Semisynthetic routes to PF1022H - A precursor for new derivatives of the anthelmintic cyclooctadepsipeptide PF1022A

Article abstract of DOI:10.1016/j.bmc.2016.01.014

The cyclooctadepsipeptide PF1022A and its semisynthetic, commercial analogue emodepside show excellent anthelmintic properties. Bis-hydroxy PF1022 (PF1022H), a minor fermentative side-product represents an interesting precursor for new PF1022 related anth

Full text of DOI:10.1016/j.bmc.2016.01.014

Bioorganic & Medicinal Chemistry 24 (2016) 873–876
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Semisynthetic routes to PF1022H—A precursor for new derivatives of
the anthelmintic cyclooctadepsipeptide PF1022A
⇑
Sivatharushan Sivanathan, Florian Körber, Jürgen Scherkenbeck
Department of Chemistry, University of Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyclooctadepsipeptide PF1022A and its semisynthetic, commercial analogue emodepside show
excellent anthelmintic properties. Bis-hydroxy PF1022 (PF1022H), a minor fermentative side-product
represents an interesting precursor for new PF1022 related anthelmintics. We report herein two comple-
mentary routes which allow a highly efficient conversion of PF1022A to a regioisomeric mixture consist-
ing mainly of the bis-para isomer PF1022H and the meta–para analogue.
Received 21 October 2015
Revised 5 January 2016
Accepted 7 January 2016
Available online 8 January 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Anthelmintic
Cylooctadepsipeptide
Baeyer–Villiger oxidation
PF1022H
1. Introduction
R
N
O
According to the World Health Organization (WHO) parasitic
worm infections constitute the most important class of neglected
tropical diseases.1 Those worm infections are a major cause of mor-
bidity and loss of disability-adjusted life years in several underde-
veloped African and Asian countries.2,3 In addition, worm
infections cause tremendous health problems and economic losses
in livestock and domestic animals. In particular, in the livestock
industry, treatment with standard anthelmintics such as the
macrolides avermectin and milbemycin or derivatives of these nat-
ural products has become problematic due to rapidly developing
resistances.4–6
O
O
O
O
O
O
O
N
O
O
O
N
O
N
R
1
R = H
PF1022A ( ):
2
PF1022H ( ):
emodepside (3):
R = OH
R =
N
O
The 24-membered cyclooctadepsipeptide PF1022A (1, Fig. 1), a
metabolite of Mycelia sterilia (Rosselinia sp.) has been established as
the only novel, resistance-breaking anthelmintic during the past
two decades. A semi-synthetic analogue of PF1022A, emodepside
(3), has been introduced recently into the market for the treatment
of parasitic helminth infections in companion animals.4,7
Structure–activity studies have demonstrated that the two
phenyllactic acids are the positions of choice for modifications of
PF1022A (1).4,8–13 However, the introduction of functionality into
the phenyl rings is far from being trivial. The drastic reaction con-
ditions required to introduce for instance nitro- or sulfonic acid-
groups, cause side-reactions and partial decomposition of the
macrocycle. Bromine or iodine substituents can be introduced
Figure 1. Structures of cyclooctadepsipeptides PF1022A, PF1022H and emodepside.
under milder conditions but subsequent Pd-catalyzed cross-cou-
pling reactions to obtain aryl or aryl-substituted derivatives fail
completely. The additional synthetic steps needed for the prepara-
tion of advanced PF1022A analogs turn out cumbersome and
costly.
The bis-hydroxy derivative PF1022H (2), a minor side-product
in the fermentation process of PF1022A (1), might be an interesting
alternative. Some lipophilic derivatives of PF1022H (2), accessible
in only one step, show excellent anthelmintic activities.8 Unfortu-
nately, PF1022H (2) is currently available only in limited amounts
from the fermentation broth. Thus, an efficient access to PF1022H
(2) appears mandatory for the preparation of a larger number of
⇑
Corresponding author.
E-mail address: Scherkenbeck@uni-wuppertal.de (J. Scherkenbeck).
http://dx.doi.org/10.1016/j.bmc.2016.01.014
0968-0896/Ó 2016 Elsevier Ltd. All rights reserved.

