First asymmetric synthesis of stigmolone: The fruiting body inducing pheromone of the myxobacterium Stigmatella aurantiaca

Article abstract of DOI:10.1055/s-2000-8219

The asymmetric synthesis of (S)- and (R)-stigmolone [(S)- and (R)-1], an aggregation pheromone of the myxobacterium Stigmatella aurantiaca, starting from 4-methylpentan-2-one is described. The stereogenic centre at the C-5 position of the pheromone was generated via the SAMP/RAMP hydrazone method with high enantiomeric purity. It could be shown again that both enantiomers induce the fruiting body formation of the myxobacterium at concentrations of 1.0-30.0 nM.

Full text of DOI:10.1055/s-2000-8219

1848
SPECIAL TOPIC
First Asymmetric Synthesis of Stigmolone: The Fruiting Body Inducing
Pheromone of the Myxobacterium Stigmatella Aurantiaca
Dieter Enders,* André Ridder
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8888127; E-mail: Enders@RWTH-Aachen.de
Received 10 July 2000
We now want to present the first asymmetric synthesis of
Abstract: The asymmetric synthesis of (S)- and (R)-stigmolone
(S)- and (R)-stigmolone [(S)- and (R)-1] and describe the
[(S)- and (R)-1], an aggregation pheromone of the myxobacterium
results for the bioassays, which were carried out by Plaga.
Stigmatella aurantiaca, starting from 4-methylpentan-2-one is de-
scribed. The stereogenic centre at the C-5 position of the pheromone
was generated via the SAMP/RAMP hydrazone method with high
enantiomeric purity. It could be shown again that both enantiomers
induce the fruiting body formation of the myxobacterium at concen-
trations of 1.0-30.0 nM.
O
CH3
CH3
O
CH3
CH3
H3C CH3
HO
H3C CH3
HO
CH3
(S)-1
CH3
(R)-1
Key words: asymmetric synthesis, pheromones, hydrazones, natu-
ral products, Stigmatella aurantiaca
The target molecule contains one stereogenic centre re-
sulting from the methyl branching at the C-5 position a to
the carbonyl group. Therefore, the RAMP/SAMP hydra-
zone method10 was chosen to generate both enantiomers
of the pheromone based on either enantiomer of the chiral
auxiliary. As shown in the Scheme, 4-methylpentan-2-
one (2) was treated with (R)-1-amino-2-(methoxy-
methyl)pyrrolidine (RAMP), both commercially avail-
able, under azeotropic removal of water giving the corre-
sponding RAMP-hydrazone (R)-3 in virtually quantitative
yield after distillation.11 The regioselective deprotonation
of (R)-3 was achieved with LDA at 0 °C and after reaction
with 1-bromo-3-methylbut-2-ene at -78 °C RAMP-hy-
drazone (R)-4, was isolated in an excellent 93% yield. The
regioselective introduction of the C-5 stereogenic centre
was next investigated. As expected from steric and stere-
oelectronic effects, the homoallylic methylene group at C-
5 and not the methylene group at C-3 was regioselectively
metalated with LDA for 24 h and alkylated with methyl
iodide at -100 °C. The hydrazone (S,R)-5 was obtained
after chromatographic purification in 48% yield. For the
regioselective metalation the use of a sterically demand-
ing base is as important as the metalation temperature of
-78 °C. Product hydrazones may be isomerised to the
thermodynamically more stable E-form, prior to deter-
mining the de. In this case such isomerisation did not
readily occur. Therefore the epimer (R,R)-5 was synthe-
sised through synthon control10 in a test run by reversing
the order of the electrophile addition. Comparative 13C
NMR analysis established the diastereomeric excess of
(S,R)-5 to be greater than 85%. In addition the de-value
could be increased by HPLC to ≥ 99%.
Myxobacteria like Stigmatella aurantiaca are Gram-neg-
ative, sticklike soil bacteria, which live in swarms on in-
soluble polymer surfaces like rotten wood. Gliding in a
swarm has an immense profit for the food intake. This is
due to an increase in the local density of secreted hydro-
lytic enzymes and therefore the amount of available solu-
ble nutrients. The swarm and also the secreted slime
serves as a carpet which prevents the loss of enzymes and
nutrients. Typically for myxobacteria, S. aurantiaca ex-
ists in two different life cycles. In the vegetative growth
cycle the population rises like normal bacteria through
cell division, but under conditions of starvation the bacte-
ria form multicellular fruiting bodies.1, 2 These fruiting
bodies have a treelike structure and contain the myxo-
spores, which are dormant cells. The change from the veg-
etative growth to the so-called development cycle is in-
duced by the aggregation pheromone 8-hydroxy-2,5,8-
trimethylnonan-4-one, which is named stigmolone after
its biological origin and structure according to Plaga et al.
Furthermore, this group published the first isolation3, 4 as
well as a synthesis5 of the racemate of this pheromone.
The natural product was isolated in racemic form perhaps
due to the extensive isolation and purification procedures
and the sensitivity of a-substituted ketones to racemisa-
tion. Plaga et al. also discovered an active concentration
of 1.0 nM for the fruiting body formation, which makes
this pheromone one of the most effective, non-peptidic
bacterial pheromones known.4 Mori et al. reported an ’ex-
chiral-pool’ synthesis starting either with (R)- or (S)-cit-
ronellol shortly after the first publication of stigmol-
one.6, 7 The bioassay of the enantiomers showed the same
active concentration for the fruiting body formation as for
the racemate and therefore the natural product seemed to
be an enantiomeric mixture.8 For further biological tests
Mori et al. developed a new and short synthesis of the ra-
cemic pheromone.9
The formation of ketone (S)-6 was attained by hydrolytic
cleavage using copper(II) chloride.12 The product was iso-
lated in 59% yield and an enantiomeric excess greater
than 93%, attributed to partial racemisation during cleav-
Synthesis 2000, No. 13, 1848–1851 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
First Asymmetric Synthesis of Stigmolone
1849
age. This ketone was also an intermediate in the synthesis
of racemic 1 by Plaga et al.5 In this work, rac-6 was con-
verted to the Markovnikov alcohol by treatment with tri-
fluoroacetic acid followed by alkaline workup, which is
not compatible with our asymmetric synthesis. In addi-
tion, under these conditions there was always a partial for-
mation of a dihydropyran via a lactol intermediate, which
was also discovered in Mori’s approaches.5, 7, 9 Yamada et
al. recently published a neutral oxidation-reduction hy-
dration using oxygen and bis(1,1,1-trifluoropentane-2,4-
dionato)cobalt(II) (Co(tfa)2)13 as catalyst for the hydration
of various alkenes according to the Markovnikov
rules.14, 15 Pleasingly, application of these conditions to
unsaturated ketone (S)-6 yielded (S)-stigmolone in 75%
yield without detectable racemisation. No dihydropyran
and no lactol formation was detected by NMR analysis.
As Yamada et al. noted, it must be reiterated that an effi-
cient azeotropic removal of the reaction water is necessary
to obtain a good yield. Furthermore, our system needs a
higher amount of catalyst (50 mol%), perhaps due to par-
tial chelation. Similarly, we synthesised the enantiomer
(R)-1 with 89% ee starting from 4-methylpentan-2-one (2)
using SAMP as chiral auxiliary. In this case the diastere-
oisomeric excess of the alkylation was also excellent.
(R,S)-5 was isolated in 71% yield and ≥ 95% de. The
SAMP-hydrazone cleavage was achieved using ammoni-
um dihydrogen phosphate buffer according to a method
developed by Carlsen et al. for dimethylhydrazone cleav-
age.16 This method afforded the ketone (R)-6 in 23% yield
and 92% ee. Finally, comparison of the rotation values
with those given in the literature7 confirms the absolute
configurations given and is in accordance with the estab-
lished mechanism for the SAMP/RAMP-hydrazone alkyl-
ations.
