A synthesis of an ionomycin calcium complex

Full text of DOI:10.1002/anie.200901608

Communications
DOI: 10.1002/anie.200901608
Total Synthesis
A Synthesis of an Ionomycin Calcium Complex**
Zhanghua Gao, Yingfa Li, John P. Cooksey, Thomas N. Snaddon, Stefan Schunk,
Eddy M. E. Viseux, Stephen M. McAteer, and Philip J. Kocienski*
Ionomycin is a narrow-spectrum ionophore antibiotic isolated
from Streptomyces conglobatus.[1] X-ray crystallographic
analysis of its calcium complex (1; see Scheme 1)[2] revealed
a carboxylic acid group and an unusual b-diketone moiety
which, in combination, are responsible for its avidity for
divalent cations. Ionomycin has little value as an antibiotic but
it is widely used as a tool in cell biology for the investigation of
processes requiring calcium mobilization.[3] The three total
syntheses reported to date exemplify the utility of chiral
enolate chemistry (Evans et al.),[4] the chiron approach
(Hanessian et al.),[5] and asymmetric ring-opening of sym-
metrical 8-oxabicyclo[3.2.1]oct-6-enes (Lautens et al.)[6] for
the construction of polypropionate chains. In addition,
numerous fragment syntheses have also been reported.[7]
Herein, we describe a synthesis of ionomycin and its calcium
complex (1) from four key fragments 2–5 (Scheme 1). Our
synthesis features: 1) the use of a stereoselective gold(III)-
catalyzed cycloisomerization of an a-hydroxyallene to create
a dihydrofuran ring, and 2) the use of a rhodium-catalyzed
rearrangement of an a-diazo-b-hydroxyketone to generate
the b-diketone moiety.
Our synthesis began with the construction of the C22–C32
bis(tetrahydrofuran) fragment 2. Thus, addition of lithium
TMS-acetylide to the known aldehyde 6[8] gave a racemic
propargylic alcohol which was oxidized to the corresponding
ketone 7 using pyridinium dichromate (Scheme 2). The
Scheme 1. Structure and retrosynthetic analysis of the ionomycin
calcium complex (1). PMB=p-methoxybenzyl, TBDPS=tert-butyldiphe-
asymmetric hydrogen-transfer reaction of ketone 7 by the
method of Noyori and Ohkuma[9] led to (R)-9 in 95% yield
and e.r. = 97:3, as determined by 1H NMR spectroscopic
analysis of the mandelate ester. Simultaneous cleavage of the
TMS and acetate groups using potassium carbonate in
methanol resulted in a water soluble diol (R)-10. This species
underwent Sharpless asymmetric epoxidation to form the
epoxide intermediate 11, which spontaneously cyclized to the
tetrahydrofuran 12. The primary hydroxy group was then
removed by tosylation and subsequent reduction using
nylsilyl, TBS=tert-butyldimethylsilyl.
lithium triethylborohydride gave the secondary alcohol 14,
which was protected as its TBS silyl ether 15.
Addition of the freshly prepared aldehyde 16 to the
titanium derivative of alkyne 15 gave the desired propargylic
alcohol 17 (anti/syn = 6:1) in accord with the Felkin–Anh
model of asymmetric induction (Scheme 3).[10] The corre-
sponding mesylate 18 was treated with MeCu·MgBr2·LiCl by
an anti-selective SN2’ mechanism[11] to give allene 19 (d.r. =
6:1) in 93% yield. Selective removal of the isopropylidene
group was accomplished using 0.10m PPTS in isopropanol at
508C to give a mixture of diastereomeric diols (6:1), which
were separated by column chromatography. Pure diol 20 was
isolated in 53% overall yield (63% brsm) for the four steps
starting from alkyne 15. In the key step of the sequence, the
diol 20 was treated with 1 mol% AuCl3 in THF at room
temperature to afford the dihydrofuran 21 as a single
diastereoisomer in 92% yield. By using the donor solvent
THF in the cyclization, decomposition and removal of the
TBS group were minimized.[12] To complete the sequence, the
alkene in 21 was hydrogenated and the primary alcohol
[*] Dr. Z. Gao, Dr. Y. Li, Dr. J. P. Cooksey, Dr. T. N. Snaddon,
Dr. S. Schunk, Dr. E. M. E. Viseux, Dr. S. M. McAteer,
Prof. Dr. P. J. Kocienski
The School of Chemistry and The Institute of Process Research and
Development, Leeds University, Leeds LS2 9 JT (UK)
Fax: (+44)113-343-6401
E-mail: p.j.kocienski@leeds.ac.uk
[**] We thank Prof. Norbert Krause (University of Dortmund) for helpful
advice as well as the Deutsche Forschungsgemeinschaft, the
Engineering and Physical Sciences Research Council, and Pfizer
Central Research (Sandwich) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200901608.
