Chemo-enzymatic synthesis of chiral epoxides ethyl and methyl (S)-3-(Oxiran-2-yl)propanoates from Renewable levoglucosenone: An access to enantiopure (S)-dairy lactone

Article abstract of DOI:10.3390/molecules21080988

Chiral epoxides-such as ethyl and methyl (S)-3-(oxiran-2-yl)propanoates ((S)-1a/1b)-are valuable precursors in many chemical syntheses. Until recently, these compounds were synthesized from glutamic acid in four steps (deamination, reduction, tosylation and epoxide formation) in low to moderate overall yield (20%-50%). Moreover, this procedure requires some harmful reagents such as sodium nitrite ((eco)toxic) and borane (carcinogen). Herein, starting from levoglucosenone (LGO), a biobased chiral compound obtained through the flash pyrolysis of acidified cellulose, we propose a safer and more sustainable chemo-enzymatic synthetic pathway involving lipase-mediated Baeyer-Villiger oxidation, palladium-catalyzed hydrogenation, tosylation and treatment with sodium ethoxide/methoxide as key steps. This route afforded ethyl and methyl (S)-3-(oxiran-2-yl)propanoates in 57% overall yield, respectively. To demonstrate the potentiality of this new synthetic pathway from LGO, the synthesis of high value-added (S)-dairy lactone was undertaken from these epoxides and provided the target in 37% overall yield from LGO.

Full text of DOI:10.3390/molecules21080988

molecules
Article
Chemo-Enzymatic Synthesis of Chiral Epoxides Ethyl
and Methyl (S)-3-(Oxiran-2-yl)propanoates from
Renewable Levoglucosenone: An Access to
Enantiopure (S)-Dairy Lactone
Aurélien A. M. Peru 1,2, Amandine L. Flourat 1,2, Christian Gunawan 3, Warwick Raverty 3,
Martyn Jevric 4, Ben W. Greatrex 4,* and Florent Allais 1,5,
*
1
Chaire ABI—AgroParisTech, CEBB, 3 rue des Rouges Terres, 51110 Pomacle, France;
florent.allais@agroparistech.fr (A.A.M.P.); florent.allais@agroparistech.fr (A.L.F.)
Institut Jean-Pierre Bourgin, INRA, AgroParisTech, CNRS, Université Paris-Saclay, RD10,
78026 Versailles Cedex, France
Circa Group Pty Ltd., 34 Norkfolk Court, Coburg, 3058 Victoria, Australia;
christian.gunawan@circagroup.com.au (C.G.); warwick.raverty@circagroup.com.au (W.R.)
School of Science and Technology, University of New England, Armidale, 2350 New South Wales, Australia;
jevric.m@gmail.com
2
3
4
5
UMR 782 GMPA, INRA, AgroParisTech, CNRS, Université Paris-Saclay, Avenue Lucien Brétignières,
78850 Thiverval-Grignon, France
*
Correspondence: ben.greatrex@une.edu.au (B.W.G.); florent.allais@agroparistech.fr (F.A.);
Tel.: +33-633-698-126 (F.A.)
Academic Editor: Christophe Len
Received: 28 June 2016; Accepted: 23 July 2016; Published: 29 July 2016
Abstract: Chiral epoxides—such as ethyl and methyl (S)-3-(oxiran-2-yl)propanoates ((S)-1a/1b)—are
valuable precursors in many chemical syntheses. Until recently, these compounds were synthesized
from glutamic acid in four steps (deamination, reduction, tosylation and epoxide formation) in low
to moderate overall yield (20%–50%). Moreover, this procedure requires some harmful reagents
such as sodium nitrite ((eco)toxic) and borane (carcinogen). Herein, starting from levoglucosenone
(LGO), a biobased chiral compound obtained through the flash pyrolysis of acidified cellulose, we
propose a safer and more sustainable chemo-enzymatic synthetic pathway involving lipase-mediated
Baeyer-Villiger oxidation, palladium-catalyzed hydrogenation, tosylation and treatment with sodium
ethoxide/methoxide as key steps. This route afforded ethyl and methyl (S)-3-(oxiran-2-yl)propanoates
in 57% overall yield, respectively. To demonstrate the potentiality of this new synthetic pathway from
LGO, the synthesis of high value-added (S)-dairy lactone was undertaken from these epoxides and
provided the target in 37% overall yield from LGO.
