Structure elucidation and synthesis of dioxolanes emitted by two triatoma species (Hemiptera: Reduviidae)

Article abstract of DOI:10.1021/np100748r

Volatiles from the metasternal glands of two species of true bugs of the Triatominae subfamily, Triatoma brasiliensis and Triatoma infestans, were analyzed by SPME-GC/MS. Two sets of new natural products were found: (4S,5S)- and (4R,5R)-2,2,4-triethyl-5-methyl-1,3-dioxolane (1) (major component) and (4S*,5S*)-2,4-diethyl-2,5-dimethyl-1,3-dioxolane (2) (trace component), (2R/S,4S,5S)- as well as (2R/S,4R,5R)-4-ethyl-5-methyl-2-(1- methylethyl)-1,3-dioxolane (3) (minor component), (2R/S,4S*,5S*)-4- ethyl-5-methyl-2-(1-methylpropyl)-1,3-dioxolane (4) (trace component), and (2R/S,4S*,5S*)-4-ethyl-5-methyl-2-(2-methylpropyl)-1,3-dioxolane (5) (trace component). Syntheses of optically active 1 and 3 were carried out by reacting pure enantiomers of 2,3-pentanediol with 3-pentanone or 2-methylpropanal. The preparation of pure stereoisomers of 2,3-pentanediol involved a novel key step for the synthesis of secondary alcohols: the reduction of a carboxylic ester by means of DIBAH and in situ alkylation of the intermediate by Grignard reaction at low temperature. Starting from the pure enantiomers of methyl lactate, all four stereoisomers of 2,3-pentanediol were synthesized and transformed to the corresponding isomers of 1 and 2. Relative configurations of the natural products and enantiomeric compositions of naturally occurring 1 and 2 were determined by comparison of their mass spectra and gas chromatographic retention times (co-injection) with those of authentic reference samples.

Full text of DOI:10.1021/np100748r

ARTICLE
pubs.acs.org/jnp
Structure Elucidation and Synthesis of Dioxolanes Emitted by Two
Triatoma Species (Hemiptera: Reduviidae)
B. Bohman,†,# A. Tr€oger,‡ S. Franke,‡,4 M. G. Lorenzo,§ W. Francke,‡ and C. R. Unelius*,†,^
†School of Natural Sciences, Linnaeus University, SE-391 82 Kalmar, Sweden
‡Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany
§Laboratꢀorio de Triatomíneos e Epidemiologia da Doenc-a de Chagas, Centro de Pesquisas Renꢀe Rachou/FIOCRUZ, 30.190-002,
Belo Horizonte, Minas Gerais, Brazil
S Supporting Information
b
ABSTRACT: Volatiles from the metasternal glands of two
species of true bugs of the Triatominae subfamily, Triatoma
brasiliensis and Triatoma infestans, were analyzed by SPME-GC/
MS. Two sets of new natural products were found: (4S,5S)- and
(4R,5R)-2,2,4-triethyl-5-methyl-1,3-dioxolane (1) (major com-
ponent) and (4S*,5S*)-2,4-diethyl-2,5-dimethyl-1,3-dioxolane
(2) (trace component), (2R/S,4S,5S)- as well as (2R/S,4R,5R)-4-ethyl-5-methyl-2-(1-methylethyl)-1,3-dioxolane (3) (minor
component), (2R/S,4S*,5S*)-4-ethyl-5-methyl-2-(1-methylpropyl)-1,3-dioxolane (4) (trace component), and (2R/S,4S*,5S*)-
4-ethyl-5-methyl-2-(2-methylpropyl)-1,3-dioxolane (5) (trace component). Syntheses of optically active 1 and 3 were carried
out by reacting pure enantiomers of 2,3-pentanediol with 3-pentanone or 2-methylpropanal. The preparation of pure
stereoisomers of 2,3-pentanediol involved a novel key step for the synthesis of secondary alcohols: the reduction of a carboxylic
ester by means of DIBAH and in situ alkylation of the intermediate by Grignard reaction at low temperature. Starting from the
pure enantiomers of methyl lactate, all four stereoisomers of 2,3-pentanediol were synthesized and transformed to the
corresponding isomers of 1 and 2. Relative configurations of the natural products and enantiomeric compositions of naturally
occurring 1 and 2 were determined by comparison of their mass spectra and gas chromatographic retention times (co-injection)
with those of authentic reference samples.
