Angewandte Chemie International Edition
10.1002/anie.201915895
This biscyclopropanation of 1,5-dienes was applied to the first
total synthesis of waitziacuminone (9),[ 14 , 15 ] a sesquiterpene
isolated from the aerial parts of Waitzia acuminata, known as
orange immortelle, an annual herb native to Australia (Scheme 6).
With geranyl acetone (8) as the substrate and catalyst F, the
natural product was produced as a racemate in only one step as a
single diastereomer. The relative configuration of waitziacuminone
biscyclopropyl compounds 5, and tricyclo[5.1.0.02,4]octanes 6. The
latter transformation was applied to the first total synthesis of the
sesquiterpene waitziacuminone (9) by the stereoselective
formation of four C-C bonds and three rings in a single step.
O
O
‡
H
LAu+.
∆G = 29.7
∆Gº = 27.8
(
9) was confirmed by X-ray diffraction of its crystalline 2,4-
H
H
H
LAu+
dinitrophenylhydrazone 10.
H
O
Int7b
Int5b
Me
O
Me
Me
Me
TSInt6a-Int7a
CaC2, H2O
Me
H
∆G‡ = 13.8
∆G = 26.5
∆G‡ = 8.6
∆G = -16.2
º
º
Me
F (5 mol%)
H
CH2Cl2, 23 °C
O
O
O
geranyl acetone (8)
H
5
9%
Me
Me
‡
8
‡
∆
G
= 8.9
∆G = 7.7
waitziacuminone (9)
º
º
∆G
= -15.0
∆G = -14.8
H
H
LAu+
+
AuL
LAu+
+
H
Int6b
H
H
H
Int6a
10
H
H
Int1a
‡
‡
∆
G
= 8.3
∆G = 3.4
Scheme 6. One step total synthesis of (±)-waitziacuminone (9) and X-ray crystal
structure of its 2,4-dinitrophenylhydrazone 10 (CYLview depiction).
∆Gº = -16.1
∆Gº = -22.8
O
O
The different pathways for the reaction between acetylene and
geranyl acetone (8) were studied computationally[12] (Scheme 7).
In principle, four possible cyclopropyl gold carbenes can be formed
∆G‡ = 3.2
º
∆G = -21.5
H
H
LAu+.
H
LAu+
H
H
2
by reaction of both alkenes of 8 with ( -alkyne)gold(I) complex
TSInt5a-Int7a
Int5a
Int7a
Int1a. The most favorable cyclopropanation gives Int6a, which
immediately undergoes a second cyclopropanation through TSInt6a-
Int7a to form Int7a, and finally waitziacuminone (9). This pathway
could compete with the initial cyclopropanation of the internal
alkene of 8 leading to Int5a, which would similarly undergo an
intramolecular cyclopropanation to form Int7a. The two other
alternative pathways have slightly higher activation energies and
the corresponding intermediates Int5b and Int6b would be
unproductive, since the second cyclopropanation would generate
a highly strained tricyclo[5.1.0.02,4]octane bearing a trans-fused
cyclopropane, as shown by the high activation energies of these
endergonic processes.
In conclusion, we have developed catalytic systems for the
incorporation of acetylene gas into complex frameworks by means
of gold(I) catalysis under experimentally very simple conditions.
Acetylene is activated by gold(I) as a dicarbene equivalent that
allows for the stereoselective synthesis of Z,Z-dienes 4,
Scheme 7. Different mechanistic pathways to form Int7a-b by double
cyclopropanation reactions. L=PMe . DFT calculations performed with M06-D3/6-
1G(d) (C, H, P, O) and SDD (Au) in CH Cl (SMD). Free energies in Kcal/mol.
3
3
2
2
Acknowledgements
We thank the Agencia Estatal de Investigación (AEI)/FEDER,
UE (CTQ2016-75960-P, FPU predoctoral fellowship to H.A.-R. and
Severo Ochoa predoctoral fellowship to M.E.d.O.), the European
Research Council (Advanced Grant No. 835080), the AGAUR
(2017 SGR 1257), and CERCA Program/Generalitat de Catalunya
for financial support. D.S. acknowledges the receipt of
a
postdoctoral fellowship from the Deutsche Forschungs-
gemeinschaft. We also thank the ICIQ X-ray diffraction unit and Dr.
Rémi Blieck for helpful discussions.
Keywords: gold catalysis · acetylene · cyclopropanation · total
synthesis
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