A formal synthesis of ionomycin featuring a permanganate-mediated oxidative cyclisation

Article abstract of DOI:10.1055/s-0030-1258327

Key steps in a synthesis of the C17-C32 fragment of iono-mycin are (a) an auxiliary-directed oxidative cyclisation of a diene with potassium permanganate to construct a tetrahydrofuran ring and four stereogenic centres in a single operation, and (b) a cha

Full text of DOI:10.1055/s-0030-1258327

104
PAPER
A Formal Synthesis of Ionomycin Featuring a Permanganate-Mediated
Oxidative Cyclisation
S
ynthesis of Ionom
i
ycin ngfa Li, John P. Cooksey, Zhanghua Gao, Philip J. Kocieński,* Stephen M. McAteer, Thomas N. Snaddon
The School of Chemistry and the Institute of Process Research and Development, Leeds University, Leeds LS2 9JT, UK
Fax +44(113)3436401; E-mail: p.j.kocienski@leeds.ac.uk
Received 15 July 2010; revised 3 October 2010
were very sensitive to the quality of the reagent 10, with
the best results being obtained with freshly prepared re-
agent.15 After protection of the secondary alcohol as its p-
methoxybenzyl ether, the alkene function of 12 was con-
Abstract: Key steps in a synthesis of the C17–C32 fragment of iono-
mycin are (a) an auxiliary-directed oxidative cyclisation of a diene
with potassium permanganate to construct a tetrahydrofuran ring
and four stereogenic centres in a single operation, and (b) a chain-
appendage reaction featuring the alkylation of an enolsilane by an verted into the ketone 13 through a Wacker oxidation.16
oxocarbenium ion generated from a 2-phenylsulfonyl-substituted
Finally, the ketone was converted into its enolsilane deriv-
tetrahydrofuran.
ative in the usual way, to afford fragment 3 in 30% overall
yield from commercial ester 5.
Key words: ionomycin, permanganate oxidation, directed reduc-
tion, crotylboration, carbocupration
Our synthesis of the sulfone fragment 4 was predicated on
an auxiliary-directed diastereoselective oxidative cyclisa-
tion of the (Z,Z)-diene 18 (Scheme 3). A related reaction
had previously featured as a key step in our synthesis of
salinomycin.17 The C26,27-trisubstituted alkene was
sourced from inexpensive neryl acetate, but the C30,31-
trisubstituted alkene required construction. Neryl acetate
(14) was first converted into the terminal alkyne 15 in six
steps as previously described (35% overall).17 An efficient
Ionomycin (1) is an ionophore isolated from Streptomyces
conglobatus with a high affinity for divalent cations.1–3
A
detailed competitive binding study revealed the following
selectivity: Pb2+ > Cd2+ > Zn2+ > Mn2+ > Ca2+ > Cu2+
>
Co2+ > Ni2+ > Sr2+.4 It is widely used as a tool in cell biol-
ogy for the investigation of processes requiring calcium
mobilisation and its use in lead detoxification has been
mooted. In 2009 we reported a total synthesis of ionomy-
cin and its calcium complex based on (a) a highly stereo-
selective Au3+-catalysed cycloisomerisation of an a-
hydroxyallene to create the tetrahydrofuran B, and (b) a
rhodium-catalysed rearrangement of an a-diazo-b-hy-
droxyketone to generate the b-diketone moiety.5 A key in-
termediate in our synthesis was the C17–C32 alcohol 2
(Scheme 1), which had also featured in the preceding syn-
theses developed by Evans6 and Hanessian7 reported in
1990.8 We now report an alternative synthesis of the C17–
C32 alcohol 2, and hence a formal synthesis of ionomy-
cin, which features (a) a permanganate-mediated oxida-
tive cyclisation reaction9 to create the tetrahydrofuran ring
A in fragment 4 and four of its stereogenic centres in a sin-
gle operation, and (b) a Ley a-heteroalkylation reaction to
append fragment 3 to C23 of fragment 4.
