Enantioselective synthesis of three stereoisomers of 5,9- dimethylpentadecane, sex pheromone component of Leucoptera coffeella, from (-)-isopulegol

Article abstract of DOI:10.1016/j.tetasy.2003.09.030

The coffee leaf miner, Leucoptera coffeella, is an economically important pest of coffee trees in Brazil. It has been demonstrated that the main sex pheromone component of this species is 5,9-dimethylpentadecane, however the stereochemistry of the natural

Full text of DOI:10.1016/j.tetasy.2003.09.030

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3787–3795
Enantioselective synthesis of three stereoisomers of
5,9-dimethylpentadecane, sex pheromone component of
Leucoptera coffeella, from (−)-isopulegol
Jardel A. Moreira and Arlene G. Correˆa*
Departamento de Qu´ımica, Universidade Federal de Sa˜o Carlos, 13565-905 Sa˜o Carlos, SP, Brazil
Received 5 August 2003; accepted 12 September 2003
Abstract—The coffee leaf miner, Leucoptera coffeella, is an economically important pest of coffee trees in Brazil. It has been
demonstrated that the main sex pheromone component of this species is 5,9-dimethylpentadecane, however the stereochemistry of
the natural pheromone remains unknown. We describe herein an enantioselective synthesis of three stereoisomers of 5,9-
dimethylpentadecane from commercial (−)-isopulegol.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In this paper we present the enantioselective synthesis
of (5S,9S)-5,9-dimethylpentadecane and its
1
The coffee leaf miner moth, Leucoptera coffeella, is an
important pest of coffee trees in Brazil. The female-pro-
duced sex pheromone of this leaf miner moth has been
proposed by Francke et al. to consist of 5,9-
dimethylpentadecane and 5,9-dimethylhexadecane as
the major and minor components, respectively.1
Although it was identified in 1988, the stereochemistry
of the natural pheromone remains unknown.
diastereoisomers (5R,9S)- and (5S,9R)-1 starting from
commercially available (−)-isopulegol. Our synthetic
strategy was based on a methodology developed by
Ferreira et al. and applied for the synthesis of two
isomers of methyl 2,6,10-trimethyldodecanoate, male-
produced pheromone of stink bugs Euschistus sp.,6 and
of (2R,3R,7S)-diprionol, sex pheromone component of
the pine sawfly, Neodiprion sertifer.7
Compounds having stereochemically defined alkyl-
branched hydrocarbon chains are widespread in nature.
This fact is particularly important when enantiomeri-
cally active pheromones are considered.2 Several insect
pheromones present the 1,5-dimethyl skeleton.3 It is
evident from the facts discussed above that it is neces-
sary to develop new synthetic methodologies for the
preparation of this class of compound.
2. Results and discussion
Scheme 1 shows the retrosynthetic route to prepare
three of the four possible stereoisomers of 5,9-
dimethylpentadecane. (5S,9S)-1 was obtained directly
from (−)-isopulegol 2 following the synthetic route
described in the Scheme 2, while (5R,9S)- and (5S,9R)-
1 were obtained from (+)-neoisopulegol 2a, prepared
from 2 in 72% yield in two steps using Bohlmann’s
conditions (Scheme 3).8
Kuwahara et al. have prepared all four 5,9-
dimethylpentadecane isomers using
a
convergent
approach in 15 steps.4 The methyl esters of (S)- and
(R)-3-hydroxy-2-methylpropanoic acid were used as
chiral sources, following the procedure reported by
Mori et al.5
In the key step, the stereogenic center at C-5 of
(5S,9S)-1 was established through a stereoselective
hydroboration of (−)-isopulegol 2, with a diastereoiso-
meric ratio of 7:1 (measured by chiral GC).9 The two
stereoisomers of diol 4 formed were readily separated
by flash column chromatography followed by recrystal-
lization, affording pure (1R,3R,4S,8R)-diol 4 in 84%
yield.
* Corresponding author. Tel./fax: +55-16-2608281; e-mail: agcorrea@
dq.ufscar.br
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.030

3788
J. A. Moreira, A. G. Correˆa / Tetrahedron: Asymmetry 14 (2003) 3787–3795
Scheme 1. Retrosynthetic analysis.
Scheme 2. Synthetic route for the preparation of (5S,9S)-dimethylpentadecane 1.
Selective protection of the primary alcohol with benzyl
bromide furnished alcohol 5, which was oxidized with
PCC to produce ketone 6. Bayer–Villiger oxidation of
this ketone with m-CPBA gave lactone 7. Methanolysis
of this lactone furnished hydroxyester 8. To remove the
oxygen function at C-3, the tosylate 9 was prepared.

J. A. Moreira, A. G. Correˆa / Tetrahedron: Asymmetry 14 (2003) 3787–3795
3789
respectively, using commercially available (−)-isopule-
gol as starting material. The remaining stereoisomer
(5R,9R)-1 can be prepared employing the same
methodology from commercial (+)-isopulegol. Since no
chiroptical data of the natural pheromone are available,
we have to rely on the careful comparison of
pheromone activity of the 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.
Scheme 3. Preparation of neoisopulegol.
Reduction of both tosylate and methyl ester groups
with LiAlH4 gave alcohol 10. In this step, initially, we
obtained a 4:1 mixture of the desired product 10 and an
olefin, resulting from an elimination of the tosyl group.
To overcome this problem, the reaction mixture was
cooled to 0°C.
3. Experimental
Unless otherwise noted, all commercially available
reagents were purchased 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 mea-
sured on a Bomem M102 spectrometer. 1H and 13C
NMR spectra were recorded on a Bruker ARX-200
(200 and 50 MHz, respectively) and DRX-400 (400 and
100 MHz, respectively). Optical rotations were mea-
sured on a Perkin–Elmer 241 polarimeter. Mass Spectra
were recorded on a Shimadzu GCMS-QP5000. HRMS
were obtained by direct injection in a VG-Autospec.
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. Chiral GC was performed in a HP 5890 with
H2 as carrier (14 psi) and using an heptakis(2,6-di-O-
methyl-3-O-phenyl)-b-cyclodextrin column (20% in OV
1701, w/w, 25 m, 0.25 mm i.d.). Elemental analyses
were performed on a Fisons EA 1108 CHNS-O.
Alcohol 10 was converted into its corresponding tosyl-
ate 11 and then coupled with n-butyl magnesium bro-
mide, using Li2CuCl4 as catalyst,10 affording 12. Cata-
lytic hydrogenation of the benzyl group furnished
alcohol 13. In our first attempt to prepare (5S,9S)-1,
alcohol 13 was converted into its corresponding tosyl-
ate and then coupled with n-propyl magnesium bro-
mide, following the same procedure described to pre-
pare 12, but the desired product was not obtained.
Several experiments were carried out, changing the
ratio of the Grignard reagent/ROTs, catalyst amount
and temperature, but we just obtained the starting
material and a by-product resulting from substitution
of the tosyl group by bromine. Finally, alcohol 13 was
converted into its corresponding mesylate which was
successfully coupled with n-propyl magnesium bromide
affording the desired alkane (5S,9S)-1 in 91% yield.
In the same manner as described above, (+)-neoisopule-
gol 2a was transformed into tosylate (3R,7S)-11, which
was then converted to (5R,9S)-1 and (5S,9R)-1 only
changing the alkylation sequence, as shown in the
Scheme 4.
3.1. Isopulegone 3
In conclusion, we have prepared three stereoisomers of
(5S,9S)-5,9-dimethylpentadecane 1 in 12 steps and 16%
overall yield, and its diastereoisomers (5R,9S)- and
(5S,9R)-1 in 14 steps, 7.2 and 6.5% overall yield,
(−)-Isopulegol 2 (7.50 g; 48.7 mmol) was added to a
suspension of PCC (15.75 g; 73.0 mmol) in dry CH2Cl2
(230 mL) at room temperature. After 3 h, dry ether
(230 mL) was added and the mixture was filtered
Scheme 4. Synthesis of (5R,9S)- and (5S,9R)-1.

3790
J. A. Moreira, A. G. Correˆa / Tetrahedron: Asymmetry 14 (2003) 3787–3795
through three layer column containing Celite, silica gel
and charcoal and then concentrated and distilled under
vacuum yielding ketone 3 (6.53 g, 88.2% yield) as a
1.8, 3.9 and 12.1 Hz, 1H), 3.36 (br s, 1H), 3.45 (td, J 4.3
and 10.6 Hz, 1H), 3.56 (dd, J 3.4 and 10.7 Hz, 1H),
3.65 (dd, J 5.5 and 10.7 Hz, 1H). 13C NMR (100 MHz,
CDCl3) l 11.92, 22.07, 29.48, 31.44, 34.56, 38.58, 44.60,
48.48, 67.18, 70.16. MS (rel. intensity) m/z 172 (M+,
0.55), 154 (4.79), 139 (8.81), 112 (19.90), 95 (36.57), 81
(96.38), 71 (42.75), 55 (100).
colorless oil. [h]2D5=−7.25 (c 6.20, CHCl3). IR (wmax.
,
film cm−1): 3073, 2953, 2928, 3870, 1712, 1647. 1H
NMR (200 MHz, CDCl3) l 1.04 (d, J 6.0 Hz, 3H),
1.39–1.50 (m, 1H), 1.75 (dd, J 0.8 and 1.4 Hz, 3H),
1.80–2.12 (m, 5H), 2.41 (ddd, J 2.2, 3.2 and 12.8 Hz,
1H), 2.96 (dd, J 5.2, and 12.8 Hz, 1H), 4.70–4.75 (m,
1H), 4.91–4.96 (m, 1H). 13C NMR (50 MHz, CDCl3) l
21.26, 22.25, 31.11, 33.78, 35.24, 50.48, 57.64, 112.76,
143.42, 210.18.
3.4. (+)-(1R,3S,4S,8S)-p-Menthane-3,9-diol 4a
Similarly, (+)-neoisopulegol 2a (6.10 g, 39.6 mmol) gave
4a/4b (5.90 g) with a diastereoisomeric ratio of 3:1 in
87.6% overall yield. The oil obtained was purified by
column chromatography (hexane/ethyl acetate, 1:2)
affording pure (1R,3R,4S,8R)-diol 4a (1.60 g). [h]2D5=
+17.2 (c 4.00, CHCl3), lit.:6 [h]D20=+17.0 (c 10.0,
CHCl3). IR (wmax., film, cm−1): 3317, 2947, 2920, 2869,
3.2. (+)-Neoisopulegol 2a
A solution of L-Selectride in THF (1.0 M, 64.0 mL,
64.0 mmol) was added dropwise at −78°C to a previ-
ously prepared solution of isopulegone 3 (6.50 g, 42.7
mmol) in dry THF (130 mL). The reaction temperature
was raised slowly at rt (2 h). After stirring for 14 h, the
mixture was cooled to 0°C, H2O2 (22 mL, 30 wt.%
solution in water) was slowly added, followed by
aqueous NaOH (15 mL, 15%), and stirred for an
additional 30 min at room temperature. The organic
layer was washed with brine (100 mL), dried over
MgSO4, filtered, and then concentrated and distilled
under vacuum yielding compound 2a (6.11 g, 92.7%
yield) as a colorless oil. [h]2D5=+28.7 (c 17.2, CHCl3).
IR (wmax., film cm−1): 3457, 3085, 2947, 2925, 2868,
1
2843, 1455, 1036. H NMR (200 MHz, CDCl3) l 0.87
(d, J 6.2 Hz, 3H), 0.99 (d, J 7.0 Hz, 3H), 1.07–1.32 (m,
2H), 1.41–1.91 (m, 7H), 3.45–3.70 (m, 3H), 3.66 (dd, J
2.8 and 10.8 Hz, 1H), 4.12 (s, 1H). 13C NMR (50 MHz,
CDCl3) l 15.93, 22.44, 25.48, 26.17, 35.40, 38.17, 42.27,
46.04, 64.80, 66.34. Anal. calcd for C10H20O2: C, 69.72;
H, 11.70. Found: C, 69.50, H, 11.42.
3.5. (−)-(1R,3R,4S,8R)-9-Benzyloxy-p-menthan-3-ol 5
Diol 4 (1.60 g, 9.3 mmol) was added dropwise to a
stirred suspension of NaH (0.41 g, 10.2 mmol, 50% in
mineral oil) in dry DMF (32 mL) under N2 at 0°C. The
resulting solution was cooled at −10°C and stirred for
1.5 h. The mixture was cooled at −60°C and a solution
of benzyl bromide (1.10 mL, 9.3 mmol) in DMF (6.0
mL) was slowly added. The mixture was stirred at
−60°C for 2 h, then the reaction temperature was raised
to room temperature, and stirred for an additional 12
h. Saturated aqueous NH4Cl (30 mL) was added, and
the resulting mixture was extracted with ethyl acetate
(3×40 mL). The organic layer was washed with brine
(30 mL) and dried over Na2SO4, concentrated and the
oil obtained was purified by column chromatographic
(hexane:ethyl acetate, 5:1) to afford 2.01 g of the com-
pound 5 (83% yield) as a colorless oil. [h]2D5=−13.1 (c
1.88, CHCl3), lit.6 [h]D25=−12.4 (c 14.6, CHCl3). IR
(wmax., film cm−1): 3423, 3963, 3030, 2940, 2919, 1454,
1096. 1H NMR (200 MHz, CDCl3) l 0.84–0.89 (m,
1H), 0.91 (d, J 6.4 Hz, 3H), 0.96 (d, J 7.4 Hz, 3H), 1.14
(dd, J 3.4 and 12 Hz, 1H), 1.22–1.80 (m, 5H), 1.85–2.15
(m, 2H), 3.36–3.55 (m, 3H), 3.62 (br s, 1H), 4.48 (d, J
12.0 Hz, 1H), 4.56 (d, J 12.0 Hz, 1H), 7.26–7.55 (m,
5H). 13C NMR (50 MHz, CDCl3) l 13.56, 22.19, 27.91,
31.48, 34.74, 35.51, 43.98, 48.99, 70.47, 73.36, 74.37,
127.72, 128.45, 137.57. MS (rel intensity) m/z 171
(2.67), 153 (15.52), 138 (14.54), 123 (6.62), 107 (14.34),
95 (30.17), 91 (100), 81 (34.28), 55 (34.26), 41 (44.06).
1
1643, 1450. H NMR (200 MHz, CDCl3) l 0.89 (d, J
6.4 Hz, 3H), 0.92–1.16 (m, 2H), 1.40–1.52 (m, 2H),
1.65–1.77 (m, 3H), 1.79 (s, 3H), 1.92–2.00 (m, 2H), 4.00
(br s, 1H), 4.79 (s, 1H), 4.95 (s, 1H). 13C NMR (50
MHz, CDCl3) l 22.20, 22.79, 23.94, 25.81, 34.77, 40.92,
48.42, 66.28, 111.28, 147. 34. Anal. calcd for C10H18O:
C, 77.87; H, 11.76. Found: C, 77.75, H, 11.64.
