Optimised total syntheses of the F-furan fatty acids F5 and F6 and some deuterated derivatives Dedicated, with the greatest respect, to the memory of Professor Alan R. Katritzky

Article abstract of DOI:10.1016/j.tet.2015.05.061

Optimised syntheses of F₅- and F₆-furan fatty acids 2 and 3 are described in full. Key steps include furan formation from a single 3-alkyne-1,2-diol 6 using 5-endo-dig cyclisations triggered by silver(I) nitrate or iodine. Introducti

Full text of DOI:10.1016/j.tet.2015.05.061

Tetrahedron 71 (2015) 7436e7444
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Optimised total syntheses of the F-furan fatty acids F5 and F6 and
some deuterated derivatives
*
David W. Knight , Andrew W.T. Smith
School of Chemistry, Cardiff University, Main College, Park Place, Cardiff, CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Optimised syntheses of F5- and F6-furan fatty acids 2 and 3 are described in full. Key steps include furan
formation from a single 3-alkyne-1,2-diol 6 using 5-endo-dig cyclisations triggered by silver(I) nitrate or
iodine. Introduction of the final carboxylic acid function and one-carbon homologation were achieved by
cross metathesis with benzyl acrylate and hydrogenation. Iodine-methyl exchange of intermediate io-
dofurans was achieved by direct treatment with methyl lithium, which gave trideuterated derivatives 16
of the F6 acid by using CD3Li. The two acids 2 and 3 proved very unstable; thus, if samples are to be stored
for extended periods, this should be as an ester and not as the free acids. This instability does raise
questions regarding previously determined levels of these free acids (and perhaps some of their struc-
turally close relatives) in various natural sources.
Received 30 January 2015
Received in revised form 15 May 2015
Accepted 18 May 2015
Available online 22 May 2015
Dedicated, with the greatest respect, to the
memory of Professor Alan R. Katritzky
Keywords:
F-acids
Ó 2015 Elsevier Ltd. All rights reserved.
Furan fatty acids
Synthesis
Assay
Alkyne-diol cyclisation
Cross metathesis
1. Introduction
anti-oxidant activity, which may even help protect against ath-
erosclerosis and cardiovascular disease amongst others.3
Concerns with the perceived deleterious effects of modern di-
etary habits in general on Public Health in the Developed World
have led to many ideas for change, one of the most prominent being
to increase the consumption of fish and related food sources, due to
the likely benefits imparted by the relatively high concentrations of
omega-3 fatty acids, which these contain. Indeed, this is now offi-
cial advice from the UK Government,1 as well as a general view
amongst the medical profession.2 Typically, eating fish twice
a week is advocated; this arguably relatively low amount is, ironi-
cally, seemingly due to largely human-generated levels of pollution
in rivers and the oceans.2 A significant component of such fish oils
are the furan fatty acids 13 although, despite the foregoing advice,
nothing like so much is known about the possible roles of these
metabolites and the potential benefits to human health (Fig. 1). The
compounds were first discovered in 19613 and have been detected
in just about all organisms that have been investigated for their
presence since this discovery.4 Despite such a remarkable ubiquity
in Nature, their precise role currently remains uncertain but is
believed to be associated with potent radical scavenging and hence
The most common furan fatty acids (F-acids) are tri- or tetra-
substituted derivatives [1; R¼H or Me]. Typical values for m and n
are 2 or 4 and 8, 10 or 12, respectively. In common with other fatty
acid series, various abbreviated nomenclature systems have been
developed, the first being suggested by Glass et al. and based on GC
retention times of the corresponding methyl esters.5 This system is
the origin of the terms ‘F5’ and ‘F6’ associated with the furan fatty
acids 2 and 3, respectively, which are the topics of this present paper
and which will be used throughout this report, although more de-
scriptive alternatives have beenproposed recently.6,7 Their common
occurrence is illustrated by an initial isolation from the Northern
pike, Esox Lucius,5,8 which was soon followed by their detection in
other freshwater9,10 and marine fish species10e16 various mam-
mals,17 crustaceans,18e20 amphibians and reptiles;19 of course, the
presence of the acids in many animal species probably reflects the
nature of their diet. Exceptional F-acids with extremely lengthy
unsaturated side chains have been identified in some species of
marine sponges, along with more common examples.21 In addition,
members of the F-acid group have also been found in marine
bacteria,22e24 algae,25,26 terrestrial plants27,28 and various types of
yeast and fungi.29 Given such a diverse range of sources, it is hardly
surprising that the F-acids occur in many foodstuffs; recently
identified examples include a surprisingly high concentration in
* Corresponding author. Tel.: þ44 (0) 2920874210; fax: þ44 (0) 2920874030;
e-mail address: knightdw@cf.ac.uk (D.W. Knight).
http://dx.doi.org/10.1016/j.tet.2015.05.061
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

D.W. Knight, A.W.T. Smith / Tetrahedron 71 (2015) 7436e7444
7437
R
R
CO2H
( )n
( )m
CO2H
O
O
1
2 R = H, F5
3 R = Me, F6
Fig. 1. The common furan fatty acids and the F5 and F6 furan fatty acids.
butter on sale in Germany30 and in virgin olive oil.28 No doubt, many
other processed foods also contain variable amounts of the F-acids,
which biosynthetically, generally seem to arise by the oxidation of
polyunsaturated fatty acids;3,31 remarkably, despite their instability
(see below), levels of furan fatty acids have been recently been re-
ported to increase during the deep-fat frying of fish.32
Previous total chemical syntheses of the F5 and F6 fatty acids 2
and 3 have been few. The first approach by the Glass group resulted
in overall yields of 2 and 8%, respectively, but was notable for
proving their structures.33 A major problem in these schemes was
reasons for choosing a terminal alkene function as the precursor to
the final carboxylic acid function were threefold: firstly, we antic-
ipated that the alkene should survive unmolested during the pre-
ceding steps, secondly that the necessary acid function and the
additional carbon could readily be introduced using a cross me-
tathesis reaction (and, if not that there were many plausible alter-
natives); finally, and crucially, the starting material 9 is cheap and
readily available, being derived from the corresponding carboxylic
acid, itself an important antifungal compound, which is obtained by
pyrolysis of castor oil.40
introduction of the longer side chain, which was addressed by an
The steps from this initial compound 9 seemed likely to be
relatively straightforward: addition of ethyne, hydration of the
resulting alkynol 8 to give the hydroxyl-ketone 7 and finally addi-
tion of 1-heptyne, to arrive at the common intermediate 6.
In the event, (Scheme 2), an optimum method featured the
addition of commercial ethynylmagnesium bromide to the alde-
hyde 9 in ice-cold tetrahydrofuran, which delivered an essentially
quantitative yield of the desired alcohol. However, as the antici-
pated optimum method for the subsequent alkyne hydration step
required the alcohol to be protected as the corresponding acetate,
the reaction was instead quenched using acetic anhydride at the
same temperature. After 1 h, yields of the acetoxy derivative 10
were routinely at least 92%. Using the alternative alkyne nucleo-
phile, lithium acetylideeethylene diamine complex (LAEDA), was
considerably less effective, with yields typically not much
above 60% overall, following an aqueous work-up to give the in-
termediate alkynol and separate acetylation (Ac2O, DMAP, CH2Cl2,
0e20 ꢀC, 3 h).
34
€
alternative strategy reported by Schodel and Spiteller, which
featured sequential FriedeleCrafts acylation and Wolff-Kishner
reduction to arrive at the required saturated long chain carboxylic
acid substituent in F-acid F6 3. Glass followed this with a neat
synthesis of a 14C-labelled F6 derivative using sequential Vilsmeier
formylation, Wittig homologation and hydrogenation to arrive at
the longer side chain.6 The more recent synthesis of F-acid F5 by
€
Bach and Kruger is even more appealing and well illustrates the
synthetic power of modern catalysed coupling technology.35
Starting with 4,5-dibromofuran-2-carboxaldehyde, sequential
regiospecific Sonogashia and Negishi-type couplings serve to in-
troduce the lengthier side chain and a b-methyl group; later Wittig
homologation and hydrogenation completes this highly practical
synthesis. Our own first foray into this area36 will be mentioned
later, as a contrast to the successful and optimised synthesis, aimed
in particular at producing useable amounts of a labelled derivative,
which is described in full below.37
9
2. Results and discussion
i) HCCMgBr
THF, 0 oC, 0.5 h
ii) Ac2O, 0 oC, 1 h
>92%
2 mol% NaAuCl4.2H2O
aq. MeOH, reflux, 3 h
O
Both targets 2 and 3 appeared to be accessible from a common
yne-diol 6 using methodology developed by us: firstly, a silver-
catalysed 5-endo-dig cyclisation38 of this diol 6 was expected to
deliver the advanced intermediate furan 4 while a similar cyclisa-
tion but induced by molecular iodine39 would result in formation of
the related iodofuran 5, which should then allow incorporation of
the final methyl group on the way to F-acid F6 3 (Scheme 1). The
9
( )8
( )8
AcO
RO
K2CO3, aq. MeOH,
0 oC, 1 h
10
7 a) R = Ac
b) R = H
77%
2.2 eq. C5H11CCLi
THF, -78 oC, 1 h
89%
C5H11
2 (F5)
OH
C5H11
( )8
C5H11
O
OH
4
( )8
HO
6
( )8
I
HO
6
Scheme 2. The initial steps leading to common intermediate 6.
