Synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal: the common aggregation pheromone of flour beetles

Article abstract of DOI:10.1016/j.tetlet.2006.05.066

The synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal 1 and 1a has been achieved connecting the chiral building block (R)-2-methyl-1-bromobutane 4 with (R)- and (S)-citronellol derivatives. The key intermediate 4 was obtained optically pure in five steps from methyl (S)-3-hydroxy-2-methylpropionate 2.

Full text of DOI:10.1016/j.tetlet.2006.05.066

Tetrahedron Letters 47 (2006) 5135–5137
Synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal:
the common aggregation pheromone of flour beetles
Ellen M. Santangelo,a Arlene G. Correˆaa and Paulo H. G. Zarbinb,*
aDepartamento de Quı´mica, Universidade Federal do Parana´, CP 19081, CEP 81531-990 Curitiba-PR, Brazil
bDepartamento de Quı´mica, Universidade Federal de Sa˜o Carlos, CEP 13565-905 Sa˜o Carlos-SP, Brazil
Received 20 April 2006; revised 10 May 2006; accepted 11 May 2006
Available online 6 June 2006
Abstract—The synthesis of (4R,8R)- and (4S,8R)-4,8-dimethyldecanal 1 and 1a has been achieved connecting the chiral building
block (R)-2-methyl-1-bromobutane 4 with (R)- and (S)-citronellol derivatives. The key intermediate 4 was obtained optically pure
in five steps from methyl (S)-3-hydroxy-2-methylpropionate 2.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The aggregation pheromone of the stored foodstuffs
pests Tribolium castaneum and Tribolium confusum was
isolated and identified by Suzuki as 4,8-dimethyldecanal
1.1 Mori and co-workers2 developed the first total syn-
thesis of all of the four possible isomers of 1, stabilising
the absolute configuration of the natural pheromone as
(4R,8R)-1. Later, bioassays had shown that a mixture of
the isomers (4R,8R) and (4R,8S), in a ratio of 8:2, was
about 10 times more active than (4R,8R) itself.3
compound (R)-2-methyl-1-bromobutane 4 was em-
ployed as a chiral source to connect with the tosylates
8 and 8a, derivate from (R)- and (S)-citronellol, respec-
tively. This key intermediate 4 was synthesized optically
pure from methyl (S)-3-hydroxy-2-methylpropionate 2
(see Schemes 1 and 2).
The (R)-2-methyl-1-(2-tetrahydropyranyloxy)butane 3
was readily obtained from 2 as previously described.11,12
Compound 3 was converted into its corresponding bro-
mine 4 using triphenylphosphine and bromine,13 in 75%
yield. In order to verify the enantiomeric excess of 4, due
to its high volatility, the measures were made preparing
the Mosher ester of the corresponding synthetic alcohol
(R)-2-methyl-1-butanol 5, which was readily obtained
from deprotection of 3 in methanol, using Amberlystꢁ
15 as catalyst14 (Scheme 1).
We have previously reported a versatile approach to the
synthesis of the isomers (4R,8S)- and (4S,8S)-1,4 and sev-
eral other racemic and stereoselective synthesis have been
published since the identification of this pheromone.5–10
Here we are describing the synthesis of two other iso-
mers, (4R,8R)-1 and (4S,8R)-1a. In this approach, the
O
Refs. 11 and 12
PPh3, Br2
HO
OMe
THPO
Br
CH2Cl2, 75%
(S)-2
(R)-3
(R)-4
(R)-5
Amberlyst 15,
MeOH
HO
Scheme 1. Synthesis of the key intermediate (R)-4.
*
Corresponding author. Tel.: +55 41 3361 3174; fax: +55 41 3361 3186; e-mail: pzarbin@quimica.ufpr.br
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.066

