Synthetic approach toward cis-disubstituted γ- And δ-lactones through enantioselective dialkylzinc addition to aldehydes: Application to the synthesis of optically active flavors and fragrances

Article abstract of DOI:10.1016/j.tet.2012.05.028

A versatile and straightforward approach to optically active cis-4,5-disubstituted γ- and δ-lactones by catalytic enantioselective addition of dialkyzincs to cinnamic aldehydes and RCM ring closure has been reported. The synthetic importance of the enantioselective dialkylzinc alkylation of aldehydes has been thus widened. Such an approach has then been employed for the enantioselective synthesis of naturally occurring γ-lactone flavors like (S)-5-ethyl-butanolide (6a) and (4S,5S)-cis-whisky lactone (6b) and extended to the preparation of δ-lactones like (5S,6S)-5-methyl-6-ethylpentanolide (9a), precursor of the pheromone serricornin.

Full text of DOI:10.1016/j.tet.2012.05.028

Tetrahedron 68 (2012) 5779e5784
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic approach toward cis-disubstituted g- and d-lactones through
enantioselective dialkylzinc addition to aldehydes: application to the synthesis
of optically active flavors and fragrances
y
*
Laura Pisani, Stefano Superchi , Alessandra D’Elia, Patrizia Scafato, Carlo Rosini
ꢀ
Dipartimento di Chimica, Universita della Basilicata, via dell’Ateneo Lucano 10, 85100 Potenza, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A versatile and straightforward approach to optically active cis-4,5-disubstituted g- and d-lactones by
Received 13 February 2012
Received in revised form 19 April 2012
Accepted 8 May 2012
catalytic enantioselective addition of dialkyzincs to cinnamic aldehydes and RCM ring closure has been
reported. The synthetic importance of the enantioselective dialkylzinc alkylation of aldehydes has been
thus widened. Such an approach has then been employed for the enantioselective synthesis of naturally
Available online 15 May 2012
occurring g-lactone flavors like (S)-5-ethyl-butanolide (6a) and (4S,5S)-cis-whisky lactone (6b) and ex-
tended to the preparation of
pheromone serricornin.
d
-lactones like (5S,6S)-5-methyl-6-ethylpentanolide (9a), precursor of the
Keywords:
Asymmetric catalysis
Enantioselective alkylation
Alkylzinc
Ó 2012 Elsevier Ltd. All rights reserved.
Optically active lactones
Whisky lactone
1. Introduction
We recently developed a new family of chiral aminoalcohols,
endowed with C2 symmetric 1,10-binaphthylazepine structure,
which efficiently catalyze the enantioselective addition of dialkyl,
diphenyl, and dialkynyl zinc reagents to aldehydes, providing good
to excellent enantioselectivity.8 Such results prompted us to ex-
plore the synthetic potential of these reactions in order to dem-
onstrate that they can provide not only a feasible test of the
catalysts activity, but also a reliable tool for the asymmetric syn-
thesis of complex intermediates.
The enantioselective alkylation of aldehydes by dialkylzinc re-
agents is by far one of the most studied asymmetric trans-
formations.1 This reaction was described for the first time in 1984
by Oguni and Omi, employing (S)-leucinol as a chiral catalyst.2
Since then a very large amount of different chiral catalytic pre-
cursors have been developed, often leading to high levels of
enantioinduction. Moreover, contrary to other popular enantiose-
lective reactions, in this case deep experimental and theoretical
investigations have defined with a good degree of certainty the
mechanism determining the asymmetric induction.3 The knowl-
edge of the reaction mechanism, joined to the ease of the operating
conditions made this reaction a popular benchmark to test the ef-
ficiency of new chiral ligands as chirality inducers.4 Surprisingly,
despite the vast number of reactivity studies undertaken over
a couple of decades, this reaction has found, until now, very few
synthetic applications.5 The only synthetic studies reported so far
concern the employment of such reaction in the preparation of
chiral methyl carbinol synthons, precursors of natural products,6
and the preparation of optically active 3-alkylphthalides.7
Generally speaking, the asymmetric alkylation of aldehydes af-
fords high ee’s with aryl and a,b-unsaturated aldehydes. Therefore,
in principle, it can provide access to optically active benzylic and
allylic alcohols. In particular, the latter compounds are potentially
valuable chiral intermediates and precursors of important natural
products. Interestingly, some recent works point out the role of
allylic alcohols as precursors of racemic
g b,g-un-
-lactones9 and
saturated
d
-lactones10 through esterification with, respectively,
acrylic or 3-butenoic acid followed by a ring closing metathesis
(RCM) reaction.11 We then envisaged that the catalytic enantiose-
lective dialkylzinc addition to aldehydes could be employed as
a key step for a new general approach to the synthesis of optically
active cis-4,5-disubstituted
g-lactones and cis-5,6-disubstituted d-
lactones as showed in Scheme 1.