874
S. Sivanathan et al. / Bioorg. Med. Chem. 24 (2016) 873–876
screening-compounds needed for the identification of a ‘second-
generation’ PF1022 derived anthelmintic with improved spectrum
of activity, drug metabolism and pharmacokinetics.
The most straightforward route to PF1022H (2) would be of
course a direct hydroxylation of PF1022A (1). Unfortunately, stan-
dard procedures for the direct hydroxylation of benzene rings such
as the Cu(NO3)2 catalyzed oxidation with H2O2 failed completely in
our hands.14 Instead of a one-step hydroxylation of PF1022A (1),
we established two short sequences which provide PF1022H (2)
in good to excellent yields.
which hamper both, oxidation and hydrolysis reactions of the
amide functions. Subsequent hydrogenation under standard condi-
tions afforded the bis-amino PF1022 (5) again in almost quantita-
tive yield (Scheme 1). Diazotization with NaNO2 in TFA (1 h, 65 °C)
followed by a weakly basic hydrolysis with an aqueous NaHCO3
solution afforded in a one-pot reaction the bis-hydroxy PF1022 iso-
mers in 80% yield after chromatographic purification (Scheme 1).
2.2. Route 2: PF1022H by Baeyer–Villiger oxidation of PF1022A
and subsequent ester cleavage
One of the few methods which allow the direct introduction of a
hydroxy-group in a phenyl-ring under mild conditions is the
Baeyer–Villiger oxidation of the corresponding acetophenone
which can be obtained easily by a Friedel–Crafts acylation. How-
ever, for PF1022A (1), the acylation turned out to be troublesome.
With the standard Lewis acid AlCl3 and a mixture of acetic anhy-
dride and acetyl chloride in nitromethane or dichloromethane no
reaction was observed even with an excess (2–5 equiv) of AlCl3.
2. Results and discussion
2.1. Route 1: PF1022H by diazotization of bis-amino PF1022 and
subsequent hydrolysis
The basic route to bis-amino PF1022 (5) and subsequent diazo-
tation has already been described in
a previous patent by
Nishiyama et al., albeit with remarkably low yields in each step.15
Based on this basic procedure we developed a process which
allows the preparation of PF1022H (2) in an excellent yield and
gram-amounts. First, PF1022A was nitrated in almost quantitative
yield with fumic nitric acid in acetic anhydride (Scheme 1). The
regioisomers formed, correspond to bis-para nitro-PF1022 (4)
(45%), followed by the para–meta (42%) and meta–meta (13%) iso-
mers. Those were not separated since it is known, that the anthel-
mintic activities of the different regioisomers are similar. The
remarkable stability of PF1022A (1) against concentrated nitric
and also sulfuric acid can be attributed to the N-methyl groups
Other Lewis acids employed for Friedel–Crafts acylations such as
16
Sc(OTf)3,
Bi(OTf)3,17 Ga(OTf)3,18 Hf(OTf)4,19 TiCl4, ZnO,20
BF3 Â OEt2 or AlBr3 in nitromethane resulted in either no reaction
or decomposition of PF1022A (1). Even the addition of LiClO4
which is a known Lewis acid activator did not improve the acety-
lation reaction at all.19 Remarkably, the 1-methyl-3-ethylimida-
zolium chloride–aluminum(III) chloride ([EMIM]–AlCl3) ionic
liquid which has been described as an exceptionally mild and
selective acylation system caused a complete decomposition of
the cyclodepsipeptide.21 As an alternative to the direct acetylation
NO2
NH2
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
O
O
O
O
O
HNO3, Ac2O,
3 h, rt
Pd/C, H2 (1 bar),
MeOH, 3 h
N
N
O
O
O
O
99 %
99 %
N
N
O2N
H2N
4
5
1. NaNO2, TFA,
65 °C, 1 h
80 %
N
2. NaHCO3, H2O
N
O
O
OH
O
O
O
O
O
O
O
N
O
O
O
O
O
N
N
PF1022A (1)
PF1022H (2)
O
O
O
O
N
O
O
O
O
O
N
O
N
HO
NaBO3xH2O,
MeOH, rt, 1 h
51%
N
O
N
O
O
O
O
O
O
AcCl, AlCl3,
rt, 16 h
mCPBA, DCM
O
O
O
O
O
O
N
reflux, 16 h
O
O
O
O
N
O
O
O
O
O
N
92%
O
78%
N
O
O
O
O
O
N
N
O
O
6
7
Scheme 1. Semisynthetis routes to PF1022H.

