Exploration of the Bis(thio)urea-Catalyzed Atropselective Synthesis of Marinopyrrole A

Article abstract of DOI:10.1002/ejoc.201600147

The marinopyrroles are a new class of natural products with highly interesting biomedical and structural features. We herein provide a concise, nitrogen-protective-group-free synthesis of marinopyrrole A, constituting the as yet most efficient route. The

Full text of DOI:10.1002/ejoc.201600147

DOI: 10.1002/ejoc.201600147
Full Paper
Atropselective Halogenation
Exploration of the Bis(thio)urea-Catalyzed Atropselective
Synthesis of Marinopyrrole A
Maciej Stodulski,[a] Stefanie V. Kohlhepp,[b] Gerhard Raabe,[a] and Tanja Gulder*[a,b]
Abstract: The marinopyrroles are a new class of natural prod- cient route. The presented studies elaborate a straightforward
ucts with highly interesting biomedical and structural features. and mild chlorination protocol. Moreover, the first study to-
We herein provide a concise, nitrogen-protective-group-free wards the atropselective synthesis of marinopyrrole A, using
synthesis of marinopyrrole A, constituting the as yet most effi- chiral, C2-symmetric bisthiourea catalysts, is presented.
Introduction
The halogenated bipyrroles are a recently discovered class of
antimicrobial natural products, exemplified by (–)-marinopyrr-
ole A (1) and B (2) (Figure 1).[1] These two compounds were
isolated from the marine Streptomyces strain CNQ-418 by Feni-
cal et al. in 2008,[2] and they show highly potent in vitro activi-
ties. Their pronounced activity, especially against MRSA strains
and a colon cancer cell line, makes them promising lead struc-
tures for the development of new drugs.[3] In addition, these
compounds have an unprecedented structural core with an axi-
ally chiral N,C-linkage connecting the two densely chlorinated
Figure 1. Marinopyrroles A [(M)-1] and B [(M)-2].
pyrrole portions. The formation of this very rare heterobiaryl
axis follows an unexpected biosynthetic pathway catalyzed by
an FADH2-dependent halogenase.[4] The involvement of the
flavoenzyme suggests an electrophilic aromatic substitution as
the biosynthetic mechanism for the homocoupling. Such a bio-
synthesis is in clear contrast to the phenol oxidative coupling
usually observed for C,C-coupled biaryls.[5] Rotation around the
heterobiaryl axis in 1 and 2 is hampered at ambient tempera-
tures, leading to separable enantiomers, of which only the (M)
isomer has been found in the bacterial producer. Their interest-
ing antibiotic and anticancer properties, together with their re-
markable structural features, make the marinopyrroles attract-
ive targets not only for biological and medicinal studies, but
also for natural product synthesis. This attention has resulted in
four approaches to 1 and 2, to date; however, these have only
been racemic syntheses, involving a Paal–Knorr condensation
or a copper-mediated N-arylation as the key step.[6]
lytic tetrachlorination step. By this approach, the dechloro-
marinopyrrole analog 8, the key intermediate for an atrop-
selective preparation of 1, is easily available in multigram quan-
tities. This set the scene for an intensive exploration of the
structural properties of 8 and its interaction with thioureas,
which were used as chiral catalysts. These molecules can, in
principle, act as chiral molecular tweezers giving the opportu-
nity to envisage an atropselective chlorination using the con-
cept of dynamic kinetic resolution.[7]
Results and Discussion
Our synthesis of racemic marinopyrrole A (1) began with the
formation of bipyrrole 5 (Scheme 1). This was achieved by con-
densation of aminopyrrole 3[8] and α-keto ester 4[9] in 75 %
yield. After conversion of both ester groups into the corre-
sponding Weinreb amides (91 %), diamide 6 was treated with
o-lithiated anisole 7 to give ketone 8 in one step in 86 % yield.
It is worth mentioning that the use of organolithium reagent 7
was crucial for the success of this transformation. Other metal-
ated anisoles resulted in either no or only a sluggish reaction.
For example, when the corresponding Grignard reagent (not
shown) was used, a complex reaction mixture was obtained,
with the monoaddition products being the major products.