The approach described herein then has the double aim of
showing the underexplored synthetic utility of the enantioselective
dialkylzinc addition and to provide a straightforward and versatile
* Corresponding author. Tel.: þ39 0971 206098; fax: þ39 0971 205678; e-mail
address: stefano.superchi@unibas.it (S. Superchi).
y
Deceased, February 18, 2010.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.028

5780
L. Pisani et al. / Tetrahedron 68 (2012) 5779e5784
Scheme 1.
method to obtain important intermediates. Five- and six-
membered lactones are in fact ubiquitous structures among natu-
ral products and in particular many pheromones and important
flavors and fragrances contain mono and dialkyl
In particular, while -lactones are important aroma components of
fruits, teas, wines, and spirits, -lactones are more commonly
g- or d
-lactones.12
g
d
detected in dairy products and other fermented foods. In such
compounds a direct correlation between the aromatic properties
and the absolute configuration at C-5 has been observed. Therefore,
the preparation of such compounds in optically active form de-
serves a high scientific and industrial relevance.
Scheme 2. Dialkylzinc enantioselective addition to cinnamic aldehydes.
2. Results and discussion
Table 1
Enantioselective addition of R2Zn to cinnamic aldehydes mediated by ligands 1aeca
At first, we investigated the key step for the preparation of the
required allylic alcohols, that is, the enantioselective dialkylzinc
Run Aldehyde
Ligand Time (h) Product Yieldb (%) ee (%)c (ac)d
R
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2b
2b
Me 1ae
Me 1be
Me 1ce
40
23
20
1
1
1
40
25
20
4
1
1
3a
3a
3a
3b
3b
3b
3c
3c
3c
3d
3d
3d
3e
3e
3e
72
99
99
91
99
99
50
60
70
99
99
99
18
52
97
46 (S)
72 (S)
72 (S)
68 (S)
78 (S)
78 (S)
36 (S)
56 (S)
60 (S)
76 (S)
90 (S)
90 (S)
82 (S)
90 (S)
94 (S)
addition to a,b-unsaturated aldehydes in the presence of ligands
1aec previously developed by us (Fig. 1).8
Et
Et
Et
1af
1bf
1cf
According to Scheme 1 the required starting chiral allylic alco-
hols could be derived from alkylation of propenals or 2-
alkylpropenals. Some preliminary attempts of dialkylzinc addi-
tions to both 2-methylpropenal and 2,3-dimethylpropenal were
however unsuccessful, providing mainly by-products deriving from
both aldehyde self-condensation and 1,4-addition of the alkylzinc
reagent.13 We then attempted to employ less reactive cinnamic
aldehydes. Much to our delight these substrates were found to be
much more stable under the reaction conditions and afforded good
to excellent yields and ee’s in the alkylation reaction with dia-
lkylzincs (vide infra).
Me 1ae
Me 1be
Me 1ce
9
10
11
12
13
14
15
Et
Et
Et
1af
1bf
1cf
Bu 1ae
Bu 1be
Bu 1ce
28
24
5
a
Reactions performed at rt in toluene.
Chromatographic (GLC) yield. No traces of benzylalcohols were detected.
Enantiomeric excess determined by HPLC on Chiralcel OD-H and OJ columns.
The reaction was carried out in dry toluene at 20 ꢀC in the
presence of 8e10 mol % of the chiral ligand and monitored by TLC
and GCeMS. When complete conversion of the aldehyde was
detected, the mixture was quenched by addition of 10% aqueous
HCl. After extraction with Et2O, drying, and evaporation of solvent,
the product ratio was directly determined on the crude mixture by
GCeMS and the ee of the product 1-alkyl-3-phenylpropanol 3 was
measured by HPLC or GC on chiral stationary phases (Scheme 2 and
Table 1).
b
c
d
Absolute configuration determined by comparison of [a]D with literature values:
see Experimental section.
e
10 mol% of aminoalcohol was used.
8 mol% of aminoalcohol was used.
f
The absolute configuration of carbinols 3aed was assigned by
comparison of optical rotations with literature values (see
Experimental section), while (S) absolute configuration was ten-
tatively assigned to the unknown optically active alcohol 3e taking
into account that previous studies8d,e have shown that binaph-
thylazepine aminoalcohols bearing an (S) configured binaphthyl
moiety promote alkylzinc attack on the Si face of aldehydes.
As inferred from Table 1, ligands 1b and 1c provided complete
conversion and good enantiomeric excess in both methylation and
ethylation of (E)-cinnamaldehyde. The corresponding carbinols 3a
and 3b being obtained in 72% and 78% ee, respectively (see runs 2,
3, 5, and 6). Conversely, lower yields and ee’s were achieved
employing ligand 1a. Ligands 1b and 1c proved to be more efficient
Fig. 1. 1,10-Binaphthylazepine aminoalcohol ligands.

