Chemoenzymatic Total Synthesis of (+)- & (?)-cis-Osmundalactone

Article abstract of DOI:10.1016/j.molcatb.2016.11.010

Both optical antipodes of the cis-isomers of osmundalactone, a hydroxypyranone natural product and core structure of the angiopterlactones, have been synthesized from acetylfuran in only three steps through a redox cascade utilizing oxidoreductases and tr

Full text of DOI:10.1016/j.molcatb.2016.11.010

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Contents lists available at ScienceDirect
Journal of Molecular Catalysis B: Enzymatic
journal homepage: www.elsevier.com/locate/molcatb
Chemoenzymatic Total Synthesis of (+)- & (−)-cis-Osmundalactone
Fabian Blume, Yu-Chang Liu, Daniel Thiel, Jan Deska∗
Department of Chemistry, Aalto-yliopisto, FI-02150 Espoo, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Both optical antipodes of the cis-isomers of osmundalactone, a hydroxypyranone natural product and core
structure of the angiopterlactones, have been synthesized from acetylfuran in only three steps through
a redox cascade utilizing oxidoreductases and transition metal catalysis in a concerted fashion. The key
step in this fully catalytic strategy is the enzyme-mediated Achmatowicz reaction via selective furan
oxygenation to furnish the pyran core structure.
Received 15 July 2016
Received in revised form
10 November 2016
Accepted 10 November 2016
Available online xxx
© 2016 Elsevier B.V. All rights reserved.
Keywords:
Biocatalysis
Natural products
Peroxidase
Dehydrogenase
Oxidative rearrangement
Chemoenzymatic
1. Introduction
text, we constructed a three-step sequence to yield the cis-isomer
of osmundalactone from simple acetylfuran in a purely catalytic
Osmundalactone (1), 5-hydroxy-6-methyl-5,6-dihydro-2H-
pyran-2-one, is naturally found in various organisms [1], and it
is thought to play a role in e.g. pest control [2]. Moreover, the
osmundalactone motif is incorporated into a number of more
complex natural products [3], hence making it a prominent target
for total synthetic approaches [4]. While the free osmundalactone
and many conjugates thereof commonly found in nature display
a trans-configuration, some structurally related metabolites such
as angiopteroside [5] and the angiopterlactone family (e.g. 4) [6]
feature a cis-osmundalactone subunit. So it came to no surprise
that soon after the report on the angiopterlactones, in 2010 also
the (–)-cis-osmundalactone (–)-epi-1 was identified as constituent
in Angiopteris esculenta [7] (Fig. 1).
As a result of our recent studies on the enzymatic oxygenative
rearrangement of furfuryl alcohols yielding functionalized pyra-
nones [8], we became interested in small natural product molecules
of the ␦-lactone type, as targets for the design of synthetic multi-
enzyme cascades and their potential (bio)synthetic connections to
oligomeric, more complex secondary metabolite relatives. As a first
test for our previously reported artificial “Achmatowicz monooxy-
genase” (using chloroperoxidase from C. fumago as oxygenating
catalyst for functionalized furans) in a preparative-synthetic con-
fashion. Here, the choice of a suitable alcohol dehydrogenase for the
initial ketone reduction will offer perfect control over the absolute
stereochemistry while, after Achmatowicz-type rearrangement
[9] of the intermediate alcohol, a metal-catalyzed redoxisomer-
ization ensures high diastereoselectivity in favor of the desired
cis-configured ␦-lactone (Scheme 1).
2. Results and discussion
In order to be able to provide sufficient amounts of enan-
tiomerically pure synthetic starting materials and intermediates
en route to the osmundalactones, and eventually to conduct
follow-up studies on its more complex dimers, we began our stud-
ies with revisiting the previously described biocatalytic scheme
accessing pyranone 7 both with regard to scalability as well
as to an optimization towards an integrated, yet illusive one-
pot protocol. To our delight, the asymmetric reduction protocol
employing two commercial alcohol dehydrogenases (evo-1.1.200
and evo-1.1.030, respectively, as known enantiocomplementary
reduction biocatalysts) proved to be very robust and reliable.
