Titanium(II)-based Z-reduction of alkynes. Syntheses of deuterium labelled linolenic and oleic acids and (3E,8Z,11Z)-tetradeca-3,8,11-trienyl acetate, the sex pheromone of a tomato pest, Scrobipalpuloides absoluta

Article abstract of DOI:10.1039/a800674a

An operationally simple Ti^II-mediated, stereo- and regio-specific reduction of isolated, conjugated and methylene 'skipped' polyynes to the corresponding Z-polyenes in a one-pot procedure is described and applied inter alia to the syntheses of deuterium labelled linolenic and oleic acids. Final quenching with D₂O (instead of H₂O) results in regio- and stereo-specific Z-dideuteration of the alkyne. The synthesis of (3E,8Z,11Z)-tetradeca-3,8,11-trienyl acetate, the major sex pheromone of Scrobipalpuloides absoluta, a destructive pest of tomatoes, and the (3Z,8Z,11Z)-isomer, utilises this methodology in key reduction steps, and under- or over-reduction are negligible.

Full text of DOI:10.1039/a800674a

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Titanium(II)-based Z-reduction of alkynes. Syntheses of deuterium
labelled linolenic and oleic acids and (3E,8Z,11Z)-tetradeca-3,8,11-
trienyl acetate, the sex pheromone of a tomato pest,
Scrobipalpuloides absoluta
Natasha L. Hungerford and William Kitching*
Department of Chemistry, The University of Queensland, Brisbane, Qld. 4072, Australia
An operationally simple TiII-mediated, stereo- and regio-specific reduction of isolated, conjugated and
methylene ‘skipped’ polyynes to the corresponding Z-polyenes in a one-pot procedure is described and
applied inter alia to the syntheses of deuterium labelled linolenic and oleic acids. Final quenching with
D2O (instead of H2O) results in regio- and stereo-specific Z-dideuteration of the alkyne. The synthesis
of (3E,8Z,11Z)-tetradeca-3,8,11-trienyl acetate, the major sex pheromone of Scrobipalpuloides absoluta,
a destructive pest of tomatoes, and the (3Z,8Z,11Z)-isomer, utilises this methodology in key reduction
steps, and under- or over-reduction are negligible.
A very large number of biologically important molecules
incorporate carbon-carbon double bonds, in particular patterns
and with defined (Z or E) configurations. An important
illustrative series spans oleic, linoleic, linolenic and arachidonic
acids, all with Z-configured double bonds, and excepting oleic
acid, incorporate the methylene skipped polyene arrangement.
There has been considerable interest in the acquisition of
labelled polyunsaturated fatty acids for use in biosynthetic
studies, particularly of insect pheromones, and in the synthesis
of the pheromones themselves. The vast majority of Lepi-
dopteran pheromones are straight chain, unsaturated esters,
alcohols etc. with quite precise requirements regarding double-
bond configuration for the maintenance of biological activity.1
This general situation has stimulated much of the work directed
towards the stereospecific creation of carbon-carbon double
bonds.
of under- and over-reduction.6 Meinwald also observed that a
modified P2-Nickel reduction of a substrate containing only a
single triple bond, provided the desired compound (90%),
mixed with starting material (5%) and the completely reduced
material (5%).5
Trost and Braslau7 obtained the Z-olefin from the corre-
sponding alkyne by employing an homogenous PdO-catalysed
reduction in the presence of acetic acid and a silicon hydride,
and achieved the formation of a Z,Z-diene in about 93% geo-
metric purity. A more selective transfer hydrogenation protocol
was described by Tani et al.8 and employed HCO2H–NEt3 as
the hydrogen donor with a PdO-catalyst. A high Z:E ratio was
achieved in the product and this method was promising for the
synthesis of polyene systems.
Deuterium incorporation
Traditional methods for the formation of olefins include
the Wittig reaction and the selective partial reduction of
alkynes. However, these approaches are often unable to provide
the geometric purity necessary for many studies, particu-
larly physioactivity studies involving pheromones. Methods
developed to provide increased stereocontrol have included the
hydro- or carbo-metallation/hydrolysis of alkynes,2 and the
transition metal catalysed couplings of allylic substrates with
vinylic organometallic reagents.3 The use of cycloalkenes as
starting materials, as a means of controlling the double bond
geometry, has also found application.4 Despite these develop-
ments, the reduction of polyynes to obtain the corresponding
polyenes remains an attractive route, particularly for methylene
skipped polyenes, as the required skipped polyynes are access-
ible by metal-mediated coupling of alk-1-ynes and prop-2-
ynylic halides. In these reductions, the geometric purity of the
resultant alkene is an abiding concern, as is the efficiency of the
conversion that ideally should occur without under- or over-
reduction of the triple bonds.
The partial reduction of alkynyl systems to give polyene sys-
tems was recently discussed by Meinwald and co-workers,5 and
a number of procedures for the reduction of the skipped triyne
system to the corresponding skipped triene system were
explored. Heterogeneous hydrogenation with Lindlar catalyst
(Pd–CaCO3, poisoned with quinoline), gave the product con-
taminated with other isomers, although after column chrom-
atography on AgNO3–SiO2 the required compound was
obtained in 40% yield.5 Hydrogenation using a Cu–Zn couple
also resulted in contamination with trans-isomers and products
For some biosynthetic studies, the regioselective incorporation
of deuterium is necessary. Deuteration via heterogeneous
catalysis results in undesirable deuterium scrambling.9 The
homogeneous Wilkinson’s catalyst, which reacts with alkynes
in a sequence of two separate reductions (i.e. acetylene to olefin
followed by olefin to saturated compound), overcomes this
scrambling. Although the rate of alkene reduction is slowed,
relative to the initial alkyne hydrogenation, by the addition of
relatively acidic alcohols (2,2,2-trifluoroethanol or phenol),10
further refinement of this method is required for it to become a
synthetically useful preparation of alkenes. The methods
described by Trost et al.7 and Tani et al.,8 while homogeneous
and therefore amenable to regioselective deuterium incorpor-
ation, would require more expensive deuterium sources.
The methodology utilised by Meinwald and co-workers5 to
provide both stereoselective reduction and regioselective deu-
terium incorporation, involved the Z-reduction of the skipped
triyne using bis(2-deuteriocyclohexyl)borane-D (formed in situ
from NaBD4, BF3ؒEt2O and cyclohexene) based on the
procedure described by Brown and Zweifel,11 and later
modified by Brown and Molander.12 The subsequent treatment
with CH3CO2D cleaved the vinyl borane, and released the
Z-dideuterio triene.
Skipped polyynes
In designing synthetic routes to these systems, consideration
must be given to the reactivity of the skipped polyyne pre-
cursors which are reported, and have been observed in the
current study, to be unstable and to decompose on standing.13
J. Chem. Soc., Perkin Trans. 1, 1998
1839

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R1
R2
Necessarily, access to skipped polyenes via selective reduction
of the corresponding polyynes requires efficient construction
of the latter. Alka-1,4-diynes 1 are usually prepared via CuI
catalysed cross-couplings between terminal acetylenes and
prop-2-ynylic halides or toluene-p-sulfonates (tosylates). How-
ever, the basic conditions employed (e.g. Grignard reagents)
often lead to isomeric products such as alka-1,2-dien-4-ynes 2,14
owing to the acidity of the doubly prop-2-ynylic methylene
protons (see Scheme 1).
Ti(OPri)2
Ti(OPri)2
R1
R2
2 PriMgCl
Ti(OPri)2
Ti(OPri)4
–78 to –50 °C
Et2O
R3
O
R4
HO
H
R1
R2
H
R3
R4
R1
Ti(OPri)2
O
H
R3
R4
+
H2O
R1, R2
R2
C
H
HO
R4
R3
1
2
R
R
R′
R
R′
Scheme 1
PriMgBr
TiII(OPri)2
(+C3H8)
Ti(OPri)4
Ti(OPri)2
(2 equiv.)
This problem can be avoided by treatment of prop-2-ynylic
halides or tosylates with alk-1-ynes in the presence of CuII,
Bun NCl and Na2CO3 in DMF.15 Similarly, alka-1,4-diynes
4
were reported to be readily available via the mild CuII mediated
coupling of alk-1-ynes and prop-2-ynylic chlorides or tosylates
in the presence of NaI and K2CO3 in DMF at room temper-
ature.16 A similar procedure was used in the synthesis of
(3Z,6Z,8E)-dodeca-3,6,8-trien-1-ol, a pheromone of Reticuli-
termes termites.17 These methods therefore provide ready access
to polyyne systems and consequently to the polyene system via
appropriate reduction.
R
E
R′
R′
E+
Ti(OPri)2
E
4
eg. E = D
Scheme 3
as shown in Scheme 3. This is consistent with a titanacyclopro-
pene 4 experiencing formal electrophilic substitution with
retention of alkene configuration (Scheme 3).
We now describe a method for the formation of Z-olefins,
applicable to the formation of polyenes, including skipped sys-
tems (i.e. Z,Z-alka-1,4-dienes), in geometrically pure form.
Deuterium can also be introduced regiospecifically via this
reduction, which employs TiII-based chemistry and the form-
ation of alkoxytitanium–acetylene complexes.
In connection with our studies of the biosynthesis of fruit-
fly pheromones, we required various 2H-labelled methylene
skipped trienes, and other Z-configured systems, and were
considering procedures that were versatile enough to afford
stereo- and regio-specific reduction of isolated, conjugated
and methylene-skipped alkyne systems to the corresponding
Z-dideuterio alkenes. This report describes these procedures
and various applications.
Results and discussion
Alkoxytitanium() mediated transformations are of increasing
importance and much of the recent progress made can be
traced to the remarkable observations of Kulinkovich and co-
workers,18 who described the formation of 1-substituted cyclo-
propanols from a Ti(OPri)4-catalysed reaction of esters with
ethylmagnesium bromide. This system, which was postulated to
involve a titanacyclopropane 3 functioning as a vicinal dicarb-
anion equivalent (Scheme 2), was then extensively developed by
Corey et al.19
Isolated systems
Initially the procedure was tested on the triple bond of the bis-
THP ether of oct-4-yne-1,8-diol 5. In the presence of an excess
of Ti(OPri)4 (2 equiv.) and PriMgBr (5 equiv.) (with respect to
the alkyne 5), the reaction provided, upon D2O quenching, a
single product 6 (by GC analysis) in 81% yield (Scheme 4). No
THPO
OTHP
1. EtMgBr
Ti(OPri)4
Et2O, –78 to –40 °C, 1h
R
OMe
R
OH
5
76–95%
1. 2 equiv. Ti(OPri)4
5 equiv. PriMgBr
O
2. 5% H2SO4, 5 °C
2. D2O
(81%)
2 EtMgBr 2 PriOMgBr
–
–
CH2
CH2
Et
Et
Ti(OPri)2
Ti(OPri)4
Ti(OPri)2
≡
3
C2H6
THPO
OTHP
D
D
Scheme 2
6
A new general thrust in this area was provided by Sato and
co-workers,20 who described the formation of alkoxytitanium–
alkyne complexes 4 by ligand exchange of the initially formed
diisopropoxytitanocyclopropane complex with the appropriate
alkyne. These derived complexes could be regarded as possess-
ing titanacyclopropene characteristics, and hence viewed as a
cis-vicinal alkene dianion synthon. This capability has been
demonstrated in a variety of reactions, for example, to provide
allylic alcohols (Scheme 3).21 Although the isolation and charac-
terisation of titanacyclopropene complexes have not been
achieved, Sato20 provided evidence for their intermediacy by
cleavage with D2O, which afforded the Z-configured [2H2]alkene
Scheme 4
vinylic hydrogens were present (1H NMR spectral analysis), but
in the 13C NMR spectrum, a triplet was observed at δ 129.13
due to ᎐CD, which exhibited a 13C᎐2H coupling constant of
᎐
22.9 Hz. Additionally, in the 2H NMR spectrum, a single peak
was observed at δ 5.41. Thus the spectra obtained were con-
sistent with the formation of alkene 6. The configuration of
the double bond was not confirmed in this case, and because
of the symmetrical nature of the product, incorporation of
protium instead of deuterium would not provide further
information.
1840
J. Chem. Soc., Perkin Trans. 1, 1998

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A further application of this methodology to isolated
alkenes, is discussed later when the synthesis of deuterated oleic
acid (pure Z isomer) is described.
1H coupling constants for vinylsilanes are 18–19 Hz for E- and
14 Hz for Z-configured systems.22
The reduction of skipped enynes was also examined, as
shown in Scheme 6. Enynes 10 and 11 were synthesised via a
coupling reaction between crotyl bromide and the THP ether of
but-3-ynol in a modification of the procedure of Lapitskaya
et al. (alkyne, bromide, CuII, K2CO3 and NaI in DMF).16 This
reaction provided a 3:1 mixture of 10 and the allylic rearrange-
ment product 11 in 55% yield, following flash chromatography.
Enyne 10 showed a coupling constant of 15.0 Hz for H6᎐H7
corresponding to the E-configured double bond.
Skipped systems
Initial investigations involving the formation of skipped poly-
ene systems from the corresponding polyynes were conducted
with Me3Si-protected skipped diyne 7 (refer to Scheme 5). In the
Me3Si
OTHP
Utilisation of this mixture in the TiII-reduction protocol,
7
[Ti(OPri)4 (5 equiv.) and PriMgBr (13 equiv.)] and subsequent
1. 4 equiv. Ti(OPri)4
11 equiv. PriMgBr, Et2O
O quenching, provided a mixture of dideuterio 12 and 13,
D2
with no detectable signals assignable to vinylic protons attached
to C3 and C4 (only the vinylic protons of C6 and C7 were
observed in this region of the spectrum). In the 13C NMR
spectrum of octa-3,6-dienol derivative 12, triplets were observed
corresponding to deuterated C3 and C4 at δ 129.20 and 125.63
with a 13C–2H coupling of 23.5 Hz. The corresponding carbon
signals of the hepta-3,6-dienol derivative 13 were not detected.
Application of this methodology to the synthesis of deuterated
linolenic acid (which contains the methylene-skipped Z,Z,Z-
triene system) and to the syntheses of a Z,Z-8,11-diene and a
Z,Z,Z-3,8,11-triene are described later.
2. D2O
26%
Me3Si
5
1
OTHP
D
D
D
D
8
Me3Si
OTHP
7
Conjugated systems
The TiII reduction procedure was also applied to a conju-
gated diyne system, as shown in Scheme 7. Treatment of
conjugated diyne 14 with Ti(OPri)4 (4 equiv.) and PriMgBr
(11 equiv.) resulted in the formation of conjugated tetra-
deuterio-15 which was isolated in 46% yield. A single Z,Z-diene
system was observed. In this case, small isotopically shifted
signals were observed in the high field region due to two and
1. 4 equiv. Ti(OPri)4
11 equiv. PriMgBr, Et2O
2. H2O
53%
Me3Si
5
1
OTHP
H
H H
H
possibly three bonded isotope effects of adjacent ᎐CH or ᎐CD
9
᎐
᎐
units.
Scheme 5
The reaction was repeated, this time using Ti(OPri)4 (5 equiv.)
and PriMgBr (13 equiv.), with respect to the diyne 14, to ensure
completeness of the reaction. Addition of H2O as the electro-
phile provided conjugated Z,Z-diene 16 in 41% yield after flash
chromatography. Homodecoupling experiments enabled the
identification of the overlapping signals for 9-H and 12-H, and
also the H10 and H11 signals (also overlapping). Although the
10-H/11-H multiplets were not fully analysed, the largest coup-
ling constants were ca. 9 Hz.
This is consistent with the formation of a Z,Z-configured
system. The yield of this compound was increased to 55–60%
(after chromatography) by quenching with H2O–NH4Cl or 10%
aqueous HCl. A summary of the results with a variety of yne
systems is presented in Table 1.
presence of an excess of Ti(OPri)4 (4 equiv.) and PriMgBr (11
equiv.), the diyene 7 (1 equiv.), was transformed to a single
tetradeuterio-product (by GC analysis) upon D2O quenching.
Following flash chromatography, the diene 8 was recovered in
26% yield. NMR spectral analysis showed only a small amount
of residual protium on C5. No signals were observed for
1
residual protium on C1, C2 or C4. In the H NMR spectrum,
residual H5 integrated for 0.2 protons, while in the 13C NMR
spectrum a C5 signal was observed at δ 130.59 due to residual
2
᎐CH. (Signals due to ᎐CD were not observed for C5.) The H
᎐
᎐
NMR spectrum exhibited only the expected four signals at δ
6.25, 5.53, 5.43 and 5.35 ppm (relative to CDCl3 at δ 7.24). The
reaction, when repeated with H2O quenching, provided the
corresponding protium containing product 9, in 53% yield after
flash chromatography. GC–MS Analysis indicated that a single
Synthesis of deuterated C18 fatty acids
1
isomer was formed. In this case, the H NMR spectrum con-
The synthesis of isotopically labelled fatty acids has been
reviewed.23 In our work, we required both linolenic and oleic
acids in geometrically pure form, and regiospecifically
2H-labelled, for administration to certain insect species, and
TiII-mediated reactions were employed.
firmed the Z,Z-configuration of the skipped diene. The coup-
ling constant (3J) between H4 and H5 was 10.7 Hz with that
between H1 and H2 being 14.0 Hz. Although a coupling of 14
Hz might be considered high for a Z-double bond, typical 1H–
3
OTHP
5
6
3
OTHP
OTHP
6
OTHP
5
D
D
10
1. 5 equiv. Ti(OPri)4
12
+
+
13 equiv. PriMgBr, Et2O
Br
NaI, CuI, K2CO3
DMF (53%)
3
OTHP
2. D2O
(70%)
3
6
5
5
6
D
D
13
11
Scheme 6
J. Chem. Soc., Perkin Trans. 1, 1998
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regiospecific introduction of deuterium, via the TiII-mediated
CH3
reduction, using D2O. The three retrosynthetic fragments
(Scheme 8), 19, 20 and 21 were to be linked to provide the
triyne, by successive CuI mediated couplings in the presence of
NaI and K2CO3 in DMF, as described by Lapitskaya et al.16
This procedure avoids isomerisation of alka-1,4-diynes as can
occur under basic conditions.14 The fragments 19, 20 and 21 all
trace to the THP ether of prop-2-ynyl alcohol as summarised in
Scheme 9.
OTHP
OTHP
OTHP
14
1. 4 equiv. Ti(OPri)4
11 equiv. PriMgBr, Et2O
2. D O
(46%)
2
D
D
9
11
CH3
1. BunLi, THF, HMPA
D
D
D
D
2.
D
D
15
14
I
OTHP
Br
CH3
3. Ph3P, Br2, CH2Cl2
22
19
Me3Si
1. EtMgBr, Et2O
2. Me3SiCl
22
OTHP
1. Distill
1. 5 Ti(OPri)4
2. Ph3P, Br2,
CH2Cl2
13 PriMgBr, Et2O
2. H2O
(41%)
Me3Si
H
H
OTHP
9
Br
CH3
11
H
H
20
16
1. BunLi, THF,
–78 °C
(55–60% with H2O-NH4Cl work-up)
22
2. 1-lodoheptane,
HMPA
3. p-TsOH, MeOH
OH
Scheme 7
23
2H-Labelled linolenic acid
1. KH (3 equiv.)
NH2(CH2)3NH2
2. H2O
3. DHP, p-TsOH, CH2Cl2
(38% from 22)
Linolenic acid, deuterated in the C9᎐C17 portion of the mole-
cule was required, along with the 9Z,12Z,15Z-triene system in
geometrically pure form and with regiospecific deuterium
incorporation. This is shown in 17 below (Scheme 8). Interest-
(CH2)6
OTHP
D
D
D
OH
21
D D
D D
D
Me3Si
O
20, Cul, Nal
K2CO3, DMF
(CH2)6
OTHP
17
21
(67%)
7
D
D
TBAF
(see text)
OTHP
18
(CH2)6
OTHP
D
D
14
or
CH3
Br
19
(CH2)6
OTHP
+
Br
24
Me3Si
20
Scheme 9
+
Clean removal of the Me3Si group in 7 proved troublesome,
and treatment with TBAF (2 equiv.) in THF (Ϫ5 ЊC for 1 h,
then 25 ЊC for 2 h), resulted in the isomerised, conjugated diyne
14, on the basis of mass spectra, and 1H and 13C NMR spectra.
(The terminal CH3 had δC 4.11 and δH 1.88). Repetition of the
procedure with TBAF (1 equiv., 0 ЊC, 30 min), yielded the
desired diyne 24 but in low yield (13%) after flash chrom-
atography. However, this was sufficient to trial the next coupling
reaction (Scheme 10) with the deuterated bromide 19, using the
CuI, K2CO3, NaI, DMF protocol.16
OTHP
21
Scheme 8
ingly, syntheses of various deuterated [2H3, 2H6 and 2H8]-
linolenic acids were reported recently by Meinwald and
co-workers5 for use in biosynthetic studies of insect derived
alkaloids, and Haffner et al.24 reported the use of [9,10,12,
13,15,16-2H6]linolenic acid for studies of the formation of
δ-lactones in yeast.
The desired triyne 18 was thus obtained in 71% yield, but on
storage underwent decomposition. Further efforts were made
to prepare diyne 24 in good yield, by varying the conditions for
Our plan was that skipped Z,Z,Z-triene would be obtained
from the corresponding skipped triyne 18 with concomitant
1842
J. Chem. Soc., Perkin Trans. 1, 1998