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Scheme 3. Synthesis of the bis(tetrahyrdofuran) fragment 2. Reagents
Scheme 2. Synthesis of alkyne 15. Reagents and conditions: a) TMS-
acetylene, nBuLi, THF, ꢀ788C, 30 min; then add 6, ꢀ788C, 2 h, 96%;
b) PDC, CH2Cl2, RT, 40 h; c) 8 (0.010 equiv), iPrOH, 20 h, 90% (over 2
steps), e.r. 97:3; d) K2CO3, MeOH, RT, 2 h; e) (ꢀ)-DIPT, Ti(O-iPr)4,
tBuOOH, CH2Cl2, ꢀ208C, 12 h, 63% (over 2 steps); f) Bu2SnO, TsCl,
Et3N, CH2Cl2, RT, 17 h; g) LiBHEt3, THF, ꢀ108C; h) TBSOTf, Et3N,
CH2Cl2, 08C, 77% (over 3 steps). DIPT=diisopropyl tartrate,
PDC=pyridinium dichromate, THF=tetrahydrofuran, TMS=trimethyl-
silyl, Ts=4-toluenesulfonyl.
and conditions: a) 15, nBuLi, THF, ꢀ658C; then add ClTi(O-iPr)3,
ꢀ788C!ꢀ608C, 90 min; then add 16, ꢀ788C ! ꢀ408C, 2 h, 82%
(97% brsm), d.r.=6:1; b) MsCl, Et3N, CH2Cl2, 08C, 90%; c) MeMgCl/
LiBr/CuBr (1:1:1), THF, ꢀ608C, 50 min; then warm to ꢀ208C, 93%,
d.r.=6:1; d) PPTS, iPrOH, 508C, 2.5 h; then separate diastereoisomers
by chromatography, 77% of pure 20; e) 1 mol% AuCl3, THF, RT,
30 min, 92%; f) H2, 10% Pd/C, MeOH, 98%; g) 1-phenyl-1H-tetrazole-
5-thiol, DIAD, Ph3P, THF, RT, 2 h; h) mCPBA, NaHCO3, CH2Cl2, 24 h,
73% (over 2 steps). brsm=based on recovered starting material,
DIAD=diisopropylazodicarboxylate, mCPBA=m-chloroperbenzoic
acid, Ms=methanesulfonyl, PT=1-phenyl-1H-tetrazolyl, PPTS=pyridi-
nium p-toluenesulfonate.
subjected to a Mitsunobu reaction with 1-phenyl-1H-tetra-
zole-5-thiol. Oxidation of the resultant thioether 23 with
mCPBA gave the crystalline 1-phenyl-1H-tetrazolyl sulfone
2, whose structure and configuration were established by X-
ray crystallography.
The synthesis of fragment 3 is summarized in Scheme 4.
Diol 24,[13] prepared according to the protocol of Kishi and co-
workers,[14] was converted into its p-methoxyphenyl acetal
derivative 25 by an acetal exchange process. The acetal 25
underwent regioselective reductive cleavage using DIBAL-
H[15] to give the primary alcohol 26. Finally, oxidation of the
primary alcohol with Dess–Martin periodinane gave the
aldehyde 3 in 94% yield.
The readily available meso-3,5-dimethylglutaric anhy-
dride (27)[16] is a common precursor for the synthesis of
fragments 4 and 5 (Scheme 5). Thus, anhydride 27 was
converted into the phenyltetrazolyl sulfone 4 in eight steps
via the known alcohol 28.[17] A noteworthy step in the
synthesis of fragment 5 was the construction of the stereo-
genic centre at C4 by the nucleophilic addition of the cuprate
30 to the neutral h3-allyliron complex 31. After oxidative
decomplexation of the iron, the enamide 32 was obtained in
51% yield.[17]
Scheme 4. Synthesis of fragment 3. Reagents and conditions: a) PPTS,
CH2Cl2, RT; b) DIBAL-H, ꢀ608C!RT, 87% (over 2 steps); c) DMP, py,
CH2Cl2, 94%. DIBAL-H=diisobutylaluminium hydride, DMP=Dess–
Martin periodinane, PMP=p-methoxyphenyl, py=pyridine.
