Scalable preparation of enantioenriched (S)-5-methylhept-2-en-4-one. Synthesis and aroma properties of achiral analogues thereof

Article abstract of DOI:10.3390/molecules24244497

(S)-5-Methylhept-2-en-4-one is a key flavour compound in hazelnuts. We have performed its chiral-pool-based chemoenzymatic synthesis with 39% overall yield (73% ee). The four-step aldol-based sequence avoids the use of highly reactive and/or toxic reagents, does not require anhydrous conditions and uses only distillation as the purification method. Thus, such methodology represents a green and scalable alternative to only two stereoselective approaches towards this natural product known so far. In addition, we have designed and prepared a set of new (di)enones as achiral synthetic analogues of the title compound. The results of their sensory analyses clearly show that relatively minor structural changes of the natural molecule significantly alter its olfactory properties. Thus, simple (poly)methylation completely changes the original hazelnut aroma of (S)-5-methylhept-2-en-4-one and shifts the odour of its analogues to eucalyptus, menthol, camphor, and sweet aroma.

Full text of DOI:10.3390/molecules24244497

ASrcticalelable Preparation of Enantioenriched (S)-5-
methylhept-2-en-4-one. Synthesis and Aroma
Properties of Achiral Analogues Thereof
1
1
2
1,
Eva Puchľová , Michal Dendys , Ivan Špánik and Peter Szolcsányi *
1
Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, SK-812 37 Bratislava,
Slovakia; puchlova.eva@gmail.com (E.P.); michaldendys@gmail.com (M.D.)
Department of Analytical Chemistry, Slovak University of Technology, Radlinského 9, SK-812 37
2
Bratislava, Slovakia; ivan.spanik@stuba.sk
* Correspondence: peter.szolcsanyi@stuba.sk
Academic editor: Domenico Montesano
Received: 29 October 2019; Accepted: 4 December 2019; Published: 8 December 2019
Abstract: (S)-5-Methylhept-2-en-4-one is a key flavour compound in hazelnuts. We have performed
its chiral-pool-based chemoenzymatic synthesis with 39% overall yield (73% ee). The four-step aldol-
based sequence avoids the use of highly reactive and/or toxic reagents, does not require anhydrous
conditions and uses only distillation as the purification method. Thus, such methodology represents
a green and scalable alternative to only two stereoselective approaches towards this natural product
known so far. In addition, we have designed and prepared a set of new (di)enones as achiral
synthetic analogues of the title compound. The results of their sensory analyses clearly show that
relatively minor structural changes of the natural molecule significantly alter its olfactory
properties. Thus, simple (poly)methylation completely changes the original hazelnut aroma of (S)-
5-methylhept-2-en-4-one and shifts the odour of its analogues to eucalyptus, menthol, camphor, and
sweet aroma.
Keywords: hazelnut; enzymatic hydrolysis; fragrant enones; allylic oxidation; sensory analysis
1. Introduction
(E)-5-Methylhept-2-en-4-one is a key flavour compound in fruits of hazelnut trees Corylus
maxima and C. avellana. The enantiomeric content in hazelnuts of different geographic origin ranges
from 54 to 73% ee in favour of (S)-enantiomer 1 (Scheme 1). Due to unique sensory properties, it has
found practical applications in perfumery, flavour and food industry. Moreover, it is recently used
for analytical purposes as a key marker for the detection of adulteration of olive oil and/or
authenticity evaluation of hazelnut-based products [1]. Consequently, there is an emerging interest
in its straightforward and cost-efficient stereoselective synthesis as a reliable source of an
enantioenriched 1 for direct use.
To date, only three enantioselective syntheses of (S)-5-methylhept-2-en-4-one 1 are known [2–4],
and all employ enantiomerically pure (S)-2-methylbutanol as substrate, with 40% overall yield (75%
and 92% ee). However, these strategies rely on synthetic methods either requiring strictly anhydrous
conditions (organolithium addition, hydride reduction) or use/generate toxic reagents/waste
(chromium salts), and thus, severely limiting their scaling potential. Therefore, green yet efficient
approaches towards the synthesis of enantioenriched 1 are clearly needed.
Moreover, its relatively simple structure associated with unique flavour profile is an ideal
scaffold for the design of novel analogues. Advantageously in this context, the chirality of 1 has a
negligible influence on the quality of its sensory properties as the odours of all stereoisomers are
Molecules 2019, 24, 4497; doi:10.3390/molecules24244497
www.mdpi.com/journal/molecules

Molecules 2019, 24, 4497
2 of 10
typical of hazelnuts [5]. Thus, rationally designed, preferably achiral derivatives of 1 could provide
a useful insight into the structure–sensory correlations (SAR) necessary for future identification of
the key molecular features associated with the hazelnut aroma.
2. Results and Discussion
2.1. Chemoenzymatic Preparation of Enantioenriched 1
Inspired by the aldol-based approach [6] to racemic 5-methylhept-2-en-4-one [7–16], we have
designed our synthetic strategy towards enantioenriched 1 with key focus on the suppression of the
associated epimerisation and use of naturally occurring substrates throughout the multigram
sequence (Scheme 1). Thus, the initial activation [17] of natural (S)-2-methylbutanoic acid 2 (88% ee)
followed by one-pot condensation of intermediary acyl imidazole with potassium ethyl malonate
furnished the β-ketoester 3 in 90% yield in 2 steps. While the extensive screening of various
Lewis/Brønsted acids or bases for hydrolysis of 3 yielded completely racemic product only, its
enzymatic hydrolysis [18] with immobilised lipase from Candida antarctica afforded crude β-ketoacid
4 with preserved stereointegrity and quantitative yield (100% GC, 88% ee). This intermediate was
directly used in the decarboxylative Knoevenagel condensation with acetaldehyde to furnish ketol 5
in 53% yield after distillation. The extensive screening of final acid-catalysed dehydration [19] of the
latter afforded the enantioenriched 1 in 82% yield with an acceptable epimerisation (73% ee) when
using p-toluene sulfonic acid in hydrocarbon solvent (see Supplementary Material). Overall, the total
yield of (S)-5-methylhept-2-en-4-one 1 obtained in four steps reached 39%, with the enantiomeric
purity conforming to the purest material isolated from natural sources (vide supra). Moreover, our
protocol is based on generally innocuous synthetic transformations, avoids the use of highly reactive
organometallic and/or toxic reagents, does not require strictly anhydrous reaction conditions and
uses vacuum distillation as the only purification method. Thus, such methodology represents a green
and scalable alternative to the very few approaches towards the stereoselective synthesis of
enantioenriched 1 known so far.