Keywords: epoxide; flavor; levoglucosenone; chirality; total synthesis
1. Introduction
Chiral epoxides are widely used as intermediates in organic synthesis. For example, methyl
(S)-3-(oxiran-2-yl)propanoate (1a) has been employed for the synthesis of many compounds such
as elicitor [
1], Streptrubin B [2] or chiral β-3-substituted homopropargyl [3], thiobutyrolactone [4],
γ-hydroxyesters [5], diol-γ or δ-lactones [6], keto-esters [7], (+/´)-4-alkanolides [8] (Figure 1).
Molecules 2016, 21, 988; doi:10.3390/molecules21080988
www.mdpi.com/journal/molecules

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S
O
RO
O
O
O
Si
OH
O
O
O
OH
CO2Me
O
O
O
C7H15
(+/-)-1a
O
HO
O
O
O
R
2
R=Me, Bu or n-C7H15
O
O
O
Figure 1. Some chemical intermediates synthesized from epoxide (+/´)-1a.
Classically, epoxides such as 1a are obtained from (S)-
2H-HBO ), itself derived from glutamic acid (Scheme 1) [
by fermentation on a commercial scale [20]. Glutamic acid is first deaminated to give the intermediate
(S)- -carboxy- -butyrolactone, which was first reported by Austin et al. using nitrous acid [11].
γ
-hydroxymethyl-
γ
-butyrolactone
(
,
2
9–19], a natural amino acid that is produced
γ
γ
The protocol then evolved in 1978 with the use of a light excess of sodium nitrite and HCl instead of
nitrous acid [12] and, to the best of our knowledge, remains unchanged today [13]. Three different
routes have been reported for the reduction of (S)-
is a 2-step procedure involving the esterification of the carboxylic acid followed by its reduction
with NaBH4 [12 14 16]. The second route is quite similar but uses an acid chloride instead of the
carboxylic acid [10]. Finally, the third and last route consists of a one-step reduction of the carboxylic
acid into the alcohol in presence of borane-methylsulfide (BH3-Me2S) [ 17] or borane-THF [18]. It is
noteworthy that the substitution of borane-methylsulfide by borane-THF to obviate odor problems on
large scale [12 19] resulted in over-reduction to the lactol [16]. Although these three routes provide in
γ-carboxy-γ-butyrolactone into 2. The first one
,
–
3,
,
2
good yields, they either require two steps or use a carcinogenic reagent (i.e., BH3-Me2S). The epoxides
are then obtained via the tosylation of 2 followed by treatment with sodium alkoxide.
O
O
O
TsCl, Pyr
DCM
NaNO2, HCl
H2O
BH3.Me2S
O
HO
O
HO
O
HO
OH
O
NH2
2
(S)-γ-carboxy-γ-butyrolactone
L-glutamic acid
NaOMe/MeOH
or
NaOEt/EtOH
O
CO2R
TsO
O
O
(S)-1a (R = Me)
(S)-1b (R = Et)
3a
Scheme 1. Synthesis of epoxides (S)-1a/1b from L-glutamic acid [3,17].
Recently, we reported on the eco-friendly synthesis of
2 by a chemo-enzymatic process from
levoglucosenone (LGO) [21
cellulosic residues, such as softwood sawdust (Furacell
–
25] a valuable chiral chemical platform obtained from flash pyrolysis of
process) [26]. Providing in very good yield
™
2
and high purity through a lipase-based mediated oxidation, this sustainable synthetic pathway has
been studied further by our group as an alternative to the one involving L-glutamic acid to achieve the
synthesis of epoxides (S)-1a and (S)-1b (Scheme 2).

Molecules 2016, 21, 988
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FuracellTM
process
O
O
CO2R
HO
O
O
Cellulose
O
O
2
LGO
(S)-1a (R = Me)
(S)-1b (R = Et)
Scheme 2. Synthesis of epoxides (S)-1a/1b from levoglucosenone (LGO).
Dairy lactone is the common name given by flavor specialists to (Z)-5-(oct-2-en-1-yl)
dihydrofuran-2(3H)-one ( ) (CAS 18679-18-0) of unspecified enantiomeric purity. This lactone, which
occurs naturally in cows’ milk and also the mycelia of Fusarium poae, exhibits a very fruity nuanced
odor (also described as fatty, waxy) as well as a creamy and dairy-like taste, hence its name [27 28].
