Chemoenzymatic one-pot synthesis of γ-butyrolactones

Article abstract of DOI:10.1002/adsc.201100110

The synthesis of enantio- and diastereomerically pure γ- butyrolactones is described using a one-pot, two-enzyme cascade. Ethyl 2-methyl-4-oxopent-2-enoate (2) was reduced selectively first in a 1,4-reduction using the old yellow enzyme (OYE1) [EC 1.6.99.1] and consecutively in a 1,2-reduction by an alcohol dehydrogenase [EC 1.1.1.2]. Copyright

Full text of DOI:10.1002/adsc.201100110

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DOI: 10.1002/adsc.201100110
Chemoenzymatic One-Pot Synthesis of g-Butyrolactones
Margarete Korpaka and Jçrg Pietruszkaa,*
a
Institut fꢀr Bioorganische Chemie der Heinrich-Heine-Universitꢁt Dꢀsseldorf im Forschungszentrum Jꢀlich, Stetternicher
Forst, Geb. 15.8, 52426 Jꢀlich, Germany
Fax : (+49)-2461-616-196; e-mail: j.pietruszka@fz-juelich.de
Received: February 14, 2011; Published online: June 16, 2011
Abstract: The synthesis of enantio- and diastereo-
merically pure g-butyrolactones is described using a
one-pot, two-enzyme cascade. Ethyl 2-methyl-4-
oxoACHTUNGTRENNUNGpent-2-enoate (2) was reduced selectively first
in a 1,4-reduction using the old yellow enzyme
(OYE1) [EC 1.6.99.1] and consecutively in a 1,2-re-
duction by an alcohol dehydrogenase [EC 1.1.1.2].
Keywords: alcohol dehydrogenase; asymmetric cat-
alysis; asymmetric synthesis; ene reductase; en-
zymes; reduction
Figure 1. g-Butyrolactones 1 – key building blocks in natural
Although enzymes cannot replace every traditional product syntheses, for example, for amphidinolide B1.
heavy metal catalyst, biocatalysts are recognized as a
promising alternative to improve the efficiency and
sustainability of reactions.[1] It is not only basic chemi- multiple reaction and purification steps. Therefore,
cals that are produced by means of biotechnological elaboration of novel, efficient routes to prepare 2,4-
processes: also key building blocks for natural prod- dimethylbutyrolactone (1) or its derivatives is highly
uct synthesis are increasingly synthesized using bioca- desirable. Here, we present for the first time the che-
talytical steps or sequences.[2] Recently, ene reductases moenzymatic synthesis of lactone 1 in a two-step,
have attracted considerable interest due to their abili- one-pot reaction from ethyl 2-methyl-4-oxopent-2-
ty to reduce C=C-double bonds bearing an electron- enoate (2) using an ene reductase (old yellow
withdrawing group in a defined, well understood and enzyme, OYE1) and different alcohol dehydrogenases
stereoselective manner.[3] However, while high con- (ADH) (Figure 2).
version and excellent selectivity were regularly ob-
The first step in our route was the preparation of
served, compared to alcohol dehydrogenases scalable the substrate for the enzymatic transformations: g-
applications for the synthesis beyond model com-
pounds are scarce.
In this context and in view of our on-going interest
in chemoenzymatic approaches towards lactones for
natural products,[4] we also intended to approach g-
lactones.[5] Substituted enantiomerically pure g-lac-
tones are precursors for structural elements of various
natural product families as well as pharmacologically
active compounds. In particular, the subclass of a,g-
disubstituted g-butyrolactones 1 has been utilized as
key building block in a variety of syntheses, including
natural targets such as milbemycin b3, jasplakinolide,
and the amphidinolides (Figure 1).[6] However, the
syntheses described for building blocks 1 regularly
depend on cost intensive starting materials or require Figure 2. Routes towards lactones 1 from olefin 2.
