A new approach to the synthesis of polycyclic structures

Article abstract of DOI:10.1016/j.tetlet.2004.06.035

A general, convergent approach to the synthesis of polycyclic structures has been developed, based on the tandem radical addition/cyclisation of xanthates to dienones followed by an ionic ring closure to give, finally, a number of variously substituted tricyclic compounds.

Full text of DOI:10.1016/j.tetlet.2004.06.035

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6017–6020
A new approach to the synthesis of polycyclic structures
*
€
Michael E. Briggs, Myriem El Qacemi, Chakib Kalaı and Samir Z. Zard
Laboratoire de Synthꢀese Organique associꢁe au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France
Received 15 April 2004; revised 3 June 2004; accepted 8 June 2004
Available online 26 June 2004
This paper is dedicated with respect and affection to the memory of Anne Ghosez-Giese
Abstract—A general, convergent approach to the synthesis of polycyclic structures has been developed, based on the tandem radical
addition/cyclisation of xanthates to dienones followed by an ionic ring closure to give, finally, a number of variously substituted
tricyclic compounds.
Ó 2004 Elsevier Ltd. All rights reserved.
Radical cyclisations are among the most powerful and
versatile reactions available for the construction of
mono- and polycyclic systems.1 However, many radical
processes can only easily be applied to intramolecular
radical cascades. The radical chemistry of xanthates
offers a flexible method for the creation of carbon–car-
bon bonds in either an intramolecular or, more impor-
tantly, an intermolecular fashion.2 By combining both
classes of bond forming reactions in a radical sequence,
it is possible to assemble quickly complex carbon
frameworks. In addition, variation of the functionality
present on the starting xanthate allows further ionic
cyclisations.
O
S
O
Et
O
S
Radical
initiator
m
O
n
O
O
O
S
Et
n
m
1. Reduction of xanthate
2. Intramolecular aldol
S
m
n
Scheme 1. General route to polycyclic compounds.
The general concept is outlined in Scheme 1. Addition of
a xanthate containing a suitably located ketone group to
the diene should result in the formation of the cis-fused
bicyclic compound as indicated in the first step. The
xanthate group could then be reductively cleaved or
used to introduce various functional groups and an
intramolecular aldol-crotonisation reaction would
finally lead to a tricyclic structure.
but heated at 195 °C for 50 min in a sealed tube to afford
the rearranged aldehyde 2.3 Exposure of the crude
aldehyde to the action of vinyl magnesium bromide
furnished the allylic alcohol, 3, which was oxidised with
IBX to enone 4 in an acceptable overall yield (Scheme 2).
Similarly, 3-methylcyclopent-2-enone, 5, was converted
to diene 8 by the same reaction sequence (Scheme 3),
although in this case PCC was found to be a superior
oxidising agent to IBX. As the Claisen rearrangement is
stereospecific,4 the use of an enantiopure alcohol would
give access to chiral alkenes and hence allow absolute
stereocontrol in the formation of the final polycyclic
products.
Dienes 4 and 8, derived, respectively, from ( )-isophorol
and 3-methylcyclopent-2-enone were chosen as model
substrates. Treatment of ( )-isophorol 1 with butyl vinyl
ether in the presence of mercuric acetate afforded the
corresponding allyl vinyl ether, which was not purified
Keywords: Radical cascades; Xanthate addition; Robinson annelation.
* Corresponding author. Tel.: +33-1693-34872; fax: +33-1693-33851;
e-mail: zard@poly.polytechnique.fr
Dienes 4 and 8 successfully underwent radical addition/
cyclisation with a-xanthyl ketones, 9a–c, to afford
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.035