5136
E. M. Santangelo et al. / Tetrahedron Letters 47 (2006) 5135–5137
OH
OTs
The synthesis of (R,R)-1 and (S,R)-1a could then be
TsCl, Py, 0oC
CHCl3, 86%
*
*
finished, as described in Scheme 2. (R)-Citronellol 7
(Aldrich, 97% ee) and (S)-7a (Aldrich, 67% ee) were
transformed into the known tosylates 8 and 8a17 in
86% yield. Coupling of these compounds with a Grig-
nard reagent prepared from (R)-2-methyl-1-bromo-
butane 4, using Li2CuCl4 as catalyst,18 yielded the
hydrocarbons 9 and 9a in 82%.19 Compounds 9 and
9a were submitted to ozonolysis in methanol–dichloro-
methane at ꢀ78 ꢂC, followed by treatment with
DMS,20 affording the desired pheromones (4R,8R)-1
and (4S,8R)-1a, respectively,21 in 83% yield.
(R)-7 or (S)-7a
(R)-8 or (S)-8a
O3, CH2Cl2
DMS, 83%
(R)-4, Mg, THF
*
Li2CuCl4, 82%
(R,R)-9 or (S,R)-9a
*
O
(R,R)-1 or (S,R)-1a
Scheme 2. Synthesis of the pheromone 1 and 1a.
In summary, two isomers of 4,8-dimethyldecanal were
readily synthesized in good yields and enantiomeric pur-
ity [(4R,8R)-1, [a]D ꢀ7.12 (c 9.15, CHCl3), lit.:2,22 [a]D
ꢀ7.37 (c 2.04, CHCl3); (4S,8R)-1a, [a]D ꢀ7.85 (c 8.10,
CHCl3), lit.:2,22 [a]D ꢀ9.92 (c 2.51, CHCl3)] and, in addi-
tion with our previous work,4 we have synthesized all of
the four possible stereoisomers of pheromone 1. The dif-
ference observed on the value of the optical rotation
among our synthetic (4S,8R)-1a and the one reported
in the literature is due to the low enantiomeric enrich-
ment of (S)-citronellol 6a, used as starting material.
Mosher ester derivatives 6, 6a and 6b were prepared by
the reaction of (S)-(+)-a-methoxy-a-(trifluoromethyl)
phenyl acetic acid (MTPA) chloride with the racemic-,
(S)- and (R)-2-methyl-1-butanol 5, respectively.15,16
The resulting esters were analyzed by 1H NMR spectro-
scopy, as shown in Figure 1.
The ester (20R/S,2R)-6 showed a multiplet (two double
doublets and a doublet) between 4.04 and 4.30 ppm,
corresponding to the carbinolic hydrogens. The ester
(20S,2R)-6a showed a single doublet at 4.16 ppm, while
the ester (20R,2R)-6b showed two double doublets, at
4.09 and 4.24 ppm, respectively (Fig. 1).
Acknowledgements
This work was supported by the International Founda-
tion for Science (Sweden), Organization for Prohibition
of Chemical Weapons (Netherlands), CNPq and Funda-
A comparative analysis of the signals at these spectrum
region indicated that (R)-3 was obtained in high enan-
tiomeric excess (>99%). Considering that no racemiza-
tion takes place during the conversion of 3 into its
bromine 4, the compound (R)-4 should also appear with
the same ee.
´
c¸ao Araucaria (Brazil).
˜
References and notes
1. (a) Suzuki, T. Agric. Biol. Chem. 1981, 45, 1357–1363;
(b) Suzuki, T. Agric. Biol. Chem. 1981, 45, 2641–
2643.
2. Mori, K.; Kuwahara, S.; Ueda, H. Tetrahedron 1983, 39,
2439–2444.
3. Suzuki, T.; Kozaki, J.; Sugawara, R.; Mori, K. Appl.
Entomol. Zool. 1984, 19, 15.
4. Zarbin, P. H. G.; Cruz, W. O.; Ferreira, J. T. B. J. Braz.
Chem. Soc. 1998, 9, 511–513.
F3C
O
MeO
H
H
O
(2'R/S, 2R)-6
5. For a parcial review see: Mori, K. In The Synthesis of
Insect Pheromones. In The Total Synthesis of Natural
Products; ApSimon, J., Ed.; John Wiley & Sons: New
York, 1992; Vol. 9.
6. Moiseenkov, A. M.; Cheskis, B. Dokl. Akad. Nauk SSSR
1986, 290, 1379–1383.
F3C
O
MeO
7. Fuganti, C.; Grasselli, P.; Servi, S.; Ho¨gberg, H.-E.
J. Chem. Soc., Perkin Trans. 1 1988, 12, 3061–3065.
8. Chenevert, R.; Desjardins, M. J. Org. Chem. 1996, 61,
1219–1222.
H
O
H
(2'S, 2R)-6a
9. Sankaranarayanan, S.; Sharma, A.; Chattopadhyay, S.
Tetrahedron: Asymmetry 2002, 13, 1373–1378.
10. Ismuratov, G. Y.; Yakovleva, M. P.; Galyautdinova, A.
V.; Tolstikov, G. A. Chem. Nat. Compd. 2003, 39, 31–
33.
F3C
O
MeO
11. (a) Mori, K. Tetrahedron 1983, 39, 3107; (b) Mori, K.;
Takikawa, H. Liebigs Ann. Chem. 1991, 497–500.
12. Santangelo, E. M.; Zarbin, P. H. G.; Cass, Q. B.; Ferreira,
J. T. B.; Correa, A. G. Synth. Commun. 2001, 31, 3685–
3698.
H
O
H
(2'R, 2R)-6b
Figure 1.