L. Pisani et al. / Tetrahedron 68 (2012) 5779e5784
5781
also in the alkylation of (E)-2-methyl cinnamaldehyde. In all the
cases tested, ligand 1c provided faster reactions and slightly higher
enantioselectivity that 1b, affording 60, 90, and 94% ee in the ad-
dition of Me2Zn, Et2Zn, and Bu2Zn, respectively (see runs 9, 12, and
15). The latter result being particularly interesting, being, to the
best of our knowledge, the first example of enantioselective Bu2Zn
addition to this aldehyde. The relative efficiency of these three li-
gands was the same as observed in the alkylzinc addition to aro-
matic aldehydes.8e As far as Et2Zn addition is concerned, the ee
values reached are comparable with those reported in the literature
on the same aldehydes,14 while the results obtained with addition
of Bu2Zn and Me2Zn are particularly noteworthy, in terms of
chemical yields and enantioselectivity. In fact these two alkylzinc
reagents are generally much less reactive than the more commonly
used Et2Zn and often provide lower ee’s.3a,d
after chromatographic purification. Final catalytic hydrogenation of
5a in the presence of Raney-Ni,21 provided the
-lactone (S)-6a in
96% yield. The optical purity of all the intermediates was thor-
oughly checked after any synthetic step, confirming the retention of
the starting 78% ee.
g
A similar strategy was followed for the preparations of (4S,5S)-
cis-whisky lactone 6b. The lactone and its (4S,5R)-trans isomer are
released by oak barrels in wines and spirits during the aging pro-
cess and give appreciated aromas to these beverages.22 In particular
the (4S,5S)-cis-whisky lactone is regarded as the most important to
the sensory characteristics of wine.23 The importance of whisky
lactones led to the development of a number of syntheses of both
diastereoisomers in optically active form using either chiral pool24
or chiral auxiliaries.25 However, only a few reports employing
enantioselective catalysis26 and biocatalysis17a,27 are described.
Moreover these approaches are directed only toward the synthesis
of trans-whisky lactone and, to the best of our knowledge, no
enantioselective catalytic routes to optically active cis-whisky lac-
tone have been described to date. The synthesis of lactone 6b was
approached (Scheme 3) starting from allylic alcohol 3e, obtained in
94% ee (see Table 1, run 15) by enantioselective Bu2Zn addition to
(E)-2-methyl cinnamaldehyde. Alcohol 3e was transformed in the
corresponding acrylate 4b and the latter submitted to RCM with
first generation Grubbs’ catalyst 10. The obtained 4-methyl-5-ethyl
butenolide 5b was finally hydrogenated in the presence of Raney-
Ni,21 providing (4S,5S)-cis-whisky lactone 6b in a 9:1 cis/trans di-
astereoisomeric ratio. After chromatographic purification (4S,5S)-
cis-6b was recovered in 94% ee and overall 50% yield. This simple
and straightforward approach to optically active cis-whisky lactone
represents the first route to this important compound based on
enantioselective catalysis.
To demonstrate the generality and feasibility of the approach
depicted in Scheme 1 for the synthesis of optically active cis-4,5-
disubstituted
g-lactones and cis-5,6-disubstituted d-lactones, car-
binols 3b, 3d, and 3e were then employed as starting material for
the preparation of valuable
g and d lactones. Both g- and d-lactones
are present, among the others, in tobacco flavor,15 and in the scent
of some flowers,16,17 as well as in many other artificial or natural
fragrances.18
At first, the synthesis of optically active 5-alkyl
portant components of aroma of fruits, flowers, and beverages, was
attempted. 5-Ethyl -lactone 6a, endowed with an intense aroma of
g-lactones, im-
g
caramel and liquorice, is found in many fruits, but also in different
foods and beverages, like butter, beer, brandy, tea, and added to
tobacco as flavoring agent.19 It has been also identified as a phero-
mone of the Trogoderma glabrum beetle.20 Its preparation was then
attempted (Scheme 3) starting from the alcohol 3b, obtained in 78%
ee (see Table 1, run 6) by enantioselective Et2Zn addition to (E)-
cinnamaldehyde.
Following the synthetic analysis reported in Scheme 1, allylic
alcohols obtained by enantioselective alkylation of cinnamic alde-
hydes can also be employed as starting materials for obtaining
lactones.10,28 To test the feasibility of such an approach the syn-
thesis of optically active -lactone (5S,6S)-9a, a synthetic precursor
d-
d
of serricornin,29 the sex pheromone of the cigarette beetle (Lasio-
derma serricorne), was attempted. Accordingly, alcohol 3d, obtained
in 90% ee (see Table 1, run 12) by enantioselective Et2Zn addition to
2-methyl cinnamaldehyde, was transformed into the correspond-
ing ester with 3-butenoic acid (Scheme 4). The esterification was
performed in the presence of DCC, in CH2Cl2 at 0 ꢀC to avoid shift of
the acid double bond. Ester 7a was then submitted to RCM reaction
to afford the unsaturated six-membered lactone 8a. In this case
Scheme 3. Synthesis of g-lactones 6a,b.
