Synthesis of biliverdin derivative bearing the sterically fixed E-anti C/D-ring component

Article abstract of DOI:10.1246/cl.2005.800

Biliverdin (BV) derivative bearing the E-anti C/D-ring component, which is sterically fixed by 8-membered ring, was synthesized toward investigation of the structure and function of the chromophore in phytochrome. Copyright

Full text of DOI:10.1246/cl.2005.800

800
Chemistry Letters Vol.34, No.6 (2005)
Synthesis of Biliverdin Derivative Bearing the Sterically Fixed E-anti C/D-Ring Component
Hideki Kinoshita,ꢀ Mostafa A. S. Hammam, and Katsuhiko Inomataꢀ
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa, Ishikawa 920-1192
(Received February 28, 2005; CL-050259)
Biliverdin (BV) derivative bearing the E-anti C/D-ring
Me
Me
O
O
component, which is sterically fixed by 8-membered ring, was
synthesized toward investigation of the structure and function
of the chromophore in phytochrome.
O
O
A
NH
E
A
Me
NH
Me
HN
HN
D
D
HN
HN
anti
N
NH
B
C
Me
C
B
Me
CHO
Light is one of the major environmental signals that influ-
ence plant growth and development. Plants can detect almost
all facets of light, e.g. wavelength and quantity, by using photo-
receptors such as phytochromes. Plant phytochromes carry ei-
ther phytochromobilin (PꢀB) or phycocyanobilin (PCB) as
chromophore which binds covalently to the protein by a thioeth-
er bond through the A-ring ethylidene side chain, and responds
to red/far-red light which interchanges between Z- and E-forms
at C-15 position of the chromophore. Some bacterial phyto-
chromes carry biliverdin (BV) as natural chromophore, and it
was found that the BV covalently binds to the apoprotein of
Agrobacterium phytochrome Agp1 via its A-ring vinyl side
chain.1 The interchange between the physiologically inactive
red-light absorbing Pr (Z-form) and the active far red-light ab-
sorbing Pfr (E-form) is the most essential for the light absorbing
and biological processes in the phytochrome chromophore func-
tion (Figure 1).2
CO2R
CO2R
CO2Allyl
CO2Allyl
4
1, R = H
2, R = Allyl
3
Figure 2.
In the present work, we developed an efficient method for
the synthesis of the sterically locked E-anti BV derivative corre-
sponding to Pfr form (Figure 2).
The A/B-ring component 3 common to locked BV deriva-
tives was prepared according to our previous method.6
On the other hand, the C/D-ring component 4 was prepared
starting from 5-hydroxypentanal (6), which can be obtained from
the commercially available 3,4-dihydro-2H-pyran (5) as shown
in Scheme 1. The Henry reaction with 1-nitropropane followed
by acetylation in the presence of 4-(dimethylamino)pyridine
(DMAP) gave the nitro-diacetate compound 7, which was
allowed to react with t-butyl isocyanoacetate in the presence
of DBU in THF applying Barton’s method7 to give the pyrrole
derivative 8 in 67% yield.
Iodination of ꢀ-position of the pyrrole 8 with N-iodosuc-
cinimide (NIS) followed by oxidation utilizing Pb(OAc)4 in tol-
uene gave the pyrrolinone derivative 9 in 90% yield from 8 in
two steps. The ꢀ-acetoxy group of the pyrrolinone derivative 9
was replaced with Ts group using anhydrous sodium p-toluene-
sulfinate (TsNa) in refluxing THF, followed by protection of the
pyrrolinone-NH using di-t-butyl dicarbonate in MeCN. Then,
hydrolysis of the acetate group in 0.5 M methanolic HCl afford-
ed the N-protected tosylpyrrolinone derivative 10 in 92% yield
from 9 in three steps. Iodination of the resulting alcohol using
iodine and triphenylphosphine in the presence of imidazole in
MeCN followed by nitration using sodium nitrite in the presence
of phloroglucinol in DMF gave the tosylpyrrolinone derivative
bearing a nitro group in its side chain in 38% yield. The resulting
nitro compound was allowed to react with allyl 4-oxobutanoate
according to the Henry reaction to construct the nitro-alcohol
side chain of the tosylpyrrolinone derivative 11 in 64% yield.
Acetylation of the resulting alcohol 11 followed by reaction with
t-butyl isocyanoacetate gave the dipyrrole derivative 12 in 82%
yield from 11 in two steps.
Protein
S
Me
A
R
Me
O O
Me
R
Me
Me
B
Me
15
D
NH HN
A
D
15
Za
O
O
N
N
Za
H
H
N
HN
NH
HN
C
B
C
Me
Me
Me
Me
Zs
CO2H
CO2H
Pr
CO2
CO2
R = Vinyl, Phytochromobilin (PΦB)
R = Ethyl, Phycocyanobilin (PCB)
ca. 660 nm
ca. 730 nm
Me
Me
A
R
O O
O
S
Protein
Me
15
D
HN
NH
O
A
HN
NH
D
Me
15
N
HN
Zs
R
C
B
Me
Me
Ea
NH HN
C
Me
Me
B
Me
Zs
CO2H
CO2H
CO2
CO2
Pfr
R = Vinyl, Biliverdin (BV)
Figure 1.