O
O
a) 1. CDI
b) Novozym 435
CO2H
CO2Et
CO2H
2. MgCl2
O
O
4
3
2
KO
OEt
O
O
O
OH
c) MeCHO
d) TsOH
CO2H
1
4
5
Scheme 1. Synthesis of enantioenriched (S)-5-methylhept-2-en-4-one 1. Reagents and conditions: (a)
CDI (1.2 equiv), THF, RT, 4 h; potassium ethyl malonate (1.5 equiv), MgCl2 (1.5 equiv), THF, 60 °C, 5
h; then 50 °C, 5 h → RT, overnight, vacuum distillation, 90% (2 steps); (b) Novozym 435 (5% wt),
phosphate buffer, RT, 22 h, crude (100% GC, 88% ee); (c) MeCHO (1.1 equiv), TBAHSO4 (0.005 equiv),
RT → 40 °C, 21 h, vacuum distillation, 53%; and (d) p-TsOH.H2O (0.05 equiv), cyclohexane, 70 °C, 2.5
h, vacuum distillation, 82% (73% ee).
2.2. Synthesis of Achiral Analogues 6–9

Molecules 2019, 24, 4497
3 of 10
In the next part, we were further interested in the design, synthesis and properties of new achiral
analogues of 1. Our aim was to gain an insight into the structure–sensory correlations (SAR)
necessary for identifying the key molecular features associated with its unique hazelnut aroma. Thus,
we have designed a small set of (poly)alkylated enones 6–9, all featuring the structural core of 1 with
extra added (m)ethyl groups. These included previously unknown acyclic enones 6, 7 and dienones
8, 9 as well as the known [20–22] cyclic dienone 10 for comparison purposes (Figure 1).
O
6
O
O
O
10
7
1
O
O
8
9
Figure 1. Achiral analogues 6–10 of (S)-5-methylhept-2-en-4-one 1.
At this preliminary stage, we chose the most direct synthetic route employing reliable and
powerful (organo)metallic transformations regardless of their non-greenness. Thus, our preparation
of new (di)enones 6–9 is based on a short two-step protocol: in the first step, the addition of 1,2-
dimethylpropenyllithium 12, freshly made [23] by halogen-metal exchange [24] of commercial 2-
bromo-2-methylbutene 11 and tert-butyl lithium, to a range of commercial carbonyl electrophiles
furnished corresponding (di)allyl alcohols 13–16 in good to high yields (67–84%). These were finally
transformed by allylic oxidation with manganese dioxide to target (di)enones 6–9 in overall yields of
50–62% over two steps (Scheme 2, see Supplementary Material).
OH
O
O
4
c) MnO2
4
4
13
14
15
16
6
7
8
9
OH
O
O
c) MnO2
b)
X
OH
OH
O
O
c) MnO2
c) MnO2
11 (X=Br)
12 (X=Li)
a)tBuLi
O
HCO2Et

Molecules 2019, 24, 4497
4 of 10
Scheme 2. Preparation of new achiral analogues 6–9. Reagents and conditions: (a) tBuLi (2.1 equiv),
THF, −78 °C, 30 min → RT, 1 h, crude; (b) 12 (1.05 equiv), THF, −50 or −30 °C → RT, 15 h, vacuum
distillation, 13 (84%), 14 (67%), 15 (84%), 16 (71%); and (c) MnO2 (20 equiv), pentane, RT, 48 h to 4 d,
crude, 6 (71%), 7 (74%), 8 (74%), 9 (76%).
2.3. Olfactory Evaluation
With new (di)enones 6–9 in hands, we have undertaken their sensory evaluation. For
comparison purposes, we have also included (di)allyl alcohols 13–16 and known cyclic dienone 10 in
the olfactory screening. The results are summarised in Table 1. Firstly, and most importantly,
methylation/alkylation of target molecule led to a complete change of olfactory properties as none of
its analogues 6–9 exhibited any hazelnut aroma. Thus, their sensory characteristics can be divided
into three distinct classes according to major odour. (Di)enones 7–10 possess a fresh camphoraceous–
minthy–eucalypty scent with additional floral, sweet and spicy tones. Interestingly, similar major
aspects were also exhibited by allyl alcohol 14 with accompanying terpenic notes. While major sweet
aroma with tropical fruit notes is typical for enone 6, an analogous alcohol 13, however, exhibits an
earthy scent of root vegetables with an interesting tone of dried poppy heads. Into the latter odour
group also belong diallyl alcohols 15 with celery aspect and 16 with potato note, respectively. The
obtained results clearly show the shift of the hazelnut aroma of 1 to the potentially exploitable
eucalyptus, camphor, menthol, and/or sweet odours exhibited by volatile new (di)enones 6–9. In
addition, the analogous (di)allyl alcohols 13, 15–16 also display potentially useful earthy aromas
strongly reminiscent of root vegetables.
Table 1. Olfactory properties of compounds 6–10, 13–16 prepared via Scheme 2.