3 (F6)
( )8
C5H11
O
5
Hydration of the alkyne group was accomplished using Utimo-
to’s excellent gold-catalysed method41 employing ca. 2 mol % of
sodium gold(III) chloride as the catalyst, in refluxing aqueous
methanol, for, which use of freshly distilled water was essential if
high yields of the acetoxy-ketone 7a were to be obtained. We then
found that it was also essential to carry out an aqueous work-up of
this reaction, rather than to directly basify it, in order to hydrolyse
the acetoxy group. Given that the latter reaction was carried out
separately with ice cooling rather than at ambient temperature,
O
( )8
( )8
( )8
HO
RO
O
9
8
7
Scheme 1. The overall retrosynthetic plan to F-acids F5 and F6.

7438
D.W. Knight, A.W.T. Smith / Tetrahedron 71 (2015) 7436e7444
when yields fell away dramatically, then just below 80% combined
yields of the hydroxyl-ketone 7b were routinely obtained for these
two steps.
to reduce the amount of acrylate to only 1.3 equiv without reducing
the yield of ester 11, which resulted in negligible fumarate forma-
tion and hence product contamination by only a small amount of
acrylate. Optimised conditions for both the model and actual cross
metatheses were to heat the reactants and catalyst at reflux in dry
dichloromethane for 2 h and consistently delivered around 90%
isolated yields, after chromatographic separation of the excess
acrylate.
Addition of the second acetylide, 1-lithioheptyne, was then
carried out in the simplest way by adding 2.2 equiv of the latter to
the hydroxyl-ketone 7b without using any protection of the alcohol
group; this delivered typically a 90% yield of pure common in-
termediate alkyne-diol 6, as a 4:1 mixture of diastereoisomers.42
While this might seem wasteful in terms of 1-heptyne and butyl-
lithium, overall it is more atom efficient than, say, protection of the
alcohol in the hydroxyl-ketone 7 using a TBDMS group. This would
not only add two steps, which while no doubt efficient, would not
give quantitative yields, it would also produce waste, which would
be difficult to recycle, whereas, in principle, the excess 1-heptyne
could be recovered. The cost overall is also lower.
We first pursued a synthesis of F-acid F5 2 and so exposed the
alkyne-diol 6e10 mol % silver(I) nitrate on silica gel in dichloro-
methane, conditions which were successful in our initial studies38
and were very pleased to isolated the desired furan 4 in essentially
quantitative yield after 4 h reaction time at ambient temperature
followed by a simple filtration through Celite (Scheme 3). The
product was completely pure according to the quality of all its NMR
data.
However, this separation was not necessary, once the penulti-
mate intermediate 11 had been fully characterised: the anticipated
final combined alkene hydrogenationeester hydrogenolysis
worked extremely well and in the process converted any excess
acrylate into propanoic acid, which was easily removed by a water
wash (Scheme 4). Unfortunately, attempts to combine the two
steps, that is, to replace the metathesis reaction nitrogen atmo-
sphere with hydrogen and utilise the ruthenium present as a hy-
drogenation catalyst, were unsuccessful, despite some precedent.44
A final purification using a short silica gel column typically
provided an 83% yield of pure furan fatty acid F5 2, which displayed
spectroscopic and analytical data identical to those previously
recorded.33e35 We were surprised to find that the F-acid F5 2 is
rather unstable; significant decomposition set in even when it was
stored for a day at ꢁ20 ꢀC in the dark under nitrogen. If left in the
open laboratory without any special protection, very noticeable
disintegration had occurred within 3 h; much the same was true of
solutions in deuteriochloroform used to record NMR spectra. For-
tunately, the penultimate precursor, the unsaturated benzyl ester 11
and the foregoing alkene 4, are much more stable, but still require
care if they are to be preserved, which is typical of many aliphatic
furan derivatives. If pure samples are stored at ꢁ20 ꢀC in the dark
under nitrogen, these compounds survive well for many months.
C5H11
OH
10% AgNO3-SiO2 (cat.)
CH2Cl2, 20 oC, 4 h
~100%
( )8
C5H11
O
( )8
HO
Scheme 3. Formation of the furan precursor 4 to F-acid F5 2.
This has two implications. Firstly, when samples of the F-acid F5
2
We then addressed the final steps, using 1-octene as a model
alkene. The key idea was to carry out a cross metathesis using
benzyl acrylate, which was expected to introduce both the required
carboxylate group and the additional carbon atom and give an in-
termediate unsaturated benzyl ester, hydrogenation of which
would lead directly to the desired saturated acid. Initial studies
using Grubbs second generation catalyst43 failed to give more than
traces of the desired model product, (E)-benzyl 2-nonenoate, de-
spite some literature precedent.44 Two key changes led to success:
firstly, we turned to the alternative GrubbseHoveyda catalyst45 and
used only freshly distilled benzyl acrylate;46 these changes were
spectacular in effect, typically affording around 90% yields of the 2-
nonenoate, and continued to work in the real example of alkene 4
(Scheme 4). Initially, 3 equiv of benzyl acrylate were used to ensure
complete reaction of the more precious furan alkene 4, but this
inevitably resulted in contamination of the desired product 11 by
the excess acrylate and also by variable amounts of the cross me-
tathesis homodimer, dibenzyl fumarate. Fortunately, we were able
are required for analytical work, especially when this is of a quan-
titative nature, then reference samples must be prepared immedi-
ately prior to the work and preferably stored at as low a temperature
as possible. Of course, one of the wonders of the metathesis
chemistry is that despite its mechanistic sophistication, it is a very
easy reaction to perform, given due attention to the cleanliness of all
the components.48 We therefore have no hesitation in recom-
mending this approach for the regular synthesis of pure analytical
samples to the ‘synthetically inexperienced,’ because the last or last
two steps are so relatively simple to carry out and to work-up. A
second key point, which might be addressed by the foregoing rec-
ommendation, is to question the accuracy of previous de-
terminations of the levels of F-acids in their various sources, in view
of the obvious variations in the unstable F-acid standards as well as
the isolated F-acids themselves, which could influence such results.
Obviously, this is a moot point and is made with no intent to criticise
previous research in this area but merely to sound a note of caution.
It is also clear that rapid derivatisation of the free F-acids from
whatever source, preferably as simple esters, is a firm recommen-
dation to improve the accuracy and reproducibility in such analyt-
ical results.7 The very recent report32 of an increase in F-acid
concentrations when fish is deep-fried does, however, provide an
interesting contrast to these conclusions and suggestions!
CO2Bn
CO2Bn
C5H11
( )8
C5H11
( )8
O
O
2 mol% catalyst
[Grubbs-Hoveyda Mk II]
CH2Cl2, reflux, 2 h
89%
4
11
We then turned to using the common intermediate 6 as a pre-
cursor to the F-acid F6 3. In our initial model studies of the iodo-
5% Pd-C
MeOH, 20 o
1 h
H2
83%
cyclisation approach to b
-iodofurans,39 we had found that either
C
dichloromethane or acetonitrile were highly suitable solvents, the
use of which routinely resulted in ca. 90% yields of the desired
iodofurans. It therefore came as an unpleasant surprise when such
cyclisations of much more ‘fatty’ precursors such as yne-diol 6 were
found to give very poor yields of iodofurans. Fortunately, a brief
solvent screen revealed that ethyl acetate restored the high level of
iodofuran formation.36 However, when this was used in the case of
yne-diol 6, only around 60% conversion to the corresponding
CO2H
( )10
C5H11
O
2 [F-acid F5]
Scheme 4. The final steps leading to F-acid F5 2.

