Synthesis and absolute configuration of a constitutionally-new [5.6] spiroacetal from B. tryoni (Queensland fruit fly)

Article abstract of DOI:10.1039/b701833a

A novel spiroacetal, (2S,6R,8S)-2-methyl-8-ethyl-1,7-dioxaspiro[5.6] dodecane (1), has been identified from the volatile secretions of female B. tryoni by mass spectral analysis and synthesis of an authentic, enantioenriched sample. This journal is The Ro

Full text of DOI:10.1039/b701833a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and absolute configuration of a constitutionally-new [5.6]
spiroacetal from B. tryoni (Queensland fruit fly)†
Yvonne K. Booth,a Patricia Y. Hayes,a Christopher J. Moore,b Lynette K. Lambert,c William Kitchinga and
James J. De Voss*a
Received 6th February 2007, Accepted 12th February 2007
First published as an Advance Article on the web 7th March 2007
DOI: 10.1039/b701833a
A novel spiroacetal, (2S,6R,8S)-2-methyl-8-ethyl-1,7-dioxaspiro[5.6]dodecane (1), has been identified
from the volatile secretions of female B. tryoni by mass spectral analysis and synthesis of an authentic,
enantioenriched sample.
Introduction
Spiroacetals are widespread in the insect world,1 having been
identified in the volatile secretions of various species of bees,
wasps, beetles and fruit flies.2 To date, just over 30 constitutionally-
different spiroacetals have been characterised, representing
five basic ring systems: 1,6-dioxaspiro[4.4]nonanes (2), 1,6-
dioxaspiro[4.5]decanes (3), 1,6-dioxaspiro[4.6]undecanes (4), 1,7-
dioxaspiro [5.5]undecanes (5) and 1,7-dioxaspiro[5.6]dodecanes
(6) (Fig. 1). Until now, the 1,7-dioxaspiro[5.6]dodecane sys-
tem (6) was represented by a single example, 2-methyl-1,7-
Fig. 1 Spiroacetal ring systems.
member of system 6 and as the first example of a disubstituted
derivative. This work, therefore, enhances the overall landscape of
insect-derived spiroacetals.
dioxaspiro[5.6]dodecane (7), identified from the solitary bee
Andrena haemorrhoa3 and the fruit fly species Bactrocera cucumis,4
taxonomically close to B. tryoni. The constitutionally-new spiroac-
etal described herein is noteworthy as the second characterised
We recently reported that female Bactrocera tryoni (Frogatt)
(Queensland fruit fly), the most destructive horticultural pest in
Australia,5 release a diverse suite of spiroacetals, which ranges
from nine to thirteen carbons and includes the presence of
unusual even carbon-numbered spiroacetals, as well as the novel
branched chain spiroacetal, (2S,6R,8S)–2-ethyl-2,8-dimethyl-1,7-
dioxaspiro[5.5]undecane ((2S,6R,8S)-14) (Fig. 2).6 The identifi-
cation of these spiroacetals was confirmed either by compari-
son of retention times and co-injection studies with authentic
aChemistry, School of Molecular and Microbial Sciences, University
of Queensland, St. Lucia, Brisbane, Australia 4072. E-mail: j.devoss@
uq.edu.au; Fax: +61 (0)7 3365 4299; Tel: +61 (0)7 3365 3825
bDepartment of Primary Industries, Yeerongpilly, Brisbane, Australia 4105
cCentre for Magnetic Resonance, University of Queensland, St. Lucia,
Brisbane, Australia 4072
† Electronic supplementary information (ESI) available: Synthesis of
alcohols 16 and 26, and alkyne 21. See DOI: 10.1039/b701833a
Fig. 2 Enantioselective GCMS of the spiroacetals present in a pentane extract of female B. tryoni abdomens. Peak F set to 100 units.
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standards,7 or by comparison with the mass spectra of authentic
compounds.8
this analysis, the component was considered likely to be 2-
methyl-8-ethyl-1,7-dioxaspiro[5.6]dodecane (1) and, therefore, a
constitutionally-new spiroacetal.
Progress in our ongoing biosynthetic investigations required
the identification and characterisation of an exceptionally minor
(<0.2% abundance) but biosynthetically-significant spiroacetal
component, observed to elute after (2S,6R,8S)-15 and the
previously reported amide, N-(3-methylbutyl)acetamide, in the
enantioselective GCMS trace (Fig. 3).
Fig. 4 Mass spectral fragmentation analysis of the newly-identified
spiroacetal.
To confirm this deduction, 1 was synthesised in racemic form
as outlined in Scheme 1. Oxidation (PCC) of alcohol 16 (syn-
thesised in five steps from commercially available 1,6-hexanediol,
see the ESI†), followed by addition of key alkyne 187 to the
resulting aldehyde (17) furnished propargylic alcohol 19 with the
required carbon backbone and oxygenation pattern. Oxidation
to ketone 20, followed by reduction of the triple bond, produced
the saturated ketone, ready for deprotection and cyclisation to
spiroacetal 1 under acidic conditions. However, even following
experimentation with a variety of acidic conditions (75% aqueous
acetic acid at 55 ◦C, trifluoroacetic acid in CH2Cl2 and tosic acid in
methanol) cyclisation repeatedly proceeded in low yield with the
formation of only one isolable diastereomer, which was purified by
a combination of flash chromatography and preparative GC. The
sole diastereomer was presumed to be the (E,E)-isomer,‡ with
Fig. 3 (a) Enantioselective GC trace of a pentane extract of female
B. tryoni abdomens, showing newly identified spiroacetal 1. (b) Mass
spectrum of naturally occurring (2S,6R,8S)-1.
Results and discussion
As summarised previously,1 spiroacetals have characteristic frag-
mentation patterns which guide structural conclusions for un-
known compounds. This newly observed spiroacetal, with an
apparent molecular ion of 212, has fragment ions at m/z 197 and
183, corresponding to the loss of methyl and ethyl substituents,
respectively. Given this alkyl-substituent pattern, the fragment
ions at m/z 112, 115 and 125 are indicative of a methyl substituted
six-membered ring, and the ions at m/z 140 and 143 are suggestive
of an ethyl-substituted seven-membered ring (Fig. 4). Based on
‡ Substituted spiroacetals are designated (E)- when the substituent group
and oxygen atom of the alternate ring are on opposite sides of the reference
plane (the substituted ring) and (Z) when on the same side.
Scheme 1 Synthesis of 1 in both racemic and enantioenriched form. Reagents and conditions: (i) PCC, CH2Cl2, 83%; (ii) 18, n-BuLi, THF, −78 ◦C, 59%;
(iii) PDC, CH2Cl2, 84%; (iv) H2(g), Pd/C, THF, 92%; (v) TsOH·H2O, MeOH, 14%; (vi) 21, MeLi, THF, −40 ◦C, 84%; (vii) H2(g), Pd/C, Et3N, EtOAc,
90%; (viii) 75% AcOH, 55 ◦C, 31%.
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maximum anomeric stabilisation from two axially directed oxygen
atoms (Fig. 5).
Fig. 5 Observed NOE interactions in (E,E)-1 and possible (E,Z)-isomers.
This product bias presumably reflects, under reversible condi-
tions, the free energy differences between the possible isomers.
In comparison with [5.5] spiroacetals such as 2,8-dimethyl-1,7-
dioxaspiro[5.5]undecane (10) containing only six-membered rings,
the additional free energy of the seven-membered ring in 1 is best
counteracted in the (E,E)-manifold. Thus, it is understandable
that formation of the (E,E)-isomer‡ of 1, with two stabilising
anomeric effects (1.4 kcal mol−1 each),9 would be heavily favoured
in comparison with the (E,Z)-isomers, which would possess only
one such stabilising effect.
To demonstrate that the sole product was indeed the (E,E)-
isomer as rationalised above, comprehensive NMR analyses were
undertaken. Unsurprisingly, the spiroacetal exhibited an extended
region of overlapping protons, and 1D-TOCSY experiments were
utilised to isolate the two ring systems. Analysis of the multiplet
for H-2 (d 4.00, dqd, J 12.0, 6.3, 2.5 Hz), revealed one large and
one small coupling, consistent with an axial proton, confirming
an equatorial orientation for the methyl substituent and a chair
conformation for the six membered ring. The H-8 multiplet (d
3.77, dddd, J 10.3, 6.8, 4.8, 1.1) also displayed one large and
one small coupling to ring protons, suggestive of a pseudo-axial
orientation for the proton, and a pseudo-equatorial geometry for
the ethyl substituent. In addition, the downfield shifts for both
of these protons result from 1,3-diaxial interactions with oxygen
rather than with carbon,10 and suggest that the spiroacetal adopts
an (E,E)-configuration.‡ This is supported by the chemical shift
of the axial H-4 proton (d 1.95), again indicative of a 1,3-diaxial
interaction with oxygen (O-7). These analyses effectively eliminate
the formation of either of the (E,Z) isomers‡ (Fig. 5), as H-8 in
the first structure and H-4 in the second are 1,3-diaxial to a C–C
bond and so their chemical shifts would be expected to be upfield
of d 3.77 and d 1.95, respectively.
Furthermore, the anticipation would be that NOEs would be
observed between H-2 and H-8 for the (E,E) isomer‡ but not
for the (E,Z) isomers,‡ even though the more-flexible seven-
membered ring would not adopt the pseudochair conformation as
rigidly as the spiroacetal containing a six-membered ring. Indeed,
spatial interactions were identified between H-2 and H-8 and also
between H-2 and both the methylene and methyl groups of the
ethyl substituent (Fig. 5). This confirmed that the synthesised
spiroacetal was (E,E)-1, rather than either of the possible (E,Z)-
isomers.
Fig. 6 Total ion current (TIC) of enantioselective GC traces employing
single ion monitoring of m/z 212, 183, 143, 125, and 112. (a) Racemic
(E,E)-1. (b) Mass spectrum of synthetic 1. (c) Enantiomerically pure
(2S,6R,8S)-1. (d) Concentrated pentane extract of female B. tryoni
abdomens. (e) Co-injection of concentrated extract with racemic (E,E)-1.
dioxaspiro[5.6]dodecane, ((E,E)-1). The absolute stereochemistry
of (1) now required determination.
Synthesis of enantiomerically pure (E,E)-1 employed
a
previously-developed methodology for the synthesis of enantiop-
ure spiroacetals.7 Thus, alkyne 21, synthesised from 4-pentyn-
1-ol in three steps (see the ESI†), on addition to key Weinreb
amide (2S)-227 provided unsaturated ketone (2S)-23 (Scheme 1).
Palladium catalysed reduction of the alkyne moieties, followed
by acetic acid-induced cyclisation, delivered only a single isolable
enantiomer of (E,E)-1 upon purification by flash chromatography.
This enantiomer necessarily possessed (2S,6R,8S) stereochemistry
and exhibited NMR and mass spectral data identical with those of
the racemic product. In agreement with our previous observations
on spiroacetal elution orders,6,11 (2S,6R,8S)-1 (possessing an (R)-
spirocentre) was found to elute after (2R,6S,8R)-1 under our
enantioselective GC conditions (Fig. 6A and C). To enable
retention time comparisons with the natural extract, single-ion
monitoring of several predominant spiroacetal fragmentations
(m/z 212, 183, 143, 125, 112) was employed to distinguish the
spiroacetals from amide, hydrocarbon and ester components
of the extract. From these retention times, (2S,6R,8S)-1 was
identified as the predominant isomer in vivo (Fig. 6D). This was
Comparisons of the mass spectral data of synthetic (E,E)-
1 with that of the natural extract (Fig. 6B and 3B) identified
the natural spiroacetal as the novel (E,E)-2-methyl-8-ethyl-1,7-
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confirmed by co-injection of the natural extract with the racemic
standard, which showed a marked increase in intensity for the
later-eluting (2S,6R,8S)-isomer in comparison with that of the
racemic standard (Fig. 6E, cf. A). This absolute stereochemistry
is in agreement with determinations for the major spiroacetals
found in B. tryoni volatiles viz (2S,6R,8S)-10, (2S,6R,8S)-12 and
(2S,6R,8S)-15 (Fig. 2,). However, the presence of a low level of
(2R,6S,8R)-1 could not be discounted, and so the enantiomeric
excess of the newly identified (2S,6R,8S)-2-methyl-8-ethyl-1,7-
dioxaspiro[5.6]dodecane (1), although high, is imprecise.