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Table 1 TiII-mediated reduction of alkynes to Z-alkenes
Isolated
Entry Starting alkyne
Reagentsa
5:2
Productb
yield(%)c
THPO
OTHP
THPO
1
81 (crude)
74d,e
OTHP
D
D
6
5
H
D
2
5:2
5:2
D
H
(CH2)3
(CH2)3
(CH2)3
OTHP
(CH2)3
OTHP
50
D
D
H
D
H
49
3
53d,e,f
H
D
D
D
D
D D
D
(CH2)3
D
H
OTHP
D
H
D
D
D
H
D
(CH2)3
OTHP
52
D
H
51
OTHP
OTHP
OTHP
4
5
13:5
11:4
42
26
H
H
H
H
OTHP
57
56
Me3Si
(CH2)6
Me3Si
Me3Si
D
D
D
D
(CH2)6
(CH2)6
OTHP
OTHP
8
7
6
7
11:4
20:8
Me3Si
53
33
(CH2)6
H
H
D
H
H
9
7
D
D
(CH2)6
OTHP
(CH2)6
OTHP
D
D
D
D
D
D
D
18
27
(CH2)6
OTHP
8
9
20:8
11:4
25
46
(CH2)6
OTHP
D
D
D
D
D
D
30
(CH2)6
OTHP
D
D
CH3
14
(CH2)6
CH3
OTHP
OTHP
D
D
(CH2)6
OTHP
OTHP
15
H
H
H
10
11
CH3
13:5
13:5
55–60
14
10
(CH2)6
CH3
H
16
D
D
70 (crude)
OTHP
OTHP
OTHP
12
11
D
D
13
a Ratio of PriMgBr:Ti(OPri)4. Per mole of starting alkynyl compound. Excess reagents were utilised to ensure complete reaction. These ratios were
optimised in the indicated cases by titration of Grignard reagent. b Deuterium-containing Z-alkenes were obtained by quenching with ca. 99.5%
D2O; others from quenching with H2O. c Refers to purified products after flash chromatography, except where indicated. d This yield was calculated
(after chromatography) by quenching with 10% aqueous HCl. e The concentration of the Grignard reagent was determined by titration with menthol
in the presence of 1,10-phenanthroline as indicator. Optimisation of the reagent ratio resulted. f This yield was lowered by the presence of an inert
contaminant which was carried through from an earlier step.
J. Chem. Soc., Perkin Trans. 1, 1998
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D
D
Br
(CH2)6
OTHP
+
Br
29
Steps as
before
19
24
Cul, Nal,
K2CO3, DMF
(71%)
14
11
(CH2)6 OTHP
(CH2)6
OTHP
D
D
D
D
D
D
30
D
D
18
1. p-TsOH–MeOH
2. PDC, DMF
Scheme 10
O
TBAF desilylation, but in addition to the desired skipped diyne
24, conjugated diyne 14 and probably two allenes [on the basis
of MS and IR (1941 cmϪ1) data] were formed. With these
impediments to obtention of the diyne 24, a new approach to
18 was developed,, involving a change in the order of coupling,
and avoidance of the trimethylsilyl (TMS)-protected alkyne 20.
The altered sequence is shown in Scheme 11.
OH
(CH2)6
D
D
D
D
D
D
32
Scheme 12
which both acid- and base-sensitive functionality are stable.25
The resulting [9,10,12,13,15,16-2H6]linolenic acid 32 was
slightly contaminated with the aldehyde (an intermediate in the
oxidation process).
D
D
D
D
23, Cul, Nal,
K2CO3, DMF
OTHP
Br
Synthesis of 2H-labelled oleic acid: (9Z)-[2,7,13,13,14,15,15-
2H7]octadec-9-en-1-oic acid
OTHP
22
19
25
Syntheses of deuterated oleic acid (Z-octadec-9-enoic acid)
have been reported.26 However, apart from the perdeuterated
oleic acid produced by incubation of S. obliquus with D2O26
and syntheses that produce oleic acid deuterated at the double
bond 26b–f (C9 and C10), few reports have described the syn-
thesis of oleic acid deuterated in both halves of the mole-
cule.26f,27,28 This is the focus of this report.
Ph3P, Br2
D
D
Br
26
The present approach to geometrically pure, deuterium
labelled oleic acid 33 was based on carbon-carbon coupling
between the C10-alkyne 34 and C8-iodide 35 (shown in Scheme
13), and including deuterium content in both C9 portions of
21, Cul, Nal,
K2CO3, DMF
(CH2)6
OTHP
D
D D
D
D
H
D
D
18
OH
1. 8 equiv. Ti(OPri)4
20 equiv. PriMgBr
2. D2O
H
H
D
D
O
33
3. p-TsOH, MeOH
D
D
(CH2)6
OH
D
D
D
D
D
D
D D
D
D
D H
28
I
OTHP
Scheme 11
H
D
H
D
34
35
The above steps were conducted as expeditiously as possible
to avoid polymerisation of diyne and triyne intermediates,
which were stored if necessary, for short periods at low temper-
atures (Ϫ20 ЊC). The [2H8]alcohol 28 was characterised and
used for biosynthetic studies.
Scheme 13
the molecule. The C10᎐C8 coupling then would provide the
alkyne ready for TiII mediated Z-reduction, in contrast to
Wittig linking of two C9 fragments, for which Z-control of
double bond configuration is more difficult.
Acquisition of labelled linolenic acid (Scheme 12) com-
menced with 1-bromopent-2-yne, 29, rather than with [4,4-2H2]-
1-bromopent-2-yne 19 utilised in the above sequence (Scheme
11). This led directly to the [2H6]-labelled tetrahydropyran-2Ј-yl
ether 30, after coupling and TiII-D2O reduction of the skipped
triyne. Normally under Jones’ oxidation conditions, THP
removal and oxidation to the carboxylic acid can be achieved in
a ‘one-pot’ operation, but with THP ether 30, this resulted in
apparent rearrangement of the skipped trienyl system, as only a
low intensity 1H NMR signal for 11-H and 14-H was observed.
Consequently, initial deprotection (p-TsOH–CH3OH) was
conducted, but again Jones’ conditions largely removed the
skipped trienyl system. The conversion to the carboxylic acid
was best accomplished using PDC/DMF — conditions under
The synthesis of alkyne 34 (see Scheme 14) commenced with
the inexpensive cyclohexane-1,3-dione 36 which was converted
to the α,β-unsaturated ketone 38 in 90% yield from the enol
ether 37.29 Epoxidation with alkaline H2O2 provided the epoxy
ketone 3930 which was fragmented cleanly via the tosylhydra-
zone, according to the Eschenmoser procedure,31 to give 6-
oxodecyne 40. The α-hydrogens (to the ketone function) were
exchanged in the presence of a large excess of basic D2O, and
with the expected exchange of the terminal alkynyl hydrogen as
well, the H5-derivative ([2H5]-40) was obtained. Conversion to
the required alkyne required reduction of the ketone without
deuterium loss, and the most expedient route was LiAlD4
2
1844
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
lactone to the corresponding lactol.)32 [2H4]Cyclooctanone 42
O
O
O
underwent Baeyer–Villiger oxidation at a very slow rate to yield
the lactone 43, but the subsequent Ti-based reduction to the
lactol was not successful. The deep-blue colour, which indicated
the presence of the TiIII species, disappeared rapidly upon
addition of the lactone, which was then recovered unchanged.
Despite thorough purification of the lactone 43, including
the recommended neutral alumina filtration,32 premature
quenching of the reductant still occurred. This method was not
pursued, and although the method works well for five- and six-
membered ring lactones, its application to other systems has
not been developed.
1. BunLi, Et2O
2. H*
O
EtOH, p-TsOH
C6H6
O
38
36
37
30% H2O2
6 M NaOH
MeOH
O
TsNHNH2
HOAc
O
CH2Cl2
O
Other methods for terminal differentiation of the deuterated
C8 system were considered, which might also circumvent the
very slow Baeyer–Villiger oxidation of cyclooctanone. These
included methods34,35,36 which provide chemodifferentiated
termini from symmetrical cyclic olefins.
40
39
1. NaOD/D2O/THF
2. LiAlD4
1. MsCl,
D
D D
D
Utilisation of the available [2H4]cyclooctanone 42 and appli-
cation of one of Schreiber’s chemodifferentiating ozonolysis
procedures,35 required Shapiro37 conversion of the ketone 42 to
cyclooctene, using TMEDA as the solvent38 which enables high
deuterium incorporation by exclusive reaction of the inter-
mediate vinyllithium species with D2O. In TMEDA, formation
of the vinyllithium is fast compared to the rate of its proton-
ation by solvent. [2H4]Cyclooctene should therefore be
obtained. However, the procedure employed (see Scheme 16),
D
D D D
Et3N,
CH2Cl2
2. LiAlH4,
Et2O
D
OH
41
H
D
D
D
34
Scheme 14
reduction followed by mesylation of the formed alcohol 41 and
hydride displacement of the mesylate. (Deuteride displacement
would permit further H incorporation). In this way, alkyne
2
D
34 was obtained in 98% yield from deuterated 6-oxodecyne
([2H5]-40) and in 14% overall yield (8 steps) from cyclohexane-
1,3-dione 36.
O
NNHTs
D
D
H2NNHTs
MeOH, HCl
D
A number of possibilities were available for the formation of
deuterated iodide 35. The use of cyclooctanone as the source of
the C8 system would enable the ready introduction of deuter-
ium, again via exchange of the α-hydrogens in the presence of
excess D2O to provide 42 (see Scheme 15). Baeyer–Villiger
42
46
(i) BunLi, TMEDA
(ii) D2O
D
D
D
D
D
D
O
O
D
O
D
D
not
D
Na, D2O
THF
mCPBA/CH2Cl2
slow
D
O
47
D
Scheme 16
D
42
43
resulted in [2H1]cyclooctene 47 and NMR spectral analysis of
the intermediate tosylhydrazone 46 revealed deuterium loss
during its formation. This problem could be overcome by using
CH3OD–DCl in the formation of the tosylhydrazone, but was
not pursued.
Cp2Ti
O
Cl
2
TBAF/Alumina
PMHS
toluene
or DlBAL-H
A more expedient route was then adopted which involved
deuterioboration–oxidation39 of octa-1,7-diene to form 48.
Monoprotection followed by flash chromatographic separation
gave the mono-tetrahdropyran-2Ј-yl ether in 43% yield. The
available hydroxy group was then mesylated and converted to
the iodide 35 (Scheme 17).
OH
O
D
D
O
Steps
I
O
D
D
D
D
D
D
45
44
The conditions for the alkyne–alkyl iodide coupling reaction
were trialled using oct-1-yne and labelled iodide 35, and use of
Scheme 15
oxidation would then provide the corresponding tetradeuterio-
lactone 43, with chemo-differentiation of the ends of the C8
chain. Reduction to the lactol 44 would enable the masked
aldehydic function to be protected as the ethylene acetal, enabl-
ing the free alcohol to be converted to the iodide, 45.
1. NaBD4
BF3•OEt2
H
D
HO
2. NaOH
H2O2
OH
D
H
48
1. DHP, pTsOH
2. MsCl, Py
3. Nal, acetone
A report by Verdaguer et al.32 described a method for the
reduction of lactones to lactols which employed catalytic
Cp2Ti(p-ClC6H4O)2 with polymethylhydrosiloxane (PMHS) in
the presence of TBAF. A TiIII hydride has been assumed to be
the active catalyst for conversion of the lactone to the silyl
lactol. This new procedure would avoid certain of the difficul-
ties associated with use of DIBAL-H, the widely used reagent
for this reduction.33 Thus the route shown in Scheme 15 was
performed (based on a successful trial reduction of δ-valero-
H
D
I
OTHP
D
H
35
Scheme 17
J. Chem. Soc., Perkin Trans. 1, 1998
1845

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salt-free Bun Li in hexane, a substantial proportion of HMPA
(overall 60% of solvent) and a reaction temperature of Ϫ30 ЊC,
led to the desired coupling. Alkyne 49 was obtained in satisfac-
tory yield (61%) after flash chromatography, and was then
reduced to Z-alkene 50, using the Ti(OPri)4–PriMgBR–H2O
quench protocol, in good yield (74%) (see Scheme 18).
D
D D
D
D
H
34
1. BunLi, THF, –78°C
2. HMPA, lodide 35
(64%)
D
D D
D
D
H
1. BunLi, THF, –78 °C
2. HMPA, Iodide 35
(61%)
D
H
OTHP
D
H
51
1. 2 equiv. Ti(OPri)4 5 equiv. PriMgBr,
Et2O, –70 to –30 °C
D
H
2. H2O (53%)
OTHP
H
D
D
D
D D
D
D
D
D
D
D
H
H
H
D
49
OTHP
1. 2 equiv. Ti(OPri)4 5 equiv. PriMgBr,
Et2O, –70 to –30 °C,
2. H2O
D
D
(74%)
H
H
52
D
H
p-TsOH, MeOH
(89%)
OTHP
D D
9
H
D
OH
50
D
D
H
H
Scheme 18
53
Application of the above procedure to deuterated alkyne 34
and iodide 35, provided the desired octadec-9-ynyl system 51 in
satisfactory yield (Scheme 19). Reduction to the Z-alkene then
afforded the deuterated Z-octadec-9-enyl compound 52 in 53%
yield, after its separation by AgNO3-impregnated silica gel
chromatography from a minor contaminate, the THP ether of
[2,7-2H2]dodecanol, apparently formed from reaction of BunLi
with iodide 35. Deprotection provided octadecenol 53 which
was oxidised with PDC in DMF quite cleanly (82%) to the
PDC/DMF
(82%)
D D
OH
D
D
H
H
O
33
Scheme 19
Attygalle et al.,13,42 who also synthesised the triene 54 (7% over-
all yield and 97% isomeric purity) to confirm its identity and to
provide material for biological testing.
deuterated oleic acid 33 (Scheme 19). The H and 13C NMR
1
spectra of 33 were consistent with the reported spectra40 for
oleic acid after allowances for the effects of the seven deuterium
atoms. The signals for C9 and C10 were appropriate for Z-oleic
acid with no signals to indicate the presence of the E-isomer.
The resonances for allylic carbons in monoenoic acids in which
the double bond is remote from CO2H groups are particularly
diagnostic,41 with those in a Z-configured system found in the
range of δ 27.2–27.4, and those for the E-isomer generally
between δ 32.6–32.7. For the presently acquired oleic acid 33
these shifts for C8 and C11 were δ 27.05 and 27.16, confirming
the Z-nature of the system and the specificity of the reduction.
The overall yield of 33 was 3.5% for the twelve steps from
cyclohexane-1,3-dione 36 or 4.7% from octa-1,7-diene (eight
steps), with regiospecific deuterium incorporation in both
‘halves’ of the molecule. No scrambling of deuterium was
detected by NMR or GC–MS analysis. Additionally, labelling
at C9, C10 could have been effected merely by quenching with
D2O in the Ti-mediated reduction step.
The important steps in the preparation of 54 relate to the
specificity for Z-reduction of the methylene skipped diyne
and isolated yne functions. Attygalle et al.13,42 utilised hydro-
boration–acetic acid cleavage and LiAlH4 reduction of a
homoprop-2-ynylic alcohol to effect the specific Z- and E-
reductions, respectively. Hydride reduction (LiAlH4, diglyme,
120–140 ЊC, 2–5 h) was adopted because attempted Na–NH3(l)
reduction to install the 3E double bond led to a hydrocarbon
mixture associated with OTHP elimination.13 A similar con-
struction of the C14 chain was executed in the current work, but
with different reduction methods. The synthesis of 54 is shown
in Scheme 20.
Diyne 56 was obtained in 54% yield (after flash chrom-
atography) via the coupling reaction between prop-2-ynylic
bromide 29 and protected pentynol 55 [CuII/K2CO3/NaI/DMF
protocol).16 This unstable diyne was then reduced to the
Z,Z-diene 57 using the TiII-methodology, in 42% yield follow-
ing chromatography. Direct conversion to the bromide was
achieved using triphenylphosphine dibromide in CH2Cl2.
However, iodide exchange [CuII/K2CO3/NaI/DMF)16 with this
bromide provided iodide 58 which was employed in the BunLi-
mediated coupling with THP-protected butynol 59 to yield
dienyne 60 in 43% yield following flash chromatography
(Scheme 20).
Deuterated oleic acid acquired in this way has potential
application in a number of biosynthetic studies and several of
these are being pursued.
Synthesis of (3E,8Z,11Z)-tetradeca-3,8,11-trienyl acetate — the
sex pheromone of Scrobilpalpuloides absoluta
The finding that skipped diynes are readily reduced to skipped
Z,Z-dienes with no detectable isomerisation can now be applied
to the synthesis of a natural system incorporating such a sub-
structure. The moth species Scrobipalpuloides absoluta Meyrick
(Lepidoptera:Gelechiidae:Gelechiinae) is a destructive pest of
tomatoes in Brazil and a number of other South American
countries and females of this species release a sex pheromone to
attract conspecific males. The methylene skipped Z,Z-diene,
(3E,8Z,11Z-tetradeca-3,8,11-trienyl acetate, was identified by
No elimination problems were encountered when Na in
liquid NH3 was employed to reduce the triple bond of dienyne
60 to the 3E-double bond and the triene 61 was obtained in
quantitative yield. After deprotection, the trienol was then con-
verted to the corresponding acetate 54 using acetic anhydride–
pyridine. The overall yield from skipped diyne 56 was 8.4% over
six steps, with purifications after each step. The H and 13C
1
1846
J. Chem. Soc., Perkin Trans. 1, 1998

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O
O
54
1. BunLi, EtBr
THF, DMPU
OTHP
55
Br
OTHP
O
O
2. Ph3P, Br2
CH2Cl2
CuI, NaI, K2CO3, DMF
29
56
22
1. 5 equiv. Ti(OPri)4
13 equiv. PriMgBr, Et2O
2. H2O
1. Ph3P, Br2, CH2Cl2
OTHP
I
2. CuI, NaI
57
58
OTHP
BunLi,
59
THF, HMPA
OTHP
Na, NH3
Et2O
OTHP
61
60
62
1. H+, MeOH, 1 h
2. Ac2O , py
1. 2.5 equiv. Ti(OPri)4, Et2O
1 equiv. PriMgBr
2. H2O
12
11
9
8
OAc
OTHP
54
+ 2 minor isomers
1. H+, MeOH, 1 h
2. Ac2O , py
OAc
63
1. Ti(OPri)4
PriMgBr, Et2O
2. H2O
OTHP
OTHP
62
64
Scheme 20
NMR and EI mass spectra for this compound were identical
with those reported.13
in the 3Z-isomer 63, C2 and C5 resonances were observed
between δ 26.79 and 26.91.
The Z-configured isomer 63 was synthesised for comparative
purposes. As also shown in Scheme 20, dienyne 60 was treated
with Ti(OPri)4 and PriMgBr and then quenched with H2O in the
normal way to provide Z,Z,Z-triene 62. Two other isomers of
62 were also formed as significant components. All three iso-
mers were converted to the corresponding acetates as before,
and the required 63 was purified by chromatography (on SiO2–
AgNO3). The minor components were isomers of 63 but did
not contain the methylene skipped diene system on the basis of
1H NMR spectra. Some isomerisation of the Z,Z-methylene
skipped diene system had therefore occurred. However, syn-
thesis of the corresponding triene 64 would enable the direct
formation of the Z,Z,Z-triene system 62 using the TiII-based
chemistry, and should provide 63 as a single isomer, based on
Summary
A TiII-based method for the Z-reduction of alkynes has been
applied to a variety of alkyne systems, and this general
approach is attractive as it employs cheap commercially avail-
able materials [Ti(OPri)4 and PriMgBr] and an inexpensive
source of deuterium (D2O), should labelling be required. The
conversion appears to be regio- and stereo-specific, affording
pure Z-configured alkenes, and no scrambling when 2H-
labelling is conducted. The method is also operationally simple
and occurs with negligible under- or over-reduction.
Experimental
1
our results with conjugated systems. The H NMR signal for
General experimental and instrumentation
3
4-H (δ 5.49) in 63 was identified and exhibited J couplings of
1H and 13C NMR spectra were recorded on a Bruker DRX500,
Bruker AMX500, JEOL JMN-GX400, Bruker AMX400 or
Bruker AC200F NMR spectrometer, with the individual fre-
quencies indicated in the text. Chemical shifts, unless otherwise
stated, are relative to residual CHCl3 (δ 7.24) in deuterochloro-
form for 1H NMR, and are relative to the central component of
the CDCl3 triplet at δ 77.00 for 13C NMR spectroscopy; J values
10.8 Hz with 3-H (Z-configured double bond), 7.3 Hz with H5
and 1.5 Hz with 2-H. Similarly the signal at δ 5.28 due to 9-H or
11-H showed a coupling of 10.6 Hz typical of the Z-configured
double bond. The allylic resonances of the 3E- and 3Z-isomers
in the 13C NMR spectrum were diagnostic.41 In the 3E-isomer
54, C2 and C5 resonated at δ 31.95 and 32.13, respectively, while
J. Chem. Soc., Perkin Trans. 1, 1998
1847