That the addition of organometallic species to C-3-substituted
In this paper, we describe the most efficient route to date to
the antibiotic marinopyrrole A (1), featuring a mild, organocata-
[a] Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52056 Aachen, Germany
[b] Department Chemie and Catalysis Research Center (CRC),
Technische Universität München,
Lichtenbergstrasse 4, 85747 Garching, Germany
E-mail: tanja.gulder@tum.de
http://www.halogene.ch.tum.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600147.
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Scheme 1. Highly efficient route to racemic marinopyrrole A (1). pTSA = 4-toluenesulfonic acid; LiHMDS = lithium hexamethyldisilazide.
and thus sterically demanding pyrroles tends to be very sensi- (Table 1, Entries 13 and 14), or activating NCS with a Brøn-
tive was already observed by Sarli et al.[6c] when they tried to sted[12] (Table 1, Entries 6 and 7) or Lewis acid (Table 1, Entry 8)
transform 3-bromopyrrole derivatives by treatment with aryl resulted in lower yields of 11 together with the formation of
Grignard reagents. Using our conditions, this crucial step was side-products. Cleavage of the O-methyl groups under standard
carried out on a gram scale, allowing the generation of large Lewis-acidic conditions[6d] completed the formation of 1 in only
quantities of key intermediate 8, thus providing the bipyrrole five steps in an excellent 42 % overall yield, and without the
in sufficient quantities to facilitate studies on the asymmetric need for protection of the pyrrole nitrogen atom.
synthesis of 1.
Table 1. Optimization of the tetrachlorination of 8 (NCS = N-chlorosuccin-
imide).
In the next step, optimum conditions for a mild aromatic
tetrachlorination were evaluated (Table 1). Treatment of 8 with
Entry
Cl+
Additive
Solvent
Time
Conversion [%]
NCS (N-chlorosuccinimide) in CH2Cl2 under standard conditions
at room temperature gave 11, but the yield was only 35 % after
2 d (Table 1, Entry 1). Changing the solvent did not lead to an
improvement of the conversion (Table 1, Entries 2–4). The only
exception was the use of MeCN (Table 1, Entry 5). This rate
enhancement was not surprising, as Lewis-basic solvents are
prone to activate electrophilic halogenating reagents, such as
NCS. A similar, but more pronounced effect was observed by
using 10 mol-% of the Lewis base PPh3, which provided 11 in
58 % yield overnight (Table 1, Entry 9). The best results were
obtained by the addition of catalytic amounts of either thio-
carbanilide 9 (10 mol-%) or iodobenzamide 10 (10 mol-%).[10]
Both of these additives significantly accelerated the electro-
philic chlorination, giving O,O′-dimethylmarinopyrrole (11) in
76 and 84 % yields, respectively (Table 1, Entries 10 and 11).
When 10 is used as an additive (Table 1, Entry 11), the electro-
philic chlorination most probably proceeds via a cyclic iodane-
chloro species, which is formed by the oxidation of 10 by NCS,
and should be significantly more reactive than NCS. Another
hint towards an actual hypervalent iodine(III)-triggered chlorin-
ation came from the use of the preformed iodine(III) reagent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
–
–
–
–
–
CH2Cl2
EtOAc
THF
2 d
1 d
1 d
1 d
1 d
0.5 h
0.5 h
1 d
16 h
16 h
5 h
10 h
8 h
1 h
42 (35)[a]
<10
15
toluene
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
<10
34
HCl[b]
TsOH[b]
Zn(OAc)2
>99 (40)[a]
>99 (63)[a]
<10
[b]
>99 (58)[a]
>99 (76)[a]
>99 (84)[a]
>99 (78)[a]
>99 (20)[a]
>99 (53)[a]
[b]
PPh3
NCS
NCS
9[b]
10[b]
–
PhICl2
Palau'chlor
SOCl2
–
–
[a] Isolated yield. [b] 10 mol-% of additive was used.
