Solid- and solution-phase synthesis of vancomycin and vancomycin analogues with activity against vancomycin-resistant bacteria

Article abstract of DOI:10.1002/1521-3765(20010903)7:17<3798::AID-CHEM3798>3.0.CO;2-6

Vancomycin, the prototypical member of the glycopeptide family of antibiotics, is a clinically used antibiotic employed against a variety of drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA). The recent emergence of vancomycin resistance, viewed as a growing threat to public health, prompted us to initiate a program aimed at restoring the potency of this important antibiotic through chemical manipulation of the vancomycin structure. Herein, we describe the development of synthetic technology based on the design of a novel selenium safety catch linker, application of this technology to a solid-phase semisynthesis of vancomycin, and the solid- and solution-phase synthesis of vancomycin libraries. Biological evaluation of these compound libraries led to the identification of a number of in vitro highly potent antibacterial agents effective against vancomycin-resistant bacteria. In addition to aiding these investigations, the solid-phase chemistry described herein is expected to enhance the power of combinatorial chemistry and facilitate chemical biology and medicinal chemistry studies.

Full text of DOI:10.1002/1521-3765(20010903)7:17<3798::AID-CHEM3798>3.0.CO;2-6

FULL PAPER
Solid- and Solution-Phase Synthesis of Vancomycin and Vancomycin
Analogues with Activity against Vancomycin-Resistant Bacteria
K. C. Nicolaou,*[a] Suk Young Cho,[a] Robert Hughes,[a] Nicolas Winssinger,[a]
Christian Smethurst,[a] Harald Labischinski,[b] and Rainer Endermann[b]
Abstract: Vancomycin, the prototypical
member of the glycopeptide family of
antibiotics, is a clinically used antibiotic
employed against a variety of drug-
resistant bacterial strains including meth-
icillin-resistant Staphylococcus aureus
(MRSA). The recent emergence of van-
comycin resistance, viewed as a growing
threat to public health, prompted us to
initiate a program aimed at restoring the
potency of this important antibiotic
through chemical manipulation of the
vancomycin structure. Herein, we de-
scribe the development of synthetic
technology based on the design of a
novel selenium safety catch linker, ap-
plication of this technology to a solid-
phase semisynthesis of vancomycin, and
the solid- and solution-phase synthesis
of vancomycin libraries. Biological eval-
uation of these compound libraries led
to the identification of a number of in
vitro highly potent antibacterial agents
effective against vancomycin-resistant
bacteria. In addition to aiding these
investigations, the solid-phase chemistry
described herein is expected to enhance
the power of combinatorial chemistry
and facilitate chemical biology and me-
dicinal chemistry studies.
Keywords: antibiotics
´ biological
evaluation ´ combinatorial synthesis
´ synthesis design ´ vancomycin
Introduction
OH
HO
HO
H2N
Vancomycin[1] (1, Figure 1), the prototypical member of the
glycopeptide class[2] of antibiotics, has been clinically used for
the past 40 years to treat infection by Gram-positive bacteria.
Its utility against methicillin-resistant Staphylococcus aureus
(MRSA) has made it the drug of last resort for the treatment
of this scourge.[3] However, the recent emergence of vanco-
mycin-resistant Enterococci (VRE)[4] and vancomycin-inter-
mediate resistant Staphylococcus aureus (VISA)[5] is raising
serious public health concerns.[6] Accordingly, there is cur-
rently a vigorous effort to develop novel antibacterial drugs
with activity against VRE and VISA.[7±9] Vancomycinꢀs
OH
O
vancosamine
glucose
O
O
O
Cl
O
O
O
OH
HO
Cl
H
O
H
N
O
H
H
NMe
N
N
N
N
H
H
H
O
O
O
H
O
NH
O
HO
NH2
OH
[a] Prof. Dr. K. C. Nicolaou, Dr. S. Y. Cho, R. Hughes, Dr. N. Winssinger,
Dr. C. Smethurst
amino acid one
OH
HO
Department of Chemistry
1 : vancomycin
Figure 1. Chemical structure of vancomycin (1).
and The Skaggs Institute for Chemical Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037 (USA)
and
antibacterial activity stems from its ability to inhibit bacterial
cell-wall peptidoglycan biosynthesis. Specifically, vancomycin
binds to the terminal d-Ala-d-Ala fragment of the immature
cell wall through an intricate network of five hydrogen bonds
(Figure 2), and thereby inhibits cell wall construction.[10] This
inhibition eventually leads to bacterial death due to the
weakened cell wallꢀs loss of ability to withstand high osmotic
pressure. Vancomycin resistance (van A and van B) is pri-
marily conferred through the mutation of the terminal d-Ala-
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, California 92093 (USA)
Fax : (‡1)858784-2469
E-mail: kcn@scripps.edu
[b] Dr. H. Labischinski, Dr. R. Endermann
Bayer AG, PH-R-Antiinfectives, 42096 Wuppertal (Germany)
Supporting information for this article is available on the WWW under
http://www.wiley-vch.de/home/chemistry/ or from the author.
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3798±3823
d-Ala to a terminal d-Ala-d-Lac.[11] This structural change
results in the loss of one hydrogen bond from the vancomycin/
peptide complex (Figure 2), thereby decreasing vancomycinꢀs
affinity for the cell-wall by a thousand-fold, and, as a
consequence, rendering the antibiotic ineffective against such
mutants.
particularly against drug-resistant strains. However, there has
been little modification of the constitution of the sugar
moieties themselves. The absence of such studies is undoubt-
edly due to the synthetic challenges associated with modifying
these domains of the molecule; although, some progress has
been made toward this goal by coaching the biosynthetic
machinery of the producing organism to produce certain
modified analogues.[19] Enabled by our recent total synthesis
of vancomycin,[20, 21] we decided to pursue the design and
construction of such vancomycin variants. We reasoned that a
solid-phase semisynthesis of vancomycin could even further
facilitate the construction of compound libraries for biological
screening, and therefore, considered such an endeavor.
Despite the recent advances in the area of solid-phase
synthesis of natural products, the highly complex nature of
the vancomycin molecule necessitated the development of
In contemplating new weapons against bacteria, several
strategies may be considered to reinstate the antibacterial
activity of vancomycin against VRE and VISA. One of the
most obvious tactics to potentially accomplish this goal would
be to modify the binding surface between vancomycin and its
ligand within the cell wall. Attractive as it may seem the re-
engineering of the binding pocket of vancomycin through a
systematic replacement of internal amino acids, its imple-
mentation, appears at present as synthetically complex,
although a number of attempts along these lines have been
made.[12±14] A second, more practical approach to restoring
antibacterial activity to vancomycin-type structures has been
explored by scientists at Eli Lilly[15] and rationalized by
Williams.[16] Specifically, it was recognized that peripheral
modification of the vancomycin core (particularly at the
N-terminal d-LeuNMe residue, and more so at the vancos-
amine nitrogen) could enhance the antibioticꢀs activity against
VRE. Specifically, it was observed that lypophilic anchors
such as those present on the naturally occurring glycopeptide
antibiotic teicoplanin[17] facilitate the delivery of the molecule
at its site of action within the cell wall and thus improve its
effectiveness against bacteria. A third approach for restoring
and enhancing the antibacterial activity of vancomycin is
through covalent dimerization, a strategy that will be further
discussed in the following article.[18]
new chemistry applicable to the problem at hand.[22]
A
practical solid-phase semisynthesis of vancomycin, therefore,
became our initial objective.[23]
Solid-phase semisynthesis of vancomycin: Cognizant that the
appropriate choice of linking[24] and protecting group strat-
egies would be crucial for the success of a solid-phase
semisynthesis of vancomycin and analogues thereof, we
decided, by analogy to our solution-phase synthesis of
vancomycin, to employ persilylation as a means of protection
and chose to link vancomycin to the solid phase through its
C-terminus. The next issue we addressed was the nature of the
linker itself. Requirements of such a linker included both acid
and base stability, cleavage under mild conditions, and
compatibility with silicon protecting groups. In principle, the
photocleavable resin linkers 2 and 3[25] (Figure 3) met these
stringent criteria. However, while protected vancomycin,
prepared as shown in Scheme 1, was readily loaded onto
resin 2, through Mitsunobu reaction, cleavage of the substrate
could not be effected. Conversely, resin 3 could only be loaded
Results and Discussion
As mentioned above peripheral modification of vancomycin
can lead to striking improvements in antibacterial activity,
Figure 2. The hydrogen-bond network between vancomycin (dark structure) and the tripeptide l-Lys-d-Ala-d-Ala in ChemDraw format (left) and as a wire
frame representation (center). The diagram on the right depicts the hydrogen-bond network between vancomycin and l-Lys-d-Ala-d-Lac.
Chem. Eur. J. 2001, 7, No. 17
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K. C. Nicolaou et al.
FULL PAPER
thesis, or alkylation reactions, respectively (see Scheme 1,
insert). Importantly, vancomycin derivatives could be cleaved
easily from all of the allyl resins upon exposure to palla-
dium(0)-mediated allyl transfer conditions {[Pd(PPh3)4],
nBu3SnH}. Unfortunately, as events transpired during the
solid-phase synthesis, problems with all three linkers, 6 ± 8,
emerged along the charted solid-phase sequence. Specifically,
after the glycosidation procedure which required Lewis acidic
conditions (BF3 ´ Et2O), the vancomycin-loaded resins 9 and
10 (Scheme 1) suffered from low cleavage efficiency, a fact
attributed to a presumed [3,3]-sigmatropic rearrangement[27]
as depicted in Figure 4. It was after several unsuccessful
attempts to reverse this latter reaction or to otherwise
improve the cleavage yield that we turned to acrylate linker,
8, and the corresponding vancomycin-loaded resin 11
(Scheme 1). In this case the trouble-causing [3,3]-sigmatropic
rearrangement was expected to be electronically disfavored,
NO2
NO2 Me
OH
OH
OMe
2
3
Figure 3. Photolabile linkers that failed to solve the vancomycin linker
problem.
with a suitable vancomycin scaffold in low yield, presumably
due to increased steric congestion. Unable to reach an
acceptable compromise between loading and cleavage con-
ditions, we turned our attention to the allyl linkers 6, 7, and 8
(Scheme 1).[26] Onto all three resins (6 ± 8) a suitably protected
vancomycin derivative could be efficiently loaded under mild
conditions employing either Mitsunobu, olefin cross-meta-
OTBS
OTBS
TBSO
CbzHN
TBSO
TBSO
CbzHN
TBSO
OTBS
OTBS
O
O
O
O
O
O
O
O
O
O
Cl
Cl
linker
O
O
O
O
OTBS
O
[see insert]
OTBS
O
TBSO
Cl
TBSO
Cl
Cbz
Cbz
O
H
H
O
H
H
N
H
H
N
N
NMe
N
NMe
N
N
g. [Pd(PPh3)4] (cat.),
nBu3SnH
(>90 %)
N
N
H
N
N
H
H
H
H
H
O
O
O
H
O
O
O
O
H
O
NH
O
X
NH
O
HO
Y
O
NH2
NH2
OTBS
OTBS
OTBS
OTBS
O
TBSO
TBSO
9 - 11
4
HO
protected
vancomycin
a. TBSOTf, 2,6-lut.
b. Cbz-Cl, NaHCO3
O
OH
O
O
(52 % for two steps)
6
HO
c. DEAD, Ph3P
(66 %)
protected
vancomycin
O
O
protected
vancomycin
4
OH
9
HO
H2N
HO
f. allylBr,
CsCO3
OH
O
O
(97 %)
O
O
O
7
O
O
Cl
d. [(Cy3P)2Cl2RuCHPh]
(60 %)
O
O
O
O
O
protected
vancomycin
protected
vancomycin
5
10
11
OH
HO
Cl
H
O
O
O
H
N
H
H
NMe
N
N
N
H
N
O
H
H
O
O
H
O
N
H
OMs
O
O
O
O
NH
O
8
HO
N
O
HO
NH2
e. NaHCO3
protected
vancomycin
protected
vancomycin
H
OH
OH
(72 %)
4
HO
1: vancomycin
Scheme 1. Loading of vancomycin onto a variety of allyl ester resins. a) TBSOTf (excess), 2,6-lut. (120 equiv), CH2Cl2/DMF 10:1, 238C, sonication, 8 h;
b) Cbz-Cl (5.0 equiv), NaHCO3 (10.0 equiv), 1,4-dioxane/H2O 3:1, 238C, 3 h, 52% over two steps; c) 6 (7.0 equiv), DEAD (7.0 equiv), Ph3P (7.0 equiv), THF,
158C, 1.5 h, 66%; d) 7 (10.0 equiv), [(Cy3P)2Cl2RuCHPh] (2  0.1 equiv), benzene, 658C, 15 h, 60%; e) 8 (4.0 equiv), NaHCO3 (10.0 equiv), 4 Š MS, 238C
(vacuum), 0.5 h; then 658C, 18 h, 72%; f) allylBr (10.0 equiv), NaHCO3 (10.0 equiv), 4 Š MS, DMF, 238C (vacuum), 0.5 h; then 8 h, 97%; g) [Pd(PPh3)4]
(0.1 equiv), nBu3SnH (4.0 equiv), CH2Cl2, 0.5 h, 94%. Cbz ˆ benzyloxycarbonyl, Cy ˆ cyclohexyl, DEAD ˆ diethyl azodicarboxylate, DMF ˆ N,N'-
dimethylformamide, 2-6-lut. ˆ 2-6-lutidine, Ms ˆ methanesulfonyl, TBS ˆ tert-butyldimethylsilyl.
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Synthesis of Vancomycin
3798±3823
allyl and pro-alloc resins. Thus,
loading of resin 14 or resin 15 with
4-bromobenzoate in the presence of
Cs2CO3 or DCC, respectively,
and subsequent cleavage with H2O2
and removal of the allyl group with
polymer-bound tin hydride[22k, 29]
O
Lewis acid
O
O
O
O
protected
[3.3]-sigmatropic
rearrangement
vancomycin
protected
vancomycin
9 [10]
12
O
O
O
and
catalytic
amounts
of
Nu
N
H
O
N
H
Nu
protected
vancomycin
[Pd(PPh3)4] gave 17 in 83% overall
yield. The use of polymer-bound tin
hydride instead of a soluble source
of nBu3SnH facilitates the removal
of tin by-products as required for
reliable biological assays. In a sim-
ilar manner, pro-alloc resin was
loaded with 4-iodobenzyl alcohol
Nu
11
+
O
HO
protected
vancomycin
4
Figure 4. Presumed side reactions of allyl linkers 9, 10, and 11.
and indeed the cleavage efficiency from the resin was not
diminished after glycosidation. However, during further
manipulation, this allylic acrylate resin was found to suffer
premature cleavage, presumably due to nucleophilic addition
to the acrylate moiety as rationalized in Figure 4. Reluctantly,
we were forced, at this juncture, to conclude that despite the
efficient loading and cleavage protocols offered by these
novel allyl and acrylate resins, they were not appropriate for
the solid-phase semisynthesis of vancomycin.
In searching for a solution to this problem, it occurred to us
that a facile oxidation/elimination sequence involving the
recently described phenylselenenyl resin[28] could be adopted
to design a masked allyl group (see Figure 5). This pro-allyl
a. LiBH4;
I
Se
I
I
14
15
(92 %)
b. LiBH4;
OH
Se
Se Br
I
OH
(94 %)
c. COCl2
O
O
Cl
Se
16
SeBr
13
Scheme 2. Synthesis of pro-allyl and pro-alloc selenium resins. a) LiBH4
(1.5 equiv), THF, 08C, 0.5 h, wash; then 1,3-diiodopropane (4.0 equiv),
THF/DMF 1:1, 238C, 5 h, 92%; b) LiBH4 (1.5 equiv), THF, 08C, 0.5 h,
wash; then 3-iodopropanol (4.0 equiv), THF/DMF 1:1, 238C, 5 h, 94%;
c) COCl2 (4.0 equiv), THF, 238C, 5 h.
Se
X
O
H2O2
II
x = I or OH
O
R
Se
III
O
(19) or methoxyaniline (21) in the presence of triethylamine
and catalytic amounts of 4-DMAP to give, after cleavage and
deprotection, 19 and 21 in 75 and 76% overall yield,
respectively (Scheme 3). More importantly, loading of the
protected vancomycin derivative 4 onto resin 14 employing
CsHCO3 and 4 Š MS gave polymer-bound vancomycin
derivative 23 in 86% yield (Scheme 4). Cleavage facilitated
by the action of H2O2, followed by removal of the C-terminal
allyl group employing [Pd(PPh3)4] and nBu3SnH) gave non-
asilylated bis-Cbz vancomycin 4 in 77% overall yield without
any of the apparent drawbacks associated with the allyl and
acrylate resins described above.
O
HO
R
Se
O
O
R
I
+
-
nBu nBu
H
H
Sn
H
VI
IV
1,2-syn elimination
O
[Pd(PPh3)4] (cat.)
O
R
V
Figure 5. Conceptual framework for selenium-based pro-allyl and pro-
alloc safety catch resins.
safety catch linker would retain the advantages of allyl
protection for the C-terminus, but should be more stable to
chemical manipulation and subsequent elaboration. The
requisite pro-allyl selenium resin was easily prepared from
the known selenium bromide resin 13 as shown in Scheme 2.
Thus, treatment of resin 13 with LiBH4 provided the
corresponding lithio-selenium species which was quenched
by either 1,3-diiodopropane or 3-iodopropanol to give resin 14
or 15, respectively, and in high yield. Resin 15 was converted
into the corresponding polymer-bound chloroformate by
exposure to phosgene. In model reactions (see Scheme 3),
both loading and cleavage proceeded smoothly for the pro-
With a suitable linking strategy now operational, we were in
a position to focus our attention on completing the solid-
phase semisynthesis of vancomycin. Scheme 5 details the
successful deglycosidation/reglycosidation sequence starting
with the vancomycin loaded resin 23. Thus, exposure of 23 to
TFA/Me2S/CH2Cl2 (1:1:1) caused hydrolysis of both sugar
moieties and provided the polymer-bound phenol 24. Glyco-
sidation of this polymer-bound vancomcyin scaffold with
trichloroacetimidate 25 (6.0 equiv) in the presence of BF3 ´
Et2O (9.0 equiv) gave the polymer-bound monosaccharide 26
in >90% yield. Liberation of the C-2 alloc-protected
hydroxyl group proceeded smoothly under standard palla-
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K. C. Nicolaou et al.
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Semisynthesis of vancomycin
O
a. 14, Cs2CO3 or 15, DCC
O
O
monosaccharide
analogues:
OH
17
O
O
Se
Se
b. i. H2O2 (86 % from 17)
ii. VI, [Pd(PPh3)4] (cat.)
The development of the solid-
phase semisynthesis of vanco-
mycin provided a convenient
route through which various
vancomycin analogues could
be rapidly accessed. Our initial
proposal was to replace vanco-
mycinꢀs disaccharide segment
with a new saccharide unit in
order to furnish a vancomycin
monosaccharide library. The
synthesis proceeded as sum-
marized in Scheme 6.
Br
18
20
Br
(96 %)
c. 16, Et3N, 4-DMAP
O
OH
b. i. H2O2 (78 % from 19)
ii. VI, [Pd(PPh3)4] (cat.)
I
19
(97 %)
I
OMe
O
d. 16, Et3N, 4-DMAP
O
N
H
MeO
NH2
Se
e. i. H2O2 (82 % from 21)
ii. VI, [Pd(PPh3)4] (cat.)
22
21
(93 %)
Scheme 3. Loading and cleavage of pro-allyl and pro-alloc resins. a) 4 (1.0 equiv), 17 (4.0 equiv), Cs2CO3
(4.0 equiv), DMF, 508C, 5 h or 15 (1.0 equiv), 17 (4.0 equiv), DCC (4.0 equiv), DMF, 238C, 15 h; b) i. H2O2
(2.0 equiv), THF, 238C, 2 h; Me2S (4.0 equiv), 238C, 10 h, 86% from 14 and 78% from 15; ii. VI (3.0 equiv),
Pd(PPh3)4 (0.1 equiv), CH2Cl2, 238C, 0.5 h, 96% for 17 and 97% for 19; c) 16 (4.0 equiv), Et3N (5.0 equiv),
4-DMAP (0.1 equiv), 238C, 6 h; d) 16 (4.0 equiv), Et3N (5.0 equiv), 4-DMAP (0.1 equiv), 238C, 3 h; e) i. H2O2
(2.0 equiv), THF, 238C, 2 h; Me2S (4.0 equiv), 238C, 10 h, 82% from 21; ii. VI (3.0 equiv), [Pd(PPh3)4] (0.1 equiv),
AcOH (4.0 equiv), CH2Cl2, 238C, 0.5 h, 93%. DCC ˆ dicyclohexyldiimide, 4-DMAP ˆ 4-dimethylaminopyr-
idine.
Thus, persilylation of vanco-
mycin hydroxyl groups fol-
lowed by alloc protection of
both basic nitrogens (a choice
that will save a deprotection
dium-catalyzed allyl transfer conditions {[Pd(PPh3)4],
nBu3SnH} to give polymer-bound acceptor 27 in >95% yield.
This result underscores the importance of the selenium-based
safety catch allyl resin in terms of simplifying the choice of C-2
glucose protecting group. Glycosidation of the newly formed
acceptor 27 with vancosamine glycosyl fluoride 28 (4.0 equiv)
under the influence of BF3 ´ Et2O gave the fully protected,
polymer-bound vancomycin derivative 29 in >85% yield.
Oxidative cleavage of resin 29 with H2O2 yielded the allyl
protected vancomycin derivative 5 in 80% yield. Treatment of
the released compound 5 with K2CO3 in MeOH induced
cleavage of the acetates and the phenol-bound silyl groups,
and subsequent removal of the remaining TBS groups with
CsF in DMF gave the bis-Cbz-O-allyl ester derivative 30 in
53% overall yield. Removal of the C-terminal allyl protecting
group {[Pd(PPh3)4], nBu3SnH}, followed by transfer hydro-
genation (10% Pd/C, NH3CO2H), provided synthetic vanco-
mycin (1) in 76% overall yield for the two steps. The four-step
deprotection sequence proceeded smoothly and required only
two purifications (after the CsF step, and then at the final stage).
step) yielded vancomycin derivative 31. Compound 31 was
then loaded onto the selenium resin 14, via the carboxylic acid
group, by the action of CsHCO3 and 4 Š MS and from the
resulting conjugate was removed the glycosyl moiety (TFA/
Me2S/CH2Cl2 1:1:1) to give intermediate 32. For the purposes
of introducing amino sugar moieties we chose to employ
suitably protected azide sugars. Thus, for the attachment of
the sugar moieties onto the phenol scaffold 32 we utilized the
corresponding trichloroacetimidates (33, see Figure 6) in the
presence of excess BF3 ´ Et2O which gave polymer-bound
vancomycin glycosides 34. An azide reduction-acylation
sequence was then used to produce a number of analogues.
Thus, polymer-bound azide 34 was treated with Et3P under
carefully controlled conditions (5.0 equiv Et3P, THF/H2O
10:1, 238C) to avoid acyl transfer from the neighboring
position, and subsequently acylated with a variety of acid
chlorides (RCOCl) to afford a series of polymer-bound
amides 35 (azide reduction under standard Staudinger con-
ditions (Ph3P, 60 8C) resulted in complete transfer of the
neighboring acetate to give the undesired hydroxy acet-
OTBS
OTBS
TBSO
CbzHN
TBSO
TBSO
CbzHN
TBSO
O
OTBS
OTBS
O
O
O
O
O
O
I
Se
(14)
O
O
Cl
Cl
a. CsHCO3, 4 Å MS,
(86 %)
O
O
O
O
O
OTBS
O
OTBS
O
TBSO
Cl
TBSO
Cl
Cbz
Cbz
O
H
H
O
H
H
(82 %)
b. i. H2O2
H
H
NMe
N
N
N
NMe
N
N
N
ii. [Pd(PPh3)4]
N
N
H
N
H
N
H
nBu3SnH (94 %)
H
H
H
O
O
O
H
O
O
O
O
H
O
NH
O
NH
O
O
HO
Se
NH2
NH2
OTBS
OTBS
OTBS
OTBS
TBSO
TBSO
4
23
Scheme 4. Application of the pro-allyl selenium-based safety catch linker to the vancomycin problem. a) 14 (8.0 equiv), CsHCO3 (5.0 equiv), DMF, 238C
(vacuum), 0.5 h, 508C, 5 h, 86%; b) i. H2O2 (2.0 equiv), THF, 238C, 2 h; Me2S (4.0 equiv), 238C, 48 h, 82%; ii. [Pd(PPh3)4] (0.1 equiv), nBu3SnH (4.0 equiv),
CH2Cl2, 0.5 h, 94%.
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Synthesis of Vancomycin
3798±3823
OTBS
TBSO
CbzHN
TBSO
OTBS
O
O
O
O
OH
Cl
O
O
O
Cl
O
O
O
OTBS
TBSO
Cl
a. TFA/Me2S/CH2Cl2
1:1:1
OTBS
O
Cbz
TBSO
Cl
O
O
H
H
H
Cbz
N
NMe
N
O
H
H
N
H
N
N
N
NMe
N
N
H
H
N
N
H
H
O
O
O
H
O
(>95 %)
Se
H
H
O
O
O
H
NH
O
NH
O
O
O
NH2
O
NH2
OTBS
OTBS
Se
24
OTBS
OTBS
TBSO
23
TBSO
b. BF3•Et2O
(>90 %)
O
OC(NH)CCl3
OAlloc
TBSO
OAc
O
AcO
AcO
OAc
OAc
OTBS
AcO
OTBS
25
HO
O
AllocO
O
Cl
O
O
O
Cl
c. [Pd(PPh3)4] (cat.),
nBu3SnH
OTBS
O
O
TBSO
Cl
Cbz
NMe
O
O
H
O
H
H
OTBS
O
N
TBSO
Cl
N
N
N
H
N
Cbz
(>95 %)
O
O
H
N
H
H
H
H
O
O
H
O
O
NMe
N
N
N
N
H
NH
O
H
H
O
O
O
H
O
O
NH
O
NH2
Se
OTBS
OTBS
27
O
NH2
Se
TBSO
OTBS
OTBS
d. BF3•Et2O
(>85 %)
26
TBSO
Me
O
F
OAc
AcO
CbzHN
AcO
AcO
OTBS
Me NHCbz
OAc
O
O
AcO
AcO
CbzHN
28
OTBS
O
O
O
O
Cl
O
O
O
O
OTBS
O
TBSO
Cl
Cl
Cbz
O
O
O
O
H
H
H
N
NMe
N
N
OTBS
O
N
H
N
H
e. H2O2
(80 %)
TBSO
Cl
H
Cbz
O
O
O
O
H
O
O
H
H
H
N
NMe
N
N
NH
O
N
N
H
H
H
O
O
O
H
O
O
NH2
5
NH
O
OTBS
OTBS
TBSO
O
NH2
Se
f. K2CO3, MeOH (86 %)
g. CsF (62 %)
OTBS
OTBS
29
TBSO
OH
O
OH
O
HO
CbzHN
HO
HO
H2N
HO
OH
OH
O
O
O
O
O
O
Cl
Cl
O
O
O
O
O
h. [Pd(PPh3)4] (cat.),
nBu3SnH (95 %)
OH
OH
HO
Cl
HO
Cl
Cbz
H
O
O
O
O
H
H
N
H
O
H
H
H
NMe
N
N
N
NMe
N
N
N
N
N
H
N
H
H
H
i. Pd/C,
NH4HCO2 (81 %)
H
H
O
O
H
O
O
O
H
O
O
NH
O
O
NH
O
O
HO
NH2
NH2
OH
OH
OH
OH
HO
HO
30
1: vancomycin
Scheme 5. Solid-phase semisynthesis of vancomycin (1). a) TFA/Me2S/CH2Cl2 1:1:1, 238C, 3 h, >95%; b) 25 (6.0 equiv), BF3 ´ Et2O (9.0 equiv), 4 Š MS,
40 ! 08C, 12 h, >90%; c) [Pd(PPh3)4] (0.1 equiv), nBu3SnH (10.0 equiv), CH2Cl2, 238C, 2 h, >95%; d) 28 (4.0 equiv), BF3 ´ Et2O (6.0 equiv), 4 Š MS,
40 ! 08C, 4 h, >85%; e) H2O2, THF, 238C, 48 h, 80%; f) K2CO3, MeOH, 238C, 6 h, 86%; g) CsF, DMF, 238C, 15 h, 62%; h) [Pd(PPh3)4] (0.1 equiv),
nBu3SnH, DMF, 238C, 1 h, 95%; i) 10% Pd/C, NH4HCO2, H2O/AcOH 1:1, 238C, 4 h, 81%. Ac ˆ acetate, TFA ˆ trifluoroacetic acid.
Chem. Eur. J. 2001, 7, No. 17
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3803