Main Odour(s)
Compound
Minor Aspect(s)
Odour Intensity
O
8
Fresh, spicy, floral
Strong
O
9
Herbal, medicinal
Floral
Strong
Mild
Eucalyptus
Menthol
O
7
OH
Camphor
14
Terpenic
Mild
O
O
Medicinal, sweet, oily
Mild
10
6
Sweet
Tropical, fruity, spicy
Dried poppy-head
Strong
Mild
Mild
Mild
4
OH
13
4
OH
Root vegetables
Earthy
15
16
Celery, lovage
OH
Parsley, celery, sprouting potatoes

Molecules 2019, 24, 4497
5 of 10
3. Materials and Methods
3.1. General Experimental
Chemicals and reagents were purchased from commercial sources (Alfa Aesar, Sigma-Aldrich)
and were used without further purification. In case of anhydrous solvents, these were prepared either
by filtration through a column of activated alumina or by standing over activated 4Å molecular sieves
and stored under argon atmosphere. Hexanes refer to a mixture of C-6 alkanes (b.p. 60–80 °C). Yields
1
refer to chromatographically and spectroscopically ( H NMR) homogeneous material, unless
otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on
aluminium sheets pre-coated with silica gel 60 F254 (Merck) or aluminium oxide 60 F254 (neutral,
Merck). Visualisation was performed using shortwave UV light followed by dipping TLC plates in
either basic solution of KMnO4, acidic solution of vanillin or acidic solution of ceric ammonium
nitrate followed by heating with a heat gun. Flash column chromatography (FLC) was performed
using Silica Gel 60 (particle size 0.040–0.063 mm). NMR spectra were recorded in CDCl3 on a Varian
1
13
1
INOVA 300 (300 MHz for H, 75 MHz for C nuclei) or Varian VNMRS 600 (600 MHz for H, 151
13
MHz for C nuclei) NMR spectrometer and were correctly shifted using residual non-deuterated
solvent or tetramethylsilane as an internal reference (CHCl3: δH = 7.26 ppm, δC = 77.16 ppm (central
peak of a 1:1:1 triplet), TMS: δH = δC = 0.00 ppm). Chemical shifts (δ) are quoted in ppm. LC-MS
analyses were performed on Agilent 1200 Series instrument equipped with a multimode MS detector
using the MM ESI/APCI ionisation method (column Zorbax Eclipse XDB-18, 150 × 4.6 mm, particle
size 5 μm, eluent water with 0.1% HCO2H/CH3CN, 70:30, flow 1.5 mL/min). GC analyses were
performed on a gas chromatograph Agilent 7820A equipped with FID and a split–splitless injector
(column DB-5 30 m × 0.25 mm × 0.25 μm, injection 0.1 μL, split 20:1, temperature gradient 40 °C (2
min) → 15 °C/min → 220 °C (15 min), carrier gas H2, flow 1.2 mL/min). Chiral GC analyses were
performed on a gas chromatograph Agilent 7890A equipped with FID and a split–splitless injector
(column Cyclosil-B 30 m × 0.32 mm × 0.25 μm, injection 0.2 μL, split 50:1, temperature gradient 40 °C
(0 min) → 10 °C/min → 80 °C (0 min) → 25 °C/min → 220 °C (2 min), carrier gas H2, flow 2.0
mL/min). GC-MS analyses were performed on a gas chromatograph Agilent 7890A and coupled with
Agilent 5975C inert MSD with Triple-Axis Detector (column DB-Wax 30 m × 0.25 mm × 0.15 μm,
injection 1 μL, split 20:1, temperature gradient 40 °C (2 min) → 15 °C/min → 220 °C (15 min), carrier
gas H2, flow 1.2 mL/min). High-resolution mass spectra (HR-MS) were recorded on a Thermo
Scientific Orbitrap Velos mass spectrometer with a heated electrospray ionisation (HESI) source in
positive and/or negative mode. FTIR spectra were obtained on a Nicolet 5700 spectrometer (Thermo
Electron) equipped with a Smart Orbit (diamond crystal ATR) accessory using the reflectance
–1
technique (4000–400 cm ). The sensory analysis was performed by authors in a clean and odourless
environment at 22 °C. The prepared compounds were evaluated as 10% solutions in aqueous ethanol
(95% w/w) by using testing strips.
