Total synthesis of the antibiotic erypoegin H and cognates by a PtCl 2-catalyzed cycloisomerization reaction

Article abstract of DOI:10.1002/anie.200700895

(Chemical Equation Presented) Fighting back: A concise route to the pterocarpene derivative erypoegin H, a natural product endowed with considerable activity against a range of methicillin-resistant Staphyllococcus aureus strains and vancomycin-resistant

Full text of DOI:10.1002/anie.200700895

Communications
DOI: 10.1002/anie.200700895
Natural Products
Total Synthesis of the Antibiotic Erypoegin H and Cognates by a PtCl2-
Catalyzed Cycloisomerization Reaction**
Alois Fürstner,* Eike K. Heilmann, and Paul W. Davies
The growing number of methicillin-resistant Staphylococcus
aureus (MRSA) strains that are also resistant to other
antibiotics in clinical use, including vancomycin, constitutes
a serious threat worldwide. Even though the urgent need for
innovative therapeutic agents capable of combating such
deadly bacteria has been widely recognized, the number of
new lead structures fueling that quest remains alarmingly
low.[1]
A promising candidate in this regard is the pterocarpene
nucleus (G, Scheme 1) which constitutes the core of a sizeable
number of bioactive natural products, mainly derived from
plants of the Leguminosae family. Amongst the recent
publications highlighting the potential of this heterocyclic
scaffold as a pharmacophore,[2,3] a report on the secondary
metabolites of Erythrina poeppigiana is particularly note-
worthy.[4] It showed that erypoegin H (1), the most active
isoflavonoid isolated from the roots of this ornamental plant,
not only exhibits a broad spectrum of activity against Gram-
positive bacteria in general, but also exhibits a significant and
uniform activity against a panel of 13 different MRSA strains
and vancomycin-resistant enterococci (minimum inhibitory
concentration (MIC) 12.5 mgmLꢀ1).[4]
Preliminary data suggest that 1 interferes with the nucleic
acids and/or the metabolism of MRSA bacteria, whilst
seemingly leaving their cell walls intact.[4] To fully assess the
potential of this lead compound, more detailed studies on its
mode of action and toxicity are warranted, and exploration of
pertinent structure/activity relationships (SAR) should allow
the activity to be further improved. To this end, it was
necessary to developa concise and inherently flexible route
that delivers meaningful amounts of 1 and congeners (for
example, 2–6).
We reasoned that the benzofuran synthesis recently
developed by our group would lend itself to this goal
(Scheme 1).[5–7] Based on a PtCl2-catalyzed carboalkoxylation
[*] Prof. A. Fürstner, Dipl.-Chem. E. K. Heilmann
Max-Planck-Institut für Kohlenforschung
45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2994
Scheme 1. Synthesis of the pterocarpene nucleus by a PtCl2-catalyzed
carboalkoxylation reaction of an alkyne.
E-mail: fuerstner@mpi-muelheim.mpg.de
Dr. P. W. Davies
School of Chemistry
University of Birmingham
Edgbaston, Birmingham, B152TT (UK)
reaction, the underlying concept diverges broadly from the
established construction modes of pterocarpenes.[8] Activa-
tion of the alkyne moiety in a substrate of type A by the
carbophilic p acid PtCl2 engenders nucleophilic attack from
an oxygen atom of the adjacent acetal, thereby resulting in a
trans-alkoxyplatination (B!C).[5,9] The released oxocarbe-
[**] Generous financial support by the MPG and the Fonds der
Chemischen Industrie is gratefully acknowledged. We thank Dr. R.
Mynott and his team for expert NMR assistance and Umicore AG &
Co KG, Hanau, for a gift of noble metal salts.
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nium ion E then shifts to the most nucleophilic position in D
to give product F,[10] which can be readily elaborated into the
targeted scaffold G by conventional means.
