Ene Reductase Enzymes for the Aromatisation of Tetralones and Cyclohexenones to Naphthols and Phenols

Article abstract of DOI:10.1002/adsc.201500818

Ene reductases (EREDs) have great potential as oxidation biocatalysts, as demonstrated by their efficient conversion of a number of tetralones to the corresponding naphthols. Of 96 enzymes tested, 57 were able to produce 2-naphthol in this way. Further tests with substituted tetralones revealed typically high conversions up to >99%. The reactions were performed under mild conditions in aqueous buffer with only co-solvent, biocatalyst and oxidation substrate required for conversion. Production of a methoxy-substituted naphthol was also successfully performed on a gram scale, with 91% yield. This methodology provides a new avenue to produce substituted naphthols as valuable building blocks, with the possibility to extend the approach to the production of phenols also being demonstrated.

Full text of DOI:10.1002/adsc.201500818

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DOI: 10.1002/adsc.201500818
Ene Reductase Enzymes for the Aromatisation of Tetralones and
Cyclohexenones to Naphthols and Phenols
Paul P. Kelly,a,* David Lipscomb,a Derek J. Quinn,a Ken Lemon,a Jill Caswell,a
Jenny Spratt,a Birgit Kosjek,b Matthew Truppo,b and Thomas S. Moodya
a
Almac, Department of Biocatalysis Isotope Chemistry, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD, Northern
Ireland, U.K.
Fax: (+44)-(0)28-3833-2299, phone: (+44)-(0)28-3833-2200; e-mail: paul.kelly@almacgroup.com
Merck & Co., Inc., Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey
b
07065, USA
Received: September 2, 2015; Revised: December 17, 2015; Published online: February 17, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500818.
Abstract: Ene reductases (EREDs) have great po-
tential as oxidation biocatalysts, as demonstrated by
their efficient conversion of a number of tetralones
to the corresponding naphthols. Of 96 enzymes
tested, 57 were able to produce 2-naphthol in this
way. Further tests with substituted tetralones re-
vealed typically high conversions up to >99%. The
reactions were performed under mild conditions in
aqueous buffer with only co-solvent, biocatalyst and
oxidation substrate required for conversion. Pro-
duction of a methoxy-substituted naphthol was also
successfully performed on a gram scale, with 91%
yield. This methodology provides a new avenue to
produce substituted naphthols as valuable building
blocks, with the possibility to extend the approach
to the production of phenols also being demonstrat-
ed.
accept a wide range of activated alkene substrates in-
cluding a,b-unsaturated ketones, aldehydes and ni-
triles, as well as carboxylic acids and their esters and
nitroalkenes, as discussed in detail by several review-
ers.[3] Examples of synthetically relevant chiral ERED
products include (R)-levodione,[4] (S)-citronellal,[5]
Roche ester derivatives[6] and g-butyrolactones (when
coupled with alcohol dehydrogenase).[7] ERED en-
zymes are also highly amenable to scale-up as demon-
strated by the one-pot, three-enzyme system used to
produce a chiral intermediate on a 70-g scale within
our laboratories.[8]
Besides alkene reduction, EREDs also exhibit
a flavin-catalysed, disproportionation activity. During
this reaction the flavin mononucleotide (FMN) pros-
thetic group is reduced by a suitable substrate (typi-
cally a conjugated enone), rather than NAD(P)H.
Subsequent reduction of an activated alkene or of
molecular oxygen (generating H2O2) by the FMN
group completes the reaction cycle.[9]
Keywords: aromatisation; biocatalysis; ene reduc-
tases; enzyme catalysis; naphthols; oxidation; phe-
nols
Recently, Faber and colleagues[9a] demonstrated
how a range of cyclohexenones and cyclic ketones
could be used, as an alternative to NAD(P)H, to
drive the asymmetric reduction of a number of indus-
trially relevant, activated alkenes. This approach re-
The application of biocatalysis in organic synthesis sulted in two products: the reduction product from
continues to grow year on year for a number of rea- the main target substrate and the oxidation product
sons including the high chemoselectivity, regioselec- from the sacrificial co-substrate. Removal of [2H]
tivity and enantioselectivity that enzyme catalysis from the co-substrate was typically followed by tauto-
offers to the organic chemist.[1] In addition, the appli- merisation to give the aromatic (phenolic) compound,
cation of enzymatic processes translates into hard cost as illustrated in Scheme 1.
