Total synthesis of platensimycin

Article abstract of DOI:10.1002/anie.200603892

(Chemical Equation Presented) Beat the superbugs: The newly discovered antibiotic platensimycin (1) promises to combat current drug-resistant infections. The natural product shows potent activity against Gram-positive bacteria and contains a novel molecul

Full text of DOI:10.1002/anie.200603892

Communications
Antibiotics
DOI: 10.1002/anie.200603892
Total Synthesis of Platensimycin**
K. C. Nicolaou,* Ang Li, and David J. Edmonds
Infectious disease remains a menace to society despite the
isolation of many new antibiotics over the last few decades.
The drugs that are currently available to defend against such
ailments are becoming progressively less effective because of
the development of bacterial resistance, leading to an increase
in potentially fatal, drug-resistant infections. The rather
sporadic success in the development of antibiotics since the
1960s has led to a pressing need to discover new antibiotics to
combat drug resistance.[1] Compounds that act through new
mechanisms are particularly attractive as they offer the
prospect of combating effectively infections resistant to all
existing drugs. Platensimycin (1, Scheme 1) was isolated
recently from a strain of Streptomyces platensis by a Merck
research group as part of a high-throughput screening
program of metabolites to identify inhibitors of bacterial
fatty acid biosynthesis.[2] Platensimycin represents a new
structural class of antibiotic, operating through a novel
mechanism of action and, as such, presents a ray of hope for
the development of a powerful new therapy. Specifically, the
Merck research group showed that platensimycin inhibits the
elongation–condensing enzymes b-ketoacyl-(acyl carrier pro-
tein) synthases I/II (FabF/B) in the type II bacterial fatty acid
biosynthetic pathway by binding to the acyl–enzyme inter-
mediate involved. These enzymes are essential for lipid
biosynthesis and are found in many pathogenic species.
Indeed, platensimycin was found to be the most potent
inhibitor of these enzymes known to date and exhibited
potent broad-spectrum antibacterial activity against Gram-
positive bacterial strains, including methicillin-resistant
Staphylococcus aureus, vancomycin-intermediate Staphylo-
coccus aureus, and vancomycin-resistant Enterococcus
faecium. In light of the gravity of the situation arising from
drug-resistant bacteria and because of the activity and novelty
[*] Prof. Dr. K. C. Nicolaou, A. Li, Dr. D. J. Edmonds
Department of Chemistry
and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA92037 (USA)
Fax: (+1)858-784-2469
E-mail: kcn@scripps.edu
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA92093 (USA)
[**] We thank Dr. D. H. Huang and Dr. G. Siuzdak for assistance with
NMR spectroscopy and mass spectrometry, respectively. We also
gratefully acknowledge helpful discussions with Dr. P. G. Bulger and
Dr. L. A. McAllister. Financial support for this work was provided by
the National Institutes of Health (USA), the Skaggs Institute of
Chemical Biology, and by Merck Sharp & Dohme (postdoctoral
fellowship to D.J.E.).
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Chemie
The synthesis of the pentacyclic carboxylic acid 3 began
with the preparation of enone 11 from 8[3] in a manner
analogous to that recently employed by Hayashi et al.,[4] and
proceeded as shown in Scheme 2. Thus, sequential alkylation
of 8 with allylic bromide 9[5] (LDA, 92%) and propargyl
Scheme 1. Structure and retrosynthetic analysis of platensimycin (1).
MOM=methoxymethyl, TBS=tert-butyldimethylsilyl.
of the structure of platensimycin, we undertook the total
synthesis of this newly discovered antibiotic. Herein we report
the first total synthesis of this potentially useful molecule in
racemic form.
Platensimycin consists of an unusual 3-amino-2,4-di-
hydroxybenzoic acid polar domain linked through an amide
bond to a relatively lipophilic, compact, pentacyclic ketolide
structural motif, and thus presents an intriguing synthetic
challenge. While the amide bond provides an apparent and
reasonable site for coupling the two rather disparate frag-
ments, the construction of the two domains is less predictable,
despite the many possibilities that can be imagined. Scheme 1
shows the retrosynthetic analysis of one such possibility. Thus,
disconnection of the amide bond reveals two subtargets: the
aromatic amine 2 and the carboxylic acid 3. The acid 3 can
then be disconnected to remove the propionate and methyl
substituents, leaving the cagelike core of the target molecule,
compound 4, as the next subtarget. Of the many disconnec-
tions possible for the further retrosynthesis of 4, the one
involving cleavage of the ether bond to leave a tertiary
carbocation synthon, followed by rupture of the carbon–
carbon bond adjacent to the generated secondary alcohol to
reveal a spirocyclic cyclohexadienone (see structures 4 and 5,
Scheme 1) appealed to us because of its potential expediency.