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2
are given in Hz. H NMR were recorded on either a JEOL
(0.328 g, 1.16 mmol) in Et2O (5 ml), PriMgBr (2.54 ml, 3.18
JMN-GX400 or a Bruker AMX400 in CHCl3 with a small
amount of CDCl3 for reference at δ 7.24. All 2D NMR experi-
ments were performed on a Bruker AMX500 or DRX500 spec-
trometer. GC–MS spectra were recorded using a 30 m × 0.25
mm BP5 column fitted in a Hewlett Packard HP5890 combined
with a Hewlett Packard HP5970 mass selective detector. High
resolution mass spectra were obtained on a Kratos MS25RFA
instrument. IR spectra were recorded on a Perkin-Elmer Model
397 FTIR spectrometer using liquid films between 5 mm
sodium chloride disks. Light petroleum refers to the fraction of
bp 40–60 ЊC.
mmol, ~1.25  solution in dry Et2O) and D2O (1.0 ml) accord-
ing to the general procedure. Work-up procedure A and flash
chromatography (Et2O–hexane, 1:20) provided deuterated
diene 8 (0.027 g, 26%) (Found: C, 72.2, H, 11.4. C21H36O2-
SiD4(C21H40O2Si) requires C, 71.5, H, 11.4%); δH(400 MHz,
CDCl3) 0.11 (9H, s, SiMe3), 1.22–1.38 (10H, m), 1.43–1.60 (6H,
m), 1.69 (1H, m), 1.81 (1H, m), 2.01 (2H, t, J 6.7, 6-H), 2.84
(2H, s, 3-H), 3.36 (1H, dt, J 9.7, 6.7, 13-Ha), 3.46 (1H, m,
6Ј-Ha), 3.70 (1H, dt, J 9.7, 6.9, 13-Hb), 3.85 (1H, m, 6Ј-Hb),
4.55 (1H, dd, J 4.6, 2.4, 2Ј-H), 5.38 (0.2H, t, J 7.2, residual 5-H);
δ (100 MHz, CDCl ) 130.59 (C5, residual CH᎐), 98.83, 67.66,
᎐
C
3
62.30, 31.42 (br), 30.79, 29.74, 29.61 (C7, 3 bond isotope effect
when C9 is CH᎐), 29.59 (C7, 3 bond isotope effect when C9 is
General procedure for TiII-based reductions20
᎐
Mg turnings (0.729 g, 0.03 mol) were dry-stirred for 30 min
under an N2 atmosphere and then Et2O (5 ml) was added. 2-
Bromopropane (3.075 g, 0.025 mol) in anhydrous Et2O (10 ml)
was added dropwise until the reaction commenced. Additional
Et2O (5 ml), was then added to the Mg turnings, while the
2-bromopropane addition was continued at such a rate as to
maintain gentle refluxing. Occasional cooling in an ice-bath
was required. After the addition was completed, the mixture
was stirred for 30 min and then transferred to a graduated flask
fitted with a rubber septum. Additional Et2O was added to give
20 ml of a ~1..25  PriMgBr solution.
CH᎐), 29.45, 29.43, 29.23, 27.30 (C6, adjacent to residual
᎐
CH᎐), 27.19 (C6, adjacent to residual CD᎐), 26.22, 25.52,
᎐
᎐
19.68, 0.14. Signals due to C1, C2 and C4 (CD᎐) were not
᎐
2
detected; δ H(61.3 MHz, CDCl3) 5.35, 5.43, 5.53, 6.25; m/z 356
(Mϩ, 0.2%), 173 (1), 159 (3), 156 (3), 103 (7), 101 (7), 85 (100),
83 (10), 75 (15), 73 (51), 67 (13).
(1Z,4Z)-1-Trimethylsilyl-13-(tetrahydropyran-2Ј-yloxy)trideca-
1,4-diene 9
From alkyne 7 (0.050 g, 0.289 mmol) in Et2O (3 ml), Ti(OPri)4
(0.163 g, 0.575 mmol) in Et2O (2 ml), PriMgBr (1.26 ml, 1.58
mmol, ~1.25  solution in dry Et2O) and H2O (1.0 ml) accord-
ing to the general procedure. Work-up procedure A and flash
chromatography (Et2O–hexane, 1:20) provided diene 9 (0.027
g, 53%) (Found: C, 72.5, H, 11.5. C21H40O2Si requires C, 71.5,
H, 11.4%); δH(500 MHz, CDCl3) 0.11 (9H, s, SiMe3), 1.24–1.36
[10H, m, 2 × (11-H, 10-H, 9-H, 8-H, 7-H)], 1.43–1.60 (6H, m,
2 × 12-H, 3Ј-Ha, 4Ј-Ha, 2 × 5Ј-H), 1.69 (1H, m, 3-Hb), 1.81
(1H, m, 4Ј-Hb), 2.02 (2H, q, J 7.0, 6-H), 2.85 (2H, br t, J 7.3,
3-H), 3.36 (1H, dt, J 9.6, 6.7, 13-Ha), 3.48 (1H, m, 6Ј-Ha),
3.71 (1H, dt, J 9.6, 6.9, 13b-H), 3.85 (1H, ddd, J 11.2, 7.7, 3.5,
6Ј-Hb), 4.55 (1H, dd, J 4.4, 2.9, 2Ј-H), 5.30 (1H, dtt, J 10.7, 7.1,
1.5, 4-H), 5.39 (1H, dtt, J 10.7, 7.2, 1.5, 5-H), 5.48 (1H, dt, J
13.9, 1.4, 1-H), 6.20 (1H, dt, J 14.0, 7.3, 2-H); δC(125 MHz,
CDCl3) 146.91 (C2), 130.74 (C5), 129.17 (C1), 127.24 (C4),
98.83 (C2Ј), 67.66 (C13), 62.31 (C6Ј), 31.69 (C3), 30.79 (C3Ј),
29.74, 29.60, 29.45, 29.43, 29.23, 26.22 (C12, C11, C10, C9, C8,
C7), 27.33 (C6), 25.51 (C5Ј), 19.69 (C4Ј), 0.11 [Si(CH3)3]; m/z
352 (Mϩ, 0.1%), 279 (0.1), 103 (7), 101 (6), 95 (8), 85 (100), 73
(61), 59 (22), 43 (20), 41 (32).
To the alkyne dissolved in Et2O, was added Ti(OPri)4 in
Et2O in one portion. The solution was cooled to Ϫ78 ЊC and
PriMgBr (~1.25  solution in dry Et2O) was added dropwise,
via cannula, to give a bright yellow solution. The reaction
mixture was then warmed to Ϫ30 ЊC for 2 h, during which time
the reaction mixture turned dark brown. Upon re-cooling to
Ϫ78 ЊC, D2O (or H2O) was added, and the mixture allowed to
warm to room temperature overnight.
Work-up procedure A. After filtration through Celite and
washing with Et2O, the filtrate was dried (MgSO4) and concen-
trated to yield an oil, which was purified by flash chrom-
atography.
Work-up procedure B. H2O–NH4Cl or 10% aqueous HCl was
added to quench the reaction. The organic layer was separated
and the aqueous layer extracted with Et2O. The combined
extracts were dried over MgSO4 and concentrated to yield an
oil, which was purified by flash chromatography.
1,8-Bis(tetrahydropyran-2Ј-yloxy)oct-4-yne 5
Prepared according to the known procedure.43 Crude alkyne
5 was purified by flash chromatography (Et2O–hexane, 1:5)
(Found: Mϩ, 310.2132. C18H30O4 requires Mϩ, 310.2144);
δH(400 MHz, CDCl3) 1.45–1.60 (8H, m), 1.62–1.85 (8H, m),
2.22 (4H, t, J 7.0, 3-H and 6-H), 3.43 (2H, dt, J 9.7, 6.2, 1-H
and 8-H), 3.46 (2H, m, 2 × 6Ј-Ha), 3.77 (2H, dt, J 9.7, 6.5, 1-H
and 8-H), 3.83 (2H, m, 2 × 6Јb-H), 4.56 (2H, dd, J 4.0, 2.7,
2 × 2Ј-H); δC(100 MHz, CDCl3) 98.72, 79.73, 66.05, 62.08,
30.67, 29.28, 25.48, 19.48, 15.62.
(6E)-1-(Tetrahydropyran-2Ј-yloxy)oct-6-en-3-yne 10 and
5-methyl-1-(tetrahydropyran-2Ј-yloxy)hept-6-en-3-yne 1116
Illustrative alkyne-allylic/prop-2-ynylic halide, CuI mediated
coupling procedure. Anhydrous sodium iodide (2.220 g, 14.81
mmol), copper() iodide (1.411 g, 7.41 mmol) and potassium
carbonate (2.047 g, 14.81 mmol) were stirred in dry DMF
(5 ml). 1-(Tetrahydropyran-2Ј-yloxy)but-3-yne (1.141 g, 7.41
mmol) in DMF (5 ml) was added, followed by (2E)-1-
bromobut-2-ene (1.00 g, 7.41 mmol) in DMF (5 ml). The
resultant heterogeneous yellow–green suspension was stirred
under a N2 atmosphere. Additional bromide (0.5 g) and
copper() iodide (0.7 g) were added, and stirring was continued
until the reaction was complete (GC analysis, 93% product,
48 h). Saturated aqueous NH4Cl (100 ml) was added, followed
by Et2O (80 ml) and the layers were separated and the aqueous
layer was further extracted with Et2O (5 × 50 ml). The ethereal
layers were combined and washed with 10% aqueous Na2S2O3
and saturated aqueous NaCl. The solution was dried over
MgSO4 and concentrated to give the crude products, as a 3:1
mixture. Purification by flash chromatography (Et2O–hexane,
1:20) gave a 3:1 mixture of (6E)-1-(tetrahydropyran-2Ј-
yloxy)oct-6-en-3-yne 10 and 5-methyl-1-(tetrahydropyran-2Ј-
yloxy)hept-6-en-3-yne 11 (0.851 g, 55%).
(4Z)-[4,5-2H2]-1,8-Bis(tetrahydropyran-2Ј-yloxy)oct-4-ene 6
From alkyne 5 (0.150 g, 0.484 mmol) in Et2O (5 ml), Ti(OPri)4
(0.275 g, 0.968 mmol) in Et2O (5 ml), PriMgBr (1.94 ml, 2.42
mmol, ~1.25  solution in dry Et2O) and D2O (1.0 ml) accord-
ing to the general procedure. Work-up procedure A provided 6
(0.123 g, 81%); δH(400 MHz, CDCl3) 1.42–1.88 (16H, m), 2.09
(4H, m, H3, H6), 3.35 (2H, dt, J 9.7, 6.7, 1-Ha, 8-Ha), 3.45 (2H,
m, 6Ј-Ha), 3.71 (2H, dt, J 9.7, 6.7, 1b-H, 8b-H), 3.84 (2H, m,
6Јb-H), 4.54 (1H, dd, J 4.3, 2.7, 2Ј-H); δC(100 MHz, CDCl3)
13C–2H
129.13 (t, J
22.9), 98.83, 66.98, 62.25, 30.75, 29.72,
ϩ
2
25.50, 23.71, 19.63; δ H(61.3 MHz, CDCl3) 5.41; m/z 314 (M ,
0.1%), 229 (1), 85 (100), 69 (6), 68 (5), 67 (12), 57 (13), 56 (8),
55 (9), 43 (14), 41 (19).
(1Z,4Z)-[1,2,4,5-2H4]-1-Trimethylsilyl-13-(tetrahydropyran-2Ј-
yloxy)trideca-1,4-diene 8
(6E)-1-(Tetrahydropyran-2Ј-yloxy)oct-6-en-3-yne 10. δH(400
MHz, CDCl3) 1.43–1.60 (4H, m), 1.64 (3H, ddt, J 6.5, 1.6, 1.6,
From alkyne 7 (0.100 g, 0.289 mmol) in Et2O (5 ml), Ti(OPri)4
1848
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
8-H), 1.69 (1H, m), 1.80 (1H, m), 2.46 (2H, m, 2-H), 2.82 (2H,
m, 5-H), 3.43–3.54 (2H, m, 1-Ha, 6Ј-Ha), 3.77 (1H, dt, J 9.7,
7.3, 1-Hb), 3.85 (1H, m, 6Ј-Hb), 4.61 (1H, dd, J 3.5, 3.5, 2Ј-H),
5.37 (1H, dtq, J 15.0, 5.6, 1.6), 5.64 (1H, dqt, J 14.8, 6.5, 1.6,
7-H); δC(100 MHz, CDCl3) 126.35, 125.65 (C6, C7), 98.67
(C2Ј), 78.71, 78.54 (C3, C4) 66.09 (C6Ј), 62.11 (C1), 30.55
(C3Ј), 25.42 (C5Ј), 21.92 (C5), 20.24 (C4Ј), 19.37 (C2), 17.53
(C8); m/z 207 (MϩϪ1, 0.1%), 193 (0.4), 91 (29), 85 (100), 57
(17), 55 (14), 43 (20), 41 (38), 39 (23).
(9Z,11Z)-(Tetrahydropyran-2Ј-yloxy)trideca-9,11-diene 16
From alkyne 14 (0.100 g, 0.362 mmol) in Et2O (5 ml), Ti(OPri)4
(0.515 g, 1.81 mmol) in Et2O (5 ml), PriMgBr (3.8 ml, 4.71
mmol, ~1.25  solution in dry Et2O) and H2O (1.0 ml) accord-
ing to the general procedure. Work-up procedure A and flash
chromatography (Et2O–hexane, 1:100) gave diene 16 (0.041 g,
41%) (Found: Mϩ, 280.2400. C18H32O2 requires M, 280.2402);
δH(400 MHz, CDCl3) 1.20–1.40 (10H, m), 1.43–1.61 (6H, m),
1.67 (1H, m), 1.72 (3H, br d, J 6.5, 13-H), 1.80 (1H, m), 2.12
(2 H, m, 8-H), 3.35 (1H, dt, J 9.7, 6.7, 1-Ha), 3.47 (1H, m, 6Ј-
Ha), 3.70 (1H, dt, J 9.7, 7.0, 1-Hb), 3.84 (1H, m, 6Ј-Hb), 4.54
(1H, dd, J 4.3, 2.7, 2Ј-H), 5.42 (1H, m, 9-H), 5.48 (1H, m, 12-
H), 6.24 (1H, br d, J 9, 10-H), 6.24 (1H, br d, J 9, 11-H); 9-H/
12-H versus 10-H/11-H were identified by homodecoupling
experiments; δC(100 MHz, CDCl3) 131.94, 125.83, 124.59,
123.29, 98.83, 67.65, 62.30, 30.79, 29.74, 29.60, 29.42, 29.40,
29.20, 27.48, 26.21, 25.52, 19.68, 13.07; m/z 280 (Mϩ, 0.4%),
262 (2), 196 (0.4), 135 (2), 121 (2), 85 (100), 41 (33).
5-Methyl-1-(tetrahydropyran-2Ј-yloxy)hept-6-en-3-yne
11.
δH(400 MHz, CDCl3) 1.19 (3H, d, J 7.0, 5-Me), 1.43–1.60 (4H,
m), 1.69 (1H, m), 1.80 (1H, m), 2.46 (2H, m, 2-H), 3.08 (1H, m,
5-H), 3.43–3.54 (2H, m, 1-Ha, 6Ј-Ha), 3.77 (1H, dt, J 9.7, 7.3,
1-Hb), 3.85 (1H, m, 6Ј-Hb), 4.61 (1H, dd, J 3.5, 3.5, 2Ј-H), 4.98
(1H, ddd, J 9.9, 1.6, ~1, 7-Ha), 5.22 (1H, ddd, J 16.9, 1.6, ~1,
7ϪHb), 5.76 (1H, ddd, J 16.9, 10.2, 5.6, 6-H); δC(100 MHz,
CDCl3) 139.82 (C6), 113.56 (C7), 98.63 (C2Ј), 82.82, 79.09 (C3,
C4), 66.09 (C6Ј), 62.04 (C1), 30.55 (C3Ј), 29.59 (C5), 25.42
(C5Ј), 21.41 (CH3), 20.24 (C4Ј), 19.32 (C2); m/z 208 (Mϩ, 0%),
193 (0.2), 91 (31), 85 (100), 79 (19), 77 (13), 67 (17), 65 (9), 57
(15), 55 (12), 43 (19), 41 (33), 39 (18).
Deuterated linolenic acid
1-(Tetrahydropyran-2Ј-yloxy)prop-2-yne 22
Prop-2-ynol (30.0 g, 0.535 mol) and toluene-p-sulfonic acid
(10.179 g, 0.054 mol) were dissolved in dry CH2Cl2 (400 ml) and
cooled to 0 ЊC. 3,4-Dihydro-2H-pyran (67.55 g, 0.803 mol) in
CH2Cl2 (100 ml) was added dropwise. Stirring was continued at
room temperature overnight. The reaction mixture was poured
into saturated aqueous NaHCO3. The aqueous layer was then
extracted with CH2Cl2 (3 × 100 ml). The combined organic
layers were washed with saturated aqueous NaCl, dried
(MgSO4) and concentrated. Flash chromatography (Et2O–
hexane, 1:20) gave 1-(tetrahydropyran-2Ј-yloxy)prop-2-yne 22
(8.048 g, 11%); m/z 140 (Mϩ, 1%), 139 (8), 111 (1), 101 (4),
85 (88), 83 (11), 82 (13), 57 (32), 56 (53), 55 (43), 41 (74), 39
(100).
(3Z,6E)-[3,4-2H2]-1-(Tetrahydropyran-2Ј-yloxy)octa-3,6-diene
12 and (3Z)-[3,4-2H2]-5-methyl-1-(tetrahydropyran-2Ј-
yloxy)hepta-3,6-diene 13
From alkyne mixture 10–11 (0.200 g, 0.962 mmol) in Et2O (10
ml), Ti(OPri)4 (1.367 g, 4.81 mmol) in Et2O (10 ml), PriMgBr
(10.0 ml, 12.5 mmol, ~1.25  solution in dry Et2O) and D2O (1.0
ml) according to the general procedure. Work-up procedure A
provided the mixture of products 12–13 (0.146 g, 70%).
(3Z,6E)-[3,4-2H2]-1-(Tetrahydropyran-2Ј-yloxy)octa-3,6-
diene 12. δH(400 MHz, CDCl3) 1.43–1.60 (4H, m), 1.61 (3H, br
d, J 5.4, 8-H), 1.67 (1H, m), 1.80 (1H, m), 2.32 (2H, br t, J 7.0,
2-H), 2.70 (2H, br d, J 4.8, 5-H), 3.37 (1H, dt, J 9.7, 7.0, 1-Ha),
3.46 (1H, m, 6Ј-Ha), 3.70 (1H, dt, J 9.7, 7.3, 1-Hb), 3.84 (1H, m,
6Ј-Hb), 4.56 (1H, dd, J 4.0, 3.0, 2Ј-H), 5.39 (2H, m, 6-H, 7-H);
δC(100 MHz, CDCl3) 129.30 (C6 or C7), 129.20 (C3 or C4, t,
[4,4-2H2]-1-Bromopent-2-yne 19
[4,4-2H2]-1-(Tetrahydropyran-2Ј-yloxy)pent-2-yne.44. Alkyne
22 (4.03 g, 28.77 mmol) was dissolved in THF (80 ml) in a three-
neck flask and cooled to Ϫ78 ЊC. BunLi (2.5 , 13.8 ml, 34.52
mmol) was added dropwise via syringe. The reaction mixture
was stirred at Ϫ60 to Ϫ50 ЊC for 1 h. Upon recooling to
Ϫ78 ЊC, [1,1-2H2]iodoethane (5.0 g, 31.65 mmol), dissolved in a
mixture of THF (2 ml) and HMPA (12 ml), was added drop-
wise from a dropping funnel. The resulting mixture was allowed
to warm to RT overnight. Hexane (250 ml) and water (300 ml)
were added, and the layers separated. The aqueous layer was
extracted with hexane (3 × 100 ml). After washing with satur-
ated aqueous NaCl, the combined organic layers were dried
(MgSO4) and concentrated (reduced pressure). Purification
using flash chromatography (Et2O–hexane, 1:20) yielded
pure [4,4-2H2]-1-(tetrahydropyran-2Ј-yloxy)pent-2-yne (2.759 g,
13C–2H
J
13C–2H
23.5), 125.63 (C3 or C4, t, J 23.5), 125.17 (C6 or
C7), 98.65 (C2Ј), 66.92 (C6Ј), 62.16 (C1), 30.67, 30.32, 27.70,
25.46, 19.51, 17.78 (C8); m/z 212 (Mϩ, 0.1%), 128 (1), 111 (2),
110 (3), 101 (8), 95 (6), 85 (100).
(3Z)-[3,4-2H2]-5-Methyl-1-(tetrahydropyran-2Ј-yloxy)hepta-
3,6-diene 13. δH(400 MHz, CDCl3) 1.03 (3H, d, J 7.0, 5-Me),
1.43–1.60 (4H, m), 1.67 (1H, m), 1.80 (1H, m), 2.32 (2H, br t,
J 7.0, 2-H), 3.15 (1H, m, 5-H), 3.37 (1H, dt, J 9.7, 7.0, 1-Ha),
3.46 (1H, m, 6Ј-Ha), 3.70 (1H, dt, J 9.7, 7.3, 1-Hb), 3.84 (1H, m,
6Ј-Hb), 4.56 (1H, dd, J 4.0, 3.0, 2Ј-H), 4.88 (1H, ddd, J 10.5,
1.6, ~1, 7-Ha), 4.95 (1H, ddd, J 17.1, 1.6, ~1, 7-Hb), 5.74 (1H,
ddd, J 16.9, 10.7, 6.2, 6-H); δC(100 MHz, CDCl3) 142.76 (C6),
112.28 (C7). Other signals were not detected.
2
(9Z,11Z)-[9,10,11,12-2H4]-1-(Tetrahydropyran-2Ј-yloxy)-
trideca-9,11-diene 15
56%) (Found: Mϩ Ϫ 1, 169.1214. C10H13O2 H2 requires Mϩ Ϫ
1, 169.1198); δH(400 MHz, CDCl3) 1.10 (3H, s, 5-H), 1.55 (4H,
m, 3Ј-H, 4Ј-H or 5Ј-H), 1.71 (1H, m, 3Ј-H, 4Ј-H or 5Ј-H), 1.81
(1H, m, 3Ј-H, 4ЈH or 5Ј-H), 3.50 (1H, m, 6Ј-Ha), 3.82 (1H, ddd,
J 11.6, 9.1, 3.2, 6Ј-Hb), 4.16 (1H, d, J 15.3, 1-Ha), 4.27 (1H, d,
J 15.3, 1-Hb), 4.78 (1H, t, J 3.5, 2Ј-H); δC(100 MHz, CDCl3)
96.69, 87.95, 75.11, 61.95, 54.65, 30.29, 25.38, 19.10, 13.54,
11.95 (quintet, J 19.8); m/z 170 (Mϩ, 0.1%), 101 (37), 85 (100),
69 (86), 67 (56), 55 (61), 43 (87), 42 (68), 41 (88), 40 (46), 39 (43).
[4,4-2H2]-1-Bromopent-2-yne 1945 (illustrative procedure for
conversion of THP ether to the corresponding bromide). Tri-
phenylphosphine (4.24 g, 16.2 mmol) was dissolved in dry
CH2Cl2 (60 ml) and the solution was cooled to 0 ЊC. Bromine
(0.83 ml, 2.59 g, 16.2 mmol) dissolved in CH2Cl2 (25 ml) was
added dropwise from a dropping funnel and a white precipitate
was formed. Towards the end of the addition, the yellow colour
of bromine in solution persisted. The solution was stirred for 30
min, after which time the yellow colour remained. Sufficient
triphenylphosphine was added to discharge the coloration.
From alkyne 14 (0.100 g, 0.362 mmol) in Et2O (5 ml), Ti(OPri)4
(0.412 g, 1.45 mmol) in Et2O (5 ml), PriMgBr (3.19 ml, 3.99
mmol, ~1.25  solution in dry Et2O) and D2O (1.0 ml) accord-
ing to the general procedure. Work-up procedure A and flash
chromatography (Et2O–hexane, 1:20) gave deuterated diene 15
(0.047 g, 46%) (Found: C, 78.4, H, 11.7. C18H28O2D4 (C18H32O2)
requires C, 77.1, H, 11.5%); δH(400 MHz, CDCl3) 1.20–1.40
(10H, m), 1.43–1.63 (6H, m), 1.68 (1H, m), 1.71 (3H, s, 13-H),
1.80 (1H, m), 2.13 (2H, t, J 7.0, 8-H), 3.36 (1H, dt, J 9.4,
6.7, 1-Ha), 3.47 (1H, m, 6Ј-Ha), 3.70 (1H, dt, J 9.4, 7.0, 1-Hb),
3.85 (1H, m, 6Ј-Hb), 4.55 (1H, dd, J 4.3, 2.7, 2Ј-H); δC(100
MHz, CDCl3) 98.83, 67.65, 62.30, 30.81, 29.76, 29.61, 29.43,
29.42, 29.22, 27.36, (26.23, 26.22Ϫ signals due to residual
protium), 26.20, 25.53, 19.68, 12.98 (C13). No signals were
detected for C9, C10, C11 or C12 (CD᎐); m/z 284 (Mϩ, 0.2%),
᎐
266 (1), 207 (1), 167 (1), 137 (1), 110 (3), 109 (3), 101 (9),
85 (100).
J. Chem. Soc., Perkin Trans. 1, 1998
1849

View Article Online
[4,4-2H2]-1-(Tetrahydropyran-2Ј-yloxy)pent-2-yne (2.50 g, 14.7
mmol) in CH2Cl2 was added in one portion and stirring was
continued overnight. Et2O (10 ml) was added, followed by
saturated aqueous NaHCO3 (200 ml). This aqueous layer was
extracted with CH2Cl2 (5 × 80 ml). The combined organic
layers were then washed with saturated aqueous Na2S2O3 and
aqueous NaCl, dried (MgSO4) and evaporated. Flash chrom-
atography (100% light petroleum) gave [4,4-2H2]-1-bromopent-
2-yne 19 (1.856 g, 85%); δH(500 MHz, CDCl3) 1.10 (3H, s, 5-H),
3.90 (2H, s, 1-H); δC(125 MHz, CDCl3) 89.38, 74.65, 15.66,
13.24, 12.01 (quintet, J 20.0); m/z 150, 148 (Mϩ, 10, 8%), 135
(2), 133 (1), 81 (9), 79 (8), 69 (100), 43 (45), 42 (46), 41 (28),
40 (33).
Dec-2-yn-l-ol 23. The crude THP ether was dissolved in
Analar MeOH (500 ml). Toluene-p-sulfonic acid (1.357 g, 7.14
mmol) was added and the mixture was stirred overnight. Satur-
ated aqueous NaHCO3 (1000 ml) and Et2O (300 ml) were
added. After separation of the layers, the aqueous layer was
further extracted with Et2O (3 × 200 ml). The combined
organic layers were washed with aqueous NaCl, dried and con-
centrated. Purification of the crude product by flash chrom-
atography (Et2O–hexane, 1:7) yielded dec-2-yn-l-ol 23 (6.967 g,
63% over two steps) (Found: Mϩ Ϫ 1, 153.1282. C10H17O
requires Mϩ Ϫ 1, 153.1279); δH(400 MHz, CDCl3) 0.86 (3H, t,
J 7.0, 10-H), 1.21–1.39 (8H, m, 6-H to 9-H), 1.48 (2H, quintet,
J 7.1, 5-H), 1.52 (1H, br s, OH), 2.18 (2H, tt, J 7.1, 2.2, 4-H),
4.22 (2H, br s, 1-H); δC(100 MHz, CDCl3) 86.66, 78.28, 51.42,
31.71, 28.82, 28.78, 28.61, 22.60, 18.72, 14.03; m/z 111
(Mϩ Ϫ 43, 10%), 107 (12), 81 (44), 79 (44), 70 (46), 69 (33), 67
(61), 55 (83), 43 (73), 41 (100), 39 (62).
3-Bromo-1-trimethylsilylpropyne 20
3-(Tetrahydropyran-2Ј-yloxy)-1-trimethylsilylpropyne.
1-
Bromoethane (55.0 g, 0.5 mol) in anhydrous THF (150 ml) was
added dropwise to a mixture of Mg turnings (12.2 g, 0.12 mol)
and THF (50 ml), under a N2 atmosphere. Heat was evolved as
the Grignard reagent formed. Upon completion of the add-
ition, the mixture was stirred and immersed in a hot water bath
for 30 min. 1-(Tetrahydropyran-2Ј-yloxy)prop-2-yne 22 (70.0
g, 0.5 mol) was dissolved in THF (150 ml) and added to the 0 ЊC
Grignard solution. The reaction mixture was then stirred at
0 ЊC for 10 min and then at RT for 30 min. Chlorotrimethyl-
silane (11.95 g, 0.11 mol) in THF (50 ml) was added dropwise
over a period of an hour. The mixture was then warmed to
50 ЊC for 1 h. The reaction mixture was poured into saturated
aqueous NH4Cl (800 ml), Et2O was added and the layers separ-
ated before the aqueous portion was further extracted with Et2O
(3 × 400 ml). The combined organic layers were washed with
saturated aqueous NaCl, dried (MgSO4) and concentrated in
vacuo. Distillation (80 ЊC, 1.5 mm Hg) afforded pure 3-(tetra-
hydropyran-2Ј-yloxy)-1-trimethylsilylpropyne (29.6 g, 36%);
δH(400 MHz, CDCl3) 0.13 (9H, s, SiMe3), 1.44–1.85 (6H, m,
3Ј-H, 4Ј-H, 5Ј-H), 3.45–3.51 (1H, m, 6Ј-Ha), 3.79 (1H, ddd,
J 3.0, 9.3, 12.2, 6Ј-Hb), 4.17 (1H, d, J 15.9, 3-Ha), 4.24 (1H, d,
J 15.9, 3-Hb), 4.77 (1H, t, J 3.4, 2Ј-H); δC(100 MHz, CDCl3)
101.51, 96.70, 90.77, 61.83, 54.74, 30.18, 25.32, 18.93, Ϫ0.23;
m/z 212 (Mϩ, 0.4%), 211 (1), 173 (13), 111 (40), 103 (37), 101
(49), 85 (100), 83 (78), 75 (44), 73 (60), 55 (53), 43 (47), 41 (42).
3-Bromo-1-trimethylsilylpropyne 20. This was prepared from
3-(tetrahydropyran-2Ј-yloxy)-1-trimethylsilylpropyne (25.0 g,
0.118 mol) in the manner described for obtaining bromide 19.
Distillation under reduced pressure (46 ЊC, 2 mm Hg) gave pure
3-bromo-1-trimethylsilylpropyne 20 (18.3 g, 81%); δH(400
MHz, CDCl3) 3.88 (2H, s, 3-H), 0.15 (9H, s, SiMe3); δC(100
MHz, CDCl3) 99.98, 92.29, 14.61, Ϫ0.37; m/z 192, 190 (Mϩ,
1%), 177 (100), 175 (98), 149 (95), 147 (87), 139 (51), 137 (49),
111 (30), 96 (41), 53 (52), 43 (84).
1-(Tetrahydropyran-2Ј-yloxy)dec-9-yne 21
Dec-9-yn-l-ol.46 Potassium hydride (mineral oil dispersion,
2.4 ml, 35 wt%) was transferred to a three-necked flask (flame-
dried under N2). Dry Et2O (20 ml) was added, with stirring, to
wash the KH, which was then allowed to settle, before the Et2O
was drawn off with a syringe. This procedure was repeated
twice. Residual Et2O was removed in vacuo. The system was
then flushed with N2 again. 1,3-Diaminopropane (30 ml) was
transferred to the flask and stirred for 1.5 h. A yellow–green
solution resulted. Dec-2-yn-l-ol 23 (1.042 g, 6.77 mmol) in 1,3-
diaminopropane (5 ml) was added dropwise, via syringe, to the
reaction mixture, at 0 ЊC. A precipitate was observed to form
and the reaction mixture was left to stir at RT overnight. A
green–brown cloudy mixture resulted. The mixture was poured
into iced-water and the aqueous layer was then extracted with
Et2O. The combined ethereal layers were washed with aqueous
HCl (3 ) and then with H2O until the washes were of neutral
pH. After washing with saturated aqueous NaCl, the organic
layers were dried (MgSO4) and concentrated to yield crude dec-
9-yn-1-ol which was used in the next step without further puri-
fication; δH(400 MHz, CDCl3) 1.21–1.41 (8H, m), 1.45–1.58
(4H, m), 1.59 (1H, br s, OH), 1.90 (1H, t, J 2.7, 10-H), 2.15 (2H,
dt, J 7.1, 2.7, 8-H), 3.60 (2H, t, J 6.6, 1-H); δC(100 MHz,
CDCl3) 84.69, 68.05, 62.97, 32.71, 29.22, 29.00, 28.62,
28.42, 25.64, 18.34; m/z 121 (4%), 95 (25), 94 (9), 93 (34), 91
(9), 81 (46), 80 (21), 79 (67), 67 (64), 55 (81), 41 (100), 39 (57).
1-(Tetrahydropyran-2Ј-yloxy)dec-9-yne 21. Crude dec-9-yn-
l-ol (1.042 g, 6.77 mmol) was dissolved in dry CH2Cl2 (100 ml).
Toluene-p-sulfonic acid (0.129 g, 0.67 mmol) was then added
and dihydropyran (0.854 g, 10.15 mmol) in CH2Cl2 (20 ml) was
added dropwise. The reaction mixture was left stirring over-
night and then poured into saturated aqueous NaHCO3, which
was extracted with CH2Cl2 (2 × 20 ml). The combined organic
fractions were washed with saturated aqueous NaCl, dried over
MgSO4 and the solvent removed under reduced pressure. Flash
chromatography (Et2O–hexane, 1:20) gave 1-(tetrahydropyran-
2Ј-yloxy)dec-9-yne 21 (0.929 g, 58%) (Found: Mϩ, 238.1929; C,
77.4, H, 11.3%; C15H26O2 requires Mϩ, 238.1933; C, 75.6, H,
11.0%); δH(400 MHz, CDCl3) 1.22–1.41 (8H, m), 1.42–1.61
(8H, m), 1.62–1.85 (2H, m), 1.91 (1H, t, J 2.6, 10-H), 2.15 (2H,
dt, J 7.0, 2.6, 8-H), 3.36 (1H, dt, J 9.7, 6.7, 1-Ha), 3.47 (1H, m,
6Ј-Ha), 3.70 (1H, dt, J 9.7, 6.9, 1-Hb), 3.85 (1H, ddd, J 11.3,
7.5, 3.7, 6Ј-Hb), 4.55 (1H, dd, J 4.6, 2.4, 2Ј-H); δC(100 MHz,
CDCl3) 98.86, 84.74, 68.03, 67.64, 62.33, 30.81, 29.74, 29.31,
29.02, 28.68, 28.47, 26.19, 25.53, 19.70, 18.38; m/z 238 (Mϩ,
0.2%), 237 (1), 101 (29), 85 (100), 81 (18), 67 (22), 57 (11), 56
(20), 55 (27), 41 (40).
Dec-2-yn-1-ol 23
1-(Tetrahydropyran-2Ј-yloxy)dec-2-yne. 1-(Tetrahydropyran-
2Ј-yloxy)prop-2-yne 22 (10.00 g, 71.4 mmol) was dissolved in
THF (200 ml) in a three-necked flask and cooled to Ϫ78 ЊC.
BunLi (2.5 , 34.3 ml, 85.7 mmol) was added dropwise via
syringe and the reaction mixture was stirred for 3 h between
Ϫ78 and Ϫ50 ЊC. After re-cooling to Ϫ78 ЊC, 1-iodoheptane
(17.765 g, 78.6 mmol), dissolved in a mixture of THF (100 ml)
and HMPA (10 ml), was added dropwise. The resulting mixture
was allowed to warm to RT overnight. Hexane (300 ml) and
iced-water (600 ml) were added, and the layers were separated.
The aqueous layer was extracted with hexane (3 × 150 ml).
After washing with H2O and saturated aqueous NaCl, the
combined organic layers were dried (MgSO4) and concentrated
(reduced pressure) to give the crude product which was used
directly in the next reaction; m/z 238 (Mϩ, 0.1%), 237 (0.1), 209
(0.2), 183 (1), 167 (2), 154 (1), 153 (2), 111 (13), 101 (29), 95
(46), 85 (100), 81 (50), 79 (25), 67 (48), 55 (48), 43 (41), 41 (64),
39 (22).
1-Trimethylsilyl-13-(tetrahydropyran-2Ј-yloxy)trideca-1,4-diyne 7
This was formed from 1-(tetrahydropyran-2Ј-yloxy)dec-9-yne
21 (4.00 g, 16.8 mmol) and 3-bromo-1-trimethylsilylpropyne 20
(3.86 g, 20.0 mmol) according to the procedure described for
1850
J. Chem. Soc., Perkin Trans. 1, 1998

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the preparation of 10 and 11. The title compound 7 (3.63 g,
62%) was purified by flash chromatography (Et2O–hexane,
1:19); δH(400 MHz, CDCl3) 0.13 (9H, s, Me3Si), 1.20–1.40 (8H,
m), 1.41–1.61 (8H, m), 1.62–1.85 (2H, m), 2.12 (2H, tt, J 7.0,
2.4, 6-H), 3.15 (2H, t, J 2.3, 3-H), 3.35 (1H, dt, J 9.4, 6.7,
13-Ha), 3.45 (1H, m, 6Ј-Ha), 3.70 (1H, dt, J 9.7, 7.0, 13-Hb),
3.84 (1H, ddd, J 11.0, 7.8, 3.8, 6Ј-Hb), 4.54 (1H, dd, J 4.3, 2.4,
2Ј-H); δC(100 MHz, CDCl3) 100.84, 98.83, 84.59, 81.03, 73.34,
67.63, 62.30, 30.79, 29.73, 29.34, 29.06, 28.78, 28.65, 26.19,
25.53, 19.69, 18.71, 10.86, Ϫ0.09; m/z 275 (Mϩ Ϫ 73, 1%), 173
(3), 159 (3), 145 (3), 135 (4), 133 (4), 131 (5), 103 (9), 101 (12), 85
(100), 75 (14), 73 (48).
276 (Mϩ Ϫ 1, 0.1%), 163 (1), 135 (3), 133 (2), 131 (4), 117 (11),
115 (3), 105 (9), 91 (24), 85 (100), 41 (37).
Attempted rearrangement of 7 with HF. 1-Trimethylsilyl-13-
(tetrahydropyran-2Ј-yloxy)trideca-1,4-diyne 7 (0.015 g, 0.043
mmol) was dissolved in acetonitrile (1 ml) and aqueous HF
(170 µl, 50%) was added dropwise via syringe at 0 ЊC. Stirring
was continued for 30 min when solid NaHCO3 was added, and
the reaction mixture was then washed through a short plug of
MgSO4 with Et2O, and concentrated in vacuo. GC–MS analysis
indicated the presence of a new product which was not identi-
fied, but still exhibited m/z 85 (THP) and 73 (SiMe3); m/z 173
(6%), 131 (9), 119 (8), 103 (13), 101 (13), 85 (100), 73 (53), 55
(23), 44 (62), 43 (24), 41 (22).
Attempted formation of 1-(tetrahydropyran-2Ј-yloxy)trideca-
9,12-diyne 24
Attempted rearrangement of 7 with K2CO3. 1-Trimethylsilyl-
13-(tetrahydropyran-2Ј-yloxy)trideca-1,4-diyne
7 (0.010 g,
Rearrangement of 7 to 1-(tetrahydropyran-2Јyloxy)trideca-
9,11-dinye 14. 1-Trimethylsilyl-13-(tetrahydropyran-2Ј-yloxy)-
trideca-1,4-diyne 7 (3.40 g, 9.83 mmol) was dissolved in THF
(200 ml) and cooled to Ϫ5 ЊC. TBAF (19.7 ml, 1.0  in THF)
was added dropwise via syringe. The reaction mixture immedi-
ately went black, but was left to stir for 1 h at Ϫ5 ЊC and then at
25 ЊC for 2 h. It was then diluted with Et2O (500 ml) and washed
with saturated aqueous NaCl (2 × 100 ml), dried (MgSO4) and
concentrated. Flash chromatography (Et2O–hexane, 1:19) gave
1-(tetrahydropyran-2Ј-yloxy)trideca-9,11-diyne 14 (2.28 g,
94%) (Found: Mϩ, 276.2087. C18H28O2 requires Mϩ, 276.2089);
δH(400 MHz, CDCl3) 1.20–1.86 (18H, m, 9 × CH2), 1.88 (3H, s,
13-H), 2.20 (2H, t, J 7.0, 8-H), 3.35 (1H, dt, J 9.7, 6.7, 1-Ha),
3.46 (1H, m, 6Ј-Ha), 3.70 (1H, dt, J 9.7, 7.0, 1-Hb), 3.85 (1H,
ddd, J 11.0, 7.8, 3.8, 6Ј-Hb), 4.55 (1H, dd, J 4.3, 2.7, 2Ј-H);
δC(100 MHz, CDCl3), 98.85, 76.91, 72.91, 67.63, 65.30, 64.58,
62.32, 30.79, 29.72, 29.28, 29.00, 28.74, 28.31, 26.17, 25.52,
19.69, 19.12, 4.11; m/z 276 (Mϩ, 0.4%), 261 (9), 119 (12), 117
(11), 105 (20), 101 (11), 91 (32), 85 (100), 79 (18), 77 (21), 67
(23), 41 (46).
Rearrangement of 7 to 1-(tetrahydropyran-2Ј-yloxy)trideca-
9,12-diyne 24. 1-Trimethylsilyl-13-(tetrahydropyran-2Ј-yloxy)-
trideca-1,4-diyne 7 (0.277 g, 0.801 mmol) was dissolved in THF
(16 ml) and cooled to Ϫ10 ЊC. TBAF (0.801 ml, 1.0  in THF)
was added dropwise via syringe. The reaction mixture immedi-
ately went black, but was left to stir for 30 min between Ϫ10
and 0 ЊC. It was then diluted with Et2O (50 ml) and washed with
saturated aqueous NaCl (2 × 10 ml), dried (MgSO4) and con-
centrated. Flash chromatography (Et2O–hexane, 1:19) gave
1-(tetrahydropyran-2Ј-yloxy)trideca-9,12-diyne 24 (0.030 g,
13%); δH(500 MHz, CDCl3) 1.25–1.60 (18H, m), 1.65–1.72 (1H,
m), 1.76–1.83 (1H, m), 2.03 (1H, t, J 2.5, 13-H), 2.13 (2H, tt,
J 7.0, 2.4, 8-H), 3.13 (2H, q, J 2.5, 11-H), 3.36 (1H, dt, J 9.6,
6.7, 1-Ha), 3.47 (1H, m, 6Ј-Ha), 3.71 (1H, dt, J 9.6, 6.9, 1-Hb),
3.85 (1H, m, 6Ј-Hb), 4.54 (1H, dd, J 2.8, 4.5, 2Ј-H); m/z 275
(Mϩ Ϫ 1, 0.4%), 237 (1), 119 (4), 117 (5), 105 (9), 101 (25), 91
(23), 85 (100), 55 (22), 41 (34).
Rearrangement of 7 to allenes and conjugated isomers. 1-
Trimethylsilyl-13-(tetrahydropyran-2Ј-yloxy)trideca-1,4-diyne 7
(0.504 g, 1.45 mmol) was dissolved in THF (30 ml) and cooled
to Ϫ10 ЊC. TBAF (1.45 ml, 1.0  in THF) was added dropwise
via syringe. The reaction mixture immediately went black,
but was left to stir for 30 min between Ϫ10 and 0 ЊC. The
reaction was then diluted with Et2O (50 ml) and washed with
saturated aqueous NaCl (2 × 10 ml), dried (MgSO4) and con-
centrated to give (0.41 g) of an oil which by GC–MS analysis
was a mixture of four components, corresponding to 1-(tetra-
hydropyran-2Ј-yloxy)trideca-9,12-diyne 24 (12% by GC), and
rearrangement products 1-(tetrahydropyran-2Ј-yloxy)trideca-
9,11-diyne 14 (25%), 1-(tetrahydropyran-2Ј-yloxy)trideca-9,10-
dien-12-yne (19%), and 1-(tetrahydropyran-2Ј-yloxy)trideca-
11,12-dien-9-yne (43%). νmax(thin film)/cmϪ1 1941 (br, allene);
1-(tetrahydropyran-2Ј-yloxy)trideca-9,10-dien-12-yne; m/z 275
(Mϩ Ϫ 1, 0.2%), 163 (1), 133 (2), 131 (2), 117 (5), 85 (100), 41
(39). 1-(Tetrahydropyran-2Ј-yloxy)trideca-11,12-dien-9-yne; m/z
0.029 mmol) was dissolved in MeOH (1 ml) and K2CO3 (10 mg)
was added. Upon stirring overnight, GC–MS examination of
the crude product showed that no reaction had occurred, with
only starting material being observed.
[17,17-2H2]-1-(Tetrahydropyran-2Ј-yloxy)octadeca-9,12,15-
triyne 18
Prepared according to the procedure described for the prepar-
ation of 10 and 11, from 1-(tetrahydropyran-2Ј-yloxy)trideca-
9,12-diyne 24 (30 mg, 0.109 mmol) and [4,4-2H2]-1-bromopent-
2-yne 19 (19 mg, 0.130 mmol). The crude product was purified
by flash chromatography (Et2O–hexane, 1:20) to yield [17,
17-2H2]-1-(tetrahydropyran-2Ј-yloxy)octadeca-9,12,15-triyne18
(0.029 g, 71%); δH(400 MHz, CDCl3), 1.07 (3H, s, 18-H), 1.15–
1.38 (8H, m), 1.42–1.60 (8H, m), 1.68 (1H, m), 1.80 (1H, m),
2.12 (2H, br t, J 6.7, 8-H), 3.11 (4H, m), 3.36 (1H, dt, J 9.7, 6.7,
1-Ha), 3.47 (1H, m, 6Ј-Ha), 3.70 (1H, dt, J 9.7, 7.0, 1-Hb), 3.84
(1H, m, 6Ј-Hb), 4.55 (1H, m, 2Ј-H); δC(100 MHz, CDCl3) 98.85,
82.03, 80.84, 74.89, 74.80, 73.76, 73.19, 67.66, 62.33, 30.79,
29.73, 29.33, 29.06, 28.81, 28.70, 26.19, 25.52, 19.69, 18.70,
13.62, 9.78, 9.74 [C17 (CD2) not observed]; m/z 329 (Mϩ Ϫ 15,
0.4%), 159 (5), 157 (5), 155 (4), 145 (7), 143 (10), 131 (13), 130
(16), 129 (15), 101 (15), 85 (100), 55 (25), 43 (20), 41 (36).
[7,7-2H2]-1-(Tetrahydropyran-2Ј-yloxy)octa-2,5-diyne 25
Formed according to the procedure described for the prepar-
ation of 10 and 11, from 1-(tetrahydropyran-2Ј-yloxy)prop-2-
yne 22 (0.473 g, 3.38 mmol) and [4,4-2H2]-1-bromopent-2-yne
19 (0.500 g, 3.38 mmol). Purification by flash chromatography
(Et2O–hexane, 1:20) yielded [7,7-2H2]-1-(tetrahydropyran-2Ј-
yloxy)octa-2,5-diyne 25 (0.292 g, 42%); δH(500 MHz, CDCl3),
1.06 (3H, t, J 1.0, 8-H), 1.45–1.84 (6H, m), 3.14 (2H, t, J 2.1,
4-H), 3.49 (1H, m, 6Ј-Ha), 3.79 (1H, ddd, J 12.0, 9.2, 3.0,
6Ј-Hb), 4.17 (1H, dt, J 15.3, 2.1, 1-Ha), 4.26 (1H, dt, J 15.3, 2.2,
1-Hb), 4.76 (1H, t, J 3.5, 2Ј-H); δC(125 MHz, CDCl3) 96.79,
82.20, 80.83, 75.98, 72.77, 61.89, 54.47, 30.20, 25.32, 19.01,
13.56, 9.83 [C7 (CD2) not observed]; m/z 207 (Mϩ Ϫ 1, 1%), 108
(23), 107 (30), 105 (31), 93 (42), 85 (100), 81 (50), 80 (49), 79
(51), 78 (55), 55 (48), 43 (45), 41 (70).
[7,7-2H2]-1-Bromoocta-2,5-diyne 26
Prepared from [7,7-2H2]-1-(tetrahydropyran-2Ј-yloxy)octa-2,5-
diyne 25 (0.250 g, 1.20 mmol) in the manner described for
obtaining bromide 19. Flash column chromatography (100%
light petroleum) gave [7,7-2H2]-1-bromoocta-2,5-diyne 26 (0.107
g, 48%); δH(400 MHz, CDCl3) 1.08 (3H, s, 8-H), 3.18 (2H, t, J
2.4, 4-H), 3.89 (2H, t, J 2.4, 1-H); δC(100 MHz, CDCl3) 82.63,
82.10, 75.25, 72.19, 14.79, 13.56, 11.78 (C7, quintet, J 20.2),
10.05; m/z 188, 186 (Mϩ, 22, 21%), 173 (6), 171 (6), 107 (100),
105 (54), 81 (72), 80 (70), 79 (76), 78 (85), 77 (35), 52 (40), 51 (50).
[17,17-2H2]-1-(Tetrahydropyran-2Ј-yloxy)octadeca-9,12,15-
triyne 18
Formed according to the procedure described for the prepar-
ation of 10 and 11, from 1-(tetrahydropyran-2Ј-yloxy)dec-9-yne
21 (0.141 g, 0.591 mmol) and [7,7-2H2]-1-bromoocta-2,5-diyne
J. Chem. Soc., Perkin Trans. 1, 1998
1851

