A simple synthesis of (-)-(R)-ipsdienol and (-)-(S)-ipsenol

Article abstract of DOI:10.1016/S0957-4166(99)00482-6

A short and efficient synthesis of the unnatural enantiomer of (+)-(S)- ipsdienol 1 and (-)-(S)-ipsenol 2 is presented via an asymmetric allylboration. The synthesis was achieved by using a one-pot reduction- methylenation of an exo-methylene lactone intermediate. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00482-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4281–4284
A simple synthesis of (−)-(R)-ipsdienol and (−)-(S)-ipsenol
Karine Draillard, Jacques Lebreton ∗ and Jean Villiéras
Laboratoire de Synthèse Organique, CNRS UMR 6513, Faculté des Sciences et des Techniques, 2 rue de la Houssinière,
BP 92208, 44322 Nantes Cedex 3, France
Received 18 October 1999; accepted 29 October 1999
Abstract
A short and efficient synthesis of the unnatural enantiomer of (+)-(S)-ipsdienol 1 and (−)-(S)-ipsenol 2 is
presented via an asymmetric allylboration. The synthesis was achieved by using a one-pot reduction–methylenation
of an exo-methylene lactone intermediate. © 1999 Elsevier Science Ltd. All rights reserved.
The synthesis of isoprenylated naturally occurring materials, especially the synthesis (+)-(S)-ipsdienol
1 and (−)-(S)-ipsenol 2, principal components of the aggregation pheromones of Ips paraconfusus,1 a
bark beetle of California ponderosa pine, has been the subject of numerous synthetic approaches.2 In
connection with our synthetic studies on the application of the allylation of aldehydes with chiral allylic
boron reagents,3 we found that (+)-(1R,2R,3R,4S)-2-endo-phenyl-2,3-exo-bornanediol β-functionalized
allylboronate 34 provides one of the most convenient and simple routes to this series of natural
compounds and we describe herein the synthesis of the unnatural enantiomer of (+)-(S)-ipsdienol 1 and
of (−)-(S)-ipsenol 2 (Scheme 1).
Scheme 1.
Condensation of the chiral allylic β-functionalized allylboronate 3 with β,β-dimethylacrolein 5 in
toluene at room temperature gave, after 8 days, the homoallylic alcohol 6 in 82% yield after purification
(Scheme 2). Analysis of the proton NMR spectrum of the (R)-O-acetylmandelic ester derivative from
alcohol 6 indicated an enantiomeric excess of 88%, as well as unambiguous proof of the (R)-absolute
configuration.5,6 This absolute configuration is in agreement with the proposed transition state of this
∗
Corresponding author. E-mail: lebreton@chimie.univ-nantes.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00482-6
tetasy 3118

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K. Draillard et al. / Tetrahedron: Asymmetry 10 (1999) 4281–4284
allylation.3,7 The homoallylic alcohol 6 was carefully8 treated with sodium hydride to afford the cor-
responding lactone 7 in high yield. We next examined the one-pot two-step reactions: reduction/Wittig
methylenation of lactone 7. Thus, reduction of this chiral material 7 with diisobutylaluminium hydride
(DIBAL-H) in toluene at low temperature,9,10 followed by in situ condensation of the corresponding
exo-methylene aldehyde intermediate 8 with triphenyl(methylidene)phosphorane (formed from the phos-
phonium bromide using n-BuLi as a base), afforded the (−)-(R)-ipsdienol 1 in an acceptable yield
(50–60%)10 and in 88% ee, as determined by (R)-O-acetylmandelic ester analysis. Attempts to improve
the yield of this one-pot procedure by changing either the nature of the base used to form the ylide [tert-
BuOK, sodium bis(trimethylsilyl)amide (NaHMDS)] and/or the solvent used in the reduction step (THF
instead of toluene) were unsuccessful. Nevertheless, close analysis of the proton NMR spectrum of the
crude product showed that no by-product was formed in this step. Thus, it seems reasonable to consider
that the modest yield is essentially due to the high volatility of the (−)-(R)-ipsdienol 1. To underline the
efficiency of this transformation, it should be pointed out that under our conditions no migration and/or
over-reduction of the exo-methylene occurred.
Scheme 2. Reagents and conditions: (a) toluene, 8 days, rt, 82%; (b) 1.0 equiv. NaH, THF, 1 min, 0°C, 93%; (c) 1.3 equiv.
DIBAL-H, toluene, 1 h, −78°C; (d) 2.3 equiv. Ph3P_CH2, THF, rt, 50–60%
The (−)-(S)-ipsenol 2 (40% overall yield, 82% ee) was synthesized using the same sequence starting
from 3-methylbutyraldehyde 9 as described in Scheme 3.
Scheme 3. Reagents and conditions: see Scheme 2
To complete this work, the synthesis of (+)-(S)-ipsdienol 1 and the unnatural enantiomer of (−)-(S)-
ipsenol 2 was attempted using the (1R,2S,3S,4S)-3-endo-phenyl-2,3-exo-bornanediol allylboronate 12
(R=CO2Me), an isomer of 3. The chiral intermediate diol of 12 was prepared from natural (−)-camphor
following Hoffmann’s procedure.4

K. Draillard et al. / Tetrahedron: Asymmetry 10 (1999) 4281–4284
4283
As reported in the literature,4,11 the condensation of 13 (R=H) with acetaldehyde afforded the
corresponding (R)-(−)-pent-4-en-2-ol 14 in 86% yield with 86% ee. On the other hand, with the
allylboronate 4 (R=H) the (S)-(+)-pent-4-en-2-ol 15 is obtained in 92% yield with only 38% ee. From 12
(R=CO2Me) the sequence described in Schemes 2 and 3 was applied from β,β-dimethylacrolein 5 and
3-methylbutyraldehyde 9 to give the corresponding (+)-(S)-ipsdienol 1 and the unnatural enantiomer of
(−)-(S)-ipsenol 2, respectively, with 25 and 20% ee.
Obviously, if the absolute configurations observed in all the cases summarized in Table 1 are in accord
with the proposed transition state,3,7 the disappointing values of the ees in our cases with the chiral
reagent 12 are difficult to explain. The β-functionalized allylboronates are less reactive compared to
simple allylboronates. However, the position of the methyl group on C-1 in these chiral auxiliaries seems
to be crucial for the enantioselectivity. It is noteworthy that moving the methyl group in the allylboronate
3 from C-1 to C-4 should give the enantiomer of 12, in which the ee is lower. The same observation may
be done between 4 and 13, but in this case the ee with the late allylboronate is higher.
Table 1
Enantiomeric excesses and absolute configuration of homoallylic alcohols from condensation of
aldehydes with chiral allylic boron reagents (3, 4, 12 and 13)
Our synthetic samples of ipsdienol 1 and ipsenol 2 exhibit spectral data in agreement with those
reported.2
Compared to the reported methods, our synthesis constitutes a straightforward route to these natural
products. If desired, this synthesis could also be applied for the preparation of either natural antipode of
1 starting from commercially available unnatural (−)-camphor to prepare the (−)-(1S,2S,3S,4R)-2-endo-
phenyl-2,3-exo-bornanediol β-functionalized allylboronate 3.
Acknowledgements
We thank Mr. Gilbert Nourrisson for his valuable help with NMR analysis and Dr. Isabelle Chataigner
is gratefully acknowledged for valuable discussions and advice.
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