K. C. Nicolaou et al.
FULL PAPER
HO
HO
TBSO
TBSO
HO
TBSO
allocNH
H2N
OH
OTBS
O
O
O
O
O
O
O
O
Cl
Cl
O
a. TBSOTf, 2,6-lut.
b. alloc-Cl, NaHCO3
O
O
O
O
OH
OTBS
alloc
HO
Cl
TBSO
Cl
(60 % for two steps)
O
O
O
H
N
H
H
H
O
O
H
H
N
N
NHMe
N
N
NMe
N
N
N
H
N
N
H
H
H
H
H
O
O
O
H
O
H
O
O
O
O
NH
O
NH
O
HO
HO
NH2
NH2
OH
OH
OTBS
OTBS
31
HO
TBSO
1: vancomycin
(14)
I
Se
R1
c. CsHCO3, 4 Å MS,
(>86 %)
d. TFA/ Me2S/CH2Cl2 1:1:1
(>95 %)
O
OH
Cl
O
O
Cl
O
O
R1
O
O
OC(NH)CCl3
OTBS
O
TBSO
Cl
OTBS
TBSO
Cl
alloc
NMe
33
O
H
alloc
NMe
O
H
H
N
O
O
H
O
H
N
H
N
N
N
N
N
H
N
N
H
N
e. BF3•Et2O
(>90 %)
H
H
H
O
O
O
H
O
H
O
O
O
H
O
NH
O
NH
O
O
NH2
Se
O
NH2
Se
OTBS
OTBS
OTBS
OTBS
TBSO
TBSO
34
32
f. Et3P
g. R2COCl
(>85 %)
R3
R2
O
O
O
O
Cl
Cl
O
O
O
O
h. H2O2
i. K2CO3
OH
OTBS
O
HO
Cl
TBSO
Cl
H
alloc
NMe
O
O
O
O
H
H
H
H
O
H
H
NMe
j. CsF
k. [Pd(PPh3)4],
nBu3SnH, ca. 30 %
N
N
N
N
N
N
N
H
N
N
H
N
H
H
H
H
O
O
O
O
H
O
O
O
H
O
NH
O
NH
O
HO
O
NH2
NH2
35
Se
OH
OH
OTBS
OTBS
36
HO
TBSO
Scheme 6. Solid-phase semisynthesis of a library of vancomycin monosaccharides 36. a) TBSOTf (60 equiv), 2,6-lut. (120 equiv), CH2Cl2/DMF 10:1, 238C,
sonication, 8 h; b) alloc-Cl (5.0 equiv), NaHCO3 (10.0 equiv), 1,4-dioxane/H2O 3:1, 238C, 3 h, 60% over two steps; c) 14 (8.0 equiv), CsHCO3 (5.0 equiv),
DMF, 238C (vacuum), 0.5 h, 508C, 5 h, 86%; d) TFA/Me2S/CH2Cl2 1:1:1, 238C, 3 h, >95%; e) trichloroacetimidate 33 (5.0 equiv), BF3 ´ Et2O (7.5 equiv),
40 ! 08C, CH2Cl2, 12 h, >90%; f) Et3P (5.0 equiv), THF/H2O 10:1, 238C, 4 h; g) R2COCl (5.0 equiv), Et3N (10.0 equiv), CH2Cl2, 8 h, >85% (for two
steps); h) H2O2, THF, 238C, 48 h; i) K2CO3 (10.0 equiv), MeOH, 238C, 6 h; j) CsF (5.0 equiv), DMF, 238C, 15 h; k) [Pd(PPh3)4] (0.25 equiv), nBu3SnH
(10.0 equiv), DMF, 238C, 1 h (30% for three steps). alloc ˆ allyloxycarbonyl, see Figure 6 for the respective trichloroacetimidates 33.
amide). A cleavage/deprotection sequence similar to that
developed for the vancomycin semisynthesis, as summarized
in Scheme 6, provided an initial library of vancomycin
analogues for biological evaluation.
Table 1 includes the structures of the synthesized com-
pounds along with MIC values against vancomycin-suscep-
tible strains, vancomycin-intermediate resistant strains, and a
vancomycin-resistant strain. The monosaccharide vancomycin
derivatives were found to be uniformly less active than the
parent vancomycin against all strains examined. The location
of the amino group appears to be important as evidenced by
the fact that compounds 36a and 36b (amine at the C-6
position of glucose) are at least two-fold more active than
compound 36c (amine at the C-3 position of glucose). Also,
these results show that incorporation of a moderate degree of
lipophilicity (compounds 36d and 36e) leads to a further
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Synthesis of Vancomycin
3798±3823
Scheme 7) from the appropriate phenols by initial Mitsunobu
reaction followed by a radical-based regioselective thioace-
tate addition to the terminal double bond.
N3
OAc
O
8
AcO
OAc
OAc
AcO
OAc
N3
AcO
OAc
N3
Cl3C
O
O
Cl3C
O
O
Cl3C
O
O
Scheme 8 summarizes the synthesis of the targeted com-
pounds in which regioselective reductive amination at the
vancosamine site was the key step. Reaction of vancomycin
with aldehydes 37, 38, or 39 in the presence of iPr2NEt
followed by addition of NaCNBH3 at 658C led to compounds
40a ± yy. The presence of iPr2NEt was found, in our experi-
ence, to be essential for ensuring smooth conversion and high
regioselectivity. As depicted in Figure 7, the regioselectivity of
the reaction was evident from mass spectroscopic fragmenta-
NH
NH
NH
33a
33d
33b
Cl
O
O
O
O
4
AcO
OAc
N3
AcO
OAc
N3
AcO
OAc
OAc
Cl3C
O
O
Cl3C
O
O
Cl3C
O
O
1
NH
NH
NH
tion and H NMR analysis of the products 40 obtained.
33c
33e
33f
Compounds synthesized in this manner were evaluated for
their antibacterial activity against a variety of vancomycin-
Figure 6. Trichloroacetimidates 33 used for the generation of vancomycin-
derived monosaccharides.
restoration of activity; howev-
er, too much lipophilicity has
deleterious effects on antibac-
terial activity as demonstrated
by compound 36 f. The conclu-
sion from this initial study was
that retaining both sugar moi-
eties on vancomcyin was a more
desirable feature for the even-
tual development of highly po-
tent vancomycin analogues.
Olefinic and thioacetate vanco-
mycin analogues: Having rec-
ognized the importance of the
vancosamine moiety for anti-
bacterial activity we proceeded
to design and synthesize a new
series of vancomycin analogues
with the intact skeleton of the
molecule in place. Since regio-
selective derivatization of ei-
ther of vancomycinꢀs two amino
groups had already been dem-
onstrated, initial strategies to-
ward such compounds proceed-
ed through intermediates de-
rived via such chemical mani-
pulation. Interestingly, the anti-
bacterial activity of some of
these newly synthesized mono-
meric vancomycin derivatives
rivaled the action of some of
the most effective, previously
known, antibacterial agents
against vancomycin-resistant
strains as will be discussed be-
Scheme 7. Preparation of substituted benzaldehydes 37 ± 39 used in the preparation of vancomycin derivatives.
a) DEAD (1.5 equiv), Ph3P (1.5 equiv), alcohol (1.5 equiv), THF, 238C, 4 h; b) AcSH (2.0 equiv), AIBN
(0.2 equiv), benzene, 858C, 2 h; c) NaH (1.0 equiv), R1Br (1.0 equiv), DMF, 0 ! 238C, 12 h. AIBN ˆ 2,2'-
azobisisobutyronitrile, alcohol ˆ allyl alcohol or 3-buten-1-ol or 4-penten-1-ol or 5-hexen-1-ol or 9-decen-1-ol or
1-hexanol or 1-octanol or benzyl alcohol or p-chlorobenzyl alcohol, R1Brˆ butyl bromide, heptyl bromide, benzyl
bromide, p-chlorobenzyl bromide.
low.
Construction of these ana-
logues began with the synthesis
of the requisite benzalde-
hyde derivatives (37 ± 39, see
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K. C. Nicolaou et al.
FULL PAPER
OH
OH
HO
HO
HO
H2N
HO
H
N
OH
OH
R1
O
O
O
R2
O
O
O
O
O
O
a.
R2
Cl
Cl
R1
O
O
O
O
O
O
37, 38, or 39
OH
O
Cl
OH
HO
Cl
HO
H
N
H
N
H
N
O
O
H
N
H
N
H
N
O
DMF/MeOH 1:1, iPr2NEt;
then NaCNBH3
NHMe
NHMe
N
H
N
N
H
N
H
H
H
O
H
O
O
O
H
O
O
O
H
NH
O
NH
O
O
HO
HO
NH2
NH2
OH
OH
OH
OH
HO
HO
40a – 40yy
1
Scheme 8. Regioselective reductive alkylation of vancomycin (1) with benzaldehyde derivatives 37 ± 39. a) 37, 38, or 39 (1.1 equiv), iPr2NEt (1.2 equiv),
DMF/MeOH 1:1, 658C, 2 h; then NaCNBH3 (2.0 equiv), 658C, 2 h. See Tables 2, 3, and 4 for definitions of R1 and R2.
the remarkable activity of Ly333328.[30] Further results and
OH
HO
analysis are, however, required before final judgment as to the
cause of this effect.[31] In order to determine the antibacterial
spectrum of activity of these lipophilic vancomycin deriva-
tives we screened a select number of compounds against a
larger set of vancomycin-resistant strains. The collected data
are summarized in Table 4. Interestingly, while the moder-
ately lypophilic compounds 40ii, 40dd, 40ss, 40vv, and 40ww
exhibited good activity against a range of vancomycin-
resistant bacteria, the much more lipophilic compounds
40xx and 40yy showed almost no activity. These observations
are consistent with previously reported results[15] suggesting
that too much lipophilicity is detrimental to the antibacterial
activity.
HO
HN
OH
O
R
O
O
O
mode a
HO
mode b
Cl
O
O
O
OH
Cl
O
O
H
N
H
H
NHMe
N
N
N
N
H
H
H
O
H
O
O
O
NH
O
HO
NH2
OH
OH
40
HO
Figure 7. Molecular fragmentation of alkylated vancomycins 40 during
mass spectrometric analysis. Both modes of fragmentation (a and b) are
diagnostic for determining the site of reductive amination (vancosamine or
amino acid 1).
Amino acid core modified vancomycin derivatives: A small
number of N-terminus modified vancomycin analogues were
also synthesized and tested as shown in Table 2 (40q ± y).
While none of these compounds were as active as vancomycin
itself against the strains examined, some of them exhibited
significant activity against a number of strains. This phenom-
enon most likely reflects the diminished, but not extinct,
ability of these compounds to bind to their target[32] within the
bacterial cell-wall. In order to probe the effect of such
substitutions further, we proceeded to apply solid-phase
chemistry to construct an expanded library of vancomycin
with various amino acids attached at the N-terminus of the
molecule.
The strategy for the synthesis of the vancomycin monomers
described above is depicted in Scheme 9. Thus, selective Boc
protection of vancomycin (1) on the N-terminus followed by
reductive alkylation under standard conditions (1.1 equiv 39e
or 40e, 1.4 equiv iPr2NEt; then NaCNBH3, 658C) cleanly
afforded 42a or 42b, respectively. Boc protection facilitated
the large-scale procurement of material as it allowed the
reductive alkylation to be driven to completion with absolute
regioselectivity. Removal of the Boc group with dilute TFA
followed by Edman degradation[33] gave vancomycin hexa-
peptide 40x or 44. The preceding sequence could be
conducted with no other purification necessary other than
susceptible, vancomycin-intermediate resistant, and vanco-
mycin-resistant bacteria, and these data are summarized in
Table 2 and Table 3, respectively. Most interestingly, several
of the compounds tested exhibited good activity against VRE
(strain L4001). Specifically, olefins 40d and 40i (Table 2),
showed an MIC value of 8 mgmL 1 against L4001 and olefins
40h and 40k ± p demonstrated potencies in the range of 1 to
2 mgmL 1 against this strain. Similarly, the lipophilic thioace-
tates 40dd and 40kk ± oo (Table 3) exhibited good antibacte-
1
rial activity with MIC values ranging from 2 ± 4 mgmL .
Perhaps, the lower potencies of the thioacetates as compared
to their olefinic counterparts are due to their more polar
terminus, which renders them less capable of anchoring into
the bacteriumꢀs membrane. Interestingly, the chlorobenzyl
thioacetate derivatives 40pp and 40qq were found to be two-
fold more active than the corresponding benzyl derivatives
40nn and 40oo. It is tempting to speculate that this
observation is a manifestation of an additional localizing
effect by the chlorine atom on the bacteriumꢀs cell wall as a
similar effect has been postulated in attempting to rationalize
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Chem. Eur. J. 2001, 7, No. 17

Synthesis of Vancomycin
3798±3823
OH
HO
OH
HO
HO
H2N
HO
H
N
OH
OH
O
O
O
O
O
O
O
O
O
X
Cl
Cl
O
O
O
O
O
O
a. Boc2O, NaHCO3
dioxane/H2O 1:1 (>95 %)
OH
OH
HO
Cl
HO
Cl
Boc
O
O
O
H
N
H
O
H
N
H
H
b. iPr2NEt, DMF/MeOH 3:1;
then NaCNBH3 (>90 %)
H
N
NHMe
N
NMe
N
N
N
N
N
N
H
H
H
H
H
H
O
O
H
O
O
O
O
H
O
O
NH
O
O
NH
O
HO
HO
NH2
NH2
X
OH
OH
OH
OH
O
HO
HO
38b: X = CH=CH2
39a: X = CH2SAc
1 : vancomycin
42a: X = CH=CH2
42b: X = CH2SAc
OMe
c. TFA, CH2Cl2
d. PhNCS, py./H2O 1:1
e. TFA, CH2Cl2
(>85 % over three steps)
OH
j. EDC, CH2Cl2/DMF 1:1
O
(45)
NHFmoc
HO
OH
OH
R1
OH
HO
HO
HO
HO
H
k. pip, DMF
H
N
N
OH
OMe
O
O
O
O
O
O
O
O
O
O
O
X
X
O
NH2
Cl
(46)
R1
f. HBTU, iPr2NEt, DMF
Cl
O
O
O
O
O
OH
HO
Cl
OH
O
HO
Cl
O
H
N
O
H
N
H
N
O
H
N
H
H
NH2
N
N
N
NH2
N
N
H
H
g. HBTU, iPr2NEt, DMF
H
H
O
O
H
H
O
O
R2
O
H
O
O
O
NH
O
R1
O
NH
O
(47)
NHFmoc
HO
HO
HO
NH2
N
R2
NH2
OH
H
OH
O
OH
OH
HO
HO
h. pip, DMF
i. TFA, CH2Cl2
(> 40 % over four steps)
40x: X = CH=CH2
44: X = CH2SAc
48a − 48ooo
O
O
O
O
O
O
O
O
NH2
HO
NH
NH2
NH2
NH2
NH2
NH2
HO
HO
NH2
HO
HO
HO
HO
HO
HO
R2
(47)
Gly
Sar
β-Ala
D-Ala
O
L-Ile
O
D-Leu
O
L-Val
O
O
O
O
NH2
NH2
NH2
NH2
NH2
NH2
NH2
S
HO
HO
HO
HO
HO
HO
H
S
N
γ-Abu
ε-Ahx
N
OH
L-Phe
L-Tyr
L-His
L-Met
L-Thi
O
O
O
O
O
O
O
NH2
OH
NH2
OH
NH2
NH2
NH2
NH2
OH
NH2
HO
HO
HO
HO
HO
HO
HO
O
NH
NH2
O
OH
L-Ser
L-Thr
L-Orn
NH2
NH2
O
L-Lys
L-Asp
L-Cit
L-Glu
Scheme 9. Solid-phase synthesis of vancomycin analogues 48a ± 48ooo. a) Boc2O (1.2 equiv), NaHCO3 (2.0 equiv), dioxane/H2O 1:1, 238C, 4 h; b) 39e or
ˆ ˆ
40e (2.0 equiv), iPr2NEt (2.5 equiv), NaCNBH3 (2.2 equiv), 658C, 20 h; c) 10% TFA in CH2Cl2, 238C, 1 h, 90%; d) PhN C S (1.2 equiv), pyridine/H2O 1:1,
238C, 2 h, 100%; e) 10% TFA in CH2Cl2, 238C, 2 h, 75%; f) iPr2NEt (6.0 equiv), HBTU (3.0 equiv), DMF, 238C, 1 h; g) amino acid Fmoc-derivative
(3.0 equiv), iPr2NEt (4.0 equiv), HBTU (2.0 equiv), DMF, 238C, 2 h; h) 5% piperidine in DMF, 30 min, 238C; i) 5% TFA in CH2Cl2, 2 h, 238C; j) EDC
(3 equiv), 45 (2.5 equiv), DMF/CH2Cl2 (1:1), 238C, 4 h; k) 5% piperidine in DMF, 238C, 1 h. EDC ˆ 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, HBTU ˆ O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate, pip ˆ piperidine, py ˆ pyridine.
Chem. Eur. J. 2001, 7, No. 17
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3807

K. C. Nicolaou et al.
FULL PAPER
30 min. High resolution mass spectra were obtained by MALDI on a VG
AZB ZSE spectrometer. LCMS was performed on a Hewlett ± Packard
1100 series system.
filtration. In further experiments and in order to expedite the
synthesis of several monomers, the vancomycin scaffold was
loaded onto a solid support by a method similar to that used
by Griffin.[34] Thus, treatment of hexapeptide 40x or 44 with
polymer-bound amino acid 46 for one hour in the presence of
HBTU gave a polymer-bound heptapeptide (Scheme 9).
Coupling of Fmoc-protected amino acids to the polymer-
bound heptapeptide proceeded rapidly in the presence of
HBTU leading to an octapeptide which was deprotected and
cleaved from the solid support as follows: i) exposure to
piperidine; and ii) treatment with dilute TFA. The amino acid
building blocks shown in Scheme 9 were utilized in this
sequence to produce a small library of analogues which was
screened against a range of vancomycin-susceptible, vanco-
mycin-intermediate resistant and vancomycin-resistant
strains. Table 5 summarizes some of the results from the
antibacterial activity assays for the most active compounds
synthesized in Scheme 9. The remaining compounds showed
little, if any, activity against the strains examined, confirming
the low profitability of this substitution pattern.[35]
N,N'-Di-Cbz-nona-TBS-vancomycin (4): TBSOTf (47.6 mL, 207 mmol)
was added dropwise to a solution of vancomycin ´ HCl (2.00 g, 1.35 mmol)
and 2,6-lutidine (18.8 mL, 161 mmol) in CH2Cl2/DMF (10:1, 13.3 mL) at
08C. The reaction mixture was sonicated for 8 h keeping the temperature
below 358C. The reaction was quenched by slow addition of saturated
aqueous NaHCO3 (200 mL) and the resulting mixture was stirred at 258C
for 12 h. The organic layer was separated, and the aqueous phase was
extracted with Et2O (3 Â 150 mL). The combined organic layers were dried
(MgSO4), concentrated on a rotary evaporator and the residue obtained
was purified by flash column chromatography (silica gel, 1 ! 8% MeOH in
CH2Cl2) to afford nona-TBS-vancomycin as a white foam (2.22 g, 65%). A
solution of this compound (4.00 g, 1.62 mmol, 1.0 equiv) in dioxane/H2O
(10:1, 36 mL) was treated sequentially with solid NaHCO3 (1.36 g,
16.0 mmol, 10.0 equiv) and CbzCl (1.32 g, 8.08 mmol, 5.0 equiv) at 08C.
After stirring for 3 h, the reaction was quenched by the addition of
saturated aqueous NaHCO3 (10 mL) and 4-DMAP (196 mg, 1.62 mmol,
1.0 equiv). The mixture was stirred for 6 h at ambient temperature and then
extracted with Et2O (3 Â 120 mL). The combined organic layers were dried
(MgSO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 0 ! 4% MeOH in CH2Cl2) to provide N,N'-di-
Cbz-nona-TBS-vancomycin (4) (3.54 g, 80%) as a white foam. 4: Rf ˆ 0.36
(silica gel, 5% MeOH in CH2Cl2); 1H NMR (600 MHz, CD3OD, 330 K):
d ˆ 7.65 (d, J ˆ 1.5 Hz, 1H), 7.52 (dd, J ˆ 7.0, 1.5 Hz, 1H), 7.36 ± 7.20 (m,
15H), 7.06 (d, J ˆ 1.5 Hz, 1H), 6.99 (dd, J ˆ 7.0, 1.5 Hz, 1H), 7.04 (s, 1H),
6.77 (d, J ˆ 8.5 Hz, 1H), 6.57 (d, J ˆ 1.0 Hz, 1H), 6.39 (d, J ˆ 2.0 Hz, 1H),
6.06 (d, J ˆ 4.0 Hz, 1H), 5.77 (s, 1H), 5.75 (s, 1H), 5.61 (s, 1H), 5.42 (d, J ˆ
3.0 Hz, 1H), 5.33 (s, 1H), 5.13 (brd, J ˆ 1.0 Hz, 1H), 5.00 (d, J ˆ 16.5 Hz,
1H, Cbz), 4.92 (d, J ˆ 16.5 Hz, 1H, Cbz), 4.88 (s, 1H), 4.86 ± 4.83 (m, 1H),
4.71 ± 4.68 (m, 1H), 4.61 (s, 1H), 4.58 (s, 2H), 4.47 (q, J ˆ 7.0 Hz, 1H), 4.27
(t, J ˆ 1.0 Hz, 1H), 4.22 (d, J ˆ 2.0 Hz, 1H), 4.13 ± 4.07 (m, 2H), 4.02 (d, J ˆ
10.0 Hz, 1H), 3.94 ± 3.91 (m, 2H), 3.60 (s, 1H), 2.91 (s, 3H), 2.46 ± 2.38 (m,
2H), 1.96 (dd, J ˆ 10.0, 4.0 Hz, 1H), 1.83 ± 1.80 (m, 2H), 1.59 (s, 3H), 1.58 ±
1.47 (m, 2H), 1.03 (d, J ˆ 6.5 Hz, 3H), 1.01 (s, 9H), 0.93 (s, 9H), 0.96 ± 0.92
(m, 6H), 0.90 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.84 (s, 9H),
0.73 (s, 9H), 0.61 (s, 9H), 0.23 (s, 3H), 0.22 (s, 3H), 0.18 (s, 3H), 0.16 (s,
3H), 0.13 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.07 (s, 6H), 0.06 (s, 3H), 0.05
Conclusion
In conclusion, we have accomplished the solid-phase semi-
synthesis of vancomycin (1) and in the process developed a
selenium-based safety catch linker which may enjoy wider
applicability to the solid-phase manipulation of polyfunc-
tional natural products and other molecules of medicinal
interest. Using the methods developed, we designed and
synthesized several vancomycin libraries with molecular
diversity at the sugar moieties, the amino acid 1 site, and the
C-terminus. Biological evaluation of these analogues, re-
vealed several highly potent compounds effective against
vancomycin-resistant strains. Among them were a few which
rival the most active agents known in this series. Most
importantly, this work set the stage for the next phase of the
program which aimed at producing covalently linked dimeric
vancomycin constructs, some of which proved to be extremely
potent against vancomycin-resistant bacteria. The following
article describes these investigations.
(s, 6H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H), 0.02 (s, 3H), 0.03 (s, 3H),
‡
0.09 (s, 3H); HRMS: calcd for
2889.2032, found 2889.2237.
C
137H215Cl2N9O28Si9Cs [M‡Cs] :
Preparation of resin 14: LiBH4 (1.5 equiv) was added at 08C to a stirred
suspension of resin 13 (5.0 g, 1.0 equiv) in THF (60 mL). After 30 min the
resin had completely decolorized. After removal of the supernatant and
washing of the resin with THF (150 mL) the resin was re-suspended in
THF/DMF (1:1, 50 mL). To this suspension was added at 238C, 1,3-
diiodopropane (4.0 equiv) and the suspension gently stirred for 5 h.
Filtration of the reaction mixture and washing of the resin with CH2Cl2
(200 mL), MeOH (200 mL), and Et2O (200 mL) provided resin 14.
Polymer-bound protected vancomycin 23: Protected vancomycin carbox-
ylic acid 4 (3.20 g, 1.17 mmol, 1.0 equiv) was dissolved in DMF (80 mL) and
CsHCO3 (1.13 g, 5.85 mmol, 5.0 equiv) and flame-dried 4 Š MS (1.0 g)
were added. The reaction mixture was stirred under reduced pressure
(vacuum pump) for 30 min after which time the resin (14) (6.00 g,
9.0 mmol, 7.7 equiv) was added. The reaction mixture was stirred at 508C
for 5 h, then filtered and washed with Et2O (400 mL). The resin was dried
Experimental Section
General: All reactions were carried out under an argon atmosphere with
dry, freshly distilled solvents under anhydrous conditions, unless otherwise
noted. Tetrahydrofuran (THF), toluene and diethyl ether were distilled
from sodium/benzophenone, and methylene chloride (CH2Cl2) from
calcium hydride. Anhydrous solvents were also obtained by passing them
through commercially available alumina columns. Yields refer to chroma-
tographically and spectroscopically (1H NMR) homogeneous materials,
unless otherwise stated. Reagents were purchased at highest available
commercial quality and used without further purification unless otherwise
stated. NMR spectra were recorded on Bruker DRX-600, AMX-500 or
AMX-400 instruments and calibrated using residual undeuterated solvent
as an internal reference. The following abbreviations were used to
designate multiplicities: s ˆ singlet, d ˆ doublet, t ˆ triplet, q ˆ quartet,
m ˆ multiplet, brˆ broad. Semipreparative HPLC was performed on either
a VYDAC C18, 10 mm  250 mm, column with flow rate 3.5 mLmin 1, 0 !
100% CH3CN in H2O over 20 min or on VYDAC C18, 25 mm  250 mm,
column with flow rate 6.5 mLmin 1, 0 ! 100% CH3CN in H2O over
to a constant weight of 8.71 g (89% yield based on mass gain). The
1
calculated loading of this resin was 0.119 mmolg
.
Polymer-bound vancomycin aglycon 24
Hydrolysis of disaccharide from resin 23: The resin 23 (8.49 g, 1.01 mmol)
was suspended in CH2Cl2 (30 mL) and Me2S (30 mL) and then treated with
TFA (30 mL) and stirred gently for 3 h (the reaction mixture turns deep
red). The reaction mixture was then diluted with Et2O (100 mL), filtered,
washed (CH2Cl2 2 Â 200 mL, MeOH 2 Â 200 mL, Et2O 2 Â 200 mL) and
dried to a constant weight of 7.51 g. A small portion of the resin was cleaved
1
and the product obtained was analyzed 24: H NMR (600 MHz, CD3OD,
330 K): d ˆ 7.69 (brs, 2H), 7.54 (dd, J ˆ 8.0, 1.0 Hz, 1H), 7.42 (s, 1H), 7.35 ±
7.30 (m, 6H), 7.12 (d, J ˆ 2.0 Hz, 1H), 7.01 (dd, J ˆ 8.5, 2.0 Hz, 1H), 6.79 (d,
J ˆ 8.5 Hz, 1H), 6.78 ± 5.85 (m, 1H), 6.41 (d, J ˆ 2.0 Hz, 1H), 6.38 (d, J ˆ
3808
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3808 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 17

