Syntheses of the sixteen stereoisomers of 3,7,11-trimethyl-2-tridecanol, including the (2S,3S,7S,11R) and (2S,3S,7S,11S) stereoisomers identified as pheromone precursors in females of the pine sawfly Microdiprion pallipes (Hymenoptera: Diprionidae)

Article abstract of DOI:10.1002/1099-0690(200101)2001:2<353::aid-ejoc353>3.0.co;2-z

All sixteen stereoisomers of 3,7,11-trimethyl-2-tridecanol were synthesised in high stereoisomerical purities (> 95%), for use in the identification of the stereoisomers present in females of the pine sawfly Microdiprion pallipes (Fallén) (Hymenoptera: Diprionidae) as the precursor of the actual sex pheromone (which is the propionate), and also for investigation of the biological activities of the esters. The key step in the syntheses was the coupling of each of the enantiomers of cis-3,4-dimethyl-γ-butyrolactone with each of the four pure stereoisomers of 1-lithio-2,6-dimethyloctanes. The four corresponding alcohols were obtained by lipase-catalysed (Amano PS) kinetic separation, based on selective acylation of either (2R/S,6S)- or (2R/S,6R)-2,6-dimethyl-1-octanol (obtained from the optically pure enantiomers of citronellal). Additionally, a mixture of the 16 possible stereoisomers of 3,7,11-trimethyl-2-tridecanol was also prepared. Wiley-VCH Verlag GmbH, 2001.

Full text of DOI:10.1002/1099-0690(200101)2001:2<353::aid-ejoc353>3.0.co;2-z

FULL PAPER
Syntheses of the Sixteen Stereoisomers of 3,7,11-Trimethyl-2-tridecanol,
Including the (2S,3S,7S,11R) and (2S,3S,7S,11S) Stereoisomers Identified as
Pheromone Precursors in Females of the Pine Sawfly Microdiprion pallipes
(Hymenoptera: Diprionidae)[‡]
Michael Larsson,[a] Ba-Vu Nguyen,[a] Hans-Erik Högberg,[a] and Erik Hedenström*[a]
Keywords: Asymmetric synthesis / Microdiprion pallipes / Lipase / Pheromones / Total synthesis
All sixteen stereoisomers of 3,7,11-trimethyl-2-tridecanol
were synthesised in high stereoisomerical purities (Ͼ 95%),
for use in the identification of the stereoisomers present in
of cis-3,4-dimethyl-γ-butyrolactone with each of the four
pure stereoisomers of 1-lithio-2,6-dimethyloctanes. The four
corresponding alcohols were obtained by lipase-catalysed
´
females of the pine sawfly Microdiprion pallipes (Fallen) (Hy- (Amano PS) kinetic separation, based on selective acylation
menoptera: Diprionidae) as the precursor of the actual sex
pheromone (which is the propionate), and also for investi-
of either (2R/S,6S)- or (2R/S,6R)-2,6-dimethyl-1-octanol (ob-
tained from the optically pure enantiomers of citronellal). Ad-
gation of the biological activities of the esters. The key step ditionally, a mixture of the 16 possible stereoisomers of
in the syntheses was the coupling of each of the enantiomers
3,7,11-trimethyl-2-tridecanol was also prepared.
Introduction
Pine sawflies of the Diprionidae family are severe pests
of conifers, particularly pine trees.[1] Until recently, all pine
sawfly species were considered to use the acetates and/or
propionates of the two stereoisomers of diprionol Ϫ either
(2S,3S,7S)- or (2S,3R,7R)-3,7-dimethyl-2-pentadecanol
(1H) Ϫ as their sex pheromone.[2] However, during the last
five years, several pine sawfly species have been found to
use sex pheromones representing structural types different
from that of the diprionyl esters. Thus, the pheromone of
Diprion pini was identified as either the propionate or the
acetate of one stereoisomer of a chain-shortened diprionol,
i.e., (2S,3R,7R)-3,7-dimethyl-2-tridecanol (SRR-2H).[3,4] An
even shorter homologue, the propionate of (2S,3R,7R/S)-
3,7-dimethyl-2-undecanol (SRR/S-3Pr), was identified as
the pheromone of the Japanese pine sawfly Diprion nippon-
ica by Tai et al.[5] Recently, the sex pheromone of Microdip-
rion pallipes was identified as the propionate of one or sev-
eral stereoisomers of 3,7,11-trimethyl-2-tridecanol, and two
erythro isomers of this alcohol Ϫ SSSR-4H and SSSS-4H
Ϫ were found to be present in females of that species.[6,7]
Yet another structural variation is found in the female of
Macrodiprion nemoralis, which produces (2S,3R,7R,9S)-
3,7,9-trimethyl-2-tridecanol (SRRS-5H) as the precursor
for the acetate that acts as the active sex pheromone.[8]
Several syntheses of sex pheromones of pine sawflies have
been described during the last decade in papers from our
laboratory, among them the syntheses of the acetates of the
eight stereoisomers of 3,7-dimethyl-2-pentadecanol (1Ac),[9]
the acetates and propionates of 3,7-dimethyl-2-tridecanol,
including the biologically active compounds SRR-2Ac and
SRR-2Pr,[4] and very recently the syntheses of the sixteen
stereoisomers of acetylated 3,7,9-trimethyl-2-tridecanol
were also published.[10] In this paper we wish to present the
syntheses of all sixteen stereoisomers of 3,7,11-trimethyl-2-
tridecanol, including the (2S,3S,7S,11R) and (2S,3S,7S,11S)
stereoisomers (SSSR-4H and SSSS-4H, respectively) found
to be present[7] in the female of M. pallipes. The preparation
of the two stereoisomers (2S,3S,7S,11R)- and
(2S,3R,7R,11R)-3,7,11-trimethyl-2-tridecanol has recently
been reported by others.[11] [Nakamura and Mori[11] claim
that (2S,3S,7S,11R)- and (2S,3R,7R,11R)-3,7-dimethyl-2-
[‡]
Part of this work was presented by us as Poster No. 15 at
the EUCHEM Conference, Ecological Chemistry: Chemical
Communications, Sundsvall, Sweden, August 12Ϫ15, 1998.
[a]
Department of Chemistry and Process Technology, Mid
Sweden University,
85170 Sundsvall, Sweden
Fax: (internat.) ϩ 46-60/148802
E-Mail: erik.hedenstrom@kep.mh.se
Eur. J. Org. Chem. 2001, 353Ϫ363
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0102Ϫ0353 $ 17.50ϩ.50/0
353

M. Larsson, B.-V. Nguyen, H.-E. Högberg, E. Hendenström
FULL PAPER
tridecanol, in the form of their propionate esters, are com- SS-8 was obtained after two sequential, diastereoselective
ponents of the sex pheromone of the pine sawfly M. pal- acylation reactions catalysed by Amano PS in chloroform
lipes. However, the latter isomer (in alcohol form) is not at low water activity (aw ഠ 0) with vinyl butyrate as the acyl
found in the female extract, whereas the former is.[7]] We donor, resulting in a practically irreversible[14] reaction. For
also present the synthesis of the propionate ester of a six- resolution of racemates under such conditions, the enanti-
teen isomer mixture of 3,7,11-trimethyl-2-tridecanol for oselectivity (E value) can be calculated using the equations
field tests.[6]
derived by Chen et al.[15] [E ϭ {ln[1 Ϫ c·(1ϩeep)]}/{ln[1 Ϫ
c·(1 Ϫ eep)]} (where E is enantiomeric ratio), c (conver-
sion) ϭ ees/(ees ϩ eep), ees and eep are the enantiomeric
excess of the substrate and product, respectively]. However,
in the case of compounds R- or S-8, there were two ste-
reogenic centres present in the starting alcohols, so use of
the E value is not strictly appropriate. However, we did
make use of the Chen formula to calculate the diastereose-
Results and Discussion
All new compounds tested as potential pheromone com-
ponents were prepared using essentially the same methodo-
logy as previously used in our laboratory for the syntheses
of the stereoisomers of other diprionid pheromones and re-
lated compounds[4,9,10,12]. Accordingly, the propionates 4Pr
of the pure stereoisomers of 3,7,11-trimethyl-2-tridecanol
were prepared as follows.
The individual isomers of (S)- and (R)-3,7-dimethyl-6-oc-
tenal were reduced to give R-6 or S-6, respectively, under
HuangϪMinlon conditions similar to those in the literature
procedure[13] (see Scheme 1). Selenium dioxide oxidation of
these alkenes, followed by in situ reduction with NaBH4,
furnished the allylic oxidation products 2,6-dimethyl-2-
octen-1-ol R-7 or S-7, respectively. These allylic alcohols
were subjected to catalytic hydrogenation with Raney nickel
to give 2,6-dimethyl-1-octanol (R-8 or S-8, respectively), as
mixtures of two diastereomers.
The optically pure stereoisomers of alcohol 8 were pro-
duced from the alcohols S-8 (see Scheme 2) and R-8 (see
Scheme 3) by enzyme-catalysed reactions. Thus, the alcohol
Scheme 3. a) Lipase-catalysed kinetic acylation; Amano PS,
CHCl3, vinyl butyrate, aw ഠ 0, c ϭ 40% or 64% and then LC sep-
aration of the product and the substrate; b) KOH/MeOH; c) sub-
strate ii, lipase-catalysed kinetic acylation; Amano PS, CHCl3, vinyl
butyrate, aw ഠ 0, c ϭ 40% and then LC separation of the product
and the substrate; d) 1. lipase-catalysed kinetic acylation; Amano
PS, CHCl3, vinyl butyrate, aw ഠ 0, c ϭ 70% and then LC separation
of the product and the substrate; 2. KOH/MeOH; e) CrO3/H2SO4
Scheme 1. a) N2H4 ϫ H2O, KOH, diethylene glycol, 170 °C; b) 1.
tBuOOH, SeO2, CH2Cl2, 2. NaBH4, NaOH, MeOH, 0Ϫ30 °C; c) acetone, 0 °C; f) lipase-catalysed kinetic acylation; Im-CRL, 1-
Raney Ni, H2, MeOH, 40 °C
hexadecanol, aw ഠ 0.8, cyclohexane, c ϭ 40%; g) LiAlH4, Et2O
Scheme 2. a) Lipase-catalysed kinetic acylation; Amano PS, CHCl3, vinyl butyrate, aw ഠ 0, c ϭ 50% and then LC separation of the
product and the substrate; b) KOH/MeOH; c) lipase-catalysed kinetic acylation; Amano PS, CHCl3, vinyl butyrate, aw ഠ 0, c ϭ 60% and
then LC separation of the product and the substrate; d) 1. lipase-catalysed kinetic acylation; Amano PS, CHCl3, vinyl butyrate, aw ഠ 0,
c ϭ 51% and then LC separation of the product and the substrate; 2. KOH/MeOH
354
Eur. J. Org. Chem. 2001, 353Ϫ363

Syntheses of the Sixteen Stereoisomers of 3,7,11-Trimethyl-2-tridecanol
FULL PAPER
lectivity ‘‘E’’ of the lipase towards the stereogenic centre at (2R,6R)-dimethyl-1-octanol RR-8, with 96.9% (R) config-
C-2 in the alcohols R- or S-8. In this case, the ees and eep uration at C-2 (see Scheme 3) Ϫ was subjected to a second
values are accordingly replaced by diastereomeric excess enzymatic diastereoselective acylation catalysed by Amano
values (des and dep, respectively).
