Efficient synthesis of isoplagiochin D, a macrocyclic bis(bibenzyls), by utilizing an intramolecular Suzuki-Miyaura reaction

Article abstract of DOI:10.1016/j.tetlet.2004.07.068

Isoplagiochin D, a highly strained macrocyclic bis(bibenzyls) isolated from the liverwort Pladiochila fruticosa, was synthesized in 10.6% overall yield for the 11 steps by using Horner-Wadsworth-Emmons and Suzuki-Miyaura protocols. Isoplagiochin D, a highly strained macrocyclic bis(bibenzyls) with two biaryl units isolated from the liverwort Pladiochila fruticosa, was prepared in 10.6% overall yield for the 11 steps by an efficient synthetic approach involving the construction of two bibenzyl and one biaryl units using Horner-Wadsworth-Emmons and Suzuki-Miyaura protocols.

Full text of DOI:10.1016/j.tetlet.2004.07.068

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6941–6945
Efficient synthesis of isoplagiochin D, a macrocyclic
bis(bibenzyls), by utilizing an intramolecular
Suzuki–Miyaura reaction
Tomoyuki Esumi, Mitsumasa Wada, Eri Mizushima, Norimasa Sato, Mitsuaki Kodama,
Yoshinori Asakawa and Yoshiyasu Fukuyama*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, 770-8514, Japan
Received 18 June 2004; revised 12 July 2004; accepted 16 July 2004
Available online 10 August 2004
Abstract—Isoplagiochin D, a highly strained macrocyclic bis(bibenzyls) with two biaryl units isolated from the liverwort Pladiochila
fruticosa, was prepared in 10.6% overall yield for the 11 steps by an efficient synthetic approach involving the construction of two
bibenzyl and one biaryl units using Horner–Wadsworth–Emmons and Suzuki–Miyaura protocols.
Ó 2004 Elsevier Ltd. All rights reserved.
Macrocyclic bis(bibenzyls) natural products1 are specific
chemical constituents of the liverworts and are presum-
ably biosynthesized by the dimerization of lunularin
through several modes of oxidative phenol coupling
such as biaryl C–C bond and/or biphenyl ether bond
formations. The unique structural characteristics and
versatile biological activities2 have made cyclic bis(bi-
benzyls) natural products attractive synthetic targets.3
To date, a few syntheses of cyclic bis(bibenzyls) were re-
ported, for example, reccardin B,4,5 and plagiochins C
and D.6 Most of them underwent the crucial macrocy-
clization between two bibenzyl positions by intramolecu-
lar Horner–Wadsworth–Emmons reaction or Wurtz
type reaction. Independently, we also reported on the
successful syntheses7 of plagiochins A and D by apply-
ing the tandem Stille–Kelly reaction8 for the macrocyc-
lization between two aryl units, which mimicked their
proposed biosynthetic route. Although it is the first
example to construct the macrocyclic structure of bis(bi-
benzyls) natural products by the aryl–aryl bond forma-
tion, these processes suffer from drawbacks such as low
yield of the macrocyclization and being unable to isolate
mono-stannyl intermediate requisite for the subsequent
Stille reaction.9 In this paper, we report on the extension
of this strategy to the synthesis of isoplagiochin D (1),
which consists of more strained cyclic system containing
two biaryl units than the plagicohin type with one biaryl
and one biphenyl ether units.
Compound 1 was isolated together with a structurally
similar derivative, isoplagiochin C (2), from the liverwort
Pladiochila fruticosa by Asakawa and co-workers in
1996,10 and then was first synthesized by Eicher et al.
in 199811 (Fig. 1).
As described above, our key strategy is the construction
of macrocyclic structure 3 from 4a or 4b by palla-
dium(0)-catalyzed Stille12 or Suzuki–Miyaura13 cross-
coupling between positions 14 and 120 at which some
stannyl or boronate group and a triflate are attached,
respectively (Scheme 1).
OH
OH
OH
OH
OH
HO
OH
Isoplagiochin D (1)
Figure 1. Structure of isoplagiochin D (1) and C (2).
HO
Isoplagiochin C (2)
*
Corresponding author. Tel.: +81-88-6229611; fax: +81-88-
6553051; e-mail: fukuyama@ph.bunri-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.068

6942
T. Esumi et al. / Tetrahedron Letters 45 (2004) 6941–6945
OR
OR
OR
OR
Pd(0)
X
14
RO
OR
RO
OR
12'
Y
1; R = H
3a; R = Me
3b; R = MOM
4a; R = Me, X = Br, Y = TfO
4b; R = Me, X = B(OCMe2)2, Y = TfO
4c; R = MOM, X = Y = Br
Scheme 1. Key strategy toward synthesis of isoplagiochin D (1).
Our synthesis of isoplagiochin D (1) was commenced
with the preparation of three coupling units 5, 6, and
8. Unit 5 was prepared by methylation of 2,20-biphenol
with excess amount of MeI in the presence of K2CO3
followed by regioselective formylation with hexamethyl-
enetetramine in TFA in 72% overall yield. Bromination
of m-anisaldehyde with Br2 in CHCl3 gave rise to o-bro-
mide 7 in 84% yield. Subsequent reduction of 7 with
NaBH4, followed by bromination with CBr4–PPh3 and
Arbuzov reaction, provided unit 8 in 96% yield. Unit 6
was also prepared from vanillin in 67% overall yield
by similar procedures (Scheme 2).
PtO2 catalyst in CH2Cl2 under a H2 atmosphere was
able to reduce two double bonds and remove a benzyl
group without touching benzene rings, thereby leading
to the desired product 4a in 97% yield after converting
the liberated phenol to a triflate with Tf2O and Et3N
in CH2Cl2 (Scheme 3).
Before moving a step forward, we examined the inter-
molecular version of cross-coupling between tri-
methylbisbibenzyltin 11 or pinacol boronate ester 12
and a triflate 13 to search for optimal conditions suitable
for attempting next intramolecular cross-coupling of 4a.
Namely, the cross-coupling proceeded smoothly be-
tween 12 and 13 under Suzuki–Miyaura conditions,
10mol% of PdCl2(dppf) with K2PO4 in 1,4-dioxane, to
give rise to 14, but the Stille coupling between 11 and
13 did not work sufficiently. These results suggest that
Stille reaction is not suitable for our purpose. Therefore,
we decided to apply the Suzuki–Miyaura protocol for
the crucial cyclization of 4a (Table 1).
With all the coupling units 5, 6, and 8 in hand, next, they
were assembled by repeating Horner–Wadsworth–Em-
mons reaction leading to a precursor 4a for Pd (0)-cata-
lyzed macrocyclization as following: phosphonate 8 was
treated with NaH, and then reacted with dialdehyde 5 to
give the desired mono-coupling product 9 in 73% yield
contaminated with 10% of the undesired di-coupled
product. Coupling reaction between 9 and phosphonate
6 was repeated under similar conditions as above, giving
rise to di-(E)-olefin 10 in 75% yield. Although hydrogen-
ation of two double bonds in 10 was troublesome in the
case of using Pd–C or Lindlar catalysts, giving the com-
plex mixture including over-reduction of benzene rings
into cyclohexanes, we were pleased to find that use of
Consequently, selective preparation of boronate 4b
from 4a was required for this macrocyclization. First,
under typical Suzuki–Miyaura conditions,13 10mol%
of PdCl2(dppf) and 1,4-dioxane as a solvent at 80°C,
the reaction was carried out to give the desirable boro-
nate 4b in 27% yield with 23% of starting material 4a
O
P(OMe)2
CHO
OMe
CHO
OMe
OH
OH
c-f
a,b
64% (4 steps)
OMe
OMe
72%
(2 steps)
OBn
OH
Vaniline
CHO
CHO
2,2'-Biphenol
6
5
O
P(OMe)2
CHO
Br
Br
g
h-j
96% (3 steps)
84%
MeO
MeO
m-Anisaldehyde
MeO
8
7
Scheme 2. Preparation of units 5, 6, and 8. Reagents and conditions: (a) MeI, K2CO3, acetone, 80°C, overnight; (b) hexamethylenetetramine, TFA,
0 ! 90°C, overnight; (c) BnBr, K2CO3, acetone, rt, 3h; (d) LiAlH4, THF, 0°C!rt, 1h; (e) CBr4, PPh3, MeCN, rt, 9h; (f) P(OMe)3, 90°C, 3h; (g)
Br2, CHCl3, 70°C, 24h; (h) NaBH4, THF, 0°C, 4h; (i) CBr4, PPh3, MeCN, rt, overnight; (j) P(OMe)3, 90°C, 2h, reflux.

