Total Synthesis of the Tetrasubstituted Furan Fatty Acid Metabolite CeDFP via Au-Catalyzed Intermolecular Alkyne Hydroarylation

Article abstract of DOI:10.1021/acs.orglett.9b01786

The first total synthesis of the tetrasubstituted furan fatty acid (FFA) metabolite 5-[(1E)-2-carboxyethenyl]-3,4-dimethyl-2-furanpentanoic acid (CeDFP) is reported. CeDFP is a FFA metabolite isolated from shark livers and is related to the known FFA metabolites CMPF and CMPentylF. Key elements of the synthetic route to CeDFP include an iodine-promoted 5-endo-dig cyclization of a 1,2-alkyne diol, a methyllithium-mediated insertion of the C₃-methyl group, and a Au(I)-catalyzed intermolecular hydroarylation to introduce the unsaturated ester.

Full text of DOI:10.1021/acs.orglett.9b01786

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of the Tetrasubstituted Furan Fatty Acid Metabolite
CeDFP via Au-Catalyzed Intermolecular Alkyne Hydroarylation
Yamin Wang, Gareth J. Pritchard,* and Marc C. Kimber*
Department of Chemistry, School of Science, Loughborough University, Loughborough LE11 3TU, U.K.
S
* Supporting Information
ABSTRACT: The first total synthesis of the tetrasubstituted
furan fatty acid (FFA) metabolite 5-[(1E)-2-carboxyethenyl]-
3,4-dimethyl-2-furanpentanoic acid (CeDFP) is reported.
CeDFP is a FFA metabolite isolated from shark livers and is
related to the known FFA metabolites CMPF and
CMPentylF. Key elements of the synthetic route to CeDFP
include an iodine-promoted 5-endo-dig cyclization of a 1,2-
alkyne diol, a methyllithium-mediated insertion of the C3-methyl group, and a Au(I)-catalyzed intermolecular hydroarylation to
introduce the unsaturated ester.
he furan fatty acids (1, FFAs) make up an important class
of natural products and metabolites due to their observed
propyl-2-furanpropionic acid (CMPF, 2a) and 3-carboxy-4-
methyl-5-pentyl-2-furanpropionic acid (CMPentylF, 2b) (Fig-
ure 1b), have been detected, with the levels of 2a being
elevated in patients suffering from renal failure.1c,3 However,
the exact role and mode of action of CMPF (2a) in renal
failure and particularly type 2 diabetes have been intensely
debated and have not yet been fully elucidated.1a
T
nutritional health benefits and impact on inflammatory and
cardiovascular diseases.1 To date, more than 25 members have
been discovered, and they are structurally characterized by a
furan ring with a fatty acid side chain at the α1 position, a short
alkyl side chain at the α2 position, a methyl group at the β1
position, and a hydrogen or methyl group at the β2 position
(Figure 1a). The FFAs are understood to originate from plants,
Another important catabolite is the tetrasubstituted furan, 5-
[(1E)-2-carboxyethenyl]-3,4-dimethyl-2-furanpentanoic acid
(CeDFP, 3). This urofuran acid has been detected in the
urine of cattle4a and, more significantly, can be found in
appreciable amounts within the bile of sharks, making up
almost 10% of the dry weight of the liver.4b Metabolite 3 differs
significantly from CMPF (2a) and CMPentylF (2b) as the β1
methyl group remains intact and both the α1 and α2 side chains
have undergone incomplete β-oxidation. To date, this
metabolite can be obtained only through isolation from
shark livers, and consequently, this method is unsustainable.
Therefore, given this and the recent attention that the FFAs
have garnered due to their potent antioxidant potential, we
deemed that a first chemical synthesis of 3 was warranted.1,4b,5
Our approach to the total synthesis of 3 is outlined in the
retrosynthetic analysis shown in Scheme 1. Judicious selection
of the protecting group (PG1) on the carboxyl group, and
masking of the terminal acid of 5 as the protected (PG2)
primary alcohol, will give tetrasubstituted furan 4. We
envisaged using two key transformations to deliver this key
tetrasubstituted furan 4: (i) a Au-catalyzed intermolecular
alkyne hydroarylation between a furan and a propiolate (5)
and (ii) a metal-mediated cross coupling to introduce the
methyl group of the furan. This approach reveals a
trisubstituted furan 6 as a suitable precursor that can be
Figure 1. (a) General structure of the eight predominant furan fatty
acids. (b) Three significant urofuran acid metabolites of the FFAs.
