Stereoselective reduction, methylation, and phenylation of the 13-carbonyl group in chlorophyll derivatives

Article abstract of DOI:10.1016/j.tetasy.2013.04.018

Regioselective reduction of the 13-carbonyl group on the five-membered exo-ring of methyl pyropheophorbide-a, one of the chlorophyll-a derivatives, with sodium borohydride gave an epimeric mixture of (13¹R/S)-hydroxy- chlorins. The stereoselectivity was controlled by the steric effect of the (17S)-methoxycarbonylethyl group to afford the (13¹S)-rich secondary alcohol (25% de). The use of sterically large lithium tri(sec-butyl)borohydride as the reductant enhanced the stereoselectivity to 55% de. The regio- and stereoselective methylation and phenylation of the 13-CO of pyropheophorbide-a were observed using methyl and phenyl lithium, respectively. The major diastereomer of the tertiary alcohols obtained had the same configuration at the 13¹-stereogenic center as in the reduced product. All of the anion species (H^-, CH₃^-, and C₆H ₅^-) favorably attacked the 13¹-carbon atom from the reverse side of the 17-propionate residue, that is, the less sterically crowded face of the 13-CO plane.

Full text of DOI:10.1016/j.tetasy.2013.04.018

Tetrahedron: Asymmetry 24 (2013) 677–682
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective reduction, methylation, and phenylation of the 13-carbonyl
group in chlorophyll derivatives
Hitoshi Tamiaki , Rie Monobe a,b, Shun Koizumi a,b, Tomohiro Miyatake , Yusuke Kinoshita
a,
⇑
b
a
a
Graduate School of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
Department of Materials Chemistry, Faculty of Science and Technology, Ryukoku University, Otsu, Shiga 520-2194, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 March 2013
Accepted 19 April 2013
Regioselective reduction of the 13-carbonyl group on the five-membered exo-ring of methyl pyropheo-
phorbide-a, one of the chlorophyll-a derivatives, with sodium borohydride gave an epimeric mixture
1
of (13 R/S)-hydroxy-chlorins. The stereoselectivity was controlled by the steric effect of the (17S)-meth-
1
oxycarbonylethyl group to afford the (13 S)-rich secondary alcohol (25% de). The use of sterically large
lithium tri(sec-butyl)borohydride as the reductant enhanced the stereoselectivity to 55% de. The regio-
and stereoselective methylation and phenylation of the 13-C@O of pyropheophorbide-a were observed
using methyl and phenyl lithium, respectively. The major diastereomer of the tertiary alcohols obtained
1
had the same configuration at the 13 -stereogenic center as in the reduced product. All of the anion spe-
À
À À
1
cies (H , CH
pionate residue, that is, the less sterically crowded face of the 13-C@O plane.
Ó 2013 Elsevier Ltd. All rights reserved.
3 6 5
, and C H ) favorably attacked the 13 -carbon atom from the reverse side of the 17-pro-
R3
R3
1
. Introduction
Asymmetric hydrogenation at the C@C double bond is observed
in the biosynthesis of (bacterio)chlorophylls [(B)Chls]. For exam-
ple, the C17@C18 bond in protochlorophyllide-a is enzymatically
N
N
N
N
N
N
N
N
+
2H
M
M
reduced to the C17H(S)–C18H(S) array in chlorophyllide-a
1
(
Scheme 1a). It is difficult to mimic such a stereoselective hydro-
*
1
8
*
genation in solution, and the regioselective hydrogenation at the
C17@C18 bond was only achieved by photoreduction of the zinc
H
1
7
H
protochlorophyll-a derivatives without any chiral control
O
O
E
E
2
COOR
(Scheme 1b).
COOR
In contrast, the stereoselective reduction of the 3-acetyl group
porphyrin
chlorin
in (B)Chl derivatives was reported to take place in solution using
3
a chiral catalyst (Scheme 2a). The synthetic procedures are effec-
Scheme 1. Hydrogenation of C17@C18 in porphyrins to C17H–C18H in chlorins. (a)
Stereoselective enzymatic anti-reduction of protochlorophyllide-a to (17S,18S)-
tive for the preparation of BChl-d and its analogues possessing a
chiral 1-hydroxyethyl group at the 3-position. Reduction of the
chlorophyllide-a: R3 = CH@CH
, E = COOCH
photoinduced syn-reduction of zinc protoChl derivatives to (17R,18S)- and
17S,18R)-Zn-Chl derivatives: R3 = CH
CH or CH OH, E = H, R = CH , M = Zn.
2
3
, R = H, M = Mg; (b) non-stereoselective
3
3
-COCH in a Chl-a derivative bearing (17S,18S)-stereochemistry
(
2
3
2
3
1
with an achiral reagent gave a 1:1 3 -epimeric mixture of the sec-
ondary alcohol (Scheme 2b).4 No chiral induction was observed,
affect the reduction of the 3-Ac moiety: that is, 1,6-induction
through the five bonds. The lack of asymmetric reduction of the
-acetyl group in the above chiral (B)Chls with an achiral reagent
would be ascribable to free rotation of the C3–C3 bond enabling
it to take two conformers (Fig. 1) where the 3-Ac was coplanar
1
partially because the reactive site (C3 ) was distant from the stere-
ogenic centers (C17 and C18) in the molecule: a 1,7/8-induction
through six/seven bonds between the C31 and C18/17 positions.
A similar reduction of a BChl-a derivative bearing (7R,8R)-stereo-
chemistry also gave the corresponding alcohol with no diastereo-
3
1
6
with the cyclic tetrapyrrole p-system.
3
,5
meric control. The neighboring C7 stereogenic center did not
All photosynthetically active (B)Chls have a keto-carbonyl
group at the 13-position and the oxo moiety located on the five-
membered exo-ring (E-ring, see the left drawing of Scheme 2).7
⇑
Corresponding author. Tel.: +81 77 561 2765; fax: +81 77 561 2659.
E-mail address: tamiaki@fc.ritsumei.ac.jp (H. Tamiaki).
The 13-C@O is more
p-conjugated with the tetrapyrrole ring and
0
957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.018

6
78
H. Tamiaki et al. / Tetrahedron: Asymmetry 24 (2013) 677–682
H
reochemistry of the diastereomers was determined by two-dimen-
sional (2D) NMR spectroscopy. The diastereomeric control is also
discussed with regard to the steric effect in the molecule.
