Total synthesis of vancomycin - Part 1: Design and development of methodology

Article abstract of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2584::AID-CHEM2584>3.0.CO;2-B

o-Halosubstituted aromatic triazenes (e.g. I, Scheme 1) react with aryloxides (e.g. II, Scheme 1) in the presence of CuBr · Me₂S, K₂CO₃ and pyridine in acetonitrile at reflux to afford biaryl ethers (e.g. V, Scheme 1). This general methodology (Tables 1 and 2) was applied to the construction of the C-O-D and D-O-E vancomycin model systems 37 (Scheme 2) and 50 (Scheme 3), demonstrating its potential in a projected total synthesis of vancomycin (1. Figure 1). For the construction of the vancomycin model AB biaryl ring system, a sequential strategy involving a Suzuki coupling of the C-O-D aryl iodide 74 (Scheme 7) and boronic acid 53 (Scheme 4), followed by macrolactamization was demonstrated, in which the preformed C-O-D ring framework served to preorganize the precursor for cyclization. The latter investigation led to Suzuki-coupling-based asymmetric synthesis of biaryl systems in which 2,2-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) was found to be the optimum ligand (Tables 3 and 4).

Full text of DOI:10.1002/(SICI)1521-3765(19990903)5:9<2584::AID-CHEM2584>3.0.CO;2-B

FULL PAPER
Total Synthesis of VancomycinÐPart 1: Design and Development of
Methodology
K. C. Nicolaou,* Hui Li, Christopher N. C. Boddy, Joshi M. Ramanjulu, Tai-Yuen Yue,
Swaminathan Natarajan, Xin-Jie Chu, Stefan Bräse, and Frank Rübsam[a]
Abstract: o-Halosubstituted aromatic
triazenes (e.g. I, Scheme 1) react with
aryloxides (e.g. II, Scheme 1) in the
presence of CuBr´ Me2S, K2CO3 and
pyridine in acetonitrile at reflux to
afford biaryl ethers (e.g. V, Scheme 1).
This general methodology (Tables 1 and
2) was applied to the construction of the
C-O-D and D-O-E vancomycin model
systems 37 (Scheme 2) and 50
(Scheme 3), demonstrating its potential
in a projected total synthesis of vanco-
mycin (1, Figure 1). For the construction
of the vancomycin model AB biaryl ring
system, a sequential strategy involving a
Suzuki coupling of the C-O-D aryl
iodide 74 (Scheme 7) and boronic acid
53 (Scheme 4), followed by macrolac-
tamization was demonstrated, in which
the preformed C-O-D ring framework
served to preorganize the precursor for
cyclization. The latter investigation led
to Suzuki-coupling-based asymmetric
synthesis of biaryl systems in which 2,2-
bis(diphenylphosphino)-1,1'-binaphthyl
(BINAP) was found to be the optimum
ligand (Tables 3 and 4).
Keywords: amino acids ´ antibiotics
´ synthetic methods ´ total synthesis
´ vancomycin
Introduction
The discovery and development of penicillin[1] as a drug to
fight infectious diseases followed by an avalanche of several
other antibacterial agents meant a milestone victory of
humankind over bacteria. While these agents saved millions
of lives, they did not tame bacteria. On the contrary, this war
led to the emergence of newer and more dangerous bacterial
strains, which responded defiantly against the known anti-
bacterial agents. Vancomycin (1, Figure 1), a prominent
member of the glycopeptide class of antibiotics,[2] proved to
be, for a number of decades now, the last line of defense
against such bacteria. But even vancomycin (1) has elicited
evolution of bacterial strains which are resistant to its action
and which are beginning to threaten the very foundation of
[a] Prof. Dr. K. C. Nicolaou, H. Li, C. N. C. Boddy, Dr. J. M. Ramanjulu,
Dr. T.-Y. Yue, Dr. S. Natarajan, Dr. X. J. Chu, Dr. S. Bräse,
Dr. F. Rübsam
Department of Chemistry and The Skaggs Institute for Chemical
Biology
The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, CA 92037 (USA)
and
Department of Chemistry and Biochemistry
University of California, San Diego
9500 Gilman Drive, La Jolla, CA 92093 (USA)
Fax: (‡1)858-784-2469
Figure 1. Molecular structures of vancomycin (1) and vancomycinꢀs
aglycon (2).
E-mail: kcn@scripps.edu
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2584±2601
our defenses against the bacterial kingdom.[3, 4] Because of the
need for newer antibiotics effective against drug-resistant
bacteria and in search of new basic knowledge that may
facilitate the drug discovery process within the vancomycin
field, we embarked on a program directed at the total
synthesis of vancomycin (1). In this and the following three
articles,[5±7] we lay out the details of our investigations that
culminated in the development of a number of synthetic
technologies and strategies[8] and the eventual total synthesis
of both vancomycin (1)[9] and its aglycon (2).[10] Both the
Evans[11] and the Boger[12] groups have achieved the total
synthesis of the vancomycin aglycon. The novel and challeng-
ing molecular architecture of vancomycin (1) ensured an
adventurous journey, rich in exciting discoveries and enabling
technologies for biology and medicine. The present paper
describes the design and development of suitable method-
ologies for potential application to the vancomycin problem.
Vancomycin (1) was discovered by scientists at Eli Lilly in
1956[13] from fermentation broths of Streptomyces orientalis
(later renamed Nocardia orientalis, and finally reclassified as
Amycolatopsis orientalis),[14] which was grown from a soil
sample collected in the jungles of Borneo. Approved as an
antibiotic by the FDA in 1958, vancomycin became increas-
ingly popular, especially against methicillin-resistant Staph-
ylococcus aureus (MRSA) and coagulase negative Staphylo-
cocci (CNS). Its mechanism of action involves binding to the
d-Ala-d-Ala fragment of the peptidoglycan and inhibiting its
biosynthesis. This binding is enhanced by spontaneous
dimerization of the antibiotic.[15] Bacteria have learned,
however, to evade vancomycinꢀs targeting by evolving d-
Ala-d-Ala to d-Ala-d-Lac, which suffers from the depletion
of one hydrogen bond in the binding complex.[16] The
observation of drug resistance towards vancomycin by Staph-
ylococcus aureus (MRSA) in three geographically different
locations in 1997,[4c] rung bells of alarm among scientists and
clinicians, and the race is now on for the development of new
antibiotics against vancomycin-resistant bacteria.
C-O-D (16-membered), and the D-O-E (16-membered)
biaryl ether ring systems reside in the specific conformations
shown in structure 1. It is also noteworthy that one of the two
amide bonds within the 12-membered ring exists in its cisoid
form. Rotation around the appropriate C C and C O bonds
could place the substituents of the aromatic rings (OH and Cl)
in different spatial orientations, giving rise to other atro-
pisomers. But the energy barriers for such processes are too
high for them to occur at ambient temperatures, leading to the
observed stability of the indicated atropisomers. These
structural features amounted to a multifaceted synthetic
challenge, including the need to discover and invent new
synthetic technologies and strategies for the construction of
the two biaryl ether macrocycles (C-O-D and D-O-E) and the
AB biaryl system. Below we describe the design and develop-
ment of such technologies and strategies.
Results and Discussion
The triazene-driven biaryl ether synthesis
Due to the importance of the biaryl ether linkage, consid-
erable efforts have been expanded towards the development
of methods for its construction.[2] Amongst the most prom-
inent reactions for the synthesis of biaryl ethers are those
involving oxidative phenolic coupling,[18, 19] o-nitro-activated
nucleophilic aromatic substitution,[20-25] metal-activated nucleo-
philic aromatic substitution,[26, 27] the classic Ullmann-type
reactions,[28, 29] and boronic-acid-driven biaryl ether synthesis.[30]
Despite the plethora of such reactions, however, the sensitivity
and challenging structures of the vancomycin-type antibiotics
dictated the search for new synthetic technologies and
strategies for the formation of the biaryl ether linkages within
the context of viable synthetic routes to these molecules.
Because of their ease of formation and also due to their
susceptibility to chemical manipulations, aryl triazenes[31]
were deemed attractive substrates for biaryl ether formation.
The mechanistic rationale behind the design of the triazene-
driven biaryl ether synthesis is shown in Scheme 1. Thus, it
Vancomycin (1) possesses a unique molecular architec-
ture.[17] It consists of a cyclic heptapeptide framework
providing a highly rigid scaffold onto which is attached a
disaccharide moiety consisting of a glucose unit and a
vancosamine moiety. The cyclic core of vancomycin includes
three macrocyclic systems, all of which are associated with
atropisomerism. Thus, because of their substitution patterns
and strained nature, the AB (12-membered) biaryl ring, the
N
N
N
N
N
N
N
N
N
Cu
X
X
X
O
a
Abstract in Greek:
I'
I
III
O
N
N
N
N
II
N
N
Cu
O
- [ X
]
O
X
V
IV
Scheme 1. Strategy and presumed mechanistic rationale for the triazene-
based synthesis of biaryl ethers. a) 5.0 equiv of PhOH, 5.0 equiv of CuBr´
Me2S, 5.0 equiv of K2CO3, MeCN/pyr. (5:1, v/v, 0.005m), 808C.
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K. C. Nicolaou et al.
FULL PAPER
Table 1. Synthesis of monoaryl ethers by triazene-driven etherification.
N
N
N
N
N
N
Y
ArOH, CuBr•Me2S,
Base, Solvent
X
OAr
Y
S
P
Entry
Yield (%)
53
Temp (°C)
115
100
100
100
80
X
Br
Br
Br
Br
Br
F
Y
H
H
H
H
H
H
H
H
H
H
H
H
Br
S
3
3
3
3
3
4
5
3
6
3
3
3
7
Base
K2CO3
NaH
Solvent
pyr.
ArO
PhO
Time (h)
16
4
P
8
1
2
71
dioxane
PhO
8
3
87
NaH
dioxane
p-Me-PhO
o-Cl-p-Me-PhO
PhO
4
9
4
58
NaH
dioxane
4
10
8
5
NR
NR
NR
65
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
MeCN
16
16
16
16
16
16
16
16
16
6
80
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
PhO
8
7
80
Cl
Br
I
PhO
8
8
80
PhO
8
9
78
80
PhO
8
10
11
12
13
70
80
Br
Br
Br
H
o-Cl-PhO
p-Me-PhO
o-Cl-p-Me-PhO
PhO
11
9
64
80
67
80
10
12
NR
80
was reasoned that an ortho-substituted haloarene (I) could be
encouraged to react with an aryloxide, such as II, through a
copper bridge (or other complexing metal) as shown in III.
Attack on the halogen-bearing carbon atom by the oxy-anion,
followed by expulsion of halide, as shown in IV, to afford
biaryl ether V, was considered a reasonable proposition. This
expectation was rewarded with a mild method for the
construction of biaryl ether bonds as demonstrated in Tables
1 (mono-biaryl) and 2 (bis-triaryl).
The requisite triazene compounds are usually crystalline
and readily available from the corresponding anilines by
diazotization followed by reaction with pyrrolidine. As seen in
Tables 1 and 2, the triazene-based biaryl ether formation is
highly efficient and quite general. Conditions were developed
for the displacement of one or two iodides or bromides from
the aromatic nucleus with one or two aryloxide units at
relatively low temperatures in comparison to the classical
Ullmann reaction. In all cases investigated, no reductive
dehalogenation or biaryl coupling was observed. It was also
established that the reactivities of halides were in the order of
I > Br ꢀ Cl, F, which is in accord with the Ullmann
reaction,[28] but opposite to that of the o-nitro-activated
nucleophilic aromatic substitution, in which fluorides are the
preferred substrates.[20] Furthermore, these studies established
that only halides at the ortho position of triazenes enter the
etherification reaction (entries 8 and 13, Table 1; entry 13,
Table 2). Also, electron-deficient triazene halides reacted
faster than electron-rich substrates (c.f. entries 10 and 14,
Table 2). The same trend was also observed in the reaction of
2,6-dibromo-4-methyl triazene 13 with phenol. Thus, while the
first substitution was complete within 1.5 h, the second one
required a further 3.5 h for completion. In general, it was
interesting to note that triazenes, with substitutions on both
ortho positions, were found to be more reactive as compared
with their mono-substituted counterparts (entry 8, Table 1
and entry 10, Table 2). All of these observations are in accord
with the mechanistic rationale shown in Scheme 1. Thus, it was
presumed that conformation I' (Scheme 1), which is not
available in the o,o'-disubstituted triazenes, is detrimental to
the desired substitution reaction. In support of this postulate,
it was found that the substrate 15 with an o-methyl group in
place of a bromine had a similar reaction rate to the o,o'-
dibromotriazenes (entry 12, Table 2). This observation sug-
gested that the effect of the second ortho substitution was
more steric than electronic.
The effect of base and solvent were also investigated rather
extensively. As seen from Tables 1 and 2, the most consistent
results were obtained when CuBr´ Me2S was used in con-
junction with K2CO3 and pyridine in MeCN as solvent.
Interestingly, the presence of pyridine was essential in the
cases of the milder base (K2CO3) (see entry 5, Table 1 and
entry 9, Table 2) as opposed to the use of a stronger base
(NaH), which did not require pyridine (entries 2 ± 4, Table 1
and entries 2 ± 4, 6 and 8, Table 2).
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 1
2584±2601
Table 2. Synthesis of biaryl ethers by triazene-driven etherification.
N
N
N
N
N
N
ArOH, CuBr•Me2S,
Base, Solvent
X
Y
A
OAr
Z
Z
S
P
Base
K2CO3
NaH
ArO
A
Temp (°C) Time (h)
P
Yield (%)
Entry
1
X
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
Y
Z
S
Solvent
PhO
PhO
PhO
PhO
115
100
100
100
100
65
4
1
18
18
19
20
18
18
18
18
18
18
18
21
22
23
20
19
24
25
84
79
82
50
81
79
77
65
NR
89
83
56
91
82
78
70
74
84
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Br
13
13
13
13
13
13
13
13
13
13
14
15
16
pyr.
2
dioxane
NaH
p-Me-PhO
o-Cl-PhO
PhO
p-Me-PhO
o-Cl-PhO
PhO
1
3
dioxane
NaH
4
1
dioxane
K2CO3
NaH
5
3.5
4
dioxane-pyr.
THF
PhO
PhO
6
K2CO3
NaH
PhO
PhO
65
20
20
4
7
THF-pyr.
Et2O
PhO
PhO
35
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
PhO
PhO
80
9
MeCN
PhO
PhO
80
5
10
11
12
13
14
15
16
17
18
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
MeCN-pyr.
PhO
PhO
80
4
PhO
Me
80
5
Me
Br
Br
Br
Br
Br
Br
Br
Br
PhO
PhO
80
2
PhO
PhO
80
2
Br CO2Me 17
o-Cl-PhO
p-Me-PhO
o-Cl-p-Me-PhO
PhS
o-Cl-PhO
p-Me-PhO
80
5
Br
Br
Br
Br
Me
Me
Me
Me
13
13
13
13
80
5
o-Cl-p-Me-PhO
PhS
80
5
80
4
Vancomycin C-O-D and D-O-E model systems
ing epimer of 35. NMR spectroscopic (500 MHz) studies on 35
and its epimer showed less than 5% epimerization at the
phenylglycine center in each case, underscoring the mildness
of this method. In order to demonstrate the chemical fertility
of the triazene moiety, particularly in the context of a
vancomycin total synthesis, compound 35 was subjected to
Raney Ni reduction, resulting in the formation of aniline
derivative 36 (71% yield). Subsequent diazotization of 36
(tBuNO2-BF3 ´ Et2O), followed by treatment of the resulting
diazonium salt with Cu(NO3)2-Cu2O, furnished phenol 37 in
60% overall yield.
The application of the triazene-driven cyclization reaction
to the construction of the D-O-E vancomycin model system
50 is shown in Scheme 3. Thus, p-aminobenzoic acid (38) was
first methylated (SOCl2, MeOH, 98% yield) and then
brominated (Br2, AcOH, 99% yield) to afford dibromide 40
via compound 39. Reduction of the methyl ester functionality
in 40 with LiAlH4 gave primary alcohol 41 (93% yield). The
amino group of the latter compound (41) was diazotized
(NaNO2, aq HCl), and thence converted to triazene 42 by
reaction of the resulting diazonium salt with pyrrolidine (73%
overall yield). The primary hydroxyl group of 42 was then
converted to an azide functionality[34] (DPPA, Ph3P, DEAD,
Having developed the triazene-driven biaryl ether synthesis,
and prior to embarking on the total synthesis of vancomycin,
we proceeded to test its applicability to the construction of the
C-O-D and D-O-E vancomycin model systems 37 and 50.
Scheme 2 summarizes the successful application of this
reaction to the C-O-D model system 37. Thus, (4-amino-
phenyl)ethyl alcohol (26) was sequentially dibrominated,
diazotized, and treated with pyrrolidine to afford triazene
28 via intermediate 27 (83% overall yield). The latter
compound (28) was then oxidized to carboxylic acid 29
(82% yield) by the action of TEMPO (for abbreviations of
reagents, see legends in Schemes) and NaOCl. The dipeptide
33 [obtained by coupling of amino acid derivatives 30 and 31
(EDC, HOBt, 91% yield)[32] followed by deprotection (H2,
10% Pd/C, 100%)] was coupled with acid 29 (HBTU, Et3N,
63% yield)[33] to afford tripeptide 34. The precursor 34 was
then subjected to the ring closure procedure (2.5 equiv of
K2CO3, 2.5 equiv of CuBr´ Me2S, 3.0equiv of pyridine, MeCN,
758C) to afford the C-O-D ring system 35 in 77% yield. The
phenylglycine epimer of 34 was also prepared and subjected
to the same cyclization conditions, leading to the correspond-
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NH2
NH2
NH2
Br
Br
Br
Br
N
N
N
N
b. Br2
c. LiAlH4
NH2
N
N
R
R
Br
Br
Br
Br
CO2R
COOMe
b. NaNO2;
pyrrolidine
c. TEMPO,
NaOCl
OH
40
41
38: R = H
a. SOCl2,
MeOH
d. NaNO2;
pyrrolidine
39: R = Me
OH
OH
COOH
29
26: R = H
27: R = Br
28
a. Br2
N
N
N
+
N
N
N
N
N
OH
N
e. Ph3P,
Br
Br
Br
Br
Br
Br
OH
O
DEAD,
DPPA
O
f. Ph3P, H2O
NHCbz
NHR
O
HO
N
H
NH2
OMe
N3
d. EDC, HOBt
OH
+
O
NH2
44
43
42
OMe
OH
+
30
31
32: R = Cbz
33: R = H
OH
e. H2
O
O
g. EDC,
HOBt
H
N
f. HBTU, Et3N
NH2
Me
46
+
NHBoc
MeO
RO
HO
NHBoc
O
Me
N
N
N
N
O
45
N
47: R = Me
48: R = H
N
OH
Br
h. LiOH
O
Br
Br
g. CuBr•Me2S
i. EDC, HOBt
K2CO3, pyr.
O
H
N
O
O
H
N
O
N
N
N
N
H
H
N
OMe
O
OMe
O
N
N
N
HO
Br
O
O
Br
Br
j. K2CO3,
pyr.,
D
E
35
34
CuBr•Me2S
O
H
N
h. Raney Ni
NH2
O
H
N
OH
NHBoc
NHBoc
N
H
N
H
O
O
Me
49
O
Me
50
C
D
O
O
H
H
N
Scheme 3. Synthesis of D-O-E model system 50. a) 1.1 equiv of SOCl2,
MeOH, reflux, 2 h, 98%; b) 2.2 equiv of Br2, AcOH, 258C, 0.5 h, 99%;
c) 3.0 equiv of LiAlH4, THF, 08C, 4 h, 93%; d) 1.3 equiv of NaNO2,
5.0 equiv of 12n aq HCl, THF/H2O (10:1), 08C, 0.5 h; then 10.0 equiv of
pyrrolidine, sat. aq K2CO3, 08C, 1 h, 73%; e) 1.5 equiv of Ph3P, 1.5 equiv of
DEAD, 1.5 equiv of DPPA, THF, 258C, 2 h, 82%; f) 2.0 equiv of Ph3P,
10.0 equiv of H2O, THF, 458C, 8 h, 80%; g) 1.5 equiv of EDC, 1.5 equiv of
HOBt, DMF, 08C, 8 h; h) 1.5 equiv of LiOH , MeOH/H2O (1:1), 08C, 1 h,
85% from 45; i) 1.5 equiv of 48, 3.0 equiv of EDC, 1.5 equiv of HOBt,
DMF, 08C, 8 h, 45%; j) 2.5 equiv of K2CO3, 2.5 equiv of CuBr´ Me2S,
3.0 equiv of pyr., MeCN (0.01m), 758C, 6 h, 54% (87% conversion).
