An improved synthesis of sitophilure

Article abstract of DOI:10.1139/V08-032

The asymmetric synthesis of sitophilure was carried out in 8 steps, with 42% overall yield and 97% enantiomeric excess from propionaldehyde. The synthesis relied on an approach employing an asymmetric acyl-thiazolidinethione propionate aldol reaction to e

Full text of DOI:10.1139/V08-032

30
An improved synthesis of sitophilure1
Cuifen Lu, Junqi Nie, Guichun Yang, and Zuxing Chen
Abstract: The asymmetric synthesis of sitophilure was carried out in 8 steps, with 42% overall yield and 97%
enantiomeric excess from propionaldehyde. The synthesis relied on an approach employing an asymmetric acyl-
thiazolidinethione propionate aldol reaction to establish two stereogenic centers.
Key words: sitophilure, thiazolidinethione, chiral auxiliary, synthesis.
Résumé : Utilisant le propionaldéhyde comme produit de départ, on a réalisé une synthèse asymétrique du sitophilure
en huit étapes, avec un rendement global de 42% et un excès énantiomérique de 97%. La synthèse repose sur une ap-
proche dans laquelle on utilise une réaction asymétrique aldolique acyl-propionate de thiazolidinethione pour générer
deux centres stéréogéniques.
Mots-clés : sitophilure, thiazolidinethione, auxiliaire chiral, synthèse.
[Traduit par la Rédaction] Lu et al. 32
Introduction
For these reasons, we have chosen to pursue this line of
work and applied this system to the synthesis of the phero-
mone sitophilure using 4-monosubstituted thiazolidine-
thiones as chiral auxiliary (Scheme 1). In comparison with
the published syntheses, this synthesis is very short and the
overall yield very high.
The rice weevil Sitophilus oryzae L. and the maize weevil
Sitophilu zeamaais M. are both pests that cause commer-
cially serious damage to stored cereal grains. Effective, cost-
efficient grain weevil management could be accomplished
by monitoring the pest populations with pheromone-baited
insect traps and applying control methods only when pest
densities reach economic thresholds. Their common aggre-
gation pheromone, sitophilure, was identified by Schmuff et
al. (1) as (4R, 5S)-5-hydroxy-4-methyl-3-heptanone. A syn-
thesis of the four sitophilure stereoisomers was reported by
Mori (2) to clarify the stereochemistry–bioactivity relation-
ship. Bioassay of Mori’s samples by Walgenbach et al. (3)
revealed (4S,5R) stereoisomer 1 to be the pheromone sito-
philure (Fig. 1). Since effective and cost-efficient control of
both maize and rice weevils populations can be foreseen
with the aid of the aggregation pheromone, several total syn-
theses of the racemic and the natural forms of sitophilure 1
have been published (4).
Carbon–carbon bond-forming reactions involving asym-
metric aldol additions have emerged as powerful tools in or-
ganic synthesis. As demonstrated by the pioneering work of
Evans et al. (5), Heathcock and co-workers (6), and Crimmins
et al. (7), additions of enolates of acyl oxazolidinones, oxa-
zolidinethiones, and thiazolidinethiones to aldehydes can be
highly effective at selectively generating enantiomerically
pure syn and anti aldol products. Among these chiral
auxilaries, 4-mono substituted thiazolidinethiones derived
from natural amino acids are more useful in asymmetric syn-
thesis because they can be removed from the thiazolidin-
thiones after completion of the chiral induction easily (8).