O
31
OH
31
*
3
7
8
N
N
N
N
N
N
N
2. Results and discussion
+
2H
M
M
2
.1. Stereoselective reduction of the 13-carbonyl group in
N
methyl pyropheophorbide-a 1a
1
8
1
7
E
13
O
Methyl pyropheophorbide-a 1a has two carbonyl groups at the
2
1
3- and 17 -positions (see the left upper drawing of Scheme 4).
O
COOR
COOR
3-(1-hydroxyethyl)-(B)Chls
The former keto-carbonyl group was more reactive than the latter
ester-carbonyl group. Conventional reduction by NaBH occurred
regioselectively at the 13-C@O moiety to give methyl 13 -deoxo-
13 -hydroxy-pyropheophorbide-a 2 as the product. The carbinol
obtained was a 13 -epimeric mixture (see the lower drawing of
Scheme 4, X = H) and the de values were reported to be 0 or
0–20%. Here we re-examined the reduction of 1a in dichloro-
methane (CH Cl ) with NaBH in methanol (MeOH) at room tem-
perature. The H NMR spectra of product 2 purified by silica gel
chromatography showed the ratio to be 1:1.7. Analysis by RP-HPLC
supported this ratio (Fig. 2a). The present reduction proceeded in
25 ± 3% de (from 5 independent experiments), which was slightly
larger than the reported values. The stereoisomers were easily sep-
arated by RP-HPLC; the fast (major) and slow eluting (minor)
bands are called 2#1 and 2#2, respectively: the separation ratio
4
3
-Ac-(B)Chls
1
1
Scheme 2. Reduction of 3-acetyl-(B)Chl derivatives to 3-(1-hydroxyethyl) ana-
logues. (a) Stereoselective reduction with a chiral reagent: R = CH , M = H , C7@C8/
C17@C18, C7@C8/C17S–C18S or C7R–C8R/C17S–C18S; (b) non-stereoselective
reduction with achiral NaBH : R = CH or phytyl, M = H or Mg, C7@C8/C17S–
1
3
2
14
4
3
2
1
3
1
C18S (for a Chl-a derivative) or C7R–C8R/C17S–C18S (for a BChl-a derivative). One
of the naturally occurring BChls-d is drawn in the right structure with R = farnesyl,
M = Mg and C7@C8/C17S–C18S.
2
2
4
1
31
O
CH3
N
H C
O
3
H
H
3
H3C
H3C
N
s
(R ) was 2.4. The isolated epimers were analyzed by 1D- and
1
1
1
2
D- H NMR including H- H COSY and NOESY in deuterated chlo-
roform (CDCl ) at room temperature. The stereochemistry at the
7-stereogenic position of both the epimers was fixed in the (S)-
configuration. Since the 17-H was located near the 13 -H and
removed from the 13 -H , both the 13 -H and H signals were
Fig. 1. Conformers (rotamers) around the 3-acetyl group in (B)Chl derivatives.
3
1
2
b
less reactive than the 3-C@O.8,9 Prolonged reactions or harsh con-
ditions could modify the 13-C@O group to the corresponding alco-
hol, 13-CX(OH). Methyl pyropheophorbide-a 1a was typically
2
a
2
a
b
1
0
reduced in a solution with sodium borohydride (NaBH
4
) to give a
The stere-
1
11–15
1
3 -epimeric mixture of (R)-2 and (S)-2 (Scheme 3).
oselectivity was reported to be nearly zero to 20% diastereomeric
excess (de) and slightly more (S)-2 was produced than (R)-2. The
small but apparent diastereomeric control was ascribable to con-
formational restriction of the 13-C@O group: a 1,5-induction
NH
N
N
HN
131
NH
N
N
(ii)
1
HN
through the four bonds between C13 and C17S. Moreover, a sim-
ilar asymmetric methylation of the 13-C@O as well as its reduction
18
72
were observed in methyl bacteriopheophorbide-d 1c.16
17
13
O
1
32
1
Herein we report the stereoselective reduction, methylation,
and phenylation of the 13-carbonyl group in Chl-a derivatives 1
bearing (17S,18S)-stereogenic centers with achiral reagents in a
solution. The resulting alcohols were epimeric mixtures and easily
separated by conventional reverse phase (RP)-HPLC while the ste-
O
COOH
O
1a
1b
OCH3
(i)
(iii)
R3
R3
NH
N
N
NH
N
N
HN
131
+
HN
31
NH
N
N
NH
N
N
1
3
13
1
HN
HN
X
OH
OH
X
1
8
COOCH3
COOCH3
1
7
31
13
O
131
1
Ra
2
(S)- : X = H
2
(R)- : X = H
Rb
(
R)- : X = CH3
3
(S)- : X = CH3
(R)-4: X = C H
6 5
3
COOCH3
COOCH3
3
(S)-4: X = C H
6
5
3
(R)-2: R = CH=CH2, R = H, Rb = OH
a
1
1
a: R = CH=CH2
c: R = CH(OH)CH3
3
(S)-2: R = CH=CH2, R = OH, Rb = H
3
a
Scheme 4. Reaction of the 13-C@O in pyropheophorbides 1 to carbinols (R/S)-2–4.
Reagents and conditions: (i) NaBH /CH Cl –MeOH or -selectride/THF, rt; (ii)
SO /H O–THF; (iii) CH Li/Et O or C Li/Bu
O, TMEDA/THF, À40 or À60 °C to rt
and CH /Et O.
4
2
2
L
H
2
4
2
3
2
6
H
5
2
1
Scheme 3. Reaction of the 13-C@O in (B)Chl derivatives 1 to 13 -hydroxy-chlorins.
2
N
2
2

H. Tamiaki et al. / Tetrahedron: Asymmetry 24 (2013) 677–682
679
of the propionate residue at the 17-position. The two polar
1
2
substituents, 13 -OH and 17 -COOMe, gave an anti-configuration
in (R)-2. The other epimer, (S)-2 had the syn-configuration for the
two substituents and was less hydrophilic than (R)-2. Therefore,
the relatively hydrophilic (R)-2 eluted more rapidly in RP-HPLC
than the relatively hydrophobic (S)-2. The partition coefficient be-
tween the 1-octanol and aqueous phases (P) was calculated from a
molecular structure and the ClogP values of (R)-2 and (S)-2 were
8
.6 and 10.1, respectively. The difference showed that (R)-2 was
more hydrophilic than (S)-2. The elution order supports the above
structural assignments of the separated epimers.