savings for the fine chemical and pharmaceutical in-
dustry, by increasing net yield and purity and reducing ꢀaromatasesꢁ in their own right is investigated, focus-
waste for enantiopure products.[2]
ing on the production of naphthols. Naphthols are val-
In the present work, the potential of EREDs as
The synthetic potential of flavin-dependent ene re- uable building blocks for a wide variety of synthetic
ductases (EREDs) in the asymmetric bioreduction of drugs and natural products. Several well-known phar-
activated olefins has been well studied to date. They maceuticals including Propranolol, Naproxen and
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Paul P. Kelly et al.
Scheme 1. Disproportionation of an example substrate (2-
tetralone), as catalysed by flavin-dependent EREDs. The re-
duced flavin can be re-oxidised by molecular oxygen to give
peroxide, or via typical ERED reduction of an activated
alkene.
Scheme 2. Range of tetralones tested for the production of
naphthols using EREDs.
varied in their levels of conversion of substrate 9a,
Agomelatine are naphthol derived, highlighting the giving 19%, 48% and 70%, respectively (Table 1).
importance of this moiety in commercial drugs
As the reactions were conducted in air there was
(Figure 1).[10] A proposed route to the anti-Ebola no expectation that the oxidation and reduction prod-
compound BCX4430 uses (S)-1-(a-aminobenzyl)-2- uct conversions would match, and indeed this was the
naphthol as a key chiral auxiliary in the synthesis.[11]
case. Atmospheric oxygen provides an alternative
Substituted naphthols provide a route to biological- route for FMN oxidation as shown in Scheme 1, and
ly active naphthopyrans, similar to the natural product can therefore uncouple naphthol production from re-
mollugin.[12] The methoxylated naphthyl compound duction of 9a. As the primary aim was to promote
guieranone A (isolated from the leaves of Guiera sen- naphthol production, the fate of the compound 9a
egalensis), has been shown to have potent antifungal was of less concern in any case.
activity.[13] Furthermore, synthetic approaches to oxi-
In subsequent experiments a range of substituted
dative coupling of naphthols have attempted to mimic tetralones was used (Scheme 2). Small-scale reactions
the natural biosynthesis of compounds such as niger- were carried out with a number of 2-tetralones 1a–7a
one, hypocrellin, calphostin D, phleichrome, and cer- and with 1-tetralone 8a, either with or without 9a as
cosporin.[14]
a target substrate for reduction. The results, summar-
Towards the ERED-catalysed production of naph- ised in Table 1, showed that tetralones were very well
thols, a screen of 96 enzymes from Almacꢁs selectA- accepted in general, with moderate to excellent con-
Zyme collection was initially undertaken with 2-tetra- versions (up to >99%).
lone 1a and 4-phenyl-3-buten-2-one 9a as model sub-
For the 2-tetralone series, the position of the aro-
strates (Scheme 2). Compound 9a was an inexpensive, matic substituent did appear to influence the tetra-
readily available starting material and found to be lone acceptance. Specifically, position 6 was sensitive
well accepted by the ERED panel in previous work to substitutions, with drops in conversions most no-
(unpublished data). Of the enzymes tested here, 57 ticeable for the 6-methoxy compound 3a, although
produced detectable levels of 2-naphthol 1b, and 3 of the 6-chloro (4a) and 6-bromo (5a) compounds were
these hits were taken forward in further tests. EREDs more readily accommodated, with up to 91% and
61, 69 and 82 all gave >67% of the naphthol and >99% conversions respectively (ERED-69 – see
Table 1). Methoxy derivatives 2a, 6a and 7a per-
formed similarly to the unsubstituted compound 2-tet-
ralone 1a. The 7-methoxy compound 6a in particular
gave the best conversions overall, with consistently
over 90% and up to >99% of the corresponding
naphthol produced.
The lowest conversions were evident with 1-tetra-
lone 8a (although 44% conversion was still achieved),
indicating that the position of the ketone moiety is
important. This is consistent with the fact that sub-
strate binding and orientation in EREDs is promoted
by hydrogen bonding of the activating group with
conserved histidine/histidine or histidine/asparagine
residue pairs.[3d]
In light of the above results it would be interesting
Figure 1. Pharmaceuticals derived from naphthols.
to test EREDs 61, 69 and 82 with more highly substi-
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COMMUNICATIOENnSe Reductase Enzymes for the Aromatisation of Tetralones and Cyclohexenones
Table 1. Naphthol production from various tetralones using selected EREDs as oxidation catalysts.
