Ruthenium-promoted diaryl ether synthesis in the construction of the F- O-G ring system of a teicoplanin model

Article abstract of DOI:10.1016/S0040-4039(00)00030-7

An end-game approach is described for the synthesis of glycopeptide antibiotics related to teicoplanin, using ruthenium-promoted diaryl ether formation, followed by cycloamidation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00030-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1671–1675
Ruthenium-promoted diaryl ether synthesis in the construction of
the F-O-G ring system of a teicoplanin model
Anthony J. Pearson ∗ and Philippe O. Belmont
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
Received 2 December 1999; accepted 22 December 1999
Abstract
An end-game approach is described for the synthesis of glycopeptide antibiotics related to teicoplanin, using
ruthenium-promoted diaryl ether formation, followed by cycloamidation. © 2000 Elsevier Science Ltd. All rights
reserved.
Considerable attention has been focused recently on synthesis of the vancomycin group of antibiotics,
as a result of their molecular complexity, which poses a significant challenge to the synthetic chemist,
as well as the emergence of vancomycin resistant strains of infectious bacteria.1 The development of
successful approaches to the total synthesis of these compounds can be expected to pave the way for
the design of analogs that might overcome bacterial resistance, and in this regard the recent syntheses of
vancomycin and its aglycone represent milestones toward such a goal.2 Our own efforts have focused on
methodology for the construction of the ristocetin (2) and teicoplanin (3) structures, which are somewhat
more complex than vancomycin owing to the presence of an extra aryl ether ring (F-O-G) as well as
two extra arylglycine residues. These particular amino acids are prone to base catalyzed racemization
under quite mild conditions, therefore placing extra demands on the methods for making the diaryl
ether units. We have recently described a ‘left-to-right’ strategy, indicated on structure 4, that is dictated
by a proclivity of the ring D residue to thermodynamically driven epimerization when this is present
as a carboxyl ester terminus.3 Such tendencies prohibit an alternate ‘right-to-left’ synthesis, and this
has also been recognized by Boger2c and Nicolaou.2b However, the ‘left-to-right’ approach requires an
efficient method for introducing the final F-O-G ring system onto an advanced intermediate of general
structure 4. Prior to embarking on the total synthesis of ristocetin A or teicoplanin, we considered it
essential to determine the feasibility of this undertaking. While we have previously shown that arene-
manganese chemistry can be used for the construction of similar F-O-G ring structures,4 this approach
is not applicable as an end-game of the type required. Alternate approaches to the synthesis of related
structures have been described by Chakraborty5 and Beugelmans6 but those methods have not been
utilized with the intact arylglycine subunits that are needed in the final product. This letter describes a
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00030-7
tetl 16310

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successful and efficient approach that we expect will be useful for building on the final peptido aryl ether
ring of teicoplanin, though the methodology is also appropriate for ristocetin.
In our previous studies on the construction of molecules that represent the C-O-D-O-E aryl ether rings
of ristocetin and teicoplanin, we showed that peptide coupling followed by intramolecular ether forma-
tion, promoted by complexation of the chlorophenylalanine residue with cyclopentadienylruthenium(+),
provided an efficient approach to the synthesis.3,7 This strategy has also been employed for the total
synthesis of similar cyclic peptido aryl ethers by Rich and co-workers, and by Krämer.8 Cycloetherifica-
tion leads to formation of the 16-membered ring 6 in good yield, whereas the alternative ring closure by
cycloamidation is highly problematic.7,9 On the other hand, construction of the 14-membered ring system
corresponding to the F-O-G linkage has been achieved by using either cycloamidation techniques,4,5 or
by cycloetherification.6 Therefore, we decided to study both of these strategies for the construction of
the F-O-G system in a manner that would be appropriate for its addition onto an advanced intermediate
of type 4.
The key building block for addition of the final F-O-G ring of teicoplanin or ristocetin, using
ruthenium-promoted aryl etherification, is the complex 11 (Scheme 1). This compound was readily
prepared in essentially quantitative yield from the protected amino acid 10, which itself was made (>98%

1673
e.e.) by using standard Evans asymmetric azidation technology.10 It should be noted that complex 11 is
quite stable and can be stored indefinitely in the refrigerator.
Scheme 1.
We first studied the use of 11 in a cycloetherification approach to the requisite F-O-G model system
(Scheme 2). The protected dipeptide 16 was prepared according to standard methodology, and was
obtained in stereochemically homogeneous form after chromatographic purification. Deprotection of 16
followed by peptide coupling with complex 11 afforded 17 but in low yields. The use of different coupling
reagents (EDCI, DCC, etc.) did not improve the situation, which we ascribe to increased steric hindrance
at the activated ester due to the neighboring arene-ruthenium system. Indeed, the same coupling between
deprotected 16 and the uncomplexed derivative 10 afforded the corresponding tripeptide in high yield
(ca. 80%), supporting this hypothesis. Attempted cycloetherification of 17, under a variety of conditions
that we have previously shown to effect cyclization of complexes such as 5, failed to produce the
desired material, instead giving multiple unidentified products. This situation was not unexpected, as
the benzylic proton on the arene-Ru system is now quite acidic, being flanked by an amide carbonyl
and the electron deficient arene-RuCp cation. On this basis we surmised that the source of the problem
lay in competing deprotonation of the G-ring residue in complex 17, and proceeded to investigate the
alternative etherification/cycloamidation approach in an effort to solve the problem.
Scheme 2.

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Reaction of 16 with 11, using potassium di-t-butylphenoxide (2.2 equiv.) as base in the presence of
18-crown-6 (THF solvent), afforded complex 18, which was directly demetallated under photochemical
conditions to afford 19 in 60% yield for two steps. The acidity of the benzylic proton on complex 11 is
not a problem for this coupling reaction, because its pKa is raised by the carboxylate anion that is formed
coincidentally. Removal of the Cbz protecting group, followed by cycloamidation using pentafluorophe-
nyl diphenylphosphinate (FDPP) as coupling reagent, to generate the active pentafluorophenyl ester in
situ,11 afforded the cyclized product 20 in 70% yield (Scheme 3).
Scheme 3.
Conclusions: We have shown in this paper that a convenient building block approach can be used
for the construction of the F-O-G peptido aryl ether ring system of ristocetin or teicoplanin molecules.
The final subunit for a ‘left-to-right’ strategy, complex 11, is readily prepared on a multigram scale,
and is easily stored and used when needed. While the amidation/cycloetherification approach, that has
been used for building the 16-membered rings such as 6, is problematic, the successful alternative is in
fact even more attractive from the standpoint of ruthenium chemistry, because the stoichiometric RuCp
system is retained for only one coupling step, and the ruthenium may be more efficiently recovered, as
Cp(CH3CN)3RuPF6, and recycled.
Acknowledgements
We are grateful to the National Institutes of Health for financial support of this research (GM-36925),
and to Penglie Zhang for preliminary experiments leading to this work. P.O.B. is grateful to the ARC,
Association pour la Recherche sur le Cancer, for partial personal financial support.
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