Asymmetric Synthesis of a Bacteriochlorophyll Model Compound Containing trans-Dialkyl Substituents in Ring D

Article abstract of DOI:10.1021/acs.joc.0c00608

Challenges to the de novo synthesis of bacteriochlorophyll a (BChl a), the chief pigment for anoxygenic bacterial photosynthesis, include creating the macrocycle along with the trans-dialkyl substituents in both pyrroline rings (B and D). A known route to a model bacteriochlorophyll with a gem-dimethyl group in each pyrroline ring has been probed for utility in the synthesis of BChl a by preparation of a hybrid macrocycle (BC-1), which contains a trans-dialkyl group in ring D and a gem-dimethyl group in ring B. Stereochemical definition began with the synthesis of (2S,3S)-2-ethyl-3-methylpent-4-ynoic acid, a precursor to the trans-dialkyl-substituted AD dihydrodipyrrin. Knoevenagel condensation of the latter and a gem-dimethyl, β-ketoester-substituted BC dihydrodipyrrin afforded the enone (E, 70%; Z, 3%); subsequent double-ring cyclization of the E-enone (via Nazarov, electrophilic aromatic substitution, and elimination reactions) gave BC-1 (53% yield) along with a trace of chlorin byproduct (1.4% relative to BC-1 upon fluorescence assay). BC-1 exhibited the desired trans-dialkyl stereochemistry in ring D and was obtained as a 7:1 mixture of (expected) epimers owing to the configuration of the 13²-carbomethoxy substituent. The strategy wherein trans-dialkyl substituents are installed very early and carried through to completion, as validated herein, potentially opens a synthetic path to native photosynthetic pigments.

Full text of DOI:10.1021/acs.joc.0c00608

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Asymmetric Synthesis of a Bacteriochlorophyll Model Compound
Containing trans-Dialkyl Substituents in Ring D
Khiem Chau Nguyen, Pengzhi Wang, Roger D. Sommer, and Jonathan S. Lindsey*
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ABSTRACT: Challenges to the de novo synthesis of bacteriochlorophyll a
(BChl a), the chief pigment for anoxygenic bacterial photosynthesis, include
creating the macrocycle along with the trans-dialkyl substituents in both
pyrroline rings (B and D). A known route to a model bacteriochlorophyll
with a gem-dimethyl group in each pyrroline ring has been probed for utility
in the synthesis of BChl a by preparation of a hybrid macrocycle (BC-1),
which contains a trans-dialkyl group in ring D and a gem-dimethyl group in
ring B. Stereochemical definition began with the synthesis of (2S,3S)-2-ethyl-
3-methylpent-4-ynoic acid, a precursor to the trans-dialkyl-substituted AD
dihydrodipyrrin. Knoevenagel condensation of the latter and a gem-dimethyl,
β-ketoester-substituted BC dihydrodipyrrin afforded the enone (E, 70%; Z,
3%); subsequent double-ring cyclization of the E-enone (via Nazarov, electrophilic aromatic substitution, and elimination reactions)
gave BC-1 (53% yield) along with a trace of chlorin byproduct (1.4% relative to BC-1 upon fluorescence assay). BC-1 exhibited the
desired trans-dialkyl stereochemistry in ring D and was obtained as a 7:1 mixture of (expected) epimers owing to the configuration of
the 132-carbomethoxy substituent. The strategy wherein trans-dialkyl substituents are installed very early and carried through to
completion, as validated herein, potentially opens a synthetic path to native photosynthetic pigments.
may provide some resistance to adventitious dehydrogenation
compared with the fully unsubstituted chromophore). A recent
synthesis of model bacteriochlorophylls, wherein a gem-
dimethyl group is positioned in each pyrroline ring is shown
in Scheme 1.7 The synthesis employs reaction of two
dihydrodipyrrins: a gem-dimethyl-substituted AD half (I)
and a gem-dimethyl-substituted BC half (II). A Knoevenagel
condensation joins the two-halves via a propenone linkage
(III), whereas the second set of reactions constructs the
macrocycle and forms the isocyclic ring to afford the
bacteriochlorophyll model compound (IV). The second set
of reactions is carried out as a one-flask process and entails
Nazarov cyclization, electrophilic aromatic substitution (SEAr),
and elimination of methanol. The conditions are relatively mild
in the overall transformation. The strategy has been extended
to afford chlorophyll model compounds by use of a
dipyrromethane (rather than dihydrodipyrrin) as the BC half.8
We recently began exploring the extension of the reaction
processes shown in Scheme 1 to accommodate trans-dialkyl
rather than gem-dimethyl substitution in the pyrroline ring.
1. INTRODUCTION
Bacteriochlorophylls provide the chief pigments for anoxygenic
bacterial photosynthesis analogous to chlorophylls in oxygenic
plant and cyanobacterial photosynthesis.1,2 It is somewhat
paradoxical that anoxygenic photosynthesis is far simpler than
oxygenic photosynthesis, yet bacteriochlorophylls are structur-
ally more complex than chlorophylls. Bacteriochlorophyll a (a
bacteriochlorin) contains two pyrroline rings (B and D),
whereas chlorophyll a (a chlorin) contains only a single
pyrroline ring (D). Each pyrroline ring bears a trans-dialkyl
group (Chart 1). Bacteriochlorophyll a absorbs in the near-
infrared (771 nm) spectral region, whereas chlorophyll a
absorbs in the red (660 nm) spectral region.3,4 Anoxygenic
photosynthesis has been the object of ongoing study for many
decades now, yet bacteriochlorophylls (and their free base
analogues, bacteriopheophytins) have remained outside the
scope of chemical synthesis.5
Over the years, we have worked on developing routes to
non-natural chlorins and bacteriochlorins. In these routes, we
have employed a gem-dimethyl group in each pyrroline ring.
The rationale6 for the gem-dimethyl group is chiefly two-fold:
(1) in the absence of gem-dimethyl groups, the pyrroline ring
is susceptible to adventitious oxidative dehydrogenation, which
converts the chlorin to a porphyrin, and the bacteriochlorin to
a chlorin and then also the porphyrin. The progressive loss of
saturation affords a commensurate loss of long-wavelength
absorption. (2) Synthetic installation has proved far simpler for
the gem-dimethyl moiety than the trans-dialkyl group (which
Received: March 6, 2020
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tion in both rings would give the porphyrin. Second, beyond
the little appreciated abyss upon tautomerization of
dihydrodipyrrins, the problem of adventitious oxidation
remains a paramount concern. Adventitious dehydrogenation
of hydroporphyrins lacking stabilizing structural features (such
as gem-dimethyl groups) is well known,10−13 and the same
susceptibility is expected to manifest with hydrodipyrrins. Both
rings B and D of the dihydrodipyrrins are susceptible to
dehydrogenation on routine handling to form the correspond-
ing dipyrrins, which would also give the chlorin or porphyrin.
The dihydrodipyrrins (V and VI), propenone derived
therefrom, and target bacteriochlorin are all susceptible to
adventitious dehydrogenation. In short, tautomerization and
dehydrogenation must be avoided at all stages following
dihydrodipyrrin construction for the success of the proposed
synthetic route to trans-dialkyl hydroporphyrins. Stereo-
chemical inversion would afford the undesired bacteriochlorin
isomer, whereas tautomerization or dehydrogenation would
cause loss of stereochemistry and loss of the bacteriochlorin
chromophore. None of those problems arise with the gem-
dimethyl-substituted counterparts, where extensive develop-
ment chemistry has been carried out,6−8 yet the applicability of
such chemistry to the trans-dialkyl counterparts has heretofore
not been addressed.
Chart 1. Native Photosynthetic Pigments
To ascertain the viability of the proposed synthetic route, we
elected to prepare a model bacteriochlorin that contains one
trans-dialkyl-substituted pyrroline ring (D) and one gem-
dimethyl-substituted pyrroline ring (B). The resulting
bacteriochlorin (BC-1) and precursors have one point of
vulnerability toward dehydrogenation, tautomerization, and/or
stereochemical inversion, and the choice of BC-1 as a target
thus enables the aforementioned issues to be singularly
scrutinized. Here, we report the synthesis of BC-1, wherein
the trans-dialkyl configuration of ring D is set at the earliest
stage, namely, the synthesis of an alkynoic acid (analogous to
pre-D). Six subsequent steps lead to the target BC-1. The
stereochemistry of the two alkyl groups in BC-1 is identical to
that of the native bacteriochlorophyll macrocycles. Extensive
characterization studies of intermediates and products support
the validity of the synthetic strategy proposed herein.
The purpose for doing so is to establish robust routes to the
native photosynthetic pigments, including the bacteriochloro-
phylls and chlorophylls. The proposed route to BChl a (R =
phytyl, R3 = Ac, M = Mg) and analogues mirrors the synthesis
of IV, as is shown in Scheme 2. The route installs the trans-
dialkyl configuration at a very early stage of the synthesis (e.g.,
pre-B and pre-D) and carries the trans-dialkyl groups through
multiple stages to the target macrocycle. The potential
advantages of this strategy are the ability to rely on (1) well-
established stereoselective synthetic methods to prepare the
alkynoic acids pre-B and pre-D, (2) straightforward access to
the pyrroles including pre-C,9 and (3) a concise route from
AD and BC dihydrodipyrrins to the target macrocycle.
