Total synthesis of pentabromo- and pentachloropseudilin, and synthetic analogues-allosteric inhibitors of myosin ATPase

Article abstract of DOI:10.1002/anie.200903743

Stopping myo: The total syntheses of the title compounds have been achieved using a highly efficient silver(I)- catalyzed cyclization of N-tosyl-homopropargylamines. The pseudilin derivatives represent a novel class of myosin inhibitors. A new allosteric

Full text of DOI:10.1002/anie.200903743

Communications
DOI: 10.1002/anie.200903743
Myosin Inhibition
Total Synthesis of Pentabromo- and Pentachloropseudilin, and
Synthetic Analogues—Allosteric Inhibitors of Myosin ATPase**
Renꢀ Martin, Anne Jꢁger, Markus Bꢂhl, Sabine Richter, Roman Fedorov, Dietmar J. Manstein,
Herwig O. Gutzeit, and Hans-Joachim Knꢂlker*
The pyrrole ring is a pivotal structural unit of many
pharmacologically active natural products, for example, the
lamellarins[1] and prodigiosins.[2] Recently, we have developed
thesis in 1978,[11] and in the same year it was isolated by
Cavalleri et al. from Actinoplanes ATCC 33002.[12]
To achieve a silver(I)-catalyzed cyclization of the homo-
propargylamines, we introduced a protecting group at the
nitrogen center. The N-protected homopropargylamines have
been cyclized previously to give the corresponding pyrroles
by treatment with iodine or various transition metals.[13]
Moreover, Reissig and others have shown that buta-2,3-
dienyl-N-tosylamines react with catalytic amounts of silver(I)
nitrate to give 2,5-dihydropyrroles, which can then be
converted into pyrroles.[14]
a
novel silver(I)-promoted oxidative cyclization of
homopropargylamines to generate pyrroles,[3] which has
been applied to the synthesis of the anti-leishmania active
(Æ )-harmicine and the antitumor active (Æ )-crispine A.[4]
Homopropargylamines are most conveniently prepared by
the addition of trimethylsilylpropargylmagnesium bromide to
Schiff bases and thus, the silver(I)-promoted cyclization
provides a short access to 2-arylpyrroles.
Over the last decades, a broad range of bioactive
halogenated natural products has been isolated from diverse
natural sources.[5] Pentabromo- (1) and pentachloropseudilin
(2) are highly halogenated natural products containing the 2-
arylpyrrole moiety. Pentabromopseudilin (1) was isolated in
Starting from commercially available 2-methoxybenz-
aldehyde (3a), 3,5-dichloro-2-methoxybenzaldehyde (3b),
and 3,5-difluoro-2-methoxybenzaldehyde (3c) the corre-
sponding N-tosylaldimines 4a–4c were prepared by adapta-
tion of a literature procedure (Scheme 1a).[15] Addition of
trimethylsilylpropargylmagnesium bromide to the N-tosyl-
aldimines 4a–4c provided the N-tosylhomopropargylamines
5a–5c.[16] Desilylation of 5a–5c using TBAF afforded, almost
quantitatively, the terminal acetylenes 6a–6c. Treatment of
the terminal acetylenes 6a–6c with catalytic amounts (10–
15 mol%) of silver(I) acetate in acetone or dichloromethane
under reflux temperatures provided the 2-aryl-2,3-dihydro-
pyrroles 7a–7c in excellent yields. The structure of the 2-aryl-
2,3-dihydropyrrole framework has been unambiguously con-
firmed by an X-ray crystal structure analysis of the parent
compound 7a (Figure 1).[17]
In an investigation of the silver(I)-catalyzed cyclization
reaction of 6a giving the 2,3-dihydropyrrole 7a, we varied the
amount of catalyst and the metal salt. Lower amounts of
silver(I) acetate still gave high product yields by using
extended reaction times (5 mol% of AgOAc, 4 days, 86%
yield of 7a). Among the different transition-metal salts tested,
only cuprous acetate led to the 2,3-dihydro-1H-pyrrole 7a,
albeit in low yield. Treatment of 6a with palladium(II)
acetate, gold(I) chloride, and gold(III) chloride resulted in
decomposition or re-isolation of starting material.