With all four fragments 2–5 in hand, all that remained to
complete the synthesis was to link them sequentially
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Communications
(Scheme 6). Fragments 2 and 3 were coupled through a Julia–
Kocienski olefination.[18] The reaction proceeded in good
yield but a mixture of double-bond isomers 33 was generated
with an excess of the Z isomer (Z/E = 2.3:1). The mixture was
converted into the dimethylsilyl ethers 35, which underwent
an easy intramolecular Pt-catalyzed hydrosilylation.[19] To
obtain a good diastereomeric ratio (11:1) for the reaction it
was required that both the E and Z isomers reacted with a
similar stereochemical bias in favor of the desired siloxane
36.[20] The isomers were separated by column chromatography
and the major siloxane 36 (67% from 35) was oxidized in
DMF by using the protocol developed by Tamao (30% H2O2,
KOH).[21] Unfortunately, the oxidation was accompanied by
partial removal of the TBDPS group, thus the TBDPS group
had to be restored so that the remaining 1,3-diol could be
protected as its isopropylidene derivative to give 37 in 65%
overall yield (85% brsm) from 36. Selective cleavage of the
TBDPS group in the presence of the secondary TBS ether was
accomplished by treatment of 37 with NaOH powder in DMF,
and the resultant primary alcohol was oxidized with TPAP/
Scheme 5. Synthesis of fragments 4 and 5. Reagents and conditions:
a) PTSH, DIAD, Ph3P, THF, RT, 98%; b) mCPBA, CH2Cl2, 79%.
Scheme 6. Completion of the total synthesis of ionomycin calcium complex (1). Reagents and conditions: a) add LHMDS (1.1 equiv) to a mixture
of 2 (1.0 equiv) and 3 (1.6 equiv) in THF, ꢀ788C, 1 h; then warm to 08C, 80%; b) DDQ, CH2Cl2/H2O, RT, 80 min; c) Me2SiHCl, Et3N, CH2Cl2, RT,
10 min; d) Pt(DVTMS)2 (0.00044 equiv), n-hexane, RT, 10 min, 67% (over 2 steps); e) KOH, 30% H2O2, DMF, RT, 2 h; f) TBDPSCl, imidazole,
DMF, H2O, RT; g) Me2C(OMe)2, PPTS (cat.), RT, 85% brsm (over 3 steps); h) powdered NaOH, DMF, RT, 18 h, 70%; i) TPAP, NMO, CH2Cl2, RT,
15 min, 92%; j) add KHMDS to a mixture of sulfone 4 and aldehyde 39 in THF, ꢀ788C, 1 h; then warm to RT, 60%; k) LiOH, THF/MeOH/H2O
(2:2:1); l) (COCl)2, DMF (0.3 mol%), CH2Cl2, RT; m) CH2N2, Et2O, 63% (over 3 steps); n) LDA added to 41 (1.0 equiv) and 5 (2.7 equiv), THF,
ꢀ78!ꢀ208C; o) [Rh2(OAc)4] (8 mol%), DME, RT, 20 min, 66% (over 2 steps); p) HF, MeCN/H2O, RT; q) LiOH, DME/H2O (10:1), RT; r) CaCl2,
pH 8 buffer, 76% (over 3 steps). DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DME=1,2-dimethoxyethane, DMF=N,N-dimethylformamide,
DVTMS=1,3-divinyltetramethyldisiloxane, HMDS=hexamethyldisilazane, LDA=lithium diisopropylamide, NMO=N-methylmorpholine N-oxide,
TPAP=tetra-n-propylammonium perruthenate.
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[5] S. Hanessian, N. G. Cooke, B. Dehoff, Y. Sakito, J. Am. Chem.
NMO to give aldehyde 39 in 64% yield (from 37). A second
Julia–Kocienski olefination[18] was then used to append
Soc. 1990, 112, 5276.
[6] M. Lautens, J. T. Colucci, S. Hiebert, N. D. Smith, G. Bouchain,
Org. Lett. 2002, 4, 1879.