On the other hand, key issues are whether the trans-dialkyl
group can be carried through multiple transformations with
high fidelity. Racemization and epimerization are obvious
concerns in essentially all syntheses using stereodefined
precursors. Yet here, the dihydrodipyrrin intermediates are
fraught with two potential problems of greater severity. First,
tautomerization9 in ring B or D would convert the
dihydrodipyrrins V and VI to the corresponding dipyrro-
methanes, losing the essential saturation of the corresponding
target macrocycle. Tautomerization in either ring B or D would
give rise to the chlorin, not the bacteriochlorin; tautomeriza-
2. RESULTS AND DISCUSSION
2.1. Synthesis of a Model AD Half. The route for the
preparation of the AD-half relies on a synthetic procedure first
described by Jacobi and co-workers, wherein a 2-halopyrrole is
reacted with a 4-pentynoic acid.14 As a model synthesis for
bacteriochlorophyll a, which contains an acetyl group at the 3-
position, we chose a carboethoxy analogue. Thus, van Leusen
cycloaddition15,16 of p-toluenesulfonylmethyl isocyanide (Tos-
Scheme 1. Established Route to Gem-Dimethyl-Substituted Model Bacteriochlorophylls
B
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Scheme 2. Proposed Route to Native Bacteriochlorophylls (Top) and Potential Side Reactions (Bottom)
MIC) with ethyl acrylate followed by treatment of the resulting
pyrrole 117 with N-iodosuccinimide (NIS) gave pyrrole 2
(Scheme 3) in 5-fold larger quantity than in the prior reports.18
the predominant formation of an adduct possessing the desired
stereocenters, which can be easily purified from its
diastereomeric byproduct through chromatography. A one-
flask conversion of commercial 3-(trimethylsilyl)propynal (4)
to ( )hexacarbonyldicobalt-stabilized propargylic ether 521
was developed (Scheme 4). Thus, reaction of MeLi with 4 at
low temperature followed by treatment with dimethyl sulfate
and then Co2(CO)8 at room temperature gave 5, which was
easily purified by column chromatography. Treatment of the
lithium salt of (R)-4-isopropyloxazolidin-2-one (6) with
butyryl chloride afforded (R)-3-butyryl-4-isopropyloxazolidin-
2-one (722). Reaction of the latter with Bu2BOTf in a basic
medium generated the corresponding boron enolate, which
underwent an aldol-type condensation with 5 to exclusively
form 8 containing the expected two S-stereocenters. Mild
oxidation with ceric ammonium nitrate (CAN) caused removal
of the hexacarbonyldicobalt moiety. In the final step,
treatment23 of 9 with LiOOH (generated from LiOH and
Scheme 3. Synthesis of Pyrrole Ring A
The two vicinal stereocenters in the substituted pentynoic
acid (3) can be simultaneously assembled via the Nicholas
reaction,19 where a hexacarbonyldicobalt-stabilized propargylic
ether is reacted with the boron enolate of the appropriate N-
acyl oxazolidinone.20 The appropriate choice of the enantio-
merically pure oxazolidinone (Evans chiral auxiliary) results in
Scheme 4. Synthesis of a Stereodefined Precursor to Ring D
C
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Scheme 5. Synthesis of a Model AD Half
Figure 1. Absorption spectra (in acetonitrile at room temperature) for the hydrolysis of 11-E/Z (left), followed by Paal−Knorr cyclization of 11-
diketo to form 12 (right).
H2O2) was required to provide24 alkynoic acid 3, which was
obtained without stereochemical scrambling of the established
chiral centers. The base LiOOH is weaker than LiOH, thus
reducing the possible deprotonation at the α-carbonyl
stereocenter.25,26
The absorption of 11-E/Z (272 nm) disappeared within 5 min
because of formation of the putative intermediate diketone
(11-diketo). Upon addition of ammonium acetate and
triethylamine, the absorption (314 nm) steadily grew in over
the course of 10 min because of amination yielding
dihydrodipyrrin 12 (Figure 1). The conversion of 11-E/Z to
12 can be regarded as a type of Paal−Knorr reaction, which
dates to the late-19th century conversion of a 1,4-diketone to
the corresponding furan. A comprehensive review29 of the
Paal−Knorr reaction shows the well-known extension beyond
furans to access diverse pyrroles30 and also thiophenes, but to
our knowledge, the extension to form a pyrroline has been
limited (with rare exceptions31) to the cases of hydrodipyrrin
precursors leading to hydroporphyrins.6 Mechanistic consid-
erations indicate the Paal−Knorr reaction leading to pyrroles
proceeds via a hemiaminal rather than an imine intermediate.29
A similar route is expected to be followed here from 11-diketo,
via putative 11-hemiaminal, to form the dihydrodipyrrin 12, as
is illustrated in Scheme 5.
Pd-mediated coupling of 2 and 3 gave the lactone-pyrrole
10-E/Z as a relatively inseparable mixture of isomers in 9:1
ratio (E/Z, unknown assignment) along with deiodinated
1
pyrrole 1 as determined by H NMR spectroscopy (Scheme
5). The product 10-E/Z was isolated in crude form via column
chromatography (estimated 87% 10-E/Z, 13% pyrrole 1).
Formation of such deiodinated pyrroles in Pd(0)-mediated
reactions is commonly noted.14,27 Preparative TLC of a small
sample afforded 10-E. For synthetic purposes, the crude
mixture of 10-E/Z and 1 was carried forward by reaction with
the Petasis reagent to give 11-E/Z (wherein impurity 1 was
removed upon chromatography). The selective reactivity of the
lactone carbonyl group versus that of the carboethoxy group
despite an excess of the Petasis reagent is attributed to the
lessened reactivity of the latter owing to conjugation with the
pyrrole ring.28
Unlike in the classical Paal−Knorr process leading to the
pyrrole, several distinct side reactions can occur on the path
from 11-E/Z to dihydrodipyrrin 12. Such reactions include
epimerization, particularly for 11-diketo in the presence of
ammonium acetate and triethylamine, and two-fold tautomer-
ization leading to the dipyrromethane 12-DPM. To prepare 12
Compound 11-E/Z was hydrolyzed with aqueous HCl in
DMF at room temperature, followed by amination at 55 °C
(Scheme 5). The two steps were carried out as a one-flask
transformation with monitoring by absorption spectroscopy.
D
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with intact stereochemical integrity, we examined a variety of
procedures for amination of 11-diketo. Key observations are as
follows:
gave 12 in 56% yield, which is comparable to yields recorded
for unsubstituted ene−lactones.14 While the dipyrromethane is
believed to be the thermodynamic product, the conditions
identified for the Paal−Knorr reaction with 11-E/Z enabled
formation of the dihydrodipyrrin 12 with limited or no
competing formation of the dipyrromethane.
(i) Reaction of 11-diketo at 55 °C for 4 h as reported for
gem-dimethyl analogues18 afforded dipyrromethane 12-
DPM as the predominant product (Scheme 6, top). The
The Riley oxidation33,34 of 12 with SeO2 to form aldehyde
13 was monitored by absorption spectroscopy. The absorbance
of 12 (314 nm) decreased, whereas that of aldehyde 13 (423
nm) increased over time (Figure 2). The reaction proceeded
Scheme 6. Paal−Knorr Transformation of 11 (Top) and
Data14 for Analogues (Bottom)
Figure 2. Absorption spectra (in acetonitrile) for the conversion of 12
to aldehyde 13 in wet dioxane.
slowly in dry dioxane but more rapidly with the addition of a
small quantity of water33 (5 μL with respect to 3 mL of
dioxane). Purification on a short column packed with
deactivated silica (pretreated with Et3N/hexanes) gave 13 as
a dark yellow paste, which was fairly stable for weeks at −20
°C. The transformation proceeded in low yield (21%), the
origin of which is unknown, but the remediation of which will
be required to streamline this synthetic route.
2.2. Stereochemical Features of Dihydrodipyrrins.
The integrity of the desired trans-dialkyl configuration was
examined in dihydrodipyrrins 12 and 13. The stereochemical
relationship of H2 and H3 in the pyrroline ring was probed by
analysis of the coupling constants in one-dimensional 1H NMR
and correlations in NOESY spectroscopy. The protons H2 and
H3 of aldehyde 13 gave similar chemical shifts (δ 2.72−2.78
ppm) and hence a strong second-order coupling effect,
complicating analysis. On the other hand, the precursor 12
gave distinct chemical shifts for the same protons and was used
for the following analysis. The assignment of H2, H3, and two
H2a atoms to the observed resonances was easily achieved by
COSY analysis (see the Supporting Information, Figure S1). In
Figure 3 panel A, the two vicinal protons H3 and H2 appear as
first-order multiplets, which was further analyzed as a quartet
dipyrromethane is an isomer of 12 and originates via
tautomerization, not oxidation. No such side product
can occur for analogous ene−lactones with a gem-
dimethyl substituent.18,32 Ene−lactones lacking a gem-
dimethyl moiety (VII) have been reported to give
dipyrromethanes (VIII-DPM) in yields enhanced by a
basic medium at elevated temperature (Scheme 6,
bottom). On the other hand, reactions at room
temperature or without base selectively gave the desired
dihydrodipyrrin (VIII) versus the dipyrromethane
(VIII-DPM).14
(ii) Upon shortening the reaction time with 11-diketo to 15
min, dihydrodipyrrin 12 was formed preferentially;
however, the isolated yield was inconsistent. We found
that minor variations during the work-up and
chromatography could engender tautomerization of
dihydrodipyrrin 12 to dipyrromethane 12-DPM. In an
extreme case, 12 and 12-DPM were obtained in yields of
9 and 72%, respectively, after concentration of the crude
sample in a warm water bath, drying overnight under
vacuum, and chromatography on silica.
