An inverse electron-demand diels-alder-based total synthesis of urolithin M7

Article abstract of DOI:10.1055/s-0030-1261203

Urolithin M7 was synthesized from 2-hydroxy-4-methoxybenzaldehyde in 8 steps and 48% overall yield. The key step was an inverse electron demand Diels-Alder (IEDDA) reaction between diene 10 and the enamine (7) derived from dimethoxyacetaldehyde and pyrrolidine, which generated the 6H-dibenzo[b,d]pyran- 6-one skeleton. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261203

LETTER
2245
An Inverse Electron-Demand Diels–Alder-Based Total Synthesis of Urolithin
M7
Total
Sy
a
nthesis of
U
n
rolithin M7 R. Pottie,1 Penchal Reddy Nandaluru, Graham J. Bodwell*
Department of Chemistry, Memorial University, St. John’s, NL, A1B 3X7, Canada
Fax +1(709)8643702; E-mail: gbodwell@mun.ca
Received 30 May 2011
7, which is derived from pyrrolidine and dimethoxyacetal-
Abstract: Urolithin M7 was synthesized from 2-hydroxy-4-meth-
oxybenzaldehyde in 8 steps and 48% overall yield. The key step was
an inverse electron demand Diels–Alder (IEDDA) reaction between
diene 10 and the enamine (7) derived from dimethoxyacetaldehyde
dehyde, to afford xanthone 8 (Scheme 1).8 In this case, the
new aromatic ring is generated by a formal IEDDA reac-
tion followed by two successive 1,2-elimination reac-
and pyrrolidine, which generated the 6H-dibenzo[b,d]pyran-6-one tions. With both a concise approach to the 6H-
skeleton.
dibenzo[b,d]pyran-6-one skeleton and means to generate
a 1,3-disubstituted aromatic ring, an opportunity to syn-
thesize urolithin M7 (2) using this methodology was iden-
tified.
Key words: inverse electron demand Diels–Alder, domino reac-
tion, dibenzopyranone, urolithin M7
O
O
Ellagitannins are present in a variety of foods, such as ber-
ries, pomegranates, walnuts, and almonds.2 They exhibit a
range of biological properties including antimicrobial,3a,b
CO2Me
NR2
CO2Me
O
O
CH2Cl2, r.t.
3 h, 43%
antiviral,3c
antioxidant,3d
antimutagenic,3e
and
antitumor3f,g activity. The urolithins, which are metabo-
lites of ellagitanins, for example, ellagic acid (1,
Figure 1),4 have a common tricyclic aromatic core {6H-
dibenzo[b,d]pyran-6-one} and differ in the number and
position of hydroxyl substituents. Kim and co-workers re-
ported the isolation of urolithin M74d {2, 3,8,10-trihy-
droxy-6H-dibenzo[b,d]pyran-6-one} from the dried feces
of a squirrel, Trogopterus xanthipes.5 These feces (excre-
mentum pteropi) have been used in Chinese traditional
medicine for the treatment of angiostasis and dysmenor-
rhea.6
3
4
5
O
O
O
CO2Et
CO2Et
benzene, 80 °C
2 h, 71%
MeO
O
N
OMe
6
7
8
OMe
Scheme 1 Examples of IEDDA-driven domino reactions of couma-
rin-fused diene 3 and chromone-fused diene 6
A retrosynthetic analysis of 2 (Scheme 2) began with
functional-group interconversions to provide trisubstitut-
ed dibenzo[b,d]pyran-6-one 9, which is the anticipated
product of an IEDDA-driven domino reaction between
coumarin-fused diene 10 and enamine 7.
O
O
OH
OH
OH
O
O
HO
HO
O
OH
HO
O
1
2
O
O
CO2Me
CO2Me
Figure 1 Structures of ellagic acid (1) and urolithin M7 (2)
O
O
2
MeO
N
Previously, we reported that coumarin-fused electron-de-
ficient diene 3 reacts with enamines (electron-rich dieno-
philies) such as 4 to afford dibenzo[b,d]pyran-6-ones.7
This occurs by a domino sequence involving a formal in-
verse electron-demand Diels–Alder reaction followed by
a 1,2-elimination of pyrrolidine and a dehydrogenation
(presumably a transfer hydrogenation). More recently,
chromone-fused diene 6 was found to react with enamine
OMe
OMe
MeO
MeO
9
10
7
Scheme 2 Retrosynthetic analysis of urolithin M7
The synthesis commenced with reaction between com-
mercially available salicylaldehyde 11 and dimethyl
glutaconate 12 (E/Z = ca. 4:1) to produce coumarin-fused
diene 10 (78%) and chromene 13 (22%, Scheme 3). Diene
10 precipitated from the reaction mixture upon cooling,
which rendered separation of the two products trivial. The
E configuration of the double bond in the side chain was
SYNLETT 2011, No. 15, pp 2245–2247
x
x
.x
x
.2
0
1
1
Advanced online publication: 30.08.2011
DOI: 10.1055/s-0030-1261203; Art ID: S04811ST
© Georg Thieme Verlag Stuttgart · New York

2246
I. R. Pottie et al.
LETTER
O
indicate that the 1-pyrrolidinyl group is a more effective
CO2Me
p-donor than the two methoxy groups combined.
