Total synthesis of vancomycin - Part 4: Attachment of the sugar moieties and completion of the synthesis

Article abstract of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2648::AID-CHEM2648>3.0.CO;2-Q

The total synthesis of vancomycin (1, Figure 1) is described. The successful plan for this synthesis involves sequential and stereoselective coupling of vancomycin aglycon acceptor 6 and glycosyl donors, trichloroacetimidate 50 and glycosyl fluoride 27 (Scheme 8). Acceptor 6 was synthesized from vancomycin aglycon (2) (Scheme 1), which was derived both by total synthesis and by semisynthesis from vancomycin itself (1) (Scheme 2). The vancosamine derivative 27 was obtained by total synthesis (Scheme 3) while the glycosyl derivative 50 was prepared from glucal (46) (Scheme 6). A number of glycosidation model studies, carried out in order to establish the final route to vancomycin (1), are also described and so are a number of failed attempts to secure the target molecule (1).

Full text of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2648::AID-CHEM2648>3.0.CO;2-Q

FULL PAPER
Total Synthesis of VancomycinÐPart 4: Attachment of the Sugar Moieties and
Completion of the Synthesis
K. C. Nicolaou,* Helen J. Mitchell, Nareshkumar F. Jain, Toshikazu Bando,
Robert Hughes, Nicolas Winssinger, Swaminathan Natarajan, Alexandros E. Koumbis[a]
Abstract: The total synthesis of vanco-
mycin (1, Figure 1) is described. The
successful plan for this synthesis in-
volves sequential and stereoselective
coupling of vancomycin aglycon accept-
or 6 and glycosyl donors, trichloroaceti-
midate 50 and glycosyl fluoride 27
(Scheme 8). Acceptor 6 was synthesized
(Scheme 1), which was derived both by
total synthesis and by semisynthesis
from vancomycin itself (1) (Scheme 2).
The vancosamine derivative 27 was
obtained by total synthesis (Scheme 3)
while the glycosyl derivative 50 was
prepared from glucal (46) (Scheme 6).
A number of glycosidation model stud-
ies, carried out in order to establish the
final route to vancomycin (1), are also
described and so are a number of failed
attempts to secure the target molecule
(1).
Keywords: amino acids ´ antibiotics
´ synthetic methods ´ total synthesis
´ vancomycin
from
vancomycin
aglycon
(2)
Introduction
In the preceding papers,[1±3] we delineated chemistry leading
to the total synthesis of vancomycinꢀs aglycon[4] (2, Figure 1).
In this article, we present the completion of the synthesis[5] of
vancomycin (1)[6] by attachment of the carbohydrate moieties
onto the aglycon, followed by final deprotections.
Results and Discussion
The plan
The plan for the final stages of the total synthesis of
vancomycin (1, Figure 1) was layed out according to the
retrosynthetic analysis shown in Figure 2. Thus, it was
envisioned that a suitably protected vancomycin aglycon
acceptor would react with appropriately functionalized glu-
cose and vancosamine derivatives to afford the entire
vancomycin network. From our experience in the vancomycin
[*] Prof. Dr. K. C. Nicolaou, H. J. Mitchell, Dr. N. F. Jain, Dr. T. Bando,
R. Hughes, N. Winssinger, Dr. S. Natarajan, Dr. A. E. Koumbis
Department of Chemistry and The Skaggs Institute for Chemical
Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
Fax: (‡1)858-784-2469
Figure 1. Molecular structures of vancomycin (1) and vancomycin aglycon
(2).
E-mail: kcn@scripps.edu
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Chem. Eur. J. 1999, 5, No. 9

2648±2667
field, we felt that the aglycon derivative 6 (Figure 2) would be
the most suitable precursor in that it exposed only the desired
functionality towards glycosidation, and its protecting groups
appeared compatible with the projected coupling and depro-
tection operations. With regards to the sugar moieties, the
plan called for either a sequential attachment using activated
systems of the two sugars, such as 3 (e.g. X ˆ trichloroaceti-
midate) and 4 (e.g. Yˆ F), or a block-type glycosidation em-
ploying a suitable disaccharide, such as 5 (e.g. X ˆ trichloro-
acetimidate). In addition to aiming for efficiency in the glyco-
sidation, our objective was to achieve high stereoselectivity
with regards to the glycoside bonds. To this end, we had to rely
on a participating protecting group at C2 of the glucose moiety
in order to facilitate b-glycosidation, and on the anomeric
effect to deliver the required a-glycoside bond, linking the
two sugar units. To test the implementation of this strategy we
needed efficient routes to key building blocks 3 ± 6.
OH
HO
HO
H2N
O
OH
O
O
Glycosidation
O
D
Glycosidation
Cl
O
O
E
C
OH
O
HO
Cl
O
O
H
H
N
H
H
N
N
N
O
N
N
H
Me
Me
H
H
H
H
O
O
O
Synthesis of the vancomycin aglycon carbohydrate acceptor
HN
HO2C
B
Me
NH2
H
The design of pentasilylated vancomycinꢀs aglycon derivative
6 as a suitable carbohydrate acceptor was based on the
premise that deprotection after glycosidation would be
possible, since the silyl groups could potentially be removed
by fluoride ion, the Cbz group by mild hydrogenolysis, and the
methyl ester by selective, base-induced hydrolysis. The syn-
thesis of 6 was, of course, the most crucial prerequisite for the
success of the designed plan towards vancomycin (1).
A
OH
OH
HO
1
OR3
Y
O
O
R2O
X
R2O
N
H
R4O
OR1
Cbz
Persilylation of vancomycin aglycon (2) with excess
TBSOTf in the presence of 2,6-lutidine, followed by aqueous
workup, furnished hexa-TBS derivative 7 in 72% yield
(Scheme 1). Exposure of 7 to excess diazomethane in ether
led to methyl ester 8 (91% yield), whose treatment with
CbzCl in dioxane and aqueous NaHCO3 gave the Cbz
derivative 9 (92% yield). It was after some experimentation
3
4
OR
OR
O
RO
RO
N
Cbz
H
O
OR
O
[7]
that we found KF ´ Al2O3 to be a suitable reagent for
Z
selectively removing the more sensitive silyl group from the
phenolic hydroxyl of ring D. Thus, exposure of the pentasilyl
ether 9 to this reagent in MeCN at 08C for 2 h, furnished the
desired hexasilyl phenol 6 in 60% yield.
5
OH
D
Cl
O
O
O
E
C
O
The same intermediate (6) was obtained more conveniently
from vancomycin (1) itself (Scheme 2). Thus, vancomycin (1)
was persilylated with excess TBSOTf and 2,6-lutidine in
CH2Cl2/DMF (10:1) furnishing, after aqueous workup, non-
asilyl ether 10 in 65% yield. Prolonged aqueous exposure
during workup was necessary to ensure complete rupture of
the N Si and C(O)O Si bonds in this step. Exposure of 10 to
excess diazomethane in ether led to methyl ester 11 (90%
yield), which was treated with excess CbzCl in aqueous
NaHCO3 providing di-Cbz derivative 12 in 80% yield. Finally,
and fortunately, hydrolysis of the sugar moieties from the
aglycon proceeded smoothly in TFA/Me2S/CH2Cl2 (1:1:1) at
ambient temperature, and under carefully controlled condi-
tions, to afford the required acceptor phenol 6 in 60% yield.
Scheme 2 also summarizes the conversion of vancomycin
(1) to compound 13 [di-Cbz-vancomycin methyl ester] which
was encountered as a key intermediate in the total synthesis of
vancomycin (1) (vide infra, see Scheme 8). These degradation
studies provided important comparison stages and, by enrich-
ing our supplies of the key intermediates, facilitated the
eventual total synthesis of vancomycin (1). In addition, the
readily available intermediate so obtained (13) provides
OTBS
O
TBSO
Cl
Cbz
N
H
H
N
H
N
N
O
N
N
Me
Me
H
H
H
H
H
O
O
O
HN
MeO2C
B
Me
NH2
H
A
OTBS
OTBS
TBSO
6
Figure 2. Retrosynthetic analysis of vancomycin (1).
Abstract in Greek:
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K. C. Nicolaou et al.
FULL PAPER
OR
e. (i) TESOTf
(ii) CH2N2
Cl
O
O
1: vancomycin
13, Scheme 8
OR
O
(iii) CbzCl
RO
Cl
O
(iv) HF•pyr.
O
H
H
N
H
N
H
N
a. TBSOTf,
2,6-lutidine
N
O
N
N
H
Me
Me
H
H
H
H
O
O
OTBS
O
TBSO
H2N
HN
HO2C
TBSO
O
Me
NH2
H
OTBS
O
2: R = H
7: R = TBS
OR
OR
a. TBSOTf,
2,6-lutidine
O
RO
O
Cl
b. CH2N2
O
O
OTBS
TBSO
O
Cl
OTBS
Cl
O
O
H
N
O
H
H
H
O
O
N
N
N
N
H
O
N
H
Me
Me
OTBS
O
H
H
H
TBSO
O
Cl
O
O
O
R
N
O
HN
H
H
N
H
N
N
Me
NH2
N
H
O
N
Me
Me
RO2C
H
H
H
H
H
O
O
OTBS
OTBS
10: R = H
11: R = Me
HN
b. CH2N2
Me
NH2
MeO2C
TBSO
H
c. CbzCl, NaHCO3
OTBS
OTBS
OTBS
8: R = H
c. CbzCl, NaHCO3
9: R = Cbz
TBSO
TBSO
CbzNH
TBSO
d. KF•Al2O3
OTBS
O
O
O
OH
Cl
O
O
O
Cl
O
O
E
C
D
OTBS
O
TBSO
Cl
O
Cbz
N
OTBS
O
O
TBSO
O
H
Cl
H
N
H
N
O
Cbz
N
N
O
H
O
H
N
N
Me
Me
H
N
N
H
N
H
H
H
N
H
N
H
Me
Me
O
O
O
H
H
H
HN
MeO2C
H
O
O
O
B
Me
HN
NH2
H
Me
NH2
MeO2C
A
OTBS
OTBS
H
OTBS
OTBS
TBSO
6
12
TBSO
Scheme 1. Synthesis of phenol 6 from vancomycin aglycon (2). a) 20 equiv
of TBSOTf, 60 equiv of 2,6-lutidine, CH2Cl2/DMF (10:1), 0 !258C, 7 h,
72%; b) CH2N2 (excess), Et2O, 08C, 0.5 h, 91%; c) 5.0 equiv of CbzCl,
10.0 equiv of NaHCO3, 1,4-dioxane/H2O (10:1), 08C, 0.5 h, 92%;
d) 1.0 equiv of KF ´ Al2O3, MeCN, 08C, 2 h, 60%. TBS ˆ tert-butyldime-
thylsilyl; DMF ˆ dimethylformamide; Cbz ˆ benzyloxycarbonyl; Tf ˆ tri-
fluoromethanesulfonyl.
d. TFA, Me2S
OH
D
Cl
O
O
E
C
OTBS
O
TBSO
Cl
H
N
O
H
N
Cbz
N
O
H
N
O
N
N
H
Me
Me
H
opportunities for the construction of combinatorial libraries
of vancomycin analogs for biological screening.
H
H
H
O
O
O
HN
MeO2C
B
Me
NH2
H
A
OTBS
OTBS
Synthesis of vancosamine donors
6
TBSO
Scheme 2. Degradation of vancomycin (1) and synthesis of intermediates 6
and 13. a) 60 equiv of TBSOTf, 180 equiv of 2,6-lutidine, CH2Cl2/DMF
(10:1), 0 !258C, 18 h; saturated aq. NaHCO3, 258C, 60 h, 65%; b) CH2N2
(excess), Et2O, 08C, 0.5 h, 90%; c) 6.0 equiv of CbzCl, 10.0 equiv of
NaHCO3, 1,4-dioxane/H2O (10:1), 08C, 0.5 h, 80%; d) TFA, Me2S, CH2Cl2
(1:1:1, 0.01m), 258C, 3 h, 60%; e) (i) 60 equiv of TESOTf, 180 equiv of 2,6-
lutidine, CH2Cl2/DMF (10:1), 0 !258C, 18 h; sat. aq. NaHCO3, 258C, 60 h;
(ii) CH2N2 (excess), Et2O, 08C, 0.5 h; (iii) 5.0 equiv of CbzCl, 10.0 equiv of
NaHCO3, 1,4-dioxane/H2O (10:1), 08C, 0.5 h; (iv) HF ´ pyr./pyr. (1:1), THF,
0 !258C, 12 h, 40% overall yield. TES ˆ triethylsilyl; TFA ˆ trifluoro-
acetic acid.
In order to explore the chemistry of the projected glycosida-
tions, we required a flexible sequence towards potential
vancosamine and glucose donors by which we could vary the
protecting groups on these sugars. To this end, we embarked
on a rapid and stereoselective synthesis[8] of vancosamine in
order to gain access to such intermediates as they were needed
(Scheme 3). In our planning, we envisioned a stereoselective
anti addition[9] of an acyl anion equivalent to an aldehyde
derived from l-lactic acid as a means to install the C4
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Total Synthesis of VancomycinÐPart 4
2648±2667
reduction of 15 with DIBAL and addition of EVE-Li[11] to the
resulting aldehyde at 1008C, followed by acidic hydrolysis,
afforded the corresponding hydroxy ketone as a mixture of
diastereoisomers (85% de, 65% combined yield for three
steps). After chromatographic separation, the desired anti
isomer (major) was condensed with O-benzylhydroxylamine
in pyridine, to afford the two readily separable oxime ethers
16 (97% yield, E:Z ca. 4:1). Pleasantly, chain extension of the
E isomer of 16 by addition of allylmagnesium bromide at
358C afforded hydroxylamine 17 as a single diastereoisomer
(95% yield based on ca. 50% conversion). Interestingly,
despite considerable experimentation and the excellent over-
all recovery of materials, this reaction could not be pushed to
completion. Since the C4 configuration of 17 is opposite to the
one required for vancosamine, an inversion at this center was
necessary. To this end, alcohol 17 was oxidized under Swern
conditions [(COCl)2, DMSO, Et3N] to afford the correspond-
ing ketone (91% yield), which was subjected to chelation-
controlled reduction with NaBH4 in Et2O/MeOH (5:1)
affording the desired hydroxy compound 18 (92% de, 90%
yield). While other methods may have provided the desired
C4 stereoisomer directly, we should recall[8] that the objective
of this lactate sequence was a broader one, namely the
synthesis of both vancosamine and evernitrose, the latter
being accessible directly from diastereoisomer 17, which
served as a common intermediate for both syntheses. At the
stage of intermediate 18, we could vary the protecting group
at C4. Thus, for our first-generation glycosidation studies we
chose a benzyl ether at this position and proceeded towards
vancosamine donor 22 as follows. The hydroxy group in 18
was benzylated (NaH, BnBr, nBu4NI cat., 88% yield) and the
resulting product was subjected to the action of LiAlH4 which
cleaved both the N-O and O Si bonds,[12] furnishing amino
alcohol 19. Selective formation of the N-Cbz derivative by
exposure of 19 to CbzCl in aqueous NaHCO3 led to
compound 20 in 78% yield for the two steps. Finally, cleavage
of the terminal olefin in 20 by ozonolysis, followed by
exposure of the resulting ozonide to Ph3P, furnished an
approximate 1:1.8 mixture of a:b lactols 21 in 95% yield.
Fluoride 22, our favorite choice as a vancosamine donor, was
prepared smoothly by reacting 21 with DAST[13] in CH2Cl2 at
08C (85% yield, a:b ca. 16:1). As matters transpired, we
needed a second vancosamine donor, fluoride 27 (Scheme 3),
equipped with an acetate group at C4. While we will save the
discussion for the rationale of its design for later, we will
discuss here its synthesis from intermediate 18. Thus, the
hydroxy group of the latter compound (18) was temporarily
protected as a PMB ether (NaH, PMBCl, 93% yield), and the
resulting compound was exposed to LiAlH4, furnishing amino
alcohol 23 by cleavage of the N O and O Si bonds as before.
The amino group of 19 was selectively engaged by treatment
with CbzCl in aqueous NaHCO3, furnishing hydroxy Cbz
derivative 24 in 81% yield (two steps). Cleavage of the
terminal olefin in 24 by ozonolysis, followed by reaction with
Me2S and acetylation (Ac2O, Et3N, 4-DMAP cat.), led to
vancosamine derivative 25 in 88% overall yield. Exposure of
O
OH
b. DIBAL
Me
Me
Me
c. EVE-Li
OEt
d. BnONH2 •HCl
OR
iPr3SiO
NOBn
16
14: R = H
15: R = iPr3Si
a. iPr3SiCl
e. allylMgBr
OH
OH
4
5
3
Me
Me
f. Swern [O]
g. NaBH4
Me NH
OBn
Me NH
iPr3SiO
iPr3SiO
OBn
18
17
h. NaH, BnBr
i. LiAlH4
OPMB
3
OBn
m. NaH, PMBCl
n. LiAlH4
Me
5
Me
HO
Me NH2
Me NHR
HO
23
19: R = H
20: R = Cbz
j. CbzCl, NaHCO3
o. CbzCl,
NaHCO3
k. O3; Ph3P
OPMB
O
X
Me
N
Cbz
Me NHCbz
BnO
HO
H
24
21: X = OH
22: X = F
l. DAST
p. O3; Me2S
q. Ac2O
O
O
r. PhSH,
BF3•Et2O
OAc
X
N
Cbz
N
Cbz
PMBO
H
AcO
H
s. Ac2O
25
26: X = SPh
27: X = F
t. NBS
u. DAST
Scheme 3. Synthesis of vancosamine donors 22 and 27. a) 1.1 equiv of
iPr3SiCl, 2.0 equiv of imidazole, DMF, 0 !258C, 10 h, 99%; b) 1.6 equiv of
DIBAL, CH2Cl2, 788C, 45 min; c) 1.8 equiv of EVE-Li, THF, 1008C,
5 min; then 5% aq HCl, THF/H2O (4:1), 65% for three steps, 85% de;
d) 1.1 equiv of BnONH2 ´ HCl, pyr., 0 !258C, 2 h, 97% (E:Z ca. 4:1);
e) 2.5 equiv of allylMgBr, Et2O,
358C, 1 h, 95% based on 50%
conversion; f) 2.0 equiv of (COCl)2, 2.5 equiv of DMSO, 788C, 2 h;
4.0 equiv of Et3N, 78 !08C, 2 h, 91%; g) 3.0 equiv of NaBH4, Et2O/
MeOH (5:1), 258C, 0.5 h, 90%, 92% de ; h) 1.1 equiv of NaH, 1.2 equiv of
BnBr, 0.2 equiv of nBu4NI, DMF, 0 !258C, 2 h, 88%; i) 1.6 equiv of
LiAlH4, Et2O, 258C, 24 h; j) 3.0 equiv of CbzCl, 10.0 equiv of NaHCO3,
H2O/THF (1:5), 0 !258C, 0.5 h, 78% for two steps; k) (i) O3, CH2Cl2,
788C, 1 h; (ii) 2.0 equiv of Ph3P, 78 !258C, 12 h, 95%, a:b ca. 1.8:1;
l) 1.4 equiv of DAST, CH2Cl2, 08C, 20 min, 85%; m) 1.1 equiv of NaH,
1.3 equiv of PMBCl, THF, 0 !258C, 4 h, 93%; n) 4.0 equiv of LiAlH4,
Et2O, reflux, 5 h; o) 1.5 equiv of CbzCl, 2.0 equiv of NaHCO3, 1,4-dioxane/
H2O (4:1), 0 !258C, 18 h, 81% for two steps; p) O3 (excess), CH2Cl2,
788C, 1 h; Me2S, 78 !258C, 6 h, 92%; q) 2.0 equiv of Ac2O, 3.0 equiv
of Et3N, 0.1 equiv of 4-DMAP, CH2Cl2, 258C, 2 h, 96%; r) 4.0 equiv of
PhSH; 4.0 equiv of BF3 ´ Et2O, CH2Cl2, 208C, 1 h, 91%; s) 2.0 equiv of
Ac2O, 3.0 equiv of Et3N, 0.1 equiv of 4-DMAP, CH2Cl2, 258C, 2 h,
97%; t) 1.5 equiv of NBS, acetone/H2O (9:1), 08C, 0.5 h, 87%; u) 1.5 equiv
of DAST, CH2Cl2, 08C, 20 min, 100%. NBS ˆ N-bromosuccinimide;
DASTˆ diethylaminosulfur trifluoride; DIBAL ˆ diisobutylaluminum hy-
dride; 4-DMAP ˆ 4-dimethylaminopyridine; allyl ˆ CH2 ˆ CHCH2; EVE-
Li ˆ CH2 ˆ C(OEt)Li; Bn ˆ benzyl; DMSO ˆ dimethyl sulfoxide; PMB ˆ
p-methoxybenzyl.
stereocenter (numbering based on the final carbohydrate
ring) and a nucleophilic addition to an oxime[10] to craft the C3
functionality. Thus, ethyl l-lactate (14, Scheme 3) was pro-
tected with a bulky silicon group (iPr3Si) under standard
conditions, furnishing silyl ether 15 in 99% yield. Sequential
25 to excess PhSH and BF3 ´ Et2O in CH2Cl2 at
208C
removed cleanly, both the PMB and acetate groups (91%
yield), leading, after acetylation of the C4 hydroxyl group as
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K. C. Nicolaou et al.
FULL PAPER
above (97% yield), to phenylthioglycoside 26. Formation of
vancosamine fluoride 27 required cleavage of the PhS group
with NBS in acetone/H2O (9:1) (87% yield) and exposure of
the resulting mixture of a/b lactol anomers to DAST in
CH2Cl2 at 08C (100% yield, a:b ca. 16:1).
glycosidation reaction in the b direction by the well-known
neighboring group participation, as required. Thus, phenyl-
thioglucoside 28 (readily available form tribenzyl glucal by
dihydroxylation, dibenzoylation, and reaction with PhSH/
BF3 ´ Et2O, see Experimental Section) was treated with NBS
in acetone/H2O (10:1) to afford lactol 29 in 87% yield (ca.
10:1 mixture of a:b anomers). Conversion to imidate 30 was
smoothly effected by treatment with trichloroacetonitrile and
DBU (90% yield).
First-generation glycosidation studies
Using 2,6-dimethoxyphenol as a phenol representative of
the bulky vancomycin aglycon, we found that its coupling with
trichloroacetimidate donor 30 proceeded smoothly in the
presence of BF3 ´ Et2O at 30 !258C to afford the desired
glucoside 31 in excellent yield (95%) and high anomeric
stereoselectivity (b:a ca. 13:1). Debenzoylation at C2 under
basic conditions (NaOH, 90%) gave direct access to acceptor
32, setting the stage for an attempt at the second glycosidation
utilizing vancosamine donor 22. A combination of BF3 ´ Et2O
and TMSOTf was found, in this instance, to be highly effective
for the attachment of 22 to 32, furnishing the desired a-
glycoside 33 as the major product (89% yield based on 90%
conversion, a:b ca. 10:1). Hydrogenolysis of the Cbz and
benzyl groups from 33 (H2, 10% Pd/C), followed by
benzoylation of the resulting amino-tetraol gave disaccharide
34. The spectroscopic data of 34 matched those reported by
Danishefsky et al., who had previously developed an inde-
pendent route to this vancomycin model.[15] Of particular
value in confirming the stereochemistry of the glycosidic
linkages were the coupling constants J1,2ax ˆ 4.5 Hz for vancos-
amine, and J1,2 ˆ 7.5 Hz for glucose.
With the C4-benzyl protected vancosamine donor 22 ready,
we turned our attention to model glycosidation studies
directed at exploring a strategy for an eventual coupling of
the vancomycin aglycon and the sugar moieties.[8] For these
studies, we required a suitable glucose donor. We initially
chose trichloroacetimidate[14] 30 (Scheme 4), in which the C2
position was occupied by a benzoate group and the remaining
three hydroxy groups were carrying benzyl groups for
protection. The C2 benzoyl group was expected to direct the
OH
OBn
OBn
OMe
MeO
BnO
O
BnO
BnO
OBn
OMe
c.
BzO
X
RO
O
b. Cl3CCN,
DBU
29: X = OH
30: X = OC(NH)CCl3
O
MeO
a. NBS
OBn
31: R = Bz
32: R = H
BnO
d. NaOH
O
OBn
In order to explore the ground for the possibility of a block-
type installation of the two sugar units onto the vancomycin
aglycon, we proceeded to synthesize the disaccharide trichlor-
oacetimidate 38, as outlined in Scheme 4. Thus, debenzoyla-
tion of 28 (NaOH) gave acceptor 35 in 90% yield. Coupling of
35 with vancosamine donor 22 in CH2Cl2 at 108C in the
presence of SnCl2, proceeded in excellent yield (85%), but
led to only modest anomeric selectivity in favor of the desired
a-glycoside 36 (a:b ca. 3.3:1). Varying the temperature of the
reaction, or the catalyst, did not improve significantly this
result. On the other hand, these studies revealed that a major
controlling factor in terms of reactivity and diastereoselectiv-
ity was the size and electronic nature of the glucose anomeric
substituent: the smaller the substituent, the faster the
coupling with the vancosamine donor, but the lower the
anomeric selectivity. After separation of the isomers, the
desired a-anomer 36 was treated with NBS in acetone/H2O
(10:1), releasing disaccharide lactol 37 (85% yield), which was
converted to its trichloroacetimidate 38 by exposure to
CCl3CN in the presence of DBU in CH2Cl2 at 08C (90%
yield, a:b ca. 20:1).
RO
O
F
e.
SPh
22
N
28: R = Bz
35: R = H
Cbz
BnO
H
g. NaOH
OR2
R2O
R1
R2O
N
H
O
h. 22
OR2
OBn
BnO
BnO
O
O
N
Cbz
H
O
OBn
O
OMe
MeO
O
O
X
36: X = SPh
i. NBS
33: R1 = Cbz, R2 = Bn
37: X = OH
f. (i) H2, (ii) BzCl
j. Cl3CCN, DBU
34: R1 = R2 = Bz
38: X = OC(NH)CCl3
Scheme 4. Synthesis of first-generation vancomycin disaccharides 34 and
38. a) 2.0 equiv of NBS, acetone/H2O (10:1), 08C, 0.5 h, 87%, a:b ca. 10:1;
b) 10.0 equiv of Cl3CCN, 0.05 equiv of DBU, CH2Cl2, 308C, 0.5 h, 90%;
c) 1.6 equiv of 30, 0.6 equiv of BF3 ´ Et2O, CH2Cl2, 4 Š MS, 30 !258C,
24 h, 95%, b:a ca. 13:1; d) 2.5 equiv of NaOH, MeOH, 258C, 3 h, 90%;
e) 2.0 equiv of 22, 0.4 equiv of BF3 ´ Et2O, 0.4 equiv of Me3SiOTf, CH2Cl2,
4 Š MS, 30 !258C, 72 h, 89% based on 90% conversion, a:b ca. 10:1;
f) (i) H2, 10% Pd/C, EtOAc, 258C, 12 h; (ii) 7.0 equiv of BzCl, pyr., 08C,
6 h, 85% for two steps; g) 1% aq. NaOH, MeOH, 258C, 3 h, 90%; h)
1.3 equiv of 22, 1.9 equiv of SnCl2, CH2Cl2, 4 Š MS, 108C, 2 h, 85%, a:b
ca. 3.3:1; i) 1.5 equiv of NBS, acetone/H2O (10:1), 08C, 0.5 h, 85%;
j) 20 equiv of Cl3CCN, 0.05 equiv of DBU, CH2Cl2, 08C, 15 min, 90%, a:b
ca. 20:1. DBU ˆ 1,8-diazabicyclo[5.4.0]undec-7-ene; Bz ˆ benzoyl.
The successful synthesis of disaccharides 34 and 36
(Scheme 4) established the feasibility of attaching, stereo-
selectively, the carbohydrate units onto vancomycinꢀs aglycon,
either stepwise or in a block-type fashion. Early experimen-
tation with the benzoyl-containing glucose donor 30 and the
pentasilylated aglycon derivative 6 indicated that basic
removal of the C2 benzoate from the glucose moiety would
be problematic due to significant TBS cleavage from some of
2652
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 4
2648±2667
OBn
O
BnO
BnO
O
N
Cbz
H
O
OBn
OBn
O
BnO
BnO
O
N
Cbz
H
OH
Cl
O
O
OBn
Cl
O
O
O
O
OTBS
O
OR
O
TBSO
O
Cl
RO
Cl
38
d.
O
O
Cbz
N
Cbz
N
OC(NH)CCl3
O
O
H
H
H
H
H
H
N
N
N
N
N
N
N
O
N
N
Me
Me
N
H
Me
Me
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
HN
HN
MeO2C
Me
Me
NH2
MeO2C
NH2
H
H
OTBS
OTBS
OR
OR
42: R = TBS
43: R = H
e. nBu4NF
TBSO
RO
6
OBn
c.