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Chemoenzymatic One-Pot Synthesis of g-Butyrolactones
oxoACHTUNGTRENNUNGpentenoate 2 was readily available starting with a (92%), whereas enantiomerically pure product (S)-6
Wittig olefination of ethyl pyruvate (3) with phos- was synthesized from (S)-ethyl lactate (7). Aldehyde
phoranylideneacetone (4). The (E)-olefin 2 was ob- 8 was formed after TBS-protection (TBS: tert-butyldi-
tained as the major isomer in the presence of the methylsilyl) and selective reduction with DiBAlH
minor (Z)-olefin 2 in good yield (90%, dr 95:5).[7] Al- (90% yield over two steps).[8] Olefination with phos-
ternatively, employing the Still–Gennari protocol uti- phonate 9 yielded the silyl ether 10 (78%, dr 80:20)
lizing phosphonate 5, the (Z)-product 2 was obtained that was readily deprotected with TBAF forming the
as major component (90%, dr 38:62; Scheme 1).
desired reference compound (S)-6 (69%).[9] Gas chro-
matographic separation of the enantiomers was ach-
ieved using Lipodex G as chiral stationary phase
(vide infra).
Initial activity tests for the reduction of ketone (E)-
2 with a number of alcohol dehydrogenases indicated
that highest conversion was observed using the en-
zymes ADH-T (from Thermoanaerobacter species re-
combinant in Escherichia coli) and ADH-LK (from
Lactobacillus kefir).[10] The enantioselectivity as deter-
mined by GLC was excellent (ee>99%) in both cases
providing (R)- and (S)-alcohols 6, respectively. The
findings could be completely reproduced on a prepa-
rative scale now including the recycling of the cofac-
tor with isopropyl alcohol (9 vol%; Scheme 3): reduc-
tion with ADH-T led to the (S)-enantiomer (S)-6 (in
100 mM KPi buffer, pH 7: 95%, ee>99%) while
ADH-LK provided the (R)-enantiomer (R)-6 (in
100 mM KPi buffer, pH 7: 85%, ee>99%). The abso-
lute configurations were confirmed by comparison of
the retention times (see Figure 3) as well as the opti-
Scheme 1. Synthesis of g-oxopentenoates 2. Reagents and
conditions: a) THF, 3 h, À788C to room temperature; b)
KHMDS, 18-C-6, THF, 3 h, À788C to room temperature.
Next, we wished to investigate the enzymatic reduc-
tion. To enable reliable detection and assignment of
product 6, reference compounds were synthesized by
conventional methods (Scheme 2). Racemic alcohol 6
was obtained from ketone (E)-2 by NaBH4 reduction
Scheme 2. Synthesis of reference compounds. Reagents and
conditions: a) NaBH4, Et2O/MeOH, 08C, 30 min; b) TBSCl,
DMAP, imidazole, CH2Cl2, 3 h, 08C to room temperature;
c) DiBAlH, CH2Cl2, 3 h, À788C to room temperature; d)
KHMDS, 18-C-6, THF, 3 h, À788C to room temperature; e)
TBAF, THF, 2 h, room temperature.
Scheme 3. Enzymatic reduction of ketone 2 on a preparative
scale. Reagents and conditions: substrate 2 (6.4 mmol), KPi
buffer (100 mM, pH 7, 1 mM MgCl2), NADP (0.032 mmol),
ADH-solution (~40 U), 9 vol% i-PrOH, 308C, 24 h.
Adv. Synth. Catal. 2011, 353, 1420 – 1424
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Margarete Korpak and Jçrg Pietruszka
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Scheme 5. Enzymatic reduction of olefin 2 on a preparative
scale. Reagents and conditions: Substrate 2 (6.4 mmol), KPi
buffer (100 mM, pH 7), NADP (0.064 mmol), glucose
(250 mM), GDH (~10 U), OYE1 (~15 U), 308C, 250 rpm,
8 h.
