Lipase-Induced Oxidative Furan Rearrangements

Article abstract of DOI:10.1055/s-0036-1591889

Lipase B from Candida antarctica catalyzes the oxidative ring expansion of furfuryl alcohols using aqueous hydrogen peroxide to yield functionalized pyranones under mild conditions. The method further allows for the preparation of corresponding piperidinone derivatives by enzymatic rearrangement of N-protected furfurylamines.

Full text of DOI:10.1055/s-0036-1591889

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
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F. Blume et al.
Letter
Synlett
Lipase-Induced Oxidative Furan Rearrangements
Fabian Blumea
Petra Sprengartb
Jan Deska*a
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a Department of Chemistry & Materials Science, Aalto-yliopisto,
Kemistintie 1, 02150 Espoo, Finland
jan.deska@aalto.fi
b Department of Chemistry, Universität zu Köln, Greinstrasse 4,
50939 Cologne, Germany
Published as part of the Special Section 9th EuCheMS Organic
Division Young Investigator Workshop
Received: 30.10.2017
Accepted: 17.12.2017
Published online: 15.01.2018
DOI: 10.1055/s-0036-1591889; Art ID: st-2017-b0806-l
Abstract Lipase B from Candida antarctica catalyzes the oxidative ring
expansion of furfuryl alcohols using aqueous hydrogen peroxide to yield
functionalized pyranones under mild conditions. The method further al-
lows for the preparation of corresponding piperidinone derivatives by
enzymatic rearrangement of N-protected furfurylamines.
Petra Sprengart (left) studied chemistry at the University of Cologne
(Germany) and conducted her MSc thesis work in the group of Jan Des-
ka. She is currently pursuing doctoral studies in Cologne under the su-
pervision of Prof. Hans-Günther Schmalz.
Key words Achmatowicz, ring expansion, furan, pyranone, synthetic
Fabian Blume (center) received his Diploma degree in chemistry under
the supervision of Prof. Dirk Menche at the Rheinische Friedrich-Wil-
helms University of Bonn (Germany). In 2013, he joined the Deska
group at the University of Cologne and he is currently finalizing his doc-
toral thesis at Aalto University in Espoo (Finland) about the biocatalytic
construction of heterocyclic building blocks.
Jan Deska (right) studied chemistry at the Saarland University (Germa-
ny) obtaining his doctoral degree under the supervision of Prof. Uli Kaz-
maier. After graduating in 2007, he pursued postdoctoral studies at the
Indian Institute of Science in Bangalore (India) under guidance of Prof.
Goverdhan Mehta and at Stockholm University (Sweden) in the group
of Prof. Jan-E. Bäckvall. Deska started his independent scientific career
in 2010 as Liebig junior group leader at the University of Cologne (Ger-
many) before being appointed as Professor in Synthetic Organic Chem-
istry at Aalto University, Espoo (Finland) in 2015. His research interests
include the design of new biocatalytic reactions and their application in
natural product synthesis.