D.W. Knight, A.W.T. Smith / Tetrahedron 71 (2015) 7436e7444
7439
iodofuran 12 occurred, with the remainder being unidentified de-
composition or other products. Happily, by changing the solvent to
tetrahydrofuran, the high return was restored in this case, with
pure iodofuran 12 being isolated in 85% yield after the simplest of
work-ups (Scheme 5).
As well as greatly diminishing the amount of non-methylated
product formed in the halogen-methyl exchange step, this idea
had its origins in the commercial availability of d3-methyllithium
because, if successful, it would allow the easy introduction of a fully
deuterated methyl group into the F-acid F6 3. As expected in the
light of the chemistry shown in Scheme 7, this did indeed work well
and delivered the first deuterated intermediate 15, which was then
smoothly converted in similarly excellent yields into the
trideuterio-F-acid F6 16 with no interference from or loss of the new
deuterium atoms (Scheme 8).
The additional
b
-methyl group in F-acid F6 3 was then in-
C5H11
I
OH
3 eq. I2
3 eq.NaHCO3, THF, 20 oC, 1 h
85%
( )8
C5H11
O
( )8
HO
6
12
D3C
C5H11
D3C
C5H11
Scheme 4
Scheme 5. The key iodocyclisation step.
D3CLi.LiI.OEt2
12
CO2H
( )10
THF, -78 oC, 0.5 h
( )8
O
O
15
16 [d3-F-acid F6]
troduced by the standard method of halogen-metal exchange using
butyllithium followed by quenching with iodomethane. Clean
samples of the fully substituted furan 13 were isolated in around
75% yields but these were always contaminated with significant
amounts (up to 5e15%) of the corresponding demethyl derivative,
the precursor 4 of F-acid F5, presumably because of the difficulties
of completely removing all water from the iodomethane used as
the electrophile, as well as from other sources (Scheme 6).
Scheme 8. Synthesis of d3-F-acid F6 16 using D3CLi$LiI complex.
In similar fashion, cross metathesis of the deuterated furan 15
with methyl acrylate worked equally well; subsequent hydroge-
nation of the resulting unsaturated methyl ester 17 now delivered
the methyl ester 18 (Scheme 9). This is a particularly useful stan-
dard for F-acid analysis, as these are best derivatised as their methyl
esters7 and being an ester, compound 18 doers not suffer from the
instability of the free F-acids and hence will survive for lengthy
periods if stored carefully. It can also readily be converted into the
corresponding acid 16 by base-induced hydrolysis if required.
i) BuLi, THF,
-78 oC, 5 min.
12
ii) MeI
C5H11
( )8
O
13
as Scheme 4
D3C
CO2Me
15
CO2Me
as Scheme 4
87%
( )8
C5H11
O
H2, 10% Pd-C
MeOH, 20 oC, 1 h
91%
CO2H
( )10
CO2Bn
C5H11
C5H11
( )8
O
O
17
3 [F-acid F6]
14
D3C
Scheme 6. Completion of the first approach to F-acid F6 3.
CO2Me
( )10
C5H11
O
Not surprisingly, the synthesis of F-acid F6 3 was readily com-
pleted using exactly the same methodology shown in Scheme 4, via
the homologated benzyl ester 14 in essentially the same excellent
yields (Scheme 6). The acid 3 proved to be just as unstable and
sensitive as F5 2 and hence exactly the same comments made above
apply to this more substituted derivative.
18
Scheme 9. Synthesis of the saturated, trideuterated methyl ester 18 of F-acid F6.
3. Conclusions
There remained the irritation that the samples of F-acid F6
3
This present approach is capable of providing at least hundreds
of milligrams of both F-acids 2 and 3. This is in contrast to our two
previous approaches, which while achieving the final goals of F-
acids total syntheses, are, as they stand, not suitable for producing
the final products on this scale (Scheme 10).36 In the first, the
Sonogashira product 19 was regiospecifically bis-hydroxylated at
the alkene group; subsequent iodocyclisation of the resulting
alkyne-diol 20 gave the iodofuran 21.
were always contaminated with small amounts of F-acid F5 2,
which could not be separated by HPLC on a preparative scale in our
hands. We also had to address the problem of how to incorporate
a useful and safe label into F6. These two features led one of us
(AWTS) to suggest that the halogen-metal exchange be carried out
using methyllithium rather than the conventional butyllithium,
thereby generating iodomethane in situ, which would then trap the
intermediate furyl b-carbanion without the need to add any addi-
We were never able to optimise introduction of the required
methyl group at this stage, using Stille-type couplings and the
synthesis also no doubt suffered from the small scale we were
working on, without the knowledge of the extreme sensitivity of
the final F-acid F5 2. This potentially briefer approach, which
could have been adapted to a synthesis of F-acid F6 3, was
modified to a relative of the present approach but incorporating
an intact side chain carrying a distal protected alcohol group;
a key step was the highly efficient Ag(I)-catalysed cyclisation of
yne-diol 22 into the furan 23. An unsolved problem in this case,
along with a number of unoptimised earlier steps, was the final
oxidation, which was never especially efficient despite trying
a range of typical reagents, possibly at least partly due once again
to product decomposition.
tional reactant. There seems to be no precedent for this and so we
were delighted to find that the idea worked very well and routinely
produced the F-acid F6 precursor 13 in around 90% isolated yields
from the iodofuran 12, which was contained by <3% of the corre-
sponding demethyl compound 4 (Scheme 7).
I
MeLi.LiBr.OEt2
( )8
( )8
C5H11
C5H11
THF, -78 oC, 0.5 h
~90%
O
O
12
13
Scheme 7. Iodine-methyl exchange using methyllithium.

7440
D.W. Knight, A.W.T. Smith / Tetrahedron 71 (2015) 7436e7444
otherwise stated, in which case such data were obtained using
OH
a Waters LCT Premier XE instrument (LRMS) or Agilent 5975C Se-
ries GC/MSD (GCeMS) and atmospheric pressure chemical ionisa-
tion (APCI) or electrospray ionisation (ES). High resolution mass
spectrometric (HRMS) data were determined with the molecular
formula corresponding to the observed signal using the most
abundant isotopes of each element.
C5H11
C5H11
CO2Me
( )10
CO2Me
( )10
HO
19
20
I
4.1.1. 3-Acetoxytridec-12-en-2-one 10. To an oven-dried 250 ml
three neck round-bottomed flask fitted with a gas bubbler and
under an atmosphere of dry nitrogen were added ethynylmagne-
sium bromide (50.0 ml of a 0.5 M solution in tetrahydrofuran,
25.0 mmol) and dry tetrahydrofuran (160 ml). The solution was
stirred and cooled in an ice-water bath for 10 minutes then unde-
cylenic aldehyde 9 (4.55 ml, 20.83 mmol) was added dropwise via
syringe. After 0.5 h (TLC monitoring), acetic anhydride (2.75 ml,
29.16 mmol) was added dropwise. After 1 h, the reaction mixture
was quenched by the addition of ice-cold saturated aqueous am-
monium chloride (30 ml) and concentrated under reduced pres-
sure. The residue was extracted with ether (3ꢂ25 ml) and the
combined extracts washed with water (50 ml) and brine (50 ml)
then dried, filtered though a plug of silica gel with dichloromethane
(100 ml) and the solvents evaporated to yield the acetate 10 as
a colourless oil (4.87 g, 99%), which was pure according to the
following data: Rf 0.28 (5:95 EtOAcehexanes); nmax/cmꢁ1 (film)
3308, 3077, 2927, 2856, 2333, 1744,1641, 1372, 1234, 1022, 910, 630;
dH (400 MHz, CDCl3) 5.81 (1H, ddt, J¼17.0, 10.2 and 6.8, 12-H), 5.34
(1H, td, J¼6.7 and 2.1, 3-H), 5.00 (1H, app. ddd, J¼17.0, 3.5 and 1.4,
13-Ha), 4.93 (1H, ddt, J¼10.2, 2.2 and 1.4, 13-Hb), 2.45 (1H, d, J¼2.1,
1-H), 2.09 (3H, s, Me), 2.07e2.00 (2H, m, CH2), 1.80e1.70 (2H, m,
CH2), 1.48e1.32 (2H, m, CH2), 1.26 (10H, br s, 5ꢂ CH2); dC (100 MHz,
CDCl3) 169.9 (C]O), 139.1 (12-CH), 114.1 (13-CH2), 81.4 (2-C), 77.4
(3-CH), 73.4 (1-CH), 34.6 (CH2), 33.8 (CH2), 29.47 (CH2), 29.44 (CH2),
29.3 (CH2), 29.1 (CH2), 28.9 (CH2), 24.9 (CH2), 21.0 (Me); m/z (EI) 236
[M]þ (15%), 59 (100); HRMS: m/z (EI) calcd for C15H24O2 [M],
236.1776, found, [M]þ, 236.1770.
