An efficient entry to amino-substituted resorcylic acid derivatives for the synthesis of platensimycin and analogues

Article abstract of DOI:10.1055/s-2007-983843

An efficient entry to protected amino-substituted resorcylic acid derivatives, methyl 3- or 5-amino-2,4-bis(methoxymethoxy)benzoate, is reported. Both derivatives can be used for the synthesis of platensimycin and its analogues. Georg Thieme Verlag Stuttg

Full text of DOI:10.1055/s-2007-983843

2614
SHORT PAPER
An Efficient Entry to Amino-Substituted Resorcylic Acid Derivatives for the
Synthesis of Platensimycin and Analogues
A
mino-Substit
h
uted Resorcy
i
lic Ac
l
ivativespp Heretsch, Athanassios Giannis*
Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(0341)9736599; E-mail: giannis@uni-leipzig.de
Received 21 May 2007
OH
O
Abstract: An efficient entry to protected amino-substituted resor-
O
Me
cylic acid derivatives, methyl 3- or 5-amino-2,4-bis(methoxy-
methoxy)benzoate, is reported. Both derivatives can be used for the
synthesis of platensimycin and its analogues.
HO
N
H
O
OH
Key words: amino-resorcylic acid, antibiotic, arene, natural prod-
ucts, platensimycin
O
Me
1
The recently discovered antibiotic (–)-platensimycin (1)
exhibits remarkable broad-spectrum activity against
gram-positive pathogens, among them strains of methicil-
lin-resistant Staphylococcus aureus (MRSA), vancomy-
cin-resistant Enterococcus faecalis (VRE), and penicillin-
resistant Streptococcus pneumoniae (PRSP). Its mecha-
nism of action entails inhibition of bacterial fatty acid syn-
thesis by affecting b-ketoacyl-[acyl-carrier-protein
(ACP)] synthase I/II (Fab F/B). Hence, it acts by the same
mechanism as the long known, but much weaker, inhibi-
tors cerulenine and thiolactomycin.1,2
O
O
Me
OMOM
NH2
HO
+
MeO
O
OMOM
O
Me
3
2
Scheme 1 The retrosynthetic approach to platensimycin
Several nitration and nitrosation/oxidation procedures
were carefully investigated (such as NaNO2 in AcOH,
NaNO2 in Ac2O–AcOH,7 NaNO2 in Ac2O–AcOH and
concd HNO3–H2SO4). Eventually we decided to use in
situ formed acetyl nitrate8 (by adding fuming HNO3 in
AcOH to a soln of the arene in Ac2O–AcOH) as a suitable
nitration agent.
Although 7 and its known isomer 89 were formed in al-
most 1:1 ratio in the reaction, separation was easily effect-
ed by complete precipitation of 8 by addition of water to
the reaction mixture followed by isolation of 7 by extrac-
tion and chromatography. The use of 1.1 equivalents of
nitric acid therein represents a compromise between com-
plete conversion of the substrate and formation of undes-
ired dinitration products.
The first total synthesis of racemic platensimycin by
Nicolaou and co-workers3 applied a retrosynthetic scis-
sion to form an arene 2 and a ketolide subunit 3
(Scheme 1); this route was later used in the formal
racemic4 as well as in the enantioselective5 syntheses by
Nicolaou’s group and a formal racemic synthesis by the
Snider group.6
The aromatic subunit of platensimycin was synthesized
by Nicolaou and co-workers in five steps from commer-
cially available 2-nitroresorcinol (4) and its key features
were directed ortho-metalation to attach the carboxylic
acid moiety and microwave-assisted tert-butoxycarbonyl
(Boc) deprotection (Scheme 2).
Much to our surprise there are no other procedures report-
ed in literature for the synthesis of such tetrasubstituted
amino-resorcylic acids or their derivatives.
Nitro-substituted dihydroxybenzoates 7 and 8 were now
converted in two steps into the bis(methoxymethyl)-pro-
tected amino-substituted resorcylic acid derivatives 9 and
10, respectively. Methoxymethyl-protection of 7 proceed-
Since a facile and efficient synthetic pathway to multi-
gram quantities of appropriately protected 2 and deriva-
tives was required for our ongoing work on platensimycin
analogues, a strategy starting from commercially avail-
able methyl 2,4-dihydroxybenzoate (6) making use of a
nitration to form the appropriately substituted arene was
examined.
