Total synthesis of vancomycin - Part 2: Retrosynthetic analysis, synthesis of amino acid building blocks and strategy evaluations

Article abstract of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2602::AID-CHEM2602>3.0.CO;2-X

Retrosynthetic analysis of vancomycin (1) defined vancomycin's aglycon (2) and protected triazene 3 (Figure 1) as advanced intermediates for an eventual total synthesis. Sequential assembly of 3 as shown in Figure 2 (strategy I) and Figure 3 (strategy II) led to amino acid building blocks 8-10 and 12-15, respectively, representing vancomycin's amino acids AA-1 to AA-7. These amino acid fragments were constructed by stereoselective routes and the two synthetic strategies were tested for feasibility. Strategy I, postulating construction of the vancomycin main framework in the order of D-O-E→D-O-E/C-O-D→D-O-E/C-O-D/A-B, suffered from serious epimerization problems at the AA-4 stereocenter; while strategy II, involving the sequence C-O-D→C-O-D/AB→C-O-D/AB/D-O-E proved viable. These findings set the stage for the final drive towards vancomycin's aglycon (2) and vancomycin (1).

Full text of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2602::AID-CHEM2602>3.0.CO;2-X

FULL PAPER
Total Synthesis of VancomycinÐPart 2: Retrosynthetic Analysis, Synthesis of
Amino Acid Building Blocks and Strategy Evaluations
K. C. Nicolaou,* Christopher N. C. Boddy, Hui Li, Alexandros E. Koumbis,
Robert Hughes, Swaminathan Natarajan, Nareshkumar F. Jain, Joshi M. Ramanjulu,
Stefan Bräse, and Michael E. Solomon[a]
Abstract: Retrosynthetic analysis of
vancomycin (1) defined vancomycinꢀs
aglycon (2) and protected triazene 3
(Figure 1) as advanced intermediates for
an eventual total synthesis. Sequential
assembly of 3 as shown in Figure 2
(strategy I) and Figure 3 (strategy II)
led to amino acid building blocks 8 ± 10
and 12 ± 15, respectively, representing
vancomycinꢀs amino acids AA-1 to
AA-7. These amino acid fragments were
constructed by stereoselective routes
and the two synthetic strategies were
tested for feasibility. Strategy I, postu-
lating construction of the vancomycin
main framework in the order of D-O-
E !D-O-E/C-O-D !D-O-E/C-O-D/A-
B, suffered from serious epimerization
problems at the AA-4 stereocenter;
while strategy II, involving the sequence
C-O-D !C-O-D/AB !C-O-D/AB/D-
O-E proved viable. These findings set
the stage for the final drive towards
vancomycinꢀs aglycon (2) and vancomy-
cin (1).
Keywords: amino acids ´ antibiotics
´ synthetic methods ´ total synthesis
´ vancomycin
construction of the vancomycin main skeleton. In this paper,
we describe our investigations along these lines and project
forward to the next phase of the program.
Introduction
In the preceding article, we described the design and
development of methodologies which were considered suit-
able for application to the daunting challenge of the total
synthesis of vancomycin (1, Figure 1).[1] Specifically, a tria-
zene-driven mild cyclization method was developed, and its
power was demonstrated in the construction of vancomycin
model C-O-D and D-O-E biaryl ether ring systems.[1, 2]
Furthermore, a strategy for the formation of the AB/C-O-D
bicyclic framework of vancomycin based on sequential Suzuki
coupling ± macrolactamization approach was successfully test-
ed.[1, 3] These technologies laid the foundation for the next
phase of the program, namely, a focused retrosynthetic
analysis, the preparation of the requisite amino acid building
blocks,[4] and the evaluation of possible strategies towards the
Results and Discussion
Retrosynthetic analysis
The structure of vancomycin[5] (1) comprises of a complex
polycyclic framework carrying a colorful collection of appen-
dages that includes amino, hydroxy, amido, carboxylic,
phenolic, and chloride groups. The molecule can be divided
into two segments, the vancomycin aglycon (2, Figure 1) and
the disaccharide domain made of a vancosamine unit linked to
a glucose unit through an a-glycoside bond. The disaccharide
moiety is attached to the aglycon through a b-glycoside
linkage at the phenolic group on ring-D. The admirable
architecture of vancomycin presents an agonizing challenge to
synthetic chemists.[6±11] Thus, in addition to the five aromatic
rings of its heptapeptide framework, this diabolical core
carries eight stereogenic centers (plus one on the appended N-
methyl leucine). This structure is also cursed with three sites
of atropisomerism which are associated with the macrocyclic
systems AB, C-O-D, and D-O-E. The latter phenomenon has
its origins in the substitution patterns of the aromatic rings
involved (A, B, C and E) and the congested nature of the
corresponding 12- and 16-membered macrocycles. Overall,
[a] Prof. Dr. K. C. Nicolaou, C. N. C. Boddy, H. Li, Dr. A. E. Koumbis,
R. Hughes, Dr. S. Natarajan, Dr. N. F. Jain, Dr. J. M. Ramanjulu,
Dr. S. Bräse, Dr. M. E. Solomon
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
E-mail: kcn@scripps.edu
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Chem. Eur. J. 1999, 5, No. 9

2602±2621
the vancomycin framework is highly rigid and strained,
providing synthetic chemists additional challenges with re-
gard to its construction. Postponing the issue of transforming
the triazene functionality to a phenolic group and attaching
the sugar moieties onto a suitable acceptor enabled protected
triazene 3 to be defined as the key subtarget for the synthesis
(Figures 2 and 3). The indicated disconnections are discussed
below.
The first retrosynthetic analysis of the basic framework of
the vancomycin aglycon is shown in Figure 2 (Strategy I).
Based on our model studies described in the preceding
paper,[1] we chose the retrosynthetic disconnection at the
indicated amide bond of the AB ring system, unraveling
potential macrolactamization precursor 4. The C-O-D macro-
cycle was then disconnected at the indicated aryl ether
linkage, giving the precursor (5) for the triazene-driven biaryl
ether formation reaction developed as part of this project. The
cyclization substrate 5, upon disconnection at the marked
peptide bond, led to fragments 6 and 7 as the most logical
precursors. Disassembly of intermediate 6 by a retro Suzuki
coupling and a retro peptide bond formation as indicated, led
to key building blocks 8, 9 and 10, respectively. Macrocyclic
system 7 was sequentially disconnected by a retro triazene-
driven cyclization, leading to potential precursor 11, which
was simply disassembled to its component amino acid frag-
ments 12 ± 15 by peptide bond disconnections as shown in
Figure 2. The key question in this analysis was the sequence in
which the macrocyclic rings were to be constructed. More
specifically, while we were confident of the need to have the
C-O-D ring in place in order to facilitate the construction of
the AB ring system (requirement for preorganization), we
had no basis to predict whether the construction of C-O-D
should precede that of the of D-O-E (Figure 2) or vice versa.
An alternative (Strategy II) was, therefore, considered
(Figure 3). Thus, the C-O-D ring would be constructed first by
the triazene-driven cyclization of precursor 20, which should
be accessible from building blocks 10, 12, and 21 (derived
from building blocks 8 and 9). This C-O-D macrocycle should
direct the construction of the C-O-D/AB system 18, which
upon coupling with tripeptide acid 17, should lead to
penultimate precursor 16. Tripeptide 17 could easily be
prepared from amino acid building blocks 13 ± 15. A final
triazene-driven cyclization of compound 16 was then expected
to allow entry into the desired skeleton 3.
Abstract in Greek:
Figure 1. Structure and retrosynthetic analysis of vancomycin (1) and
vancomycinꢀs aglycon (2) (AA-1 to AA-7 represent the seven amino acids
of vancomycin, see numbering on structure 2).
Both strategies start from the same building blocks and are
characterized by high degree of convergence. Both strategies
leave the question of atropisomerism open and at the mercy of
experimentation, even though possible solutions were con-
templated. Such potential solutions included: a) thermal
equilibration of the undesired atropisomers to the desired
ones;[7d] b) temporary use of bulky substituents on the
Chem. Eur. J. 1999, 5, No. 9
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K. C. Nicolaou et al.
FULL PAPER
Triazene-driven
ring closure
N
N
N
N
N
Macrolactamization
N
Cl
Cl
O
O
O
Cl
O
O
E
C
D
C
E
D
OTBS
O
OTBS
O
TBSO
O
TBSO
O
Cl
Boc
N
O
Boc
N
O
H
H
H
H
N
O
H
N
N
N
N
N
H
O
N
H
Me
Me
N
H
O
N
H
Me
Me
H
N
H
H
H
H
H
H
O
O
H
H
O
O
HN
OH
NH2
B
Me
NHDdm
B
Me
NHDdm
H
BnO
BnO
A
OMe
OMe
A
OMe
OMe
MeO
3
4
MeO
Cl
N
N
OH
Cl
C
Peptide
bond formation
N
C
Cl
TBSO
OH
Br
O
O
N
N
E
Triazene-driven
ring closure
D
H
OTBS
O
NH2
TBSO
O
O
O
N
Boc
O
N
H
H
Cl
H
N
N
OEt
N
Br
O
N
H
N
H
Me
Me
N
H
N3
+
H
H
E
D
H
O
OTBS
O
B
OEt
O
O
O
Boc
BnO
N3
H
N
Me
NHDdm
Peptide bond formation
B
N
A
HO
OMe
OMe
N
H
O
N
Me
Me
BnO
H
H
O
MeO
O
A
OMe
OMe
Suzuki coupling
Me
NHDdm
MeO
7
6
5
N
N
Cl
E
N
N
N
HO
Br
Br
O
O
NH2
D
OTBS
O
N
BnO
MeO
Br
Br
Boc
B(OH)
OMe
O
H
D
N
A
O
HO
N
N
H
Me
Me
N
MeO
H
H
HO
O
O
NHDdm
13 (AA-3)
NHBoc
O
Me
NHDdm
8 (AA-7)
12 (AA-4)
Peptide bond formation
11
Cl
C
O
BnO
O
Boc
OH
NHBoc
E
MeO
I
N
OH
HO
Me
Me
TBSO
O
O
B
NH2
NH2
Me
OEt
OEt
10 (AA-6)
OMe
14 (AA-2)
15 (AA-1)
9 (AA-5)
Figure 2. Retrosynthetic analysis of protected triazene 3. Strategy I.
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 2
2602±2621
Triazene-driven
ring closure
N
N
N
N
Cl
E
N
N
Cl
HO
Br
O
O
O
O
OTBS
C
E
D
C
OTBS
O
D
TBSO
O
Cl
TBSO
O
Cl
Boc
N
Boc
O
O
O
H
O
H
H
N
H
H
H
N
N
N
N
N
N
N
H
N
H
Me
Me
N
Me
Me
N
H
H
H
H
H
H
H
H
O
O
O
H
O
O
O
HN
HN
B
Me
B
Me
NHDdm
NHDdm
H
H
BnO
BnO
A
OMe
OMe
Peptide bond formation
A
OMe
OMe
MeO
MeO
16
3
N
N
Triazene-driven
ring closure
N
Macrolactamization
N
N
Cl
N
Br
O
HO
Br
O
C
D
E
OTBS
O
C
D
TBSO
O
Cl
TBSO
O
Cl
H
N
Boc
N
O
H
O
O
N
H
H
+
NHBoc
N
N
N
H
NH2
N
H
Me
Me
HO
H
H
O
H
H
O
O
OH
O
HN
NH2
B
B
Me
NHDdm
BnO
H
A
OMe
BnO
Peptide bond formation
A
OMe
OMe
18
OMe
MeO
MeO
19
17
N
N
Cl
N
OH
Br
Br
C
TBSO
O
O
BnO
D
O
Boc
N
NH2
E
O
H
N
MeO
O
OH
HO
Me
Me
NHBoc
N
H
H
EtO
H
O
NH2
OEt
N3
Me
O
B
NHDdm
Peptide bond formation
BnO
13 (AA-3)
14 (AA-2)
15 (AA-1)
A
OMe
OMe
MeO
20
O
NHBoc
MeO
OH
O
N
Cl
C
NHBoc
N
OH
O
N
MeO
I
BnO
MeO
B
Br
Br
B(OH)
OMe
TBSO
O
BnO
D
B
A
A
OMe
OMe
NH2
HO
MeO
OMe
NHBoc
OEt
Suzuki coupling
O
12 (AA-4)
10 (AA-6)
8 (AA-7)
9 (AA-5)
21
Figure 3. Retrosynthetic analysis of protected triazene 3. Strategy II.
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K. C. Nicolaou et al.
FULL PAPER
aromatic nuclei to direct the chlorines to their proper
orientations during ring closure;[12] c) utilization of chiral side
chains within the triazene moiety to direct the ring closures;
and d) use of designed chiral copper ligands to exert influence
on the stereoselectivity during the cyclization process.
In order to charter the final plan and to set the stage for the
next phase of the synthesis, we proceeded to synthesize the
required amino acid building blocks and evaluate the
proposed strategies.
Amino acid building block 9 (AA-5):[17] The vancomycin AA-
5 building block equivalent, compound 9, was prepared from
commercially available (d)-4-hydroxyphenylglycine 26, as
shown in Scheme 2. Thus, mild esterification of 26 in methanol
O
O
O
NHBoc
NH2
NHBoc
d. I2
MeO
I
RO
MeO
b. Boc2O
B
OMe
OH
OR
28: R = H
9
Synthesis of amino acid building blocks
26: R = H
a.TMSCl,
MeOH
c. MeI
27: R = Me
29: R = Me
Below, the synthesis of the required (according to Figures 2
and 3) vancomycin amino acid building blocks (8 ± 10 and 12 ±
15) will be discussed.
Scheme 2. Synthesis of amino acid building block 9 (AA-5). a) 2.1 equiv of
TMSCl, MeOH, 258C, 15 h, 98%; b) 1.1 equiv of Boc2O, 4.0 equiv of
K2CO3, dioxane/H2O (1:1), 258C, 4 h, 95%; c) 2.0 equiv of MeI, 4.0 equiv
of K2CO3, DMF, 258C, 6 h, 93%; d) 1.2 equiv of I2, 2.2 equiv of
CF3COOAg, CHCl3, 258C, 12 h, 90%. TMS ˆ trimethylsilyl; Boc ˆ tert-
butoxycarbonyl; DMF ˆ dimethylformamide.
Amino acid building block 8 (AA-7):[13] Boronic acid deriv-
ative 8 required for the construction of the AA-7 amino acid
building block was synthesized as summarized in Scheme 1.
proceeded at ambient temperature under the influence of
TMSCl[18] to afford methyl ester 27 in 98% yield. Protection
of the amino group in 27 with Boc2O in the presence of K2CO3
furnished derivative 28 (95% yield), which upon treatment
with K2CO3 and MeI led to fully protected compound 29 in
93% yield. Finally, regioselective iodination of 29 was
effected by I2 in the presence of CF3COOAg, furnishing the
desired amino acid building block 9 in 90% yield.
Amino acid building block 10 (AA-6):[19] An expedient route
to building block 10 (AA-6) took advantage of the recently
disclosed Sharpless asymmetric aminohydroxylation reac-
tion,[20] as shown in Scheme 3. The required starting material
for this reaction, cinnamate 32, was obtained from p-
hydroxybenzaldehyde (30) by benzylation (K2CO3, BnBr,
KI cat., 98% yield), followed by reaction with the anion
derived from (EtO)2P(O)CH2COOEt (KOH, 95% yield).
Substrate 32 entered the Sharpless asymmetric aminohydrox-
Scheme 1. Synthesis of amino acid building block 8 (AA-7). a) 1.3 equiv of
nBuLi, 1.5 equiv of CH3P Ph3Br , THF, 208C, 10 h, 91%; b) AD-b,
‡
1.4 gmmol 1, tBuOH/H2O (1:1), 258C, 8 h, 96% ee, 92%; c) 1.0 equiv of
nBu2SnO, toluene, reflux, 1 h; then 1.5 equiv of BnBr, 0.5 equiv of nBu4NI,
708C, 2 h, 89%; d) 2.2 equiv of nBuLi, benzene, 0 !258C, 2 h; then
3.0 equiv of B(OMe)3, THF, 78 !258C, 6 h; 5% aq HCl, 55%. Bn ˆ
benzyl.
ylation
reaction
[NaOH,
BnOCONH2,
tBuOCl,
(DHQD)2AQN, K2OsO2(OH)4, nPrOH/H2O (1:1)], afford-
ing directly amino alcohol 33 in its Cbz-protected form in
45% yield and 87% ee. The undesired enantiomer was
removed later in the sequence upon formation of diaster-
eomers (vide infra). The hydroxy group in 33 was then
protected as its TBS ether (TBSOTf, 2,6-lutidine, 98% yield),
leading to compound 34, at which stage both the benzyl and
benzyloxycarbonyl groups were removed by hydrogenolysis
[H2, 20% Pd(OH)2/C, 97% yield] to afford amino phenol 35.
Finally, introduction of the chlorine atom ortho to the phenol
group of 35 was smoothly accomplished through the use of
SO2Cl2,[21] furnishing the desired amino acid building block 10
in 80% yield.
Thus, commercially available 3,5-dimethoxy benzaldehyde
(22) was converted to terminal olefin 23 by a Wittig
olefination reaction (91% yield) and the latter compound
(23) was subjected to the Sharpless asymmetric dihydroxyla-
tion reaction[14] (AD-b) to furnish diol 24 in 96% ee and 92%
yield of isolated product. Monobenzylation of 24 was
achieved by the action of nBu2SnO to afford a tin acetal
derivative,[15] which upon reaction with BnBr in the presence
of catalytic amount of nBu4NI, led to selective protection of
the terminal hydroxy group in 25, (89% yield). Directed
lithiation of 25 with 2.2 equivalents of nBuLi,[16] followed by
quenching the intermediate dilithio derivative with freshly
distilled B(OMe)3 and aqueous acidic workup, led to the
desired boronic acid 8 in 55% overall yield.
Amino acid building block 12 (AA-4):[22] The central amino
acid building block 12 (AA-4) was synthesized from p-
aminobenzoic acid (36), as summarized in Scheme 4. The
sequence utilized the Sharpless asymmetric dihydroxylation
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Total Synthesis of VancomycinÐPart 2
2602±2621
OBn
OR
b. KOH,
(EtO)2(O)PCH2COOEt
H
O
O
OEt
30: R = H
31: R = Bn
32
a. BnBr
c. Sharpless
AA
OBn
OBn
TBSO
O
HO
O
d. TBSOTf, 2,6-lutidine
NHCbz
NHCbz
OEt
OEt
34
33
e. H2, Pd(OH)2/C
OH
Cl
OH
C
TBSO
O
TBSO
f. SO2Cl2
O
NH2
35
NH2
10
OEt
OEt
Scheme 3. Synthesis of amino acid building block 10 (AA-6). a) 1.5 equiv
of K2CO3, 1.0 equiv of BnBr, 0.1 equiv of KI, DMF, 258C, 12 h, 98%;
b) 1.1 equiv of (EtO)2(O)PCH2COOEt, 1.5 equiv of KOH, THF, 258C,
12 h, 95%; c) 3.0 equiv of NaOH, 3.1 equiv of BnOCONH2, 3.0 equiv of
tBuOCl, 0.05 equiv of (DHQD)2AQN, 0.04 equiv of K2OsO2(OH)4,
nPrOH/H2O (1:1), 258C, 12 h, 87% ee, 45%; d) 1.1 equiv of TBSOTf,
1.5 equiv of 2,6-lutidine, CH2Cl2, 08C, 0.5 h, 98%; e) H2, 20% Pd(OH)2/C,
MeOH, 258C, 0.5 h, 97%; f) 1.0 equiv of SO2Cl2, Et2O/CH2Cl2 (1:10), 08C,
1 h, 80%. Cbz ˆ benzyloxycarbonyl; TBS ˆ tert-butyldimethylsilyl; Tf ˆ
trifluoromethanesulfonyl. (DHQD)2AQN ˆ 1,4-bis(dihydroquinidinyl)an-
thraquinone.
reaction to introduce the desired chirality, producing the
targeted intermediate in its naturally occurring form and high
overall yield. Thus, methylation of 36 (SOCl2, MeOH) gave
methyl ester 37 (100% yield), which upon treatment with
bromine in acetic acid provided dibromide 38 (98% yield).
Reduction of the ester functionality in 38 with LiAlH4 (95%
yield), followed by diazotization (HCl, NaNO2, AcOH/H2O)
and reaction of the resulting diazonium salt with pyrrolidine,
furnished triazene 40 via amino alcohol 39 in 75% overall
yield. Oxidation of 40 (PCC, 88% yield), followed by Wittig
olefination of the resulting aldehyde 41, furnished styrene
derivative 42 (92% yield). Asymmetric dihydroxylation of 42
with AD-a in tBuOH/H2O (1:1) led to dihydroxy compound
43 in 95% ee and 95% yield. Selective protection of the
primary hydroxy group in the latter compound (43) was
accomplished with TBSCl in the presence of imidazole,
furnishing 44 in 88% yield. The secondary alcohol function-
ality in the resulting mono-TBS ether 44 was subjected to a
Mitsunobu reaction with diphenylphosphoryl azide (DPPA)
in the presence of Ph3P and DEAD[23] to afford azide 45 in
79% yield. Accompanied by complete inversion of config-
uration of the secondary alcohol, this reaction set the stage for
the generation of the desired amino group. This task was
accomplished by a mild reduction with Ph3P/H2O[24] at 608C,
furnishing compound 46 (78% yield), which was then
protected with Boc2O in the presence of Et3N to give
Scheme 4. Synthesis of amino acid building block 12 (AA-4). a) 1.0 equiv
of SOCl2, MeOH, reflux, 2 h, 100%; b) 2.0 equiv of Br2, AcOH, 258C,
0.5 h, 98%; c) 1.5 equiv of LiAlH4, THF, 08C, 2 h, 95%; d) 5.0 equiv of 6m
aq HCl, 1.2 equiv of NaNO2, AcOH/H2O (1:1), 08C, 0.5 h; then 30 equiv of
KOH, 1.5 equiv of pyrrolidine, 08C, 0.5 h, 75%; e) 1.5 equiv of PCC,
‡
CH2Cl2, 258C, 2 h, 88%; f) 1.4 equiv of nBuLi, 1.5 equiv of CH3P Ph3Br ,
THF, 208C, 2 h, 92%; g) AD-a, 1.4 gmmol 1, tBuOH/H2O (1:1), 258C,
6 h, 95% ee, 95%; h) 1.1 equiv of TBSCl, 1.5 equiv of imidazole, DMF, 08C,
5 h, 88%; i) 2.5 equiv of Ph3P, 2.5 equiv of DEAD, 2.5 equiv of DPPA, THF,
08C, 2 h, 79%; j) 3.0 equiv of Ph3P, 10.0 equiv of H2O, THF, 608C, 3 h, 78%;
k) 1.1 equiv of Boc2O, 3.0 equiv of Et3N, CH2Cl2, 258C, 4 h, 95%;
l) 1.2 equiv of nBu4NF, THF, 08C, 2 h, 93%; m) 1.0 equiv of TEMPO,
3.0 equiv of 5% aq NaOCl, 0.1 equiv of KBr, 5% NaHCO3/acetone (1:1),
08C, 1 h, 75%. PCC ˆ pyridinium chlorochromate; DEAD ˆ diethyl
azodicaboxylate; DPPA ˆ diphenylphosphoryl azide; TEMPO ˆ 2,2,6,6-
tetramethyl-1-piperidinyloxy, free radical.
derivative 47 (95% yield). Finally, fluoride-induced desilyla-
tion of 47 (nBu4NF, 93% yield) followed by oxidation with
TEMPO and NaOCl led to the desired amino acid derivative
12 (AA-4) in 75% yield.
