A total synthesis of yellowish aphid pigment furanaphin through fries rearrangement assisted by boron trifluoride-acetic acid complex

Article abstract of DOI:10.1055/s-0031-1290429

The yellowish aphid pigment furanaphin, isolated from Aphis spiraecola and possessing cytotoxicity against HL-60 (human promyelocytic leukemia-60) cells, was synthesized by utilizing the Fries rearrangement assisted with a BFmiddot;2AcOH complex as a key step. It was confirmed that the complex effectively mediated the reaction even though the compounds had an electron-withdrawing substituent.

Full text of DOI:10.1055/s-0031-1290429

LETTER
▌1789
lAetteTr otal Synthesis of Yellowish Aphid Pigment Furanaphin through Fries
Rearrangement Assisted by Boron Trifluoride-Acetic Acid Complex
Total Synthesis of Furanaphin
Taichi Nishimura, Takeki Iwata, Hironori Maegawa, Takeshi Nishii, Masami Matsugasako, Hiroto Kaku,
Mitsuyo Horikawa, Makoto Inai, Tetsuto Tsunoda*
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan
Fax +81(88)6553051; E-mail: tsunoda@ph.bunri-u.ac.jp
Received: 23.04.2012; Accepted after revision: 22.05.2012
Wadsworth–Emmons reaction of aldehyde 5 with 6 fol-
lowed by intramolecular cyclization, would be used to
prepare methyl ketone 3.
Abstract: The yellowish aphid pigment furanaphin, isolated from
Aphis spiraecola and possessing cytotoxicity against HL-60 (hu-
man promyelocytic leukemia-60) cells, was synthesized by utilizing
the Fries rearrangement assisted with a BF3·2AcOH complex as a
key step. It was confirmed that the complex effectively mediated the
reaction even though the compounds had an electron-withdrawing
substituent.
PGO
PGO
OH
O
MeO
O
Key words: dyes, pigments, Fries rearrangement, total synthesis,
natural products
OH
HO
MeO
furanaphin (1)
2
Aphids produce novel polyketide pigments such as pro-
toaphins (yellow pigments),1–7 uroleuconaphines (yellow
and red pigments),8,9 viridaphin A1 glucoside (green pig-
ment),10 furanaphin (1; yellow pigment having fluores-
cence),11 and megouraphin glucosides (yellow pigments
having fluorescence).12 The presence of pigments is im-
portant for expressing aphid body color and, presumably,
subtle differences in body coloration (color polymor-
phism) affect predator–prey interactions.13 Currently,
aphid coloration has generated interest from the perspec-
tives of host–endosymbiont and evolutionary–coevolu-
tionary relationships.14,15 Furthermore, based on their
cytotoxic and antibacterial activities, aphid pigments have
been proposed to protect aphids from invasive species
such as viruses, bacteria, and fungi.10
MeO
OAc
MeO
OH
O
MeO
CO2Et
MeO
CO2Et
3
4
MeO
CO2t-Bu
O
+
EtO P
EtO
CO2Et
MeO
CHO
6
5
Scheme 1 Retrosynthesis of 1
Furanaphin (1; Scheme 1) was isolated from Aphis spirae-
cola (max. 1.5 mm long) as a yellowish hydrophobic
compound having a unique naphthofuran ring system,
which was found to be active (IC50 25 μM) against HL-60
cells.11 To continue our investigations into the biological
activities of 1, including antiviral, antibacterial, and anti-
fungal activities, an adequate supply of 1 was required.
Herein, we report the total synthesis of 1 by utilizing the
Fries rearrangement as a key step.
For the preparation of rearrangement precursor 4 (Scheme
2), according to the method of Rizzacasa,16 we chose 3,5-
dimethoxybenzaldehyde (5) as a starting material and
converted it into unsaturated ester 7 with E geometry at
the double bond by the Horner–Wadsworth–Emmons re-
action with 6 (61% yield). The tert-butyl group of ester 7
was removed by treatment with trifluoroacetic acid (TFA)
MeO
6 (1 equiv)
NaH (1.2 equiv)
Our retrosynthetic analysis of 1 is illustrated in Scheme 1.
Methyl ketone 3 would be used as a key intermediate in
the synthesis of 1. After selective reduction of the ethoxy-
carbonyl group of 3, the resulting product 2 was expected
to undergo spontaneous cyclization upon acidic treatment
to generate the dihydrofuran ring. Fries rearrangement of
acetate 4, which could be afforded by Horner–
CO2t-Bu
TFA
5
CH2Cl2, 10 h
THF, 0 °C, 3 h
61%
MeO
CO2Et
7
MeO
NaOAc (1 equiv)
CO2H
4
Ac2O, 160 °C
10 min
96% (2 steps)
MeO
CO2Et
SYNLETT 2012, 23, 1789–1792
8
Advanced online publication: 29.06.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290429; Art ID: ST-2012-U0349-L
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Preparation of rearrangement precursor 4