3.2. Synthetic Procedures and Analytical Data
(S)-Ethyl 4-methyl-3-oxohexanoate (3) A mixture of potassium ethyl malonate (100.0 g, 0.587
mol, 1.5 equiv) was treated with magnesium chloride (56.0 g, 0.587 mol, 1.5 equiv) in tetrahydrofuran
(360 mL), and the resulting grey slurry was stirred at 60 °C for 5 h. During that time, in a separate
reaction vessel, a solution of (S)-2-methylbutanoic acid 2 (88% ee, 40.0 g, 0.343 mol) in THF (160 mL)
was added to a solution of carbonyldiimidazole (66.0 g, 0.407 mol, 1.2 equiv) in THF (140 mL) and
the resulting yellow solution was stirred at 28 °C for 4 h. Then, after 5 h reaction time, a THF solution
containing a mixture of malonate and MgCl2 was cooled to RT and a THF solution of crude acyl
imidazole formed from acid 2 was added dropwise over 30 min. The resulting white suspension was
stirred at 50 °C for 5 h and subsequently at RT overnight. The reaction mixture was then added to 1M
aqueous HCl solution (1600 mL). The resulting pale-yellow solution was stirred at RT for 30 min,
ethyl acetate (600 mL) was added, phases were separated, and aq ueous layer was extracted with
EtOAc (600 mL). Combined organic extracts were sequentially washed with 1M aq ueous HCl
solution (400 mL), water (500 mL), 2% aqueous Na2CO3 solution (700 mL), water (500 mL) and brine

Molecules 2019, 24, 4497
6 of 10
(500 mL), subsequently dried over anhydrous Na2SO4 and concentrated in vacuo to give pale-yellow
oil (76.23 g). The crude product was purified by vacuum distillation (b.p. 64–67 °C/3.4 mbar) to yield
(S)-ketoester 3 (60.54 g, 90%) as a colourless liquid; δH (300 MHz, CDCl3) 4.19 (q, J = 7.1 Hz, 2H,
OCH2CH3), 3.47 (s, 2H, H-2), 2.58 (m, J = 6.8 Hz, 1H, H-4), 1.79–1.62 (m, 1H, H-5A), 1.42 (m, 1H, H-
5B), 1.27 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.10 (d, J = 6.9 Hz, 3H, Me), 0.90 (t, J = 7.4 Hz, 3H, H-6); δC (75
MHz, CDCl3) 206.6 (C-3), 167.4 (C-1), 61.3 (OCH2), 48.1 (C-4), 47.8 (C-2), 25.7 (C-5), 15.5 (Me), 14.2
(OCH2CH3), 11.5 (C-6), NMR spectra of (S)-3 are in full accordance with literature data [25–27] for
racemic 3; in addition, signals of the enol form of 3 are clearly detectable in both proton and carbon
spectra measured in deuterochloroform: δH (300 MHz, CDCl3) 12.11 (d, J = 0.7 Hz, 1H, OH), 4.97 (s,
1H, H-2), 4.18 (q, J = 7.1 Hz, 2H, OCH2CH3), 2.15 (m, J = 7.0 Hz, 1H, H-4), 1.79–1.62 (m, 1H, H-5A),
1.42 (m, 1H, H-5B), 1.29 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.12 (d, J = 6.9 Hz, 3H, Me), 0.89 (t, J = 7.4 Hz,
3H, H-6); δC (75 MHz, CDCl3) 182.7 (C-3), 173.0 (C-1), 88.1 (C-2), 60.0 (OCH2), 41.2 (C-4), 27.1 (C-5),
17.7 (Me), 14.4 (OCH2CH3), 11.7 (C-6); GC: tR = 7.73 min (keto-form), tR = 7.54 min (enol-form); GC-
+
MS: m/z (%) 172 (6, M ), 157 (1), 144 (9), 127 (3), 115 (27), 98 (5), 85 (31), 69 (12), 57 (100), 43 (36).
(S)-4-Methyl-3-oxohexanoic acid (4) To a solution of ketoester 3 (8.0 g, 46.5 mmol) in an aqueous
sodium phosphate buffer (32 mL, pH~7) was added Novozym 435 (400 mg) and the suspension was
stirred at RT for 22 h, while the pH was kept neutral by addition of aqueous NaOH. Solids were
filtered off and the filtrate containing ketoacid 4 (100% GC yield, 88% ee) was directly used for the
subsequent Knoevenagel condensation with acetaldehyde. The enantiomeric purity of crude 4 was
determined by chiral GC via (S)-3-methylpent-2-on (tR = 3.53 min) formed in situ by thermal
decarboxylation of 4 during analysis.
(S)-2-Hydroxy-5-methylhept-4-one (5) To a solution of crude ketoacid 4 (8 g, 46.5 mmol) in an
aqueous phosphate buffer (42.5 mL) was added tetrabutylammonium hydrogen sulphate (79 mg)
and the pH was adjusted to approx. 8 by aqueous NaOH solution. Acetaldehyde (2.6 mL, 51.4 mmol,
1.1 equiv) was added and the resulting soln. was stirred at RT for 1.5 h and then at 40 °C for 21 h. The
reaction mixture was extracted with diethyl ether (3 × 70 mL), separated organic layer was dried over
anhydrous Na2SO4 and the solvent was evaporated in vacuo to yield pale-yellow liquid (6.865 g). The
crude product was purified by vacuum distillation (b.p. 63-64 °C/3.6 mbar) to afford ketol 5 (3.577 g,
53%) as a colourless liquid; δH (600 MHz, CDCl3) 4.23–4.17 (m, 1H, H-2), 3.01 (bs, 1H, exchange with
D2O, OH), 2.62 (ddd, J = 17.8, 13.0, 2.8 Hz, 1H, H-3a), 2.51 (ddd, J = 17.8, 13.5, 9.0 Hz, 1H, H-3b), 2.46–
2.39 (m, 1H, H-5), 1.72–1.63 (m, 1H, H-6a), 1.43–1.35 (m, 1H, H-6b), 1.18 (dd, J = 6.4, 0.7 Hz, 3H, H-1),
1.06 (dd, J = 7.0, 1.3 Hz, 3H, Me), 0.87 (t, J = 7.5 Hz, 3H, H-7), NMR spectrum is in accordance with the
+
literature data [28]; GC: tR = 7.67 min; GC-MS: m/z (%) 144 (2, M ), 116 (4), 103 (18), 87 (85), 85 (26), 69
(23), 57 (75), 43 (100).