ꢀ
fragment 4 and forge the C16 C17 E-alkene 40 exclusively.
In their total syntheses of ionomycin, Evans,[4] Hanes-
sian[5], and Lautens[6] generated the b-diketone moiety
spanning C9–C11 by consecutive boron-mediated aldol and
CrVI oxidation reactions. We exploited a protocol devised by
Pellicciari et al.[22] based on a-diazocarbonyl chemistry. The
requisite a-diazoketone 41 was synthesized in three steps
from ester 40 (Scheme 6). Lithium diisopropylamide
(2 equiv) was added to a mixture of aldehyde 5[17] and
a-diazoketone 41 at ꢀ788C. The metalated a-diazoketone 42,
which was generated in situ, was added to the aldehyde to
form the b-hydroxy-a-diazoketone 43 after aqueous work-up,
and was then treated with [Rh2(OAc)4] (3 mol%) in DME at
room temperature. The resultant carbene inserted into the
[7] P. G. M. Wuts, R. Dcosta, W. Butler, J. Org. Chem. 1984, 49,
2582; S. L. Schreiber, Z. Wang, J. Am. Chem. Soc. 1985, 107,
5303; C. Spino, L. Weiler, Tetrahedron Lett. 1987, 28, 731; D. A.
Nicoll-Griffith, L. Weiler, Tetrahedron 1991, 47, 2733; M. J.
Taschner, Q. Z. Chen, Bioorg. Med. Chem. Lett. 1991, 1, 535; H.
von der Emde, A. Langels, M. Noltemeyer, R. Bruckner,
Tetrahedron Lett. 1994, 35, 7609; Y. Guindon, C. Yoakim, V.
Gorys, W. W. Ogilvie, D. Delorme, J. Renaud, G. Robinson, J. F.
Lavallee, A. Slassi, G. Jung, J. Rancourt, K. Durkin, D. Liotta,
J. Org. Chem. 1994, 59, 1166; T. Q. Hu, L. Weiler, Can. J. Chem.
1994, 72, 1500; A. M. Montaꢀa, F. Garcia, P. M. Grima,
Tetrahedron Lett. 1999, 40, 1375; C. Spino, M. Allan, Can. J.
Chem. 2004, 82, 177; J. Cooksey, P. Kocienski, Y. Li, Collect.
Czech. Chem. Commun. 2005, 70, 1653; T. Novak, Z. Tan, B.
Liang, E. Negishi, J. Am. Chem. Soc. 2005, 127, 2838; J. A.
Marshall, A. M. Mikowski, Org. Lett. 2006, 8, 4375.
[8] D. S. Dodd, A. C. Oehlschlager, N. H. Georgopapadakou, A. M.
Polak, P. G. Hartman, J. Org. Chem. 1992, 57, 7226.
[9] R. Noyori, T. Ohkuma, Angew. Chem. 2001, 113, 40; Angew.
Chem. Int. Ed. 2001, 40, 40.
[10] B. M. Trost, Z. T. Ball, K. M. Laemmerhold, J. Am. Chem. Soc.
2005, 127, 10028.
[11] J. L. Luche, E. Barreiro, J. M. Dollat, P. Crabbꢁ, Tetrahedron
Lett. 1975, 16, 4615; N. Krause, A. Hoffmann-Rꢂder, Tetrahe-
dron 2004, 60, 11671; H. Ohno, K. Tomioka in Science of
Synthesis, Vol. 44 (Ed.: N. Krause), 2008, p. 71.
[12] F. Volz, N. Krause, Org. Biomol. Chem. 2007, 5, 1519; J. Erdsack,
N. Krause, Synthesis 2007, 3741.
[13] M. Born, C. Tamm, Helv. Chim. Acta 1990, 73, 2242.
[14] M. R. Johnson, T. Nakata, Y. Kishi, Tetrahedron Lett. 1979, 20,
4343.
ꢀ
adjacent C H bond to generate the b-diketone 44 in 66%
overall yield from 41. The 1H and 13C NMR spectra of 44 were
identical to the data reported by Evans et al.[4] Finally, the
TBS ether and isopropylidene groups were removed from 44
with aqueous HF and the methyl ester was hydrolyzed with
LiOH to give ionomycin, which was isolated as its crystalline
calcium salt. 1H and 13C NMR spectroscopic data for our
synthetic material were identical to those of a commercial
sample of the ionomycin calcium salt. The structure was also
confirmed by X-ray analysis of our synthetic material, which
was recrystallized from heptane (see the Supporting Infor-
mation).