1790
T. Nishimura et al.
LETTER
to give carboxylic acid 8, without purification, which un-
derwent cyclization to afford naphthalene derivative 4
through a mixed acid anhydride, in 96% yield (two steps).
MeO
OAc
BF3⋅OEt2 (10 equiv)
ClCH2CH2Cl, reflux, 30 min
MeO
CO2Et
OH
With the desired precursor 4 in hand, we tried the Fries
rearrangement17 of acetate 4 using 10 equiv of BF3·OEt2
in 1,2-dichloroethane heated to reflux for 30 min (Scheme
3). Although the desired product 3 was produced, the
yield was only 42%, with 49% of hydrolyzed compound
9.
4
MeO
O
MeO
OH
+
MeO
CO2Et
MeO
CO2Et
A previous study reported that the efficiency of the Fries
rearrangement was decreased by the presence of an elec-
tron-withdrawing group.18 In the course of our studies to
refine the yield of the rearrangement, we found that the
BF3·2AcOH complex19 assisted the reaction significantly.
To confirm the generality and usefulness of this complex
for the Fries rearrangement, we tested several compounds
4 and 10–13. The results, shown in Table 1, compare the
outcome of the reaction using this complex to those
achieved with BF3·OEt2.
9 (49%)
3 (42%)
Scheme 3 Fries rearrangement of acetate 4
When BF3·OEt2 was employed, we confirmed that the
presence of electron-withdrawing groups retarded the ef-
ficiency of acyl migration dramatically (compare Table 1,
entry 3 vs. entry 5 and entry 7 vs. entry 9), and the yields
of the desired reaction products were low to moderate in
all cases (entries 1, 3, 5, 7 and 9). In contrast, use of the
Table 1 Optimization of the Fries Rearrangement; Scope of Substrates and Comparison of BF3 Complexes
OH
OH
OAc
Ac
boron complex
+
ClCH2CH2Cl,
reflux
R
R
R
A
B
Entry
Compounds
Conditions
Yield (%)
Boron (equiv)
Time (h)
A
B
OAc
1
2
BF3·OEt2 (10)
BF3·2AcOH (5)
24
3
34
92
27
–
10
OAc
3
4
BF3·OEt2 (10)
BF3·2AcOH (5)
15
2
50
98
44
–
11
OAc
5
6
BF3·OEt2 (10)
BF3·2AcOH (10)
24
12
15
74
68
2
CO2Et
OAc
12
MeO
7
BF3·OEt2 (10)
BF3·2AcOH (10)
0.5
1
63
89
32
11
8a
MeO
13
MeO
OAc
9
BF3·OEt2 (10)
BF3·2AcOH (10)
0.5
0.5
42
91
49
8
10a
MeO
CO2Et
4
a In CH2Cl2 at reflux.
Synlett 2012, 23, 1789–1792
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of Furanaphin
1791
MeO
OR OR
TBSOTf (3 equiv)
2,6-lutidine (4 equiv)
OH
O
MeO
OR OR
LiAlH4 (2 equiv)
BBr3 (10 equiv)
CH2Cl2, 0 °C
10 min, quant.
O
THF, 0 °C
10 min, quant.
CH2Cl2, 0°C
12 h, 18 %
OH
MeO
CO2Et
HO
MeO
furanaphin (1)
14: R = TBS
15: R = TBS
3
BBr3 (5 equiv)
CH2Cl2, 0 °C, 2 h
50%
OH OH
O
OR OR OR
OR OR OR
TBSOTf (5 equiv)
2,6-lutidine (10 equiv)
LiAlH4 (2 equiv)
BCl3 (10 equiv)
CH2Cl2, 0 °C to r.t.
10 h, 87%
CH2Cl2, 0 °C
CO2Et 10 min, quant.
MeO
THF, 0 °C to r.t.
10 min, quant.
CO2Et
OH
MeO
MeO
18: R = TBS
16
17: R = TBS
Scheme 4 Synthesis of furanaphin (1)
(2) Brown, B. R.; Ekstrand, T.; Johnson, A. W.; MacDonald,
S. F.; Todd, A. R. J. Chem. Soc. 1952, 4925.
(3) Cameron, D. W.; Cromartie, R. I. T.; Kingston, D. G. I.;
Todd, L. J. Chem. Soc. 1964, 51.
(4) Cameron, D. W.; Chan, H. W.-S.; Kingston, D. G. I.
J. Chem. Soc. 1965, 4363.
(5) Cameron, D. W.; Chan, H. W.-S. J. Chem. Soc. C 1966,
1825.
BF3·2AcOH complex made a remarkable difference (en-
tries 2, 4, 6, 8 and 10), even for the reactions with sub-
strates having an electron-withdrawing group (entries 6
and 10).
With the desired product 3 obtained in 91% yield (Table
1, entry 10),20 the hydroxyl and acetyl groups of 3 were
protected as a silyl ether and a silyl enol ether (TBSOTf,
2,6-lutidine in CH2Cl2), respectively (Scheme 4). Reduc-
