An efficient total synthesis of (±)-laurene

Article abstract of DOI:10.1039/a706510h

A short and efficient total synthesis of (±)-laurene using a Wittig olefination-Claisen rearrangement-Wacker oxidation protocol is described.

Full text of DOI:10.1039/a706510h

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An efficient total synthesis of ( )-laurene
Mukund G. Kulkarni*,† and Dhananjay S. Pendharkar
Department of Chemistry, University of Pune, Pune 411 007, India
A short and efficient total synthesis of ( )-laurene using
a Wittig olefination–Claisen rearrangement–Wacker oxid-
ation protocol is described.
(1:1) diastereomeric mixture of cyclopent-2-enone 5 was
obtained in good yield (90%) when the keto aldehyde 4 was
treated with KOH (5% in aqueous methanol) at ambient tem-
perature for 2 h. Hydrogenation of the cyclopent-2-enone 5
over 5% Pd/C at ambient temperature afforded the cyclo-
pentanone 6 as a mixture of diastereomers (1:1) in 97% yield.
On subjecting this cyclopentanone 6 to Lambardo methylen-
ation conditions5 (Zn, TiCl4, CH2Br2 room temp., 12 h) a 1:1
mixture of ( )-laurene 1 and ( )-epilaurene 7 was obtained in
80% yield.
Laurene 1, a sesquiterpene isolated from Laurentia glandulifera1
is structurally related to the cuparane class of sesquiterpenes.
Like other members of this class, laurene has significant steric
crowding around a compact cyclopentane ring. Several strat-
egies2 have been adopted for the synthesis of this sterically con-
gested molecule. We report herein a short and efficient synthesis
of ( )-laurene (Scheme 1) adopting the Wittig olefination
methodology3 developed in our laboratory.
Experimental
O
General
O
CHO
All solvents were distilled before use. Dry THF was prepared by
distillation over benzophenone and sodium under an argon
atmosphere, and toluene was distilled and stored over sodium
wire. All the anhydrous reactions were carried out under an
argon atmosphere. IR Spectra were recorded on a Perkin-Elmer
a
b
74%
95%
2
3
1
model 1600 series FTIR instrument. H NMR Spectra [ppm,
c
82%
TMS internal standard; J values in Hz] in CDCl3 were recorded
on a JEOL FX90Q instrument and a Bruker AC-200 instru-
ment. Elemental analysis was obtained on a HOSLI semiauto-
matic C, H analyser. Silica gel (100–200) mesh was used for
column chromatography.
O
O
CHO
e
d
97%
90%
1-But-2-enyloxy-2-(4-methylphenyl)-2-methylethene 2
O
But-2-enyloxymethylenetriphenylphosphonium chloride (4.98
g, 13 mmol) and 4-methylacetophenone (1.34 g, 10 mmol) were
suspended in dry THF (20 cm3). Potassium tert-butoxide (1.5 g,
13 mmol) in tert-butyl alcohol (10 cm3) was added to it at 0 ЊC