View Article Online
26 (0.092 g, 0.492 mmol). Purification by flash chromatography
(Et2O–hexane, 1:20) yielded [17,17-2H2]-1-(tetrahydropyran-2Ј-
yloxy)octadeca-9,12,15-triyne 18 (0.094 g, 56%). NMR and
GC–MS spectra were identical to those reported earlier.
(9Z,12Z,15Z)-[9,10,12,13,15,16-2H6]-1-(Tetrahydropyran-2Ј-
yloxy)octadeca-9,12,15-triene 30
1-(Tetrahydropyran-2Ј-yloxy)octa-2,5-diyne.
Prepared
according to the procedure described for the preparation of 10
and 11, from 1-(tetrahydropyran-2Ј-yloxy)prop-2-yne 22 (1.417
g, 10.12 mmol) and 1-bromopent-2-yne 29 (1.488 g, 10.12
mmol). Purification of the crude product by flash chroma-
tography (Et2O–hexane, 1:2) yielded 1-(tetrahydropyran-2Ј-
yloxy)octa-2,5-diyne (0.696 g, 33%); m/z 205 (Mϩ Ϫ 1, 1%), 121
(5), 119 (5), 117 (5), 111 (8), 105 (30), 103 (37), 91 (65), 85 (88),
79 (75), 78 (39), 77 (100), 41 (83), 39 (61).
1-Bromoocta-2,5-diyne. Prepared from 1-(tetrahydropyran-
2Ј-yloxy)octa-2,5-diyne (0.696 g, 3.38 mmol) according to the
general procedure described for bromide 19. Purification by
flash chromatography (100% light petroleum) gave 1-bromo-
octa-2,5-diyne (0.416 g, 67%); δH(200 MHz, CDCl3) 1.10 (3H, t,
J 7.5, 8-H), 2.15 (2H, qt, J 7.5, 2.4, 7-H), 3.19 (2H, tt, J 2.4, 2.3,
4-H), 3.89 (2H, t, J 2.3, 1-H); δC(50 MHz, CDCl3) 82.68, 82.06,
75.24, 72.15, 14.86, 13.77, 12.33, 10.06.
(9Z,12Z,15Z)-[9,10,12,13,15,16,17,17-2H8]-1-(Tetrahydro-
pyran-2Ј-yloxy)octadeca-9,12,15-triene 27
From triyne 18 (0.085 g, 0.247 mmol) in Et2O (5 ml), Ti(OPri)4
(0.562 g, 1.98 mmol) in Et2O (5 ml), PriMgBr (3.95 ml, 0.94
mmol, ~1.25  solution in dry Et2O) and D2O (1.0 ml) accord-
ing to the general procedure. Work-up procedure A and flash
chromatography (Et2O–hexane, 1:20) provided pure triene 27
2
(33 mg, 38%) (Found: Mϩ, 356.3533. C23H32O2 H8 requires Mϩ,
356.3530); δH(500 MHz, CDCl3) 0.93 (3H, br s, 18-H), 1.22–
1.48 (12H, m), 1.46–1.61 (6H, m), 1.66–1.72 (1H, m), 1.77–1.85
(1H, m), 2.02 (2H, br t, J 7.0, 8-H), 2.77 (4 H, m, 11-H, 14-H),
3.36 (1H, dt, J 9.6, 6.7, 1-Ha), 3.47 (1H, m, 6Ј-Ha), 3.70 (1H,
dt, J 9.6, 6.9, 1-Ha), 3.85 (1H, m, 6Ј-Hb), 4.55 (1H, dd, J 4.4,
2.8, 2Ј-H); δC(125 MHz, CDCl3) 98.83 (C2Ј), 67.67, 62.31,
30.79 (C3Ј), 29.75, 29.62, 29.48, 29.45, 27.87, 27.09, 26.23,
25.51 (C5Ј), 25.26, 22.14, 19.69 (C4Ј), 14.03 (C18); m/z
356 (Mϩ, 0.2%), 101 (11), 85 (100), 83 (19), 82 (14), 55 (13), 43
(16), 41 (22).
1-(Tetrahydropyran-2Ј-yloxy)octadeca-9,12,15-triyne.
Formed according to the procedure described for the prepar-
ation of 10 and 11, from 1-(tetrahydropyran-2Ј-yloxy)dec-9-yne
21 (0.545 g, 2.29 mmol) and 1-bromoocta-2,5-diyne (0.400 g,
2.17 mmol). The product was purified by flash chromatography
(Et2O–hexane, 1:20) to yield 1-(tetrahydropyran-2Ј-yloxy)octa-
deca-9,12,15-triyne (0.407 g, 55%); δH(500 MHz, CDCl3) 1.09
(3H, t, J 7.5, 18-H), 1.23–1.36 (8H, m), 1.42–1.59 (8H, m), 1.68
(1H, m), 1.81 (1H, m), 2.13 (4H, m, 8-H, 17-H), 3.11 (4H, m,
11-H and 14-H), 3.35 (1H, dt, J 9.6, 6.7, 1-Ha), 3.47 (1H, m,
6Ј-Ha), 3.70 (1H, dt, J 9.6, 6.9, 1-Hb), 3.84 (1H, ddd, J 11.2,
7.7, 3.6, 6Ј-Hb), 4.55 (1H, dd, J 4.3, 2.8, 2Ј-H); δC(125 MHz,
CDCl3) 98.83, 82.09, 80.82, 74.86, 74.77, 73.73, 73.14, 67.64,
62.32, 30.78, 29.72, 29.33, 29.06, 28.81, 28.68, 26.19, 25.50,
19.69, 18.68, 13.83, 12.35, 9.77, 9.74.
(9Z,12Z,15Z)-[9,10,12,13,15,16,17,17-2H8]Octadeca-9,12,15-
trienol 28
Deuterated triene 27 (0.033 g, 0.093 mmol) and toluene-p-
sulfonic acid (1.8 mg, 0.009 mmol) were dissolved in MeOH
(1 ml), and stirred for 90 min at RT when TLC analysis indi-
cated the absence of starting material. Solid NaHCO3 was then
added and left to stir for 1 h. Solid MgSO4 was then added and
the solution was filtered. The MeOH was removed on the rotary
evaporator. Flash chromatography (Et2O–hexane, 1:5) pro-
vided pure 28 (0.008 g, 32%); δH(400 MHz, CDCl3) 0.94 (3H, br
s, 18-H),1.22–1.38 (10 H, m), 1.53 (1H, s, OH), 1.55 (2H, m,
2-H), 2.03 (2H, br t, J 7.1, 8-H), 2.78 (4H, m, 14-H), 3.62 (2H,
br t, J 6.5, 1-H).
(9Z,12Z,15Z)-[9,10,12,13,15,16-2H6]-1-(Tetrahydropyran-2Ј-
yloxy)octadeca-9,12,15-triene 30. From the triyne prepared
above (0.202 g, 0.591 mmol) in Et2O (5 ml), Ti(OPri)4, (1.343 g,
4.73 mmol) in Et2O (10 ml), PriMgBr (9.45 ml, 11.81 mmol,
~1.25  solution in Et2O) and D2O (1.0 ml) according to the
general procedure. Work-up procedure A and flash chrom-
atography (Et2O–hexane, 1:20) provided pure 30 (52 mg, 25%)
1-Bromopent-2-yne 29
1-(Tetrahydropyran-2Ј-yloxy)pent-2-yne.
1-(Tetrahydro-
pyran-2Ј-yloxy)prop-2-yne 22 (4.08 g, 29.14 mmol) was dis-
solved in THF (80 ml) in a three-necked flask and cooled to
Ϫ78 ЊC. BunLi (2.5 , 14.0 ml, 35.0 mmol) was added dropwise
via syringe and the reaction mixture was stirred at Ϫ60 ЊC to
Ϫ50 ЊC for 2 h. Upon recooling to Ϫ78 ЊC, iodoethane (5.0 g,
32.1 mmol), dissolved in a mixture of THF (5 ml) and DMPU
(5 ml), was added dropwise from a dropping funnel. The result-
ing mixture was allowed to warm to RT overnight. Hexane (250
ml) and water (300 ml) were added, and the layers were separ-
ated. The aqueous layer was extracted with hexane (3 × 100
ml). After washing with saturated aqueous NaCl, the combined
organic layers were dried (MgSO4) and concentrated (reduced
pressure). Purification using flash chromatography (Et2O–
hexane, 1:20) yielded pure fractions of 1-(tetrahydropyran-2Ј-
yloxy)pent-2-yne (2.287 g, 47%); δH(500 MHz, CDCl3) 1.12
(3H, t, J 7.7, 5-H), 1.51 (2H, m), 1.58 (2H, m), 1.71 (1H, m),
1.81 (1H, m), 2.21 (2H, qt, J 7.6, 2.1, 4-H), 3.50 (1H, m, 6Ј-Ha),
3.82 (1H, ddd, J 11.6, 9.2, 3.0, 6Ј-Hb), 4.16 (1H, dt, J 15.0, 2.1,
1-Ha), 4.26 (1H, dt, J 15.0, 2.1, 1-Hb), 4.78 (1H, t, J 3.5, 2Ј-H);
δC(125 MHz, CDCl3) 96.67, 87.96, 75.09, 61.93, 54.64, 30.28,
25.37, 19.09, 13.74, 12.49; m/z 167 (Mϩ Ϫ 1, 0.3%), 111 (12),
101 (30), 85 (63), 83 (13), 79 (10), 67 (74), 66 (22), 65 (30), 55
(40), 41 (100), 39 (52).
2
(Found: Mϩ, 354.3401. C23H34O2 H6 requires Mϩ, 354.3405).
δH(500 MHz, CDCl3) 0.95 (3H, t, J 7.6, 18-H), 1.22–1.40 (12H,
m), 1.45–1.60 (6H, m), 1.65–1.72 (1H, m), 1.76–1.85 (1H, m),
2.02 (4H, m, 8-H, 17-H), 2.77 (4H, m, 11-H, 14-H), 3.36 (1H,
dt, J 9.6, 6.7, 1-Ha), 3.47 (1H, m, 6Ј-Ha), 3.70 (1H, dt, J 9.6,
6.9, 1-Hb), 3.85 (1H, m, 5Ј-Hb), 4.55 (1H, dd, J 4.4, 2.9, 2Ј-H);
δC(125 MHz, CDCl3) 98.81, 67.65, 62.29, 30.77 (C3Ј), 29.74,
29.61, 29.46, 29.44, 29.24, 27.87, 27.08, 26.22, 25.50 (C5Ј),
25.25, 21.11, 20.39, 19.67 (C4Ј), 14.22 (C18); δ2 (61 MHz,
CHCl3) 5.40, 5.37, 5.32; m/z 354 (Mϩ, 0.1%), 112 H(6), 111 (4),
101 (7), 97 (7), 96 (7), 85 (100), 83 (18), 82 (16), 43 (19), 41 (29).
(9Z,12Z,15Z)-[9,10,12,13,15,16-2H6]Octadeca-9,12,15-trienoic
acid 32
Attempted oxidation of 30. [9,10,12,13,15,16-2H6]-1-(Tetra-
hydropyran-2Ј-yloxy)octadeca-9,12,15-triene 30 (0.005 g, 0.014
mmol) was dissolved in dry acetone (1 ml) and excess Jones’
reagent was added dropwise to the stirred solution until the
orange colour persisted for a period of 20 min. Concentration
of the solution in vacuo gave a residue, to which water (5 ml)
and Et2O (5 ml) were added. Further extracts (Et2O, 2 × 3 ml)
were combined with the initial extract, dried over MgSO4 and
concentrated, but 32 was not present in the product mixture on
the basis of 1H NMR analysis.
1-Bromopent-2-yne 29. Prepared from 1-(tetrahydropyran-2Ј-
yloxy)pent-2-yne (4.80 g, 28.6 mmol) utilising the general pro-
cedure described for bromide 19. Flash chromatography (100%
light petroleum) gave purified 1-bromopent-2-yne 29 (3.66 g,
87%); δH(500 MHz, CDCl3) 1.12 (3H, t, J 7.5, 5-H), 2.24 (2H,
qt, J 7.5, 2.4, 4-H), 3.90 (2H, t, J 2.4, 1-H); δC(125 MHz,
CDCl3) 89.43, 74.63, 15.66, 13.45, 12.64; m/z 148, 146 (Mϩ, 8,
8%), 133 (1), 131 (1), 81 (12), 79 (11), 67 (100), 41 (94), 39 (67).
(9Z,12Z,15Z)-[9,10,12,13,15,16-2H6]Octadeca-9,12,15-
trienol 31. THP ether 30 (0.043 g, 0.12 mmol) and toluene-p-
sulfonic acid (2.3 mg, 0.012 mmol) were stirred in MeOH (2 ml)
for 1 h at RT. Solid NaHCO3 was added and left to stir for 1 h.
Solid MgSO4 was then added to dry the solution which was
1852
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
then filtered. MeOH was removed on the rotary evaporator and
the oil obtained was subjected to flash chromatography (Et2O–
hexane, 1:5) to provide pure product trienol 31 (0.030 g, 91%)
(Found: Mϩ, 270.2830. C18H26O2H6 requires Mϩ, 270.2830);
δH(400 MHz, CDCl3) 0.95 (3H, t, J 7.5, 18-H), 1.2–1.4 (10H, m,
3-H to 7-H), 1.54 (2H, m, 2-H), 2.04 (4H, m, 8-H, 17-H), 2.77
(4H, m, 11-H, 14-H), 3.61 (2H, t, J 6.6, 1-H); δC(100 MHz,
CDCl3) 63.05 (C1), 32.78, 29.60, 29.47, 29.38, 29.22, 27.08,
mixture was stirred at 0 ЊC for 30 min and at room temperature
for 2 h. It was then poured into iced ~1  HCl (~300 ml). The
Et2O layer was separated and washed with saturated aqueous
NaHCO3 (2 × 100 ml) and saturated aqueous NaCl (1 × 100
ml). The Et2O solution was then dried (MgSO4) and concen-
trated under reduced pressure. Flash chromatography (Et2O–
light petroleum, 1:6) gave 3-butylcyclohex-2-enone 38 (4.866 g,
90%); δH(400 MHz, CDCl3) 0.89 (3H, t, J 7.3, 4Ј-H), 1.46 (2H,
m), 1.31 (2H, ~sextet, J ~7.3), 1.95 (2H, ~quintet, J 6.2), 2.18
(2H, br t, J 7.6), 2.25 (2H, ~br t, J ~6.2), 2.32 (2H, dd, J 7.1,
6.3), 5.84 (1H, ~quintet, J 1.3, 2-H); δC(100 MHz, CDCl3)
199.91, 166.66, 125.65, 37.74, 37.34, 29.66, 29.05, 22.73, 22.32,
13.79; m/z 152 (Mϩ, 10%), 123 (10), 110 (9), 82 (100), 67 (12), 53
(10), 41 (19), 39 (22).
25.72, 25.35, 25.26, 20.39, 14.21 (C18); δ2 (61 MHz, CHCl3)
H
5.40, 5.37, 5.33; m/z 270 (Mϩ, 2%), 212 (3), 154 (3), 140 (5), 112
(34), 98 (36), 97 (42), 83 (100), 82 (92), 81 (60), 43 (60), 41 (73).
Attempted oxidation of trienol 31. To a stirred solution of
[9,10,12,13,15,16-2H6]octadeca-9,12,15-trienol 31 (0.005 g,
0.019 mmol) in dry acetone (1 ml) was added Jones’ reagent
(dropwise). Addition of excess Jones’ reagent was indicated by
the persistence of the orange colour of CrVI. Concentration in
vacuo gave a residue, to which water (5 ml) and Et2O (5 ml) were
added. Further extracts (Et2O, 2 × 3 ml) were combined with
the initial extract, dried over MgSO4 and concentrated. This
product was extracted from Et2O into an alkaline solution,
which was then reacidified and extracted with Et2O. This Et2O
solution was dried over MgSO4 and concentrated to give a
mixture of unidentified rearrangement products, on the basis of
1H NMR analysis.
3-Butyl-2,3-epoxycyclohexanone 39
Enone 38 (3.00 g, 19.7 mmol) was dissolved in MeOH (160 ml)
and to the solution was added H2O2 (13.42 ml, 118.4 mmol) and
6  NaOH (1.55 ml, 9.28 mmol). The reaction mixture was left
to stir overnight and then water (350 ml) was added and the
mixture was extracted with Et2O (3 × 150 ml). The combined
organic extracts were washed with saturated aqueous NaCl,
dried (MgSO4) and concentrated to yield crude product. Purifi-
cation via flash chromatography (Et2O–light petroleum, 1:9)
provided 3-butyl-2,3-epoxycyclohexanone 39 (2.663 g, 80%);
δH(400 MHz, CDCl3) 0.87 (3H, t, J 7.2, 4Ј-H), 1.25–1.41 (4H,
m), 1.54–1.71 (2H, m), 1.79–2.11 (4H, m), 2.45 (1H, t, J 4.5,
6-Ha), 2.49 (1H, t, J 4.7, 6-Hb), 3.04 (1H, s, 2-H); δC(100 MHz,
CDCl3) 206.95, 65.43, 61.17, 35.91, 35.69, 26.74, 26.39, 22.56,
17.38, 13.85; m/z 168 (Mϩ, 17%), 139 (12), 126 (14), 112 (20),
111 (18), 97 (76), 71 (83), 55 (95), 53 (17), 43 (40), 41 (100),
39 (52).
(9Z,12Z,15Z)-[9,10,12,13,15,16-2H6]Octadeca-9,12,15-
trienoic acid 32.25 [9,10,12,13,15,16-2H6]Octadeca-9,12,15-
trienol 31 (0.026 g, 0.0963 mmol) was dissolved in DMF (2 ml)
and PDC (0.163 g, 0.43 mmol) was added in one portion. The
reaction mixture was left stirring for 24 h. GC–MS Analysis
showed the absence of starting alcohol, but indicated the pres-
ence of some aldehyde en route to acid 32. A small amount of
additional PDC was added and stirring was continued for
another 2 h before Et2O (10 ml) and H2O (20 ml) were added.
Upon separation of the layers, the aqueous layer was further
extracted with Et2O. The combined ether extracts were washed
with saturated aqueous NaCl and dried over MgSO4. Removal
of the solvent in vacuo gave acid 32 and a trace amount of the
corresponding aldehyde (0.015 g, 56%). Acid 32; δH(400 MHz,
CDCl3) 0.95 (3H, t, J 7.6, 18-H), 1.20–1.40 (8H, m), 1.54–1.67
(2H, m, 3-H), 1.95–2.08 (4H, m, 8-H, 17-H), 2.33 (2H, t, J 7.4,
2-H), 2.78 (4H, br s, 11-H, 14-H). (9Z,12Z,15Z)-[9,10,12,13,15,
16-2H6]Octadeca-9,12,15-trienal; m/z 268 (4), 210 (5), 155 (3),
154 (3), 153 (3), 112 (34), 99 (45), 98 (44), 97 (44), 84 (55),
83 (100), 82 (92), 70 (53), 69 (53), 43 (57), 41 (62).
6-Oxodec-1-yne 40
Epoxy ketone 39 (1.2 g, 7.14 mmol) was dissolved in a mixture
of CH2Cl2 (16 ml) and acetic acid (8 ml) and cooled to 0 ЊC.
Toluene-p-sulfonylhydrazide (1.330 g, 7.14 mmol) was added in
one portion and the reaction mixture left to stir for 3 h at 0 ЊC.
After continued stirring for 3 h at room temperature, the mix-
ture was poured into water (100 ml), light petroleum was added
and the layers separated. Further extraction of the aqueous
layer with light petroleum (2 × 50 ml) was performed and the
combined organic extracts were washed with H2O (20 ml),
NaHCO3 (20 ml) and NaCl (20 ml) and then dried over MgSO4.
Concentration and flash chromatography (Et2O–light petrol-
eum, 1:9) gave 6-oxodec-1-yne 40 (1.061 g, 98%). δH(400 MHz,
CDCl3) 0.88 (3H, t, J 7.3, 10-H), 1.28 (2H, sextet, J 7.3, 9-H),
1.53 (2H, quintet, J 7.5, 4-H or 8-H), 1.76 (2H, quintet, J 7.0,
4-H or 8-H), 1.92 (1H, t, J 2.6, 1-H), 2.20 (2H, dt, J 6.9, 2.6,
3-H), 2.38 (2H, t, J 7.5, 5-H or 7-H), 2.52 (2H, t, J 7.2, 5-H or
7-H); δC(100 MHz, CDCl3) 210.56, 83.62, 68.93, 42.68, 40.99,
25.96, 22.33, 22.25, 17.76, 13.80; m/z 152 (Mϩ, 6%), 123 (7), 110
(12), 109 (10), 95 (62), 85 (65), 67 (59), 58 (57), 57 (98), 55 (54),
41 (100), 39 (61).
Synthesis of deuterated oleic acid
3-Ethoxycyclohex-2-enone 37
In a flask fitted with a Dean-Stark trap, was placed cyclo-
hexane-1,3-dione 36 (20.0 g, 0.178 mmol), toluene-p-sulfonic
acid (0.406 g, 0.0021 mol), ethanol (95 ml) and benzene (340
ml). The mixture was refluxed for 6 h, and the benzene–
ethanol–water azeotrope was collected. Upon cooling, the
residual solution was washed with 10% aqueous NaOH which
had been saturated with NaCl (4 × 80 ml). It was then washed
with H2O until the washes were of neutral pH. Concentration
under reduced pressure gave 24.56 g of crude product which
was distilled (88–90 ЊC, 1.6 mbar) to yield (12.67 g, 51%) pure
37; δH(400 MHz, CDCl3) 1.30 (3H, t, J 7.0, 2Ј-H), 1.91 (2H, m,
5-H), 2.27 (2H, dd, J 7.3, 6.0, 3-H or 5-H), 2.34 (2H, br t, J 6.3,
3-H or 5-H), 3.84 (2H, q, J 7.0, 1Ј-H), 5.28 (1H, br s, 2-H);
δC(100 MHz, CDCl3) 199.62, 177.75, 102.61, 64.04, 36.67,
29.00, 21.16, 14.01; m/z 140 (Mϩ, 45%), 112 (45), 84 (100), 69
(81), 68 (64), 43 (49), 39 (53).
[1,5,5,6,7,7-2H6]Dec-1-yn-6-ol 41
[1,5,5,7,7-2H5]-6-Oxodec-1-yne. Alkynyl ketone 40 (0.512 g,
3.37 mmol) was stirred vigorously overnight in a THF (10 ml)
and D2O (25 ml) mixture to which Na metal (50 mg) had been
added. DCl (38%) in D2O was added to achieve pH 1–2. Extrac-
tion with Et2O (3 × 100 ml) gave the combined ethereal extracts
which were washed with saturated aqueous NaCl, dried
(MgSO4) and concentrated under reduced pressure to give a
product (0.496 g, 94%) which exhibited only one GC peak and
was used in the subsequent step without further purification;
m/z 157 (Mϩ, 10%), 128 (6), 115 (13), 114 (12), 98 (68), 87 (81),
70 (49), 68 (34), 67 (14), 62 (74), 59 (100).
3-Butylcyclohex-2-enone 38
3-Ethoxycyclohex-2-enone 37 (5.0 g, 35.7 mmol) was dissolved
in Et2O (250 ml) in a three-necked flask under a dry N2 atmos-
phere, and cooled to 0 ЊC. BunLi (21.1 ml, 38.0 mmol) was
added dropwise via cannula to the reaction flask. The resulting
[1,5,5,6,7,7-2H6]Dec-1-yn-6-ol 41. LiAlD4 (200 mg, 4.8
mmol) was stirred in dry Et2O (10 ml) and cooled to Ϫ20 ЊC. In
a separate flask, [1,5,5,7,7-2H5]-6-oxodec-1-yne (0.755 g, 4.81
mmol) was dissolved in Et2O (5 ml) and transferred via cannula
J. Chem. Soc., Perkin Trans. 1, 1998
1853