6018
M. E. Briggs et al. / Tetrahedron Letters 45 (2004) 6017–6020
OH
S
Et
O
O
a, b
O
S
O
H
a
2
c
8
1
(38 %,
O
R1
over 3 steps)
O
S
O
Et
12a,b
O
d
OH
S
R1
b,c
(86 %)
9a or b
R1
O
4
3
Scheme 2. Reagents and conditions: (a) butyl vinyl ether, Hg(OAc)2,
D, 24 h; (b) sealed tube, 195 °C, 50 min; (c) vinyl magnesium bromide,
THF, 0 °C, 45 min; (d) IBX, DMSO, THF, 20 °C, 2 h.
13a,b
Scheme 5. Reagents and conditions: (a) DLP 5 mol % initially and
then 3 mol % every 2 h, 1,2-dichloroethane, D, 3-6 h; (b) n-Bu3SnH,
AIBN, PhMe, D, 2 h; (c) 2 M KOH , THF, D, 18 h.
ðaqÞ
O
unstable under basic conditions; however, the presence of
the xanthate is a powerful asset, since it could alterna-
tively be used as a point of entry into the extremely rich
ionic chemistry of sulfur or for the implementation of
another radical sequence. Aldol condensation under
basic conditions afforded the desired enones, 11a–c and
13a,b, in moderate yields. The reaction proved more
problematic than initially anticipated and resisted at-
tempts to find a general high yielding procedure. Table 1
gives the yields obtained for the three steps and the dia-
stereoisomeric ratios (dr) of the enone products. As the
stereocentres formed in the radical cascade are epimeri-
sable (except the two at the cis-ring fusion) and as the
reaction is carried out under thermodynamic control,
the dr was expected to reflect the relative stabilities of the
diastereomeric enone products. Such an effect was dem-
onstrated by separating 10a into two nonidentical mix-
tures of diastereoisomers. The two mixtures were then
separately subjected to the reduction and aldol conden-
sation procedures described above. After reduction of the
xanthate moiety, 1H and 13C NMR analysis showed
the major diastereoisomers to be different. However, after
the aldol condensation the spectroscopic data of the tri-
cyclic derivative 11a obtained in both cases were identical.
O
a-c
H
6
5
d
(30 %,
over 4 steps)
e
O
OH
56 %
8
7
Scheme 3. Reagents and conditions: (a) DIBAL-H, THF, 0 °C 1 h; (b)
butyl vinyl ether, Hg(OAc)2, D, 18 h; (c) sealed tube, 190 °C, 30 min; (d)
vinyl magnesium bromide, THF, 0 °C, 45 min; (e) PCC, DCM, 20 °C,
3 h.
cis-fused bicyclic compounds, 10a–c and 12a,b, respec-
tively (Schemes 4 and 5). The bicycles were obtained as
mixtures of diastereoisomers due to the chiral centre(s) a
to the carbonyl(s). For convenience, the xanthate group,
presumably in an exo-position, was reductively cleaved
prior to the aldol condensation as it is known to be
Acyl xanthates have been used for the formation of the
corresponding alkyl xanthates via radical decarbonyl-
ation.5 They have also been shown to undergo intra-
molecular radical additions to double bonds in
moderate yields. However, there are only a few examples
of intermolecular additions of acyl xanthates to double
bonds. In our case, starting the cascade with an acyl
radical would result in the formation of a cyclopente-
none ring after the aldol condensation. To this end, acyl
xanthate 16 was prepared from the corresponding acid
chloride 14 and the potassium salt of xanthic acid
(Scheme 6). The salt must be added portionwise over 1 h
while the reaction temperature is maintained below
)30 °C in order to avoid decomposition of the acyl
xanthate by unreacted xanthate salt.2
R2
O
S
O
Et
O
S
R1
a
4
O
O
O
S
R2
Et
10a-c
R1
S
R1
b,c
9a-c
O
R2
11a-c
Scheme 4. Reagents and conditions: (a) lauroyl peroxide (DLP)
5 mol % initially and then 3 mol % every 2 h, 1,2-dichloroethane, D, 12–
24 h; (b) n-Bu3SnH, AIBN, PhMe, D, 2 h; (c) KOH, ethanol, D, 30 min
The radical cascade was carried out by irradiating a
refluxing solution of the diene and the xanthate with
visible light. Reduction of the xanthate followed by
or 2 M KOH , THF, D, 18 h.
ðaqÞ