A
B
32
23
22
O
O
H
H
OH
OH
HO2C
1
OH
17
16
O
OH
11
9
Ionomycin (1)
32
23
O
22
O
H
H
O
OTBS
The anti,anti-stereotriad in fragment 3 was installed by a
crotylmetallation reaction on the known aldehyde 8
(Scheme 2).10 Initial attempts to use Roush’s easily acces-
sible tartrate-derived (E)-crotylboronic ester reagent 9
were thwarted by poor diastereoselectivity (dr = 2:1).11–13
Better results were obtained with (E)-crotyldiisopinocam-
pheylborane (10) derived from (+)-a-pinene; in this case
the desired adduct 11 was obtained in a modest 52% yield
but excellent diastereoselectivity (dr >95:5).14 The yield
and diastereoselectivity of the crotylmetallation reaction
O
17
2
OH
22
A
O
32
OTMS
OPMB
23
O
+
O
H
O
S
H
OTBS
Ph
4
17
OTBS
SYNTHESIS 2011, No. 1, pp 0104–0108
Advanced online publication: 15.11.2010
x
x
.
x
x
.2
0
1
0
3
DOI: 10.1055/s-0030-1258327; Art ID: M05110SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

PAPER
Synthesis of Ionomycin
105
equiv) to a rapidly stirring solution of diene 18 in acetone
containing pH 6 acetate buffer at –35 °C. The acetic acid
was essential to neutralise the potassium hydroxide gener-
ated during the oxidation. The product was isolated in
54% yield as an inseparable 7:1 mixture of diastereoiso-
mers in which the major component was the desired tet-
rahydrofuran diol 19. Oxidation of the dioxolan function
by exposure to ozone in ethyl acetate at low temperature
afforded the intermediate ester 20, which lactonised on
exposure to a catalytic amount of p-toluenesulfonic acid
(PTSA) to give the lactone 21 (mp 172–174 °C) as a sin-
gle enantiomer in 69% overall yield from 19.30 Reductive
cleavage of the sultam chiral auxiliary afforded the crys-
talline diol 22, the structure and stereochemistry of which
was established previously by Robinson and co-work-
ers.31
OMe
O
OMe
O
a
b
OH
OTBS
7
94%
ca. 92%
OTBS
OH
5
6
c(i)
c(ii)
d
O
OH
OPMB
52%
dr > 95:5
75%
OTBS
OTBS
OTBS
8
11
12
OTMS
O
e
f
To complete the sequence, the primary hydroxy group of
diol 22 was selectively tosylated via the stannylene inter-
mediate, and the resultant tosylate 23 was reduced via its
iodoalkane derivative with tributyltin hydride. Protection
of the remaining hydroxy group gave the crystalline TBS
ether 25 in 80% overall yield from diol 22. Finally, reduc-
tion of the lactone 25 gave a diastereoisomeric mixture of
lactols that was treated with freshly prepared benzene-
sulfinic acid in the presence of calcium chloride as a de-
hydrating agent.32 The desired sulfones 4 were obtained in
93% yield as an inseparable mixture of diastereoisomers
(dr = 4:1).
OPMB
OPMB
89%
ca. 100%
OTBS
OTBS
13
3
i-PrO2C
i-PrO2C
B
O
B
O
2
9
10
Scheme 2 Reagents and conditions: (a) TBSCl (1.0 equiv), imida-
zole (1.2 equiv), DMAP (10 mol%), CH2Cl2, 0 °C, 3 d, 94%; (b)
DIBAL-H (2.5 equiv),CH2Cl2–toluene, –78 to –30 °C, 3.5 h, ca. 92%;
(c) (1) (COCl)2 (1.3 equiv), DMSO (2.6 equiv), Et3N (6.5 equiv),
CH2Cl2, –78 °C to r.t.; (2) 10, THF, –78 °C; (3) NaOH, H2O2, –78 °C
to r.t., 52%; (d) p-methoxybenzyl trichloroacetimidate (1.3 equiv),
TfOH (0.3 mol%), CH2Cl2–cyclohexane (1:2), 0 °C to r.t., 18 h, 75%;
(e) PdCl2 (20 mol%), Cu(OAc)2·H2O (2.0 equiv), O2 (1 atm), N,N-di-
methylacetamide–H2O, r.t., 3 d, 89%; (f) LDA (2.6 equiv), TMSCl
(6.6 equiv), THF, –78 °C to r.t., ca. 100%.
The ozonolysis of dioxolan 19 deserves further comment.