The 13-carbonyl group of 1a has two faces; the front and back
faces shown in Scheme 4 are the si- and re-faces. A hydride at-
1
tacked the 13-C@O moiety from the si- and re-face to give 13 -epi-
mers (R)-2 and (S)-2, respectively. The si-face was sterically
crowded with the 17-propionate residue, while the re-face was
hindered less by the small and far 18-methyl group. During the
À
present reduction, the H of NaBH
4
favorably attacked the partially
1
positively-charged 13 -carbon atom from the less sterically
demanding re-face and more (S)-2 was produced than (R)-2 (see
also the Graphical abstract). It should be noted that no epimeriza-
tion between (R)-2 and (S)-2 was observed during the reduction as
well as their purification and analysis.
Lithium tri(sec-butyl)borohydride (
a sterically larger reductant than NaBH
a tetrahydrofuran (THF) solution of -selectride gave an epimeric
L-selectride) is known to be
1
7
4
.
Treatment of 1a with
L
1
mixture of (R)-2 and (S)-2 as the products. The H NMR and HPLC
analyses of the mixture showed that (S)-2 was produced in a 3.4-
fold higher yield than (R)-2 (Fig. 2b). The (S)-preference was the
same as in the reduction by NaBH
by an -selectride was 55% and approximately two fold larger than
that by NaBH . When the hydride of a large -selectride reacted
with the 13-C@O of 1a, the reagent greatly interacted with the
4
. The de value in the reduction
L
4
L
1
1
7-propionate residue and attacked the C13 -atom from the re-
face to favorably give (S)-2. These results indicate that steric fac-
tors affected the stereoselective reduction.
Fig. 2. RP-HPLC of (a) 2#1/2 (= 2(R)/(S)-2, by NaBH
selectride), (c) 3#1/2 (= (R/S)-3), and (d) 4#1/2 (= (R/S)-4). Conditions: Cosmosil
18-AR-II (4.6 mm O = 95:5 (v/v), and 1.0 mL/min.
 150 mm), MeOH/H
4
), (b) 2#1/2 (= 2(R)/(S)-2, by
L
-
2.2. Stereoselective methylation of the 13-carbonyl group in
pyropheophorbide-a 1b
5
C
u
2
Methylation of the 13-carbonyl group in 1a was also examined.
The Grignard reaction of 1a with CH
3
MgI gave complex products
assigned from their NOESY spectra (Fig. 3). The NOESY spectrum of
1
2
a
containing methylated tertiary alcohol 3, since the reagent was
2
#1 showed that its 13 -H was correlated with the 13 -H but not
1
8
2
b
1
so reactive. The methyl Grignard reagent partially attacked the
with 13 -H (Fig. 3a). The stereochemistry at the 13 -position of
#1 was confirmed to have an (R)-configuration: 2#1 = (R)-2.
2
1
3-C@O and also abstracted the proton on the 13 -carbon. The for-
2
1
2
b
mer gave the desired product 3 while the latter afforded a cyclized
Based on the NOE-correlation of 13 -H with 13 -H (Fig. 3b), the
product through intramolecular Claisen-type reaction with the
major fraction 2#2 was assigned as (S)-2.
2
9
1
7 -COOMe. A similar situation has already been observed. In or-
In one of the reduced products, (R)-2, the hydroxy group at the
1
der to suppress the undesired cyclization, the methyl ester of 1a
was first hydrolyzed and the resulting carboxylic acid 1b was used
for the methylation of the 13-C@O group. Treatment of 1b in THF
1
3 -position was located in the same direction as the methyl group
at the 18-position based on the chlorin p-plane, and in the reverse
with methyl lithium (CH
3 2
Li) in diethyl ether (Et O) in the presence
9
of N,N,N’,N’-tetramethylethylenediamine (TMEDA) at À40 °C first
2
1
(
a)
(b)
produced the lithium carboxylate (17 -COOLi) and then the 13 -
methylated compound [13-CCH (OLi)]. The initially produced salt
3
2
N
HN
N
HN
could not be reacted with the 13 -anion due to the negative charge
2
À
1
7
17
H
on the 17 -COO . Double protonation of the product followed by
methyl esterification gave an epimeric mixture of (R)-3 and (S)-3.
The tertiary alcohol obtained was slightly unstable on silica gel;
thus alumina column chromatography was necessary for its
purification.
32
131
1
H
Hb
Hb
OH
X
Ha
Ha OH
X
COOMe
COOMe
#
1
#2
The epimeric mixture of (R/S)-3 was fully separated by RP-HPLC
(
s
Fig. 2c, R = 2.4) and the first and second fractions 3#1/2 were ana-
1
a
b
2
a
b
Fig. 3. Specific NOE correlations among the 13 -X /X , 13 -H /H and 17-H in (a)
1
1
lyzed by H NMR. Using the NOE correlations of the 13 -CH
3
with
3 -H, 3#1 and 3#2 were assigned as (R)-3 and (S)-3, respectively.
The elution order was consistent with that of 2. The ClogP values of
the first and minor fractions, 2#1 (= (R)-2) (X = H), 3#1 (= (R)-3) (X = CH
3
), and 4#1
, ortho-H); (b) the second and major fractions, 2#2 (= (S)-2)
X = H), 3#2 (= (S)-3) (X = CH ), and 4#2 (= (R)-4) (X = C , ortho-H).
2
1
(
(
6 5
= (S)-4) (X = C H
3
6 5
H

6
80
H. Tamiaki et al. / Tetrahedron: Asymmetry 24 (2013) 677–682
(R)-3 and (S)-3 were 8.7 and 10.7, respectively; (R)-3 should be
more hydrophilic than (S)-3, thus supporting the elution order.
Figure 2c shows that the ratio of (R)-3 and (S)-3 was 1:2.3. The
1
1
3 -epimer (S)-3 produced by the methylation from the sterically
less crowded re-face of 1b was the major product, similar to the
above reduction. The stereoselectivity (ca. 40% de) was higher than
that in the reduction by NaBH
the finding that the methylating reagent (a methyl anion) was
bulkier than the reducing reagent (hydride) in NaBH , although
the effect of the hydrolysis of methyl ester 1a to the carboxylic acid
b cannot be ruled out. It is noteworthy that no epimerization at
4
. This enhancement could be due to
4
1
1
the 3 -postion occurred during purification and that the separated
epimer (R)-3 could not be isomerized to (S)-3 after standing in its
aqueous MeOH solution at room temperature for one week and
vice versa.
