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Total Syntheses of the Antibacterial Natural Product Abyssomicin C.

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Highlights
DOI: 10.1002/anie.200602409
Total Synthesis
Total Syntheses of the Antibacterial Natural Product
Abyssomicin C
Ren Peters* and Daniel F. Fischer
Keywords:
abyssomicin · antibiotics · cycloaddition ·
total synthesis
In 2004 Sssmuth et al. reported the
isolation of the polyketide-type antibiotic abyssomycin C (1), which inhibits
Gram-positive bacteria, and of the two
related non-antibiotic compounds abyssomicin B (2) and D (3) from the rare
actinomycete Verrucosispora strain
AB 18-032, which was found in a sediment sample collected in the Sea of
Japan at a depth of almost 300 m.[1]
Compound 1 inhibits the bacterial
biosynthetic pathway to tetrahydrofolate between chorismate and p-aminobenzoic acid (PABA), by mimicking
chorismate and then presumably covalently binding the enzyme. The biosyn[*] Prof. Dr. R. Peters, D. F. Fischer
Laboratory of Organic Chemistry
ETH Z.rich
Wolfgang-Pauli-Strasse 10
H2nggerberg HCI E 111
8093 Z.rich (Switzerland)
Fax: (+ 41) 44-633-1226
E-mail: peters@org.chem.ethz.ch
Homepage: www.peters.ethz.ch
5736
thesis of PABA is a highly attractive
target since it is essential for many
microorganisms but absent in humans.
Abyssomicin C has been reported to be
the first known substance derived from a
bacterial source that inhibits the biosynthesis of PABA. Sssmuth et al. suggested a possible mode of action based on
the unique and intriguing structure,
which was elucidated by NMR-spectroscopic studies and X-ray structure analysis. Abyssomicin C (1) contains a tetronic acid motif, an oxabicyclo[2.2.2]octane system, and an a,b-unsaturated ketone moiety. The oxabicyclo[2.2.2]octane system was proposed to be
a mimic of chorismate (and is similar to
transition-state analogues of chorismate
mutase inhibitors). Presumably after
noncovalent binding to the targeted
enzyme, the enone part of 1 covalently
traps a nucleophilic amino acid side
chain from the enzyme by 1,4-addition.
This would also explain why
the related species 2 and 3
show no antibiotic activity:
they lack the enone functionality.
Because abyssomicin C is
a very attractive lead structure for the development of
new inhibitors of pathogenic
bacteria, compound 1 and analogues thereof are targets of
prime importance. Indeed,
two total syntheses have already been reported. This article highlights the syntheses
by Sorensen et al. and Nicolaou et al. which both rely on
a Diels–Alder reaction as the
key step in the construction of
the oxabicyclo[2.2.2]octane
core.
Scheme 1.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
In 2005 the Sorensen group reported
the first synthesis of abyssomicin C
based on an intramolecular, highly diastereoselective Diels–Alder reaction.
The advanced diene intermediate 5,
containing all the carbon atoms of the
natural product, was cyclized to form an
11-membered
macrocycle
(Scheme 1).[2, 3] They speculated that
the biosynthesis of 1 also proceeds by a
Diels–Alder macrocyclization. Intermediate 5 was obtained by a convergent
strategy from fragments 6–8, which were
coupled by two carbonyl addition reactions, namely, an aldol reaction of a
synthetic equivalent of enolate 6 and
commercially available trans,trans-2,4hexadienal (7), followed by the addition
of a lithiated tetronate 8 to an aldehyde
carbonyl group.
The synthetic equivalent of 6, ketone
10 (Scheme 2), was prepared in six steps
(40 % overall yield) from meso-2,4-di-
Sorensen’s retrosynthetic analysis.
Angew. Chem. Int. Ed. 2006, 45, 5736 – 5739
Angewandte
Chemie
meric mixture (1:1) of a secondary
alcohol, which was protected as
TBS ether to form the sensitive
triene moiety during the cycloaddition by a b-elimination of the silyloxy group.
