Construction of the Bacteriochlorin Macrocycle with Concomitant Nazarov Cyclization To Form the Annulated Isocyclic Ring: Analogues of Bacteriochlorophyll a

Article abstract of DOI:10.1021/acs.joc.6b02878

Bacteriochlorophylls contain a bacteriochlorin macrocycle bearing an annulated fifth ring. The fifth ring, termed the isocyclic ring or ring E, is equipped with 13¹-oxo and 13²-carbomethoxy substituents. Herein, a general route to st

Full text of DOI:10.1021/acs.joc.6b02878

Article
pubs.acs.org/joc
Construction of the Bacteriochlorin Macrocycle with Concomitant
Nazarov Cyclization To Form the Annulated Isocyclic Ring:
Analogues of Bacteriochlorophyll a
Shaofei Zhang and Jonathan S. Lindsey*
Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695-8204, United States
*
S Supporting Information
ABSTRACT: Bacteriochlorophylls contain a bacteriochlorin
macrocycle bearing an annulated fifth ring. The fifth ring,
1
termed the isocyclic ring or ring E, is equipped with 13 -oxo
2
and 13 -carbomethoxy substituents. Herein, a general route to
stable, synthetic bacteriochlorophyll analogues is described.
Knoevenagel condensation (∼40 mM, rt, CH Cl , piperidine/
2
2
AcOH/molecular sieves) of a dihydrodipyrrin−carboxalde-
hyde (AD half) and a dihydrodipyrrin substituted with a β-
ketoester (BC half) forms a propenone bearing the two halves
(
a hydrobilin analogue). Subsequent treatment (0.2 mM) with
acid (Yb(OTf) , CH CN, 80 °C) promotes a double ring-
closure process: (i) condensation between the α-position of
3
3
pyrrole ring A and the α-acetal unit attached to pyrroline ring B forms the bacteriochlorin macrocycle, and (ii) Nazarov
cyclization of the β-(propenoyl)-substituted ring C forms the isocyclic ring (E). Five new bacteriochlorins bearing various
2
substituents (alkyl/alkyl, aryl, and alkyl/ester) at positions 2 and 3 (β-pyrrole sites, ring A) and 13 carboalkoxy groups (R = Me
or Et) were constructed in 37−61% yield from the hydrobilin analogues. The BC half and AD half are available in five and eight
steps, respectively, from the corresponding pyrrole-2-carboxaldehyde and unsaturated ketone. The bacteriochlorins exhibit
absorption spectra typical of bacteriopheophytins (free base bacteriochlorophylls), with a strong near-infrared absorption band
(
707−751 nm).
INTRODUCTION
(aerobic) dehydrogenation leading to the more unsaturated
chlorin or porphyrin. Incorporation of the gem-dimethyl group
has proved synthetically more expedient than the trans-dialky6l
(or alkyl/alkylidene) configuration of the natural macrocycles.
An alternative route (not shown) employs a Northern−
Southern self-condensation of a dihydrodipyrrin−acetal similar
■
Bacteriochlorins are attractive candidates for a variety of
photophysical studies owing to their strong absorption in the
1
,2
near-infrared (NIR) spectral region. The core chromophore
of bacteriochlorophylls a, b, and g, the chief light-harvesting
pigments in anoxygenic photosynthetic bacteria, is a bacterio-
chlorin (Scheme 1). Bacteriochlorins are members of the
tetrapyrrole family and contain alternating pyrrole and
pyrroline rings. Bacteriochlorophylls also contain a fifth,
annulated ring (the “isocyclic” ring, or ring E) that spans
positions 13 and 15; the ring is equipped with an integral keto
group that lies coplanar with the organic π-system. In addition,
an auxochrome is present at the 3-position, distal to the
coplanar keto group of the isocyclic ring. Bacteriochlorophyll b
differs from bacteriochlorophyll a in the presence of an
exocyclic ethylidene group in ring B, whereas bacteriochloro-
phyll g contains the exocyclic ethylidene group in ring B as well
as a 3-vinyl group and farnesyl (or other hydrocarbon) rather
7
to that in the Eastern−Western route. Regardless, a chief
limitation of both de novo syntheses originates with the
dimerization processwhatever substituents are present on the
pyrrole unit of the dihydrodipyrrin species are conveyed to the
two pyrroles of the bacteriochlorin.
Rational approaches to bacteriochlorins with nonidentical
substituents on the two pyrrole units have been severely limited
(
Scheme 2): (1) Sonogashira coupling of a 3,13-dibromo-5-
methoxybacteriochlorin (I-a) proceeds selectively at the
unhindered 13-position, after which more forcing Pd-mediated
conditions could be employed to install diverse substituents at
the 3-position en route to the differentially substituted
8
3
bacteriochlorin (I-b). (2) A 3,13-diacetyl-5-methoxybacterio-
than phytol as the esterifying unit at the 17 -position.
chlorin (I-c) underwent 15-bromination (I-d), setting up Pd-
To access synthetically malleable analogues of bacterio-
chlorophylls, we have been developing a de novo synthesis of
bacteriochlorins (I). The route relies on the self-condensation
of a dihydrodipyrrin−acetal (II-acetal) or dihydrodipyrrin−
carboxaldehyde (II-CHO) (Scheme 1). A gem-dimethyl group
mediated α-arylation to close the annulated 5-membered ring
1
spanning positions 13 and 15, thereby forming the bacterio-13 -
3
,4
5
Received: December 1, 2016
is positioned in each pyrroline ring to block any adventitious
©
XXXX American Chemical Society
A
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Scheme 1. Bacteriochlorophylls and Self-Condensations To Form Bacteriochlorins
oxophorbine (I-e). To date, I-e is the only bacterio-131-
modifications to the native structure.
13,14
To date, names for
oxophorbine prepared by de novo synthesis. (3) A route to
tetrapyrrole macrocycles bearing isocyclic rings derive from
those of the natural compounds.
9
−11
15
tolyporphin A diacetate,
a derivative of a naturally
occurring dioxobacteriochlorin (not shown), is ingenious yet
inordinately lengthy for our purposes. An alternative approach
toward bacteriochlorins entails derivatization of porphyrins or
The synthesis of bacteriochlorins that are unsymmetrically
substituted with diverse groups in the pyrrole (A, C) and
pyrroline (B, D) rings remains an unmet challenge. Access to
such macrocycles would open a number of scientific
opportunities, of which the following are representative: (1)
incorporation of distinct auxochromes for wavelength-tuning;
(2) introduction of a single tether (for bioconjugation or
surface attachment) and/or a single water-solubilizing group;
1
2
chlorins.
In contrast with these synthetic limitations, bacteriochloro-
phylls a, b, and g contain distinct substituents in rings A−C as
well as the isocyclic ring (E) bearing a carbomethoxy group at
2
the 13 -position (Scheme 1). The synthesis shown in Scheme 2
1
13
(
right panel) affords the 13 -oxobacteriophorbine macrocycle
(3) site-selective incorporation of single isotopes (e.g., C or
2
15
but lacking the 13 -carbomethoxy group. The resulting
macrocycles are akin to bacteriopyropheophorbides (Chart
N) for vibronic studies; (4) introduction of distinct
substituents on opposite sides of the macrocycle to engender
self-assembly; and (5) incorporation of the resulting tailored
macrocycles as building blocks in the construction of
multipigment arrays for studies of light-harvesting and energy
transduction.
In this paper, we describe a rational route to bacteriochlorin
macrocycles that incorporate the β-ketoester-containing iso-
cyclic ring as well as diverse substituents at the 2- and 3-
positions. The route relies on directed joining of two distinct
dihydrodipyrrins (BC and AD halves) by mild Knoevenagel
1
), which are the natural bacteriochlorophyll derivatives
2
obtained upon demetalation and pyrolytic loss of the 13 -
carbomethoxy substituent. The functional role of the 13 -
2
carbomethoxy group remains unclear, whereas the coplanar
keto group (13-position) is known to cause a bathochromic
shift of the long-wavelength absorption band and to interact via
1
hydrogen bonding with protein sites. Note that the term
isocyclic ring is typically used regardless of the presence or
2
absence of the 13 -carbomethoxy group, as well as vast other
B
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Scheme 2. Rational Routes to Unsymmetrically Substituted
Bacteriochlorins
RESULTS
■
I. Reconnaissance. After several years of study (for an
earlier attempt, see ref 16), two precedents proved enlightening
for developing a directed synthesis of unsymmetrically
substituted bacteriochlorins. The first precedent was Wood-
ward’s pioneering synthesis of chlorin e trimethyl ester, a
6
precursor of chlorophyll, which relies on directed joining of an
AD half and a BC half to form an unsymmetric porphyrin
17−19
(
Scheme 3).
Acid-catalyzed condensation of a dipyrro-
Scheme 3. Macrocycle Formation in Woodward’s Approach
to Chlorophyll
Chart 1. Bacteriopheophytin Derivatives and Bacterio-131-
oxophorbine
19
methane−thioaldehyde (W-31, Woodward numbering ) and a
dipyrromethane−amine (W-32) gave a Schiff’s base (W-33).
Intramolecular condensation of the juxtaposed rings A and B in
W-33 generated a single bilene-b salt; subsequent condensation
between rings C and D under more forcing acidic conditions
deftly closed the macrocycle and, upon dehydrogenation and
acetylation, afforded the desired porphyrin (W-35) in 50%
overall yield. In our case, to prepare an unsymmetric
bacteriochlorin, dihydrodipyrrins would be the constituents
instead of dipyrromethanes. Also required is a unit at the β-
pyrrole position of one dihydrodipyrrin to direct intermolecular
joining of the BC and AD halves followed by an intramolecular
joining of the resulting linear intermediate to close the
macrocycle.
condensation followed by one-flask, mild acid-mediated
electrophilic aromatic substitution and Nazarov cyclization to
form the macrocycle along with the isocyclic ring. We describe
the routes to the BC and AD halves, studies of the conditions
for conversion to the bacteriochlorins, and application to the
synthesis of five new bacteriochlorins. The static absorption and
fluorescence spectroscopic properties of the new bacteriochlor-
ins are reported and compared with those of the natural
bacteriopheophytin a (Bpheo a).
C
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The second precedent emerged from studies of the Nazarov
Scheme 4. Retrosynthetic Analysis
20
cyclization with heteroaromatic compounds. Examples of
Nazarov cyclization with pyrroles bearing appended propenoyl
substituents have emerged only in the past decade. In the first
two reports, Knight and co-workers employed an N-protected
21
pyrrole and a propenoic acid, whereas Frontier and co-
2
2
workers employed an unprotected pyrrole bearing a
propenoyl substituent at the β-position. The latter appeared
ideal for our case. Under a catalytic amount of Sc(OTf) (10
3
mol %) and in the presence of LiClO4 for 1.25 h, β-
(
propenoyl)pyrrole III underwent ring closure at the α-position
22
in 68% yield (eq 1). The resulting annulated pyrrole IV bears
the same structural motif as in the isocyclic ring of
bacteriochlorophylls a, b, and g. The Nazarov cyclization of
unprotected β-(propenoyl)pyrroles also was reported to
proceed with other catalysts and to be tolerant of various
2
3,24
substituents.
The Nazarov substrate III could be easily
prepared via Knoevenagel condensation of the β-ketoester−
22
pyrrole and butanal.