(iii) Cooling the reaction mixture before quenching with cold
aqueous saturated KH2PO4, concentrating the sample in
a cooled water bath, and chromatographing on
deactivated silica pretreated with Et3N limited the
unwanted tautomerization process.
3
3a
2
3
of doublets of doublets (JH −H = 7.4 Hz, JH −H = 4.0 Hz, and
3
5
long-range JH −H = 1.6 Hz) and a doublet of doublets of
doublets (JH −H = 8.6 Hz, JH −H = 4.3 Hz, and JH −H = 4.0
Hz), respectively. The experimental JH −H value (4.0 Hz) in
this case coheres with those reported for trans proton−proton
coupling in other well-studied, rigid, five-membered cyclic
systems (Figure 3 panel B).35 The 2- and 3-positions of the
dihydrodipyrrin correspond to the respective 17- and 18-
2
2a
2
2a
2
3
2
3
17−H18
In summary, the process of reaction of 11-diketo with
NH4OAc and Et3N at 55 °C for 15 min, rapid quenching at 0
°C, and purification by chromatography on deactivated silica
positions of the chlorin macrocycle. The JH
values of
chlorophyll a (in acetone-d6 or THF-d8), pheophytin a (in
CDCl3), and methyl pheophorbide a (in CDCl3) are 1.8, 2.0,
E
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1
Figure 3. (A) Observed (red) and simulated (blue) H NMR patterns of selected protons of 12. (B) Vicinal H−H coupling constants in
hexachlorobicyclo[2.2.1]heptenes.35 (C) NOESY correlations of selected protons of 12.
and 1.6 Hz, respectively (Chart 2).36 On the basis of the
derived experimental coupling constants, the simulated
Finally, the NOESY spectrum of 12 shows a strong
correlation of H3 with the ethyl group bearing two H2a and
three H2b atoms, in addition to the inevitable correlation of H3
with the vicinal methyl group (Figure 3, panel C). This
observation implies that H3 and the adjacent ethyl substituent
must be on the same side of the five-membered ring.
Analogous NOE correlations were observed for H18 and the
methylene groups in the ester chain at C17 in the NOESY
spectrum of a 3-substituted analogue of methyl pyropheo-
phorbide a (IX, Chart 2).37 In summary, all of the
spectroscopic results are consistent with a trans-dialkyl
configuration in dihydrodipyrrin 12.
Chart 2. Derivatives of Chlorophyll a
2.3. Macrocycle Formation. We next examined the
reaction of dihydrodipyrrin−carboxaldehyde 13 in the
formation of a bacteriochlorophyll model compound (Scheme
7). Thus, the Knoevenagel reaction38−40 of 13 and II
proceeded under mild conditions at room temperature to
furnish two separately isolated enone isomers in a total yield of
73% (3 and 70%). The E or Z configuration of each enone
(14) could not be assigned by NOESY spectroscopy (Figures
S2−S5); however, in each isomer, the multiplicities of protons
at or near the key stereocenters in the pyrroline ring resembled
those found in the precursor 12, indicating successful retention
multiplets (via MestreNova software) corresponding to H2,
H3, and two diastereotopic H2a protons were constructed
(Figure 3 panel A), which essentially recapitulated the
experimental spectrum except for a shoulder on the high-
field edge of the H2 multiplet at 2.30 ppm.
Scheme 7. Bacteriochlorin Macrocycle Formation
F
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Figure 4. (A) Selected NOESY correlations supporting the assignments and ratio of two epimeric forms of bacteriochlorin BC-1. (B) Observed
(red) and simulated (blue) 1H NMR patterns of selected protons of BC-1. The vicinal H17−H18 coupling constant was 2.5 Hz, consistent with the
trans configuration.
of the preinstalled trans-dialkyl stereochemistry. A single-
crystal X-ray structure determination of the major isomer
(from acetonitrile/diethyl ether) was carried out (Figures S6−
S11). The structure clearly revealed the E configuration of the
enone and the trans-dialkyl (17-S, 18-S) configuration in the
pyrroline ring, despite considerable positional disorder at
several sites such as the carboethoxy group (which can assume
multiple orientations). To our knowledge, only one single-
crystal X-ray structure has been reported for a Knoevenagel
enone derived from a heteroaromatic β-keto ester [Ar-
C(O)CH2CO2Me], which was also the E isomer.41 The E
and Z isomers of related enones are known to interconvert
under the conditions of the Nazarov reaction.41−45 Here, we
employed the major Knoevenagel enone (14-E, previously
referred to as a hydrobilin)7 in the subsequent one-flask
reaction to form the desired bacteriochlorin BC-1.
The reaction of enone 14-E to form the bacteriochlorin was
carried out under the conditions employed previously,7
namely, reaction of the enone (∼0.2 mM) in the presence of
10 equiv of Yb(OTf)3 in acetonitrile at 80 °C for 20 h under
argon. The overall reaction entails Nazarov cyclization46,47 to
form the isocyclic ring, SEAr to form the macrocycle, and
elimination of MeOH to achieve aromaticity; the order of the
reaction steps is not known. The reaction was carried out with
24 mg of 14-E, affording a purple reaction mixture after 20 h.
Standard work-up followed by purification by preparative TLC
gave the bacteriochlorophyll model compound BC-1 in 53%
yield.
region (−0.67 and 0.66 ppm), while signals due to the two
methine protons in ring D and two methylene protons in ring
B were downfield (3.89−4.33 ppm) with respect to those in
the precursor 14-E (2.47−2.62 ppm) due to the ring current of
the aromatic macrocycle. The vicinal H17−H18 coupling
constant was 2.5 Hz, in accord with the trans configuration35
and consistent with the spectra for chlorophyll and
derivatives.36 The existence of two epimers, which is well
documented in natural chlorophylls and bacteriochloro-
phylls,48−50 was apparent in the 1H NMR spectrum: two
peaks (6.09 and 5.99 ppm) with a 7:1 ratio were observed for
the 132 proton, reflecting the major and minor epimers.
NOESY spectroscopy led to assignment of the major epimer
with trans−trans configuration with respect to three methine
protons in rings D and E (i.e., 17−18 and 18−132) and hence
the trans−cis configuration for the minor epimer (Figure 4).
Such epimers are known to interconvert via an intermediate
enol of the β-ketoester with rate that depends strongly on the
structure and electronic properties of the macrocycle,48−50 as
well as the nature and polarity of the medium.48 The reported
ratio of 132-epimers for bacteriochlorophyll a ranges from
7:351 to 3:149 to >10:1,52 which encompass the observed ratio
of 7:1 for BC-1. The rates for bacteriopheophytins are
apparently not known, but pheophytins generally epimerize
20−40 times faster than chlorophylls.49 Fundamental studies
to explore this process, including the effects of conditions and
coordinated metals, are now possible but are beyond the scope
of the present paper. The more pressing issue here concerned
the stereochemical integrity of the alkyl groups at positions 17
and 18. The NMR results indicate that the two alkyl groups in
the pyrroline ring are present in the expected trans stereo-
chemistry.