Given the diverse suite of spiroacetals that female B. tryoni
produce, it was of interest to determine whether the corresponding
known C11 spiroacetal, 2-methyl-1,7-dioxaspiro[5.6]dodecane (7)12
and the C12 spiroacetal 2,8-dimethyl-1,7-dioxaspiro[5.6]dodecane
(25) were also biosynthesised. As such, (E,E)-25 was synthesised
in racemic form following an analogous procedure to that used
for (E,E)-1, except that the initial alcohol (26) was one carbon
shorter (Scheme 2). Once again, a low yield of a single isolable
diastereomer was obtained after purification by preparative GC.
Scheme 3 Proposed penultimate biosynthetic step of spiroacetal biosyn-
thesis in B. tryoni.
play a pivotal role in determining the biogenesis of spiroacetals
in this pestiferous fruit fly species and consequently provide a
platform from which we aim to develop a novel inhibition-based
control method. The diverse range of spiroacetals produced by
B. tryoni also makes this fly an ideal model for studying the
biosynthesis of this class of compounds in insects.
Experimental
General methods
All reactions involving moisture or air sensitive reagents were
carried out under a nitrogen atmosphere in oven-dried glassware
with anhydrous solvents. THF and Et2O were distilled from
sodium and CH2Cl2 distilled from calcium hydride. Purifications
by flash chromatography were carried out using Scharlau silica
gel 60 (230–400 mesh). NMR spectra were recorded on either a
Bruker Avance AV500 MHz or AV400 MHz. CDCl3 and C6D6
were purchased from Cambridge Isotope Laboratories. 1H NMR
spectra were calibrated to 7.24 ppm for residual CHCl3 or 7.15 ppm
for C6D6. 13C NMR spectra were calibrated from the central
triplet peak, to 77.0 ppm for CDCl3 or to 128.0 ppm for C6D6.
Coupling constants are reported in Hz. GCMS data was recorded
on a Shimadzu GC-17A fitted with a DB5 column and attached
to either a Shimadzu GCMS-QP5050 or QP5000 detector. The
standard temperature program was: 100 ◦C for two minutes,
Scheme 2 Synthesis of (E,E)-25 in racemic form. Reagents and conditions:
(i) PCC, CH2Cl2, 65%; (ii) alkyne 18, n-BuLi, THF, −78 ◦C, 78%; (iii) PDC,
CH2Cl2, 86%; (iv) H2(g), Pd/C, THF, 96%; (v) TsOH·H2O, MeOH, 19%.
However, thorough scrutiny of the enantioselective GCMS
trace of the pentane extract of female abdomens failed to
reveal the presence of either spiroacetal 7 or 25. The clear
presence of the C13 spiroacetal, (2S,6R,8S)-2-methyl-8-ethyl-1,7-
dioxaspiro[5.6]dodecane (1), when the corresponding C11 and C12
spiroacetals are absent (or at vanishingly low concentrations) has
interesting biosynthetic implications.
◦
◦
followed by a 16 C min−1 temperature rise until 250 C, which
was held for ten minutes.
Although the details of the origin of these spiroacetals in
B. tryoni is still uncertain, it is postulated to involve P450
catalysed oxidation of an alkyltetrahydropyranol precursor as the
penultimate biosynthetic step.13 It is therefore feasible that B. tryoni
may produce several components of its spiroacetal blend simply
by permitting a certain degree of regiochemical flexiblity in this
oxidation, in particular with longer chain precursors (Scheme 3).
These and related aspects of the biogenesis require studies with
suitable, labelled precursors.
Synthesis of racemic (E,E)-1
6-(tert-Butyldimethylsilyloxy)octanal (17). PCC (1.44 g,
6.68 mmol) was added portionwise to a solution of alcohol 16
(1.13 g, 4.34 mmol, see the ESI†) in dry CH2Cl2 (20 mL) and the
mixture stirred for two hours. Et2O (50 mL) was added to dilute
the mixture and the brown solution filtered through a celite/silica
plug. The organic filtrate was concentrated in vacuo and the crude
product purified by flash chromatography (1 : 20 EtOAc–hexane)
to give aldehyde 17 (0.93 g, 83%) as a colourless oil. Anal. found:
C, 65.1; H, 12.0. Calc. for C14H30O2Si: C, 65.1; H, 11.7%; dH
(500 MHz, CDCl3) 0.00 (3 H, s), 0.01 (3 H, s), 0.82 (3 H, t, J
7.4), 0.85 (9 H, s), 1.21–1.47 (6 H, m), 1.60 (2 H, pentet, J 7.4),
2.40 (2 H, t, J 7.4), 3.55 (1 H, pentet, J 5.6), 9.73 (1 H, bs); dC
(125 MHz, CDCl3) −4.5, −4.4, 9.5, 18.1, 22.3, 24.9, 25.9 (3 C),
29.7, 36.2, 43.9, 73.1, 202.7; m/z (EI) 257 (M+-1, 0.1%), 229 (3),
Conclusions
In summary, the structure and absolute stereochemistry of
a novel spiroacetal from the volatile secretions of B. tryoni
has been determined to be (2S,6R,8S)-2-methyl-8-ethyl-1,7-
dioxaspiro[5.6]dodecane (1). This new compound is expected to
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201 (19), 173 (7), 159 (10), 131 (38), 109 (27), 75 (100), 73 (68),
67 (45).
dH (500 MHz, CDCl3) 0.002 (3 H, s), 0.007 (3 H, s), 0.018 (3 H, s),
0.020 (3 H, s), 0.82 (3 H, t, J 7.4), 0.86 (18 H, s), 1.09 (3 H, d, J
6.1), 1.18–1.67 (12 H, m), 2.359 (2 H, t, J 7.5), 2.363 (2 H, t, J 7.4),
3.54 (1 H, pentet, J 5.7), 3.76 (1 H, sextet, J 6.1); dC (125 MHz,
CDCl3) −4.74, −4.49, −4.44, −4.40, 9.6, 18.10, 18.13, 20.2, 23.7,
24.1, 25.0, 25.88 (3 C), 25.90 (3 C), 29.7, 36.3, 39.1, 42.7, 42.8,
68.3, 73.2, 211.2; m/z (EI) 457 (M+-1, 0.1%), 429 (0.04), 401 (5),
269 (16), 227 (10), 185 (19), 173 (18), 159 (15), 145 (25), 95 (19),
75 (100), 73 (66).