Utilizing isopropanol as solubilizer and terminal reducing agent,
both enantiomers of alcohol 6 were obtained on a gram scale
in high yields. A simplified workup protocol helped to over-
come previously observed limitations and led to excellent yields
after extraction (diethyl ether/pentane 2/1) of analytically pure
6. Due to the low intrinsic enantioselectivity of our recently
∗
Corresponding author.
E-mail address: jan.deska@aalto.fi (J. Deska).
http://dx.doi.org/10.1016/j.molcatb.2016.11.010
1381-1177/© 2016 Elsevier B.V. All rights reserved.
Please cite this article in press as: F. Blume, et al., Chemoenzymatic Total Synthesis of (+)- & (−)-cis-Osmundalactone, J. Mol. Catal. B:
Enzym. (2016), http://dx.doi.org/10.1016/j.molcatb.2016.11.010

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2
Fig. 1. Natural products featuring the osmundalactone motif.
Scheme 2. Stepwise synthesis of the optically pure pyranones (R)- and (S)-7.
Scheme 3. Sequential reduction/rearrangement cascade with intermediate pH
adjustment.
for all involved enzymes to remain a certain activity as required
for a true one-pot reaction. As indicated by GC traces of our initial
cascade studies, no alcohol intermediate (6) was detected in most
cases but in situ analysis revealed the formation of minor amounts
of pyranone 7 along with unconverted ketone (5). A more in-depth
NMR study confirmed these observations. Employing the reduction
and oxidation catalyst (dehydrogenase and chloroperoxidase) in a
1:5 ratio (100 U/mmol ADH, 500 U/mmol CPO, 100 U/mmol GOx)
only 5% conversion to the enantiomerically pure (R)-7 was detected
(Table 1, entry 1). At pH 5.5, the optimal medium for the oxidative
rearrangement, apparently the dehydrogenase system, despite not
being entirely silent, lacked the necessary activity. Not surprisingly,
the increase of the amount of ADH by a factor of five (and doubling
the concentration of NADH) resulted in a substantially more pro-
ductive system providing (R)-7 as major component in the reaction
mixture (Table 1, entry 2). A subsequent pH screening revealed an
optimal pH of 6.0 giving rise to 90% of the desired pyranone in opti-
cally pure form (Table 1, entry 3). With further decrease in acidity,
a partial loss of Achmatowicz activity was noted and under neutral
conditions, only the intermediate alcohol (R)-6 was accumulated
(Table 1, entries 4 & 5). These results
confirm the previously recorded pH optima of the individual
transformations. However with the optimized conditions in hand,
we are convinced that the triple-enzyme system represents a highly
interesting module for the design of more complex synthetic cas-
cades and will therefore be included in much more detail in our
future studies.
For the finalization of the fully catalytic total synthesis of the
cis-osmundalactones (epi-1), a redoxisomerization was required,
providing oxidation of the lactol moiety by concomitant 1,2-
reduction of the enone carbonyl. In lack of reports on biocatalytic
protocols for this particular transformation [12], we turned our
attention to transition metal catalysis that has shown great poten-
tial in various kinds of redox-neutral isomerization processes
[13]. Initial attempts employing various Ru- and Rh-complexes
Scheme 1. Triple-catalytic strategy towards stereodefined osmundalactones.
developed enzymatic Achmatowicz rearrangement, both enan-
tiomers were subsequently converted smoothly to the corre-
sponding six-membered heterocycles (R)-7 and (S)-7, respectively,
without any apparent matched-mismatched effects. Here, the com-
bination of glucose oxidase (GOx, A. niger) as oxygen-activating
catalyst and chloroperoxidase (CPO, C. fumago) as oxygenation
mediator exhibited high activity in the desired ring expansion, and
a ten-fold upscaling compared to our original protocol was toler-
ated without any problem, giving rise to the pyranones in around
80% isolated yield. Different other combinations of commercial
peroxidases (including horseradish, soybean and lactoperoxidase)
and hydrogen peroxide-releasing systems (L-alanin + amino acid
oxidase and methanol + alcohol oxidase/formaldehyde dismutase
[10]) have been tested, but none of them performed as good as the
original GOx/CPO setup [11] (Scheme 2).
