Chemo-Enzymatic Metathesis/Aromatization Cascades for the Synthesis of Furans: Disclosing the Aromatizing Activity of Laccase/TEMPO in Oxygen-Containing Heterocycles

Article abstract of DOI:10.1021/acscatal.9b02452

The unprecedented Trametes versicolor laccase/TEMPO-catalyzed aromatization of 2,5-dihydrofurans to furans is described. A variety of furan derivatives have been synthesized in moderate to high conversions (21-99%) and yields (20-76%) under mild reaction

Full text of DOI:10.1021/acscatal.9b02452

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Letter
Chemo-enzymatic Metathesis/Aromatization Cascades for
the Synthesis of Furans: Disclosing the Aromatizing Activity
of Laccase/TEMPO in Oxygen-containing Heterocycles
Caterina Risi, Fei Zhao, and Daniele Castagnolo
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02452 • Publication Date (Web): 05 Jul 2019
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Page 1 of 6
ACS Catalysis
Chemo-Enzymatic Metathesis/Aromatization Cascades for the
Synthesis of Furans: Disclosing the Aromatizing Activity of
Laccase/TEMPO in Oxygen-Containing Heterocycles
Caterina Risi,‡ Fei Zhao‡ and Daniele Castagnolo*
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School of Cancer and Pharmaceutical Sciences, King’s College London, Franklin Wilkins Building, 150 Stamford Street, SE1
9NH London.
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ABSTRACT: The unprecedented Trametes versicolor laccase/TEMPO catalyzed aromatization of 2,5-dihydrofurans to furans is
described. A variety of furan derivatives have been synthesized in moderate to high conversions (21-99%) and yields (20-76%) under
mild reaction conditions. This work reveals the aromatization ability of the Trametes versicolor laccase/TEMPO system in
synthesizing oxygen-containing heterocycles. Moreover, the direct synthesis of furans from aliphatic diallyl ethers through a chemo-
enzymatic metathesis/aromatization cascade which combines Grubbs’ catalyzed ring-closing metathesis and laccase/TEMPO
aromatization in the same reaction medium has been successfully developed.
KEYWORDS. Furan • Metathesis • Aromatization • Chemo-enzymatic cascade • Laccase • TEMPO
Furans are natural and synthetic five-membered heterocycles which
find broad application in pharmaceutical, material and
agrochemical industries.1 As shown in Figure 1, the furan ring is a
privileged scaffold in many pharmaceutical ingredients such as the
best-selling drug Ranitidine 1, the antiprotozoal agent Nifurtimox
2 and the muscle relaxant Dantrolene 3. Flavouring agents such as
the 2-furfurylthiol 4 and furfural 5, which are responsible for the
toasty smell of coffee or cooked meat, contain a furan nucleus as
well.2 Furans can be synthesised through different synthetic routes
including the classical Paal-Knorr3 and Feist-Bernary4 reactions
from 1,4-dicarbonyl compounds or the TFA mediated cyclization
of -keto-tert-butyl esters.5 Other typical methods for furan
synthesis include the metal-catalysed inter- or intra-molecular
cyclization of alkynyl, allenyl or cyclopropyl ketones and alcohols
under harsh reaction conditions,6 and the aromatization of 2,5-
dihydrofuran precursors7 in the presence of stoichiometric
tBuOOH8, DDQ,9 Shvo’s catalyst9 or TFA at high temperature.10
Recently, a more sustainable method to synthesise furan derivatives
by dehydration of renewable feedstock has also been described.11
However, despite the remarkable achievements made in the last
decades, no report on furan synthesis employing enzymes is known
to date. This reflects the great challenge in developing enzymatic
processes for the generation of furan compounds.
methodologies are only limited to the synthesis of nitrogen-
containing heterocycles and are not suitable for the synthesis of
oxygen-containing heterocycles like furans.