The synthetic venture commenced with the di-iodination
of resorcinol 7[11] followed by consecutive attachment of a
pivaloyl and a trimethylsilylethoxymethyl group (Scheme 2).
molecular sieves to sequester traces of adventitious water that
might protonate the putative organoplatinum intermediate of
type C and/or D and hence reduce the efficiency of the O!C
shift. Under these optimized conditions, the cycloisomeriza-
tion of 13 proceeded exceedingly well and afforded 14 in 84%
yield on a multigram scale (see the Experimental Section).
The efficiency and operational simplicity of this particular
transformation highlights once again the remarkable appli-
cation profile of noble-metal-catalyzed skeletal rearrange-
ments in general[9,15] and toward heterocycle syntheses in
particular.[9,16] The pronounced migratory aptitude of the
SEM acetal in 13 stands in striking contrast to the behavior of
the symmetry-related pivaloyl group occupying an ortho
position on the substrateꢀs other benzene ring, which does not
engage at all in such a O!C transfer and hence merely serves
as a nonparticipating protecting group. Moreover, the com-
patibility of the iodide substituent is particularly noteworthy,
and highlights the orthogonal nature of platinum catalysis to
established redox-based transition-metal catalysts.[9] In syn-
thetic terms, the intact iodide was not only instrumental for
the successful completion of the synthesis of erypoegin H but
also constitutes a valuable entry point into late-stage diver-
gent modifications of the target, as required for future SAR
studies.
Next, the benzylic OH grouphad to be unmasked. This
stepturned out to be more difficult than anticipated, with a
host of fluoride and Lewis acid based reagents failing to
induce effective cleavage of the trimethylsilylethyl ether in 14.
Gratifyingly, oxidative conditions (CAN, aq MeCN)[17,18] were
found to deliver the corresponding aldehyde 15 in excellent
yield and purity.
With this compound in hand, the stage was set for the
introduction of the prenyl side chain[18] which was originally
envisaged to be carried out by conventional cross-coupling
methodology. However, despite considerable experimenta-
tion, the yields remained invariably low and the reactions
were plagued by the formation of various side-products.
Recourse to the advanced metalation technology developed
by Knochel and co-workers provided a most effective solution
to this problem.[19] Thus, in the presence of catalytic amounts
of [Li(acac)] as a nucleophilic promoter of the exchange
process, the reaction of 15 with Zn(iPr)2 in NMP afforded a
highly functionalized organozinc compound which could be
cleanly alkylated with excess prenyl bromide in the presence
of a catalytic amount of CuCN·2LiCl. It is remarkable that
neither the aldehyde function nor the three ester moieties in
15 interfere with this reaction to any noticeable extent,[19] as
can be deduced from the 86% yield of 16, which could be
isolated on a gram scale. We have no doubt that this
methodology is amenable to further scale-upand will allow
a host of other substituents to be introduced onto this
advanced synthetic intermediate at a later stage of the project.
Treatment of 16 with LiAlH4 reduced the aldehyde and
removed the peripheral ester groups concurrently. The
resulting crude product 17 was subjected to an intramolecular
etherification under standard conditions to complete the
tetracyclic framework of erypoegin H (1), which was obtained
in a respectable 28% yield over the nine steps of the longest
linear sequence. The spectroscopic data of the synthetic
Scheme 2. a) KI, KIO3, aq HCl, 61%; b) PivCl, Et3N, CH2Cl2, 64%;
c) SEMCl, Et3N, DMAP (cat.), toluene, 94%; d) PivCl, Et3N, CH2Cl2,
ꢁ
99%; e) Me3SiC CH, [PdCl2(PPh3)2] (1.5 mol%), CuI (1.5 mol%),
Et3N, Ar/H2 (1 atm), 93%; f) AgNO3 (10 mol%), aq acetone, 99%;
g) [PdCl2(PPh3)2] (3 mol%), CuI (3 mol%), Et3N, Ar/H2 (1 atm), 74%;
h) PtCl2 (10 mol%), CO (1 atm), 4-Š MS, toluene, 808C , 84%;
i) (NH4)2Ce(NO3)6 (CAN), MeCN/H2O, 82%; j) 1. Zn(iPr)2, [Li(acac)]
(10 mol%), NMP; 2. CuCN·2LiCl (10 mol%), prenyl bromide, 86%;
k) LiAlH4; THF; l) I2, PPh3, imidazole, Et2O/MeCN, 70% (over both
steps); Piv=pivaloyl, DMAP=4-dimethylaminopyridine, SEM=trime-
thylsilylethoxymethyl, MS=molecular sieves, acac=acetylacetone,
NMP=N-methylpyrrolidine.