6
,
Dairy lactone is commonly used in as flavor for bakery and milk products at up to 1 ppm, imitation
dairy at 5 ppm, and fruit sorbet at 1 ppm [29]. Despite its very attractive flavoring properties,
commercial production of dairy lactone remains relatively low (ca. 50 kg/year worldwide). Indeed,
not only is it produced using a costly fermentation process (dairy lactone is sold at ca. 10,000 €/kg) [30
but some customers also complain of a rancid aftertaste in some batches of the flavor. Under these
considerations, an enantioselective synthetic route to individual S and R enantiomers of that leads
]
6
to the commercial production of pure enantiomers is attractive as a solution to these problems
(i.e., production cost and aftertaste). While the enantiomeric composition of commercial dairy lactone
appears not to have been published, there is at least one publication that states that the S-enantiomer
from Fusarium poae is some 3 times stronger in stimulating olefactory response in humans than the
R-enantiomer [28]. Two synthetic pathways have been reported for the preparation of (S)-dairy lactone
(Scheme 3). The first one, reported by Habel et al. [31] starts from an enantiopure glycidyl alkene and
involves an alkynylation with heptynyl lithium followed by an osmium tetroxide-mediated oxidative
cleavage of the double bound to form the lactone, and finally a syn-hydrogenation of the triple bound.
The second pathway developed by Falck consists of the addition of the high order cuprate generated
from (Z)-1-iodo-hept-1-ene onto the epoxides 1a [1,32,33]. Considering that (Z)-1-iodo-hept-1-ene
needs to be synthesized prior to cuprate formation and that its synthesis involves the use of CuCN
˝
and low temperature (
´
78 C), the nucleophilic addition of lithiated 1-heptyne on glycidyls (
S)
-1a/
1b
followed by a syn-hydrogenation of the triple bound (as described in scheme 3—New route), which is
a simpler and safer way to perform this synthesis, has been devised and is described herein.
1)1-Heptyne, BuLi
1) OsO4, oxone, DMF, rt
2) BF3.Et2O, THF, -78 °C
2) H2, Lindlar cat., hexane, rt
C5H11
OH
O
Habel's route28
Falck's route1
New route
87% yield, >>99% ee
85% overall yield, >99% ee
O
O
C5H11
Dairy lactone (6)
C5H11
I
, n-BuLi, Et2O, -60 °C, 20 min
CuCN, -78 °C to -45 °C, 30 min
84%
CO2Me
O
(S)-1a
1-Heptyne
n-BuLi, BF3.Et2O
THF
O
O
OH
p-TsOH, DCM
Lindlar cat., H2, AcOEt
CO2R
O
then H2O
C5H11
CO2R
5
C5H11
(S)-1a (R = Me)
(S)-1b (R = Et)
4a (R = Me)
4b (R = Et)
Scheme 3. Synthetic routes to (S)-dairy lactone (6).

Molecules 2016, 21, 988
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The efficiency (in terms of yield) and green aspects of these new synthetic pathways to ethyl and
methyl (S)-3-(oxiran-2-yl)propanoates as well as (S)-dairy lactone will be discussed with regard to the
yields and green aspects of the route involving L-glutamic acid.
2. Results and Discussion
Herein, we report the use of LGO as starting material to produce ethyl and methyl (S)-3-(oxiran-
2-yl)propanoates (1a and 1b). (S)-Dairy lactone 6, a potentially high-value commercial flavor chemical,
was then synthesized from the two epoxides via an efficient and straightforward pathway.
2.1. Synthesis of Epoxides from Levoglucosenone (LGO)
2.1.1. Synthesis of (S)-γ-Hydroxymethyl-γ-butyrolactone (2)
The synthesis of the epoxides (
-hydroxymethyl- -butyrolactone (
previously developed and optimized [24
palladium-catalyzed hydrogenation of LGO (87%) followed by the Baeyer-Villiger oxidation of the
S)
-1a and (
) from LGO using the two chemo-enzymatic pathways we
25] (Scheme 4). The first one consisted in performing a
S)-1b started with the preparation of key intermediate
(S)-
γ
γ
2
,
resulting saturated LGO (2H-LGO, or Cyrene™) in ethyl acetate and in the presence of hydrogen
peroxide and CAL-B (aka Novozyme 435®, N435 or immobilized lipase Candida antarctica type B);
the subsequent acid hydrolysis of the reaction mixture with Amberlyst 15 IR dry in ethanol then
provides
2 in 65% overall yield. The second pathway involves the exact same reactions but in a
reversed fashion (i.e., Baeyer-Villiger oxidation of LGO, acid hydrolysis and palladium-catalyzed
hydrogenation) providing 2 in 70% overall yield from LGO.
