Total synthesis of vancomycin - Part 3: Synthesis of the aglycon

Article abstract of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2622::AID-CHEM2622>3.0.CO;2-T

The total synthesis of the vancomycin aglycon (2, Figure 1) is described. Construction of the key intermediate, tricyclic triazene 3 a (Figure 2), was accomplished in the order C-O-D →AB/C-O-D →AB/C-O-D/D-O-E. The C-O-D ring system 18a (Scheme 2) was form

Full text of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2622::AID-CHEM2622>3.0.CO;2-T

FULL PAPER
Total Synthesis of VancomycinÐPart 3: Synthesis of the Aglycon
K. C. Nicolaou,* Alexandros E. Koumbis, Masaru Takayanagi, Swaminathan Natarajan,
Nareshkumar F. Jain, Toshikazu Bando, Hui Li, and Robert Hughes[a]
Abstract: The total synthesis of the
vancomycin aglycon (2, Figure 1) is
described. Construction of the key in-
termediate, tricyclic triazene 3a (Fig-
ure 2), was accomplished in the order
C-O-D !AB/C-O-D !AB/C-O-D/D-
O-E. The C-O-D ring system 18a
(Scheme 2) was formed by using the
triazene ring-closure methodology from
a precursor (17) already possessing the
AB biaryl fragment 6, synthesized by a
Suzuki coupling reaction. At this point,
a macrolactamization reaction furnished
the AB ring system. Tripeptide 5 was
incorporated in the main framework and
the triazene ring-closure methodology
was applied again to achieve the forma-
tion of D-O-E ring system, providing
tricyclic triazene 3a (Scheme 6). The
latter was converted to the fully pro-
tected vancomycin aglycon 45a by first
introducing the phenolic moiety (deriv-
ative 43a) and then oxidizing the AA-7
side chain (Scheme 12). Finally, global
deprotection afforded vancomycinꢀs
aglycon (2). Atropisomerization was
successfully performed for D-O-E ring
systems.
Keywords: amino acids ´ antibiotics
´ synthetic methods ´ total synthesis
´ vancomycin
Introduction
In the preceding two papers[1, 2] in this series, we described the
development of basic methodology for the construction of
vancomycinꢀs key amino acid building blocks and the evalua-
tion of a number of strategies towards the vancomycin
skeleton. These studies helped to shape our final plan towards
the total synthesis of vancomycin[3] (1, Figure 1) and its
aglycon[4] (2, Figure 1). The subject of this article is the
implementation of this strategy and the total synthesis of
vancomycin aglycon (2).[5]
Results and Discussion
Retrosynthetic analysis and strategy
It was presumed that vancomycin (1, Figure 1) could be
synthesized from its aglycon (2, Figure 1). Furthermore, it was
[a] Prof. Dr. K. C. Nicolaou, Dr. A. E. Koumbis, Dr. M. Takayanagi,
Dr. S. Natarajan, Dr. N. F. Jain, Dr. T. Bando, H. Li, R. Hughes
Department of Chemistry and The Skaggs Institute for Chemical
Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, CA 92037
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093
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

2622±2647
anticipated that 2 could be derived from the protected
triazene 3a (Figure 2), a structure containing the entire
skeleton of the aglycon, plus functionality suitable for its
potential conversion to 2, and thence to 1. This strategic
analysis defined for us compound 3a as the key advanced
subtarget, whose retrosynthetic disassembly is shown in
Figure 2. Thus, the four building blocks 4 ± 7 emerged as the
second generation of subtargets. Below, we describe the
forward synthetic sequences that led to the construction and
assembly of these intermediates to the desired targets and
related systems. As a reminder from the preceding papers,[1, 2]
the chosen path will entail construction of ring systems C-O-
D, AB, and D-O-E, in that order.
1
Triazene-driven
ring closure
4
Triazene-driven
ring closure
N
N
N
Cl
O
O
E
C
D
OTBS
O
TBSO
Cl
O
Boc
O
H
H
N
H
N
N
N
O
N
H
N
Me
Me
H
H
H
H
O
O
Construction of biaryl systems
HN
O
B
Me
NHDdm
Scheme 1 depicts the construction of the key amino acid
derivative 6 and its atropisomer (14) from building blocks 8
and 9, whose synthesis has already been described in the
H
BnO
A
OMe
OMe
MeO
Macrolactamization
2
3
Peptide bond formation
O
3a
NHBoc
O
BnO
MeO
MeO
I
B(OH)
OMe
Cl
Cl
HO
O
OMe
OH
E
OTBS
O
9
8
C
Boc
N
TBSO
O
H
N
a. Pd(Ph3P)4, Na2CO3
HO
O
N
H
Me
Me
H
NH2
O
OEt
O
O
NHDdm
Me
4
5
NHBoc
NHBoc
MeO
OH
MeO
O
N
N
NHBoc
MeO
MeO
HO
N
BnO
OH
OMe
OMe
Br
Br
OBn
OMe
12
N3
D
B
MeO
10
BnO
b. DPPA
O
b. DPPA
HO
A
OMe
OMe
NHBoc
O
O
MeO
NHBoc
NHBoc
7
MeO
N3
MeO
6
Figure 2. Retrosynthetic analysis of protected triazene 3a. Bn ˆ benzyl;
Boc ˆ tert-butoxycarbonyl; Ddm ˆ 4,4'-dimethoxyldiphenylmethyl; TBS ˆ
tert-butyldimethylsilyl.
MeO
MeO
BnO
N3
OMe
OMe
OBn
OMe
13
c. LiOH
MeO
Abstract in Greek:
11
c. LiOH
O
O
NHBoc
NHBoc
HO
A
HO
N3
B
B
MeO
MeO
BnO
N3
A
OMe
OMe
OBn
OMe
MeO
14
6
Scheme 1. Construction of biaryl system by Suzuki reaction. a) 0.2 equiv
of Pd(Ph3P)4, 1.2 equiv of Na2CO3, PhMe/MeOH/H2O (10:1:0.5), 908C,
4 h, 10:12 ca. 2:1 ratio of atropisomers, 84% combined yield; b) 2.5 equiv of
DPPA, 2.5 equiv of DEAD, 2.5 equiv of Ph3P, THF, 208C, 2 h, 95% of 11,
90% of 13; c) 1.5 equiv of LiOH, THF/H2O (1:1), 08C, 2 h, 99% of 6, 99%
of 14. DEAD ˆ diethyl azodicarboxylate; DPPA ˆ diphenylphosphoryl
azide.
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K. C. Nicolaou et al.
FULL PAPER
preceding paper.[2] Thus, aryl iodide 8 and boronic acid 9
entered smoothly into
a
Suzuki[6] coupling reaction
[Pd(Ph3P)4, Na2CO3, 908C] to afford a 2:1 mixture of
atropisomers 10 and 12 in 84% combined yield. Chromato-
graphic separation of these two atropisomers allowed sepa-
rate elaboration of each.[7] The desired atropisomer (10,
major) was directly converted to azide 11 (95% yield) by the
action of DPPA (for abbreviations of reagents see legends in
Schemes) in the presence of DEAD and Ph3P.[8] Similarly,
azide 13 was obtained from alcohol 12 in 90% yield. Both 11
and 13 underwent clean saponification to carboxylic acids 6
and 14, respectively, when treated with LiOH in THF/H2O
(1:1) at 08C (99% yield in each case).
Construction of AB/C-O-D systems
Scheme 2 presents the peptide coupling of key intermediates
4, 6, and 7 and ring closure of the resulting tripeptide (17) to
C-O-D rings 18a and 18b. Thus, mixing 6 and 4 in the
presence of EDC and HOAt[9] at low temperature ( 30 !
108C) resulted in the formation of 15 (87% yield).
Exposure of 15 to excess TMSOTf (3.3 equiv) and 2,6-lutidine
(3.0 equiv) precipitated loss of the Boc group,[10] furnishing 16
(90% yield), whose coupling with amino acid fragment 7 to
afford 17 was facilitated by the action of EDC and HOAt
(85% yield). Ring closure of 17 was induced by CuBr´ Me2S,
K2CO3, and pyridine in refluxing MeCN[11] and afforded C-O-
D ring products 18a (natural atropisomer) and 18b (unnatural
atropisomer) in about 1:1 ratio and 67% combined yield. The
structural assignment of these atropisomers was based on
NOE studies which revealed the indicated crucial effects (see
structures 18a and 18b and Table 1).
Table 1. Diagnostic NOEs for structural determination of selected atrop-
isomers.[a]
[a] COSY and ROESY, 600 MHz, 300 K. [b] For the atom labeling see
structures in Schemes 2, 3, 4 and 5.
The unnatural atropisomer served as a model to scout the
territory ahead and secure a safe sequence before the more
precious natural atropisomer was committed. Scheme 3 shows
the push forward of both 18a and 18b to the stage of the AB/
C-O-D systems 23a and 23b. Thus, it was found experimen-
tally that the correct sequence to prepare the required
precursors, amino acids 21a and 21b, was the one involving:
a) TBS removal (nBu4NF, 95% for 19a; 98% for 19b);
Scheme 2. Formation of C-O-D ring systems 18a and 18b from natural
biaryl atropisomer. a) 3.0 equiv of EDC, 3.3 equiv of HOAt, THF,
30 ! 108C, 12 h, 87%; b) 3.3 equiv of TMSOTf, 3.0 equiv of 2,6-
lutidine, CH2Cl2, 08C, 3 h, 90%; c) 3.0 equiv of EDC, 3.3 equiv of HOAt,
THF, 78 !08C, 12 h, 85%; d) 2.0 equiv of CuBr´ Me2S, 2.0 equiv of
K2CO3, 1.9 equiv of pyr., MeCN, reflux, 1.5 h, 18a:18b ca. 1:1 ratio of
atropisomers, 67% combined yield. EDC ˆ 1-ethyl-3-(3-dimethylamino)-
propylcarbodiimide hydrochloride; HOAt ˆ 1-hydroxy-7-azobenzotria-
zole; Tf ˆ trifluoromethanesulfonyl; TMS ˆ trimethylsilyl.
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Total Synthesis of VancomycinÐPart 3
2622±2647
iPr2NEt, furnishing AB/C-O-D ring systems 22a and 22b in
86 and 60% yield respectively. The stereochemical assign-
ment of the C-O-D atropisomers as well as the stereochemical
arrangement of the AB biaryl system were based on NOE
studies, and specifically on the effects indicated on the
structures of 22a and 22b (see Scheme 3 and Table 1). Finally,
the free hydroxy group in 22a and 22b was silylated (5.0 equiv
of TBSOTf, 15 equiv of 2,6-lutidine, 85% for 23a; 80% for
23b) in preparation for the next act.
In order to investigate the atropisomerization of AB/C-O-
D system on the C-O-D site, five intermediates of the
sequence shown in Scheme 3 (18a, 19a, 20a, 22a and 23a)
and their atropisomers were selected for thermal treatment.
Unfortunately these intermediates failed to atropisomerize in
various solvents and led either to decomposition upon heating
at the conditions described by Boger et al.[14] or to recovery of
starting material at lower temperatures.
At this stage it was decided to explore the elaboration of the
unnatural atropisomer of the biaryl system, compound 14, in
the hope that atropisomerization at some future juncture
could bring it back to the proper stereochemistry. Schemes 4
and 5 present our findings along these lines.
Amino acid derivatives 14 and 4 were joined together
through the action of EDC and HOAt, leading to compound
24 in 83% yield (Scheme 4). The Boc group was then removed
from the latter compound (24) by treatment with excess
TMSOTf (3.4 equiv) and 2,6-lutidine (3.0 equiv), furnishing
amino compound 25. Coupling of 25 with central amino acid
triazene derivative 7 (EDC, HOAt) led to tripeptide 26 in
70% yield, while cyclization of the latter by the usual protocol
(CuBr´ Me2S, K2CO3, pyridine, MeCN, reflux)[11] gave C-O-D
ring systems 27a and 27b (ca. 1:1 ratio) in 61% combined
yield. NOE studies aided the stereochemical assignments of
these atropisomers (see arrows on structures, Scheme 4 and
Table 1).
The further elaboration of the atropisomeric C-O-D ring
systems 27a and 27b (Scheme 5) revealed some interesting
stereochemical effects. Thus, following the same sequence
developed for the conversion of compounds 18a and 18b to
their amino acid derivatives (see Scheme 3), the TBS group
was first removed from 27a (nBu4NF, 90% yield) and 27b
(nBu4NF, 92% yield) to afford 28a and 28b, respectively. The
azido group was then reduced[15] (Ph3P, H2O, 608C) in each
isomer, furnishing amines 29a (82% yield) and 29b (71%
yield), respectively. Exposure of ethyl esters 29a and 29b to
LiOH in MeOH/H2O (10:1) at 08C resulted in saponification
of the ethyl ester group, but with essentially complete
epimerization at the adjacent center (indicated on the
structure and based on NOE studies) leading to amino acids
30a (92% yield) and 30b (90% yield), respectively. Finally,
macrolactamization of 30a and 30b was carried out in DMFat
ambient temperature with HATU[16] and iPr2NEt, furnishing
AB/C-O-D ring systems 31a (50% yield) and 31b (51%
yield), respectively. Stereochemical assignments were made
based on NOE studies again, as indicated on structures 31a
and 31b (see also Table 1).
Scheme 3. Construction of AB/C-O-D bicyclic systems 23a and 23b from
natural biaryl system. a) 1.1 equiv of nBu4NF, THF, 25 ! 158C, 3 h,
95% of 19a, 98% of 19b; b) 2.0 equiv of Et3P, MeCN/H2O (4:1), 258C,
20 h, 78% of 20a, 79% of 20b; c) 5.0 equiv of LiOH, THF/H2O (1:1),
5 !08C, 10 min, 92% of 21a, 90% of 21b, crude yields; d) 3.0 equiv of
FDPP, 5.0 equiv of iPr2NEt, DMF, 0 !258C, 12 h, 86% of 22a, 60% of
22b; e) 5.0 equiv of TBSOTf, 15 equiv of 2,6-lutidine, CH2Cl2, 208C, 2 h,
85% of 23a, 80% of 23b. DMF ˆ dimethylformamide; FDPP ˆ penta-
fluorophenyl diphenylphosphinate.
b) reduction[12] of the azide (Et3P-H2O, 78% for 20a; 79% for
20b); and c) ester hydrolysis [LiOH, THF/H2O (1:1), 92% for
21a; 90% for 21b, crude yields]. It should be noted that the
ester moiety resisted hydrolysis under a variety of conditions
in the presence of the bulky TBS group. The macrolactam-
ization of 21a and 21b proceeded smoothly in DMF at
ambient temperatures in the presence of FDPP[13] and
It was quite apparent at this stage that with their drastic
stereochemical differences from the natural systems, com-
pounds 31a and 31b could not be brought into the main-
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FULL PAPER
Scheme 5. Construction of AB/C-O-D bicyclic systems 31a and 31b from
unnatural biaryl system. a) 1.5 equiv of nBu4NF, THF, 08C, 2 h, 90% of
28a, 92% of 28b; b) 3.0 equiv of Ph3P, 10.0 equiv of H2O, THF, 608C, 3 h,
82% of 29a, 71% of 29b; c) 1.5 equiv of LiOH, MeOH/H2O (10:1), 08C,
2 h, 92% of 30a, 90% of 30b; d) 1.5 equiv of HATU, 3.0 equiv of iPr2NEt,
DMF, 258C, 8 h, 50% of 31a, 51% of 31b. HATU ˆ N-[(dimethylamino)-
1H-1,2,3-triazole[4,5-b]-pyridin-1-ylmethylene]-N-methylmethanaminium
hexafluorophosphate.
Scheme 4. Formation of C-O-D ring systems 27a and 27b from unnatural
biaryl atropisomer. a) 3.0 equiv of EDC, 3.3 equiv of HOAt, THF, 08C,
10 h, 83%; b) 3.4 equiv of TMSOTf, 3.0 equiv of 2,6-lutidine, CH2Cl2, 08C,
3 h, 91%; c) 3.0 equiv of EDC, 3.3 equiv of HOAt, THF, 08C, 10 h, 70%;
d) 3.0 equiv of CuBr´ Me2S, 3.0 equiv of K2CO3, 3.0 equiv of pyr., MeCN,
reflux, 20 min, 27a:27b ca. 1:1 ratio of atropisomers, 61% combined yield.
of the non-epimerized acids under the same conditions as for
30a and 30b proceeded less efficiently and gave the same
epimerized products 31a and 31b. These results indicated that
the AB/C-O-D frameworks with the unnatural AB atrop-
structure prefer to reside in their epimeric form at C6a.
stream chemistry of the program in a reasonable way. The
saponification of esters 29a and 29b was also carried out in
THF/H2O mixtures, conditions which suppressed, to some
extent, the epimerization. Interestingly, macrolactamization
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Total Synthesis of VancomycinÐPart 3
2622±2647
and 2,6-lutidine (3.0 equiv) to afford 32 in 96% yield. The
anticipated union of 32 with tripeptide 5 was brought about in
the presence of EDC and HOAt, furnishing the long-sought
cyclization precursor 33 in 86% yield. The presence of the
free phenolic group on ring E required the use of carefully
controlled conditions for the success of this coupling. Finally,
cyclization of 33 was effected by the use of CuBr´ Me2S in the
presence of K2CO3 and pyridine in refluxing MeCN in the
usual way, and the two formed atropisomers 3a and 3b (ca. 1:3
ratio, 74% combined yield) were chromatographically sepa-
rated. The stereochemical assignments for the two atropisom-
ers 3a and 3b were made on the basis of NOE studies,
revealing the effects shown in Figure 3.
Construction of AB/C-O-D/D-O-E systems
We will now return to the main path of the chartered strategy
towards the target, vancomycin aglycon (2). Scheme 6 depicts
the processing of the natural atropisomer 23a to the amino
derivative 32, setting the stage for the incorporation of
tripeptide 5 whose synthesis has already been discussed in the
preceding paper.[2] Thus, the Boc group was removed from the
TBS ether 23a by the action of excess TMSOTf (2.0 equiv)
N
N
N
Br
O
TBSO
Cl
Cl
O
H
HO
H
N
N
O
NHR
OTBS
O
H
H
O
O
Boc
N
HN
H
N
HO
N
H
Me
Me
H
H
O
BnO
O
OMe
OMe
Me
NHDdm
MeO
23a: R = Boc
32: R = H
5
a. TMSOTf,
2,6-lutidine
b. EDC, HOAt
N
N
N
Cl
Br
O
HO
OTBS
O
TBSO
Cl
O
H
N
Boc
N
O
H
H
N
N
O
N
H
O
N
H
Me
Me
H
H
O
H
O
HN
Me
NHDdm
H
BnO
OMe
OMe
33
MeO
c. CuBr•Me2S, K2CO3, pyr.
Figure 3. Stereochemical assignment of atropisomers 3a and 3b based on
1H-1H NOE measurements (COSY and ROESY, 600 MHz, CD3OD,
323 K).
N
N
N
Y
O
O
E
C
D
OTBS
O
X
O
TBSO
Cl
Removal of triazene functionality from AB/C-O-D/D-O-
E ring systems
Boc
O
H
H
H
N
N
N
N
O
N
H
O
N
H
Me
Me
H
H
H
O
O
Having secured the triazene subtarget 3a, the next task was to
convert the triazene moiety to a phenolic group as required
for vancomycin (1) and its aglycon (2). The chemical literature
abounds with reports for this conversion and, indeed, our own
model studies[11] were encouraging in this regard. Unfortu-
nately, however, triazene 3a proved stubbornly defiant to our
attempts to transform it directly to the corresponding phenol.
Various acidic conditions,[17, 18] including sequential BF3 ´ Et2O,
Cu3(NO3)2 and Cu2O treatment, or sulfonic acid resin, or
aqueous H2SO4 in various solvents and at temperatures
ranging from 0 to 808C, failed to produce significant amounts
HN
B
Me
NHDdm
H
BnO
OMe
OMe
A
MeO
3a: X = H, Y = Cl
3b: X = Cl, Y = H
Scheme 6. Construction of AB/C-O-D/D-O-E tricyclic systems 3a and 3b.
a) 2.0 equiv of TMSOTf, 3.0 equiv of 2,6-lutidine, CH2Cl2, 108C, 0.5 h,
96%; b) 2.0 equiv of EDC, 10.0 equiv of HOAt, THF, 15 !08C, 12 h,
86%; c) 5.0 equiv of CuBr´ Me2S, 5.0 equiv of K2CO3, 5.0 equiv of pyr.,
MeCN, reflux, 2 h, 3a:3b ca. 1:3 ratio of atroipisomers, 74% combined
yield.
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K. C. Nicolaou et al.
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of the desired phenol. Instead, reduced product 34a and 34b
were obtained from 3a and 3b, respectively, in most cases
where recovery of starting material or decomposition did not
occur (Scheme 7 and Table 2). Indirect methods for the
installment of the phenolic group on ring D were then sought.
N
N
N
O
O
OTBS
O
Cl
O
TBSO
Cl
Boc
N
O
H
H
H
N
N
N
O
N
H
O
N
Me
Me
H
H
H
H
O
O
N
N
HN
Me
NHDdm
N
Y
H
O
O
BnO
OMe
OMe
OTBS
O
X
O
TBSO
Cl
MeO
Boc
N
3b
O
H
H
H
N
N
N
a. Raney Ni
O
N
N
H
Me
Me
H
H
H
H
O
O
NH2
O
HN
O
O
Me
NHDdm
H
OTBS
O
Cl
BnO
TBSO
Cl
O
H
N
OMe
OMe
Boc
N
O
H
H
N
N
O
MeO
N
N
H
Me
Me
3a: X = H, Y = Cl
3b: X = Cl, Y = H
H
H
H
H
O
O
O
HN
acidic conditions
Me
NHDdm
H
H
RO
Y
OMe
OMe
O
O
MeO
E
C
D
OTBS
O
X
TBSO
Cl
35: R = Bn
36: R = H
b. H2, 10% Pd/C
O
H
Boc
N
O
H
H
N
N
N
O
N
N
H
Me
Me
c. HBF4, i-amylONO
H
H
H
H
O
O
O
HN
X
B
Me
NHDdm
O
O
H
E
C
D
BnO
OTBS
O
Cl
O
A
OMe
OMe
TBSO
Cl
Boc
N
O
H
H
H
N
MeO
N
N
34a: X = H, Y = Cl
34b: X = Cl, Y = H
O
N
N
Me
Me
H
H
H
H
H
O
O
O
HN
Scheme 7. Removal of triazene moiety from 3a and 3b under acidic
conditions: reduction. For reagents and conditions see Table 2.
B
Me
NHDdm
H
HO
A
OMe
OMe
37: X = N2+BF4
38: X = I
39: X = H
40: X = B(OMe)2
41b: X = OH
MeO
-
Table 2. Studies of removal of triazene moiety under acidic conditions.
c. KI
d. MeMgBr, iPrMgCl;
then B(OMe)3
d. H2O2-NaOH
Scheme 8. Reductive removal of the triazene moiety from unnatural
atropisomer 3b. a) Raney Ni, MeOH, 258C, 10 h; b) H2, 10% Pd/C,
MeOH, 258C, 4 h, 60% overall from 3b; c) 20 equiv of HBF4, 20 equiv of
i-amylONO, MeCN, 208C, 0.5 h; then saturated aq. KI, 45 !258C, 2 h;
d) 30 equiv of MeMgBr, THF, 50 ! 208C, 1 h; 30 equiv of iPrMgCl,
60 ! 408C, 2 h; 100 equiv of B(OMe)3, 50 !08C, 1 h; 1:1 mixture of
30% aq. H2O2 and 10% aq. NaOH solution, 20 !08C, 20 min, 28% of 39
and 30% of 41b overall from 36.
[a] AG 50W-X12 (BIO-RAD). [b] 78% of 34a from 3a; 74% of 34b from 3b.
[c] Decomposition.
which was, however, accompanied by partial hydrogenolysis
of the benzyl ether leading to 35 and 36 as an approximate 1:1
mixture. This mixture was then subjected to hydrogenation in
the presence of 10% Pd/C to afford 36 in 60% overall yield
from 3b. The amino group in 36 was then diazotized by
sequential treatment[18a, 20] with HBF4 and i-amylONO, fur-
nishing diazonium salt 37, whose treatment with KI furnished
a mixture of iodide 38 and reduced product 39. This
As an alternative approach to the desired phenolic com-
pound, we chose reduction of the triazene to the correspond-
ing aniline, followed by diazotization, iodination, boronation,
and oxidation. To explore this chemistry, the unnatural
atropisomer 3b was utilized first as shown in Scheme 8. Thus,
Raney Ni[19] reduction of 3b resulted in triazene cleavage,
2628
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
inseparable mixture (38 ‡ 39) was taken through the follow-
ing sequence and the desired product, phenol 41b, was
chromatographically separated from the unreacted, reduced
compound 39: a) deprotonation of all NH groups and iodine-
metal exchange through the use of excess MeMgBr and
iPrMgCl;[21] b) quenching of the so-formed aryl Grignard
reagent with excess B(OMe)3 to afford boronate 40;[22] and,
finally c) oxidation with H2O2 in the presence of aqueous
NaOH, leading to phenol 41b. This sequence afforded, after
chromatographic separation, phenol 41b in 30% overall yield
from anilino compound 36, and 28% reduced product 39.
These steps were carried out without observing any changes at
the stereocenters or at the various functional groups of the
moleculeꢀs framework.
N
N
N
O
O
OTBS
O
Cl
O
TBSO
Cl
Boc
O
H
H
H
N
N
N
N
O
N
H
O
N
H
Me
H
H
H
O
O
Me
Me
HN
NHDdm
H
BnO
OMe
OMe
MeO
3b
a. NaI, I2, TMSCl
Z
O
O
Following the successful conversion of the unnatural
atropisomer 3b to the corresponding phenol (41b), we
proceeded to apply the same chemistry to the natural isomer
3a. Much to our surprise and disappointment, however, the
reduction step with Raney Ni, and then Pd/C or Pd(OH)2/C in
the case of the natural atropisomer, led to inseparable
mixtures of desired products and reduced compounds formed
by rupture of the triazene and one aromatic chlorine bond, the
latter most likely involving ring E. Furthermore, it was
observed that the reduction process was significantly slower
than in the case of the unnatural atropisomer 3b. Apparently,
the outside orientation of the chlorine on ring E in the natural
atropisomer 3a makes it vulnerable to hydrogenolysis, where-
as in the case of 3b, both C Cl bonds are shielded inside the
macrocyclic rings. Additionally, in the latter case (3b) the
triazene functionality would be more accessible. Even though
this sequence gave the desired products and eventually
furnished phenol 41a (see Scheme 12), its low efficiency and
irreproducibility led us to explore a new approach to the
desired aryl iodide of the natural atropisomer.
A direct method for the conversion of aryl triazenes to aryl
iodides involves reaction with TMSI.[23] In order to test this
methodology in our system, we initially performed experi-
ments with the unnatural atropisomer 3b, as shown in
Scheme 9. Despite our expectations, however, treatment of
3b with TMSCl-NaI in MeCN at ambient temperature led to
the reduced product 34b containing small amounts (ca. 5%)
of the desired iodide 42b. Assuming that the mechanism of
this substitution reaction involved activation of the triazene
moiety, followed by nucleophilic attack, we increased the
amounts of iodide, but the result did not change significantly.
To prove that the desired iodide was not the main product,
some of the mixtures were subjected to the phenol formation
sequence (as described above) and phenol 43b, as well as
reduced derivative 34b, were isolated in a combined yield of
55 ± 60% and ratios of ca. 1:20 (see Table 3). An experiment
which involved heating of triazene 3b in the presence of I2
only in a sealed tube[24] afforded again the reduced derivative
34b as the main product. The observation that changing
concentration of reagents and temperature had no positive
effect led to the hypothesis that a radical mechanism was
involved in this substitution reaction. It was, therefore,
reasoned that elemental iodine may serve as an effective
trapping agent of the intermediate benzenoid radical, furnish-
ing higher amounts of the desired halogenated product.
OTBS
O
Cl
TBSO
Cl
O
H
N
Boc
O
H
H
N
N
N
O
N
N
H
Me
H
H
H
O
H
O
Me
Me
O
HN
NHDdm
H
BnO
OMe
OMe
MeO
42b: Z = I
34b: Z = H
b. MeMgBr, iPrMgCl
c. B(OMe)3
d. H2O2-NaOH
OH
D
O
O
E
C
OTBS
O
Cl
O
TBSO
Cl
Boc
O
H
H
H
N
N
N
N
O
N
N
Me
H
H
H
H
H
O
O
Me
Me
O
HN
B
NHDdm
H
BnO
A
OMe
OMe
MeO
43b
Scheme 9. Removal of triazene moiety from unnatural atropisomer 3b
with TMSI-I2. a) 6.0 equiv of NaI, 6.0 equiv of I2, 1.5 equiv of TMSCl,
MeCN, 258C, 15 min; b) 30 equiv of MeMgBr, THF, 50 ! 208C, 1 h;
30 equiv of iPrMgCl,
60 ! 408C, 2 h; c) 100 equiv of B(OMe)3,
50 !08C, 1 h; d) 1:1 mixture of 30% aq. H2O2 and 10% aq. NaOH
solution, 20 !08C, 20 min, 29% of 34b and 32% of 43b overall from 3b.
Table 3. Studies of conversion of triazene 3b to iodide 42b with TMSI.[a]
Entry Temp.
(°C)
NaI
(equiv) (equiv)
I2
Yield[f] (%)
Conc.[c]
(M)
Ratio[d] Ratio[e]
(42b:34b) (43b:34b)
(43b+34b)
-
-
2
6
6
6
6
6
6
60
6
6
6
6
6
-
-
-
1
2
0
0
0.005
0.005
0.005
0.005
0.001
0.005
0.001
0.005
0.005
0.005
0.005
0.005
0.005
0.015
ca. 1:20
ca. 1:20
ca. 1:20
ca. 1:20
ca. 1:20
ca. 1:20
ca. 1:20
ca. 1:20
1:2
5:95
60
-
-
-
3
-30
25
25
60
60
25
0
-
8:92
58
-
4
-
-
5
-
-
-
-
6
-
-
7
-
5:95
39:6
41:59
52:48
50:50
-
55
57
61
61
58
-
8
2
2
6
6
10
1.1
9
10
11
12
13
14
25
25
0
1:2
1:1
1:1
25
80[b]
[g]
-
-
ca. 1:20
[a] All experiments were performed by using 1.5 equiv of TMSCl unless,
otherwise stated. [b] Reaction was performed in a sealed tube without TMSCl.
[c] Concentration in MeCN. [d] Ratio determined by mass spectrometry. [e] Ratio
based on yields of isolated productts. [f] Combined yield of isolated products.
[g] Formation of Boc-deprotected products was observed.
Chem. Eur. J. 1999, 5, No. 9
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2629

K. C. Nicolaou et al.
FULL PAPER
Indeed, experimentation with iodine as an additive estab-
lished an optimum procedure for the formation of an
inseparable mixture of the desired iodide 42b and the reduced
product 34b (ca. 1:1) in 61% combined yield (see Scheme 9
and Table 3). It was interesting to observe that increasing the
number of equivalents of iodine resulted in Boc removal.
The application of the developed procedure for the install-
ment of the iodide on ring D was then applied to the natural
atropisomer, triazene 3a, and, as shown in Scheme 10, it
afford the desired phenol 43a (34% overall yield form 3a)
and reduced product 34a (34% yield). The two compounds
(43a and 34a) were separated by silica gel chromatography.
The final stages of the synthesis of the vancomycin aglycon
With the installment of the phenolic group on ring D, all that
remained before the completion of the synthesis of the
aglycon of vancomycin was the liberation and oxidation of the
primary alcohol of AA-7 and global deprotection. Again, the
unnatural atropisomer 43b served as the substrate of choice
for the first wave of experiments towards the aglycon
(Scheme 11). Thus, hydrogenolysis of 43b (H2, 10% Pd/C)
N
N
N
Cl
O
O
OH
OTBS
O
TBSO
Cl
O
Boc
N
O
O
O
H
H
H
N
N
N
OTBS
O
O
Cl
O
N
N
H
Me
Me
TBSO
Cl
H
H
H
Boc
N
H
O
O
O
H
H
O
H
N
HN
N
N
O
N
N
H
Me
Me
Me
NHDdm
H
H
H
H
O
O
O
H
BnO
HN
OMe
OMe
Me
NHDdm
H
MeO
RO
3a
OMe
OMe
a. NaI, I2, TMSCl
MeO
a. H2, 10% Pd/C
43b: R = Bn
41b: R = H
Z
Cl
O
O
b. MeI, Cs2CO3
OTBS
O
TBSO
Cl
O
H
N
Boc
N
OMe
O
H
H
N
N
O
O
O
N
N
H
Me
Me
H
H
H
O
H
OTBS
O
O
Cl
O
TBSO
Cl
HN
O
H
N
Boc
N
O
H
H
N
Me
NHDdm
N
O
N
H
N
H
Me
Me
H
BnO
H
H
O
H
O
OMe
OMe
O
HN
MeO
Me
42a: Z = I
NHDdm
34a: Z = H
H
HO
b. MeMgBr, iPrMgCl
c. B(OMe)3
d. H2O2/NaOH
OMe
OMe
MeO
44b
c. Dess-Martin periodinane
d. KMnO4, Na2HPO4
e. CH2N2
OH
D
Cl
O
O
E
C
OTBS
O
OMe
D
TBSO
Cl
O
H
N
Boc
N
O
O
H
O
H
N
N
E
O
C
N
N
H
Me
Me
OTBS
O
Cl
O
H
TBSO
Cl
H
H
O
H
O
Boc
O
O
H
H
HN
H
N
N
N
N
Me
Me
B
O
N
H
N
H
Me
NHDdm
H
H
H
H
O
O
O
BnO
HN
MeO2C
A
OMe
OMe
B
Me
NHDdm
MeO
H
43a
A
OMe
OMe
Scheme 10. Removal of triazene moiety from natural atropisomer 3a with
TMSI-I2. a) 6.0 equiv of NaI, 6.0 equiv of I2, 1.5 equiv of TMSCl, MeCN,
258C, 15 min; b) 30 equiv of MeMgBr, THF, 50 ! 208C, 1 h; 30 equiv
of iPrMgCl, 60 ! 408C, 2 h; b) 100 equiv of B(OMe)3, 50 !08C, 1 h;
c) 1:1 mixture of 30% aq. H2O2 and 10% aq. NaOH solution, 20 !08C,
20 min, 34% of 34a and 34% of 43a overall from 3a.
MeO
45b
Scheme 11. Synthesis of fully protected unnatural vancomycin aglycon
45b. a) H2, 10% Pd/C, MeOH, 258C, 1.5 h, 94%; b) 10.0 equiv of Cs2CO3,
50 equiv of MeI, DMF, 08C, 2 h, 94%; c) 1.5 equiv of Dess ± Martin
periodinane, 2.0 equiv of NaHCO3, CH2Cl2, 258C, 0.5 h; d) 10.0 equiv of
KMnO4 (1m aq. solution), tBuOH/5% aq. Na2HPO4 (3.5:1), 308C, 1.5 h;
e) CH2N2, Et2O, 258C, 12 h, 84% overall from 44b.
worked equally well. Thus, treatment of 3a with TMSCl-NaI-
I2 in MeCN at room temperature, furnished an inseparable
mixture of aryl iodide 42a and reduced product 34a which was
subjected to the phenol forming protocol described above
(iodine ± magnesium exchange, boronation, and oxidation) to
led smoothly to primary alcohol 41b (94% yield). Methyl-
ation of the phenolic group of 41b proceeded selectively with
MeI in the presence of Cs2CO3 at 08C, furnishing 44b in 94%
2630
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
yield. Finally, oxidation of the primary alcohol with Dess ±
Martin periodinane,[25] followed by further oxidation[26] with
aqueous KMnO4 and exposure to diazomethane, gave the
fully protected compound 45b via the corresponding alde-
hyde and carboxylic acid, in 84% overall yield from 44b.