With Reduction Substrate (9a)
Conv. [%] (9b)[a] Conv. [%] (1b–8b)[a]
Without Reduction Substrate (9a)
Oxidation Substrate
Enzyme
Conv. [%] (1b–8b)[a]
1a[b]
ERED-61
ERED-69
ERED-82
19
48
70
67
67
88
84
>99
>99
2a[c]
3a[b]
4a[c]
5a[c]
ERED-61
ERED-69
ERED-82
16
35
48
72
95
97
70
94
96
ERED-61
ERED-69
ERED-82
1
14
7
23
41
39
16
53
23
ERED-61
ERED-69
ERED-82
15
45
48
47
60
69
53
91
67
ERED-61
ERED-69
ERED-82
14
39
46
36
78
50
43
>99
71
ERED-61
ERED-69
ERED-82
31
44
73
70
>99
>99
93
>99
95
6a[b]
7a[c]
ERED-61
ERED-69
ERED-82
21
32
68
81
84
91
71
>99
96
8a[b]
ERED-61
ERED-69
ERED-82
25
13
16
43
19
19
44
10
2
[a]
Conversions determined by GC-FID peak area.
Corresponding naphthol products determined by comparison to reference standards on GC-FID.
Corresponding naphthol products determined by GC-MS to confirm loss of [2H] in the molecular ion.
[b]
[c]
tuted tetralones, perhaps affording access to natural Table 1) show that the absence of 9a generally does
products such as guieranone A. Screening of the addi- not affect the ability of the enzyme to oxidise the tet-
tional 54 EREDs shown to produce 2-naphthol, may ralones. Indeed, conversions were often improved in
also reveal even better activities with novel tetralone many cases. In a separate experiment, ERED-69 was
substrates.
incubated in sealed vials under nitrogen, with sub-
For a given ERED, the ratio of the conversion of strate 6a, in the presence and absence of reduction
the reduction target 9a to that of the tetralone varied substrate 9a (see the Supporting Information, S4).
depending on the tetralone substrate used. This ratio Under these conditions <1% conversion to the naph-
should be constant if it is assumed that, following thol was seen without the reduction target whereas, in
flavin reduction by the tetralone, the likelihood of 9a the presence of 9a, the conversion was 92%, in line
being reduced by the flavin is always the same. As the with 94% conversion to the saturated ketone 9b (see
ratio is not consistent, this may indicate that different Scheme 1). This result supports the idea that, in air,
tetralones vary in their ability to promote FMNH2 ox- the dominant pathway for re-oxidation of the flavin,
idation by O2, or in their propensity to occupy the following reduction by the tetralone, is by oxygen
enzyme active site to the exclusion of 9a.
(giving H2O2). In the absence of oxygen, 9a serves as
The requirement for the reduction substrate 9a was an efficient reduction target to drive the oxidation of
also of interest. Alongside the reactions that included the tetralone.
9a, reactions were also run with the tetralone as the
In choosing a reaction scheme to move forward, it
sole substrate in each case. The results (also given in seemed preferable to omit the additional substrate 9a,
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Paul P. Kelly et al.
thus avoiding the need for sealed reactions under no substantial difference in conversions was seen
inert atmosphere and simplifying subsequent attempts beyond 16 h reaction time or by varying the tempera-
at scale-up and product isolation.
ture to 258C or 378C from the original 308C (see the
With this in mind, the best performing substrate (7- Supporting Information, S5).
methoxy compound 6a) and the best performing
With the optimised conditions in hand, the reaction
enzyme (ERED-69) were selected for preparation of was scaled to 190 mL (158 mL buffer, 32 mL tBME)
the corresponding naphthol on a gram scale. In order with 2 g of substrate (60 mM or 10.6 gLÀ1) and 3.8 g
to increase the substrate loading, a number of co-sol- of freeze-dried ERED-69 enzyme powder. Following
vents were screened at the 500-mL scale. In initial re- extraction, 1.82 g of product was isolated, giving 91%
1
actions, up to 17% (v/v) DMSO, tBME, toluene or yield, with product confirmed by H NMR (Support-
THF was tested, with up to 42 mM (for DMSO) or ing Information, S7).