O
O
F
a.
OC(NH)CCl3
OBn
f. H2
BnO
BnO
N
Cbz
BnO
ClAcO
H
39
22
OH
HO
H2N
BnO
HO
OBn
O
OH
RO
O
O
O
O
O
Cl
O
O
O
O
E
OTBS
O
OH
O
TBSO
Cl
HO
Cl
O
O
Cbz
N
O
O
H
H
H
N
H
H
N
H
H
N
N
N
N
N
O
N
O
N
N
H
Me
Me
N
H
Me
Me
H
H
H
H
H
H
H
O
H
O
O
O
O
O
HN
MeO2C
HN
RO2C
Me
Me
NH2
NH2
H
H
OTBS
OTBS
OH
OH
40: R = C(O)CH2Cl
41: R = H
44: R = Me
45: R = H
g. LiOH
b. K2CO3
TBSO
HO
Scheme 5. First-generation approach to vancomycin (1). a) 1.7 equiv of 39, 4.0 equiv of BF3 ´ Et2O, CH2Cl2, 78 ! 308C, 18 h, 70%; b) 3.0 equiv of
K2CO3,THF/MeOH (2:1), 258C, 10 min, 75%; c) 10.0 equiv of 22, 5.0 equiv of BF3 ´ Et2O, CH2Cl2, 0 !258C, 24 h, 5%; d) 5.0 equiv of 38, 10.0 equiv of BF3 ´
Et2O, CH2Cl2, 78 ! 308C, 24 h, 70%; e) 30 equiv of nBu4NF, THF, 108C, 2 h; f) H2, 10% Pd/C, MeOH, 258C, 16 h; g) 5.0 equiv of LiOH, THF/H2O
(1:1), 08C, 20 min. ClAc ˆ C(O)CH2Cl.
the phenolic groups under the required basic conditions.
Anticipating a more selective C2 deprotection of the chlor-
oacetate group, trichloroacetimidate 39 (Scheme 5) [prepared
by an analogous route to its benzoate counterpart (29) as
shown in Scheme 4] was, therefore, utilized in our first
attempt to install the glucose moiety onto the aglycon.
Reaction of the aglycon derivative 6 with carbohydrate donor
39 in the presence of BF3 ´ Et2O in CH2Cl2 at 78 ! 308C
furnished the desired glycoside 40 in 70% yield. The
chloroacetate group was then removed from the C2 carbohy-
drate position by controlled reaction with K2CO3 in THF/
MeOH, providing acceptor 41 (75% yield). However, the
second glycosidation step with vancosamine donor 22 pro-
ceeded sluggishly, and furnished only poor yields of the
desired disaccharide, even after prolonged reaction times.
Thus, reaction of 41 with excess 22 in CH2Cl2 and in the
presence of BF3 ´ Et2O at 0 ! 238C resulted in only 5% yield
of the desired compound (42). Confronted with these
disappointing results, we opted for the more convergent,
block-type attachment of the disaccharide domain onto the
aglycon acceptor (6). This strategy, of course, could poten-
tially suffer from the absence of a b-directing group to control
the anomeric stereochemistry of the newly generated glyco-
sidic linkage (joining the disaccharide to the aglycon), but, at
this point, we counted on the bulkiness of the glucose C2
substituent to provide some degree of selectivity. Indeed, the
coupling of disaccharide donor 38 with phenol 6 proceeded
smoothly in CH2Cl2 at 78 ! 308C, affording a single
coupling product, which was presumed to be the desired b-
glycoside. Stereochemical assignment of the newly formed
glycoside bond, however, was not possible at this stage and
had to await deprotection and comparison with authentic
vancomycin methyl ester. To this end, the TBS groups were
cleaved from 42 by exposure to TBAF, furnishing pentahy-
droxy vancomycin derivative 43, which was subjected to
hydrogenolysis (H2, 10% Pd/C, MeOH, 258C) and saponifi-
cation (LiOH, THF/H2O, 1:1, 08C) to remove the benzyl
ethers and the methyl ester, respectively. Spectroscopic
analysis, however, clearly indicated that the hydrogenolysis
of the benzyl ethers was accompanied by scission of the C Cl
Chem. Eur. J. 1999, 5, No. 9
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2653

K. C. Nicolaou et al.
FULL PAPER
bond of ring E, and that compounds 44 and 45 lacking one
chlorine substituent were the products, rather than the
expected vancomycin and its methyl ester. Other methods
for removing the benzyl ethers from 43 were attempted;
however, none were successful. It was, therefore, decided to
abandon the benzyl groups and search for different protecting
groups as part of second-generation glycosidation studies.
furnished diol 48 in 84% yield. The selective allylcarbonyla-
tion of the C2 hydroxy group in 48 was accomplished by
reaction with nBu2SnO, followed by quenching with AllocCl,
leading to compound 49 (67% yield). Exposure of 49 to
CCl3CN in CH2Cl2 in the presence of DBU gave the desired
trichloroacetimidate 50 in 89% yield (a:b ca. 14:1).
With the newly designed carbohydrate donors now avail-
able, and before attempting the real task of constructing
vancomycin (1), we proceeded to test their coupling and
loading onto a model phenolic acceptor as shown in Scheme 7.
Second-generation glycosidation studies
OH
With the decision to move away from benzyl protecting
groups on the sugars, we were faced with the option of using
silyl and/or acetate groups for the protection of the hydroxy
groups of these moieties. Fully silylated (e.g. TBS) mono- and
disaccharide systems were synthesized and proved to be poor
candidates as glycosidation donors. On the other hand, fully
acetylated systems were considered to be too deactivated for
the projected glycosidations. We, therefore, chose to explore a
combination of silyl and acetyl groups as a possible scenario
for the construction of the vancomycin system. Our own
experiences demonstrated that silyl groups could be removed
successfully from vancomycin and, drawing comfort from the
recent work of Kahne et al.,[16] we projected that cleavage of
acetate and alloc (allyloxycarbonyl) groups would be com-
patible with the molecule. For a glucose donor, therefore, we
designed trichloroacetimidate 50 (Scheme 6) with a TBS
OTBS
OAc
OMe
MeO
AcO
O
AcO
AcO
OTBS
OMe
a.
AllocO
OC(NH)CCl3
RO
O
50
O
MeO
d. PhSH
OAc
51: R = Alloc
52: R = H
AcO
b. nBu3SnH,
Pd(0)
OTBS
RO
O
O
F
c.
SPh
27
N
Cbz
54: R = Alloc
55: R = H
AcO
AcO
e. nBu3SnH,
Pd(0)
H
OAc
AcO
O
N
f. 27
Cbz
OH
OTBS
H
a. TBSCl, imid.
b. Ac2O, Et3N
O
OTBS
O
O
O
OAc
AcO
HO
HO
AcO
AcO
AcO
N
Cbz
H
46
47
O
OTBS
O
c. OsO4, NMO
OMe
MeO
O
O
OTBS
SPh
OTBS
d. nBu2SnO;
AllocCl
56
53
O
O
AcO
AcO
AcO
AcO
Scheme 7. Synthesis of second-generation vancomycin model disacchar-
ides 53 and 56. a) 1.7 equiv of 50, 0.2 equiv of BF3 ´ Et2O, CH2Cl2, 4 Š MS,
788C, 20 min, 95%; b) 0.05 equiv of Pd(Ph3P)4, 1.5 equiv of nBu3SnH,
CH2Cl2, 258C, 0.5 h, 83%; c) 1.6 equiv of 27, 1.1 equiv of BF3 ´ Et2O,
CH2Cl2, 4 Š MS, 308C, 2 h, 91%, a:b ca. 9:1; d) 1.2 equiv of PhSH,
0.3 equiv of BF3 ´ Et2O, CH2Cl2, 4 Š MS, 788C, 45 min, 95%, b:a >99:1;
e) 0.05 equiv of Pd(Ph3P)4, 1.5 equiv of nBu3SnH, CH2Cl2, 258C, 0.5 h,
87%; f) 1.6 equiv of 27, 1.1 equiv of BF3 ´ Et2O, CH2Cl2, 4 Š MS, 308C,
2 h, 98%, a:b ca. 3:2.
OH
AllocO
OH
X
49: X = OH
50: X = OC(NH)CCl3
48
e. Cl3CCN, DBU
Scheme 6. Synthesis of glucose donor 50. a) 1.0 equiv of TBSCl, 2.2 equiv
of imidazole, DMF, 0 !258C, 1 h, 82%; b) 2.5 equiv of Ac2O, 4.0 equiv of
Et3N, 0.1 equiv of 4-DMAP, CH2Cl2, 0 !258C, 1 h, 97%; c) 0.05 equiv of
OsO4, 1.5 equiv of NMO, acetone/H2O (9:1), 258C, 12 h, 84%; d) 1.2 equiv
of nBu2SnO, toluene, reflux, 6 h; 1.1 equiv of AllocCl, 08C, 0.5 h, 67%;
e) 20 equiv of Cl3CCN, 0.05 equiv of DBU, CH2Cl2, 108C, 20 min, 89%,
a:b ca. 14:1. NMO ˆ 4-methylmorpholine N-oxide; Alloc ˆ allyloxycar-
bonyl.
Stability of protecting groups, reactivity of donors, and
stereoselectivity were the issues to be explored. To this end,
glucose donor 50 was treated with 2,6-dimethoxyphenol in
CH2Cl2 and in the presence of BF3 ´ Et2O at 788C, affording,
rapidly and in 95% yield, the desired b-glycoside 51 as a single
stereoisomer. Liberation of the C2 hydroxy group from 51
proceeded selectively in the presence of nBu3SnH and a
catalytic amount of Pd(Ph3P)4,[17] yielding acceptor 52 in 83%
yield. The coupling of 52 with vancosamine donor 27
proceeded smoothly in CH2Cl2 at 308C and in the presence
of BF3 ´ Et2O, furnishing disaccharide 53 in high yield and
excellent anomeric diastereoselectivity (91%, a:b ca. 10:1).
Starting again from glucose donor 50, and repeating the
sequence with thiophenol instead of 2,6-dimethoxyphenol,
group at C6, acetate groups at C4 and C3, and an alloc group
at C2. As a vancosamine donor, we chose the 4-acetoxy
glycosyl fluoride 27 (Scheme 3). The synthesis of the latter
intermediate (27) has already been described above (see
Scheme 3), whereas the construction of trichloroacetimidate
50 is summarized in Scheme 6. Thus, 46 (obtained from
commercially available glucal triacetate by deacetylation with
K2CO3, MeOH, 100%), was selectively monosilylated (C6,
TBSCl, imidazole, 82% overall yield) and acetylated (C4 and
C3, Ac2O, Et3N, 4-DMAP, 97% yield) to afford 47. Dihy-
droxylation of 47 with NMO/OsO4 cat. in acetone/H2O (9:1)
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 4
2648±2667
OAc
O
OTBS
AcO
O
AcO
AcO
OTBS
RO
AllocO
OC(NH)CCl3
50
OH
Cl
O
Cl
O
O
O
O
OTBS
O
OTBS
O
TBSO
O
TBSO
Cl
Cl
O
O
Cbz
N
Cbz
N
O
O
H
H
H
H
H
N
H
N
N
N
N
N
O
N
N
N
H
Me
Me
N
Me
H
H
H
H
H
H
H
a. BF3•Et2O
H
H
O
O
O
O
Me
O
O
HN
HN
MeO2C
Me
Me
NH2
NH2
MeO2C
H
H
OTBS
OTBS
OTBS
OTBS
TBSO
TBSO
57: R = Alloc
58: R = H
6
b. nBu3SnH, Pd (0)
O
F
c. BF3•Et2O
N
Cbz
AcO
H
27
OH
OAc
AcO
HO
AcO
HO
N
N
R2
Cbz
H
H
OR
O
OH
O
O
O
O
O
O
O
Cl
Cl
O
O
O
O
OH
O
OR
O
HO
RO
Cl
Cl
R2
O
O
Cbz
O
O
H
H
N
H
H
H
H
N
N
N
N
N
N
N
O
O
N
N
N
Me
Me
e. K2CO3
N
Me
Me
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
HN
R1O2C
HN
MeO2C
Me
Me
NH2
NH2
H
H
OR
OR
OH
OH
RO
HO
13: R1 = Me; R2 = Cbz
61: R1 = Me; R2 = H
1: vancomycin: R1 = R2 = H
59: R = TBS
60: R = H
f. Raney Ni
g. LiOH
d. HF•pyr.
Scheme 8. Synthesis of vancomycin (1). a) 5.0 equiv of 50, 10.0 equiv of BF3 ´ Et2O, CH2Cl2, 788C, 6 h, 82%; b) 4.0 equiv of nBu3SnH, 0.1 equiv of
Pd(Ph3P)4, CH2Cl2, 258C, 0.5 h, 85%; c) 4.0 equiv of 27, 3.0 equiv of BF3 ´ Et2O, CH2Cl2, 358C, 2 h, 84%; d) HF ´ pyr./pyr. (1:1), THF, 0 !258C, 12 h, 80%;
e) 5.0 equiv of K2CO3, MeOH, 258C, 4 h, 95%; f) Raney Ni, nPrOH/H2O (2:1), 258C, 0.5 h; g) 5.0 equiv of LiOH, THF/H2O (1:1), 08C, 20 min, 85% from 13.
intermediates 54 (95% yield, b:a > 99:1), 55 (87% yield), and
finally disaccharide 56 (98%, a:b ca. 3:2) were obtained in
excellent yield (Scheme 7). Thus, while the stereoselectivity of
the first glycosidation was excellent, that of the second coupling
was only modest, pointing to the overriding effect of the size
and electronic nature of the glucose C1 substituent. The C4
acetate group of vancosamine, apparently, did not influence the
outcome of this glycosidation reaction, even at lower tem-
peratures. It was with this knowledge at hand that we
proceeded to apply this strategy to the real case, being
cautiously confident of the outcome.
(1): a stepwise glycosidation approach utilizing acceptor 6 and
donors 50 and 27 as shown in Scheme 8. Glycosidation of
phenol 6 with excess trichloroacetimidate 50 in CH2Cl2 and in
the presence of BF3 ´ Et2O at 788C proceeded smoothly to
afford monosaccharide 57 in 82% yield, together with a minor
product, presumed to be the undesired a-anomer. The b-
stereochemistry of the major product (57) was tentatively
assigned at this stage based solely on the results of the model
studies described above, and was later confirmed by NMR
spectroscopy and conversion to vancomycin (1). Proceeding
with the synthesis, the C2 hydroxy group of the glucose moiety
of 57 was liberated by reaction with nBu3SnH/Pd(Ph3P)4 in
wet CH2Cl2, leading to the new glycoside acceptor 58 (85%
yield). At this stage we were also pleased to observe in the
Completion of the synthesis
1H NMR spectrum of 58 a revealing coupling constant (J1,2
ˆ
7.7 Hz) associated with the anomeric position, characteristic
The model studies described above helped shape the final
plan for the completion of the total synthesis of vancomycin
of a b-glycoside linkage.
Chem. Eur. J. 1999, 5, No. 9
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2655

K. C. Nicolaou et al.
FULL PAPER
We were now in a position to attempt the second
glycosidation with vancosamine donor 27. Reaction of 58
with glycosyl fluoride 27 in CH2Cl2 and in the presence of
BF3 ´ Et2O at 358C gave the fully protected vancomycin
derivative 59 in 84% yield and about 8:1 a:b stereoselectivity.
Chromatographically separated 59 was then subjected to
desilylation (excess HF ´ pyr./pyr.), furnishing hexahydroxy
compound 60 in 80% yield. Exposure of 60 to the action of
K2CO3 in MeOH at ambient temperature removed the three
acetate groups, leading to di-Cbz vancomycin methyl ester 13
(95% yield). The latter compound (13) was found to be
identical with a sample derived from vancomycin (1) as
summarized in Scheme 2 [(i) TESOTf, 2,6-lutidine, 65%; (ii)
CH2N2; (iii) CbzCl, NaHCO3, 80% for two steps; (iv) HF ´
pyr./pyr., 80%]. Finally, treatment of 13 with Raney-Ni in
nPrOH/H2O (2:1) led in clean removal of the Cbz groups
without dechlorination (as occasionally observed under
hydrogenolysis conditions using H2-Pd/C systems) and sap-
onification of the resulting vancomycin methyl ester with
LiOH in THF/H2O (1:1) at 08C, furnished vancomycin (1) in
85% yield from 13. Synthetic vancomycin (1) was identical
with an authentic sample by the usual criteria (HPLC,
vancomycin (1). Well designed degradation studies on vanco-
mycin (1) opened additional avenues to certain key synthetic
intermediates rendering them readily available for semisyn-
thetic studies. In conjunction with solid-phase and combina-
torial chemistry, such studies may prove extremely valuable in
delivering vancomycin libraries for biological screening. Thus,
the chemistry developed during this program enriched our
knowledge in the field of chemical synthesis and set the stage
for possible contributions to the chemical biology and
medicine of the glycopeptide antibiotics.
Experimental Section
General techniques: See paper 1 in this series.[1]
Hexa-TBS-aglycon 7: TBSOTf (20.1 mL, 8.7 mmol) was added dropwise to
a solution of vancomycin aglycon (2) (500 mg, 0.437 mmol) and 2,6-lutidine
(30.5 mL, 26.2 mmol) in CH2Cl2/DMF (10:1, 40 mL) at 08C. The reaction
mixture was slowly warmed to 258C and stirred for 7 h. The reaction was
quenched by the addition of saturated aqueous NaHCO3 (30 mL) and
stirred at 258C for 10 h. The organic layer was separated and the aqueous
phase was extracted with EtOAc (3 Â 50 mL). The combined organic layers
were dried (Na2SO4), concentrated and the residue was purified by flash
column chromatography (silica gel, 1 !5% MeOH in CH2Cl2, gradient
elution) to afford hexa-TBS-aglycon 7 (574 mg, 72%) as a white foam. 7:
1
1H NMR, mixed H NMR, MS).[18] Kahneꢀs group has also
accomplished a synthesis of vancomycin (1) from vancomy-
cin-derived derivatives of a pseudoaglycon (containing the
glucose residue only)[16] and an aglycon derivative.[20]
Rf ˆ 0.22 (silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
19.3 (c ˆ 0.89,
CHCl3); IR (thin film): nÄmax ˆ 3403, 2927, 2856, 1675, 1498, 1471, 1256,
1
1175, 1105, 1060, 1021, 916, 838, 782 cm
;
1H NMR (600 MHz, CD3OD,
330 K): d ˆ 7.65 (s, 1H), 7.55 ± 7.52 (m, 2H), 7.43 (s, 1H), 7.23 (d, J ˆ 8.5 Hz,
1H), 7.18 ± 7.16 (m, 1H), 7.05 (d, J ˆ 2.5 Hz, 1H), 6.98 (dd, J ˆ 8.5, 2.5 Hz,
1H), 6.75 (d, J ˆ 8.5 Hz, 1H), 6.58 (br.s, 1H), 6.39 (d, J ˆ 2.0 Hz, 1H), 5.72
(br.s, 1H), 5.67 ± 5.64 (m, 1H), 5.42 (d, J ˆ 4.0 Hz, 1H), 5.37 (s, 1H), 5.33
(br.s, 1H), 4.90 (s, 1H), 4.83 (d, J ˆ 4.0 Hz, 1H), 4.63 ± 4.61 (m, 1H), 4.59 (s,
1H), 4.53 (s, 1H), 4.09 (s, 1H), 3.13 ± 3.11 (m, 1H), 2.52 ± 2.49 (m, 1H), 2.40
(s, 3H), 1.83 ± 1.80 (m, 1H), 1.62 ± 1.59 (m, 1H), 1.53 ± 1.50 (m, 1H), 1.06 (s,
9H), 1.01 (s, 9H), 0.96 (d, J ˆ 6.5 Hz, 3H), 0.95 (d, J ˆ 6.5 Hz, 3H), 0.92 (s,
9H), 0.89 (s, 9H), 0.73 (s, 9H), 0.61 (s, 9H), 0.36 (s, 3H), 0.35 (s, 3H), 0.23
(s, 3H), 0.23 (s, 3H), 0.16 (s, 3H), 0.13 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H),
0.08 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.09 (s, 3H); 13C NMR (150 MHz,
CDCl3:CD3OD (9:1), 310 K): d ˆ 173.9, 173.8, 171.2, 168.8, 168.3, 156.3,
155.4, 154.5, 152.6, 151.9, 151.3, 141.2, 139.3, 136.4, 134.2, 130.1, 129.5, 129.3,
129.2, 128.6, 128.0, 127.6, 126.9, 125.1, 117.2, 113.7, 111.7, 107.5, 105.5, 74.1,
73.1, 71.0, 67.8, 64.0, 63.3, 60.9, 56.2, 54.9, 53.1, 52.5, 42.3, 37.3, 35.2, 30.4,
29.6, 26.7, 26.5, 26.0, 26.0, 25.8, 23.6, 22.9, 22.3, 19.6, 19.1, 19.0, 2.0, 1.7, 3.3,
Conclusion
In this and the preceding three articles,[1±3] we described the
total synthesis of vancomycin (1). During this campaign a
number of new synthetic technologies and strategies were
designed and developed, among which the triazene-driven
biaryl ether synthesis is perhaps the most prominent. The
successful strategy employed modern catalytic asymmetric
reactions for the construction of the required amino acid
building blocks which were then assembled to appropriate
peptide fragments, whose cyclization in the order C-O-
D !AB/C-O-D !AB/C-O-D-O-E led to the framework of
vancomycinꢀs aglycon. While both the C-O-D and D-O-E
macrocycles were constructed by the triazene-driven cycliza-
tion process, the AB-containing ring system was formed by a
sequential Suzuki coupling ± macrolactamization procedure.
The latter cyclization became possible only after formation of
the C-O-D ring system which provided the necessary pre-
organization for ring closure. Interestingly, while the unnatu-
ral atropisomer of the D-O-E ring system equilibrated at
1308C to a 1:1 mixture of both, the natural and the unnatural
isomers, the AB and C-O-D macrocycles maintained their
natural integrity. The catalytic asymmetric Suzuki coupling
based synthesis of biaryl systems, developed during this
program, is also worth noting since it allows the stereo-
selective and efficient construction of this important moiety.
Furthermore, this reaction played a crucial role in the
eventual construction of the vancomycin aglycon.
3.5,
3.7,
3.8,
4.0,
4.1,
4.3,
4.6; HRMS (FAB) calcd for
‡
C89H136Cl2N8O17Si6Cs [M ‡ Cs ] 1959.7071, found 1959.6976.
Hexa-TBS-aglycon methyl ester 8: A solution of hexa-TBS-aglycon 7
(400 mg, 0.218 mmol) in ether (5.0 mL) was treated with CH2N2 (solution
in ether, excess) at 08C. The reaction mixture was stirred for 0.5 h, argon
was then bubbled through for 5 min, and then the solvent was removed
under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 20 !60% EtOAc in benzene, gradient elution)
to afford hexa-TBS-aglycon methyl ester 8 (367 mg, 91%) as a yellow
foam. 8: Rf ˆ 0.24 (silica gel, 5% MeOH in CH2Cl2); [a]2D2 ˆ ‡9.0 (c ˆ 0.92,
CHCl3); IR (film) nÄmax ˆ 3403, 2956, 2929, 2858, 1676, 1508, 1473, 1425,
1
1255, 1176, 1110, 1061, 1022, 919, 838, 782 cm
;
1H NMR (600 MHz,
CD3OD, 330 K): d ˆ 7.60 (d, J ˆ 2.0 Hz, 1H), 7.54 (dd, J ˆ 8.5, 2.0 Hz, 1H),
7.52 (dd, J ˆ 8.5, 2.0 Hz, 1H), 7.42 (d, J ˆ 2.0 Hz, 1H), 7.24 (d, J ˆ 8.5 Hz,
1H), 7.10 (br.d, J ˆ 8.5 Hz, 1H), 7.04 (d, J ˆ 2.5 Hz, 1H), 6.99 (dd, J ˆ 8.5,
2.5 Hz, 1H), 6.76 (d, J ˆ 8.5 Hz, 1H), 6.41 (d, J ˆ 2.0 Hz, 1H), 6.32 (d, J ˆ
2.0 Hz, 1H), 5.73 (d, J ˆ 2.0 Hz, 2H), 5.42 (d, J ˆ 4.0 Hz, 1H), 5.36 (s, 1H),
5.34 (s, 1H), 4.92 (s, 1H), 4.83 (d, J ˆ 4.0 Hz, 1H), 4.64 (t, J ˆ 5.5 Hz, 1H),
4.59 (s, 1H), 4.47 (s, 1H), 4.10 (s, 1H), 3.75 (s, 3H), 3.12 (dd, J ˆ 8.5, 5.5 Hz,
1H), 2.54 ± 2.47 (m, 1H), 2.39 (s, 3H), 1.84 ± 1.79 (m, 1H), 1.65 ± 1.58 (m,
1H), 1.53 ± 1.48 (m, 1H), 1.11 (s, 9H), 1.01 (s, 9H), 0.96 (d, J ˆ 6.0 Hz, 3H),
0.95 (d, J ˆ 6.0 Hz, 3H), 0.92 (s, 9H), 0.90 (s, 9H), 0.73 (s, 9H), 0.61 (s, 9H),
0.36 (s, 3H), 0.35 (s, 3H), 0.23 (s, 6H), 0.17 (s, 3H), 0.13 (s, 3H), 0.12 (s,
3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H), 0.08 (s, 3H);
Finally, sequential attachment of the sugar moieties onto a
suitably protected aglycon derivative (phenol 6), followed by
deprotection, allowed a stereoselective total synthesis of
2656
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0947-6539/99/0509-2656 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 4
2648±2667
13C NMR (150 MHz, CD3OD, 330 K): d ˆ 177.9, 174.4, 172.8, 171.9, 171.4,
170.2, 169.4, 157.2, 156.4, 155.2, 153.5, 152.8, 152.4, 152.1, 142.1, 140.0, 137.3,
134.8, 132.1, 130.4, 129.3, 129.0, 128.7, 128.6, 128.0, 127.7, 126.8, 125.7, 125.1,
121.1, 113.6, 112.2, 108.1, 106.3, 75.0, 74.5, 64.9, 64.7, 61.3, 58.3, 56.5, 55.8,
53.3, 52.6, 43.4, 37.8, 35.7, 26.6, 26.5, 26.4, 26.2, 26.1, 23.6, 22.7, 19.8, 19.3,
19.2, 18.8, 3.5, 3.6, 3.8, 3.9, 4.0, 4.2, 4.4, 4.5, 4.6, 4.7;
4.7, 4.7, 5.0, 5.0; HRMS (FAB) calcd for C92H130Cl2N8O19Si5Cs
[M ‡ Cs ] 1993.6730, found 1993.6606.
‡
Nona-TBS-vancomycin 10: TBSOTf (47.6 mL, 207 mmol) was added
dropwise to a solution of vancomycin free base (1) (5.00 g, 3.45 mmol)
and 2,6-lutidine (72.4 mL, 621 mmol) in CH2Cl2/DMF (10:1, 340 mL) at
08C. The reaction mixture was slowly warmed to 258C and was stirred for
18 h. The reaction was quenched by the addition of saturated aqueous
NaHCO3 (200 mL) and stirred at 258C for 60 h. The organic layer was
separated, and the aqueous layer was extracted with EtOAc (2 Â 400 mL).
The combined organic layers were dried (Na2SO4), concentrated, and the
residue was purified by flash column chromatography (silica gel, 1 !8%
MeOH in CH2Cl2, gradient elution) to afford nona-TBS-vancomycin 10
(5.56 g, 65%) as a white foam. 10: Rf ˆ 0.17 (silica gel, 5% MeOH in
‡
HRMS (FAB) calcd for C90H138Cl2N8O17Si6Cs [M ‡ Cs ] 1976.7239, found
1976.7397.