The known methyl tetronate 13
was subsequently lithiated using
LDA (Scheme 3) and the resulting
carbanion was reacted with aldehyde 12, obtained by direct exposure of the primary TES ether 11 to
Swern oxidation conditions. The
yield for the coupling reaction was
poor and variable (35–55 %), which
Scheme 2. Synthesis of intermediate 12. Reagents
might be ascribed to chemoselecand conditions: a) LDA, THF, 78 8C; then 7
tivity problems because of the pres(94 %, d.r. 1:1); b) TBSOTf, 2,6-lutidine, CH2Cl2,
ence of the unprotected keto group
0 8C (85 %); c) (COCl)2, DMSO, Et3N, CH2Cl2, 40
to 78 8C (60–70 %). DMSO = dimethylsulfoxide,
in 12. However, the reaction could
LDA = lithium diisopropylamide, TBS = tert-butyldibe performed on a gram scale giving
methylsilyl, TES = triethylsilyl, Tf = trifluoromethane- access to the Diels–Alder substrate
sulfonyl.
14 by oxidation of the generated
secondary alcohol. An impressive
methylglutaric anhydride (9) using an tandem b-elimination/diastereoselective
efficient enzymatic desymmetrization cycloaddition to provide tricycle 4 was
described by Lautens et. al as a key then accomplished in the presence of
step.[4] The kinetically formed enolate 10 mol % of La(OTf)3 in toluene at
derived from 10 was joined with dienal 7 100 8C. No regioisomeric cycloadducts
in excellent yield furnishing a diastereo- were detected. Alternatively, the b-
Scheme 3. Synthesis of abyssomicin C (1) by Sorensen et al. Reagents and conditions: a) LDA,
toluene, 78 8C, 6 min; then aldehyde 12, (35–55 %, d.r. 1:1); b) DMP, CH2Cl2, 0 to 23 8C
(84 %); c) La(OTf)3 (10 mol %), toluene, 100 8C (50 %); d) DMDO, acetone, 0!23 8C (67 %);
e) LiCl, DMSO, 50 8C (quant.); f) p-TsOH, LiCl, CH3CN, 50 8C, (50 %). DMDO = dimethyldioxirane, DMP = Dess–Martin periodinane, IMDA = intramolecular Diels–Alder reaction, p-TsOH =
toluene-4-sulfonic acid.
Angew. Chem. Int. Ed. 2006, 45, 5736 – 5739
elimination was performed in a separate
step prior to the cycloaddition.
Oxidation of the generated cyclohexene with dimethyldioxirane gave
regio- and diastereoselective access to
epoxide 15, which was opened by acidcatalyzed nucleophilic intramolecular
attack of the vinylogous carboxylic acid
moiety being released by nucleophilic
demethylation of the tetronate subunit.
Unfortunately, the epoxide opening was
not regioselective. The resulting 1:1
mixture of the target molecule abyssomicin C (1) and isoabyssomicin C could
be separated by column chromatography. The undesired isomer would be
interesting for further elucidation of the
structure–activity relationship (SAR).
The target molecule has thus been
synthesized by a convergent approach
with a longest linear sequence of
15 steps (overall yield: 0.9–1.7 %).
In 2006 Nicolaou and Harrison reported an alternative synthesis featuring
an intermolecular Diels–Alder approach followed by an epoxidation and
an epoxide-ring-opening sequence to
form the oxabicyclo[2.2.2]octane core
structure 18; the strained 11-membered
macrocycle in 1 was obtained by a ringclosing
metathesis
reaction
(Scheme 4).[5, 6] This approach led not
only to the total synthesis of abyssomicin C (1) but also to the formation of
atrop-abyssomicin C (21), a conformer
of the naturally occurring product 1
exhibiting even more potent antibiotic
activity.
Like SorensenEs synthesis, NicolaouEs approach is characterized by its
high convergency and diversity making
it possible to synthesize new analogues
for SAR studies. Hydroxydiene 20,
which was prepared in two steps from
the known Weinreb amide 22, underwent a remarkable Diels–Alder reaction
with an excess of methyl acrylate in a
protocol based on a procedure originally
developed by Ward and Abaee[7]
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5737
Highlights
Scheme 4. Nicolaou’s retrosynthetic analysis. RCM = ring-closing metathesis.