2,11-Bis(tert-butyldimethylsilyloxy)tridec-4-yn-6-ol (19). Butyl-
lithium (1.2 M solution in hexanes, 3.0 mL, 3.60 mmol) was added
dropwise to a stirred solution of alkyne 18 (0.70 g, 3.53 mmol)
in dry THF (15 mL) at −10 ◦C under nitrogen. The solution
was stirred at −10 ◦C for 30 minutes and aldehyde 17 (0.83 g,
3.21 mmol) in dry THF (6 mL) added slowly by syringe. After
stirring for 30 minutes, saturated NH4Cl solution (20 mL) was
added, the organic layer diluted with Et2O (20 mL) and the layers
separated. The aqueous phase was extracted with Et2O (3 × 20
mL) and the combined organic extracts washed with H2O (20
mL) and saturated NaCl solution (20 mL), dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography (1 : 20
EtOAc–hexane) yielded a diastereomeric mixture of propargylic
alcohols 19 (0.86 g, 59%), as a colourless oil. Anal. found: C, 66.1;
H, 11.8. Calc. for C25H52O3Si2: C, 65.7; H, 11.5%; dH (500 MHz,
CDCl3) 0.012 (6 H, s), 0.044 (3 H, s), 0.051 (3 H, s), 0.83 (3 H, t, J
7.4), 0.862 (9 H, s), 0.864 (9 H, s), 1.19 (3 H, d, J 6.1), 1.21–1.48
(8 H, m), 1.59–1.68 (2 H, m), 1.70 (1 H, bs), 2.24 (1 H, dddd, J
16.4, 7.1, 2.0, 1.1), 2.35 (1 H, ddd, J 16.4, 5.6, 1.9), 3.55 (1 H,
pentet, J 5.6), 3.91 (1 H, sextet, J 6.1), 4.30–4.34 (1 H, m); dC
(125 MHz, CDCl3) −4.76, −4.65, −4.48, −4.44, 9.6, 18.10, 18.15,
23.3, 25.03 and 25.05, 25.41 and 25.43, 25.8 (3C), 25.9 (3C), 29.6,
29.7, 36.4, 38.1, 62.68 and 62.69, 67.62 and 67.63, 73.3, 82.70 and
82.72, 82.76 and 82.78; m/z (EI) 427 (M+−29, 0.1%), 399 (0.2),
267 (5), 185 (2), 173 (9), 159 (66), 119 (57), 103 (31), 75 (91), 73
(100).
2-Methyl-8-ethyl-1,7-dioxaspiro[5.6]dodecane ((E,E)-1). TsOH·
H2O (69 mg, 0.36 mmol) was added to a stirred solution of
saturated ketone 24 (80 mg, 0.17 mmol) in MeOH (2 mL), and
the reaction stirred at room temperature for 22 hours. H2O (5 mL)
and pentane (5 mL) were added to the mixture and the layers
separated. The aqueous phase was extracted with pentane (3 × 5
mL) and the combined organic extracts washed with cold saturated
NaHCO3 solution (2 × 10 mL) and saturated NaCl solution (10
mL), dried over MgSO4 and concentrated cautiously in vacuo (the
ro◦tary evaporator bath was chilled to 5 ◦C and receiving flask
0 C). The crude product was purified by flash chromatography
(10% CH2Cl2 in pentane), and then further purified by preparative
GC (Shimadzu GC-9A, OV3 column, isothermal temperature of
150 ◦C) to give (E,E)-1 (5 mg, 14%). dH (750 MHz, C6D6) 0.93 (3
H, t, J 7.5), 1.09–1.19 (2 H, m), 1.18 (3 H, d, J 6.3), 1.21 (1 H, td,
J 13.0 and 4.1), 1.33–1.55 (7 H, m), 1.56–1.62 (1 H, m), 1.66–1.70
(1 H, m), 1.83–1.93 (3 H, m), 1.95 (1 H, qt, J 13.1 and 3.8), 3.77 (1
H, dddd, J 10.3, 6.8, 4.8, 1.1), 4.00 (1 H, dqd, J 12.0, 6.3 and 2.5);
dC (187.5 MHz, C6D6) 10.2, 19.8, 22.4, 22.8, 29.7, 30.7, 33.6, 35.1,
35.9, 42.5, 66.8, 71.9, 100.1; m/z (EI) 212 (M+, 1%), 197 (0.4), 183
(19), 168 (2), 154 (9), 143 (30), 140 (14), 125 (64), 115 (100), 112
(78), 97 (54), 83 (20), 69 (22), 55 (50), 41 (32); HRMS (ESI) found:
235.1671. Calc. for C13H24O2Na: 235.1674.
2,11-Bis(tert-butyldimethylsilyloxy)tridec-4-yn-6-one
(20).