3.3. (−)-(1R,3R,4S,8R)-p-Menthane-3,9-diol 4
BF3·Et2O (2.8 mL, 22.2 mmol) was added dropwise to
a stirred suspension of NaBH4 (0.74 g, 19.6 mmol) in
diglyme (13 mL) at room temperature under nitrogen.
The generated diborane was transferred via a cannula
into a solution of (−)-isopulegol 2 (2.00 g, 13.0 mmol)
in dry THF (52 mL) under nitrogen at 0°C. After
stirring for 3 h, H2O (2.0 mL) was slowly added,
followed by H2O2 (3.0 mL, 30 wt% solution in water)
and aqueous NaOH (3.0 mL, 30%), and stirred for an
additional 30 min at room temperature. The reaction
mixture was extracted with ether (3×40 mL) and the
separated organic layer was washed with brine (30 mL)
and dried over MgSO4. The oil obtained was purified
by column chromatography (hexane/ethyl acetate, 1:2)
followed by recrystallization (cyclohexane:CH2Cl2, 2:1)
to afford 1.88 g of diol 4 (84% yield) as colorless
crystals. [h]D25=−18.5 (c 5.00, CHCl3), lit.6 [h]2D5=−18.6
(c 10.0, CHCl3). IR (wmax. film, cm−1): 3234, 2961, 2945,
2912, 1451, 1037. 1H NMR (400 MHz, CDCl3) l
0.83–1.02 (m, 2H), 0.92 (d, J 6.5 Hz, 3H), 0.96 (d, J 7.3
Hz, 3H), 1.24 (dq, J 3.5 and 12.8 Hz, 1H), 1.35 (ddd, J
2.0, 3.2 and 9.8 Hz, 1H), 1.38–1.46 (m, 1H), 1.56 (dq, J
3.2 and 13.0 Hz, 1H), 1.64 (dqui, J 3.0 and 12.5 Hz,
1H), 1.78 (br s, 1H), 1.80–1.88 (m, 1H), 1.96 (ddd, J
3.6. (+)-(1R,3S,4S,8S)-9-Benzyloxy-p-menthan-3-ol 5a
Similarly, 4a (1.55 g, 9.0 mmol) gave 5a (2.10 g, 89.4%)
as a colorless oil. [h]2D5=+3.6 (c 5.60, CHCl3). IR (wmax.
,
1
film cm−1): 3428, 2945, 2916, 2867, 1453. H NMR (200
MHz, CDCl3) l 0.86 (d, J 6.2 Hz, 3H), 0.97 (d, J 7.0
Hz, 3H), 1.05–1.19 (m, 2H), 1.40–1.93 (m, 7H), 3.28

J. A. Moreira, A. G. Correˆa / Tetrahedron: Asymmetry 14 (2003) 3787–3795
3791
(dd, J 1.4 and 2.9 Hz, 1H), 3.40 (dd, J 6.6 and 9.2 Hz,
1H), 3.48 (dd, J 3.0 and 9.2 Hz, 1H), 4.02 (br s, 1H),
4.51 (s, 2H), 7.22–7.36 (m, 5H). 13C NMR (50 MHz,
CDCl3) l 16.49, 22.46, 25.38, 26.16, 35.38, 36.17,
41.90, 46.64, 66.63, 73.47, 74.16, 127.77, 128.46,
137.68. Anal. calcd for C17H26O2: C, 77.82; H, 9.99.
Found: C, 77.59, H, 9.65.
2.45 g of lactone 7 (75% yield). [h]2D5=+2.5 (c 0.85,
CHCl3), IR (wmax., film cm−1): 3033, 2959, 2928, 2871,
1729, 1454, 1102. H NMR (400 MHz, CDCl3) l 0.96
1
(d, J 7.0 Hz, 3H), 1.04 (d, J 6.7 Hz, 3H), 1.29–1.38
(m, 1H), 1.66–1.78 (m, 2H), 1.78–1.88 (m, 1H), 1.88–
1.98 (m, 2H), 2.45 (dt, J 1.8 and 13.4 Hz, 1H), 2.54
(dd, J 11.5 and 13.4 Hz, 1H), 3.36 (dd, J 5.3 and 9.2
Hz, 1H), 3.49 (t, J 9.0 Hz, 1H), 4.49 (s, 2H), 4.49–4.52
(m, 1H), 7.26–7.35 (m, 5H). 13C NMR (100 MHz,
CDCl3) l 10.23, 23.96, 30.29, 32.11, 37.29, 39.39,
42.47, 71.79, 73.16, 79.03, 127.65, 128.38, 138.28,
174.96. MS (rel intensity) m/z 276 (M+, 3.43), 230
(1.22), 170 (1.60), 152 (9.75), 128 (10.09), 11 (71.66),
91 (100), 69 (51.01), 55 (65.54).
3.7. (−)-(1R,4S,8R)-9-Benzyloxy-p-menthan-3-one 6
Alcohol 5 (3.38 g; 12.9 mmol) was added to a suspen-
sion of PCC (4.20 g, 19.3 mmol) in dry CH2Cl2 (105
mL) at room temperature. After 3 h, dry ether (100
mL) was added and the mixture was filtered through a
three layer column containing Celite, silica gel and
charcoal and then concentrated. The oil was purified
by column chromatography (hexane:ethyl acetate, 5:1)
to afford 3.11 g of the ketone 6 (93% yield). [h]2D5=
−10.8 (c 1.30, CHCl3), lit.6 [h]D25=−10.5 (c 36.8,
CHCl3). IR (wmax., film cm−1): 3088, 3063, 3030, 2953,
2926, 2869, 1708, 1454, 1099. 1H NMR (200 MHz,
CDCl3) l 1.00 (d, J 6.3 Hz, 3H), 1.01 (d, J 6.9 Hz,
3H), 1.32–1.44 (m, 1H), 1.70–1.78 (m, 1H), 1.79–1.89
(m, 2H), 1.90–2.00 (m, 1H), 2.01–2.08 (m, 1H), 2.09–
2.20 (m, 1H), 2.31–2.37 (m, 2H), 3.38 (dd, J 6.0 and
9.1 Hz, 1H), 3.48 (dd, J 5.4 and 9.1 Hz, 1H), 4.46 (d,
J 15.2 Hz, 1H), 4.49 (d, J 15.2 Hz, 1H), 7.24–7.27 (m,
5H). 13C NMR (50 MHz, CDCl3) l 15.48, 22.30,
29.47, 32.65, 34.09, 35.48, 50.97, 52.20, 72.92, 73.02,
127.48, 128.25, 138.73, 212.01. MS (rel. intensity) m/z
260 (M+, 1.18), 202 (21.40), 169 (24.92), 139 (24.95),
112 (80.75), 91 (100), 69.15 (53.15), 55 (61.17).
3.10. (−)-(3R,6S)-3-Methyl-6-[(1%R)-1%-methyl-2-benzyl-
oxymethyl]-o-caprolactone 7a
Similarly, 6a (1.92 g, 7.4 mmol) gave 7a (1.55 g,
76.0%) as a white solid. [h]2D5=−7.3 (c 1.05, CHCl3).
IR (wmax., film cm−1): 3063, 3030, 2961, 1927, 2871,
1729, 1454, 1292, 1102, 739. 1H NMR (200 MHz,
CDCl3) l 0.99 (d, J 7.0 Hz, 3H), 1.04 (d, J 6.6 Hz,
3H), 1.10–1.40 (m, 1H), 1.40–1.70 (m, 1H), 1.70–2.00
(m, 3H), 2.14 (hept, J 7.0 Hz, 1H), 2.40–2.70 (m, 2H),
3.42 (dd, J 6.6 and 9.4 Hz, 1H), 3.48 (dd, J 5.8 and
J=9.0 Hz, 1H), 4.35 (dd, J 5.1 and 9.0 Hz, 1H), 4.45
(d, J 12.2 Hz, 1H), 4.52 (d, J 12.2 Hz, 1H), 7.10–7.50
(m, 5H). 13C NMR (50 MHz, CDCl3) l 13.18, 24.31,
30.20, 30.68, 37.68, 38.81, 42.75, 71.80, 73.45, 81.65,
127.93, 127.98 (2C), 128.74 (2C), 138.67, 175.26. Anal.
calcd for C17H24O3: C, 73.88; H, 8.75. Found: C,
73.67, H, 8.56.
3.8. (−)-(1R,4S,8S)-9-Benzyloxy-p-menthan-3-one 6a
3.11. (−)-Methyl (3R,6S,7S)-8-benzyloxy-6-hydroxy-
Similarly, 5a (2.05 g, 7.8 mmol) gave 6a (1.93 g,
94.4%) as a colorless oil. [h]2D5=−7.7 (c 0.7, CHCl3).
IR (wmax., film cm−1): 3086, 3064, 3030, 2953, 2926,
3,7-dimethyl-octanoate 8
Concentrated H2SO4 (five drops) was added to a solu-
tion of lactone 7 (2.30 g, 8.3 mmol) in MeOH (25
mL), and the mixture was refluxed for 30 min. After
cooling, saturated aqueous NaHCO3 (10 mL) was
added, most of the MeOH was evaporated and the
residue was extracted with ether (3×25 mL). The
organic phase was washed with brine (20 mL), dried
over Na2SO4, concentrated and the residue was
purified by column chromatography (hexane/ethyl ace-
tate, 5:2) to afford 2.39 g of the desired hydroxy ester
8 (93% yield). [h]D25=−1.7 (c 2.88, CHCl3), lit.6 [h]2D5=
−1.1 (c 3.6, CHCl3). IR (wmax., film cm−1): 3491, 3063,
3030, 2954, 2672, 1725, 1454, 1099, 1010. 1H NMR
(400 MHz, CDCl3) l 0.92 (d, J 7.0 Hz, 3H), 0.94 (d, J
6.6 Hz, 3H), 1.12–1.23 (m, 1H), 1.38–1.47 (m, 2H),
1.48–1.58 (m, 1H), 1.84–2.03 (m, 2H), 2.12 (dd, J 8.2
and 14.8 Hz, 1H), 2.32 (dd, J 5.9 and 14.8 Hz, 1H),
2.57 (sl, 1H), 3.52 (d, J 6.0 Hz, 1H), 3.52 (d, J 5.0 Hz,
1H), 3.65 (s, 3H), 3.72 (td, J 2.5 and 6.7 Hz, 1H), 4.48
(d, J 11.7 Hz, 1H), 4.52 (d, J 11.7 Hz, 1H), 7.26–7.37
(m, 5H). 13C NMR (100 MHz, CDCl3) l 10.59, 19.72,
30.39, 31.19, 33.22, 37.67, 41.43, 51.32, 73.34, 74.14,
74.66, 127.63, 128.36, 137.93, 173.63. MS (rel. inten-
sity) m/z 276 (1.84), 230 (0.76), 184 (0.76), 152 (6.62),
127 (6.56), 110 (40.99), 91 (100), 81 (20.38), 69 (30.81),
55 (37.04).
1
2969, 1707, 1454, 1204, 737, 698. H NMR (200 MHz,
CDCl3) l 0.85 (d, J 6.8 Hz, 3H), 1.01 (d, J 6.0 Hz,
3H), 1.16–1.48 (m, 2H), 1.70–2.10 (m, 4H), 2.30–2.60
(m, 3H), 3.30 (dd, J 6.9 and 9.4 Hz, 1H), 3.36 (dd, J
6.0 and 9.4 Hz), 4.44 (d, J 12.1 Hz, 1H), 4.51 (d, J
12.1 Hz, 1H), 7.10–7.40 (m, 5H). 13C NMR (50 MHz,
CDCl3) l 13.22, 22.35, 26.78, 30.94, 33.84, 35.20,
50.14, 50.74, 72.81, 73.20, 127.51, 127.57 (2C), 128.34
(2C), 138.68. 212.11. Anal. calcd for C17H24O2: C,
78.42; H, 9.29. Found: C, 78.12, H, 9.00.
3.9. (+)-(3R,6S)-3-Methyl-6-[(1%S)-1%-methyl-2-benzil-
oxymethyl]-o-caprolactone 7
Ketone 6 (3.07 g, 11.8 mmol) was added to a stirred
solution of m-CPBA (40%, 6.04 g, 15.3 mmol) in
CH2Cl2 (80 mL) containing a suspension of NaHCO3
(6.00 g, 71 mmol). After stirring for 20 h at room
temperature, aqueous KI (24 mL, 40%) and aqueous
NaHSO3 (40%, 24 mL) were added to reduce the
excess of oxidant. The resulting two phase system was
stirred for 10 min. After separation the organic phase
was washed with brine (20 mL), dried over Na2SO4,
concentrated and the residue was purified by column
chromatography (hexane/ethyl acetate, 5:1) to afford

3792
J. A. Moreira, A. G. Correˆa / Tetrahedron: Asymmetry 14 (2003) 3787–3795
3.12. (−)-Methyl (3R,6S,7R)-8-benzyloxy-6-hydroxy-
3,7-dimethyl-octanoate 8a
C25H34O6S: C, 64.91; H, 7.41; S, 6.93. Found: C, 64.66,
H, 7.24; S, 6.90.
Similarly, 7a (1.53 g, 5.0 mmol) gave 8a (1.58 g, 91.3%)
as a colorless oil. [h]2D5=−14.1 (c 3.97, CHCl3). IR
(wmax., film cm−1): 3494, 3088, 3063, 2955, 2873, 1736,
3.15. (+)-(3R,7R)-8-Benzyloxy-3,7-dimethyloctan-1-ol
10
1
1454, 1096, 737, 699. H NMR (200 MHz, CDCl3) l
Tosylate 9 (2.20 g, 4.8 mmol) was dissolved in dry ether
(200 mL) and then LiAlH4 (1.63 g, 42.8 mmol) was
added. After stirring at room temperature for 3 h,
excess of the hydride was destroyed with addition of
water (2.0 mL), aqueous solution of NaOH (15%, 2.0
mL) and water (8.0 mL) again. The suspension was
filtered through Celite, dried over Na2SO4 and concen-
trated. The product obtained was purified by column
chromatography (hexane:ethyl acetate, 5:1) affording
0.84 g of the alcohol 10 (67% yield). [h]2D5=+3.3 (c 1.70,
CHCl3), lit.6 [h]D25=+3.6 (c 2.80, CHCl3). IR (wmax., film
cm−1): 3374, 3064, 3030, 2953, 2928, 1454, 1100. 1H
NMR (200 MHz, CDCl3) l 0.89 (d, J 6.8 Hz, 3H), 0.92
(d, J 7.0 Hz, 3H), 1.00–1.19 (m, 2H), 1.25–1.43 (m, 6H),
1.53–1.61 (m, 2H), 1.67–1.80 (m, 1H), 3.24 (dd, J 6.6
and 9.0 Hz, 1H), 3.32 (dd, J 6.4 and 9.0 Hz, 1H),
3.50–3.60 (m, 2H), 4.50 (s, 2H), 7.26–7.35 (m, 5H). 13C
NMR (50 MHz, CDCl3) l 17.12, 19.60, 24.24, 29.41,
33.44, 33.85, 37.30, 40.00, 61.19, 72.98, 76.04, 127.42,
127.54, 128.30, 138.80. MS (rel. intensity) m/z 264 (M+,
3.04), 155 (2.00), 107 (34.01), 91 (100), 69 (26.44), 55
(43.18).
