A biosynthetically inspired route to substituted furans using the Appel reaction: Total synthesis of the furan fatty acid F5

Article abstract of DOI:10.1039/c7cc03229c

Appel reaction conditions have been harnessed to affect a mild biosynthetically inspired dehydration of endoperoxides to deliver multi-substituted electron rich furans. Unlike traditional dehydrative procedures, this method is metal and acid free, and can be achieved under redox neutral conditions. It is general for a range of aryl and alkyl substituted endoperoxides, and is functional group tolerant. Furthermore, this procedure has been used to deliver an effective total synthesis of the furan fatty acid (FFA) F₅.

Full text of DOI:10.1039/c7cc03229c

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A biosynthetically inspired route to substituted furans using the
Appel reaction: total synthesis of the furan fatty acid F5
Robert J. Lee,a Martin R. Lindley,b Gareth J. Pritcharda* and Marc C. Kimbera*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Appel reaction conditions have been harnessed to affect a mild interesting, and rarely seen, group of fatty acids which may be
biosynthetically inspired dehydration of endoperoxides to deliver classified as omega-4; the 3-position of the furan ring is
multi-substituted electron rich furans. Unlike traditional methylated across all FFAs reported to date; and finally, the 4-
dehydrative procedures, this method is metal and acid free, and position bears either a hydrogen atom or an additional methyl
can be achieved under redox neutral conditions. It is general for a group. FFAs have been isolated from both marine2 and
range of aryl and alkyl substituted endoperoxides, and is terrestrial plant origins,3 however the former were shown
functional group tolerant. Furthermore, this procedure has been ultimately to derive from ingested algae.4 The protective
used to deliver an effective total synthesis of the furan fatty acid abilities of FFAs are thought to derive from the electron-rich
(FFA) F5.
multi-substituted heterocyclic furanyl core,1a as it has been
shown as a potent radical scavenger, which ultimately lends to
their antioxidant qualities.1b
The Furan Fatty Acids (FFAs) are a sizeable class of natural
products and metabolites that have shown to be protective
toward the development of a number of chronic inflammatory
diseases in humans (scheme 1(a); 1a-h).1
Previous total syntheses of FFAs have seen the use of regio-
selective palladium mediated couplings on halogenated furans,
and the selective modification of existing furan nuclei via
functional group inter-conversions.5 Alternatively, the
heterocyclic nucleus has been constructed by means of Hg(II)
mediated rearrangement of appropriately substituted α-
hydroxy-β-alkynyl epoxides,6 acid catalysed rearrangement of
bis-epoxides,7 or by the treatment of alkynediols with Ag(I) or
iodine to effect cyclisation to the heterocycle.8 In contrast,
synthetic methods that deliver FFAs via plausible biosynthetic
routes are distinctly absent within the chemical literature. For
example, the proposed biosynthetic route that delivers FFAs in
marine bacteria9 is thought to proceed via a sequential
(a)
(b)
R
Me
Me
Methylation
4
8
( )
(
)
8
)
Me
(
Me
CO2H
(
)
CO2H
4
Me
CO2H
(
)
(
)
n
O
m
3
2
1a: F1 m = 2; n = 8; R = Me
1b: F2 m = 4; n = 8; R = H
1c: F3 m = 4; n = 8; R = Me
1d: F4 m = 2; n = 10; R = Me
1e: F5 m = 4; n = 10; R = H
1f: F6 m = 4; n = 10; R = Me
1g: F7 m = 4; n = 12; R = H
1h: F8 m = 4; n = 12; R = Me
Desaturation
Me
(
Oxidation/
cyclisation
Me
8
)
Me
(
Me
CO2H
(
)
4
CO2H
(
)
)
8
4
O
1b
4
R2
R3
(c)
R2
R3
R2
R3
mild
dehydration &
1O2
H
H
R1
R4
R1
R4
aromatisation
R1
R4
O
7
O
O
5
6
oxidation/cyclisation pathway of 1,3-dienes (4, scheme 1(b))
Scheme 1. (a) The eight most common FFAs, F1-8; (b) The proposed biosynthetic
pathway of FFAs; (c) Plausible route to FFAs.
which are themselves produced by the enzymatic methylation
and desaturation of bioavailable monounsaturated fatty acids
such as cis-vaccenic acid; the bis-methyl FFAs are postulated to
be the result of a further methylation step after construction
of the heterocyclic nucleus.
FFAs are characterised by either a tri- or tetra-substituted
furan; at the 2-position a C9, C11, or C13 alkyl chain terminates
with a carboxyl functionality; at the 5-position, a straight chain
propyl- or pentyl-chain is present, the former forming an
A potent method for the incorporation of oxygen into organic
substrates is the use of singlet oxygen (1O2), either via a cyclo-
addition event ([4+2] or [2+2]) or ene-type reaction.10 In the
1
context of the proposed biosynthesis of FFAs in scheme 1, O2
could plausibly be used as a mimic for the conversion of
via a subsequent dehydrative cyclisation (scheme 1(c)). The
direct conversion of endoperoxides ( ) to furans (11) can be
5 to 7,
8
grouped into (i) homolytic and (ii) heterolytic processes, both
involving cleavage of the peroxide bond (scheme 2(a)).