(Scheme 5). Mixing 1 equivalent of 20
with 3 equivalents of the achiral ligand
23 and 4 equivalents of MeMgBr in
toluene at 0 8C, followed by the addition
of 10 equivalents of methyl acrylate and
warming to 55 8C for 24 h provided
cycloadduct 25 as a single diastereomer
in 80 % yield, presumably via the Lewis
acid templated transition state 24. Further applications in catalytic asymmetric
synthesis utilizing chiral enantiopure
ligand motifs can be envisioned.
The resulting cycloaddition product
was then hydroxylated diastereoselec-
tively in the position a to the carbonyl
group of the g-lactone moiety (25!19).
A reductive elimination of PhSH provided diene 26, which subsequently
underwent a [VO(OEt)3]-promoted
highly regio- and diastereoselective epoxidation utilizing tBuOOH. The reaction occurred exclusively at the bottom
face of the molecule, and subsequently
the tertiary hydroxy group was acetylated (19!26!27). In an elegant manner, deprotonation of the acetyl group
followed by an intramolecular Claisen–
Dieckmann cyclization and a subse-
Scheme 5. Synthesis of TES-protected oxabicyclo[2.2.2]octane intermediate 18. Reagents and
conditions: a) PhCH3, 0 8C, then methyl acrylate (10 equiv), 55 8C, 24 h (80 %); b) LiHMDS,
THF, 78 8C; then (EtO)3P, O2 (74 %); c) 4,4’-di-tert-butylbiphenyl, Li, THF, 0 8C, then 40 8C,
19, then MeOH quenching, then DMF, K2CO3, MeI, 60 8C (97 %); d) [VO(OEt)3], tBuOOH,
CH2Cl2, 25 8C (90 %); e) Ac2O, DMAP, Et3N, 25 8C (93 %); f) LiHMDS, THF, 78 to 25 8C; then
NH4Cl, reflux; g) TESCl, imidazole, DMAP, DMF, 25 8C (97 %, two steps). DABCO = 1,4diazabicyclo[2.2.2]octane, DMAP = 4-(dimethylamino)pyridine, DMF = N,N-dimethylformamide,
LiHMDS = lithium bis(trimethylsilyl)amide.
5738
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2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
quent regioselective epoxide opening
directly furnished the tricyclic core
structure in an almost quantitative yield.
After silylation under standard conditions, the lithiation of 18 with tBuLi at
78 8C, followed by reaction with enantioenriched lactone 17 gave a lactol
which was directly subjected to thioketalization with 1,2-ethanedithiol giving
28 in 75 % overall yield (Scheme 6).
Chemoselective oxidation of the
primary hydroxy group with IBX (oiodoxybenzoic acid), followed by nucleophilic addition of vinylmagnesium
chloride to the generated aldehyde gave
a diastereomeric mixture of allylic alcohols 16 (ca. 3:2). Formation of the
macrocycle by ring-closing metathesis
catalyzed by the Grubbs II catalyst (29)
and a second chemoselective IBX oxidation converted the diastereomeric
secondary allylic alcohols into a single
hydroxy enone diastereomer 30, which
was trans-configured about the newly
formed double bond.
Surprisingly, however, regeneration
of the keto functionality protected as a
thioketal with PIFA (PhI(O2CCF3)2) did
not give the expected target molecule 1
but the atropisomer 21 (structure determined by X-ray analysis); the overall
yield was ca. 3.4 %, the longest linear
sequence was 16 steps. Comparison of
the X-ray crystal data of abyssomicin C
(1) to those of atrop-abyssomicin C (21)
reveals that the enone carbonyl group
adopts a more transoid conformation in
the natural product 1 (dihedral angle O=
CC=C 144.88), whereas the conformation of this group in 21 is more cisoid
(dihedral angle O=CC=C 26.48). Because 21 exhibits an increased degree of
conjugation between the carbonyl group
and the double-bond moiety, it is a
better Michael acceptor than 1, resulting
in higher antibacterial activity [preliminary minimal inhibitory concentration
(MIC) assays of 1: 5.2 mg mL1; and of
21: 3.5 mg mL1 for antibacterial activity
against MRSA (methicillin-resistant
Staphylococcus aureus)]. This finding
supports the hypothesis by Sssmuth
et al. on the origin of the bioactivity.
Compound 21 was finally transformed
into 1 under mild acidic conditions
(CDCl3 without a stabilizer) giving a
2:1 mixture of 1 and 21, which can be
separated by column chromatography.
