An easy and versatile approach to the synthesis of chiral pheromone lactones via 4,4-dimethyl-2-oxazoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.08.083

As part of our ongoing investigation on the versatility of 4,4-dimethyl-2-oxazoline derivatives, we present a straightforward synthesis of chiral lactone pheromones from readily available starting materials. As an application, we describe the diastereoselective synthesis of cis and trans-2-methyl-5-hexanolide (1), a pheromone component of the carpenter bee Xylocopa hirutissima, and a formal synthesis of (4R,5Z)-5-tetradecen-4-olide (2), the sex pheromone of the Japanese beetle Popillia japonica.

Full text of DOI:10.1016/j.tetlet.2004.08.083

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7399–7400
An easy and versatile approach to the synthesis of chiral pheromone
lactones via 4,4-dimethyl-2-oxazoline derivatives
*
Paulo H. G. Zarbin, Alfredo R. M. Oliveira, Fabio Simonelli, Jose A. F. P. Villar and
´
Orlando Delay, Jr.
´ ´
Departamento de Quımica, Universidade Federal do Parana, CP 19081, 81531-990 Curitiba-PR, Brazil
Received 23 June 2004; revised 13 August 2004; accepted 16 August 2004
Abstract—As part of our ongoing investigation on the versatility of 4,4-dimethyl-2-oxazoline derivatives, we present a straightfor-
ward synthesis of chiral lactone pheromones from readily available starting materials. As an application, we describe the diastereo-
selective synthesis of cis and trans-2-methyl-5-hexanolide (1), a pheromone component of the carpenter bee Xylocopa hirutissima,
and a formal synthesis of (4R,5Z)-5-tetradecen-4-olide (2), the sex pheromone of the Japanese beetle Popillia japonica.
Ó 2004 Elsevier Ltd. All rights reserved.
Lactone structures are found in many natural products
among which there are a number with strong biological
activity.1 Lactones were isolated from insects and are
part of the intriguing communication systems of bees,
beetles and other taxa.2 During previous years, several
methodologies to synthesize lactones were developed.3
Here we describe a way to synthesize chiral lactones,
employing a coupling reaction of 4,4-dimethyl-2-oxazo-
line derivatives with alkyl iodides as the key step
(Scheme 1). We choose cis- and trans-2-methyl-5-hex-
anolide (1) as an example of a diastereoselective synthe-
sis, and a formal synthesis of (4R,5Z)-5-tetradecen-4-
olide (2) as an enantioselective one.
is the sex pheromone of the Japanese beetle Popillia
japonica.5
All four possible isomers of (1) were synthesized using
the optically pure hydroxy iodides (R)- and (S)-(4),
obtained from PHB and by microbiological reduction
of ethyl acetoacetate, respectively,6 as electrophilic
source. The reaction of 2-ethyl-4,4-dimethyl-2-oxazoline
N
OH
+
N
1) n-BuLi/THF
O
O
OH
(3)
(5)
H O
I
2)
(S)-(4)
While compound cis-2-methyl-5-hexanolide (1) is a com-
ponent of the pheromone blend of the carpenter bee
Xylocopa hirutissima4 (4R,5Z)-5-tetradecen-4-olide (2)
3
O
O
O
O
H
OH
+
H
O
R1
N
*
R
I
cis-(1a)
trans-(1b)
O
n
O
*
R1
R
(cis/trans = 7:3)
n
R1=H, n=1 (4)
R1=OH, n=0 (6)
R=CH3 (3)
R=H (3a)
R=H, R1=OH, n=0 (9)
R=CH3, R1=H, n=1 (1)
O
O
(R)-(4)
similarly
O
O
+
H
H
Scheme 1. General strategy to chiral lactones.
cis-(1c)
trans-(1d)
Keywords: Pheromones; Synthesis; Chiral lactones; Oxazoline.
*
Scheme 2. Synthesis of the lactones (2R,5S)-(1a)/(2S,5S)-(1b) and
(2S,5R)-(1c)/(2R,5R)-(1d).
Corresponding author. Tel.: +55 41 361 3174; fax: +55 41 361
3186; e-mail: armo@quimica.ufpr.br
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.083

