A concise total synthesis of the purported structure of flossonol

Article abstract of DOI:10.1055/s-0032-1317848

We report the first total synthesis of flossonol in only five steps and of one of its isomers in seven steps using a radical addition/cyclization sequence as the key step. Comparison of our spectroscopic data with those of the literature indicates a misas

Full text of DOI:10.1055/s-0032-1317848

LETTER
▌157
lAetteCr oncise Total Synthesis of the Purported Structure of Flossonol
Concise Total Synthesis of the Purported Structure of Flossonol
Raphaël F. Guignard*
Laboratoire de Synthèse Organique, CNRS UMR 7652, Ecole Polytechnique, 91128 Palaiseau, France
Fax +33(1)69335972; E-mail: guignard@dcso.polytechnique.fr
Received: 03.09.2012; Accepted after revision: 15.11.2012
methylanisole (3), as shown by the retrosynthetic analysis
in Scheme 2. The key intermediate would be xanthate 2,
which should be readily accessible from 2-methylanisole
(3).
Abstract: We report the first total synthesis of flossonol in only
five steps and of one of its isomers in seven steps using a radical
addition/cyclization sequence as the key step. Comparison of our
spectroscopic data with those of the literature indicates a misassign-
ment in the structure of flossonol.
O
Key words: radical reaction, addition, cyclization, total synthesis,
bicyclic compounds
1
S
OEt
MeO
MeO
2
3
S
Flossonol was isolated in 1987 by Cassady et al. from
Pararistolochia Flos-Avi.1 It was assigned 4-hydroxy-
tetralone structure 1 on the basis of various spectroscopic
data. This molecule has shown cytotoxicity at 1.32 × 10–5
mol·L–1 against PS cells in culture.2 We wish to report the
first synthesis of the purported structure of flossonol and
point out the need for a possible revision (Figure 1).
Scheme 2
Indeed, Friedel–Crafts reaction of 2-methylanisole (3)
with 2-bromopropionyl bromide in the presence of alumi-
num chloride in anhydrous 1,2-dichloroethane gave bro-
moketone 4 in good yield as only one regioisomer.
Without purification, nucleophilic substitution of the bro-
mide 4 by potassium O-ethyl xanthate in cold acetone
yielded product 2 quantitatively (Scheme 3).
O
MeO
O
OH
1
O
O
Br
KSCSOEt
Br
Figure 1 Putative structure of flossonol
3
AlCl3
DCE
S
S
Br
4, 82%
acetone
0 °C, 1 h
MeO
MeO
Tetralones are often found as substructures of natural
products.3 Unfortunately, few ionic4 or radical5 methods
exist to synthesize this moiety. Recently, Zard and co-
workers described a general approach to tetralones based
on the degenerative radical addition transfer of xanthates,
as outlined in Scheme 1.6
r.t., 3 h
2, quant.
OEt
Scheme 3
With the key xanthate 2 in hand, the two-step radical
sequence could be tested. Addition to vinyl acetate in re-
fluxing ethyl acetate gave compound 5 in 66% yield. This
material was then cyclized using a stoichiometric amount
of lauroyl peroxide (DLP). Unfortunately, an inseparable
1:0.16 ratio of regioisomers 6a and 6b was obtained in
56% yield. In order to avoid cyclization onto the position
ortho to the methyl group, the steric hindrance of the ester
moiety was increased by using vinyl pivalate instead of
vinyl acetate. Under the same reaction conditions, the rad-
ical addition of 2 afforded compound 7 in a 68% yield and
cyclization gave specifically the expected 4-pivaloxy-
tetralone 8 in a 59% yield. This compound was produced
as the sole regioisomer with the cyclization occurring on
the position para to the methyl group (Scheme 4).
O
O
O
R
lauroyl
peroxide
(substoich.)
S
S
lauroyl
peroxide
(stoich.)
S
R
S
OEt
R
EtO
Scheme 1
Various alkenes may be used in this radical sequence al-
lowing access to tetralones with a broad range of substitu-
tion patterns, including 4-hydroxytetralones. A short
route to flossonol may thus be envisaged starting from 2-
Final saponification of the ester by treatment of 4-pival-
oxytetralone 8 with potassium hydroxide in ethanol af-
forded the desired product as a 1:0.6 mixture of two
epimers. Separation of the two epimers by column chro-
matography afforded 9a and 9b in 90% overall yield
SYNLETT 2013, 24, 0157–0160
Advanced online publication: 21.12.2012
DOI: 10.1055/s-0032-1317848; Art ID: ST-2012-B0735-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