(E,S)-5-Methylhept-2-en-4-one (1) To a mixture of ketol 5 (2.85 g, 19.8 mmol) in cyclohexane (49
mL) was added p-toluenesulfonic acid monohydrate, (190 mg, 1.0 mmol, 0.05 equiv) and resulting
mixture was stirred at 70 °C for 2.5 h. Subsequently, the mixture was washed with saturated aqueous
NaHCO3 solution (25 mL), aqueous phase was extracted with diethyl ether (3 × 60 mL) and organic
phase was dried over anhydrous Na2SO4 and concentrated in vacuo to give a colourless liquid (2.60
g). The crude product was purified by bulb-to-bulb vacuum distillation (b.p. 75–76 °C/4 mbar) to
afford a (S)-enantioenriched enone 1 (2.03 g, 82% yield, 73% ee) as a colourless liquid; (the (S)-
configuration of 1 as the major enantiomer was determined by the comparison with the analytical
sample of (S)-1 prepared independently from (S)-2-methylbutanol by previously reported
stereoselective synthesis, cf. Ref. [4]); δH (300 MHz, CDCl3) 6.85 (dq, J = 15.6, 6.9 Hz, 1H, H-2), 6.16
(dd, J = 15.6, 1.7 Hz, 1H, H-3), 2.62 (m, J = 6.8 Hz, 1H, H-5), 1.86 (dd, J = 6.9, 1.7 Hz, 3H, H-1), 1.74 –
1.59 (m, 1H, H-6A), 1.46 – 1.25 (m, 1H, H-6B), 1.04 (d, J = 6.9 Hz, 3H, Me), 0.84 (t, J = 7.4 Hz, 3H, H-7);
δC (75 MHz, CDCl3) 203.9 (C-4), 142.3 (C-2), 130.7 (C-3), 45.4 (C-5), 26.2 (C-6), 18.3 (C-1), 16.2 (Me), 11.8
(C-7), NMR spectra of (S)-1 are in full accordance with the literature data [2]; Chiral GC: tR = 5.74 min
+
for (S)-1 (tR = 5.59 min for (R)-1); GC-MS: m/z (%) 126 (1, M ), 111 (11), 98 (12), 69 (100), 57 (4), 41 (21).
3.3. General experiment for the preparation of (di)allyl alcohols (13–16)

Molecules 2019, 24, 4497
7 of 10
To a freshly prepared solution of 1,2-dimethylpropenyl lithium 12 in anhydrous THF was added
the respective aldehyde or ester dropwise at low temperature over 5 min. under argon. The mixture
was gradually warmed to RT and stirred overnight. The reaction was quenched with saturated
aqueous NH4Cl solution, diluted with water and extracted with diethyl ether. Combined organic
extracts were dried over MgSO4 and concentrated in vacuo (34 °C, 650 → 250 mbar). Crude product
was purified by bulb-to-bulb vacuum distillation to furnish a corresponding allyl alcohol 13–16.
2,3-Dimethylnon-2-en-4-ol (13) 12 (1.35 mmol, 1.05 equiv), THF (2 mL), −50 °C, hexanal (0.16 mL,
1.28 mmol), RT, overnight, NH4Cl (5 mL), H2O (5 mL), Et2O (3 × 10 mL), vacuum distillation (130 °C,
50 mbar), alcohol 13 (165 mg, 84%) as colourless oil; Rf (hexanes/AcOEt 4:1) 0.43; νmax (ATR) 3342
−1
(OH), 2955, 2927, 2859, 1457, 1375, 1010 cm ; δH (300 MHz, CDCl3) 4.63 (t, J = 6.96 Hz, 1H, H-4), 1.71,
1.67, 1.61 (s, 2 × m, 3 × 3H, H-1, 2 × Me), 1.40 (m, 8H, H-5, H-6, H-7, H-8), 0.89 (m, 3H, H-9); δC (75
MHz, CDCl3) 129.6, 127.4 (C-2, C-3), 71.2 (C-4), 35.1 (C-5), 31.9 (C-7), 25.6 (C-6), 22.7 (C-8), 21.1, 19.8
+
+
(C-1, Me); 14.1 (C-9), 11.6 (Me); m/z (ESI) 153 (100, M-OH ), 154 (14%); HR-MS (HESI): M , found
170.1665. C11H22O requires 170.1665.
2,3,5,5-Tetramethylhept-2-en-4-ol (14) 12 (2.62 mmol, 1.05 equiv), THF (2 mL), −30 °C, 2,2-
dimethylbutanal (0.31 mL, 2.5 mmol), RT, overnight, NH4Cl (10 mL), H2O (10 mL), Et2O (3 × 15 mL),
vacuum distillation (130 °C, 80 mbar), alcohol 14 (285 mg, 67%) as yellowish oil; Rf (hexanes/AcOEt
−1
4:1) 0.59; νmax (ATR) 3398 (OH), 2962, 2917, 2879, 1462, 1373, 1002 cm ; δH (300 MHz, CDCl3) 4.42 (d,
J = 3.75 Hz, 1H, H-4), 1.69, 1.66 (2 × m, 3H, 6H, H-1, 2 × Me), 1.35 (d, J = 3.75 Hz, OH), 1.31 (m, 2H, H-
6), 0.86 (m, 3H, H-7), 0.88, 0.80 (2 × s,2 × 3H, 2 × Me); δC (75 MHz, CDCl3) 128.4, 129.2 (C-2, C-3), 76.9
(C-4), 39.7 (C-5), 31.9 (C-6), 23.5, 22.6 (2 × Me), 21.4, 21.3 (C-1, Me); 14.6 (Me), 8.5 (C-7); m/z (ESI) 153
+
+
(100, M-OH ), 154 (12%); HR-MS (HESI): M , found 170.1665. C11H22O requires 170.1665.
(E)-2,3,5-Trimethylhept-2,5-dien-4-ol (15) 12 (1.35 mmol, 1.05 equiv), THF (2 mL), −45 °C, (E)-2-
methylbutanal (0.13 mL, 1.28 mmol), RT, overnight, NH4Cl (5 mL), H2O (5 mL), Et2O (3 × 10 mL),
vacuum distillation (155 °C, 27 mbar), alcohol 15 (165 mg, 84%) as yellowish oil; Rf (hexanes/AcOEt
−1
8:1, 2x) 0.45; νmax (ATR) 3363 (OH), 2916, 2861, 1444, 1375, 1047, 998 cm ; δH (300 MHz, CDCl3) 5.58
(m, 1H, H-6), 5.00 (s, 1H, H-4), 1.77 (m, 3H, Me), 1.69 (s, 3H, H-1), 1.64 (m, 3H, H-7), 1.50, 1.47 (2 × m,
2 × 3H, 2 × Me); δC (75 MHz, CDCl3) 136.3 (C-5), 128.7, 120.0 (C-2, C-3); 117.2 (C-6), 74.3 (C-4), 21.2 (C-
+
+
1), 20.1, 13.3, (2 × Me), 13.0 (C-7), 11.8 (Me); m/z (ESI) 137 (100, M-OH ), 138 (11%); HR-MS (HESI): M ,
found 154.1351. C10H18O requires 154.1352.