2.4. Macrocycle Characterization. The product BC-1
exhibited the expected protonated molecular ion peak [M +
H]+ at m/z 555.2591 upon LC-HRMS analysis with an
identical isotopic distribution pattern to theoretical calculation
1
for C32H35N4O5 at m/z 555.2602. The H NMR spectrum
Bacteriochlorin BC-1 in toluene at room temperature
revealed peaks due to the distinct NH protons in the upfield
exhibits absorption bands (at 356, 379, 536, and 749 nm)
G
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characteristic of a bacteriopheophytin π system.3 The long-
wavelength (Qy) band (749 nm) exhibited intensity versus the
Scheme 8. Ring-B Chlorins: Formation Here (Top) and
Known Previously (Bottom)
near-UV (B) band [IQ /IB] of 0.94, a full width at half-
y
maximum of 22 nm, and a molar absorption coefficient (ε) of
72,100 M−1 cm−1 (Figure S12). The fluorescence properties,
also in toluene at room temperature, include λem at 753 nm
(Stokes shift of 4 nm) and fluorescence quantum yield (Φf) of
0.17. The spectral properties can be compared with those of
bacteriopheophytin a, the free base ligand of bacteriochloro-
phyll a (Chart 1), which exhibits λabs = 748 nm, ε = 67,600
M−1 cm−1,3,4 [IQ /IB] = 0.64, λem at 765 nm, and Φf of 0.126
y
(in diethyl ether)53 or 0.094 (in acetone/methanol 7:3).54,55
2.5. Macrocycle Dehydrogenation. Treatment of hydro-
porphyrins with the high-potential quinone DDQ56 is well
established,57 and with native bacteriochlorophylls and
derivatives causes dehydrogenation of pyrroline ring B
preferentially over ring D.10,58−60 Here, the trans-dialkyl-
substituted ring D is susceptible to dehydrogenation, whereas
the gem-dimethyl-substituted ring B is not. The reaction of
bacteriochlorin BC-1 with DDQ at room temperature afforded
the chlorin C-1 in 35% yield (Scheme 8, top). The C-1
contains a saturated ring B, in contrast to native chlorophylls,
wherein ring D is saturated. Although obtained in tiny quantity
(1.4 mg), the chlorin C-1 was characterized by HRMS, 1H and
13C NMR spectroscopy, and absorption and fluorescence
spectroscopy (Figure 5, bottom panel), including fluorescence
quantum yield determination (Φf = 0.41). Although BC-1 is
composed of a mixture of diastereomers (epimers at the 132-
position), C-1 is expected as a pair of enantiomers. Relatively
few ring-B chlorins containing an intact isocyclic ring are
known (Scheme 8, bottom), all of which have been prepared
by semisynthesis beginning with bacteriochlorophyll a (by
selective dehydrogenation with FeCl3)59,60 or a porphyrin
derived from chlorophyll a (by selective vicinal hydroxylation
with OsO4).61 The known ring-B chlorins exhibit the following
red-region absorption properties: C-2, λ = 691 nm, ε691nm
=
=
4.31 × 104 M−1 cm−1 (CH2Cl2);59 C-3, λ = 682 nm, ε682nm
3.65 × 104 M−1 cm−1 (CH2Cl2/THF);60 and C-4, λ = 683 nm
(CH2Cl2).61
The availability of C-1 provided a valuable marker to address
one of the key questions posed at the outset of this research,
namely, does adventitious dehydrogenation occur during the
course of macrocycle formation leading to a chlorin byproduct
accompanying the bacteriochlorin BC-1? The chlorin C-1 was
used as an authentic standard to search for chlorin
contamination via fluorescence spectroscopy. A series of
mock samples was prepared by mixing BC-1 and C-1, with
the latter in serially diluted quantities (i.e., 1:10−1, 1:10−2,
1:10−3, and 1:10−4), and fluorescence spectra (650−800 nm)
were collected upon illumination at 406, 420, 430, 440, and
553 nm; the wavelengths were chosen where the chlorin
absorbs strongly but the bacteriochlorin absorbs weakly
(Figures S13 and S14). Excitation at 406 nm proved superior,
where the limit of detection of the chlorin was found to be
0.1% of the bacteriochlorin (2 μM), as shown in Figure 6. With
these calibrants in hand, the reaction of 14-E was repeated to
form bacteriochlorin BC-1. Following reaction for 21 h at 80
°C, a sample from the crude reaction mixturewithout any
workup other than dilution in toluenegave the absorption
spectrum and the fluorescence spectrum (λex 406 nm) shown
in Figure 6. Comparison of the fluorescence spectra shows that
the amount of chlorin present corresponds to 0.014 times that
of the bacteriochlorin (i.e., 1:71 ratio). The presence of such a
small quantity of impurity is likely undetectable by most
methods but is observable by careful fluorescence spectrosco-
py; indeed, there is no chlorin detectable by absorption
spectroscopy at 692 nm, a wavelength where the chlorin
absorbs strongly compared with that of the bacteriochlorin.
3. OUTLOOK
The work described herein is part of a program focused on
developing a de novo synthesis of native bacteriochlorophylls.
The installation of trans-dialkyl groups in the two pyrroline
rings is essential to such a synthesis. The strategy we have
employed installs the groups at a very early stage of the
synthesis, in an acyclic precursor to the pyrroline ring, and has
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oxidation (SeO2, rt, 15 min), Knoevenagel condensation
(piperidine/AcOH in MeCN, rt, 40 h), and a one-flask
domino process of Nazarov cyclization, SEAr, and elimination
of methanol (Yb(OTf)3 in MeCN, 80 °C, 20 h). The trans-
dialkyl configuration is retained to a high degree over the
course of the synthesis. The Riley oxidation of 1-methyldihy-
drodipyrrin 12 affords dihydrodipyrrin−carboxaldehyde 13 in
a yield that is less than half that of many gem-dimethyl-
substituted dihydrodipyrrins.34 Aside from such reactions that
require amelioration to achieve high yields throughout, three
possibly precarious aspects of the synthesis bear on the
integrity of the trans-dialkyl configuration in ring D:
(i) Epimerization of the dihydrodipyrrin 2-position (equiv-
alent to the bacteriochlorin 17-position) could occur by
site-localized inversion and also by imine−enamine
tautomerization (Δ1,10 → Δ1,2). See Schemes 2 and 5
for position numbering. Such processes can proceed in
all structures containing a dihydrodipyrrin unit: 12, 13,
and 14.
Figure 5. Spectra in toluene at room temperature. Absorption of 14-E
(top); and absorption and fluorescence (red dotted lines) of
bacteriochlorin BC-1 (middle) and chlorin C-1 (bottom).
(ii) Imine−enamine tautomerization (Δ1,10 → Δ1,2) fol-
lowed by alkene migration (dihydrodipyrrin Δ4,5
→
Δ3,4) together would convert the 2,3-dihydrodipyrrin to
the dipyrromethane (see Scheme 6 for the conversion).
The dipyrromethane is regarded as the thermodynamic
product. Such isomerization would not only cause loss of
the trans-dialkyl stereochemistry but would also yield a
chlorin rather than a bacteriochlorin.
(iii) Adventitious dehydrogenation of the dihydrodipyrrin
2,3-positions would afford the dipyrrin; similar dehy-
drogenation of the bacteriochlorin 17,18-positions
would afford the chlorin. Dehydrogenation of bacterio-
chlorins (that lack stabilizing structural features such as
gem-dimethyl groups) to form chlorins on routine
handling in air is a well-established phenomenon.10−13
An explicit search in the crude reaction mixture for the
chlorin byproduct, using an authentic sample (C-1), revealed
the presence of the latter at 1.4% relative to that of
bacteriochlorin BC-1. The presence of the chlorin could not
be observed by the routine method of absorption spectroscopy
but was detectable by the sensitive technique of fluorescence
spectroscopy. While the quantity of chlorin byproduct is
already quite low, the fluorescence assay may prove useful in
further studies of reaction conditions that further decrease the
yield of chlorin.
The reaction conditions for conversion of 14-E to BC-1
have been developed by extension of methods reported for the
Nazarov reaction of pyrrole-substituted enones43 and the
macrocyclization of dihydrodipyrrin−acetals leading to bacter-
iochlorins.17,62 While Nazarov cyclization is an essential step in
the overall reaction process, the conditions here are 1000-fold
more dilute (∼0.2 mM) and use a greater relative amount of
acid (10 equiv) versus the typical Nazarov cyclization of
divinyl ketones (0.1−0.3 M substrate, catalytic quantities of
acid).43,44,63 The Nazarov cyclization entails (conrotatory)
electrocyclization of a pentadienyl cationic intermediate. While
E−Z isomerization is facile for divinyl ketones and heteroaryl
vinyl ketones upon exposure to the acidic conditions of the
Nazarov reaction,41−45 we employed exclusively the major
isomer (14-E) for studies herein. The electrocyclization yields
two stereocenters, here at the 15- and 132-positions, of which
the former is lost upon subsequent aromatization. The origin
of the 7:1 ratio of epimeric 132-CO2Me substituents is
Figure 6. Absorption spectrum (toluene, room temperature) of the
final (21 h) crude mixture upon reaction of 14-E (top). Fluorescence
spectra upon excitation at 406 nm of (i) standard samples containing
BC-1 and serially diluted C-1 (solid lines) overlaid with (ii) the final
crude reaction mixture of 14-E (dotted line).
been demonstrated for methyl and ethyl substituents in ring D.
The trans-dialkyl configuration is achieved by Nicholas
reaction to afford a 2,3-disubstituted pent-4-ynoic acid.
Subsequent reactions (conditions) include TMS cleavage
(LiOOH, 0 °Crt, 4 h), Pd-mediated coupling (Et3N in
MeCN, 80 °C, 18 h), Petasis olefination (toluene, 80 °C, 5 h),
aqueous hydrolysis (1 M HCl in DMF, rt, 30 min), Paal−
Knorr-like reaction (NH4OAc and Et3N, 55 °C, 15 min), Riley
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attributed50 to the stereochemistry and size of the adjacent 17-
substituent, which is an ethyl group in BC-1 versus a phytyl
propionate in BChl a. Further studies of diverse conditions
(perhaps including the effects of chiral catalysts) are required
to understand the reaction of Knoevenagel enones (14-E and
analogues) as well as the kinetic stability of the observed
epimeric ratio at the 132-position.
14.5, 59.8, 109.7, 116.6, 118.8, 123.5, 165.3; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C7H10NO2, 140.0706; found, 141.0708.
4.1.2. Ethyl 5-Iodo-1H-pyrrole-3-carboxylate (2). Following a
literature procedure18 at a 5-fold larger scale, a solution of 1 (7.24 g,
52 mmol) in DMF (130 mL) at 0 °C was treated with NIS (11.70 g,
52 mmol) in portions over 15 min. The reaction mixture was
continuously stirred at 0 °C for 1 h, followed by dilution with water
(100 mL). The resulting solution was extracted with diethyl ether (4
× 150 mL). The combined organic extract was dried (Na2SO4),
concentrated, and chromatographed [silica, hexanes/ethyl acetate
(2:1), 6.5 cm × 40 cm] to afford a slightly yellow solid (8.98 g, 65%):
silica TLC Rf 0.38 in hexanes/ethyl acetate (2:1); mp 64−66 °C; 1H
NMR (500 MHz, CDCl3): δ 1.34 (t, J = 7.1 Hz, 3H), 4.28 (q, J = 7.1
Hz, 2H), 6.78 (dd, J = 2.5 and 1.7 Hz, 1H), 7.42 (dd, J = 2.9 and 1.6
Hz, 1H), 8.93 (br, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 14.4,
60.2, 63.5, 119.1, 119.2, 127.3, 163.9; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C7H9INO2, 265.9673; found, 265.9666.
