Total synthesis of four stereoisomers of methyl 4,8,12-trimethylpentadecanoate, a major component of the sex pheromone of the stink bug: Edessa meditabunda

Article abstract of DOI:10.1039/d0ob00862a

The male-produced sex pheromone of the stink bug Edessa meditabunda was previously identified as a mixture of the esters methyl 4,8,12-trimethylpentadecanoate (1) and methyl 4,8,12-trimethyltetradecanoate (2), produced in a ratio of 92 : 8, respectively.

Full text of DOI:10.1039/d0ob00862a

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DOI: 10.1039/D0OB00862A
Total synthesis of four stereoisomers of methyl 4,8,12-trimethylpentadecanoate,
major component of the sex pheromone of the stink bug Edessa meditabunda
Daiane Szczerbowskia,b, Stefan Schulzb and Paulo Henrique Gorgatti Zarbina*
aLaboratório de Semioquímicos, Chemistry Department, Federal University of Paraná,
81531-990 Curitiba, Brazil
bInstitute of Organic Chemistry, Technische Universität Braunschweig, 38106
Braunschweig, Germany
*pzarbin@ufpr.br
Abstract
The male produced sex pheromone of the stink bug Edessa meditabunda was previously
identified as a mixture of the esters methyl 4,8,12-trimethylpentadecanoate (1) and
methyl 4,8,12-trimethyltetradecanoate (2), produced in a ratio of 92:8, respectively.
Bioassays showed that the synthetic major compound alone is sufficient to elicit a
response from females, and that it is as attractive as the natural extract. Here we present
a
stereoselective synthesis of four stereoisomers of methyl 4,8,12-
trimethylpentadecanoate. The synthetic route was based on the connection of three
chiral building blocks. High stereoisomeric purity was achieved by using commercially
available compounds with defined stereochemistry, (R) and (S)-citronellol and methyl
(S)-3-hydroxy-2-methylpropionate. Different stereoisomers were synthesized by
swapping the sequence by which the building blocks were inserted into the synthetic
route. The key steps in the synthesis were coupling reactions using the Fouquet-
Schlosser variant of the Grignard reaction. Although the absolute configuration of the
natural product remained elusive due to chromatographic inseparability of the
stereoisomers, the syntheses gave access to both enantiomers of the biosynthetically
most likely stereoisomer syn,syn-1, while all other stereoisomers can be efficiently
synthesized by our straightforward approach.
Introduction
In the last decades there was an increase in the interest of studying semiochemicals,
compounds transmitting information between living individuals, e.g. pheromones,1 and
to understand the role of chemical communication in insects that are pests in
agriculture.2 These substances can be applied in the field as an alternative to the use of
agrochemicals, leading potentially to an improvement of crop production, with lower
environmental impact and reduced costs compared to insecticides.3 Usually,
semiochemicals are isolated in very low amounts and consequently must be synthesized
to get access to material for various studies. In pheromone chemistry, synthesis has
three main purposes: providing synthetic standards to prove structure proposals, supply
material for bioassays in the lab and in the field, and allow studies in structure-activity-
relationships.4

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DOI: 10.1039/D0OB00862A
Brazil is the second major producer of soybean in the world. Every year, great losses
in the production are caused by a variety of insects. The stink bug Edessa meditabunda
is one of these pests that attack soybean crops. The insects feeds not only on the
soybean pods but also suck the sap of the stems, causing serious injuries to the plant.5
The male specific sex pheromone of E. meditabunda was previously identified as a
mixture of two compounds, the major one being methyl 4,8,12-trimethylpentadecanoate
(1) that is accompanied by methyl 4,8,12-trimethyltetradecanoate (2) (Figure 1).6
Synthesis of a mixture of racemic stereoisomers and bioassays proved that the major
compound alone elicits a response from females.6
It is well established that chirality plays a key role in pheromonal systems of insects,
and the correct stereochemistry can be crucial for high attractiveness.7 Therefore, we
developed an efficient stereoselective approach to the synthesis of pure stereoisomers of
1 and prepared both enantiomers with syn,syn-configuration as well as an anti,syn- and
a syn,anti-diastereomer. The structure of 1, and its co-occurrence with 2, strongly point
to the fatty acid pathway for the biosynthesis of these compounds, involving malonate-
and methylmalonate-units.8 Among the possible stereoisomers of the molecule, we
predominantly aimed at the synthesis of the two syn,syn-stereoisomers, because we
believe that one of them might be the natural product, as in the stink bug Pallantia
macunaima.9, 10
O
(1)
O
O
(2)
O
Figure 1: Sex pheromone components of males of Edessa meditabunda.
Results and discussion
Retroanalysis of the target compound (1) showed that it can be divided into three
building blocks (A, B and C), as shown in Scheme 1. A convergent and economic
synthesis was planned, with repeated use of the same building block in different
syntheses. Chiral pool starting materials were selected for a high enantiomeric excess,
which was needed to scrutinize the compounds’ biological activities. The two outer
building blocks (A and B) can be traced back to citronellol, which is available in both
enantiomeric forms in high stereochemical purity. The middle part can be derived from
building block C, a stereochemically pure, but regiochemically differentiated compound
readily obtainable from commercial Roche ester, methyl (S)-3-hydroxy-2-
methylpropionate.
To establish the strategy, we aimed to synthesize building blocks B and C only in the
S-configuration. The key steps of coupling reactions between the blocks were achieved

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using the Fouquet-Schlosser variant of the Grignard reaction.11 With the buildiDnOgI: b10l.o10c3k9/sD0OB00862A
obtained we could synthesize four possible stereoisomers of 1. However, this synthetic
approach can easily be extended to all stereoisomers by using building blocks B and C
in the R-configuration. Optimization of all steps in the synthetic route was initially
performed by using racemic compounds.
OH
*
(R) or (S)-citronellol
TBSO
*
Br
Br
Block A
Block B
O
*
*
*
(1)
O
THPO
HO
OTs
O
Block C
O
Methyl (S)-3-hydroxy-2-methylpropionate
Scheme 1: Retrosynthetic analysis of the major pheromone component 1.
The building block (S)-6 and its enantiomer (R)-6 (Block A) were obtained from (S)-
and (R)-citronellol (3) respectively, as shown in Scheme 2. Bromination of 3 by the
Appel reaction afforded the products in 92% yield for the S-enantiomer and 93% for
R.12 The following ozonolysis of the double bond furnished alcohol (S)-5 in 92% yield
after reductive treatment with sodium borohydride.13 Final protection with tert-
butyldimethylsilyl chloride (TBSCl) produced building blocks (S)-6 and (R)-6 in good
overall yield, 75% and 78% respectively.14
Building block (S)-8 (Block B) was needed only in S-configuration. The intermediate
(S)-5 served as branching point, as shown in Scheme 2. In this case, the hydroxyl group
of (S)-5 was first converted into the tosylate, forming compound (S)-7 in 88% yield.15
For the selective removal of the tosyl group, LiAlH4 reduction as reported by
Krishnamurthy was used.16 They propose that ether solvents with lower solving power
for the Li ion, e.g. diethyl ether, lead to preferred removal of the tosylate group as
compared to bromide as leaving group. This selectivity is attributed to the complexation
of a lithium ion to the tosyl group, thus enhancing its leaving ability and directing the
hydride attack to the carbon next to it. The only product isolated was (S)-8 without any
by-products. The moderate yield (76%) can be attributed to the high volatility of 8 that
led to some loss during workup.

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DOI: 10.1039/D0OB00862A
CBr4, PPh3
OH DCM, 0°C
Br
(S)-3
(S)-4
1) O3
DCM/MeOH
92%
2) NaBH4
92%
TBSCl, DMAP
Et3N, DCM
89%
TBSO
HO
Br
Br
Br
(S)-5
(S)-6
TsCl, Py
DCM
88%
LiAlH4
TsO
Br
Diethyl ether
76%
(S)-8
(R)-3
(S)-7
Similarly:
TBSO
Br
OH
(R)-6
Scheme 2: Synthesis of chiral building blocks (S)-6, (R)-6, and (S)-8.
For the construction of the last chiral building block, (S)-12 (Block C), commercially
available methyl (S)-3-hydroxy-2-methylpropionate ((S)-9) was used, a compound often
used in the stereoselective synthesis of pheromones.8, 17-19 The first step was the
protection of the hydroxyl group using dihydropyran (DHP) and p-toluenesulfonic acid
(p-TSA), to furnish compound (S)-10 in 95% yield. Reduction of the ester group with
LiAlH4 led to alcohol (R)-11 (92%),20 that was converted into the corresponding
tosylate, building block (S)-12, in 74% overall yield through the three steps (Scheme 3).
After the synthesis of all building blocks, coupling reactions following the synthetic
route shown in Scheme 4 led to the first two stereoisomers, (4R,8S,12S)-1, an anti,syn-
stereoisomer, and (4S,8S,12S)-1, a syn,syn-stereoisomer. The Grignard reagent of
bromide (S)-6 was prepared in THF and reacted with tosylate (S)-12 under Li2CuCl4
catalysis at -78°C. The orthogonally protected diol (2R,6R)-13, obtained in 70% yield,
allowed access to different stereoisomers of 1, depending on the elaboration of the two
protecting groups. Selective removal of the THP group was achieved by application of
the method of Kim et al. using anhydrous magnesium bromide in THF, furnishing the
alcohol (2R,6R)-14 in high yield (87%).21 No TBS cleavage or diol formation was
observed.