The allylic alcohol 3b was esterified by treatment with acryloyl
chloride at 0 ꢀC in CH2Cl2, in the presence of anhydrous Et3N. After
treatment and chromatographic purification, ester 4a was obtained
in 70% yield. Compound 4a was then submitted to RCM heating at
40 ꢀC in CH2Cl2 in the presence of the first generation Grubbs’
catalyst 10. 5-Ethyl butenolide 5a was then obtained in 93% yield
Scheme 4. Synthesis of d-lactone 9a.

5782
L. Pisani et al. / Tetrahedron 68 (2012) 5779e5784
better results were obtained employing Grubbs’ second-generation
catalyst 11. Finally hydrogenation of 8a in the presence of Raney-Ni,
provided the saturated lactone (5S,6S)-9a with complete diaster-
eocontrol and 90% ee.
in hexane (1.0 M, 1.25 mL, 1.25 mmol). The mixture was stirred for
30 min, then a solution of aldehyde (0.62 mmol) in dry toluene
(1.3 mL) was added. The reaction was monitored by GCeMS and
when no more traces of the aldehyde were detected the reaction
was quenched by addition of 10% aqueous HCl. The mixture was
extracted with Et2O and the organic phase was washed with
brine, and dried over anhydrous Na2SO4. After evaporation of the
solvent the crude extract was directly analyzed by GCeMS to
determine the yield and either by HPLC or GC to establish the ee.
The reaction mixture was then purified by column chromatogra-
phy (SiO2; petroleum ether/Et2O 8:2) affording alcohols 3aee as
colorless oils.
3. Conclusions
We have reported herein a versatile and straightforward ap-
proach to optically active cis-4,5-disubstituted
g- and d-lactones
through catalytic enantioselective addition of dialkyzincs to cin-
namic aldehydes and RCM ring closure. This result extends the
synthetic importance of the enantioselective dialkylzinc alkylation
of aldehydes, a well-known reaction which, however, has found to
date few synthetic applications. Such an approach has been
employed for the synthesis of natural aromas like (S)-5-ethyl
butenolide (6a) and (4S,5S)-cis-whisky lactone (6b). In the latter
case the procedure described herein constitutes the first approach
reported for the synthesis of optically active cis-whisky lactone by
enantioselective catalysis. The same strategy was extended to the
4.2.1. (S)-(E)-1-Phenylpent-1-en-3-ol (3b).34 Yield 99%; ee 78% by
HPLC on Chiralcel OJ (hexane/2-propanol 98:2, flow 0.5 mL/
25
min, tR (R) 44.51 min, tR (S) 47.46 min). [
a
]
ꢁ7.3 (c 1.01,
D
25
CHCl3); Rf (20% Et2O/petroleum ether) 0.27; lit.14a
1.73, CHCl3) for S enantiomer in 87.6% ee; 1H NMR (400 MHz,
CDCl3) (ppm):0.91 (3H, t, J 7.3 Hz), 1.56e1.61 (2H, m), 2.28
[
a
]
ꢁ6.3 (c
D
d
preparation of
d
-lactones and tested in the synthesis of
d
-lactone
(1H, s), 4.12e4.18 (1H, m), 6.18 (1H, dd, J 6.8, 16.4 Hz), 6.53 (1H,
(5S,6S)-9a, a precursor of the pheromone serricornin. Moreover, the
employment of the novel 1,1-binaphthylazepine aminoalcohols
1aec as catalysts in the asymmetric addition of dialkylzinc com-
pounds to cinnamic aldehydes allowed the desired allylic alcohols
to be obtained in good to high ee’s, thus confirming the efficiency of
these atropisomeric binaphthyl ligands in asymmetric catalysis.
d, J 16.4 Hz), 7.21e7.27 (5H, m); 13C NMR (100 MHz, CDCl3)
d
(ppm): 10.4, 30.8, 74.9, 127.0, 128.1, 129.1, 130.9, 132.9, 137.4.
Anal. Calcd for C11H14O: C, 81.44; H, 8.70. Found: C, 81.42;
H, 8.71.
