Application of oxetane ring opening toward stereoselective synthesis of zincophorin fragment

Article abstract of DOI:10.1016/j.tetlet.2014.05.020

A stereoselective synthesis of the C1-C11 fragment of zincophorin was achieved by using an intramolecular oxetane ring opening reaction as the key step. The oxetane moiety was synthesized by employing a desymmetrization protocol developed at our group and a non-Evans syn aldol as the key steps toward the synthesis.

Full text of DOI:10.1016/j.tetlet.2014.05.020

Accepted Manuscript
Application of oxetane ring opening towards stereoselective synthesis of zin-
cophorin fragment
Jhillu Singh Yadav, Eppa Gyanchander, Saibal Das
PII:
S0040-4039(14)00798-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.020
TETL 44611
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 March 2014
5 May 2014
7 May 2014
Please cite this article as: Yadav, J.S., Gyanchander, E., Das, S., Application of oxetane ring opening towards
stereoselective synthesis of zincophorin fragment, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.05.020
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Jhillu Singh Yadav,* Eppa Gyanchander and Saibal Das

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lsevier .com
Application of oxetane ring opening towards stereoselective synthesis of zincophorin
fragment
Jhillu Singh Yadav,* Eppa Gyanchander and Saibal Das
Natural Products Chemistry Division, CSIR- Indian Institute of Chemical Technology, Tarnaka, Hyderabad – 500 007, Andhra Pradesh, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A stereoselective synthesis of the C1-C11 fragment of zincophorin was achieved by using an
intramolecular oxetane ring opening reaction as the key step. The oxetane moiety was
synthesized by employing a desymmetrization protocol developed at our group and a non-Evans
syn aldol as the key steps towards the synthesis.
Received in revised form
Accepted
Available online
Keywords:
Oxetane ring opening
Desymmetrization protocol
Tetrahydropyran
Non-Evans syn aldol
Ionophores
2014 Elsevier Ltd. All rights reserved.
Many naturally occurring polyoxygenated ionophores exhibit
potential antibacterial properties due to their ability to bind with
different mono or divalent metal cations to form lipophilic
complexes.1 Zincophorin, isolated by two individual groups from
Streptomyces griseus in 1984,2 is also referred to as M144255 or
griseochellin.3 Its ability to bind especially with Zn2+ is the origin
of its trivial name. The structure was established first by
extensive NMR4 experiments and its three dimensional structure
as well as its absolute configuration assigned by X-ray diffraction
of its zinc-magnesium salt.3 Zincophorin exhibits good in vitro
activity against gram positive bacteria and its methyl ester also
shows antiviral activity. The ammonium or sodium salts of
zincophorin exhibit significant anticoccidial activity against
Eimeria tanella W/CAM.5 Recently a review on zincophorin has
been published by Hsung et al.6 In light of its novel structure and
biological profile, it has attracted the interest of the synthetic
community. To date, four elegant total syntheses and several
elaborated fragments syntheses have been reported.7
method the required stereochemistry is generated with ease and
one can get either cis or trans THP ring depending upon the
target molecule.
Me
OH OH
TIPSO
(+)-Zincophorin (1)
O
H
H
Me
Me Me
3
Intra molecular oxetane opening
Non Evans
syn aldol
Me
Me Me Me
OBn
O
TBSO
OPMB
4
Desymmetrization
protocol
Me
O
OH OH OH
OH
O
O
RO
O
O
H
H
Me
Me Me Me
Me Me Me
5
O
1
R= H:(+) Zincophorin
6
OPMB
2
R= Me:(+) Zincophorin methyl ester
Figure 1: Structure of zincophorin
Our group has focused on the area of tetrahydropyran (THP)
ring containing natural products using different synthetic
methods.8 Recently we developed a method for the formation of
THP ring using intramolecular SN2 oxetane ring opening.9 In this
____________________________
Scheme 1: Retrosynthetic analysis
Herein we report a stereoselective synthesis of zincophorin
C1-C11 fragment by employing a desymmetrizaton strategy10 and
non-Evans syn aldol using our recently disclosed intramolecular
oxetane ring opening as key reaction.
The retrosynthetic analysis of C1-C11 zincophorin is outlined
in Scheme 1. The THP ring 3 could be constructed by using intra
* Corresponding author. Tel.: +91-40- 2719 -3737; fax: +91-40-
2716-0512. E-mail address: yadavpub@iict.res.in