Angew. Chem. Int. Ed. 2006, 45, 5736 – 5739
Angewandte
Chemie
Scheme 6. Completion of the total synthesis of atrop-abyssomicin C (21) and abyssomicin (1).
Reagents and conditions: a) tBuLi, THF, 78 8C; then 17, 10 min; b) 1,2-ethanedithiol, CH2Cl2,
78 8C; then TMSOTf; then 1 n aq. HCl, 78 to 25 8C, 75 %, two steps; c) IBX, DMSO, 25 8C;
d) vinyl MgCl, THF, 78 8C, 65 %, two steps; e) 29, CH2Cl2 (0.002 m), D, 85 %; f) IBX, DMSO,
25 8C, 50 %; g) PhI(OTFA)2, CH3CN/H2O (5:1), 50 %; h) CDCl3. Cy = cyclohexyl, IBX = o-iodoxybenzoic acid, MES = trimethylphenyl, TFA = trifluoroacetyl.
Both synthetic approaches highlight
impressively the power of the Diels–
Alder reaction, either intramolecular to
form a strained macrocyclic system, or
intermolecular via a Lewis acid templated transition state. Both synthetic routes
appear to be well suited to synthesize
new analogues to enable further studies
of the structure–activity relationship. It
will be exciting to see if SssmuthEs
hypothesis about the origin of the antibacterial activity of abyssomicin C will
be proved right and if new antibacterial
Angew. Chem. Int. Ed. 2006, 45, 5736 – 5739
drugs will finally emerge based on these
studies.
Published online: August 14, 2006
[1] a) B. Bister, D. Bischoff, M. StrIbele, J.
Riedlinger, A. Reicke, F. Wolter, A. T.
Bull, H. ZKhner, H.-P. Fiedler, R. D.
Sssmuth, Angew. Chem. 2004, 116,
2628; Angew. Chem. Int. Ed. 2004, 43,
2574; b) J. Riedlinger, A. Reicke, H.
ZKhner, B. Krismer, A. T. Bull, L. A.
Maldonado, A. C. Ward, M. Goodfellow,
B. Bister, D. Bischoff, R. D. Sssmuth,
H.-P. Fiedler, J. Antibiot. 2004, 57, 271.
[2] C. W. Zapf, B. A. Harrison, C. Drahl,
E. J. Sorensen, Angew. Chem. 2005, 117,
6691; Angew. Chem. Int. Ed. 2005, 44,
6533.
[3] For other Diels–Alder macrocyclizations, see: a) E. J. Corey, M. Petrzilka,
Tetrahedron Lett. 1975, 16, 2537; b) G.
Stork, E. Nakamura, J. Am. Chem. Soc.
1983, 105, 5510; c) H. Dyke, P. G. Steel,
E. J. Thomas, J. Chem. Soc. Perkin
Trans. 1 1989, 525; d) K. Takeda, Y.
Igarashi, K. Okazaki, E. Yoshii, K.
Yamaguchi, J. Org. Chem. 1990, 55,
3431; e) J. A. McCauley, K. Nagasawa,
P. A. Lander, S. G. Mischke, M. A.
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Peters, M. Anada, S. S. Harried, J.
Hao, Y. Kishi, J. Am. Chem. Soc. 2006,
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[4] M. Lautens, J. T. Colucci, S. Hiebert,
N. D. Smith, G. Bouchain, Org. Lett.
2002, 4, 1879.
[5] K. C. Nicolaou, S. T. Harrison, Angew.
Chem. 2006, 118, 3334; Angew. Chem. Int.
Ed. 2006, 45, 3256.
[6] For further synthetic studies see: a) J.-P.
Rath, S. Kinast, M. E. Maier, Org. Lett.
2005, 7, 3089; b) B. B. Snider, Y. Zou,
Org. Lett. 2005, 7, 4939; c) A. L. Zografos, A. Yiotakis, D. Georgiadis, Org. Lett.
2005, 7, 4515; d) J.-P. Rath, M. Eipert, S.
Kinast, M. E. Maier, Synlett 2005, 314;
e) E. A. Couladouros, E. A. Bouzas,
A. D. Magos, Tetrahedron 2006, 62, 5272.
[7] D. E. Ward, M. S. Abaee, Org. Lett. 2000,
2, 3937.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5739
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