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K. C. Nicolaou et al.
FULL PAPER
Amino acid building block 13 (AA-3): Amino acid building
block 13 was prepared from the known asparagine-derived
compound 49, as shown in Scheme 5. Thus, asparagine was
converted to the corresponding N-Cbz compound and thence
O
O
O
NHCbz
b. H2
NH2
NHCbz
MeO
O
HO
O
MeO
O
a. MeI, K2CO3
NHDdm
NHDdm
NHDdm
13
49
50
Scheme 5. Synthesis of amino acid building block 13 (AA-3). a) 2.0 equiv
of MeI, 2.0 equiv of K2CO3, DMF, 258C, 12 h, 70%; b) H2, 20% Pd(OH)2/
C, MeOH, 258C, 1 h, 99%. Ddm ˆ 4,4'-dimethoxydiphenylmethyl.
to the dimethoxydiphenyl methyl (Ddm) derivative 49
according to Koenigꢀs procedure.[25] Methylation of 49
(K2CO3, MeI, 70% yield), followed by removal of the Cbz
protecting group by hydrogenolysis (H2, 20% Pd(OH)2/C,
99% yield), furnished the desired AA-3 building block 13.
Amino acid building block 14 (AA-2):[26] The synthesis of
amino acid building block 14 (Scheme 6) commenced with
ethyl cinnamate 32 (see Scheme 3). The relatively low
reactivity of the double bond of this substrate (32) required
longer reaction time for the Sharpless asymmetric dihydrox-
ylation procedure (AD-b) to give diol 51 in 92% ee and 79%
yield. The latter compound (51) was then converted to mono-
nosylate 52 (68% yield) by the selective action of one equi-
valent of NosCl[10e] in the presence of Et3N. This substrate
underwent smooth SN2 type displacement with NaN3, furnish-
ing azide 53 (90% yield) with complete inversion of config-
uration. Finally, reduction of the azide group in 53, accom-
plished by the action of SnCl2 ´ 2H2O, resulted in the
formation of the desired amino acid building block 14 (AA-
2) in 90% yield.
Intermediate 14 was further converted to AA-6 derivative
58 as shown in Scheme 6. Thus, exposure of 14 to phosgene
allowed the formation of cyclic urethane 54 in 93% yield,
which underwent smooth epimerization exclusively at the a-
center to the ester functionality in the presence of ethanolic
KOH, leading to compound 56 after methylation (K2CO3,
MeI, 87% overall yield for two steps) of the resulting
carboxylic acid 55. Conversion of 56 to its Boc derivative 57
(Boc2O, 4-DMAP, 53% yield), followed by selective hydrol-
ysis of the five-membered ring under basic conditions
(Cs2CO3, MeOH, 80% yield) led to compound 58, demon-
strating an alternative route to such structure from the one
shown in Scheme 3.
Scheme 6. Synthesis of amino acid building block 14 (AA-2) and precursor
58 (for AA-6). a) AD-b, 1.4 gmmol 1, 1.0 equiv of MeSO2NH2, tBuOH/
H2O (1:1), 258C, 12 h, 92% ee, 79%; b) 1.0 equiv of NosCl, 2.0 equiv of
Et3N, CH2Cl2, 08C, 5 h, 68%; c) 1.5 equiv of NaN3, DMF, 558C, 12 h, 90%;
d) 2.0 equiv of SnCl2 ´ 2H2O, MeOH, 258C, 2 h, 90%; e) 1.0 equiv of COCl2,
2.0 equiv of pyr., CH2Cl2, 788C, 2 h, 93%; f) 1.05 equiv of KOH, EtOH,
reflux, 1 h; g) 1.5 equiv of MeI, 1.0 equiv of K2CO3, DMF, 258C, 12 h, 87%
from 54; h) 1.1 equiv of Boc2O, 0.15 equiv of 4-DMAP, THF, 258C, 2 h,
53%; i) 0.4 equiv of Cs2CO3, MeOH, 258C, 2 h, 80%. Nos ˆ 4-nitro-
benzene sulfonyl; 4-DMAP ˆ 4-dimethylaminopyridine.
which strategy to adopt for their assembly into the desired
heptapeptide skeleton of vancomycin. As a prelude for the
comparison between these two routes, the AA-1/AA-2/AA-3
tripeptide 17 required for both strategies I (Figure 2) and II
(Figure 3) was first prepared from its residues as outlined in
Scheme 7. Thus, coupling of amino alcohol 14 with Boc-
protected N-methyl leucine 15, facilitated by EDC/HOBt,
resulted in the formation of dipeptide 59 (93% yield), which
was subsequently converted to its carboxylic acid 60, without
significant epimerization, by LiOH in THF/H2O (1:1) at 08C
(99% yield). Attachment of the third amino acid building
block, asparagine derivative 13, was accomplished by EDC/
HOAt induced coupling, leading to tripeptide 61 in 82%
yield. Protection of the hydroxy group in 61 (TBSOTf, 2,6-
lutidine, 81% yield) provided TBS ether 62. Hydrogenolysis
of the benzyl group from 62 [H2, 20% Pd(OH)2/C, 99% yield]
liberated phenol 63, which was subjected to chlorination at
the ortho position (SO2Cl2) to afford chlorophenol methyl
Amino acid building block 15 (AA-1): Amino acid building
block 15 (N-methyl leucine Boc derivative, see Scheme 7) is
commercially available.
Evaluation of strategies
With the requisite amino acid building blocks (8 ± 10 and 12 ±
15) in hand, we were at the crossroads to make a decision as to
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 2
2602±2621
BnO
BnO
O
Boc
N
N
N
Cl
OH
O
N
N
OH
Boc
N
N
HO
O
HO
Me
N
Br
Br
RO
+
OTBS
a. EDC, HOBt
Me
N
Me
Me
EtO
Br
Br
NH2
H
17
O
O
Boc
N
H
Me
O
N
b. EDC, HOAt
HO
Me
N
Me
Me
N
14
15
H
RO
H
O
59: R = Et
60: R = H
O
NH2
b. LiOH
Me
NHDdm
66
46: R = TBS
65: R = H
c. EDC
HOAt
a. nBu4NF
13
c. K2CO3, pyr.
BnO
BnO
O
CuBr•Me2S
OTBS
O
OH
N
N
N
N
N
O
Boc
N
O
Boc
d. TBSOTf
2,6-lutidine
H
N
N
H
N
Cl
N
Br
O
Br
O
+
MeO
O
N
H
Me
Me
MeO
N
Me
Me
H
Cl
O
OTBS
OTBS
O
O
O
Boc
Boc
O
O
O
H
H
N
NHDdm
Me
HO
N
N
NHDdm
Cl
Me
HO
N
N
H
N
H
Me
Me
N
N
H
Me
H
62
61
O
Me
O
O
O
e. H2, Pd(OH)2
Me
Me
NHDdm
NHDdm
HO
HO
67b
67a
OTBS
OTBS
O
d. TEMPO
NaOCl
O
O
Boc
O
Boc
N
H
H
N
N
Cl
N
f. SO2Cl2
MeO
O
N
Me
Me
RO
O
N
H
Me
Me
OH
H
O
O
N
TBSO
N
NHDdm
63
Me
NHDdm
g. LiOH
Me
N
Cl
O
Br
O
O
NH2
64: R = Me
17: R = H
O
N
H
OTBS
O
Boc
N
OEt
H
N3
Scheme 7. Synthesis of tripeptide 17. a) 3.0 equiv of EDC, 3.3 equiv of
HOBt, THF, 08C, 12 h, 93%; b) 2.0 equiv of LiOH, THF/H2O (1:1), 08C,
1 h, 99%; c) 3.0 equiv of EDC, 3.3 equiv of HOAt, THF, 08C, 12 h, 82%;
d) 1.3 equiv of TBSOTf, 2.2 equiv of 2,6-lutidine, CH2Cl2, 08C, 2 h, 81%;
e) H2, 20% Pd(OH)2/C, MeOH, 258C, 1 h, 99%; f) 1.1 equiv of SO2Cl2,
Et2O, 08C, 75%; g) 4.0 equiv of LiOH, tBuOH/H2O (2:1), 08C, 0.5 h, 95%.
HOAt ˆ 1-hydroxy-7-azobenzotriazole; HOBt ˆ 1-hydroxybenzotriazole;
EDC ˆ 1-ethyl-3-(3-dimethylamino)propylcarbodiimide hydrochloride.
HO
N
N
H
N
H
Me
Me
BnO
O
O
O
OMe
OMe
Me
NHDdm
MeO
6
7
e. EDC, HOAt
N
N
ester 64 in 75% yield. Finally, LiOH-induced saponification of
64 in tBuOH/H2O (2:1) at 08C furnished tripeptide acid 17 in
95% yield without significant epimerization.
Cl
C
N
Cl
O
OH
Br
E
D
OTBS
O
TBSO
O
Having prepared tripeptide carboxylic acid 17, we proceed-
ed to test the feasibility of Strategy I (Figure 2), in which
construction of the D-O-E macrocycle was to precede that of
the C-O-D ring system. As shown in Scheme 8, central amino
acid derivative 46 (see Scheme 4 for its preparation) was
desilylated with nBu4NF, furnishing amino alcohol 65 (92%
yield), which upon coupling with tripeptide acid 17 in the
presence of EDC and HOAt, afforded tetrapeptide 66 in 84%
yield. Cyclization of 66 under the influence of K2CO3, CuBr´
Me2S, and pyridine in MeCN at reflux led to a separable
mixture of atropisomers 67a and 67b (67a:67b, ca. 3:1) in
87% combined yield. NOE studies (Figure 4) revealed that
the major product 67a had the same chlorine orientation as in
vancomycin. However, the benefit of this favorable atrop-
selectivity did not compensate for the serious epimerization
drawback which was soon to emerge along the sequence.
Thus, the natural chlorine atropisomer (67a) was then
subjected to TEMPO/NaOCl oxidation, affording the corre-
sponding carboxylic acid (7) in 65% yield. Attempted
coupling of 7 with amine 6[27] under the influence of EDC
O
H
N
Boc
O
H
N
N
N
H
O
N
H
Me
N
H
H
H
H
O
O
Me
Me
OEt
N3
NHDdm
B
BnO
epimerization
A
OMe
OMe
5a+5b
MeO
Scheme 8. Synthesis of D-O-E ring system 7 and further elaboration.
a) 1.1 equiv of nBu4NF, THF, 08C, 2 h, 92%; b) 3.0 equiv of EDC, 3.3 equiv
of HOAt, THF, 08C, 10 h, 84%; c) 3.0 equiv of CuBr´ Me2S, 3.0 equiv of
K2CO3, 3.0 equiv of pyr., MeCN, reflux, 15 min, 67a:67b ca. 3:1, 87%
combined yield; d) 1.1 equiv of TEMPO, 0.1 equiv of KBr, 5% NaHCO3/
acetone (1:1), 3.0 equiv of 5% aqueous NaOCl, 08C, 1 h, 65%; e) 3.0 equiv
of EDC, 3.3 equiv of HOAt, THF, 158C, 5 h, 72%, 5a:5b ca. 2:1 ratio.
and HOAt led to a mixture of two products in 72% yield (ca.
2:1 ratio). These products were presumed to be the two
epimers 5a and 5b at the indicated position (no assignment of
stereochemistry was made). Screening of different coupling
Chem. Eur. J. 1999, 5, No. 9
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K. C. Nicolaou et al.
FULL PAPER
acid building block. Thus, ester 29 (see Scheme 2) was
hydrolyzed to carboxylic acid 68 (LiOH, 99% yield), which
was then coupled with amine 35 (see Scheme 3) under the
influence of EDC and HOBt to give dipeptide 69 in 81% yield
(Scheme 9). The resulting phenol 69 was subjected to
chlorination (SO2Cl2, 88% yield) to provide monochlorine
derivative 70, which upon exposure to excess TMSOTf
(3.4 equiv) and 2,6-lutidine (3.0 equiv) followed by aqueous
workup, furnished free amine 71 (75% yield). Incorporation
of the triazene carboxylic acid 12 (see Scheme 4) into the
growing peptide chain was then accomplished by the action of
EDC and HOAt, leading to tripeptide 72 (79% yield). Ring
closure of the latter compound (72) under the standard
cylization conditions (K2CO3, CuBr´ Me2S, pyridine, MeCN,
reflux) gave the desired C-O-D ring system 73a together with
its atropisomer 73b (73a:73b, ca. 1:1, 52% combined yield).
The two atropisomers were chromatographically separated
and their stereo assignments were determined by NOE
studies (see Figure 5).
N
N
N
N
N
N
Cl
Br
O
Br
O
O
Cl
OTBS
NH
OTBS
NH
O
H
H
HO
HO
N
N
N
H
N
Boc
N
Boc
H
O
O
N
O
O
Me
O
O
Me
Me
Me
NHDdm
67b
NHDdm
Me
Me
67a
Figure 4. Assignment of stereochemistry of atropisomers 67a and 67b by
1H-1H NOE studies (COSY, ROSEY, 600 MHz, CD3COCD3).
reagents failed to solve this epimerization problem and only
made the testing of strategy II (Figure 3) a more urgent priority.
To test strategy II (Figure 3), according to which formation
of macrocycle C-O-D was to precede the construction of the
D-O-E ring, the simpler p-methoxyphenylglycine derivative
68 (Scheme 9) was chosen in place of the AB biaryl amino
OH
O
N
N
N
N
TBSO
OH
NHBoc
O
RO
N
N
TBSO
O
O
NHBoc
Cl
N
Br
O
Br
O
+
b. EDC, HOBt
a. LiOH
H
OEt
NH2
TBSO
O
Cl
TBSO
O
OEt
OMe
O
OMe
69
O
H
H
N
35
29: R = Me
68: R = H
N
NHBoc
NHBoc
N
N
H
H
O
O
OEt
OEt
c. SO2Cl2
N
Cl
O
Cl
N
N
OH
OMe
73a
OMe
OH
Br
Br
TBSO
O
73b
TBSO
O
Figure 5. Assignment of stereochemistry of atropisomers 73a and 73b by
O
NHR
12
H
1H-1H NOE studies (COSY, ROESY, 600 MHz, CD3COCD3).
N
N
H
N
H
NHBoc
OEt
e. EDC, HOAt
OEt
O
The preparation of the requisite dipeptide 80 is summarized
in Scheme 10. Thus, compound 14 was protected as its N-Boc
derivative 74 (Boc2O, Et3N, 93% yield), which was then
hydrolyzed with LiOH at 08C to afford carboxylic acid 75 in
96% yield. Coupling of 75 with protected asparagine deriv-
ative 13 (EDC, HOBt) provided dipeptide 76 (65% yield),
which upon treatment with TBSCl in the presence of
imidazole gave fully protected compound 77 (75% yield).
Deprotection of the benzyl group was accomplished by
hydrogenolysis with 10% Pd/C to furnish phenol 78 (99%
yield), which was then subjected to selective monochlorina-
tion to afford 79 in 91% yield. Final hydrolysis of the methyl
ester functionality of 79 with LiOH provided carboxylic acid
80 (76% yield), which was further elaborated as shown in
Scheme 11. Thus, treatment of 73a with TMSOTf and 2,6-
lutidine generated the free amine (81, 80% yield), which was
coupled with dipeptide acid 80 by the action of EDC and
HOAt, affording the cyclization precursor 82 in 81% yield.
Finally, D-O-E cyclization of phenolic bromotriazene 82 in
the presence of K2CO3, CuBr´ Me2S, and pyridine in MeCN at
reflux, furnished the anticipated C-O-D/D-O-E framework 83
in 40% yield. However, the chlorine orientation within the
OMe
OMe
72
f. CuBr•Me2S,
K2CO3, pyr.
70: R = Boc
71: R = H
d.TMSOTf,
2,6-lutidine
N
N
N
N
N
N
Cl
Br
O
Br
O
C
O
D
C
O
D
TBSO
O
TBSO
O
Cl
+
H
H
N
N
N
H
NHBoc
N
H
NHBoc
OEt
OEt
O
O
B
B
OMe
OMe
73a
73b
Scheme 9. Synthesis of C-O-D model systems 73a and 73b. a) 1.5 equiv of
LiOH, THF/H2O (1:1), 08C, 0.5 h, 99%; b) 3.0 equiv of EDC, 3.3 equiv of
HOBt, DMF, 20 !08C, 12 h, 81%; c) 1.0 equiv of SO2Cl2, Et2O/CH2Cl2
(5:1), 10 !08C, 0.5 h, 88%; d) 3.4 equiv of 2,6-lutine, CH2Cl2, 108C,
1 h, 75%; e) 3.0 equiv of EDC, 3.3 equiv of HOAt, THF, 108C, 2 h, 79%;
f) 3.0 equiv of CuBr´ Me2S, 3.0 equiv of K2CO3, 3.0 equiv of pyr., MeCN,
reflux, 0.5 h, 73a:73b ca. 1:1, 52% combined yield.
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 2
2602±2621
BnO
BnO
BnO
N
N
OH
OH
OH
a. Boc2O
b. LiOH
N
EtO
HO
EtO
Cl
Br
O
NH2
NHBoc
NHBoc
HO
O
O
O
O
TBSO
O
Cl
14
74
75
OTBS
O
H
N
c. EDC,
HOBt
H
N
NHR
N
13
+
H
O
HO
NHBoc
O
OEt
HO
BnO
O
OTBS
OR
NHDdm
O
O
OMe
H
N
H
e. H2, Pd(OH)2/C
N
73a: R = Boc
81 : R = H
MeO
O
NHBoc
MeO
O
NHBoc
a. TMSOTf, 2,6-lutidine
80
O
O
NHDdm
NHDdm
b. EDC, HOAt
78
76: R = H
d. TBSCl,
imid.
77: R = TBS
f. SO2Cl2
N
N
Cl
Cl
E
Cl
N
HO
HO
O
HO
O
Br
O
OTBS
OTBS
OTBS
TBSO
Cl
O
g. LiOH
H
H
H
N
O
H
N
N
N
O
NHBoc
MeO
O
NHBoc
HO
O
NHBoc
O
N
N
H
H
O
O
O
OEt
O
NHDdm
NHDdm
NHDdm
79
80
82
Scheme 10. Synthesis of dipeptide 80. a) 1.1 equiv of Boc2O, 1.2 equiv of
Et3N, CH2Cl2, 08C, 5 h, 93%; b) 2.0 equiv of LiOH, THF/H2O (1:1), 08C,
1 h, 96%; c) 3.0 equiv of EDC, 3.5 equiv of HOBt, THF, 20 !08C, 4 h,
65%; d) 4.0 equiv of TBSCl, 8.0 equiv of imidazole, DMF, 258C, 24 h, 75%;
e) H2, 10% Pd(OH)2/C, EtOH, 258C, 16 h, 99%; f) 1.1 equiv of SO2Cl2,
Et2O/CH2Cl2 (5:1), 08C, 0.5 h, 91%; g) 1.5 equiv LiOH, tBuOH/H2O (4:1),
5 !108C, 1 h, 76%.
OMe
c. CuBr•Me2S, K2CO3, pyr.
N
N
N
O
O
Cl
C
O
D
E
newly formed ring was of the unnatural configuration with
regards to vancomycin (see Figure 6 for crucial NOEs). It
appeared that strategy II might also be plagued with serious
stereochemical problems of a different kind from those
encountered in our explorations of strategy I. Of the two
devilish problems, we chose to face the atropisomerism in the
hope that the presence of the vancomycinꢀs AB ring system
would, perhaps, favor, at least to a satisfying degree, the
natural configuration.
OTBS
TBSO
O
Cl
O
H
H
N
N
NHBoc
N
N
H
H
O
O
OEt
O
B
NHDdm
OMe
83
Scheme 11. Synthesis of C-O-D/D-O-E model system 83. a) 10.0 equiv of
TMSOTf, 16 equiv of 2,6-lutidine, CH2Cl2, 208C, 1 h, 80%; b) 2.5 equiv
of EDC, 11 equiv of HOAt, 15 !08C, 2 h, 81%; c) 5.5 equiv of CuBr´
Me2S, 5.5 equiv of K2CO3, 5.5 equiv of pyr., MeCN, reflux, 2 h, 40%.
Conclusion
In this article, the structure of vancomycin (1) was analyzed
retrosynthetically and two alternate strategies were devised
(Strategies I and II). The required building blocks for
implementation of these strategies were synthesized by
efficient routes and two sequences were tested for their
feasibility as viable routes to vancomycin (1).
describes our detailed journey to the aglycon of vancomycin
(2), while the fourth paper in the series[29] provides a full
account of the conversion of aglycon 2 to vancomycin (1)
itself.
These preliminary studies established strategy II, in which
the sequence of formation of vancomycinꢀs macrocycles
followed C-O-D !C-O-D/AB !C-O-D/AB/D-O-E, as the
least hazardous, but still risky approach to the target
molecule. The road was now chosen for the final launch
towards vancomycin (1). The third article in this series[28]
Experimental Section
General techniques: See paper 1 in this series.[1]
Diol 24: To a solution of olefin 23 (4.26 g, 26 mmol) in tBuOH/H2O (1:1,
130 mL) at 258C was added AD-mix-b (36.4 g, 1.4 gmmol 1) and the
reaction mixture was stirred at that temperature for 8 h. The reaction was
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2611

K. C. Nicolaou et al.
FULL PAPER
163.0, 158.5, 138.0, 129.3, 127.8, 127.7, 98.4, 97.6, 80.4, 76.7, 73.6, 73.5, 55.5,
‡
55.3; HRMS (FAB) calcd for C17H20BO5 [M ‡ H ] 315.1404, found
N
N
315.1414.