CO2Me
( )10
C5H11
O
21
C5H11
OH
( )10
C5H11
OH
O
( )10
HO
22
OTBS
23
Scheme 10. Our previous approaches to the F-acids.
In summary, the present optimised procedure can provide
useful quantities of both F-acids 2 and 3 and, more importantly for
analytical purposes, esterified derivatives with much greater sta-
bility, which can be used as accurate standards for the quantifica-
tion and hence reasoned exploration of the relevance or otherwise
of these and homologous F-acids to human health.
4. Experimental
4.1. General
Reagents were obtained from Aldrich, Alfa Aesar, Lancaster,
Fluka and Strem chemical suppliers and used as received unless
otherwise specified. Solvents and reagents were purified according
to the procedures of Perrin, Armarego and Perrin.49
All non-aqueous reactions, unless otherwise stated, were con-
ducted in oven- or flame-dried glassware under an atmosphere of
dry nitrogen with magnetic stirring. Solid carbon dioxide and an
acetone bath (ꢁ78 ꢀC) or an ice-water bath (0 ꢀC) were used to
obtain low temperature.
All solutions of crude products were dried by brief exposure to
dried magnesium sulfate (MgSO4). Column chromatography refers
to flash column chromatography using Merck Kieselgel 60H silica
or Matrix silica 60 as the stationary phase.
4.1.2. 3-Hydroxytridec-12-en-2-one 7b.
i) 3-Acetoxytridec-12-en-2-one 7a
Sodium gold chloride (0.131 g, 0.33 mmol) was added to a stir-
red solution of acetate 10 (3.89 g, 16.46 mmol) in aqueous methanol
(40 ml, 9:1 methanol/distilled water) and the resulting mixture
heated at reflux for 3 h. The cooled solution was then concentrated
and the residue diluted with ether (50 ml) and washed with brine/
2 M aqueous ammonia (1:1, 2ꢂ50 ml), water (50 ml) and brine
(50 ml) then dried, filtered and evaporated to yield the acetoxy-
Infra-red spectra were recorded in the range 4000e600 cmꢁ1
using a PerkineElmer 1600 series Fourier Transform Infrared
Spectrometer, as liquid films between sodium chloride plates [film],
unless otherwise stated. All absorptions are quoted in wave num-
bers (cmꢁ1). Proton (1H) NMR spectra were recorded using an
Avance Bruker DPX 400 instrument (400 MHz); the same in-
strument operating at 100.6 MHz was used to obtain 13C spectra.
Spectra were obtained as dilute solutions in deuteriochloroform,
unless otherwise stated. The chemical shifts were recorded relative
to residual chloroform (7.27 or 77.0 ppm) as an internal standard.
Deuterium NMR spectra were recorded using a Jeol Eclipse (þ)
(300 MHz) instrument for dilute solutions in chloroform containing
a trace of deuteriochloroform. The chemical shifts were recorded
relative to deuteriochloroform (7.27 ppm). All coupling constants
(J) are recorded in Hertz (Hz). Assignments were made on the basis
of chemical shift and coupling constant data using DEPT-90, DEPT-
135, COSY, NOESY, HSQC and HMBC experiments where required.
Mass spectrometric data were determined using a Waters GCT
Premier instrument and electron impact ionisation (EI) unless
ketone 7a as a pale yellow oil (3.56 g, 85%), which showed nmax
/
cmꢁ1 (film) 3076, 2927, 1745, 1734, 1641, 1435, 1372, 1240, 1044,
994, 909; dH (400 MHz, CDCl3) 5.82 (1H, ddt, J¼16.9, 10.2 and 6.7,
12-H), 5.03e4.97 (2H, m, 13-Ha and 3-H), 4.94 (1H, ddt, J¼10.2, 2.1
and 1.0, 13-Hb), 2.17 (3H, s, Me), 2.16 (3H, s, Me), 2.08e2.00 (2H, m,
CH2),1.80e1.70 (2H, m, 4-CH2),1.42e1.32 (2H, m, CH2),1.28 (10H, br
s, 5ꢂ CH2); dC (100 MHz, CDCl3) 205.5 (2-C]O), 170.8 (C]O), 139.3
(12-CH), 114.3 (13-CH2), 78.9 (3-CH), 33.9 (CH2), 30.4 (CH2), 29.5
(CH2), 29.4 (CH2), 29.3 (CH2), 29.2 (CH2), 29.0 (CH2), 26.2 (Me), 25.3
(CH2), 20.8 (Me).
The sample was used immediately in the next step.
ii) 3-Hydroxytridec-12-en-2-one 7b
Potassium carbonate (4.55 g, 32.92 mmol) was added to a stirred
solution of foregoing acetoxy-ketone 7a (3.56 g, 14.00 mmol) in
aqueous methanol (40 ml, 9:1 methanol/water) cooled in an ice-
water bath. After 0.5 h, the solution was concentrated and the

D.W. Knight, A.W.T. Smith / Tetrahedron 71 (2015) 7436e7444
7441
residue extracted with ether (3ꢂ25 ml). The combined organic
extracts were washed with water (50 ml) and brine (50 ml) then
dried, filtered and evaporated. The residue was purified by column
chromatography (15:85 EtOAcepetroleum ether) to yield the hy-
droxyl-ketone 7b (2.68 g, 90%) as a colourless oil: Rf 0.65 (15:85
EtOAcehexane); nmax/cmꢁ1 (film) 3477, 3076, 2925, 2854, 1714,
1640, 1464, 1438, 1358, 1247, 1130, 1087, 994, 909, 722; dH
(400 MHz, CDCl3) 5.82 (1H, ddt, J¼17.0,10.2 and 6.7,12-H), 5.00 (1H,
app. ddd, J¼17.0, 3.7 and 1.6, 13-Ha), 4.94 (1H, ddt, J¼10.2, 2.2 and
1.2, 13-Hb), 4.19 (1H, dd, J¼7.3 and 3.7, 3-H), 2.21 (3H, s, 1-Me),
2.09e1.99 (2H, m, CH2), 1.90e1.80 (1H, m, 4-Ha), 1.65e1.52 (2H, m,
CH2), 1.51e1.43 (1H, m, 4-Hb), 1.40e1.36 (4H, m, 2ꢂ CH2), 1.30 (6H,
br s, 3ꢂ CH2); dC (100 MHz, CDCl3) 209.9 (C]O),139.1 (12-CH),114.1
(13-CH2), 76.9 (3-CH), 33.7 (CH2), 33.6 (CH2), 29.46 (CH2), 29.42
(CH2), 29.3 (CH2), 29.1 (CH2), 28.9 (CH2), 25.1 (1-Me), 24.8 (CH2); m/
z (EI) 212 [M]þ 10%, 149 (40), 109 (50), 84 (100); HRMS: m/z (EI)
calcd for C13H24O2, [M], 212.1776, found, [M]þ, 212.1781.
5.75 (1H, s, 4-H), 5.01 (1H, app. ddd, J¼17.0, 3.5 and 1.6, 100-Ha), 4.94
(1H, ddt, J¼10.2, 2.1 and 1.1, 100-Hb), 2.53 (2H, t, J¼6.2, furyl-CH2),
2.51 (2H, t, J¼6.1, furyl-CH2), 2.10e2.01 (2H, m, CH2), 1.91 (3H, s, 3-
Me), 1.66e1.54 (4H, m, 2ꢂ CH2), 1.43e1.33 (4H, m, 2ꢂ CH2), 1.31
(10H, br app. s, 5ꢂ CH2), 0.91 (3H, t, J¼7.0, 500-Me); dC (100 MHz,
CDCl3) 153.5 (C), 149.4 (C), 139.2 (90-CH), 114.1 (100-CH2), 113.8 (3-
C). 107.6 (4-CH), 33.8 (CH2), 31.5 (CH2), 29.46 (CH2), 29.41 (CH2),
29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 28.8 (CH2), 28.0 (CH2), 27.9 (CH2),
25.9 (CH2), 22.5 (CH2), 14.0 (500-Me), 9.9 (3-Me); m/z (APCI) 291
[MþH, 100%], 115 (40); HRMS: m/z (APCI) calcd for C20H35O, [MþH],
291.2688, found [MþH], 291.2699.