O
CH3
CH3
O
CH3
CH3
H3C CH3
HO
H3C
2
CH3
(S)-1
a
quant.
ee = 93%
OCH3
CH3
CH3
e
75%
O
N
N
CH3
CH3
CH3
H3C
H3C
(R)-3
CH3
(S)-6
b
93%
d
59%
OCH3
CH3
CH3
OCH3
CH3
CH3
N
N
CH3
N
CH3
N
c
48%
H3C
H3C
(R)-4
CH3
(S,R)-5
via
SAMP
O
CH3
CH3
O
CH3
CH3
H3C CH3
HO
H3C
2
CH3
(R)-1
ee = 89%
Reagents and conditions: (a) RAMP/benzene, p-TsOH (cat.), reflux
(b) LDA/THF, 0 °C, 5 h then 1-bromo-3-methylbut-2-ene, -78 °C to
r.t. (c) LDA/THF, -78 °C, 24 h then CH3I, -100 °C to r.t. (d) 1M
CuCl2/THF (e) Co(tfa)2, O2, i-PrOH, reflux, 5 h.
Scheme
The biological tests of the two enantiomers (S)- and (R)-1
were carried out by Plaga under normal bioassay
conditions4 and showed again that both enantiomers in-
duced the fruiting body formation at concentrations of
1.0-30.0 nM in the same way as the racemate. Due to the
high enantiomeric purity of the pheromones we concluded
that there are two possible interpretations for the biotest
results. Firstly, the bacterium does not differ between the
enantiomers or secondly, there is a racemisation during
the biotest. At this moment we are not able to give a final
answer.
Aldrich. Preparative column chromatography: Merck silica gel 60,
particle size 0.040-0.063 mm (230-400 mesh, flash). Analytical
TLC: Silica gel 60 F254 plates, Merck, Darmstadt. Optical rotation
values were measured on a Perkin-Elmer P241 polarimeter, sol-
vents used were of Merck UVASOL-quality. Microanalyses were
obtained from a Heraeus CHN-O-RAPID element analyzer.
HR-MS: Finnigan MAT 95. Mass spectra: Finnigan MAT 212 (CI
100 eV; EI 70 eV). IR spectra: Perkin-Elmer FT/IR 1750. 1H NMR
spectra (300 and 400 MHz), 13C NMR (75 and 100 MHz): Gemini
300 or Varian Inova 400 (CDCl3 as solvent, TMS as internal stan-
dard).
In conclusion, we have achieved the first asymmetric syn-
thesis of both enantiomers of the fruiting body inducing
pheromone from the myxobacterium S. aurantiaca. The
yield over five steps of (S)-1 (ee = 93%) was 18% (20%
based on recovered starting material) and of (R)-1
(ee = 89%) was 6% (18% based on recovered starting ma-
terial) from 2.
(R)-N2-[2-Methoxymethyltetrahydro-1H-1-pyrrolyl]-4-methyl-
2-pentan-2-imine [(R)-3]
To a solution of RAMP (6.51 g, 50 mmol) and p-TsOH (0.05 g, cat.)
in benzene (50 mL) was added 4-methylpentan-2-one (2) (12.52
mL, 100 mmol) and the mixture was refluxed overnight using a
Dean-Stark trap. After cooling the mixture, the solvent and excess
of 2 were evaporated and the crude product purified by distillation
under reduced pressure to yield hydrazone (R)-3 as a colourless liq-
uid; yield: 10.62 g (quantitative); bp 82 °C/1mbar (Lit.17: 83 °C/
1Torr).
1H NMR (400 MHz) (E/Z-isomeric mixture): d = 0.88-0.95 (m, 6
H, CH(CH3)2), 1.60-1.71 (m, 1 H, CH(CH3)2), 1.77-1.86 (m, 2 H,
NCHCH2CH2), 1.89, 1.91 (2 s, 3 H, NCCH3), 1.90-2.53 (m, 5 H,
NCHHCH2CH2, NCCH2CH, NCHHCH2CH2), 3.08-3.26 (m, 3 H,
All reagents were of commercial quality used from freshly opened
containers. Solvents were dried and purified by conventional meth-
ods prior to use. THF was freshly distilled from sodium/lead alloy
under Ar. BuLi (1.5 M in hexane) was purchased from Merck,
Darmstadt. Cobalt(II) chloride hexahydrate was purchased from
Synthesis 2000, No. 13, 1848–1851 ISSN 0039-7881 © Thieme Stuttgart · New York

1850
D. Enders, A. Ridder
SPECIAL TOPIC
NCH, CHHO, NCHHCH2CH2), 3.32, 3.33 (2 s, 3 H, OCH3), 3.35-
3.45 (m, 1 H, CHHO).
