Stereoselective total synthesis of the ionophore antibiotic zincophorin

Article abstract of DOI:10.1002/anie.200460434

Acyclic stereocontrol is the basis of an original strategy adopted for the first, highly stereoselective total synthesis of the free acid zincophorin (1), a unique ionophore antibiotic. The stereoselective synthesis of the trisubstituted tetrahydropyran moiety and the construction of the eight contiguous stereogenic centers were key challenges in the synthesis.

Full text of DOI:10.1002/anie.200460434

Angewandte
Chemie
Natural Products Synthesis
Stereoselective Total Synthesis of the Ionophore
Antibiotic Zincophorin**
Kei Komatsu, Keiji Tanino, and Masaaki Miyashita*
The ionophore antibiotics, often polyethers and peptides, are
known to transport a specific metal ion or specific metal ions
through membranes in organisms.[1,2] Ionophore antibiotics
have also been shown to transport a specific metal cation by
forming a metal chelate. Zincophorin (1), isolated from a
strain of Streptomyces griseus, is a unique ionophore antibiotic
with a very high affinity for ZnII cations.[3,4] This affinity also
extends to MgII ions.[3,4] Several novel structural features of
zincophorin, as well as its strong antibacterial properties,
render this ionophore a worthy target for synthetic explora-
tion.[5] The Danishefsky group reported the first total syn-
thesis of zincophorin methyl ester based on a hetero-
[*] K. Komatsu, Dr. K. Tanino, Prof. Dr. M. Miyashita
Division of Chemistry, Graduate School of Science
Hokkaido University
060-0810 Sapporo (Japan)
Fax: (+81)11-706-4920
E-mail: miyasita@sci.hokudai.ac.jp
[**] Financial support from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan (a Grant-in-Aid for Scientific
Research (A) (No. 12304042) and a Grant-in-Aid for Scientific
Research on Priority Areas (A): “Exploitation of Multi-Element Cyclic
Molecules” (No. 13029003)) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460434
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Diels–Alder strategy,[6] and very recently Cossy and co-
workers also reported the successful synthesis of zincophorin
methyl ester.[7] However, the total synthesis of zincophorin (1)
itself has not been reported, probably because of the difficulty
in characterizing the free acid.[6]
We report herein the first and highly stereoselective total
synthesis of the free acid zincophorin based on our original
strategy of acyclic stereocontrol (Scheme 1). Retrosyntheti-
cally, zincophorin (1) was disconnected at the C15–C16 bond
and divided into the fragments 2, which contains a terminal
alkyl borane, and 3, with a trisubstituted double bond and a
terminal vinyl iodide. These two fragments could be con-
nected by a Suzuki coupling.[8] Fragment 2, which consists of
the 2,5,6-trisubstituted tetrahydropyran moiety and a poly-
propionate-derived chain, contains eight contiguous asym-
metric carbon atoms as well as two further stereogenic
centers. Thus, the stereoselective synthesis of the trisubsti-
tuted tetrahydropyran moiety and construction of the con-
tiguous stereogenic centers are the key points in the present
synthesis.
To prepare the requisite trisubstituted tetrahydropyran 4
highly stereoselectively, we designed a synthetic route via the
d-lactone 6. A stereospecific allylation reaction of the lactol 5
with a chiral allyl silane was envisaged. We planned to
construct the crucial intermediate 6 stereoselectively by an
SN2’ methylation reaction of the cis-epoxy unsaturated ester 8
to give 7, since it has been reported that a methylation of d-
lactones that bear an alkyl substituent at the C5 position
generally leads to a 1:1 mixture of stereoisomers.[9]
The trisubstituted tetrahydropyran 4 was synthesized
highly stereoselectively according to Scheme 2. Thus, (S)-3-
(triisopropylsilyloxy)-2-methylpropanol (9) was converted
into the expected Z unsaturated ethyl ester by a Swern
oxidation followed by a Horner–Emmons reaction with the
Scheme 1. Retrosynthetic analysis of zincophorin (1).