4.1.5. (E)-Benzyl 11-(3-methyl-5-pentylfuran-2-yl)undec-2-enoate
11. GrubbseHovayda Mk II catalyst (42 mg, 0.067 mmol) was
added to a stirred solution of the foregoing furan 4 (0.391 g,
1.35 mmol) in dry dichloromethane (12 ml). Freshly distilled benzyl
acrylate (0.26 ml, 1.76 mmol) was added and the solution gently
heated to reflux under an atmosphere of dry nitrogen for 2 h. The
solution was then cooled and filtered through a plug of silica gel
and the solvent evaporated to yield the benzyl ester 11 (0.510 g, 89%)
as a colourless oil: nmax/cmꢁ1 (film) 3065, 3033, 2928, 2856, 1724,
1654, 1597, 1497, 1456, 1406, 1377, 1264, 1172, 1046, 1017, 981, 809,
735, 697; dH (400 MHz, CDCl3) 7.41e7.34 (5H, m, 5ꢂ AreH), 7.03
(1H, dt, J¼14.3 and 7.0, 90-CH), 5.87 (1H, d, J¼14.3, 100-CH), 5.74 (1H,
s, 4-H), 5.18 (2H, s, OCH2), 2.52 (2H, t, J¼7.5, furyl-CH2), 2.50 (2H, t,
J¼7.5, furyl-CH2), 2.20 (2H, app. q, J¼7.0, 80-CH2), 1.90 (3H, s, furyl-
3-Me), 1.65e1.53 (2H, m, CH2), 1.50e1.40 (2H, m, CH2), 1.36e1.31
(4H, m, 2ꢂ CH2), 1.29 (10H, app. br s, 5ꢂ CH2), 0.90 (3H, t, J¼6.8, 500-
Me); dC (100 MHz, CDCl3) 166.6 (C]O), 153.5 (C), 150.2 (3-CH),
149.4 (C), 136.2 (C), 128.6 (2ꢂ AreCH), 128.3 (AreCH), 128.2 (2ꢂ
AreCH), 120.9 (2-CH), 107.6 (4-CH), 66.0 (OCH2), 32.3 (CH2), 31.4
(CH2), 30.4 (CH2), 29.3 (CH2), 29.3 (CH2), 29.1 (CH2), 28.7 (CH2), 28.0
(CH2), 28.0 (CH2), 27.9 (CH2), 25.9 (CH2), 22.5 (CH2), 14.0 (500-Me),
9.9 (3-Me); m/z 425 [Mþ, 15%], 317 (5), 165 (100); HRMS m/z (EI)
calcd for C28H40O3 [M], 422.2977, found [M]þ, 424.2975.
4.1.3. (RS, RS)- and (RS, SR)-8-Methylnonadec-18-en-6-yne-8,9-diol
6. Butyllithium (11.63 ml of a 2.5 M solution in tetrahydrofuran,
29.08 mmol) was added dropwise to a stirred solution of 1-heptyne
(3.84 ml, 29.08 mmol) in tetrahydrofuran (50 ml) cooled in an ice-
water bath. After stirring for 0.5 h, the contents were transferred to
an oven-dried pressure-equalising dropping funnel attached to
a second flask containing a stirred solution of hydroxy-ketone 7b
(2.058 g, 9.69 mmol) in tetrahydrofuran (50 ml) maintained at
ꢁ78 ꢀC. The lithiated 1-heptyne was carefully added dropwise and
the resulting solution stirred at the same temperature for 1 h and
then quenched by the addition of saturated aqueous ammonium
chloride (20 ml). The bulk of the organic solvents were then
evaporated and the residue extracted with ethyl acetate (3ꢂ25 ml).
The combined extracts were washed with water (50 ml) and brine
(50 ml) then dried, filtered and evaporated. Separation of the res-
idue by column chromatography yielded the diol 6 (2.68 g, 89%) as
a pale yellow oil consisting of a mixture of diastereomers in a 4:1
ratio, which were not separated. The major diastereomer had Rf
0.21 and the minor diastereomer Rf 0.29 in 1:4 EtOAcehexanes. The
mixture showed ymax/cmꢁ1 (film) 3407, 3077, 2927, 2856, 2245,
1641, 1466, 1378, 1329, 1207, 1078, 993, 909, 734; dH (400 MHz,
CDCl3) 5.82 (1H, ddt, J¼17.0, 10.2 and 6.7, 18-H), 5.00 (1H, app. ddd,
J¼17.0, 3.6 and 1.6, 19-Ha), 4.94 (1H, ddt, J¼10.2, 2.1 and 1.1, 19-Hb),
3.54 (0.80H, dd, J¼7.8 and 2.0, 9-H), 3.36 (0.20H, dd, J¼10.0 and 1.8,
9-H), 2.24e2.17 (2H, m), 2.08e2.03 (2H, m), 1.69e1.57 (2H, m),
1.55e1.46 (2H, m), 1.40 (3H, s, 8-Me), 1.38e1.33 (8H, m, 4ꢂ CH2),
1.29 (8H, br s, 4ꢂ CH2); dC (100 MHz, CDCl3) major diastereomer:
139.2 (18-CH), 119.1 (19-CH2), 85.6 (C), 77.9 (9-CH), 73.5 (C), 71.2
(C), 33.8 (CH2), 31.0 (CH2), 31.0 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4
(CH2), 29.1 (CH2), 28.9 (CH2), 28.3 (CH2), 26.6 (CH2), 23.6 (8-Me),
22.1 (CH2), 18.6 (CH2), 14.0 (1-Me); minor diastereomer: 139.2 (18-
CH), 119.1 (19-CH2), 82.4 (C), 78.5 (9-CH), 74.5 (C), 71.9 (C), 38.2
(CH2), 36.2 (CH2), 32.4 (CH2), 31.1 (CH2), 29.97 (CH2), 29.93 (CH2),
29.8 (CH2), 29.48 (CH2), 29.42 (CH2), 28.3 (CH2), 26.2 (CH2), 26.0 (8-
Me),18.6 (CH2), 16.0 (1-Me). The whole sample showed m/z (EI) 291
4.1.6. 11-(3-Methyl-5-pentylfuran-2-yl)undecanoic acideF5 furan
fatty acid 2. A 250 ml round-bottomed flask was fitted with
a three-way tap and charged with 10% w/w palladium on carbon
(72 mg). Methanol (50 ml) was added carefully followed by the
benzyl ester 11 (0.573 g, 1.35 mmol). The flask was evacuated,
flushed with hydrogen (ꢂ3) and the mixture stirred for 1 h at
ambient temperature and then filtered through a silica gel plug,
which was washed with methanol. The combined filtrates were
concentrated, the residue dissolved in ether (30 ml) and the
resulting solution washed with water (3ꢂ 20 ml) then dried, fil-
tered and evaporated. The residue was rapidly purified by column
chromatography (pentane/diethyl ether, 95:5) to yield the furan
fatty acid 2 (0.376 g, 83%) as a colourless oil, ymax/cmꢁ1 (film) 3095,
3037, 2927, 2855, 2673, 1710, 1576, 1466, 1432, 1413, 1284, 1235,
949, 795, 722; dH (400 MHz, CDCl3) 12.0e10.5 (1H, br s, OH), 5.74
(1H, s, 4-H), 2.53 (2H, t, J¼6.4, furyl-CH2), 2.50 (2H, t, J¼6.2, furyl-
CH2), 2.36 (2H, t, J¼7.5, 100-CH2), 1.91 (3H, s, 3-Me), 1.69e1.54 (6H,
m, 3ꢂ CH2),1.37e1.32 (6H, m, 3ꢂ CH2), 1.29 (10H, br s, 5ꢂ CH2), 0.90
(3H, t, J¼6.9, 500-Me); dC (100 MHz, CDCl3) 180.1 (C]O), 153.5 (C),
149.4 (C), 113.8 (C), 107.6 (4-CH), 34.1 (CH2), 31.4 (CH2), 29.5 (CH2),
29.4 (CH2), 29.3 (CH2), 29.26 (CH2), 29.21 (CH2), 29.1 (CH2), 28.7
(CH2), 28.0 (CH2), 27.9 (CH2), 25.9 (CH2), 24.7 (CH2), 22.4 (CH2), 14.0
(500-Me), 9.9 (3-Me); m/z (EI) 336 [Mþ, 50%], 86 (100); HRMS m/z
(EI) calcd for C21H36O3 [M], 336.2664, found [M], 336.2669.
[MeH2O, 5%], 169 (100); HRMS: m/z (EI) calcd for C20H34
O
[MꢁH2O], 290.2610, found [MeH2O]þ, 290.2607.