One obvious advantage of biocatalysis lies in the relative ease
to construct catalytic cascades. However, as discussed in our pre-
vious report, initial attempts to execute the reduction-oxidation
sequence from ketone 5 to pyranone 7 in a one-step fash-
ion remained fruitless which was attributed to incompatibilities
between the dehydrogenase system and the peroxidase catalyst.
Nonetheless, instead of a fully integrated all-at-once approach, we
were able to successfully perform the two-step process in one
pot in a sequential manner. After asymmetric reduction based
on a glucose dehydrogenase/alcohol dehydrogenase couple at pH
7, slight acidification and addition of the Achmatowicz-inducing
biocatalysts led to the formation of (R)-7 in 47% yield and per-
fect enantiopurity. Even better results were obtained when using
isopropanol instead of the GDH/D-Glc recycling system with an
isolated yield of the heterocyclic product of 59% (Scheme 3).
We were however convinced that further fine-tuning of the
reaction parameters would allow to identify suitable conditions
Please cite this article in press as: F. Blume, et al., Chemoenzymatic Total Synthesis of (+)- & (−)-cis-Osmundalactone, J. Mol. Catal. B:
Enzym. (2016), http://dx.doi.org/10.1016/j.molcatb.2016.11.010

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Table 1
Optimization of a one-pot biocatalytic reduction/rearrangement cascade for the synthesis of (R)-7.
Entry
ADH/GOx/CPO
pH
5 (%)
6 (%)
7 (%)
ee (7) (%)
1
2
3
4
5
1/1/5
5/1/5
5/1/5
5/1/5
5/1/5
5.5
5.5
6.0
6.5
7.0
95
12
0
3
2
0
2
10
17
98
5
99
99
99
99
–
86
90
80
0
Reaction conditions: 5 (100 ␮mol), D-glucose (125 ␮mol), NADH (10–20 ␮mol), ADH (10–50 U), GOx (10 U), CPO (50 U), citrate or phosphate buffer (9 mL, 100 mM), isopropanol
(1 mL), 30 ◦C, 5 h. Yields were determined by 1H NMR against N-formylmorpholine as standard; optical purities were determined by GC analysis on chiral phase. The bold
value indicates the optimal conditions in the table.
6-hydroxy-2-methyl-2H-pyran-3(6)-one
based
on
a
dehydrogenase-mediated asymmetric reduction and
a
subse-
quent oxidase/peroxidase-catalyzed Achmatowicz-type ring
expansion. An iridium-based redoxisomerization system finally
furnished the target lactones with nearly perfect stereocontrol.
Based on this work, we will explore the potential synthetic and
biosynthetic relationship of cis-osmundalactone to the more
complex angiopterlactone family. Furthermore, an expansion of
the one-pot biotransformation design will include an entirely
enzyme-based route towards stereodefined complex lactone
natural products.
4. Experimental
Scheme 4. Synthesis of the cis-osmundalactones via iridium-catalyzed redoxiso-
merization.
4.1. Experimental details
previously described in the context of redoxisomerizations
remained fruitless. Very recently, however, Guo and Tang reported
on precisely the required transformation using a simple commer-
cial iridium dimer in combination with an acidic cocatalyst [14].
Here, the transition metal complex performs a dehydrogenation-
reduction sequence via the intermediate ␥-keto-␦-lactone while
2,6-dichlorobenzoic acid is described to facilitate epimerization
of the stereochemically labile hemiacetal resulting in a dynamic
stereoconvergent isomerization. We were pleased to see that the
iridium-catalyzed osmundalactone synthesis indeed proceeded
with excellent diastereocontrol and provided both enantiomers
of the desired cis-lactones epi-1 in nearly stereoisomerically pure
form after 19 h (Scheme 4). Worth mentioning, however, the reac-
tion proved to be rather unreliable and TLC indicated numerous
apolar products as an undesired side effect of the acid cocata-
lyst. Hence, the reported very high yields were never achieved
and the desired target compounds (−)-epi-1 and (+)-epi-1 were
obtained in only moderate yields of 39% and 16%, respectively,
underlining the necessity for further investigations including the
design of a yet elusive enzyme-based alternative of this reac-
tion. In absence of dichlorobenzoic acid, the iridium-catalyzed
transformation exhibited much better product selectivity but the
stereoselectivity dropped from greater 95% de to a mixture of epi-
osmundalactone (epi-1) and osmundalactone (1) in a ratio of 2:1.