13C NMR (100 MHz) (E/Z-major isomer): d = 17.84 (NCCH3),
22.07 (NCH2CH2), 22.19, 22.54 (CH(CH3)2), 26.30 (CH(CH3)2),
26.61 (NCHCH2CH2), 48.04 (NCCH2), 53.98 (NCH2), 59.17
(OCH3), 66.16 (NCH), 75.54 (CH2O), 166.02 (NC).
ed slowly and the yellow solution was maintained for 24 h at this
temperature. Afterwards the solution was cooled to -100 °C and
then CH I (2.55 g, 17.98 mmol) was gradually added to the solu-
3
tion. The mixture was maintained for 5 h at this temperature, then
was allowed to warm to r.t. over a period of 15 h and finally was
quenched with sat. aq NH4Cl (4.5 mL). The aqueous phase was ex-
tracted with Et2O (3 x 75 mL), the combined organic extracts
washed with brine (10 mL), dried (MgSO4) and concentrated in vac-
uo. Purification by flash chromatography (silica gel; pentane/Et2O,
10:1, containing 1% Et3N; Rf 0.23) gave (S,R)-5; yield: 1.271 g
(48%); de ≥ 85% (13C NMR); further purification by HPLC (Merck
Fertigsäule) gave (R)-6 in ≥ 99% de.
The other analytical data were consistent with the data given in the
literature.17
(S)-N2-[2-Methoxymethyltetrahydro-1H-1-pyrrolyl]-4-methyl-
pentan-2-imine [(S)-3]
In the same manner as described above 2 (4.70 g, 36.1 mmol) was
converted to (S)-3 (7.10 g, 93%) using SAMP as chiral auxilary.
The analytical data were identical with those of the (R)-isomer.
IR (capillary in CHCl3): n = 3372, 2956, 2925, 2870, 1627, 1459,
1377, 1365, 1278, 1198, 1185, 1129, 1101, 1048, 974, 950, 922,
879, 758 cm-1.
1H NMR (400 MHz) (E/Z-isomeric mixture): d = 0.91 (d, 6 H,
(R)-N4-[2-Methoxymethyltetrahydro-1H-1-pyrrolyl]-2,8-dime-
thylnon-7-en-4-imine [(R)-4]
3
3JH-H = 6.6 Hz, CH(CH3)2), 1.00 (d, 3 H, JH-H = 7.1 Hz,
4
NCCHCH3), 1.60 (broad d, JH-H = 0.8 Hz, 3 H, CCH3, (Z)), 1.61-
To a cooled solution (0 °C) of diisopropylamine (0.78 mL, 5.5
mmol) in anhyd THF (30 mL) under Ar was slowly added BuLi (1.5
M in hexane, 3.67 mL, 5.5 mmol) and the mixture was stirred for 30
min. (R)-3 (1.061 g, 5.0 mmol) was added slowly and stirring main-
tained at 0 °C for 5 h. The resulting yellow solution was cooled to
-78 °C and 1-bromo-3-methylbut-2-ene (0.82 g, 5.5 mmol) was
added dropwise. The mixture was allowed to warm to r.t. over a pe-
riod of 15 h and was quenched with sat. aq NH4Cl (5 mL). The
aqueous phase was extracted with Et2O (3 x 75 mL), the combined
organic extracts washed with brine (10 mL), dried (MgSO4) and
concentrated in vacuo. Distillative purification gave hydrazone (R)-
4 as a colourless liquid; yield: 1.30 g (93%); bp 92 °C/0.02mbar.