In contrast to the large repertoire available for the stereo-
PhICl2 (Table 1, Entry 12). Here, product 11 was produced in selective formation of C,C-axes,[13] optically pure N,C-coupled
comparable yields (78 %), albeit after extended reaction times. compounds are mostly obtained by chiral resolution[6d,14] due
Other conditions for the tetrachlorination step, e.g., using more to the lack of suitable procedures for establishing N,C-biaryl
reactive chlorination reagents such as Palau'chlor[11] or SOCl2 connectivities in a stereochemically controlled fashion. To date,
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only an auxiliary-based method using a nucleophilic aromatic carbonyl groups are pointing in one direction, separated by a
substitution of planar-chiral arylchromium complexes,[15] and distance of 4.5 Å. These properties make them perfectly suited
two transition-metal-catalyzed cyclization reactions have been as anchor points.
reported.[16] Our efforts to close this methodological gap, and,
in particular, to gain stereoselective access to marinopyrrole 1
involve an enantiotopos-differentiating electrophilic chlorin-
ation of 8, applying a dynamic kinetic resolution. We speculated
that C2-symmetric compounds possessing two hydrogen-bond-
donor entities (cf. Figure 2) could simultaneously coordinate
both of the carbonyl groups in 8. In the resulting diastereo-
meric complexes, one axial configuration is thermodynamically
favored. At the same time, the rotational barrier of the axis
in the complexed biaryls should be increased, decreasing the
interconversion of the atropepimers, and thus locking bipyrrole
8 as a single atropisomer. A now diastereomer-differentiating
chlorination terminates the reaction by introducing two further
Figure 2. Studied (thio)urea catalysts.
substituents adjacent to the N,C-connection. This conversion
Based on this structural information, we selected (thio)urea
compounds 12–18,[19] which differ in their aryl substitution pat-
terns and in the number of carbon atoms linking the hydrogen-
bond-donor entities. An examination of their binding ability to-
wards the two carbonyl groups in 8 by 13C NMR spectroscopy
revealed that CF3 substituents on the N-phenyl rings as well as
thiourea groups are necessary for the formation of noncovalent
interactions between 8 and the N–H moieties in the putative
catalysts (see Supporting Information).
fixes the absolute configuration, and results in the formation of
only one specific enantiomer of 11. Based on our experience in
the mild tetrachlorination of 8 (cf. Table 1) and the application
of (thio)ureas as powerful catalysts in numerous asymmetric re-
actions in general,[17] the use of such chiral hydrogen-bond do-
nors seemed to be very promising. The catalysts would play a
double role: coordination to the carbonyl groups, thus prevent-
ing rotation around the bipyrrole axis, and activation of the
electrophilic chlorination reagent for the aromatic halogena-
tion. This hypothesis was further corroborated by the X-ray
This observation is completely consistent with the noncova-
structure analysis of compound 8 (cf. Scheme 1).[18] There, both lent binding of 8 with our organocatalysts through hydrogen
Figure 3. Comparison of the 13C NMR signals of the carbonyl and thiocarbonyl groups in (1) a 1:1 mixture of 8 and (R,R)-18, (2) bipyrrole 8, and (3) bisthiourea
(R,R)-18.
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bonding. Earlier studies by Schreiner showed that the presence reactive Palau'chlor, result in the desired improvement of the
of CF3 groups had a dramatic impact on the hydrogen-bond- enantiomeric excess (Table 2, Entries 11 and 12).
donor abilities of such systems.[20] The coordination of bipyrrole
8 to 12 or 14 was clearly visible by the downfield shift of the
C=O signals in the 13C NMR spectra, although the interaction
with one of the carbonyl groups was stronger (see Supporting
Information). A rather equal shift of the ketone signals was ob-
served using 13, in which two methylene groups are located
between the thiourea fragments, apparently reaching an opti-
mal tether length. Similar shifts of the diagnostic NMR signals
were observed (Figure 3) when the ethyldiamine chain was re-
placed by (R,R)-cyclohexyl-1,2-diamine, thus making 18 per-
fectly suited as the catalyst scaffold for the enantiotopos-differ-
entiating chlorination.