PS. This resulted, after 70% conversion, in the alcohol RR-
The first enzymatic diastereoselective acylation of alcohol 8, with 99.4% (R) configuration at C-2 (98.1% of the RR-8
S-8 was stopped at 50% conversion. The dep of the faster stereoisomer, see Table 1).
reacting stereoisomer, of (S) configuration at C-2, was de-
The observed difference in enzyme selectivity ‘‘E’’ for the
termined to be 73%, corresponding to an ‘‘E’’ value of 13.8. two diastereomeric pairs R-8 and S-8 (4.8 and 13.8, respect-
The intermediate ester product was hydrolysed, using KOH/ ively) in these lipase PS catalysed acylation reactions, is sig-
MeOH, to give the (2S,6S)-alcohol SS-8, which was sub- nificant and intriguing, because the configuration at the re-
sequently subjected to a second cycle of lipase-catalysed motely located, methyl-substituted C-6 obviously has a
acylation (c ϭ 51%), followed by base-promoted hydrolysis large influence on the selectivity of lipase PS. We are cur-
to yield SS-8 (see Scheme 2) with a stereoisomeric purity rently studying this phenomenon further. Similar observa-
at C-2 of 97.2% (S) and a diastereomeric purity of 96.0% tions have recently been made in cases of CRL-catalysed
(see Table 1).
esterification of diastereomeric dimethyl-substituted ac-
ids.[16]
Table 1. Stereoisomeric composition of the four individual ste-
reoisomers (2S,6S)-, (2S,6R)-, (2R,6S)-, and (2R,6R)-2,6-dimethyl-
1-octanol
The optical rotations obtained by us for the alcohols SR-
8 ([α]2D5 ϭ Ϫ21.4) and RS-8 ([α]2D5 ϭ ϩ18.3) were much
larger than those previously published.[17Ϫ20] Furthermore,
the optical rotations for the alcohols SS-8 ([α]2D5 ϭ Ϫ2.41)
and RR-8 ([α]2D5 ϭ ϩ2.58) prepared by us were significantly
smaller than those previously reported.[17Ϫ21] Most of the
previously published syntheses[17Ϫ20] involved catalytic hy-
drogenation of an enantiomerically enriched unsaturated al-
cohol with the stereogenic centre located between the alco-
hol and the double bond. In many cases, reductions are
known to give a certain degree of epimerisation,[13,22Ϫ26]
Isomer SS-8
SR-8
RS-8
RR-8
ee[a]
dr[b]
SS-8 Ͼ 96.0% 1.2%
Ͻ 2.8% Ͻ 0.1% Ͼ 99.8% Ͼ 96:4
SR-8 1.3% Ͼ 98.4% Ͻ 0.1% Ͻ 0.3% Ͼ 99.8% Ͼ 98.4:1.6
RS-8 Ͻ 0.8% Ͻ 0.1% Ͼ 97.9% 1.2%
Ͼ 99.8% Ͼ 98:2
RR-8 Ͻ 0.1% Ͻ 0.6% 1.3%
Ͼ 98.1% Ͼ 99.8% Ͼ 98.1:1.9
[a]
[b]
Enantiomeric excess of the major isomer. Ϫ
Diastereomeric
ratio [(SS-8 ϩ RR-8)/(SR-8 ϩ RS-8) or (SR-8 ϩ RS-8)/(SS-8 ϩ
RR-8)].
In order to produce the diastereomerically pure RS-8, the leading to lower than expected stereoisomeric purity at C-
remaining substrate from both reactions above, (2R,6S)-al- 6 in the final products.
cohol RS-8, was collected [68.5% (R) at C-2] and subjected
In order to establish the optical rotation values for the
to a new enzymatic diastereoselective acylation. At 60% individual isomers of 8, we used an independent and unam-
conversion, RS-8 was obtained with a stereoisomeric purity biguous synthetic route to prepare two of the stereoisomers
at C-2 of 99.2% (R) and with 97.9% diastereomeric purity of 2,6-dimethyl-1-octanol: namely RS- and SS-8 (see Exp.
(see Table 1).
Sect. for details). Hence, enantiomerically pure (S)-2-
The double kinetic, enzymatic, diastereoselective acyl- methyl-1-butanol (Ͼ 99% ee) was converted into the brom-
ation technique described above for alcohol S-8 was also ide and then transformed into (S)-4-methylhexanoic acid
applied to the alcohol R-8, which after the first (40% con- (Ͼ 98% ee) by a malonic ester two-carbon chain-extension
version) and second (70% conversion) enzymatic steps gave sequence. This acid was reduced (LiAlH4) to the alcohol,
alcohol SR-8 with 89.7% (S) configuration at C-2 (see which was converted into the iodide. When this was used in
Scheme 3). In this case, the ‘‘E’’ value was calculated to be a diastereoselective alkylation of either one of the enolates
4.8 from the measured dep and c (54.5% and 40%, respect- obtained from the pure enantiomers of propionylated
ively) At this stage, for our requirements, the diastereomeric pseudoephedrine, according to the general procedure re-
purity at C-2 was unacceptably low. Candida rugosa lipase ported for such amide alkylations,[27] two diastereomeric
(CRL) had recently been used by two of us for successful 2,6-dimethyloctanoic amides were obtained. These were re-
catalysis of kinetic stereoselective separation by ester- duced (LiH2NBH3)[28] to give the target molecules RS-8
ification of some dimethylcarboxylic acids, such as 2,6-di- and SS-8, with optical rotation values of [α]2D5 ϭ ϩ20.4,
methyloctanoic acid.[16] Therefore, we decided to apply this (c ϭ 2.83, CHCl3) and [α]D25 ϭ Ϫ2.71, (c ϭ 2.65, CHCl3), re-
method to enhance the stereoisomeric purity of the ob- spectively.
tained alcohol SR-8. Accordingly, this alcohol was oxidised
The four individual stereoisomers of 2,6-dimethyl-1-oc-
to the carboxylic acid using Jones reagent (see Scheme 3) tanol (RR-, RS-, SR-, and SS-8) were converted into the
and then subjected to an esterification reaction, catalysed chlorides (RR-, RS-, SR-, or SS-9) (see Scheme 4). From
by immobilised CRL, with 1-hexadecanol in cyclohexane at these, the corresponding alkyllithium compounds were pre-
aw ϭ 0.8. After reduction (LiAlH4) of the (2S,6R)-ester (the pared and each was allowed to react with each of the en-
faster reacting isomer), obtained at 40% conversion, the al- antiomers of cis-3,4-dimethyl-γ-butyrolactone. This gave in
cohol SR-8 was obtained with Ͼ 99.5% (S) configuration each case an oxo alcohol, which after HuangϪMinlon re-
at C-2 and a diastereomeric purity of 98.4% (See Table 1).
duction yielded one of the eight erythro-3,7,11-trimethyl-2-
The remaining substrate obtained from the first Amano tridecanols (erythro-4H). Each one of the eight individual
PS catalysed transesterification step mentioned above Ϫ erythro isomers was obtained separately, with a diastereom-
Eur. J. Org. Chem. 2001, 353Ϫ363
355

M. Larsson, B.-V. Nguyen, H.-E. Högberg, E. Hendenström
FULL PAPER
Conclusion
eric purity of Ͼ 97.6%, except for the (2S,3S,7S,11S) and
(2R,3R,7S,11S) isomers, which had diastereomeric purities
of 95.9% and 95.7%, respectively.
In conclusion, we have synthesised the propionate esters,
4Pr, of 3,7,11-trimethyl-2-tridecanol both as one mixture of
all isomers, and as sixteen highly pure individual stereoiso-
mers. The results from biological studies of the stereoiso-
mers produced by female M. pallipes, from electrophysiolo-
gical experiments and from field tests with M. pallipes will
be published elsewhere.[7]
Experimental Section
Commercially available chemicals were used without further puri-
fication unless stated otherwise. Amano PS and Candida rugosa
Lipase (CRL) were purchased from LABKEMI and Sigma Aldrich
respectively, and stored at 4 °C over dry silica gel. Alkyl halides
were distilled prior to use and stored under argon. The reactions
involving lithium derivatives were carried out under anhydrous
conditions and argon. Dry diethyl ether and tetrahydrofuran were
distilled from LiAlH4 and potassium/benzophenone, respectively.
The (3S,4S)- and (3R,4R)-cis-dimethyl-γ-butyrolactones used were
obtained from the same batches as those prepared by Bergström et
al.:[4] (SS): Ͼ 99.9% ee and Ͻ 0.04% trans; (RR): Ͼ 99.7% ee and
Ͻ 0.03% trans. (R)- and (S)-3,7-dimethyl-6-octenal were purchased
from Fluka, checked by 1H NMR and their optical rotations meas-
ured as ϩ15.5 (neat) and Ϫ15.9 (neat), respectively. Ϫ The enanti-
omeric purity of these was determined by GC, 30 m ϫ 0,25 mm
I.D. capillary column coated with β-dex 225, df ϭ 0.25 µm; carrier
gas He 15 psi, split ratio 30:1 (GC programme: 90 °C/20 min, 1 °C/
min, 120 °C); retention time (min): 37.4 [(S) enantiomer] and 37.9.
[(R) enantiomer]. Ϫ (S)-(Ϫ)-2-Methyl-1-butanol was purchased
Scheme 4. a) PPh3, CCl4, reflux, b) 1. Li(s), reflux, n-hexane,
2. addition to one of the enantiomers of cis-3,4-dimethyl-γ-butyrol-
actone at Ϫ78 °C, 3. N2H4 ϫ H2O, KOH, diethylene glycol, 170
°C, 1 h, then 210 °C, 3 h; c) 1. PPh3, PhCO2H, N2(CO2Et)2, 2.
NaOH, H2O/MeOH/dioxane; d) 10 equiv. CH3CH2COCl, CH2Cl2
The eight individual threo isomers (threo-4H) were ob-
tained from the erythro isomers by Mitsunobu inversion at
C-2, followed by basic hydrolysis of the resulting benzoate.