General methods: Reactions carried out under argon atmo-
sphere were performed with dry solvents using anhydrous
conditions. Anhydrous solvents were obtained from an MBraun
MB-SPS800 drying system. Commercially available reagents were
used without further purification. Catalysts and cofactors were
obtained from: NADH, Carbolution Chemicals GmbH; Chloroperox-
idase from Caldariomyces fumago (CPO), 9.9 kU/mL, Sigma; Glucose
oxidase type II (GOx), 17.3 U/mg, Sigma; Alcohol dehydrogenase
recombinant (ADH 200), 17.6 U/mg evocatal GmbH; Alcohol dehy-
drogenase, recombinant (ADH 030), 18.8 U/mg, evocatal GmbH;
Glucose dehydrogenase, recombinant from Escherichia coli (GDH
060), 214 U/mg, evocatal GmbH; [Ir(cod)Cl]2, TCI Chemicals. All
products were purified by column chromatography over silica
gel (Macherey-Nagel MN-Kieselgel 60, 40–60 ␮m, 240–400 mesh).
Reactions were monitored by thin layer chromatography (TLC) car-
ried out on precoated silica gel plates (Macherey-Nagel, TLC Silica
gel 60 F254) using UV light and KMnO4-solution or Hanessian’s stain
for visualization. 1H NMR and 13C NMR spectra were recorded at
room temperature on a Bruker Avance 400 instrument. Chemi-
cal shifts are reported in parts per million (ppm) calibrated using
residual non-deuterated solvents as internal reference (CHCl3 at
7.26 ppm (1H NMR) and 77.00 ppm (13C NMR)). Infrared spectra
were recorded on a Bruker Alpha ECO-ATR FT-IR-Spectrometer,
absorption bands are reported in wave numbers [cm−1]. Optical
rotations were measured on an Atago Polax-2L at 589 nm. High
performance liquid chromatography was performed on a Waters
system using a Waters 501 pump and a Waters 2487 dual detec-
tor. Gas chromatography was performed on a Hewlett Packard
HP 6890 Series GC System using a Macherey-Nagel FS-Lipodex
A and Macherey-Nagel FS-Lipodex E column (25 m × 0.25 mm),
N2, 1.0 mL/min; method: 50 ◦C (1 min)/5 ◦C min−1 (35 min)/120 ◦C
(15 min).
3. Conclusion
In summary, a fully catalytic synthetic cascade for the prepa-
ration of both enantiomers of cis-osmundalactone was developed
merging bio- and metal catalysis in a synergistic manner. Herein,
we described
a novel triple-enzymatic one-pot protocol for
the direct transformation of acetylfuran to optically pure
Please cite this article in press as: F. Blume, et al., Chemoenzymatic Total Synthesis of (+)- & (−)-cis-Osmundalactone, J. Mol. Catal. B:
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(R)-1-(2-Furyl)ethanol ((R)-6): Acetylfuran (5, 550 mg,
5.0 mmol) was dissolved in isopropanol (25 mL) and added to
a solution of NADH (0.5 mmol) and alcohol dehydrogenase (evo-
1.1.200, 250 U) in phosphate buffer (pH 7.0, 100 mM, 225 mL). The
reaction mixture was incubated at 35 ◦C (125 rpm) for 12 h until
TLC indicated full conversion. The solution was saturated with
NaCl and afterwards extracted with diethyl ether/pentane (2:1,
4 × 50 mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo to yield the analytically pure alcohol
(R)-6 (528 mg, 4.72 mmol, 94%, 99% ee) as pale yellow liquid.