0.91 (d, J=7.0 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H),
1.15–1.60 (m, 4H), 1.60–1.70 (m, 1H), 1.70–2.00 (m,
1H), 2.11 (dd, J 8.2 Hz and 14.5 Hz, 1H), 2.34 (dd, J
5.6 and 14.5 Hz, 1H), 3.36 (br s, 1H), 3.46 (dd, J 7.3
and 9.2 Hz, 1H), 3.61 (dd, J 4.3 and 9.2 Hz, 1H), 3.66
(s, 3H), 4.51 (s, 2H), 7.20–7.40 (m, 5H). 13C NMR (50
MHz, CDCl3) l 13.96, 19.86, 30.49, 32.12, 32.23, 38.08,
41.35, 51.32, 73.42, 75.03, 76.20, 127. 61 (2C), 127.73,
128.40 (2C), 137.65, 173.71. Anal. calcd for C18H28O4:
C, 70.10; H, 9.15. Found: C, 70.10, H, 9.15.
3.13. (+)-Methyl (3R,6S,7S)-8-benzyloxy-3,7-dimethyl-
6-p-toluenesulfonyloxyoctanoate 9
Tosyl chloride (2.61 g, 13.6 mmol) was added in small
portions (1 h) to ester 8 (2.10 g, 6.8 mmol) in dry
pyridine (1.61 g, 20.4 mmol), DMAP (20 mg) and
chloroform (10 mL), with magnetic stirring at 0°C.
After 12 h, ethyl ether (15 mL) was added and the
solution was thoroughly washed with aqueous HCl
(10%, 10 mL) and saturated solution of NaHCO3 (10
mL). The organic layer was dried over Na2SO4, concen-
trated and the oil obtained was purified by column
chromatographic (hexane:ethyl acetate, 9:1) to afford
2.26 g of 9 as a colorless oil (72% yield). [h]2D5=+5.6 (c
1.54, CHCl3). IR (wmax., film cm−1): 3063, 3030, 2955,
2873, 1736, 1362, 1175, 903. 1H NMR (200 MHz,
CDCl3) l 0.86 (d, J 6.6 Hz, 3H), 0.89 (d, J 7.0 Hz, 3H),
1.01–1.36 (m, 2 H), 1.58–1.70 (m, 2H), 1.78–1.96 (m,
1H), 1.97–2.10 (m, 2 H), 2.19 (dd, J 6.2 and 15.0 Hz,
1H), 2.42 (s, 3H), 3.25 (d, J 6.6 Hz, 2H), 3.64 (s, 3H),
4.31 (d, J 11.8 Hz, 1H), 4.41 (d, J 11.8 Hz, 1H), 4.79
(td, J 3.0 and 7.0 Hz, 1H), 7.26–7.35 (m 7H), 7.77 (d, J
8.0 Hz, 2H). 13C NMR (50 MHz, CDCl3) l 11.00,
19.48, 21.60, 29.40, 30.05, 31.98, 36.55, 41.29, 51.42,
71.71, 72.97, 84.48, 127.57 (3C), 127.71 (2C), 128.35
(2C), 129.66 (2C), 134.73, 138.38, 144.38, 173.31.
3.16. (+)-(3R,7S)-8-Benzyloxy-3,7-dimethyloctan-1-ol
10a
Similarly, 9a (1.80 g, 3.5 mmol) gave 10a (0.71 g,
69.2%) as a colorless oil. [h]2D5=+2.5 (c 0.70, CHCl3).
IR (wmax., film cm−1): 3379, 3064, 3031, 2953, 2928,
1
2857, 1454, 1363, 1100, 1072, 735. H NMR (200 MHz,
CDCl3) l 0.89 (d, J 6.5 Hz, 3H), 0.93 (d, J 6.7 Hz, 3H),
1.00–1.40 (m, 8H), 1.45–1.80 (m, 3H), 3.23 (dd, J 6.7
and 9.0 Hz, 1H), 3.33 (dd, J 6.1 and 9.0 Hz, 1H),
3.50–3.75 (m, 2H), 4.50 (s, 2H), 7.20–7.40 (m, 5H). 13C
NMR (50 MHz, CDCl3) l 17.20, 19.67, 24.23, 29.49,
33.47, 33.91, 37.39, 39.89, 61.19, 72.97, 75.97, 127.41,
127.53 (2C), 128.30 (2C). 138.79. Anal. calcd for
C17H28O2: C, 77.22; H, 10.67. Found: C, 77.00, H,
10.59.
3.14. (−)-Methyl (3R,6S,7R)-8-benzyloxy-3,7-dimethyl-
6-p-toluene-sulfonyloxyoctanoate 9a
3.17. (+)-(3R,7R)-8-Benzyloxy-3,7-dimethyloctyl-1-p-
toluenesulfonylate 11
Similarly, 8a (1.50 g, 4.9 mmol) gave 9a (1.82 g, 80.5%)
as a colorless oil. [h]2D5=−0.75 (c 2.55, CHCl3). IR
(wmax., film cm−1): 3088, 3063, 3031, 2955, 2872, 1735,
1495, 1454, 1361, 1306, 1290. 1H NMR (200 MHz,
CDCl3) l 0.83 (d, J 6.6 Hz, 3H), 0.88 (d, J 7.0 Hz, 3H),
0.90–1.35 (m, 2H), 1.40–1.65 (m, 2H), 1.65–1.90 (m,
1H), 1.90–2.21 (m, 2H), 2.01 (dd, J 8.0 and 14.7 Hz,
1H), 2.42 (s, 3H), 3.25 (dd, J 5.9 and 9.6 Hz, 1H), 3.35
(dd, J 6.7 and 9.6 Hz, 1H), 3.64 (s, 3H), 4.36 (d, J 12.0
Hz, 1H), 4.45 (d, J 12.0 Hz, 1H), 4.68 (td, J 4.8 and 6.9
Hz, 1H), 7.20–7.40 (m 7H), 7.77 (d, J 8.3 Hz, 2H). 13C
NMR (50 MHz, CDCl3) l 12.31, 19.63, 21.58, 27.62,
30.14, 31.58, 36.74, 41.18, 51.36, 71.55, 72.90, 85.51,
127.50 (2C), 127.56, 127.79 (2C), 128.35 (2C), 129.67
(2C), 134.69, 138.38, 144.42, 173.30. Anal. calcd for
Tosyl chloride (1.17 g, 6.0 mmol) was added in small
portions, during 1 h, to a solution containing alcohol
10 (0.80 g, 3.0 mmol), dry pyridine (0.8 mL, 9.0 mmol),
DMAP (10 mg) and chloroform (10 mL), with mag-
netic stirring at 0°C. After 12 h, ethyl ether (10 mL)
was added and the solution was thoroughly washed
with aqueous HCl (10%, 5 mL), saturated solution of
NaHCO3 (5 mL), dried, concentrated and the oil
obtained was purified by column chromatography (hex-
ane:ethyl acetate, 9:1) to afford 1.19 g of tosylate 11 as
a colorless oil (93% yield). [h]2D5=+1.9 (c 7.40, CH2Cl2).