The eight threo isomers were all obtained with diastereom-
eric purities of Ͼ 97.4%, except for the (2R,3S,7S,11S) and
(2S,3R,7S,11S) isomers, which had diastereomeric purities
of 95.3 and 95.5%, respectively. Acylation of the individual
erythro and threo isomers (erythro-4H and threo-4H) using
propionyl chloride furnished the sixteen isomers of 4Pr.
The propionate, 4Pr, of 3,7,11-trimethyl-2-tridecanol was
also prepared as a mixture of all 16 possible stereoisomers
(erythro/threo ratio 58:42 mixture), by essentially the same
method as that used for the syntheses of each of the sixteen
individual stereoisomers in their pure forms. However, in
this case the synthesis started from racemic citronellol,
which was converted into a tosylate and reduced with Li-
AlH4 to yield racemic 2,6-dimethyl-2-octene (6) (see
Scheme 5).[6]
1
from Fluka, checked by H NMR and its enantiomeric purity de-
termined by GC, 30 m ϫ 0.25 mm I.D. capillary column coated
with β-dex 325, df ϭ 0.25 µm; carrier gas He 15 psi, split ratio 30:1
(GC programme: 40 °C/20 min, 0.5 °C/min, 50 °C); retention time
(min): 33.5 [(R) enantiomer] and 34.9 [(S) enantiomer]. Preparative
liquid chromatography (LC) was performed on straight-phase silica
gel (Merck 60, 230Ϫ400 mesh, 0.040Ϫ0.063 mm) employing a gra-
dient technique using an increasing concentration of distilled di-
ethyl ether in distilled n-pentane or of distilled ethyl acetate in dis-
tilled cyclohexane (0 Ǟ 100%), as eluent. Progress was monitored
by GC or thin layer chromatography, which was performed on sil-
ica gel plates (Merck 60 F254, precoated aluminium foil) eluted with
ethyl acetate (20Ϫ40%) in cyclohexane and developed by means of
ultraviolet light and/or by spraying with vanillin/sulfuric acid in
ethanol and heating at 120 °C. Ϫ NMR spectra were recorded with
a Bruker DMX 250 (250 MHz 1H and 62.9 MHz 13C) spectrometer,
using CDCl3 as solvent and TMS as internal reference. Ϫ Optical
rotations were measured with a PerkinϪElmer 241 polarimeter, us-
ing a 1-dm cell. Ϫ Mass spectra were recorded with a Saturn 2000
instrument, operating in the EI or CI (CH3CN as chemical ionis-
ation gas) mode, coupled to a Varian 3800 GC instrument. Exact
masses (HRMS) were obtained using a VG-70E mass spectrometer.
Unless otherwise stated, conversions and purities were monitored
on a 30 m ϫ 0.25 mm I.D. capillary column coated with CP-Sil
19CB, df ϭ 0.25 µm; carrier gas N2 100 kPa, split ratio 30:1 (flow
1 mL/min). Ϫ The erythro/threo ratio of 4H and the individual iso-
mers of erythro-4H and threo-4H were determined using a 30 m ϫ
0.25 mm I.D., df ϭ 0.25µm, capillary column coated with CP-WAX
52 CB, carrier gas He 16 psi, split ratio 30:1 (GC programme: 80
°C, 1 °C/min, 150 °C); retention time (min): 66.0 (erythro) and 67.2
(threo). Ϫ Unless otherwise stated, ‘‘extractive workup’’ consisted
Scheme 5. a) 1. pTsCl, pyridine, 2. LiAlH4, Et2O; b) 1. tBuOOH,
SeO2, 2. NaBH4; c) Raney Ni, H2, MeOH, 40 °C; d) PPh3, CCl4,
reflux; e) 1. Li(s), reflux, n-hexane, 2. addition to a cis/trans mixture
(58:42) of rac-3,4-dimethyl-γ-butyrolactone at Ϫ78 °C, 3. N2H4 ϫ
H2O, KOH, diethylene glycol, 170 °C, 1 h, then 210 °C, 3 h; f) 10
equiv. CH3CH2COCl, CH2Cl2
356
Eur. J. Org. Chem. 2001, 353Ϫ363

Syntheses of the Sixteen Stereoisomers of 3,7,11-Trimethyl-2-tridecanol
FULL PAPER
of extraction with the given solvent followed by drying with anhyd-
rous MgSO4, filtering, and solvent removal in a rotary evaporator.
Boiling points are uncorrected and given as air-bath temperatures
(bath temp./mbar) in a bulb-to-bulb (Büchi-GKR-51) apparatus. Ϫ
Elemental analysis was performed by Mikrokemi AB, SE-752 28
Uppsala, Sweden.
(S)-(؉)-2,6-Dimethyl-2-octen-1-ol (S-7): Similarly, S-6 (21.5 g, 0.15
mol) gave S-7 (20 g, 83%), 98.5% pure by GC. B.p. 60 °C/5 mbar.
Ϫ [α]2D5 ϭ ϩ10.5. (c ϭ 1.65, EtOH), ref.[37] [α]3D8 ϭ ϩ9.8 (c ϭ 5.2,
1
EtOH). Ϫ H NMR, 13C NMR, and MS (EI) spectral data match
those of R-7.
2,6-Dimethyl-2-octen-1-ol (7): Similarly, 6 (12.5 g, 89.3 mmol) fur-
nished 7 (11.5 g, 83%), Ͼ 99.0% pure by GC. 1H NMR, 13C NMR,
and MS (EI) spectral data match those of (R)-7.
(R)-(؊)-2,6-Dimethyl-2-octene (R-6): (S)-Citronellal (20.2 g, 0.13
mol) (Ͼ 97.3% ee) was added to a solution of freshly distilled di-
ethylene glycol (277 mL, 2.92 mol) containing KOH (38.8 g, 0.69
mol) and hydrazine monohydrate (10.1 mL, 0.21 mol). The solution
was slowly heated to 170 °C, at which temperature it was kept for
1 h before cooling and distillation. The product, together with some
water, was collected between 105Ϫ110 °C. The water phase was
extracted with 50 mL of n-pentane, the pooled organic phases were
washed with 2 ϫ 75 mL of H2O and 75 mL of brine, dried, and
concentrated to give the product (13.3 g, 73% after distillation, b.p.
155 °C/1 atm), Ͼ 99% pure by GC. Ϫ [α]2D5 ϭ Ϫ11.0 (neat), ref.[29]
(2R/S,6R)-(؊)-2,6-Dimethyl-1-octanol (R-8): Compound R-7
(11.4 g, 73.0 mmol) was stirred under H2 in MeOH (100 mL) with
a suspension of Raney Ni in water (ca. 5 g) at 40 °C for 24 h.
The suspension was filtered and the collected solid was washed
thoroughly with MeOH (5 ϫ 15 mL). The MeOH was evaporated
off and the crude product was subjected to LC followed by distilla-
tion (b.p. 55 °C/13 mbar) to give R-8 (8.43 g, 73%), 99% pure by
GC. Ϫ [α]2D5 ϭ Ϫ7.19 (c ϭ 23.6, CHCl3), ref.[18] [α]2D0 ϭ Ϫ7.40 (c ϭ
1
2.16, CHCl3). Ϫ H NMR: δ ϭ 0.85 (d, 3 H, J ϭ 5.6 Hz), 0.86 (t,
1
[α]2D5 ϭ Ϫ10.54 (neat). Ϫ H NMR: δ ϭ 0.86 (d, 3 H, J ϭ 6.3 Hz),
3 H, J ϭ 7.2 Hz), 0.92 (3 H, dd, J ϭ 0.5 and 6.7 Hz), 1.02Ϫ1.66
(11 H, m), 3.42 (dd, 1 H, J ϭ 6.5 and 10.5 Hz), 3.52 (1 H, ddd,
J ϭ 1.0, 5.8 and 10.5 Hz). Ϫ 13C NMR: δ ϭ 11.4 (2 C), 16.6 (2
C), 19.2 (2 C), 24.4 (2 C), 29.4, 29.6, 33.4, 33.5, 34.4 (2 C), 35.8 (2
C), 36.8, 36.9, 68.4, 68.5. Ϫ MS (EI); m/z (%) 125 (5), 111 (61), 97
(8), 83 (20), 85 (25), 69 (100), 55 (64). Ϫ The 1H NMR and 13C
NMR spectral data are similar to those reported in the literature.[18]
0.86 (t, 3 H, J ϭ 7.3 Hz), 1.08Ϫ1.19 (m, 2 H), 1.26Ϫ1.39 (m, 3 H),
1.60 (3 H, s), 1.68 (d, 3 H, J ϭ 1.0 Hz), 1.91Ϫ1.99 (m, 2 H), 5.11
(1 H, tq, J ϭ 1.3 and 7.1 Hz). 13C NMR: δ 11.3, 17.6, 19.1, 25.6,
25.7, 29.4, 34.0, 36.7, 125.1, 130.9. Ϫ MS (EI); m/z (%): 140 (17)
[Mϩ], 125 (10), 111 (24), 83 (18), 69 (100), 55 (70). Ϫ 1H NMR
and 13C NMR spectral data correspond well with those reported
in the literature.[30Ϫ33]
(2R/S,6S)-(؉)-2,6-Dimethyl-1-octanol (S-8): Similarly, S-7 (19.5 g,
0.13 mol) gave S-8 (15.5 g, 75%), 99% pure by GC. B.p. 52 °C/
10 mbar. Ϫ [α]2D5 ϭ ϩ7.39 (c ϭ 2.11, CHCl3), ref.[18] [α]2D0 ϭ ϩ7.32
(S)-(؊)-2,6-Dimethyl-2-octene (S-6): Similarly, (R)-citronellal
(30.2 g, 0.20 mol) (97.5% ee) gave (S)-6 (22 g, 80%), Ͼ 99.5% pure
by GC. B.p. 153Ϫ155 °C/1 atm. Ϫ [α]2D5 ϭ ϩ11.0 (neat), ref.[29] [α]
1
(c ϭ 2.33, CHCl3). Ϫ H NMR, 13C NMR, and MS (EI) spectral
ϭ ϩ10.54 (neat). Ϫ H NMR, 13C NMR, and MS (EI) spectral
25
1
D
data coincid with those of R-8.
data match those of R-6.
2,6-Dimethyl-1-octanol (8): Similarly, 7 (11.2 g, 71.7 mmol) fur-
2,6-Dimethyl-2-octene (6): Use of the tosylation method of Byström
et al.,[34] but starting from citronellol (20 g, 0.13 mol), gave the
tosylate, which was reduced with LiAlH4 (5.3 g, 0.14 mol) accord-
ing to the procedure of Rapoport and Bonner.[35] Compound 6
(13.2 g, 74%) was obtained after LC and distillation, (b.p. 82 °C/
72 mbar), 98% pure by GC. 1H NMR, 13C NMR, and MS (EI)
spectral data match those of R-6.
