Phenazines and natural products; novel synthesis of saphenic acid

Article abstract of DOI:10.1055/s-1999-3587

The natural product saphenic acid (6-(1-hydroxyethyl)1- phenazinecarboxylic acid) was synthesized from readily accessible starting materials. The desired product was obtained in an overall yield of 22% for four steps with the key steps being formation of

Full text of DOI:10.1055/s-1999-3587

PAPER
1763
Phenazines and Natural Products; Novel Synthesis of Saphenic Acid
Lars Petersen, Knud J. Jensen, John Nielsen*
Technical University of Denmark, Department of Organic Chemistry, Building 201, DK-2800 Lyngby, Denmark
Fax +(45) 45933968; E-mail: okjni@pop.dtu.dk
Received 14 May 1999; revised 29 June 1999
bers of structurally related compounds and plays a
prominent role in modern drug discovery.7 For the prepa-
ration of combinatorial libraries of saphenic acid deriva-
tives, we needed an efficient synthesis of core structure 1.
Abstract: The natural product saphenic acid (6-(1-hydroxyethyl)-
1-phenazinecarboxylic acid) was synthesized from readily accessi-
ble starting materials. The desired product was obtained in an over-
all yield of 22% for four steps with the key steps being formation of
a diphenylamine, followed by cyclization under alkaline and reduc-
ing conditions. Assignments of 1H NMR spectra were achieved by
homo- and heteronuclear 1D and 2D correlations. Double pulsed
field gradient spin-echo one-dimensional NOESY proved especial-
ly valuable for assignment of aromatic protons.
Several synthetic routes to phenazines have been reported
but few are mild, efficient and simple to carry out.8 Bahn-
müller et al. have reported the preparation of saphenic
acid in an overall yield of 3% using the Wohl-Aue reaction
to fuse 2-aminobenzoic acid and a masked 2-nitroace-
tophenone at 200∞C in sand and solid potassium hydrox-
ide.9 This synthesis failed in our hands. Ring closure of
various diphenylamines is another route to phenazines.
Breitmaier and Hollstein prepared 1,6-phenazinedicar-
boxylic acid by cyclization of a 2-nitrodiphenylamine.10
This type of reaction is assumed to proceed via an attack
of a resonance stabilized anion on the nitro group11 yield-
ing the 1,6-isomer rather than the 1,8-isomer.
Key words: antibiotics, heterocycles, natural products, phenazine,
DPFGSE-NOE
An interesting class of marine1 compounds with antibiotic
and antitumor activity contains heteroaromatic phenazine
structures.2 A sub-class of phenazine antibiotics contain
6-(1-hydroxyethyl)-1-phenazinecarboxylic acid, also re-
ferred to as saphenic acid, 1 (Figure 1, R1 = R2 = H). Nat-
urally occurring 1 is optically active, but it has not been
established whether it has the R or S configuration. It has
been shown that 1 easily racemizes in the presence of ei-
ther mild acids or bases.3 Saphenic acid itself is reported
to be biologically inactive, whereas proper substitutions at
either the carboxy or at the secondary hydroxy group
leads to biologically active compounds. For example,
simple esters4 as in saphenamycin5 or the more complex
esmeraldines6 contain the saphenic acid scaffold. Like-
wise esters of the rare carbohydrate L-quinovose (6-
deoxy-L-glucose),3 are active against a broad range of
bacteria (Figure 1).
Here we describe a novel and efficient synthesis of
saphenic acid with the two key steps being formation of an
appropriately substituted 2-nitrodiphenylamine, followed
by ring closure under alkaline and reducing conditions.
The first building block, protected 3-aminoacetophenone
4, has previously been synthesized.12 However, in an op-
timized protocol starting from easily available 3-
nitroacetophenone13 2 which was masked as the ketal, 3,
to prevent polymerization, hydrogenation over Pd/C gave
4 in 83% overall yield. (Scheme 1). A second building
block is a 2-halo-3-nitrobenzoic acid with 2-chloro-3-ni-
trobenzoic acid, 5, being commercially available.
Copper metal or copper salts are often used to mediate the
formation of diphenylamines.14 However, an experiment
without catalyst revealed no difference in rate of reaction,
indicating that copper bronze or powder had no catalytic
activity. Thus, in the absence of any catalyst, coupling of
4 and 5 in refluxing 1-pentanol in the presence of potassi-
um carbonate for 18 h gave the diphenylamine ketal 6.
