A concise synthesis of isoxazole-based side chain of Micafungin

Article abstract of DOI:10.1080/00397911.2019.1615509

A concise synthesis of key isoxazole-based side chain of Micafungin, an USFDA approved anti-fungal agent, has been delineated. The route design notably involves a one pot regioselective isoxazole construction from the corresponding aryl aldehyde and alkyne intermediates.

Full text of DOI:10.1080/00397911.2019.1615509

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A concise synthesis of isoxazole-based side chain
of Micafungin
Pallavi Rao, Ismail Hussain, Venkataramanarao Rao, Saikat Sen & Srinivas
Oruganti
To cite this article: Pallavi Rao, Ismail Hussain, Venkataramanarao Rao, Saikat Sen & Srinivas
Oruganti (2019): A concise synthesis of isoxazole-based side chain of Micafungin, Synthetic
Communications, DOI: 10.1080/00397911.2019.1615509
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SYNTHETIC COMMUNICATIONS
https://doi.org/10.1080/00397911.2019.1615509
A concise synthesis of isoxazole-based side chain
of Micafungin
Pallavi Rao, Ismail Hussain, Venkataramanarao Rao, Saikat Sen, and
Srinivas Oruganti
Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad,
Telangana, India
ABSTRACT
ARTICLE HISTORY
A concise synthesis of key isoxazole-based side chain of Micafungin,
an USFDA approved anti-fungal agent, has been delineated. The
route design notably involves a one pot regioselective isoxazole con-
struction from the corresponding aryl aldehyde and alkyne inter-
mediates.
Received 29 January 2019
KEYWORDS
Antifungals; Chloramine T;
Copper(I) catalyzed
cycloaddition;
Isoxazoles; Micafungin
GRAPHICAL ABSTRACT
"
One pot isoxazole synthesis"
CHO
O
O
O
+
MeO
O
N
COOMe
Micafungin side chain
Introduction
Discovery of drugs for invasive fungal infections based on echinocandin class of semi-
synthetic lipopeptides offers a renewed hope for treatment of fungal related life threat-
[
1]
ening infections which contribute to significant mortalities.
For example, the
echinocandins caspofungin 1 and anidulafungin 2 have already been approved by
USFDA for treatment of Candidiasis and operate by impairing fungal cell wall forma-
[
2]
tion via inhibition of the enzyme (1!3)-b-D-glucan synthase.
FunguardVR , Fujisawa Pharmaceutical Co. Ltd), a second generation echinocandin based
antifungal agent, is a similar (1!3)-b-D-glucan synthase inhibitor that received FDA
Micafungin 3
(
[
3,4]
approval in March 2005 for treatment of Candidiasis and Aspergillosis
(Fig. 1).
Structurally, 3 is a semi-synthetic lipopeptide FK463 derived from the acylated cyclic
hexapeptide FR901379, a natural product obtained from the fungus Coleophoma empe-
dra. One of the key features of 3 is its unnatural isoxazole-based side chain, namely,
4-(5-(4-(pentyloxy)phenyl)isoxazol-3-yl)benzoic acid FR195752 4, which is appended
onto the cyclic lipopeptide core via an amide linkage.
CONTACT Srinivas Oruganti
soruganti@drils.org
Dr. Reddy’s Institute of Life Sciences, University of Hyderabad
Campus, Gachibowli, Hyderabad, Telangana, 500 046, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
P. RAO ET AL.
NH
2
OHHO
NH
OH
HN
OH HN
NH
OH
O
NH
O
OH
N
OH
N
O
O
O
O
O
O
H
2
N
O
HN
OH
O
HN
O
O
HN
OH
O
O
N
OH
N
H
N
OH
N
H
OH
HO
OH
OH
(Anidulafungin)
HO
O
1
(Caspofungin)
2
HO
O
O
S
O
O
OH
OH
HO
HO
HO
2 4 3
O(CH ) CH
H
N
N
O
N
4
(Side chain of Micafungin)
O
O
HN
O
O
OH
HO
HN
O
O
O
H
2
N
N
NH
OHHO
(Micafungin)
N
H
O
OH
O
N
O
3
Figure 1. Representative examples of antifungal agents.
Isoxazoles are important and versatile building blocks with many pharmacological prop-
erties. Several interesting methods have been reported in literature to construct the isoxa-
zoles from activated nitro compounds and alkynes using reagents like polyethylene glycol,
[5]
DABCO, Copper(II)/base, ammonium cerium nitrate, etc. Our interest in the synthesis
[6]
of complex active pharmaceutical ingredients, prompted us to devise a concise synthetic
route to the key unnatural isoxazole-based side-chain 4 of Micafungin 3. The reported
[
3a,c]
medicinal chemistry route
2 via a classical Huisgen 1,3-dipolar cycloaddition between the alkyne 11 and a nitrile
oxide generated in situ by base mediated HCl elimination in the hydroxamoyl chloride 7
to 4 involved the construction of the 3,5-diarylisoxazole in
1
[3d]
(
Scheme 1). An improved process chemistry route
was later reported and involved con-
struction of the isoxazole 12 from the b-diketone 15 via an enamine exchange strategy
with hydroxylamine hydrochloride (Scheme 2). The medicinal chemistry route suffers from
disadvantages like low yield, lack of reproducibility in chlorination reactions and use of
expensive metal catalyst while the process chemistry route gave a mixture of regioisomers
and involved the recycling of the disfavored regioisomer after hydrolysis to get back the
starting material. Against this background, we decided to investigate if certain key modifi-
cations might be efficaciously introduced in the existing medicinal chemistry route in order
to render the synthesis of 4 more concise. This endeavor was a part of our continued inter-
est in designing synthesis of APIs with a key focus on the principles of green chemistry.
Results and discussion
Our pursuit began with synthesis of the alkyne intermediate 11. Thus, potassium car-
bonate mediated alkylation of 4-bromophenol 8a with 1-bromopentane in acetone gave