1
nished 8 (6.02 g, 53%), 95% pure by GC. B.p 110 °C/10 mbar. H
NMR, 13C NMR, and MS (EI) spectral data matched those of R-
8 and the 1H NMR spectrum is similar to that reported in the liter-
ature.[39]
Method A for Sequential Separation by Lipase PS Catalysed Kinetic
Acylation of (2S/R,6R)-(؊)-2,6-Dimethyl-1-octanol (R-8) and (2R/
S,6S)-(؉)-2,6-dimethyl-1-octanol (S-8): A chloroform solution (1
vol.) containing a given alcohol (0.57 ), tridecane (internal stand-
ard, 0.16 ), lipase PS (13.3 mg/mL solvent) and molecular sieves
(R)-(؊)-2,6-Dimethyl-2-octen-1-ol (R-7): Following the protocol of
Umbreit and Sharpless,[36] R-6 (13.2 g, 94.1 mmol) was added drop-
wise at 15 °C to a magnetically stirred suspension of 70% tert-butyl
hydroperoxide (32.5 mL, 338 mmol), SeO2 (0.21 g, 1.88 mmol), sa-
licylic acid (1.30 g, 9.4 mmol), and CH2Cl2 (30 mL). The reaction
mixture was kept at room temperature for 44 h and then quenched
by addition of 70 mL of MeOH and a solution of NaBH4 (5.7 g,
150 mmol) in 30 mL 0.2  aq. NaOH at 0 °C. The solution was
stirred at room temperature overnight and then treated with
150 mL of H2O and 150 mL of n-pentane. The water phase was
extracted with 2 ϫ 50 mL of n-pentane and the pooled organic
phases were washed with 100 mL brine. The mixture, containing
the product and the starting material, was subjected to LC to give
the title alcohol (11.5 g, 78% after distillation, b.p. 60 °C/5 mbar),
Ͼ 99% pure by GC. Ϫ [α]2D5 ϭ Ϫ10.4 (c ϭ 4.84, EtOH), ref.[33]
˚
(4 A) was stirred under argon at room temperature at 500 rpm. The
reaction was started by addition of dry vinyl butyrate (2.17 ) to
the flask. Conversion was followed by periodic withdrawal of
samples. When the reaction had reached the desired degree of con-
version, the mixture was filtered under argon and the solid washed
with n-pentane (3 ϫ 1 vol.). The mixture was concentrated and
subjected to LC, the remaining alcohol was collected and the isol-
ated ester was hydrolysed in 1 vol. of 2.4  KOH/MeOH at reflux
overnight. After cooling, water (1 vol.) and n-pentane (1 vol.) were
added; this was followed by extractive workup with n-pentane (3 ϫ
0.75 vol.) and a 3:2 mixture of Et2O/n-pentane (3 ϫ 0.75 vol.) to
give the alcohol after drying (MgSO4) and evaporation of the solv-
ent. If necessary, the two alcohols were subjected to new cycles of
the above reactions.
1
[α]2D5 ϭ Ϫ9.7 (c ϭ 0.6, EtOH). Ϫ H NMR: δ ϭ 0.86 (t, 3 H, J ϭ
7.1 Hz), 0.87 (d, 3 H, J ϭ 6.2 Hz), 1.08Ϫ1.25 (m, 2 H), 1.27Ϫ1.41
(m, 3 H), 1.43 (1 H, ϪOH, d, J ϭ 0.3 Hz), 1.67 (d, 3 H, J ϭ (2S,6R)-(؊)-2,6-Dimethyl-1-octanol (SR-8): According to Method
0.3 Hz), 1.97Ϫ2.07 (m, 2 H), 4.00 (s, 2 H), 5.40 (1 H, tq, J ϭ 1.2
A, the reaction was performed from R-8 (6.21 g, 39.2 mmol). How-
and 7.1 Hz). Ϫ 13C NMR: δ ϭ 11.4, 13.6, 19.1, 25.2, 29.4, 34.0, ever, although the reaction was run over two cycles that reached
36.3, 69.1, 126.9, 134.4. Ϫ MS (EI); m/z (%): 156 (7) [Mϩ], 138 (10) conversions of 40% and 70%, respectively, the diastereomeric purity
[M Ϫ H2O]ϩ, 123 (20), 109 (52), 96 (33), 83 (42), 67 (100), 55 (80).
at C-2 was unacceptably low (89.7% S). Therefore, the partially
1
Ϫ The H NMR and 13C NMR spectral data are similar to those enriched (2S,6R)-alcohol (1.64 g, 10.4 mmol) was oxidised with
reported in the literature.[31,33]
Jones reagent (50 mL) at 0 °C as described in ref.[38] After 10 min
Eur. J. Org. Chem. 2001, 353Ϫ363
357

M. Larsson, B.-V. Nguyen, H.-E. Högberg, E. Hendenström
FULL PAPER
of stirring, Celite was added and the mixture was filtered and
ϩ15.7 (c ϭ 2.8, CHCl3). Ϫ 1H NMR, 13C NMR, and MS (EI)
1
washed with Et2O. The organic phase was extracted with sat. aq. spectral data match those of SR-8; the H NMR is also similar to
Na2CO3 (3 ϫ 50 mL), the combined water phases were acidified
with HCl (15 mL, 6 ), the obtained acid was extracted into Et2O
(7 ϫ 50 mL), dried (MgSO4), and concentrated to give the acid,
with a purity by GC of 98.7%. According to the methodology given
by Nguyen and Hedenström,[16] the acid (1.67 g, 9.67 mmol) was
mixed with cyclohexane (58 mL, 8.70 mmol), 1-hexadecanol
(2.11 g, 8.70 mmol), tridecane (0.88 g, 4.78 mmol), Na2SO4 (1.66 g,
11.7 mmol), and Na2SO4 ϫ 10 H2O (1.87 g, 5.81 mmol). The mix-
ture was stirred for 1 h at 500 rpm at room temperature to allow
equilibration to aw ϭ 0.8. Immobilised CRL (1.18 g) was added,
and after 6.7 h (ca. 40% conversion) the CRL was filtered off, fol-
lowed by extractive workup with Et2O (150 mL) and Na2CO3 (3 ϫ
40 mL, sat. aq.), and then the organic phase was dried and concen-
trated to give the ester, which was purified by LC. The ester was
added to LiAlH4 (150 mg, 3.96 mmol) in dry Et2O (20 mL) and
stirred for 1 h at ambient temperature followed by extractive
workup and a bulb-to-bulb distillation (b.p. 90 °C/9 mbar) to give
the alcohol SR-8 (0.63 g, 20% based on the amount of SR-8 present
in R-8) Ͼ 99% pure by GC and 99.7% (S) configuration at C-2. Ϫ
[α]2D5 ϭ Ϫ21.4 (c ϭ 3.18, CHCl3), ref.[18] [α]2D0 ϭ Ϫ9.07 (c ϭ 1.10,
that reported in the literature.[19]
Determination of the Stereoisomeric Purity at C-2 of the Alcohols
SR-8, RS-8, RR-8, and SS-8: The stereoisomeric purity at C-2 of
the alcohols SR-8, RS-8, RR-8, SS-8 was determined after oxida-
tion of the alcohols to the acids using Jones reagent, followed by
conversion into the corresponding phenylethylamides obtained
from the enantiomerically pure (S)-1-phenylethylamine (for alco-
hols SR-8 and RR-8) and (R)-1-phenylethylamine (for alcohols RS-
8 and SS-8) as described in the literature.[38] The diastereoisomeric
ratios of the amides were determined using a Varian 3700 gas chro-
matograph equipped with a CP-WAX-52CB, 30 m ϫ 0.25 mm, df ϭ
0.25 µm, carrier gas He, 15 psi, split 1:30, isothermal 200 °C; reten-
tion time (min): 27.0 (SR-8 and RS-8) and 29.2 (SS-8 and RR-8)
for the amide derivatives. Alternatively, the Varian 3700 gas chro-
matograph was equipped with an EC-WAX 30 m ϫ 0.25 mm, df ϭ
0.25 µm, carrier gas He, 16 psi, split 1:30, isothermal 200 °C; reten-
tion time (min): 36.3 (RR-8 and SS-8) and 33.0 (RS-8 and SR-8).
(2R,6R)-1-Chloro-2,6-dimethyloctane (RR-9): According to the pro-
tocol of Hedenström and Högberg[40] RR-8 (0.40 g, 2.53 mmol) was
mixed with triphenylphosphane (0.73 g, 2.80 mmol) and CCl4
(1.5 mL, 16.0 mmol) and refluxed for 3 h. MeOH (0.5 mL) was
poured into the crude product, which was immediately subjected
to LC and bulb-to-bulb distillation, giving a colourless oil (0.42 g,
95%), Ͼ 98% pure by GC. B.p. 60 °C/1.3 mbar. Ϫ [α]2D5 ϭ Ϫ5.47
1
CHCl3). Ϫ H NMR: δ ϭ 0.84 (d, 3 H, J ϭ 6.1 Hz), 0.86 (t, 3 H,
J ϭ 7.2 Hz), 0.92 (d, 3 H, J ϭ 6.7 Hz), 1.05Ϫ1.65 (11 H, m), 3.42
(dd, 1 H, J ϭ 6.5 and 10.5 Hz), 3.52 (dd, 1 H, J ϭ 5.8 and 10.5 Hz).
Ϫ
13C NMR: δ ϭ 11.4, 16.6, 19.2, 24.4, 29.6, 33.4, 34.4, 35.8, 36.8,
68.5. Ϫ MS (EI); m/z (%): 141 (2) [M Ϫ OH]ϩ, 125 (5), 111 (63),
97 (10), 83 (23), 69 (100), 55 (67).
1
(c ϭ 0.85, n-hexane). Ϫ H NMR: δ ϭ 0.85 (d, 3 H, J ϭ 6.3 Hz),
(2R,6R)-(؉)-2,6-Dimethyl-1-octanol (RR-8): The first lipase-cata-
lysed acylation reaction of R-8 was stopped at 64% conversion. The
remaining substrate (2.12 g, 13.4 mmol) was subjected to a second
lipase-catalysed acylation reaction, which was allowed to reach 40%
conversion. After LC, the alcohol RR-8 (0.51 g, 48% based on the
amount of RR-8 present in R-8) was isolated, Ͼ 98% pure by GC
and with 99.4% (S) configuration at C-2. B.p. 100 °C/11 mbar. Ϫ
[α]2D5 ϭ ϩ2.58 (c ϭ 7.32, CHCl3), ref.[20] [α]2D0 ϭ ϩ6.9 (c ϭ 5,
0.86 (t, 3 H, J ϭ 7.0 Hz), 1.00 (d, 3 H, J ϭ 6.7 Hz), 1.05Ϫ1.52 (m,
9 H), 1.75Ϫ1.85 (m, 1 H), 3.41 (dd, 1 H, J ϭ 6.2 and 10.6 Hz),
3.49 (dd, 1 H, J ϭ 5.2 and 10.5 Hz). Ϫ 13C NMR: δ ϭ 11.4, 17.8,
19.2, 24.3, 29.4, 34.3 (2 C), 35.5, 36.7, 51.3. Ϫ MS (EI); m/z (%):
147 (2) [M35Cl Ϫ C2H5]ϩ, 119 (29), 111 (53), 83 (42), 69 (100),
57 (46).