Scheme 2. Synthesis of the trisubstituted tetrahydropyran 4a: a) 1. Swern oxidation; 2. (o-CH3C6H4O)2P(O)CH2CO2Et, NaH, THF, ꢀ788C, 92%
(2 steps); 3. DIBAL-H, THF, ꢀ78!08C; 4. MCPBA, CH2Cl2, ꢀ78!ꢀ458C, 88% (2 steps); b) 1. Swern oxidation; 2. (iPrO)2P(O)CH2CO2Et, tBuOK,
THF, ꢀ788C, 84% (2 steps); c) Me2Zn–CuCN, DMF, 08C, 99% (a/g=97:3); d) 1. H2, PtO2, EtOH, room temperature; 2. Ti(OiPr)4, DMF, 1008C,
89% (2 steps); e) DIBAL-H, CH2Cl2, ꢀ788C, then Ac2O, pyridine, DMAP, ꢀ788C!RT, 97%; f) TiCl3(OiPr), CH2Cl2, ꢀ788C, 81%; g) TIPSOTf, 2,6-
lutidine, CH2Cl2, 08C, 100%. Bn=benzyl, DIBAL-H=diisobutylaluminium hydride, MCPBA=m-chloroperoxybenzoic acid, DMF=N,N-dimethyl-
formamide, DMAP=4-(dimethylamino)pyridine, RT=room temperature, TIPS=triisopropylsilyl, Tf=trifluoromethanesulfonyl.
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Ando reagent[10] in 92% yield (Z/E = 93:7). After reduction
of the ester with DIBAL-H, the resulting Z allylic alcohol was
oxidized stereoselectively with MCPBA to afford the b-epoxy
alcohol 10 (a/b = 7:93, 88% yield),[11] which was then trans-
formed into the epoxy unsaturated ester 8 by a Swern
oxidation followed by a Horner–Emmons reaction in 84%
yield from 10. The crucial SN2’ methylation reaction of 8
occurred highly stereoselectively in the presence of a new
Me2Zn–CuCN reagent in DMF recently discovered in our
laboratory,[12] to give the product of SN2’ methylation 7
quantitatively. The syn product was obtained exclusively in
this reaction and was readily converted into the key a-methyl-
d-lactone intermediate 6 by a two-step reaction sequence:
1) hydrogenation of the alkene double bond, and 2) lactoni-
zation with Ti(OiPr)4 in DMF. The lactone was transformed
routinely into the acetal 5 by reduction with DIBAL-H
followed by acetylation of the resulting lactol in a one-pot
operation.
The key allylation of 5 with the chiral allyl silane 11[13]
occurred stereospecifically in the presence of the Lewis acid
TiCl3(OiPr) in CH2Cl2 at ꢀ788C to give 4a and 4b, each as a
single stereoisomer, in 70 and 11% yield, respectively. The
latter compound was readily converted quantitatively into the
former by treatment with TIPSOTf. As expected, the
allylation reaction of 5 proceeded highly stereoselectively,
probably via the transition state 12 in which the double bond
of the oxonium ion derived from 5 and that of the allyl silane
occupy the favorable antiperiplanar conformation with max-
imum overlap of the p orbitals.[14]
Thus, the critical intermediate 4a with five stereogenic
centers was synthesized with complete stereoselectivity.