S. Sivanathan et al. / Bioorg. Med. Chem. 24 (2016) 873–876
875
Table 1
Conditions tested for the selective ester cleavage of PF1022 bis-acetate X
4.2. Experimental procedures
4.2.1. Cyclo-[( )-MeLeu-( )-Lac-(L)-MeLeu-(D)-(NO2)PhLac]2 (4)
L
D
Entry
Reagent
Reaction condition
Result
To a solution of PF1022A (1, 200.00 mg, 0.21 mmol) in acetic
anhydride nitric acid (10 mL, 111.09 mmol, 70%) was added drop-
wise at 0 °C. After stirring for 3 h at room temperature ethyl acet-
ate (40 mL) was added and the mixture was extracted with water
(3 Â 30 mL). The combined organic phases were dried over sodium
sulfate. Concentration under reduced pressure and chromato-
graphic purification (solvent: cyclohexane/ethyl acetate, 1:1) of
the residue gave product 4 (229.00 mg, 0.22 mmol) as a yellow
solid in quantitative yield. 1H NMR (600 MHz, CDCl3): d = 0.66–
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
LiOH
LiOH
NaHCO3
p-TsOH on silica gel
CH3COONH4
Yb(TOf)3
Esterase
NaBO3*H2O
THF/H2O, 0 °C
MeOH, 0 °C
EtOH, 0 °C
iPrOH, 0 °C
THF/H2O, 0 °C
MeOH, 0 °C
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
Decomposition
No conversion
Decomposition
Traces PF1022H (2)
Decomposition
No conversion
51 % PF1022H (2)
THF/H2O, rt
H2O/toluene, 80 °C
MeOH/H2O, rt
iPrOH, reflux
pH ꢀ8, H2O/Et2O, rt
MeOH, rt
9
10
11
12
1.47 (m, 34H, CH3-Leu, CH3-Lac, C H-Leu), 1.49–1.81 (m, 8H,
c
CbH-Leu), 2.62–3.04 (m, 12H, NCH3), 3.05–3.41 (m, 4H, CbH-Phe-
Lac), 4.50 (m, 1H, C H-Leu), 5.03–5.90 (m, 7H, C H-Leu, C H-Phe-
a
a
a
Lac, C H-Lac), 7.06–8.23 (m, 8H, Ar-H) ppm. 13C{1H} NMR
a
a Ni-catalyzed Negishi coupling of bis-bromo PF1022, prepared
according to a literature procedure and acetyl chloride, was tested
unsuccessfully, too.22 No turn-over could be observed using the
reaction conditions described.