(2S,6S)-1-Chloro-2,6-dimethyloctane (SS-9): Similarly, SS-8 (2.31 g,
14.6 mmol) gave SS-9 (2.31 g, 90%), Ͼ 99% pure by GC. B.p. 115
1
CHCl3). Ϫ H NMR: δ ϭ 0.85 (d, 3 H, J ϭ 6.3 Hz), 0.86 (t, 3 H,
J ϭ 7.2 Hz), 0.92 (d, 3 H, J ϭ 6.7 Hz), 1.01Ϫ1.65 (11 H, m), 3.42
(dd, 1 H, J ϭ 6.5 and 10.5 Hz), 3.52 (dd, 1 H, J ϭ 5.8 and 10.5 Hz).
1
°C/7.5 mbar. Ϫ [α]2D5 ϭ ϩ4.89 (c ϭ 0.35, n-hexane). Ϫ H NMR,
13C NMR, and MS (EI) spectral data match those of RR-9.
Ϫ
13C NMR: δ ϭ 11.4, 16.6, 19.2, 24.4, 29.4, 33.5, 34.4, 35.8, 36.9,
68.4. Ϫ MS (EI); m/z (%): 140 (3) [M Ϫ H2O]ϩ, 125 (5), 111 (63),
(2S,6R)-1-Chloro-2,6-dimethyloctane (SR-9): Similarly, SR-8
(0.58 g, 3.65 mmol) gave SR-9 (0.40 g, 62%), Ͼ 99% pure by GC.
97 (10), 85 (40), 69 (100), 55 (50). Ϫ The H NMR and 13C NMR
1
spectral data are similar to those reported in the literature.[21]
1
B.p 50 °C/1.1 mbar. Ϫ [α]2D5 ϭ Ϫ12.5 (c ϭ 2.79, n-hexane). Ϫ H
NMR: δ ϭ 0.85 (d, 3 H, J ϭ 6.0 Hz), 0.86 (t, 3 H, J ϭ 7.1 Hz),
1.00 (d, 3 H, J ϭ 6.7 Hz), 1.07Ϫ1.46 (m, 9 H), 1.77Ϫ1.85 (m, 1
H), 3.40 (dd, 1 H, J ϭ 6.3 and 10.6 Hz), 3.49 (dd, 1 H, J ϭ 5.2
and 10.6 Hz). Ϫ 13C NMR: δ ϭ 11.4, 17.8, 19.2, 24.3, 29.5, 34.3
(2 C), 35.5, 36.6, 51.4. Ϫ MS (EI); m/z (%): 147 (3) [M35Cl Ϫ
C2H5]ϩ, 119 (34), 111 (49), 83 (76), 69 (100), 57 (73).
(2S,6S)-(؊)-2,6-Dimethyl-1-octanol (SS-8): According to Method
A, the title compound was prepared from 11.1 g (70.2 mmol) of S-
8. The first reaction (conv. ϭ 50%, dep ϭ 73%) gave the ester, which
was hydrolysed and subjected to a second reaction (conv. ϭ 51%,
dep ϭ 94.4%). Workup followed by bulb-to-bulb distillation (b.p.
103 °C/11 mbar) furnished the title alcohol SS-8 (2.55 g, 46% based
on the amount of SS-8 present in S-8), Ͼ 99% pure by GC and
with 97.2% (S) configuration at C-2. Ϫ [α]2D5 ϭ Ϫ2.41 (c ϭ 2.24,
(2R,6S)-1-Chloro-2,6-dimethyloctane (RS-9): Similarly, RS-8
(2.50 g, 15.8 mmol) gave RS-9 (2.42 g, 87%), Ͼ 99% pure by GC.
1
CHCl3), ref.[18] [α]2D0 ϭ Ϫ7.32 (c ϭ 1.68, CHCl3). Ϫ H NMR, 13C
1
B.p 113 °C/7.5 mbar. Ϫ [α]2D5 ϭ ϩ12.3 (c ϭ 1.49, n-hexane). Ϫ H
NMR, and MS (EI) spectral data match those of RR-8.
NMR, 13C NMR and MS (EI) spectral data match those of SR-9.
(2R,6S)-(؉)-2,6-Dimethyl-1-octanol (RS-8): The recovered re-
maining substrate alcohol RS-8 [8.17 g, 51.7 mmol, 68.5% (R) con-
figuration at C-2] obtained from both steps of the above lipase-
catalysed kinetic acylation of S-8 was subjected to Method A. The
reaction was stopped at 60% conversion and worked up as de-
scribed. Bulb-to-bulb distillation (b.p. 90 °C/9 mbar) gave the alco-
hol RS-8 (2.94 g, 53% based on the amount of present RS-8 in S-
8) with a chemical purity of Ͼ 99% and with 99.1% (S) configura-
1-Chloro-2,6-dimethyloctane (9): Similarly, 8 (3.01 g, 19.0 mmol)
gave 9 (2.80 g, 84%), Ͼ 99% pure by GC. B.p. 65 °C/0.3 mbar. Ϫ
1H NMR: δ ϭ 0.85 (d, 3 H, J ϭ 5.7 Hz), 0.86 (t, 3 H, J ϭ 7.1 Hz),
1.00 (d, 3 H, J ϭ 6.7 Hz), 1.07Ϫ1.46 (m, 9 H), 1.75Ϫ1.87 (m, 1
H), 3.41 (dd, 1 H, J ϭ 6.3 and 10.6 Hz), 3.49 (1 H, ddd, J ϭ 0.9,
5.2 and 10.6 Hz). Ϫ 13C NMR: δ ϭ 11.4 (2 C), 17.8 (2 C), 19.2 (2
C), 24.3 (2 C), 29.4, 29.5, 34.3 (3 C), 35.5 (2 C), 36.6, 36.7, 51.3,
51.4. Ϫ MS (EI); m/z (%): 147 (2) [M35Cl Ϫ C2H5]ϩ, 111 (72), 82
tion at C-2. Ϫ [α]2D5 ϭ ϩ18.3 (c ϭ 3.16, CHCl3), ref.[20] [α]2D5
ϭ
358
Eur. J. Org. Chem. 2001, 353Ϫ363

Syntheses of the Sixteen Stereoisomers of 3,7,11-Trimethyl-2-tridecanol
(32), 69 (100), 59 (73). Ϫ (HRMS, EI): [M35Cl Ϫ C2H5]ϩ 147.0961, 4 H, respectively. For spectral and physical data for the individual
FULL PAPER
C8H16Cl requires 147.0941.
stereoisomers, see Table 2.
3,7,11-Trimethyl-2-tridecanol (4H): A known lithiation method[41]
was modified to suit the preparation of 1-lithio-2,6-dimethyloctane.
Accordingly, lithium (400 mg, 57.6 mmol) was washed with n-hept-
ane, flattened to a thin sheet using a hammer, then, under argon,
cut into very thin pieces directly into the reaction vessel and finally
refluxed for 0.08 h in n-hexane (5 mL, freshly distilled and degassed
by argon bubbling for 1 h). The solvent was removed, another 5 mL
of freshly distilled and degassed n-hexane was added and heated to
reflux. Distilled chloride 9 (0.50 g, 2.84 mmol) was added slowly
(0.08 h) via syringe into the reaction flask. GC analysis indicated
full conversion after 3 h. The suspension was cooled to Ϫ78 °C and
taken up in a syringe (leaving the remaining lithium metal behind)
and then added slowly (0.25 h) into a Ϫ78 °C solution of freshly
distilled 3,4-dimethyl-γ-butyrolactone (cis/trans 62:38) (262 mg,
2.30 mmol) in Et2O (5 mL, degassed by argon). The reaction mix-
ture was kept for 10 h at Ϫ78 °C, after which it was quenched with
NH4Cl (3 mL, sat. aq.). The resulting mixture was extracted with
Et2O (5 ϫ 10 mL), dried (MgSO4) and concentrated. LC gave the
oxo alcohol, which was immediately dissolved in distilled diethylene
glycol (7 mL) containing KOH (0.62 g, 11.1 mmol) and hydrazine
monohydrate (0.30 mL, 6.2 mmol). The solution was heated at 170
°C for 1 h and then at 210 °C for 3 h. After cooling, water (2 mL)
was added. Extraction with Et2O (5 ϫ 10 mL), drying (MgSO4)
and concentration furnished a yellow oil, which after LC and distil-
lation (b.p. 95 °C/0.85 mbar) gave the alcohol 4H (0.17 g, 31%
based on the lactone) Ͼ 98% pure and with a erythro/threo ratio
of 58:42 by GC. Ϫ 1H NMR: δ ϭ 0.83Ϫ1.53 (33 H, m), 3.64Ϫ3.75
(m, 1 H). Ϫ 13C NMR: δ ϭ 11.4 (2 C), 14.1, 14.5, 19.2, 19.3, 19.4,
19.7, 20.3, 24.5 (2 C), 24.8, 29.5, 29.6, 32.8 (2 C), 32.9 (2 C), 33.0,
34.4, 36.9, 37.0, 37.3, 37.4, 37.5 (2 C), 39.8 (2 C), 71.4, 71.5, 71.8
(2 C). Ϫ MS (EI); m/z (%): 224 (6) [M Ϫ H2O]ϩ, 140 (12), 125
(90), 111 (49), 97 (58), 85 (72), 71 (87), 57 (100). Ϫ (HRMS, EI):
[M Ϫ H2O]ϩ 224.2464 and [M Ϫ C2H5]ϩ 213.2186, C16H32 requires
224.2504 and 213.2218, respectively.
Preparation of the Propionate Ester of 3,7,11-Trimethyl-2-tridecanol
(4Pr): Propionyl chloride (0.06 mL, 0.83 mmol) was added to a so-
lution of the alcohol (4H) (19.4 mg, 0.08 mmol) in CH2Cl2
(0.5 mL) and the mixture was stirred for 12 h at room temperature.