Synthesis of Vancomycin
3798±3823
2.0 Hz, 1H), 5.92 (ddt, J ˆ 16.0, 8.0, 6.5 Hz, 1H), 5.68 (s, 1H), 5.48 (m, 1H),
5.36 (s, 2H), 5.35 (ddt, J ˆ 16.0, 1.5, 1.5 Hz, 1H), 5.22 (ddt, J ˆ 8.0, 1.5,
1.5 Hz, 1H), 5.22 ± 5.17 (m, 2H), 4.96 (brs, 2H), 4.90 ± 4.83 (m, 1H), 4.77 ±
4.70 (m, 1H), 4.72 (dddd, J ˆ 10.0, 6.5, 1.5, 1.5 Hz, 1H), 4.61 (s, 1H), 4.72
(dddd, J ˆ 10.0, 6.5, 1.5, 1.5 Hz, 1H), 4.11 (s, 1H), 2.93 (s, 3H, NCH3), 2.45 ±
2.39 (m, 2H), 1.84 ± 1.81 (m, 1H), 1.53 ± 1.45 (m, 2H), 1.01 (s, 9H), 0.94 (s,
9H), 0.93 ± 0.90 (m, 6H), 0.86 (s, 9H), 0.75 (s, 9H), 0.64 (s, 9H), 0.23 (s,
6H), 0.18 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.09 (s, 3H), 0.08
(s, 3H), 0.02 (s, 3H), 0.09 (s, 3H); MS (ES): calcd for C94H132Cl2N8O19Si5
[M‡H] : 1889.1, found 1889.1.
Vancomycin monosaccharide 26
Glycosidation of polymer-bound phenol 24: Glucose imidate 25[20a]
(915 mg, 1.51 mmol) was azeotroped with benzene (3 Â 10 mL) and then
dried under high vacuum for 1 h. The imidate was then transferred as a
CH2Cl2 (15 mL) solution to a flask containing resin 24 (2.00 g, 0.252 mmol)
and flame-dried 4 Š MS (1.0 g). This mixture was stirred at ambient
product obtained was analyzed 29: 1H NMR (600 MHz, CD3COD, 330 K):
d ˆ 7.65 ± 7.45 (m, 3H), 7.40 ± 7.20 (m, 12H), 7.10 ± 7.08 (m, 2H), 7.03 (m,
2H), 6.80 (d, J ˆ 8.5 Hz, 1H), 6.78 (d, J ˆ 8.5 Hz, 1H), 6.44 (d, J ˆ 2.0 Hz,
1H), 6.40 (s, 1H), 5.91 (m, 1H), 5.83 ± 5.78 (m, 2H), 5.64 ± 5.45 (m, 2H),
5.44 ± 5.28 (m, 5H), 5.26 ± 5.10 (m, 5H), 4.90 (q, J ˆ 12.5 Hz, 2H), 4.64 (m,
2H), 4.18 ± 4.07 (m, 2H), 3.85 ± 3.80 (m, 2H), 3.64 (m, 1H), 2.94 (s, 3H),
2.48 (m, 2H), 2.03 (s, 3H), 2.00 (s, 3H), 1.98 (s, 3H), 2.05 ± 1.98 (m, 2H),
1.55 (brs, 3H), 1.29 (s, 3H), 1.09 (m, 3H), 1.02 (s, 9H), 0.97 (s, 9H), 0.93 (m,
6H), 0.88 (s, 9H), 0.82 (s, 9H), 0.79 (s, 9H), 0.71 (s, 9H), 0.24 (s, 3H), 0.23
(s, 3H), 0.19 (s, 3H), 0.18 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.10 (m, 9H),
‡
0.04 (s, 3H), 0.03 (s, 3H), 0.06 (s, 3H), 0.08 (s, 3H); MS (ES): calcd for
‡
C
127H181Cl2N9O31Si6 [M‡Na] : 2592.9, found 2592.6.
Fully protected vancomycin 5
Cleavage from resin 29: Resin 29 (300 mg, 34.5 mmol of vancomycin,
0.24 mmol of Se) was suspended in THF (4 mL) and treated with H2O2
(30% in water, 48 mL, 0.48 mmol, 2.0 equiv) and stirred for 2 h after which
time, Me2S (111 mL, 1.76 mmol, 4.0 equiv relative to H2O2) was added to
the reaction mixture which was stirred for an additional 48 h. The reaction
mixture was filtered, concentrated, and passed through a short plug of silica
gel (eluting with CH2Cl2, then 10% MeOH in CH2Cl2) to recover 5 as a
single product (54.1 mg, 80%).
temperature for 2 h, then cooled to
408C and BF3 ´ Et2O (330 mL,
2.26 mmol) was added dropwise. The reaction mixture was allowed to
warm up to 08C over the course of 12 h. The reaction mixture was cooled
back to 408C and quenched with Et3N (0.64 mL, 4.56 mmol, 2.0 equiv
relative to BF3 ´ Et2O). The resin was filtered and washed (MeOH 2 Â
20 mL and CH2Cl2 2 Â 20 mL). A small portion of this resin was cleaved
and the product obtained was analyzed 26: Rf ˆ 0.33 (silica gel, 5% MeOH
in CH2Cl2); 1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.64 (brs, 2H), 7.39 ±
7.24 (m, 8H), 7.06 (m, 1H), 7.01 (dt, J ˆ 8.5, 2.0 Hz, 1H), 6.79 (d, J ˆ 8.5 Hz,
1H), 6.78 ± 5.85 (m, 1H), 6.42 (d, J ˆ 2.0 Hz, 1H), 6.40 (d, J ˆ 2.0 Hz, 1H),
5.92 (m, 2H), 5.72 (d, J ˆ 7.0 Hz, 1H), 5.52 ± 5.44 (m, 3H), 5.40 (s, 2H), 5.35
(m, 2H), 5.33 ± 5.26 (m, 3H), 5.22 (m, 2H), 5.23 ± 5.16 (m, 2H), 5.05 ± 5.02
(m, 1H), 4.96 (brs, 2H), 4.93 ± 4.92 (m, 1H), 4.89 ± 4.83 (m, 1H), 4.77 ± 4.70
(m, 1H), 4.72 ± 4.58 (m, 6H), 4.61 (s, 1H), 4.43 (m, 1H), 4.19 (m, 1H), 4.10
(s, 1H), 3.92 ± 3.74 (m, 2H), 3.62 (m, 1H), 2.94 (s, 3H), 2.45 ± 2.39 (m, 2H),
2.01 (s, 6H), 1.84 ± 1.81 (m, 1H), 1.53 ± 1.45 (m, 2H), 1.29 (s, 9H), 1.11 (s,
9H), 0.93 ± 0.90 (m, 6H), 0.88 (s, 9H,), 0.77 (s, 9H), 0.61 (s, 9H), 0.25 (s,
6H), 0.14 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.02 (s, 3H), 0.08
(s, 3H), 0.10 (s, 3H), 0.14 (s, 3H); MS (ES): calcd for C114H164Cl2N8O28-
Deprotection of 5 to give vancomycin (1) via intermedite 30
Deacetylation and desilylation: Fully protected vancomycin derivative 5
(48 mg, 18.7 mmol, 1.0 equiv) was dissolved in MeOH (5 mL) and treated
with solid K2CO3 (5.2 mg, 37.4 mmol, 2.0 equiv) and stirred at room
temperature for 6 h, at which point TLC analysis of the reaction mixture
indicated complete disappearance of the starting material. The crude
reaction mixture was filtered through Celite and concentrated. The crude
residue thus obtained was dissolved in wet DMF (0.5 mL), and solid
NaHCO3 (30 mg, 0.36 mmol, 20 equiv) and CsF (30 mg, 0.197 mmol,
12 equiv) were added. The resulting heterogeneous mixture was stirred
vigorously for 15 h. The crude reaction mixture was purified directly by
HPLC to give vancomycin ester derivative 30 (20.4 mg, 62%) as a white
solid: 30: HPLC: tR ˆ 9.8 min (LiChrospher C18, 4 mm  250 mm, flow
rate ˆ 1.0 mLmin 1, 5 ! 100% CH3CN in H2O (0.1% TFA) over 15 min);
‡
Si6 [M‡H] : 2334.2, found 2334.3.
1
30: H NMR (500 MHz, CD3COD, 330 K): d ˆ 7.66 (brs, 1H), 7.56 (d, J ˆ
Vancomycin monosaccharide alcohol 27
2.0 Hz, 1H), 7.55 (d, J ˆ 2.0 Hz, 1H), 7.44 (s, 1H), 7.40 ± 7.29 (m, 12H), 6.13
(brd, J ˆ 9.0 Hz, 1H), 7.08 (d, J ˆ 1.5 Hz, 1H), 7.01 (dd, J ˆ 8.5, 2.5 Hz, 1H),
6.83 (d, J ˆ 6.5 Hz, 1H), 6.47 (d, J ˆ 2.0 Hz, 1H), 6.32 (d, J ˆ 2.0 Hz, 1H),
5.96 (ddt, J ˆ 16.0, 10.0, 6.5 Hz, 1H), 5.75 (brs, 2H), 5.47 (d, J ˆ 2.5 Hz,
1H), 5.46 (s, 1H), 5.39 (ddt, J ˆ 16.0, 1.5, 1.5 Hz, 1H), 5.37 (s, 1H), 5.36 (s,
1H), 5.34 (s, 1H), 5.22 (ddt, J ˆ 10.0, 1.5, 1.5 Hz, H), 5.22 ± 5.17 (m, 2H),
5.01 (d, J ˆ 6.0 Hz, 1H), 4.92 ± 4.86 (m, 2H), 4.85 (s, 2H), 4.74 (m, 2H), 4.65
(s, 1H), 4.21 (s, 1H), 3.87 (d, J ˆ 9.0 Hz, 1H), 3.84 (dd, J ˆ 10.5, 2.0 Hz,
1H), 3.77 (dd, J ˆ 10.5, 4.5 Hz, 1H), 3.69 (brt, J ˆ 8.0 Hz, 1H), 3.56 (t, J ˆ
9.0 Hz, 1H), 3.55 (q, J ˆ 8.0 Hz, 1H), 3.43 (s, 1H), 2.94 (s, 3H), 2.38 (dd, J ˆ
10.5, 5.5 Hz, 1H), 2.19 (d, J ˆ 13.0 Hz, 1H), 1.92 (dd, J ˆ 10.5, 4.0 Hz, 1H),
1.74 ± 1.68 (m, 1H), 1.61 (d, J ˆ 8.0 Hz, 1H), 1.53 (s, 3H), 1.21 (d, J ˆ 6.5 Hz,
3H), 1.17 (d, J ˆ 6.5 Hz, 3H), 0.90 (brd, J ˆ 6.5 Hz, 3H), 0.89 (brd, J ˆ
Removal of the alloc group from 26: Resin 26 (1.82 g, 0.215 mmol,
1.0 equiv) was suspended in CH2Cl2 (25 mL) at 238C and treated
sequentially with [Pd(PPh3)4] (21 mg, 21 mmol, 0.1 equiv) and nBu3SnH
(623 mg, 2.15 mmol, 10 equiv). The reaction mixture was stirred for 2 h at
238C after which time the resin was filtered and washed (CH2Cl2 2 Â 50 mL,
MeOH 2 Â 50 mL, Et2O 2 Â 20 mL). A small amount of this resin was
cleaved and the product obtained was analyzed 27: 1H NMR (600 MHz,
CD3OD, 330 K): d ˆ 7.59 (brs, 2H), 7.54 (dd, J ˆ 8.0, 1.0 Hz, 1H), 7.39 ± 7.30
(m, 7H), 7.14 (d, J ˆ 2.0 Hz, 1H), 6.98 (dd, J ˆ 8.5, 2.0 Hz, 1H), 6.78 (d, J ˆ
8.5 Hz, 1H), 6.76 ± 5.84 (m, 1H), 6.42 (d, J ˆ 2.0 Hz, 1H), 6.39 (d, J ˆ
2.0 Hz, 1H), 5.92 (ddt, J ˆ 16.0, 8.0, 6.5 Hz, 1H), 5.68 (s, 1H), 5.47 (m,
1H), 5.34 (s, 2H), 5.35 (m, 1H), 5.30 (m, 1H), 5.21 (m, 1H), 5.22 ± 5.17 (m,
2H, CH2-Cbz), 4.96 (brs, 2H), 4.90 ± 4.83 (m, 1H), 4.77 ± 4.70 (m, 1H), 4.72
(m, 1H), 4.61 (s, 1H), 4.72 (m, 1H), 4.29 ± 4.18 (m, 1H), 4.11 (s, 1H), 4.09
(m, 1H), 3.96 ± 3.92 (m, 1H), 3.80 ± 3.75 (m, 1H), 3.58 (dd, J ˆ 11.0, 3.5 Hz,
1H), 2.93 (s, 3H), 2.55 ± 2.40 (m, 2H), 2.03 (s, 3H), 2.00 (s, 3H), 1.78 ± 1.75
(m, 1H), 1.53 ± 1.49 (m, 2H), 1.01 (s, 9H), 0.94 (s, 9H), 0.93 ± 0.91 (m, 6H),
0.89 (s, 9H), 0.77 (s, 9H), 0.73 (s, 9H), 0.63 (s, 9H), 0.23 (s, 6H), 0.18 (s,
3H), 0.12 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.04
‡
6.5 Hz, 3H); MS (ES): calcd for C85H91Cl2N9O28Na [M‡Na] : 1780, found
1780.
Removal of the allyl group: A fresh solution of [Pd(PPh3)4] (1.0 mm in
DMF, 176 mL, 0.176 mmol, 0.1 equiv) followed by nBu3SnH (2.5 mg,
8.8 mmol, 5.0 equiv) was added at room temperature to a solution of the
above allyl ester (30, 3.1 mg, 1.76 mmol, 1.0 equiv) in DMF (100 mL). The
reaction mixture was stirred vigorously for 30 min after which time HPLC
analysis of the reaction mixture indicated complete deprotection. The
crude reaction mixture was injected directly into the HPLC instrument to
recover 2.8 mg (92% isolated) of product as a white solid. HPLC: tR ˆ
6.1 min (LiChrospher C18, 4 mm  250 mm, low rate ˆ 1.0 mLmin 1, 5 !
100% CH3CN in H2O (0.1% TFA) over 15 min); 1H NMR (500 MHz,
CD3OD, 330 K): d ˆ 7.68 (brs, 1H), 7.53 (d, J ˆ 7.0 Hz, 1H), 7.43 (brs, 1H),
7.40 ± 7.29 (m, 7H), 7.14 (t, J ˆ 7.0 Hz, 2H), 7.04 (brs, 1H), 6.98 (dd, J ˆ 9.0,
1.0 Hz, 1H), 6.83 (d, J ˆ 8.5 Hz, 1H), 6.63 (d, J ˆ 1.5 Hz, 1H), 6.43 (d, J ˆ
1.5 Hz, 1H), 5.75 (brs, 2H), 5.46 (d, J ˆ 2.5 Hz, 1H), 5.39 (s, 1H), 5.36 (brs,
2H), 5.23 (brs, 1H), 5.01 (s, 1H), 4.92 ± 4.81 (m, 3H), 4.70 (s, 1H), 4.67 (s,
1H), 4.14 (s, 1H), 3.89 ± 3.82 (m, 2H), 3.77 (dd, J ˆ 10.5, 4.5 Hz, 1H), 3.69
(brt, J ˆ 8.0 Hz, 1H), 3.56 (t, J ˆ 9.0 Hz, 1H), 3.55 (q, J ˆ 8.0 Hz, 1H), 3.43
(s, 1H), 2.94 (s, 3H), 2.39 (dd, J ˆ 10.5, 5.5 Hz, 1H), 2.21 (m, 1H), 1.74 ± 1.68
(m, 2H), 1.63 (m, 1H), 1.53 (s, 3H), 1.22 (d, J ˆ 6.5 Hz, 3H), 1.17 (d, J ˆ
(s, 3H), 0.03 (s, 3H), 0.08 (s, 3H), 0.09 (s, 3H); MS (ES): calcd for
‡
C
110H160Cl2N8O26Si6 [M‡H] : 2247.6, found 2247.5.
Fully protected polymer-bound vancomycin 29
Second glycosidation: Freshly prepared vancosamine fluoride 28[20]
(0.367 mmol, 6.0 equiv) was azeotroped with benzene (3 Â 10 mL) and
then dried under high vacuum for 1 h. The glycosyl fluoride was then
transferred as a CH2Cl2 (5 mL) solution to a flask containing resin 27
(51 mg, 61.2 mmol) and flame-dried 4 Š MS (0.5 g). The mixture was stirred
at ambient temperature for 2 h, then cooled to 408C and BF3 ´ Et2O
(80 mL, 0.550 mmol) was added dropwise. The reaction mixture was
allowed to warm up to 08C over the course of 4 h. The reaction mixture
was cooled back to 408C and quenched with Et3N (0.152 mL, 1.10 mmol,
2.0 equiv relative to BF3 ´ Et2O). The resin was filtered, washed (CH2Cl2
2 Â 50 mL, MeOH 2 Â 50 mL), a small amount was cleaved, and the
Chem. Eur. J. 2001, 7, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3809 $ 17.50+.50/0
3809

K. C. Nicolaou et al.
FULL PAPER
Table 1. Antibacterial activity (MIC: mgmL 1) of vancomycin-derived monosaccharides (36a ± k) against vancomycin-susceptible, vancomycin-intermediate
resistant, and vancomycin-resistant bacteria.
OR
Cl
O
O
OH
O
HO
Cl
O
H
O
H
H
N
NH
N
N
N
N
H
H
H
O
O
H
O
O
NH
O
HO
NH2
OH
OH
36
HO
Com-
R
Sa8250[a]
Sp670[a]
27266[b]
4002[b]
27261[b]
48N[c]
25701[c]
LO3[c]
133[c]
MU50[d]
4001[e]
pound
ampicillin
0.4
3.13
50
3.13
100
3.13
100
3.13
50
50
25
25
25
<0.2
<0.2
12.5
25
50
50
tetracycline
3.13
>100
<0.2
vancomycin
1
0.5
4
0.25
2
0.5
2
1
4
1
0.5
2
4
>16
0.25
OH
2
8
4
8
8
4
8
>16
36a
HO
HO
HO
OH
NH2
O
OH
36b
36c
36d
OH
NHAc
4
8
2
8
8
4
8
4
4
4
4
8
>16
>16
O
NHAc
>16
16
>16
16
>16
16
16
16
OH
OH
O
0.25
0.125
0.5
0.25
0.25
>16
>16
>16
>16
>16
16
O
O
8
HO
OH
NHAc
OH
HO
OH
36e
36f
4
2
4
4
4
2
4
4
2
4
>16
16
H
N
decyl
O
O
Cl
O
>16
16
>16
16
16
>16
>16
16
16
16
HO
OH
H
N
biphenyl
O
O
O
Cl
Cl
36g
36h
4
4
2
4
8
8
8
4
8
4
8
4
16
8
4
4
4
8
4
8
>16
>16
HO
HO
OH
NH2
O
O
OH
NHAc
O
O
O
4
HO
OH
36i
36j
4
8
4
8
8
8
8
4
8
4
4
8
4
8
8
>16
>16
OH
O
16
16
16
16
16
HO
OH
OH
OH
O
O
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
36k
O
HO
OH
OH
O
[a] Vancomycin-susceptible strains of Streptooccus pneumoniae. [b] Vancomycin-susceptible strains of Enterococcus faecalis. [c] Vancomycin-susceptible
strains of Staphylococcus aureus. [d] Vancomycin-intermediate resistant Staphylococcus aureus. [e] Vancomycin-resistant (van A) Enterococcus faecium.
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3810 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 17
3810

