Synthesis of the four possible stereoisomers of N-2′-methylbutyl-2-Methylbutylamide, the sex pheromone of the longhorn beetle Migdolus fryanus westwood

Article abstract of DOI:10.1081/SCC-100107019

The four stereoisomers of N-2′-methylbutyl-2-methylbutylamide, the sex pheromone of the longhorn beetle Migdolus fryanus, an economically important pest of sugarcane in South America, were synthesized. The key intermediate 2-methylbutan-1-ol is commercially available only in its (S)-(-)-form. The (R)-(+)-enantiomer was obtained optically pure from methyl (S)-(+)-3-hydroxy-2-methylpropionate in five steps.

Full text of DOI:10.1081/SCC-100107019

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SYNTHESIS OF THE FOUR POSSIBLE STEREOISOMERS
OF N-2′-METHYLBUTYL-2-METHYLBUTYLAMIDE,
THE SEX PHEROMONE OF THE LONGHORN BEETLE
MIGDOLUS FRYANUS WESTWOOD
Ellen M. Santangelo a , Paulo H. G. Zarbin b , Quezia B. Cass a , José T. B. Ferreira a &
Arlene G. Corrêa c
a Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP,
13565-905, Brazil
b Departamento de Química, Universidade Federal do Paraná, Curitiba, PR, 81539-990,
U.S.A.
c Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP,
13565-905, Brazil
Version of record first published: 16 Aug 2006.
To cite this article: Ellen M. Santangelo , Paulo H. G. Zarbin , Quezia B. Cass , José T. B. Ferreira & Arlene G. Corrêa
(2001): SYNTHESIS OF THE FOUR POSSIBLE STEREOISOMERS OF N-2′-METHYLBUTYL-2-METHYLBUTYLAMIDE, THE SEX
PHEROMONE OF THE LONGHORN BEETLE MIGDOLUS FRYANUS WESTWOOD, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 31:23, 3685-3698
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SYNTHETIC COMMUNICATIONS, 31(23), 3685–3698 (2001)
SYNTHESIS OF THE FOUR
POSSIBLE STEREOISOMERS OF
N-20-METHYLBUTYL-2-
METHYLBUTYLAMIDE, THE
SEX PHEROMONE OF THE
LONGHORN BEETLE MIGDOLUS
FRYANUS WESTWOOD
Ellen M. Santangelo,1 Paulo H. G. Zarbin,2
Quezia B. Cass,1 Jose T. B. Ferreira,1
and Arlene G. Correa1,
*
1Departamento de Quımica, Universidade
Federal de Sao Carlos-13565-905-Sao
Carlos-SP, Brazil
2Departamento de Quımica, Universidade
Federal do Parana-81539-990-
Curitiba-PR, Brazil
ABSTRACT
The four stereoisomers of N-20-methylbutyl-2-methylbutyla-
mide, the sex pheromone of the longhorn beetle Migdolus
fryanus, an economically important pest of sugarcane in
South America, were synthesized. The key intermediate
* Corresponding author.
3685
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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SANTANGELO ET AL.
2-methylbutan-1-ol is commercially available only in its (S)-
(À)-form. The (R)-(þ)-enantiomer was obtained optically
pure from methyl (S)-(þ)-3-hydroxy-2-methylpropionate in
five steps.
The longhorn beetle Migdolus fryanus is an economically important
pest of sugarcane in South America. The major problem in control of
this pest by use of traditional pesticides is that the insect spends most of
its lifetime in the subsoil.1 In this context, the use of pheromones, an envir-
onmentally friendly control, has a potential application. Della Lucia and
co-workers2 have described that males of the sugarcane borer are attracted
to females by means of a sex pheromone. In Sao Paulo State, Brazil, mating
usually occurs during a few days between October and March. Based on
these results, Leal and co-workers3 have isolated and identified the female
sex pheromone from volatile extracts of the insect.
Although two female-specific compounds, namely, N-20-methylbutyl-
2-methylbutylamide (1) and N-formyl L-isoleucine methyl ester, were iden-
tified, field tests with synthetic chemicals revealed that only the amide was
active and that the amino acid derivative neither increased or decreased trap
catches by the amide. This is the first known long-range female-released sex
pheromone for the family Cerambycidae and the first identification of an
amide as a sex pheromone.
In order to establish the correct structure of the natural pheromone,
several amides were synthesized by the reaction of appropriate commercially
available anhydrides or acid chlorides with amines. Those compounds
were compared with the natural product by gas chromatography-mass spec-
troscopy (GC-MS) and chiral gas chromatography.3 Partial separation of
the stereoisomers was achieved on a CP-Cyclodextrin column. Separation of
the diastereoisomers (20S,2S )-1 and (20S,2R)-1 was almost baseline, how-
ever, there was no resolution of the diastereoisomers (20S,2S )-1 and
(20R,2S )-1, probably because the stereocenter is separated from the func-
tional group (N) by a methylene group. The natural product gave a single
peak, which had the same retention time and co-eluted with the diastereoi-
someric mixture (20S,2R/S )-1. Based on biosynthesis reasoning, the absolute
configuration of the natural product has been suggested by Leal as N-(20S )-
methylbutyl-(2S )-methylabutylamide (1), although the stereochemistry at
C-2 remains to be analytically determined.
Thus, the synthesis of all of the four possible stereoisomers of N-20-
methylbutyl-2-methylbutylamide (1) is necessary to establish the absolute
configuration of the naturally occurring pheromone and also to clarify the
relationship between absolute configuration and the bioactivity of the chiral
pheromone.4

