NMR and MS data see (2E,6E,10R/S,11R/
S-4). HRMS: calcd. for C15H22O3 250.1569; found 250.1579. The
ee values were determined by GC on a chiral hydrodex-6-TBDMS
phase, operated isothermally at 125 °C; Tr(S,S) ϭ 86.89 min,
Tr(R,R) ϭ 86.65 min. ee ϭ 91%. [α]2D0 ϭ ϩ3.0 (c ϭ 1, diethyl ether).
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft and
the Fonds der chemischen Industrie is gratefully acknowledged, as
well as the Kenyan research permit to M. B. We thank Prof. W.
Francke for many helpful discussions in the early stage of the pro-
ject.
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