methodology, heterocyclic chemistry
The rich chemistry of furans as readily available organic
building blocks, and particularly their prominent role as
one of the major players in modern lignocellulose biorefin-
ery,1 have led to an increasing interest in their use for the
construction of more complex molecular architectures.2
Here, the oxidative ring expansion of furfuryl alcohols and
amines to six-membered, highly functionalized O- and N-
heterocycles, respectively, represents a paramount example
for the synthetic utility of the furyl platform. Based on the
original reports using classical oxidants by Cavill (Br2,
1969),3 Achmatowicz (Br2, 1971),4 or Lefebvre (peracetic ac-
id, 1972),5 a wide repertoire of methodologies for the selec-
tive furan oxidation has been developed over the years,6
and the Achmatowicz rearrangement has reached an im-
portant role in modern organic synthesis.7 In 2014, we re-
ported, for the first time, of an aerobic biocatalytic version
of this reaction featuring a direct furan oxygenation by
chloroperoxidase.8 While this method stood out with re-
spect to catalytic turnover, selectivity in presence of other
oxidation-labile functional groups, and the ability to act in
more complex biocatalytic cascades,9 chloroperoxidase
from Caldariomyces fumago generally fails to convert steri-
cally biased furfuryl substrates bearing branched alkyl side
chains or substituents on the heterocyclic core. We there-
fore became interested in the use of enzyme-generated dif-
fusible redox mediators that would allow for the transfer of
oxidation equivalents outside the biocatalyst's active site as
previously illustrated in successful examples of this ap-
proach including enzyme-mediator couples such as halo-
peroxidase/hypobromite10 or laccase/TEMPO.11 Inspired by
our observation that lipases can act as peracid-generating
catalyst in hydrogenperoxide-containing acetate buffer,8,12
the aim of this study was to establish a preparatively simple
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
F. Blume et al.
Letter
Synlett
Lefebvre-type Achmatowicz protocol based on the enzyme-
induced peroxide activation. Here, the combination of
Candida antarctica lipase B and hydrogen peroxide in ali-
phatic esters (as acyl donor and solvent) has already been
shown to be a powerful system for the in situ generation of
peracetic acid to provide mild reaction conditions for Prile-
zhaev-type epoxidations,13 Baeyer–Villiger reactions,14 and
other electrophilic oxygenations,15 and was therefore con-
sidered a promising tool also for the oxygenative ring rear-
rangement of furan-based alcohols and amines.
The 5-methyl-substituted furfuryl alcohol 1a was cho-
sen as model substrate for the optimization study since it
proved to be particularly challenging in the Achmatowicz
oxidation by the chloroperoxidase/oxidase couple. The orig-
inal protocol by Allais, using aqueous hydrogen peroxide
in ethyl acetate in the presence of lipase B from Candida
antarctica and a so-called solid buffer based on 4-(2-
hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES),14a
provided reasonable conversion of the alcohol 1a and deliv-
ered the desired pyranone 2a in 56% yield (Table 1, entry 1).
We also tested an alternative solid buffer consisting of
mono- and dibasic phosphate as well as MgSO4 as desiccant
which, however, resulted in reduced product formation (Ta-
ble 1, entry 2). With the rational to minimize the competi-
tion between the peroxide and water in the perhydrolysis
process, next, MgSO4 was used as sole additive leading to
both increased conversion and yield of 2a (Table 1, entry 3).
At higher substrate concentrations, excellent levels of con-
version were maintained but the selectivity for the pyra-
none 2a dropped significantly (Table 1, entry 4 and 5). Sur-
prisingly, even in absence of any desiccant (or other addi-
tive), very good conversions could be conserved (Table 1,
entry 6), and minor modifications with regard to the equiv-
alents of H2O2 rendered a high-yielding, selective, enzyme-
induced Achmatowicz protocol (Table 1, entry 7 and 8). In-
stead of aqueous peroxide (50% w/w), also fine-powdered
urea H2O2 could be employed, with slightly reduced selec-
tivities (Table 1, entry 10 and 11). As one crucial factor to
achieve reproducible results and high product yields, it was
necessary to remove excess peroxides by the addition of
aqueous catalase prior to purification.
The previously developed chloroperoxidase-catalyzed
Achmatowicz protocol did not only exhibit poor perfor-