Synthesis of Vancomycin
3798±3823
6.5 Hz, 3H), 0.94 (brd, J ˆ 6.5 Hz, 3H), 0.90 (brd, J ˆ 6.5 Hz, 3H); MS
reaction mixture was allowed to stir for 10 min whereupon the appro-
priate benzyl or alkyl bromide was added (1.0 equiv). After warming to
238C with stirring over a period of 12 ± 18 h, the reaction was quenched
with 10% aq HCl and extracted with EtOAc (200 mL). After concen-
tration, the crude residue was purified by flash column chromatography
(silica gel, mixtures of EtOAc and hexanes) to give the desired phenol
(37b ± e).
‡
(ES): calcd for C82H87Cl2N9O28 [M‡H] : 1717.4, found 1717.5.
Removal of the Cbz group: To a solution of the resulting di-Cbz-
vancomycin derivative (2.1 mg, 1.22 mmol, 1.0 equiv) in H2O/MeOH (1:1,
200 mL) under an argon atmosphere was added 10% Pd/C (ꢀ0.5 mg,
ꢀ0.5 equiv) followed by NH4HCO2 (2.0 mg, 31 mmol, 26 equiv) and the
reaction mixture was stirred at room temperature for 2 h after which time
HPLC analysis indicated complete and clean conversion to vancomycin.
The reaction mixture was filtered through a 20 mm syringe fritt and the fritt
was washed with H2O/MeOH/AcOH (1:1:1, 2 Â 0.2 mL). The combined
filtrates were diluted with acetone (2 mL) and centrifuged at 15000 rpm to
obtain a white solid. Purification of this material by HPLC afforded 1.5 mg
of vancomycin (1) (85%) which was identical to authentic material
37b: Rf ˆ 0.43 (40% EtOAc in hexanes); IR (thin film): nÄmax ˆ 3409, 1681,
1
1606, 1508, 1277, 1123, 804 cm 1; H NMR (500 MHz, CDCl3): d ˆ 9.90 (s,
1H), 7.51 (d, J ˆ 1.8 Hz, 1H), 7.49 ± 7.47 (m, 1H), 7.02 (d, J ˆ 8.0 Hz, 1H),
5.93 (s, 1H), 4.21 (t, J ˆ 6.2 Hz, 2H), 1.93 ± 1.90 (m, 2H), 1.60 ± 1.56 (m,
2H), 1.06 (t, J ˆ 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): d ˆ 191.4, 151.7,
146.6, 130.8, 124.9, 114.4, 111.2, 69.3, 31.4, 19.5, 14.1; HRMS: calcd for
(1H NMR, HPLC, HRMS). 1: HPLC: tR ˆ 4.9 min (LiChrospher C18,
‡
C11H14O3 [M‡Na] : 217.0835, found 217.0839.
1
4 mm  250 mm, flow rate ˆ 1.0 mLmin
,
5 ! 100% CH3CN in H2O
37c: Rf ˆ 0.56 (40% EtOAc in hexanes); IR (thin film): nÄmax ˆ 3223, 1674,
(0.1% TFA) over 15 min); 1H NMR (600 MHz, D2O, 330 K): d ˆ 8.03 (s,
1H), 7.96 (s, 1H), 7.91 ± 7.88 (m, 2H), 7.79 ± 7.78 (m, 2H), 7.42 (s, 1H), 7.34 ±
7.32 (m, 1H), 7.28 (s, 1H), 6.91 (s, 1H), 6.82 (s, 1H), 6.14 (brs, 1H), 6.06
(brs, 1H), 5.86 (s, 1H), 5.82 (d, J ˆ 6.5 Hz, 1H), 5.75 (d, J ˆ 4.0 Hz, 1H),
5.71 (s, 1H), 5.67 (s, 1H), 5.23 (brs, 1H), 5.17 (q, J ˆ 6.6 Hz, 1H), 5.03 ± 5.00
(m, 2H), 4.55 (s, 1H), 4.41 (t, J ˆ 7.4 Hz, 1H), 4.18 ± 4.16 (m, 1H), 4.14 ±
4.07 (m, 1H), 3.94 (t, J ˆ 8.8 Hz, 1H), 3.87 ± 3.84 (m, 1H), 3.78 (s, 1H),
3.40 ± 3.39 (m, 1H), 3.15 ± 3.14 (m, 1H), 3.11 (s, 1H), 2.72 ± 2.70 (m, 1H),
2.42 ± 2.40 (m, 1H), 2.38 ± 2.34 (m, 1H), 2.16 ± 2.13 (m, 1H), 2.06 ± 2.02 (m,
1H), 1.99 ± 1.94 (m, 1H), 1.76 (s, 3H), 1.49 (d, J ˆ 6.6 Hz, 3H), 1.24 (d, J ˆ
6.5 Hz, 3H), 1.20 (d, J ˆ 6.5 Hz, 3H); HRMS (MALDI): calcd for
1
1606, 1581, 1507, 1465, 1265, 1248, 1124, 802 cm
;
1H NMR (500 MHz,
CDCl3): d ˆ 9.90 (s, 1H), 7.51 (d, J ˆ 1.9 Hz, 1H), 7.49 ± 7.47 (m, 1H), 7.02
(d, J ˆ 8.1 Hz, 1H), 5.89 (s, 1H), 4.20 (t, J ˆ 6.6 Hz, 2H), 1.94 ± 1.90 (m,
2H), 1.56 ± 1.52 (m, 2H), 1.46 ± 1.38 (m, 6H), 0.97 (t, J ˆ 6.6 Hz, 3H);
13C NMR (125 MHz, CDCl3): d ˆ 191.4, 151.6, 146.6, 130.8, 124.8, 114.4,
111.2, 69.7, 32.1, 29.4, 29.3, 26.2, 22.9, 14.4; HRMS: calcd for C14H20O3
‡
[M‡Na] : 259.2960, found 259.2962.
37d: Rf ˆ 0.34 (50% EtOAc in hexanes); IR (thin film): nÄmax ˆ 3242, 1675,
1
1604, 1510, 1456, 1281, 1117, 1010 cm 1; H NMR (400 MHz, CDCl3): d ˆ
9.80 (s, 1H), 7.45 ± 7.38 (m, 7H), 7.03 (d, J ˆ 8.5 Hz, 1H), 6.04 (s, 1H), 5.19
(s, 2H); 13C NMR (100 MHz, CDCl3): d ˆ 191.1, 151.1, 146.3, 135.2, 130.7,
‡
C66H75Cl2N9O24Na [M‡Na] : 1470.4200, found 1470.4231.
‡
128.8, 127.8, 124.4, 99.9, 71.2; HRMS: calcd for C14H12O3 [M‡Na] :
General procedure for the synthesis of vancomycin monosaccharides
analogues: The preparation of these compounds proceeded in a similar
manner to the solid-phase semisynthesis of vancomycin. Conversion of
compounds 34 to 35 is detailed below.
251.0678, found 251.0683.
37e: Rf ˆ 0.34 (50% EtOAc in hexanes); IR (thin film): nÄmax ˆ 3372, 1678,
1
1606, 1545, 1579, 1277, 1124, 1007 cm 1; H NMR (400 MHz, CDCl3): d ˆ
9.82 (s, 1H), 7.45 ± 7.26 (m, 6H), 7.00 (d, J ˆ 8.1 Hz, 1H), 5.89 (s, 1H), 5.16
(s, 2H); 13C NMR (100 MHz, CDCl3): d ˆ 191.0, 150.6, 146.2, 134.7, 133.6,
130.9, 129.2, 129.1, 124.3, 114.5, 111.5, 70.4; HRMS: calcd for C14H11ClO3
Conversion of compounds 34 to 35: Resin 34 (200 mg) was suspended in
THF (2 mL) and H2O (2 mL) was added. To this suspension, at 238C, was
added Et3P (5.0 equiv) and the mixture was stirred for 4 h. The resin was
filtered and washed (CH2Cl2 2 Â 20 mL, MeOH 2 Â 20 mL, Et2O 2 Â
20 mL) and then re-suspended in CH2Cl2 (20 mL) at 238C and Et3N
(10.0 equiv) followed by the appropriate acid chloride (5.0 equiv) were
added. After 8 h of stirring the resin was filtered off and washed (CH2Cl2
2 Â 20 mL, MeOH 2 Â 20 mL, Et2O 2 Â 20 mL). Product was cleaved from
the resin and globally deprotected as described above for the conversion of
5 to 1 to yield 36a ± k (analytical HPLC: LiChrospher C18, 6 mm Â
250 mm, flow rate 1.0 mLmin 1, 0 ! 100% CH3CN (0.05% TFA) in
H2O (0.05% TFA) over 10 min).
‡
[M‡Na] : 285.0289, found 285.0283.
General procedure for the conversion of phenols 37 to olefins 38: The
appropriate olefinic alcohol (1.5 equiv), triphenylphosphine (1.5 equiv) and
diethyl azodicarboxylate (1.5 equiv) were added to a solution of phenol 37
(1.0 equiv) in THF (0.5m) at 238C. The mixture was stirred for 5 h at
ambient temperature and then concentrated. The residue was purified by
flash column chromatography (silica gel, EtOAc/hexanes mixtures) to give
the desired olefin 38.
38a: Rf ˆ 0.36 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1698, 1595,
1
1263, 990, 929, 787 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 9.98 (s, 1H),
‡
36a: tR ˆ 5.1 min; LCMS (ES): calcd for C59H63Cl2N9O21 [M‡H] : 1306.1,
7.53 ± 7.46 (m, 3H), 7.30 ± 7.25 (m, 1H), 6.16 ± 6.11 (m, 1H), 5.55 (dd, J ˆ 3.5,
19.3 Hz, 1H), 5.41 (dd, J ˆ 3.5, 19.3 Hz, 1H), 4.67 ± 4.66 (m, 2H); 13C NMR
(125 MHz, CDCl3): d ˆ 192.4, 159.5, 138.2, 133.0, 130.4, 123.9, 122.4, 18.4,
found 1306.1.
‡
36b: tR ˆ 5.5 min; LCMS (ES): calcd for C61H65Cl2N9O22 [M‡H] : 1348.1,
found 1348.4.
‡
113.5, 69.7; HRMS: calcd for C10H10O2 [M‡Na] : 185.0573, found 185.0579.
‡
36c: tR ˆ 5.9 min; LCMS (ES): calcd for C61H65Cl2N9O22 [M‡H] : 1348.2,
38b: Rf ˆ 0.45 (15% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1697, 1597,
found 1348.2.
1
1487, 1451, 1263, 1146, 1039, 919 cm
;
1H NMR (500 MHz, CDCl3): d ˆ
‡
36d: tR ˆ 6.5 min; LCMS (ES): calcd for C71H85Cl2N9O22 [M‡H] : 1488.4,
10.0 (s, 1H), 7.49 ± 7.44 (m, 3H), 7.23 ± 7.21 (m, 1H), 6.00 ± 5.94 (m, 1H), 5.55
(dd, J ˆ 3.5, 19.3 Hz, 1H), 5.41 (dd, J ˆ 3.5, 19.3 Hz, 1H), 4.13 ± 4.11 (m,
2H), 2.64 ± 2.60 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 192.5, 159.8,
138.1, 134.5, 130.4, 123.8, 117.7, 67.8, 33.8; HRMS: calcd for C11H12O2
found 1488.4.
‡
36e: tR ˆ 7.7 min; LCMS (ES): calcd for C71H85Cl2N9O22 [M‡H] : 1488.4,
found 1488.4.
‡
‡
[M‡Na] : 199.0729, found 199.0721.
36 f: tR ˆ 7.6 min; LCMS (ES): calcd for C79H76Cl3N9O22 [M‡H] : 1610.8,
found 1610.3.
38c: Rf ˆ 0.48 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1697, 1597,
1488, 1391, 1263, 1148 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 10.0 (s, 1H),
7.54 ± 7.51 (m, 2H), 7.46 ± 7.45 (m, 1H), 7.26 ± 7.22 (m, 1H), 5.96 ± 5.86 (m,
1H), 5.15 ± 5.11 (m, 1H), 5.09 ± 5.06 (m, 1H), 4.08 (t, J ˆ 7.0 Hz, 2H), 2.31
(q, J ˆ 7.0 Hz, 2H), 2.00 ± 1.95 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ
192.5, 160.0, 138.2, 137.9, 130.4, 123.7, 122.2, 116.9, 113.2, 37.8, 30.4, 28.7;
‡
36g: tR ˆ 5.8 min; LCMS (ES): calcd for C66H68Cl3N9O22 [M‡H] : 1430.6,
found 1430.6.
‡
36 h: tR ˆ 6.8 min; LCMS (ES): calcd for C68H70Cl3N9O22 [M‡H] : 1472.6,
found 1472.5.
‡
36i: tR ˆ 6.2 min; LCMS (ES): calcd for C65H72Cl2N8O22 [M‡H] : 1388.2,
‡
HRMS: calcd for C12H14O2 [M‡Na] : 213.0886, found 213.0890.
found 1388.2.
38d: Rf ˆ 0.77 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1697.5,
1592.4, 1447.0, 1261.7, 1042.1, 912.6 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ
10.0 (s, 1H), 7.52 ± 7.50 (m, 2H), 7.25 ± 7.24 (m, 1H), 5.93 ± 5.86 (m, 1H), 5.12
(d, J ˆ 17.5 Hz, 1H), 5.06 (d, J ˆ 10.3 Hz, 1H), 4.10 (t, J ˆ 6.6 Hz, 2H),
2.29 ± 2.19 (m, 2H), 1.93 ± 1.87 (m, 2H), 1.69 ± 1.63 (m, 2H); 13C NMR
(125 MHz, CDCl3): d ˆ 199.9, 160.0, 138.7, 138.1, 130.4, 123.7, 122.3, 115.2,
‡
36j: tR ˆ 6.1 min; LCMS (ES): calcd for C66H68Cl2N8O23 [M‡H] : 1412.2,
found 1412.2.
‡
36k: tR ˆ 6.7 min; LCMS (ES): calcd for C69H72Cl2N8O23 [M‡H] : 1453.3,
found 1453.3.
Preparation of substituted phenols 37b ± e: NaH (694 mg, 1.0 equiv, 60%
suspension) was added to a solution of 3,4-dihydroxybenzaldehyde (37a,
2.50 g, 18.1 mmol, 1.0 equiv) in DMF (25 mL, 0.7m) cooled to 08C. The
‡
113.1, 68.4, 33.7, 28.9, 25.6; HRMS: calcd for C13H16O2 [M‡Na] : 227.2537,
found 227.2540.
Chem. Eur. J. 2001, 7, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3811 $ 17.50+.50/0
3811

K. C. Nicolaou et al.
FULL PAPER
Table 2. Antibacterial activity (MIC: mgmL 1) of vancomycin-derived olefins (40a ± y) against vancomycin-susceptible, vancomycin-intermediate resistant,
and vancomycin-resistant bacteria.
HO
HO
HO
H
OH
N
R1
O
R2
O
O
O
Cl
O
O
OH
HO
Cl
O
O
H
O
H
H
N
N
NHMe
N
N
N
H
H
H
O
O
O
H
O
NH
O
HO
NH2
OH
OH
HO
40
Compound
R
R2
R3
Sa8250[a] Sp670[a] 27266[b] 4002[b] 27261[b] 48N[c] 25701[c] LO3[c] 133[c] MU50[d] 4001[e]
vancomycin
1
0.5
0.25
2
0.5
2
1
1
0.5
4
>16
16
0.25
O
40a
H
D-NMeLeu
D-NMeLeu
0.06
<0.03
0.125
<0.03
0.25
0.25
0.06
0.125 0.06
0.5
O
40b
1
H
H
0.06
0.06
0.25
0.25
0.25
0.25
0.06
0.13
0.06
16
16
0.125
0.5
0.5
40c
O
<0.03
<0.03
D-NMeLeu
<0.03
0.125
0.125
0.125
<0.03
2
40d
O
H
D-NMeLeu
D-NMeLeu
D-NMeLeu
D-NMeLeu
0.25
0.25
0.25
0.25
2
0.5
1
8
8
0.06
0.5
4
4
8
>16
>16
16
6
O
40e
40f
H
0.5
0.5
0.125
0.25
1
0.5
1
0.25
0.25
0.25
1
O
H
0.125
<0.03
0.06
0.5
0.25
0.125 0.06
0.5
0.5
0.13
0.06
O
2
40g
<0.03
0.125
0.125 <0.03
<0.03
H
H
O
6
40h
40i
1
<0.03
0.125
1
<0.03
0.06
1
0.5
0.25
2
0.06
0.125
2
0.25
0.25
2
2
0.125
0.125
2
0.25
2
0.5
0.25
4
2
8
D-NMeLeu
D-NMeLeu
O
O
O
0.125
2
0.125
2
40j
O
D-NMeLeu
D-NMeLeu
2
16
O
O
40k
40l
O
0.06
<0.03
0.25
1
1
1
2
1
8
0.5
0.5
1
2
3
3
O
D-NMeLeu
D-NMeLeu
D-NMeLeu
0.125
0.06
0.06
0.06
0.06
2
0.5
2
2
2
2
2
2
2
40m
40n
40o
O
0.125
0.25
0.125
0.125
0.25
0.25
0.125
1
0.125
0.5
0.125 0.5
0.25
1
O
Ph
Ph
O
0.125
0.25
0.25
4
O
O
O
PhpCl
PhpCl
D-NMeLeu
0.25
0.06
0.25
1
0.06
0.25
0.5
0.25
1
0.25
1
0.25
0.5
1
1
O
O
40p
40q
D-NMeLeu
L-Asn
0.125
0.06
8
0.25
16
1
4
2
>16
16
O
H
H
H
H
4
1
>16
>16
>16
16
16
8
>16
40r
40s
40t
O
2
L-Asn
β-Ala
β-Ala
2
4
4
4
4
>16
16
2
8
O
1
1
2
2
8
4
4
4
8
4
4
4
16
8
8
4
1
4
8
4
>16
>16
O
2
16
O
O
40u
40v
γ-Abu
H
H
8
2
4
4
16
8
4
4
16
8
4
4
4
4
8
8
>16
>16
16
16
>16
L-Phe
O
O
40w
L-Arg
H
4
2
4
2
16
16
8
16
8
16
16
2
8
>16
40x
40y
H
H
H
H
16
16
4
8
4
4
16
>16
>16
O
2
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
[a] Vancomycin susceptible strains of Streptococcus pneumoniae. [b] Vancomycin susceptible strains of Enterococcus faecalis. [c] Vancomycin susceptible
strains of Staphylococcus aureus. [d] Vancomycin-intermediate resistant Staphylococcus aureus. [e] Vancomycin-resistant (van A) Enterococcus faecium.
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3812 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 17
3812

Synthesis of Vancomycin
3798±3823
38e: Rf ˆ 0.67 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1698, 1597,
5.12 (m, 4H), 4.14 (t, J ˆ 6.7 Hz, 2H), 2.63 (t, J ˆ 6.5 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d ˆ 190.9, 153.9, 149.4, 136.2, 134.1, 130.4, 128.6, 128.0,
126.9, 126.5, 117.3, 112.9, 111.1, 70.7, 68.2, 33.5; HRMS: calcd for C18H18O3
[M‡Na] : 305.1148, found 305.1146.
1
1487, 1451, 1386, 1263, 1147, 1040 cm
;
1H NMR (500 MHz, CDCl3): d ˆ
10.0 (s, 1H), 7.52 ± 7.48 (m, 2H), 7.45 (d, J ˆ 2.71 Hz, 1H), 7.26 ± 7.22 (m,
1H), 5.91 ± 5.83 (m, 1H), 5.08 ± 5.07 (m, 1H), 5.01 ± 5.00 (m, 1H), 4.08 (t,
J ˆ 6.5 Hz, 2H), 2.09 ± 2.08 (m, 2H), 1.92 ± 1.84 (m, 2H), 1.55 ± 1.48 (m, 2H),
1.41 ± 1.26 (m, 8H); 13C NMR (125 MHz, CDCl3): d ˆ 192.5, 160.1, 139.5,
138.2, 130.3, 123.6, 122.3, 114.5, 113.1, 68.7, 34.1, 29.7, 29.5, 29.4, 29.4, 29.3
‡
38n: Rf ˆ 0.3 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1693, 1600,
1
1575, 1508, 1256, 1161, 832 cm 1; H NMR (500 MHz, CDCl3): d ˆ 9.90 (s,
1H), 7.90 (d, J ˆ 9.5 Hz, 2H), 7.05 (d, J ˆ 9.5 Hz, 2H), 5.98 ± 5.91 (m, 1H),
5.51 ± 5.48 (m, 1H), 5.40 ± 5.37 (m, 1H), 4.69 ± 4.68 (m, 2H); 13C NMR
(125 MHz, CDCl3): d ˆ 191.2, 164.0, 132.7, 130.4, 118.7, 115.4, 69.3; HRMS:
‡
26.3; HRMS: calcd for C17H24O2 [M‡Na] : 283.1668, found 283.1675.
38 f: Rf ˆ 0.5 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1687, 1591,
1510, 1435, 1268, 1132, 1027 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.90 (s,
1H), 7.51 (dd, J ˆ 1.9, 8.0 Hz, 1H), 7.48 (d, J ˆ 1.9 Hz, 1H), 7.02 (d, J ˆ
8.0 Hz, 1H), 5.95 ± 5.88 (m, 1H), 5.55 (dd, J ˆ 3.5, 19.3 Hz, 1H), 5.41 (dd,
J ˆ 3.5, 19.3 Hz, 1H), 4.15 ± 4.11 (m, 4H), 2.73 ± 2.67 (m, 2H), 1.99 ± 1.89 (m,
2H), 1.62 ± 1.53 (m, 2H), 1.07 (t, J ˆ 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d ˆ 191.3, 155.1, 149.6, 134.5, 130.2, 127.1, 117.6, 112.3, 111.8, 69.2,
‡
calcd for C19H20O3 [M‡Na] : 319.3491, found 319.3498.
38o: Rf ˆ 0.28 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1686, 1589,
1
1502, 1433, 1267, 1132, 1011, 809 cm
;
1H NMR (500 MHz, CDCl3): d ˆ
9.91 (s, 1H), 7.51 ± 7.42 (m, 6H), 7.05 (d, J ˆ 8.05, 1H), 6.20 ± 6.12 (m, 1H),
5.52 (d, J ˆ 18.7 Hz, 1H), 5.39 (d, J ˆ 9.2 Hz, 1H), 5.27 (s, 2H), 4.75 ± 4.74
(m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 191.1, 154.0, 149.4, 135.1, 134.3,
133.0, 130.9, 129.2, 128.8, 126.8, 118.5, 113.3, 112.0, 70.5, 70.1; HRMS: calcd
‡
68.8, 33.9, 31.4, 19.5, 14.2; HRMS: calcd for C14H18O3 [M‡Na] : 257.1148,
found 257.1152.
‡
for C17H15ClO3 [M‡Na] : 325.0602, found 325.0608.
38g: Rf ˆ 0.64 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1687, 1590,
1508, 1435, 1268, 1132, 1021 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.90 (s,
1H), 7.51 (dd, J ˆ 1.9, 8.0 Hz, 1H), 7.48 (d, J ˆ 1.9 Hz, 1H), 7.02 (d, J ˆ
8.0 Hz, 1H), 5.95 ± 5.88 (m, 1H), 5.55 (dd, J ˆ 3.5, 19.0 Hz, 1H), 5.41 (dd,
J ˆ 3.5, 19.0 Hz, 1H), 4.15 ± 4.11 (m, 4H), 2.34 ± 2.30 (m, 2H), 2.02 ± 1.98
(m, 2H), 1.93 ± 1.87 (m, 2H), 1.62 ± 1.49 (m, 2H), 1.05 (t, J ˆ 7.7 Hz, 3H);
13C NMR (125 MHz, CDCl3): d ˆ 191.2, 155.1, 149.7, 138.1, 130.2, 127.0,
115.6, 112.1, 111.5, 69.1, 68.7, 31.4, 30.4, 28.7, 19.5, 14.2; HRMS: calcd for
38p: Rf ˆ 0.18 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1686, 1589,
1
1507, 1434, 1388, 1267, 1130, 1012 cm 1; H NMR (500 MHz, CDCl3): d ˆ
10.0 (s, 1H), 7.53 ± 7.40 (m, 6H), 7.05 (d, J ˆ 8.1 Hz, 1H), 6.03 ± 5.95 (m,
1H), 5.29 ± 5.15 (m, 4H), 4.19 (t, J ˆ 7.5 Hz, 2H), 2.70 ± 2.66 (m, 2H);
13C NMR (125 MHz, CDCl3): d ˆ 191.2, 154.0, 149.9, 135.2, 134.5, 134.2,
131.0, 129.3, 128.8, 126.7, 117.7, 113.5, 111.6, 71.4, 68.6, 33.9; HRMS: calcd
‡
for C18H17ClO3 [M‡Na] : 339.0758, found 339.0760.
38q: Rf ˆ 0.18 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1686, 1589,
‡
C15H20O3 [M‡Na] : 271.1304, found 271.1300.
1
1508, 1434, 1388, 1266, 1130, 1012 cm 1; H NMR (500 MHz, CDCl3): d ˆ
38 h: Rf ˆ 0.58 (30% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1687, 1589,
1435, 1266, 1131 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 9.82 (s, 1H), 7.51 ±
7.45 (m, 2H), 7.01 (d, J ˆ 8.1 Hz, 1H), 5.96 ± 5.76 (m, 1H), 5.24 ± 5.06 (m,
2H), 4.18 ± 4.10 (m, 4H), 2.32 (q, J ˆ 6.8 Hz, 2H), 2.02 ± 1.99 (m, 2H), 1.95 ±
1.88 (m, 2H), 1.60 ± 1.51 (m, 2H), 1.05 (t, J ˆ 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d ˆ 191.2, 155.1, 149.7, 138.1, 130.2, 127.0, 115.6, 112.3,
112.1, 111.5, 111.2, 69.2, 31.4, 30.5, 30.4, 28.7, 19.6, 14.2; HRMS: calcd for
9.89 (s, 1H), 7.49 ± 7.40 (m, 8H), 7.04 (d, J ˆ 8.1 Hz, 1H), 5.22 (s, 2H), 5.13
(d, J ˆ 17.2 Hz, 1H), 5.08 (d, J ˆ 10.2 Hz, 1H), 4.15 (t, J ˆ 6.2 Hz, 2H), 2.34
(q, J ˆ 6.9 Hz, 2H), 2.05 ± 1.99 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ
191.2, 154.0, 150.0, 138.0, 135.2, 134.2, 131.0, 129.2, 128.8, 128.7, 126.6, 115.7,
‡
113.3, 111.4, 70.4, 68.6, 30.5, 28.7; HRMS: calcd for C19H19ClO3 [M‡Na] :
353.0915, found 353.0912.
‡
38r: Rf ˆ 0.4 (15% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1690, 1599,
1506, 1425, 1310, 1256, 1160 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 9.87 (s,
1H), 7.80 (d, J ˆ 9.0 Hz, 2H), 7.01 (d, J ˆ 9.0 Hz, 2H), 6.09 ± 5.99 (m, 1H),
5.40 (d, J ˆ 17.0 Hz, 1H), 5.32 (d, J ˆ 11.0 Hz, 1H), 4.66 (d, J ˆ 6.0 Hz, 2H);
13C NMR (100 MHz, CDCl3): d ˆ 191.9, 164.5, 133.0, 1327.7, 130.7, 119.0,
C16H22O3 [M‡Na] : 285.1461, found 285.1462.
38i: Rf ˆ 0.73 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1691, 1591,
1
1508, 1435, 1268, 1132, 808 cm 1; H NMR (500 MHz, CDCl3): d ˆ 9.92 (s,
1H), 7.51 (dd, J ˆ 1.9, 8.0 Hz, 2H), 7.48 (d, J ˆ 1.9 Hz, 1H), 7.02 (d, J ˆ
8.0 Hz, 1H), 5.98 ± 5.90 (m, 1H), 5.55 (dd, J ˆ 3.5, 19.0 Hz, 1H), 5.41 (dd,
J ˆ 3.5, 19.0 Hz, 1H), 4.14 (q, J ˆ 5.1 Hz, 4H), 2.34 (q, J ˆ 7.0 Hz, 2H),
2.04 ± 1.99 (m, 2H), 1.96 ± 1.90 (m, 2H), 1.58 ± 1.52 (m, 2H), 1.50 ± 1.41 (m,
2H), 1.38 ± 1.37 (m, 4H), 0.96 (t, J ˆ 6.9 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d ˆ 191.3, 155.1, 149.7, 138.1, 130.2, 127.0, 115.6, 112.1, 111.5, 69.5,
68.7, 32.1, 30.4, 29.3, 28.7, 26.3, 22.9, 14.4; HRMS: calcd for C17H24O3
‡
114.9, 69.4; HRMS: calcd for C10H10O2 [M‡Na] : 185.0573, found 185.0576.
38s: Rf ˆ 0.4 (15% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1695, 1600,
1
1575, 1508, 1256, 1159, 832 cm 1; H NMR (500 MHz, CDCl3): d ˆ 9.90 (s,
1H), 7.90 (d, J ˆ 9.5 Hz, 2H), 7.05 (d, J ˆ 9.5 Hz, 2H), 5.98 ± 5.91 (m, 1H),
5.28 ± 5.16 (m, 2H), 4.15 ± 4.09 (m, 2H), 2.60 ± 2.59 (m, 2H); 13C NMR
(125 MHz, CDCl3): d ˆ 191.2, 164.3, 134.3, 132.2, 130.2, 117.8, 115.0, 67.9,
‡
[M‡Na] : 299.1617, found 299.1612.
‡
33.7; HRMS: calcd for C11H12O2 [M‡Na] : 199.0729, found 199.0734.
38j: Rf ˆ 0.57 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1688, 1590,
1510, 1268, 1132 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.90 (s, 1H), 7.51 ±
7.48 (m, 2H), 7.03 (d, J ˆ 8.1 Hz, 1H), 6.03 ± 5.95 (m, 1H), 5.25 (d, J ˆ
17.2 Hz, 1H), 5.19 (d, J ˆ 10.3 Hz, 1H), 4.13 ± 3.97 (m, 2H), 2.69 ± 2.65 (m,
2H), 1.95 ± 1.90 (m, 2H), 1.57 ± 1.55 (m, 2H), 1.46 ± 1.38 (m, 7H), 0.98 ± 0.95
(m, 3H); 13C NMR (125 MHz, CDCl3): d ˆ 191.3, 155.1, 149.5, 134.5, 130.2,
127.1, 117.6, 112.2, 111.8, 69.5, 68.7, 33.9, 32.1, 29.3, 26.2, 22.9, 14.4; HRMS:
38t: Rf ˆ 0.42 (15% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1696, 1601,
1
1575, 1256, 1159, 832 cm 1; H NMR (500 MHz, CDCl3): d ˆ 9.90 (s, 1H),
7.90 (d, J ˆ 9.5 Hz, 2H), 7.05 (d, J ˆ 9.5 Hz, 2H), 5.88 ± 5.79 (m, 1H), 5.08 ±
4.99 (m, 2H), 4.06 (t, J ˆ 6.5 Hz, 2H), 2.29 ± 2.25 (m, 2H), 1.97 ± 1.91 (m,
2H); 13C NMR (125 MHz, CDCl3): d ˆ 191.1, 164.5, 137.8, 132.3, 130.4,
‡
115.8, 115.0, 68.1, 30.4, 28.5; HRMS: calcd for C12H14O2 [M‡Na] :
‡
213.0806, found 213.0799.
calcd for C18H26O3 [M‡Na] : 313.1774, found 313.1778.
38u: Rf ˆ 0.41 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1696, 1601,
38k: Rf ˆ 0.61 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1691, 1591,
1508, 1466, 1435, 1288, 1132 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.98 (s,
1H), 7.50 ± 7.46 (m, 2H), 7.02 (d, J ˆ 8.1 Hz, 1H), 5.98 ± 5.90 (m, 1H), 5.18 ±
5.05 (m, 2H), 4.16 ± 4.12 (m, 4H), 2.33 (q, J ˆ 8.0 Hz, 2H), 2.06 ± 1.97 (m,
2H), 1.96 ± 1.90 (m, 2H), 1.58 ± 1.52 (m, 2H), 1.50 ± 1.35 (m, 6H), 0.96 (t, J ˆ
6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): d ˆ 191.3, 155.1, 149.7, 138.1,
130.2, 127.0, 115.6, 112.1, 111.5, 69.5, 68.7, 32.1, 30.4, 29.3, 28.7, 26.3, 22.9,
1
1575, 1256, 1159 cm 1; H NMR (500 MHz, CDCl3): d ˆ 10.0 (s, 1H), 7.90
(d, J ˆ 9.5 Hz, 2H), 7.05 (d, J ˆ 9.5 Hz, 2H), 5.88 ± 5.79 (m, 1H), 5.08 ± 4.99
(m, 2H), 4.04 (t, J ˆ 6.4 Hz, 2H), 2.16 ± 2.12 (m, 2H), 1.86 ± 1.80 (m, 2H),
1.62 ± 1.56 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 191.0, 164.5, 138.7,
132.4, 130.2, 115.2, 115.1, 68.1, 33.7, 28.9, 25.6; HRMS: calcd for C13H13O2
‡
[M‡Na] : 227.1043, found 227.1048.
‡
14.1; HRMS: calcd for C19H28O3 [M‡Na] : 327.1930, found 327.1932.
38v: Rf ˆ 0.5 (15% EtOAc in hexanes); IR (thin film): nÄmax ˆ 2926, 1695,
1601, 1575, 1509, 1257, 1158 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.97 (s,
1H), 7.89 (d, J ˆ 10.0 Hz, 2H), 7.06 (d, J ˆ 10.0 Hz, 2H), 5.91 ± 5.83 (m, 1H),
5.08 ± 5.07 (m, 1H), 5.01 ± 5.00 (m, 1H), 4.08 (t, J ˆ 6.5 Hz, 2H), 2.09 ± 2.08
(m, 2H), 1.92 ± 1.84 (m, 2H), 1.55 ± 1.48 (m, 2H), 1.41 ± 1.26 (m, 8H);
13C NMR (125 MHz, CDCl3): d ˆ 191.1, 164.6, 139.4, 132.3, 130.1, 115.1,
114.5, 68.7, 34.1, 29.9, 29.7, 29.6, 29.4, 29.2, 26.3; HRMS: calcd for C17H24O2
38l: Rf ˆ 0.61 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1686, 1589,
1
1507, 1434.8, 1266, 1131, 1015 cm 1; H NMR (500 MHz, CDCl3): d ˆ 9.90
(s, 1H), 7.53 ± 7.40 (m, 7H), 7.09 (d, J ˆ 8.1 Hz, 1H), 6.20 ± 6.13 (m, 1H),
5.53 (d, J ˆ 17.2 Hz, 1H), 5.39 (d, J ˆ 10.6 Hz, 1H), 5.32 (s, 2H), 4.76 (d, J ˆ
5.1 Hz, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 191.2, 154.4, 149.4, 136.6,
133.1, 130.7, 129.0, 128.5, 127.4, 126.9, 118.4, 113.3, 112.1, 71.2, 70.1; HRMS:
‡
‡
[M‡Na] : 283.1668, found 283.1660.
calcd for C17H16O3 [M‡Na] : 291.0991, found 291.0988.
38m: Rf ˆ 0.48 (30% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1686, 1588,
1507, 1435, 1268, 1130, 1019 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 9.83 (s,
1H), 7.38 ± 7.26 (m, 7H), 7.00 (d, J ˆ 8.2 Hz, 1H), 5.96 ± 5.88 (m, 1H), 5.18 ±
38w: Rf ˆ 0.30 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 2926, 2856,
1
1687, 1588, 1508, 1436, 1389, 1268, 1131, 1018 cm
;
1H NMR (400 MHz,
CDCl3): d ˆ 9.82 (s, 1H), 7.45 ± 7.32 (m, 7H), 6.98 (d, J ˆ 8.2 Hz, 1H), 5.23
Chem. Eur. J. 2001, 7, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3813 $ 17.50+.50/0
3813