Results and discussion
As shown in Scheme 1, we used 4-benzyl-1,3-thiazoli-
dine-2-thione as starting material. Acylation of thiazolidi-
nethione by propionyl chloride using DMAP as catalyst at
room temperature afforded N-acylthiazolidinthiones 2 in
95% yield (7a). Compound 2 was treated with TiCl4, N,N-
diisopropylethylamine (DIPEA), and N-methylpyrrolidone
(NMP) in turn, and the resulting complex reacted with
propionaldehyde to give alcohol 3 in 98% yield (7c). The
aldol product could be easily protected with tert-
butyldimethylsilyl chloride (TBDMSCl) using lutidine as
base (9). The compound, obtained by the protection of 3,
was reduced to alcohol 4 with sodium borohydride in the
presence of ethanol. Oxidation of alcohol 4 with Py·O3 in
the presence of DIPEA gave aldehyde 5 in 84% yield. Com-
pound 5 was treated with excess EtMgBr to give a diastereo-
isomeric mixture of alcohols 6 (4c). The diastereoisomeric
mixtures were not separated and were directly treated with
pyridinium chlorochromate (PCC) and anhydrous sodium
acetate in CH2Cl2, affording a ketone. Deprotection of the
TBS group with tetrabutylammonium fluoride afforded sito-
philure 1 (89% yield, 42% overall yield, and 97% ee, based
on the reported rotation of +27.0) (2).
Received 8 December 2007. Accepted 18 February 2008. Published on NRC Research Press Web site at canjchem.nrc.ca on
27 May 2008.
C. Lu,2 J. Nie, G. Yang, and Z. Chen. Ministry of Education, Key Laboratory for the Synthesis and Application of Organic
Functional Molecules & School of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China.
1This article is part of a Special Issue dedicated to Professor R. Puddephatt.
2Corresponding author (e-mail: lucf@hubu.edu.cn)
Can. J. Chem. 87: 30–32 (2009)
doi:10.1139/V08-032
© 2008 NRC Canada

Lu et al.
31
Fig. 1. Sitophilure 1.
and the organic phase was separated. The aqueous layer was
extracted with CH2Cl2 (50 mL) and the organic extracts
were combined, washed with aqueous saturated NaHCO3
and brine, dried over MgSO4, and the solvent was evapo-
rated. The crude product was recrystallized from CH3CN to
yield a yellow solid 2 (9.03 g, 95%), mp 101.1–101.5 °C. IR
1
(KBr, cm–1): 1703, 1261, 1163, 1033, 759, 706. H NMR
(600 MHz, CDCl3) δ: 7.27-7.35 (m, 5H), 5.38 (m, 1H), 3.21
(dd, J = 9.6 Hz, 3.6 Hz, 1H), 3.13 (dd, J = 10.8 Hz, 7.2 Hz,
1H), 3.05 (dd, J = 10.8 Hz, 2.4 Hz, 1H), 2.88 (dd, J =
10.2 Hz, 3.0 Hz, 1H),1.19 (t, J = 7.2 Hz, 3H). 13C NMR
(150 MHz, CDCl3) δ: 202.5, 174.8, 137.4, 130.0, 129.3,
69.1, 37.3, 33.0, 32.3, 9.8.
Scheme 1. Improved synthesis of sitophilure 1. Reagents and
conditions: a) DMAP (0.2 equiv.), Et3N (1.2 equiv.), propionyl
chloride (1.3 equiv.), CH2Cl2, RT, 3 h; b) TiCl4 (1.05 equiv.),
DIPEA (1.1 equiv.), NMP (2.0 equiv.), propionaldehyde
(1.1 equiv.), CH2Cl2, 0 °C, 3 h; c) TBDMSCl (2.5 equiv.),
lutidine (1.5 equiv.), CH2Cl2, RT, 3 h; d) NaBH4 (4.0 equiv.),
EtOH, 0 °C, 1 h; e) Py·SO3 (3.7 equiv.), DIPEA (2.3 equiv.),
CH2Cl2, 0 °C, 3 h; f) EtMgBr (2.8 equiv.), Et2O, –78 °C ~ RT,
2 h; g) PCC (1.5 equiv.), NaOAc (0.3 equiv.), CH2Cl2, RT,
4 h; h) Bu4NF (1.0 equiv.), THF, RT, 18 h.