In the course of our studies on the phytochrome chromo-
phores, we synthesized natural and unnatural chromophores to
analyze the structure and function of the chromophores in the re-
constituted phytochromes.3–5 Furthermore, we have recently
succeeded for the first time in synthesizing the sterically locked
Z-anti BV derivative corresponding to Pr form,6 which made
it possible to directly confirm the stereochemistry around C-15
position.2
Compound 12 was subjected to the Vilsmeier reaction to
afford the formylated dipyrrole derivative 13 in 68% yield as
shown in Scheme 2. Compound 13 was then treated with 99%
formic acid to cleave the Boc and t-butyl esters giving the
dicarboxylic acid derivative, which was subjected to our original
Wittig-type coupling reaction using tri(n-butyl)phosphine in the
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.6 (2005)
801
presence of DBU in THF/DMF at ꢁ75 ꢂC–rt to give the pyrro-
methenone derivative 14 in 74% yield. Compound 14 was
formylated by treating with trimethyl orthoformate in TFA to
give the desired formylated E-anti C/D-ring component 4 in
40% yield.8
O
NH
O2N
Me
OAc
Me
H
CO2tBu
b, c
d
a
O
OH
5
6
7
OAc
8
OAc
O
O
The coupling reaction between the C/D- and A/B-ring
components (4 and 3) was carried out under acidic conditions
to afford the sterically fixed BV diallyl ester derivative 2 in
71% yield.
NH
NBoc
CO2tBu
Ts
Me
Me
CO2tBu
e, f
g, h, i
j, k, l
OAc
Finally, the deprotection of the allyl esters was achieved by
Pd(0)-catalyzed reaction in the presence of sodium p-toluenesul-
finate as nucleophile in THF/MeOH to give the desired BV de-
rivative 1 bearing the E-anti C/D-ring component in 70% yield.9
The chromophore 1 thus prepared was assembled with Agp1
apoprotein and found to form covalent bond showing the absorp-
tion spectrum corresponding to Pfr form.10
9
10
OAc
O
OH
O
Me
NBoc
NBoc
CO2tBu
Ts
Me
CO2tBu
m, n
Ts
NH
NO2
OH
CO2tBu
AllylO2C
The present work was financially supported in part by Grant-
in-Aid for Scientific Research (B) (No. 15350021) from Japan
Society for the Promotion of Science (JSPS). One of the authors
(K. I.) gratefully acknowledges Dr. Tilman Lamparter of Freie
AllylO2C
11
12
Scheme 1. a) In 0.1 M aq HCl, rt, 30 min. b) 1-Nitropropane (2.0
equiv.), KOH (0.2 equiv.) in MeOH, 0 ꢂC–rt, 3.5 h. c) Ac2O
(2.2 equiv.), DMAP (0.2 equiv.) in THF, 0 ꢂC–rt, 1 h. 7, 38% from
5. d) CNCH2CO2-t-Bu (1.0 equiv.), DBU (2.2 equiv.) in THF,
0 ꢂC–rt, overnight, 8, 67%. e) NIS (1.2 equiv.) in acetone, rt,
1 h. f) Pb(OAc)4 (1.5 equiv.) in toluene, rt, 2 d. 9, 90% from 8.
g) TsNa (2.1equiv.) in THF, reflux, 1.5 h. h) Boc2O (1.5 equiv.),
DMAP (0.2 equiv.) in MeCN, ꢁ40 ꢂC–rt, 1 h. i) In 0.5 M meth-
anolic HCl (prepared by diluting 12 M HCl with MeOH), rt, over-
night, 10, 92% from 9. j) I2 (1.2 equiv.), Ph3P (1.2 equiv.), imi-
dazole (2.5 equiv.) in MeCN, rt, 1 h. k) NaNO2 (2.0 equiv.), phloro-
glucinol dihydrate (1.1 equiv.) in DMF, rt, 7 h. l) OHCCH2-
CH2CO2-Allyl (2.0 equiv.), KOH (0.3 equiv.) in THF, 0 ꢂC–rt,
overnight, 11, 24% from 10. m) Ac2O (1.1 equiv.), DMAP
(0.2 equiv.) in THF, 0 ꢂC, 2 h. n) CNCH2CO2-t-Bu (4.0 equiv.),
DBU (5.0 equiv.) in MeCN, 0 ꢂC–rt, 4 h. 12, 82% from 11.
Universitat Berlin for giving us helpful information.
¨
References and Notes
1
2
3
T. Lamparter, N. Michael, O. Caspani, T. Miyata, K. Shirai, and K.
Inomata, J. Biol. Chem., 278, 33786 (2003).
M. A. Mroginski, D. H. Murgida, D. von Stetten, C. Kneip, F. Mark,
and P. Hildebrandt, J. Am. Chem. Soc., 126, 16734 (2004).
a) K. Kohori, M. Hashimoto, H. Kinoshita, and K. Inomata, Bull.