N-Cbz-hexa-TBS-aglycon methyl ester 9: A solution of hexa-TBS-aglycon
methyl ester 8 (350 mg, 0.191 mmol) in dioxane/H2O (10:1, 3.0 mL) was
treated with NaHCO3 (160 mg, 1.91 mmol) and CbzCl (136 mL,
0.948 mmol) at 08C. After stirring for 0.5 h, the reaction mixture was
diluted with EtOAc (200 mL) and washed with saturated aqueous NaHCO3
(30 mL) and brine (30 mL). The organic layer was dried (Na2SO4),
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 10 !50% EtOAc in hexanes, gradient elution) to afford
N-Cbz-hexa-TBS-aglycon methyl ester 9 (347 mg, 92%) as a viscous oil. 9:
Rf ˆ 0.36 (silica gel, 5% MeOH in CH2Cl2); [a]2D2 ˆ ‡7.4 (c ˆ 2.51, CHCl3);
IR (film) nÄmax ˆ 3403, 2954, 2928, 2856, 1677, 1507, 1472, 1419, 1255, 1173,
1109, 1060, 1020, 918, 838, 782 cm 1; 1H NMR (600 MHz, CD3OD, 330 K):
d ˆ 7.57 (s, 1H), 7.53 (dd, J ˆ 8.5, 2.0 Hz, 1H), 7.38 (br.d, J ˆ 8.0 Hz, 1H),
7.37 (s, 1H), 7.32 ± 7.26 (m, 6H), 7.06 (d, J ˆ 2.5 Hz, 1H), 7.01 (dd, J ˆ 8.5,
2.5 Hz, 1H), 7.00 (br.s, 1H), 6.75 (d, J ˆ 8.5 Hz, 1H), 6.37 (d, J ˆ 2.0 Hz,
1H), 6.33 (d, J ˆ 2.0 Hz, 1H), 5.84 ± 5.82 (m, 1H), 5.70 (s, 1H), 5.46 (d, J ˆ
4.5 Hz, 1H), 5.37 (s, 1H), 5.35 (br.s, 1H), 5.19 ± 5.17 (m, 2H), 4.96 ± 4.93 (m,
1H), 4.93 (s, 1H), 4.89 ± 4.85 (m, 1H), 4.79 ± 4.74 (m, 1H), 4.62 (s, 1H), 4.11
(s, 1H), 3.75 (s, 3H), 2.94 (s, 3H), 2.49 ± 2.42 (m, 2H), 1.89 ± 1.83 (m, 1H),
1.53 ± 1.45 (m, 2H), 1.13 (s, 9H), 1.01 (s, 9H), 0.92 (s, 9H), 0.89 ± 0.87 (m,
6H), 0.87 (s, 9H), 0.74 (s, 9H), 0.62 (s, 9H), 0.39 (s, 3H), 0.38 (s, 3H), 0.23
(s, 6H), 0.18 (s, 3H), 0.12 (s, 3H), 0.10 (s, 6H), 0.08 (s, 6H), 0.02 (s, 3H),
0.09 (s, 3H); 13C NMR (150 MHz, CD3OD, 330 K): d ˆ 174.0, 173.5, 172.7,
171.8, 169.4, 157.1, 156.3, 155.2, 153.6, 152.8, 152.3, 151.8, 142.8, 142.1, 139.7,
137.8, 137.2, 137.0, 134.8, 131.7, 130.6, 130.4, 129.7, 129.3, 129.0, 128.5, 128.2,
128.0, 127.7, 126.7, 125.8, 125.0, 121.0, 113.6, 112.2, 106.1, 74.9, 73.9, 69.1,
65.3, 64.8, 60.9, 58.3, 58.2, 56.4, 55.7, 53.0, 52.6, 30.7, 26.5, 26.4, 26.4, 26.3,
26.0, 26.0, 25.8, 23.8, 22.1, 19.8, 19.3, 19.1, 18.8, 3.6, 3.7, 3.9, 4.0,
CH2Cl2); [a]2D2
ˆ
27.2 (c ˆ 0.90, CHCl3); IR (thin film): nÄmax ˆ 3406, 2956,
1
2930, 2858, 1677, 1490, 1473, 1256, 1109, 1060, 837, 780 cm
;
1H NMR
(600 MHz, CD3OD, 295 K): d ˆ 7.80 (s, 1H), 7.53 (br.d, J ˆ 8.5 Hz, 1H),
7.50 (dd, J ˆ 8.5, 2.0 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J ˆ 8.5 Hz, 2H), 7.08 (d,
J ˆ 2.5 Hz, 1H), 6.95 (dd, J ˆ 8.5, 2.5 Hz, 1H), 6.75 (s, 1H), 6.73 ± 6.71 (m,
1H), 6.35 (d, J ˆ 2.5 Hz, 1H), 6.00 (d, J ˆ 5.5 Hz, 1H), 5.80 (s, 1H), 5.72 ±
5.70 (m, 1H), 5.41 (d, J ˆ 4.5 Hz, 1H), 5.39 (s, 1H), 5.38 (s, 1H), 5.20 (d, J ˆ
4.5 Hz, 1H), 4.70 ± 4.64 (m, 1H), 4.62 (s, 1H), 4.53 ± 4.51 (m, 1H), 4.27 (br.s,
1H), 4.17 (d, J ˆ 5.5 Hz, 1H), 4.10 (s, 1H), 4.03 ± 3.99 (m, 2H), 3.90 ± 3.86
(m, 2H), 3.40 (s, 1H), 3.17 ± 3.15 (m, 1H), 2.49 ± 2.45 (m, 1H), 2.38 (s, 3H),
2.06 ± 2.02 (m, 1H), 1.86 ± 1.82 (m, 1H), 1.73 ± 1.71 (m, 1H), 1.62 ± 1.50 (m,
2H), 1.50 (s, 3H), 1.28 (d, J ˆ 6.5 Hz, 3H), 1.01 (s, 9H), 0.98 (s, 9H), 0.97 ±
0.96 (m, 6H), 0.95 (s, 9H), 0.90 (s, 9H), 0.90 (s, 9H), 0.89 (s, 9H), 0.87 (s,
9H), 0.73 (s, 9H), 0.59 (s, 9H), 0.24 (s, 6H), 0.20 (s, 3H), 0.16 (s, 3H), 0.15
(s, 3H), 0.14 (s, 3H), 0.13 (s, 6H), 0.12 (s, 3H), 0.11 (s, 6H), 0.09 (s, 3H),
0.08 (s, 3H), 0.05 (s, 6H), 0.01 (s, 3H), 0.00 (s, 3H), 0.12 (s, 3H); 13C NMR
(150 MHz, CD3OD, 330 K): d ˆ 177.1, 174.2, 172.2, 172.0, 171.3, 170.2,
168.4, 156.8, 155.8, 155.2, 153.7, 153.6, 151.3, 143.2, 140.2, 139.6, 137.8, 135.6,
135.3, 130.6, 130.2, 129.1, 129.0, 128.8, 127.7, 127.4, 126.8, 125.9, 125.2, 121.0,
115.2, 111.6, 106.8, 102.3, 95.9, 83.1, 79.5, 76.2, 76.0, 74.7, 74.5, 71.2, 65.6,
65.5, 64.7, 64.4, 60.8, 56.6, 56.1, 55.2, 53.6, 42.7, 38.9, 36.3, 35.0, 30.8, 26.9,
26.7, 26.6, 26.5, 26.4, 26.2, 26.1, 25.9, 24.6, 23.5, 22.9, 19.6, 19.3, 19.3, 19.1,
19.0, 18.8, 18.6, 3.1, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.7, 4.8, 4.8;
4.1,
4.2,
4.6,
4.6,
4.8,
4.9; HRMS (FAB) calcd for
‡
HRMS (FAB) calcd for C120H201Cl2N9O24Si9Cs [M ‡ Cs ] 2607.1139, found
‡
C98H144Cl2N8O19Si6Cs [M ‡ Cs ] 2107.7595, found 2107.7462.
2607.1324.
Aglycon acceptor 6: A mixture of potassium fluoride (18.5 g) and basic
alumina (63.0 g) in water (100 mL) was stirred for 0.5 h at 258C. The
resulting solution was concentrated in vacuo and dried at 858C under
vacuum. A solution of N-Cbz-hexa-TBS-aglycon methyl ester 9 (600 mg,
0.303 mmol) in MeCN (2.0 mL) was treated with the above activated KF ´
Al2O3 (600 mg, 1.0 wt.equiv) at 08C, and the reaction mixture was stirred
for 2 h. After diluting with EtOAc (150 mL), the reaction mixture was
filtered and the solvents were removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel, 10 !50%
EtOAc in hexanes, gradient elution) to afford aglycon acceptor 6 (338 mg,
60%) as a white foam. 6: Rf ˆ 0.31 (silica gel, 5% MeOH in CH2Cl2);
Nona-TBS-vancomycin methyl ester 11: A solution of nona-TBS-vanco-
mycin 10 (2.00 g, 0.800 mmol) in ether (20 mL) was treated with CH2N2
(solution in ether, excess) at 08C. After stirring the mixture for 0.5 h, argon
was bubbled through for 5 min, and the solvents were removed under
reduced pressure. The residue was purified by flash column chromatog-
raphy (silica gel, 20 !80% EtOAc in hexanes, gradient elution) to afford
nona-TBS-vancomycin methyl ester 11 (1.79 g, 90%) as a yellow foam. 11:
Rf ˆ 0.24 (silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
14.9 (c ˆ 1.33,
CHCl3); IR (film) nÄmax ˆ 3406, 2929, 2856, 1685, 1490, 1473, 1256, 1112,
1061, 838, 780 cm 1; H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.64 (d, J ˆ
1
[a]2D2
ˆ
14.0 (c ˆ 1.21, CHCl3); IR (thin film): nÄmax ˆ 3403, 2995, 2857, 1751,
2.0 Hz, 1H), 7.53-7.49 (m, 2H), 7.43 (d, J ˆ 2.0 Hz, 1H), 7.23 (d, J ˆ 8.5 Hz,
1H), 7.20 (d, J ˆ 8.5 Hz, 1H), 7.03 (d, J ˆ 2.5 Hz, 1H), 7.00 (dd, J ˆ 8.5,
2.5 Hz, 1H), 6.77 (d, J ˆ 8.5 Hz, 1H), 6.41 (d, J ˆ 2.0 Hz, 1H), 6.32 (d, J ˆ
2.0 Hz, 1H), 6.04 (d, J ˆ 5.0 Hz, 1H), 5.81 (s, 1H), 5.63 (s, 1H), 5.41 (d, J ˆ
4.5 Hz, 1H), 5.36 (s, 1H), 5.35 (d, J ˆ 2.0 Hz, 1H), 5.14 (d, J ˆ 4.0 Hz, 1H),
4.91 (s, 1H), 4.83 (d, J ˆ 4.5 Hz, 1H), 4.61 (d, J ˆ 5.5 Hz, 1H), 4.60 (s, 1H),
4.50 (s, 1H), 4.46 ± 4.43 (m, 1H), 4.25 (br.s, 1H), 4.17 (d, J ˆ 5.0 Hz, 1H),
4.10 (s, 1H), 4.06 ± 4.02 (m, 2H), 3.91 ± 3.89 (m, 2H), 3.75 (s, 3H), 3.19 (s,
1H), 3.10 (dd, J ˆ 8.5, 5.5 Hz, 1H), 2.49 ± 2.47 (m, 1H), 2.37 (s, 3H), 1.85-
1.80 (m, 2H), 1.59 ± 1.47 (m, 3H), 1.31 (s, 3H), 1.05 (d, J ˆ 6.5 Hz, 3H), 1.01
(s, 9H), 0.96 (s, 9H), 0.97 ± 0.96 (m, 6H), 0.94 (s, 9H), 0.91 (s, 9H), 0.89 (s,
9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.73 (s, 9H), 0.60 (s, 9H), 0.23 (s, 6H), 0.19
(s, 3H), 0.17 (s, 3H), 0.15 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H),
0.10 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s,
3H), 0.03 (s, 3H), 0.00 (s, 3H), 0.01 (s, 3H), 0.08 (s, 3H); 13C NMR
(150 MHz, CD3OD, 320 K): d ˆ 177.8, 174.1, 172.6, 172.1, 171.7, 171.0, 170.0,
169.3, 157.0, 156.3, 155.0, 153.9, 153.6, 153.3, 151.5, 142.3, 139.9, 137.2, 135.7,
135.0, 130.4, 130.2, 129.1, 129.0, 128.8, 128.5, 127.8, 127.7, 127.6, 126.6, 125.8,
125.1, 121.0, 113.4, 112.1, 110.2, 106.9, 102.2, 96.8, 82.8, 79.4, 78.7, 76.3, 74.7,
74.3, 71.4, 66.3, 65.7, 64.7, 64.6, 61.0, 58.1, 56.5, 55.7, 53.0, 52.6, 52.0, 43.3,
39.1, 37.9, 35.5, 30.6, 26.7, 26.5, 26.5, 26.5, 26.4, 26.3, 26.3, 26.2, 25.9, 25.9,
23.4, 22.7, 19.5, 19.2, 19.1, 19.0, 18.9, 18.7, 18.7, 3.3, 3.4, 3.8, 3.9, 4.0,
1
1676, 1670, 1658, 1508, 1472, 781 cm
;
1H NMR (600 MHz, CD3OD,
330 K): d ˆ 7.49 (br.s, 2H, H-6b and H-6f), 7.38 (br.d, J ˆ 8.0 Hz, 1H,
H-2f), 7.37 (s, 1H, H-2b), 7.35 ± 7.30 (m, 6H, Cbz(ArH) and H-2e), 7.08 (d,
J ˆ 2.0 Hz, 1H, H-5b), 7.01 (dd, J ˆ 8.5, 2.0 Hz, 1H, H-5f), 6.77 (d, J ˆ
8.5 Hz, 1H, H-6e), 6.65 (br.s, 1H, H-5e), 6.41 (d, J ˆ 2.0 Hz, 1H, H-7d),
6.35 (d, J ˆ 2.0 Hz, 1H, H-7f), 6.05-6.02 (m, 1H, H-1a), 5.72 (s, 1H, H-4f),
5.49 (d, J ˆ 4.5 Hz, 1H, H-2b), 5.37 (s, 2H, H-6b and H-4b), 5.20 ± 5.17 (m,
2H, CH2 of Cbz), 4.97 (br.s, 1H, H-2a), 4.94 (s, 1H, H-4a), 4.90 ± 4.86 (m,
1H, H-3a), 4.85 ± 4.80 (m, 1H, H-7a), 4.64 (s, 1H, H-5a), 4.11 (s, 1H,
H-6a), 3.75 (s, 3H, OCH3), 2.94 (s, 3H, NCH3), 2.45 ± 2.39 (m, 2H, H-3b),
1.84 ± 1.81 (m, 1H, H-1b), 1.53 ± 1.45 (m, 2H, H-1b and H-1g), 1.01 (s, 9H,
tBuSi), 0.94 (s, 9H, tBuSi), 0.93 ± 0.90 (m, 6H, H-1g), 0.86 (s, 9H, tBuSi),
0.75 (s, 9H, tBuSi), 0.64 (s, 9H, tBuSi), 0.23 (s, 6H, CH3Si), 0.18 (s, 3H,
CH3Si), 0.12 (s, 3H, CH3Si), 0.10 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si), 0.09 (s,
3H, CH3Si), 0.08 (s, 3H, CH3Si), 0.02 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si);
13C NMR (150 MHz, CD3CN, 330 K): d ˆ 172.2, 171.8, 171.4, 171.1, 170.6,
169.1, 167.9, 156.4, 155.8, 154.3, 151.7, 151.6, 149.4, 147.7, 141.5, 139.7, 138.0,
136.7, 136.5, 135.4, 130.6, 129.9, 129.3, 129.2, 129.0, 128.8, 128.0, 127.2, 126.9,
126.4, 125.3, 124.7, 121.3, 113.1, 112.1, 106.1, 105.5, 74.4, 73.6, 68.1, 64.3, 60.4,
57.7, 57.6, 55.3, 55.2, 52.7, 52.5, 38.9, 37.3, 30.3, 26.2, 26.1, 26.0, 25.6, 25.5, 25.3,
23.5, 22.1, 18.9, 18.8, 18.7, 18.3, 18.3, 3.9, 4.0, 4.2, 4.3, 4.5, 4.6,
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2657 $ 17.50+.50/0
2657

K. C. Nicolaou et al.
FULL PAPER
4.1, 4.2, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9; HRMS (FAB) calcd for
C121H203Cl2N9O24Si9Cs [M ‡ Cs ] 2624.1321, found 2624.1503.
separated, and the aqueous phase was extracted with ether (3 Â 50 mL).
The combined organic phase was dried (MgSO4), filtered, and concentrated
under reduced pressure. The crude aldehyde was azeotroped with benzene
(2 Â 10 mL) and then used directly in the next reaction. Ethyl vinyl ether
(10.6 mL, 0.111 mol, distilled from calcium hydride) was dissolved in THF
(100 mL), cooled to 788C, and then tert-butyllithium (31.0 mL, 1.7m in
pentane, 0.052 mol) was added by cannula. The dark orange solution was
allowed to warm to 08C over 1 h, during which time the solution became
pale yellow. The anion solution was cooled to 1008C and to it was added
the crude aldehyde [dissolved in THF (50 mL) and cooled to 788C] by
fast addition by cannula. After stirring for 5 min, the reaction mixture was
poured into saturated aqueous NH4Cl (100 mL), and diluted with ether
(200 mL). Aqueous HCl (5%, 50 mL) was added and the mixture was
stirred for 0.5 h. The reaction mixture was further diluted with ether
(300 mL) and washed with H2O (50 mL). The combined organic fractions
were dried (MgSO4), concentrated, and the residue was purified by flash
column chromatography (silica gel, 1 !10% ether in hexanes, gradient
elution) to afford the anti-alcohol and the syn-alcohol in a ratio of about
10:1 as colorless oils. anti-Alcohol: (4.36 g, 59%): Rf ˆ 0.40 (silica gel, 25%
‡
N,N'-diCbz-nona-TBS-vancomycin methyl ester 12: A solution of nona-
TBS-vancomycin methyl ester 11 (2.91 g, 1.16 mmol) in dioxane/H2O (10:1,
60 mL) was treated sequentially with NaHCO3 (487 mg, 5.80 mmol) and
CbzCl (1.1 mL, 5.8 mmol) at 08C. After stirring the reaction mixture for
0.5 h, the reaction was quenched by the addition of saturated aqueous
NaHCO3 (10 mL), extracted with EtOAc (2 Â 50 mL), and washed with
brine (25 mL). The combined organic layers were dried (Na2SO4),
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 5 !40% EtOAc in hexanes, gradient elution) to provide
N,N'-diCbz-nona-TBS-vancomycin methyl ester 12 (2.55 g, 80%) as a white
foam. 12: Rf ˆ 0.36 (silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
13.9 (c ˆ
0.77, CHCl3); IR (film) nÄmax ˆ 3404, 2954, 2923, 2886, 2857, 1684, 1490, 1472,
1
1256, 1108, 1060, 837, 780 cm 1; H NMR (600 MHz, CD3OD, 330 K): d ˆ
7.63 (s, 1H), 7.53 (br.d, J ˆ 8.5 Hz, 1H), 7.36 ± 7.28 (m, 12H), 7.25 (d, J ˆ
8.5 Hz, 1H), 7.22 (d, J ˆ 8.5 Hz, 1H), 7.04 (s, 1H), 7.00 (br.d, J ˆ 8.5 Hz,
1H), 6.77 (d, J ˆ 8.5 Hz, 1H), 6.41 (d, J ˆ 2.0 Hz, 1H), 6.32 (d, J ˆ 2.0 Hz,
1H), 6.03 (d, J ˆ 4.5 Hz, 1H), 5.80 (s, 1H), 5.64 (s, 1H), 5.44 (s, 1H), 5.37 (s,
1H), 5.36 (s, 1H), 5.13 (br.s, 1H), 5.05 ± 5.00 (m, 4H), 4.95 ± 4.92 (m, 1H),
4.91 (s, 1H), 4.87 ± 4.85 (m, 1H), 4.71 ± 4.69 (m, 1H), 4.62 (s, 1H), 4.37 ± 4.34
(m, 1H), 4.28 ± 4.20 (m, 1H), 4.22 ± 4.20 (m, 1H), 4.11 (s, 1H), 4.08 (d, J ˆ
11.0 Hz, 1H), 4.04 (d, J ˆ 3.5 Hz, 1H), 3.94 ± 3.90 (m, 2H), 3.75 (s, 3H), 3.62
(s, 1H), 2.92 (s, 3H), 2.46 ± 2.38 (m, 2H), 2.09 ± 2.06 (m, 1H), 1.83 ± 1.80 (m,
2H), 1.60 (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), 0.89 (s, 9H), 0.88 (s, 9H), 0.85
(s, 9H), 0.84 (s, 9H), 0.74 (s, 9H), 0.62 (s, 9H), 0.23 (s, 6H), 0.17 (s, 3H),
0.14 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.07 (s, 6H), 0.06 (s,
3H), 0.05 (s, 6H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H), 0.01 (s, 3H),
0.03 (s, 3H), 0.09 (s, 3H); 13C NMR (150 MHz, CD3COCD3, 300 K):
d ˆ 172.0, 171.5, 171.3, 170.6, 169.1, 168.3, 156.6, 156.0, 155.2, 154.3, 153.2,
152.9, 151.0, 143.4, 142.1, 139.8, 138.3, 137.8, 137.3, 136.4, 135.0, 134.6, 130.2,
129.4, 129.3, 129.2, 129.1, 128.9, 128.7, 128.5, 128.5, 128.3, 127.9, 127.7, 127.5,
127.4, 127.3, 127.0, 126.3, 125.7, 124.9, 120.5, 113.4, 111.9, 109.2, 106.2, 102.1,
96.0, 82.0, 78.5, 75.4, 75.1, 74.4, 73.8, 70.7, 68.1, 67.0, 66.0, 65.9, 65.5, 65.3,
64.7, 63.8, 59.9, 57.8, 57.6, 56.1, 55.3, 54.9, 52.7, 52.2, 39.0, 37.4, 36.6, 35.4, 26.7,
26.6, 26.4, 26.3, 26.2, 26.1, 25.7, 25.7, 25.4, 24.4, 23.6, 22.6, 19.3, 19.2, 19.0,
18.9, 18.9, 18.7, 18.7, 18.6, 18.3, 3.4, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3,
4.5, 4.6, 4.8, 5.0; HRMS (FAB) calcd for C137H215Cl2N9O28Si9Cs
ether in hexanes); [a]D22 ˆ ‡39.7 (c ˆ 1.0, CHCl3); IR (thin film): nÄmax
ˆ
1
3474, 2943, 2867, 1715, 1463, 1381, 1356, 1140, 1103, 883 cm
;
1H NMR
(500 MHz, CDCl3): d ˆ 4.23 (dq, J ˆ 6.5, 3.5 Hz, 1H, H-4), 4.11 (br.s, 1H,
H-3), 3.22 (br.d, 1H, OH), 2.23 (s, 3H, H-1), 1.18 (d, J ˆ 6 Hz, 3H, H-5),
1.06 ± 1.03 (m, 21H, iPr3Si); 13C NMR (125 MHz, CDCl3): d ˆ 209.2. 81.6,
‡
70.6, 27.8, 18.9, 18.1, 12.5; HRMS (FAB) calcd for C14H31O3Si [M ‡ H ]
275.2042, found 275.2047; syn-Alcohol: (460 mg, 6%): Rf ˆ 0.52 (silica gel,
25% ether in hexanes); [a]D22
ˆ
76.5 (c ˆ 0.70, CHCl3); IR (thin film):
1
nÄmax ˆ 3472, 2943, 2867, 1713, 1463, 1382, 1360, 1239, 1107, 1009, 883 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 4.25 (dq, J ˆ 6.5, 3.5 Hz, 1H, H-4), 4.10
(br.s, 1H, H-3), 3.60 (br.s, 1H, OH), 2.30 (s, 3H, H-1), 1.10 (d, J ˆ 6.0 Hz,
3H, H-5), 1.08 ± 1.04 (m, 21H, iPr3Si); 13C NMR (125 MHz, CDCl3): d ˆ
209.8, 80.8, 69.9, 27.6, 18.7, 18.2, 18.1, 12.5; HRMS (FAB) calcd for
‡
C14H31O3Si [M ‡ H ] 275.2042, found 275.2047. The anti-alcohol (6.60 g,
0.024 mol) was dissolved in pyridine (100 mL), cooled to 08C, and O-benzyl
hydroxylamine ´ HCl (4.22 g, 0.026 mol) was added. The reaction mixture
was stirred at 08C for 1 h and then at 258C for 1 h. The reaction mixture was
diluted with hexanes (800 mL), and washed with H2O (100 mL) and brine
(100 mL). The combined organic layers were dried (MgSO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
2 !10% ether in hexanes, gradient elution) to afford a 4:1 mixture of E and
‡
[M ‡ Cs ] 2889.2032, found 2889.2237.
Z
oximes (9.1 g, 97%) as colorless oils. Separation (flash column
Aglycon acceptor 6 [from vancomycin (1)]: A solution of N,N'-diCbz-nona-
TBS-vancomycin methyl ester 12 (1.12 g, 0.406 mmol) in trifluoroacetic
acid/dimethyl sulfide/CH2Cl2 (1:1:1, 12 mL) was stirred at 258C for 3 h. The
reaction mixture was then diluted with EtOAc (50 mL), and concentrated
in vacuo (Â4). The residue was purified by flash column chromatography
(silica gel, 5 !30% EtOAc in hexanes, gradient elution) to afford aglycon
acceptor 6 (454 mg, 60%) as a white foam (spectroscopically identical to 6
derived from the aglycon 2).
chromatography, silica gel, 2 !10% ether in hexanes, gradient elution)
of an analytical sample of the oximes yielded the pure oximes. E-oxime
16a: Rf ˆ 0.50 (silica gel, 25% ether in hexanes); [a]2D2 ˆ ‡5.2 (c ˆ 0.56,
CHCl3); IR (thin film): nÄmax ˆ 3416, 2913, 2866, 1463, 1367, 1145, 1053, 1014,
883, 764, 698, 679 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.34 ± 7.30 (m, 5H,
ArH), 5.11 (s, 2H, CH2Ar), 4.15 ± 4.08 (m, 2H, H-3, H-4), 2.86 (br.d, J ˆ
5.0 Hz, 1H, OH), 1.93 (s, 3H, H-1), 1.13 (d, J ˆ 6.0 Hz, 3H, H-5), 1.11 ± 1.04
(m, 21H, iPr3Si); 13C NMR (125 MHz, CDCl3): d ˆ 157.1, 138.0, 128.3,
128.0, 127.7, 76.6, 75.6, 70.9, 18.4, 18.1, 12.4, 12.1; HRMS (FAB) calcd for
Silylated ethyl lactate 15: Triisopropylsilyl chloride (19.1 mL, 0.089 mol)
‡
was added dropwise to
a solution of (S)-ethyl lactate (14) (9.60 g,
C21H38NO3Si [M ‡ H ] 380.2621, found 380.2633; Z-oxime 16b: Rf ˆ 0.63
(silica gel, 25% ether in hexanes); [a]D22
ˆ
31.3 (c ˆ 0.50, CHCl3); IR (thin
0.081 mol) and imidazole (11.1 g, 0.162 mol) in DMF (160 mL) at 08C.
The reaction mixture was allowed to warm to 258C and stirred for 10 h. The
reaction mixture was diluted with hexanes (1 L) and washed with H2O (3 Â
75 mL). The organic layer was dried (MgSO4), concentrated, and the
residue was purified by flash column chromatography (silica gel, 0 !4%
ether in hexanes, gradient elution) to provide ester 15 (22.2 g, 99%) as a
film): nÄmax ˆ 2942, 2866, 1464, 1381, 1208, 1139, 1096, 1029, 969, 883, 754,
1
678 cm 1; H NMR (500 MHz, CDCl3): d ˆ 7.34 ± 7.26 (m, 5H, ArH), 5.03
and 4.98 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.90 (br.s, 1H, H-3), 4.40 (dq, J ˆ
6.0, 3.5 Hz, 1H, H-4), 1.26 (br.s, 1H, OH), 1.94 (s, 3H, H-1), 1.08 (d, J ˆ
6.5 Hz, 3H, H-5), 0.99 ± 0.98 (m, 21H, iPr3Si); 13C NMR (125 MHz, CDCl3):
d ˆ 159.2, 137.3, 128.4, 128.3, 127.9, 76.0, 72.1, 67.6, 17.9, 17.2, 16.7, 12.1;
colorless oil. 15: Rf ˆ 0.68 (silica gel, 40% ether in hexanes); [a]D22
ˆ
19.5
‡
(c ˆ 2.6, CHCl3); IR (thin film): nÄmax ˆ 2943, 2867, 1755, 1464, 1371, 1273,
1147, 1062, 1017, 971, 883, 682 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 4.38
(q, J ˆ 6.7 Hz, 1H, H-2), 4.14 (q, J ˆ 7.1 Hz, 2H, OCH2), 1.39 (d, J ˆ 6.7 Hz,
3H, H-3), 1.24 (t, J ˆ 7.1 Hz, 3H, CH3), 1.04-1.01 (m, J ˆ 6.5 Hz, 21H,
iPr3Si); 13C NMR (125 MHz, CDCl3): d ˆ 174.1, 68.4, 68.4, 60.5, 21.7, 17.7,
HRMS (FAB) calcd for C21H38O3NSi [M ‡ H ] 380.2621, found 380.2633.