IR (wmax., film cm−1): 3063, 3031, 2956, 2928, 2857,
1
1454, 1362, 1177, 944. H NMR (400 MHz, CDCl3) l
0.79 (d, J 6.5 Hz, 3H), 0.90 (d, J 6.7 Hz, 3H), 1.02–1.10

J. A. Moreira, A. G. Correˆa / Tetrahedron: Asymmetry 14 (2003) 3787–3795
3793
(m, 2H), 1.10–1.27 (m, 3H), 1.30–1.46 (m, 2H), 1.48–
3.20. (+)-(2S,6S)-1-Benzyloxy-2,6-dimethyldodecane
12a
1.54 (m, 1H), 1.61–1.75 (m, 2H), 2.44 (s, 3H), 3.23 (dd,
J 6.6 and 9.0 Hz, 1H), 3.29 (dd, J 6.2 and 9.2 Hz, 1H),
4.05 (dt, J 2.7 and 6.4 Hz, 2H), 4.78 (d, J 12.2 Hz, 1H),
4.51 (d, J 12.2 Hz, 1H), 7.25–7.34 (m, 7H), 7.79 (d, J
8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) l 17.02,
19.02, 21.59, 24.02, 29.08, 33.36, 33.49, 35.68, 36.77,
69.03, 72.91, 75.89, 127.39, 127.49, 127.83, 128.06,
128.27, 129.77, 133.08, 138.70, 144.61. MS (rel. inten-
sity) m/z 246 (0.83), 155 (2.38), 137 (7.29), 107 (9.47),
91 (100), 69 (29.57), 55 (52.43). Anal. calcd for
C24H34O4S: C, 68.87; H, 8.19; S, 7.66. Found: C, 68.83;
H, 8.38; S, 7.93.
In the same manner as that described for the prepara-
tion of 11, 10a (0.150 g, 0.36 mmol) gave 11a (0.099 g,
90.8%) as a colorless oil. [h]2D5=+1.6 (c 1.73, CHCl3).
IR (wmax., film cm−1): 3067, 3030, 2955, 2925, 2854,
1
1454, 1376, 1363, 1099, 733, 696. H NMR (200 MHz,
CDCl3) l 0.83 (d, J 6.3 Hz, 3H), 0.88 (t, J 6.4 Hz, 3H),
0.93 (d, J 6.7 Hz, 3H), 1.00–1.50 (m, 17H), 1.60–1.90
(m, 1H), 3.23 (dd, J 6.7 and 9.0 Hz, 1H), 3.33 (dd, J 6.0
and 9.0 Hz, 1H), 4.50 (s, 2H), 7.10–7.50 (m, 5H). 13C
NMR (50 MHz, CDCl3) l 14.10, 17.21, 19.72, 22.68,
24.36, 27.02, 29.67, 31.94, 32.74, 33.48, 34.00, 37.02,
37.34, 72.94, 76.04, 127.36, 127.49 (2C), 128.27 (2C),
138.86. Anal. calcd for C21H36O: C, 82.83; H, 11.92.
Found: C, 82.82; H, 11.90.
3.18. (+)-(3R,7S)-8-Benzyloxy-3,7-dimethyloctyl-1-p-
toluenesulfonylate 11a
Similarly, 10a (0.61 g, 2.3 mmol) gave 11a (0.97 g,
96.8%) as a colorless oil. [h]2D5=+1.9 (c 1.45, CHCl3).
IR (wmax., film cm−1): 3063, 3031, 2956, 2928, 1598,
3.21. (+)-(2S,6S)-1-Benzyloxy-2,6-dimethyldecane 15
In the same manner as that described for the prepara-
tion of 11, 10a (0.150 g, 0.36 mmol) gave 15 (0.088 g,
89%) as a colorless oil. [h]2D5=+2.4 (c 0.82, CHCl3). IR
(wmax., film cm−1): 3087, 3067, 3030, 2955, 2926, 2855,
1
1454, 1361, 1188, 1177, 944, 890, 738. H NMR (200
MHz, CDCl3) l 0.79 (d, J 6.2 Hz, 3H), 0.90 (d, J 6.7
Hz, 3H), 1.00–1.80 (m, 10H), 2.43 (s, 3H), 3.22 (dd, J
6.6 and 9.0 Hz, 1H), 3.30 (dd, J 6.1 and 9.0 Hz, 1H),
4.05 (t, J 6.5 Hz, 2H), 4.55 (s, 2H), 7.20–7.40 (m, 7H),
7.79 (d, J 8.3 Hz, 2H). 13C NMR (50 MHz, CDCl3) l
17.16, 19.16, 21.62, 24.05, 29.18, 33.43, 33.79, 35.64,
36.89, 69.08, 72.97, 75.88, 127.43, 127.53 (2C), 127.86
(2C), 128.31 (2C), 129.80 (2C), 133.20, 138.77, 144.63.
Anal. calcd for C24H34O4S: C, 68.87; H, 8.19; S.7.66
Found: C, 68.68; H, 7.98; S, 7.43.
1
1454, 1376, 1100, 696. H NMR (200 MHz, CDCl3) l
0.83 (d, J 6.2 Hz, 3H), 0.88 (t, J 5.4 Hz, 3H), 0.92 (d,
J 6.7 Hz, 3H), 1.00–1.50 (m, 13H), 1.62–1.85 (m, 1H),
3.22 (dd, J 6.8 and 9.1 Hz, 1H), 3.33 (dd, J 6.0 and 9.1
Hz, 1H), 4.50 (s, 2H), 7.10–7.40 (m, 5H). 13C NMR (50
MHz, CDCl3) l 14.17, 17.24, 19.76, 23.05, 24.39, 29.33,
32.74, 33.51, 34.03, 36.72, 37.36, 72.97, 76.07, 127.37
(2C), 128.60 (2C), 128.82. Anal. calcd for C19H32O: C,
82.55; H, 11.67. Found: C, 82.42; H, 11.51.