N
Phenol 28: A solution of 4-hydroxyphenylglycine (26) (16.7 g, 100 mmol) in
anhydrous MeOH (500 mL) at 258C was treated with chlorotrimethylsilane
(26.6 mL, 210 mmol) dropwise. The resulting mixture was stirred at that
temperature for 15 h before the solvent was removed in vacuo. The residue
was dissolved in EtOAc (100 mL), washed with saturated aqueous
NaHCO3 (50 mL), brine (50 mL), dried (Na2SO4), and concentrated in
vacuo. The crude product 27 (17.7 g, 98%) was taken into next step without
further purification. To a solution of crude amino ester 27 (17.7 g) in
dioxane/H2O (1:1, 300 mL) at 258C was added K2CO3 (55.2 g, 400 mmol)
and Boc2O (24.0 g, 110 mmol). The resulting mixture was stirred for 4 h
before it was diluted with EtOAc (600 mL). The organic layer was
separated, washed with 1% aqueous HCl (100 mL), brine (100 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified by flash
column chromatography (silica gel, 10 !20% EtOAc in hexanes) to
provide phenol 28 (26.2 g, 95%). 28: Rf ˆ 0.16 (silica gel, 30% EtOAc in
O
O
E
C
D
Cl
OTBS
TBSO
Cl
O
O
H
H
N
N
O
NHBoc
N
N
H
H
O
O
OEt
O
B
NHDdm
OMe
83
Figure 6. Assignment of stereochemistry of atropisomers 83 by 1H-1H
NOE studies (COSY, ROESY, 600 MHz, CD3CN, 310 K).
hexanes); [a]2D2
ˆ
109.1 (c ˆ 1.7, CHCl3); IR (thin film): nÄmax ˆ 3366, 2978,
quenched by the addition of sodium sulfite (39 g, 1.5 gmmol 1) and the
mixture was extracted with EtOAc (3 Â 100 mL). The combined organic
extracts were washed with H2O (100 mL), brine (100 mL), dried (Na2SO4),
and concentrated in vacuo. The resulting residue was subjected to flash
column chromatography (silica gel, 30 !50% EtOAc in hexanes) to
provide diol 24 (4.70 g, 96% ee, 92%). 24: Rf ˆ 0.12 (50% EtOAc in
1
1766, 1684, 1514, 1443, 1367, 1255, 1226, 1154 cm
;
1H NMR (500 MHz,
CDCl3): d ˆ 7.23 (d, J ˆ 8.4 Hz, 2H, ArH), 6.80 (d, J ˆ 8.5 Hz, 2H, ArH),
5.70 (d, J ˆ 6.8 Hz, 1H, NH), 5.29 (d, J ˆ 7.1 Hz, 1H, H-5a), 3.78 (s, 3H,
OCH3), 1.51 (s, 9H, tBuO); 13C NMR (125 MHz, CDCl3): d ˆ 172.0, 156.4,
155.1, 128.4, 128.0, 115.8, 80.6, 57.0, 52.7, 28.3; HRMS (FAB) calcd for
‡
C14H19NO5Na [M ‡ Na ] 304.1161, 304.1160.
hexanes); [a]2D2
ˆ
25.7 (c ˆ 0.91, CHCl3); IR (thin film): nÄmax ˆ 3384, 2939,
1
2839, 1605, 1459, 1429, 1345, 1295, 1204, 1156, 1064 cm
;
1H NMR
Methyl ether 29: A solution of phenol 28 (28.1 g, 100 mmol) in anhydrous
DMF (200 mL) was treated with K2CO3 (55.2 g, 400 mmol) and methyl
iodide (12.5 mmol, 200 mmol). The resulting mixture was stirred at 258C
for 6 h before it was diluted with EtOAc (800 mL). The organic layer was
washed with 1% aqueous HCl (300 mL), brine (300 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, 5 !15% EtOAc in hexanes) to provide methyl
ether 29 (27.4 g, 93%). The product was identical as reported in
literature.[30]
(500 MHz, CDCl3): d ˆ 6.51 (d, J ˆ 2.0 Hz, 2H, ArH), 6.38 (t, J ˆ 2.0 Hz,
1H, ArH), 4.76-4.73 (m, 1H, H-7a), 3.78 (s, 6H, OCH3), 3.74 (dd, J ˆ 11.5,
3.5 Hz, 1H, H-7b), 3.64 (dd, J ˆ 11.5, 8.5 Hz, 1H, H-7b), 2.50 (br.s, 2H,
OH); 13C NMR (125 MHz, CDCl3): d ˆ 160.9, 143.0, 103.9, 99.7, 74.7, 68.0,
‡
55.4; HRMS (FAB) calcd for C10H14O4Na [M ‡ Na ] 221.0790, found
221.0794.
Benzyl ether 25: A solution of diol 24 (517 mg, 2.6 mmol) in toluene
(25 mL) was treated with nBu2SnO (647 mg, 2.6 mmol). The resulting
mixture was heated to reflux for 1 h with removal of H2O with a Dean ±
Stark apparatus before it was cooled to 708C. To this solution were added
BnBr (463 mL, 3.9 mmol) and nBu4NI (480 mg, 1.3 mmol) sequentially and
the reaction was stirred at 708C for 2 h before it was cooled to 258C. The
organic phase was washed with H2O (2 Â 15 mL), brine (15 mL), dried
(Na2SO4) and concentrated in vacuo. Flash column chromatography (silica
gel, 20 !30% EtOAc in hexanes, gradient elution) afforded 25 (666 mg,
Iodide 9: A solution of methyl ester 29 (1.00 g, 3.4 mmol) in CHCl3 (50 mL)
at 258C was treated with CF3COOAg (1.65 g, 7.5 mmol) and I2 (1.04 g,
4.1 mmol) sequentially. The resulting mixture was stirred at 258C for 12 h
before it was quenched by the addition of saturated aqueous Na2SO3
(20 mL). The aqueous phase was extracted with CHCl3 (2 Â 20 mL) and
the combined organic extracts were washed with H2O (40 mL), brine
(40 mL), dried (Na2SO4), and concentrated in vacuo. Flash column
chromatography of the residue (silica gel, 10 !20% EtOAc in hexanes,
gradient elution) afforded 9 (1.29 g, 90%). 9: Rf ˆ 0.22 (silica gel, 20%
89%). 25: Rf ˆ 0.47 (silica gel, 50% EtOAc in hexanes); [a]D22
ˆ
24.6 (c ˆ
0.98, CHCl3); IR (thin film): nÄmax ˆ 3446, 2937, 2854, 1601, 1456, 1426, 1347,
EtOAc in hexanes); [a]D22
3367, 2979, 1743, 1708, 1481, 1444, 1367, 1250, 1161, 1050, 1014 cm
ˆ
99.8 (c ˆ 1.2, CHCl3); IR (thin film): nÄmax
ˆ
1
1300, 1201, 1149, 1103, 1056 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 7.36-
1
;
7.34 (m, 5H, ArH), 6.55 (d, J ˆ 2.0 Hz, 2H, ArH), 6.40 (t, J ˆ 2.0 Hz, 1H,
ArH), 4.68 (dd, J ˆ 8.5, 3.5 Hz, 1H, H-7a), 4.60 (d, J ˆ 12.0 Hz, 1H,
OCHHPh), 4.56 (d, J ˆ 12.0 Hz, 1H, OCHHPh), 3.77 (s, 6H, OCH3), 3.63
(dd, J ˆ 10.0, 3.5 Hz, 1H, H-7b), 3.52 (dd, J ˆ 10.0, 8.5 Hz, 1H, H-7b), 3.22
(br.s, 1H, OH); 13C NMR (125 MHz, CDCl3): d ˆ 161.1, 142.4, 137.3, 128.5,
127.9, 127.8, 104.0, 99.8, 75.7, 73.4, 72.8, 55.3; HRMS (FAB) calcd for
1H NMR (500 MHz, CD3COCD3): d ˆ 7.82 (d, J ˆ 2.3 Hz, 1H, ArH), 7.38
(dd, J ˆ 8.6, 2.3 Hz, 1H, ArH), 6.89 (d, J ˆ 8.6 Hz, 1H, ArH), 6.69 (d, J ˆ
7.9 Hz, 1H, NH), 5.22 (d, J ˆ 7.9 Hz, 1H, H-5a), 3.81 (s, 3H, OCH3), 3.63 (s,
3H, OCH3), 1.35 (s, 9H, tBuO); 13C NMR (125 MHz, CD3COCD3): d ˆ
171.9, 158.7, 155.6, 138.9, 132.0, 129.8, 111.7, 86.1, 79.5, 57.1, 56.7, 52.7, 28.4;
‡
‡
HRMS (FAB) calcd for C15H21INO5 [M ‡ H ] 422.0465, found 422.0450.
C17H21O4 [M ‡ H ] 289.1440, found 289.1448.
Boronic acid 8: A solution of alcohol 25 (950 mg, 3.3 mmol) in benzene
(7 mL) was treated with nBuLi (1.6m in hexanes, 4.5 mL, 7.2 mmol) at 08C
dropwise and the resulting bright orange mixture was slowly warmed to
258C. After 2 h, the reaction was cooled to 788C and diluted with THF
(15 mL). To this solution, freshly distilled B(OMe)3 (1.12 mL, 9.9 mmol)
was added and the resulting mixture was slowly warmed to 258C and stirred
for 6 h. The reaction was quenched by the addition of 5% HCl (20 mL) and
the resulting mixture was extracted with EtOAc (3 Â 25 mL), and the
combined organic phases were washed with H2O (30 mL), brine (30 mL),
dried (Na2SO4), and concentrated in vacuo. Flash column chromatography
of the residue (silica gel, 20 !30% EtOAc in hexanes, gradient elution)
afforded 8 (595 mg, 55%). 8: Rf ˆ 0.38 (silica gel, 50% EtOAc in hexanes);
Cinnamate 32: A solution of benzaldehyde 31 (2.30 g, 11.0 mmol) in THF
(25 mL) was treated with potassium hydroxide (924 mg, 16.5 mmol),
followed by dropwise addition of triethyl phosphonoacetate (2.4 mL,
12 mmol) over a period of 1 h. The reaction mixture was stirred vigorously
for 12 h at 258C and then quenched by the addition of saturated aqueous
NH4Cl (10 mL). The resulting mixture was extracted with EtOAc (3 Â
15 mL) and the combined organic phases were washed with H2O
(25 mL), saturated aqueous NH4Cl (25 mL), and dried (Na2SO4). The
solvent was removed in vacuo and the resulting residue was recrystalized
twice from MeOH to afford cinnamate 32 (2.90 g, 95%). 32: Rf ˆ 0.53
(silica gel, 25% EtOAc in hexanes); IR (thin film): nÄmax ˆ 2969, 2910, 2859,
1714, 1634, 1604, 1511, 1454, 1285, 1262, 1174, 1012, 983, 832, 816, 748, 697,
524 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 7.69 (d, J ˆ 15.5 Hz, 1H, CH ˆ
CHCO2Et), 7.48-7.32 (m, 7H, ArH), 6.97 (d, J ˆ 8.8 Hz, 2H, ArH), 6.31 (d,
J ˆ 16.0 Hz, 1H, CH ˆ CHCO2Et), 5.08 (s, 2H, OCH2Ph), 4.25 (q, J ˆ
7.1 Hz, 2H, CH2CH3), 1.24 (t, J ˆ 7.0 Hz, 3H, CH2CH3); 13C NMR
(100 MHz, CDCl3): d ˆ 167.3, 160.5, 144.2, 136.5, 129.7, 128.6, 128.1, 127.4,
115.9, 115.2, 70.0, 60.3, 14.4; HRMS (FAB) calcd for C18H18O3Na [M ‡
[a]2D2
ˆ
15.1 (c ˆ 0.85, MeOH); IR (thin film): nÄmax ˆ 3405, 2933, 2841,
1
1605, 1585, 1462, 1421, 1400, 1328, 1201, 1149, 1077, 1075 cm
;
1H NMR
(500 MHz, CDCl3): d ˆ 7.35 ± 7.26 (m, 5H, ArH), 6.47 (s, 1H, ArH), 6.34 (s,
1H, ArH), 5.28 (dd, J ˆ 6.5, 5.0 Hz, 1H, H-7a), 5.05 (s, 1H, BOH), 4.66 (d,
J ˆ 12.5 Hz, 1H, OCHHPh), 4.60 (d, J ˆ 12.5 Hz, 1H, OCHHPh), 3.85 (s,
3H, OCH3), 3.81 (s, 3H, OCH3), 3.74 (dd, J ˆ 10.5, 5.0 Hz, 1H, H-7b), 3.66
(dd, J ˆ 10.5, 6.5 Hz, 1H, H-7b); 13C NMR (125 MHz, CDCl3): d ˆ 166.1,
‡
Na ] 283.1334, found 283.1326.
2612
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2612 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 2
2602±2621
Amino acid 33: Amino acid 33 was prepared from cinnamate 32 according
(125 MHz, CDCl3): d ˆ 141.4, 132.3, 130.8, 108.7, 63.9; HRMS (FAB) calcd
‡
to Sharpless AA protocol[20] (45% yield, 87% ee).
for C7H7Br2NO [M ] 280.9464, found 280.9471.
TBS ether 34: To a solution of alcohol 33 (500 mg, 1.11 mmol) in CH2Cl2
(10 mL) at 08C were added 2,6-lutidine (194 mL, 1.67 mmol) and tert-
butyldimethylsilyl trifluoromethanesulfonate (284 mL, 1.22 mmol). The
reaction was stirred at 08C for 0.5 h and then quenched by the addition
of saturated aqueous NaHCO3 (2 mL). The aqueous phase was extracted
with CH2Cl2 (2 Â 5 mL) and the combined organic layers were washed
sequentially with saturated aqueous NaHCO3 (10 mL), H2O (10 mL), brine
(10 mL), and dried (Na2SO4). The solvent was removed in vacuo and the
resulting residue was purified by flash column chromatography (silica gel,
0 !20% EtOAc in hexanes, gradient elution) to afford TBS ether 34
Triazene alcohol 40: To a suspension of aniline 39 (10.0 g, 35.6 mmol) in
acetic acid/H2O (1:1, 80 mL) at 08C were added sequentially 6m aqueous
HCl (30 mL) and NaNO2 (2.95 g, 42.7 mmol in 5 mL of H2O). The resulting
mixture was stirred at that temperature for 0.5 h before it was transferred
dropwise to a flask charged with KOH (60 g, 1.07 mol) and pyrrolidine
(4.4 mL, 53 mmol) in H2O (250 mL) at 0oC. The resulting precipitate was
filtered and purified by flash column chromatography (silica gel, 10 !20%
EtOAc in hexanes, gradient elution) to afford 40 (9.69 g, 75%). 40: Rf ˆ
0.16 (silica gel, 20% EtOAc in hexanes); IR (thin film): nÄmax ˆ 3331, 2872,
1537, 1408, 1343, 1308, 1214, 1190, 1049 cm 1; 1H NMR (500 MHz, CDCl3):
d ˆ 7.47 (s, 2H, ArH), 4.59 (s, 2H, CH2OH), 3.96 (s, 2H, NCH2), 3.72 (s, 2H,
NCH2), 2.11 (s, 2H, NCH2CH2), 2.06 (s, 2H, NCH2CH2); 13C NMR
(125 MHz, CDCl3): d ˆ 146.6, 140.2, 130.2, 117.8, 63.5, 51.3, 46.7, 23.9, 23.7;
(613 mg, 98%). 34: Rf ˆ 0.34 (silica gel, 20% EtOAc in hexanes); [a]D22
ˆ
31.7 (c ˆ 0.87, EtOAc); IR (thin film): nÄmax ˆ 2930, 1728, 1610, 1509, 1299,
1251, 1085, 836 cm 1; 1H NMR (400 MHz, CDCl3): d ˆ 7.45 ± 7.21 (m, 12H,
ArH), 6.89 (d, J ˆ 8.6 Hz, 2H, ArH), 5.50 (d, J ˆ 9.7 Hz, 1H, NH), 5.24 (d,
J ˆ 2.2 Hz, 1H, H-6b), 5.02 (s, 2H, NHCO2CH2), 4.97 (s, 2H, OCH2Ph),
4.41 (dd, J ˆ 9.7, 2.2 Hz, 1H, H-6a), 4.23 (dq, J ˆ 10.8, 7.3 Hz, 1H,
CHHCH3), 4.14 (dq, J ˆ 10.8, 7.3 Hz, 1H, CHHCH3), 1.28 (t, J ˆ 7.3 Hz,
3H, CH2CH3), 0.84 (s, 9H, tBuSi), 0.04 (s, 3H, CH3Si), 0.18 (s, 3H,
CH3Si); 13C NMR (100 MHz, CDCl3): d ˆ 170.1, 158.2, 155.9, 136.7, 136.2,
132.6, 128.3, 128.2, 127.8, 127.8, 127.7, 127.3, 127.2, 114.1, 74.1, 69.7, 66.5, 61.3,
61.0, 25.5, 17.8, 13.9, 4.8, 5.7; HRMS (FAB) calcd for C32H41NO6SiCs
‡
HRMS (FAB) calcd for C11H14Br2N3O [M ‡ H ] 361.9504, found 361.9515.
Benzaldehyde 41: A solution of alcohol 40 (3.61 g, 10 mmol) in CH2Cl2
(50 mL) was treated with pyridium chlorochromate (PCC, 3.24 g, 15 mmol)
at 258C. The suspension was stirred for 2 h before it was filtered through a
pad of celite. The solvent was removed in vacuo and the resulting residue
was purified by flash column chromatography (silica gel, 5 !10% EtOAc
in hexanes, gradient elution) to afford 41 (3.18 g, 88%). 41: Rf ˆ 0.32 (silica
gel, 10% EtOAc in hexanes); IR (thin film): nÄmax ˆ 2962, 1691, 1580, 1534,
‡
[M ‡ Cs ] 696.1757, found 696.1782.
1
1408, 1342, 1302, 1250, 1226, 1200 cm 1; H NMR (500 MHz, CDCl3): d ˆ
Phenol 35: To a solution of protected amine 34 (430 mg, 0.76 mmol) in
MeOH (8 mL) was added 20% Pd(OH)2/C (25 mg) at 258C. Hydrogen was
bubbled through the solution for 0.5 h and the resulting suspension was
filtered through a pad of celite. The celite was washed with MeOH (2 Â
5 mL) and the filtrate was concentrated. The resulting residue was purified
by flash column chromatography (silica gel, 5% MeOH in CH2Cl2) to
afford phenol 35 (250 mg, 97%). 35: Rf ˆ 0.23 (silica gel, 50% EtOAc in
9.84 (s, 1H, CHO), 8.04 (s, 2H, ArH), 3.99 (s, 2H, NCH2), 3.74 (s, 2H,
NCH2), 2.14 ± 2.09 (m, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ
188.9, 152.8, 134.1, 133.6, 118.5, 51.4, 46.9, 24.0, 23.5; HRMS (FAB) calcd
‡
for C11H12Br2N3O [M ‡ H ] 361.9327, found 361.9336.
Styrene 42: A suspension of methyltriphenylphosphonium bromide (6.43 g,
18.0 mmol) in THF (30 mL) at 208C was treated with nBuLi (1.6m
solution in hexanes, 10.5 mL, 16.8 mmol) dropwise over 10 min and the
resulting solution was stirred for 0.5 h. To this reaction mixture was added a
solution of 41 (4.33 g, 12.0 mmol) in THF (25 mL) and the resulting orange
suspension was stirred at that temperature for 2 h before it was quenched
by the addition of H2O (30 mL). The mixture was extracted with EtOAc
(4 Â 40 mL) and the combined organic phases were washed with H2O (2 Â
40 mL), brine (2 Â 40 mL), dried (Na2SO4), and concentrated in vacuo.
Flash column chromatography of the residue (silica gel, 4 !8% ether in
hexanes, gradient elution) afforded 42 (3.96 g, 92%). 42: Rf ˆ 0.39 (silica
gel, 10% ether in hexanes); IR (thin film): nÄmax ˆ 2972, 2801, 1524, 1413,
hexanes); [a]2D2
ˆ
17.9 (c ˆ 0.98, EtOAc); IR (thin film): nÄmax ˆ 3362, 2936,
1738, 1614, 1515, 1255, 1080, 837 cm 1; 1H NMR (400 MHz, CD3OD): d ˆ
7.16 (d, J ˆ 8.6 Hz, 2H, ArH), 6.76 (d, J ˆ 8.6 Hz, 2H, ArH), 5.00 (d, J ˆ
4.0 Hz, 1H, H-6b), 4.15 (dq, J ˆ 10.8, 7.0 Hz, 1H, CHHCH3), 4.06 (dq, J ˆ
10.8, 7.0 Hz, 1H, CHHCH3), 3.47 (d, J ˆ 4.0 Hz, 1H, H-6a), 1.21 (t, J ˆ
7.0 Hz, 3H, CH2CH3), 0.89 (s, 9H, tBuSi), 0.01 (s, 3H, CH3Si), 0.18 (s, 3H,
CH3Si); 13C NMR (100 MHz, CD3OD): d ˆ 173.5, 158.4, 132.8, 128.8, 116.1,
77.1, 62.9, 62.3, 26.3, 19.0, 14.4, 4.3, 5.2; HRMS (FAB) calcd for
‡
C17H30NO4Si [M ‡ H ] 340.1944, found 340.1948.
Chloride 10: To a solution of amine 35 (1.63 g, 4.8 mmol) in CH2Cl2/ether
(10:1, 5 mL) at 08C was added sulfuryl chloride (386 mL, 4.8 mmol)
dropwise. The reaction mixture was stirred at that temperature for 1 h and
then it was quenched by the addition of saturated aqueous NaHCO3
(5 mL). The resulting mixture was diluted with EtOAc (15 mL) and the
organic layer was washed with H2O (10 mL), brine (10 mL), and dried
(Na2SO4). The solvent was removed in vacuo and the resulting residue was
purified by flash column chromatography (silica gel, 10 !20% EtOAc in
hexanes, gradient elution) to afford chloride 10 (1.44 g, 80%). 10: Rf ˆ 0.24
1
1337, 1312, 1256, 1220 cm 1; H NMR (400 MHz, CDCl3): d ˆ 7.55 (s, 2H,
ArH), 6.54 (dd, J ˆ 17.5, 10.8 Hz, 1H, ArCH), 5.69 (d, J ˆ 17.5 Hz, 1H,
ArCH ˆ CHH), 5.26 (d, J ˆ 10.8 Hz, 1H, ArCH ˆ CHH), 3.95 (s, 2H,
NCH2), 3.70 (s, 2H, NCH2), 2.06 (s, 4H, NCH2CH2); 13C NMR (125 MHz,
CDCl3): d ˆ 147.2, 136.4, 134.1, 130.0, 117.6, 115.2, 51.6, 46.9, 23.8, 23.4;
‡
HRMS (FAB) calcd for C12H14Br2N3 [M ‡ H ] 357.9554, found 357.9564.
Diol 43: To a stirred suspension of AD-a (14 g, 1.4 gmmol 1) in tBuOH/
H2O (1:1, 100 mL) was added styrene 42 (3.59 g, 10 mmol) at 258C. The
reaction mixture was stirred at ambient temperature for 6 h before sodium
sulfite (15.0 g, 1.5 gmmol 1) was added. The resulting mixture was stirred
for 0.5 h and then it was extracted with EtOAc (3 Â 40 mL). The combined
organic phases were washed with H2O (50 mL), brine (50 mL), dried
(Na2SO4), and concentrated in vacuo. Flash column chromatography of the
residue (silica gel, 40 !60% EtOAc in hexanes, gradient elution) afforded
43 (3.73 g, 95% ee, 95%). Chiral HPLC: chiralcell OD-H column (0.46 Â
25 cm, 30% 2-propanol/hexane, 0.5 mL min 1). Retention time ˆ 10.22
(major enantiomer). Retention time ˆ 9.23 (minor enantiomer). 43: Rf ˆ
(silica gel, 5% MeOH in CHCl3); [a]D22
ˆ
11.0 (c ˆ 1.31, EtOAc); IR (thin
film): nÄmax ˆ 3366, 2943, 2849, 2555, 1737, 1602, 1502, 1467, 1290, 1255,
1
1079 cm
;
1H NMR (400 MHz, CD3OD): d ˆ 7.29 (d, J ˆ 2.1 Hz, 1H,
H-6b), 7.09 (dd, J ˆ 8.4, 2.1 Hz, 1H, H-6f), 6.88 (d, J ˆ 8.4 Hz, 1H, H-6e),
4.99 (d, J ˆ 3.8 Hz, 1H, H-6b), 4.16 (dq, J ˆ 10.8, 7.2 Hz, 1H, CHHCH3),
4.08 (dq, J ˆ 10.8, 7.2 Hz, 1H, CHHCH3), 3.47 (d, J ˆ 3.8 Hz, 1H, H-6a),
1.22 (t, J ˆ 7.2 Hz, 3H, CH2CH3), 0.90 (s, 9H, tBuSi), 0.03 (s, 3H, CH3Si), -
0.15 (s, 3H, CH3Si); 13C NMR (100 MHz, CD3OD): d ˆ 173.8, 154.1, 134.5,
129.3, 127.1, 121.5, 117.4, 76.6, 62.8, 62.3, 26.3, 19.0, 14.4, 4.4, 5.1; HRMS
0.16 (silica gel, 50% EtOAc in hexanes); [a]2D2 ˆ ‡79.4 (c ˆ 1.21, CHCl3);
‡
(FAB) calcd for C17H29ClNO4Si [M ‡ H ] 374.1554, found 374.1549.