mance on 5-substituted furfuryl alcohols such as 1a but
also other substitution patterns were not well tolerated in a
direct enzymatic oxygen-transfer reaction.8 Thus, a com-
lipase B (C. antarctica)
aq. H2O2, EtOAc, 40 °C;
then catalase (C. glutamicum)
A
phosphate buffer (pH 7.0)
R
O
R'
R
R''
or
O
R''
R'
HO
O
OH
glucose oxidase (A. niger)
chloroperoxidase (C. fumago)
D-glucose, tBuOH
B
Table 1 Optimization of an Enzyme-Induced Lefebvre-Type Achmatowicz
1
2
Rearrangementa
citrate buffer (pH 5.5), 30 °C
O
O
O
lipase B (C. antarctica)
aq. H2O2 or urea·H2O2
O
Me
OH
Me
Me
HO
Me
O
Me
HO
O
Me
HO
O
Me
HO
O
additive
EtOAc, 40 °C, 4 h
O
Me
2a
A: 74%
B: 0%
2b
A: 51%
B: 78%
2c
A: 76%
B: 70%
1a
2a
then catalase (C. glutamicum)
phosphate buffer (pH 7)
O
O
Entry H2O2 source (equiv) 1a (M) Additiveb
Conv. (%)c 2a (%)c
Me
1
2
aqueous (1.5)
aqueous (1.5)
aqueous (1.5)
aqueous (1.5)
aqueous (1.5)
aqueous (1.5)
aqueous (1.1)
aqueous (3.0)
aqueous (3.0)
urea·H2O2 (1.5)
urea·H2O2 (3.0)
0.1
0.1
0.1
0.4
1.0
0.1
0.1
0.1
0.4
0.1
0.1
HEPES
KxHyPO4/MgSO4
MgSO4
MgSO4
MgSO4
none
75
60
95
99
98
94
90
95
99
94
99
56
30
74
60
53
79
75
82
66
77
74
HO
O
Me
HO
O
2d
A: 81%
B: 53%
2e
A: 75%
B: 0%
3
4
O
O
O
Me
5
Me
Me
Me
Me
HO
O
HO
O
Me
HO
O
6
7
none
2f
A: 80%
B: 68%
2g
A: 61%
B: 14%
2h
A: 77%
B: 5%
8
none
9
none
Me
Me
O
O
10
11
none
none
HO
O
Me
HO
O
a Reaction conditions: 1a (0.12 mmol), 600 rpm, lipase B (C. antarctica, 36 U),
40 °C, EtOAc (0.12–1.2 mL); then KPi buffer (0.4 mL, 0.1 M, pH 7.0) and 2.5
μL catalase (2.5 μL, 1.25 kU).
2i
2j
A: 70%
B: n.d.
A: 56%
B: 0%
b Additives: HEPES (20 mg/mL); MgSO4 (12 mg/mL); MgSO4/KH2PO4/K2HPO4
(1:1:1; 36 mg/mL).
Scheme 1 Substrate scope: comparison between peracetic acid medi-
ated (A) and nonmediated (B) enzymatic Achmatowicz protocols
c Compositions were determined by 1H NMR spectroscopy relative to 1,4-di-
nitrobenzene as internal standard.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
F. Blume et al.
Letter
Synlett
parative study on a wider set of furan substrates on a pre-
parative 5 mmol scale was conducted in order to point out
the pros and cons of either method (Scheme 1). Compound
1a was rapidly consumed by the lipase/peracid couple and
pyranone 2a could be isolated in 74% yield after only 4 h. All
monosubstituted furans (1b–h) reacted more sluggishly
and close to full conversion was only achieved after around
24 h. Comparing the outcome of the biocatalytic syntheses
of simple n-alkyl-decorated pyranones 2b–e, increase of
chain length clearly resulted in reduced yields for protocol B
(chloroperoxidase-mediated) while the lipase-mediated
method A exhibited a generally good performance particu-
larly for the higher homologues. A similar picture was ob-
tained for different branching patterns where both isobutyl
derivative 2g and the geminally dimethylated 2h were only
accessible in high yields by the peracid-mediated reaction
A. As for the model substrate 1a, also methylation in the
3-position of the furfuryl alcohols rendered the substrates
inactive under the conditions provided by method B where-
as decoupling of the enzymatic principle with the oxidizing
entity in form of a diffusible redox mediator (A) enabled
conversion of furans such as 1i or 1j.16 Worth noting, the
formation of the corresponding ketolactones, from over-
oxidation of the hemiacetal as reported for, e.g., the
laccase/TEMPO system,11 was never observed in transfor-
mations based on either A or B. On the other hand, a series
of functional groups such as esters and olefins were well
tolerated by the chloroperoxidase which would be readily
attacked by the lipase and/or peracetic acid.
Encouraged by the broad scope and lack of any steric
bias of the lipase-induced oxidation of furfuryl alcohols to
pyranones, we expanded the study to related N-protected
furfurylamine derivatives,17 that would give rise to synthet-
ically equally important piperidinones. Gratifyingly, lipase
B from C. antarctica readily converted monosubstituted fu-
rans carrying benzyl carbamate moieties into the corre-
sponding N-Cbz-protected N-heterocycles 4a and 4b in 65%
and 40% yield, respectively (Scheme 2). As in the case of fur-
furyl alcohols, also core-substituted furans like 3c under-
went rapid oxidative cleavage by the lipase-mediated
peracid-generating system. However, as already observed in
various other studies,18 ring closure of the resulting dike-
tones to the hemiaminals is hampered and also in our case,
the corresponding isomerized E-configured acyclic enedi-
one was obtained as major product.