M. E. Briggs et al. / Tetrahedron Letters 45 (2004) 6017–6020
6019
Table 1
Diene
Xanthate
R1
R2
Yield (%),
radical cascade
Yield (%),
reduction
Yield (%),
aldol
dr (calcd by 1H and 13C
NMR analysis of isolated
products)
4
4
4
8
8
9a
9b
9c
9a
9b
H
H
10a, 73
10b, 51
10c, 75
12a, 75
12b, 65
76
59
60
76
91
11a, 61
11b, 60
11c, 54
13a, 46
13b, 65
4:1a
10:1b
10:1b
10:1
1:1
Me
H
H
Me
H
H
Me
H
a dr > 10:1 after crystallisation.
b Single diastereoisomer after crystallisation.
S
S
Et
Et
O
O
O
O
O
S
S
a
b
Pr
8
8
(90 %)
(76 %)
O
O
S
O
O
O
S
17
20
S
O
Et
b (75 %),
c (84 %),
d (47 %)
16
S
O
c (42 %,
76 % b.r.s.m.)
a
19
(83 %)
O
S
O
Et
O
SK
Cl
18, dr 1:1
21, dr 10:1
O
14
15
Scheme 7. Reagents and conditions: (a) DLP 5 mol % initially and
then 3 mol % every 2 h, 1,2-dichloroethane, D, 6 h; (b) n-Bu3SnH,
AIBN, PhMe, D, 2 h; (c) p-TSA, THF, H2O, D, 18 h.
Scheme 6. Reagents and conditions: (a) acetone, )40 to )30 °C, 1 h;
(b) visible light, PhMe, D, 3 h; (c) n-Bu3SnH, AIBN, PhMe, D, 2 h; (d)
1 M NaOEt/ethanol, THF, D, 18 h.
aldol condensation gave enone 18 as a 1:1 mixture of
diastereoisomers. Such [5.5.5]-fused ring systems are
found in a number of natural products, including the
triquinane family of terpenes.6 This approach provides
rapid access to the carbon framework of these com-
pounds.
S
Et
O
S
a
O
19
4
(58 %)
O
22
Another approach to linear triquinanes is to use xan-
thate 19, a compound easily accessible by Michael
addition of the xanthate salt to mesityl oxide under
mildly acidic conditions.7 In this case, the radical cas-
cade would provide access to a tricyclic enone 21 con-
taining the geminal dimethyl motif often found in
polyquinane terpenes (Scheme 7). Indeed, the tertiary
xanthate 19 readily underwent the radical cascade in
excellent yield to afford the bicyclic compound 20. Re-
moval of the xanthate was followed by an acid catalysed
aldol reaction. The thermodynamic enol formed under
the acidic conditions gave rise to the [5.5.5]-fused ring
system as the only product. The low yield was due to
incomplete reaction of the starting material, which could
be readily recovered by chromatography. The ease of
creation of the quaternary centre in the intermolecular
addition step is noteworthy.
b (77 %),
c (66 %)
O
O
23
3:2
24
Scheme 8. Reagents and conditions: (a) DLP 5 mol % initially and
then 3 mol % every 2 h, 1,2-dichloroethane, D, 6 h; (b) n-Bu3SnH,
AIBN, PhMe, D, 2 h; (c) KOH, ethanol, D, 18 h.
annelation under basic conditions resulting in the for-
mation of tricyclic derivatives 23 and 24. Thus, by
simply changing the conditions of the aldol condensa-
tion, it is possible to access a cyclopentenone or a
cycloheptenone structure.
Diene 4 also underwent the radical cascade with xan-
thate 19 to furnish bicyclic compound 22 (Scheme 8).
Reduction of the xanthate was followed by Robinson