1
IR (thin film): nÄmax ˆ 3354, 2954, 2862, 2349, 1415, 1308, 1215, 1067 cm
;
Benzyl alcohol 39: A cooled suspension of LiAlH4 (1.14 g, 30 mmol) at 08C
in THF (40 mL) was treated dropwise with a solution of ester 38 [31] (6.18 g,
20 mmol) in THF (60 mL). The resulting mixture was stirred at 08C for 2 h
before it was quenched by the slow addition of saturated aqueous NH4Cl
(15 mL). The mixture was extracted with EtOAc (3 Â 200 mL) and the
combined organic extracts were washed with H2O (150 mL), brine
(150 mL), dried (Na2SO4), and concentrated in vacuo. Flash column
chromatography of the residue (silica gel, 10 !20% EtOAc in hexanes,
gradient elution) afforded 39 (5.34 g, 95%). 39: Rf ˆ 0.28 (silica gel, 30%
EtOAc in hexanes); IR (thin film): nÄmax ˆ 3307, 1614, 1578, 1472, 1402, 1349,
1H NMR (500 MHz, CDCl3): d ˆ 7.47 (s, 2H, ArH), 4.72 (dd, J ˆ 8.0, 3.5 Hz,
1H, ArCH), 3.95 (s, 2H, NCH2), 3.72 (s, 2H, NCH2), 3.65 (dd, J ˆ 11.5,
3.5 Hz, 1H, CHHOH), 3.55 (dd, J ˆ 11.5, 8.0 Hz, 1H, CHHOH), 3.49 (br.s,
1H, OH), 2.12 (d, J ˆ 5.5 Hz, 2H, NCH2CH2), 2.06 (d, J ˆ 5.5 Hz, 2H,
NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 146.8, 140.2, 129.9, 118.0,
73.0, 67.8, 51.5, 46.8, 23.9, 23.7; HRMS (FAB) calcd for C12H16Br2N3O2
‡
[M ‡ H ] 391.9609, found 391.9623.
TBS ether 44: To a solution of diol 43 (3.36 g, 8.6 mmol) in DMF (40 mL) at
08C were added sequentially TBSCl (1.43 g, 9.5 mmol) and imidazole
(8.77 g, 12.9 mmol). The resulting solution was stirred at that temperature
for 5 h before H2O (60 mL) was added. The reaction mixture was extracted
1
1284, 1198, 1067, 1026 cm 1; H NMR (500 MHz, CDCl3): d ˆ 7.40 (s, 2H,
ArH), 4.53 (s, 2H, CH2OH), 1.90 ± 1.50 (br.s, 2H, NH2); 13C NMR
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2613 $ 17.50+.50/0
2613

K. C. Nicolaou et al.
FULL PAPER
1
with EtOAc (4 Â 50 mL) and the combined organic phases were washed
with H2O (80 mL), brine (80 mL), dried (Na2SO4), and concentrated in
vacuo. Flash column chromatography (silica gel, 5 !10% EtOAc in
hexanes, gradient elution) afforded compound 44 (3.84 g, 88%). 44: Rf ˆ
0.40 (silica gel, 20% EtOAc in hexanes); [a]2D2 ˆ ‡22.8 (c ˆ 1.43, CHCl3);
IR (thin film): nÄmax ˆ 3384, 2954, 2928, 2856, 1419, 1358, 1316, 1256,
1056 cm 1; H NMR (500 MHz, CDCl3): d ˆ 7.46 (s, 2H, ArH), 5.39 (br.s,
1H, NH), 4.59 (br.s, 1H, CHN), 3.93 (br.s, 2H, NCH2), 3.75 ± 3.69 (m, 4H,
NCH2 and CH2O), 2.74 (br.s, 1H, OH), 2.08 (br.s, 2H, NCH2CH2), 2.04
(br.s, 2H, NCH2CH2), 1.42 (s, 9H, tBuO); 13C NMR (125 MHz, CDCl3):
d ˆ 155.7, 147.2, 138.9, 130.6, 117.9, 80.1, 65.8, 55.3, 51.2, 46.6, 28.3, 23.9, 23.6;
‡
HRMS (FAB) calcd for C17H24Br2N4O3Cs [M ‡ Cs ] 622.9269, found
1
1113 cm 1; H NMR (500 MHz, CDCl3): d ˆ 7.53 (s, 2H, ArH), 4.66 ± 4.64
622.9294.
(m, 1H, ArCH), 3.95 (s, 2H, NCH2), 3.74 ± 3.70 (m, 3H, NCH2 and
CHHOSi), 3.49 (dd, J ˆ 10.0, 8.5 Hz, 1H, CHHOSi), 3.06 (br.s, 1H, OH),
2.09 (s, 2H, NCH2CH2), 2.06 (s, 2H, NCH2CH2), 0.91 (s, 9H, tBuSi), 0.06 (s,
6H, CH3Si); 13C NMR (125 MHz, CDCl3): d ˆ 147.3, 139.4, 130.1, 117.6,
72.8, 68.4, 51.2, 46.6, 25.8, 24.0, 23.6, 18.3, 5.4; HRMS (FAB) calcd for
Acid 12: To a solution of alcohol 48 (246 mg, 0.50 mmol) in acetone
(2.5 mL) at 08C was added 5% aqueous NaHCO3 (2.5 mL). The resulting
suspension was stirred vigorously before the addition of KBr (1.2 mg,
0.05 mmol) and TEMPO (78 mg, 0.50 mmol). Sodium hypochlorite (5%
aqueous solution, 2.0 mL) was added dropwise over 0.5 h and the resulting
mixture was stirred at 08C for 1 h before the addition of H2O (15 mL) and
EtOAc (15 mL). The aqueous phase was extracted with EtOAc (3 Â
15 mL) and the combined organic extracts were washed with H2O
(20 mL), brine (20 mL), dried (Na2SO4), and concentrated in vacuo. Flash
column chromatography of the residue (silica gel, 5 !10% MeOH in
CHCl3, gradient elution) afforded acid 12 (386 mg, 75%). 12: Rf ˆ 0.18
‡
C18H30Br2N3O2Si [M ‡ H ] 506.0475, found 506.0496.
Azide 45: To a solution of alcohol 44 (610 mg, 1.2 mmol) in THF (1.0 mL)
at 08C were added sequentially triphenylphosphane (790 mg, 3.0 mmol),
diethyl azodicarboxylate (DEAD, 470 mL, 3.0 mmol), and diphenylphos-
phoryl azide (DPPA, 650 mL, 3.0 mmol). The reaction mixture was stirred
at 08C for 2 h and then it was concentrated in vacuo. Flash column
chromatography of the residue (silica gel, 5 !10% ether in hexanes,
gradient elution) afforded azide 45 (0.50 g, 79%). 45: Rf ˆ 0.39 (silica gel,
(silica gel, 10% MeOH in CHCl3); [a]D22
ˆ
97.4 (c ˆ 0.98, MeOH); IR
(thin film): nÄmax ˆ 3344, 2976, 2872, 1711, 1415, 1367, 1313, 1224, 1162, 1052,
1020 cm 1; 1H NMR (500 MHz, CD3OD): d ˆ 7.53 (s, 2H, ArH), 4.89 (br.s,
1H, ArCH), 3.81 (br.s, 2H, NCH2), 3.54 (br.s, 2H, NCH2), 1.99 (br.s, 2H,
NCH2CH2), 1.95 (br.s, 2H, NCH2CH2), 1.33 (s, 9H, tBuO); 13C NMR
(125 MHz, CD3OD): d ˆ 157.2, 148.7, 139.7, 132.2, 118.7, 112.0, 80.8, 52.3,
47.9, 28.7, 28.6, 24.9, 24.6; HRMS (FAB) calcd for C17H22Br2N4O4Cs [M ‡
10% EtOAc in hexanes); [a]D22
ˆ
43.8 (c ˆ 1.30, CHCl3); IR (thin film):
1
nÄmax ˆ 2953, 2929, 2857, 2100, 1418, 1317, 1257, 1112 cm
;
1H NMR
(400 MHz, CDCl3): d ˆ 7.48 (s, 2H, ArH), 4.50 (dd, J ˆ 7.6, 4.4 Hz, 1H,
ArCH), 3.96 (br.s, 2H, NCH2), 3.79 (dd, J ˆ 10.2, 4.4 Hz, 1H, CHHOSi),
3.74-3.69 (m, 3H, NCH2 and CHHOSi), 2.06 (br.s, 4H, NCH2CH2), 0.90 (s,
9H, tBuSi), 0.07 (s, 3H, CH3Si), 0.06 (s, 3H, CH3Si); 13C NMR (125 MHz,
CDCl3): d ˆ 147.9, 135.7, 131.0, 117.8, 67.8, 65.5, 51.2, 46.6, 25.8, 24.0, 23.6,
‡
Cs ] 636.9062, found 636.9087.
Amine 13: To a suspension of compound 50 (4.17 g, 8.25 mmol) in MeOH
(120 mL) at 258C was added 20% Pd(OH)2/C (100 mg). Hydrogen was
bubbled through the reaction mixture for 1 h. The resulting mixture was
filtered through a pad of celite and the celite was washed thoroughly with
MeOH (2 Â 30 mL). The combined filtrate was concentrated in vacuo to
give crude amine 13 (3.06 g, 99%). 13: Rf ˆ 0.45 (silica gel, 5% MeOH in
‡
18.2, 5.5; HRMS (FAB) calcd for C18H29Br2N6OSi [M ‡ H ] 531.0540,
found 531.0562.
Amine 46: To a solution of azide 45 (1.17 g, 2.2 mmol) in THF was added
triphenylphosphane (1.73 g, 6.6 mmol) and H2O (400 mL, 22 mmol) at
258C. The resulting solution was heated to 608C for 3 h before it was cooled
to 258C. The solvent was removed in vacuo and the residue was purified by
flash column chromatography (silica gel, 30 !45% EtOAc in hexanes,
gradient elution) to afford amine 46 (870 mg, 78%). 46: Rf ˆ 0.30 (silica gel,
CH2Cl2); [a]2D2
ˆ
7.50 (c ˆ 0.30, MeOH); IR (thin film): nÄmax ˆ 3296, 2862,
1
1738, 1650, 1610, 1538, 1513, 1247, 1176, 1032 cm
;
1H NMR (500 MHz,
CDCl3): d ˆ 7.73 (d, J ˆ 8.0 Hz, 1H, NH), 7.13 ± 7.10 (m, 4H, ArH), 6.81 (d,
J ˆ 8.0 Hz, 4H, ArH), 6.11 (d, J ˆ 8.0 Hz, 1H, CHAr2), 3.81 (d, J ˆ 2.5 Hz,
1H, CHCOOMe), 3.75 (s, 6H, OCH3), 3.67 (s, 3H, OCH3), 2.71 (dd, J ˆ
15.0, 2.5 Hz, 1H, CHHCHCOOMe), 2.55 (dd, J ˆ 15.0, 8.0 Hz, 1H,
CHHCHCOOMe); 13C NMR (125 MHz, CDCl3): d ˆ 174.4, 169.1, 158.6,
134.0, 128.3, 113.9, 55.6, 55.2, 52.4, 51.3, 39.3; HRMS (FAB) calcd for
50% EtOAc in hexanes); [a]D22
ˆ
22.0 (c ˆ 1.53, CHCl3); IR (thin film):
1
nÄmax ˆ 2952, 2928, 2856, 1537, 1466, 1418, 1337, 1316, 1256, 1107 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 7.55 (s, 2H, ArH), 3.98 (dd, J ˆ 7.5, 4.0 Hz,
1H, ArCH), 3.94 (br.s, 2H, NCH2), 3.71 (br.s, 2H, NCH2), 3.66 (dd, J ˆ 9.5,
4.0 Hz, 1H, CHHOSi), 3.46 (dd, J ˆ 9.5, 7.5 Hz, 1H, CHHOSi), 2.08 (br.s,
2H, NCH2CH2), 2.04 (br.s, 2H, NCH2CH2), 0.88 (s, 9H, tBuSi), 0.02 (s, 6H,
CH3Si); 13C NMR (125 MHz, CDCl3): d ˆ 147.0, 141.8, 130.8, 117.5, 68.9,
56.3, 51.1, 46.5, 25.8, 24.0, 23.6, 18.2, 5.4; HRMS (FAB) calcd for
‡
C20H24N2O5 [M ‡ H ] 373.1763, found 373.1770.
Ester 50: A solution of carboxylic acid 49 (24.6 g, 50 mmol) in anhydrous
DMF (200 mL) at 258C was treated with K2CO3 (13.8 g, 100 mmol) and
methyl iodide (6.23 mL, 100 mmol). The resulting mixture was stirred at
that temperature for 12 h before it was diluted with EtOAc (800 mL). The
mixture was washed with 1% aqueous HCl (400 mL), brine (400 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, 20 !40% EtOAc in hexanes) to
provide ester 50 (17.7 g, 70%). 50: Rf ˆ 0.23 (silica gel, 50% EtOAc in
‡
C18H31Br2N4OSi [M ‡ H ] 505.0634, found 505.0649.
Boc-protected amine 47: To a solution of amine 46 (710 mg, 1.4 mmol) in
CH2Cl2 (10 mL) at 258C were added Et3N (585 mL, 4.2 mmol) and Boc2O
(336 mg, 1.5 mmol). The resulting solution was stirred for 4 h before it was
concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, 15 !25% EtOAc in hexanes, gradient elution)
to afford Boc derivative 47 (810 mg, 95%). 47: Rf ˆ 0.50 (silica gel, 50%
hexanes); [a]2D2 ˆ ‡19.3 (c ˆ 1.2, CHCl3); IR (thin film): nÄmax ˆ 3301, 1742,
EtOAc in hexanes); [a]D22
ˆ
40.2 (c ˆ 1.70, CHCl3); IR (thin film): nÄmax
ˆ
1697, 1643, 1538, 1522, 1454, 1247, 1176, 1062 cm
;
1H NMR (500 MHz,
1
3449, 3332, 2953, 2930, 2858, 1715, 1490, 1418, 1365, 1336, 1256, 1188,
CDCl3): d ˆ 7.33 ± 7.30 (m, 5H, ArH), 7.08 ± 7.00 (m, 4H, ArH), 6.83 ± 6.79
(m, 4H, ArH), 6.19 (d, J ˆ 7.0 Hz, 1H, CHNHCO), 6.06 (m, 2H, NH), 5.08
(s, 2H, OCH2Ph), 4.57 ± 4.55 (m, 1H, H-3a), 3.76 (s, 3H, OCH3), 3.74 (s,
3H, OCH3), 3.69 (s, 3H, OCH3), 2.86 (dd, J ˆ 19.5, 9.0 Hz, 1H, H-3b), 2.76
(dd, J ˆ 19.5, 9.0 Hz, 1H, H-3b); 13C NMR (125 MHz, CDCl3): d ˆ 171.7,
168.7, 158.8, 156.1, 136.2, 133.4, 128.5, 128.4, 128.3, 127.8, 66.8, 56.0, 55.2,
1
1116 cm 1; H NMR (500 MHz, CDCl3): d ˆ 7.47 (s, 2H, ArH), 5.26 (br.s,
1H, NH), 4.61 (br.s, 1H, CHN), 3.94 (br.s, 2H, NCH2), 3.84 (dd, J ˆ 10.0,
4.0 Hz, 1H, CHHOSi), 3.72 ± 3.62 (m, 3H, NCH2 and CHHOSi), 2.09 (br.s,
2H, NCH2CH2), 2.07 (br.s, 2H, NCH2CH2), 1.42 (s, 9H, tBuO), 0.85 (s, 9H,
tBuSi), 0.03 (s, 3H, CH3Si), 0.05 (s, 3H, CH3Si); 13C NMR (125 MHz,
CDCl3): d ˆ 155.1, 147.0, 146.7, 130.9, 117.5, 85.1, 66.0, 51.1, 46.5, 28.3, 27.4,
25.8, 24.0, 23.6, 18.2, 5.6, 5.7; HRMS (FAB) calcd for C23H39Br2N4O3Si
‡
52.7, 50.8, 27.8; HRMS (FAB) calcd for C28H30N2O7Na [M ‡ Na ] 529.1951,
found 529.1941.
‡
[M ‡ H ] 605.1158, found 605.1135.
Diol 51: To a solution of cinnamate 32 (5.0 g, 28.3 mmol) in tBuOH/H2O
(1:1, 180 mL) at 258C were added AD-b (39.6 g, 1.4 gmmol
1
Alcohol 48: To a solution of compound 47 (665 mg, 1.1 mmol) in THF
(12 mL) at 08C was added nBu4NF (1.0m solution in THF, 1.3 mL,
1.3 mmol). The resulting solution was stirred at that temperature for 2 h
before it was quenched by the addition of saturated aqueous NH4Cl
(10 mL). The mixture was extracted with EtOAc (4 Â 15 mL), and the
combined organic extracts were washed with H2O (20 mL), brine (20 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, 30 !40% EtOAc in hexanes,
gradient elution) to afford alcohol 48 (500 mg, 93%). 48: Rf ˆ 0.36 (silica
)
and
methanesulfonamide (2.69 g, 28.3 mmol). The reaction mixture was stirred
for 12 h before sodium sulfite (42.5 g, 1.5 gmmol 1) was added. The
resulting mixture was stirred for 1 h and then it was extracted with EtOAc
(3 Â 100 mL). The combined organic layers were washed with H2O
(100 mL), brine (100 mL), dried (Na2SO4), and concentrated in vacuo.
The resulting residue was purified by flash column chromatography (silica
gel, 50% EtOAc in hexanes) to give diol 51 (7.07 g, 79%, 92% ee). Rf ˆ
0.52 (silica gel, 50% EtOAc in hexanes); [a]D22
ˆ
31.3 (c ˆ 1.15, CHCl3);
gel, 50% EtOAc in hexanes); [a]D22
film): nÄmax ˆ 3419, 2976, 2875, 1695, 1536, 1502, 1417, 1365, 1314, 1256, 1165,
ˆ
48.9 (c ˆ 1.28, CHCl3); IR (thin
IR (KBr): nÄmax ˆ 3318, 1870, 1715, 1616, 1515, 1383, 1301, 1249, 1177;
1H NMR (500 MHz, CDCl3): d ˆ 7.41 (d, J ˆ 7.5 Hz, 2H, ArH), 7.39 ± 7.36
2614
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2614 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 2
2602±2621
1
(m, 2H, ArH), 7.34 ± 7.30 (m, 3H, ArH), 6.96 (d, J ˆ 8.5 Hz, 2H, ArH), 5.05
(s, 2H, CH2Ph), 4.92 (br.s, 1H, CHArOH), 4.30 (br.s, 1H, CHCOOEt),
4.23 (q, J ˆ 7.5 Hz, 2H, OCH2CH3), 3.17 (br.s, 1H, OH), 2.77 (br.s, 1H,
OH), 1.24 (t, J ˆ 7.0 Hz, 3H, OCH2CH3); 13C NMR (125 MHz, CDCl3): d ˆ
172.7, 158.5, 136.8, 132.3, 128.5, 127.9, 127.6, 127.4, 114.7, 74.6, 74.2, 69.9,
1022 cm
;
1H NMR (500 MHz, CD3COCD3): d ˆ 7.45 (d, J ˆ 7.0 Hz, 2H,
ArH), 7.37 (t, J ˆ 7.2 Hz, 2H, ArH), 7.31 (d, J ˆ 7.0 Hz, 1H, ArH), 7.28 (d,
J ˆ 9.0 Hz, 2H, ArH), 7.02 (d, J ˆ 9.0 Hz, 2H, ArH), 5.87 (d, J ˆ 9.0 Hz, 1H,
H-2b), 5.14 (s, 2H, CH2Ph), 4.71 (d, J ˆ 9.0 Hz, 1H, CHCOOEt), 3.73-3.67
(m, 1H, OCHHCH3), 3.58-3.51 (m, 1H, OCHHCH3), 0.76 (t, J ˆ 7.0 Hz,
3H, OCH2CH3); 13C NMR (125 MHz, CD3COCD3): d ˆ 169.8, 159.9, 158.7,
137.9, 129.0, 128.4, 128.3, 128.0, 128.0, 115.1, 79.0, 70.1, 61.3, 60.3, 13.6;
‡
63.1, 14.1; HRMS (FAB) calcd for C18H20O5Na [M ‡ Na ] 339.1208, found
339.1204.
‡
HRMS (FAB) calcd for C19H19NO5Cs [M ‡ Cs ] 474.0318, found 474.0311.
Nosylate 52: To a solution of diol 51 (18.0 g, 57.0 mmol) in CH2Cl2 (285 mL)
at 08C were added 4-nitrobenzene sulfonyl chloride (14.0 g, 56.9 mmol)
and triethylamine (15.9 mL, 113.9 mmol). The reaction mixture was stirred
for 5 h before it was quenched by the addition of saturated NH4Cl (50 mL).
The organic layer was washed with 1n HCl (100 mL), H2O (100 mL), brine
(100 mL), dried (Na2SO4), and concentrated in vacuo. Flash column
chromatography of the resulting residue (silica gel, 20 !30% EtOAc in
hexanes, gradient elution) provided compound 52 (1.08 g, 68%). 52: Rf ˆ
0.25 (silica gel, 30% EtOAc in hexanes); [a]2D2 ˆ ‡43.0 (c ˆ 1.55, CHCl3);
IR (thin film): nÄmax ˆ 3546, 1761, 1609, 1531, 1511, 1374, 1349, 1187,
1027 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 8.21 (d, J ˆ 9.0 Hz, 2H, ArH),
7.83 (d, J ˆ 9.0 Hz, 2H, ArH), 7.43 ± 7.34 (m, 4H, ArH), 7.32 (t, J ˆ 7.0 Hz,
1H, ArH), 7.12 (d, J ˆ 9.0 Hz, 2H, ArH), 6.79 (d, J ˆ 9.0 Hz, 2H, ArH),
5.13 (s, 1H, CHCOOEt), 4.98 (s, 2H, CH2Ph), 4.94 (d, J ˆ 4.0 Hz, 1H,
CHOH), 4.14 (q, J ˆ 7.0 Hz, 2H, OCH2CH3), 2.63 (d, J ˆ 4.0 Hz, 1H, OH),
1.16 (t, J ˆ 7.0 Hz, 3H, OCH2CH3); 13C NMR (125 MHz, CDCl3): d ˆ 166.4,
158.9, 150.4, 141.4, 136.4, 129.5, 129.1, 128.6, 128.1, 127.5, 127.4, 124.0, 114.7,
Methyl ester 56: To a solution of compound 54 (4.0 g, 11.7 mmol) in EtOH
(13.8 mL) at 258C was added potassium hydroxide (689 mg, 12.2 mmol).
The resulting mixture was heated to reflux for 1 h before it was cooled to
258C. The reaction mixture was acidified with 10% HCl (5 mL) and
extracted with EtOAc (3 Â 20 mL). The combined extracts were washed
with H2O (30 mL), brine (30 mL), dried (Na2SO4), and concentrated in
vacuo. The crude carboxylic acid 55 was dissolved in DMF (39 mL) at 258C.
To this solution were added methyl iodide (1.1 mL, 17.6 mmol) and
potassium carbonate (1.62 g, 11.7 mmol). The resulting mixture was stirred
for 12 h before it was diluted with H2O (40 mL). The reaction mixture was
extracted with EtOAc (3 Â 60 mL) and the combined organic layers were
washed with H2O (100 mL), brine (100 mL), dried (Na2SO4), and concen-
trated in vacuo. Flash column chromatography (silica gel, 20 !40% EtOAc
in hexanes, gradient elution) of the residue gave pure methyl ester 56 (3.3 g,
87% overall yield for two steps). 56: Rf ˆ 0.30 (silica gel, 50% EtOAc in
hexanes); [a]2D2 ˆ ‡40.6 (c ˆ 0.60, CHCl3); IR (thin film): nÄmax ˆ 3285, 1764,
‡
1
82.4, 73.1, 69.9, 62.5, 13.8; HRMS (FAB) calcd C24H23NO9SCs [M ‡ Cs ]
1611, 1513, 1382, 1224, 1007 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 7.45-
634.0148, found 634.1035.