Acidic hydrolysis for 30 min yielded 7 in 81% for the two-
step sequence (Scheme 1). An important issue is the com-
plete deprotonation of 5 before adding 4. The high yield
of 7 is assured by treating 5 with potassium carbonate in
1-pentanol for 1 h. Otherwise the yield of 7 decrease dra-
matically because of cleavage of the ketal, followed by
polymerization.
O
OR1
10
5
1
4
9
N
10a
4a
9a
5a
2
3
8
7
6
N
1'
OR2
2'
1 (R1=R2=H)
Figure 1 Saphenic acid, 1, (6-(1-hydroxyethyl)-1-phenazinecar-
boxylic acid (R1 = R2 = H) and derivatives: quinovosylsaphenates
(R1 = 2-O- or 3-O-quinovosyl, R2 = H), simple esters (R1 = H,
R2 = C(O)CH2Cl or C(O)CH2OH), saphenamycin (R1 = H, R2 = C(O)-
6-CH3-2-OH-C6H3) or radical scavengers (a dimer or R1 = H, R2 = 2-
phenazinyl). General numbering of atoms in phenazines.
Attempted cyclization of nitro ketal 6 promoted by sodi-
um ethoxide and sodium borohydride in ethanol to form
phenazine ketal 8 was sluggish and required several days
at reflux to yield only minor amounts of product. Han-
Thus, 1 is an interesting core structure in the search for
novel potential antibiotics and antitumor agents. Combi-
natorial chemistry facilitates the synthesis of large num-
Synthesis 1999, No. 10, 1763–1766 ISSN 0039-7881 © Thieme Stuttgart · New York

1764
L. Petersen et al.
PAPER
velop fast and efficient NMR protocols for structural elu-
cidation of library compounds related to 1. The relative
connectivity among the two sets of three aromatic protons
was established by COSY spectra. Nuclear Overhauser
enhancement spectroscopy (NOESY) showed strong
cross peaks from H2’ and H-1’ to an aromatic proton thus
identifying H-7 and yielding the relative orientation of the
first set of correlated protons. Double pulsed field gradi-
ent spin-echo one-dimensional NOESY (DPFGSE-
NOE)17 experiments with selective excitation of H-2’
gave the expected strong NOE at H-7 and a small NOE
identifying H-4 in the other ring system. Thus, the second
set of correlated protons could be orientated.
NO2
NO2
NH2
b
a
O
O
O
O
O
2
3
4
O
OH
O
OH
H
N
Cl
+
4
NO2
NO2
The good solubility of saphenic acid in DMSO-d6 allowed
for a gradient-selected heteronuclear multiple bond corre-
lated (HMBC) spectrum which showed a three-bond cross
peak between the single carbonyl and H-2, thus confirm-
ing the assignment. Carbon resonances were assigned fol-
lowing gradient-selected heteronuclear single-quantum
coherence (HSQC) spectroscopy.18
5
HO
f
9
c
O
OH
O
OH
H
N
H
N
d
In conclusion, we have succeeded in synthesizing the nat-
ural product saphenic acid in a yield of 32% from readily
accessible 2-nitrodiphenylamine 7. The obtained yield is
about 10 times higher than previously reported and allows
for large-scale synthesis of building blocks essential for
the generation of combinatorial libraries on the saphenic
acid scaffold. DPFGSE-NOE was a fast and powerful tool
in structural elucidation by NMR. This protocol for NMR
assignment should be extendable to derivatives of 1.
NO2
NO2
O
6
O
O
7
e
e
O
OH
1
N
N
(R1=R2=H)
O
8
O
Unless otherwise stated, all chemicals were obtained from commer-
cial sources and used without further purification. TLC analysis was
performed on Merck Silica Gel 60 F254 plates and visualized by UV-
light of 254 nm. To visualize amines, TLC plates were dipped in a
standard solution of ninhydrin (220 mg) in EtOH (200 mL) fol-
lowed by heating. Melting points are uncorrected. HR-MS was per-
formed by positive ion FAB and using a m-nitrobenzoic acid/
PEG300 matrix. 1H NMR spectroscopy was performed on a Varian
Unity Inova 500 operating at 499.87 MHz equipped with a wave-
form generator and a z- (single axis) PFG inverse detection C-H-P
probe. 13C NMR spectroscopy was performed on a Varian Mercury
300 equipped with a 4-nuclei PFG probe and operating at 75.46
MHz or on a Bruker AC 200 operating at 50.32 MHz. NOESY spec-
tra were acquired with a mixing time of 4.000 sec and a relaxation
delay (d1) of 9.0 sec. DPFGSE-NOE was performed varying the
mixing time from 1.0 to 5.0 sec. in steps of 0.5 sec.