Next, chiral (thio)urea compounds 15–18 were tested as cat-
alysts (10 mol-%) in the asymmetric halogenation (Table 2). Us-
ing the optimized conditions for the nonstereoselective tetra-
chlorination corroborated the results obtained in the NMR spec-
troscopic studies. A significantly hampered reactivity or only
the formation of racemic product 11 was observed when poorly
The low ee values obtained could be explained by the ability
of ureas to coordinate imides and imidate anions through
hydrogen bonding.[21] Such noncovalent interactions would
block the hydrogen-bond-donor entities in 18, and thus se-
verely change the envisaged binding of bipyrrole 8 to the
thiourea catalyst. In order to shed light on this hypothesis, elec-
trophilic chlorine reagents without hydrogen-bond-acceptor
properties were tested. Only hypervalent iodine(III) chlorination
agents, such as PhICl2, gave (M)-11 in similar yields but with
slightly higher ee (11 %) compared to NCS (Table 2, Entry 13).
Notably, by switching catalyst (R,R)-18 to its antipode (S,S)-18
(Table 2, Entry 14), the corresponding unnatural atropisomer
[i.e., (P)-11] was predominantly obtained with the same enan-
tiomeric excess (11 %). This clearly indicates that the observed
enantioselectivity is not an artefact. Increasing the amount of
18 from 10 mol-% to 100 mol-% similarly did not give 11 with
a higher ee.
As both types of chlorination reagents gave 11 with the
binding catalysts 15–17 were used (Table 2, Entries 1–3). The same unsatisfactory ee, a common mechanism might be in-
most promising catalyst [i.e., (R,R)-18] together with NCS in volved that does not solely rely on hydrogen bonding. A nu-
CH2Cl2 at 0 °C overnight gave O,O′-dimethylmarinopyrrole A cleophilic activation of NBS (N-bromosuccinimide) or DIH (1,3-
(11) in an excellent 74 % yield and 8 % ee in favor of the (M) diiodo-5,5-dimethylhydantoin) by the Lewis-basic sulfur in
atropisomer (Table 2, Entry 4). Raising the amount of 18 to thiourea 12 was recently reported for the oxidation of alco-
100 mol-% did not improve the optical purity, but gave 11 in a hols[22] and the iodination of aromatic compounds.[23] Bearing
lower yield (ca. 50 %, 8 % ee, not shown). Variation of the reac- in mind the high affinity of sulfur-derived Lewis bases for halo-
tion conditions (Table 2, Entries 5–10) revealed that to obtain a gen atoms,[21a,24,25] a plausible explanation of the poor stereoin-
high yield, it was necessary to run the reaction at a temperature duction in the synthesis of O,O′-dimethylmarinopyrrole (11)
not lower than 0 °C, using a polar aprotic solvent, such as might be the formation of the Lewis-base–Cl+ complex, inter-
CH2Cl2, chloroform, or MeCN. An increase in the ee, however, mediate 19 (Scheme 2). Here, the chlorine atom is activated
was not achieved. Neither did changing the electrophilic halo- towards nucleophilic attack by the bipyrrole system, which
genation reagent from NCS to NCP, or the, in principle, more could lead to the observed increase in chlorination reactivity.
Table 2. Attempted atropselective transformation of 8 (NCS = N-chlorosuccinimide; NCP = N-chlorophthalimide).
Entry
Cl+
Catalyst
Solvent
Yield [%][a]
ee [%][b]
1
2
3
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
(R,R)-15
(R,R)-16
(R,R)-17
(R,R)-18
(R,R)-18
(R,R)-18
(R,R)-18
(R,R)-18
(R,R)-18
(R,R)-18
(R,R)-18
(R,R)-18
(R,R)-18
(S,S)-18
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
toluene
MeCN
EtOAc
THF
–
–
–
–
12
76
74
–
72
39
63
54
43
41
54
68
70
4
8 (M)
–
2 (M)
4 (M)
–
4 (M)
4 (M)
–
4 (M)
11 (M)
11 (P)
5[c]
6
7
8
9
10
11
12
13
14
NCS
NCP
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Palau'chlor
PhICl2
PhICl2
[a] Isolated yield. [b] ee was determined by HPLC using a chiral stationary phase. [c] Reaction was carried out at –35 °C.