Olefinic alcohol 17: Oxime 16a (235 mg, 0.62 mmol) was dissolved in ether
(5.0 mL) and cooled to 358C. Allylmagnesium bromide (1.56 mL, 1m
solution in ether, 1.56 mmol) was added dropwise and the reaction mixture
was stirred for 1 h. The reaction was quenched by the addition of saturated
aqueous NH4Cl (5 mL), diluted with ether (30 mL), and washed with H2O
(5 mL). The combined organic layers were dried (MgSO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
15% ether in hexanes) to yield alcohol 17 (130 mg, 50%) as a single
diastereoisomer and recovered oxime 16a (110 mg, 47%). Alcohol 17: Rf ˆ
‡
14.1, 12.0; HRMS (FAB) calcd for C14H31O3Si [M ‡ H ] 275.2042, found
275.2048.
Oxime alcohol 16: Ethyl ester 15 (8.00 g, 0.029 mol) was dissolved in ether
(150 mL) and cooled to 788C. Diisobutylaluminum hydride (48.0 mL, 1m
solution in CH2Cl2, 0.041 mol) was added dropwise by cannula, and the
reaction mixture was stirred at 788C for 45 min. Methanol (10 mL) was
added at 788C, followed by the addition of ether (250 mL) and saturated
aqueous sodium potassium tartrate solution (60 mL). The reaction mixture
was then allowed to warm to 258C and stirred for 1 h. The organic layer was
0.61 (silica gel, 25% ether in hexanes); [a]D22
ˆ
20.0 (c ˆ 0.56, CHCl3); IR
(thin film): nÄmax ˆ 3576, 3071, 2942, 2866, 1463, 1384, 1368, 1248, 1140, 1091,
1
1049, 1013, 913, 883, 749, 697, 679 cm 1; H NMR (500 MHz, CDCl3): d ˆ
2658
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2658 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 4
2648±2667
‡
7.34 ± 7.26 (m, 5H, ArH), 5.91 ± 5.88 (m, 1H, H-1), 5.73 (br.s, 1H, NH), 5.13
(d, J ˆ 17.0 Hz, 1H, H-1Z), 5.12 (d, J ˆ 10.0 Hz, 1H, H-1E), 4.70 (s, 2H,
CH2Ar), 4.09 (dq, J ˆ 6.3, 3.8 Hz, 1H, H-5), 3.75 (dd, J ˆ 3.5, 2.5 Hz, 1H,
H-4), 2.76 (br.s, 1H, OH), 2.53 (dd, J ˆ 13.5, 7.0 Hz, 1H, H-2a), 2.32 (dd,
J ˆ 13.5, 8.0 Hz, 1H, H-2b), 1.28 (br.s, 1H, OH), 1.28 (d, J ˆ 6.0 Hz, 3H,
H-6), 1.07 ± 1.05 (m, 21H, iPr3Si), 0.99 (s, 3H, H-3(CH3)); 13C NMR
(125 MHz, CDCl3): d ˆ 138.0, 134.3, 128.3, 128.2, 127.7, 118.3, 77.0, 76.7,
69.8, 62.0, 39.1, 19.5, 18.2, 18.2, 17.4, 12.7; HRMS (FAB) calcd for
C31H50NO3Si [M ‡ H ] 512.3560, found 512.3595. Lithium aluminum
hydride (148 mg, 3.90 mmol) was added to a solution of the above benzyl
ether (1.25 g, 2.44 mmol) in dry ether (35 mL) at 258C. The reaction
mixture was heated to reflux for 24 h, cooled to 08C, and quenched by the
addition of saturated aqueous NH4Cl (10 mL). The reaction mixture was
diluted with CH2Cl2 (200 mL) and washed with H2O (20 mL). The aqueous
layer was further extracted with CH2Cl2 (2 Â 40 mL) and EtOAc (2 Â
40 mL). The combined organic layers were dried (MgSO4), filtered, and
the solvents were removed under reduced pressure. The crude mixture was
taken to the next step. Flash column chromatography (silica gel, 20%
MeOH in CH2Cl2) gave an analytically pure sample of amino alcohol 19 as
‡
C24H44NO3Si [M ‡ H ] 422.3090, found 422.3097.
Inverted olefinic alcohol 18: Dimethyl sulfoxide (328 mL, 4.62 mmol) was
added dropwise to a solution of oxalyl chloride (322 mL, 3.69 mmol) in
CH2Cl2 (10 mL) at 788C and the resulting mixture was stirred for 10 min.
Alcohol 17 (779 mg, 1.85 mmol) was dissolved in CH2Cl2 (10 mL) and
added to the reaction mixture by cannula over 5 min. The reaction mixture
was stirred at 788C for 2 h, and then triethylamine (1.03 mL, 7.39 mmol)
was added and the reaction mixture was allowed to warm to 08C over 2 h.
The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with
H2O (15 mL). The organic layer was dried (MgSO4), concentrated, and the
residue was purified by flash column chromatography (silica gel, 3% ether
in hexanes) to yield the corresponding ketone (705 mg, 91%) as a white
a colorless oil. 19: Rf ˆ 0.45 (silica gel, 20% MeOH in CH2Cl2); [a]D22
ˆ
23.6 (c ˆ 2.4, CHCl3); IR (thin film): nÄmax ˆ 3282, 3068, 3030, 2976, 2926,
1652, 1580, 1496, 1455, 1398, 1346, 1249, 1209, 1184, 1064, 996, 918, 856, 799,
738 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.39 ± 7.25 (m, 5H, ArH), 5.83 ±
5.75 (m, 2H, H-1), 5.15 (br.d, J ˆ 15.5 Hz, 1H, H-1Z), 5.14 (d, J ˆ 11.0 Hz,
1H, H-1E), 4.72 and 4.58 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.22 (dq, J ˆ
6.5 Hz, 1H, H-5), 3.52 (br.s, 3H, NH2, OH), 2.96 (br.d, J ˆ 1.5 Hz, 1H,
H-4), 2.32 (dd, J ˆ 13.0, 7.5 Hz, 1H, H-2a), 2.25 (dd, J ˆ 13.5, 8.0 Hz, 1H,
H-2b), 1.27 (d, J ˆ 6.5 Hz, 3H, H-6), 1.20 (s, 3H, CH3(H-3)); 13C NMR
(125 MHz, CDCl3): d ˆ 138.0, 132.7, 128.2, 127.6, 119.3, 85.3, 76.6, 74.7, 67.3,
foam. Ketone: Rf ˆ 0.26 (silica gel, 10% ether in hexanes); [a]D22
ˆ
7.5
‡
56.8, 43.0, 27.2, 20.4; HRMS (FAB) calcd for C15H23NO2Na [M ‡ Na ]
(c ˆ 2.7, CHCl3); IR (thin film): nÄmax ˆ 3020, 2944, 2866, 1710, 1640, 1454,
272.1626, found 272.1619.
1
1368, 1258, 1159, 1097, 1062, 996, 918, 884, 779, 750, 697 cm
;
1H NMR
Cbz-protected hydroxylamine 20: To a solution of the above crude amino
alcohol 19 and NaHCO3 (2.58 g, 24.4 mmol) in THF/H2O (5:1) (25 mL) at
08C was added CbzCl (1.03 mL, 7.20 mmol). After stirring for 0.5 h at 258C,
the reaction mixture was diluted with CH2Cl2 (200 mL) and washed with
H2O (20 mL). The organic layer was dried (MgSO4), concentrated, and the
residue was purified by flash column chromatography (silica gel, 50% ether
in hexanes) to afford amine 20 (705 mg, 78% over two steps) as a colorless
(500 MHz, CDCl3): d ˆ 7.34 ± 7.28 (m, 5H, ArH), 6.73 (br.s, 1H, NH),
5.81 ± 5.73 (m, 1H, H-1), 5.11 (br.d, J ˆ 16.0 Hz, 1H, H-1Z), 5.10 (d, J ˆ
11.5 Hz, 1H, H-1E), 4.75 (q, J ˆ 7.0 Hz, 1H, H-5), 4.69 (s, 2H, CH2Ar), 2.54
(dd, J ˆ 14.0, 7.0 Hz, 1H, H-2a), 2.50 (dd, J ˆ 14.0, 7.3 Hz, 1H, H-2b), 1.43
(d, J ˆ 7.0 Hz, 3H, H-6), 1.29 (s, 3H, CH3(H-3)), 1.09 ± 1.05 (m, 21H,
iPr3Si); 13C NMR (125 MHz, CDCl3): d ˆ 213.2, 137.5, 133.1, 128.3, 128.2,
128.1, 127.7, 127.6, 118.5, 76.9, 74.9, 69.4, 38.7, 21.6, 21.6, 19.4, 18.2, 18.1, 12.7;
oil. 20: Rf ˆ 0.30 (silica gel, 60% ether in hexanes); [a]D22
ˆ
39.3 (c ˆ 1.8,
‡
HRMS (FAB) calcd for C24H41NO3SiCs [M ‡ Cs ] 552.1910, found
CHCl3); IR (thin film): nÄmax ˆ 3346, 3065, 3032, 2976, 2936, 1732, 1640, 1538,
552.1894. To a solution of the above ketone (705 mg, 1.68 mmol) in ether/
MeOH (5:1) (21 mL) at 258C was added sodium borohydride (109 mg,
5.04 mmol) and the reaction mixture was stirred for 0.5 h. Saturated
aqueous NH4Cl (5 mL) was added and the reaction mixture was stirred for
10 min. The reaction mixture was diluted with ether (150 mL) and washed
with brine (10 mL). The organic layer was dried (MgSO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
2% ether in hexanes) to afford alcohol 18 (636 mg, 90%, 92% de) as a
1
1456, 1373, 1242, 1072, 1002, 914, 737, 698 cm
;
1H NMR (500 MHz,
CDCl3): d ˆ 7.38 ± 7.31 (m, 10H, ArH), 5.85 ± 5.77 (m, 2H, H-1), 5.19 (br.s,
1H, NH), 5.12 (br.d, J ˆ 10.5 Hz, 1H, H-1E), 5.09 (d, J ˆ 19.0 Hz, 1H,
H-1Z), 5.12 and 5.02 (AB, J ˆ 12.5 Hz, 2H, CH2Ar), 4.74 and 4.66 (AB, J ˆ
11.0 Hz, 2H, CH2Ar), 4.69 (br.d, J ˆ 4.0 Hz, 1H, H-4), 4.00 (dq, J ˆ 8.5,
7.0 Hz, 1H, H-5), 3.88 (br.s, 3H, OH), 2.91 (dd, J ˆ 13.5, 7.0 Hz, 1H, H-2b),
2.42 (dd, J ˆ 13.5, 7.0 Hz, 1H, H-2a), 1.37 (d, J ˆ 6.5 Hz, 3H, H-6), 1.24 (s,
3H, CH3(H-3)); 13C NMR (125 MHz, CDCl3): d ˆ 154.8, 137.9, 136.6, 133.5,
128.5, 128.4, 128.0, 127.9, 127.6, 127.5, 126.9, 118.9, 84.2, 76.7, 66.2, 65.7, 65.2,
colorless oil. 18: Rf ˆ 0.28 (silica gel, 7% ether in hexanes); [a]D22
ˆ
8.1
(c ˆ 1.6, CHCl3); IR (thin film): nÄmax ˆ 3522, 3071, 3031, 2943, 2866, 1638,
‡
1
58.6, 40.4, 23.5, 20.9; HRMS (FAB) calcd for C23H30NO4 [M ‡ H ]
1464, 1454, 1372, 1256, 1133, 1057, 1014, 945, 915, 883, 748, 697 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 7.36 ± 7.29 (m, 5H, ArH), 5.87 ± 5.82 (m,
2H, H-1, NH), 5.10 (d, J ˆ 11.5 Hz, 1H, H-1E), 5.09 (br.d, J ˆ 16.0 Hz, 1H,
H-1Z), 4.65 and 4.62 (AB, 2H, J ˆ 11.5 Hz, CH2Ar), 4.37 (dq, J ˆ 6.0,
2.0 Hz, 1H, H-5), 3.32 (br.dd, J ˆ 7.5, 2.0 Hz, 1H, H-4), 3.11 (d, J ˆ 7.5 Hz,
1H, OH), 2.89 (dd, J ˆ 14.0, 8.5 Hz, 1H, H-2b), 2.28 (dd, J ˆ 13.5, 7.0 Hz,
1H, H-2a), 1.30 (d, J ˆ 6.5 Hz, 3H, H-6), 1.07 ± 1.04 (m, 21H, iPr3Si), 1.05 (s,
3H, CH3(H-3)); 13C NMR (125 MHz, CDCl3): d ˆ 138.0, 134.3, 128.3, 128.2,
127.6, 118.2, 77.2, 76.7, 67.4, 62.5, 38.7, 23.1, 18.3, 18.2, 18.1, 18.0, 13.1; HRMS
384.2175, found 384.2164.
Benzyl-protected vancosamine lactols 21: Ozone was bubbled through a
solution of alcohol 20 (159 mg, 0.410 mmol) in CH2Cl2 (25 mL) at 788C
for 1 h. Triphenylphosphane (107 mg, 0.82 mmol) was added at 788C, and
then the reaction mixture was warmed to 258C and stirred for 12 h. The
solvents were removed under reduced pressure and the residue was
purified by flash column chromatography (silica gel, 75% ether in hexanes)
to yield lactols 21 (150 mg, 95%) as a white foam. 21: Rf ˆ 0.12; (silica gel,
‡
60% ether in hexanes); [a]D22
ˆ
56.8 (c ˆ 0.5, CHCl3); IR (thin film):
(FAB) calcd for C24H43NO3SiCs [M ‡ Cs ] 554.2067, found 554.2083.
nÄmax ˆ 3410, 3064, 3032, 2930, 1713, 1517, 1453, 1380, 1350, 1280, 1240, 1208,
1160, 1068, 962, 885, 821, 753, 699, 585, 552, 486 cm 1; 1H NMR (500 MHz,
CDCl3, mixture of a:b anomers ca. 1.8:1): d ˆ 7.32 ± 7.27 (m, 10H, ArH),
5.34 (br.s, 0.4H, H-V1a), 5.03 and 4.99 (AB, J ˆ 12.5 Hz, 2H, CH2Ar), 4.92
(br.s, 1H, NH), 4.95 ± 4.85 (m, 2.5H, H-V1b, NH, CH2Ar), 4.64 and 4.54
(AB, J ˆ 11.0 Hz, 0.8H, CH2Ar), 4.62 and 4.50 (AB, J ˆ 11.0 Hz, 1.2H,
CH2Ar), 4.29 (br.q, J ˆ 6.5 Hz, 0.4H, H-V5a), 3.82 (br.q, J ˆ 6.5 Hz, 0.6H,
H-V5b), 3,56 (br.s, 0.4H, H-V4a), 3.52 (br.s, 0.6H, H-V4b), 3.15 (d, J ˆ
8.0 Hz, 0.6H, OHb), 2.61 (dd, J ˆ 8.0, 1.5 Hz, 0.4H, OHb), 1.96 (dd, J ˆ
13.0, 4.5 Hz, 0.6H, H-V2aa), 1.81 (br.d, J ˆ 11.0 Hz, 0.4H, H-V2ba), 1.78
(br.d, J ˆ 13.5 Hz, 0.6H, H-V2ab), 1.73 (s, 1.2H, H-V3a), 1.61 (dd, J ˆ 12.0,
11.0 Hz, 1H, H-V2bb), 1.55 (s, 1.8H, H-V3b), 1.30 (d, J ˆ 6.5 Hz, 0.8H,
H-V6a), 1.30 (d, J ˆ 6.5 Hz, 1.2H, H-V6b); 13C NMR (125 MHz, CDCl3):
d ˆ 154.8, 154.8, 137.9, 136.6, 136.4, 128.5, 128.4, 128.2, 128.2, 128.1, 128.1,
127.8, 92.7, 91.4, 80.1, 78.8, 75.8, 75.6, 70.1, 66.3, 66.2, 64.8, 55.3, 53.6, 40.5,
36.3, 29.7, 24.0, 22.0, 17.7, 17.5; HRMS (FAB) calcd for C22H27NO5Na [M ‡
Hydroxylamine 19: Sodium hydride (122 mg, 3.06 mmol) was added to a
solution of alcohol 18 (1.17 g, 2.71 mmol) in DMF (14 mL) at 08C. After
2 min, benzyl bromide (400 mL, 3.23 mmol) and tetra-n-butylammonium
iodide (205 mg, 0.56 mmol) were added. After stirring for 2 h, the reaction
was quenched by the addition of saturated aqueous NH4Cl (10 mL), diluted
with ether (200 mL), washed with H2O (20 mL) and then brine (20 mL).
The organic layer was dried (MgSO4), concentrated, and the residue was
purified by flash column chromatography (silica gel, 3% ether in hexanes)
to provide the benzyl ether (1.25 g, 88%) as a colorless oil. Benzyl ether:
Rf ˆ 0.50 (silica gel, 10% ether in hexanes); [a]D22
ˆ
23.0 (c ˆ 2.8, CHCl3);
IR (thin film): nÄmax ˆ 3065, 3031, 2943, 2866, 1639, 1497, 1463, 1367, 1308,
1
1249, 1209, 1163, 1106, 1057, 1028, 1014, 910, 883, 732, 697, 682 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 7.33 ± 7.27 (m, 10H, ArH), 5.99 ± 5.92 (m,
2H, H-1, NH), 5.03 (d, J ˆ 11.5 Hz, 1H, H-1E), 5.03 (br.d, J ˆ 16.0 Hz, 1H,
H-1Z), 4.77 and 4.62 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.69 and 4.65 (AB, J ˆ
11.5 Hz, 2H, CH2Ar), 4.33 (dq, J ˆ 6.2, 3.7 Hz, 1H, H-5), 3.57 (d, J ˆ 4.0 Hz,
1H, H-4), 2.42 ± 2.41 (m, 2H, H-2), 1.36 (d, J ˆ 6.5 Hz, 3H, H-6), 1.20 (s,
3H, CH3(H-3)), 1.09 ± 1.06 (m, 21H, iPr3Si); 13C NMR (125 MHz, CDCl3):
d ˆ 139.4, 138.2, 135.5, 128.3, 128.2, 127.5, 127.2, 116.9, 84.1, 76.7, 74.7, 69.2,
63.6, 39.0, 22.1, 19.6, 18.3, 18.2, 18.2, 12.9; HRMS (FAB) calcd for
‡
Na ] 408.1787, found 408.1780.
Benzyl-protected vancosamine glycosyl fluoride 22: Diethylaminosulfur
trifluoride (10 mL, 0.076 mmol) was added to a solution of lactols 21
(21.0 mg, 0.054 mmol) in CH2Cl2 (1.0 mL) at 08C. After stirring for 20 min,
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2659 $ 17.50+.50/0
2659

K. C. Nicolaou et al.
FULL PAPER
the reaction was quenched by the addition of saturated aqueous NaHCO3
(2.0 mL), diluted with CH2Cl2 (10 mL), and stirred for 5 min. The layers
were separated, and the aqueous layer was extracted with CH2Cl2 (10 mL).
The combined organic layers were dried (MgSO4), filtered, and the solvents
were removed under reduced pressure. The residue was azeotroped with
benzene (2 mL), dried under vacuum for 1 h, and used directly in the next
reaction. 22: crude 1H NMR (500 MHz, CDCl3, a:b ca. 16:1): d ˆ 7.33 ± 7.26
(m, 10H, ArH), 5.69 (dd, J ˆ 53.0, 3.0 Hz, 1H, H-V1), 5.05 and 4.99 (AB,
J ˆ 12.5 Hz, 2H, CH2Ar), 4.88 (s, 1H, NH), 4.67 and 4.53 (AB, J ˆ 11.0 Hz,
2H, CH2Ar), 4.27 (br.q, J ˆ 6.5 Hz, 1H, H-V5), 3.56 (s, 1H, H-V4), 2.03
(dd, J ˆ 14.0, 7.0 Hz, 1H, H-V2a), 1.90 (ddd, J ˆ 53.0, 14.0, 3.2 Hz, 1H,
H-V2b), 1.71 (s, 3H, H-V3), 1.31 (d, J ˆ 6.0 Hz, 3H, H-V6).
3H, OCH3), 3.73 (s, 3H, OCH3), 3.49 (br.s, 1H), 3.46 (br.s, 1H), 1.92 ± 1.89
(m, 1H, H-V2), 1.75 ± 1.66 (m, 4H, H-V3, H-V2), 1.57 ± 1.49 (m, 4H, H-V3,
H-V2), 1.25 (d, J ˆ 6.2 Hz, 3H, H-V6), 1.21 (d, J ˆ 7.0 Hz, 3H, H-V6);
13C NMR (125 MHz, CDCl3): d ˆ 159.0, 154.8, 136.4, 130.0, 129.8, 128.5,
128.4, 128.2, 128.1, 128.1, 128.0, 113.8, 113.7, 92.7, 91.4, 79.7, 78.5, 75.4, 75.1,
70.0, 66.2, 66.1, 64.7, 55.2, 53.5, 40.4, 36.3, 23.9, 21.9, 17.7, 17.5; HRMS (FAB)
‡
calcd for C23H29NO6Na [M ‡ Na ] 438.1893, found 438.1879. To a solution
of the above lactols (850 mg, 2.04 mmol), triethylamine (1.42 mL,
10.2 mmol), and 4-DMAP (10 mg, 0.08 mmol) in CH2Cl2 (4.0 mL) at 08C
was added acetic anhydride (580 mL, 6.12 mmol). After stirring the reaction
mixture for 2 h at 258C, the reaction was quenched by the addition of
saturated aqueous NaHCO3 (10 mL), and the aqueous phase was extracted
with CH2Cl2 (2Â 30 mL). The combined organic layers were dried (MgSO4),
concentrated, and the residue was purified by flash column chromatography to
afford acetate 25 (940 mg, 96%, b:a ca. 3.5:1 mixture of anomers) as a
Cbz-protected amine 24: Sodium hydride (457 mg, 60% in mineral oil,
11.94 mmol) was added to a solution of alcohol 18 (4.20 g, 9.95 mmol), p-
methoxybenzyl chloride (1.75 mL, 12.9 mmol), and tetra-n-butylammoni-
um iodide (367 mg, 0.99 mmol) in DMF (52 mL) at 08C. After stirring the
reaction mixture for 4 h at 258C, the reaction was quenched by the careful
addition of saturated aqueous NH4Cl (10 mL), the solution was diluted
with ether (300 mL), and washed with brine (30 mL). The organic layer was
dried (MgSO4), concentrated, and the residue was purified by flash column
chromatography to afford the PMB-ether (6.2 g, 93%). PMB-ether: Rf ˆ
white foam. 25: Rf ˆ 0.30 (silica gel, 40% EtOAc in hexanes); IR (thin film):
1
nÄmax ˆ 3372, 1722, 1607, 1514, 1453, 1370, 1240, 1038 cm
;
1H NMR (500
MHz, CDCl3): d ˆ 7.32 ± 7.31 (m, 5H, ArH), 7.20 (d, J ˆ 8.5 Hz, 2H, ArH),
6.80 (d, J ˆ 8.8 Hz, 2H, ArH), 6.15 (br.d, J ˆ 3.6 Hz, 1H, H-V1a), 5.81 (dd,
J ˆ 11.7, 2.5 Hz, 1H, H-V1b), 5.05 ± 5.02 (m, 3H, CH2Ar, NH), 4.61 (d, J ˆ
11.4 Hz, 1H, CH2Ar), 4.41 (d, J ˆ 11.4 Hz, 1H, CH2Ar), 3.91 (q, J ˆ 6.2 Hz,
1H, H-V5), 3.74 (s, 3H, OCH3), 3.52 (br.s, 1H, H-V4a), 3.41 (br.s, 1H,
H-V4b), 2.05 (s, 3H, COCH3), 1.89 ± 1.80 (m, 2H, H-V2a, H-V2b), 1.68 (s,
3H, H-3Va), 1.58 (s, 3H, H-V3b), 1.28 (d, J ˆ 6.6 Hz, 3H, H-V6b), 1.26 (d,
J ˆ 6.2 Hz, 3H, H-V6a); 13C NMR (125 MHz, CDCl3): d ˆ 169.3, 159.3,
154.8, 136.3, 128.7, 128.4, 128.1, 113.9, 113.8, 91.5, 90.8, 79.3, 78.6, 75.3, 70.5,
66.9, 66.2, 66.2, 55.1, 54.9, 53.1, 36.8, 35.0, 23.4, 21.8, 21.3, 17.6; HRMS
0.66 (silica gel, 20% ether in hexanes); [a]D22
ˆ
41.7 (c ˆ 1.1, CHCl3); IR
1
(thin flim) nÄmax ˆ 2942, 2865, 1607, 1513, 1463, 1366, 1248, 1171, 1082 cm
;
1H NMR (500 MHz CDCl3): d ˆ 7.33 ± 7.25 (m, 5H, ArH), 7.23 (d, J ˆ
9.0 Hz, 2H, ArH), 6.83 (d, J ˆ 9.0 Hz, 2H, ArH), 5.97 ± 5.90 (m, 2H, H-1,
NH), 5.03 ± 4.99 (m, 2H, H-1Z, H-1E), 4.68 ± 4.64 (m, 3H, CH2Ar), 4.51 (d,
J ˆ 11.0 Hz, 1H, CH2Ar), 4.31 ± 4.26 (m, 1H, H-5), 3.79 (s, 3H, OCH3), 3.54
(d, J ˆ 3.7 Hz, 1H, H-4), 2.38 (d, J ˆ 7.0 Hz, 2H, H-2a, H-2b), 1.33 (d, J ˆ
7.0 Hz, 3H, H-6), 1.17 (s, 3H, CH3(H-3)), 1.05 (s, 21H, iPr3Si); 13C NMR
(125 MHz, CDCl3): d ˆ 158.8, 138.2, 135.2, 131.4, 128.9, 128.8, 128.8, 128.7,
128.2, 128.1, 128.1, 128.0, 128.0, 127.4, 116.8, 113.5, 110.0, 83.7, 74.3, 69.2,
‡
(FAB) calcd for C25H31NO7Na [M ‡ Na ] 480.1998, found 480.1983.
Acetate-protected vancosamine thioglycoside 26: To a solution of anome-
ric acetates 25 (700 mg, 1.25 mmol) and thiophenol (630 mL, 6.11 mmol) in
CH2Cl2 (15 mL) at 208C was added BF3 ´ Et2O (390 mL, 3.05 mmol).