OH
Me
multicatalytic
Me
OH
rac-1b
O
one-pot synthesis
O
O
(+)-cis-osmundalactone
5, 22%
99% ee, 98% cis
1) kinetic resolution
2) oxidative rearrangement
3) redoxisomerization
lipase B
then addition of
(C. antarctica)
vinyl acetate
EtOAc, 25 °C
[Ir(cod)Cl]2
2,6-Cl2BzOH
EtOAc, 40 °C
then addition of
aq. H2O2
O
Me
OH
O
EtOAc
40 °C
HO
O
Me
(S)-1b
(S)-2b
Scheme 3 Application in a stereoselective one-pot reaction cascade
towards cis-osmundalactone
Although this and other studies evidently show the po-
tential of lipases to act as mediator for the in situ genera-
tion of reactive oxidizing species, the family of lipase bio-
catalysts is certainly much more renowned for their ability
to serve as resolution catalyst in the stereoselective acyla-
tion of secondary alcohols. We therefore envisaged that the
combination of a kinetic resolution of furfuryl alcohols
with the subsequent oxidative rearrangement in a one-pot
fashion would offer a direct access to enantiomerically en-
riched pyranones. In practice, not only did the coupling of
resolution (krel > 300) and ring expansion proceed smoothly
but the reaction sequence could even be extended by an
iridium-catalyzed diastereoselective redoxisomerization19
to yield the naturally occurring hexanolide (+)-cis-osmunda-
lactone (5) in high stereochemical purity (Scheme 3).20
Here, all three steps are conducted in the same solvent indi-
vidually induced by the sequential addition of the re-
agents/catalysts to the reaction mixture leading to an over-
all yield of 22% (relative to a theoretical yield of max. 50%
due to the nature of kinetic resolutions).
In summary, we have developed a practical, mild, and
scalable protocol for the peracid-mediated Achmatowicz-
type ring expansion of furfuryl alcohols. Making use of a li-
pase-catalyzed perhydrolysis of ethyl acetate and thus ren-
dering the handling of stoichiometric amounts of peracetic
acid obsolete, this approach represents a powerful and
competitive addition to the toolbox of biocatalytic furan
oxidations. The bioinduced rearrangement reaction proved
to be broadly applicable on a variety of differently decorat-
ed furyl carbinols giving rise to pyranone building blocks in
generally good yield. Moreover, the method was similarly
effective in the corresponding aza-Achmatowicz reaction
towards functionalized six-membered N-heterocycles.
O
lipase B (C. antarctica)
aq. H2O2, MgSO4
R'
R
R'
R
O
N
EtOAc, 40 °C
HO
NHCbz
Cbz
then catalase (C. glutamicum)
phosphate buffer (pH 7)
3a–c
R/R' = H/Me: 4a, 65%
H/Ph: 4b, 40%
Me/H: 4c, 0%
Scheme 2 Lipase-induced aza-Achmatowicz reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
F. Blume et al.
Letter
Synlett
Funding Information
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We gratefully acknowledge support by the Suomen Akatemia
(298250), the Deutsche Forschungsgemeinschaft (DE1599/4-1) and
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by Carbolution Chemicals.
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Supporting Information
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591889.
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(16) Representative Experimental Procedure
References and Notes
The appropriate furfuryl alcohol (5 mmol) was dissolved in
EtOAc (50 mL), and CAL-B (105 mg, 1.5 kU) and aq. H2O2 (50 %
858 μL, 15 mmol) were added. The reaction mixture was placed
on an orbital shaker at 40 °C (200 rpm). After 24 h, phosphate
buffer (15 mL, 100 mM, pH 7.0) and catalase (5 μL) were added,
and the mixture was shaken for further 15 min. The organic
phase was separated, and the aqueous phase was extracted
with EtOAc (2 × 20 mL). The combined organic layers were dried
over Na2SO4 and volatiles were removed under reduced pres-
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