Enantioselective, Catalytic One-Pot Synthesis of γ-Butyrolactone-Based Fragrances

Article abstract of DOI:10.1002/cctc.201801040

Herein the preparative (1 g scale), stereoselective syntheses of various alkyl-substituted γ-butyrolactone fragrances 1 is described. The α,β-unsaturated γ-keto esters 2 as starting materials were synthesized by a Horner-Wadsworth-Emmons reaction and are further reduced by an ene reductase and alcohol dehydrogenase in a one-pot enzyme cascade to nine desired γ-butyrolactones 1, among them whisky (1 c) and cognac lactone (1 d). The products 1 were obtained in moderate to good yields and very good diastereoselectivities. Furthermore, the position of a ⁿBu-substituent was permutated to study the effect on the enzyme cascade.

Full text of DOI:10.1002/cctc.201801040

Accepted Article
Title: Enantioselective, Catalytic One-Pot Synthesis of γ-Butyrolactone-
Based Fragrances
Authors: Ceyda Kumru, Thomas Classen, and Joerg Pietruszka
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10.1002/cctc.201801040
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Enantioselective, Catalytic One-Pot Synthesis of γ-Butyrolactone-
Based Fragrances
Ceyda Kumru,[a, b] Thomas Classen,[b] and Jörg Pietruszka*[a, b]
Abstract: Herein the preparative (1 g scale), stereoselective
syntheses of various alkyl-substituted γ-butyrolactone fragrances 1 is
described. The α,β-unsaturated γ-keto esters 2 as starting materials
were synthesized by a Horner-Wadsworth-Emmons reaction and are
further reduced by an ene reductase and alcohol dehydrogenase in
an one-pot enzyme cascade to nine desired γ-butyrolactones 1,
among them whisky (1c) and cognac lactone (1d). The products 1
were obtained in moderate to good yields and very good
n
diastereoselectivites. Furthermore, the position of a Bu-substituent
was permutated to study the effect on the enzyme cascade.
Introduction
In nature the γ-butyrolactone core structure is found in many
natural products showing various biological activities like
antibiotic, antitumor, antifungal, and cytostatic properties
(figure 1).[1] Consequently, they are also used as building blocks
for synthesis, but also for other natural products that do not
contain this structural motif, e.g. alkaloids or pheromones.[2]
Furthermore, γ-butyrolactones 1 (see Figure 2) are known as
Figure 1. Structures of some γ-butyrolactone based flavour and fragrances
and natural products.[1d, 1e, 1j, 7]
flavour and fragrance molecules making them interesting
compounds not only for pharma, but also for food industry.[3]
One common γ-butyrolactone is the quercus lactone (1c)
(figure 2). Quercus lactone (1c) is a flavour compound in alcoholic
beverages, which is extracted from oak woods during natural
seasoning. Hence, it is also known as whisky lactone (1c). The
main oak wood species in which the quercus lactones (1c) exist
are the American oak Quercus alba and the French oaks
Quercus petraea and Quercus robur, but it occurs also in the
limited Spanish oak Quercus pyrenaica.[4] The amount of quercus
lactones (1c) in some oak woods is described in the literature by
Pollnitz et al. The most amount was observed in quercus alba with
6.65 µg/g oak of trans-quercus lactone (1c) and 86.0 µg/g oak of
cis-lactone (1c).[5] The naturally occurring stereoisomers of
quercus lactone (1c) are (3S,4S)- and (3S,4R)-configured. Its
taste and odour properties are mainly coconut-like with an earthy
Figure 2. Structure of quercus lactones (1c).[8]
or celery-like note, which depends on the configurations of the
lactones.[6]
Therefore, there is a demand to synthesize the γ-butyrolactones
1 stereoselectively. Various synthesis approaches are described
in literature and a selection is depicted in figure 3: One of the
synthesis routes is the oxidative cyclisation of β,γ-unsaturated
[a]
[b]
C. Kumru, Prof. Dr. J. Pietruszka
Institut für Bioorganische Chemie
carboxylic acids using a chiral selenium catalyst (route a). Chiral
γ-butenolides are formed, which can be further modified and
reduced to the desired γ-butyrolactones.[1a, 1e, 9] Another method
is the copper-catalysed cyclopropanation of furanes followed by
Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich
Stetternicher Forst, Geb. 15.8, D-52426 Jülich, Germany
E-mail: j.pietruszka@fz-juelich.de
C. Kumru, Dr. T. Classen, Prof. Dr. J. Pietruszka
Institut fꢀr Bio- und Geowissenschaften (IBG-1: Bioorganic
Chemistry), Forschungszentrum Jꢀlich, D-52425 Jꢀlich, Germany
1j,
9]
ozonolysis (route b).[1a,
Also, [4+2]-, [3+2]-, or
[2+2]-cycloadditions are known to yield the title compound (route
c).[1j, 10] The aldol reaction using a chiral auxiliary Xc represents
another common synthesis route (route d). The homo aldol
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cctc.201801040
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reaction is more challenging due to self-condensation, but it was
also utilized in some cases,[1a, 1j, 9] as was the halo lactonisation
(route e).[1e, 9] Transition metal catalysed ring closing metathesis
is also applied leading to γ-butenolides, which then can be further
transformed to yield γ-butyrolactones like quercus lactone or
cognac lactone.[1j, 9-10] Furthermore, some enzymatic approaches
are established, e.g., the Baeyer-Villiger-oxidation with
by an acid catalysed lactonisation (Scheme 1). To choose the
best ER leading to high conversion rates and enantioselectivities,
an enzyme screening with both isomers of the α,β-unsaturated
γ-keto esters 2 was performed separately (Scheme 3). Therefore,
the available wildtype ER′s were used. In table 1 the screening
results for both isomers of C4-nBu (2c) are shown.
monooxygenases (route g) or the oxidation or reduction with
9-11]
alcohol dehydrogenases (route h).[1e,
The latter was
established by Brenna et al. by treatment with Baker′s yeast, for
example.[12]
Scheme 1. One-pot enzymatic synthesis route towards γ-butyrolactones 1.
Figure 3. Retrosynthetic approaches towards γ-butyrolactones.
Previously,
we
reported
on
the
stereoselective
chemoenzymatic one-pot synthesis of methyl-substituted
γ-butyrolactones using ene reductases (ER′s) and alcohol
dehydrogenases (ADH′s) and discussed the mechanism
concerning the enantioselectivities.[13] Brenna et al. also reported
on this synthesis route by utilising different oxidoreductases.[11b]
We expand our research in this field leading to several
γ-butyrolactone flavours 1, among them quercus lactone (1c) and
the methyl-substituted derivative of γ-nonalactone (1d), which is
also called cognac lactone, and γ-decalactone (1e). This includes
enzymologic studies on the effect of different substitution pattern
of γ-butyrolactones 1 to the enzymes.
Results and Discussion
As shown in scheme 1, α,β-unsaturated γ-keto esters 2 are used
as starting materials for the chemoenzymatic synthesis of
substituted γ-butyrolactones 1. The respective substrates were
synthesized by Horner-Wadsworth-Emmons (HWE) reaction in a
straightforward sequence. Thereby, 20–91% of (E/Z)-mixtures
were isolated, which could be separated by column
chromatography. More details on the HWE-reaction and the
synthesis of the corresponding phosphonates 3 are described in
the Supporting Information. The general synthetic route to these
substrates 2 as well as their structures are presented in
scheme 2. The following one-pot enzymatic conversion of
α,β-unsaturated γ-keto esters 2 consists of two sequential
reduction steps utilizing an ene reductase (ER) and an
alcohol dehydrogenase (ADH) via intermediates 4 and 5, followed
Scheme 2. Synthesis route to α,β-unsaturated γ-keto esters 2.
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The best results were provided with NcrZM with a conversion of
97% for the (E)-isomer [(E)-2c] and 64% for the (Z)-isomer
[(Z)-2c]. The enantioselectivities are excellent for both isomers
[(E/Z)-2c] (99% ee). NcrZM converts most of the other substrates
2a-g (29–>99%) with excellent enantioselectivities (77–>99%,
see Supporting Information). Furthermore, irrespective which
isomer (E/Z) has been subjected to the ene reductase the
(R)-enantiomer was formed, except for the substrates (E)-2g and
(Z)-2g. We assume that this is due to the activation of the
substrates 2 by the keto moiety. Thus, the hydride is transferred
on Cβ with respect to the keto moiety and the proton on Cα, so the
(E)/(Z)-flip has no effect on the enantioselectivity, if R3 is a proton
(Scheme 4). This hypothesis could be proven using deuteration
experiments as described in the Supporting Information and in
previous works.[13b] The absolute configurations were determined
In all cases NcrZM was used as the ene reductase, but for (Z)-2g,
leading to excellent enantioselectivity (≥99%) and moderate to
quantitative conversions (62–>99%). The stereochemical
outcome was always (R)-configured, if the methyl-substituent was
in α-position (4a-e). Changing the nBu-chain against the
methyl-substituent leads to the (S)-configured product 4f. A shift
of the nBu-chain to the β-position results also in the (S)-configured
product (S)-4g exclusively, if the (E)-isomer was used as starting
material. The (Z)-isomer was converted with Opr1 to the
(R)-configured
product
[(R)-4g]
with
very
good
enantioselectivities (94%) and conversion (96%).
retrospectively based on the lactones
Information).
1 (see Supporting
Scheme 4. Mechanistic explanation of the enantioselectivity of ene reductases.