With the confidence gained from these results, we pro-
ceeded to apply the same sequence to the natural atropisomer
43a (Scheme 12). Indeed, hydrogenolysis of 43a, as before,
Compounds 44a and 45a were prepared by degradation
from vancomycin hydrochloride (1 ´ HCl), as described in
Scheme 13. Vancomycin aglycon derivative 47 was prepared
OH
HO
HO
H2N
O
OH
O
O
O
Cl
O
O
OH
Cl
OH
O
O
HO
Cl
O
O
O
H
H•HCl
N
H
H
N
OTBS
O
N
N
TBSO
Cl
O
N
H
O
O
N
Me
Boc
N
O
H
H
H
H
H
H
H
O
N
O
Me
N
N
O
N
N
H
Me
Me
HN
HO2C
H
H
H
H
O
Me
O
NH2
O
HN
H
Me
NHDdm
OH
OH
H
RO
HO
OMe
OMe
1•HCl: vancomycin hydrochloride
a. CbzCl, NaOH
b. MeI, Cs2CO3
c. TFA
MeO
43a: R = Bn
41a: R = H
a. H2, 10% Pd/C
OR1
Cl
b. MeI, Cs2CO3
O
O
OMe
OR2
O
Cl
O
R2O
Cl
O
O
Cbz
N
O
H
H
H
N
OTBS
O
N
N
TBSO
Cl
O
N
N
Me
Me
O
H
N
Boc
N
H
H
O
H
H
H
H
N
H
O
O
N
O
HN
O
N
H
O
N
H
Me
Me
H
NHR3
H
O
Me
H
O
MeO2C
HN
H
OMe
OMe
Me
NHDdm
H
HO
MeO
46: R1 = H, R2 = H, R3 = H
47: R1 = Me, R2 = H, R3 = H
OMe
OMe
d. MeI, K2CO3
MeO
44a
e. TBSOTf,
2,6-lutidine
c. Dess-Martin periodinane
d. KMnO4, Na2HPO4
e. CH2N2
48: R1 = Me, R2 = TBS, R3 = H
49: R1 = Me, R2 = TBS, R3 = Ddm
f. 4,4'-dimethoxy
benzhydrol,
H2SO4
OMe
D
g. H2, 10% Pd/C
Cl
O
O
OMe
Cl
E
C
OTBS
O
O
O
TBSO
Cl
O
Boc
E
C
O
D
H
H
OTBS
O
H
N
N
TBSO
O
Cl
N
N
O
R1
N
Me
Me
O
N
H
O
N
O
H
H
N
H
H
H
H
N
H
O
O
N
N
N
H
Me
Me
HN
MeO2C
H
H
H
B
H
O
O
Me
NHDdm
O
HN
R2
H
B
Me
NHDdm
A
OMe
OMe
H
A
OMe
OMe
MeO
45a
Scheme 12. Synthesis of fully protected natural vancomycin aglycon 45a.
a) H2, 10% Pd/C, MeOH, 258C, 1.5 h, 87%; b) 10.0 equiv of Cs2CO3,
50 equiv of MeI, DMF, 08C, 2 h, 95%; c) 1.5 equiv of Dess ± Martin
periodinane, 2.0 equiv of NaHCO3, CH2Cl2, 258C, 0.5 h; d) 10.0 equiv of
KMnO4 (1m aq. solution), tBuOH/5% aq. Na2HPO4 (3.5:1), 308C, 1.5 h;
e) CH2N2, Et2O, 258C, 12 h, 89% overall from 44a.
MeO
i. DIBAL-nBuLi;
then NaBH4
50: R1 = H, R2 = CO2Me
45a: R1 = Boc, R2 = CO2Me
51: R1 = H, R2 = CH2OH
44a: R1 = Boc, R2 = CH2OH
h. Boc2O
j. Boc2O, Et3N
Scheme 13. Degradation of vancomycin (1). a) 5.0 equiv of CbzCl, 15%
aq. NaOH, MeOH, 258C, 0.5 h; b) 20 equiv of MeI, 8.0 equiv of Cs2CO3,
DMF, 0 !258C, 20 h; c) TFA, CH2Cl2, 508C, 1 h, 39% overall from 1 ´ HCl;
d) 10.0 equiv of MeI, 10.0 equiv of K2CO3, DMF, 0 !258C, 1 h, 98%;
e) 11 equiv of TBSOTf, 11 equiv of 2,6-lutidine, 108C, 0.5 h, 80%;
f) 100 equiv of 4,4' -dimethoxy benzydrol, 1m H2SO4 in AcOH, AcOH,
0 !258C, 2 h, 76%; g) H2, 10% Pd/C, MeOH/EtOAc (2:1), 258C, 2 h; h)
5.0 equiv of Boc2O, dioxane/H2O (10:1), 258C, 6 h, 90% overall from 49;
i) 12 equiv of DIBAL/nBuLi (1:1), THF, 108C, 0.5 h; 20 equiv of NaBH4
in THF/H2O (1:1), 10 !258C, 1 h, 65% overall from 49; j) 7.0 equiv of
Boc2O, 7.0 equiv of Et3N, MeOH/CH2Cl2 (1:1), 08C, 20 min, 93%.
DIBAL ˆ diisobutylaluminum hydride; Cbz ˆ benzyloxycarbonyl; TFA ˆ
trifluoroacetic acid.
led smoothly to 41a (87% yield), which proved to be identical
to a sample derived from vancomycin (1) by degradation (see
Scheme 13 below for degradation studies). Furthermore,
methylation of 41a (Cs2CO3, MeI, 95%), followed by
stepwise oxidation of the resulting derivative 44a and methyl
ester formation as described for 44b (Scheme 11), furnished
the fully protected vancomycin aglycon 45a in 89% overall
yield from 44a. This compound was also found to be identical
with an authentic sample derived from vancomycin (1).
Chem. Eur. J. 1999, 5, No. 9
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2631

K. C. Nicolaou et al.
FULL PAPER
by sequential protection of the secondary amino group,
carboxylic acid, and phenolic groups, following a known
procedure.[14b, 27] TBS protection of the two benzylic hydroxy
groups of 47 using excess of TBSOTf (11 equiv) and 2,6-
lutidine (11 equiv) afforded compound 48 in 80% yield.
Selective protection of the primary amide of 48 was achieved
by using 4,4'-dimethoxy benzhydrol (100 equiv) in the pres-
ence of catalytic amount of H2SO4 in acetic acid and yielded
49 (76%). Then, the Cbz group was removed by mild
hydrogenation conditions (10% Pd/C, MeOH/EtOAc 2:1)
to provide 50, the common synthetic intermediate for 44a and
45a. After extensive experimentation, DIBAL-ate (1:1 mix-
ture of DIBAL and nBuLi) followed by NaBH4 was found to
be the most effective system for the reduction of the ester 50
in order to obtain alcohol 51 (65% yield overall from 49).
Finally, Boc protection of the secondary amine provided the
N-Boc-alcohol 44a. Additionally, the secondary amine of
ester 50 was protected [Boc2O (7.0 equiv), Et3N (7.0 equiv),
MeOH/CH2Cl2 (1:1)] to afford the N-Boc derivative 45a in
93% yield overall from 49.
1408C for 4 h led to a mixture of starting material and the
corresponding atropisomer in a ratio of about 6:4 and 80-84%
combined yields (Table 4). Tricyclic methyl esters 45a and
45b were also heated in 1,2-dichlorobenzene for 8 h and
furnished separable mixtures of starting material and the
Table 4. Atropisomerization studies of tricyclic systems 3a,b and 45a,b.
Yield
(% a+b)
Compound
Temp
(°C)
Time Ratio
Solvent
(h)
(a:b)
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
3a
3b
140
140
130
130
4
4
8
8
62:38
41:59
54:46
43:57
84
80
87
82
45a
45b
corresponding atropisomer in a ratio of about 1:1 and 82 ±
87% combined yields (see Scheme 14 and Table 4). Signifi-
cantly, all the successful experiments proved that heating at
about 130 ± 1408C in 1,2-dichlorobenzene allows atropisome-
rization only within the D-O-E ring system, leaving the
stereochemistry of the AB and C-O-D ring systems intact, as
reported by Bogerꢀs group for similar vancomycin-derived
systems.[14]
Atropisomerization of vancomycin-like skeletons was in-
vestigated by using tricyclic triazene 3a and methyl ester 45a,
and their D-O-E atropisomers 3b and 45b (Scheme 14).
The atropisomerization of unnatural atropisomers 3b and
45b served to enrich the supplies of the desired atropisomers
3a and 45a needed for the final drive towards the vancomycin
aglycon (2).
X
Cl
O
O
E
C
D
OTBS
O
TBSO
O
Cl
O
Boc
N
The final task remaining for the total synthesis of vanco-
mycinꢀs aglycon (2) was the removal of all the residing
protecting groups from 45a. These included two TBS groups,
a Boc group, a Ddm protecting group, and five methyl
groupsÐone on the carboxylic acid and four on the phenolic
moieties. Our initial attempt to accomplish this goal involved
one step and called upon the synergistic action of AlBr3 and
EtSH[28] (Scheme 15). Pleasantly, this combination of reagents
in CH2Cl2 and at ambient temperatures resulted in the desired
global deprotection of 45a in 30 ± 50% yield, furnishing the
vancomycinꢀs aglycon (2). A stepwise deprotection involving
nBu4NF/HOAc to remove the silyl ethers, giving diol 52,
followed by exposure to AlBr3/EtSH, as above, resulted in a
43% overall yield of the aglycon. Finally, a second, stepwise
procedure employing HF ´ pyr./pyr. in THF[29] at 0 !258C and
AlBr3/EtSH improved the overall yield of vancomycin
aglycon (2) from 45a, via 52, to 62%.
O
H
H
N
H
N
N
Me
N
N
H
H
H
H
H
O
O
Me
O
HN
Y
B
Me
NHDdm
H
A
OMe
OMe
MeO
3a: X =
, Y = CH2OBn
N
N N
45a: X = OMe, Y = CO2Me
X
O
O
E
C
D
OTBS
O
Cl
O
TBSO
Cl
Boc
N
O
H
H
N
N
Me
O
N
N
H
H
H
H
H
O
O
Me
Me
O
HN
Synthetic vancomycinꢀs aglycon 2 exhibited identical prop-
B
NHDdm
1
1
erties (HPLC, IR, [a]D22 , H NMR and mixed H NMR) with
those of an authentic sample derived from vancomycin (1) by
degradation.[30]
Y
H
A
OMe
OMe
MeO
3b: X =
, Y = CH2OBn
N
N N
45b: X = OMe, Y = CO2Me
Scheme 14. Atropisomerization studies of tricyclic systems. For conditions
and equilibrium ratios see Table 4.
Conclusion
In this article we described the chemistry leading from the
essential amino acid building blocks to the vancomycin
aglycon (2). The assembly proceeded smoothly, not with-
standing the atropisomerism problem, from rings C-O-D to
AB/C-O-D to AB/C-O-D/D-O-E, furnishing a triazene
derivative, whose conversion to the required phenolic func-
Alcohols 44a (Scheme 12) and 44b (Scheme 11) were found
to be unsuitable substrates for this study, since they were not
chromatographically separable. While heating either 3a or 3b
in polar solvents (DMF or DMSO) failed to give atropisome-
rization, heating these derivatives in 1,2-dichlorobenzene at
2632
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0947-6539/99/0509-2632 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
3.70 (s, 3H, CO2CH3), 3.65 (s, 3H, 5d-OCH3), 3.63 (s, 3H, 7c-OCH3), 3.45
(dd, J ˆ 10.3, 8.4 Hz, 1H, H-7bA), 3.40 (dd, J ˆ 10.3, 3.5 Hz, 1H, H-7bB),
2.10 (br.s, 1H, OH), 1.41 (s, 9H, tBuO); 13C NMR (100 MHz, CDCl3): d ˆ
171.9, 160.4, 157.8, 156.8, 154.9, 141.2, 137.9, 131.9, 129.0, 128.4, 128.2, 127.7,
127.6, 125.2, 117.8, 111.4, 101.8, 98.5, 80.1, 74.8, 73.1, 70.0, 56.9, 55.7, 55.3,
OMe
Cl
O
O
OR
O
RO
Cl
O
Boc
N
O
H
H
H
N
‡
N
N
52.5, 28.3; HRMS (FAB) calcd for C32H39NO9Cs [M ‡ Cs ] 714.1679, found
Me
O
N
N
H
H
H
714.1654. 12: Rf ˆ 0.20 (silica gel, 40% EtOAc in hexanes); [a]D22
ˆ
48.9
H
H
O
O
Me
Me
O
(c ˆ 2.3, CHCl3); IR (thin film): nÄmax ˆ 3436, 2943, 2837, 1737, 1708, 1602,
HN
MeO2C
1
1496, 1449, 1320, 1255, 1155, 1055 cm 1; H NMR (400 MHz, CDCl3): d ˆ
NHDdm
7.35-7.27 (m, 4H, ArH), 7.24 ± 7.19 (m, 2H, ArH), 7.11 (d, J ˆ 2.4 Hz, 1H,
ArH), 6.83 ± 6.80 (m, 2H, ArH), 6.46 (d, J ˆ 2.4 Hz, 1H, ArH), 5.47 (d, J ˆ
7.4 Hz, 1H, NH), 5.28 (d, J ˆ 7.4 Hz, 1H, H-5a), 4.70-4.65 (m, 1H, H-7a),
4.40 (d, J ˆ 12.2 Hz, 1H, OCHAHPh), 4.33 (d, J ˆ 12.2 Hz, 1H,
OCHHBPh), 3.85 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.64 (s, 3H,
OCH3), 3.50 (s, 3H, OCH3), 3.34 ± 3.32 (m, 2H, H-7b), 1.43 (s, 9H, tBuO);
13C NMR (125 MHz, CDCl3): d ˆ 171.9, 160.3, 157.9, 157.6, 154.8, 140.5,
137.8, 130.4, 128.5, 128.3, 128.2, 127.6, 127.4, 125.4, 118.1, 111.0, 101.8, 98.2,
79.9, 74.4, 72.5, 69.5, 56.9, 55.7, 55.2, 55.1, 52.5, 28.2; HRMS (FAB) calcd for
H
OMe
OMe
MeO
45a: R = TBS
52: R = H
b. nBu4NF, AcOH or
c. HF•pyr.
a. AlBr3, EtSH
d. AlBr3, EtSH
OH
D
Cl
O
O
‡
E
C
C32H39NO9Cs [M ‡ Cs ] 714.1679, found 714.1654.
OH
O
H
HO
Cl
O
H
N
Natural biaryl azide 11: A solution of natural biaryl alcohol 10 (2.56 g,
4.4 mmol) in THF (40 mL) was cooled to 208C, and treated sequentially
with triphenylphosphane (2.88 g, 11 mmol), diphenylphosphorylazide
(DPPA, 2.4 mL, 11 mmol), and diethyl azodicarboxylate (DEAD, 1.7 mL,
O
H
N
H
N
N
Me
O
N
N
H
H
H
H
H
O
O
Me
O
HN
HO2C
11 mmol). The reaction mixture was stirred at
208C for 2 h, then
B
Me
NH2
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 20 !30% EtOAc in hexanes, gradient elution) to afford
natural biaryl azide 11 (2.52 g, 95% yield). 11: Rf ˆ 0.72 (silica gel, 50%
H
A
OH
OH
EtOAc in hexanes); [a]D22
ˆ
97.4 (c ˆ 0.98, MeOH); IR (thin film): nÄmax ˆ
2: vancomycin's aglycon
HO
3376, 2936, 2098, 1746, 1714, 1605, 1488, 1455, 1342, 1261, 1202, 1160, 1059,
1030, 738 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 7.36 ± 7.18 (m, 6H, ArH),
7.09 (d, J ˆ 2.2 Hz, 1H, H-5b), 6.85 (d, J ˆ 8.6 Hz, 1H, H-5e), 6.56 (d, J ˆ
2.4 Hz, 1H, H-7f), 6.46 (d, J ˆ 2.4 Hz, 1H, H-7d), 5.54 (d, J ˆ 7.3 Hz, 1H,
NH), 5.29 (d, J ˆ 7.3 Hz, 1H, H-5a), 4.50 (dd, J ˆ 8.8, 3.4 Hz, 1H, H-7a),
4.45 (d, J ˆ 12.2 Hz, 1H, OCHAHPh), 4.35 (d, J ˆ 12.2 Hz, 1H, CHHBPh),
3.82 (s, 3H, 7e-OCH3), 3.69 (s, 3H, CO2CH3), 3.63 (s, 3H, 5d-OCH3), 3.56-
3.46 (m, 2H, H-7b), 3.50 (s, 3H, 7c-OCH3), 1.42 (s, 9H, tBuO); 13C NMR
(100 MHz, CDCl3): d ˆ 171.7, 160.3, 158.0, 157.3, 154.7, 137.6, 136.9, 130.9,
128.7, 128.2, 128.1, 127.5, 127.4, 124.6, 118.8, 111.0, 102.3, 98.5, 79.9, 73.2,
72.7, 62.0, 56.7, 55.6, 55.2, 55.1, 52.5, 28.1; HRMS (FAB) calcd for
Scheme 15. Synthesis of vancomycin aglycon (2). a) 40 equiv of AlBr3,
EtSH/CH2Cl2 (1:1), 258C, 4 h, 30 ± 50%; b) 50 equiv of nBu4NF, 50 equiv of
AcOH, THF, 258C, 48 h; c) HF ´ pyr./pyr.,THF, 0 !258C, 12 h; d) 40 equiv
of AlBr3, EtSH/CH2Cl2 (1:1), 258C, 4 h, [43% of 2 overall from 45a
through b); 62% of 2 overall from 45a through c)].
tionality was accomplished by iodination, boronation and
oxidation. Final oxidation of the AA-7 side chain to the
desired carboxylic acid group, followed by global deprotec-
tion gave vancomycin aglycon (2). Atropisomerization studies
failed to convert the unnatural atropisomers at the C-O-D or
AB/C-O-D stages, but proved successful in equilibrating the
atropisomeric D-O-E domains within the final AB/C-O-D/D-
O-E framework, starting from either one. In the following
paper[31] we describe the conversion of the vancomycin
aglycon (2) to vancomycin itself (1).
‡
C32H38N4O8Cs [M ‡ Cs ] 739.1744, found 739.1766.
Unnatural biaryl azide 13: A solution of unnatural biaryl alcohol 12 (1.28 g,
2.2 mmol) in THF (20 mL) was cooled to 208C and treated sequentially
with triphenylphosphane (1.44 g, 5.5 mmol), diphenylphosphorylazide
(DPPA, 1.19 mL, 5.5 mmol), and diethyl azodicarboxylate (DEAD,
870 mL, 5.5 mmol). The reaction mixture was stirred at -208C for 2 h, then
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 20 !30% EtOAc in hexanes, gradient elution) to afford
unnatural biaryl azide 13 (1.20 g, 90% yield). 13: Rf ˆ 0.17 (silica gel, 30%
EtOAc in hexanes); [a]D22
3354, 2978, 2097, 1737, 1596, 1484, 1249, 1155, 1096 cm
ˆ
16.1 (c ˆ 1.22, CHCl3); IR (thin film): nÄmax
ˆ
1
;
1H NMR
Experimental Section
(500 MHz, CDCl3): d ˆ 7.36-7.20 (m, 6H, ArH), 7.04 (d, J ˆ 2.0 Hz, 1H,
ArH), 6.96 (d, J ˆ 8.5 Hz, 1H, ArH), 6.61 (d, J ˆ 2.5 Hz, 1H, ArH), 6.50 (d,
J ˆ 2.5 Hz, 1H, ArH), 5.45 (d, J ˆ 7.5 Hz, 1H, NH), 5.27 (d, J ˆ 7.5 Hz, 1H,
H-5a), 4.47 (dd, J ˆ 9.0, 3.5 Hz, 1H, H-7a), 4.37 (d, J ˆ 12.0 Hz, 1H,
OCHAHPh), 4.32 (d, J ˆ 12.0 Hz, 1H, OCHHBPh), 3.84 (s, 3H, OCH3),
3.74 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.44 (dd, J ˆ 10.5, 9.0 Hz, 1H,
H-7bA), 3.33 (dd, J ˆ 10.5, 3.5 Hz, 1H, H-7bB), 1.42 (s, 9H, tBuO); 13C NMR
(100 MHz, CDCl3): d ˆ 171.9, 160.4, 157.9, 156.4, 154.8, 137.9, 131.3, 128.4,
128.3, 128.0, 127.5, 127.4, 127.4, 124.5, 118.4, 111.1, 102.5, 98.7, 80.0, 73.6,
73.0, 62.6, 56.9, 55.7, 55.4, 55.3, 52.4, 28.2; HRMS (FAB) calcd for
General techniques: see paper 1 in this series.[1]
Natural biaryl 10 and unnatural biaryl 12: To a solution of aryl iodide 8
[1.08 g, 2.8 mmol, in toluene (25 mL)] were added sequentially boronic acid
[1.32 g, 4.2 mmol, dissolved in MeOH (2.5 mL)], Na2CO3 [0.36 g,
9
3.4 mmol, dissolved in H2O (1.3 mL)], and tetrakistriphenylphosphanepal-
ladium(0) [Pd(Ph3P)4, 0.65 g, 0.6 mmol]. The resulting mixture was heated
to 908C for 4 h. The reaction mixture was cooled to 258C and diluted with
EtOAc (25 mL). The organic phase was washed with H2O (25 mL), brine
(25 mL), dried (Na2SO4), concentrated, and the residue was purified by
flash column chromatography (silica gel, 20 !40% EtOAc in hexanes,
gradient elution) to afford atropisomers 10 (1.04 g, 56% yield) and 12
(0.52 g, 28% yield). 10: Rf ˆ 0.30 (silica gel, 50% EtOAc in hexanes);
‡
C32H38N4O8Cs [M ‡ Cs ] 739.1744, found 739.1766.
Natural biaryl carboxylic acid 6: A solution of natural biaryl carboxylic
ester 11 (1.0 g, 1.6 mmol) in THF/H2O (1:1) (16 mL) was cooled to 08C and
lithium hydroxide monohydrate (101 mg, 2.4 mmol) was added. After 2 h,
CH2Cl2 (100 mL) was added, and the reaction mixture was quenched by the
dropwise addition of 0.1% aqueous HCl at 08C, until pH 5 was reached.
The aqueous phase was extracted with CH2Cl2 (2 Â 100 mL). The combined
organic layers were dried (Na2SO4), concentrated, and the residue was
purified by flash column chromatography (silica gel, 2 !5% MeOH in
CH2Cl2, gradient elution) to afford natural biaryl carboxylic acid 6 (0.94 g,
[a]2D2
ˆ
79.1 (c ˆ 0.78, EtOAc); IR (thin film): nÄmax ˆ 3447, 2936, 1741,
1
1717, 1604, 1489, 1458, 1325, 1262, 1201, 1158, 1056 cm
;
1H NMR
(400 MHz, CDCl3): d ˆ 7.33 ± 7.18 (m, 6H, ArH), 7.01 (d, J ˆ 1.9 Hz, 1H,
H-5b), 6.92 (d, J ˆ 8.6 Hz, 1H, H-5e), 6.76 (d, J ˆ 2.4 Hz, 1H, H-7f), 6.46 (d,
J ˆ 2.4 Hz, 1H, H-7d), 5.41 (d, J ˆ 6.8 Hz, 1H, NH), 5.25 (d, J ˆ 6.8 Hz, 1H,
H-5a), 4.59 (dd, J ˆ 8.4, 3.5 Hz, 1H, H-7a), 4.39 (d, J ˆ 11.9 Hz, 1H,
OCHAHPh), 4.35 (d, J ˆ 11.9 Hz, 1H, OCHHBPh), 3.83 (s, 3H, 7e-OCH3),
99%). 6: Rf ˆ 0.20 (silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
32.4 (c ˆ 3.5,
Chem. Eur. J. 1999, 5, No. 9
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0947-6539/99/0509-2633 $ 17.50+.50/0
2633

K. C. Nicolaou et al.
FULL PAPER
MeOH); IR (thin film): nÄmax ˆ 3350, 2938, 2099, 1716, 1605, 1488, 1456,
in CH2Cl2); [a]2D2 ˆ ‡8.9 (c ˆ 2.0, EtOAc); IR (thin film): nÄmax ˆ 3419, 2933,
2874, 2099, 1734, 1654, 1604, 1508, 1458, 1342, 1260, 1201, 1157, 1091, 1030,
837 cm 1; 1H NMR (400 MHz, CD3OD): d ˆ 7.31 ± 7.18 (m, 7H, ArH), 7.11
(d, J ˆ 2.4 Hz, 1H, H-5b), 7.03 (dd, J ˆ 8.5, 2.0 Hz, 1H, H-6f), 6.90 (d, J ˆ
8.6 Hz, 1H, H-5e), 6.80 (d, J ˆ 8.5 Hz, 1H, H-6e), 6.60 (d, J ˆ 2.4 Hz, 1H,
H-7f), 6.52 (d, J ˆ 2.4 Hz, 1H, H-7d), 5.27 (d, J ˆ 2.4 Hz, 1H, H-6b), 4.60
(dd, J ˆ 8.4, 3.8 Hz, 1H, H-7a), 4.58 (d, J ˆ 2.4 Hz, 1H, H-6a), 4.47 (s, 1H,
H-5a), 4.34 (br.s, 2H, OCH2Ph), 4.13 (dq, J ˆ 10.8, 7.2 Hz, 1H,
OCHAHCH3), 4.05 (dq, J ˆ 10.8, 7.2 Hz, 1H, OCHHBCH3), 3.81 (s, 3H,
7e-OCH3), 3.57 (s, 3H, 7c-OCH3), 3.54 (s, 3H, 5d-OCH3), 3.59 ± 3.47 (m,
2H, H-7b), 1.16 (t, J ˆ 7.2 Hz, 3H, OCH2CH3), 0.89 (s, 9H, tBuSi), 0.01 (s,
3H, CH3Si), 0.15 (s, 3H, CH3Si); 13C NMR (100 MHz, CD3OD): d ˆ
176.0, 171.1, 161.9, 159.8, 158.8, 154.2, 139.3, 138.3, 134.2, 133.9, 131.8, 129.4,
129.2, 129.0, 128.7, 128.6, 126.9, 126.3, 121.4, 120.6, 117.4, 112.3, 103.9, 99.2,
74.9, 74.6, 73.7, 63.3, 62.8, 60.6, 59.6, 56.1, 55.9, 55.8, 26.2, 19.0, 14.4, 4.4,
1
1259, 1158, 1060, 838 cm 1; H NMR (400 MHz, CD3OD, 330 K): d ˆ 7.39
(dd, J ˆ 8.5, 2.3 Hz, 1H, H-5f), 7.29 ± 7.15 (m, 5H, ArH), 7.09 (d, J ˆ 2.3 Hz,
1H, H-5b), 6.94 (d, J ˆ 8.5 Hz, 1H, H-5e), 6.63 (d, J ˆ 2.4 Hz, 1H, H-7f),
6.55 (d, J ˆ 2.4 Hz, 1H, H-7d), 5.15 (br.s, 1H, H-5a), 4.54 (dd, J ˆ 7.8,
4.3 Hz, 1H, H-7a), 4.33 (br.s, 2H, OCH2Ph), 3.81 (s, 3H, 7e-OCH3), 3.61 (s,
3H, 5d-OCH3), 3.55 (s, 3H, 7c-OCH3), 3.56 ± 3.50 (m, 2H, H-7b), 1.40 (s,
9H, tBuO); 13C NMR (100 MHz, CD3OD, 330 K): d ˆ 174.7, 161.9, 159.7,
158.9, 157.3, 139.2, 138.1, 131.8, 131.0, 129.4, 129.2, 128.6, 128.5, 126.1, 120.4,
112.2, 103.9, 99.2, 80.7, 74.5, 73.4, 63.2, 58.7, 56.1, 55.8, 55.8, 28.7; HRMS
‡
(FAB) calcd for C31H36N4O8Cs [M ‡ Cs ] 725.1587, found 725.1611.
Unnatural biaryl carboxylic acid 14: A solution of unnatural biaryl
carboxylic ester 13 (1.0 g, 1.6 mmol) in THF/H2O (1:1, 15 mL) was cooled
to 08C, and anhydrous lithium hydroxide (58 mg, 2.4 mmol) was added.
The resulting mixture was stirred at 08C for 2 h, and then it was quenched
by the dropwise addition of saturated aqueous citric acid (1 mL). The
reaction mixture was extracted with EtOAc (4 Â 15 mL). The combined
organic layers were washed with H2O (30 mL), brine (30 mL), dried
(Na2SO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 2 !5% MeOH in CHCl3, gradient elution) to
afford unnatural biaryl carboxylic acid 14 (0.94 g, 99% yield). 14: Rf ˆ 0.25
‡
5.2; HRMS (FAB) calcd for C43H54ClN5O9SiCs [M ‡ Cs ] 980.2434,
found 980.2464.
AB/C/D tripeptide 17: A solution of carboxylic acid 7 (91 mg, 0.18 mmol)
and AB/C amine 16 (150 mg, 0.18 mmol) in THF (2 mL) was cooled to
788C. HOAt (80 mg, 0.59 mmol) and EDC (104 mg, 0.54 mmol) were
added, and the resulting mixture was left under vigorous stirring for 12 h,
while the temperature was raised to 08C. H2O (5 mL) and EtOAc (10 mL)
were added, and after 10 min, the aqueous phase was extracted with EtOAc
(2 Â 10 mL). The combined organic layers were dried (Na2SO4), concen-
trated, and the residue was purified by flash column chromatography (silica
gel, 10 !30% EtOAc in hexanes, gradient elution) to afford AB/C/D
tripeptide 17 (205 mg, 85%). 17: Rf ˆ 0.48 (silica gel, 50% EtOAc in
(silica gel, 10% MeOH in CHCl3); [a]D22
ˆ
13.8 (c ˆ 2.0, MeOH); IR
(KBr): nÄmax ˆ 3440, 2953, 2096, 1716, 1685, 1606, 1507, 1257, 1158, 1059,
1019 cm 1; 1H NMR (400 MHz, CD3OD): d ˆ 7.38 (dd, J ˆ 8.6, 2.4 Hz, 1H,
ArH), 7.25 ± 7.12 (m, 5H, ArH), 7.00 ± 6.98 (m, 2H, ArH), 6.55 (d, J ˆ
2.4 Hz, 1H, ArH), 6.52 (d, J ˆ 2.4 Hz, 1H, ArH), 5.11 (s, 1H, H-5a), 4.37
(dd, J ˆ 8.5, 3.8 Hz, 1H, H-7a), 4.24 (d, J ˆ 9.5 Hz, 1H, OCHAHPh), 4.17
(d, J ˆ 9.5 Hz, 1H, OCHHBPh), 3.75 (s, 3H, OCH3), 3.64 (s, 3H, OCH3),
3.58 (s, 3H, OCH3), 3.45 ± 3.33 (m, 2H, H-7b), 1.38 (s, 9H, tBuO); 13C NMR
(100 MHz, CD3OD): d ˆ 174.5, 162.0, 159.5, 158.0, 157.5, 139.4, 138.9, 133.1,
130.3, 129.4, 129.3, 128.7, 128.6, 126.0, 120.2, 112.4, 104.0, 99.5, 79.5, 74.7,
74.0, 63.9, 58.6, 56.2, 56.0, 55.8, 28.7; HRMS (FAB) calcd for C31H36N4O8Cs
hexanes); [a]2D2
ˆ
23.0 (c ˆ 2.7, EtOAc); IR (thin film): nÄmax ˆ 3328, 2932,
2858, 2100, 1676, 1606, 1508, 1419, 1341, 1260, 1202, 1159, 1094, 837,
1
735 cm
;
1H NMR (400 MHz, CD3OD, 330 K): d ˆ 7.58 (s, 2H, H-4b),
7.30 ± 7.18 (m, 5H, ArH), 7.20 (d, J ˆ 1.9 Hz, 1H, H-6b), 7.11 (d, J ˆ 2.4 Hz,
1H, H-5b), 7.03 (dd, J ˆ 8.5, 2.4 Hz, 1H, H-5f), 6.91 (dd, J ˆ 8.1, 1.9 Hz, 1H,
H-6f), 6.90 (d, J ˆ 8.5 Hz, 1H, H-5e), 6.75 (d, J ˆ 8.1 Hz, 1H, H-6e), 6.63 (d,
J ˆ 2.4 Hz, 1H, H-7f), 6.54 (d, J ˆ 2.4 Hz, 1H, H-7d), 5.55 (s, 1H, H-5a),
5.18 (s, 1H, H-4a), 5.16 (d, J ˆ 3.2 Hz, 1H, H-6b), 4.64 (d, J ˆ 3.2 Hz, 1H,
H-6a), 4.51 (dd, J ˆ 6.5, 5.4 Hz, 1H, H-7a), 4.42 (d, J ˆ 12.2 Hz, 1H,
OCHAHPh), 4.39 (d, J ˆ 12.2 Hz, 1H, OCHHBPh), 4.12 (dq, J ˆ 10.8,
7.1 Hz, 1H, OCHAHCH3), 4.07 (dq, J ˆ 10.8, 7.1 Hz, 1H, OCHHBCH3), 3.80
(s, 3H, 7e-OCH3), 3.76 (br.s, 4H, NCH2CH2), 3.61 (s, 3H, 5d-OCH3), 3.60-
3.55 (m, 2H, H-7b), 3.55 (s, 3H, 7c-OCH3), 2.03 (br.s, 4H, NCH2CH2), 1.37
(s, 9H, tBuO), 1.17 (t, J ˆ 7.1 Hz, 3H, OCH2CH3), 0.84 (s, 9H, tBuSi),
0.02 (s, 3H, CH3Si), 0.15 (s, 3H, CH3Si); 13C NMR (100 MHz, CD3OD,
330 K): d ˆ 171.8, 171.0, 171.0, 162.1, 160.0, 159.2, 156.9, 153.8, 149.2, 139.5,
138.6, 138.5, 134.3, 132.5, 132.5, 130.3, 129.3, 129.3, 129.2, 128.7, 128.6, 127.1,
126.7, 121.6, 121.3, 118.8, 117.6, 112.8, 104.9, 100.2, 81.5, 75.0, 74.3, 74.1, 63.3,
62.8, 61.1, 58.6, 58.2, 56.6, 56.1, 56.1, 28.7, 26.3, 24.7, 19.0, 14.4, 4.4, 5.0;
‡
[M ‡ Cs ] 725.1587, found 725.1601.
