Asymmetric synthesis of (R)- and (S)-4-methyloctanoic acids. A new route to chiral fatty acids with remote stereocenters

Article abstract of DOI:10.1016/j.tetasy.2009.02.041

The enantioselective synthesis of both enantiomers of 4-methyloctanoic acid, one major aggregation pheromone component of the rhinoceros beetles of the genus Oryctes and an important aroma compound, is described. The key step of the synthesis is based on

Full text of DOI:10.1016/j.tetasy.2009.02.041

Tetrahedron: Asymmetry 20 (2009) 420–424
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of (R)- and (S)-4-methyloctanoic acids. A new route
to chiral fatty acids with remote stereocenters
Lourdes Muñoz a, Ma Pilar Bosch a, Gloria Rosell b, Angel Guerrero a,
*
a Department of Biological Chemistry and Molecular Modelling, IQAC (CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
b Unit of Medicinal Chemistry (Associated to CSIC), Faculty of Pharmacy, University of Barcelona, Av. Diagonal, s/n, 08028 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective synthesis of both enantiomers of 4-methyloctanoic acid, one major aggregation
pheromone component of the rhinoceros beetles of the genus Oryctes and an important aroma com-
pound, is described. The key step of the synthesis is based on a stereospecific alkylation with an alco-
Received 1 December 2008
Accepted 10 February 2009
Available online 25 March 2009
hol-protected alkyl iodide using
a pseudoephedrine derivative as a chiral auxiliary followed by
subsequent removal of the auxiliary. Both enantiomers are obtained in excellent yields and enantioselec-
tivities (93–94% ee). The strategy outlined allows preparation of a wide variety of enantiopure methyl-
branched saturated and unsaturated fatty acids.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
pseudoephedrine amides undergo efficient and highly diastereose-
lective alkylation reactions with a wide range of alkyl iodides18–21
Rhinoceros beetles are one of the most important pests of coco-
nuts, oil palms, and date palms in Middle-East, North Africa, South,
and Southeast Asia.1,2 The adults burrow galleries into the growing
points of palms killing the mature trees by defoliation or producing
wounds that favor entry points for palm weevils or lethal dis-
eases.3,4 The main pheromone components emitted by males of
most of the rhinoceros beetles of the genus Oryctes are 4-methyl-
octanoic acid 1 and its corresponding ethyl ester.5 The acid has
been described also as an important aroma compound of Turkish
tobacco,6 Italian cheese,7 and in perinephric fats of various red
meat species.8
giving rise to a variety of compounds with different functional
groups, such as alcohols, carboxylic acids, aldehydes, and ke-
tones.21 Therefore, these chiral auxiliaries appeared to be suitable
for our purposes. Our approach involves two key steps: (1) stereo-
specific alkylation of pseudoephedrinepropionamides 2 with 1-
benzyloxy-3-iodopropane 3 followed by removal of the auxiliary,
and (2) Wittig reaction of the a-substituted aldehyde 6. Both steps
occurred with excellent yields and full preservation of chirality
with the acids (R)-1 and (S)-1 being obtained in 41–55% overall
yields and 93–94% ee.
Several approaches have been reported for the synthesis of
racemic 4-methyloctanoic acid.3,9–12 However, the optically active
(R)- and (S)-4-methyloctanoic acids 1 have only been obtained by
the use of citronellol as chiral starting material3,13, liquid chro-
matographic separation of diastereomeric phenylglycinol amides13
or phenylethylamides,14 or enzymatic resolution of the racemic
material,15–17 but no asymmetric synthesis involving induction of
chirality has been reported so far.
O
O
OH
OH
Me
Me
(R)-1
(S)-1
We report herein the first asymmetric synthesis of both enanti-
omers of 4-methyloctanoic acid, (R)- and (S)-1, using a pseudoe-
phedrine amide as a chiral auxiliary. The structure of these
compounds is apparently simple but the distance between the ste-
reocenter and the functional group turns the synthesis into a chal-
2. Results and discussion
The starting amides (R,R)-(ꢀ)- and (S,S)-(+)-pseudoephedrine-
propionamides 2 are enantiomerically pure and commercially
available (99% ee, Aldrich).
lenge. Moreover, conservation of the chirality at the
a-carbon to
the carbonyl during the synthesis was an additional subject of con-
cern. The selected methodology has been based on the fact that
Alkylation with 1-benzyloxy-3-iodopropane 3, obtained by a
modification of Corey’s procedure in 92% yield22, using 1.9 equiv
of LDA in the presence of anhydrous LiCl, afforded stereospecifi-
cally (S,R,R)-4 and (R,S,S)-4 in 90–98% yields (Scheme 1).