View Article Online
to the LiAlD4 suspension. The reaction was stirred at room
temperature for 5 h. GC–MS analysis suggested the reaction
was complete and Na2SO4ؒ10 H2O was added portionwise to
quench the reaction, with stirring continued until a free-moving
white solid resulted. The mixture was filtered through a sinter
and washed through with Et2O. Concentration in vacuo gave
crude material which was purified by flash chromatography
(Et2O–hexane, 1:4) to give decynol as a mixture of 41 and
[5,5,6,7,7-2H5]-41 (0.211 g, 56%); δH(400 MHz, CDCl3) 0.88
(3H, t, J 6.8, 10-H), 1.25–1.36 (4H, m, 8-H, 9-H), 1.54 (1H, dt,
J 13.8, 6.9, 4-Ha), 1.65 (1H, dt, J 13.7, 7.1, 4-Hb), 1.92 (0.1H,
t, J 2.6, 1-H), 2.18 (2H, t, J 7.1, 3-H), 4-Ha and 4-Hb were
was continued at 0 ЊC for 15 min and then at room temperature
for 2 h. GC analysis then showed the absence of diene. Water
(20 ml) was added dropwise, followed by, in one portion, NaOH
solution (3 , 20 ml) and aqueous H2O2 (30% w/v, 21 ml). The
resultant mixture was refluxed at 80 ЊC for 30 min. Upon cool-
ing, additional H2O (300 ml) was added to the mixture, which
was then extracted with Et2O (3 × 100 ml). The combined Et2O
extracts were washed with unsaturated aqueous NaCl, dried
over MgSO4 and concentrated under reduced pressure. Flash
chromatography (ethyl acetate) gave pure [2,7-2H2]octane-1,8-
diol 48 (5.042 g, 75%); δH(400 MHz, CDCl3) 1.29–1.33 (8H, m),
1.46 (2H, br s, OH), 1.52 (2H, m, 2-H), 3.61 (4H, d, J 6.6, 1-H);
13C–2H
19.2),
identified by irradiation of 3-H in a homodecoupling experi-
δC(100 MHz, CDCl3) 62.94 (C1), 32.32 (C2, t, J
᎐
ment; δ (100 MHz, CDCl ) 84.40 (C1, residual ᎐CH), 83.92
29.30, 25.53 (C3, C4).
᎐
C
3
᎐
13C–2H
13C–2H
(C1, t, J
7.5, ᎐CD), 70.77 (C6, t, J
21.4), 68.42 (C2),
᎐
36.26 (C5 or C7, quintet, J
tet, J C– H 19.1), 27.53, 24.35, 22.65, 18.32, 14.02 (C10).
19.0), 35.38 (C5 or C7, quin-
[2,7-2H2]-1,8-Bis(trimethylsilyloxy)octane
13C–2H
A small amount of [2,7-2H2]octane-1,8-diol 48 was treated with
TMSI reagent (N-trimethylsilylimidazole) in CH2Cl2 for 30 min
under reflux. GC–MS analysis revealed the presence of a peak
due to [2,7-2H2]-1,8-bis(trimethylsilyloxy)octane; m/z 292
(Mϩ, 0%), 202 (2), 187 (5), 177 (5), 150 (6), 149 (22), 147 (69),
103 (21), 75 (74), 73 (78), 71 (47), 70 (100), 56 (43).
13
2
[1,5,5,6,7,7-2H6]Dec-1-yne 34
[1,5,5,6,7,7-2H6]-6-(Methanesulfonyloxy)-dec-1-yne. To
a
0 ЊC solution of alcohol 41 (0.334 g, 2.1 mmol) in CH2Cl2 (5
ml), was added Et3N (0.35 ml, 0.255 g, 2.52 mmol), followed by
methanesulfonyl chloride (0.179 ml, 0.265 g, 2.3 mmol) via
syringe. The reaction mixture was stirred for 2 h at room tem-
perature, when TLC indicated complete conversion. Concen-
tration via rotary evaporation gave an oily white solid. Flash
chromatography (Et2O–hexane, 1:5) gave the [1,5,5,6,7,7-
2H6]mesylate, together with the [5,5,6,7,7-2H5]mesylate (0.409 g,
82%). [1,5,5,6,7,7-2H6]Mesylate; δH(400 MHz, CDCl3) 0.89
(3H, t, J 7.1, 10-H), 1.32 (4H, m, 8-H, 9-H), 1.59 (2H, m, 4-H),
1.94 (0.1H, t, J 2.7, residual 1-H), 2.21 (2H, t, J 6.9, 3-H), 2.98
(3H, s, MeSO3); δC(100 MHz, CDCl3) 83.56 (C1, residual
[2,7-2H2]-1-Iodo-8-(tetrahydropyran-2Ј-yloxy)octane 35
[2,7-2H2]-1-(Tetrahydropyran-2Ј-yloxy)octan-8-ol. Diol 48
(5.042 g, 34.1 mmol) was dissolved in dry CH2Cl2 (100 ml) and
toluene-p-sulfonic acid (0.324 g, 1.7 mmol) was added in one
portion. 3,4-Dihydro-2H-pyran (2.866 g, 34.0 mmol) in CH2Cl2
(20 ml) was added dropwise to the solution at 0 ЊC. The reaction
mixture was left stirring overnight, and then poured into satur-
ated aqueous NaHCO3. Upon separation of the layers, the
aqueous fraction was further extracted with CH2Cl2 (3 × 60
ml). The combined organic extracts were washed with saturated
aqueous NaCl, dried (MgSO4) and concentrated. Flash chrom-
atography yielded pure mono-THP-protected diol (3.414 g,
43%); δH(400 MHz, CDCl3) 1.26–1.34 (8H, m), 1.45–1.58 (6H,
m), 1.62–1.72 (1H, m), 1.75–1.84 (1H, m), 3.34 (1H, dd, J 9.4,
7.0, 1-Ha), 3.46 (1H, m, 6Ј-Ha), 3.59 (2H, d, J 6.6, 8-H), 3.68
(1H, dd, J 9.4, 7.0, 1-Hb), 3.83 (1H, m, 6Ј-Hb), 4.53 (1H, dd,
J 4.4, 2.6, 2Ј-H); δC(100 MHz, CDCl3) 98.82 (C2Ј), 67.55, 62.86,
᎐
᎐
13C–2H
᎐CH), 83.09 (C1, t, J
7.6, ᎐CD), 68.94 (C2), 38.70
᎐
᎐
13C–2H
(CH3SO3), 33.63 (C5 or C7, quintet, J
18.5), 32.39 (C5
13C–2H
or C7, quintet, J
18.6), 26.78, 23.48, 22.35, 18.02, 13.84
(C10) [no signal for C6 (CDOMs) was observed]; m/z 238 (Mϩ,
0%), 194 (2), 179 (6), 168 (12), 112 (12), 111 (8), 101 (100), 100
(47), 83 (50), 82 (49), 79 (73), 72 (65), 71 (53), 43 (66), 42 (61),
41 (60).
[1,5,5,6,7,7-2H6]Dec-1-yne 34. LiAlH4 (0.062 g, 1.65 mmol)
was stirred in Et2O and cooled to 0 ЊC. In a separate flask, the
mesylate (0.390 g, 1.65 mmol) was dissolved in Et2O and trans-
ferred via cannula to the LiAlH4 suspension. The reaction was
stirred at room temperature for 90 min. GC–MS analysis
revealed that starting material remained. Additional LiAlH4
was added to the reaction mixture at 0 ЊC. Upon stirring for an
additional 5 min, GC–MS analysis showed that the reaction
was still not complete. The reaction was then left to stir over-
night, after which time the conversion was complete. Na2SO4ؒ10
H2O was added portionwise to quench the reaction, with stir-
ring continued until the white solid moved freely. The mixture
was washed through a sinter with Et2O and concentration of
this solution gave crude material which was purified via flash
chromatography to give decyne 34 and [5,5,6,7,7-2H5]-34 (0.211
g, 90%); δH(400 MHz, CDCl3) 0.86 (3H, t, J 7.1, 10-H), 1.19–
13C–2H
62.29 (C6Ј, C1, C8), 32.32 (C2 or C7, t, J
19.2), 30.74,
13C–2H
29.35, 29.29 (C2 or C7, t, J
19.2), 29.28, 26.02, 25.55,
25.46, 19.64; m/z 232 (Mϩ, 0.1%), 231 (1), 159 (1), 147 (1), 131
(1), 113 (4), 101 (20), 85 (100), 70 (31), 56 (41), 41 (39).
[2,7-2H2]-1-(Methanesulfonyloxy)-8-(tetrahydropyran-2Ј-
yloxy)octane. The mono-THP-protected diol (2.00 g, 8.62 mmol)
was dissolved in CH2Cl2 (20 ml), and the solution was cooled to
0 ЊC. Et3N (1.44 ml, 1.047 g, 10.34 mmol), followed by mesyl
chloride (0.734 ml, 1.086 g, 9.48 mmol) were added via syringe
and the reaction mixture was stirred for 2 h at RT, when TLC
indicated complete conversion. Concentration via rotary evap-
oration gave an oily white solid. Flash chromatography (Et2O–
hexane, 1:1) gave the desired mesylate (2.317 g, 87%); δH(400
MHz, CDCl3) 1.28–1.41 (8H, m), 1.45–1.58 (5H, m), 1.64–1.72
(2H, m), 1.75–1.81 (1H, m), 2.97 (3H, s, CH3), 3.35 (1H, dd,
J 9.5, 6.7, 8-Ha), 3.46 (1H, m, 6Ј-Ha), 3.69 (1H, dd, J 9.5, 6.9,
8-Hb), 3.84 (1H, m, 6Ј-Hb), 4.18 (2H, d, J 6.5, 1-H), 4.54 (1H,
dd, J 4.5, 2.7, 2Ј-H); δC(100 MHz, CDCl3) 98.88 (C2Ј), 70.04,
67.50, 62.36 (C6Ј, C1, C8), 37.34 (Me), 30.76, 29.27 (C2 or C7,
1.31 (5H, m, 6-H, 8-H, 9-H), 1.49 (2H, m, 4-H), 1.91 (0.5H, t,
᎐
J 2.6, 1-H), 2.16 (1H, dt, J 7.2, 2.5, 3-H adjacent to ᎐CH),
᎐
᎐
2.16 (1H, t, J 7.2, 3-H adjacent to ᎐CD); δ (100 MHz, CDCl )
᎐
C
3
᎐
᎐
13C–2H
84.84 (C1, residual ᎐CH), 84.36 (C1, t, J
7.6, ᎐CD),
᎐
᎐
13C–2H
13C–2H
13C–2H
19.4),
67.98 (C2), 31.60, 28.30, 28.24 (C6, t, J
19.1), 28.16 (C5
t, J
19.4), 29.18, 28.90, 28.71 (C2 or C7, t, J
13C–2H
and C7, quintet, J
19.1), 22.59, 18.32, 14.08 (C10); m/z
25.98, 25.47, 25.23, 19.69; m/z 310 (Mϩ, 0.4%), 309 (2), 227 (2),
113 (14), 97 (14), 86 (9), 85 (100), 84 (48), 70 (53), 58 (100), 56
(71), 55 (60).
143 (Mϩ, 0%), 114 (8), 101 (8), 100 (29), 85 (74), 84 (100),
70 (84), 69 (78), 58 (54), 57 (60), 56 (59), 44 (62), 43 (89), 42 (83),
41 (75), 39 (57).
[2,7-2H2]-1-Iodo-8-(tetrahydropyran-2Ј-yloxy)octane 35. NaI
(2.90 g, 19.35 mmol) was added to the mesylate (1.507 g, 4.84
mmol) dissolved in dry acetone and the mixture was refluxed
overnight. Upon cooling, the acetone was removed on the
rotary evaporator. H2O (50 ml) and Et2O (30 ml) were added
and the mixture was transferred to a separatory funnel. The
layers were separated and the aqueous layer was further
[2,7-2H2]Octane-1,8-diol 48
Octa-1,7-diene (5.00 g, 45.4 mmol) was dissolved in dry THF
(100 ml), and NaBD4 (1.90 g, 45.4 mmol) was added in one
portion. The reaction was cooled to 0 ЊC and BF3ؒOEt2 (7.44
ml, 8.59 g, 60.4 mmol) was added dropwise via syringe. Stirring
1854
J. Chem. Soc., Perkin Trans. 1, 1998