AB/C dipeptide 15: A solution of natural biaryl carboxylic acid 6 (30.5 g,
51.5 mmol) and amine 4 (21.1 g, 56.4 mmol) in THF (600 mL) was cooled to
308C. HOAt (23.1 g, 170 mmol) and EDC (29.6 g, 154.4 mmol) were
added and the resulting mixture was left under vigorous stirring for 12 h,
while the temperature was raised slowly to 108C. H2O (1 L) and EtOAc
(2 L) were added, and the aqueous phase was extracted with EtOAc (2 Â
500 mL). The combined organic layers were dried (Na2SO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
25% EtOAc in hexanes) to afford AB/C dipeptide 15 (42.5 g, 87%). 15:
Rf ˆ 0.53 (silica gel, 50% EtOAc in hexanes); [a]D22
ˆ
13.0 (c ˆ 3.4,
EtOAc); IR (thin film): nÄmax ˆ 3421, 2931, 2874, 2099, 1734, 1684, 1606,
1
1505, 1258, 1202, 1161, 1091, 836 cm
;
1H NMR (400 MHz, CD3OD,
330 K): d ˆ 7.30 ± 7.17 (m, 7H, ArH), 7.06 (d, J ˆ 2.4 Hz, 1H, H-5b), 6.94
(dd, J ˆ 8.4, 2.2 Hz, 1H, H-6f), 6.92 (d, J ˆ 8.4 Hz, 1H, H-5e), 6.77 (d, J ˆ
8.4 Hz, 1H, H-6e), 6.64 (d, J ˆ 2.4 Hz, 1H, H-7f), 6.54 (d, J ˆ 2.4 Hz, 1H,
H-7d), 5.22 (s, 1H, H-5a), 5.18 (d, J ˆ 2.7 Hz, 1H, H-6b), 4.63 (d, J ˆ 2.7 Hz,
1H, H-6a), 4.54 (dd, J ˆ 7.3, 4.6 Hz, 1H, H-7a), 4.37 (s, 2H, OCH2Ph), 4.17
(dq, J ˆ 10.8, 7.1 Hz, 1H, OCHAHCH3), 4.11 (dq, J ˆ 10.8, 7.1 Hz, 1H,
OCHHBCH3), 3.82 (s, 3H, 7e-OCH3), 3.59 (s, 3H, 7c-OCH3), 3.57 (s, 3H,
5d-OCH3), 3.57-3.52 (m, 2H, H-7b), 1.43 (s, 9H, tBuO), 1.22 (t, J ˆ 7.1 Hz,
3H, OCH2CH3), 0.87 (s, 9H, tBuSi), 0.01 (s, 3H, CH3Si), -0.14 (s, 3H,
CH3Si); 13C NMR (100 MHz, CD3OD, 330 K): d ˆ 173.0, 171.2, 162.1, 160.1,
159.2, 157.3, 154.0, 139.5, 138.5, 134.2, 132.1, 131.4, 129.7, 129.3, 129.1, 128.7,
128.6, 127.2, 126.8, 121.7, 121.2, 117.7, 112.7, 104.8, 100.1, 81.3, 75.1, 74.4, 73.9,
63.4, 62.9, 60.8, 59.7, 56.5, 56.1, 56.1, 28.8, 26.4, 19.0, 14.4, 4.4, 5.0;
‡
HRMS (FAB) calcd for C60H74Br2ClN9O12SiCs [M ‡ Cs ] 1468.2323, found
1468.2403.
Natural AB/C-O-D azide 18a and unnatural AB/C-O-D azide 18b: In a
flame-dried flask containing AB/C/D tripeptide 17 (150 mg, 0.11 mmol)
were added anhydrous K2CO3 (31 mg, 0.22 mmol) and CuBr´ Me2S (46 mg,
0.22 mmol) followed by the addition of freshly distilled MeCN (2.2 mL).
This mixture was warmed to 708C, freshly distilled pyridine (17 mL,
0.21 mmol) was added, and the mixture was stirred at reflux for 1.5 h. After
the reaction mixture had cooled, EtOAc (5 mL) and saturated aqueous
NH4Cl (5 mL) were added and it was vigorously stirred for 10 min. The
aqueous phase was extracted with EtOAc (3 Â 5 mL). The combined
organic layers were dried (Na2SO4), concentrated, and the residue was
purified by flash column chromatography (silica gel, 0 !15% EtOAc in
benzene, gradient elution) to afford faster moving natural AB/C-O-D azide
18a (47 mg, 34%), and slower moving unnatural AB/C-O-D azide 18b
‡
HRMS (FAB) calcd for C48H62ClN5O11SiCs [M ‡ Cs ] 1080.2958, found
1080.2926.
AB/C amine 16: A solution of AB/C dipeptide 15 (5.20 g, 5.5 mmol) in
CH2Cl2 (50 mL) was cooled to 08C. Freshly distilled 2,6-lutidine (1.9 mL,
16.5 mmol) was added, followed by the dropwise addition of trimethylsilyl
trifluoromethanesulfonate (TMSOTf, 3.3 mL, 18.2 mmol). The reaction
mixture was kept at 08C for 3 h, and then it was allowed to warm to 258C .
After 2 h, it was recooled to 08C and CH2Cl2 (250 mL) was added, followed
by saturated aqueous NaHCO3 (250 mL). The aqueous phase was extracted
with CH2Cl2 (2 Â 250 mL). The combined organic layers were dried
(Na2SO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 35 !80% EtOAc in hexanes, gradient elution)
to afford AB/C amine 16 (4.2 g, 90%). 16: Rf ˆ 0.29 (silica gel, 5% MeOH
(46 mg, 33%). 18a: Rf ˆ 0.69 (silica gel, 30% EtOAc in benzene); [a]D22
ˆ
‡136.7 (c ˆ 1.4, EtOAc); IR (thin film): nÄmax ˆ 3362, 2934, 2099, 1732, 1674,
1
1605, 1505, 1416, 1338, 1259, 1201, 1158, 1098, 835 cm
;
1H NMR
(600 MHz, CD3OD, 330 K): d ˆ 7.42 (dd, J ˆ 8.3, 2.4 Hz, 1H, H-5f), 7.40
(d, J ˆ 2.2 Hz, 1H, H-6b), 7.37 (d, J ˆ 1.8 Hz, 1H, H-4f), 7.29 ± 7.18 (m, 5H,
ArH), 7.03 (d, J ˆ 8.3 Hz, 1H, H-5e), 6.91 (dd, J ˆ 8.6, 2.2 Hz, 1H, H-6f),
6.76 (d, J ˆ 1.8 Hz, 1H, H-4b), 6.67 (d, J ˆ 2.6 Hz, 1H, H-7f), 6.66 (d, J ˆ
8.6 Hz, 1H, H-6e), 6.48 (d, J ˆ 2.6 Hz, 1H, H-7d), 6.43 (br.s, 1H, H-5b),
5.41 (d, J ˆ 2.2 Hz, 1H, H-6b), 5.23 (s, 1H, H-5a), 4.95 (s, 1H, H-4a), 4.71
(d, J ˆ 2.2 Hz, 1H, H-6a), 4.62 (dd, J ˆ 8.1, 3.3 Hz, 1H, H-7a), 4.38
2634
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2634 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
(d, J ˆ 12.3 Hz, 1H, OCHAHPh), 4.30 (dq, J ˆ 10.9, 7.2 Hz, 1H, OCH-
HACH3), 4.17 (d, J ˆ 12.3 Hz, 1H, OCHHBPh), 4.12 (dq, J ˆ 10.9, 7.2 Hz,
1H, OCHHBCH3), 3.84 (s, 3H, 7e-OCH3), 3.79 (br.s, 4H, NCH2CH2), 3.61
(s, 3H, 7c-OCH3), 3.59 (s, 3H, 5d-OCH3), 3.40 (dd, J ˆ 11.0, 3.3 Hz, 1H,
H-7bA), 3.36 (dd, J ˆ 11.0, 8.1 Hz, 1H, H-7bB), 2.06 (br.s, 4H, NCH2CH2),
1.42 (s, 9H, tBuO), 1.32 (t, J ˆ 7.2 Hz, 3H, OCH2CH3), 0.81 (s, 9H, tBuSi),
0.00 (s, 3H, CH3Si), -0.15 (s, 3H, CH3Si); 13C NMR (100 MHz, CD3OD,
330 K): d ˆ 170.7, 170.4, 170.1, 162.0, 159.8, 159.6, 157.7, 155.0, 153.4, 142.6,
139.8, 138.9, 138.8, 136.3, 133.4, 129.5, 129.4, 129.2, 129.1, 128.7, 128.4, 128.1,
127.6, 127.4, 127.2, 124.0, 120.3, 119.9, 117.8, 113.0, 105.0, 100.0, 81.5, 74.9,
74.7, 73.6, 63.2, 62.4, 61.4, 61.2, 58.9, 56.6, 56.0, 28.7, 26.5, 24.7, 18.9, 14.3,
were dried (Na2SO4), concentrated, and the residue was purified by flash
column chromatography (silica gel, 25 !40% EtOAc in hexanes, gradient
elution) to afford unnatural AB/C-O-D alcohol 19b (1.12 g, 98%). 19b:
Rf ˆ 0.32 (silica gel, 40% EtOAc in benzene); [a]D22
ˆ
43.1 (c ˆ 1.1,
MeOH); IR (thin film): nÄmax ˆ 3414, 3318, 2974, 2934, 2872, 2099, 1694,
1667, 1605, 1504, 1488, 1416, 1338, 1261, 1159, 1063, 736, 699 cm 1; 1H NMR
(600 MHz, CD3OD, 330 K): d ˆ 7.66 (d, J ˆ 1.3 Hz, 1H, H-6b), 7.44 (dd, J ˆ
8.6, 2.4 Hz, 1H, H-5f), 7.30-7.20 (m, 7H, ArH), 7.09 (d, J ˆ 8.6 Hz, 1H,
H-5e), 7.08 (d, J ˆ 2.8 Hz, 1H, H-4f), 7.00 (d, J ˆ 8.8 Hz, 1H, H-6e), 6.62 (d,
J ˆ 2.3 Hz, 1H, H-7f), 6.55 (d, J ˆ 2.3 Hz, 1H, H-7d), 6.32 (s, 1H, H-4b),
5.47 (s, 1H, H-4a), 5.42 (d, J ˆ 3.9 Hz, 1H, H-6b), 5.25 (s, 1H, H-5a), 4.82
(d, J ˆ 3.9 Hz, 1H, H-6a), 4.58 (t, J ˆ 6.0 Hz, 1H, H-7a), 4.38 (d, J ˆ
12.4 Hz, 1H, OCHAHPh), 4.33 (d, J ˆ 12.4 Hz, 1H, OCHHBPh), 4.21 (q,
J ˆ 7.1 Hz, 2H, OCH2CH3), 3.85-3.81 (m, 4H, NCH2CH2), 3.82 (s, 3H, 7e-
OCH3), 3.64 (s, 3H, 5d-OCH3), 3.54 (s, 3H, 7c-OCH3), 3.53 (br.d, J ˆ
6.0 Hz, 2H, H-7b), 2.06 (br.s, 4H, NCH2CH2), 1.41 (s, 9H, tBuO), 1.23 (t,
J ˆ 7.1 Hz, 3H, OCH2CH3); 13C NMR (150 MHz, CD3OD, 330 K): d ˆ
171.6, 171.5, 170.3, 162.2, 160.1, 159.6, 155.7, 153.7, 152.6, 141.5, 140.9,
139.7, 138.7, 137.1, 132.1, 130.0, 129.8, 129.5, 129.3, 128.8, 128.7, 128.5, 128.1,
127.1, 126.0, 125.1, 120.8, 120.1, 114.4, 112.9, 104.6, 99.8, 81.4, 74.6, 73.7, 72.7,
63.3, 63.0, 61.1, 58.7, 58.5, 56.6, 56.1, 56.1, 28.8, 24.9, 14.6; HRMS (FAB)
‡
4.1, 5.3; HRMS (FAB) calcd for C60H73BrClN9O12SiCs [M ‡ Cs ]
1386.3074, found 1386.3010. 18b: Rf ˆ 0.42 (silica gel, 30% EtOAc in
benzene); [a]2D2
ˆ
32.9 (c ˆ 2.0, EtOAc); IR (thin film): nÄmax ˆ 3363, 2634,
1
2099, 1718, 1670, 1605, 1489, 1420, 1339, 1253, 1201, 1159, 1093, 837 cm
;
1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.52 (d, J ˆ 1.8 Hz, 1H, H-6b),
7.45 (dd, J ˆ 8.8, 2.4 Hz, 1H, H-5f), 7.32 ± 7.31 (m, 2H, H-6f and H-5b),
7.29 ± 7.21 (m, 5H, ArH), 7.18 (d, J ˆ 8.3 Hz, 1H, H-6e), 7.13 (d, J ˆ 8.8 Hz,
1H, H-5e), 7.08 (d, J ˆ 2.6 Hz, 1H, H-4f), 6.78 (d, J ˆ 0.8 Hz, 1H, H-4b),
6.69 (d, J ˆ 2.2 Hz, 1H, H-7f), 6.56 (d, J ˆ 2.2 Hz, 1H, H-7d), 5.44 (d, J ˆ
2.6 Hz, 1H, H-6b), 5.39 (s, 1H, H-4a), 5.34 (s, 1H, H-5a), 4.62 (d, J ˆ
2.6 Hz, 1H, H-6a), 4.61 (dd, J ˆ 7.7, 3.3 Hz, 1H, H-7a), 4.43 (br.s, 2H,
OCH2Ph), 4.27 (dq, J ˆ 10.8, 7.1 Hz, 1H, OCHAHCH3), 4.09 (dq, J ˆ 10.8,
7.1 Hz, 1H, OCHHBCH3), 3.82 (s, 3H, 7e-OCH3), 3.81 (br.s, 4H,
NCH2CH2), 3.65 (s, 3H, 5d-OCH3), 3.62 (s, 3H, 7c-OCH3), 3.61-3.56 (m,
2H, H-7b), 2.07 (br.s, 4H, NCH2CH2), 1.42 (s, 9H, tBuO), 1.27 (t, J ˆ
7.1 Hz, 3H, OCH2CH3), 0.83 (s, 9H, tBuSi), 0.02 (s, 3H, CH3Si), 0.08 (s,
3H, CH3Si); 13C NMR (100 MHz, CD3OD, 330 K): d ˆ 171.2, 170.3, 169.9,
162.1, 160.0, 157.7, 153.2, 153.1, 141.0, 140.4, 139.6, 138.8, 137.3, 134.3, 130.2,
129.7, 129.3, 128.7, 128.6, 128.1, 127.5, 127.3, 125.5, 120.7, 119.9, 115.0, 113.4,
105.4, 100.2, 81.3, 75.0, 74.3, 74.1, 63.2, 63.1, 61.1, 59.3, 58.6, 56.7, 56.2, 56.1,
‡
calcd for C54H59BrClN9O12Cs [M ‡ Cs ] 1272.2209, found 1272.2150.
Natural AB/C-O-D amine 20a: A solution of natural AB/C-O-D azide 19a
(390 mg, 0.34 mmol) in MeCN/H2O (4:1) (11.5 mL) was treated with
triethylphosphane (100 mL, 0.68 mmol) for 20 h at 258C. The reaction
mixture was concentrated, and the residue was purified by flash column
chromatography (silica gel, 1 !3% MeOH in CH2Cl2, gradient elution) to
afford the natural AB/C-O-D amine 20a (296 mg, 78%). 20a: Rf ˆ 0.29
(silica gel, 5% MeOH in CH2Cl2); [a]2D2 ˆ ‡50.5 (c ˆ 0.40, MeOH); IR
(thin film): nÄmax ˆ 3326, 2971, 2931, 2871, 1713, 1694, 1682, 1667, 1659, 1604,
1556, 1503, 1415, 1316, 1245, 1157, 1058, 735, 699 cm 1; 1H NMR (600 MHz,
CD3OD, 330 K): d ˆ 7.41 (d, J ˆ 2.2 Hz, 1H, H-6b), 7.36 (dd, J ˆ 8.7, 2.6 Hz,
1H, H-5f), 7.35 (dd, J ˆ 8.8, 2.2, 1H, H-6f), 7.31 (d, J ˆ 2.2 Hz, 1H, H-4f),
7.29-7.17 (m, 5H, ArH), 6.97 (d, J ˆ 8.8 Hz, 1H, H-5e), 6.80 (br.s, 1H,
H-4b), 6.77 (d, J ˆ 8.5 Hz, 1H, H-6e), 6.76 (d, J ˆ 2.6 Hz, 1H, H-7f), 6.50 (d,
J ˆ 2.6 Hz, 1H, H-7d), 6.48 (d, J ˆ 1.3 Hz, 1H, H-5b), 5.38 (d, J ˆ 3.5 Hz,
1H, H-6b), 5.36 (s, 1H, H-5a), 5.10 (s, 1H, H-4a), 4.82 (d, J ˆ 3.5 Hz, 1H,
H-6a), 4.32 (d, J ˆ 12.7 Hz, 1H, OCHAHPh), 4.27 (d, J ˆ 12.5 Hz, 1H,
OCHHBPh), 4.21 (dq, J ˆ 7.0, 1.7 Hz, 2H, OCH2CH3), 3.86 (dd, J ˆ 8.3,
3.5 Hz, 1H, H-7a), 3.83 (s, 3H, 7e-OCH3), 3.83 ± 3.78 (br.s, 4H, NCH2CH2),
3.63 (s, 3H, 7c-OCH3), 3.53 (s, 3H, 5d-OCH3), 3.35 (dd, J ˆ 10.1, 3.5 Hz,
1H, H-7bA), 3.30 (dd, J ˆ 10.1, 8.3 Hz, 1H, H-7bB), 2.08 (br.s, 4H,
NCH2CH2), 1.43 (s, 9H, tBuO), 1.27 (t, J ˆ 7.1 Hz, 3H, OCH2CH3); 13C
(150 MHz, CD3OD, 330 K): d ˆ 171.5, 171.3, 170.6, 162.23, 159.7, 159.7,
157.7, 154.0, 153.4, 143.4, 141.9, 140.7, 140.1, 136.9, 132.3, 129.8, 129.7, 129.5,
128.8, 128.6, 128.2, 127.9, 127.9, 127.3, 124.7, 120.7, 120.1, 116.0, 112.7, 104.0,
99.0, 81.6, 76.1, 73.5, 72.9, 63.0, 61.0, 58.8, 56.5, 56.1, 56.1, 52.5, 28.8, 24.9,
28.7, 26.5, 24.7, 18.9, 14.4,
C60H73BrClN9O12SiCs [M ‡ Cs ] 1388.3066, found 1388.3155.
4.3,
5.1; HRMS (FAB) calcd for
‡
Natural AB/C-O-D alcohol 19a: A solution of natural protected AB/C-O-
D alcohol 18a (7.9 g, 6.3 mmol) in THF (65 mL) was cooled to 258C and
tetra-n-butylammonium fluoride (TBAF, 1.0m solution in THF, 6.9 mL,
6.9 mmol) was added dropwise. The reaction mixture was allowed to stir at
158C for 3 h, and then quenched by the addition of saturated aqueous
NH4Cl (300 mL). EtOAc (300 mL) was added, and the aqueous phase was
extracted with EtOAc (100 mL). The combined organic layers were dried
(Na2SO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 25 !40% EtOAc in hexanes, gradient elution)
to afford natural AB/C-O-D alcohol 19a (6.83 g, 95%). 19a: Rf ˆ 0.39
(silica gel, 40% EtOAc in benzene); [a]2D2 ˆ ‡124.2 (c ˆ 0.90, MeOH); IR
(thin film): nÄmax ˆ 3413, 3357, 2972, 2936, 2869, 2836, 2100, 1695, 1667, 1605,
1
1502, 1462, 1413, 1338, 1263, 1201, 1158, 1057, 735, 699 cm
;
1H NMR
(600 MHz, CD3OD, 330 K): d ˆ 7.41 (dd, J ˆ 8.7, 2.5 Hz, 1H, H-5f), 7.38 (d,
J ˆ 1.8 Hz, 1H, H-6b), 7.33 (dd, J ˆ 8.4, 1.7, 1H, H-6f), 7.32 (d, J ˆ 1.8 Hz,
1H, H-4f), 7.28-7.17 (m, 5H, ArH), 6.97 (d, J ˆ 8.5 Hz, 1H, H-5e), 6.75 (d,
J ˆ 8.4 Hz, 1H, H-6e), 6.71 (d, J ˆ 1.9 Hz, 1H, H-4b), 6.62 (d, J ˆ 2.4 Hz,
1H, H-7f), 6.50 (d, J ˆ 2.4 Hz, 1H, H-7d), 6.41 (d, J ˆ 1.7 Hz, 1H, H-5b),
5.37 (d, J ˆ 3.6 Hz, 1H, H-6b), 5.34 (s, 1H, H-5a), 5.04 (s, 1H, H-4a), 4.82
(d, J ˆ 3.7 Hz, 1H, H-6a), 4.56 (dd, J ˆ 8.0, 4.0 Hz, 1H, H-7a), 4.36 (d, J ˆ
12.3 Hz, 1H, OCHAHPh), 4.22 (d, J ˆ 12.2 Hz, 1H, OCHHBPh), 4.21 (q,
J ˆ 7.1 Hz, 2H, OCH2CH3), 3.82 (s, 3H, 7e-OCH3), 3.82-3.78 (br.s, 4H,
NCH2CH2), 3.62 (s, 3H, 7c-OCH3), 3.54 (s, 3H, 5d-OCH3), 3.45 (dd, J ˆ
11.1, 4.0 Hz, 1H, H-7bA), 3.42 (dd, J ˆ 11.1, 8.0 Hz, 1H, H-7bB), 2.05 (br.s,
4H, NCH2CH2), 1.41 (s , 9H, tBuO), 1.25 (t, J ˆ 7.1 Hz, 3H, OCH2CH3);
13C NMR (600 MHz, CD3OD, 330 K): d ˆ 171.5, 171.1, 170.4, 162.2, 159.8,
159.6, 157.8, 155.0, 153.4, 141.9, 140.5, 139.8, 138.8, 136.4, 132.3, 129.9, 129.7,
129.4, 128.8, 128.6, 128.6, 128.0, 127.8, 127.3, 126.9, 124.8, 120.3, 120.3, 116.0,
112.8, 104.3, 99.6, 81.6, 74.9, 73.4, 72.9, 63.0, 62.7, 61.0, 60.5, 58.7, 56.5, 56.1,
‡
14.6; HRMS (FAB) calcd for C54H61BrClN7O12Cs [M ‡ Cs ] 1246.2304,
found 1246.2358.
Unnatural AB/C-O-D amine 20b: A solution of unnatural AB/C-O-D
azide 19b (570 mg, 0.5 mmol) in MeCN/H2O (4:1) (16.8 mL) was treated
with triethylphosphane (145 mL, 1.0 mmol) for 20 h at 258C. The reaction
mixture was concentrated, and the residue was purified by flash column
chromatography (silica gel, 1 !3% MeOH in CH2Cl2, gradient elution) to
afford the unnatural AB/C-O-D amine 20b (440 mg, 79%). 20b: Rf ˆ 0.19
(silica gel, 5% MeOH in CH2Cl2); [a]2D2 (c ˆ 1.9, EtOAc); IR (thin film):
nÄmax ˆ 3293, 2973, 2933, 2836, 1741, 166, 1608, 1556, 1490, 1416, 1262, 1158,
1057, 736 cm 1; 1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.62 (d, J ˆ 1.2 Hz,
1H, H-6b), 7.36 (dd, J ˆ 8.6, 2.4 Hz, 1H, H-5f), 7.30-7.20 (m, 7H, ArH), 7.11
(d, J ˆ 8.3 Hz, 1H, H-5e), 7.09 (s, 1H, H-4f), 7.00 (d, J ˆ 8.5 Hz, 1H, H-6e),
6.74 (d, J ˆ 2.4 Hz, 1H, H-7f), 6.51 (d, J ˆ 2.3 Hz, 1H, H-7d), 6.35 (d, J ˆ
1.5 Hz, 1H, H-4b), 5.43 (s, 1H, H-4a), 5.41 (d, J ˆ 3.8 Hz, 1H, H-6b), 5.25
(s, 1H, H-5a), 4.81 (d, J ˆ 3.8 Hz, 1H, H-6a), 4.34 (br.d, J ˆ 2.9 Hz, 2H,
OCH2Ph), 4.18 (dq, J ˆ 7.2, 1.6 Hz, 2H, OCH2CH3), 3.93 (dd, J ˆ 8.5,
3.9 Hz, 1H, H-7a), 3.82 (s, 3H, 7e-OCH3), 3.82 (br.s, 4H, NCH2CH2), 3.64
(s, 3H, 5d-OCH3), 3.52 (s, 3H, 7c-OCH3), 3.42 (dd, J ˆ 10.0, 4.0 Hz, 1H,
H-7bA), 3.39 (dd, J ˆ 10.0, 8.6 Hz, 1H, H-7bB), 2.06 (br.s, 4H, NCH2CH2),
1.41 (s, 9H, tBuO), 1.24 (t, J ˆ 7.2 Hz, 3H, OCH2CH3); 13C NMR
(150 MHz, CD3OD, 330 K): d ˆ 171.5, 171.4, 170.5, 162.2, 159.8, 159.5,
157.6, 153.5, 152.4, 143.1, 141.4, 140.9, 139.9, 137.1, 132.2, 129.9, 129.5, 129.4,
128.8, 128.6, 128.4, 128.1, 127.9, 126.0, 125.2, 120.8, 120.0, 114.3, 112.6, 104.2,
‡
56.1, 28.8, 24.9, 14.6; HRMS (FAB) calcd for C54H59BrClN9O12Cs [M ‡ Cs ]
1274.2189, found 1274.2244.
Unnatural AB/C-O-D alcohol 19b: A solution of unnatural protected AB/
C-O-D alcohol 18b (1.26 g, 1.0 mmol) in THF (1.5 mL) was cooled to
258C and tetra-n-butylammonium fluoride (TBAF, 1.0m solution in THF,
1.1 mL, 1.1 mmol) was added dropwise. The reaction mixture was allowed
to stir at 158C for 3 h, and then quenched by the addition of saturated
aqueous NH4Cl (50 mL). EtOAc (50 mL) was added, and the aqueous
phase was extracted with EtOAc (20 mL). The combined organic layers
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2635 $ 17.50+.50/0
2635

K. C. Nicolaou et al.
FULL PAPER
99.2, 81.4, 76.0, 73.7, 72.6, 63.0, 61.0, 58.6, 56.6, 56.1, 56.1, 52.7, 28.9, 24.8,
8.3 Hz, 1H, H-6e), 7.04 (d, J ˆ 2.3 Hz, 1H, H-4f), 6.97 (d, J ˆ 8.7 Hz, 1H,
H-5e), 6.90 (d, J ˆ 2.3 Hz, 1H, H-7f), 6.62 (d, J ˆ 2.3 Hz, 1H, H-7d), 5.88 (d,
J ˆ 1.4 Hz, 1H, H-4b), 5.50 (br.s, 1H, H-4a), 5.24 (s, 1H, H-6b), 4.73 (s, 1H,
H-5a), 4.61 (d, J ˆ 11.9 Hz, 1H, OCHAHPh), 4.58 (d, J ˆ 11.8 Hz, 1H,
OCHHBPh), 4.40 (dd, J ˆ 7.6, 4.2 Hz, 1H, H-7a), 4.06 (d, J ˆ 1.6 Hz, 1H,
H-6a), 3.98 (dd, J ˆ 10.2, 7.6 Hz, 1H, H-7bA), 3.90 (dd, J ˆ 10.2, 4.3 Hz, 1H,
H-7bB), 3.82 (s, 3H, 7e-OCH3), 3.82 (br.s, 4H, NCH2CH2),3.68 (s, 3H, 5d-
OCH3), 3.63 (s, 3H, 7c-OCH3), 2.05 (br.s, 4H, NCH2CH2), 1.42 (s, 9H,
tBuO); 13C NMR (150 MHz, CD3COCD3, 323 K): d ˆ 171.0, 168.3, 161.2,
159.7, 158.4, 156.0, 152.4, 152.2, 142.2, 140.8, 139.8, 139.8, 138.7, 136.3, 130.6,
129.4, 129.2, 129.1, 128.6, 128.3, 127.6, 127.4, 126.5, 126.1, 125.5, 125.4, 122.8,
119.6, 113.8, 113.7, 106.7, 98.9, 79.9, 73.8, 72.9, 70.6, 64.2, 64.1, 56.3, 55.8,
55.1, 53.1, 53.0, 28.6, 24.4; HRMS (FAB) calcd for C52H55BrClN7O11Cs
‡
14.6; HRMS (FAB) calcd for C54H61BrClN7O12Cs [M ‡ Cs ] 1246.2304,
found 1246.2252.
Natural AB/C-O-D carboxylic acid 21a: A solution of natural AB/C-O-D
carboxylic ester 20a (112 mg, 0.1 mmol) in THF/H2O (1:1) (5 mL) was
cooled at 58C, and lithium hydroxide monohydrate (21 mg, 0.5 mmol)
was added. After vigorous stirring at 08C for 10 min, the reaction was
quenched by the addition of saturated aqueous NH4Cl (5 mL). CH2Cl2
(5 mL) was added, and the pH of the mixture was adjusted to 5 by adding
dropwise a cooled 1% aqueous HCl. The aqueous phase was extracted with
CH2Cl2 (2 Â 5 mL). The combined organic layers were washed with brine
(5 mL), dried (Na2SO4), concentrated, and the residue, crude carboxylic
acid 21a (100 mg, 92%), was used in the macrolactamization reaction
without further purification.
‡
[M ‡ Cs ] 1202.1865, found 1202.1799.
Unnatural AB/C-O-D carboxylic acid 21b: A solution of unnatural AB/C-
O-D carboxylic ester 20b (89 mg, 80 mmol) in THF/H2O (1:1) (4 mL) was
cooled at 58C, and lithium hydroxide monohydrate (17 mg, 0.4 mmol)
was added. After vigorous stirring at 08C for 10 min, the reaction was
quenched by the addition of saturated aqueous NH4Cl (4 mL). CH2Cl2
(4 mL) was added, and the pH of the mixture was adjusted to 5 by adding
dropwise a cooled 1% aqueous HCl. The aqueous phase was extracted with
CH2Cl2 (2 Â 5 mL). The combined organic layers were washed with brine
(5 mL), dried (Na2SO4), concentrated, and the residue, crude carboxylic
acid 21b (78 mg, 90%), was used in the macrolactamization reaction
without further purification.
Natural AB/C-O-D silyl alcohol 23a: A solution of natural AB/C-O-D
alcohol 22a (790 mg, 0.74 mmol) in CH2Cl2 (40 mL) was cooled to 208C.
Freshly distilled 2,6-lutidine (1.3 mL, 11 mmol) was added dropwise,
followed by the dropwise addition of tert-butyldimethylsilyl trifluorome-
thanesulfonate (TBSOTf, 0.85 mL, 3.7 mmol). The reaction mixture was
stirred at 158C for 2 h, quenched by the addition of saturated aqueous
NaHCO3 (40 mL), and then left under vigorous stirring at 258C for 2 h. The
aqueous phase was extracted with EtOAc (100 mL). The combined organic
layers were washed with brine (20 mL), dried (Na2SO4), concentrated, and
the residue was purified by flash column chromatography (silica gel,
0 !50% EtOAc in hexanes, gradient elution) to afford natural AB/C-O-D
silyl alcohol 23a (744 mg, 85%). 23a: Rf ˆ 0.56 (silica gel, 40% EtOAc in
Natural AB/C-O-D bicyclic triazene 22a: A solution of crude natural AB/
C-O-D amino acid 21a (100 mg, 0.092 mmol) in freshly distilled DMF
(20 mL) was cooled to 08C. Freshly distilled iPr2NEt (80 mL, 0.46 mmol)
and pentafluorophenyl diphenylphosphinate (FDPP, 108 mg, 0.28 mmol)
were added, and the mixture was allowed to warm slowly to 258C. After
stirring for 12 h, EtOAc (100 mL) was added, and the reaction mixture was
washed with brine (3 Â 50 mL). The combined aqueous phases were
extracted with EtOAc (50 mL). The combined organic layers were dried
(Na2SO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 0.5 !1.5% MeOH in CH2Cl2, gradient elution)
to afford natural AB/C-O-D bicyclic triazene 22a (85 mg, 86%). 22a: Rf ˆ
benzene); [a]2D2 ˆ ‡38.0 (c ˆ 0.70, MeOH); IR (thin film): nÄmax ˆ 3308,
1
2953, 2928, 2857, 1680, 1655, 1486, 1262, 1158, 1104, 838, 782, 700 cm
;
1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.61 (d, J ˆ 2.0 Hz, 1H, H-6b),
7.40 (dd, J ˆ 8.3, 1.7 Hz, 1H, H-6f), 7.38-7.25 (m, 6H, ArH), 7.11 (bd, J ˆ
8.3 Hz, 1H, H-5f), 7.07 (d, J ˆ 8.5 Hz, 1H, H-6e), 7.03 (d, J ˆ 2.2 Hz, 1H,
H-5b), 6.95 (d, J ˆ 8.1 Hz, 1H, H-5e), 6.95 (s, 1H, H-7f), 6.62 (d, J ˆ 2.2 Hz,
1H, H-7d), 5.82 (s, 1H, H-4b), 5.48 (br.s, 1H, H-4a), 5.26 (s, 1H, H-6b),
4.67 (s, 1H, H-5a), 4.58 (d, J ˆ 11.4 Hz, 1H, OCHAHPh), 4.55 (d, J ˆ
11.8 Hz, 1H, OCHHBPh), 4.42-4.39 (m, 1H, H-7a), 4.04 (br.s, 1H,
H-6a), 3.92 (t, J ˆ 11.4 Hz, 1H, H-7bA), 3.84 (dd, J ˆ 11.6, 3.5 Hz, 1H,
H-7bB), 3.82 (s, 3H, 7e-OCH3), 3.82 ± 3.78 (br.s, 4H, NCH2CH2), 3.67 (s,
3H, 7c-OCH3), 3.62 (s, 3H, 5d-OCH3), 2.04 (br.s, 4H, NCH2CH2), 1.40 (s,
9H, tBuO), 0.86 (s, 9H, tBuSi), 0.02 (s, 3H, CH3Si), 0.00 (s, 3H, CH3Si);
13C NMR (150 MHz, CD3OD, 330 K): d ˆ 173.0, 172.1, 169.2, 162.0, 160.2,
159.0, 157.6, 153.4, 153.1, 142.1, 141.2, 139.9, 139.5, 137.1, 129.6, 129.5, 129.4,
129.4, 129.3, 129.0, 128.3, 128.2, 127.5, 126.2, 126.1, 124.9, 123.1, 120.3, 114.7,
114.3, 106.9, 99.7, 81.4, 75.0, 74.5, 71.0, 65.3, 56.6, 56.6, 56.3, 55.9, 53.3, 28.8,
26.4, 24.9, 19.3, 4.6, 4.7; HRMS (FAB) calcd for C58H69BrClN7O11SiCs
0.24 (silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
46.6 (c ˆ 1.1, EtOAc); IR
(thin film): nÄmax ˆ 3317, 2970, 2929, 2873, 1693, 1681, 1667, 1659, 1605, 1555,
1504, 1485, 1415, 1320, 1248, 1158, 1058, 734, 700 cm 1; 1H NMR (600 MHz,
CD3OD, 330 K): d ˆ 7.62 (d, J ˆ 2.2 Hz, 1H, H-6b), 7.46 (dd, J ˆ 8.3, 2.2 Hz,
1H, H-6f), 7.38 ± 7.25 (m, 6H, ArH), 7.14 (dd, J ˆ 8.8, 2.2 Hz, 1H, H-5f),
7.07 (d, J ˆ 2.2 Hz, 1H, H-5b), 7.06 (d, J ˆ 8.1 Hz, 1H, H-6e), 6.97 (d, J ˆ
8.8 Hz, 1H, H-5e), 6.91 (d, J ˆ 2.2 Hz, 1H, H-7f), 6.64 (d, J ˆ 2.2 Hz, 1H,
H-7d), 5.84 (s, 1H, H-4b), 5.48 (br.s, 1H, H-4a), 5.21 (s, 1H, H-6b), 4.71 (s,
1H, H-5a), 4.62 (d, J ˆ 11.8 Hz, 1H, OCHAHPh), 4.58 (d, J ˆ 11.8 Hz, 1H,
OCHHBPh), 4.42 (dd, J ˆ 7.7, 4.2 Hz, 1H, H-7a), 4.06 (d, J ˆ 1.3 Hz, 1H,
H-6a), 3.98 (dd, J ˆ 10.1, 7.9 Hz, 1H, H-7bA), 3.90 (dd, J ˆ 10.1, 4.4 Hz, 1H,
H-7bB), 3.84 (s, 3H, 7e-OCH3), 3.81 (br.s, 4H, NCH2CH2), 3.69 (s, 3H, 7c-
OCH3), 3.65 (s, 3H, 5d-OCH3), 2.06 (br.s, 4H, NCH2CH2), 1.42 (s, 9H,
tBuO); 13C NMR (150 MHz, CD3COCD3, 323 K): d ˆ 171.0, 171.0, 168.5,
161.3, 159.9, 158.5, 156.3, 153.1, 152.6, 142.3, 141.0, 140.0, 139.9, 139.0, 136.4,
129.4, 129.3, 128.9, 128.8, 128.5, 128.3, 128.3, 127.6, 127.5, 125.5, 124.5, 122.9,
119.7, 114.9, 113.9, 106.8, 99.0, 80.0, 73.9, 73.3, 70.7, 64.3, 57.0, 56.4, 56.0,
‡
[M ‡ Cs ] 1316.2742, found 1316.2684.