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R
SYNTHETIC COMMUNICATIONS
3
OH
N
OH
N
O
H
Cl
NH
2
OH.HCl,
Oxone, DMF
N HCl in 1,4-dioxane
NaOAc,EtOH
4
7
0 oC,2h, 97%
rt, 16h, 98%
2
CO Me
CO
2
Me
2
CO Me
5
6
7
O
N
OH
O
OH
O
2
MeO C
HO
cat. PdCl (PPh ) , CuI
Cl
Br
NaH / Toluene
7
110 oC, 5h
92%
K
1
2
CO3, Acetone
o
Et N, THF, 40
o
C,
2
3
2
3
6h, 60 C, 98%
PPh , Et N-pyridine
2h, 85%
X
X
3
3
o
9
0 C, 12h, 72% HO
8
8
a: X=Br
b: X=I
9a: X=Br
9b: X=I
10
11
O
O
2N NaOH,
O
Ethanol / THF
MeO
2
C
HO
O
O
N
N
0 oC, 1h, 98%
8
12
4
Scheme 1. Medicinal chemisty route.
Scheme 2. Process chemistry route.
[
7]
the known intermediate 9a (Scheme 1). As already alluded to in Scheme 1, the
[
8]
reported next step en route 11 involves a Sonogashira coupling of 9a with 2-methyl-
but-3-yn-2-ol in the presence of copper iodide, triphenylphosphine and Pd(PPh ) Cl
2.
3
2
We were interested to explore if the Sonogashira coupling could be performed under
ligand-free conditions using a readily available and cheaper Pd(0) source. Yields of
[
9]
attempted Sonogashira cross-coupling between 9a and 2-methylbut-3-yn-2-ol using
Pd–C was by and large comparable with that obtained using homogeneous Pd-catalyst,
namely Pd(dppf)Cl , Pd(PPh ) , PdCl , Pd(OAc) and Pd (dba) . However, in the
2
3 4
2
2
2
3
[
10]
absence of triphenylphosphine ligand, neither 9a nor its iodo variant 9b
desired Sonogoshira product 10.
afforded the
Having failed in our attempts to develop a ligand free Sonogashira process, we
decided to employ Corey-Fuchs reaction for the synthesis of the alkyne intermediate