At present, the only means to access native bacteriochloro-
phylls and analogues is via semisynthesis12,64,65 of biosynthe-
sized native pigments. The biosynthesis of bacteriochlorophylls
relies on first forming a porphyrin (protoporphyrin IX, the
ligand of heme), which is then subjected to two stereoselective
reduction processes to form the trans-dialkyl configuration in
rings D and B.66 The enzymes for the two processes are
protochlorophyllide reductase and chlorin reductase, respec-
tively. The availability of (nonenzymic) asymmetric catalysts
for stereoselective reduction of a porphyrin in rings B and D
would provide an attractive complementary route, as the
synthetic chemistry of porphyrins is more advanced than that
of bacteriochlorins. In the absence of such catalysts, the
introduction of stereochemically defined groups in precursors
to the pyrroline rings seems the most suitable approach. The
bacteriochlorophyll model compound (BC-1) prepared herein
is unusual, given the presence of one gem-dimethyl group and
one trans-dialkyl group in pyrroline rings B and D, respectively,
yet has the virtue of enabling focus on the integrity of only one
site of vulnerability, the trans-dialkyl-substituted ring D. The
sharp focus validates a synthetic approach that may prove
viable for gaining access to native bacteriochlorophylls and
analogues, which to date have fallen outside the scope of
chemical synthesis.
4.1.3. (2S,3S)-2-Ethyl-3-methylpent-4-ynoic Acid (3). Following a
general procedure,24 a solution of 9 (15.41 g, 47.6 mmol) in THF/
water (3:1, 600 mL) at 0 °C was treated with aqueous 0.5 M LiOH
(286 mL, 143 mmol) and 30% H2O2 (44 mL, 380 mmol). The
resulting solution was first stirred at 0 °C for 1 h and subsequently at
room temperature for 3 h. The completion of the transformation was
checked by TLC, whereupon further stirring with addition of a further
quantity of 30% H2O2 was done if needed. The reaction mixture was
then cooled to 0 °C, quenched by the slow addition of 1.5 N Na2SO3
until a negative test with KI-starch paper was obtained, stirred at room
temperature for 30 min, and then concentrated under reduced
pressure to remove THF. The resulting solution was treated with
saturated aqueous NaHCO3 (300 mL) and extracted with CH2Cl2 (3
× 200 mL). The organic extract was concentrated under reduced
pressure to recover (R)-4-isopropyloxazolidin-2-one (6). The aqueous
layer was cooled in ice followed by the dropwise addition of conc.
HCl until pH = 2. The acidic solution was extracted with ethyl acetate
(5 × 150 mL), and the combined organic extract was concentrated
under reduced pressure to afford a clear, colorless oil (6.18 g, 93%):
1H NMR (500 MHz, CDCl3): δ 0.98 (t, J = 7.4 Hz, 3H), 1.25 (d, J =
7.1 Hz, 3H), 1.69−1.74 (m, 2H), 2.11 (d, J = 2.4 Hz, 1H), 2.40 (q, J
= 7.9 Hz, 1H), 2.79−2.85 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3): δ 11.9, 17.9, 22.2, 27.7, 52.0, 69.8, 85.9, 179.8; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C8H13O2, 141.0910; found, 141.0909.
4.1.4. ( ) Hexacarbonyldicobalt Complex (5). A solution of 4
(14.67 mL, 100 mmol) in anhydrous THF (200 mL) was cooled to
−78 °C under argon and treated with 1.6 M MeLi (1.6 M in Et2O,
62.5 mL, 100 mmol). The reaction mixture was stirred for 15 min at
−78 °C, followed by addition of dimethyl sulfate (9.48 mL, 100
mmol), warming to room temperature, and stirring at room
temperature for 28 h. Then, octacarbonyldicobalt 90% (37.99 g,
100 mmol) was added batchwise to the reaction mixture under
vigorous stirring. A brisk evolution of (presumed CO) gas was noticed
over the course of addition of Co2(CO)8. The mixture was stirred at
room temperature for 12 h. The resulting dark brown solution was
concentrated and chromatographed [silica, hexanes/ethyl acetate
(50:1), 6.5 cm × 28 cm] to afford a dark red paste (35.11 g, 79%):
4. EXPERIMENTAL SECTION
4.1. General Methods. All chemicals from commercial sources
were used as received. Silica gel for column chromatography (230−
400 mesh, 60 Å) was obtained from Silicycle Inc. Preparative TLC
plates (1000 μm thickness) were purchased from Analtech. THF for
use in inert−atmosphere reactions was freshly distilled from sodium/
benzophenone ketyl. DMF and acetonitrile used as reaction media
were stirred overnight in the presence of 3 Å molecular sieves,
followed by distillation. Dichloromethane employed as a solvent for
reactions was dried overnight over 3 Å molecular sieves. All other
solvents were reagent grade from commercial suppliers.
Compounds 1,17 2,18 and 722 have been prepared and isolated in
5.12, 2.56, and 2.85 g quantities, respectively, and fully characterized.
Compound 521 has been prepared in 2.0 g quantity according to a
synthetic route that is different from the more streamlined route
reported herein. Compound 3 is listed in ACS Scifinder but without
any reference. Dihydrodipyrrin II7 is known.
1
4.1.1. Ethyl 1H-Pyrrole-3-carboxylate (1). Following a literature
procedure17 at 1.5-fold larger scale, a sample of NaH (60% in mineral
oil, 6.68 g, 167 mmol) was washed with hexanes (3 × 25 mL),
suspended in anhydrous Et2O (270 mL), and stirred at room
temperature. A solution of ethyl acrylate (10.0 g, 100 mmol) and
TosMIC (28.2 g, 144 mmol) in the anhydrous co-solvent of Et2O
(400 mL) and DMSO (200 mL) was added slowly to the ethereal
suspension of NaH. The reaction mixture was stirred overnight at
room temperature. Water (400 mL) was added slowly, followed by
extraction with ethyl acetate (4 × 200 mL). The combined organic
extract was dried (Na2SO4), concentrated, and chromatographed
[silica, hexanes/ethyl acetate (2:1), 6.5 cm × 40 cm] to afford a
yellow oil (9.15, 66%): silica TLC Rf 0.33 in hexanes/ethyl acetate
(2:1); 1H NMR (500 MHz, CDCl3): δ 1.34 (t, J = 7.1 Hz, 3H), 4.28
(q, J = 7.1 Hz, 2H), 6.66−6.67 (m, 1H), 6.75−6.76 (m, 1H), 7.43−
7.44 (m, 1H), 8.51 (br, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ
silica TLC Rf 0.30 in hexanes/ethyl acetate (50:1); H NMR (500
MHz, CDCl3): δ 0.31 (s, 9H), 1.48 (d, J = 6.2 Hz, 3H), 3.48 (s, 3H),
4.47 (q, J = 6.2 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 0.8,
22.8, 57.2, 77.8, 113.3, 200.4 (br).
4.1.5. (R)-3-Butyryl-4-isopropyloxazolidin-2-one (7). Following a
general procedure22 at a 5-fold larger scale, a solution of (R)-4-
isopropyloxazolidin-2-one (6, 10.00 g, 77 mmol) in anhydrous THF
(200 mL) at −78 °C under argon was treated slowly with n-BuLi (1.6
M in hexanes, 48 mL, 77 mmol). The resulting reaction mixture was
vigorously stirred at −78 °C for 15 min. The reaction mixture was
removed from the cooling bath and treated dropwise with butyryl
chloride (8.00 mL, 77 mmol) with vigorous stirring. The resulting
clear solution was stirred for 24 h at room temperature before
treatment with saturated aqueous NH4Cl (200 mL). The ethereal
layer was collected. The aqueous layer was extracted with CH2Cl2 (3
× 100 mL). The combined organic extract was washed with water,
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dried (Na2SO4), concentrated, and chromatographed [silica, hexanes/
ethyl acetate (2:1), 6.5 cm × 40 cm] to give a clear, colorless oil
(13.90 g, 91%): silica TLC Rf 0.45 in hexanes/ethyl acetate (2:1); 1H
NMR (500 MHz, CDCl3): δ 0.88 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 7.0
Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H), 1.64−1.75 (m, 2H), 2.33−2.42 (m,
1H), 2.81−2.87 (m, 1H), 2.94−3.00 (m, 1H), 4.20 (dd, J = 9.0 and
3.1 Hz, 1H), 4.27 (t, J = 8.7 Hz, 1H), 4.44 (dt, J = 8.3 and 3.2 Hz,
1H); 13C{1H} NMR (125 MHz, CDCl3): δ 13.7, 14.7, 17.9, 18.0,
28.4, 37.4, 58.4, 63.3, 154.1, 173.2; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C10H18NO3, 200.1281; found, 200.1274.
directly in the next synthetic transformation. Analysis of the 9.68 g of
isolated sample by 1H NMR spectroscopy showed the presence of 10-
E/Z at 87% purity (with 1 accounting for the remaining 13%),
implying a 69% yield in total for both E and Z isomeric forms. Further
purification of a small sample by preparative TLC [20 cm × 20 cm,
1000 μm thickness, silica, hexanes/ethyl acetate (5:1)] gave the E-
1
isomer of the title compound: H NMR (500 MHz, CDCl3): δ 1.03
(t, J = 7.4 Hz, 3H), 1.33−1.37 (m, 6H), 1.64−1.72 (m, 1H), 1.75−
1.83 (m, 1H), 2.35−2.39 (m, 1H), 3.17 (q, J = 7.0 Hz, 1H), 4.30 (q, J
= 7.1 Hz, 2H), 6.05 (s, 1H), 6.52 (s, 1H), 7.38 (s, 1H), 8.60 (br, 1H);
13C{1H} NMR (125 MHz, CDCl3) 11.2, 14.5, 18.6, 25.0, 37.8, 50.2,
60.0, 96.9, 107.0, 118.0, 123.1, 126.6, 155.4, 164.8, 176.3; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C15H20NO4, 278.1387; found,
218.1385.