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DHP, p-TSA
DOI: 10.1039/D0OB00862A
HO
O
THPO
THPO
O
MeOH
95%
(S)-10
(S)-9
O
O
LiAlH4, THF
92%
TsCl, Py
THPO
OTs
OH
DCM
85%
(S)-12
(R)-11
Scheme 3: Synthesis of chiral building block (S)-12.
Tosylate (2R,6R)-15 was obtained in 86% yield and coupled with the Grignard
reagent of bromide (S)-8, leading to the first trimethylated compound, (4R,8S,12S)-16 in
65% yield. Deprotection of the hydroxyl group was achieved by using
tetrabutylammonium fluoride solution (TBAF), furnishing alcohol (4R,8S,12S)-17 in
90% yield. The last steps of the synthesis were oxidation to the corresponding acid,
using Jones reagent, followed by esterification applying BF3.Et2O in methanol, which
finally lead to the first stereoisomer of compound 1, anti,syn-configured methyl
(4R,8S,12S)-trimethylpentadecanoate. The overall yield for the synthesis of this
stereoisomer was 21.5% over 10 steps in its longest sequence. Through the same
synthetic strategy, but starting with bromide (R)-6, the syn,syn-stereoisomer
(4S,8S,12S)-1 was obtained in 23.6% overall yield. Both isomers showed the same
retention index and similar mass spectra and IR spectra as the natural compound.
1) Mg°, I2
TBSO
TBSO
OTHP
TBSO
OH
MgBr2
THF, R.T.
87%
THF
Br
2) (S)-12, Li2CuCl4
THF, -78°C-R.T.
70%
(2R,6R)-14
(S)-6
(2R,6R)-13
TsCl, Py
CHCl3, 0°C 86%
1) Li2CuCl4
THF, -78°C
TBSO
TBSO
OTs
2) Mg°, I2, THF
(2R,6R)-15
(4R,8S,12S)-16
TBAF
Br
(S)-8
THF, R.T.
65%
90%
1) Jones reagent
Acetone, R.T., 96%
HO
O
O
2) BF3.Et2O
MeOH, R.T.
97%
(4R,8S,12S)-17
R
S,
(4 ,8 12 )-1
S
Overall yield 21.5%
Similarly:
TBSO
O
Br
(R)-6
(4S,8S,12S)-1
Overall yield 23.6%
O
Scheme 4: Synthetic route for stereoisomers (4R,8S,12S)-1 and (4S,8S,12S)-1.
For the synthesis of the other two stereoisomers, key compound 13 should be
deprotected by removal of the TBS group (Scheme 5). Now the alcohol could be

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reduced via its tosylate, delivering the terminal end of 1 and placing the two stDeOreI:o10g.1e0n39i/cD0OB00862A
centers at this reduced end. In this manner, we would obtain the methyl groups at C-8
and C-12 in the opposite configuration of the previous synthesis, without the necessity
to obtain building blocks 8 and 12 in R-configuration.
Starting from (2R,6R)-13, the TBS group was selectively removed by using TBAF,
furnishing alcohol (2R,6R)-18 in 90% yield. Tosylation (90%) and reduction with
LiAlH4 in THF were simple, furnishing acetal (2R,6S)-20 in 95% yield. Subsequently,
acidic methanolysis followed by tosylation of the obtained alcohol (2R,6S)-21 furnished
tosylate (2R,6S)-22 in 83% yield. Coupling with the Grignard reagent generated from
bromide (S)-6 under the described conditions, yielded (4R,8R,12S)-16 in 63% yield.
Subsequently, the synthesis followed the route as already described for the other two
stereoisomers. First, the hydroxyl group was deprotected using TBAF solution,
.
followed by Jones oxidation and finishing with esterification with BF3 Et2O in
methanol. Thus, the third stereoisomer was obtained, syn,anti-ester (4R,8R,12S)-1 in
17.6% overall yield in 13 steps over the longest sequence. Similarly, following the same
route but starting with intermediate (2S,6R)-13, the last stereoisomer, syn,syn-ester
(4R,8R,12R)-1 was synthesized in 19.9% overall yield. Both stereoisomers showed a
similar retention index and similar mass spectra and IR spectra as the natural
compound.
TBAF
TBSO
OTHP
HO
OTHP TsCl, Py
TsO
OTHP
THF, R.T.
90%
CHCl3, 0°C
90%
R R
(4 ,8 )-19
(2R,6R)-13
(2R,6R)-18
LiAlH4
THF, 0°C 95%
TsCl, Py
p-TSA
OTs
OH
OTHP
MeOH, R.T.
95%
CHCl3, 0°C
83%
(2R,6S)-22
(2R,6S)-21
(2R,6S)-20
1) Mg°, I2
THF
TBSO
TBSO
Br
TBAF
2) (2R,6S)-22, Li2CuCl4
THF, -78°C - R.T.
63%
(S)-6
(4R,8R,12S)-16
THF, R.T.
96%
1) Jones reagent
Acetone, R.T., 97%
O
HO
2) BF3.Et2O
MeOH, R.T.
95%
(4R,8R,12S)-1
(4R,8R,12S)-17
O
Overall yield 17.6%
Similarly:
TBSO
OTHP
O
(2S,6R)-13
(4R,8R,12R)-1
O
Overall yield 19.9%
Scheme 5: Synthesis of stereoisomers (4R,8R,12S)-1 and (4R,8R,12R)-1 using
intermediates (2R,6R)-13 and (2S,6R)-13.
All stereoisomers showed similar mass and infrared spectra as the natural compound.
The products were obtained in very high ee, because the stereogenic centers introduced

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by the chiral pool approach remained untouched during the syntheses. This is DimOI:p1o0.r10ta39n/tD0OB00862A
because it turned out that there is currently no method to directly determine the ee of the
compounds (see below).
We then tried to use the synthetic products for elucidation of the stereochemistry of
natural 1 by chromatography. It is not trivial to separate stereoisomers of methyl-
branched long-chain aliphatic compounds,8 especially if the first methyl group is in -
position to the functional group. Various attempts were performed, using either
enantioselective GC with different columns or employing chiral derivatization reagents,
such as (S)-2-acetoxypropionyl chloride or (R)-trans-chrysanthenoyl chloride,22-24 in
both GC and HPLC. For these derivatizations alcohols 17 were used instead of 1,
because an alcohol group in the analyte is needed for their use. Natural 1 can readily be
transformed into 17 by reduction. All these methods proved unsuccessful. This was also
true for the HPLC method developed by Ohrui et. al that had been successfully applied
to various structures similar to compound 1.25-27 Further analytical studies are, therefore,
necessary to achieve a good chromatographic separation of the stereoisomers that will
allow to determine the absolute configuration of the male pheromone of Edessa
meditabunda.
The understanding of the biosynthetic pathway leading to 1 might give some
indications on the stereochemistry of the natural pheromone. The structure of 1 and its
co-occurrence with 2 straightforwardly hint towards the fatty acid biosynthetic pathway.
Biological synthesis of fatty acids is based on variations of a conserved set of chemical
reactions in all organisms, regardless of the natural diversification in its structural
organization.28, 29 We hypothesize that the biosynthesis of compound 1 is initiated with
a methylmalonyl-CoA starting unit, which leads to the main chain with 15 carbon atoms
(Scheme 6 A). Malonyl-CoA units are inserted to elongate the chain, adding two
carbons. The methyl groups are introduced by insertion of a methylmalonyl-CoA unit
into the growing chain (Scheme 6 A). The stereochemistry of the methyl branch is
likely controlled by a stereoselective NADPH-catalyzed reduction of the resulting α,β-
unsaturated thioester by the enoyl-ACP reductase domain of the fatty acid synthase
(FAS) (Scheme 6 B).30 All these processes of the biosynthesis involve the action of a
cascade of enzymes that are repeatedly used during one elongation cycle (Scheme 6 B).
In the case of our target compound (1), the same enoyl-ACP reductase domain will
reduce all three different 2-methylalkenoyl motifs encountered during the biosynthesis
of 1. Therefore, it is most likely that all three stereogenic centers generated by the
enzyme have the same configuration. With this rationalization, we believe that the
natural stereoisomer produced by the organism might be a syn,syn-stereoisomer, either
(4R,8R,12R)-1 or (4S,8S,12S)-1. This hypothesis is strongly supported by other species
of stink bugs that had methyl branched compounds identified as sex pheromone. After
determination of absolute configuration, all the molecules showed to be syn, syn
isomers.9, 10 Compound 2 might be formed as described, using malonate-CoA instead of
methylmalonate-CoA as starting unit.