Compound 4a was then converted into the single a-epoxy
alcohol 13 by removal of the benzyl group followed by
asymmetric epoxidation (Scheme 3).[15] Upon the treatment
of 13 with the Gilman reagent,[11b] compound 14 with seven
stereogenic centers was obtained in 92% yield as the only
Scheme 3. Synthesis of 2: a) 1. Ca, NH3, THF, ꢀ788C; 2. Ti(OiPr)4, d-(ꢀ)-DIPT, TBHP, MS (4 Š), CH2Cl2, ꢀ238C, 89% (2 steps); b) Me2CuLi,
Et2O, ꢀ40!08C, 92%; c) 1. TESOTf, 2,6-lutidine, CH2Cl2, 08C; 2. Swern oxidation; 3. (iPrO)2P(O)CH2CO2Et, tBuOK, THF, ꢀ788C, 86% (3 steps);
d) 1. DIBAL-H, THF, ꢀ78!08C; 2. Ti(OiPr)4, d-(ꢀ)-DET, TBHP, MS (4 Š), CH2Cl2, ꢀ238C, 74% (2 steps), (a/b=5:95); e) 1. Swern oxidation;
2. (EtO)2P(O)CH2CO2Et, NaH, THF, 08C; 3. TBAF, THF, room temperature, 95% (3 steps); f) 1. Me3Al–D2O, CH2Cl2, ꢀ308C; 2. TESOTf, 2,6-luti-
dine, CH2Cl2, 08C, 77% (2 steps); g) 1. DIBAL-H, THF, ꢀ78!08C, 98%; 2. MCPBA, CH2Cl2, ꢀ78!08C, 88%; h) 1. PPh3, I2, imidazole, benzene,
room temperature; 2. BuLi, THF, ꢀ788C, 92% (2 steps); 3. TBSCl, DMAP, DMF, room temperature, 89%; i) 1. Swern oxidation; 2. NaClO2,
NaH2PO4, 2-methyl-2-butene, tBuOH, H2O, THF, room temperature, then TMSCHN2, CH2Cl2, room temperature, 56% (3 steps); j) 9-BBN, THF,
608C. DIPT=diisopropyl tartrate, TBHP=tert-butyl hydroperoxide, MS=molecular sieves, TES=triethylsilyl, DET=diethyl tartrate, TBAF=tetra-
butylammonium fluoride, TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl, 9-BBN=9-borabicyclo[3.3.1]nonane.
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product. It was transformed into the unsatu-
rated ester 15 by three-step reaction
a
sequence: 1) protection of the hydroxy groups
as TES ethers, 2) Swern oxidation by the Spur
protocol,[16] and 3) Horner–Emmons reaction,
in 86% overall yield. After the reduction of 15
with DIBAL-H, asymmetric epoxidation of the
resulting allylic alcohol furnished the epoxy
alcohol 16 stereoselectively. Compound 16 was
subjected to another Swern oxidation/Horner–
Emmons olefination sequence, followed by
removal of the silyl protecting groups with
TBAF, to afford the epoxy unsaturated ester 17
(95% for the three steps). The key methylation
reaction of 17 proceeded stereospecifically with
a Me3Al–water system[17] to give a single
product with nine asymmetric carbon atoms.
The treatment of this compound with TESOTf
then afforded 18 (77% yield over two steps).
When 18 was treated with DIBAL-H in THF
and then with MCPBA in CH2Cl2, the a-epoxy
alcohol 19 was obtained as a single product in
86% yield.[18]
Compound 19 was transformed in turn into
the terminal olefin 20 by a three-step reaction
sequence: 1) conversion into an epoxy iodide,
2) treatment with BuLi to give an allylic
alcohol,[19] and 3) protection of the secondary
alcohol with TBSCl (82% yield over three
steps). All that remained in the synthesis of
fragment 2 was the oxidation of the TES-
protected primary alcohol moiety to the car-
boxylic acid and subsequent hydroboration of
the terminal olefin. These transformations were
performed successfully by a Swern oxidation[16]
followed by NaClO2 oxidation of the resultant
aldehyde to the carboxylic acid, esterification
Scheme 4. Synthesis of 3 and total synthesis of zincophorin (1): a) 1. Swern oxidation;
2. CBr4, PPh3, pyridine, CH2Cl2, 08C, 91% (2 steps); b) Me2CuLi, Et2O, ꢀ788C, then I2,
=
ꢀ408C; c) 1. (E)-CH3(CH2)2CH CHZrCp2Cl, ZnBr2, [PdCl2(PPh3)2], DIBAL-H, THF,
room temperature; 2. HF, THF, room temperature, 39% from 22; d) MCPBA, CH2Cl2,
ꢀ60!ꢀ308C, (a/b=7:93); e) Me2CuLi, Et2O, ꢀ788C, 82% from 24; f) 1. TESOTf, 2,6-
lutidine, CH2Cl2, 08C, 96%; 2. HF–py, pyridine, THF, 08C, 84%; g) 1. Dess–Martin
periodinane; 2. CrCl2, CHI3, THF, 08C, 67% (2 steps); h) aqueous Cs2CO3, AsPh3,
[PdCl2(dppf)], THF, DMF, room temperature, 69%; i) TEAF, DMF, room temperature,
78%; j) LiOH, H2O, MeOH, THF, room temperature, then 1n HCl, 99%. py=pyridine,
dppf=1,1’-bis(diphenylphosphanyl)ferrocene, TEAF=tetraethylammonium fluoride.
with TMSCHN2 (56% for the three steps), and further
treatment of the product 21 with 9-BBN in THF. Thus,
fragment 2 with ten stereogenic centers was synthesized in a
straightforward and highly stereoselective manner by our
original strategy based on acyclic stereocontrol.
protection of the secondary hydroxy group in 26 with a TES
group in two steps, the product 27 was transformed into
fragment 3 by Dess–Martin oxidation followed by the Takai
reaction[23] in 67% yield.
With the segments 2 and 3 in hand, we had reached a
critical stage in the total synthesis: the coupling of the two
segments, removal of the protecting groups, and final
hydrolysis of the methyl ester moiety. The key Suzuki
coupling reaction[8,24] of 2 and 3 was performed under the
conditions given in Scheme 4 and resulted in the formation of
28 in 69% yield. The removal of the four silyl groups in 28
with tetraethylammonium fluoride (TEAF) in DMF afforded
zincophorin methyl ester (29) in 78% yield.
All spectral data of the synthetic compound 29 and its
optical rotation value ([a]2D6 = +22 (c = 0.64, CHCl3)) were
identical with those of the methyl ester derived from natural
zincophorin ([a]2D4 = +21 (c = 2.0, CHCl3)).[4] Finally, hydrol-
ysis of the methyl ester 29 with aqueous LiOH in MeOH and
THF, followed by acidification with 1n HCl, provided
zincophorin (1) in nearly quantitative yield.[25] The synthetic
compound (free acid) was identical in all respects with
naturally occurring zincophorin,[3] including spectroscopic
We next focused on the synthesis of fragment 3. Although
we presumed that the synthesis of 3 would be difficult because
of its densely functionalized stereostructure, we were able to
synthesize 3 in a straightforward fashion according to
Scheme 4. Thus, the dibromomethylene compound 22, readily
prepared from the same starting material 9 as used for the
synthesis of fragment 2, was treated with the Gilman reagent
in Et2O, and the Z vinyl copper species generated in situ was
quenched with iodine to give the Z vinyl iodide 23.[20]
A
Negishi coupling[21] with an (E)-1-pentenylzirconium reagent
then furnished the desired Z,E conjugated diene 24 (39%
yield over three steps). The homoallylic alcohol 24 was
oxidized with MCPBA to produce the b-epoxy alcohol 25
stereoselectively (a/b = 7:93). The key SN2’ methylation
reaction of 25 proceeded upon treatment with the Gilman
reagent[22] in a highly stereoselective manner to afford the syn
compound 26 as a single product in 82% yield from 24. After
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characteristics (1H and 13C NMR, IR, and mass spectra),
melting point (m.p. 65–698C; lit.:[3] m.p. 66–708C), and optical
rotation ([a]D24 = ꢀ1.9 (c = 0.59, CHCl3); lit.:[3] [a]2D5 = 0 (c =
1.0, CHCl3)).
In summary, we have reported the first, highly stereo-
selective total synthesis of zincophorin free acid through an
original strategy based on acyclic stereocontrol without the
use of aldol methodologies.
[21] a) E. Negishi, N. Okukado, A. O. King, D. E. Van Horn, B. I.
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[23] K. Takai, K. Nitta, K. Utimoto, J. Am. Chem. Soc. 1986, 108,
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[24] S. R. Chemler, D. Trauner, S. J. Danishefsky, Angew. Chem.
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[25] To isolate zincophorin free acid, it is essential to protonate the
lithium carboxylate by acidification and to isolate the resulting
carboxylic acid by extraction, as purification by column chro-
matography on silica gel gives an inseparable mixture of
zincophorin and zincophorin–metal (probably magnesium)
complexes.
Received: April 24, 2004 [Z460434]
Keywords: allylation · antibiotics · natural products ·
.
stereoselectivity · total synthesis
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