PDC (1.35 g, 3.58 mmol) was added portionwise to a solution of
propargylic alcohols 19 (0.82 g, 1.79 mmol) in dry CH2Cl2 (30
mL) at 0 ◦C. The mixture was warmed to room temperature and
stirred for 20 hours. Et2O (30 mL) was added to dilute the mixture
and the solution filtered through a celite plug. The organic filtrate
was concentrated in vacuo and the crude oil purified by flash
chromatography (1 : 20 EtOAc–hexane) to yield propargylic
ketone 20 (0.68 g, 84%). Anal. found: C, 66.1; H, 11.4. Calc. for
C25H50O3Si2: C, 66.0; H, 11.1%; dH (500 MHz, CDCl3) 0.003 (3 H,
s), 0.007 (3 H, s), 0.048 (3 H, s), 0.056 (3 H, s), 0.82 (3 H, t, J 7.5),
0.855 (9 H, s), 0.863 (9 H, s), 1.22 (3 H, d, J 6.1), 1.20–1.46 (6 H,
m), 1.58–1.67 (2 H, m), 2.41 (1 H, dd, J 17.0, 6.5), 2.48 (1 H, dd,
J 17.0, 5.8), 2.50 (2 H, t, J 7.5), 3.54 (1 H, pentet, J 5.7), 3.99
(1 H, sextet, J 6.1); dC (125 MHz, CDCl3) −4.85, −4.66, −4.51,
−4.45, 9.5, 18.01, 18.12, 23.5, 24.3, 24.7, 25.7 (3 C), 25.9 (3 C),
29.7, 29.8, 36.2, 45.5, 66.9, 73.1, 82.0, 91.3, 188.1; m/z (EI) 455
(M+ +1, 0.01%), 425 (0.1), 397 (3), 265 (17), 221 (10), 195 (10),
169 (21), 159 (62), 115 (24), 103 (36), 75 (68), 73 (100).
Synthesis of enantiomerically pure (E,E)-(2S,6R,8S)-1
(2S)-2,11-Bis(tert-butyldimethylsilyloxy)trideca-4,7-diyn-6-one
((2S)-23). To a cooled solution (−40 ◦C) of alkyne 21 (162 mg,
0.7 mmol, see the ESI†) in THF (20 mL) under an inert
atmosphere was added dropwise a solution of methyllithium
(0.7 M, 1.0 mL). The solution was left stirring for 30 min at the
same temperature and then Weinreb amide (2S)-22 (170 mg,
0.6 mmol) in THF (5 mL) was added dropwise. At the end of
the addition, the cooling bath was removed and after stirring for
another hour at room temperature, the reaction was quenched by
addition of a saturated NH4Cl solution (20 mL). After extraction
into ether (3 × 30 mL), the organic layer was washed with brine,
dried (MgSO4) and concentrated in vacuo. The crude residue was
purified by flash chromatography eluting with 5% ether in hexane
to afford (2S)-23 (190 mg, 84%) as a colourless oil. (Found:
C, 66.3; H, 10.4. Calc. for C25H46O3Si2: C, 66.6; H, 10.3%); dH
(400 MHz, CDCl3) 0.037 (3 H, s), 0.041 (3 H, s), 0.058 (3 H, s),
0.075 (3 H, s), 0.85 (3 H, t, J 7.5), 0.87 (18 H, s), 1.22 (3 H, d, J
6.1), 1.41–1.50 (2 H, m), 1.61–1.75 (2 H, m), 2.40–2.54 (4 H, m),
3.61 (1 H, quintet, J 5.8), 4.01 (1 H, sextet, J 6.1); dC (100 MHz,
CDCl3) −4.68, −4.66, −4.38, 9.2, 15.2, 18.01, 18.06, 23.7, 25.7,
25.8, 29.6, 30.0, 33.9, 66.9, 71.7, 82.2, 83.2, 91.8, 95.0, 161.2; m/z
2,11-Bis(tert-butyldimethylsilyloxy)tridecan-6-one (24). Pd/C
(60 mg, 10% wt Pd) was added to a stirred solution of propargylic
ketone 20 (0.61 g, 1.34 mmol) in dry THF (10 mL) and was
subjected to two evacuation/H2 cycles. The reaction was stirred
at room temperature, under an ambient pressure of hydrogen
(balloon) for 90 minutes before being filtered through a celite
plug and the filtrate concentrated in vacuo. The crude product
was purified by flash chromatography (1 : 20 EtOAc–hexane) to
afford saturated ketone 24 (0.57 g, 92%) as a colourless oil. Anal.
found: C, 65.7; H, 12.3. Calc. for C25H54O3Si2: C, 65.4; H, 11.9%;
•
(EI) 450 (M+ −15, 0.01%), 393 (8). 261 (9), 217 (10), 159 (38), 115
(18), 103 (26), 73 (100).
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(2S)-2,11-Bis(tert-butyldimethylsilyloxy)tridecan-6-one ((2S)-
24). Palladium adsorbed on charcoal (5 mg, 5%) was added
to a solution of (2S)-23 (175 mg, 0.4 mmol) in ethyl acetate
(5 mL) and triethylamine (0.2 mL). The flask was purged with
nitrogen, evacuated and stirred under hydrogen (balloon, 1 atm).
The reduction was followed by GC and when complete, the flask
was purged with nitrogen and the mixture filtered through a bed of
celite then concentrated in vacuo. The residue was purified by flash
chromatography (5% ether in hexane) to yield saturated ketone
(2S)-24 (160 mg, 90%) as a colourless oil. (Found: C, 65.1; H,
12.2. Calc. for C25H54O3Si2: C, 65.4; H, 11.9%); dH (400 MHz,
CDCl3) 0.006 (3 H, s), 0.012 (3 H, s), 0.023 (6 H, s), 0.83 (3 H, t,
J 7.3), 0.86 (18 H, s), 1.09 (3 H, d, J 6.0), 1.19–1.69 (12 H, m),
2.37 (4 H, t, J 6.6), 3.54 (1 H, quintet, J 5.7), 3.76 (1 H, sextet, J
6.0); dC (100 MHz, CDCl3) −4.7, −4.5, −4.42, −4.38, 9.6, 18.12,
18.15, 20.2, 23.7, 24.1, 25.0, 25.9, 29.7, 36.3, 39.1, 42.8, 42.9, 68.4,
73.2, 211.3; m/z (EI): 457 (M+• −1, 0.01%), 401 (2), 269 (9), 227
(8), 199 (12), 185 (14), 145 (27), 75 (100).