(151 MHz, CDCl3): d = 14.1, 15.8, 17.0, 20.6, 20.7, 20.9, 21.1, 21.4,
23.4, 23.5, 24.6, 24.7, 24.9, 25.0, 25.1, 29.3, 29.6, 30.1, 30.5, 30.6,
31.3, 36.8, 37.5, 53.9, 54.3, 57.1, 60.3, 66.9, 67.3, 68.5, 68.6, 69.8,
70.3, 123.5, 123.6, 123.7, 125.2, 128.1, 128.9, 130.4, 130.5, 133.2,
134.6, 137.8, 147.1, 148.3, 148.9, 149.2, 169.5, 170.4, 171.1,
171.6, 174.3 ppm. IR (ATR): 1742 (C@O), 1656 (C@O) cmÀ1. MS
(ESI): m/z (%) = 1056 (100) [M+NH4]+. HRMS (ESI): calcd for
With those disappointing results in our hands we drew back our
attention to the standard Lewis acid AlCl3. In fact, we were able to
obtain a low yield of the monoacetylation product when we used
the acetylation reagent AcCl as solvent together with an excess
of 10 equiv of AlCl3. Increasing the excess to 500 equiv of freshly
sublimated AlCl3 finally afforded a 78% yield of the bis-acetylation
product 6, obtained as 10:5:1 mixture of the bis-para, meta–para
and meta–meta isomers. The subsequent Baeyer–Villiger oxidation
with mCPBA gave regioselectively the phenol acetate 7 in an excel-
lent yield of 92%. However, the selective ester hydrolysis of the
acetates in the presence of the lactic and phenyllactic ester bonds,
not completely unexpected, turned out difficult again. Several
reaction conditions tested (Table 1) either led to decomposition
of the depsipeptide ring or for very weak bases such as NaHCO3
no reaction was observed. Though it was not a problem at all, to
hydrolyze p-cresol acetate as a test substrate with pig-liver ester-
ase, the same enzyme failed in the cleavage reaction of PF1022H
acetate 7, probably due to the steric hindrance of the large macro-
cycle. Finally, the reagent of choice proved to be NaBO3 Â H2O
which yielded 51% of PF1022H after a reaction time of 1 h.
C
52H74N6NaO+16 [M+Na]+: 1061.5054; found: 1061.5057.
4.2.2. Cyclo-[( )-MeLeu-( )-Lac-( )-MeLeu-( )-(NH2)PhLac]2 (5)
L
D
L
D
Derivative 4 (154.00 mg, 0.15 mmol) was dissolved in methanol
(20 mL). Palladium (15.77 mg, 14.82 mmol, 10% Pd/C) was added
and the mixture was stirred for 3 h at a pressure of 1 bar H2. The
catalyst was removed by filtration and washed with ethyl acetate.
The solvent was removed under reduced pressure. Product 5 was
obtained as a colorless solid (144.00 mg, 0.15 mmol) in quantita-
tive yield. 1H NMR (400 MHz, CDCl3): d = 0.66–1.48 (m, 34H,
CH3-Leu, CH3-Lac, C H-Leu), 1.50–1.92 (m, 8H, CbH-Leu), 2.68–
c
2.98 (m, 12H, NCH3), 2.99–3.11 (m, 4H, CbH-PheLac), 4.48 (m, 1H,
C H-Leu), 5.03–5.90 (m, 7H, C H-Leu, C H-PheLac, C H-Lac),
a
a
a
a
6.50–6.77, 6.95–7.14 (2 m, 8H, Ar-H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): d = 15.8, 17.1, 20.9, 21.1, 21.2, 21.4, 21.6, 21.7,
23.2, 23.4, 23.6, 24.4, 24.7, 25.1, 29.4, 29.7, 30.2, 30.5, 31.2, 31.4,
36.3, 36.5, 36.8, 37.0, 37.2, 38.0, 54.0, 57.2, 58.6, 66.8, 68.6, 69.1,
71.1, 105.9, 113.7, 115.1, 116.1, 116.4, 116.5, 117.7, 118.9, 119.4,
124.6, 125.3, 128.4, 129.4, 130.4, 131.1, 141.5, 145.4, 145.6,
146.6, 169.8, 169.9, 170.4, 170.6, 171.0, 171.1, 171.3, 171.7 ppm.
IR (ATR): 1741 (C@O), 1652 (C@O) cm1. MS (ESI): m/z (%) = 996
(100) [M+NH4]+. HRMS (ESI): calcd for C52H78N6NaO1+2 [M+Na]+:
1001.5570; found: 1001.5570.
3. Conclusions
To summarize, PF1022H (2) represents an important precursor
for new, anthelmintically highly active PF1022 derivatives. Due to
its limited availability as a minor side-product in the production
process of PF1022A (1), we developed two complementary meth-
ods which allow the preparation of PF1022H (2) in gram-amounts
from PF1022A (1) with good to excellent yields as a mixture of
mainly the bis-para and the meta–para isomer.