‡
63.5, 55.2, 38.9; HRMS (FAB) calcd for C32H51NO4SiCs [M ‡ Cs ]
After 1 h at
208C, the reaction mixture was diluted with CH2Cl2
674.2642, found 674.2619. Lithium aluminum hydride (640 mg, 16.1 mmol)
was added to a solution of the above PMB-ether (2.44 g, 4.60 mmol) in
ether (46 mL), at 08C. The reaction mixture was refluxed for 5 h, cooled to
08C, and then quenched by the addition of saturated aqueous NH4Cl
(10 mL). The reaction mixture was diluted with CH2Cl2 (200 mL) and
washed with H2O (20 mL). The aqueous layer was further extracted with
CH2Cl2 (2 Â 80 mL) and EtOAc (2 Â 80 mL). The combined organic layers
were dried (MgSO4), filtered, and the solvents were removed under
reduced pressure. To a solution of the above crude amino-alcohol and
NaHCO3 (3.85 g, 45.8 mmol) in dioxane/H2O (4:1) (55 mL) at 08C was
added CbzCl (5.39 mL, 37.7 mmol). After stirring for 18 h at 258C, the
reaction mixture was diluted with CH2Cl2 (200 mL), and washed with H2O
(20 mL). The organic layer was dried (MgSO4), concentrated, and the
residue was purified by flash column chromatography (silica gel, 50% ether
in hexanes) to afford Cbz-protected amine 24 (1.54 g, 81% over two steps)
(100 mL), and washed with NaHCO3 (25 mL). The organic layer was dried
(MgSO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 30% EtOAc in hexanes) to afford the
thioglycosides (560 mg, 95%, 1:1 mixture of a:b anomers) as a white
foam. Thioglycosides: Rf ˆ 0.29 (silica gel, 50% ether in hexanes); IR (thin
1
film): nÄmax ˆ 3045, 1713, 1498, 1453, 1274, 1220, 1006 cm
;
1H NMR
(500 MHz, CDCl3, 1:1 mixture of a:b anomers): d ˆ 7.49 (d, J ˆ 7.0 Hz, 1H,
ArH), 7.45 (d, J ˆ 7.3 Hz, 1H, ArH), 7.35 ± 7.25 (m, 9H, ArH), 5.54 (d, J ˆ
7.0 Hz, 1H, H-V1), 5.51 (d, J ˆ 6.0 Hz, 1H, H-V1), 5.07 ± 5.03 (m, 2H,
CH2Ar), 4.81 (dd, J ˆ 14.2, 2.0 Hz, 2H, CH2Ar), 4.56 (q, J ˆ 6.6 Hz, 1H,
H-V5), 3.89 (q, J ˆ 6.5 Hz, 1H, H-V5), 3.80 (s, 3H, OCH3), 3.38 (br.s, 1H,
H-V4), 3.23 (br.s, 1H, H-V4), 2.45 ± 2.42 (m, 1H, H-V2), 2.30 (d, J ˆ 7.0 Hz,
1H, H-V2), 2.13 (br.s, 1H, H-V2), 2.04 (br.s, 1H, H-V2), 1.74 (s, 3H,
H-V3), 1.54 (s, 3H, H-V3), 1.31 (d, J ˆ 6.5 Hz, 3H, H-V6), 1.27 (d, J ˆ
6.6 Hz, 3H, H-V6); 13C NMR (500 MHz, CDCl3): d ˆ 155.0, 136.4, 136.3,
135.8, 133.8, 131.5, 131.0, 128.9, 128.6, 128.5, 128.1, 128.0, 127.5, 127.1, 83.2,
81.7, 73.2, 72.5, 71.9, 66.3, 64.3, 54.9, 53.7, 37.2, 36.8, 23.2, 20.6, 17.5, 17.1;
as a colorless oil. 24: Rf ˆ 0.40 (silica gel, 50% ether in hexanes); [a]D22
ˆ
38.0 (c ˆ 0.83, CHCl3); IR (film) nÄmax ˆ 3354, 2932, 1714, 1613, 1514, 1247,
1075, 1031 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.34 ± 7.28 (m, 5H, ArH),
7.23 (d, J ˆ 9.0 Hz, 2H, ArH), 6.87 (d, J ˆ 8.5 Hz, 2H, ArH), 5.81 ± 5.74 (m,
1H, H-1), 5.14 ± 4.99 (m, 4H, H-1E, H-1Z, CH2Ar), 4.64 (d, J ˆ 10.6 Hz,
1H, CH2Ar), 4.56 (d, J ˆ10.3 Hz, 1H, CH2Ar), 3.96 (br.s, 1H, H-4), 3.83
(br.s, 1H, H-5), 3.80 (s, 3H, OCH3), 2.89 ± 2.85 (m, 1H, H-2b), 2.41 ± 2.39
(m, 1H, H-2a), 1.33 (s, 3H, CH3(H-3)), 1.21 (d, J ˆ 6.5 Hz, 3H, CH3(H-6));
13C NMR (125 MHz, CDCl3): d ˆ 159.4, 155.0, 137.0, 133.5, 130.1, 129.5,
128.5, 128.1, 118.9, 113.8, 83.9, 66.2, 65.7, 58.7, 55.3, 40.4, 23.6, 20.9; HRMS
‡
HRMS (FAB) calcd for C21H25NO4SNa [M ‡ Na ] 410.1402, found
410.1417. To a solution of the above thioglycosides (550 mg, 1.41 mmol),
triethylamine (0.99 mL, 7.05 mmol), and 4-DMAP (10 mg, 0.08 mmol) in
CH2Cl2 (4.0 mL) at 258C was added acetic anhydride (401 mL, 4.25 mmol).
After the reaction mixture was stirred 2 h, the reaction was quenched by
the addition of saturated aqueous NaHCO3 (10 mL), and the aqueous
phase was extracted with CH2Cl2 (2 Â 30 mL). The combined organic layers
were dried (MgSO4), concentrated, and the residue was purified by flash
column chromatography to give 26 (600 mg, 97%) as a white foam. 26:
Rf ˆ 0.38 (silica gel, 50% ether in hexanes); IR (thin film): nÄmax ˆ 1745,
‡
(FAB) calcd for C24H31NO5Na [M ‡ Na ] 436.2100, found 436.2109.
Vancosamine anomeric acetate 25: Ozone was bubbled through a solution
of alcohol 24 (1.10 g, 2.52 mmol) in CH2Cl2 (35 mL) at 788C for 1 h.
Dimethyl sulfide (5.0 mL) was added and the solution was allowed to warm
to 258C over 6 h. The solvents were removed under reduced pressure and
the residue was purified by flash column chromatography to afford the
1
1520, 1455, 1372, 1230, 1062, 1025 cm 1; H NMR (500 MHz, CDCl3): d ˆ
7.51 (d, J ˆ 9.0 Hz, 1H, ArH), 7.41 (d, J ˆ 7.0 Hz, 1H, ArH), 7.35 ± 7.24 (m,
8H, ArH), 5.58 (dd, J ˆ 9.1, 2.5 Hz, 1H, H-V1), 5.08 (d, J ˆ 11.7 Hz, 2H,
H-V1), 5.00 ± 4.93 (m, 5H, CH2Ar), 4.87 (br.s, 1H), 4.75 (br.s, 1H), 4.50 (q,
J ˆ 6.6 Hz, 1H, H-V5), 3.90 (q, J ˆ 6.0 Hz, 1H, H-V5), 2.53 (dd, J ˆ 7.0,
2.2 Hz, 1H, H-V2), 2.24 ± 2.16 (m, 2H, H-V2), 2.09 (s, 3H, COCH3), 2.06 (s,
3H, COCH3), 1.90 (t, J ˆ 12.5 Hz, 1H), 1.76 (s, 3H, H-V3), 1.63 (s, 3H,
H-V3), 1.19 (d, J ˆ 6.2 Hz, 3H, H-V6), 1.15 (d, J ˆ 6.6 Hz, 3H, H-V6);
13C NMR (125 MHz, CDCl3): d ˆ 137.0, 136.0, 133.5, 131.5, 131.0, 128.9,
128.8, 126.5, 128.3, 128.3, 128.2, 127.5, 127.1, 82.9, 81.0, 73.8, 72.3, 71.2, 66.2,
54.5, 53.4, 37.8, 36.8, 23.7, 21.2, 20.7, 17.8, 16.9; HRMS (FAB) calcd for
anomeric mixture of lactols (1.00 g, 92%). Lactols: Rf ˆ 0.50 (silica gel,
1
ether); IR (thin film): nÄmax ˆ 3404, 1716, 1612, 1513, 1454, 1247, 1064 cm
;
1H NMR (500 MHz, CDCl3, 1:1 mixture of a:b anomers): d ˆ 7.32 ± 7.28 (m,
4H, ArH), 7.20 (d, J ˆ 8.5 Hz, 1H, ArH), 7.16 (d, J ˆ 8.0 Hz, 2H, ArH),
6.82-6.78 (m, 2H, ArH, H-1a), 5.29 (br.s, 1H, H-V1a), 5.07 ± 4.98 (m, 4H,
CH2Ar), 4.93 (s, 1H), 4.83 (s, 1H, H-1Vb), 4.79 (d, J ˆ 9.5 Hz, 1H, CH2Ar),
4.67 (s, 1H), 4.59 (d, J ˆ 11.0 Hz, 1H), 4.50 (d, J ˆ 11.0 Hz, 1H), 4.45 (d, J ˆ
11.0 Hz), 4.39 (d, J ˆ 10.6 Hz, 1H), 4.25 (q, J ˆ 6.2 Hz, 1H, H-V5), 3.74 (s,
‡
C23H28NO5S [M ‡ H ] 430.1188, found 430.1702.
2660
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2660 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 4
2648±2667
Acetate-protected vancosamine fluoride donor 27: To a solution of the
thioglycoside 26 (160 mg, 0.24 mmol) in acetone/H2O (9:1) (5.5 mL) at 08C
was added N-bromosuccinimide (70 mg, 0.37 mmol). After stirring for
0.5 h, the reaction mixture was diluted with CH2Cl2 (150 mL) and washed
with saturated aqueous NaHCO3 (25 mL). The organic layer was dried
(MgSO4), concentrated, and the residue was purified by flash column
chromatography to afford the lactols (120 mg, 87%). Lactols: Rf ˆ 0.20
(silica gel, 70% ether in hexanes); IR (thin film): nÄmax ˆ 3362, 3033, 3020,
2983, 2969, 2942, 1738, 1734, 1718, 1714, 1538, 1508, 1453, 1372, 1251, 1131,
Benzyl-protected glucose lactols 29: To a solution of thioglycoside 28
(160 mg, 0.24 mmol) in acetone/H2O (10:1) (5.5 mL) at 08C was added N-
bromosuccinimide (90 mg, 0.49 mmol). After stirring for 0.5 h, the reaction
mixture was diluted with CH2Cl2 (150 mL) and washed with saturated
aqueous NaHCO3 (25 mL). The organic layer was dried (MgSO4),
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 50% ether in hexanes) to afford lactols 29 (120 mg, 87%)
as a white foam. 29: Rf ˆ 0.50 (silica gel, 70% ether in hexanes); IR (thin
film): nÄmax ˆ 3363, 3063, 3031, 2922, 2874, 1775, 1715, 1603, 1494, 1452, 1362,
1
1
1060, 1025 cm 1; H NMR (600 MHz, CDCl3, mixture of a:b anomers ca.
1314, 1282, 1175, 1154, 1119, 1096, 1068, 1012, 1026, 918, 856, 745, 697 cm
;
1.6:1): d ˆ 7.35 ± 7.30 (m, 10H, ArH), 5.39 (br.s, 1H, H-V1b), 5.10 (br.s, 1H,
NH), 5.08 (br.s, 1.6H, NH), 5.00 ± 4.93 (m, 6.2H, H-V1a, 2 Â CH2Ar), 4.83
(s, 1.6H, H-V4a), 4.79 (s, 1H, H-V4b), 4.36 (br.q, J ˆ 6.2 Hz, 1H, H-V5a),
3.89 (br.q, J ˆ 6.5 Hz, 1.6H, H-V5b), 3.82 (d, J ˆ 7.0 Hz, 1.6H, OHb), 2.10 ±
2.05 (m, 3.6H, H-V2aa, H-V2ab, H-V2bb), 2.07 (s, 3H, COCH3), 2.05 (s,
4.8H, COCH3), 1.96 (br.d, J ˆ 10.7 Hz, 1.6H, H-V2ba), 1.77 (s, 4.8H,
H-V3a), 1.59 (s, 3H, H-V3b), 1.18 (d, J ˆ 6.4 Hz, 4.8H, H-V6a), 1.12 (d, J ˆ
6.4 Hz, 3H, H-V6b); 13C NMR (150 MHz, CDCl3): d ˆ 171.0, 170.7, 136.4,
136.3, 128.5, 128.5, 128.3, 128.3, 128.2, 128.1, 128.1, 92.7, 91.6, 73.7, 72.2, 68.7,
63.1, 54.5, 53.0, 39.7, 35.6, 30.3, 29.5, 24.0, 22.2, 20.7, 20.6, 17.3; HRMS
1H NMR (500 MHz, CDCl3): d ˆ 8.03 (d, J ˆ 7.5 Hz, 2H, ArH), 7.54 (t, J ˆ
7.5 Hz, 2H, ArH), 7.41 (t, J ˆ 7.5 Hz, 2H, ArH), 7.32 ± 7.19 (m, 15H, ArH),
6.94 (t, J ˆ 8.5 Hz, 1H, ArH), 6.45 (d, J ˆ 8.5 Hz, 2H, ArH), 5.56 (d, J ˆ
3.5 Hz, 1H, H-G1), 5.16 (dd, J ˆ 10.0, 3.5 Hz, 1H, H-G2), 4.87 and 4.53
(AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.87-4.84 (m, 2H, CH2Ar), 4.61 and 4.53
(AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.29 (t, J ˆ 9.0 Hz, 1H, H-G3), 4.22 (ddd,
J ˆ 10.0, 5.0, 2.0 Hz, 1H, H-G5), 3.72 ± 3.66 (m, 3H, H-G4, H-G6a, H-G6b);
13C NMR (125 MHz, CDCl3): d ˆ 178.4, 166.0, 138.2, 138.0, 137.7, 130.0,
129.7, 128.5, 128.5, 128.4, 128.3, 128.0, 128.0, 127.8, 127.7, 90.5, 90.4, 79.8,
79.7, 78.3, 78.2, 77.4, 75.6, 73.4, 70.2; HRMS (FAB) calcd for C34H34O7Cs
‡
‡
(FAB) calcd for C17H23NO6Na [M ‡ Na ]: 360.1423, found 360.1415.
[M ‡ Cs ] 687.1359, found 687.1373.
Diethylaminosulfur trifluoride (65 mL, 0.49 mmol) was added to a solution
of the lactols (110 mg, 0.32 mmol) in CH2Cl2 (2 mL) at 08C. After the
reaction mixture was stirred for 20 min, the reaction was quenched by the
addition of saturated aqueous NaHCO3 (3 mL), diluted with CH2Cl2
(20 mL), and stirred for 5 min. The layers were separated, the aqueous
layer was extracted with CH2Cl2 (20 mL). The combined organic layers
were dried (MgSO4), filtered, and the solvents were removed under
reduced pressure. The residue was azeotroped with benzene (2 mL), dried
under vacuum for 1 h, and used directly in the next reaction. 27: (crude)
1H NMR (500 MHz, CDCl3, a:b ca. 16:1): d ˆ 7.37 ± 7.26 (m, 5H, ArH), 5.69
(br.d, J ˆ 53.0 Hz, 1H, H-V1), 5.08 and 4.95 (AB, J ˆ 12.0 Hz, 2H, CH2Ar),
5.00 (s, 1H, NH), 4.82 (s, 1H, H-V4), 4.32 (br.q, J ˆ 6.5 Hz, 1H, H-V5),
2.40 ± 2.37 (m, 1H, H-V2a), 2.09 (s, 3H, COCH3), 1.90 (dd, J ˆ 53.0,
14.0 Hz, 1H, H-V2b), 1.70 (s, 3H, H-V3), 1.17 (d, J ˆ 6.5 Hz, 3H, H-V6).
2,6-Dimethoxyphenolic glucoside 31: DBU (5.0 mL, 0.033 mmol) was
added to
a
solution of glucose lactols 29 (0.42 g, 0.76 mmol) and
308C. After
trichloroacetonitrile (0.60 mL, 7.4 mmol) in CH2Cl2 at
0.5 h, the solvents were removed under reduced pressure and the residue
was purified by flash column chromatography (silica gel, 35% ether in
hexanes) to afford imidate 30 (470 mg, 90%). A mixture of 2,6-dimethoxy-
phenol (17 mg, 0.11 mmol) and imidate 30 (118 mg, 1.85 mmol) was
azeotroped with benzene (3 Â 3 mL), and then dried under high vacuum
for 1 h. CH2Cl2 (0.5 mL) and 4 Š MS were added, and the mixture was
stirred for 15 min at ambient temperature. The resulting mixture was
cooled to
308C and BF3 ´ Et2O (60 mL, 0.38m solution in CH2Cl2,
0.020 mmol) was added dropwise. After 1 h and 2 h, a second and third
60 mL of BF3 ´ Et2O solution were added. The reaction mixture was warmed
slowly to 258C, and then stirred for 22 h. The reaction mixture was diluted
with EtOAc (150 mL), washed with saturated aqueous NaHCO3 (20 mL)
and brine (20 mL). The organic layer was dried (Na2SO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
(1:1:3) ether/CH2Cl2/hexanes) to yield b-glucoside 31 (72 mg, 95%, b:a ca.
13:1) as a white foam. 31: Rf ˆ 0.26 (silica gel, (1:1:3) ether/CH2Cl2/
Glucose thioglycoside 28: Osmium tetroxide (200 mL, 2.5% solution in tert-
butyl alcohol) was added to a solution of tribenzylglucal (4.30 g, 10.3 mmol)
and 4-methylmorpholine N-oxide (1.57 g, 13.4 mmol) in acetone/H2O
(10:1) (110 mL) at 258C. After stirring for 12 h, the reaction mixture was
concentrated, diluted with CH2Cl2 (100 mL), and washed with saturated
aqueous NaHCO3 (5 mL). The organic layer was dried (MgSO4), concen-
trated, and the residue was purified by flash column chromatography (silica
gel, 80% ether in hexanes) to provide the diol (4.23 g, 91%). To a solution
of the above diol (4.24 g, 9.2 mmol) in pyridine (20 mL) at 08C was added
benzoyl chloride (2.66 mL, 23.0 mmol) and 4-DMAP (0.224 g, 1.86 mmol),
and the resulting reaction mixture was warmed to 258C and stirred for 12 h.
The reaction mixture was diluted with ether (500 mL), and washed with
saturated aqueous NH4Cl (2 Â 100 mL). The organic layer was dried
(MgSO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 40% ether in hexanes) to afford the dibenzoate
(5.92 g, 98%). To a solution of the above dibenzoate (241 mg, 0.37 mmol)
and thiophenol (80 mL, 0.73 mmol) in CH2Cl2 (2 mL) at 108C was added
BF3 ´ Et2O (9.0 mL, 0.070 mmol). After 1 h, the reaction mixture was diluted
with CH2Cl2 (100 mL) and washed with saturated aqueous NaHCO3
(25 mL). The organic layer was dried (MgSO4), concentrated, and the
residue was purified by flash column chromatography (silica gel, 35% ether
in hexanes) to yield b-thioglycoside 28 (0.20 g, 84%) as a white foam. 28:
Rf ˆ 0.47 (silica gel, 50% ether in hexanes); [a]2D2 ˆ ‡ 21.7 (c ˆ 1.1, CHCl3);
hexanes); [a]2D2 ˆ ‡13.6 (c ˆ 1.0, CHCl3); IR (thin film): nÄmax ˆ 3030, 2923,
1
2854, 1730, 1600, 1496, 1478, 1456, 1365, 1259, 1111, 1027, 735, 702 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 8.03 (d, J ˆ 7.5 Hz, 2H, ArH), 7.54 (t, J ˆ
7.5 Hz, ArH), 7.41 (t, J ˆ 7.5 Hz, 2H, ArH), 7.32 ± 7.12 (m, 15H, ArH), 6.94
(t, J ˆ 8.5 Hz, 1H, ArH), 6.45 (d, J ˆ 8.5 Hz, 2H, ArH), 5.60 (br.t, J ˆ
8.0 Hz, 1H, H-G2), 5.07 (d, J ˆ 7.5 Hz, 1H, H-G1), 4.84 and 4.57 (AB, J ˆ
11.0 Hz, 2H, CH2Ar), 4.76 and 4.70 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.65 and
4.62 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 3.89 ± 3.86 (m, 2H, H-G3, H-G4), 3.80
(dd, J ˆ 11.3, 2.0 Hz, 1H, H-G6a), 3.75 (dd, J ˆ 11.5, 5.0 Hz, 1H, H-G6b),
3.57 (s, 7H, OCH3, H-G5); 13C NMR (125 MHz, CDCl3): d ˆ 165.1, 153.3,
138.4, 138.0, 137.9, 135.0, 132.7, 130.4, 129.8, 128.4, 128.2, 128.2, 128.1, 128.0,
127.8, 127.7, 127.5, 127.4, 124.3, 105.3, 102.2, 82.9, 77.8, 75.9, 74.9, 74.8, 74.3,
‡
73.7, 69.0, 55.9; HRMS (FAB) calcd for C42H42O9Cs [M ‡ Cs ] 823.1883,
found 823.1913.
Glucose acceptor 32: NaOH (10 mg, 0.25 mmol, powdered) was added to a
solution of glucoside 31 (72 mg, 0.10 mmol) in MeOH (3.0 mL) at 258C.
After the mixture was stirred for 3 h, saturated aqueous NH4Cl (5 mL) was
added, and the reaction mixture was extracted with CH2Cl2 (100 mL). The
organic layer was dried (MgSO4), concentrated, and the residue was
purified by flash column chromatography (silica gel, 30% ether in hexanes)
to provide alcohol 32 (53 mg, 90%) as a white foam. 32: Rf ˆ 0.18 (silica gel,
IR (thin film): nÄmax ˆ 3047, 3031, 2987, 2865, 1722, 1602, 1584, 1496, 1454,
1
1365, 1316, 1285, 1071, 1027, 908, 739, 710 cm
;
1H NMR (600 MHz,
CDCl3): d ˆ 8.05 (d, J ˆ 7.5 Hz, 2H, ArH), 7.59 (t, J ˆ 7.5 Hz, 1H, ArH), 7.50
(d, J ˆ 7.5 Hz, 2H, ArH), 7.46 (t, J ˆ 7.5 Hz, 2H, ArH), 7.36 ± 7.11 (m, 18H,
ArH), 5.30 (t, J ˆ 9.5 Hz, 1H, H-G2), 4.83 and 4.60 (AB, J ˆ 10.9 Hz, 2H,
CH2Ar), 4.80 (d, J ˆ 9.9 Hz, 1H, H-G1), 4.74 and 4.65 (AB, J ˆ 11.0 Hz,
2H, CH2Ar), 4.63 and 4.57 (AB, J ˆ 11.9 Hz, 2H, CH2Ar), 3.86 (t, J ˆ
9.0 Hz, 1H, H-G3), 3.83 (br.d, J ˆ 9.1 Hz, 1H, H-G6a), 3.78 (dd, J ˆ 10.0,
5.2 Hz, 1H, H-G6b), 3.75 (t, J ˆ 9.0 Hz, 1H, H-G4), 3.67 ± 3.60 (m, 1H,
H-G5); 13C NMR (150 MHz, CDCl3): d ˆ 165.0, 138.2, 137.9, 137.6, 133.2,
132.9, 132.5, 129.8, 128.8, 128.4, 128.4, 128.3, 128.2, 128.0, 128.0, 127.8, 127.7,
127.7, 127.6, 86.1, 84.3, 79.4, 77.8, 75.3, 75.1, 73.5, 72.4, 68.9; HRMS (FAB)
(1:1:3) ether/CH2Cl2/hexanes); [a]D22
ˆ
11.3 (c ˆ 0.60, CHCl3); IR (thin
film): nÄmax ˆ 3504, 3062, 3030, 2901, 1600, 1497, 1478, 1455, 1298, 1257, 1112,
1070, 1037, 984, 733, 698 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.44 (d, J ˆ
7.5 Hz, 2H, ArH), 7.54 ± 7.19 (m, 13H, ArH), 7.07 (t, J ˆ 8.5 Hz, 1H, ArH),
6.61 (d, J ˆ 8.5 Hz, 2H, ArH), 5.09 and 4.58 (AB, J ˆ 11.0 Hz, 2H, CH2Ar),
4.88 and 4.84 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.63 and 4.60 (AB, J ˆ 11.5 Hz,
2H, CH2Ar), 4.57 (d, J ˆ 7.5 Hz, 1H, H-G1), 3.99 (br.s, 1H, OH), 3.93 (t,
J ˆ 8.5 Hz, 1H, H-G3), 3.85 (s, 6H, OCH3), 3.81 (dd, J ˆ 11.0, 2.0, 1H,
H-G6a), 3.75 (dd, J ˆ 11.0, 5.5, 1H, H-G6b), 3.66-3.62 (m, 2H, H-G2,
H-G4), 3.53-3.51 (m, 1H, H-G5); 13C NMR (125 MHz, CDCl3): d ˆ 153.0,
‡
calcd for C40H38O6SCs [M ‡ Cs ] 779.1443, found 779.1455.
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2661 $ 17.50+.50/0
2661

K. C. Nicolaou et al.
FULL PAPER
138.8, 138.4, 138.1, 135.8, 128.3, 128.3, 128.2, 127.9, 127.9, 127.7, 127.7, 127.5,
124.9, 106.3, 105.4, 84.8, 77.2, 75.9, 75.6, 75.0, 74.9, 73.5, 69.4, 56.3; HRMS
(FAB) calcd for C35H38O8Cs [M ‡ Cs ] 719.1621, found 719.1598.
138.0, 132.8, 131.8, 128.9, 128.4, 128.3, 128.3, 127.0, 127.9, 127.9, 127.7, 127.6,
127.5, 88.0, 85.9, 79.3, 77.3, 75.3, 75.0, 73.4, 72.5, 68.9; HRMS (FAB) calcd
for C33H34O5SCs [M ‡ Cs ] 675.1181, found 675.1198.
‡
‡
Benzyl-protected disaccharide 33: Vancosamine fluoride 22 (30 mg,
0.06 mmol) and alcohol 32 (20 mg, 0.03 mmol) were azeotroped with
benzene (3 Â 3 mL) and then dried under high vacuum for 1 h. CH2Cl2
(0.5 mL) and 4 Š MS were added, and the mixture was stirred for 15 min.
The resulting mixture was cooled to 308C and BF3 ´ Et2O (40 mL, 0.4m
solution in CH2Cl2, 0.010 mmol) and TMSOTf (80 mL, 0.2m solution in
CH2Cl2, 0.010 mmol) were added dropwise. The reaction mixture was
warmed to 258C and stirred for 72 h. The reaction mixture was diluted with
EtOAc (150 mL) and washed with saturated aqueous NaHCO3 (20 mL)
and brine (20 mL). The organic layer was dried (Na2SO4), and the solvents
were removed under reduced pressure. The residue was purified by
preparative TLC (silica gel, 30% ether in hexanes) to afford disaccharide
33 (26 mg, 80%) (a:b ca. 10:1) as a white foam and recovered alcohol 32
Benzyl-protected thio-disaccharide 36: Vancosamine fluoride 22 (100 mg,
0.26 mmol) and alcohol 35 (120 mg, 0.21 mmol) were azeotroped with
benzene (3 Â 3 mL) and then dried under high vacuum for 1 h. CH2Cl2
(0.5 mL) and 4 Š MS were added and the mixture was stirred for 15 min.
The resulting reaction mixture was cooled to 108C and tin dichloride
(93 mg, 0.49 mmol) was added. After stirring for 2 h, the reaction mixture
was diluted with EtOAc (150 mL) and washed with saturated aqueous
NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4)
and the solvents were removed under reduced pressure. The residue was
purified by preparative TLC (silica gel, 30% ether in hexanes) to afford
disaccharide 36 (162 mg, 85%, a:b ca. 3.3:1) as a white foam and recovered
alcohol 35 (11 mg, 10%). 36: Rf ˆ 0.53 (silica gel, 50% ether in hexanes);
[a]2D2
ˆ
51.2 (c ˆ 0.38, CHCl3); IR (thin film): nÄmax ˆ 3032, 2925, 1720,
(2 mg, 10%). 33: Rf ˆ 0.18 (silica gel, 50% ether in hexanes); [a]D22
ˆ
43.8
1
1584, 1497, 1454, 1360, 1270, 1212, 1129, 1056, 738, 696 cm
;
1H NMR
(c ˆ 0.24, CHCl3); IR (thin film): nÄmax ˆ 3409, 3031, 2931, 1723, 1599, 1497,
(600 MHz, CDCl3): d ˆ 7.55 ± 7.16 (m, 30H, ArH), 5.43 (d, J ˆ 4.4 Hz, 1H,
H-V1), 5.01 and 4.95 (AB, J ˆ 12.2 Hz, 2H, CH2Ar), 4.90 ± 4.47 (AB, J ˆ
11.0, 12.0 Hz, 10H, CH2Ar), 4.86 (s, 1H, NH), 4.68 (q, J ˆ 6.5 Hz, 1H,
H-V5), 4.61 (d, J ˆ 9.7 Hz, 1H, H-G1), 3.76 (t, J ˆ 8.5 Hz, 1H, H-G3), 3.73
(dd, J ˆ 10.9, 1.7 Hz, 1H, H-G6a), 3.66 (dd, J ˆ 11.3, 5.3 Hz, 1H, H-G6b),
3.63 (t, J ˆ 8.5 Hz, 1H, H-G4), 3.59 (t, J ˆ 9.3 Hz, 1H, H-G2), 3.55 (br.s,
1H, H-V4), 3.52 ± 3.48 (m, 1H, H-G5), 1.83 (dd, J ˆ 11.4, 4.8 Hz, 1H,
H-V2a), 1.73 (d, J ˆ 11.4 Hz, 1H, H-V2b), 1.55 (s, 3H, H-V3), 1.28 (d, J ˆ
6.5 Hz, 3H, H-V6); 13C NMR (125 MHz, CDCl3): d ˆ 154.7, 138.2, 138.0,
137.9, 136.6, 134.4, 131.7, 128.9, 128.5, 128.5, 128.5, 128.4, 128.3, 128.2, 128.1,
128.0, 127.9, 127.8, 127.7, 127.7, 127.6, 127.6, 127.4, 127.3, 125.5, 98.0, 87.9, 87.4,
80.5, 79.1, 78.2, 76.2, 75.8, 75.5, 74.9, 73.4, 69.0, 66.1, 65.4, 53.4, 36.4, 30.3,
1
1478, 1455, 1363, 1297, 1256, 1215, 1111, 1062, 735, 699 cm
;
1H NMR
(500 MHz, CDCl3): d ˆ 7.31 ± 7.18 (m, 25H, ArH), 7.02 (t, J ˆ 8.5 Hz, 2H,
ArH), 6.57 (d, J ˆ 8.5 Hz, 2H, ArH), 5.32 (br.d, J ˆ 4.5 Hz, 1H, H-V1), 5.08
(d, J ˆ 7.5 Hz, 1H, H-G1), 5.01 and 4.98 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.90
(s, 1H, NH), 4.87 and 4.78 (AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.77 and 4.47
(AB, J ˆ 11.0 Hz, 2H, CH2Ar), 4.64 and 4.61 (AB, J ˆ 11.5 Hz, 2H,
CH2Ar), 4.53-4.49 (m, 1H, H-V5), 4.45 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 3.94
(t, J ˆ 8.0 Hz, 1H, H-G3), 3.77 (s, 6H, OCH3), 3.72 ± 3.65 (m, 3H, H-G2,
H-G4, H-G6a), 3.61 (dd, J ˆ 12.0, 5.5 Hz, 1H, H-G6b), 3.41 (s, 1H, H-V4),
3.39 ± 3.37 (m, 1H, H-G5), 1.84 (s, 3H, H-V3), 1.83 (d, J ˆ 13.0 Hz, 1H,
H-V2a), 1.78 (dd, J ˆ 13.0, 4.5 Hz, 1H, H-V2b), 1.09 (d, J ˆ 6.5 Hz, 3H,
H-V6); 13C NMR (125 MHz, CDCl3): d ˆ 154.9, 153.9, 138.6, 138.4, 138.1,
136.6, 134.0, 130.0, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.5, 127.4,
124.1, 105.5, 100.7, 97.7, 86.0, 80.9, 78.2, 75.8, 75.8, 75.7, 75.3, 74.7, 73.6, 68.8,
66.0, 64.3, 56.1, 53.7, 36.6, 29.7, 23.4, 17.4; HRMS (FAB) calcd for
‡
29.7, 23.6, 21.2, 17.5; HRMS (FAB) calcd for C55H59NO9SCs [M ‡ Cs ]
1042.2965, found 1042.2919.