The Scheme shows the binding of the substrate 2 within the active site of the
ER. Both binding poses result in the very same enantiomer with R3 = H.[13b]
Scheme 3. Reaction sequence for the screening of ene reductases (ER).
Table 1. Ene reductase screening results for both isomers of C4-nBu (2c).
Table 2. Results of the preparative reduction with ene reductases.
starting
material
conv.
(%)
ee
yield
(%)
product
ER
(%)
substrate
enzyme
product
99
NcrZM
>99
>48
>25
<78
>13
>18
(R)
2a
2b
2c
2d
(R)-4a
(R)-4b
(R)-4c
(R)-4d
(R)-4c
conv. (%)
ee (%)
99
99
NcrZM
NcrZM
NcrZM
NcrZM
62
(R)
NcrZM
NcrPL
OYE
97
88
58
57
90
76
15
64
25
22
1
91
86
>99
82
YqjM
Opr1
Opr3
TsER
NcrZM
NcrPL
OYE
48
(R)
(E)-2c
64
25
>99
65
91
(R)
99
95
>99
72
79
(R)
YqjM
Opr1
Opr3
TsER
79
(Z)-2c
36
36
42
13
2e
(R)-4e
16
>99
NcrZM
90
<48
65
(S)
2f
(S)-4f
(S)-4g
(R)-4g
It is also worth mentioning that by increasing substrate size the
conversion rates decreased whilst the enantioselectivities
increased. The larger substrates may have a bigger area of
Van der Waals interactions with enzyme residues in contrast to
their smaller homologues. This would stabilise the
Michaelis-complex and thus increase the enantiomeric excess.
However, the disadvantage is that the substrates remains longer
in the active site decreasing the conversion rate. The best
ene reductase with respect to enantioselectivity and conversion
of the substrates 2 NcrZM has been used for preparative scale
conversions (Table 2):
99
NcrZM
Opr1
99
96
<49
<45
(S)
(E)-2g
(Z)-2g
94
(R)
Likewise, a screening with different ADH′s concerning the
saturated γ-keto esters 4 was performed (Scheme 5). Therefore,
the more easily accessible racemic substrates (rac)-4a-g were
used. In table 3 the screening results with ADH′s for the racemic
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substrate C4-nBu [(rac)-4c] are shown. The reduction of the keto
functionalities to the saturated alcohols 5 lead to a spontaneous
lactonisation to the desired γ-butyrolactones 1. For the
nBu-substituted substrate (rac)-4c only ADH-R showed an
acceptable conversion of 48%. The stereoselectivity with
30:64:5:1 (assignments of absolute configurations were not
always possible) was in favour of the trans-configured lactones
1c. Again, the absolute configurations were determined
functionality. For comparison, references and yields for known
synthesized γ-butyrolactones 1 (as depicted in Figure 3) are also
shown in Table 4. Obviously, it is important to note that some of
these methods require enantiomeric pure starting materials or
intermediates.
Whereas the double bond reduction proceeds with
quantitative enantioselectivity and very good conversions
(76–99%), the second reduction with an ADH seems to be the
limiting step in our enzyme cascade resulting in lower overall
conversions (17–81%) and yields (9–73%). It is also worth noting
that the reduction of (Z)-2g by Opr1 never exceeded 76% and the
substrate signal overlaid with one of the lactone signals
determined by GC. Therefore, the final stereoselectivity of lactone
(2R,4S)-1g was determined after getting rid of the substrate
retrospectively based on the lactones
1 (see Supporting
Information). For all other substrates [(rac)-4b,d-g] ADH-R was
the only enzyme converting the γ-keto esters [(rac)-4b,d-g] in
acceptable conversion rates and good stereoselectivity. The
ethyl-substituted γ-keto ester (rac)-4a was transformed by ADH-R
(54% conv., sel.: 2:0:94:5) and, as the only one, by ADH-LB (63%
conv., sel.: 37:1:10:53) and ADH-T (56% conv., sel.: 1:0:99:0) in
good conversion rates. As expected, the enantioselectivity of
ADH-LB and ADH-T are complementary to each other, whereas
ADH-R and ADH-T yield the same enantiomers. If the
butyl-chain-position was permutated, the substrates were still too
bulky for ADH-LB and ADH-T, although the methyl-substituent is
next to the keto functionality making one side of the substrate
smaller. Hence, for these substrates [(rac)-4f,g] again ADH-R was
the suitable enzyme. In conclusion, the carbonyl group of the
ethyl-substituted γ-keto ester (rac)-4a could be reduced
stereocomplementary by using ADH-LB and ADH-T.[14]
Substrates with longer chain lengths [(rac)-4b-g] were only
reducible with ADH-R, so our screening results highlight ADH-R
again to reduce even ′bulky-bulky′ ketones.[15]
(Z)-2g by column chromatography. However, in
a
semi-preparative scale (100 mg) reduction of (Z)-2g, where the
substrate was completely reduced by Opr1, led to 88% ee and a
very good stereoselectivity of 0:4:1:94 with a conversion of 79%.
These results point out that the enzyme-cascade can be applied
also to (Z)-2g leading to very good stereoselectivity, but the full
conversion in gram scale was not achieved in our case due to
long reaction times and the risk of side reactions due to
contaminations of the reaction media. Nevertheless, the
γ-butyrolactones 1a-g were obtained in most cases as a single
stereoisomer with characteristic odour properties depending on
the chain length and substitution pattern. Varying the chain length
from ethyl to n-hexyl results in an odour shift from walnut over
coconut to peach. The permutation of the n-butyl chain to
3-position (1f) leads to a turpentine-like odour, whereas the
permutation to 2-position (1g) results in a less characteristic
coconut odour of quercus lactone (1c), which is more herbal.
Conclusions
Scheme 5. Reaction sequence for the screening of alcohol dehydrogenases
(ADH).
In this work, we presented the chemoenzymatic synthesis of
various γ-butyrolactones 1a-g starting from α,β-unsaturated
γ-keto esters 2 readily obtained by a HWE-reaction. The
consecutive enzyme cascade using ene reductases and
alcohol dehydrogenases enabled us to synthesize these
γ-butyrolactone fragrances 1 in preparative scale (1 g). We found
that the ene reductase NcrZM is able to reduce substrates with
different alkyl chain length and substitution pattern. Though, the
substrates 2 bind through the keto moiety rather than the ester
functionality to the active site, which lead to the same enantiomers
with E- and Z-configured α,β-unsaturated γ-keto esters 2. Only
the E/Z-isomers of substrate 2g gave different enantiomers, as
expected. This is due to the fact, that the nBu chain is located on
Cβ where the hydride transfer occurs and depending on the E/Z-
configuration the substrate flips causing a re- and si-facial
hydride-attack, respectively. The further reduction of the keto
group from n-propyl substitution on was only possible with ADH-R
as catalyst, which points out the bulkiness of the substrates 2b-g
for all other alcohol dehydrogenases. By this systematic approach,
in most cases only one stereoisomer of the γ-butyrolactones (1)
Table 3. Alcohol dehydrogenase screening results for C-4-nBu [(rac)-4c].
substrate
product
enzyme
(rac)-4c
1c
conv. (%)
dr (%)
ADH-R
ADH-LB
ADH-T
48
1
30:64:5:1
40:60:0:0
0:100:0:0
n.a.
1
ADH-HL
0
Finally, the ER and ADH were combined in a consecutive one-pot
reaction to form the different γ-butyrolactone fragrances 1a-g in a
preparative scale. The results of these reactions are summarized
in Table 4. In nearly all cases NcrZM was used as ene reductase
leading to enantioselectivity of >99% ee. Only in case of
compound (Z)-2g Opr1 was used yielding an ee-value of 82%.
ADH-LB and ADH-T were only used to convert the ethyl
substituted α,β-unsaturated γ-keto ester 2a. For all other
substrates (2b-g) ADH-R was used to reduce the keto
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Table 4. Synthesized γ-butyrolactones (1) and their odour properties.
Yield
Starting Material
Conversion[b]
Selectivities[b]
Odour[d]
ER
ADH
Product
Literature results
[(E)/(Z)-ratios][a]
36% yield
53% conv.
99% ee
ADH-LB
(68 U/mmol)
sel.: 0:2:0:98
walnut
80% yield (3R,4S)-1a;[16]
66% yield (3S,4S)-1a[17]
NcrZM
(2.5 U/mmol)
(3R,4S)-1a
(3R,4R)-1a
69% yield
80% conv.
99% ee
sel.: 0:>99:0:0
walnut
2a
[0:1]
ADH-T
(38 U/mmol)
46% yield (3R,4S)
17% yield (3R,4S + 3R,4R)
51% conv.
NcrZM
(2.5 U/mmol)
ADH-R
(276 U/mmol)
17% yield, trans:cis 16:1;[18]
42% yield, (rac)-1b[19]
>99% ee
sel.: 11:78:0:10
coconut
2b
[1:10]
(3R,4S)-1b
(3R,4S)-1c
73% yield
78% conv.
>99% ee
sel.: 0:98:0:2
coconut
NcrZM
(2.5 U/mmol)
ADH-R
(139 U/mmol)
63% yield (3S,4R)-1c;[20]
77% yield (3S,4S)-1c, dr. 98:2[21]
2c
[1:5]
35% yield (3R,4S)
7% yield (3R,4S + 3R,4R)
2% yield (3R,4R)
78% conv.
