Synthesis of a novel cyclic chlorophyll hetero-dyad as a model compound for stacked chlorophylls found in photosynthetic systems

Article abstract of DOI:10.1002/ejoc.200400027

A covalently doubly linked cyclic chlorophyll hetero-dyad was stereospecifically prepared as a model for naturally stacked chlorophyll suprastructures. In the synthetic dyad, two composite macrocycles are situated very close to each other such that the Q^y transition dipole moments intramolecularly interact to give intense circular dichroism peaks. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400027

FULL PAPER
Synthesis of a Novel Cyclic Chlorophyll Hetero-Dyad as a Model Compound
for Stacked Chlorophylls Found in Photosynthetic Systems
[a]
[a]
Nobuo Kosaka and Hitoshi Tamiaki*
Keywords: Conformation analysis / Cyclizations / Molecular modeling / Porphyrinoids / Stacking interactions
A covalently doubly linked cyclic chlorophyll hetero-dyad
was stereospecifically prepared as a model for naturally
stacked chlorophyll suprastructures. In the synthetic dyad,
two composite macrocycles are situated very close to each
y
other such that the Q transition dipole moments intramolec-
ularly interact to give intense circular dichroism peaks.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
molecular structure, even in a broad range of solvents and
temperatures, and therefore, the physical properties of such
Chlorophyll is present in primary photosynthetic systems, a conformationally frozen molecule can be explored by
light-harvesting antennae, and reaction centers, and plays a various techniques. This advantage is useful for the investi-
principal role in a series of light-harvesting, energy transfer, gation of other special properties of the stacked structure
and charge transfer processes. Its specific arrangement of chlorophylls.
causes significant interactions among the chlorophyll pig-
Systematic preparation of stacked chlorophyll hetero-dy-
ments that are highly effective for these processes. Some X- ads with a different stacking arrangements and orientations
ray crystallographic analyses have already revealed supra- is thus important for the understanding of their properties.
molecular structures of the primary photosynthetic appa- Here, we report on the synthesis and characterization of a
ratus at an atomic level.[
1Ϫ3]
In the crystal structures, many novel cyclic chlorophyll hetero-dyad, in which the two chlo-
‘
‘stacked’’ chlorophylls are found, as in a special pair of rin macrocycles are doubly linked and close to each other.
[1]
bacterial reaction centers and the B850 ring of light-har- The present synthetic strategy is so simple such that it
vesting 2 complexes.[ Studying the special properties of would provide a series of cyclic chlorophyll dyads.
naturally occurring stacked chlorophylls is meaningful for
2]
the exploration of the mechanisms of initial photosynthetic
processes. While the importance of the stacked supramo- Results and Discussion
lecular structures of chlorophylls has been recognized, par-
The cyclic chlorophyll hetero-dyad 9 was prepared ac-
cording to Scheme 1, as a model for the doubly linked cyclic
chlorophyll dyads for the stacked chlorophylls in photosyn-
thetic systems. Chlorophyll-a extracted from a cyanobacte-
rium, Spirulina geitleri, was converted into methyl pheo-
ticular features such as the orientation-dependence of the
chlorophyll pigments remains a matter of debate and ongo-
ing investigation. Such unresolved issues inspired us to in-
vestigate them further.
In order to understand the characteristic features in the
naturally stacked suprastructures composed of multiple
chlorophylls, we have explored the physical properties of
novel stacked chlorophyll dyads prepared systematically by
simple procedures. Various covalently-linked chlorophyll di-
2
phorbide-a (13 R-epimer of 1), and a small amount of the
2
[11]
1
1
3
3 S-epimer (aЈ) was also formed.
After removal of the
2
3 -methoxycarbonyl group in 1, oxidative cleavage of the
[
11,15]
-vinyl group in the resulting compound 2
and success-
mers have been reported,[
4Ϫ14]
ive acidic hydrolysis of methyl ester 3 afforded pyropheo-
phorbide-d (4). Transformation of the 3-vinyl group in 1 to
the 3-hydroxymethyl group in 6 (via the 3-formyl group in
but only two reports, to the
best of our knowledge, on the syntheses of ‘‘cyclic’’ chloro-
phyll dyads where the chlorin macrocycles are covalently
[
16]
and doubly linked to each other are available,[5,7] and no
5) was achieved by procedures reported previously.
1
Analysis of the H NMR spectrum of the resulting alcohol
shows a mixture of the 13 R- (a) and S-epimers (aЈ) (ca.
cyclic chlorophyll ‘‘hetero’’-dyad has yet been reported.