Figure 3. GLC trace for the enzymatic reduction of ketone
(E)-2 on a preparative scale. Reaction conditions: Lipodex
G, H2 (0.6 bar), 608C (5’ iso), 58CminÀ1 to 1508C, (5’ iso) tR
[(R)-6]=18.45 min, tR [(S)-6]=18.95 min.
(Scheme 5). The product 11 was isolated in good yield
(92%) and excellent enantiomeric excess (ee>99%;
Figure 4).
Finally, the g-butyrolactone 1 was obtained by sub-
cal rotations with literature data.[9a,11] It should be sequent enzymatic reduction of ketone 11 with an al-
noted that these products have been regularly used in cohol dehydrogenase. The bioreduction was per-
the synthesis of biologically active compounds see, formed using both ADH-LK and ADH-T, yielding
e.g., refs.[9,11,12]
the corresponding alcohols followed by spontaneous
After the promising results obtained for the alcohol lactonization to the substituted g-butyrolactones 1.
dehydrogenase catalyzed transformation, we focussed Based on the reported data, the assignment of config-
on the subsequent reduction of the C=C bond utiliz- uration for the lactones (and hence also for the start-
ing the flavoenzyme oxidoreductase from Saccharo- ing ketone 11) was possible, proving that the ADH-
myces carlsbergensis (OYE1 – old yellow enzyme 1; LK gave the anti-product anti-1 (60%, ee>99%),
EC 1.6.99.1),[13] a known ene reductase.[2a–e] However, whereas the syn-configurated lactone syn-1 (80%,
no conditions were found to reduce alcohol 6, while ee>99%) was formed when using ADH-T
the double-activated a,b-unsaturated alkenes 2 readi- (Scheme 6). In order to achieve the ultimate goal, a
ly reacted (Scheme 4). We were surprised to find that one-pot procedure was attempted with both biocata-
independent of the olefin configuration the reduction lytic steps – utilizing first the ene reductase followed
led to the exclusive formation of the (R)-enantiomer by the alcohol dehydrogenase – being integrated in
(ee>99%) of compound 11. When performing the re- one sequence. NADP+/GDH was used as the cofactor
action on a preparative scale, obviously a cofactor re- recycling system of choice for both enzymatic steps.
generation system was required. The use of an ADH As expected, the g-butyrolactones syn-1 and anti-1
was ruled out, since the formation of alcohol 6 would
be an expected side-product. Instead we utilized a
glucose dehydrogenase (GDH; EC 1.1.1.47)[14] oxidiz-
ing glucose. After some optimization (amount of co-
factor NADP/temperature), we could reduce the
olefin 2 on a gram-scale at 308C with high conversion
Scheme 4. Enzymatic reduction of olefins 2 and 6 on an ana-
lytical scale. Reagents and conditions: KPi buffer (50 mM,
pH 7), 20 mL NADPH (50 mM), 100 mL glucose (500 mM),
2 mL GDH, 1 U OYE1, 308C, 600 rpm, 24 h.
Figure 4. GLC trace for the enzymatic reduction of olefin
(E)-2 on a preparative scale. Reaction conditions: Lipodex
G, H2 (0.6 bar), 608C (5’ iso), 58CminÀ1 to 1508C, tR [(R)-
11]=11.60 min, tR [(S)-11]=11.95 min.
