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M. Lachia et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2123–2128
R1
8b
R1
X
O
O
R1
O
O
O
O
R1
O
C
X
C
R1
[2+2]
Baeyer-Villiger
R2
A
B
4
R2
2
3a R
R2
R2
R3
O
R3
R3
O
R3
R3
Me
GR-24 analogues
Ketene or
Ketene-iminium
Figure 1. Synthesis of analogues of GR-24 substituted at C-3a, C-4 and C-8b.
Me n-Bu
n-Bu
Sn
n-Bu
after its formation). Recently, Maulide and co-workers have
reported the use of 2-fluoropyridine to improve the formation of
ketene-iminium salt.7 This condition showed a great improvement
in our system with 67% of the desired product isolated
Me
N
1) (COCl)2,
O
OH
O
Me
CH2Cl2, DMF
2
PdP(PH3)4, toluene
reflux
2) HNMe2, 0 °C,
CH2Cl2
I
I
The low reactivity of our substrates was surprising as Ghosez
and co-workers have shown that the formation of ketene-iminium
salts and their cycloaddition tolerate two adjacent substituents on
the amide.8 In our case, in the preferred conformation of the O-tri-
fluoromethylsulfonyl iminium intermediate, the benzylic proton
suffered from steric hindrance and from reduced kinetic acidity
due to its orthogonal orientation with the aryl ring. Both steric
and electronic factors led to a slow formation of the ketene-imin-
ium salt. The synthesis of the strigolactone analogue was carried
on and tricyclic lactone 5b was obtained (Scheme 2).
1
99%
Me
N
O
1)Tf2O, collidine
CH2Cl2, rt
O
O
Me
O
H2O2
2) H2O, rt
AcOH
Me
Me
Me
3a
74%
4a
40%
5a
68%
The synthesis of the C4-Me analogue required the introduction
of an additional methyl group in the allylic position prior to the
intramolecular [2+2] cycloaddition (Scheme 3). Stille coupling of
aryl iodide 1 with stannane 6 followed by hydrolysis gave ketone
7. Then, Wittig reaction between the ketone 7 and the phospho-
nium ylide 9 led to the compound 8 in good yield when n-BuLi
was used as a base, to avoid the intramolecular Claisen condensa-
tion product. The hydrolysis with HBr was quantitative and
another Wittig reaction afforded the olefin 3c in 70%.
Scheme 1. Synthesis substituted 4-methyl tricyclic ABC skeleton.
Me
N
Me
N
O
O
Me
Me
1) tributyl allyl stannane
PdP(Ph3)4, toluene, reflux
Me
2) LiHMDS, MeI,
THF, - 78 °C
I
1
3b
The cycloaddition was carried out under our standard condi-
tions with the N,N-dimethylamide derivative 3c, expecting that
the additional methyl group in the allylic position could induce
some stereocontrol during the intramolecular [2+2] cycloaddition.
Cyclobutanone 4c was isolated in good yield, however has a
mixture of 2 regioisomers (6:1), each regioisomer being a mixture
of diastereoisomers (3:1). We had found in our recent studies on
GR-24 that the replacement of the N,N-dimethylamide by the
N,N-diisopropylamide reduced the reactivity of the ketene-imini-
um and increased the regioselectivity of the reaction.6 The N,N-
diisopropylamide 3d was prepared according to the same scheme.
Indeed, the cycloaddition of 3d gave 70% of the cyclobutanone 4c
as a single regioisomer and a 3.5:1 mixture of diastereoisomers.
The stereochemistry of the 2 compounds was determined by 1H
NMR-NOE analysis. Baeyer–Villiger oxidation of the cyclobutanone
4c afforded the tricyclic lactone 5c (The major diastereoisomer is
depicted in Scheme 3).
Finally, the incorporation of a hydroxy group at C-4 was inves-
tigated as a mimic of the natural products orobanchol and solana-
col (Scheme 4). Aldehyde 11 was obtained in 2 steps by Stille
coupling of aryl iodide 10 with vinyl stannane and oxidative
cleavage with OsO4 and NaIO4. Then vinyl magnesium bromide
was added and the resulting alcohol was protected with a TBS
group. Unfortunately, the cycloaddition was disappointing, giving
low yield of the desired cyclobutanone and with no diastereoselec-
tivity. The allylic silylether deactivates the C@C bond for the intra-
molecular [2+2] cycloaddition reaction (lowering the level of the
HOMO and the coefficient on the terminal carbon atom) and prob-
ably interferes through addition of one of the oxygen electron lone
pairs to the highly electrophilic ketene-iminium.9
79%
O
1) Tf2O, 2-F-pyridine
CH2Cl2, rt
O
Me
O
Me
H2O2
AcOH
2) H2O
4b
67%
5b
68%
Scheme 2. Synthesis of tricyclic lactone substituted at C-8b.
on the outcome of the reaction but the addition to two equivalents
of reagents and longer reaction time improved the conversion to
55% (entry 4). Different bases were then investigated (Table 1).
Diisopropylethylamine (DIPEA) gave the desired product, albeit
in only 26% yield. Triethylamine was too nucleophilic and decom-
position was observed whereas the addition of DMAP inhibited
completely the formation of the ketene-iminium (or quenched it
Table 1
Optimization of the cycloaddition of 3b
Entry
Base
Time and T (°C)
Yield 4b
1
2
Collidine (1 equiv)
Collidine (1 equiv)
Collidine (1 equiv)
Collidine (2.4 equiv)
DIPEA (1.1 equiv)
DIPEA (5 equiv)
DBU (1.1 equiv)
Triethylamine (1.1 equiv)
Collidine, DMAP
8 h at rt
10% (+85% 3b)
8% (+85% 3b)
10% (+88% 3b)
50% (+45% 3b)
26%
Decomposition
Starting material
Decomposition
Starting material
67%
24 h at rt
24 h at 40 °C
70 h at rt
8 h at rt
8 h at rt
8 h at rt
8 h at rt
8 h at rt
70 h at rt
3
4*
5
6
7
8
9
Consequently, we turned our strategy towards the direct oxida-
tion of lactone 12, in a similar manner as reported by Zwanenburg
and co-workers.5a Treatment of lactone 12 with potassium
10*
2-F-pyridine (2.4 equiv)
*
2.0 equiv of Tf2O were used in the reaction.