2.08 (m, 8 H, NCHCH2CH2, NCHCH2CH2, CHCH2CH, NCCH2),
4
1.68 (broad d, 3 H, JH-H = 1.1 Hz, CCH3, (E)), 2.10-2.15 (m, 1 H,
3
CH(CH3)2), 2.43 (q, 1 H, JH-H = 8.8 Hz, NCHH), 2.97 (m, 1 H,
NCHH), 3.09-3.21 (m, 2 H, NCH, CHHO), 3.34 (s, 3 H, OCH3),
3.39 (m, 1 H, CHHO), 3.53 (broad s, 1 H, NCCHCH3), 5.01 (t/m, 1
H, 3JH-H = 6.9 Hz, CCH).
13C NMR (100 MHz) (E/Z-major isomer): d = 17.09 (NCCHCH3),
17.86 (CCH3, (Z)), 21.76 (NCH2CH2), 22.52, 22.90 (CH(CH3)2),
25.49 (CCH3, (E)), 25.71 (CH(CH3)2), 26.38 (NCH2CH2CH2), 32.15
(CHCH2CH), 35.05 (NCCH), 40.14 (NCCH2), 55.11 (NCH2), 59.02
(OCH3), 65.85 (NCH), 75.30 (CH2O), 122.37 (CCH), 132.31
(CCH), 174.95 (NC).
IR (capillary in CHCl3): n = 3775, 2957, 2925, 2871, 2827, 2730,
1630, 1461, 1383, 1344, 1282, 1198, 1128, 1054, 973, 923, 532
cm-1.
MS (CI, isobutane): m/z (%) = 296 (16), 295 (100, M++1), 293 (5),
263 (4, -CH3O), 249 (2), 181 (6).
1H NMR (300 MHz) (E/Z-isomeric mixture): d = 0.90 (d, 3 H, 3JH-
H = 6.6 Hz, CH3CHCH3), 0.91 (d, 3 H, 3JH-H = 6.6 Hz, CH3CHCH3),
1.62 (broad s, 3 H, CCH3, (Z)), 1.62-2.54 (m, 12 H, NCHCH2CH2,
NCHCH2CH2, CCHCH2, NCCH2CH2, NCCH2CH, CH(CH3)2,
NCHH), 1.69 (broad d, 3 H, 4JH-H = 1.1 Hz, CCH3, (E)), 3.03 (m, 1
H, NCHH), 3.09-3.17 (m, 1 H, NCH), 3.17-3.24 (m, 1 H, CHHO),
3.33 (s, 3 H, OCH3), 3.37-3.42 (m, 1 H, CHHO), 5.09 (t/m, 1 H,
3JH-H = 7.0 Hz, CCH).
+
HRMS: m/z calcd for C16H29N2 (M -CH2OCH3): 249.2331.
Found: 249.2334.
(2’S,5R)-N4-[2’-Methoxymethyltetrahydro-1H-1-pyrrolyl]-
2,5,8-trimethylnon-7-en-4-imine [(R,S)-5]
In the same manner as described above (S)-4 (1.84 g, 6.57 mmol)
was converted to (R,S)-5 (1.38 g, 71%); de ≥ 95% (13C NMR). The
analytical data were identical to those of the (S,R)-isomer.
13C NMR (100 MHz) (E/Z-major isomer): d = 17.65 (CCH3, (Z)),
21.94 (NCH2CH2), 22.27, 22.66 (CH(CH3)2), 24.90 (CCHCH2),
25.63 (CCH3, (E)), 26.32 (CH(CH3)2), 26.71 (NCH2CH2CH2), 30.73
(NCCH2CH2), 44.98 (NCCH2CH), 54.89 (NCH2), 59.06 (OCH3),
65.80 (NCH), 75.57 (CH2O), 123.49 (CCH), 131.97 (CCH), 170.90
(NC).
(S)-2,5,8-Trimethylnon-7-en-4-one [(S)-6]
To a cooled solution (0 °C) of (S,R)-5 (0.842 g, 2.86 mmol) in THF
(30 mL) was added slowly 1 M copper(II) chloride (3.43 mL) and
the mixture was stirred for an additional 15 min at this temperature.