in a dropwise manner. The mixture was stirred at 0 ЊC for 1 h.
Then the reaction mixture was diluted with water and extracted
with diethyl ether (3 × 50 cm3). The combined ether extracts
were washed with water, dried over anhyd. Na2SO4 and concen-
trated. The crude product on purification by column chrom-
atography using hexane as eluent furnished pure 2 (E:Z 1:1)
(1.49 g, 74%) as a colourless liquid (Found: C, 83.04; H, 9.07;
C14H18O requires C, 83.12; H, 8.97%); νmax(film)/cmϪ1 1638,
1500, 1435, 1371, 950 and 795; δH(90 MHz; CDCl3) 1.82 (3 H, d,
6
4
5
f
80%
+
1
7
Scheme 1 Reagents and conditions: a, CH3(H)C᎐C(H)CH2OCH2Pϩ-
᎐
Ph3ClϪ, ButOϪKϩ, THF, 0 ЊC; b, toluene reflux, 18 h; c, PdCl2 (10
mol%), CuCl2 (10 mol%), O2, H2O:DME (1:9), room temp., 2 h; d, 5%
aq. methanolic KOH, room temp., 2 h; e, 5% Pd/C ethyl acetate, H2 (1
atm pressure), room temp., 8 h; f, Zn, CH2Br2, TiCl4, THF, 0 ЊC, 12 h
J 5.1, C᎐C᎐CH ), 2.21, 2.62, (3 H, s, E and Z C᎐C᎐CH ), 2.25
᎐
᎐
3
3
(3 H, s, Ar᎐CH ), 4.50 (2 H, m, O᎐CH ᎐CH᎐), 5.96 (2 H, m,
᎐
3
2
CH᎐CH), 6.45, 6.68 (1 H, s, E and Z O᎐CH᎐C), 7.4 to 7.91 (4
᎐
᎐
H, m, Ar᎐H).
On treating a suspension of 4-methylacetophenone (1.0
equiv.) and but-2-enyloxymethylenetriphenylphosphonium
chloride3 (1.0 equiv.) in dry THF with potassium tert-butoxide
(1.5 equiv.) the allyl vinyl ether 2 was obtained in 74% yield.
This allyl vinyl ether 2, on heating in refluxing toluene for 18 h,
smoothly underwent Claisen rearrangement to yield the
unsaturated aldehyde 3 in 95% yield. The 1H NMR spectrum of
this aldehyde showed it to be a 3:2 mixture of diastereomers.
Wacker oxidation4 (10 mol% PdCl2, 10 mol% CuCl2, oxygen
atmosphere) of this diastereomeric mixture of the aldehyde 3 in
H2O:DME (1:9) at ambient temperature furnished the keto
aldehyde 4 as a mixture of diastereomers (1:1) in 82% yield. A
2-(4-Methylphenyl)-2,3-dimethylpent-4-enal 3
Colourless oil 95% bp 162 ЊC/8 Torr (Found: C, 83.19; H, 8.85.
C14H18O requires C, 83.12; H, 8.97%); νmax(film)/cmϪ1 2710.1,
1724.3 and 1636.9; δH(90 MHz; CDCl3) 0.76 (2 H, d, J 7.7,
CH᎐CH3), 1.00 (1 H, d, J 7.7, CH᎐CH3), 1.34 (2 H, s, C᎐CH3),
1.52 (1 H, s, C᎐CH3), 2.53 (3 H, s, Ar᎐CH3), 3.08 (1 H, m,
CH᎐CH ), 5.10 (2 H, m, CH᎐CH ), 5.29 to 5.95 (1 H, m,
᎐
3
2
CH᎐CH ), 7.23 (4 H, s, Ar᎐H), 9.63 (1 H, s, CHO).
᎐
2
2-(4-Methylphenyl)-2,3-dimethyl-4-oxovaleraldehyde 4
In a solution of unsaturated aldehyde 3 (0.8 g, 4 mmol) in
aqueous dimethoxyethane (10 cm3, 1:9) was suspended PdCl2
(0.071 g, 0.4 mmol) and CuCl2 (0.05 g, 0.4 mmol). This mixture
† E-Mail: mgkul@chem.unipune.ernet.in
J. Chem. Soc., Perkin Trans. 1, 1997
3127