4.2.3. Cyclo-[(L)-MeLeu-(D)-Lac-(L)-MeLeu-(D)-(COCH3)PhLac]2 (6)
Freshly sublimated AlCl3 (11.23 g, 84.28 mmol) was dissolved
in acetyl chloride (40 mL). To the yellow solution PF1022A (1,
160.00 mg, 0.17 mmol) was added dropwise at room temperature.
After stirring for 16 h the mixture was poured in an ice bath. The
aqueous phase was washed with ethyl acetate (4 Â 50 mL). The
combined organic phases were extracted with a saturated NaHCO3
solution (3 Â 50 mL), dried over sodium sulfate and concentrated
under reduced pressure. Chromatographic purification (solvent:
cyclohexane/ethyl acetate, 1:1) of the residue gave the acetylation
product 6 (135.26 mg, 0.13 mmol) in a yield of 78%. 1H NMR
4. Experimental
4.1. General chemical methods
PF1022A (1) was provided by Bayer Health Care. The reagents
AlCl3, NaBO3 Â H2O, mCPBA, HNO3 (70%, aqueous solution), Pd/C
and NaNO2 were purchased. All reactions were performed in dried
solvents. Methanol was refluxed over magnesium and distilled.
Acetyl chloride and acetic anhydride were distilled. 1H and 13C
NMR spectra were measured on a 400 or 600 MHz (101 or
151 MHz) NMR spectrometer. IR-spectra were recorded on a FT-
IR instrument. Mass spectra were recorded using ESI and APCI ion-
ization methods. For the preparative low pressure chromatography
(600 MHz, CDCl3): d = 0.71–1.45 (m, 34H, CH3-Leu, CH3-Lac, C H-
c
Leu), 1.46–1.79 (m, 8H, CbH-Leu), 2.61 (s, 6H, CH3-acetyl), 2.72–
3.12 (m, 12H, NCH3), 3.12–3.29 (m, 4H, CbH-PheLac), 4.49 (m, 1H,
C H-Leu), 5.05–5.77 (m, 7H, C H-Leu, C H-PheLac, C H-Lac), 7.37
a
a
a
a
(m, 4H, Ar-H), 7.92 (m, 4H, Ar-H) ppm. 13C{1H} NMR (151 MHz,
CDCl3): d = 15.9, 16.5, 17.1, 20.8, 21.1, 21.2, 21.6, 23.1, 23.2, 23.3,
23.5, 24.5, 24.7, 24.8, 24.9, 25.1, 26.5, 29.3, 30.6, 31.3, 36.1, 36.7,
36.9, 37.5, 37.6, 37.9, 38.1, 54.0, 54.1, 54.2, 54.8, 57.1, 67.0, 67.5,
(LPLC) silica gel (60
60 F254
lm) was used. TLC was performed on Silica gel
.

876
S. Sivanathan et al. / Bioorg. Med. Chem. 24 (2016) 873–876
68.6, 70.2, 70.6, 128.5, 128.6, 128.7, 129.8, 129.9, 126.0, 136.1,
136.2, 140.6, 141.2, 169.6, 169.7, 169.9, 170.4, 170.8, 171.1,
171.6, 197.3, 197.4, 197.5 ppm. IR (ATR): 1741 (C@O), 1659
(C@O) cmÀ1. MS (ESI): m/z (%) = 1050 (100) [M+NH4]+, 1055 (1)
[M+Na]+. HRMS (ESI): calcd for C56H80N4NaO1+4 [M+Na]+:
1056.5596; found: 1056.5597.
4.72–5.90 (m, 8H, C H-Leu, C H-PheLac, C H-Lac), 6.66–6.86,
a a a
7.03–7.19 (2 m, 8H, Ar-H) ppm. 13C{1H} NMR (101 MHz, Metha-
nol-d4): d = 17.2, 17.5, 21.1, 21.3, 21.6, 21.7, 23.6, 23.7, 23.8, 23.9,
25.2, 25.5, 25.9, 26.1, 26.2, 30.0, 31.2, 31.4, 32.1, 37.5, 38.0, 38.6,
39.0, 55.5, 55.7, 58.6, 68.5, 69.5, 69.9, 72.2, 72.4, 72.6, 115.1,
116.5, 117.7, 121.5, 126.4, 126.8, 130.8, 131,8, 137.3, 137.7,
157.9, 158.9, 170.8, 171.2, 172.2, 172.3, 173.1, 173.6, 174.5 ppm.