* Corresponding author. Tel.: +34 934006120; fax: +34 932045904.
E-mail address: agpqob@iiqab.csic.es (A. Guerrero).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.041

L. Muñoz et al. / Tetrahedron: Asymmetry 20 (2009) 420–424
421
O
OBn
Me
Me
OH
Me
N
OH
O
H
O
v
N
ii
i
X
Me
BnO
I
87-89%
+
Me
O
90-98%
Me
O
(R,R)-2
(S,S)-2
3
(S,R,R)-4
(R,S,S)-4
(S)-6
(R)-6
(S)-7
(R)-7
81-88% iii
iv
75-76%
vi 97-99%
O
OH
Me
5
(S)-
(R)-5
O
O
vii
viii
O
CF3
OH
OH
Me
88-95%
91-95%
Me
Me
9
9
(R,R)-
(R,S)-
(R)-1
(S)-1
(R)-8
(S)-8
Scheme 1. Asymmetric synthesis of 4-methyloctanoic acid 1. Reagents and conditions: (i) LDA/THF, LiCl; (ii) LiAlH(OEt)3, ꢀ78 °C, TFA, 0 °C; (iii) LDA/THF, BH3ꢁNH3, 0 °C; (iv)
(COCl)2/CH2Cl2, DMSO, DIPEA, ꢀ78 °C; (v) CH3CH2CH2PPh3Br, KOtBu/THF; (vi) H2, Pd/C, EtOH, rt.; (vii) CrO3, H2SO4, 0 °C; (viii) EDCꢁHCl, Et3 N, DMAP/CH2Cl2, rt.
The absolute configuration of the newly generated stereocenter
was assumed to follow the general rule proposed by Myers
et al.18; the major alkylation product resulting from electrophilic
attack on the putative (Z)-enolate from the same face (1,4-syn) as
the C–Me group of the auxiliary when the enolate is drawn in a
planar, extended conformation.
purity of acids 1 was obtained by derivatization with (R)-(ꢀ)-2,2,2-
trifluoro-1-(9-anthryl)ethanol, a known reagent for the resolution
of enantiomers by 19F NMR and/or HPLC analysis of the corre-
sponding diastereomers27, in the presence of 1-ethyl-3-(3-dimeth-
ylaminopropyl)carbodiimide hydrochloride (EDCꢁHCl)/Et3 N/DMAP
in CH2Cl2 (Scheme 1).
Attempts to directly convert amide (S,R,R)-4 to aldehyde (S)-6
by using lithium triethoxyaluminum hydride23 under different
conditions (solvent, reagents stoichiometry, etc) failed. This re-
agent is prepared in situ by reaction of lithium aluminum hydride
with ethyl acetate in 1:1.5 molar ratio, and has been used success-
fully to prepare aldehydes in good yields and enantioselectivity.18
In our hands, however, the starting amide (S,R,R)-4 was recovered
unchanged in most cases along with the expected aldehyde (S)-6
but in poor yields (less than 40%) and with loss of enantiomeric
purity. Therefore, we decided to reduce amides (S,R,R)-4 and
(R,S,S)-4 to the corresponding alcohols (S)-5 and (R)-5 in the pres-
ence of lithium amidotrihydroborate.24 This reducing agent was
prepared in situ by reaction of LDA with borane-ammonia complex
in THF at 0 °C. The reaction provided the expected alcohols 5 in 81–
88% yields without apparent epimerization. Swern oxidation19 of
alcohols (S)-5 and (R)-5 furnished aldehydes (S)-6 and (R)-6 in
75–76% yields. Wittig reaction with propyltriphenylphosphonium
bromide/KtBuO in THF afforded benzyl-protected (S)- and (R)-(Z)-
4-methyl-5-octanol 7 in 87–89% yields without loss of enantio-
meric purity, as determined by the specific rotation values of alco-
hols (R)-8 and (S)-8 in comparison to the literature.25 This step
Derivatization occurred in excellent yields (91–95%) and the
resulting esters 9 were initially analyzed by 19F NMR in the pres-
ence of tris[3-(trifluoromethylhydroxymethylen)-(+)-camphorato]
europium (III)28 but without success. However, HPLC analysis on
a Chiralcel OD column under isocratic conditions (hexane:2-propa-
nol 95:5, flow rate 1 ml/min) resulted in a baseline separation of
both diastereomers (R,R)-9 (de 94%) and (R,S)-9 (de 93%) (Fig. 1).