5–36% yield, >99% ee;[22]
72–74% yield (3S,4R) and (3S,4S)-1d;[20-21]
78% yield, 99% ee[23]
NcrZM
(2.5 U/mmol)
ADH-R
(318 U/mmol)
99% ee
sel.: 0:87:0:13
peach (3R,4S)
walnut (3R,4R)
2d
[0:1]
(3R,4S)-1d
9% yield
17% conv.
>99% ee
sel.: 0:98:0:2
peach
NcrZM
(2.5 U/mmol)
ADH-R
(579 U/mmol)
83–84% yield (3S,4S) and (3R,4R)-1e;[24]
95% yield (3S,4R)-1e[25]
2e
[0:1]
(3R,4S)-1e
(3S,4S)-1f
16% yield
37% conv.
>99% ee
NcrZM
(4.6 U/mmol)
ADH-R
(222 U/mmol)
72% yield, trans/cis 95:5[26]
sel.: 10:2:0:88
turpentine
2f
[0:1]
49% yield
63% conv.
>99% ee
sel.: 0:82:18:0
coconut, sweet
NcrZM
(10.8 U/mmol)
ADH-R
(217 U/mmol)
74% yield, trans/cis 1:1;[27]
(E)-2g
(Z)-2g
(2S,4S)-1g
(2R,4S)-1g
51% yield, 95% ee, trans/cis 1:49[28]
26% yield
62% conv.
Opr1
(6.9 U/mmol)
ADH-R
(35 U/mmol)
82% ee
sel.: 0:58:0:42[c]
coconut, herbal
[a] Determined by 1H-NMR before adding to the reaction.
[b] Determined by chiral GC.
[c] Determined after column chromatography due to overlap of the substrate
signal with one of the lactone signals.
[d] Assigned on subjective perception.
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controlled by chiral GC. The reaction mixture was extracted three times
with diethyl ether (approx. 30 mL). The combined organic layers were dried
over MgSO4, filtered, concentrated under reduced pressure and purified
by column chromatography (n-pentane/acetone 98:2).
could be synthesized, but with excellent enantio- (82–>99%) and
in most case very good selectivity (0:58:0:42 to 0:>99:0:0).The
olfactometric properties of these lactones 1a-g vary not only with
the chain length, but also with the substitution pattern. However,
γ-butyrolactone fragrances 1a-g smelling like walnut, coconut,
peach, and celery are synthesized stereoselectively and easily by
a chemoenzymatic approach starting from achiral starting
materials.
(R)-Ethyl 3-methyl-4-oxohexanoate (4a). The desired product (R)-4a
(73 mg, 0.42 mmol, >48% yield, >99% conv., 99% ee) was obtained as
colourless oil. The analytical data are in accordance with literature.[30] Rf
(n-pentane/acetone
80:20) = 0.62.
1H-NMR
(600 MHz,
CDCl3): δ [ppm] = 1.07 (t, J = 7.3 Hz, 3 H, 6-H), 1.13 (d, J = 7.2 Hz, 3 H,
1′′-H), 1.24 (t, J = 7.1 Hz, 3 H, 2′-H), 2.29 (dd, J = 16.8 Hz, J = 5.3 Hz, 1 H,
2-H), 2.56 (qq, J = 17.9 Hz, J = 7.3 Hz, 2 H, 5-H), 2.78 (dd, J = 16.8 Hz,
J = 8.9 Hz, 1 H, 2-H), 3.01 (dqd, J = 9.0 Hz, J = 7.2 Hz, J = 5.2 Hz, 1 H,
3-H), 4.10 (q, J = 7.2 Hz, 2 H, 1′-H). 13C-NMR (151 MHz,
CDCl3): δ [ppm] = 7.87 (C-6, CH3), 14.31 (C-2′, CH3), 17.01 (C-1′′, CH3),
34.50 (C-5, CH2), 37.29 (C-2, CH2), 41.88 (C-3, CH), 60.66 (C-1′, CH2),
172.51 (C-1, Cquat), 213.67 (C-4, Cquat). IR (film), ṽ [cm-1]: 2979, 2940, 1733
(COOR), 1709 (C=O), 1460, 1411, 1377, 1347, 1272, 1252, 1186, 1095,
1027, 979, 859, 802, 734. MS (EI, 70 eV): m/z (%) = 172 (1) [(M)+], 143
(57) [(M-C2H5)+], 127 (58) [(C7H11O2)+], 115 (42) [(C6H11O2)+], 101 (6)
[(C6H13O)+], 97 (1) [(C5H5O2)+], 87 (17) [(C4H7O2)+], 73 (16) [(C3H5O2)+], 69
Experimental Section
Chemicals and materials
Chemicals were purchased from Alfa Aesar, Carl Roth and Sigma-Aldrich
in analytical grade. The phosphonates 3 for the HWE reactions are
synthesized as described in the Supporting Information. The products
were purified by column chromatography on silica gel 60
(0.040–0.063 mm) from Macherey-Nagel (40–63 μm, 230–400 mesh). The
products were followed on TLC plate purchased from Macherey-Nagel,
Polygram® SIL G/UV245. The phosphonate spots were stained with
anisaldehyde solution and the γ-keto esters with cer(IV)-containing
phosphomolybdic acid solution. NMR-spectra were recorded on
Bruker Avance/DRX 600 spectrometer using CDCl3 (δ = 7.26 ppm) with
TMS (δ = 0.00 ppm) as internal standard. For the signal assigning
DEPT135, COSY, HSQC, HMBC and NOESY were measured. IR spectra
were obtained on PerkinElmer SpectrumOne spectrometer. GC/MS
spectra were determined by Thermo Elektron MAT 95 and GC spectra by
ThermoQuest (TRACETM GC) with different types of chiral columns [FS
(8)
GC: tR [min] = 23.8 [(R), 99% ee], 24.2 [(S)] (FS Lipodex G, 60 °C-5 min,
1 °C/min to 100 °C, 10 °C/min to 150 °C-1 min). Optical
rotation: [α]20D = +46 (c = 1, CHCl3, 99% ee).
[(C4H5O)+],
57
(100)
[(C3H5O)+].
GC/MS: tR [min] = 7.14.
(R)-Ethyl 3-methyl-4-oxoheptanoate (4b). The desired product (R)-4b
(38.5 mg, 0.21 mmol, >25% yield, 62% conv., 99% ee) was obtained as
colourless oil. The analytical data are in accordance with literature.[31] Rf
(n-pentane/acetone
80:20) = 0.67.
1H-NMR
(600 MHz,
CDCl3): δ [ppm] = 0.91 (td, J = 7.4 Hz, 3 H, 7-H), 1.12 (d, J = 7.3 Hz, 3 H,
1′′-H), 1.23 (t, J = 7.1 Hz, 3 H, 2′-H), 1.57–1.65 (m, 2 H, 6-H), 2.27 (dd,
J = 16.8 Hz, J = 5.3 Hz, 1 H, 2-H), 2.42–2.58 (m, 2 H, 5-H), 2.76 (dd,
J = 16.8 Hz, J = 8.9 Hz, 1 H, 2-H), 2.99 (dqd, J = 9.2 Hz, J = 7.3 Hz,
J = 5.8 Hz, 1 H, 3-H), 4.10 (q, J = 7.1 Hz, 2 H, 1′-H). 13C-NMR (151 MHz,
CDCl3): δ [ppm] = 13.89 (C-7, CH3), 14.32 (C-2′, CH3), 16.85 (C-1′′, CH3),
17.17 (C-6, CH2), 37.15 (C-2, CH2), 42.14 (C-3, CH), 43.25 (C-5, CH2),
60.66 (C-1′, CH2), 172.51 (C-1, Cquat), 213.09 (C-4, Cquat). IR (film),
ṽ [cm-1]: 2967, 2937, 2878, 1733 (COOR), 1712 (C=O), 1459, 1409, 1376,
1271, 1185, 1120, 1096, 1025, 954, 904, 860, 747. MS (EI, 70 eV): m/z
(%) = 186 (4) [(M)+], 171 (<1) [(M-CH4)+], 158 (9) [(M-C2H4)+], 141 (52)
[(M-C2H5O)+], 125 (3) [(C7H9O2)+], 115 (36) [(C6H11O2)+], 101 (4)
[(C5H9O2)+], 95 (3) [(C6H7O)+], 87 (13) [(C4H7O2)+], 71 (100) [(C4H7O)+], 55
(7) [(C3H3O)+]. GC/MS: tR [min] = 7.98. GC: tR [min] = 30.7 [(R), 99% ee],
30.3 [(S)] (Hydrodex β-TBDAc, 60 °C-5 min, 2 °C/min to 130 °C-10 °C/min
to 150 °C-1 min). Optical rotation: [α]20D = +47 (c = 1, CHCl3, 99% ee).
Lipodex
diameter = 25 m/0.25 mm/0.40 mm),
(Macherey-Nagel, length/inner
diameter = 25 m/0.25 mm/0.40 mm), Hydrodex β-3P (Macherey-Nagel,
length/inner diameter/outer diameter = 25 m/0.25 mm/0.40 mm) and
G
(Macherey-Nagel,
length/inner
diameter/outer
β-TBDAc
diameter/outer
Hydrodex
CP-Chirasil-DEX
CB
(Agilent
Technologies,
length/inner
diameter = 25 m/0.25 mm)]. The nomenclature differs from the IUPAC
nomenclature to have a uniform formation of name and number of the
substrates throughout the paper.
Expression and purification of enzymes
The enzymes nicotinamide-dependent 2-cyclohexen-1-one reductases
from
Photorhabdus luminescence (NcrPL), 12-Oxophytodienoate reductases
(Opr1 EC: 1.3.1.42) and Opr3 EC: 1.3.1.42) from
Lycopersicon esculentum, old yellow enzyme (Oye, EC: 1.6.99.1) from
Saccharomyces carlsbergensis, YqjM (Oye homologue) from
Zymomonas mobilis
(NcrZM
,
EC: 1.6.99.1)
and
(R)-Ethyl 3-methyl-4-oxooctanoate (4c). The desired product (R)-4c
(<118 mg, 0.59 mmol, <78% yield, 82% conv., >99% ee) was obtained as
colourless oil. The analytical data are in accordance with literature.[32] Rf
Bacillus subtilis (EC: 1.6.99.1), TsER (Oye homologue, chromate
reductase[29]) from Thermus scotoductus SA-01 (EC: 1.6.99.1), alcohol
dehydrogenases from Ralstonia sp. (ADH-R), Lactobacillus brevis
(ADH-LB) (EC: 1.1.1.2), Thermoanaerobacter sp. (ADH-T, EC: 1.1.1.80)
and horse liver (ADH-HL, EC: 1.1.1.1) were overexpressed in
E. coli BL21 (DE3). The expression and purification of ene reductases was
done like described in our previous work.[13b] The purification of TsER was
done by heat shock (70 °C, 1.5 h) instead of metal chelate affinity
chromatography. The ADH′s were used as crude extracts.
(n-pentane/acetone
95:5) = 0.29.
1H-NMR
(600 MHz,
CDCl3): δ [ppm] = 0.91 (t, J = 7.4 Hz, 3 H, 8-H), 1.12 (d, J = 7.2 Hz, 3 H,
1′′-H), 1.24 (t, J = 7.1 Hz, 3 H, 2′-H), 1.31 (sext, J = 7.4 Hz, 2 H, 7-H),
1.52–1.61 (m, 2 H, 6-H), 2.27 (dd, J = 16.7 Hz, J = 5.3 Hz, 1 H, 2-H),
2.47–2.57 (m, 2 H, 5-H), 2.76 (dd, J = 16.7 Hz, J = 8.8 Hz, 1 H, 2-H), 3.00
(ddd, J = 8.9 Hz, J = 7.2 Hz, J = 5.3 Hz, 1 H, 3-H), 4.10 (q, J = 7.1 Hz, 2 H,
1′-H). 13C-NMR (151 MHz, CDCl3): δ [ppm] = 14.04 (C-8, CH3), 14.32 (C-2′,
CH3), 16.91 (C-1′′, CH3), 22.51 (C-7, CH2), 25.84 (C-6, CH2), 37.18 (C-2,
CH2), 41.08 (C-5, CH2), 42.16 (C-3, CH), 60.66 (C-1′, CH2), 172.51 (C-1,
Cquat), 213.20 (C-4, Cquat). IR (film), ṽ [cm-1]: 2961, 2935, 2875, 1733
(COOR), 1712 (C=O), 1460, 1410, 1377, 1344, 1271, 1185, 1123, 1099,
1029, 996, 859, 805, 730. MS (EI, 70 eV): m/z (%) = 200 (<1) [(M)+], 171
(<1) [(M-C2H5)+], 155 (44) [(M-C2H5O)+], 112 (32) [(C7H12O)+], 85 (91)
Enzymatic reduction with ene reductases
In a two-necked flask the α,β-unsaturated γ-keto esters 2 (150 mg, 0.66–
0.88 mmol) were dissolved in glucose (9.1 mL, 0.1 M in KPi buffer [20 mM,
pH 6.5]) with NADP+ (500 µL, 20 mM in KPi buffer [20 mM, pH 6.5]), GDH
(50 µL). NcrZM (2.5–5 U/mmol) or Opr1 (5 U/mmol) was added and the
reaction mixture was stirred overnight at 30 °C. The pH-value was kept
constant at pH 6.5 by a pH-stat with NaOH (1 M). The conversion was
[(C5H9O)+],
57
(100)
[(C4H9)+].
GC/MS: tR [min] = 8.82.
GC: tR [min] = 51.44 [(R), >99% ee], 49.3 [(S)] (Hydrodex β-TBDAc,
This article is protected by copyright. All rights reserved.

10.1002/cctc.201801040
ChemCatChem
FULL PAPER
90 °C-60 min, 5 °C/min to 150 °C-5 min). Optical rotation: [α]25D = +26.6
(c = 1, MeOH, >99% ee) [literature: [α]25D = +9.2 (c = 1, MeOH)].[32]
50 °C-60 min, 0.2 °C/min to 105 °C-5 min, 10 °C/min to 150 °C-5 min).
Optical rotation: [α]20D = -72.9 (c = 1, CHCl3, >99% ee).
(R)-Ethyl 3-methyl-4-oxononanoate (4d). The desired product (R)-4d
(20 mg, 90 µmol, >13% yield, 91% conv., >99% ee) was obtained as
colourless oil. The analytical data are in accordance with literature.[12] Rf
Ethyl 2-butyl-4-oxopentanoate (4g). The desired products (R)-4g
(<92 mg, 0.5 mmol, <45% yield, 90% conv., 94% ee) and (S)-4g (<97 mg,
0.5 mmol, <49% yield, 99% conv., >99% ee) were obtained as colourless
oils.[33] Rf (n-pentane/acetone 80:20) = 0.58. 1H-NMR (600 MHz,
CDCl3): δ [ppm] = 0.88 (t, J = 7.0 Hz, 3 H, 4′-H), 1.25 (t, J = 7.1 Hz, 3 H,
2′-H), 1.20–1.35 (m, 4 H, 2′′-H, 3′-H), 1.48 (ddd, J = 12.6 Hz, J = 8.2 Hz,
J = 6.5 Hz, 1 H, 1′′-H), 1.59 (dq, J = 13.8 Hz, J = 6.6 Hz, 1 H, 1′′-H), 2.15
(s, 3 H, 5-H), 2.48 (dd, J = 16.9 Hz, J = 3.8 Hz, 1 H, 3-H), 2.81–2.92 (m,
2 H, 2-H, 3-H), 4.13 (qd, J = 7.1 Hz, J = 1.4 Hz, 2 H, 1′-H). 13C-NMR
(151 MHz, CDCl3): δ [ppm] = 14.03 (C-4′, CH3), 14.36 (C-2′, CH3), 22.65
(C-2′′/C-3′′, CH2), 29.29 (C-2′′/C-3′′, CH2), 30.21 (C-5, CH3), 31.79 (C-1′′,
CH2), 40.27 (C-2, CH), 45.19 (C-3, CH2), 60.60 (C-1′, CH2), 175.61 (C-1,
Cquat), 207.08 (C-4, Cquat). IR (film), ṽ [cm-1]: 2959, 2934, 2863, 1717
(C=O), 1466, 1402, 1365, 1223, 1179, 1160, 1043, 1023, 952, 871, 782,
730. MS (EI, 70 eV): m/z (%) = 200 (2) [(M)+], 185 (7) [(M-CH3)+], 171 (1)
[(M-C2H5)+], 155 (88) [(M-C2H5O)+], 143 (100) [(M-C3H5O)+], 129 (22)
[(C8H17O)+], 115 (95) [(C7H15O)+], 109 (37) [(C7H9O)+], 101 (91)
[(C6H13O)+], 83 (67) [(C6H11)+], 73 (84) [(C3H5O2)+], 67 (11) [(C5H7)+], 55
(67) [(C4H7)+]. GC/MS: tR [min] = 9.76. GC: tR [min] = 144.5 [(R), 94% ee],
146.8 [(S), >99% ee] (CP-Chirasil-DEX, 50 °C-60 min, 0.5 °C/min to
120 °C-5 min). Optical rotation: [α]20D = -19.9 [c = 1, CHCl3, 97% ee, (R)],
+19.0 [c = 1, CHCl3, >99% ee, (S)].
(n-pentane/acetone
80:20) = 0.73.
1H-NMR
(600 MHz,
CDCl3): δ [ppm] = 0.89 (t, J = 7.2 Hz, 3 H, 9-H), 1.12 (d, J = 7.2 Hz, 3 H,
1′′-H), 1.24 (t, J = 7.1 Hz, 3 H, 2′-H), 1.25–1.37 (m, 4 H, 7-H, 8-H),
1.54–1.63 (m, 2 H, 6-H), 2.27 (dd, J = 16.7 Hz, J = 5.3 Hz, 1 H, 2-H),
2.45–2.60 (m, 2 H, 5-H), 2.76 (dd, J = 16.7 Hz, J = 8.8 Hz, 1 H, 2-H), 2.99
(dqd, J = 8.8 Hz, J = 7.2 Hz, J = 5.3 Hz, 1 H, 3-H), 4.10 (q, J = 7.1 Hz, 2 H,
1′-H). 13C-NMR (151 MHz, CDCl3): δ [ppm] = 14.09 (C-9, CH3), 14.32 (C-2′,
CH3), 16.90 (C-1′′, CH3), 22.64 (C-7/C-8, CH2), 23.41 (C-6, CH2), 31.58
(C-7/C-8, CH2), 37.18 (C-2, CH2), 41.34 (C-5, CH2), 42.15 (C-3, CH), 60.66
(C-1′, CH2), 172.51 (C-1, Cquat), 213.22 (C-4, Cquat). IR (film), ṽ [cm-1]: 2959,
2934, 2875, 1734 (COOR), 1714 (C=O), 1460, 1409, 1376, 1343, 1273,
1183, 1099, 1029, 859, 727. MS (EI, 70 eV): m/z (%) = 213 (1) [(M-H)+],
169 (23) [(M-C2H5O)+], 158 (32) [(M-C4H8)+], 143 (18) [(M-C5H11)+], 125
(15) [(C7H9O2)+], 112 (48) [(C6H8O2)+], 99 (100) [(C6H11O)+], 87 (8)
[(C4H7O2)+], 71 (67) [(C5H11)+], 55 (24) [(C3H3O)+]. GC/MS: tR [min] = 9.62.