500 mM substrate (Table 2, entries 1–13). Toluene and
Extending the above approach, the results in
THF were the least suitable solvents, giving at best Table 3 show how EREDs from the selectAZyme
47% and 3% conversion, respectively, at 31 mM sub- panel can also convert substituted cyclohexenones to
strate (Table 2, entries 12 and 13).
the corresponding phenols (note: as with the tetra-
Further tests focused on the better co-solvents, lones, omission of 9a did not seem to have a detrimen-
tBME and DMSO, at 60 mM substrate concentration. tal effect on conversion – see the Supporting Informa-
The reaction buffer was adjusted to pH 7.5 (as tion, S6). Starting with 3-methyl-2-cyclohexenone 10a,
normal) or pH 9.0. Improved conversions were ob- up to 96% conversion to meta-cresol 10b was ob-
served at pH 9.0, with values of 60% for 20% (v/v) served with selected EREDs. Compound 10a can also
DMSO co-solvent, 70% for 30% (v/v) DMSO and serve as a target for reduction and the saturated prod-
83% with 17% (v/v) tBME (Table 2, entries 15, 17 uct 10c was observed at low levels (typically <1%).
and 19, respectively).
Cyclohexenones with alternative substitution patterns
The effect of adding catalase was also tested at this were less efficient for phenol production. A methyl
stage, based on the assertion that any H2O2 produced group at the a-carbon greatly reduced the conversions
might be removed and thus help to drive catalysis and of 11a and 13a, with reduction to the saturated
protect against oxidative damage. In practice the ad- ketone favoured. A comparison of 11a with 13a and
dition of catalase did not improve conversions under
the conditions tested (see the Supporting Information,
S5). Finally, at 60 mM substrate the effects of reaction
duration and temperature were examined, although
Table 3. Phenol production from enones 10a–14a using se-
lected EREDs.
Table 2. Optimisation conditions towards the scale-up of 7-
methoxy-2-naphthol 6b.
Entry 6a Conc.
Co-solvent (% v/ pH Conv.
v)
[mM]
[%][a]
1
2
3
4
5
6
7
8
24
48
23
46
21
42
31
63
125
250
500
31
31
60
60
60
60
60
60
DMSO (5)
DMSO (5)
DMSO (9)
DMSO (9)
DMSO (17)
DMSO (17)
tBME (17)
tBME (17)
tBME (17)
tBME (17)
tBME (17)
toluene (17)
THF (17)
DMSO (20)
DMSO (20)
DMSO (30)
DMSO (30)
tBME (17)
tBME (17)
7.5 79
7.5 52
7.5 75
7.5 60
7.5 77
7.5 53
7.5 >99
7.5 71
7.5 32
7.5 15
Substrate Enzyme Conv. [%] 10b–
Conv. [%] 10c–
14b[a]
14c[a]
9
10a
11a
12a
13a
14a
ERED- 96
66
ERED- 13
61
ERED- 18
61
ERED- n.d.
71
<1
18
10
11
12
13
14
15
16
17
18
19
7.5
7.5 47
7.5
5
3
n.d.
10
7.5 54
9.0 60
7.5 39
9.0 70
7.5 62
9.0 83
ERED-
71
<1
n.d.
[a]
Conversions determined by GC-FID peak area; n.d.=
[a]
Conversions determined by GC-FID peak area.
not detected.
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COMMUNICATIOENnSe Reductase Enzymes for the Aromatisation of Tetralones and Cyclohexenones
10a with 14a shows that additional ring substituents Analytical Methods
curtail the aromatisation reaction. Proposed explana-
For quantitative conversion calculations GC-FID analysis
tions for this include altered (unproductive) substrate
binding modes and fewer accessible hydrogens. That
being the case, molecular modelling studies and tar-
geted mutagenesis should afford access to productive
binding modes that allow the efficient aromatisation
of these and other cyclohexenones, while mitigating
the competing reductive reaction.
Methylphenols find applications in the synthesis of
drugs such as gemfibrozil[15] and a-tocopherol (vita-
min E),[16] and also in the production of plastics and
resins.[17] Other alkylphenols such as thymol, carvacrol
and eugenol are important flavour and fragrance
compounds, besides having anti-microbial proper-
ties.[18] Substituted phenols are therefore of great syn-
thetic value and improving this new ERED-based
route via enzyme engineering is an ongoing area of
research in our laboratories.