The resulting retrosynthetic analysis for the preparation of
unsymmetrical annulated bacteriochlorins is outlined in
Scheme 4. First, the bacteriochlorin macrocycle (V) is created
upon the double ring-closure process of a linear tetrapyrrole
(
(
VI) containing two dihydropyrrins linked via a propenoyl unit:
i) electrophilic aromatic substitution of the acetal unit and the
open pyrrole α-position joins rings A and B; (ii) Nazarov
cyclization joins rings C and D, thereby constructing the
isocyclic ring (E). The oxidation state of the linear tetrapyrrole
remains unchanged during the overall double ring-closure and
aromatization processes. Second, the linear tetrapyrrole (VI) is
prepared by Knoevenagel condensation of the AD half (VII)
and BC half (VIII). The conditions for Knoevenagel
condensation must be compatible with sensitive functionalities
Four AD halves were sought (Chart 2). The synthesis of AD
4
,5
halves
generally begins with the desired β-substituted
pyrrole-2-carboxaldehyde. For the case where the pyrrole
bears two electron-releasing substituents at the β-positions
(e.g., 5-MeMe), a stabilizing ester substituent at the 5-position
(
e.g., the open pyrrole α-position and the acetal unit) and occur
specifically between the β-ketoester and the carboxaldehyde
group.
5
is required.5 AD halves 5-T and 5-MeMe are known
compounds, whereas the synthesis of 5-Ar and 5-EtEs is
II. Synthesis. 1. AD and BC Halves. The synthesis of the
reported herein.
The synthesis of 5-Ar proceeds in well practiced fashion as
4
BC halves began with the known N-tosyl-protected bromo-
2
5
26
pyrrole 1. Following a reported procedure with modifica-
tion to use cobalt carbonyl as a source of carbon monoxide,
carbonylation of 1 with a potassium monoalkyl malonate gave
the densely functionalized methyl β-ketoester 2a in 80% yield
and the ethyl β-ketoester 2b in 56% yield (Scheme 5). We were
pleased to find that this Pd-catalyzed carbonylation could be
carried out on a bromopyrrole, although more than a catalytic
shown in Scheme 6. Wittig reaction of p-bromobenzaldehyde
with (carbethoxymethylene)triphenylphosphorane afforded
cinnamate 6, which upon van Leusen reaction with TosMIC
and subsequent saponification and decarboxylation gave the 3-
arylpyrrole 7. Vilsmeier formylation of the latter gave
regioselectively the 2-formylpyrrole 8 in 77% yield. Conversion
to the 2-(2-nitroethyl) derivative 9-Ar proceeded via Henry
reaction with nitromethane and subsequent reduction with
NaBH4.
amount of Pd(OAc) (0.5 molar equiv) and a longer reaction
2
time (48 h) were required for completion of the reaction. The
remainder of the synthesis followed established procedures for
The completion of the AD half syntheses is shown in Scheme
7. The key steps involve (i) Michael addition between 2-(2-
nitroethyl)pyrroles (9-Ar, 9-EtEs ) and mesityl oxide to form
the nitrohexanone−pyrroles (10-Ar, 10-EtEs); (ii) reductive
ring closure to give the 1-methyldihydrodipyrrins (11-Ar, 11-
25
dihydrodipyrrins lacking the β-ketoester. Cleavage of the tosyl
group by refluxing in THF containing TBAF gave the free
pyrrole 3a or 3b in 70% or 64% yield, respectively. Each of the
latter was treated with NaOMe followed by a buffered
4
aqueous−organic solution of TiCl at room temperature for
EtEs); and (iii) SeO oxidation to convert the 1-methyl group
to the 1-formyl group and thereby afford the desired
dihydrodipyrrin−carboxaldehydes (5-Ar, 5-EtEs). Compounds
3
2
1
6 h to afford BC half 4a or 4b in 45% or 36% yield. Both BC
halves were readily prepared in 200 mg quantities.
D
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Scheme 5. Preparation of BC Halves
Scheme 6. Precursors of an AD Half
5
-Ar and 5-EtEs exhibit absorption spectra (λabs in CH Cl =
2 2
4
70, 451 nm, respectively) similar to those of the known
5
dihydrodipyrrin−carboxaldehydes 5-Ar and 5-T. The dihy-
drodipyrrin−carboxaldehydes generally are unstable to acidic
conditions and should be prepared immediately prior to use.
2. Conditions for Bacteriochlorin Formation. The for-
mation of the bacteriochlorin entails a two-step approach as
illustrated for the dihydrodipyrrins 5-T and 4a in Scheme 8.
For the first (intermolecular) step, Knoevenagel condensation
of the two dihydrodipyrrins, a catalytic amount of piperidine
and acetic acid (1:1) in CH Cl containing molecular sieves (3
2
2
Å powder) at room temperature for 20 h was found to produce
the target hydrobilin 12-T in 61% yield. The conditions are
quite mild, with a near-neutral catalyst combination (see the
Experimental Section) and modest concentrations (4a, 41 mM;
Chart 2. Target AD Halves
5
-T, 48 mM). Both the α-unsubstituted pyrrole and the acetal
group survived the reaction conditions. The linear intermediate
2-T was obtained following chromatography as a dark red oil
1
1
and exhibits the absorption spectrum shown in Figure 1. H
NMR spectroscopy of 12-T gave two peaks (δ 7.65 and 7.39
ppm) characteristic of the α-olefinic proton and the α-pyrrolic
proton. We know of no other molecules resembling 12-T for
spectroscopic comparisons; perhaps the closest would be a 10-
oxobiladiene-ac, yet 12-T is a vinylogous relative and also
contains two pyrroline rings.
27
For the second (intramolecular) step, the double ring-closure
process of the hydrobilin intermediate, the requirement for acid
catalysis engendered several considerations: (1) Frontier and
co-workers found that Sc(OTf) , In(OTf) , and Hf(OTf) are
3
3
4
22
more effective catalysts in the Nazarov cyclization. (2) Our
previous studies on the self-condensation of dihydrodipyrrin−
acetals identified Lewis acids suitable for the condensation
E
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Scheme 7. Synthesis of AD Halves
Scheme 8. De Novo Route to Bacteriopheophytin Analogues
3
between pyrrole and acetal units (e.g., BF ·OEt in CH CN,
3
2
3
4
TMSOTf/DTBP (2,6-di-tert-butylpyridine) in CH Cl ). (3)
2
2
Yb(OTf) and Sc(OTf) were especially efficient in catalyzing
3
3
pyrrole−acetal condensations, although tetradehydrocorrin-
type macrocycles were obtained rather than bacteriochlor-
1
6,28
ins.
Six acids were examined for the double ring-closure process
of 12-T (Table 1, entries 1−6). The reaction was conducted
with 0.2 mM 12-T and 2 mM acid with the indicated solvent or
temperature. The reactions were followed by UV−vis
absorption spectroscopy and typically were complete in 20 h.
The yield was calculated using the measured molar absorption
4
−1
−1
coefficient for BC-T of 5.0 × 10 M cm at the Q band (λ
y
Qy
=
722 nm in toluene). Among the acids examined, Hf(OTf)4
(
entry 1), TMSOTf/DTBP (entry 2), or BF ·OEt (entry 3),
3
2
Figure 1. Absorption spectrum of 12-T in CH Cl at room
temperature. The peak absorption in the visible region is at ∼505 nm.
2
2
which are all effective catalysts in the de novo synthesis
strategy, did not afford a peak characteristic of bacterio-
chlorins. On the other hand, Sc(OTf) and Yb(OTf) gave BC-
3
,4
3
3
T in 10% yield (entry 4) and 14% yield (entry 5), respectively.
All of the condensations were carried out in dilute solution
(0.2 mM of 12-T) to avoid intermolecular side reactions.
Reactions at a higher concentration (10 mM) led to only a
trace amount of an unknown bacteriochlorin (λQy = 743 nm in
toluene).
With In(OTf) , the corresponding indium bacteriochlorin (λQy
3
=
746 nm in toluene) was produced instead of the free base
bacteriochlorin (entry 6). Indium-chelated bacteriochlorins
lacking the isocyclic ring) have been formed previously upon
indium catalysis of the self-condensation of a dihydrodipyrrin−
(
The effect of temperature and solvent on bacteriochlorin
2
9
acetal.
formation was examined with Yb(OTf) as catalyst. The yield
3
F
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Table 1. Conditions for Bacteriochlorin (BC-T) Formation
from 12-T
by chromatography. To our delight, the yield of isolated
bacteriochlorin BC-T reached 56% (9.5 mg). Other hydrobilins
of type 12 were prepared by reaction with various AD halves
and BC half 4a or 4b in the same manner as for 12-T (Table
a
b
entry
Lewis acid
Hf(OTf)4
solvent
temp (°C)
yield (%)
c
1
2
3
4
5
6
7
8
9
DCE
50
20
20
50
50
50
20
35
65
80
80
80
80
40
0
2
). BC halves 4a and 4b differ only in the nature of the
c
TMSOTf/DTBP
CH Cl
0
2
2
carboalkoxy substituent (methyl, ethyl). The Knoevenagel
reaction was carried out with 1−1.5 equiv of the dihydrodi-
pyrrin−carboxaldehyde (AD half, 5) relative to the BC half (4a,
BF ·OEt2
CH CN
d
9.6
14
3
3
Sc(OTf)3
Yb(OTf)3
In(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
4b), whereupon the hydrobilins (12) were obtained in yields
e
7.6
ranging from 57−71%.
13
14
16
20
With the hydrobilins 12 in hand, conversion to the
bacteriochlorins was pursued by application of the refined
reaction conditions. First, the reaction conditions are
compatible with a bromoaryl substituent to give BC-Ar (61%
yield, entry 1). Second, a bacteriochlorin (BC-MeMe) with two
electron-donating groups was obtained in 37% yield. In
addition to the pyrrole−acetal condensation and Nazarov
cyclization, cleavage of the tert-butyl ester occurred in this
process, albeit with a lower overall yield compared with the
other examples. The presence of the tert-butyl ester was
essential to stabilize the very electron-rich dihydrodipyrrin
10
11
12
13
14
c
CH NO
0
3
2
toluene
5.6
46
CH CN
3
CH Cl
13
2
2
a
b
DCE = 1,2-dichloroethane. Yields were determined on the basis of
c
the absorption spectrum. No absorption peak was dectected >700
nm. The desired bacteriochlorin (λ = 722 nm) was not detected. A
d
Qy
trace amount of unknown bacteriochlorin (λ = 750 nm) was
Qy
e
5
observed with a yield <2%. Yield of the corresponding indium
unit. Third, a bacteriochlorin (BC-EtEs) with an electron-
bacteriochlorin.
withdrawing group at the β-pyrrole position (−CO Et) was
2
prepared in good yield (57%). Finally, starting with BC half 4b,
2
a bacteriochlorin with a 13 -carbethoxy group (BC-Ar/Et,
of bacteriochlorin in 1,2-dichloroethane increased with reaction
temperature (20−80 °C, entries 7−10). When the temperature
was maintained at 80 °C, no bacteriochlorin was obtained in
nitromethane (entry 11), while the yield was very low in
toluene (5.6%, entry 12). The reaction proceeded efficiently in
acetonitrile at 80 °C (46%, entry 13) and moderately well in
dichloromethane at 40 °C (13%, entry 14).
Frontier and co-workers identified LiClO as an effective
catalyst for the Nazarov cyclization. Here, reaction in the
presence of 10 equiv of LiClO did not affect the yield, whereas
2
where the “/Et” designates the 13 -ester substituent) was
obtained, indicating the possibility of more elaborate
modification at this site of the macrocycle.
III. Characterization. 1. Structures. The dihydrodipyrrins
typically were purified by silica gel chromatography. While the
isolated dihydrodipyrrins examined herein are relatively stable,
limiting the duration of exposure to silica gel was important.
The dihydrodipyrrins obtained in this manner were charac-
22
4
1
13
terized (by TLC, H and C NMR spectroscopy, and accurate-
mass ESI-MS) and used successfully in bacteriochlorin
formation.
4
excess LiClO (100 equiv) led to a lower yield. In summary, the
4
reaction of 12-T in dilute solution with Yb(OTf)3 in
acetonitrile at 80 °C gave the best results for bacteriochlorin
formation.