7400
P. H. G. Zarbin et al. / Tetrahedron Letters 45 (2004) 7399–7400
N
n-BuLi, THF
O
-78 oC
(3a)
N
O
O
H+, MeOH
I ,PPh
O
O
H
2
3
H
H
O
OH
O
O
O
I
imidazole, ether
(6)
(7)
(8)
N
H
Ref. 15
HO
O
O
O
O
(9)
(2)
Scheme 3. Formal synthesis of lactone (2).
1999, 10, 1895; (d) Ramachandran, P. V.; Krzeminski, M.
P.; Reddy, M. V. R.; Brown, H. C. Tetrahedron: Asym-
metry 1999, 10, 11; (e) Pansare, S. V.; Jain, R. P.; Ravi, R.
G. Tetrahedron: Asymmetry 1999, 10, 3103; (f) Upadhya,
T. T.; Gurunath, S.; Sudalai, A. Tetrahedron: Asymmetry
1999, 10, 2899.
(3) with (S)-(4) afforded compound (5) in 92% isolated
yield,7 which was hydrolyzed and cyclized in acidic
media (Ôone-potÕ), to furnish compound (1) in 85% yield
as a mixture of stereoisomers (1a) and (1b). Similarly,
isomers (1c) and (1d) were synthesized in 87% yield
using iodide (R)-(4) (Scheme 2). Mixtures of diastereo-
isomers were obtained in a ratio of 70:30 (1a/b or 1c/d)
2. (a) Pirkle, W. P.; Adams, P. E. J. Org. Chem. 1979, 44(13),
2169; (b) Bernardi, R.; Ghiringhelli, D. Gazz. Chim. Tal.
1992, 122, 395.
1
as determined by GC and H NMR analysis.8
3. (a) Mori, K. Agric. Biol. Chem. 1976, 40, 1617; (b) Kaiser,
R.; Lamparsky, D. Tetrahedron Lett. 1976, 17, 1659; (c)
Cavill, G. W. K.; Clark, D. V.; Whitefield, F. B. Aust. J.
Chem. 1968, 21, 2819.
4. Weeler, J. W.; Evans, S. L.; Blum, M. S.; Velthius, H. H.
V.; Camargo, J. M. F. Tetrahedron Lett. 1976, 45, 4029.
5. Ito, Y.; Sugimoto, A.; Kakuda, T.; Kubota, K. Agric.
Food Chem. 2002, 50(17), 4878.
Optimal yields (>90%) were obtained when compound
(5) was not isolated, but rather hydrolyzed and cyclized
straight from the alkylation step. Methods for the sepa-
ration of diastereoisomers are largely described in the
literature.9
A slightly different approach was used to synthesize
(4R,5Z)-5-tetradecen-4-olide (2). In this case, (R)-4-
hydroxymethyl-2,2-dimethyl-1,3-dioxolane (6) was
employed as a chiral element. Iodide (7) was obtained
from commercial (6) in 65% yield.10 The lithium anion
was generated from 2,4,4-trimethyl-2-oxazoline (3a)
and alkylated in situ with iodide (7), yielding (8) in
85%.11 ÔOne-potÕ hydrolysis followed by cyclization
under acidic conditions provided the known hydroxy
lactone (9) ([a]D À31.0 (c 0.4, EtOH); lit.12 [a]D
À33 2 (c 2.9, EtOH)) in 60% yield,13 which can be
employed in the syntheses of chiral pheromone lactones
like (2) and others14,15 (Scheme 3).
6. Zarbin, P. H. G.; Oliveira, A. R. M.; Delay, C. E.
Tetrahedron Lett. 2003, 44, 6849.
7. Selected spectroscopic data for compound (5). H NMR
1
(400MHz, CDCl3): d 1.2 (d, J = 6.8Hz, 6H), 1.3 (s, 3H),
1.4–1.9 (m, 4H), 2.37–2.5 (m, 1H), 3.72–3.82 (m, 1H), 3.9
(s, 2H); 13C NMR (100MHz, CDCl3): d 17.74, 18.18,
23.33, 23.53, 28.12, 28.29, 29.84, 29.89, 33.28, 33.43, 36.50,
36.93, 66.56, 66.95, 67.33, 78.80, 78.85, 169.68. IR (mmax
film, cmÀ1) 3469, 2969, 2930, 1659. MS m/z (%) 200
(M++1, 17), 184 (12), 166 (21), 140 (48), 127 (100), 112
(32), 98 (21).
8. Spectroscopic data for compounds 1a/b or 1c/d are in
agreement with data reported by Jacobs, H. K.; Mueller,
B. H.; Gopalan, A. S. Tetrahedron 1992, 48, 8891.
9. Tsunoi, S.; Ryu, I.; Sonoda, N. J. Am. Chem. Soc. 1994,
116, 5473.
In conclusion, we have explored the versatility of oxaz-
oline derivatives in the synthesis of five and six-mem-
bered ring lactones. The examples given here
demonstrate a useful application of this methodology.
10. Millar, J. G.; Underhill, E. W. J. Org. Chem. 1986, 51,
4726.
11. Selected spectroscopic data for compound (8). H NMR
1
(80MHz): d 1.14 (s, 6H), 1.34 (s, 3H), 1.39 (s, 3H), 1.68–
2.00 (m, 2H), 2.27–2.44 (m, 2H), 3.52–3.63 (m, 2H), 3.96
(s, 2H), 4.03–4.22 (m, 1H).
References and notes
12. Takle, A.; Kocienski, P. Tetrahedron 1990, 46, 4503.
13. Mann, J.; Partlett, N. K.; Thomas, A. J. Chem. Res. S
1987(11), 369.
14. Zhdankina, G. M.; Serebryakov, E. P. B. Acad. Sci. USSR
CH+ 1985, 34, 2414.
1. (a) Ramachandran, P. V.; Reddy, M. V. R.; Brown, H. C.
Tetrahedron Lett. 2000, 41, 583; (b) Bertus, P.; Ratovelo-
manana-Vidal, V.; Genet, J. P.; Touati, A. R.; Homri, T.;
Hassine, B. B. Tetrahedron: Asymmetry 1999, 10, 1369; (c)
Wang, G.; Hollingsworth, R. I. Tetrahedron: Asymmetry
15. Kang, S.-K.; Shin, D.-S.; Lee, J.-O.; Goh, H.-G. Bull.
Korean Chem. Soc. 1986, 7, 444.