4
P. RAO ET AL.
O
OH
O
O
Br
, acetone
CBr
4
, PPh
3
1
.6M n-BuLi, THF
DCM, 0 o
2h, 97%
C
K
2
CO
3
Br -78 oC, 1.5h, 90%
o
60
C, 16h, 95%
O
H
O
H
Br
17
1
4
11
1
3
Scheme 3. Synthesis of alkyne intermediate.
[
11]
11,
with the intent to avoid the expensive palladium catalyst and also 2-methylbut-3-
yn-2-ol in the sequence. The aldehyde 14 upon reaction with CBr /PPh gave the
4
3
dibromo alkene 17, which upon treatment with n-BuLi to give the alkyne intermediate
1
1 (Scheme 3).
With the phenylacetylene 11 in hand, synthesis of the known hydroxamoyl chloride 7
[
12]
was undertaken with the objective of investigating if the Sharpless’ methodology
of
Cu(I) catalyzed nitrile oxide/alkyne cycloaddition might be employed to effect a regiose-
[
13]
lective construction of the isoxazole moiety
alkynes have been reported to typically react with nitrile oxides to give both 3,5- and
,4-isoxazoles in ratios, which vary with factors like reactivity of the nitrile oxide, tem-
in 12. In the absence of a Cu(I) catalyst,
3
perature and solvent used.
For the synthesis of the hydroxamoyl chloride 7, we followed the medicinal chemistry
route (Scheme 1) wherein methyl 4-formylbenzoate 5 was treated with hydroxylamine
[
3a,c]
hydrochloride in methanol to afford the oxime 6,
which was then reacted with
potassium peroxymonosulfate (OxoneVR )/HCl to obtain 7. Although other commercially
[
14]
inexpensive and greener reagents like sodium hypochlorite solution
appeared as
potential alternatives, we were unable to obtain yields greater than 40% in mediating
the desired transformation of 6 to 7.
Having obtained both partners 7 and 11, formation of the isoxazole 12 via the envis-
aged Cu(I) catalyzed cycloaddition reaction was explored. Indeed, phenylacetylene 11
and hydroxamoyl chloride 7 reacted smoothly in presence of copper sulfate/sodium
ascorbate/potassium carbonate milieu to furnish regioselectively the desired product 12
(Scheme 4) in 85% yield upon purification by recrystallization.
In an effort to capitalize on the successful Cu(I) catalyzed cycloaddition reaction with
7
and 11, we wanted to investigate if the formation desired isoxazole 12 can be realized
without the need to isolate the hydroxamoyl chloride 7. Hydroxamoyl chlorides pose
significant challenges in their isolation in pure form and some are known to be toxic
[
15]
and skin irritants.
In devising a telescoped process amenable to scale up, we were
[
16]
inspired by the methodology reported by Fokin et al.
and envisaged, as illustrated in
Scheme 5, an extremely concise one-pot isoxazole synthesis from the benzaldehyde 5
and the alkyne 11 via intermediacy of the sequentially generated oxime 6 and the
hydroxamoyl chloride 7. Thus, the aldehyde 5 on treatment with hydroxylamine hydro-
chloride would readily form the aldoxime 6, which when treated with Chloramine T,
would generate the reactive nitrile oxide species 18 via the intermediacy of 7.
[
17]
Chloramine T
(N-chloro-N-sodio-4-methyl benzene sulphonamide) is an efficient
and green catalyst for conversion of aldoximes into nitrile oxides which are otherwise

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SYNTHETIC COMMUNICATIONS
5
N
OH
O
O
MeO C
2
Cl
7
MeO C
2
CuSO .5H O,
O
4
2
N
Na-Ascorbate,
K CO , t-BuOH-H2O (1:1),
12
2
3
rt, 5h, 85%
11
Scheme 4. CuSO .5H O mediated isoxazole formation.
4
2
(
i) NH OH.HCl, NaOH,
2
O
t-BuOH/H O, rt, 1h
O
2
CHO
(
ii) Chloramine T trihydrate,
rt, 5 min
MeO C
+
2
(
iii) CuSO .5H O,
O
4
2
N
Cat. Cu powder, rt, 16h
2
CO Me
50%
1
2
5
11
O
2
N NaOH,
O
Ethanol / THF
8
o
0
C, 2h
HO
O
N
9
2%
4
Scheme 5. Our approach to Micafungin side chain.
Cl
O
Na
O
N
S
O
O-
HO
HO
O
CHO
N
H
N
Cl
N+
11
O
2
NH OH
MeO
O
N
o
4
Cu /CuSO (Cat)
COOMe
12
COOMe
NH
2
COOMe
COOMe
18
HCl
5
6
O
S
O
7
Scheme 6. Plausible mechanism for one pot isoxazole synthesis.
[
16]
difficult to isolate due to their extreme reactivity.
Mechanistically, Chloramine T ini-
tially acts like a halogenating agent to chlorinate the aldoxime to the hydroxamoyl
[
16]
chloride and later acts as a base to form the reactive nitrile oxide (Scheme 6).
Addition of copper powder and copper(II) sulfate to the reaction medium would gener-
ate the catalytically active copper (I) species which would promote the desired cycloadd-
ition between 11 and 18. To our delight, the one-pot synthesis of 12 from 5 and 11
proceeded as desired and a simple aqueous work up, followed by recrystallization, fur-
nished the product with good conversion (Scheme 5). The structure of the product 12
[
3c]
was assigned through comparison with the reported analytical data
and later unam-
biguously confirmed through a single crystal X-ray structure determination (Fig. 2).