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3687
The synthetic pathway to prepare the four stereoisomers of amide (1)
is based on a common intermediate, the 2-methylbutan-1-ol (2), which is
commercially available only in its (S)-(À)-form. Few procedures are
described in the literature for the preparation of the chiral synthon (R)-
(þ)-2-methylbutan-1-ol, which can be used in the synthesis of a series of
chiral methyl-branched pheromones.5 Bestmann et al.6 have performed the
separation of diastereomeric phenylglycinolamides of 2-methylbutyric acid
by MPLC obtaining the pure enantiomers of the acid, which were then
reduced by LiALH4 to the corresponding alcohols (R)- and (S)-2. Geresh
et al.5 have prepared (R)-2 in 82% enantiomeric excess (e.e.) by a chemoen-
zymatic synthesis, in which the key step is a reduction catalyzed by baker’s
yeast. Guoqiang et al.7 have synthesized the (R)-2-methylbutyric acid in
84% e.e. via asymmetric alkylation of a prolinol amide derivative.
In this study, enantiomeric pure (R)-2-methylbutan-1-ol was prepared
from commercially available methyl (S)-(þ)-3-hydroxy-2-methylpropionate
using the methodology developed by Mori (Scheme 1).8 Protection of the
hydroxyl group of 3 with dihydropyran furnished the tetrahydropyran
(THP) derivative 4, in 93% yield, which was reduced by LiAlH4 in 85%
yield. Alcohol 5 was converted into its corresponding tosylate 6, in 9 5%
yield, which was then coupled with Li2CuCl4 as catalyst9 to a methyl mag-
nesium iodide affording 7 in 82% yield. When we tried to carry out this
coupling in a large scale (up to 24 mmol), by-products from nucleophilic
substitution and elimination reactions were observed. This problem was
solved by dilution and controlling very carefully the reaction temperature
at À80ꢀC. Removal of the protective group from 7 was performed either by
use p-TsOH or AmberlystÕ 15 in methanol as catalysts.10 However, due to
its high volatility, alcohol (R)-2 was always obtained with traces of metha-
nol, preventing the evaluation of its enantiomeric purity by measuring its
specific rotation.
Scheme 1.

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3688
SANTANGELO ET AL.
The enantiomeric excess of the synthetic alcohol (R)-2 was measured
by 1H-NMR spectroscopy analysis of its corresponding (S)-(þ)-a-methoxy-
a-(trifluoromethyl)-phenylacetic ester (8)11 in comparison with the esters
prepared from the racemic- and commercial (S )-2. While Mosher ester
(20R/S,2R)-8 showed a multiplet between 4.04 and 4.30 ppm corresponding
to the hydrogens at C-20, (20S,2R)-8 showed a doublet at 4.16 ppm and
(20R,2R)-8 two double doublets at 4.09and 4.24 ppm respectively.
Having prepared (R)-2-methylbutan-1-ol (2) in high enantiomeric
excess (>99%), the synthesis of the four stereoisomers of N-20-methylbu-
tyl-2-methylbutylamide (1) could then be carried out. Our synthetic strategy
is described in Schemes 2 and 3.
Acid (R)-9 was then prepared directly from (R)-7 by Jones oxidation in
76% yield. The enantiomeric purity (>99% ee) was determined by reducing
acid (R)-9 with BH3.DMS to afford (R)-2, which was then converted into
the corresponding MTPA ester (20R,2R)-8 and analyzed by H-NMR spec-
1
troscopy. (R)-9 was converted into their corresponding acyl chloride 10 with
Scheme 2.

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3689
Scheme 3.
thionyl chloride in quantitative yield. Treatment of 10 with ammonium
hydroxide (28% NH3 in water) afforded amide 11 in 74% yield.
Compound 11 was reduced using LiAlH4 in THF yielding the amine 12,
which was not isolated due to its high volatility. Finally, a solution of amine
12 in THF was added to a solution of acyl chloride 10 and pyridine in
methylene chloride to afford amide 1 in 72–76% yield over two steps
(Scheme 2).
1
The enantiomeric purity of amine 12 was investigated by H- and
19F-NMR analysis of their corresponding MTPA amides 13. Although
separation of the signal corresponding to the a-nitrogen methylene in the
1H-NMR was not baseline, it was possible to estimate an enantiomeric
excess of at least 65% for amine 12. No separation was observed for the
CF3 group in the 19F-NMR spectrum. Attempts to analyze these MTPA
amides by chiral GC and chiral HPLC also failed. According to this result,
an epimerization has occurred during the preparation of amine 12, probably
under the reaction conditions used for the formation of amide 11 from acyl
chloride 10. Further studies in order to determine how the epimerization
process occurs are in progress.
The stereoisomers (20S, 2S)-1 and (20S, 2R)-1 were obtained from
(S )-(þ)-2-methylbutyric anhydride (14) (98% ee, commercial available
from Aldrich) and (S)- and (R)-12 respectively, in dichloromethane
(Scheme 3).
In order to verify the enantiomeric purity of the final product the four
stereoisomers of amide 1 were analyzed by GC using several chiral columns,
however, no resolution was obtained. Four different chiral polysaccharide
phases in HPLC were also investigated without success.