DEAD ˆ diethyl azodicarboxylate; DPPA ˆ diphenylphosphoryl azide;
Boc ˆ t-butoxycarbonyl.
O
O
N
N
H
N
H
i. tBuNO2, BF3•Et2O;
Cu(NO3)2, Cu2O
OMe
O
OMe
O
B
36
37
Scheme 2. Synthesis of C-O-D model system 37. a) 2.2 equiv of Br2,
AcOH, 258C, 0.5 h, 99%; b) 1.3 equiv of NaNO2, 5.0 equiv of 12n aq HCl,
THF/H2O (10:1), 08C, 0.5 h; then 10.0 equiv of pyrrolidine, sat. aq K2CO3,
08C, 1 h, 84%; c) 1.5 equiv of TEMPO, 3.0 equiv of 5% aq NaOCl,
10 mol% of KBr, acetone/5% NaHCO3 (1:1), 08C, 2 h, 82%; d) 1.5 equiv
of EDC, 1.5 equiv of HOBt, DMF, 08C, 10 h, 91%; e) H2, 10% Pd/C,
MeOH, 258C, 1 h, 100%; f) 1.5 equiv of HBTU, 2.0 equiv of 33, 1.5 equiv of
Et3N, DMF, 08C, 18 h, 63%; g) 2.5 equiv of K2CO3, 2.5 equiv of CuBr´
Me2S, 3.0 equiv of pyr., MeCN (0.01m), 758C, 15 h, 77%; h) Raney Ni,
MeOH, reflux, 2 h, 71%; i) 1.5 equiv of tBuNO2, 3.0 equiv of BF3 ´ Et2O,
THF, 20 !58C, 0.5 h; then sat. Cu(NO3)2, 5.0 equiv of Cu2O, H2O, 258C,
3 h, 60%. DMF ˆ dimethylformamide; EDC ˆ 1-ethyl-3-(3-dimethylami-
no)-propyl carbodiimide hydrochloride; HOBt ˆ 1-hydroxybenzotriazole;
TEMPO ˆ 2,2,6,6-tetramethyl-1-piperidinyloxy; HBTU ˆ 2-(1H-benzo-
triazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; Cbz ˆ
benzyloxycarbonyl.
HOBt, followed by carefully controlled hydrolysis of the
methyl ester (LiOH, MeOH/H2O, 08C, 85% yield for two
steps). The coupling of 44 with 48 was facilitated by the action
of EDC/HOBt, furnishing tripeptide 49 in 45% yield and
setting the stage for the ring-closure reaction. Exposure of
precursor 49 to the developed cyclization protocol (K2CO3,
CuBr´ Me2S, pyridine, MeCN, 758C) resulted in the formation
of vancomycin D-O-E model system 50 (54% yield based on
87% conversion). No observable (NMR, 500 MHz) epimeri-
zation occurred in the formation of 50 from 49.
82%) affording compound 43, which was reduced to amine 44
by exposure to Ph3P/H2O (80% yield). The other requisite
coupling segment, dipeptide 48, was obtained by joining
amino acid derivatives 45 and 46 through the action of EDC/
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Total Synthesis of VancomycinÐPart 1
2584±2601
The successful construction of C-O-D (37) and D-O-E (50)
model systems of vancomycin boded well for the applica-
tion of the triazene-driven biaryl ether synthesis to a po-
tential total synthesis of vancomycin. These expectations
were realized as will be discussed later in this series of
papers.[5±7]
R1
H
O
H
N
R2
H
N
O
H
O
HN
3R
B
b. Lactamization
H
A
OMe
Model study for the construction of the cyclic biaryl system
(AB) of vancomycin
a. Intramolecular
C-C bond
OMe
MeO
formation
VI
a
b
The 12-membered ring of vancomycin containing the biaryl
system (AB) presents a serious synthetic challenge. Its
daunting nature has its origins in the inherent strain associ-
ated with the medium ring size, its cisoid amide bond (AA-5/
AA-6) and its highly substituted biaryl moiety. At the outset
of our work on vancomycin, only one method existed for the
construction of this strained system, that reported by the
Evans group in 1993,[35] involving a vanadium-induced oxida-
tive coupling reaction.
R1
R1
O
O
H
H
N
R2
R2
N
O
O
N
N
H
H
OH
O
O
HN
B
B
Y
H2N
X
A
A
OMe
OMe
OMe
OMe
MeO
MeO
For the construction of this unusual structural moiety we
considered two main strategies, as indicated retrosynthetically
in Scheme 4. The first strategy (a) called for first assembling
the peptide backbone and then closing the ring by a carbon ±
carbon bond forming reaction; whereas the second strategy
(b) was to rely on forming the biaryl system early in the
synthesis followed by a macrolactamization reaction to close
the ring. These strategies required key building blocks 51, 52
(for a), and 53, 54 (for b) as starting materials, respectively.
Attempted implementation of these strategies was revealing.
To test the first approach to the AB ring construction,
substrates 55a and 55b (Scheme 5) were prepared by stand-
ard chemistry involving peptide couplings. However, neither
the Suzuki coupling[36] (of 55a) nor the Stille coupling[37] (of
55b) was successful in delivering the desired 12-membered
ring under a variety of conditions. It soon became evident that
the strained nature of the targeted ring system did not allow
these processes to proceed as desired. Faced with these
negative results, we opted to test a nickel(0)-mediated strategy
to form the required C C bond between the two aromatic
rings (A and B). Scheme 6 summarizes the model study
exploring the nickel(0) technology. Thus 3,5-dimethoxybenzyl
alcohol (56) was iodinated (NIS, 91% yield) to afford
intermediate 57, which upon Mitsunobu activation provided
azide 58 in 82% yield. Reduction of azide 58 by Ph3P/H2O
(80% yield), followed by coupling of the resulting amine (59)
with N-Boc-glycine furnished dipeptide 60 (EDC, Et3N, 81%
yield). TFA-mediated Boc deprotection gave amine 61 in
quantitative yield. Carboxylic acid 63 was generated from its
readily available methyl ester (62) (LiOH, THF/H2O, 99%
yield) and coupled with amino compound 61 under the
influence of EDC and Et3N, leading to peptide 64 (92%
yield). Exposure of precursor 64 to freshly prepared nickel(0)
[generated from (Ph3P)2NiCl2, Zn dust, and Ph3P in DMF][38]
at 55 oC resulted in the formation of the desired 12-membered
ring 65 (26% yield as a mixture of two atropisomers, 65a and
65b, Figure 2). By-products in this reaction included reduced
compounds, where one or both iodine atoms were replaced by
hydrogen atoms, and dimeric materials. Despite the success in
this model study, the low yield of the desired 12-membered
Peptide bond formation
Suzuki coupling
VII (X = I, Y= B, Sn)
VIII
NH2
O
B
OH
Y
OMe
A
A
MeO
MeO
R1
OMe
51
53
+
+
R1
O
O
H
H
N
R2
R2
O
N
O
N
N
H
H
OH
OMe
O
O
B
B
I
I
OMe
OMe
54
52
Scheme 4. Retrosynthetic analysis of model biaryl system VI: strategies a
and b.
O
O
O
NHBoc
O
NHBoc
N
N
H
H
HN
HN
HO
B
B
nBu3Sn
MeO
HO
B
I
I
A
A
OMe
OMe
OMe
55b
MeO
OMe
55a
O
NHBoc
O
N
H
HN
B
OMe
A
MeO
OMe
65
Scheme 5. Attempted intramolecular biaryl coupling reactions.
Chem. Eur. J. 1999, 5, No. 9
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K. C. Nicolaou et al.
FULL PAPER
OH
OH
N3
attention to strategy b (Scheme 4). According to this ap-
proach, the central C C bond of the biaryl system was
envisioned to be formed at the early stages of the sequence by
a Suzuki coupling; while the 12-membered ring would be
constructed subsequently, by a macrolactamization process.
However, in view of previous findings by Brown et al.,[39] who
failed to cyclize such a system, and by Evans et al.,[35] who
succeeded in such an endeavor by preassembling the C-O-D
ring of vancomycin, we opted to test the preorganization
strategy summarized in Schemes 7 and 8. Thus, it was
anticipated that the preformed C-O-D macrocycle would
impose enough rigidity into the precursor chain for the AB
ring system so as to organize it into a favorable conforma-
tional state for cyclization.
b. DEAD,
DPPA,
Ph3P
I
I
a. NIS
MeO
OMe
MeO
OMe
MeO
OMe
56
57
58
c. Ph3P, H2O
O
O
NHR
NHBoc
RO
I
HN
NH2
d. N-Boc-Gly
EDC, Et3N
I
I
MeO
OMe
MeO
OMe
OMe
62: R = Me
63: R = H
60: R = Boc
61: R = H
59
e. TFA
f. LiOH
To this end, the C-O-D model system 74 was first
constructed as shown in Scheme 7. Thus, the required building
g. EDC,
Et3N
O
O
NHBoc
O
O
NHBoc
N
H
N
N
H
N
HN
HN
N
NH2
N
N
h. Ni (0)
B
N
R
I
Br
I
Br
b. NaNO2,
pyrrolidine
c. TEMPO,
NaOCl
A
OMe
OMe
OMe
MeO
MeO
OMe
OH
OH
64
65
COOH
Scheme 6. Construction of model AB biaryl system 65 by nickel (0)-
mediated coupling reaction. a) 1.5 equiv of NIS, DMF, 258C, 12 h, 91%;
b) 1.5 equiv of Ph3P, 1.5 equiv of DEAD, 1.5 equiv of DPPA, THF, 08C, 2 h,
82%; c) 3.0 equiv of Ph3P, THF/H2O (10:1), 458C, 4 h, 80%; d) 1.0 equiv of
N-Boc-Gly, 1.5 equiv of EDC, 2.5 equiv of Et3N, DMF, 08C, 12 h, 81%;
e) TFA/CH2Cl2 (1:1), 0 !258C, 2 h, 100%; f) 1.5 equiv of LiOH, THF/H2O
(1:1), 08C, 1 h, 99%; g) 1.2 equiv of 63, 1.3 equiv of EDC, 2.2 equiv of Et3N,
DMF, 08C, 12 h, 92%; h) 1.8 equiv of (Ph3P)2NiCl2, 1.8 equiv of Zn,
3.6 equiv of Ph3P, DMF (0.002m), 558C, 16 h, ca. 1:1 ratio of atropisomers,
26% combined yield. NIS ˆ N-iodosuccinimide; TFA ˆ trifluoroacetic
acid.
67
68
26: R = H
66: R = Br
a. NBS
+
OH
O
OH
HO
O
NHBoc
NHR
O
N
H
OMe
d. HBTU
+
O
NH3+ Cl-
I
I
OMe
OMe
63
OMe
69
70: R = Boc
71: R = H
e. TFA
f. HBTU
O
Boc
H
H3
N
O
H
H
4
NHBoc
NH
B
H
1
N
H
H
H
H
O
N
H
R
H
b
NH
a
N
N
O
B
O
HN
c
7
H
C
D
OH
Br
H
a
A
OMe
OMe
A
MeO
H
g. K2CO3, pyr.,
CuBr•Me2S
O
b
H
N
OMe
MeO
OMe
O
O
H
N
N
H
65a
65b
O
OMe
O
N
H
Figure 2. Assignments of stereochemistry of atropisomers 65a and 65b by
1H-1H NOE studies (COSY, NOESY, CDCl3, 600 MHz).
B
OMe
O
I
OMe
N
I
ring steered us away from this strategy and into a new
direction involving a Suzuki coupling ± macrolactamization
sequence to form the desired AB ring system. Furthermore, it
was decided at this juncture to implement the well-known
preorganization strategy to assist the pending ring closure
process.
OMe
72
N=
73: R =
74: R = H
N
h. Cu2O, TFA
Scheme 7. Construction of model C-O-D template 74. a) 1.2 equiv of NBS,
DMF, 258C, 12 h, 62%; b) 1.2 equiv of conc. aq HCl, 1.0 equiv of NaNO2,
08C, 0.5 h; then sat. aq K2CO3, 10.0 equiv of pyrrolidine, 08C, 1 h, 83%;
c) 1.0 equiv of TEMPO, 0.1 equiv of KBr, 1.3 equiv of NaOCl, acetone:5%
NaHCO3 (1:1), 08C, 1.5 h, 86%; d) 1.2 equiv of HBTU, 3.0 equiv of Et3N,
DMF, 0 !25 8C, 3 h, 90%; e) TFA:CH2Cl2 (1:1), 08C, 1 h, 100%;
f) 1.2 equiv of HBTU, 3.0 equiv of Et3N, DMF, 0 !25 8C, 3 h, 90%;
g) 2.9 equiv of CuBr´ Me2S, 2.4 equiv of K2CO3, 3.0 equiv of pyr., MeCN,
reflux, 36 h, 67% (10% recovered 72 and 6% arylglycine epimer of 73); h)
2.2 equiv of TFA, 5.0 equiv of Cu2O, THF, reflux, 1 h, 90%. NBS ˆ N-
bromosuccinimide.
The Suzuki coupling ± macrolactamization strategy towards
the AB/C-O-D bicyclic system of vancomycin
Having failed to develop an efficient method for the ring
closure of vancomycinꢀs AB ring system by formation of the
central C C bond of the biaryl system, we turned our
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Total Synthesis of VancomycinÐPart 1
2584±2601
block 68 was synthesized from aniline derivative 26 by NBS
bromination to afford bromide 66 (62% yield), diazotization
(NaNO2, aq HCl) followed by reaction of the resulting
diazonium salt with pyrrolidine, leading to triazene 67 (83%
overall yield), and TEMPO/NaOCl oxidation (86% yield).
The tripeptide precursor 72 was finally assembled by first
coupling (S)-tyrosine methyl ester derivative 69 with (R)-4-
methoxyl-3-iodophenylglycine derivative 63 (HBTU/Et3N) to
afford dipeptide 70 (90% yield), deprotecting the latter
(TFA) leading to amine 71 (100% yield), and attaching
triazene carboxylic acid 68 by HBTU/Et3N facilitated cou-
pling (90% yield). Ring closure of 72 was effected by
refluxing in MeCN in the presence of K2CO3, CuBr´ Me2S
and pyridine, furnishing C-O-D model system 73 in 67%
yield, along with 10% recovered starting material and 6% of
the arylglycine epimer of 73. Reductive removal of the
triazene group from 73 with TFA and Cu2O in refluxing THF
led to the desired intermediate 74 (90% yield).
OH
O
B
OH
a. nBuLi, B(OMe)3
MeO
OMe
MeO
OMe
56
53
+
53
74
b. Pd(Ph3P)4, Na2CO3
O
O
H
N
H
N
O
O
5
5
6
6
O
O
N
N
H
H
O
O
+
OR
X
OR
MeO
X
OMe
OMe
OMe
MeO
MeO
The further elaboration of compound 74 towards the
targeted AB/C-O-D ring system required the Suzuki partner
53, whose construction and incorporation into the molecule
are shown in Scheme 8. Thus, 3,5-dimethoxylbenzyl alcohol
(56) was directly converted to boronic acid derivative 53 by
treatment with 2.2 equivalents of nBuLi, followed by quench-
ing the derived dianion with B(OMe)3 and workup with
aqueous HCl (46% overall yield). The Suzuki coupling of
iodide 74 with boronic acid derivative 53 proceeded smoothly
in the presence of Pd(Ph3P)4 catalyst and Na2CO3 in toluene/
MeOH/H2O at 908C to afford a mixture of atropisomers 75
and 79 (ca. 1:1 ratio, 80% combined yield). The two isomers
were chromatographically separated, but their stereochemical
assignments had to await cyclization to the AB/C-O-D
framework before being revealed by NMR spectroscopy
(vide infra). While the biaryl system obtained from coupling
of 74 with the parent boronic acid corresponding to 53
(lacking the methoxyl groups) proved to be a single com-
pound (by TLC and NMR spectroscopy), due to free rotation
around the central C C biaryl bond; atropisomers 75 and 79
did not undergo isomerization even at 608C. Furthermore, no
epimerization at C5 and C6 was observed. Each atropisomer
was elaborated individually as follows. Thus, the less polar
isomer (75, Rf ˆ 0.28, silica gel, EtOAc) was treated with HN3,
DEAD, and Ph3P leading to the corresponding azide com-
pound 76 in 69% yield. The latter intermediate (76) was then
saponified by treatment with LiOH in THF/H2O (1:1) at 08C,
furnishing carboxylic acid 77 in quantitative yield. Conversion
of this acid (77) to its pentafluorophenyl ester (78), followed
by slow addition of a solution (dioxane-cyclohexene) of crude
78 to 10% Pd/C and pyrrolidinopyridine stirred in dioxane/
EtOH at 908C, led to the formation of 83, plus its 6-epimer,
compound 83-(6-epi), in 30% combined yield from 77 [83:83-
(6-epi) ca. 1:2]. The more polar isomer (79, Rf ˆ 0.23, silica
gel, EtOAc) was taken through the same sequence, leading to
compounds 84 and 84-(6-epi) in similar yields. The stereo-
chemical assignment of compounds 83, 83-(6-epi), 84, and 84-
X = OH,
R = Me
R = Me
R = H
75 :
79 :
80 :
81 :
82 :
X = OH, R = Me
X = N3, R = Me
X = N3, R = H
c.
d.
e.
c.
d.
e.
X = N
76 :
77 :
78 :
3,
X = N
3,
X = N
R = C6F5
X = N3, R = C6F5
3,
f
f
O
H
O
C
O
D
C
O
D
N
5
H
6
H
N
H
O
N
5
6
N
O
O
O
NH
NH
B
B
A
OMe
OMe
A
OMe
OMe
MeO
MeO
83 + 83-(6-epi)
84 + 84-(6-epi)
Scheme 8. Construction of AB/C-O-D model bicyclic systems 83 and 84 by
the Suzuki ± macrolactamization strategy. a) 2.2 equiv of nBuLi, benzene,
08C, 2 h; then 3.0 equiv of B(OMe)3, THF, 78 !258C, 6 h, 5% aq HCl,
46%; b) 10 mol% of Pd(PPh3)4, 1.0 equiv of Na2CO3, toluene/MeOH/H2O
(80:18:2), 908C, 2 h, 75:79 ca. 1:1, 80% combined yield; c) 5.0 equiv of
HN3, 5.0 equiv of DEAD, 5.0 equiv of Ph3P, THF, 0 !258C, 1 h, 69%;
d) 1.5 equiv of LiOH, THF/H2O (1:1), 08C, 0.5 h, 100%; e) 2.0 equiv of
C6F5OH, 1.2 equiv of DCC, 0.2 equiv of 4-DMAP, CH2Cl2, 258C, 1 h;
f) 3.0 equiv of 4-pyrrolidinopyridine, 0.3 equiv of 10% Pd/C, dioxane/
ethanol/cyclohexene (90:8:2), 0.001m, 908C, 5 h, 30% from 77 and 81.
C6F5OH ˆ pentafluorophenol;
DCC ˆ N,N'-dicyclohexylcarbodiimide;
4-DMAP ˆ 4-dimethylaminopyridine.