(9 H, s), 0.864 (9 H, s), 1.09 (3 H, d, J 6.1), 1.19 (3 H, d, J 6.1),
1.21–1.47 (6 H, m), 1.58–1.70 (2 H, m), 2.24 (1 H, dddd, J 16.4,
7.1, 1.8, 1.0), 2.35 (1 H, ddd, J 16.4, 5.6, 1.9), 3.71–3.78 (1 H, m),
3.91 (1 H, m), 4.32 (1 H, tt, J 6.6, 1.9); dC (125 MHz, CDCl3)
−4.76, −4.72, −4.65, −4.41, 18.10, 18.14, 23.3, 23.8, 25.24 and
25.26, 25.6, 25.80 (3 C), 25.90 (3 C), 29.6, 38.1, 39.6, 62.67 and
62.68, 67.62 and 67.63, 68.49, 82.70 and 82.72, 82.78 and 82.76;
m/z (EI) 442 (M+, 0.1%), 385 (0.1), 293 (4), 253 (5), 159 (72), 119
(72), 103 (38), 75 (100), 73 (93).
2,11-bis(tert-Butyldimethylsilyloxy)dodec-4-yn-6-one
(29).
PDC (1.36 g, 3.62 mmol) oxidation of propargylic alcohols 28
(0.80 g, 1.81 mmol) in dry CH2Cl2 (30 mL) was carried out as
described for the synthesis of propargylic ketone 20. Purification
by flash chromatography (1 : 20 EtOAc–hexane) gave propargylic
ketone 29 (0.68 g, 86%) as a colourless oil. Anal. found: C, 65.1;
H, 11.2. Calc. for C24H48O3Si2: C, 65.4; H, 11.0%; dH (500 MHz,
CDCl3) 0.006 (3 H, s), 0.012 (3 H, s), 0.046 (3 H, s), 0.054 (3 H,
s), 0.85 (9 H, s), 0.86 (9 H, s), 1.08 (3 H, d, J 6.1), 1.21 (3 H, d, J
6.1), 1.21–1.43 (4 H, m), 1.58–1.67 (2 H, m), 2.41 (1 H, dd, J 17.0,
6.5), 2.48 (1 H, dd, J 17.0, 5.7), 2.50 (2 H, t, J 7.5), 3.71–3.78
(1 H, m), 3.91 (1 H, sextet, J 6.1); dC (125 MHz, CDCl3) −4.85,
−4.76, −4.66, −4.42, 18.01, 18.10, 23.5, 23.8, 24.1, 25.1, 25.7 (3
C), 25.9 (3 C), 29.8, 39.3, 45.5, 66.9, 68.3, 82.0, 91.2, 188.1; m/z
(EI) 441 (M+ +1, 0.02%), 383 (3), 251 (11), 207 (14), 169 (22), 159
(90), 115 (23), 103 (43), 75 (71), 73 (100).
(2S)-2-Methyl-8-ethyl-1,7-dioxaspiro[5.6]dodecane ((E,E)-(2S,
6R,8S)-1). Saturated ketone (2S)-24 (140 mg, 0.3 mmol) was
added to an aqueous solution of acetic acid (6 mL, 75%) and
heated at 50 ◦C overnight. The solution was allowed to cool
to RT and extracted with pentane (4 × 30 mL). The organic
phase was added cautiously to ice cold NaHCO3 (20 mL, sat.)
and allowed to stir for 5 min. The pentane layer was separated,
dried with MgSO4 and concentrated cautiously in vacuo (the rotary
evaporator bath was chilled to 5 ◦C and receiving flask to 0 ◦C).
The crude oil was purified by flash chromatography eluting with
pentane to afford (E,E)-(2S,6R,8S)-1 (20 mg, 31%) as a colourless
liquid. Enantiomeric excess estimated by enantioselective GC to
be greater than 99.5%. Spectral data was identical to that reported
for racemic 1.
2,11-bis(tert-Butyldimethylsilyloxy)dodecan-6-one (30). Hy-
drogenation of propargylic ketone 29 (0.61 g, 1.38 mmol) with
Pd/C (60 mg, 10% wt Pd) and hydrogen gas in THF (10 mL)
as described for the synthesis of 24, afforded saturated ketone
30 (0.59 g, 96%) as a colourless oil, after purification by flash
chromatography (1 : 20 EtOAc–hexane). Anal. found: C, 65.0;
H, 12.0. Calc. for C24H52O3Si2: C, 64.8; H, 11.8%; dH (500 MHz,
CDCl3) 0.009 (3 H, s), 0.016 (3 H, s), 0.019 (3 H, s), 0.022 (3 H,
s), 0.85 (9 H, s), 0.86 (9 H, s), 1.08 (3 H, d, J 6.0), 1.09 (3 H, d, J
6.1), 1.20–1.45 (6 H, m), 1.47–1.66 (4 H, m), 2.360 (2 H, t, J 7.5),
2.364 (2 H, t, J 7.4), 3.71–3.80 (2 H, m); dC (125 MHz, CDCl3)
−4.7 (2 C), −4.4 (2 C), 18.10, 18.12, 20.2, 23.7, 23.8, 23.9, 25.4,
25.9 (6 C), 39.1, 39.4, 42.7, 42.8, 68.3, 68.4, 211.2; m/z (EI) 443
(M+-1, 0.03%), 387 (5), 255 (12), 213 (13), 199 (15), 185 (21), 163
(22), 145 (35), 119 (20), 75(100), 73 (69).
Synthesis of racemic (E,E)-25
6-(tert-Butyldimethylsilyloxy)heptanal (27). PCC (1.31 g,
6.08 mmol) oxidation of alcohol 26 (1.00 g, 4.06 mmol, see the
ESI†) in dry CH2Cl2 (20 mL) was performed as described for
the synthesis of aldehyde 17. Purification of the crude product by
flash chromatography (1 : 20 EtOAc–hexane) afforded aldehyde
27 (0.64 g, 65%) as a colourless oil. Anal. found: C, 63.9; H, 11.8.