Benzyl-protected disaccharide lactols 37: To a solution of thioglycoside 36
(125 mg, 0.14 mmol) in acetone/H2O (10:1) (5.5 mL) at 08C was added N-
bromosuccinimide (40 mg, 0.21 mmol). After stirring for 0.5 h, the reaction
mixture was diluted with CH2Cl2 (150 mL) and washed with saturated
aqueous NaHCO3 (25 mL). The organic layer was dried (MgSO4),
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 60% ether in hexanes) to afford lactols 37 (97 mg, 85%,
a:b ca. 5:1) as a white foam. 37: Rf ˆ 0.38 (silica gel, 70% ether in hexanes);
IR (thin film): nÄmax ˆ 3410, 3088, 3064, 3031, 2929, 2870, 1723, 1714, 1538,
1514, 1504, 1360, 1270, 1243, 1212, 1129, 1065, 912, 737, 698 cm 1; 1H NMR
(600 MHz, CDCl3): d ˆ 7.34 ± 7.16 (m, 25H, ArH), 5.36 (br.d, J ˆ 3.1 Hz,
1H, H-G1), 5.10 (br.d, J ˆ 3.1 Hz, 1H, H-V1), 5.05 and 4.99 (AB, J ˆ
12.2 Hz, 2H, CH2Ar), 4.92 (s, 1H, NH), 4.85 and 4.80 (AB, J ˆ 11.0 Hz,
2H, CH2Ar), 4.65 ± 4.50 (AB, J ˆ 11.0, 12.0 Hz, 6H, CH2Ar), 4.22 (br.q, J ˆ
6.3 Hz, 1H, H-V5), 4.05 (ddd, J ˆ 10.0, 2.6, 2.6 Hz, 1H, H-G5), 3.96 (t, J ˆ
9.4 Hz, 1H, H-G3), 3.67 ± 3.62 (m, 2H, H-G6a, H-G6b), 3.59 ± 3.56 (m, 1H,
H-G2), 3.57 (t, J ˆ 9.5 Hz, 1H, H-G4), 3.09 (br.s, 1H, H-V4), 2.01 (dd, J ˆ
13.4, 4.6 Hz, 1H, H-V2a), 1.77 (d, J ˆ 14.0 Hz, 1H, H-V2b), 1.76 (s, 3H,
H-V3), 1.28 (d, J ˆ 6.5 Hz, 3H, H-V6); 13C NMR (150 MHz, CDCl3): d ˆ
154.8, 138.6, 138.2, 138.0, 137.9, 137.8, 136.5, 128.5, 128.4, 128.4, 128.3, 128.3,
128.1, 128.0, 127.9, 127.9, 127.8, 127.7, 127.7, 127.6, 127.6, 99.2, 92.9, 84.6, 83.4,
81.2, 80.2, 80.0, 77.8, 75.6, 75.6, 74.9, 73.4, 70.1, 68.8, 66.2, 65.1, 53.6, 36.5,
‡
C57H63NO12Cs [M ‡ Cs ] 1086.3405, found 1086.3450.
Benzoyl-protected disaccharide 34: A mixture of disaccharide 33 (20 mg,
0.021 mmol) and 10% Pd/C (ca. 10 mg) in EtOAc (2.0 mL) was stirred
under an atmosphere of H2 for 12 h at 258C. The reaction mixture was then
filtered through a pad of celite, concentrated, and azeotroped with benzene
(2 mL). The residue was dissolved in pyridine (1.0 mL), cooled to 08C and
treated with benzoyl chloride (21 mL, 0.15 mmol) for 6 h. The reaction
mixture was diluted with ether (100 mL) and washed with saturated
aqueous NH4Cl (3 Â 10 mL). The organic layer was dried (MgSO4),
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 50% ether in hexanes) to yield disaccharide 34 (19 mg,
85% for two steps) as a white foam. 34: 1H NMR (500 MHz, CDCl3): d ˆ
8.08 (d, J ˆ 7.0 Hz, 2H, ArH), 7.99 (d, J ˆ 7.0 Hz, 2H, ArH), 7.90 (d, J ˆ
7.0 Hz, 2H, ArH), 7.80 (d, J ˆ 7.0 Hz, 2H, ArH), 7.63 ± 7.23 (m, 17H, ArH),
7.04 (t, J ˆ 8.5 Hz, 1H, ArH), 6.59 (s, 1H, NH), 6.57 (d, J ˆ 8.0 Hz, 2H,
ArH), 5.85 (t, J ˆ 9.0 Hz, 1H, H-G3), 5.76 (t, J ˆ 10.0 Hz, 1H, H-G4), 5.43
(d, J ˆ 7.0 Hz, 1H, H-G1), 5.26 (d, J ˆ 4.5 Hz, 1H, H-V1), 5.12 (s, 1H,
H-V4), 4.80 (q, J ˆ 6.5 Hz, 1H, H-V5), 4.50 (dd, J ˆ 11.5, 3.6 Hz, 1H,
H-G6a), 4.40 (dd, J ˆ 8.0, 7.5 Hz, 1H, H-G2), 4.37 (dd, J ˆ 11.5, 6.0 Hz, 1H,
H-G6b), 4.05-3.98 (m, 1H, H-G5), 3.81 (s, 6H, OCH3), 2.70 (d, J ˆ 14.0 Hz,
1H, H-V2a), 2.03 (s, 3H, H-V3), 2.00 (dd, J ˆ 14.0, 4.5 Hz, 1H, H-V2b),
1.11 (d, J ˆ 6.0 Hz, 3H, H-V6); HRMS (FAB) calcd for C56H53NO16Cs
‡
23.9, 17.5; HRMS (FAB) calcd for C49H55NO10Cs [M ‡ Cs ] 950.2880, found
950.2848.
‡
[M ‡ Cs ] 1122.2464, found 1112.2441.
Glucose alcohol 35: NaOH (10 mg, powdered) was added to a solution of
thioglycoside (300 mg, 0.46 mmol) in MeOH (5.0 mL) at 258C. After
stirring for 3 h, the reaction mixture was diluted with ether (150 mL) and
washed with saturated aqueous NH4Cl (25 mL). The organic layer was
dried (MgSO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 30% ether in hexanes) to provide alcohol 35
(220 mg, 90%) as a white foam. 35: Rf ˆ 0.41 (silica gel, 50% ether in
Benzyl-protected disaccharide imidate 38: DBU (5.0 mL, 0.033 mmol) was
added to a solution of the disaccharide lactols 37 (133 mg, 0.16 mmol) and
trichloroacetonitrile (200 mL, 3.2 mmol) in CH2Cl2 at 08C. After 15 min,
the solvents were removed under reduced pressure and the residue was
purified by flash column chromatography (silica gel, 30% ether in hexanes)
to yield imidate 38 (136 mg, 90%). 38: 1H NMR (500 MHz, CDCl3): d ˆ
8.65 (s, 1H, NH), 7.32 ± 7.13 (m, 25H, ArH), 6.47 (d, J ˆ 3.5 Hz, 1H, H-G1),
5.12 (d, J ˆ 4.0 Hz, 1H, H-V1), 5.01 and 4.96 (AB, J ˆ 12.5 Hz, 2H, CH2 of
Cbz), 4.85 (s, 1H, NH), 4.85 ± 4.45 (AB, J ˆ 12.0, 11.0 Hz, 8H, CH2Ar), 4.08
(q, J ˆ 6.5 Hz, 1H, H-V5), 4.01 (t, J ˆ 9.5 Hz, 1H, H-G3), 3.97 ± 3.94 (m,
1H, H-G5), 3.81 (dd, J ˆ 8.5, 3.5 Hz, 1H, H-G2), 3.97 (t, J ˆ 9.5 Hz, 1H,
H-G4), 3.77 (dd, J ˆ 11.0, 3.0 Hz, 1H, H-G6a), 3.65 (dd, J ˆ 11.0, 1.5 Hz,
1H, H-G6b), 3.51 (s, 1H, H-V4), 1.86 (dd, J ˆ 13.5, 4.5 Hz, 1H, H-V2a),
1.75 (d, J ˆ 13.0 Hz, 1H, H-V2b), 1.66 (s, 3H, H-V3), 1.20 (d, J ˆ 6.5 Hz,
3H, H-V6).
hexanes); [a]2D2
ˆ
11.1 (c ˆ 2.9, CHCl3); IR (thin film): nÄmax ˆ 3444, 3062,
3030, 2868, 1584, 1496, 1453, 1440, 1360, 1285, 1209, 1058, 911, 818, 738,
697 cm 1; 1H NMR (600 MHz, CDCl3): d ˆ 7.62 ± 7.22 (m, 20H, ArH), 4.95
and 4.87 (AB, J ˆ 11.2 Hz, 2H, CH2Ar), 4.87 and 4.62 (AB, J ˆ 10.5 Hz, 2H,
CH2Ar), 4.65 and 4.58 (AB, J ˆ 12.0 Hz, 2H, CH2Ar), 4.54 (d, J ˆ 9.6 Hz,
1H, H-G1), 3.83 (d, J ˆ 10.2 Hz, 1H, H-G6a), 3.78 (dd, J ˆ 10.9, 4.5 Hz, 1H,
H-G6b), 3.66 ± 3.60 (m, 2H, H-G3, H-G4), 3.58 ± 3.51 (m, 2H, H-G2,
H-G5), 2.50 (s, 1H, OH); 13C NMR (150 MHz, CDCl3): d ˆ 138.4, 138.2,
2662
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2662 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 4
2648±2667
Chloroacetate-protected glucose imidate 39: Chloroacetyl chloride
(440 mL, 5.5 mmol) was added to a solution of 3,4,6-tri-O-benzyl glucose
(825 mg, 1.85 mmol) and pyridine (0.74 mL, 9.2 mmol) in ether (10 mL) at
788C. After warming to 258C and stirring for 18 h, the reaction mixture
was diluted with ether (200 mL) and washed with saturated aqueous
NaHCO3 (20 mL) and saturated aqueous NH4Cl (3 Â 15 mL). The organic
layer was dried (MgSO4), concentrated, and the residue was purified by
flash column chromatography (silica gel, 50% ether in hexanes) to yield the
di-chloroacetate (720 mg, 65%). n-Butylamine (150 mL, 1.5 mmol) was
added to a solution of the above di-chloroacetate (720 mg, 1.3 mmol) in
THF (4.0 mL) at 258C. After stirring for 0.5 h, the reaction mixture was
diluted with CH2Cl2 (200 mL) and washed with saturated aqueous NH4Cl
(3 Â 15 mL). The organic layer was dried (MgSO4), concentrated, and the
residue was purified by flash column chromatography (silica gel, 70% ether
in hexanes) to afford the lactols (540 mg, 80%) as a white foam. Lactols:
Rf ˆ 0.22 (silica gel, 50% ether in hexanes); IR (thin film): nÄmax ˆ 3306,
2995, 2945, 2872, 1725, 1659, 1538, 1495, 1454, 1361, 1313, 1260, 1198, 1151,
vacuum for 1 h. CH2Cl2 (0.3 mL) and 4 Š MS were added, and the mixture
was stirred for 15 min. The resulting mixture was cooled to 08C and BF3 ´
Et2O (40 mL, 0.5m solution in CH2Cl2, 0.020 mmol) was added dropwise.
After warming to 258C and stirring for 24 h, the reaction mixture was
diluted with EtOAc (150 mL) and washed with saturated aqueous NaHCO3
(20 mL) and brine (20 mL). The organic layer was dried (Na2SO4), filtered,
and the solvents were removed under reduced pressure. The residue was
purified by preparative TLC (silica gel, 4% MeOH in CH2Cl2) to afford
disaccharide 42 (0.7 mg, 5%) as an oil. 42: Rf ˆ 0.30 (silica gel, 4% MeOH
in CH2Cl2); 1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.47 ± 7.04 (m, 38H),
6.80 (d, J ˆ 8.4 Hz, 1H), 6.43 (s, 1H), 6.39 (s, 1H), 5.87 ± 4.63 (m, 24H),
4.40 ± 4.10 (m, 6H), 3.76 (s, 3H), 2.94 (s, 3H), 2.53 ± 2.45 (m, 2H), 1.95 ± 1.77
(m, 3H), 1.51 ± 1.48 (m, 2H), 1.28 (s, 3H), 1.03 ± 1.00 (m, 12H), 0.95 ± 0.89
(m, 6H), 0.89 (s, 9H), 0.86 (s, 9H), 0.76 (s, 9H), 0.67 (s, 9H), 0.24 (s, 12H),
0.19 (s, 3H), 0.14 (s, 6H), 0.09 (s, 6H), 0.03 (s, 3H), 0.06 (s, 3H); HRMS
‡
(FAB) calcd for
2793.0253.
C
141H183Cl2N9O28Si5Cs [M ‡ Cs ] 2793.0450, found
1
1092, 1048, 827, 741, 710 cm 1; H NMR (600 MHz, CDCl3): d ˆ 7.31 ± 7.16
Benzyl-protected vancomycin 42 (from disaccharide coupling): Aglycon
acceptor 6 (17 mg, 0.010 mmol) and imidate 38 (34 mg, 0.040 mmol) were
azeotroped with benzene (3 Â 3 mL) and then dried under high vacuum for
1 h. CH2Cl2 (0.5 mL) and 4 Š MS were added, and the mixture was stirred
for 15 min. The resulting mixture was cooled to 788C and BF3 ´ Et2O
(460 mL, 0.40 mmol) was added dropwise. The reaction mixture was
warmed slowly to 308C, stirred for 24 h, and then diluted with EtOAc
(150 mL), and washed with saturated aqueous NaHCO3 (20 mL) and brine
(20 mL). The organic layer was dried (Na2SO4), filtered, and the solvents
were removed under reduced pressure. The residue was purified by
preparative TLC (silica gel, 4% MeOH in CH2Cl2) to provide disaccharide
42 (19 mg, 70%) as an oil (spectroscopically identical with 42 as described
above).
(m, 15H, ArH), 5.38 (br.t, J ˆ 3.2 Hz, 1H, H-G2), 4.87 (br.d, J ˆ 3.4 Hz,
1H, H-G1), 4.82 and 4.72 (AB, J ˆ 11.5 Hz, 2H, CH2Ar), 4.79 and 4.50 (AB,
J ˆ 10.9 Hz, 2H, CH2Ar), 4.56 and 4.48 (AB, J ˆ 12.1 Hz, 2H, CH2Ar),
4.07-4.05 (m, 1H, H-G3), 3.96 and 3.81 (AB, J ˆ 15.2 Hz, 2H, CH2Cl), 3.69-
3.58 (m, 4H, H-G4, H-G5, H-G6a, H-G6b); 13C NMR (150 MHz, CDCl3):
d ˆ 165.9, 138.3, 137.8, 137.5, 128.4, 128.3, 128.3, 128.3, 128.3, 127.9, 127.8,
127.7, 127.6, 127.5, 95.0, 89.8, 79.6, 78.0, 75.4, 75.2, 74.9, 73.3, 69.8, 69.5, 40.6;
‡
HRMS (FAB) calcd for C29H31ClO7Cs [M ‡ Cs ] 659.0813, found 659.0828.
DBU (5.0 mL, 0.033 mmol) was added to a solution of the above glucose
lactols (420 mg, 0.76 mmol) and trichloroacetonitrile (0.60 mL, 7.4 mmol)
in CH2Cl2 at 308C. After the reaction mixture was stirred for 0.5 h, the
solvents were removed under reduced pressure, and the residue was
purified by flash column chromatography (silica gel, 35% ether in hexanes)
to afford imidate 39 (470 mg, 90%).
Benzylsilyl-protected vancomycin 43: Tetra-n-butylammonium fluoride
(50 mL, 1m solution in THF) was added to a solution of disaccharide 42
(5.0 mg, 0.002 mmol) in THF (300 mL) at 108C. After stirring for 2 h, the
reaction mixture was diluted with EtOAc (50 mL), washed with saturated
aqueous NaHCO3 (2 mL) and brine (2 mL). The organic layer was dried
(Na2SO4), filtered, and the solvents were removed under reduced pressure.
The residue was purified by preparative TLC (silica gel, 4% MeOH in
CH2Cl2) to yield disaccharide 43 as an oil.
Benzyl-protected vancomycin monosaccharide 40: Aglycon acceptor 6
(125 mg, 0.07 mmol) and imidate 39 (320 mg, 0.48 mmol) were azeotroped
with benzene (3 Â 3 mL), and then dried under high vacuum for 1 h. CH2Cl2
(0.5 mL) and 4 Š MS were added, and the mixture was stirred for 15 min.
The resulting mixture was cooled to 788C and BF3 ´ Et2O (253 mL, 1.06m
solution in CH2Cl2, 0.28 mmol) was added dropwise. The reaction mixture
was warmed slowly to 308C, and then stirred for 18 h. The reaction
mixture was diluted with EtOAc (150 mL), and washed with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried
(Na2SO4), filtered, and the solvents were removed under reduced pressure.
The residue was purified by preparative TLC (silica gel, 4% MeOH in
CH2Cl2) to afford b-glucoside 40 (116 mg, 70%) as an oil. 40: Rf ˆ 0.20
(silica gel, 4% MeOH in CH2Cl2); 1H NMR (600 MHz, CD3OD, 330 K):
d ˆ 7.55 ± 7.03 (m, 28H), 6.81 (d, J ˆ 8.5 Hz, 1H), 6.43 (s, 1H), 6.37 (s, 1H),
5.80 ± 4.36 (m, 20H), 4.26-3.50 (m, 8H), 3.76 (s, 3H), 2.96 (s, 3H), 2.42 ± 2.40
(m, 2H), 1.85 ± 1.82 (m, 1H), 1.60 ± 1.50 (m, 2H), 1.02 (s, 9H), 0.98 (s, 9H),
0.93 (s, 6H), 0.88 (s, 9H), 0.76 (s, 9H), 0.67 (s, 9H), 0.24 (s, 6H), 0.20 (s,
3H), 0.14 (s, 6H), 0.12 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.08
Dechloro-vancomycin methyl ester 44: A mixture of disaccharide 43
(2.0 mg, 0.002 mmol) and 10% palladium on carbon (ca. 5.0 mg) in MeOH
(1.0 mL) was stirred under an atmosphere of H2 (1 atm) for 24 h. The
reaction mixture was filtered through a pad of celite and taken directly to
‡
the next step. HRMS (MALDI) calcd for C67H77ClN9O24Na [M ‡ Na ]
1448.9826, found 1448.9809.
Dechloro-vancomycin 45: Lithium hydroxide (5.0 mg, excess) was added to
a solution of 44 (2.0 mg, 0.001 mmol) THF/H2O (1:1) (0.5 mL) at 08C.
After the reaction mixture was stirred for 20 min, the reaction was
quenched by the addition of saturated aqueous NH4Cl (1 mL), filtered, and
then the solvents were removed under reduced pressure. The residue was
purified by HPLC [(C18 reverse-phase column (HP-LiChroCART 4 Â
250 mm), gradient solvent system 0 ± 15 min, 5 ± 100% MeCN (0.1%
TFA) in H2O, flow rate 1.5 mLmin 1, 258C, retention time 5 min 38 s) to
yield dechloro-vancomycin 45. HRMS (MALDI) calcd for C66H75ClN9O24-
‡
(s, 3H); HRMS (FAB) calcd for C121H159Cl3N8O25Si5Na [M ‡ Na ]
2391.9225, found 2391.9144.
Benzyl-protected vancomycin monosaccharide acceptor 41: K2CO3
(8.0 mg, 0.06 mmol) was added to a solution of 40 (45 mg, 0.020 mmol) in
THF/MeOH (2:1) (1.0 mL) at 258C. After stirring for 10 min, the reaction
mixture was diluted with CH2Cl2 (150 mL), and washed with saturated
aqueous NH4Cl (20 mL) and brine (20 mL). The organic layer was dried
(Na2SO4) and the solvents were removed under reduced pressure. The
residue was purified by preparative TLC (silica gel, 4% MeOH in CH2Cl2)
to yield alcohol 41 (34 mg, 75%) as an oil. 41: Rf ˆ 0.20 (silica gel, 4%
MeOH in CH2Cl2); 1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.54 ± 7.04 (m,
28H), 6.81 (d, J ˆ 8.4 Hz, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 5.83 ± 4.38 (m,
20H), 4.26 ± 3.64 (m, 6H), 3.76 (s, 3H), 2.95 (s, 3H), 2.47 ± 2.44 (m, 2H),
1.84 ± 1.82 (m, 1H), 1.56 ± 1.53 (m, 2H), 1.02 (s, 9H), 0.96 (s, 9H), 0.92 (s,
6H), 0.88 (s, 9H), 0.76 (s, 9H), 0.65 (s, 9H), 0.24 (s, 6H), 0.20 (s, 3H), 0.14
(s, 3H), 0.13 (s, 3H), 0.11 (s, 6H), 0.10 (s, 3H), 0.05 (s, 3H), 0.07 (s, 3H);
‡
Na [M ‡ Na ] 1434.9670, found 1434.9701.
Mono-TBS-glucal 47: Potassium carbonate (100 mg, 0.7 mmol) was added
to a solution of triacetyl-glucal (15.0 g, 55.1 mmol) in MeOH (100 mL) at
258C and the resulting mixture was stirred for 12 h. The solvents were
removed under reduced pressure, the residue was azeotroped with toluene
(2 Â 50 mL), and then dried under high vacuum for 2 h. The residue was
dissolved in dry DMF (100 mL), cooled to 08C, and imidazole (8.0 g,
121 mmol) and TBSCl (8.3 g, 55.1 mmol) were added. After stirring for 1 h,
the reaction mixture was diluted with CH2Cl2 (500 mL) and washed with
H2O (50 mL). The organic layer was dried (Na2SO4), concentrated, and the
residue was purified by flash column chromatography (silica gel, ether) to
afford the diol (11.7 g, 82%) as a white foam. Diol: Rf ˆ 0.39 (silica gel,
ether); [a]2D2 ˆ ‡2.22 (c ˆ 1.6, CHCl3); IR (thin film): nÄmax ˆ 3363, 2953,
‡
HRMS (FAB) calcd for C119H158Cl2N8O24Si5Cs [M ‡ Cs ] 2427.8690, found
2427.8494.
2929, 2857, 1650, 1471, 1463, 1390, 1361, 1254, 1106, 1075, 1053, 940, 878,
1
Benzyl-protected vancomycin 42 (from monosaccharide coupling): Vancos-
amine fluoride 22 (20 mg, 0.05 mmol) and alcohol 41 (10 mg, 0.004 mmol)
were azeotroped with benzene (3 Â 3 mL) and then dried under high
836, 778, 672 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 6.31 (dd, J ˆ 6.0,
1.5 Hz, 1H, H-G1), 4.72 (dd, J ˆ 6.0, 2.0 Hz, 1H, H-G2), 4.30 ± 4.25 (m, 1H,
H-G3), 3.99 (dd, J ˆ 11.0, 3.0 Hz, 1H, H-G6a), 3.91 (dd, J ˆ 11.0, 4.0 Hz,
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2663 $ 17.50+.50/0
2663

K. C. Nicolaou et al.
FULL PAPER
1H, H-G6b), 3.82 ± 3.78 (m, 2H, H-G4, OH), 3.32 (s, 1H, H-G5), 2.69 (br.s,
1H, OH), 0.90 (s, 9H, tBuSi), 0.10 (s, 6H, CH3Si); 13C NMR (125 MHz,
CDCl3): d ˆ 144.2, 102.4, 76.6, 72.3, 69.2, 63.8, 25.8, 17.4, 5.4, 5.5; HRMS
by flash column chromatography (silica gel, 35% ether in hexanes) to
afford imidate 50 (1.05 g, 89%) as a colorless oil. 50: Rf ˆ 0.35 (silica gel,
30% ether in hexanes); 1H NMR (600 MHz, CDCl3, a:b ca. 14:1): d ˆ 8.64
(s, 1H, NH), 6.63 (d, J ˆ 3.6 Hz, 1H, H-G1), 5.93 ± 5.85 (m, 1H,
‡
(FAB) calcd for C12H24O4SiNa [M ‡ Na ] 283.1342, found 283.1336. Acetic
ˆ
OCH2CH CH2), 5.55 (t, J ˆ 9.9 Hz, 1H, H-G3), 5.32 (dd, J ˆ 17.0, 1.4 Hz,
anhydride (11.1 mL, 118 mmol) was added to a solution of the above diol
(12.3 g, 47.3 mmol), triethylamine (26.3 mL, 189 mmol) and 4-DMAP
(0.58 g, 4.7 mmol) in CH2Cl2 (500 mL) at 08C. After stirring 1 h at 258C,
the reaction mixture was washed with saturated aqueous NaHCO3
(100 mL), the organic layer was dried (Na2SO4), and the solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 30% ether in hexanes) to provide glucal 47
(15.8 g, 97%) as a colorless oil. 47: Rf ˆ 0.53 (silica gel, 50% ether in
ˆ
ˆ
1H, OCH2CH CH2-Z), 5.25 (dd, J ˆ 10.4, 1.1 Hz, 1H, OCH2CH CH2-E),
5.21 (t, J ˆ 9.9 Hz, 1H, H-G4), 4.94 (dd, J ˆ 10.2, 3.6 Hz, 1H, H-G2), 4.62 ±
ˆ
4.60 (m, 2H, OCH2CH CH2), 4.06 (ddd, J ˆ 10.2, 4.1, 2.2 Hz, 1H, H-G5),
3.79 (dd, J ˆ 11.7, 2.2 Hz, 1H, H-G6a), 3.69 (dd, J ˆ 11.7, 4.2 Hz, 1H,
H-G6b), 2.02 (s, 3H, COCH3), 0.86 (s, 9H, tBuSi), 0.02 (s, 3H, CH3Si), 0.01
(s, 3H, CH3Si); 13C NMR (150 MHz, CDCl3, a:b ca. 14:1): d ˆ 170.0, 169.4,
160.8, 154.0, 131.1, 119.1, 92.9, 73.2, 72.7, 70.1, 69.0, 68.2, 61.5, 25.8, 20.7, 18.2,
5.5.
hexanes); [a]2D2
ˆ
9.4 (c ˆ 5.1, CHCl3); IR (thin film): nÄmax ˆ 2954, 2943,
2857, 1742, 1650, 1599, 1472, 1372, 1242, 1105, 1045, 962, 837, 778, 679,
Mono-TBS-protected-2,6-dimethoxyphenolic glucoside 51: 2,6-Dimethox-
yphenol (25 mg, 0.16 mmol) and imidate 50 (180 mg, 0.27 mmol) were
azeotroped with benzene (3 Â 3 mL) and then dried under high vacuum for
1 h. CH2Cl2 (0.5 mL) and 4 Š MS were added, and the mixture was stirred
for 15 min. The resulting mixture was cooled to 788C and BF3 ´ Et2O
(21 mL, 0.16 mmol) was added dropwise. After stirring for 20 min, the
reaction mixture was diluted with EtOAc (150 mL), and washed with
saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer
was dried (Na2SO4), concentrated, and the residue was purified by flash
column chromatography (silica gel, 20% ether in hexanes) to afford b-
glucoside 51 (92 mg, 95%) as a white foam. 51: Rf ˆ 0.22 (silica gel, 50%
1
602 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 6.44 (dd, J ˆ 6.3, 1.5 Hz, 1H,
H-G1), 5.30 ± 5.29 (m, 1H, H-G3), 5.24 (dd, J ˆ 7.3, 5.6 Hz, 1H, H-G4), 4.75
(dd, J ˆ 6.2, 3.3 Hz, 1H, H-G2), 4.06 (ddd, J ˆ 9.6, 4.6, 4.6 Hz, 1H, H-G5),
3.79 ± 3.77 (m, 2H, H-G6), 2.03 (s, 3H, COCH3), 2.00 (s, 3H, COCH3), 0.86
(s, 9H, tBuSi), 0.03 (s, 6H, CH3Si); 13C NMR (125 MHz, CDCl3): d ˆ 170.5,
169.4, 145.9, 98.3, 76.6, 67.5, 61.2, 25.7, 21.0, 20.8, 18.2, 5.5; HRMS (FAB)
‡
calcd for C12H24O4SiNa [M ‡ Na ] 283.1342, found 283.1336.