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Such Cl+ activation is also in agreement with the aforemen-
tioned structural requirements of the catalysts. After deprotona-
tion, thiochloro imine species 20 is generated, in which the
hydrogen-bond-donor ability is clearly decreased. NMR spectro-
scopic measurements of 18 with and without NCS showed the
formation of a new unsymmetrical species bearing an imine
structural motif, as indicated by the signal at δ = 155 ppm
in the 13C NMR spectrum (see Supporting Information), thus
supporting our mechanistic assumption.
further purification. Yields refer to chromatographically and spec-
troscopically (1H NMR) homogeneous materials, unless otherwise
stated. Reactions were monitored by thin-layer chromatography
(TLC), carried out on Merck silica gel aluminium plates with F-254
indicator using UV light as the visualizing agent, and an acidic solu-
tion of anisaldehyde, phosphomolybdic acid, or ceric ammonium
molybdate and heat as developing agents. Merck silica gel 60 (parti-
cle size 0.63–0.2 mm) was used for flash column chromatography.
Solvent mixtures are understood as volume/volume. NMR spectra
were recorded with Varian Mercury 300, V NMR 400, or Bruker
AV500-cryo spectrometers. The spectra were calibrated using resid-
ual undeuterated solvent as an internal reference (CHCl3: δ =
7.26 ppm, CH2Cl2: δ = 5.32 ppm for 1H NMR; CHCl3: δ = 77.00 ppm,
CH2Cl2: δ = 54.00 ppm for 13C NMR). The following abbreviations
(or combinations thereof) are used to explain the multiplicities: s =
singlet, d = doublet, dd = doublet of doublets, t = triplet, m =
multiplet, br. = broad. Melting points were determined with a Büchi
M-560 melting-point apparatus. IR spectra were recorded with a
JASCO FTIR 4100 (ATR) instrument or a Perkin–Elmer Spectrum 100
spectrometer, and are reported in wavenumbers (cm–1). Mass spec-
tra were recorded with Finnigan MAT SSQ 7000 (MS-EI, 70 eV; CI,
100 eV), ThermoFinnigan LCQ Deca XP plus (ESI MS), and Thermo-
Fisher Scientific LTQ Orbitrap XL (ESI HRMS) spectrometers.
Scheme 2. Proposed intermediates in the catalytic electrophilic chlorination.
In intermediate 20, the envisaged fixation of the axial confor-
mation in 8 by C2-symmetric molecular tweezers is no longer
possible, as one of the thiourea moieties is blocked. Neverthe-
less, 20 is still able to act as an in-situ-formed chiral chlorination
reagent coordinating to one of the carbonyl groups in 8. This
will lead to a hampered, but not abolished rotation around the
N,C-biaryl axis, thus giving stereochemically enriched tetra-
chlorinated 11.
Synthesis of Racemic Marinopyrrole (1)
Diethyl N′,3-Bipyrrole-2,2′-dicarboxylate (5):[6a] Ethyl 3-amino-
pyrrole-2-carboxylate hydrochloride[8] (3; 1.91 g, 10.0 mmol,
1.0 equiv.) was dissolved in toluene (25 mL, 0.4 M), and keto ester
4[9] (2.59 g, 12.00 mmol, 1.2 equiv.) and p-toluenesulfonic acid
monohydrate (17.0 mg, 0.10 mmol, 0.01 equiv.) were added at room
temperature. The mixture was heated at reflux for 10 h, and then
stirred at room temperature for additional 12 h. The mixture was
then washed with satd. aq. NaHCO3 solution (3 × 30 mL). The aque-
ous layer was reextracted with CH2Cl2 (3 × 30 mL), and the com-
bined organic phases were dried with anhydrous MgSO4. The sol-
vent was evaporated, and the brown slurry was purified by column
chromatography (SiO2; hexane/EtOAc, 7:3) to give diester 5 (2.07 g,
7.50 mmol, 75 %) as colorless crystals; m.p. 75 °C (hexane/EtOAc).
