Pheromone synthesis, CXCIII. - Simple synthesis of (±)-stigmolone (8- hydroxy-2,5,8-trimethyl-4-nonanone), the pheromone of Stigmatella aurantiaca

Article abstract of DOI:10.1002/(SICI)1099-0690(199905)1999:5<979::AID-EJOC979>3.0.CO;2-C

The racemic myxobacterial pheromone (±)-1 (stigmolone), which induces the formation of the fruiting body of Stigmatella aurantiaca, was synthesized from methyl isobutyl ketone (2) in 48% overall yield in four steps.

Full text of DOI:10.1002/(SICI)1099-0690(199905)1999:5<979::AID-EJOC979>3.0.CO;2-C

FULL PAPER
Pheromone Synthesis, CXCIII[°]
Simple Synthesis of (؎)-Stigmolone (8-Hydroxy-2,5,8-trimethyl-4-nonanone),
the Pheromone of Stigmatella aurantiaca
Kenji Domon[a] and Kenji Mori*[a]
Keywords: Ketones / Myxobacterium / Pheromones / Stigmatella aurantiaca / Stigmolone
The racemic myxobacterial pheromone (±)-1 (stigmolone),
which induces the formation of the fruiting body of
Stigmatella aurantiaca, was synthesized from methyl isobutyl
ketone (2) in 48% overall yield in four steps
Stigmatella aurantiaca, a species of myxobacteria, pro-
duces a pheromone which induces the formation of its fruit-
ing body. In 1997 Hull et al. isolated and identified the
pheromone as 8-hydroxy-2,5,8-trimethyl-4-nonanone (1)
with unknown absolute configuration at C-5.[1] Our syn-
thesis of both (R)- and (S)-1[2] enabled Morikawa et al. to
determine that both enantiomers of 1 are bioactive.[3] More
interestingly, they proved the stereochemical heterogeneity
of the naturally occurring 1. Indeed, the natural pheromone
is a mixture of (R)- and (S)-1.[3] This means that (±)-1 is
satisfactory for further biological studies of the pheromone.
We report in the present paper a simple and efficient syn-
thesis of (±)-1. After the completion of this work, Plaga
and his co-workers published two papers on the isolation
and synthesis of 1, giving the name “stigmolone” to it.[4][5]
Scheme 1 summarizes our synthetic route to (±)-stigmo-
lone (1). Methoxycarbonylation of methyl isobutyl ketone
(2) furnished the β-oxo ester 3. By employing potassium
tert-butoxide in tert-butyl alcohol as the base, 3 was first
methylated and further alkylated with 3-methyl-3-butenyl
iodide[6] to give (±)-4 in satisfactory yield. When sodium
methoxide or sodium hydride was used as the base, (±)-4
could not be obtained in good yield. Krapcho demeth-
oxycarbonylation[7] of (±)-4 with lithium chloride in wet
dimethyl sulfoxide (DMSO) afforded the olefinic ketone
(±)-5. Conventional hydrolytic decarboxylation of (±)-4 was
unsuccessful. Finally, oxymercuration-demercuration[8] of
(±)-5 yielded a mixture of the target molecule (±)-1 and
Scheme 1. Synthesis of (±)-1; reagents: (a) NaH, CO(OMe)2, dry
dioxane (95%); (b) (i) tBuOK, MeI, tBuOH, (ii) tBuOK, 3-methyl-
3-butenyl iodide, tBuOH (83%); (c) LiCl, DMSO, H2O, 170°C
(89%); (d) (i) Hg(OAc)2, THF, H2O, (ii) NaBH4, NaOH, H2O
(68%)
Experimental Section
Boiling points: Uncorrected values. Ϫ IR: Jasco A-102. Ϫ 1H
NMR: Jeol JNM-EX 90A (90 MHz) and Bruker DPX 300 (300
MHz) (TMS at δ ϭ 0.00 or CHCl3 at δ ϭ 7.26 as an internal
standard). Ϫ 13C NMR: Bruker DPX 300 (75.5 MHz) (CDCl3 at
δ ϭ 77.0 as an internal standard). Ϫ MS: Jeol JMS-SX 102A and
Hitachi M-80B. Ϫ CC: Merck Kieselgel 60 Art 1.07734. Ϫ TLC:
0.25 mm Merck silica gel plates (60F-254).
1
its hemiacetal (2RS,3SR)-6.[2] The IR, H- and 13C-NMR
Methyl 5-Methyl-3-oxohexanoate (3): To a stirred and heated (un-
der reflux) suspension of NaH (60% in mineral oil, 9.78 g, 245
mmol) in CO(OMe)2 (25.2 mL, 293 mmol) and dry dioxane (60
mL), a solution of 2 (10.5g, 105 mmol) in dry dioxane (15 mL) was
slowly added dropwise under argon. The mixture was stirred and
spectral properties of (±)-1 are in good accord with those
of (R)- and (S)-1.[2]
In conclusion, a four-step synthesis of (±)-stigmolone (1)
was achieved in 48% overall yield based on methyl isobutyl
ketone (2). The synthesis by Hull et al. was reported to give heated under reflux for 2 h and cooled. It was then quenched with
(±)-1 in 16% overall yield based on isovaleraldehyde.[5] Our
ice/water, neutralized with 1  hydrochloric acid and extracted with
diethyl ether. The organic layer was washed with water, a satd. so-
dium hydrogen carbonate solution and brine, dried with mag-
nesium sulfate and concentrated in vacuo. The residue was distilled
sample of (±)-1 was supplied to Dr. S. Yamanaka, whose
work may reveal more about the biological function of 1.
[°]
Part CXCII: H. Tamagawa, H. Takikawa, K. Mori, Eur. J. Org.
Chem. 1999, 973Ϫ978.
to give 15.8 g (95%) of 3 as an oil; b.p. 81°C/10 Torr, nD25 ϭ 1.4146.
Ϫ IR (film): ν˜ ϭ 1750 cmϪ1 (s, CϭO), 1720 (s, CϭO), 1650 (m),
1630 (m). Ϫ 1H NMR (90 MHz, CDCl3): δ ϭ 0.91 (d, J ϭ 6.5 Hz,
6 H, 5-Me, 6-H3), 1,65Ϫ2.44 (m, 3 H, 5-H, 4-H2), 3.41 (s, 2 H, 2-
H2), 3.71 (s, 3 H, OMe), 4.95 (s, 0.1 H, 2-H of the enol form), 11,98
[a]
Department of Chemistry, Faculty of Science, Science Univer-
sity of Tokyo, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-8601,
Japan
Fax: (internat.) ϩ 81-3/3235-2214
Eur. J. Org. Chem. 1999, 979Ϫ980
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0505Ϫ0979 $ 17.50ϩ.50/0
979

