Stereoselective synthesis of all-trans methyl substituted polyenes by reductive elimination and application to the synthesis of all-trans 3-methyl- nona-2,4,6-trienol

Article abstract of DOI:10.1016/S0040-4039(00)00564-5

The stereoselective synthesis of all-trans 3-methyl-nona-2,4,6-trienol 2 by reductive elimination of the corresponding 1,6-dibenzoate-2-methyl- 2(Z),4(Z)-diene is described. This result shows that reductive elimination can be extended to the formation of all-trans methyl substituted polyenes which are present in many natural products biosynthetically made from isoprenic units. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00564-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4197–4200
Stereoselective synthesis of all-trans methyl substituted polyenes
by reductive elimination and application to the synthesis of
all-trans 3-methyl-nona-2,4,6-trienol
Guy Solladié,∗ Françoise Colobert and Chakib Kalaï
Laboratoire de Stéréochimie associé au CNRS, Université Louis Pasteur, ECPM 25 rue Becquerel, 67087 Strasbourg Cedex 2,
France
Received 21 February 2000; accepted 4 April 2000
Abstract
The stereoselective synthesis of all-trans 3-methyl-nona-2,4,6-trienol 2 by reductive elimination of the corres-
ponding 1,6-dibenzoate-2-methyl-2(Z),4(Z)-diene is described. This result shows that reductive elimination can
be extended to the formation of all-trans methyl substituted polyenes which are present in many natural products
biosynthetically made from isoprenic units. © 2000 Elsevier Science Ltd. All rights reserved.
In our previous studies1 on stereoselective polyene synthesis, we reported that all-trans dienes,
trienes and tetraenes could be prepared by Na(Hg) or low valent titanium reductive elimination of 1,4-
dibenzyloxy-2-alkenes or 1,6-dibenzyloxy-2,4-dienes or 1,8-dibenzyloxy-2,4,6-trienes2 (Scheme 1).
Scheme 1.
This synthetic method was applied to the preparation of many natural products containing a triene
unit such as (6E,5S,12R) and (5S,12R) leukotriene B4,3 haminol 1,4 isobretonine A5 and also to the
synthesis of the methyl ester of β-parinaric acid2c with a tetraene unit. However, all these molecules
have unsubstituted polyenes. Many natural products, biosynthetically made from isoprene units, contain
conjugated all-trans methyl substituted polyenes. The basic unit 1 is included in a very large number of
important molecules.
∗
Corresponding author. Fax: 33 3 88 13 69 49; e-mail: solladie@chimie.u-strasbg.fr (G. Solladié)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00564-5
tetl 16843

4198
We report in this paper the stereoselective synthesis of a model molecule, all-trans 3-methyl-nona-
2,4,6-trienol 2.
Our retrosynthetic strategy is based on the reductive elimination of the 1,6-dibenzoates 3, obtained
by condensation of the appropriate aldehydes with the enylstannane 4. The (Z)-enyne will be prepared
stereoselectively by hydrostannylation of the silyldiyne 5 with a stannylcuprate (Scheme 2).
Scheme 2.
Stannylcupration of alkynes is widely used for the preparation of vinylstannanes.6 These reactions,
as well as the reactions of alkyl-7 and silylcuprates8 with terminal alkynes, generally proceed with high
regio- and stereoselectivity.
Condensation of lithiated diacetylene with trimethylsilyl chloride afforded bistrimethylsilylbutadiyne
5 which was monolithiated with a methyllithium–lithium bromide complex in THF at room temperature
in quantitative yield and reacted with methyl iodide to give trimethylsilylpentadiyne 6 in good yield.9
Hydrostannylation of the silyldiyne 6 with stannylcyanocuprate (Bu3Sn)MeCuCNLi2 led to the stereo-
selective formation of (E)- or (Z)-stannylenyne 4 according to the experimental conditions: we found that
the reaction of 6 with (Bu3Sn)MeCuCNLi2 in THF at −78°C followed by warming to −30°C during 4
h and methanolysis gave 4-(Z) in 69%; and that 4-(E) was obtained by methanolysis after only 1 h at
−78°C (Scheme 3).
Scheme 3.
After transmetallation of 4-(Z) (n-Buli,THF, −78°C), the vinyl lithium species was added to the
protected α-hydroxy aldehyde 7 (prepared by monoprotection of ethylene glycol with sodium hydride
and t-butyldiphenylsilyl chloride in 95% yield followed by Dess–Martin oxidation10 in 84% yield). In
the resulting enynol 8 the trimethylsilyl protecting group was cleaved to give enyne 9 in 76% yield
(20% of the trans-silylation product from the primary to the secondary OH was also isolated after
chromatographic separation). Condensation of the lithium derivative of 9 with propanal followed by
catalytic Lindlar hydrogenation afforded the diene-diol 10-(Z,Z) in 62% overall yield (Scheme 4).
The diene-diol 10 was then converted to the dibenzoate 11 using standard conditions (2 equiv.
PhCOCl, pyridine, 82%). Reductive elimination of the dibenzoate 11 with 6% Na(Hg)11 in THF:MeOH

4199
Scheme 4.
(3:1) gave the protected all-trans 3-methyl-nona-2,4,6-triene-1-ol 12 in 70% yield. Cleavage of the t-
butyldiphenylsilyl group with TBAF afforded the all-trans product 2 (Scheme 5).
Scheme 5.
The all-trans configuration of the triene 2 was assigned by 1H NMR spectroscopy in the presence of
a stoichiometric amount of Pr(Fod)3 to separate all the vinylic proton signals. The coupling constants
J3–4=J5–6=15 Hz were determined attesting the E configuration for the C3–4 and C5–6 double bonds. The
E geometry for the C1–2 trisubstituted double bond was established using NOE difference experiments.
In conclusion, we have shown that our method for stereospecific synthesis of dienes, trienes and
tetraenes was also efficient for the synthesis of methyl substituted trienes. We are currently investigating
synthetic applications as well as continuing new syntheses of various substituted polyene fragments.
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