An efficient method for total syntheses of avenaciolide and isoavenaciolide via tungsten-π-allyl complexes

Article abstract of DOI:10.1039/a803491e

Total syntheses of avenaciolide and isoavenaciolide were achieved in six and three steps respectively based on starting chloropropargyl derivatives; the key step in such syntheses involves intramolecular alkoxycarbonylation of tungsten-η¹-propa

Full text of DOI:10.1039/a803491e

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An efficient method for total syntheses of avenaciolide and isoavenaciolide via
tungsten-p-allyl complexes
Kesavaram Narkunan and Rai-Shung Liu*†
Department of Chemistry, National Tsing-Hua University, Hsinchu, 30043, Taiwan, ROC
OH
Total syntheses of avenaciolide and isoavenaciolide were
(1)
CpMo(NO)Cl
RCHO
RCHO
achieved in six and three steps respectively based on starting
chloropropargyl derivatives; the key step in such syntheses
involves intramolecular alkoxycarbonylation of tungsten-
Me
R
R
Me
1
OH
h -propargyl complexes.
CpMo(NO)Cl
There has been increasing interest in the utilization of
Me
Me
O
molybdenum- or tungsten-p-allyl compounds for organic
3
syntheses.1,2 Faller et al. reported3 that CpMo(NO)Cl(h -allyl)3
O
(2)
condensed with aldehydes via a chairlike transition state,
yielding homoallylic alcohols with excellent diastereoselectiv-
ities (Scheme 1). We applied this method to the syntheses of
acyclic 1,3-diols, 1,3,5-triols and other oxygen heterocycles.4
Despite numerous studies on these p-allyl species, there is no
precedent for the synthesis of natural products based on these
organometallics. Avenaciolide 1 and isoavenaciolide 2 are
secondary metabolites isolated from Aspergillus and Pen-
icillium; total syntheses of these two compounds have attracted
considerable attention4,5 because of their diverse and potent
biological activities. In this paper, we report total syntheses of
these two bislactones based on tungsten-p-allyl complexes; this
synthetic protocol is highly efficient because only a few steps
are required from the starting chloropropargyl derivatives 3 and
9.
O
O
H
H
H
H
O
O
C8H17
C8H17
O
1
O
2
Avenociolide
Isovenociolide
Scheme 1
The starting compound 3 is readily available from propargyl
chloride and n-butylglyoxalate.6 As shown in Scheme 2,
treatment of 3 with CpW(CO)3Na (1.3 equiv.) yielded tungsten-
1
h -propargyl complex A which was not isolated due to its high
reactivity. Elution of this tungsten species through a silica
O
Cl
OH
W
CO
OH
CO2Bun
O
W
W
CO
silica gel
CO2Bun
CO2Bun
3
A
4
W = CpW(CO)2
(1) NOBF4
(2) LiCl
(3) C8H17CHO
O
O
DEAD, Ph3P
W
I
O
p-TSA
O
O
NO
C8H17
or DBU
H
H
H
CO2Bun
BzOH, –78 °C
H
H
C8H17
BunO2C
C8H17
CO2Bun
O
OH
OH
O
B
6
5
H +
O
O
O
K2CO3/EtOH
3 min, 89%
p-TSA
150 °C, 4 h
O
O
O
H
H
H
H
H
H
C8H17
C8H17
C8H17
BunO2C
BunO2C
O C
BzO
OH
OH
OH
7
8
C
BzOH = p-nitro-
benzoic acid
DBU
O
O
O
O
O
O
H
H
H
H
H
C8H17
H
CO2Bun
O
O
C8H17
C8H17
O
OH
O
2
1
D
Scheme 2
Chem. Commun., 1998
1521