algae, and marine bacteria, and as a result, they then
accumulate in higher-order fish and mammals; therefore, the
furan fatty acids are not produced de novo within humans and
animals but accumulate through ingestion.1a,2
Once they accumulate, it is probable that the FFAs are
further catabolized within animals via oxidation within the
liver. This process gives rise to urofuran acids, whose structures
can vary considerably depending on the species. Significantly,
in humans, two principal urofuran acids, 3-carboxy-4-methyl-5-
Received: May 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Retrosynthetic Analysis of Furan Fatty Acid
Metabolite 3
Scheme 3. Preparation of Trisubstituted Iodofuran 6 and
Trialkylfuran 9
obtained via an electrophilic 5-endo-dig cyclization6 of
propargyl 1,2-diol 7.
There are two plausible synthetic strategies for accessing
tetrasubstituted furan 4, an intermolecular alkyne hydro-
arylation performed on 6, followed by a metal-mediated
cross coupling to give 4 (Scheme 2b, route A); alternatively,
Scheme 2. (a) Two Plausible Routes to Tetrasubstituted
Furan 4 and (b) Au-Catalyzed Hydroarylation of Ethyl
Propiolate with Furan and 2-Methylfuran
yield, which was subsequently protected as its TBDPS ether
using standard conditions giving 14 in 89% yield. Deprotona-
n
tion of 14 using BuLi followed by addition of the THP-
protected ketone 16, and subsequent acid-mediated depro-
tection of the THP group, provided 17 in 77% yield over two
steps.8 Propargyl-1,2-diol 17 could then be cyclized under the
modified conditions of Knight and co-workers6 to give the
desired trisubstituted furan 6 in 45% isolated yield. The
electrophilic 5-endo-dig cyclization of 6 using I2 proved to be
problematic on this substrate and was complicated by the
further electrophilic iodination of the product; however, this
over-iodination could be suppressed by performing the
reaction in acetonitrile and ensuring careful control of the
reaction temperature.9 Conversion of the iodine at the C3
position to the required methyl group in 9 could be achieved
using three methods. Palladium cross coupling with
trimethylboroxine under Suzuki conditions10 gave trialkylfuran
9 in a modest 52% yield. Alternatively, the action of nBuLi on 6
at low temperature, followed by subsequent treatment of the
lithiate with MeI,8 gave 9 in a more acceptable 67% yield.
Finally, we found direct iodine−methyl exchange using a
MeLi·LiBr complex in THF to be far superior, delivering 9 in
an 85% yield.
the sequence of these two reactions can be reversed, where the
key Au(I) hydroarylation transformation with 5 is performed
with trialkyl furan 9 (route B). There are few examples of using
an intermolecular hydroarylation transformation in target
synthesis;7 however, a Au(I)-catalyzed intermolecular alkyne
hydroarylation using furan and 2-methylfuran has been
reported. Reetz and co-workers demonstrated that furan
(10a) and 2-methylfuran (10b) undergo regioselective hydro-
arylation with ethyl propiolate (11), giving the Z-products
(12a and 12b, respectively) in high yields.7c
With iodofuran 6 in hand, we elected to examine route A
(Scheme 4 and Table 1). Accordingly, using conditions
Scheme 4. Au-Catalyzed Hydroarylation of Iodofuran 6 To
Give 18
Our approach began with the synthesis of the key
trisubstituted furans 6 and 9 (Scheme 3). Reduction of methyl
6-heptynoate 13 with NaBH4 gave the alcohol in 82% isolated
B
DOI: 10.1021/acs.orglett.9b01786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Au-Catalyzed Hydroarylation of Iodofuran 6 To
Give 18
Scheme 5. (a) I2-Mediated Isomerization Giving (E)-18 and
(b) Synthesis of Tetrasubstituted Furan (E)-20
a
catalyst
(mol %)
11
(equiv)
time
(h)
concn
(M)
18
(%)
b
c
entry
Z/E
d
1
2
3
4
5
6
5
10
10
10
10
5
24
24
24
24
36
48
3
3
6
3
1
1
95/5
13
33
23
37
42
58
5
5
3
3
3
48/52
67/33
45/55
34/66
25/75
5
a
Reactions performed in MeNO2 at room temperature with Au(I)
b
complex 19, unless otherwise stated. Determined by 1H NMR.
c
d
Isolated yields. PPh3AuCl/AgOTf catalyst system.
adapted from those of Reetz6c and a PPh3AuCl/AgOTf catalyst
system, we were able to hydroarylate 6 using an excess of ethyl
propiolate (11) in an encouraging 13% isolated yield (entry 1).