4.1.4. 2-(Dec-9-en-1-yl)-3-methyl-5-pentylfuran 4. 10% Silver ni-
trate on silica gel (0.253 g, 0.148 mmol) was added to a stirred
solution of the foregoing mixture of diastereomeric diols 6 (0.459 g,
1.488 mmol) in dichloromethane (5 ml), contained in a foil-
wrapped flask to prevent exposure to light. After 3 h, the mixture
was filtered through a pad of Celite, which was then washed with
fresh dichloromethane. The combined filtrates were evaporated to
leave the furan 4 (0.430 g, 100%) as a colourless oil: nmax/cmꢁ1 (film)
3077, 2926, 2855, 1641, 1597, 1463, 1379, 1261, 1157, 1105, 993, 956,
910; dH (400 MHz, CDCl3) 5.82 (1H, ddt, J¼17.0, 10.2 and 6.7, 90-H),
4.1.7. 2-(Dec-9-en-1-yl)-4-iodo-3-methyl-5-pentylfuran 12. Sodium
hydrogen carbonate (0.464 g, 5.52 mmol) was added to a stirred
solution of diol 6 (0.568 g, 1.84 mmol) in tetrahydrofuran (50 ml)
cooled in an ice-water bath. After 0.25 h, iodine (1.402 g,
5.52 mmol) was added to the solution in one portion and stirring

7442
D.W. Knight, A.W.T. Smith / Tetrahedron 71 (2015) 7436e7444
continued without further cooling for 3 h. Sufficient saturated
aqueous sodium sulphite was then added dropwise until the iodine
colouration was dissipated before evaporation of the bulk of the
tetrahydrofuran under reduced pressure. The residue was extracted
with ether (3ꢂ25 ml) and the combined extracts washed with
water (50 ml) and brine (50 ml) then dried and filtered through
a silica plug using 99:1 pentane/ether as the eluent. Evaporation of
the filtrate left the iodofuran 12 (0.649 g, 85%) as a colourless oil:
nmax/cmꢁ1 (film) 3078, 2926, 2855, 1640, 1623, 1573, 1458, 1375,
1024, 989, 909, 720, 708; dH (400 MHz, CDCl3) 5.82 (1H, ddt, J¼17.1,
10.2 and 6.7, 90-H), 5.00 (1H, app. ddd, J¼17.1, 3.5 and 1.7, 100-Ha),
4.94 (1H, ddt, J¼10.2, 2.2 and 1.2, 100-Hb), 2.62 (2H, t, J¼7.5, furyl-
CH2), 2.56 (2H, t, J¼7.4, furyl-CH2), 2.08e2.01 (2H, m, CH2), 1.87 (3H,
s, 3-Me), 1.65e1.53 (4H, m, 2ꢂ CH2), 1.42e1.31 (6H, m, 3ꢂ CH2), 1.30
(8H, app. br s, 4ꢂ CH2), 0.91 (3H, t, J¼7.1, 500-Me); dC (100 MHz,
CDCl3) 153.6 (C), 149.8 (C), 139.2 (90-CH), 116.7 (3-C), 114.1 (100-
CH2), 69.8 (4-C), 33.8 (CH2), 31.2 (CH2), 29.4 (CH2), 29.3 (CH2), 29.1
(CH2), 29.0 (CH2), 28.9 (CH2), 28.5 (CH2), 27.8 (CH2), 27.7 (CH2), 26.5
(CH2), 22.4 (CH2), 14.0 (500-Me), 11.3 (3-Me)); m/z (EI) 416 [M, 50%]þ,
84 (100); HRMS m/z (EI) calcd for C20H33IO [M], 416.1576, found
[M]þ, 416.1577.
4.1.9. (E)-Benzyl 11-(3,4-dimethyl-5-pentylfuran-2-yl)undec-2-
enoate 14. GrubbseHovayda Mk II catalyst (42 mg, 0.066 mmol)
was added to a stirred solution of furan 13 (0.405 g, 1.33 mmol) in
dry dichloromethane (12 ml). Freshly distilled benzyl acrylate
(0.60 ml, 4.00 mmol) was added and the solution gently heated to
reflux under an atmosphere of nitrogen for 2 h. The cooled solution
was then filtered through a plug of silica gel and the solid washed
with fresh dichloromethane. The combined filtrates were evapo-
rated to yield the benzyl ester 14 (0.519 g, 89%) as a colourless oil:
nmax/cmꢁ1 (film) 3065, 3033, 2928, 2856, 1724, 1654, 1497, 1377,
1264, 1173, 1046, 1017, 982, 808, 736, 698; dH (400 MHz, CDCl3)
7.42e7.32 (5H, m, 5ꢂ AreH), 7.04 (1H, dt, J¼13.0 and 7.0, 90-H), 5.87
(1H, d, J¼13.0, 100-H), 5.18 (2H, s, OCH2), 2.49 (4H, app. t, J¼7.5, 2ꢂ
furyl-CH2), 2.20 (2H, app. q, J¼7.0, 80-CH2),1.90 (6H, app. s, 2ꢂ furyl-
Me), 1.65e1.53 (2H, m, CH2), 1.50e1.40 (2H, m, CH2), 1.36e1.31 (4H,
m, 2ꢂ CH2), 1.29 (10H, m, 5ꢂ CH2), 0.89 (3H, t, J¼6.8, 500-Me); dC
(100 MHz, CDCl3) 166.6 (C]O), 150.2 (90-CH), 148.4 (2ꢂ C), 136.2
(C),128.6 (2ꢂ AreCH),128.3 (AreCH),128.2 (2ꢂ AreCH),120.9 (100-
CH), 114.4 (2ꢂ C), 66.0 (13-CH2), 33.8 (CH2), 31.4 (CH2), 30.4 (CH2),
29.35 (CH2), 29.31 (CH2), 29.1 (CH2), 28.7 (CH2), 28.05 (CH2), 28.01
(CH2), 27.9 (CH2), 25.9 (CH2), 22.5 (CH2), 14.0 (500-Me), 8.4. (Me), 8.3
(Me); m/z (EI) 439 [M,15%]þ, 332 (5),179 (100); HRMS m/z (EI) calcd
for C29H42O3 [M], 438.3134, found [M]þ, 438.3133.
4.1.8. 2-(Dec-9-en-1-yl)-3,4-dimethyl-5-pentylfuran 13
4.1.8.1. Method 1. Iodofuran 12 (0.456 g, 1.095 mmol) dissolved
in dry tetrahydrofuran (10 ml) in a 50 ml three-necked round-
bottomed flask was cooled to ꢁ78 ꢀC and stirred for 10 min.
Butyllithium (0.53 ml of a 2.5 M solution in hexanes, 1.31 mmol)
was added dropwise and the resulting solution stirred for a further
3e5 min. Freshly distilled iodomethane (0.10 ml, 1.53 mmol) was
added in one portion and the mixture stirred for a further 10 min
before warming to ambient temperature and stirring for an addi-
tional 10 min. The reaction mixture was quenched by the addition
of saturated aqueous ammonium chloride solution (2 ml). The bulk
of the tetrahydrofuran was removed under reduced pressure and
the product extracted into ether (3ꢂ5 ml). The combined extracts
were dried, filtered and evaporated and the product purified by
column chromatography (pentane/ether, 99:1) to yield the dime-
thylfuran 13 (0.248 g, 75%) as a yellow oil: Rf 0.28 (pentane/ether,
99:1); nmax/cmꢁ1 (film) 3077, 2926, 2856, 1641, 1597, 1466, 1378,
1256, 1134, 1109, 1054, 993; dH (400 MHz, CDCl3) 5.82 (1H, ddt,
J¼17.0, 10.2 and 6.7, 90-H), 5.00 (1H, app. ddd, J¼17.0, 3.6 and 1.5,
100-Ha), 4.94 (1H, ddt, J¼10.2, 2.3 and 1.2, 100-Hb), 2.49 (4H, app. t,
J¼7.5, 2ꢂ furyl-CH2), 2.05 (2H, app. q, J¼7.0, 80-CH2),1.84 (6H, app. s,
2ꢂ furyl-Me),1.63e1.51 (4H, m, 2ꢂ CH2),1.42e1.33 (4H, m, 2ꢂ CH2),
1.29 (10H, app. br s, 5ꢂ CH2), 0.88 (3H, t, J¼6.8, 500-Me); dC
(100 MHz, CDCl3) 148.4 (2ꢂ C), 139.2 (90-CH), 114.4 (2ꢂ C), 114.1
(100-CH2), 33.8 (CH2), 31.5 (CH2), 29.47 (CH2), 29.40 (CH2), 29.2
(CH2), 29.1 (CH2), 28.9 (CH2), 28.8 (CH2), 28.4 (CH2), 26.1 (CH2), 26.1
(CH2), 22.5 (400-CH2), 14.0 (500-Me), 8.3 (2ꢂ Me); m/z (EI) 304 [M,
5%]þ, 247 (50), 179 (100); HRMS m/z (EI) calcd for C21H36O [M],
304.2766, found [M]þ, 304.2766.