Fig. 4. Correlation between the t
R
(min) and ClogP of diastereomers (R)- and (S)-2-
2
.3. Stereoselective phenylation of the 13-carbonyl group in
4: see Section 4.1 for the RP-HPLC separation conditions.
pyropheophorbide-a 1b
corded on a JEOL AL-400 (400 MHz) or ECA-600 (600 MHz) spec-
trometer, respectively; CHCl (d = 7.26 ppm) was used as an
internal reference. Time-of-flight (TOF) mass data were obtained
using direct laser desorption/ionization by a Shimadzu AXIMA-
CFR plus spectrometer. Fast atomic bombardment (FAB)-MS spec-
tra were measured with a JEOL GCmate II spectrometer; FAB-MS
The 13-C@O in 1b was phenylated similarly to the aforemen-
tioned methylation. After methyl-esterification, product 4 was ob-
tained as a 13 -epimeric mixture. The isolated yield for the two
steps of 1b to 4 was 7% and was lower than that of 1b to 3 (33%).
The esterification of the carboxylic acid with diazomethane was
achieved almost quantitatively. The inefficiency in the phenylation
3
H
1
2 2
samples were dissolved in CH Cl , m-nitrobenzyl alcohol was used
was partially due to the steric bulkiness in phenyl lithium (C
The epimeric mixture 4 was readily separated by RP-HPLC
Fig. 2d, R = 3.4) and the stereochemistry of 4#1/2 was determined
6 5
H Li).
as the matrix and PEG600 was added as an internal reference for
high resolution mass measurements. Silica gel or alumina column
chromatography was performed with Kieselgel 60 (Merck, 40–
(
s
1
by their H NMR spectra to be (S)-4 and (R)-4, respectively. It should
1
63
lm, 230–400 mesh) or aluminum oxide 90 (activity I, neutral,
be noted that the relative stereochemistry at the 13 -stereogenic
Merck, 63–200
l
m, 70–230 mesh) deactivated by 10% (v/v) H O,
2
center of (S)-4 is the same as those of (R)-2 and (R)-3 while that of
1
respectively. RP-HPLC was done with a Shimadzu LC-10ADvp
pump and SPD-M10Avp photodiode-array detector: Cosmosil
(
(
R)-4 is consistent with those of (S)-2 and (S)-3, although the 13
R/S)-nomenclature is changed by X = H/CH to C
3
H
6 5
(Scheme 4).
5
H
C
18-AR-II (4.6 mm
u
 150 mm) as an ODS column and MeOH/
The phenylation from the si- and re-faces of 1b led to the formation
of (S)-4 and (R)-4, respectively. Similar to the reduction and methyl-
ation, the alcohol produced via attack of a phenyl anion from the re-
face was the major product, (R)-4 and eluted more slowly in RP-
HPLC: ClogP = 10.5 for (S)-4 < 11.9 for (R)-4. The (R)-enriched prod-
uct was obtained in approximately 65% de. The highest stereoselec-
tivity in the reactions examined herein is due to the sterically bulky
2
O = 95:5 (1.0 mL/min) as an eluent. ClogP values were calcu-
lated by a ChemDraw Ultra software (version 8.0.3).
All reactions were carried out in the dark. Methyl pyropheo-
phorbide-a 1a and pyropheophorbide-a 1b were prepared accord-
1
9
2 2
ing to the literature. Commercially available CH Cl , MeOH, and
THF (Nacalai Tesque) were used as the reaction solvents. THF
was distilled over calcium hydride just before use. NaBH4 and
TMEDA were purchased from Wako Pure Chemical Ind. and Nacalai
1
phenylation reagent. No epimerization at the 13 -position of either
(R)-4 or (S)-4 was observed in an aqueous MeOH solution.
Tesque, respectively.
L
-Selectride [LiBH(CHMeEt)
3
] in THF (ca. 1 M),
O) (1.9 M)
CH Li in Et O (1.14 M), and C
3
2
6
5
H Li in dibutyl ether (Bu
2
3
. Conclusion
were obtained from Tokyo Chemical Ind., Kanto Chemical, and Al-
drich, respectively.
Diastereo-face differentiation was achieved in the reduction,
methylation, and phenylation of the conformationally fixed 13-
C@O group in pyropheophorbides-a. The si-face was sterically
crowded by the neighboring 17-propionate residue and the major
carbinols were produced by the attack of reactants from the re-
face. The stereoselectivity was controlled by the steric interactions
of the remote and four-bond separated substituent with the reac-
tive species. The diastereomers produced can be easily separated
by RP-HPLC due to the difference of their hydrophobicity/hydro-
philicity and their stereochemistry was confirmed by their H– H
NOE correlations and HPLC elution order. Their ClogP values were
R
useful for the estimation of the HPLC retention times (t ) for the
diastereomers (see Fig. 4).
4
.2. Modification of the 13-carbonyl group in methyl pyropheo-
phorbide-a
1
1
4
.2.1. Synthesis of methyl 13 -deoxo-13 -hydroxy-pyropheo-
phorbide-a 2
Ketone 1a (51.2 mg, 93.4
20 mL), to which NaBH
were added. The mixture was stirred under N
2
l
2 2
mol) was dissolved in CH Cl
(
4
(80.9 mg, 2.13 mmol) and MeOH (2 mL)
1
1
at room tempera-
ture for approximately 1 h. After the disappearance of 1a (monitor-
ing the visible spectrum in a solution: the shift of Qy peaks from
6
68 to 653 nm), the reaction was quenched with aq 2% HCl and
stirred for 10 min. The separated organic phase was washed with
aq 4% NaHCO and H O, dried over Na SO , and filtered. After evap-