2,3,5,6-Tetramethylhept-2,5-dien-4-ol (16) 12 (2.62 mmol, 2.05 equiv), THF (2 mL), −30 °C, ethyl
formate (0.12 mL, 1.47 mmol), RT, overnight, NH4Cl (10 mL), H2O (10 mL), Et2O (3 × 15 mL), vacuum
distillation (120 °C, 80 mbar), alcohol 16 (175 mg, 71%) as yellowish oil; Rf (hexanes/AcOEt 8:1, 2x)
−1
0.43; νmax (ATR) 3339(OH), 2915, 2862, 1446, 1372, 998 cm ; δH (300 MHz, CDCl3) 5.42 (s, 1H, H-4),
1.70, 1.67, 1.65 (2 × m, s, 3 × 6H, H-1, H-7, 4 × Me); δC (75 MHz, CDCl3) 129.8, 127.0 (C-2, C-3, C-5, C-
+
6), 71.1 (C-4), 21.2, 20.0 (C-1, C-7, 2 × Me); 13.7 (2 × Me); m/z (ESI) 151 (100, M-OH ), 152 (14%); HR-
+
MS (HESI): M , found 168.1508. C11H20O requires 168.1509.
3.4. General experiment for the preparation of (di)enones (6–9)
To a solution of allyl alcohol in pentane was added activated MnO2 (heated at 140 °C/10 Torr for
30 min) at RT under Ar. The suspension was stirred at RT for the indicated time, diluted with diethyl
ether, filtered through Celite pad and solids were repeatedly washed with Et2O. Filtrate was
concentrated in vacuo (34 °C, 550 mbar) to furnish a corresponding enone pure by NMR. For
analytical purposes, an aliquot was purified by either FLC on silica gel or bulb-to-bulb vacuum
distillation.
2,3-Dimethylnon-2-en-4-one (6) Alcohol 13 (200 mg, 1.18 mmol), pentane (4 mL), MnO2 (2.05 g,
23.60 mmol, 20 equiv), RT, 4 d, Et2O (10 mL), Celite (2 × 1 cm), Et2O (4 × 10 mL), vacuum distillation
(120 °C, 80 mbar), enone 6 (140 mg, 71%) as a colourless oil; Rf (hexanes/AcOEt 10:1) 0.50; νmax (ATR)
−1
2956, 2928, 2860, 1685 (C=O), 1456, 1375, 1043, 1013 cm ; δH (300 MHz, CDCl3) 2.50 (dd, J = 7.3 Hz,
2H, H-5), 1.81, 1.73 (m, 6H, s, 3H, H-1, 2 × Me), 1.30 (m, 6H, H-6, H-7, H-8), 0.89 (t, J = 6.8 Hz, 3H, H-
9); δC (75 MHz, CDCl3) 208.9 (C=O), 136.0, 131.8, (C-2, C-3), 41.9 (C-5), 31.7 (C-6), 23.9 (C-7), 22.7 (C-

Molecules 2019, 24, 4497
8 of 10
+
+
8), 22.4, 21.3, 15.6, 14.1 (4 × Me); m/z (ESI) 169 (100, M + H ), 170 (11%); HR-MS (HESI): M , found
168.1508. C11H20O requires 168.1508.
2,3,5,5-Tetramethylhept-2-en-4-one (7) Alcohol 14 (230 mg, 1.35 mmol), pentane (4 mL), MnO2
(2.35 g, 27.0 mmol, 20 equiv), RT, 72 h, Et2O (10 mL), Celite (2 × 1 cm), Et2O (4 × 10 mL), enone 7 (175
mg, 76%) as a colourless oil; Rf (hexanes/AcOEt 10:1) 0.53; νmax (ATR) 2967, 2932, 2880, 1682 (C=O),
−1
1462, 1376, 1002, 973 cm ; δH (300 MHz, CDCl3) 1.72, 1.63, 1.56 (3 × m, 3 × 3H, 3 × Me), 1.55 (q, 2H, J =
7.4 Hz, H-6), 1.1 (s, 6H, 2 × Me), 0.82 (t, J = 7.4 Hz, 3H, H-7); δC (75 MHz, CDCl3) 218.1 (C=O), 131.9,
128.9 (C-2, C-3), 47.7 (C-5), 32.8 (C-6), 24.5 (2 × Me), 22.4, 19.4, 16.2 (C-1, 2 × Me), 8.9 (C-7); m/z (ESI)
+
+
169 (100, M + H ), 170 (12%); HR-MS (HESI): M , found 168.1506. C11H20O requires 168.1509.
(E)-2,3,5-Trimethylhept-2,5-dien-4-one (8) Alcohol 15 (113 mg, 0.73 mmol), pentane (3 mL),
MnO2 (1.28 g, 14.68 mmol, 20 equiv), RT, 48 h, Et2O (5 mL), Celite (2 × 1 cm), Et2O (3 × 10 mL), enone
8 (89 mg, 74%) as a colourless oil; Rf (pentane/Et2O 10:1) 0.64; νmax (ATR) 2979, 2918, 2860, 1639 (C=O),
−1
1444, 1376, 1285, 1045 cm ; δH (300 MHz, CDCl3) 6.64 (m, 1H, H-6), 1.86 (m, 3H, H-7), 1.80, 1.75, 1.72,
1.54 (3 × m, s, 4 × 3H, H-1, 3 × Me); δC (75 MHz, CDCl3) 204.3 (C=O), 141.6 (C-6), 137.7, 130.6, 130.0 (C-
+
2, C-3, C-5), 22.2, 19.8, 17.0, 15.1, 10.5 (C-1, C-7, 3 × Me); m/z (ESI) 153 (100, M + H ), 154 (10%); HR-
+
MS (HESI): M , found 152.1194. C10H16O requires 152.1196.