O
Having generated the core 6H-dibenzo[b,d]pyran-6-one
skeleton with functionality at all of the required positions,
it only remained to adjust the nature of the functional
groups. The main challenge here was the conversion of
the methyl ester into a hydroxyl group without affecting
the 2-pyranone system. Dibenzopyranone 14 was used to
ascertain whether the methyl ester could be reduced
chemoselectively. Unfortunately, reaction of 14 with
DIBAL at –50 °C gave multiple products (TLC analysis)
and the use of NaBH4 in DME10 resulted in the selective
reduction of the lactone to afford diol 15 in 64% yield.
Since the wrong carbonyl group was selectively reduced,
an alternative approach was investigated.
CO2Me
OH
CO2Me
CHO
MeO
12
10 78%
benzene, piperidine
80 °C, 3 h
MeO
MeO2C
11
CO2Me
O
13 22%
MeO
Scheme 3 Synthesis of diene 10
indicated by the magnitude of the coupling constant be-
Both the methyl ester and the lactone in 9 were reduced
with LiAlH4 to afford triol 16 in 94% yield (Scheme 4).
An attempt to simultaneously regenerate the lactone (via
a hemiacetal) and produce an aldehyde (i.e., 17) using
MnO2 resulted in the formation of a complex mixture of
products (TLC analysis), but changing the oxidant to PCC
afforded aldehyde 17 in 81% yield. Subsequently, it was
discovered that Fétizon’s reagent11 (Ag2CO3 on Celite) af-
forded 17 in 99% yield. Demethylation of 17 with BBr3 to
afford diol 18 (52%) was then performed in preparation
for a Dakin oxidation,12 which would convert the formyl
group into a hydroxyl group and thus complete the synthe-
sis of 2. The Dakin oxidation normally requires the pres-
ence of a hydroxyl group ortho or para to the formyl
group slated for oxidation.12 In the case of 18, it was en-
visaged that the OH substituent in extended conjugation
with the aldehyde would enable the Dakin oxidation to
proceed. However, all attempts to achieve this transfor-
mation failed.
tween the attached protons (J = 15.9 Hz).
Before proceeding with diene 10, the IEDDA-driven
domino reaction with enamine 7 was first performed with
the parent coumarin-fused diene 3. 6H-Dibenzo[b,d]pyr-
an-6-one 14 was obtained quantitatively after 1 day of re-
action (Scheme 4). The electron-donating methoxy group
in 10 is directly conjugated with the diene unit, which ren-
ders it less electron deficient than the one in 3. Conse-
quently, the reaction of 10 with enamine 7 was
considerably slower. Nevertheless, it also proceeded
quantitatively, affording 9 after 7 days of reaction.9 The
1,3 relationship between the methyl ester and the new
methoxy group in 14 and 9 is consistent with a completely
regioselective addition of the dienophile 7 to the dienes 3
and 10. Equally high regioselectivity was observed in the
reaction of 7 with chromone-fused diene 6. This seems to
O
O
CO2Me
CO2Me
O
O
O
O
7
R
OH
benzene, 80 °C
for 3: 1 d
O
O
57% HI, 127 °C
30 min, 98%
for 10: 7 d
OMe
14 R = H 100%
R
R
3
R = H
OMe
R = CO2Me
OH
MeO
HO
10 R = OMe
9 R = OMe 100%
NaBH4, DME
80 °C, 1 h
64%
2
9
NaOH, H2O, EtOH
100 °C, 2 h, 100%
LiAlH4, THF
66 °C, 12 h, 94%
19 R = CO2H
OH
OH
1. NaH, THF, 0 °C to r.t., 1 h
2. (COCl)2, 65 °C, 12 h
3. Me2Zn, Pd(PPh3)4, THF
OH
OH
OH
CO2Me
0 °C to r.t., 4 d, 84% (3 steps)
20 R = COMe
21 R = OAc
MCPBA, TFA
CH2Cl2, r.t., 4 d, 74%
OMe
OMe
15
MeO
16
Scheme 5 Completion of the synthesis of urolithin M7
Ag2CO3, Celite
benzene, 80 °C, 99%
2
The ultimately successful pathway proceeded from 9
through a hydrolysis reaction, the acidic workup of which
presumably reformed the lactone to give carboxylic acid
19 (Scheme 5). Treatment of 19 with NaH generated the
corresponding carboxylate salt, which was reacted in
crude form with oxalyl chloride at reflux. The resulting
crude acid chloride was reacted with dimethylzinc in the
presence of Pd(PPh3)4 to afford methyl ketone 20 in good
O
O
CHO
CHO
BBr3
O
O
1. NaH
CH2Cl2
2. H2O2
r.t., 24 h
52%
OH
OMe
HO
MeO
18
17
Scheme 4 Unsuccessful approach to urolithin M7 (2)
Synlett 2011, No. 15, 2245–2247 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Urolithin M7
2247
yield (84%).13 Baeyer–Villiger oxidation14 of 20 using
MCPBA/trifluroroacetic acid at room temperature now
proceeded smoothly to afford acetate 21 in 74% yield.
