Synthesis of a model 22-membered AB-C-O-D ring of vancomycin containing biaryl and biaryl ether linkages

Article abstract of DOI:10.1016/S0040-4039(00)00046-0

Synthesis of a 22-membered macrocycle with an endo aryl-aryl ether linkage and a biaryl bond related to the AB-C-O-D ring of vancomycin is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00046-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1747–1751
Synthesis of a model 22-membered AB-C-O-D ring of
vancomycin containing biaryl and biaryl ether linkages
Luc Neuville, Michèle Bois-Choussy and Jieping Zhu ∗
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-Sur-Yvette, France
Received 15 November 1999; accepted 5 January 2000
Abstract
Synthesis of a 22-membered macrocycle with an endo aryl–aryl ether linkage and a biaryl bond related to the
AB-C-O-D ring of vancomycin is described. © 2000 Elsevier Science Ltd. All rights reserved.
Vancomycin 1 (Scheme 1), an eminent example of the glycopeptide antibiotics,1 has found extensive
clinical use over the last 40 years and is the drug of last resort for the treatment of infections due
to methicillin-resistant Staphylococcus aureus and other gram positive organisms in patients allergic
to β-lactam antibiotics.2 The recent emergence of vancomycin-resistant enterococci (VRE) has further
emphasized the importance of this field since an efficient therapeutic alternative has yet to be found.3
The complex molecular architecture of this class of natural products, their intriguing mode of action,
together with their important antibiotic activity have intrigued synthetic chemists for decades.4 Intensive
research has brought about three landmark total syntheses of the vancomycin aglycon.5–7 Having
developed syntheses of a bicyclic C-O-D-O-E model of vancomycin8 as well as of the tricyclic C-O-D-
O-E-F-O-G ring of teicoplanin9 based on an efficient cycloetherification methodology,10 we turned our
attention to the synthesis of the macrocycle with a biaryl linkage. Intramolecular oxidative coupling,11
nickel catalyzed intramolecular aryl–aryl coupling12 and macrolactamization13 have previously been
developed for the construction of the 12-membered AB ring of vancomycin. Our strategy, fundamentally
different from the previous studies, is outlined in Scheme 1. Instead of synthesizing the individual AB and
C-O-D rings sequentially, our plan calls for the construction of the 22-membered AB-C-O-D macrocycle
3 followed by a transannular cycloamidation leading to the bicyclic compound 2 in one operation. We
report in this letter our preliminary results concerning the synthesis of the AB-C-O-D macrocycle 3.
The synthesis of cyclization precursor is summarized in Scheme 2. The biaryl oxazoline 5,14 obtained
as a mixture of two atropisomers,15 was first transformed to the corresponding biaryl aldehyde 6. This was
realized in three consecutive steps without isolation of any intermediate. Thus, selective N-methylation
(MeI, Me2CO) of oxazoline, reduction of the transient oxazolinium (L-Selectride®) and hydrolysis
∗
Corresponding author. Fax: 33 1 69 82 31 31; e-mail: zhu@icsn.cnrs-gif.fr (J. Zhu)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00046-0
tetl 16326

1748
Scheme 1.
(oxalic acid) of the so-produced oxazolidine gave the aldehyde 6 in 70% overall yield. Reduction of
the aldehyde 6 to alcohol 7 (LiBH4) followed by reaction with DPPA in the presence of DBU gave the
azide 8.16 This latter reaction, specific for the benzylic alcohol, worked nicely provided that the reaction
was performed at a relatively high concentration (0.6 M) in toluene. Removal of the N-Boc function in
the azide 8 (HCl, MeCN) followed by coupling with 3-hydroxyphenylacetic acid (EDC, HOBt) afforded
the amide 9 in 80% overall yield. Hydrogenolysis of 9 in the presence of Lindlar’s catalyst in ethanol
gave the corresponding benzylamine which was coupled with L-N-Boc-4-fluoro-3-nitrophenyl alanine
(10)17 to give the compound 4 as an inseparable mixture of atropoisomers.
Scheme 2.
Using various cycloetherification conditions, compounds 4 failed to give the desired 22-membered

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macrocycles. Since the failure could result from the steric hindrance caused by the bulky pivaloyl residue,
this protecting group was removed under reductive conditions (LiBH4, Et2O–MeOH). After surveying
several reaction conditions, it appeared that heating a solution of 11 in THF (0.01 M) in the presence
of K2CO3 and crown ether 18-C-6 at 50°C afforded the desired AB-C-O-D ring as a two separable
atropostereomers 12 and 13 in 77% yield (Scheme 3). It has to be noted that the 22-membered macrocycle
is quite flexible and that no planar chirality was created around the biaryl ether linkage upon cyclization.
Scheme 3.
Problems were encountered in the attempted oxidation of the primary alcohol to a carboxylic acid.
After screening of various oxidation methods, the oxoammonium salt mediated oxidation using a couple
TEMPO–NaOCl was selected for further optimization.18 Chlorination of the electron-rich aromatic ring
(ring A) was found to be the major side reaction. However, when the reaction temperature was carefully
maintained between −5°C and 0°C, the desired acid 14 was obtained in good yield. Removal of N-Boc
residue under mild acidic conditions (HCl in MeCN) gave 3 in quantitative yield. Compound 13 was
converted into 16 in a similar fashion.
In order to determine the axial chirality of compounds 12 and 13, the N-Alloc derivatives 17 and 18
with a free hydroxy group on the A ring were prepared and their thermal equilibration was examined
(Scheme 4). Assuming that the most stable atropoisomer has the natural configuration as observed earlier
by Evans,11 the atropisomerism of 17 and 18, and hence of 12 and 13,19 was tentatively assigned as
shown. Due to the conformational flexibility of 17 and 18, we were unable to determine their axial
chirality from NOE studies.
Preliminary studies on the transannular cycloamidation of compounds 3 and 16 did not give the
expected bicyclic compounds; decomposition of the starting macrocycle was instead observed. In a
control experiment, we have successfully coupled 14 with L-alanine methyl ester to give compound

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Scheme 4.
19 in 80% yield (Scheme 5). This result was encouraging and warrants a more detailed survey of
cycloamidation conditions.
Scheme 5.
Acknowledgements
A doctoral fellowship from the MRES to L. Neuville is gratefully acknowledged.
References
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