2
molecular oxetane ring opening reaction as the key step,9 and in
compound 4 C6-C10 absolute configuration can be installed by
using a desymmetrization protocol, and C2-C3 centers can be
installed by non-Evans syn aldol.
(Scheme 3). The analytical data 1H, 13C, HRMS and IR of diol 3
was in complete agreement with literature data.7k,i
In conclusion, a concise and stereoselective synthesis of C1-
C11 fragment of zincophorin was achieved by employing acid
catalyzed oxetane ring opening and a desymmetrization protocol
reaction as key steps. Further studies as well as total synthesis of
zincophorin is in progress in our lab.
As shown in Scheme 2, the synthesis commenced from known
lactone 5 which was prepared from furan 6 in seven steps. Then
reductive opening of lactone 5 with LiAlH4 in anhydrous THF
furnished triol 7 with five chiral centers established.11 Acetonide
protection of triol 7 using 2, 2-DMP, and PTSA afforded primary
alcohol 8 in 90% yield. The primary alcohol 8 was protected as
benzyl ether 9 (92%) and the resultant compound was subjected
to acid catalyzed acetonide deprotection in methanol to afford
1,3-diol 10 in 82% yield. Selective oxidation of 1,3-diol using
O
S
Me Me Me
a
H
OBn
13
N
S
O
TBSO
OPMB
Bn
15
14
Bn
bis(acetoxy)iodobenzene
(BAIB)
and
2,2,6,6-
Me
Me Me Me
tetramethylpiperidine-N-oxide (TEMPO) in CH2Cl2 gave
aldehyde, which was homologated in-situ with ethyl 2-
(triphenylphosphoranylidene) acetate provided δ-hydroxy α,β-
unsaturated ester 11 (85% for two steps). The free hydroxy group
was silylated as TBS ether using TBSOTf in the presence of Et3N
in CH2Cl2 at rt for 30 min gave 12 in 93% yield. Reduction of the
conjugate double bond of 12 with NaBH4 in the presence of
NiCl2 gave the saturated ester 13 in 88% yield(Scheme 2).12
b
S
N
OBn
S
O
OH
TBSO
OPMB
OBn
16
Me
Me Me Me
c
OH OH
Me
TBSO
17
OPMB
O
O
O
Me Me Me
Me Me Me
ref. 4
a
b
OH
OBn
d
e
O
OH OH OPMB
OTs OH
TBSO
18
OPMB
OPMB
6
5
7
Me Me Me
Me Me Me
Me Me Me
OBn
OH
Me
d
c
OBn
O
O
OPMB
O
O
OPMB
O
TBSO
OPMB
OPMB
8
9
4
Me
Me Me Me
Me Me Me
f
EtO
OBn
OBn
e
f
HO
O
OBn
O
OH OPMB
OH OH OPMB
Me
Me
Me Me
19
11
10
Me
OPMB
Me Me Me
Me Me Me
g
h
TIPSO
TIPSO
O
OBn
OH
EtO
OBn
EtO
OBn g
Me Me
O
TBSO
OPMB
20
O
TBSO
OPMB
Me
13
12
OH
Scheme 2. Reagents and conditions: a) LiAlH4,THF, rt, 4 h, 90%; b) 2,2-
DMP, p-TSA CH2Cl2, rt, 5 h, 90%; (c) NaH, BnBr, THF, rt, 3 h, 92%; d)
CSA, MeOH, rt, 6 h, 82%; e) 1) BAIB, TEMPO, CH2Cl2, 0 °C, 3 h; 2)
Ph3P=CHCO2Et, 85% for two steps; f) TBSOTf, TEA, CH2Cl2, 0 °C, 1 h,
93%; g) NiCl2·6H2O, NaBH4, MeOH, 0 °C, 30 min, 88%.
O
Me
Me Me
3
Miyashita diol
Scheme 3. Reagents and conditions: a) DiBAL-H, CH2Cl2, -78 °C, 30 min,
92%; (b) TiCl4, i-Pr2NEt, CH2Cl2, -78 °C, 88%,(10:1 de); c) NaBH4, MeOH, 0
°C, 40 min, 82%; d) Py, TsCl, CH2Cl2, rt, 12 h, 88%; e) NaH, THF, 0 °C-rt, 8
h, 77% ; f) CSA, CH2Cl2, i-PrOH, rt, overnight, 83%; g) TIPSOTf, TEA, 0
°C-rt, 1 h, 86%; h) Pd/C, ethyl acetate, rt, 4 h, 90%.
Controlled reduction of saturated ester 13 with DIBAL-H in
CH2Cl2 gave the key aldehyde 14 in 92% yield. The aldehyde
was subjected to TiCl4 mediated asymmetric non-Evan’s Syn
aldol13 reaction with (R)-1-(4-benzyl-2-thioxothiazolidin-3-
yl)propan-1-one (15) to give aldol product 16 in 88% yield and
10:1 de. Reductive removal of chiral auxiliary with NaBH4 in
methanol afforded diol 17 (82%) and regioselective tosylation of
primary alcohol using tosyl chloride and pyridine as base in
CH2Cl2 gave tosylate 18 in 88% yield. The tosylate was
converted into oxetane 4 by treating with NaH in THF in 77%
yield. The tandem silyl deprotection followed by oxetane ring
opening was achieved with catalytic amount of camphorsulfonic
acid in CH2Cl2/isopropyl alcohol (15:1) to afford the desired THP
ring 19 in 83% yield. The primary alcohol 19 was protected as
TIPS ether (TIPSOTf and Et3N in methylene dichloride at 0 °C)
to give 20 in 86% yield. Finally, one-pot deprotection of both
benzyl and PMB ether in the presence of Pd/C under hydrogen
atmosphere14 gave requisite known Miyashita diol 3 in 90% yield
Acknowledgments
E.G.C thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for research fellowship. The Authors also
thank CSIR and DST, New Delhi for Bhatnagar and J. C. Bose
Fellowships respectively. This work is partly funded by CSC-
0108, origin under XII five year plan programme.
Supporting Information
Supplementary data associated with this article can be found,
in the online version.