The scope and mechanism of the rapid and efficient oxi-
dation of acetals with ozone were described in detail by
Deslongchamps, Taillefer and co-workers.33–38 They pos-
tulated the insertion of ozone into the acetal C–H bond to
generate an intermediate hydrotrioxide such as 26
(Scheme 4), which decomposes to the hydroxyethyl ester
20 and singlet oxygen. In the case at hand, the oxidation
of dioxolan 19 required careful monitoring because ex-
cess ozone caused an analogous secondary oxidation of
the hydroxyethyl ester 20 to the lactone 29 presumably via
the intermediate 27.
carboxylation of the terminal alkyne afforded the ynoate
ester 16, which then underwent cis-carbocupration to the
a,b-unsaturated ester 17.18,19 High Z-stereoselectivity
(Z/E >97:3) was observed provided the carbocupration re-
action and the subsequent methanol quench were conducted
below –70 °C in tetrahydrofuran rather than diethyl ether.
The carboxylic acid derived from hydrolysis of methyl es-
ter 17 was activated by reaction with the Ghosez reagent
[Me2C=C(Cl)NMe2]20,21 because more conventional re-
agents, such as oxalyl chloride, caused some premature
destruction of the acetal even when the reaction was per-
formed in the presence of base. The activated ester reacted
with the sodium salt of (1R,2S)-camphor-10,2-sultam to
give the desired diene fragment 18 in 90% overall yield
from methyl ester 17.
The union of fragments 3 and 4 was accomplished by the
procedure of Ley and co-workers (Scheme 5).39 A mix-
ture of enolsilane 3 and sulfone 4 in dichloromethane was
added to a solution of Et3Al2Cl3 (freshly prepared from
equimolar quantities of Et2AlCl and EtAlCl2) in hexane at
–78 °C. After warming to –30 °C, the reaction was
quenched with aqueous ammonium chloride to give the
diastereoisomeric a-heteroalkylation products 30 and 31
in 98% yield. The diastereoisomers were separable by col-
umn chromatography and easily quantified by integration
1
of the H NMR signals for the C22 methylene protons.
The key step in the sequence, the permanganate-mediated
oxidative cyclisation of the diene 18 to the tetrahydrofu-
ran diol 19, was based on a precedent established by
Walba22 with many refinements and insights being pro-
vided recently by Brown and co-workers.23–29 The reac-
tion simply involved slow addition of an aqueous solution
of potassium permanganate (2 equiv) and acetic acid (2.2
The stereochemistry of the alkylation products could not
be assigned with confidence at this stage, but subsequent
conversion into the ionomycin intermediate 2 established
that the minor diastereoisomer 31 had the correct config-
uration at C23. Precomplexation of the ketone 31 with
MeAlCl2 (5 equiv) in dichloromethane at –78 °C, fol-
lowed by addition of tributyltin hydride (5 equiv), accom-
Synthesis 2011, No. 1, 104–108 © Thieme Stuttgart · New York

106
Y. Li et al.
PAPER
CO2Me
O
O
O
6 steps
35%
a
b
O
O
O
94%
96%
OAc
OMe
O
14
15
16
17
c
90%
OH
O
O
O
O
O
N
O
e
d
26
27 30
31
O
N
O
O
O
H
N
H
69%
54%
S
S
O
OH
OH
OH
OH
O
dr = 7:1
S
O
O
19
20
18
O
O
O
dr = 4:1
O
f
h
j
O
O
O
O
O
H
O
O
O
O
O
H
N
H
OR
H
O
O
O
S
76%
96%
93%
S
OH
OH
OR
OTBS
Ph
22 R = H
23 R = Ts
24 R = H
4
21
O
g
90%
O
i
93%
25 R = TBS
Scheme 3 Reagents and conditions: (a) (1) n-BuLi (1.1 equiv), THF, –78 to –5 °C; (2) ClCO2Me (2.0 equiv), THF, –90 °C, 94% (2 steps);
(b) MeLi·LiBr (2.2 equiv), CuI (1.1 equiv), THF, –85 °C, 3 h, 96%; (c) (1) NaOH (5.5 equiv), NaHCO3 (0.5 equiv), MeOH–H2O, reflux, 2 h;