7.35 (m, 5H, ArH), 7.33 (d, J ˆ 9.0 Hz, 2H, ArH), 7.00 (d, J ˆ 9.0 Hz, 2H,
ArH), 5.79 (br.s, 1H, NH), 5.59 (d, J ˆ 5.0 Hz, 1H, H-2b), 5.07 (s, 2H,
CH2Ph), 4.27 (d, J ˆ 5.0 Hz, 1H, CHCOOMe), 3.85 (s, 3H, OCH3);
13C NMR (125 MHz, CDCl3): d ˆ 170.0, 159.4, 136.5, 130.1, 128.6, 128.0,
127.4, 127.3, 127.0, 115.2, 79.3, 70.0, 61.2, 53.1; HRMS (FAB) calcd for
Azide 53: To a solution of nosylate 52 (14.0 g, 27.9 mmol) in DMF (110 mL)
at 258C was added sodium azide (2.73 g, 41.9 mmol). The resulting mixture
was then heated to 558C and stirred for 12 h. The reaction mixture was
diluted with H2O (200 mL) and extracted with EtOAc (3 Â 200 mL). The
combined organic phases were washed with H2O (250 mL), brine (250 mL),
dried (Na2SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, 5 !15% EtOAc in hexanes,
gradient elution) to give azide 53 (8.56 g, 90%). 53: Rf ˆ 0.32 (silica gel,
‡
C18H17NO5Na [M ‡ Na ] 350.1004, found 350.1012.
N-Boc carbamate 57: To a solution of ester 56 (3.0 g, 9.2 mmol) in THF
(18.4 mL) at 258C was added di-tert-butyl dicarbonate (2.2 g, 10.1 mmol)
and 4-dimethylaminopyridine (169 mg, 1.38 mmol). The resulting mixture
was stirred at 258C for 2 h. The solvent was removed in vacuo and the
resulting residue was purified by flash column chromatography (silica gel,
10 !20% EtOAc in hexanes, gradient elution) to give compound 57 (2.1 g,
53%). 57: Rf ˆ 0.30 (silica gel, 25% EtOAc in hexanes); [a]2D2 ˆ ‡58.0 (c ˆ
1.66, CHCl3) IR (thin film): nÄmax ˆ 1831, 1739, 1727, 1612, 1514, 1324, 1249,
1077 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.42 ± 7.36 (m, 4H, ArH), 7.33
(d, J ˆ 7.0 Hz, 1H, ArH), 7.28 (d, J ˆ 9.0 Hz, 2H, ArH), 7.00 (d, J ˆ 9.0 Hz,
2H, ArH), 5.30 (d, J ˆ 4.5 Hz, 1H, H-2b), 5.06 (s, 2H, CH2Ph), 4.62 (d, J ˆ
4.5 Hz, 1H, CHCOOMe), 3.85 (s, 3H, COOCH3), 1.49 (s, 9H, tBuO);
13C NMR (125 MHz, CDCl3): d ˆ 169.0, 159.6, 150.7, 148.4, 136.4, 129.0,
128.6, 128.1, 127.4, 126.7, 115.4, 84.8, 75.9, 70.1, 63.7, 53.2, 27.8; HRMS
20% EtOAc in hexanes); [a]2D2 ˆ ‡3.09 (c ˆ 1.26, CHCl3); IR (thin film):
1
nÄmax ˆ 3478, 2111, 1736, 1610, 1512, 1244, 1174, 1024 cm
;
1H NMR
(500 MHz, CDCl3): d ˆ 7.42 ± 7.37 (m, 5H, ArH), 7.31 (d, J ˆ 9.0 Hz, 2H,
ArH), 6.97 (d, J ˆ 9.0 Hz, 2H, ArH), 5.06 (s, 2H, CH2Ph), 4.96 (d, J ˆ
7.0 Hz, 1H, CHOH), 4.24 (q, J ˆ 7.0 Hz, 2H, OCH2CH3), 4.08 (d, J ˆ 7.0 Hz,
1H, CHCOOEt), 2.78 (br.s, 1H, OH), 1.27 (t, J ˆ 7.0 Hz, 3H, OCH2CH3);
13C NMR (125 MHz, CDCl3): d ˆ 168.0, 159.9, 137.0, 132.0, 128.6, 128.0,
127.9, 127.4, 114.9, 73.7, 70.0, 66.8, 62.2, 14.1; HRMS (FAB) calcd for
‡
C18H19N3O4Na [M ‡ Na ] 364.1273, found 364.1266.
Amine 14: To a solution of azide 53 (6.0 g, 17.6 mmol) in MeOH (88 mL) at
258C was added tin(II) chloride dihydrate (7.92 g, 35.2 mmol). The
resulting mixture was stirred for 2 h before it was concentrated. The
residue was taken up in EtOAc (50 mL) and washed with 3n aqueous
NaOH (3 Â 50 mL), H2O (50 mL), brine (50 mL), and dried (Na2SO4). The
solvent was removed in vacuo and the resulting residue was purified by
flash column chromatography (silica gel, 1 !3% MeOH in CHCl3) to give
amine 14 (5.91 g, 90%). 14: Rf ˆ 0.42 (silica gel, 5% MeOH in CH2Cl2);
‡
(FAB) calcd for C23H25NO7Na [M ‡ Na ] 450.1529, found 450.1537.
Alcohol 58: To a solution of carbamate 57 (2.0 g, 4.7 mmol) in MeOH
(70 mL) at 08C was added cesium carbonate (611 mg, 1.88 mmol). The
reaction mixture was stirred at that temperature for 2 h and then
concentrated under reduced pressure. The residue was taken up in EtOAc
(50 mL) and washed with H2O (30 mL), brine (30 mL), and dried (Na2SO4).
The solvent was removed in vacuo and flash column chromatography (silica
gel, 20 !40% EtOAc in hexanes) provided alcohol 58 (1.5 g, 80%). 58:
[a]2D2
ˆ
2.0 (c ˆ 1.14, CHCl3); IR (thin film): nÄmax ˆ 3367, 3048, 1731, 1610,
1592, 1511, 1454, 1241, 1025 cm 1; H NMR (500 MHz, CDCl3): d ˆ 7.41 ±
7.35 (m, 4H, ArH), 7.31 (t, J ˆ 7.0 Hz, 1H, ArH), 7.20 (d, J ˆ 9.0 Hz, 2H,
ArH), 6.92 (d, J ˆ 9.0 Hz, 2H, ArH), 5.03 (s, 2H, CH2Ph), 4.88 (d, J ˆ
5.5 Hz, 1H, H-2b), 4.14 ± 4.08 (m, 2H, OCH2CH3), 3.74 (d, J ˆ 5.0 Hz, 1H,
CHCOOEt), 2.30 (br.s, 1H, OH), 1.20 (t, J ˆ 7.0 Hz, 3H, OCH2CH3);
13C NMR (125 MHz, CDCl3): d ˆ 173.1, 158.5, 136.8, 132.1, 128.5, 127.9,
127.6, 127.4, 114.7, 73.9, 69.9, 61.1, 59.9, 14.1; HRMS (FAB) calcd for
1
Rf ˆ 0.43 (silica gel, 50% EtOAc in hexanes); [a]D22
ˆ
11.0 (c ˆ 0.30,
CHCl3); IR (thin film): nÄmax ˆ 3420, 2941, 1717, 1616, 1511, 1367, 1243, 1172,
1025 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.41 ± 7.31 (m, 5H, ArH), 7.31
(d, J ˆ 9.0 Hz, 2H, ArH), 6.94 (d, J ˆ 9.0 Hz, 2H, ArH), 5.29 (d, J ˆ 7.0 Hz,
1H, H-2b), 5.15 (br.s, 1H, NH), 5.04 (s, 2H, CH2Ph), 4.48 (d, J ˆ 7.7 Hz,
1H, CHCOOMe), 3.73 (s, 3H, COOCH3), 1.34 (s, 9H, tBuO); 13C NMR
(125 MHz, CDCl3): d ˆ 171.1, 170.5, 158.6, 136.8, 132.0, 128.6, 127.9, 127.4,
127.2, 127.1, 73.6, 69.9, 59.3, 52.5, 29.6, 28.1; HRMS (FAB) calcd for
‡
C18H21NO4Na [M ‡ Na ] 316.1549, found 316.1559.
Urethane 54: To a solution of hydroxy amine 14 (2.80 g, 8.8 mmol) in
CH2Cl2 (90 mL) at 788C was added pyridine (1.43 mL, 17.7 mmol) and
phosgene (1.93m in toluene, 4.6 mL, 8.8 mmol). The reaction mixture was
stirred at that temperature for 2 h and then quenched by the slow addition
of H2O (40 mL). The aqueous phase was extracted with CH2Cl2 (2 Â
50 mL) and the combined organic layers were washed with H2O
(100 mL), brine (100 mL), dried (Na2SO4), and concentrated in vacuo.
The resulting residue was purified by flash column chromatography (silica
gel, 30 !50% EtOAc in hexanes, gradient elution) to give 54 (2.80 g,
‡
C22H27NO6Na [M ‡ Na ] 424.1736, found 424.1746.
Dipeptide 59: To a solution of amine 14 (615 mg, 2.1 mmol) and acid 15
(523 mg, 2.1 mmol) in THF (22 mL) at 08C were added HOBt (956 mg,
7.0 mmol) and EDC (1.22 g, 6.4 mmol). The reaction mixture was stirred at
that temperature for 12 h before it was diluted with EtOAc (100 mL). The
resulting mixture was washed with 5% aqueous HCl (3 Â 30 mL), 5%
aqueous NaHCO3 (40 mL), H2O (40 mL), brine (40 mL) and dried
(Na2SO4). The solvent was removed in vacuo and the residue was purified
by flash column chromatography (silica gel, 20 !40% EtOAc in hexanes,
gradient elution) to provide dipeptide 59 (1.08 g, 93%). 59: Rf ˆ 0.14 (silica
93%). 54: Rf ˆ 0.18 (silica gel, 50% EtOAc in hexanes); [a]D22
ˆ
60.1 (c ˆ
0.83, CHCl3); IR (thin film): nÄmax ˆ 3299, 1773, 1751, 1731, 1515, 1255, 1204,
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2615 $ 17.50+.50/0
2615

K. C. Nicolaou et al.
FULL PAPER
gel, 30% EtOAc in hexanes); [a]2D2 ˆ ‡17.4 (c ˆ 0.87, CHCl3); IR(thin
CHOTBS), 5.01 (s, 2H, CH2Ph), 4.82 ± 4.78 (m, 1H, CHCONH), 4.65 ± 4.62
(m, 2H, CHCONH), 3.77 (s, 6H, OCH3), 3,59 (s, 3H, COOCH3), 2.74
(br.d, 1H, CHCH2), 2.65 (dd, J ˆ 18.0, 4.0 Hz, 1H, CHCH2), 2.52 (br.s, 3H,
NCH3), 1.43 (br.s, 12H, OC(CH3)3, CH(CH3)2, CHCH2), 0.89 (m, 15H,
tBuSi, CH(CH3)2), 0.02 (s, 3H, SiCH3), 0.01 (s, 3H, SiCH3); 13C NMR
(125 MHz, CDCl3): d ˆ 171.2, 171.0, 169.0, 168.8, 168.7, 158.8, 158.5, 136.9,
128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.7, 127.6, 127.5, 114.7, 114.3, 114.0,
80.7, 80.6, 73.8, 69.9, 57.2, 55.9, 55.3, 55.2, 52.6, 48.9, 48.8, 37.4, 37.2, 36.3,
36.1, 29.6, 28.3, 28.2, 25.8, 25.7, 24.6, 24.3, 23.2, 23.1, 21.6, 21.7, 21.2, 18.1,
16.1, 8.2, 7.1, 1.0, 4.8, 5.1; HRMS (FAB) calcd for C54H74N4O11SiCs
1
film): nÄmax ˆ 3410, 2958, 1737, 1693, 1681, 1510, 1454, 1243, 1152, 1025 cm
;
1H NMR (500 MHz, CDCl3, 320 K): d ˆ 7.39-7.29 (m, 5H, ArH), 7.12 (d,
J ˆ 7.0 Hz, 2H, ArH), 6.90 (d, J ˆ 8.5 Hz, 2H, ArH), 5.26 (s, 1H), 5.14 (br.s,
1H), 5.02 (s, 2H, CH2Ph), 4.87 (br.s, 1H, CHCOOEt), 4.17 (q, J ˆ 7.0 Hz,
2H, OCH2CH3), 2.57 (s, 3H, NCH3), 1.64 (br.s, 2H, NCHCH2), 1.42 (s,
10H, tBuO, CH(CH3)2), 1.22 (t, J ˆ 7.0 Hz, 3H, OCH2CH3), 0.92 (d, J ˆ
7.0 Hz, 3H, CH(CH3)2), 0.88 (d, J ˆ 7.0 Hz, 3H, CH(CH3)2); 13C NMR
(125 MHz, CDCl3): d ˆ 172.6, 169.3, 158.5, 158.4, 156.4, 155.0, 136.8, 136.6,
131.1, 128.5, 128.4, 127.9, 127.3, 127.3, 114.7, 114.5, 80.9, 80.5, 74.6, 74.5, 69.8,
61.9, 59.0, 56.9, 56.1, 36.3, 29.8, 29.0, 28.2, 24.7, 23.2, 23.1, 21.6, 21.2, 14.0;
‡
[M ‡ Cs ] 1115.4178, found 1115.4116.
‡
HRMS (FAB) calcd for C30H42N2O7Cs [M ‡ Cs ] 675.2046, found 675.2022.
Phenol 63: To a solution of compound 62 (517 mg, 0.53 mmol) in MeOH
(6 mL) was added 20% Pd(OH)2/C (20 mg). Hydrogen was bubbled
through the reaction mixture for 1 h. The solution was filtered through a
pad of celite and the celite was washed thoroughly with MeOH (2 Â 5 mL).
The filtrate was concentrated in vacuo to give phenol 63 (480 mg, 99%). 63:
Rf ˆ 0.45 (60% EtOAc in hexanes); [a]2D2 ˆ ‡15.7 (c ˆ 0.73, CHCl3); IR
(thin film): nÄmax ˆ 3328, 2955, 1743, 1661, 1612, 1512, 1465, 1249, 1175,
1086 cm 1; 1H NMR (500 MHz, CDCl3, 315 K): d ˆ 7.16 (d, J ˆ 9.0 Hz, 2H,
ArH), 7.14 ± 7.08 (m, 4H, ArH), 6.85 ± 6.81 (m, 4H, ArH), 6.71 (d, J ˆ
9.0 Hz, 2H, ArH), 6.07 (d, J ˆ 10.6 Hz, 1H, CHAr2), 5.14 (d, J ˆ 4.5 Hz,
1H, CHOTBS), 4.81 ± 4.79 (m, 1H, CHCONH), 4.63 ± 4.61 (m, 2H,
CHCONH), 3.77 (s, 6H, OCH3), 3.61 (s, 3H, COOCH3), 2.85 (dd, J ˆ
18.0, 6.5 Hz, 1H, CHCHH), 2.65 (dd, J ˆ 18.0, 4.5 Hz, 1H, CHCHH), 2.56
(s, 3H, NCH3), 1.50 (m, 3H, CHCH2, CH(CH3)2), 1.40 (br.s, 9H, tBuO),
0.89 ± 0.83 (m, 15H, tBuSi, CH(CH3)2), 0.01 (s, 3H, SiCH3), 0.13 (s, 3H,
SiCH3); 13C NMR (125 MHz, CDCl3): d ˆ 171.1, 169.1, 168.8, 158.9, 158.8,
156.3, 133.6, 128.8, 128.6, 128.4, 128.3, 128.1, 127.9, 127.8, 115.5, 115.4, 115.2,
114.0, 113.9, 74.0, 59.9, 57.0, 55.9, 55.2, 52.6, 49.0, 40.3, 37.0, 36.2, 36.0, 29.7,
28.3, 25.8, 25.7, 24.6, 24.3, 23.3, 21.2, 18.1, 1.0, 4.8, 5.2; HRMS (FAB)
Carboxylic acid 60: To a solution of ester 59 (390 mg, 0.72 mmol) in THF/
H2O (1:1, 7 mL) at 08C was added lithium hydroxide monohydrate (62 mg,
1.4 mmol) and the resulting mixture was stirred at that temperature for 1 h.
The reaction mixture was carefully acidified with 5% aqueous HCl at 08C
to pH 4 and then extracted with EtOAc (3 Â 15 mL). The combined organic
layers were washed with H2O (25 mL), brine (25 mL), dried (Na2SO4), and
concentrated in vacuo to give carboxylic acid 60 (370 mg, 99%). 60: Rf ˆ
0.13 (silica gel, 5% MeOH in CH2Cl2); [a]2D2 ˆ ‡23.3 (c ˆ 0.75, CHCl3); IR
(thin film): nÄmax ˆ 3410, 1731, 1681, 1513, 1454, 1392, 1368, 1322, 1245, 1154,
1
1064, 1025, 909, 734 cm
;
1H NMR (500 MHz, CDCl3, 315 K): d ˆ 7.37 ±
7.32 (m, 5H, ArH), 7.20 (d, J ˆ 8.5 Hz, 2H, ArH), 6.89 (d, J ˆ 8.1 Hz, 2H,
ArH), 5.08 (br.s, 1H, H-2b), 5.00 (s, 2H, CH2Ph), 4.92-4.88 (m, 1H,
CHCOOH), 4.66 (br.s, 1H, COCHN) 2.51 (br.s, 3H, NCH3), 1.56 ± 1.52 (m,
2H, NCHCH2), 1.45 ± 1.40 (m, 10H, tBuO, CH(CH3)2), 0.91 (d, J ˆ 6.5 Hz,
3H, CH(CH3)2), 0.87 (d, J ˆ 5.8 Hz, 3H, CH(CH3)2); 13C NMR (125 MHz,
CDCl3): d ˆ 171.7, 158.5, 155.7, 136.7, 128.5, 127.4, 127.3, 114.5, 87.9, 81.3,
74.4, 74.2, 69.8, 58.6, 58.0, 57.7, 36.3, 29.5, 28.3, 24.5, 23.3, 23.0, 21.8, 21.1;
‡
HRMS (FAB) calcd for C28H38N2O7 [M ‡ H ] 515.2757, found 515.2770.
‡
calcd for C47H68N4O11SiCs [M ‡ Cs ] 1025.3708, found 1025.3770.
Tripeptide 61: To a solution of carboxylic acid 60 (2.66 g, 7.19 mmol) and
amine 13 (3.69 g, 7.19 mmol) in THF (100 mL) at 08C was added HOAt
(3.22 g, 23.7 mmol). The resulting mixture was stirred for 5 min before
EDC (4.12 g, 21.6 mmol) was added. The reaction was allowed to warm to
258C and stirred for 12 h before it was diluted with EtOAc (400 mL). The
reaction mixture was washed with aqueous 5% HCl (3 Â 100 mL), 5%
aqueous NaHCO3(200 mL), H2O (200 mL), brine (200 mL). The organic
layer was dried (Na2SO4), and the solvent was removed in vacuo. Flash
column chromatography of the residue (silica gel, 50 !70% EtOAc in
hexanes, gradient elution) provided tripeptide 61 (4.50 g, 82%). Rf ˆ 0.28
(silica gel, 70% EtOAc in hexanes); [a]2D2 ˆ ‡35.4 (c ˆ 0.94, CHCl3);
Chloride 64: To a solution of phenol 63 (470 mg, 0.53 mmol) in ether
(5 mL) at 08C under darkness was added thionyl chloride (50 mL,
0.64 mmol). The reaction mixture was stirred for 1 h and then it was
quenched by the addition of 5% aqueous NaHCO3 (5 mL). The aqueous
layer was extracted with EtOAc (3 Â 5 mL) and the combined organic
layers were washed with H2O (10 mL), brine (10 mL), dried (Na2SO4), and
concentrated in vacuo. Flash column chromatography (silica gel, 10 !30%
EtOAc in hexanes, gradient elution) provided chloride 64 (360 mg, 75%).
64: Rf ˆ 0.5 (silica gel, 60% EtOAc in hexanes); [a]2D2 ˆ ‡12.5 (c ˆ 0.68,
1
CHCl3); IR (thin film): nÄmax ˆ 3319, 1737, 1666, 1652, 1510, 1249, 1176 cm
;
IR(thin film): nÄmax ˆ 3312, 1742, 1650, 1610, 1511, 1453, 1387, 1247, 1175,
1H NMR (500 MHz, CD3SOCD3, 320 K): d ˆ 9.80 (s, 1H, ArOH), 8.61 (d,
J ˆ 7.3 Hz, 1H, NH), 8.26 (d, J ˆ 5.0 Hz, 1H, NH), 7.20 (s, 1H, ArH), 7.10
(d, J ˆ 7.1 Hz, 4H, ArH), 6.99 (d, J ˆ 6.9 Hz, 1H, ArH), 6.84 ± 6.80 (m, 5H,
ArH), 5.97 (d, J ˆ 7.1 Hz, 1H, CHAr2), 5.48 (d, J ˆ 6.3 Hz, 1H, CHOTBS),
4.64 (d, J ˆ 4.7 Hz, 1H, CHCONH), 4.51 (t, J ˆ 7.5 Hz, 1H, CHCONH),
4.42 (br.s, 1H, CHCONH), 3.69 (s, 6H, OCH3), 3.49 (s, 3H, COOCH3),
2.67 (dd, J ˆ 19.5, 6.5 Hz, 1H, CHCHH), 2.56 (dd, J ˆ 17.4, 4.6 Hz, 1H,
CHCHH), 2.40 (s, 3H, NCH3), 1.40 (s, 12H, tBuO, CH(CH3)2, CHCH2),
0.81 ± 0.79 (m, 6H, CH(CH3)2), 0.70 (s, 9H, tBuSi), 0.08 (s, 3H, SiCH3),
0.23 (s, 3H, SiCH3); 13C NMR (125 MHz, CD3SOCD3): d ˆ 171.2, 171.2,
170.8, 168.8, 168.5, 168.2, 158.8, 158.7, 151.4, 133.5, 133.5, 132.8, 132.5, 128.7,
128.4, 128.3, 128.2, 127.5, 126.6, 126.2, 120.0, 119.8, 116.4, 114.0, 113.8, 80.9,
80.2, 73.3, 60.4, 59.8, 55.9, 55.2, 52.6, 48.9, 37.2, 36.3, 29.9, 29.2, 28.2, 25.6,
24.6, 24.3, 23.3, 23.2, 21.6, 21.1, 21.0, 18.0, 14.1, 4.8, 5.1, 5.3; HRMS
1
1148, 1033, 830, 732 cm
;
1H NMR (500 MHz, CD3SOCD3, 315 K): d ˆ
8.61 (d, J ˆ7.0 Hz, 1H, NH), 8.18 (d, J ˆ 6.5 Hz, 1H, NH), 7.38 ± 7.28 (m,
5H, ArH), 7.17 (d, J ˆ 7.0 Hz, 2H, ArH), 7.11 ± 7.09 (m, 5H, ArH), 6.85 ±
6.82 (m, 5H, ArH), 5.96 (d, J ˆ 7.5 Hz, 1H, CHAr2), 5.32 (br.s, 1H,
CHOH), 5.02 (s, 2H, CH2Ph), 4.71 (d, J ˆ 6.5 Hz, 1H, CHCONH), 4.66 (q,
J ˆ 6.2 Hz, 1H, CHCONH), 4.49 (t, J ˆ 7.0 Hz, 1H, CHCONH), 3.68 (s,
6H, ArOCH3), 3.49 (s, 3H, COOCH3), 2.68 (dd, J ˆ 18.5, 5.5 Hz, 1H,
CHCHH), 2.60 (dd, J ˆ 18.5, 5.5 Hz, 1H, CHCHH), 2.34 (br.s, 3H, NCH3),
1.39 (br.s, 12H, tBuO, CH(CH3)2, CH2CH), 0.83 (m, 6H, CH(CH3)2);
13C NMR (125 MHz, CD3SOCD3): d ˆ 171.3, 170.9, 168.6, 158.8, 158.6,
136.9, 133.4, 128.6, 128.5, 128.4, 128.3, 127.9, 127.4, 114.8, 114.7, 114.6, 114.0,
80.9, 80.1, 76.8, 69.9, 57.8, 55.9, 55.2, 52.8, 49.5, 37.4, 36.1, 28.3, 24.5, 23.3,
‡
21.6; HRMS (FAB) calcd for C48H60N4O11Cs [M ‡ Cs ] 1001.3313, found
‡
1001.3360.