Calc. for C13H28O2Si: C, 63.9; H, 11.55%; dH (500 MHz, CDCl3)
0.00 (3 H, s), 0.01 (3 H s), 0.85 (9 H, s), 1.08 (3 H, d, J 6.10),
1.25–1.45 (4 H, m), 1.56–1.65 (2 H, m), 2.40 (2 H, td, J 7.4, 1.8),
3.71–3.79 (1 H, m), 9.73 (1 H, t, J 1.8); dC (125 MHz, CDCl3) −4.8,
−4.4, 18.1, 22.1, 23.8, 25.3, 25.9 (3 C), 39.3, 43.9, 68.3, 202.7; m/z
(EI) 243 (M+-1, 0.1%), 187 (18), 159 (8), 145 (15), 131 (42), 95 (35),
75 (100), 73 (51).
2,8-Dimethyl-1,7-dioxaspiro[5,6]dodecane ((E,E)-25). TsOH·
H2O (0.22 g, 1.16 mmol) was added to a stirred solution of
saturated ketone 30 (0.25 g, 0.56 mmol) in anhydrous MeOH (3
mL), and the reaction stirred at room temperature for 22 hours.
The mixture was diluted by the addition of pentane (10 mL),
and solid NaHCO3 added to basify the solution (pH 9). After
the addition of H2O (15 mL), the two phases were separated
and the aqueous phase was extracted with pentane (3 × 15 mL).
The combined organic extracts were washed with brine (20 mL),
dried over MgSO4 and concentrated cautiously in vacuo (the rotary
evaporator bath was chilled to 5 ◦C and receiving flask 0 ◦C). The
crude residue was purified by preparative GC (Shimadzu GC-9A,
OV3 column, isothermal temperature of 150 ◦C) to afford (E,E)-
25 (21 mg, 19%) as the only isolable product. dH (500 MHz, C6D6)
1.07–1.23 (3 H, m), 1.15 (3 H, d, J 6.3), 1.18 (3 H, d, J 6.3), 1.32–
1.47 (6 H, m), 1.59–1.67 (1 H, m), 1.82–1.91 (3 H, m), 1.97 (1 H,
qt, J 13.3, 3.9), 3.91–3.99 (2 H, m); dC (125 MHz, C6D6) 19.7, 22.4,
2,11-bis(tert-Butyldimethylsilyloxy)dodec-4-yn-6-ol (28). De-
protonation of alkyne 18 (0.54 g, 2.72 mmol) with n-BuLi
(2.27 mL, 1.2 M solution in hexanes, 2.72 mmol) and addition
to aldehyde 27 (0.60 g, 2.45 mmol) in anhydrous THF (15 mL),
was carried out as described for the preparation of propargylic
alcohol 19. Purification by flash chromatography (1 : 20 EtOAc–
hexane) yielded a diastereomeric mixture of propargylic alcohols
28 (0.85 g, 78%) as a colourless oil. Anal. found: C, 65.3; H, 11.8.
Calc. for C24H50O3Si2: C, 65.1; H, 11.4%; dH (500 MHz, CDCl3)
0.017 (3 H, s), 0.021 (3 H, s), 0.044 (3 H, s), 0.051 (3 H, s), 0.859
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22.7, 23.6, 29.9, 33.6, 35.7, 38.2, 42.7, 66.77, 66.82, 100.0; m/z (EI)
198 (M+, 3%), 183 (4), 154 (8), 129 (39), 126 (25), 125 (42), 115
(69), 112 (78), 111 (40), 97 (43), 83 (50), 69 (74), 55 (100), 41 (93);
HRMS (ESI) found: 221.1518. Calc. for C12H22O2Na: 221.1517.
(E,Z)-2-Ethyl-7-methyl-1,6-dioxaspiro[4.5]decane ((E,Z)-11).
m/z (EI) 184 (M+, 9%), 169 (3), 155 (38), 140 (11), 126 (7), 115
(100), 114 (27), 112 (69), 97 (77), 85 (43), 83 (31), 69 (52), 57 (40),
55 (91), 43 (70), 42 (49), 41 (54).
Mass spectral data of 2-methyl-1,7-dioxaspiro[5.6]dodecane (7).
m/z (EI) 184 (M+, 10%), 169 (0.6), 154 (1), 140 (5), 125 (52), 115
(93), 112 (100), 97 (67), 83 (23), 73 (36), 69 (89), 55 (97), 41 (91)
(E,E)-2-Ethyl-8-methyl-1,7-dioxaspiro[5.5]undecane ((2S,6R,
8S)-12). m/z (EI) 198 (M+, 19%), 183 (2), 169 (16), 154 (10),
140 (17), 129 (52), 128 (23), 126 (34), 115 (100), 114 (35), 112 (84),
111(42), 97 (65), 83 (52), 69 (55), 68(45), 55 (98), 43 (64), 41 (72).
Chiral GCMS conditions
(E,Z)-2,8-Dimethyl-1,7-dioxaspiro[5.5]undecane ((2S,6S,8R)-
13 and (2R,6R,8S)-13). m/z (EI) 184 (M+, 7%), 169 (3), 140
(4), 125 (5), 115 (100), 114 (34), 112 (40), 97 (78), 83 (10), 73 (17),
69 (45), 55 (44), 43 (44), 42 (26), 41 (39).
Chiral GCMS analyses were performed on a Shimadzu GC-
17A, with a Shimadzu GCMS-QP5050 detector, using a 25 m
b-cyclodextrin column (0.22 mm internal diameter) at a column
pressure of 92.7 kPa and total flow of 8.7 ml min−1.
(2S,6R,8S)-2-Ethyl-2,8-dimethyl-1,7-dioxaspiro[5.5]undecane
((2S,6R,8S)-14). m/z (EI) 212 (M+, 2), 197 (3), 183 (13), 143
(15), 142 (11), 140 (8), 125 (37), 115 (21), 112 (33), 97 (19), 83 (29),
55 (93), 43 (100).
Temper◦ature program: 40 ◦◦C for 2 minutes, 5 C min−1 until
◦
120 ◦C; 1 C min−1 until 180 C.
MS Parameters: single ion monitoring (SIM) m/z 212, 183, 143,
125, 112.