The proposed synthetic sequence at this juncture would
involve selective generation of a ketyl radical from the
corresponding aldehyde, stereoselective conjugate addition of
the carbon-centered radical onto one side of the bis-enone,
and regioselective ether formation between the hydroxy
group of the resultant secondary alcohol and the proximal
exo-methylene group to give the desired cagelike structure.
The substrate for this key step, the spirocyclic cyclohexadiene
6, can then be further disconnected to reveal the simple enyne
7 as a potential precursor.
Scheme 2. Construction of the pentacyclic carboxylic acid 3. Reagents
and conditions: a) LDA(1.2 equiv), 9 (1.5 equiv), THF, ꢀ78!228C,
6 h, 92%; b) LDA(1.4 equiv), propargyl bromide (3.0 equiv), THF,
ꢀ78!228C, 13 h, 97%; c) DIBAL-H (1.2 equiv), toluene, ꢀ78!
ꢀ208C, 2 h; then MeOH, 2n aq HCl, ꢀ20!228C, 2 h; d) TBSCl
(1.2 equiv), imidazole (3.0 equiv), DMF, 228C, 20 min, 84% (two
steps); e) [CpRu(MeCN)3]PF6 (0.02 equiv), acetone, 228C, 1.5 h, 92%,
1:1 diastereomeric mixture; f) LiHMDS (2.0 equiv), TMSCl (1.5 equiv),
THF, ꢀ788C, 2 h; g) Pd(OAc)2 (1.1 equiv), MeCN, 228C, 1.5 h, 68%
(two steps); h) 1n aq HCl/THF (1:1), 228C, 2 h, 85%; i) SmI2 (0.1m in
THF, 2.2 equiv), HFIP (1.5 equiv), THF/HMPA(10:1), ꢀ788C, 1 min,
46%, ca. 2:1 d.r.; j) TFA/CH2Cl2 (1.8:1), 08C, 1.5 h, 87%; k) KHMDS
(0.5m in toluene, 1.5 equiv), MeI (8.0 equiv), THF/HMPA(5:1),
ꢀ78!ꢀ108C, 2 h, 88%; l) KHMDS (0.5m in toluene, 4.0 equiv), allyl
iodide (8.0 equiv), THF/HMPA(5:1), ꢀ78!ꢀ108C, 2 h, 79%; m) 18
(6.0 equiv), 17 (0.25 equiv), CH2Cl2, 408C, 6 h, 85%, ca. 6:1 E/Z;
n) Me3NO (5.0 equiv), THF, 658C, 2 h, 95%; o) NaClO2 (3.0 equiv), 2-
methyl-2-butene (10 equiv), NaH2PO4 (5.0 equiv), tBuOH/H2O (1:1),
228C, 15 min, 95%. Cp=cyclopentadienyl, Cy=cyclohexyl, DIBAL-
H=diisobutylaluminum hydride, DMP=Dess–Martin periodinane,
HFIP=1,1,1,3,3,3-hexafluoropropan-2-ol, HMDS=hexamethyldisil-
azide, HMPA=hexamethylphosphoramide, LDA=lithium diisopropyl-
amide, Mes=mesityl=2,4,6-trimethylphenyl, TFA=trifluoroacetic
acid, TMS=trimethylsilyl.
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bromide (LDA, 97%) afforded the bis-alkylated enone 10 as
involved olefin cross-metathesis between 16 and vinyl pinacol
boronate under the influence of the Grubbs second-gener-
ation catalyst 17,[11] which furnished vinyl boronate 19 in 85%
yield as a mixture of E and Z isomers (ca. 6:1).[12] This
intermediate underwent smooth oxidation[13] upon treatment
with trimethylamine N-oxide to give 20 in 95% yield, which
was further oxidized to furnish the desired carboxylic acid 3 in
excellent yield (95%) by using the Pinnick protocol.[14]
The synthesis of the aromatic amine, fragment 2, pro-
ceeded smoothly from 2-nitroresorcinol (21) as outlined in
Scheme 3. Protection of 21 as the bis-MOM ether (NaH,
a single regioisomer. Reduction of 10 using DIBAL-H
followed by acidic hydrolysis and reintroduction of the TBS
ether gave enone 11 in 84% overall yield. Cycloisomerization
of 11 was achieved by using the method of Trost et al., which
involved exposure of the substrate to the catalyst [CpRu-
(MeCN)3]PF6 in an acetone solution[6] to give spirocycle 12 in
92% yield as an inconsequential 1:1 mixture of diastereoiso-
mers. The bis-enone 13 was then generated from mono-enone
12 through the oxidation (Pd(OAc)2) of the intermediate
TMS enol ether (LiHMDS, THF, ꢀ788C) in 68% overall
yield.[7] Finally, the anticipated aldehyde
6 was
unmasked by acidic hydrolysis of the TBS enol ether
in 85% yield.