K. C. Nicolaou et al.
FULL PAPER
Table 3. Antibacterial activity (MIC: mgmL 1) of vancomycin-derived thioacetate (40z ± qq) against vancomycin-susceptible, vancomycin-intermediate
resistant, and vancomycin-resistant bacteria.
HO
HO
HO
H
OH
N
R1
O
R2
O
O
O
Cl
O
O
OH
HO
Cl
O
O
H
O
H
H
N
N
NHMe
N
N
N
H
H
H
O
O
O
H
O
NH
O
HO
NH2
OH
OH
HO
40
27266[b] 4002[b] 27261[b] 48N[c]
Compound
R1
R2
vancomycin
Sa8250[a] Sp670[a]
25701[c] LO3[c] 133[c]
MU50[d] 4001[e]
1
0.25
0.25
0.5
0.5
0.25
0.25
2
0.5
0.5
1
1
0.5
0.5
4
2
>16
>16
2
1
O
SAc
40z
H
0.5
0.5
0.5
O
40aa
0.5
0.5
0.5
0.25
0.5
0.125
0.125
0.125
0.125
0.125
0.125
0.25
0.25
0.125
0.125
0.125
0.25
0.06 <0.03
0.06 <0.03
0.125 <0.03
0.5
0.5
0.5
16
16
16
H
H
H
H
SAc
SAc
O
O
0.125
0.125
40bb
40cc
0.5
0.125
SAc
SAc
2
6
O
40dd
40ee
0.5
0.5
0.5
2
1
1
1
1
4
4
4
2
8
2
4
O
SAc
H
H
0.25
0.5
0.5
0.5
0.5
0.25
>16
O
40ff
0.5
0.5
0.5
0.25
0.25
0.25
0.25
0.25
0.25
0.5
0.25
0.25
0.25
0.125 0.06
0.125 <0.03
0.06 <0.03
1
>16
>16
16
SAc
SAc
O
40gg
0.125
0.125
0.25
0.125
0.125
0.125
1
H
H
O
O
SAc
SAc
SAc
0.125
0.125
0.5
40hh
40ii
2
1
0.5
4
2
2
8
8
8
4
4
8
8
8
H
6
O
O
40jj
0.5
0.25
0.25
0.25
0.5
0.25
0.25
0.25
0.5
O
O
40kk
40ll
SAc
SAc
0.06
0.06
0.5
1
0.25
2
0.06
0.5
0.25
1
0.25
2
0.125
2
0.125 0.125 0.5
1
2
2
4
4
0.125
0.125
1
O
O
2
8
1
2
4
1
3
O
O
O
40mm
2
0.5
2
8
2
4
SAc
SAc
3
O
Ph
Ph
O
O
40nn
40oo
1
0.5
0.25
0.5
0.5
0.5
0.5
O
SAc
SAc
2
0.25
0.5
0.25
0.5
0.25
0.25
0.5
0.5
1
0.5
0.5
0.5
0.5
1
1
1
4
2
0.5
0.5
0.25
40pp
40qq
O
O
PhpCl
PhpCl
O
0.25
0.125
0.5
0.25
0.5
1
1
1
0.5
1
2
SAc
[a] Vancomycin-susceptible strains of Streptococcus pneumoniae. [b] Vancomycin-susceptible strains of Enterococcus faecalis. [c] Vancomycin-susceptible
strains of Staphylococcus aureus. [d] Vancomycin-intermediate resistant Staphylococcus aureus. [e] Vancomycin-resistant (van A) Enterococcus faecium.
(s, 2H), 4.08 (t, J ˆ 6.7 Hz, 2H), 1.88 ± 1.84 (m, 2H), 1.51 ± 1.47 (m, 2H),
1.33 ± 1.29 (m, 8H), 0.89 ± 0.87 (m, 3H); 13C NMR (100 MHz, CDCl3): d ˆ
191.0, 153.9, 149.6, 136.3, 130.3, 128.6, 128.0, 126.9, 126.3, 112.8, 110.8, 70.7,
69.0, 31.7, 29.3, 29.2, 29.0, 26.0, 22.6, 14.1; HRMS: calcd for C22H28O3
112.8, 110.8, 70.7, 69.0, 31.8, 29.6, 29.5, 29.3, 29.0, 26.0, 22.6, 14.1; HRMS:
‡
calcd for C24H32O3 [M‡Na] : 391.2243, found 391.2239.
38y: Rf ˆ 0.16 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1685, 1588,
1
1507, 1434, 1434, 1387, 1269, 1129 cm 1; H NMR (400 MHz, CDCl3): d ˆ
‡
[M‡Na] : 363.1930, found 363.1935.
9.81 (s, 1H), 7.50 ± 7.36 (m, 12H), 7.01 (d, J ˆ 8.1 Hz, 1H), 5.26 (s, 2H), 5.22
(s, 2H); 13C NMR (100 MHz, CDCl3): d ˆ 190.8, 154.2, 149.1, 136.5, 136.2,
130.2, 128.6, 128.5, 128.1, 128.0, 127.3, 127.0, 126.7, 113.0, 112.2, 70.9, 70.7;
38x: Rf ˆ 0.33 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 2924, 2854,
1
1688, 1588, 1508, 1436, 1389, 1268, 1131, 1016 cm
;
1H NMR (400 MHz,
‡
HRMS: calcd for C21H18O3 [M‡Na] : 341.1148, found 341.1156.
CDCl3): d ˆ 9.82 (s, 1H), 7.45 ± 7.32 (m, 7H), 6.99 (d, J ˆ 8.0 Hz, 1H), 5.23
(s, 2H), 4.08 (t, J ˆ 6.7 Hz, 2H), 1.89 ± 1.82 (m, 2H), 1.50 ± 1.47 (m, 2H),
1.36 ± 1.26 (m, 12H), 0.88 (t, J ˆ 6.72 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d ˆ 191.0, 153.9, 149.6, 136.3, 130.3, 128.6, 128.0, 126.9, 126.9, 126.3,
38z: Rf ˆ 0.35 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 2924, 2854,
1686, 1586, 1509, 1270, 1126 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 9.83 (s,
1H), 7.42 ± 7.35 (m, 6H), 6.96 (d, J ˆ 8.0 Hz, 1H), 5.18 (s, 2H), 4.07 (t, J ˆ
3814
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0947-6539/01/0717-3814 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 17

Synthesis of Vancomycin
3798±3823
6.4 Hz, 2H), 1.88 ± 1.83 (m, 2H), 1.49 ± 1.46 (m, 2H), 1.34 ± 1.28 (m, 10H),
0.88 (t, J ˆ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 190.9, 153.5,
149.7, 134.8, 133.8, 130.5, 128.7, 128.3, 126.2, 112.8, 110.8, 70.0, 69.0, 31.7,
39g: Rf ˆ 0.20 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1691, 1589,
1509, 1435, 1268, 1132, 1025 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.87 (s,
1H), 7.47 (d, J ˆ 8.5 Hz, 1H), 7.42 (s, 1H), 7.00 (d, J ˆ 8.0 Hz, 1H), 4.12 (m,
4H), 3.01 (t, J ˆ 7.4 Hz, 2H), 2.40 (s, 3H), 1.98 ± 1.94 (m, 2H), 1.93 ± 1.81 (m,
4H), 1.60 ± 1.52 (m, 2H), 1.04 (t, J ˆ 7.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d ˆ 196.1, 191.1, 155.1, 149.5, 130.2, 127.1, 119.4, 112.1, 111.5, 69.1,
‡
29.3, 29.2, 29.0, 26.0, 22.6, 14.1; HRMS: calcd for C23H29ClO3 [M‡Na] :
411.1697, found 411.1691.
38aa: Rf ˆ 0.36 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 2921, 2850,
1684, 1585, 1508, 1462, 1270, 1234, 1124 cm 1; 1H NMR (400 MHz, CDCl3):
d ˆ 9.82 (s, 1H), 7.41 ± 7.32 (m, 6H), 6.95 (d, J ˆ 8.2 Hz, 1H), 5.19 (s, 2H),
4.06 (t, J ˆ 6.2 Hz, 2H), 1.86 ± 1.82 (m, 2H), 1.49 ± 1.43 (m, 2H), 1.35 ± 1.27
(m, 14H), 0.87 (t, J ˆ 6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 190.9,
153.5, 149.7, 134.8, 133.8, 130.5, 128.7, 128.3, 126.2, 112.8, 110.8, 69.9, 69.0,
31.8, 29.6, 29.6, 29.5, 29.3, 29.0, 26.0, 22.6, 14.1; HRMS: calcd for
‡
68.9, 31.4, 29.5, 26.1, 25.5, 19.6, 14.2; HRMS: calcd for C17H24O4S [M‡Na] :
347.1287, found 347.1292.
39 h: Rf ˆ 0.58 (30% EtOAc in hexanes); IR (thin film): nÄmax ˆ 2928, 1691,
1588, 1510, 1268, 1132, 1014 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.90 (s,
1H), 7.50 ± 7.45 (m, 2H), 7.02 (d, J ˆ 8.5 Hz, 1H), 4.16 ± 4.10 (m, 4H), 2.97
(t, J ˆ 7.4 Hz, 2H), 2.39 (s, 3H), 1.96 ± 1.90 (m, 4H), 1.79 ± 1.72 (m, 2H),
1.65 ± 1.63 (m, 2H), 1.56 ± 1.52 (m, 2H), 1.43 ± 1.37 (m, 6H), 0.96 (t, J ˆ
7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): d ˆ 196.2, 191.3, 155.0, 149.6,
130.2, 127.0, 112.1, 111.4, 69.5, 69.2, 32.1, 31.0, 29.6, 29.3, 28.9, 26.9, 25.7, 22.9,
‡
C25H33ClO3[M‡Na] : 439.2010, found 439.2016.
38bb: Rf ˆ 0.08 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1686, 1590,
1
1506, 1435, 1269, 1130, 1012, 809 cm
;
1H NMR (400 MHz, CDCl3): d ˆ
‡
14.4; HRMS: calcd for C19H28O4S [M‡Na] : 375.1200, found 375.1201.
9.81 (s, 1H), 7.46 ± 7.26 (m, 10H), 7.00 (d, J ˆ 8.2 Hz, 1H), 5.19 (s, 2H), 5.15
(s, 2H); 13C NMR (100 MHz, CDCl3): d ˆ 190.7, 153.8, 148.9, 134.9, 134.5,
134.0, 133.8, 130.4, 128.8, 128.7, 128.6, 128.4, 126.9, 112.9, 112.0, 70.0;
HRMS: calcd for C21H16Cl2O3 [M‡Na] : 409.0364, found 409.0364.
39i: Rf ˆ 0.51 (30% EtOAc in hexanes); IR (thin film): nÄmax ˆ 2928, 1686,
1588, 1509, 1268, 1131 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 9.82 (s, 1H),
7.43 ± 7.37 (m, 2H), 6.94 (d, J ˆ 8.2 Hz, 1H), 4.06 (t, J ˆ 6.1 Hz, 2H), 2.97 (t,
J ˆ 6.1 Hz, 2H), 2.30 (s, 3H), 1.93 ± 1.77 (m, 8H), 1.48 ± 1.30 (m, 8H), 0.89
(t, J ˆ 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): d ˆ 195. 0, 190.9, 154.6,
149.1, 129.7, 126.7, 111.6, 110.9, 69.0, 68.4, 31.7, 30.6, 28.9, 28.8, 28.7, 28.0,
‡
Preparation of thioacetates 39 from olefins 38: Thioacetic acid (2.0 equiv)
followed by AIBN (0.2 equiv) was added to a solution of olefinic aldehyde,
38, (1.0 equiv) in benzene (0.1m). The reaction mixture was heated to reflux
and stirred for 1.5 h. After cooling, the solvent was removed under reduced
pressure and the residue was purified by flash column chromatography
(silica gel, EtOAc/hexanes mixtures) to give the desired thioacetate 39.
‡
26.3, 25.8, 22.5, 14.0; HRMS: calcd for C20H30O4S [M‡Na] : 389.1757,
found 389.1759.
39j: Rf ˆ 0.50 (30% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1686, 1587,
1506, 1435, 1267, 1132, 1025 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.91 (s,
1H), 7.53 ± 7.47 (m, 7H), 7.08 (d, J ˆ 8.0 Hz, 1H), 5.23 (s, 2H), 4.22 (t, J ˆ
6.3 Hz, 2H), 3.17 (t, J ˆ 7.0 Hz, 2H), 2.41 (s, 3H), 2.23 ± 2.20 (m, 2H);
13C NMR (125 MHz, CDCl3): d ˆ 196.0, 191.2, 154.4, 149.7, 136.6, 130.7,
129.0, 128.5, 127.4, 113.3, 111.8, 71.2, 67.8, 31.0, 29.5, 26.2; HRMS: calcd for
39a: Rf ˆ 0.44 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1695, 1592,
1
1260, 1137, 1038, 955 cm 1; H NMR (500 MHz, CDCl3): d ˆ 10.0 (s, 1H),
7.54 ± 7.51 (m, 2H), 7.46 ± 7.45 (m, 1H), 7.26 ± 7.22 (m, 1H), 4.14 (t, J ˆ
6.3 Hz, 2H), 3.01 (t, J ˆ 6.3 Hz, 2H), 2.40 (s, 3H), 2.17 ± 2.13 (m, 2H);
13C NMR (125 MHz, CDCl3): d ˆ 196.0, 193.0, 160.3, 138.5, 130.9, 124.5,
‡
C19H20O4S [M‡H] : 344.1082, found 344.1081.
‡
123.2, 113.9, 68.5, 31.1, 30.6, 26.8; HRMS: calcd for C12H14O3S [M‡Na] :
39k: Rf ˆ 0.34 (30% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1687, 1588,
1508, 1436, 1268, 1131 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 9.82 (s, 1H),
7.44 ± 7.32 (m, 7H), 6.99 (d, J ˆ 7.9 Hz, 1H), 5.21 (s, 2H), 4.09 (t, J ˆ 6.5 Hz,
2H), 2.96 (t, J ˆ 6.5 Hz, 2H), 2.32 (s, 3H), 1.94 ± 1.91 (m, 2H), 1.80 ± 1.76
(m, 2H); 13C NMR (100 MHz, CDCl3): d ˆ 195.8, 290.9, 153.9, 149.4, 136.2,
130.0, 128.6, 128.0, 127.0, 126.5, 112.7, 111.0, 70.7, 68.4, 30.6, 28.7, 28.0, 26.3;
261.0556, found 261.0559.
39b: Rf ˆ 0.43 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1696, 1594,
1
1487, 1450, 1263, 1134, 789 cm 1; H NMR (500 MHz, CDCl3): d ˆ 10.0 (s,
1H), 7.54 ± 7.51 (m, 2H), 7.46 ± 7.45 (m, 1H), 7.26 ± 7.22 (m, 1H), 4.14 (t, J ˆ
6.3 Hz, 2H), 3.01 (t, J ˆ 6.3 Hz, 2H), 2.40 (s, 3H), 1.97 ± 1.92 (m, 2H), 1.97 ±
1.81 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 196.2, 192.5, 159.8, 138.1,
130.4, 123.8, 122.3, 113.1, 67.9, 31.0, 29.1, 28.5, 26.6; HRMS: calcd for
‡
HRMS: calcd for C20H22O4S [M‡Na] : 358.1239, found 358.1237.
‡
C13H16O3S [M‡Na] : 275.0712, found 275.0719.
39l: Rf ˆ 0.38 (30% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1692, 1591,
1
1508, 1435, 1267, 1012, 811 cm 1; H NMR (500 MHz, CDCl3): d ˆ 9.90 (s,
39c: Rf ˆ 0.2 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1695, 1596,
1
1488, 1263, 1137, 951 cm 1; H NMR (500 MHz, CDCl3): d ˆ 10.0 (s, 1H),
1H), 7.49 ± 7.39 (m, 6H), 7.05 (d, J ˆ 7.9 Hz, 1H), 5.27 (s, 2H), 4.18 (t, J ˆ
11.8 Hz, 2H), 3.14 (t, J ˆ 9.7 Hz, 2H), 2.40 (s, 3H), 2.24 ± 2.17 (m, 2H);
13C NMR (125 MHz, CDCl3): d ˆ 195.2, 191.2, 154.1, 149.7, 135.1, 134.3,
130.9, 129.2, 128.8, 126.9, 113.3, 111.7, 70.4, 67.8, 31.0, 29.5, 26.2; HRMS:
7.54 ± 7.51 (m, 2H), 7.46 ± 7.45 (m, 1H), 7.26 ± 7.22 (m, 1H), 4.09 (t, J ˆ
6.9 Hz, 2H), 2.98 (t, J ˆ 6.9 Hz, 2H), 2.40 (s, 3H), 1.93 ± 1.87 (m, 2H),
1.76 ± 1.72 (m, 2H), 1.66 ± 1.61 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ
196.3, 192.5, 160.0, 138.2, 130.4, 123.7, 122.3, 113.1, 68.3, 31.0, 29.7, 29.3, 29.0,
‡
calcd for C19H19O4ClS [M‡Na] : 401.0585, found 401.0589.
‡
25.6; HRMS: calcd for C14H18O3S [M‡Na] : 289.0869, found 289.0873.
39m: Rf ˆ 0.42 (30% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1686, 1589,
1508, 1435, 1267, 1132, 1011, 811 cm 1; 1H NMR (500 MHz, CDCl3) d ˆ 9.90
(s, 1H), 7.51 ± 7.44 (m, 6H), 7.05 (d, J ˆ 7.9 Hz, 1H), 5.28 (s, 2H), 4.15 (t, J ˆ
6.2 Hz, 2H), 3.05 (t, J ˆ 6.6 Hz, 2H), 2.40 (s, 3H), 2.03 ± 1.96 (m, 2H), 1.92 ±
1.84 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 196.1, 191.2, 154.0, 149.9,
135.1, 134.3, 130.9 129.2, 128.8, 128.7, 126.7, 113.2, 111.5, 70.4, 68.8, 31.0,
39d: Rf ˆ 0.3 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1695, 1596,
1
1488, 1263, 1137, 951 cm 1; H NMR (500 MHz, CDCl3): d ˆ 9.97 (s, 1H),
7.45 ± 7.44 (m, 2H), 7.39 ± 7.38 (m, 1H), 7.18 ± 7.14 (m, 1H), 4.01 (t, J ˆ
6.6 Hz, 2H), 2.89 (t, J ˆ 6.6 Hz, 2H), 2.31 (s, 3H), 1.84 ± 1.79 (m, 2H),
1.65 ± 1.54 (m, 4H), 1.51 ± 1.43 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ
196.1, 192.4, 160.0, 138.1, 130.3, 128.6, 123.5, 122.1, 113.2, 68.4, 30.9, 29.8,
‡
29.1, 28.5, 26.8; HRMS: calcd for C20H21ClO4S [M‡Na] : 415.0741, found
‡
415.0749.
29.4, 29.3, 28.8, 25.9, 25.4; HRMS: calcd for C15H20O3S [M‡Na] : 303.1025,
found 303.1018.
39n: Rf ˆ 0.27 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1693, 1600,
1
1577, 1510, 1254, 1160, 1029, 956, 833 cm
;
1H NMR (500 MHz, CDCl3):
39e: Rf ˆ 0.37 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1695, 1595,
1
1451, 1262, 1138, 1039, 953 cm 1; H NMR (500 MHz, CDCl3): d ˆ 10.0 (s,
d ˆ 10.0 (s, 1H), 7.90 (d, J ˆ 9.5 Hz, 2H), 7.05 (d, J ˆ 9.5 Hz, 2H), 4.10 (t,
J ˆ 6.4 Hz, 2H), 3.01 (t, J ˆ 6.3 Hz, 2H), 2.40 (s, 3H), 2.17 ± 2.13 (m, 2H);
13C NMR (125 MHz, CDCl3): d ˆ 196.3, 191.2, 164.1, 132.4, 130.2, 119.5,
1H), 7.52 ± 7.48 (m, 2H), 7.45 (d, J ˆ 2.7 Hz, 1H), 7.26 ± 7.22 (m, 1H), 4.08 (t,
J ˆ 6.5 Hz, 2H), 2.93 (t, J ˆ 7.36 Hz, 2H), 2.39 (s, 3H), 1.89 ± 1.85 (m, 2H),
1.66 ± 1.61 (m, 2H), 1.55 ± 1.53 (m, 2H), 1.43 ± 1.34 (m, 10H); 13C NMR
(125 MHz, CDCl3): d ˆ 196.4, 192.6, 160.1, 138.1, 130.9, 123.7, 122.3, 113.1,
68.6, 31.0, 29.9. 29.8, 29.7, 29.6, 29.5, 29.5, 29.4, 29.1, 26.3; HRMS: calcd for
‡
115.1, 68.4, 31.5, 29.8, 26.0; HRMS: calcd for C12H14O3S [M‡Na] :
261.0556, found 261.0547.
39o: Rf ˆ 0.39 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1695, 1600,
1575, 1509, 1258, 1159 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 10.0 (s, 1H),
7.90 (d, J ˆ 9.5 Hz, 2H), 7.05 (d, J ˆ 9.5 Hz, 2H), 4.10 (t, J ˆ 6.4 Hz, 2H),
2.97 (t, J ˆ 7.2 Hz, 2H), 2.36 (s, 3H), 1.93 ± 1.87 (m, 2H), 1.75 ± 1.70 (m, 2H);
13C NMR (125 MHz, CDCl3): d ˆ 196.3, 191.2, 164.1, 132.4, 130.2, 119.5,
‡
C19H28O3S [M‡Na] : 359.1651, found 359.1649.
39 f: Rf ˆ 0.31 (20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1692, 1592,
1509, 1434, 1268, 1132 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.89 (s, 1H),
7.50 (dd, J ˆ 1.9, 8.1 Hz, 1H), 7.46 (d, J ˆ 1.85 Hz, 1H), 7.02 (d, J ˆ 8.1 Hz),
4.17 ± 4.13 (m, 4H), 3.14 (t, J ˆ 7.0 Hz, 2H), 2.40 (s, 3H), 2.20 ± 2.15 (m,
2H), 1.96 ± 1.88 (m, 2H), 1.60 ± 1.54 (m, 2H), 1.05 (t, J ˆ 7.3 Hz, 3H);
13C NMR (125 MHz, CDCl3): d ˆ 195.9, 191.2, 155.1, 149.4, 130.2, 127.2,
119.4, 112.2, 69.2, 67.8, 31.4, 29.5, 26.1, 25.5, 19.6, 14.2; HRMS: calcd for
‡
115.1, 68.4, 31.0, 29.7, 29.2, 25.6; HRMS: calcd for C13H16O3S [M‡Na] :
275.0712, found 275.0717.
39p: Rf ˆ 0.26 (15% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1695, 1600,
1
1509, 1257, 1159, 833 cm 1; H NMR (500 MHz, CDCl3): d ˆ 10.0 (s, 1H),
‡
C16H22O4S [M‡Na] : 333.1131, found 333.1140.
7.90 (d, J ˆ 9.5 Hz, 2H), 7.05 (d, J ˆ 9.5 Hz, 2H), 4.10 (t, J ˆ 7.0 Hz, 2H),
Chem. Eur. J. 2001, 7, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3815 $ 17.50+.50/0
3815