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O
Cl
OH
W
CO
OH
CO2Et
MeOH–CH2Cl2
p-TSA
O
W
W
CO
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
E
9
10
(1) NOBF4
(2) NaI
(3) C8H17CHO
O
O
O
O
O
O
MgCl2•6H2O
150 °C, 3 h
H
H
H
C8H17
CO2Et
H
CO2Et
CO2Et
O
O
C8H17
C8H17
O
O
OH
F
2
11
Scheme 3
column induced intramolecular alkoxycarbonylation4a,b to yield
sequential treatment with NOBF4 (1.0 equiv.) and NaI (2.0
equiv.), which then reacted with C8H17CHO to yield a 62%
yield of bislactone species 11 which was presumably produced
via lactonization of the primary species F. Decarboxylation of
11 proceeded smoothly through heating its dimethylacetamide
solution (150 °C, 3 h) containing MgCl2·6H2O (5.0 equiv.)9 to
afford the desired isoavenaciolide 2 in 59% yield.
In summary, we report here the first example of the use of
tungsten-p-allyl complexes for the efficient syntheses of
naturally occurring compounds such as avenaciolide and
isoavenaciolide. The overall synthetic scheme‡ is considered to
be the most efficient of the known methods. This demonstration
highlights the use of tungsten-allyl complexes in the syntheses
of natural products.
tungsten-syn-p-allyl complex 4 in 70% yield. The syn-
configuration of 4 is indicated by the coupling constant J34
=
3.1 Hz.4a,b Sequential treatment of 4 with NOBF4 (1.0 equiv.)
and LiCl (2.0 equiv.) in CH3CN generated an allyl anion
equivalent3 that reacted with C8H17CHO to yield a-methylene
butyrolactone 5 in 62% isolated yield. The trans-configuration
of 5 was confirmed by a proton NOE experiment. Determina-
tion of the remaining CH(OH)C8H18 configuration relies on its
transacylation product 6. The stereochemistry of 5 can be
rationalized based on a chairlike transition structure B in which
the new carbon–carbon bond is formed opposite the CO2Bun
substituent. Although compound 5 has a structural skeleton like
those for avenaciolide 1 and isoavenaciolide 2, inversions of
configuration of the C(5) and C(1A) carbons and at the C(5)
carbon of 5 are required to produce bislactones 1 and 2
respectively. Notably, epimerization at the C(5) carbon of 5 is
expected to give isoavenaciolide 2. Toward this direction,
compound 5 was heated in toluene for 7 hours with the DBU
catalyst (0.30 equiv.), however transacylation occurred to yield
a new a-methylene butyrolactone 6 in 86% yield that also has a
trans-configuration. Under the same conditions, the p-TSA
(p-toluenesulfonic acid) catalyst (0.20 equiv.) also gave com-
pound 6 in 91% yield. Hence, we sought to invert the
configuration at the CH(OH) carbon of 6; this was achieved by
the Mitsunobu reaction,7 sequentially giving 7 and 8 in 90% and
89% yields respectively. Heating 8 with excess p-TSA·H2O (2.0
equiv.) in toluene in a sealed tube (150 °C, 4 h) produced the
desired avenaciolide 1 in 62% yield together with iso-
avenaciolide 2 in 5% yield. The generation of 1 can be
envisaged to proceed from intramolecular attack of the acid
group of 8 at its C(5) carbon to invert its stereoconfiguration,5c,d
ultimately yielding avenaciolide 1. Attempts to synthesise
isoavenaciolide 2 via base-catalyzed transacylation of com-
pound 8 were unsuccessful. Heating a mixture of DBU (0.2–2.0
equiv.) and 8 in toluene at reflux for 72 h did not show any sign
of chemical reaction, and the starting material 8 was recovered
exclusively.
Notes and References
† E-mail: rsliu@faculty.nthu.edu.tw
‡ All the new compounds gave satisfactory microanalytical data.
1 A. J. Pearson, Synlett, 1990, 10.
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4
(a) W.-J. Vong, S.-M. Peng, S.-H. Peng, S.-H. Lin, W.-J. Lin and R.-S.
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We sought to develop an alternative approach to the synthesis
of isoavenaciolide 2 via tungsten-p-allyl complexes; the whole
synthesis requires only a few steps from chloropropargyl
species 9.8 As shown in Scheme 3, treatment of 9 with
CpW(CO)3Na (2.0 equiv.) in THF at 23 °C gave the expected
6 L. Brandsma, in Preparative Acetylenic Chemistry, Elsevier, Amsterdam,
1988.
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1
tungsten-h -propargyl species E which was subsequently
treated with p-TSA·H2O (1.0 equiv.) in a MeOH–CH2Cl2
mixture (volume ratio = 1 : 10) to induce alkoxycarbonylation
to yield tungsten-p-allyl complex 10 in 65% yield. Further
conversion of 10 produced a p-allyl anion equivalent via
Received in Cambridge, UK, 11th May 1998; 8/03491E
1522
Chem. Commun., 1998