Considering that no racemization occurred during the derivati-
zation step, the enantiomeric purity of (R)-1 and (S)-1 was 94% and
93% ee, respectively, which agrees with the calculated values based
on the specific rotation data previously obtained.
allows the possibility to prepare a large variety of 4-methyl
D-5
fatty acids of cis stereochemistry of different chain lengths.
Hydrogenation of compounds 7 with Pd/C promoted reduction
of the double bond and concomitant removal of the benzyl protect-
ing group to produce the corresponding alcohols 8 in almost quan-
titative yields. Finally, oxidation with Jones reagent26 afforded the
desired (R)-1 and (S)-1 acids in 88–95% yields and with specific
rotations consistent with those reported previously.14
Figure 1. Enantiomeric resolution of derivatives (R,R)-9 (left) and (R,S)-9 (right) by
chiral HPLC using a Chiralcel OD column (250 mm ꢂ 4.6 mm i.d.).
3. Conclusion
Determination of diastereomeric/enantiomeric purity of the dif-
ferent intermediates 4–8 was based in most cases on their specific
rotation values and subsequent comparison with those from the
literature. Direct calculation of the enantiomeric purity of diaste-
reomers 4 and enantiomers 1, 7, and 8 was not possible by chiral
GC on a Cydex-B column because of the very low volatility of the
compound (in the case of diastereomers 4) or due to the enhanced
separation difficulty induced by the remote location of the stereo-
genic center from the functional group (in the case of compounds
1, 7, and 8). Finally, unequivocal determination of the enantiomeric
The first asymmetric synthesis of (R)- and (S)-4-methyloctanoic
acid has been achieved in good overall chemical yields and enanti-
oselectivities by induction of chirality through Myers alkylation
methodology. The strategy outlined here allows the preparation
of a wide variety of enantiopure methyl-branched saturated and
unsaturated fatty acids just by the simple choice of the alkylating
electrophile with different chain lengths and the required ylid for
the hydrophobic part of the molecule.

422
L. Muñoz et al. / Tetrahedron: Asymmetry 20 (2009) 420–424
afforded amide (S,R,R)-4 as a highly viscous yellow oil (4.86 g,
4. Experimental
4.1. General
90%). ½a 2D0
ꢃ
¼ ꢀ55:3 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3), (ma-
jor rotamer): d 7.29 (m, 10H); 4.50–4.61 (m, 1H); 4.48 (s, 2H); 4.44
(m, 1H); 3.49 (m, 2H); 3.42 (t, J = 6.3 Hz, 2H); 2.81 (s, 3H); 2.63 (m,
1H); 1.38–1.74 (m, 4H); 1.1 (m, 6H) ppm. 13C NMR (100 MHz,
CDCl3), (major rotamer): d 178.8 (C); 142.5 (C); 138.5 (C); 128.7
(CH); 128.3 (CH); 128.2 (CH); 127.6 (CH); 127.5 (CH); 126.3
(CH); 76.4 (CH); 72.9 (CH2); 70.2 (CH2); 57.8 (CH); 36.3 (CH);
33.1 (CH3); 30.6 (CH2); 27.5 (CH2); 17.3 (CH3); 14.4 (CH3) ppm.