1H NMR (300 MHz, CDCl3): δ = 9.12 (br., 1 H, NH), 7.06 (dd, J = 3.9,
1.8 Hz, 1 H, CHar), 6.91 (dd, J = 3.3, 2.8 Hz, 1 H, CHar), 6.88 (dd, J =
2.7, 1.8 Hz, 1 H, CHar), 6.31 (t, J = 2.9 Hz, 1 H, CHar), 6.25 (dd, J =
3.9, 2.7 Hz, 1 H, CHar), 4.22–4.07 (m, 4 H, OCH2), 1.22 (t, J = 7.1 Hz,
3 H, Me), 1.11 (t, J = 7.1 Hz, 3 H, Me) ppm. MS (ESI): m/z = 277.4 [M
+ H]+. The obtained physical and spectroscopic data of 5 were in
agreement with those published in the literature.[6a]
Conclusions
We have developed an efficient, N-protecting-group-free syn-
thesis of the structurally and biologically intriguing natural
product marinopyrrole A (1) involving a mild, Lewis-base- or
iodine(III)-catalyzed tetrachlorination step. This strategy for the
synthesis of racemic 1, combined with structural analysis of
configurationally labile bipyrrole 8, and NMR binding studies of
C2-symmetric bis(thio)urea catalysts 13–18, paved the way for
the first attempts at the asymmetric generation of 1 using an
atropselective chlorination. Although all the bis(thio)ureas
tested had an impact on the chlorination rate, their stereoin-
duction did not exceed 11 %. Nevertheless, these experiments
provide an explicit proof-of-principle, and show that such a
strategy is, in general, feasible. Preliminary investigations into
the interactions of the electrophilic chloro reagents and catalyst
18 revealed the importance of the Lewis-basic sulfur atom for
enhancing the reaction rate. Unfortunately, this Cl+ activation is
also responsible for breaking the hydrogen bonds to at least
N′,3-Bipyrrole-2,2′-bis(N′′-methoxy-N′′-methylamide) (6):
A
stirred suspension of N,O-dimethylhydroxylamine hydrochloride
(2.82 g, 29.0 mmol, 4.0 equiv.) and diester 5 (2.00 g, 7.24 mmol,
1.0 equiv.) in dry THF (60 mL, 0.5
solution in THF; 36.2 mL, 36.2 mmol, 5.0 equiv.) at –78 °C. After 1 h,
one of the carbonyl groups in bipyrrole 8. Based on the mecha- the mixture was warmed to room temperature and stirred for 6 h.
M) was treated with LiHMDS (1 M
After this time, it was recooled to 0 °C, and further LiHMDS (1
M
nistic information obtained here, a more streamlined and ra-
tional catalyst design becomes possible, and this is currently
underway in our laboratory.
solution in THF; 36.2 mL, 36.2 mmol, 5.0 equiv.) and N,O-dimethyl-
hydroxylamine hydrochloride (2.82 g, 29.0 mmol, 4.0 equiv.) were
added. The reaction mixture was stirred at room temperature for
further 16 h. The latter procedure [addition of LiHMDS (36.2 mL,
36.2 mmol, 5.0 equiv.) and N,O-dimethylhydroxylamine hydro-
chloride (2.82 g, 29.0 mmol, 4.0 equiv.)] was repeated once again.
Then, the reaction mixture was treated with satd. aq. NH4Cl solution
(100 mL), followed by the addition of water (100 mL). The THF was
removed, and the aqueous residue was extracted with CH2Cl2 (3 ×
200 mL). The combined organic extracts were dried with MgSO4,
and the solvent was evaporated under reduced pressure. The crude
Experimental Section
General Information: Solvents used in reactions were p.a. grade.