n rural areas of the Southern Cone of South America and
Northeastern Brazil, Triatoma infestans and Triatoma brasilien-
1-butanol, (R)-4-methyl-1-heptanol, and (R)-1-phenylethanol,
together with the same unknown compound that was found in T.
infestans. The ketone, chiral alcohols, and the unknown com-
pound triggered electrophysiological responses, i.e., EAD deflections,
in the antennae of male T. brasiliensis.6 In a recent short communica-
tion we reported the identification of the unknown as 2,2,4-triethyl-5-
methyl-1,3-dioxolane (1), which in T. brasiliensis is produced as a
mixture of (4S,5S)-1 and (4R,5R)-1 in a ratio of about 4:1.7
Further investigations have now revealed that a number of
additional acetals are produced in T. brasiliensis. Here we present
the synthesis of highly pure stereoisomers of 1, as well as the
structure elucidation and synthesis of four new naturally occurring
alkylated dioxolanes (2ꢀ5) found in theMGs ofthese triatomines.
I
sis (Hemiptera: Reduviidae) are main vectors of Chagas disease,
the principal health and socioeconomic burden caused by a
parasitic infection in Latin America.1ꢀ3 Triatomine bugs fre-
quently invade human dwellings, where they develop colonies
through blood-feeding on humans and domestic animals. In this
context, the insects can transmit Trypanosoma cruzi, a parasite
that acts as the etiological agent of Chagas disease. Since no
vaccine is available for human immunization against T. cruzi and
no effective treatment exists to cure chronic patients, the
elimination of triatomine vectors is essential for Latin American
national health programs.
Volatile constituents of the metasternal glands (MGs) of
T. infestans, Rhodnius prolixus, and T. brasiliensis have been sug-
gested to be emitted during copulation and to play a role in sexual
communication.4ꢀ6 Manrique et al. identified five volatile com-
pounds, predominantly 3-pentanone and short-chain alcohols,
in the secretion produced by the MGs of T. infestans.4 The second
most abundant compound of this secretion was reported
as unknown, although its mass spectrum was published. During
studies on volatiles from MGs of T. brasiliensis,6 3-pentanone
was again identified as a major component, as well as (S)-2-methyl-
Received: October 17, 2010
Published: April 12, 2011
r
Copyright
2011 American Chemical Society and
690
dx.doi.org/10.1021/np100748r J. Nat. Prod. 2011, 74, 690–694
American Society of Pharmacognosy
|

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’ RESULTS AND DISCUSSION
All four stereoisomers of 1 were synthesized individually and
were easily distinguished by enantioselective GC. The order of
elution was (4R,5R); (4S,5S); (4S,5R); (4R,5S) with significant
differences in R-values between the cis-/trans-isomers: R tr4S,5S
/
tr4R,5R = 1.04, R tr4S,5R/tr4S,5S = 1.54, and R tr4R,5S/tr4S,5R = 1.05.
The two trans-isomers (4S,5S)-1 and (4R,5R)-1 were found to be
present in the glands in a ratio of about 4:1.
In addition to 1, a trace of trans-2,4-diethyl-2,5-dimethyl-1,
3-dioxolane (2) was identified. The mass spectrum of dioxolane 2
(Figure 1) showed the same principal fragmentation pattern as 1.7
Mass spectra and gas chromatographic retention times of syn-
thetic samples of (4S*,5S*)-1 and (2R/S,4S*,5S*)-2 matched the
data of the natural products.
Figure 1. EI-mass spectrum (70 eV) of (2R/S,4S*,5S*)-2,4-diethyl-2,5-
dimethyl-1,3-dioxolane (2).