OH
OMOM
a–c
d–e
2
NO2
NHBoc
OMOM
OH
4
5
Scheme 2 Nicolaou’s synthesis of the aromatic subunit 2 of platen-
simycin. Reagents and conditions: (a) NaH, MOMCl; (b) H2, Pd/C;
(c) Boc2O; (d) BuLi, TMSCl, then BuLi, methyl cyanoformate; (e)
1,2-dichlorobenzene, 205 °C.
SYNTHESIS 2007, No. 17, pp 2614–2616
Advanced online publication: 08.08.2007
DOI: 10.1055/s-2007-983843; Art ID: P06007SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
7

SHORT PAPER
Amino-Substituted Resorcylic Acid Derivatives
2615
OH
MeO
O
OH
6
a
NO2
OR
OR
MeO
+
MeO
NO2
O
OR
O
OR
7: R = H
9: R = MOM
8: R = H
10: R = MOM
c
b
d
d
d
NH2
OH
OMOM
OMOM
MeO
MeO
NH2
NH2
OMOM
MeO
O
OH
12
O
O
OMOM
2
11
Scheme 3 Synthesis of platensimycin’s aromatic subunit 2, isomer 11 and parent arene 12. Reagents and conditions: (a) HNO3, Ac2O–AcOH;
(b) MOMCl, NaI, DIPEA; (c) NaH, MOMCl; (d) H2, Pd/C.
mixture of fuming HNO3 (100%) (3.80 g, 60 mmol, 1.1 equiv) in
glacial AcOH (30 mL) was added over 1 min. When addition was
complete, the temperature of the light brown soln was allowed to
rise to 22 °C and stirring was continued for a further 15 min after
which an ochre-colored suspension had formed. H2O (130 mL) was
added, whereupon the mixture was aged for another 30 min without
stirring. The precipitate was filtered, rinsed with small amounts of
H2O, and dried under vacuum to give crude 8, which was recrystal-
lized (MTBE, 250 mL) to give pure 8 (3.10 g, 33% based on recov-
ered 6) as pale yellow cubes.
ed smoothly to give 9 when using an excess of methoxy-
methyl chloride and sodium iodide in a DME–DMF
mixture; hydrogenation of 9 using 10% palladium on car-
bon and an ambient pressure of hydrogen furnished the
desired arene 2 in 34% yield over three steps. Furthermore
isomer 8 was protected and hydrogenated in a total yield
of 28%. Finally the unknown parent compound 12 was
obtained by hydrogenation of 7 in nearly quantitative yield.
In summary, we have developed an efficient entry to pro-
tected amino-substituted resorcylic acid derivatives 2 and
11. Compound 2 is a crucial intermediate for platensimy-
cin synthesis. Both derivatives will facilitate the synthesis
of this unique antibiotic and its analogues.
The clear brown soln and combined washings were extracted with
Et2O (3 × 150 mL) and the solvents were removed under reduced
pressure to give crude 7 as an deeply orange colored solid. Purifica-
tion was carried out by chromatography (silica gel, n-hexane–
EtOAc, 1:1) to yield pure 7 (3.40 g, 35% based on recovered 6) as
bright yellow needles and recovered starting material (1.40 g, 8.3
mmol).
All reagents were commercially obtained from Acros, Aldrich, Alfa
Aesar [methyl 2,4-dihydroxybenzoate (6)] and Fluka and used with-
out further purification. Melting points were measured with a Boe-
tius-micro hot stage and are uncorrected. 1H and 13C NMR spectra
were recorded on a Varian Gemini 300 (300 MHz for 1H NMR; 75
MHz for 13C NMR) and Bruker Avance-DRX 400 (400 MHz for 1H
NMR; 100 MHz for 13C NMR); the residual solvent peak was used
as an internal reference. HRMS were obtained on a Bruker Dalton-
ics APEX II (for ESI). Reactions involving moisture-sensitive reac-
tants were performed in flame-dried glassware under an argon
atmosphere; reactants were added via syringe. Flash column chro-
matography was performed on silica gel (Acros 60 A, 0.035–0.070
mm) and analytical TLC on pre-coated silica gel plates (Merck 60
Methyl 2,4-Dihydroxy-5-nitrobenzoate (8)
Mp 167–168 °C, Rf = 0.42 (n-hexane–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 4.00 (s, 3 H, CH3), 6.62 (s, 1 H,
arom), 8.74 (s, 1 H, arom), 11.00 (s, 1 H, OH), 11.45 (s, 1 H, OH).
13C NMR (100 MHz, CDCl3): d = 53.1, 105.9, 106.9, 127.5, 129.8,
160.5, 168.0, 169.1.