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DOI: 10.1039/D0OB00862A
O
A
O
Starting unit
Malonyl-CoA
unit inserted
Methyl malonyl-CoA
unit inserted
Methyl malonyl-CoA
B
COOH
O
O
O
O
H
O
HO
R
3-Ketoacyl-ACP synthase
-SACP, -CO2
3-Ketoacyl-ACP reductase
SACP
+
R
SACP
SACP
R
SCoA
NADPH
Growing chain
Methyl malonyl-CoA
O
O
Enoyl-ACP reductase
NADPH + H+
3-Hydroxyacyl-ACP dehydrase
R
SACP
R
SACP
-H2O
NADPH,
Scheme 6: A) Proposed biosynthetic building blocks in the biosynthesis of compound 1.
B) Enzymes involved in the incorporation of a new methylmalonyl-CoA unit in the
growing chain leading to the methyl branches.
Conclusions
In summary, we developed the total synthesis of the two syn-syn-enantiomers of
methyl 4,8,12-trimethylpentadecanoate (1), the most likely stereoisomeric arrangement
in natural 1. In addition, pure stereoisomers with anti,syn- and syn,anti-configuration
were produced. A convergent synthetic route was developed, employing compounds
from the chiral pool, (R) and (S)-citronellol (3) and methyl (S)-3-hydroxy-2-
methylpropionate (9), thus ensuring a high ee of the target compounds. The three chiral
building blocks obtained (6, 8 and 12) were coupled through a Fouquet-Schlosser
Grignard approach. The longest sequence of the route had 13 steps, and it was possible
to obtain the target compounds in good overall yields ranging from 17.6% to 23.6%.
Our approach can be modified to the synthesis of other stereoisomers and may also be
used in the synthesis of structurally related compounds. More studies are necessary to
achieve chromatographic separation of the stereoisomers of alcohol 17 or of 1, to
elucidate the absolute configuration of the natural pheromone. The four synthetic
compounds will now be used in olfactometer tests, aiming to establish the
stereochemistry-biological activity relationship for this pheromone.
Experimental
General information
When necessary, reagents and solvents used in the reactions were purified following
methods described in the literature.31 Anhydrous reactions were performed in flame
dried glassware under an argon atmosphere. GC-MS analyses were performed in a
Shimadzu QP2010 Plus mass spectrometer (EI 70 eV), coupled with a Shimadzu GC-
2010 gas chromatograph. The samples were analysed using a capillary column RTX-5
(30m x 0,25mm i.d. x 0,25μm film thickness; Restek Chromatography Products, EUA),

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with a helium flow of 1 mL/min. The oven was initially held at 50°C, kept for one
minute, followed by an increase of 7°C/min until finally 250°C were achieved,
followed by 5 min isothermal period. GC/FTIR analysis were performed on a
Shimadzu GC-2010 gas chromatograph coupled to a DiscovIR-GC (Spectra Analysis)
detection system. The oven program started with 100°C for 1 minute, increasing with a
rate of 10°C/min until 270°C were obtained, followed by a 10 min hold period. The
samples were analysed using a capillary column RTX-5 (30m x 0,25mm i.d. x 0,25μm
film thickness; Restek Chromatography Products, EUA), with a helium flow of 1
mL/min. NMR analyses were performed on Bruker ARX-200 and Bruker DPX-300
spectrometers. The chemical shifts (δ) are expressed in ppm and the coupling constants
(J) are expressed in Hertz (Hz). All spectra were recorded in CDCl3 with
tetramethylsilane (TMS) as internal standard. HRMS Spectra were measured with a
Bruker Daltonics micrOTOF II-ESI-TOF mass spectrometer.
Experimental procedure
Preparation of Li2CuCl4 solution (0.1 M):32 Lithium chloride (0.34 g, 8 mmol) was
added to a flask, previously dried for 12 h at 200°C and equipped with a magnetic
stirring bar. The system was submitted to vacuum and heated at 120°C for 3 h. After
this period, the flask was cooled to room temperature and the pressure was equalized by
the introduction of argon. Anhydrous CuCl2 (0.536 g, 4 mmol) was added to the flask
and the mixture was submitted to vacuum for additional 2 h at room temperature. Argon
was introduced to the flask, anhydrous THF (40 mL) was added and the mixture was
stirred for 1 h. The solution was stored under an argon atmosphere at room temperature.
Preparation of Jones reagent: Chromium trioxide (10 g, 0.1 mol) was dissolved in
water (14 mL) and cooled in an ice bath. A solution of H2SO4 (8.7 mL, 0.16 mol, 18 M
solution) and water (28 mL) are carefully added with manual stirring.
8-Bromo-2,6-dimethyloct-2-ene [(S) and (R)-4]: A solution of triphenylphosphine
(5.03 g, 19.2 mmol) in DCM (13 mL) was added to a solution of (S)-citronellol [(S)-3]
(2.32 mL, 12.8 mmol) and tetrabromomethane (5.1 g, 15.36 mmol) in DCM (38 mL),
previously cooled in an ice bath. The ice bath was removed and the reaction mixture
was stirred at room temperature for one hour. The reaction mixture was monitored by
TLC. The solvent was removed by rotary evaporation under reduced pressure. The
crude product was purified by column chromatography using hexane as eluent.
Compound (S)-4 was obtained in 92% yield. [α]D25 = +5.55 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ 0.90 (d, J = 6.5 Hz, 3H), 1.10-1.25 (m, 1H), 1.27-1.42 (m, 1H),
1.57-1.76 (m, 8H), 1.81-2.11 (m, 3H), 3.34-3.51 (m, 2H), 5.05-5.13 (m, 1H); 13C NMR
(75 MHz, CDCl3): δ 131.4, 124.4, 40.0, 36.5, 32.0, 31.3, 25.7, 25.3, 18.8, 17.6; MS (70
eV) m/z (%): 220 (17), 218 (17), 164 (10), 162 (10), 150 (6), 148 (6), 97 (15), 95 (9), 70
(15), 69 (100), 56 (17), 55 (47); IR (υmax, cm-1): 566, 647, 973, 1263, 1379, 1456, 1723,
2872, 2925, 2963, 3368.
In the same manner, (R)-4 was prepared starting from (R)-citronellol [(R)-3] (5.5 mL,
30.3 mmol), tetrabromomethane (10.62 g, 32 mmol) and triphenylphosphine (8.43 g, 32
mmol) in 93% yield. [α]D25 = -5.79 (c = 1.1, CHCl3).
6-Bromo-4-methylhexan-1-ol [(S) and (R)-5]: A solution of (S)-4 (2.52 g, 11.56
mmol) in a mixture of DCM (129 mL) and methanol (86 mL) was prepared in a two-
necked flask and was cooled to -60°C. Ozone was bubbled in the solution at a flow rate