This sequence takes advantage of the greatly different
accessibility of the two phenolic OH groups in 8. Steric
reasons also explain the regioselective course of the subse-
quent Sonogashira reaction of di-iodide 9 with alkyne 12,
which derives from compound 10[12] in a few high yielding
reactions; this transformation had to be carried out under a
reducing atmosphere to avoid extensive homocoupling of the
alkyne partner.[13] The resulting compound 13, on exposure to
catalytic amounts of PtCl2 in toluene under a CO atmos-
phere,[5,14] underwent a remarkably clean cycloisomerization
with formation of the desired benzofuran derivative 14. This
reaction was best performed in the presence of powdered
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Communications
samples were in excellent agreement with those reported in
of the putative “isosojagol” but closely match the reported
spectra of “phaseol”, an isomeric coumestan for which
structure 5 had been proposed.[22] Since the constitution of
our synthetic sample is unambiguous, we must conclude that
the original structure assignments of isosojagol and phaseol
are both incorrect. While our study now shows that “phaseol”
is definitely represented by structure 2 rather than by 5, the
actual constitution of “isosojagol” remains to be elucidated.
the literature (Table 1).[4]
Cleavage of the pivaloyl groups under nonreducing
conditions converted aldehyde 16 into the des-methyl ana-
Table 1: Reference data set of compounds 1–3.
1
1: H NMR (400 MHz, CDCl3): d=7.36 (d, J=8.1 Hz, 1H), 7.04 (d,
J=8.3 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.45 (dd, J=8.1, 2.4 Hz, 1H),
6.43 (d, J=2.3 Hz, 1H), 5.54 (s, 2H), 5.39 (thept, J=7.3, 1.3 Hz, 1H),
5.26 (brs, 1H), 5.01 (brs, 1H), 3.69 (d, J=7.3 Hz, 2H), 1.89–1.90 (m,
3H), 1.78 ppm (d, J=1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=156.7, 155.1, 154.5, 152.0, 147.0, 135.3, 121.2, 120.9, 119.2, 116.1,
112.6, 111.2, 110.2, 108.4, 106.2, 103.9, 65.7, 25.8, 23.1, 17.9 ppm; UV
(MeOH/H2O 4:1): lmax =350, 334, 242, 210, 204 nm; MS (EI): m/z (%):
322 (77) [M]+, 266 (100), 237 (6), 152 (5); HRMS (EI): m/z: calcd for
C20H18O4: 322.1205; found: 322.1207
Experimental Section
14:
A Schlenk flask was charged with compound 13 (4.25 g,
5.66 mmol), 4-Š MS (1.77 g, powdered), and toluene (30 mL). After
addition of PtCl2 (150 mg, 0.56 mmol), the mixture was purged with
CO through a canula for 7 min before it was vigorously stirred at 858C
under an atmosphere of CO (1 atm) for 5.5 h. For work up, the
mixture was filtered through a pad of silica, the filtrate was
evaporated, and the residue purified by flash chromatography
(hexanes/EtOAc, 10:1) to give benzofuran 14 as an off-white foam