K. C. Nicolaou et al.
FULL PAPER
Table 4. Antibacterial activity (MIC: mgmL 1) of monomeric vancomycin derivatives against vancomycin-susceptible, vancomycin-intermediate resistant,
and vancomycin-resistant bacteria.
HO
HO
HO
H
OH
N
R1
O
R2
O
O
O
Cl
O
O
OH
Cl
H
N
HO
O
H
N
H
N
O
O
NHMe
N
H
N
H
H
O
O
O
H
O
NH
O
HO
NH2
OH
OH
HO
40
Compound R1
R2
MU50[a] 133[a] 4002[b] 1528[c] 2689[c] 2741[c] 2781[c] 2805[c] 4001[d] 1669[e] 2671[e] 2823[e] 1803[f] 1924[f] 1944[f]
tetracycline
50
0.2
50
100
100 >100
50 >100
50
100
2
50
25
2
50
>100
2
100
100
50
50
1
25
>100
50
25
25
50
50
vancomycin
1
3.13 0.39
0.39 >100
100
O
8
2
2
1
1
2
0.5
1
1
0.125
1
40gg
40dd
SAc
SAc
Ph
H
4
O
SAc
H
4
2
4
0.5
4
2
4
4
8
4
4
4
8
8
8
1
1
2
1
2
4
0.5
1
0.125
0.06
2
9
O
0.5
2
2
8
1
40ii
H
9
40rr
O
O
Ph
Ph
OH
0.25 0.125
0.25
16
0.5
4
2
8
8
4
1
1
1
4
40ss
40tt
O
1
4
8
1
0.5
8
0.5
8
0.5
0.5
2
2
4
0.25
2
2
8
0.125
4
2
8
2
4
2
8
0.25
1
O
O
8
16
2
O
O
Ph
Ph
6
40uu
40vv
>16 >16
16
>16
>16
>16
>16
>16
>16
>16
2
>16
>16
16
16
16
8
O
O
O
O
PhpCl
PhpCl
PhpCl
PhpCl
OH
1
0.25
2
0.25
0.25
2
0.125
1
0.125
4
2
0.25
4
0.5
0.5
0.25
0.5
40ww
40xx
O
PhpCl
4
4
>16
>16
1
4
>16
>16
4
>16
>16
4
1
0.5
8
2
16
4
4
2
O
O
>16 >16
>16 >16
16
>16
>16
>16
>16
>16
>16
>16
>16
>16
16
6
8
40yy
>16
>16
>16
>16
>16
>16
>16
[a] Vancomycin-intermediate resistant Staphylococcus aureus. [b] Vancomycin-susceptible Enterococcus faecalis. [c] Vancomycin-resistant (van A) Enter-
ococcus faecalis. [d] Vancomycin-resistant (van A) Enterococcus faecium. [e] Vancomycin-resistant (van A) and Synercid-resistant (sat G) Enterococcus
faecium. [f] Vancomycin-resistant (van A) and Synercid-resistant (sat A) Enterococcus faecium.
2.98 (t, J ˆ 6.9 Hz, 2H), 2.39 (s, 3H), 1.92 ± 1.87 (m, 2H), 1.75 ± 1.69 (m,
2H), 1.65 ± 1.59 (m, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 196.2, 191.1,
164.5, 132.3, 130.2, 119.4, 115.1, 68.4, 31.0, 29.6, 29.2, 25.5; HRMS: calcd for
appropriate aldehyde (37, 38, or 39, ꢀ18.0 mg, 1.3 equiv, 89.6 mmol). The
solution was heated at 658C for 2 h and then allowed to cool to room
temperature prior to addition of NaCNBH3 (8.6 mg, 2.0 equiv, 138.0 mmol).
The reaction mixture was then stirred at 658C for an additional 2 h and
allowed to cool to ambient temperature overnight (12 ± 18 h). Purification
by preparative reverse-phase HPLC (VYDAC C18, 25 mm  250 mm, flow
rate 6.5 mLmin 1, 0 ! 100% CH3CN (0.1% TFA) in H2O over 30 min)
gave the desired compounds 40 (analytical HPLC data given below for
LiChrospher C18, 6 mm  250 mm, flow rate 1.0 mLmin 1, 0 ! 100%
CH3CN (0.05% TFA) in H2O (0.05% TFA) over 10 min for 40a ± qq, over
8 min for 40rr± yy.).
‡
C14H18O3S [M‡Na] : 289.0869, found 289.0868.
39q: Rf ˆ 0.25 (15% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1695, 1600,
1
1510, 1257, 1159, 833 cm 1; H NMR (500 MHz, CDCl3): d ˆ 9.96 (s, 1H),
7.90 (d, J ˆ 9.5 Hz, 2H), 7.05 (d, J ˆ 9.5 Hz, 2H), 4.10 (t, J ˆ 7.0 Hz, 2H),
2.98 (t, J ˆ 7.1 Hz, 2H), 2.38 (s, 3H), 1.91 ± 1.85 (m, 2H), 1.72 ± 1.66 (m, 2H),
1.59 ± 1.49 (m, 4H); 13C NMR (125 MHz, CDCl3): d ˆ 196.2, 191.1, 164.5,
132.3, 130.2, 115.1, 68.5, 31.0, 29.8, 29.3, 28.8, 25.9, 25.5; HRMS: calcd for
‡
C15H20O3S [M‡Na] : 303.1025, found 303.1030.
40a: tR ˆ 7.0 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.92 (d, J ˆ
9.0 Hz, 2H), 7.76 (d, J ˆ 15.0 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.48 (br,
1H), 7.22 (d, J ˆ 8.5 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J ˆ 9.5 Hz, 2H), 6.78 (brs,
2H), 6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.98 ± 5.91 (m,
1H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz,
2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 5.28 ± 5.10 (m, 2H), 4.90 (q, J ˆ 6.6 Hz, 1H),
4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 ± 3.88 (m, 6H), 3.72
(d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.60 ± 2.59 (m,
2H), 2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.77 (s, 3H), 1.36 (m, 2H), 1.25
(d, J ˆ 6.25 Hz, 3H), 1.00 ± 0.97 (m, 6H); LCMS (ES): calcd for
39r: Rf ˆ 0.34 (10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 1683, 1601,
1257, 1159, 833 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 9.97 (s, 1H), 7.89 (d,
J ˆ 10.0 Hz, 2H), 7.06 (d, J ˆ 10.0 Hz, 2H), 4.08 (t, J ˆ 6.5 Hz, 2H), 2.93 (t,
J ˆ 7.4 Hz, 2H), 2.39 (s, 3H), 1.89 ± 1.85 (m, 2H), 1.66 ± 1.61 (m, 2H),
1.55 ± 1.53 (m, 2H), 1.43 ± 1.34 (m, 10H); 13C NMR (125 MHz, CDCl3): d ˆ
196.4, 192.5, 164.6, 132.4, 130.1, 115.1, 68.6, 31.0, 29.9, 29.7, 29.6, 29.5, 29.4,
‡
29.1, 26.3, 25.5; HRMS: calcd for C19H28O3S [M‡Na] : 359.1651, found
359.1652.
General procedure for the reductive alkylation of vancomycin: DIEA
(15.0 mL, 1.2 equiv, 82.7 mmol) was added to a solution of vancomycin (1,
100.0 mg, 1.0 equiv, 69.0 mmol) in DMF/MeOH (1:1, 0.01m) and the
‡
C78H89Cl2N9O25 [M‡H] : 1623.5, found 1623.5.
3816
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3816 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 17

Synthesis of Vancomycin
3798±3823
40b: tR ˆ 7.2 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.80 (d, J ˆ
9.2 Hz, 2H), 7.80 (s, 1H), 7.73 (d, J ˆ 13.0 Hz, 2H), 7.60 (d, J ˆ 10.0 Hz, 1H),
7.48 (br, 1H), 7.24 (d, J ˆ 8.5 Hz, 1H), 7.11 (s, 1H), 7.06 (d, J ˆ 10.0 Hz, 2H),
6.80 (s, 2H), 6.65 (s, 1H), 6.50 (d, J ˆ 2.5 Hz, 1H), 6.08 (s, 2H), 5.88 ± 5.79
(m, 1H), 5.63 ± 5.57 (m, 2H), 5.47 (d, J ˆ 15.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz,
1H), 5.08 ± 4.99 (m, 2H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H),
4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.06 ± 3.88 (m, 6H), 3.72 (d, J ˆ
8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.29 ± 2.25 (m, 2H),
2.15 (m, 2H), 2.01 ± 1.91 (m, 3H), 1.78 (s, 3H), 1.36 (m, 2H), 1.25 (d, J ˆ
6.25 Hz, 3H), 1.04 ± 1.00 (m, 6H); LCMS (ES): calcd for C79H91Cl2N9O25
4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.08 ± 3.88 (m, 6H), 3.72 (d, J ˆ
8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.15 ± 2.01 (m, 5H),
1.92 ± 1.70 (m, 11H), 1.55 ± 1.48 (m, 2H), 1.41 ± 1.25 (m, 12H), 1.03 ± 0.99 (m,
6H); LCMS (ES): calcd for C83H99Cl2N9O25 [M‡H] : 1693.7, found 1693.8.
‡
40i: tR ˆ 8.5 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.76 ± 7.72 (m,
2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.50 ± 7.47 (m, 3H), 7.22 (d, J ˆ 8.45 Hz, 1H),
7.11 (s, 1H), 7.02 ± 7.00 (m, 1H), 6.80 (s, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ
2.2 Hz, 1H), 6.08 (brs, 2H), 5.95 ± 5.88 (m, H), 5.65 ± 5.57 (m, 2H), 5.58 (d,
J ˆ 4.4 Hz, 1H), 5.46 ± 5.42 (m, 3H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ
6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 ± 3.88
(m, 9H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.73 ± 2.67 (m, 2H), 2.15
(m, 2H), 2.01 ± 1.85 (m, 3H), 1.77 (s, 3H), 1.62 ± 1.53 (m, 2H), 1.36 (m, 2H),
1.25 (d, J ˆ 6.25 Hz, 3H), 1.05 ± 0.99 (m, 9H); LCMS (ES): calcd for
‡
[M‡H] : 1637.5, found 1637.5.
40c: tR ˆ 7.3 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.91 (d, J ˆ
9.8 Hz, 2H), 7.68 (d, J ˆ 13.0 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.58 (brs,
1H), 7.24 (d, J ˆ 8.6 Hz, 1H), 7.11 (s, 1H), 7.10 (d, J ˆ 10.0 Hz, 2H), 6.8 (s,
2H), 6.62 (s, 1H), 6.50 (d, J ˆ 2.5 Hz, 1H), 6.10 (s, 2H), 5.88 ± 5.79 (m, 1H),
5.65 (d, J ˆ 7.7 Hz, 1H), 5.56 (d, J ˆ 4.5 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H),
5.35 (d, J ˆ 3.9 Hz, 1H), 5.08 ± 4.99 (m, 2H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82
(s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.04 ± 3.88 (m,
6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.16 ±
2.12 (m, 4H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.86 ± 1.74 (m, 5H), 1.62 ± 1.56 (m,
2H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.25 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz, 3H), 1.02
‡
C81H95Cl2N9O26 [M‡H] : 1682.6, found 1682.6.
40j: tR ˆ 8.8 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.82 (s, 1H),
7.77 (d, J ˆ 13.7 Hz, 2H), 7.69 (d, J ˆ 9.3 Hz, 1H), 7.50 ± 7.48 (m, 3H), 7.25
(d, J ˆ 8.70 Hz, 1H), 7.13 (s, 1H), 7.02 ± 7.00 (m, 1H), 6.78 (brs, 2H), 6.62 (s,
1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.95 ± 5.88 (m, 1H), 5.65 ± 5.57
(m, 2H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 ± 5.42 (m, 3H), 5.35 (d, J ˆ 3.9 Hz,
1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz,
1H), 4.20 ± 4.11 (m, 5H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49
(m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.34 ± 2.30 (m, 2H), 2.15 (m, 2H), 2.03 ±
1.99 (m, 2H), 1.80 ± 1.74 (m, 6H), 1.62 ± 1.49 (m, 2H), 1.36 (m, 2H), 1.25 (d,
J ˆ 6.3 Hz, 3H), 1.05 ± 1.00 (m, 9H); LCMS (ES): calcd for C82H97Cl2N9O26
‡
(d, J ˆ 5.85 Hz, 3H); LCMS (ES): calcd for C80H93Cl2N9O25 [M‡H] :
1651.5, found 1651.4.
40d: tR ˆ 9.0 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.92 (d, J ˆ
9.0 Hz, 2H), 7.80 (s, 1H), 7.75 (d, J ˆ 13.0 Hz, 2H), 7.48 (br, 1H), 7.20 (d,
J ˆ 8.2 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J ˆ 9.9 Hz, 2H), 6.80 (s, 2H), 6.63 (s,
1H), 6.50 (d, J ˆ 2.5 Hz, 1H), 6.08 (brs, 2H), 5.91 ± 5.83 (m, 1H), 5.65 (d,
J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.47 ± 5.35 (m, 3H), 5.08 ± 5.07 (m,
1H), 5.01 ± 5.00 (m, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H),
4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.08 ± 3.88 (m, 6H), 3.72 (d, J ˆ
8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.15 ± 2.01 (m, 5H),
1.92 ± 1.74 (m, 5H), 1.41 ± 1.36 (m, 10H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.04 (d,
J ˆ 5.8 Hz, 3H), 1.02 (d, J ˆ 5.8 Hz, 3H); LCMS (ES): calcd for
‡
[M‡H] : 1696.0, found 1696.0.
40k: tR ˆ 9.8 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.76 (s, 1H),
7.73 (d, J ˆ 15.0 Hz, 2H), 7.64 (d, J ˆ 9.4 Hz, 1H), 7.51 ± 7.48 (m, 3H), 7.22
(d, J ˆ 8.5 Hz, 1H), 7.11 ± 7.05 (m, 2H), 6.76 (s, 2H), 6.62 (s, 1H), 6.49 (d,
J ˆ 2.2 Hz, 1H), 6.05 ± 5.97 (m, 3H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ
4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.30 ± 5.20 (m, 3H), 4.90 (q, J ˆ
6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 ± 3.75
(m, 8H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.70 ± 2.66 (m, 2H), 2.00 ±
1.90 (m, 6H), 1.83 ± 1.77 (m, 3H), 1.73 ± 1.33 (m, 12H), 1.25 (d, J ˆ 6.2 Hz,
‡
‡
C83H99Cl2N9O25 [M‡H] : 1693.7, found 1693.8.
3H), 1.03 ± 0.95 (m, 9H); LCMS (ES): calcd for C84H101Cl2N9O26 [M‡H] :
40e: tR ˆ 7.1 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.78 (s, 1H),
7.76 (d, J ˆ 15.0 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.49 ± 7.44 (m, 4H), 7.23 ±
7.21 (m, 2H), 7.11 (s, 1H), 6.80 (s, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H),
6.08 ± 5.94 (m, 3H), 5.65 ± 5.55 (m, 3H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 ± 5.35
(m, 3H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69
(s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.13 ± 4.10 (m, 2H), 4.04 ± 3.88
(m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H),
2.64 ± 2.60 (m, 2H), 2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.77 (m, 3H),
1.36 (m, 2H), 1.25 (d, J ˆ 6.25 Hz, 3H), 1.04 ± 0.98 (m, 6H); LCMS (ES):
1724.6, found 1724.7.
40l: tR ˆ 10.1 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.82 (s, 1H),
7.73 (d, J ˆ 15.3 Hz, 2H), 7.63 (d, J ˆ 9.3 Hz, 1H), 7.51 ± 7.48 (m, 4H), 7.22
(d, J ˆ 8.4 Hz, 1H), 7.13 (s, 1H), 7.08 (d, J ˆ 8.0 Hz, 1H), 6.80 (s, 2H), 6.62
(s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.98 ± 5.90 (m, 1H), 5.65 (d,
J ˆ 7.7 Hz, 1H), 5.58 ± 5.52 (m, 2H), 5.46 ± 5.41 (m, 3H), 5.35 (d, J ˆ 3.9 Hz,
1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz,
1H), 4.20 ± 4.13 (m, 5H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49
(m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.37 ± 2.34 (m, 2H), 2.15 (m, 2H), 2.04 ±
1.98 (m, 3H), 1.96 ± 1.90 (m, 2H), 1.77 (m, 3H), 1.58 ± 1.52 (m, 2H), 1.50 ±
1.36 (m, 4H), 1.38 ± 1.26 (m, 7H), 1.25 (d, J ˆ 6.25 Hz, 3H), 1.04 ± 0.95 (m,
‡
calcd for C78H89Cl2N9O25 [M‡H] : 1623.5, found 1623.5.
40 f: tR ˆ 7.2 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.78 ± 7.75 (s,
1H), 7.73 (d, J ˆ 17.0 Hz, 2H), 7.60 (d, J ˆ 9.0 Hz, 1H), 7.54 ± 7.45 (m, 4H),
7.26 ± 7.22 (d, J ˆ 8.5 Hz, 2H), 7.11 (s, 1H), 6.78 (brs, 2H), 6.62 (s, 1H), 6.49
(d, J ˆ 2.2 Hz, 1H), 5.96 ± 5.86 (m, 1H), 5.66 (d, J ˆ 8.0 Hz, 1H), 5.58 (d,
J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 5.15 ±
5.06 (m, 2H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ
8.8 Hz, 1H), 4.20 (s, 1H), 4.08 ± 3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49
(m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.20 (m, 4H), 2.01 ± 1.95 (m, 3H), 1.76 (s,
3H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.25 Hz, 3H), 1.02 ± 1.00 (m, 6H); LCMS
‡
9H); LCMS (ES): calcd for C85H103Cl2N9O26 [M‡H] : 1738.6, found 1738.6.
40m: tR ˆ 7.4 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.76 (d, J ˆ
15.0 Hz, 2H), 7.63 (d, J ˆ 10.0 Hz, 1H), 7.50 ± 7.47 (m, 3H), 7.38 ± 7.23 (m,
6H), 7.12 (s, 1H), 7.05 (m, 2H), 6.78 (brs, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ
2.2 Hz, 1H), 6.20 ± 6.15 (m, 1H), 6.08 (brs, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H),
5.58 ± 5.48 (m, 4H), 5.41 ± 5.35 (m, 2H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s,
1H), 4.77 (s, 2H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.16 ±
3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 ± 2.94 (m, 3H),
2.29 ± 2.20 (m, 4H), 2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.77 (s, 3H),
1.36 (m, 2H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.05 ± 1.01 (m, 6H); LCMS (ES):
‡
(ES): calcd for C79H91Cl2N9O25 [M‡H] : 1637.5, found 1637.4.
40g: tR ˆ 7.5 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.80 (s, 1H),
7.73 (d, J ˆ 13.5 Hz, 2H), 7.63 (d, J ˆ 10.0 Hz, 1H), 7.52 ± 7.45 (m, 4H),
7.24 ± 7.22 (m, 2H), 7.11 (s, 1H), 6.78 (s, 2H), 6.62 (s, 1H), 6.50 (d, J ˆ
2.5 Hz, 1H), 6.00 ± 5.90 (m, 3H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ
4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 5.12 ± 5.06
(m, 2H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ
8.8 Hz, 1H), 4.20 (s, 1H), 4.10 ± 3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49
(m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.30 ± 2.15 (m, 4H), 2.00 ± 1.90 (m, 3H),
1.80 ± 1.74 (m, 3H), 1.70 ± 1.64 (m, 5H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.25 Hz,
3H), 1.04 (d, J ˆ 5.8 Hz, 3H), 1.02 (d, J ˆ 5.85 Hz, 3H); LCMS (ES): calcd
‡
calcd for C85H95Cl2N9O26 [M‡H] : 1730.6, found 1731.0.
40n: tR ˆ 7.1 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.79 (s, 1H),
7.73 (d, J ˆ 14.7 Hz, 2H), 7.62 (d, J ˆ 9.0 Hz, 1H), 7.46 ± 7.23 (m, 9H), 7.11 (s,
1H), 6.80 (brs, 2H), 7.00 (d, J ˆ 8.0 Hz, 1H), 6.64 (s, 1H), 6.49 (d, J ˆ
2.2 Hz, 1H), 6.08 (brs, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.96 ± 5.88 (m, 1H),
5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H),
5.18 ± 5.14 (m, 4H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36
(d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.14 ± 3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz,
2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.63 ± 2.60 (m, 2H), 2.15 (m,
2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.80 ± 1.72 (m, 6H), 1.36 (m, 2H), 1.25 (d,
J ˆ 6.2 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz, 3H), 1.02 (d, J ˆ 5.8 Hz, 3H); LCMS
‡
for C80H93Cl2N9O25 [M‡H] : 1651.6, found 1651.6.
40 h: tR ˆ 9.4 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.85 (s, 1H),
7.73 (d, J ˆ 15.5 Hz, 2H), 7.68 (d, J ˆ 9.0 Hz, 1H), 7.52 ± 7.48 (m, 4H), 7.26 ±
7.22 (m, 2H), 7.11 (s, 1H), 6.83 (s, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H),
6.08 (brs, 2H), 5.91 ± 5.83 (m, 1H), 5.60 ± 5.45 (m, 4H), 5.35 (d, J ˆ 3.9 Hz,
1H), 5.28 ± 5.10 (m, 2H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H),
‡
(ES): calcd for C84H93Cl2N9O26 [M‡H] : 1716.6, found 1716.3.
40o: tR ˆ 7.7 min; 1H NMR (500 MHz, CD3OD, 330 K); 7.90 ± 7.80 (m, 3H),
7.68 (d, J ˆ 9.3 Hz, 1H), 7.48 (br, 1H), 7.23 (d, J ˆ 8.4 Hz, 1H), 7.10 ± 7.05 (m,
3H), 6.80 (s, 2H), 6.61 (s, 1H), 6.50 (d, J ˆ 2.4 Hz, 1H), 6.10 (brs, 2H),
Chem. Eur. J. 2001, 7, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3817 $ 17.50+.50/0
3817