O
O
H
C
D
C
O
D
H
H
H
N
H
O
H
H
N
N
O
N
H
O
H
H
O
H
H
O
H
NH
H
H
NH
B
B
A
OMe
OMe
A
OMe
1
(6-epi) were based on H-1H NOESY experiments. Figure 3
MeO
OMe
83
MeO
indicates the crucial NOE values which were used to define
the stereostructure of 83 and 84 (both of the natural stereo-
chemistry at C6 and both containing cisoid amide bonds).
84
Figure 3. Assignments of stereochemistry of bicyclic systems 83 and 84 by
1H-1H NOE studies (COSY, NOESY, 600 MHz, CDCl3, 323 K).
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K. C. Nicolaou et al.
FULL PAPER
Table 3. Catalytic asymmetric synthesis of biaryl systems by Suzuki
coupling: acyclic model system.
Despite the observed epimerization at C-6, which is pre-
sumed to occur after ring closure, these results were encour-
aging and boded well for application to vancomycin. For one,
we learned that we could potentially rely on the Suzuki ±
macrolactamization strategy to construct the notorious AB
macrocycle. Secondly, we could optimistically speculate that
epimerization at C-6 may not necessarily surface in the real
case where the proper substitutions and additional rings may
change the thermodynamics of the system.
O
NHBoc
O
B
MeO
I
OH
MeO
OMe
OMe
62
53
Ligand, Pd(OAc)2
Na2CO3, Solvent
O
O
NHBoc
NHBoc
MeO
A
MeO
Catalytic asymmetric synthesis of biaryl systems by Suzuki
coupling
B
B
HO
+
MeO
MeO
OH
Substituted biaryl systems are common structural moieties in
natural products. Their synthesis, especially in enantiomeri-
cally pure form, is, therefore, deemed important.[40] The
Suzuki coupling reaction has proven quite valuable in
assembling such structures in racemic form. Despite the
obvious potential for an asymmetric version of the Suzuki
biaryl coupling, there have been no reports for the asymmetric
version of this process. The only claim for an asymmetric
synthesis of a biaryl system is that by Hayashi et al.,[41] who
reported a modest asymmetric induction in the coupling of a
chromium tricarbonyl complex. As part of our program
directed towards the total synthesis of vancomycin, we
investigated the possibility of asymmetric induction in the
Suzuki coupling synthesis of biaryl systems already mentioned
above. Specifically, it was observed that the Suzuki coupling of
iodoarene-containing C-O-D model system 74 with boronic
acid derivative 53 in the presence of Ph3P proceeded with no
diastereoselectivity. This observation, coupled with our desire
to control the atrop-selectivity during our synthesis, gave us
the impetus to develop an asymmetric version of this reaction.
Table 3 summarizes our findings so far, which clearly suggest
that it may be possible to control the atrop-selectivity of the
Suzuki biaryl synthesis. As expected, achiral ligands, such as
Ph3P and DPPP, led to no selectivity. Screening of a number of
readily available chiral ligands revealed that BINAP[42] was
the best in inducing diastereoselectivity in the coupling of
compound 62 and 53. Moreover, in the BINAP case, the
observed diastereoselectivity was reversed upon switching the
chirality of the ligand. The solvent effect was also studied,
leading to the observation that THF at 608C provided the
highest diastereoselectivity (ca. 3.5:1 ratio for 85 and 86, 75%
combined yield, entries 14 and 15, Table 3). (S,S)-(‡)-
DIOP,[43] (R,R)-( )-Me-DuPHOS,[44] ( )-PPFA,[45] and (S)-
( )-BINAPAs[46] catalysts gave lower selectivities in this reac-
tion. The relatively high temperatures required for the Suzuki
coupling reactions led to the suspicion that atropisomeriza-
tion during the reaction may have been responsible for the
loss of partial asymmetric induction. Heating of a 3:1 mixture
of atropisomers 85 and 86 in toluene at 908C for 3 h led to
complete scrambling, furnishing a 1:1 mixture of 85 and 86,
thus, confirming the atropisomerization hypothesis. On the
other hand, when the same 3:1 mixture of 85 and 86 was
heated in THF at 608C for 3 h, no isomerization was detected,
leading to the conclusion that entries 14 and 15 (Table 3)
represent true asymmetric induction. It is also clear that in
OMe
A
OMe
OMe
MeO
85
86
Entry
Ligand
Ph3P
Solvent
Time(h) Yield (%)
Temp(°C)
90
Ratio[a]
1:1
1
2
3
PhMe
PhMe
PhMe
2
5
83
77
70
68
80
80
53
51
40
42
52
45
70
75
75
DPPP[b]
(S,S)-DIOP[c]
90
1:1
7
90
1.5:1
1:1.5
3:1
4 (R,R)-Me-DuPHOS[d] PhMe
2
90
5
6
(R)-BINAP[e]
(S)-BINAP[e]
(S)-PPFA[f]
PhMe
PhMe
PhMe
PhMe
PhH
10
10
12
14
15
3
90
90
1:3
7
90
1:1.2
1:1.2
2:1
8
(S)-BINAPAs[g]
(R)-BINAP[e]
(R)-BINAP[e]
(S)-BINAP[e]
(R)-BINAP[e]
(S)-BINAP[e]
(R)-BINAP[e]
(S)-BINAP[e]
90
9
80
10
11
12
13
14
15
DMSO
DMF
90
1.2:1
1:2
2.5
3.5
10
2
80
DMPU
dioxane
THF
80
1.2:1
1:1.2
3.5:1
1:3.5
90
60
THF
2
60
[a] Absolute configuration not determined, ratio measured by 1H NMR
integration of signals at d ˆ 3.66 and 3.67. [b] DPPP: 1,3-bis(diphenylpho-
sphino)propane. [c] (S,S)-DIOP: (4S,5S)-(‡)-o-isopropylidene-2,3-dihy-
droxy-1,4-bis(diphenylphosphino)butane. [d] (R,R)-Me-DuPHOS: ( )-1,2-
bis[(2R,5R)-2,5-dimethyl-phospholano]benzene. [e] BINAP: 2,2(-bis(di-
phenylphosphino)-1,1'-binaphthyl. [f] PPFA: (R)-1-[(S)-2(diphenylphos-
phino)-ferrocenyl]ethyldimethylamine. [g] BINAPAs: 2,3'-bis(diphenylar-
sino)-1,1'-binaphthyl. DMSO ˆ dimethyl sulfoxide; DMF ˆ dimethylfor-
mamide; DMPU ˆ 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.
toluene, the diastereoselectivity of this reaction must be higher
than the one observed, and that the 3:1 ratio is a result of slow
deterioration of the kinetic ratio via atropisomerization.
In order to explore the possibility of obtaining even higher
diastereoselectivities in the Suzuki coupling reaction, we
decided to attempt the incorporation of the boronic acid aryl
system 53 into the main frame after the construction of the
C-O-D macrocycle. Having studied the properties of the
expected products 75 and 79 (Table 4) previously, we were
cognizant of the fact that they do not suffer atropisomeriza-
tion at 908C. Palladium(0)-induced coupling of 74 and 53 in
the presence of Ph3P led smoothly and in 80% yield to a 1:1
mixture of atropisomers 75 and 79, indicating that the chirality
of the macrocyclic ring had no influence on the diastereose-
lectivity. The same reaction with (R)- or (S)-BINAP in toluene
2592
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0947-6539/99/0509-2592 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 1
2584±2601
Table 4. Catalytic asymmetric synthesis of biaryl systems by Suzuki
coupling: cyclic model system.
biaryl ethers which was ultimately applied successfully to the
total synthesis of vancomycin (1) relies on the ability of the
triazene moiety to complex copper ions, thus bringing
together the two components for facile interaction. This
methodology was sequentially demonstrated in open-chain
systems, as well as C-O-D, D-O-E, and AB/C-O-D model
systems of the targetꢀs main framework. For the AB biaryl
system of vancomycin, the failure of the attempts involving
intramolecular Suzuki or Stille coupling processes to form the
strained, 12-membered ring, led us to a nickel(0)-mediated
cyclization reaction, which, however, was overshadowed by a
more reliable process involving sequential intermolecular
Suzuki coupling and macrolactamization. The development of
the latter protocol was accompanied by an asymmetric Suzuki
coupling synthesis of substituted biaryl systems employing
BINAP as a chiral ligand. With these methodologies well
established, we were then ready to address the retrosynthetic
analysis and strategy for a total synthesis of vancomycin and
to embark on the construction of the required amino acid
building blocks as well as to explore preliminary plans for
their assembly to the desired framework. The articles[5±7] that
follow deal with these issues.
O
D
C
O
H
O
O
N
B
OH
N
H
OMe
O
A
+
MeO
OMe
B
I
OMe
74
53
Pd(OAc)2 , Na2CO3
Solvent
(R)-BINAP
(S)-BINAP
O
O
C
D
D
C
O
H
N
H
N
O
O
O
N
N
H
H
O
O
OMe
HO
OMe
MeO
B
B
OH
A
OMe
OMe
A
OMe
MeO
MeO
79
75
Experimental Section
Entry Ligand
Solvent
Time Yield
Temp
(oC)
90
Ratio
(h)
2
(%)
80
(75:79)
1:1
General techniques: All reactions were carried out under an argon
atmosphere with dry, freshly distilled solvents under anhydrous conditions,
unless otherwise noted. Tetrahydrofuran (THF), toluene, and diethyl ether
(ether) were distilled from sodium benzophenone; methylene chloride
(CH2Cl2) was freshly distilled from calcium hydride. Anhydrous solvents
were also obtained by passing them through activated commercially
available alumina columns. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless otherwise
stated.
1
2
3
4
5
6
Ph3P
BINAP
BINAP
PhMe
PhMe
THF
12
12
8
trace
trace
60
90
-
65
-
(S)-BINAP
DMF
80
2.3:1
>95:5[b]
<5:95[b]
(S)-BINAP PhMe:THF(1:1)
(R)-BINAP PhMe:THF(1:1)
5
40(70[a]
40(70[a]
)
)
70
5
70
[a] Conversion based on recovered starting material. [b] The other
atropisomer was not detectable by 1H NMR spectroscopy (500 MHz).
BINAP ˆ 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.
Reagents were purchased at the highest commercial quality and used
without further purification, unless otherwise stated. Reactions were
monitored by thin-layer chromatography (TLC) carried out on 0.25 mm E.
Merck silica gel plates (60F-254) using UV light as a visualizing agent and
7% ethanolic phosphomolybdic acid or p-anisaldehyde solution, and heat
as developing agent. E. Merck silica gel (60, particle size 0.040 ± 0.063 mm)
was used for flash column chromatography. Preparative thin-layer chro-
matography (PTLC) separations were carried out on 0.25, 0.50, or 1 mm E.
Merck silica gel plates (60F-254).
at 908C failed to produce significant amount of product (entry
2, Table 4), presumably due to the insolubility of the ligand-
substrate complex in this solvent. Similarly disappointing
results were obtained in THF. Using DMF as solvent improved
the yield of the products to 60%, but the diastereoselectivity
was only ca. 2.3:1 (75:79) (entry 4, Table 4). However, when a
mixture of PhMe/THF (1:1) was used as solvent, BINAP led
to the exclusive formation of one of the two isomers,
depending on the chirality of the ligand (entries 5 and 6,
Table 4). Unfortunately, the reaction in PhMe/THF was
rather sluggish, producing 75 or 79 only in 40% yield based
on 70% conversion (entries 5 and 6, Table 4). It is expected
that new ligands capable of effecting higher asymmetric
induction and at lower temperature could improve even
further the state of affairs in this important area of synthesis.
NMR spectra were recorded on Bruker DRX-600, AMX-500, or AMX-400
instruments and calibrated by using residual undeuterated solvent as an
internal reference. The following abbreviations were used to explain the
multiplicities: s ˆ singlet, d ˆ doublet, t ˆ triplet, q ˆ quartet, sept ˆ septet,
m ˆ multiplet, br. ˆ broad, br. s ˆ broad singlet. IR spectra were recorded
on a Perkin-Elmer 1600 series FT-IR spectrometer. Optical rotations were
recorded on a Perkin-Elmer 241 polarimeter. High-resolution mass spectra
(HRMS) were recorded on a VG ZAB-ZSE mass spectrometer under fast
atom bombardment (FAB) conditions with nitrobenzyl alcohol (NBA) as
the matrix or IONSPEC FTMS spectrometer (MALDI) with DHB as
matrix. Melting points (m.p.) are uncorrected, and were recorded on a
Thomas-Hoover Unimelt capillary melting point apparatus.
General procedure (A) for reactions between o-haloaryl triazenes and
phenols (Table 1):
A flame-dried flask was charged with triazene
(1.0equiv), CuBr´ Me2S (5.0 equiv), phenol (1.2 equiv), and the specified
base (5.0 equiv). The mixture was diluted with solvent to yield a solution
approximately 0.1m in triazene halide, and pyridine (Table 1, entries 6 ± 13,
20 vol% of solvent) was added. The reaction mixture was heated at the
indicated temperature (Table 1) for the specified time before it was allowed
to cool to 258C. The resulting slurry was filtered through a pad of celite and
the celite was washed thoroughly with ether. The product was isolated by
Conclusion
In this article, we laid out the challenge of vancomycin (1) and
described the rational design and development of method-
ology for its total synthesis. The triazene-driven synthesis of
Chem. Eur. J. 1999, 5, No. 9
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0947-6539/99/0509-2593 $ 17.50+.50/0
2593

K. C. Nicolaou et al.
FULL PAPER
flash column chromatography. The example below illustrates further the
procedure.
azo]pyrrolidine (13) (173 mg, 0.5 mmol), phenol (113 mg, 1.2 mmol), CuBr´
Me2S (1.03 g, 5.0 mmol), and K2CO3 (690 mg, 5.0 mmol) in acetonitrile
(5 mL) in a flame-dried flask was treated with pyridine (1 mL). The
reaction mixture was heated to 808C and stirred at that temperature for 5 h
before it was cooled to 258C. The mixture was filtered through a pad of
celite, and the celite was washed thoroughly with ether (3 Â 10 mL). The
combined organic extracts were washed with saturated aqueous NH4Cl
(15 mL), H2O (15 mL), brine (15 mL), and dried over Na2SO4. The solvent
was removed in vacuo and the residue was subjected to flash column
chromatography (silica gel, 3 !6% ether in petroleum ether, gradient
elution), furnishing compound 18 (166 mg, 89%). 18: m.p. 84 ± 858C
(EtOAc in petroleum ether); Rf ˆ 0.36 (silica gel, 10% ether in petroleum
ether); IR (KBr): nÄmax ˆ 2966, 2868, 1593, 1563, 1483, 1452, 1421, 1329, 1213,
1164, 1041, 857, 753, 691 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.28 ± 7.22
(m, 4H, ArH), 6.97 (dd, J ˆ 9.0, 8.0 Hz, 2H, ArH), 6.91 (d, J ˆ 8.0 Hz, 4H,
ArH), 6.73 (s, 2H, ArH), 3.55 (br.s, 2H, NCH2), 3.15 (br.s, 2H, NCH2), 2.28
(s, 3H, CH3), 1.76 (br.s, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ
158.4, 148.7, 135.4, 134.3, 129.0, 121.6, 118.3, 117.0, 51.1, 46.5, 23.4, 23.3, 20.9;
(2-Phenoxy-phenyl)-pyrrolidin-1-yl-diazene (8) (Table 1, entry 8): General
procedure (A). To a flame-dried flask charged with a mixture of [(2-
bromophenyl)azo]pyrrolidine (3) (254 mg, 1.0 mmol), phenol (113 mg,
1.2 mmol), CuBr´ Me2S (1.03 g, 5.0 mmol), and K2CO3 (690 mg, 5.0 mmol)
was added acetonitrile (10 mL), followed by pyridine (2 mL). The reaction
mixture was heated to 808C and maintained at that temperature for 16 h
before it was allowed to cool to 258C. The mixture was filtered through a
pad of celite and the celite was washed thoroughly with ether (3 Â 20 mL).
The combined organic phases were washed with 5% aqueous NH4Cl
(20 mL), H2O (20 mL), brine (20 mL), and dried over Na2SO4. The solvent
was removed in vacuo and the product was purified by flash column
chromatography (silica gel, 3 !5% ether in petroleum ether, gradient
elution), furnishing 8 (174 mg, 65%). 8: m.p. 84 ± 85 8C (petroleum ether);
Rf ˆ 0.52 (silica gel, 10% ether in petroleum ether); IR (KBr): nÄmax ˆ 2966,
1
2868, 1581, 1483, 1409, 1371, 1342, 1237, 1090 cm
;
1H NMR (500 MHz,
CDCl3): d ˆ 7.47 ± 7.45 (m, 1H, ArH), 7.26 ± 7.22 (m, 2H, ArH), 7.15 ± 7.12
(m, 2H, ArH), 7.09 ± 7.06 (m, 1H, ArH), 6.98 ± 6.91 (m, 3H, ArH), 3.95 ±
3.75 (br.s, 2H, NCH2), 3.46 ± 3.24 (br.s, 2H, NCH2), 1.92 ± 1.88 (m, 4H,
NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 159.6, 147.0, 142.7, 129.1,
125.9, 124.8, 122.0, 121.4, 118.9, 116.9, 50.8, 46.2, 23.7; HRMS (FAB) calcd
‡
HRMS (FAB) calcd for C23H24N3O2 [M ‡ H ] 374.1869, found 374.1862.
(4-Methyl-2,6-bis-p-tolyloxy-phenyl)-pyrrolidin-1-yl-diazene (19) (Table 2,
entry 16): This compound was prepared according to general procedure (B)
in 70% yield. 19: Rf ˆ 0.36 (silica gel, 10% ether in petroleum ether); IR
(KBr): nÄmax ˆ 2969, 2858, 2367, 1606, 1569, 1501, 1421, 1329, 1219, 1164,
1041 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.04 (d, J ˆ 8.5 Hz, 4H, ArH),
6.82 (d, J ˆ 8.5 Hz, 4H, ArH), 6.63 (s, 2H, ArH), 3.59 (br.s, 2H, NCH2),
3.25 (br.s, 2H, NCH2), 2.29 (s, 6H, CH3), 2.23 (s, 3H, CH3), 1.81-1.76 (m,
4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 156.0, 149.4, 135.3,
131.1, 129.5, 117.4, 117.3, 50.9, 45.8, 23.5, 21.0, 20.5; HRMS (FAB) calcd for
‡
for C16H18N3O [M ‡ H ] 268.1450, found 268.1455.
Pyrrolidin-1-yl-(2-p-tolyloxy-phenyl)-diazene (9) (Table 1, entry 11): This
compound was prepared according to general procedure (A) in 64% yield.
9: Rf ˆ 0.50 (silica gel, 10% ether in petroleum ether); IR (KBr): nÄmax
ˆ
1
2970, 2861, 1583, 1502, 1482, 1407, 1346, 1319, 1238, 1102 cm
;
1H NMR
(500 MHz, CDCl3): d ˆ 7.45 ± 7.43 (m, 1H, ArH), 7.11 ± 7.08 (m, 2H, ArH),
7.04 (d, J ˆ 8.5 Hz, 2H, ArH), 7.02 ± 7.01 (m, 1H, ArH), 6.83 (d, J ˆ 8.5 Hz,
2H, ArH), 3.95 ± 3.60 (br.s, 2H, NCH2), 3.60 ± 3.25 (br.s, 2H, NCH2), 2.28
(s, 3H, CH3), 1.93 ± 1.88 (m, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3):
d ˆ 156.9, 149.5, 143.4, 130.9, 129.6, 125.8, 124.4, 121.5, 118.9, 117.2, 50.8,
‡
C25H28N3O2 [M ‡ H ] 402.2182, found 402.2170.