4.2.2. (S)-(E)-2-Methyl-1-phenylpent-1-en-3-ol (3d).35 Yield 99%;
ee 90% by HPLC on Chiralcel OD-H (hexane/2-propanol 99:1, flow
25
4. Experimental section
4.1. General
0.7 mL/min, tR (R) 63.87 min, tR (S) 72.22 min). [
a
a
]
þ28 (c 1.01,
D
CHCl3); Rf (20% Et2O/petroleum ether) 0.26; lit.14b
[
]
D
25 þ29.2 (c 1.1,
CHCl3) for S enantiomer in 83% ee; 1H NMR (400 MHz, CDCl3)
d
(ppm): 0.94 (3H, t, J 7.5 Hz), 1.44e1.71 (3H, m), 1.85 (3H, s), 4.10
(1H, t, J 6.5 Hz), 6.48 (1H, s), 7.20e7.34 (5H, m); 13C NMR (100 MHz,
CDCl3) (ppm): 10.1, 13.1, 27.9, 79.5, 126.1, 126.4, 128.1, 128.9,
1H NMR and 13C NMR spectra were recorded in CDCl3 on Bruker
Aspect 300 MHz and Varian INOVA 400 MHz spectrometers using
TMS as internal standard. Optical rotations were measured with
a JASCO DIP-370 digital polarimeter. GCeMS analyses were per-
formed on a Hewlett Packard 6890 chromatograph equipped with
an HP-5973 mass detector. Column chromatography was carried
out using Macherey-Nagel silica gel 60 (70e230 mesh). Analytical
thin-layer chromatography (TLC) was performed on Macherey-
Nagel aluminum sheets precoated with silica gel (0.25 mm). Tolu-
ene was freshly distilled prior its use on sodium benzophenone
ketyl and stored under nitrogen atmosphere. CH2Cl2 was freshly
distilled over CaH2 prior to its use. Triethylamine was distilled over
CaH2 and stored under nitrogen on KOH. Addition of dialkyzincs
was performed using syringe-septum cap techniques under a ni-
trogen atmosphere. Diethylzinc (1.0 M in hexane), dibutylzinc
(1.0 M in heptane), and dimethylzinc (2.0 M in toluene) were used
as purchased (Aldrich). Commercially available (Aldrich) (E)-cin-
namaldehyde and (E)-2-methyl cinnamaldehyde were distilled
prior their use and stored under a nitrogen atmosphere. Unless
otherwise specified the reagents were used without any purifica-
tion. Enantiopure ligands 1a,8b 1b,8c and 1c8e were prepared as
previously described. Spectroscopic data for allylic alcohols 3a30
and 3c31 and for all other known compounds fully matched those
reported in the literature. Enantiomeric excesses of alcohols 3aee
were determined by HPLC analysis performed on a JASCO PU-1580
pump with a Varian 2550 UV detector and Daicel Chiralcel OD-H
column. Absolute configuration of alcohols 3a,32 3b,14a 3c,33 and
3d14b was assigned by comparison of optical rotations with litera-
ture values.
d
137.6, 140.1. Anal. Calcd for C12H16O: C, 81.77; H, 9.15. Found: C,
81.80; H, 9.14.
4.2.3. (S)-(E)-2-Methyl-1-phenylhept-1-en-3-ol (3e).31 Yield 97%;
ee 94% by HPLC on Chiralcel OD-H (hexane/2-propanol 99:1, flow
0.7 mL/min, tR (R) 28.48 min, tR (S) 32.55 min); Rf (20% Et2O/pe-
troleum ether) 0.25; [
CDCl3)
a
]
25 þ18 (c 0.88, CHCl3); 1H NMR (300 MHz,
D
d
(ppm): 0.91 (3H, t, J 6.5 Hz), 1.14e1.36 (4H, m), 1.59e1.63
(2H, m), 1.85 (3H, s), 2.03 (1H, s), 4.12e4.16 (1H, t, J 6.5 Hz), 6.46
(1H, s), 7.20e7.34 (5H, m); 13C NMR (75 MHz, CDCl3)
d
(ppm):
13.1, 14.1, 22.7, 28.1, 34.8, 78.1, 125.7, 126.4, 128.1, 129.1, 137.8,
140.6. Anal. Calcd for C14H20O: C, 82.30; H, 9.87. Found: C, 82.25;
H, 9.91.
