Catalytic site-selective thiocarbonylations and deoxygenations of vancomycin reveal hydroxyl-dependent conformational effects

Article abstract of DOI:10.1021/ja302692j

We have examined peptide-based catalysts for the site-selective thiocarbonylation of a protected form of vancomycin. Several catalysts were identified that either enhanced or altered the inherent selectivity profile exhibited by the substrate. Two catalysts, one identified through screening and another through rational design, were demonstrated to be effective on 0.50-g scale. Deoxygenations led ultimately to two new deoxy-vancomycin derivatives, and surprising conformational consequences of deoxygenation were revealed for one of the new compounds. These effects were mirrored in the biological activities of the new analogues and support a structural role for certain hydroxyls in the native structure.

Full text of DOI:10.1021/ja302692j

Article
pubs.acs.org/JACS
Catalytic Site-Selective Thiocarbonylations and Deoxygenations of
Vancomycin Reveal Hydroxyl-Dependent Conformational Effects
Brandon S. Fowler, Kai M. Laemmerhold, and Scott J. Miller*
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: We have examined peptide-based catalysts for the site-
selective thiocarbonylation of a protected form of vancomycin. Several
catalysts were identified that either enhanced or altered the inherent
selectivity profile exhibited by the substrate. Two catalysts, one identified
through screening and another through rational design, were demonstrated
to be effective on 0.50-g scale. Deoxygenations led ultimately to two new
deoxy-vancomycin derivatives, and surprising conformational consequences
of deoxygenation were revealed for one of the new compounds. These
effects were mirrored in the biological activities of the new analogues and
support a structural role for certain hydroxyls in the native structure.
INTRODUCTION
■
The selective alteration of complex, biologically active natural
products is a long-standing objective for chemists. The allure of
catalytic modification stems from the potential for one- or two-
step access to new, complex analogues that might provide
improved pharmacological properties. This potential is
particularly significant when the natural products are readily
accessible by fermentation. The identification of catalysts,
whether they are enzymes or synthetic catalysts, for selective
diversification of complex scaffolds represents a significant
chemical challenge. Our laboratory has been pursuing this goal
with peptide-based catalysts. To date we have identified
catalysts for the selective derivatization of polyols, including
selective acylations of simple sugars1 as well as erythromycin
and apoptolidin.2
Figure 1. Structure of vancomycin and its protected form, 2.
the possible biosynthetic significance of individual functional
groups, the deletion of which can cause significant perturbation
Site-selective deoxygenation has become an increasing focus
of our attention, given the appeal of interrogation of the
structure−activity relationships (SAR) that might be associated
with individual hydroxyl groups within a polyol. Hydroxyl
groups have been implicated in drug specificity, toxicity,
potency, and bioavailability.3 Furthermore, hydroxyls may be
targeted by drug-resistant organisms as sites of acylation or
phosphorylation for “deactivation” of the drug.4 Recent studies
from our group demonstrated the chemical capacity to remove
oxygen atoms in this sense in the context of simple sugars5 and,
more recently, in erythromycin A.6 We have now turned our
attention to the significantly more complex glycopeptide
antibiotics, including vancomycin (1; Figure 1). These studies
have culminated in strikingly selective catalysts for modification
of a minimally protected form of 1. Moreover, these studies
have revealed structural control elements within 1 that were
unexpected. In light of other observations in our laboratory, we
believe that site-selective catalysts may provide a general tool
for studying not only (a) selectivity issues in catalysis and (b)
SAR associated with individual hydroxyl groups, but also (c)
of a natural product’s native structure.
Vancomycin represents an important, complex scaffold that
plays a significant role in the treatment of infectious disease.
Analogues of vancomycin have been accessed through total
synthesis,7 enzymatic derivatization,8 and biosynthetic engi-
neering.9 Semisynthesis of vancomycin analogues has been
examined by many groups and, indeed, has led to important,
biologically active analogues.10 To our knowledge, systematic
studies of hydroxyl group deletions have not been reported for
1. We thus describe studies of this type and report catalyst-
dependent syntheses of two previously unknown deoxy-
vancomycins,11 their biological activity profiles, and intrigu-
ingly, unexpected aspects of their structure.