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extracted with Et2O (3 × 30 ml). The Et2O extracts were washed
with saturated aqueous NaCl, dried over MgSO4 and concen-
trated to give a dark brown oil. Flash chromatography (Et2O–
hexane, 1:11) gave pure 35 (1.118 g, 67%); δH(400 MHz,
CDCl3) 1.28–1.40 (8H, m), 1.47–1.59 (5H, m), 1.66–1.72 (1H,
m), 1.73–1.85 (2H, m), 3.15 (2H, d, J 7.0, 1-H), 3.36 (1H, dd,
J 9.6, 6.7, 8-Ha), 3.48 (1H, m, 6Ј-Ha), 3.70 (1H, dd, J 9.6, 6.9,
8-Hb), 3.85 (1H, m, 6Ј-Hb), 4.55 (1H, dd, J 4.4, 2.7, 2Ј-H);
δC(100 MHz, CDCl3) 98.88 (C2Ј), 67.55, 62.37 (C6Ј, C8), 33.16
[2,7-2H2]-1-(Tetrahydropyran-2Ј-yloxy)hexadec-9-ene 50
PriMgBr was titrated at 0.97  by its reaction with menthol in
the presence of 1,10-phenanthroline indicator. From alkyne 49
(0.070 g, 0.216 mmol) in Et2O (5 ml), Ti(OiPr)4 (0.123 g, 0.423
mmol) in Et2O (15 ml), PriMgBr (0.97 , 1.11 ml, 1.08 mmol)
and H2O (1 ml) according to the general procedure. Work-up
procedure B and flash chromatography (Et2O–light petroleum,
1:25) gave 50 (0.052 g, 74%). δH(400 MHz, CDCl3) 0.86 (3H, t,
J 7.1, 16-H), 1.20–1.32 (17H, m), 1.45–1.59 (5H, m), 1.63–1.72
(1H, m), 1.77–1.85 (1H, m), 1.98 (4H, m, 8-H, 11-H), 3.35 (1H,
dd, J 9.5, 6.9, 1-Ha), 3.47 (1H, m, 6Ј-Ha), 3.70 (1H, dd, J 9.5,
6.9, 1-Hb), 3.84 (1H, m, 6Ј-Hb), 4.54 (1H, dd, J 4.3, 2.6, 2Ј-H),
5.32 (2H, m, 9-H, 10-H); δC(100 MHz, CDCl3) 129.89, 129.82
(C9, C10), 98.82 (C2Ј), 67.60, 62.28 (C1, C6Ј), 31.76, 30.78
(C3Ј), 29.72, 29.44, 29.42, 29.13, 28.96, 27.20, 27.08, 26.12,
25.51 (C5Ј), 22.63, 19.67 (C4Ј), 14.06 (C16) [C2 and C7 (CDH)
were not detected]; m/z 326 (Mϩ, 0.2%), 253 (1), 240 (1), 101 (8),
98 (5), 97 (7), 96 (6), 86 (7), 85 (100), 83 (12), 69 (13), 67 (11), 57
(12), 56 (21), 55 (24), 41 (26).
13C–2H
13
2
(C2 or C7, t, J C– H 19.6), 30.79, 30.34, 29.31 (C2 or C7, t, J
19.2), 29.21, 28.45, 26.04, 25.51, 19.71, 7.06 (C1); m/z 342 (Mϩ,
4%), 341 (23), 101 (14), 85 (100), 71 (11), 70 (24), 56 (36), 41 (32).
Attempted formation of [2,7-2H2]-1-(tetrahydropyran-2Ј-yloxy)-
hexadec-9-yne 49
Formation of [2,7-2H2]-1-bromo-8-(tetrahydropyran-2Ј-yloxy)-
octane. Octyne (0.012 g, 0.11 mmol) was dissolved in THF (5
ml) and cooled to Ϫ78 ЊC. BunLi (1.6  in Et2O, 0.068 ml, 0.11
mmol) was added dropwise via syringe to the reaction mixture
which was stirred for 90 min at Ϫ50 ЊC. A small amount of the
reaction mixture was quenched with D2O, with GC–MS anal-
ysis indicating complete deprotonation. The reaction mixture
was re-cooled to Ϫ78 ЊC. In a separate flask, iodide 35 (0.037 g,
0.11 mmol) was dissolved in HMPA (0.5 ml, freshly distilled
from CaH2) and THF (5 ml) and then transferred via cannula to
the flask containing the deprotonated alkyne. The reaction was
left stirring at room temperature overnight, and then quenched
by pouring into H2O (20 ml), which was extracted with hexane
(3 × 30 ml). The combined hexane extracts were washed with
saturated aqueous NaCl, dried over MgSO4 and concentrated.
Flash chromatography (Et2O–hexane, 1:10) gave [2,7-2H2]-1-
bromo-8-(tetrahydropyran-2Ј-yloxy)octane (0.022 g, 63%) and
none of the desired product 49; δH(500 MHz, CDCl3) 1.27–1.38
(8H, m), 1.47–1.59 (5H, m), 1.65–1.72 (1H, m), 1.77–1.85 (2H,
m), 3.35 (1H, dd, J 9.6, 6.6, 8-Ha), 3.37 (2H, d, J 6.8, 1-H), 3.47
(1H, m, 6Ј-Ha), 3.70 (1H, dd, J 9.6, 6.9, 8-Hb), 3.84 (1H, m,
6Ј-Hb), 4.55 (1H, dd, J 4.3, 2.7, 2Ј-H); δC(125 MHz, CDCl3)
98.86 (C2Ј), 67.53, 62.35 (C6Ј, C8), 33.85 (C1), 32.41 (C2 or C7,
[2,7,13,13,14,15,15-2H7]-1-(Tetrahydropyran-2Ј-yloxy)octadec-
9-yne 51
Deuterated decyne 34 (0.147 g, 1.03 mmol) was dissolved in
THF (1.8 ml) and cooled to Ϫ30 ЊC. BunLi (1.11 , 1.018 ml,
1.13 mmol) was added dropwise via syringe to the reaction mix-
ture which was stirred between Ϫ30 and Ϫ10 ЊC for 1 h. A small
amount of the reaction mixture was quenched with D2O, with
GC–MS analysis indicating complete deprotonation. The reac-
tion mixture was re-cooled to Ϫ30 ЊC. In a separate flask,
iodide 35 (0.387 g, 1.13 mmol) was dissolved in HMPA (3.6 ml,
freshly distilled from CaH2) and THF (1.8 ml) and then trans-
ferred via cannula to the flask containing the deprotonated
alkyne. The reaction was left stirring at room temperature over-
night, and then quenched by pouring into H2O (40 ml), which
was extracted with hexane (3 × 30 ml). The combined organic
extracts were washed with saturated aqueous NaCl, dried
over MgSO4 and concentrated. Flash chromatography (Et2O–
hexane, 1:30) gave 51 (0.233 g, 64%) and minor amounts of
[2,7-2H2]-1-(tetrahydropyran-2Ј-yloxy)dodecane; δH(400 MHz,
CDCl3) 0.85 (3H, t, J 7.0, 18-H), 1.18–1.37 (14H, m), 1.42 (2H,
t, J 6.8), 1.45–1.59 (5H, m), 1.67 (1H, m), 1.80 (1H, m), 2.10
(4H, m, 8-H, 11-H), 3.34 (1H, dd, J 7.0, 9.4, 1-Ha), 3.47 (1H, m,
6Ј-Ha), 3.69 (1H, dd, J 7.0, 9.5, 1-Hb), 3.84 (1H, m, 6Ј-Hb),
4.55 (1H, m, J 4.4, 2.6, 2Ј-H); δC(100 MHz, CDCl3) 98.81 (C2Ј),
80.23, 80.12 (C9, C10), 67.58, 62.28, 31.60, 30.77 (C3Ј), 29.34,
29.06, 28.94, 28.68, 26.09, 25.50 (C5Ј), 22.58, 19.67 (C4Ј), 18.69,
18.63 (C8, C11), 14.06 (C18); m/z 357 (Mϩ, 0.4%), 239 (2), 137
(2), 125 (2), 112 (3), 111 (4), 110 (3), 101 (18), 85 (100), 83 (14),
82 (13), 70 (10), 69 (12), 68 (13), 67 (13), 57 (17), 56 (22), 41 (25).
13C–2H
13C–2H
19.2), 29.21,
t, J
19.6), 30.78, 29.29 (C2 or C7, t, J
28.66, 28.00, 26.02, 25.49, 19.70; m/z 296, 294 (Mϩ, 0.4, 1%),
295 (3), 293 (2), 223 (1), 221 (1), 195 (1), 151 (1), 149 (1), 115 (1),
113 (3), 101 (6), 86 (6), 85 (100).
[2,7-2H2]-1-(Tetrahydropyran-2Ј-yloxy)hexadec-9-yne 49
Octyne (0.040 g, 0.363 mmol) was dissolved in THF (0.5 ml)
and cooled to Ϫ30 ЊC. BunLi (1.11 , 0.359 ml, 0.399 mmol)
was added dropwise via syringe to the reaction mixture which
was stirred between Ϫ30 and Ϫ10 ЊC for 1 h. A small amount
of the reaction mixture was quenched with D2O, with GC–MS
analysis indicating complete deprotonation. The reaction mix-
ture was re-cooled to Ϫ30 ЊC. In a separate flask, iodide 35
(0.136 g, 0.399 mmol) was dissolved in HMPA (1 ml, freshly
distilled from CaH2) and THF (0.5 ml) and then transferred via
cannula to the flask containing the deprotonated alkyne. The
reaction was left stirring at room temperature overnight, and
then quenched by pouring into H2O (20 ml), which was
extracted with hexane (3 × 30 ml). The combined hexane
extracts were washed with saturated aqueous NaCl, dried over
MgSO4 and concentrated. Flash chromatography (Et2O–
hexane, 1:20) gave pure 49 (0.079 g, 61%); δH(400 MHz,
CDCl3) 0.86 (3H, t, J 7.0, 16-H), 1.20–1.58 (22H, m), 1.64–1.72
(1H, m), 1.75–1.82 (1H, m), 2.08–2.12 (4H, m, 8-H, 11-H), 3.34
(1H, dd, J 9.5, 6.7, 1-Ha), 3.69 (1H, dd, J 9.5, 6.9, 1-Hb), 3.84
(1H, m, 6Ј-Hb), 4.54 (1H, dd, J 4.3, 2.6, 2Ј-H); δC(100 MHz,
CDCl3) 98.83 (C2Ј), 80.22, 80.16 (C9, C10), 67.59, 62.30 (C1,
C6Ј), 31.36, 30.78, 29.34, 29.12, 29.07, 28.68, 28.51, 26.09,
25.50, 22.55, 19.68, 18.74, 18.63, 14.01 (C16) [C2 and C7
(CDH) were not detected]; m/z 324 (Mϩ, 0.3%), 253 (1), 239 (1),
124 (3), 110 (4), 109 (3), 101 (17), 97 (5), 96 (10), 95 (7), 94 (4),
86 (6), 85 (100).
(9Z)-[2,7,13,13,14,15,15-2H7]-1-(Tetrahydropyran-2Ј-yloxy)-
octadec-9-ene 52
PriMgBr was titrated at 0.99  by its reaction with menthol in
the presence of 1,10-phenanthroline indicator. From alkyne 51
{mixed with unreactive [2,7-2H2]-1-(tetrahydropyran-2Ј-yloxy)-
dodecane} (0.150 g, 0.42 mmol) in Et2O (5 ml), Ti(OPri)4 (0.239
g, 0.84 mmol) in Et2O (25 ml), PriMgBr (0.99 , 2.12 ml, 2.10
mmol) and H2O (2 ml) according to the general procedure.
Work-up procedure B and flash chromatography (Et2O–light
petroleum, 1:50) gave a mixture of 52 and [2,7-2H2]-1-(tetra-
hydropyran-2Ј-yloxy)dodecane (0.121 g, 80%). Separation of 52
from [2,7-2H2]-1-(tetrahydropyran-2Ј-yloxy)dodecane using
SiO2–AgNO3 based flash chromatography (Et2O–light petrol-
eum, 1:50) gave 52 (0.052 g, 53%) (Found: Mϩ, 359.3786.
C23H37D7O2 requires Mϩ, 359.3781); δH(400 MHz, CDCl3) 0.85
(3H, t, J 7.0, 18-H), 1.17–1.32 (16H, m), 1.45–1.59 (5H, m),
1.64–1.72 (1H, m), 1.76–1.84 (1H, m), 1.97 (4H, m, 8-H, 11-H),
3.34 (1H, dd, J 9.5, 6.9, 1-Ha), 3.47 (1H, m, 6Ј-Ha), 3.69 (1H,
dd, J 9.5, 7.0, 1-Hb), 3.84 (1H, m, 6Ј-Hb), 4.54 (1H, dd, J 4.3,
2.6, 2Ј-H), 5.31 (2H, m, 9-H, 10-H); δC(100 MHz, CDCl3)
J. Chem. Soc., Perkin Trans. 1, 1998
1855