As expected, the product isolated was predominantly of Z-
1
configuration, with the H NMR signals for the double bond
appearing as doublets at δ 6.51 (J = 12.4 Hz) and δ 5.71 (J =
12.8 Hz), respectively. Johnphos Au(I) complex 19 has been
shown to be a superior Au(I) complex in a diverse range of
inter- and intramolecular processes,11 and therefore, this was
selected as our preferred Au(I) complex for optimization over
the PPh3AuCl/AgOTf system.
Replacing the PPh3AuCl/AgOTf catalyst system with Au(I)
complex 19 had an immediate effect, giving the desired
product 18 in 33% isolated yield (entry 2), whereas a doubling
of the concentration of the reaction mixture had a detrimental
effect on yield (entry 3). A reduction of catalyst loading to 3
mol % was tolerated without any reduction in yield (entry 4).
To improve purification, it was desirable to reduce the amount
of ethyl propiolate (11), and accordingly, we observed that
with a decrease in the concentration, and an increase in the
reaction time, the number of equivalents of ethyl propiolate
could be reduced significantly while maintaining the overall
chemical yield (entry 5). Finally, by extending the reaction
time further to 48 h, we achieved an acceptable yield of 58%
for 18 (entry 6).
unsuccessful due to the presence of the sensitive unsaturated
ester at C5. This result confirms that route B (Scheme 2) is the
most efficient method for accessing (E)-20. First, the cross
coupling of the C3-iodo is superior when performed on furan 6,
and second, the resultant trialkyfuran 9 is better suited to the
subsequent Au(I)-catalyzed alkynyl hydroarylation transforma-
tion, likely due to its increased nucleophilicity compared to
that of furan 6.
The completion of the synthesis of 3 is shown in Scheme 6.
Silyl deprotection of (E)-20 was achieved using TBAF in a
Scheme 6. Completion of the Synthesis of CeDFP (3)
From Table 1, one can observe that Johnphos Au(I)
complex 19 gives significant Z/E mixtures in product 18, as
compared to PPh3Au(I)OTf. It transpires that extended
reaction times lead to increased amounts of the E-stereo-
isomer, as highlighted in entries 5 and 6. However, the Z/E
ratio from the Au(I)-catalyzed hydroarylation was incon-
sequential, as we were able to cleanly isomerize the Z/E
mixtures obtained from the hydroarylation of 6 to its E-isomer
upon treatment with I2 (Scheme 5a).12 This was confirmed by
1
the double bond signals of (E)-18 now appearing in the H
NMR spectrum at δ 7.44 (J = 15.6 Hz) and δ 6.21 (J = 15.6
Hz), respectively.
quantitative yield, giving primary alcohol 21. Oxidation to the
2-furanpentanoic acid proved to be capricious, with standard
PDC conditions under several solvent conditions proving
unproductive; however, the use of TPAP, with an NMO co-
oxidant, finally gave the desired acid 22 in 50% isolated yield.
The ethyl ester of 22 was then saponified using LiOH giving
the 3 in 45% isolated yield.