K. Domon, K. Mori
(s, 0.1 H, 3-OH of the enol form). Ϫ C8H14O3 (158.2): calcd. C Then sodium hydroxide (3 , ca. 4 mL) was added to the mixture,
FULL PAPER
60.74, H 8.92; found C 60.57, H 8.68.
and sodium tetrahydroborate (334 mg, 7.96 mmol) in 3  sodium
hydroxide (5 mL) was added slowly. It was then added sodium chlo-
ride and the mixture was extracted with diethyl ether. The ethereal
extract was washed with water and brine, dried with magnesium
sulfate, and concentrated in vacuo. The residue was purified by
chromatography on silica gel (20 g, hexane/ethyl acetate,
20:1Ϫ10:1) to give 689 mg (48%) of (±)-5 and 565 mg [35%, 68%
based on the consumed (±)-5] of (±)-1 as a colorless oil, b.p.
(±)-Methyl
2,5-Dimethyl-2-(3-methyl-3-butenyl)-3-oxohexanoate
[(±)-4]: To a solution of potassium tert-butoxide (3.55 g, 31.6
mmol) in dry tert-butyl alcohol (18 mL), 3 (5.00 g, 31.6 mmol) was
added dropwise at 50°C under argon. Methyl iodide (2.00 mL, 31.6
mmol) was added dropwise to the mixture, and the mixture was
stirred and heated under reflux for 1 h. A solution of potassium
tert-butoxide (3.55 g, 31.6 mmol) in dry tert-butyl alcohol (18 mL)
was added dropwise to the mixture, and the mixture was heated
under reflux for 30 min. Then 3-methyl-3-butenyl iodide (9.30 g,
4.74 mmol) was added dropwise, and the mixture was stirred under
reflux for 1 h. It was then poured into ice/satd. ammonium chloride
solution and extracted with diethyl ether. The ethereal extract was
washed with water and brine, dried with magnesium sulfate, and
concentrated in vacuo. The residue was chromatographed on silica
gel (150 g, hexane/ethyl acetate, 50:1) to give 6.34 g (83%) of (±)-4
23
113Ϫ115°C/0.4 Torr; nD ϭ 1.4485. Ϫ IR(film): ν˜ ϭ 3450 cmϪ1
(s, OϪH), 2960 (s, CϪH), 2870 (s, CϪH), 1710 (s, CϭO), 1455 (m,
CϪH), 1365 (m), 1215 (w), 1170 (m, CϪO), 1035 (m), 950 (m), 920
1
(m), 905 (m). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.905 (d, J ϭ
6.6 Hz, 3 H, 1-H3), 0.909 (d, J ϭ 6.6 Hz, 3 H, 2-Me), 1.08 (d, J ϭ
7.0 Hz, 3 H, 5-Me), 1.21 (s, 6 H, 8-Me, 9-H3), 1.35Ϫ1.47 (m, 3 H,
7-H2, OH), 1.59Ϫ1.78 (m, 2 H, 6-H2), 2.09Ϫ2.20 (m, 1 H, 2-H),
2.28Ϫ2.33 (m, 2 H, 3-H2), 2.43Ϫ2.49 (m, 1 H, 5-H). Ϫ 13C NMR
(75.5 MHz, CDCl3): δ ϭ 16.4, 22.5, 22.6, 24.1, 27.2, 29.1, 41.1,
46.7, 50.2, 70.6, 214.4 [signals due to (±)-1]; small signals due to
(2RS,3SR)-6 were also observable; these spectral data are in good
accord with those reported for (R)- and (S)-1. Ϫ C12H24O2
(200.32): calcd. C 71.95, H 12.08; found C 71.57, H 11.88. Ϫ
HMRS (C12H24O2 Ϫ H2O): calcd. 182.1671; found 182.1670.
25
as a colorless oil; nD ϭ 1.4434. Ϫ IR (film): ν˜ ϭ 3080 cmϪ1 (m,