1
All new bacteriochlorins were characterized by H NMR and
C NMR spectroscopy, accurate-mass ESI-MS, and static
13
3
. Scope of Reaction. The reaction using the refined
absorption and fluorescence spectroscopy. A single-crystal X-
ray structure was obtained for bacteriochlorin BC-Ar (see the
Supporting Information). In general, the H NMR spectra of
catalysis conditions was carried out with 20 mg of the
hydrobilin 12-T, and the resulting bacteriochlorin was purified
1
Table 2. Investigation of the Scope of Bacteriochlorin Formation
compounds
substituents
R3
yield (%)
entry
5
4
12
12-T
BC
BC-T
R2
p-tolyl
X
R
12
BC
1
2
3
4
5
5-T
4a
4a
4a
4a
4b
H
H
H
Me
Me
Me
Me
Et
61
68
71
61
57
56
61
37
57
48
5-Ar
12-Ar
BC-Ar
p-Br-phenyl
Me
H
t
2
5-MeMe
5-EtEs
5-Ar
12-MeMe
12-EtEs
12-Ar/Et
BC-MeMe
BC-EtEs
BC-Ar/Et
Me
CO Bu
Et
CO Et
H
H
2
p-Br-phenyl
H
G
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the bacteriochlorins were complex due to the nonequivalent A,
B, C, and D rings as well as the presence of the additional E
1
ring. The structure and H NMR spectrum of BC-MeMe are
illustrative: (1) The four distinct protons around the perimeter
of the bacteriochlorin (meso-protons at the 5-, 10-, and 20-
positions and one β-pyrrolic proton) give rise to four singlets in
2
the region δ 7.62−7.97 ppm. (2) The proton at the 13 -
position resonates as a singlet at δ 5.64 ppm, which is
2
30
comparable to that of the 13 -H in Bpheo a (δ 6.08 ppm ).
(
2
3) The presence of a stereocenter at the 13 -position causes
the pyrroline CH protons (ring D, position 17: δ 3.62−3.74
2
ppm) flanking the isocyclic ring (E) to be split into an AB
pattern, while the pyrroline CH2 protons distal to the
stereocenter resonate as an apparent singlet (ring B, position
7: δ 3.97 ppm). (4) The two methyl groups of a gem-dimethyl
unit are similarly inequivalent, and those at the 18-position
resonate as two singlets (1.72 and 1.80 ppm). (5) The N−H
protons give rise to two broad upfield peaks (1.16 and 1.62
ppm). No peaks upfield of 0 ppm were observed.
1
Comparing the H NMR spectra of BC-MeMe, BC-EtEs,
3
0
and Bpheo a yields the following observations: (1) The
chemical shifts of the peripheral protons of BC-MeMe (with
two electron-donating groups) are in the range of 7.63−7.97
ppm, while those of BC-EtEs (with one electron-withdrawing
group) are in the range of 8.20−9.16 ppm; the latter are more
similar to those of Bpheo a (8.39−8.96 ppm). (2) The N−H
protons in BC-EtEs resonate at −0.07 and 1.59 ppm, compared
to those in BC-MeMe (δ1.16, 1.62 ppm) and Bpheo a (δ −
3
0
0.99, 0.44 ppm).
2
. Absorption and Fluorescence Spectra. Figure 2
shows the absorption spectra and fluorescence emission spectra
of four synthetic, isocyclic ring-containing bacteriochlorins
BC-MeMe, BC-T, BC-Ar, and BC-EtEs) in toluene. The
spectral data shown in Table 3 include the position and the
relative intensity of the characteristic absorption bands, the full-
width at half-maximum (fwhm) value of the long-wavelength
absorption band (Q ), and the ratio of the intensity of the Q to
B band (I /I ratio). For comparison, the table also includes
spectral data for BPheo a and the benchmark Me -BC. The
Figure 2. Absorption (solid line) and fluorescence spectra (dashed
line; λex at the Q band near 520 nm) in toluene at room temperature
x
of bacteriochlorins (normalized at the Q bands). The colors in the
(
y
graph are as follows: BC-MeMe (black), BC-T (red), BC-Ar (blue),
and BC-EtEs (purple).
y
y
The fluorescence emission spectra of the four synthetic
bacteriochlorins (BC-MeMe, BC-T, BC-Ar, and BC-EtEs) in
toluene at room temperature are shown in Figure 2. In each
y
Qy By
31
5
4
4
−1
molar absorption coefficient of BC-T in toluene (5.0 × 10 M
case, the Q (0,0) emission band is shifted 6−15 nm to longer
y
−
1
cm , determined using ∼6 mg of BC-T) is close to that
wavelength than the Q (0,0) absorption band, to be compared
y
−1
−1
reported for BPheo a (42−49 mM cm in acetone−
with a Stokes shift for Me -BC of ∼2 nm. The comparatively
4
−1
−1
32
methanol (7:2, v/v) and 63−73 mM cm in ether). The
spectrum of BC-Ar/Et matches almost identically that of BC-
Ar and is not shown in Figure 2; for comparison, the spectra of
large Stokes shift of the isocyclic ring-containing bacterio-
chlorins indicates more substantial structural changes or solvent
interactions upon photoexcitation. The fwhm of the Q (0,0)
y
BC-Ar/Et, Me -BC, and Bpheo a are provided in the
Supporting Information.
4
emission band is in the range of 26−32 nm.
The spectrum of each bacteriochlorin contains three main
DISCUSSION
■
absorption bands termed the B band (a mixture of B and B
x
y
The development of new routes to bacteriochlorins remains a
pressing need given the importance of such molecules in
harvesting NIR light. The route described herein constitutes a
new approach for macrocycle construction that concomitantly
forms the isocyclic ring while maintaining a gem-dimethyl group
in each pyrroline ring. The gem-dimethyl motif secures the
macrocycle from adventitious dehydrogenation processes that
are likely in an aerobic environment. In this section, we first
compare methods for installation of the isocyclic ring. We then
describe features (including stereochemistry) of the Nazarov
cyclization in the context of the new route to bacteriochlorins,
followed by a side-by-side evaluation with a prior de novo route
to bacteriochlorins from dihydrodipyrrin halves. The final
section sketches synthetic possibilities of the new route.
2
transitions), Q band, and Q band. The spectral features
x
y
resemble those of Bpheo a but differ to some degree from
those of bacteriochlorins lacking the isocyclic ring. In
comparison with the 2,3,12,13-tetramethylbacteriochlorin
Me -BC (Chart 3), which lacks the isocyclic ring, the following
4
features are noteworthy: (1) The I /I ratio is much lower
Qy By
(
0.38−0.62 vs 0.97), indicating a relatively lower intensity of
the Q band. (2) The I /I ratio is much lower (1.1−
2
y
Qy(0,0) Qx(0,0)
.0 vs 5.3), indicating a relatively greater intensity of the Qx
band. (3) The IQx(0,0)/IQx(1,0) ratio also is greater (3.1−4.1 vs
1
3
.9). (4) The fwhm of the Q (0,0) band is in the range of 27−
y
3 nm, which is slightly broader than reported for
31
bacteriochlorins lacking the isocyclic ring (11−25 nm).
H
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The Journal of Organic Chemistry
Article
a
Table 3. Spectral Characteristics of Bacteriochlorins
b
absorption in nm (relative intensity )
flu
fwhm (nm)
intensity ratios
c
compd
BC-T
B(0,0)
356
Q (1,0)
Q (0,0)
Q (1,0) Q (0,0) Q (0,0) in nm Q (0,0) abs Q em IQy/IB IQx(0,0)/ IQx(1,0) IQy(0,0)/ IQx(0,0)
x
x
y
y
y
y
y
489
(0.18)
490
520
(0.62)
521
660
721
736
737
707
751
737
768
723
29
26
0.55
0.62
0.38
0.58
0.62
0.63
0.97
3.4
3.8
3.1
3.8
4.1
4.6
1.9
1.6
1.9
1.1
1.9
1.9
2.0
5.3
(1.8)
(0.31)
664
(1.0)
727
BC-Ar
356
27
29
31
32
28
27
(1.6)
(0.14)
480
(0.54)
511
(0.25)
640
(1.0)
696
BC-MeMe
BC-EtEs
BC-Ar/Et
351
29
(2.6)
(0.28)
501
(0.87)
533
(0.45)
680
(1.0)
745
357
33
(1.7)
(0.14)
490
(0.53)
521
(0.21)
665
(1.0)
728
357
28
(1.6)
(0.13)
492
(0.53)
524
(0.24)
681
(1.0)
749
d
e
e
BPheo a
356
31
(1.6)
(0.11)
462
(0.51)
490
(0.18)
685
(1.0)
721
f
Me -BC
346, 374
11.9
15.5
4
(1.0, 1.1)
(0.10)
(0.19)
(0.10)
(1.0)
a
b
c
Obtained in toluene at room temperature. Relative intensity of the indicated peak versus that of the Q (0,0) band. Mixture of the B (0,0) and
y
x
d
e
f
B (0,0) absorption bands. Absorption data (in diethyl ether) from ref 33. Fluorescence data (in toluene) from ref 31. Data from ref 5.
y
Chart 3. Benchmark Bacteriochlorin
lated α-acylpyrrole. In the same year, Frontier and co-workers
reported examples of both α-(propenoyl)pyrroles and β-
2
2
(
propenoyl)pyrroles without any N-protection (eq 1).
While >50 examples of Nazarov cyclization have since been
48−57
reported with α-(propenoyl)pyrroles,
to our knowledge
there are only three prior examples of analogous β-substituted
22−24
pyrroles.
Moreover, regardless of pyrrole substitution
position, most such examples stem from model studies rather
than as integral to total syntheses. Examples of the latter
49,50,52,54,56
include synthesis of (±)-roseophilin.
The Nazarov reaction process also can be regarded as an
intramolecular Michael addition (5-endo-trig) of the pyrrole
with the appended propenoyl substituent. Intermolecular
examples of such pyrrole C-alkylations date to as early as
Installation of the Isocyclic Ring. A handful of
approaches for installation of a fifth ring spanning positions
58
1
3 and 15 in tetrapyrrole macrocycles has been developed over
the years (Scheme 9). Fischer dehydrated (hydroxymethyl-
1
951 and were typically carried out with either activated
carbonyl)porphyrin A in concd H SO to give the porphyrin
2
4
59−66
34
reactants or somewhat forcing conditions.
Research in the
bearing the isocyclic ring (B). Lash condensed dipyrro-
1
2
past 15 years has shifted to unactivated reactants and
implementation with mild Lewis acid catalysts and/or
enantioselective catalysts (for a comprehensive set of
references, see the Supporting Information; for a partial review,
see ref 67).
methane C and dipyrromethane C bearing an annulated
35
1
oxocyclopentanyl ring to form D (which lacks the 13 -oxo
group). Both B and D are porphyrins. Fischer also converted
3
6
chlorin e trimethyl ester (E) via Dieckmann cyclization to
6
37,38
methyl pheophorbide a (F),
a chlorin degradation product
of chlorophyll a. Smith extended Kenner’s thallium-photo-
The Nazarov cyclization is regarded to proceed via a 4π-
electrocyclization of a pentadienyl cation derived from a
3
9−42
chemical route
for conversion of the β-ketoester-
43
20
substituted chlorin G to methyl pheophorbide a (F).
A
divinylketone species; here, the pyrrole moiety provides one
more recent method entails 15-bromination and Pd-mediated
α-arylation (Scheme 2), which has been applied to gem-
dimethyl stabilized chlorins and bacteriochlorins but requires
bromination of the macrocycle and lacks provisions for
of the “vinyl” units. The resulting conrotatory ring closure
creates two stereocenters. Here, one of the stereocenters is lost
upon elimination, leading to the aromatic, 18π-electron
bacteriochlorin chromophore. The remaining stereocenter is
2
44−47
2
incorporation of the 13 -carboalkoxy group.
To our
at the 13 -position, whereupon the resulting bacteriochlorin is
2
knowledge, only the method shown in Scheme 2 has been
applied with bacteriochlorins. The formation of the isocyclic
ring concomitantly with macrocycle construction described
herein affords considerable simplicity, and does so while
enabling distinct substituents in the two halves of the
bacteriochlorin.
racemic. The carboalkoxy group at the 13 -position in
(bacterio)chlorophylls is susceptible to epimerization given
1
3,14
the presence of the β-keto group.