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Homolytic processes typically employ transition metals (e.g. 2). A variation in the temperature of the reaction indicated
Ru(II),11 Co(II),12 Pd(II),13 Sn(II),14) to mediate the that a reaction window between 10-20°C was optimal (entries
transformation, however examples of thermal homolysis do 3 and 4), while undertaking the reaction in the absence of
exist.15 Indeed, the tetraphenylporphyrin Co(II) (CoTPP) either PPh3 (entry 5) or CBr4 (entry 6) showed no conversion to
catalysed method developed by Foote and co-workers was the furan and recovery of 14a. A switch to THF was shown to
postulated to be
a plausible biosynthetic mimic, that be detrimental to the reaction giving the furan in only 58%
circumvented some of the harsher one-pot methods; however, conversion, and moreover, the reaction was distinctly less
the substrate scope within this disclosure was narrow, and the clean under these conditions (entry 7).
use of Co(II) can, in some cases, be complicated by the
Table 1. Optimisation of Appel-conditions.a
formation of bis-epoxide side-products.16 Heterolytic cleavage
of the peroxide bond can be accomplished in a two-step
process via a Kornblum DeLaMare (KDM) rearrangement,17
16
with the resultant cis-γ-hydroxyenone
(
9)
undergoing
dehydration.18 Direct conversion to the furan under acidic
conditions19 can also be performed with TsCl20 and FeSO4,21
however the substrate scope is limited and may potentially be
incompatible with electron rich furan products such as the
FFAs.
Entry
1
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Temp (°C)
Yield [%]b
RT
RT
0
55
96[85]d
2c
3
74
88
-
4
10
RT
RT
RT
5e
6f
(a)
Homolytic or
Dehydration
H
R
H
R
H
R
-
R
R
R
O
Heterolytic
bond-cision
R
R
O
O
O
O OH
HO
H
7
58
8
9
10
11
aConditions: 14a (0.1 mmol), CBr4 (1.1 equiv), PPh3 (1.1 equiv), CH2Cl2, RT, 0.1 M,
16h, unless stated otherwise. bConversion calculated by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard. cFreshly sublimed CBr4. dIsolated
chemical yields. eNo PPh3. fNo CBr4.
(b)
CX3
R
R
R
H
H
R
R
R
R
H
H
H
O
O
O
O
O
R
O
H
O
O
B
CX3
HCX3
8
9
10
H
Ph3
P
X
KDM
PR3
X
+
CX3
rearrange-
ment
PR3
+
CX4
X
With effective conditions to hand, we progressed to
expanding the endoperoxide substrate scope (table 2). The
X
H
R
P
R
O
R
R
R
O
O
H
R
R
R
O
H
O
OH
Ph3
endoperoxides (14b
corresponding 1,3-dienes with oxygen with
photosensitizer.23 Endoperoxides 14b
all dehydrated to give
the required furans 15b in high chemical yield (entries 1-3).
-m) were prepared by the treatment of the
HX
PPh3
O
11
13
12
a
suitable
-d
Scheme 2. (a) Conversion of endoperoxides to furans; (b) Appel-type
dehydration of endoperoxides to furans. KDM Kornblum DeLaMare
rearrangement.
=
-d
Endoperoxides 14e and 14f, which were both isolated as a
mixtures of diastereomers in the preceding photo-oxidation as
a consequence of the 1,3-dienes, smoothly dehydrated to give
the furans 15e and 15f in 76% and 50 % yield, respectively
In this communication we would like to report a new,
biosynthetically inspired method for the preparation of
electron rich multi-substituted furan nuclei, which is general
for a variety of endoperoxides. To achieve this we have
employed Appel-type conditions, commonly applied in the
mild, redox neutral synthesis of alkyl halides from alcohols.22
The initial hypothesis for using the Appel reaction is outlined in
scheme 2(b). Mirroring the Appel reaction, we hoped the CX3
carbanion, generated from PR3 and CX4, would be suitably
(entries 4 and 5). The process was also tolerant of
a
preinstalled cyclopropyl motif within the endoperoxide 14g
,
giving the tri-substituted furan 15g in 93% yield (entry 6).
Endoperoxides 14h,i have pre-installed functionality on the
alkyl chain at the C3, C6 positions, and both cleanly gave their
individual furans (15h,i) in high yield (entries 7 and 8).
basic to promote the KDM rearrangement giving enone 9 16,17
.
