HETEROCYCLES, Vol. 53, No. 3, 2000, pp.

703 - 707, Received, 25th October, 1999

A NEW SYNTHESIS OF (-)-(5R,6S)-6-ACETOXY-5-HEXADECANOLIDE,

THE MOSQUITO CULEX PIPIENS FATIGANS OVIPOSITION
ATTRACTANT PHEROMONE

John K. Gallos,* Demetrios S. Mihelakis, Constantinos C. Dellios, and Minodora

E. Pozarentzi

Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 540

06, Greece, e-mail: igallos@chem.auth.gr

Abstract- A new synthesis of (-)-(5R,6S)-6-acetoxy-5-hexadecanolide, the main

component of the mosquito Culex pipiens fatigans oviposition attractant
pheromone, from D-ribose is reported.

Since its isolation and identification, (-)-(5R,6S)-6-acetoxy-5-hexadecanolide1 (1, Figure 1) the main
component of the mosquito Culex pipiens fatigans oviposition attractant pheromone, has become a
popular synthetic target. Several syntheses have been reported in the literature, including inter alia
Sharpless asymmetric epoxidation or dihydroxylation of a double bond as the key-step and enzymatic
resolution of racemic diols.2 Commercially available chiral compounds such as ascorbic acid and 2-
desoxy-D-ribose have also been used as starting materials.2 We now report a new and efficient synthesis
of 1 starting from D-ribose.

O HO 5 O
O 4 1 OH
3 2

HO OH
OAc 1 D-ribose
Figure 1
It becomes evident when comparing the structures of 1 and D-ribose, that the two chiral centres of the
hexadecanolide have the configuration of the C-2 and C-3 carbons of the ribose molecule, from which 1
could be prepared by simple transformations: (i) introduction of the long chain at C-1 of D- ribose by a
Wittig reaction, (ii) deoxygenation of the C-4 carbon and (iii) elongation at C-5 position by oxidation and
Wittig olefination.
The known compounds (3),3 (Scheme 1) readily prepared from D-ribose in three steps, have already been
lengthened at the C-5 carbon by the proper size and functionality. In our hands, compounds (3) were
prepared from 2 as a ca. 10:1 inseparable mixture of E/Z isomers, by oxidation4 followed by Wittig
olefination with Ph3P=CHCO2R (R = Me or Et).
RO 2C
HO OMe OMe MeO 2C MeO2C
O O
O O
i, ii iii iv

O O O O O O O O

2 3a R = Me 4 5
b R = Et

MeO2C HO2C O

C9H19 C9H19 O
v vi ref. 2g
O O 2 steps
O O
OAc
6 7 8
Scheme 1 Reagents and Conditions: i, CrO3, dry pyridine, CH2Cl2, 20 ºC, 20 min; ii,
Ph3P=CHCO2R (R = Me or Et), PhCO2H (10%), CH2Cl2, 20 ºC, 12 h, 65-70% from 2, E/Z ca. 10/1;
iii, 0.15 M solution of 3 in MeOH, Mg (10 equiv.), 0 ºC, 1 h, 52% (40% recovered); iv, H2, 10%
Pd/C, MeOH, 20 ºC, 30 min 86%; v, (a) Ph3P+(CH2)8MeBr-, 1.6 M n-Buli in pentane, –78 ºC, THF,
(b) H2, 10% Pd/C, MeOH, 20 ºC, 1 h, 42% overall; vi, 10% aqueous KOH, MeOH, 20 ºC, 2 h, 90%.
It is known5 that magnesium in methanol (Mg/MeOH) causes a reductive cleavage of γ-functionalized
α,β-unsaturated esters. Since this is the case of compounds (3), it was expected that magnesium in
methanol could deoxygenate the C-4 carbon, as desired. Indeed, when 3a was allowed to react with Mg in
methanol, aldehyde (4) was formed in a reaction reminiscent of the Vasella rearangement.6 The reaction
conditions were crucial at this step and we found that the best results were obtained when a ca. 0.15 M
solution of 3a in methanol was allowed to react with excess of Mg (10 equiv.) at 0 ºC for 1 h. At this
point more than half of 3a was consumed (recovered 40% of 3a) and aldehyde (4) was isolated in 52%
yield after chromatographic separation (87% yield based on the consumed compound (3a)). At longer
reaction times - expected to achieve complete reaction of ester (3a) - aldehyde (4) started to decompose
and several new undesired byproducts were formed, reducing the yield of 4. Ester (3b) gave also aldehyde
(4), evidently by transesterification during the reaction progress.
Attempted Wittig olefination of aldehyde (4), in order to indroduce the long chain, was unsuccessful.
Thus, the double bond of 4 was selective hydrogenated over 10% Pd/C to aldehyde (5) before the Wittig
reaction with the appropriate phosphorus ylide, which proceeded smoothly. Both aldehydes (4) and (5)
were found to be quite unstable and used further without complete characterisation. The Wittig product
was again hydrogenated over 10% Pd/C to give the desired methyl ester (6), which has spectral data
analogous to those reported for the respective ethyl ester.7 Further basic hydrolysis of the ester (6)
afforded the known acid (7),2g which can be easily transformed to the desired pheromone (8) by simple
manipulations according to the literature.2g
In conclusion, we have achieved a new synthesis of (-)-(5R,6S)-6-acetoxy-5-hexadecanolide from D-
ribose utilising cheap and easily available reagents and applying simple and convenient methods. The key-
step involves a reductive elimination of the readily prepared unsaturated ester (3) by Mg in MeOH to
aldehyde (4), which by further formal manipulations is transformed to the target molecule.

EXPERIMENTAL

Methyl (5R,6S)-(E)-7-Oxo-5,6-isopropylidenedioxyhept-3-enoate (4). To a solution of 3a (0.590 g, 2.283

mmol) in dry MeOH (15 mL) was added magnesium turnings (0.555 g, 22.83 mmol) and the reaction
mixture was stirred at 0 ºC for 1 h. H2O (10 mL) was then added and the mixture was extracted with
CH2Cl2 (2x10 mL). The organic layer was dried over MgSO4, the solvent was then evaporated and the
residue was chromatographed on silica gel with hexane/EtOAc 5:1 as the eluent to give first unchanged
3a (0.236 g, 40%) followed by compound (4) as an oil (0.271 g, 52% or 87% based on the consumed 3a),
which was used in the next step without further purification; δH (CDCl3, 300 MHz) 1.44 (s, 3 H), 1.62 (s,
3 H), 3.12 (t, J 6.8, 2 H), 3.69 (s, 3 H), 4.42 (dd, J 7.3, 3.3, 1 H), 4.87 (dd as t, J 7.3, 1 H), 5.52 (dd, J
15.6, 7.3, 1 H), 6.03 (dt, J 15.6, 6.8, 1 H) and 9.57 (d, J 3.3, 1 H); δC (CDCl3, 75 MHz) 25.21, 27.28,
37.18, 51.90, 78.27, 82.15, 111.17, 126.92, 128.02, 171.14 and 200.54.
Methyl (5R,6S)-7-Oxo-5,6-isopropylidenedioxyheptanoate (5). To a solution of compound (4) obtained as
above (0.228 g, 1 mmol) in MeOH (20 mL) was added 10% Pd/C (catalytic) and the mixture was stirred
at rt under 1 atm H2 for 30 min. The solids were filtered off, the solvent evaporated and the residue was
chromatographed on silica gel using CH2Cl2 as the eluent to give compound (5) as an oil (0.199 g, 86%),
which was used in the next step without further purification; δH (CDCl3, 300 MHz) 1.41 (s, 3 H), 1.58 (s,
3 H), 1.72 (centered, m, 4 H), 2.36 (t, J 7.3, 2 H), 3.67 (s, 3 H), 4.27 (dd, J 7.2, 3.4, 1 H), 4.35 (ddd, J 7.3,
7.2, 3.9, 1 H), and 9.57 (d, J 3.4, 1 H); δC (CDCl3, 75 MHz) 21.85, 25.21, 27.51, 29.03, 33.43, 51.48,
78.17, 81.86, 110.70, 173.47 and 202.10.
Methyl (5R,6S)-5,6-Isopropylidenedioxyhexadecanoate (6). To a stirred solution of Ph3P+(CH2)8MeBr-
(0.482 g, 1.242 mmol) in THF (30 mL), 1.6 M of n-BuLi solution in pentane (0.8 mL, 1.28 mmol) was
added dropwise at –78 ºC and the mixture was allowed to warm to 0 ºC. The solution was cooled again to
–78 ºC and was added to aldehyde (5) (0.130 g, 0.565 mmol) dissolved in THF (5 mL). The mixture was
allowed overnight stirring to warm to rt, quenched by adding H2O (100 mL) and extracted with Et2O (50
mL). The organic layer was dried over MgSO4, the solvent was then evaporated and the residue was
chromatographed on silica gel with hexane/EtOAc 15:1 as the eluent to give the Wittig product as an oil,
which was dissolved in MeOH (15 mL), 10% Pd/C (catalytic) was added and the mixture was stirred at rt
under 1 atm H2 for 1 h. The solids were filtered off, the solvent evaporated and the residue was
chromatographed on silica gel using hexane/EtOAc 20:1 as the eluent to give compound (6) as an oil
(0.081 g, 42%); [α]D25 +4.6 º (c 0.6, CHCl3); δH (CDCl3, 300 MHz) 0.86 (t, J 7.0, 3 H), 1.26 (br s, 18 H),
1.33 (s, 3 H), 1.42 (s, 3 H), 1.51 (m, 2 H), 1.69 (m, 1 H), 1.86 (m, 1 H), 2.38 (t, J 7.3, 2 H), 3.67 (s, 3 H),
and 4.02 (m, 2 H); δC (CDCl3, 75 MHz) 14.02, 21.65, 22.59, 25.89, 26.22, 28.51, 29.07, 29.26, 29.51,
29.61, 31.84, 33.79, 51.37, 77.55, 77.94, 107.35, and 173.79; m/z (%) 327 (40, M+-15), 285 (9), 253 (23),
235 (15) 217 (9). Anal. Calcd for C20H38O4: C, 70.13; H, 11.18. Found: C, 70.33; H, 11.02.

(5R,6S)-5,6-Isopropylidenedioxyhexadecanoic Acid (7). A mixture of compound (6) (0.052 g, 0.152

mmol), MeOH (2.5 mL) and 10% aqueous KOH (2.5 mL) was stirred at rt for 2 h, then neutralised with
AcOH and extracted with CH2Cl2 (30 mL). The organic layer was dried over MgSO4, the solvent was then
evaporated and the residue was chromatographed on silica gel with hexane/EtOAc 7:1 as the eluent to
give acid 7 as a syrup (0.045 g, 90%); [α]D25 +4.1 º (c 1.1, CHCl3) [lit.,2g [α]D22 +5.65 º (c 1.0, CHCl3)]; δH
(CDCl3, 300 MHz) 0.88 (t, J 6.8, 3 H), 1.26 (br s, 18 H), 1.33 (s, 3 H), 1.43 (s, 3 H), 1.49 (m, 2 H), 1.68
(m, 1 H), 1.84 (m, 1 H), 2.42 (t, J 7.3, 2 H), 4.02 (m, 2 H) and 10.4 (br s, 1 H); δC (CDCl3, 75 MHz)
14.08, 21.44, 22.66, 25.92, 26.26, 28.53, 29.04, 29.32, 29.58, 29.66, 31.87, 33.79, 51.37, 77.60, 78.00,
107.52, and 179.34; HRMS (MALDI-FTMS) Calcd for C19H36O4Na [M+Na]+: 351.2506. Found:
351.2508; 0.6 ppm error. Anal. Calcd for C19H36O4: C, 69.47; H, 11.05. Found: C, 69.55; H, 10.98.

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particular compound can not justify more than two peaks at δ 10-20 (the CH3 of the ethyl group and
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