In summary, a first total synthesis of the furan fatty acid
metabolite 5-[(1E)-2-carboxyethenyl]-3,4-dimethyl-2-furan-
pentanoic acid (CeDFP, 3) has been accomplished in 10
steps (4.1% overall yield) from commercially available methyl
6-heptynoate (12). The spectroscopic data for the synthesized
Having established conditions for the hydroarylation and
synthesis of 18, we then applied these reaction conditions to
trialkyfuran 9 (Scheme 5b). Pleasingly, we observed full
conversion to the desired tetrasubstituted furan 20 after a
reaction time of 64 h, and upon exposure to I2, we
subsequently converted this to (E)-20 in 85% yield over
these two steps. Alternatively, (E)-20 could be synthesized
upon exposure of iodofuran (E)-18 to palladium cross
coupling conditions with trimethylboroxine, albeit in a very
poor yield of 9%. Attempts to introduce the C3-methyl group
using the transmetalation protocols outlined in Scheme 3 were
C
DOI: 10.1021/acs.orglett.9b01786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
material are in agreement with those reported4b for the isolated
natural product. Features of this synthesis include (a) an
iodine-promoted 5-endo-dig cyclization of an 1,2-alkyne diol
under the conditions adapted from those of Knight,6 (b) a
methyllithium-mediated insertion of the C3-methyl group, and
notably (c) a Au(I)-catalyzed intermolecular hydroarylation to
introduce the unsaturated ester. Importantly, in the approach
described, the sequence in which steps b and c were
implemented was found to be crucial. Given the importance
of the furan fatty acids, and their oxidation metabolites (the
urofuran acids), this first total synthesis can provide an
effective model for synthesizing analogues of CeDFP.
Furthermore, this approach highlights the use of Au(I)
intermolecular hydroarylation as a suitable tactic in synthesiz-
ing these valuable natural products and metabolites.
2017, 65, 7919. (c) Lee, R. J.; Lindley, M. R.; Pritchard, G. J.; Kimber,
M. C. Chem. Commun. 2017, 53, 6327.
(6) (a) Knight, D. W.; Smith, A. W. T. Tetrahedron 2015, 71, 7436.
(b) Knight, D. W.; Smith, A. W. T. Heterocycles 2012, 84, 361.
(c) Evans, A. B.; Flugge, S.; Jones, S.; Knight, D. W.; Tan, W. − F.
̈
Arkivoc 2008, 95. (d) Bew, S. P.; El-Taeb, G. M. M.; Jones, S.; Knight,
D. W.; Tan, W. − F. Eur. J. Org. Chem. 2007, 2007, 5759.
(7) For reviews, see: (a) Muratore, M. E.; Echavarren, A. M. Gold-
catalyzed hydroarylation of alkynes. In The Chemistry of Organogold
Compounds; Rappoport, Z., Leibman, J. F., Marek, I., Eds.; John Wiley
& Sons: Chichester, U.K., 2014; p 805. (b) Kitamura, T. Eur. J. Org.
Chem. 2009, 2009, 1111. For the hydroarylation of propiolates with
furan, see: (c) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003,
2003, 3485.
(8) A TBS protecting group was initially trialed in this synthetic
sequence but ultimately proved to be unstable during the THP
deprotection, hence the judicious selection of the TBDPS protecting
group.
(9) See the Supporting Information for details of the reaction
conditions that were screened.
(10) (a) Moody, C. J.; Kimber, M. C. Chem. Commun. 2008, 591.
(b) Gray, M.; Andrews, I. P.; Hook, D. F.; Kitteringham, J.; Voyle, M.
Tetrahedron Lett. 2000, 41, 6237.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01786.
́
́
̃
oz, M. P.; Cardenas,
(11) (a) Nieto-Oberhuber, C.; Lopez, S.; Mun
D. J.; Bunuel, E.; Nevado, C.; Echavarren, A. M. Angew. Chem., Int. Ed.
̃
General experimental procedures, characterization data,
and 1H and 13C NMR spectra of new compounds
(PDF)
2005, 44, 6146. (b) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int.
Ed. 2006, 45, 1105. (c) Menon, R. S.; Findlay, A. D.; Bissember, A.
C.; Banwell, M. G. J. Org. Chem. 2009, 74, 8901.
(12) A palladium-catalyzed Heck coupling of ethyl acrylate with 6
failed to deliver (E)-18. See: Tsuji, J.; Nagashima, H. Tetrahedron
1984, 40, 2699.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: M.C.Kimber@lboro.ac.uk.
*E-mail: G.J.Pritchard@lboro.ac.uk.
ORCID
Gareth J. Pritchard: 0000-0002-2925-1722
Marc C. Kimber: 0000-0003-2943-1974
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial support from
Loughborough University. The authors also thank Dr. Mark
Edgar (Loughborough University) for assistance with NMR
assignments.
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DOI: 10.1021/acs.orglett.9b01786
Org. Lett. XXXX, XXX, XXX−XXX