GC: tR [min] = 71.8 [(R), >99% ee], 72.1 [(S)] (Hydrodex β-TBDAc,
90 °C-60 min, 5 °C/min to 150 °C-5 min). Optical rotation: [α]25D = +37
(c = 1, CHCl3, >99% ee).
(R)-Ethyl 3-methyl-4-oxodecanoate (4e). The desired product (R)-4e
(27 mg, 0.12 mmol, >18% yield, 79% conv., >99% ee) was obtained as
colourless oil. Rf (n-pentane/acetone 80:20) = 0.81. 1H-NMR (600 MHz,
CDCl3): δ [ppm] = 0.88 (t, J = 6.8 Hz, 3 H, 10-H), 1.12 (d, J = 7.2 Hz, 3 H,
1′′-H), 1.24 (t, J = 7.2 Hz, 3 H, 2′-H), 1.28 (tq, J = 8.6 Hz, J = 5.1 Hz, 4 H,
7-H, 8-H, 9-H), 1.54–1.63 (m, 2 H, 6-H), 2.28 (dd, J = 16.7 Hz, J = 5.3 Hz,
1 H, 2-H), 2.52 (q, J = 7.6 Hz, 2 H, 5-H), 2.76 (dd, J = 16.7 Hz, J = 8.8 Hz,
1 H, 2-H), 3.00 (ddt, J = 8.6 Hz, J = 6.9 Hz, J = 3.5 Hz, 1 H, 3-H), 4.10 (q,
J = 7.1 Hz, 2 H, 1′-H). 13C-NMR (151 MHz, CDCl3): δ [ppm] = 14.19 (C-10,
CH3), 14.33 (C-2′, CH3), 16.90 (C-1′′, CH3), 22.66 (C-7/C-8/C-9, CH2),
23.70 (C-6, CH2), 29.07 (C-7/C-8/C-9, CH2), 31.79 (C-7/C-8/C-9, CH2),
37.19 (C-2, CH2), 41.39 (C-5, CH2), 42.15 (C-3, CH), 60.66 (C-1′, CH2),
172.52 (C-1, Cquat), 213.23 (C-4, Cquat). IR (film), ṽ [cm-1]: 2930, 2859, 1734
(COOR), 1714 (C=O), 1460, 1410, 1377, 1271, 1185, 1030, 861, 755. MS
(EI, 70 eV): m/z (%) = 228 (1) [(M)+], 199 (<1) [(M-C2H5)+], 183 (34)
[(M-C2H5O)+], 171 (1) [(M-C4H5)+], 158 (55) [(M-C5H10)+], 143 (23)
[(M-C7H11O3)+], 125 (13) [(C8H13O)+], 113 (100) [(C7H13O)+], 95 (8)
[(C6H7O)+], 85 (13) [(C6H13)+], 69 (9) [(C4H5O)+], 55 (18) [(C3H3O)+].
GC/MS: tR [min] = 10.23. GC: tR [min] = 46.2 [(R), >99% ee], 47.1 [(S)]
(Hydrodex β-3P, 60 °C-5 min, 5 °C/min to 130 °C-30 min, 10 °C/min to
180 °C-5 min). Optical rotation: [α]20D = -83.9 (c = 0.49, CHCl3, >99% ee).
One-pot enzyme cascade towards γ-butyrolactones (1)
In a two-necked flask the α,β-unsaturated γ-keto esters 2 (1.00 g,
4.42–5.88 mmol), NADP+ (3.33 mL, 20 mM in KPi buffer [20 mM, pH 6.5]),
GDH (333 µL), glucose (61 mL, 0.1 M in KPi buffer [20 mM, pH 6.5]) and
NcrZM (2.5–10.8 U/mmol) or Opr1 (6.9 U/mmol) were dissolved. The
reaction mixture was stirred overnight at 30 °C and the pH-value was kept
constant at pH 6.5 by a pH-stat with NaOH (1 M). The conversion was
controlled by chiral GC. Then, ADH-LB (68 U/mmol), ADH-T (38 U/mmol)
or ADH-R (35–579 U/mmol) was added together with NADP+ (3.33 mL,
20 mM in KPi buffer [100 mM, pH 7]), GDH (333 µL), glucose (61 mL, 0.1 M
in KPi buffer [100 mM, pH 7]) and MgCl2 (6.5 mL, 1 mM, 5-Vol%). The
reaction mixtures were stirred at 30 °C until maximal conversions could be
reached and the pH-value was kept constant at pH 6.5 by a pH-stat with
NaOH (1 M). The conversion was controlled by chiral GC. Afterwards the
mixtures were extracted three times with diethyl ether (approx. 200 mL).
Due to a bad phase separation, the interphases were centrifuged (5 min,
max. rcf). The combined organic layers were dried over MgSO4, filtered,
concentrated under reduced pressure. Lactonisation occurred by
acidification with conc. H2SO4 in diethyl ether, if necessary. Purification
was done by column chromatography [n-pentane/acetone (98:2) or
n-pentane/CH2Cl2 (60:40)] for the separation of lactone 1g from the
saturated γ-keto ester 4g. For the detection of the lactones 1, the fractions
were led to concentrate overnight in the fume hood and then observed by
TLC, GC and through its olfactometric properties, resulting in lower
isolated yields.
(S)-Ethyl 3-butyl-4-oxopentanoate (4f). The desired product (S)-4f
(<98 mg, 0.5 mmol, <48% yield, 90% conv., >99% ee) was obtained as
colourless oil. Rf (n-pentane/acetone 80:20) = 0.72. 1H-NMR (600 MHz,
CDCl3): δ [ppm] = 0.89 (t, J = 7.1 Hz, 3 H, 4′-H), 1.24 (t, J = 7.2 Hz, 3 H,
2′-H), 1.21–1.28 (m, 2 H, 3′-H), 1.29–1.35 (m, 2 H, 2′′-H), 1.41 (dq,
J = 13.7 Hz, J = 7.2 Hz, 1 H, 1′′-H), 1.60 (ddt, J = 18.7 Hz, J = 11.8 Hz,
J = 4.8 Hz, 1 H, 1′′-H), 2.23 (d, J = 1.2 Hz, 3 H, 5-H), 2.34 (dd, J = 16.8 Hz,
J = 4.5 Hz, 1 H, 2-H), 2.73 (dd, J = 16.8 Hz, J = 9.8 Hz, 1 H, 2-H), 2.97
(ddd, J = 10.9 Hz, J = 8.8 Hz, J = 5.7 Hz, 1 H, 3-H), 4.10 (q, J = 7.4 Hz,
2 H, 1′-H). 13C-NMR (151 MHz, CDCl3): δ [ppm] = 13.98 (C-4′, CH3), 14.31
(C-2′, CH3), 22.82 (C-2′′, CH2), 29.20 (C-3′, CH2), 29.72 (C-5, CH3), 31.18
(C-1′′, CH2), 35.46 (C-2, CH2), 48.03 (C-3, CH), 60.73 (C-1′, CH2), 172.67
(C-1, Cquat), 211.23 (C-4, Cquat). IR (film), ṽ [cm-1]: 2959, 2934, 2863, 1733
(COOR), 1712 (C=O), 1467, 1412, 1372, 1352, 1251, 1184, 1161, 1099,
1026, 963, 860, 787, 730. MS (EI, 70 eV): m/z (%) = 201 (<1) [(M+H)+],
185 (1) [(M-CH3)+], 171 (<1) [(M-C2H5)+], 155 (64) [(M-C2H5O)+], 144 (86)
[(M-C4H8)+], 129 (7) [(C8H17O)+], 115 (76) [(C7H15O)+], 98 (100)
[(C5H6O2)+], 88 (16) [(C4H8O2)+], 83 (38) [(C6H11)+], 73 (42) [(C3H5O2)+], 67
(3R,4R)-4-Ethyl-3-methyldihydrofuran-1(3H)-one (1a). The desired
product (3R,4R)-1a (273 mg, 2.13 mmol, 36% yield, 57% conv., 99% ee,
sel.: 0:>99:0:0) was obtained as colourless oil and has a walnut odour. The
analytical data are in accordance with literature.[17,
Rf
34]
(n-pentane/acetone 80:20) = 0.57. (600 MHz,
1H-NMR
CDCl3): δ [ppm] = 0.96–1.06 (m, 6 H, 1′-H, 2′-H), 1.52–1.61 (m, 1 H, 1′′-H),
1.69 (ddq, J = 14.5 Hz, J = 8.9 Hz, J = 7.4 Hz, 1 H, 1′′-H), 2.19 (dd,
J = 17.0 Hz, J = 4.1 Hz, 1 H, 2-H), 2.59 (dddd, J = 13.4 Hz, J = 7.5 Hz,
J = 4.5 Hz, J = 2.9 Hz, 1 H, 3-H), 2.69 (dd, J = 17.0 Hz, J = 7.9 Hz, 1 H,
2-H), 4.35 (dt, J = 8.9 Hz, J = 5.5 Hz, 1 H, 4-H). 13C-NMR (151 MHz,
CDCl3): δ [ppm] = 10.44 (C-2′, CH3), 13.87 (C-1′, CH3), 23.17 (C-1′′, CH2),
32.96 (C-3, CH), 37.71 (C-2, CH2), 85.21 (C-4, CH), 177.03 (C-1, Cquat).