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of 4 mL/min for approximately 40 min or until the appearance of the characteristic blue
color of ozone. Excess ozone was removed by an air stream passed through thDeOrI:e1a0c.1t0i3o9n/D0OB00862A
flask for 30 min at 0°C with magnetic stirring. NaBH4 (4.0 g, 105.74 mmol) was added
in small portions during 1 h. After reaching room temperature, the solution was stirred
for an additional 1 h. Aqueous sat. NH4Cl solution (50 mL) was carefully added and the
stirring was maintained for another 30 min. The solvent was removed under reduced
pressure. Water was added (50 mL) and the reaction mixture was extracted with DCM
(4 x 60 mL). The organic phase was washed with brine, dried over MgSO4, and the
solvent was removed. The crude product was used in the next step without further
purification. (S)-5 was obtained in 92% yield. [α]D25 = +7.42 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ 0.93 (d, J = 6.3 Hz, 3H), 1.11-1.29 (m, 1H), 1.32-1.77 (m, 5H),
13
1.79-1.98 (m, 2H), 3.36-3.53 (m, 2H), 3.63 (t, J = 6.6 Hz, 2H); C NMR (75 MHz,
CDCl3): δ 63.0, 39.8, 32.3, 32.0, 31.4, 29.9, 18.8; MS (70 eV) m/z (%): 178 (0.2), 176
(0.2), 150 (64), 148 (64), 97 (45), 81 (16), 70 (16), 69 (100), 55 (60), 41 (42); IR (υmax
,
cm-1): 897, 1058, 1266, 1381, 1464, 2868, 2935, 2957, 3277.
In the same manner, (R)-5 was prepared starting from (R)-4 (2.70 g, 24.77 mmol), yield
96%. [α]D25 = -7.59 (c = 1.0, CHCl3).
6-Bromo-4-methylhexyl-1-oxy-tert-butyldimethylsilane [(S) and (R)-6]: A solution
of (S)-5 (0.84 g, 4.3 mmol), triethylamine (1.10 mL, 5.8 mmol) and catalytic amount of
DMAP in anhydrous DCM (26 mL) was cooled to 0°C. tert-butyldimethylsilyl chloride
(0.77 g, 5.16 mmol) was added to the mixture in 3 portions with intervals of 10 min.
After 18 h the reaction mixture was washed with water and brine. The organic phase
was dried over MgSO4 and the solvent was removed under reduced pressure. The
product was purified by flash chromatography using hexane/ethyl acetate 9.5:0.5 as
25
1
mobile phase. (S)-6 was obtained in 89% yield. [α]D = +2.88 (c = 1.0, CHCl3). H
NMR (300 MHz, CDCl3): δ 0.07 (s, 6H), 0.87-0.95 (m, 12H), 1.11-1.27 (m, 1H), 1.31-
1.45 (m, 1H), 1.47-1.61 (m, 2H), 1.65-1.78 (m, 2H), 1.81-1.98 (m, 1H), 3.36-3.51 (m,
2H), 3.61 (t, J = 6.5 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 63.3, 40.0, 32.5, 32.0, 31.4,
30.0, 26.0, 18.9, 18.3, -5.3; MS (70 eV) m/z (%): 251 (0.2), 169 (3), 97 (36), 75 (18), 73
(11), 69 (24), 55 (100); IR (υmax, cm-1): 774, 833, 1096, 1253, 1467, 2857, 2889, 2930,
2954.
In the same manner, (R)-6 was prepared starting from (R)-5 (1.0 g, 5.1 mmol),
triethylamine (1.32 mL, 6.96 mmol) and tert-butyldimethylsilyl chloride (0.91 g, 6.09
mmol), yield of 88%. [α]D25 = -3.01 (c = 1.0, CHCl3).
(S)-6-Bromo-4-methylhexyl tosylate [(S)-7]: A solution of (S)-5 (1.86 g, 9.59 mmol)
in chloroform (7.5 mL) was cooled in an ice bath. Pyridine (1.5 mL, 19.2 mmol) was
added, followed by the addition of p-toluenesulfonyl chloride (2.74 g, 14.6 mmol) in
small portions with magnetic stirring. After 1 h, the mixture was diluted with ethyl
acetate (40 mL) and water (10 mL) was added. The organic phase was successively
washed with aqueous sat. CuSO4 solution and then washed with water, dried over
anhydrous MgSO4 and the solvent was removed under reduced pressure. The product
was purified by flash chromatography using hexane/ethyl acetate 9:1 as mobile phase.
The yield was 88%. 1H NMR (200 MHz, CDCl3): δ 0.85 (d, J = 6.4 Hz, 3H), 1.03-1.44
(m, 2H), 1.51-1.91 (m, 5H), 2.45 (s, 3H), 3.25-3.44 (m, 2H), 4.02 (t, J = 6.5 Hz, 2H),
7.22-7.42 (m, 2H), 7.69-7.84 (m, 3H); 13C NMR (50 MHz, CDCl3): δ 144.7, 133.0,
129.8, 127.8, 70.7, 39.5, 31.9, 31.7, 30.9, 26.2, 21.6, 18.5; MS (70 eV) m/z (%): 240 (2),
173 (38), 172 (17), 155 (30), 150 (15), 148 (15), 97 (38), 91 (100), 69 (71), 68 (26), 55

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(90); IR (υmax, cm-1): 736, 818, 920, 967, 1101, 1178, 1191, 1356, 1456, 16D0O1I:,102.1805395/D, 0OB00862A
2876, 2929, 2962.
(S)-1-Bromo-3-methylhexane [(S)-8]: A solution of (S)-7 (1.5 g, 4.45 mmol) in
anhydrous diethyl ether (18 mL) was added dropwise to a suspension of lithium
aluminum hydride (0.253 g, 6.68 mmol) in anhydrous diethyl ether (27 mL), previously
cooled to 0°C. After 30 min with stirring the reaction mixture was diluted with diethyl
ether (20 mL), water was carefully added (0.25 mL), followed by sodium hydroxide
solution (0.25 mL, 15% aqueous solution) and again water (0.75 mL). The mixture was
allowed to warm to room temperature and stirred for 15 min. MgSO4 was added and the
mixture was filtered. The solvent was removed under reduced pressure at room
temperature. The product was purified through flash chromatography using
1
hexane/ethyl acetate 9:1 as mobile phase The yield was 76%. H NMR (300 MHz,
CDCl3): δ 0.84-0.95 (m, 6H), 1.07-1.39 (m, 4H), 1.58-1.72 (m, 2H), 1.78-1.95 (m, 1H),
3.33-3.53 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 40.0, 38.7, 32.2, 31.4, 19.9, 18.9,
14.3; MS (70 eV) m/z (%): 180 (2), 178 (2), 151 (28), 149 (28), 71 (100), 70 (34), 69
(35), 57 (51), 56 (25), 55 (76), 43 (92), 41 (58); IR (υmax, cm-1): 648, 1379, 1461, 1782,
2871, 2927, 2958; [α]D25 = +1.42 (c = 1.0, CHCl3).
Methyl
(S)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)-propanoate
[(S)-10]:
Dihydropyran (0.59 mL, 6.44 mmol) and a catalytic amount of p-toluenesulfonic acid
were added to a solution of methyl (S)-3-hydroxy-2-methylpropanoate [(S)-9] (1.15 g,
5.48 mmol) in DCM (5.4 mL). The reaction mixture was stirred at room temperature for
4 h. The solution was washed with brine, the organic phase was dried over anhydrous
MgSO4, and the solvent removed under reduced pressure. The crude product was used
1
in the next step without further purification. The yield was 95%. H NMR (200 MHz,
CDCl3): δ 1.20 (dd, J = 7.0 Hz, 1.5 Hz, 3H), 1.46-1.90 (m, 6H), 2.79 (m, 1H), 3.40-3.69
(m, 2H), 3.71 (s, 3H), 3.73-3.99 (m, 2H), 4.56-4.69 (m, 1H); 13C NMR (50 MHz,
CDCl3): δ 175.3, 99.0 and 98.4, 69.3 and 68.9, 62.1 and 61.8, 51.6, 40.2 and 40.0, 30.6
and 30.5, 25.4, 19.3 and 19.2, 14.0; MS (70 eV) m/z (%):201 (1), 115 (13), 101 (59), 85
(100), 69 (18), 59 (28), 57 (17), 56 (17), 41 (27); IR (υmax, cm-1): 906, 974, 1035, 1126,
1205, 1365, 1460, 1741, 2881, 2947, [α]D25 = +7.21 (c = 1.0, CHCl3).
(R)-2-Methyl-3-(tetrahydro-2H-pyran-2-yloxy)-propan-1-ol [(R)-11]: A solution of
(S)-10 (4.0 g, 19.76 mmol) in anhydrous THF (80 mL) was slowly added to a
suspension of lithium aluminum hydride (1.48g, 39.47 mmol) in anhydrous THF (140
mL) at 0°C. The mixture was allowed to reach room temperature and stirred for 5 h.
The reaction mixture was cooled to 0° C again, diluted with THF (70 mL), and water
was carefully added (1.48 mL), followed by addition of NaOH solution (1.48 mL, 15%
aqueous solution) and water again (4.44 mL). The mixture was allowed to warm to
room temperature and stirred for 30 min. MgSO4 was added and the mixture was
filtered. The solvent was removed under reduced pressure. The crude product was used
in the next step without further purification and the yield was 92%. 1H NMR (200 MHz,
CDCl3): δ 0.93 (d, J = 6.9 Hz, 3H), 1.40-1.92 (m, 7H), 3.16 (s, 1H), 3.30-3.96 (m, 6H),
13
4.50-4.66 (m, 1H); C NMR (50 MHz, CDCl3): δ 99.0 and 98.8, 71.2 and 71.1, 66.2
and 66.1, 62.1, 35.6 and 35.4, 30.3, 25.1, 19.3, 13.5 and 13.3; MS (70 eV) m/z (%): 173
(2), 144 (2), 101 (37), 85 (100), 84 (29), 67 (11), 57 (25), 56 (30), 55 (46), 41 (27); IR
(υmax, cm-1): 1037, 1129, 1356, 1454, 2874, 2947, 3311; [α]D25 = +6.17 (c = 1.0, CHCl3).

Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB00862A
(S)-2-Methyl-3-(tetrahydro-2H-pyran-2-yloxy)-propyl tosylate [(S)-12]: Compound
(S)-12 was prepared in the same manner as (S)-7, starting from (R)-11 (0.70 g, 4.02
mmol), pyridine (3 mL) and p-toluenesulfonyl chloride (0.84 g, 4.4 mmol). The product
was purified through flash chromatography using hexane/ethyl acetate 8:2 as mobile
1
phase. Compound (S)-12 was obtained in 85% yield. H NMR (300 MHz, CDCl3): δ
0.94 (dd, J = 6.9 Hz, 1.8 Hz, 3H), 1.39-1.82 (m, 6H), 2.02-2.17 (m, 1H), 2.45 (s, 3H),
3.16-3.30 (m, 1H), 3.41-3.52 (m, 1H), 3.54-3.65 (m, 1H), 3.67-3.81 (m, 1H), 3.90-4.17
(m, 2H), 4.41-4.50 (m, 1H), 7.31-7.37 (m, 2H), 7.76-7.83 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 144.6, 133.1, 129.8, 127.9, 99.1 and 98.6, 72.20 and 72.18, 68.4 and 67.9,
62.2 and 61.9, 33.6 and 33.5, 30.4, 25.4, 21.6, 19.4 and 19.3, 13.7 and 13.6; MS (70 eV)
m/z (%): 227 (2), 173 (45), 172 (17), 155 (28), 101 (51), 91 (94), 85 (100), 84 (46), 72
(25), 65 (42), 57 (32), 55 (85), 54 (14); IR (υmax, cm-1): 664, 811, 966, 1174, 1357,
1598, 2874, 2942; [α]D25 = +5.92 (c = 1.0, CHCl3).
2,6-Dimethyl-9-(tert-butyldimethylsiloxy)-nonyloxy-tetrahydro-2H-pyran [(2S,6R)
and (2R,6R)-13]: A Grignard reagent was prepared by slow addition of bromide (S)-6
(1.0 g, 3.24 mmol) to magnesium turnings (0.087 g, 3.56 mmol previously dried and
activated with iodine) in anhydrous THF (4.9 mL) under an argon atmosphere. The
reaction mixture was stirred for 30 min after finishing the addition of the bromide. A
solution of tosylate (S)-12 (0.165 g, 0.5 mmol) in anhydrous THF (0.9 mL) was cooled
to -78°C. After 30 min, a solution of Li2CuCl4 (3%, 0.15 mL, 0.1 M in THF) was added,
the resulting mixture was stirred for 15 min and kept at -78°C. The previously prepared
Grignard reagent of bromide (S)-6 was added dropwise through a syringe to the
solution, during 30 min. After the addition, the reaction mixture was kept at -78°C for 1
h. After this period the solution was allowed to reach room temperature and was stirred
for 12 h. The reaction mixture was quenched by careful addition of aqueous sat. NH4Cl
solution and was extracted with ethyl acetate (3 x 5 mL). The organic phase was washed
with brine, dried over MgSO4, and the solvent was removed under reduced pressure.
The product was purified through flash chromatography using hexane/ethyl acetate
25
9.5:0.5 as mobile phase. Compound (2R,6R)-13 was obtained in 70% yield. [α]D
=
+1.34 (c = 1.0, CHCl3); MS (70 eV) m/z (%): 329 (0.4) 227 (9), 159 (100), 157 (4), 101
(25), 97 (69), 85 (97), 83 (50), 75 (83), 69 (66), 55 (64), 41 (47); IR (υmax, cm-1): 834,
1
1032, 1054, 1253, 1433, 2856, 2929; (2R,6R)-13: H NMR (200 MHz, CDCl3): δ 0.05
(s, 6H), 0.80-1.03 (m, 15H), 1.04-1.19 (m, 3H), 1.23-1.63 (m, 12H), 1.66-1.83 (m, 3H),
3.05-3.32 (m, 1H), 3.40-3.75 (m, 4H), 3.78-4.00 (m, 1H), 4.52-4.65 (m, 1H); 13C NMR
(50 MHz, CDCl3): δ 99.0 and 98.6, 73.2 and 73.1, 63.6, 62.1 and 62.0, 37.2, 34.0, 33.4
and 33.3, 33.0, 32.6, 30.7, 30.4, 26.0 (3 x CH3), 25.6, 24.3, 19.6, 18.3, 17.2 and 17.1, -
5.28.
In the same manner, compound (2S,6R)-13 was prepared starting from (R)-6 (1.0 g, 3.26
mmol) and magnesium (0.12 g, 4.85 mmol). The suspension of the Grignard reagent
formed was added to a solution of tosylate (S)-12 (0.20 g, 0.61 mmol) and Li2CuCl4
(3%, 0.18 mL, 0.1 M in THF). The yield was 71%. [α]D25 = +7.36 (c = 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3): δ 0.05 (s, 6H), 0.79-0.97 (m, 15H), 0.99-1.17 (m, 3H), 1.19-
1.64 (m, 12H), 1.65-1.93 (m, 3H), 3.08-3.28 (m, 1H), 3.44-3.66 (m, 4H), 3.81-3.92 (m,
13
1H), 4.54-4.60 (m, 1H); C NMR (75 MHz, CDCl3): δ 99.1 and 98.8, 73.2 and 73.0,
63.7, 62.2 and 62.1, 37.29 and 37,27; 34.1 and 34.0, 33.5 and 33.4, 32.90 and 32.89,
32,57 and 32,55, 30.7, 30.4, 25.9 (3 x CH3), 25.6, 24.4 and 24.3, 19.7, 19.6 and 19.5,
18.4, 17.3 and 17.2, -5.3.

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9-(tert-Butyldimethylsilyloxy)-2,6-dimethylnonan-1-ol [(2R,6S) and (2R,6R)-14]:
Anhydrous MgBr2 (0.131 g, 0.71 mmol) was added to a solution of (2R,6R)-D1O3I: (100.1.003995/D0OB00862A
g, 0.23 mmol) in anhydrous diethyl ether (2.7 mL) at room temperature. After stirring
for 4 h water was added and the reaction mixture was extracted with ethyl acetate (3 x 4
mL). The organic phase was washed with brine, dried over MgSO4 and the solvent was
removed under reduced pressure. The crude product was used in the next step without
further purification. Compound (2R,6R)-14 was obtained in 87% yield. [α]D25 = +5.27 (c
= 1.0, CHCl3); MS (70 eV) m/z (%): 243 (1), 227 (1), 97 (88), 95 (22), 83 (64), 75 (69),
69 (100), 57 (27), 55 (76), 41 (21); IR (υmax, cm-1): 1042, 1063, 1384, 1468, 2858, 2871,
1
2931, 3288; (2R,6R)-14: H NMR (200 MHz, CDCl3): δ 0.05 (s, 6H), 0.80-1.00 (m,
15H), 1.04-1.18 (m, 2H), 1.21-1.43 (m, 6H), 1.45-1.74 (m, 4H), 3.33-3.51 (m, 2H), 3.59
13
(t, J = 6.6 Hz, 2H); C NMR (50 MHz, CDCl3): δ 68.3, 63.6, 37.2, 35.7, 33.4, 33.0,
32.5, 30.4, 26.0, 24.3, 19.6, 18.3, 16.5, -5.28.
In the same manner, compound (2R,6S)-14 was prepared starting from (2R,6S)-13 (
0.127 g, 0.31 mmol) and MgBr2 ( 0.175 g, 0.95 mmol), in 90% yield. [α]D25 = +6.46 (c =
1
1.0, CHCl3). H NMR (200 MHz, CDCl3): δ 0.03-0.16 (m, 6H), 0.80-1.01 (m, 15H),
1.04-1.22 (m, 4H), 1.23-1.47 (m, 6H), 1.49-1.70 (m, 2H), 3.33-3.54 (m, 2H), 3.59 (t, J =
6.6 Hz, 2H); 13C NMR (50 MHz, CDCl3): δ 68.3, 63.6, 37.2, 35.7, 33.5, 32.9, 32.5,
30.3, 25.9, 24.3, 19.7, 18.3, 16.6, -5.31.
9-(tert-Butyldimethylsilyloxy)-2,6-dimethylnonyl tosylate [(2R,6S)- and (2R,6R)-
15]: Compounds 15 were prepared in the same manner as described for compound (S)-
7, starting from (2R,6R)-14 (0.050 g, 0.17 mmol), pyridine (0.03 mL), and p-
toluenesulfonyl chloride (0.040 g, 0.21 mmol). The product was purified through flash
chromatography using hexane/ethyl acetate 9.5:0.5 as mobile phase. Compound
(2R,6R)-15 was obtained in 86% yield. [α]D25 = -1.54 (c = 1.0, CHCl3); MS (70 eV) m/z
(%): 287 (1), 271 (2), 230 (16), 229 (100), 227 (10), 111 (15), 97 (64), 91 (18), 83 (39),
1
75 (59), 69 (49), 55 (31); (2R,6R)-15: H NMR (200 MHz, CDCl3): δ 0.05-0,019 (m,
6H), 0.83-1.08 (m, 15H), 1.11-1.40 (m, 9H), 1.44-1.63 (m, 3H), 2.50 (s, 3H), 3.56-3.76
(m, 2H), 3.81-4.08 (m, 2H), 7.34-7.54 (m, 2H), 7.79-8.03 (m, 2H); 13C NMR (50 MHz,
CDCl3): δ 144.6, 133.2, 129.8, 127.9, 75.2, 63.6, 37.0, 32.9, 32.8, 32.5, 30.3, 26.0, 24.0,
21.6, 19.6, 18.3, 16.4, -5.3.
In the same manner, compound (2R,6S)-15 was prepared starting from (2R,6S)-14
(0.057 g, 0.19 mmol), pyridine (0.05 mL) and p-toluenesulfonyl chloride (0.048 g, 0.25
1
mmol), in 88% yield. H NMR (200 MHz, CDCl3): δ 0.03-0.18 (m, 6H), 0.76-0.98 (m,
15H), 0.99-1.17 (m, 4H), 1.21-1.40 (m, 6H), 1.42-1.62 (m, 2H), 2.44 (s, 3H), 3.52-3.70
(m, 2H), 3.74-3.97 (m, 2H), 7.29-7.46 (m, 2H), 7.73-7.89 (m, 2H); 13C NMR (50 MHz,
CDCl3): δ 144.6, 133.2, 129.8, 127.9, 75.1, 63.6, 36.9, 32.9, 32.9, 32.8, 32.4, 30.3, 25.9,
23,9, 21.6, 19.6, 18.3, 16.4, -5.27.
4,8,12-Trimethylpentadecyloxy-tert-butyldimethylsilane [(4R,8S,12S), (4S,8S,12S),
(4R,8R,12S) and (4R,8R,12R)-16]: Compounds 16 were prepared in the same manner
as described for the stereoisomers of compound 13. Bromide (S)-8 (0.40 g, 2.22 mmol)
and magnesium turnings (0.09 g, 3.30 mmol) were used. The suspension of the
Grignard reagent formed was added to a solution of tosylate (2R,6R)-15 (0.067 g, 0.22
mmol) and Li2CuCl4 (3%, 0.09 mL, 0.1 M in THF). The product was purified through
flash chromatography using hexane as mobile phase. Compound (4R,8S,12S)-16 was
obtained in 65% yield. [α]D25 = +0.95 (c = 1.0, CHCl3); MS (70 eV) m/z (%): 384 (1),
369 (2), 329 (7), 328 (29), 327 (100), 139 (18), 125 (47), 111 (87), 97 (99), 83 (60), 75
(88), 71 (54), 69 (52), 57 (55), 43 (45); IR (υmax, cm-1): 777, 837, 940, 1099, 1252,