During our investigation of volatile components of metaste-
rnal glands of T. brasiliensis, we identified an additional set of
compounds with retention times (GC) and mass spectrometric
fragmentation patterns very similar to those of 1 and 2. On the
achiral polar stationary phase, two peaks in a ratio of about 1:1
with virtually identical mass spectra, indicative of a pair of
diastereomers, were found. On a polar column the Kovats indices
were 1116 and 1120, respectively, even lower than that of 1,
which was 1156.6 The 70 eV EI-mass spectrum (Figure 2)
showed a base peak at m/z 115, while the highest visible fragment
appeared at m/z 157. On the basis of the experience gained
during our structure assignment of 1, we postulated a 1,3-
dioxolane structure for the target compound. Proposing a
molecular mass of M = 158, the signal at m/z 157 = (M ꢀ
H)þ suggested a dioxolane formed from an aldehyde.8 As a
consequence, m/z 115 was assumed to be formed by loss of a
propyl unit upon R-cleavage at C2. Thus, the parent carbonyl
compound of the proposed dioxolane should be either butanal or
2-methylpropanal. Two less abundant but diagnostic signals, at
m/z 114 (Mþ ꢀ 44) and m/z 100 (Mþ ꢀ 58), indicated the
same substitution pattern at C4 and C5 as in 1.7,9 Since isobutyric
acid is known as a volatile from Brindley’s glands in T. infestans,4
it was reasonable to assume that the corresponding aldehyde
could be produced by this closely related species. Using synthetic
compounds as reference samples, our hypothesis, that the target
acetals were 4-ethyl-5-methyl-2-(1-methylethyl)-1,3-dioxolanes
(3), proved to be correct.
Of the eight possible stereoisomers of 3, only those showing
trans-configuration at positions 4/5 were found in the MGs.
Ratios varied between the samples, but all contained mixtures of
C2-epimers, and (2R/S,4S,5S)-3 and (2R/S,4R,5R)-3 were the
most abundant ones in the glands. Due to very similar retention
times and coelution with other compounds in the biological
samples, the assignment of absolute configuration of the trans-
isomers is tentative, but a general excess of (2R/S,4S,5S)-3 was
observed, which is in line with the established configuration of 1.
In addition to 3, trace amounts of 4-ethyl-5-methyl-2-(1-
methylpropyl)-1,3-dioxolane (4) and 4-ethyl-5-methyl-2-(2-
methylpropyl)-1,3-dioxolane (5) were identified. Again, as the
substances showed trans-configuration at C4/C5, the general
motif of syn-2,3-pentanediol as a substructure in all acetals was
repeated. The mass spectrometric fragmentation patterns of 4
and 5 resembled that of 3. Mass spectra and gas chromatographic
retention times of synthetic samples corresponded well with data
of the natural products. Due to the minute amounts of the natural
products, the absolute configuration of these acetals could not be
unambigously determined, although it is most likely that the
Figure 2. EI-mass spectrum (70 eV) of (2R/S,4S*,5S*)-4-ethyl-
5-methyl-2-(1-methylethyl-1,3-dioxolane (3).
configuration at the diol part of the acetals follows the general
pattern (major isomer showing (S,S)-configuration).
The absolute configuration of the acetals 1 and 3, found in the
glands, was determined by synthesis and co-injections of pure
stereoisomers. These dioxolanes were prepared from the pure
enantiomers of methyl lactate by a modified method of Lacey et al.10
The decisive novelty in our approach, which reduced the number
of steps, was the Grignard reaction carried out in situ on the
intermediate formed upon DIBAH-mediated reduction at low
temperature, with some similarity to the known procedure for
the transformation of carboxylic esters to alkenes.11
The target compounds were prepared from the two enantiomers
of methyl lactate, which were protected using 3,4-dihydro-2H-
pyran in CH2Cl2 and catalytic amounts of p-TsOH (Figure 4).12
Using DIBAH in toluene,13,14 the resulting tetrahydropyranyl
derivatives were reduced to the corresponding aldehyde equiva-
lents, which were alkylated in situ at low temperature by Grignard
reactions with ethyl magnesium bromide. The THP-protected
2,3-pentanediols were deprotected to the corresponding 2,3-
pentanediols (Figure 3).12
The two diastereomers of 2,3-pentanediol were separated on
silica gel10 and distinguished by their significantly different NMR
spectra.15 Each of the four stereoisomers of 2,3-pentanediol was
transformed to the corresponding dioxolane via standard acid-
catalyzed acetalization,16 yielding pure stereoisomers of 1 and 3
in >95% isomeric purity (Figure 4).