IR (film), ṽ [cm-1]: 2970, 2882, 1765 (lactone), 1461, 1422, 1387, 1339,
1292, 1215, 1174, 1147, 1075, 1026, 975, 958, 930, 883, 862, 775, 701.
(5)
[(C5H7)+],
55
(49)
[(C4H7)+].
GC/MS: tR [min] = 9.91.
GC: tR [min] = 221.2 [(S), >99% ee], 223.8 [(R)] (CP-Chirasil-DEX,
This article is protected by copyright. All rights reserved.

10.1002/cctc.201801040
ChemCatChem
FULL PAPER
MS (EI, 70 eV): m/z (%) = 128 (2) [(M)+], 99 (100) [(M-C2H5)+], 84 (4)
[(C6H12)+], 71 (40) [(C5H11)+], 59 (55) [(C2H3O2)+]. GC/MS: tR [min] = 6.52.
GC: tR [min] = 31.9 [(3R,4R), 99% ee, dr: 0:>99:0:0] 31.3 (3S,4S), 27.5
sel.: 0:98:2:0], 71.1 (3S,4R), 73.3 (3S,4S), 73.6 (3R,4R) (Hydrodex
β-TBDAc,
90 °C-60 min,
5 °C/min
to
150 °C-5 min).
Optical
rotation: [α]20D = -89.0 (3R,4S) (c = 1, MeOH, >99% ee, >99% de)
[literature: [α]20D = -95 (3R,4S), +96 (3S,4R) (c = 1.0-1.6, MeOH)].[8]
(3S,4R), 28.8 (3R,4S) (FS Lipodex G, 60 °C-5 min, 1 °C/min to 100 °C,
10 °C/min to 150 °C-1 min). Optical rotation: [α]20D = +75 (3R,4R) (c = 2,
CHCl3, >99% ee, >99% de) [literature: [α]D = -34.4 (3S,4S) (c = 2,
CHCl3)].[17]
(3R,4S)-
and
(3R,4R)-3-Methyl-4-pentyldihydrofuran-2(3H)-one
(cognac lactone) (1d). The desired product (3R,4S)-1d (282 mg,
1.66 mmol, 35% (3R,4S), 7% (3R,4S + 3R,4R), 2% (3R,4R) yield, 79%
conv., 99% ee, sel.: 0:87:0:13) was obtained as colourless oil and has a
(3R,4S)-4-Ethyl-3-methyldihydrofuran-2(3H)-one (1a). The desired
product (3R,4S)-1a (516 mg, 4.03 mmol, 69% yield, 87% conv., 99% ee,
sel.: 0:2:0:98) was obtained as colourless oil and has a walnut odour. The
peach (3R,4S) or walnut (3R,4R) odour. The analytical data are in
23, 37]
accordance with literature.[21,
(3R,4S)-1d: Rf (n-pentane/acetone
80:20) = 0.57. 1H-NMR (600 MHz, CDCl3): δ [ppm] = 0.87–0.92 (m, 3 H,
5-H), 1.13 (d, J = 6.5 Hz, 3 H, 1′-H), 1.26–1.37 (m, 4 H, 3′-H, 4′-H),
1.34–1.45 (m, 1 H, 1′′-H), 1.52 (dddd, J = 12.6 Hz, J = 7.0 Hz, J = 5.7 Hz,
J = 3.5 Hz, 1 H, 1′′-H), 1.55–1.63 (m, 1 H, 2′-H), 1.67 (dddd, J = 14.2 Hz,
J = 10.1 Hz, J = 5.9 Hz, J = 3.9 Hz, 1 H, 2′-H), 2.13–2.28 (m, 2 H, 2-H,
3-H), 2.60–2.73 (m, 1 H, 2-H), 4.00 (td, J = 7.8 Hz, J = 3.9 Hz, 1 H, 4-H).
13C-NMR (151 MHz, CDCl3): δ [ppm] = 14.12 (C-5, CH3), 17.64 (C-1′, CH3),
22.63 (C-3′/C-4′, CH2), 25.55 (C-1′′, CH2), 31.71 (C-3′/C-4′, CH2), 34.13
(C-2′, CH2), 36.22 (C-3, CH), 37.28 (C-2, CH2), 87.61 (C-4, CH), 176.73
(C-1, Cquat). IR (film), ṽ [cm-1]: 2959, 2933, 2862, 1772 (lactone), 1459,
1423, 1382, 1330, 1206, 1169, 1125, 1072, 1002, 937, 861, 815, 756, 728,
662. MS (EI, 70 eV): m/z (%) = 170 (<1) [(M)+], 142 (2) [(M-C2H4)+], 128
(4) [(M-C3H6)+], 110 (5) [(C6H6O2)+], 99 (100) [(C5H7O2)+], 83 (12)
[(C4H3O2)+], 71 (26) [(C5H11)+], 55 (15) [(C4H7)+]. GC/MS: tR [min] = 9.13.
GC: tR [min] = 7.0 [(3R,4S), 99% ee, sel.: 0:87:0:13], 6.6, 8.8, 9.5 (3R,4R)
(Hydrodex β TBDAc, 150 °C-10 min). Optical rotation: [α]20D = -96.8
(3R,4S) (c = 1, CHCl3, >99% ee, >99% de) [literature: [α]25D = +72.3
(3S,4R) (c = 1, CHCl3), [α]20D = -73.4 (3R,4S) (c = 0.22, CHCl3)].[23]
(3R,4R)-1d: Rf (n-pentane/acetone 80:20) = 0.48. 1H-NMR (600 MHz,
CDCl3): δ [ppm] = 0.90 (td, J = 5.6 Hz, J = 4.4 Hz, J = 2.2 Hz, 3 H, 5-H),
1.01 (d, J = 7.1 Hz, 3 H, 1′-H), 1.28–1.42 (m, 5 H, 2′-H, 3′-H, 4′-H),
1.44–1.56 (m, 2 H, 1′′-H, 2′-H), 1.60–1.74 (m, 1 H, 1′′-H), 2.19 (dd,
J = 17.1 Hz, J = 4.0 Hz, 1 H, 2-H), 2.57 (dddd, J = 10.4 Hz, J = 8.8 Hz,
J = 7.0 Hz, J = 2.9 Hz, 1 H, 3-H), 2.69 (dd, J = 17.0 Hz, J = 7.9 Hz, 1 H,
2-H), 4.43 (ddd, J = 9.3 Hz, J = 5.7 Hz, J = 4.1 Hz, 1 H, 4-H). 13C-NMR
(151 MHz, CDCl3): δ [ppm] = 13.99 (C-1′, CH3), 14.12 (C-5, CH3), 22.64
(C-3′/C-4′, CH2), 25.73 (C-2′, CH2), 30.01 (C-1′′, CH2), 31.77 (C-3′/C-4′,
CH2), 33.17 (C-3, CH), 37.71 (C-2, CH2), 83.85 (C-4, CH), 177.07 (C-1,
Cquat). IR (film), ṽ [cm-1]: 2930, 2861, 1772 (lactone), 1459, 1422, 1382,
1334, 1290, 1213, 1166, 1077, 1007, 975, 932, 863, 730. MS (EI,
70 eV): m/z (%) = 169 (<1) [(M-H)+], 142 (2) [(M-C2H4)+], 128 (3)
[(M-C3H6)+], 110 (5) [(C6H6O2)+], 99 (100) [(C5H7O2)+], 83 (16) [(C4H3O2)+],
71 (24) [(C5H11)+], 55 (17) [(C4H7)+]. GC/MS: tR [min] = 9.43.
GC: tR [min] = 9.5 [(3R,4R), >99% ee, sel.: 0:87:0:13], 6.6 (3S,4R), 7.0
(3R,4S), 8.8 (3S,4S) (Hydrodex β-TBDAc, 150 °C-10 min). Optical
rotation: [α]20D = +46 (3R,4R) (c = 1, CHCl3, >99% ee, >99% de)
[literature: [α]20D = -64.8 (3S,4S) (c = 1.23, CHCl3)].[21]
35]
analytical data are in accordance with literature.[16,
Rf
(n-pentane/acetone
80:20) = 0.55.