Solvents for chromatography were technical grade, distilled before
use. Anhydrous dichloromethane and THF were obtained from an
MBraun MB-SPS 800 solvent purification system. Reagents were pur-
chased at the highest commercial quality, and were used without
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product was purified by column chromatography on silica gel using
a solvent gradient (hexane/EtOAc, 3:7, to EtOAc) to give compound
6 (2.02 g, 6.59 mmol, 91 %) as a white solid; m.p. 146 °C (hexane/
was cooled to 0 °C. BBr3 (1
M
solution in CH2Cl2; 1.0 mL, 1.04 mmol,
4.0 equiv.) was added dropwise, and the mixture was stirred at 0 °C
for 1 h. Saturated aqueous NaHCO3 solution (10 mL) was then
added, and the biphasic mixture was extracted with CH2Cl2 (3 ×
20 mL). The combined organic phases were dried (MgSO4), filtered,
and concentrated. The residue was purified by column chromatog-
1
EtOAc). H NMR (400 MHz, CDCl3): δ = 9.30 (br., 1 H, NH), 6.92 (dd,
J = 3.9, 1.7 Hz, 1 H, CHar), 6.87–6.85 (m, 2 H, CHar), 6.25 (dd, J = 3.9,
2.7 Hz, 1 H, CHar), 6.22 (t, J = 2.9 Hz, 1 H, CHar), 3.70 (s, 3 H, OMe),
3.62 (s, 3 H, OMe), 3.25 (s, 3 H, NMe), 3.13 (s, 3 H, NMe) ppm. 13C
raphy (SiO2; hexane/EtOAc, 4:1) to give marinopyrrole (1) (126 mg,
1
NMR (101 MHz, CDCl3): δ = 162.1 (C=O), 160.4 (C=O), 129.4 (Car), 0.25 mmol, 95 %) as a yellow solid; m.p. 201 °C (hexane/EtOAc). H
128.2 (Car), 124.8 (Car), 120.0 (Car), 119.8 (Car), 116.7 (Car), 115.8 (Car),
108.4 (Car), 61.32 (OMe), 61.06 (OMe), 34.09 (NMe), 33.96 (NMe)
NMR (400 MHz, CDCl3): δ = 11.18 (s, 1 H, OH), 10.41 (s, 1 H, OH),
9.79 (br., 1 H, NH), 7.58 (dd, J = 8.0, 1.7 Hz, 1 H, CHar), 7.55–7.44 (m,
2 H, CHar), 7.35 (ddd, J = 8.6, 7.2, 1.7 Hz, 1 H, CHar), 7.02 (dd, J =
8.5, 1.1 Hz, 1 H, CHar), 6.95–6.86 (m, 2 H, CHar), 6.72 (s, 1 H, CHar),
6.52 (ddd, J = 8.2, 7.2, 1.1 Hz, 1 H, CHar) ppm. The obtained physical
and spectroscopic data of 1 are in agreement with those published
in the literature.[2b]
ppm. IR (film): ν = 3224, 1623, 1429, 1374, 1071, 852, 732 cm–1
.
˜
HRMS (ESI): calcd. for C14H18N4O4Na [M + Na]+ 329.1223; found
329.1220.
Dechloro-O,O′-dimethylmarinopyrrole A (8): A solution of 2-
bromoanisole (12.2 g, 65.3 mmol, 10.0 equiv.) in THF (25 mL, 2.9
M)
was cooled to –78 °C, and tBuLi (1.6 in pentane; 40.8 mL,
65.3 mmol, 10.0 equiv.) was added dropwise. The mixture was
stirred at 0 °C for 1 h, then it was added to a solution of Weinreb
M
Atropselective Chlorination of 8
O,O′-Dimethylmarinopyrrole A (11). Method A: Bipyrrole 8
(100 mg, 0.25 mmol, 1.0 equiv.), bisthiourea 18 (16.4 mg,
0.025 mmol, 0.1 equiv.), and NCS (144 mg, 1.08 mmol, 4.3 equiv.)
amide 6 (2.00 g, 6.53 mmol, 1.0 equiv.) in dry THF (22.5 mL, 0.29 M)
by cannula. The reaction mixture was stirred at –78 °C for 1 h and
then warmed to 0 °C overnight. After this time, satd. aq. NH4Cl
solution (60 mL) was added slowly at 0 °C, and the mixture was
extracted with CH2Cl2 (3 × 100 mL). The combined organic phases
were dried with MgSO4, and the solvent was evaporated. The resi-
due was purified by column chromatography (SiO2; hexane/EtOAc,
4:6) to give 8 (5.62 mmol, 86 %) as slightly yellow crystals; m.p.
