Total Synthesis of Zincophorin Methyl Ester

Article abstract of DOI:10.1021/ol035177n

(Equation presented) A convergent total synthesis of the methyl ester of zincophorin, an ionophore antibiotic, has been realized relying on a diastereoselective titanium-mediated aldol coupling between the C1-C12 and C13-C25 subunits. The latter fragment

Full text of DOI:10.1021/ol035177n

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4037-4040
Total Synthesis of Zincophorin Methyl
Ester
Magali Defosseux, Nicolas Blanchard, Christophe Meyer,* and Janine Cossy*
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
christophe.meyer@espci.fr; janine.cossy@espci.fr
Received June 25, 2003
ABSTRACT
A convergent total synthesis of the methyl ester of zincophorin, an ionophore antibiotic, has been realized relying on a diastereoselective
titanium-mediated aldol coupling between the C1−C12 and C13−C25 subunits. The latter fragment was prepared by using a Carroll−Claisen
rearrangement.
Many naturally occurring polyoxygenated ionophores exhibit
useful antiinfectious properties due to their capacity to form
lipophilic complexes with various cations, which affects
proton-cation exchange processes across biological mem-
branes.1,2 In 1984, two independent reports described the
isolation of apparently the same new monocarboxylic acid
ionophore antibiotic from strains of Streptomyces griseus,
which on the basis of its exceptional high affinity for divalent
cations and especially zinc was given the trivial name
zincophorin (Scheme 1).3,4 Zincophorin exhibits good in vitro
activity against Gram-positive bacteria,3,4 and its methyl ester
also possesses antiviral activity, with reduced host cell
toxicity compared to the free acid.5 Although the preparation
of elaborated fragments of zincophorin has been reported,6-8
to date, only a single total synthesis has been completed by
Danishefsky’s group.6 Herein, we report a total synthesis of
zincophorin methyl ester 1 featuring new approaches toward
the preparation and the coupling of two subunits.
With the aim of performing a convergent synthesis of
zincophorin, a challenging goal involved the disconnection
of the carbon framework within the C9-C13 stereopentad
segment. As anti,anti-methyl-hydroxyl-methyl arrays have
Scheme 1. Structure of Zincophorin and Retrosynthetic
Disconnections
(1) Polyether Antibiotics; Westley, J. W., Ed.; Marcel Dekker: New
York, 1982; Vols. 1 and 2.
(2) Dobler, M. In Ionophores and their Structures; Wiley: New York,
1981.
(3) (a) Gra¨fe, U.; Schade, W.; Roth, M.; Radics, L.; Incze, M.; Ujszaszy,
K. J. Antibiot. 1984, 37, 836. (b) Radics, L. J. Chem. Soc., Chem. Commun.
1984, 599.
(4) Brooks, H. A.; Gardner, D.; Poyser, J. P.; King, T. J. J. Antibiot.
1984, 37, 1501.
(5) (a) Gra¨fe, U.; Tonew, E.; Schade, W.; Reinhardt, G.; Ha¨rtl, A. Ger.
(East) Patent DD 231 793, 1986. (b) Tonew, E.; Tonew, M.; Gra¨fe, U.;
Zopel, P. Pharmazie 1988, 43, 717.
10.1021/ol035177n CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/08/2003

been recognized to be the most difficult to synthesize,9 a
plausible disconnection was the C12-C13 bond, and in the
forward sense, its construction was envisaged by performing
an aldol condensation between the (Z)-enolate derived from
ethyl ketone 2 and aldehyde 3. The ethyl ketone 2 could be
prepared by an appropriate stereoselective chain exten-
sion of alcohol 4 incorporating the C1-C9 subunit of
zincophorin.8 On the other hand, the synthesis of aldehyde
3 was envisaged from the homopropargylic alcohol 5,
possessing the C18 and C19 stereocenters of zincophorin,
which can be prepared from (S)-ethyl lactate.10 Our synthetic
plan for aldehyde 3 relied on the introduction of the C13-
C15 three-carbon unit by alkylation of the terminal alkyne
moiety in 5, a stereoselective reduction of the triple bond
for the elaboration of the C16-C17 disubstituted (E)-alkene,
and a [3,3]-sigmatropic rearrangement for the creation of the
C20-C21 (E)-trisubstituted alkene, as well as the installation
of the C22 stereocenter with the requisite configuration
(Scheme 1).
Scheme 2. Synthesis of the C1-C12 Subunit of Zincophorina
a Reagents and conditions: (a) DMP, pyr, CH2Cl2; (b) (R)-8,
cat. Pd(OAc)2, PPh3, Et2Zn, THF, -30 °C; (c) H2, cat. Pd/BaSO4,
quinoleine, toluene; (d) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C;
(e) cat. OsO4, NMO, acetone-H2O; (f) NaIO4, THF-H2O; (g)
Et2CuLi, Et2O, -78 °C.
An efficient synthetic approach toward the C1-C9 subunit
4 has already been reported, in which an intramolecular
oxymercuration of a cyclopropanemethanol was used as a
key step for the elaboration of the oxygen heterocycle.8 The
transformation of alcohol 4 to ethyl ketone 2 was therefore
investigated and required the installation of two new stereo-
centers (C9 and C10), which was considered to be a
challenging task due to the anti,anti relative configuration
of the C8-C10 stereotriad.9
Oxidation of alcohol 4 with Dess-Martin periodinane
(DMP) afforded aldehyde 6 (100%), and the requisite C8-
C9 anti relative configuration suggested that the chain
extension using aldol, crotylmetal (or related reagents)
additions to aldehyde 6 had to involve a disfavored anti
Felkin-Anh transition state.7h,9,11 Among the reagents sur-
veyed, the chiral allenylzinc (P)-7 generated from the
mesylate (R)-8 of (R)-but-3-yn-2-ol was one of the most
efficient for this purpose.12 However the double asymmetric
condensation of (P)-7 with aldehyde 6, occurring in the
mismatched manifold, afforded a diastereomeric mixture of
three homopropargylic alcohols 9, 10, and 11 in a 80/12/8
ratio (Scheme 2).
the homopropargylic alcohol 9, with the partial hydrogenation
of the triple bond and the protection of the hydroxyl group
at C9 as a TBS ether to afford 12 (81%). This compound
was transformed to ethyl ketone 2 by using a four-step
sequence (68% overall yield) involving the dihydroxylation
of the double bond, the oxidative cleavage of the resulting
1,2-diol to the corresponding aldehyde, the addition of excess
lithium diethylcuprate, and subsequent oxidation of the
secondary alcohol (Schemes 1 and 2).
Having successfully completed the synthesis of the C1-
C12 subunit 2, we next investigated the preparation of the
C13-C25 subunit 3. The homopropargylic alcohol 5 was
easily accessible by addition of the chiral allenylzinc reagent
(M)-7 derived from the propargylic mesylate (S)-8 to
aldehyde 13 (derived from (S)-ethyl lactate).10 Protection of
the hydroxyl group of 5 as a MOM ether and alkylation of
the terminal alkyne with the benzyl ether of 3-bromopropanol
afforded the disubstituted alkyne 14 (86%). Deprotection of
the TBS protecting group and oxidation of the resulting
secondary alcohol with DMP gave the methyl ketone 15
(12) (a) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201.
(b) Marshall, J. A. Chem. ReV. 2000, 100, 3163.
The major diastereomer 9, which possesses the requisite
anti,anti relative configuration at C8-C10, was easily
separated and isolated in 63% yield.13-15 The synthesis of
the C1-C12 subunit of zincophorin was then pursued from
(13) Structural assignment of the minor diastereomer 10 was supported
by the fact that this compound was the only diastereomer generated
(dr > 96/4) when the enantiomeric chiral allenylzinc (M)-7 derived from
the mesylate (S)-8 was used as the nucleophile in the double-asymmetric
condensation with aldehyde 6, which occurs in the matched manifold. The
formation of 10 therefore arose from a partial racemization of the
allenylmetal reagent during the condensation with aldehyde 6.
(6) (a) Zelle, R. E.; DeNinno, M. P.; Selnick, H. G.; Danishefsky, S. J.
J. Am. Chem. Soc. 1986, 51, 5032. (b) Danishefsky, S. J.; Selnick, H. G.;
Zelle, R. E.; DeNinno, M. P. J. Am. Chem. Soc. 1988, 110, 4368.
(7) (a) Balestra, M.; Wittman, M. D.; Kallmerten, J. Tetrahedron Lett.
1988, 29, 6905. (b) Cywin, C. L.; Kallmerten, J. Tetrahedron Lett. 1993,
34, 1103. (c) Booysen, J. F.; Holzapfel, C. W. Synth. Commun. 1995, 25,
1473. (d) Burke, S. D.; Ng, R. A.; Morrison, J. A.; Alberti, M. J. J. Org.
Chem. 1998, 63, 3160. (e) Marshall, J. A.; Palovich, M. R. J. Org. Chem.
1998, 63, 3701. (f) Chemler, S. R.; Roush, W. R. J. Org. Chem. 1998, 63,
3800. (g) Guindon, Y.; Murtagh, L.; Caron, V.; Landry, S. R.; Jung, G.;
Bencheqroun, M.; Faucher, A.-M.; Gue´rin, B. J. Org. Chem. 2001, 66, 5427.
(h) Chemler, S. R.; Roush, W. R. J. Org. Chem. 2003, 68, 1319.
(8) Cossy, J.; Blanchard, N.; Defosseux, M.; Meyer, C. Angew. Chem.,
Int. Ed. 2002, 41, 2144.
(14) Condensation of aldehyde 6 with the chiral (E)-crotylcyclopenta-
dienyl-[(4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diphenylmethanolato]tita-
nium reagent15 also occurred in the mismatched manifold and afforded a
70/30 diastereomeric mixture of two homoallylic alcohols of anti relative
configuration at C9-C10 (52%). These two compounds were also
respectively obtained by partial hydrogenation of the homopropargylic
alcohols 9 and 10, respectively, thereby supporting their stereochemical
assignment. The relative configuration of the C8-C10 stereotriad in the
third minor diastereomer 11 was anticipated to be syn,syn, although this
was not unambiguously established. Indeed, syn homopropargylic alcohols
are obtained as minor diastereomers in allenylzinc additions to aldehydes.12
Addition of the chiral allenylzinc (P)-7 to aldehyde 6 according to a Felkin-
Anh transition state (substrate control) could explain the formation of 11.
(15) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321. (b) BouzBouz, S.;
Cossy, J. Org. Lett. 2001, 3, 3995.
(9) (a) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489.
(b) Hoffmann, R. W. Synthesis 1994, 629.
(10) Marshall, J. A.; Chobanian, H. R. J. Org. Chem. 2000, 65, 8357.
(11) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191.
4038
Org. Lett., Vol. 5, No. 22, 2003

(92%). The Cram-chelated addition11 of (Z)-prop-1-enyl-
magnesium bromide to ketone 15 afforded the tertiary alcohol
16 (93%, 9/1 diastereomeric mixture at C20).
rt) to produce the corresponding alcohol 20 (85%). Due to
the presence of a homopropargylic hydroxyl group at C19,
the triple bond in 20 was slowly but efficiently hydro-
aluminated with LiAlH4 in refluxing THF to elaborate the
(E)-disubstituted C16-C17 double bond of compound 21
(61%). The hydroxyl group at C19 was reprotected as a TBS
ether and the benzyl protecting group at C13 was removed
by a Birch reduction. The primary alcohol was subsequently
oxidized with DMP, thereby affording aldehyde 3 (64%) and
concluding the synthesis of the C13-C25 subunit (Schemes
1 and 3).
Whereas this hindered tertiary alcohol failed to be acetyl-
ated under a variety of conditions, ruling out the possibility
of performing a subsequent Ireland-Claisen rearrangement,16
reaction with diketene in the presence of a catalytic amount
of DMAP proceeded smoothly to afford the â-ketoester 17
(88%), and the diastereomers at C20 were easily separated
at this stage. This result led us to investigate the possible
use of the Carroll version of the [3,3]-Claisen sigmatropic
rearrangement16,17 in order to perform the carbon chain
extension and control the configurations of the C22 stereo-
center and the C20-C21 trisubstituted alkene. Among the
different reaction conditions tested, only the adsorption of
the â-ketoester 17 on neutral alumina, followed by heating
at 60 °C,18 was successful at promoting the Carroll-Claisen
rearrangement of 17 and afforded the unsaturated ketone 18
(72%) with high stereoselectivity (E/Z ) 96/4, geometric
isomers easily separated) and complete chirality transfer at
C22 (Scheme 3).19,20
The coupling of ethyl ketone 2 and aldehyde 3 was next
attempted (Scheme 4).
Scheme 4. Total Synthesis of Zincophorin Methyl Estera
Scheme 3. Synthesis of the C13-C25 Subunit of
Zincophorina
a Reagents and conditions: (a) TiCl4, i-Pr2NEt, CH2Cl2, -78 °C,
then add 3, -78 °C; (b) NaBH4, MeOH, 0 °C; (c) HF‚pyr, THF.
On the basis of literature precedents, the stereochemical
outcome of the aldol condensation between the (Z)-titanium
enolate21 of 2 and aldehyde 3 lacking R and â stereocenters
was anticipated to be exclusively controlled by the config-
uration of the methyl-substituted C10 stereocenter.22 Ac-
cordingly, the (Z)-titanium enolate of ethyl ketone 2 was
(16) (a) Ziegler, F. E. Chem. ReV. 1988, 88, 1423. (b) Frauenrath, H. In
Houben Weyl (Methods of Organic Chemistry), StereoselectiVe Synthesis;
Helmchen, G. Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme-
Verlag: Stuttgart, 1995; Vol. E21d, p 3301.
(17) (a) Wilson, S. R.; Price, M. F. J. Org. Chem. 1984, 49, 722. (b)
Enders, D.; Knopp, M.; Runsink, J.; Raabe, G. Angew. Chem, Int. Ed. Engl.
1995, 34, 2278 and references therein. (c) Hatcher, M. A.; Posner, G. H.
Tetrahedron Lett. 2002, 43, 5009.
(18) Pogrebnoi, S. I.; Kalyan, Y. B.; Krimer, M. Z.; Smit, W. A.
Tetrahedron Lett. 1987, 28, 4893.
(19) This result could be explained on the basis of the well-established
preference for the [3,3]-sigmatropic rearrangements to proceed through a
chairlike transition state (acyclic series),16 in which the bulkier branched
carbon chain, rather than the methyl group, should preferentially occupy
the less congested equatorial position (Scheme 3).
(20) Carroll rearrangement of the related tertiary allylic â-ketoester 23,
which affords ketone 24 as the major stereomer, has also been studied as
a model. Ozonolysis of 24 led to the known (S)-keto aldehyde 25
(unpublished results).
a Reagents and conditions: (a) MOMCl, i-Pr2NEt, CH2Cl2; (b)
n-BuLi, THF, -78 °C then RBr, HMPA, -78 °C to room
temperature; (c) TBAF, THF; (d) DMP, pyr, CH2Cl2; (e) (Z)-prop-
1-enylMgBr, MgBr2‚OEt2, Et2O-THF, -78 °C; (f) diketene, cat.
DMAP, THF; (g) neutral Al2O3, 60 °C; (h) DIBAL-H, Et2O,
-78 °C; (i) MsCl, i-Pr2NEt, CH2Cl2, 0 °C; (j) LiAlH4, THF, reflux;
(k) p-TsOH, MeOH; (l) TBSOTf, 2,6-lutidine, CH2Cl2, -78 °C;
(m) Li, liq. NH3, THF-t-BuOH, -78 °C. R ) (CH2)3OBn.
The removal of the carbonyl group at C24 was ac-
complished by reducing ketone 18 to the secondary alcohol,
formation of the mesylate, and subsequent reduction with
LiAlH4 to give compound 19 (86%). Since the deprotection
of the hydroxyl group at C19 later in the synthesis turned
out to be difficult, the troublesome methoxymethyl protecting
group was cleanly cleaved at this stage (p-TsOH, MeOH,
(21) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047.
(22) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem.
Soc. 1995, 117, 9073 and references therein.
Org. Lett., Vol. 5, No. 22, 2003
4039

generated in the standard manner21,22 and its condensation
with aldehyde 3 afforded aldol 22 (70%) with high dia-
stereoselectivity (dr > 96/4). The diastereoselective reduction
of the carbonyl group in compound 22 could be conveniently
carried out by simply using NaBH4 in methanol, and
subsequent final cleavage of the TBS protecting groups of
the alcohol moieties at C9 and C19 afforded zincophorin
methyl ester 1 (66% yield from 22), whose analytical and
spectroscopic data such as Rf in two solvent systems,5 IR,5,6
1H NMR spectra,6 and [R]D +21.3 (c 0.4, CHCl3) were in
perfect agreement with those previously reported in the
literature ([R]D +22.4 (c 0.89, CHCl3);6 authentic sample,
[R]D +20.9 (c 2.0, CHCl3)1,6). Although zincophorin could
be in principle generated from its methylester by saponifica-
tion, characterization of the metal salt-free acid was claimed
to be difficult and this compound was therefore treated with
CH2N2 to afford 1.6
of a tertiary allylic â-ketoester, and a chain extension of the
previously synthesized C1-C9 fragment8 was performed by
using an allenylzinc-aldehyde condensation to produce the
C1-C12 fragment. Moreover, the synthetic plan used for
the elaboration of the C13-C25 subunit (intermediacy of
ketone 18) should also enable access to the antibiotic
CP-78,545, the related C24-C25 unsaturated analogue of
zincophorin.23
Acknowledgment. M.D. and N.B. thank the MRES for
a grant.
Supporting Information Available: Characterization
data for compounds 1-3, 9, 18, and 22, experimental
procedures for the synthesis of compounds 1 and 22, and
copies of the NMR spectra of 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have reported a convergent total
synthesis of zincophorin methyl ester relying on a dia-
stereoselective titanium-mediated aldol coupling between the
C1-C12 and C13-C25 subunits. The latter fragment was
prepared by a stereoselective Carroll-Claisen rearrangement
OL035177N
(23) Dirlam, J. P.; Belton, A. M.; Chang, S. P.; Cullen, W. P.; Huang,
L. H.; Kojima, Y.; Maeda, H.; Nishiyama, S.; Oscarson, J. R.; Sakakibara,
T. J. Antibiot. 1989, 42, 1213.
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Org. Lett., Vol. 5, No. 22, 2003