1H-NMR
(600 MHz,
CDCl3): δ [ppm] = 1.03 (t, J = 7.4 Hz, 3 H, 2′-H), 1.14 (d, J = 7.4 Hz, 3 H,
1′-H), 1.58–1.68 (m, 1 H, 1′′-H), 1.70–1.80 (m, 1 H, 1′′-H), 2.14–2.30 (m,
2 H, 2-H, 3-H), 2.63–2.72 (m, 1 H, 2-H), 3.96 (td, J = 7.5 Hz, J = 4.2 Hz,
1 H, 4-H). 13C-NMR (151 MHz, CDCl3): δ [ppm] = 10.12 (C-2′, CH3), 17.74
(C-1′, CH3), 27.06 (C-1′′, CH2), 35.68 (C-3, CH), 37.31 (C-2, CH2), 88.77
(C-4, CH), 176.70 (C-1, Cquat). IR (film), ṽ [cm-1]: 2969, 2936, 2881, 1770
(lactone), 1460, 1423, 1384, 1360, 1334, 1283, 1266, 1216, 1175, 1156,
1119, 1071, 1034, 972, 926, 859, 844, 776, 756, 661. MS (EI, 70 eV): m/z
(%) = 128 (3) [(M)+], 99 (100) [(M-C2H5)+], 84 (5) [(C6H12)+], 71 (39)
[(C5H11)+], 59 (40) [(C2H3O2)+]. GC/MS: tR [min] = 6.22. GC: tR [min] = 28.8
[(3R,4S), 99% ee, dr: 0:2:0:98], 27.5 (3S,4R), 31.3 (3S,4S), 31.9 (3R,4R)
(FS Lipodex G, 60 °C-5 min, 1 °C/min to 100 °C, 10 °C/min to
150 °C-1 min). Optical rotation: [α]25D = -148 (3R,4S) (c = 1, CHCl3,
>99% ee, >99% de) [literature: [α]D = +66.7 (3S,4R) (neat)].[16]
(3R,4S)-3-Methyl-4-propyldihydrofuran-2(3H)-one (1b). The desired
product (3R,4S)-1b (484 mg, 3.40 mmol, 46% (3R,4S) and 17%
(3R,4S + 3R,4R) yield, 63% conv., >99% ee, sel.: 0:88:0:12) was obtained
as colourless oil and has a coconut odour. The analytical data are in
accordance with literature.[18, 35-36] Rf (n-pentane/acetone 80:20) = 0.42.
1H-NMR (600 MHz, CDCl3): δ [ppm] = 0.95 (t, J = 7.3 Hz, 3 H, 3′-H), 1.13
(d, 3J = 6.0 Hz, 3 H, 1′-H), 1.44 (tdd, J = 13.4 Hz, J = 11.6 Hz, J = 7.0 Hz,
2 H, 2′-H), 1.51–1.72 (m, 2 H, 1′′-H), 2.05–2.28 (m, 2 H, 2-H, 3-H),
2.56–2.74 (m, 1 H, 2-H), 4.01 (td, J = 7.3 Hz, J = 3.9 Hz, 1 H, 4-H).
13C-NMR (151 MHz, CDCl3): δ [ppm] = 14.00 (C-3′, CH3), 17.60 (C-1′,
CH3), 19.19 (C-2′, CH2), 36.25 (C-3, C-1′′, CH2, CH), 37.27 (C-2, CH2),
87.35 (C-4, CH), 176.74 (C-1, Cquat). IR (film), ṽ [cm-1]: 2962, 2936, 2876,
1772 (lactone), 1459, 1424, 1383, 1330, 1309, 1255, 1214, 1173, 1123,
1074, 1018, 977, 934, 889, 862, 821, 747, 662. MS (EI, 70 eV): m/z
(%) = 142 (1) [(M)+], 128 (<1) [(M-CH2)+], 124 (3) [(C8H12O)+], 114 (5)
[(C6H10O2)+], 99 (100) [(M-C3H7)+], 71 (35) [(C4H7O)+], 55 (20) [(C4H7)+].
GC/MS: tR [min] = 7.23.
GC: tR [min] = 24.8
[(3R,4S),
99% ee,
sel.: 11:78:0:10], 23.5 (3S,4R), 25.9 (3S,4S), 26.2 (3R,4R) (FS Lipodex G,
60 °C-5 min, 2 °C/min to 130 °C-10 °C/min to 150 °C-1 min). Optical
rotation: [α]20D = -36.2 (3R,4S) (c = 1, CHCl3, >99% ee, >99% de).
(3R,4S)-4-Hexyl-3-methyldihydrofuran-2(3H)-one (1e). The desired
product (3R,4S)-1e (73.6 mg, 0.40 mmol, 9% yield, 17% conv., >99% ee,
sel.: 0:98:0:2) was obtained as colourless oil and has a peach odour. The
(3R,4S)-4-Butyl-3-methyldihydrofuran-2(3H)-one (quercus lactone)
(1c). The desired product (3R,4S)-1c (578 mg, 3.70 mmol, 73% yield, 78%
conv., >99% ee, sel.: 0:98:2:0) was obtained as colourless oil and has a
coconut odour. The analytical data are in accordance with literature.[8] Rf
38]
analytical data are in accordance with literature.[24-25,
Rf
(n-pentane/acetone
80:20) = 0.55.
1H-NMR
(600 MHz,
(n-pentane/acetone
95:5) = 0.12.
1H-NMR
(600 MHz,
CDCl3): δ [ppm] = 0.89 (t, J = 6.8 Hz, 3 H, 6-H), 1.14 (d, J = 6.3 Hz, 3 H,
1′-H), 1.24–1.36 (m, 6 H, 3′-H, 4′-H, 5-H), 1.39 (dddd, J = 13.0 Hz,
J = 9.5 Hz, J = 6.3 Hz, J = 3.6 Hz, 1 H, 2′-H), 1.47–1.56 (m, 1 H, 1′′-H),
1.56–1.64 (m, 1 H, 1′′-H), 1.67 (dddd, J = 14.2 Hz, J = 10.1 Hz, J = 5.8 Hz,
J = 3.9 Hz, 1 H, 2′-H), 2.13–2.27 (m, 2 H, 2-H, 3-H), 2.61–2.72 (m, 1 H,
2-H), 4.00 (td, J = 7.3 Hz, J = 3.8 Hz, 1 H, 4-H). 13C-NMR (151 MHz,
CDCl3): δ [ppm] = 14.20 (C-6, CH3), 17.65 (C-1′, CH3), 22.69 (C-4′, CH2),
25.84 (C-1′′, CH2), 29.21 (C-3′, CH2), 31.80 (C-5, CH2), 34.19 (C-2′, CH2),
36.23 (C-3, CH), 37.30 (C-2, CH2), 87.62 (C-4, CH), 176.74 (C-1, Cquat).
IR (film), ṽ [cm-1]: 2930, 2859, 1775 (lactone), 1459, 1423, 1381, 1331,
1289, 1256, 1209, 1168, 1156, 1126, 1075, 1002, 968, 937, 863, 726, 662.
MS (EI, 70 eV): m/z (%) = 185 (<1) [(M+H)+], 155 (<1) [(M-C2H5)+], 142
(14) [(M-C3H6)+], 124 (8) [(C7H8O2)+], 115 (6) [(C7H15O)+], 99 (100)
CDCl3): δ [ppm] = 0.92 (t, J = 7.1 Hz, 3 H, 4′-H), 1.14 (d, J = 6.3 Hz, 3 H,
1′-H), 1.37 (dddd, J = 13.8 Hz, J = 10.5 Hz, J = 9.1 Hz, J = 6.0 Hz, 3 H,
3′-H, 2′-H), 1.47–1.54 (m, 1 H, 1′′-H), 1.56–1.64 (m, 1 H, 1′′-H), 1.68 (dddd,
J = 14.3 Hz, J = 10.1 Hz, J = 5.5 Hz, J = 3.9 Hz, 1 H, 2′′-H), 2.15–2.26 (m,
2 H, 2-H, 3-H), 2.63–2.71 (m, 1 H, 2-H), 4.01 (td, J = 7.8 Hz, J = 3.9 Hz,
1 H, 4-H). 13C-NMR (151 MHz, CDCl3): δ [ppm] = 13.89 (C-4′, CH3), 17.50
(C-1′, CH3), 22.48 (C-2′/C-3′, CH2), 27.83 (C-2′/C-3′, CH2), 33.70 (C-1′′,
CH2), 36.07 (C-3, CH), 37.13 (C-2, CH2), 87.46 (C-4, CH), 176.59 (C-1,
Cquat). IR (film), ṽ [cm-1]: 2959, 2933, 2874, 1772 (lactone), 1459, 1424,
1383, 1331, 1284, 1255, 1210, 1170, 1124, 1078, 984, 926, 942, 855, 786,
733, 662. MS (EI, 70 eV): m/z (%) = 157 (4) [(M+H)+], 138 (6) [(M-H2O)+],
99 (100) [(M-C4H9)+], 84 (54) [(C4H4O2)+], 69 (15) [(C5H9)+], 51 (47).
GC/MS: tR [min] = 7.79.
GC: tR [min] = 71.5
[(3R,4S),
>99% ee,
This article is protected by copyright. All rights reserved.

10.1002/cctc.201801040
ChemCatChem
FULL PAPER
[(M-C6H13)+], 86 (2) [(C4H6O2)+], 71 (24) [(C5H11)+], 55 (18) [(C4H7)+].
130 °C, 2 °C/min to 160 °C-5 min). Optical rotation: [α]20D = -36.9 (2S,4S)
(c = 0.73, CHCl3, >99% ee, 96% de, 98% purity).