n-Butyllithium (1.6 or 2.5 M in hexane), (R)-(ꢀ)-2,2,2-trifluoro-
1-(9-anthryl)ethanol, (1R,2R)-(ꢀ)- and (1S,2S)-(+)-pseudoephe-
drinepropionamide, were purchased from Aldrich. All reactions
employing organometallic compounds were carried out under ar-
gon atmosphere. All solvents were dried and distilled according to
standard procedures. IR spectra were recorded on a Bomen MB-
120 or on a Nicolet Avatar 360 FT-IR spectrometer. NMR spectra
were recorded at 300, 400, or 500 MHz for 1H, 75 or 100 MHz for
13C, and 282 MHz for 19F, on a Varian Unity 300, Varian Mercury
400, or Varian Inova 500 spectrometer. Mass spectra (MS) were
obtained on a Fisons MD 800 instrument and high resolution
mass spectra LC/ESI-MS were run on a UPLC Acquity (Waters
USA) coupled to a mass spectrometer LCT Premier XE (Waters
IR (film) m: 3369, 3034, 2975, 2940, 2861, 1614, 1451, 1111, 731,
695 cmꢀ1. MS (EI) m/z (%): 351 (M-18, 12); 237 (39); 205 (48);
148 (54); 147 (71); 146 (70); 131 (63); 92 (58); 91 (100); 77
(30); 71 (10); 58 (57); 56 (60). HRMS Calcd for C23H32NO3 (M+):
370.2382; Found: 370.2388.
4.2.3. (2S)-5-Benzyloxy-2-methyl-1-pentanol (S)-530
A
solution of n-butyllithium in hexanes (2.5 M, 9.5 ml,
23.84 mmol) was added dropwise to a cold (ꢀ78 °C) solution
of diisopropylamine (3.6 ml, 25.10 mmol) in THF (25 ml). The
solution was warmed to 0 °C and stirred for 10 min, and then
the borane-ammonia complex (0.82 g, 23.84 mmol) was added
in a single portion. The reaction was stirred at 0 °C for an addi-
tional 15 min and then warmed to room temperature for
15 min. The reaction was re-cooled (0 °C) for the dropwise addi-
tion of amide (S,R,R)-4 (2.20 g, 5.96 mmol) in THF (15 ml), and
then warmed to room temperature until the reaction was com-
pleted by TLC (2 h). The mixture was cooled to 0 °C and 3 N HCl
was added carefully. The slurry was stirred for 30 min at 0 °C
and extracted with ether. The combined organics were washed
with 1 N HCl, 1 N NaOH, brine, dried over MgSO4, filtered, con-
centrated, and purified on column chromatography (hex-
ane:ether; 7:3) to give (S)-5 (1.00 g, 81%) as a pale yellow oil,
USA) with
a
TOF analyzer using
a
BEH C18 1.7 lm
(2.1 ꢂ 50 mm) column. Elemental analyses were determined on
a Carlo Erba-1106, Carlo Erba EA-1108, or Perkin Elmer CHN
2400 analyzer. Optical rotations were measured on a Perkin–El-
mer 341 polarimeter.
4.2. Synthesis of acids (R)-1 and (S)-1
29
4.2.1. 1-Benzyloxy-3-iodopropane 3
This compound was prepared by a modified procedure to that
described by Corey.22 To a stirred, cooled (0 °C) solution of 3.00 g
(18.05 mmol) of 3-benzyloxy-1-propanol, 10.41 g (39.71 mmol)
of recrystallized triphenylphosphine, and 2.70 g (39.71 mmol) of
imidazole in 40 ml of acetonitrile and 80 ml of Et2O was slowly
added 10.08 g (39.71 mmol) of iodine. After being stirred for 2 h,
the reaction mixture was diluted with ether and sequentially
washed with saturated aqueous Na2S2O3, saturated aqueous
CuSO4, and water. The organic layer was dried over MgSO4, filtered,
and concentrated to give 4.58 g (92%) of 1-benzyloxy-3-iodopro-
pane 3 as a yellow oil, which was used without further purification.