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Adv. Synth. Catal. 2011, 353, 1420 – 1424

Chemoenzymatic One-Pot Synthesis of g-Butyrolactones
the organic layer dried over MgSO4, filtered, and the sol-
vents removed under reduced pressure. The crude product
was purified by flash column chromatography on silica gel
(n-pentane:Et2O, 80:20) to afford product syn-1 as a colour-
less oil; yield: 670 mg (5.8 mmol, 90%); [a]2D0: À4.6 (c 1.1 in
CHCl3),[6c] 99% ee as determined by GLC [Lipodex G, H2
(0.6 bar), 608C (5ꢃ iso), 58CminÀ1 to 1508C (iso)]: (2R,4S)-1:
1
tR =10.2 min; H NMR (600 MHz, CDCl3): d=1.28 (d, 3H,
3JMe,2 =7.1 Hz, Me), 1.42 (d, 3JMe,4 =6.2 Hz, 3H, Me), 1.49
(ddd, 2J3a,3b =12.4 Hz, 3J3a,2 =12.1 Hz, 3J3a,4 =10.3 Hz,1H, 3-
3
Ha), 2.50 (ddd, 2J3b,3a =12.4 Hz, 3J3b,2 =8.3 Hz, J3b,4
=
5.3 Hz,1H, 3-Hb), 2.68 (ddq, 2J2,3a =12.1 Hz, 3J2,3b =8.3 Hz,
3
3J2,Me =7.1 Hz, 1H, 2-H), 4.48 (dqd, 3J4,3a =10.3 Hz, J4,Me
=
6.2 Hz, 3J4,3b =5.3 Hz, 1H, 4-H); 13C NMR (151 MHz,
CDCl3): d=15.1 (Me at C-2), 20.9 (Me at C-4), 36.4 (C-2),
Scheme 6. Enzymatic reductions. Reagents and conditions:
substrate 2 or 11 (6.4 mmol), a) KPi buffer (100 mM, pH 7,
1 mM MgCl2), NADP (0.064 mmol), 9 vol% i-PrOH, ADH-
T solution (~70 U), 308C, 250 rpm; b) KPi buffer (100 mM,
pH 7, 1 mM MgCl2), NADP (0.064 mmol), glucose
(250 mM), GDH (~10 U), ADH-LK solution (~160 U),
308C, 250 rpm; c) KPi buffer, NADP, glucose, OYE1
˜
39.1 (C-3), 74.9 (C-4), 179 (C-1); IR (film): n=2977, 2935,
1767, 1455, 1388, 1350, 1180, 1122, 1043, 951, 872, 703 cmÀ1
;
MS (EI, 70 eV): m/z (%)=114 (3) [M+], 99 (21) [MÀCH3 ],
+
+
+
70 (72) [MÀCO2 ], 55 (100) [C4H7 ].[6d]
Synthesis of (2R,4R)-2,4-dimethylbutyrolactone ACHTUNGTRENUNG(anti-1):
Enone 2 (1 g, 6.4 mmol) was placed in 250-mL flask and
100 mL KPi buffer (pH 7), NADP (50 mg, 0.064 mmol),
4.50 g Glucose (250 mM), 10 mL GDH-solutions (~10 U in
KPi buffer, pH 7), 10 mg OYE (lyophilized powder, ~15 U).
The reaction was run for 12 h at 308C. Reaction pH was
controlled through the automated addition of 1M NaOH.
After full conversion was detected (as determined by GLC),
200 mL ADH-LK solution (~50% in glycerol, 160 U) and
10 mL GDH were added. The reaction mixture was stirred
at 308C and 250 rpm (quant. conversion as judged by GLC)
and worked up as described above; yield: 670 mg (5.8 mmol,
90%); [a]20: +36.5 (c 1.1 in CHCl3),[6g] 99% ee as deter-
mined by DGLC [Lipodex G, H2 (0.6 bar), 608C (5ꢃ iso),
58CminÀ1 to 1508C (iso)]: (2R,4R)-1: tR =10.1 min;
ACHTUNGTRENNUNG(~15 U), GDH (~10 U), 308C, 250 rpm, 12 h, then i-PrOH,
ADH-T solution (~70 U), 24 h; d) KPi buffer, NADP, glu-
cose, OYE1 (~15 U), GDH (~10 U), 308C, 250 rpm, 12 h
then ADH-LK solution (~160 U), GDH (~10 U), 24 h. For
details of the one-pot procedures see Experimental Section.
were again synthesized in high enantiopurity (ee>
99%), but gratifyingly also in excellent yields (90%
and 80%, respectively).