[2,6-Bis-(2-chloro-phenoxy)-4-methyl-phenyl]-pyrrolidin-1-yl-diazene (20)
(Table 2, entry 15): This compound was prepared according to general
procedure (B) in 78% yield. 20: Rf ˆ 0.46 (silica gel, 10% ether in
petroleum ether); IR (KBr): nÄmax ˆ 2953, 2874, 1589, 1479, 1447, 1408, 1328,
1265, 1233, 1059, 1035, 750 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.35 (dd,
J ˆ 7.5, 1.5 Hz, 2H, ArH), 7.09 ± 7.07 (m, 2H, ArH), 6.93 ± 6.90 (m, 2H,
ArH), 6.79 (s, 2H, ArH), 6.76 (dd, J ˆ 8.5, 1.5 Hz, 2H, ArH), 3.56 (br.s, 2H,
NCH2), 3.02 (br.s, 2H, NCH2), 2.31 (s, 3H, CH3), 1.75 (br.s, 4H,
NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 154.1, 148.1, 135.4, 133.5,
129.8, 127.3, 122.8, 122.4, 119.1, 117.5, 50.4, 45.1, 23.4, 23.4; HRMS (FAB)
‡
46.4, 23.7, 20.6; HRMS (FAB) calcd for C17H20N3O [M ‡ H ] 282.1606,
found 282.1601.
[2-(2-Chloro-4-methyl-phenoxy)-phenyl]-pyrrolidin-1-yl-diazene (10) (Ta-
ble 1, entry 12): This compound was prepared according to general
procedure (A) in 67% yield. 10: Rf ˆ 0.54 (silica gel, 10% ether in
petroleum ether); IR (KBr): nÄmax ˆ 2956, 2875, 1482, 1407, 1339, 1312, 1252,
1102, 1055 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.47 (dd, J ˆ 7.5, 2.5 Hz,
1H, ArH), 7.20 (d, J ˆ 1.5 Hz, 1H, ArH), 7.14 ± 7.08 (m, 2H, ArH), 7.06 ±
7.04 (m, 1H, ArH), 6.85 (dd, J ˆ 8.0, 2.0 Hz, 1H, ArH), 6.62 (d, J ˆ 8.0 Hz,
1H, ArH), 3.91 ± 3.74 (br.s, 2H, NCH2), 3.45 ± 3.25 (br.s, 2H, NCH2), 2.26
(s, 3H, CH3), 1.93 ± 1.88 (m, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3):
d ˆ 152.7, 149.0, 142.8, 132.1, 130.3, 127.9, 125.7, 124.9, 121.5, 118.8, 117.7,
‡
calcd for C23H22N3O2Cl2 [M ‡ H ] 442.1089, found 442.1073.
(2,4-Dimethyl-6-phenoxy-phenyl)-pyrrolidin-1-yl-diazene (21) (Table 2,
entry 12): This compound was prepared according to general procedure
(B) in 56% yield. 21: m.p. 76 ± 778C (EtOAc in petroleum ether); Rf ˆ 0.54
(silica gel, 10% ether in petroleum ether); IR (KBr): nÄmax ˆ 2956, 2874,
1590, 1560, 1490, 1423, 1323, 1216, 1163, 1043, 857, 757, 690 cm 1; 1H NMR
(500 MHz, CDCl3): d ˆ 7.24 ± 7.21 (m, 2H, ArH), 6.96 ± 6.93 (m, 1H, ArH),
6.87 ± 6.84 (m, 3H, ArH), 6.96 ± 6.93 (m, 1H, ArH), 3.70 (br.s, 2H, NCH2),
3.40 (br.s, 2H, NCH2), 2.28 (s, 3H, CH3), 2.26 (s, 3H, CH3), 1.92 ± 1.88 (m,
4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 158.1, 146.9, 140.5,
134.8, 132.8, 129.0, 127.4, 121.2, 120.2, 116.8, 48.0 (very br.), 23.7, 20.9, 18.1;
‡
50.8, 46.1, 24.2, 20.3; HRMS (FAB) calcd for C17H19ClN3O [M ‡ H ]
316.1217, found 316.1209.
[2-(2-Chloro-phenoxy)-phenyl]-pyrrolidin-1-yl-diazene (11) (Table 1, entry
10): This compound was prepared according to general procedure (A) in
70% yield. 11: Rf ˆ 0.56 (silica gel, 10% ether in petroleum ether); IR
(KBr): nÄmax ˆ 2966, 2868, 1575, 1477, 1409, 1342, 1317, 1268, 1237, 1099, 1058,
1
1034 cm 1; H NMR (500 MHz, CDCl3): d ˆ 7.49 (dd, J ˆ 6.5, 1.5 Hz, 1H,
‡
HRMS (FAB) calcd for C18H21N3OCs [M ‡ Cs ] 428.0739, found 428.0749.
ArH), 7.38 (dd, J ˆ 8.0, 1.5 Hz, 1H, ArH), 7.17 ± 7.12 (m, 3H, ArH), 7.06 ±
7.03 (m, 1H, ArH), 6.91 ± 6.87 (m, 1H, ArH), 6.69 (dd, J ˆ 6.5, 1.5 Hz, 1H,
ArH), 3.91 ± 3.81 (br.s, 2H, NCH2), 3.38 ± 3.17 (br.s, 2H, NCH2), 1.91 ± 1.86
(m, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 155.2, 148.5, 142.8,
129.9, 127.3, 125.8, 125.3, 123.0, 122.1, 118.8, 117.5, 50.4, 46.1, 23.7; HRMS
(4-Bromo-2,6-bis-phenoxy-phenyl)-pyrrolidin-1-yl-diazene (22) (Table 2,
entry 13): This compound was prepared according to general procedure
(B) in 91% yield. 22: Rf ˆ 0.41 (silica gel, 10% ether in petroleum ether);
IR (KBr): nÄmax ˆ 3051, 2970, 2861, 1563, 1489, 1400, 1339, 1312, 1211, 1156,
‡
1
1075, 1034, 750, 682 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 7.29 (t, J ˆ
(FAB) calcd for C16H17ClN3O [M ‡ H ] 302.1060, found 302.1069.
9.0 Hz, 4H, ArH), 7.04 (t, J ˆ 9.0 Hz, 2H, ArH), 7.00 (s, 2H, ArH), 6.95 (d,
J ˆ 9.0 Hz, 4H, ArH), 3.62 (br.s, 2H, NCH2), 3.15 (br.s, 2H, NCH2), 1.80 (s,
4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 157.6, 150.1, 135.7,
129.2, 122.5, 120.1, 117.6, 116.7, 50.8, 45.5, 23.6, 23.3; HRMS (FAB) calcd for
General procedure (B) for reactions between 2,6-dihalo triazenes and
phenols (Table 2): A flame-dried flask was charged with 2,6-dihalo triazene
(1.0 equiv), CuBr´ Me2S (10.0 equiv), phenol (2.4 equiv), and the specified
base (10.0 equiv). To this mixture was added acetonitrile, furnishing a
solution approximately 0.1m in triazene, and pyridine (Table 2, entries 10 ±
18, 20 vol% of solvent) was introduced. The reaction mixture was heated at
the indicated temperature (Table 2) for the specified time before it was
cooled to 258C. The resulting slurry was filtered through a pad of celite, and
the celite was washed thoroughly with ether. The product was isolated by
flash column chromatography. The following example further illustrates
this procedure.
‡
C22H21BrN3O2 [M ‡ H ] 438.0817, found 438.0804.
3,5-Diphenoxy-4-(pyrrolidin-1-yl-azo)-benzoic acid methyl ester (23) (Ta-
ble 2, entry 14): Compound 23 was prepared according to general
procedure (B) in 82% yield. 23: Rf ˆ 0.16 (silica gel, 10% EtOAc in
hexanes); IR (KBr): nÄmax ˆ 2917, 2856, 1718, 1566, 1490, 1413, 1312, 1211,
1
1043 cm 1; H NMR (500 MHz, CDCl3): d ˆ 7.57 (s, 2H, ArH), 7.27 ± 7.24
(m, 4H, ArH), 7.00 (t, J ˆ 7.5 Hz, 2H, ArH), 6.90 (d, J ˆ 7.5 Hz, 4H, ArH),
3.83 (s, 3H, OCH3), 3.60 (br.s, 2H, NCH2), 3.14 (br.s, 2H, NCH2), 1.78
(br.s, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 166.0, 158.1,
(4-Methyl-2,6-bis-phenoxy-phenyl)-pyrrolidin-1-yl-diazene (18) (Table 2,
entry 10). General procedure (B): A mixture of [(2,6-dibromophenyl)-
2594
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0947-6539/99/0509-2594 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 1
2584±2601
149.3, 141.0, 129.3, 126.8, 122.3, 118.9, 117.4, 52.2, 51.0, 45.7, 23.7, 23.3;
HRMS (FAB) calcd for C24H24N3O4 [M ‡ H ] 418.1767, found 418.1775.
(silica gel, 10 !30% EtOAc in hexanes, gradient elution) afforded
dipeptide 32 (324 mg, 91%). 32: m.p. 132 8C (EtOAc in hexanes); Rf ˆ
‡
0.50 (silica gel, 50% EtOAc in hexanes); [a]D22
ˆ
1.27 (c ˆ 1.0, MeOH);
[2,6-Bis-(2-chloro-4-methyl-phenoxy)-4-methyl-phenyl]-pyrrolidin-1-yl-di-
azene (24) (Table 2, entry 17): This compound was prepared according to
general procedure (B) in 74% yield. 24: Rf ˆ 0.48 (silica gel, 10% ether in
IR (KBr): nÄmax ˆ 3065, 3032, 2956, 1734, 1687, 1651, 1616, 1541, 1515, 1452,
1384, 1232, 1113, 1053 cm 1; 1H NMR (500 MHz, CD3OD): d ˆ 7.34 ± 7.26
(m, 10H, ArH), 6.73 (d, J ˆ 7.5 Hz, 2H, ArH), 6.53 (d, J ˆ 7.5 Hz, 2H,
ArH), 5.26 (s, 1H, CHCON), 4.60 ± 4.50 (m, 1H, CH2CHCO), 3.69 (s, 2H,
CH2O), 3.30 (s, 3H, OCH3), 2.97 ± 2.85 (m, 2H, CH2CH); 13C NMR
(125 MHz, CD3OD): d ˆ 181.1, 173.2, 172.0, 157.3, 138.6, 131.2, 129.8, 129.7,
129.5, 129.3, 129.1, 128.9, 128.5, 128.1, 116.3, 68.1, 60.5, 55.3, 52.8, 52.3, 37.6;
petroleum ether); IR (KBr): nÄmax ˆ 2966, 2866, 1759, 1605, 1569, 1489, 1415,
1
1323, 1244, 1207, 1059, 1035, 992, 808 cm
;
1H NMR (500 MHz, CDCl3):
d ˆ 7.17 (d, J ˆ 2.0 Hz, 2H, ArH), 6.89 (dd, J ˆ 8.5, 2.0 Hz, 2H, ArH), 6.69
(d, J ˆ 8.5 Hz, 2H, ArH), 6.68 (s, 2H, ArH), 3.55 (br.s, 2H, NCH2), 3.15
(br.s, 2H, NCH2), 2.26 (s, 9H, CH3), 1.81-1.77 (m, 4H, NCH2CH2);
13C NMR (125 MHz, CDCl3): d ˆ 151.9, 148.9, 135.4, 132.6, 130.3, 128.0,
122.9, 118.1, 118.0, 51.1, 46.5, 23.7, 21.2, 20.4; HRMS (FAB) calcd for
‡
HRMS (FAB) calcd for C26H27N2O6 [M ‡ H ] 463.1869, found 463.1879.
Tripeptide 34: A solution of dipeptide 32 (85 mg, 0.18 mmol) in MeOH
(2 mL) was stirred with 10% Pd(OH)2/C (8 mg) under H2 at ambient
temperature for 1 h. Filtration through a pad of celite, followed by removal
of solvent under reduced pressure afforded crude amine 33 (82 mg, 100%),
which was used in the next step without further purification. A solution of
acid 29 (77 mg, 0.20 mmol) and amine 33 (183 mg, 0.40 mmol) in DMF
(2 mL) was treated with HBTU (114 mg, 0.30 mmol) and Et3N (42 mL,
0.30 mmol) at 08C. The reaction mixture was stirred at that temperature for
18 h before the addition of saturated aqueous NH4Cl solution (2 mL). The
mixture was extracted with EtOAc (3 Â 10 mL) and the combined organic
layers were washed with H2O (5 mL), brine (5 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was subjected to flash column
chromatography (silica gel, 1 !3% MeOH in CH2Cl2, gradient elution)
to afford pure tripeptide 34 (88 mg, 63%). 34: m.p. 202 8C (EtOAc in
‡
C25H26Cl2N3O2 [M ‡ H ] 470.1402, found 470.1424.
(4-Methyl-2,6-bis-phenylsulfanyl-phenyl)-pyrrolidin-1-yl-diazene (25) (Ta-
ble 2, entry 18): This compound was prepared from thiophenol according to
general procedure (B) in 84% yield. 25: Rf ˆ 0.52 (silica gel, 10% ether in
petroleum ether); IR (KBr): nÄmax ˆ 3052, 2966, 2866, 1575, 1538, 1477, 1415,
1
1317, 1256, 1213, 1158, 1023, 851, 783, 740, 685 cm 1; H NMR (500 MHz,
CDCl3): d ˆ 7.43-7.41 (m, 4H, ArH), 7.33-7.26 (m, 6H, ArH), 6.62 (s, 2H,
ArH), 3.85 (br.s, 2H, NCH2), 3.55 (br.s, 2H, NCH2), 2.02 (s, 3H, CH3), 1.97
(br.s, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 145.0, 135.5,
134.5, 132.9, 130.6, 129.0, 128.2, 127.3, 51.1, 46.9, 23.8, 20.6; HRMS (FAB)
‡
calcd for C23H24N3S2 [M ‡ H ] 406.1412, found 406.1424.
Triazene alcohol 28: A solution of amino alcohol 26 (1.64 g, 12 mmol) in
glacial acetic acid (100 mL) at 258C was treated dropwise with Br2 (1.4 mL,
26.4 mmol). The resulting mixture was stirred for 0.5 h before it was poured
into ice-water (250 mL). The precipitate was filtered and washed with H2O
(3 Â 30 mL). The product was taken into the next step without further
purification. A solution of alcohol 27 (2.95 g, 10 mmol) in THF/H2O (10:1,
100 mL) was treated with concentrated HCl (4.2 mL) at 08C, and then
aqueous NaNO2 (0.90 g, 13 mmol in 5 mL of H2O) was added dropwise
over 0.5 h. The resulting solution was slowly transferred to a flask charged
with pyrrolidine (8.4 mL, 100 mmol) and K2CO3 (8.28 g, 60 mmol) in H2O
(200 mL) at 08C and stirred for 1 h. The aqueous phase was extracted with
EtOAc (3 Â 200 mL) and the combined organic layers were washed with
saturated aqueous NH4Cl (200 mL), brine (200 mL), and dried over
Na2SO4. The solvent was removed in vacuo and the residue was subjected
to flash column chromatography (silica gel, 20 !30% EtOAc in hexanes,
gradient elution) to furnish triazene 28 (3.17 g, 84%). 28: m.p. 66 ± 678C
hexanes); Rf ˆ 0.35 (silica gel, 5% MeOH in CH2Cl2); [a]D22
ˆ
2.72 (c ˆ
0.52, MeOH); IR (KBr): nÄmax ˆ 3296, 2953, 2923, 2873, 1745, 1643, 1537,
1515, 1416, 1360, 1222 cm 1; 1H NMR (500 MHz, CD3OD): d ˆ 7.51 (s, 2H,
ArH), 7.32 ± 7.21 (m, 5H, ArH), 6.73 (d, J ˆ 8.5 Hz, 2H, ArH), 6.52 (d, J ˆ
8.5 Hz, 2H, ArH), 5.50 (s, 1H, CHCON), 4.63 (d, J ˆ 9.0, 5.0 Hz, 1H,
CH2CHCO), 3.88 (br.s, 2H, NCH2), 3.67 (s, 3H, OCH3), 3.64 (br.s, 2H,
NCH2), 3.52 (br.s, 2H, CH2CO), 2.97 (dd, J ˆ 14.0, 5.0 Hz, 1H, CH2CH),
2.78 (dd, J ˆ 14.0, 9.0 Hz, 1H, CH2CH), 2.02 (br.s, 4H, NCH2CH2);
13C NMR (125 MHz, CD3OD): d ˆ 173.2, 172.0, 172.0, 157.3, 148.2, 138.6,
136.1, 131.2, 129.9, 129.9, 128.6, 128.3, 122.6, 118.7, 116.3, 58.5, 55.4, 52.8,
52.3, 48.5, 41.7, 37.5, 24.9, 24.9; HRMS (FAB) calcd for C30H31Br2N5O5Cs
‡
[M ‡ Cs ] 831.9746, found 831.9723.
C-O-D ring system 35: A solution of tripeptide 34 (70 mg, 0.10 mmol) and
CuBr´ Me2S (72 mg, 0.25 mmol) in degassed acetonitrile (10 mL) was
treated with K2CO3 (35 mg, 0.25 mmol) and pyridine (25 mL, 0.30 mmol).
The resulting mixture was heated to 758C and stirred at that temperature
for 15 h. The reaction mixture was cooled to 258C and filtered through a
pad of celite with thorough washing with EtOAc (3 Â 20 mL). The
combined organic layers were washed with H2O (20 mL), brine (20 mL),
and dried over Na2SO4. The solvent was removed in vacuo and the residue
was subjected to flash column chromatography (silica gel, 2 !4% MeOH
in CHCl3, gradient elution) to afford product 35 (48 mg, 77%). 35: Rf ˆ
0.27 (silica gel, 5% MeOH in CHCl3); [a]2D2 ˆ ‡16.4 (c ˆ 0.53, CHCl3); IR
(KBr): nÄmax ˆ 3062, 2955, 2873, 1743, 1643, 1596, 1504, 1412, 1331, 1317,
(MeOH); Rf ˆ 0.30 (silica gel, 40% EtOAc in hexanes); IR (KBr): nÄmax
ˆ
1
3383, 2947, 2872, 1589, 1535, 1416, 1338, 1314, 1223, 1047 cm
;
1H NMR
(500 MHz, CDCl3): d ˆ 7.41 (s, 2H, ArH), 3.95 (br.s, 2H, NCH2), 3.80 (br.s,
2H, NCH2), 3.71 (br.s, 2H, CH2O), 2.77 (t, J ˆ 6.5 Hz, 2H, CH2Ar), 2.09
(br.s, 4H, NCH2CH2), 1.65 (br.s, 1H, OH); 13C NMR (125 MHz, CDCl3):
d ˆ 146.4, 137.6, 132.7, 117.6, 63.1, 51.1, 46.5, 37.8, 24.1, 22.5; HRMS (FAB)
‡
calcd for C12H16Br2N3O [M ‡ H ] 378.0670, found 378.0856.
Carboxylic acid 29: A solution of 28 (50 mg, 0.13 mmol) in acetone
(400 mL) at 08C was added to a 5% aqueous NaHCO3 solution (400 mL).