Unnatural AB/C-O-D silyl alcohol 23b: A solution of unnatural AB/C-O-
D alcohol 22b (1.07 g, 1.0 mmol) in CH2Cl2 (50 mL) was cooled to 208C.
Freshly distilled 2,6-lutidine (1.7 mL, 15 mmol) was added dropwise,
followed by the dropwise addition of tert-butyldimethylsilyl trifluorome-
thanesulfonate (TBSOTf, 1.15 mL, 5.0 mmol). The reaction mixture was
stirred at 158C for 2 h, quenched by the addition of saturated aqueous
NaHCO3 (50 mL), and then left under vigorous stirring at 258C for 2 h. The
aqueous phase was extracted with EtOAc (120 mL). The combined organic
layers were washed with brine (25 mL), dried (Na2SO4), concentrated, and
the residue was purified by flash column chromatography (silica gel,
0 !50% EtOAc in hexanes, gradient elution) to afford unnatural silyl
alcohol 23b (945 mg, 80%). 23b: Rf ˆ 0.29 (silica gel, 30% EtOAc in
‡
55.3, 53.1, 28.6, 24.5; HRMS (FAB) calcd for C52H55BrClN7O11Cs [M ‡ Cs ]
1202.1875, found 1202.1933.
Unnatural AB/C-O-D bicyclic triazene 22b: A solution of crude unnatural
AB/C-O-D aminoacid 21b (109 mg, 0.1 mmol) in freshly distilled DMF
(20 mL) was cooled to 08C. Freshly distilled iPr2NEt (87 mL, 0.50 mmol)
and pentafluorophenyl diphenylphosphinate (FDPP, 115 mg, 0.30 mmol)
were added, and the mixture was allowed to warm slowly to 258C. After
stirring for 12 h, EtOAc (100 mL) was added, and the mixture was washed
with brine (3 Â 60 mL). The combined aqueous phases were extracted with
EtOAc (50 mL). The combined organic layers were dried (Na2SO4),
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 1.0 !1.5% MeOH in CH2Cl2, gradient elution) to afford
unnatural bicyclic triazene 22b (64 mg, 60%). 22b: Rf ˆ 0.17 (silica gel, 5%
benzene); [a]2D2
ˆ
43.7 (c ˆ 1.1, MeOH); IR (thin film): nÄmax ˆ 3406, 3283,
2951, 2928, 2855, 1692, 1681, 1658, 1504, 1486, 1416, 1324, 1256, 1201, 1157,
1098, 838, 781, 699 cm 1; 1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.56 (d,
J ˆ 1.8 Hz, 1H, H-6b), 7.40-7.32 (m, 6H, ArH), 7.30 ± 7.27 (m, 1H, ArH),
7.15 (dd, J ˆ 8.3, 1.8 Hz, 1H, H-6f), 7.12 (d, J ˆ 8.3 Hz, 1H, H-6e), 7.02 (d,
J ˆ 2.6 Hz, 1H, H-4f), 6.97 (d, J ˆ 8.3 Hz, 1H, H-5e), 6.96 (d, J ˆ 2.2 Hz,
1H, H-7f), 6.62 (d, J ˆ 2.2 Hz, 1H, H-7d), 5.87 (d, J ˆ 1.3 Hz, 1H, H-4b),
5.52 (br.s, 1H, H-4a), 5.32 (s, 1H, H-6b), 4.71 (s, 1H, H-5a), 4.59 (d, J ˆ
11.8 Hz, 1H, OCHAHPh), 4.56 (d, J ˆ 11.8 Hz, 1H, OCHHBPh), 4.41 (s,
1H, H-7a), 4.06 (d, J ˆ 1.8 Hz, 1H, H-6a), 3.92 (br.t, J ˆ 9.0 Hz, 1H,
H-7bA), 3.86 (dd, J ˆ 9.7, 3.5 Hz, 1H, H-7bB), 3.83 (s, 3H, 7e-OCH3), 3.83-
3.79 (m, 4H, NCH2CH2), 3.68 (s, 3H, 5d-OCH3), 3.63 (s, 3H, 7c-OCH3),
2.06 (br.s, 4H, NCH2CH2), 1.43 (s, 9H, tBuO), 0.89 (s, 9H, tBuSi), 0.04 (s,
3H, CH3Si), 0.02 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3OD, 330 K):
MeOH in CH2Cl2); [a]D22
3415, 3274, 2973, 2934, 2871, 2837, 1659, 1485, 1416, 1318, 1264, 1158,
ˆ
14.7 (c ˆ 1.6, EtOAc); IR (thin film): nÄmax ˆ
1
1056 cm
;
1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.63 (d, J ˆ 2.0 Hz,
1H, H-6b), 7.38 (dd, J ˆ 8.5, 2.0 Hz, 1H, H-6f), 7.37-7.21 (m, 5H, ArH),
7.28 ± 7.25 (m, 1H, ArH), 7.15 (dd, J ˆ 8.6, 2.3 Hz, 1H, H-5f), 7.08 (d, J ˆ
2636
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2636 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
d ˆ 173.1, 172.1, 169.2, 161.9, 160.2, 159.0, 157.6, 153.1, 152.9, 142.1, 141.2,
140.0, 139.5, 137.0, 131.3, 129.6, 129.4, 129.0, 128.6, 128.6, 128.1, 126.8, 126.2,
126.1, 125.9, 123.1, 120.4, 114.3, 113.9, 107.0, 99.7, 81.4, 74.8, 74.5, 71.0, 65.2,
56.6, 56.5, 56.3, 55.9, 53.4, 28.8, 26.4, 24.9, 19.3, 4.6, 4.7; HRMS (FAB)
[a]2D2
ˆ
35.5 (c ˆ 1.5, CHCl3); IR (thin film): nÄmax ˆ 3410, 2932, 2100, 1675,
1
1606, 1499, 1418, 1342, 1259, 1201, 1158, 1094 cm
;
1H NMR (500 MHz,
CD3COCD3): d ˆ 8.67 (s, 1H), 8.08 (d, J ˆ 7.5 Hz, 1H), 7.76 (d, J ˆ 9.0 Hz,
1H), 7.67 (s, 2H), 7.33 ± 7.24 (m, 5H), 7.16 (d, J ˆ 2.0 Hz, 1H), 7.01 (d, J ˆ
8.0 Hz, 1H), 6.92 (d, J ˆ 9.0 Hz, 1H), 6.88 (d, J ˆ 8.0 Hz, 1H), 6.71 (d, J ˆ
8.5 Hz, 1H), 6.64 (d, J ˆ 2.5 Hz, 1H), 6.59 (d, J ˆ 2.5 Hz, 1H), 6.56 ± 6.55
(m, 1H), 5.60 (d, J ˆ 8.0 Hz, 1H), 5.36 (d, J ˆ 7.5 Hz, 1H), 5.22 (d, J ˆ
2.3 Hz, 1H), 4.57 (dd, J ˆ 9.0, 2.3 Hz, 1H), 4.40 (dd, J ˆ 8.0, 4.0 Hz, 1H),
4.35 (d, J ˆ 12.5 Hz, 1H, OCHHBPh), 4.32 (d, J ˆ 12.5 Hz, 1H, OCHHBPh),
4.15 ± 4.12 (m, 1H, OCHAHCH3), 4.08 ± 4.04 (m, 1H, OCHHBCH3), 3.91 ±
3.88 (m, 2H, NCH2CH2), 3.83 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.66 (s,
3H, OCH3), 3.63 ± 3.60 (m, 2H, NCH2CH2), 3.49 ± 3.44 (m, 2H, H-7b), 2.04
(br.s, 4H, NCH2CH2), 1.31 (s, 9H, tBuO), 1.19 (t, J ˆ 7.0 Hz, 3H,
OCH2CH3), 0.83 (s, 9H, tBuSi), 0.02 (s, 3H, CH3Si), 0.18 (s, 3H,
CH3Si); 13C NMR (125 MHz, CD3COCD3): d ˆ 170.8, 170.1, 169.2, 161.2,
159.1, 157.2, 155.4, 153.0, 148.5, 139.6, 138.9, 138.6, 133.9, 132.7, 132.2, 131.1,
129.0, 128.6, 128.2, 128.0, 127.9, 127.0, 124.9, 120.4, 120.1, 118.0, 117.2, 111.7,
104.0, 99.1, 79.7, 74.3, 74.2, 73.2, 63.3, 61.9, 60.1, 57.4, 56.7, 56.1, 55.7, 55.6,
51.7, 47.3, 28.4, 26.0, 24.6, 24.1, 18.6, 14.4, 4.5, 5.3; HRMS (FAB) calcd
‡
calcd for C58H69BrClN7O11SiCs [M ‡ Cs ] 1314.2751, found 1314.2680.
AB/C dipeptide 24: A solution of amine 4 (1.68 g, 4.5 mmol) and unnatural
biaryl carboxylic acid 14 (2.67 g, 4.5 mmol) in THF (50 mL) was cooled to
08C. HOAt (2.02 g, 14.9 mmol) and EDC (2.59 g, 13.5 mmol) were added,
and the reaction mixture was stirred at 08C for 10 h. The reaction was
quenched by the addition of saturated aqueous citric acid (10 mL) and the
resulting mixture was extracted with EtOAc (4 Â 60 mL). The combined
organic layers were washed with H2O (100 mL), brine (100 mL), dried
(Na2SO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 20 !30% EtOAc in hexanes, gradient elution)
to afford AB/C dipeptide 24 (3.54 g, 83% yield). 24: Rf ˆ 0.09 (silica gel,
30% EtOAc in hexanes); [a]D22
ˆ
24.5 (c ˆ 1.6, CHCl3); IR (thin film):
nÄmax ˆ 3425, 2943, 2861, 2097, 1696, 1602, 1496, 1349, 1255, 1202, 1155, 1091,
1026 cm 1; 1H NMR (500 MHz, CD3COCD3): d ˆ 8.67 (s, 1H), 7.68 (d, J ˆ
8.5 Hz, 1H), 7.37 (s, 1H), 7.32-7.22 (m, 5H), 7.14 (dd, J ˆ 8.5, 2.0 Hz, 1H),
7.11 (d, J ˆ 2.0 Hz, 1H), 6.99 (d, J ˆ 8.5 Hz, 1H), 6.95 (d, J ˆ 8.5 Hz, 1H),
6.81 (d, J ˆ 8.0 Hz, 1H), 6.63 (d, J ˆ 2.0 Hz, 1H), 6.58 (d, J ˆ 2.0 Hz, 1H),
6.46 (d, J ˆ 7.5 Hz, 1H), 5.31 ± 5.29 (m, 2H), 4.62 (dd, J ˆ 9.0, 2.5 Hz, 1H),
4.41 (dd, J ˆ 9.0, 4.0 Hz, 1H), 4.29 (d, J ˆ 12.0 Hz, 1H, OCHAHPh), 4.26 (d,
J ˆ 12.0 Hz, 1H, OCHHBPh), 4.20-4.17 (m, 1H, OCHAHCH3), 4.12 ± 4.09
(m, 1H, OCHHBCH3), 3.83 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.65 (s, 3H,
OCH3), 3.49 (dd, J ˆ 10.8, 9.0 Hz, 1H, H-7bA), 3.41 (dd, J ˆ 10.8, 3.7 Hz,
1H, H-7bB), 1.38 (s, 9H, tBuO), 1.25 (t, J ˆ7.1 Hz, 3H, OCH2CH3), 0.87 (s,
9H, tBuSi), 0.02 (s, 3H, CH3Si), 0.15 (s, 3H, CH3Si); 13C NMR (125 MHz,
CD3COCD3): d ˆ 171.5, 170.4, 161.2, 159.1, 157.2, 155.7, 153.1, 139.5, 138.5,
134.0, 132.5, 131.7, 130.4, 128.9, 128.6, 128.2, 128.0, 127.0, 125.1, 120.5, 120.0,
117.2, 111.7, 103.9, 99.0, 79.4, 74.4, 74.3, 73.1, 63.1, 62.0, 60.0, 58.1, 56.0, 55.7,
‡
for C60H74Br2ClN9O12SiCs [M ‡ Cs ] 1468.2315, found 1468.2410.
AB/C-O-D azide 27a and AB/C-O-D azide 27b: To a solution of AB/C
tripeptide 26 (1.60 g, 1.2 mmol) in degassed acetonitrile (150 mL) were
added sequentially CuBr´ Me2S (1.04 g, 3.6 mmol), K2CO3 (497 mg,
3.6 mmol), and pyridine (300 mL, 3.6 mmol). The reaction mixture was
heated at reflux for 20 min and then it was cooled to 258C. The reaction
mixture was diluted with EtOAc (400 mL) and the organic layers were
washed with 5% aqueous NH4Cl (200 mL), H2O (200 mL), brine (200 mL),
dried (Na2SO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 10 !30% EtOAc in hexanes, gradient elution)
to afford AB/C-O-D azide 27a (452 mg, 30% yield) and AB/C-O-D azide
27b (467 mg, 31% yield). 27a: Rf ˆ 0.53 (silica gel, 40% acetone in
55.6, 28.5, 26.1, 18.6, 14.4,
C48H62ClN5O11SiCs [M ‡ Cs ] 1080.2958, found 1080.2997.
4.4,
5.3; HRMS (FAB) calcd for
hexanes); [a]2D2 ˆ ‡41.9 (c ˆ 1.1, CHCl3); IR (thin film): nÄmax ˆ 3411, 2944,
‡
1
2844, 2099, 1707, 1602, 1488, 1463, 1414, 1334, 1255, 1155, 1096 cm
;
AB/C amine 25: A solution of AB/C dipeptide 24 (1.61 g, 1.7 mmol) in
CH2Cl2 (20 mL) was cooled to 08C. Trimethylsilyl trifluoromethanesulfo-
nate (TMSOTf, 1.04 mL, 5.8 mmol) and 2,6-lutidine (594 mL, 5.1 mmol)
were added, and the reaction mixture was stirred at 08C for 3 h. The
reaction was quenched by the addition of saturated aqueous NaHCO3
(10 mL) and the resulting mixture was extracted with CH2Cl2 (2 Â 10 mL).
The combined organic layers were washed with H2O (20 mL), brine
(20 mL), dried (Na2SO4), concentrated, and the residue was purified by
flash column chromatography (silica gel, 30 !50% EtOAc in hexanes,
gradient elution) to afford AB/C amine 25 (1.31 g, 91% yield). 25: Rf ˆ 0.15
1H NMR (500 MHz, CDCl3): d ˆ 7.51 (s, 1H), 7.40 (d, J ˆ 2.0 Hz, 1H),
7.31 ± 7.23 (m, 5H), 7.19 (d, J ˆ 7.0 Hz, 1H), 7.08 (d, J ˆ 9.0 Hz, 1H), 7.04 (d,
J ˆ 8.5 Hz, 1H), 6.95 (d, J ˆ 1.5 Hz, 1H), 6.91 (d, J ˆ 8.5 Hz, 1H), 6.86 ± 6.84
(m, 1H), 6.61 (d, J ˆ 2.2 Hz, 1H), 6.52 (d, J ˆ 2.2 Hz, 1H), 5.78 (d, J ˆ
9.0 Hz, 1H), 5.63 (d, J ˆ 8.0 Hz, 1H), 5.51 (d, J ˆ 6.0 Hz, 1H), 5.31-5.28 (m,
2H), 5.12 (br.s, 1H), 4.61 (dd, J ˆ 7.7, 1.5 Hz, 1H), 4.49 (dd, J ˆ 8.5, 4.0 Hz,
1H), 4.41-4.36 (m, 2H, OCH2Ph), 4.31-4.28 (m, 1H, OCHAHCH3), 4.09 ±
4.05 (m, 1H, OCHHBCH3), 3.98 (br.s, 2H, NCH2CH2), 3.85 (s, 3H, OCH3),
3.77 (br.s, 2H, NCH2CH2), 3.76 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.41
(dd, J ˆ 10.0, 9.0 Hz, 1H, H-7bA), 3.32 (dd, J ˆ 10.0, 4.0 Hz, 1H, H-7bB),
2.04 (br.s, 4H, NCH2CH2), 1.40 (s, 9H, tBuO), 1.32 (t, J ˆ 7.0 Hz, 3H,
OCH2CH3), 0.70 (s, 9H, tBuSi), 0.10 (s, 3H, CH3Si), 0.20 (s, 3H,
CH3Si); 13C NMR (125 MHz, CDCl3): d ˆ 169.3, 168.4, 167.8, 160.5, 158.0,
156.7, 155.1, 153.0, 138.3, 137.9, 137.7, 137.1, 135.9, 134.8, 130.3, 128.5, 128.4,
128.2, 127.6, 127.5, 127.4, 127.0, 126.5, 126.0, 125.8, 125.1, 121.6, 119.1, 117.6,
111.8, 102.3, 98.7, 79.9, 73.6, 73.4, 73.1, 62.7, 61.8, 60.0, 57.8, 55.6, 55.5, 55.4,
51.2, 46.4, 29.7, 28.3, 25.4, 23.9, 23.6, 17.7, 14.1, 4.6, 5.8; HRMS (FAB)
(silica gel, 50% EtOAc in hexanes); [a]D22
ˆ
28.1 (c ˆ 1.6, CHCl3); IR
(thin film): nÄmax ˆ 3448, 2097, 1713, 1696, 1646, 1608, 1508, 1490, 1261, 1155,
1
1061, 1020 cm
;
1H NMR (500 MHz, CD3COCD3): d ˆ 8.92 (br.s, 1H),
8.55 (d, J ˆ 10.0 Hz, 1H), 7.44 (dd, J ˆ 8.5, 2.0 Hz, 1H), 7.35 (s, 1H), 7.30 ±
7.27 (m, 2H), 7.23 ± 7.22 (m, 3H), 7.15-7.13 (m, 2H), 6.99 (d, J ˆ 8.5 Hz, 1H),
6.89 (d, J ˆ 8.5 Hz, 1H), 6.63 (d, J ˆ 2.0 Hz, 1H), 6.59 (d, J ˆ 2.0 Hz, 1H),
5.37 (s, 1H), 4.78 (s, 1H), 4.63 (dd, J ˆ 10.0, 1.9 Hz, 1H), 4.47 (dd, J ˆ 9.0,
3.5 Hz, 1H), 4.27 (d, J ˆ12.0 Hz, 1H, OCHAHPh), 4.21 (d, J ˆ 12.0 Hz, 1H,
OCHHBPh), 4.16-4.12 (m, 1H, OCHAHCH3), 4.06-4.02 (m, 1H,
OCHHBCH3), 3.83 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.64 (s, 3H,
OCH3), 3.53 (dd, J ˆ 11.0, 9.0 Hz, 1H, H-7bA), 3.43 (dd, J ˆ 11.0, 3.5 Hz,
1H, H-7bB), 1.19-1.16 (m, 3H, OCH2CH3), 0.95 (s, 9H, tBuSi), 0.05 (s, 3H,
CH3Si), 0.15 (s, 3H, CH3Si); 13C NMR (125 MHz, CD3COCD3): d ˆ
171.9, 170.5, 169.8, 161.3, 159.1, 156.8, 153.3, 139.4, 138.5, 134.2, 132.9,
132.8, 129.2, 128.9, 128.8, 128.0, 126.7, 124.9, 120.5, 119.9, 117.0, 111.7, 103.8,
99.0, 74.7, 74.6, 73.1, 67.9, 63.5, 62.0, 58.4, 56.0, 55.7, 55.6, 26.0, 18.6, 14.3,
‡
calcd for C60H73BrClN9O12SiCs [M ‡ Cs ] 1388.3066, found 1388.3138. 27b:
Rf ˆ 0.41 (silica gel, 40% acetone in hexanes); [a]D22
ˆ
25.9 (c ˆ 0.58,
CHCl3); IR (thin film): nÄmax ˆ 3411, 3341, 2934, 2854, 2357, 2099, 1707, 1672,
1
1602, 1488, 1463, 1414, 1339, 1255, 1160, 1091 cm
;
1H NMR (500 MHz,
CDCl3): d ˆ 7.51 (s, 1H), 7.41 (d, J ˆ 8.0 Hz, 1H), 7.30 (d, J ˆ 7.0 Hz, 1H),
7.29 ± 7.26 (m, 5H), 7.18 (m, 1H), 7.17 (d, J ˆ 7.0 Hz, 1H), 7.09 ± 7.07 (m,
2H), 7.04 (s, 1H), 6.98 (s, 1H), 6.63 (d, J ˆ 2.5 Hz, 1H), 6.53 (d, J ˆ 2.5 Hz,
1H), 5.79-5.77 (m, 2H), 5.38 ± 5.34 (m, 2H), 5.29 (d, J ˆ 7.5 Hz, 1H), 5.21
(br.s, 1H), 4.67 (d, J ˆ 8.5 Hz, 1H), 4.51 (dd, J ˆ 8.5, 4.0 Hz, 1H), 4.39 ± 4.36
(m, 2H, OCH2Ph), 4.32 ± 4.29 (m, 1H, OCHAHCH3), 4.11 ± 4.06 (m, 1H,
OCHHBCH3), 3.99 (br.s, 2H, NCH2CH2), 3.85 (s, 3H, OCH3), 3.78 (s, 3H,
OCH3), 3.77 (br.s, 2H, NCH2CH2), 3.73 (s, 3H, OCH3), 3.40 (dd, J ˆ 10.5,
8.5 Hz, 1H, H-7bA), 3.30 (dd, J ˆ 10.5, 4.0 Hz, 1H, H-7bB), 2.09 (br.s, 4H,
CH2CH2), 1.41 (s, 9H, tBuO), 1.33 (t, J ˆ 7.5 Hz, 3H, OCH2CH3), 0.73 (s,
9H, tBuSi), 0.06 (s, 3H, CH3Si), 0.17 (s, 3H, CH3Si); 13C NMR
(125 MHz, CDCl3): d ˆ 169.1, 168.3, 168.2, 160.5, 158.0, 156.8, 152.5, 151.9,
140.7, 138.7, 138.0, 137.8, 135.3, 134.6, 133.9, 129.6, 128.9, 128.3, 127.6, 127.4,
127.3, 126.9, 126.8, 125.7, 125.6, 125.0, 124.9, 117.7, 115.0, 111.8, 102.3, 98.8,
80.0, 73.5, 73.3, 73.0, 62.7, 61.8, 60.0, 59.0, 58.1, 55.6, 55.5, 55.4, 51.1, 46.5,
28.2, 25.4, 23.9, 23.6, 17.7, 14.1, 4.5, 5.8; HRMS (FAB) calcd for
‡
4.4, 5.4; HRMS (FAB) calcd for C43H54ClN5O9SiCs [M ‡ Cs ] 980.2434,
found 980.2404.
AB/C tripeptide 26: A solution of AB/C amine 25 (1.27 g, 1.5 mmol) and
carboxylic acid 7 (756 mg, 1.5 mmol) in THF (15 mL) was cooled to 08C.
HOAt (673 mg, 5.0 mmol) and EDC (867 mg, 4.5 mmol) were added, and
the reaction mixture was stirred at 08C for 10 h. The reaction was quenched
by the addition of saturated NH4Cl (5 mL) and the resulting mixture was
extracted with EtOAc (4 Â 15 mL). The combined organic layers were
washed with H2O (30 mL), brine (30 mL), dried (Na2SO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
15 !35% EtOAc in hexanes, gradient elution) afforded AB/C tripeptide
26 (1.40 g, 70% yield). 26: Rf ˆ 0.25 (silica gel, 40% EtOAc in hexanes);
‡
C60H73BrClN9O12SiCs [M ‡ Cs ] 1388.3066, found 1388.2990.
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2637 $ 17.50+.50/0
2637

K. C. Nicolaou et al.
FULL PAPER
1
AB/C-O-D alcohol 28a: A solution of AB/C-O-D TBS-ether 27a (1.13 g,
0.9 mmol) in THF (10 mL) was cooled to 08C. Tetra-n-butylammonium
fluoride (TBAF, 1.0m solution in THF, 1.4 mL, 1.4 mmol) was added, and
the reaction mixture was stirred at 08C for 2 h. The reaction was quenched
by the addition of saturated aqueous NH4Cl (5 mL) and the resulting
mixture was extracted with EtOAc (4 Â 10 mL). The combined organic
layers were washed with 5% aqueous NH4Cl (20 mL), H2O (20 mL), brine
(20 mL), dried (Na2SO4), concentrated, and the residue was purified by
flash column chromatography (silica gel, 20 !40% EtOAc in hexanes,
gradient elution) to afford AB/C-O-D alcohol 28a (925 mg, 90% yield).
28a: Rf ˆ 0.26 (silica gel, 40% acetone in hexanes); [a]2D2 ˆ ‡52.2 (c ˆ 1.86,
CHCl3); IR (thin film): nÄmax ˆ 3316, 2965, 2097, 1698, 1659, 1605, 1488, 1415,
1337, 1317, 1244, 1181, 1064, 1025 cm 1; 1H NMR (400 MHz, CD3COCD3):
d ˆ 7.90 (d, J ˆ 8.4 Hz, 1H), 7.68 (d, J ˆ 7.1 Hz, 1H), 7.56 (d, J ˆ 8.4 Hz, 1H),
7.54 (d, J ˆ 1.5 Hz, 1H), 7.49 (d, J ˆ 8.1 Hz, 1H), 7.32 ± 7.21 (m, 5H), 7.19 (d,
J ˆ 2.4 Hz, 1H), 7.15 (d, J ˆ 8.4 Hz, 1H), 7.06 (d, J ˆ 8.7 Hz, 1H), 6.65 (d,
J ˆ 2.4 Hz, 1H), 6.58 (d, J ˆ 2.4 Hz, 1H), 6.37 (d, J ˆ 1.5 Hz, 1H), 6.36-6.34
(m, 1H), 5.79 (d, J ˆ 9.2 Hz, 1H), 5.59 (d, J ˆ 8.5 Hz, 1H), 5.48 (dd, J ˆ 9.0,
4.1 Hz, 1H), 5.36 (d, J ˆ 8.6 Hz, 1H), 4.92 (dd, J ˆ 7.3, 4.3 Hz, 1H), 4.51 (t,
J ˆ 6.1 Hz, 1H), 4.36 (d, J ˆ 12.3 Hz, 1H, OCHAHPh), 4.30 (d, J ˆ 12.3 Hz,
1H, OCHHBPh), 4.15 (q, J ˆ 7.1 Hz, 2H, OCH2CH3), 3.90 (br.s, 2H,
NCH2CH2), 3.83 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.65 (br.s, 2H,
NCH2CH2), 3.64 (s, 3H, OCH3), 3.55 (d, J ˆ 6.2 Hz, 2H, H-7b), 2.06 (br.s,
4H, NCH2CH2), 1.35 (s, 9H, tBuO), 1.22 (t, J ˆ 4.1 Hz, 3H, OCH2CH3);
13C NMR (100 MHz, CD3COCD3): d ˆ 170.8, 169.6, 169.3, 161.3, 159.1,
157.4, 152.9, 151.9, 140.7, 140.6, 139.5, 138.5, 137.1, 132.8, 129.8, 129.3, 129.1,
128.9, 128.1, 128.1, 128.0, 127.1, 126.8, 125.4, 125.3, 124.6, 119.7, 119.3, 114.7,
111.8, 103.9, 99.0, 79.7, 74.4, 73.1, 71.7, 63.5, 61.9, 61.3, 57.6, 57.0, 56.0, 55.7,
55.6, 51.6, 47.0, 28.4, 24.5, 24.1, 14.4; HRMS (FAB) calcd for
1654, 1600, 1488, 1415, 1317, 1259, 1200, 1157, 1059, 1030 cm
;
1H NMR
(500 MHz, CD3COCD3): d ˆ 7.92 (d, J ˆ 8.3 Hz, 1H), 7.64 (br.s, 1H), 7.58
(d, J ˆ 8.5 Hz, 1H), 7.53 (d, J ˆ 1.5 Hz, 1H), 7.47 (d, J ˆ 8.3 Hz, 1H), 7.30 (s,
1H), 7.27 ± 7.24 (m, 4H), 7.19 ± 7.16 (m, 4H), 7.03 (d, J ˆ 9.0 Hz, 1H), 6.90 (d,
J ˆ 2.5 Hz, 1H), 6.47 (d, J ˆ 2.5 Hz, 1H), 6.39 (s, 1H), 6.31 (d, J ˆ 7.5 Hz,
1H), 5.60 (d, J ˆ 8.5 Hz, 1H), 5.47 ± 5.44 (m, 1H), 5.35 (d, J ˆ 8.5 Hz, 1H),
4.91-4.88 (m, 1H), 4.55 (t, J ˆ 6.0 Hz, 1H), 4.25 (d, J ˆ 12.5 Hz, 1H,
OCHAHPh), 4.18 (d, J ˆ 12.5 Hz, 1H, OCHHBPh), 4.17 ± 4.11 (m, 2H,
OCH2CH3), 3.89 (br.s, 2H, NCH2CH2), 3.79 (s, 3H, OCH3), 3.66 (br.s, 2H,
NCH2CH2), 3.65 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 3.57 (br.d, J ˆ 6.0 Hz,
2H, H-7b), 2.05 ± 2.03 (m, 4H, NCH2CH2), 1.36 (s, 9H, tBuO), 1.19 (t, J ˆ
7.0 Hz, 3H, OCH2CH3); 13C NMR (125 MHz, CD3COCD3): d ˆ 170.8,
169.6, 169.3, 160.9, 158.9, 157.8, 156.1, 152.9, 152.0, 143.0, 140.7, 140.6, 140.3,
137.2, 133.0, 129.6, 129.3, 128.9, 128.4, 127.9, 127.7, 127.1, 126.7, 126.6, 125.5,
124.7, 119.7, 119.2, 114.8, 111.5, 105.4, 97.7, 79.7, 76.3, 72.8, 71.9, 61.9, 61.4,
61.3, 57.6, 57.1, 56.1, 55.6, 55.4, 51.6, 47.0, 28.5, 24.5, 24.1, 14.4; HRMS (FAB)
‡
calcd for C54H62BrClN7O12 [M ‡ H ] 1114.3328, found 1114.3355.
AB/C-O-D amine 29b: To a solution of AB/C-O-D azide 28b (870 mg,
0.8 mmol) in THF (8 mL) were added triphenylphosphane (629 mg,
2.4 mmol) and H2O (144 mL, 8.0 mmol). The reaction mixture was heated
to 608C for 3 h. The reaction mixture was cooled to 258C and diluted with
EtOAc (40 mL). The organic layer was washed with 5% aqueous NaHCO3
(20 mL), H2O (20 mL), brine (20 mL), dried (Na2SO4), concentrated, and
the residue was purified by flash column chromatography (silica gel,
1 !4% MeOH in CHCl3, gradient elution) to afford AB/C-O-D amine
29b (635 mg, 71% yield). 29b: Rf ˆ 0.11 (silica gel, 5% MeOH in CHCl3);
[a]2D2
ˆ
24.6 (c ˆ 1.2, CHCl3); IR (thin film): nÄmax 3307, 2948, 2858, 1699,
1
1660, 1604, 1486, 1413, 1312, 1261, 1200, 1155, 1059 cm
;
1H NMR
‡
C54H59BrClN9O12Cs [M ‡ Cs ] 1272.2209, found 1272.2275.
(500 MHz, CD3COCD3): d ˆ 8.12 (d, J ˆ 8.5 Hz, 1H), 7.73 (s, 1H), 7.68
(br.s, 1H), 7.43 (d, J ˆ 7.5 Hz, 1H), 7.38 ± 7.35 (m, 1H), 7.29 ± 7.17 (m, 7H),
7.10 (d, J ˆ 8.5 Hz, 1H), 7.01 (d, J ˆ 8.5 Hz, 1H), 6.92 (d, J ˆ 2.0 Hz, 1H),
6.47 (d, J ˆ 2.5 Hz, 1H), 6.31 (d, J ˆ 8.0 Hz, 1H), 6.26 (s, 1H), 5.84 (d, J ˆ
8.0 Hz, 1H), 5.54 (d, J ˆ 8.4 Hz, 1H), 5.48 (d, J ˆ 4.1 Hz, 1H), 5.37 (d, J ˆ
8.5 Hz, 1H), 4.98 (dd, J ˆ 7.5, 5.0 Hz, 1H), 4.56 ± 4.53 (m, 1H), 4.25 (d, J ˆ
12.5 Hz, 1H, OCHAHPh), 4.18 (d, J ˆ 12.5 Hz, 1H, OCHHBPh), 4.14 ± 4.10
(m, 2H, OCH2CH3), 3.90 (br.s, 2H, NCH2CH2), 3.79 (s, 3H, OCH3), 3.67 ±
3.65 (m, 2H, NCH2CH2), 3.65 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 3.58 ±
3.55 (m, 2H, H-7b), 2.06 ± 2.00 (m, 4H, NCH2CH2), 1.36 (s, 9H, tBuO),
1.20 ± 1.14 (m, 3H, OCH2CH3); 13C NMR (125 MHz, CD3COCD3): d ˆ
171.0, 169.8, 169.4, 160.9, 158.9, 157.7, 155.9, 152.8, 151.6, 143.0, 141.1, 140.4,
140.2, 137.1, 132.9, 129.9, 129.3, 128.9, 128.2, 128.0, 128.0, 127.7, 127.6, 126.5,
124.5, 124.3, 119.7, 119.3, 113.9, 111.4, 105.4, 97.7, 79.7, 76.3, 72.7, 71.5, 61.9,
61.3, 60.8, 57.8, 57.3, 56.0, 55.6, 55.4, 51.6, 47.0, 28.4, 24.5, 24.1, 14.5; HRMS
AB/C-O-D alcohol 28b: A solution of AB/C-O-D TBS-ether 27b (1.13 g,
0.9 mmol) in THF (10 mL) was cooled to 08C. Tetra-n-butylammonium
fluoride (TBAF, 1.0m solution in THF, 1.4 mL, 1.4 mmol) was added, and
the reaction mixture was stirred at 08C for 2 h. The reaction was quenched
by the addition of saturated aqueous NH4Cl (5 mL) and the resulting
mixture was extracted with EtOAc (4 Â 10 mL). The combined organic
layers were washed with 5% aqueous NH4Cl (20 mL), H2O (20 mL), brine
(20 mL), dried (Na2SO4), concentrated, and the residue was purified by
flash column chromatography (silica gel, 20 !40% EtOAc in hexanes,
gradient elution) to afford AB/C-O-D alcohol 28b (945 mg, 92% yield).