158
R. F. Guignard
LETTER
O
Table 1 Comparison, in ppm, of the Chemical Shifts
Flossonola
Compound 9ab Compound 9bb
S
OEt
MeO
a
4
H2
H4
H5
H9
3.17
4.33
6.77
1.46
2.56
4.96
7.11
1.26
3.01
4.93
6.84
1.25
S
c
O
O
S
S
a As given by Cassady et al.,1 measured with 470 MHz NMR instru-
ment in CDCl3 using TMS as internal standard.
b As measured with 400 MHz NMR instrument in CDCl3 using TMS
as internal standard.
MeO
MeO
S
OEt
7, 68%
S
OEt
PivO
AcO
5, 66%
b
b
O
O
O
AcO
MeO
O
+
MeO
MeO
OH
MeO
OPiv
OAc
10
6a
6b
8, 59%
trans/cis
1:0.6
1:0.16
56%
Figure 2 Other possible structure for flossonol
Scheme 4 Reagents and conditions: (a) vinyl acetate, DLP (25 mol%),
EtOAc, reflux; (b) DLP (140 mol%), EtOAc, reflux; (c) vinyl piva-
late, DLP (20 mol%), EtOAc, reflux.
aromatic ring (Figure 2). Our new synthetic target thus
becomes compound 10.
The synthesis of the corresponding key intermediate 16
proved to be more complicated than that of its regioiso-
meric analogue 3. To this end, Weinreb amide 12 was first
prepared in 87% yield from 2-chloropropionyl chloride
(11; Scheme 6). In parallel, commercially available 5-bro-
mo-2-methylphenol (13) was methylated to provide com-
pound 14 in 93% yield. Lithium–halogen exchange on 14
using BuLi followed by addition of Weinreb amide 12 af-
forded the desired chloroketone 15 in 75% yield. Finally,
nucleophilic substitution of 15 by potassium O-ethyl
xanthate produced 16 smoothly in 93% yield.
(Scheme 5). NMR spectroscopy using the values of
the coupling constants indicated 9a to be the cis isomer
(J2-3trans = 13.4 Hz, J2-3cis = 4.3 Hz, J4-3trans = 11.3 Hz, J4-3cis
= 4.7 Hz).7 2D NOESY experiments confirmed these re-
sults. In addition, treatment of 9b with triethylamine in di-
chloromethane afforded a 9a/9b mixture with the same
1:0.6 isomeric ratio as before.
O
O
9
KOH
2
+
8
In view of our previous observation, we used directly
vinyl pivalate in order to favor cyclization on the position
para to the methoxy group. Both the addition and the
cyclization reactions proceeded as expected to give xan-
thate 17 and 4-pivaloxytetralone 18 in 48% and 64%
yield, respectively (Scheme 7).
H
EtOH
50 °C, 1 h
90%
3
MeO
MeO
4
5
H
OH
OH
9a
1:0.6
9b
CH2Cl2, Et3N (cat.)
40 °C, 1 h
Surprisingly, cleavage of the pivaloyl ester proved to be
problematic. Indeed, despite numerous attempts, no suc-
cessful conditions for the deprotection of 18 could be
found. Naphthalene 19 and decomposition products were
invariably formed instead of the desired 4-hydroxy-
tetralone 20 (Scheme 8). This is certainly due to the pres-
ence of the methoxy group in the para position, which
weakens further the benzylic C–O bond and causes elim-
ination rather than cleavage of the ester.
quant.
Scheme 5
Unfortunately, neither the NMR data of compound 9a nor
those of 9b matched those of the natural flossonol report-
ed by Cassady et al. The main differences lay in the chem-
ical shifts of protons H2, H4, H5 and H9 and some are too
significant to be attributed to lack of precision of the NMR
apparatus, especially that for H4 which is greater than
0.6 ppm (Table 1).
To circumvent this problem of ester cleavage, we decided
to return to the acetyl analogue of 18, which was expected
to be more easily removable, in spite of the danger of
We therefore decided to investigate the possibility of an
inversion of the methyl and the methoxy groups on the
Synlett 2013, 24, 157–160
© Georg Thieme Verlag Stuttgart · New York

LETTER
Concise Total Synthesis of the Purported Structure of Flossonol
159
Me
OMe
O
O
N
H
⋅HCl
OMe
Cl
N
Et3N
DCM
r.t., 4 h
Cl
Cl
Me
11
12, 87%
O
1) BuLi, THF
MeO
HO
Br
MeO
Br
–78 °C
MeI
Cl
2) 12
K2CO3
DMF
r.t., 3 h
13
14, 93%
15, 75%
KSCSOEt
acetone
0 °C, 1 h
O
MeO
S
S
OEt
16, 93%
Scheme 6
O
O
OPiv
MeO
MeO
S
16
DLP
(10 mol%)
AcEtO
DLP
(160 mol%)
AcEtO
S
OEt
PivO
OPiv
18, 64%
reflux
reflux
17, 48%
cis/trans
1:0.5
Scheme 7
OH
tive and gave exclusively product 22 in 60% yield
O
(Scheme 9).
MeO
MeO
18
The final saponification step proceeded smoothly with so-
dium hydroxide in ethanol at room temperature to afford
hydroxytetralones 20 as a 1:0.7 mixture of the two epi-
mers. Separation of the two epimers by column chroma-
tography afforded 20a and 20b in an 89% overall yield
(Scheme 10). Once again, NMR studies using the value of
the coupling constants indicated 20a to be the cis isomer
(J2-3trans = 13.4 Hz, J2-3cis = 4.3 Hz, J4-3trans = 11.4 Hz, J4-3cis
= 4.6 Hz).7 Those two compounds were fragile and de-
hydrated spontaneously upon standing to give naphtha-
lene 19.
basic
conditions
19
up to 69%
OH
20
Scheme 8
forming difficult to separate regioisomeric products. Even
a small amount of impure compound 20 would allow us to
compare its spectroscopic data with those of the natural
flossonol. To our pleasant surprise, after radical addition
of xanthate 15 to vinyl acetate in a yield of 71%, cycliza-
tion of compound 21 proved to be completely regioselec-
O
O
OAc
MeO
MeO
S
16
DLP
DLP
(160 mol%)
EtOAc
(17.5 mol%)
EtOAc
reflux
S
O
AcO
OAc
22, 60%
cis/trans
1:0.6
reflux
21, 71%
Scheme 9
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 157–160