177 °C (hexane/EtOAc). 1H NMR (500 MHz, CD2Cl2): δ = 9.72 (s, 1 H,
NH), 7.39 (ddd, J = 8.4, 7.4, 1.8 Hz, 1 H, CHar), 7.21 (ddd, J = 8.4, 7.4,
1.8 Hz, 1 H, CHar), 7.16 (dd, J = 7.5, 1.7 Hz, 1 H, CHar), 7.13 (dd, J =
7.6, 1.8 Hz, 1 H, CHar), 7.08 (dd, J = 3.3, 2.7 Hz, 1 H, CHar), 6.98–6.93
(m, 2 H, CHar), 6.78–6.73 (m, 1 H, CHar), 6.70 (d, J = 8.9 Hz, 1 H,
CHar), 6.69–6.67 (m, 1 H, CHar), 6.29 (t, J = 2.8 Hz, 1 H, CHar), 6.26
(dd, J = 4.0, 1.8 Hz, 1 H, CHar), 5.85 (dd, J = 4.0, 2.6 Hz, 1 H, CHar),
3.77 (s, 3 H, OMe), 3.67 (s, 3 H, OMe) ppm. 13C NMR (125 MHz,
CD2Cl2): δ = 184.3 (C=O), 183.8 (C=O), 157.40 (O Car), 156.9 (OCar),
133.0 (Car), 132.8 (Car), 131.6 (Car), 131.5 (Car), 131.3 (Car), 130.4 (Car),
129.5 (Car), 129.1 (Car), 128.7 (Car), 126.7 (Car), 123.7 (Car), 123.2 (Car),
120.5 (Car), 120.1 (Car), 111.9 (Car), 111.11 (Car), 111.07 (Car), 109.1
(Car), 56.08 (OMe), 55.80 (OMe) ppm. MS (ESI): m/z = 423.4 [M +
Na]+. The obtained physical and spectroscopic data of 8 are in
agreement with those published in the literature.[6d]
were stirred in CH2Cl2 (2.5 mL, 0.1 M) at 0 °C for 16 h. The reaction
mixture was directly submitted to column chromatography on silica
gel (hexane/EtOAc, 7:3) to give 11 (99.6 mg, 0.19 mmol, 74 %) as
slightly yellow crystals. The enantiomeric excess of O,O′-dimethyl-
marinopyrrole (11) was determined by HPLC using a Daicel Chiracel
OD-RH column (4.6 × 250 mm, 5 μm), hexane/iPrOH, 75:25, 1 mL/
min. Method B: Bipyrrole 8 (100 mg, 0.25 mmol, 1.0 equiv.), bis-
thiourea 18 (16.4 mg, 0.025 mmol, 0.1 equiv.), and NCS (297 mg,
1.08 mmol, 4.3 equiv.) were stirred in CH2Cl2 (2.5 mL, 0.1 M) at 0 °C
for 16 h. The reaction mixture was directly submitted to column
chromatography on silica gel (hexane/EtOAc, 7:3) to give 11
(91.5 mg, 0.17 mmol, 68 %) as slightly yellow crystals. The enantio-
meric excess of O,O′-dimethylmarinopyrrole (11) was determined
by HPLC on an analytical scale using a Phenomenex Lux Cellulose-
1 column (4.6 × 250 mm, 5 μm), hexane/iPrOH, 75:25, 1 mL/min.
Acknowledgments
This work was funded by a Max-Buchner Fellowship of the DE-
CHEMA and the Emmy-Noether program of the DFG (GU 1134/
3-1).
O,O′-Dimethylmarinopyrrole A (11). Method A: Bipyrrole 8
(100 mg, 0.25 mmol, 1.0 equiv.), thiocarbanilide 9 (6.00 mg,
0.025 mmol, 0.1 equiv.), and NCS (144 mg, 1.08 mmol, 4.3 equiv.)
Keywords: Atropisomerism · Asymmetric synthesis · Natural
products · Total synthesis · Biaryls · Chlorine
were stirred in CH2Cl2 (2.5 mL, 0.1 M) at room temperature for 16 h.
The reaction mixture was directly submitted to column chromatog-
raphy on silica gel (hexane/EtOAc, 7:3) to give 11 (103 mg,
0.19 mmol, 76 %) as slightly yellow crystals. Method B: Bipyrrole
8 (100 mg, 0.25 mmol, 1.0 equiv.), iodobenzamide 10 (7.63 mg,
0.025 mmol, 0.1 equiv.), and NCS (144 mg, 1.08 mmol, 4.3 equiv.)
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M), and the solution
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[18] The structure of 8 was determined by X-ray crystallographic analysis.
CCDC 1415488 (for 8) contains the supplementary crystallographic data
Received: February 10, 2016
Published Online: April 5, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim