Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris

Article abstract of DOI:10.1016/S0040-4039(03)01716-7

A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.

Full text of DOI:10.1016/S0040-4039(03)01716-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6849–6851
Diastereoselective route to (2R,5S)- and
(2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone
component of the wasp Paravespula vulgaris
Paulo H. G. Zarbin,* Alfredo R. M. de Oliveira and Carlos E. Delay
Departamento de Qu´ımica, Universidade Federal do Parana´, CP 19081, CEP 81531-990, Curitiba-PR, Brazil
Received 5 July 2003; accepted 12 July 2003
Abstract—A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The
route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3,
derived from the enantiomers of ethyl b-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated
products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a
subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.
© 2003 Elsevier Ltd. All rights reserved.
Bicyclic acetals play an important role as volatiles
signals in system of chemical communication between
many insect species. Among the multitude of semio-
chemicals known today, this class of compounds
appears as a distinct group.1 The spiroketal 2-methyl-
1,6-dioxaspiro[4.5]decane 1 (Fig. 1) was identified by
Francke et al.2,3 as a pheromone component of the
common wasp Paravespula vulgaris. Since its identifica-
tion, the number of racemic4–6 and optically active7–9
syntheses described in literature is remarkable, but even
today, little is known about the stereochemistry of
naturally occurring 1.10 Herein we wish to report an
alternative and simple method for the synthesis of the
titled compounds. Our plan was to utilize chiral build-
ing blocks [(R)-3 and (S)-3] to control the stereocenter
at C-2 of the molecule, while the stereoselctivity at C-5
must be attributed to stereoelectronic effects involved
on the internal spiroketalization step.11
acetate, respectively12 (see Schemes 1 and 2). Reduction
of PHB with LiAlH4 afforded diol (R)-2 in 85% yield;
[h]D22=−30.1 (c 1.66, CHCl3); lit.13 [h]2D0=−30.0 (c 1.00,
C2H5OH). Mono tosylation at the primary position of
(R)-2, followed by halogenation with KI and protection
of the free hydroxyl group with t-BDMSCl, yielded
iodide (R)-314 in an e.e. >99%, as detected by chiral GC
analysis [h]2D2=−44.5 (c 1.66, CHCl3) (Scheme 1).
Microbiological reduction of ethyl acetoacetate with
baker’s yeast generated (S)-4 in an e.e. <94%.15 In
order to improve the optical purity, we recrystalize its
3,5-dinitrobenzoate (S)-5.16 The enantiomeric enhanced
(S)-4, [h]2D2=+43.8 (c 1.35, CHCl3); lit.15 [h]2D0=+43.9 (c
1.66, CHCl3), was reduced over LiAlH4 to the diol
(S)-2, [h]2D2=+29.4 (c 1.66, CHCl3), which was straight-
forward transformed into iodide (S)-3,14 [h]D22=+45.9 (c
Optically pure (R)-3 and (S)-3 were obtained from
PHB and by a microbiological reduction of ethyl aceto-
Figure 1.
* Corresponding author. E-mail: pzarbin@quimica.ufpr.br
Scheme 1. Synthesis of the chiral iodide (R)-3.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01716-7