Reactions a-f: a) (CH2OH)2/p-toluenesulfonic acid in benzene, reflux
18h (89%); b) H2/Pd(C) in EtOH, r.t. 30 min (93%); c) K2CO3 in 1-
pentanol, reflux 18 h; d) 4M aq HCl, r.t. 30 min (81%, 2 steps); e)
NaOEt and NaBH4 in EtOH, reflux 18 h (32%); f) NaBH4 in EtOH,
r.t. 1h (81%).
Scheme 1
dling and isolation of compound 6 was difficult as it was
easily hydrolyzed and non-crystalline.
We therefore decided to perform the cyclization on nitro
ketone 7 assuming that it would proceed through interme-
diate 9.15 Treatment of 7 with sodium ethoxide and sodi-
um borohydride at room temperature first yielded 9 which
upon heating at reflux for 18 h reacted further to 1. After
extractive workup and recrystallization, 1 was obtained in
an isolated yield of 32%. A critical issue in this synthesis
is the use of a large excess of sodium borohydride. With-
out excess of borohydride the reaction mixture turns dark,
and the colored impurities16 formed hamper purification,
as this type of compounds are poorly suited for chroma-
tography on silica gel. Synthesis on a larger scale (17
mmol) showed no change in the isolated percentage yield.
2-Methyl-2-(3-nitrophenyl)-1,3-dioxolane (3)
Compound 2 (4.00 g; 24.2 mmol), ethylene glycol (1.88 g, 30.2
mmol), and p-toluenesulfonic acid (20 mg) were dissolved in
benzene19 (40 ml) in a round bottomed flask equipped with a Dean-
Stark separator. After heating at reflux for 16 h, TLC indicated that
2 had been consumed and a new compound formed (Rf 0.52;
EtOAc/hexane 1:3). The mixture was diluted with CHCl3 (60 mL),
washed with H2O (3 ¥ 20 mL), dried (MgSO4) and concentrated to
dryness. The remaining solid was recrystallized from acetone/hex-
ane to yield 89% of a colorless, crystalline solid with identical melt-
ing point (71–72∞C) and 1H NMR data to literature data for 3.12b
1
The original structural elucidation of 1 by H NMRwas
13C NMR (50 MHz, CDCl3): d = 27.4 (CH3), 64.7 (OCH2CH2O),
107.9, 120.5, 122.8, 129.3, 131.5, 145.9.
carried out in CDCl3 solution at 300 MHz.5 We performed
NMR studies in CDCl3, DMSO-d6, and pyridine-d5 to de-
Synthesis 1999, No. 10, 1763–1766 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Phenazines and Natural Products; Novel Synthesis of Saphenic Acid
1765
Table 1 1H NMR data (500 MHz) of saphenic acid (1) in CDCl3, DMSO-d6, and pyridine-d5, d-values in ppm (J-values in Hz).