4.3. (S)-(E)-1-Phenylpent-1-en-3-yl acrylate (4a)
To a solution of alcohol (S)-3b (0.26 g; 1.60 mmol) in dry CH2Cl2
(37 mL) was added Et3N (0.44 mL; 3.20 mmol) and the mixture was
cooled to 0 ꢀC. To this solution was added dropwise acryloyl chlo-
ride (0.2 mL; 2.45 mmol) in dry CH2Cl2 (12 mL). The reaction was
monitored by TLC, and after 1 h, was quenched by the addition of
water. The mixture was extracted with CH2Cl2, the organic phase
was washed with brine, and dried over anhydrous Na2SO4. After
evaporation of the solvent, the residue was purified by column
chromatography (SiO2; petroleum ether/Et2O 10:1) affording ester
4a as a colorless oil (190.0 mg, 56%); Rf (9% Et2O/petroleum ether)
0.44; [
0.91 (3H, t, J 7.0 Hz), 1.76e1.82 (2H, m), 5.42 (1H, q, J 7.0 Hz), 5.85
(1H, dd, J 1.5, 10.5 Hz), 6.08e6.18 (2H, m), 6.41 (1H, d, J 16.0 Hz),
6.60 (1H, d, J 16.0 Hz), 7.20e7.31 (5H, m); 13C NMR (100 MHz,
25
a]
ꢁ3.2 (c 1.1, CHCl3); 1H NMR (400 MHz, CDCl3)
d (ppm):
D
4.2. Typical procedure for the dialkylzinc addition to
aldehydes
CDCl3) d (ppm): 9.6, 27.6, 76.2,126.6,127.4, 127.9, 128.5, 128.8, 130.6,
To a solution of the ligand (0.05 mmol) in dry toluene (3 mL)
under a nitrogen atmosphere at rt, was added a solution of R2Zn
132.6, 136.4, 165.6. Anal. Calcd for C14H16O2: C, 77.74; H, 7.46.
Found: C, 77.72; H, 7.48.

L. Pisani et al. / Tetrahedron 68 (2012) 5779e5784
5783
4.4. (S)-5-Ethylfuran-2(5H)-one (5a)36
4.8. (4S,5S)-5-Butyl-dihydro-4-methylfuran-2(3H)-one (6b)25d
A solution of the Grubbs’ catalyst 10 (first generation) (0.074 g;
0.09 mmol) in CH2Cl2 (9 mL) was added dropwise to solution of 4a
(0.19 g; 0.88 mmol) in CH2Cl2 (88 mL) at reflux. The reaction was
monitored by GCeMS. After 60 h the reaction was completed, the
solvent was removed by evaporation, and the crude extract was
purified by column chromatography (SiO2; petroleum ether/Et2O
3:1) affording 5a as a yellow oil (92.0 mg, 93%); Rf (20% Et2O/pe-
To a solution of 5b (52.0 mg, 0.33 mmol) in dry ethanol (5 mL)
was added Raney-Ni and the mixture was set under hydrogen at-
mosphere. The reaction was monitored by GCeMS and after 3 h the
mixture was filtered through Celite. After evaporation of the sol-
vent, the crude extract was checked by GCeMS, showing the
presence of 6b in 9:1 cis/trans ratio. The crude extract was then
purified by column chromatography (SiO2; petroleum ether/Et2O
3:1) affording cis-6b a colorless oil (42.0 mg, 82%, 94% ee). The
minor trans isomer was not isolated from the mixture; Rf (25% Et2O/
troleum ether) 0.15; [
a]
25 þ64 (c 1.0, CHCl3); lit.27a
[
a
]
25 þ95 (c 3.61,
D
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d (ppm): 0.91 (3H, t, J 7.0 Hz),
1.71e1.78 (2H, m), 4.94e4.97 (1H, m), 6.30 (1H, dd, J 1.5, 5.5 Hz),
pentane) 0.40; [
a
]
D
25 ꢁ66.0 (c 1.01, CH3OH); lit.25d
[a
]
25 ꢁ76.9 (c 1.73,
D
7.42 (1H, dd, J 1.5, 5.5 Hz); 13C NMR (100 MHz, CDCl3)
d
(ppm): 8.9,
CH3OH); 1H NMR (300 MHz, CDCl3)
d
(ppm): 0.91 (3H, t, J 7.0 Hz),
26.2, 84.4, 121.5, 156.2, 173.4. Anal. Calcd for C6H8O2: C, 64.27; H,
7.19. Found: C, 64.23; H, 7.21.
1.10 (3H, d, J 7.0 Hz), 1.10e1.80 (6H, m), 2.21 (1H, dd, J 3.7, 16.8 Hz),
2.51e2.62 (1H, m), 2.70 (1H, dd, J 8.1, 16.8 Hz), 4.36e4.44 (1H, m);
13C NMR (100 MHz, CDCl3)
d (ppm): 13.8, 13.9, 22.5, 28.1, 29.6, 33.1,
4.5. (S)-5-Ethyl-dihydrofuran-2(3H)-one (6a)37
37.5, 84.1, 177.1. Anal. Calcd for C9H16O2: C, 69.19; H, 10.32. Found: C,
69.22; H, 10.30.