1H NMR (300 MHz, CDCl3): d 7.35 (m, 5H); 4.53 (s, 2H); 3.56 (t,
J = 5.7 Hz, 2H); 3.32 (t, J = 6.9 Hz, 2H); 2.11 (tt, J1 = 6.9 Hz,
J2 = 5.7 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3): d 138.2 (C);
128.4 (CH); 127.6 (CH); 73.1 (CH2); 69.5 (CH2); 33.5 (CH2); 3.5
½
a 2D0
ꢃ
¼ ꢀ9:4 (c 6.6, CHCl3); lit.30 = ꢀ8.7 (c 1, MeOH). 1H NMR
(300 MHz, CDCl3): d 7.32 (m, 5H); 4.50 (s, 2H); 3.46 (m, 4H);
1.43–1.78 (m, 3H); 1.10–1.28 (m, 2H); 0.92 (d, J = 6.6 Hz, 3H)
ppm. 13C NMR (75 MHz, CDCl3):
d 138.5 (C); 128.3 (CH);
127.6 (CH); 127.5 (CH); 72.9 (CH2); 70.6 (CH2); 68.1 (CH2);
35.6 (CH); 29.5 (CH2); 27.1 (CH2); 16.5 (CH3) ppm. IR (film)
m
: 3395, 2898, 1455, 1357, 1095, 905, 725 cmꢀ1. MS (EI) m/z
(%): 208 (M+, 30); 147 (18); 108 (77); 107 (91); 105 (61);
104 (58); 99 (68); 92 (86); 91 (100); 89 (49); 83 (54); 69
(64); 65 (72); 55 (63)
(CH2) ppm. IR (film)
m: 3089, 3067, 3030, 2936, 2883, 2854,
1494, 1447, 1368, 1174, 1096, 1021, 735, 693 cmꢀ1. MS (EI): m/z
(%) 277 (M+1, 28); 276 (M+, 1); 275 (M-1, 20); 217 (15); 169
(43); 149 (42); 130 (59); 127 (40); 121 (53); 105 (57); 90 (100);
80 (24); 77 (99); 75 (20); 74 (22); 71 (11); 65 (99); 63 (42); 50
(82); 41 (95).
4.2.4. (2S)-5-Benzyloxy-2-methyl-1-pentanal (S)-631
DMSO (264
(224
ll, 3.72 mmol) was added to oxalyl chloride
l, 2.65 mmol) in cold (ꢀ78 °C) dichloromethane (18 ml),
l
and the mixture was stirred for 10 min before alcohol (S)-5
(0.37 g, 1.78 mmol) was added. After stirring for an additional
20 min, diisopropylethylamine (924 ll, 5.30 mmol) was added in
a single portion, and the cold bath was subsequently removed.
The reaction was allowed to warm for 30 min before being
quenched via the addition of water. The product was extracted
with ether and the combined organic layers were dried over
MgSO4. The solvent was removed under reduced pressure using
an ice bath. The crude mixture was flashed through a silica chro-
matographic column eluting with pentane:ether (9:1) to give a
4.2.2. (2S)-N-Methyl-N-[(1R,2R)-2-hydroxy-1-methyl-2-
phenylethyl]-2-methyl-5-benzyloxypentamide (S,R,R)-4
A
solution of n-butyllithium in hexanes (1.5 M, 41 ml,
61.50 mmol) was added to a suspension of lithium chloride
(8.31 g, 196.04 mmol) and diisopropylamine (9.4 ml, 66.33 mmol)
in THF (40 ml) at ꢀ78 °C. The resulting suspension was briefly
warmed to 0 °C and then cooled to ꢀ78 °C. An ice-cooled solution
pale yellow oil (0.27 g, 75%). ½a D20
ꢃ
¼ þ9:3 (c 1.3, CHCl3). 1H NMR
of
(1R,2R)-(ꢀ)-pseudoephedrinepropionamide
(7.16 g,
(300 MHz, CDCl3): d 9.62 (d, J = 1.8 Hz, 1H); 7.32 (m, 5H); 4.50
(s, 2H); 3.49 (t, J = 6.0 Hz, 2H); 2.36 (tqd, J1 = J2 = 6.9 Hz,
J3 = 1.8 Hz, 1H); 1.41–1.88 (m, 4H); 1.11 (d, J = 3.9 Hz) ppm. 13C
NMR (75 MHz, CDCl3): d 205.0 (C); 138.4 (C); 128.4 (CH); 127.6
(CH); 127.5 (CH); 72.9 (CH2); 69.9 (CH2); 46.0 (CH); 27.1 (CH2);
32.35 mmol) in THF (90 ml) was added via cannula. The mixture
was stirred at ꢀ78 °C for 1 h, at 0 °C for 15 min, and at room tem-
perature for 5 min. The mixture was cooled to 0 °C, and iodide 3
(4.26 g, 15.43 mmol) was added neat to the reaction mixture. After
being stirred at 0 °C for 2 h and room temperature overnight, the
mixture was treated with saturated aqueous ammonium chloride
solution and extracted with ethyl acetate. The combined organic
extracts were dried over MgSO4 and concentrated. Purification of
the residue by flash column chromatography (hexane:AcOEt; 3:2)
13.3 (CH3) ppm. IR (film)
m: 2935, 2862, 1729, 1456, 1361,
1119, 742 cmꢀ1. MS (EI) m/z (%): 206 (M+, 9); 188 (3); 173 (11);
115 (44); 107 (82); 99 (40); 91 (100); 79 (60); 69 (78); 65
(68); 57 (61); 43 (39).