O
N+
HN
N
O-
N+
O-
N
O
S
O
N
N
H
S
O
O
O
2
1
O
N
N
NH
O
-O
O
O
O
SH
O
N+
3
4
5
O
(a) Previous chemo-enzymatic approaches to aromatic N-heterocycles
Ref. 12
R1
R1
R1
Approaches limited to
n
or
N
nitrogen heterocycles
N
MAO-N
Ar/Alk
N
R
(n=1, R=H)
(n=0)
6
7
R
COOR
Ref. 14
O
O
N
H
9
R
R
With the aim to develop alternative, greener and more sustainable
methods for the synthesis of pharmaceutical and flavouring
ingredients,12-13 we started to explore novel biocatalytic and
chemo-enzymatic approaches to generate aromatic heterocycles.13
Biocatalysis represents a powerful and green technology for the
synthesis of a wide variety of chiral molecules in enantiomerically
pure form.14 However, its use in the manufacturing of non-chiral
flat heteroaromatic structures, which constitute the core of most
drugs and pharmaceutical ingredients, has been poorly explored to
date. Nevertheless, the synthesis of heteroaromatic compounds
with enzymes offers a greener and more sustainable way as
compared with chemical reagents. Within this context, we have
recently demonstrated that enzymes can be successfully exploited
in the synthesis of heteroaromatic molecules by replacing
hazardous aromatizing reagents or oxidants, which are generally
used in a stoichiometric amount at high temperature. We first
disclosed the aromatizing properties of MAO-N biocatalysts in the
synthesis of pyrroles 6 and pyridines 7.13 MAO-N enzymes are able
to catalyse the aromatization of aliphatic precursors through the
oxidation of their C-N bonds into imine/iminium intermediates
followed by tautomerization. More recently, Turner’s group
described another chemo-enzymatic approach to pyrroles 9 and
pyrazines 10 using transaminase (ATA) biocatalysts (Figure 1a).15
However, due to the nature of the enzymes used, these
ATA
R
N
NH2
O
8
N
R
10
(b) This work - chemo-enzymatic strategy to aromatic O-heterocycles (furans)
chemocatalytic
cyclization
enzymatic
aromatization
R
R
R
O+
O
R
Laccase
TEMPO
air
O
B
O
A
D
C
Figure 1. Representative drugs and flavouring agents with the
furan motif. Previous works on chemo-enzymatic syntheses of
nitrogen heterocycles and proposed chemo-enzymatic approach to
furans.
Laccase enzymes are widely used in combination with O2 or the
oxy-radical TEMPO to catalyse the oxidation of alcohols to
aldehydes or ketones.16 Laccases can also promote the oxidative
cleavage of ether bonds in lignine,17 as well as the oxidation of
nifedipine and tetrahydroquinazolines.18
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Table 1. Aromatization of 2,5-dihdrofuran 12a into furan 13a.
Screening and reaction optimization.