The mixture was treated sequentially with KBr (1.6 mg, 0.013 mmol) and
TEMPO (31 mg, 0.20 mmol). Sodium hypochlorite (aqueous 4 ± 6%,
400 mL) was added dropwise over 20 min, and the mixture was stirred at
08C for 2 h. The reaction was quenched by the addition of saturated
aqueous NH4Cl (10 mL) and the resulting mixture was extracted with
EtOAc (2 Â 10 mL). The combined organic phases were washed with H2O
(15 mL), brine (15 mL) and dried over Na2SO4. The solvent was removed
in vacuo and the residue was subjected to flash column chromatography
(silica gel, 5 !10% MeOH in CH2Cl2, gradient elution) to afford
carboxylic acid 29 (42 mg, 82%). 29: m.p. 80 ± 858C (decomp); Rf ˆ 0.40
(silica gel, 15% MeOH in CH2Cl2); IR (KBr): nÄmax ˆ 3441, 2972, 2873, 1711,
1632, 1589, 1537, 1416 cm 1; 1H NMR (500 MHz, CD3OD): d ˆ 7.51 (s, 2 H,
ArH), 3.91 (br.s, 2H, NCH2), 3.64 (br.s, 2H, NCH2), 3.54 (br.s, 2H,
CH2CO2), 2.07 (br.s, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ
175.9, 148.0, 136.2, 134.4, 118.6, 52.5, 47.5, 41.0, 24.7, 22.9; HRMS (FAB)
1
1267, 1211, 1120, 1105, 1032 cm 1; H NMR (400 MHz, CD3OD): d ˆ 7.42
(dd, J ˆ 8.2, 2.5 Hz, 1H, ArH), 7.36 ± 7.27 (m, 5H, ArH), 7.17 (dd, J ˆ 8.2,
2.1 Hz, 1H, ArH), 7.09 (d, J ˆ 1.5 Hz, 1H, ArH), 6.95 (dd, J ˆ 8.5, 2.5 Hz,
1H, ArH), 6.80 (dd, J ˆ 8.5, 2.5 Hz, 1H, ArH), 6.15 (d, J ˆ 1.5 Hz, 1H,
ArH), 5.48 (s, 1H, CHCON), 4.65-4.62 (m, 1H, CH2CHCO), 3.90 (br.s, 2H,
NCH2), 3.67 (s, 3H, OCH3), 3.67 (br.s, 2H, NCH2), 3.52 (d, J ˆ 14.4 Hz, 1H,
CH2CO), 3.43 (dd, J ˆ 14.0, 5.0 Hz, 1H, CH2CH), 3.30 (d, J ˆ 14.0 Hz, 1H,
CH2CO), 3.05 (dd, J ˆ 14.0, 9.0 Hz, 1H, CH2CH), 2.06 (br.s, 4H,
NCH2CH2); 13C NMR (125 MHz, CD3OD): d ˆ 171.2, 170.9, 169.3, 155.3,
154.1, 138.4, 137.7, 133.8, 133.3, 132.0, 131.2, 128.0, 127.6, 127.0, 126.0, 121.5,
121.2, 117.9, 114.9, 56.2, 52.9, 52.8, 51.1, 48.0, 41.2, 34.8, 23.3, 23.3; HRMS
‡
(FAB) calcd for C30H30BrN5O5Cs [M ‡ Cs ] 752.0485, found 752.0466.
Amine 36: A solution of triazene 35 (62 mg, 0.10 mmol) in MeOH (1 mL)
was treated with excess of Raney Ni (W2). The resulting mixture was
heated to reflux for 2 h and then cooled to 258C. The reaction mixture was
filtered through a pad of celite and the celite was washed with EtOAc (3 Â
5 mL). The filtrate was concentrated and flash column chromatography of
the resulting residue (silica gel, 50 !70% EtOAc in hexanes, gradient
elution) afforded product 36 (37 mg, 71%). 36: Rf ˆ 0.16 (silica gel, 70%
‡
calcd for C12H14Br2N3O2 [M ‡ H ] 389.9453, found 389.9440.
Dipeptide 32: A solution of amine 30 (150 mg, 0.77 mmol), acid 31 (438 mg,
1.5 mmol) and HOBt (135 mg, 1.0 mmol) in DMF (6 mL) was treated with
EDC (177 mg, 0.92 mmol) at 08C for 10 h. The reaction mixture was
diluted with EtOAc (25 mL) and washed with 5% aqueous citric acid
(10 mL), 5% aqueous NaHCO3 (10 mL), brine (10 mL), dried over Na2SO4
and concentrated in vacuo. Flash column chromatography of the residue
EtOAc in hexanes); [a]D22 ˆ ‡10.1 (c ˆ 0.22, CH2Cl2); IR (KBr): nÄmax
ˆ
1
3038, 1743, 1632, 1510, 1440, 1345, 1282, 1218 cm
;
1H NMR (600 MHz,
CD3OD/CDCl3, 1:1): d ˆ 7.41 ± 7.37 (m, 3H, ArH), 7.35 (br.d, J ˆ 8.0 Hz,
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2595 $ 17.50+.50/0
2595

K. C. Nicolaou et al.
FULL PAPER
1H, ArH), 7.21 (br.d, J ˆ 8.0 Hz, 1H, ArH), 6.99 (d, J ˆ 7.1 Hz, 2H, ArH),
6.82 (d, J ˆ 8.2 Hz, 1H, ArH), 6.75 (br. d, J ˆ 8.3 Hz, 2H, ArH), 6.59 (br.s,
1H, ArH), 6.18 (d, J ˆ 6.7 Hz, 1H, NH), 6.06 (d, J ˆ 8.2 Hz, 1H, ArH), 5.75
(d, J ˆ 8.4 Hz, 1H, NH), 5.46 (br.s, 1H, CHCON), 4.74 ± 4.69 (m, 1H,
CH2CHCO), 3.76 (s, 3H, OCH3), 3.57 (d, J ˆ 16.4 Hz, 1H, CH2CO), 3.33
(d, J ˆ 16.4 Hz, 1H, CH2CO), 3.25 (dd, J ˆ 13.3, 4.0 Hz, 1H, CH2CH), 2.45
(dd, J ˆ 13.3, 11.3 Hz, 1H, CH2CH); 13C NMR (125 MHz, CD3OD): d ˆ
172.3, 171.6, 169.2, 159.4, 154.1, 136.6, 133.0, 132.9, 132.2, 130.2, 129.7,
128.3, 125.8, 123.3, 121.3, 120.3, 117.1, 58.3, 54.3, 43.5, 39.7; HRMS (FAB)
Triazene azide 43: A solution of triazene alcohol 42 (542 mg, 1.5 mmol) in
THF (15 mL) at 258C was treated sequentially with triphenylphosphane
(590 mg, 2.25 mmol), DEAD (360 mL, 2.25 mmol) and DPPA (485 mL,
2.25 mmol). The resulting solution was stirred at 258C for 2 h. The solvent
was removed in vacuo and the residue was subjected to flash column
chromatography (silica gel, 20 !30% EtOAc in hexanes, gradient elution)
to afford triazene azide 43 (475 mg, 82%). 43: Rf ˆ 0.39 (silica gel, 10%
EtOAc in hexanes); IR (KBr): nÄmax ˆ 3381, 2970, 2871, 2351, 1416, 1336,
1
1313, 1223, 1119, 1069, 1027, 902, 738, 541 cm
;
1H NMR (500 MHz,
‡
calcd for C26H25N3O5 [M ] 460.1872, found 460.1886.
CDCl3): d ˆ 7.52 (s, 2H, ArH), 3.94 (br.s, 2H, NCH2), 3.81 (br.s, 2H,
CH2N3), 3.71 (br.s, 2H, NCH2), 2.30 (br.s, 2H, CH2), 2.09 (br.s, 2H,
NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 147.9, 133.9, 131.8, 118.0,
53.0, 51.1, 46.5, 23.9, 23.5; HRMS (FAB) calcd for C11H12Br2N6Na [M ‡
Phenol 37: Amine 36 (55 mg, 0.12 mmol) dissolved in THF (1 mL) was
added dropwise to a chilled ( 208C) solution of BF3 ´ Et2O (59 mL,
0.48 mmol) in THF (200 mL). To this solution was added tBuNO2 (50 mL,
0.42 mmol) dissolved in THF (200 mL) over 0.5 h. The reaction mixture was
stirred at 208C for 10 min, and was then allowed to reach 58C. Cold
(08C) Et2O (2 mL) was added and the resulting precipitate was collected by
filtration and dried under vacuum. To this precipitate was added saturated
aqueous Cu(NO3)2 (12 mL), followed by Cu2O (86 mg, 0.60 mmol) and the
reaction mixture was stirred at 258C for 3 h before it was extracted with
EtOAc (3 Â 20 mL). The combined organic layers were washed with H2O
(20 mL), brine (20 mL) and dried over Na2SO4. The solvent was removed
in vacuo and the residue was subjected to flash column chromatography
(silica gel, 30 !50% EtOAc in hexanes, gradient elution), furnishing
phenol 37 (33 mg, 60%). 37: Rf ˆ 0.22 (silica gel, 70% EtOAc in hexanes);
‡
Na ] 408.9389, found 408.9393.
Amine 44: A solution of azide 43 (463 mg, 1.2 mmol) in THF (12 mL) was
treated with triphenylphosphane (629 mg, 2.4 mmol) and H2O (220 mL,
12 mmol). The resulting solution was heated to 458C and stirred at that
temperature for 8 h. The solvent was removed in vacuo and the residue was
subjected to flash column chromatography (silica gel, 20 !30% EtOAc in
hexanes, gradient elution) to afford amine 44 (346 mg, 80%). 44: Rf ˆ 0.23
(silica gel, 40% EtOAc in hexanes); IR (KBr): nÄmax ˆ 3400, 3060, 2978,
1
2860, 1637, 1584, 1531, 1408, 1261, 1161, 1114 cm
;
1H NMR (500 MHz,
CDCl3): d ˆ 7.48 (s, 2H, ArH), 3.94 (br.s, 2H, NCH2), 3.81 (br.s, 2H,
CH2NH2), 3.71 (br.s, 2H, NCH2), 2.30 (br.s, 2H, NCH2CH2), 2.09 (br.s,
2H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 146.7, 132.8, 131.1, 117.7,
51.0, 46.4, 44.7, 23.9, 23.5; HRMS (FAB) calcd for C11H14Br2N4Na [M ‡
[a]22 ˆ ‡10.2 (c ˆ 0.25, CH2Cl2); IR (KBr): nÄmax ˆ 3318, 3038, 2945, 2910,
D
1
1737, 1644, 1592, 1510, 1434, 1347, 1277, 1218 cm
;
1H NMR (600 MHz,
‡
CDCl3): d ˆ 7.44 ± 7.38 (m, 6H, ArH), 7.22 (dd, J ˆ 7.1, 2.4 Hz, 1H, ArH),
7.10 (d, J ˆ 6.8 Hz, 1H, ArH), 6.96 (d, J ˆ 8.2 Hz, 1H, ArH), 6.82 (dd, J ˆ
8.2, 2.4 Hz, 1H, ArH), 6.78 (dd, J ˆ 8.2, 1.7 Hz, 1H, ArH), 6.70 (br.s, 1H,
ArH), 6.67 (d, J ˆ 1.8 Hz, 1H, ArH), 6.11 (d, J ˆ 7.9 Hz, 1H, NH), 6.00 (s,
1H, OH), 5.73 (d, J ˆ 8.8 Hz, 1H, NH), 5.45 (d, J ˆ 8.0 Hz, 1H,
COCHNH), 4.72 (ddd, J ˆ 10.8, 8.8, 4.4 Hz, 1H, CH2CHCO), 3.77 (s, 3H,
OCH3), 3.60 (d, J ˆ 16.9 Hz, 1H, CH2CO), 3.39 (d, J ˆ 16.9 Hz, 1H,
CH2CO), 3.24 (dd, J ˆ 13.3, 4.4 Hz, 1H, CH2CH), 2.47 (dd, J ˆ 13.5,
10.8 Hz, 1H, CH2CH); 13C NMR (125 MHz, CD3OD): d ˆ 172.2, 171.3,
169.3, 158.6, 149.4, 146.7, 136.4, 133.7, 133.2, 132.5, 130.2, 129.8, 128.4, 127.9,
126.1, 123.5, 121.4, 119.9, 117.0, 58.4, 54.4, 43.6, 39.7; HRMS (FAB) calcd for
Na ] 382.9471, found 382.9483.
Dipeptide 47: A solution of amine 46 (557 mg, 5.4 mmol), acid 45 (1.52 g,
5.4 mmol), and HOBt (948 mg, 7.0 mmol) in DMF (25 mL) was treated
with EDC (1.24 g, 6.5 mmol) at 08C for 8 h. The reaction mixture was
diluted with EtOAc (100 mL) and washed with saturated aqueous citric
acid (2 Â 30 mL), 5% aqueous NaHCO3 (30 mL), brine (30 mL), dried over
Na2SO4, and concentrated in vacuo. Flash column chromatography of the
residue (silica gel, 2 !4% MeOH in CHCl3, gradient elution) afforded
dipeptide 47 (1.62 g, 85%). 47: Rf ˆ 0.30 (silica gel, 5% MeOH in CHCl3);
[a]2D2
ˆ
0.85 (c ˆ 1.0, MeOH); IR (KBr): nÄmax ˆ 2931, 1759, 1640, 1543
cm 1; 1H NMR (500 MHz, CD3SOCD3): d ˆ 7.73 (d, J ˆ 8.5 Hz, 2 H, ArH),
7.34 (d, J ˆ 8.5 Hz, 2H, ArH), 4.93 ± 4.84 (m, 2H, CHCH2, CHCH3), 4.87 ±
4.84 (m, 1H, CHCH2O), 4.40 (br.t, J ˆ 7.0 Hz, 1H, CHCH2N), 3.53 ± 3.30
(m, 2H, NCHCH2), 2.02 (s, 9H, tBuO), 1.92 (d, J ˆ 7.0 Hz, 3H, CHCH3);
13C NMR (125 MHz, CD3SOCD3): d ˆ 174.0, 171.4, 155.8, 155.1, 130.3,
130.2, 128.1, 114.8, 78.0, 55.8, 47.5, 37.1, 28.2, 17.5; HRMS (FAB) calcd for
‡
C26H24N2O6Cs [M ‡ Cs ] 593.0669, found 593.0656.
Amino alcohol 41: A solution of amino ester 40 (1.38 g, 4.47 mmol) in THF
(30 mL) at 08C was treated with LiAlH4 (510 mg, 13.4 mmol) portionwise.
The resulting mixture was stirred at 08C for 4 h and then it was quenched
by slow addition of H2O (1 mL). The reaction mixture was extracted with
EtOAc (3 Â 40 mL) and the combined organic phases were washed with
5% aqueous NaHCO3 (50 mL), H2O (50 mL), brine (50 mL) and dried
over Na2SO4. The solvent was removed in vacuo and the solid product
obtained was recrystallized from EtOH to afford pure amino alcohol 41
‡
C17H25N2O6 [M ‡ H ] 353.1713, found 353.1716.
D-O-E cyclization precursor 49: A solution of dipeptide ester 47 (915 mg,
2.6 mmol) in MeOH/H2O (1:1, 25 mL) at 08C was treated with anhydrous
LiOH (94 mg, 3.9 mmol). The resulting solution was stirred at 08C for 1 h
before 5% aqueous citric acid (5 mL) was added. The mixture was
extracted with EtOAc (3 Â 20 mL) and the combined organic layers were
washed with H2O (20 mL), brine (20 mL), dried (Na2SO4), and concen-
trated in vacuo to give crude carboxylic acid 48 (880 mg, 100%), which was
used in the next step without further purification. A solution of amine 44
(936 mg, 2.6 mmol), acid 48 (1.32 g, 3.9 mmol) and HOBt (527 mg,
3.9 mmol) in DMF (25 mL) was treated with EDC (1.50 g, 7.8 mmol) at
08C. The resulting mixture was stirred at 08C for 8 h and then was diluted
with EtOAc (100 mL). The organic layer was washed with saturated
aqueous NH4Cl (30 mL), 5% aqueous NaHCO3 (30 mL), brine (30 mL),
dried over Na2SO4 and concentrated in vacuo. Flash column chromatog-
raphy of the resulting residue (silica gel, 2 !5% MeOH in CHCl3, gradient
elution) afforded product 49 (812 mg, 45%). 49: Rf ˆ 0.15 (silica gel, 5%
(1.22 g, 93%). 41: Rf ˆ 0.28 (silica gel, 30% EtOAc in hexanes); IR (KBr):
1
nÄmax ˆ 3307, 1614, 1578, 1472, 1402, 1349, 1284, 1198, 1067, 1026 cm
;
1H NMR (500 MHz, CDCl3): d ˆ 7.40 (s, 2H, ArH), 4.53 (s, 2H, CH2),
1.90 ± 1.50 (br.s, 2H); 13C NMR (125 MHz, CDCl3): d ˆ 141.4, 132.3, 130.7,
‡
108.7, 63.9; HRMS (FAB) calcd for C7H7Br2NO [M ] 278.8894, found
278.8886.
Triazene alcohol 42: A solution of amine 41 (2.81 g, 10 mmol) in THF/H2O
(10:1, 100 mL) was treated with concentrated HCl (4.2 mL) at 08C. A
chilled aqueous solution (08C) of NaNO2 (0.90 g, 13 mmol in 5 mL H2O)
was added dropwise over 0.5 h. The resulting solution was slowly trans-
ferred to a flask charged with pyrrolidine (8.4 mL, 100 mmol) and K2CO3
(8.28 g, 60 mmol) in H2O (200 mL) at 08C and stirred for 1 h. The aqueous
phase was extracted with EtOAc (3 Â 150 mL) and the combined organic
layers were washed with saturated aqueous NH4Cl (200 mL), brine
(200 mL), and dried over Na2SO4. The solvent was removed in vacuo and
the residue was purified by flash column chromatography (silica gel,
20 !30% EtOAc in hexanes, gradient elution) to afford triazene 42 (2.64 g,
73%). 42: m.p. 698C (MeOH); Rf ˆ 0.40 (silica gel, 40% EtOAc in
hexanes); IR (KBr): nÄmax ˆ 3436, 1618, 1548, 1468, 1432, 1403, 1345, 1283,
1201, 1027 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 7.41 (s, 2H, ArH), 4.52
(d, J ˆ 4.5 Hz, 2H, CH2O), 3.81 (br.s, 4H, NCH2), 3.13 (br.s, 1H, OH), 2.05
(br.s, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 145.8, 140.8,
129.8, 117.6, 62.9, 51.1, 46.7, 23.8, 23.6; HRMS (FAB) calcd for
MeOH in CHCl3); [a]D22
2978, 2931, 1666, 1594, 1515, 1454, 1416, 1366, 1314, 1249, 1165, 1018 cm
ˆ
2.13 (c ˆ1.7, MeOH); IR (KBr): nÄmax ˆ 3306,
1
;
1H NMR (500 MHz, CDCl3): d ˆ 7.62 (s, 1H, NH), 7.42 (s, 2H, ArH), 6.91
(d, J ˆ 8.5 Hz, 2H, ArH), 6.78 (br.s, 1H, NH), 6.65 (d, J ˆ 8.5 Hz, 2H,
ArH), 5.55 (br.s, 1H, NH), 4.45-4.42 (m, 1H, CHCH2Ar), 4.39-4.21 (m, 3H,
NCH2Ar, CHCH3), 3.92 (br.s, 2H, NCH2), 3.69 (br.s, 2H, NCH2), 2.93 (dd,
J ˆ 13.5, 6.5 Hz, 1H, NCHCH2), 2.88 (dd, J ˆ 13.5, 7.5 Hz, 1H, NCHCH2),
2.26 (s, 1H, OH), 2.07 (br.s, 2H, CH2), 2.04 (br.s, 2H, NCH2CH2), 1.37 (s,
9H, tBuO), 1.20 (d, J ˆ 6.5 Hz, 3H, CHCH3); 13C NMR (125 MHz, CDCl3):
d ˆ 172.3, 171.9, 171.3, 155.4, 146.9, 137.1, 135.6, 131.4, 130.4, 128.2, 127.1,
117.9, 115.5, 80.4, 56.4, 51.1, 48.8, 46.6, 41.8, 37.3, 28.3, 23.8, 23.3, 17.5;
‡
C11H13Br2N3ONa [M ‡ Na ] 383.9323, found 383.9337.
2596
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2596 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 1
2584±2601
‡
HRMS (FAB) calcd for C28H36Br2N6O5Cs [M ‡ Cs ] 827.0168, found
stirred at 08C for 12 h, and then the reaction was quenched by the addition
of saturated NH4Cl solution (3 mL). The resulting mixture was extracted
with EtOAc (3 Â 10 mL) and the combined organic layers were washed
with 5% aqueous NaHCO3 (20 mL), brine (20 mL), and dried (Na2SO4).