28b: Rf ˆ 0.22 (silica gel, 40% acetone in hexanes); [a]D22
ˆ
27.8 (c ˆ 1.5,
CHCl3); IR (thin film): nÄmax ˆ 3405, 3321, 2973, 2926, 2353, 2100, 1702, 1660,
1
1599, 1486, 1416, 1341, 1317, 1256, 1195, 1153, 1064, 1026 cm
;
1H NMR
(500 MHz, CD3COCD3): d ˆ 8.09 (d, J ˆ 8.0 Hz, 1H), 7.71 (s, 1H), 7.68
(br.s, 1H), 7.45 (d, J ˆ 8.0 Hz, 1H), 7.35 ± 7.32 (m, 1H), 7.31 ± 7.24 (m, 5H),
7.18 (d, J ˆ 2.5 Hz, 1H), 7.07 (d, J ˆ 8.5 Hz, 1H), 7.03 (d, J ˆ 8.5 Hz, 1H),
6.64 (d, J ˆ 2.5 Hz, 1H), 6.57 (d, J ˆ 2.5 Hz, 1H), 6.36 (d, J ˆ7.5 Hz, 1H),
6.26 (s, 1H), 5.84 (d, J ˆ 9.5 Hz, 1H), 5.55 (d, J ˆ 8.5 Hz, 1H), 5.48 (dd, J ˆ
8.5, 5.0 Hz, 1H), 5.38 (d, J ˆ 9.5 Hz, 1H), 4.97 (dd, J ˆ 7.5, 4.5 Hz, 1H), 4.50
(t, J ˆ 6.0 Hz, 1H), 4.36 (d, J ˆ 12.5 Hz, 1H, OCHAHPh), 4.30 (d, J ˆ
12.5 Hz, 1H, OCHHBPh), 4.15 (q, J ˆ 7.0 Hz, 2H, OCH2CH3), 3.92-3.88
(m, 2H, NCH2CH2), 3.83 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.66 ± 3.65 (m,
2H, NCH2CH2), 3.64 (s, 3H, OCH3), 3.53 (d, J ˆ 6.5 Hz, 2H, H-7b), 2.08 ±
2.06 (m, 2H, NCH2CH2), 2.03 ± 2.01 (m, 2H, NCH2CH2), 1.34 (s, 9H,
tBuO), 1.20 (t, J ˆ 6.5 Hz, 3H, OCH2CH3); 13C NMR (125 MHz,
CD3COCD3): d ˆ 171.0, 169.7, 169.4, 161.3, 159.1, 157.4, 155.0, 152.8,
151.7, 141.1, 140.2, 139.6, 138.6, 137.0, 132.6, 130.2, 129.3, 129.0, 128.9, 128.1,
128.0, 127.9, 127.7, 125.4, 124.5, 124.4, 119.6, 119.3, 113.9, 111.8, 103.9, 99.0,
79.7, 74.4, 73.2, 71.5, 63.5, 61.9, 60.9, 57.9, 57.3, 56.1, 55.8, 55.7, 51.6, 47.0, 28.4,
‡
(FAB) calcd for C54H61BrClN7O12Cs [M ‡ Cs ] 1248.2294, found 1248.2347.
AB/C-O-D carboxylic acid 30a: To a solution of AB/C-O-D amino ester
29a (1.23 g, 1.1 mmol) in MeOH/H2O (10:1, 11 mL) at 08C was added
anhydrous Lithium hydroxide (39 mg, 1.7 mmol) and the reaction mixture
was stirred at 08C for 2 h. The reaction was quenched by the slow addition
of saturated aqueous NH4Cl (3 mL) and the resulting mixture was
extracted with EtOAc (3 Â 10 mL). The combined organic layers were
washed with H2O (15 mL), brine (15 mL), dried (Na2SO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
5 !12% MeOH in CHCl3, gradient elution) to afford AB/C-O-D
carboxylic acid 30a (1.10 g, 92% yield). 30a: Rf ˆ 0.25 (silica gel, 15%
MeOH in CHCl3); [a]2D2 ˆ ‡28.6 (c ˆ 0.83, MeOH); IR (thin film): nÄmax
ˆ
1
3371, 2975, 1658, 1606, 1491, 1408, 1246, 1199, 1158, 1059 cm
;
1H NMR
(600 MHz, CD3SOCD3): d ˆ 8.91 (d, J ˆ 8.3 Hz, 1H), 8.77 (d, J ˆ 9.9 Hz,
1H), 8.56 (br.s, 2H), 7.51 (dd, J ˆ 8.6, 1.6 Hz, 1H), 7.44 (s, 1H), 7.33 ± 7.25
(m, 7H), 7.18 (d, J ˆ 8.4 Hz, 1H), 7.11 (s, 1H), 7.01 ± 6.98 (m, 3H), 6.64 (s,
1H), 6.08 (s, 1H), 5.51 (d, J ˆ 8.9 Hz, 1H), 5.35 (d, J ˆ 8.3 Hz, 1H), 4.66 (d,
J ˆ 10.3 Hz, 1H), 4.58 ± 4.51 (m, 1H), 4.38 ± 4.28 (m, 2H, OCH2Ph), 3.87
(br.s, 2H, NCH2CH2), 3.82 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.60 (br.s,
2H, NCH2CH2), 3.59 (s, 3H, OCH3), 3.45 ± 3.35 (2H, obscured by solvent,
H-7b), 2.02 (br.s, 2H, NCH2CH2), 1.97 (br.s, 2H, NCH2CH2), 1.30 (s, 9H,
tBuO); 13C NMR (125 MHz, CD3SOCD3): d ˆ 171.8, 168.3, 168.1, 160.1,
158.0, 155.6, 155.2, 150.7, 150.0, 149.4, 140.9, 138.2, 137.8, 136.6, 135.1, 131.1,
130.9, 130.7, 130.4, 128.1, 127.7, 127.3, 124.6, 124.4, 124.0, 123.1, 118.7, 117.9,
112.4, 111.0, 103.4, 98.9, 78.3, 73.1, 72.2, 71.0, 57.2, 55.8, 55.6, 55.6, 55.5, 54.3,
51.3, 50.8, 46.5, 28.0, 23.5, 23.0; HRMS (FAB) calcd for C52H57BrClN7O12Cs
‡
24.2, 24.1, 14.5; HRMS (FAB) calcd for C54H59BrClN9O12Cs [M ‡ Cs ]
1272.2209, found 1272.2289.
AB/C-O-D amine 29a: To a solution of AB/C-O-D azide 28a (870 mg,
0.8 mmol) in THF (8 mL) were added triphenylphosphane (629 mg,
2.4 mmol) and H2O (144 mL, 8.0 mmol). The reaction mixture was heated
to 608C for 3 h. The reaction mixture was cooled to 258C and diluted with
EtOAc (40 mL). The organic layer was washed with 5% aqueous NaHCO3
(20 mL), H2O (20 mL), brine (20 mL), dried (Na2SO4), concentrated, and
the residue was purified by flash column chromatography (silica gel,
1 !4% MeOH in CHCl3, gradient elution) to afford AB/C-O-D amine 29a
(732 mg, 82% yield). 29a: Rf ˆ 0.17 (silica gel, 5% MeOH in CHCl3);
[a]2D2 ˆ ‡51.9 (c ˆ 1.1, CHCl3); IR (thin film): nÄmax ˆ 3306, 2965, 2926, 1698,
‡
[M ‡ Cs ] 1220.1980, found 1220.2052.
2638
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2638 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
AB/C-O-D carboxylic acid 30b: To a solution of AB/C-O-D amino ester
29b (1.23 g, 1.1 mmol) in MeOH/H2O (10:1, 11 mL) at 08C was added
anhydrous Lithium hydroxide (39 mg, 1.7 mmol) and the reaction mixture
was stirred at 08C for 2 h. The reaction was quenched by the slow addition
of saturated aqueous NH4Cl (3 mL) and the resulting mixture was
extracted with EtOAc (3 Â 10 mL). The combined organic layers were
washed with H2O (15 mL), brine (15 mL), dried (Na2SO4), concentrated,
and the residue was purified by flash column chromatography (silica gel,
5 !12% MeOH in CHCl3, gradient elution) to afford AB/C-O-D
carboxylic acid 30b (1.08 g, 90% yield). 30b: Rf ˆ 0.19 (silica gel, 15%
1H, H-5e), 7.01 (dd, J ˆ 8.5, 2.0 Hz, 1H, H-6f), 6.93 (d, J ˆ 10.0 Hz, 1H,
NH), 6.83 (d, J ˆ 2.5 Hz, 1H, H-6e), 6.76 (d, J ˆ 1.5 Hz, 1H, H-5b), 6.61 (d,
J ˆ 2.5 Hz, 1H, H-7f), 6.58 (d, J ˆ 2.5 Hz, 1H, H-7d), 6.44 (d, J ˆ 1.9 Hz,
1H, H-4b), 6.35 (d, J ˆ 9.0 Hz, 1H, NH), 5.68 ± 5.66 (m, 2H, H-4a and OH),
5.46 (d, J ˆ 8.0 Hz, 1H, H-5a), 5.16-5.11 (m, 1H, H-7a), 4.76 (d, J ˆ 9.5 Hz,
1H, H-6b), 4.49 (d, J ˆ 12.0 Hz, 1H, OCHAHPh), 4.39 (t, J ˆ 10.5 Hz, 1H,
H-6a), 4.32 (d, J ˆ 12.0 Hz, 1H, OCHHBPh), 3.85 (s, 3H, OCH3), 3.84 ± 3.80
(m, 2H, NCH2CH2), 3.69 (s, 3H, OCH3), 3.68 ± 3.61 (m, 2H, NCH2CH2),
3.63 (s, 3H, OCH3), 3.24 (dd, J ˆ10.5, 5.5 Hz, 1H, H-7bA), 3.06 (dd, J ˆ
10.5, 9.0 Hz, 1H, H-7bB), 2.06 ± 1.96 (m, 4H, NCH2CH2), 1.43 (s, 9H,
tBuO); 13C NMR (125 MHz, CD3COCD3): d ˆ 171.4, 170.9, 170.5, 161.0,
159.9, 158.8, 155.6, 153.1, 152.0, 141.5, 139.5, 139.0, 138.7, 137.9, 133.0, 133.0,
130.4, 129.6, 128.8, 128.7, 128.2, 128.0, 126.9, 126.6, 124.9, 121.4, 119.2, 118.9,
114.8, 112.5, 108.7, 98.4, 79.4, 74.2, 72.5, 72.4, 57.4, 56.5, 55.9, 55.8, 55.7, 55.7,
55.4, 51.3, 46.7, 28.2, 24.2, 23.8; HRMS (FAB) calcd for C52H55BrClN7O11Cs
MeOH in CHCl3); [a]2D2 ˆ ‡6.3 (c ˆ 0.68, MeOH); IR (thin film): nÄmax
ˆ
3319, 2966, 1661, 1602, 1490, 1414, 1361, 1314, 1261, 1202, 1155, 1067,
1026 cm 1; 1H NMR (400 MHz, CD3SOCD3): d ˆ 9.10 (d, J ˆ 9.1 Hz, 1H),
8.25 (br.s, 1H), 7.64 ± 7.61 (m, 2H), 7.43 (d, J ˆ 9.4 Hz, 1H), 7.39 (d, J ˆ
8.6 Hz, 1H), 7.34 ± 7.24 (m, 6H), 7.10 (s, 1H), 7.02 (d, J ˆ 8.6 Hz, 1H), 6.84
(s, 1H), 6.54 (s, 1H), 6.37 (d, J ˆ 8.0 Hz, 1H), 6.01 (s, 1H), 5.55 (d, J ˆ
9.3 Hz, 1H), 5.44 (br.s, 1H), 5.20 (d, J ˆ 8.9 Hz, 1H), 5.03 ± 5.00 (m, 1H),
4.27 (br.s, 2H, OCH2Ph), 3.91 (br.s, 2H, NCH2CH2), 3.81 (s, 3H, OCH3),
3.67 (s, 3H, OCH3), 3.66-3.63 (br.s, 2H, NCH2CH2), 3.61 (s, 3H, OCH3),
3.33 ± 3.30 (m, 2H, H-7b), 2.04 ± 2.00 (br.s, 4H, NCH2CH2), 1.35 (s, 9H,
tBuO); 13C NMR (100 MHz, CD3SOCD3): d ˆ 170.0, 169.0, 168.9, 159.7,
157.7, 156.3, 155.3, 151.8, 149.5, 140.2, 138.6, 138.5, 135.9, 130.9, 129.8, 128.3,
128.2, 127.4, 127.4, 127.3, 127.2, 126.5, 125.4, 124.8, 124.5, 123.0, 118.5, 118.1,
112.5, 110.9, 103.3, 97.5, 78.6, 74.7, 71.8, 69.8, 59.8, 59.5, 56.6, 55.6, 55.5, 55.2,
51.3, 50.8, 46.5, 28.1, 23.6, 23.1; HRMS (FAB) calcd for C52H57BrClN7O12Cs
‡
[M ‡ Cs ] 1202.3142, found 1202.3206.
AB/C-O-D bicyclic amine 32: A solution of natural AB/C-O-D Boc-
protected amine 23a (59 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was cooled to
158C. Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 18 mL,
0.1 mmol) was added dropwise. After stirring at 108C for 1 h, freshly
distilled 2,6-lutidine (18 mL, 0.15 mmol) was added dropwise, and the
mixture was stirred at 108C for 0.5 h. Then, the reaction mixture was
quenched by the addition of saturated aqueous NaHCO3 (1 mL), and left
for 0.5 h at 08C. The aqueous phase was extracted with CH2Cl2 (3 Â 2 mL).
The combined organic layers were washed with brine (3 mL), dried
(Na2SO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 0 !20% EtOAc in hexanes, gradient elution,
and then 20 !40% EtOAc in CH2Cl2, gradient elution) to afford AB/C-O-
D bicyclic amine 32 (52 mg, 96%). 32: Rf ˆ 0.14 (silica gel, 5% MeOH in
‡
[M ‡ Cs ] 1218.1991, found 1218.1919.
AB/C-O-D bicycle 31a: To a solution of AB/C-O-D amino acid 30a
(109 mg, 0.1 mmol) and iPr2NEt (52 mL, 0.3 mmol) in DMF (4 mL) at 258C
was added HATU (57 mg, 0.15 mmol) and the reaction mixture was stirred
for 8 h at 258C. The reaction was quenched by the addition of saturated
aqueous NH4Cl (1 mL), and the resulting mixture was extracted with
EtOAc (4 Â 5 mL). The combined organic layers were washed with 5%
aqueous NH4Cl (10 mL), H2O (10 mL), brine (10 mL), dried (Na2SO4),
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 10 !20% acetone in hexanes, gradient elution) to afford
AB/C-O-D bicycle 31a (54 mg, 50% yield). 31a: Rf ˆ 0.35 (silica gel, 40%
CH2Cl2); [a]2D2 ˆ ‡29.5 (c ˆ 1.2, MeOH); IR (thin film): nÄmax ˆ 3363, 2939,
1
2857, 1672, 1486, 1416, 1321, 1263, 1105, 837 cm
;
1H NMR (600 MHz,
CD3OD, 330 K): d ˆ 7.61 (d, J ˆ 2.0 Hz, 1H, H-6b), 7.39 (dd, J ˆ 8.4, 2.0 Hz,
1H, H-6f), 7.51 (s, 1H, H-4f), 7.37 ± 7.26 (m, 5H, ArH), 7.11 (dd, J ˆ 8.6,
2.3 Hz, 1H, H-5f), 7.07 (d, J ˆ 8.4 Hz, 1H, H-6e), 7.04 (d, J ˆ 2.3 Hz, 1H,
H-5b), 6.95 (d, J ˆ 1.7 Hz, 1H, H-7f), 6.94 (d, J ˆ 8.2 Hz, 1H, H-5e), 6.62 (d,
J ˆ 2.2 Hz, 1H, H-7d), 5.80 (d, J ˆ 1.1 Hz, 1H, H-4b), 5.26 (s, 1H, H-6b),
4.69 (s, 1H, H-5a), 4.58 (s, 1H, H-4a), 4.57 (d, J ˆ 11.8 Hz, 1H,
OCHAHPh), 4.55 (d, J ˆ 11.8 Hz, 1H, OCHHBPh), 4.41 ± 4.39 (m, 1H,
H-7a), 4.04 (s, 1H, H-6a), 3.90 (t, J ˆ 10.0 Hz, 1H, H-7bA), 3.84 (dd, J ˆ
10.0, 3.4 Hz, 1H, H-7bB), 3.82 (s, 3H, 7e-OCH3), 3.82 ± 3.79 (m, 4H,
NCH2CH2), 3.67 (s, 3H, 7c-OCH3), 3.61 (s, 3H, 5d-OCH3), 2.04 (br.s, 4H,
NCH2CH2), 0.86 (s, 9H, tBuSi), 0.02 (s, 3H, CH3Si), 0.00 (s, 3H, CH3Si);
13C NMR (150 MHz, CD3OD, 330 K): d ˆ 175.8, 173.1, 172.2, 162.0, 160.2,
159.0, 153.6, 153.0, 142.0, 141.0, 140.9, 139.9, 139.5, 137.1, 129.6, 129.4, 129.1,
129.0, 128.7, 128.3, 128.1, 127.4, 126.1, 124.9, 123.1, 120.3, 114.4, 114.3, 106.9,
99.7, 75.0, 74.5, 71.0, 65.2, 58.4, 56.6, 56.6, 56.3, 55.7, 53.3, 26.4, 24.8, 19.3,
4.6, 4.7; HRMS (MALDI-FTMS) calcd for C53H61BrClN7O9Na [M ‡
acetone in hexanes); [a]D22 ˆ ‡17.5 (c ˆ 0.86, CHCl3); IR (thin film): nÄmax
1
3399, 2917, 2847, 1658, 1403, 1318, 1282, 1162, 1085, 1028 cm
;
1H NMR
(600 MHz, CD3COCD3): d ˆ 8.14 (d, J ˆ 8.5 Hz, 1H, NH), 7.64 (d, J ˆ
7.6 Hz, 1H, H-6f), 7.52 (d, J ˆ 7.4 Hz, 1H, H-5f), 7.38 (s, 1H, H-4f), 7.33 ±
7.31 (m, 2H), 7.28-7.24 (m, 3H), 7.21 (d, J ˆ 2.1 Hz, 1H, H-6b), 7.14 (d, J ˆ
8.2 Hz, 1H, H-6e), 7.11 (d, J ˆ 8.2 Hz, 1H, H-5e), 6.88 (d, J ˆ 9.8 Hz, 1H,
NH), 6.75 (s, 1H, H-5b), 6.61 (d, J ˆ 2.1 Hz, 1H, H-7f), 6.57 (d, J ˆ 3.0 Hz,
1H, H-7d), 6.34 (d, J ˆ 9.2 Hz, 1H, NH), 6.18 (s, 1H, H-4b), 5.62 ± 5.58 (m,
2H, H-4a and H-5a), 5.34 ± 5.33 (m, 1H), 5.15 ± 5.14 (m, 1H, H-7a), 4.75 (d,
J ˆ 9.8 Hz, 1H, H-6b), 4.50 (d, J ˆ 11.7 Hz, 1H, OCHAHPh), 4.47 (d, J ˆ
9.8 Hz, 1H, H-6a), 4.33 (d, J ˆ 11.7 Hz, 1H, OCHHBPh), 3.90 ± 3.89 (m,
2H, NCH2CH2), 3.84 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 3.66-3.63 (br.s,
2H, NCH2CH2), 3.63 (s, 3H, OCH3), 3.27 ± 3.24 (m, 1H, H-7bA), 3.07 ± 3.03
(m, 1H, H-7bB), 2.04 (m, 4H, NCH2CH2), 1.19 (s, 9H, tBuO); 13C NMR
(125 MHz, CD3COCD3): d ˆ 171.4, 170.7, 170.2, 161.0, 159.9, 158.8, 152.7,
145.0, 141.0, 140.3, 139.0, 138.7, 137.9, 133.0, 132.7, 130.7, 130.2, 128.8, 128.2,
128.1, 128.0, 126.7, 126.6, 125.6, 125.4, 124.9, 119.1, 119.0, 114.7, 112.5, 108.7,
98.4, 79.3, 74.4, 74.3, 72.6, 72.4, 57.1, 57.0, 56.6, 55.8, 55.7, 55.4, 51.3, 46.8,
‡
Na ] 1104.3070, found 1104.3135.
AB/C-O-D/E heptapeptide 33: A solution of AB/C-O-D bicyclic amine 32
(438 mg, 0.4 mmol) and tripeptide carboxylic acid 5 (812 mg, 0.89 mmol) in
THF (8 mL) was cooled to 158C. HOAt (544 mg, 4 mmol) was added,
and the mixture was stirred vigorously for 10 min. EDC (153 mg, 0.8 mmol)
was then added, and the resulting mixture was stirred for 12 h while the
temperature was raised slowly to 08C. H2O (10 mL) and EtOAc (10 mL)
were added, and after 10 min the aqueous phase was extracted with EtOAc
(2 Â 10 mL). The combined organic layers were washed with brine (10 mL),
dried (Na2SO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 0 !50% EtOAc in hexanes, gradient elution)
to afford AB/C-O-D/E heptapeptide 33 (680 mg, 86%). 33: Rf ˆ 0.25 [silica
gel, acetone/EtOAc/benzene (1:2:7)]; [a]2D2 ˆ ‡21.9 (c ˆ 2.6, MeOH); IR
(thin film): nÄmax ˆ 3307, 2954, 2930, 2856, 1655, 1508, 1418, 1322, 1249, 1106,
837 cm 1; 1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.59 (d, J ˆ 1.8 Hz, 1H,
H-6b), 7.39 (dd, J ˆ 8.4, 1.8 Hz, 1H, H-6f), 7.37 ± 7.26 (m, 7H, ArH), 7.09 ±
7.01 (m, 9H, ArH), 6.94 (d, J ˆ 1.9 Hz, 1H, H-4f), 6.87 (d, J ˆ 8.7 Hz, 1H,
H-5e), 6.84 ± 6.78 (m, 4H, ArH), 6.60 (d, J ˆ 2.2 Hz, 1H, H-7d), 6.03 (br.s,
1H, H-4b), 5.83 (br.s, 1H, NHCH (Ddm)), 5.26 (br.s, 1H, H-6b), 4.86-4.84
(m, 2H, H-2b and H-5a), 4.64 (br.s, 1H, H-2a), 4.57 (d, J ˆ 11.7 Hz, 1H,
OCHAHPh), 4.54 (d, J ˆ 11.7 Hz, 1H, OCHHBPh), 4.39 (br.s, 1H, H-4a),
4.02 (br.s, 1H, H-6a), 3.90 (dd, J ˆ 10.0, 7.6 Hz, 1H, H-7a), 3.84 ± 3.76 (m,
6H, H-7b and NCH2CH2), 3.81 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.74 (s,
3H, OCH3), 3.64 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 2.75 (dd, J ˆ 15.6,
‡
28.2, 24.2, 23.8; HRMS (FAB) calcd for C52H55BrClN7O11Cs [M ‡ Cs ]
1202.3142, found 1202.3197.
AB/C-O-D bicycle 31b: To a solution of AB/C-O-D amino acid 30b
(109 mg, 0.1 mmol) and iPr2NEt (52 mL, 0.3 mmol) in DMF (4 mL) at 258C
was added HATU (57 mg, 0.15 mmol). The reaction mixture was stirred for
8 h at 258C. The reaction was quenched by the addition of saturated
aqueous NH4Cl (1 mL) and the resulting mixture was extracted with
EtOAc (4 Â 5 mL). The combined organic layers were washed with 5%
aqueous NH4Cl (10 mL), H2O (10 mL), brine (10 mL), dried (Na2SO4),
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 10 !20% acetone in hexanes, gradient elution) to afford
AB/C-O-D bicycle 31b (55 mg, 51% yield). 31b: Rf ˆ 0.23 (silica gel, 40%
acetone in hexanes); [a]D22 ˆ ‡2.64 (c ˆ 0.83, CHCl3); IR (thin film): nÄmax
ˆ
1
3401, 3295, 2931, 1661, 1602, 1496, 1414, 1361, 1314, 1255, 1155, 1085 cm
;
1H NMR (500 MHz, CD3COCD3): d ˆ 8.31 (d, J ˆ 7.5 Hz, 1H, NH), 7.79 (d,
J ˆ 1.5 Hz, 1H, H-6b), 7.62 (d, J ˆ 10.5 Hz, 1H, NH), 7.52 (dd, J ˆ 8.2,
2.2 Hz, 1H, H-5f), 7.40 (s, 1H, H-4f), 7.32 ± 7.23 (m, 5H), 7.10 (d, J ˆ 8.5 Hz,
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2639 $ 17.50+.50/0
2639

K. C. Nicolaou et al.
FULL PAPER
5.1 Hz, 1H, H-3bA), 2.73 (dd, J ˆ 15.6, 7.2 Hz, 1H, H-3bB), 2.44 (s, 3H,
NCH3), 2.03 (br.s, 4H, NCH2CH2), 1.43-1.33 (m, 3H, H-1b and H-1g), 1.38
(br.s, 9H, tBuO), 0.86 (s, 9H, tBuSi), 0.85 (d, J ˆ 6.2 Hz, 3H, H-1d), 0.82 (d,
J ˆ 6.0 Hz, 3H, H-1d') 0.75 (s, 9H, tBuSi), 0.02 (s, 3H, CH3Si), 0.00 (s, 3H,
CH3Si), -0.05 (s, 3H, CH3Si), 0.22 (s, 3H, CH3Si); 13C NMR (150 MHz,
CD3COCD3, 323 K): d ˆ 171.4, 171.0, 170.7, 170.1, 169.9, 169.8, 167.8, 161.1,
159.7, 159.7, 159.6, 158.2, 153.3, 153.0, 152.3, 141.6, 140.7, 139.8, 139.4, 138.0,
136.1, 135.5, 135.5, 134.1, 129.6, 129.3, 129.0, 128.7, 128.3, 128.1, 127.9, 127.5,
127.3, 126.0, 125.3, 124.4, 122.5, 121.0, 119.7, 117.6, 114.6, 114.6, 113.6, 106.4,
98.8, 80.2, 74.8, 74.5, 73.7, 70.6, 66.0, 64.2, 57.2, 56.4, 56.2, 55.7, 55.5, 55.2,
52.7, 51.0, 38.8, 37.5, 30.7, 28.7, 26.2, 26.1, 25.4, 24.3, 23.5, 22.0, 18.9, 18.7,
4.6, 4.7, 4.8, 4.9; HRMS (FAB) calcd for C99H124BrCl2N11O19Si2Cs
1.68 (m, 1H, H-1g), 1.50 (s, 9H, tBuO), 1.38 ± 1.34 (m, 2H, H-1b), 0.89 (s,
9H, tBuSi), 0.88 (s, 9H, tBuSi), 0.87 (d, J ˆ 6.5 Hz, 3H, H-1d), 0.86 (d, J ˆ
6.6 Hz, 3H, H-1d'), 0.11 (s, 3H, CH3Si), 0.07 (s, 3H, CH3Si), 0.03 (s, 3H,
CH3Si), 0.02 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3COCD3, 323 K): d ˆ
172.4, 171.8, 171.3, 170.6, 167.9, 161.3, 159.9, 159.9. 158.3, 153.5, 153.3, 153.0,
152.0, 142.0, 140.2, 139.7, 136.4, 135.8, 129.7, 129.6, 129.5, 129.3, 129.0, 128.9,
128.6, 128.5, 128.1, 127.8, 126.8, 125.5, 125.2, 122.8, 114.9, 114.8, 114.0, 108.1,
106.7, 106.2, 99.1, 80.7, 74.9, 74.4, 73.9, 70.9, 64.6, 60.3, 56.7, 56.7, 56.4, 56.4,
56.0, 55.7, 55.7, 53.0, 52.8, 37.8, 30.7, 29.0, 26.6, 26.5, 25.8, 24.6, 23.9,
22.5, 19.3, 19.2,
C99H123Cl2N11O19Si2Cs [M ‡ Cs ] 2028.6967, found 2028.7090.
4.4,
4.5,
4.6,
4.7; HRMS (FAB) calcd for
‡
‡
‡
Treatment of natural tricyclic triazene 3a with H -resin: H -resin (AG
50W-X12, BIO-RAD) (200 mg) was suspended in H2O (1 mL) and heated
to 808C. A solution of natural tricyclic triazene 3a (9.0 mg, 0.005 mmol) in
MeCN (1 mL) was added dropwise over a period of 45 min, while the
temperature was kept at 808C. After 10 min, the mixture was cooled to
258C. EtOAc (3 mL), H2O (3 mL) and solid NaHCO3 (100 mg) were
added, and the mixture was stirred vigorously for 0.5 h. The aqueous phase
was extracted with EtOAc (2 Â 2 mL). The combined organic layers were
dried (Na2SO4), concentrated, and the residue was purified by preparative
TLC (silica gel, 5% MeOH in CH2Cl2) to afford natural tricyclic reduced
compound 34a (7.0 mg, 78%). 34a: Rf ˆ 0.26 (silica gel, 5% MeOH in
‡
[M ‡ Cs ] 2110.6208, found 2110.6068.
Natural tricyclic triazene 3a and unnatural tricyclic triazene 3b: In a flame-
dried flask containing AB/C-O-D/E heptapeptide 33 (33 mg, 0.017 mmol)
were added anhydrous K2CO3 (12 mg, 0.083 mmol) and CuBr´ Me2S
(17 mg, 0.083 mmol), followed by the addition of anhydrous MeCN
(0.85 mL). After 5 min at 258C, freshly distilled pyridine (6.7 mL,
0.083 mmol) was added and the mixture was stirred at reflux for 2 h. After
it was cooled to 08C, EtOAc (5 mL) and saturated aqueous NH4Cl (5 mL)
were added, and the mixture was stirred vigorously for 0.5 h at 08C. The
aqueous phase was extracted with EtOAc (3 Â 5 mL). The combined
organic layers were washed with brine (5 mL), dried (Na2SO4), filtered
through a pad of silica gel, concentrated, and the residue was purified by
flash column chromatography (silica gel, 0 !25% EtOAc in CH2Cl2,
gradient elution) to afford faster moving natural tricyclic triazene 3a
(6.0 mg, 19%), and slower moving unnatural tricyclic triazene 3b (17.5 mg,
55%). 3a: Rf ˆ 0.40 (silica gel, 60% EtOAc in benzene); [a]2D2 ˆ ‡33.8 (c ˆ
2.4, MeOH); IR (thin film): nÄmax ˆ 3000, 2953, 2930, 2855, 1668, 1648, 1509,
1486, 1244, 1106, 834, 778, 700 cm 1; 1H NMR (600 MHz, CD3OD, 330 K):
d ˆ 7.60 (br.s, 1H, H-2b), 7.55 (d, J ˆ 1.7 Hz, 1H, H-6b), 7.47 (dd, J ˆ 8.3,
1.7 Hz, 1H, H-6f), 7.36 ± 7.25 (m, 7H, H-2f, H-6e and ArH (Bn)), 7.04 ± 7.01
(m, 2H, H-2e and H-5b), 6.98 (d, J ˆ 8.3 Hz, 2H, ArH (Ddm)), 6.92 (br.s,
1H, H-5f), 6.91 ± 6.88 (m, 3H, H-7f and ArH (Ddm)), 6.83 (br.d, J ˆ
8.8 Hz, 3H, H-5e and ArH (Ddm)), 6.71 (d, J ˆ 8.3 Hz, 2H, ArH
(Ddm)), 6.56 (d, J ˆ 2.2 Hz, 1H, H-7d), 5.88 (br.s, 1H, NHCH (Ddm)),
5.86 (br.s, 1H, H-4b), 5.80 (br.s, 1H, H-4f), 5.49 (d, J ˆ 4.9 Hz, 1H, H-2b),
5.45 (br.s, 1H, H-4a), 5.29 (br.s, 1H, H-6b), 4.94 ± 4.92 (m, 1H, H-2a),
4.90 ± 4.87 (m, 1H, H-3a), 4.78 ± 4.76 (m, 1H, H-1a), 4.62 (br.s, 1H, H-5a),
4.58 ± 4.53 (m, 2H, OCH2Ph), 4.48 ± 4.37 (m, 1H, H-7a), 4.04 (br.s, 1H,
H-6a), 3.92 ± 3.89 (m, 1H, H-7bA), 3.86 ± 3.84 (m, 5H, H-7bB and
NCH2CH2), 3.80 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3),
3.67 (s, 3H, OCH3), 3.42 (s, 3H, OCH3), 2.78 (s, 3H, NCH3), 2.65 ± 2.59 (m,
1H, H-3bA), 2.57 (dd, J ˆ 16.2, 6.1 Hz, 1H, H-3bB), 2.06 (br.s, 4H,
NCH2CH2), 1.75 ± 1.71 (m, 1H, H-1g), 1.48 (br.s, 9H, tBuO), 1.39 ± 1.37
(m, 2H, H-1b), 0.90 (s, 9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.84 (d, J ˆ 6.6 Hz,
3H, H-1d), 0.80 (d, J ˆ 6.2 Hz, 3H, H-1d'), 0.11 (s, 3H, CH3Si), 0.07 (s, 3H,
CH3Si), 0.04 (s, 3H, CH3Si), 0.03 (s, 3H, CH3Si); 13C NMR (150 MHz,
CD3COCD3, 323 K): d ˆ 172.1, 171.7, 171.3, 167.9, 161.3, 159.9, 159.9, 159.8,
158.4, 153.7, 153.4, 152.0, 142.0, 140.2, 139.9, 139.7, 136.3, 135.7, 131.9, 130.1,
129.7, 129.6, 129.5, 129.4, 129.3, 129.1, 129.0, 128.6, 128.4, 128.1, 127.8, 125.7,
125.5, 125.1, 122.8, 114.9, 114.8, 114.1, 106.7, 106.5, 99.1, 80.7, 74.8, 74.4, 73.9,
70.9, 64.6, 60.3, 56.7, 56.6, 56.4, 56.3, 56.0, 55.9, 55.7, 55.6, 37.6, 30.7, 28.9,
26.6, 26.5, 25.8, 24.6, 23.9, 22.5, 19.2, 19.2, 4.2, 4.4, 4.6; HRMS (FAB)
CH2Cl2); [a]2D2 ˆ ‡16.2 (c ˆ 1.2, MeOH); IR (thin film): nÄmax ˆ 3304, 2955,
1
2931, 2856, 1681, 1659, 1650, 1513, 1505, 1486, 1249, 1110, 837, 781 cm
;
1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.60 (br.s, 1H, H-2b), 7.48 ± 7.46
(m, 2H, H-6b and H-6f), 7.36 ± 7.23 (m, 7H, H-2f, H-6e and ArH (Bn)), 7.08
(br.d, J ˆ 8.8 Hz, 1H, H-2e), 7.02 (br.s, 2H, H-4d and H-5b), 6.98 (d, J ˆ
8.8 Hz, 2H, ArH (Ddm)), 6.96 (d, J ˆ 8.8 Hz, 1H, H-5f), 6.92 (br.s, 1H,
H-7f), 6.86 (bd, J ˆ 8.3 Hz, 3H, H-5e and ArH (Ddm)), 6.82 (d, J ˆ 8.8 Hz,
2H, ArH (Ddm)), 6.68 (d, J ˆ 7.4 Hz, 2H, ArH (Ddm)), 6.56 (d, J ˆ 2.1 Hz,
1H, H-7d), 6.21 (br.s, 1H, NHCH (Ddm)), 5.85 (br.s, 1H, H-4b), 5.72 (br.s,
1H, H-4f), 5.53 (d, J ˆ 4.8 Hz, 1H, H-2b), 5.42 (br.s, 1H, H-4a), 5.31 (br.s,
1H, H-6b), 4.98 ± 4.93 (m, 2H, H-2a and H-3a), 4.74 ± 4.71 (m, 1H, H-1a),
4.62 (br.s, 1H, H-5a), 4.58 ± 4.53 (m, 2H, OCH2Ph), 4.00 (br.s, 1H, H-6a),
3.92 ± 3.89 (m, 1H, H-7a), 3.86 ± 3.78 (m, 2H, H-7b), 3.79 (s, 3H, OCH3),
3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.39 (s, 3H,
OCH3), 2.77 (s, 3H, NCH3), 2.66 ± 2.63 (m, 1H, H-3bA), 2.61 (dd, J ˆ 16.3,
5.7 Hz, 1H, H-3bB), 1.73 ± 1.70 (m, 1H, H-1g), 1.48 (br.s, 9H, tBuO), 1.38 ±
1.34 (m, 2H, H-1b), 0.92 (s, 9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.82 (d, J ˆ
6.1 Hz, 3H, H-1d), 0.78 (d, J ˆ 6.1 Hz, 3H, H-1d'), 0.12 (s, 3H, CH3Si), 0.08
(s, 3H, CH3Si), 0.06 (s, 3H, CH3Si), 0.05 (s, 3H, CH3Si); 13C NMR
(150 MHz, CD3COCD3, 323 K): d ˆ 172.1, 171.7, 171.6, 171.0, 169.1, 162.0,
161.3, 161.0, 160.0, 159.8, 159.8, 158.3, 152.1, 151.4, 142.2, 140.4, 140.3, 139.7,
136.6, 135.8, 130.5, 129.8, 129.5, 129.5, 129.3, 129.3, 129.0, 129.0, 129.0, 128.6,
128.3, 127.9, 125.6, 125.5, 124.9, 122.8, 114.9, 114.8, 114.2, 106.7, 106.5, 106.2,
105.6, 99.1, 80.7, 75.0, 74.3, 73.8, 70.9, 64.8, 60.3, 56.8, 56.4, 56.3, 56.0, 55.9,
55.7, 55.7, 52.7, 51.5, 39.9, 37.5, 30.5, 28.9, 26.6, 26.6, 25.8, 23.8, 22.6, 19.3,
19.3, 4.1, 4.3, 4.5, 4.6; HRMS (FAB) calcd for C95H116Cl2N8O19Si2Cs
‡
[M ‡ Cs ] 1933.6343, found 1933.6456.