6
P. RAO ET AL.
Figure 2. Ortep diagram of compound 13 at 50% probability. X-ray data was collected at 291 K on a
Bruker Kappa APEX II diffractometer with graphite monochromated MoKa radiation (k ¼ 0.7107Å). The
crystal structure was solved by direct methods (SIR92) and refined by full-matrix least-squares method
2
on F using SHELXL-97. Crystal data of 13: C H NO , M ¼ 365.41, orthorhombic. Pbca, a ¼
22
23
4
3
3
7
.7722(8), b ¼ 10.7234(10), c ¼ 45.225(5) Å, V ¼ 3769.3(7) Å , Z ¼ 8, q
¼ 1.288 g/cm , 32555 reflec-
calcd
tions measured, 3355 unique (R ¼ 0.1961), R1 ¼ 0.0772 and wR2 ¼ 0.1481 for 1668 observed reflec-
int
tions. CCDC 1835116 is provided in the supplementary material. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data
cC ae mn t. ra ec . u( Ck C] .DC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44(0)1223 762911; email: deposit@ccdc.
Base mediated hydrolysis of 12 was carried out to complete the synthesis of isoxazole-
[
3c,d]
based side chain of Micafungin 4 with complete structural assignment.
Conclusion
In summary, we have demonstrated a simple concise synthesis of isoxazole-based side
chain of Micafungin 4 using a one pot approach from the corresponding alkyne 11 and
aldehyde 5, and a key regioselective isoxazole formation using copper(I) catalyzed cyclo-
addition reaction. This method is operationally simple, greener than previous known
synthesis and avoids the isolation of a potentially toxic hydroxamoyl chloride 7 species.
Experimental
One pot synthesis procedure for methyl 4-(5-(4-(pentyloxy)phenyl)isoxazol-3-
[
3c]
yl)benzoate (12)
Methyl 4-formylbenzoate 5 (0.750 g, 0.004 mol) was added to the solution of hydroxyl-
amine hydrochloride (0.349 g, 0.005 mol) in t-BuOH:H O (1:1, 28 mL). NaOH (0.201 g,
2
0.005 mol) was added to the reaction mixture, and stirred for 2 h at ambient tempera-
ture. TLC analysis indicated oxime formation complete. Chloramine-T trihydrate
(
(
(
1.14 g, 0.005 mmol) was added in small portions over 15 min followed by CuSO .5H O
0.022 g, 0.00009 mol) and cat. copper powder (0.0142 g, 0.00016 moles). 1-Ethynyl-4-
pentyloxy)benzene 11 (0.945 g, 0.005 mol) was added to this reaction mixture. pH of
4 2
the reaction was adjusted to 7.5 by the addition of a few drops of 1 M NaOH and fur-
ther stirred for 16 h. The reaction mixture was poured into ice cold water (50 mL) and
aq. NH OH (10 mL). Obtained copper salts were filtered on celite bed and washed with
4
dichloromethane (100 mL). The layers were separated and the aq. layer was extracted

V
R
SYNTHETIC COMMUNICATIONS
7
with dichloromethane (3 ꢀ 100 mL), washed with brine (1 ꢀ 25 mL), dried over anhy.
Na SO and filtered. Evaporation of solvent under reduced pressure gave the crude
2
4
product, which was dissolved in DCM (50 mL) and added to (400 mL) of Hexane, while
stirring for 15 min. Solid obtained was filtered, washed with hexane (300 mL) and dried
to furnish methyl 4-(5-(4-(pentyloxy)phenyl)isoxazol-3-yl)benzoate 12 as off-white solid
(
0.830 g, 50% yield).
1
13
Experimental procedures, H and C NMR spectral data associated with this article
have been provided in the Supplementary material.
Acknowledgements
We thank Dr. Reddy’s Institute of Life Sciences for its support. We thank Mahesh Tammineni
for his help in synthesis of compound 12.
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