Rapid addition of a solution of the single-electron
reductant samarium(II) iodide[8,9] to a dilute, solution
of 6 and HFIP in THF/HMPA (10:1) at ꢀ788C,
followed by immediate quenching with saturated
aqueous NH4Cl solution, gave an approximately 2:1
mixture (as indicated by 1H NMR spectroscopy) of
secondary alcohol 14 and its diastereoisomer in 46%
combined yield. Treatment of this inseparable mixture
with TFA led to smooth etherification, thus reflecting
the proximity of the hydroxy group of the desired
diastereoisomer to the exocyclic olefin, and thereby
gave the cagelike structure 4 in 87% yield based on the
quantity of the correct isomer of 14 present. The
undesired alcohol diastereoisomer was recovered
unchanged from the etherification reaction. It was surmised
from these experiments that the major isomer generated in
the SmI2-mediated cyclization reaction had the desired
stereochemistry (14, Scheme 2). The conversion of 6 into 4
could also be achieved in a single reaction vessel by quenching
the excess SmI2 with oxygen at ꢀ788C followed by addition of
TFA to the resulting mixture and stirring at ambient temper-
ature. This one-pot procedure allowed the isolation of 4 in
around 25% overall yield, and streamlines to some extent this
segment of the synthetic sequence. The required alkyl
substituents adjacent to the carbonyl group were then
stereoselectively and efficiently installed by treatment of 4
with KHMDS and MeI (88%) followed by KHMDS and allyl
iodide (79%). In each case, the diastereomeric products were
undetectable (< 2%) in the crude reaction mixture by
1H NMR spectroscopy. The use of allyl bromide in the
second alkylation gave lower yields of 16, accompanied by
significant quantities of the O-alkylated isomer. The excellent
stereocontrol observed in the alkylation sequence is ration-
alized by inspection of molecular models of ketones 4 and 15,
in which the rigid cage structure effectively shields the top
face of the corresponding enolate. The conversion of terminal
olefin 16 into the required carboxylic acid 3 was carried out
through two different pathways, both involving aldehyde 20.
In the first case, hydroboration of 16 gave a diol (resulting
from concomitant 1,2-reduction of the enone), which could be
oxidized to give aldehyde 20 using excess Dess–Martin
reagent[10] in CH2Cl2 (ca. 40% from 16). The disappointing
yield of this sequence and the low reactivity of the terminal
olefin towards hydroboration led us to seek an alternative
route for the conversion of 16 into 20. The preferred method
Scheme 3. Construction of the aromatic amine fragment 2. Reagents and
conditions: a) NaH (2.5 equiv), MOMCl (2.3 equiv), THF, 0!228C, 1.5 h,
82%; b) H2 (balloon), 10% Pd/C (0.1 equiv), MeOH/EtOAc (10:1), 228C,
12 h, 99%; c) Boc2O (3.0 equiv), 408C, 4 h, 99%; d) nBuLi (2.2m in pentane,
1.0 equiv), TMSCl (1.0 equiv), ꢀ788C, 15 min; then nBuLi (2.2m in pentane,
2.2 equiv), methyl cyanoformate (1.0 equiv), THF, ꢀ788C, 30 min; then 1n aq
HCl, 228C, 30 min, 54%; e) 1,2-dichlorobenzene, 2058C (microwave), 5 min,
83%. Boc=tert-butoxycarbonyl.
MOMCl, 82%) followed by catalytic hydrogenation (99%) of
the resulting compound gave aniline 23. Protection of the
amino group of 23 with a Boc group was achieved by stirring
the neat amine with Boc2O at 408C to furnish 24 in 99% yield.
Interestingly, treatment of 23 with Boc2O in CH2Cl2 in the
presence of a catalytic amount of 4-dimethylaminopyridine
led to formation of the corresponding isocyanate. Compound
24 was successfully carboxymethylated by using in situ
silylation of the carbamate (nBuLi, TMSCl), followed by
lithiation of the aromatic ring (nBuLi), and quenching with
methyl cyanoformate (54% overall yield). Finally, thermol-
ysis of the Boc group under microwave radiation (1,2-
dichlorobenzene) promoted clean conversion into the
required aniline 2 in 83% yield.