Global deprotection of all three phenolic OH groups was
achieved upon heating 21 in aqueous concentrated HI so-
lution for 30 minutes to afford the natural product 2 in
98% yield. The overall yield of urolithin M7 from the
commercially available salicylaldehyde 11 was 48% over
Trunchado, P.; Ito, H.; Espín, J. C.; Tomás-Barberán, F. A.
J. Agric. Food Chem. 2011, 59, 1152. (e) Ito, H.; Iguchi, A.;
Hatano, T. J. Agric. Food Chem. 2008, 56, 393. (f) Doyle,
B.; Griffiths, L. A. Xenobiotica 1980, 10, 247.
(5) Jeong, S.-J.; Kim, N.-Y.; Kim, D.-H.; Kang, T.-H.; Ahn, N.-
H.; Miyamoto, T.; Higuchi, R.; Kim, Y.-C. Planta Med.
2000, 66, 76.
(6) The Dictionary of Chinese Drugs; Shanghai Scientific and
Technical Publishers: Shougakukan Tokyo, 1985, 875–877.
(7) Bodwell, G. J.; Pi, Z.; Pottie, I. R. Synlett 1999, 477.
(8) Dang, A.-T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org.
Lett. 2008, 10, 233.
1
eight steps. The H NMR and 13C NMR spectra of 2
matched the reported data from the original isolation pa-
per.5
(9) Experimental Procedure for 9
A solution of dimethoxyacetaldehyde (60 wt% solution in
H2O, 19.6 mL, 0.130 mol) and pyrrolidine (9.76 mL, 0.117
mol) in benzene (150 mL) was heated at reflux with
azeotropic removal of H2O for 1 h. The resulting mixture
was allowed to cool for 10 min, and solid 10 (3.38 g, 13.0
mmol) was added in one portion. The resulting mixture was
heated at reflux for 7 d. The reaction mixture was cooled to
r.t. and then concentrated under reduced pressure. The
residue was taken up in CH2Cl2 (150 mL) and washed with
aq 1 M HCl solution (5 × 50 mL), dried over MgSO4, gravity
filtered, and concentrated under reduced pressure to afford 9
(4.08 g, 100%) as a tan solid: mp 195–196 °C. IR (Nujol):
n = 1735 (s), 1715 (s), 1607 (m), 1121 (s) cm–1. 1H NMR
(500 MHz, CDCl3): d = 8.76 (d, J = 9.3 Hz, 1 H), 8.57 (d,
J = 1.1 Hz, 1 H), 7.80 (d, J = 1.0 Hz, 1 H), 6.81 (dd, J = 9.6,
3.0 Hz, 1 H), 6.76 (d, J = 2.6 Hz, 1 H), 4.08 (s, 3 H), 3.96 (s,
3 H), 3.87 (s, 3 H). 13C NMR (125.8 MHz, CDCl3):
d = 165.6, 161.3, 160.7, 156.4, 152.7, 130.0, 129.1, 128.0,
124.0, 121.3, 116.1, 111.7, 110.0, 101.3, 56.1, 55.3, 52.4.
MS (EI): m/z (%) = 314 (100) [M+], 299 (53), 283 (13), 212
(4), 157 (4). Anal. Calcd for C17H14O6: C, 64.97; H, 4.49.
Found C, 65.03; H, 4.61.
In summary, a concise, high-yielding total synthesis of
urolithin M7 has been completed. The key step was an
IEDDA-driven domino reaction of coumarin-fused diene
10.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The authors gratefully acknowledge the National Science and Engi-
neering Research Council (NSERC) of Canada for financial support
of this work.
References and Notes
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