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SANTANGELO ET AL.
The optical rotation obtained for (20S,2S)-1 was [a]D20 ¼ þ 27.83
(c ¼ 3.18, diethyl ether) and we assumed that its enantiomeric excess is
>99.5% because it was synthesized from commercial available reagents
(S )-12 and (S )-13. By analogy, the ee of amide (20R,2R)-1 would be >80%.
In conclusion, a simple synthetic route for all four possible stereoi-
somers of N-20-methylbutyl-2-methylbutylamide (1), the sex pheromone of
the longhorn beetle Migdolus fryanus, has been achieved using as key inter-
mediate the 2-methylbutan-1-ol (2). While the chiral synthon (S )-2 is com-
mercially available, the (R)-enantiomer was obtained with high e.e (>99%)
from the commercial available methyl (S )-(þ)-3-hydroxy-2-methylpropio-
nate (3). Since no chiroptical data of the natural pheromone are available,
we have to rely on the careful comparison of pheromone activity of the four
stereoisomers of 1 in order to deduce the absolute configuration of the
natural product. The biological study is in progress and will be published
elsewhere in due course.
EXPERIMENTAL
Unless otherwise noted, all commercially available reagents were pur-
chased from Aldrich Chemical Co. Reagents and solvents were purified
when necessary according to the usual procedures described in the literature.
The IR spectra refer to films and were measured on a Bomen M102 spectro-
meter. 1H- and 13C-NMR spectra were recorded on a Bruker ARX-200 (200
and 50 MHz respectively) and ARX-400 (400 and 100 MHz respectively).
19F-NMR spectra were recorded on a Brucker ARX-400 (376.5 MHz).
Optical rotations were measured on a Perkin–Elmer 241 polarimeter.
Mass Spectra were recorded on a Shimadzu GCMS-QP5000. Analytical
thin-layer chromatography was performed on a 0.25 mm film of silica gel
containing fluorescent indicator UV254 supported on an aluminum sheet
(Sigma–Aldrich). Flash column chromatography was performed using
silica gel (Kieselgel 60, 230–400 mesh, E. Merck). Gas chromatography
was performed in a Shimadzu GC-17A with H2 as carrier and using a
DB-5 column. Elemental analyses were performed on a Fisons EA 1108
CHNS-O.
Methyl (S )-(Q)-3-(tetrahydro-2-pyranyloxy)-
2-methylpropionate (4)
In a 250 mL flask equipped with a magnetic stir bar and rubber septum
was added methyl (S )-(þ)-3-hydroxy-2-methylpropionate (3) (Aldrich, 99%