The mixture was allowed to warm to r.t., stirred for 15 h and
quenched with sat. aq NH4Cl (30 mL). The aqueous phase was ex-
tracted with Et2O (3 x 75 mL), the combined organic extracts
washed with brine (10 mL), dried (MgSO4) and concentrated in vac-
uo. Purification of the reddish crude product by flash chromatogra-
phy (silica gel; pentane/Et2O, 20:1; Rf 0.64) gave the colourless
liquid (S)-6; 0.308 g (59%); ee ≥ 93%; GC-CSP (column: Lipodex
G 25 m, 60-1-140, H2 = 1 bar, tR = 16.6 min). Further elution gave
(S,R)-5 (0.070 g, 8%). The yield based on recovered starting mate-
rial was 64%. [a]D25 = +28.2 (c = 1.26, CHCl3).
MS (CI, isobutane): m/z (%) = 282 (15), 281 (100, M+ +1), 279 (7),
249 (7, -CH3O), 235 (18), 167 (11), 125 (6), 70 (1, M+
+1).
dihydropyrrole
+
HRMS: m/z calcd for C15H27N2 (M -CH2OCH3): 235.2174.
Found: 235.2174.
(S)-N4-[2-Methoxymethyltetrahydro-1H-1-pyrrolyl]-2,8-dime-
thylnon-7-en-4-imine [(S)-4]
In the same manner as described above (S)-3 (1.0 g, 4.71 mmol) was
converted to (S)-4 (1.18 g, 89%). The analytical data were identical
to those of the (R)-isomer.
1H NMR (300 MHz): d = 0.90 (d, 6 H, 3JH-H = 6.6 Hz, CH(CH3)2),
3
1.04 (d, 3 H, JH-H = 6.9 Hz, COCHCH3), 1.60 (broad s, 3 H,
CCH3, (Z)), 1.69 (broad d, 3 H, 4JH-H = 1.1 Hz, CCH3, (E)), 2.02 (broad
3
3
quin, 1 H, JH-H = 7.4 Hz, CCHCHH), 2.15 (sep, 1 H, JH-H = 6.7
Hz, CH(CH3)2), 2.29 (broad quin, 1 H, CCHCHH), 2.31 (d, 2 H,
(2’R,5S)-N4-[2’-Methoxymethyltetrahydro-1H-1-pyrrolyl]-
2,5,8-trimethylnon-7-en-4-imine [(S,R)-5]
To a cooled solution (0 °C) of diisopropylamine (1.37 mL, 9.9
mmol) in anhyd THF (50 mL) under Ar was added slowly BuLi (1.5
M in hexane, 6.7 mL, 9.9 mmol) and the mixture was stirred for 30
min before cooling to -78 °C. (R)-4 (2.521 g; 8.99 mmol) was add-
3JH-H = 6.6 Hz, COCH2), 2.50 (sep,
1 H, JH-H = 6.9 Hz,
3
COCHCH3), 5.04 (t/m, 1 H, 3JH-H = 7.4 Hz, CCH).
13C NMR (75 MHz): d = 16.08 (COCHCH3), 17.90 (CCH3, (Z)),
22.73 (CH3CHCH3), 22.75 (COCH2CH), 24.31 (CH3CHCH3),
Synthesis 2000, No. 13, 1848–1851 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
First Asymmetric Synthesis of Stigmolone
1851
25.87 (CCH3, (E)), 31.56 (CCHCH2), 46.96 (COCH), 50.67
(COCH2), 121.76 (CCHCH2), 133.49 (CCHCH2), 214.32 (CO).
(HOCCH3, (Z)), 29.26 (HOCCH3, (E)), 41.19 (HOCCH2), 46.80
(COCHCH3), 50.30 (COCH2), 70.77 (HOC), 214.41 (CO).
Anal. calcd. for C12H22O (182.2): C 79.06, H 12.16. Found: C 79.24,
H 12.26.