Mono-TBS-glucose diol 48: Osmium tetroxide (0.5 mL, 2.5% solution in
tert-butyl alcohol) was added dropwise to a solution of glucal 47 (6.0 g,
22.6 mmol) and 4-methylmorpholine N-oxide (4.00 g, 33.9 mmol) in
acetone/H2O (9:1) (200 mL) at 258C and the resulting mixture was stirred
for 12 h. Saturated aqueous NaHCO3 (50 mL) was added and the solvents
were removed under reduced pressure. The residue was diluted with
CH2Cl2 (200 mL) and washed with brine (15 mL). The organic layer was
dried (MgSO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 75% ether in hexanes) to yield diol 48 (7.2 g,
84%) as a colorless oil. 48: Rf ˆ 0.15 (silica gel, 70% ether in hexanes); IR
(thin film): nÄmax ˆ 3435, 2958, 2924, 2857, 1753, 1463, 1432, 1366, 1251, 1151,
ether in hexanes); [a]D22 ˆ ‡13.7 (c ˆ 0.60, CHCl3); IR (thin film): nÄmax
ˆ
2931, 2856, 1759, 1734, 1601, 1480, 1366, 1296, 1259, 1234, 1113, 1062, 971,
1
832, 779 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 6.99 (t, J ˆ 8.5 Hz, 1H,
ˆ
ArH), 6.53 (d, J ˆ 8.5 Hz, 2H, ArH), 5.91 ± 5.84 (m, 1H, OCH2CH CH2),
ˆ
5.30 (br.dd, J ˆ 11.0, 1.3 Hz, 1H, OCH2CH CH2-Z), 5.28 (t, J ˆ 9.5 Hz, 1H,
ˆ
H-G3), 5.20 (br.dd J ˆ 10.5, 7.2 Hz, 1H, OCH2CH CH2-E), 5.13 (t, J ˆ
10.0 Hz, 1H, H-G4), 5.11 (d, J ˆ 8.0 Hz, 1H, H-G1), 5.03 (dd, J ˆ 9.0,
ˆ
7.5 Hz, 1H, H-G2), 4.65 ± 4.59 (m, 2H, OCH2CH CH2), 3.78 (s, 6H,
1
1087, 837, 778 cm 1; H NMR (500 MHz, CDCl3, major anomer): d ˆ 5.29
OCH3), 3.67 ± 3.65 (m, 2H, H-G6), 3.48 ± 3.44 (m, 1H, H-G5), 2.01 (s, 3H,
COCH3), 1.98 (s, 3H, COCH3), 0.79 (s, 9H, tBuSi), 0.01 (s, 3H, CH3Si),
0.09 (s, 3H, CH3Si); 13C NMR (125 MHz, CDCl3): d ˆ 170.3, 169.4, 154.0,
153.1, 134.2, 131.3, 124.7, 118.5, 105.3, 101.1, 75.8, 74.8, 68.7, 68.6, 62.2, 56.1,
56.0, 25.6, 20.6, 18.1, 15.1, 5.7, 5.8; HRMS (FAB) calcd for C28H42O12-
(t, J ˆ 6.5 Hz, 1H, H-G1), 5.25 (t, J ˆ 9.7 Hz, 1H, H-G3), 4.97 (t, J ˆ 9.7 Hz,
1H, H-G4), 4.15 (br.s, 1H, OH), 4.03 (ddd, J ˆ 10.1, 3.5, 3.5 Hz, 1H, H-G5),
3.72 ± 3.62 (m, 3H, H-G2, H-G6a, H-G6b), 2.66 (br.s, 1H, OH), 2.06 (s, 3H,
COCH3), 2.03 (s, 3H, COCH3), 0.88 (s, 9H, tBuSi), 0.04 (s, 6H, CH3Si);
13C NMR (125 MHz, CDCl3, major anomer): d ˆ 171.6, 169.6, 96.7, 92.2,
76.8, 75.0, 74.8, 73.7, 73.4, 71.0, 70.2, 68.9, 68.6, 62.6, 62.4, 25.9, 25.9, 20.9,
‡
SiCs [M ‡ Cs ] 731.1500, found 731.1526.
Mono-TBS-alcohol 52: A catalytic amount of palladium tetrakistriphenyl-
phosphane (ca. 10 mg, 0.01 mmol) was added to a solution of b-glucoside 51
(110 mg, 0.18 mmol) and tri-n-butyltin hydride (74 mL, 0.27 mmol) in wet
CH2Cl2 (5.0 mL) at 258C. After the reaction mixture was stirred for 0.5 h,
the solvents were removed under reduced pressure, and the residue was
purified by flash column chromatography (silica gel, 30% ether in hexanes)
to afford 52 (79 mg, 83%) as a white foam. 52: Rf ˆ 0.2 (silica gel, 70%
‡
20.7, 18.4, 5.4; HRMS (FAB) calcd for C18H30O5SiNa [M ‡ Na ] 401.1608,
found 401.1621.
Alloc-protected lactol 49: Di-n-butyltin oxide (960 mg, 3.9 mmol) was
added to a solution of diol 48 (1.21 g, 3.2 mmol) in toluene (150 mL) at
258C and the resulting solution was refluxed with removal of H2O with a
Dean ± Stark apparatus for 6 h. The reaction mixture was cooled to 08C,
and Alloc-Cl (360 mL, 3.3 mmol) was added dropwise. After stirring for
0.5 h, the reaction mixture was diluted with CH2Cl2 (100 mL) and washed
with brine (15 mL). The organic layer was dried (MgSO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
35% ether in hexanes) to afford the lactol 49 (840 mg, 67%,) as a white
ether in hexanes); [a]D22 ˆ ‡ 14.0 (c ˆ 4.7, CHCl3); IR (thin film): nÄmax
ˆ
3453, 2929, 2860, 2856, 1755, 1734, 1718, 1600, 1480, 1474, 1444, 1367, 1299,
1256, 1113, 998, 838, 777 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.03 (t, J ˆ
8.4 Hz, 1H, ArH), 6.58 (d, J ˆ 8.4 Hz, 2H, ArH), 5.15 (t, J ˆ 9.5 Hz, 1H,
H-G3), 5.04 (t, J ˆ 9.5 Hz, 1H, H-G4), 4.68 (d, J ˆ 7.8 Hz, 1H, H-G1),
3.92 ± 3.90 (m, 1H, OH), 3.85 ± 3.83 (m, 7H, OCH3, H-G2), 3.74 ± 3.67 (m,
2H, H-G6), 3.50 ± 3.44 (m, 1H, H-G5), 2.07 (s, 3H, COCH3), 1.99 (s, 3H,
COCH3), 0.85 (s, 9H, tBuSi), 0.03 (s, 3H, CH3Si), 0.02 (s, 3H, CH3Si);
13C NMR (125 MHz, CDCl3): d ˆ 170.7, 169.5, 152.8, 135.2, 125.0, 105.5,
105.4, 105.4, 105.3, 75.3, 74.8, 72.5, 68.9, 66.7, 65.8, 62.6, 56.2, 56.2, 30.2, 27.7,
26.7, 25.7, 20.8, 20.7, 18.2, 17.4, 13.5, 5.6, 5.7; HRMS (FAB) calcd for
foam. 49: Rf ˆ 0.27 (silica gel, 50% ether in hexanes); IR (thin film): nÄmax
ˆ
3468, 2945, 2930, 2885, 2857, 1759, 1462, 1432, 1367, 1233, 1157, 1055, 1007,
970, 837, 784 cm 1; 1H NMR (500 MHz, CDCl3, a:b ca. 3:1): d ˆ 5.94 ± 5.87
ˆ
(m, 1.3H, OCH2CH CH2), 5.52 (t, J ˆ 9.6 Hz, 1H, H-G3), 5.49 (t, J ˆ
ˆ
3.6 Hz, 1H, H-G1), 5.34 (br.dd, J ˆ 15.8, 1.3 Hz, 1.3H, OCH2CH CH2-
ˆ
Z), 5.26 (br.dd, J ˆ 10.4, 1.0 Hz, 1.3H, OCH2CH CH2-E), 5.24 (t, J ˆ
‡
9.6 Hz, 0.3H, H-G3), 5.09 (t, J ˆ 9.6 Hz, 0.3H, H-G4), 5.05 (t, J ˆ 9.6 Hz,
1H, H-G4), 4.76 (t, J ˆ 8.0 Hz, 0.3H, H-G2b), 4.73 (dd, J ˆ 10.3, 3.6 Hz,
C24H38O10SiNa [M ‡ Na ] 537.2132, found 537.2148.
Mono-TBS-disaccharide 53: Vancosamine fluoride 27 (82 mg, 0.22 mmol)
and alcohol 52 (79 mg, 0.15 mmol) were azeotroped with benzene (3 Â
3 mL) and then dried under high vacuum for 1 h. CH2Cl2 (0.6 mL) and 4 Š
MS were added, and the mixture was stirred for 15 min. The resulting
mixture was cooled to 308C and BF3 ´ Et2O (18 mL, 0.13 mmol) was added
dropwise. After stirring for 2 h, the reaction mixture was diluted with
EtOAc (150 mL) and washed with saturated aqueous NaHCO3 (20 mL)
and brine (20 mL). The organic layer was dried (Na2SO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
30% ether in hexanes) to give disaccharide 53 (116 mg, 91%, a:b ca. 9:1) as
ˆ
1H, H-G2a), 4.66 ± 4.56 (m, 2.6H, OCH2CH CH2), 4.10 (ddd, J ˆ 10.1, 3.4,
3.4 Hz, 1.3H, H-G5), 3.75 ± 3.70 (m, 0.3H, OH), 3.70-3.68 (m, 2.6H, H-G6),
3.57 (ddd, J ˆ 9.9, 4.6, 2.4 Hz, 0.3H, H-G5b), 3.45 (d, J ˆ 3.7 Hz, 1H, OH),
2.01 (s, 3.9H, COCH3), 2.00 (s, 3.9H, COCH3), 0.88 (s, 11.7H, tBuSi), 0.04
(s, 3.9H, CH3Si), 0.03 (s, 3.9H, CH3Si); 13C NMR (125 MHz, CDCl3, a:b ca.
3:1): d ˆ 170.3, 170.2, 169.6, 169.4, 154.8, 154.1, 131.1, 131.1, 119.2, 119.1,
95.2, 89.9, 76.8, 74.8, 74.3, 72.4, 70.2, 69.8, 69.0, 68.9, 62.2, 62.1, 25.9, 25.8,
20.7, 20.6, 18.4, 4.0, 5.4, 5.5, 5.7; HRMS (FAB) calcd for C20H34O10-
‡
SiNa [M ‡ Na ] 485.1819, found 485.1805.
Mono-TBS-glucose imidate 50: DBU (5.0 mL, 0.033 mmol) was added to a
solution of lactol 49 (950 mg, 2.1 mmol) and trichloroacetonitrile (3.3 mL,
41.1 mmol) in CH2Cl2 (50 mL) at 108C. After stirring for 20 min, the
solvents were removed under reduced pressure. The residue was purified
a white foam. 53: Rf ˆ 0.2 (silica gel, 70% ether in hexanes); [a]D22
ˆ
54.8
(c ˆ 1.3, CHCl3); IR (thin film): nÄmax ˆ 3379, 2935, 2871, 1747, 1600, 1514,
1
1495, 1480, 1372, 1255, 1219, 1113, 1061, 1032, 912, 838, 777, 734 cm
1H NMR (600 MHz, CDCl3): d ˆ 7.36 ± 7.30 (m, 5H, ArH), 6.99 (t, J ˆ
;
2664
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2664 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 4
2648±2667
8.4 Hz, 1H, ArH), 6.55 (d, J ˆ 8.4 Hz, 2H, ArH), 5.28 (d, J ˆ 7.4 Hz, 1H,
H-G1), 5.25 (t, J ˆ 9.1 Hz, 1H, H-G3), 5.09 (br.d, J ˆ 4.6 Hz, 1H, H-V1),
5.08 and 4.95 (AB, J ˆ 12.2 Hz, 2H, CH2Ar), 5.07 (t, J ˆ 9.6 Hz, 1H, H-G4),
4.89 (s, 1H, H-V4), 4.72 (s, 1H, NH), 4.51 (br.q, J ˆ 6.3 Hz, 1H, H-V5), 3.99
(dd, J ˆ 8.9, 7.5 Hz, 1H, H-G2), 3.78 (s, 6H, OCH3), 3.60 ± 3.58 (m, 2H,
H-G6), 3.47 ± 3.42 (m, 1H, H-G5), 2.10 (d, J ˆ 13.4 Hz, 1H, H-V2a), 2.04 (s,
3H, COCH3), 2.03 (s, 3H, COCH3), 1.99 (s, 3H, COCH3), 1.94 (dd, J ˆ 13.5,
4.6 Hz, 1H, H-V2b), 1.79 (s, 3H, H-V3), 0.95 (d, J ˆ 6.4 Hz, 3H, H-V6),
0.76 (s, 9H, tBuSi), 0.06 (s, 3H, CH3Si), 0.19 (s, 3H, CH3Si); 13C NMR
(150 MHz, CDCl3): d ˆ 171.2, 171.1, 169.7, 153.4, 136.6, 133.3, 128.5, 128.2,
128.1, 128.0, 124.2, 105.4, 99.9, 97.7, 76.1, 74.8, 74.1, 69.2, 63.3, 62.6, 55.9,
55.8, 53.1, 33.8, 30.3, 25.7, 20.8, 20.8, 20.7, 18.1, 16.7, 5.8; HRMS (FAB),
(t, J ˆ 9.0 Hz, 1H, H-G3), 5.14 ± 4.73 (m, 9.9H, H-V1, H-V1, NH, H-G3,
H-G4, H-V4, H-V4, CH2Ar), 4.93 (t, J ˆ 9.0 Hz, 1H, H-G4), 4.75 ± 4.73 (m,
2.7H, H-V5, H-V5), 4.67 (d, J ˆ 9.7 Hz, 1H, H-G1), 4.62 (d, J ˆ 9.9 Hz, 1H,
H-G1), 3.78 (dd, J ˆ 9.0, 8.8 Hz, 1H, H-G2), 3.73 (dd, J ˆ 9.0, 8.8 Hz, 1.7H,
H-G2), 3.69 ± 3.64 (m, 3.4H, H-G6a, H-G6b, H-G6a, H-G6b), 3.56 ± 3.50
(m, 2.7H, H-G5, H-G5), 2.02 (s, 3H, COCH3), 2.01 (s, 2.1H, COCH3), 2.01
(s, 2.1H, COCH3), 1.99 (s, 3H, COCH3), 2.10-1.92 (m, 2H, H-V2), 1.67 (s,
3H, H-V3), 1.60 (s, 3H, H-V3), 1.53 (dd, J ˆ 12.3, 10.0 Hz, 0.7H, H-V2a),
1.38 (d, J ˆ 6.4 Hz, 3H, H-V6), 1.06 (d, J ˆ 6.4 Hz, 2.1H, H-V6), 0.90 (s,
6.3H, tBuSi), 0.87 (s, 9H, tBuSi), 0.06 (s, 2.1H, CH3Si), 0.04 (s, 3H, CH3Si),
0.04 (s, 3H, CH3Si), 0.04 (s, 2.1H, CH3Si), 0.01 (s, 3H, CH3Si); 13C NMR
(150 MHz, CDCl3): d ˆ 170.8, 170.4, 170.3, 169.8, 169.6, 169.4, 136.5, 133.6,
133.1, 131.7, 131.5, 129.0, 129.0, 128.4, 128.3, 128.1, 128.1, 128.0, 127.7, 128.6,
98.8, 97.9, 87.3, 87.1, 78.8, 78.6, 77.3, 76.5, 75.4, 74.6, 73.8, 72.1, 68.8, 68.4, 68.1,
64.3, 62.5, 62.3, 62.3, 54.04, 52.7, 30.3, 25.8, 23.9, 20.9, 20.7, 20.6, 20.5, 18.2,
‡
calcd for C41H59NO15SiCs [M ‡ Cs ] 966.2708, found 966.2746.
Mono-TBS-thioglucoside 54: Thiophenol (32 mL, 0.31 mmol) was added to
a solution of imidate 50 (120 mg, 0.21 mmol) in CH2Cl2 (0.5 mL) containing
4 Š MS and the mixture was stirred at ambient temperature for 15 min. The
‡
17.4, 16.9, 13.5, 5.5; HRMS (FAB) calcd for C39H55NO12SSiCs [M ‡ Cs ]
922.2269, found 922.2239.
resulting mixture was cooled to
788C and BF3 ´ Et2O (8.0 mL,
0.062 mmol) was added dropwise. After stirring for 45 min, the reaction
mixture was diluted with EtOAc (150 mL), and washed with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried
(Na2SO4), filtered, and the solvents were removed under reduced pressure.
The residue was purified by flash column chromatography (silica gel, 30%
ether in hexanes) to afford b-thioglucoside 54 (110 mg, 95%) as a white
foam. 54: Rf ˆ 0.30 (silica gel, 50% ether in hexanes); [a]2D2 ˆ ‡15.7 (c ˆ
Mono-TBS-protected vancomycin monosaccharide 57: Glucose imidate 50
(310 mg, 0.54 mmol) and aglycon acceptor 6 (200 mg, 0.11 mmol) were
azeotroped with benzene (3 Â 3 mL) and then dried under high vacuum for
1 h. CH2Cl2 (1.5 mL) and 4 Š MS were added, and the mixture was stirred
at ambient temperature for 15 min. The resulting mixture was cooled to
788C and BF3 ´ Et2O (160 mL, 1.1 mmol) was added dropwise. After
stirring for 6 h at 788C, the reaction mixture was diluted with EtOAc
(150 mL) and washed with saturated aqueous NaHCO3 (20 mL) and brine
(20 mL). The organic layer was dried (Na2SO4), filtered and the solvents
were removed under reduced pressure. The residue was purified by flash
column chromatography (silica gel, 10 !30% acetone in CH2Cl2, gradient
elution), followed by preparative TLC (silica gel, 3% MeOH in CH2Cl2) to
afford b-glucoside 57 (203 mg, 82%) as a white foam. 57: Rf ˆ 0.33 (silica
gel, 5% MeOH in CH2Cl2); [a]D22 ˆ ‡7.9 (c ˆ 0.3, CHCl3); IR (thin film):
nÄmax ˆ 3550, 2956, 2929, 2874, 2857, 1760, 1691, 1667, 1644, 1599, 1504, 1471,
1.3, CHCl3); IR (thin film): nÄmax ˆ 2954, 2930, 2884, 2857, 1760, 1462, 1440,
1
1369, 1259, 1230, 1052, 1005, 967, 912, 837, 781, 748, 692 cm
;
1H NMR
(600 MHz, CDCl3): d ˆ 7.55 ± 7.20 (m, 5H, ArH), 5.95 ± 5.85 (m, 1H,
ˆ
ˆ
OCH2CH CH2), 5.36 (ddd, J ˆ 17.0, 2.8, 1.3 Hz, 1H, OCH2CH CH2-Z),
ˆ
5.26 (ddd J ˆ 10.3, 2.4, 1.1 Hz, 1H, OCH2CH CH2-E), 5.25 ± 5.22 (m, 1H,
H-G2), 5.02 (t, J ˆ 9.8 Hz, 1H, H-G3), 4.73 (d, J ˆ 6.4 Hz, 1H, H-G1),
ˆ
4.73 ± 4.68 (m, 1H, H-G4), 4.65 ± 4.64 (m, 2H, OCH2CH CH2), 3.73 (dd,
J ˆ 11.5, 2.2 Hz, 1H, H-G6a), 3.68 (dd, J ˆ 11.5, 5.1 Hz, 1H, H-G6b), 3.57
(ddd, J ˆ 9.9, 5.0, 2.2 Hz, 1H, H-G5), 1.99 (s, 3H, COCH3), 1.97 (s, 3H,
COCH3), 0.88 (s, 9H, tBuSi), 0.06 (s, 3H, CH3Si), 0.03 (s, 3H, CH3Si);
13C NMR (150 MHz, CDCl3): d ˆ 170.0, 169.2, 153.7, 132.9, 131.7, 131.2,
128.8, 128.2, 118.8, 85.4, 78.8, 74.1, 73.7, 68.8, 68.5, 62.2, 25.8, 20.6, 18.2, 15.2,
1
1416, 1362, 1307, 1234, 1172, 1111, 1062, 948, 923, 837, 781 cm 1; H NMR
(500 MHz, CD3CN, 330 K): d ˆ 7.57 ± 7.54 (m, 2H), 7.50 7.31 (m, 9H), 7.27
(s, 2H), 7.10 (s, 1H), 6.94 (s, 3H), 6.46 (d, J ˆ 2.2 Hz, 1H), 6.34 (d, J ˆ
2.2 Hz, 1H), 6.32 (br.s, 1H), 6.10 ± 6.02 (m, 2H), 5.79 (s, 2H), 5.56 (s, 2H),
5.48 (t, J ˆ 9.5 Hz, 1H), 5.49 ± 5.42 (m, 3H), 5.35 (t, J ˆ 9.5 Hz, 1H), 5.32-
5.16 (m, 5H), 5.01 (dd, J ˆ 17.3, 1.4 Hz, 1H), 4.96 (d, J ˆ 10.6 Hz, 1H),
4.95 ± 4.80 (m, 4H), 4.57 (s, 1H), 4.45 (dd, J ˆ 12.9, 6.0 Hz, 1H), 4.27 (dd,
J ˆ 12.8, 5.4 Hz, 1H), 3.96 ± 3.94 (m, 1H), 3.83 ± 3.80 (m, 1H), 3.73 (s, 3H),
3.73 ± 3.70 (m, 1H), 3.66 (dd, J ˆ 10.3, 1.9 Hz, 1H), 2.92 (s, 3H), 2.41 ± 2.31
(m, 2H), 2.01 (s, 3H), 1.99 (s, 3H), 1.78 (br.t, J ˆ 10.2 Hz, 1H), 1.61 ± 1.40
(m, 2H), 1.02 (s, 9H), 0.96 (s, 9H), 0.94 ± 0.91 (m, 6H), 0.88 (s, 9H), 0.76 (s,
9H), 0.74 (s, 9H), 0.61 (s, 9H), 0.24 (s, 6H), 0.19 (s, 3H), 0.15 (s, 3H), 0.13
(s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.04 (s, 3H), 0.5 (s, 3H),
0.10 (s, 3H), 0.15 (s, 3H); 13C NMR (150 MHz, CD3CN, 330 K): d ˆ
172.2, 172.1, 171.8, 171.3, 171.1, 171.0, 170.7, 170.3, 170.1, 169.1, 167.9, 167.8,
156.5, 155.7, 154.8, 154.5, 154.3, 153.1, 151.8, 151.5, 141.4, 139.6, 137.9, 137.4,
136.7, 136.7, 136.5, 135.6, 132.3, 129.3, 129.3, 128.9, 128.9, 128.9, 128.9, 128.8,
128.8, 128.2, 127.3, 126.9, 126.4, 126.0, 125.5, 124.5, 121.3, 118.7, 113.1, 112.1,
106.2, 105.1, 76.7, 74.5, 74.4, 74.1, 73.6, 70.2, 69.2, 68.2, 66.0, 64.5, 63.5, 60.4,
60.1, 57.7, 57.6, 57.6, 55.3, 55.3, 55.2, 52.6, 52.5, 37.1, 30.2, 26.3, 26.3, 26.1, 26.1,
26.1, 26.1, 26.1, 26.1, 26.0, 26.0, 25.7, 25.7, 25.7, 25.7, 25.7, 25.7, 25.3, 23.6, 22.1,
21.0, 20.8, 19.0, 18.9, 18.8, 18.8, 18.4, 18.3, 3.9, 4.0, 4.2, 4.3, 4.5,
‡
5.5; HRMS (FAB) calcd for C26H38O9SSiNa [M ‡ Na ] 577.1904, found
577.1922.
Mono-TBS-alcohol 55: A catalytic amount of palladium tetrakistriphenyl-
phosphane (ca. 10 mg, 0.01 mmol) was added to a solution of b-glucoside 54
(90 mg, 0.16 mmol) and tri-n-butyltin hydride (65 mL, 0.24 mmol) in wet
CH2Cl2 (5.0 mL) at 258C. After the reaction mixture was stirred for 0.5 h,
the solvents were removed under reduced pressure, and the residue was
purified by flash column chromatography (silica gel, 30% ether in hexanes)
to provide 55 (66 mg, 87%) as a white foam. 55: Rf ˆ 0.30 (silica gel, 70%
ether in hexanes); [a]2D2 ˆ ‡6.2 (c ˆ 3.3, CHCl3); IR (thin film): nÄmax ˆ 3478,
3061, 2929, 2857, 1760, 1733, 1714, 1584, 1470, 1441, 1372, 1254, 1043, 914,
1
835, 776 cm 1; H NMR (600 MHz, CDCl3): d ˆ 7.59 ± 7.25 (m, 5H, ArH),
5.10 (t, J ˆ 9.3 Hz, 1H, H-G3), 4.96 (t, J ˆ 9.8 Hz, 1H, H-G4), 4.96 (d, J ˆ
9.7 Hz, 1H, H-G1), 3.74 (dd, J ˆ 11.4, 2.2 Hz, 1H, H-G6a), 3.67 (dd, J ˆ
11.5, 5.1 Hz, 1H, H-G6b), 3.56 (ddd, J ˆ 10.0, 5.1, 2.2 Hz, 1H, H-G5), 3.48 ±
3.44 (m, 1H, H-G2), 2.65 (d, J ˆ 3.2 Hz, 1H, OH), 2.03 (s, 3H, COCH3),
1.99 (s, 3H, COCH3), 0.89 (s, 9H, tBuSi), 0.06 (s, 3H, CH3Si), 0.04 (s, 3H,
CH3Si); 13C NMR (150 MHz, CDCl3): d ˆ 170.9, 169.5, 133.1, 131.0, 129.0,
128.3, 87.8, 78.9, 76.2, 70.1, 68.4, 62.3, 25.8, 20.8, 20.6, 18.2, 17.5, 15.2, 13.5,
4.5,
4.7,
4.7,
4.9,
4.9,
5.4,
5.5; HRMS (FAB) calcd for
‡
‡
C112H162Cl2N8O28Si6Cs [M ‡ Cs ] 2440.8874, found 2440.8738.
5.4; HRMS (FAB) calcd for C22H34O7SSiNa [M ‡ Na ] 493.1692, found
493.1681.