oration, the residue was purified by silica gel column chromatogra-
phy (CH Cl ) to give alcohol 2 (29.5 mg, 53.6 mol, 57%) as a 1:1.7
mixture of (13 R)- and (13 S)-epimers: Vis (CH
3
2
2
4
4
4
. Experimental
.1. General
2
2
l
1
1
Cl
2 2
) kmax = 652
(
4
1
relative absorbance, 0.27), 597 (0.03), 546 (0.01), 502 (0.09),
Visible absorption spectra were measured with a Hitachi U-
500 spectrophotometer. 1D- or 2D- H NMR spectra were re-
1
1
01 nm (1.00);
H
NMR (400 MHz, CDCl
3
)
d
(13 R/S = 1/
1
3
.7) = 9.88 (1H, s, 5-H), 9.65 (1H, s, 10-H), 8.91 (1H, s, 20-H), 8.24

H. Tamiaki et al. / Tetrahedron: Asymmetry 24 (2013) 677–682
681
1
1
(
1H, dd, J = 12, 18 Hz, 3-CH), 6.53 (1H, m, 13-CH), 6.35 (1H, dd,
56.7
Vis (CH
3
(0.09), 402 nm (1.00); H NMR (400 MHz, CDCl ) d (13 R/S = 1/
l
mol, 33%) as a 1:2.3 mixture of (13 R)- and (13 S)-epimers:
1
1
J = 2, 18 Hz, 3 -CH trans to 3-C–H), 6.18 (1H, dd, J = 2, 12 Hz, 3 -
CH cis to 3-C–H), 5.41/5.31 (1H, dd, J = 6, 16 Hz, 13 -CH cis to 13-
C–H), 4.62/4.76 (1H, d, J = 16 Hz, 13 -CH trans to 13-C–H), 4.65
2
Cl ) kmax = 652 (relative absorbance, 0.28), 596 (0.03), 502
2
1
1
1
1
2.3) = 9.88 (1H, s, 5-H), 9.63 (1H, s, 10-H), 8.93 (1H, s, 20-H), 8.23
(1H, dd, J = 12, 18 Hz, 3-CH), 6.35 (1H, d, J = 18 Hz, 3 -CH trans to
3-C–H), 6.18 (1H, d, J = 12 Hz, 3 -CH cis to 3-C–H), 5.07/5.03 (1H,
1
(
1H, q, J = 7 Hz, 18-H), 4.46 (1H, m, 17-H), 3.85 (2H, q, J = 8 Hz, 8-
CH ), 3.63 (3H, s, 12-CH ), 3.57 (3H, s, 2-CH ), 3.57/3.43 (3H, s,
), 3.42 (3H, s, 7-CH ), 2.81–2.74, 2.62–2.53, 2.45–
.31, 2.25–2.17 (each 1H, m, 17-CH CH ), 1.85 (3H, d, J = 7 Hz,
), À1.37, À3.22 (each 1H, s,
1
2
3
3
2
1
1
2
1
7 -COOCH
3
3
d, J = 16 Hz, 13 -CH cis to 13-C–CH
3
), 4.84/4.94 (1H, d, J = 16 Hz,
), 4.64 (1H, q, J = 7 Hz, 18-H), 4.43 (1H,
d, J = 9 Hz, 17-H), 3.86 (2H, q, J = 8 Hz, 8-CH ), 3.62 (3H, s, 12-
), 3.57 (3H, s, 2-CH ), 3.42
), 2.75–2.71, 2.59–2.48, 2.41–2.33, 2.30–2.23 (each
1
2
2
13 -CH trans to 13-C–CH
3
1
8-CH
3
), 1.76 (3H, t, J = 8 Hz, 8 -CH
3
2
+
2
NH Â 2); MS (TOF) found: m/z 550.0. Calcd for C34
50.3. Please also see the spectroscopic data in the literature.
The above diastereomeric mixture was separated by RP-HPLC to
H
38
N
4
O
3
: M ,
CH
(3H, s, 7-CH
1H, m, 17-CH
J = 7 Hz, 18-CH
1H, s, NH Â 2); MS (TOF) found: m/z 565.8. Calcd for C35
3
), 3.59/3.38 (3H, s, 17 -COOCH
3
3
1
2,13
5
3
1
2
CH
2
), 2.30/2.20 (3H, s, 13 -CH
3
), 1.87 (3H, d,
), À1.47, À3.24 (each
1
1
1
afford (13 R)-epimer (R)-2 at t
at 7.9 min. (R)-2: Vis (CH Cl
.26), 599 (0.03), 544 (0.03), 502 (0.10), 402 nm (1.00); H NMR
400 MHz, CDCl ) d = 9.88 (1H, s, 5-H), 9.65 (1H, s, 10-H), 8.91
1H, s, 20-H), 8.23 (1H, dd, J = 12, 18 Hz, 3-CH), 6.56 (1H, d,
R
= 6.7 min and (13 S)-epimer (S)-2
3
), 1.78 (3H, t, J = 8 Hz, 8 -CH
3
2
2
) kmax = 653 (relative absorbance,
41 4 3
H N O :
1
+
0
(
(
MH , 565.3; HRMS (FAB) found: m/z 565.3176. Calcd for
+
3
35 41 4 3
C H N O : MH , 565.3179.
The above diastereomeric mixture was separated by RP-HPLC
1
1
1
J = 6 Hz, 13-CH), 6.35 (1H, dd, J = 1, 18 Hz, 3 -CH trans to 3-C–H),
6
1
(
to afford (13 R)-epimer (R)-3 at t
(S)-3 at 7.7 min. (R)-3: Vis (CH Cl
R
= 6.7 min and (13 S)-epimer
) kmax = 653 (relative absor-
bance, 0.27), 597 (0.03), 502 (0.10), 402 nm (1.00); H NMR
3
(400 MHz, CDCl ) d = 9.88 (1H, s, 5-H), 9.64 (1H, s, 10-H), 8.91
1
.18 (1H, dd, J = 1, 12 Hz, 3 -CH cis to 3-C–H), 5.41 (1H, dd, J = 6,
2
2
1
1
6 Hz, 13 -CH cis to 13-C–H), 4.65 (2H, q, J = 7.5 Hz, 18-H), 4.63
1
1H, d, J = 16 Hz, 13 -CH trans to 13-C–H), 4.47 (1H, d, J = 9 Hz,
1
7-H), 3.85 (2H, q, J = 7.5 Hz, 8-CH
2
), 3.63 (3H, s, 12-CH
), 3.565 (3H, s, 2-CH ), 3.42 (3H, s, 7-CH
.78–2.71, 2.62–2.54, 2.37–2.31, 2.24–2.18 (each 1H, m, 17-
CH ), 1.85 (3H, d, J = 7.5 Hz, 18-CH ), 1.77 (3H, t, J = 7.5 Hz,
), À1.34, À3.20 (each 1H, s, NH Â 2); MS (TOF) found: m/z
3
), 3.571
(1H, s, 20-H), 8.25 (1H, dd, J = 12, 18 Hz, 3-CH), 6.35 (1H, dd,
2
1
(
3H, s, 17 -COOCH
3
3
3
),
J = 1.5, 18 Hz, 3 -CH trans to 3-C–H), 6.18 (1H, dd, J = 1.5,
1
1
2
12 Hz, 3 -CH cis to 3-C–H), 5.12 (1H, d, J = 16 Hz, 13 -CH cis to
1
CH
2
2
3
3 3
13-C–CH ), 4.90 (1H, d, J = 16 Hz, 13 -CH trans to 13-C–CH ),
1
8
-CH
50.6. Calcd for
3
4.65 (2H, q, J = 7.5 Hz, 18-H), 4.44 (1H, d, J = 9 Hz, 17-H), 3.85
+
2
5
C
34
H
38
N
4
O
3
:
M , 550.3. (S)-2: Vis (CH
2
Cl
2
)
(2H, q, J = 7.5 Hz, 8-CH
COOCH ), 3.57 (3H, s, 2-CH
2.36–2.22, (each 1H, m, 17-CH
2
2
), 3.65 (3H, s, 12-CH
), 3.42 (3H, s, 7-CH
), 2.63–2.57, 2.24–2.18 (each
3
), 3.58 (3H, s, 17 -
kmax = 652 (relative absorbance, 0.27), 597 (0.03), 549 (0.01), 502
3
3
3
), 2.77–2.71,
1
(
0.10), 401 nm (1.00); H NMR (400 MHz, CDCl
3
) d = 9.88 (1H, s,
1
1
5
1
1
-H), 9.65 (1H, s, 10-H), 8.91 (1H, s, 20-H), 8.24 (1H, dd, J = 12,
8 Hz, 3-CH), 6.52 (1H, d, J = 6 Hz, 13-CH), 6.35 (1H, dd, J = 2,
1H, m, 17 -CH
18-CH ), 1.76 (3H, t, J = 7.5 Hz, 8 -CH
other NH could not be observed.]; MS (TOF) found: m/z 564.5.
