Concise asymmetric syntheses of (S)-ethyl 4-methyloctanoate and its acid: Aggregation pheromones of rhinoceros beetles of the genus Oryctes

Article abstract of DOI:10.24820/ark.5550190.p010.477

A concise stereoselective approach to the asymmetric syntheses of (S)-ethyl 4-methyloctanoate and its acid, main aggregation pheromones of the genus Oryctes and an important fragrance compounds, is described. The synthesis utilizes the organocatalyzed Mac

Full text of DOI:10.24820/ark.5550190.p010.477

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Arkivoc 2018, vii, 0-0
Concise asymmetric syntheses of (S)-ethyl 4-methyloctanoate and its acid:
aggregation pheromones of rhinoceros beetles of the genus Oryctes
Rachana Pandey and Ranjana Prakash*
School of Chemistry and Biochemistry, Thapar Institute of Engineering and Technology, Patiala 147 001, India
Email: rprakash@thapar.edu
Received 01-09-2018
Accepted 10-15-2018
Published on line 12-07-2018
Abstract
A concise stereoselective approach to the asymmetric syntheses of (S)-ethyl 4-methyloctanoate and its acid,
main aggregation pheromones of the genus Oryctes and an important fragrance compounds, is described. The
synthesis utilizes the organocatalyzed MacMillan’s cross aldol reaction as key step. The synthetic approach
outlined permits synthesis of a variety of enantiopure branched methyl unsaturated and saturated fatty acids.
Keywords: Rhinoceros Beetle, Aggregation Pheromone, MacMillan’s cross Aldol reaction, Wittig olefination,
Fragrance
DOI: https://doi.org/10.24820/ark.5550190.p010.477
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Introduction
Rhinoceros beetles and rhynchophorus weevil of the genus Oryctes and Rhynchophorus, respectively, are the
two most significant destructive pests of commercial coconut (Cocos nucifera), date and oil palm plantations in
1-3
Africa, South-east Asia and Indian islands. Rhinoceros beetle attacks kill adult palms, provide entry point for
palm weevils, destructive insects and lethal diseases, reduce photosynthetically and damage inflorescences
4
and thereby, deteriorating revenue of coconuts and date and oil palms production. The ethyl 4-
methyloctanoate (1) and its acid derivative 2 are the two most important aggregation pheromone
5
components emitted by male rhinoceros beetles. The 4-methyl-5-nonanol (3) and 4-methyl-5-nonanone (4)
6-9
are recognized as Rhynchophorus ferrugineus Oliv. aggregation pheromones (Figure 1).
The 4-
methyloctanoic acid 2 has been also identified as a main fragrance compound of various foods such as Italian
10
11
12
cheese, Turkish tobacco, and within perinephric fats of a variety of red meat species.
O
O
Me
OR
Me
OH
R = Et 1
R = H 2
3
Me
OR
Me
O
R = Et 1a
R = H 2a
4
Figure 1. Structure of aggregation pheromones of rhinoceros beetles (1,2) and rhynchophorus weevils (3,4).
Various methods for the racemic synthesis of ethyl 4-methyloctanoate (1) and its acid derivative 2 have
4,13-17
been documented in the literature.
Most of the asymmetric syntheses for (R)- and (S)-ethyl 4-
methyloctanoate (1) and its acid 2 described employed either use of chromatographic diastereomeric
1
8
19
separation of phenylethylamides or phenylglycinol amides, chiral citronellol as starting material or
20-22
enzymatic resolution.
More recently, Guerrero and co-worker reported the asymmetric synthesis of (R)-
and (S)-4-methyloctanoic acid (2) via chirality induction through Myers alkylation reaction as key step.
23
Herein, we are reporting a simple synthetic approach to the ethyl 4-methyloctanoate (1) and its acid 2 and
further its application to the asymmetric syntheses (S)-ethyl 4-methyloctanoate (1a) and its acid 2a from
monosilylated ethylene glycol as a starting material employing organocatalyzed MacMillan’s cross aldol
reaction and Wittig olefination as key steps.
Results and Discussion
Our retrosynthetic analysis to the synthesis of (S)-ethyl 4-methyloctanoate (1a) and its acid 2a is displayed in
Scheme 1. The α,β-unsaturated ester derivative 6 was visualized as a synthetic intermediate from which ethyl
4-methyloctanoate (1) and its acid 2 could be synthesized via silyl ether deprotection, oxidative cleavage of
diol, Wittig homologation and reduction following standard organic functional group transformations. The α,β-
unsaturated ester derivative 6 envisaged from readily available monosilylated ethylene glycol derivative 7 via
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organocatalyzed MacMillan’s cross aldol reaction of aldehyde derived from 7 with propionaldehyde and Wittig
homologation reaction. The (R)- and (S)- configuration of the target compounds ethyl 4-methyloctanoate (1)
and its acid 2 can be manipulated by simply changing organocatalyst under MacMillan’s cross aldol conditions.
O
O
*
*
OEt
OR
Me
Me
5
R = Et 1
R = H 2
OH
O
TBDPSO
TBDPSO
*
OH
*
OEt
6
7
Scheme 1. Retrosynthetic approach to asymmetric syntheses of ethyl 4-methyloctanoate (1) and its
corresponding ethyl ester 2.
Our approach for the asymmetric synthesis of (S)-ethyl 4-methyloctanoate (1a) and its acid 2a is depicted
in Scheme 2. Syntheses of target compounds (S)-1a and (S)-2a began with readily available monosilylated
ethylene glycol 7 which was subjected to a two-step sequence including Swern oxidation followed by L-
proline catalyzed MacMillan’s cross aldol reaction to afford the diastereomeric mixture of aldehyde 5 with
26
>99% ee (anti/syn 9:1)
and subsequent 2C-Wittig olefination without separation with
(
ethoxycarbonylmethyl-ene)triphenylphosphorane furnished unsaturated ester 6a following a literature
27-28
procedure.
With olefin derivative 6a in hand, we then subjected it to silyl ether deprotection to get the diol
intermediate 9. Pleasingly, the minor diastereomer was separated out during column chromatography
purification. The NaIO mediated oxidative cleavage of terminal diol 9 followed by treatment of aldehyde
4
intermediate with phosphonium salt (propyltriphenyl-phosphonium bromide) in presence of n-BuLi as a base
furnished the olefin derivative 10. In view of the fact that the incipient olefin would be ultimately
hydrogenated to get the target compound 1a we did not examine the olefin geometry of derivative 10.
Accordingly, the olefin derivative 10 on hydrogenation at one atmospheric pressure in the presence of 10%
2
5
Pd-C furnished the target compound (S)-ethyl 4-methyloctanoate (1a) in 76% yield (over three steps); [α]
D
4
20
+1.61 (c 1.0, CHCl
3
); {lit. [α]
D
+1.67 (c 1.35, CHCl )}. Finally, saponification reaction of the (S)-ethyl 4-
3
methyloctanoate (1a) with LiOH in aqueous THF solvent at room temperature afforded the target compound
25
23
20
(
S)-4-methyloctanoic acid (2a) in 92% Yield; [α]
D
+1.46 (c 1.0, CHCl
3
); {lit. [α]
D
+1.5 (c 1.4, CHCl )}. The
3
physical and spectroscopic data were in full agreement with those reported literature.
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OH
OH
O
a
b
TBDPSO
TBDPSO
TBDPSO
OH
HO
O
OEt
Me
Me
7
8
6a
O
OH
O
c
d
OEt
OH
OEt
Me
Me
9
10
O
O
e
f
OEt
Me
Me
1a
2a
o
Scheme 2. Reagents and conditions: (a) i) (COCl)
L-Proline, dioxane, 4 C, 48 h, 94% (over two steps); (b) Ph
2
, DMSO, Et
3
N, dry CH
2
Cl
2
, -78 C to rt, 3 h; ii) C
3
H O, 10 mol %
6
o
3
PCHCOOEt, dry THF, rt, 24 h, 92%; (c) TBAF, THF, rt,
O (1:1), rt, 20 min.; ii) propyltriphenylphosphonium bromide, n-BuLi, THF, -78 °C
, 10% Pd-C, MeOH, rt, 4 h, 76% (over three steps); (f) LiOH, THF:H O (4:1), rt, 6h, 92%.
4
h, 95%; (d) i) NaIO
4
, THF:H
2
to rt, 3 h; (e) H
2
2
Conclusions
In conclusion, we have developed a simple and flexible approach to the total syntheses of (S)-ethyl 4-
methyloctanoate (1a) and its acid 2a from readily available starting materials. The synthetic sequence
demonstrates the application of organocatalyzed MacMillan’s cross aldol reaction and Wittig olefination as
the key steps. The synthetic approach described has significant potential for stereochemical variations and
further extension to other stereoisomers and their analogues.
Experimental Section
Ethyl (4R,5R,E)-5,6-dihydroxy-4-methylhex-2-enoate (9). To a stirred solution of unsaturated ester 6a (1.4 g,
3
.28 mmol) in dry THF (10 mL) TBAF (4.91 mL, 4.92 mmol) was added dropwise at room temperature. After
stirring the reaction mixture at room temperature for 4 h, the reaction mixture was diluted with water and
ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na SO and the solvent was
evaporated under reduced pressure. Silica gel column chromatography (hexane/EtOAc, 4:1) furnished olefin
2
4
25
diol 9 (988 mg, 95%) as a colorless liquid. [α]
D
+9.56 (c 1.0, CHCl
) δ: 6.97 (dd, J 8.28, 15.6 Hz, 1H), 5.87 (d, J 14.68 Hz, 1H), 4.19
q, J 7.32, 14.2 Hz, 2H), 3.71-3.59 (m, 2H), 3.56-3.49 (m, 1H), 3.08 (brs, 2H), 2.54-2.45 (m, 1H), 1.29 (t, J 7.32
3
); IR (CH
2 2
Cl ) ν: 3425, 2957, 2926, 1720,
-
1 1
1
(
478, 1268, 1220 cm ; H NMR (400 MHz, CDCl
3
1
3
Hz, 3H), 1.1 (d, J 6.84 Hz, 3H); C NMR (100 MHz, CDCl
3
) δ: 166.8, 150.3, 121.9, 74.8, 64.5, 60.4, 39.5, 15.8,
Na [M + Na] 211.0941; found 211.0952.
+
14.2. HRMS (ESI), m/z calcd for C
9
H
16
O
4
Ethyl (S)-4-methyloctanoate (1a). To a stirred solution of NaIO
was added a suspension of olefin diol 9 (100 mg, 0.53 mmol) in THF (3 mL) and stirred for 20 min at room
4
(226 g, 1.06 mmol) in H O:THF (1:1, 10 mL)
2
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temperature. To the reaction mixture EtOAc and water were added, the aqueous layer was extracted with
EtOAc (3 x 15 mL). The combined organic layer was washed with brine, dried over anhydrous Na SO , and
2
4
concentrated in vacuo. The aldehyde intermediate obtained was used as such for next reaction without
further purification.
To a suspension of propyltriphenylphosphonium bromide (264 mg, 0.69 mmol) in dry THF (5 mL) dropwise n-
o
BuLi (2.5 M in hexane, 0.3 mL, 0.79 mmol) at -78 C was added. The reaction mixture was warmed to rt over a
o
period of 1 h before being cooled to -78 C. To the obtained orange solution above crude aldehyde dissolved
in THF (3 mL) was added and the reaction mixture was left to warm to rt over 2 h before the addition of H
10 mL). The resulting suspension was extracted with EtOAc (3 x 10 mL). The combined organic layers were
washed with brine, dried over anhydrous Na SO and concentrated under reduced pressure to afford olefin
2
O
(
2
4
intermediate 10 as a colorless liquid which was used for the next reaction.