a
d
O
HO
O
87%
80%
FuracellTM
process
O
O
HO
O
Cellulose
O
O
2
O
d
a, b or c
80%, 85% or 75%
LGO
O
O
87%
a: CAL-B, H2O2, AcOEt; b: m-CPBA, p-TsOH; c: AcOOH, H2O; d: Pd/C, H2, EtOH
Scheme 4. Syntheses of (S)-γ-hydroxymethyl-γ-butyrolactone (2) from cellulose.
It is noteworthy that the above Baeyer-Villiger oxidation of LGO can be performed either
chemically—using AcOOH (75%) [34
,
35], zeolites (96% HPLC yield) [36] or m-CPBA (85%) [34,35]—or
enzymatically with a lipase (80%) [24
,
25]. Even though the m-CPBA- and zeolites-based Baeyer-Villiger
oxidations lead to slightly better yields, lipase-mediated Baeyer-Villiger oxidation is preferred
because it avoids not only the use of potentially explosive organic peroxide and harmful organic
solvent (dichloromethane), but also the production of stoichiometric amount of by-product
(i.e., m-chlorobenzoic acid). In addition, the enzyme is used in catalytic amount and can be easily
recycled by simple filtration [24,25].
2.1.2. Synthesis of Ethyl and Methyl (S)-3-(Oxiran-2-yl)propanoates ((S)-1a and ((S)-1b)
Ethyl and methyl (S)-3-(oxiran-2-yl)propanoates ((
steps from (Scheme 5). The primary hydroxyl moiety in compound
tosylation (3a, 84%) and mesylation (3b, 64%) in pyridine/dichloromethane with TsCl and MesCl,
respectively. Epoxides ( -1a and ( -1b were then efficiently obtained by treating the activated
S
)-1a and ((
S)
-1b) were synthesized in two
2
2
was first activated through
S)
S)
lactones with sodium methoxide or ethoxide. The mechanism involves two steps: (1) nucleophilic
attack of sodium methoxide or ethoxide on the lactone to form the corresponding secondary alcoholate

Molecules 2016, 21, 988
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intermediate; and (2) SN2 intramolecular substitution of the tosylate/mesylate by the alkoxide oxygen.
Crude methyl-4,5-epoxypentanoate (( -1a) and ethyl-4,5-epoxypentanoate (( -1b) were thus obtained
in 97% and 96% yields from 3a and in 42% and 86% yields from 3b, respectively. Once purified by
distillation, the optical activity of ( -1a and ( -1b were measured and proved in accordance with
S)
S)
S)
S)
those already reported in the literature (see Materials and Methods section), demonstrating that no
epimerization occurs in the process. In terms of atom economy, using mesylate 3b would be the greener
option; however, tosylate 3a appears as a better choice as it was obtained in better yield, is crystalline
allowing for simple purification and also proved more reactive in the next step. Alternatively, if sodium
methoxide and ethoxide give the same yield, the latter will be preferred due to the lower toxicity of
ethanol compared to methanol.
Starting from LGO, the most efficient synthetic route in terms of yield is the one involving tosyl
chloride and sodium methoxide (81% overall yield). The greener route, that involves mesyl chloride
and sodium ethoxide provides the chiral epoxides in 60% overall yield.
NaOMe/MeOH
or NaOEt/EtOH
TsCl or MsCl
Pyr/DCM
CO2R2
O
R1O
CO2R2
O
O
HO
O
O
O
OR1
3a (R1 = Ts); 84%
3b (R1 = Ms); 62%
(S)-1a (R2 = Me); 97%
(S)-1b (R2 = Et); 96%
2
Scheme 5. Syntheses of epoxides (S)-1a/1b from (S)-γ-hydroxymethyl-γ-butyrolactone (2).
2.2. Synthesis of (S)-Dairy Lactone
(S)-Dairy lactone was thus synthesized in three steps from epoxides: (1) regioselective opening of
the epoxides, (2) acid-mediated lactonization, and (3) syn-stereoselective hydrogenation (Scheme 6).
