An unusual approach to spirolactones and related structures

Article abstract of DOI:10.1039/b516020k

Spirocyclic structures can be obtained by an ipso-type radical cyclisation onto a furan or a suitably substituted pyrrole followed by oxidation of the stabilised radical adduct. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b516020k

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An unusual approach to spirolactones and related structures
Soizic Guindeuil and Samir Z. Zard*
Received (in Cambridge, UK) 14th November 2005, Accepted 20th December 2005
First published as an Advance Article on the web 6th January 2006
DOI: 10.1039/b516020k
were separable. Curiously, the substrate with the smaller methyl
Spirocyclic structures can be obtained by an ipso-type radical
cyclisation onto a furan or a suitably substituted pyrrole
followed by oxidation of the stabilised radical adduct.
group exhibited a better selectivity during the spirocyclisation than
the analogous ethyl substituted derivative (entries 4 and 5, Table 1).
The intramolecular radical cyclisation to aryl rings followed by re-
aromatisation is well known for the synthesis of polycyclic
derivatives. In contrast, the ipso-type radical cyclisation, which
proceeds with overall de-aromatisation, is less well documented,
although spirocyclisation examples exist of various aromatic rings
such as benzenes,1 pyrroles,2 indoles3,4 or benzofurans.4 This
reaction has also been studied with furans, but only in the
particular case of vinyl radicals, resulting in a mixture of the
spirocyclic compound and the product of fragmentation.5
We have previously noted, in one particular case, that a furan
could lead to a product of spirocyclisation upon radical addition.
This may be due to the poorer aromatic character of a furan in
comparison with a benzene ring, which furnishes the product of
normal cyclisation and re-aromatisation under the same condi-
tions.6 We have now found that this process is in fact quite general
with furans and opens the way to complex spirocyclic structures. In
the past, such structures have been constructed by electrosynthesis7
or through a vinylogous Mannich reaction of 5-alkoxyfurans.8
We first prepared xanthate 1a and found that it was converted
into spirocyclic derivative 2a in good yield upon exposure to
stoichiometric quantities of lauroyl peroxide in a refluxing 3 : 1
mixture of 1,2-dichloroethane (DCE) and methanol (Scheme 1). In
a first step, the radical generated from the xanthate cyclises onto
the C-2 position of the furan and not the C-3. The allylic radical
thus produced is then oxidised to the allylic cation by electron
transfer to lauroyl peroxide. The cation is then quenched with a
nucleophile present in the medium, methanol in this case.
Scheme 1 Reagents and conditions: (i) Lauroyl peroxide (DLP), 1,2-
DCE–MeOH, reflux, 76%.
Scheme 2 Reagents and conditions: (i) mCPBA, BF3?OEt2, CH2Cl2,
220/215 uC, 66% (ii) allylTMS, TMSOTf, CH2Cl2, 278 uC, 63% (3 : 1).
Spirolactam 2a was obtained in good yield and the acetal
function could be oxidised to lactone 3a by mCPBA.9 This
eliminated one asymmetric center and facilitated the interpretation
of the NMR spectra. However the acetal could also be used to
introduce other functionalities such as an allyl group by a Sakurai
reaction with allyltrimethylsilane (Scheme 2).
Table 1
In the first instance, we briefly studied the influence of
substituent R1 on the nitrogen (entries 1 and 2, Table 1). The
best result was obtained with the bulkier group (t-Bu). We next
introduced substituents on the a position to the carbonyl (R3) or a
to the nitrogen (R2) of the amide function (entries 3 to 5, Table 1).
In all cases, good yields were obtained with the formation of two
major diastereoisomers. In the case of the R2 substituent, a to the
nitrogen, the selectivity was much better and the diastereoisomers
(i) 180–210% DLP, 1,2-DCE–MeOH, reflux (ii) mCPBA, BF3?OEt2,
CH2Cl2
Entry R1
R2 R3 Yield (2) (ratio)
Yield (3) (ratio)
1
2
3
4
5
a
t-Bu
Boc
t-Bu
t-Bu Me
t-Bu Et
H
H
H
H
H
2a 76% (1 : 1)
2b 59% (1 : 1)
3a 66%
3b 23%
3c 84% (3 : 1)
Me 2c 73% (3 : 3 : 1 : 1)
H
H
2d 68% (10 : 10 : 1 : 1)a 3d 67%b
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole
Polytechnique, 91128 Palaiseau cedex, France.
E-mail: zard@poly.polytechnique.fr; Fax: +33 (0)1 69 33 38 51;
Tel: +33 (0)1 69 33 48 72
2e 52% (6 : 6 : 1 : 1)a
3e 76%b
b
Separable diastereoisomers.
diastereoisomers.
Obtained from the two major
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Table 3
Fig. 1 (-)-Securinine and asperparaline A (1).
(i) 300% DLP, 1,2-DCE/–MeOH, reflux (ii) mCPBA, BF3?OEt2,
CH2Cl2
Table 2
Entry
X
Yield (13) (ratio)
Yield (14) (ratio)
1
2
3
S
no reaction
degradation
34% (1 : 1)
—
—
79%
N–Me
N–Ts
In this preliminary study, we have further briefly examined
replacing the furan moiety by other aromatic systems such as a
thiophene or a pyrrole (Table 3). No identifiable reaction took
place with the thiophene but the radical spirocyclisation was
observed with the pyrrole, as long as an electron withdrawing
group was placed on the nitrogen. A simple methyl group only led
to degradation, presumably because of the instability of the
primary spiro adduct. In summary, we have developed a new
radical spirocyclisation onto furans which uses tin-free radical
chemistry and exploits the possibility of a cross-over from a radical
to a polar manifold. This reaction gives access to new spirocyclic
and heterocyclic structures, some of which could be used in the
synthesis of a number of alkaloids containing such subunits.{
(i) 180–210% DLP, 1,2-DCE–MeOH, reflux (ii) mCPBA, BF3?OEt2,
CH2Cl2
Entry
n
Yield (6) (ratio)
Yield (7) (ratio)
1
2
3
a
0
1
2
6a 65% (3 : 3 : 1 : 1)
6b 48% (1 : 1 : 1 : 1)
6c 50% (1 : 1 : 1 : 1)a
b
7a 68% (3 : 1)
7b 65% (1 : 1)a
7c 74% or 46%b
Separable diastereoisomers.
These yields correspond to the
oxidation of the separated pairs of diastereoisomers 6c.
The two major diastereoisomers gave only one isomer after
oxidation. 2D NOESY experiments indicated a relative configu-
ration where the R2 group is anti to the furan oxygen.
We applied this approach to the expedient synthesis of the
tricyclic A,B,D system of securinine (Fig. 1) and analogues.10,11
This system was obtained in good yield in the case of a 5, 6 and
7-membered ring A but unfortunately with little or no selectivity
(Table 2).
Notes and references
{ Typical experimental procedures.
Radical spirocyclisation. A solution of the xanthate (1 mmol) in 1,2-
dichloroethane and methanol (3 : 1, 5 mL) was heated to reflux for 15 min
under a nitrogen atmosphere. Lauroyl peroxide (10 mol%) was then added
every 1 h until complete consumption of the xanthate was observed. The
solvent was removed under reduced pressure and the residue purified by
chromatography on a silica gel column (ethyl acetate–petroleum ether) to
furnish the desired product.
Oxidation of the cyclic acetal lactone. A solution of mCPBA (1.1 mmol)
in dichloromethane (2 mL) was added to a solution of the acetal (1 mmol)
in dichloromethane (4 mL) at 220/215 uC followed by BF3?OEt2
(1.1 mmol). When TLC indicated complete transformation, the reaction
was quenched with saturated NaHCO3 solution and extracted twice with
dichloromethane. The combined organic extracts were dried over MgSO4,
filtered and concentrated in vacuo. The residue was purified by
chromatography on a silica gel column (ethyl acetate–petroleum ether) to
furnish the desired product.
As some natural compounds, such as the potent insecticidal
asperparalines12 (Fig. 1), possess a spirocyclic imide function, we
replaced the amide with an imide group. Unfortunately, the results
were not very satisfactory (Scheme 3). In the case of a methyl
group on the nitrogen (8a), a competing hydrolysis of the imide by
methanol occurred to give amide 9. The use of a less nucleophilic
solvent such as t-BuOH, CF3CH2OH or AcOH did not improve
the result. With a bulkier iso-propyl group (8b) on the nitrogen, the
product of hydrolysis was not observed but the improvement in
the overall yield of the reaction remained modest.
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Scheme 3 Reagents and conditions: (i) Lauroyl peroxide (DLP), 1,2-
DCE–MeOH, reflux (ii) mCPBA, BF3?OEt2, CH2Cl2, 220/215 uC.
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666 | Chem. Commun., 2006, 665–667
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