‡
‡
Treatment of unnatural tricyclic triazene 3b with H -resin: H -resin (AG
50W-X12, BIO-RAD) (275 mg) was suspended in H2O (1.2 mL) and
heated to 808C. A solution of unnatural tricyclic triazene 3b (12.0 mg,
0.0063 mmol) in MeCN (1 mL) was added dropwise over a period of
45 min, while the temperature was kept at 808C. After 10 min, the mixture
was cooled to 258C. EtOAc (3 mL), H2O (3 mL), and solid NaHCO3
(120 mg) were added, and the mixture was stirred vigorously for 0.5 h.
The aqueous phase was extracted with EtOAc (2 Â 2.5 mL). The combined
organic layers were dried (Na2SO4), concentrated, and the residue was
purified by preparative TLC (silica gel, 5% MeOH in CH2Cl2) to afford
unnatural tricyclic reduced compound 34b (8.4 mg, 74%). 34b: Rf ˆ 0.26
‡
calcd for C99H123Cl2N11O19Si2Cs [M ‡ Cs ] 2028.6967, found 2028.6849. 3b:
Rf ˆ 0.30 (silica gel, 60% EtOAc in benzene); [a]D22
ˆ
20.3 (c ˆ 1.8,
MeOH); IR (thin film): nÄmax ˆ 3307, 2954, 2928, 2859, 1667, 1651, 1510, 1488,
1
1251, 1103, 835, 780, 698 cm
;
1H NMR (600 MHz, CD3OD, 330 K): d ˆ
7.68 (br.s, 1H, H-2b), 7.57 (d, J ˆ 1.9 Hz, 1H, H-6b), 7.46 (dd, J ˆ 8.3, 2.0,
1H, H-6f), 7.35 ± 7.27 (m, 6H, H-2e and ArH (Bn)), 7.19 ± 7.12 (m, 2H, H-2f
and H-6e), 7.07 ± 6.98 (m, 4H, H-5b, H-5f and ArH (Ddm)), 6.94 ± 6.92 (m,
3H, H-7f and ArH (Ddm)), 6.87 ± 6.85 (m, 1H, H-5e), 6.82 (d, J ˆ 8.2 Hz,
2H, ArH (Ddm)), 6.72 (d, J ˆ 7.1 Hz, 2H, ArH (Ddm)), 6.57 (d, J ˆ 2.3 Hz,
1H, H-7d), 5.88 (br.s, 1H, H-4b), 5.87 (br.s, 1H, NHCH (Ddm)), 5.79 (br.s,
1H, H-4f), 5.50 (d, J ˆ 4.6 Hz, 1H, H-2b), 5.45 (br.s, 1H, H-4a), 5.29 (br.s,
1H, H-6b), 4.87 ± 4.85 (m, 2H, H-2a and H-3a), 4.81 ± 4.79 (m, 1H, H-1a),
4.65 (br.s, 1H, H-5a), 4.57 (d, J ˆ 11.6 Hz, 1H, OCHAHPh), 4.54 (d, J ˆ
11.5 Hz, 1H, OCHHBPh), 4.05 (br.s, 1H, H-6a), 3.90 ± 3.87 (m, 1H, H-7a),
3.84 ± 3.81 (m, 6H, H-7b and NCH2CH2), 3.80 (s, 3H, OCH3), 3.75 (s, 3H,
OCH3), 3.70 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 2.77 (s,
3H, NCH3), 2.75 ± 2.50 (m, 2H, H-3b), 2.05 (br.s, 4H, NCH2CH2), 1.70 ±
(silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
6.7 (c ˆ 1.5, MeOH); IR (thin
film): nÄmax ˆ 3306, 2954, 2930, 2856, 1682, 1667, 1660, 1650, 1609, 1513, 1504,
1
1486, 1251, 1109, 837, 781 cm 1; H NMR (600 MHz, CD3OD, 323 K): d ˆ
7.72 (br.s, 1H, H-2b), 7.54 (br.s, 1H, H-6b), 7.45 (bd, J ˆ 8.2 Hz, 1H, H-6f),
7.36 ± 7.35 (m, 2H, ArH (Bn)), 7.32-7.30 (m, 2H, ArH (Bn)), 7.28 ± 7.23 (m,
3H, H-2e, H-6e and ArH (Bn)), 7.18 (bd, J ˆ 7.9 Hz, 1H, H-2f), 7.03-6.98
(m, 5H, H-5b, H-5f, H-4d and ArH (Ddm)), 6.92 ± 6.88 (m, 4H, H-5e and
H-7f ArH (Ddm)), 6.82 (d, J ˆ 8.5 Hz, 2H, ArH (Ddm)), 6.71 (d, J ˆ
8.7 Hz, 2H, ArH (Ddm)), 6.56 (d, J ˆ 2.2 Hz, 1H, H-7d), 5.96 (br.s, 1H,
H-4b), 5.87 (br.s, 1H, NHCH (Ddm)), 5.80 (br.s, 1H, H-4f), 5.53 (d, J ˆ
4.7 Hz, 1H, H-2b), 5.38 (br.s, 1H, H-4a), 5.29 (br.s, 1H, H-6b), 4.85 ± 4.84
2640
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2640 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
(m, 2H, H-2a and H-3a), 4.78 (br.d, J ˆ 9.0 Hz, 1H, H-1a), 4.61 (br.s, 1H,
H-5a), 4.57 (d, J ˆ 11.7 Hz, 1H, OCHAHPh), 4.54 (d, J ˆ 11.7 Hz, 1H,
OCHHBPh), 4.02 (br.s, 1H, H-6a), 3.90 (t, J ˆ 8.5 Hz, 1H, H-7a), 3.84 ±
3.80 (m, 2H, H-7b), 3.80 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.70 (s, 3H,
OCH3), 3.66 (s, 3H, OCH3), 3.45 (s, 3H, OCH3), 2.76 (s, 3H, NCH3), 2.62 ±
2.58 (m, 1H, H-3bA), 2.53 (dd, J ˆ 15.0, 6.6 Hz, 1H, H-3bB), 1.71 ± 1.69 (m,
1H, H-1g), 1.49 (s, 9H, tBuO), 1.42 ± 1.40 (m, 2H, H-1b), 0.89 (s, 18H,
tBuSi), 0.84 (d, J ˆ 6.3 Hz, 3H, H-1d), 0.81 (d, J ˆ 5.7 Hz, 3H, H-1d'), 0.12
(s, 3H, CH3Si), 0.09 (s, 3H, CH3Si), 0.05 (s, 3H, CH3Si), 0.04 (s, 3H, CH3Si);
13C NMR (150 MHz, CD3COCD3, 323 K): d ˆ 172.4, 171.8, 171.3, 170.5,
169.0, 167.7, 161.6, 161.3, 159.9, 159.9, 159.8, 158.4, 152.0, 151.2, 142.5, 140.5,
140.2, 139.7, 136.5, 135.8, 129.7, 129.6, 129.4, 129.3, 129.0, 128.5, 128.0, 127.8,
126.6, 125.6, 124.8, 122.7, 115.0, 114.9, 114.0, 107.0, 106.7, 106.5, 105.5, 99.1,
80.7, 74.9, 74.3, 73.9, 70.9, 64.6, 60.4, 56.8, 56.7, 56.6, 56.4, 56.3, 56.0, 55.7,
52.7, 39.8, 37.7, 30.5, 29.0, 26.6, 26.5, 25.8, 23.8, 22.6, 19.3, 19.2, 4.3, 4.4,
unnatural tricyclic aniline 36 (16.4 mg, 60% overall from 3b). 36: Rf ˆ 0.24
(silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
5.8 (c ˆ 0.83, MeOH); IR (thin
1
film): nÄmax ˆ 3311, 2956, 1685, 1654, 1560, 1508, 1458, 1252, 840 cm
;
1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.73 (br.s, 1H, H-2b), 7.56 (d, J ˆ
2.0 Hz, 1H, H-6b), 7.48 (dd, J ˆ 8.3, 2.0 Hz, 1H, H-6f), 7.30 (d, J ˆ 8.2 Hz,
1H, H-2e ), 7.19 (br.d, J ˆ 7.0 Hz, 1H, H-2f), 7.07 (d, J ˆ 8.3 Hz, H-6e),
7.02 ± 6.98 (m, 4H, H-5b, H-5f and ArH (Ddm)), 6.92 ± 6.90 (m, 3H, H-7f
and ArH (Ddm)), 6.87 (d, J ˆ 8.1 Hz, 1H, H-5e), 6.73 (d, J ˆ 8.7 Hz, 2H,
ArH (Ddm)), 6.59 (d, J ˆ 2.3 Hz, 1H, H-7d), 6.29 (d, J ˆ 8.7 Hz, 2H, ArH
(Ddm)), 5.86 (br.s, 1H, H-4b), 5.78 (br.s, 1H, NHCH (Ddm)), 5.77 (br.s,
1H, H-4f), 5.54 (d, J ˆ 4.8 Hz, 1H, H-2b), 5.34 (br.s, 1H, H-4a), 5.31 (br.s,
1H, H-6b), 4.89 ± 4.87 (m, 2H, H-2a and H-3a), 4.80 ± 4.79 (m, 1H, H-1a),
4.63 (br.s, 1H, H-5a), 4.21 ± 4.19 (m, 1H, H-7a), 4.07 (br.s, 1H, H-6a), 4.00
(dd, J ˆ 10.9, 8.2 Hz, 1H, H-7bA), 3.92 (dd, J ˆ 10.8, 4.9 Hz, 1H, H-7bB),
3.88 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.67 (s, 3H,
OCH3), 3.46 (s, 3H, OCH3), 2.77 (s, 3H, NCH3), 2.57 ± 2.53 (m, 2H, H-3b),
1.70 ± 1.69 (m, 1H, H-1g), 1.50 (s, 9H, tBuO), 1.39 ± 1.38 (m, 2H, H-1b), 0.92
(s, 9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.83 (d, J ˆ 6.3 Hz, 3H, H-1d), 0.80 (d,
J ˆ 5.1 Hz, 3H, H-1d'), 0.12 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si), 0.08 (s, 3H,
CH3Si), 0.05 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3COCD3, 323 K): d ˆ
172.2, 171.3, 171.2, 170.7, 169.4, 161.2, 159.6, 158.1, 157.0, 151.5, 147.8, 147.6,
147.4, 141.7, 139.9, 139.7, 136.0, 135.5, 129.5, 129.3, 128.7, 128.3, 128.2, 127.8,
127.5, 127.2, 126.6, 125.2, 124.9, 122.5, 114.6, 114.5, 113.7, 107.3, 106.3, 105.4,
98.7, 80.5, 74.5, 74.1, 64.2, 64.0, 60.1, 57.0, 56.4, 56.1, 55.9, 55.7, 55.5, 55.3,
52.4, 39.8, 37.4, 30.4, 28.7, 26.3, 26.2, 25.5, 23.6, 22.3, 19.0, 18.9, 4.7, 4.7,
‡
4.6; HRMS (FAB) calcd for C95H116Cl2N8O19Si2Cs [M‡ Cs ] 1931.6327,
found 1931.6151.
‡
Treatment of natural tricyclic triazene 3a with BF3 ´ Et2O and Cu2‡/Cu in
MeCN: A solution of natural tricyclic triazene 3a (4 mg, 0.002 mmol) in
MeCN (0.5 mL) was cooled to 08C. BF3 ´ Et2O (10 mL, 0.008 mmol) was
added, and the reaction mixture was stirred for 15 min at 08C. Then,
saturated aqueous Cu(NO3)2 (100 mL) and Cu2O (1 mg) were added, and
the reaction mixture was warmed to 258C and stirred for 0.5 h. EtOAc
(30 mL) was added, and the aqueous phase was extracted with EtOAc
(30 mL). The combined organic layers were dried (Na2SO4), concentrated,
and the residue was purified by preparative TLC (silica gel, 60% EtOAc in
hexanes) to afford natural tricyclic reduced compound 34a (1.2 mg, 32%).
‡
4.9; HRMS (FAB) calcd for C88H111Cl2N9O19Si2Cs [M ‡ Cs ] 1856.5966,
found 1856.6084.
‡
Treatment of natural tricyclic triazene 3a with BF3 ´ Et2O and Cu2‡/Cu in
Sandmeyer reaction of aniline 36: A solution of unnatural tricyclic aniline
36 (22.7 mg, 0.0132 mmol) in MeCN (2 mL) was cooled to 208C. 48%
Aqueous HBF4 (34.5 mL, 0.264 mmol) and i-amylONO (35.5 mL, 0.264 mmol)
were added, and the reaction mixture was vigorously stirred at 208C.
After 0.5 h, the reaction mixture was cooled to 458C, and a saturated
solution of KI (1 mL) was added in one shot. The reaction mixture was
vigorously stirred for 2 h, while the temperature was raised slowly to 258C.
EtOAc (5 mL), saturated aqueous NaHCO3 (5 mL) and saturated aqueous
Na2SO3 (5 mL) were added sequentially, and the mixture was allowed to
stir for 15 min. The aqueous phase was extracted with EtOAc (2 Â 5 mL).
The combined organic layers were dried (Na2SO4), concentrated, and the
residue was purified by flash column chromatography (silica gel, 50%
EtOAc in CH2Cl2) to afford an inseparable mixture of unnatural tricyclic
iodide 38 and unnatural tricyclic reduced compound 39 (18.6 mg, ca. 6:4
THF: A solution of natural tricyclic triazene 3a (4 mg, 0.002 mmol) in THF
(0.5 mL) was cooled to 08C. BF3 ´ Et2O (10 mL, 0.008 mmol) was added, and
the reaction mixture was stirred for 15 min at 08C. Then, saturated aqueous
Cu(NO3)2 (100 mL) and Cu2O (1 mg) were added, and the reaction mixture
was warmed to 258C and stirred for 0.5 h. EtOAc (30 mL) was added, and
the aqueous phase was extracted with EtOAc (30 mL). The combined
organic layers were dried (Na2SO4), concentrated, and the residue was
purified by preparative TLC (silica gel, 60% EtOAc in hexanes) to afford
natural tricyclic reduced compound 34a (2.2 mg, 58%).
‡
Treatment of natural tricyclic triazene 3a with BF3 ´ Et2O and Cu2‡/Cu in
MeOH: A solution of natural tricyclic triazene 3a (4 mg, 0.002 mmol) in
MeOH (0.5 mL) was cooled to 08C. BF3 ´ Et2O (10 mL, 0.008 mmol) was
added, and the reaction mixture was stirred for 15 min at 08C. Then,
saturated aqueous Cu(NO3)2 (100 mL) and Cu2O (1 mg) were added, and
the reaction mixture was warmed to 258C and stirred for 0.5 h. EtOAc
(30 mL) was added, and the aqueous phase was extracted with EtOAc
(30 mL). The combined organic layers were dried (Na2SO4), concentrated,
and the residue was purified by preparative TLC (silica gel, 60% EtOAc in
hexanes) to afford natural tricyclic reduced compound 34a (2.6 mg, 69%).
1
from H NMR). This mixture was used directly in the next reaction.
Unnatural tricyclic phenol 41b: A solution in anhydrous THF (12 mL) of a
ca. 6:4 mixture of iodide 38 and reduced compound 39 (18.6 mg), prepared
as described above, was cooled to 508C. MeMgBr (1.4m solution in THF,
0.28 mL, 0.396 mmol) was added dropwise and the mixture was allowed to
warm to 208C. After stirring for 1 h, the reaction mixture was recooled to
608C, and iPrMgCl (2.0m solution in THF, 0.20 mL, 0.4 mmol) was added
dropwise. The mixture was kept at 408C for 2 h, and then cooled to
508C before the addition of freshly distilled trimethyl borate (0.15 mL,
1.32 mmol). After vigorously stirring for 1 h at 08C, the reaction mixture
was recooled to 208C. A mixture of 30% aqueous H2O2 and 10%
aqueous NaOH (1:1, 1 mL) was added, and vigorous stirring was applied
for 20 min at 08C. Without allowing the temperature to raise, EtOAc
(4 mL) and saturated aqueous Na2S2O3 ´ 5H2O (1 mL) were added. The
reaction mixture was stirred for 5 min, and the aqueous phase was
extracted with EtOAc (3 Â 5 mL). The combined organic layers were dried
(Na2SO4), concentrated, and the residue was purified by preparative TLC
(silica gel, 5% MeOH in CH2Cl2) to afford faster moving unnatural
tricyclic reduced compound 39 (6.3 mg, 28% overall from 36), and slower
moving unnatural tricyclic phenol 41b (6.8 mg, 30% overall from 36). 39:
Treatment of natural tricyclic triazene 3a with H2SO4 in MeCN: A solution
of natural tricyclic triazene 3a (12 mg, 0.0063 mmol) in MeCN (1.5 mL)
was cooled to 08C. 30% aqueous H2SO4 (1.5 mL) was added, and the
reaction mixture was warmed to 508C and stirred for 3 h. EtOAc (5 mL)
and H2O (2 mL) were added and the aqueous phase was extracted with
EtOAc (10 mL). The combined organic layers were dried (Na2SO4),
concentrated, and the residue was purified by preparative TLC (silica gel,
60% EtOAc in hexanes) to afford natural tricyclic reduced compound 34a
(8 mg, 70%).
Treatment of natural tricyclic triazene 3a with H2SO4 in MeOH: A solution
of natural tricyclic triazene 3a (12 mg, 0.0063 mmol) in MeOH (1.5 mL)
was cooled to 08C. 30% Aqueous H2SO4 (1.5 mL) was added, the reaction
mixture was warmed to 508C and stirred for 1.5 h. TLC indicated formation
of a complicated mixture.
Rf ˆ 0.24 (silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
23.4 (c ˆ 1.1, EtOAc);
1
Unnatural tricyclic aniline 36: Raney Ni (30 mg) was added to a solution of
unnatural tricyclic triazene 3b (30 mg, 0.0158 mmol) in MeOH (5 mL). The
reaction mixture was stirred at 258C for 10 h, filtered through celite,
concentrated, and the residue was checked with 1H NMR spectroscopy and
proved to be a mixture of 35 and 36 (ca. 1:1). This mixture was subjected to
debenzylation by addition of 10% Pd/C (15 mg) to a solution of the residue
in MeOH (5 mL). H2 was bubbled through the mixture for 4 h. The reaction
mixture was filtered through celite, concentrated, and the residue was
purified by preparative TLC (silica gel, 7% MeOH in CH2Cl2) to afford
IR (thin film): nÄmax ˆ 3300, 2955, 1672, 1609, 1512, 1253, 1107, 837 cm
;
1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.75 (br.s, 1H, H-2b), 7.56 (d, J ˆ
1.9 Hz, 1H, H-6b), 7.46 (dd, J ˆ 8.4, 2.0 Hz, 1H, H-6f), 7.25 (d, J ˆ 8.2 Hz,
1H, H-2e ), 7.18 (br.d, J ˆ 8.6 Hz, 1H, H-2f), 7.04 ± 7.00 (m, 5H, H-5b, H-5f,
H-6e and ArH (Ddm)), 6.92 ± 6.88 (m, 5H, H-4d, H-5e, H-7f and ArH
(Ddm)), 6.82 (d, J ˆ 8.7 Hz, 2H, ArH (Ddm)), 6.72 (d, J ˆ 8.7 Hz, 2H, ArH
(Ddm)), 6.58 (d, J ˆ 2.2 Hz, 1H, H-7d), 5.91 (br.s, 1H, H-4b), 5.87 (br.s,
1H, NHCH (Ddm)), 5.81 (br.s, 1H, H-4f), 5.53 (d, J ˆ 4.7 Hz, 1H, H-2b),
5.39 (br.s, 1H, H-4a), 5.31 (br.s, 1H, H-6b), 4.87 ± 4.84 (m, 2H, H-2a and
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2641 $ 17.50+.50/0
2641

K. C. Nicolaou et al.
FULL PAPER
H-3a), 4.78 ± 4.77 (m, 1H, H-1a), 4.63 (br.s, 1H, H-5a), 4.20 (dd, J ˆ 7.6,
4.9 Hz, 1H, H-7a), 4.06 (br.s, 1H, H-6a), 4.00 (dd, J ˆ 10.2, 8.2 Hz, 1H,
H-7bA), 3.93 (dd, J ˆ 10.0, 4.9 Hz, 1H, H-7bB), 3.87 (s, 3H, OCH3), 3.75 (s,
3H, OCH3), 3.71 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.46 (s, 3H, OCH3),
2.77 (s, 3H, NCH3), 2.62 ± 2.60 (m, 1H, H-3bA), 2.52 (dd, J ˆ 16.1, 6.8 Hz,
1H, H-3bB), 1.70-1.68 (m, 1H, H-1g), 1.50 (s, 9H, tBuO), 1.39 ± 1.37 (m, 2H,
H-1b), 0.92 (s, 9H, tBuSi), 0.90 (s, 9H, tBuSi), 0.84 (d, J ˆ 6.3 Hz, 3H,
H-1d), 0.81 (d, J ˆ 4.0 Hz, 3H, H-1d'), 0.12 (s, 3H, CH3Si), 0.09 (s, 3H,
CH3Si), 0.08 (s, 3H, CH3Si), 0.05 (s, 3H, CH3Si); 13C NMR (150 MHz,
CD3COCD3, 323 K): d ˆ 172.3, 171.6, 171.2, 170.4, 170.3, 168.8, 161.3, 161.1,
159.6, 158.1, 151.8, 151.0, 142.5, 142.4, 142.1, 140.2, 139.7, 136.1, 135.5, 129.5,
129.4, 129.3, 129.2, 128.7, 128.3, 127.8, 127.4, 126.3, 125.3, 124.6, 122.5, 114.6,
114.5, 113.7, 106.8, 106.3, 105.3, 98.7, 80.5, 74.6, 74.1, 64.3, 63.7, 60.2, 57.2,
56.5, 56.5, 56.3, 56.1, 55.7, 55.5, 55.4, 52.4, 39.6, 37.4, 30.5, 28.7, 26.3, 26.2,
25.5, 23.6, 19.0, 18.9, 4.7, 4.9; HRMS (FAB) calcd for C88H110Cl2N8O19-
complicated mixture was formed. The crude mixture of iodide 42b and
reduced compound 34b was used in the next reaction (phenol formation
protocol, see unnatural tricyclic phenol 43b). Faster moving unnatural
tricyclic reduced compound 34b and slower moving unnatural tricyclic
phenol 43b were isolated in the yields given in Table 3.
Treatment of unnatural tricyclic triazene 3b with I2 in a sealed tube
(Table 3, entry 14): I2 (1.4 mg, 0.0055 mmol) was added to a solution of
unnatural tricyclic triazene 3b (9 mg, 0.005 mmol) in freshly distilled and
well degassed (with Ar) MeCN (0.35 mL) in a sealed tube. This mixture was
heated at 808C for 1 h and then cooled to 258C. 5% aqueous Na2S2O3 ´
5H2O (0.5 mL) was added, and the reaction mixture was vigorously stirred
for 10 min. The aqueous phase was extracted with ether (3 Â 1 mL). The
combined organic layers were dried (Na2SO4), filtered through a pad of
silica gel, and concentrated. The desired unnatural tricyclic iodide 42b was
detected as a trace (>5%) by mass spectrometry.
‡
Si2Cs [M ‡ Cs ] 1841.5857, found 1841.5712. 41b: Rf ˆ 0.32 (silica gel, 7.5%
Natural tricyclic iodide 42a: NaI (36 mg, 0.24 mmol) and I2 (61 mg,
0.24 mmol) were added to a solution of natural tricyclic triazene 3a (76 mg,
0.04 mmol) in MeCN (8 mL). After 5 min, trimethylsilyl chloride (7.6 mL,
0.06 mmol) was added dropwise, and the mixture was allowed to stir at
258C for 15 min. Then, 5% aqueous NaHCO3 (3.5 mL) was added,
followed by the addition of 5% aqueous Na2S2O3 ´ 5H2O (3.5 mL). After
10 min, the aqueous phase was extracted with ether (3 Â 10 mL). The
combined organic layers were dried (Na2SO4), filtered through a pad of
silica gel, and concentrated. The inseparable mixture of natural tricyclic
iodide 42a and natural tricyclic reduced compound 34a (ca. 1:1 by mass
spectrometry) was used in the next reaction without further purification.
MeOH in CH2Cl2); [a]D22
3306, 2954, 2930, 2857, 1660, 1510, 1250, 1107, 837, 780 cm
ˆ
23.3 (c ˆ 2.80, MeOH); IR (thin film): nÄmax
ˆ
1
;
1H NMR
(600 MHz, CD3OD, 330 K): d ˆ 7.74 (br.s, 1H, H-2b), 7.57 (br.s, 1H, H-6b),
7.48 (dd, J ˆ 8.3, 1.7 Hz, 1H, H-6f), 7.28 (d, J ˆ 8.3 Hz, 1H, H-2e ), 7.19
(br.d, J ˆ 7.0 Hz, 1H, H-2f), 7.07 (d, J ˆ 8.2 Hz, H-6e), 7.01 ± 6.99 (m, 4H,
H-5b, H-5f and ArH (Ddm)), 6.92 ± 6.90 (m, 3H, H-7f and ArH (Ddm)),
6.87 (d, J ˆ 9.5 Hz, 1H, H-5e), 6.82 (d, J ˆ 8.6 Hz, 2H, ArH (Ddm)), 6.73
(d, J ˆ 8.6 Hz, 2H, ArH (Ddm)), 6.59 (d, J ˆ 2.0 Hz, 1H, H-7d), 5.86 (br.s,
1H, H-4b), 5.82 (br.s, 1H, NHCH (Ddm)), 5.79 (br.s, 1H, H-4f), 5.53 (d,
J ˆ 4.8 Hz, 1H, H-2b), 5.40 (br.s, 1H, H-4a), 5.32 (br.s, 1H, H-6b), 4.90 ±
4.87 (m, 2H, H-2a and H-3a), 4.81 ± 4.79 (m, 1H, H-1a), 4.63 (br.s, 1H,
H-5a), 4.20 (t, J ˆ 5.0 Hz, 1H, H-7a), 4.07 (br.s, 1H, H-6a), 4.00 (t, J ˆ
10.8 Hz, 1H, H-7bA), 3.93 (dd, J ˆ 10.8, 4.9 Hz, 1H, H-7bB), 3.87 (s, 3H,
OCH3), 3.75 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.46 (s,
3H, OCH3), 2.77 (s, 3H, NCH3), 2.62 ± 2.59 (m, 1H, H-3bA), 2.52 (dd, J ˆ
15.3, 5.8 Hz, 1H, H-3bB), 1.70 ± 1.68 (m, 1H, H-1g), 1.50 (s, 9H, tBuO),
1.39 ± 1.38 (m, 1H, H-1bA), 1.29 ± 1.28 (m, 1H, H-1bB), 0.91 (s, 9H, tBuSi),
0.89 (s, 9H, tBuSi), 0.83 (d, J ˆ 4.4 Hz, 3H, H-1d), 0.81 (d, J ˆ 4.9 Hz, 3H,
H-1d'), 0.12 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si), 0.08 (s, 3H, CH3Si), 0.05 (s,
3H, CH3Si); 13C NMR (150 MHz, CD3COCD3, 323 K): d ˆ 172.2, 171.5,
171.2, 170.5, 168.9, 161.2, 159.6, 158.1, 152.3, 151.4, 148.7, 148.6, 141.8, 140.1,
139.7, 136.0, 135.6, 135.5, 129.9, 129.8, 129.7, 129.5, 129.3, 128.8, 128.5, 128.3,
128.0, 127.8, 127.5, 126.4, 125.3, 124.8, 122.5, 114.6, 114.5, 113.7, 107.8, 106.3,
106.0, 98.7, 80.5, 74.6, 74.1, 64.2, 63.8, 60.0, 57.2, 56.4, 56.1, 55.7, 55.5, 55.5,
Natural tricyclic phenol 43a: An approximate 1:1 mixture of natural
tricyclic iodide 42a and natural tricyclic reduced compound 34a (prepared
as described above) in THF (12 mL) was cooled to 508C. MeMgBr (1.4m
solution in THF, 0.86 mL, 1.2 mmol) was added dropwise, and the mixture
was allowed to warm to 208C. After stirring for 1 h, the mixture was
recooled to 608C, and iPrMgCl (2.0m solution in THF, 0.6 mL, 1.2 mmol)
was added dropwise. The mixture was kept at 408C for 2 h, and then
cooled to 508C before the addition of freshly distilled trimethyl borate
(0.45 mL, 4 mmol). The reaction mixture was vigorously stirred for 1 h at
08C and then recooled to 208C. A mixture of 30% aqueous H2O2 and
10% aqueous NaOH (1:1, 3 mL) was added, and vigorous stirring at 08C
was applied for 20 min. Without allowing the temperature to raise, EtOAc
(10 mL) and saturated aqueous Na2S2O3 ´ 5H2O (2 mL) were added. The
mixture was stirred for 5 min, and the aqueous phase was extracted with
EtOAc (3 Â 5 mL). The combined organic layers were dried (Na2SO4),
concentrated, and the residue was purified by preparative TLC (silica gel,
5% MeOH in CH2Cl2) to afford faster moving natural tricyclic reduced
compound 34a (24.3 mg, 34% overall from 3a), and slower moving natural
tricyclic phenol 43a (24.5 mg, 34% overall from 3a). 43a: Rf ˆ 0.23 (silica
gel, 5% MeOH in CH2Cl2); [a]2D2 ˆ ‡8.8 (c ˆ 1.2, MeOH); IR (thin film):
nÄmax ˆ 3304, 2955, 2930, 2857, 1667, 1659, 1652, 1511, 1487, 1247, 838,
55.3, 52.4, 39.7, 37.4, 30.5, 28.7, 26.3, 26.2, 25.5, 23.6, 22.3, 19.0, 18.9, 4.6,
‡
4.7,
4.9; HRMS (FAB) calcd for C88H110Cl2N8O20Si2Cs [M ‡ Cs ]
1857.5806, found 1857.5693.
Treatment of unnatural tricyclic triazene 3b with TMSI (Table 3, entries
1 ± 8): NaI (1.5 ± 4.5 mg, 0.01 ± 0.30 mmol) was added to a solution of
unnatural tricyclic triazene 3b (9 mg, 0.005 mmol) in MeCN (1 ± 5 mL).
After 5 min, trimethylsilyl chloride (1 mL, 0.0075 mmol) was added
dropwise, and the mixture was allowed to stir at the temperatures shown
in Table 3, for 15 min. Then, 5% aqueous NaHCO3 (0.5 mL) was added,
and the mixture was stirred vigorously for 10 min. The aqueous phase was
extracted with ether (3 Â 1 mL). The combined organic layers were dried
(Na2SO4), filtered through a pad of silica gel, and concentrated. In all cases,
desired unnatural tricyclic iodide 42b was detected only as a trace (< 5%)
by mass spectrometry. For entries 2, 4, and 8, the crude mixture was
subjected to the next reaction (phenol formation protocol, see unnatural
tricyclic phenol 43b). Faster moving unnatural tricyclic reduced compound
34b and slower moving unnatural tricyclic phenol 43b were isolated in the
yields given in Table 3.
1
780 cm 1; H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.60 (br.s, 1H, H-2b),
7.49 ± 7.46 (m, 2H, H-6b and H-6f), 7.35 ± 7.25 (m, 7H, H-2f, H-6e and ArH
(Bn)), 7.08 (br.d, J ˆ 7.4 Hz, 1H, H-2e), 7.02 (br.s, 1H, H-5b), 6.98 (d, J ˆ
8.8 Hz, 2H, ArH (Ddm)), 6.95 (d, J ˆ 8.8 Hz, 1H, H-5f), 6.91 (br.s, 1H,
H-7f), 6.86 (br.d, J ˆ 8.3 Hz, 3H, H-5e and ArH (Ddm)), 6.82 (d, J ˆ
8.8 Hz, 2H, ArH (Ddm)), 6.69 (br.d, J ˆ 7.5 Hz, 2H, ArH (Ddm)), 6.56
(d, J ˆ 2.2 Hz, 1H, H-7d), 6.18 (br.s, 1H, NHCH (Ddm)), 5.84 (br.s, 1H,
H-4b), 5.74 (br.s, 1H, H-4f), 5.54 (d, J ˆ 4.4 Hz, 1H, H-2b), 5.44 (br.s, 1H,
H-4a), 5.29 (br.s, 1H, H-6b), 5.00 ± 4.94 (m, 2H, H-2a and H-3a), 4.76 ±
4.74 (m, 1H, H-1a), 4.61 (br.s, 1H, H-5a), 4.57 (d, J ˆ 15.4 Hz, 1H,
OCHAHPh), 4.53 (d, J ˆ 15.5 Hz, 1H, OCHHBPh), 4.42 ± 4.39 (m, 1H,
H-7a), 4.00 (br.s, 1H, H-6a), 3.92 ± 3.88 (m, 1H, H-7bA), 3.82 ± 3.80 (m, 1H,
H-7bB), 3.79 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.68 (s,
3H, OCH3), 3.40 (s, 3H, OCH3), 2.78 (s, 3H, NCH3), 2.70 ± 2.65 (m, 2H,
H-3b), 1.72 ± 1.69 (m, 1H, H-1g), 1.48 (br.s, 9H, tBuO), 1.40 ± 1.36 (m, 2H,
H-1b), 0.92 (s, 9H, tBuSi), 0.89 (s, 9H, tBuSi), 0.82 (d, J ˆ 6.1 Hz, 3H,
H-1d), 0.78 (d, J ˆ 6.1 Hz, 3H, H-1d'), 0.12 (s, 3H, CH3Si), 0.09 (s, 3H,
CH3Si), 0.06 (s, 3H, CH3Si), 0.05 (s, 3H, CH3Si); 13C NMR (150 MHz,
CD3COCD3, 323 K): d ˆ 172.1, 171.6, 171.0, 169.2, 161.3, 159.9, 159.8, 159.8,
158.3, 152.6, 151.8, 149.5, 148.4, 142.0, 140.3, 140.1, 139.7, 136.5, 136.2, 135.8,
130.5, 129.8, 129.6, 129.5, 129.3, 129.1, 129.0, 128.5, 128.3, 127.9, 127.7, 127.6,
125.7, 125.5, 125.1, 122.8, 114.9, 114.8, 114.1, 107.4, 106.7, 106.2, 99.1, 80.7,
74.9, 74.3, 73.8, 70.9, 65.0, 64.8, 60.3, 56.8, 56.4, 56.3, 55.9, 55.7, 52.7, 55.7,
52.6, 37.5, 30.5, 28.9, 26.6, 26.6, 25.8, 23.8, 22.5, 19.3, 4.1, 4.3, 4.5, 4.6;
Treatment of unnatural tricyclic triazene 3b with TMSI-I2 (Table 3, entries
9 ± 13): NaI (4.5 mg, 0.03 mmol) and I2 (2.5 ± 12.7 mg, 0.01 ± 0.05 mmol)
were added to
a solution of unnatural tricyclic triazene 3b (9 mg,
0.005 mmol) in MeCN (1 mL). After 5 min, trimethylsilyl chloride
(1.0 mL, 0.0075 mmol) was added dropwise, and the mixture was allowed
to stir at the temperatures shown in Table 3, for 15 min. Then, 5% aqueous
NaHCO3 (0.5 mL) was added, followed by the addition of 5% aqueous
Na2S2O3 ´ 5H2O (0.5 mL). After 10 min, the aqueous phase was extracted
with ether (3 Â 1 mL). The combined organic layers were dried (Na2SO4),
filtered through a pad of silica gel, and concentrated. The ratio of
inseparable unnatural tricyclic iodide 42b and unnatural tricyclic reduced
compound 34b was determined by mass spectrometry (see Table 3). In one
case (entry 13), excess I2 caused removal of the Boc group, and a
2642
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2642 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
‡
HRMS (FAB) calcd for C95H116Cl2N8O20Si2Cs [M ‡ Cs ] 1949.6292, found
1H, H-6e), 7.10 (br.d, J ˆ 7.9 Hz, 1H, H-2e), 7.03 (br.d, J ˆ 0.6 Hz, 1H,
H-5b), 6.99 (d, J ˆ 8.3 Hz, 2H, ArH (Ddm)), 6.95 (d, J ˆ 9.2 Hz, 1H, H-5f),
6.91 (br.d, J ˆ 0.5 Hz, 1H, H-7f), 6.88 (br.d, J ˆ 8.8 Hz, 3H, H-5e and ArH
(Ddm)), 6.83 (d, J ˆ 8.3 Hz, 2H, ArH (Ddm)), 6.71 (br.d, J ˆ 7.9 Hz, 2H,
ArH (Ddm)), 6.59 (br.s, 1H, H-7d), 6.13 (br.s, 1H, NHCH (Ddm)), 5.86
(br.s, 1H, H-4b), 5.75 (br.s, 1H, H-4f), 5.55 (d, J ˆ 4.4 Hz, 1H, H-2b), 5.46
(br.s, 1H, H-4a), 5.33 (br.s, 1H, H-6b), 5.00 ± 4.94 (m, 2H, H-2a and H-3a),
4.79 ± 4.75 (m, 1H, H-1a), 4.66 (br.s, 1H, H-5a), 4.24 ± 4.21 (m, 1H, H-7a),
4.06 (br.s, 1H, H-6a), 4.03 ± 4.00 (m, 1H, H-7bA), 3.93 (dd, J ˆ 10.5, 4.4 Hz,
1H, H-7bB), 3.88 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.72 (s, 3H, OCH3),
3.70 (s, 3H, OCH3), 3.43 (s, 3H, OCH3), 2.79 (s, 3H, NCH3), 2.70 ± 2.60 (m,
2H, H-3b), 1.75 ± 1.72 (m, 1H, H-1g), 1.49 (br.s, 9H, tBuO), 1.40 ± 1.37 (m,
2H, H-1b), 0.95 (s, 9H, tBuSi), 0.90 (s, 9H, tBuSi), 0.83 (d, J ˆ 6.2 Hz, 3H,
H-1d), 0.80 (d, J ˆ 6.2 Hz, 3H, H-1d'), 0.13 (s, 3H, CH3Si), 0.10 (s, 3H,
CH3Si), 0.09 (s, 3H, CH3Si), 0.08 (s, 3H, CH3Si); 13C NMR (150 MHz,
CD3COCD3, 323 K): d ˆ 172.2, 171.6, 171.6, 171.2, 171.0, 161.4, 159.9, 159.9,
158.3, 152.7, 151.9, 149.5, 148.4, 142.0, 140.2, 140.1, 136.4, 136.2, 135.8, 130.5,
129.8, 129.7, 129.5, 129.2, 128.3, 127.8, 125.7, 125.6, 125.1, 122.8, 114.9, 114.8,
114.1, 106.5, 106.2, 99.0, 80.8, 74.9, 74.4, 64.7, 64.0, 60.3, 56.8, 56.4, 56.3, 56.0,
55.7, 55.7, 52.7, 37.5, 29.0, 26.6, 25.8, 23.8, 22.7, 19.3, 19.2, 4.3, 4.5, 4.7;
1949.6134.
Unnatural tricyclic iodide 42b: NaI (27 mg, 0.18 mmol) and I2 (46 mg,
0.18 mmol) were added to a solution of unnatural tricyclic triazene 3b
(57 mg, 0.03 mmol) in MeCN (6 mL). After 5 min, trimethylsilyl chloride
(5.7 mL, 0.045 mmol) was added dropwise, and the mixture allowed to stir at
258C for 15 min. Then, 5% aqueous NaHCO3 (2.5 mL) was added,
followed by the addition of 5% aqueous Na2S2O3 ´ 5H2O (2.5 mL). After
10 min, the aqueous phase was extracted with ether (3 Â 10 mL). The
combined organic layers were dried (Na2SO4), filtered through a pad of
silica gel, and concentrated. The inseparable mixture of unnatural tricyclic
iodide 42b and unnatural tricyclic reduced compound 34b (ca. 1:1 by mass
spectrometry) was used in the next reaction without further purification.
Unnatural tricyclic phenol 43b: An approximate 1:1 mixture of unnatural
tricyclic iodide 42b and unnatural tricyclic reduced compound 34b
(prepared as described above) in THF (10 mL) was cooled to 508C.
MeMgBr (1.4m solution in THF, 0.65 mL, 0.9 mmol) was added dropwise,
and the mixture was allowed to warm to 208C. After stirring for 1 h, the
mixture was recooled to 608C, and iPrMgCl (2.0m solution in THF,
0.45 mL, 0.9 mmol) was added dropwise. The mixture was kept at 408C
for 2 h, and then cooled to 508C, before the addition of freshly distilled
trimethyl borate (0.34 mL, 3 mmol). The reaction mixture was vigorously
stirred for 1 h at 08C and then recooled to 208C. A mixture of 30%
aqueous H2O2 and 10% aqueous NaOH (1:1, 2.5 mL) was added and
vigorous stirring at 08C was applied for 20 min. Without allowing the
temperature to raise, EtOAc (10 mL), and saturated aqueous Na2S2O3 ´
5H2O (2 mL) were added. The mixture was stirred for 5 min, and the
aqueous phase was extracted with EtOAc (3 Â 5 mL). The combined
organic layers were dried (Na2SO4), concentrated, and the residue was
purified by preparative TLC (silica gel, 5% MeOH in CH2Cl2) to afford
faster moving unnatural tricyclic reduced compound 34b (15.7 mg, 29%
overall from 3b), and slower moving unnatural tricyclic phenol 43b
(17.4 mg, 32% overall from 3b). 43b: Rf ˆ 0.21 (silica gel, 5% MeOH in
‡
HRMS (FAB) calcd for C88H110Cl2N8O20Si2Cs [M ‡ Cs ] 1857.5806, found
1857.5919.
Unnatural tricyclic alcohol 41b: 10% Pd/C (30 mg) was added to a solution
of unnatural tricyclic phenol 43b (36.3 mg, 0.02 mmol) in MeOH (3 mL),
and H2 was bubbled through the solution for 1.5 h at 258C. The reaction
mixture was filtered through celite, concentrated, and the residue was
purified by preparative TLC (silica gel, 5% MeOH in CH2Cl2) to afford
unnatural tricyclic alcohol 41b (32.5 mg, 94%).
Natural tricyclic methylated phenol 44a: Cs2CO3 (32.3 mg, 0.1 mmol) was
added to a solution of natural tricyclic alcohol 41a (17.1 mg, 0.01 mmol) in
DMF (1 mL), and the mixture was cooled to 08C. Then, MeI (31 mL,
0.5 mmol) was added dropwise. After 2 h at 08C, saturated aqueous NH4Cl
(1 mL) and EtOAc (1 mL) were added. The aqueous phase was extracted
with EtOAc (2 Â 5 mL). The combined organic layers were washed with
brine (3 Â 5 mL), dried (Na2SO4), and the residue was purified by flash
column chromatography (silica gel, 50 !80% EtOAc in hexanes, gradient
elution) to afford natural tricyclic methylated phenol 44a (16.4 mg, 95%).
CH2Cl2); [a]2D2
ˆ
5.6 (c ˆ 3.6, MeOH); IR (thin film): nÄmax ˆ 3304, 2955,
1
2931, 2856, 1668, 1612, 1513, 1486, 1251, 1107, 838 cm
;
1H NMR
(600 MHz, CD3OD, 330 K): d ˆ 7.75 (br.s, 1H, H-2b), 7.54 (br.s, 1H,
H-6b), 7.45 (br.d, J ˆ 8.3, Hz, 1H, H-6f), 7.37 (d, J ˆ 5.8 Hz, 2H, ArH (Bn)),
7.31 (t, J ˆ 7.4 Hz, 2H, ArH (Bn)), 7.28 ± 7.23 (m, 2H, H-2e and ArH (Bn)),
7.19 ± 7.18 (m, 1H, H-2f), 7.00 ± 6.98 (m, 4H, H-6e, H-7f and ArH (Ddm)),
6.92 ± 6.90 (m, 4H, H-5b, H-5f and ArH (Ddm)), 6.87 (d, J ˆ 9.3 Hz, 1H,
H-5e), 6.82 (d, J ˆ 8.6 Hz, 2H, ArH (Ddm)), 6.72 (d, J ˆ 8.6 Hz, 2H, ArH
(Ddm)), 6.57 (br.s, 1H, H-7d), 5.95 (br.s, 1H, H-4b), 5.87 (br.s, 1H, NHCH
(Ddm)), 5.77 (br.s, 1H, H-4f), 5.54 (d, J ˆ 4.8 Hz, 1H, H-2b), 5.40 (br.s,
1H, H-4a), 5.29 (br.s, 1H, H-6b), 4.92 ± 4.90 (m, 2H, H-2a and H-3a),
4.81 ± 4.80 (m, 1H, H-1a), 4.61 (br.s, 1H, H-5a), 4.54 (2H, obscured by
solvent, OCH2Ph), 4.20 ± 4.19 (m, 1H, H-7a), 4.03 (br.s, 1H, H-6a), 3.90 ±
3.89 (m, 1H, H-7bA), 3.82 (dd, J ˆ 10.6, 3.7 Hz, 1H, H-7bB), 3.79 (s, 3H,
OCH3), 3.74 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.45 (s,
3H, OCH3), 2.77 (s, 3H, NCH3), 2.63 ± 2.61 (m, 1H, H-3bA), 2.52 (dd, J ˆ
15.6, 6.3 Hz, 1H, H-3bB), 1.70 ± 1.69 (m, 1H, H-1g), 1.49 (s, 9H, tBuO),
1.42 ± 1.40 (m, 2H, H-1b), 0.89 (s, 18H, tBuSi), 0.84 (d, J ˆ 10.6 Hz, 3H,
H-1d), 0.82 (d, J ˆ 7.5 Hz, 3H, H-1d'), 0.12 (s, 3H, CH3Si), 0.09 (s, 3H,
CH3Si), 0.05 (s, 3H, CH3Si), 0.04 (s, 3H, CH3Si); 13C NMR (150 MHz,
CD3COCD3, 323 K): d ˆ 172.2, 171.5, 171.2, 170.7, 170.4, 168.9, 167.6, 161.0,
159.6, 159.5, 158.1, 157.0, 152.4, 151.4, 148.8, 148.6, 141.9, 139.9, 139.4, 136.2,
135.5, 135.5, 129.5, 129.4, 129.3, 129.2, 129.0, 128.9, 128.7, 128.5, 128.3, 128.2,
127.6, 127.5, 127.3, 126.3, 125.2, 124.8, 122.5, 114.6, 114.5, 113.7, 107.7, 106.5,
106.0, 98.8, 80.5, 74.7, 74.1, 73.6, 70.6, 64.4, 57.1, 56.4, 56.1, 55.9, 55.7, 55.5,
52.6, 52.4, 39.8, 37.5, 30.2, 28.7, 26.3, 26.2, 25.5, 23.6, 22.3, 19.0, 19.0, 4.6,
44a: Rf ˆ 0.35 (silica gel, 7.5% MeOH in CH2Cl2); [a]D22
ˆ
7.5 (c ˆ 0.44,
EtOAc); IR (thin film): nÄmax ˆ 3301, 2954, 2930, 2856, 1681, 1667, 1659, 1651,
1513, 1504, 1487, 1246, 838, 780 cm 1; 1H NMR (600 MHz, CD3OD, 330 K):
d ˆ 7.62 (br.s, 1H, H-2b), 7.54 (br.s, 1H, H-6b), 7.50 (br.d, J ˆ 8.6 Hz, 1H,
H-6f), 7.36 ± 7.33 (m, 1H, H-2f), 7.26 (d, J ˆ 8.4 Hz, 1H, H-2e), 7.07 (br.d,
J ˆ 8.7 Hz, 1H, H-6e), 7.02 (d, J ˆ 2.2 Hz, 1H, H-5b), 6.96 (d, J ˆ 6.8 Hz,
2H, ArH (Ddm)), 6.94 (d, J ˆ 8.7 Hz, 1H, H-5f), 6.91 (d, J ˆ 2.1 Hz, 1H,
H-7f), 6.88 (br.d, J ˆ 8.4 Hz, 3H, H-5e and ArH (Ddm)), 6.83 (d, J ˆ
8.7 Hz, 2H, ArH (Ddm)), 6.72-6.70 (m, 2H, ArH (Ddm)), 6.58 (d, J ˆ
2.1 Hz, 1H, H-7d), 5.96 (br.s, 1H, NHCH (Ddm)), 5.85 (br.s, 1H, H-4b),
5.73 (br.s, 1H, H-4f), 5.52 (d, J ˆ 4.7 Hz, 1H, H-2b), 5.45 (br.s, 1H, H-4a),
5.32 (br.s, 1H, H-6b), 4.93 ± 4.90 (m, 2H, H-2a and H-3a), 4.75-4.73 (m,
1H, H-1a), 4.63 (br.s, 1H, H-5a), 4.23-4.19 (m, 1H, H-7a), 4.17 (s, 3H,
OCH3), 4.06 (br.s, 1H, H-6a), 4.00 (t, J ˆ 10.0 Hz, 1H, H-7bA), 3.92 (dd,
J ˆ 10.9, 4.9 Hz, 1H, H-7bB), 3.87 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.71
(s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.42 (s, 3H, OCH3), 2.78 (s, 3H, NCH3),
2.64 ± 2.61 (m, 1H, H-3bA), 2.58 (dd, J ˆ 16.4, 6.0 Hz, 1H, H-3bB), 1.72 ± 1.70
(m, 1H, H-1g), 1.51 (br.s, 9H, tBuO), 1.38 ± 1.34 (m, 2H, H-1b), 0.94 (s, 9H,
tBuSi), 0.90 (s, 9H, tBuSi), 0.83 (d, J ˆ 6.5 Hz, 3H, H-1d), 0.79 (d, J ˆ
6.2 Hz, 3H, H-1d'), 0.13 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si), 0.08 (s, 3H,
CH3Si), 0.07 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3CN, 335 K): d ˆ
172.8, 172.2, 171.8, 170.8, 169.5, 168.9, 161.5, 160.1, 159.7, 158.6, 154.8, 153.6,
152.0, 151.7, 141.9, 140.4, 139.6, 138.7, 136.0, 135.5, 130.3, 129.7, 129.6, 129.5,
129.3, 129.2, 128.6, 128.3, 127.4, 127.0, 125.9, 125.4, 124.9, 122.5, 115.1, 115.0,
114.7, 107.1, 106.8, 106.4, 99.1, 81.0, 74.5, 74.2, 65.2, 63.8, 62.1, 60.5, 57.1, 56.9,
56.8, 56.4, 56.1, 55.9, 55.8, 55.5, 52.4, 37.7, 30.6, 29.0, 26.6, 26.5, 25.7, 23.8,
‡
4.8; HRMS (FAB) calcd for C95H116Cl2N8O20Si2Cs [M ‡ Cs ] 1947.6276,
found 1947.6470.
Natural tricyclic alcohol 41a: 10% Pd/C (20 mg) was added to a solution of
natural tricyclic phenol 43a (21 mg, 0.0116 mmol) in MeOH (2 mL), and H2
was bubbled through the solution for 1.5 h at 258C. The reaction mixture
was filtered through celite, concentrated, and the residue was purified by
preparative TLC (silica gel, 5% MeOH in CH2Cl2) to afford natural
tricyclic alcohol 41a (17.4 mg, 87%). 41a: Rf ˆ 0.22 (silica gel, 5% MeOH
in CH2Cl2); [a]2D2 ˆ ‡3.5 (c ˆ 0.40, MeOH); IR (thin film): nÄmax ˆ 3306,
2953, 2932, 2857, 1680, 1666, 1659, 1651, 1514, 1505, 1487, 1248, 837,
22.3, 19.2, 19.2,
C89H112Cl2N8O20Si2Cs [M ‡ Cs ] 1871.5963, found 1871.5844.
4.0,
4.3,
4.4,
4.6; HRMS (FAB) calcd for
‡
Unnatural tricyclic methylated phenol 44b: Cs2CO3 (49 mg, 0.15 mmol)
was added to a solution of alcohol 41b (26 mg, 0.015 mmol) in DMF
(1 mL), and the mixture was cooled to 08C. Then, MeI (47 mL, 0.75 mmol)
was added dropwise. After 2 h at 08C, saturated aqueous NH4Cl (1.5 mL)
and EtOAc (1.5 mL) were added. The aqueous phase was extracted with
EtOAc (2 Â 5 mL). The combined organic layers were washed with brine
780 cm 1; H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.62 (br.s, 1H, H-2b),
1
7.50 ± 7.47 (m, 2H, H-6b and H-6f), 7.32 (br.s, 1H, H-2f), 7.28 (d, J ˆ 8.3 Hz,
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2643 $ 17.50+.50/0
2643

K. C. Nicolaou et al.
FULL PAPER
(3 Â 8 mL), dried (Na2SO4), and the residue was purified by flash column
chromatography (silica gel, 50 !80% EtOAc in hexanes, gradient elution)
to afford unnatural tricyclic methylated phenol 44b (24.5 mg, 94%). 44b:
153.7, 152.0, 151.8, 141.9, 140.4, 138.8, 137.0, 136.2, 135.8, 135.6, 135.6, 130.5,
129.8, 129.7, 129.3, 128.5, 128.1, 126.9, 125.4, 124.9, 122.5, 115.3, 115.2, 115.0,
107.0, 106.4, 106.3, 100.2, 81.1, 74.7, 74.3, 64.9, 62.2, 61.1, 60.6, 58.1, 57.2, 57.0,
56.9, 56.6, 56.2, 56.0, 55.8, 53.1, 52.5, 39.9, 37.8, 30.7, 29.2, 26.8, 26.7, 25.8,
23.8, 22.4, 19.3, 19.2, 4.1, 4.2, 4.4, 4.5; HRMS (MALDI-FTMS)
Rf ˆ 0.35 (silica gel, 7.5% MeOH in CH2Cl2); [a]D22
ˆ
16.5 (c ˆ 0.98,
MeOH); IR (thin film): nÄmax ˆ 3306, 2953, 2929, 2856, 1681, 1667, 1660, 1651,
1513, 1504, 1486, 1250, 837, 781 cm 1; 1H NMR (600 MHz, CD3OD, 330 K):
d ˆ 7.77 (br.s, 1H, H-2b), 7.56 (d, J ˆ 1.8 Hz, 1H, H-6b), 7.48 (dd, J ˆ 8.3,
1.8 Hz, 1H, H-6f), 7.24 ± 7.17 (m, 2H, H-2e and H-2f), 7.12 (br.d, J ˆ 8.7 Hz,
1H, H-6e), 7.02 ± 6.98 (m, 4H, H-5b, H-5f and ArH (Ddm)), 6.94 ± 6.88 (m,
3H, H-7f and ArH (Ddm)), 6.84 ± 6.81 (m, 3H, H-5e and ArH (Ddm)), 6.73
(d, J ˆ 8.5 Hz, 2H, ArH (Ddm)), 6.59 (d, J ˆ 2.2 Hz, 1H, H-7d), 5.97 (br.s,
1H, H-4b), 5.86 (br.s, 1H, NHCH (Ddm)), 5.80 (br.s, 1H, H-4f), 5.40 (d,
J ˆ 4.8 Hz, 1H, H-2b), 5.44 (br.s, 1H, H-4a), 5.32 (br.s, 1H, H-6b), 4.92-
4.90 (m, 2H, H-2a and H-3a), 4.80-4.78 (m, 1H, H-1a), 4.63 (br.s, 1H,
H-5a), 4.20 (br.s, 4H, H-7a and 4d-OCH3), 4.08 (br.s, 1H, H-6a), 4.00 (t,
J ˆ 8.1 Hz, 1H, H-7bA), 3.92 (dd, J ˆ 10.9, 5.0 Hz, 1H, H-7bB), 3.87 (s, 3H,
OCH3), 3.75 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 3.46 (s,
3H, OCH3), 2.77 (s, 3H, NCH3), 2.63 ± 2.61 (m, 1H, H-3bA), 2.53 (dd, J ˆ
15.8, 6.2 Hz, 1H, H-3bB), 1.72 ± 1.71 (m, 1H, H-1g), 1.50 (s, 9H, tBuO),
1.43 ± 1.40 (m, 2H, H-1b), 0.93 (s, 9H, tBuSi), 0.90 (s, 9H, tBuSi), 0.84 (d,
J ˆ 6.4 Hz, 3H, H-1d), 0.82 (d, J ˆ 4.4 Hz, 3H, H-1d'), 0.13 (s, 3H, CH3Si),
0.10 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si), 0.07 (s, 3H, CH3Si); 13C NMR
(150 MHz, CD3COCD3, 323 K): d ˆ 172.2, 171.6, 171.4, 170.7, 170.4, 170.3,
168.8, 161.2, 159.6, 158.1, 154.0, 153.8, 151.7, 151.0, 142.0, 140.3, 139.7, 138.2,
136.1, 135.6, 135.5, 135.1, 129.5, 129.3, 129.0, 128.5, 128.3, 127.8, 127.7, 127.5,
126.4, 125.3, 125.1, 124.6, 122.5, 114.6, 114.5, 113.8, 107.2, 106.3, 106.0, 98.8,
80.5, 74.7, 74.1, 64.3, 63.8, 61.2, 60.1, 57.2, 56.5, 56.1, 56.1, 56.0, 55.7, 55.5, 55.4,
52.5, 39.7, 37.4, 30.5, 28.7, 26.3, 26.2, 25.5, 23.6, 22.3, 19.0, 4.6, 4.9; HRMS
‡
calcd for C90H112Cl2N8O21Si2Na [M ‡ Na ] 1789.6755, found 1789.6784.
Unnatural tricyclic methyl ester 45b: NaHCO3 (1.7 mg, 0.02 mmol) and
Dess ± Martin periodinane reagent (6.4 mg, 0.015 mmol) were added to a
solution of alcohol 44b (17.4 mg, 0.01 mmol) in CH2Cl2 (2.5 mL). After
0.5 h at 258C, EtOAc (5 mL) and saturated aqueous NaHCO3 (containing
380 mg of Na2S2O3 ´ 5H2O) (5 mL) were added. The reaction mixture was
allowed to stir vigorously for 0.5 h and then EtOAc (5 mL) was added. The
organic layer was washed sequentially with saturated aqueous NaHCO3
(2 mL) and H2O (2 mL), dried (Na2SO4) and concentrated. The residue was
dissolved in tBuOH (3.5 mL) and warmed to 308C. 5% Aqueous NaH2PO4
(0.9 mL) and 1m aqueous KMnO4 (1.3 mL) were added, and the reaction
mixture was stirred vigorously at 308C for 1.5 h. EtOAc (25 mL) was
added, and the reaction mixture was cooled to 08C. Saturated aqueous
Na2SO3 was added dropwise under vigorous stirring in order to reduce
excess of KMnO4 to MnO2 (purple color to brown). Then, a cooled 4%
aqueous solution of HCl was added to adjust the pH to 3, at 08C. The
aqueous phase was extracted with EtOAc (3 Â 5 mL). The combined
organic layers were dried (Na2SO4), concentrated, and the residue was
treated with a solution of CH2N2 in ether for 12 h at 258C. The reaction
mixture was concentrated, and the residue was purified with preparative
TLC (silica gel, 5% MeOH in CH2Cl2) to afford unnatural tricyclic methyl
ester 45b (14.8 mg, 84%). 45b: Rf ˆ 0.36 (silica gel, 5% MeOH in CH2Cl2);
[a]2D2
ˆ
7.0 (c ˆ 0.43, MeOH); IR (thin film): nÄmax ˆ 3300, 2953, 2930, 2857,
‡
(FAB) calcd for C89H112Cl2N8O20Si2Cs [M‡ Cs ] 1871.5963, found 1871.5840.
1
1681, 1667, 1660, 1651, 1512, 1505, 1486, 1250, 838, 780 cm
;
1H NMR
(600 MHz, CD3OD, 330 K): d ˆ 7.77 ± 7.75 (m, 1H, H-2b), 7.58 (d, J ˆ
1.9 Hz, 1H, H-6b), 7.48 (dd, J ˆ 8.3, 1.8 Hz, 1H, H-6f), 7.23 (d, J ˆ 8.3 Hz,
1H, H-2e), 7.20 (br.d, J ˆ 8.2 Hz, 1H, H-2f), 7.03 (d, J ˆ 8.0 Hz, 1H, H-6e),
7.00 ± 6.98 (m, 4H, H-5b, H-5f and ArH (Ddm)), 6.91-6.90 (m, 3H, H-5e
and ArH (Ddm)), 6.82 (d, J ˆ 8.5 Hz, 2H, ArH (Ddm)), 6.72 (d, J ˆ 8.7 Hz,
2H, ArH (Ddm)), 6.40 (d, J ˆ 2.2 Hz, 1H, H-7d), 6.35 (d, J ˆ 2.2 Hz, 1H,
H-7f), 5.95 (br.s, 1H, H-4b), 5.85 (br.s, 1H, NHCH (Ddm)), 5.80 (br.s, 1H,
H-4f), 5.54 (d, J ˆ 4.8 Hz, 1H, H-2b), 5.42 (br.s, 1H, H-4a), 5.36 (br.s, 1H,
H-6b), 4.88 ± 4.86 (m, 2H, H-2a and H-3a), 4.81 (s, 1H, H-7a), 4.81 ± 4.77
(m, 1H, H-1a), 4.58 (br.s, 1H, H-5a), 4.20 (s, 3H, 4d-OCH3), 4.05 (br.s, 1H,
H-6a), 3.83 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.71 (s,
3H, OCH3), 3.70 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 2.78 (s, 3H, NCH3),
2.63 ± 2.60 (m, 1H, H-3bA), 2.51 (dd, J ˆ 15.0, 5.5 Hz, 1H, H-3bB), 1.70 ± 1.69
(m, 1H, H-1g), 1.50 (s, 9H, tBuO), 1.39 ± 1.38 (m, 1H, H-1bA), 1.29 ± 1.27
(m, 1H, H-1bB), 0.91 (s, 9H, tBuSi), 0.90 (s, 9H, tBuSi), 0.84 (d, J ˆ 6.3 Hz,
3H, H-1d), 0.81 (d, J ˆ 6.1 Hz, 3H, H-1d'), 0.12 (s, 3H, CH3Si), 0.10 (s, 3H,
CH3Si), 0.09 (s, 3H, CH3Si), 0.08 (s, 3H, CH3Si); 13C NMR (150 MHz,
CD3COCD3, 323 K): d ˆ 172.2, 171.8, 171.6, 170.7, 170.4, 168.7, 161.2, 160.1,
159.6, 158.2, 153.9, 153.7, 151.6, 151.0, 142.0, 140.3, 138.1, 137.7, 137.1, 136.2,
135.4, 135.1, 129.5, 129.5, 129.1, 129.0, 128.5, 128.2, 128.0, 127.5, 126.4, 124.6,
124.3, 122.3, 114.6, 114.5, 113.8, 107.3, 106.1, 105.9, 99.3, 80.5, 74.5, 74.1, 69.4,
64.0, 61.1, 60.1, 57.6, 56.5, 56.2, 56.1, 55.8, 55.5, 52.5, 52.2, 39.6, 37.4, 30.4,
28.7, 26.3, 26.2, 25.5, 23.6, 22.3, 19.0, 18.9, 4.7, 4.8, 4.9; HRMS
Natural tricyclic methyl ester 45a: NaHCO3 (1.3 mg, 0.015 mmol) and
Dess ± Martin periodinane reagent (4.8 mg, 0.011 mmol) were added to a
solution of natural tricyclic alcohol 44a (13 mg, 0.0075 mmol) in CH2Cl2
(2.5 mL). After 0.5 h at 258C, EtOAc (4 mL) and saturated aqueous
NaHCO3 (containing 300 mg of Na2S2O3 ´ 5H2O) (4 mL), were added. The
reaction mixture was allowed to stir vigorously for 0.5 h and then EtOAc
(4 mL) was added. The organic layer was washed sequentially with
saturated aqueous NaHCO3 (1.5 mL) and H2O (1.5 mL), dried (Na2SO4),
and concentrated. The residue was dissolved in tBuOH (2.5 mL), and
warmed to 308C. 5% Aqueous NaH2PO4 (0.7 mL) and 1m aqueous KMnO4
(1 mL) were added, and the reaction mixture was stirred vigorously at 308C
for 1.5 h. EtOAc (20 mL) was added and the reaction mixture was cooled to
08C. Saturated aqueous Na2SO3 was added dropwise under vigorous
stirring in order to reduce excess of KMnO4 to MnO2 (purple color to
brown). Then, a cooled 4% aqueous solution of HCl was added to adjust
the pH to 3, at 08C. The aqueous phase was extracted with EtOAc (3 Â
5 mL). The combined organic layers were dried (Na2SO4), concentrated,
and the residue was treated with a solution of CH2N2 for 12 h at 258C. The
reaction mixture was concentrated, and the residue was purified by
preparative TLC (silica gel, 5% MeOH in CH2Cl2) to afford natural
tricyclic methylester 45a (11.8 mg, 89%). 45a: Rf ˆ 0.40 (silica gel, 5%
MeOH in CH2Cl2); [a]D22 ˆ ‡5.8 (c ˆ 0.12, CHCl3); IR (thin film): nÄmax
ˆ
3405, 2954, 2856, 1671, 1583, 1508, 1488, 1420, 1391, 1365, 1323, 1247, 1203,
‡
(MALDI-FTMS) calcd for C90H112Cl2N8O21Si2Na [M ‡ Na ] 1791.6726,
1
1176, 1157, 1111, 1061, 1024, 838, 781 cm 1; H NMR (600 MHz, CD3OD,
found 1791.6737.
330 K): d ˆ 7.60 ± 7.57 (m, 1H, H-2b), 7.57 (br.s, 1H, H-6b), 7.52 (dd, J ˆ 8.3,
1.3 Hz, 1H, H-6f), 7.34 (br.s, 1H, H-2f), 7.25 (d, J ˆ 8.3 Hz, 1H, H-6e), 7.08
(br.d, J ˆ 7.0 Hz, 1H, H-2e), 7.01 (d, J ˆ 2.2 Hz, 1H, H-5b), 6.98 (d, J ˆ
8.8 Hz, 2H, ArH (Ddm)), 6.96 (br.d, J ˆ 8.5 Hz, 1H, H-5f), 6.88 (br.d, J ˆ
8.3 Hz, 3H, H-5e and ArH (Ddm)), 6.82 (d, J ˆ 8.8 Hz, 2H, ArH (Ddm)),
6.71 (br.d, J ˆ 8.8 Hz, 2H, ArH (Ddm)), 6.63 (d, J ˆ 2.2 Hz, 1H, H-7d),
6.36 (d, J ˆ 2.2 Hz, 1H, H-7f), 5.84 (br.s, 2H, H-4b and NHCH (Ddm)),
5.72 (br.s, 1H, H-4f), 5.52 (d, J ˆ 4.9 Hz, 1H, H-2b), 5.43 (br.s, 1H, H-4a),
5.36 (br.s, 1H, H-6b), 4.92 ± 4.88 (m, 2H, H-2a and H-3a), 4.82 (br.s, 1H,
H-7a), 4.76 ± 4.73 (m, 1H, H-1a), 4.54 (br.s, 1H, H-5a), 4.16 (s, 3H, OCH3),
4.06 (br.s, 1H, H-6a), 3.83 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.76 (s, 3H,
OCH3), 3.73 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.44 (s, 3H, OCH3), 2.78 (s,
3H, NCH3), 2.64-2.60 (m, 1H, H-3bA), 2.57 (dd, J ˆ 15.8, 5.7 Hz, 1H,
H-3bB), 1.75 ± 1.70 (m, 1H, H-1g), 1.47 (br.s, 9H, tBuO), 1.38 ± 1.34 (m, 2H,
H-1b), 0.91 (s, 9H, tBuSi), 0.90 (s, 9H, tBuSi), 0.84 (d, J ˆ 6.1 Hz, 3H,
H-1d), 0.79 (d, J ˆ 6.1 Hz, 3H, H-1d'), 0.12 (s, 3H, CH3Si), 0.08 (s, 6H,
CH3Si), 0.07 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3CN, 335 K): d ˆ
172.9, 172.1, 171.9, 171.6, 171.1, 169.6, 168.3, 161.8, 160.3, 160.1, 158.8, 154.9,
Trimethylated N-Cbz-vancomycin aglycon methyl ester 46: Vancomycin
hydrochloride, 1 ´ HCl, (0.50 g, 0.35 mmol) in MeOH (10 mL) was treated
with CbzCl (0.25 mL, 1.75 mmol) at 258C for 0.5 h. Then, 15% aqueous
NaOH was slowly added to the reaction mixture to adjust the pH to 7. The
reaction mixture was stirred for 0.5 h, filtered through a pad of silica gel,
and concentrated. The residue was triturated with CH2Cl2, and dried in
vacuo to afford N-Cbz-vancomycin as a crude residue. A solution of the
crude N-Cbz-vancomycin in DMF (1 mL) was treated sequentially with
Cs2CO3 (0.91 g, 2.8 mmol) and MeI (0.43 mL, 6.90 mmol) at 08C. The
reaction mixture was slowly warmed to 258C and stirred for 20 h. The
reaction mixture was dried in vacuo to afford trimethylated N-Cbz-
vancomycin methyl ester as a crude residue. A solution of the crude
trimethylated N-Cbz-vancomycin methyl ester in CH2Cl2 (5 mL) was
treated with trifluoroacetic acid (5 mL) and the resulting solution was
stirred at 508C for 1 h. The reaction mixture was concentrated, and the
residue was purified by flash column chromatography (silica gel, 0 !5%
MeOH in CH2Cl2, gradient elution) to afford trimethylated N-Cbz-
2644
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2644 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
vancomycin aglycon methyl ester 46 (180 mg, 39% overall from 1 ´ HCl).
46: Rf ˆ 0.32 (silica gel, 10% MeOH in CH2Cl2); [a]2D2 ˆ ‡40.0 (c ˆ 0.28,
MeOH); IR (thin film): nÄmax ˆ 3397, 2956, 1735, 1670, 1508, 1490, 1437, 1400,
1322, 1233, 1177, 1159, 1081, 1060, 1009 cm 1; 1H NMR (600 MHz, CD3OD,
323 K): d ˆ 7.62 (d, J ˆ 2.0 Hz, 1H), 7.58 (dd, J ˆ 8.5, 2.0 Hz, 1H), 7.43 (br.s,
1H), 7.38 ± 7.30 (m, 6H), 7.23 (d, J ˆ 8.5 Hz, 1H), 7.17 ± 7.12 (m, 2H), 7.05 (d,
J ˆ 2.5 Hz, 1H), 6.97 (d, J ˆ 9.0 Hz, 1H), 6.70 (d, J ˆ 2.0 Hz, 1H), 6.38 (d,
J ˆ 2.0 Hz, 1H), 5.72 (s, 1H), 5.71 (d, J ˆ 2.0 Hz, 1H), 5.40 (s, 1H), 5.37
(br.s, 1H), 5.32 (s, 1H), 5.20 (br.s, 3H), 4.93 (br.d, J ˆ 4.5 Hz, 1H), 4.85
(br.s, 1H), 4.80 (s, 1H), 4.64 (s, 1H), 4.13 (br.s, 1H), 3.87 (s, 3H), 3.83 (s,
3H), 3.72 (s, 3H), 3.68 (s, 3H), 2.96 (s, 3H), 2.62 (br.s, 1H), 2.37 (dd, J ˆ
15.5, 7.0 Hz, 1H), 1.78 ± 1.76 (m, 1H), 1.64 ± 1.63 (m, 1H), 1.52 (br.s, 1H),
0.95 (d, J ˆ 6.5 Hz, 3H), 0.93-0.88 (m, 3H); 13C NMR (150 MHz,
CD3COCD3, 315 K): d ˆ 172.1, 171.9, 171.3, 170.1, 168.8, 161.2, 160.1,
158.2, 158.0, 151.9, 151.0, 148.7, 142.2, 138.0, 136.7, 136.6, 135.9, 135.4, 129.5,
129.3, 129.2, 128.9, 128.7, 128.4, 128.0, 127.6, 127.2, 125.7, 125.4, 124.9, 124.1,
122.3, 113.8, 108.1, 105.9, 105.7, 99.3, 73.2, 72.5, 68.2, 68.0, 63.7, 59.7, 58.2,
57.8, 56.3, 56.2, 56.1, 55.8, 55.2, 52.5, 37.3, 31.0, 25.5, 25.4, 23.6, 22.2; HRMS
171.6, 171.4, 169.9, 169.0, 161.8, 160.2, 158.8, 154.7, 153.7, 152.9, 151.8, 141.8,
139.8, 139.0, 137.6, 136.8, 136.6, 134.9, 130.4, 130.2, 129.5, 128.9, 128.3, 128.2,
128.0, 127.4, 125.6, 124.9, 124.8, 122.4, 114.1, 108.1, 107.3, 106.5, 106.3, 99.6,
74.6, 73.6, 68.8, 64.9, 62.2, 60.5, 58.1, 57.9, 56.5, 56.4, 56.1, 55.8, 55.7, 52.7,
52.3, 37.7, 30.6, 26.5, 26.3, 25.7, 23.7, 21.8, 19.2, 18.9, 4.5, 4.7, 4.8, 4.9;
‡
HRMS (FAB) calcd for C78H96Cl2N8O19Si2Cs [M ‡ Cs ] 1707.4762, found
1707.4844.
Tetramethylated N-Cbz-N-Ddm-di-TBS-vancomycin aglycon methyl ester
49: A solution of tetramethylated N-Cbz-di-TBS-vancomycin aglycon
methyl ester 48 (33 mg, 0.021 mmol) in AcOH (2.1 mL) was treated
sequentially with 4,4'-dimethoxy benzhydrol (0.5 g, 2.0 mmol) and H2SO4
(1.0m solution in AcOH, 0.1 mL, 0.1 mmol) at 08C. The reaction mixture
was slowly warmed to 258C and stirred for 2 h. The reaction mixture was
diluted with EtOAc (10 mL), washed with H2O (10 mL Â 3), and neutral-
ized by the addition of saturated aqueous NaHCO3 (10 mL). The combined
organic layers were washed with brine (5 mL), dried (Na2SO4), concen-
trated, and the residue was purified by flash column chromatography (silica
gel, 5 !80% EtOAc in hexanes, gradient elution) to afford tetramethy-
lated N-Cbz-N-Ddm-di-TBS-vancomycin aglycon methyl ester 49 (29 mg,
‡
(FAB) calcd for C65H66Cl2N8O19Cs [M ‡ Cs ] 1465.2876, found 1465.2962.
76%). 49: Rf ˆ 0.34 (silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
2.3 (c ˆ
Tetramethylated N-Cbz-vancomycin aglycon methyl ester 47: A solution of
trimethylated N-Cbz-vancomycin aglycon methyl ester 46 (80 mg,
0.06 mmol) in DMF (0.4 mL) was treated sequentially with K2CO3
(83 mg, 0.60 mmol) and MeI (37 mL, 0.60 mmol) at 08C. The reaction
mixture was slowly warmed to 258C and stirred for 1 h. The reaction
mixture was dried in vacuo, and the residue was purified by flash column
chromatography (silica gel, 2 !5% MeOH in CH2Cl2, gradient elution) to
afford tetramethylated N-Cbz-vancomycin aglycon methyl ester 47 (79 mg,
98%). 47: Rf ˆ 0.34 (silica gel, 10% MeOH in CH2Cl2); [a]2D2 ˆ ‡27.7 (c ˆ
1.1, MeOH); IR (thin film): nÄmax ˆ 3387, 2952, 1668, 1505, 1412, 1320, 1233,
1060, 1022 cm 1; 1H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.58 (s, 1H), 7.58
(br.d, J ˆ 8.5 Hz, 1H), 7.44 (br.s, 1H), 7.35 ± 7.26 (m, 6H), 7.13 (br.s, 1H),
7.07 (br.d, J ˆ 8.5 Hz, 1H), 7.02 (d, J ˆ 2.0 Hz, 1H), 7.01 (d, J ˆ 8.5 Hz, 1H),
6.95 (d, J ˆ 8.5 Hz, 1H), 6.67 (d, J ˆ 2.0 Hz, 1H), 6.35 (d, J ˆ 2.0 Hz, 1H),
5.85 (s, 1H), 5.70 (s, 1H), 5.40 (s, 1H), 5.33 (br.s, 1H), 5.29 (s, 1H), 5.17
(br.s, 3H), 4.93 (br.d, J ˆ 4.0 Hz, 1H), 4.82 (br.s, 1H), 4.76 (s, 1H), 4.61 (s,
1H), 4.15 (s, 3H), 4.11 (br.s, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.69 (s, 3H),
3.65 (s, 3H), 2.93 (s, 3H), 2.65 (br.s, 1H), 2.35 (dd, J ˆ 15.5, 7.0 Hz, 1H),
1.77 ± 1.74 (m, 1H), 1.64 ± 1.62 (m, 1H), 1.49 (br.s, 1H), 0.91 (d, J ˆ 6.5 Hz,
3H), 0.88 (br.s, 3H); 13C NMR (150 MHz, CD3OD, 330 K): d ˆ 173.3,
172.9, 171.7, 171.1, 170.9, 169.5, 161.4, 160.0, 158.4, 153.6, 153.5, 152.3, 150.8,
142.1, 138.0, 137.4, 136.3, 136.2, 134.4, 129.7, 129.5, 129.0, 128.3, 128.1, 128.0,
127.7, 127.6, 125.0, 124.4, 124.3, 122.1, 113.6, 107.9, 105.9, 99.1, 93.9, 72.4,
71.9, 68.4, 64.1, 61.4, 60.1, 58.3, 57.7, 56.0, 55.9, 55.6, 55.2, 52.4, 52.3, 37.0,
0.52, CHCl3); IR (thin film): nÄmax ˆ 3405, 2954, 2856, 1670, 1506, 1490, 1247,
1176, 1111, 1061, 1025, 838 cm 1; 1H NMR (600 MHz, CD3CN, 340 K): d ˆ
9.03 (br.s, 1H), 7.54 (br.s, 1H), 7.48 (s, 1H), 7.44 (d, J ˆ 8.5 Hz, 1H), 7.37 ±
7.07 (m, 10H), 7.03 (d, J ˆ 8.5 Hz, 2H), 6.89 ± 6.82 (m, 1H), 6.87 (d, J ˆ
8.5 Hz, 2H), 6.83 (d, J ˆ 8.5 Hz, 2H), 6.70 (d, J ˆ 2.0 Hz, 1H), 6.59 (br.s,
1H), 6.40 (d, J ˆ 2.0 Hz, 1H), 6.30 ± 6.10 (m, 2H), 5.88 (d, J ˆ 7.5 Hz, 1H),
5.77 (s, 1H), 5.51 (d, J ˆ 4.5 Hz, 1H), 5.48 (s, 1H), 5.34 (s, 1H), 5.17 (br.s,
2H), 4.94 ± 4.91 (m, 1H), 4.91 (br.s, 1H), 4.84 ± 4.81 (m, 1H), 4.76 (d, J ˆ
6.5 Hz, 1H), 4.56 (d, J ˆ 5.0 Hz, 1H), 4.21 (s, 3H), 3.94 (d, J ˆ 12.0 Hz, 1H),
3.88 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.77 (s, 3H), 3.74 (s, 3H), 3.62 (s,
3H), 2.95 (s, 3H), 2.55 ± 2.51 (m, 1H), 2.47 ± 2.44 (m, 1H), 1.78 ± 1.71 (m,
1H), 1.55 ± 1.49 (m, 2H), 0.94 (s, 9H), 0.92 (s, 9H), 0.89 (d, J ˆ 5.5 Hz, 3H),
0.83 (br.s, 3H), 0.12 (s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.06 (s, 3H);
13C NMR (150 MHz, CD3CN, 340 K): d ˆ 172.6, 172.1, 171.9, 171.5, 171.1,
169.5, 168.3, 161.9, 160.4, 160.2, 158.8, 154.9, 153.7, 152.1, 151.8, 142.0, 140.4,
138.8, 138.5, 137.1, 136.3, 135.7, 135.6, 130.5, 129.7, 129.7, 129.6, 129.4, 129.3,
129.1, 128.6, 128.3, 128.2, 127.0, 125.5, 125.0, 122.5, 115.3, 115.2, 115.0, 107.2,
106.4, 100.2, 74.7, 74.2, 68.4, 64.9, 62.2, 60.7, 58.1, 57.2, 57.1, 56.9, 56.6, 56.2,
56.1, 55.9, 53.1, 52.5, 39.9, 37.9, 31.4, 30.5, 26.6, 26.5, 25.9, 23.7, 22.4, 19.3,
19.2, 4.2, 4.3, 4.5; HRMS (FAB) calcd for C93H110Cl2N8O21Si2Cs [M ‡
‡
Cs ] 1935.5771, found 1935.5665.
Tetramethylated N-Ddm-di-TBS-vancomycin aglycon methyl ester 50: A
solution of tetramethylated N-Cbz-N-Ddm-di-TBS-vancomycin aglycon
methyl ester 49 (45 mg, 0.025 mmol) in MeOH/EtOAc (2:1) (3 mL) was
treated with 10% Pd-C (5 mg) at 258C under H2. The reaction mixture was
stirred for 2 h. Then it was filtered through celite, concentrated, and dried
in vacuo to afford tetramethylated N-Ddm-di-TBS-vancomycin aglycon
methyl ester 50 (41 mg) as a crude residue.
‡
30.4, 25.4, 23.0, 21.4; HRMS (FAB) calcd for C66H68Cl2N8O19Cs [M ‡ Cs ]
1479.3032, found 1479.3110.
Tetramethylated N-Cbz-di-TBS-vancomycin aglycon methyl ester 48: A
solution of tetramethylated N-Cbz-vancomycin aglycon methyl ester 47
(104 mg, 0.077 mmol) in CH2Cl2 (2 mL) was treated sequentially with 2,6-
lutidine (0.2 mL, 0.87 mmol) and tert-butyldimethylsilyl trifluoromethane-
sulfonate (TBSOTf, 0.1 mL, 0.86 mmol) at 108C. The resulting mixture
was stirred at 108C for 0.5 h. The reaction mixture was diluted with
CH2Cl2 (5 mL) and quenched by the addition of saturated aqueous
NaHCO3 (1 mL). The aqueous phase was extracted with CH2Cl2 (2 Â
2 mL). The combined organic layers were washed with brine (2 mL), dried
(Na2SO4), concentrated, and the residue was purified by flash column
chromatography (silica gel, 30 !80% EtOAc in hexanes; then 5% MeOH
in CH2Cl2, gradient elution) to afford tetramethylated N-Cbz-di-TBS-
vancomycin aglycon methyl ester 48 (98 mg, 80%). 48: Rf ˆ 0.29 (silica gel,
5% MeOH in CH2Cl2); [a]2D2 ˆ ‡11.9 (c ˆ 0.32, CHCl3); IR (thin film):
nÄmax ˆ 3398, 2929, 2855, 1750, 1654, 1609, 1583, 1508, 1489, 1420, 1323, 1234,
Tetramethylated N-Ddm-di-TBS-vancomycin aglycon alcohol 51: A sol-
ution of crude tetramethylated N-Ddm-di-TBS-vancomycin aglycon meth-
yl ester 50 (41 mg) in THF (1.5 mL) was treated with DIBAL/nBuLi (1:1)
ate complex (1.5m solution in THF, 0.2 mL, 0.3 mmol) at 108C. The
reaction mixture was stirred for 0.5 h. A solution of NaBH4 (19 mg,
0.50 mmol) in THF/H2O (1:1, 2.3 mL) was added and the reaction mixture
was slowly warmed at 258C and stirred for 1 h. The reaction mixture was
diluted with EtOAc (60 mL), filtered through celite, dried (Na2SO4),
concentrated, and the residue was purified by flash column chromatog-
raphy (silica gel, 20 ± 80% EtOAc in hexanes, gradient elution) to afford
tetramethylated N-Ddm-di-TBS-vancomycin aglycon alcohol 51 (28 mg,
65%). 51: Rf ˆ 0.66 (silica gel, EtOAc); [a]D22
ˆ
38.3 (c ˆ 0.23, CHCl3); IR
1
1203, 1159, 1111, 1062, 1025, 839, 782 cm 1; H NMR (600 MHz, CD3OD,
(thin film): nÄmax ˆ 3402, 2954, 2856, 1670, 1609, 1584, 1509, 1246, 1176, 1108,
1
330 K): d ˆ 7.65 (br.s, 1H), 7.54 (s, 1H), 7.49 (br.d, J ˆ 8.5 Hz, 1H), 7.34 ±
7.28 (m, 7H), 7.11 (d, J ˆ 2.0 Hz, 1H), 7.00 ± 6.97 (m, 2H), 6.67 (d, J ˆ
2.0 Hz, 1H), 6.54 (br.s, 1H), 6.38 (d, J ˆ 2.0 Hz, 1H), 6.08 (br.s, 1H), 5.75
(s, 1H), 5.52 (d, J ˆ 4.5 Hz, 1H), 5.43 (s, 1H), 5.36 (s, 1H), 5.21 (br.s, 3H),
4.98 (d, J ˆ 4.5 Hz, 1H), 4.83 ± 4.81 (m, 1H), 4.82 (s, 1H), 4.59 (s, 1H), 4.21
(s, 3H), 4.07 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.70 (s, 3H), 3.64 (s, 3H),
2.95 (s, 3H), 2.49 (br.s, 1H), 2.36 (dd, J ˆ 15.5, 5.5 Hz, 1H), 1.82 ± 1.80 (m,
1H), 1.53 ± 1.50 (m, 2H), 0.93 (s, 9H), 0.90 (d, J ˆ 6.0 Hz, 3H), 0.87 (s,
18H), 0.13 (s, 3H), 0.13 (s, 3H), 0.12 (s, 3H), 0.06 (s, 3H); 13C NMR
[150 MHz, CD3OD/CDCl3 (10:1), 330 K] d ˆ 174.6, 173.6, 172.6, 171.9,
1061, 1028, 838 cm 1; H NMR (600 MHz, CD3CN, 330 K): d ˆ 8.70 (br.s,
1H), 8.06 (br.s, 1H), 7.57 (s, 1H), 7.53 (d, J ˆ 8.0 Hz, 1H), 7.26 (d, J ˆ
8.0 Hz, 1H), 7.18-7.05 (m, 7H), 6.96 (s, 1H), 6.86 (d, J ˆ 8.5 Hz, 2H), 6.81
(d, J ˆ 8.5 Hz, 2H), 6.62 (s, 1H), 6.57 (br.s, 1H), 6.48 (br.s, 1H), 5.94 ± 5.91
(m, 2H), 5.81 (s, 1H), 5.57 ± 5.53 (m, 1H), 5.47 (s, 1H), 5.21 (br.s, 1H),
4.92 ± 4.68 (m, 3H), 4.40 (br.s, 2H), 4.14 (s, 3H), 4.11-4.10 (m, 3H), 3.89 (s,
3H), 3.76 (s, 3H), 3.72 (s, 3H), 3.65 (s, 3H), 3.62 (s, 3H), 2.91 ± 2.88 (m,
1H), 2.79 (br.s, 1H), 2.30 (s, 3H), 1.75 ± 1.73 (m, 1H), 1.51 ± 1.41 (m, 2H),
0.98 (s, 9H), 0.96 (s, 9H), 0.93 (d, J ˆ 6.5 Hz, 3H), 0.89 (d, J ˆ 6.5 Hz, 3H),
0.15 (s, 3H), 0.13 (s, 3H), 0.06 (s, 3H), 0.00 (s, 3H); 13C NMR (150 MHz,
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2645 $ 17.50+.50/0
2645

K. C. Nicolaou et al.
FULL PAPER
CD3CN, 330 K): d ˆ 175.4, 172.2, 171.0, 168.8, 168.6, 161.0, 159.8, 159.2,
158.1, 153.7, 151.2, 150.9, 142.0, 140.8, 139.3, 137.9, 135.3, 135.1, 134.9, 130.0,
129.2, 129.1, 128.9, 128.7, 128.1, 127.6, 126.5, 125.8, 125.0, 121.9, 114.8, 114.8,
114.0, 105.8, 98.5, 73.6, 65.6, 61.6, 56.8, 56.6, 56.5, 56.2, 56.0, 55.8, 55.8, 54.6,
52.6, 43.4, 38.5, 35.9, 30.1, 26.2, 25.7, 23.6, 23.1, 21.7, 18.8, 4.3, 4.5, 4.8,
(10 mL), dried (Na2SO4), and concentrated to afford crude diol 52.
Aluminum tribromide (29 mg, 0.108 mmol) was added to 1,2-dibromo-
ethane (0.1 mL), and the resulting mixture was stirred for 10 min at 258C.
Ethanethiol (0.2 mL) was added, and the mixture was vigorously stirred for
10 min at 258C. Then, a solution of crude diol 52 in CH2Cl2 (0.2 mL) was
added, and the mixture was stirred for 4 h at 258C. EtOAc (10 mL) was
added, and the reaction was quenched by the addition of MeOH (1 mL).
After 0.5 h of vigorous stirring at 258C, the reaction mixture was dried
(Na2SO4), concentrated at 258C, and the residue was purified by HPLC
[rt ˆ 28.9 min, gradient: 0 ± 20 min, MeCN/H2O (‡0.1% TFA) (5:95 !
30:70); 20 ± 30 min, MeCN/H2O (‡0.1% TFA) (30:70 !60:40), RP C18,
9 mLmin 1] to afford vancomycin aglycon 2 (1.3 mg, 43% overall from
45a).
‡
5.1; HRMS (FAB) calcd for C84H104Cl2N8O18Si2Cs [M ‡ Cs ] 1771.5439,
found 1771.5310.
Tetramethylated N-Boc-N-Ddm-di-TBS-vancomycin aglycon alcohol 44a
(from degradation): A solution of tetramethylated N-Ddm-di-TBS-vanco-
mycin aglycon alcohol 51 (28 mg, 0.0165 mmol) in MeOH/CH2Cl2 (1:1,
1.9 mL) was treated sequentially with Boc2O (25 mg, 0.116 mmol) and
triethylamine (42.5 mL, 0.116 mmol) at 08C, and the reaction mixture was
stirred for 20 min. Then, it was diluted with CH2Cl2 (20 mL), and washed
with H2O (50 mL), dried (Na2SO4), concentrated, and the residue was
purified by flash column chromatography (silica gel, 5 !60% EtOAc in
hexanes, gradient elution) to afford tetramethylated N-Boc-N-Ddm-di-
TBS-vancomycin aglycon alcohol 44a (26.7 mg, 93%).
Vancomycin aglycon 2 (two-step deprotection, with HF ´ pyr.): A solution
of fully protected vancomycin aglycon 45a (5.0 mg, 0.00283 mmol) in THF
(0.2 mL) in a polyethylene vial was cooled to 08C. Then, pyridine (0.1 mL)
and HF ´ pyridine (0.1 mL) were added, and the reaction mixture was
stirred for 12 h while the temperature was raised slowly to 258C. The
reaction mixture was quenched by the addition of saturated aqueous
NaHCO3 (0.5 mL) and extracted with EtOAc (5 mL). The organic phase
was washed with brine (1 mL), dried (Na2SO4), and concentrated to afford
crude diol 52. Aluminum tribromide (30 mg, 0.113 mmol) was added to 1,2-
dibromoethane (0.1 mL) and the resulting mixture was stirred for 10 min at
258C. Ethanethiol (0.2 mL) was added, and the mixture was vigorously
stirred for 10 min at 258C. Then, a solution of crude diol 52 in CH2Cl2
(0.2 mL) was added, and the mixture was left for 4 h at 258C. EtOAc
(10 mL) was added, and the reaction was quenched by the addition of
MeOH (1 mL). After 0.5 h of vigorous stirring at 258C, the reaction
mixture was dried (Na2SO4), concentrated at 258C, and the residue was
purified by HPLC [rt ˆ 28.9 min, gradient: 0 ± 20 min, MeCN/H2O (‡0.1%
Tetramethylated N-Boc-N-Ddm-di-TBS-vancomycin aglycon methyl ester
45a (from degradation): A solution of crude tetramethylated N-Ddm-di-
TBS-vancomycin aglycon methyl ester 50 (41 mg) in dioxane/H2O (10:1)
(1 mL) was treated with Boc2O (27 mg, 0.125 mmol) at 258C. The reaction
mixture was stirred for 6 h, cooled at 08C, and then quenched by the
addition of saturated aqueous NaHCO3 (5 mL). The aqueous phase was
extracted with EtOAc (2 Â 30 mL). The combined organic layers were
washed with brine (15 mL), dried (Na2SO4), concentrated, and the residue
was purified by flash column chromatography (silica gel, 5 !80% EtOAc
in hexanes, gradient elution) to afford tetramethylated N-Boc-N-Ddm-di-
TBS-vancomycin aglycon methyl ester 45a (40 mg, 90%).
Atropisomerization of unnatural tricyclic triazene 3b to natural tricyclic
triazene 3a and vice versa: A solution of unnatural tricyclic triazene 3b or
natural tricyclic triazene 3a (10 mg, 0.005 mmol) in freshly distilled and
thoroughly degassed 1,2-dichlorobenzene (2.5 mL) was heated under Ar at
1408C for 4 h. The reaction mixture was concentrated, and the residue was
purified by preparative TLC (silica gel, 5% MeOH in CH2Cl2). By using
unnatural atropisomer 3b as starting material, natural atropisomer 3a
(3.3 mg, 33%) and recovered unnatural atropisomer 3b (4.7 mg, 47%)
were isolated in a ratio of 41:59. Using natural atropisomer 3a as starting
material, unnatural atropisomer 3b (3.2 mg, 32%) and recovered natural
atropisomer 45a (5.2 mg, 52%) were isolated in a ratio of 38:62.
TFA)
(5:95 !30:70);
20-30 min,
MeCN/H2O
(‡0.1%
TFA)
(30:70 !60:40), RP C18, 9 mLmin 1] to afford vancomycin aglycon 2
(2.0 mg, 62% overall from 45a). 2: HPLC rt ˆ 20.4 min [gradient: 0-20 min,
MeCN/H2O (‡0.1% TFA) (5:95 !30:70); 20-24 min, MeCN/H2O
(‡0.1% TFA) (30:70), RP C18, 1 mL/min]; [a]2D2 ˆ ‡65.4 (c ˆ 0.22,
MeOH); IR (thin film): nÄmax ˆ 3304, 2957, 2924, 1667, 1644, 1514, 1488,
1429, 1224, 1201, 1139, 1060, 1011, 839, 800, 718 cm 1; 1H NMR (600 MHz,
CD3OD, 330 K): d ˆ 7.75 (d, J ˆ 8.8 Hz, 1H, H-6f), 7.70 (s, 1H, H-2b), 7.63
(d, J ˆ 1.8 Hz, 1H, H-6b), 7.55 (d, J ˆ 7.9 Hz, 1H, H-6e), 7.51 ± 7.48 (m, 1H,
H-2f), 7.16 (d, J ˆ 8.8 Hz, 1H, H-2e), 7.07 (d, J ˆ 1.8 Hz, 1H, H-5b), 6.70 ±
6.67 (m, 2H, H-5e and H-5f), 6.45 (d, J ˆ 2.2 Hz, 1H, H-7f), 6.43 (d, J ˆ
2.2 Hz, 1H, H-7d), 6.00 (s, 1H, H-4a), 5.94 (br.s, 1H, H-4f), 5.35 (br.s, 2H,
H-4b and H-6b), 5.26 (d, J ˆ 3.5 Hz, 1H, H-2b), 4.74 (s, 1H, H-5a), 4.71 (s,
1H, H-7a), 4.28 (d, J ˆ 7.9 Hz, 1H, H-3a), 4.16 (s, 1H, H-6a), 3.98 (t, J ˆ
6.8 Hz, 1H, H-1a), 2.96 (br.d, J ˆ 15.8 Hz, 1H, H-3bA), 2.77 (s, 3H, NCH3),
2.05 (dd, J ˆ 16.2, 9.2 Hz, 1H, H-3bB), 1.85 ± 1.83 (m, 1H, H-1bA), 1.70 ± 1.63
(m, 2H, H-1bB and H-1g), 0.92 (d, J ˆ 5.7 Hz, 3H, H-1d), 0.91 (d, J ˆ
5.3 Hz, 3H, H-1d'); 13C NMR (150 MHz, CD3OD, 323 K): d ˆ 175.1, 174.2,
171.9, 171.3, 169.6, 168.8, 168.3, 158.7, 157.5, 156.0, 152.9, 151.1, 149.4, 147.9,
141.9, 140.4, 137.0, 136.7, 135.6, 129.7, 128.6, 128.2, 127.9, 127.4, 126.8, 125.0,
124.7, 121.7, 118.3, 118.0, 107.5, 106.1, 103.7, 73.7, 72.8, 63.5, 61.6, 59.3, 58.1,
56.0, 54.8, 52.3, 39.8, 35.9, 32.5, 25.0, 22.5, 22.2; HRMS (MALDI-FTMS)
Atropisomerization of unnatural methyl ester 45b to natural methyl ester
45a and vice versa: A solution of unnatural methyl ester 45b or natural
methyl ester 45a (10 mg, 0.0057 mmol) in freshly distilled and thoroughly
degassed 1,2-dichlorobenzene (2.5 mL) was heated under Ar at 1308C for
8 h. The reaction mixture was concentrated and the residue was purified by
preparative TLC (silica gel, 3% MeOH in CH2Cl2). By using unnatural
atropisomer 45b as starting material, natural atropisomer 45a (3.5 mg,
35%) and recovered unnatural atropisomer 45b (4.7 mg, 47%) were
isolated in a ratio of 43:57. By using natural atropisomer 45a as starting
material, unnatural atropisomer 45b (4 mg, 40%) and recovered natural
atropisomer 45a (4.7 mg, 47%) were isolated in a ratio of 46:54.
Vancomycin aglycon 2 (one-step deprotection): Aluminium tribromide
(31 mg, 0.118 mmol) was added to 1,2-dibromoethane (0.1 mL) and the
resulting mixture was stirred for 10 min at 258C. Ethanethiol (0.2 mL) was
added, and the mixture was vigorously stirred for 10 min at 258C. Then, a
solution of fully protected vancomycin aglycon 45a (5.2 mg, 0.00294 mmol)
in CH2Cl2 (0.2 mL) was added, and the mixture was stirred for 4 h at 258C.
EtOAc (10 mL) was added, and the reaction was quenched by the addition
of MeOH (1 mL). After 0.5 h of vigorous stirring at 258C, the reaction
mixture was dried (Na2SO4), concentrated at 258C, and the residue was
purified by preparative HPLC [rt ˆ 28.9 min, gradient: 0 ± 20 min, MeCN/
H2O (‡0.1% TFA) (5:95 !30:70); 20 ± 30 min, MeCN/H2O (‡0.1% TFA)
(30:70 !60:40), RP C18, 9 mLmin 1] to afford vancomycin aglycon 2
(1.0 mg, 30%).
‡
calcd for C53H53Cl2N8O17 [M ‡ H ] 1143.2906, found 1143.2911. 2 (from
degradation): HPLC rt ˆ 20.4 min [gradient: 0 ± 20 min, MeCN/H2O
(‡0.1% TFA) (5:95 !30:70); 20 ± 24 min, MeCN/H2O (‡0.1% TFA)
(30:70), RP C18, 1 mLmin 1]; [a]2D2 ˆ ‡70.0 (c ˆ 0.22, MeOH); IR (thin
film): nÄmax ˆ 3294, 3041, 2963, 2925, 1669, 1643, 1513, 1490, 1427, 1229, 1201,
1
1181, 1137, 1061, 1011, 840, 800, 720 cm
;
1H NMR (600 MHz, CD3OD,
330 K): d ˆ 8.85 (d, J ˆ 6.5 Hz, 1H, NH partially exchanged), 8.60 (d, J ˆ
6.2 Hz, 1H, NH partially exchanged), 7.75 (d, J ˆ 8.8 Hz, 1H, H-6f), 7.70 (s,
1H, H-2b), 7.64 (br.s, 1H, H-6b), 7.55 (d, J ˆ 8.3 Hz, 1H, H-6e), 7.51 ± 7.48
(m, 1H, H-2f), 7.16 (d, J ˆ 8.3 Hz, 1H, H-2e), 7.07 (d, J ˆ 2.2 Hz, 1H, H-5b),
6.71-6.65 (m, 2H, H-5e and H-5f), 6.45 (d, J ˆ 2.2 Hz, 1H, H-7f), 6.43 (d,
J ˆ 2.2 Hz, 1H, H-7d), 6.00 (s, 1H, H-4a), 5.94 (br.s, 1H, H-4f), 5.35 (br.s,
2H, H-4b and H-6b), 5.26 (d, J ˆ 3.5 Hz, 1H, H-2b), 4.74 (br.d, J ˆ 6.1 Hz,
1H, H-5a), 4.71 (br.s, 1H, H-7a), 4.28 (d, J ˆ 7.4 Hz, 1H, H-3a), 4.16 (br.s,
1H, H-6a), 3.98 (t, J ˆ 7.0 Hz, 1H, H-1a), 2.96 (br.d, J ˆ 14.0 Hz, 1H,
H-3bA), 2.77 (s, 3H, NCH3), 2.05 (dd, J ˆ 15.4, 9.7 Hz, 1H, H-3bB), 1.86-1.83
(m, 1H, H-1bA), 1.70-1.63 (m, 2H, H-1bB and H-1g), 0.92 (d, J ˆ 5.2 Hz,
3H, H-1d), 0.91 (d, J ˆ 5.7 Hz, 3H, H-1d'); HRMS (MALDI-FTMS) calcd
Vancomycin aglycon 2 (two-step deprotection, with nBu4NF): A solution of
fully protected vancomycin aglycon 45a (4.8 mg, 0.00271mmol) in THF
(0.25 mL) was treated with tetra-n-butylammonium fluoride (TBAF, 1.0m
solution in THF, 0.14 mL, 0.14 mmol) and AcOH (80 mL, 0.14 mmol) for
48 h at 258C. Then, the reaction mixture was cooled to 08C, quenched by
the addition of H2O (5 mL) and extracted with EtOAc (3 Â 10 mL). The
combined organic layers were washed with H2O (2 Â 10 mL) and brine
‡
for C53H53Cl2N8O17 [M ‡ H ] 1143.2906, found 1143.2940.
2646
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0947-6539/99/0509-2646 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 3
2622±2647
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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 (AI38893), The
Skaggs Institute for Chemical Biology, and grants from Pfizer, Schering
Plough, Hoffmann La Roche, Merck, Boehringer Ingelheim, Abbott
Laboratories and Glaxo.
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Received: March 29, 1999 [F 1707]
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2647 $ 17.50+.50/0
2647