K. C. Nicolaou et al.
FULL PAPER
Table 5. Antibacterial activity (MIC: mgmL 1) of amino acid 1 modified vancomycin derivatives against vancomycin-susceptible, vancomycin-intermediate
resistant, and vancomycin-resistant bacteria.
HO
HO
HO
H
OH
N
O
O
O
O
X
O
Cl
O
O
OH
HO
Cl
O
H
O
H
H
N
N
N
N
H
NHR2
H
O
O
O
H
O
NH
O
R1
NH2
OH
OH
X1: CH2Ac
HO
X2: CH=CH2
48
Com- R1
pound
R2
X
MU50[a] 133[a] 4002[b] 1528[c] 2689[c] 2741[c] 2781[c] 2805[c] 4001[d] 1669[e] 2671[e] 2823[e] 1803[f] 1924[f] 1944[f]
vancomycin
1
3.13 0.39 0.39 >100
50
>16
>16
>16
>16
>16
>100
>16
4
100
>16
>16
>16
>16
>16
>16
>16
>16
25 >100
100
>16
>16
>16
>16
>16
>16
>16
>16
50
>16
16
100
>16
16
50
>16
8
25
>16
16
50
X1
>16
8
>16
2
>16
4
>16
8
>16
>16
>16
>16
>16
>16
>16
>16
>16
48a
48c
>16
Gly
Gly
H
L-Ala
X1
X1
>16
16
8
>16
8
48g
Gly ε-Ahx
16
8
4
4
8
8
>16
>16
16
>16
16
16
>16
16
>16
>16
16
X1
X1
X1
48i
Gly
4
4
8
4
16
L-Val
L-Leu
L-Ser
48k
48l
8
4
4
16
>16
>16
>16
4
16
16
8
16
Gly
Gly
16
8
4
4
>16
>16
>16
16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
16
>16
>16
>16
>16
>16
>16
8
L-Lys X1
48s
48w
48x
48z
48ee
48ff
48gg
Gly
Gly
Gly
Gly
Gly
2
4
>16
>16
X2
H
>16
>16
>16
X2
L-Val
2
8
1
4
2
4
8
16
>16
>16
>16
>16
>16
>16
2
16
16
16
8
16
8
16
8
16
8
16
8
8
8
16
16
8
8
X2
X2
L-Cha
L-Lys
8
4
1
4
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
16
>16
>16
>16
>16
>16
>16
>16
>16
16
16
16
X2
X2
H
>16
4
>16
4
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
8
>16
>16
>16
L-Val
L-Val
>16
>16
>16
>16
8
L-Val
X2
L-Phe L-Lys
8
4
4
48ww
48ddd
48hhh
48ooo
[g] X2
L-Glu
L-Lys
4
8
1
1
1
2
2
4
16
>16
>16
>16
>16
>16
4
8
>16
>16
>16
16
>16
>16
>16
16
>16
16
>16
16
>16
16
16
8
16
8
L-Thi
L-Val X2
X2
16
L-Lys L-Lys
16
>16
16
>16
>16
16
16
16
[a] Vancomycin-intermediate resistant Staphylococcus aureus. [b] Vancomycin-susceptible Enterococcus faecalis. [c] Vancomycin-resistant (van A) Enter-
ococcus faecalis. [d] Vancomycin-resistant (van A) Enterococcus faecium. [e] Vancomycin-resistant (van A) and Synercid-resistant (sat G) Enterococcus
faecium. [f] Vancomycin-resistant (van A) and Synercid-resistant (sat A) Enterococcus faecium. [g] Thi is b-(2-thienyl)alanine.
5.88 ± 5.70 (m, 2H), 5.60 (d, J ˆ 5.0 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35
(d, J ˆ 3.9 Hz, 1H), 5.05 ± 4.90 (m, 3H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d,
J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.04 ± 3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H),
3.49 (m, 1H), 3.05 ± 3.00 (m, 1H), 2.15 ± 2.10 (m, 4H), 2.01 (d, J ˆ 13.5 Hz,
1H), 1.83 ± 1.74 (m, 5H), 1.64 ± 1.59 (m, 5H), 1.36 (m, 2H), 1.25 (d, J ˆ
6.2 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz, 3H), 1.02 (d, J ˆ 5.8 Hz, 3H); LCMS (ES):
40z: tR ˆ 6.9 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.90 (d, J ˆ
9.5 Hz, 2H), 7.74 ± 7.67 (m, 4H), 7.48 (br, 1H), 7.22 (d, J ˆ 8.5 Hz, 1H), 7.11
(s, 1H), 7.05 (d, J ˆ 9.4 Hz, 2H), 6.78 (brs, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ
2.2 Hz, 1H), 6.08 (brs, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz,
1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz,
1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.10 ±
3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.05 ± 3.01 (m, 3H),
2.40 (s, 3H), 2.17 ± 2.13 (m, 4H), 2.03 ± 2.00 (m, 1H), 1.79 (s, 3H), 1.36 (m,
2H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.02 ± 0.98 (m, 6H); LCMS (ES): calcd for
‡
calcd for C85H94Cl3N9O26 [M‡H] : 1765.0, found 1766.0.
40p: tR ˆ 7.6 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.80 (s, 1H),
7.75 (d, J ˆ 13.0 Hz, 2H), 7.62 (d, J ˆ 10.0 Hz, 1H), 7.51 ± 7.39 (m, 7H), 7.25
(d, J ˆ 8.6 Hz, 1H), 7.13 (s, 1H), 7.05 ± 7.04 (m, 1H), 6.72 (s, 2H), 6.62 (s,
1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 ± 5.97 (m, 3H), 5.65 (d, J ˆ 7.7 Hz, 1H),
5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 ± 5.27 (m, 5H), 4.90
(q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H),
4.20 ± 4.18 (m, 3H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m,
1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.70 ± 2.68 (m, 2H), 2.15 (m, 2H), 2.01 (d,
J ˆ 13.5 Hz, 1H), 1.77 (s, 3H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.2 Hz, 3H), 1.03 ±
‡
C78H89Cl2N9O26S [M‡H] : 1671.6, found 1671.6.
40aa: tR ˆ 7.1 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.89 (d, J ˆ
9.3 Hz, 2H), 7.78 ± 7.76 (m, 3H), 7.70 (d, J ˆ 9.6 Hz, 1H), 7.48 (br, 1H), 7.24
(d, J ˆ 8.50 Hz, 1H), 7.11 ± 7.05 (m, 3H), 6.80 (s, 2H), 6.62 (s, 1H), 6.49 (d,
J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz,
1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz,
1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.10 ±
3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.05 ± 3.01 (m, 3H),
2.40 (s, 3H), 2.17 ± 2.13 (m, 4H), 2.01 ± 1.87 (m, 3H), 1.80 ± 1.70 (m, 8H),
‡
1.00 (m, 6H); LCMS (ES): calcd for C84H92Cl2N9O26 [M‡H] : 1751.9, found
1752.0.
3818
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3818 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 17

Synthesis of Vancomycin
3798±3823
1.65 ± 1.59 (m, 2H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.25 Hz, 3H), 1.03 ± 1.00 (m,
2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.59 (d, J ˆ 4.3 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz,
2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s,
1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.03 ± 3.88 (m, 6H), 3.72 (d, J ˆ
8.0 Hz, 2H), 3.49 (m, 1H), 3.01 ± 2.90 (m, 3H), 2.30 (s, 3H), 2.15 (m, 2H),
2.01 (d, J ˆ 13.5 Hz, 1H), 1.85 ± 1.75 (m, 5H), 1.65 ± 1.55 (m, 5H), 1.52 ± 1.40
(m, 2H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.25 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz, 3H),
‡
6H); LCMS (ES): calcd for C79H91Cl2N9O26S [M‡H] : 1685.6, found
1685.6.
40bb: tR ˆ 7.2 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.90 ± 7.80 (m,
3H), 7.75 (d, J ˆ 13.5 Hz, 2H), 7.67 (d, J ˆ 9.6 Hz, 1H), 7.48 (br, 1H), 7.32
(d, J ˆ 8.5 Hz, 1H), 7.10 ± 7.07 (m, 3H), 6.78 (brs, 2H), 6.62 (s, 1H), 6.50 (d,
J ˆ 2.3 Hz, 1H), 6.10 (s, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz,
1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz,
1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.10 ±
3.90 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.05 ± 2.95 (m, 3H),
2.38 (s, 3H), 2.15 (m, 2H), 2.05 ± 1.87 (m, 3H), 1.64 ± 1.48 (m, 7H), 1.36 (m,
2H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz, 3H), 1.02 (d, J ˆ 5.8 Hz,
‡
1.02 (d, J ˆ 5.85 Hz, 3H); LCMS (ES): calcd for C81H95Cl2N9O26S [M‡H] :
1713.6, found 1713.6.
40ii: tR ˆ 9.2 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.82 (s, 1H),
7.75 (d, J ˆ 15.5 Hz, 2H), 7.63 (d, J ˆ 9.6 Hz, 1H), 7.52 ± 7.48 (m, 4H), 7.26 ±
7.22 (m, 2H), 7.11 (s, 1H), 6.78 (s, 2H), 6.62 (s, 1H), 6.50 (d, J ˆ 2.2 Hz, 1H),
6.08 (brs, 2H), 5.67 (d, J ˆ 8.0 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ
14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H),
4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.08 ± 3.88 (m, 6H), 3.72
(d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 ± 2.93 (m, 3H), 2.39 (s, 3H), 2.15 (m,
2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.89 ± 1.74 (m, 8H), 1.66 ± 1.61 (m, 2H),
1.55 ± 1.53 (m, 2H), 1.43 ± 1.34 (m, 12H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.25 Hz,
‡
3H); LCMS (ES): calcd for C80H93Cl2N9O26S [M‡H] : 1699.6, found
1699.6.
40cc: tR ˆ 7.4 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.90 (d, J ˆ
9.2 Hz, 2H), 7.78 (s, 1H), 7.76 (d, J ˆ 15.0 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H),
7.48 (br, 1H), 7.22 (d, J ˆ 8.5 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J ˆ 9.4 Hz, 2H),
6.78 (brs, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.65 (d,
J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d,
J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d,
J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.10 ± 3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H),
3.49 (m, 1H), 3.01 ± 2.98 (m, 3H), 2.38 (s, 3H), 2.15 (m, 2H), 2.01 (d, J ˆ
13.5 Hz, 1H), 1.91 ± 1.74 (m, 5H), 1.72 ± 1.66 (m, 2H), 1.59 ± 1.49 (m, 4H),
1.36 (m, 2H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.02 ± 0.98 (m, 6H); LCMS (ES):
‡
3H), 1.04 ± 1.00 (m, 6H); LCMS (ES): calcd for C85H103Cl2N9O26S [M‡H] :
1769.7, found 1769.7.
40jj: tR ˆ 7.2 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.78 (s, 1H),
7.76 (d, J ˆ 15.0 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.50 ± 7.46 (m, 3H), 7.22
(d, J ˆ 8.5 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J ˆ 8.1 Hz, 1H), 6.78 (brs, 2H),
6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (s, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H),
5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H),
4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H),
4.20 ± 4.13 (m, 5H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m,
1H), 3.14 (t, J ˆ 7.0 Hz, 2H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.40 (s, 3H), 2.20 ±
2.15 (m, 4H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.96 ± 1.88 (m, 2H), 1.79 (m, 3H),
1.60 ± 1.54 (m, 2H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.05 ± 1.00 (m,
‡
calcd for C81H95Cl2N9O26S [M‡H] : 1713.6, found 1713.6.
40dd: tR ˆ 8.9 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.90 (d, J ˆ
10.0 Hz, 2H), 7.78 (s, 1H), 7.76 (d, J ˆ 15.0 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H),
7.48 (br, 1H), 7.22 (d, J ˆ 8.5 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J ˆ 9.7 Hz, 2H),
6.78 (brs, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.65 (d,
J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d,
J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d,
J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.12 ± 3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H),
3.49 (m, 1H), 3.01 ± 2.95 (m, 3H), 2.38 (s, 3H), 2.15 (m, 2H), 2.01 (d, J ˆ
13.5 Hz, 1H), 1.89 ± 1.74 (m, 5H), 1.66 ± 1.61 (m, 2H), 1.55 ± 1.53 (m, 2H),
1.43 ± 1.34 (m, 12H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.04 ± 1.00 (m, 6H); LCMS
‡
9H); LCMS (ES): calcd for C82H97Cl2N9O27S [M‡H] : 1743.6, found
1743.6.
1
40kk: tR ˆ 7.4 min; H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.80 (s, 1H),
7.75 (d, J ˆ 14.7 Hz, 2H), 7.63 (d, J ˆ 9.8 Hz, 1H), 7.48 ± 7.47 (m, 2H), 7.42 (s,
1H), 7.22 (d, J ˆ 8.5 Hz, 1H), 7.11 (s, 1H), 7.00 (d, J ˆ 7.9 Hz, 2H), 6.62 (s,
1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 5.66 (d, J ˆ 7.8 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz,
1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz,
1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.12 ±
4.10 (m, 2H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H),
3.05 ± 3.01 (m, 3H), 2.40 (s, 3H), 2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H),
1.80 ± 1.74 (m, 10H), 1.60 ± 1.52 (m, 4H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.2 Hz,
‡
(ES): calcd for C85H103Cl2N9O26S [M‡H] : 1769.7, found 1769.7.
40ee: tR ˆ 7.0 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.90 (s, 1H),
7.75 (d, J ˆ 13.5 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.54 ± 7.45 (m, 4H), 7.26 ±
7.22 (m, 2H), 7.11 (s, 1H), 6.78 (brs, 2H), 6.63 (s, 1H), 6.50 (d, J ˆ 2.4 Hz,
1H), 6.08 (brs, 2H), 5.67 (d, J ˆ 7.6 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46
(d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82
(s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.14 (t, J ˆ
6.3 Hz, 2H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H),
3.03 ± 3.01 (m, 3H), 2.40 (s, 3H), 2.17 ± 2.13 (m, 4H), 2.01 (d, J ˆ 13.5 Hz,
1H), 1.80 ± 1.74 (m, 6H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.03 ± 0.99
‡
3H), 1.04 ± 0.98 (m, 9H); LCMS (ES): calcd for C83H99Cl2N9O27S [M‡H] :
1757.9, found 1758.0.
40ll: tR ˆ 8.1 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.90 (s, 1H),
7.76 (d, J ˆ 15.0 Hz, 2H), 7.65 (d, J ˆ 9.3 Hz, 1H), 7.50 ± 7.44 (m, 3H), 7.22
(d, J ˆ 8.4 Hz, 1H), 7.11 (s, 1H), 7.00 ± 6.92 (m, 3H), 6.62 (s, 1H), 6.49 (d,
J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.67 (d, J ˆ 7.2 Hz, 1H), 5.59 (d, J ˆ 4.5 Hz,
1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz,
1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 ± 4.10 (m, 5H),
4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.02 ± 2.91 (m,
3H), 2.37 (s, 3H), 2.15 (m, 2H), 2.00 ± 1.75 (m, 10H), 1.65 ± 1.50 (m, 7H),
1.44 ± 1.20 (m, 11H), 1.05 ± 1.00 (m, 9H); LCMS (ES): calcd for
‡
(m, 6H); LCMS (ES): calcd for C78H89Cl2N9O26S [M‡H] : 1671.6, found
1671.6.
1
40 ff: tR ˆ 7.2 min; H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.77 ± 7.75 (m,
1H), 7.75 (d, J ˆ 15.3 Hz, 2H), 7.63 (d, J ˆ 9.3 Hz, 1H), 7.54 ± 7.45 (m, 4H),
7.25 ± 7.22 (m, 2H), 7.11 (s, 1H), 6.78 (brs, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ
2.2 Hz, 1H), 6.08 (brs, 2H), 5.62 (d, J ˆ 7.8 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz,
1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz,
1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.14 (t,
J ˆ 6.2 Hz, 2H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H),
3.04 ± 3.00 (m, 3H), 2.39 (s, 3H), 2.15 (m, 2H), 2.01 ± 1.92 (m, 3H), 1.78 (s,
3H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.2 Hz, 3H), 1.02 ± 0.99 (m, 6H); LCMS
‡
C85H103Cl2N9O27S [M‡H] : 1785.7, found 1785.6.
40mm: tR ˆ 8.4 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.81 (s, 1H),
7.76 (d, J ˆ 15.2 Hz, 2H), 7.76 (d, J ˆ 9.6 Hz, 1H), 7.50 ± 7.40 (m, 3H), 7.22
(d, J ˆ 8.5 Hz, 1H), 7.11 (s, 1H), 6.94 ± 6.90 (m, 1H), 6.78 (brs, 2H), 6.62 (s,
1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.63 ± 5.55 (m, 2H), 5.45 (d,
J ˆ 13.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s,
1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.05 ± 3.90 (m, 6H),
3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.05 ± 2.90 (m, 3H), 2.73 (s, 3H), 2.15
(m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.80 ± 1.74 (m, 3H), 1.65 ± 1.20 (m, 18H),
‡
(ES): calcd for C79H91Cl2N9O26S [M‡H] : 1685.6, found 1685.6.
40gg: tR ˆ 7.8 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.80 ± 7.75 (m,
3H), 7.68 (d, J ˆ 10.0 Hz, 1H), 7.54 ± 7.48 (m, 4H), 7.26 ± 7.22 (m, 2H), 7.11
(s, 1H), 6.65 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.63 (d, J ˆ
7.5 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ
3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ
8.8 Hz, 1H), 4.20 (s, 1H), 4.14 (t, J ˆ 6.3 Hz, 2H), 4.08 ± 3.88 (m, 6H), 3.72
(d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.05 ± 3.01 (m, 3H), 2.40 (s, 3H), 2.15 (m,
2H), 2.01 ± 1.92 (m, 7H), 1.77 (s, 3H), 1.66 ± 1.62 (m, 2H), 1.36 (m, 2H), 1.25
(d, J ˆ 6.2 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz, 3H), 1.02 (d, J ˆ 5.8 Hz, 3H); LCMS
‡
1.05 ± 1.00 (m, 9H); LCMS (ES): calcd for C86H105Cl2N9O27S [M‡H] :
1799.7, found 1799.7.
40nn: tR ˆ 8.6 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.78 ± 7.73 (m,
2H), 7.53 ± 7.48 (m, 8H), 7.22 (d, J ˆ 8.5 Hz, 1H), 7.11 ± 7.08 (m, 2H), 6.78
(brs, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.60 ± 5.58
(m, 2H), 5.47 (d, J ˆ 14.1 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ
6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.22 ± 4.20
(m, 3H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.17 ±
3.15 (m, 2H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.40 (s, 3H), 2.23 ± 2.15 (m, 4H),
2.01 (d, J ˆ 13.5 Hz, 1H), 1.77 (s, 3H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.3 Hz,
‡
(ES): calcd for C80H93Cl2N9O26S [M‡H] : 1699.6, found 1699.7.
1
40 hh: tR ˆ 7.7 min ; H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.80 (s, 1H),
7.73 (d, J ˆ 14.5 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.55 ± 7.44 (m, 3H), 7.40 ±
7.10 (m, 4H), 6.78 (s, 2H), 6.62 (s, 1H), 6.50 (d, J ˆ 2.5 Hz, 1H), 6.08 (brs,
Chem. Eur. J. 2001, 7, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3819 $ 17.50+.50/0
3819

K. C. Nicolaou et al.
FULL PAPER
‡
3H), 1.04 ± 1.02 (m, 6H); LCMS (ES): calcd for C85H95Cl2N9O27S [M‡H] :
4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.07 ± 3.81
(m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H),
2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.83 ± 1.75 (m, 8H), 1.50 ± 1.45 (m,
1778.7, found 1778.7.
1
40oo: tR ˆ 8.8 min; H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.79 (s, 1H),
‡
2H), 1.36 ± 1.00 (m, 23H); LCMS (ES): calcd for C90H107Cl2N9O26 [M‡H] :
7.76 (d, J ˆ 15.1 Hz, 2H), 7.63 (d, J ˆ 9.7 Hz, 1H), 7.50 ± 7.32 (m, 8H), 7.20 ±
6.95 (m, 3H), 6.78 (brs, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs,
2H), 5.67 (d, J ˆ 7.9 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz,
2H), 5.37 ± 5.25 (m, 3H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H),
4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 ± 3.90 (m, 7H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49
(m, 1H), 3.00 ± 2.95 (m, 3H), 2.36 (s, 3H), 2.15 (m, 2H), 2.03 ± 1.74 (m, 7H),
1.64 (s, 3H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz, 3H),
1802.7, found 1802.7.
40vv: tR ˆ 7.0 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.78 (s, 1H),
7.76 (d, J ˆ 15.0 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.45 ± 7.20 (m, 8H), 7.08 ±
7.00 (m, 2H), 6.78 (brs, 2H), 6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs,
2H), 5.89 (m, 5H), 5.65 (d, J ˆ 8.0 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d,
J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 5.16 (s, 2H), 4.90 (q, J ˆ 6.6 Hz,
1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.04 ±
3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz,
1H), 2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.78 ± 1.70 (m, 6H), 1.36 (m,
2H), 1.25 (d, J ˆ 6.2 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz, 3H), 1.02 (d, J ˆ 5.8 Hz,
‡
1.02 (d, J ˆ 5.8 Hz, 3H); LCMS (ES): calcd for C86H97Cl2N9O27S [M‡H] :
1792.3, found 1792.3.
40pp: tR ˆ 7.7 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.76 (d, J ˆ
15.0 Hz, 2H), 7.68 (d, J ˆ 9.5 Hz, 1H), 7.50 ± 7.45 (m, 5H), 7.22 (d, J ˆ
8.45 Hz, 1H), 7.11 (s, 1H), 7.02 (d, J ˆ 8.0 Hz, 1H), 6.78 (brs, 2H), 6.62
(s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (s, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58
(d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 4.90
(q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H),
4.20 ± 4.10 (m, 5H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m,
1H), 3.01 ± 2.97 (m, 3H), 2.39 (s, 3H), 2.15 (m, 2H), 2.01 ± 1.90 (m, 5H),
1.80 ± 1.74 (m, 5H), 1.65 ± 1.63 (m, 2H), 1.56 ± 1.37 (m, 5H), 1.25 (d, J ˆ
6.2 Hz, 3H), 1.04 ± 0.96 (m, 9H); LCMS (ES): calcd for C85H94Cl3N9O27S
‡
3H); LCMS (ES): calcd for C80H86Cl3N9O26 [M‡H] : 1696.9, found 1696.8.
1
40ww: tR ˆ 8.0 min; H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.77 (d, J ˆ
14.7 Hz, 2H), 7.67 (d, J ˆ 9.5 Hz, 1H), 7.51 ± 7.26 (m, 12H), 7.11 (s, 1H),
7.00 ± 6.9 (m, 3H), 6.62 (s, 1H), 6.51 (d, J ˆ 2.5 Hz, 1H), 6.10 (s, 1H), 5.65
(d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35
(d, J ˆ 3.9 Hz, 1H), 5.21 ± 5.16 (m, 4H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s,
1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.04 ± 3.88 (m, 4H),
3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.15 (m,
2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.80 ± 1.74 (m, 3H), 1.64 (s, 3H), 1.36 (m,
2H), 1.25 (d, J ˆ 6.25 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz, 3H), 1.02 (d, J ˆ 5.85 Hz,
‡
[M‡H] : 1813.1, found 1813.8.
1
40qq: tR ˆ 7.8 min; H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.78 (s, 1H),
‡
3H); LCMS (ES): calcd for C87H91Cl4N9O26 [M‡H] : 1821.5, found 1822.0.
7.76 (d, J ˆ 15.0 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.51 ± 7.44 (m, 5H), 7.22
(d, J ˆ 8.5 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J ˆ 8.0 Hz, 1H), 6.78 (brs, 2H),
6.62 (s, 1H), 6.50 (d, J ˆ 2.5 Hz, 1H), 6.08 (brs, 2H), 5.67 (d, J ˆ 7.9 Hz,
1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 ± 5.28 (m, 3H),
(d, J ˆ 3.9 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36
(d, J ˆ 8.8 Hz, 1H), 4.20 ± 4.15 (m, 3H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ
8.0 Hz, 2H), 3.49 ± 3.45 (m, 1H), 3.05 ± 3.01 (m, 3H), 2.40 (s, 3H), 2.15 (m,
2H), 2.03 ± 1.96 (d, J ˆ 13.5 Hz, 3H), 1.92 ± 1.74 (m, 5H), 1.36 (m, 2H), 1.25
(d, J ˆ 6.2 Hz, 3H), 1.04 ± 1.02 (m, 6H); LCMS (ES): calcd for
40xx: tR ˆ 9.2 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.78 ± 7.74 (m,
3H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.44 ± 7.12 (m, 9H), 6.92 ± 6.78 (m, 2H), 6.60
(s, 1H), 6.50 (d, J ˆ 2.0 Hz, 1H), 6.05 (s, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58
(d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H),
5.20 ± 4.90 (m, 2H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20
(s, 1H), 4.08 ± 3.89 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d,
J ˆ 14.6 Hz, 1H), 2.15 (m, 2H), 1.96 ± 1.70 (m, 9H), 1.50 ± 1.39 (m, 4H),
1.34 ± 1.20 (m, 10H), 1.05 ± 0.90 (m, 9H); LCMS (ES): calcd for
‡
‡
C88H102Cl3N9O26 [M‡H] : 1809.1, found 1809.2.
C86H96Cl3N9O27S [M‡H] : 1826.1, found 1826.2.
40yy: tR ˆ 9.8 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.76 (d, J ˆ
15.0 Hz, 2H), 7.65 (d, J ˆ 9.8 Hz, 1H), 7.42 ± 7.22 (m, 8H), 7.02 ± 6.82 (m,
4H), 6.60 ± 6.50 (m, 3H), 6.14 (s, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ
4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 5.22 (s, 2H),
4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H),
4.20 (s, 1H), 4.08 ± 3.88 (m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01
(d, J ˆ 14.6 Hz, 1H), 2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.81 ± 1.70 (m,
8H), 1.50 ± 1.20 (m, 21H), 1.09 ± 0.80 (m, 9H); LCMS (ES): calcd for
40rr: tR ˆ 6.6 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.78 (s, 1H),
7.76 (d, J ˆ 15.0 Hz, 2H), 7.66 (d, J ˆ 9.5 Hz, 1H), 7.50 ± 7.38 (m, 8H), 7.22
(d, J ˆ 8.4 Hz, 1H), 7.11 (s, 1H), 7.03 ± 6.78 (m, 3H), 6.62 (s, 1H), 6.49 (d,
J ˆ 2.2 Hz, 1H), 6.10 ± 6.04 (m, 3H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ
4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 (d, J ˆ 3.9 Hz, 1H), 5.20 (s, 2H),
4.90 (q, J ˆ 6.6 Hz, 1H), 4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H),
4.20 (s, 1H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01
(d, J ˆ 14.6 Hz, 1H), 2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.80 ± 1.74 (m,
3H), 1.64 (s, 3H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.04 (d, J ˆ 5.8 Hz,
3H), 1.02 (d, J ˆ 5.8 Hz, 3H); LCMS (ES): calcd for C80H87Cl2N9O26
‡
C90H106Cl3N9O26 [M‡H] : 1836.2, found 1835.9.
Preparation of Boc-protected 42a and 42b: NaHCO3 (430.0 mg, 1.5 equiv,
5.3 mmol) and Boc2O (1.6 g, 2.2 equiv, 7.7 mmol) were was added at 08C to
a solution of vancomycin (1, 5.0 g, 1.0 equiv, 3.5 mmol) in 1,4-dioxane/H2O
(1:1, 60.0 mL, 0.06m). After stirring for 4 h at 08C, acetone (500 mL) was
added to precipitate the desired product. After filtration, the residue was
dissolved in MeOH/DMF (1:1, 50 mL) and precipitated by the addition of
acetone (500 mL). A portion of the isolated precipitate (1.0 g, 1.0 equiv,
0.6 mmol) was dissolved in DMF/MeOH (4:1, 25 mL) and the appropriate
aldehyde (39e or 40e) was added (ꢀ250 mg, 2.0 equiv, 1.2 mmol) followed
by iPr2NEt (460 mL, 4.0 equiv, 2.4 mmol) and NaCNBH3 (160.0 mg,
4.0 equiv, 2.4 mmol). The mixture was warmed to 658C and stirred for
20 h. After cooling of the reaction mixture, Et2O (200 mL) was added to
precipitate the product (42a or 42b; HPLC data: LiChrospher C18,
6 mm  250 mm, flow rate ˆ 1.0 mLmin 1, 0 ! 100% CH3CN (0.05%
TFA) in H2O (0.05% TFA) over 10 min) which was then collected by
filtration and used without further purification.
‡
[M‡H] : 1661.5, found 1661.5.
40ss: tR ˆ 7.7 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.77 (s, 1H),
7.75 (d, J ˆ 14.5 Hz, 2H), 7.66 (d, J ˆ 9.6 Hz, 1H), 7.50 ± 7.20 (m, 14H), 7.11
(s, 1H), 7.01 ± 6.78 (m, 3H), 6.62 (s, 1H), 6.49 (d, J ˆ 2.2 Hz, 1H), 6.08 (brs,
2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz, 1H), 5.46 (d, J ˆ 14.0 Hz,
2H), 5.35 ± 5.26 (m, 5H), 4.90 (q, J ˆ 6.6 Hz, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ
8.8 Hz, 1H), 4.20 (s, 1H), 4.04 ± 3.88 (m, 4H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49
(m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H), 2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H),
1.80 ± 1.74 (m, 3H), 1.36 (m, 2H), 1.25 (d, J ˆ 6.3 Hz, 3H), 1.04 (d, J ˆ
5.8 Hz, 3H), 1.02 (d, J ˆ 5.8 Hz, 3H); LCMS (ES): calcd for C87H93Cl2N9O26
‡
[M‡H] : 1752.6, found 1752.6.
40tt: tR ˆ 8.5 min; 1H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.80 (s, 1H),
7.73 (d, J ˆ 14.9 Hz, 2H), 7.67 (d, J ˆ 9.4 Hz, 1H), 7.50 ± 7.32 (m, 5H), 7.23
(d, J ˆ 8.5 Hz, 1H), 7.11 (s, 1H), 6.96 ± 6.86 (m, 3H), 6.62 (s, 1H), 6.49 (d,
J ˆ 2.2 Hz, 1H), 6.08 (brs, 2H), 5.65 (d, J ˆ 7.7 Hz, 1H), 5.58 (d, J ˆ 4.4 Hz,
1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.35 ± 5.32 (m, 3H), 4.90 (q, J ˆ 6.6 Hz, 1H),
4.82 (s, 1H), 4.69 (s, 1H), 4.36 (d, J ˆ 8.8 Hz, 1H), 4.20 (s, 1H), 4.10 ± 3.92
(m, 6H), 3.72 (d, J ˆ 8.0 Hz, 2H), 3.49 (m, 1H), 3.01 (d, J ˆ 14.6 Hz, 1H),
2.15 (m, 2H), 2.01 (d, J ˆ 13.5 Hz, 1H), 1.85 ± 1.70 (m, 8H), 1.51 ± 1.45 (m,
2H), 1.35 ± 1.25 (m, 13H), 1.00 ± 0.86 (m, 9H); LCMS (ES): calcd for
‡
42a: tR ˆ 8.5 min; LCMS (ES): calcd for C77H87Cl2N9O25 [M‡H] : 1610.5,
found 1610.5.
‡
42b: tR ˆ 9.0 min; LCMS (ES): calcd for C78H89Cl2N9O26S [M‡H] : 1672.6,
found 1672.6.
General procedure for the conversion of 42a and 42b to 40x and 44: TFA
(10 mL) was added dropwise at ambient temperature to a vigorously stirred
suspension of Boc-protected vancomycin derivative (42a or 42b, 2.0 g,
ꢀ1.1 mmol) in CH2Cl2 (90 mL). After stirring for 1 h, the reaction mixture
was concentrated under reduced pressure and the residue was dissolved in
MeOH (40 mL). Et2O (250 mL) was then added to precipitate the desired
product. A portion of this product (1.00 g, 1.0 equiv, ꢀ0.68 mmol) was
‡
C88H103Cl2N9O26 [M‡H] : 1774.7, found 1774.7.
1
40uu: tR ˆ 9.4 min; H NMR (500 MHz, CD3OD, 330 K): d ˆ 7.82 (s, 1H),
7.76 (d, J ˆ 15.0 Hz, 2H), 7.67 (d, J ˆ 9.7 Hz, 1H), 7.49 ± 7.30 (m, 8H), 7.23
(d, J ˆ 8.4 Hz, 1H), 7.05 ± 7.00 (m, 2H), 6.80 (brs, 2H), 6.63 (s, 1H), 6.49 (d,
J ˆ 2.2 Hz, 1H), 6.01 (s, 2H), 5.65 (d, J ˆ 7.5 Hz, 1H), 5.59 (d, J ˆ 4.5 Hz,
1H), 5.46 (d, J ˆ 14.0 Hz, 2H), 5.33 ± 5.23 (m, 3H), 4.90 (q, J ˆ 6.6 Hz, 1H),
3820
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3820 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 17