T. Esumi et al. / Tetrahedron Letters 45 (2004) 6941–6945
6943
OMe
OMe
OMe
OMe
OMe
OMe
5
a
b
c,d
CHO
73%
75%
97%
(2 steps)
8
Br
Br
Br
(1.1 equiv.)
MeO
OMe
MeO
MeO
OMe
9
Y
OBn
10
4a; Y = OTf
Scheme 3. Preparation of intermediate 4a. Reagents and conditions: (a) 60% NaH, THF, 0°C ! rt, overnight; (b) 6, 60% NaH, THF, 0°C!rt, 3h;
(C) H2 gas (1atm), PtO2 (0.73equiv), CH2Cl2, rt, 6h; (d) Tf2O, Et3N, CH2Cl2, 0°C ! rt, 4h.
Table 1. Model studies for Stille–Kelly reaction and Suzuki–Miyaura reaction
TfO
OMOM
13 (1.5 equiv.)
X
R
condition
OMOM
MOMO
11; X = SnMe3
12; X = B(OCMe2)2
MOMO
MOMO
14
15; R = H (18%)
16; R = CH3 (15%)
Entry
Substrate
Condition
10mol% Pd(PCy3)2, DMF, 70°C, 40h
10mol% PdCl2(dppf), dppf, K3PO4, 1,4-dioxane, 80°C, 29h
Yield (%) 14:15:16
1
2
11
12
0:18:15
48:0:0
Table 2. PdCl2(dppf) catalyzed borylation of 4a
O
O
O
O
B
B
OMe
OMe
O
O
17
4b; X' =
, Y = OTf
B
10 mol% PdCl2(dppf)
AcOK (3 equiv.)
4a
18; X' = H, Y = OTf
condition
X'
O
19; X', Y =
B
MeO
OMe
O
Y
Entry
17 (equiv)
Ligand (mol%)
Solvent (10ꢀ2 M)
Temperature (°C)
Time (h)
Yield 4b (%) 4a:4b:18:19
1
2
3
4
5
6
7
1.2
1.2
1.2
1.2
2.4
2.4
2.4
dppf (10)
dppf (10)
dppf (10)
––
1,4-Dioxane
1,4-Dioxane
DMSO
DMF
80
110
80
48
24
12
12
3
23:27:0:0
0:33:34:0
0:0:50:0
80
80
0:24:11:0
0:56:0:40
0:63:0:19
17:63:0:0
––
––
DMF
DMF
DMF
80
80
2
1.5
––
(Table 2, entry 1). Although elevating the reaction tem-
perature (110°C) enhanced a boronate–bromine ex-
change, the protonated product 18 was produced in
34% yield (Table 2, entry 2). Changing the solvent to
more polar one,14 DMF was found to be suitable solvent
for this reaction (Table 2, entry 4). Additionally, when
the reaction was carried out in DMF using 2.4equiv of
bis(pinacol)diborate for 2–3h, the conversion of the

6944
T. Esumi et al. / Tetrahedron Letters 45 (2004) 6941–6945
OMe OMe
BBr3, CH2Cl2
10 mol% Pd(PPh3)4, 3 equiv. K3PO4
Isoplagiochin D (1)
4b
-78 °C rt., 8 hr
DMF (10-2 M), 80 C, 12 hr
°
41%
89%
MeO
OMe
3a
Scheme 4. Macrocyclization of 18 and completion of total synthesis of isoplagiochin D (1).
3. For review: Keseru, G. M.; Nogradi, M. Nat. Prod. Rep.,
1995, 69–75.
4. Iyoda, M.; Sakaitani, M.; Otsuka, H.; Oda, M. Tetrahe-
dron Lett. 1985, 26, 4777–4780.
5. Kodama, M.; Shiobara, Y.; Sumitomo, H.; Matsumura,
K.; Tsukamoto, M.; Harada, C. J. Org. Chem. 1988, 53,
72–77.
desired product 4b was increased up to 56–63% yield to-
gether with the generation of bis(pinacolate) 19 (Table 2,
entries 5 and 6). In the shorter reaction time (1.5h) the
desired product 4b was obtained in 63% yield with start-
ing material 4a in 17% yield. (Table 2, entry 7) Eventu-
ally, the pinacolborate 4b was obtained in 76% yield
after repeating the same reaction three times. However,
no generation of cyclized product was observed under
these conditions.15
6. Keseru, G. M.; Mezey-Vandor, G.; Nogradi, M.; Vermes,
¨
B.; Kajtar-Peredy, M. Tetrahedron 1992, 48, 913–922.
7. (a) Fukuyama, Y.; Yaso, H.; Nakamura, K.; Kodama, M.
Tetrahedron Lett. 1999, 40, 105–108; (b) Fukuyama, Y.;
Yaso, H.; Mori, T.; Takahashi, H.; Minami, H. Hetero-
cycles 2001, 54, 259–274.
8. (a) Kosugi, M.; Shimizu, K.; Ohtani, T.; Migita, T. Chem.
Lett. 1981, 829–830; (b) Kelly, T. R.; Li, Q.; Bhushan, V.
Tetrahedron Lett. 1990, 31, 161–164.
9. The intramolecular cross-coupling of 4c under the previ-
ous Stille–Kelly conditions gave the cyclized product 3b in
9% yield.
10. Hashimoto, T.; Kanayama, S.; Kan, Y.; Tori, M.;
Asakawa, Y. Chem. Lett. 1996, 741–742.
Now, we address the issue of the final macrocyclization
in this synthesis. In this case, the intramolecular Suzuki–
Miyaura reaction of 18 with 10mol% of Pd(PPh3)4 in
13c,16
DMF in the presence of 3equiv K3PO4
proceeded
smoothly and afforded the expected macrocyclic product
21 in 41% yield. Finally, Removal of all methyl groups
in 21 with BBr3 led to the total synthesis of isoplagiochin
D (1) (Scheme 4), which was identical in all the spectra
data17 (1H NMR, 13C NMR, EIMS, IR) with the natu-
ral product.
11. Eicher, T.; Fey, S.; Puhl, W.; Buchel, E.; Speicher, A. Eur.
J. Org. Chem. 1998, 877–888.
¨
12. (a) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am. Chem.
Soc. 1984, 106, 4630–4634; (b) McKean, D. R.; Parrinello,
G.; Renaldo, A. F.; Stille, J. K. J. Org. Chem. 1987, 52,
422–424; (c) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc.
1987, 109, 813–817; (d) Roth, G. P.; Farina, V. Tetrahe-
dron Lett. 1995, 36, 2191–2194; (e) Kosugi, M.; Fugami,
K. In Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley–Interscience: New York, 2002; pp
263–283.
13. (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun.
1981, 11, 513–519; (b) Watanabe, T.; Miyaura, N.; Suzuki,
A. Synlett 1992, 207–210; (c) Oh-e, T.; Miyaura, N.;
Suzuki, A. J. Org. Chem. 1993, 58, 2201–2208; (d) Suzuki,
A. In Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley-Interscience: New York, 2002; pp
249–262.
In conclusion, we could improve the yield of palladium-
catalyzed macrocyclization between two aryl units in the
synthesis of cyclic bis(bibenzyls) natural products more
significantly than the previously used tandem Stille–Kelly
protocol7 by utilizing intramolecular Suzuki–Miyaura
reaction, and thereby achieve the efficient synthesis of
isoplagiochin D (1) in 10.6% overall yield for the 11
steps. Further application of this methodology is cur-
rently underway in our laboratory in an attempt to syn-
thesize riccarrdin A and cavicularin, the most complex
cyclic bis(bibenzyls).18
Acknowledgements
14. (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem.
1995, 60, 7508–7510; (b) Ishiyama, T.; Itoh, Y.; Kitano,
T.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447–3450.
15. It is well known that use of the weak bases such as AcOK
does not afford the cross-coupling products. See Ref. 14a.
16. First, we applied the same conditions for the macrocy-
clization as used in the model study. However, the reaction
did not occur.
This work is supported by Grant-in-Aids (16510172 and
1670023) for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology,
Japan.
1
References and notes
17. Spectra data of isoplagiochin D (1): H NMR (300MHz,
acetone-d6): d 2.78–3.08 (8H, m), 6.39 (1H, d, J = 2.2Hz),
6.50 (1H, d, J = 2.2Hz), 6.71(1H, dd, J = 2.5, 8.2Hz),
6.74 (1H, d, J = 2.5Hz), 6.75 (1H, dd, J = 2.5, 8.0Hz),
6.78 (1H, d, J = 8.2Hz), 6.84 (1H, d, J = 2.7Hz), 6.89 (1H,
d, J = 8.2Hz), 6.99 (1H, d, J = 8.0Hz), 7.00 (1H, dd,
J = 2.2, 8.2Hz), 7.07 (1H, d, J = 7.7Hz), 7.13 (1H, dd,
1. Asakawa, Y. In Progress in the Chemistry of Organic
Natural Products; Hertz, W., Grisebach, H., Kirby, G. W.,
Eds.; Springer: Wien, New York, 1995; Vol. 65, pp 5–562.
2. Asakawa, Y. Rev. Latitinoam. Quim. 1984, 109, 109–
114.

T. Esumi et al. / Tetrahedron Letters 45 (2004) 6941–6945
6945
J = 2.2, 8.2Hz); 13C NMR (75MHz, acetone-d6): d 36.2,
38.1, 38.6, 39.1, 113.3, 116.0, 116.1, 117.0, 117.4, 121.5,
126.0, 127.2, 127.6, 128.1, 129.4, 129.5, 132.0, 132.4, 133.9,
133.9, 134.3, 136.0, 142.6, 144.0, 151.7, 152.2, 155.2, 157.4;
HREIMS calcd 424.1674 for C28H24O4, found 424.1660
(M+); IR (KBr) 3389, 1419, 1255cmꢀ1
18. Toyota, M.; Yoshida, T.; Kan, S.; Takaoka, S.; Asakawa,
.
Y. Tetrahedron Lett. 1996, 37, 4745–4748.