The total synthesis of platensimycin was completed as
shown in Scheme 4. Coupling of carboxylic acid 3 with aniline
2 was achieved by treatment with HATU in 85% yield. The
methyl ester of 26 was then hydrolyzed on exposure to
aqueous LiOH. Following complete hydrolysis of the ester as
determined by TLC analysis, 2n aqueous HCl was added to
effect cleavage of the MOM ethers, thus furnishing (ꢁ )-
platensimycin (ꢁ )-1 in excellent overall yield (ca. 90%). The
spectral data for (ꢁ )-1 were consistent with the reported
data[2a,b] and its structure (Table 1). The possibility of achiev-
ing an enantioselective synthesis of platensimycin exists at the
cycloisomerization stage, where in principle a chiral, enan-
tiomerically pure organometallic species, such as a rhodium
catalyst,[15] could be employed to induce asymmetric induc-
tion. Alternatively, a resolution, either by classical means or
by HPLC on a chiral stationary phase, at the carboxylic acid
stage, may be used to provide the enantiomerically pure form
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Table 1: Selected physical properties for compounds 1, 3, 4, and 6.
1: Rf =0.11 (silica gel, acetone/hexane/AcOH 60:40:1); IR (film):
n˜ =3316brm, 2961m, 2921m, 2870w, 1664s, 1656s, 1605s, 1534m,
1448m, 1400m, 1380m, 1282m, 1218m, 1150m, 1102m, 1091m, 1072m,
953w, 831m, 786m cmꢀ1; 1H NMR (500 MHz, C5D5N): d=8.12 (d,
J=8.7 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.37 (d, J=10.0 Hz, 1H), 5.95
(d, J=10.0 Hz, 1H), 4.50 (brs, 1H), 2.84 (ddd, J=14.6, 11.7, 5.3, Hz,
1H), 2.76 (ddd, J=14.3, 11.4, 4.6 Hz, 1H), 2.72–2.66 (m, 1H), 2.45 (s,
1H), 2.20 (t, J=6.5 Hz, 1H), 2.08–2.02 (m, 1H), 1.94–1.90 (m, 1H),
1.82 (d, J=11.6 Hz, 2H), 1.73 (dd, J=11.2, 3.0 Hz, 1H), 1.58 (dd,
J=11.6, 6.9 Hz, 1H), 1.49 (d, J=10.9 Hz, 1H), 1.40 (s, 3H), 1.15 ppm
(s, 3H); 13C NMR (150 MHz, C5D5N): d=203.7, 175.2, 174.9, 158.8,
158.5, 154.4, 129.9, 127.7, 115.7, 110.4, 107.5, 87.3, 76.9, 55.4, 47.2, 47.0,
46.6, 45.5, 43.5, 41.2, 32.6, 32.2, 24.9, 23.7 ppm; 1H NMR (600 MHz,
CDCl3): d=8.14 (s, 1H), 7.61 (d, J=8.9 Hz, 1H), 6.55 (d, J=10.0 Hz,
1H), 6.51 (d, J=8.9 Hz, 1H), 5.97 (d, J=10.0 Hz, 1H), 4.64 (brs, 1H),
2.68–2.63 (m, 1H), 2.52–2.46 (m, 4H), 2.19–2.15 (m, 1H), 2.11 (dd,
J=12.0, 3.4 Hz, 1H), 2.07 (d, J=11.7 Hz, 1H), 1.96 (dd, J=11.4, 3.4 Hz,
1H), 1.88 (td, J=11.4, 5.0 Hz, 1H), 1.84 (dd, J=11.7, 7.2 Hz, 1H) 1.69
(d, J=11.4 Hz, 1H), 1.57 (s, 3H), 1.31 (s, 3H); 13C NMR (150 MHz,
CDCl3): d=203.8, 173.4, 172.2, 155.1, 154.2, 153.9, 128.2, 127.2, 114.3,
111.1, 103.7, 88.0, 76.4, 54.7, 46.5, 46.1, 45.9, 44.7, 42.9, 40.4, 31.5, 31.2,
24.4, 22.7; HR-MS (ESI TOF): m/z calcd for C24H28NO7 [M+H]+:
442.1860; found 442.1853.
Scheme 4. Total synthesis of platensimycin. Reagents and conditions:
a) 3 (1.0 equiv), 2 (2.0 equiv), HATU (4.0 equiv), Et3N (5.9 equiv),
DMF, 228C, 26 h, 85%; b) LiOH (55 equiv), THF:H2O (4:1), 458C,
2 h; then 2n aq HCl, THF:H2O (3:1) 458C, 10 h, ca. 90% overall.