(FAB) calcd for C47H67ClN4O11SiCs [M ‡ Cs ] 1059.3318, found 1059.3388.
TBS ether 62: To a solution of alcohol 61 (500 mg, 0.58 mmol) in CH2Cl2
(6 mL) at 08C was added 2,6-lutidine (143 mL, 1.3 mmol) and tert-
butyldimethylsilyl trifluoromethanesulfonate (171 mL, 0.75 mmol). The
reaction mixture was stirred at that temperature for 2 h and then it was
quenched by the addition of 5% aqueous NaHCO3 (5 mL). The aqueous
phase was extracted with CH2Cl2 (2 Â 10 mL) and the combined organic
layers were washed with saturated aqueous CuSO4 (2 Â 10 mL), brine
(15 mL), dried (Na2SO4). The solvent was removed in vacuo and the
resulting residue was subjected to flash column chromatography (silica gel,
10 !30% EtOAc in hexanes, gradient elution) to yield compound 62
Carboxylic acid 17: To a solution of tripeptide ester 64 (3.82 g, 4.1 mmol) in
tBuOH (36 mL) at 08C was added H2O (18 mL). The reaction mixture was
further cooled to 58C for 15 min and then lithium hydroxide monohy-
drate (0.69 g, 16.4 mmol) was added. The resulting slurry was stirred
vigorously at 08C for 0.5 h and then it was quenched by the addition of
saturated aqueous NH4Cl (50 mL). The mixture was diluted with CH2Cl2
(50 mL) and stirred at 08C for 0.5 h. The aqueous phase was acidified to pH
5 by dropwise addition of 5% aqueous HCl at 08C and then extracted with
CH2Cl2 (2 Â 25 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 !100% EtOAc in hexanes, then
10% MeOH in EtOAc, gradient elution) to afford tripeptide carboxylic
acid 17 (3.55 g, 95%). 17: Rf ˆ 0.22 (silica gel, 7.5% MeOH in CH2Cl2);
[a]2D2 ˆ ‡5.29 (c ˆ 2.61, MeOH); IR (thin film): nÄmax ˆ 3306, 2958, 2931,
2857, 1650, 1508, 1251, 836 cm 1; 1H NMR (600 MHz, CD3OD, 330 K): d ˆ
(462 mg, 81%). 62: Rf ˆ 0.54 (silica gel, 60% EtOAc in hexanes); [a]D22
ˆ
‡12.9 (c ˆ 0.96, CHCl3); IR (thin film): nÄmax ˆ 2936, 1741, 1697, 1611, 1511,
1247, 1175, 1086, 1029 cm 1; 1H NMR (500 MHz, CDCl3, 315 K): d ˆ 7.39 ±
7.22 (m, 5H, ArH), 7.12 ± 7.07 (m, 6H, ArH), 6.89 (d, J ˆ 8.5 Hz, 2H, ArH),
6.84 ± 6.81 (m, 4H, ArH), 6.04 (br.s, 1H, CHAr2), 5.10 (d, J ˆ 4.0 Hz, 1H,
2616
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2616 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 2
2602±2621
7.28 (d, J ˆ 2.0 Hz, 1H, H-2b), 7.14 (d, J ˆ 2.6 Hz, 2H, ArH (Ddm)), 7.13 (d,
J ˆ 2.6 Hz, 2H, ArH (Ddm)), 7.07 (dd, J ˆ 8.4, 1.9 Hz, 1H, H-2f), 6.84 (d,
J ˆ 1.7 Hz, 2H, ArH (Ddm)), 6.84-6.83 (m, 1H, H-2e), 6.83 (d, J ˆ 1.5 Hz,
2H, ArH (Ddm)), 6.08 (s, 1H, NHCH (Ddm)), 5.00 (d, J ˆ 7.0 Hz, 1H,
H-2b), 4.64 (d, J ˆ 7.0 Hz, 1H, 2a), 4.58 ± 4.44 (m, 2H, H-1a and H-3a), 3.75
(s, 3H, Ddm-OCH3), 3.75 (s, 3H, Ddm-OCH3), 2.84 (d, J ˆ 14.2 Hz, 1H,
H-3bA), 2.77 (d, J ˆ 14.2 Hz, 1H, H-3bB), 2.51 (s, 3H, NCH3), 1.51 ± 1.35 (m,
3H, H-1b and H-1g), 1.45 (s, 9H, tBuO), 0.87 (d, J ˆ 6.7 Hz, 3H, H-1d),
0.85 (d, J ˆ 6.5 Hz, 3H, H-1d'), 0.80 (s, 9H, tBuSi), 0.00 (s, 3H, CH3Si),
0.16 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3COCD3, 323 K): d ˆ 173.6,
173.3, 171.1, 161.0, 155.0, 136.7, 136.0, 130.8, 130.7, 130.4, 128.9, 122.2, 118.9,
115.9, 81.7, 75.8, 61.8, 58.9, 57.8, 56.8, 38.7, 29.9, 27.5, 26.6, 24.7, 23.2, 19.9,
1245, 1166, 1107, 1028 cm 1; 1H NMR (600 MHz, CD3COCD3, 323 K): d ˆ
7.99 (d, J ˆ 8.2 Hz, 1H, NH), 7.64 ± 7.50 (br.s, 2H, NH and H-2f), 7.31 (d,
J ˆ 1.9 Hz, 1H, H-2b), 7.26 (d, J ˆ 8.3 Hz, 1H, H-2e), 7.21 (d, J ˆ 1.5 Hz,
1H, H-4b), 7.17 ± 7.13 (m, 5H, NH and 4ArH), 6.88 ± 6.85 (m, 5H, NH and
4ArH), 6.11 (d, J ˆ 8.4 Hz, 1H, CHAr2), 6.05 (br.s, 1H, H-4f), 5.54 (d, J ˆ
5.0 Hz, 1H, H-2b), 4.90 (br.s, 1H, H-2a), 4.79 (br.s, 1H, H-4a), 4.66 (br.s,
1H, H-3a), 4.59 (br.s, 1H, H-1a), 3.82 ± 3.72 (m, 6H), 3.77 (s, 3H, OCH3),
3.77 (s, 3H, OCH3), 2.86 (s, 3H, NCH3), 2.85 ± 2.66 (m, 2H, H-3b), 2.05
(br.s, 4H, NCH2CH2), 1.73 ± 1.66 (m, 3H, H-1b and H-1g), 1.50 (s, 9H,
tBuO), 0.92 (s, 9H, tBuSi), 0.89 ± 0.86 (m, 6H, CH(CH3)2), 0.14 (s, 3H,
CH3Si), 0.11 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3COCD3, 323 K): d ˆ
173.1, 171.4, 170.8, 170.7, 159.9, 159.9, 154.0, 148.0, 141.1, 135.7, 135.7, 134.4,
132.0, 129.8, 129.6, 129.5, 128.0, 118.0, 117.7, 114.7, 114.7, 80.6, 74.7, 66.0,
62.2, 56.6, 55.8, 55.7, 51.3, 37.5, 37.3, 28.7, 26.3, 25.5, 24.5 (br), 23.6, 22.1, 18.7,
‡
3.3; HRMS (FAB) calcd for C46H64ClN4O11SiCs2 [M H ‡ 2Cs ]
1177.2138, found 1177.2088.
‡
4.4, 4.6; HRMS (FAB) calcd for C58H78BrClN8O11Cs [M ‡ Cs ] calcd
Amino alcohol 65: To a solution of TBS ether 46 (1.31 g, 2.6 mmol) in THF
(25 mL) at 08C was added nBu4NF (1.0m solution in THF, 2.9 mL,
2.9 mmol). The resulting solution was stirred at that temperature for 2 h
and then it was quenched by the addition of saturated aqueous NH4Cl
(15 mL). The mixture was extracted with EtOAc (3 Â 40 mL) and the
combined organic phases were washed with H2O (50 mL), brine (50 mL),
dried (Na2SO4), and concentrated in vacuo. Flash column chromatography
(silica gel, 5 !15% MeOH in CHCl3, gradient elution) afforded 65
1339.3477, found 1339.3543. 67b: Rf ˆ 0.13 (silica gel, 40% acetone in
hexanes); [a]2D2 ˆ ‡8.54 (c ˆ 0.89, CHCl3); IR (KBr): nÄmax ˆ 3389, 2941,
1
2862, 1673, 1509, 1410, 1318, 1245, 1166, 1100, 1034 cm
;
1H NMR
(500 MHz, CD3COCD3, 323 K): d ˆ 8.12 (s, 1H, NH), 7.69 ± 7.50 (m, 2H),
7.31 (s, 1H, NH), 7.21 (d, J ˆ 1.5 Hz, 1H), 7.17 ± 7.11 (m, 5H, ArH), 6.93 ±
6.91 (m, 1H, ArH), 6.88-6.85 (m, 5H, ArH), 6.23 ± 6.21 (m, 1H, H-4f), 6.09
(d, J ˆ 8.2 Hz, 1H, CHAr2), 5.53 (d, J ˆ 4.8 Hz, 1H, H-2b), 4.90 (br.s, 1H,
H-2a), 4.77 (br.s, 1H), 4.65 (br.s, 1H), 4.54 (br.s, 1H), 3.90 (br.s, 2H,
NCH2), 3.77 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.80 ± 3.73 (m, 1H), 3.65
(br.s, 2H, NCH2), 3.49 (br.s, 1H), 2.87 (s, 3H, NCH3), 2.60 ± 2.55 (m, 2H,
H-3b), 2.04 (br.s, 4H, NCH2CH2), 1.75 ± 1.71 (m, 3H, H-1b and H-1g), 1.53
(s, 9H, tBuO), 1.50 ± 1.47 (m, 6H, CH(CH3)2), 0.91 (s, 9H, tBuSi), 0.13 (s,
3H, CH3Si), 0.11 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3COCD3, 323 K):
d ˆ 172.7, 171.3, 170.8, 168.6, 159.6, 158.0, 157.0, 153.8, 153.1, 139.8, 138.9,
138.6, 135.1, 129.4, 129.3, 128.7, 125.8, 125.4, 123.3, 122.8, 118.9, 118.8, 115.9,
115.4, 114.5, 80.6, 73.8, 73.6, 65.5, 60.9, 57.2, 56.7, 56.3, 55.5, 51.6, 51.1, 46.9,
39.2, 37.2, 28.6, 26.2, 25.4, 24.5, 24.1, 23.7, 22.1, 18.9, 4.8, 4.8; HRMS
(938 mg, 92%). 65: Rf ˆ 0.23 (silica gel, 20% MeOH in CHCl3); [a]D22
ˆ
33.4 (c ˆ 1.12, CHCl3); IR (thin film): nÄmax ˆ 3344, 3292, 2971, 2866, 1415,
1
1338, 1309, 1223, 1046 cm 1; H NMR (400 MHz, CDCl3): d ˆ 7.48 (s, 2H,
ArH), 3.90 (br.s, 2H, NCH2), 3.87 (dd, J ˆ 7.8, 4.3 Hz, 1H, ArCH), 3.67
(br.s, 2H, NCH2), 3.60 (dd, J ˆ 10.8, 4.3 Hz, 1H, CHHOH), 3.42 (dd, J ˆ
10.8, 7.8 Hz, 1H, CHHOH), 2.45 (br.s, 3H, OH and NH2), 2.02 (br.s, 4H,
CH2); 13C NMR (100 MHz, CDCl3): d ˆ 147.0, 141.6, 130.4, 117.7, 67.4, 56.1,
‡
51.1, 46.5, 23.8, 23.5; HRMS (FAB) calcd for C12H17Br2N4O [M ‡ H ]
392.9749, found 392.9747.
Tetrapeptide 66: A solution of hydroxy amine 65 (216 mg, 0.55 mmol), acid
17 (503 mg, 0.55 mmol) and HOAt (250 mg, 1.82 mmol) in THF (5 mL) at
08C was treated with EDC (315 mg, 1.65 mmol). The reaction mixture was
stirred for 10 h and then quenched by the addition of saturated aqueous
NH4Cl (5 mL). The resulting mixture was extracted with EtOAc (3 Â
10 mL) and the combined organic phases were washed with H2O
(15 mL), brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Flash
column chromatography of the residue (silica gel, 10 !20% EtOAc in
hexanes, gradient elution) afforded tetrapeptide 66 (594 mg, 84%). 66:
‡
(FAB) calcd for C58H78BrClN8O11Cs [M ‡ Cs ] calcd 1339.3477, found
1339.3544.
Carboxylic acid 7: To a solution of alcohol 67a (500 mg, 0.414 mmol) in 5%
aqueous NaHCO3/acetone (1:1, 4 mL) at 08C were added TEMPO (71 mg,
0.46 mmol) and potassium bromide (5 mg, 0.04 mmol). Sodium hypochlor-
ite (5% aqueous, 2 mL) was added dropwise and the resulting mixture was
stirred for 1 h before it was quenched by the addition of saturated aqueous
NH4Cl (5 mL). The mixture was extracted with EtOAc (3 Â 10 mL) and the
combined organic extracts were washed with brine, dried (Na2SO4), and
concentrated in vacuo. The resulting residue was purified by column
chromatography (silica gel, 5 !10% MeOH in CHCl3) to afford carboxylic
acid 7 (330 mg, 65%). 7: 1H NMR (500 MHz, CD3OD): d ˆ 7.65 (br.s, 1H),
7.54 (br.s, 1H), 7.35 ± 7.32 (m, 1H), 7.23 ± 7.20 (m, 1H), 7.08 ± 7.05 (m, 4H),
6.86 ± 6.82 (m, 4H), 6.08 (s, 1H), 5.89 (s, 1H), 5.51 ± 5.48 (m, 1H), 5.16 ± 5.10
(m, 1H), 5.04 ± 4.80 (m, 2H), 4.66 ± 4.59 (br.s, 1H), 3.90 ± 3.75 (m, 4H), 3.77
(s, 3H), 3.76 (s, 3H), 2.84 (s, 3H), 2.65 ± 2.60 (m, 2H), 2.08 (br.s, 4H), 1.60 ±
1.50 (m, 12H), 0.87 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H); HRMS (FAB) calcd
Rf ˆ 0.20 (silica gel, 50% EtOAc in hexanes); [a]D22
ˆ
47.5 (c ˆ 1.14,
CHCl3); IR (thin film): nÄmax ˆ 3314, 2945, 1658, 1502, 1417, 1247, 1169, 1092,
1035 cm 1; 1H NMR (600 MHz, CD3COCD3, 323 K): d ˆ 8.60 (s, 1H, OH),
8.05 (d, J ˆ 8.1 Hz, 1H, NH), 7.94 (d, J ˆ 7.7 Hz, 1H, NH), 7.89 (d, J ˆ
8.1 Hz, 1H, NH), 7.56 (s, 2H, ArH), 7.50 (s, 1H, ArH), 7.29 (d, J ˆ 8.3 Hz,
1H, ArH), 7.18 (t, J ˆ 8.9 Hz, 4H, ArH), 7.01 (d, J ˆ 8.3 Hz, 1H, ArH),
6.88-6.84 (m, 4H, ArH), 6.72 (br.s, 1H, NH), 6.15 (d, J ˆ 8.2 Hz, 1H,
CHAr2), 4.99 (d, J ˆ 8.0 Hz, 1H), 4.90 (dd, J ˆ 13.1, 5.9 Hz, 1H), 4.77 ± 4.73
(m, 1H), 4.64 (br.s, 1H), 4.41 (dd, J ˆ 7.8, 6.1 Hz, 1H), 3.97 (t, J ˆ 6.4 Hz,
1H), 3.80 (br.s, 2H, NCH2), 3.78 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.75
(br.s, 2H, NCH2), 3.07 (dd, J ˆ 15.7, 3.8 Hz, 1H), 2.74 ± 2.66 (m, 2H, H-3b),
2.44 (s, 3H, NCH3), 2.06 (br.s, 4H, NCH2CH2), 1.53-1.49 (m, 1H), 1.42 (s,
9H, tBuO), 1.45 ± 1.34 (m, 2H), 0.87-0.84 (m, 6H, CH(CH3)2), 0.83 (s, 9H,
tBuSi), 0.02 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si); 13C NMR (100 MHz,
CD3COCD3, 323 K): d ˆ 173.1, 171.3, 170.9, 170.4, 159.6, 159.6, 153.8, 147.7,
140.9, 135.5, 135.4, 134.2, 131.8, 129.4, 129.2, 127.9, 117.9, 117.5, 114.4, 80.4,
74.2, 65.8, 62.2, 56.3, 55.5, 55.5, 51.6, 51.0, 47.2, 36.9, 28.6, 28.5, 26.2, 26.1,
25.2, 24.5, 24.1, 23.6, 21.5, 18.5, 4.6, 4.8; HRMS (FAB) calcd for
‡
for C58H76BrClN8O12SiCs [M ‡ Cs ] 1353.3270, found 1353.3362.
Epimers 5a and 5b: A solution of acid 7 (140 mg, 0.11 mmol) and amine 6
(97 mg, 0.11 mmol) at 158C in THF (2.5 mL) was treated sequentially
with HOAt (52 mg, 0.38 mmol) and EDC (66 mg, 0.33 mmol). The reaction
mixture was stirred for 5 h before it was quenched by the addition of
saturated aqueous NH4Cl (5 mL). The resulting mixture was extracted with
EtOAc (3 Â 10 mL) and the combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified
by flash column chromatography (silica gel, 20 !40% EtOAc in hexanes)
to afford 5a (114 mg, 48%) and 5b (57 mg, 24%). 5a: Rf ˆ 0.08 (silica gel,
‡
C58H79Br2ClN8O11SiCs [M ‡ Cs ] 1419.2734, found 1419.2734.
1
D-O-E cyclic system 67a and 67b: To a solution of tetrapeptide 66 (232 mg,
0.18 mmol) and CuBr´ Me2S (156 mg, 0.54 mmol) in degassed MeCN
(18 mL) at 258C was added K2CO3 (75 mg, 0.54 mmol) and pyridine (44 mL,
0.54 mmol). The resulting mixture was refluxed and stirred for 15 min. The
reaction mixture was cooled to 258C and filtered through a pad of celite.
The celite was washed thoroughly with EtOAc (3 Â 20 mL) and the
combined organic layers were washed with H2O (20 mL), brine (20 mL),
and dried (Na2SO4). The solvent was removed in vacuo and flash column
chromatography of the residue (silica gel, 10 !30% acetone in hexanes,
gradient elution) afforded 67a (141 mg, 65%) and 67b (47 mg, 22%). 67a:
Rf ˆ 0.22 (silica gel, 40% acetone in hexanes); [a]2D2 ˆ ‡31.2 (c ˆ 1.18,
CHCl3); IR (KBr): nÄmax ˆ 3442, 2954, 2493, 1673, 1647, 1502, 1416, 1324,
50% EtOAc in hexanes); H NMR (600 MHz, CD3OD, 330 K): d ˆ 7.55 ±
7.49 (m, 5H, ArH), 7.48 ± 7.45 (m, 2H, ArH), 7.45 ± 7.44 (m, 2H, ArH), 7.40
(d, J ˆ 2.4 Hz, 1H, ArH), 7.38 (d, J ˆ 8.7 Hz, 2H, ArH), 7.29 (d, J ˆ 8.7 Hz,
2H, ArH), 7.24 (dd, J ˆ 8.7, 2.5 Hz, 1H, ArH), 7.17 (dd, J ˆ 8.7, 2.0 Hz, 1H,
ArH), 7.12 (d, J ˆ 8.7 Hz, 2H, ArH), 7.10 (d, J ˆ 8.7 Hz, 2H, ArH), 7.12-7.10
(m, 2H, ArH), 7.02 (d, J ˆ 8.7 Hz, 1H, ArH), 6.89 (d, J ˆ 2.4 Hz, 1H, ArH),
6.78 (d, J ˆ 2.4 Hz, 1H, ArH), 6.31 (s, 1H, ArH), 6.20 (s, 1H, CHAr2), 5.88
(s, 1H), 5.76 (s, 1H), 5.67 (m, 1H), 5.42 (d, J ˆ 3.2 Hz, 1H), 5.15 (m, 1H),
5.03 (d, J ˆ 4.8 Hz, 1H), 4.99 (d, J ˆ 3.4 Hz, 1H), 4.85 ± 4.82 (m, 2H), 4.72 ±
4.67 (m, 2H), 4.42 ± 4.35 (m, 2H), 4.10 ± 4.09 (m, 4H), 4.08 (s, 3H, OCH3),
4.05 (s, 3H, OCH3), 4.04 (s, 3H, OCH3), 3.90 ± 3.88 (m, 2H), 3.87 (s, 3H,
OCH3), 3.75 (s, 3H, OCH3), 3.12 (s, 3H, NCH3), 2.86 ± 2.81 (m, 1H), 2.77 ±
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2617 $ 17.50+.50/0
2617

K. C. Nicolaou et al.
FULL PAPER
2.73 (m, 1H), 2.04 (br.s, 2H), 1.94 (br.s, 2H), 1.56 (s, 9H, tBuO), 1.48 (t, J ˆ
7.2 Hz, 3H), 1.23 ± 1.18 (m, 9H), 1.17 (s, 9H, tBuSi), 1.09 (s, 9H, tBuSi), 0.38
(s, 3H, CH3Si), 0.34 (s, 3H, CH3Si), 0.25 (s, 3H, CH3Si), 0.11 (s, 3H, CH3Si);
electrospray MS calcd for C101H128BrCl2N13O20Si2Na [M ‡ Na ] 2073, found
was stirred at
108C for 0.5 h at which time 2,6-lutidine (320 mL,
2.75 mmol) was added. After stirring for 0.5 h, the reaction was quenched
by the addition of saturated aqueous NaHCO3 (60 mL). The resulting
mixture was extracted with EtOAc (3 Â 50 mL) and the combined organic
extracts were washed with brine (50 mL), dried (Na2SO4), and concen-
trated in vacuo. Flash column chromatography of the residue (silica gel,
10% MeOH in CH2Cl2) afforded amine 71 (384 mg, 75%). 71: Rf ˆ 0.21
‡
2073. 5b: Rf ˆ 0.12 (silica gel, 50% EtOAc in hexanes); 1H NMR
(600 MHz, CD3OD, 330 K): d ˆ 7.23 ± 7.15 (m, 5H, ArH), 7.12 (d, J ˆ
8.3 Hz, 1H, ArH), 7.10 (d, J ˆ 1.8 Hz, 1H, ArH), 7.04 ± 7.00 (m, 4H), 6.91
(d, J ˆ 8.6 Hz, 2H, ArH), 6.83 (dd, J ˆ 8.5, 2.0 Hz, 1H, ArH), 6.79 ± 6.74 (m,
6H, ArH), 6.69 ± 6.65 (m, 2H, ArH), 6.51 (d, J ˆ 2.3 Hz, 1H, ArH), 6.41 (d,
J ˆ 2.3 Hz, 1H, ArH), 5.94 (s, 1H, ArH), 5.79 (br.s, 1H), 5.54 (s, 1H), 5.42
(s, 1H), 5.35 5.30 (m, 2H), 5.11 ± 5.10 (m, 1H), 4.80 ± 4.70 (m, 3H), 4.67
(d, J ˆ 3.3 Hz, 1H), 4.52 ± 4.50 (m, 2H), 4.38 ± 4.32 (m, 2H), 4.04 (br.s, 2H),
3.86 (br.s, 2H), 3.73 (s, 3H, OCH3), 3.70 (s, 6H, OCH3), 3.72 ± 3.68 (m, 2H),
3.51 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 2.78 (s, 3H, NCH3), 2.42 ± 2.39 (m,
2H), 1.98 (br.s, 4H), 1.41 (s, 9H, tBuO), 1.18 ± 1.14 (m, 3H), 0.89 ± 0.82 (m,
9H), 0.80 (s, 9H, tBuSi), 0.76 (s, 9H, tBuSi), 0.02 (s, 3H, CH3Si), 0.02 (s,
3H, CH3Si), 0.10 (s, 3H, CH3Si), 0.24 (s, 3H, CH3Si); electrospray MS
(silica gel, 80% EtOAc in hexanes); [a]D22
ˆ
27.4 (c ˆ 1.6, MeOH); IR
1
(thin film): nÄmax ˆ 3347, 2957, 1733, 1661, 1514, 1552, 1091, 1030 cm
;
1H NMR (600 MHz, CDCl3): d ˆ 7.47 (d, J ˆ 9.5 Hz, 1H, NH), 7.30 (d, J ˆ
8.5 Hz, 2H, H-5b), 7.17 (d, J ˆ 2.0 Hz, 1H, H-6b), 6.97 (dd, J ˆ 8.5, 2.0 Hz,
1H, H-6f), 6.89 (d, J ˆ 8.5 Hz, 2H, H-5c), 6.84 (d, J ˆ 8.5 Hz, 1H, H-6e),
5.23 (d, J ˆ 2.0 Hz, 1H, H-6b), 4.59 (dd, J ˆ 9.5, 2.0 Hz, 1H, H-6a), 4.42 (s,
1H, H-5a), 4.22 ± 4.18 (m, 1H, OCHHCH3), 4.14 ± 4.10 (m, 1H,
OCHHCH3), 3.80 (s, 3H, OCH3), 1.26 (t, J ˆ 7.0 Hz, 3H, OCH2CH3),
0.86 (s, 9H, tBuSi), 0.03 (s, 3H, CH3Si), 0.20 (s, 3H, CH3Si); 13C NMR
(150 MHz, CDCl3): d ˆ 174.0, 170.7, 160.3, 151.8, 134.8, 133.7, 129.3, 127.5,
126.7, 120.4, 116.9, 115.2, 74.2, 62.5, 60.1, 59.8, 56.1, 26.4, 18.8, 14.9, 3.8,
‡
calcd for C101H128BrCl2N13O20Si2Na [M ‡ Na ] 2073, found 2073.