The solvent was removed in vacuo and the residue was subjected to flash
column chromatography (silica gel, 20 !40% EtOAc in hexanes, gradient
elution) to give dipeptide 60 (200 mg, 81%). 60: Rf ˆ 0.13 (silica gel, 40%
EtOAc in hexanes); IR (thin film): nÄmax ˆ 3314, 2924, 1675, 1650, 1583,
1504, 1449, 1314, 1156, 1064 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 6.60 (d,
J ˆ 2.5 Hz, 1H, ArH), 6.36 (d, J ˆ 2.5 Hz, 1H, ArH), 6.62 (br.s, 1H, NH),
5.11 (br.s, 1H, NH), 4.51 (d, J ˆ 6.5 Hz, 2H, CH2), 3.85 (s, 3H, OCH3), 3.82
(br.s, 2H, CH2), 3.80 (s, 3H, OCH3), 1.43 (s, 9H, tBuO); 13C NMR
(125 MHz, CDCl3): d ˆ 169.2, 161.3, 158.9, 156.0, 142.1, 106.6, 98.2, 80.4,
79.9, 56.5, 55.6, 48.3, 44.5, 28.3; HRMS (FAB) calcd for C16H24IN2O5 [M ‡
827.0195.
D-O-E ring system 50: A solution of tripeptide 49 (76 mg, 0.11 mmol) and
CuBr´ Me2S (80 mg, 0.28 mmol) in degassed acetonitrile (11 mL) was
treated with K2CO3 (38 mg, 0.28 mmol) and pyridine (27 mL, 0.33 mmol).
The resulting mixture was heated to 758C, stirred at that temperature for
6 h, and then cooled to 258C. The reaction mixture was filtered through a
pad of celite and the celite was washed thoroughly with EtOAc (3 Â
20 mL). The combined organic layers were washed with H2O (20 mL),
brine (20 mL), and dried over Na2SO4. The solvent was removed in vacuo
and the residue was subjected to flash column chromatography (silica gel,
2 !4% MeOH in CHCl3, gradient elution) to afford model system 50
(36 mg, 54%) and recovered tripeptide 49 (10 mg, 13%). 50: Rf ˆ 0.23
(silica gel, 5% MeOH in CHCl3); [a]2D2 ˆ ‡10.6 (c ˆ 0.91, MeOH); IR
(KBr): nÄmax ˆ 3401, 3306, 3072, 2976, 2936, 2873, 1714, 1651, 1599, 1563,
1504, 1412, 1366, 1335, 1250, 1203, 1163 cm 1; 1H NMR (500 MHz, CD3OD,
323 K): d ˆ 7.47 (dd, J ˆ 8.5, 2.5 Hz, 1H, ArH), 7.09 (s, 1H, ArH), 7.07 (dd,
J ˆ 8.5, 2.5 Hz, 1H, ArH), 7.00 (dd, J ˆ 8.5, 2.5 Hz, 1H, ArH), 6.80 (dd, J ˆ
8.5, 2.5 Hz, 1H, ArH), 6.02 (br.s, 1H, ArH), 4.69 (d, J ˆ 16.0 Hz, 1H,
ArCH2N), 4.30-4.29 (m, 1H, CHCH2Ar), 4.36 (q, J ˆ 7.0 Hz, 1H, CHCH3),
3.90 (br.s, 4H, NCH2), 3.72 (d, J ˆ 16.0 Hz, 1H, ArCH2N), 3.25 (dd, J ˆ
14.0, 5.5 Hz, 1H, CHCH2Ar), 2.94 (dd, J ˆ 14.0, 2.7 Hz, 1H, CHCH2Ar),
2.01 (br.s, 4H, NCH2CH2), 1.48 (s, 9H, tBuO), 1.20 (d, J ˆ 7.0 Hz, 3H,
CHCH3); 13C NMR (125 MHz, CD3OD, 323 K): d ˆ 174.6, 171.9, 156.6,
155.1, 139.8, 138.0, 134.3, 132.9, 131.9, 124.7, 123.5, 123.1, 119.3, 114.5, 82.0,
58.3, 53.0, 49.8, 49.5, 48.4, 42.1, 37.2, 28.6, 23.7, 23.7, 20.0; HRMS (FAB)
‡
H ] 451.0730, found 451.0722.
Carboxylic acid 63: A solution of ester 62 (809 mg, 2.1 mmol) in THF/H2O
(1:1, 15 mL) was treated with anhydrous LiOH (76 mg, 3.2 mmol) at 08C
for 1 h. The reaction was quenched by the addition of saturated NH4Cl
solution (10 mL) and the mixture was extracted with EtOAc (3 Â 20 mL).
The combined organic layers were washed with H2O (30 mL), brine
(30 mL), and dried (Na2SO4). The solvent was removed in vacuo to afford
crude 63 (778 mg, 99%), which was taken into next step without further
purification.
Tripeptide 64: A solution of dipeptide 60 (300 mg, 0.67 mmol) in CH2Cl2
(1 mL) at 08C was treated with TFA (1 mL). The solution was allowed to
reach ambient temperature and stirred for 2 h before it was quenched by
the addition of saturated aqueous NaHCO3 (10 mL). The resulting mixture
was extracted with EtOAc (3 Â 10 mL) and the combined organic layers
were washed with 5% aqueous NaHCO3 (2 Â 10 mL), H2O (10 mL), brine
(10 mL), and dried (Na2SO4). The solvent was removed in vacuo and the
resulting crude dipeptide amine 61 (233 mg, 100%) was taken into the next
step without further purification. To a solution of amine 61 (70 mg,
0.2 mmol), acid 63 (97 mg, 0.24 mmol), and Et3N (61 mL, 0.44 mmol) in
DMF (2 mL) was added EDC (50 mg, 0.26 mmol) at 08C, and the resulting
solution was stirred at that temperature for 12 h. The reaction was
quenched by the addition of saturated NH4Cl (5 mL) and the resulting
mixture was extracted with EtOAc (3 Â 10 mL). The combined organic
layers were washed with 5% NaHCO3 (15 mL), brine (15 mL) and dried
(Na2SO4). The solvent was removed in vacuo and the residue was subjected
to flash column chromatography (silica gel, 20 !40% EtOAc in hexanes,
gradient elution) to afford tripeptide 64 (136 mg, 92%). 64: Rf ˆ 0.14 (silica
‡
calcd for C28H35BrN6O5Cs [M ‡ Cs ] 747.0907, found 747.0888.
Iodide alcohol 57: A solution of alcohol 56 (437 mg, 2.6 mmol) in DMF
(10 mL) at 258C was treated with N-iodosuccinimide (878 mg, 3.9 mmol).
The resulting solution was stirred at that temperature for 12 h, and then it
was quenched by the addition of aqueous saturated Na2SO3 (10 mL). The
mixture was extracted with EtOAc (3 Â 15 mL) and the combined organic
layers were washed with 5% aqueous NaHCO3 (20 mL), brine (20 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 give product 57 (696 mg, 91%). 57: Rf ˆ 0.17
(silica gel, 40% EtOAc in hexanes); IR (thin film) nÄmax ˆ 3366, 2931, 1578,
1449, 1420, 1314, 1196, 1155, 1038, 1008 cm 1; 1H NMR (500 MHz, CDCl3):
d ˆ 6.67 (d, J ˆ 2.5 Hz, 1H, ArH), 6.32 (d, J ˆ 2.5 Hz, 1H, ArH), 4.60 (s,
2H, CH2), 3.81 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 2.72 (br.s, 1H, OH);
13C NMR (125 MHz, CDCl3): d ˆ 161.1, 158.3, 144.6, 105.0, 97.8, 77.5, 69.3,
gel, 40% EtOAc in hexanes); [a]D22
ˆ
42.6 (c ˆ 0.39, CHCl3); IR (KBr):
‡
56.3, 55.5; HRMS (FAB) calcd for C9H11IO3 [M ] 293.9753, found 293.9755.
1
nÄmax ˆ 3333, 2966, 2355, 1743, 1670, 1590, 1486, 1456, 1364, 1248, 1162 cm
;
Azide 58: A solution of alcohol 57 (588 mg, 2.0 mmol) in THF (15 mL) at
08C was treated sequentially with DEAD (470 mL, 3.0 mmol), triphenyl-
phosphane (786 mg, 3.0 mmol), and DPPA (650 mL, 3.0 mmol). The
resulting solution was stirred at 08C for 2 h, and then concentrated in
vacuo to afford an oil, which was purified by flash column chromatography
(silica gel, 10 !30% ether in hexanes, gradient elution), furnishing azide 58
(523 mg, 82%). 58: Rf ˆ 0.35 (silica gel, 20% EtOAc in hexanes); IR (thin
film) nÄmax ˆ 2942, 2355, 2098, 1578, 1450, 1425, 1340, 1315, 1205, 1156, 1083
cm-1; 1H NMR (400 MHz, CDCl3): d ˆ 6.62 (d, J ˆ 2.6 Hz, 1H, ArH), 6.40
(d, J ˆ 2.6 Hz, 1H, ArH), 4.48 (s, 2H, CH2), 3.88 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3): d ˆ 161.2, 159.1, 140.0, 106.2, 98.4,
1H NMR (500 MHz, CDCl3): d ˆ 7.77 (d, J ˆ 2.0 Hz, 1H, ArH), 7.37 (br.s,
1H, NH), 7.28 (dd, J ˆ 8.5, 2.0 Hz, 1H, ArH), 7.00 (br.s, 1H, NH), 7.67 (d,
J ˆ 8.5 Hz, 1H, ArH), 6.48 (d, J ˆ 2.5 Hz, 1H, ArH), 6.30 (d, J ˆ 2.5 Hz,
1H, ArH), 5.83 (d, J ˆ 6.5 Hz, 1H, CH), 5.15 (br.s, 1H, NH), 4.38 (d, J ˆ
6.0 Hz, 2H, CH2), 3.98-3.85 (m, 2H, CH2), 3.80 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 3.73 (s, 3H, OCH3), 1.34 (s, 9H, tBuO); 13C NMR (125 MHz,
CDCl3): d ˆ 170.9, 168.5, 161.1, 158.7, 158.0, 155.2, 141.7, 137.9, 131.4, 128.5,
110.9, 106.1, 97.8, 86.3, 80.3, 79.4, 57.4, 56.4, 56.3, 55.5, 48.5, 43.3, 28.2;
‡
HRMS (FAB) calcd for C25H31I2N3O7Cs [M ‡ Cs ] 871.9306, found:
871.9329.
‡
AB model system 65: To a stirred solution of (Ph3P)2NiCl2 (59 mg,
0.09 mmol) and triphenylphosphane (48 mg, 0.18 mmol) in degassed DMF
(10 mL) at 558C was added zinc dust (5.9 mg, 0.09 mmol). After stirring for
0.5 h, a solution of tripeptide 64 (37 mg, 0.05 mmol) in DMF (15 mL) was
slowly transferred to the reaction mixture by cannula. The resulting
solution was stirred at 558C for 16 h, and then it was quenched by the
addition of saturated NH4Cl (15 mL). The mixture was extracted with
EtOAc (3 Â 20 mL) and the combined organic layers were washed with
H2O (30 mL), brine (30 mL), and dried (Na2SO4). The solvent was removed
in vacuo and the residue was subjected to flash column chromatography
(silica gel, 0 !2% MeOH in CHCl3, gradient elution) to afford 65a
(3.2 mg, 13%) and 65b (3.2 mg, 13%). 65a: Rf ˆ 0.20 (silica gel, 2.5%
79.8, 59.4, 56.5, 55.5; HRMS (FAB) calcd for C9H11IN3O2 [M ‡ H ]
319.9896, found 319.9892.
Amine 59: To a solution of azide 58 (510 mg, 1.6 mmol) in THF/H2O (10:1,
10 mL) was added triphenylphosphane (1.26 g, 4.8 mmol) and the resulting
solution was heated to 458C for 4 h with stirring. The solution was cooled to
258C and the solvent was removed in vacuo. The residue was subjected to
flash column chromatography (silica gel, 1 !5% MeOH in CHCl3,
gradient elution) to afford amine 59 (375 mg, 80%). 59: Rf ˆ 0.37 (silica
gel, 10% MeOH in CHCl3); IR (thin film): nÄmax ˆ 3366, 2931, 1578, 1449,
1420, 1320, 1202, 1155, 1067, 1002 cm 1; H NMR (500 MHz, CDCl3): d ˆ
1
6.62 (d, J ˆ 2.5 Hz, 1H, ArH), 6.34 (d, J ˆ 2.5 Hz, 1H, ArH), 3.86 (s, 2H,
CH2), 3.85 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 1.74 (s, 2H, NH2); 13C NMR
(125 MHz, CDCl3): d ˆ 161.3, 158.8, 147.2, 105.6, 97.3, 79.6, 56.4, 55.5, 51.7;
MeOH in CHCl3); [a]D22
2924, 1673, 1611, 1585, 1501, 1366, 1324, 1256, 1157, 1110, 1063 cm
ˆ
45.7 (c ˆ 0.37, CH2Cl2); IR (KBr): nÄmax ˆ 3320,
1
;
‡
HRMS (FAB) calcd for C9H13INO2 [M ‡ H ] 293.9991, found 293.9994.
1H NMR (600 MHz, CDCl3) (see Figure 2 for numbering): d ˆ 7.82 (t, J ˆ
6.6 Hz, 1H, N3H), 7.40 (br.s, 1H, N6H), 7.30 (dd, J ˆ 8.3, 2.1 Hz, 1H,
ArAHb), 7.08 (br.s, 1H, ArAHa), 6.95 (d, J ˆ 8.3 Hz, 1H, ArAHc), 6.85 (br.s,
1H, NHBoc), 6.58 (d, J ˆ 2.2 Hz, 1H, ArBHb), 6.56 (d, J ˆ 2.2 Hz, 1H,
Dipeptide 60: A solution of amine 59 (162 mg, 0.55 mmol), N-Boc-Gly
(97 mg, 0.55 mmol), and Et3N (190 mL, 1.38 mmol) in DMF (3 mL) was
treated with EDC (158 mg, 0.83 mmol) at 08C. The resulting solution was
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2597 $ 17.50+.50/0
2597

K. C. Nicolaou et al.
FULL PAPER
ArBHa), 4.81 (br.s, 1H, H1), 3.86 ± 3.84 (m, 1H, H7), 3.76 ± 3.74 (m, 1H, H4),
3.72 (s, 3H, OCH3), 3.66 ± 3.64 (m, 1H, H4), 3.63 (s, 6H, OCH3), 3.30-3.28
(m, 1H, H7), 1.34 (s, 9H, tBuO); 13C NMR (150 MHz, CD3SOCD3): d ˆ
172.1, 170.4, 167.5, 159.5, 158.1, 156.7, 137.4, 132.9, 129.9, 127.7, 124.1,
120.8, 110.8, 107.9, 97.9, 78.3, 59.7, 55.7, 55.5, 55.3, 43.7, 43.3, 28.1; HRMS
mixture was slowly warmed to 258C, stirred for 3 h, and then diluted with
EtOAc (60 mL). The organic phase was washed with 5% aqueous HCl
(2 Â 20 mL), 5% aqueous NaHCO3 (20 mL), brine (20 mL), and dried over
Na2SO4. The solvent was removed in vacuo, and flash column chromatog-
raphy (silica gel, 20 !40% EtOAc in hexanes, gradient elution) of the
residue afforded product 70 (736 mg, 90%). 70: Rf ˆ 0.28 (silica gel, 50%
‡
(FAB) calcd for C25H31N3O7Na [M ‡ Na ] 508.2060, found 508.2067. 65b:
Rf ˆ 0.25 (silica gel, 2.5% MeOH in CHCl3); [a]D22
ˆ
18.1 (c ˆ 0.63,
EtOAc in hexanes); [a]D22 ˆ ‡1.23 (c ˆ 2.6, CHCl3); IR (thin film): nÄmax
ˆ
1
CH2Cl2); IR (KBr): nÄmax ˆ 3314, 2924, 2853, 1677, 1581, 1504, 1459, 1366,
3344, 1740, 1663, 1510, 1488, 1439, 1368, 1252, 1165, 1050 cm 1; H NMR
(500 MHz, CDCl3): d ˆ 7.69 (d, J ˆ 2.5 Hz, 1H, ArH), 7.24 (s, 1H, OH), 7.20
(dd, J ˆ 8.5, 1.5 Hz, 1H, ArH), 6.87 (d, J ˆ 8.5 Hz, 1H, ArH), 6.73-6.65 (m,
2H, ArH), 6.54 (s, 2H, ArH), 6.15 (br.s, 1H, NH), 5.79 (br.s, 1H, NH), 5.00
(br.s, 1H, CH), 4.77 (dd, J ˆ 5.5, 5.5 Hz, 1H, CHCH2), 3.86 (s, 3H, OCH3),
3.72 (s, 3H, OCH3), 2.89 (d, J ˆ 6.0 Hz, 2H, CH2), 1.38 (s, 9H, tBuO);
13C NMR (125 MHz, CDCl3): d ˆ 171.7, 169.9, 169.6, 158.0, 155.2, 154.8,
137.9, 132.2, 130.2, 128.5, 126.2, 121.6, 115.5, 111.0, 86.4, 80.3, 57.0, 56.3, 53.1,
1
1320, 1262, 1160, 1110 cm
;
1H NMR (600 MHz, CD3SOCD3): d ˆ 8.57
(br.s, 1H, N3H), 8.29 (br.s, 1H, N6H), 7.38 ± 7.36 (m, 2H, NHBoc, ArAHb),
7.18 (s, 1H, ArAHa), 6.98 (d, J ˆ 8.6 Hz, 1H, ArAHc), 6.50 (s, 2H, ArBHa,b),
5.13 ± 5.12 (m, 1H, H1), 4.24 ± 4.13 (m, 2H, H7), 3.81 (s, 3H, OCH3), 3.86 ±
3.82 (m, 1H, H4), 3.74 (s, 3H, OCH3), 3.70 ± 3.68 (m, 1H, H4), 3.67 (s, 3H,
OCH3), 1.32 (s, 9H, tBuO); 13C NMR (150 MHz, CD3SOCD3): d ˆ 171.1,
168.9, 160.8, 158.4, 156.4, 155.3, 142.3, 130.2, 130.1, 129.8, 128.2, 127.8, 110.0,
105.4, 97.4, 78.7, 57.6, 56.5, 55.5, 55.1, 47.8, 42.4, 28.1; HRMS (FAB) calcd for
‡
52.5, 36.6, 28.2; HRMS (FAB) calcd for C24H29IN2O7Cs [M ‡ Cs ] 717.0074,
‡
C25H31N3O7Na [M ‡ Na ] 508.2060, found 508.2069.
found 717.0098.
Amine 66: A solution of 26 (343 mg, 2.5 mmol) in DMF (20 mL) was
treated with N-bromosuccinimide (534 mg, 2.0 mmol) at 258C for 12 h. The
reaction was quenched by the addition of saturated aqueous Na2SO3
solution (20 mL) and the resulting mixture was extracted with EtOAc
(3 Â 30 mL). The combined organic layers were washed with H2O (30 mL),
brine (30 mL), and dried over Na2SO4. The solvent was removed in vacuo
and the residue was subjected to flash column chromatography (silica gel,
10 !40% EtOAc in hexanes, gradient elution) to give amine 66 (333 mg,
62%). 66: Rf ˆ 0.26 (silica gel, 50% EtOAc in hexanes); IR (thin film)
nÄmax ˆ 3281, 1616, 1495, 1051, 1018, 836 cm 1; 1H NMR (500 MHz, CDCl3):
d ˆ 7.25 (s, 1 H, ArH), 6.93 (d, J ˆ 8.0 Hz, 1 H, ArH), 6.68 (d, J ˆ 7.5 Hz, 1H,
ArH), 3.73 (t, J ˆ 6.50 Hz, 2H, CH2OH), 3.60-3.30 (br.s, 2H, NH2), 2.68 (t,
J ˆ 7.0 Hz, 2H, CH2); 13C NMR (125 MHz, CDCl3): d ˆ 142.4, 132.7, 129.7,
Tripeptide 72: To a solution of dipeptide 70 (1.2 g, 2.2 mmol) in CH2Cl2
(10 mL) at 08C was added TFA (10 mL). The resulting solution was stirred
for 1 h before it was concentrated under reduced pressure. The crude
product (71, 970 mg) was taken into next step without further purification.