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was stirred at room temp. under an oxygen atmosphere. On
completion of reaction (TLC check, 3 h), the mixture was
diluted with water and extracted with diethyl ether (3 × 25 cm3).
The combined ether layer was washed with water and dried over
anhyd. Na2SO4. The ether layer was concentrated and the crude
product was purified by column chromatography using hexane–
ethyl acetate (20:1) as eluent to obtain pure 4 (0.707 g, 82%) as
a colourless oil, bp 97–99 ЊC/0.2 Torr (Found: C, 77.14; H, 8.19.
C14H18O2 requires C, 77.03; H, 8.31%); νmax(film)/cmϪ1 2748,
1732 and 1725; δH(90 MHz; CDCl3) 0.95, 1.14 (3 H, d, J 7.7,
CH᎐CH3), 1.59, 1.64 (3 H, s, C᎐CH3), 2.28 (3 H, s, COCH3),
2.35 (3 H, s, Ar᎐CH3), 3.34 (1 H, m, CH᎐CH3), 7.25 (4 H, s,
Ar᎐H), 9.57 (1 H, s, CHO ).
solution of ketone 6 (0.08 g, 0.4 mmol) in THF (2 cm3) and the
reaction mixture was stirred at ambient temperature for 12 h. It
was then diluted with diethyl ether (10 cm3) and treated with
10% HCl (5 cm3). The mixture was extracted with diethyl ether
and the extract was washed with NaHCO3 and brine. The ether
layer was dried over anhyd. Na2SO4 and concentrated. The
crude product was purified by column chromatography using
pentane as eluent to give a mixture of 1 and 7 (1:1) (0.063 g,
80%) as a colourless oil, bp 87–89 ЊC/10 Torr (Found: C, 89.67;
H, 10.00. C15H20 requires C, 89.94; H, 10.06%); νmax(film)/cmϪ1
1654.1, 1519.0 and 1447.8; δH(200 MHz; CDCl3) 0.73, 1.02
(3 H, d, J 7.3, CH᎐CH3), 1.1, 1.61 (3 H, s, C᎐CH3), 1.6 to 2.05
(2 H, m, CH2᎐C), 2.39 (3 H, s, Ar᎐CH3), 2.5 to 2.91 (3 H, m,
CH᎐CH , C᎐C᎐CH ), 5.0 (2 H, br s, C᎐CH ), 7.35 (4 H, m,
᎐
᎐
3
2
2
4-(4-Methylphenyl)-4,5-dimethylcyclopent-2-enone 5
Ar᎐H).
Colourless oil, 90% (Found: C, 83.81; H, 8.13. C14H16O requires
C, 83.96; H, 8.05%); νmax(film)/cmϪ1 1715.6, 1588.8, 1513.6 and
1453.5; δH(90 MHz; CDCl3) 0.63, 1.18 (3 H, d, J 7.2, CH᎐CH3),
1.41, 1.68 (3 H, s, C᎐CH3), 2.32 (3 H, s, Ar᎐H), 2.45 (1 H, m,
Acknowledgements
One of the authors (D. S. P.) wishes to thank CSIR, New Delhi,
for a research fellowship.
CH᎐CH ), 6.52 (1 H, t, J 5.1, CO᎐CH᎐CH), 7.38 (4 H, m,
᎐
3
Ar᎐H), 7.8, 8.0 (1 H, d, J 5.1, COCH᎐CH).
᎐
References
3-(4-Methylphenyl)-2,3-dimethylcyclopentanone 6
1 T. Irie, Y. Yasunari, T. Suzuki, N. Imai, E. Kurosawa and T.
Masamune, Tetrahedron Lett., 1965, 3619.
2 T. Irie, T. Suzuki, Y. Yasunari, E. Kurosawa and T. Masamune,
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Lett., 1997, 38, 1459.
Colourless oil, 97% (Found: C, 83.25; H, 8.91. C14H18O requires
C, 83.12; H, 8.97%); νmax(film)/cmϪ1 1740.6, 1515.0 and 1454.9;
δH(90 MHz; CDCl3) 0.79, 1.07 (3 H, d, J 6.9, CH᎐CH3), 1.21,
1.43 (3 H, s, C᎐CH3), 1.28 (1 H, m, ᎐CH2᎐), 1.71 (1 H, m,
᎐CH2᎐), 2.08 (2 H, m, COCH2), 2.27 (3 H, s, Ar᎐CH3), 2.59 (1
H, m, CO᎐CH᎐CH3), 7.24 (4 H, m, Ar᎐H).
4 M. G. Kulkarni and T. S. Mathew, Synth. Commun., 1991, 21, 581.
5 K. Takai, T. Kakiuchi, Y. Kataoka and K. Utimoto, J. Org. Chem.,
1994, 59, 2668 and references cited therein.
Laurene 1 and epilaurene 7
To a stirred suspension of Zn powder (5.6 g, 85.6 mmol) in
THF (16 cm3), a 1  solution of titanium tetrachloride in di-
chloromethane (14 cm3) and dibromomethane (3.2 cm3, 45
mmol) were added successively at 0 ЊC and the stirring was con-
tinued for 15 min at room temp. To this mixture was added a
Paper 7/06510H
Received 9th September 1997
Accepted 9th September 1997
3128
J. Chem. Soc., Perkin Trans. 1, 1997