tion of 14 with LiAlH4 at 0 °C gave alcohol 15 in quanti-
tative yield; subsequent treatment of 15 with BBr3 cleaved
the methyl and silyl ethers and induced spontaneous cycli-
zation under acidic reaction conditions to give furanaphin
(1) in 18% yield.
(6) Bowie, J. H.; Cameron, D. W.; Findlay, J. A.; Quartey,
J. A. K. Nature 1966, 210, 395.
(7) Banks, H. J.; Cameron, D. W. Aust. J. Chem. 1972, 25, 2199.
(8) Horikawa, M.; Hashimoto, T.; Asakawa, Y.; Takaoka, S.;
Tanaka, M.; Kaku, H.; Nishii, T.; Yamaguchi, K.; Masu, H.;
Kawase, M.; Suzuki, S.; Sato, M.; Tsunoda, T. Tetrahedron
2006, 62, 9072.
(9) Horikawa, M.; Tanaka, M.; Kaku, H.; Nishii, T.; Tsunoda, T.
Tetrahedron 2008, 64, 5515.
(10) Horikawa, M.; Hoshiyama, T.; Matsuzawa, M.; Shugyo, T.;
Tanaka, M.; Suzuki, S.; Sato, M.; Ito, T.; Asakawa, Y.;
Kaku, H.; Nishii, T.; Inai, M.; Takahashi, S.; Tsunoda, T.
J. Nat. Prod. 2011, 74, 1812.
(11) Horikawa, M.; Noguchi, T.; Takaoka, S.; Kawase, M.; Sato,
M.; Tsunoda, T. Tetrahedron 2004, 60, 1229.
(12) Horikawa, M.; Kikuchi, D.; Imai, T.; Tanaka, M.; Kaku, H.;
Nishii, T.; Inai, M.; Takahashi, S.; Tsunoda, T. Heterocycles
2012, 85, 95.
As an alternative route, selective cleavage of the methyl
ether of 3 was carried out with BCl3 to give 16, which was
silylated with TBSOTf (5 equiv) in the presence of 2,6-
lutidine in CH2Cl2 to afford silyl enol ether 17 in quanti-
tative yield. After reduction of 17, the resulting alcohol 18
was subjected to cleavage of the ether linkages with BBr3
to give 121 in 50% yield. All spectroscopic data (1H, 13C
NMR, IR, and HRMS) for the synthetic furanaphin (1)
agreed with those reported previously in the literature.11
(13) Losey, J. E.; Ives, A. R.; Harmon, J.; Ballantyne, F.; Brown,
C. Nature 1997, 388, 269.
(14) Tsuchida, T.; Koga, R.; Horikawa, M.; Tsunoda, T.; Maoka,
T.; Matsumoto, S.; Simon, J.; Fukatsu, T. Science 2010, 330,
1102.
(15) Moran, N. A.; Jarvik, T. Science 2010, 328, 624.
(16) (a) Rizzacasa, M. A.; Sargent, M. V. Aust. J. Chem. 1987,
40, 1737. (b) For an alternative synthetic route to 4, see:
Hauser, F. M.; Sengupta, D.; Corlett, S. A. J. Org. Chem.
1994, 59, 1967.
(17) (a) Rizzacasa, M. A.; Sargent, M. V. Aust. J. Chem. 1988,
41, 1087. (b) Singh, S. B.; Graham, P. L.; Reamer, R. A.;
Cordingley, M. G. Bioorg. Med. Chem. Lett. 2001, 11, 3143.
(18) Blatt, A. H. Org. React. 1942, 1, 342.
(19) The Fries rearrangement using the BF3·2CH3CO2H complex
was reported. The complex acts as an acyl donor, but the
rearrangement of reactants having electron-withdrawing
groups was not investigated, see: Davies, J. S. H.; McCrea,
P. A.; Norris, W. L.; Ramage, G. R. J. Chem. Soc. 1950,
3206.
In summary, we have achieved the total synthesis of fu-
ranaphin (1) by utilizing the Fries rearrangement as a key
step and found that the BF3·2AcOH complex satisfactorily
provided the desired product. Further applications of this
reaction and biological activities of 1 are under investiga-
tion in our laboratory and will be reported in due course.
Acknowledgment
This work was supported partially by a Grant-in-Aid for Scientific
Research (C) from MEXT (the Ministry of Education, Culture,
Sports, Science and Technology of Japan). We are also thankful to
MEXT-Senryaku, 2008-2012.
References and Notes
(1) Duewell, H.; Human, J. P. E.; Johnson, A. W.; MacDonald,
S. F.; Todd, A. R. Nature 1948, 162, 759.
(20) Fries Rearrangement of 4: To a solution of acetate 4
(104.1 mg, 0.327 mmol) in CH2Cl2 (0.5 mL) was added
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1789–1792