(2) Me2C=C(Cl)NMe2 (1.25 equiv), Et2O, 0 °C, 30 min; (3) sodium salt of (1R,2S)-camphor-10,2-sultam (1.0 equiv), toluene, r.t., 3.5 h, 90%
(3 steps); (d) KMnO4 (2.0 equiv), AcOH (2.2 equiv), pH 6 acetate buffer, acetone–H2O, –35 °C, 5 h, 54% (dr = 7:1); (e) (1) O3, EtOAc, –80 °C;
(2) PTSA (cat.), CH2Cl2, r.t., 8 h, 69% (2 steps); (f) BH3·SMe2 (1.5 equiv), NaBH4 (0.9 equiv), THF–toluene, –10 °C, 2 h, 76%; (g) (1) Bu2SnO
(1.2 equiv), benzene, reflux, 3 h; (2) TsCl (1.1 equiv), TBAB (0.5 equiv), r.t., 30 min, 90% (2 steps); (h) Bu3SnH (1.0 equiv), NaI (2.5 equiv),
1,1¢-azobis(cyclohexanecarbonitrile) (10 mol%), DME, 80 °C, 18 h, 96%; (i) TBSCl (1.2 equiv), Et3N (1.2 equiv), DMAP (0.1 equiv), CH2Cl2,
reflux, 3 d, 93%; (j) (1) DIBAL-H (1.2 equiv), toluene, –78 °C, 2 h; (2) PhSO2H (1.8 equiv), CaCl2 (3.0 equiv), CH2Cl2, r.t., 18 h, 93%, dr = 4:1,
(2 steps).
plished the simultaneous reduction of the ketone and less abundant conformer 35, with the tetrahydrofuran ring
deprotection of the PMB ether to give the syn-diol 32 in at C26 in a pseudoaxial position. A complementary model
62% yield.40 Treatment of diol 32 with 2,2-dimethoxypro- proposed by Woerpel and co-workers45 posits that facial
pane and a catalytic amount of camphorsulfonic acid in selectivity is a consequence of product development con-
acetone afforded a mixture of the fully protected ace- trol. Thus ‘inside’ attack is favoured because rehybridiza-
tonide 33 (53%) together with the target C17 alcohol 2 tion in the transition state during addition to the
(35%). The syn stereochemistry of the acetonide was es- oxocarbenium ion leads to a staggered conformation with
tablished from the 13C NMR signals at d = 19.4 and 30.3 the adjacent methylene at C24, whereas ‘outside’ attack
ppm for the gem-dimethyl groups.41 To complete the se- leads to a higher-energy, eclipsed conformation.
quence, the primary TBS ether in 33 was selectively
In an effort to improve the stereochemical outcome of the
cleaved using HF·pyridine in tetrahydrofuran at room
Ley a-heteroalkylation, we attempted to equilibrate ke-
temperature to afford pure 2 in 72% yield. The structure
tones 30 and 31 through a base-catalysed b-elimination to
and stereochemistry of 2 was identified by comparison of
the enone 36 (Scheme 6) followed by re-addition, but
its 1H and 13C NMR spectra and [a]D value with the data
were unsuccessful; 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) in refluxing benzene, or caesium carbonate in
methanol did nothing, whereas application of sodium
recorded on a sample of 2 prepared by a different route5
and with the data reported by Hanessian and co-workers.7
The adverse stereochemistry observed in the Ley a-het- methoxide in methanol or potassium tert-butoxide in tet-
eroalkylaton reaction can be rationalised by the stereo- rahydrofuran destroyed the substrates. Other base–solvent
electronic model developed by Schmitt and Reissig42–44 combinations – with or without apotropaic chants – were
(Scheme 6) in which the reaction proceeds through a five- equally fruitless and led to a change in strategy that was
membered-ring oxocarbenium ion that may exist in two ultimately successful.5
distinct envelope conformations (34 and 35) in rapid equi-
In conclusion, intermediate 2, harbouring nine of the four-
librium. The major (undesired) isomer forms as a conse-
teen stereogenic centres of ionomycin, has been synthe-
quence of Felkin–Anh addition (i.e., ‘inside’ attack) of the
sised. The first key step was the auxiliary-directed