H-2
8.99
7.0
H-3
H-4
8.52
8.5
H-7
7.98
8.5
H-8
H-9
8.19
8.5
H-1’
5.86
6.6
H-2’
1.82
6.6
a
CDCl3
8.06
7.99
3J(H,H) (Hz)
7.0
8.5
8.5
8.5
4J(H,H) (Hz)
1.3
1.3
1.3
NOE (%)c
0.41
8.51
8.5
9.57
8.13
6.4
19.32
5.98
6.4
b
DMSO-d6
3J(H,H) (Hz)
4J(H,H) (Hz)
NOE (%)d
Pyridine-d5
3J(H,H) (Hz)
8.56
6.8
8.08
8.08
8.24
8.5
1.56
6.4
1.3
1.3
1.3
1.7
1.21
8.46
8.9
5.13
8.51
7.0
20.45
6.52
b
8.89
6.7
7.89
7.97
8.10
8.9
1.95
8.5
6.7
8.9
6.7
4J(H,H) (Hz)
1.3
1.3
1.3
1.3
NOE (%)d
0.46
1.93
7.89
a) 8 mg in ~0.7 mL, 303.1 K
b) 10mg in ~0.7 mL, 303.1 K
c) Excitation of H-2’, mixing time 4.0 sec
d) Excitation of H-2', mixing time 2.0 sec
3-(2-Methyl-1,3-dioxolane-2-yl)aniline (4)
further purification. An analytical sample was recrystallized from
To compound 3 (10.78 g; 51.5 mmol), dissolved in anhyd EtOH
(400 mL), activated charcoal was added, and the suspension was re-
fluxed for 5 min to remove any catalyst poisons. The solution was
cooled to r.t. and filtered into a cylinder glass, flushed with N2 and
Pd-catalyst (0.5 g 5% Pd/C) was added. Then the mixture was hy-
drogenated at 50 bar. After 30 min, consumption of hydrogen
ceased and the apparatus was disassembled. TLC showed only one
spot which colored bright pink with ninhydrin (Rf 0.23; EtOAc/hex-
ane 1:3). The reaction mixture was filtered, the filter cake was
washed with more EtOH (2 ¥ 30 mL) and the combined filtrates
were evaporated to yield 4, colorless crystals (8.59 g, 93%) with mp
86-88∞C (lit.12c 80–81∞C).
H2O/EtOH to yield bright yellow blades (mp 223–224∞C).
1H NMR (300 MHz, DMSO-d6): d = 2.50 (s, 3H; CH3), 7.20–7.12
(m., 2H), 7.36 (t, J = 8.0 and 7.8 Hz, 1H), 7.42 (t, J = 2.4 Hz, 1H),
7.54 (dt, J = 7.7 and 1.1 Hz, 1H), 8.09 (dd, J = 8.0 and 1.7 Hz, 1H),
8.18 (dd, J = 7.8 and 1.7 Hz; 1H), 9.77 (br s, 1H; NH), 13.7 (br s,
1H; COOH).
13C NMR (50 MHz, DMSO-d6): d = 26.8 (CH3) ppm, 116.7, 120.2,
122.6, 122.7, 129.7, 130.6, 136.7 (tertiary arom. CH), 121.9, 137.6,
137.9, 140.7, 142.4 (quaternary arom. C), 168.4 (COOH), 197.5
(COCH3).
Anal. calcd. for C15H12N2O5: C, 60.00; H, 4.03; N, 9.32. Found: C,
59.85; H, 4.07; N, 9.18.
1H NMR was identical with literature data.12c
13C NMR (50 MHz, CDCl3): d = 27.5 ppm (CH3), 64.4
(OCH2CH2O), 108.8, 112.1, 114.5, 115.6, 129.2, 144.6, 146.2.
HR-MS: calcd. m/z: 300.0746, found:300.0746 [M]+, calcd. m/z:
301.0824, found: 301.0815 [M+H]+
2-[3-(1-Hydroxyethyl)anilino]-3-nitrobenzoic Acid (9)
2-(3-Acetylanilino)-3-nitrobenzoic Acid (7)
Compound 7 (304 mg; 1.01 mmol) was suspended in anhyd EtOH
(20 mL). NaBH4 was added (190 mg; 5.05 mmol) and the red solu-
tion was stirred for 1 h at r.t. H2O (20 mL) was added, EtOH evap-
orated under vacuum and the solution acidified with 4 M aq HCl to
pH<1. The orange oil was extracted with CHCl3 (20 and 4¥10 mL),
dried (MgSO4) and evaporated to yield yellow crystals of com-
pound 9 (248 mg, 81%; mp. 147–152∞C). The crude product was re-
crystallized from EtOAc to constant mp of 159.5–160.5∞C.
1H NMR (500 MHz, DMSO-d6): d = 1.25 (d, J = 6.0 Hz, 3H; CH3),
4.60 (q, J = 6.0 Hz, 1H; CH), 5.04 (br s, 1H; OH), 6.76 (d, J = 7.5
Hz, 1H), 6.86 (s, 1H), 6.96 (d, J = 7.3 Hz, 1H), 7.08 (t, J = 7.9 Hz,
1H), 7.16 (t, J = 7.6 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 8.20 (d,
J = 7.3 Hz, 1H), 9.88 (s, 1H; NH), 13.7 (br s, 1H; COOH).
Compound 5 (4.40 g; 21.9 mmol) and K2CO3 (6.06 g; 43.9 mmol)
were suspended in 1-pentanol (44 mL; dried over 4 Å molecular
sieves), heated on an oil bath at 150 ∞C for 1 h whereby 5 dissolved.