In conclusion, we have described a convenient che-
moenzymatic method for the preparation of the two
diastereoisomeric lactones 1 from enone 2 in good
yields and enantiopurity in a one-pot set-up. The ene
reductase catalyzed steps were shown to be scalable
providing enantiomerically pure products in high
yield. It should be noted that also the simple alcohol
6 is a highly desirable building block that was conven-
iently obtained by a direct enzymatic reduction.
3
1H NMR (600 MHz, CDCl3): d=1.28 (d, 3H, JMe,2 =7.4 Hz,
Me), 1.38 (d, 3H, 3JMe3,4 =6.4 Hz, Me), 2.04 (ddd, J3a,3b
=
2
12.8 Hz, 3J3a,2 =7.4 Hz, J3a,4 =7.4 Hz, 1H, 3-Ha), 2.08 (ddd,
2J3b,3a =12.8 Hz, J3b,2 =8.8 Hz, J3b,4 =4.9 Hz, 1H, 3-Hb), 2.73
3
3
3
3
3
(dqd, J2,3b =8.8 Hz, J2,3a =7.8 Hz, J2,Me =7.4 Hz, 1H, 2-H),
3
3
3
4.68 (dqd, J4,3a =7.4 Hz, J4,Me =6.4 Hz, J4,3a =4.9 Hz, 1H, 4-
H); 13C NMR (151 MHz, CDCl3): d=15.7 (Me at C-2), 21.1
(Me at C-4), 34.0 (C-2), 37.1 (C-3), 74.6 (C-4), 179.9 (C-1);
˜
IR (film): n=2977, 2935, 1767, 1455, 1388, 1350, 1180, 1122,
1043, 951, 872, 703 cmÀ1; MS (EI, 70 eV): m/z=114 (3)
+
+
[M+], 99 (36) [MÀCH3 ], 70 (75) [MÀCO2 ], 55 (100)
+
[C4H7 ].[15]
Experimental Section
Representative Procedures for the One-Pot
Reduction:
Acknowledgements
Synthesis of (2R,4S)-2,4-dimethylbutyrolactone ACTHNUGRTNEUNG(syn-1):
Enone 2 (1 g, 6.4 mmol) was placed in 250-mL flask and
50 mL KPi buffer (pH 7), NADP (50 mg, 0.064 mmol),
2.25 g glucose (250 mM), 10 mL GDH solution (~10 U in
KPi buffer, pH 7), 10 mg OYE (lyophilized powder, ~15 U)
were added. The reaction was run for 12 h at 308C. Reac-
tion pH was controlled through the automated addition of
1M NaOH. After full conversion was detected (as deter-
mined by GLC), 200 mL ADH-T solution (~50% in glycerol,
as supplied by Julich Chiral Solutions, 70 U) and 5 mL i-
PrOH (9 vol%) were added. The reactions mixture was
stirred at 308C and 250 rpm (quant. conversion as judged by
GLC). After 48 h the products were extracted with Et2O,
We gratefully acknowledge the Ministry of Innovation, Sci-
ence and Research of the German federal state of North
Rhine-Westphalia, the Deutsche Forschungsgemeinschaft, the
Heinrich Heine University Dꢀsseldorf, and the Forschungs-
zentrum Jꢀlich GmbH for the support of our projects. Gener-
ous gifts of enzymes from Julich Chiral Solutions GmbH
(now Codexis), evocatal GmbH, Prof. Dr. W. Hummel, Prof.
Dr. M. Pohl, and Dipl.-Bioing. Daniel Minçr are greatly ap-
ˇ
ˇ
preciated. We thank Dr. Jirꢁ Palecek for preliminary experi-
ments. We are indebted to Monika Gehsing for performing
the enzyme activity tests.
Adv. Synth. Catal. 2011, 353, 1420 – 1424
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Margarete Korpak and Jçrg Pietruszka
COMMUNICATIONS
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Adv. Synth. Catal. 2011, 353, 1420 – 1424