‡
4.8; HRMS (FAB) calcd for C26H37N2O6SiClCs [M ‡ Cs ] 669.1164,
Carboxylic acid 68: To a solution of amino acid 29 (8.80 g, 0.030 mol) in
THF/H2O (1:1, 150 mL) at 08C was added anhydrous LiOH (1.08 g,
0.045 mol). The resulting mixture was stirred at 08C for 0.5 h before it was
quenched by the addition of saturated aqueous citric acid (150 mL). The
aqueous phase was extracted with EtOAc (3 Â 200 mL) and the combined
organic extracts were washed with H2O (50 mL), brine (100 mL), dried
(Na2SO4), and concentrated in vacuo to afford crude carboxylic acid 68
(8.45 g, 99%), which was used in the next step without further purification.
found 669.1148.
Tripeptide 72: A solution of carboxylic acid 12 (320 mg, 0.630 mmol) and
amine 71 (368 mg, 0.686 mmol) in THF (25 mL) at 108C was sequentially
treated with HOAt (284 mg, 2.08 mmol) and EDC (363 mg, 1.89 mmol).
The resulting mixture was stirred at 108C for 2 h before it was quenched
by the addition of H2O (40 mL). The aqueous phase was extracted with
EtOAc (3 Â 50 mL) and the combined organic extracts were washed with
saturated aqueous NH4Cl (40 mL), saturated aqueous NaHCO3 (40 mL),
brine (40 mL), dried (Na2SO4), and concentrated in vacuo. Flash column
chromatography of the residue (silica gel, 70% acetone in hexanes)
afforded tripeptide 72 (512 mg, 79%). 72: Rf ˆ 0.43 (silica gel, 30% EtOAc
Phenol 69: A solution of carboxylic acid 68 (911 mg, 3.23 mmol) and amine
35 (1.0 g, 2.95 mmol) in DMF (30 mL) at 208C was sequentially treated
with HOBt (1.49 g, 9.73 mmol) and EDC (3.0 mg, 8.85 mmol). The
resulting mixture was stirred at 08C for 12 h before it was quenched by
the addition of saturated aqueous citric acid (60 mL). The aqueous phase
was extracted with EtOAc (3 Â 75 mL) and the combined organic extracts
were washed with H2O (50 mL), brine (50 mL), dried (Na2SO4), and
concentrated in vacuo. Flash column chromatography of the residue (silica
gel, 0 !50% EtOAc in hexanes, gradient elution) afforded phenol 69
in benzene); [a]D22
2930, 1668, 1514, 1417, 1253, 1094, 1029 cm
ˆ
43.2 (c ˆ 0.63, MeOH); IR (thin film): nÄmax ˆ 3321,
1
;
1H NMR (500 MHz,
CD3COCD3): d ˆ 8.72 (s, 1H, OH), 8.05 (br.s, 1H, NH), 7.70 (s, 2H,
H-4b), 7.46 (d, J ˆ 9.5 Hz, 1H, NH), 7.25 (s, 1H, H-6b), 7.21 (d, J ˆ 9.0 Hz,
2H, H-5b), 6.89 ± 6.82 (m, 3H, H-5c and H-6f), 6.75 (d, J ˆ 8.5 Hz, 1H,
H-6e), 6.63 (br.s, 1H, NH), 5.56 (d, J ˆ 8.0 Hz, 1H, H-5a), 5.37 (br.s, 1H,
H-4a), 5.24 (d, J ˆ 3.0 Hz, 1H, H-6b), 4.55 (dd, J ˆ 9.5, 3.0 Hz, 1H, H-6a),
4.18 ± 4.05 (m, 2H, OCH2CH3), 3.91 ± 3.86 (br.s, 2H, NCH2), 3.80 (s, 3H,
OCH3), 3.63 ± 3.58 (br.s, 2H, NCH2), 2.13 ± 2.02 (br.d, 4H, NCH2CH2), 1.36
(s, 9H, tBuO), 1.21 (t, J ˆ 7.5 Hz, 3H, OCH2CH3), 0.83 (s, 9H, tBuSi),
0.03 (s, 3H, CH3Si), 0.21 (s, 3H, CH3Si); 13C NMR (125 MHz, CD3CN):
d ˆ 170.3, 170.1, 169.3, 160.1, 155.6, 152.3, 148.5, 138.0, 134.1, 132.0, 130.7,
129.0, 128.8, 128.2, 126.5, 120.1, 116.8, 114.8, 80.2, 73.7, 62.3, 59.8, 57.3, 56.8,
55.7, 51.8, 47.2, 28.2, 25.7, 24.4, 23.9, 18.3, 14.2, 4.8, 5.5; HRMS (FAB)
(1.44 g, 81%). 69: Rf ˆ 0.15 (silica gel, 30% EtOAc in hexanes); [a]D22
ˆ
49.6 (c ˆ 1.2, MeOH); IR (thin film): nÄmax ˆ 3343, 2931, 1694, 1514, 1252,
1
1169, 1082, 1039 cm 1; H NMR (600 MHz, CD3COCD3): d ˆ 8.28 (s, 1H,
OH), 7.33 (d, J ˆ 8.5 Hz, 1H, NH), 7.26 (d, J ˆ 8.5 Hz, 2H, H-5b), 6.98 (d,
J ˆ 8.0 Hz, 2H, H-6b), 6.88 (d, J ˆ 8.0 Hz, 2H, H-5c), 6.64 (d, J ˆ 8.0 Hz,
2H, H-6c), 6.41 (br.s, 1H, NH), 5.27 ± 5.21 (m, 2H, H-5a and H-6b), 4.53
(dd, J ˆ 11.0, 2.0 Hz, 1H, H-6a), 4.21 ± 4.10 (m, 2H, OCH2CH3), 3.80 (s,
3H, OCH3), 1.39 (s, 9H, tBuO), 1.27 (t, J ˆ 7.0 Hz, 3H, OCH2CH3), 0.08 (s,
9H, tBuSi), 0.03 (s, 3H, CH3Si), 0.23 (s, 3H, CH3Si); 13C NMR
(150 MHz, CD3COCD3): d ˆ 170.7, 160.2, 157.7, 132.4, 129.7, 129.5, 128.9,
128.5, 128.5, 115.6, 114.6, 75.0, 61.9, 60.1, 58.3, 55.5, 28.5, 26.1, 18.6, 14.4,
‡
calcd for C43H59N6O9ClSiBr2Cs [M ‡ Cs ] 1157.1049, found 1157.1103.
C-O-D Ring System 73a and 73b: To a solution of tripeptide 72 (540 mg,
0.527 mmol), CuBr´ Me2S (294 mg, 1.43 mmol) and K2CO3 (192 mg,
1.39 mmol) in degassed MeCN (20 mL) at 258C was added pyridine
(106 mL, 1.31 mmol). The resulting mixture was refluxed for 0.5 h and then
it was cooled to 258C, diluted with EtOAc (40 mL) and quenched with
saturated aqueous NH4Cl (40 mL). The reaction mixture was stirred for
0.5 h and then extracted with EtOAc (3 Â 50 mL). The combined organic
extracts were washed with brine (40 mL) and dried (Na2SO4). The solvent
was removed in vacuo and flash column chromatography of the residue
(silica gel, 10 !30% acetone in hexanes, gradient elution) afforded C-O-D
ring system 73a (122 mg, 25%) and 73b (136 mg, 27%). 73a: Rf ˆ 0.12
(silica gel, 30% EtOAc in hexanes); [a]2D2 ˆ ‡19.5 (c ˆ 0.98, MeOH); IR
(thin film): nÄmax ˆ 3307, 2928, 1714, 1514, 1416, 1337, 1252, 1178, 1097,
‡
4.5, 5.3; HRMS (FAB) calcd for C31H46N2O8SiCs [M ‡ Cs ] 735.2078,
found 735.2063.
Chloride 70: A solution of phenol 69 (1.48 g, 2.46 mmol) in Et2O/CH2Cl2
(5:1, 30 mL) at 108C was treated with SO2Cl2 (0.25 mL, 2.50 mmol). The
resulting reaction mixture was stirred at 08C for 0.5 h and then quenched
with saturated aqueous NaHCO3 (60 mL). The mixture was then extracted
with EtOAc (3 Â 60 mL) and the combined organic extracts were washed
with brine (50 mL), dried (Na2SO4), and concentrated in vacuo. Flash
column chromatography of the residue (silica gel, 30% EtOAc in hexanes)
afforded chloride 70 (1.38 g, 88%). 70: Rf ˆ 0.15 (silica gel, 30% EtOAc in
hexanes); [a]2D2
ˆ
51.6 (c ˆ 0.68, MeOH); IR (thin film): nÄmax ˆ 3417, 2930,
1682, 1513, 1252, 1167, 1090, 1030 cm 1; 1H NMR (600 MHz, CD3COCD3):
d ˆ 8.66 (s, 1H, OH), 7.34 (s, 1H, H-6b), 7.28 ± 7.22 (m, 3H, H-5b and H-6f),
6.91 (s, 1H, NH), 6.88 (d, J ˆ 8.0 Hz, 2H, H-5c), 6.80 (d, J ˆ 7.0 Hz, 1H,
H-6e), 6.35 (br.s, 1H, NH), 5.27 (s, 1H, H-5a), 5.25 (d, J ˆ 7.0 Hz, 1H,
H-6b), 4.59 (dd, J ˆ 9.0, 2.0 Hz, 1H, H-6a), 4.25 ± 4.12 (m, 2H, OCH2CH3),
3.80 (s, 3H, OCH3), 1.39 (s, 9H, tBuO), 1.29 (t, J ˆ 7.0 Hz, 3H, OCH2CH3),
0.85 (s, 9H, tBuSi), 0.00 (s, 3H, CH3Si), 0.19 (s, 3H, CH3Si); 13C NMR
(150 MHz, CD3COCD3): d ˆ 171.2, 170.4, 160.2, 154.3, 153.1, 143.4, 134.2,
129.3, 128.6, 126.8, 120.5, 117.1, 114.7, 79.3, 74.3, 62.0, 59.9, 58.2, 55.5, 28.5,
26.0, 18.6, 14.4, 4.5, 5.3; HRMS (FAB) calcd for C31H53N2O8SiCl [M ‡
1
1030 cm 1; H NMR (600 MHz, CD3COCD3): d ˆ 7.53 (d, J ˆ 2.0 Hz, 1H,
H-6b), 7.44 ± 7.39 (m, 3H, H-4f and H-5b), 7.28 ± 7.18 (m, 2H, NH, H-6f),
7.14 (d, J ˆ 8.5 Hz, 1H, H-6e), 7.12 (s, 1H, H-4b), 7.02 (d, J ˆ 9.0 Hz, 2H,
H-5c), 6.38 (br.s, 1H, NH), 5.80 (d, J ˆ 9.0 Hz, 1H, NH), 5.46 (d, J ˆ 8.0 Hz,
1H, H-4a), 5.44 (d, J ˆ 2.0 Hz, 1H, H-6b), 5.31 ± 5.23 (br.s, 1H, H-5a), 4.46
(d, J ˆ 8.5 Hz, 1H, H-6a), 4.25-4.17 (m, 1H, OCHHCH3), 4.12 ± 4.04 (m,
1H, OCHHCH3), 3.96 ± 3.85 (br.s, 2H, NCH2), 3.82 (s, 3H, OCH3), 3.69 ±
3.61 (br.s, 2H, NCH2), 2.14 ± 2.03 (br.d, 4H, NCH2CH2), 1.37 (s, 9H,
tBuO), 1.27 (t, J ˆ 7.0 Hz, 3H, OCH2CH3), 0.77 (s, 9H, tBuSi), 0.03 (s,
3H, CH3Si), 0.14 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3COCD3): d ˆ
169.4, 168.7, 168.5, 160.9, 154.2, 152.5, 138.8, 132.3, 130.7, 129.5, 128.6, 128.0,
126.8, 126.7, 123.0, 119.0, 118.4, 115.3, 114.7, 114.5, 79.5, 74.4, 62.4, 61.0, 58.2,
57.7, 55.6, 51.6, 47.0, 28.5, 26.0, 24.5, 24.1, 18.4, 14.3, 4.3, 5.6; HRMS
‡
H ] 637.2712, found 637.2736.
Amine 71: Chloride 70 (583 mg, 0.915 mmol) was dissolved in CH2Cl2
(20 mL) and cooled to 108C. Trimethylsilyl trifluoromethanesulfonate
(550 mL, 3.04 mmol) was added dropwise over 5 min. The reaction mixture
2618
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 2
2602±2621
‡
(FAB) calcd for C43H56N6O9SiClBrCs [M ‡ Cs ] 1077.1790, found
gel, 30% EtOAc in hexanes) afforded TBS ether 77 (227 mg, 75%). 77:
1077.1759. 73b: Rf ˆ 0.21 (silica gel, 30% acetone in hexanes); [a]D22
ˆ
Rf ˆ 0.24 (silica gel, 45% EtOAc in hexanes); [a]D22
ˆ
23.6 (c ˆ 1.0,
11.5 (c ˆ 0.46, CH3OH); IR (thin film): nÄmax ˆ 3417, 2929, 1714, 1514,
1416, 1336, 1253, 1164, 1093, 1031 cm 1; 1H NMR (600 MHz, CD3CN): d ˆ
7.37 (dd, J ˆ 8.5, 2.0 Hz, 1H, H-6f), 7.34 (dd, J ˆ 2.0, 1.0 Hz, 1H, H-6b), 7.26
(d, J ˆ 8.5 Hz, 1H, H-6e), 7.22 (s, 1H, H-4f), 7.14 (br.s, 2H, H-5b), 7.01 (d,
J ˆ 8.5 Hz, 2H, H-5c), 6.83 (s, 1H, H-4b), 6.77 (d, J ˆ 4.5 Hz, 1H, NH), 5.92
(s, 1H, NH), 5.68 (d, J ˆ 9.0 Hz, 1H, NH), 5.42 (d, J ˆ 2.0 Hz, 1H, H-6b),
5.12 (d, J ˆ 4.5 Hz, 1H, H-5a), 5.00 (s, 1H, H-4a), 4.67 (s, 1H, H-6a), 4.22 ±
4.17 (m, 1H, OCHHCH3), 4.08-4.04 (m, 1H, OCHHCH3), 3.97 ± 3.90 (br.s,
2H, NCH2), 3.80 (s, 3H, OCH3), 3.72 ± 3.62 (br.s, 2H, NCH2), 2.12 ± 2.06
(br.s, 2H, NCH2CH2), 2.05 ± 1.98 (br.s, 2H, NCH2CH2), 1.39 (s, 9H, tBuO),
1.26, (t, J ˆ 7.0 Hz, 3H, OCH2CH3), 0.75 (s, 9H, tBuSi), 0.05 (s, 3H,
CH3Si), 0.18 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3CN): d ˆ 169.8,
169.4, 168.9, 161.0, 158.4, 152.3, 151.8, 140.3, 130.3, 129.8, 128.2, 128.0, 127.1,
126.5, 125.2, 119.7, 119.1, 117.2, 115.2, 114.8, 74.9, 73.8, 62.7, 60.5, 59.1, 58.6,
55.9, 51.8, 47.1, 28.3, 25.8, 25.6, 24.1, 18.3, 14.1, 4.9, 5.3; HRMS (FAB)
MeOH); IR (thin film): nÄmax ˆ 3306, 2931, 1738, 1714, 1514, 1455, 1372,
1250, 1176, 1091, 1037 cm 1; 1H NMR (500 MHz, CD3COCD3): d ˆ 7.96 (d,
J ˆ 8.5 Hz, 1H, NH), 7.55 (d, J ˆ 8.0 Hz, 1H, NH), 7.47 (d, J ˆ 7.5 Hz, 2H,
H-2b), 7.39 ± 7.29 (m, 5H, ArH), 7.20 ± 7.10 (m, 4H, ArH), 6.95 (d, J ˆ
8.5 Hz, 2H, H-2c), 6.86 (d, J ˆ 9.0 Hz, 4H, ArH), 6.11 (d, J ˆ 8.5 Hz, 1H,
CHAr2), 5.59 (d, J ˆ 8.5 Hz, 1H, H-2b), 5.15 (d, J ˆ 6.0 Hz, 1H, NH), 5.06
(s, 2H, CH2Ph), 4.82 ± 4.74 (m, 1H, H-3a), 4.38 ± 4.29 (m, 1H, H-2a), 3.76
(s, 6H, OCH3), 3.54 (s, 3H, COOCH3), 2.90 ± 2.82 (m, 1H, H-3b), 2.73 (dd,
J ˆ 16.0, 5.5 Hz, 1H, H-3b), 1.33 (s, 9H, tBuO), 0.87 (s, 9H, tBuSi), 0.06 (s,
3H, CH3Si), 0.11 (s, 3H, CH3Si); 13C NMR (125 MHz, CD3COCD3): d ˆ
171.7, 169.6, 169.1, 159.4, 159.3, 159.1, 155.5, 138.1, 135.3, 135.2, 133.5, 129.2,
129.0, 129.0, 128.9, 128.7, 128.3, 128.2, 114.8, 114.3, 114.2, 79.1, 74.8, 70.2,
61.8, 56.0, 55.3, 52.1, 49.5, 37.6, 28.2, 26.0, 18.4, 4.9, 5.1; HRMS (FAB)
‡
calcd for C47H61N3O10SiCs [M ‡ Cs ] 988.3157, found 988.3181.
Phenol 78: To a solution of TBS ether 77 (219 mg, 0.256 mmol) in ethanol
(5 mL) was added 10% Pd(OH)2/C (20 mg). The suspension was placed
under a H2 atmosphere. After stirring for 16 h, the reaction mixture was
filtered through celite and concentrated in vacuo. Flash column chroma-
tography of the residue (silica gel, 50% EtOAc in hexanes) afforded
phenol 78 (195 mg, 99%). 78: Rf ˆ 0.40 (silica gel, 50% EtOAc in hexanes);
‡
calcd for C43H56N6O9SiClBrCs [M ‡ Cs ] 1077.3030, found 1077.3067.
Alcohol 74: To a solution of amine 14 (230 mg, 0.73 mmol) in CH2Cl2
(7.3 mL) at 08C was added triethylamine (0.13 mL, 0.95 mmol) and Boc2O
(183 mg, 0.84 mmol). The reaction mixture was stirred for 5 h and
concentrated in vacuo. Flash column chromatography of the residue (silica
gel, 30% EtOAc in hexanes) afforded alcohol 74 (300 mg, 93%). 74: Rf ˆ
[a]2D2
ˆ
23.2 (c ˆ 1.2, MeOH); IR (thin film): nÄmax ˆ 3310, 1650, 1513, 1248,
0.33 (silica gel, 30% EtOAc in hexanes); [a]D22
(thin film): nÄmax ˆ 3347, 1733, 1667, 1513, 1257, 1091, 1030 cm
ˆ
62.4 (c ˆ 1.0, CHCl3); IR
1093 cm 1; 1H NMR (500 MHz, CD3COCD3): d ˆ 8.29 (s, 1H, OH), 7.94 (d,
J ˆ 7.5 Hz, 1H, NH), 7.54 (d, J ˆ 7.5 Hz, 1H, NH), 7.23 (d, J ˆ 8.0 Hz, 2H,
ArH), 7.20 ± 7.14 (m, 4H, ArH), 6.87 (d, J ˆ 8.5 Hz, 4H, ArH), 6.78 (d, J ˆ
8.5 Hz, 2H, ArH), 6.10 (d, J ˆ 8.5 Hz, 1H, CHAr2), 5.54 (d, J ˆ 9.0 Hz, 1H,
H-2b), 5.11 (d, J ˆ 5.5 Hz, 1H, NH), 4.82 ± 4.76 (m, 1H, H-2a), 4.33 ± 4.27
(m, 1H, H-3a), 3.76 (s, 6H, OCH3), 3.57 (s, 3H, COOCH3), 2.88 (dd, J ˆ
14.5, 3.0 Hz, 1H, H-3b), 2.73 (dd, J ˆ 14.5, 5.5 Hz, 1H, H-3b), 1.32 (s, 9H,
tBuO), 0.84 (s, 9H, tBuSi), 0.04 (s, 3H, CH3Si), 0.12 (s, 3H, CH3Si);
13C NMR (125 MHz, CD3COCD3): d ˆ 171.7, 169.7, 169.0, 159.4, 159.3,
157.5, 155.5, 135.3, 135.2, 131.9, 129.2, 129.0, 128.3, 115.4, 114.2, 114.2, 79.1,
74.6, 61.9, 56.0, 55.2, 49.4, 37.6, 28.2, 25.9, 19.2, 4.9, 5.2; HRMS (FAB)
1
;
1H NMR
(500 MHz, CDCl3): d ˆ 7.35-7.24 (m, 4H, ArH), 7.32-7.30 (m, 1H, ArH),
7.18 (d, J ˆ 8.5 Hz, 2H, H-2b), 6.92 (d, J ˆ 8.0 Hz, 2H, H-2c), 5.28 (bd, J ˆ
7.5 Hz, 1H, H-2b), 5.13 (br.s, 1H, NH), 5.04 (s, 2H, CH2Ph), 4.65 ± 4.63 (m,
1H, H-2a), 4.14 (q, J ˆ 7.0 Hz, 2H, OCH2CH3), 3.94 (br.s, 1H, OH), 1.42 (s,
9H, tBuO), 1.19 (t, J ˆ 7.5 Hz, 3H, OCH2CH3); 13C NMR (125 MHz,
CDCl3): d ˆ 169.8, 158.7, 156.3, 136.8, 131.6, 128.6, 128.5, 127.4, 127.3, 114.5,
80.5, 74.7, 69.9, 61.6, 59.6, 28.2, 14.0; HRMS (FAB) calcd for C23H29NO5Na
‡
[M ‡ Na ] 438.1897, found 438.1904.
