The first total synthesis of gravicycle

Article abstract of DOI:10.1246/cl.2012.87

The total synthesis of gravicycle, isolated from Grevillea robusta, has been achieved for the first time. The key step of our synthetic process is the efficient assembly of a highly functionalized biaryl ether via the copper-catalyzed O-arylation of suita

Full text of DOI:10.1246/cl.2012.87

doi:10.1246/cl.2012.87
Published on the web December 30, 2011
87
The First Total Synthesis of Gravicycle
Katsuaki Ueda,1 Itaru Sato,*2 and Masahiro Hirama1
1Department of Chemistry, Graduate School of Science, Tohoku University,
Sendai, Miyagi 980-8578
2Research and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku University, Sendai, Miyagi 980-8578
(Received October 15, 2011; CL-111012; E-mail: isato@m.tohoku.ac.jp)
The total synthesis of gravicycle, isolated from Grevillea
robusta, has been achieved for the first time. The key step of
our synthetic process is the efficient assembly of a highly
functionalized biaryl ether via the copper-catalyzed O-arylation
of suitably protected pyrogallol-5-carboxylate, using triarylbis-
muth(V) diacetate.
phenols and aryl halides, whereas reactions of 2,6-disubstituted
phenols and functionalized aryl halides have resulted in low
yields.5 There are few methods that allow the preparation of
highly substituted biaryl ethers under mild conditions.
In the 1980s, Barton and Finet developed a copper-catalyzed
O-arylation of phenol which proceeded at room temperature
using phenylbismuth(V) reagents.6 No examples have been
reported, however, in which this methodology has been used for
the synthesis of more sterically crowded biaryl ethers. Herein,
we describe copper-catalyzed coupling reactions of crowded
phenols using triarylbismuth(V) diacetate. In addition, we
present the first total synthesis of gravicycle (1).
Our synthetic strategy is outlined in Scheme 1. The macro-
cycle of 1 was to be produced by ring-closing metathesis
(RCM)7 of 2. The biaryl ether 3c was to be synthesized via
copper-catalyzed O-arylation of properly protected pyrogallol-5-
carboxylate 4b8 with the triarylbismuth diacetate 5c.
Initially, we examined the copper-catalyzed O-arylation of a
series of pyrogallol derivatives 4 with a series of triarylbismuth
diacetate derivatives 59 (Table 1). When 3,5-dimethoxy-4-
hydroxybenzaldehyde (4a) was treated with 5a and copper
powder in the presence of triethylamine, formation of the biaryl
Gravicycle, a novel cyclic biaryl ether, was first isolated
from Grevillea robusta A. Cunn. (Proteaceae) in 2007.1 This
compound has demonstrated significant cytotoxicity against
human breast carcinoma (MCF-7), lung carcinoma (NCI-H460),
and central nervous system carcinoma (SF-268) cell lines. As
shown in Scheme 1, the structure of 1 includes a biaryl ether
formed from two resorcinol units, resulting in a 22-membered
cyclic ether which contains a chiral benzylic alcohol. Although
highly functionalized biaryl ether linkages are common in a
variety of natural products,2 their production by synthetic
methods has been quite limited to date.3
The bond formations resulting in biaryl ethers have often
been achieved through the use of transition-metal-catalyzed
reactions between aryl halides and phenols,4 including Ullmann-
type reactions.3,4d,4e However, these reactions generally require
harsh reaction conditions.3a-3c Under such conditions, good
yields via O-arylation are realized only in the case of simple
Table 1. Copper-catalyzed O-arylation of pyrogallol deriva-
tives 4 using bismuth diacetate derivatives 5
OR1
OH
OH
O
OH
OH
R2
OR1
HO
1. RCM
2. deprotection
OR1
4
Cu 20 mol%
NEt3
O
OR3
+
OBn
CH2Cl2, rt
24 h
OAc
Bi
O
OBn
R2
OR1
OR3
AcO
R4
1
BnO
OBn
3
R4
OBn
5
6
OH
3
2
5
MeO2C
OBn
OBn
1. alkylation
2. reduction
4
5a
R3 R4
Me
Me CH2OTBS 90 (3b)
Me CH2OTBS 68 (3b)
Bn CH2OTBS 50 (3c)
Bn CH2OTBS 68 (3c)
4b
+
Entry
Yield/%
83 (3a)
OBn
R1 R2
OAc
Bi
O
OBn
O-arylation
MeO2C
1
a
a
a
b
b
Me CHO
Me CHO
Me CHO
Bn CO2Me
Bn CO2Me
a
b
b
c
c
b
H
AcO
2b
3b,c
4b
5
OBn
OTBS
OTBS
5c
3c
3
a1.5 molar equivalents used. NEt3 (6.0 mol equiv) not added.
c1.2 mol equiv of 5 used.
Scheme 1. Retrosynthetic analysis of gravicycle (1).
Chem. Lett. 2012, 41, 87-89
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