3
18.1, 14.4, 13.9, 12.0, 11.4 ppm; ESI-HRMS: m/z calcd for C24H50O4
[M+H]+ : 431.3551, found 431.3533.
References and notes
1
a) Polyether Antibiotics; Westley, J. W., Ed.; Marcel Dekker: New York,
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2
3
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5
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6
7
For a review on the biological properties and synthetic approaches
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8
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15 (2S,3S,4S)-2-methyl-4-((2S,3S,6S)-3-methyl-6-((R)-1-(triisopropylsilyl
oxy)propan-2-yl)tetrahydro-2H-pyran-2-yl)pentane-1,3-diol (3): To a
solution of compound 20 (0.05 g, 0.08 mmol) in dry EtOAc (2 mL) was
added 10 mol% of Pd/C and the reaction mixture was stirred at room
temperature under hydrogen atmosphere for 2 h. The reaction mixture
was filtered off, washed with ethyl acetate, the filtrate was concentrated
under reduced pressure, and purified by silica gel column
chromatography (30% EtOAc in hexane as eluent) to afford compound 3
(0.03 g, 90%) as a colorless liquid, Rf = 0.60 (1:1 EtOAc and hexane).
[α]25D: (+) 36.5 (c 1.0, CHCl3); IR (neat): 3422(bs), 2930, 2866, 2725,
1462, 1382, 1249, 1239, 1219, 1095, 1074, 1012, 991, 968, 883, 772, 682
1
cm–1; H NMR (CDCl3, 500 MHz): 4.10 (d, J = 7.8 Hz, 1H), 3.90 (ddd, J
= 9.9, 4.3, 3.4 Hz, 1H), 3.81 (dd, J = 9.7 , 4.4 Hz, 1H), 3.75 (dd, J = 9.6,
3.2 Hz, 1H), 3.66-3.55 (m, 3H), 3.42-3.37 (ddd, J = 9.2, 7.5, 3.3 Hz, 1H),
2.22-2.16 (m, 1H), 1.93-1.88 (m, 1H), 1.86-1.80 (m, 1H), 1.74-1.64 (m,
3H), 1.61-1.55 (m, 1H), 1.54-1.51 (m, 1H), 1.30-1.21 (m, 1H), 1.08 (d, J
= 7.3 Hz, 3H), 1.04-1.07 (m, 21H), 0.92 (d, J = 6.9 Hz, 3H), 0.82 (d, J =
6.5 Hz, 3H), 0.77 (d, J = 6.9 Hz, 3H) ppm. 13C NMR (CDCl3, 125 MHz):
δ 83.1, 76.0, 73.4, 68.9, 65.1, 38.0, 34.2, 33.7, 31.9, 27.2, 26.1, 18.2,