[␣]20D: +21.0 (c 1.00, CHCl3), 99% ee. Rf (cyclohexane/ethyl acetate,
2/1): 0.60. 1H NMR (400 MHz, CDCl3): ␦ [ppm] = 7.39 (d, 3J = 1.3 Hz,
1H), 6.23 (dd, 3J = 3.0 Hz, 3J = 1.7 Hz, 1H), 6.32 (d, 3J = 3.0 Hz,1H),
4.92-4.84 (m, 1H), 1.99 (d, 3J = 3.7 Hz, 1H), 1.54 (d, 3J = 6.5 Hz, 3H).
13C NMR (100 MHz, CDCl3): ␦ [ppm] = 157.7, 141.9, 110.1, 105.9,
63.6, 21.3. FT-IR (neat, ATR): ꢀ [cm−1] = 3344 (br), 2980 (w), 2875
(w), 1450 (w), 1371 (w), 1328 (w), 1228 (w), 1149 (m), 1066 (m),
1008 (m), 991 (m), 927 (m), 877 (m), 810 (m), 734 (s). GC: method
A, Lipodex E: (S)-6 = 13.3 min, (R)-6 = 13.9 min.
(5R,6R)-5-Hydroxy-6-methyl-5,6-dihydro-2H-pyran-2-one
((−)-epi-1): Under argon, (R)-7 (64 mg, 0.5 mmol), [Ir(cod)Cl]2
(16.8 mg, 25 ␮mol), 2,6-dichlorobenzoic acid (47.7 mg, 0.25 mmol)
and anhydrous chloroform (5 mL) were added to an oven-dried
flask and the pale yellow reaction mixture was stirred at room
temperature for 19 h. The reaction was quenched by addition of
saturated sodium bicarbonate solution (20 mL), the aqueous phase
was extracted with chloroform (3 × 10 mL) and the combined
organic layers were dried over sodium sulfate and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography on silica gel (cyclohexan/ethyl acetate
1/1) to afford the lactone (−)-epi-1 (25 mg, 195 ␮mol, 39%, 99%
ee, 96% de) was a pale yellow oil. Rf (cyclohexane/ethyl acetate,
2/1): 0.16. [␣]23D: −230 (c 0.50, CHCl3). epi-1: 1H NMR (400 MHz,
CDCl3): ␦ [ppm] = 7.02 (dd, 3J = 9.7 Hz, 3J = 5.7 Hz, 1H), 6.12 (d,
3J = 9.7 Hz, 1H), 4.55 (dd, 3J = 6.6 Hz, 3J = 2.8 Hz, 1H), 4.05 (dd,
3J = 5.7 Hz, 3J = 2.8 Hz, 1H), 2.49 (br s, 1H), 1.52 (d, 3J = 6.6 Hz, 3H).
13C NMR (100 MHz, CDCl3): ␦ [ppm] = 163.9, 144.6, 122.6, 77.2,
62.9, 15.7. 1 (selected signals): 1H NMR (400 MHz, CDCl3): ␦
[ppm] = 4.36 (dd, 3J = 7.4 Hz, 3J = 5.4 Hz, 1H), 3.81 (dd, 3J = 6.1 Hz,
3J = 5.4 Hz, 1H), 1.68 (d, 3J = 6.6 Hz, 3H).
(S)-1-(2-Furyl)ethanol ((S)-6): Acetylfuran (550 mg, 5.0 mmol)
was reduced according to the protocol employed for the prepa-
ration of (R)-6, using the (S)-selective dehydrogenase evo-1.1.030
(200 U) instead. Full conversion was achieved after 44 h. Extraction
yielded the analytically pure alcohol (S)-6 (474 mg, 4.23 mmol, 85%,
99% ee) as pale yellow liquid. [␣]20D: −21.1 (c 1.00, CHCl3), 99%
ee.
(5S,6S)-5-Hydroxy-6-methyl-5,6-dihydro-2H-pyran-2-one
((+)-epi-1): (+)-epi-1 was obtained under identical conditions
as described for (–)-epi-1 from (S)-7 as
a pale yellow oil
(10 mg, 78 ␮mol, 16%, 99% ee, de = 95%). [␣]23D: 235 (c 0.50,
CHCl3).