88
Ph
Ph
H
O
N
B
Me
OBn
OBn
OBn
10
BrMg
O
OBn
O
OBn
O
OBn
10 (25 mol%)
catechol borane
5
7
X
RO
R
THF, 0 °C to rt
83%
R
OBn
OBn
OBn
THF, −20 °C to rt
82%, 91% ee
OTBS
OTBS
11: R = H
OTBS
5
5
1) LiAlH4, Et2O, 0 °C to rt
2) DMPI, CH2Cl2,
84% (2 steps)
3c: R = CO2Me
6: R = CHO
8: X = OH, H
9: X = O
DMPI
CH2Cl2
84%
NaH, BnBr
THF/ DMF
82%
12: R = Bn
TBAF
THF
81%
N
N
Mes
Ph
Mes
Cl
Cl
OBn
O
Ru
OBn
BrMg
OBn
PCy3
OBn
O
5
O
OBn
OBn
OBn
BnO
7
15
Li2CuCl4
BnO
BnO
15 (5 mol%)
OBn
OBn
THF, −20 °C
77%
CH2Cl2, 40 °C
71%
X
6
5
5
2
16
1
13: X = OH
14: X = Br
1) Ms2O, Et3N, CH2Cl2, 0 °C
2) LiBr, THF, 60 °C
95% (2 steps)
Pd(OH)2/C, H2
CHCl3
38%
Scheme 2. Synthesis of gravicycle (1).
ether proceeded at room temperature to give the ether 3a in good
yield (Entry 1). The reaction of 4a with 5b also gave the biaryl
ether 3b in high yield (Entry 2). Triethylamine was necessary to
obtain 3c in good yield reproducibly (Entries 4 and 5). These
results show that arylbismuth(V) reagents are suitable for use
with crowded phenols in copper-catalyzed Ullmann-type cou-
pling reactions.
yield. When the E/Z olefin mixture 16 was mixed with
palladium hydroxide on carbon in CHCl3 under a hydrogen
atmosphere, hydrogenation of the olefin and hydrogenolysis of
the four benzyl ethers proceeded to give 1 (38% yield). The use
of CHCl3 as a solvent in this step was necessary in order to
dissolve 16, since it was insoluble in both ethyl acetate and
alcohols. The hydrogenolysis was slow and not completed under
these conditions. The spectral data (1H, 13C, IR, and HRMS) of
the synthetic product 1 were identical with those reported for a
sample of 1 obtained from natural sources.16
In conclusion, we have achieved the first total synthesis of
gravicycle (1), via a process which features the copper-catalyzed
O-arylation of the pyrogallol derivative 4b using triarylbismuth
diacetate 5c. Furthermore, the development of this synthesis
demonstrated that the formation of highly functionalized biaryl
ethers can be carried out under mild reaction conditions. The
methodology presented here should be more generally appli-
cable to the O-arylation of sterically crowded alkyl alcohols18 as
a means to the synthesis of highly functionalized alkyl aryl
ethers. Further research along these lines is currently underway
in our laboratory.
Our total synthesis of 1 commenced with 3c (Scheme 2).
Reduction of methyl ester 3c with LiAlH4 followed by oxidation
with Dess-Martin periodinane (DMPI)10 afforded aldehyde 6 in
84% yield (2 steps). Addition of the Grignard reagent 7 to 6 gave
benzyl alcohol 8 in 83% yield. Following the oxidation of 8, the
resultant ketone 9 was reduced with oxazaborolidine 1011 and
catecholborane in THF at ¹20 °C to give chiral benzyl alcohol
11 in 82% yield. The enantiomeric excess of this chiral product
was found to be 91% by HPLC using Chiralpak AD-Hμ
analysis. The (R)-configuration of 11 was determined using the
modified Mosher’s method.12 The hydroxy functional group of
11 was protected by conversion to a benzyl ether to give 12 in
82% yield. The TBS ether of 12 was cleaved by reaction with
TBAF in THF. Mesylation of 13 with methanesulfonic an-
hydride (Ms2O) and triethylamine in CH2Cl2 at 0 °C, followed
by bromination with lithium bromide in THF at 60 °C, afforded
benzyl bromide 14 in 95% yield.13 Alkylation of 14 with 7 in the
presence of Li2CuCl4 in THF at ¹20 °C proceeded efficiently to
give 2 in 77% yield.14 Cyclization of 2 via RCM was conducted
using the Grubbs second generation catalyst 1515 at 40 °C in
a 2.5 mM CH2Cl2 solution. Under these conditions, 2 was
consumed completely, and only the desired cyclic product 16
was obtained as a 2.6:1 mixture of (E)- and (Z)-olefins in 71%
This work was supported financially by a Grant-in-Aid for
Specially Promoted Research from the Ministry for Education,
Culture, Sports, Science and Technology (MEXT).
Reference and Notes
1
2
T.-H. Chuang, P.-L. Wu, J. Nat. Prod. 2007, 70, 319.
a) D. A. Evans, M. R. Wood, B. W. Trotter, T. I. Richardson,
J. C. Barrow, J. L. Katz, Angew. Chem., Int. Ed. 1998, 37,
Chem. Lett. 2012, 41, 87-89
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

