DOI: 10.1002/chem.201500050
Communication
&
Enantioselective Synthesis
Enantioselective Allylation of (2E,4E)-2,4-Dimethylhexadienal:
Synthesis of (5R,6S)-(+)-Pteroenone
[a]
Petr Koukal and Martin Kotora*
enantioselective allylations and served as the key steps in the
Abstract: Allylation, trans- and cis-crotylation of (2E,4E)-
,4-dimethylhexadienal, a representative a,b,g,d-unsaturat-
[2]
[5]
syntheses of papulacandinD and macrolactinA. The remain-
ing two syntheses were based on diastereoselective allylations
using a chiral borane and a chiral titanium complex. They were
2
ed aldehyde, was carried out under different catalytic and
stoichiometric conditions. The reactions catalyzed by orga-
nocatalysts TRIP-PA and N,N’-dioxides gave the best re-
sults with respect to yields, asymmetric induction, and cat-
alyst load in comparison to other procedures. The devel-
oped methodology was applied in the enantioselective
synthesis of (5R,6S)-(+)-pteroenone, a defensive metabo-
lite (ichthyodeterrent) of the Antarctic pteropod Clione
antarctica.
[6]
used in the syntheses of macrolactinA and natural (5’-oxo-
[7]
heptene-1’E,3’E-dienyl)-5,6-dihydro-2H-pyran-2-one.
In view of the aforementioned, along with the fact that
enantioselective allylation could be an important step in syn-
theses of various natural compounds such as pteroenone—
a defensive metabolite (ichthyodeterrent) isolated from the
[8]
Antarctic pteropod Clione antarctica, tiacumicin antibiotics
[9]
isolated from Dactylosporangium aurantiacum, antillatoxin
[
10]
isolated from marine cyanobacterium Lyngbya majuscula
[11]
(
Figure 1) and other compounds —we decided to screen vari-
Enantioselective allylation (and related processes such as croty-
lation) of various aldehydes (aryl, heteroaryl, alkenyl, and alkyl),
which provides chiral homoallylic alcohols, has been intensive-
ly studied in past decades and has become a standard tool of
[
1]
synthetic organic chemistry. Allylation can be carried out
under catalytic conditions utilizing Lewis acid or base activa-
tion to promote the reaction or by using stoichiometric chiral
reagents. However, allylation of a,b,g,d-unsaturated aldehydes
has received little attention from organic chemists and, hence,
only a handful of reports are known. Moreover, most of these
reports do not deal with the subject exclusively, but rather as
a part of other studies. Typical examples are exemplified by
the groups of: a) Denmark, who studied allylation of (S)-
Figure 1. Pteroenone 1, tiacumicin, and antillatoxin—natural compounds
with highlighted sections showing how they could be potentially prepared
by allylation of a,b,g,d-unsaturated aldehydes.
(2E,4E)-2,8-dimethyldecadienal and related substances under
different catalytic and stoichiometric conditions as a part of
[
2]
their synthetic efforts to prepare papulacandinD; b) Morken,
who performed a nickel complex catalyzed allylboration of sev-
eral a,b,g,d-unsaturated aldehydes within the framework of
ous reaction conditions to assess the scope of allylation with
respect to catalytic conditions. We chose (2E,4E)-2,4-dimethyl-
hexadienal (2), prepared by using the previously published
procedures from ethyl 2-bromopropionate, as a model com-
pound because its structural feature, represented by the sub-
stituted diene moiety, can be found in the aforementioned
natural compounds.
[
3]
their reaction mechanism studies; c) Ko cˇ ovsk y´ , who tested his
[
4]
METHOX catalyst on a couple of examples; and d) Campagne,
who studied AgX/BINAP (2,2’-bis(diphenylphosphino)-1,1’-bi-
[
5]
naphthyl) catalyzed allylations. As far as synthetic applica-
tions of enantioselective allylation of a,b,g,d-unsaturated alde-
hydes is concerned, there are, to the best of our knowledge,
only four examples. Two of them were based on catalytic
At the outset we decided to screen several enantioselective
allylation procedures based on Lewis acid, Brønsted acid, or
Lewis base catalytic or stoichiometric protocols (Figure 2 and
Table 1). First of all, the AgOTf/BINAP/KF/ [18]crown-6 catalyzed
allylation with allyltrimethoxysilane developed by Yamamoto
[a] P. Koukal, Prof. Dr. M. Kotora
Department of Organic Chemistry, Faculty of Science
Charles University in Prague
Hlavova 8, 123 43, Praha 2 (Czech Republic)
Fax: (+420)221-951-236
[12]
was tested. It furnished the desired product 3 in a rather
low yield (27%) and with mediocre enantioselectivity of 77%
ee (Entry 1). The Keck allylation using a stoichiometric amount
E-mail: kotora@natur.cuni.cz
of Ti(OiPr) /BINOL (1,1’-bi-2-naphthol) and allyltributylstan-
nane proceeded in a similar manner, giving 3 with 63% ee
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500050.
4
[13]
Chem. Eur. J. 2015, 21, 7408 – 7412
7408
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim