New access to a tricyclo[3.2.1.02,7]oct-3-ene structure

Article abstract of DOI:10.1055/s-2007-970761

A thermally induced reaction cascade including an electrocyclic rearrangement, two Diels-Alder reactions and a 1,4-elimination from a simple cyclobutene carbonate can explain the synthesis of a complex tricyclo[3.2.1.0^2,7]oct-3-ene core structu

Full text of DOI:10.1055/s-2007-970761

800
LETTER
New Access to a Tricyclo[3.2.1.02,7]oct-3-ene Structure
New
A
cce
u
ss to a Tricylclo[3.2 2,7
i
.1.0 ]o
e
ct-3-ene
S
n
tructure Dubarle-Offner,a Jérôme Marrot,b Marie-Noëlle Rager,c Franck Le Bideau,*a Gérard Jaouena
a
Laboratoire de Chimie et Biochimie des Complexes Moléculaires, UMR CNRS 7576, Ecole Nationale Supérieure de Chimie de Paris,
11 Rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Fax +33(1)43260061; E-mail: franck-lebideau@enscp.fr
b
c
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles Saint-Quentin-en-Yvelines, 45 Avenue des Etats-Unis,
78035 Versailles Cedex, France
Service de RMN, Ecole Nationale Supérieure de Chimie de Paris, 11 Rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Received 12 September 2006
a
b
Abstract: A thermally induced reaction cascade including an elec-
trocyclic rearrangement, two Diels–Alder reactions and a 1,4-elim-
ination from a simple cyclobutene carbonate can explain the
synthesis of a complex tricyclo[3.2.1.02,7]oct-3-ene core structure.
Ph
O
Ph
Ph
O
Ph
Cl
Cl
1
2
3
Key words: 1,4-elimination, Diels–Alder, electrocyclic reaction,
polycycles, stereoselective synthesis
c
d
HO
Ph
MeO2CO
5
4
The strained tricyclo[3.2.1.02,7]oct-3-ene motif has been
found as the core of a few molecules of biological interest1
and in intermediate compounds in the synthesis of cafes-
tol.2 Among the most efficient ways to synthesize such an
interesting structure are base-induced3 or metal-catalyzed
rearrangements,4 the cobalt-catalyzed [4+2+2] cycloaddi-
tions,5 the homo-Diels–Alder reactions6 and the intramo-
lecular Diels–Alder (IMDA) reactions.7 This last method,
involving the cyclization of a 5-vinyl-1,3-cyclohexadiene
framework (Scheme 1) has been the most encountered
and studied to date.
Scheme 2 Reagents and conditions: (a) CCl3COCl, Zn(Cu), DME,
Et2O; (b) Zn, TMEDA, AcOH, EtOH (39% from 1); (c) i. CeCl3,
NaBH4, MeOH, 10 min, r.t.; (d) ClCO2Me, Et3N, DMAP, CH2Cl2, r.t.,
1.5 h (52% from 2).
Ph
Ph
DMSO, ∆, 1.5 h
MeO2CO
Ph
33%
MeO2CO
H
5
6
Scheme 3
Heating of compound 5 in refluxing DMSO for 90 min-
utes led to the formation of the tricyclic structure 612 in
33% yield as a single diastereomer (Scheme 3) which was
elucidated by extensive NMR studies including COSY,
NOESY, HMQC and HMBC analysis.
Scheme 1
We now report a route to a compound containing such a
motif from methyl 3-phenylcyclobut-2-enyl carbonate (5)
which was synthesized from phenyl acetylene
(Scheme 2).
3
Ph
4
2
H8
H6 Ph1
Ph
7
H5
1
NOE H8' H8
The 3-phenylcyclobutenone (3) was prepared following
a procedure reported in the literature8 except that the 3-
phenyl-4,4-dichlorocyclobutenone (2) was not isolated
prior to reduction. The cyclobutenone 3 was selectively
reduced in high yield with sodium borohydride in metha-
nol in the presence of cerium trichloride according to the
Luche methodology9 to the unstable allylic alcohol 4.10
H8'
H6
RO
Figure 1 Observed NOE for 6 (R = CO2Me)
The NOE experiment, in particular, allowed the determi-
nation of the relative configuration at C6 (Figure 1).
This species was immediately reacted with methyl chloro-
formate, triethylamine and 4-dimethylamino pyridine in
dichloromethane to give the corresponding carbonate 511
(Scheme 2) in 20% overall yield from phenyl acetylene in
four steps.
To confirm the unusual structure of this product, crystals
were grown by slow diffusion of pentane into a dichloro-
methane solution of 6 and its structure (Figure 2) was
determined by an X-ray diffraction study.
In order to elucidate the mechanistic nature of the trans-
formation, we turned to reaction conditions with lower
temperature. Compound 5 was heated at 140 °C in the
absence of solvent for 30 minutes (Scheme 4) to give four
products isolated by flash chromatography and a large
SYNLETT 2007, No. 5, pp 0800–0802
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970761; Art ID: D27106ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
New Access to a Tricyclo[3.2.1.02,7]oct-3-ene Structure
801
any analysis in this study and our attempt to generate it in
basic conditions (t-BuOK, 18-crown-6 ether, toluene, r.t.)
as reported in the literature for a similar compound15 led
to an intractable mixture. The IMDA process in that case
is probably too rapid to allow the isolation of such a spe-
cies. It is worth noting that the E-geometry of the dieno-
phile part in 9 is required to deliver the OR group of
compound 6 in the equatorial position. This configuration
is observed in the precursors 7 (as mentioned above in the
text) and 8 (both diastereomers had large coupling con-
stants of 12.6 Hz and 12.7 Hz).
Both compounds 7 and 8 were refluxed in DMSO for 90
minutes to give 6 in 43% and 78% yields, respectively,
indicating their participation as intermediate compounds
on the route to the tricyclic structure.
Figure 2 X-ray crystal structure of compound 6
In summary, we have reported the synthesis of a new
substituted tricyclo[3.2.1.02,7]oct-3-ene structure from a
simple cyclobutene carbonate. The yield of the overall
transformation (33%) is high, taking into account the four
steps involved in this one-pot process and the large num-
ber of possible diastereomers. A few other cyclobutene
carbonates (where the phenyl group was replaced by alkyl
or silyl substituents) were not transformed into the desired
tricyclic species. We are now working on elucidating the
nature of the substitution in order to expand these cascade
reactions.
amount of degradation.13 The diene 7 (5%), resulting from
a conrotatory ring opening14 showed a doublet with a large
coupling constant (J = 12.4 Hz) at 7.09 ppm for the ole-
finic proton consistent with an E-configuration. An in-
separable mixture of two diastereomers 8 (1:1; 19%) was
characterized by NMR (1H, 13C and DEPT) and HRMS
while compound 6 was synthesized in 21% yield.
RO
RO
Ph
+
Ph
Ph
a
Ph
References and Notes
+
b
5
6
(1) (a) Pelletier, S. W.; Mody, N. V.; Djarmati, Z.; Lajsic, S. D.
J. Org. Chem. 1976, 41, 3042. (b) Bohlmann, F.; Jakupovic,
J.; Ahmed, M.; Grenz, M.; Suding, H.; Robinson, H.; King,
R. M. Phytochemistry 1981, 20, 113.
(2) Corey, E. J.; Wess, G.; Xiang, Y. B.; Singh, A. K. J. Am.
Chem. Soc. 1987, 109, 4717.
7
8 (1:1)
RO
RO
Scheme 4 Reagents and conditions: (a) 140 °C, 30 min; (b) r.t.,
3 months.
(3) (a) Hodgson, D. M.; Marriott, R. E. Tetrahedron Lett. 1997,
38, 887. (b) Mehta, G.; Ravikrishna, Ch. Tetrahedron Lett.
1996, 37, 2655.
(4) Hoberg, J. O.; Jennings, P. W. J. Am. Chem. Soc. 1990, 112,
5347.
(5) Kiattansakul, R.; Snyder, J. K. Tetrahedron Lett. 1999, 40,
1079.
(6) Zimmerman, H. E.; Grunewald, G. L. J. Am. Chem. Soc.
1964, 86, 1434.
(7) (a) Abad, A.; Agullo, C.; Cunat, A. C.; De Alfonso, I.;
Navarro, I.; Vera, N. Molecules 2004, 9, 287. (b) Moses, J.
E.; Baldwin, J. E.; Adlington, R. M.; Cowley, A. R.;
Marquez, R. Tetrahedron Lett. 2003, 44, 6625. (c) Ng, S.
M.; Beaudry, C. M.; Trauner, D. Org. Lett. 2003, 5, 1701.
(8) Danheiser, R. L.; Savariar, S.; Cha, D. D. Org. Synth. 1990,
68, 32.
(9) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
5454.
(10) Manatt, S. L.; Vogel, M.; Knutson, D.; Roberts, J. D. J. Am.
Chem. Soc. 1964, 86, 2645.
1
The H NMR spectra of a sample of diene 7 kept three
months at room temperature showed the disappearance of
this species with the formation of 8 (1:1) as the major
products and, according to the presence of a multiplet be-
tween 3.9 and 3.4 ppm corresponding to the methoxy
group, to degradation compounds. This totally regio- and
chemoselective process thus allows for the formation of
only two products out of eight possible stereoisomers.
RO
Ph
Ph
Ph
Ph
Ph
OR
Ph
RO
H
RO
8
9
6
Scheme 5
(11) Methyl 3-Phenylcyclobut-2-enyl Carbonate (5).
To a solution of 3-phenylcyclobutenone (3, 2.1 g, 14.5
mmol) and CeCl3·7H2O (5.6 g, 22.7 mmol) in MeOH (50
mL) at r.t. was slowly added NaBH4 (580 mg, 15 mmol) over
15 min. The reaction mixture was stirred at that temperature
for 5 min, hydrolyzed with brine (50 mL) and extracted with
Et2O (3 × 50 mL). The organic layer was dried over MgSO4
The logical missing link between 8 and 6 is the vinyl
cyclohexadiene 9 (Scheme 5), which could arise from 8
through a rare thermal 1,4-elimination step,15 and could
cyclize via an IMDA reaction to furnish the tricyclic
structure 6. This compound was not isolated or detected in
Synlett 2007, No. 5, 800–802 © Thieme Stuttgart · New York

802
J. Dubarle-Offner et al.
LETTER
and evaporated to give a residue (2.1 g) which was dissolved
in CH2Cl2 (150 mL) in the presence of Et3N (8 mL, 57
mmol) and 4-dimethylamino pyridine (1 g, 8 mmol). Then,
ClCO2Me (4.7 mL, 60 mmol) was slowly added and the
reaction mixture was stirred for 75 min at r.t. After dilution
in CH2Cl2 (50 mL), it was hydrolyzed with brine (100 mL)
and extracted with Et2O (3 × 100 mL). The organic layer
was dried over MgSO4, evaporated and the residue was
purified by flash chromatography (pentane–CH2Cl2 = 70:30)
to give the carbonate 5 as a yellow oil (1.83 g, 62%). 1H
NMR (400 MHz, CDCl3): d = 7.50–7.30 (m, 5 H), 6.34 (br
s, 1 H), 5.40 (dt, J = 3.9, 1.0 Hz, 1 H), 3.81 (s, 3 H), 3.23
(ddd, J = 13.1, 3.9, 1.0 Hz, 1 H), 2.83 (dt, J = 13.1, 1.0 Hz,
1H) ppm. 13C NMR (75 MHz, CDCl3): d = 155.4, 148.6,
133.0, 129.1, 128.4, 125.6, 125.0, 71.1, 54.6, 36.9 ppm. IR
(CHCl3): n = 3062–2850, 1743, 1444, 1259 cm–1. MS (EI):
m/z = 146 [MNH4+ – MeOCO2H].
(KBr): 3031, 2922, 2856, 1742, 1440, 1292, 1265, 968, 755,
697 cm–1. Anal. Calcd for C22H20O3: C, 79.50; H, 6.06.
Found: C, 79.50; H, 6.31.
(13) The carbonate 5 (368 mg, 1.8 mmol) was heated at 140 °C
(neat) for 30 min. The residue was purified by flash
chromatography (pentane–Et2O = 95:5, followed by
pentane–Et2O = 80:20) to afford successively the tricyclic
compound 6 as a white solid (62 mg, 21%), a mixture of the
diastereomers 8 (69 mg, 19%) and diene 7 (10 mg, 5%).
Diastereomers 8: 1H NMR (300 MHz, CDCl3): d = 7.50–
7.20 (m, 20 H, Ph), 6.95 (d, J = 12.6 Hz, 1 H, CHtrans), 6.91
(d, J = 12.7 Hz, 1 H, CHtrans), 6.32 (br d, J = 5.1 Hz, 1 H,
CH), 6.29 (dt, J = 4.3, 1.6 Hz, 1 H, CH), 5.73 (d, J = 12.6 Hz,
1 H, CHtrans), 5.65 (d, J = 4.3 Hz, 1 H, CHO), 5.63 (d,
J = 12.7 Hz, 1 H, CHtrans), 5.51 (d, J = 5.1 Hz, 1 H, CHO),
3.82 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 3.77 (s, 3 H, OMe),
3.55 (s, 3 H, OMe), 2.70–2.40 (m, 4 H, CH2), 2.40–2.10 (m,
4 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): d = 155.4,
155.0, 153.4, 153.3 (CO), 142.9, 142.2, 142.1, 142.0 (Cipso),
140.1, 140.0 (CQ), 138.9, 138.4 (CH), 128.4, 128.3, 128.2,
128.1, 127.9, 127.3, 126.9, 126.8, 126.7, 125.6, 125.5,
120.6, 119.5, 118.9, 118.7 (CH), 77.2, 75.7 (CH), 55.2, 55.1,
54.8, 54.6 (CH3), 44.4, 44.1 (CQ), 29.7, 27.7, 25.5, 25.1
(CH2) ppm. HRMS: m/z calcd for C24H28O6N [M + NH4]:
426.1917; found: 426.1915.
(12) Compounds 6:
The carbonate 5 (300 mg, 1.5 mmol) in DMSO (1 mL) was
heated at DMSO reflux for 1.5 h under argon. The crude
reaction mixture was diluted with brine (15 mL) and
extracted with EtOAc (3 × 10 mL). The organic layer was
dried over MgSO4, evaporated and the residue was purified
by flash chromatography (CH2Cl2–pentane = 1:2) to give the
compound 6 as a white solid (84 mg, 33%). 1H NMR (300
MHz, CDCl3): d = 7.50–7.20 (m, 10 H, arom.), 6.59 (dd,
J = 6.2, 2.3 Hz, H3), 5.26 (dd, J = 4.7, 2.3 Hz, 1 H, H6), 3.71
(t, J = 3.9 Hz, 1 H, H5), 3.69 (s, 3 H, H10), 2.35 (dd, J = 6.8,
2.4 Hz, 1 H, H7), 2.23 (dd, J = 8.0, 6.2 Hz, 1 H, H2), 2.18 (dd,
J = 11.7, 5.1 Hz, 1 H, H8¢), 1.57 (d, J = 11.7 Hz, 1 H, H8)
ppm. 13C NMR (75 MHz, CDCl3): d = 155.5 (C=O), 141.2
(Ph), 139.2 (C4), 135.9, 127.5, 126.7, 126.2, 126.0, 124.9
(Ph), 120.4 (C3), 75.5 (C6), 54.5 (methoxy), 38.3 (C5), 31.9
(C1), 31.2 (C8), 28.2 (C2), 27.2 (C7) ppm. Mp 117 °C. IR
Diene 7: 1H NMR (300 MHz, CDCl3): d = 7.09 (d, J = 12.4
Hz, 1 H), 6.32 (dd, J = 12.4, 0.8 Hz, 1 H), 5.27 (dd, J = 1.5,
0.6 Hz, 1 H), 5.15 (d, J = 1.5 Hz, 1 H), 3.84 (s, 3 H) ppm. 13
NMR (75 MHz, CDCl3): d = 153.3, 143.6, 140.3, 139.5,
128.4, 127.8, 117.2, 116.5, 55.3 ppm. MS (EI): m/z = 178
[MNH4+ – CO2].
C
(14) Keana, F. W.; Taneja, H. R.; Erion, M. Synth. Commun.
1982, 12, 167.
(15) Hill, R. K.; Bock, M. G. J. Am. Chem. Soc. 1978, 100, 637.
Synlett 2007, No. 5, 800–802 © Thieme Stuttgart · New York