2
), 2.42 (3H, s, 13 -CH
3
), 1.84 (3H, d, J = 7.5 Hz,
1
3
3
), À3.22 (1H, s, NH) [an-
1
1
8 Hz, 3 -CH trans to 3-C–H), 6.18 (1H, dd, J = 2, 12 Hz, 3 -CH cis
1
+
to 3-C–H), 5.30 (1H, dd, J = 6, 16 Hz, 13 -CH cis to 13-C–H), 4.75
Calcd for
565.3180. Calcd for
(CH Cl
(0.09), 402 nm (1.00); H NMR (400 MHz, CDCl
C
35
40
H N
4
O
3
:
M , 564.3; HRMS (FAB) found: m/z
H N O : MH , 565.3179. (S)-3: Vis
35 41 4 3
2
) kmax = 652 (relative absorbance, 0.28), 597 (0.03), 503
1
+
(
1H, d, J = 16 Hz, 13 -CH trans to 13-C–H), 4.65 (1H, q, J = 7.5 Hz,
C
1
3
3
8-H), 4.45 (1H, d, J = 9 Hz, 17-H), 3.85 (2H, q, J = 7.5 Hz, 8-CH2),
2
2
1
.63 (3H, s, 12-CH
3
), 3.57 (3H, s, 2-CH
), 2.81–2.74, 2.61–2.53, 2.45–2.36, 2.24–2.17
CH ), 1.86 (3H, d, J = 7.5 Hz, 18-CH ), 1.77
3H, t, J = 7.5 Hz, 8 -CH
), À1.37, À3.32 (each 1H, s, NH Â 2); MS
TOF) found: m/z 550.6. Calcd for C34
3
), 3.421 (3H, s, 17 -COOCH
3
),
3
) d = 9.89 (1H,
.418 (3H, s, 17-CH
3
s, 5-H), 9.64 (1H, s, 10-H), 8.91 (1H, s, 20-H), 8.24 (1H, dd,
1
(
(
(
each 1H, m, 17-CH
2
2
3
J = 12, 18 Hz, 3-CH), 6.35 (1H, dd, J = 1.5, 18 Hz, 3 -CH trans to
1
1
3
3-C–H), 6.18 (1H, dd, J = 1.5, 12 Hz, 3 -CH cis to 3-C–H), 5.07
+
1
H
38
N
4
O
3
: M , 550.3. Please
(1H, d, J = 16 Hz, 13 -CH cis to 13-C–CH
3
), 4.99 (1H, d,
15
1
also see the spectroscopic data in the literature.
Similar to the above synthesis, the reduction of 1a (54.0 mg,
J = 16 Hz, 13 -CH trans to 13-C–CH
H), 4.45 (1H, d, J = 9 Hz, 17-H), 3.85 (2H, q, J = 7.5 Hz, 8-CH
3.65 (3H, s, 12-CH ), 3.57 (3H, s, 2-CH ), 3.42 (3H, s, 7-CH
3.38 (3H, s, 17 -COOCH
17-CH ), 2.59–2.51, 2.23–2.15 (each 1H, m, 17 -CH
3
), 4.64 (1H, q, J = 7.5 Hz, 18-
2
),
),
9
1
8.5
l
mol) in THF (5 mL) with
mol) for 30 min gave a 1:3.4 mixture of (R)-2 and (S)-2
mol, 20%) and 1a (42.6 mg, 77.7 mol) was recov-
ered. The yield based on consumed 1a was 95%. Using 5 equiv of
L
-selectride in THF (1 M, 100
lL,
3
3
3
2
00
l
3
), 2.80–2.72, 2.44–2.37, (each 1H, m,
1
(
10.9 mg, 19.8
l
l
2
1
2
), 2.32 (3H,
3 3
s, 13 -CH ), 1.87 (3H, d, J = 7.5 Hz, 18-CH ), 1.76 (3H, t,
L
-
1
selectride, 1a was completely reduced to afford the same 1:3.4
mixture of (R)-2/(S)-2, while by-products bearing a 17-hydroxy-
propyl group were partially produced through further reduction
J = 7.5 Hz, 8 -CH
3
), À1.17, À3.01 (each 1H, s, NH Â 2); MS (TOF)
+
found: m/z 564.6. Calcd for
C
35
40
H N
4
O
3
:
M , 564.3; HRMS
+
(FAB) found: m/z 565.3179. Calcd for
C
35
H
41
N
4
O
3
:
MH ,
2
of the 17 -COOMe to CH
2
OH.
565.3179.