160
R. F. Guignard
LETTER
References
O
O
MeO
MeO
(1) Sun, N.; Chang, C.; Cassady, J. M. Phytochemistry 1987, 26,
3051.
(2) Geran, R. I.; Greenberg, N. H.; MacDonald, M. M.;
Schumacher, A. M.; Abbott, B. J. Cancer Chemother. 1972,
3, 1.
NaOH
+
22
2
H
EtOH
r.t., 1 h
89%
3
4
H
OH
OH
1:0.7
20b
20a
(3) (a) Hernandez-Romero, Y.; Rojas, J. I.; Castillo, R.; Rojas,
A.; Mata, R. J. Nat. Prod. 2004, 67, 160. (b) Tezuka, Y.;
Morikawa, K.; Li, F.; Auw, L.; Awale, S.; Nobukawa, T.;
Kadota, S. J. Nat. Prod. 2011, 74, 102. (c) Park, B. M.;
Hong, S. S.; Lee, C.; Lee, M. S.; Kang, S. J.; Shin, Y. S.;
Jung, J. K.; Hong, J. T.; Kim, Y.; Lee, M. K.; Hwang, B. Y.
Arch. Pharm. Res. 2010, 33, 381. (d) Messiano, G. B.; Silva,
T.; Nascimento, I. R.; Lopes, L. M. X. Phytochemistry 2009,
70, 590.
(4) (a) Haworth, R. D. J. Chem. Soc. 1932, 1125. (b) Esteban,
G.; Lopez-Sanchez, M.; Martinez, M. E.; Plumet, J.
Tetrahedron 1998, 54, 197. (c) Caro, Y.; Masaguer, C. F.;
Ravina, E. Tetrahedron: Asymmetry 2003, 14, 381. (d) Cui,
D. M.; Kawamura, M.; Shimada, S.; Hayashi, T.; Tanaka, M.
Tetrahedron Lett. 2003, 44, 4007.
(5) (a) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1972, 94,
2888. (b) Russel, G. A.; Kulkarni, S. V.; Khanna, R. K. J.
Org. Chem. 1990, 55, 1080. (c) Snider, B. B.; Kwon, T. J.
Org. Chem. 1990, 55, 4786. (d) Russell, G. A.; Chen, P.;
Kim, B. H.; Rajaratnam, R. J. Am. Chem. Soc. 1997, 119,
8795.
(6) (a) Liard, A.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett.
1997, 38, 1759. (b) Cordero-Vargas, A.; Pérez-Martin, I.;
Quiclet-Sire, B.; Zard, S. Z. Org. Biomol. Chem. 2004, 2,
3018. (c) Petit, L.; Zard, S. Z. Chem. Commun. 2010, 46,
5148. (d) Cordero-Vargas, A.; Quiclet-Sire, B.; Zard, S. Z.
Org. Lett. 2003, 5, 3717.
Scheme 10
Unfortunately, neither of these two compounds had spec-
tra that matched those reported for flossonol (Table 2).
It appears that the structure proposed by Cassady et al.
should be revised, unless an error was introduced in re-
cording the NMR spectra or in transcribing the chemical
shifts. Nevertheless, the strategy we have developed to
access this family of compounds is flexible and efficient.
Table 2 Comparison, in ppm, of the Chemical Shifts
Flossonola
Compound 20ab Compound 20bb
H2
H4
H5
H9
3.17
4.33
6.77
1.46
2.59
4.97
7.42
1.29
3.10
4.94
7.21
1.27
a As given by Cassady et al.,1 measured with 470 MHz NMR instru-
ment in CDCl3 using TMS as internal standard.
b As measured with 400 MHz NMR instrument in CDCl3 using TMS
as internal standard.
(7) Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tabellen zur
Strukturaufklärung organischer Verbindungen mit
spektroskopischen Methoden; Springer-Verlag: Berlin,
1986.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
Synlett 2013, 24, 157–160
© Georg Thieme Verlag Stuttgart · New York