In summary, an efficient enzymatic method for the
production of substituted naphthols from the corre-
sponding tetralones was presented. This approach
takes advantage of the natural ability of ene reductas-
es of the Old Yellow Enzyme family to work ꢀin re-
verseꢁ. This ability was shown to be widespread
among the selectAZyme panel of EREDs, with 60%
of the panel giving 2-naphthol when presented with 2-
tetralone as a substrate. Selected EREDs from the
panel proved highly effective in the production of
a set of substituted naphthols, with moderate to excel-
lent conversions of up to >99%. A representative re-
action was performed on a 2-g scale with 91% isolat-
ed yield, demonstrating the robustness of these
enzyme catalysts towards solvents and elevated sub-
strate loadings. The selectAZyme EREDs are there-
fore an invaluable tool for synthetic organic chemists
seeking clean, safe and efficient ways to make substi-
tuted naphthols, for incorporation into new and exist-
ing synthetic APIs and natural products. In addition,
the methodology can also easily be applied to the pro-
duction of phenols, an area of ongoing active research
within Almac.
was performed using either a Perkin–Elmer AUTOSYS-
TEM XL Gas Chromatograph fitted with a Zebron ZB-5
column (30 m, 0.25 mm I.D., 0.25 mm film thickness) or
a Finnigan Trace GC fitted with an Agilent HP5-MS column
(30 m, 0.25 mm I.D., 0.25 mm film thickness).
For tetralone substrates with no commercially available
naphthol product standard (5-methoxy-2-naphthol, 6-chloro-
2-naphthol, 6-bromo-2-naphthol and 8-methoxy-2-naphthol),
GC-MS analysis was carried out to allow assignment of
product peaks. For this purpose, a Thermo Finnigan Trace
GC with PolarisQ mass spectrometer was used, and fitted
with a Zebron ZB-5 column (30 m, 0.25 mm I.D., 0.25 mm
film thickness).
Following product isolation from the scaled up 7-me-
thoxy-2-naphthol reaction, the naphthol product was dis-
1
solved in CDCl3 and analysed by H NMR using a Bruker
500 MHz Ultrashield system.
Conditions for the Enzymatic Oxidation/Reduction of
Tetralones and Enones
For small-scale screening, enzymatic reactions were carried
out in 2-mL 96-well deep-well plates containing 10 mg per
well of lyophilised cell free extract for each ERED in the
selectAZyme panel. To each well, 500 mL of 100 mM Tris
buffer, pH 7.5, were added. Substrates were dissolved in
DMSO to 80 mM and 12.5 mL added to the reaction mix.
Where the reduction substrate 9a was included, 12.5 mL of
an 80 mM DMSO stock were also added or alternatively
12.5 mL of DMSO when 9a was omitted. Plates were cov-
ered with a SealPlate film (Sigma Aldrich) and left to shake
overnight (16–18 h) at 308C and 1400 rpm in an Aosheng
MB 100–4 A Thermo Shaker.
During optimisation of the ERED-69 reaction with 7-me-
thoxy-2-tetralone, test reactions were carried out as above,
except that 2 mL microfuge tubes were used (laid horizon-
tally during shaking), and reaction parameters varied as de-
scribed (see the Supporting Information, S5).
For GC analysis, an equal volume of ethyl acetate was
added to each reaction and samples moved into 2 mL micro-
fuge tubes. Tubes were shaken vigorously by hand for 1 min,
vortexed briefly and then centrifuged at 16,000”g for 5 min.
The organic layer was pipetted off to fresh tubes and dried
over MgSO4.
Experimental Section
Acknowledgements
General experimental approaches are described below. For
more specific details see the Supporting Information, includ-
ing section S1.
Almac wish to thank Invest NI for research and development
funding that contributed to this body of work. Invest NIꢀs
Grant for Research and Development programme is part fi-
nanced by the European Regional Development Fund under
the Investment for Growth and Jobs Programme 2014–2020.
Chemicals and Enzymes
Chemicals were purchased from Sigma Aldrich UK. All en-
zymes were obtained from Almac as freeze dried cell free
extracts of Escherichia coli.
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Paul P. Kelly et al.
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