1792
T. Nishimura et al.
LETTER
BF3·2AcOH (440 μL, 3.16 mmol) under an Ar atmosphere,
and the resulting mixture was heated at reflux for 30 min.
After addition of H2O (3 mL) at 0 °C, the resulting mixture
was extracted with CH2Cl2 (3 × 5 mL), and the combined
organic extracts were washed with brine (10 mL), dried over
MgSO4, filtered, and concentrated. The residue was purified
by silica gel column chromatography (n-hexane–EtOAc,
8:1) to give ethyl 3-acetyl-4-hydroxy-5,7-dimethoxy-2-
naphthoate (3) in 91% yield as colorless crystals; mp 100–
101 °C (EtOAc). 1H NMR (400 MHz, CDCl3): δ = 9.64 (s,
1 H), 7.75 (d, J = 0.4 Hz, 1 H), 6.77 (d, J = 2.0 Hz, 1 H),
6.57 (d, J = 2.0 Hz, 1 H), 4.35 (q, J = 7.2 Hz, 2 H), 4.04 (s,
3 H), 3.90 (s, 3 H), 2.65 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 203.7, 166.7, 159.0, 157.7,
152.2, 136.5, 128.4, 122.0, 120.7, 111.9, 100.5, 100.2, 61.5,
56.4, 55.5, 31.8, 14.0. IR (ATR): 3329, 1708, 1624, 1578,
1364, 1250, 1198, 1153, 1111, 1045 cm–1. MS (EI):
m/z (%)= 318 [M]+, 303, 275 (100). HRMS (EI): m/z calcd
for C17H18O6: 318.1103; found: 318.1128.
(21) Furanaphin (1): Orange-yellow needles (MeOH); mp 218–
219 °C (MeOH) {Lit11 211–214 °C (dec)}. 1H NMR (400
MHz, acetone-d6): δ = 14.28 (s, 1 H), 9.17 (s, 1 H), 6.40 (dd,
J = 2.4, 2.4 Hz, 1 H), 6.35 (d, J = 2.4 Hz, 1 H), 6.17 (d,
J = 2.4 Hz, 1 H), 5.51 (d, J = 2.4 Hz, 2 H), 2.67 (s, 3 H). 13
C
NMR (100 MHz, acetone-d6): δ = 184.8, 184.3, 167.4, 164.7,
143.9, 143.5, 115.2, 111.7, 107.4, 104.7, 100.5, 77.6, 16.1.
IR (ATR): 3333, 1650, 1569, 1382, 1170, 1153, 1130, 1085,
985, 887, 823 cm–1. MS (EI): m/z (%) = 231 [M+H]+, 230
(100) [M]+. HRMS (EI): m/z calcd for C13H10O4: 230.0579;
found: 230.0575.
Synlett 2012, 23, 1789–1792
© Georg Thieme Verlag Stuttgart · New York

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