89
2700. b) K. C. Nicolaou, H. J. Mitchell, N. F. Jain, N.
Winssinger, R. Hughes, T. Bando, Angew. Chem., Int. Ed.
1999, 38, 240. c) H. Shimamura, S. P. Breazzano, J.
Garfunkle, F. S. Kimball, J. D. Trzupek, D. L. Boger, J. Am.
Chem. Soc. 2010, 132, 7776. d) D. L. Boger, S. M. Sakya, D.
Yohannes, J. Org. Chem. 1991, 56, 4204. e) W. Schuehly, W.
Voith, H. Teppner, O. Kunert, J. Nat. Prod. 2010, 73, 1381.
a) S. V. Ley, A. W. Thomas, Angew. Chem., Int. Ed. 2003,
42, 5400. b) R. Frlan, D. Kikelj, Synthesis 2006, 2271. c) F.
Theil, Angew. Chem., Int. Ed. 1999, 38, 2345. d) J. R.
Cannon, B. W. Metcalf, Aust. J. Chem. 1973, 26, 2277.
a) M. Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem.
Soc. 1996, 118, 10333. b) G. Mann, C. Incarvito, A. L.
Rheingold, J. F. Hartwig, J. Am. Chem. Soc. 1999, 121,
3224. c) Q. Shelby, N. Kataoka, G. Mann, J. Hartwig, J. Am.
Chem. Soc. 2000, 122, 10718. d) D. Maiti, S. L. Buchwald,
J. Am. Chem. Soc. 2009, 131, 17423. e) D. Maiti, S. L.
Buchwald, J. Org. Chem. 2010, 75, 1791.
2386.
10 a) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
b) D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113,
7277.
11 a) E. J. Corey, C. J. Helal, Angew. Chem., Int. Ed. 1998, 37,
1986. b) C. Y. Hong, N. Kado, L. E. Overman, J. Am. Chem.
Soc. 1993, 115, 11028.
3
4
12 I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am.
Chem. Soc. 1991, 113, 4092.
13 H. Hashizume, H. Ito, T. Morikawa, N. Kanaya, H.
Nagashima, H. Usui, H. Tomoda, T. Sunazuka, H.
Kumagai, S. Ōmura, Chem. Pharm. Bull. 1994, 42, 2097.
14 a) T. B. Nguyen, A.-S. Castanet, T.-H. Nguyen, K. P. P.
Nguyen, J.-F. Bardeau, A. Gibaud, J. Mortier, Tetrahedron
2006, 62, 647. b) M. Schlosser, H. Bossert, Tetrahedron
1991, 47, 6287.
15 M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett.
1999, 1, 953.
23
5
6
C. Paizs, U. Bartlewski-Hof, J. Rétey, Chem.®Eur. J. 2007,
16 1: Colorless amorphous solid, ½¡ꢀD = +11.5 (c 0.45,
13, 2805.
MeOH) [lit1,17 [¡]D = +13.1 (c 0.45, CHCl3)]; IR (film): ¯
3343, 1597, 1501, 1460 cm¹1; 1H NMR (400 MHz, CD3OD):
¤ 1.27 (20H, m), 1.45 (2H, m), 1.73 (2H, m), 2.34 (2H, t,
J = 6.0 Hz), 4.46 (1H, t, J = 6.0 Hz), 5.82 (1H, dd, J = 2.4,
1.6 Hz), 6.26 (1H, dd, J = 2.4, 1.6 Hz), 6.46 (2H, brs), 6.48
(1H, dd, J = 2.4, 2.4 Hz); 13C NMR (100 MHz, CD3OD): ¤
26.4, 27.9, 28.5, 28.6, 28.8, 28.9, 29.0, 29.1, 29.4, 30.1,
32.2, 37.0, 40.0, 75.3, 102.7, 105.2, 106.7, 109.9, 130.4,
143.9, 146.0, 151.8, 159.2, 160.8; HRMS (ESI) m/z:
[M + Na]+ calcd for C26H36NaO5 451.2460, found
451.2460.
a) D. H. R. Barton, J.-P. Finet, J. Khamsi, C. Pichon,
Tetrahedron Lett. 1986, 27, 3619. b) D. H. R. Barton, B.
Charpiot, W. B. Motherwell, Tetrahedron Lett. 1982, 23,
3365. For related O-arylation with arylboronic acid, see: c)
D. A. Evans, J. L. Katz, T. R. West, Tetrahedron Lett. 1998,
39, 2937.
a) Handbook of Metathesis, ed. by R. H. Grubbs, Wiley-
VCH, Weinheim, 2003, Vol. 2, pp. 296-319. b) K. C.
Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem., Int. Ed.
2005, 44, 4490.
7
8
9
G. Cainelli, C. Angeloni, R. Cervellati, P. Galletti, D.
Giacomini, S. Hrelia, R. Sinisi, Chem. Biodiversity 2008, 5,
811.
17 The optical rotation of 1 was not measured in CHCl3,
because synthetic product 1 was insoluble in CHCl3.
18 T. Mukaiyama, N. Sakurai, K. Ikegai, Chem. Lett. 2006, 35,
1140.
J.-P. Finet, A. Yu. Fedorov, J. Organomet. Chem. 2006, 691,
Chem. Lett. 2012, 41, 87-89
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/