3.19. (−)-(2R,6S)-1-Benzyloxy-2,6-dimethyldodecane 12
3.22. (+)-(2R,6S)-2,6-Dimethyldodecan-1-ol 13
Magnesium turnings (0.087 g, 3.6 mmol) were added to
a solution of 1-bromobutane (0.49 g, 3.6 mmol) in dry
ethyl ether (12 mL) at rt. After 6 h the solution
containing the Grignard reagent was added dropwise at
−78°C to a previously prepared solution of tosilate 11
(0.30 g, 0.7 mmol) in dry THF (12 mL). Then, a
solution of Li2CuCl4 in THF (0.1 M, 0.15 mL, 0.015
mmol) was added to the mixture. The temperature was
raised slowly until rt during 2 h and then stirred for 10
h. The reaction was quenched with saturated solution
of NH4Cl (20 mL) and the resulting mixture was
extracted with ether (3×40 mL). The organic layer was
washed with saturated NaHCO3 solution (2×20 mL)
and brine (50 mL), dried over MgSO4, filtered, and
evaporated in vacuo. The residue was chromatographed
over silica gel (hexane:ethyl acetate, 95:5) and 0.177 g
of 12 was obtained (81% yield). [h]2D5=−0.6 (c 1.32,
CH2Cl2). IR (wmax., film cm−1): 3087, 3064, 2955, 2926,
A mixture of benzyl ether 12 (0.170 g, 0.5 mmol) and
10% Pd/C (0.020 g) in ethanol (5 mL) was hydro-
genated at room temperature under hydrogen atmo-
sphere for 12 h. The mixture was filtered through
Celite, and the filtrate evaporated at reduced pressure
to afford alcohol 12 (0.108 g) in 86% yield. [h]2D5=+9.6
(c 7.35, CHCl3). IR (wmax., film cm−1): 3373, 2957, 2926,
1
2855, 1639, 1464, 1377, 1036, 724. H NMR (200 MHz,
CDCl3) l 0.84 (d, J 6.3 Hz, 3H), 0.88 (t, J 6.2 Hz, 3H),
0.91 (d, J 6.7 Hz, 3H), 1.00–1.40 (m, 17H), 1.50–1.67
(m, 1H), 1.73 (br s, 1H), 3.40 (dd, J 6.6 and 10.5 Hz,
1H), 3.51 (dd, J 5.8 and 10.5 Hz, 1H). 13C NMR (50
MHz, CDCl3) l 14.16, 16.59, 19.67, 22.73, 24.41, 27.10,
29.73, 31.99, 32.76, 33.47, 35.79, 37.19, 37.33, 68.43.
Anal. calcd for C14H30O: C, 78.43; H, 14.10. Found: C,
78.42; H, 14.00.
1
2855, 1376, 1363, 1100, 735, 697. H NMR (200 MHz,
3.23. (−)-(2S,6S)-2,6-Dimethyldodecan-1-ol 13a
CDCl3) l 0.83 (d, J 6.3 Hz, 3H), 0.88 (t, J 5.0 Hz, 3H),
0.92 (d, J 6.7 Hz, 3H), 1.00–1.50 (m, 7H), 1.63–1.85 (m,
1H), 3.23 (dd, J 6.7 and 9.0 Hz, 1H), 3.33 (dd, J 6.1
and 9.0 Hz, 1H), 4.50 (s, 2H), 7.10–7.40 (m, 5H). 13C
NMR (50 MHz, CDCl3) l 14.13, 17.15, 19.67, 22.71,
24.36, 27.08, 29.71, 31.98, 32.75, 33.49, 33.98, 37.17,
37.32, 72.97, 76.12, 127.39, 127.52 (2C), 128.30 (2C),
138.85. Anal. calcd for C21H36O: C, 82.83; H, 11.92.
Found: C, 82.63; H, 11.88.
Similarly, 12a (0.090 g, 0.30 mmol) gave 13a (0.052 g,
82.0%) as a colorless oil. [h]2D5=−7.1 (c 0.73, CHCl3).
IR (wmax., film cm−1): 3422, 2955, 2925, 2855, 1639,
1
1463, 1377, 1098, 1030, 733, 696. H NMR (200 MHz,
CDCl3) l 0.84 (d, J 6.3 Hz, 3H), 0.88 (t, J 6.3 Hz, 3H),
0.92 (d, J 6.7 Hz, 3H), 0.95–1.40 (m, 17H), 1.45–1.70
(m, 1H), 3.41 (dd, J 6.5 and 10.5 Hz, 1H), 3.52 (dd, J
5.7 and 10.5 Hz, 1H). 13C NMR (50 MHz, CDCl3) l

3794
J. A. Moreira, A. G. Correˆa / Tetrahedron: Asymmetry 14 (2003) 3787–3795
14.08, 16.61, 19.70, 22.66, 24.38, 27.00, 29.66, 31.92,
32.71, 33.47, 35.77, 37.01, 37.32, 68.37. Anal. calcd for
C14H30O: C, 78.43; H, 14.10. Found: C, 78.43, H, 14.10.
(wmax., film cm−1): 3030, 2957, 2927, 2857, 1464, 1356,
1177, 959, 819, 529. H NMR (200 MHz, CDCl3) l
1
0.85 (d, J 6.2 Hz, 3H), 0.89 (t, J 5.9 Hz, 3H), 0.99 (d,
J 6.7 Hz, 3H), 1.02–1.50 (m, 13H), 1.70–1.90 (m, 1H),
3.00 (s, 3H), 4.00 (dd, J 6.7 and 9.5 Hz, 1H). 4.10 (dd,
J 5.7 and 9.5 Hz, 1H). 13C NMR (50 MHz, CDCl3) l
14.12, 16.49, 19.66, 23.00, 24.09, 29.27, 32.64, 33.03,
33.08, 36.64, 37.09, 37.19, 74.65. Anal. calcd for
C13H28O3S: C, 59.05; H, 10.67; S.12.12 Found: C,
58.98; H, 11.03; S, 12.03.
3.24. (−)-(2S,6S)-2,6-Dimethyldecan-1-ol 16
Similarly, 15 (0.080 g, 0.29 mmol) gave 16 (0.042 g,
78.0%) as a colorless oil. [h]2D5=−7.95 (c 1.85, CHCl3).
IR (wmax., film cm−1): 3423, 2956, 2926, 2856, 1639,
1463, 1030, 696. 1H NMR (200 MHz, CDCl3) l 0.84 (d,
J 6.2 Hz, 3H), 0.88 (t, J 6.6 Hz, 3H), 0.92 (d, J 6.7 Hz,
3H), 0.94–1.70 (m, 15H), 3.41 (dd, J 6.5 and 10.5 Hz,
1H), 3.52 (dd, J 5.7 and 10.5 Hz, 1H). 13C NMR (50
MHz, CDCl3) l 14.13, 16.62, 19.71, 23.01, 24.40, 29.31,
32.71, 33.45, 35.78, 36.70, 37.34, 68.36. Anal. calcd for
C12H26O: C, 77.35; H, 14.06. Found: C, 77.30, H, 14.00.
3.28. (+)-(5S,9S)-5,9-Dimethylpentadecane 1
Magnesium turnings (0.102 g, 4.2 mmol) were added to
a solution of 1-bromopropane (0.38 mL, 4.2 mmol) in
dry ethyl ether (12 mL) at rt. After 6 h the solution
containing the Grignard reagent (7.3 mL, 2.6 mmol)
was added dropwise at −78°C to a previously prepared
solution of mesilate 14 (0.050 g, 0.17 mmol) in dry THF
(3 mL). Then, a solution of Li2CuCl4 in THF (0.1 M,
0.40 mL) was added to the mixture. The reaction
temperature was raised slowly at rt (2 h) and stirred for
14 h. The reaction was quenched with saturated solu-
tion of NH4Cl (5 mL) and the resulting mixture was
extracted with ether (3×15 mL). The organic layer was
washed with saturated NaHCO3 solution (2×10 mL)
and brine (30 mL), dried over MgSO4, filtered, and
evaporated in vacuo. The residue was chromatographed
over silica gel (hexane:ethyl acetate, 95:5) and 0.037 g
of (5S,9S)-1 was obtained (90% yield). [h]2D5=+4.2 (c
3.25. (+)-(2R,6S)-1-Methanesulfonate-2,6-dimethyldode-
cane 14
Methanesulfonyl chloride (0.07 mL, 0.94 mmol) was
added in small portions during 1 h to a solution of
alcohol 13 (0.100 g, 0.47 mmol) in dry pyridine (0.12
mL, 1.4 mmol) and CH2Cl2 (2 mL), with magnetic
stirring at 0°C. After 5 h, ethyl ether (10 mL) was
added and the solution was thoroughly washed with
aqueous HCl (10%, 1 mL), saturated solution of
NaHCO3 (5 mL), brine (5 mL), dried, concentrated and
the oil obtained was purified by column chromatogra-
phy (hexane:ethyl acetate, 9:1) to afford 0.126 g of
compound 14 (93% yield) as a colorless oil. [h]2D5=+1.8
(c 1.96, CHCl3). IR (wmax., film cm−1): 3031, 2957, 2926,
0.98, CHCl3). lit.4 [h]D25=+6.2 (c 1.30, CHCl3). IR (wmax.