4.1.6. Nicholas Adduct (8) and Its Decomplexed Derivative (9).
Following a general procedure23 with modification, a solution of 7
(12.75 g, 64 mmol) in anhydrous CH2Cl2 (200 mL) at 0 °C with
vigorous stirring under argon was treated dropwise with Bu2BOTf (1
M in CH2Cl2, 100 mL, 100 mmol) and then dropwise with
diisopropylethylamine (11.15 mL, 64 mmol). After stirring at 0 °C
for 15 min, the mixture was cooled to −78 °C. A solution of
hexacarbonyldicobalt complex 5 (28.30 g, 64 mmol) in anhydrous
CH2Cl2 (170 mL) was added dropwise via a syringe to the in situ
generated boronate ester. After the addition, the reaction mixture was
allowed to warm to 0 °C, then left at 0 °C for 20 min, then allowed to
warm to room temperature, and then left at room temperature for 20
min. The reaction was quenched by the addition of a phosphate buffer
solution at pH 7 (0.1 M, made from K2HPO4 and KH2PO4, 400 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 150 mL). The
combined organic extract was washed with water, dried (Na2SO4),
concentrated, and chromatographed [silica, hexanes/ethyl acetate
(5:1), 6.5 cm × 40 cm] to yield the Nicholas adduct 8 as a dark red
paste (29.95 g, 77%): silica TLC Rf 0.35 in hexanes/ethyl acetate
4.1.8. Ethyl 5-(((3S,4S)-4-Ethyl-3-methyl-5-methylenedihydrofur-
an-2(3H)-ylidene)methyl)-1H-pyrrole-3-carboxylate (11-E/Z). Prep-
aration of the Petasis reagent and application in the olefination of 10-
E/Z were conducted according to a standard procedure.18 A solution
of Cp2TiCl2 (33.12 g, 133 mmol) in anhydrous toluene (350 mL) at 0
°C under argon was treated dropwise with MeLi (1.6 M in Et2O, 182
mL, 291 mmol). The reaction mixture was stirred at 0 °C for 1 h, and
then, saturated aqueous NH4Cl (400 mL) was added. The organic
layer was washed with water and brine, dried (Na2SO4), and filtered.
The filtrate (containing the Petasis reagent) was treated with the
above postcolumn chromatographed sample of 10-E/Z (8.93 g, 87%
pure, 28 mmol) and additional Cp2TiCl2 (418 mg). The reaction
mixture was heated at 80 °C in an oil bath for 5 h in the dark under
argon. Then, the resulting solution was allowed to cool to room
temperature, followed by the addition of MeOH (33 mL), NaHCO3
(1.39 g), and water (333 μL). The resulting mixture was stirred at 40
°C in an oil bath for 12 h, diluted with CH2Cl2, and then filtered
through Celite. The filtrate (clear yellow) was concentrated and
chromatographed [silica, hexanes/ethyl acetate (2:1) in the presence
of 1% Et3N, 6.5 cm × 40 cm, Rf 0.38 in hexanes/ethyl acetate (2:1)]
1
(5:1); H NMR (500 MHz, CDCl3): δ 0.34 (s, 9H), 0.85−0.89 (m,
6H), 0.94 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 7.1 Hz, 3H), 1.54−1.60
(m, 1H), 1.95−2.05 (m, 1H), 2.29−2.36 (m, 1H), 3.43 (qd, J = 7.1
and 1.9 Hz, 1H), 4.00 (d, J = 11.9 Hz, 1H), 4.21 (dd, J = 9.1 and 3.0
Hz, 1H), 4.30 (t, J = 8.8 Hz, 1H), 4.55 (dt, J = 8.5 and 4.2 Hz, 1H);
13C{1H} NMR (125 MHz, CDCl3): δ 1.0, 11.9, 14.4, 17.2, 17.8, 18.2,
28.5, 41.5, 50.8, 58.1, 63.0, 79.3, 115.0, 153.2, 173.7, 200.2 (br), 200.6
(br); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H30Co2NO9Si,
610.0348; found, 610.0345.
1
to yield an orange solid. Characterization by H NMR spectroscopy
and LC-HRMS indicated the presence of the E and Z isomers in 7:1
ratio (4.95 g, 64%): mp 70−72 °C; the following NMR listing is for
1
the E isomer only: H NMR (500 MHz, CDCl3): δ 0.95 (t, J = 7.4
Hz, 3H), 1.24 (d, J = 7.1 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.48
(quintd, J = 7.3 and 0.9 Hz, 2H), 2.36 (t, J = 7.1 Hz, 1H), 2.96 (q, J =
7.1 Hz, 1H), 4.08 (d, J = 1.7 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.51
(d, J = 1.5 Hz, 1H), 5.73 (s, 1H), 6.43 (s, 1H), 7.32−7.33 (m, 1H),
8.18 (br, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 11.3, 14.5, 18.2,
27.8, 39.8, 50.6, 59.8, 84.4, 91.7, 105.3, 117.8, 122.2, 128.7, 161.4,
162.9, 165.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C16H22NO3, 276.1594; found, 276.1589.
A solution of the entire sample of 8 (29.95 g, 49 mmol) in acetone
(400 mL) was treated in portions with CAN (∼115 g total) under
vigorous stirring until the brisk evolution of (presumed CO) gas as
well as the dark brown color of solution was no longer detected. The
resulting solution was diluted with water, concentrated under reduced
pressure, and then extracted with CH2Cl2 (5 × 150 mL). The
combined organic extract was washed with water, dried (Na2SO4),
1
and concentrated to afford a clear, colorless oil (15.41 g, 97%): H
4.1.9. Ethyl 5-((Z)-((3S,4S)-4-Ethyl-3,5-dimethyl-3,4-dihydro-2H-
pyrrol-2-ylidene)methyl)-1H-pyrrole-3-carboxylate (12). Following
a general procedure18 with some modifications, aqueous 1 M HCl
(3.4 mL) was added to a solution of 11-E/Z (1.58 g, 5.75 mmol) in
DMF (67 mL). The reaction mixture was stirred at room temperature
for 30 min. Afterward, NH4OAc (8.86 g, 115 mmol) and Et3N (16.0
mL, 115 mmol) were added, and the resulting solution was stirred at
55 °C in an oil bath for 15 min. The reaction was rapidly cooled to 0
°C in an ice bath before being quenched and diluted by sequential
addition of cold saturated aqueous KH2PO4 (150 mL) solution and
ethyl acetate (150 mL). The organic layer was washed with water,
dried (Na2SO4), concentrated, and chromatographed [deactivated
silica prepared by pretreating with Et3N in hexanes and then removing
the solvent under reduced pressure, hexanes/ethyl acetate (2:1), 4.5
cm × 40 cm] to afford the title dihydrodipyrrin (0.88 g, 56%, Rf 0.48
in hexanes/ethyl acetate (2:1)) and dipyrromethane byproduct 12-
DPM (0.27 g, 17%, Rf 0.35 in hexanes/ethyl acetate (2:1)) as a brown
and yellow solid, respectively.
NMR (500 MHz, CDCl3): δ 0.11 (s, 9H), 0.85−0.94 (m, 9H), 1.18
(d, J = 7.2 Hz, 3H), 1.71 (quint, J = 7.2 Hz, 2H), 2.35−2.44 (m, 1H),
2.92 (quint, J = 7.2 Hz, 1H), 3.94 (q, J = 6.9 Hz, 1H), 4.20 (d, J = 9.0
Hz, 1H), 4.26 (t, J = 8.7 Hz, 1H), 4.49−4.50 (m, 1H); 13C{1H} NMR
(125 MHz, CDCl3): δ 0.1, 11.0, 15.0, 17.5, 18.0, 21.8, 28.4, 28.6, 48.4,
58.6, 63.1, 85.2, 109.4, 153.6, 174.3; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C17H30NO3Si, 324.1990; found, 324.1983.