To a solution of above olefin intermediate 10 in methanol (4 mL) catalytic amount of palladium on carbon
(
10%) was added and resulting reaction mixture was stirred under hydrogen atmosphere for 4 h at room
temperature, at which point TLC indicated the completion of reaction. The reaction mixture was filtered
through a pad of Celite, solvent was removed in vacuo and silica gel column chromatography (hexane/ EtOAc
2
5
1
0:1) furnished ethyl (S)-4-methyloctanoate (1a) (73 mg, 76%) as a colourless liquid. [α]
D
+1.61 (c 1.0, CHCl
3
)
4
20
-1
1
{lit. [α]
D
+1.67 (c 1.35, CHCl
3
)}; IR (CH
Cl
2 2
) ν: 2957, 2946, 1735, 1478, 1268, 1215 cm ; H NMR (400 MHz,
CDCl ) δ: 4.12 (d, J 7.32, 14.2 Hz, 2H), 2.33-2.26 (m, 2H), 1.70-1.60 (m, 1H), 1.47-1.41(m, 2H) 1.31-1.27 (m, 5H);
3
1
3
1
1
2
.26 (t, J 6.88, 3H) 1.15-1.09 (m, 1H), 0.89 (t, J 6.88, 3H), 0.88 (d, J 6.40, 3H); C NMR (100 MHz, CDCl
3
) δ:
+
74.2, 60.2, 36.3, 32.4, 32.2, 31.9, 29.1, 22.9, 19.2, 14.2, 14.1. HRMS (ESI), m/z calcd for C11
H
22
O Na [M + Na]
2
09.1512; found 209.1514.
(
S)-4-methyloctanoic acid (2a). A mixture of ethyl (S)-4-methyloctanoate (1a) (50 mg, 0.27 mmol), LiOH (34
mg, 0.81 mmol), THF (2 mL) and water (0.5 mL) was stirred at room temperature for 6 h. The organic solvent
was removed under reduced pressure, and the residue obtained was then acidified to pH 5 with 1 N HCl, and
the reaction mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with
brine, dried over anhydrous Na
2
SO
4
and concentrated under reduced pressure. Silica gel column
chromatography (hexane /EtOAc 9:1) afforded the target compound (S)-4-methyloctanoic acid (2a) (39 mg,
2
5
23
20
9
2
1
3
2%) as a colorless liquid. [α]
D
+1.46 (c 1.0, CHCl
3
); {lit. [α]
D
+1.5 (c 1.4, CHCl
) δ: 2.42-2.31 (m, 2H); 1.73-1.63 (m, 1H);
3
)}. IR (CH
2
Cl ) ν: 3450, 3071,
2
-
1
1
957, 2946, 1715, 1468, 1268, 1215 cm ; H NMR (400 MHz, CDCl
.50-1.40 (m, 2H); 1.33-1.10 (m, 6H), 0.92-0.80 (m, 6H); C NMR (100 MHz, CDCl
1.6, 29.1, 22.9, 19.2, 14.1. HRMS (ESI), m/z calcd for C
3
13
3
) δ: 180.3, 36.3, 32.3, 31.8,
+
9
H
18
O
2
Na [M + Na] 181.1199; found 181.1219.
Acknowledgements
The authors acknowledge the research grant No. 02(0283)/16/EMR-II) facilitated by the Council for Scientific
and Industrial Research (CSIR), New Delhi, India for the carrying out the study. R. Pandey thanks Thapar
Institute of Engineering and Technology for the research associateship. We are thankful to Dr. Pradeep Kumar
Tripathi, NCL Pune for HPLC data analysis.
Supplementary Material
1
13
Copies of H and C NMR spectra of compounds 9, 1a and 2a are available in the supplementary material file.
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