Carboxylic acid 75: A solution of alcohol 74 (3.34 g, 8.03 mmol) in THF/
H2O (1:1, 50 mL) at 08C was treated with anhydrous LiOH (385 mg,
16.2 mmol). The resulting mixture was stirred for 1 h before it was acidified
to pH 3 by the addition of saturated aqueous KHSO4. The aqueous phase
was extracted with EtOAc (3 Â 150 mL) and the combined organic extracts
were washed with brine (75 mL), dried (Na2SO4) and concentrated in vacuo
to afford crude carboxylic acid 75 (3.00 g, 96%), which was taken into the
next step without further purification.
‡
calcd for C40H55N3O10SiCs [M ‡ Cs ] 898.2711, found 898.2732.
Chloride 79: A solution of phenol 78 (244 mg, 0.318 mmol) in Et2O/CH2Cl2
(5:1, 6 mL) at 08C was treated dropwise with SO2Cl2 (40 mL, 0.400 mmol).
The resulting solution was stirred for 0.5 h before it was quenched by the
addition of saturated aqueous NaHCO3 (20 mL). The aqueous phase was
extracted with EtOAc (3 Â 50 mL) and the combined organic extracts were
washed with brine (40 mL), dried (Na2SO4), and concentrated in vacuo.
Flash column chromatography of the residue (silica gel, 2% MeOH in
CH2Cl2) afforded chloride 79 (232 mg, 91%). 79: Rf ˆ 0.42 (silica gel, 50%
Dipeptide 76: A solution of acid 75 (1.90 g, 5.14 mmol) and amine 13
(1.60 g, 4.28 mmol) in THF (45 mL) at 208C was sequentially treated with
HOBt (1.91 g, 14.1 mmol) and EDC (2.44 mg, 12.8 mmol). The resulting
mixture was stirred at 08C for 4 h before it was quenched by the addition of
saturated aqueous NH4Cl (90 mL). The aqueous phase was extracted with
EtOAc (3 Â 125 mL) and the combined organic extracts were washed with
H2O (75 mL), brine (75 mL), dried (Na2SO4), and concentrated in vacuo.
Flash column chromatography of the residue (silica gel, 20 !70% EtOAc
in hexanes, gradient elution) afforded dipeptide 76 (2.03 g, 65%). 76: Rf ˆ
EtOAc in hexanes); [a]D22
3316, 2930, 1742, 1667, 1514, 1250, 1176, 1092, 1036 cm
ˆ
26.4 (c ˆ 0.89, MeOH); IR (thin film): nÄmax
ˆ
1
;
1H NMR
(500 MHz, CD3COCD3): d ˆ 8.72 (s, 1H, OH), 7.96 (d, J ˆ 8.0 Hz, 1H,
NH), 7.66 (d, J ˆ 8.0 Hz, 1H, NH), 7.39 (s, 1H, H-2b), 7.21 ± 7.14 (m, 5H,
ArH), 6.95 (d, J ˆ 8.5 Hz, 1H, H-2e), 6.87 (d, J ˆ 8.5 Hz, 4H, ArH), 6.11 (d,
J ˆ 8.0 Hz, 1H, CHAr2), 5.72 (d, J ˆ 8.5 Hz, 1H, H-2b), 5.06 (d, J ˆ 5.5 Hz,
1H, NH), 4.83 ± 4.78 (m, 1H, H-2a), 4.34 ± 4.29 (m, 1H, H-3a), 3.76 (s, 6H,
OCH3), 3.57 (s, 3H, COOCH3), 2.93-2.89 (m, 1H, H-3b), 2.75 (dd, J ˆ 15.5,
5.5 Hz, 1H, H-3b), 1.31 (s, 9H, tBuO), 0.85 (s, 9H, tBuSi), 0.04 (s, 3H,
CH3Si), 0.11 (s, 3H, CH3Si); 13C NMR (125 MHz, CD3COCD3): d ˆ
172.1, 170.1, 169.4, 159.8, 159.7, 155.9, 153.4, 135.7, 134.3, 129.6, 129.4,
0.25 (silica gel, 70% EtOAc in hexanes); [a]D22
ˆ
3.98 (c ˆ 0.93, MeOH);
1
IR (thin film): nÄmax ˆ 3323, 2953, 1737, 1657, 1511, 1247, 1175, 1033 cm
;
1H NMR (600 MHz, CD3SOCD3): d ˆ 8.77 (d, J ˆ 8.5 Hz, 1H, NH), 8.28 (d,
J ˆ 8.0 Hz, 1H, NH), 7.40 ± 7.27 (m, 5H, ArH), 7.23 (d, J ˆ 8.5 Hz, 2H,
ArH), 7.12 (d, J ˆ 7.5 Hz, 4H, ArH), 6.89 (d, J ˆ 8.5 Hz, 2H, ArH), 6.85 (d,
J ˆ 8.5 Hz, 4H, ArH), 6.57 (d, J ˆ 9.5 Hz, 1H, NH), 5.96 (d, J ˆ 8.5 Hz, 1H,
CHAr2), 5.43 (d, J ˆ 5.0 Hz, 1H, H-2b), 5.04 (s, 2H, CH2Ph), 4.69 ± 4.64 (m,
1H, OH), 4.59 (dd, J ˆ 8.5, 5.0 Hz, 1H, H-2a), 4.09 ± 4.02 (m, 1H, H-3a),
3.69 (s, 6H, OCH3), 3.53 (s, 3H, COOCH3), 2.70 (dd, J ˆ 15.5, 7.0 Hz, 1H,
H-3b), 2.58 (dd, J ˆ 15.5, 5.0 Hz, 1H, H-3b), 1.20 (s, 9H, tBuO); 13C NMR
(150 MHz, CD3SOCD3): d ˆ 172.9, 171.7, 169.4, 159.4, 159.4, 158.8, 156.0,
138.5, 136.0, 135.9, 129.7, 129.6, 129.5, 129.0, 128.6, 115.2, 115.0, 114.9, 79.2,
73.5, 70.4, 60.9, 56.4, 56.0, 53.2, 50.1, 38.4, 29.3; HRMS (FAB) calcd for
127.7, 120.7, 114.6, 79.5, 74.8, 62.0, 56,4, 55,6, 52.5, 49.9, 38.0, 28.5, 26.3, 18.8,
‡
4.5,
4.7; HRMS (FAB) calcd for C40H54N3O10SiClCs [M ‡ Cs ]
932.2321, found 932.2344.
Carboxylic acid 80: A solution of chloride 79 (132 mg, 0.165 mmol) in
tBuOH/H2O (4:1, 10 mL) was cooled to 58C and the resulting slurry was
treated with a solution of LiOH monohydrate (9 mg, 0.214 mmol) in H2O
(1 mL). The mixture was warmed to 108C and stirred for 1 h. The reaction
was quenched with 1% aqueous HCl (1 mL), diluted with H2O (10 mL),
and extracted with EtOAc (3 Â 50 mL). The combined organic extracts
were washed with brine (25 mL), dried (Na2SO4), and the solvent was
removed in vacuo. Flash column chromatography of the residue (silica gel,
10% MeOH in CH2Cl2) afforded carboxylic acid 80 (98 mg, 76%). 80: Rf ˆ
‡
C41H47N3O10Cs [M ‡ Cs ] 874.2316, found 874.2345.
TBS ether 77: A solution of dipeptide 76 (263 mg, 0.361 mmol) in DMF
(5 mL) was treated with TBSCl (200 mg, 1.33 mmol) and imidazole (200mg,
2.94 mmol) at 258C. The resulting mixture was stirred for 24 h. The reaction
was quenched by the addition of saturated aqueous NH4Cl (40 mL) and the
resulting mixture was extracted with EtOAc (3 Â 50 mL) and the combined
organic extracts were washed with brine (30 mL), dried (Na2SO4), and
concentrated in vacuo. Flash column chromatography of the residue (silica
0.08 (silica gel, 10% MeOH in CH2Cl2); [a]D22
ˆ
21.7 (c ˆ 1.2, MeOH); IR
(thin film): nÄmax ˆ 3362, 2930, 1660, 1513, 1249, 1176, 1093 cm 1; H NMR
(600 MHz, CD3OD): d ˆ 7.30 (s, 1H, H-2b), 7.13 (d, J ˆ 6.0 Hz, 4H, ArH),
7.10 (d, J ˆ 8.0 Hz, 1H, H-2f), 6.87 ± 6.81 (m, 5H, ArH), 6.41 (d, J ˆ 9.5 Hz,
1H, CHAr2), 6.05 (br.s, 1H, H-2b), 4.92 (d, J ˆ 6.0 Hz, 1H, NH), 4.62 (br.s,
1
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2619 $ 17.50+.50/0
2619

K. C. Nicolaou et al.
FULL PAPER
1H, H-2a), 4.23 ± 4.19 (m, 1H, H-3a), 3.75 (s, 6H, OCH3), 2.82 ± 2.71 (br.s,
2H, H-3b), 1.31 (s, 9H, tBuO), 0.82 (s, 9H, tBuSi), 0.02 (s, 3H, CH3Si),
0.15 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3OD): d ˆ 171.0, 160.0,
159.7, 159.7, 156.6, 156.1, 153.6, 135.0, 134.9, 133.6, 129.3, 129.2, 127.3, 120.7,
116.6, 114.2, 80.0, 75.0, 62.0, 56.5, 55.1, 49.3, 39.0, 28.1, 25.8, 18.5, 5.1,
C-O-D/D-O-E System 83: To a solution of pentapeptide 82 (8.0 mg,
0.005 mmol), CuBr´ Me2S (5.7 mg, 0.028 mmol) and K2CO3 (4.0 mg,
0.29 mmol) in degassed MeCN (0.6 mL) at 258C was added pyridine
(2 mL, 0.026 mmol). The resulting mixture was refluxed for 2 h. The
reaction mixture was cooled to 258C, diluted with EtOAc (10 mL) and
quenched with saturated aqueous NH4Cl (5 mL). The mixture was stirred
for 0.5 h and then the aqueous phase was extracted with EtOAc (3 Â
10 mL). The combined organic extracts were washed with brine (40 mL),
dried (MgSO4), and filtered through a pad of silica gel. The solvent was
removed in vacuo and the residue was purified by preparative TLC (silica
gel, 40% acetone in hexanes) to afforded C-O-D/D-O-E system 83 (3.0 mg,
‡
5.3; HRMS (FAB) calcd for C39H52N3O10SiClCs [M ‡ Cs ] 918.2165,
found 918.2143.
Amine 81: To a solution of compound 73a (12.8 mg, 0.0136 mmol) in
CH2Cl2 (4 mL) at 208C was added trimethylsilyl trifluoromethanesulfo-
nate (25 mL, 0.138 mmol). The reaction mixture was stirred at 208C for
1 h. 2,6-Lutidine (25 mL, 0.215 mmol) was then added and the reaction
mixture was stirred for an additional 20 min. The reaction was then
quenched by the addition of saturated aqueous NaHCO3 (10 mL). The
aqueous phase was extracted with EtOAc (3 Â 30 mL) and the combined
organic extracts were washed sequentially with saturated aqueous NaH-
CO3 (10 mL), brine (10 mL), and dried (Na2SO4). The solvent was removed
in vacuo and the resulting residue was purified by flash column
chromatography (silica gel, EtOAc) to afford amine 81 (9.1 mg, 80%).
40%). 83: Rf ˆ 0.40 (silica gel, 40% acetone in hexanes); [a]D22
ˆ
43.2 (c ˆ
0.25, MeCN); IR (thin film): nÄmax ˆ 3402, 2926, 1668, 1513, 1350, 1251,
1097 cm 1; 1H NMR (600 MHz, CD3CN, 310 K): d ˆ 7.54 (s, 1H, H-2b), 7.48
(s, 1H, H-6b), 7.39 ± 7.36 (m, 1H, NH), 7.33 ± 7.28 (m, 3H, NH and H-5b),
7.17 (s, 2H, H-2f and H-4f), 7.08 ± 7.03 (m, 6H, H-6f, ArH and NH), 6.99 (d,
J ˆ 8.5 Hz, 2H, H-5c), 6.89 (d, J ˆ 8.0 Hz, 1H, NH), 6.85 (d, J ˆ 8.5 Hz, 1H,
H-6e), 6.82 ± 6.77 (m, 5H, H-2e and ArH), 6.61 (s, 1H, H-4b), 5.88 (d, J ˆ
7.5 Hz, 1H, CHAr2), 5.75 (d, J ˆ 8.5 Hz, 1H, NH), 5.71 (s, 1H, H-2b), 5.42
(s, 1H, H-6b), 5.40 (d, J ˆ 8.5 Hz, 1H, H-4a), 5.30 (d, J ˆ 8.0 Hz, 1H,
H-5a), 4.63 ± 4.59 (m, 2H, H-2a and H-3a), 4.54 (d, J ˆ 7.0 Hz, 1H, H-6a),
4.20 ± 4.13 (m, 1H, OCHHCH3), 4.07 ± 4.01 (m, 1H, OCHHCH3), 3.81 (s,
3H, 5-OCH3), 3.80 ± 3.74 (br.s, 4H, NCH2), 3.73 (s, 3H, OCH3), 3.73 (s, 3H,
OCH3), 2.67 ± 2.63 (m, 1H, H-3b), 2.42 (dd, J ˆ 16.0, 6.0 Hz, 1H, H-3b),
2.08-2.05 (br.s, 4H, NCH2CH2), 1.39 (s, 9H, tBuO), 1.23 (t, J ˆ 7.0 Hz, 3H,
OCH2CH3), 0.91 (s, 9H, tBuSi), 0.83 (s, 9H, tBuSi), 0.13 (s, 3H, CH3Si), 0.01
(s, 3H, CH3Si), 0.02 (s, 3H, CH3Si), 0.09 (s, 3H, CH3Si); 13C NMR
(150 MHz, CD3CN): d ˆ 174.6, 171.5, 170.0, 169.5, 169.3, 168.6, 160.9, 159.6,
159.5, 157.7, 152.5, 152.2, 151.5, 151.3, 140.1, 135.2, 135.1, 134.5, 131.6, 130.6,
130.5, 129.9, 129.3, 129.0, 128.5, 127.8, 127.4, 125.9, 125.6, 120.3, 119.6, 116.9,
115.5, 114.6, 114.5, 108.5, 79.7, 74.0, 73.4, 62.6, 62.0, 60.9, 60.9, 57.8, 56.9,
81: Rf ˆ 0.36 (silica gel, EtOAc); [a]2D2 ˆ ‡36.9 (c ˆ 0.55, MeCN); IR (thin
1
film): nÄmax ˆ 3418, 2926, 1770, 1668, 1514, 1417, 1336, 1250, 1099 cm
;
1H NMR (600 MHz, CD3CN): d ˆ 7.69 (br.s, 1H, NH), 7.47 (d, J ˆ 2.0 Hz,
1H, H-6b), 7.34 (d, J ˆ 2.0 Hz, 1H, H-4f), 7.01 (d, J ˆ 8.5 Hz, 1H, H-6f),
6.91 (d, J ˆ 9.0 Hz, 2H, H-5b), 6.87 ± 6.84 (m, 3H, H-5c and H-6e), 6.82 (d,
J ˆ 2.0 Hz, 1H, H-4b), 5.72 (d, J ˆ 10.0 Hz, 1H, NH), 5.37 (d, J ˆ 2.0 Hz,
1H, H-6b), 4.96 (d, J ˆ 3.0 Hz, 1H, H-5a), 4.77 (dd, J ˆ 10.0, 2.0 Hz, 1H,
H-6a), 4.25 (s, 1H, H-4a), 4.25 ± 4.18 (m, 1H, OCHHCH3), 4.09-4.04 (m,
1H, OCHHCH3), 3.94 ± 3.84 (br.s, 2H, NCH2), 3.77 (s, 3H, OCH3), 3.69 ±
3.62 (br.s, 2H, NCH2), 2.10 ± 1.96 (br.d, 4H, NCH2CH2), 1.27, (t, J ˆ 7.0 Hz,
3H, OCH2CH3), 0.71 (s, 9H, tBuSi), 0.06 (s, 3H, CH3Si), 0.25 (s, 3H,
CH3Si); 13C NMR (150 MHz, CD3CN): d ˆ 176.7, 170.0, 169.4, 160.8, 154.3,
153.9, 138.6, 134.2, 130.0, 128.8, 128.5, 128.4, 126.9, 123.8, 119.4, 118.7, 117.5,
114.7, 110.1, 73.6, 62.6, 61.5, 60.1, 58.6, 55.7, 47.2, 40.7, 30.1, 29.8, 25.7, 18.2,
55.9, 55.7, 54.0, 51.6, 38.3, 28.5, 26.0, 25.9, 24.2, 18.7, 18.4, 14.1, 4.3, 4.9,
‡
5.1,
5.7; HRMS (FAB) calcd for C77H97N9O16Si2Cl2Cs [M ‡ Cs ]
‡
1662.5023, found 1662.5108.
14.1, 4.5, 5.7; HRMS (FAB) calcd for C38H48N6O7SiClBrCs [M ‡ Cs ]
975.1280, found 975.1256.
Pentapeptide 82: A solution of amine 81 (7.0 mg, 0.0083 mmol) and
carboxylic acid 80 (5.0 mg, 0.0064 mmol) in THF (0.3 mL) at 158C was
stirred for 15 min before the addition of HOAt (9.8 mg, 0.071 mmol). After
5 min EDC (3.0 mg, 0.016 mmol) was added and stirring was continued for
an additional 2 h while the temperature was raised to 08C. The reaction was
quenched by the addition of H2O (5 mL) and diluted with EtOAc (5 mL).
The mixture was extracted with EtOAc (3 Â 10 mL) and the combined
organic extracts were washed with brine (5 mL), dried (Na2SO4) and the
solvent was removed in vacuo. The resulting residue was purified by flash
column chromatography (silica gel, 40% EtOAc in benzene) to afford
pentapeptide 82 (8.3 mg, 81%). 82: Rf ˆ 0.21 (silica gel, 5% MeOH in
Acknowledgments
We thank Drs. D. H. Huang and G. Suizdak for NMR spectroscopic and
mass spectrometric assistance, respectively. This work was financially
supported by the National Institutes of Health, USA (AI-38893), The
Skaggs Institute for Chemical Biology, postdoctoral fellowships from the
National Institutes of Health, USA (to J. M. R.), the NATO/DAAD (to S.
B.), and grants from Pfizer, Schering Plough, Hoffmann La Roche, Merck,
the George Hewitt Foundation, Abbott Laboratories, Boehringer Ingel-
heim, and Glaxo.
CH2Cl2); [a]2D2 ˆ ‡5.54 (c ˆ 0.83, MeCN); IR (thin film): nÄmax ˆ 3318, 2928,
1
1663, 1513, 1415, 1250, 1177, 1098, 1032 cm
;
1H NMR (600 MHz,
CD3CN): d ˆ 7.49 (s, 1H, NH), 7.47-7.44 (br.s, 1H, NH), 7.41 (dd, J ˆ 1.5,
0.5 Hz, 1H, H-6b), 7.37 (br.s, 1H, OH), 7.31 (d, J ˆ 2.0 Hz, 1H, H-4f), 7.24
(d, J ˆ 8.5 Hz, 2H, H-5b), 7.20 ± 7.16 (m, 3H, H-2b, H-6f and NH), 7.09 ±
7.05 (m, 5H, H-6e and ArH), 7.02 ± 6.98 (m, 3H, H-4b and H-5c), 6.96 (d,
J ˆ 8.0 Hz, 1H, H-2f), 6.83 (d, J ˆ 12.0 Hz, 2H, ArH), 6.80 ± 6.75 (m, 3H,
H-2e and ArH), 6.67 (d, J ˆ 7.5 Hz, 1H, NH), 5.94 (d, J ˆ 8.0 Hz, 1H,
CHAr2), 5.76 (d, J ˆ 9.0 Hz, 1H, NH), 5.42 (d, J ˆ 7.5 Hz, 1H, H-5a), 5.37
(d, J ˆ 1.5 Hz, 1H, H-6b), 5.28 (d, J ˆ 7.0 Hz, 1H, H-4a), 5.21 (br.s, 1H,
H-2b), 4.96 (br.s, 1H, NH), 4.67 ± 4.61 (m, 1H, H-3a), 4.51 (d, J ˆ 9.5 Hz,
1H, H-6a), 4.21 ± 4.16 (m, 2H, H-2a and OCHHCH3), 4.09 ± 4.02 (m, 1H,
OCHHCH3), 3.95 ± 3.87 (br.s, 2H, NCH2), 3.80 (s, 3H, 5-OCH3), 3.74 (s,
3H, OCH3), 3.69 (s, 3H, OCH3), 3.67 ± 3.61 (br.s, 2H, NCH2), 2.75 ± 2.69
(m, 1H, H-3b), 2.58 ± 2.53 (m, 1H, H-3b), 2.17 ± 2.09 (bd, 4H, NCH2CH2),
1.23 (s, 9H, tBuO), 1.20 (t, J ˆ 7.0 Hz, 3H, OCH2CH3), 0.82 (s, 9H, tBuSi),
0.76 (s, 9H, tBuSi), 0.00 (s, 3H, CH3Si), -0.05 (s, 3H, CH3Si), 0.15 (s, 3H,
CH3Si), 0.17 (s, 3H, CH3Si); 13C NMR (150 MHz, CD3CN): d ˆ 171.3,
170.8, 170.1, 169.3, 169.1, 168.1, 161.0, 159.6, 159.5, 157.5, 153.6, 152.9, 152.5,
141.6, 139.1, 137.1, 135.2, 135.2, 134.2, 130.9, 129.8, 129.2, 129.2, 129.1, 127.1,
127.0, 126.6, 123.1, 120.7, 119.6, 119.3, 119.0, 117.7, 117.6, 115.4, 114.6, 113.1,
112.1, 80.0, 74.3, 74.2, 62.7, 61.1, 60.8, 58.3, 56.5, 56.1, 55.9, 55.7, 55.6, 51.9,
51.1, 47.2, 37.5, 28.3, 25.9, 25.8, 24.5, 24.1, 18.6, 18.3, 14.4, 4.4, 4.8, 5.0,
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found 1742.4194.
2620
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0947-6539/99/0509-2620 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 2
2602±2621
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Received: March 29, 1999 [F 1706]
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2621 $ 17.50+.50/0
2621