While the trans-
2
configuration (13 - relative to the 17-position) is typically
more stable, macrocycles with the cis-configuration of the two
groups have been considered as possible minority pigments in
selected photosynthetic systems. The mole fraction of the cis-
isomer was found to range from 0.12−0.25 over a set of eight
chlorophylls, bacteriochlorophylls, and analogues. Accord-
ingly, the natural tetrapyrroles bearing an isocyclic ring often
exist as diastereomeric mixtures owing to unavoidable
68
Features of the Nazarov Cyclization. Nazarov cyclization
20
is a classical synthetic method for producing a cyclic ketone.
While known for some time with a variety of substrates, in
006, Song, Knight, and Whatton reported the first example
69
2
21
involving a pyrrole. The reaction was carried out with an N-
tosylpyrrole and a propenoic acid in the presence of
trifluoroacetic anhydride, affording the corresponding annu-
2
epimerization of the 13 -carbomethoxy group. Thus, while
the synthetic bacteriochlorins obtained herein are racemic, even
I
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The Journal of Organic Chemistry
Article
Scheme 9. Routes for Installation of the Isocyclic Ring
bromination of the bacteriochlorin is not required. Hence,
halogens can be installed on the AD half (e.g., 5-Ar) for
subsequent exploitation following formation of the macrocycle
(
e.g., BC-Ar, BC-Ar/Et).
A direct comparison of two routes for constructing the
bacteriochlorin macrocycle is provided in Scheme 10. The self-
Scheme 10. Comparison of Bacteriochlorin Syntheses
an asymmetric synthesis is likely to yield products that
spontaneously racemize owing to the intrinsic features of the
β-ketoester.
Comparison of Routes. The Eastern−Western (or
Northern−Southern) route to bacteriochlorins is concise, but
installation of the isocyclic ring requires 15-bromination
followed by Pd-mediated α-arylation. Even then, the isocyclic
condensation of two dihydrodipyrrin−acetal molecules (II-
acetal) results in successive elimination of two molecules of
methanol, whereupon a 5,15-dihydro-5,15-dimethoxybacterio-
chlorin (X) is obtained. Elimination of a third molecule of
2
ring lacks the 13 -carbomethoxy group. The synthesis described
70
herein entails preparation of BC and AD components, joining
of these two halves to form a hydrobilin intermediate under
conditions wherein neither half undergoes self-condensation
leading to a symmetrical bacteriochlorin, and the one-flask
double ring-closure process of the hydrobilin to form the
bacteriochlorin macrocycle along with the isocyclic ring (E). In
this manner, a Pd-mediated coupling is still required (attach-
ment of the β-ketoester to the pyrrole of the BC half), but
methanol affords the 5-methoxybacteriochlorin (XI). The
presence of the 5-methoxy group provides a convenient
71
directive entity for 15-bromination, but otherwise may be
undesired. By contrast, for purposes of comparison the reaction
of AD (VII) and BC (VIII) halves can be envisaged as
proceeding via Nazarov cyclization following the Knoevenagel
condensation (XII). Subsequent cyclization and elimination of
one molecule of methanol affords the 5,15-dihydro-5-
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The Journal of Organic Chemistry
Article
methoxybacteriochlorin (XIII). Elimination of the second
molecule of methanol aromatizes the macrocycle to give
bacteriochlorin V. The difference in 5-position substitution
patterns of V versus XI originates early in the reaction process:
two carbon−carbon bonds are formed upon Knoevenagel
condensation and Nazarov cyclization (giving XII) versus only
one upon electrophilic aromatic substitution (giving IX). Side-
by-side comparison of intermediates X (5,15-dimethoxy) and
XIII (5-methoxy) illustrates that while aromatization is likely
similar in the two syntheses, requisite elimination of only one
molecule of methanol leaves one methoxy group remaining in
XI, whereas none is left in the isocyclic ring (E)-containing
bacteriochlorin V.
Chart 4. Chlorophyll Catabolite
synthetic studies, and hence knowledge of reactivity and
photochemical features depends on isolation of species along
the slippery slope of enzymatic catabolism. Whether analogous
phyllobilins derive from anoxygenic photosynthetic bacteria
remains to be determined. For both types of hydroporphyrins,
the synthesis of putative intermediates could prove vital.
Synthetic Attributes. There are now four distinct routes
for de novo construction of the bacteriochlorin chromophore
(
excluding derivatization of porphyrins or chlorins). The routes
include (1) the Kishi synthesis of tolyporphin A diacetate and
9
−11
analogues;
(2) the Eastern−Western synthesis shown in
7
Scheme 1; (3) a Northern−Southern route; and (4) the
directed AD + BC route described herein. Only the latter
enables simultaneous construction of the macrocycle and the
isocyclic ring. The utility of a general route to bacteriochlorins
with distinct substituents in the various A−D rings is outlined
in the Introduction. Because the present route enables such
capabilities yet also constructs the isocyclic ring (E), further
applications and extensions can be envisaged, of which five are
described here.
EXPERIMENTAL SECTION
■
General Methods. H NMR and 13C NMR spectra were collected
1
at room temperature in CDCl . Absorption spectra were obtained in
3
toluene at room temperature unless noted otherwise. Electrospray
ionization mass spectrometry (ESI-MS) data, obtained via ion trap
mass analyzer, are reported for the molecular ion or protonated
molecular ion. THF used in all reactions was freshly distilled from Na/
benzophenone ketyl. Molecular sieves (3 Å, powder) were heated
(
>100 °C) overnight prior to use. All commercially available
compounds were used as received. Noncommercially available
2
5
5
5
4
First, the preparation of bacteriochlorins with progressive
extent of substitution ranging from the fully unsubstituted to
the fully decorated analogue of BPheo a is essential for
understanding the molecular origins of bacteriochlorophyll
compounds including 1, 5-T, 5-MeMe, and 9-EtEs were prepared
as described in the literature. The dihydrodipyrrin−carboxaldehyde
and dihydrodipyrrin−acetal compounds were chromatographed by
gravity flow with short columns (∼12 cm in length) to limit duration
of exposure to silica gel.
5
photophysics. The present route appears ideal for preparing
6
-[4-(3-Methoxy-3-oxopropanoyl)-N-tosylpyrrol-2-yl]-1,1-di-
methoxy-4,4-dimethyl-5-nitrohexan-2-one (2a). A mixture of 1
1.34 g, 2.50 mmol), methylpotassium malonate (585 mg, 3.80 mmol),
more elaborate analogues along this progression.
Second, the Nazarov cyclization is compatible with other
(
2
0
heterocycles; hence, core-modified ring-C analogues should
be accessible.
Xantphos (725 mg, 1.30 mmol), MgCl (357 mg, 3.80 mmol), and
2
imidazole (330 mg, 5.00 mmol) was placed in a 50 mL Schlenk flask,
Third, the new route might enable synthetic access to the
natural macrocycles themselves. The synthesis of chlorophylls
would require one enantiopure dipyrrin and one dipyrro-
methane rather than two dihydrodipyrrins yet would offer a
fundamental alternative to the route devised by Woodward and
which was charged with argon. THF (25.0 mL) was added followed by
Et N (520 μL, 3.80 mmol). The mixture was degassed by three
3
freeze−pump−thaw cycles. Then Pd(OAc) (280 mg, 1.30 mmol) and
2
Co (CO) (430 mg, 1.30 mmol) were added. The flask was sealed
2
8
immediately and heated at 65 °C for 48 h, with reaction progress
monitored by TLC analysis. If the reaction was not complete,
Pd(OAc) (140 mg, 0.65 mmol) and Co (CO) (215 mg, 0.65 mmol)
1
7−19
co-workers.
The synthesis of bacteriochlorophylls, which
2
2
8
has never been reported, would require two enantiopure
dihydrodipyrrins.
Fourth, the isocyclic ring has been the site of extensive
derivatization chemistry over the years, including reactions at
were added, and the reaction was continued for another 24 h. The
reaction mixture was diluted with ethyl acetate and filtered through a
Celite pad. The filtrate was washed with brine and water, dried
(Na SO ), concentrated and chromatographed (silica, ethyl acetate) to
2
4
1
2
2
1
each of the sites (13 oxo, 13 methylene, 13 -carboalkoxy) as
well as allomerization and splitting of the ring (by scission of
give a light-yellow solid (1.10 g, 80%): mp 138−140 °C; H NMR
(
300 MHz) δ 1.14 (s, 3H), 1.23 (s, 3H), 2.45 (s, 3H), 2.57−2.73 (AB,
2
2
1
2
13,14
J = 18.6 Hz, 2H), 3.11−3.17 (ABX, J = 16.0 Hz, 1H), 3.35−3.45
the 13 −13 C−C bond).
chlorophylls, analogous chemistry with bacteriochlorophylls has
been less investigated owing to the lability of the natural
macrocycles. The stability of the macrocycles prepared herein
should provide an entree into diverse derivatives by reactions in
the isocyclic ring.
While widely exploited with
2 3
(
(
6
ABX, J = 16.0 Hz, J = 12.3 Hz, 1H), 3.42 (s, 6H), 3.73 (s, 3H), 3.75
2
3
s, 2H), 4.37 (s, 1H), 5.21−5.26 (ABX, J = 12.0 Hz, J = 2.1 Hz, 1H),
.42 (d, J = 1.5 Hz, 1H), 7.37−7.40 (d, J = 8.2 Hz, 2H), 7.70−7.73 (d,
7
2
13
J = 8.2 Hz, 2H), 7.93 (d, J = 1.8 Hz, 1H); C NMR (75 MHz) δ 21.8,
́
2
3.8, 24.0, 26.3, 36.4, 44.5, 46.6, 52.5, 55.1, 92.8, 104.7, 112.5, 126.1,
127.1, 128.0, 130.7, 130.9, 134.8, 146.5, 167.5, 186.5, 203.1; ESI-MS
m/z [M + H] calcd for C H N O S 553.1850, found 553.1846.
+
Finally, very little is known about the in vivo degradation of
bacteriochlorophylls, in contrast with the results from the
intensive study of the enzymatic degradation of chlorophylls in
25
33
2
10
6-[4-(3-Ethoxy-3-oxopropanoyl)-N-tosylpyrrol-2-yl]-1,1-di-
methoxy-4,4-dimethyl-5-nitrohexan-2-one (2b). A mixture of 1
(
267 mg, 0.500 mmol), ethylpotassium malonate (128 mg, 0.750
senescent plants. Krau
characterized a variety of “phyllobilin” species such as the red
chlorophyll catabolite (RCC) shown in Chart 4.
̈
tler and co-workers have identified and
mmol), Pd(OAc) (56.0 mg, 0.250 mmol), Xantphos (145 mg, 0.250
2
mmol), MgCl (71.4 mg, 0.750 mmol), and imidazole (66.0 mg, 1.00
73−75
2
The
mmol) was placed in a 10 mL Schlenk tube, which was charged with
structure of the phyllobilins closely resembles that of the
Nazarov intermediate XII shown in Scheme 9. To our
knowledge, phyllobilins have not been the target of reported
argon. THF (4.0 mL) was added followed by Et N (104 μL, 0.750
3
mmol) and Co (CO) (86.0 mg, 0.250 mmol). The tube was sealed
2
8
immediately and heated at 65 °C for 48 h. The reaction mixture was
K
DOI: 10.1021/acs.joc.6b02878
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The Journal of Organic Chemistry
Article
diluted with ethyl acetate and filtered through a Celite pad. The filtrate
1H), 7.50 (m, 1H), 11.20 (br, 1H); 13C NMR (75 MHz) δ 29.0, 40.3,
was washed with brine and water, dried (Na SO ), concentrated, and
46.8, 48.4, 52.4, 54.7, 102.5, 106.4, 108.4, 125.1, 125.6, 132.7, 162.2,
2
4
+
chromatographed (silica, ethyl acetate) to give a light-yellow oil (160
168.6, 176.2, 187.1; ESI-MS m/z [M + H] calcd for C H N O
1
8
25
2
5
1
mg, 56%): H NMR (400 MHz) δ 1.14 (s, 3H), 1.23 (s, 3H), 1.26 (t, J
349.1758, found 349.1758.