4.1.7. Ethyl 5-(((3S,4S)-4-Ethyl-3-methyl-5-oxodihydrofuran-
2(3H)-ylidene)methyl)-1H-pyrrole-3-carboxylate (10-E/Z and 10-
E). Following a general procedure18 with modification, a 500 mL
Schlenk flask was charged with 2 (11.66 g, 44 mmol), 3 (6.17 g, 44
mmol), BnNEt3Cl (12.22 g, 44 mmol), and Et3N (52.5 mL) in 250
mL of acetonitrile. The mixture was degassed by three cycles of
freeze−pump−thaw prior to addition of Pd(PPh3)4 (2.54 g, 2.20
mmol). The resulting mixture was subjected to one more degassing
cycle and then stirred at 80 °C in an oil bath for 18 h. The mixture
was allowed to cool to room temperature, diluted by addition of water
(300 mL), and extracted with CH2Cl2 (4 × 200 mL). The combined
organic extract was dried (Na2SO4), concentrated, and chromato-
graphed [silica, hexanes/ethyl acetate (2:1), 6.5 cm × 40 cm, Rf 0.28
in hexanes/ethyl acetate (2:1)] to deliver a brown paste (9.68 g),
which was found to comprise a mixture of two (E, Z) isomers in 9:1
ratio along with deiodinated compound 1. This mixture, referred to as
the postcolumn chromatographed sample of 10-E/Z, was used
12: Characterization by 1H NMR spectroscopy and LC-HRMS
indicated the presence of a single isomer (Z only): mp 57−59 °C; 1H
NMR (500 MHz, CDCl3): δ 0.94 (t, J = 7.4 Hz, 3H), 1.19 (d, J = 7.1
Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.38−1.45 (m, 1H), 1.74−1.80 (m,
1H), 2.18 (s, 3H), 2.31−2.34 (m, 1H), 2.60−2.63 (m, 1H), 4.27 (q, J
= 7.1 Hz, 2H), 5.75 (s, 1H), 6.45 (s, 1H), 7.41−7.42 (m, 1H), 11.21
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(br, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 11.1, 14.5, 18.9, 20.9,
24.3, 40.5, 59.3, 59.5, 104.8, 108.2, 116.3, 124.0, 132.1, 157.6, 165.4,
182.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H23N2O2,
275.1754; found, 275.1759.
4.1.10. 8-Carboethoxy-2-ethyl-1,3-dimethyldipyrromethane (12-
DPM). mp 102−104 °C; 1H NMR (500 MHz, CDCl3): δ 1.07 (t, J =
7.5 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H), 1.97 (s, 3H), 2.10 (s, 3H), 2.37
(q, J = 7.5 Hz, 2H), 3.84 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 6.42 (s,
1H), 7.28 (br, 2H), 8.20 (br, 1H); 13C{1H} NMR (125 MHz,
CDCl3): δ 9.0, 10.9, 14.5, 15.7, 17.7, 24.2, 59.7, 107.0, 114.2, 116.7,
120.8, 120.9, 121.9, 122.8, 130.9, 165.1; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C16H23N2O2, 275.1754; found, 275.1744.
4.1.11. (2S,3S)-8-Carboethoxy-2-ethyl-1-formyl-3-methyl-2,3-di-
hydrodipyrrin (13). Following a general procedure,18 SeO2 (1.33 g,
12.0 mmol) was added in one portion to a solution of compound 12
(1.10 g, 4.00 mmol) in distilled 1,4-dioxane (120 mL) in the presence
of added deionized water (200 μL). The reaction mixture was stirred
at room temperature for 15 min. Upon completion, ethyl acetate (150
mL) and saturated aqueous NaHCO3 (150 mL) were added. The
organic layer was washed with water, dried (Na2SO4), concentrated,
and chromatographed [deactivated silica prepared by pretreating with
Et3N in hexanes and then removing the solvent under reduced
pressure, hexanes/ethyl acetate (2:1), 4.5 cm × 30 cm, Rf 0.47 in
hexanes/ethyl acetate (2:1)] to give a yellow paste (247 mg, 21%):
1H NMR (500 MHz, CDCl3): δ 0.90 (t, J = 7.4 Hz, 3H), 1.21 (d, J =
7.0 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.40−1.51 (m, 1H), 1.84−1.92
(m, 1H), 2.72−2.78 (m, 2H), 4.29 (q, J = 7.1 Hz, 2H), 6.21 (s, 1H),
6.69 (s, 1H), 7.54 (dd, J = 3.1 and 1.5 Hz, 1H), 9.98 (s, 1H), 10.84
(br, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 11.0, 14.5, 21.5, 24.5,
41.2, 53.8, 59.8, 112.8, 114.9, 117.4, 126.5, 131.3, 157.2, 164.7, 173.9,
190.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H21N2O3,
289.1547; found, 289.1543.
4.1.12. 2-Carbomethoxy-3-[(2S,3S)-8-carboethoxy-2-ethyl-1-
formyl-3-methyl-2,3-dihydrodipyrrin-1-yl]-1-[1-(1,1-dimethoxy-
methyl)-3,3-dimethyl-2,3-dihydrodipyrrin-8-yl]prop-2-en-1-one
(14). Following a literature procedure7 with modification, samples of
13 (38.0 mg, 132 μmol), II (50.0 mg, 143 μmol), and dried molecular
sieves powder (3 Å, 45 mg) were added to a solution of piperidine/
acetic acid in acetonitrile (15 mM/15 mM, 3.50 mL, 52.8 μmol/52.8
μmol). The reaction mixture was stirred at room temperature for 20
h, whereupon an additional amount of II (9.2 mg, 26 μmol) was
added. Then, the resulting reaction mixture was stirred at room
temperature for another 20 h, followed by filtration on a Celite pad.
The filtrate was concentrated and purified by preparative TLC [20 cm
× 20 cm, 1000 μm thickness, silica, hexanes/ethyl acetate (1:1)] to
afford two orange bands, which were characterized as two isomeric
forms of the title compound. Band 2 was subsequently found by
single-crystal X-ray crystallography to be the E isomer (see the
Supporting Information).
Band 1, implied to be the Z isomer (Rf 0.55 in hexanes/ethyl
acetate (1:1), 2.3 mg, 3%): 1H NMR (500 MHz, CDCl3): δ 0.94 (t, J
= 7.4 Hz, 3H), 1.21−1.23 (m, 9H), 1.34 (t, J = 7.1 Hz, 3H), 1.41−
1.50 (m, 1H), 1.72−1.80 (m, 1H), 2.54−2.57 (m, 1H), 2.66 (s, 2H),
2.68−2.71 (m, 1H), 3.46 (s, 6H), 3.78 (s, 3H), 4.28 (q, J = 7.1 Hz,
2H), 5.04 (s, 1H), 5.86 (s, 1H), 5.99 (s, 1H), 6.57 (s, 1H), 6.59 (s,
1H), 7.11 (s, 1H), 7.52 (dd, J = 3.1 and 1.6 Hz, 1H), 7.57 (dd, J = 3.1
and 1.5 Hz, 1H), 10.79 (br, 1H), 11.26 (br, 1H); 13C{1H} NMR (125
MHz, CDCl3): δ 10.9, 14.5, 21.2, 25.0, 28.9, 40.2, 40.7, 48.4, 52.7,
54.5, 57.8, 59.6, 102.3, 106.2, 109.1, 110.2, 110.7, 116.6, 124.1, 125.9,
126.5, 130.0, 131.5, 132.7, 140.0, 157.2, 162.3, 165.0, 168.6, 172.8,
176.3, 183.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C34H43N4O7, 619.3126; found, 619.3123.
(125 MHz, CDCl3): δ 11.0, 14.5, 21.1, 25.1, 28.92, 28.94, 40.2, 40.6,
48.4, 52.9, 54.57, 54.58, 58.0, 59.5, 102.4, 106.3, 108.0, 110.5, 110.8,
116.2, 125.0, 126.2, 126.4, 131.4, 131.5, 133.0, 138.8, 157.1, 162.4,
165.0, 165.1, 171.9, 176.4, 188.9; HRMS (ESI-TOF) m/z [M + H]+
calcd for C34H43N4O7 619.3126; found, 619.3119.
4.1.13. (17S,18S)-3-Carboethoxy-132-carbomethoxy-17-ethyl-
8,8,18-trimethyl-131-oxo-bacteriophorbine (BC-1). Following a
literature procedure7 with modification, a sample of Yb(OTf)3 (241
mg, 388 μmol) was added to a solution of 14-E (24.0 mg, 38.8 μmol)
in acetonitrile (200 mL) in a glovebox. The reaction mixture was then
stirred at 80 °C in a sand bath for 20 h under the argon atmosphere
inside the glovebox. Then, the reaction mixture was allowed to cool to
room temperature, withdrawn from the glovebox, and filtered through
a Celite pad. The filtrate was concentrated and purified by preparative
TLC [20 cm × 20 cm, 1000 μm thickness, silica, hexanes/ethyl
acetate (3:1)] to yield a purple solid comprising two epimeric forms
in 7:1 ratio (11.5 mg, 53%). The major product determined by
NOESY spectroscopy possesses a trans−trans configuration with
1
respect to the three stereocenters in the molecule: H NMR (500
MHz, CDCl3): δ −0.67 (br, 1H), 0.66 (br, 1H), 1.00 (t, J = 7.4 Hz,
3H), 1.66 (t, J = 7.1 Hz, 3H), 1.73 (d, J = 7.4 Hz, 3H), 1.86 (s, 3H),
1.90 (s, 3H), 1.95−2.04 (m, 1H), 2.25−2.33 (m, 1H), 3.85 (s, 3H),
3.89−3.92 (m, 1H), 4.23−4.33 (m, 3H), 4.68−4.77 (m, 2H), 6.09 (s,
1H), 8.40 (s, 1H), 8.44 (s, 1H), 8.50 (s, 1H), 9.15 (d, J = 1.9 Hz,
1H), 9.49 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 10.8, 14.7,
22.9, 27.6, 31.05, 31.12, 44.5, 49.5, 52.97, 53.00, 53.3, 61.5, 64.3, 98.9,
100.2, 100.6, 108.4, 109.2, 126.6, 129.8, 131.2, 137.7, 137.8, 141.0,
149.6, 159.5, 164.7, 165.2, 169.6, 171.2, 171.4, 188.9; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C32H35N4O5, 555.2602; found,
555.2591. λabs = 749 nm, λem = 753 nm, Φf = 0.17 (λex = 536 nm), in
toluene.