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LONGHORN BEETLE PHEROMONE
3691
ee/GLC) (14.0 mL; 127 mmol) in dry diethyl ether (127 mL), followed by
dihydropyran (DHP) (13.88 mL; 152.4 mmol) and p-toluenesulfonic acid
(0.25 g; 12.7 mmol). The reaction mixture was stirred for 12 h at RT and
then washed with saturated NaHCO3 solution (10 mL), dried over Na2SO4
and concentrated in vacuo. The residue was purified by distillation (75ꢀC at
0.5 mmHg) to give 23.8 g (93% yield) of the desired ester 4 as a colorless oil:
purity >98%. [a]2D5:þ16.3 (c ¼ 3.9, diethyl ether). IR (nmax, film cmÀ1): 2944,
2874, 1741, 1457, 1439, 1354, 1201, 1125, 1075, 1034, 969, 903, 870, 815.
1H-NMR (400 MHz, CDCl3) d [1.18 (d, J ¼ 2.74 Hz) and 1.20 (d,
J ¼ 2.74 Hz), 3H]; 1.48–1.82 (m, 6H); 2.78 (sext, J ¼ 6.9Hz, 1H); 3.41–3.61
(m, 2H); [3.69(s) and 3.70 (s), 3H]; 3.74–3.93 (m, 2H); [4.59(t, J ¼ 3.36 Hz)
and 4.62 (t, J ¼ 3.36 Hz], 1H]. 13C-NMR (100 MHz, CDCl3) d 13.83; (18.94
and 19.16); 25.27; (30.32 and 30.43); (39.86 and 40.03); 51.44; (61.59
and 62.69); (68.85 and 69.18); (98.26 and 98.85); (175.10 and 175.17).
MS (rel intensity) m/z 50 (1.8); 51 (2.0); 53 (6.0); 54 (6.9); 55 (47.7);
56 (41.5); 57 (38.5); 58 (4.2); 59(60.1); 60 (2.1); 61 (1.7); 67 (17.3);
68 (1.8); 69(29.2); 70 (1.9); 71 (1.8); 73 (10.6); 74 (1.5); 83 (6.8); 84 (18.4);
85 (100); 86 (7.0); 87 (8.7); 88 (10.0); 100 (4.5); 101 (60.3); 102 (5.1);
115 (14.4); 129(3.2); 147 (1.3). Anal. Calcd. for C 10H18O4: C, 59.38; H,
8.97. Found: C, 59.32; H, 9.06.
(R)-(Q)-2-Methyl-3-(tetrahydro-2-pyranyloxy)-
propan-1-ol (5) (as a diastereomeric mixture)
To a stirred solution of LiAlH4 (3.29g; 86.4 mmol) in diethyl
ether (220 mL) was added a solution of ester 4 (21.94 g; 108 mmol) in diethyl
ether (110 mL) at 0–5ꢀC. After stirring for 12 h at rt, the mixture was cooled
and water (3.3 mL) was added followed by 15% aqueous NaOH (3.3 mL)
and water (9.9 mL). The resulting mixture was filtered through celite using
diethyl ether (150 mL) as eluent. The organic layer was dried over MgSO4
and concentrated in vacuo. Distillation afforded (bp ¼ 98ꢀC, 0.5 mmHg)
15.94 g (85% yield) of the alcohol 5 as a colorless oil: purity >99%.
[a]D:þ1.2 (c ¼ 1.471, diethyl ether). IR (nmax, film cmÀ1): 3441; 2942; 1455;
1353; 1201; 1122; 1030; 975. 1H-NMR (400 MHz, CDCl3); d [0.91 (d,
J ¼ 3.85 Hz) and 0.93 (d, J ¼ 3.85 Hz), 3H]; 1.51–2.03 (m, 7H); 3.26
(bs, 1H); [3.34 (dd, J ¼ 6.9, 9.52 Hz) and 3.42 (dd, J ¼ 6.9, 9.52 Hz), 1H];
3.48–3.59(m, 3H); [3.67 (dd, J ¼ 6.9, 9.52 Hz) and 3.77 (dd, J ¼ 6.9, 9.52 Hz),
1H]; 3.87 (oct, J ¼ 3.85, 1H); 4.58 (t, J ¼ 4.32 Hz, 1H). 13C-NMR (100 MHz,
CDCl3): d (13.36 and 13.48); 19.36; 25.09; 30.33; (35.33 and 35.56); 62.20;
(66.16 and 66.22); 71.17; (98.82 and 98.02). MS (rel intensity) m/z 50 (2.9);
51 (3.3); 53 (8.2); 54 (11.1); 55 (98.7); 56 (67.5); 57 (42.2); 58 (2.9); 59 (2.9);

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SANTANGELO ET AL.
67 (15.8); 68 (1.4); 69(3.4); 70 (1.5); 71 (3.0); 72 (7.9); 73 (17.0); 74 (3.2); 77
(1.7); 83 (7.8); 84 (24.2); 85 (100); 86 (5.6); 101 (26.6); 102 (1.8); 103 (1.5);
115 (1.5); 144.2 (0.8). Anal. Calcd. for C9H18O3: C, 62.04; H, 10.41. Found:
C, 62.03; H, 10.52.
(R )-(Q)-2-Methyl-3-(tetrahydro-2-pyranyloxy)-propyl-
p-toluenesulfonate (6) (as a diastereomeric mixture)
A solution of 5 (15.0 g; 86.21 mmol) in anhydrous pyridine (110 mL)
was cooled to 0–5ꢀC and then p-toluenesulfonyl chloride (21.87 g;
115 mmol) wad added. The mixture was maintained at this temperature
for 12 h. The reaction was quenched with ice-water (30mL) and the aqueous
layer was extracted with ether (3 ꢁ 20 mL). The combined ether extracts
were washed with 10% aqueous CuSO4 (3 ꢁ 10 mL), saturated NaHCO3
(10 mL) and brine (10 mL), then dried over anhydrous Na2SO4. Solvent
removal followed by Baeckstrom’s chromatography, using a gradient of
hexane and ethyl acetate as eluent, yielded 26 g of 6 (92%), as a colorless
oil: purity >99%. [a]D:þ6.8 (c ¼ 7.01, diethyl ether). IR (nmax, film cmÀ1):
1
2942; 1602; 1364; 1182; 1037; 971; 817, 733. H-NMR (400 MHz, CDCl3)
d [0.93 (d, J ¼ 1.98 Hz) and 0.94 (d, J ¼ 1.98 Hz), 3H]; 1.44–1.62 (m, 6H);
[1.71–1.73 (m) and 2.05–2.11 (m), 1H]; 2.44 (s, 3H); 3.22 (ddd, J ¼ 4.9, 9.7,
27.5 Hz, 1H), 3.43–3.48 (m, 1H), 3.60 (ddd, J ¼ 5.2, 9.7, 20.3 Hz, 1H);
3.70–3.75 (m, 1H); [3.94 (dd, J ¼ 5.9, 9.3 Hz) and 4.06 (dd, J ¼ 5.9,
9.3 Hz), 1H); 4.01 (m, 1H]; [4.44 (t, J ¼ 3.7) and 4.47 (t, J ¼ 3.7 Hz), 1H];
7.34 (d, J ¼ 8.1 Hz, 2H); 7.79(d, J ¼ 8.2 Hz, 2H). 13C-NMR (100 MHz,
CDCl3), d (13.49 and 13.57); (19.19 and 19.32); 21.50, 25.31; (30.36 and
30.60); (33.43 and 33.57); 35.46; (61.89 and 62.09); 63.54; (67.92 and
68.35); (72.14 and 72.17); (98.54 and 98.05), 127.81; 129.75; 133.21; 144.61.
MS (rel intensity) m/z 50 (5.2); 51 (7.1); 52 (2.5); 53 (10.9); 54 (15.6); 55
(100); 56 (34.6); 57.1 (30.2); 58.2 (2.0); 59(1.5); 63 (3.2); 65 (13.9); 67 (10.1);
69(7.5); 71 (7.3); 72 (10.4); 73 (4.2); 77 (2.0); 83 (12.7); 84 (32.6); 85 (56.6);
86 (3.2); 89 (3.2); 91 (33.2); 92 (6.1); 101.2 (27.6); 107.1 (2.3); 108 (2.3); 155
(17.0); 156 (4.9); 172 (4.5); 173 (14.5); 227 (1.4). Anal. Calcd. for C16H24O5S:
C, 58.51; H, 7.37; S, 9.76. Found: C, 58.56; H, 7.61; S, 9.68.
(R)-(R)-2-Methyl-1-(tetrahydro-2-pyranyloxy)-
butan-1-ol (7) (as a diastereomeric mixture)
To a mixture of magnesium turnings (1.46 g; 61.0 mmol) in anhydrous
diethyl ether (64 mL) was added methyl iodide (3.8 mL; 61.0 mmol). After

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3693
disappearance of the metal, this solution was transferred via a cannula to a
solution containing tosylate 6 (4.00 g; 12 mmol) in anhydrous THF (120 mL)
at À80ꢀC under nitrogen. Then a 0.10 M solution of lithium tetrachlorocup-
rate in THF (2.29mL) was added. The mixture was allowed to warm to
room temperature and stirred for 12 h and then it was washed with saturated
aqueous solution of NH4Cl (20 mL). The aqueous layer was extracted with
ether (3 ꢁ 20 mL), then the combined organic layers were washed with H2O
(10 mL), dried over MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography, using a gradient from 0 to 40% v/v
of ethyl acetate in hexane, to give 1.72 g (82% yield) of the desired product 7
as a colorless oil: purity >99%. [a]D: À3.04 (c ¼ 2.07, ethyl ether). IR (nmax
,
film cmÀ1): 2951; 2874; 1461; 1376; 1351; 1129; 1031. H-NMR (400 MHz,
CDCl3) d [0.90 (t, J ¼ 6.8 Hz) and 0.92 (d, 6.6 Hz), 3H]; 1.14 (oct,
J ¼ 7.35 Hz, 1H), 1.42–1.83 (m, 8H); [3.15 (dd, J ¼ 6.0, 9.4 Hz) and 3.24
(dd, J ¼ 6.0, 9.4 Hz), 1H]; 3.60 (dd, J ¼ 6.4, 9.4 Hz, 1H); 3.47–3.53 (m,
1H); 3.86 (ddd, J ¼ 3.6, 7.6, 11.2 Hz, 1H], 4.56 (t, J ¼ 3.6 Hz, 1H).
13C NMR (100 MHz, CDCl3), d (11.27 and 11.34); (16.53 and 16.67);
(19.51 and 19.55); 25.49; (26.23 and 26.29); 30.68; 34.97; (62.05 and
62.12); (72.70 and 72.81); (98.77 and 98.97). MS (rel intensity) m/z 50
(1.3); 51 (1.8); 53 (5.1); 54 (15.6); 55 (35.3); 56 (55.9); 57 (28.4); 58 (2.3);
59(1.0); 67 (12.8); 69(1.7); 70 (11.4); 71 (30.7); 72 (1.7); 74 (1.9); 83 (2.7); 84
(7.4); 85 (100); 86 (5.9); 101 (8.8); 114 (1.2); 115 (10.2); 142 (0.9). Anal.
Calcd. for C10H20O2: C, 69.72; H, 11.70. Found: C, 69.69; H, 11.76.
1
(R)-(Q)-2-Methylbutan-1-ol (2)
AmberlystÕ 15 (0.697 g) was added to a solution of 7 (4 g; 23.25 mmol)
in methanol (46.5 mL). The mixture was stirred at 45ꢀC for 40 min, then the
resin was filtered and the solution was concentrated by fractionated distilla-
tion at 1 atm. GC analysis of the crude product showed 100% conversion to
the desired alcohol (R)-2 which contained traces of methanol. The IR and
NMR spectra were identical with those of commercial (S )-2.
General Procedure for the Preparation
of the Mosher Esters 8
To a solution of 2-methylbutan-1-ol (0.0035 g, 0.040 mmol) in
anhydrous CH2Cl2 (300 mL) were added anhydrous pyridine (10 mL) and
(S )-(þ)-MTPA chloride (0.0025 g, 0.010 mmol) at À20ꢀC. After stirring

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3694
SANTANGELO ET AL.
for 4 h, the reaction was quenched with water (2 mL) and extracted with
ethyl ether (3 ꢁ 3 mL). The combined organic layer was dried over
anhydrous Na2SO4 and concentrated in vacuo. The desired product 8
was obtained (0.0028 g, 92% yield) after purification by flash column
chromatography.
(20R/S)-20-Methylbutyl (2R)-a-methoxy-a-(trifluoromethyl)phenylace-
tate [(20R/S,2R)-8]: colorless oil: purity >97%. 1H-NMR (400 MHz,
CDCl3), d 0.85–0.93 (m, 6H); 1.20–1.39 (m, 2H); 1.76 (oct, J ¼ 6.7 Hz,
1H); 3.55 (s, 3H); {[4.09(dd, J ¼ 6.1, 10.7 Hz) and 4.24 (dd, J ¼ 6.1,
10.7 Hz)] and 4.16 (d, J ¼ 6.1 Hz), 2H}; 7.38–7.53 (m, 5H). 19F-NMR
(376.5 MHz, CDCl3), d À72.42 (s); À72.02 (s).
(20S)-20-Methylbutyl (2R)-a-methoxy-a-(trifluoromethyl)phenylacetate
[(20S,2R)-8]: colorless oil: purity >96%. 1H-NMR (400MHz, CDCl3),
d 0.88 (t, J ¼ 7.4 Hz, 3H); 0.91 (d, J ¼ 6.7 Hz, 3H); 1.13–1.25 (m, 1H); 1.34–
1.44 (m, 1H); 1.78 (oct, J ¼ 6.7 Hz , 1H); 3.55 (s, 3H); 4.16 (d, J ¼ 6.1 Hz, 2H);
7.38–7.53 (m, 5H). 19F-NMR (376.5MHz, CDCl3), d À72.42 (s).
(20R)-20-Methylbutyl (2R)-a-methoxy-a-(trifluoromethyl)phenylacetate
[(20R,2R)-8]: colorless oil: purity >96%. 1H-NMR (400MHz, CDCl3), d
0.89(t, J ¼ 7.4 Hz, 3H); 0.91 (d, J ¼ 6.7 Hz, 3H); 1.14–1.26 (m, 1H); 1.33–
1.46 (m, 1H); 1.78 (oct, J ¼ 6.7 Hz, 1H); 3.55 (s, 3H); 4.09(d, J ¼ 6.1 Hz, 1H);
4.24 (dd, J ¼ 6.1, 10.7 Hz, 1H); 7.38–7.53 (m, 5H). 19F-NMR (376.5 MHz,
CDCl3), d À72.02 (s).
(R)-(R)-2-Methylbutyric acid [(R)-9]
To a solution of CrO3 (2.80 g; 0.028 mol) in water (4 mL), sulfuric acid
(2.44 mL) was added dropwise at 0ꢀC. Acetone (75 mL) was then added,
followed by a dropwise addition of 7 (6.88 g; 0.04 mol). The mixture was
stirred for 1h then a saturated solution of sodium bisulfide was added until
the solution became green. The solvent was then evaporated under vacuum
and the crude product was extracted with ethyl ether (4 ꢁ 20 mL). The com-
bined organic layers was washed with brine (20 mL), dried over anhydrous
MgSO4, filtered and concentrated in vacuum. The desired acid (R)-9 was
obtained in 75% yield (3.06 g) without further purification. IR (nmax, film
cmÀ1): 3445; 2983; 1710; 1462; 1262, 1253, 942. 1H-NMR (400 MHz,
CDCl3), d 0.95 (t, J ¼ 7.60 Hz, 3H); 1.17(d, J ¼ 7.20 Hz, 3H); 1.50 (dquint,
J ¼ 15.20, 7.20 Hz, 1H); 1.69(dquint, J ¼ 15.20, 7.20 Hz, 1H); 2.39(sext,
J ¼ 7.20 Hz, 1H); 11.05 (bs, 1H). 13C-NMR (100 MHz, CDCl3), d 11.57,
16.68, 26.59, 41.01, 183.64.