Received: March 20, 2012
Published: May 23, 2012
© 2012 American Chemical Society
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RESULTS AND DISCUSSION
■
Our studies began with the examination of catalyst-dependent
thiocarbonylation of vancomycin as a prelude to deoxygenation
through the venerable Barton−McCombie method.12 Previous
studies from our laboratory had shown that peptide-dependent
regioselectivity was possible in the selective manipulation of
simple sugar derivatives.5a As noted in Figure 2, regioselective
Figure 2. Peptide-catalyzed thiocarbonylation of diol 3.
thiocarbonylation of 3 could be achieved such that 4 or 5 could
be efficiently accessed in a catalyst and condition-dependent
fashion. Conventional deoxygenation of these compounds led
to the corresponding deoxy-sugars. Extrapolation of these
findings to vancomycin was then addressed. In order to apply
this method directly, we elected to initially pursue the selective
modification of a readily available vancomycin derivative.13 The
known alloc- and allyl-protected vancomycin derivative 2
(Figure 1, above) proved readily amenable to study.
Vancomycin derivative 2 retains six hydroxyl groups, relative
to the nine of 1, reducing the site-selectivity challenge
somewhat. Compound 2 also exhibits excellent solubility
properties in the organic solvents where the peptide-catalyzed
thiocarbonylation chemistry developed to date works best.
Vancomycin itself is readily available by fermentation,14 and
we prepared its protected analogue 2 on a 30-g scale. We were
then pleased to find that the conditions we had developed for
the selective thiocarbonylation of simple sugars proved quite
portable to the study of selective modification of 2. Figure 3
shows the results of our initial study. These conditions
provided a negligible background reaction in the absence of a
catalyst (entry 1). However, the achiral control catalyst N-
methylimidazole (NMI, 8) did result in modest rate
acceleration, yielding moderate conversion to a major and a
minor product, each of which we were able to isolate from the
reaction mixture.
The structures of the thionocarbonate products were
identified by NMR spectroscopy (Figure 4). Using an edited
HSQC experiment, we were able to observe clear changes in
the chemical shifts of modified sites, relative to the spectrum
recorded for 2 (Figure 4a). The faster-eluting peak was assigned
as the G6-thionocarbonate (6), while the slower-eluting peak
was assigned as the Z6-thionocarbonate (7). In Figure 4b, we
see a large change in the G6-methylene and smaller changes in
the G5- and G4-methines. Likewise, in Figure 4c, we see a large
change in the Z6-methine as well as smaller changes in the X6-
and X5-methines.15
Figure 3. Background and achiral catalyst control reactions of 2 under
the optimized conditions. (a) The reaction of 2 under the optimized
thiocarbonylation conditions. (b) Tabulated and raw HPLC data
revealing the product distributions observed when N-methylimidazole
(NMI, 8) is employed as a catalyst.
Figure 4. 1H−13C correlation with DEPT; methyls and methines
shown in red, methylenes shown in blue. (a) Partial HSQC spectrum
of 2. (b) Partial HSQC spectrum of 6 with 2 overlaid in gray. (c)
Partial HSQC spectrum of 7 with 2 overlaid in gray. HSQC =
heteronuclear single-quantum correlation. DEPT = distortionless
enhancement by polarization transfer.
approach, one of our initial catalyst screens examined a library
(25 members) of previously synthesized catalysts from
historical projects focused on enantioselective or regioselective
reactions of alcohols and amides.2c,16 Strikingly, from this small
test library, we found two catalysts, peptide 9 and peptide 10,
that could either reverse or enhance the product selectivity
observed with NMI (Figure 5). Peptide 9 and the enantiomer
of 10 have been reported previously for the enantioselective
phosphorylation of tribenzyl-myo-inositol.17 Peptide 9 provided
a clear reversal in selectivity, in comparison to the selectivity
exhibited by NMI, to give primarily the G6-thionocarbonate
Having established a sense of the inherent reactivity, we
evaluated peptide-based catalysts for perturbations in the
product ratio. We initiated two approaches to catalyst
discovery: one in which we would screen libraries of peptides,
and one in which we would design peptides based on the
natural binding site of vancomycin. Upon pursuing the first
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particular, we assessed the catalyst scaffold based on Lys-DAla-
DPmh. Our concept was that we might further enhance the
targeting of the glucosyl residue by this strategy.
We were initially concerned that the affinity of 2 for catalysts
based on the Lys-DAla-DAla motif might be too high to allow
for catalyst turnover. Thus, we examined these catalysts with a
full (100 mol %) loading (Figure 7). Despite the increase in
Figure 5. Tabulated and raw HPLC data revealing the product
distributions observed when catalysts 9, 10, and 11 were employed as
catalysts for the derivatization of 2.