CϭC-H), 1740 (s, CϭO), 1710 (s, CϭO), 1650 (m, CϭC), 890
1
(m, ϭCH2). Ϫ H NMR (90 MHz, CDCl3): δ ϭ 0.89 (d, J ϭ 6.2
Hz, 6 H, 6-H3, 5-Me), 1.20Ϫ2.21 (m, 5 H, 5-H 1Ј-H2, 2Ј-H2), 1.34
(s, 3 H, 2-Me), 1.73 (br. s, 3 H, 3Ј-Me), 2.21Ϫ2.40 (m, 2 H, 4-H2),
3.72 (s, 3 H, OMe), 4.71 (br. s, 2 H, 4Ј-H2). Ϫ This compound was
employed in the next step without further purification.
(±)-2,5,8-Trimethyl-8-nonen-4-one [(±)-5]: To a solution of (±)-4
(2.50 g, 10.4 mmol) in dimethyl sulfoxide (15 mL) and H2O (0.2
mL) was added lithium chloride (880 mg, 20.8 mmol). The mixture
was stirred at 170°C for 1.5 h. It was then poured into water and
extracted with diethyl ether. The ethereal extract was washed with
water and brine, dried with magnesium sulfate, and concentrated
in vacuo. The residue was chromatographed on silica gel (50 g,
hexane/ethyl acetate, 20:1) and then distilled to give 1.70 g (89%)
of (±)-5 as a colorless oil; b.p. 84Ϫ84.5°C/12.5 Torr, nD25 ϭ 1.4189.
Ϫ IR (film): ν˜ ϭ 3080 cmϪ1 (m, CϭCϪH), 1710 (s, CϭO), 1650
(m, CϭC), 890(m, ϭCH2). Ϫ 1H NMR (90 MHz, CDCl3): δ ϭ
0.91 (d, J ϭ 6.4 Hz, 6 H, 1-H3, 2-Me), 1.06 (d, J ϭ 6.9 Hz, 3 H,
5-Me), 1.19Ϫ2.68 (m, 8 H, 2-H, 3-H2, 5-H, 6-H2, 7-H2), 1.71 (br.
s, 3 H, 8-Me), 4.68 (br. s, 2 H, 9-H2). ϪThis ketone was too volatile
to give correct combustion analytical data. Ϫ HMRS (C12H22O):
calcd. 182.1670; found 182.1669.
Acknowledgments
We thank Dr. S. Yamanaka (Ajinomoto Co., Inc., Kawasaki) for
discussion. This work was financially supported by the Ajinomoto
Co., Inc.
[1]
W. E. Hull, A. Berkessel, J. Stamm, W. Plaga, Abstract of papers,
24th International Conference on the Biology of the Myxobac-
teria, New Braunfels, Texas, USA, 1997, p. 25.
[2]
K. Mori, M. Takenaka, Eur. J. Org. Chem. 1998, 2181Ϫ2184.
[3]
Y. Morikawa, S. Takayama, R. Fudo, S. Yamanaka, K. Mori,
A. Isogai, FEMS Microbiol. Lett. 1998, 165, 29Ϫ34.
[4]
W. Plaga, I. Stamm, H. U. Schairer, Proc. Natl. Acad. Sci. USA
1998, 95, 11263Ϫ11267.
[5]
W. E. Hull, A. Berkessel, W. Plaga, Proc. Natl. Acad. Sci. USA
1998, 95, 11268Ϫ11273.
[6]
A. F. Houri, Z. Xu, D. A. Cogan, and A. H. Hoveyda, J. Am.
Chem. Soc. 1995, 117, 2743Ϫ2744.
[7]
A. P. Krapcho, Synthesis 1982, 805Ϫ822.
(±)-Stigmolone [8-Hydroxy-2,5,8-trimethyl-4-nonanone, (±)-1]: To a
stirred solution of (±)-5 (1.45 g, 7.96 mmol) in THF (8 mL) and
H2O (8 mL) was added mercury(II) acetate (2.56 g, 7.96 mmol).
After addition, the mixture was stirred at room temp. for 6 min.
[8]
H. C. Brown, P. Geoghegan, Jr., J. Am. Chem. Soc. 1967, 89,
1522Ϫ1524.
Received December 8, 1998
[O98550]
980
Eur. J. Org. Chem. 1999, 979Ϫ980