Synthesis of Vancomycin
3798±3823
dissolved in pyridine/H2O (1:1, 22 mL, 0.03m) and phenylthioisocyanate
(82.5 mL, 1.5 equiv, 1.03 mmol) was added. After stirring for 4 h at ambient
temperature, Et2O (250 mL) was added to precipitation the desired
C18, 6 mm  250 mm, flow rate 1.0 mLmin 1, 0 ! 100% CH3CN (0.05%
TFA) in H2O (0.05% TFA) over 10 min.
‡
48a: tR ˆ 7.4 min; LCMS (ES): calcd for C73H79Cl2N9O26S [M‡H] : 1601.4,
thiourea which was isolated by filtration. To
a suspension of the
found 1600.9.
intermediate thiourea in CH2Cl2 (50 mL) was added of TFA (2.5 mL)
dropwise. After 2 h, MeOH (100 mL) was added and the solution was
carefully evaporated to dryness without heating. Dissolution of the residue
in MeOH (25 mL) and precipitation with Et2O (200 mL) followed by
filtration gave the pure hexapeptide. HPLC data: LiChrospher C18,
6 mm  250 mm, flow rate ˆ 1.0 mLmin 1, 0 ! 100% CH3CN (0.05%
TFA) in H2O (0.05% TFA) over 10 min.
‡
48b: tR ˆ 7.4 min; LCMS (ES): calcd for C75H82Cl2N10O27S [M‡H] : 1659.5,
found 1659.6.
‡
48c: tR ˆ 7.2 min; LCMS (ES): calcd for C76H84Cl2N10O27S [M‡H] : 1673.5,
found 1673.2.
‡
48d: tR ˆ 7.3 min; LCMS (ES): calcd for C76H84Cl2N10O27S [M‡H] : 1673.5,
found 1673.5.
‡
‡
40x: tR ˆ 6.9 min; LCMS (ES): calcd for C70H74Cl2N8O24 [M‡H] : 1483.2,
48e: tR ˆ 7.3 min; LCMS (ES): calcd for C76H84Cl2N1O27S [M‡H] : 1673.5,
found 1483.2.
found 1673.5.
‡
‡
44: tR ˆ 6.8 min; LCMS (ES): calcd for C71H76Cl2N8O25S [M‡H] : 1545.3,
48 f: tR ˆ 7.2 min; LCMS (ES): calcd for C77H86Cl2N10O27S [M‡H] : 1687.5,
found 1545.3.
found 1687.5.
‡
40y (Table 2, prepared in a similar manner as above): tR ˆ 7.2 min; LCMS
48g: tR ˆ 7.4min; LCMS (ES): calcd for C79H90Cl2N10O27S [M‡H] : 1714.6,
‡
(ES): calcd for C72H78Cl2N8O24 [M‡H] : 1511.3, found 1511.4.
found 1715.0.
‡
Preparation of compounds 40q ± w (Table 2) Acylation of the hexapeptide
(40x or 40y): iPr2NEt (7.0 mL, 3.0 equiv, 40.0 mmol) followed by HBTU
(7.7 mg, 1.5 equiv, 20.0 mmol) were added room tempeature to a solution of
the hexapeptide 40x or 40y (20.0 mg, 1.0 equiv, ꢀ13.3 mmol) in DMF
(660 mL, 0.02m) and the appropriate Fmoc-protected amino acid
(Scheme 6, ꢀ6.6 mg, 1.5 equiv, 20.0 mmol). After stirring for 2 h, Et2O
(15 mL) was added to precipitate the product. After filtration, dissolution
of the residue in MeOH/DMF (1:1, 2.0 mL) followed by precipitation with
Et2O (10 mL) gave the desired Fmoc-protected heptapeptide. Dissolution
of this compound in 5% piperidine in DMF (600 mL, 0.02m) gave, after
30 min, the desired heptapeptide 40q or 40y which was precipitated by
addition of Et2O (10 mL) and purified by preparative HPLC (VYDAC
C18, 25 mm  250 mm, flow rate 6.5 mLmin 1, 0 ! 100% CH3CN (0.01%
TFA) in H2O over 30 min). Analytical HPLC data given below for
LiChrospher C18, 6 mm  250 mm, flow rate ˆ 1.0 mLmin 1, 0 ! 100%
CH3CN (0.05% TFA) in H2O (0.05% TFA) over 8 min.
48 h: tR ˆ 7.6 min; LCMS (ES): calcd for C79H90Cl2N10O27S [M‡H] : 1715.5,
found 1715.6.
‡
48i: tR ˆ 7.3 min; LCMS (ES): calcd for C78H88Cl2N10O27S [M‡H] : 1701.6,
found 1701.5.
‡
48j: tR ˆ 8.1 min; LCMS (ES): calcd for C82H94Cl2N10O27S [M‡H] : 1755.7,
found 1755.6.
‡
48k: tR ˆ 7.4 min; LCMS (ES): calcd for C79H90Cl2N10O27S [M‡H] : 1715.5,
found 1715.5.
‡
48l: tR ˆ 7.3 min; LCMS (ES): calcd for C76H84Cl2N10O28S [M‡H] : 1689.5,
found 1689.5.
‡
48m: tR ˆ 7.4 min; LCMS (ES): calcd for C77H86Cl2N10O28S [M‡H] :
1703.5, found 1703.6.
‡
48n: tR ˆ 7.6 min; LCMS (ES): calcd for C78H88Cl2N10O27S2 [M‡H] :
1733.6, found 1733.6.
‡
48o: tR ˆ 7.7 min; LCMS (ES): calcd for C82H88Cl2N10O27S [M‡H] : 1749.6,
‡
40q: tR ˆ 6.6 min; LCMS (ES): calcd for C74H80Cl2N10O26 [M‡H] : 1597.3,
found 1749.6.
found 1597.4.
‡
48p: tR ˆ 7.5 min; LCMS (ES): calcd for C82H80Cl2N10O28S [M‡H] : 1765.6,
‡
40r: tR ˆ 7.2 min; LCMS (ES): calcd for C76H84Cl2N10O26 [M‡H] : 1625.4,
found 1764.9.
found 1625.6.
‡
48q: tR ˆ 7.6 min; LCMS (ES): calcd for C80H86Cl2N10O27S [M‡H] : 1755.6,
‡
40s: tR ˆ 6.4 min; LCMS (ES): calcd for C73H79Cl2N9O25 [M‡H] : 1554.3,
found 1755.6.
found 1554.2.
‡
48r: tR ˆ 7.7 min; LCMS (ES): calcd for C78H89Cl2N11O27S [M‡H] : 1715.5,
‡
40t: tR ˆ 7.0 min; LCMS (ES): calcd for C75H83Cl2N9O25 [M‡H] : 1582.4,
found 1715.5.
found 1582.4.
‡
48s: tR ˆ 7.3 min; LCMS (ES): calcd for C79H91Cl2N11O27S [M‡H] : 1730.6,
‡
40u: tR ˆ 6.5 min; LCMS (ES): calcd for C74H81Cl2N9O25 [M‡H] : 1568.3,
found 1730.5.
found 1568.3.
‡
48t: tR ˆ 7.2 min; LCMS (ES): calcd for C79H90Cl2N12O28 [M‡H] : 1759.6,
‡
40v: tR ˆ 6.8min; LCMS (ES): calcd for C79H83Cl2N9O25 [M‡H] : 1630.4,
found 1759.6.
found 1630.4.
‡
48u: tR ˆ 7.5 min; LCMS (ES): calcd for C81H92Cl2N10O29S [M‡H] : 1772.6,
‡
40w: tR ˆ 7.00 min; LCMS (ES): calcd for C83H99Cl2N13O26 [M‡H] : 1766.6,
found 1771.9.
found 1766.5.
‡
48v: tR ˆ 7.6 min; LCMS (ES): calcd for C82H94Cl2N10O29S [M‡H] : 1787.6,
General procedure for the solid phase synthesis of analogues 48a ± 48ooo
(Scheme 9): A solution of vancomycin-derived olefin 40x or thioacetate 44
(ꢀ260 mg, 2.0 equiv, 0.18 mmol) in DMF (10.0 mL) was added to a
suspension of the appropriate resin-bound amino acid (46, 250.0 mg)
followed by the addition of iPr2NEt (62.0 mL, 4.0 equiv, 0.35 mmol) and
HBTU (66.0 mg, 2.0 equiv, 0.18 mmol). The reaction mixture was shaken at
room temperature for 1 h, the resin was collected by filtration and washed,
sequentially, with DMF (10 mL), MeOH (10 mL) and CH2Cl2 (10 mL). A
portion (25 mg) of the vancomycin-loaded resin thus obtained was mixed
with the appropriate Fmoc-protected amino acid 47, (Scheme 9, ꢀ5 mg,
2.0 equiv, 14.0 mmol) and suspended in DMF (1.0 mL). To this suspension
was added iPr2NEt (5.0 mL, 4.0 equiv, 28.0 mmol) at ambient temperature,
followed by HBTU (5.3 mg, 2.0 equiv, 14.0 mmol). The suspension was
shaken for 2 h before the resin was collected and washed as described
above. After re-suspension of the resin in 2% piperidine in DMF (1 mL)
and shaking for 1 h at room temperature to remove the Fmoc protecting
group, the resin was collected and washed as above. To cleave the
vancomycin derivative from the resin, a suspension of the resin in CH2Cl2
containing 2.5% TFA (1.5 mL) was stirred for 1.5 h at ambient temper-
ature. The resin was filtered, washed with MeOH (10 mL), and the
combined washings were concentrated to afford vancomycin analogue 48 in
essentially pure form. Analytical HPLC data given below for LiChrospher
found 1787.6.
‡
48x: tR ˆ 7.3 min; LCMS (ES): calcd for C77H86Cl2N10O26 [M‡H] : 1638.5,
found 1638.5.
‡
48y: tR ˆ 7.6 min; LCMS (ES): calcd for C78H88Cl2N10O26 [M‡H] : 1653.5,
found 1653.4.
‡
48z: tR ˆ 8.0 min; LCMS (ES): calcd for C81H92Cl2N10O26 [M‡H] : 1693.5,
found 1693.5.
‡
48aa: tR ˆ 7.5 min; LCMS (ES): calcd for C77H86Cl2N10O26S [M‡H] :
1671.5, found 1671.5.
‡
48bb: tR ˆ 7.2 min; LCMS (ES): calcd for C75H82Cl2N10O27 [M‡H] : 1627.4,
found 1627.5.
‡
48cc: tR ˆ 7.6 min; LCMS (ES): calcd for C79H84Cl2N10O26S [M‡H] :
1693.5, found 1693.5.
‡
48dd: tR ˆ 7.7 min; LCMS (ES): calcd for C81H86Cl2N10O26 [M‡H] : 1687.5,
found 1687.5.
‡
48ee: tR ˆ 7.3 min; LCMS (ES): calcd for C78H89Cl2N11O26 [M‡H] : 1668.5,
found 1668.5.
‡
48 ff: tR ˆ 7.5 min; LCMS (ES): calcd for C75H83Cl2N9O25 [M‡H] : 1582.4,
found 1582.4.
Chem. Eur. J. 2001, 7, No. 17
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3821 $ 17.50+.50/0
3821

K. C. Nicolaou et al.
FULL PAPER
‡
‡
48gg: tR ˆ 7.8 min; LCMS (ES): calcd for C80H92Cl2N10O26 [M‡H] : 1681.5,
48mmm: tR ˆ 7.6 min; LCMS (ES): calcd for C83H93Cl2N11O26S [M‡H] :
found 1681.5.
1764.7, found 1764.7.
‡
‡
48nnn: tR ˆ 7.7 min; LCMS (ES): calcd for C85H95Cl2N11O26 [M‡H] :
48 hh: tR ˆ 8.3 min; LCMS (ES): calcd for C81H94Cl2N10O26 [M‡H] :
1758.6, found 1758.6.
1694.6, found 1694.6.
‡
‡
48ooo: tR ˆ 6.9 min; LCMS (ES): calcd for C82H98Cl2N12O26 [M‡H] :
48ii: tR ˆ 8.3 min; LCMS (ES): calcd for C84H98Cl2N10O26 [M‡H] : 1735.6,
1739.6, found 1739.6.
found 1735.5.
‡
48jj: tR ˆ 7.8 min; LCMS (ES): calcd for C80H92Cl2N10O26S[M‡H] : 1713.6,
found 1716.6.
‡
48kk: tR ˆ 7.6 min; LCMS (ES): calcd for C78H88Cl2N10O27 [M‡H] : 1669.5,
found 1669.5.
Acknowledgements
‡
48ll: tR ˆ 8.0 min; LCMS (ES): calcd for C82H90Cl2N10O26 [M‡H] : 1735.6,
found 1735.6.
We thank Dr. D. H. Huang and Dr. G. Suizdak for NMR and mass
spectroscopic assistance, respectively. Financial support for this work was
provided by The Skaggs Institute for Chemical Biology and the National
Institutes of Health (USA), fellowships from the American Chemical
Society Division of Organic Chemistry (sponsored by Hoechst Marion
Roussel to R.H.) and the George Hewitt Foundation (to N.W.), and grants
from Amgen, Bayer AG, Boehringer-Ingelheim, Glaxo, Hoffmann-La
Roche, DuPont, Merck, Novartis, Pfizer, and Schering Plough.
‡
48mm: tR ˆ 8.1 min; LCMS (EI):calcd for C84H92Cl2N10O26 [M‡H] :
1729.5, found 1729.5.
‡
48nn: tR ˆ 7.7 min; LCMS (ES): calcd for C81H95Cl2N11O26 [M‡H] : 1710.6,
found 1710.6.
‡
48oo: tR ˆ 7.9 min; LCMS (ES): calcd for C79H83Cl2N9O25 [M‡H] : 1630.4,
found 1630.6.
‡
48pp: tR ˆ 8.1 min; LCMS (ES): calcd for C84H92Cl2N10O26 [M‡H] : 1729.6,
found 1729.7.
‡
48qq: tR ˆ 8.0 min; LCMS (ES): calcd for C85H94Cl2N10O26 [M‡H] : 1742.6,
[1] For recent reviews, see: a) D. H. Williams, B. Bardsley, Angew. Chem.
1999, 111, 1264 ± 1286; Angew. Chem. Int. Ed. 1999, 38, 1172 ± 1193;
b) K. C. Nicolaou, C. N. C. Boddy, S. Bräse, N. Winssinger, Angew.
Chem. 1999, 111, 2230 ± 2287; Angew. Chem. Int. Ed. 1999, 38, 2096 ±
2152.
[2] For more extended reviews on the glycopeptide class of antibiotics,
see: a) Glycopeptide Antibiotics (Ed.: R. Nagarajan), Marcel Dekker,
New York, 1994; b) R. C. Yao, L. W. Crandall, Drugs Pharm. Sci.
1994, 63, 1 ± 27.
[3] J. F. Levine, Med. Clin. North Am. 1987, 71, 1135 ± 1145.
[4] R. Leclerq, E. Derlot, J. Duval, P. Courvalin, N. Engl. J. Med. 1988,
319, 157 ± 161.
[5] a) K. Hiramatsu, Drug Resist. Updates 1998, 1, 135 ± 150; b) S. B. Levy,
Sci. Am. 1998, March, 46 ± 53.
[6] T. L. Smith, M. L. Pearson, K. R. Wilcox, C. Cruz, M. V. Lancaster, B.
Robinson-Dunn, F. C. Tenover, M. J. Zervos, J. D. Band, E. White,
W. R. Jarvis, N. Engl. J. Med. 1999, 340, 493 ± 501.
[7] D. Felmingham, J. Antimicrob. Chemother. 1993, 32, 663 ± 666.
[8] J. Zhu, Exp. Opin. Ther. Patents 1999, 9, 1005 ± 1019.
[9] T. J. Dougherty, J. F. Barrett, Curr. Opin. Anti-Infect. Invest. Drugs
1999, 1, 18 ± 25.
[10] D. H. Williams, M. P. Williamson, D. W. Butcher, S. J. Hammond, J.
Am. Chem. Soc. 1983, 105, 1332 ± 1339.
[11] For reviews, see: a) C. T. Walsh, S. L. Fisher, I.-S. Park, M. Prahalad,
Z. Wu, Chem. Biol. 1996, 3, 21 ± 28; b) G. D. Wright, C. T. Walsh, Acc.
Chem. Res. 1992, 25, 468 ± 473.
found 1742.6
‡
48rr: tR ˆ 8.7 min; LCMS (ES): calcd for C88H98Cl2N10O26 [M‡H] : 1783.6,
found 1783.6.
‡
48ss: tR ˆ 8.3min; LCMS (ES): calcd for C84H92Cl2N10O26S [M‡H] : 1761.6,
found 1761.6.
‡
48tt: tR ˆ 8.0 min; LCMS (ES): calcd for C78H86Cl2N10O29 [M‡H] : 1699.4,
found 1699.5.
‡
48uu: tR ˆ 8.3 min; LCMS (ES): calcd for C86H90Cl2N10O26S[M‡H] :
1783.7, found 1783.7.
‡
48vv: tR ˆ 8.3 min; LCMS (ES): calcd for C88H92Cl2N10O26 [M‡H] : 1777.6,
found 1777.6.
‡
48ww: tR ˆ 8.1 min; LCMS (ES): calcd for C85H95Cl2N11O26 [M‡H] :
1758.6, found 1758.6.
‡
48xx: tR ˆ 7.0 min; LCMS (ES): calcd for C75H81Cl2N9O27 [M‡H] : 1612.4,
found 1612.3.
‡
48yy: tR ˆ 7.4 min; LCMS (ES): calcd for C80H90Cl2N10O28 [M‡H] : 1711.5,
found 1711.5.
‡
48zz: tR ˆ 7.6 min; LCMS (ES): calcd for C81H92Cl2N10O28 [M‡H] : 1725.5,
found 1725.5.
‡
48aaa: tR ˆ 8.0 min; LCMS (ES): calcd for C84H96Cl2N10O28 [M‡H] :
1765.6, found 1765.6.
‡
48bbb: tR ˆ 7.6 min; LCMS (ES): calcd for C80H90Cl2N10O28S [M‡H] :
1743.5, found 1743.5.
[12] M. I. Cristofaro, D. A. Beauregard, H. Yan, N. J. Osborn, D. H.
Williams, J. Antibiot. 1995, 48, 805.
[13] R. Xu, G. Greiveldinger, L. Marenus, A. Cooper, J. A. Ellman, J. Am.
Chem. Soc. 1999, 121, 2898 ± 4899.
[14] K. C. Nicolaou, R. Hughes, S. Y. Cho, N. Winssinger, C. Smethurst, H.
Labischinski, R. Endermann, Angew. Chem. Int. Ed. 2000, 39, 3823 ±
3828.
‡
48ccc: tR ˆ 7.3min; LCMS (ES): calcd for C78H86Cl2N10O29 [M‡H] : 1699.4,
found 1699.4.
‡
48ddd: tR ˆ 6.9 min; LCMS (ES): calcd for C82H88Cl2N10O28 [M‡H] :
1765.5, foud 1765.5.
‡
48eee: tR ˆ 7.7 min; LCMS (ES): calcd for C84H90Cl2N10O28 [M‡H] :
1758.5, found 1785.5.
[15] a) R. Nagarajan, A. A. Schabel, J. L. Occolowitz, F. T. Counter, J. L.
Ott, A. M. Felty-Duckworth, J. Antibiot. 1989, 42, 63 ± 72; b) T. I.
Nicas, C. T. Cole, D. A. Preston, A. A. Schabel, R. Nagarajan,
Antimicrob. Agents Chemother. 1989, 33, 1477 ± 1481; c) R. Nagarajan,
A. A. Schabel, J. L. Occolowitz, F. T. Counter, J. L. Otto, J. Antibiot.
1988, 41, 1430 ± 1438; d) for a review, see: R. Nagarajan, J. Antibiot.
1993, 46, 1181 ± 1195.
‡
48 fff: tR ˆ 7.3 min; LCMS (ES): calcd for C81H93Cl2N11O28 [M‡H] : 1740.5,
found 1740.5.
‡
48ggg: tR ˆ 7.0 min; LCMS (ES): calcd for C76H86Cl2N10O25 [M‡H] :
1611.5, found 1611.6.
‡
48 hhh: tR ˆ 7.3 min; LCMS (ES): calcd for C81H95Cl2N11O26 [M‡H] :
1710.6, found 1710.6.
‡
[16] D. A. Beauregard, D. H. Williams, M. N. Gwynn, D. J. C. Knowles,
Antimicrob. Agents Chemother. 1995, 39, 781 ± 785.
48iii: tR ˆ 7.6 min; LCMS (ES): calcd for C82H97Cl2N11O26 [M‡H] : 1723.6,
found 1723.6.
[17] a) S. Somma, L. Gastaldo, A. Corti, Anitmicrob. Agents Chemother.
1984, 26, 917 ± 923; b) J. C. Barna, D. H. Williams, D. J. M. Stone,
T. W. C. Leung, D. M. Doddrel, J. Am. Chem. Soc. 1984, 106, 4895 ±
4902.
[18] K. C. Nicolaou, R. Hughes, S. Y. Cho, N. Winssinger, H. Labischinski,
R. Endermann, Chem. Eur. J. 2001, 7, 3824 ± 3843, see following paper
in this issue.
‡
48jjj: tR ˆ 8.1 min; LCMS (ES): calcd for C85H101Cl2N11O26 [M‡H] :
1764.6, found 1764.5.
‡
48kkk: tR ˆ 7.6 min; LCMS (ES): calcd for C81H95Cl2N11O26S [M‡H] :
1742.6, found 1742.6.
‡
48lll: tR ˆ 7.2 min; LCMS (ES): calcd for C79H91Cl2N11O27 [M‡H] : 1698.5,
found 1698.5.
3822
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0717-3822 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 17

Synthesis of Vancomycin
3798±3823
[19] P. J. Solenberg, P. Matsushima, D. R. Stack, S. C. Wilkie, R. C.
Thompson, R. H. Baltz, Chem. Biol. 1997, 4, 195 ± 202.
N. Winssinger, Y. He, S. Ninkovic, F. Sarabia, H. Vallberg, F.
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found in the Supporting Information.
Received: April 9, 2001 [F3189]
Chem. Eur. J. 2001, 7, No. 17
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