MS (EI): m/z (%) = 185 (16, M+ -CH3), 182 (38, M+ -H2O), 167
(11), 164 (5), 149 (5), 141 (8, M+-C3H7O+), 127 (37), 125 (39), 115
(14), 114 (52), 111 (13), 109 (10), 103 (41), 99 (6), 98 (9), 97 (67),
95 (5), 91 (10), 86 (5), 85 (84), 74 (7), 73 (9), 72 (36), 71 (25), 70
(15), 69 (32), 59 (59), 58 (19), 57 (97), 56 (100), 55 (42), 49 (5), 45
(25).
The other analytical data were consistent with those given in the lit-
erature.5
(R)-2,5,8-Trimethylnon-7-en-4-one [(R)-6]
The other analytical data were consistent with those given in the lit-
erature.5, 7
Hydrazone (R,S)-5 (1.296 g, 4.40 mmol) was dissolved in THF (4.4
mL), sat. aq ammonium dihydrogen phosphate (176 mL) was added
and the solution was stirred at r.t. for 94 h. The aqueous phase was
extracted with Et2O (4 x 100 mL), the combined organic extracts
washed with brine (20 mL), dried (MgSO4) and concentrated in vac-
uo. Purification by flash chromatography (silica gel; pentane/Et2O,
20:1; Rf 0.64) yielded the colourless liquid (R)-5; 0.183 g (23%);
ee ≥ 92%; GC-CSP (column: Lipodex G 25 m, 60-1-140, H2 = 1
bar, tR = 16.2 min). Further elution gave (R,S)-5 (0.932 g, 72%).
The yield based on recovered starting material was 81%.
[a]D25 = - 26.9 (c = 1.30, CHCl3).
(R)-8-Hydroxy-2,5,8-trimethylnonan-4-one [(R)-1]
In the same manner as described above (R)-5 (0.115 g; 0.631 mmol)
was converted to (R)-1 (0.059 g, 47%); ee ≥ 89%; GC-CSP (col-
umn: Lipodex G 25 m, 50-1-80-3-190, H2 = 1 bar, tR = 175.7 min).
[a]D25 = - 9.1 (c = 0.69, CHCl3). (Lit.7 [a]D22 = - 7.85 (c = 0.53,
CHCl3).
The other analytical data were identical with those of the (S)-enan-
tiomer.
The other analytical data were identical with those of the (S)-iso-
mer.
Acknowledgement
Bis(1,1,1-trifluoropentane-2,4-dionato)cobalt(II) [Co(tfa)2]
To a emulsion of 1,1,1-trifluoropentane-2,4-dione (3.08 g, 20
mmol) in H2O (29 mL) was added aq NaOH (2 M, 10 mL). After
stirring for 30 min at r.t. an aqueous solution (10 mL) of cobalt(II)
chloride hexahydrate (2.38 g, 10.0 mmol) was added and stirring
was maintained for 1 h. The resulting precipitate was filtered and
washed with H2O (3 x 30 mL). The resulting red powder was dried
in vacuo at 90 °C for 6 h to give Co(tfa)2, which was used in the next
step without any further purification; yield: 1.849 g (51%).
We thank Dr. W. Plaga for carrying out the bioassays and also for
interesting discussions. This work was supported by the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie.
We thank Degussa AG, BASF AG and Bayer AG for the donation
of chemicals.
References
(1) Dworkin, M. Microbiol. Rev. 1996, 60, 70.
(2) Losick, R.; Kaiser, D. Sci. Am. 1997, 2, 52.
(3) Hull, W. E.; Berkessel, A.; Stamm, I.; Plaga, W. Abstract of
Papers, 24th Annual Meeting on the Biology of the
Myxobacteria. New Braunfels, Texas, USA 1997, p. 25.
(4) Plaga, W.; Stamm, I.; Schairer, H. U. Proc. Natl. Acad. Sci.
USA 1998, 95, 11263.
IR (KBr): n = 3431, 1619, 1535, 1460, 1367, 1297, 1232, 1192,
1142, 862, 789, 731, 581 cm-1.