HRMS-ESI: m/z [M – H]– calcd for C8H6NO6: 212.02006; found:
212.02002.
Methyl 2,4-Dihydroxy-3-nitrobenzoate (7)
Mp 125–126 °C, Rf = 0.48 (n-hexane–EtOAc, 2:1).
1H NMR (300 MHz, CDCl3): d = 3.97 (s, 3 H, CH3), 6.63 (d,
3J = 9.3 Hz, 1 H, arom), 7.99 (d, 3J = 9.3 Hz, 1 H, arom), 11.17 (s,
1 H, OH), 12.87 (s, 1 H, OH).
F
254, 0.25 mm).
Methyl 2,4-Dihydroxy-3-nitrobenzoate (7) and Methyl 2,4-Di-
hydroxy-5-nitrobenzoate (8)
Methyl 2,4-dihydroxybenzoate (6, 9.15 g, 54.4 mmol) was dis-
solved in a mixture of glacial AcOH (66 mL) and Ac2O (34 mL) us-
ing ultrasonication. After cooling the clear soln to 0 °C (ice bath), a
13C NMR (100 MHz, CDCl3): d = 53.0, 105.9, 109.4, 129.5, 136.9,
160.3, 160.9, 170.0.
Synthesis 2007, No. 17, 2614–2616 © Thieme Stuttgart · New York

2616
P. Heretsch, A. Giannis
SHORT PAPER
Methyl 5-Amino-2,4-bis(methoxymethoxy)benzoate (11)
HRMS-ESI: m/z [M + Na]+ calcd for C8H7NO6Na: 236.01656;
found: 236.01652.
Using the typical procedure for 2 with methyl 3-amino-2,4-
bis(methoxymethoxy)benzoate (10, 301 mg, 1.0 mmol) gave pure
11 (271 mg, quantitative) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 3.49 (s, 3 H, OCH3), 3.53 (s, 3 H,
OCH3), 3.84 (s, 3 H, COOCH3), 5.12 (s, 2 H, OCH2O), 5.23 (s, 2 H,
OCH2O), 6.89 (1 H, arom), 7.23 (1 H, arom).
13C NMR (75 MHz, CDCl3): d = 51.9, 56.4, 56.6, 95.0, 97.3, 105.9,
115.1, 117.5, 131.6, 148.8, 150.9, 166.3.
HRMS-ESI: m/z [M + H]+ calcd for C12H18NO6: 272.11286; found:
272.11327.
Methyl 2,4-Bis(methoxymethoxy)-3-nitrobenzoate (9); Typical
Procedure
To a stirred solution of NaH (9.00 g, 60.0 mmol) in anhyd DME
(100 mL) was added MOMCl (90%, technical, 6.0 mL, 70.0 mmol),
a solution of 7 (3.20 g, 15.0 mmol) in anhyd DMF (50 mL) and DI-
PEA (13.7 mL, 80.0 mmol) consecutively. The yellow suspension
was heated to 55 °C for 1 h. After this time the reaction mixture was
diluted with H2O (150 mL) and sat. aq NaHCO3 (300 mL) and ex-
tracted with Et2O (4 × 150 mL). The organic phase was washed with
1 M HCl (50 mL) and brine (50 mL) and was dried with MgSO4 and
filtered. The solvent was removed in vacuo and the resulting yellow
oil was filtered through a short plug of silica gel (n-hexane–EtOAc,
3:1) yielding pure 9 (4.40 g, 14.6 mmol, 98%) as a pale yellow sol-
id; mp 66–68 °C.
1H NMR (400 MHz, CDCl3): d = 3.48 (s, 3 H, OCH3), 3.49 (s, 3 H,
OCH3), 3.89 (s, 3 H, COOCH3), 5.15 (s, 2 H, OCH2O), 5.28 (s, 2 H,
OCH2O), 7.06 (d, 3J = 9.0 Hz, 1 H, arom), 7.97 (d, 3J = 9.0 Hz, 1 H,
arom).
13C NMR (100 MHz, CDCl3): d = 52.6, 57.0, 58.0, 95.1 (2 ×),
102.3, 110.8, 118.2, 134.1, 150.9, 152.4, 164.4.
Methyl 3-Amino-2,4-dihydroxybenzoate (12)
Methyl 2,4-dihydroxy-3-nitrobenzoate (7, 300 mg, 1.4 mmol) was
hydrogenated with ambient pressure of H2 using 10% Pd/C (150
mg, 10 mol%) in EtOAc (30 mL) for 16 h. The resulting suspension
was filtered through a pad of Celite and washed with EtOAc and the
solvent was removed under reduced pressure to give pure 12 (250
mg, 97%) as colorless prisms; mp 215 °C (dec.).