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DOI: 10.1039/D0OB00862A
1379, 1467, 2858, 2896, 2928, 2957; (4R,8S,12S)-16: H NMR (200 MHz, CDCl3): δ
0.05 (s, 6H), 0.79-0.94 (m, 21H), 1.03-1.14 (m, 4H), 1.18-1.38 (m, 15H), 1.43-1.60 (m,
4H), 3.59 (t, J = 6.6 Hz, 2H); 13C NMR (50 MHz, CDCl3): δ 63.7, 39.4, 37.5, 37.5, 37.4,
34.7, 34.5, 33.1, 32.8, 32.6, 32.5, 31.6, 30.4, 26.0, 25.3, 24.5, 22.7, 20.7, 20.2, 19.7,
18.4, 14.4, -5.3.
In the same manner, compound (4S,8S,12S)-16 was prepared starting from bromide (S)-
8 (0.30 g, 1.68 mmol) and magnesium turnings (0.061 g, 2.5 mmol). The suspension of
the Grignard reagent formed was added to a solution of tosylate (2R,6S)-15 (0.052 g,
0.17 mmol) and Li2CuCl4 (3%, 0.08 mL, 0.1 M in THF). Compound (4S,8S,12S)-16
was obtained in 63% yield. [α]D25 = +2.19 (c = 1.0, CHCl3).
In the same manner, compound (4R,8R,12S)-16 was prepared starting from bromide (S)-
6 (0.123 g, 0.40 mmol) and magnesium turnings (0.02 g, 0.73 mmol). The suspension of
the Grignard reagent formed was added to a solution of tosylate (2R,6S)-22 (0.018 g,
0.055 mmol) and Li2CuCl4 (3%, 0.025 mL, 0.1 M in THF). Compound (4R,8R,12S)-16
25
1
was obtained in 63% yield. [α]D = -1.66 (c = 1.0, CHCl3); H NMR (200 MHz,
CDCl3): δ 0.05 (s, 6H), 0.78-0.93 (m, 21H), 1.00-1.17 (m, 4H), 1.19-1.44 (m, 15H),
13
1.46-1.62 (m, 4H), 3.59 (t, J = 6.6 Hz, 2H); C NMR (50 MHz, CDCl3): δ 63.7, 39.5,
37.5, 37.4, 37.4, 34.2, 33.0, 32.8, 32.61, 32.57, 32.5, 30.4, 30.4, 29.5, 26.0, 24.5, 20.2,
19.8, 19.7, 19.6, 19.2, 14.4, -5.2.
In the same manner, compound (4R,8R,12R)-16 was prepared starting from bromide
(S)-6 (0.185 g, 0.60 mmol) and magnesium turnings (0.025 g, 0.90 mmol). The
suspension of the Grignard reagent formed was added to a solution of tosylate (2R,6R)-
22 (0.030 g, 0.09 mmol) and Li2CuCl4 (3%, 0.04 mL, 0.1 M in THF). Compound
1
(4R,8R,12R)-16 was obtained in 70% yield. [α]D25 = -2.30 (c = 1.0, CHCl3); H NMR
(300 MHz, CDCl3): δ 0.05 (s, 6H), 0.82-0.92 (m, 19H), 0.98-1.19 (m, 4H), 1.21-1.42
13
(m, 15H), 1.44-1.61 (m, 4H), 3.59 (t, J = 6.7 Hz, 2H); C NMR (75 MHz, CDCl3): δ
63.7, 39.4, 37.4, 34.2, 32.9, 32.8, 32.6, 32.6, 32.5, 30.4, 29.5, 26.0, 24.5, 20.2, 19.8,
19.2, 18.4, 14.4, -5.3.
4,8,12-Trimethylpentadecan-1-ol [(4R,8S,12S), (4S,8S,12S), (4R,8R,12S) and
(4R,8R,12R)-17]: A solution of Bu4NF (0.19 mL, 0.19 mmol, 1 M in THF) was added
to a solution of (4R,8S,12S)-16 (0.051 g, 0.13 mmol) in anhydrous THF (0.5 mL) at
room temperature. After stirring for 4 h water was added (1 mL) and the reaction
mixture was extracted with ethyl acetate (3 x 2 mL). The organic phase was washed
with aqueous sat. NaHCO3 solution and brine, dried over MgSO4 and the solvent was
removed under reduced pressure. The product was purified through flash
chromatography using hexane/ethyl acetate 9.5:0.5 as mobile phase. Compound
(4R,8S,12S)-17 was obtained in 90% yield. [α]D25 = +3.07 (c = 1.0, CHCl3); MS (70 eV)
m/z (%): 269 (1), 252 (1), 154 (22), 111 (38), 98 (25), 97 (49), 85 (51), 84 (57), 83 (57),
71 (56), 70 (49), 69 (100), 57 (73), 56 (43), 55 (73), 43 (71), 41 (51); IR (υmax, cm-1):
1
737, 1063, 1381, 1466, 2846, 2859, 2872, 2928, 2962, 3278; (4R,8S,12S)-17: H NMR
(300 MHz, CDCl3): δ 0.79-0.92 (m, 12H), 1.00-1.19 (m, 5H), 1.20-1.46 (m, 15H), 1.48-
1.65 (m, 3H), 3.63 (t, J = 6.7 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 63.5, 39.4, 37.5,
37.4, 37.3, 37.3, 33.0, 32.8, 32.6, 32.5, 30.4, 24.5, 24.4, 20.1, 19.7, 19.6, 14.4.
In the same manner, compound (4S,8S,12S)-17 was prepared starting from (4S,8S,12S)-
16 (0.012 g, 0.03 mmol) and Bu4NF (0.045 mL, 0.045 mmol, 1 M in THF), in 92%
1
yield. [α]D25 = +1.15 (c = 1.0, CHCl3); H NMR (300 MHz, CDCl3): δ 0.71-0.88 (m,