L. Muñoz et al. / Tetrahedron: Asymmetry 20 (2009) 420–424
423
4.2.5. (4S)-1-Benzyloxy-4-methyl-5-octene (S)-7
370.2382; Found: 370.2385. The spectroscopic data are identical to
n-Propyltriphenylphosphonium bromide (1.02 g, 2.65 mmol)
was added in one portion to a cooled (0 °C) suspension of KtBuO
(0.30 g, 2.65 mmol) in THF (4 ml). The suspension turned bright
yellow, was warmed to room temperature, and was stirred for
45 min. Aldehyde (S)-6 (0.38 g, 1.85 mmol) was dissolved in THF
(2 ml) and added to the reaction mixture at room temperature.
Stirring was continued for 45 min, the reaction quenched with
water and extracted with hexane. The combined organics were
washed with brine, dried over MgSO4, filtered, concentrated,
and chromatographed (hexane:ether; 98:2) to give (S)-7 (0.37 g,
those of (S,R,R)-4.
4.2.9. (2R)-5-Benzyloxy-2-methyl-1-pentanol (R)-532
Following the procedure described above for (S)-5 and starting
from (R,S,S)-4 (3.00 g, 8.12 mmol), DIPA (4.8 ml, 34.10 mmol), n-
BuLi (2.2 M, 14.8 ml, 32.48 mmol), and BH3ꢁNH3 (1.11 g,
32.48 mmol), the corresponding alcohol (R)-5 (1.49 g, 88%) was ob-
tained as a yellow oil after purification on column chromatogra-
phy. ½a 2D0
ꢃ
¼ þ9:5 (c 1.0, CHCl3); lit.32 = +8.2 (c 6.8, CHCl3). The
spectroscopic data are identical to those of (S)-5.
87%) as a colorless oil, ½a D20
ꢃ
¼ ꢀ4:4 (c 1.1, CHCl3). 1H NMR
4.2.10. (2R)-5-Benzyloxy-2-methyl-1-pentanal (R)-631
A procedure identical to that described above for (S)-6 was fol-
lowed. Thus, from alcohol (R)-5 (1.45 g, 6.97 mmol), DMSO (1 ml),
oxalyl chloride (886 ll, 10.47 mmol), and DIPEA (3.3 ml,
18.75 mmol), aldehyde (R)-6 (1.09 g, 76%) was obtained as a pale
(300 MHz, CDCl3): d 7.26–7.37 (m, 5H); 5.32 (m, 1H); 5.09 (m,
1H); 4.51 (s, 2H); 3.46 (t, J = 6.6 Hz, 2H); 2.44 (m, 1H); 2.03 (m,
2H); 1.14–1.71 (m, 4H); 0.96 (t, J = 7.5 Hz, 3H); 0.95 (d,
J = 6.6 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): d 138.6 (C);
135.3 (CH); 130.3 (CH); 128.3 (CH); 127.6 (CH); 127.4 (CH);
72.8 (CH2); 70.6 (CH2); 33.9 (CH2); 31.5 (CH); 27.8 (CH2); 21.5
yellow oil after purification by column chromatography.
½
a 2D0
ꢃ
¼ ꢀ9:1 (c 1.0, CHCl3). The spectroscopic data are identical to
(CH3); 20.8 (CH2); 14.6 (CH3) ppm. IR (film)
m: 2956, 2859,
2236, 1456, 1359, 1104, 734 cmꢀ1. MS (EI) m/z (%): 232 (M+, 1);
203 (3); 175 (10); 141 (62); 123 (68); 107 (44); 91 (100); 81
(71); 67 (60); 55 (67). Elem. Anal. Calcd for C16H24O: C, 82.70;
H, 10.41. Found: C, 82.59; H, 10.33.
those of (S)-6.
4.2.11. (4R)-1-Benzyloxy-4-methyl-5-octene (R)-7
Compound (R)-7 was prepared in the same manner as (S)-7
starting from (R)-6 (0.95 g, 4.61 mmol), propyltriphenylphosphoni-
um bromide (2.54 g, 6.60 mmol), and KOtBu (0.74 g, 6.60 mmol) to
4.2.6. 4-Methyl-1-octanol (R)-825
Compound (S)-7 (0.15 g, 0.65 mmol) was dissolved in EtOH
(5 ml) and stirred under a balloon of H2 for 2 h at room tempera-
ture with a catalytic amount of Pd/C (10% active, ꢄ5 mg). After fil-
tration through Celite, the filtrate was concentrated to afford
alcohol (R)-8 (93 mg, 99%) as a pale yellow oil without need of fur-
give (R)-7 (0.95 g, 89%) as a colorless oil. ½a D20
¼ þ4:5 (c 1.0, CHCl3).
ꢃ
Elem. Anal. Calcd for C16H24O: C, 82.70; H, 10.41. Found: C, 82.86;
H, 10.37. The spectroscopic data are identical to those of (S)-7.
4.2.12. (4S)-4-Methyl-1-octanol (S)-825
ther purification. ½a D20
ꢃ
¼ þ0:5 (c 1.4, CHCl3); lit.25 +0.6 (c 1.6,
Following the procedure described above for (R)-8 and starting
from (R)-7 (0.69 g, 8.12 mmol) and Pd/C (10% active, ꢄ20 mg), the
corresponding alcohol (S)-8 (0.41 g, 97%) was obtained as a pale
MeOH). 1H NMR (300 MHz, CDCl3): d 3.62 (t, J = 6.9 Hz, 2H);
1.06–1.67 (m, 11H); 0.85–0.90 (m, 6H) ppm. 13C NMR (75 MHz,
CDCl3): d 63.4 (CH2); 36.6 (CH2); 32.9 (CH2); 32.6 (CH); 30.3
(CH2); 29.2 (CH2); 23.0 (CH2); 19.6 (CH3); 14.1 (CH3) ppm. IR (film)
yellow oil, without need of further purification. ½a D20
¼ ꢀ0:5 (c
ꢃ
1.4, CHCl3); lit.25 = ꢀ0.5, (c 1.8, MeOH). The spectroscopic data
are identical to those of (R)-8.
m
: 3335, 2956, 2928, 2871, 1460, 1378, 1058 cmꢀ1. MS (EI) m/z (%):
126 [(M-18)+, 1]; 98 (17); 84 (33); 69 (100); 56 (80); 43 (43); 41
(50).
4.2.13. (4S)-4-Methyloctanoic acid [(S)-1]14
4.2.7. (4R)-4-Methyloctanoic acid (R)-114
Following similar procedure as for (R)-1, oxidation of alcohol
(S)-8 (0.22 g, 1.51 mmol) with Jones reagent (1.8 ml, 5.03 mmol)
afforded the expected acid (S)-1 (0.23 g, 98%) as a pale yellow oil,
To a solution of alcohol (R)-8 (47 mg, 0.33 mmol) in acetone
(2 ml), previously cooled to 0 °C, was added dropwise 0.4 ml
(1.1 mmol) of Jones reagent over a period of 30 min. The mixture
was stirred for one additional hour at room temperature and then
2-propanol (2 ml) and ether (50 ml) were added. The organic layer
was decanted, washed with brine, and the solvent removed in va-
cuo. The crude mixture was purified by column chromatography
eluting with CH2Cl2:MeOH (98:2) to obtain (R)-1 (46 mg, 88%) as
after purification on column chromatography. ½a D20
¼ þ1:5 (c 1.4,
ꢃ
CHCl3); lit.14 = +1.45 (c 1.1, CHCl3). The spectroscopic data are iden-
tical to those of (R)-1.
4.3. Synthesis of derivatives (R,R)-9 and (R,S)-9
a pale yellow oil. ½a D20
ꢃ
¼ ꢀ1:5 (c 1.4, CHCl3); lit.14 = ꢀ1.53 (c 1.1,
4.3.1. (1R,4R)-[1-(9-Anthryl)-2,2,2-trifluoro]ethyl
4-methyloctanoate (R,R)-9
CHCl3). 1H NMR (300 MHz, CDCl3): d 2.34 (m, 2H); 1.68 (m, 1H);
1.45 (m, 2H); 1.10–1.33 (m, 6H); 0.87–0.90 (m, 6H) ppm. 13C
NMR (75 MHz, CDCl3): d 180.3 (C); 36.3 (CH2); 32.3 (CH); 31.8
(CH2); 31.6 (CH2); 29.1 (CH2); 22.9 (CH2); 19.2 (CH3); 14.1 (CH3)
To a solution of carboxylic acid (R)-1 (13.40 mg, 0.08 mmol) in
CH2Cl2 (1 ml) was added (R)-(ꢀ)-2,2,2-trifluoro-1-(9-anthryl)-eth-
anol (25 mg, (0.09 mmol). Then, EDCꢁHCl (51 mg, 0.26 mmol), Et3 N
(25 ll, 0.17 mmol) and DMAP (15 mg, 0.12 mmol) were added and
ppm. IR (film)
m: 3091, 2957, 2926, 2865, 1710, 1458, 1286,
1218, 1110, 939 cmꢀ1. MS (EI) m/z (%): 159 (M+, 1); 129 (24);
101 (95); 99 (97); 83 (90); 73 (100); 69 (77); 60 (87); 59 (76);
57 (99).
the mixture was stirred at room temperature for 24 h. Dichloro-
methane was then added and the organic phase was washed with
brine to afford (R,R)-9 (30 mg, 91%) as a yellow oil, after solvent
evaporation. 1H NMR (500 MHz, CDCl3): d 8.76 (d, J = 9.0 Hz, 1H);
8.57 (s, 1H); 8.38 (d, J = 9.0 Hz, 1H); 8.04 (t, J = 7.5 Hz, 2H); 7.84
(q, J = 8.0 Hz, 1H); 7.64 (t, J = 7.5 Hz, 1H); 7.57 (t, J = 8.0 Hz, 1H);
7.50 (dt, J1 = 7.5 Hz, J2 = 7.0 Hz, 2H); 2.39–2.58 (m, 2H); 1.03–1.71
(m, 9H); 0.81–0.91 (m, 6H) ppm. 19F NMR (376 MHz, CDCl3): d
ꢀ72.3 (d, J = 7.5 Hz, 3F, –CF3) ppm. HPLC analysis on a Chiralcel
OD column under isocratic conditions using a mixture of hex-
ane:isopropanol 95:5 (flow rate 1 ml/min) gave a diastereomeric
purity of (R,R)-9 of 94%.
4.2.8. (2R)-N-Methyl-N-[(1S,2S)-2-hydroxy-1-methyl-2-
phenylethyl]-2-methyl-5-benzyloxypentamide (R,S,S)-4
Compound (R,S,S)-4 was prepared in the same way as (S,R,R)-4
starting from (1S,2S)-(+)-pseudoephedrinepropionamide (4.57 g,
20.65 mmol), LiCl (5.33 g, 125.82 mmol), DIPA (6 ml, 42.27 mmol),
n-BuLi (1.5 M, 26.2 ml, 39.32 mmol), and iodide
3 (2.72 g,
9.83 mmol) to obtain amide (R,S,S)-4 (3.56 g, 98%) as a pale yellow
oil. ½a 2D0
ꢃ
¼ þ55:7 (c 1.26, CHCl3). HRMS Calcd for C23H32NO3 (M+):

424
L. Muñoz et al. / Tetrahedron: Asymmetry 20 (2009) 420–424
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4.3.2. (1R,4S)-[1-(9-Anthryl)-2,2,2-trifluoro]ethyl
4-methyloctanoate [(R,S)-9]
A similar procedure to that described for (R,R)-9 was followed.
Thus, starting from carboxylic acid (S)-1 (15 mg, 0.09 mmol), (R)-
(ꢀ)-2,2,2-trifluoro-1-(9-anthryl)-ethanol (29 mg, 0.10 mmol),
EDCꢁHCl (57 mg, 0.30 mmol), Et3 N (30
ll, 0.20 mmol), and DMAP
(16 mg, 0.13 mmol), diastereomer (R,S)-9 (35 mg, 95%) was ob-
tained as a yellow oil. The spectroscopic data are identical to those
of (R,R)-9. HPLC analysis on a Chiralcel OD column under isocratic
conditions using a mixture of hexane:2-propanol 95:5 (flow rate
1 ml/min) gave a diastereomeric purity of (R,S)-9 of 93%.
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Acknowledgments
We gratefully acknowledge EC (Biosynthetic Infochemical Com-
munication project, contract 032275) for a contract to L.M., and CI-
CYT (AGL2006-13489-C02-01/AGR) for financial support.
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