2: 1H NMR (400 MHz, [D6]acetone): d=7.92 (d, J=8.6 Hz, 1H), 7.62 (d,
J=8.4 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 7.02 (dd, J=8.6, 2.3 Hz, 1H),
6.95 (d, J=2.2 Hz, 1H), 5.43 (thept, J=7.4, 1.4 Hz 1H), 3.70 (d,
J=7.4 Hz, 2H), 1.91–1.92 (m, 3H), 1.69 ppm (d, J=1.1 Hz, 3H);
13CNMR (100 MHz, [D 6]acetone): d=161.9, 160.6, 158.5, 156.1, 156.0,
155.0, 132.6, 123.5, 122.5, 118.9, 116.6, 114.5, 114.4, 113.4, 106.1, 104.1,
103.9, 25.8, 23.4, 18.0 ppm; UV (MeOH): lmax =346, 304, 253, 209 nm;
MS (EI): m/z (%): 337 (13), 336 (54) [M]+, 281 (44), 280 (100), 252 (7);
HRMS (ESI): m/z: calcd for C20H16O5 + Na: 359.0890; found: 359.0894
3: 1H NMR (400 MHz, [D6]acetone): d=7.90 (d, J=8.6 Hz, 1H), 7.66 (d,
J=8.5 Hz, 1H), 7.01 (dd, J=8.6, 2.2 Hz, 1H), 6.95 (d, J=2.2 Hz, 1H),
6.88 (d, J=8.5 Hz, 1H), 3.09 (t, J=6.8 Hz, 2H), 1.96 (t, J=6.8 Hz, 2H),
1.39 ppm (s, 6H); 13CNMR (75 MHz, [D 6]acetone): d=162.0, 160.6,
158.5, 156.1, 155.1, 154.2, 123.5, 119.4, 116.2, 116.2, 114.4, 107.3, 106.0,
104.1, 103.9, 75.6, 32.1, 26.8, 17.3 ppm. MS (EI): m/z (%): 337 (26), 336
(75) [M]+, 319 (4), 280 (100), 252 (7); HRMS (ESI): m/z: calcd for
C20H16O5 + Na: 359.0890; found: 359.0887.
1
(3.56 g, 84%). H NMR (400 MHz, CDCl3): d = 7.65 (d, J = 8.3 Hz,
1H), 7.53 (d, J = 8.4 Hz, 1H), 7.09 (dd, J = 8.4, 2.3 Hz, 1H), 7.03 (d,
J = 2.3 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 4.53 (s, 2H), 3.51–3.55 (m,
2H), 1.45 (s, 9H), 1.38 (s, 9H), 1.17 (s, 9H), 0.92–0.96 (m, 2H),
ꢀ0.01 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d = 176.4 (2C),
176.2, 155.6, 152.8, 151.0, 150.3, 149.4, 132.3, 126.1, 120.5, 120.3, 118.9,
118.0, 117.0, 116.7, 71.9, 67.7, 62.7, 39.4, 39.2, 39.1, 27.4, 27.1 (2C),
18.3, ꢀ1.4 ppm; MS (EI): m/z (%): 750 (87) [M]+, 722 (11), 666 (35),
638 (26), 633 (16), 553 (12), 548 (15), 464 (27), 380 (31), 85 (12), 73
(25), 57 (100); HRMS (ESI): m/z: calcd for C35H47IO8Si + Na:
773.1977; found: 773.1969; elemental analysis calcd (%) for
C35H47IO8Si: C 56.00, H 6.31; found: C 55.95, H 6.35.
Received: February 28, 2007
Published online: May 10, 2007
Keywords: alkynes · antibiotics · heterocycles · natural products ·
platinum
.
logue of erypoegin F 4, another flavonoid from E. poeppigi-
ana endowed with considerable antimicrobial activity.[4b]
Furthermore, oxidation of 16, deprotection of the ester
moieties, and treatment of the resulting acid 19 with H2SO4/
HOAc led to concomitant lactonization and addition of the
phenolic OH group onto the adjacent prenyl side chain;
sojagol (3) thus formed is a well known phytoalexin originally
isolated from Glycine max (soybeans) and Phaseolus aureus
(mung beans; Scheme 3).[20] Uncoupling of the two cyclization
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