(entry 1). Catalyst 10, on the other hand, enhanced the Z6-
selectivity afforded by NMI (entry 2). Moreover, both catalysts
were significantly more active than NMI. Peptide 11, which
differs from 10 by substituting the expensive DHyp(Ot-Bu)
amino acid with DPro, showed similar Z6-selectivity (entry 3).
While it is presently unclear exactly how these peptides interact
with 2, one can imagine various hydrogen-bonding schemes
that could lead to the site selectivity observed.
On the other hand, the interaction between vancomycin and
peptides that mimic its native binding site (the Lys-DAla-DAla
terminus of the Gram-positive bacterial peptidoglycan) is well-
known and has been observed in X-ray crystallographic (Figure
6a)18 and NMR studies.19 We hypothesized that this motif
could enhance our ability to control the site of thiocarbony-
lation with judicious localization of the catalytic alkylimidazole
moiety.20 We thus designed several catalysts based on
incorporation of the catalytic histidine residue, Pmh (π-
methylhistidine) in the D-form, as illustrated in Figure 6b. In
Figure 7. Tabulated and raw HPLC data revealing the product
distributions observed when Lys-DAla-DPmh catalysts 12−14 were
employed as catalysts for the derivatization of 2.
catalyst loading, the first two peptides we examined, with amide
and ester functionality at the C-terminal position (e.g., 12 and
13, entries 1−2), showed low conversions. In addition, the
slight selectivity that was observed favored the Z6-position,
contrary to our hypothesis (Figure 6b). However, maintaining
the C-terminal carboxylate that is critical to the biological
binding of vancomycin to the Lys-DAla-DAla motif proved
decisive. Thus, the organic soluble tetrabutylammonium salt 14
led to a dramatic increase in reactivity. Furthermore, selectivity
for the G6-thionocarbonate proved to be very high (entry 3).
Also of significant note, the reaction is very efficient with a 20
mol % catalyst loading (entry 4). Indeed, we found the reaction
proceeded to higher conversion while maintaining excellent
selectivity, allaying concerns about a possible lack of catalyst
turnover.21 Importantly, control experiments revealed that
tetrabutylammonium chloride is not a catalyst for the reaction.
A combination of equimolar tetrabutylammonium chloride and
NMI provided results that were essentially indistinguishable
from those observed with NMI alone. Moreover, reactions
catalyzed by peptide 14, performed in the presence of Cbz-
Lys(Cbz)-DAla-DAla/NBu4 as a putative competitive inhibitor
resulted in lower levels of conversion and selectivity.22
With selective catalysts 11 and 14 in hand, we wished to
assess their performance on a significant scale. These
experiments would set the stage for deoxygenation and
deprotection experiments. We were pleased to find that the
reactions proceeded with equivalent or better efficiency when
conducted on 0.50-g scale, as shown in Figure 8. While the
results for catalyst 14 were almost identical to the smaller-scale
Figure 6. (a) X-ray crystal structure of Ac-Lys(Ac)-DAla-DAla-O−
(yellow) bound to vancomycin (gray). (b) Proposed model for
delivery of phenyloxythiocarbonyl to the G6-hydroxyl by Cbz-
Lys(Cbz)-DAla-DPmh-O− (green). X-ray structure adapted from ref
18, PDB 1FVM.
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reaction, we observed a significant improvement in conversion
and selectivity for catalyst 11.
deoxy-vancomycin) and 16 (Z6-deoxy-vancomycin) were
obtained, each in five efficient steps from 1.
Preparative HPLC purification of deoxy-vancomycins 15 and
16 provided access to high-purity samples for structural
characterization and biological evaluation. G6-Deoxy-vancomy-
cin (15), perhaps unsurprisingly, revealed close analogy to
vancomycin structurally. As shown in Figure 10a, samples could
Figure 8. Tabulated and raw HPLC data revealing the product
distributions observed when catalysts 11 and 14 were employed as
catalysts for the derivatization of 2 on half-gram scale.
We then turned our attention to deoxygenation and
deprotection. We expected that the G6- (6) and Z6-
thionocarbonate (7) might require different conditions for
radical deoxygenation since 6 is a primary thionocarbonate
while 7 is benzylic. Under traditional Barton−McCombie
conditions,12 we observed complete reaction of the primary G6-
thionocarbonate at 80 °C, whereas the reduction of the
benzylic Z6-thionocarbonate proceeded at 70 °C (Figure 9).