2
=
3
7.2 Hz, 3H), 2.46 (s, 3H), 2.57−2.72 (AB, J = 18.8 Hz, 2H), 3.12−
8-(3-Ethoxy-3-oxopropanoyl)-2,3-dihydro-1-(1,1-dimethox-
2
2
3
.17 (ABX, J = 16.4 Hz, 1H), 3.35−3.40 (ABX, J = 16.4 Hz, J = 12.4
ymethyl)-3,3-dimethyldipyrrin (4b). Following a standard proce-
4
Hz, 1H), 3.42 (s, 3H), 3.43 (s, 3H), 3.72 (d, J = 0.8 Hz, 2H), 4.16−
dure, a solution of 3b (75 mg, 0.18 mmol) in THF (1.8 mL) and
2
4
.22 (q, J = 7.2 Hz, 2H), 4.36 (s, 1H), 5.21−5.24 (ABX, J = 12.4 Hz,
MeOH (50. μL) was treated with NaOCH (39 mg, 0.73 mmol) in a
3
3
J = 1.6 Hz, 1H), 6.42 (d, J = 2.0 Hz, 1H), 7.37−7.40 (d, J = 8.8 Hz,
20 mL flask under argon at 0 °C. The mixture was stirred at 0 °C for
13
2
H), 7.69−7.72 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 1.6 Hz, 1H);
C
45 min. In a 100 mL flask, NH OAc (1.42 g, 18.2 mmol) in distilled
4
NMR (75 MHz) δ 14.3, 22.0, 24.0, 24.3, 26.5, 36.6, 44.7, 47.1, 55.35,
THF (18 mL) was bubbled with argon for 15 min before a solution of
5
1
5.38, 61.8, 93.1, 104.9, 112.7, 126.3, 127.3, 128.1, 130.8, 131.1, 135.0,
TiCl (12 wt % in 2 N HCl, 1.8 mL, 1.46 mmol) was added. The
mixture was stirred for another 15 min. Then the mixture in the first
3
46.6, 167.3, 168.8, 203.3; ESI-MS m/z [M + H]+ calcd for
C H N O S 567.2003, found 567.2007.
flask was transferred via cannula to the buffered TiCl solution in the
26
35
2
10
3
6
-[4-(3-Methoxy-3-oxopropanoyl)pyrrol-2-yl]-1,1-dime-
second flask. The resulting mixture was stirred at room temperature
under argon for 20 h. The reaction mixture was poured into saturated
aqueous NaHCO3 solution and extracted with ethyl acetate. The
organic extract was combined, washed (brine/water), dried (Na SO ),
thoxy-4,4-dimethyl-5-nitrohexan-2-one (3a). Following a stand-
25
ard procedure, a sample of 2a (1.10 g, 2.00 mmol) was treated with
TBAF (1.0 M in THF, 2.0 mL, 2.0 mmol) in a 20 mL flask and heated
to 65 °C for 1 h. The mixture was allowed to cool to room
temperature, quenched by the addition of saturated aqueous NaHCO3
solution, and then extracted with ethyl acetate. The organic extract was
washed (brine and water), dried (Na SO ), concentrated, and
2
4
concentrated, and chromatographed [silica, CH Cl , then CH Cl /
2
2
2
2
1
ethyl acetate (1:1)] to give a yellow oil (24 mg, 36%): H NMR (300
MHz) δ 1.22 (s, 6H), 1.26 (t, J = 7.2 Hz, 3H), 2.64 (s, 2H), 3.46 (s,
2
4
6H), 3.77 (s, 2H), 4.16−4.23 (q, J = 7.2 Hz, 2H), 5.03 (s, 1H), 5.84 (s,
chromatographed [silica, hexanes/ethyl acetate (1:1)] to give a yellow
oil (566 mg, 70%): H NMR (300 MHz) δ 1.13 (s, 3H), 1.21 (s, 3H),
13
1
H), 6.53 (m, 1H), 7.50 (m, 1H), 11.18 (br, 1H); C NMR (75
1
MHz) δ 14.4, 29.2, 40.4, 47.3, 48.6, 54.8, 61.5, 102.6, 106.6, 108.6,
2
2
3
2
2
3
(
1
.57−2.76 (AB, J = 18.6 Hz, 2H), 2.99−3.05 (ABX, J = 15.6 Hz, J =
25.3, 125.6, 132.8, 162.2, 168.3, 176.3, 187.4; ESI-MS m/z [M + H]+
1
2
3
.4 Hz, 1H), 3.29−3.37 (ABX, J = 15.6 Hz, J = 12.0 Hz, 1H), 3.43 (s,
H), 3.43 (s, 3H), 3.72 (s, 3H), 3.75 (s, 2H), 4.37 (s, 1H), 5.15−5.20
calcd for C H N O 363.1916, found 363.1915.
19
27
2
5
7
-(4-Bromophenyl)-1-formyl-2,3-dihydro-3,3-dimethyldi-
2
3
5
ABX, J = 11.7 Hz, J = 2.7 Hz, 1H), 6.40 (m, 1H), 7.33−7.35 (m,
pyrrin (5-Ar). Following a standard procedure, a solution of 11-Ar
H), 9.14 (br, 1H); 13C NMR (100 MHz) δ 24.2, 24.3, 26.5, 36.6,
(300 mg, 0.87 mmol) in 1,4-dioxane (17.4 mL) was treated with SeO2
4
1
5.1, 46.6, 52.5, 55.3, 94.2, 104.7, 107.8, 124.8, 125.3, 128.8, 168.6,
87.3, 203.9; ESI-MS m/z [M + H] calcd for C H N O 399.1762,
(288 mg, 2.60 mmol) under argon. The progress of the reaction was
+
18
27
2
8
monitored by absorption spectroscopy. After 90 min, ethyl acetate
200 mL) was added. The organic layer was washed [aqueous
found 399.1755.
6
(
-[4-(3-Ethoxy-3-oxopropanoyl)pyrrol-2-yl]-1,1-dimethoxy-
NaHCO solution (200 mL); water/brine (2 × 200 mL)], dried,
3
4
,4-dimethyl-5-nitrohexan-2-one (3b). Following a standard
concentrated and chromatographed [silica, hexanes/ethyl acetate
25
procedure, a sample of 2b (160 mg, 0.283 mmol) was treated
with TBAF (1.0 M in THF, 0.34 mL, 0.34 mmol) in a 20 mL flask and
heated to 65 °C for 1 h. The mixture was allowed to cool to room
temperature, quenched by the addition of saturated aqueous NaHCO3
solution, and then extracted with ethyl acetate. The organic extract was
washed (brine and water), dried (Na SO ), concentrated, and
1
(
3:1)] to afford a red solid (67 mg, 22%): H NMR (400 MHz) δ
1
.22 (s, 6H), 2.72 (s, 2H), 6.29 (s, 1H), 6.33 (m, 1H), 7.00 (m, 1H),
7
.29−7.31 (d, J = 8.8 Hz, 2H), 7.53−7.55 (d, J = 8.8 Hz, 2H), 9.99 (s,
13
1
H), 10.81 (br, 1H); C NMR (100 MHz) δ 29.2, 41.2, 46.1, 109.9,
1
1
12.4, 120.4, 122.1, 127.2, 127.7, 130.4, 131.8, 135.3, 161.2, 169.3,
2
4
+
90.1; ESI-MS m/z [M + H] calcd for C H BrN O 357.0597, found
18
18
2
chromatographed [silica, hexanes/ethyl acetate (1:1), then ethyl
acetate] to give a yellow oil (75 mg, 64%): H NMR (300 MHz) δ
1
357.0592; λabs in CH Cl = 470 nm.
2 2
2
8-Carbethoxy-7-ethyl-1-formyl-2,3-dihydro-3,3-dimethyldi-
1
=
3
(
5
(
4
1
.20 (s, 3H), 1.21 (s, 3H), 1.24 (t, J = 6.9 Hz, 3H), 2.56−2.75 (AB, J
5
pyrrin (5-EtEs). Following a standard procedure, a solution of 11-
2
3
18.6 Hz, 2H), 2.98−3.04 (ABX, J = 15.3 Hz, J = 2.4 Hz, 1H),
2 3
EtEs (100 mg, 0.33 mmol) in 1,4-dioxane (6.6 mL) was treated with
.28−3.37 (ABX, J = 15.3 Hz, J = 11.7 Hz, 1H), 3.42 (s, 3H), 3.43
SeO (111 mg, 1.0 mmol) under argon. Progress of the reaction was
2
s, 3H), 3.72 (s, 2H), 4.14−4.21 (q, J = 6.9 Hz, 2H), 4.36 (s, 1H),
2
3
monitored by absorption spectroscopy. After 90 min, ethyl acetate
(100 mL) was added. The organic layer was washed with aqueous
NaHCO3 solution (100 mL) and brine (2 × 100 mL), dried,
.14−5.19 (ABX, J = 12.0 Hz, J = 2.4 Hz, 1H), 6.39 (m, 1H), 7.32
m, 1H), 9.06 (br, 1H); 13C NMR (100 MHz) δ 14.3, 24.3, 26.6, 36.7,
5.3, 46.9, 55.4, 61.6, 94.3, 104.7, 107.8, 125.1, 125.4, 129.0, 168.5,
87.9, 204.0; ESI-MS m/z [M + H] calcd for C H N O 413.1918,
+
concentrated, and chromatographed [silica, hexanes/ethyl acetate
19
29
2
8
1
(
(
3:1)] to afford a red solid (32 mg, 32%): H NMR (400 MHz) δ 1.20
t, J = 7.2 Hz, 3H), 1.27 (s, 6H), 1.36 (t, J = 6.8 Hz, 3H), 2.73 (s, 2H),
found 413.1918.
2
,3-Dihydro-1-(1,1-dimethoxymethyl)-8-(3-methoxy-3-oxo-
2
.84−2.89 (q, J = 7.2 Hz, 2H), 4.26−4.32 (q, J = 6.8 Hz, 2H), 6.18 (s,
propanoyl)-3,3-dimethyldipyrrin (4a). Following a standard
13
4
1H), 7.53 (d, J = 3.2 Hz, 1H), 9.98 (s, 1H), 10.82 (br, 1H); C NMR
100 MHz) δ 14.6, 16.5, 18.2, 29.3, 41.1, 46.1, 59.6, 111.1, 115.0+,
27.4, 128.3, 130.4, 160.7, 165.0, 169.4, 190.0; ESI-MS m/z [M + H]
calcd for C H N O 303.1703, found 303.1699; λ in CH Cl = 451
procedure, a solution of 3a (566 mg, 1.42 mmol) in THF (14.0
mL) was treated with NaOCH (307 mg, 5.68 mmol) in a 20 mL flask
under argon at 0 °C. The mixture was stirred at room temperature for
5 min. In a 250 mL flask, NH OAc (11.1 g, 142 mmol) in distilled
THF (36.0 mL) was bubbled with argon for 15 min before a solution
of TiCl (12 wt % in 2 N HCl, 14.0 mL, 11.4 mmol) was added. The
mixture was stirred for another 15 min. Then the mixture in the first
flask was transferred via cannula to the buffered TiCl solution in the
second flask. The resulting mixture was stirred for 20 h at room
temperature under argon. The reaction mixture was poured into
saturated aqueous NaHCO solution, filtered through a Celite pad
the filter cake was washed with ethyl acetate), and extracted with
ethyl acetate. The organic extract was combined, washed (brine/
water), dried (Na SO ), concentrated, and chromatographed [silica,
(
1
3
4
17 23
2
3
abs
2
2
4
nm.