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(R)-2-Methylbutyryl chloride (10)
3695
In a flask adapted with a condenser containing 9 (1 g; 9.8 mmoles) was
added SOCl2 (1.73 mL; 14.7 mmoles). The resulting mixture was stirred under
reflux for 4 h, then benzene (10 mL) was added. The solvent was distilled at
60ꢀC, followed by the desired acyl chloride 10 (1.67 g), at 80ꢀC, as a colorless
oil: purity >99%. IR (nmax, film) cmÀ1: 2967; 2361; 1793; 1460; 919.
(R)-2-Methylbutylamide (11)
To a 28% solution of ammonium hydroxide (0.25 mL) was added 10
(0.10 g, 0.83 mmol) dropwise at 0–5ꢀC. A white solid appeared instanta-
neously. The mixture was diluted in ethyl acetate (10 mL) and water
(10 mL). The organic layer was dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The desired amide 11 was obtained in 74% yield
1
(0.062 g) without further purification. H-NMR (400 MHz, CDCl3), d 0.94
(t, J ¼ 7.40 Hz, 3H); 1.18 (d, J ¼ 7.00 Hz, 3H); 1.36–1.83 (m, 2H); 2.19(sext,
J ¼ 7.20 Hz, 1H); 5.60 (bs, 2H). 13C-NMR (100 MHz, CDCl3), d 11.67,
17.27, 27.13, 42.30, 179.63.
(R)-(Q)-2-Methylbutylamine (12)
To a stirred solution of LiAlH4 (0.023 g; 0.60 mmol) in anhydrous
THF (5 mL) was added a solution of amide 11 (0.051 g; 0.51 mmol) in
THF (0.5 mL) at 0–5ꢀC. After stirring for 6h at rt, the mixture was cooled
and water (0.02 mL) was added followed by 10% aqueous NaOH (0.02 mL)
and water (0.069mL) again. The resulting mixture was filtered through celite
with THF (3 mL) as eluent. The solution containing amine 12 was employed
in the next step without concentration or purification. Colorless oil: purity
1
>98%. IR (nmax, film) cmÀ1: 3423; 2920; 2363; 1958; 1598; 1463; 886. H-
NMR (400 MHz, CDCl3), d: 0.87 (t, J ¼ 6.8 Hz, 3H); 0.88(d, J ¼ 7.6 Hz, 3H);
1.07–1.19(m, 2H); 1.27 (5, 2H); 1.30–1.45 (m, 2H); (2.47 (dd, J ¼ 12.8,
6.8 Hz) and 2.61 (dd, J ¼ 12.8, 5.6 Hz), 1H). 13C-NMR (100 MHz, CDCl3),
d: 11.24, 16.87, 25.52, 37.88; 47.97.
General Procedure for the Preparation
of the Mosher Amides 13
To a solution of 2-methylbutylamine 12 (0.0035 g, 0.040 mmol) in
anhydrous CH2Cl2 (300 mL) anhydrous pyridine (10 mL) and (S )-(þ)-
MTPA chloride (0.0025 g, 0.010 mmol) at À20ꢀC were added. After stirring

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SANTANGELO ET AL.
for 4 h, the reaction was quenched with water (2 mL) and extracted
with ethyl ether (3 ꢁ 3 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated in vacuo. The desired product
13 was obtained (0.0028 g, 92% yield) after purification by flash column
chromatography.
N-(20R/S )-Methylbutyl (2R)-a-methoxy-a-(trifluoromethyl)phenylace-
tamide [(20R/S,2R)-13]: colorless oil: purity >97%. H-NMR (400 MHz,
1
CDCl3), d 0.9(t, J ¼ 7.4 Hz, 3H); 0.89(d, J ¼ 7.7 Hz, 3H); 1.10–1.46 (m,
2H); 1.60 (oct, J ¼ 6.2 Hz, 1H); (3.11 (ddd, J ¼ 6.10, 7.23, 13.35 Hz, 1H);
3.31 (ddd, J ¼ 6.10, 7.23, 13.35 Hz, 1H)); 3.23 (ddd, J ¼ 5.9, 7.0, 12.8 Hz,
2H); 3.42 (s, 3H); 6.82 (bs, 1H); 7.40 (t, J ¼ 3.8 Hz, 3H); 7.52 (t,
J ¼ 3.9Hz, 2H).
N-(20S )-Methylbutyl (2R)-a-methoxy-a-(trifluoromethyl)phenylaceta-
mide [(20S,2R)-13]: colorless oil: purity >98%. 1H-NMR (400 MHz,
CDCl3), d 0.9(t, J ¼ 7.4 Hz, 3H); 0.89(d, J ¼ 7.7 Hz, 3H); 1.10–1.42 (m,
2H); 1.63 (oct, J ¼ 6.2 Hz, 1H); 3.11 (ddd, J ¼ 6.10, 7.23, 13.35 Hz, 1H);
3.31 (ddd, J ¼ 6.10, 7.23, 13.35 Hz, 1H), 3.42 (s, 3H); 6.82 (bs, 1H); 7.40
(t, J ¼ 3.8 Hz, 3H); 7.52 (t, J ¼ 3.9Hz, 2H).
N-(20R)-Methylbutyl (2R)-a-methoxy-a-(trifluoromethyl)phenylaceta-
mide [(20R,2R)-13]: colorless oil: purity >97%. 1H-NMR (400 MHz,
CDCl3), d 0.90 (t, J ¼ 7.4 Hz, 3H); 0.91 (d, J ¼ 6.7 Hz, 3H); 1.15–1.39
(m, 2H); 1.78 (oct, J ¼ 6.7 Hz, 1H); 3.23 (ddd, J ¼ 5.9, 7.0, 12.8 Hz, 2H);
3.42 (s, 3H); 7.40 (t, J ¼ 3.8 Hz, 3H); 7.52 (t, J ¼ 3.9Hz, 2H).
General Procedure for the Preparation of
the Amides (20S,2S) and (20S,2R)-1
To a solution of CH2Cl2 (0.5 mL) and (S )-(þ)-2-methylbutyric anhy-
dride (14) (98% ee from Aldrich) (0.10 mL, 0.5 mmol), was added (R)-12 or
(S )-(À)-2-methylbutylamine (99% ee, from Aldrich) (0.059 mL, 0.5 mmol).
The mixture was stirred at RT for 2 h and then diluted with ethyl ether
(10 mL). The organic layer was washed with water (3ꢁ3 mL), dried over
MgSO4 and concentrated under reduced pressure. The crude was purified
by flash chromatography with 5% ethyl acetate in hexane as eluent afford-
ing the desired amide (20S,2S ) and (20S,2R )-1 (0.085 g) in quantitative yield.
(Q)-N-(20S )-Methylbutyl-(2S )-methylbutylamide [(20S,2S )-1] (1.48 g,
76% yield). Colorless oil: purity >99%. [a]2D0 ¼þ27.83 (c ¼ 3.18, diethyl
ether). IR (nmax, film) cmÀ1: 3302; 2953; 2372; 1957; 1648; 1550; 1461;
1234. 1H-NMR (400 MHz-CDCl3) d: 0.88 (t, J ¼ 6.8 Hz, 9H), 1.1 (d,
J ¼ 6.8Hz, 3H), 1.23–1.30 (m, 1H), 1.34–1.39(m, 2H), 1.49–1.57 (m, 1H),
1.59–1.72 (m, 1H), 2.06 (sext, J ¼ 6.8 Hz, 1H), 3.04–3.11 (m, 1H), 3.12–3.20