(E)-2,3,5,6-Tetramethylhept-2,5-dien-4-one (9) Alcohol 16 (113 mg, 0.67 mmol), pentane (2 mL),
MnO2 (1.17 g, 13.45 mmol, 20 equiv), RT, 4 d, Et2O (5 mL), Celite (2 × 1 cm), Et2O (3 × 10 mL), enone 9
(85 mg, 76%) as a colourless oil; Rf (pentane/Et2O 10:1) 0.64; νmax (ATR) 2915, 2863, 1629 (C=O), 1445,
−1
1373, 1294, 1003 cm ; δH (300 MHz, CDCl3) 1.82, 1.79, 1.76 (3 × m, 3 × 6H, H-1, H-7, 4 × Me); δC (75
MHz, CDCl3) 204.7 (C=O), 138.1, 132.1 (C-2, C-3, C-5, C-6), 22.0, 21.7 (C-1, C-7, 2 × Me), 15.6 (2 × Me);
+
+
m/z (ESI) 167 (100, M + H ), 168 (11%); HR-MS (HESI): M , found 166.1952. C11H18O requires 166.1952.
2,5-Diisopropylidene-cyclopentanone (10) Prepared according to the reported procedure [9c] as
a colourless oil; Rf (hexanes/AcOEt 10:1) 0.51; νmax (ATR) 2956, 2905, 2849 (C-H), 1682, 1613 (C=O),
−1
1435, 1363, 1267, 1195, 978, 796 cm ; δH (300 MHz, CDCl3) 2.51 (s, 4H, H-3, H-4), 2.27 (s, 6H, 2 × Me),
1.81 (s, 6 H, 2 × Me); δC (75 MHz, CDCl3) 196.6 (C=O), 146.2, 134.4 (4 × Cq), 25.4 (2 × CH2), 24.4, 20.4 (4
+
+
× Me); m/z (ESI) 165 (100, M + H ), 166 (13%); HR-MS (HESI): M , found 164.1195. C11H16O requires
164.1196.
4. Conclusions
We have performed a chiral-pool-based chemoenzymatic synthesis of enantioenriched (S)-5-
methylhept-2-en-4-one 1 in 39% overall yield and with 73% ee. This four-step aldol-based sequence
employs natural substrates and innocuous reactions, avoids the use of highly reactive and/or toxic
reagents, does not require anhydrous conditions and uses only distillation as a purification method.
Thus, such methodology represents a green and scalable alternative to only two approaches towards
enantioenriched 1 known so far.
In addition, we have designed and prepared (di)enones 6–9 as achiral synthetic analogues of the
naturally occurring 1. Their short two-step preparation features the initial alkenyl lithium addition
to carbonyl electrophiles with subsequent allylic oxidation of alkenols to desired targets. The results
of their sensory analysis clearly show that relatively minor structural changes of the natural’s
molecule significantly alter its olfactory properties. Thus, simple (poly)methylation completely
changes the original hazelnut aroma of (S)-5-methylhept-2-en-4-one 1 and shifts the odour of its
analogues 6–9 to eucalyptus, menthol, camphor, and sweet aroma, respectively.
Supplementary Materials: The following are available online. Copies of spectra (chiral GC, NMR) of prepared
compounds are available.
Author Contributions: Conceptualisation and methodology, E.P., M.D., and P.S.; synthesis, E.P. and M.D.;
writing—original draft preparation, review and editing, P.S.; supervision and project administration, P.S.;
analytics and funding acquisition, I.Š.
Funding: This research was funded by the Science and Technology Assistance Agency under contract No.
APVV-15-0355.
Acknowledgements: We thank Mr. Karol Červenčík for help with the sensory evaluation.

Molecules 2019, 24, 4497
9 of 10
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the
study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
References
1.
2.
Puchľová, E.; Szolcsányi, P. Filbertone: A Review. J. Agric. Food Chem. 2018, 66, 11221–11226.
Jauch, J.; Schmalzing, D.; Schurig, V.; Emberger, R.; Hopp, R.; Köpsel, M.; Silberzahn, W.; Werkhoff, P.
Isolation, Synthesis, and Absolute Configuration of Filbertone – the Principal Flavor Component of the
Hazelnut. Angew. Chem. Int. Ed. 1989, 28, 1022–1023.
3.
4.
5.
Jauch, J.; Czesla, H.; Schurig, V. Improved synthesis of (S, E)-(+)-5-methylhept-2-en-4-one, the major aroma
compound of hazelnuts. Tetrahedron 1999, 55, 9787–9792.
Zarbin, P.H.G.; Yonashiro, M.; Perissini, W. An Alternative Route for the Synthesis of (E)-(+)-5 (S)-
Methylhept-2-en-4-one (Filbertone). J. Braz. Chem. Soc. 1998, 9, 583–585.
Güntert, M.; Emberger, R.; Hopp, R.; Köpsel, M.; Silberzahn, W.; Werkhoff, P.Z. Chirospecific analysis in
flavor and essential oil chemistry Part A. Filberton - the character impact compound of hazel-nuts.
Lebensm.-Unters. Forsch. 1991, 192, 108–110.
6.
Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. A new protocol for a regioselective aldol
condensation as an alternative convenient synthesis of β-ketols and α, β-unsaturated ketones. J. Org. Chem.
2002, 67, 4615–4618.
7.
8.
Stutsman, P.S.; Adkins, H. Hydrogenation of 1, 3-Diketones to Ketols. J. Am. Chem. Soc. 1939, 61, 3303–3306.