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12H), 0.91-1.08 (m, 6H), 1.10-1.37 (m, 15H), 1.41-1.58 (m, 3H), 3.56 (t, J = 6.7 Hz,
2H); 13C NMR (75 MHz, CDCl3): δ 63.5, 39.4, 37.5, 37.4, 37.37, 37.32, 3D2O.9I:,103.1023.98/D, 0OB00862A
32.7, 32.5, 30.4, 24.4, 24.3, 20.1, 19.8, 19.7, 19.6, 14.4.
In the same manner, compound (4R,8R,12S)-17 was prepared starting from
(4R,8R,12S)-16 (0.012 g, 0.03 mmol) and Bu4NF (0.045 mL, 0.045 mmol, 1 M in THF),
in 96% yield. [α]D25 = -1.66 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 0.79-0.93
(m, 12H), 0.96-1.12 (m, 6H), 1.18-1.37 (m, 15H), 1.42-1.59 (m, 3H), 3.63 (t, J = 6.7
13
Hz, 2H); C NMR (75 MHz, CDCl3): δ 63.4, 39.5, 37.5, 37.4, 37.3, 32.9, 32.8, 32.7,
32.5, 30.4, 29.7, 24.4, 24.1, 20.2, 19.7, 19.65, 19.63, 14.4.
In the same manner, compound (4R,8R,12R)-17 was prepared starting from
(4R,8R,12R)-16 (0.020 g, 0.052 mmol) and Bu4NF (0.078 mL, 0.078 mmol, 1 M in
THF), in 90% yield. [α]D25 = -1.05 (c = 1.0, CHCl3).
(4R,8S,12S),
(4S,8S,12S),
(4R,8R,12S)
and
(4R,8R,12R)-4,8,12-
Trimethylpentadecanoic acid: Jones reagent was added dropwise to a solution of
alcohol (4R,8S,12S)-17 (0.032 g, 0.12 mmol) in acetone (2 mL) at room temperature,
until the characteristic orange color remained. After stirring for 20 min water was added
(2 mL) and the reaction mixture was extracted with hexane (3 x 2 mL). The organic
phase was dried over MgSO4 and the solvent was removed under reduced pressure. The
crude product was used in the next step right after preparation, without further
purification. The yield was 96% for (4R,8S,12S)-4,8,12-trimethylpentadecanoic acid.
[α]D25 = +1.61 (c = 1.0, CHCl3); MS (70 eV) m/z (%): 41 (48), 43 (100), 55 (66), 57
(92), 69 (46), (77), 73 (62), 85 (64), 99 (31), 127 (18), 143 (27), 224 (1), 227 (17), 255
(1), 284 (6); IR (υmax, cm-1): 949, 1214, 1287, 1378, 1462, 1710, 2857, 2870, 2924,
2957.
In the same manner, (4S,8S,12S)-4,8,12-trimethylpentadecanoic acid was prepared
starting from (4S,8S,12S)-17 (0.007 g, 0.027 mmol), in 96% yield. [α]D25 = +5.86 (c =
1.0, CHCl3).
In the same manner, (4R,8R,12S)-4,8,12-trimethylpentadecanoic acid was prepared
starting from (4R,8R,12S)-17 (0.007 g, 0.027 mmol), in 97% yield. [α]D25 = -2.57 (c =
1.0, CHCl3).
In the same manner, (4R,8R,12R)-4,8,12-trimethylpentadecanoic acid was prepared
starting from (4R,8R,12R)-17 (0.012 g, 0.046 mmol), in 95% yield. [α]D25 = -5.80 (c =
1.0, CHCl3). HRMS: Calculated for C18H35O2 [M-H]- 283.2643; found 283.2631.
Methyl 4,8,12-trimethylpentadecanoate [(4R,8S,12S), (4S,8S,12S), (4R,8R,12S) and
.
(4R,8R,12R)-1]: BF3 Et2O (0.041 mL, 0.33 mmol) was added to a solution of
(4R,8S,12S)-4,8,12-trimethylpentadecanoic acid (0.031 g, 0.11 mmol) in anhydrous
methanol (1 mL). This mixture was stirred for 14 h at room temperature. After this
period aqueous sat. NaHCO3 solution was added and the reaction mixture was extracted
with hexane (3 x 2 mL). The organic phase was dried over MgSO4 and the solvent
removed under reduced pressure. It was not necessary to purify the final compound.
25
Compound (4R,8S,12S)-1 (anti,syn-stereoisomer) was obtained in 97% yield. [α]D
=
+1.39 (c = 1.0, CHCl3); MS (70 eV) m/z (%): 43 (42), 57 (34), 74 (32), 87 (100), 157
(18), 227 (4), 241 (12), 269 (1), 298 (2); IR (υmax, cm-1): 1713, 1196, 1379, 1435, 1463,
1
1743, 2847, 2860, 2873, 2929, 2957; H NMR (300 MHz, CDCl3): δ 0.77-0.91 (m,
12H), 1.01-1.14 (m, 4H), 1.18-1.49 (m, 16H), 1.58-1.73 (m, 1H), 2.21-2.40 (m, 2H),

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3.66 (s, 3H); C NMR (75 MHz, CDCl3): δ 174.7, 51.5, 39.5, 37.6, 37.5, 3D7O.4I: ,103.1073.91/D, 0OB00862A
32.9, 32.5, 32.3, 32.1, 29.8, 24.6, 24.4, 20.2, 19.8, 19.3, 19.3, 14.5.
In the same manner, compound (4S,8S,12S)-1 (syn,syn-stereoisomer) was obtained from
(4S,8S,12S)-4,8,12-trimethylpentadecanoic acid (0.007 g, 0.025 mmol) and BF3.Et2O
(0.009 mL, 0.075 mmol), in 96% yield. [α]D25 = +1.37 (c = 1.0, CHCl3); 1H NMR (300
MHz, CDCl3): δ 0.78-0.93 (m, 12H), 1.01-1.12 (m, 4H), 1.19-1.47 (m, 16H), 1.63-1.72
13
(m, 1H), 2.23-2.38 (m, 2H), 3.66 (s, 3H); C NMR (75 MHz, CDCl3): δ 174.6, 51.4,
39.4, 37.5, 37.4, 37.3, 37.0, 32.8, 32.5, 32.4, 31.9, 29.7, 24.5, 24.3, 20.1, 19.8, 19.7,
19.3, 14.4.
In the same manner, compound (4R,8R,12S)-1 (syn,anti-stereoisomer) was obtained
from (4R,8R,12S)-4,8,12-trimethylpentadecanoic acid (0.007 g, 0.025 mmol) and
1
BF3.Et2O (0.009 mL, 0.075 mmol), in 95% yield. [α]D25 = -2.05 (c = 1.0, CHCl3); H
NMR (300 MHz, CDCl3): δ 0.77-0.90 (m, 12H), 1.01-1.13 (m, 4H), 1.19-1.51 (m, 16H),
1.60-1.74 (m, 1H), 2.21-2.38 (m, 2H), 3.66 (s, 3H); 13C NMR (75 MHz, CDCl3): δ
174.6, 51.5, 39.5, 37.5, 37.5, 37.3, 37.0, 32.8, 32.5, 32.4, 32.0, 29.8, 24.5, 24.4, 20.2,
19.8, 19.5, 19.2, 14,5.
In the same manner, compound (4R,8R,12R)-1 (syn,syn-stereoisomer) was obtained
from (4R,8R,12R)-4,8,12-trimethylpentadecanoic acid (0.012 g, 0.044 mmol) and
BF3.Et2O (0.016 mL, 0.13 mmol), in 97% yield. (4R,8R,12R)-1: [α]D25 = -1.43 (c = 0.57,
CHCl3).
2,6-Dimethyl-9-(tetrahydro-2H-pyran-2-yloxy)-nonan-1-ol [(2R,6R) or (2S,6R)-18]:
Compounds 18 were prepared in the same manner as described for the stereoisomers of
compound 17. Compound (2R,6R)-18 was prepared starting from (2R,6R)-13 (0.075 g,
0.20 mmol) and Bu4NF (0.3 mL, 0.30 mmol, 1 M in THF). The product was purified
through flash chromatography using hexane/ethyl acetate 9:1 as mobile phase.
Compound (2R,6R)-18 was obtained in 90% yield. MS (70 eV) m/z (%): 55 (45), 57
(20), 69 (29), 85 (100), 101 (10), 187 (1), 199 (1); IR (υmax, cm-1): 1026, 1060, 1120,
1459, 2868, 2927, 3396; (2R,6R)-18: 1H NMR (200 MHz, CDCl3): δ 0.71-0.91 (m, 6H),
0.95-1.35 (m, 9H), 1.40-1.88 (m, 9H), 2.98-3.22 (m, 1H), 3.33-3.60 (m, 4H), 3.69-3.86
(m, 1H), 4.43-4.58 (m, 1H); 13C NMR (50 MHz, CDCl3): δ 98.9 and 98.7, 73.2 and
73.0, 63.0, 62.0 and 61.9, 37.1, 33.9, 33.31 and 33.26, 33.0, 32.5, 30.6, 30.2, 25.4, 24.2,
19.5, 19.45 and 19.39, 17.1 and 17.0.
In the same manner, compound (2S,6R)-18 was prepared starting from (2S,6R)-13
(0.154 g, 0.39 mmol) and Bu4NF (0.51 mL, 0.51 mmol, 1 M in THF), in 89% yield.
[α]D25 = -5.14 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 0.82-0.98 (m, 6H), 1.06-
1.46 (m, 9H), 1.47-1.91 (m, 9H), 3.07-3.31 (m, 1H), 3.44-3.65 (m, 4H), 3.80-3.93 (m,
13
1H), 4.52-4.61 (m, 1H); C NMR (75 MHz, CDCl3): δ 98.9 and 98.7, 73.1 and 72.9,
63.2, 62.1 and 62.0, 37.2, 34.0 and 33.9, 33.4 and 33.3, 32.8, 32.5, 30.6, 30.2, 25.4, 24.2
and 24.1, 19.6, 19.5 and 19.4, 17.2 and 17.1.
4,8-Dimethyl-9-(tetrahydro-2H-pyran-2-yloxy)-nonyl tosylate [(4R,8R) and
(4S,8R)-19]: Compounds 19 were prepared in the same manner as for compound (S)-7.
Compound (4R,8R)-19 was prepared starting from (2R,6R)-18 (0.049 g, 0.18 mmol),
pyridine (0.3 mL) and p-toluenesulfonyl chloride (0.045 g, 0.23 mmol). The product
was purified through flash chromatography using hexane/ethyl acetate 9:1 as mobile
phase, giving (4R,8R)-19 in 89% yield. MS (70 eV) m/z (%): 39 (27), 41 (57), 55 (66),
67 (29), 69 (63), 84 (62), 85 (100), 91 (52), 97 (47), 101 (12), 109 (16), 11 (17), 123