The stereoisomers of 2, 4, and 5 were produced from
cis-2-ethyl-3-methyloxirane and the corresponding carbonyl
compound following the procedure of Blackett et al.7,17
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as the carrier gas. The GC was equipped with a BPX-70 column (30 m ꢁ
0.25 mm i.d., 0.25 μm film, SGE Australia). Enantioselective GC of
synthetic compounds was performed with an HP 5890 GC (Hewlett-
Packard, Palo Alto, CA, USA) equipped with a CYCLOSILB column
(30 m ꢁ 0.25 mm i.d., 0.25 μm film, J & W Scientific, USA).
All chemicals used for the syntheses were purchased from Sigma-Aldrich
(Sweden or Germany), Alfa Aesar (Germany), and Merck (Germany).
Anhydrous solvents were employed when appropriate, and reactions were
carried out under nitrogen when required. Preparation and analysis of
metasternal glands as well as co-injection with peak enhancement, including
the corresponding instrumental setup, were described earlier.4 Column
chromatography (CC) on silica gel was carried out using a medium-
pressure liquid chromatography (MPLC) system from Separo.21
Coupled gas chromatography/mass spectrometry GC/MS was car-
ried out according to Vitta et al.6 or the following protocol: A SPME fiber
(Carboxen/PDMS Supelco, USA) was preheated for 30 min at 140 ꢀC
in the injection port of the GC and subsequently held for 30 min at 50 ꢀC
in the vial with the sample of metasternal glands. The fiber was desorbed
in the injection port for 50 s. Mass spectra were obtained with an HP
5890 GC (Hewlett-Packard, Palo Alto, CA, USA) linked to a VG 70-250
SE double-focusing mass spectrometer (Vacuum Generators, Manche-
ster, UK). GC-conditions: 50 m Optima FFAP (0.25 mm i.d., 0.25 μm
film), 1 min 50 ꢀC, then programmed to 75 ꢀC at a rate of 10 ꢀC/min,
then programmed to 240 ꢀC at a rate of 15 ꢀC/min, 1 min splitless
injection. High-resolution GC/MS analyses, GC/HR-EI-MS (RP:5000)
and GC/CI-MS (isobutane, TP:600), respectively, were carried out
under the same conditions.
Figure 3. Diastereoselective syntheses of 2,3-pentanediol.
Figure 4. Syntheses of dioxolanes.
Gas chromatographic analyses and NMR investigations showed
that the reaction of syn-2,3-pentanediol with 2-methylpropanol
yielded a 1:1-mixture of the C2-epimers of the C4/C5-trans-
configured dioxolane 3. In contrast, erythro-2,3-pentanediol
produced almost exclusively one stereoisomer. These results
may be due to differences in the geometry of the transition state
of the condensation step (alkyl group versus aldehyde proton;
data not shown).
All stereoisomers of 1,3-dioxolanes were formed by reaction of 2,3-
pentanediol with 3-pentanone, butanone, 2-methylpropanal, 2-methyl-
butanal, and 3-methylbutanal, as described below.
Vitta et al. have shown that adult T. brasiliensis produce a
complex blend of volatile compounds in their metasternal glands
and also that the odor blend produced by female MGs induces
males to orientate toward associated airstreams.6 Similar results
have been presented from the related species R. prolixus in two
recent reports,5,18 reinforcing the idea that MG volatiles act as
semiochemicals mediating triatomine sexual behavior. Further-
more, Vitta et al. showed that the attractiveness of female T.
brasiliensis was lost when their MGs were mechanically blocked,
that only males responded to female MG secretions, and that at
least some of the dioxolanes described in this report triggered
antennal responses in males.6 The combination of the results
from behavioral bioassays and EADs suggests the dioxolanes to
be semiochemicals in triatomine bugs.
Interestingly, in contrast to pheromones with structures of
bicyclic acetals19 or spiroacetals20 originating from intramolecular
cyclization of corresponding ketodiols, the new 1,3-dioxolanes are
probably products of intermolecular condensations. If these
compounds, which are detected by the bugs,6 play a role in the
chemical communication of adult triatomines, they could be used
in chemical baits in traps for monitoring or controlling Chagas
disease vectors. Investigations on behavior-mediating activities of
the new 1,3-dioxolanes will be a subject of further studies.