In conclusion, we have accomplished a synthesis of
ionomycin calcium complex (1) in 33 steps from aldehyde 6
in 0.68% overall yield. Noteworthy features of our approach
include: 1) an efficient asymmetric synthesis of an allene
using a copper(I)-mediated anti-selective SN2’ reaction (18!
19), 2) a highly stereoselective gold(III)-catalyzed cycloiso-
merization reaction of an a-hydroxyallene to a 2,5-dihydro-
furan (20!21),[23] and 3) the construction of the b-diketone
moiety by a rhodium-catalyzed rearrangement of an a-diazo-
b-hydroxyketone (43!44). Our synthesis of ionomycin
provides further evidence for the value of gold-catalyzed
cycloisomerization reactions in the construction of complex
natural products.[24]
[15] A. B. Smith, K. J. Hale, L. M. Laakso, K. Chen, A. Riꢁra,
Tetrahedron Lett. 1989, 30, 6063; D. A. Evans, S. W. Kaldor, T. K.
Jones, J. Clardy, T. J. Stout, J. Am. Chem. Soc. 1990, 112, 7001.
[16] P. F. Wiley, K. Gerzon, E. H. Flynn, M. V. Sigal, Jr., O. Weaver,
U. C. Quarck, R. R. Chauvette, R. Monahan, J. Am. Chem. Soc.
1957, 79, 6062; N. L. Allinger, J. Am. Chem. Soc. 1959, 81, 232.
[17] J. P. Cooksey, P. J. Kocienski, Y. Li, S. Schunk, T. N. Snaddon,
Org. Biomol. Chem. 2006, 4, 3325.
[18] P. R. Blakemore, W. J. Cole, P. J. Kocienski, A. Morley, Synlett
1998, 26.
[19] G. Chandra, P. Y. Lo, P. B. Hitchcock, M. F. Lappert, Organo-
metallics 1987, 6, 191.
[20] Hydrosilylation of a pure sample of (Z)-33 gave the siloxane 36
with a d.r. of 20:1. As hydrosilylation of the mixture of 33
(Z:E 2.3:1) gave siloxane 36 with a d.r. of 11:1, we estimate that
the d.r. for the hydrosilylation of (E)-33 was 2.6–5.0:1.
[21] K. Tamao, T. Nakajima, R. Sumiya, H. Arai, N. Higuchi, Y. Ito,
J. Am. Chem. Soc. 1986, 108, 6090; K. Tamao, Y. Nakagawa, Y.
Ito, Org. Synth. 1996, 73, 94.
Received: March 24, 2009
Published online: June 3, 2009
Keywords: allenes · copper · diazo compounds · gold ·
.
total synthesis
[22] R. Pellicciari, R. Fringuelli, E. Sisani, M. Curini, J. Chem. Soc.
Perkin Trans. 1 1981, 2566.
[1] C. M. Liu, T. E. Hermann, J. Biol. Chem. 1978, 253, 5892; W. C.
Liu, D. S. Slusarchyk, G. Astle, W. H. Trejo, W. E. Brown, E.
Meyers, J. Antibiot. 1978, 31, 815.
[2] B. K. Toeplitz, A. I. Cohen, P. T. Funke, W. L. Parker, J. Z.
Gougoutas, J. Am. Chem. Soc. 1979, 101, 3344.
[3] Calcium Signaling, 2nd ed. (Ed.: J. W. Putney), CRC, Boca
Raton, 2006.
[23] There is precedent for the central!axial!central chirality
transfer in gold-catalyzed cycloisomerization of a-hydroxyal-
lenes to 2,5-dihydrofurans: J. Erdsack and N. Krause, Synthesis
2007, 3741, and references therein.
[24] A. Fꢃrstner, P. W. Davies, Angew. Chem. 2007, 119, 3478; Angew.
Chem. Int. Ed. 2007, 46, 3410.
[4] D. A. Evans, R. L. Dow, T. L. Shih, J. M. Takacs, R. Zahler,
J. Am. Chem. Soc. 1990, 112, 5290.
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