4.1.10. (3,4-Dimethyl-5-pentylfuran-2-yl)undecanoic acideF6 furan
fatty acid 3. A 250 ml round-bottomed flask was fitted with
a three-way tap and charged with 10% w/w palladium on carbon
(71 mg). Methanol (50 ml) was added carefully followed by the
foregoing benzyl ester 14 (0.583 g, 1.33 mmol). The flask was
evacuated, flushed with hydrogen (ꢂ3) and then the mixture stir-
red for 1 h, filtered through a silica gel plug, which was then
washed with methanol. The combined filtrates were evaporated
and the residue dissolved in ether (30 ml). The resulting solution
was washed with water (3ꢂ20 ml) then dried, filtered and evapo-
rated. Immediate purification of the residue by column chroma-
tography, eluting with pentane/diethyl ether (95:5), then gave the
F6 furan fatty acid 3 (0.424 g, 90%) as a colourless oil: ymax/cmꢁ1
(film) 3375, 2926, 2856, 2672, 1710, 1597, 1457, 1413, 1379, 1282,
1260, 1105, 910, 796, 734; dH (400 MHz, CDCl3) 2.50 (4H, app. t,
J¼7.5, 2ꢂ furyl-CH2), 2.36 (2H, t, J¼7.5, 100-CH2), 1.85 (6H, app. s, 2ꢂ
furyl-Me), 1.70e1.60 (4H, m, 2ꢂ CH2), 1.59e1.52 (4H, m, 2ꢂ CH2),
1.38e1.30 (4H, m, 2ꢂ CH2), 1.29 (10H, app. br s, 5ꢂ CH2), 0.90 (3H, t,
J¼7.0, 500-Me); dC (100 MHz, CDCl3) 179.9 (C]O), 148.4 (2ꢂ C), 114.4
(2ꢂ C), 34.1 (CH2), 31.4 (CH2), 29.54 (CH2), 29.50 (CH2), 29.45 (CH2),
29.40 (CH2), 29.2 (CH2), 29.1 (CH2), 28.8 (CH2), 28.4 (CH2), 26.14
(CH2), 26.10 (CH2), 24.7 (CH2), 22.4 (CH2),14.0 (500-Me), 8.3 (2ꢂ Me);
m/z (EI) 350 [M, 58%]þ, 86 (100); HRMS m/z (EI) calcd for C22H38O3
[M], 350.2821, found [M], 350.2819.
4.1.11. 2-(Dec-9-en-1-yl)-3-methyl-4-trideuteriomethyl-5-
pentylfuran 15
4.1.11.1. Method 1. Iodofuran 12 (0.558 g, 1.34 mmol) dissolved
in tetrahydrofuran (15 ml) in a 50 ml three-necked round-bot-
tomed flask was cooled to ꢁ78 ꢀC and stirred for 10 min. Butyl-
lithium (0.64 ml of a 2.5 M solution in hexanes, 1.61 mmol) was
then added dropwise. After 3 min, freshly distilled d3-iodomethane
(0.12 ml,1.88 mmol) was added in one portion. Subsequent reaction
and work-up as described above for the synthesis of furan 13 then
gave the 4-d3-furan 15 (0.381 g, 92%) as a yellow oil: Rf 0.28 (pen-
tane/diethyl ether, 99:1); nmax/cmꢁ1 (film) 3077, 2926, 2855, 1641,
1597, 1463, 1379, 1261, 1156, 1102, 993, 956, 909; dH (400 MHz,
CDCl3) 5.82 (1H, ddt, J¼17.0, 10.2 and 6.7, 90-H), 5.00 (1H, app. ddd,
J¼17.0, 3.7 and 1.6,100-Ha), 4.94 (1H, ddt, J¼10.2, 2.2 and 1.2,100-Hb),
2.49 (4H, app. t, J¼7.5, 2ꢂ furyl-CH2), 2.05 (2H, app. q, J¼7.0, 80-
CH2), 1.84 (3H, s, 3-Me), 1.63e1.51 (4H, m, 2ꢂ CH2), 1.42e1.33 (4H,
4.1.8.2. Method 2. Methyl lithium$lithium bromide complex
(2.63 ml of a 1.5 M solution in ether, 3.94 mmol) was added
dropwise to a stirred solution of iodofuran 12 (0.328 g, 0.787 mmol)
in tetrahydrofuran (10 ml) maintained at ꢁ78 ꢀC and the solution
stirred for 0.5 h. After warming to ambient temperature and stirring
for a further 0.5 h, the reaction mixture was quenched by the ad-
dition of saturated aqueous ammonium chloride (5 ml). The bulk of
the tetrahydrofuran was evaporated and the product extracted into
ether (3ꢂ10 ml). The combined extracts were washed with water
(30 ml) and brine (30 ml) then dried, filtered and evaporated to
yield the furan 13 (0.210 g, 88%) as a pale yellow oil. All spectro-
scopic and analytical data were identical to those recorded for the
sample prepared by Method 1.

D.W. Knight, A.W.T. Smith / Tetrahedron 71 (2015) 7436e7444
7443
m, 2ꢂ CH2), 1.29 (10H, br s, 5ꢂ CH2), 0.91 (3H, t, J¼7.0, 500-Me); dD
(46 MHz, CHCl3) 1.83 (s, 4-CD3); dC (100 MHz, CDCl3) 148.4 (2ꢂ C),
139.2 (90-CH), 114.4 (C), 114.3 (C), 114.1 (100-CH2), 33.8 (CH2), 31.4
(CH2), 29.4 (2ꢂ CH2), 29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 28.8 (CH2),
28.0 (CH2), 26.1 (CH2), 26.0 (CH2), 22.4 (400-CH2), 14.0 (500-Me), 8.3
(Me); HRMS m/z (EI) calcd for C21H33D3O [M], 307.2954, found
[M]þ, 307.2959.
(C]O),148.40 (C), 148.40 (C), 114.41 (C), 114.41 (C), 34.1 (CH2),
31.4 (CH2), 29.52 (CH2), 29.50 (CH2), 29.42 (CH2), 29.41 (CH2),
29.2 (CH2), 29.1 (CH2), 28.8 (CH2), 28.4 (CH2), 26.14 (CH2),
26.12 (CH2), 24.7 (CH2), 22.4 (CH2),14.0 (500-Me), 8.3 (Me); m/z
(EI) 350 [M, 58%]þ, 86 (100); HRMS m/z calcd for C22H35D3O3
[M], 353.3009, found [M], 353.3011.
[No 13C data is given for the CD3 group, because the signal was so
highly split that a complete set of resonances was not visible. This
also applies to the other deuterated compounds described below].
4.1.13. (E)-Methyl 11-(3-methyl-4-trideuteriomethyl-5-pentylfuran-
2-yl)undec-2-enoate 17. GrubbseHovayda Mk II catalyst (37 mg,
0.060 mmol) was added to a stirred solution of d3-furan 15 (0.366 g,
1.190 mmol) in dichloromethane (20 ml). Freshly distilled methyl
acrylate (0.16 ml, 1.785 mmol) was added and the solution heated
to reflux under an atmosphere of dry nitrogen for 2 h then cooled
and filtered through a plug of silica gel. The combined filtrate and
washings were evaporated to give the unsaturated methyl ester 17
(0.378 g, 87%) as a colourless oil: nmax/cmꢁ1 (film) 3030, 2928, 2856,
1728, 1658, 1457, 1435, 1317, 1269, 1196, 1175, 1042, 979, 920, 851,
799, 703; dH (400 MHz, CDCl3) 6.98 (1H, dt, J¼15.6 and 7.0, 90-CH),
5.82 (1H, dt, J¼15.6 and 1.5, 100-CH), 3.73 (3H, s, 130-Me), 2.49 (4H,
app. t, J¼7.5, 2ꢂ furyl-CH2), 2.19 (2H, app. qd, J¼7.0 and 1.5, 80-CH2),
1.84 (3H, s, 3-Me), 1.63e1.52 (4H, m, 2ꢂ CH2), 1.49e1.41 (2H, m,
CH2), 1.37e1.31 (4H, m, 2ꢂ CH2),1.29 (8H, br s, 4ꢂ CH2), 0.89 (3H, t, J
7.1, 500-Me); dD (46 MHz, CHCl3) 1.82 (s, 4-CD3); dC (100 MHz, CDCl3)
167.1 (C]O),149.7 (90- CH),148.4 (C),148.3 (C),120.8 (100-CH),114.5
(C), 114.3 (C), 51.3 (13-Me), 32.1 (CH2), 31.4 (CH2), 29.34 (CH2), 29.31
(CH2), 29.3 (CH2), 29.22 (CH2), 29.22 (CH2), 29.1 (CH2), 28.7 (CH2),
28.5 (CH2), 26.1 (CH2), 22.4 (CH2), 14.0 (500-Me), 8.3 (3-Me); m/z 442
(EI) [M, 15%]þ, 365 (10), 105 (100); HRMS m/z (EI) calcd for
4.1.11.2. Method 2. Methyl-d3lithium (20.0 ml of a 0.5 M solu-
tion in diethyl ether complexed with LiI, 10.0 mmol) was added
dropwise to a stirred solution of iodofuran 12 (1.23 g, 2.96 mmol) in
tetrahydrofuran (10 ml) maintained at ꢁ78 ꢀC and stirred for 0.5 h.