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129.90, 129.79 (C9, C10), 98.80 (C2Ј), 67.59, 62.28 (C1, C6Ј),
31.66, 30.75 (C3Ј), 29.52, 29.44, 29.41, 29.12, 27.13 (C8 or C11),
27.07 (C8 or C11), 26.11, 25.48 (C5Ј), 22.61, 19.66 (C4Ј), 14.09
(C18) [C2, C7, C13, C14, and C15 (CD2 or CDH) were not
detected]; m/z 359 (Mϩ, 0.2%), 286 (1), 127 (1), 126 (1), 125 (1),
112 (3), 111 (2), 101 (9), 98 (5), 97 (5), 86 (10), 85 (100), 83 (10),
57 (14), 56 (19), 55 (14), 43 (13), 42 (11), 41 (20).
ation of 10 and 11, from 1-(tetrahydropyran-2Ј-yloxy)pent-4-
yne 55 (2.08 g, 12.38 mmol) and 1-bromopent-2-yne 29 (1.92 g,
12.38 mmol). The crude product was purified by flash chrom-
atography (Et2O–hexane, 1:20) to yield 1-(tetrahydropyran-2Ј-
yloxy)deca-4,7-diyne 56 (1.56 g, 54%); δH(500 MHz, CDCl3)
1.09 (3H, t, J 7.5, 10-H), 1.75 (2H, quintet, J 6.5, 2-H), 1.44–
1.85 (6H, m, 3Ј-H, 4Ј-H,5Ј-H), 2.15 (2H, qt, J 7.5, 2.4, 9-H),
2.24–2.30 (2H, m, 3-H), 3.08 (2H, quintet, J 2.4, 6-H), 3.40–
3.51 (2H, m, 1-Ha and 6Ј-Ha), 3.78 (1H, dt, J 9.8, 6.4, 1-Hb),
3.84 (1H, ddd, J 11.4, 8.2, 3.1, 6Ј-Hb), 4.57 (1H, dd, J 3.0, 4.1,
2Ј-H); δC(125 MHz, CDCl3) 98.74, 81.79, 79.74, 74.80, 73.76,
66.01, 62.13, 30.66, 28.88, 25.48, 19.48, 15.64, 13.87, 12.37,
9.68; m/z 233 (Mϩ Ϫ 1, 0.2%), 219 (0.4), 205 (1), 177 (2), 175 (2),
167 (22), 150 (6), 149 (6), 117 (15), 115 (16), 91 (44), 85 (100), 79
(21), 77 (30), 67 (25), 57 (24), 55 (29), 43 (32), 41 (76), 39 (31).
(9Z)-[2,7,13,13,14,15,15-2H7]Octadec-9-en-1-ol 53
THP-Protected alkene 52 (0.078 g, 0.217 mmol) was dissolved
in MeOH (2 ml), and toluene-p-sulfonic acid (215 µl, 0.11  in
MeOH, 4.13 mg, 0.022 mmol) was added. The reaction was
monitored by TLC and stirred for 2 h. Solid NaHCO3 was then
added and stirring was continued for an additional hour. The
solvent was then removed in vacuo before Et2O (5 ml) and H2O
(5 ml) were added. The Et2O and aqueous layers were separated
and the latter was further extracted with Et2O (3 × 5 ml). The
combined extracts were washed (saturated aqueous NaCl),
dried (MgSO4) and concentrated to give an oil which was puri-
fied by flash chromatography (Et2O–hexane, 1:5), giving
octadecenol 53 (0.053 g, 89%); δH(400 MHz, CDCl3) 0.85 (3H,
t, J 7.0, 18-H), 1.18–1.32 (16H, m), 1.47–1.55 (1H, m, 2-H),
1.59 (1H, br s, OH), 1.95–2.01 (4H, m, 8-H, 11-H), 3.60 (2H,
d, J 6.6, 1-H), 5.32 (2H, m, 9-H, 10-H); δC(100 MHz, CDCl3)
129.94, 129.76 (C9, C10), 62.94 (C1), 32.34 (C2, C7 or C14, t,
(4Z,7Z)-1-(Tetrahydropyan-2Ј-yloxy)deca-4,7-diene 57
From alkyne 56 (1.559 g, 6.66 mmol) in Et2O (40 ml), Ti(OPri)4
(9.469 g, 33.3 mmol) in Et2O (40 ml), PriMgBr (69.3 ml, 86.6
mmol, ~1.25  solution in dry Et2O) and H2O (2.5 ml) accord-
ing to the general procedure. Work-up procedure A and flash
column chromatography (Et2O–hexane, 1:20) provided pure 57
(0.669 g, 42%) (Found: Mϩ, 238.1932; C, 77.3; H, 11.3%;
C15H26O2 requires Mϩ, 238.1933; C, 75.6; H, 11.0%); δH(500
MHz, CDCl3) 0.95 (3H, t, J 7.5, 10-H), 1.46–1.60 (4H, m,
3Ј-Ha, 5Ј-Ha, 4Ј-Ha, 5Ј-Hb), 1.65 (2H, ~quintet, J 6.8, 2-H),
1.67–1.73 (1H, m, 3Ј-Hb), 1.76–1.86 (1H, m, 4Ј-Hb), 2.01–2.09
(2H, m, 9-H), 2.09–2.20 (2H, m, 3-H), 2.77 (2H, br t, J 6.5,
6-H), 3.38 (1H, dt, J 9.7, 6.6, 1-Ha), 3.48 (1H, m, 6Ј-Ha), 3.73
(1H, dt, J 9.7, 6.7, 1-Hb), 3.85 (1H, ddd, J 11.2, 7.8, 3.4, 6Ј-Hb),
4.56 (1H, dd, J 4.3, 2.9, 2Ј-H), 5.28 (1H, dtt, J 1.5, 7.2, 10.6, 5-H
or 7-H), 5.32–5.41 [3H, m, 4-H, 8-H and (5-H or 7-H)]; δC(125
MHz, CDCl3) 131.84, 129.32, 128.61, 127.29, 98.85, 66.95,
62.30, 30.77, 29.69, 25.51, 25.50, 23.89, 20.53, 19.65, 14.26; m/z
238 (Mϩ, 0%), 1.55 (1), 154 (1), 136 (2), 126 (1), 121 (2), 108 (3),
107 (5), 95 (8), 94 (4), 93 (6), 91 (4), 85 (100), 79 (19), 67 (31), 57
(15), 55 (18), 43 (18), 41 (41), 39 (12).
13C–2H
J
19.1), 31.65, 29.52, 29.46, 29.36, 29.11, 27.13 (C8 or
C11), 27.06 (C8 or C11), 25.61, 22.61, 14.09 (C18) (the
other deuterated carbon signals were not detected); m/z 257
(Mϩ Ϫ 1, 4%), 256 (3), 255 (2), 228 (1), 227 (1), 200 (1), 199
(1), 198 (1), 185 (1), 171 (1), 170 (1), 157 (2), 156 (2), 155 (2),
140 (6), 139 (5), 128 (6), 127 (7), 126 (11), 125 (11), 112 (17),
111 (18), 110 (12), 98 (45), 97 (52), 96 (37), 86 (26), 85 (32), 83
(87), 82 (65), 81 (26), 70 (52), 69 (68), 68 (78), 59 (27), 58 (46),
57 (62), 56 (100), 55 (71), 54 (45), 45 (37), 44 (57), 43 (65), 42
(90), 41 (81).
(9Z)-[2,7,13,13,14,15,15-2H7]Octadec-9-enoic acid 33
Octadecenol 53 (0.050 g, 0.182 mmol) was dissolved in dry
DMF (3 ml). Freshly prepared PDC (0.308 g, 0.818 mmol) was
added in one portion and the reaction was stirred for 16 h at
room temperature. GC analysis showed the reaction had
reached completion. H2O (20 ml) was added and the mixture
extracted with Et2O (3 × 10 ml). The Et2O extracts were washed
with saturated aqueous CuSO4, H2O and saturated aqueous
NaCl and then dried (MgSO4) and concentrated. Purification
involved the use of alkaline extraction. The resulting oil was
dissolved in Et2O (10 ml) and extracted with 0.1  NaOH solu-
tion (3 × 10 ml). This basic solution was acidified to pH 1–2
with aqueous HCl and extracted again with Et2O (3 × 10 ml).
The combined Et2O extracts were dried over MgSO4 and con-
centrated to give deuterated oleic acid 33 (0.043 g, 82%)
(Found: Mϩ, 289.2997; C, 74.8; H, 11.9%. C18H27O2D7 (C18-
H34O2) requires Mϩ, 289.2998; C, 76.5; H, 12.1%); δH(400 MHz,
CDCl3) 0.86 (3H, t, J 7.0, 18-H), 1.18–1.32 (14H, m), 1.61 (2H,
m, 3-H), 1.98 (4H, m, 8-H, 11-H), 2.31 (1H, m, 2-H), 5.32 (2H,
m, 9-H, 10-H); δC(100 MHz, CDCl3) 180.08 (C1), 130.03,
(4Z,7Z)-1-Iododeca-4,7-diene 58
(4Z,7Z)-1-Bromodeca-4,7-diene. Obtained according to the
procedure described for bromide 19 from (4Z,7Z)-1-(tetra-
hydropyran-2Ј-yloxy)deca-4,7-diene 57 (0.660 g, 2.77 mmol).
Flash chromatography (100% light petroleum) gave 1-bromo-
deca-4,7-diene (0.536 g, 89%) (Found: Mϩ, 216.0508.
C10H1779Br requires Mϩ, 216.0514); δH(500 MHz, CDCl3) 0.96
(3H, t, J 7.5, 10-H), 1.91 (2H, quintet, J 6.7, 2-H), 2.06 (2H,
qdd, J 7.5, 7.1, 1.6, 9-H), 2.21 (2H, tdd, J 6.7, 7.3, 1.6, 3-H),
2.79 (2H, dddd, J 7.2, 7.5, 1.6, 1.6, 6-H), 3.39 (2H, t, J 6.7, 1-H),
5.28 (1H, dtt, J 10.7, 1.6, 7.2, 7-H), 5.31 (1H, dtt, J 10.6, 7.3, 1.6,
4-H), 5.38 (1H, dtt, J 10.6, 7.1, 1.6, 8-H), 5.41 (1H, dtt, J 10.7,
1.6, 7.5, 5-H); δC(125 MHz, CDCl3) 132.04, 129.86, 127.66,
126.97, 33.26, 32.52, 25.62, 25.57, 20.55, 14.24; m/z 218, 216
(Mϩ, 5, 6%), 189 (3), 187 (3), 176 (4), 174 (3), 162 (2), 160 (2),
109 (11), 107 (12), 95 (58), 93 (12), 91 (13), 82 (13), 81 (53), 79
(40), 77 (20), 68 (31), 67 (100), 65 (14), 55 (31), 54 (15), 53 (23),
41 (71), 39 (50).
13C–2H
129.69 (C9, C10), 33.74 (C2, t, J
19.5), 31.67 (C16),
(4Z,7Z)-1-Iododeca-4,7-diene 58. Formed when 1-bromo-
deca-4,7-diene (0.530 g, 2.44 mmol) and 1-(tetrahydropyran-2Ј-
yloxy)but-3-yne 59 (0.451 g, 2.93 mmol) were treated according
to the procedure described for the preparation of 10 and 11.
Flash chromatography (Et2O–hexane, 1:20) yielded a fraction
containing the recovered halide, as 1-iododeca-4,7-diene 58
(0.502 g, 78%); δH(400 MHz, CDCl3) 0.96 (3H, t, J 7.5, 10-H),
1.87 (2H, quintet, J 6.9, 2-H), 2.06 (2H, br quintet, J 7.6, 9-H),
2.16 (2H, br q, J 7.3, 3-H), 2.80 (2H, m, 6-H), 3.18 (2H, t, J 6.9,
1-H), 5.25–5.45 (4H, m, 4-H, 5-H, 7-H and 8-H); δC(100 MHz,
CDCl3) 132.04, 129.87, 127.51, 127.00, 33.30, 27.93, 25.68,
20.57, 14.24, 6.39; m/z 264 (Mϩ, 5%), 222 (2), 155 (11), 127 (8),
109 (7), 95 (46), 81 (44), 79 (28), 77 (17), 67 (100), 55 (37), 53
(22), 41 (73), 39 (58).
13C–2H
29.54, 29.26 (C7, t, J
C6, C12), 28.68 (C14, t, J
19.2), 29.10, 29.00, 28.95 (C4, C5,
13C–2H
19.0), 27.16, 27.05 (C8, C11),
24.59 (C3), 22.61 (C17), 14.08 (C18) [C13 and C15 (CD2) were
not detected]; m/z 289 (Mϩ, 2%), 288 (2), 271 (11), 270 (9), 269
(4), 227 (5), 226 (5), 212 (2), 185 (3), 184 (3), 171 (3), 169 (3), 168
(3), 167 (3), 126 (12), 125 (12), 115 (19), 114 (19), 113 (18), 112
(18), 99 (45), 86 (42), 85 (57), 84 (45), 72 (47), 71 (52), 70 (65), 69
(52), 58 (58), 57 (72), 56 (100), 55 (78), 54 (42), 45 (59), 44 (72),
43 (81), 42 (96), 41 (88).
Synthesis of trienyl acetate pheromone
1-(Tetrahydropyran-2Ј-yloxy)deca-4,7-diyne 56
Formed according to the procedure described for the prepar-
1856
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
Eluting with a more polar solvent system (Et2O–hexane, 1:1)
gave 1,8-Bis(tetrahydropyran-2Ј-yloxy)octa-3,5-diyne (0.078 g);
δC(100 MHz, CDCl3) 98.67, 74.37, 66.05, 65.15, 62.07, 30.42,
25.32, 20.65, 19.24.
separation of the two layers, the aqueous layer was further
extracted with Et2O (2 × 5 ml). The combined extracts were
then washed with saturated aqueous NaCl, dried (MgSO4) and
concentrated to give crude (3E,8Z,11Z)-tetradeca-3,8,11-trien-
1-ol (~0.025 g), which was used in the next step without further
purification; m/z 179 (Mϩ Ϫ 29, 1%), 165 (2), 163 (3), 161 (2),
140 (3), 126 (6), 121 (10), 108 (10), 107 (13), 95 (19), 93 (42), 81
(37), 79 (81), 67 (100), 55 (54), 41 (96).
(8Z,11Z)-1-(Tetrahydropyran-2Ј-yloxy)tetradeca-8,11-dien-3-
yne 60
1-(Tetrahydropyran-2Ј-yloxy)but-3-yne 59 (0.060 g, 0.39 mmol)
was dissolved in THF (5 ml) in a three-necked flask and cooled
to Ϫ78 ЊC. BunLi (2.5 , 1.56 µl, 0.39 mmol) was added drop-
wise via syringe and the reaction mixture was stirred at Ϫ60 to
Ϫ50 ЊC for 2 h. Upon recooling to Ϫ78 ЊC, 1-iododeca-4,7-
diene 58 (0.074 g, 0.28 mmol), dissolved in a mixture of THF
(0.5 ml) and HMPA (0.5 ml), was added dropwise. The resulting
mixture was allowed to warm to RT overnight. Hexane (20 ml)
and water (20 ml) were added, and the layers were separated.
The aqueous layer was extracted with hexane (3 × 10 ml). After
washing with saturated aqueous NaCl, the combined organic
layers were dried (MgSO4) and concentrated (reduced pres-
sure). Purification using flash chromatography (Et2O–hexane,
1:20) yielded pure fractions of dienyne 60 (0.034 g, 43%); δH(400
MHz, CDCl3) 0.95 (3H, t, J 7.5, 14-H), 1.51 (2H, quintet, J 7.2,
6-H), 1.40–1.83 (6H, m, 3Ј-H, 4Ј-H, 5Ј-H), 2.05 (2H, m, 13-H),
2.10–2.16 (4H, m, 5-H and 7-H), 2.43 (2H, tt, J 7.3, 2.4, 2-H),
2.76 (2H, br t, J 6.4, 10-H), 3.50 (1H, dt, J 9.6, 7.3, 1-Ha), 3.45–
3.55 (1H, m, 6Ј-Ha), 3.76 (1H, dt, J 9.6, 7.2, 1-Hb), 3.86 (1H,
ddd, J 11.4, 8.2, 3.2, 6Ј-Hb), 4.61 (1H, dd, J 4.1, 3.0, 2Ј-H),
5.20–5.40 (4H, m, 8-H, 9-H, 1-H and 12-H); δC(100 MHz,
CDCl3) 131.83, 128.93, 128.93, 127.24, 98.70, 80.98, 76.98,
66.18, 62.16, 30.54, 28.82, 26.22, 25.50, 25.40, 20.50, 20.19,
19.40, 18.21, 14.27; m/z 290 (Mϩ, 0.1%), 261 (0.1), 217 (1), 205
(1), 175 (1), 159 (5), 117 (5), 91 (14), 85 (100), 79 (15), 67 (24), 57
(13), 55 (13), 43 (17), 41 (36).
(3E,8Z,11Z)-Tetradeca-3,8,11-trien-1-yl acetate 54. Crude
(3E,8Z,11Z)-tetradeca-3,8,11-trien-1-ol (~0.025 g, 0.12 mmol)
was dissolved in dry pyridine (0.2 ml, 1.92 mmol) and to this
solution was added acetic anhydride (0.073 g, 0.72 mmol). Stir-
ring was continued for 1 h, after which time GC–MS analysis
indicated complete conversion to the acetate. The reaction mix-
ture was then poured into saturated aqueous NaHCO3 (20 ml),
and extracted with Et2O (3 × 20 ml). The combined ethereal
extracts were washed with H2O and saturated aqueous CuSO4,
dried (MgSO4) and concentrated under reduced pressure to
give, after flash chromatographic purification, pure 54 (0.020 g,
67%) (Found: Mϩ, 250.1928; C, 76.4, H, 10.5%; C16H26O2
requires Mϩ, 250.1933; C, 76.8; H, 10.5%); δH(400 MHz,
CDCl3) 0.95 (3H, t, J 7.5, 14-H), 1.40 (2H, tt, J 7.7, 7.3, 6-H),
2.01 (3H, s, COMe), 2.03 (6H, m, 5-H, 7-H and 13-H), 2.29
(2H, br qd, J 6.8, 1.2, 2-H), 2.75 (2H, br tt, J 7.1, 1.3, 10-H),
4.04 (2H, t, J 6.9, 1-H), 5.27 (1H, dtt, J 10.7, 7.1, 1.4, 9-H or
11-H), 5.34 [3H, m, 8-H, 12-H and (9-H or 11-H)], 5.36 (1H,
dtt, J 15.3, 6.8, 1.3, 3-H), 5.50 (1H, dtt, J 15.3, 6.6, 1.2, 4-H);
δ (100 MHz, CDCl ) 171.06 (C᎐O), 133.17 (C4), 131.82 (CH᎐),
᎐
᎐
C
3
129.69 (CH᎐), 128.35 (CH᎐), 127.33 (CH᎐), 125.39 (CH᎐),
᎐
᎐
᎐
᎐
64.10 (C1), 32.13 (C5), 31.95 (C2), 29.31 (C6), 26.62 (C7), 25.53
(C10), 20.93 (COCH3), 20.52 (C13), 14.24 (C14); m/z 190
(Mϩ Ϫ 60, 2%), 161 (5), 147 (6), 133 (7), 119 (9), 108 (17), 93
(35), 80 (34), 79 (62), 67 (57), 43 (100), 41 (46).
(3Z,8Z,11Z)-1-(Tetrahydropyran-2Ј-yloxy)tetradeca-3,8,11-
triene 62
(3E,8Z,11Z)-1-(Tetrahydropyran-2Ј-yloxy)tetradeca-3,8,11-
triene 61
From alkyne 60 (0.162 g, 0.56 mmol) in dry Et2O (2 ml),
Ti(OPri)4 (0.401 g, 1.41 mmol) in Et2O (3 ml), PriMgBr (2.71
ml, 3.39 mmol, ~1.25  solution in dry Et2O), H2O (1.0 ml)
according to the general procedure. Work-up Procedure A and
flash chromatography (Et2O–hexane, 1:20) provided 62 (0.025
g, 42%) mixed with minor amounts of isomeric products, which
lacked the ‘methylene-skipped’ diene system by 1H NMR spec-
troscopy. Major component 62, δH(400 MHz, CDCl3) 0.95 (3H,
t, J 7.5, 14-H), 1.20–1.85 (8H, m, 6-H, 3Ј-H, 4Ј-H, 5Ј-H), 1.98–
2.10 (6H, m, 5-H, 7-H, 13-H), 2.33 (2H, m, 2-H), 2.75 (2H, br t,
J 6.4, 10-H), 3.39 (1H, dt, J 9.6, 7.1, 1-Ha), 3.44–3.51 (1H, m,
6Ј-Ha), 3.71 (1H, dt, J 9.5, 7.2, 1-Hb), 3.86 (1H, ddd, J 11.2,
7.9, 3.6, 6Ј-Hb), 4.58 (1H, dd, J 4.3, 2.7, 2Ј-H), 5.24–5.50 (6H,
m, 3-H, 4-H, 8-H, 9-H, 11-H, 12-H); δC(100 MHz, CDCl3)
131.81, 131.57, 129.75, 128.36, 127.36, 125.92, 98.77, 67.10,
62.29, 30.74, 29.63, 28.00, 26.98, 26.85, 25.55, 25.50, 20.54,
19.61, 14.26; m/z 292 (Mϩ, 0.1%), 149 (1), 121 (2), 115 (1), 101
(7), 93 (5), 85 (100), 67 (24), 41 (28).
Sodium (0.016 g, 0.703 mmol) was added to liquid NH3 (2 ml)
in a three-necked flask fitted with a dry-ice condenser, and
immersed in a bath at Ϫ78 ЊC. A deep blue solution resulted.
(8Z,11Z)-1-(Tetrahydropyran-2Ј-yloxy)tetradeca-8,11-dien-3-
yne 60 in Et2O (0.2 ml) was added and after 1 h, additional
NH3. The mixture was then stirred at Ϫ30 ЊC for 3 h and NH4Cl
(0.4 g) was added to quench the reaction. Additional Et2O was
added and stirring continued overnight while the NH3 evapor-
ated. Water (20 ml) was added and the product extracted with
Et2O (3 × 10 ml). The combined extracts were washed with
saturated aqueous NaHCO3 and aqueous NaCl, then dried
with MgSO4 and concentrated to yield (3E,8Z,11Z)-1-(tetra-
hydropyran-2Ј-yloxy)tetradeca-3,8,11-triene 61 (0.034 g, 100%).
Further purification was not necessary prior to subsequent
reaction; δH(400 MHz, CDCl3) 0.95 (3H, t, J 7.5, 14-H), 1.40
(2H, quintet, J 7.3, 6-H), 1.45–1.85 (6H, m, 3Ј-H, 4Ј-H, 5Ј-H),
1.95–2.10 (6H, m, 5-H, 7-H and 13-H), 2.27 (2H, br q, J 7.1,
2-H), 2.75 (2H, br t, J 6.3, 10-H), 3.39 (1H, dt, J 9.6, 7.0, 1-Ha),
3.44–3.51 (1H, m, 6Ј-Ha), 3.71 (1H, dt, J 9.6, 7.1, 1-Hb), 3.85
(1H, ddd, J 11.2, 7.6, 3.6, 6Ј-Hb), 4.57 (1H, dd, J 4.2, 2.9, 2Ј-H),
5.24–5.52 (6H, m, 3-H, 4-H, 8-H, 9-H, 11-H and 12-H); δC(100
MHz, CDCl3) 132.18, 131.78, 129.80, 128.26, 127.36, 126.64,
98.74, 67.37, 62.27, 33.07, 32.20, 30.72, 29.42, 26.65, 25.53,
25.51, 20.52, 19.60, 14.24; m/z 292 (Mϩ, 0.1%), 219 (0.1), 208
(0.1), 175 (0.1), 149 (1), 121 (2), 101 (7), 85 (100), 67 (24), 57 (9),
55 (12), 43 (10), 41 (27).
(3Z,8Z,11Z)-Tetradeca-3,8,11-trien-1-yl acetate 63
(3Z,8Z,11Z)-Tetradeca-3,8,11-trien-1-ol.
(3Z,8Z,11Z)-1-
(Tetrahydropyran-2Ј-yloxy)tetradeca-3,8,11-triene 62 (and
isomers) (0.025 g, 0.086 mmol) and toluene-p-sulfonic acid (1.6
mg, 0.009 mmol) were dissolved in MeOH (1 ml), and stirred
for 1 h, at room temperature. Solid NaHCO3 was added and the
solvent removed in vacuo. Et2O (5 ml) and H2O (5 ml) were then
added. After separation of the two layers, the aqueous layer was
further extracted with Et2O (2 × 5 ml). The combined extracts
were then washed with saturated aqueous NaCl, dried
(MgSO4) and concentrated to give crude (3Z,8Z,11Z)-
tetradeca-3,8,11-trien-1-ol (~0.018 g), which was used in the
next step without further purification.
(3E,8Z,11Z)-Tetradeca-3,8,11-trien-1-yl acetate 54
(3E,8Z,11Z)-Tetradeca-3,8,11-trien-1-ol.
(3E,8Z,11Z)-1-
(Tetrahydropyran-2Ј-yloxy)tetradeca-3,8,11-triene 61 (0.034 g,
0.1 mmol) and toluene-p-sulfonic acid (2 mg, 0.011 mmol) were
dissolved in MeOH (1 ml), and stirred for 1 h, at room temper-
ature. Solid NaHCO3 was added and the solvent was removed
in vacuo. Et2O (5 ml) and H2O (5 ml) were then added. After
(3Z,8Z,11Z)-Tetradeca-3,8,11-trien-1-yl acetate 63. Crude
(3Z,8Z,11Z)-tetradeca-3,8,11-trien-1-ol (and isomers) (~0.018
J. Chem. Soc., Perkin Trans. 1, 1998
1857

View Article Online
J. Am. Chem. Soc., 1995, 117, 3881; (c) A. Kasakin, S. Okamoto
g, 0.086 mmol) was dissolved in dry pyridine (0.2 ml, 1.92
mmol) and to this solution was added acetic anhydride (0.073 g,
0.72 mmol). Stirring was continued for 1 h, after which time
GC–MS analysis indicated complete conversion to the acetate.
The reaction mixture was then poured into saturated aqueous
NaHCO3 (20 ml), which was then extracted with Et2O (3 × 20
ml). The combined ethereal extracts were washed with H2O,
saturated aqueous CuSO4, then dried (MgSO4) and concen-
trated under reduced pressure. Flash column purification on
SiO2–AgNO3 yielded pure 63 (0.010 g, 46%) (Found: Mϩ,
250.1932. C16H26O2 requires Mϩ, 250.1933); δH(500 MHz,
CDCl3) 0.95 (3H, t, J 7.5, 14-H), 1.41 (2H, tt, J 7.7, 7.3, 6-H), 2.02
(3H, s, COMe), 2.05 (6H, m, 5-H, 7-H and 13-H), 2.36 (2H, br
qd, J 7.0, 1.0, 2-H), 2.76 (2H, br tt, J 7.2, 1.5, 10-H), 4.04 (2H, t,
J 6.9, 1-H), 5.28 (1H, dtt, J 10.6, 7.2, 1.4, 9-H or 11-H), 5.35
[4H, m, 3-H, 8-H, 12-H and (9-H or 11-H)], 5.49 (1H, dtt,
and F. Sato, Tetrahedron Lett., 1995, 36, 6075; (d) A. Kasatkin and
F. Sato, Tetrahedron Lett., 1995, 36, 6079; (e) A. Kasatkin,
K. Kobayashi, S. Okamoto and F. Sato, Tetrahedron Lett., 1996, 37,
1849; ( f ) Y. Takayanagi, K. Yamashita, Y. Yoshida and F. Sato,
Chem. Commun., 1996, 1725; (g) J. Lee, H. Kim and J. K. Cha,
J. Am. Chem. Soc., 1995, 117, 9919; (h) J. Lee, C. H. Kang, H. Kim
and J. K. Cha, J. Am. Chem. Soc., 1996, 118, 291; (i) J. Lee, H. Kim
and J. K. Cha, J. Am. Chem. Soc., 1996, 118, 4198; (j) J. Lee and
J. K. Cha, Tetrahedron Lett., 1996, 37, 3663.
22 (a) K. Tamao, T. Nakajima and M. Kumada, Organometallics, 1984,
3, 1655; (b) G. Stork and E. Colvin, J. Am. Chem. Soc., 1971, 93, 2080;
(c) A. Alexakis, G. Cahiez and J. F. Normant, Synthesis, 1979, 826.
23 (a) A. P. Tulloch, Chem. Phys. Lipids, 1979, 24, 391; (b) H. Rakoff,
Prog. Lipid Res., 1982, 21, 225; (c) E. A. Emken, ‘Synthesis of
Isotope Labeled Fatty Acids’, in Fatty Acids, ed. E. H. Pryde,
American Oil Chemists Society, Champaign, 1979, ch. 5, pp. 90–
109; (d) E. A. Emken, ‘Synthesis and Analysis of Stable Isotope-
and Radioisotope-Labeled Fatty Acids’, in Handbook of Lipid
Research, ed. A. Kuksis, Plenum Press, New York, 1978, vol. 1,
ch. 2, pp. 77–121.
J 10.8, 7.3, 1.5, 4-H); δ (125 MHz, CDCl ) 171.11 (C᎐O),
᎐
C
3
132.54 (C4), 131.84 (CH᎐), 129.60 (CH᎐), 128.46 (CH᎐), 127.29
᎐
᎐
᎐
24 T. Haffner, A. Nordsieck and R. Tressl, Helv. Chim. Acta, 1996, 79,
(CH᎐), 124.67 (CH᎐), 63.95 (C1), 32.13 (C5), 29.54 (C6), 26.91,
᎐
᎐
2088.
26.84, 26.79 (C2, C5, C7), 25.54 (C10), 20.97 (COCH3), 20.54
(C13), 14.26 (C14); m/z 250 (Mϩ, 0.1%), 190 (1), 161 (4), 147
(5), 133 (6), 119 (8), 108 (13), 93 (30), 91 (16), 81 (21), 80 (28), 79
(54), 67 (51), 43 (100), 41 (42).
25 E. J. Corey and G. Schmidt, Tetrahedron Lett., 1979, 20, 399.
26 (a) G. Graff, P. Szczepanik, P. D. Klein, J. R. Chipault and R. T.
Holman, Lipids, 1970, 5, 786; (b) T. Haffner and R. Tressl, J. Agric.
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Chim. Fr., 1966, 2775; (e) T. L. Mounts, E. A. Emken, W. K.
Rohwedder and H. J. Dutton, Lipids, 1971, 6, 912; ( f ) P. H. Buist
and D. B. MacLean, Can. J. Chem., 1981, 59, 828.
Acknowledgements
One of the authors (N. H.) is grateful to the Australian
Research Council for the provision of an Australian Postgrad-
uate Award.
27 W. J. Dejarlais and E. A. Emken, Lipids, 1976, 11, 594.
28 L. Crombie and S. J Holloway, J. Chem. Soc., Perkin Trans. 1, 1985,
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Paper 8/00674A
Received 26th January 1998
Accepted 27th February 1998
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1858
J. Chem. Soc., Perkin Trans. 1, 1998