A solution of acid 68 (499 mg, 1.6 mmol), amine 71 (726 mg, 1.6 mmol), and
Et3N (670 mL, 4.8 mmol) in DMF (15 mL) was treated with HBTU
(728 mg, 1.92 mmol) at 08C. The resulting solution was allowed to reach
ambient temperature and stirred for 3 h. The reaction was diluted with
EtOAc (60 mL) and the organic phase was washed with saturated aqueous
NH4Cl (30 mL), 5% aqueous NaHCO3 (30 mL), brine (30 mL), and dried
over Na2SO4. The solvent was removed in vacuo and the residue was
purified by flash column chromatography (silica gel, 30 !60% EtOAc in
hexanes, gradient elution) to afford tripeptide 72 (1.12 g, 90%). 72: Rf ˆ
0.47 (silica gel, 80% EtOAc in hexanes); [a]2D2 ˆ ‡21.7 (c ˆ 0.49, CHCl3);
IR (thin film): nÄmax ˆ 3289, 2950, 1740, 1642, 1510, 1389, 1252 cm-1; 1H NMR
(500 MHz, CDCl3): d ˆ 9.18 (s, 1H, OH), 8.76-8.72 (m, 2H, NH), 7.74 (d,
J ˆ 2.0 Hz, 1H, ArH), 7.48 (s, 1H, ArH), 7.24 (d, J ˆ 8.0 Hz, 1H, ArH),
7.16 ± 7.14 (m, 2H, ArH), 6.84 (d, J ˆ 9.0 Hz, 1H, ArH), 6.79 (d, J ˆ 8.5 Hz,
2H, ArH), 6.53 (d, J ˆ 8.7 Hz, 2H, ArH), 5.47 (d, J ˆ 8.0 Hz, 1H, CH),
4.35 ± 4.25 (m, 1H, CHCH2), 3.88 (br.s, 2H, NCH2), 3.79 (s, 3H, OCH3),
3.61 (s, 2H, CH2CO), 3.55 (br.s, 2H, NCH2), 3.31 (s, 3H, OCH3), 2.93 ± 2.79
(m, 2H, CHCH2), 2.02 (br.s, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3):
d ˆ 172.0, 170.0, 169.0, 157.1, 155.2, 144.0, 138.3, 133.7, 132.0, 131.7, 130.3,
130.0, 128.8, 128.5, 126.0, 121.1, 120.0, 118.9, 118.0, 115.7, 111.1, 56.4, 55.8,
53.2, 52.5, 51.0, 47.0, 42.3, 38.5, 24.0, 23.5; HRMS (FAB) calcd for
‡
128.9, 115.8, 109.3, 63.5, 37.8; HRMS (FAB) calcd for C8H11BrNO [M ‡ H ]
216.0024, found 216.0029.
Triazene alcohol 67: A solution of amine 66 (1.67 g, 5.6 mmol) in 0.1n
aqueous HCl (6.7 mL) at 08C was treated with aqueous NaNO2 (386 mg in
1 mL H2O, 5.6 mmol). The resulting solution was stirred for 0.5 h before it
was transferred slowly to a flask charged with pyrrolidine (4.7 mL,
56 mmol) in saturated aqueous K2CO3 (100 mL) at 08C. The mixture was
stirred for 1 h and then it was extracted with EtOAc (3 Â 50 mL) and the
combined organic layers were washed with H2O (50 mL), brine (50 mL),
and dried over Na2SO4. The solvent was removed in vacuo and the residue
was purified by flash column chromatography (silica gel, 10 !30% EtOAc
in hexanes, gradient elution) to afford triazene alcohol 67 (1.38 g, 83%). 67:
Rf ˆ 0.34 (silica gel, 50% EtOAc in hexanes); IR (thin film): nÄmax ˆ 3366,
2950, 2862, 1477, 1417, 1395, 1340, 1313, 1039 cm-1; 1H NMR (500 MHz,
CDCl3): d ˆ 7.37 (s, 1 H, ArH), 7.27 (d, J ˆ 8.0 Hz, 1H, ArH), 7.02 (dd, J ˆ
8.0, 1.0 Hz, 1H, ArH), 3.84 (br.s, 2H, NCH2), 3.69 (t, J ˆ 6.5 Hz, 2H,
CH2O), 3.65 (br.s, 2H, NCH2), 2.70 (t, J ˆ 7.0 Hz, 2H, CH2), 2.48 (br.s, 1H,
OH), 1.95 (br.s, 4H, NCH2CH2); 13C NMR (125 MHz, CDCl3): d ˆ 146.9,
136.7, 133.0, 128.3, 118.9, 118.3, 63.1, 50.8, 46.5, 38.0, 23.5, 23.5; HRMS
‡
C31H33BrIN5O6Cs [M ‡ Cs ] 909.9713, found 909.9743.
C-O-D ring system 73: To a solution of tripeptide 72 (78 mg, 0.10 mmol)
and CuBr´ Me2S (84 mg, 0.29 mmol) in degassed acetonitrile (10 mL) were
added K2CO3 (33 mg, 0.24 mmol) and pyridine (25 mL, 0.30 mmol). The
resulting mixture was heated to reflux and stirred for 36 h. The reaction
mixture was cooled to 258C and filtered through celite. The celite was
washed thoroughly with EtOAc (3 Â 20 mL) and the combined filtrate was
washed with H2O (20 mL), brine (20 mL) and dried over Na2SO4. The
solvent was removed in vacuo and the residue was subjected to flash
column chromatography (silica gel, 30 !60% EtOAc in hexanes, gradient
elution) to afford compound 73 (47 mg, 67%), 73 epimer (4 mg, 6%), and
recovered tripeptide 72 (8 mg, 10%). 73: Rf ˆ 0.28 (silica gel, 80% EtOAc
‡
(FAB) calcd for C12H17BrN3O [M ‡ H ] 298.0555, found 298.0550.
Carboxylic acid 68: A solution of alcohol 67 (300 mg, 1.0 mmol) in acetone
(3.1 mL) at 08C was added to a 5% aqueous NaHCO3 solution (3.1 mL),
and the resulting mixture was treated sequentially with KBr (12 mg,
0.1 mmol) and TEMPO (155 mg, 1.0 mmol). Sodium hypochlorite (5% in
H2O, 4 mL) was added dropwise over 20 min, and the mixture was stirred at
08C for 1 h. The reaction was quenched with saturated aqueous NH4Cl
(10 mL) and the resulting mixture was extracted with EtOAc (2 Â 20 mL).
The organic layer was washed with H2O (20 mL), brine (20 mL) and dried
over Na2SO4. The solvent was removed in vacuo and the residue was
subjected to flash column chromatography (silica gel, 20 !40% EtOAc in
hexanes, gradient elution) to give carboxylic acid 68 (267 mg, 86%). 68:
in hexanes); [a]D22
ˆ
46.2 (c ˆ 1.0, THF); IR (thin film): nÄmax ˆ 3285, 2948,
1
2874, 1744, 1644, 1506, 1487, 1212 cm 1; H NMR (500 MHz, CDCl3): d ˆ
7.42 (d, J ˆ 2.7 Hz, 1H), 7.37 (d, J ˆ 10.2 Hz, 1H), 7.31 (dd, J ˆ 10.5,
2.6 Hz, 1H, ArH), 7.22 (dd, J ˆ 10.4, 3.1 Hz, 1H, ArH), 7.13 (dd, J ˆ 10.5,
2.7 Hz, 1H, ArH), 6.99 (dd, J ˆ 10.3, 2.1 Hz, 1H, ArH), 6.84 (dd, J ˆ 12.7,
2.7 Hz, 1H, ArH), 6.79 (dd, J ˆ 7.8, 2.3 Hz, 1H, ArH), 6.78 (d, J ˆ 10.5 Hz,
1H, ArH), 6.64 (d, J ˆ 2.2 Hz, 1H, ArH), 6.15 (d, J ˆ 8.6 Hz, 1H, ArH),
5.68 (d, J ˆ 11.3 Hz, 1H), 5.24 (d, J ˆ 8.7 Hz, 1H), 4.79 ± 4.68 (m, 1H), 3.90-
3.70 (m, 4H, NCH2), 3.87 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.56 (d, J ˆ
18.3 Hz, 1H), 3.38 (d, J ˆ 18.3 Hz, 1H), 3.24 (dd, J ˆ 16.9, 5.9 Hz, 1H), 2.53
(dd, J ˆ 16.8, 13.3 Hz, 1H), 2.03 (br.s, 4H, NCH2CH2); 13C NMR
(100 MHz, CDCl3): d ˆ 172.9, 172.7, 170.5, 167.4, 159.5, 156.7, 155.5,
140.7, 139.3, 134.5, 133.6, 132.6, 130.2, 129.8, 123.8, 123.2, 122.8, 119.6, 116.4,
116.2, 111.9, 71.6, 69.8, 56.2, 55.8, 54.4, 52.8, 43.0, 36.3, 24.8, 19.3; HRMS
Rf ˆ 0.22 (silica gel, 50% EtOAc in hexanes); IR (thin film): nÄmax ˆ 3460,
1
2920, 2861, 1760, 1713, 1461, 1261, 1096 cm
;
1H NMR (500 MHz,
CD3OD): d ˆ 7.47 (s, 1 H, ArH), 7.30 ± 7.29 (m, 1H, ArH), 7.14 ± 7.11 (m,
1H, ArH), 3.81 (br.s, 2H, NCH2), 3.60 (br.s, 2H, NCH2), 3.48 (s, 2H,
CH2CO), 1.94 (br.s, 4H, NCH2CH2); 13C NMR (125 MHz, CD3OD): d ˆ
177.6, 148.4, 134.9, 134.5, 129.8, 119.9, 119.2, 67.4, 51.6, 48.4, 24.6, 24.6;
‡
HRMS (FAB) calcd for C12H15BrN3O2 [M ‡ H ] 312.0348, found 312.0340.
‡
(FAB) calcd for C31H32IN5O6Cs [M ‡ Cs ] 830.0452, found 830.0438.
Dipeptide 70: To a stirred solution of tyrosine methyl ester 69 (478 mg,
1.4 mmol), acid 63 (570 mg, 1.4 mmol), and Et3N (580 mL, 4.2 mmol) in
DMF (15 mL) was added HBTU (637 mg, 1.7 mmol) at 08C. The reaction
C-O-D template 74: A solution of compound 73 (80 mg, 0.11 mmol) in
THF (1 mL) was treated with TFA (20 mL, 0.25 mmol) at 258C. After
2598
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
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Chem. Eur. J. 1999, 5, No. 9

Total Synthesis of VancomycinÐPart 1
2584±2601
stirring for 15 min, Cu2O (83 mg, 0.55 mmol) was added and the resulting
mixture was heated at reflux for 1 h. After cooling to 258C, the reaction
mixture was filtered through a pad of celite with thorough washing
(EtOAc). 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 give product 74 (59 mg, 90%). 74: Rf ˆ 0.55 (silica gel,
OCH3), 3.67 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 3.43 (d, J ˆ 14.9 Hz, 1H),
3.36 (d, J ˆ 14.9 Hz, 1H), 3.30 ± 3.26 (m, 1H), 3.17 (dd, J ˆ 13.8, 5.5 Hz,
1H), 2.89 ± 2.85 (m, 1H); 13C NMR (150 MHz, CDCl3/CD3OD, 1:1): d ˆ
172.4, 171.6, 170.5, 162.0, 161.5, 158.4, 158.3, 157.1, 142.4, 137.0, 133.4,
133.1, 131.8, 131.7, 130.7, 129.3, 128.3, 126.4, 124.1, 123.3, 122.4, 118.5, 117.6,
116.8, 112.0, 104.8, 98.4, 62.8, 58.0, 56.5, 56.4, 56.0, 54.2, 54.1, 53.1, 44.1;
‡
70% EtOAc in hexanes); [a]D22
ˆ
55.8 (c ˆ 2.8, THF); IR (thin film)
HRMS (FAB) calcd for C36H36N2O9Cs [M ‡ Cs ] 773.1475, found 773.1495.
1
nÄmax ˆ 3331, 3060, 1741, 1649, 1591, 1504, 1440, 1231, 1169, 1030, 755 cm
;
Azide 76: To a solution of alcohol 75 (367 mg, 0.55 mmol) dissolved in THF
(5 mL) at 08C were sequentially added triphenylphosphane (721 mg,
2.75 mmol), DEAD (435 mL, 2.75 mmol), and hydrazoic acid (HN3)
(118 mg in 0.5 mL of toluene, 2.75 mmol) [Caution: hydrazoic acid is toxic
and explosive!]. The reaction was allowed to reach 258C and stirred for 1 h.
The solution was diluted with brine (5 mL) and extracted with EtOAc (3 Â
10 mL). The organic layer was washed with H2O (10 mL), brine (10 mL),
and dried over Na2SO4. The solvent was removed in vacuo and the residue
was subjected to flash column chromatography (silica gel, 20 !50%
EtOAc in hexanes, gradient elution) to give azide 76 (252 mg, 69%). 76:
Rf ˆ 0.60 (silica gel, EtOAc); [a]2D2 ˆ ‡23.2 (c ˆ 0.31, CHCl3); IR (thin
film): nÄmax ˆ 3334, 2938, 2099, 1738, 1651, 1601, 1505, 1442, 1237, 1154,
1H NMR (500 MHz, CDCl3): d ˆ 7.41 (d, J ˆ 2.0 Hz, 1H, ArH), 7.32 ± 7.27
(m, 2H, ArH), 7.19 ± 7.16 (m, 1H, ArH), 7.12 (dd, J ˆ 8.0, 2.0 Hz, 1H, ArH),
7.01 ± 6.95 (m, 2H, ArH), 6.84 (d, J ˆ 7.5 Hz, 1H, ArH), 6.78 (d, J ˆ 8.0 Hz,
1H, ArH), 5.88 (d, J ˆ 8.5 Hz, 1H, ArH), 6.56 (s, 1H), 6.20 (d, J ˆ 6.5 Hz,
1H, NH), 5.88 (d, J ˆ 8.5 Hz, 1H, NH), 5.27 (d, J ˆ 7.0 Hz, 1H, CH), 4.72 ±
4.70 (m, 1H, CH), 3.89 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.60 (d, J ˆ
12.0 Hz, CHH, 1H), 3.41 (d, J ˆ 12.0 Hz, CHH, 1H), 3.23 (dd, J ˆ 13.0,
10.0 Hz, CHH, 1H), 2.68 (dd, J ˆ 13.0, 11.5 Hz, CHH, 1H); 13C NMR
(125 MHz, CDCl3): d ˆ 170.8, 169.2, 168.6, 160.6, 157.4, 154.6, 137.3, 136.1,
132.3, 131.4, 130.7, 128.9, 128.3, 127.8, 121.8, 121.2, 121.0, 115.0, 114.8, 113.2,
110.0, 55.2, 54.0, 52.5, 51.1, 41.7, 34.6; HRMS (FAB) calcd for C27H25I-
‡
N2O6Cs [M ‡ Cs ] 732.9812, found 732.9831.
1
1038 cm 1; H NMR (600 MHz, CDCl3): d ˆ 7.31 (dd, J ˆ 8.5, 2.2 Hz, 1H,
ArH), 7.26 ± 7.22 (m, 1H, ArH), 7.14 ± 7.07 (m, 3H, ArH), 6.95 (d, J ˆ
8.5 Hz, 1H, ArH), 6.89 (d, J ˆ 7.8 Hz, 1H, ArH), 6.82 (d, J ˆ 7.5 Hz, 1H,
ArH), 6.79 (dd, J ˆ 8.2, 2.2 Hz, 1H, ArH), 6.61 ± 6.56 (m, 3H), 6.49 (d, J ˆ
2.4 Hz, 1H, ArH), 6.05 (d, J ˆ 7.3 Hz, 1H), 5.85 (d, J ˆ 8.9 Hz, 1H), 5.35 (d,
J ˆ 7.3 Hz, 1H, CH), 4.82-4.75 (m, 1H, CHCH2), 4.11 (d, J ˆ 13.8 Hz, 1H),
4.07 (d, J ˆ 13.8 Hz, 1H), 3.85 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.72 (s,
3H, OCH3), 3.62 (d, J ˆ 16.8 Hz, 1H), 3.41 (d, J ˆ 16.8 Hz, 1H), 3.53 (s, 3H,
OCH3), 3.25 (dd, J ˆ 13.5, 4.7 Hz, 1H, CHCH2), 2.55 (dd, J ˆ 13.5, 10.5 Hz,
1H, CHCH2); 13C NMR (150 MHz, CDCl3): d ˆ 172.1, 170.5, 169.8, 162.2,
161.2, 159.0, 158.1, 157.8, 137.3, 137.2, 133.3, 133.2, 133.1, 132.3, 130.8, 129.6,
128.2, 125.9, 124.8, 123.7, 121.7, 119.1, 118.7, 118.3, 112.3, 105.5, 99.5, 58.1,
56.5, 56.4, 56.2, 54.3, 53.9, 53.4, 44.2, 39.5; HRMS (FAB) calcd for
Boronic acid 53: A stirred solution of alcohol 56 (370 mg, 2.2 mmol) in
benzene (4 mL) at 08C was treated with nBuLi (1.6m in hexanes, 3.0 mL,
4.8 mmol). The resulting solution was stirred for 2 h, and then it was cooled
to 788C. THF (8.0 mL) was added, followed by freshly distilled B(OMe)3
(1.3 mL, 11.0 mmol). The reaction mixture was slowly warmed to 258C and
stirred at that temperature for 6 h. The reaction was quenched by the
addition of 5% aqueous HCl (5 mL) and the resulting mixture was diluted
with EtOAc (25 mL). The organic phase was washed with H2O (2 Â 15 mL),
brine (15 mL) and dried over Na2SO4. The solvent was removed in vacuo
and the residue was subjected to flash column chromatography (silica gel,
10 !40% EtOAc in hexanes, gradient elution) to afford boronic acid
derivative 53 (172 mg, 46%). 53: Rf ˆ 0.27 (silica gel, 50% EtOAc in
hexanes); IR (thin film): nÄmax ˆ 3388, 2927, 1765, 1693, 1555, 1149, 1108,
1087 cm 1; 1H NMR (500 MHz, CDCl3): d ˆ 6.31 (d, J ˆ 0.7 Hz, 1H, ArH),
6.23 (d, J ˆ 0.7 Hz, 1H, ArH), 4.87 (s, 2H, OCH2), 3.76 (s, 3H, OCH3), 3.71
(s, 3H, OCH3); 13C NMR (125 MHz, CDCl3): d ˆ 164.4, 164.2, 162.5, 157.4,
‡
C36H35N5O8Cs [M ‡ Cs ] 798.1540, found 798.1562.
Azide 80: Azide 80 was similarly prepared from 79 according to the above
procedure in 69% yield. 80: Rf ˆ 0.46 (silica gel, EtOAc); [a]2D2 ˆ ‡51.3
(c ˆ 0.24, CHCl3); IR (thin film): nÄmax ˆ 3328, 2929, 2100, 1741, 1648, 1601,
‡
1
1505, 1444, 1343 cm 1; H NMR (600 MHz, CDCl3): d ˆ 7.35 (dd, J ˆ 8.3,
104.3, 96.9, 70.5, 55.1, 54.9; HRMS (FAB) calcd for C9H11BO4Na [M ‡ Na ]
193.0787, found 193.0791.