The aromatization of the 2,5-dihdrofuran 12a (13.7 mol) was first
investigated (Table 1). Substrate 12a was suspended in a 1:2
mixture of buffer acetate (pH = 4.5)16 and tert-butyl methyl ether
(MTBE) (total volume 420 L) and then treated with the enzyme
laccase (8.1 U) and an excess of TEMPO co-catalyst (2 eq) at 30
oC under air atmosphere. The aromatic furan 13a was obtained with
an excellent conversion (>99%) in 24 h (entry 1), clearly
confirming the aromatization ability of laccase/TEMPO system. In
order to make the biotransformation greener, the same reaction was
carried out with 0.5 equivalent of TEMPO. To our delight, a full
conversion was also observed in 24 h (entry 2). However, only an
80% conversion was observed, even after 48 h, when 0.2 equivalent
of TEMPO was used (entry 4). A further optimization disclosed
that changing the buffer solution proved to be beneficial. In fact,
when NaPBS buffer solution (pH = 6.5) was used, substrate 12a
was completely converted into product 13a in the presence of 0.2
equivalent of TEMPO after 30 h (entry 7). In addition, an attempt
to reduce the loading of laccase to 7.5 U per 13.7 mol 12a turned
out to be successful, even though a slightly longer time (36 h) was
required to obtain a full conversion (entry 8). The replacement of
MTBE with other co-solvents such as isooctane or CH3CN (entries
9-10), and the use of the AZADO19 co-catalyst instead of TEMPO
(entries 11-12) adversely affected the enzymatic reaction, leading
to lower conversions. Finally, in order to determine if the
aromatization was truly catalysed by the laccase/TEMPO system
rather than promoted by only one of them or by spontaneous air, a
set of blank experiments, in which the enzyme or the co-catalyst
was selectively removed from the reaction, were performed. As a
result, no or negligible formation of the product 13a was observed
even in the presence of a higher loading of the single enzyme or co-
catalyst (entries 13 and 14). Besides, when laccase and TEMPO
were both removed from the reaction, the desired product was not
detected at all (entry 15), indicating that the air itself cannot
promote this transformation. These results clearly confirmed the
crucial catalytic role of the laccase/TEMPO system in the
aromatization of 12a.
1
2
3
4
5
6
7
8
Laccase/
co-catalyst
O
O
Buffer/co-solvent = 1:2
air, 30 oC, Time
12a
13a
U
Buffer[b]/
Time Conv.
(h)
Entry
Cocatalyst
(%)[c]
Laccase[a]
Cosolvent
9
TEMPO
(2 eq)
Acetate/
MTBE
1
8.1
24
>99
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8.1
TEMPO
(0.5 eq)
Acetate/
MTBE
2
24
24
48
24
24
30
36
36
36
24
36
24
48
24
>99
40
8.1
8.1
8.1
8.1
8.1
TEMPO
(0.2 eq)
Acetate/
MTBE
3
TEMPO
(0.2 eq)
Acetate/
MTBE
4
80
TEMPO
(0.2 eq)
NaPBS/
MTBE
5
80
TEMPO
(0.5 eq)
NaPBS/
MTBE
6
>99
>99[d]
TEMPO
(0.2 eq)
NaPBS/
MTBE
7
TEMPO
(0.2 eq)
NaPBS/
MTBE
>99[d],
68[e]
8
7.5
7.5
TEMPO
(0.2 eq)
NaPBS/
isooctane
9
75
8
7.5
7.5
7.5
TEMPO
(0.2 eq)
NaPBS/
CH3CN
10
11
12
13
14
15
AZADO
(0.2 eq)
NaPBS/
MTBE
8
AZADO
(0.2 eq)
NaPBS/
MTBE
14
<5
0
TEMPO
(2 eq)
Acetate/
MTBE
-
N
O
Acetate/
MTBE
N
O
19
-
-
-
12a
O
laccase
ox.
laccase
red.
Oxoamonium
ion
TEMPO
Acetate/
MTBE
0
H2O
laccase
ox.
1/2 O2 / 2H+
Reaction conditions: 12a (13.7 mol), Laccase/co-catalyst,
O
H
o
buffer/co-solvent = 1:2 (420 L), air, 30 C, 24-48 h. [a] Units of
O
N
TS
laccase per 13.7 mol 12a. Commercially available Trametes
versicolor laccase (0.94 U/mg of crude lyophilized enzyme
powder). [b] Buffer acetate = HOAc/NaOAc (pH = 4.5, 0.05 M);
N
OH
reduced TEMPO
[c]
Buffer NaPBS = Na2HPO4/NaH2PO4 (pH = 6.5, 0.05 M).
1
[d]
[e]
-H+
Calculated by H-NMR integration.
Calculated by HPLC.
O
O
Isolated yield of 13a when the reaction was scaled up to 0.35 mmol
of 12a; MTBE = tert-butyl methyl ether.