Synthesis of (S)-4-benzyl-3-((2′S, 3′R)-3′-hydroxy-2′-
methylpentanoyl)-thiazolidine-2-thione (3)
To solution of compound 2 (4.99 g, 18.82 mmol) in
anhyd. CH2Cl2 (100 mL) at 0 °C under N2 was added TiCl4
(2.17 mL, 19.76 mmol), and the solution was stirred for 15
min. DIPEA (3.60 mL, 20.70 mmol) was added dropwise to
the mixture, and the solution was stirred for 40 min. NMP
(3.61 mL, 37.65 mmol) was added at 0 °C and the mixture
was stirred for an additional 10 min. Freshly distilled
propionaldehyde (1.51 mL, 20.70 mmol) was then added to
the enolate. The reaction was allowed to stir for 2 h followed
by the addition of satd. NH4Cl (10 mL). The organic layer
was separated and the aqueous layer was extracted with
CH2Cl2 (50 mL). The combined organic layers were dried
over anhyd. MgSO4, filtered and concentrated, the crude
product was purified by column chromatography on silica
gel (n-hexane/EtOAc, 10:1 v/v) to afford a yellow oil 3
(5.95 g, 98%). [α] D25 = +130.3° (c 1.30, CHCl3). IR
Conclusion
In summary, an efficient synthesis (8 steps, 42% overall
yield, and 97% enantiomeric excess) of enantiomerically en-
riched sitophilure 1 was developed from propionaldehyde
using 4-benzyl-1,3-thiazolidine-2-thione as chiral auxiliary.
1
(KBr, cm–1): 3344, 2963, 1693, 1260, 1164, 743, 701. H
NMR (600 MHz, CDCl3) δ: 7.12–7.27 (m, 5H), 5.25 (m,
1H), 4.43 (m, 1H), 3.77 (m, 1H), 3.31 (dd, J = 6.6 Hz,
4.8 Hz, 1H), 3.13 (dd, J = 9.6 Hz, 3.6 Hz, 1H), 2.95 (dd, J =
10.2 Hz, 2.4 Hz, 1H), 2.80 (d, J = 11.4 Hz, 1H), 1.46 (q, J =
7.2 Hz, 1H), 1.37 (q, J = 6.0 Hz, 1H), 1.16 (d, J = 7.2 Hz,
3H), 0.87 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3)
δ: 201.2, 178.1, 136.2, 129.3, 128.9, 128.8, 128.7, 127.2,
73.5, 68.7, 42.7, 37.9, 31.9, 27.1, 10.2, 10.1.
Experimental
General
All organic solvents and base were dried by standard
methods. TLCs were performed on precoated plates of silica
gel HF254 (0.5 mm, Yantai, China). Flash column chroma-
tography was performed on silica gel H (Yantai, China).
Melting points were measured on a WRS-1A digital melting
point apparatus and are uncorrected. Optical rotations were
determined with a PerkinElmer Model 241 MC polarimeter.
IR spectra were recorded on an IR-spectrum one (PE) spec-
Synthesis of (2R, 3R)-3-(t-butyldimethylsilanyloxy)-2-
methyl-1-pentanol (4)
To a stirred solution of 3 (4.89 g, 15.13 mmol) in CH2Cl2
(50 mL) was added lutidine (2.65 mL, 22.74 mmol) and t-
butyldimethylsilyl chloride (4.56 g, 37.77 mmol). After stir-
ring for 3 h at room temperature, the reaction mixture was
diluted with CH2Cl2 and washed with CH2Cl2 (50 mL) and
brine. The organic layers were dried over MgSO4, filtered,
and concentrated in vacuum to give a green oil product
(5.30 g). The green oil product (5.30 g, 14.18 mmol) was
dissolved in anhyd. ethanol (50mL) and treated with sodium
borohydride (2.25 g, 14.25 mmol) with cooling (ice-water
bath) and stirring. After stirring for 1 h, 1 N HCl was added
to quench the reaction. The reaction mixture was extracted
with ethyl acetate and dried over MgSO4. The solvent was
evaporated and the crude product was purified by column
chromatography on silica gel (n-hexane/EtOAc, 5:1 v/v) to
afford a colorless oil 4 (2.92 g, 72%). [α] 2D5 = +6.68°
(c 1.30, CHCl3) [lit. value (4c) [α] 2D5 = +6.65° (c 1.30,
1
trometer. H NMR (600 MHz) and 13C NMR (150 MHz)
spectra were recorded on a Varian Unity INOVA 600 spec-
trometer in CDCl3 using TMS as internal standard. Mass
spectra were recorded on Finnigan LCQ DUO MS system.