The crude product was concentrated, chromatographed and dis-
tilled (b.p. 130Ϫ150 °C/1.0 mbar). This furnished the sixteen-com-
ponent mixture of stereoisomers of the product 4Pr (22.1 mg, 92%)
1
Ͼ 98% pure by GC. Ϫ H NMR: δ ϭ 0.83Ϫ1.60 (35 H, m), 2.31
(2 H, q, J ϭ 7.6 Hz), 4.80Ϫ4.87 (m, 1 H). Ϫ 13C NMR: δ ϭ 9.31,
11.4, 17.0, 19.2, 19.3, 24.5, 28.0, 29.5, 29.6, 32.7, 32.8, 34.4, 36.9,
37.0, 37.3, 37.6, 37.7, 73.8, 73.9, 74.0, 174.1. Ϫ MS (EI); m/z (%):
224 (5) [M Ϫ C3H6O2]ϩ, 140 (8), 125 (32), 111 (18), 97 (13), 86
(35), 70 (30), 57 (100). Ϫ (HRMS, EI): [M Ϫ C3H6O2]ϩ 224.2502,
C16H32 requires 224.2504.
Preparation of the Sixteen Stereoisomerically Pure Propionates of
3,7,11-Trimethyl-2-tridecanols: Prepared as above for 4Pr. For spec-
tral and physical data for the individual stereoisomers, see Table 3.
Alternative Method for the Preparation of SS-8 and SR-8
(S)-1-Bromo-2-methylbutane: Br2 (3.64 mL, 68.1 mmol) was added
to a solution of PPh3 (17.9 g, 68.1 mmol) and imidazole (4.32 g,
63.5 mmol) in CH2Cl2 (50 mL) at 0 °C. (2S)-2-Methyl-1-butanol
(4.0 g, 45.4 mmol) {Ͼ 99% ee, [α]2D5 ϭ Ϫ5.65 (c ϭ 10.3, EtOH)}
was added at that temperature and the reaction mixture was al-
lowed to stand overnight. MeOH (1 mL) was poured into the reac-
tion mixture, which was then subjected to LC and bulb-to-bulb
distillation. The title compound was obtained as a colourless oil
(3.95 g, 57%), Ͼ 98.3% pure by GC. B.p 75 °C/120 mbar. Ϫ [α]2D5
ϩ4.17 (neat), ref. [α]2D5 ϭ ϩ3.98 (neat),[42] [α]2D5 ϭ ϩ4.00 (neat).[43]
1H NMR: δ ϭ 0.91 (t, 3 H, J ϭ 7.4 Hz), 1.01 (d, 3 H, J ϭ
ϭ
Ϫ
6.6 Hz), 1.19Ϫ1.78 (m, 3 H), 3.33 (dd, 1 H, J ϭ 6.0 and 9.8 Hz),
3.40 (dd, 1 H, J ϭ 5.2 and 9.8 Hz). Ϫ 13C NMR: δ ϭ 11.2, 18.4,
27.7, 36.9, 41.0. Ϫ MS (EI); m/z (%): 151 (0.2) [M81Br]ϩ, 149 (0.2)
1
[M79Br]ϩ, 71 (100). Ϫ The H NMR and 13C NMR spectral data
are similar to those reported in the literature.[44]
(2S,3S,7S,11R)-, (2S,3S,7S,11S)-, (2S,3S,7R,11S)-, (2S,3S,7R,
11R)-, (2R,3R,7S,11R)-, (2R,3R,7S,11S)-, (2R,3R,7R11S)- and
(2R,3R,7R,11R)-3,7,11-Trimethyl-2-tridecanol (erythro-4H): Sim-
ilarly prepared: The appropriate enantiomer of cis-3,4-dimethyl-γ-
butyrolactone and stereoisomerically pure alkyl chloride (SS-9,
RR-9, SR-9, or RS-9) gave 30Ϫ40% overall yields (based on the
lactone) of the title compounds and with Ͻ 1.2% of threo-4H con-
firmed by GC analysis, except for the (2S,3S,7S,11S) and
(2R,3R,7S,11S) isomers, which were found to contain 2% and 2.1%
of threo-4 H, respectively. For spectral and physical data for the
individual stereoisomers, see Table 2.
(S)-4-Methylhexanoic Acid: Diethyl malonate (5.39 mL,
35.7 mmol) was added to a sodium ethoxide solution [Na (s) 0.78 g,
33.4 mmol dissolved in 25 mL of EtOH] at room temperature and
the solution was refluxed for 0.08 h. After cooling to room temper-
ature, (S)-1-bromo-2-methylbutane (3.87 g, 25.6 mmol) was added.
Overnight reflux, followed by evaporation of the EtOH (15 mL),
gave the crude diethyl (S)-2-(2-methylbutyl)malonate. Hydrolysis
with KOH/MeOH (19 mL, 4.0 ) at reflux overnight, concentration
and treating with Et2O (3 ϫ 25 mL), HCl (5 mL, 6 ), Et2O (5 ϫ
25 mL) and brine (25 mL), drying (MgSO4), and evaporation of
the solvent furnished a crude diacid product, which was heated to
Preparation of (2R,3S,7S,11R)-, (2R,3S,7S,11S)-, (2R,3S,7R,11S)-,
(2R,3S,7R,11R)-, (2S,3R,7S,11R)-, (2S,3R,7S,11S)-, (2S,3R, 190 °C for 4 h. Extractive workup as above furnished the title acid.
7R11S)-, and (2S,3R,7R,11R)-3,7,11-trimethyl-2-tridecanol (threo-
4H): The title compounds were prepared using the Mitsunobu
methodology described by Högberg et al.,[9] but starting from the
Bulb-to-bulb distillation gave a colourless oil (2.58 g, 77%), Ͼ 99%
pure by GC. B.p 85 °C/0.7 mbar. Ϫ [α]2D5 ϭ ϩ10.1 (c ϭ 4.92,
CHCl3), ref. [α]2D2.5 ϭ ϩ10.3 (c ϭ 2.14, CHCl3),[45] [α]2D5 ϭ ϩ10.8
appropriate erythro-3,7,11-trimethyl-2-tridecanols. This gave pure (c ϭ 10.170, CHCl3),[46] [α]2D5 ϭ ϩ10.89 (c ϭ 1, CHCl3),[47] [α]2D5
ϭ
benzoate esters, which were directly hydrolysed to the correspond-
ing alcohols (reflux overnight in a 1:1:1 mixture of 1.2  NaOH in
H2O/MeOH/dioxane). The crude reaction mixtures were extracted
with Et2O (3 ϫ 10 mL), dried (MgSO4), and concentrated. After
LC and bulb-to-bulb distillation, the desired products were ob-
tained as colourless oils, with chemical purities of Ͼ 98% by GC.
All threo isomers were obtained in 50Ϫ60% yield and with Ͻ 1.3%
ϩ10.3 (c ϭ 4.4, CHCl3).[48] 1H NMR: δ ϭ 0.88 (t, 3 H, J ϭ
Ϫ
7.1 Hz), 0.88 (d, 3 H, J ϭ 6.1 Hz), 1.03Ϫ1.76 (m, 5 H), 2.10Ϫ2.46
(m, 2 H), 11.6 (1 H, br. s). Ϫ 13C NMR: δ ϭ 11.3, 18.8, 29.1, 31.2,
32.0, 33.9, 181.0. Ϫ The 1H NMR and 13C NMR spectral data
are similar to those reported in the literature.[49] MS spectral data
matched those reported in the literature.[30] The enantiomeric pur-
ity of the acid (Ͼ 97.5% ee) was determined after derivatisation to
erythro-4H by GC analysis, except for the (2S,3R,7S,11S) and the corresponding phenylethylamide, obtained as described in the
(2R,3S,7S,11S) isomers, which contained 2.2% and 2.3% of erythro-
Eur. J. Org. Chem. 2001, 353Ϫ363
literature[38] from (S)-1-phenylethylamine(Ͼ 99.5% ee). The diaster-
359

M. Larsson, B.-V. Nguyen, H.-E. Högberg, E. Hendenström
Table 2. Spectral and physical data for the sixteen individual 3,7,11-trimethyl-2-tridecanols 4H
FULL PAPER
4H
1H NMR
13C NMR
MS-EI
[α]2D5 (c)
in hexane
B.p.