Methyl (R)-2-(Tetrahydropyran-2-yloxy)propanoate. (R)-
Methyl lactate (4.40 g, 42.3 mmol, 96% ee) was dissolved in DCM
(15 mL), and p-TsOH (10 mg) was added. At 0 ꢀC, DHP (5.34 g, 63.5
mmol, 5.77 mL) was added dropwise by syringe while stirring. The
reaction mixture was allowed to warm to rt under continuous stirring.
After 3 h at rt the mixture was washed with saturated aqueous solutions
of NaHCO3 and brine, dried over magnesium sulfate, and concentrated
in vacuo. The crude product (9.77 g) was purified by MPLC, yielding 7.7
g of a mixture of diastereomers in a ratio of 2:1 and 90% purity, which
was used for the next step. EIMS m/z 129 (7), 101 (32), 88 (8), 87 (7),
85 (100), 71 (7), 67 (10), 59 (7), 57 (10), 56 (8), 55 (12), 45 (9), 43 (9),
41 (10). NMR data corresponded to published data.22,23
Methyl (S)-2-(Tetrahydropyran-2-yloxy)propanoate.
(S)-Methyl lactate (8.80 g, 84.6 mmol, 97% ee) was protected in the
same manner as described for methyl (R)-2-(tetrahydropyran-2-yloxy)
propanoate. After MPLC, 9.40 g of product of 84% purity was used for
the next step. For analytical data see methyl (R)-2-(tetrahydropyran-2-
yloxy)propanoate.
(R)-2-(Tetrahydropyran-2-yloxy)-3-pentanol. Magnesium
(6.9 g, 0.29 mol) and some crystals of iodine were added to a round-
bottom flask, which was heated until iodine vapors were formed. After
cooling, THF (100 mL) was added, followed by ethyl bromide (28.5 g,
19.5 mL, 0.27 mol, dropwise addition via syringe) while maintaining
spontaneous reflux to form the Grignard reagent. Subsequently, reflux was
continued for 30 min before the mixture was allowed to cool to rt.
Methyl (R)-2-(tetrahydropyran-2-yloxy)propanoate (7.05 g, 0.034
mol (calcd on 90% purity)) was dissolved in toluene (30 mL), and the
mixture was cooled to ꢀ75 ꢀC. DIBAH (1.5 M in toluene, 28 mL, 0.042
mol) was added dropwise by syringe to the stirred solution, maintaining
the temperature of the reaction mixture at ꢀ70 ꢀC. Stirring was
continued at this temperature for 30 min.
’ EXPERIMENTAL SECTION
General Experimental Procedures. For synthesized com-
1
pounds H NMR and 13C NMR spectra were recorded at 500 and
125 MHz, using a Varian Unity spectrometer. Alternatively, Bruker AV
400 and DRX 500 instruments were used. Tetramethylsilane served as
the internal standard. Mass spectra (70 eV, EI) of synthetic compounds
were obtained with an HP 6890 GC interfaced to an HP 5973 mass
selective detector (Hewlett-Packard, Palo Alto, CA, USA), using helium
To the stirred solution of the product, obtained from the reaction of
methyl (R)-2-(tetrahydropyran-2-yloxy)propanoate and DIBAH, ethyl
magnesium bromide (60 mL, ca. 0.16 mol) was added dropwise
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Journal of Natural Products
ARTICLE
at ꢀ70 ꢀC. The mixture was stirred continuously for 20 min and during
the following 40 min slowly warmed to rt. Subsequently, the mixture was
poured into iceꢀwater, and HCl (aq, 10%) was added until all
precipitate was dissolved. The aqueous phase was extracted with
THF/toluene, and the combined organic layers were washed with
NaOH (1 M), NaOH (2 M), and brine, dried over MgSO4, and
concentrated in vacuo. The residue was distilled under reduced pressure
(bp 22 ꢀC at 32 Torr). The crude product, a slightly yellow oil with a
purity of 87% (7.55 g) containing traces of solvents, was used for the next
step. EIMS m/z 129 (3), 101 (3), 87 (11), 86 (8), 85 (100), 84 (8), 69
(5), 67 (8), 57 (11), 56 (7), 55 (5), 45 (9), 43 (6), 41 (8).
solution of 398 mg (77%, 1.77 mmol) of m-CPBA in 5 mL of DCM the
mixture was stirred at rt for 16 h. Subsequently, 10 mL of hexane was
added, and the solution was condensed into a cooled receiver under
reduced pressure. The DCM/hexane solution of the crude (2R*,3S*)-2-
ethyl-3-methyloxirane was used in the next step without purification.