HATU=O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexa-
fluorophosphate, HOAt=1-hydroxy-7-azabenzotriazole.
3: Rf =0.35 (silica gel, EtOAc); IR (film): n˜ =2968brm, 1719s, 1657s,
1469w, 1445w, 1410w, 1297m, 1231m, 1183s, 1164m, 1151m, 1104m,
1095m, 953m, 831s, 758m cmꢀ1; 1H NMR (600 MHz, CDCl3): d=6.48
(d, J=10.1 Hz, 1H), 6.90 (d, J=10.1 Hz, 1H), 4.43 (brs, 1H), 2.41 (t,
J=6.5 Hz, 1H), 2.37 (brs, 1H), 2.35–2.24 (m, 3H), 2.10–2.07 (m, 1H),
2.04–2.00 (m, 2H), 1.88 (dd, J=11.2, 3.5 Hz, 1H), 1.79–1.73 (m, 2H),
1.62 (d, J=11.2 Hz, 1H), 1.45 (s, 3H), 1.24 ppm (s, 3H); 13C NMR
(150 MHz, CDCl3): d=203.4, 178.5, 153.6, 127.3, 87.1, 76.5, 54.9, 46.5,
46.0, 45.9, 44.6, 43.2, 40.5, 30.6, 29.0, 24.5, 23.0 ppm; HR-MS (ESI TOF):
m/z calcd for C17H23O4 [M+H]+: 291.1591; found 291.1581.
of platensimycin. Further improvements of this route to
platensimycin are envisaged.
The described chemistry renders platensimycin (1) readily
available by chemical synthesis in its racemic form and sets
the stage for the synthesis of designed analogues for structure-
activity relationship (SAR) studies in search of new anti-
bacterial agents. Certainly, numerous other synthetic sequen-
ces to this molecule can be imagined and no doubt many total
syntheses will be reported following this one.
4: Rf =0.20 (silica gel, EtOAc/hexane 3:7); IR (film): n˜ =2951m, 1677s,
1448w, 1379w, 1327w, 1282w, 1248w, 1138w, 1082w, 1037w, 993w, 820w,
778w cmꢀ1; 1H NMR (600 MHz, CDCl3): d=6.62 (d, J=10.0 Hz, 1H),
5.94 (d, J=10.0 Hz, 1H), 4.17 (t, J=3.4 Hz, 1H), 2.43–2.29 (m, 4H,),
1.97–1.94 (m, 2H), 1.90 (d, J=11.6 Hz, 1H), 1.79–1.74 (m, 2H), 1.66 (d,
J=11.2 Hz, 1H), 1.45 ppm (s, 3H); 13C NMR (150 MHz, CDCl3):
d=199.1, 155.2, 128.9, 87.2, 79.0, 51.7, 46.2, 44.2, 42.7, 42.2, 37.9, 37.5,
23.1 ppm; HR-MS (ESI TOF): m/z calcd for C13H17O3 [M+H]+: 205.1223;
found 205.1216.
Received: September 21, 2006
Published online: September 29, 2006
Keywords: antibiotics · drug resistance · natural products ·
.
samarium diiodide · total synthesis
6: Rf =0.31 (silica gel, EtOAc/hexane 1:1); IR (film): n˜ =2831w, 2725w,
1718s, 1657s, 1621s, 1406m, 1284w, 1259m, 1180w, 1090w, 1059w,
1023w, 888w, 858s, 706w cmꢀ1; 1H NMR (500 MHz, CDCl3): d=9.83 (t,
J=1.3 Hz, 1H), 6.98–6.96 (m, 1H), 6.79–6.76 (m, 1H), 6.27–6.23 (m,
2H), 5.11–5.09 (m, 1H), 4.99–4.97 (m, 1H), 3.31–3.23 (m, 1H), 2.85
(ddd, J=17.9, 4.9, 1.2 Hz, 1H), 2.68 (dq, 16.0, 2.4 Hz, 1H), 2.64 (ddd,
J=17.8, 8.3, 1.4 Hz, 1H), 2.47 (dd, J=16.0, 1.6 Hz, 1H), 2.15 (ddd,
J=13.0, 8.0, 1.6 Hz, 1H), 1.69 ppm (dd, J=13.0, 10.3 Hz, 1H);
13C NMR (125 MHz, CDCl3): d=200.5, 185.8, 154.2, 152.1, 151.2, 128.7,
127.7, 108.5, 49.2, 46.8, 44.4, 43.7, 36.2 ppm; HR-MS (ESI TOF): m/z
calcd for C13H15O2 [M+H]+: 203.1067; found 203.1067.
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