Synthesis of (S)-4-benzyl-3-propionyl-1, 3-thiazolidine-2-
thione (2)
To
a
solution of the thiazolidinethione (7.5 g,
35.89 mmol) in dry CH2Cl2 (150 mL) at room temperature
was added DMAP (0.88 g, 7.18 mmol) and triethylamine
(6.0 mL, 43.06 mmol). Freshly distilled propionyl chloride
(4.1 mL, 46.65 mmol) was added dropwise over 5 min and
the mixture was stirred for 3 h at room temperature. The re-
action mixture was quenched into saturated NH4Cl (25 mL)
© 2008 NRC Canada

32
Can. J. Chem. Vol. 87, 2009
1
CHCl3)]. IR (KBr, cm–1): 3362, 2959, 1463, 1254. H NMR
(600 MHz, CDCl3) δ: 3.61 (m, 2H), 3.44 (m, 1H), 2.43 (s,
1H), 1.91 (m, 1H), 1.44 (m, 2H), 0.83 (s, 9H), 0.74 (t, J =
7.2 Hz, 3H), 0.02 (m, 6H). 13C NMR (150 MHz, CDCl3) δ:
66.0, 39.2, 25.8, 25.2, 18.0, 11.8, 10.7, -4.4, -4.6.
dried over MgSO4, and concentrated under reduced pressure.
The residue (0.36 g) was dissolved in anhyd. THF (15 mL)
and treated with tetrabutyl ammonium fluoride (0.37 g,
1.41 mmol). The resulting solution was stirred for 18 h be-
fore being diluted with ether (20 mL). The mixture was
washed with satd. aq. NH4Cl and brine, dried over MgSO4,
filtered, and concentrated, and the crude product was puri-
fied by column chromatography (n-hexane/EtOAc, 10:1 v/v)
to afford a colorless oil 1 (0.18 g, 89%), [α] 2D5 = +26.3° (c
1.24, Et2O) [lit. value (2) [α] 2D5 = +27.0° (c 1.24, Et2O)]. IR
Synthesis of 3-(t-butyldimethylsilanyloxy)-2-
methylpentanal (5)
A solution of Py·SO3 (1.88 g, 11.80 mmol) in dry DMSO
(15 mL) was added dropwise to a solution of 4 (0.74 g,
3.19 mmol) and DIPEA (4.5 mL, 27.2 mmol) in dry CH2Cl2
(5 mL) and stirred in an ice-water bath. The mixture was
stirred for 3 h, added to brine, and extracted with ether. The
combined organic fractions were dried over MgSO4, filtered
and concentrated in vacuum, and the residue was
chromatographed on silica gel (n-hexane/EtOAc, 10:1 v/v) to
yield a colorless oil 5 (0.62 g, 84%). [α] 2D5 = +22.9° (c 2.4,
CHCl3) [ lit. value (10) [α] 2D5 = +22.7° (c 2.4, CHCl3)]. IR
1
(KBr, cm–1): 3445, 2959, 2930, 1710, 1462, 1255. H NMR
(600 MHz, CDCl3) δ: 3.75 (m, 1H), 3.55 (s, 1H), 2.51 (m,
1H), 1.29–1.50 (m, 4H), 1.06 (d, J = 3.6 Hz, 3H), 0.98 (t,
J = 7.2 Hz, 6.6 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). 13C NMR
(150 MHz, CDCl3) δ: 216.6, 72.5, 49.2, 34.7, 26.7, 11.5,
10.2, 9.9.
Acknowledgements
(KBr, cm–1): 2959, 1727, 1463, 1258. H NMR (600MHz,
1
This work is supported by the National Natural Sciences
Fundation of China (No. 20772026) and the Natural Sci-
ences Foundation of Hubei Province (2007ABA031).
CDCl3) δ: 9.73 (s,1H), 4.01 (m, 1H), 2.42 (m, 1H), 1.49 (m,
2H), 1.02 (m, 3H), 0.84 (s, 9H), 0.03 (m, 6H). 13C NMR
(150 MHz, CDCl3) δ: 205.3, 73.3, 50.7, 27.3, 25.7, 17.9,
10.0, 7.4, –4.3, –4.8.
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1
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© 2008 NRC Canada