The whole amount of (2R*,3S*)-2-ethyl-3-methyloxirane obtained in
theprevious step wasdissolved in20 mLof a dry1:1mixture of DCM and
hexane and cooled to 0 ꢀC, and 50 μL (57 mg, 0.40 mmol) of BF3 Et2O
3
was added. After the addition of 113 mg (1.57 mmol) of freshly destilled
2-butanone, thesolution was stirred at rt for12 h. Subsequently, 2 mL of a
saturated aqueous solution of NaHCO3 was added. After stirring for 15
min the organic layer was dried over magnesium sulfate, filtered, and
concentrated. The residue was chromatographed on silica gel using
pentane/diethyl ether (10:1) as the eluent, to give 129 mg (0.82 mmol,
57% over two steps) of (2R/S,4S*,5S*)-2 as a colorless oil. The chemical
purity of the product was 97%, and the diastereomeric purity 96%. EIMS
m/z 143 (17), 130 (5), 129 (70), 114 (5), 100 (18), 87 (15), 74 (3), 73
(28), 72 (45), 71 (4), 70 (6), 69 (96), 59 (8), 58 (6), 57 (49), 56 (19), 55
(14), 53 (3), 45 (23), 43 (100), 42 (3), 41 (33), 39(10); HR-GC/MS
(M þ H)þ m/z 159.1382 (calcd for C9H19O2, 159.1385). Although the
C2-epimers could not be separated chromatographically, NMR assign-
ments were made to the two different stereoisomers on the basis of two-
dimensional NMR experiments.
(S)-2-(Tetrahydropyran-2-yloxy)-3-pentanol. In the same
manner as described above, methyl (S)-2-(tetrahydropyran-2-yloxy)
propanoate (9.4 g, 0.042 mol (calcd on 84% purity) was converted to a
product of ca. 70% purity (5.06 g), which was immediately used for the
next step. For MS data see (R)-2-(tetrahydropyran-2-yloxy)-3-pentanol.
(2R,3R)- and (2R,3S)-Pentanediol. A stirred solution of (R)-
2-(tetrahydropyran-2-yloxy)-3-pentanol (7.55 g, 87% purity) in MeOH
(100 mL) was kept at 45 ꢀC while Amberlyst 15 (3.0 g) was added. After
2 h the reaction mixture was filtered through cotton, and the solvent was
removed in vacuo. The crude product (3.10 g) was purified, and the
obtained diastereomers of 2,3-pentanediol were separated by repetitive
MPLC (2 times). In total 522 mg of (2R,3R)-pentanediol (99% chemical
purity and 98% enantiomeric purity as checked by enantioselective GC)
and 707 mg of (2R,3S)-pentanediol were obtained (99% chemical purity
and 96% enantiomeric purity as checked by enantioselective GC). EIMS
m/z 89 (1), 75 (10), 71 (4), 60 (4), 59 (100), 58 (37), 57 (21), 55 (2),
47 (2), 46 (2), 45 (44), 44 (2), 43 (14), 42 (5), 41 (18), 40 (1), 39 (4).
(2S,3S)- and (2S,3R)-Pentanediol. In the same manner as above,
5.06 g of (S)-2-(tetrahydropyran-2-yloxy)-3-pentanol (70% purity)
were deprotected. The crude diol (2.79 g) was obtained in 47% purity.
The diastereomers were separated by repetitive MPLC (3 times). In
total, 491 mg of (2S,3S)-pentanediol (98% chemical purity and 96%
enantiomeric purity) and 473 mg of (2S,3R)-pentanediol were obtained
(99% chemical purity and 95% enantiomeric purity). Spectroscopic data
were in accord with the corresponding isomers derived from (R)-
2-(tetrahydropyran-2-yloxy)-3-pentanol and with literature data.15
(4R,5S)-2,2,4-Triethyl-5-methyl-1,3-dioxolane, (4R,5S)-1.