Deoxygenation of 7 was also performed at room temperature
using BEt3/air as the radical initiator.23,24 Allyl- and alloc-
removal from the protected deoxy-vancomycins proceeded
smoothly under conditions similar to those in the litera-
ture.13b,25 Notably, HSnBu3 could be substituted with PhSiH3
without loss of reaction efficiency. Thus, compounds 15 (G6-
Figure 10. (a) HPLC trace of 15 after purification. (b) Partial HSQC
spectrum of 15.
be obtained in significant quantity and in high purity. NMR
analysis, exemplified by the HSQC spectrum in Figure 10b,
revealed a highly homogeneous structure, for which analogy to
the spectra of 1 itself was excellent.15
Z6-Deoxy-vancomycin (16) presented surprising differences
from 1 and 15. HPLC purification and LC/MS analysis of 16
consistently revealed the presence of two peaks (Figure 11a) of
equivalent mass. Moreover, isolation of the fast-eluting peak
and reinjection for HPLC analysis revealed the same doubling
of the peaks. Isolation and reinjection of the slow-eluting peak
produced an identical HPLC trace. These observations led us
to conclude that the Z6-deoxy-vancomycin (16) exists at room
temperature as a conformationally mobile species of at least two
interconverting states, in stark contrast to either 1 or 15. The
conformational heterogeneity was supported by NMR studies,
which revealed doubling of cross-peaks in the aromatic and α-
CH regions of the HSQC spectrum (e.g., Figure 11b).
The exact nature of the conformational equilibrium exhibited
by 16 is difficult to establish unambiguously. We have
considered several possibilities. Our first proposal, stimulated
by conformational studies of synthetic vancomycin fragments in
the literature,26 was that of possible atropisomerism about the
chloroarene ring-6 of 16 (Figure 12a). However, when 16 was
subjected to dechlorination conditions (Pd/C, H4N2, NH4OH,
MeOH/H2O),27 the HPLC trace exhibited by didechloro-Z6-
deoxy-vancomycin 17 retains its apparent conformational
heterogeneity (Figure 12b).
There are at least three other possibilities that one can
consider for the observed conformational equilibrium: (a) a cis-
Figure 9. Deoxygenation and deprotection of thionocarbonates 6 and
7 to yield the corresponding deoxy-vancomycins 15 and 16.
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Figure 11. (a) HPLC trace of 16 after purification. (b) Partial HSQC
spectrum of 16.
Figure 13. (a) cis/trans-Isomerization of the C5−W6 amide bond. (b)
syn/anti-Conformational change within the (5-6-7)-macrocycle about
the C6−W7 amide. (c) A proposed hydrogen bond that may rigidify
the syn/anti-isomer shown.
programming of native natural product conformations has
surfaced in our previous studies of catalytic polyol modification,
with analogous structural reorganizations of erythromycin upon
site-selective acylation of individual hydroxyl groups.2c,31
Of note, the conformational mobility of the Z6-deoxy-
vancomycin 16 appears to have biological consequences. The
minimum inhibitory concentrations (MICs) exhibited by 1 and
the new compounds were measured as an indicator of antibiotic
activity (Table 1). Interestingly, G6-deoxy-vancomycin (15)
Table 1. MIC Values for Deoxy-vancomycins 15 and 16
against Selected Bacterial Strains
Figure 12. (a) Proposed atropisomers about the chloroarene ring-6 of
16. (b) HPLC analysis of didechloro-Z6-deoxy-vancomycin (17).
a
,
b
c
d
e
f
entry cmpd MSSA
MRSA VSE
VRE (VanB) VRE (VanA)
1
2
3
1
0.5
0.5
2
1
1
4
2
2
8
16
16
>64
>64
>64
15
16
amide/trans-amide isomerization about the C5−W6 amide bond
(Figure 13a);28 (b) medium ring isomerization associated with
the allylic strain conformers induced by the C6−W7 amide bond
(Figure 13b);29 and (c) atropisomerization about the biaryl
moiety of the 5- and 7-arenes (not shown).30 Of course, these
issues could also operate simultaneously and synergistically.