Doubly linked chlorophyll moieties provide a well-defined
2
6
6:1). Esterification of the 17-propionic acid side chain in 4
[
a]
Department of Bioscience and Biotechnology, Faculty of with the 3-hydroxymethyl group in 6 gave a singly-linked
Science and Engineering,
linear chlorophyll dyad 7 in a 89% yield, using 1-ethyl-3-[3-
Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
(dimethylamino)propyl]carbodiimide hydrogen chloride
Fax: (internat.) ϩ81-77-561-2659
E-mail: tamiaki@se.ritsumei.ac.jp
(EDC·HCl) as a coupling reagent and 4-(N,N-dimethylami-
Eur. J. Org. Chem. 2004, 2325Ϫ2330
DOI: 10.1002/ejoc.200400027
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2325

N. Kosaka, H. Tamiaki
FULL PAPER
2
no)pyridine (DMAP) as a coupling promoter agent in di- possessing the 13 -ester is ‘‘B’’ (see the lower portion of
[
14]
chloromethane.
The 3-formyl group in 7 reacted with Scheme 1 and Figure 1). Additionally, we apply the facial
tert-butylamine borane complex (tBuNH BH ) in dichloro- nomenclature at the 13-keto carbonyl group to the facial
2
3
methane to give the corresponding alcohol 8 in a 88% yield. asymmetry of the chlorin π-plane: the si-face of a chlorin
Both synthetic singly-linked dyads 7 and 8 were ca. 6:1 moiety is the same as the si-face of the CϭO plane and the
2
2
1
3 R/S mixtures, as confirmed by their 13 -H signals (see re-face of the chlorin is the reverse as shown in Figure 1.
Exp. Sect.). Intramolecular β-keto transesterification of 8
was readily accomplished at low concentration (45 µ) by
action of 2-chloro-1-methylpyridinium iodide (CMPI) and
DMAP in refluxing toluene,[
12,17,18]
to give the doubly
linked cyclic chlorophyll dyad 9 in a 37% yield (8 was com-
pletely used up). Under the above conditions, undesired
high molecular weight products were also obtained through
the intermolecular transesterification of 8. All the synthetic
dyads 7Ϫ9 were purified with gel permeation or flash col-
umn chromatography (GPC or FCC) and recrystallization,
1
and characterized by visible absorption, H NMR and fast
atomic bombardment mass (FAB-MS) spectral analyses.
Figure 1. Definition the of chlorin macrocycle and the facial dis-
crimination
Intramolecular cyclization of 8 was a key step in the
preparation of the corresponding cyclic dyad 9. Since trans-
esterification occurs specifically for a β-keto ester with an
alcohol, no cleavage was observed at the other esters, A-
2
1
7 -CO CH -3-B, the linkage between the macrocycles A
2
2
2
and B, and B-17 -CO Me in 8 and 9. It is also worth noting
that the B-13 -CO Me group was unreactive under the
2
2
2
standard EDC-DMAP coupling of an acid with an alcohol
as in 4 ϩ 6 Ǟ 7.
The absolute configuration at the B-13 -position and the
2
stacking manner between the two macrocycles in the re-
sulting cyclic product 9 were considered, and four isomeric
dyads are proposed in Figure 2. These energy-minimized
molecular structures were obtained by MMϩ and PM3
[
19Ϫ21]
calculations.
The side-view and top-view structures
are drawn showing the macrocycle A plane perpendicular
and parallel to the page face, respectively. In the top view,
the Q transition dipole moments of macrocycles A and B
y
are depicted by arrows.
In the major B-13 R-epimer of 8, the activated B-13 -
ester could be intramolecularly attacked by the A-3 -OH
2
2
1
group from the direction of the re- or si- face of macrocycle
A to the re-face of macrocycle B, giving isomers I and II,
respectively. On the other hand, in the minor B-13 S-epimer
of 8, the similar cyclization from the direction of the si- or
re-face of macrocycle A to the si-face of macrocycle B, gave
isomers III and IV, respectively. GPC and NMR spectro-
Scheme 1. Synthesis of cyclic dyad 9; i) collidine, reflux;
2
ii) OsO
CH Cl
flux
4
ϪNaIO
4
/aq. AcOH/THF; iii) conc. HCl; iv) tBuNH
2
BH
3
/
2
2 2 2
; v) EDC-DMAP/CH Cl ; vi) CMPI-DMAP/toluene, re-
In the present hetero-dyads, two different chlorin macro- scopic analyses of the cyclization mixture showed that a
cycles are defined as follows: a ‘‘pyro’’-chlorin moiety lack- single stereoisomer was obtained as an isolated dyad, indi-
2
ing the 13 -ester is called macrocycle ‘ ‘A ’’, and the other cating that product 9 is one of the four isomers IϪIV.
2326
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2400, 2325Ϫ2330

A Cyclic Chlorophyll Hetero-Dyad as a Model Compound for Stacked Chlorophylls
2
FULL PAPER
at the B-13 -position in 9 were ruled. Isomers I and II, with
an R-configuration remained as the candidates.
Figure 3. Specific observed NOE correlations of synthetic cyclic
chlorophyll hetero-dyad 9 (right) and confirmed stereostructure of
9
(left)
Significant NOE correlations between specific protons on
the A and B macrocycles in 9 were observed at A-12-CH3
2
o B-5-H, A-13 -H o B-5-H/7-CH , and A-18-CH o B-2-
3
3
CH (see the lower-right portion of Figure 3). In isomer I,
3
all the distances between the above protons are estimated
˚
to be 3.7Ϫ6.3 A, which are shorter than those of II
˚
(
7.1Ϫ12.4 A). Isomer I is thus determined to be isolated
cyclic dyad 9.
Additionally, the total energies obtained by molecular
Figure 2. Four possible energy minimized stereostructures IϪIV of modeling support the above stereochemical determination.
cyclic dyads for the coupling product 9
The energies of isomers IϪIV were Ϫ31, Ϫ18, Ϫ21, and
Ϫ1
2
Ϫ20 kcal·mol , respectively, while those of the B-13 R/S-
Ϫ1
epimers of 8 were Ϫ3 and Ϫ1 kcal·mol , respectively, and
1
Ϫ1
The following two-dimensional H NMR spectral analy- that of methanol was 2 kcal·mol . The energetic differ-
ses were useful for the stereochemical determination of the ences ∆E that occur when intramolecular transesterification
isolated cyclic dyad 9: the data were collected at 100 °C takes place [ϭ E(isomeric 9) ϩ E(methanol) Ϫ E(epimeric
with a mixing time of 0.15 s in Cl DCϪCDCl , since less 8)] were estimated from the above values and ∆E(I) was
2
2
Ϫ1
resolved and broadened signals were obtained at room tem- Ϫ26 kcal·mol which is lower than the other ∆E values,
1
1
2
Ϫ1
perature. The H- H ROESY spectrum around the B-13 - Ϫ13 for II, Ϫ18 for III, and Ϫ20 kcal·mol for IV. The
2
position reveals that the correlation between B-13 -H and largest difference, obtained for the process 8 Ǟ isomer I,
1
2
B-17 -H is stronger than that between B-13 -H and B-17- indicates that isomer I has the highest thermodynamic sta-
H (see the upper-right portion of Figure 3), indicating that bility among them. The results from the molecular
2
1
2
1
3 -H is closer to 17 -H than 17-H in macrocycle B: 13 -H modeling study also support that isomer I would be readily
is situated in the ‘‘syn’’-configuration to 17-CH and in the formed in the intramolecular cyclization from a thermo-
2
2
‘
‘anti’’ configuration to 17-H. The relationship is consistent dynamic aspect. Therefore, in the B-13 R-epimer of 8, the
with the R-configuration at the B-13 -position in 9. Since activated B-13 -ester by CMPI-DMAP was intramolecu-
no epimerization at the B-13 position of 1 occurred under larly attacked by the A-3 -OH from the direction of the re-
the same conditions as those for the intramolecular esterifi- face of macrocycle A to the re-face of macrocycle B, stereos-
cation, the isolated yield (37%) in the cyclization of a mix- pecifically giving isomer I as the cyclic hetero-dyad 9.
2
2
2
1
2
2
ture of 13 R-8 (ca. 86%) and 13 S-8 (ca. 14%) also supports
the finding of an R-configuration at B-13 . As a result, the right portion of Figure 4) as a reference compound for cy-
We prepared a single-linked linear dyad 10 (see the top-
2
two isomers, III and IV, which possessed an S-configuration clic dyad 9 through the esterification of the A-3-hydroxy-
Eur. J. Org. Chem. 2004, 2325Ϫ2330
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2327

N. Kosaka, H. Tamiaki
FULL PAPER
methyl group in 8 with acetic acid. In dyad 10, there are
ester functionalities on both of the 3-positions of macro-
cycles A and B, as in 9. UV/visible absorption and circular
Conclusion
In summary, we synthesized for the first time a cyclic
dichroism (CD) spectra of cyclic dyad 9 in CH Cl were chlorophyll hetero-dyad as a model for the naturally occur-
2
2
compared with those of the linear dyad 10 (Figure 4). The ring stacked structures of chlorophylls in a photosynthetic
Q absorption maximum of 9 (664 nm) was the same as that system. The present synthetic strategy has great potential
y
of 10. The Q and Soret bands of 9 were slightly broader for the systematic preparation of a series of cyclic chloro-
y
in the red and the blue regions, respectively, relative to those phyll dyads: EDC-DMAP esterification of a formyl-pyro-
of 10. The broadening in 9 (diluted solution, ca. 5 µ) can chlorophyllide (as in 4) with a hydroxy-chlorophyll (as in 6)
be ascribed to some interaction of the two chlorin macro- and successive reduction of the formyl group of the re-
cycles in a molecule. Intense S-shaped and reversed S- sulting linear dyad (as in 7), followed by CMPI-DMAP
2
shaped CD signals in the Q and Soret regions, respectively, transesterification of the 13 -CO Me group of the chloro-
y
2
of 9 demonstrated that the two macrocycles in 9 are close phyll moiety with the hydroxymethyl group of the pyrochlo-
enough to give rise to an intramolecular transition dipole- rophyll moiety in the molecule gives the desired cyclic het-
dipole moment interaction. By applying the CD exciton chi- ero-dyad (as in 9).
[
22]
rality method,
the S-shaped signal observed in the Qy
region of 9 reveals a ‘‘clockwise’’ rotational orientation of
the two Q transition dipole moments on the N21ϪN23 Experimental Section
y
axis. This configuration is seen in isomers I and IV (see
Figure 2). This analysis also supports the above determi-
General: EDC·HCl and DMAP for the coupling of the pigments,
and CH Cl (analytical grade) for spectroscopic measurements
were purchased from Nacalai tesque. tBuNH BH and CMPI were
purchased from the Aldrich Chemical Company and Tokyo Chemi-
cal Industry, respectively. Toluene, CH Cl , and CHCl , used for
2
2
nation of isomer I from the proposed isomers I and II with
2
2
3
the B-13 R configuration.
2
2
3
the syntheses, were commercially available as normal grade and
used without further purification. GPC was carried out with recy-
cling preparative high-performance liquid chromatography LC-908
(
Japan analytical industry) with three connected polystyrene
packed columns (Jaigel 1H, 2H, 3H). FCC was carried out on silica
gel (Merck, Kieselgel 60, 9385 or Wako, Wakogel C-300). FAB-
MS were recorded on a JEOL GCmate II spectrometer. FAB-MS
2 2
samples were dissolved in CH Cl , and polyethylene glycol was
used as the internal reference and m-nitrobenzyl alcohol and glyc-
1
erol were used as the matrix. H NMR spectroscopic measurements
were performed on a JEOL JNM-A-400 spectrometer, and an in-
ternal standard in CDCl
3
or Cl
DCϪCDCl signal at δ ϭ 5.93 ppm, respectively.
C NMR measurements were performed on a JEOL JNM-ECA-
00 spectrometer, and an internal standard in CDCl or
77.0 ppm and
signal at δ ϭ 75.5 ppm, respectively. UV/visible
Cl
2 2 3
DCϪCDCl , CHCl signal at δ ϭ
7
.26 ppm and Cl
2
2
1
3
6
Cl
Cl
3
1
3
2
2
DCϪCDCl
D CϪCDCl
2
,
CDCl
3
signal at
δ
ϭ
1
3
2
absorption and CD spectra were measured in air-saturated CH
2
2
at room temperature on a Hitachi U-3500 spectrophotometer and
Jasco J-720 W spectropolarimeter, respectively.
Synthesis: All synthetic procedures were performed in the dark.
[
11,15]
Methyl pyropheophorbide-d (3)
(
and methyl 3-devinyl-3-
hydroxymethyl)pheophorbide-a/aЈ (6)[ were prepared according
16]
to reported procedures.
Pyropheophorbide-d (4): A concentrated aqueous HCl solution (20
mL) of methyl ester 3 (30 mg, 54 µmol) was stirred at room tem-
perature. After stirring for 3 h, the reaction mixture was poured
into ice water and extracted with CHCl
re-extracted with several portions of CHCl
phases were washed with aqueous KHSO
over Na SO , and the solvents were evaporated to dryness. The
residue was purified by recrystallization from CHCl /hexane to give
carboxylic acid 4 (24 mg, 45 µmol; 83% yield). Vis (CH Cl
94 (relative intensity, 76%), 668 (14), 633 (9), 554 (16), 522 (15),
3
. The aqueous phase was
. The combined CHCl
(5%) and H O, dried
3
3
4
2
2
4
3
2
2
) λmax ϭ
6
4
1
26 (100), 388 nm (90). H NMR (CDCl , 22 °C): δ ϭ 11.51 (s, 1
3
Figure 4. Visible spectra normalized at the Q
A) and the corresponding CD spectra (B) in a CH
cyclic dyad 9 (solid line) and linear dyad 10 (broken line)
y
absorption intensity
H, 3-CHO), 10.26 (s, 1 H, 5-H), 9.57 (s, 1 H, 10-H), 8.82 (s, 1 H,
20-H), 5.33, 5.18 (d, JH,H ϭ 20.0 Hz, 1 H each, 13 -CH
(
2
Cl solution of
2
1
2
), 4.57 (br.
2328
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org Eur. J. Org. Chem. 2400, 2325Ϫ2330

A Cyclic Chlorophyll Hetero-Dyad as a Model Compound for Stacked Chlorophylls
FULL PAPER
), 1.93 (br. s, 1 H, A-3 -OH), 1.78 (d,
1
q, JH,H ϭ 7.4 Hz, 1 H, 18-H), 4.40 (br. d, JH,H ϭ 9.2 Hz, 1 H, 17-
H), 3.75 (s, 3 H, 2-CH ), 3.69 (q, JH,H ϭ 7.6 Hz, 2 H, 8-CH ), 3.68
s, 3 H, 12-CH ), 3.28 (s, 3 H, 7-CH ), 2.8Ϫ2.7, 2.3Ϫ2.2 (m, 1 H 18-CH
each, 17-CH ), 2.7Ϫ2.6, 2.4Ϫ2.3 (m, 1 H each, 17 -CH
H,H ϭ 7.4 Hz, 3 H, 18-CH ), 1.69 (t, JH,H ϭ 7.6 Hz, 3 H, 8 -CH
.88, Ϫ2.09 ppm (s, each, NH). MS (FAB) found:
(m, 1 H each, B-17-CH
2
3
2
JH,H ϭ 7.6 Hz, 3 H, B-18-CH
3
), 1.61 (d, JH,H ϭ 7.2 Hz, 3 H, A-
1
(
3
3
3
), 1.60 (t, JH,H ϭ 7.2 Hz, 3 H, A-8 -CH
7.6 Hz, 3 H, B-8 -CH
3
3
), 1.51 (t, JH,H
), 0.19, 0.12, Ϫ1.98, Ϫ2.04 (s, 1 H each, A
3
), and B-NH) ppm. MS (FAB) found: m/z ϭ 1131.5328. Calcd. for
ϭ
1
1
2
2
), 1.85 (d,
1
J
0
3
ϩ
1
H
C
67
H
71
N
8
O
9
: MH , 1131.5344.
ϩ
33 4 4
m/z ϭ 537.2479. Calcd. for C32H N O : MH , 537.2502.
Cyclic Dyad 9: A toluene solution (10 mL) of 8 (20.0 mg, 17.7
(Methyl 3-devinylpheophorbide-a)-3-yl]methyl Pyropheophorbide-d µmol) was added to CMPI (100 mg, 391 µmol) and DMAP
[
(
7): EDC·HCl (90 mg, 469 µmol) and DMAP (160 mg, (100 mg, 819 µmol) toluene (400 mL) under reflux. After refluxing
.31 mmol) were added to a CH Cl solution (30 mL) of carboxylic for 4 h under N , the reaction mixture was cooled to room tempera-
acid 4 (60 mg, 112 µmol). Alcohol 6 (67 mg, 110 µmol) was added ture, washed with aqueous saturated Na CO and brine, dried over
at 0 °C under an N atmosphere. After stirring for 15 h, the reac- Na SO , and the solvents were evaporated to dryness. The residue
tion mixture was warmed to room temperature, washed with aque- was purified by FCC with 0.6% CH OH/CH Cl (v/v) and recrys-
ous HCl (2%), aqueous NaHCO (4%) and H O, dried with tallized from CH Cl /hexane to give cyclic dyad 9 (7.2 mg, 6.6
Na SO , and the solvents were evaporated to dryness. The residue µmol; 37% yield). Vis (CH Cl ) λmax ϭ 664 (rel., 50), 610 (9), 537
was purified by GPC with CHCl and recrystallized from CH Cl (11), 506 (11), 396 (100), 377 nm (94). H NMR (Cl
hexane to give ca. a 1:6 B-13 R/S mixture of the linear dyad 7 100 °C): δ ϭ 9.44 (s, 1 H, A-10-H), 9.32 (s, 1 H, B-5-H), 8.92 (s, 1
111 mg, 98.3 µmol; 89% yield). Vis (CH Cl ) λmax ϭ 694 (rel., 35), H, A-5-H), 8.72 (br. s, 1 H, B-10-H), 7.46 (s, 1 H, B-20-H), 6.79,
65 (39), 638 (7), 608 (7), 555 (9), 533 (10), 507 (10), 410 nm (100). 5.40 (d, JH,H ϭ 12.6 Hz, 1 H each, A-3-CH ), 6.64, 6.19 (d, JH,H
, 22 °C): δ ϭ 11.29 (s, 1 H, A-3-CHO), 10.02 (s, 12.4 Hz, 1 H each, B-3-CH ), 6.08 (s, 1 H, B-13 -CH-(R)), 5.72 (br.
H, A-5-H), 9.44 (s, 1 H, A-10-H), 9.37 (s, 1 H, B-10-H), 9.10 (s, s, 1 H, A-20-H), 5.05 (s, 2 H, A-13 -CH
H, B-5-H), 8.532, 8.526 (s, 1 H each, A- and B-20-H), 6.27/6.16 7.6 Hz, 2 H, A-8-CH ), 3.70 (s, 3 H, A-12-CH
1
2
2
2
2
3
2
2
4
3
2
2
3
2
2
2
2
4
2
2
1
3
2
2
/
2 2
CDϪCDCl ,
2
(
2
2
6
2
ϭ
1
1
H NMR (CDCl
1
1
3
2
1
2
), 3.77 (br. q, JH,H
ϭ
2
3
2
), 3.67 (m, 1 H, B-
1
(
s, 1 H, B-13 -CH-R/S), 6.26, 6.09 (d, JH,H ϭ 13.0 Hz, 1 H each,
17-H), 3.55, 3.52 (s, 3 H each, B-12-CH
H,H ϭ 7.6 Hz, 2 H, B-8-CH ), 3.33 (s, 3 H, A-7-CH
.5Ϫ4.4 (m, 2 H, A- and B-18-H), 4.34 (br. d, JH,H ϭ 8.4 Hz, 1 H, H, B-7- CH ), 3.06 (m, 1 H, A-17-H), 2.98 (s, 3 H, B-2-CH
A-17-H), 4.20 (br. d, JH,H ϭ 8.4 Hz, 1 H, B-17-H), 3.88 (s, 3 H, B- 1.78 (m, 1 H each, A-17 -CH
), (m, 1 H each, A-17-CH ), 2.47, 2.11 (m, 1 H each, B-17-CH
3
, B-17 -CO
2
CH
), 3.19 (s, 3
), 2.93,
), 2.86 (m, 1 H, A-18-H), 2.76, 1.80
), 2.23,
3
), 3.47 (q,
1
B-3-CH
4
2
), 5.31, 5.05 (d, JH,H ϭ 19.6 Hz, 1 H each, A-13 -CH
2
),
J
2
3
3
3
1
2
2
1
3
3
3
3 -CO
.57 (q, JH,H ϭ 7.6 Hz, 2 H, A-8-CH
.44 (s, 3 H, A-2-CH ), 3.39 (q, JH,H ϭ 7.6 Hz, 2 H, B-8-CH
.28 (s, 3 H, B-2-CH ), 3.12 (s, 3 H, A-7-CH
), 2.81, 2.45 (m, 1 H each, A-17-CH ), 2.72, 2.42 (m, 1 H each,
), 2.64, 2.30 (m, 1 H each, B-17-CH ), 2.53, 2.25 (m, 1 Ϫ3.80 ppm (br. s, 1 H each, A- and B-NH).
), 1.79 (d, JH,H ϭ 7.2 Hz, 3 H, B-18-CH ), 1.65 (Cl DCϪCDCl , 100 °C): δ ϭ 196.9, 191.4, 174.5, 174.4, 172.8,
), 1.64 (d, JH,H ϭ 7.6 Hz, 3 H, A-
2
CH
3
), 3.66 (s, 3 H, A-12-CH
3
), 3.64 (s, 3 H, B-12-CH
3
3
2
2
2
2
1
1
2
), 3.56 (s, 3 H, 17 -CO
2
CH
), 2.01 (m, 1 H each, B-17 -CH
), CH ), 1.69 (m, 1 H, B-18-H), 1.55 (br. t, JH,H ϭ 7.6 Hz, 3 H, B-
8 -CH ), 0.844 (br. d, JH,H ϭ 7.2 Hz, 3 H, A-18-CH ), 0.835 (br. s,
3 H, A-2-CH ), Ϫ0.29 (br. s, 3 H, B-18-CH ), Ϫ0.06, Ϫ1.20, Ϫ3.09,
2
), 1.85 (t, JH,H ϭ 7.6 Hz, 3 H, A-8 -
3
3
1
3
3
), 2.85 (s, 3 H, B-7-
3
3
CH
3
2
3
3
1
13
A-17 -CH
H each, B-17 -CH
t, JH,H ϭ 7.6 Hz, 3 H, A-8 -CH
8-CH ), 1.51 (t, JH,H ϭ 7.6 Hz, 3 H, B-8 -CH
2
2
C NMR
1
2
3
2
2
1
(
1
3
170.0, 169.7, 162.8, 160.6, 156.2, 155.8, 152.2, 151.6, 150.7, 150.2,
), 0.18, Ϫ0.31, 146.3, 145.8, 141.8, 139.9, 139.4, 139.1, 137.7, 137.1, 137.1, 136.8,
1
3
3
Ϫ2.00, Ϫ2.32 ppm (s, 1 H each, A- and B-NH). MS (FAB) found:
m/z ϭ 1129.5256. Calcd. for C67H N O : MH , 1129.5188.
69 8 9
136.1, 135.1, 134.3, 132.1, 131.9, 131.6, 130.4, 129.3, 106.8, 105.9,
105.1, 104.8, 98.2, 97.2, 93.9, 91.6, 66.8, 59.3, 58.1, 53.2, 52.9, 51.7,
ϩ
5
0.8, 50.3, 50.1, 35.1, 32.6, 31.4, 30.6, 22.8, 21.0, 20.8, 20.7, 18.8,
[
(Methyl 3-devinylpheophorbide-a)-3-yl]methyl 3-Devinyl-3-(hy-
droxymethyl)pyropheophorbide-a (8): Aldehyde 7 (260 mg, 230
µmol) was dissolved in CH Cl (40 mL) and tBuNH BH (20 mg,
30 µmol) was added to the solution while stirring at 0 °C under [(Methyl 3-devinylpheophorbide-a)-3-yl]methyl 3-Devinyl-3-acetoxy-
an N atmosphere. After stirring for 15 h, the reaction mixture was methylpyropheophorbide-a (10): EDC·HCl (38 mg, 198 µmol) and
warmed to room temperature, washed with aqueous HCl (2%), DMAP (61 mg, 499 µmol) were added to a CH Cl solution (30
aqueous NaHCO (4%) and H O, dried with Na SO , and the sol- mL) of acetic acid (10 µL, 175 µmol). Alcohol 8 (20 mg, 17.7 µmol)
vents were evaporated to dryness. The residue was purified by FCC was added while stirring at 0 °C under an N atmosphere. After
with 1.2% CH OH/CH Cl (v/v) and recrystallized from CH Cl stirring for 15 h, the reaction mixture was warmed to room tem-
hexane to give a ca. 1:6 B-13 R/S mixture of alcohol 8 (228 mg, perature, washed with aqueous HCl (2%), aqueous NaHCO (4%)
) λmax ϭ 663 (rel., 50), 606 (8), and H O, dried with Na SO , and the solvents were evaporated to
35 (9), 504 (10), 410 nm (100). H NMR (CDCl , 22 °C): δ ϭ 9.32 dryness. The residue was purified by FCC with 0.6% CH OH/
Cl (v/v) and recrystallized from CH Cl /hexane to give acetyl
ester 10 (16 mg, 13.6 µmol; 77% yield). Vis (CH
18.5, 13.4, 13.1, 12.8, 12.6, 12.5, 10.3 ppm. MS (FAB) found:
ϩ
m/z ϭ 1099.5044. Calcd. for C H N O : MH , 1099.5082.
6
6
67
8
8
2
2
2
3
2
2
2
2
3
2
2
4
2
3
2
2
2
2
/
2
3
2
5
(
(
6
02 µmol; 88% yield). Vis (CH
2
Cl
2
2
2
4
1
3
3
s, 1 H, B-10-H), 9.31 (s, 1 H, A-10-H), 9.11 (s, 1 H, A-5-H), 9.05 CH
s, 1 H, B-5-H), 8.50 (s, 1 H, B-20-H), 8.26 (s, 1 H, A-20-H), 6.25/
2
2
2
2
2
Cl
2
) λmax ϭ 664
1
1
.19 (s, 1 H, B-13 -CH-R/S), 6.11, 5.90 (d, JH,H ϭ 13.2 Hz, 1 H (rel., 51), 608 (8), 535 (9), 505 (11), 410 nm (100). H NMR
each, B-3-CH
9.6 Hz, 1 H each, A-13 -CH
B-18-H), 4.35 (br. q, JH,H ϭ 7.2 Hz, 1 H, A-18-H), 4.21 (br. d, 20-H), 6.26, 6.15 (d, JH,H ϭ 13.0 Hz, 1 H each, B-3-CH
2
), 5.55 (br. s, 2 H, A-3-CH
2
), 5.19, 4.95 (d, JH,H
ϭ
(CDCl
5-H), 9.19 (s, 1 H, B-5-H), 8.55 (s, 1 H, B-20-H), 8.40 (s, 1 H, A-
), 6.26/
6.16 (s, 1 H, B-13 -CH-R/S), 5.25, 5.00 (d, JH,H ϭ 19.6 Hz, 1 H
3
, 22 °C): δ ϭ 9.42 (s, 2 H, A- and B-10-H), 9.26 (s, 1 H, A-
1
1
2
), 4.44 (br. q, JH,H ϭ 7.6 Hz, 1 H,
2
1
J
H,H ϭ 9.6 Hz, 1 H, A-17-H), 4.19 (br. d, J ϭ 8.8 Hz, 1 H, B-17-
2
1
H), 3.89 (s, 3 H, B-13 -CO
2
CH
and A-12-CH
.36 (q, JH,H ϭ 7.6 Hz, 2 H, B-8-CH
.05 (s, 3 H, A-7-CH ), 3.03 (s, 3 H, A-2-CH
), 2.70, 2.38 (m, 1 H each, A-17 -CH
each, A-17-CH ), 2.60, 2.32 (m, 1 H each, B-17 -CH
3
), 3.62 (s, 3 H, B-12-CH
), 3.5Ϫ3.6 (m, 2 H, A-8-CH
), 3.21 (s, 3 H, B-2-CH
), 2.88 (s, 3 H, B-7-
), 2.63, 2.34 (m, 1 H 3.60 (q, JH,H ϭ 7.6 Hz, 2 H, A-8-CH
3
), 3.56 (s, each, A-13 -CH
), (br. q, JH,H ϭ 7.6 Hz, 1 H, A-18-H), 4.27 (br. d, JH,H ϭ 8.4 Hz, 1
), H, A-17-H), 4.20 (br. d, J ϭ 8.8 Hz, 1 H, B-17-H), 3.89 (s, 3 H, B-
2
), 4.45 (br. q, JH,H ϭ 7.6 Hz, 1 H, B-18-H), 4.40
2
6
3
3
H, B-17 -CO
2
CH
3
3
2
2
3
2
3
3
2 3 3 3
13 -CO CH ), 3.66 (s, 3 H, A-12-CH ), 3.61 (s, 3 H, B-12-CH ),
1
2
CH
3
2
2
), 3.55 (s, 3 H, B-17 -
), 3.47 (q, JH,H ϭ 7.6 Hz, 2 H, B-8-CH ), 3.31 (s, 3 H, B-
1
2
2
), 2.52, 2.23 CO
2
CH
3
2
Eur. J. Org. Chem. 2004, 2325Ϫ2330
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2329

N. Kosaka, H. Tamiaki
FULL PAPER
[
[
[
5]
6]
7]
2
-CH
3
), 3.22 (s, 3 H, A-2-CH
), 2.77, 2.40 (m, 1 H each, A-17 -CH
H each, A-17-CH ), 2.63, 2.27 (m, 1 H each, B-17 -CH
.22 (m, 1 H each, B-17-CH ), 2.12 (s, 3 H, A-3 -OCOCH
3
3
), 3.18 (s, 3 H, A-7-CH
3
), 2.95 (s, 3
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H, B-7-CH
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2
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), 1.64 (d, JH,H ϭ 7.6 Hz, 3 H, A-18-CH ), 1.55 (t, JH,H
), 0.24, 0.17, Ϫ1.91, Ϫ1.97 ppm (s, 1 H each,
A- and B-NH). C NMR (CDCl , 22 °C): δ ϭ 196.0, 189.5, 173.3,
73.0, 172.0, 171.0, 170.99, 169.5, 161.2, 160.0, 155.2, 155.0, 151.1,
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A-8 -CH
.6 Hz, 3 H, B-8 -CH
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51.0, 149.4, 148.7, 145.1, 145.0, 141.1, 140.6, 138.0, 137.9, 136.3,
36.2, 136.0, 135.8, 135.5, 135.1, 132.0, 131.8, 130.6, 129.3, 129.1,
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2Ϫ99.
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This work was partially supported by Grants-in-Aid for Scientific
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Received January 15, 2004
Early View Article
Published Online April 26, 2004
2330
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2400, 2325Ϫ2330