To a solution of 324 mg (3.8 mmol) of 3-pentanone in 25 mL of
pentane were added 10 mg of p-TsOH, 100 mg of 4 Å molecular sieves
(powdered), and 200 mg of (2S,3R)-pentanediol (1.92 mmol). The
mixture was stirred at rt. Over the next 6 days, additional 3-pentanone
was added (200 mg/d). The product was isolated by MPLC to yield a
colorless oil (138 mg, 42%) of 99% isomeric purity and 96% chemical
purity. EIMS m/z 144 (5), 143 (52), 128 (1), 114 (5), 87 (12), 86 (14),
75 (3), 70 (4), 69 (39), 58 (4), 57 (100), 56 (4), 55 (9), 45 (7), 43 (5),
42 (4), 41 (13), 39 (4); TOF-MS (M þ H)þ m/z 173.1529 (calcd for
C10H21O2, 173.1542); NMR data matched those reported earlier.7
(4S,5R)-2,2,4-Triethyl-5-methyl-1,3-dioxolane, (4S,5R)-1:
colorless oil from 3-pentanone and (2R,3S)-pentanediol; same proce-
dure as for (4R,5S)-1; for MS see (4R,5S)-1; NMR data matched those
reported earlier.7
(2R/S,4S,5S)-4-Ethyl-5-methyl-2-(1-methylethyl)-1,3-di-
oxolane, (2R/S,4S,5S)-3. To a solution of 2-methylpropanal (163
mg, 2.3 mmol) in diethyl ether (25 mL) were added p-TsOH (ca. 10
mg), 4 Å molecular sieves (powdered, ca. 100 mg), and (2S,3S)-
pentanediol (200 mg, 1.92 mmol). The mixture was stirred at rt
overnight and then filtered through cotton. The product was washed
twice with saturated aqueous NaHCO3 and brine, dried over MgSO4,
and concentrated in vacuo to yield a slightly yellow oil (201 mg, 66%).
The chemical purity was 99%, and the diastereomeric purity 96%, while
the C2-epimers were present in a ratio of 1:1. EIMS m/z 157 (4), 116
(7), 115 (100), 114 (4), 100 (7), 87 (3), 73 (3), 72 (3), 71 (4), 70 (6), 69
(80), 57 (13), 56 (33), 55 (8), 45 (23), 43(14), 41 (17), 39 (5); TOFMS
(M þ H)þ m/z 159.1349 (calcd for C9H19O2, 159.1385). Although the
C2-epimers could not be separated chromatographically, NMR assign-
ments were made to two different stereoisomers on the basis of two-
dimensional NMR experiments.
(2R/S,4R,5R)-4-Ethyl-5-methyl-2-(1-methylethyl)-1,3-di-
oxolane, (2R/S,4R,5R)-3: colorless oil from 2-methylpropanal and
(2R,3R)-pentanediol; same procedure as for (2R/S,4S,5S)-3; for spec-
troscopic data see (2R/S,4S,5S)-3.
(2S*,4S*,5S*,10R/S)-and(2R*,4S*,5S*,10R/S)-4-Ethyl-5-methyl-
2-(1-methylpropyl)-1,3-dioxolane, (2S*,4S*,5S*,10R/S)-4 and (2R*,
4S*,5S*,10R/S)-4. Following the procedure described for the synthesis
of (2R/S,4S*,5S*)-2, 100 mg (1.43 mmol) of (E)-2-pentene dissolved in
5 mL of dry DCM was transformed to the epoxide and subsequently
reacted with 135 mg (1.57 mmol) of freshly distilled rac-2-methylbuta-
nal to give 92 mg (0.53 mmol, 37% over two steps) of a mixture of
(2S*,4S*,5S*,10R/S)-4 and (2R*,4S*,5S*,10R/S)-4 as a colorless oil:
EIMS m/z 171 (3), 128 (5), 116 (7), 115 (100), 114 (3), 99 (2), 87
(5), 86 (4), 85 (3), 71 (6), 70 (27), 69 (85), 59 (3), 58 (3), 57 (14), 55
(13), 45 (30), 43 (5), 42 (6), 41 (23), 39 (7); HR-GC/MS (M þ H)þ
m/z 173.1539 (calcd for C21H19O2, 173.1542). Although the C2-
epimers could not be separated chromatographically, NMR data could
be assigned on the basis of NOESY experiments including the protons at
C2, C4, and C5 and on two-dimensional NMR experiments.