After warming to ambient temperature and stirring for a further
0.5 h the reaction was quenched by the addition of aqueous am-
monium chloride (5 ml). Tetrahydrofuran was evaporated and the
residue diluted with diethyl ether (10 ml). The product was
extracted into diethyl ether (2ꢂ10 ml) and the combined organic
extracts washed with water (30 ml) and brine (30 ml) before the
solvent was dried, filtered and evaporated to yield the d3-furan 15
(0.783 g, 86%) as a pale yellow oil. All data obtained were in accord
with those previously obtained from the conventional approach.
4.1.12. 11-(3-Methyl-4-trideuteriomethyl-5-pentylfuran-2-yl)un-
decanoic acided3-F6 furan fatty acid 16.
i) GrubbseHovayda Mk II catalyst (9 mg, 0.015 mmol) was
added to a stirred solution of the d3-furan 15 (0.090 g,
0.290 mmol) in dichloromethane (5 ml). Freshly distilled
benzyl acrylate (0.05 ml, 0.38 mmol) was added and the so-
lution heated to reflux under an atmosphere of nitrogen for
2 h, then filtered through a plug of silica gel. The combined
filtrate and washings were evaporated to leave (E)-benzyl 11-
(3-methyl-4-trideuteriomethyl-5-pentylfuran-2-yl)undec-2-
enoate (0.111 g, 86%) as a colourless oil: nmax/cmꢁ1 (film) 3033,
2928, 2856, 1724, 1654, 1497, 1455, 1405, 1377, 1294, 1266,
1174, 1047, 982, 809, 736, 697; dH (400 MHz, CDCl3) 7.42e7.32
(5H, m, 5ꢂ AreH), 7.04 (1H, dt, J¼13.0 and 7.0, 90-CH), 5.87
(1H, d, J¼13.0, 100-CH), 5.18 (2H, s, OCH2), 2.49 (4H, app. t,
J¼7.5, 2ꢂ furyl-CH2), 2.20 (2H, app. q, J¼7.0, 80-CH2), 1.83 (3H,
s, 3- Me), 1.60e1.50 (2H, m, CH2), 1.50e1.40 (2H, m, CH2),
1.36e1.31 (4H, m, 2ꢂ CH2), 1.29 (10H, app. br s, 5ꢂ CH2), 0.89
(3H, t, J¼7.0, 500-Me); dD (46 MHz, CHCl3) 1.82 (s, 4-CD3); dC
166.6 (C]O), 150.1 (90-CH), 148.44 (C), 148.40 (C), 136.2 (C),
128.6 (2ꢂ AreCH), 128.3 (AreCH), 128.2 (2ꢂ AreCH), 120.9
(100-CH), 114.44 (C), 114.40 (C), 66.0 (13-CH2), 32.4 (CH2), 31.4
(CH2), 30.4 (CH2), 29.35 (CH2), 29.31 (CH2), 29.1 (CH2), 28.7
(CH2), 28.04 (CH2), 28.01 (CH2), 27.9 (CH2), 26.1 (CH2), 22.4
(CH2), 14.0 (500-Me), 8.3 (3-Me); m/z (EI) 442 [M, 15%]þ, 335
(5), 182 (100); HRMS m/z (EI) calcd for C29H39D3O3 [M],
441.3322, found [M]þ, 441.3321.
ii) In the same manner as for the synthesis of unlabelled F6-fu-
ran fatty acid 3, hydrogenation of the foregoing deuterated
benzyl ester (0.426 g, 0.965 mmol) in the presence of 10% w/
w palladium on carbon (50 mg) in methanol (40 ml) gave,
after column chromatography (pentane/diethyl ether, 95:5),
the d3-F6-furan fatty acid 16 (0.314 g, 92%) as a colourless oil:
ymax/cmꢁ1 (film) 3375, 2926, 2856, 2672, 1710, 1597, 1457,
1413, 1379, 1282, 1260, 1105, 910, 796, 734; dH (400 MHz,
CDCl3) 2.50 (4H, app. t, J¼7.5, 2ꢂ furyl-CH2), 2.36 (2H, t, J¼7.5,
100-CH2), 1.85 (3H, s, 3-Me), 1.70e1.60 (4H, m, 2ꢂ CH2),
1.59e1.52 (4H, m, 2ꢂ CH2), 1.38e1.30 (4H, m, 2ꢂ CH2), 1.29
(10H, app. br s, 5ꢂ CH2), 0.90 (3H, t, J¼7.0, 500-Me); dD
(46 MHz, CHCl3) 1.84 (s, 4-CD3); dC (100 MHz, CDCl3) 179.9
C
23H35D3O3 [M], 365.3009, found [M]þ, 365.3008.
4.1.14. Methyl 11-(3-methyl-4-trideuteriomethyl-5-pentylfuran-2-yl)
undecanoate 18. A 100 ml round-bottomed flask fitted with a three
way tap was charged with 10% w/w palladium on carbon (15 mg).
Methanol (10 ml) was added carefully followed by the foregoing
unsaturated methyl ester 17 (0.104 g, 0.285 mmol). The flask was
evacuated, flushed with hydrogen (ꢂ3) and the mixture stirred for
1 h. The mixture was then filtered through a silica plug and the
solvent and washings evaporated. The residue was diluted with
diethyl ether (10 ml) and the solution washed with water (3ꢂ10 ml)
then dried, filtered and evaporated and the product purified by
column chromatography (pentane/diethyl ether, 95:5) to yield the
d3-furan fatty acid methyl ester 18 (0.095 g, 91%) as a colourless oil:
ymax/cmꢁ1 (film) 2926, 2855, 2672, 1741, 1642, 1434, 1170; dH
(400 MHz, CDCl3) 3.67 (3H, s, 130-Me), 2.49 (4H, app. t, J¼7.5, 2ꢂ
furyl-CH2), 2.31 (2H, t, J 7.6, 100-CH2), 1.84 (3H, s, 3-Me), 1.67e1.59
(4H, m, 2ꢂ CH2), 1.59e1.52 (4H, m, 2ꢂ CH2), 1.36e1.24 (14H, m, 7ꢂ
CH2), 0.89 (3H, t, J¼7.1, 500-Me); dD (46 MHz, CHCl3) 1.81 (s, 4-CD3) dC
(100 MHz, CDCl3) 174.3 (C]O), 148.40 (C), 148.40 (C), 114.42 (C),
114.41 (C), 51.4 (130-Me) 34.1 (CH2), 31.4 (CH2), 29.5 (CH2), 29.42
(CH2), 29.42 (CH2), 29.21 (CH2), 29.21 (CH2), 29.20 (CH2), 29.20
(CH2), 28.8 (CH2), 28.5 (CH2), 26.1 (CH2), 25.0 (CH2), 22.4 (CH2), 14.0
(500-Me), 8.3 (3-Me); m/z (EI) 367 [M, 10%]þ, 105 (100); HRMS m/z
(EI) calcd for C23H37D3O3 [M], 367.3166, found [M], 367.3165.
Acknowledgements
We thank Professor W. Vetter (Hohenheim) and Dr. R. L. Jenkins
(Cardiff) for helpful advice and discussions and the Engineering and
Physical Sciences Research Council for funding.
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