1
1
1
1
1
1
4
.2.2. Synthesis of methyl 13 -deoxo-13 -hydroxy-13 -methyl-
pyropheophoride-a 3
Ketone 1b (91.2 mg, 171
À40 °C, to which TMEDA (2 mL, 13.4 mmol) and CH
1.14 M, 6.00 mL, 6.84 mmol) were added. The mixture was stirred
4.2.3. Synthesis of methyl 13 -deoxo-13 -hydroxy-13 -phenyl-
pyropheophoride-a 4
l
mol) was dissolved in THF (40 mL) at
Similar to the synthesis of 3, the reaction of 1b (105 mg,
lmol) with C H Li in Bu O (1.9 M, 10 mL, 19 mmol) at
6 5 2
3
Li in Et
2
O
197
(
À60 °C to room temperature gave phenyl carbinol 4 (8.4 mg,
1
1
under Ar at À40 °C until the disappearance of 1b (monitoring the
13.4
Vis (CH
3
502 (0.10), 402 nm (1.00); H NMR (400 MHz, CDCl ) d (13 S/
l
mol, 7%) as a 1:4.5 mixture of (13 S)- and (13 R)-epimers:
visible spectrum in a solution: the shift of Qy peaks from 668 to
2
Cl ) kmax = 653 (relative absorbance, 0.29), 598 (0.03),
2
1
1
6
53 nm) and quenched with aq 2% HCl (10 mL) at À40 °C. The solu-
tion was diluted with CHCl and the separated organic phase was
washed with aq 4% NaHCO and H O, dried over Na SO , and fil-
tered. After evaporation, the residue was dissolved in THF
40 mL) and stirred with an excess amount of CH in Et O at
3
R = 1/4.5) = 9.89 (1H, s, 5-H), 9.60 (1H, s, 10-H), 8.91 (1H, s,
20-H), 8.25 (1H, dd, J = 12, 18 Hz, 3-CH), 7.82/7.69 (2H, d,
J = 7.5 Hz, o-H of 13 -Ph), 7.41/7.38 (2H, t, J = 7.5 Hz, m-H of
13 -Ph), 7.38/7.32 (1H, t, J = 7.5 Hz, p-H of 13 -Ph), 6.37 (1H, d,
J = 18 Hz, 3 -CH trans to 3-C–H), 6.19 (1H, d, J = 12 Hz, 3 -CH
3
2
2
4
1
1
1
(
2
N
2
2
1
1
room temperature for 15 min. All the solvents were distilled in va-
cuo and the residue was purified by alumina column chromatogra-
1
cis to 3-C–H), 5.31/5.24 (1H, d, J = 16 Hz, 13 -CH cis to 13-C–
Ph), 5.18/5.37 (1H, d, J = 16 Hz, 13 -CH trans to 13-C–Ph), 4.64
1
phy (CH
2
Cl
2
/hexane = 1:3) to give methyl carbinol 3 (32.0 mg,

6
82
H. Tamiaki et al. / Tetrahedron: Asymmetry 24 (2013) 677–682
(
1H, q, J = 7 Hz, 18-H), 4.40 (1H, d, J = 8 Hz, 17-H), 3.84 (2H, q,
Acknowledgments
2
J = 8 Hz, 8-CH
COOCH ), 3.42 (3H, s, 7-CH
.57–2.51, 2.48–2.43, 2.20–2.15 (each 1H, m, 17-CH
2
), 3.58 (3H, s, 2-CH
3
), 3.55/3.31 (3H, s, 17 -
), 2.79–2.74,
CH ), 1.86
), 1.76 (3H, t, J = 8 Hz, 8 -CH
), À1.47,
À3.24 (each 1H, s, NH Â 2); MS (TOF) found: m/z 626.7. Calcd
3
3
), 3.39 (3H, s, 12-CH
3
This work was partially supported by a Grant-in-Aid for Scien-
tific Research (A) (No. 22245030) from the Japan Society for the
Promotion of Science (JSPS).
2
(
2
2
1
3H, d, J = 7 Hz, 18-CH
3
3
+
for C40
Calcd for C40
The above diastereomeric mixture was separated by RP-HPLC
H
42
N
4
O
3
: M , 626.3; HRMS (FAB) found: m/z 627.3315.
References
+
43 4 3
H N O : MH , 627.3335.
1.
(a) Muraki, N.; Nomata, J.; Ebata, K.; Mizoguchi, T.; Shiba, T.; Tamiaki, H.;
Kurisu, G.; Fujita, Y. Nature 2010, 465, 110–114; (b) Reinbothe, C.; Bakkouri, M.
E.; Buhr, F.; Muraki, N.; Nomata, J.; Kurisu, G.; Fujita, Y.; Reinbothe, S. Trends
Plant Sci. 2010, 15, 614–624; (c) Gabruk, M.; Grzyb, J.; Kruk, J.; Mysliwa-
Kurdziel, B. Photosynthetica 2012, 50, 529–540; (d) Moser, J.; Lange, C.; Krausze,
J.; Rebelein, J.; Schubert, W.-D.; Ribbe, M. W.; Heinz, D. W.; Jahn, D. Proc. Natl.
Acad. Sci. U.S.A. 2013, 110, 2094–2098.
1
1
to afford (13 S)-epimer (S)-4 at t
R)-4 at 9.7 min. (S)-4: Vis (CH Cl
bance, 0.29), 598 (0.03), 502 (0.09), 402 nm (1.00); H NMR
R
= 7.8 min and (13 R)-epimer
(
2
2
) kmax = 653 (relative absor-
1
(
3
400 MHz, CDCl ) d = 9.88 (1H, s, 5-H), 9.65 (1H, s, 10-H), 8.92
(
1H, s, 20-H), 8.24 (1H, dd, J = 12, 18 Hz, 3-CH), 7.82 (2H, d,
2. (a) Wolf, H.; Scheer, H. Justus Liebigs Ann. Chem. 1973, 1710–1740; (b) Tamiaki,
H.; Watanabe, T.; Kunieda, M. Res. Chem. Int. 2007, 33, 161–168.
3. Tamiaki, H.; Kouraba, M.; Takeda, K.; Kondo, S.; Tanikaga, R. Tetrahedron:
Asymmetry 1998, 9, 2101–2111.
1
1
J = 7.5 Hz, o-H of 13 -Ph), 7.46 (2H, t, J = 7.5 Hz, m-H of 13 -
Ph), 7.38 (1H, t, J = 7.5 Hz, p-H of 13 -Ph), 6.35 (1H, dd, J = 1.5,
1
CH cis to 3-C–H), 5.34 (1H, d, J = 16 Hz, 13 -CH cis to 13-C–Ph),
5
J = 7.5 Hz, 18-H), 4.45 (1H, d, J = 9 Hz, 17-H), 3.83 (2H, q,
1
1
1
8 Hz, 3 -CH trans to 3-C–H), 6.19 (1H, dd, J = 1.5, 12 Hz, 3 -
4.
(a) Sasaki, S.; Omoda, M.; Tamiaki, H. J. Photochem. Photobiol. A: Chem. 2004,
162, 307–315; (b) Tamiaki, H.; Hamada, K.; Kunieda, M. Tetrahedron 2008, 64,
5721–5727; (c) Huber, V.; Sengupta, S.; Würthner, F. Chem. Eur. J. 2008, 14,
1
1
.18 (1H, d, J = 16 Hz, 13 -CH trans to 13-C–Ph), 4.66 (2H, q,
7791–7807.
