Concise synthesis of riccardin C, macrocyclic bisbibenzyl natural product

Article abstract of DOI:10.1246/cl.2011.1069

Riccardin C (1) has been synthesized by exploiting an intramolecular SNAr reaction of α-sulfinylfluorobenzene by an internal phenolate, providing the key 18-membered ring closure in excellent yield.

Full text of DOI:10.1246/cl.2011.1069

doi:10.1246/cl.2011.1069
Published on the web September 17, 2011
1069
Concise Synthesis of Riccardin C, Macrocyclic Bisbibenzyl Natural Product
Hiromu Takiguchi, Ken Ohmori, and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551
(Received June 16, 2011; CL-110503; E-mail: ksuzuki@chem.titech.ac.jp)
F
Riccardin C (1) has been synthesized by exploiting an
O
F
O
O
intramolecular SNAr reaction of ¡-sulfinylfluorobenzene by an
internal phenolate, providing the key 18-membered ring closure
in excellent yield.
sp3
sp2
F–
I
A
II
Riccardin C (1) represents a class of macrocyclic bisbiben-
zyl natural products, which are phenolic metabolites character-
istic to liverworts.1 The intriguing structure of 1 featuring an
18-membered macrocycle as well as the interesting biological
activities2 stimulated considerable synthetic interests toward this
and related compounds.3
The major synthetic challenge is the construction of the
strained macrocyclic ring including ortho-, meta-, and two para-
substituted benzenes. Upon comparison of five previous syn-
theses of 1 by how the 18-membered ring was constructed
(Figure 1), four syntheses employed intramolecular C-C bond
formation at the benzylic positions (bond a or b),3a-3d whereas
one relied on biaryl bond formation (bond c).3e The critical
issue, however, is that these macrocyclizations generally suffer
from poor yields, due mostly to the molecular strain within the
macrocycle.
Figure 2. SNAr cyclization to strained macrocycle.
Scheme 1 shows the retrosynthesis, assuming the cycliza-
tion of seco-precursor 2. The cyclization would hopefully be
achieved by an SNAr reaction of ¡-sulfinylfluorobenzene6
(A-ring) by the internal phenolate (C-ring). The acyclic
precursor 2 would be assembled from four fragments, 3-6.7-9
O
F
p-Tol
S
d
O
OH
OH
C
OMe
C
p
p
O
A
A
O
HO
a
m
o
c
B
D
HO
HO
b
D
B
MeO
HO
HO
MeO
riccardin C (1)
riccardin C (1)
2
OMe
C
I
B(OH)2
Figure 1. Riccardin C (1) and the disconnectivity.
O
p-Tol
TBSO
S
OHC
D
B
F
O
A
OMe
P
OEt
OH
OMe
In our recent interest in cyclophanes,4 we became interested
OEt
3
4
6
5
in the synthesis of 1 by exploiting the biaryl ether formation
(bond d in Figure 1) through an intramolecular SNAr reaction,
converting the acyclic starting material I to the strained cyclized
product II (Figure 2). Our hope was that the Meisenheimer
intermediate A would be less strained by the nonplanar structure
around the ether linkage. The conversion of A to II would
increase the strain, which would, however, be compensated by
the aromatization energy.
Scheme 1. Retrosynthesis.
Scheme 2 illustrates preparation of phosphonate 3.18 The
aryllithium species, generated from bromide 7,10 (n-BuLi, THF,
¹78 °C, 1 h) was combined with sulfinate 8,11,12 and removal of
the THP protection afforded alcohol 9 in 87% yield (2 steps).
Mesylation of alcohol 9 followed by the reaction with NaH and
diethyl phosphite gave the desired phosphonate 3 in 78% yield
(2 steps).
Herein, we describe a positive answer to this assumption,
achieving the concise synthesis of 1 via the high-yield SNAr
reaction for the key macrocyclization.5
Chem. Lett. 2011, 40, 1069-1071
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1070
Scheme 4 illustrates the end game.18 Pleasingly, the crucial
macrocyclization of 14 was achieved via an intramolecular SNAr
reaction under high-dilution conditions [CsF, CaCO3, MS3A,
DMF (1.0 mM), 140 °C, 4 h],15 giving the cyclized product 15 in
92% yield.16 Upon sulfoxide-lithium exchange17 of 15 followed
by quenching with MeOH, macrocyclic ether 16 was obtained in
95% yield. Finally, removal of three methyl groups by using
BBr3 afforded riccardin C (1), whose physical data (1H and
13C NMR, IR, and combustion analysis) were fully consistent
with those reported in the literature.1
O
p-Tol
O
p-Tol
S
Br
S
F
F
F
c, d
a, b
O
P
OTHP
OH
OEt
OEt
7
9
3
O
S
p-Tol
menthyl-O
8
Scheme 2. (a) n-BuLi, THF, ¹78 °C, 1 h; 8, THF, ¹78 °C,
10 min; (b) PPTS, EtOH, 65 °C, 3 h, 87% (2 steps); (c)
CH3SO2Cl, Et3N, CH2Cl2, 0 °C, 5 min; (d) NaH, HP(=O)(OEt)2,
THF, room temp., 2 h, 78% (2 steps); THP: tetrahydropyranyl,
PPTS: pyridinium p-toluenesulfonate.
O
p-Tol
F
p-Tol
S
O
S
OMe
OMe
HO
O
Scheme 3 shows the assembly of four fragments.18 Coupling
of alkyne 57 and iodobenzene 68 proceeded smoothly in the
presence of [Pd(PPh3)4] and CuI, and triflation of the resulting
phenol 10 gave triflate 11 in 83% yield. Biarylcarbaldehyde 12,
obtained by the coupling of triflate 11 and boronic acid 4,9 was
subjected to the Horner-Wadsworth-Emmons reaction with
phosphonate 3 to give stilbene 13 in 70% yield in two steps.
Having enyne 13 with the full carbon skeleton of 1, the next
stage needed saturation of the double and triple bonds in 13
while keeping the sulfinyl group intact. After several unsuccess-
ful trials by catalytic hydrogenations,13 the projected conversion
was achieved in excellent yield by diimide reduction.14
a
MeO
MeO
MeO
MeO
15
14
OR
O
b
RO
OMe
OMe
RO
TBSO
TBSO
16 : R = Me
1 : R = H (riccardin C)
OMe
c
a
HO
Scheme 4. (a) CsF, CaCO3, MS3A, DMF, 140 °C, 4 h, 92%;
(b) t-BuLi, THF, ¹78 °C, 10 min; MeOH, ¹78 °C, 10 min, 95%;
(c) BBr3, CH2Cl2, 0 °C ¼ room temp., 2 h, 93%.
5
c
I
OMe
OR
10 : R = H
11 : R = Tf
OMe
b
OMe
OHC
In summary, a concise synthesis of riccardin C (1) was
achieved by an intramolecular SNAr reaction to form the key
18-membered ring. This strategy would be effective for the
synthesis of other more complex bisbibenzyl natural products.
OH
B(OH)2
6
OHC
OMe
12
OMe
O
p-Tol
4
S
We thank Profs. Yoshinori Asakawa and Toshihiro
Hashimoto for providing us with a comparison sample of 1.
This work was partially supported by Global COE Program
(Chemistry) and Grant-in-Aid for Scientific Researches (A) and
(B) (Nos. 22245012 and 21350050).
OMe
F
HO
O
S
F
p-Tol
P(OEt)2
3
OMe
O
HO
e
d
O
p-Tol
S
F
References and Notes
1
OMe
MeO
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MeO
E/Z = 12/1
OMe
13
14
Scheme 3. (a) [Pd(PPh3)4], CuI, THF, NEt3, room temp.,
10 min; (b) PhNTf2, K2CO3, acetone, room temp., 1 h, 83% (2
¹
steps); (c) [Pd(PPh3)4], K3PO4, (n-Bu)4N+Br , DME, H2O,
2
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steps), E/Z = 12/1; (e) TsNHNH2, NaHCO3, EtOCH2CH2OH,
reflux, 1 h, 92%.
Chem. Lett. 2011, 40, 1069-1071
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1071
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9
3
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© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/