MS (CI, isobutane): m/z (%) = 406 (6), 367 (7), 366 (100, M+ +1),
295 (5), 155 (7, ligand +1).
The other analytical data were consistent with those given in the lit-
erature.13
(5) Hull, W. E.; Berkessel, A.; Plaga, W. Proc. Natl. Acad. Sci.
USA 1998, 95, 11268.
(S)-8-Hydroxy-2,5,8-trimethylnonan-4-one [(S)-1]
(6) Mori, K. Eur. J. Org. Chem. 1998, 1479.
(7) Mori, K.; Takenaka, M. Eur. J. Org. Chem. 1998, 2181.
(8) Morikawa, Y.; S. Takayama, S.; Fudo, R.; Yamanaka, S.;
Mori, K.; Isogai, A. FEMS Microbiol. Lett. 1998, 165, 29.
(9) Domon, K.; Mori, K. Eur. J. Org. Chem. 1999, 979.
(10) Enders, D. In Asymmetric Synthesis, Vol. 3B; Morrision, J. D.,
Ed.; Academic: Orlando 1984; p 275.
(11) Corey, E. J.; Enders, D. Chem. Ber. 1978, 111, 1337.
(12) Enders, D.; Hundertmark, T.; Lazny, R. Synth. Commun.
1999, 29, 27.
(13) Holm, R. H.; Cotton, F. A. J. Inorg. Chem. 1960, 15, 63.
(14) Kato, K.; Yamada, T.; Takai, T.; Inoki, S.; Isayama, S. Bull.
Chem. Soc. Jpn. 1990, 63, 179.
(15) Mukaiyama, T.; Yamada, T. Bull. Chem. Soc. Jpn. 1995, 68,
17.
To a solution of Co(tfa)2 (0.183 g, 0.5 mmol) in i-PrOH (20 mL)
was added a solution of (S)-6 (0.182 g, 1.0 mmol) in i-PrOH (10
mL). A Soxhlet apparatus with a thimble containing molecular
sieves (4 Å, 1.0 g) was fitted and compressed air was bubbled
through the mixture at reflux. After 5 h the volatiles were removed
in vacuo. Purification by flash chromatography (silica gel; pentane/
Et2O, 1:1; Rf 0.41) gave (S)-1; yield: 0.151 g (75%); ee ≥ 93%; GC-
CSP (column: Lipodex G 25 m, 50-1-80-3-190, H2 = 1 bar,
tR = 176.4 min); [a]D25 = +8.3 (c = 1.05, CHCl3). (Lit.7
[a]D22 = +7.63 (c = 0.51, CHCl3).
1H NMR (400 MHz): d = 0.90, 0.91 (2 x d, 6 H, 3JH-H = 6.6 Hz and
3
3JH-H = 6.8 Hz, CH3CHCH3), 1.08 (d, 3 H, JH-H = 7.1 Hz,
COCHCH3), 1.21 (d, 6 H, 4JH-H = 1.1 Hz, CH3COHCH3), 1.32 (s, 1
H, COH), 1.35-1.46 (m, 3 H, HOCCH2CHH, HOCCH2CHH),
3
1.66-1.78 (m, 1 H, HOCCH2CHH), 2.16 (sep/m, 1 H, JH-H = 6.6
(16) Ulven, T.; Sørbye, K. A.; Carlsen, H. J. Acta Chem. Scand.
1997, 51, 1041.
(17) Schmitz, T. Dissertation, RWTH Aachen 1990.
Hz, CH3CHCH3), 2.26-2.38 (m, 2 H, COCH2), 2.42-2.51 (m, 1 H,
COCH).
13C NMR (75 MHz): d = 16.47 (COCHCH3), 22.62, 22.69
(CH3CHCH3), 24.21 (CH3CHCH3), 27.30 (COCHCH2), 29.20
Article Identifier:
1437-210X,E;2000,0,13,1848,1851,ftx,en;E10100SS.pdf
Synthesis 2000, No. 13, 1848–1851 ISSN 0039-7881 © Thieme Stuttgart · New York