The Lewis acid-mediated opening of the epoxide in the presence of lithiated hept-1-yne resulted
in the addition of the latter on the less substituted carbon, providing
Acid-catalyzed lactonization of crude 4a or 4b was then performed in presence of p-toluenesulfonic
acid to give lactone in 45% and 74% yields, respectively. Finally, (S)-dairy lactone was obtained
γ-hydroxyesters 4a and 4b.
5
6
via syn-selective hydrogenation of the alkyne moiety by using Lindlar palladium catalyst (94% yield).
In summary, (S)-dairy lactone was successfully synthesized in seven steps and in 37% overall yield
from LGO (69% overall yield from (S)-1a/(S)-1b).
1-Heptyne
n-BuLi, BF3.Et2O
O
O
OH
O
Lindlar Pd, H2
AcOEt
p-TsOH, DCM
THF
O
CO2R
O
then H2O
CO2R
C5H11
C5H11
C5H11
(S)-1a (R = Me)
(S)-1b (R = Et)
4a (R = Me)
4b (R = Et)
5, 45% from (S)-1a
75% from (S)-1b
6, 94%
Dairy lactone
Scheme 6. Synthesis of (S)-dairy lactone from epoxide (S)-1a/1b.
3. Materials and Methods
Levoglucosenone (LGO) was kindly supplied by Circa Group. Novozyme 435® (aka N435,
immobilized lipase Candida antarctica type B or CAL-B) was purchased from Univar. Other reagents
were purchased from Sigma-Aldrich and used as received. Solvents were purchased from
ThermoFisher Scientific. When necessary, they were dried on mBraun SPS 800. CDCl3 was purchased
from Euriso-top. Evaporations were conducted under reduced pressure at temperature below 40 ˝C.
Column chromatography was carried out with an automated flash chromatography (PuriFlash 4100,
Interchim) and pre-packed INTERCHIM PF-30SI-HP (30 µm silica gel) columns. IR and UV analyses

Molecules 2016, 21, 988
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were performed on Cary 630 FTIR and Cary 60 UV-Vis from Agilent technologies, respectively.
1
NMR analyses were recorded on a Bruker Fourier 300. H-NMR spectra of samples were recorded
in CDCl3 at 300 MHz, chemical shifts were reported in parts per million relative to residual solvent
peak (δ = 7.26 ppm). 13C-NMR spectra of samples were recorded at 75 MHz (CDCl3 residual signal at
δ = 77.16 ppm).
3.1. Chemo-Enzymatic Synthesis of (S)-γ-Hydroxymethyl-γ-butyrolactone (2)
N435 (237 PLU/mmol of LGO) was suspended in ethyl acetate (210 mL, c = 0.75 M), then LGO
(20 g, 159 mmol) and finally H2O2 (30% w/w in water, 18 mL, 159 mmol, 1 equiv) were added.
˝
The reaction mixture was incubated at 40 C and 150 rpm during 16 h. Then, N435 was filtered off and
ethyl acetate was removed under reduced pressure. Crude residue was diluted with ethanol (40 mL)
and added to a suspension of Amberlyst 15 IR dry (40 g) in ethanol (80 mL). After a night of incubation
at 37 ˝C and 150 rpm, Amberlyst was filtered off. The crude mixture was flushed with nitrogen and
10% w palladium on carbon (2 g) was added, the reaction was then stirred at atmospheric pressure
under hydrogen flux for a night. The crude mixture was filtered through a pad of Celite® and the
filtrate was concentrated to dryness. The resulting orange oil was purified by silica gel chromatography
(elution with 50 to 100% ethyl acetate in cyclohexane) to yield pure 2H-HBO
(
2
) as a colorless oil (70%);
max 207 nm; FT-IR (neat, cm´1):
δ 2.20 (m, 2H, H-3), 2.61 (m, 3H,
˝
˝
[
αs2D0 +52.9 (c 0.01, CHCl3); Lit. [26] +55.2 (c 0.1, CHCl3); UV (EtOH)
λ
3420 (OH), 2938, 1752 (C=O), 1353, 1181; 1H-NMR (CDCl3, 300 MHz):
H-2a, H-2b, OH), 3.66 (dd, 1H, J = 12.6 and 4.5 Hz, H-5a), 3.92 (dd, 1H, J = 12.6 and 2.7 Hz, H-5b), 4.64
(m, 1H, H-4); 13C-NMR (CDCl3, 75 MHz):
δ 23.1 (t, C-2), 28.7 (t, C-3), 64.1 (t, C-5), 80.8 (d, C-4), 177.7
(s, C-1); HRMS: m/z [M + Na]+ calcd for C5H8NaO3: 139.0371, found: 139.0379.