What is remarkable about this observation of conformational
heterogeneity exhibited by 16 is that our catalytic studies have
unveiled conformational programming induced by the Z6-
hydroxyl in native vancomycin. Thus, its presence is not associated
with a simple SAR but carries with it significant conformational
consequences. Our current assessment of the role of the hydroxyl
is that it may form a hydrogen bond with the C6-amide
carbonyl, stabilizing the peptidoglycan-binding conformation,
as illustrated in Figure 13c (the OC −OZ distance is 3.2 Å in
>64
a
b
MIC values reported in μg/mL. MSSA = methicillin-susceptible
Staphylococcus aureus, ATCC 29213. MRSA = methicillin-resistant S.
aureus, ATCC 43300. VSE = vancomycin-susceptible enterococci,
ATCC 29212. VRE = vancomycin-resistant enterococci, ATCC
c
d
e
f
51299. MMX 486. See Supporting Information for additional details.
showed identical activity against all tested bacterial strains. Z6-
Deoxy-vancomycin (16), however, proved to be consistently
less active; this result likely reflects the conformational
heterogeneity and the differential activity (high and low)
associated with each interconverting structure.32
CONCLUSIONS
■
In summary, we have discovered site-selective catalysts that
allow hydroxyl group-selective thiocarbonylation of a minimally
protected version of 1. These catalysts ultimately allowed
6
6
the X-ray structure of vancomycin complexed with Ac-Lys(Ac)-
DAla-DAla).18 We also note in passing that this structural
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see: Haque, M. E.; Kikuchi, T.; Kanemitsu, K.; Tsuda, Y. Chem. Pharm.
Bull. 1987, 35, 1016−1029.
preparation of two deoxy-vancomycins that differ from 1 only
in that a singular oxygen atom is missing from either 15 or 16.
We have shown that two methods of catalyst discovery, library
screening and binding site-based design, are both viable
strategies to selective modification of natural product
derivatives. The prospects for generalizing this catalytic
approach seem encouraging, given the substantially divergent
site-selectivity exhibited by catalysts 11 and 14. The
observation of near total conformational homology between 1
and 15 is mirrored in their essentially indistinguishable
biological profiles. On the other hand, the removal of the O-
atom from the Z6-position of 1 revealed a pronounced
conformational role for the Z6-hydroxyl group. The biological
effects of reducing the inherent rigidity of 1 manifest in the
attenuated activity of 16 in the MIC assays. Perhaps most
notable, however, is the capacity of site-selective catalysis to
unveil conformational programming in complex structures,
perhaps encoded by biosynthesis,33 which we will now look for
in systematic ways.
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
scott.miller@yale.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Institutes of General Medical
Sciences of the National Institute of Health (GM-068649) for
support. K.M.L. was supported by a postdoctoral fellowship
from the German Academic Exchange Service (DAAD). We
also thank Dr. Bret E. Huff and Eli Lilly and Company for
providing samples of 1.
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(5) (a) Sanchez-Rosello, M.; Puchlopek, A. L. A.; Morgan, A. J.;
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(17) Intriguingly, catalysts 9 and ent-10 deliver, with high
enantioselectivity, inositol-1-phosphate and inositol-3-phosphate,
respectively. Correspondingly, 9 and 10 would both lead to
phosphorylation of the same position of tribenzyl-myo-inositol;
interestingly, however, these catalysts selectively thiocarbonylate
different sites of vancomycin. Sculimbrene, B. R.; Morgan, A. J.;
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(18) Nitanai, Y.; Kikuchi, T.; Kakoi, K.; Hanamaki, S.; Fujisawa, I.;
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(19) (a) Williams, D. H.; Maguire, A. J.; Tsuzuki, W.; Westwell, M. S.
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Recognit. 1997, 10, 73−87. Hawkes, G. E.; Molinari, H.; Singh, S. J.
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(f) Williams, D. H.; Williamson, M. P.; Butcher, D. W.; Hammond, S.
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(29) A similar conformational change has been proposed about the
C2-W3 amide at room temperature. This presumably becomes one
conformation upon hydrogen bonding with the DAla-DAla motif:
(a) Waltho, J. P.; Williams, D. H.; Stone, D. J. M.; Skelton, N. J. J. Am.
Chem. Soc. 1988, 110, 5638−5643. (b) Williams, D. H.; Waltho, J. P.
Biochem. Pharmacol. 1988, 37, 131−141. This conformational change
was also proposed for Z6-deoxy-teicoplanin: see reference 28d.
(30) For atropisomerization of the 5-7 biaryl in the related
semisynthetic glycopeptide, oritavancin: Zhou, C. C.; Stoner, E. J.;
Kristensen, E. W.; Stewart, K. D.; Rasmussen, R. R.; Hollis, L. S.;
Wittenberger, S. J.; Matayoshi, E. D.; Christesen, A. C.; Brill, G. M.