Oxonium
13a
Scheme 1. Proposed mechanism for the laccase/TEMPO
aromatization of 2,5-dihydrofuran 12a into furan 13a.
Inspired by these transformations, we envisaged that laccases could
also catalyse the oxidation of the ether bond in 2,5-dihdrofuran
substrates B, thus leading to the formation of the oxonium
intermediates C which tautomerize to the aromatic furans D. In the
present work, we describe a novel chemo-enzymatic aromatization
strategy to furan heterocycles D from 2,5-dihdrofuran precursors B
exploiting the laccase/TEMPO catalytic system (Figure 1b). To the
best of our knowledge, this is the first example to date of
aromatization reactions of oxygen heterocycles exploiting
enzymes.
A plausible mechanism for the enzymatic aromatization of 2,5-
dihydrofuran 12a is proposed in Scheme 1. The TEMPO is oxidised
into the oxoamonium ion intermediate by laccase, which can be
regenerated by atmospheric O2. The oxoamonium ion can react
with the 2,5-dihydrofuran 12a to form a 5-membered transition
state TS in which a hydrogen transfer occurs to generate the
reduced TEMPO and an oxonium ion. The latter is converted into
the desired product 13a by deprotonation. Finally, the reduced
TEMPO can be oxidised into TEMPO by the laccase enzyme.
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ACS Catalysis
Once the reaction conditions were optimised, we began to explore
aromatized into the corresponding furans 16 and 19a-c in moderate
to good yields (20-69%), respectively, while no conversion was
observed for the bulkier 2,3,4-trisubstituted substrate 18d.
1
2
3
4
5
6
7
8
the substrate scope of the chemo-enzymatic transformation. At first,
a set of substituted 2,5-dihydrofuran substrates were synthesised.
As illustrated in Scheme 2, precursors 12a-p and 15 were
synthesised via ring-closing metathesis (RCM) reactions from
appropriate diallyl ethers 11a-p and 14, respectively. Ethers 11a-o
were obtained from appropriate aldehydes through Grignard
reaction with vinyl magnesium bromide followed by alkylation
with an appropriate allyl bromide. Ether 11p was obtained through
a slightly different approach as described in the literature19. The
furan 15 was synthesised from 2-vinyloxirane through ring opening
by thiol, alkylation of the resulting alcohol and the final RCM.
Attempts to prepare 18a-d through the RCM (path a) proved to be
unsuccessful.20 On the other hand, chalcones 17a-d, which are
readily available from appropriate aldehydes and ketones, were
promptly converted into 18a-d in good yields using Me3S+I- in the
presence of KOtBu.21
Table 2. Laccase/TEMPO aromatization of 2,5-dihyrofurans[a]
Laccase/
TEMPO
R
R
O
O
NaPBS (pH 6.5)/
MTBE 1:2
air, 30 oC, 48-67 h
12a-p
15
18a-d
13a-p
16
19a-d
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
MeO
Cl
F
13b
conv. >99%
y = 61% (48 h)
13c
conv. >99%
y = 52% (48 h)
13d
conv. 90%
y = 41% (48 h)
13e
conv. 85%
y = 60% (48 h)
R1
path a
R2
R1
R2
O
Grubbs' Cat.
2nd gen. (3 mol%)
R1
R
O
MgBr
THF, 0 o
R2
O
F3C
O
1)
2)
C
R
O
Cl
O
R
O
DCM, r.t.
13f
13g
conv. 50%
y = 38% (67 h) y = 72% (48 h)
13h
13i
R = aryl, alkyl
Br
conv. >99%
y = 45% (48 h)
conv. >99%
conv. >99%
y = 46% (67 h)
11a-p
12a-p
NaH, NaI, THF, reflux
COOMe
path b
Grubbs' Cat.
2nd gen. (3 mol%)
1) DBU, THF, r.t.
O
O
O
O
PMPS
O
PMPS
O
Br
NaH, NaI,
+
O
14
2)
DCM, r.t.