3.2. Synthesis of 2 Using m-CPBA
To a stirred solution of dihydrolevoglucosenone (4.0 g, 31.2 mmol) in dichloromethane
(50 mL) cooled using a water bath was added 70% meta-chloroperbenzoic acid (11.5 g, 47 mmol).
p-TsOH (800 mg, 5 mmol) was then added and the resulting solution stirred for 16 h. Volatiles were
removed under reduced pressure and then 1 M HCl (20 mL) was added and the resulting solution
stirred overnight. The mixture was filtered, the precipitate washed with water and the filtrate
concentrated under reduced pressure. Purification of the residue by flash chromatography to remove
residual m-chloroperbenzoic acid afforded 2 as colorless crystals (3.07 g, 85%).
3.3. Synthesis of (S)-γ-Tosyloxymethyl-γ-butyrolactone (3a)
Under nitrogen,
2 (2.5 g, 21.5 mmol) and p-toluenesulfonyl chloride (6.16 g, 32.3 mmol, 1.5 equiv)
were dissolved in a mixture of dry dichloromethane (10 mL) and pyridine (4.3 mL) and stirred at
room temperature for 9 h. The reaction mixture was diluted with dichloromethane (100 mL), washed
thrice with HCl solution (3 M, 50 mL), and twice with a saturated solution of NaHCO3 (50 mL)
and with brine (50 mL). The organic layer was then dried over anhydrous MgSO4, filtered and
concentrated. The crude mixture was triturated in Et2O (20 mL) to yield 3a as a beige powder (4.88 g,
˝
84%); m.p.: 83.3 C
;
[αs2D0 +47.9˝ (c 0.11, CHCl3); Lit. [
7 λmax 237,
] +44.5˝ (c 0.95, CHCl3); UV (CDCl3)
263, 274 nm; FT-IR (neat,): 2961, 1765 (C=O), 1595 (C=Carom), 1448 (C=Carom), 1364, 1169 cm´1
;
1H-NMR (CDCl3, 300 MHz):
4.68 (m, 1H, H-4), 7.36 (d, 2H, J = 8.1 Hz, H-8), 7.78 (d, 2H, J = 8.1 Hz, H-7); 13C-NMR (CDCl3, 75 MHz):
21.8 (q, C-10), 23.7 (t, C-2), 28.0 (t, C-3), 70.1 (t, C-5), 76.5 (d, C-4), 128.1 (d, C-7), 130.2 (d, C-8), 132.3
δ 2.25 (m, 2H, H-3), 2.45, (s, 3H, H-10), 2.55 (m, 2H, H-2), 4.16 (m, 2H, H-5),
δ
(s, C-9), 145.6 (s, C-6), 176.2 (s, C-1).
3.4. Synthesis of (S)-γ-Mesyloxymethyl-γ-butyrolactone (3b)
Under nitrogen,
2 (5.0 g, 43.1 mmol) and methanesulfonyl chloride (5.0 mL, 64.7 mmol, 1.5 equiv),
were dissolved in a mixture of dry dichloromethane (22 mL) and pyridine (8.7 mL) and stirred
at room temperature for 3 h. The reaction mixture was diluted with dichloromethane (200 mL),

Molecules 2016, 21, 988
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washed thrice with HCl solution (3 M, 100 mL), twice with a saturated solution of NaHCO3 (100 mL)
and with brine (100 mL). The organic layer was then dried over anhydrous MgSO4, filtered and
concentrated. The crude mixture was triturated in Et2O (40 mL)˝to yield 3b as a beige powder
˝
20
˝
(
5.2 g, 62%); m.p.: 46.5 C; [αsD +30.6 (c 0.10, CHCl3); Lit. [15] +33.7 (c 1, CHCl3); FT-IR (neat): 3012,
2936, 1758 (C=O), 1338, 1157 cm´1; 1H-NMR (CDCl3, 300 MHz):
δ 2.12 (m, 1H, H-3a), 2.36 (m, 1H,
H-3b), 2.56 (m, 2H, H-2), 3.05 (s, 3H, H-6), 4.26 (m, 1H, H-5a), 4.42, (m, 1H, H-5b), 4.75 (m, 1H, H-4);
13C-NMR (CDCl3, 75 MHz):
(s, C-1).