Tetrahedron 2004, 60, 10611−10618. For atropisomerization studies
in synthetic vancomycin precursors: see references 28b and 28c.
(31) Everett, J. R.; Hunt, E.; Tyler, J. W. J. Chem. Soc., Perkin Trans. 2
1991, 1481−1487.
(32) (a) Whether the attenuated biological activity is due to the
canonical binding of the vancomycin derivative to the DAla-DAla target
has not been established at this time. Analysis of the binding of Ac-
Lys(Ac)-DAla-DAla to vancomycin and the synthetic analogues reveals
high similarity between 1 and 15, and significant differences between 1
and 16, consistent with the differential biological activities. Please see
Supporting Information for the details. (b) For a pioneering study of
alternative mechanisms of action, see reference 10f.
(20) We recently applied a related strategy for targeting a peptide to
the binding site of vancomycin with the goal of inducing selective
bromination. See: Pathak, T. P.; Miller, S. J. J. Am. Chem. Soc. 2012,
134, 6120−6123.
(33) Walsh, C. T.; Fischbach, M. A. J. Am. Chem. Soc. 2010, 132,
2469−2493.
(21) We note that when catalyst 14 is applied to the attempted
thiocarbonylation of native 1 (i.e., without the protecting groups found
in 2) under phase-transfer conditions (pH = 7 phosphate buffer/
CH2Cl2/THF), a sluggish reaction results, presumably due to
competitive hydrolysis of the reagent under these conditions.
(22) Reactions catalyzed by peptide 14, as well as those catalyzed by
NMI, in the presence of Cbz-Lys(Cbz)-DAla-DAla/NBu4, are described
in the Supporting Information.
(23) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29,
6125−6126. See the Supporting Information for details.
(24) In general, alternative H-atom sources such as silanes or
dimethylphosphite led to sluggish reactions or no reaction at
temperatures up to 80 °C. (a) Barton, D. H. R.; Jang, D. O.;
Jaszberenyi, J. C. J. Org. Chem. 1993, 58, 6838−6842. (b) Barton, D.
H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron 1993, 49, 2793−
2804. (c) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron
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(25) (a) Dessolin, M.; Guillerez, M.-G.; Thieriet, N.; Guibe,
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F.;
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(26) For atropisomerization studies in synthetic vancomycin
precursors: (a) Boger, D. L.; Castle, S. L.; Miyazaki, S.; Wu, J. H.;
Beresis, R. T.; Loiseleur, O. J. Org. Chem. 1999, 64, 70−80. (b) Boger,
D. L.; Loiseleur, O.; Castle, S. L.; Beresis, R. T.; Wu, J. H. Bioorg. Med.
Chem. Lett. 1997, 7, 3199−3202. For related isomerization observed
in the rearranged vancomycin derivative CDP-I: (c) Harris, C. M.;
Kopecka, H.; Harris, T. M. J. Am. Chem. Soc. 1983, 105, 6915−6922.
(27) This procedure was derived from the following two precedents:
(a) Hoke, J. B.; Gramiccioni, G. A.; Balko, E. N. Appl. Catal., B 1992,
285−296. (b) Harris, C. M.; Kannan, R.; Kopecka, H.; Harris, T. M. J.
Am. Chem. Soc. 1985, 107, 6652−6658.
Information for details.
See the Supporting
(28) For amide isomerization in the vancomycin-type antibiotic, UK-
69542: (a) Skelton, N. J.; Williams, D. H.; Rance, M. J.; Ruddock, J. C.
J. Am. Chem. Soc. 1991, 113, 3757−3765. For amide isomerization
studies in synthetic vancomycin precursors: (b) Evans, D. A.;
Dinsmore, C. J.; Watson, P. S.; Wood, M. R.; Richardson, T. I.;
Trotter, B. W.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2704−2707.
(c) Evans, D. A.; Dinsmore, C. J. Tetrahedron Lett. 1993, 34, 6029−
6032. For the proposed amide isomerization in Z6-deoxy-teicoplanin
derivatives, see: (d) Malabarba, A.; Ciabatti, Kettenring, J.; Ferrari, P.;
Scotti, R.; Goldstein, B. P.; Denaro, M. J. Antibiot. 1994, 47, 1493−
1506.
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