Compound 4 (3.93 g; 21.9 mmol) was added and the mixture heated
at reflux for 16 h. Upon cooling, 4 M aq HCl (35.2 mL) was added
and the two-phase system was stirred vigorously for 30 min to com-
plete the deprotection. Aq NaOH (45 mL; 15% w/w) was added to
pH >11, and the solution was diluted with H2O to a total volume of
440 mL. This solution was washed with CHCl3 (170 mL) and the or-
ganic phase extracted with 0.5 M aq NaOH (1 x 50 mL). The aque-
ous phases were combined and acidified with aq conc. HCl and after
stirring for 30 min the yellow solid was collected by filtration (5.33
g, 81%). The product melted at 217–220∞C and was used without
Synthesis 1999, No. 10, 1763–1766 ISSN 0039-7881 © Thieme Stuttgart · New York

1766
L. Petersen et al.
PAPER
b) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev.
13C NMR (75 MHz, DMSO-d6): d = 26.37 (CH3), 68.54 (CHOH),
115.26, 117.04, 119.46, 120.98, 129.52, 131.50, 137.31, 139.55,
140.53, 141.76, 149.29 (Carom), 169.30 (COOH).
1997, 97, 449.
c) A Practical Guide to Combinatorial Chemistry; Czarnik, A.
W.; DeWitt, S. H., Eds.; American Chemical Society:
Washington, DC, 1997.
Anal. calcd. for C15H14N2O5: C, 59.60; H, 4.66; N,9.26. Found: C,
59.06; H, 4.72; N, 9.03.
d) Solid-Supported Combinatorial and Parallel Synthesis of
Small-Molecular-Weight Compound Libraries; Obrecht, D.;
Villalgordo, J. M., Eds.; Pergamon: Oxford, UK, 1998.
(8) In general about phenazines, see: Katritzky, A. R.; Rees, C.
W. Comprehensive Heterocyclic Chemistry, Vol. 3, Boulton,
A.J.; McKillop, A., Eds.; Pergamon Press: New York, 1984.
For some of the older methods and historical preparations see:
Swan, G.A.; Felton, D. G. I. The Chemistry of Heterocyclic
Compounds, Phenazines; Interscience: New York and
London, 1957.
(9) Bahnmüller, U.; Keller-Schierlein, W.; Brandl, M.; Zähner,
H.; Diddens, H. J. Antibiot. 1988, 41, 1552.
(10) a) Flood, M. E.; Herbert, R. B.; Holliman, F. G. J. Chem. Soc.
Perkin Trans. I 1972, 622.
b) Breitmaier, E.; Hollstein, U. J. Org. Chem. 1976, 41, 2104.
(11) For the mechanism see: Cross, B.; Williams, P. J.; Woodall, R.
E. J. Chem. Soc. (C) 1971, 2085.
(12) a) Synthesis of 3 by a procedure similar to the present, but
with no yield stated: Risley, J. M.; DeFrees, S. A.; Van Etten,
R. L. Org. Magn. Reson. 1983, 21, 28.
HR-MS: calcd. m/z: 303.0981, found: 303.0970 [M+H]+.
6-(1-Hydroxyethyl)phenazine-1-carboxylic Acid (1)
A solution of NaOEt was prepared by dissolving Na (18.2 g, 0.76
mol) in anhyd EtOH (880 mL). NaBH4 (16.74 g, 0.441 mmol) was
added and the mixture stirred for 5 min, followed by addition of 7
(4.40 g, 14.6 mmol). After stirring for another 15 min, the mixture
was heated at reflux for 18 h. Upon cooling, the bright yellow solu-
tion was evaporated partially under vacuum, H2O was added (1200
mL) and remaining EtOH evaporated. The aq solution was acidified
with 4 M aq HCl to pH 6.0 (pH-meter) and extracted with CHCl3 (8
¥ 250 mL) until the organic phase was colorless. The combined or-
ganic phases were dried (MgSO4) and evaporated which yielded a
brown-yellow solid (3.1 g). This was dissolved in EtOAc by heating
at reflux, which yielded yellow crystals with mp. 198–200 ∞C (lit.