Ethyl 3-(4-Bromophenyl)prop-2-enoate (6). Following a stand-
3
4
ard procedure, a solution of 4-bromobenzaldehyde (17.4 g, 94.0
mmol) and (carbethoxymethylene)triphenylphosphorane (35.8 g, 103
3
mmol) in CH
mixture was allowed to cool to room temperature and then
concentrated. The residue was diluted with Et O and filtered. The
filtrate was washed with brine, dried (Na SO ), concentrated, and
Cl (120 mL) was refluxed for 20 h. The reaction
2 2
3
2
(
2
4
chromatographed [silica, hexanes/ethyl acetate (2:1)] to give a
1
colorless oil (21.9 g, 91%): H NMR (400 MHz) δ 1.33 (t, J = 7.2
2
4
CH Cl , then CH Cl /ethyl acetate (1:1)] to give a yellow oil (223
Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.41 (d, J = 16.0 Hz, 1H), 7.37 (d, J
2
2
2
2
1
13
mg, 45%): H NMR (300 MHz) δ 1.22 (s, 6H), 2.64 (s, 2H), 3.46 (s,
H), 3.73 (s, 3H), 3.77 (s, 2H), 5.04 (s, 1H), 5.84 (s, 1H), 6.53 (m,
= 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 16.0 Hz, 1H);
C
6
NMR (100 MHz) δ 14.4, 60.7, 119.0, 124.5, 129.5, 132.2, 133.4, 143.2,
L
DOI: 10.1021/acs.joc.6b02878
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
+
2
2
1
2
66.8; ESI-MS m/z [M + H] calcd for C H BrO 255.0015, found
(m, 1H), 7.20−7.22 (d, J = 8.4 Hz, 2H), 7.49−7.52 (d, J = 8.4 Hz,
2H), 8.20 (br, 1H); 13C NMR (100 MHz) δ 24.2, 24.5, 25.2, 31.9,
37.1, 51.5, 94.4, 109.4, 118.1, 120.1, 122.5, 122.7, 130.1, 120.2, 131.7,
11
12
2
55.0011.
-(4-Bromophenyl)pyrrole (7). Following a standard procedure,
4
3
+
a suspension of 6 (21.9 g, 85.8 mmol) and TosMIC (16.7 g, 85.8
mmol) in dry ether/DMSO (2:1, 150 mL) was added dropwise to a
suspension of NaH (60% in mineral oil, 5.16 g, 129 mmol) in dry
ether (70 mL) under argon. The mixture was stirred at room
temperature for 5 h. Water (200 mL) was added. The aqueous phase
was extracted with ethyl acetate (2 × 200 mL). The organic layer was
separated, dried (Na SO ), and concentrated to a brown solid. The
131.8, 125.6, 206.9; ESI-MS m/z [M + H] calcd for C H BrN O
393.0808, found 393.0808.
7-(4-Bromophenyl)-2,3-dihydro-1,3,3-trimethyldipyrrin (11-
Ar). Following a standard procedure, a solution of 10-Ar (4.63 g, 11.8
mmol) in distilled THF (22 mL) and dry methanol (1.0 mL) under
argon was treated with NaOMe (1.91 g, 35.4 mmol), and the mixture
was stirred for 45 min at room temperature. In a second flask, TiCl
(20 wt % in 3% HCl solution, 60. mL), THF (160 mL), and NH OAc
1
8
22
2
3
5
2
4
3
brown solid was dissolved in ethylene glycol (200 mL) in a 500 mL
4
flask and bubbled with argon for 10 min. Powdered NaOH (17.2 g,
(45 g) were combined under argon, and the mixture was degassed by
bubbling with argon for 45 min. The solution in the first flask
containing the nitronate anion was transferred via a cannula to the
4
30 mmol) was added. The flask was heated to 160 °C in an oil bath.
After 2.5 h, the reaction mixture was allowed to cool to room
temperature, whereupon brine (200 mL) was added. The resulting
mixture was extracted with CH Cl . The organic extract was dried
buffered TiCl mixture in the second flask. The resulting mixture was
3
stirred at room temperature for 16 h under argon. The reaction
mixture was poured over a pad of Celite and eluted with ethyl acetate.
2
2
(
Na SO ), concentrated, and recrystallized (hot ethanol) to afford a
2 4
1
yellow solid (10.9 g, 57%): mp 142−143 °C; H NMR (400 MHz) δ
6
2
MHz) δ 106.5, 114.8, 119.0, 119.3, 123.9, 126.9, 131.7, 134.9; ESI-MS
m/z [M + H] calcd for C H BrN 221.9913, found 221.9910.
The eluant was washed with aqueous NaHCO
3
solution. The organic
.49 (m, 1H), 6.81 (m, 1H), 7.04 (m, 1H), 7.37−7.39 (d, J = 8.4 Hz,
phase was dried (Na SO ), concentrated and chromatographed [silica,
2
4
13
H), 7.42−7.44 (d, J = 8.4 Hz, 2H), 8.24 (br, 1H); C NMR (100
hexanes/ethyl acetate (1:1)] to afford a light yellow solid (1.50 g,
1
37%): mp 119−121 °C; H NMR (400 MHz) δ 1.19 (s, 6H), 2.23 (s,
+
3H), 2.52 (s, 2H), 5.89 (s, 1H), 6.26 (m, 1H), 6.85 (m, 1H), 7.31−
7.33 (d, J = 8.0 Hz, 2H), 7.49−7.51 (d, J = 8.0 Hz, 2H), 11.10 (br,
10
9
3
-(4-Bromophenyl)-2-formylpyrrole (8). Following a standard
4
13
procedure, a solution of 7 (10.9 g, 49.0 mmol) in DMF (15.2 mL, 196
mmol) and CH Cl (200 mL) at 0 °C under argon was treated
dropwise with POCl (5.5 mL, 58.8 mmol). After 1 h, the ice bath was
1H); C NMR (100 MHz) δ 20.8, 29.2, 41.3, 53.8, 102.4, 108.7,
118.6, 119.2, 122.1, 127.6, 130.2, 131.2, 136.3, 162.0, 177.3; ESI-MS
2
2
+
m/z [M + H] calcd C H BrN 343.0804, found 343.0807.
3
18 20
2
removed and the mixture was stirred overnight. Then, the reaction
mixture was cooled to 0 °C again, whereupon 2.0 M aqueous NaOH
solution (350 mL) was added. The mixture was extracted with
CH Cl . The organic extract was washed with brine, dried (Na SO ),
8-Carbethoxy-7-ethyl-1,3,3-trimethyl-2,3-dihydrodipyrrin
5
(11-EtEs). Following a standard procedure, a mixture of 9-EtEs (5.1
g, 21 mmol) and mesityl oxide (4.1 g, 42 mmol) was treated with DBU
(10 mL, 64 mmol) at room temperature. After 16 h, water was added,
and then the mixture was extracted with ethyl acetate (2 × 100 mL).
The organic layer was washed thoroughly with brine and water, dried
2
2
2
4
concentrated, and chromatographed [silica, CH Cl ] to give a yellow
2
2
1
solid (9.44 g, 77%): mp 163−164 °C; H NMR (400 MHz) δ 6.43 (m,
1
8
1
H), 7.17 (m, 1H), 7.35−7.37 (d, J = 8.0 Hz, 2H), 7.56−7.58 (d, J =
(Na SO ), and concentrated. The resulting brown oil was dried
2 4
.0 Hz, 2H), 9.59 (s, 1H), 10.41 (br, 1H); 13C NMR (100 MHz) δ
overnight under high vacuum to give a crude material (4.2 g) that was
used directly in the next step. In a first flask, a solution of the crude
material in distilled THF (20 mL) and dry methanol (1.0 mL) under
argon was treated with NaOMe (2.0 g, 37 mmol), and the mixture was
11.6, 122.2, 126.3, 128.8, 130.8, 132.0, 132.8, 136.2, 179.7; ESI-MS
m/z [M + H] calcd for C H BrNO 249.9862, found 249.9863.
+
11
9
3
-(4-Bromophenyl)-2-(2-nitroethyl)pyrrole (9-Ar). Following a
4
standard procedure, a mixture of pyrrole 8 (9.44 g, 37.8 mmol),
stirred for 45 min at room temperature. In a second flask, TiCl
% in 3% HCl solution, 63 mL, 100 mmol), THF (160 mL), and
NH OAc (47 g, 620 mmol) were combined under argon, and the
3
(20 wt
potassium acetate (4.08 g, 41.6 mmol), methylamine hydrochloride
(
2.87 g, 41.6 mmol), and nitromethane (75 mL) was stirred at room
4
temperature under argon. The progress of the reaction was monitored
via TLC analysis. After 2 h, brine was added. The resulting mixture was
extracted with ethyl acetate. The organic extract was washed with brine
and water, dried (Na SO ), and concentrated to afford an orange solid.
mixture was degassed by bubbling with argon for 45 min. The solution
in the first flask containing the nitronate anion was transferred via
cannula to the buffered TiCl mixture in the second flask. The
3
resulting mixture was stirred at room temperature for 16 h under
argon. The reaction mixture was poured over a pad of Celite and
eluted with ethyl acetate. The eluant was washed with aqueous
2
4
The crude solid was dissolved in anhydrous THF/MeOH (166 mL,
9
:1) under argon at 0 °C. The mixture was stirred vigorously and
treated with NaBH (2.51 g, 66.4 mmol) in one portion. Stirring was
NaHCO solution. The organic phase was dried (Na SO ),
3
2
4
4
continued for 1 h at 0 °C and then for 2 h at room temperature. The
reaction mixture was neutralized to pH 7 with acetic acid. Water was
added followed by extraction with ethyl acetate. The organic extract
was washed with brine and water, dried (Na SO ), concentrated, and
concentrated, and chromatographed [silica, hexanes/ethyl acetate
1
(3:1)] to afford a yellow oil (1.4 g, 23%): H NMR (400 MHz) δ 1.16
(t, J = 7.6 Hz, 3H), 1.22 (s, 6H), 1.34 (t, J = 7.0 Hz, 3H), 2.21 (s, 3H),
2.52 (s, 2H), 2.78−2.83 (q, J = 7.6 Hz, 2H), 4.24−4.29 (q, J = 7.0 Hz,
2
4
1
3
chromatographed [silica, hexanes/ethyl acetate (1:1)] to give a yellow
2H), 5.71 (s, 1H), 7.40 (d, J = 3.2 Hz, 1H), 11.15 (br, 1H); C NMR
(100 MHz) δ 14.6, 16.4, 18.1, 20.8, 29.3, 41.3, 53.9, 59.2, 101.4, 114.0,
1
solid (8.01 g, 72%): mp 93−94 °C; H NMR (400 MHz) δ 3.42 (t, J =
+
6
7
1
1
.6 Hz, 2H), 4.54 (t, J = 6.6 Hz, 2H), 6.26 (m, 1H), 6.74 (m, 1H),
.19−7.21 (d, J = 8.0 Hz, 2H), 7.49−7.51 (d, J = 8.0 Hz, 2H), 8.33 (br,
H); 13C NMR (100 MHz) δ 24.2, 75.0, 109.4, 117.9, 119.9, 122.0,
124.5, 125.1, 128.6, 161.3, 165.7, 177.1; ESI-MS m/z [M + H] calcd
for C17H N O 289.1911, found 289.1907.
25 2 2
2-Carbomethoxy-3-(2,3-dihydro-3,3-dimethyl-7-p-tolyldi-
pyrrin-1-yl)-1-[2,3-dihydro-1-(1,1-dimethoxymethyl)-3,3-dime-
thyldipyrrin-8-yl]prop-2-en-1-one (12-T). Samples of 4a (17 mg,
+
22.2, 129.6, 131.8, 135.2; ESI-MS m/z [M + H] calcd for
C H BrN O 295.0077, found 295.0078.