,
film cm−1):2957, 2925, 2857, 1464, 1377, 717. H NMR
(200 MHz, CDCl3) l 0.65–0.95 (m, 12H), 0.96–1.50 (m,
24H). 13C NMR (50 MHz, CDCl3) l 14.08, 14.13, 19.67
(2C), 22.67, 23.02, 24.44, 27.03, 29.33, 29.67, 31.94,
32.70, 32.72, 36.82, 37.14, 37.36 (2C). MS (rel. inten-
sity) m/z 240 (M+.0.90), 225 (1.28), 211 (0.87), 183
(7.35), 155 (14.74), 141 (2.83), 127 (8.83), 113 (20.30),
99 (31.85), 85 (79.09), 71 (93.47), 57 (100).. HRMS
(m/z). Found: 240.2817: calcd for C17H36: 240.2817.
1
1
2856, 1459, 1358, 1177, 958, 824, 529. H NMR (200
MHz, CDCl3) l 0.84 (d, J 6.3 Hz, 3H), 0.88 (t, J 6.2
Hz, 3H), 0.99 (d, J 6.7 Hz, 3H), 1.05–1.50 (m, 17H),
1.70–2.00 (m, 1H), 3.01 (s, 3H), 4.00 (dd, J 6.6 and 9.4
Hz, 1H), 4.10 (dd, J 5.8 and 9.4 Hz, 1H). 13C NMR (50
MHz, CDCl3) l 14.05, 16.36, 19.55, 22.63, 24.04, 26.98,
29.61, 31.89, 32.62, 32.97, 33.00, 37.03 (2C), 37.14,
74.68. Anal. calcd for C15H32O3S: C, 61.60; H, 11.03; S,
10.96. Found: C, 61.61; H, 11.03; S, 10.93.
3.29. (−)-(5R,9S)-5,9-Dimethylpentadecane 1
3.26. (−)-(2S,6S)-1-Methanesulfonate-2,6-dimethyldode-
cane 14a
Similarly, 14a (0.040 g, 0.14 mmol) gave (5R,9S)-1
(0.029 g, 85.3%) as a colorless oil. [h]2D5=−1.2 (c 0.88,
CHCl3) lit.4 [h]D25=−1.0 (c 4.18, CHCl3). IR (wmax., film
cm−1): 2957, 2925, 2871, 2857, 1459, 1377, 722. 1H
NMR (200 MHz, CDCl3) l 0.63–0.95 (m, 12H), 0.95–
1.50 (m, 24H). 13C NMR (50 MHz, CDCl3) l 14.12,
14.17, 19.77 (2C), 22.70, 23.06, 24.48, 27.05, 29.35,
29.71, 31.97, 32.77, 32.79, 36.76, 37.08, 37.45 (2C). MS
(rel. intensity) m/z identical with those of (5S,9S)-1.
HRMS (m/z) Found: 240.2817: calcd for C17H36:
240.2817.
Similarly, 13a (0.040 g, 0.19 mmol) gave 14a (0.051 g,
93.0%) as a colorless oil. [h]2D5=−1.2 (c 0.93, CHCl3).
IR (wmax., film cm−1): 3031, 2957, 2927, 2857, 1465,
1
1356, 1177, 989, 829, 750, 529. H NMR (200 MHz,
CDCl3) l 0.85 (d, J 6.3 Hz, 3H), 0.88 (t, J 6.1 Hz, 3H),
0.99 (d, J 6.7 Hz, 3H), 1.05–1.48 (m, 17H), 1.75–2.00
(m, 1H), 3.00 (s, 3H), 4.00 (dd, J 6.6 and 9.4 Hz, 1H).
4.10 (dd, J 5.7 and 9.4 Hz, 1H). 13C NMR (50 MHz,
CDCl3) l 14.07, 16.47, 19.63, 22.64, 24.08, 26.97, 29.62,
31.90, 32.64, 33.00, 33.06, 36.95, 37.08, 37.16, 74.65.
HRMS (m/z) Found: 292.2072: calcd for C15H32O3S:
292.2072.
3.30. (+)-(5S,9R)-5,9-Dimethylpentadecane 1
Similarly, 17 (0.020 g, 0.08 mmol) gave (5S,9R)-1
(0.015 g, 82.5%) as a colorless oil. [h]2D5=+1.4 (c 1.10,
3.27. (−)-(2S,6S)-1-Methanesulfonate-2,6-dimethylde-
1
cane 17
CHCl3) lit.4 [h]D25=+1.1 (c 3.81, CHCl3). The IR, H
and 13C NMR spectra were identical with those of
(5R,9S)-1. HRMS (m/z) Found: 240.2817: calcd for
C17H36: 240.2817.
Similarly, 16 (0.035 g, 0.19 mmol) gave 17 (0.044 g,
89.0%) as a colorless oil. [h]2D5=−1.2 (c 1.8, CHCl3). IR

J. A. Moreira, A. G. Correˆa / Tetrahedron: Asymmetry 14 (2003) 3787–3795
3795
Acknowledgements
4. Kuwahara, S.; Liang, T.; Leal, W. S.; Ishikawa, J.;
Kodama, O. Biosci. Biotechnol. Biochem. 2000, 64, 2723–
2726.
The authors are grateful to FAPESP, CAPES and
CNPq (Brazil), and IFS (Sweden) for financial support.
5. Mori, K.; Takikawa, H. Liebigs Ann. Chem. 1991, 497–
500.
6. Ferreira, J. T. B.; Zarbin, P. H. G. Bioorg. Med. Chem.
1996, 4, 381–388.
7. Moreira, J. A.; Correˆa, A. G. J. Braz. Chem. Soc. 2000,
11, 614–620.
References
8. Friedrich, D.; Bohlmann, F. Tetrahedron 1988, 44, 1369–
1392.
9. Schulte-Elte, K. H.; Ohloff, G. Helv. Chim. Acta 1967,
50, 153–165.
1. Franckie, W.; Toth, M.; Szo¨cs, G.; Krieg, W.; Ernst, H.;
Buschmann, E. Z. Naturforsch. 1988, 43C, 787–789.
2. Diaz, D. D.; Martin, V. S. J. Org. Chem. 2000, 65,
7896–7901.
10. (a) Burns, D. H.; Miller, J. D.; Chan, H.; Delaney, M. O.
J. Am. Chem. Soc. 1997, 119, 2125–2133; (b) Krause, N.;
Gerold, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 187–
204.
3. (a) Mori, K. Tetrahedron 1989, 45, 3233–3298; (b) Maier,
C. T.; Gries, R.; Gries, G. J. Chem. Ecol. 1998, 24,
491–500; (c) Kimura, T.; Carlson, D. A.; Mori, K. Eur. J.
Org. Chem. 2001, 3385–3390.