E. M. Santangelo et al. / Tetrahedron Letters 47 (2006) 5135–5137
5137
13. Typical procedure: To a stirred suspension of PH3PÆBr2
(16.5 mmol) in dry CH2Cl2 (80 mL) was added a solution
of the tetrahydropyranyl ether 3 (2.58 g, 15 mmol) in dry
CH2Cl2(10 mL). After the yellow solution had been stirred
at room temperature for 30 min, it was washed with water
(2 · 40 mL) and the organic layer was separated and dried
(MgSO4). Removal of the solvent followed by flash
chromatography of the residual oil in silica gel, provided
1.7 g (75% yield) of compound 4. 1H NMR (400 MHz,
CDCl3) d: 0.91 (t, J = 7.4 Hz, 3H); 1.01 (d, J = 7.4 Hz,
3H); 1.20–1.35 (m, 1H); 1.39–1.56 (m, 1H); 1.67–1.77 (m,
1H); 3.29–3.45 (m, 2H).
16. The racemic- and (S)-5 are commercial available
(Aldrich).
17. Mori, K.; Wu, J. Liebigs Ann. Chem. 1991, 783–788.
18. Fouquet, G.; Schlosser, M. Angew Chem., Int. Ed. Engl.
1974, 86, 50–51.
19. Zarbin, P. H. G.; Reckziegel, A.; Plass, E.; Francke, W.
J. Chem. Ecol. 2000, 26, 2737–2746.
20. Chan, T.; Xin, Y. J. Org. Chem. 1997, 62, 3500–3504.
21. Anal. Calcd for C12H24O: C 78.20; H 13.12. Found:
(4R,8R)-1: C, 78.29; H, 13.19; (4S,8R)-1a: C, 78.14; H,
13.07. (4S,8R)-1a: IR (mmax film cmꢀ1): 2927, 2718, 1727,
1
1462, 1381, 1126; H NMR (400 MHz, CDCl3) d: 0.84 (d,
14. Typical procedure: Amberlystꢁ 15 (0.14 g) was added to a
solution of 3 (0.8 g; 4.65 mmol) in methanol (9.3 mL). The
mixture was stirred at 45 ꢂC for 1 h, then the resin was
filtered and the solution was concentrated by fractionated
distillation at 1 atm, due to the volatility of product. GC
analysis of the crude product showed 100% conversion to
the desired alcohol 5, which was employed directly in the
next step without further purification.
J = 6.4 Hz, 3H); 0.85 (t, J = 6.8 Hz, 3H); 0.88 (d,
J = 6.4 Hz, 3H); 1.04–1.14 (m, 3H); 1.20–1.35 (m, 5H);
1.42–1.46 (m, 2H); 1.63–1.69 (m, 2H); 2.40–2.46 (m, 2H);
9.77 (t, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d:
11.4; 19.2; 19.4; 24.4; 28.9; 29.4; 32.4; 34.4; 36.8; 37.0; 41.2;
203.0; GC–MS (70 eV) m/z %: 140 (M+ꢀ44, 4.05), 125
(3.28), 111 (10.09), 85 (28.74), 70 (57.00), 57 (81.00), 43
(100).
15. Shi, X. W.; Leal, W. S.; Meinwald, J. Bioorg. Med. Chem.
1996, 4, 297–303.
22. Levinson, H. Z.; Mori, K. Naturwissenschaften 1983, 70,
190–192.