12
12
2
2
4
9 μmol), 5-T (17 mg, 58 μmol, 1.2 equiv), and dried molecular sieves
3 Å (17 mg, powder form) were placed in a 20 mL vial under argon. A
solution of piperidine/acetic acid in CH Cl (15 mM/15 mM, 1.2 mL,
6
-[3-(4-Bromophenyl)pyrrol-2-yl]-4,4-dimethyl-5-nitrohex-
5
an-2-one (10-Ar). Following a standard procedure, a mixture of 9-
Ar (8.01 g, 27.1 mmol) and mesityl oxide (6.2 mL, 54.2 mmol) was
treated with DBU (8.1 mL, 54 mmol) at room temperature. After 16
h, water was added, and the mixture was extracted with ethyl acetate (2
2
2
18 μmol/18 μmol) was added, and the mixture was stirred at room
temperature for 20 h. The mixture was filtered through a Celite pad.
The filtrate was concentrated and chromatographed [silica, hexanes/
ethyl acetate (3:1 then 1:1)] to give an orange-red gum (19 mg, 61%):
×
100 mL). The organic layer was washed thoroughly with brine and
water, dried (Na SO ), concentrated, and chromatographed [silica,
2
4
1
1
hexanes/ethyl acetate (3:1)] to give a brown oil (4.63 g, 44%): H
H NMR (400 MHz) δ 1.07 (s, 6H), 1.22 (s, 6H), 2.37 (s, 3H), 2.56
NMR (300 MHz) δ 1.08 (s, 3H), 1.19 (s, 3H), 2.11 (s, 3H), 2.34−
(s, 2H), 2.64 (s, 2H), 3.44 (s, 6H), 3.78 (s, 3H), 5.00 (s, 1H), 5.85 (s,
1H), 6.12 (s, 1H), 6.27 (m, 1H), 6.57 (s, 1H), 6.91 (m, 1H), 7.19−
7.21 (d, J = 7.6 Hz, 2H), 7.30−7.32 (d, J = 7.6 Hz, 2H), 7.39 (s, 1H),
2
2
3
2
.59 (AB, J = 18.0 Hz, 2H), 3.12−3.18 (ABX, J = 15.6 Hz, J = 2.7
2 3
Hz, 1H), 3.35−3.44 (ABX, J = 15.6 Hz, J = 11.4 Hz, 1H), 5.19−5.23
2
3
13
(
ABX, J = 11.4 Hz, J = 2.4 Hz, 1H), 6.21−6.22 (m, 1H), 6.68−6.70
7.65 (s, 1H), 10.68 (br, 1H), 11.27 (br, 1H); C NMR (100 MHz) δ
M
DOI: 10.1021/acs.joc.6b02878
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2
2
1
1
1
6
1
1.3, 29.07, 29.09, 40.4, 41.8, 48.5, 50.4, 52.9, 54.7, 102.4, 106.4, 108.2,
08.8, 109.4, 121.0, 126.0, 126.5, 126.9, 127.4, 128.7, 129.3, 129.4,
33.3, 133.9, 134.9, 135.6, 138.0, 161.0, 162.5, 165.7, 167.3, 176.6,
13 -Carbomethoxy-8,8,18,18-tetramethyl-2-p-tolylbacterio-
1
13 -oxophorbine (BC-T). A solution of 12-T (19 mg, 30 μmol) in
acetonitrile (ACS grade, 150 mL) was degassed by bubbling with
argon for 20 min. Yb(OTf) (186 mg, 0.300 mmol) was added in one
portion under argon. The reaction mixture was immediately heated to
80 °C and stirred under argon for 20 h, during which time the solution
changed from orange-red to dark green. Then, the reaction mixture
+
88.5; ESI-MS m/z [M + H] calcd for C H N O 623.3228, found
3
3
7
43
4
5
4
−1
−1
23.3224; λ (CH Cl ) 319 nm (ε 2.6 × 10 M cm ), 505 nm (ε
.6 × 10 M cm ). Note that addition of piperidine and acetic acid
abs
−1
2
2
4
−1
(
15 mM each) in water afforded a pH = 6.7, reflecting the near-neutral
conditions of this combination of reagents for the Knoevenagel
condensation.
was allowed to cool to room temperature, whereupon excess Et N (0.5
mL) was added. The reaction mixture was concentrated and
3
3
-[7-(4-Bromophenyl)-2,3-dihydro-3,3-dimethylpyrrin-1-yl]-
-carbomethoxy-1-[2,3-dihydro-1-(1,1-dimethoxymethyl)-3,3-
dimethyldipyrrin-8-yl]prop-2-en-1-one (12-Ar). Reaction of 4a
31 mg, 90 μmol) and 5-Ar (32 mg, 90 μmol) under the general
chromatographed [silica, hexanes/ethyl acetate (3:1 then 1:1)] to
afford a blue-green solid (9.5 mg, 56%): H NMR (400 MHz) δ 0.52
1
2
(
br, 1H), 1.72 (s, 3H), 1.82 (s, 9H), 2.03 (br, 1H), 2.58 (s, 3H), 3.76−
(
3
7
1
.88 (AB, J = 16.8 Hz, 2H), 3.83 (s, 3H), 4.09 (s, 2H), 5.79 (s, 1H),
.52−7.54 (d, J = 7.8 Hz, 2H), 7.91−7.93 (d, J = 7.8 Hz, 2H), 8.08 (s,
procedure for 12-T followed by chromatography [silica, hexanes/ethyl
acetate (3:1 then 1:1)] gave an orange-red gum (38 mg, 68%): H
NMR (400 MHz) δ 1.08 (s, 6H), 1.22 (s, 6H), 2.57 (s, 2H), 2.64 (s,
H), 3.44 (s, 6H), 3.79 (s, 3H), 5.01 (s, 1H), 5.85 (s, 1H), 6.03 (s,
1
13
H), 8.11 (m, 2H), 8.21 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H); C NMR
(100 MHz) δ 21.6, 29.7, 30.1, 30.9, 31.0, 43.9, 45.6, 49.0, 52.9, 53.3,
2
1
6
1
1
4.7, 95.1, 98.2, 100.2, 106.0, 108.1, 126.3, 128.6, 130.1, 130.5, 131.8,
H), 6.25 (m, 1H), 6.56 (s, 1H), 6.92 (m, 1H), 7.25−7.28 (d, J = 8.4
38.7, 140.1, 140.3, 141.9, 142.3, 149.8, 152.2, 165.5, 169.4, 169.8,
Hz, 2H), 7.39 (s, 1H), 7.48−7.50 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H),
+
77.3, 188.6; ESI-MS m/z [M + H] calcd for C H N O 559.2704,
35
35
4
3
1
4
1
1
0.70 (br, 1H), 11.27 (br, 1H); 13C NMR (100 MHz) δ 29.1, 40.4,
1.7, 48.6, 50.5, 53.0, 54.7, 102.4, 106.4, 108.1, 108.2, 109.2, 119.8,
21.1, 125.0, 125.9, 126.8, 127.6, 130.3, 131.7, 133.3, 134.6, 135.8,
found 559.2702; λabs 356, 489, 520, 660, 721 nm.
2
2
-(4-Bromophenyl)-13 -carbomethoxy-8,8,18,18-tetrame-
1
thylbacterio-13 -oxophorbine (BC-Ar). Reaction of 12-Ar (18 mg,
6 μmol) under the general procedure for BC-T followed by
+
38.4, 161.6, 162.6, 165.6, 167.9, 176.6, 188.4; ESI-MS m/z [M + H]
calcd for C H BrN O 687.2177, found 687.2168.
2
36
40
4
5
chromatography [silica, hexanes/ethyl acetate (3:1 then 3:2)] gave a
2
-Carbomethoxy-3-(2,3-dihydro-3,3,7,8-tetramethyldipyr-
1
blue-green solid (10.5 mg, 61%): H NMR (400 MHz) δ 0.31 (br,
rin-1-yl)-1-[2,3-dihydro-1-(1,1-dimethoxymethyl)-3,3-dime-
1
H), 1.73 (s, 3H), 1.78 (br, 1H), 1.82 (s, 3H), 1.83 (s, 6H), 3.79−3.91
thyldipyrrin-8-yl]prop-2-en-1-one (12-MeMe). Reaction of 4a
(
7
8
AB, J = 16.8 Hz, 2H), 3.84 (s, 3H), 4.14 (s, 2H), 5.83 (s, 1H), 7.85−
(
35 mg, 100 μmol) and 5-MeMe (41 mg, 120 μmol, 1.2 equiv) under
the general procedure for 12-T followed by chromatography [silica,
hexanes/ethyl acetate (3:1 then 1:1)] gave an orange-red gum (47 mg,
1%): H NMR (400 MHz) δ 1.08 (s, 6H), 1.22 (s, 6H), 1.63 (s, 9H),
.03 (s, 3H), 2.25 (s, 3H), 2.51 (s, 2H), 2.64 (s, 2H), 3.44 (s, 6H),
.78 (s, 3H), 5.01 (s, 1H), 5.85 (s, 1H), 5.88 (s, 1H), 6.54 (s, 1H),
.36 (s, 1H), 7.73 (s, 1H), 11.02 (br, 1H), 11.29 (br, 1H); C NMR
100 MHz) δ 9.0, 10.6, 28.6, 29.06, 29.09, 40.4, 42.2, 48.5, 49.6, 52.9,
4.7, 80.3, 102.4, 106.4, 106.8, 108.2, 121.0, 121.6, 126.3, 127.2, 130.4,
33.5, 135.9, 139.1, 161.0, 162.6, 162.9, 165.5, 170.1, 176.7, 188.1;
ESI-MS m/z [M + H] calcd for C H N O 661.3596, found
61.3590.
2
dimethyldipyrrin-1-yl)-1-[2,3-dihydro-1-(1,1-dimethoxymeth-
yl)-3,3-dimethyldipyrrin-8-yl]prop-2-en-1-one (12-EtEs). Reac-
tion of 4a (25 mg, 71 μmol) and 5-EtEs (32 mg, 106 μmol, 1.5 equiv)
under the general procedure for 12-T followed by chromatography
silica, hexanes/ethyl acetate (3:1 then 1:1)] gave an orange-red gum
27 mg, 61%): H NMR (400 MHz) 1.12 (s, 6H), 1.14 (t, J = 7.2 Hz,
.87 (d, J = 8.4 Hz, 2H), 7.88−7.90 (d, J = 8.4 Hz, 2H), 8.07 (s, 1H),
13
.17 (s, 1H), 8.19 (s, 1H), 8.27 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H);
C
1
NMR (100 MHz) δ 29.8, 30.2, 31.0, 31.1, 44.0, 45.8, 48.9, 52.9, 53.2,
7
2
3
7
6
1
4.7, 94.8, 98.6, 100.4, 106.5, 108.3, 123.2, 126.5, 128.9, 132.1, 132.5,
33.7, 139.7, 140.2, 141.5, 149.7, 152.5, 165.2, 169.6, 169.8, 177.0,
+
13
188.6; ESI-MS m/z [M + H] calcd for C34
H32BrN
O
4
3
623.1652,
found 623.1647; λ 356, 490, 521, 664, 727 nm.
abs
(
2
1
1
3 -Carbomethoxy-2,3,8,8,18,18-hexamethylbacterio-13 -
5
1
oxophorbine (BC-MeMe). Reaction of 12-MeMe (23 mg, 35 μmol)
under the general procedure for BC-T followed by chromatography
+
37
49
4
7
[
3
silica, hexanes/ethyl acetate (3:1 then 1:1)] gave a blue solid (6.7 mg,
7%): H NMR (400 MHz) δ 1.16 (br, 1H), 1.62 (br, 1H), 1.72 (s,
6
1
-Carbomethoxy-3-(8-carbethoxy-7-ethyl-2,3-dihydro-3,3-
3
H), 1.75 (s, 6H), 1.80 (s, 3H), 2.93 (s, 3H), 2.95 (s, 3H), 3.62−3.74
(
AB, J = 16.8 Hz, 2H), 3.82 (s, 3H), 3.97 (s, 2H), 5.64 (s, 1H), 7.63 (s,
1
1
1
H), 7.74 (s, 1H), 7.85 (s, 1H), 7.97 (s, 1H); 13C NMR (100 MHz) δ
0.9, 29.6, 29.9, 30.8, 30.9, 43.3, 45.1, 49.0, 52.8, 53.7, 64.4, 91.5, 94.3,
00.0, 104.6, 107.9, 127.7, 133.8, 134.2, 139.7, 142.4, 144.7, 150.6,
[
(
+
1
151.6, 166.3, 168.5, 169.9, 177.9, 188.5; ESI-MS m/z [M + H] calcd
for C H N O 497.2547, found 497.2548; λ 351, 480, 511, 640,
3
2
(
H), 1.22 (s, 6H), 1.35 (t, J = 7.0 Hz, 3H), 2.58 (s, 2H), 2.64 (s, 2H),
.76−2.82 (q, J = 7.2 Hz, 2H), 3.44 (s, 6H), 3.78 (s, 3H), 4.25−4.30
q, J = 7.0 Hz, 2H), 5.01 (s, 1H), 5.86 (s, 1H), 5.89 (s, 1H), 6.55 (s,
30 33
4
3
abs
6
96 nm.