°C/mbar
RRRR 0.84 (d, 3 H,
J ϭ 6.2 Hz), 0.85 (d, 3 H,
11.4, 14.2, 19.3, 19.8,
20.3, 24.5, 24.8, 29.5,
32.8, 33.0, 34.4, 37.0,
37.3, 37.4, 39.8, 71.4
224 (2) [M Ϫ H2O]ϩ, 140
(10), 125 (68), 111 (43),
97 (45), 85 (53), 71 (73),
57 (100)
ϩ5.51 (0.89)
150/1.6
ϩ5.7 (0.98)[11]
J ϭ 6.4 Hz), 0.86 (t, 3 H,
J ϭ 7.1 Hz), 0.89 (d, 3 H,
J ϭ 6.7 Hz), 1.15 (d, 3 H,
J ϭ 6.4 Hz), 0.93Ϫ1.50 (18 H, m), 3.71 (1 H, dq,
J ϭ 4.2 and 6.3 Hz)
SSSS Same as RRRR
SSSR 0.85 (6 H, d, J ϭ 6.4 Hz), 0.86 (t, 3 H,
J ϭ 6.9 Hz), 0.89 (d, 3 H,
Same as RRRR
Same as RRRR
Ϫ5.78 (0.51)
Ϫ19.9 (0.82)
Ϫ20.0 (1.02)[11]
Same as RRRR
100/0.65
11.5, 14.2, 19.2, 19.7,
20.3, 24.5, 24.8, 29.6,
32.8, 33.0, 34.4, 36.9,
37.3, 37.5, 39.8, 71.4
224 (5) [M Ϫ H2O]ϩ, 140
(9), 125 (10), 111 (15), 97
(15), 85 (71), 71 (93), 57
(100)
J ϭ 6.7 Hz), 1.15 (d, 3 H,
J ϭ 6.4 Hz), 0.96Ϫ1.50
(18 H, m), 3.71 (1 H, dq,
J ϭ 4.2 and 6.4 Hz)
RRRS Same as SSSR
SSRR 0.84 (d, 3 H, J ϭ 6.2 Hz) 0.85 (d, 3 H,
J ϭ 6.4 Hz), 0.86 (t, 3 H,
Same as SSSR
Same as SSSR
ϩ19.4 (1.39)
Ϫ18.9 (0.94)
Same as SSSR
120/1.5
11.4, 14.1, 19.3, 19.7,
20.3, 24.5, 24.7, 29.5,
32.8, 32.9, 34.4, 37.0,
37.3, 37.5, 39.8, 71.5
224 (4) [M Ϫ H2O]ϩ, 140
(7), 125 (53), 111 (32), 97
(33), 85 (57), 71 (73), 57
(80), 45 (100)
J ϭ 6.9 Hz), 0.89 (d, 3 H,
J ϭ 6.7 Hz), 1.15 (d, 3 H,
J ϭ 6.3 Hz), 0.93Ϫ1.50 (18 H, m), 3.71 (1 H, dq,
J ϭ 4.3 and 6.3 Hz)
RRSS Same as SSRR
SRRR 0.84 (d, 3 H, J ϭ 6.2 Hz), 0.85 (d, 3 H,
J ϭ 6.3 Hz), 0.85 (t, 3 H,
Same as SSRR
Same as SSRR
ϩ17.7 (0.33)
ϩ10.4 (0.82)
ϩ10.5 (0.99)[11]
Same as SSRR
140/1.7
11.4, 14.5, 19.3 (2 C),
19.8, 24.5, 24.7, 29.5,
32.8, 32.9, 34.4, 37.0,
37.3, 37.4, 40.1, 71.8
224 (1) [M Ϫ H2O]ϩ, 140
(109, 125 (62), 111 (34),
97 (40), 85 (52), 71 (66),
57 (97), 45 (100)
J ϭ 7.2 Hz), 0.87 (d, 3 H,
J ϭ 6.7 Hz), 1.13 (d, 3 H,
J ϭ 6.3 Hz), 0.93Ϫ1.58 (18 H, m), 3.67 (1 H, dq,
J ϭ 5.4 and 6.3 Hz)
RSSS Same as SRRR
RSRR 0.84 (d, 3 H, J ϭ 6.3 Hz), 0.85 (d, 3 H,
J ϭ 6.3 Hz), 0.86 (t, 3 H,
Same as SRRR
11.4, 14.5, 19.3, 19.4,
19.7, 24.5, 24.6, 29.5, 32.8 (9), 125 (63), 111 (36), 97
Same as SRRR
Ϫ11.1 (1.30)
Ϫ22.0 (0.93)
Same as SRRR
150/1.7
224 (3) [M Ϫ H2O]ϩ, 140
J ϭ 7.4 Hz), 0.87 (d, 3 H,
J ϭ 6.6 Hz), 1.13 (d, 3 H,
(2 C), 34.4, 37.0, 37.3,
37.5, 40.0, 71.8
(42), 85 (56), 71 (73), 57
(96), 45 (100)
J ϭ 6.3 Hz), 0.90Ϫ1.55 (18 H, m), 3.66 (1 H, dq,
J ϭ 5.4 and 6.3 Hz)
SRSS Same as RSRR
SRSR 0.84 (d, 3 H, J ϭ 6.6 Hz), 0.85 (d, 3 H,
J ϭ 6.5 Hz), 0.86 (t, 3 H,
Same as RSRR
Same as RSRR
ϩ21.1 (1.47)
ϩ11.3 (1.14)
Same as RSRR
110/0.6
11.4, 14.5, 19.2, 19.4,
19.6, 24.5, 24.7, 29.6,
32.7, 32.8, 34.4, 36.9,
37.4, 37.5, 40.0, 71.8
224 (2) [M Ϫ H2O]ϩ, 140
(10), 125 (75), 111 (34),
97 (47), 85 (56), 71 (81),
57 (100)
J ϭ 7.4 Hz), 0.87 (d, 3 H,
J ϭ 6.8 Hz), 1.13 (d, 3 H,
J ϭ 6.3 Hz), 0.99Ϫ1.55 (18 H, m), 3.66 (1 H, dq,
J ϭ 5.5 and 6.3 Hz)
RSRS Same as SRSR
RSSR 0.84 (d, 3 H, J ϭ 6.6 Hz), 0.85 (d, 3 H,
J ϭ 6.2 Hz), 0.85 (t, 3 H,
Same as SRSR
Same as SRSR
Ϫ10.7 (1.37)
Ϫ25.8 (0.90)
Same as SRSR
110/0.46
11.4, 14.5, 19.2, 19.3,
19.7, 24.5, 24.7, 29.6,
32.8, 32.9, 34.4, 36.9,
37.3, 37.5, 40.1, 71.8
224 (1) [M Ϫ H2O]ϩ, 140
(8), 125 (71), 111 (43), 97
(45), 85 (59), 71 (75), 57 (100)
J ϭ 7.0 Hz), 0.87 (d, 3 H,
J ϭ 6.5 Hz), 1.13 (d, 3 H,
J ϭ 6.3 Hz), 1.00Ϫ1.55 (18 H, m), 3.67 (1 H, dq,
J ϭ 5.4 and 6.3 Hz)
SRRS Same as RSSR
RRSR 0.84 (6 H, d, J ϭ 6.5 Hz), 0.86 (t, 3 H,
J ϭ 6.4 Hz), 0.89 (d, 3 H,
Same as RSSR
Same as RSSR
ϩ25.0 (1.47)
ϩ6.94 (0.98)
Same as RSSR
120/1.3
11.4, 14.1, 19.2, 19.6,
20.3, 24.5, 24.8, 29.6,
32.7, 32.9, 34.4, 36.9,
224 (6) [M Ϫ H2O]ϩ, 140
(7), 125 (75), 111 (45), 97
(47), 85 (63), 71 (85), 57 (100)
J ϭ 6.7 Hz), 1.15 (d, 3 H,
J ϭ 6.3 Hz), 0.99Ϫ1.49 (18 H, m), 3.71 (1 H, dq, 37.4, 37.5, 39.8, 71.5
J ϭ 4.3 and 6.4 Hz)
SSRS Same as RRSR
Same as RRSR
Same as RRSR
Ϫ6.60 (1.25)
Same as RRSR
eoisomeric ratio of the amide was determined using a 30 m ϫ (1.94 g, 86%) Ͼ 99% pure by GC. B.p 45 °C/1.1 mbar. Ϫ [α]2D5
0.25 mm I.D capillary column coated with β-dex 120, df ϭ 0.25
ϩ7.64 (c ϭ 4.01, CHCl3), ref. [α]2D3 ϭ ϩ8.62 (c ϭ 3.65, CHCl3),[50]
µm, carrier gas He 15 psi, split ratio 30:1; retention time (min): [α]2D5 ϭ ϩ8.5 (c ϭ 1.16, CHCl3).[51] Ϫ H NMR: δ ϭ 0.87 (t, 3 H,
ϭ
1
131.7 and 133.1 min for the amide diastereomers.
J ϭ 7.2 Hz), 0.87 (d, 3 H, J ϭ 6.4 Hz), 1.09Ϫ1.65 (8 H, m), 3.63
(t, 2 H, J ϭ 6.7 Hz). Ϫ 13C NMR: δ ϭ 11.4, 19.1, 29.4, 30.4, 32.5,
34.3, 63.5. Ϫ MS (EI); m/z (%): 115 (3) [M Ϫ 1]ϩ, 99 (32) [M Ϫ
(S)-4-Methyl-1-hexanol: A solution of (S)-4-methylhexanoic acid
(2.54 g, 19.5 mmol, 97.5% ee) in dry Et2O (10 mL) was added drop-
wise to LiAlH4 (0.74 g, 19.5 mmol) in dry Et2O (15 mL) at room
temperature. After stirring overnight, the reaction was quenched
with HCl (5 mL, 2 ). Extractive workup with Et2O (3 ϫ 25 mL)
and brine (1 ϫ 20 mL), drying (MgSO4), and concentration fol-
1
OH]ϩ, 98 (15) [M Ϫ OH2]ϩ, 70 (64), 69 (54), 57 (100). Ϫ The H
NMR spectral data is similar to that reported in the literature.[52,53]
(S)-1-Iodo-4-methylhexane: According to the methodology of
Smith et al.,[54] (S)-4-methyl-1-hexanol (1.94 g, 6.7 mmol) was ad-
lowed by LC and bulb-to-bulb distillation gave the title compound ded to a mixture of triphenylphosphane (6.13 g, 23.4 mmol) and
360 Eur. J. Org. Chem. 2001, 353Ϫ363

Syntheses of the Sixteen Stereoisomers of 3,7,11-Trimethyl-2-tridecanol
Table 3. Spectral data for the sixteen individual propionates 4Pr obtained from the individual 3,7,11-trimethyl-2-tridecanols
FULL PAPER
4Pr
1H NMR
13C NMR
MS-EI
RRRR
0.84 (6 H, d, J ϭ 6.3 Hz), 0.85 (t, 3 H,
J ϭ 6.7 Hz), 0.90 (d, 3 H,
J ϭ 6.8 Hz), 1.14 (t, 3 H,
9.3, 11.4, 14.8, 17.0, 19.3, 19.8, 24.5 (2 C),
28.0, 29.5, 32.7, 32.8, 34.4, 37.0,
37.3, 37.4, 37.6, 73.8, 174.2
224 (4) [M Ϫ C3H6O2]ϩ, 140
(5), 125 (30), 111 (15), 97
(11), 86 (28), 69 (20), 57 (100)
J ϭ 7.6 Hz), 1.16 (d, 3 H,
J ϭ 6.4 Hz), 0.93Ϫ1.63 (17 H, m),
2.31 (2 H, q, J ϭ 7.6 Hz),
4.85 (1 H, dq, J ϭ 4.8 and 6.4 Hz)
Same as RRRR
0.84 (6 H, d, J ϭ 6.5 Hz), 0.85 (t, 3 H,
J ϭ 6.8 Hz), 0.90 (d, 3 H,
SSSS
SSSR
Same as RRRR
Same as RRRR
9.3, 11.4, 14.8, 17.0, 19.2, 19.7, 24.5
(2 C), 28.0, 29.6, 32.7, 32.8, 34.4, 36.9,
37.3, 37.4, 37.7, 73.8, 174.2
224 (3) [M Ϫ C3H6O2]ϩ, 140
(5), 125 (30), 111 (15), 97
(10), 86 (35), 69 (20), 57 (100)
J ϭ 6.8 Hz), 1.14 (t, 3 H,
J ϭ 7.6 Hz), 1.16 (d, 3 H,
J ϭ 6.4 Hz), 0.99Ϫ1.63
(17 H, m), 2.31 (2 H, q, J ϭ 7.6 Hz), 4.85
(1 H, dq, J ϭ 4.8 and 6.4 Hz)
Same as SSSR
0.84 (6 H, d, J ϭ 6.4 Hz), 0.85 (t, 3 H,
J ϭ 6.1 Hz), 0.89 (d, 3 H,
J ϭ 6.8 Hz), 1.14 (t, 3 H, J ϭ 7.6 Hz), 1.16 (d, 3 H,