(4R,5R)-2,2,4-Triethyl-5-methyl-1,3-dioxolane, (4R,5R)-1:
colorless oil from 3-pentanone and (2R,3R)-pentanediol; same procedure
as for (4R,5S)-1. EIMS m/z 144 (5), 143 (57), 128 (2), 114 (10), 87 (11),
86 (22), 75 (3), 70 (7), 69 (65), 58 (4), 57 (100), 56 (5), 55 (14), 45 (8),
43(6), 42 (6), 41 (18), 39(5);NMRdatamatchedthose reportedearlier.7
(4S,5S)-2,2,4-Triethyl-5-methyl-1,3-dioxolane, (4S,5S)-1:
colorless oil from 3-pentanone and (2S,3S)-pentanediol; same proce-
dure as for (4R,5S)-1; for MS see (4R,5R)-1; NMR data matched those
reported earlier.7
(2S*,4S*,5S*)- and (2R*,4S*,5S*)-4-Ethyl-5-methyl-2-(2-methyl-
propyl)-1,3-dioxolane, (2S*,4S*,5S*)-5 and (2R*,4S*,5S*)-5. Fol-
lowing the procedure described for the synthesis of (2R/S,4S*,5S*)-
2, 100 mg (1.43 mmol) of (E)-2-pentene dissolved in 5 mL of dry
CH2Cl2 was transformed to the epoxide and subsequently reacted with
135 mg (1.57 mmol) of freshly distilled 3-methylbutanal to give 107 mg
(2R/S,4S*,5S*)-2,4-Diethyl-2,5-dimethyl-1,3-dioxolane,
(2R/S,4S*,5S*)-2. A solution of 100 mg (1.43 mmol) of (Z)-2-pentene
in 5 mL of dry CH2Cl2 was cooled to 0 ꢀC. After the addition of a dried
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Journal of Natural Products
ARTICLE
(0.62 mmol, 43% over two steps) of a mixture of (2S*,4S*,5S*)-5 and
(2R*,4S*,5S*)-5. EIMSm/z 171 (4), 128 (2), 116 (6), 115 (100), 114 (4),
113 (7), 99 (15), 87 (5), 85 (8), 71 (12), 70 (6), 69 (81), 68 (3), 59 (2),
58 (2), 57(11), 55 (6), 45 (27), 43 (12), 42(4), 41(23), 39 (7); HR-GC/
MS (M þ H)þ m/z 173.1537 (calcd for C10H21O2, 73.1542). Although
the C2-epimers could not be separated chromatographically, NMR data
wereassignedon thebasisof NOESYexperimentsincluding the protonsat
C2, C4, and C5 and upon two-dimensional NMR experiments.
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’ ASSOCIATED CONTENT
S
Supporting Information. NMR and mass spectra of all
b
new compounds are available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: þ46 480 446271. Fax: þ46 480 446262. E-mail: rikard.
(22) Mash, E. A.; Arterburn, J. B.; Fryling, F. A.; Mitchell, S. H. J. Org.
Chem. 1991, 56, 1088–1093.
(23) Buffet, M. F.; Dixon, D. J.; Ley, S. V.; Reynold, D. J.; Storer, R. I.
Org. Biomol. Chem. 2004, 2, 1145–1154.
unelius@lnu.se.
Notes
4Stephan Franke passed away in December 2010; his scientific
achivements keep him among us.
Present Addresses
#Research School of Chemistry and Research School of Biology,
The Australian National University, Canberra, ACT 0200,
Australia.
^The Plant & Food Research Institute of New Zealand, P.O. 51
Lincoln, New Zealand.
’ ACKNOWLEDGMENT
The authors are grateful to the Swedish International Devel-
opment Cooperation Agency (SIDA) and to the Linnaeus
University (Sweden) for financial support. This work was also
supported by FAPEMIG, CNPq, and FIOCRUZ (Brazil). The
New Zealand Institute for Plant & Food Research Ltd, Lincoln,
New Zealand, provided some research facilities for B.B. and C.R.U.
during a short period of this work. W.F. thanks the Fonds der
Chemischen Industrie for financial support.
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