Asymmetric synthesis of phoenicol, ferrugineol and cruentol, aggregation pheromones of Rhynchophorus spp.

Article abstract of DOI:10.1016/S0957-4166(99)00528-5

Syntheses of phoenicol, ferrugineol, and cruentol, aggregation pheromones of Rhynchophorus palm weevils, have been achieved with an overall yield of 42, 40 and 41%, respectively (five steps), in high enantiomeric purity. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00528-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4627–4632
Asymmetric synthesis of phoenicol, ferrugineol and cruentol,
aggregation pheromones of Rhynchophorus spp.
José M. Odriozola, Jesús M. García, Alberto González and Pilar Gil ∗
Departamento Química Aplicada, Edificio Acebos, Universidad Pública de Navarra, Campus Arrosadía, 31006 Pamplona,
Spain
Received 11 November 1999; accepted 22 November 1999
Abstract
Syntheses of phoenicol, ferrugineol, and cruentol, aggregation pheromones of Rhynchophorus palm weevils,
have been achieved with an overall yield of 42, 40 and 41%, respectively (five steps), in high enantiomeric purity.
© 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Rhynchophorus palm weevils are major pests of coconut and oil palm crops. They produce single
isomers of methyl-branched secondary alcohols as aggregation pheromones. Rhynchophorus phoenicis
(F.), the African palm weevil, produces 3-methyl-4-octanol;1 Mori et al.2 achieved the synthesis of all
the stereoisomers in order to determine the absolute configuration of the naturally occurring isomer
(3S,4S). Two other Asian palm weevils, R. ferrugineus (Oliv.) and R. vulneratus (Panz.) produce 4-
methyl-5-nonanol;3,4 its absolute configuration was shown to be (4S,5S).5,6 Recently, R. ferrugineus
has been reported as a new pest in Europe (Granada, Spain).7 R. cruentatus (F.), the palmetto weevil,
produces 5-methyl-4-octanol;8 the absolute configuration of the naturally occurring stereoisomer was
established by Oehlschlager et al. as (4S,5S);9 Mori et al. carried out its synthesis10 starting from an
enantiomerically pure epoxy alcohol as the source of chirality. Continuing our work on the synthesis of
insect pheromones,11–13 we now report the synthesis of the palm weevil pheromones mentioned above
(Scheme 1) based on Evans’ methodology.14–16 This approach involves the use of a chiral oxazolidinone
which allows an effective control of the relative and absolute stereochemistry of the aldol reaction.
∗
Corresponding author. E-mail: pgr@unavarra.es
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00528-5
tetasy 3163

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Scheme 1. Structures of palm weevil pheromones
2. Results and discussion
The syntheses were carried out as shown in Scheme 2. Thus, following the procedure of Evans for
the asymmetric aldol condensations, the boron enolate derived from chiral imide 1 was treated with the
corresponding aldehyde at −78°C to afford syn adducts 2 in 91 and 81% yield, respectively. Satisfactory
spectral and analytical data were obtained and, as expected, the stereoselectivity reached was high: >99%
d.e. based on NMR analysis. Cleavage of the oxazolidinone auxiliary was accomplished using lithium
borohydride17 to yield diols 3 (85, 87%) which were converted to the corresponding tosylates 4 (83, 86%
yield) under standard conditions. The remaining steps of the synthesis were protection of the secondary
hydroxy group as the tetrahydro-2H-pyran-2-yl (THP) ether followed by elongation of the carbon chain.
Thus, treatment of 4a with DHP provided the crude protected tosylate which was added to lithium
dimethylcuprate. Subsequent removal of the THP group with PPTS furnished the desired phoenicol 5
in 65% yield. In a similar manner, using lithium diethylcuprate, ferrugineol 6 was obtained in 63%
yield. Finally, the synthesis of cruentol 7 was accomplished from 4b and lithium diethylcuprate in 67%
yield. The overall yield of pheromones was 42, 40 and 41%, respectively, based on 1. In all cases the
analytical and spectral data were in accord with the literature as well as the specific rotation values for
the enantiomerically pure compounds (>99% e.e.).2,5,10
Scheme 2. Reagents and conditions: (i) nBu2BOTf/DIPEA, −78°C, R1CHO (91% of 2a, 81% of 2b); (ii) LiBH4, Et2O, 0°C
(85% of 3a, 87% of 3b); (iii) TsCl/Py, rt, 14 h (83% of 4a, 86% of 4b); (iv) DHP, rt, 4 h; (v) Me2CuLi or Et2CuLi, then
PPTS/MeOH (65% of 5 based on 4a, 63% of 6 based on 4a, 67% of 7 based on 4b)
In summary, an efficient five-step synthesis of phoenicol, ferrugineol, and cruentol has been achieved
in high overall yield, suitable for large-scale application and affording high enantiomeric purity phero-
mones.