Lion, C.; Dubois, J.-É. Synthesis of beta, gamma-ethylenic ketones-reaction of allylic organomagnesium
compounds with substituted 4, 4-dimethyl-2-oxazilines. Bull. Soc. Chim. Fr. 1973, 2673–2676.
Emberger, R.; Köpsel, M.; Brüning, J.; Hopp, R.; Sand, T. Flavoring with 5-methyl-hept-2-en-4-one. U.S.
Patent 4,563,365, 1 July 1986.
9.
10. Huang, Y.; Wang, H.; Lu, M. Method for synthesizing nut type perfumery 5-methyl-2-hepten-4-one. CN
Patent 1,198,432, 11 November 1998.
11. Wang, L.; Qin, J.; Luo, X.; Liu, X.; Jiang, M. Preparation method of 5-methyl-hepta-2-en-4-one from
butyrolactone. CN Patent 1,060,458,33, 21 June 2016.
12. Schulte-Elte, K.H.; Snowden, R.L.; Müller, B.L. Process for the preparation of - and -
unsaturated ketones. U.S. Patent 4,453,011, 5 June 1984.
13. Snowden, R.L.; Müller, B.L.; Schulte-Elte, K.H. Fragmentation of homoallylic alkoxides. Synthesis of
propenyl and 2-methylpropenyl ketones from carboxylic esters. Tetrahedron Lett. 1982, 23, 335–338.
14. Snowden, R.L.; Linder, S.M.; Müller, B.L.; Schulte-Elte, K.H. β-Cleavage of Bis(homoallylic) Potassium
Alkoxides. Two-Step Preparation of Propenyl Ketones from Carboxylic Esters. Synthesis of ar-Turmerone,
α-Damascone, β-Damascone, and β-Damascenone. Helv. Chim. Acta 1987, 70, 1858–1878.
15. Cheng, C. Method for synthesizing filbertone. CN Patent 1,015,972,23, 9 September 2009.
16. Lidong, L.; Yanwei, Z.; Weimin, J.; Zhijian, W. Method for preparing 5-methyl-2-hepten-4-one. CN Patent
1,020,306,26, 27 April 2011.
17. Zhang,J.; Blazecka, P.G.; Pflum, D.A.; Bozelak, J.; Vrieze, D.; Colbry, N.L.; Hoge, G.; Boyles, D.C.; Samas,
B.; Curran, T.T.; Osuma, A.T.; et al. The efficient synthesis of (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic
acid, a chiral β-amino acid with potent affinity for the α2δ protein. Tetrahedron Lett. 2009, 50, 1167–1170.
18. Felluga, F.; Pitacco, G.; Valentin, E.; Venneri, C.D. A facile chemoenzymatic approach to chiral non-racemic
β-alkyl-γ-amino acids and 2-alkylsuccinic acids. A concise synthesis of (S)-(+)-Pregabalin. Tetrahedron:
Asymmetry 2008, 19, 945–955.
19. Schanen, P. Asymmetric cyclopentannulation reactions: Scope and limitation. Ph.D. Thesis, Universite
Catholique de Louvain, Ottignies-Louvain-la-Neuve, Belgium, 2003.
20. Conia, J.-M.; Sandre, J.-P. Cyclobutanones and Cyclobutenones in Nature and in Synthesis. Bull. Soc. Chim.
Fr. 1963, 726, 744–752.
21. Poirier, Y.; Lozach; N. Heterocyclic sulfur-compounds. XXII. Sulfuration of 2-alkylidene-1-indanones and
2-arylmethylene-1-indanones. Bull. Soc. Chim. Fr. 1966, 1062–1068.
22. Krauss, S.R.; Smith, S.G. Kinetics and mechanism of the conjugate addition of lithium dimethylcuprate to
α,β-unsaturated ketones. J. Am. Chem. Soc. 1981, 103, 141–148.
23. Liu, Q.; Wang, Z.Y.; Peng, X.S.; Wong, H.N.C. Ligand-Free Iron-Catalyzed Carbon(sp2)–Carbon(sp2) Cross-
Coupling of Alkenyllithium with Vinyl Halides. J. Org. Chem. 2018, 83, 6325–6333.

Molecules 2019, 24, 4497
10 of 10
24. The attempted Br → Mg exchange using either activated metallic magnesium (dust or turnings) or Turbo
Grignard solution (iPrMgCl.LiCl) led to zero conversion of bromide 11 only, cf.: Krasovskiy, A.; Knochel,
P. A LiCl-Mediated Br/Mg Exchange Reaction for the Preparation of Functionalized Aryl- and
Heteroarylmagnesium Compounds from Organic Bromides. Angew. Chem. Int. Ed. 2004, 43, 3333–3336.
25. Appel, W.P.; Portale, G.; Wisse, E.; Dankers, P.Y.; Meijer, E.W. Aggregation of Ureido-Pyrimidinone
Supramolecular Thermoplastic Elastomers into Nanofibers: A Kinetic Analysis. Macromolecules 2011, 44,
6776–6784.
26. Crombie, L.; Jones, R.C.; Palmer, C.J.J. Synthesis of the Mammea coumarins. Part 1. The coumarins of the
mammea A, B, and C series. Chem. Soc., Perkin Trans. 1 1987, 317–331.
27. Schweizer, E.; Gaich, T.; Brecker, L.; Mulzer, J. Synthetic Studies towards the Total Synthesis of
Providencin. Synthesis 2007, 24, 3807–3814.
28. Seebach, D.; Ehrig, V.; Teschner, M. Erzeugung und Reaktionen des chiralen Lithiumenolats von (+)-(S)-3-
Methyl-2-pentanon. Justus Liebigs Ann. Chem. 1976, 7/8, 1357–1369.
Sample Availability: Samples of the compounds are not available from the authors, as the compounds are rather
volatile samples.
© 2019 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/).