δ 23.4 (t, C-3), 28.0 (t, C-2), 37.7 (q, C-6), 70.0 (t, C-5), 76.8 (d, C-4), 176.3
3.5. Synthesis of (S)-Methyl 4,5-epoxypentanoate ((S)-1a) and (S)-Ethyl 4,5-epoxypentanoate ((S)-1b)
Under nitrogen, 3a (2.0 g, 7.37 mmol) or 3b (1.4 g, 7.37 mmol) was dissolved in MeOH/EtOH
(10 mL) and sodium methoxide (400 mg, 1.1 equiv)/sodium ethoxide (510 mg, 1.1 equiv) was added.
The reaction was stirred at room temperature for 3 h and then the solvent was evaporated and water
(10 mL) was added. The aqueous layer was extracted twice with Et2O (15 mL), the organic layers were
combined, washed with brine (20 mL), dried over anhydrous MgSO4 and concentrated to dryness.
(
S
)
-1a (0.93 g, 97%) orange oil. A small quantity of the product was distilled under reduced
20
˝
˝
pressure to give a colorless oil. [αsD
´
17.0 (c 0.11, CHCl3); Lit. [
7]
´
17.9 (c 7.4, CHCl3); FT-IR (neat):
2952, 1731 (C=O), 1437, 1360, 1256, 1172 cm´1; H-NMR (CDCl3, 300 MHz):
δ
1.78 (m, 1H, H-3a),
1
1.98 (m, 1H, H-3b), 2.48 (m, 3H, H-2, H-5a), 2.77 (m, 1H, H-5b), 2.98 (m, 1H, H-4), 3.69 (s, 3H, H-6);
13C-NMR (CDCl3, 75 MHz):
(s, C-1).
δ 27.7 (t, C-3), 30.3 (t, C-2), 47.2 (t, C-5), 51.4 (d, C-4), 51.8 (q, C-6), 173.4
(
S
)
-1b (1.02 g, 96%) orange oil. A small quantity of the product was distilled under reduced
20
pressure to give a colorless oi˝l. FT-IR (neat, cm´1): 2982, 1729 (C=O), 1371, 1254, 1176; [αsD
´
15.6˝
(
c 0.11, CHCl3); Lit. [15
]
´
17.1 (c 0.8, CHCl3); 1H-NMR (CDCl3, 300 MHz):
δ
1.22 (td, 3H, J = 7.2 and
1.2 Hz, H-7), 1.74 (m, 1H, H-3), 1.92 (m, 1H, H-3), 2.42 (m, 3H, H-2, H-5), 2.72 (m, 1H, H-5), 2.94 (m, 1H,
H-4), 4.10 (qd, 2H, J = 7.2 and 1.2 Hz, H-6); 13C-NMR (CDCl3, 75 MHz):
δ 14.4 (q, C-7), 27.8 (t, C-3),
30.6 (t, C-2), 47.2 (t, C-5), 51.4 (d, C-4), 60.7 (t, C-6), 173.0 (s, C-1).
3.6. Synthesis of (S)-5-(Oct-2-yn-1-yl)-γ-butyrolactone (5)
Under nitrogen at
(11 mL), then n-butyl lithium 2.5 M in hexane (3.0 mL, 7.53 mmol, 1.4 equiv) was added. After 5 min,
boron trifluoride etherate (0.93 mL, 7.53 mmol, 1.4 equiv) was added, and 30 min later, ( -1a (0.70 g,
-1b (0.78 g, 5.38 mmol, 1 equiv), was added. The reaction media was stirred
´
78 ˝C, 1-heptyne (1.0 mL, 7.53 mmol, 1.4 equiv) was dissolved in dry THF
S
)
5.38 mmol, 1 equiv), or (
S
)
˝
at
´
78 C for 3 h, then quenched with a saturated solution of NaHCO3 (6 mL) and water (50 mL) was
added. The aqueous layer was extracted with dichloromethane (3
ˆ
20 mL). The organic layers were
combined, washed with brine, dried over anhydrous MgSO4 and concentrated to dryness. The crude
product was diluted in dichloromethane (50 mL) and p-TsOH monohydrate (270 mg, 1.4 mmol,
0.25 equiv) was added. After 3 h, the reaction was quenched with a saturated solution of NaHCO3.