J. M. Odriozola et al. / Tetrahedron: Asymmetry 10 (1999) 4627–4632
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3. Experimental
3.1. General
Solvents were dried by distillation from drying agents as follows: THF, Et2O (Na–benzophenone);
dichloromethane (P2O5); MeOH (Mg). Column chromatography was performed by using 230–400 mesh
silica gel. 1H and 13C NMR spectra were obtained in CDCl3 solutions on a Varian Gemini 200. Elemental
analyses were performed in a Carlo Erba EA 1108 Analyzer. Mass spectra were recorded on a Finnigan
MAT GCQ. Infrared spectra were recorded on a Nicolet 510M FT-IR as films or KBr pellets. Optical
rotations were measured in a JASCO-DIP-370 polarimeter.
3.2. (4R,5S)-[(2R,3S)-3-Hydroxy-2-methylheptanoyl]-4-methyl-5-phenyl-2-oxazolidinone 2a
To a cooled (0°C), stirred solution of imide 1 (1.17 g, 5 mmol) in dry CH2Cl2 (15 ml) was added
dropwise di-n-butylboryltriflate (1.19 ml, 5.5 mmol) followed by freshly distilled DIPEA (1.05 ml, 6
mmol). The mixture was maintained at 0°C for 30 min and then cooled to −78°C. Freshly distilled
valeraldehyde (0.58 ml, 5.5 mmol) was added in one portion and the mixture was held at −78°C for 30
min, allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was then quenched
by the addition of 4 ml of phosphate buffer solution (pH 7) and MeOH (12 ml). This cloudy solution was
treated with 12 ml of methanol:30% aqueous hydrogen peroxide solution (2:1) and the resulting mixture
was stirred for an additional hour at rt. The organic solvents were removed in vacuo and the resulting
slurry was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), filtered,
and concentrated to afford, after flash chromatrography (EtOAc:hexane, 1:3), 1.45 g (91%) of 2a as a
25
white solid: mp 98–99°C (hex.); [α]D +11.3 (c 1, CH2Cl2); IR (KBr): ν=3455 (OH), 1782 (C_O),
1
1688 (C_O) cm−1; H NMR: δ=0.92 (d, J=6.6 Hz, 3H), 0.94 (t, J=6.4 Hz, 3H), 1.26 (d, J=7.0 Hz,
3H), 1.18–1.63 (m, 6H), 2.91 (d, J=2.9 Hz, 1H), 3.80 (dq, J=2.6 and 7.0 Hz, 1H), 3.96–4.00 (m, 1H),
4.76–4.89 (m, 1H), 5.71 (d, J=7.3 Hz, 1H), 7.26–7.51 (m, 5H); 13C NMR: δ=10.19, 14.10, 14.45, 22.71,
28.22, 33.61, 42.14, 54.76, 71.50, 78.92, 125.54, 128.69, 128.79, 133.04, 152.52, 177.38; anal. calcd for
C18H25NO4: C, 67.69; H, 7.89; N, 4.39. Found: C, 67.53; H, 7.80; N, 4.41.
3.3. (4R,5S)-[(2R,3S)-3-Hydroxy-2-methylhexanoyl]-4-methyl-5-phenyl-2-oxazolidinone 2b
Prepared as described for 2a, starting from 1 (1.17 g, 5 mmol) and using butyraldehyde (0.5 ml, 5.5
mmol), 2b was obtained as an oil (1.24 g, 81%): [α]D25 +13.1 (c 1.4, CH2Cl2); IR (neat): ν=3508 (OH),
1
1778 (C_O), 1698 (C_O) cm−1; H NMR: δ=0.91 (d, J=6.6 Hz, 3H), 0.97 (t, J=7.0 Hz, 3H), 1.25
(d, J=7.0 Hz, 3H), 1.30–1.66 (m, 4H), 2.93 (br s, 1H), 3.79 (dq, J=2.6 and 7.0 Hz, 1H), 4.00 (m, 1H),
4.75–4.89 (m, 1H), 5.71 (d, J=7.3 Hz, 1H), 7.30–7.50 (m, 5H); 13C NMR: δ=10.22, 14.05, 14.42, 19.25,
36.03, 42.16, 54.73, 71.22, 78.89, 125.51, 128.66, 128.75, 133.02, 152.51, 177.29; MS (70 eV): m/z
(%)=118 (80.73), 134 (69.83), 172 (63.03), 233 (100), 306 (M) (0.52).
3.4. (2S,3S)-2-Methyl-1,3-heptanediol 3a
To a cooled solution (0°C) of 2a (1.28 g, 4 mmol) in Et2O (80 ml) was added water (1 ml) followed
by LiBH4 (0.23 g, 10.4 mmol). The solution was stirred for 1 h at 0°C and then for 1 h at rt. Aqueous
NaOH solution (1N, 44 ml) was added dropwise, and the mixture was stirred for 1 h at rt. The aqueous
layer was extracted with EtOAc (4×40 ml), the combined organic layers were dried (MgSO4), filtered,

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and concentrated in vacuo. Purification of the crude product by flash chromatography (EtOAc:hexane,
25
1:10→1:1) yielded 3a as an oil: 0.5 g (85%); [α]D −6.7 (c 2.4, CH2Cl2); IR (neat): ν=3357 (OH)
cm−1; 1H NMR: δ=0.91 (d, J=7.3 Hz, 3H), 0.92 (t hidden, J=6.2 Hz, 3H), 1.26–1.53 (m, 6H), 1.71–1.87
(m, 1H), 2.72 (br s, 1H), 2.95 (br s, 1H), 3.70 (d, J=5.5 Hz, 2H), 3.79–3.83 (m, 1H); 13C NMR: δ=10.04,
14.08, 22.74, 28.42, 33.70, 39.01, 67.03, 74.41.
3.5. (2S,3S)-2-Methyl-1,3-hexanediol 3b
Under the same conditions described for 3a, by reduction of 2b (1.22 g, 4 mmol), the title compound
25
1
was isolated as an oil: 0.46 g (87%); [α]D −4.8 (c 1.5, CH2Cl2); IR (neat): ν=3359 (OH) cm−1; H
NMR: δ=0.90–0.99 (m, 6H), 1.27–1.60 (m, 4H), 1.71–1.88 (m, 1H), 2.48 (br s, 1H), 2.66 (br s, 1H), 3.72
(d, J=5.1 Hz, 2H), 3.80–3.87 (m, 1H); 13C NMR: δ=10.14, 14.13, 19.41, 36.22, 39.10, 67.14, 74.25.
3.6. (2S,3S)-2-Methyl-1-tosyloxy-3-heptanol 4a
To a cooled solution (0°C) of 3a (292 mg, 2 mmol) in dichloromethane (15 ml) was added pyridine
(0.66 ml, 8 mmol) and then tosyl chloride (0.44 g, 2.3 mmol). The mixture was stirred for 14 h at room
temperature. The reaction was quenched with water (15 ml) and then diethyl ether (15 ml) was added.
The aqueous phase was extracted with diethyl ether (3×15 ml) and the combined organic phases were
washed with 2N HCl (5×10 ml), brine (5 ml), dried with magnesium sulfate and concentrated in vacuo.
This crude product was purified by flash chromatography (EtOAc:hexane, 1:10→1:1) yielding 4a as an
25
oil: 500 mg (83%); [α]D −4.3 (c 2.07, CH2Cl2); IR (neat): ν=3375 (OH), 1355, 1172 (S_O) cm−1
;
1H NMR: δ=0.82 (d, J=6.9 Hz, 3H), 0.89 (t, J=6.5 Hz, 3H), 1.14–1.51 (m, 6H), 1.72 (br s, 1H), 1.89 (m,
1H), 2.45 (s, 3H), 3.69 (m, 1H), 3.88 (dd, J=6.0 and 9.6 Hz, 1H), 4.07 (dd, J=7.9 and 9.6 Hz, 1H), 7.35
(d, J=8.4 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H); 13C NMR: δ=9.51, 14.09, 21.70, 22.68, 28.33, 34.11, 37.74,
70.48, 72.78, 127.79, 129.76, 132.85, 144.68.
3.7. (2S,3S)-2-Methyl-1-tosyloxy-3-hexanol 4b
Prepared as described for 4a, starting from 3b (264 mg, 2 mmol) the title compound was isolated as an
25
oil (492 mg, 86%): [α]D −5.1 (c 1.6, CH2Cl2); IR (neat): ν=3528 (OH), 1356, 1171 (S_O) cm−1; 1H
NMR: δ=0.86 (d, J=7.0 Hz, 3H), 0.92 (t, J=7.1 Hz, 3H), 1.22–1.58 (m, 5H), 1.91–2.00 (m, 1H), 2.46 (s,
3H), 3.73 (m, 1H), 3.90 (dd, J=6.0 and 9.5 Hz, 1H), 4.09 (dd, J=7.7 and 9.5 Hz, 1H), 7.37 (d, J=8.4 Hz,
2H), 7.81 (d, J=8.4 Hz, 2H); 13C NMR: δ=9.53, 14.03, 19.33, 21.66, 36.53, 37.78, 70.22, 72.77, 127.78,
129.77, 132.89, 144.69.
3.8. Phoenicol [(3S,4S)-3-methyl-4-octanol] 5
To a stirred solution of the tosylate 4a (390 mg, 1.3 mmol) DHP (0.24 ml, 2.6 mmol) and PPTS (0.13
g, 0.52 mmol) in dichloromethane (10 ml) were added at room temperature. The mixture was stirred
for 4 h and then diethyl ether (20 ml) was added. The organic solution was washed with water (10 ml),
NaHCO3 (3×10 ml), brine (5 ml), dried with magnesium sulfate and concentrated in vacuo. This crude
product was used in the next step without further purification. Methyllithium in diethyl ether (1.6 M, 8.13
ml, 13 mmol) was added to a cooled suspension of copper(I) iodide (1.23 g, 6.5 mmol) in dry diethyl
ether (20 ml) at 0°C under nitrogen. This mixture was stirred for 30 min and then cooled to −78°C. To
this was added a solution of the above-described tosylate in dry diethyl ether (5 ml). The reaction mixture

J. M. Odriozola et al. / Tetrahedron: Asymmetry 10 (1999) 4627–4632
4631
was stirred for 2 h at rt and then poured at 0°C into a mixture of satd. aq. ammonium chloride solution
and 29% aq. ammonia solution (4:1). The aqueous layer was extracted with diethyl ether (3×15 ml) and
the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The
obtained oil was dissolved in MeOH (5 ml) and PPTS (0.1 g, 0.4 mmol) was added. The reaction mixture
was refluxed for 4 h. The methanol was removed under atmospheric pressure and after the usual workup
the residue was chromatographed over silica gel (n-pentane:diethyl ether, 100:1→10:1) and distilled to
25
20
give 5 as a colorless liquid (122 mg, 65%): [α]D −21.9 (c 1.23, Et2O) {lit.2 [α]D −20.7 (c 1.01,
Et2O)}; IR (neat): ν=3407 (OH) cm−1; 1H NMR: δ=0.84–0.98 (m, 9H), 1.15–1.53 (m, 10H), 3.49–3.57
(m, 1H); 13C NMR: δ=11.93, 13.21, 14.12, 22.83, 26.09, 28.49, 34.26, 40.00, 74.88; MS (70 eV): m/z
(%)=143 (M−1) (1.68), 69 (100).
3.9. Ferrugineol [(4S,5S)-4-methyl-5-nonanol] 6
Prepared as described for 5, starting from 4a (390 mg, 1.3 mmol) and using ethyllithium the title
25
19
product was isolated as a colorless liquid: 130 mg (63%); [α]D −28.0 (c 1.0, Et2O) {lit.5 [α]D −26.5
(c 0.88, Et2O)}; IR (neat): ν=3416 (OH) cm−1; H NMR: δ=0.83–0.92 (m, 9H), 1.12–1.47 (m, 12H),
1
3.48 (br s, 1H); 13C NMR: δ=13.56, 14.12, 14.37, 20.50, 22.83, 28.51, 34.20, 35.64, 37.92, 75.16; MS
(70 eV): m/z (%)=157 (M−1) (2.61), 69 (100).
3.10. Cruentol [(4S,5S)-5-methyl-4-octanol] 7
Prepared as described for 5, starting from 4b (372 mg, 1.3 mmol) and using ethyllithium the title
25
19
product was isolated as a colorless liquid: 126 mg (67%); [α]D −32.5 (c 1.32, Et2O) {lit.10 [α]D
−33.1 (c 1.14, Et2O)}; IR (neat): ν=3420 (OH) cm−1; H NMR: δ=0.86–0.98 (m, 9H), 1.14–1.56 (m,
10H), 3.47–3.54 (m, 1H); 13C NMR: δ=13.60, 14.21, 14.39, 19.49, 20.52, 35.63, 36.69, 37.97, 74.91;
MS (70 eV): m/z (%)=143 (M−1) (0.74), 55 (100).
1
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