GC/MS: tR [min] = 9.91.
sel.: 0:98:0:2], 29.2 (3S,4R), 32.9 (3S,4S), 34.0 (3R,4R) (Hydrodex
β-TBDAc, 60 °C-5 min, 5 °C/min to 150 °C-15 min). Optical
GC: tR [min] = 29.9
[(3R,4S),
>99% ee,
rotation: [α]20D = -65.6 (3R,4S) (c = 1, CHCl3, >99% ee, >99% de)
[literature: [α]23D = -57.6 (3S,4S) (c = 1.06, CHCl3)], [α]12D = +56.7 (3R,4R)
(c = 2.47, CHCl3)].[24]
Acknowledgements
We gratefully acknowledge the Heinrich-Heine-Universität
Düsseldorf and the Forschungszentrum Jülich GmbH for the
support of our projects. We thank Dr. Frank Hollmann and
Diederik Johannes Opperman for providing the gene of TsER, as
well as Birgit Henßen, Bea Paschold, Dr. Dalia Bulut, Julia
Lackner and Lisa Seibt for their support in syntheses, cloning and
protein purification, and establishing of GC-methods.
(3S,4S)-3-Butyl-4-methyldihydrofuran-2(3H)-one (1f). The desired
product (3S,4S)-1f (129 mg, 0.83 mmol, 16% yield, 37% conv., >99% ee,
sel.: 10:2:0:88) was obtained as colourless oil and has a turpentine odour.
39]
The analytical data are in accordance with literature.[26,
Rf
(n-pentane/acetone
80:20) = 0.49.
1H-NMR
(600 MHz,
CDCl3): δ [ppm] = 0.91 (t, J = 7.0 Hz, 3 H, 4′-H), 1.19–1.29 (m, 4 H, 1′-H,
2′-H, 3′-H), 1.27 (d, J = 6.6 Hz, 3 H, 1′′-H), 1.29–1.38 (m, 4 H, 1′-H, 2′-H,
3
3′-H), 1.41–1.51 (m, 1 H, 1′-H), 2.27 (dd, J = 16.3 Hz, J2,3 = 8.0 Hz, 1 H,
2-H), 2.46–2.59 (m, 2 H, 2-H, 3-H), 4.70 (quin, J = 6.6 Hz, 1 H, 4-H).
13C-NMR (151 MHz, CDCl3): δ [ppm] = 14.08 (C-4′, CH3), 15.57 (C-1′′,
CH3), 22.84 (C-2′/3′, CH2), 28.50 (C-1′, CH2), 30.05 (C-2′/3′, CH2), 33.94
(C-2, CH2), 39.07 (C-3, CH), 79.54 (C-4, CH), 176.90 (C-1, Cquat). IR (film),
ṽ [cm-1]: 2958, 2931, 2874, 2860, 1772 (lactone), 1459, 1387, 1336, 1171,
1043, 973, 924, 831, 647, 555. MS (EI, 70 eV): m/z (%) = 156 (1) [(M)+],
141 (7) [(M-CH3)+], 128 (1) [(M-C2H4)+], 112 (5) [(M-C3H8)+], 99 (1) [(M-
C7H9)+], 95 (13) [(C7H11)+], 84 (100) [(C4H4O2)+], 70 (41) [(C4H6O)+], 56 (80)
[(C4H8)+]. GC/MS: tR [min] = 9.78. GC: tR [min] = 22.9 [(3S,4S), >99 %ee,
sel.: 10:2:0:88], 21.6, 21.9, 22.7 (3R,4R) (CP-Chirasil-DEX, 60 °C-5 min,
5 °C/min to 150 °C-5 min). Optical rotation: [α]20D = +17.9 (3S,4S) (c = 1,
CHCl3, >99% ee, 99% de) [literature: [α]D = -44 (3R,4S) (c = 0.4,
CDCl3)].[39c]
Keywords: γ-butyrolactone • flavour and fragrance •
ene reductase • enzyme cascade • alcohol dehydrogenase
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a) R. Bandichhor, B. Nosse, O. Reiser, Top. Curr. Chem. 2005,
243, 43-72; b) L. Lv, B. Shen, Z. Li, Angew. Chem. Int. Ed. Engl.
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(2R,4S)- and (2S,4S)-2-Butyl-4-methyldihydrofuran-2(3H)-one (1g).
The desired product (2R,4S)-1g (208 mg, 1.33 mmol, 26% yield, 62%
conv., 82% ee, sel.: 0:58:0:42) was obtained as colourless oil and has a
sweet coconut odour. The product (2S,4S)-1g (382.3 mg, 2.45 mmol, 49%
yield, 63% conv., >99% ee, sel.: 0:82:18:0) was obtained as colourless oil
and has a herbal coconut odour. The analytical data are in accordance
with literature.[27-28] (2R,4S)-1g: Rf (n-pentane/acetone 80:20) = 0.65.
1H-NMR (600 MHz, CDCl3): δ [ppm] = 0.91 (t, J = 7.0 Hz, 3 H, 4′-H), 1.37
(d, J = 6.4 Hz, 3 H, 1′′-H), 1.29–1.41 (m, 4 H, 2′-H, 3′-H), 1.41–1.51 (m,
1 H, 1′-H), 1.78–1.89 (m, 1 H, 1′-H), 1.41–2.01 (ddd, J = 12.8 Hz,
J = 9.0 Hz, J = 5.0 Hz, 1 H, 3-H), 2.08 (dt, J = 12.8 Hz, J = 7.4 Hz, 1 H,
3-H), 2.62 (tdd, J = 9.1 Hz, J = 7.4 Hz, J = 5.1 Hz, 1 H, 2-H), 4.61–4.71 (m,
1 H, 4-H). 13C-NMR (151 MHz, CDCl3): δ [ppm] = 14.00 (C-4′, CH3), 21.40
(C-1′′, CH3), 22.58 (C-2′/3′, CH2), 29.67 (C-2′/3′, CH2), 30.57 (C-1′, CH2),
35.28 (C-3, CH2), 39.47 (C-2, CH), 75.02 (C-4, CH), 179.48 (C-1, Cquat).
IR (film), ṽ [cm-1]: 2958, 2933, 2859, 1764 (lactone), 1458, 1384, 1343,
1170, 1103, 1034, 959. MS (EI, 70 eV): m/z (%) = 156 (<1) [(M)+], 141 (7)
[(M-CH3)+], 113 (14) [(M-C3H7)+], 100 (100) [(M-C4H8)+], 84 (8) [(C6H12)+],
69 (20) [(C5H9)+], 55 (43) [(C4H7)+]. GC/MS: tR [min] = 9.22.
GC: tR [min] = 24.7 [(2R,4S), 82% ee, sel.: 0:58:0:42], 23.9 (2R,4R), 24.2
(2S,4S), 24.4 (2S,4R) (Hydrodex β-TBDAc, 60 °C-5 min, 5 °C/min to
130 °C, 2 °C/min to 160 °C-5 min). Optical rotation: [α]20D = -4.6 (2R,4S)
(c = 1, CHCl3, 99% ee, >99% de). (2S,4S)-1g: Rf (n-pentane/acetone
80:20) = 0.69. 1H-NMR (600 MHz, CDCl3): δ [ppm] = 0.88–0.95 (m, 3 H,
4′-H), 1.27–1.38 (m, 4 H, 2′-H, 3′-H), 1.41 (d, J = 6.2 Hz, 4 H, 1′-H, 1′′-H),
1.48 (td, J = 12.2 Hz, J = 10.4 Hz, 2 H, 3-H), 1.87–1.99 (m, 1 H, 1′-H), 2.47
(ddd, J = 12.3 Hz, J = 8.5 Hz, J = 5.4 Hz, 1 H, 3-H), 2.59 (dtd, J = 13.0 Hz,
J = 8.8 Hz, J = 4.6 Hz, 1 H, 2-H), 4.47 (dt, J = 10.0 Hz, J = 5.8 Hz, 1 H,
4-H). 13C-NMR (151 MHz, CDCl3): δ [ppm] = 14.04 (C-4′, CH3), 21.15
(C-1′′, CH3), 22.61 (C-2′/3′, CH2), 29.69 (C-2′/3′, CH2), 30.17 (C-1′, CH2),
37.18 (C-3, CH2), 41.64 (C-2, CH), 75.22 (C-4, CH), 179.22 (C-1, Cquat).
IR (film), ṽ [cm-1]: 2959, 2931, 2858, 1769 (lactone), 1457, 1388, 1343,
1279, 1175, 1120, 1069, 952, 700, 628. MS (EI, 70 eV): m/z (%) = 156
(<1) [(M)+], 141 (2) [(M-CH3)+], 113 (13) [(M-C3H7)+], 100 (100) [(M-C4H8)+],
69 (16) [(C5H9)+], 55 (38) [(C4H7)+]. GC/MS: tR [min] = 9.16. GC:
tR [min] = 24.2 [(2S,4S), >99% ee, sel.: 0:82:18:0], 23.9 (2R,4R), 24.7
(2R,4S), 24.4 (2S,4R) (Hydrodex β-TBDAc, 60 °C-5 min, 5 °C/min to
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a) J. Fenneteau, S. Vallerotto, L. Ferrié, B. Figadère, Tetrahedron
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Org. Chem. 2004, 2004, 4995-5002; d) B. Cheng, F. Wu, X. Yang,
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Entry for the Table of Contents
Layout 1:
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Choosing the odour:
Ceyda Kumru, Thomas Classen, and
Jörg Pietruszka*
An enzymatic cascade reaction
utilizing an ene reductase and alcohol
dehydrogenases allows the
Page No. – Page No.
Enantioselective, Catalytic One-Pot
Synthesis of γ-Butyrolactone-Based
Fragrances
enantioselective synthesis of various
fragrances the scent depending not
only on the substituent, but also on
their configuration.
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