(E,E)-2-Methyl-8-propyl-1,7-dioxaspiro[5.5]undecane ((2S,6R,
8S)-15). m/z (EI) 212 (M+, 13), 169 (16), 143 (34), 140 (39),
140 (8), 125 (38), 115 (21), 114 (26), 112 (81), 97 (87), 83 (26), 69
(36), 55 (99), 43 (88), 42 (52), 41 (75).
B. tryoni abdominal extracts
Female B. tryoni were laboratory reared on a standard artificial
diet of protein hydrolysate, sugar and water for 10–14 days post
emergence. The abdominal tips of 150 flies were then removed
by dissection and soaked in pentane (∼1 mL). The extract was
analysed under chiral GCMS conditions.
Acknowledgements
The authors are grateful for IPRS scholarship support for
Y. Booth, to Thelma Peek (Department of Primary Industries)
for the supply of fruit fly pupae and to Mary Fletcher and Brett
Schwartz for GCMS data from an extract of concentrated female
B. tryoni abdomens.
Mass spectral data of B. tryoni spiroacetals
2,7-Dimethyl-1,6-dioxaspiro[4.5]decane (8, isomer 1). m/z (EI)
170 (M+, 4%), 155 (4), 126 (15), 115 (14), 111 (7), 101 (100), 100
(27), 99 (13), 98 (87), 83 (30), 69 (15), 57 (24), 55 (59), 43 (83), 41
(41).
References
1 W. Francke and W. Kitching, Curr. Org. Chem., 2001, 233–251.
2 M. T. Fletcher and W. Kitching, Chem. Rev., 1995, 95, 789–828.
3 W. Francke, W. Reith, G. Bergstroem and J. Tengoe, Z. Naturforsch.,
Teil C, 1981, 36, 928–932.
2-Methyl-1,6-dioxaspiro[4.5]decane (9, isomer 1). m/z (EI) 156
(M+, 2%), 141 (1), 128 (3), 112 (10), 101 (74), 100 (26), 98 (34), 83
(24), 55 (41), 43 (100), 41 (57).
4 W. Kitching, J. A. Lewis, M. T. Fletcher, R. A. I. Drew, C. J. Moore
and W. Francke, J. Chem. Soc., Chem. Commun., 1986, 853–854; W.
Kitching, J. A. Lewis, M. V. Perkins, R. Drew, C. J. Moore, V. Schurig,
W. A. Konig and W. Francke, J. Org. Chem., 1989, 54, 3893–3902.
5 R. A. I. Drew, G. H. S. Hooper and M. A. Bateman, Economic Fruit
Flies of the South Pacific Region, 2nd edn, Department of Primary
Industries, Brisbane, 1982.
6 Y. K. Booth, B. D. Schwartz, M. T. Fletcher, L. K. Lambert, W. Kitching
and J. J. De Voss, Chem. Commun., 2006, 3975–3977.
7 B. D. Schwartz, P. Y. Hayes, W. Kitching and J. J. De Voss, J. Org.
Chem., 2005, 70, 3054–3065.
8 J. A. Lewis, PhD thesis, University of Queensland, 1987.
9 P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry,
Pergamon Press, New York, 1983.
10 Y. Q. Tu, A. Hubener, H. Zhang, C. J. Moore, M. T. Fletcher, P. Hayes,
K. Dettner, W. Francke, C. S. P. McErlean and W. Kitching, Synthesis,
2000, 1956–1978.
2,7-Dimethyl-1,6-dioxaspiro[4.5]decane (8, isomer 2). m/z (EI)
170 (M+, 6%), 155 (4), 126 (9), 115 (9), 111 (7), 101 (100), 100 (22),
99 (9), 98 (76), 83 (27), 69 (16), 57 (28), 55 (54), 43 (98), 41 (56).
2-Methyl-1,6-dioxaspiro[4.5]decane (9, isomer 2). m/z (EI) 156
(M+, 5%), 141 (3), 128 (4), 112 (9), 101 (100), 100 (42), 98 (43), 83
(34), 55 (50), 43 (81), 41 (55).
(E,E)-2,8-Dimethyl-1,7-dioxaspiro[5.5]undecane ((2R,6S,8R)-
10 and (2S,6R,8S)-10). m/z (EI) 184 (M+, 12%), 169 (2), 140
(14), 125 (7), 115 (91), 114 (44), 112 (100), 97 (68), 83 (20), 69 (41),
55 (58), 43 (46), 41 (35).
(E,E)-2-Ethyl-7-methyl-1,6-dioxaspiro[4.5]decane ((E,E)-11).
m/z (EI) 184 (M+, 5%), 169 (3), 155 (27), 140 (10), 126 (7), 115
(100), 114 (33), 112 (59), 97 (66), 85 (35), 83 (23), 69 (33), 57 (42),
55 (65), 43 (83), 42 (57), 41 (58).
11 C. S. P. McErlean, M. T. Fletcher, B. J. Wood, J. J. De Voss and W.
Kitching, Org. Lett., 2002, 4, 2775–2778; C. S. P. McErlean, PhD thesis,
University of Queensland, 2002.
12 R. Ballini and M. Petrini, J. Chem. Soc., Perkin Trans. 1, 1992, 3159–
3160.
13 J. E. Stok, C.-S. Lang, B. D. Schwartz, M. T. Fletcher, W. Kitching
and J. J. De Voss, Org. Lett., 2001, 3, 397–400; M. T. Fletcher, B. E.
Mazomenos, J. H. Georgakopoulos, M. A. Konstantopoulou, B. J.
Wood, J. J. De Voss and W. Kitching, Chem. Commun., 2002, 1302–
1303.
2,7-Dimethyl-1,6-dioxaspiro[4.5]decane (8, isomer 3). m/z (EI)
170 (M+, 20%), 155 (3), 125 (8), 115 (21), 112 (20), 101 (86), 100
(30), 98 (100), 83 (48), 70 (23), 69 (23), 56 (39), 55 (76), 43 (22), 42
(22), 41 (48).
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1111–1117 | 1117
©