Mono-TBS-protected vancomycin monosaccharide acceptor 58: A cata-
lytic amount of palladium tetrakistriphenylphosphane (ca. 10 mg,
0.01 mmol) was added to a solution of the b-glucoside 57 (100 mg,
0.040 mmol) and tri-n-butyltin hydride (44 mL, 0.16 mmol) in wet CH2Cl2
(0.5 mL) at 258C. After the reaction mixture was stirred for 0.5 h, the
solvents were removed under reduced pressure, and the residue was
purified by flash column chromatography (silica gel, 10 !30% acetone in
CH2Cl2), followed by preparative TLC (silica gel, 3% MeOH in CH2Cl2) to
provide alcohol 58 (76 mg, 85%) as a white foam. 58: Rf ˆ 0.34 (silica gel,
Mono-TBS-disaccharide 56: Vancosamine fluoride 27 (76 mg, 0.22 mmol)
and alcohol 55 (66 mg, 0.162 mmol) were azeotroped with benzene (3 Â
3 mL) and then dried under high vacuum for 1 h. CH2Cl2 (0.6 mL) and 4 Š
MS were added, and the mixture was stirred at ambient temperature for
15 min. The resulting mixture was cooled to 308C and BF3 ´ Et2O (16 mL,
0.12 mmol) was added dropwise. After stirring for 2 h, the reaction mixture
was diluted with EtOAc (150 mL) and washed with saturated aqueous
NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4)
and the solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (silica gel, 30% ether in hexanes)
to afford disaccharide 56 (109 mg, 98%, a:b ca. 3:2) as a white foam. 56:
5% MeOH in CH2Cl2); [a]D22
3306, 2956, 2876, 2858, 1755, 1682, 1651, 1599, 1504, 1491, 1470, 1416, 1299,
1254, 1175, 1112, 1051, 1026, 838, 781cm
ˆ
4.0 (c ˆ 1.5, CHCl3); IR (thin film): nÄmax ˆ
;
1H NMR (600 MHz, CD3CN,
1
Rf ˆ 0.24 (silica gel, 70% ether in hexanes); IR (thin film): nÄmax ˆ 3369,
340 K): d ˆ 7.55 ± 7.52 (m, 2H), 7.46 ± 7.38 (m, 7H), 7.35 (d, J ˆ 7.2 Hz, 1H),
7.30 (s, 1H), 7.26 (br.s, 2H), 7.11 (s, 2H), 6.96 (s, 2H), 6.87 (br.s, 2H), 6.62
(br.s, 1H), 6.47 (d, J ˆ 2.2 Hz, 1H), 6.35 (d, J ˆ 2.2 Hz, 1H), 6.35 ± 6.33 (m,
1
2931, 2857, 1734, 1520, 1462, 1448, 1372, 1240, 1058, 913, 839, 778, 775 cm
;
1H NMR (600 MHz, CDCl3, a:b ca. 3:2): d ˆ 7.53 ± 7.26 (m, 17H, ArH), 5.21
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2665 $ 17.50+.50/0
2665

K. C. Nicolaou et al.
FULL PAPER
2H), 6.02 (br.s, 1H), 5.85 (s, 1H), 5.56 (s, 1H), 5.45 (d, J ˆ 4.5 Hz, 1H), 5.34
(t, J ˆ 9.6 Hz, 1H, H-G3), 5.33 (s, 1H), 5.25 (d, J ˆ 7.7 Hz, 1H, H-G1), 5.20
(t, J ˆ 9.7 Hz, 1H, H-G4), 4.95 ± 4.84 (m, 6H), 4.61 (s, 1H), 4.03 (br.t, J ˆ
7.7 Hz, 1H, H-G2), 3.99 ± 3.95 (m, 1H), 3.87 ± 3.86 (m, 1H, H-G5), 3.82 (s,
1H), 3.74 (s, 3H, OCH3), 3.75 ± 3.73 (m, 1H, H-G6a), 3.68 (dd, J ˆ 11.0,
3.2 Hz, 1H, H-G6b), 2.92 (s, 3H, NCH3), 2.49 ± 2.23 (m, 2H, H-3b), 2.06 (s,
3H, COCH3), 2.02 (s, 3H, COCH3), 1.78 ± 1.75 (m, 1H, H-1b), 1.57 ± 1.51
(m, 2H, H-1b, H-1g), 1.03 (s, 9H, tBuSi), 0.96 (s, 9H, tBuSi), 0.94 ± 0.92 (m,
6H, H-1d), 0.89 (s, 9H, tBuSi), 0.77(s, 9H, tBuSi), 0.75 (s, 9H, tBuSi), 0.63
(s, 9H, tBuSi), 0.25 (s, 6H, CH3Si), 0.20 (s, 3H, CH3Si), 0.15 (s, 3H, CH3Si),
0.13 (s, 3H, CH3Si), 0.12 (s, 3H, CH3Si), 0.12 (s, 3H, CH3Si), 0.09 (s, 3H,
CH3Si), 0.04 (s, 3H, CH3Si), 0.05 (s, 3H, CH3Si), 0.10 (s, 3H, CH3Si),
0.12 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3CN, 340 K): d ˆ 172.3,
172.2, 171.8, 171.4, 171.2, 171.1, 170.2, 169.1, 167.8, 167.8, 156.5, 155.8, 154.4,
152.9, 151.5, 151.4, 141.6, 139.9, 138.0, 137.1, 136.8, 136.7, 136.5, 136.3, 136.3,
135.5, 132.6, 132.6, 130.6, 130.2, 129.4, 129.3, 129.3, 129.3, 129.2, 128.7, 128.7,
128.7, 128.2, 128.1, 127.4, 126.9, 126.4, 126.3, 125.2, 124.5, 121.3, 113.1, 112.1,
107.0, 106.3, 81.3, 76.2, 75.0, 74.4, 73.6, 73.5, 70.3, 68.2, 63.6, 60.7, 57.8, 57.7,
57.6, 55.3, 52.6, 52.4, 30.6, 30.3, 26.3, 26.3, 26.3, 26.2, 26.2, 26.2, 26.1, 26.1,
26.1, 26.0, 26.0, 26.0, 25.6, 25.6, 25.6, 25.4, 23.3, 22.1, 21.1, 20.9, 18.9, 18.9,
18.8, 18.7, 18.3, 18.3, 3.9, 4.0, 4.3, 4.3, 4.5, 4.5, 4.7, 4.8, 4.9,
4.9, 5.3, 5.3; HRMS (MALDI) calcd for C108H158Cl2N8O26Si6Cs [M ‡
MeOH in CH2Cl2); [a]D22
3401, 3290, 2943, 1725, 1713, 1678, 1666, 1642, 1501, 1455, 1419, 1396, 1372,
1320, 1226, 1063, 1032 cm
ˆ
3.94 (c ˆ 0.33, CHCl3); IR (thin film): nÄmax ˆ
;
1H NMR (600 MHz, CD3CN/D2O (20:1),
1
340 K): d ˆ 7.62 (s, 1H, H-6b), 7.50 ± 7.45 (m, 1H), 7.41 ± 7.27 (m, 13H), 7.13
(d, J ˆ 8.3 Hz, 1H), 7.10 (d, J ˆ 2.2 Hz, 1H), 6.97 (dd, J ˆ 8.5, 2.3 Hz, 1H),
6.88 (d, J ˆ 8.6 Hz, 1H), 6.51 (d, J ˆ 2.2 Hz), 6.24 (d, J ˆ 2.2 Hz, 1H), 5.79
(s, 1H), 5.65 (s, 1H), 5.53 (d, J ˆ 7.6 Hz, 1H), 5.40 (s, 1H), 5.33 (s, 2H),
5.21 ± 5.17 (m, 2H), 5.18 (t, J ˆ 9.2 Hz, 1H), 5.11 (d, J ˆ 4.3 Hz, 1H), 4.98
and 4.85 (AB, J ˆ 12.5 Hz, 2H), 4.98 (s, 1H), 4.88 ± 4.86 (m, 1H), 4.80-4.77
(m, 3H), 4.69 (s, 1H), 4.56 (s, 1H), 4.24 (dd, J ˆ 12.2, 4.2 Hz, 1H), 4.20 (dd,
J ˆ 11.9, 2.0 Hz, 1H), 4.06 (s, 1H), 3.91 (bt, J ˆ 8.8 Hz, 1H), 3.80 (s, 3H,
OCH3), 3.78 ± 3.74 (m, 1H), 2.89 (s, 3H, NCH3), 2.56 ± 2.54 (m, 1H), 2.32
(dd, J ˆ 15.9, 6.7 Hz, 1H), 2.09 (s, 3H, COCH3), 1.96 (s, 3H, COCH3),
1.94 ± 1.91 (m, 2H), 1.90 (s, 3H, COCH3), 1.69-1.61 (m, 3H), 1.49 (s, 3H),
0.99 (d, J ˆ 6.4 Hz, 3H), 0.91-0.85 (m, 6H); 13C NMR (150 MHz,
CD3CN/D2O (20:1), 340 K): d ˆ 173.3, 172.9, 172.3, 171.9, 171.9, 171.8,
171.0, 170.7, 169.1, 158.5, 157.2, 156.0, 155.6, 153.7, 153.4, 150.4, 141.9, 139.8,
138.1, 137.7, 136.7, 132.7, 130.1, 129.4, 129.4, 129.4, 129.4, 129.3, 129.3, 129.3,
129.3, 129.2, 128.9, 128.7, 128.7, 128.7, 128.6, 128.5, 128.5, 128.1, 127.8, 127.4,
127.3, 127.3, 121.9, 112.7, 107.7, 107.5, 105.7, 104.2, 102.3, 99.2, 78.7, 78.2, 74.6,
74.4, 72.3, 71.8, 69.1, 68.4, 66.5, 64.5, 64.3, 64.1, 64.0, 60.0, 58.4, 58.3, 57.8,
56.0, 55.3, 53.4, 53.3, 52.2, 36.7, 30.9, 26.0, 25.4, 24.1, 23.2, 21.9, 21.1, 20.8,
‡
‡
Cs ] 2243.9178, found 2243.9198.
20.7, 17.8; HRMS (MALDI) calcd for C89H95Cl2N9O31Na [M ‡ Na ]
1878.5409, found 1878.5450.
Fully protected vancomycin 59: Vancosamine fluoride 27 (40 mg,
0.13 mmol) and alcohol 58 (70 mg, 0.030 mmol) were azeotroped with
benzene (3 Â 3 mL) and then dried under high vacuum for 1 h. CH2Cl2
(0.5 mL) and 4 Š MS were added, and the mixture was stirred at ambient
temperature for 15 min. The resulting mixture was cooled to 358C and
BF3 ´ Et2O (10 mL, 0.012 mmol) was added dropwise. After stirring for 2 h,
the reaction mixture was diluted with EtOAc (150 mL) and washed with
saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic layer
was dried (Na2SO4) and the solvents were removed under reduced
pressure. The residue was purified by flash column chromatography (silica
gel, 10 !30% acetone in CH2Cl2), followed by preparative TLC (silica gel,
3% MeOH in CH2Cl2) to furnish fully protected vancomycin 59 (65 mg,
84%) as a white foam and a trace of the other anomer. 59: Rf ˆ 0.36 (silica
N,N'-di-Cbz-vancomycin methyl ester 13: Potassium carbonate (3.0 mg,
0.020 mmol) was added to a solution of the protected vancomycin 60
(10 mg, 0.005 mmol) in dry MeOH (0.5 mL) at 258C. The reaction mixture
was stirred for 4 h, filtered, and then the solvents were removed under
reduced pressure. The residue was purified by preparative TLC (silica gel,
50% MeOH in CH2Cl2) to yield N,N'-di-Cbz-vancomycin methyl ester 13
(8.0 mg, 95%) as a white solid. 13: Rf ˆ 0.46 (silica gel, 30% MeOH in
CH2Cl2); [a]2D2
ˆ
10.0 (c ˆ 0.12, CHCl3); IR (thin film): nÄmax ˆ 3542-3119,
2931, 2872, 1719, 1684, 1655, 1590, 1496, 1466, 1431, 1378, 1226, 1149, 1067,
1020, 903, 732, 656, 591 cm 1; 1H NMR (600 MHz, CD3CN/[D7]DMF (3:1),
340 K): d ˆ 8.47 (br.s, 1H), 8.19 (d, J ˆ 5.9 Hz, 1H), 8.12 (bs 1H), 7.96 (s,
1H), 7.79 (d, J ˆ 1.7 Hz, 2H), 7.46 ± 7.29 (m, 14H), 7.19 (d, J ˆ 2.0 Hz, 1H),
7.17 (d, J ˆ 8.4 Hz, 1H), 6.96 (dd, J ˆ 8.5, 2.0 Hz, 1H), 6.91 (br.d, J ˆ 7.4 Hz,
1H), 6.88 (d, J ˆ 8.5 Hz, 1H), 6.85 ± 6.80 (m, 2H), 6.64 (br.d, J ˆ 11.4 Hz,
1H), 6.61 (d, J ˆ 2.1 Hz, 1H), 6.30 (d, J ˆ 2.1 Hz, 1H), 5.90 (br.d, J ˆ
8.1 Hz, 2H), 5.77 (s, 1H), 5.64 (s, 1H), 5.54 (d, J ˆ 7.2 Hz, 1H), 5.43 (s,
1H), 5.39 (s, 1H), 5.36 (d, J ˆ 3.9 Hz, 1H), 5.32 (d, J ˆ 4.4 Hz, 1H), 5.25 ±
5.20 (m, 2H), 5.01 (s, 2H), 4.88 (dd, J ˆ 7.8, 4.2 Hz, 1H), 4.82 (bq, J ˆ
6.2 Hz, 1H), 4.79 ± 4.77 (m, 1H), 4.73 (d, J ˆ 6.0 Hz, 1H), 4.57 ± 4.55 (m,
1H), 4.35 (br.d, J ˆ 12.3 Hz, 1H), 3.79 (s, 3H), 3.76 ± 3.67 (m, 3H), 3.56 ±
3.53 (m, 3H), 2.93 (s, 3H), 2.70 ± 2.66 (m, 1H), 2.65 ± 2.20 (m, 6H), 2.33 ±
2.30 (m, 1H), 2.18 (d, J ˆ 12.0 Hz, 1H), 1.92 (dd, J ˆ 12.4, 4.4 Hz, 1H),
1.74 ± 1.68 (m, 3H), 1.53 (s, 3H), 1.18 (d, J ˆ 6.4 Hz, 3H), 0.94 (br.d, J ˆ
6.6 Hz, 3H), 0.89 (br.d, J ˆ 6.2 Hz, 3H); 13C NMR (150 MHz, CD3CN/
[D7]DMF (3:1), 340 K): d ˆ 172.9, 172.1, 171.9, 171.3, 170.5, 169.7, 168.4,
168.2, 158.6, 157.5, 155.8, 155.3, 153.4, 153.0, 151.1, 150.0, 142.2, 140.0, 138.1,
137.6, 137.1, 136.3, 135.6, 133.3, 129.3, 128.9, 128.9, 128.7, 128.3, 128.3, 128.0,
128.0, 127.9, 127.6, 127.1, 127.0, 125.0, 124.7, 124.1, 121.6, 107.6, 107.3, 106.9,
105.9, 105.4, 104.7, 103.5, 102.3, 98.5, 79.1, 78.0, 77.4, 77.3, 76.5, 75.2, 73.3,
72.6, 71.8, 71.4, 71.2, 67.6, 65.7, 64.0, 63.4, 62.4, 62.3, 59.9, 57.9, 57.4, 56.2, 55.9,
55.1, 54.0, 52.1, 52.0, 49.3, 36.9, 35.6, 25.1, 23.5, 22.8, 21.5, 17.3; HRMS
gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
9.0 (c ˆ 0.30, CHCl3); IR (thin film):
nÄmax ˆ 3550, 2928, 2856, 1755, 1718, 1682, 1654, 1504, 1470, 1458, 1416, 1298,
1
1252, 1062, 837 cm
;
1H NMR (600 MHz, CD3CN, 340 K): d ˆ 7.60 ± 7.50
(m, 2H), 7.46 ± 7.20 (m, 16H), 7.11 (s, 3H), 6.97 (s, 2H), 6.90 ± 6.84 (m, 2H),
6.65-6.55 (m, 2H), 6.47 (d, J ˆ 2.2 Hz, 1H), 6.35 (d, J ˆ 2.2 Hz, 1H), 6.10-
6.01 (m, 1H), 5.85 (s, 1H), 5.60 ± 5.50 (m, 2H), 5.47 (d, J ˆ 4.5 Hz, 1H),
5.34 ± 5.13 (m, 4H), 4.98 and 4.80 (AB, J ˆ 12.6 Hz, 2H), 4.93 ± 4.80 (m,
7H), 4.61 (s, 1H), 4.60 (s, 1H), 4.01 ± 3.97 (m, 3H), 3.87 ± 3.84 (m, 1H), 3.75-
3.67 (m, 2H), 3.74 (s, 3H), 2.91 (s, 3H), 2.35 ± 2.25 (m, 2H), 2.02 (s, 3H),
2.02 ± 1.90 (m, 1H), 1.97 (s, 3H), 1.95 (s, 3H), 1.79 ± 1.75 (m, 2H), 1.53 ± 1.48
(m, 2H), 1.45 (s, 3H), 1.06 (d, J ˆ 6.2 Hz, 3H), 1.03 (s, 9H), 0.98 (s, 9H),
0.93 ± 0.92 (m, 6H), 0.89 (s, 9H), 0.79 (s, 9H), 0.72 (s, 9H), 0.62 (s, 9H), 0.24
(s, 6H), 0.20 (s, 3H), 0.15 (s, 3H), 0.13 (s, 3H), 0.12 (s, 6H), 0.06 (s, 3H),
0.04 (s, 3H), 0.09 (s, 3H), 0.11 (s, 3H), 0.17 (s, 3H); 13C NMR
(125 MHz, CDCl3): d ˆ 172.2, 171.7, 171.3, 171.1, 171.0, 170.6, 170.2, 169.1,
167.9, 156.5, 156.5, 155.8, 155.5, 154.4, 154.4, 152.9, 151.4, 151.4, 141.7, 139.7,
138.4, 138.0, 136.8, 136.4, 136.4, 130.0, 130.0, 129.5, 129.3, 129.3, 129.3, 129.2,
129.2, 129.2, 128.9, 128.8, 128.8, 128.8, 128.6, 128.6, 128.6, 128.5, 128.5, 128.5,
128.4, 128.4, 128.4, 128.4, 127.3, 126.9, 126.4, 125.0, 124.8, 121.3, 113.1, 112.1,
106.4, 99.9, 74.4, 74.3, 73.6, 68.1, 66.2, 66.2, 64.7, 64.5, 60.7, 57.7, 57.7, 55.3,
53.6, 52.7, 52.4, 37.1, 36.9, 30.6, 30.2, 26.3, 26.3, 26.3, 26.3, 26.3, 26.3, 26.2,
26.2, 26.1, 26.1, 26.1, 26.0, 26.0, 26.0, 25.6, 25.6, 25.6, 25.6, 25.6, 25.3, 24.2,
23.5, 22.1, 22.1, 21.2, 20.9, 20.9, 18.9, 18.8, 18.8, 18.3, 18.3, 18.3, 4.0, 4.0,
4.3, 4.3, 4.4, 4.7, 4.7, 4.7, 4.9, 4.9, 5.3, 5.3; HRMS (FAB)
‡
(MALDI) calcd for C88H89Cl2N9O28Cs [M ‡ Cs ] 1864.4260, found
1864.4373.
Vancomycin methyl ester (61): Raney Ni (W-2) (ca. 100 mg, slurry in H2O)
was added to a solution of the Cbz-protected vancomycin methyl ester 13
(10 mg, 0.006 mmol) in nPrOH/H2O (2:1) (3 mL) at 258C. The reaction
mixture was stirred for 0.5 h, filtered through a pad of celite, and then the
solvents were removed under reduced pressure. The residue was purified
by HPLC [(C18 reverse-phase column (HP-LiChroCART 4 Â 250 mm),
‡
calcd for C125H179Cl2N9O31Si6Cs [M ‡ Cs ] 2676.1712, found 2676.1552.
Triacetylated-vancomycin 60: HF ´ pyr. (40 mL) was added dropwise to a
solution of the protected vancomycin 59 (10 mg, 0.004 mmol) and freshly
distilled pyridine (40 mL) in THF (0.5 mL) at 08C. The reaction mixture
was slowly warmed to 258C and stirred for 12 h. The reaction was quenched
by the careful addition of saturated aqueous NaHCO3 (5 mL), diluted with
5% MeOH in EtOAc (100 mL), and washed with saturated aqueous
NaHCO3 (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4)
and the solvents were removed under reduced pressure. The residue was
purified by preparative TLC (silica gel, 15% MeOH in CH2Cl2) to afford
triacetate 60 (6.0 mg, 80%) as a white solid. 60: Rf ˆ 0.22 (silica gel, 15%
gradient solvent system 0 ± 15 min, 5 ± 100% MeCN (0.1% TFA) in H2O,
1
flow rate 1.5 mLmin
,
258C, retention time 8 min 29s)] to yield
27.3 (c ˆ 0.3, H2O); IR (KBr):
vancomycin methyl ester 61. 61: [a]D22
ˆ
nÄmax ˆ 3500, 1731, 1666, 1649, 1596, 1555, 1502, 1414, 1384, 1337, 1302, 1220,
1114, 1061, 1032, 967, 803, 761 cm 1; 1H NMR (500 MHz, CD3OD, 330 K):
d ˆ 7.70 (s, 1H), 7.61 (s, 1H), 7.57 (br.d, J ˆ 6.6 Hz, 2H), 7.20 ± 7.18 (m, 1H),
7.11 (s, 2H), 6.89 (br.s, 2H), 6.56 (d, J ˆ 1.9 Hz, 1H), 6.28 (d, J ˆ 1.9 Hz,
1H), 5.92 (br.s, 1H), 5.79 (br.s, 1H), 5.48 (br.s, 2H), 5.33 (br.s, 4H), 4.84 ±
2666
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2666 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 4
2648±2667
4.81 (m, 1H), 4.73 (s, 1H), 4.68 (s, 1H), 4.22 (s, 1H), 4.11 ± 4.03 (m, 1H),
3.85 (s, 3H), 3.80 ± 3.78 (m, 3H), 3.76-3.75 (m, 1H), 3.67-3.65 (m, 1H),
3.50 ± 3.48 (m, 1H), 3.43 (s, 1H), 3.33 (s, 2H), 2.77 (s, 3H), 2.20 ± 2.15 (m,
2H), 1.84 ± 1.80 (m, 1H), 1.70 ± 1.68 (m, 1H), 1.63 ± 1.58 (m, 1H), 1.49 (s,
3H), 1.24 ± 1.20 (m, 1H), 1.16 (d, J ˆ 6.4 Hz, 3H), 0.89 (br.s, 3H), 0.84 (br.s,
3H); 13C NMR (150 MHz, CD3OD, 330 K): d ˆ 173.6, 171.6, 171.0, 171.0,
169.6, 157.1, 157.1, 155.9, 155.9, 154.9, 154.9, 153.0, 152.3, 151.5, 151.2, 149.5,
141.0, 135.9, 135.5, 128.9, 128.7, 128.2, 127.0, 124.7, 124.0, 121.1, 119.4, 119.2,
119.2, 118.1, 118.1, 118.0, 117.5, 115.5, 113.6, 107.3, 105.4, 103.7, 98.1, 79.7,
76.7, 76.3, 72.1, 71.7, 71.2, 69.9, 64.2, 60.9, 57.4, 55.2, 54.9, 53.5, 51.8, 39.2,
36.8, 36.5, 33.3, 32.0, 24.2, 22.5, 22.2, 22.0, 21.7, 17.1, 16.5; HRMS (MALDI)
[1] K. C. Nicolaou, H. Li, C. N. C. Boddy, J. M. Ramanjulu, T.-Y. Yue, S.
Natarajan, X.-J. Chu, S. Bräse, Chem. Eur. J. 1999, 5, 2584 ± 2601.
[2] K. C. Nicolaou, C. N. C. Boddy, H. Li, A. E. Koumbis, R. Hughes, S.
Natarajan, N. F. Jain, J. M. Ramanjulu, S. Bräse, M. E. Solomon,
Chem. Eur. J. 1999, 5, 2602 ± 2621.
[3] K. C. Nicolaou, A. E. Koumbis, M. Takayanagi, S. Natarajan, N. F.
Jain, T. Bando, H. Li, R. Hughes, Chem. Eur. J. 1999, 5, 2622 ± 2647.
[4] For preliminary communications, see: a) K. C. Nicolaou, S. Natarajan,
H. Li, N. F. Jain, R. Hughes, M. E. Solomon, J. M. Ramanjulu, C. N. C.
Boddy, M. Takayanagi, Angew. Chem. 1998, 110, 2872 ± 2878; Angew.
Chem. Int. Ed. 1998, 37, 2708 ± 2714; b) K. C. Nicolaou, N. F. Jain, S.
Natarajan, R. Hughes, M. E. Solomon, H. Li, J. M. Ramanjulu, M.
Takayanagi, A. E. Koumbis, T. Bando, Angew. Chem. 1998, 110,
2879 ± 2881; Angew. Chem. Int. Ed. 1998, 37, 2714 ± 2717; c) K. C.
Nicolaou, M. Takayanagi, N. F. Jain, S. Natarajan, A. E. Koumbis, T.
Bando, J. M. Ramanjulu, Angew. Chem. 1998, 110, 2881 ± 2883;
Angew. Chem. Int. Ed. 1998, 37, 2717 ± 2719.
[5] For preliminary communication, see: K. C. Nicolaou, H. J. Mitchell,
N. F. Jain, N. Winssinger, R. Hughes, T. Bando, Angew. Chem. 1999,
111, 253 ± 257; Angew. Chem. Int. Ed. 1999, 38, 240 ± 244.
[6] For key references on vancomycin and the glycopeptide antibiotics,
see: a) ref. [1]; b) K. C. Nicolaou, C. N. C. Boddy, S. Bräse, N.
Winssinger, Angew. Chem. 1999, 111, 2230; Angew. Chem. Int. Ed.
1999, 38, 2096 ± 2152.
‡
calcd for C67H77Cl2N9O24Na [M ‡ Na ] 1484.4356, found 1484.4339.
Vancomycin (1): Lithium hydroxide (1.0 mg, 0.034 mmol) was added to a
solution of vancomycin methyl ester (10 mg, 0.006 mmol) in THF/H2O
(1:1) (0.5 mL) at 08C. The reaction mixture was stirred for 20 min, and then
quenched by the addition of saturated aqueous NH4Cl (1 mL). The reaction
mixture was filtered and the solvents were removed under reduced
pressure. The residue was purified by HPLC [C18 reverse-phase column
(HP-LiChroCART 4 Â 250 mm), gradient solvent system 0 ± 15 min, 5 ±
100% MeCN (0.1% TFA) in H2O, flow rate 1.5 mLmin 1, 258C, retention
time 5 min 38s] to yield vancomycin 1 (7.4 mg, 85% for two steps). 1:
[a]2D2
ˆ
25.6 (c ˆ 0.30, H2O); IR (KBr): nÄmax ˆ 3676 ± 2940, 1718, 1684,
1
1654, 1638, 1584, 1491, 1390, 1232, 1120, 1067, 1020, 991, 714, 615 cm
;
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 (br.s, 1H), 6.06 (br.s, 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
(br.s, 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);13C NMR (150 MHz, D2O, 330 K): d ˆ 177.8, 175.7, 172.5, 171.8, 170.5,
169.7, 169.3, 157.9, 156.4, 155.6, 154.1, 150.5, 141.7, 140.0, 138.7, 136.4, 136.3,
134.1, 130.2, 129.6, 129.6, 129.3, 128.6, 127.9, 127.7, 127.7, 125.8, 125.0, 122.7,
119.4, 119.0, 118.9, 109.6, 106.8, 104.5, 102.9, 98.9, 80.6, 77.7, 77.3, 73.3, 72.7,
72.1, 72.1, 70.6, 65.2, 62.1, 62.0, 62.0, 60.6, 59.1, 56.3, 56.0, 55.4, 52.8, 39.9,
39.9, 37.0, 34.3, 33.2, 25.3, 25.6, 23.1, 23.1, 17.6; HRMS (MALDI) calcd for
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Ã
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‡
C66H75Cl2N9O24Na [M ‡ Na ]: 1470.4200/1472.4170, found 1470.4231/
1472.4240.
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[18] We thank Dr. Homer Pearce of Lilly Research Laboratories for a
generous gift of natural vancomycin (1).
Acknowledgments
We thank Dr. D. H. Huang and Dr. G. Suizdak for NMR spectroscopic and
mass spectrometric assistance, respectively. This work was financially
supported by the National Institutes of Health, USA (AI-38893), The
Skaggs Institute for Chemical Biology, and grants from Pfizer, Schering
Plough, Hoffmann La Roche, Merck, the George Hewitt Foundation,
Boehringer Ingelheim, Abbott Laboratories and Glaxo.
[20] C. Thompson, M. Ge, D. Kahne, J. Am. Chem. Soc. 1999, 121, 1237 ±
1244.
Received: March 29, 1999 [F 1708]
Chem. Eur. J. 1999, 5, No. 9
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