15
F
PMPSH
13j
13k
13l
conv. 0% (48 h)
13m
THF, reflux
conv. 30%
y = 25% (67 h)
conv. 40%
conv. 5% (67 h)
Ar
y = 36% (67 h)
R3
path c
O
Me3S+I-
KOtBu
Ar = Ph
o-Py
m-Py
MeOOC
O
S
Ar
O
R3
O
O
O
DMSO, 8 o
C
MeO
MeO
18a-d
17a-d
MeO
F
13n
16
13o
13p
conv. trace (67 h)
Scheme 2. Synthesis of 2,5-dihydrofuran precursors 12a-p, 15 and
18a-d.
conv. 30%
y = 27% (67 h)
conv. 77%
y = 63% (67 h)
conv. 25%
y = 20% (67 h)
N
All the 2,5-dihydrofurans 12a-p were then subjected to the
laccase/TEMPO catalytic system as shown in Table 2. Generally,
good to excellent conversions (up to 99%) and isolated yields (up
to 72%) were observed for most of the substrates 12.22 For instance,
substrates 12b-g bearing diverse phenyl groups at the C2 position
were converted into the corresponding products 13b-g in good to
high conversions (50-99%) and good yields (38-61%). The
aromatization of 2-aryl-5-methyl substituted substrates 12h-i also
took place smoothly, providing the desired products 13h-i in full
conversions and good yields (46-72%). Lower conversions (30-
40%) and yields (25-36%) were observed with the fluorinated
derivative 12j as well as furan 12k bearing an ester moiety. This
may be attributed to the electron withdrawing effects of the
substituents. The 2-alkyl substituted substrates 12l-m were fully
consumed within 48-67 h when treated with laccase/TEMPO, but
no desired furans 13l-m were detected and only degradation
products were observed by 1H NMR. It has been recently reported
that some 2,5-dialkylsubstituted furans can be deconstructed into
diketones by the laccase/TEMPO system in the presence of
atmospheric oxygen.23 Even if the mechanism for this
transformation is not fully clear, the presence of an alkyl substituent
at both position C2 and C5 of the furan ring seems to be essential.
We thus hypothesised that furans 13l-m could have been formed
during the aromatization reaction, but then immediately degraded
by the same catalytic system into volatile side-products.23b The 2,3-
disubstituted substrates 12n-p proved to be more resistant to the
oxidation, affording desired furans 13n-p in lower conversions and
yields. Finally, the 2,5-dihydrofurans 15 and 18a-c were
N
O
O
O
O
MeO
MeO
MeO
MeO
19d
19a
19b
19c
conv. 0% (67 h)
conv. 21%
y = 20% (67 h)
conv. 67%
y = 65% (67 h)
conv. 71%
y = 69% (67 h)
Reaction conditions: substrates 12a-m, 15, 18a-d (0.14 mmol),
laccase (75 U of 0.94 U/mg T. versicolor laccase lyophilized
powder), TEMPO (0.028 mmol), NaPBS/MTBE = 1:2 (4.2 mL),
air, 30 oC, 48-67 h. [a] Conversions were calculated by 1H-NMR
integration, “y” refers to isolated yield.
With the aim to develop a more straightforward methodology
avoiding multi-step synthesis and purification, the possibility to
access furans 13 directly from diallyl ethers 11 through a chemo-
enzymatic cascade reaction was then investigated. A one-pot two-
step cascade reaction was initially set up (Table 3, entry 1). Ether
11a was dissolved in a 1:2 mixture of NaPBS buffer and MTBE
and then treated with 3 mol% of Grubbs’ catalyst. After 24 h, the
laccase/TEMPO catalytic system was added to the metathesis
reaction mixture. This led to the formation of furan 13a with a
disappointing conversion (14%). Even if Grubbs’ catalyst tolerates
a variety of solvents including MTBE and water, the reaction rates
and yields of RCM reactions can be affected by different reaction
media.24 In fact, when the RCM cyclization of 11a was carried out
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in NaPBS/MTBE (1:2), the 2,5-dihydrofuran intermediate 12a was
laccase/TEMPO system under mild and aqueous conditions has
been developed.