1H NMR (300 MHz, CDCl3/CD3OD): d = 3.85 (s, 3 H, COOCH3),
3
4.29 (br, 2 H, NH2), 6.33 (d, J = 8.8 Hz, 1 H, arom), 7.19 (d,
3J = 8.8 Hz, 1 H, arom).
13C NMR (75 MHz, DMSO-d6): d = 52.0, 103.9, 107.2, 117.8,
123.5, 149.0, 149.5, 170.4.
HRMS-ESI: m/z [M + Na]+ calcd for C8H9NO4Na: 206.04238;
HRMS-ESI: m/z [M + Na]+ calcd for C12H15NO8Na: 324.06899;
found: 324.06923.
Methyl 2,4-Bis(methoxymethoxy)-5-nitrobenzoate (10)
To a stirred suspension of NaH (60% in paraffin oil, 1.20 g, 30.0
mmol), which was previously washed with anhyd n-petane (2 × 5
mL), in anhyd DMF (30 mL) was added dropwise a solution of 8
(2.13 g, 10.0 mmol) in anhyd DMF (30 mL) at 0 °C (ice bath). The
deep-red solution was stirred until no more hydrogen evolution
could be detected (20 min). Then, MOMCl (90%, technical, 1.85 g,
23.0 mmol) was added dropwise. After complete addition the ice
bath was removed and stirring at r.t. was continued for 1 h. After
this time the reaction mixture was diluted with H2O (100 mL) and
stirred for 1 h. The mixture was extracted with Et2O (200 mL) and
the organic phase was washed with H2O (2 × 200 mL) and brine (50
mL). The organic phase was dried with MgSO4 and filtered, the sol-
vent was removed in vacuo to yield pure 10 (2.57 g, 8.5 mmol, 85%)
as a light yellow oil.
1H NMR (400 MHz, CDCl3): d = 3.55 (s, 3 H, OCH3), 3.56 (s, 3 H,
OCH3), 3.90 (s, 3 H, COOCH3), 5.34 (s, 2 H, OCH2O), 5.36 (s, 2 H,
OCH2O), 7.12 (1 H, arom), 8.54 (1 H, arom).
13C NMR (100 MHz, CDCl3): d = 52.4, 57.0, 57.2, 95.2, 95.5,
103.5, 110.8, 113.9, 130.5, 155.3, 161.7, 164.1.
HRMS-ESI: m/z [M + H]+ calcd for C12H16NO8: 302.08704; found:
302.08709.
found: 206.04237.
Acknowledgment
Philipp Heretsch is grateful for a Ph.D. fellowship from Fonds der
Chemischen Industrie (VCI).
References
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Methyl 3-Amino-2,4-bis(methoxymethoxy)benzoate (2); Typi-
cal Procedure
Methyl 2,4-bis(methoxymethoxy)-3-nitrobenzoate (9, 1.51 g, 5.0
mmol) was hydrogenated with ambient pressure of H2 using 10%
Pd/C (530 mg, 10 mol%) in EtOAc (100 mL) for 16 h. The resulting
suspension was filtered through a pad of Celite and washed with
EtOAc and the solvent was removed under reduced pressure to give
pure 2 (1.36 g, quantitative) as a colorless oil.
1H NMR (300 MHz, CDCl3): d = 3.49 (s, 3 H, OCH3), 3.60 (s, 3 H,
OCH3), 3.85 (s, 3 H, COOCH3), 4.20 (br, 2 H, NH2), 5.10 (s, 2 H,
3
OCH2O), 5.24 (s, 2 H, OCH2O), 6.50 (d, J = 8.7 Hz, 1 H, arom),
7.25 (d, 3J = 8.7 Hz, 1 H, arom).
(8) Maleski, R. J.; Kluge, M.; Sicker, D. Synth. Commun. 1995,
25, 2327.
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13C NMR (100 MHz, CDCl3): d = 52.0, 56.5, 57.8, 94.9, 101.3,
109.6, 118.1, 120.2, 131.8, 145.6, 148.7, 166.4.
HRMS-ESI: m/z [M + Na]+ calcd for C12H17NO6Na: 294.09481;
found: 294.09506.
Synthesis 2007, No. 17, 2614–2616 © Thieme Stuttgart · New York