202–204 ∞C) (1.26 g, 32%) after cooling overnight (5 ∞C) and filtra-
tion. TLC showed only one yellow spot (Rf 0.17, 2.5% MeOH/
CHCl3). The isolated product showed the same mp as previously
reported9 for racemic 1 as well as correct MS and microanalysis da-
ta.
b) Synthesis of 3 by nitration of 2-methyl-2-phenyl-1,3-
dioxolane: Suzuki, H.; Yonezawa, S.; Mori, T. Bull. Chem.
Soc. Jpn. 1995, 68, 1535.
c) Synthesis of 4 by different route: Zhang, M.Q.; Levshin, I.;
Haemers, A.; Vanden Berghe, D.; Pattyn, S.R.; Bollaert, W.
J.Heterocycl.Chem. 1991, 28, 673.
1H NMR (500 MHz, CDCl3) was identical with literature data.5
13C NMR (125 MHz, DMSO-d6): d = 25.548 (C-2'), 63.410 (C-1'),
126.824 (C-7 or C-9), 126.690 (C-7 or C-9), 127.675, 130.240 (C-
3 or C-8), 132.812 (C-3 or C-8), 133.906 (C-4), 134.265(C-2),
139.250 (C-4a), 140.411, 140.624, 141.432, 146.186 (C-6),
166.205 (COOH).
(13) 3-Nitroacetophenone is commercially available or can easily
be prepared by nitration of acetophenone (Corson, B. B.;
Hazen, R. K. Org. Synth. Coll. Vol II, 434).
(14) For a review on nucleophilic substitution of aromatic halogen
assisted by copper see: Lindley, J. Tetrahedron 1984, 40,
1433.
Anal. calcd. for C15H12N2O3: C, 67.15; H, 4.50; N,10.44. Found: C,
66.90; H, 4.57; N, 10.27.
HR-MS: calcd. m/z: 269.0926, found: 269.0906 [M+H]+.
(15) Standard reduction of 7 with NaBH4 in EtOH gave nitro
alcohol 9, which we required as a reference compound.
(16) It is well known that this type of reaction can give by-
products: Rewcastle, G. W.; Denny, W. A. Synth. Commun.
1987, 17, 1171.
References
(1) Fenical, W. Chem. Rev. 1993, 93, 1673.
(2) Activities arise from DNA intercalation thus inhibiting
expression of certain proteins, see:
(17) a) Stott, K.; Stonehouse, J.; Keeler, J.; Hwang, T.-L.; Shaka,
A. J. J. Am. Chem. Soc. 1995, 117, 4199.
a) Hollstein, U.; van Gemert, R. J. jr. Biochemistry 1971, 10,
497.
b) Hollstein, U.; Butler, P. L. Biochemistry 1972, 11, 1345.
(c) Inhibitors of aquired multidrug resistance: van Rensburg,
C. E. J.; Anderson, R.; Jooné, G.; Myer, M. S.; O’Sullivan, J.
F. Anti-Cancer Drugs 1997, 8, 708.
b) Stott, K.; Keeler, J.; Van, Q. N.; Shaka, A. J. J. Magn. Res.
1997, 125, 302.
(18) We observed a significant change of 0.43 ppm in the chemical
shift for H-2 on going from CDCl3 to DMSO-d6. Here we
should note that Geiger et al. in the study of phenazines from
Streptomyces antibioticus used the chemical shift for H-2 to
differentiate between derivatives with a free carboxylic acid
or an ester at the neighboring position.5
(19) Substituting benzene with toluene was disadvantageous as the
ethylene glycol under these conditions distilled into the water
separator.
(3) Pathirana, C.; Jensen, P. R.; Dwight, R.; Fenical, W. J. Org.
Chem. 1992, 57, 740.
(4) Takahashi, K.; Takahashi, I.; Morimoto, M. J. Antibiot. 1986,
39, 624.
(5) Geiger, A.; Keller-Schierlein, W.; Brandl, M.; Zähner, H. J.
Antibiot. 1988, 41, 1542.
(6) Keller-Schierlein, W.; Geiger, A.; Zähner, H.; Brandl, M.
Helv. Chim. Acta. 1988, 71, 2058.
(7) a) Lam, K. S.; Lebl, M.; Krchnák, V. Chem. Rev. 1997, 97,
411.
Article Identifier:
1437-210X,E;1999,0,10,1763,1766,ftx,en;xH02799SS.pdf
Synthesis 1999, No. 10, 1763–1766 ISSN 0039-7881 © Thieme Stuttgart · New York