Treatment of 7a–7c with potassium tert-butoxide in
DMSO led, via elimination of p-toluenesulfinic acid, to the
pyrroles 8a–8c.[14] Cleavage of the methyl ether 8a with
sodium sulfide to pseudilin (9) and subsequent electrophilic
bromination using pyridinium tribromide[18] afforded penta-
bromopseudilin (1; Scheme 1b).[19] Electrophilic chlorination
of 8b with NCS to afford O-methylpentachloropseudilin (10)
and subsequent treatment with boron tribromide provided
pentachloropseudilin (2) in high yield.[19] The spectroscopic
data of our products[19] were in good agreement with those
reported for 1[8,10] and 2 in the literature.[11] Electrophilic
bromination of the pyrrole 8b and then ether cleavage of 11
1966 from Pseudomonas bromoutilis[6] and several years later
from Chromobacteria.[7] Pentabromopseudilin (1) exhibits a
range of useful pharmacological activities (antibiotic, anti-
tumor, phytotoxic) and has been subject of detailed biosyn-
thetic studies.[7–9] As a result of the strong interest in 1, several
total syntheses of 1 have been described.[8,10] The weaker
antibiotic, pentachloropseudilin (2), was obtained by syn-
[*] Dr. R. Martin, A. Jꢀger, Prof. Dr. H.-J. Knꢁlker
Department of Chemistry, Technische Universitꢀt Dresden
Bergstrasse 66, 01069 Dresden (Germany)
Fax: (+49)351-463-37030
E-mail: hans-joachim.knoelker@tu-dresden.de
Homepage: http://www.chm.tu-dresden.de/oc2/
Dr. M. Bꢁhl, Dr. S. Richter, Prof. Dr. H. O. Gutzeit
Institute of Zoology, Technische Universitꢀt Dresden
Zellescher Weg 20b, 01217 Dresden (Germany)
Dr. R. Fedorov, Prof. Dr. D. J. Manstein
Institute for Biophysical Chemistry
Hannover Medical School, 30623 Hannover (Germany)
[**] Part 92 of “Transition Metals in Organic Synthesis”. For part 91, see:
M. Schmidt, H.-J. Knꢁlker, Synlett 2009, 2421.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903743.
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Scheme 1. Total synthesis of pentabromopseudilin (1), pentachloropseudilin (2) and synthetic derivatives 12 and 14. Reagents and conditions:
ꢀ
a) p-TsNH2, Si(OEt)4, 1608C; b) BrMgCH2C CSiMe3, CH2Cl2, RT; c) Bu4NF, THF, RT; d) 10–15 mol% AgOAc, acetone, 568C or CH2Cl2, 408C;
e) KOtBu, DMSO, RT or 508C; f) Na2S, NMP, 1608C, 2.5 h (93%); g) Py·HBr·Br2, EtOH, RT, 3 d (59%); h) NCS, MeCN, À408C to RT (81%);
i) BBr3, CH2Cl2, À78 to 08C, 2 h (79%); j) Py·HBr·Br2, EtOH, RT, 30 min (91%); k) BBr3, CH2Cl2, À78 to 08C, 1.5 h (78%); l) Py·HBr·Br2, EtOH,
RT, 60 min (87%); m) BBr3, CH2Cl2, À78 to 08C, 2.5 h (76%). NMP=1-methyl-2-pyrrolidinone, py=pyridine, NCS=N-chlorosuccinimide.
(Et2O, RT, 15 h, 56% yield).[10d,21] N-Methylation was ach-
ieved by treatment of intermediate 7a with KOtBu and
quenching with methyl iodide. Subsequent ether cleavage
with sodium sulfide and bromination using pyridinium
tribromide led to the novel N-methylpentabromopseudilin
(16; 31% overall yield based on 7a).
Figure 1. Molecular structure of the 2,3-dihydropyrrole 7a in the
crystal.
using boron tribromide provided the tribromodichloropseu-
dilin (12; Scheme 1c).[19] Electrophilic bromination of the
difluoro compound 8c and ether cleavage of 13 afforded the
tribromodifluoropseudilin (14).[19] Compound 14 represents
the first fluoro analogue of the natural antibiotics 1 and 2. The
specific effect of carbon–fluorine bonds on docking interac-
tion with proteins have led to an increasing importance of
organofluorine compounds for pharmaceuticals.[20]
For an investigation of the structure–activity relationships,
pentabromopseudilin (1) was converted into the correspond-
ing O-methyl and N-methyl derivatives. Both compounds
would provide information as to whether hydrogen bonding
We achieved the total synthesis of pentabromopseudilin
(1) and pentachloropseudilin (2), as well as the synthetic
analogues 12 and 14–16 using a highly efficient silver(I)-
catalyzed cyclization of N-tosylhomopropargylamines to 2,3-
dihydropyrroles. The seven-step total syntheses of pentabro-
mopseudilin (1; 23% overall yield) and pentachloropseudilin
(2; 19% overall yield) are straightforward and flexible
enough to provide access to a range of structural analogues.
Specific inhibitors of myosins hold great promise for the
treatment of a broad range of diseases including cancer,
malaria, and most obviously a range of muscle malfunctions.
In a screen for motor protein inhibitors, some of the
pseudilins described above proved to be very efficient
inhibitors of skeletal muscle myosin-2 ATPase activity
À
À
of the N H and O H bonds of pentabromopseudilin is
essential for bioactivity. O-Methylpentabromopseudilin (15)
was prepared by reaction with trimethylsilyldiazomethane
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higher for vertebrate class-5 myosins than observed with
skeletal muscle myosin-2 isoforms.[24] Moreover, some pseu-
dilin derivatives appear to activate myosin function.
X-ray crystallographic analysis of the complex formed by
the Dictyostelium myosin-2 motor domain, Mg2+–ADP–meta-
vanadate, and pentabromopseudilin (1) revealed a new
allosteric binding pocket that is located 16 ꢀ away from the
nucleotide binding pocket (Figure 3).[24,25] Moreover, the
Figure 2. Assay for the inhibition of skeletal muscle myosin-2 ATPase
activity. The graph shows the inhibition of the basal ATPase activity of
myosin 2 relative to the control (no inhibitor added, 100% activity).
(À)=control. The known inhibitors (À)-blebbistatin (17) and N-
benzyl-p-toluenesulfonamide (=BTS) (18) were included as positive
controls. The bars represent the mean value of three measurements.
The error bars indicate the standard deviation. All substances were
tested at 25 mm concentration.
(Figure 2). The efficacy of pentabromopseudilin (1) is in the
same range as observed for (À)-blebbistatin (17)[22] and much
superior to that of N-benzyl-p-toluenesulfonamide (BTS)
Figure 3. Structure of the myosin-2 motor-domain complex with Mg2+
ADP–meta-vanadate and pentabromopseudilin (1).
–
allosteric binding pocket of pentabromopseudilin (1) is
7.5 ꢀ away from the allosteric binding pocket of blebbistatin
(17) (Figure 4). The identification of a second allosteric
binding pocket paves the way for structure-based design
approaches leading to the development of more potent and
isoform-specific myosin inhibitors.
In conclusion, we developed a practical silver(I)-catalyzed
synthesis of 2-arylpyrroles which has been utilized for a highly
efficient route to the naturally occurring pentabromo- (1) and
pentachloropseudilin (2), as well as synthetic analogues. The
pentahalogenated pseudilins 1, 2, and 12 are members of a
new class of myosin ATPase inhibitors. Further studies on the
(18).[23] For comparison, both known inhibitors have been
included in our assay (Figure 2). The assay results obtained
with skeletal muscle myosin-2 demonstrate the effect of
structural modifications at the pseudilins on the inhibitory
potency of this class of compounds. We observed no inhibition
with pseudilin (9) itself. Pentabromopseudilin (1) is the most
potent inhibitor, followed by tribromodichloropseudilin (12)
and then pentachloropseudilin (2). The residual activity of
myosin-2 ATPase observed by inhibition with pentachloro-
pseudilin (2) was in the same range as with BTS (18).
Tribromodifluoropseudilin (14) is a weak inhibitor of myosin-
2 ATPase. Methylation of pentabromopseudilin (1) to O-
methylpentabromopseudilin (15) or to N-methylpentabro-
mopseudilin (16) significantly reduces the inhibitory potency.
Residual ATPase activities of 90% (for 15) and 80% (for 16)
have been found. These findings indicate that the free OH
and NH groups are required for hydrogen bonding to the
enzyme. The O-methyl derivatives 10 and 11 also showed a
considerably reduced inhibiting activity as compared to their
non-methylated counterparts 2 and 12.
Further investigations showed that the pseudilins inhibit
the ATPase and motor activities of a range of different
myosins. Individual compounds showed variations in their
potency for specific myosin isoforms. In particular, the
inhibitory potency of pentabromopseudilin (1) is 25-fold
Figure 4. Structure of the myosin-2 motor-domain complex with Mg2+
ADP–meta-vanadate and pentabromopseudilin (1) in super-position
with the structure of the corresponding complex with blebbistatin (17)
–
[22b].
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Chemie
[17] Crystallographic data for 7a: C18H19NO3S, M = 329.40 gmolÀ1
,
mechanism of myosin inhibition by pseudilin derivatives are
currently in progress.
crystal size: 0.45 ꢄ 0.16 ꢄ 0.16 mm3, monoclinic, space group P21/
c, a = 7.7320(10), b = 20.232(2), c = 12.8800(10) ꢀ, b =
126.540(10)8, V= 1618.8(3) ꢀ3, Z = 4, 1calcd = 1.352 gcmÀ3, m =
Received: July 8, 2009
Published online: September 8, 2009
0.214 mmÀ1
, l = 0.71073 ꢀ, T= 198(2) K, qrange = 3.28–30.008,
reflections collected: 39066, independent: 4697 (Rint = 0.0598),
210 parameters. The structure was solved by direct methods and
refined by full-matrix least-squares on F2; final R indices [I >
2s(I)]: R1 = 0.0414; wR2 = 0.1092; maximal residual electron
density: 0.416 eꢀÀ3. CCDC 738984 (7a) contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Keywords: alkaloids · halogenation · heterocycles · inhibitors ·
silver
.
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111.90 (C), 113.21 (C), 119.29 (C), 125.05 (C), 130.86 (CH),
133.13 (CH), 147.19 (C); MS (EI, 70 eV): m/z (%) = 559 (7), 557
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474 (100), 472 (67), 470 (17), 451 (5), 449 (21), 447 (33), 445 (23),
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1308C); H NMR (500 MHz, CDCl3): d = 6.12 (s, 1H), 7.28 (d,
J = 2.4 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 9.55 ppm (br s, 1H);
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(C), 112.32 (C), 118.57 (C), 120.48 (C), 121.31 (C), 126.33 (CH),
126.36 (C), 127.06 (CH), 145.42 ppm (C); MS (EI, 70 eV): m/z
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decomp.); 1H NMR (500 MHz, CDCl3): d = 6.07 (s, 1H), 7.31
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13C NMR and DEPT (125 MHz, CDCl3): d = 99.30 (C), 100.98
(C), 103.87 (C), 118.94 (C), 121.30 (C), 125.12 (C), 126.05 (C),
127.17 (CH), 127.58 (CH), 145.89 ppm (C); MS (EI, 70 eV): m/z
(%) = 471 (2), 469 (18), 467 (62), 465 (100), 463 (73), 461 (20)
[M+], 390 (5), 388 (32), 386 (86), 384 (93), 382 (35), 361 (14), 359
(40), 357 (45), 355 (18), 309 (8), 307 (41), 305 (84), 303 (50);
HRMS: m/z calc. for C10H4Br3Cl2NO [M+]: 460.7220, found:
460.7220. 2,3,4-Tribromo-5-(3,5-difluoro-2-hydroxyphenyl)-1H-
pyrrole (tribromodifluoropseudilin)(14): light green solid, m.p.
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1328C (decomp.); H NMR (500 MHz, CDCl3): d = 5.47 (d, J =
4.6 Hz, 1H), 6.85 (ddd, J = 10.2, 7.7, 2.7 Hz, 1H), 7.68 (ddd, J =
10.0, 2.7, 2.1 Hz, 1H), 9.68 ppm (br s, 1H); 13C NMR and DEPT
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27.6, 22.4 Hz, CH), 104.00 (C), 109.85 (dd, J = 25.7, 3.2 Hz, CH),
118.78 (C), 125.31 (m, C), 136.23 (d, J = 16.6 Hz, C), 150.70 (dd,
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