5
6
7
.
.
.
(a) Struck, A.; Cmiel, E.; Katheder, I.; Schäfer, W.; Scheer, H. Biochim. Biophys.
Acta 1992, 1101, 321–328; (b) Kunieda, M.; Mizoguchi, T.; Tamiaki, H.
Photochem. Photobiol. 2004, 79, 55–61.
2
J = 7.5 Hz, 8-CH
.42 (3H, s, 7-CH
each 1H, m, 17-CH
2
), 3.57 (3H, s, 2-CH
), 3.34 (3H, s, 12-CH
), 2.62–2.54, 2.31–2.26 (each 1H, m, 17 -
3
), 3.55 (3H, s, 17 -COOCH
3
),
3
(
3
3
), 2.73–2.71, 2.25–2.20,
(a) Gudowska-Nowak, E.; Newton, M. D.; Fajer, J. J. Phys. Chem. 1990, 94, 5795–
1
2
5801; (b) Tamiaki, H.; Kotegawa, Y.; Mizutani, K. Bioorg. Med. Chem. Lett. 2008,
1
CH
CH
6
2
), 1.85 (3H, d, J = 7.5 Hz, 18-CH
3
), 1.75 (3H, t, J = 7.5 Hz, 8 -
18, 6037–6040.
Tamiaki, H.; Shibata, R.; Mizoguchi, T. Photochem. Photobiol. 2007, 83, 152–162.
3
), À1.25, À3.22 (each 1H, s, NH Â 2); MS (TOF) found: m/z
+
8. Tamiaki, H.; Miyatake, T.; Tanikaga, R. Tetrahedron Lett. 1997, 38, 267–270.
25.7. Calcd for C40
42 4 3
H N O : M , 626.3; HRMS (FAB) found: m/
9.
Yagai, S.; Miyatake, T.; Shimono, Y.; Tamiaki, H. Photochem. Photobiol. 2001, 73,
+
z 626.3249. Calcd for C40
H
42
N
4
O
3
: M , 626.3257. (R)-4: Vis
153–163.
10. Tamiaki, H.; Kunieda, M. Handb. Porphyr. Sci. 2011, 11, 223–290.
(
(
CH
0.09), 402 nm (1.00); H NMR (400 MHz, CDCl
2 2
Cl ) kmax = 653 (relative absorbance, 0.29), 598 (0.03), 502
1
11. Wolf, H.; Scheer, H. Justus Liebigs Ann. Chem. 1971, 745, 87–98.
3
) d = 9.89 (1H,
12. Ma, L.; Dolphin, D. Can. J. Chem. 1997, 75, 262–275; Katterle, M.; Holzwarth, A.
s, 5-H), 9.66 (1H, s, 10-H), 8.92 (1H, s, 20-H), 8.25 (1H, dd,
J = 12, 18 Hz, 3-CH), 7.69 (2H, d, J = 7.5 Hz, o-H of 13 -Ph), 7.38
(
1
d, J = 12 Hz, 3 -CH cis to 3-C–H), 5.37 (1H, d, J = 16 Hz, 13 -CH
trans to 13-C–Ph), 5.24 (1H, d, J = 16 Hz, 13 -CH cis to 13-C–
Ph), 4.64 (1H, q, J = 7.5 Hz, 18-H), 4.40 (1H, d, J = 9 Hz, 17-H),
R.; Jesorka, A. Eur. J. Org. Chem. 2006, 414–422.
13. (a) Maruyama, K.; Yamada, H.; Osuka, A. Bull. Chem. Soc. Jpn. 1990, 63, 3462–
3466; (b) Tamiaki, H.; Watanabe, T.; Miyatake, T. J. Porphyr. Phthalocya. 1999, 3,
1
1
2H, t, J = 7.5 Hz, m-H of 13 -Ph), 7.32 (1H, t, J = 7.5 Hz, p-H of
45–52.
1
1
3 -Ph), 6.37 (1H, d, J = 18 Hz, 3 -CH trans to 3-C–H), 6.19 (1H,
14. Jesorka, A.; Balaban, T. S.; Holzwarth, A. R.; Schaffner, K. Angew. Chem., Int. Ed.
1
1
Engl. 1996, 35, 2861–2863.
15. Jesorka, A.; Holzwarth, A. R.; Eichhöfer, A.; Reddy, C. M.; Kinoshita, Y.; Tamiaki,
1
H.; Katterle, M.; Naubron, J.-V.; Balaban, T. S. Photochem. Photobiol. Sci. 2012,
1
1, 1069–1080.
3
7
2
.84 (2H, q, J = 7.5 Hz, 8-CH
-CH ), 3.39 (3H, s, 12-CH
.72, 2.48–2.42, (each 1H, m, 17-CH
2
), 3.58 (3H, s, 2-CH
3
), 3.42 (3H, s,
), 3.30 (3H, s, 17 -COOCH ), 2.80–
), 2.54–2.50, 2.23–2.17
), 1.86 (3H, d, J = 7.5 Hz, 18-CH ), 1.76
16. Yagai, S.; Miyatake, T.; Tamiaki, H. J. Org. Chem. 2002, 67, 49–58.
17. Brown, H. C.; Krishnamurthy, S. J. Am. Chem. Soc. 1972, 94, 7159–7161.
2
3
3
3
1
8. Other alkyl Grignard reagents have been reacted successfully with methyl
2
1 1
pyropheophorbides to give the corresponding 13 -alkyl-13 -oxo-chlorins, see:
1
(
each 1H, m, 17 -CH
2
3
Wang, J.-J.; Han, G.-F.; Shim, Y. K. J. Photosci. 2001, 8, 75–77.
1
19. (a) Wasielewski, M. R.; Svec, W. A. J. Org. Chem. 1980, 45, 1969–1974; (b) Smith,
K. M.; Goff, D. A.; Simpson, D. J. J. Am. Chem. Soc. 1985, 107, 4946–4954; (c)
Tamiaki, H.; Takeuchi, S.; Tsudzuki, S.; Miyatake, T.; Tanikaga, R. Tetrahedron
1998, 54, 6699–6718.
(
3H, t, J = 7.5 Hz, 8 -CH
3
), À1.27, À3.17 (each 1H, s, NH Â 2);
+
MS (TOF) found: m/z 626.1. Calcd for C40
HRMS (FAB) found: m/z 626.3261. Calcd for C40
26.3257.
H
42
N
4
O
3
: M , 626.3;
+
42
H N
4
O
3
: M ,
6