-Carbethoxy-2-ethyl-13 -carbomethoxy-8,8,18,18-tetrame-
2
3
1
thylbacterio-13 -oxophorbine (BC-EtEs). Reaction of 12-EtEs (13
mg, 21 μmol) under the general procedure for BC-T followed by
chromatography [silica, hexanes/ethyl acetate (4:1 then 2:1)] gave a
1
1
2
1
1
H), 7.39 (s, 1H), 7.45 (d, J = 3.2 Hz, 1H), 7.60 (s, 1H), 10.60 (br,
H), 11.28 (br, 1H); 13C NMR (100 MHz) δ 14.6, 16.5, 18.1, 29.1,
9.2, 40.4, 41.6, 48.5, 50.7, 53.0, 54.7, 59.4, 102.4, 106.4, 106.9, 108.1,
14.3, 125.8, 126.8, 128.2, 128.7, 133.3, 134.3, 138.4, 160.9, 162.6,
65.4, 165.5, 167.8, 176.6, 188.5; ESI-MS m/z [M + H] calcd for
1
purple solid (6.6 mg, 57%): H NMR (400 MHz) δ − 0.07 (br, 1H),
+
1.59 (br, 1H), 1.66−1.69 (t, J = 7.6 Hz, 3H), 1.67−1.71 (t, J = 7.6 Hz,
3
H), 1.81 (s, 3H), 1.83 (s, 6H), 1.91 (s, 3H), 3.81−3.91 (AB, J = 16.2
C H N O 633.3283, found 633.3268.
5
3
45
4
7
Hz, 2H), 3.84 (s, 3H), 3.91−3.98 (q, J = 7.6 Hz, 2H), 4.20 (s, 2H),
4.71−4.78 (q, J = 7.6 Hz, 2H), 5.85 (s, 1H), 8.20 (s, 1H), 8.23 (s, 1H),
8.30 (s, 1H), 9.16 (s, 1H); 13C NMR (100 MHz) δ 14.7, 17.1, 20.8,
30.1, 30.4, 31.0, 31.1, 44.0, 45.9, 48.8, 52.9, 53.7, 61.5, 64.7, 94.0, 98.0,
100.4, 107.0, 108.6, 124.0, 129.3, 138.3, 139.5, 140.6, 148.1, 149.6+,
153.1, 165.5, 165.8, 169.7, 170.4, 176.0, 188.6; ESI-MS m/z [M + H]
calcd for C H N O 569.2758, found 569.2753; λ 357, 501, 533,
3
-[7-(4-Bromophenyl)-2,3-dihydro-3,3-dimethylpyrrin-1-yl]-
2
-carbethoxy-1-[2,3-dihydro-1-(1,1-dimethoxymethyl)-3,3-di-
methyldipyrrin-8-yl]prop-2-en-1-one (12-Ar/Et). Reaction of 4b
31 mg, 84 μmol) and 1-Ar (36 mg, 100 μmol, 1.2 equiv) under the
general procedure for 12-T followed by chromatography [silica,
(
hexanes/ethyl acetate (3:1 then 1:1)] gave an orange-red gum (33 mg,
1
5
7
7
6
1
1
4
1
1
7%): H NMR (300 MHz) δ 1.08 (s, 6H), 1.22 (s, 6H), 1.25 (t, J =
.2 Hz, 3H), 2.57 (s, 2H), 2.64 (s, 2H), 3.43 (s, 6H), 4.22−4.29 (q, J =
.2 Hz, 2H), 5.00 (s, 1H), 5.84 (s, 1H), 6.03 (s, 1H), 6.24 (m, 1H),
.56 (m, 1H), 6.91 (m, 1H), 7.25−7.28 (d, J = 8.4 Hz, 2H), 7.38 (m,
H), 7.48−7.51 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 10.71 (br, 1H),
1.24 (br, 1H); 13C NMR (100 MHz) δ 14.26, 14.32, 29.1, 40.4, 41.7,
8.6, 50.6, 54.7, 62.0, 102.5, 106.5, 108.0, 108.2, 109.2, 119.8, 121.1,
24.9, 126.0, 126.7, 127.6, 130.3, 131.7, 133.2, 134.2, 135.9, 139.0,
33
37
4
5
abs
680, 745 nm.
2
2-(4-Bromophenyl)-13 -carbethoxy-8,8,18,18-tetramethyl-
1
bacterio-13 -oxophorbine (BC-Ar/Et). Reaction of 12-Ar/Et (16
mg, 23 μmol) under the general procedure for BC-T followed by
chromatography [silica, hexanes/ethyl acetate (3:1)] gave a blue-green
1
solid (7.1 mg, 48%): H NMR (400 MHz) δ 0.27 (br, 1H), 1.23−1.27
(t, J = 6.8 Hz, 3H), 1.73 (br, 1H), 1.75 (s, 3H), 1.81 (s, 3H), 1.83 (s,
6H), 3.81−3.92 (AB, J = 16.8 Hz, 2H), 4.14 (s, 2H), 4.29−4.34 (q, J =
6.8 Hz, 2H), 5.80 (s, 1H), 7.85−7.87 (d, J = 8.0 Hz, 2H), 7.89−7.91
+
61.6, 162.5, 165.0, 168.1, 176.6, 188.4; ESI-MS m/z [M + H] calcd
for C H BrN O 701.2333, found 701.2334.
37
42
4
5
N
DOI: 10.1021/acs.joc.6b02878
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
d, J = 8.0 Hz, 2H), 8.08 (s, 1H), 8.18 (s, 1H), 8.20 (s, 1H), 8.27 (s,
(12) Bru
̈
ckner, C.; Samankumara, L.; Ogikubo, J. In Handbook of
1
3
1
1
H), 8.40 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz) δ 14.4, 30.0,
0.1, 31.0, 31.3, 44.1, 45.8, 48.9, 53.3, 61.8, 65.0, 94.8, 98.6, 100.4,
06.6, 108.5, 123.2, 126.4, 129.1, 132.1, 132.5, 133.8, 139.7, 140.1,
Porphyrin Science; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; World
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Eds.; Academic Press: New York, 1966; pp 67−109.
40.2, 141.4, 149.7, 152.5, 165.1, 169.3, 169.6, 176.8, 188.8; ESI-MS
+
m/z [M] calcd for C H BrN O 636.1652, found 636.1652; λ
35
33
4
3
abs
(14) Hynninen, P. H. In Chlorophylls; Scheer, H., Ed.; CRC Press:
Boca Raton, 1991; pp 145−209.
3
57, 489, 521, 665, 728 nm.
(
15) Moss, G. P. Pure Appl. Chem. 1987, 59, 779−832.
ASSOCIATED CONTENT
Supporting Information
(16) Deans, R. M.; Mass, O.; Diers, J. R.; Bocian, D. F.; Lindsey, J. S.
■
New J. Chem. 2013, 37, 3964−3975.
*
S
(17) Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.;
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02878.
Bonnett, R.; Buchschacher, P.; Closs, G. L.; Dutler, H.; Hannah, J.;
Hauck, F. P.; Ito, S.; Langemann, A.; Le Goff, E.; Leimgruber, W.;
̂
Nomenclature of the linear tetrapyrroles; absorption
spectral data for three bacteriochlorins; X-ray data for
BC-Ar; list of 27 references for Michael reactions with
pyrroles; and characterization data for all new com-
pounds (PDF)
Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. J. Am. Chem. Soc. 1960,
82, 3800−3802.
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Bonnett, R.; Buchschacher, P.; Closs, G. L.; Dutler, H.; Hannah, J.;
Hauck, F. P.; Ito, S.; Langemann, A.; Le Goff, E.; Leimgruber, W.;
Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. Tetrahedron 1990, 46,
̂
X-ray data for BC-Ar (CIF)
7
599−7659.
AUTHOR INFORMATION
Corresponding Author
E-mail: jlindsey@ncsu.edu.
(20) Wenz, D. R.; Read de Alaniz, J. R. Eur. J. Org. Chem. 2015, 2015,
3−37.
■
*
2
(
21) Song, C.; Knight, D. W.; Whatton, M. A. Org. Lett. 2006, 8,
1
63−166.
22) Malona, J. A.; Colbourne, J. M.; Frontier, A. J. Org. Lett. 2006, 8,
5661−5664.
23) Fujiwara, M.; Kawatsura, M.; Hayase, S.; Nanjo, M.; Itoh, T.
Adv. Synth. Catal. 2009, 351, 123−128.
24) Vaidya, T.; Atesin, A. C.; Herrick, I. R.; Frontier, A. J.;
Eisenberg, R. Angew. Chem., Int. Ed. 2010, 49, 3363−3366.
25) Krayer, M.; Balasubramanian, T.; Ruzie, C.; Ptaszek, M.;
ORCID
(
Jonathan S. Lindsey: 0000-0002-4872-2040
Notes
(
The authors declare the following competing financial
interest(s): J.S.L. is a cofounder of NIRvana Sciences, which
has licensed technology described herein. Also, the two
coauthors have filed a patent application on 11/30/2016 on
the same technology.
X-ray crystallographic data for compound BC-Ar have been
deposited with the Cambridge Crystallographic Data Centre
(
(
́
Cramer, D. L.; Taniguchi, M.; Lindsey, J. S. J. Porphyrins
Phthalocyanines 2009, 13, 1098−1110.
(
26) Baburajan, P.; Elango, K. P. Tetrahedron Lett. 2014, 55, 3525−
3
528.
(
CCDC 1528392).
(27) Khoury, R. G.; Senge, M. O.; Colchester, J. E.; Smith, K. M. J.
Chem. Soc., Dalton Trans. 1996, 3937−3950.
(28) Aravindu, K.; Krayer, M.; Kim, H.-J.; Lindsey, J. S. New J. Chem.
ACKNOWLEDGMENTS
■
2
(
011, 35, 1376−1384.
This work was funded by the Division of Chemical Sciences,
Geosciences, and Biosciences, Office of Basic Energy Sciences
of the U.S. Department of Energy (FG02-05ER15651). Mass
spectra were obtained at the Mass Spectrometry Laboratory for
Biotechnology at North Carolina State University. We thank
Dr. Roger D. Sommer, who carried out the X-ray structural
study.
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Sluder, C. E.; Diers, J. R.; Kirmaier, C.; Bocian, D. F.; Holten, D.;
Lindsey, J. S. Inorg. Chem. 2011, 50, 4607−4618.
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Diers, J. R.; Bocian, D. F.; Lindsey, J. S.; Holten, D. J. Phys. Chem. B
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DOI: 10.1021/acs.joc.6b02878
J. Org. Chem. XXXX, XXX, XXX−XXX