To a solution of 5a (50.0 mg, 0.44 mmol) in dry ethanol (5.5 mL)
was added Raney-Ni and the mixture was set under a hydrogen
atmosphere. The reaction was monitored by GCeMS and after 3 h
the mixture was filtered through Celite. After evaporation of the
solvent, the crude extract was purified by column chromatography
4.9. (S)-(E)-2-Methyl-1-phenylpent-1-en-3-yl but-3-enoate (7a)
A solution of DCC in NMP (1 M, 1.1 mL, 1.10 mmol) was added to
a mixture of (S)-3d (180 mg, 1.01 mmol), 3-butenoic acid (90 mL,
(SiO2; petroleum ether/Et2O 3:1) affording 6a as a pale yellow oil
1.01 mmol), and DMAP (12.0 mg, 0.10 mmol) in CH2Cl2 (4 mL) at
0 ꢀC. The mixture was stirred for 5 h and then saturated aqueous
NaHCO3 and Et2O were added. The mixture was filtered and the
filtrate was extracted with Et2O. After evaporation of the solvent,
the crude extract was purified by column chromatography (SiO2;
petroleum ether/Et2O 9:1) to afford compound 7a as a colorless oil
25
(48.0 mg, 96%, 78% ee); Rf (25% Et2O/pentane) 0.42; [
a
]
ꢁ36 (c
D
0.65, CH3OH); lit.38
CDCl3)
[
a
]
D
25 ꢁ48.8 (c 1.0, CH3OH); 1H NMR (400 MHz,
d
(ppm): 0.95 (3H, t, J 7.0 Hz), 1.50e1.81 (3H, m), 2.26e2.29
(1H, m), 2.48 (2H, dd, J 7.0, 9.5 Hz), 4.34e4.40 (1H, quint., J 7.0 Hz);
13C NMR (100 MHz, CDCl3)
d
(ppm): 9.4, 27.4, 28.4, 28.8, 82.2, 177.4.
Anal. Calcd for C6H10O2: C, 63.14; H, 8.83. Found: C, 63.13; H, 8.84.
(200 mg, 82%); Rf (9% Et2O/petroleum ether) 0.42; [
a]
25 ꢁ6.4 (c 1.04,
D
CHCl3); 1H NMR (400 MHz, CDCl3)
d
(ppm): 0.91e0.98 (3H, m),
4.6. (S)-(E)-2-Methyl-1-phenylhept-1-en-3-yl acrylate (4b)
1.70e1.81 (2H, m), 1.86 (3H, s), 3.52 (2H, d, J 6.6 Hz), 5.16e5.20 (2H,
m), 5.21e5.29 (1H, m), 5.90e5.99 (1H, m), 6.48 (1H, s), 7.21e7.39
To a solution of (S)-3e (0.16 g; 0.81 mmol) in dry CH2Cl2 (19 mL)
was added Et3N (0.23 mL; 1.62 mmol) and the mixture was cooled
to 0 ꢀC. To this solution was added dropwise acryloyl chloride
(0.11 mL, 1.24 mmol) in dry CH2Cl2 (6 mL). The reaction was mon-
itored by TLC and after 1 h the reaction was quenched by addition of
water. The mixture was extracted with CH2Cl2, the organic phase
was washed with brine, and dried over anhydrous Na2SO4. After
evaporation of solvent, the residue was purified by column chro-
matography (SiO2; petroleum ether/Et2O 97:3) affording 4b as
(5H, m); 13C NMR (100 MHz, CDCl3)
d (ppm): 9.9, 13.6, 25.8, 39.5,
80.9, 118.4, 126.6, 127.8, 128.1, 129.0, 130.4, 135.6, 137.2, 170.8. Anal.
Calcd for C16H20O2: C, 78.65; H, 8.25. Found: C, 78.63; H, 8.26.
4.10. (S)-6-Ethyl-5-methyl-3H-pyran-2(6H)-one (8a)40
A solution of the Grubbs’ catalyst 11 (second generation)
(42.0 mg; 0.05 mmol) in CH2Cl2 (5 mL) was added dropwise to
a solution of 7a (130 mg; 0.50 mmol) in CH2Cl2 (50 mL) at reflux.
The reaction was monitored by GCeMS. After 20 h the reaction was
completed, the solvent was removed, and the crude extract was
purified by column chromatography (SiO2; petroleum ether/Et2O
a pale yellow oil (140 mg, 68%); Rf (9% Et2O/petroleum ether) 0.45;
25
[
a]
ꢁ1.9 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d (ppm): 0.91
D
(3H, t, J 6.6 Hz), 1.35e1.41 (6H, m), 1.60e1.88 (3H, m), 5.36 (1H, t, J
6.9 Hz), 5.82 (1H, d, J 10.4 Hz), 6.15 (1H, dd, J 17.2, 10.4 Hz), 6.43 (1H,
d, J 17.2 Hz), 6.53 (1H, s), 7.26e7.32 (5H, m); 13C NMR (75 MHz,
3:1) to afford 8a as a colorless oil (60.0 mg, 86%); Rf (25% Et2O/
25
petroleum ether) 0.16; [
a
]
D
þ40.6 (c 0.97; CHCl3); 1H NMR
CDCl3)
d
(ppm): 13.1, 14.1, 22.7, 28.1, 34.8, 78.1, 125.7, 126.4, 128.1,
(400 MHz, CDCl3) d (ppm): 0.96 (3H, t, J 7.5 Hz), 1.18e1.30 (2H, m),
128.5, 129.0, 129.2, 137.8, 140.6, 166.0. Anal. Calcd for C17H22O2: C,
79.03; H, 8.58. Found: C, 79.06; H, 8.57.