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P. H. G. Zarbin et al. / Tetrahedron Letters 44 (2003) 6849–6851
1
acidic conditions.6,20 All physical data19 (MS, H and
13C NMR) were found identical in all respect with those
reported in literature.20,21
In summary, we have introduced a new diastereoselec-
tive synthesis to the spiroketals 1 and 1a. This conver-
gent protocol has merits of the operational simplicity,
and a complete description of the work will appear in
due course.
Acknowledgements
Scheme 2. Synthesis of the chiral iodide (S)-3.
We thank the IFS (Sweden), OPCW (Netherlands),
CNPq and Fundac¸a˜o Arauca´ria (Brazil) for financial
support (grant to PHGZ). We are in debt with Profes-
sor Dr. Antonio G. Ferreira (DQ-UFSCar) for running
1H and 13C NMR of the synthetic compounds.
1.66, CHCl3), similarly as described for its enantiomer
(Scheme 2).
Having a successful preparation of the chiral iodides
(R)-3 and (S)-3, the next step was to employ them as
alkylating agents to the cyclopentanone N,N-dimethyl
hydrazone 617 carbanions (see Scheme 3). The carbonyl
function of diastereoisomeric mixture of compounds 7
or 7a was recovered by treatment with CuCl2.18 Forma-
tion of diols 8 or 8a was accomplished by Bayer–Vil-
liger oxidation and total reduction over LiAlH4. These
diols were protected with TBS group at the primary
position and then oxidized (PCC) to the enantiomeric
ketones 9 or 9a {(R)-9, [h]2D2=−37.8 (c 1.66, CHCl3);
(S)-9a, [h]2D0=+38.5 (c 1.66, CHCl3)}. Differently from
the previous diastereoisomeric compounds, the signals
in the 13C NMR spectra of these molecules are not
duplicated and could be easily attributed, as the
carbinolics C-1 and C-8, at l 62.85 and 67.57 ppm, and
the carbonyl at l 211.30 ppm.
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Finally, removal of the TBS protecting groups of
ketones 9 or 9a under acidic conditions, gave rise to an
intramolecular ketalization process,10 affording the
expected (2R,5S)-1,19 [h]D22=−12.9 (c 1.66, CHCl3); lit.20
[h]2D0=−12.1 (c 1.00, CHCl3), or (2S,5S)-1a,19 [h]D22=
+13.4 (c 1.66, CHCl3); lit.8 [h]D20=+13.9 (c 1.04, CHCl3),
in a 1:2 mixture of Z:E isomers, attributable to
anomeric effects.11 This composition is identical with
that reported for the natural material and with that
observed after equilibration at the spiro center under
Scheme 3. Synthesis of the compounds 1 and 1a.

P. H. G. Zarbin et al. / Tetrahedron Letters 44 (2003) 6849–6851
6851
19. Selected spectroscopic data for compounds (2R,5S)-1 and
(2S,5S)-1a (E/Z=2/1): IR (KBr): 2937, 2870, 1080, 1042,
14. Selected spectroscopic data for iodides (R)-3 and (S)-3:
IR (KBr): 2955, 2929, 1127, 1063, 967 cm−1 1H NMR
;
1
991 cm−1; H NMR (200 MHz, CDCl3) l: 1.22 (d, J=6.6
(400 MHz, CDCl3) l: 0.12 (s, 3H), 0.14 (s, 3H), 0.93 (s,
9H), 1.20 (d, J=6.8 Hz, 3H), 1.95–1.97 (m, 2H), 3.24–
3.29 (m, 2H), 3.89–3.96 (m, 1H); 13C NMR (100 MHz,
CDCl3) l: −4.61, −4.23, 3.62, 18.00, 23.45, 25.84, 43.22,
68.24; MS m/z (%) 314 (M+, 1), 271 (4), 257 (61), 229
(100), 215 (18), 185 (29), 129 (21), 75 (24), 59 (7) (ion
trap).
Hz, 3H), 1.52–2.17 (m, 10H), 3.55–3.93 (m, 2H), 4.22
(sext, J=6.6 Hz, 1H) for E isomer; 1.32 (d, J=6.6 Hz,
1H), 4.20 (sext, J=6.6 Hz, 1H) for Z isomer; 13C NMR
(50 MHz, CDCl3) l: 105.81, 105.60, 76.73, 73.98, 61.56,
61.42, 38.97, 37.74, 34.14, 34.02, 31.68, 31.35, 25.35,
25.25, 23.18, 21.23, 20.33, 20.27; MS m/z (%) 157 (M++1,
73), 141 (6), 128 (6), 112 (9), 111 (15), 101 (100), 100 (43),
98 (26), 85 (7), 83 (28), 71 (4), 59 (5), 57 (9), 56 (14), 55
(53), 43 (28), 41 (13) (ion trap).
15. Wipf, B.; Kupfer, E.; Bertazzi, R.; Leuenberger, H. G.
W. Helv. Chim. Acta 1983, 66, 485–489.
16. Hungerbu¨hler, E.; Seebach, D.; Wasmuth, D. Helv.
Chim. Acta 1981, 64, 1467–1487.
17. Mitra, R. B.; Reddy, G. B. Synthesis 1989, 694–698.
18. Corey, E. J.; Knap, S. Tetrahedron Lett. 1976, 41, 3667–
3668.
20. Hintzer, K.; Weber, R.; Schurig, V. Tetrahedron Lett.
1981, 22, 55–58.
21. Ley, S. V.; Lygo, B.; Wonnacott, A. Tetrahedron Lett.
1985, 26, 535–538.