(2R)-6-Hydroxy-2-methyl-2H-pyran-3(6)-one ((R)-7): In
a
round bottom flask (250 mL), the alcohol (R)-6 (224 mg, 2.0 mmol)
was dissolved in a mixture of citrate buffer (pH 6.0, 100 mM,
72 mL) and tert-butanol (8 mL). Chloroperoxidase (500 U), glucose
oxidase (100 U) and D-glucose (3.0 mmol) were added and the
reaction mixture was incubated at 30 ◦C (150 rpm) under air for
4.5 h until TLC indicated full conversion. L-Methionine (5 mmol)
was added and the solution was extracted with diethyl ether
(3 × 50 mL). The combined organic phases were washed with brine
and dried over Na2SO4. After removal of all volatiles in vacuo
(R)-7 (199 mg, 1.56 mmol, 78%, 99% ee, ␣/␤ = 67/33) was obtained
as colorless waxy solid. [␣]20D: −79.6 (c 0.50, CHCl3), 99% ee.
M.p.: 61 ◦C. Rf (cyclohexane/ethyl acetate, 2/1): 0.25. ␣-7: 1H NMR
(400 MHz, CDCl3): ␦ [ppm] = 6.89 (dd, 3J = 10.2 Hz, 3J = 3.2 Hz, 1H),
6.10 (d, 3J = 10.2 Hz, 1H), 5.63 (m, 1H), 4.71 (q, 3J = 6.7 Hz, 1H), 3.53
(d, 3J = 5.0 Hz, 1H), 1.38 (d, 3J = 6.7 Hz, 3H). 13C NMR (100 MHz,
CDCl3): ␦ [ppm] = 197.0, 144.5, 127.3, 87.7, 70.4, 15.3. ␤-7: 1H
NMR (400 MHz, CDCl3): ␦ [ppm] = 6.94 (d, 3J = 10.2 Hz, 1H), 6.15
(d, 3J = 10.2 Hz, 1H), 5.67 (d, 3J = 7.2 Hz, 1H), 4.23 (1H, m), 3.87 (d,
3J = 7.2 Hz, 1H), 1.45 (d, 3J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3):
␦ [ppm] = 196.5, 148.1, 128.6, 91.0, 75.3, 16.2. FT-IR (neat, ATR): ꢀ
[cm−1] = 3294 (br), 3051 (w), 2987 (w), 1676 (s), 1435 (m), 1371
(m), 1334 (w), 1273 (w), 1232 (m), 1143 (m), 1109 (m), 1091 (m),
1031 (s), 937 (m), 900 (m), 808 (m), 690 (m). GC: method A, Lipodex
E: ␣-(2R)-7 = 37.0 min, ␣-(2S)-7 = 37.6 min.
Acknowledgments
We gratefully acknowledge support provided by the Suomen
Akatemia (298250), the Dr.-Otto-Röhm-Gedächtnisstiftung, and
Carbolution Chemicals.
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dehydrogenase (evo-1.1.200, 50 U) and D-glucose (22.5 mg,
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100 ␮mol), NADH (14.4 mg, 20 ␮mol), chloroperoxidase (50 U), glu-
cose oxidase (5 U) and isopropanol (1 mL) in citrate buffer (9 mL,
100 mM, pH 6.0) and the mixture was incubated for 5 h at 30 ◦C
(200 rpm). Then, the reaction mixture was extracted with ethyl
acetate (3 × 5 mL) and the combined organic layers were dried over
MgSO4, evaporated under reduced pressure and yields/product
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Enzym. (2016), http://dx.doi.org/10.1016/j.molcatb.2016.11.010

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Please cite this article in press as: F. Blume, et al., Chemoenzymatic Total Synthesis of (+)- & (−)-cis-Osmundalactone, J. Mol. Catal. B:
Enzym. (2016), http://dx.doi.org/10.1016/j.molcatb.2016.11.010