Chem. Soc. Jpn., 67, 3088 (1994). b) T. Kakiuchi, H. Kato, K. P.
Jayasundera, T. Higashi, K. Watabe, D. Sawamoto, H. Kinoshita,
and K. Inomata, Chem. Lett., 1998, 1001. c) K. P. Jayasundera, H.
Kinoshita, and K. Inomata, Chem. Lett., 1998, 1227. d) T. Kakiuchi,
H. Kinoshita, and K. Inomata, Synlett, 1999, 901. e) A. Ohta, D.
Sawamoto, K. P. Jayasundera, H. Kinoshita, and K. Inomata, Chem.
Lett., 2000, 492. f) D. Sawamoto, H. Nakamura, H. Kinoshita, S.
Fujinami, and K. Inomata, Chem. Lett., 2000, 1398. See also the refer-
ences cited therein.
4
5
H. Hanzawa, K. Inomata, H. Kinoshita, T. Kakiuchi, K. P.
Jayasundera, D. Sawamoto, A. Ohta, K. Uchida, K. Wada, and M.
Furuya, Proc. Natl. Acad. Sci. U.S.A., 98, 3612 (2001); A related paper
was reported: U. Robben, I. Lindner, W. Gartner, and K. Schaffner,
¨
Angew. Chem., Int. Ed., 40, 1048 (2001).
a) H. Hanzawa, T. Shinomura, K. Inomata, T. Kakiuchi, H. Kinoshita,
K. Wada, and M. Furuya, Proc. Natl. Acad. Sci. U.S.A., 99, 4725
(2002). b) K. Inomata, Chemistry Today, No. 398, 56 (2004).
M. A. S. Hammam, Y. Murata, H. Kinoshita, and K. Inomata, Chem.
Lett., 33, 1258 (2004).
O
O
Me
Me
NBoc
CO2tBu
NH
CO2H
Ts
Ts
CHO
CHO
b
a
12
NH
NH
CO2tBu
CO2H
6
7
8
AllylO2C
O
AllylO2C
O
13
D. H. R. Barton, J. Kervogoret, and S. Z. Zard, Tetrahedron, 46, 7587
(1990).
NH
Me
NH
Me
D
1H NMR spectrum of compound 4: (CDCl3, 400 MHz) ꢁ 1.13 (t J ¼
7:6 Hz, 3H), 1.96 (p 6.4, 2H), 2.36–2.42 (m, 4H), 2.51 (t 6.6, 2H),
2.64 (t 7.7, 2H), 3.08 (t 7.7, 2H), 4.57 (d 5.9, 2H), 5.23 (dd 10.5,
1.2, 1H), 5.28 (dd 17.3, 1.5, 1H), 5.88 (ddt 17.2, 10.5, 5.9, 1H), 6.19
(s, 1H), 8.31 (brs, 1H), 9.63 (s, 1H), 9.98 (brs, 1H).
c
d
NH
NH
C
CO2H
CHO
CO2Allyl
14
CO2Allyl
9
1H NMR spectrum of compound 1: (C5D5N, 400 MHz) ꢁ 1.17 (t
J ¼ 7:5 Hz, 3H), 1.94 (m, 2H), 2.06 (s, 3H), 2.12 (s, 3H), 2.32 (t 6.1,
2H), 2.44 (q 7.5, 2H), 2.53 (t 6.1, 2H), 2.88 (t 7.3, 4H), 3.20 (t 7.1,
2H), 3.21 (t 7.3, 2H), 5.60 (d 11.7, 1H), 6.74 (d 17.8, 1H), 6.27
(s, 1H), 6.72 (dd 11.4, 17.8, 1H), 6.72 (s, 1H), 7.59 (s, 1H), 8.42 (s,
1–2H), 11.76 (s, 1H). CO2H protons were not observed clearly. UV–
vis (MeOH) ꢂmax 381 (" ¼ 40;533), 630 (" ¼ 29;260) nm; HRMS
(FAB) [M þ 1]þ, Found: m=z 597.2741. Calcd for C34H37N4O6:
597.2713.
4
e
f
2
1
Scheme 2. a) POCl3 (2.0 equiv.) in DMF, 65 ꢂC, 2 h, then aq
10% NaOAc. 13, 68%. b) 99% HCO2H, rt, overnight. c) n-Bu3P
(2.5 equiv.), DBU (1.5 equiv.) in THF/DMF, ꢁ75 ꢂC–rt, over-
night. 14, 74%. d) TFA/(MeO)3CH (2/1, v/v), 0 ꢂC–rt, 1 h, then
H2O. 4, 40%. e) 3, H2SO4 (2.0 equiv.) in MeOH, rt, 1 h. 2, 71%. f)
[Pd(PPh3)4] (0.2 equiv.), TsNa (2.1 equiv.) in THF/MeOH (1/1,
v/v), rt, 10 min. 1, 70%.
10 Personal communication to K. I. from T. Lamparter and S. Noack,
Freie Universitat Berlin. The detailed investigation for the resulting
¨
holoprotein is in progress.
Published on the web (Advance View) May 14, 2005; DOI 10.1246/cl.2005.800