1.72 (3H, s), 3.02 (2H, s), 4.81 (1H, s), 5.71 (1H, s); 13C NMR
(100 MHz, CDCl3) (ppm): 8.2, 18.8, 26.9, 29.9, 84.0, 116.6, 132.5,
d
169.5. Anal. Calcd for C8H12O2: C, 68.54; H, 8.63. Found: C, 68.55;
H, 8.63.
4.7. (S)-5-Butyl-4-methylfuran-2(5H)-one (5b)39
A solution of the Grubbs’ catalyst 10 (first generation) (41.0 mg;
0.05 mmol) in CH2Cl2 (5 mL) was added dropwise to solution of
ester 4b (0.13 g; 0.50 mmol) in CH2Cl2 (50 mL) at reflux. The re-
action was monitored by GCeMS. When the reaction was com-
pleted, after 80 h, the solvent was removed by evaporation and the
crude extract was purified by column chromatography (SiO2; pe-
4.11. (5S,6S)-6-Ethyl-tetrahydro-5-methylpyran-2-one (9a)29
To a solution of 8a (20.0 mg, 0.14 mmol) in dry ethanol (1.7 mL)
was added Raney-Ni and the mixture was set under a hydrogen
atmosphere. The reaction was monitored by GCeMS and after 3 h
the mixture was filtered through Celite. After evaporation of the
solvent, the crude extract was purified by column chromatography
troleum ether/Et2O 4:1) affording 5b as a yellow oil (68.0 mg, 88%);
25
Rf (25% Et2O/petroleum ether) 0.18; [
NMR (400 MHz, CDCl3)
a
]
D
þ2.7 (c 1.07, CHCl3); 1H
(SiO2; petroleum ether/Et2O 3:1) to afford 9a as a colorless oil
25
d
(ppm): 0.87 (3H, t, J 6.9 Hz), 1.19e1.51 (4H,
(17.0 mg, 85%, 90% ee); Rf (25% Et2O/pentane) 0.40; [
a]
ꢁ58.2 (c
D
24
m), 1.83e1.90 (2H, m), 2.02 (3H, s), 4.77e4.86 (1H, m), 5.75 (1H, s);
1.01; CHCl3); lit.41
[
a]
ꢁ65.8 (c 1.02; CHCl3); 1H NMR (400 MHz,
D
13C NMR (100 MHz, CDCl3)
d
(ppm): 13.8, 13.9, 22.2, 26.2, 31.6, 84.6,
CDCl3) d (ppm): 0.91 (3H, t, J 6.7 Hz), 0.96 (3H, d, J 7.6 Hz), 1.40e1.75
116.5, 168.3, 173.3. Anal. Calcd for C9H14O2: C, 70.10,; H, 9.15. Found:
C, 70.06; H, 9.16.
(3H, m),1.90e2.05 (2H, m), 2.47 (2H, t, J 7.6 Hz), 4.14 (1H, ddd, J 11.5,
5.5, 2.8 Hz); 13C NMR (100 MHz, CDCl3)
(ppm): 10.1, 12.3, 25.1,
d

5784
L. Pisani et al. / Tetrahedron 68 (2012) 5779e5784
ꢁ
ꢀ
Jimeno, C.; Pasto, M.; Riera, A.; Pericas, M. A. J. Org. Chem. 2003, 68,
3130e3138; (d) Rodríguez-Escrich, S.; Reddy, K. S.; Jimeno, C.; Colet, G.;
26.2, 26.7, 30.1, 84.6, 171.9. Anal. Calcd for C8H14O2: C, 67.57; H, 9.92.
Found: C, 67.60; H, 9.95.
ꢀ
ꢀ
Rodríguez-Escrich, C.; Sola, L.; Vidal-Ferran, A.; Pericas, M. A. J. Org. Chem.
2008, 73, 5340e5353.
15. Petterson, T.; Eklund, A. M.; Wahlberg, I. J. Agric. Food Chem. 1993, 41,
2097e2103.
Acknowledgements
16. Tamogami, S.; Awano, K.; Amaike, M.; Takagi, Y.; Kitahara, T. Flavour Fragrance J.
2004, 19, 1e5.
ꢀ
Financial support from Universita della Basilicata (Potenza) and
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of new efficient methods and their application to bioactive mole-
cules’) is gratefully acknowledged.
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