J ϭ 6.4 Hz), 0.96Ϫ1.60
RRRS
SSRR
Same as SSSR
Same as SSSR
9.31, 11.4, 14.8, 17.0, 19.3, 19.7, 24.5
(2 C), 28.0, 29.5, 32.7 (2 C), 34.4, 37.0,
37.2, 37.5, 37.6, 73.9, 174.1
224 (3) [M Ϫ C3H6O2]ϩ, 140
(6), 125 (32), 111 (17), 97
(12), 86 (33), 69 (25), 57 (100)
(17 H, m), 2.31 (2 H, q, J ϭ 7.6 Hz), 4.84 (1 H, dq,
J ϭ 4.9 and 6.3 Hz)
Same as SSRR
0.84 (6 H, d, J ϭ 6.0 Hz), 0.85 (t, 3 H,
J ϭ 7.0 Hz), 0.88 (d, 3 H,
J ϭ 6.8 Hz), 1.13 (d, 3 H, J ϭ 6.4 Hz),
1.14 (t, 3 H, J ϭ 7.6 Hz),
RRSS
SRRR
Same as SSRR
Same as SSRR
9.28, 11.4, 14.6, 15.8, 19.3, 19.8, 24.5
(2 C), 28.0, 29.5, 32.8, 33.0, 34.4, 37.0,
37.3 (3 C), 74.0, 174.1
224 (5) [M Ϫ C3H6O2]ϩ, 140
(9), 125 (30), 111 (13), 97
(11), 86 (33), 69 (25), 57 (100)
0.92Ϫ1.73 (17 H, m), 2.30 (2 H, q, J ϭ 7.6 Hz),
4.82 (1 H, app. quint, J ϭ 6.4 Hz)
Same as SRRR
0.84 (6 H, d, J ϭ 6.5 Hz), 0.85 (t, 3 H,
J ϭ 7.3 Hz), 0.88 (d, 3 H,
J ϭ 6.8 Hz), 1.13 (d, 3 H, J ϭ 6.4 Hz),
1.14 (t, 3 H, J ϭ 7.6 Hz),
RSSS
RSRR
Same as SRRR
Same as SRRR
9.28, 11.4, 14.6, 15.9, 19.3, 19.7, 24.5
(2 C), 28.0, 29.5, 32.7, 32.9, 34.4, 37.0,
37.2, 37.3, 37.5, 74.1, 174.1
224 (5) [M Ϫ C3H6O2]ϩ, 140
(7), 125 (32), 111 (18), 97
(12), 86 (37), 69 (20), 57 (100)
0.93Ϫ1.71 (17 H, m), 2.31 (2 H, q, J ϭ 7.6 Hz), 4.82
(1 H, app. quint, J ϭ 6.4 Hz)
Same as RSRR
0.84 (6 H, d, J ϭ 6.7 Hz), 0.85 (t, 3 H,
J ϭ 7.5 Hz), 0.88 (d, 3 H,
J ϭ 6.8 Hz), 1.13 (d, 3 H, J ϭ 6.4 Hz),
1.14 (t, 3 H, J ϭ 7.6 Hz),
SRSS
SRSR
Same as RSRR
Same as RSRR
9.28, 11.4, 14.6, 15.9, 19.2, 19.6, 24.5
(2 C), 28.0, 29.6, 32.7, 32.9, 34.4, 36.9,
37.3 (2 C), 37.4, 74.1, 174.1
224 (4) [M Ϫ C3H6O2]ϩ, 140
(6), 125 (30), 111 (15), 97
10), 86 (35), 70 (27), 57 (100)
0.92Ϫ1.70 (17 H, m), 2.31 (2 H, q, J ϭ 7.6 Hz),
4.82 (1 H, app. quint, J ϭ 6.2 Hz)
Same as SRSR
0.84 (6 H, d, J ϭ 6.4 Hz), 0.85 (t, 3 H,
J ϭ 7.1 Hz), 0.88 (d, 3 H,
J ϭ 6.8 Hz), 1.13 (d, 3 H, J ϭ 6.4 Hz),
1.14 (t, 3 H, J ϭ 7.6 Hz), 1.04Ϫ1.71
(17 H, m), 2.31 (2 H, q, J ϭ 7.6 Hz), 4.82 (1 H, app. quint,
J ϭ 6.4 Hz)
RSRS
RSSR
Same as SRSR
Same as SRSR
9.28, 11.4, 14.6, 15.8, 19.2, 19.7, 24.5
(2 C), 28.0, 29.6, 32.7, 32.9, 34.4, 36.9,
37.3 (2 C), 37.4, 74.1, 174.1
224 (5) [M Ϫ C3H6O2]ϩ, 140
(7), 125 (30), 111 (12), 97 (9),
86 (38), 69 (23), 57 (100)
SRRS
RRSR
Same as RSSR
0.84 (6 H, d, J ϭ 6.5 Hz), 0.85 (t, 3 H,
J ϭ 6.5 Hz), 0.89 (d, 3 H,
J ϭ 6.8 Hz), 1.13 (t, 3 H, J ϭ 7.6 Hz), 1.16
(d, 3 H, J ϭ 6.4 Hz), 1.02Ϫ1.63
(17 H, m), 2.31 (2 H, q, J ϭ 7.6 Hz), 4.84 (1 H, dq,
J ϭ 4.9 and 6.4 Hz)
Same as RSSR
Same as RSSR
9.31, 11.4, 14.8, 17.0, 19.2, 19.6, 24.5
(2 C), 28.0, 29.6, 32.6, 32.7, 34.4, 36.9,
37.3, 37.4, 37.6, 73.9, 174.2
224 (3) [M Ϫ C3H6O2]ϩ, 140
(8), 125 (33), 111 (12), 97
(12), 86 (39), 69 (24), 57 (100)
SSRS
Same as RRSR
Same as RRSR
Same as RRSR
imidazole (1.71 g, 25.1 mmol) in CH2Cl2 (25 mL) at 0 °C. Iodine δ ϭ 7.65, 11.3, 19.1, 29.3, 31.3, 33.7, 37.4. Ϫ MS (EI); m/z (%):
(6.79 g, 26.7 mmol) was added and after 5 h of stirring the reaction
was quenched with methanol (1 mL). Extractive workup with
197 (1), 169 (4), 155 (3), 141 (2), 99 (8), 57 (100).
Na2S2O3 (aq. sat., 10 mL), Et2O (3 ϫ 25 mL) and brine (20 mL), (2S,6S)-N-[(1R,2R)-N-(2-Hydroxy-1-methyl-2-phenyl-
followed by concentration and LC, gave the product (3.09 g, 82%),
ethyl]-N,2,6-trimethyloctanamide: A solution of n-butyllithium in
hexane (16.6 mL, 26.6 mmol, 1.6 ) was added to a suspension of
lithium chloride (dried under vacuum at 150 °C for 14 h in the
Ͼ 99% pure by GC. B.p. 40 °C/0.8 mbar. Ϫ [α]2D5 ϭ ϩ10.2 (c ϭ
1
2.47, hexane), ref.[55] [α]2D5 ϭ ϩ3.63 (neat). Ϫ H NMR: δ ϭ 0.87
(t, 3 H, J ϭ 7.1 Hz), 0.87 (d, 3 H, J ϭ 6.1 Hz), 1.10Ϫ1.47 (m, 5 reaction flask, 3.94 g, 93.0 mmol) and dry diisopropylamine
H), 1.73Ϫ1.90 (m, 2 H), 3.18 (t, 2 H, J ϭ 7.0 Hz). Ϫ 13C NMR:
(4.00 mL, 28.6 mmol) in dry THF (25 mL) at Ϫ78 °C. The solution
Eur. J. Org. Chem. 2001, 353Ϫ363
361

M. Larsson, B.-V. Nguyen, H.-E. Högberg, E. Hendenström
FULL PAPER
was warmed to room temperature for 0.08 h and then cooled to
Acknowledgments
Ϫ78 °C. (R,R)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N-methyl-
We wish to thank Mr. Fredrik Andersson for the synthesis of the
(2S,6R)-2,6-dimethyl-1-octanol. The research was supported by the
Swedish Natural Science Research Council (NFR), Swedish Coun-
cil for Forestry and Agricultural Research (SJFR) and the Com-
mission of the European Communities, Agriculture and Fisheries
(FAIR), specific RTD programme, contract No. FAIR1 Ϫ CT95-
0339, ‘‘Pine sawfly pheromones for sustainable management of
European forests’’ (This study does not necessarily reflect the Com-
mission’s view and in no way anticipates its future policies in this
area).
propionamide {[α]2D5
ϭ Ϫ100.4 (c ϭ 0.57, MeOH), 3.08 g,
13.9 mmol} in dry THF (50 mL) at 0 °C was added via cannula at
such a speed that the temperature did not exceed Ϫ60 °C. The
mixture was kept at Ϫ78 °C for 1 h and then allowed to reach ϩ16
°C for 0.17 h, followed by lowering the temperature to Ϫ40 °C.
To this mixture, (4S)-1-iodo-4-methylhexane (1.5 g, 6.64 mmol) was
added neat and the reaction mixture was left stirring overnight.
The reaction was quenched with NH4Cl (aq. sat., 20 mL) and the
resulting mixture was extracted with EtOAc (6 ϫ 70 mL), dried
with Na2SO4, and concentrated. The crude product was diluted
with 50 mL of n-hexane and the crystalline starting material was
filtered off. The product was isolated by LC, which yielded the
octylamide as a viscous, yellow oil (1.83 g, 86%) Ͼ 98% pure by
GC. Ϫ [α]2D5 ϭ Ϫ46.0 (c ϭ 2.61, MeOH). Ϫ 1H NMR (asterisk
denotes minor rotamer peaks): δ ϭ 0.83 (d, 3 H, J ϭ 6.0 Hz), 0.85
(t, 3 H, J ϭ 7.2 Hz), 1.01Ϫ1.63 (m, 9 H), 1.09 (d, 3 H, J ϭ 6.8 Hz),
1.14 (d, 3 H, J ϭ 6.9 Hz), 2.6 0 (sext, 1 H, J ϭ 6.6 Hz), 2.85 (s, 2
H), 2.92* (s, 1 H), 3.74 (1 H, br. s), 4.00Ϫ4.18* (0.3 H, m),
4.33Ϫ4.49 (0.7 H, m), 4.58Ϫ4.63 (m, 1 H), 7.23Ϫ7.35 (m, 5 H). Ϫ
13C NMR (asterisk denotes minor rotamer peaks): δ ϭ 11.4, 14.5,
15.5*, 17.4, 18.0*, 19.2, 19.3*, 24.9, 25.1*, 29.3*, 29.5, 33.3, 34.2,
34.3, 35.9*, 36.6, 36.7, 36.8*, 58.0*, 59.3, 75.5*, 76.6, 126.3,
126.9*, 127.5, 128.3, 128.7*, 141.1*, 142.6, 178.1*, 179.3. Ϫ MS
(CI, CH3CN); m/z (%): 320 (100) [M ϩ H]ϩ, 303 (3), 302 (8), 148
(24). Ϫ C20H33NO2: C 75.2; H 10.4; N 4.4; found C 74.8; H 10.5;
N 4.4.
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75.5*, 76.5, 126.3, 126.9*, 127.5, 128.3, 128.7*, 141.2*, 142.6,
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303 (10), 302 (75), 148 (12).
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