2.0 Hz, 1H, ArH), 7.22 (d, J ˆ 6.1 Hz, 1H), 7.19 ± 7.16 (m, 2H), 7.06 (dd, J ˆ
8.1, 2.1 Hz, 1H), 6.96 (d, J ˆ 7.5 Hz, 1H), 6.83 (d, J ˆ 7.5 Hz, 1H), 6.70 (dd,
J ˆ 8.2, 2.2 Hz, 1H), 6.60 (s, 1H), 6.54 (d, J ˆ 2.3 Hz, 2H), 6.51 (d, J ˆ
2.3 Hz, 1H), 6.30 (dd, J ˆ 8.2, 2.5 Hz, 1H), 6.16 (d, J ˆ 6.3 Hz, 1H), 5.79 (d,
J ˆ 9.4 Hz, 1H), 5.28 (d, J ˆ 6.3 Hz, 1H, CH), 4.88 ± 4.83 (m, 1H, CHCH2),
3.86 (s, 3H, OCH3), 3.85 (d, J ˆ 14.0 Hz, 1H), 3.66 (d, J ˆ 14.0 Hz, 1H), 3.77
(s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.62 (d, J ˆ 16.7 Hz,
1H), 3.39 (d, J ˆ 16.7 Hz, 1H), 3.29 (dd, J ˆ 13.3, 4.4 Hz, 1H, CHCH2), 3.40
(dd, J ˆ 13.3, 11.8 Hz, 1H, CHCH2); 13C NMR (150 MHz, CDCl3): d ˆ
172.4, 170.3, 169.9, 162.0, 161.2, 158.9, 158.5, 158.3, 137.3, 137.2, 133.6,
133.0, 131.9, 131.8, 130.9, 129.8, 127.3, 126.3, 124.9, 123.6, 121.9, 119.5, 119.0,
118.5, 112.2, 105.7, 99.2, 58.4, 56.6, 56.5, 56.3, 54.2, 53.5, 53.3, 44.6, 39.8;
Biaryl atropisomers 75 and 79: Iodide 74 (1.98 g, 3.3 mmol) was dissolved in
toluene (30 mL). To the resulting solution were added sequentially
Pd(Ph3P)4 (381 mg, 0.33 mmol), boronic acid 53 (1.28 g, 6.6 mmol) dis-
solved in MeOH (3 mL), and aqueous Na2CO3 (350 mg, 3.3 mmol) at 258C.
The reaction mixture was stirred vigorously for 5 min and then it was
heated at 908C for 2 h. The reaction mixture was diluted with EtOAc
(60 mL) and washed with H2O (30 mL), brine (30 mL), and dried over
Na2SO4. The solvent was removed in vacuo and the residue was subjected
to flash column chromatography (silica gel, 40 !80% EtOAc in hexanes,
gradient elution) to afford two atropisomers 75 (845 mg, 40%) and 79
(845 mg, 40%). 75: Rf ˆ 0.28 (silica gel, EtOAc); [a]2D2 ˆ ‡29.1 (c ˆ 0.26,
CHCl3); IR (thin film): nÄmax ˆ 3324, 2944, 1734, 1652, 1601, 1508, 1437, 1237,
1149 cm 1; 1H NMR (600 MHz, CDCl3): d ˆ 7.31 (dd, J ˆ 6.2, 2.1 Hz, 1H),
7.26 (d, J ˆ 8.0 Hz, 1H), 7.14 ± 7.06 (m, 3H), 6.95 (d, J ˆ 8.5 Hz, 1H), 6.89 (d,
J ˆ 2.3 Hz, 1H), 6.81 (d, J ˆ 7.5 Hz, 1H), 6.78 (dd, J ˆ 6.1, 2.1 Hz, 1H), 6.70
(d, J ˆ 2.3 Hz, 1H), 6.59 (dd, J ˆ 5.7, 2.5 Hz, 1H), 6.52 (s, 1H), 6.47 (d, J ˆ
2.4 Hz, 1H), 6.14 (d, J ˆ 6.9 Hz, 1H), 5.87 (d, J ˆ 8.9 Hz, 1H), 5.30 (d, J ˆ
6.9 Hz, 1H, CH), 4.80-4.76 (m, 1H, CHCH2), 4.31 (d, J ˆ 12.1 Hz, 1H), 4.25
(d, J ˆ 12.1 Hz, 1H), 3.85 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.73 (s, 3H,
OCH3), 3.58 (d, J ˆ 16.5 Hz, 1H), 3.38 (d, J ˆ 16.5 Hz, 1H), 3.55 (s, 3H,
OCH3), 3.22 (dd, J ˆ 13.5, 4.8 Hz, 1H), 2.59 (dd, J ˆ 13.5, 10.3 Hz, 1H);
13C NMR (150 MHz, CDCl3): d ˆ 171.4, 169.5, 169.0, 161.2, 160.4, 157.8,
157.1, 157.0, 141.1, 136.3, 132.5, 132.3, 132.1, 131.3, 129.9, 128.3, 127.3, 125.6,
123.8, 122.7, 121.0, 117.7, 117.4, 117.3, 111.6, 104.4, 98.3, 63.6, 57.3, 55.7, 55.6,
‡
HRMS (FAB) calcd for C36H35N5O8Cs [M ‡ Cs ] 798.1540, found 798.1566.
AB/C-O-D bicyclic system 83: To
a solution of ester 76 (520 mg,
0.75 mmol) in THF/H2O (1:1, 7.5 mL) at 08C was added anhydrous LiOH
(27 mg, 1.13 mmol), and the resulting mixture was stirred at that temper-
ature for 0.5 h. The reaction mixture was diluted with H2O (10 mL) and
acidified with citric acid to pH 4 at 08C. The mixture was extracted with
EtOAc (3 Â 10 mL) and the combined organic layers were washed with
H2O (15 mL), brine (15 mL), and dried over Na2SO4. The solvent was
removed in vacuo and the crude product 77 was taken into the next step
without further purification. To a stirred solution of acid 77 (39 mg,
0.06 mmol) in CH2Cl2 (0.6 mL) at 258C were sequentially added DCC
(15 mg, 0.072 mmol), 4-DMAP (1.5 mg, 0.012 mmol), and pentafluorophe-
nol (22 mg, 0.12 mmol). After stirring for 1 h at 258C, the reaction mixture
was filtered through a pad of celite, concentrated, and the crude product
was taken directly to the next step. To a stirred mixture of freshly distilled
dioxane (30 mL) containing 10% Pd/C (5 mg), absolute EtOH (1.5 mL),
and 4-pyrrolidinopyridine (27 mg, 0.18 mmol) at 908C was added, over a
‡
55.3, 53.3, 52.5, 43.4, 38.4; HRMS (FAB) calcd for C36H36N2O9Cs [M ‡ Cs ]
773.1475, found 773.1447. 79: Rf ˆ 0.23 (silica gel, EtOAc); [a]2D2 ˆ ‡48.5
(c ˆ 0.40, CHCl3); IR (thin film): nÄmax ˆ 3332, 1738, 1646, 1603, 1501, 1436,
1237, 1145 cm 1; 1H NMR (600 MHz, CDCl3/CD3OD, 1:1): d ˆ 7.41 (s, 1H),
7.21 ± 7.18 (m, 2H, ArH), 7.12 ± 7.11 (m, 1H, ArH), 7.00 ± 6.97 (m, 2H, ArH),
6.93 ± 6.90 (m, 2H, ArH), 6.78 (d, J ˆ 7.7 Hz, 1H, ArH), 6.68 (d, J ˆ 2.3 Hz,
1H, ArH), 6.62 ± 6.61 (m, 1H, ArH), 6.46 ± 6.41 (m, 2H, ArH), 6.27 (s, 1H,
ArH), 5.27 (d, J ˆ 6.5 Hz, 1H, CH), 4.67 ± 4.63 (m, 1H, CHCH2), 4.05 (d,
J ˆ 13.2 Hz, 1H), 3.86 (d, J ˆ 13.2 Hz, 1H), 3.82 (s, 3H, OCH3), 3.68 (s, 3H,
period of 1.5 h,
a solution of the crude pentafluorophenol ester in
cyclohexene (4 mL) and dioxane (10 mL). After the addition was
completed, the reaction mixture was allowed to stir at 908C for an
additional 5 h, after which time it was cooled to 258C and filtered through a
pad of celite. The celite was washed thoroughly with EtOAc (2 Â 15 mL),
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2599 $ 17.50+.50/0
2599

K. C. Nicolaou et al.
FULL PAPER
the combined filtrate was concentrated under reduced pressure and the
residue was subjected to flash column chromatography (silica gel, 0 !5%
MeOH in CHCl3, gradient elution) to give compounds 83 (46 mg, 10%)
and 83-(6-epi) (91 mg, 20%). 83: Rf ˆ 0.16 (silica gel, 5% MeOH in
General procedure for the asymmetric Suzuki coupling (Table 3): To a
stirred solution of Pd(OAc)2 (2.2 mg, 0.01 mmol) in toluene at ambient
temperature was added the specified ligand (0.03 mmol), and the resulting
solution was heated at 508C for 1 h. Iodide 62 (19 mg, 0.05 mmol) in
toluene (1 mL), boronic acid 53 (19 mg, 0.1 mmol) in MeOH (300 mL), and
Na2CO3 (7.4 mg, 0.07 mmol) in H2O (70 mL) were added sequentially. The
reaction mixture was heated at the indicated temperature for specified
period of time and then it was cooled to 258C and diluted with EtOAc
(3 mL). The organic layer was washed with 5% aqueous NaHCO3 (3 mL),
brine (3 mL), and dried (Na2SO4). The solvent was removed under reduced
pressure and the products were isolated by preparative thin-layer
chromatography (PTLC) as a mixture of atropisomers 85 and 86 in the
indicated yields.
CHCl3); [a2D2] ˆ ‡8.20 (c ˆ 0.30, CHCl3); IR (thin film): nÄmax ˆ 3349, 2916,
1
1661, 1650, 1603, 1582, 1487, 1455, 1255, 1022 cm
;
1H NMR (600 MHz,
CDCl3, 323 K): d ˆ 7.90 (d, J ˆ 7.2 Hz, 1H), 7.34 (d, J ˆ 7.9 Hz, 1H), 7.23 ±
7.21 (m, 1H), 7.11 ± 7.08 (m, 3H), 7.03 ± 6.99 (m, 4H), 6.79 (d, J ˆ 6.4 Hz,
1H), 6.75 (s, 1H), 6.52 (s, 1H), 6.49 (s, 1H), 5.79 (br.s, 1H), 5.51 (br.s, 1H),
5.45 (d, J ˆ 11.7 Hz, 1H), 4.84 (d, J ˆ 4.8 Hz, 1H), 4.09 ± 4.05 (m, 1H),
3.95 ± 3.93 (m, 1H), 3.84 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 3.68 (s, 3H,
OCH3), 3.52 ± 3.42 (m, 3H), 2.52 ± 2.48 (m, 1H); 13C NMR (125 MHz,
CDCl3): d ˆ 172.8, 172.5, 168.1, 160.6, 160.0, 158.3, 156.8, 155.0, 136.8,
136.3, 134.1, 132.9, 132.4, 130.8, 129.5, 129.3, 128.7, 126.2, 124.3, 122.4, 122.3,
119.7, 115.5, 112.8, 112.4, 107.6, 98.2, 55.8, 55.7, 55.2, 54.1, 45.4, 42.2, 35.2,
‡
29.4; HRMS (FAB) calcd for C35H33N3O7Cs [M ‡ Cs ] 740.1373, found
740.1401. 83-(6-epi): Rf ˆ 0.21 (silica gel, 5% MeOH in CHCl3); [a]D22
ˆ
Acknowledgments
53.0 (c ˆ 0.37, CHCl3); IR (thin film): nÄmax ˆ 3263, 2923, 1724, 1644, 1501,
1459, 1268, 1119, 1066, 1019 cm 1; 1H NMR (600 MHz, CDCl3, 323 K): d ˆ
7.46 (dd, J ˆ 8.4, 6.1 Hz, 1H, ArH), 7.19-7.16 (m, 1H, ArH), 7.11 (dd, J ˆ 8.3,
1.9 Hz, 1H, ArH), 7.01 (dd, J ˆ 8.1, 2.1 Hz, 1H, ArH), 6.98 (dd, J ˆ 6.5,
3.9 Hz, 1H, ArH), 6.98 ± 6.97 (br.s, 1H, NH), 6.93 (dd, J ˆ 8.3, 2.1 Hz, 1H,
ArH), 6.88 (d, J ˆ 8.4 Hz, 1H, ArH), 6.82 (dd, J ˆ 8.2, 2.1 Hz, 1H, ArH),
6.77 (d, J ˆ 2.4 Hz, 1H, ArH), 6.66 (d, J ˆ 7.5 Hz, 1H, ArH), 6.57 (d, J ˆ
2.3 Hz, 1H, ArH), 6.54 (d, J ˆ 2.3 Hz, 1H, ArH), 6.04 (s, 1H, ArH), 5.65
(br.s, 1H, NH), 5.50 (d, J ˆ 8.6 Hz, 1H, CH), 5.39 (d, J ˆ 9.3 Hz, 1H, NH),
4.35-4.31 (m, 1H, CHCH2), 3.97 (dd, J ˆ 12.9, 5.1 Hz, 1H, CH2N), 3.87 (s,
3H, OCH3), 3.68 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.46 (dd, J ˆ 12.9,
2.3 Hz, 1H, CH2N), 3.35 (d, J ˆ 14.6 Hz, 1H), 3.31 (d, J ˆ 14.6 Hz, 1H), 2.98
(dd, J ˆ 13.4, 4.3 Hz, 1H, CHCH2), 2.75 ± 2.71 (m, 1H, CHCH2); 13C NMR
(150 MHz, CDCl3): d ˆ 173.3, 171.6, 170.2, 161.2, 160.0, 158.6, 155.3, 139.6,
138.1, 137.0, 134.4, 133.1, 132.9, 132.2, 131.7, 130.4, 128.3, 125.9, 124.0, 122.9,
122.0, 121.8, 117.4, 113.4, 112.1, 108.6, 99.4, 56.9, 56.6, 56.3, 55.5, 46.4, 43.8,
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 the Alexander von Humboldt-Stiftung (to F. R.), and grants from
Pfizer, Schering Plough, Hoffmann La Roche, Merck, the George Hewitt
Foundation, Abbott Laboratories, Boehringer Ingelheim, and Glaxo.
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‡
35.2, 30.5; HRMS (FAB) calcd for C35H34N3O7 [M ‡ H ] 608.2397, found
608.2416.
Bicyclic systems 84 and 84-(6-epi): Compounds 84 and 84-(6-epi) were
similarly prepared from compound 80 according to the above procedure in
10% and 20% yield, respectively. 84: Rf ˆ 0.31 (silica gel, 5% MeOH in
CHCl3); [a]2D2
1725, 1640, 1605, 1504, 1459, 1228, 1152, 1092 cm
ˆ
31.5 (c ˆ 0.20, CHCl3); IR (thin film): nÄmax ˆ 2919, 2848,
1
;
1H NMR (600 MHz,
CDCl3, 323 K): d ˆ 7.29 (dd, J ˆ 8.1, 2.0 Hz, 1H, ArH), 7.22 (d, J ˆ 6.3 Hz,
1H, ArH), 7.20 (dd, J ˆ 8.8, 2.3 Hz, 1H, ArH), 7.08 (d, J ˆ 8.1 Hz, 1H,
ArH), 7.05-7.03 (m, 3H, ArH), 6.81 (dd, J ˆ 8.1, 2.4 Hz, 1H, ArH), 6.94 (d,
J ˆ 8.7 Hz, 1H, ArH), 6.78 (d, J ˆ 7.2 Hz, 1H, ArH), 6.57 (d, J ˆ 2.0 Hz, 1H,
ArH), 6.48 (d, J ˆ 2.0 Hz, 1H, ArH), 6.32 (br.s, 1H, ArH), 5.78 (br.s, 1H,
ArH), 5.65 ± 5.62 (m, 1H, NH), 5.12 (m, 1H, NH), 5.04 (d, J ˆ 5.8 Hz, 1H,
CH), 4.30 ± 4.20 (m, 1H, CH2), 4.16 (ddd, J ˆ 13.2, 11.4, 2.7 Hz, 1H, CH),
3.74 (dd, J ˆ 14.9, 5.9 Hz, 1H, CH2), 3.72 (dd, J ˆ 12.0, 2.7 Hz, 1H, CH2),
3.81 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.57 (d, J ˆ 15.0 Hz, 1H, CH2CO),
3.45 (d, J ˆ 15.0 Hz, 1H, CH2CO), 3.47 (s, 3H, OCH3), 2.47 (dd, J ˆ 13.2,
12.0 Hz, 1H, CH2); 13C NMR (150 MHz, CDCl3, 323 K): d ˆ 171.3, 170.7,
169.1, 160.9, 160.0, 158.1, 156.9, 154.1, 137.7, 136.6, 135.5, 134.4, 132.9, 130.5,
130.0, 129.1, 125.6, 123.4, 122.1, 121.1, 119. 7, 116.9, 114.1, 112.4, 111.9, 108.2,
99.2, 56.8, 56.6, 56.1, 55.1, 49.2, 43.6, 43.4, 35.0; HRMS (FAB) calcd for
‡
C35H33N3O7Cs [M ‡ Cs ] 740.1373, found 740.1398. 84-(6-epi): Rf ˆ 0.35
(silica gel, 5% MeOH in CHCl3); [a]D22
film): nÄmax ˆ 3318, 2919, 2849, 1650, 1544, 1503, 1450, 1233, 1151 cm
ˆ
11.1 (c ˆ 0.27, CHCl3); IR (thin
1
;
1H NMR (600 MHz, CDCl3, 323 K): d ˆ 7.23-7.20 (m, 2H, ArH), 7.17 (dd,
J ˆ 8.6, 2.4 Hz, 1H, ArH), 7.12 (d, J ˆ 2.4 Hz, 1H, ArH), 7.03 (dd, J ˆ 10.5,
2.2 Hz, 1H, ArH), 7.00 (d, J ˆ 8.6 Hz, 1H, NH), 7.00 ± 6.96 (m, 1H, ArH),
6.88 (d, J ˆ 8.6 Hz, 1H, ArH), 6.83 (d, J ˆ 7.5 Hz, 1H, ArH), 6.62-6.57 (m,
3H, 1 NH, 2 ArH), 6.50 (d, J ˆ 2.3 Hz, 1H, ArH), 6.42 (d, J ˆ 2.3 Hz, 1H,
ArH), 6.01 (s, 1H, ArH), 5.72 (d, J ˆ 8.6 Hz, 1H, CH), 5.60 (d, J ˆ 9.7 Hz,
1H, NH), 4.52 (dd, J ˆ 14.8, 10.3 Hz, 1H, CH2N), 4.41-4.36 (m, 1H,
CHCH2), 3.78 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 3.65 (d, J ˆ 14.5 Hz, 1H),
3.52 (d, J ˆ 14.5 Hz, 1H), 3.55 (dd, J ˆ 14.8, 2.5 Hz, 1H, CH2N), 3.45 (s, 3H,
OCH3), 3.46-3.43 (m, 1H, CHCH2), 2.50 ± 2.48 (m, 1H, CHCH2); 13C NMR
(100 MHz, CDCl3): d ˆ 171.2, 170.7, 169.1, 160.8, 160.0, 158.5, 157.1, 156.9,
154.1, 137.7, 136.6, 134.3, 132.6, 132.4, 130.0, 129.1, 125.6, 124.8, 123.1, 122.1,
121.0, 119.6, 116.9, 112.4, 111.9, 106.6, 98.3, 55.8, 55.6, 55.3, 54.2, 49.2, 43.6,
‡
43.3, 35.0; HRMS (FAB) calcd for C35H33N3O7Cs [M ‡ Cs ] 740.1373,
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found 740.1396.
2600
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0509-2600 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 9

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Received: March 29, 1999 [F 1705]
Chem. Eur. J. 1999, 5, No. 9
ꢁ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
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