IR (ATR): 3270 (O–H), 1743 (C@O), 1647 (C@O) cmÀ1. MS (ESI):
m/z (%) = 998 (100) [M+NH4]+, 1003 (3) [M+Na]+. HRMS (ESI): calcd
for C52H76N4NaO+14 [M+Na]+: 1003.5250, found: 1003.5252.
4.2.4. Cyclo-[(L)-MeLeu-(D)-Lac-(L)-MeLeu-(D)-(COCH3O)PhLac]2
(7)
Acetyl derivative 6 (16.70 mg, 16.16
lmol) was dissolved in
DCM (20 mL). mCPBA (199.22 mg, 808.13
lmol) was added at
0 °C. The mixture was stirred for 6 h under reflux. After adding
an aqueous saturated solution of Na2SO3 and stirring for additional
30 min at room temperature, the two phases were separated. The
aqueous phase was washed with ethyl acetate (3 Â 20 mL). The
combined organic phases were dried over sodium sulfate and
the solvent was removed under reduced pressure. Chromatographic
purification (solvent: cyclohexane/ethyl acetate 1:1) of the residue
Acknowledgement
Generous financial support by Bayer Animal Health GmbH is
gratefully acknowledged.
References and notes
furnished ester 7 (15.90 mg, 14.93 l
mol, 92%). 1H NMR (400 MHz,
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CDCl3): d = 0.67–1.45 (m, 34H, CH3-Leu, CH3-Lac, C H-Leu),
c
1.46–1.81 (m, 8H, CbH-Leu), 1.92, 2.01, 2.14, 2.29 (4s, 6H,
CH3-O-acetyl), 2.78–3.21 (m, 16H, NCH3, CbH-PheLac), 4.43–6.18
(m, 8H, C H-Leu, C H-PheLac, C H-Lac), 6.90–7.41 (m, 8H, Ar-H)
a
a
a
ppm. 13C{1H} NMR (101 MHz, CDCl3): d = 21.0, 21.7, 22.4, 23.1,
23.2, 24.7, 29.7, 31.8, 37.1, 37.3, 52.1, 54.1, 67.9, 71.6, 120.3,
121.7, 122.5, 126.2, 126.9, 128.5, 129.6, 130.3, 149.8, 150.8,
169.3, 169.8, 170.1, 170.5, 171.6, 173.2 ppm. IR (ATR): 1747
(C@O), 1664 (C@O) cmÀ1. MS (ESI): m/z (%) = 1082 (100) [M
+NH4]+. HRMS (ESI): calcd for C56H80N4NaO1+6 [M+Na]+:
1087.5462; found: 1087.5464.
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4.2.5. Cyclo-[(
(PF1022H, 2)
L)-MeLeu-(D)-Lac-(L)-MeLeu-(D)-(OH)PhLac]2
A solution of derivative 7 (17.00 mg, 15.96
(2 mL) was treated with sodium perborate (12.27 mg, 79.79
lmol) in methanol
14. Nasreen, A.; Adapa, A. R. OPPI Briefs 2000, 32, 373.
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The mixture was stirred for 1 h at room temperature. After that
time the solvent was removed under reduced pressure. Chromato-
graphic purification (solvent: toluene/IPA, 15:1) yielded a yellow
solid (8.00 mg, 8.15 l
mol, 51%). 1H NMR (400 MHz, Methanol-
d4): d = 0.76–1.46 (m, 34H, CH3-Leu, CH3-Lac, C H-Leu), 1.47–1.93
(m, 8H, CbH-Leu), 2.79–3.20 (m, 16H, NCH3, CbH-PheLac),
c