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3697
(m, 1H), 5.4 (bs, 1H). 13C-NMR (100 MHz, CDCl3) d: 176.6, 44.8, 43.2,
34.8, 27.2, 26.9, 17.5, 17.0, 11.8, 11.2. MS (rel intensity): m/z 50 (0.5); 51
(0.9); 53 (3.3); 54 (2.5); 55 (17.4); 56 (10.7); 57 (100); 58 (24.3); 59 (1.7); 67.2
(0.6); 68 (0.8); 69(3.2); 70 (4.5); 71 (11.6); 72 (5.6); 73 (3.5); 74 (6.1); 84 (1.9);
85 (40.5); 86 (22); 87 (7.9); 100 (6.3); 102 (1.8); 114 (7.8); 115 (5.4); 116 (0.9);
142 (3.7); 143 (6.0); 156 (3.4); 171 (Mþ, 2.1). Anal. Calcd. for C10H21NO: C,
70.12; H, 12.36; N, 8.18. Found: C, 69.91; H, 12.39; N, 8.23.
(Q)-N-(20S )-Methylbutyl-(2R)-methylbutylamide [(20S,2R)-1] (1.48 g,
76% yield). Colorless oil: purity >99%. [a]2D0:þ17.23 (c ¼ 3.36, diethyl
ether). 1H-NMR (400 MHz, CDCl3) d: 0.86 (t, J ¼ 7.2 Hz, 9H), 1.09 (d,
J ¼ 6.8 Hz, 3H), 1.19–1.25 (m, 1H), 1.30–1.44 (m, 2H), 1.46–1.55 (m, 1H),
1.56–1.67 (m, 1H), 2.06 (sext, J ¼ 6.8 Hz, 1H), 2.96–3.02 (m, 1H), 3.15–3.22
(m, 1H), 5.6 (bs, 1H). 13C-NMR (100 MHz, CDCl3) d: 176.5, 44.8, 43.3,
34.9, 27.3, 26.9, 17.6, 17.0, 11.9, 11.2.
General Procedure for the Preparation
of the Amides (20R,2S ) and (20R,2R )-1
To a solution of amine (S )-12 (from Aldrich) or (R)-12 in THF, were
added pyridine (1 eq.) and acyl chloride 10 (1.04 eq.). The mixture was stir-
red for 30 min at rt, then 10% aqueous NaOH (5mL) was added. The
organic layer was separated and dried over Na2SO4. Concentration under
reduced pressure followed by flash chromatography with 5% ethyl acetate in
hexane as eluent gave the desired amide 1.
(À)-N-(20R)-Methylbutyl-(2S )-methylbutylamide [(20R,2S)-1] (50 mg,
72% yield). colorless oil: purity >98%. [a]2D0: À21.68 (c¼3.18, diethyl
ether). The IR and NMR spectra were identical with those of (20S,2R)-1.
(À)-N-(20R)-Methylbutyl-(2R)-methylbutylamide [(20R,2R)-1] (50 mg,
72% yield). Colorless oil: purity >99%. [a]2D0: À22.26 (c¼3.14, diethyl
ether). The IR and NMR spectra were identical with those of (20S,2S)-1.
ACKNOWLEDGMENTS
The authors are grateful to FAPESP, CNPq (Brazil) and IFS
(Sweden) for financial support, and Assoc. Prof. Rikard Unelius for helpful
discussions.

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Received in the USA February 8, 2001

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