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(8), 155 (12), 173 (16), 252 (6), 396 (1); IR (υmax, cm-1): 662, 1030, 1175, 1359, 2870,
2927.
In the same manner, compound (4S,8R)-19 was prepared starting from (2S,6R)-18
(0.070 g, 0.26 mmol), pyridine (0.5 mL) and p-toluenesulfonyl chloride (0.079 g, 0.41
1
mmol), in 90% yield. [α]D25 = +7.24 (c = 1.0, CHCl3); H NMR (300 MHz, CDCl3): δ
0.77-0.84 (m, 3H), 0.87-0.96 (m, 3H), 1.04-1.38 (m, 9H), 1.48-1.86 (m, 9H), 2.45 (s,
3H), 3.09-3.27 (m, 1H), 3.44-3.65 (m, 2H), 3.80-3.91 (m, 1H), 3.97-4.05 (t, J = 6.6 Hz,
2H), 4.52-4.60 (m, 1H), 7.31-7.38 (m, 2H), 7.76-7.83 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 144.6, 133.3, 129.8, 127.9, 99.1 and 98.8, 73.1 and 73.0, 71.1, 62.2 and 62.1,
37.1 and 37.0, 34.0 and 33.9, 33.4, 33.3, 32.4, 32.27 and 32.25, 30.7, 26.4, 25.5, 24.3
and 24.2, 21.6, 19.6, 19.5 and 19.4, 17.2 and 17.1.
2-(2,6-dimethylnonyloxy)-tetrahydro-2H-pyran
[(2R,6S)
and
(2R,6R)-20]:
Compounds 20 were prepared in the same manner as (S)-10. Compound (2R,6S)-20 was
prepared starting from (4R,8R)-19 (0.060 g, 0.15 mmol) and LiAlH4 (0.011 g, 0.30
mmol). The product was purified through flash chromatography using hexane as mobile
phase, yielding (2R,6S)-20 in 95% yield. [α]D25 = +2.19 (c = 1.0, CHCl3); MS (70 eV)
m/z (%): 53 (2), 55 (22), 57 (33), 69 (7), 71 (13), 85 (100), 101 (4), 198 (1); IR (υmax
,
cm-1): 817, 968, 1099, 1180, 1190, 1358, 1469, 1603, 2858, 2874, 2929, 2968; (2R,6S)-
20: 1H NMR (200 MHz, CDCl3): δ 0.78-0,99 (m, 9H), 1.01-1.45 (m, 11H), 1.49-1.97
(m, 7H), 3.05-3.33 (m, 1H), 3.40-3.71 (m, 2H), 3.77-3.98 (m, 1H), 4.50-4.67 (m, 1H);
13C NMR (50 MHz, CDCl3): δ 99.0 and 98.7, 73.2 and 73.1, 62.1 and 62.0, 39.4, 37.3,
34.0, 33.4, 33.3, 32.4, 30.7, 25.5, 24.3, 20.1, 19.6, 17.2 and 17.1, 14.3.
In the same manner, compound (2R,6R)-20 was prepared starting from (4S,8R)-19 (0.10
g, 0.24 mmol) and LiAlH4 (0.018 g, 0.48 mmol), in 96% yield. [α]D25 = +2.31 (c = 1.0,
1
CHCl3); H NMR (300 MHz, CDCl3): δ 0.73-0.96 (m, 9H), 1.00-1.15 (m, 3H), 1.18-
1.45 (m, 8H), 1.50-1.95 (m, 7H), 3.03-3.33 (m, 1H), 3.40-3.70 (m, 2H), 3.75-4.00 (m,
13
1H), 4.47-4.67 (m, 1H); C NMR (75 MHz, CDCl3): δ 99.0 and 98.7, 73.2 and 73.0,
62.1 and 62.0, 39.4 and 39.3, 37.34 and 37.33, 34.1 and 34.0, 33.5, 33.4, 32.46 and
32.45, 30.7, 25.5, 24.4 and 24.3, 20.1, 19.7 and 19.5, 17.3 and 17.2, 14.4.
2,6-Dimethylnonan-1-ol [(2R,6R) and (2R,6S)-21]: Catalytic amount of p-TSA was
added to a solution of (2R,6S)-20 (0.066 g, 0.26 mmol) in methanol (1 mL) at room
temperature. The evolution of the reaction was monitored by TLC. After 4 h the solvent
was remover under reduced pressure and the residue was dissolved in ethyl acetate (4
mL). The organic phase was washed with aqueous sat. NaHCO3 solution and brine,
dried over MgSO4 and the solvent removed. The crude product was used in the next
step without further purification and the yield was 95% for (2R,6S)-21. [α]D25 = + 12.47
(c = 1.0, CHCl3); MS (70 eV) m/z (%): 43 (83), 55 (75), 57 (61), 69 (100), 70 (69), 71
(53), 84 (71), 85 (49), 97 (28), 111 (86), 126 (5), 154 (2), 171 (1); IR (υmax, cm-1): 738,
1036, 1378, 1462, 2870, 2925, 2956, 3335; (2R,6S)-21: 1H NMR (200 MHz, CDCl3): δ
0.73-0.99 (m, 8H), 1.01-1.17 (m, 3H), 1.18-1.42 (m, 8H), 1.50-1.78 (m, 2H), 1.88 (s,
1H), 3.30-3.61 (m, 2H); 13C NMR (50 MHz, CDCl3): δ 68.4, 39.4, 37.3, 35.7, 33.4,
32.4, 24.3, 20.1, 19.6, 16.5, 14.3.
In the same manner, compound (2R,6R)-21 was prepared starting from (2R,6R)-20
1
(0.050 g, 0.19 mmol), in 94% yield. [α]D25 = + 7.12 (c = 1.0, CHCl3) H NMR (300
MHz, CDCl3): δ 0.79-0.96 (m, 9H), 0.97-1.15 (m, 3H), 1.17-1.45 (m, 8H), 1.51-1.68
13
(m, 2H), 3.40 (dd, J = 10.5 Hz, 6.6 Hz, 1H), 3.52 (dd, J = 10.5 Hz, 5.7 Hz, 1H); C
NMR (75 MHz, CDCl3): δ 68.4, 39.3, 37.3, 35.8, 33.5, 32.6, 24.4, 20.1, 19.7, 16.6, 14.4.

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2,6-Dimethylnonyl tosylate [(2R,6S) or (2R,6R)-22]: Compounds 22 were prepared in
the same manner as (S)-7. Compound (2R,6S)-22 was prepared starting from (2R,6S)-21
(0.042 g, 0.25 mmol), pyridine (0.04 mL) and p-toluenesulfonyl chloride (0.048 g, 0.25
mmol). The product was purified through flash chromatography using hexane/ethyl
acetate 9.5:0.5 as mobile phase, giving (2R,6S)-22 in 83% yield. [α]D25 = -1.27 (c = 1.0,
CHCl3); MS (70 eV) m/z (%): 43 (38), 55 (37), 69 (52), 84 (52), 91 (88), 97 (20), 111
(75), 154 (41), 155 (63), 173 (100), 228 (1), 327 (1); IR (υmax, cm-1): 665, 961, 1174,
1360, 2870, 2927, 2966; (2R,6S)-22: 1H NMR (300 MHz, CDCl3): δ 0.81 (d, J = 6.5 Hz,
3H), 0.84-0.91 (m, 6H), 0.94-1.12 (m, 3H), 1.15-1.36 (m, 8H), 1.68-1.85 (m, 1H), 2.45
(s, 3H), 3.80 (dd, J = 9.3 Hz, 6.5 Hz, 1H), 3.89 (dd, J = 9.3 Hz, 5.7 Hz, 1H), 7.31-7.37
13
(m, 2H), 7.76-7.82 (m, 2H); C NMR (75 MHz, CDCl3): δ 144.5, 133.2, 129.8, 127.9,
75.2, 39.4, 37.0, 32.9, 32.8, 32.4, 24.0, 21.6, 20.1, 19.5, 16.4, 14.4.
In the same manner, compound (2R,6R)-22 was prepared starting from (2R,6S)-21
(0.032 g, 0.19 mmol), pyridine (0.36 mL) and p-toluenesulfonyl chloride (0.058 g, 0.30
1
mmol), in 85% yield. [α]D25 = -3.46 (c = 1.0, CHCl3); H NMR (300 MHz, CDCl3): δ
0.79 (d, J = 6.5 Hz, 3H), 0.83-0.92 (m, 7H), 0.93-1.12 (m, 4H), 1.13-1.40 (m, 9H), 1.69-
1.84 (m, 1H), 2.45 (s, 3H), 3.80 (dd, J = 9.3 Hz, 6.5 Hz, 1H), 3.89 (dd, J = 9.3 Hz, 5.7
13
Hz, 1H), 7.31-7.38 (m, 2H), 7.76-7.82 (m, 2H); C NMR (75 MHz, CDCl3): δ 144.6,
133.2, 129.8, 127.9, 75.1, 39.3, 37.0, 32.9, 32.8, 32.3, 24.0, 21.6, 20.1, 19.6, 16.5, 14.4.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors are thankful for financial support from INCT Semioquímicos na
Agricultura, CNPq and CAPES (fellowship from PDSE program 99999.010692/2014-
02).
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DOI: 10.1039/D0OB00862A
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