Endoperoxide 14j
,
containing
a
OTBS group, neatly
transformed into the furan 15j in 63% yields; however trace
amounts of a furan, identified as the bromide 15j’, were
observed as a by-product of this reaction (entry 9). This
product was postulated to arise from an in situ deprotection of
the OTBS, followed by conversion of the primary alcohol to the
bromide under the Appel conditions. However, access to
bromide 15j’ was perceived to be advantageous, as it could be
utilised in subsequent cross-coupling reactions or direct
conversion to the carboxylic acids. Therefore, to increase its
yield, we exposed 14j to 2.2 equiv of CBr4 and PPh3,
respectively, and this gave 15j’ in an excellent isolated yield of
91% (entry 10). Endoperoxides 14k-m contain a pentyl side
This enone will be in equilibrium with the cyclic form 10, with
this latter intermediate undergoing a subsequent dehydration
via the expulsion of Ph3PO to deliver the desired furan 11
.
Our initial work focused on the dehydration of
endoperoxide 14a, obtained by the addition of singlet oxygen
to commercially available trans, trans-1,4-diphenylbutadiene
(table 1). We discovered that the treatment of 14a with 1.1
equivalents of PPh3 and 1.1 equivalents of CBr4 in
dichloromethane led to a moderate yield of the desired furan
15a after 16h (table 1, entry 1). Encouraged by this we carried
out a small optimisation study, focusing on temperature and
the stoichiometry of PPh3 and CBr4. Repeating the reaction at
RT with freshly sublimed CBr4 led to dramatic increase in
conversion, and we were able to isolate 15a in 85% yield (entry
chain common to the FFAs F2,3 and F5-8 and all could be
,
efficiently converted to their furan derivatives (15k-m) using
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the Appel protocol, and importantly, 15m contains functional product 18 in 86% isolated yield (scheme 3). The reaction
groups that can be potentially further functionalised (entry 11- outcome was the same whether undertaken with Rose Bengal
13). Finally, 14a was dehydrated on a 5.0 mmol scale to give or Methylene Blue as the photo-sensitizer. This product
the furan 15a in very high chemical yield (entry 14).
presumably results from an initial [4+2]-cycloaddition event on
16 giving 17, followed by a subsequent ene-reaction on the
electron rich alkene of 17 to ultimately furnish 18. However,
while initially discouraging, this reaction manifold does give
rapid access to structures such as 18 that are reminiscent of
the important antimalarial artemisinin.24,25
Table 2. Substrate scope for the preparation of multi-substituted furans.a
Entry
1
Endoperoxide
Furan
Yieldb
82
2
91
Scheme 3. Photo-oxidation of tetra-substituted 1,3-diene 18
.
3
4
5
87
76
50
Finally, to demonstrate the applicability of this dehydrative
process we targeted the synthesis of the FFA F5 methyl ester
(scheme 4). The synthesis began with conversion of the alcohol
19 to its phosphonium salt 21 under standard conditions, with
21 undergoing olefination with ketone 22, giving triene 23 as a
mixture of E/Z isomers in a ratio of 1:2.2. Selective [4+2]-
cycloaddition of 23 with singlet oxygen initially proved
6
7
93
98
problematic; however
a change in solvent and the
photosensitizer yielded the required endoperoxide 24 in an
isolated yield of 49%. With 24 in hand, dehydration under our
conditions proved successful and we were able to deliver the
desired furan 25 in 66% yield, but importantly with a terminal
alkene within the side chain. Previous work by Knight and co-
workers8c has established that the furan heterocycle is
compatible with cross-metathesis conditions; therefore,
exposure of 25 to methyl acrylate under mild cross-metathesis
conditions, followed by introduction of catalytic PtO2 under a
hydrogen atmosphere gave the desired F5 methyl ester (1e) in
near quantitative yield over these two-steps.
8
9
94
63
10c
11
91
83
12
72
13
54
95
14d
Scheme 4. Total synthesis of the methyl ester of the furan fatty acid F5.
aConditions, endoperoxide (0.1 to 1.1 mmol), CBr4 (1.1 equiv), PPh3 (1.1 equiv),
CH2Cl2, RT, 0.1 M unless otherwise stated. bIsolated yields. cCBr4 (2.2 equiv), PPh3
(2.2 equiv) at reflux. dUndertaken with 5.0 mmol of 14a.
In conclusion, we have developed a unique application of
the Appel reaction to effect the transformation of
endoperoxides to furans, without the involvement of
a
The proposed biomimetic synthesis of tetra-substituted FFAs
necessitates the introduction of the final methyl group on the
furan ring after its formation. This proposition is partially
supported by the performance of a tetra-substituted 1,3-diene
under our photo-oxidation conditions. We observed that tetra-
transition metal or strong acid. This approach is functional
group tolerant and amenable to target synthesis as
demonstrated by the successful construction of the methyl
ester derivative of the furan fatty acid F5, in only 7-steps from
a
commercially available alcohol. Optimisation of the
substituted 1,3-diene 16
, did not give the expected
biosynthetic oxidation pathway, for the formation of the
endoperoxide 17, but gave predominantly an over-oxidised
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