6020
M. E. Briggs et al. / Tetrahedron Letters 45 (2004) 6017–6020
8. Typical experimental procedures: Lauroyl peroxide (DLP;
36 mg, 5 mol %) was added to a refluxing degassed solution
of diene 4 (0.35 g, 1.82 mmol) and xanthate 9a (1.79 g,
10.1 mmol, 5.5 equiv) in 1,2-dichloroethane (19 mL). Addi-
tional DLP (22 mg, 3 mol %) was added every 2 h to the
refluxing solution until no starting material was observed
by TLC. After cooling to rt, the solvent was removed in
vacuo to give a crude oil, which was purified using column
chromatography (diethyl ether–petroleum ether 1:9–2:8) to
afford the bicycle 10a (0.49 g, 73%) as a colourless oil.
A solution of the xanthate 10a (0.49 g, 1.32 mmol) in
toluene (13.2 mL) was heated at reflux for 30 min under a
nitrogen atmosphere. Tributyltin hydride (0.52 mL,
1.96 mmol) was added and heating was continued for a
further 1.5 h. AIBN (24 mg) was added and the reaction
was heated at reflux for a further 2 h before cooling to rt.
The solvent was removed in vacuo, the residue was
redissolved in MeCN and washed with pentane. The
MeCN was removed in vacuo and the crude oil purified
by column chromatography (diethyl ether–petroleum ether
2:8) to afford the reduced product (0.25 g, 76%) as a
colourless oil.
In summary, these preliminary model studies demon-
strate the feasibility and flexibility of this strategy for the
synthesis of polycyclic structures.8 Various combina-
tions of rings can be constructed by modifying both the
xanthate and the dienone, as well as the conditions for
the ionic cyclisation step. Last but not least, the ste-
reochemistry follows ultimately from that of the initial
allylic alcohol since the stereochemical information is
conserved in the powerful Claisen rearrangement. This
approach to polycyclic compounds is currently being
applied to natural product synthesis.
Acknowledgements
We thank Ecole Polytechnique for a grant (M.E.B.) and
Rhodia for generous financial support.
References and notes
A solution of the dione (0.25 g, 1.0 mmol) in THF (10 mL)
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and 2 M KOH
After cooling to rt, 1 M HCl
(2.0 mL) was heated at reflux for 18 h.
(10 mL) was added and the
ðaqÞ
ðaqÞ
mixture was stirred for a further 5 min before the solution
was extracted with Et2O. The combined organic extracts
were washed with brine, dried (MgSO4) and the solvent
removed in vacuo. The crude residue was purified by
column chromatography (diethyl ether–petroleum ether
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colourless solid. Recrystallisation from petroleum ether
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1
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CDCl3): dH (ppm): 5.85 (1H, d, J ¼ 2 Hz, olefinic H), 2.78–
2.74 (1H, m, CH), 2.50–2.45 (2H, m), 2.34–2.32 (2H, m),
2.18–2.13 (1H, m), 1.86–1.77 (1H, tt, J ¼ 14:4 and 4 Hz),
1.59–1.48 (2H, m), 1.42–1.3 (2H, m), 1.26–1.20 (3H, m),
1.20 (3H, s, CH3), 1.01 (3H, s, CH3), 0.90 (3H, s, CH3). 13
C
NMR (100 MHz, CDCl3): dC (ppm) 199.6 (CO), 174.5 (C
olefinic), 122.6 (CH olefinic), 49.6 (CH2), 49.1 (CH), 47.4
(CH2), 42.6 (CH), 39.1 (C), 37.1 (CH2), 34.6 (CH3), 32.1
(CH2), 30.4 (C), 28.1 (CH2), 27.7 (CH3), 26.7 (CH3), 18.7
(CH2). IR (CH2Cl2) mmax (cmꢀ1): 2917s, 1734w, 1716w,
1667s. Combustion analysis: Found C 82.4%, H 10.3%;
Required C 82.7%, H 10.4%. MS (CI) m=z (%): 233 (100%,
MH).
7. Binot, G.; Quiclet-Sire, B.; Saleh, T.; Zard, S. Z. Synlett
2003, 382–386.