1
2
3
4
5
6
7
8
obtained with only 60% conversion after 24 h, while a full
conversion (98%) was observed when isooctane was used as the
co-solvent under the same conditions (entries 2-3). Moreover, the
co-existence of Grubbs’ catalyst and enzymes in chemo-enzymatic
cascade reactions may be problematic because of the mutual
inactivation of the enzymes and the ruthenium carbene, thus
leading to a significant decrease in the reaction yield. However, as
previously demonstrated, the use of biphasic systems with low
mass transfer, which contains isooctane as the co-solvent, can
prevent the Grubbs’-enzyme deactivation in chemo-enzymatic
Table 4. One-pot chemo-enzymatic cascade for the synthesis of
furans 13 from diallyl ethers 11.
R1
R1
Grubbs' Cat. 2nd gen. (3 mol%)
Laccase/TEMPO
NaPBS (pH = 6.5)/
isoctane 1:2
O
R
O
R
13
11
air, 30 oC, 24-72 h
9
Ether
substrate
Time
Furan
(h)
Conv.
(%)[a]
Yield
(%)[b]
transformations.25,13
Therefore,
a
one-pot
two-step
Entry
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
metathesis/aromatization cascade of 11a was carried out in
NaPBS/isooctane (1:2) media. This afforded furan 13a with an
81% conversion (entry 5). It is noteworthy that it is preferable to
add the laccase/TEMPO catalyst as soon as the RCM reaction was
completed after 3 h, since a longer reaction time resulted in lower
conversion (entry 4), probably due to the formation of side
products.
1
2
3
4
5
6
7
8
9
24
56
74
93
36
55
92
68
82
61
31
[c]
11a
48
65
65
65
72
72
72
72
13a
-
62
[c]
11b
11c
11d
11f
11h
11j
13b
13c
13d
13f
13h
13j
-
28
76
36
52
40
Once the best reaction media was identified, the combination of the
RCM reaction and the enzymatic aromatization in a one-pot
cascade was attempted (Table 4). Ether 11a was suspended in a 1:2
NaPBS/isooctane mixture and simultaneously treated with Grubbs’
catalyst (3 mol%) and laccase/TEMPO, leading to furan 13a with
56% conversion after 24 h (entry 1). Increasing the reaction time
up to 65 h proved to be beneficial, providing a remarkable
improvement in the conversion (93%) and yield (62%) of 13a
(entry 3). The chemo-enzymatic cascade was then extended to
other ether substrates 11b-j, which were all converted into the
corresponding furans 13b-j in moderate to good yields (entries 4-
9).
Reaction conditions: substrates 11 (0.08 mmol), Grubbs’
catalyst (0.0024, 3 mol%), laccase (67 U), TEMPO (0.016
o
mmol), NaPBS (pH = 6.5)/isooctane = 1/2 (2 mL), air, 30 C,
24-72 h. [a] Conversion was calculated by 1H-NMR integration.
[b] Isolated yields are reported. [c] Not calculated
The approach described in this work reveals the previously
undisclosed aromatization ability of laccase/TEMPO in
synthesising oxygen-containing heterocycles like furans. In general,
2-aryl substituted dihydrofurans were aromatized with good to
excellent conversions and moderate to good isolated yields, while
2-alkyl-substituted and 2,3,4-trisubstituted substrates proved to be
less reactive. The low yields observed in some cases could be
ascribable to the volatility of the furan products as well as
instability of the laccase in the reaction system.26 Finally, a chemo-
enzymatic cascade reaction to furan derivatives directly from
diallyl ethers has also been developed through the combination of
Grubbs’ catalyst and laccase/TEMPO in the same reaction medium,
affording a variety of furan derivatives with good conversions and
yields. This work represents the first example of a chemo-
enzymatic synthesis of aromatic oxygen heterocycles like furans
and a robust, alternative and sustainable method for the industrial
synthesis of furans.
Table 3. Reaction optimization of the one-pot two-step chemo-
enzymatic cascade.
Grubbs' Cat.
2nd gen.
(3 mol%)
O
13a
O
12a
O
NaPBS
(pH = 6.5)/
cosolvent
1:2
Laccase/TEMPO
air, 30 oC, 48 h
11a
r.t. 3-24 h
Conv.
Conv.
Time
12a[a]
13a[a]
(%)
14
-
Entry
Cosolvent
(h)
(%)
1
MTBE
24+48
24
n.d.[c]
60[d]
98
2[b]
3[b]
4
MTBE
isooctane
isooctane
isooctane
5
-
n.d.[c]
n.d.[c]
71
81
AUTHOR INFORMATION
16+48
3+48
5
Corresponding Author
*daniele.castagnolo@kcl.ac.uk
Reaction conditions: compound 11a (0.08 mmol), Grubbs’
catalyst (0.0024 mmol, 3 mol%), NaPBS (pH = 6.5)/cosolvent
= 1/2 (2 mL), room temperature, 3-24 h, then laccase (67 U),
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript. ‡Co-first authors; these authors contributed equally.
o
[a]
TEMPO (0.016 mmol), air, 30 C, 48 h.
Conversion was
1
[b]
calculated by H-NMR integration or HPLC.
The reaction
was stopped after the RCM reaction was completed (monitored
by TLC). [c] Not determined. [d] When the same reaction was
carried out in 100% DCM medium, a >95% conversion (67%
yield) was observed by 1H NMR after 24 h.
Funding Sources
EPSRC King’s College Strategic Fund. K.C. Wong Education
Foundation.
In summary, a novel green and enzymatic methodology for the
aromatization of 2,5-dihydrofurans into furans exploiting the
ASSOCIATED CONTENT
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Page 5 of 6
ACS Catalysis
in Furan Syntheses. Angew. Chem., Int. Ed. 2005, 44, 850–852;
g) Pridmore, S. J.; Slatford, P. A.; Taylor, J. E.; Whittlesey, M.
K.; Williams, J. M. J. Synthesis of Furans, Pyrroles and
Experimental details, procedures and copies of spectra are reported
in the Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
2
3
4
5
6
7
8
Pyridazines by
a Ruthenium-Catalysed Isomerisation of
Alkynediols and In Situ Cyclisation. Tetrahedron 2009, 65,
8981–8986; h) Feng, X.; Tan, Z.; Chen, D.; Shen, Y.; Guo, C.-
G.; Zhu, J. X. C. Synthesis of Tetrasubstituted Furans via In-
Catalyzed Propargylation of 1,3-Dicarbonyl Compounds-
Cyclization Tandem Process. Tetrahedron Lett. 2008, 49, 4110–
4112.
ACKNOWLEDGMENT
EPSRC KCL Strategic Fund is acknowledged for funding. CR
acknowledges the University of Siena for a PhD period of leave.
FZ and DC acknowledge K.C. Wong Education Foundation for
financial support. Dr Francesca Mazzacuva at Mass Spectrometry
Facility at King’s College London is gratefully acknowledged for
HRMS experiments.
7)
Donohoe, T. J.; Bower, J. F.; Basutto, J. A. Olefin Cross-
Metathesis–Based Approaches to Furans: Procedures for the
Preparation of Di- And Trisubstituted Variants. Nature Protoc.
2010, 5, 2005–2010.
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SYNOPSIS TOC.
Chemo-
cyclization
R
O
MesN NMes
buffer pH = 6.5
cosolvent,
Cl
Cl
Ru
R
O
Ph
R
PCy3
O
air, 30 o
C
Enzymatic Laccase/TEMPO
aromatization
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