enolsilane nucleophile on the more abundant conformer
oxidative cyclisation of a diene to generate a tetrahydro-
furan ring and four stereogenic centres in a single opera-
34, with the bulkier tetrahydrofuran substituent at C26 oc-
cupying the pseudoequatorial position. The minor (de-
tion. Recent results by Brown and co-workers suggest that
sired) isomer is derived from Felkin–Anh addition to the
a similar oxidative cyclisation of a suitable triene sub-
Synthesis 2011, No. 1, 104–108 © Thieme Stuttgart · New York

PAPER
Synthesis of Ionomycin
107
19
Nu
H
OTBS
O3, EtOAc, –78 °C
H
O
H
+
O
O
H
H
26
H
H
O
O
26
OTBS
+
O
H
O
O
N
H
35
O
34
O
Nu
O
H
S
OH
OH
O
O
26
31
(minor)
30
(major)
– O2
OH
OH
O
O
–O
O
H
OTBS
O
N
O
O
H
S
OH
O
20
O
OPMB
36
OTBS
O3, EtOAc, –78 °C
Scheme 6
OH
O
O
N
O
O
O
O
S
O
OH
strate could deliver both tetrahydrofuran rings in a single
operation.46–48 Moreover, by using asymmetric phase-
transfer catalysis, the asymmetric oxidative cyclisation
could be accomplished without the need for a chiral aux-
iliary.49 The second key step, the a-heteroalkylation of
enolsilane 3, has rarely been applied to the synthesis of
substituted tetrahydrofurans.39,50 In our hands the reaction
was very efficient in terms of yield (99%), but the diaste-
reoselectivity was modest (2:1) and favoured the unwant-
ed diastereoisomer – a problem we were unable to fix.
O
H
O
O
H
27
– H2O2
O
OH
O
O
+
O
N
O
O
S
OH
O
O
28
29
Scheme 4
2.61 (dd)
2.87 (dd)
2.51 (dd)
2.94 (dd)
23
23
O
O
H
O
O
H
22H
22H
OTMS
2:1
+
Et3Al2Cl3 (1.2 equiv)
OTBS
OTBS
O
O
O
O
O
H
O
S
CH2Cl2, –78 to –30 °C
98% (dr = 2:1)
OPMB
OTBS
Ph
OPMB
OPMB
OTBS
3 (1.2 equiv)
4 (1.0 equiv)
OTBS
30
OTBS
31
1. MeAlCl2 (5.0 equiv), CH2Cl2, –78 °C, 2 min
2. Bu3SnH (5.0 equiv), –78 °C, 1 h
62%
O
O
O
O
H
O
O
H
H
+
CSA (0.15 equiv)
H
H
O
H
Me2C(OMe)2 (2.0 equiv)
OTBS
OTBS
OTBS
O
OH
acetone, 0 °C, 1 h
O
O
OH
OH
2 (35%)
32
OTBS
OTBS
33 (53%)
HF⋅py
py–THF (1:3), r.t., 30 h
72%
Scheme 5
Synthesis 2011, No. 1, 104–108 © Thieme Stuttgart · New York

108
Y. Li et al.
PAPER
(20) Ghosez, L.; Haveaux, B.; Viehe, H. G. Angew. Chem. Int.
Ed. Engl. 1969, 8, 454.
(21) Haveaux, B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.;
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7269.
Supporting Information and Primary Data
Experimental details, 1H and 13C NMR spectra and their associated
FIDs for compounds 2, 3, 4, 11, 12, 13, 17, 18, 21, 22, 23, 24, 25,
29, 30, 31, 32, and 33 are available online free of charge at http://
www.thieme-connect.com/ejournals/toc/synthesis. Primary data for
this article can be cited using the following DOI: 10.4125/pd0007th.
(25) Cecil, A. R. L.; Hu, Y. L.; Vicent, M. J.; Duncan, R.; Brown,
R. C. D. J. Org. Chem. 2004, 69, 3368.
(26) Head, G. D.; Whittingham, W. G.; Brown, R. C. D. Synlett
2004, 1437.
Acknowledgment
We thank Professor Richard Brown (Southampton University) for
helpful advice and Pfizer Central Research for a CASE Studentship
(S. M. McAteer).
(27) Hu, Y. L.; Brown, R. C. D. Chem. Commun. 2005, 5636.
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K. R.; Brown, R. C. D. Org. Lett. 2008, 10, 2489.
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(30) The relative and absolute stereochemistry of the lactone 21
was established by a single crystal X-ray analysis of its
enantiomer prepared by an analogous route. See the
electronic Supporting Information for details
(31) Russell, S. T.; Robinson, J. A.; Williams, D. J. J. Chem. Soc.,
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