4.1.14. 3-Carboethoxy-132-carbomethoxy-17-ethyl-8,8,18-tri-
methyl-131-oxophorbine (C-1). A solution of bacteriochlorin BC-1
(4.0 mg, 7.2 μmol) and DDQ (3.27 mg, 14.4 μmol) in toluene (7.2
mL) was stirred at room temperature for 17 h in a glovebox filled with
argon. The reaction mixture was then quenched by the addition of
saturated aqueous NaHCO3 (10 mL). The organic phase was
collected. The aqueous phase was extracted with Et2O (3 × 10 mL).
The combined organic extract was dried (Na2SO4) and concentrated
to give a crude brown solid, which was then chromatographed in a
Pasteur pipette (silica, CH2Cl2) to yield a greenish deposit (1.4 mg,
35%): 1H NMR (500 MHz, CDCl3): δ 1.53 (t, J = 7.6 Hz, 3H), 1.70
(t, J = 7.1 Hz, 3H), 1.98 (s, 3H), 2.03 (s, 3H), 3.22 (s, 3H), 3.56 (ddt,
J = 18.5, 14.9, and 7.5 Hz, 2H), 3.79 (s, 3H), 4.54 (s, 2H), 4.78 (q, J =
7.2 Hz, 2H), 6.64 (s, 1H), 8.77 (s, 1H), 8.87 (s, 1H), 9.43 (d, J = 3.2
Hz, 1H), 9.58 (d, J = 4.1 Hz, 1H), 9.83 (s, 1H), two exchangeable
protons bound to nitrogen atoms were not unambiguously
determined; 13C{1H} NMR (125 MHz, CDCl3): 11.3, 14.8, 16.3,
20.2, 31.1, 31.3, 45.4, 52.7, 53.4, 61.5, 66.2, 97.5, 98.5, 104.2, 115.0,
143.5, 165.0, 169.6, 188.9, signals for 2 methine carbons and 11
quaternary carbons in the tetrapyrrole macrocycle were not observed;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C32H33N4O5, 553.2446;
found, 553.2435. λabs = 692 nm, λem = 695 nm, Φf = 0.41 (λex = 553
nm), in toluene.
4.2. Crystallization Protocol. Enone 14-E (20 mg) was dissolved
in acetonitrile (1 mL) and then divided equally among six 500 μL
glass insert tubes. Each insert tube was placed in a 5 mL vial
containing 1 mL of one of the following solvents: pentane, hexane,
heptane, diethyl ether, toluene, or benzene (Figure S6). The vials
were allowed to stand at room temperature for vapor diffusion. The
sample in acetonitrile/diethyl ether yielded the crystalline sample
used for X-ray crystallography analysis.
Band 2, E-isomer (Rf 0.48 in hexanes/ethyl acetate (1:1), 57.3 mg,
70%): mp 155−157 °C; 1H NMR (500 MHz, CDCl3): δ 0.92 (t, J =
7.4 Hz, 3H), 1.12 (d, J = 7.1 Hz, 3H), 1.20 (d, J = 2.8 Hz, 6H), 1.33
(t, J = 7.1 Hz, 3H), 1.39−1.47 (m, 1H), 1.74−1.81 (m, 1H), 2.47−
2.50 (m, 1H), 2.57−2.58 (m, 1H), 2.62 (s, 2H), 3.42 (d, J = 1.6 Hz,
6H), 3.78 (s, 3H), 4.26 (q, J = 7.1 Hz, 2H), 4.99 (s, 1H), 5.83 (s,
1H), 5.85 (s, 1H), 6.46 (s, 1H), 6.51 (s, 1H), 7.37 (s, 1H), 7.43 (s,
1H), 7.45 (s, 1H), 10.36 (br, 1H), 11.20 (br, 1H); 13C{1H} NMR
4.3. Molar Absorption Coefficient of BC-1. A stock solution of
1.30 mM BC-1 (7.20 mg, 13.0 μmol) in HPLC-grade toluene (10
mL) was serially diluted to form six solutions with concentrations
spanning a range from 0.13 to 6.5 μM. The absorption spectrum of
each solution was recorded. The graph of the absorbance at λ = 749
nm versus concentration was plotted, and the molar coefficient was
determined to be 72,100 M−1 cm−1 from the slope of the graph
(Figure S12).
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4.4. Fluorescence Spectroscopy. The fluorescence spectro-
meter instrument parameters were as follows: excitation and emission
slit widths = 1.5 nm (0.375 mm); photomultiplier tube (Hamamatsu
R928P) voltage = 1000; and integration time = 1 nm/s. The
fluorescence spectra were corrected for sample absorption at the
wavelength of excitation and for instrument sensitivity as a function of
wavelength. Fluorescence quantum yields were determined with use
of the standard 2,12-di-p-tolyl-8,8,18,18-tetramethylbacteriochlorin
(Φf = 0.18, toluene).67 The Φf of C-1 is 0.41, whereas that of BC-1 is
0.17.
Authors
Khiem Chau Nguyen − Department of Chemistry, North
Carolina State University, Raleigh, North Carolina 27695-
8204, United States; orcid.org/0000-0002-6968-6405
Pengzhi Wang − Department of Chemistry, North Carolina
State University, Raleigh, North Carolina 27695-8204, United
States; orcid.org/0000-0003-4813-6639
Roger D. Sommer − Molecular Education, Technology, and
Research Innovation Center, North Carolina State University,
Raleigh, North Carolina 27695-8204, United States;
orcid.org/0000-0003-1422-5967
4.5. Spectroscopic Examination of the Chlorin Content in
the Bacteriochlorin-Forming Reaction Mixtures. Stock solutions
of bacteriochlorin BC-1 and chlorin C-1 were prepared in toluene.
The concentrations were estimated as 4.0 and 2.0 μM, respectively,
from the absorbance of the Qy band in the absorption spectrum and
reported values of the molar absorption coefficient for the analogues
bacteriopheophytin a (BPheo a, λabs = 748 nm, ε = 67,600 M−1
cm−1)3,4 and C-3 (λ = 682 nm, ε682nm = 3.65 × 104 M−1 cm−1,
CH2Cl2/THF).60 Four mock solutions with a constant concentration
of BC-1 at 2.0 μM and serially diluted concentrations of C-1 ranging
from 0.2 to 0.0002 μM were made from the two stock solutions.
To determine the most appropriate excitation wavelength, the
fluorescence spectrum was examined at five excitation wavelengths:
406, 420, 430, 440, and 553 nm (Figure S13). A strong emission of C-
1 (λem = 695 nm) versus low emission of BC-1 (λem = 753 nm) was
achieved upon excitation at 406 nm. The graph of integrated
fluorescence intensity at λem = 695 nm versus concentration of C-1 in
mock solutions is plotted in Figure S14. An aliquot from the crude
mixture (of 14-E at 80 °C for 21 h) was taken and diluted in toluene
to achieve a concentration of bacteriochlorin BC-1 of ∼2.0 μM
(determined by absorption spectroscopy). The resulting solution was
analyzed by emission spectroscopy, showing that chlorin C-1 was
present at the concentration of 0.028 μM (interpolated from the
linear plot in Figure S14), which corresponds to the molar ratio 1:71
with respect to BC-1 in the same sample (Figure 6). Note that the
intensity of fluorescence emission depends on (1) the absorption at
the wavelength of excitation (which in turn depends on the
concentration and the molar absorption coefficient at that wave-
length) and (2) the value of the fluorescence quantum yield.
4.6. Nomenclature. Compound BC-1 shares a common
hydrocarbon skeleton with a free base bacteriochlorophyll (i.e., a
bacteriopheophytin) but also differs significantly with regard to
peripheral substituents, namely, the lack of the phytyl ester and the
lack of the trans-dialkyl groups in ring B. For a more exact description,
BC-1 is (1) a bacteriochlorin owing to the presence of pyrroline rings
B and D, and (2) a phorbine68 (with 7,8-saturation) owing to the
presence of the isocyclic ring. The hydrocarbon skeleton of BC-1 is
hence a bacteriophorbine.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00608
Notes
The authors declare the following competing financial
interest(s): J.S.L. is a cofounder of NIRvana Sciences, which
may license aspects of the technology described herein, for
which a patent has been applied.
ACKNOWLEDGMENTS
■
This work was supported by the NSF (CHE-1760839). This
work was performed in part by the Molecular Education,
Technology, and Research Innovation Center (METRIC) at
NC State University, which is supported by the State of North
Carolina. We thank NC Biotechnology Center for partial
funding for the D8Venture X-ray instrument (2019-IDG-
1010).
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c00608.
1H NMR and 13C{1H} NMR data for all new
compounds; single-crystal X-ray data for 14-E; fluor-
escence spectra for the chlorin assay; and molar
absorption coefficient data for BC-1 (PDF)
(6) Lindsey, J. S. De Novo Synthesis of Gem-Dialkyl Chlorophyll
Analogues for Probing and Emulating our Green World. Chem. Rev.
2015, 115, 6534−6620.
Crystallographic data for compound 14 (CIF)
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Macrocycle with Concomitant Nazarov Cyclization to Form the
Annulated Isocyclic Ring: Analogues of Bacteriochlorophyll a. J. Org.
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AUTHOR INFORMATION
■
Corresponding Author
Jonathan S. Lindsey − Department of Chemistry, North
Carolina State University, Raleigh, North Carolina 27695-
8204, United States; orcid.org/0000-0002-4872-2040;
Phone: 919-515-6406; Email: jlindsey@ncsu.edu
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