The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The orange oil was
purified by silica gel chromatography (elution with 95% to 90% ethyl acetate in cyclohexane) to yield
20
pure
(
5
as a yellow oil (70% from (
S)
-1b and 45% from (
S
)
-1a); [αsD
´
29.5˝ (c 0.12, CHCl3); FT-IR
neat, cm´1): 2929, 2858, 1772 (C=O), 1349, 1172; 1H-NMR (CDCl3, 300 MHz):
1.31 (m, 4H, H-10, H-11), 1.47 (m, 2H, H-9), 2.13 (m, 3H, H-3, H-8), 2.38 (m, 1H, H-3), 2.58 (m, 4H,
H-2, H-5), 4.60 (m, 1H, H-4); 13C-NMR (CDCl3, 75 MHz):
14.1 (q, C-12), 18.7 (t, C-8), 22.3 (t, C-11),
δ 0.89 (m, 3H, H-12),
δ
25.6 (t, C-5), 26.6 (t, C-3), 28.6 (t, C-2, C-9), 31.1 (t, C-10), 73.6 (s, C-6), 78.2 (d, C-4), 83.7 (s, C-7), 177.0
(s, C-1).
3.7. Synthesis of (S)-Dairy Lactone (6)
5
(2.72 g, 14.0 mmol) was dissolved in ethyl acetate (56 mL, c = 0.25 M) and Lindlar palladium
(0.20 g, 7.5% w/w) was added. The reaction was vigorously stirred under 1 atmosphere of hydrogen

Molecules 2016, 21, 988
8 of 10
until complete by GC. The crude mixture was filtered through a pad of Celite® and the filtrate
was concentrated to dryness. The resulting orange oil was purified by silica gel chromatography
(elution with 20%–50% ethyl acetate in cyclohexane) to yield pure S-dairy lactone
6 (2.59 g, 94%);
[
αs2D0 +7.5˝ (c 0.51, CHCl3); Lit. [29] +17.7˝ (c 0.37, MeOH); FT-IR (neat): 2923, 2854, 1771 (C=O), 1459,
1
1348, 1173 cm´1; H-NMR (CDCl3, 300 MHz):
δ 0.82 (m, 3H, H-12), 1.23 (m, 6H, H-9, H-10, H-11),
1.84 (m, 1H, H-3a), 1.98 (m, 2H, H-8), 2.23 (m, 1H, H-3b), 2.37 (m, 1H, H-5a), 2.47 (m, 3H, H-2, H-5b),
4.47 (q, 1H, J = 6.6 Hz, H-4), 5.29 (m, 1H, H-6), 5.51 (m, 1H, H-7); 13C-NMR (CDCl3, 75 MHz):
14.0
q, C-12), 22.5 (t, C-10), 27.1 (t, C-3), 27.4 (t, C-8), 28.7 (t, C-2), 29.1 (t, C-11), 31.4 (t, C-9), 32.8 (t, C-5),
δ
(
80.2 (d, C-4), 122.2 (d, C-6), 134.0 (d, C-7), 177.1 (s, C-1).
1H- and 13C-NMR spectra for compounds
found in Supplementary Materials.
2, 3a, 3b, crude (S)-1a, crude (S)-1b, 5 and 6 can be
4. Conclusions
A greener and more efficient synthetic method to access chiral epoxides ethyl and methyl
(S)-3-(oxiran-2-yl)propanoates has been developed from renewable levoglucosenone using a
lipase-mediated enzymatic Baeyer-Villiger oxidation. The total synthesis of (S)-dairy lactone has
then been successfully achieved in three steps and in 69% overall yield from these chiral epoxides
using alkynylation with heptynyl lithium, and Lindlar catalyst-mediated syn-hydrogenation as the
key steps.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
8/988/s1.
Acknowledgments: The authors are grateful to the Region Champagne-Ardenne, the Conseil Départemental de
la Marne and Reims Métropole for their financial support.
Author Contributions: A.A.M.P., B.W.G. and F.A. conceived and designed the experiments; A.A.M.P., M.J.
performed the experiments; A.A.M.P., A.L.F., M.J., B.W.G. and F.A. analyzed the data; C.G. and W.R. contributed
reagents; A.L.F., W.R., B.W.G. and F.A. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).