A new access to 16-membered macrocycles: Synthesis of the model c-o-d ring system of vancomycin

Article abstract of DOI:10.1055/s-0029-1216937

A simple methodology for construction of the C-O-D diphenyl ether 16-membered ring system present in vancomycin by an intramolecular O-arylation reaction of arylboronic acid with substituted phenol for formation of the macrocyclic biaryl ether is described.

Full text of DOI:10.1055/s-0029-1216937

3322
PAPER
A New Access to 16-Membered Macrocycles:
Synthesis of the Model C–O–D Ring System of Vancomycin
Synthesis of th
a
e
M
odel
C
m
i
of Va
n
r
comycin Ghosh,a A. Sanjeev Kumar,a G. N. Mehta,b R. Soundararajan*a
a
Chemical Research and Development Department, Pfizer Ltd., Mumbai 400705, India
Fax +91(22)67932444; E-mail: soundara1959@yahoo.com
b
Applied Chemistry Department, S. V. National Institute of Technology, Surat 395007, India
Received 27 April 2009; revised 12 May 2009
of challenges and some disadvantages still exist, such as
tedious reaction conditions, low yields, and multistep se-
quences. Therefore, developing a synthetic strategy that is
efficient having a low number of steps and providing di-
verse access to these bioactive compounds is an important
goal. In this paper, we report a new, concise, and efficient
approach for the construction of aryl ethers and its appli-
cation to the synthesis of the vancomycin model C–O–D
ring system.
Abstract: A simple methodology for construction of the C–O–D
diphenyl ether 16-membered ring system present in vancomycin by
an intramolecular O-arylation reaction of arylboronic acid with sub-
stituted phenol for formation of the macrocyclic biaryl ether is de-
scribed.
Key words: vancomycin, antibiotics, arylboronate, ring closure,
O-arylation
Within the class of the glycopeptide antibiotics,1
vancomycin2 (1) (Figure 1) occupies a commanding posi-
tion as a highly effective and widely used clinical agent
for combating severe bacterial infections caused by drug-
resistant pathogens.1–3 This novel antibiotic, isolated from
the actinomycetes Streptomyces orientalis (later renamed
Nocardia orientalis and finally reclassified as Amyco-
latopsis orientalis2c), has recently3 moved to center stage
by virtue of its increasing importance in chemistry, biolo-
gy, and medicine. The glycopeptide antibiotics of the van-
comycin family are clinically important for the treatment
of infections due to methicillin-resistant Staphylococcus
aureus and other Gram-positive organisms.2e,4 After more
than 35 years of clinical use, resistance to the drug has
been detected5 and has led to renewed interest in this field.
Both structural modifications of antibiotics6 and the syn-
theses of designed nonnatural products7 have appeared
addressing the vancomycin-resistance phenomenon. The
complex structure of vancomycin makes it a challenging
synthetic target.3a Until now, the thallium trinitrate pro-
moted oxidative phenolic coupling method developed by
Yamamura8 and Evans9 and co-workers is among the
most efficient.
OH
Me
O
N+H3
HO
Me
Cl
O
O
O
O
HO
HO
O
O
O
D
H
C
O
E
Cl
H
HO
HN
OH
O
H
N
N
N
H
O
H
N
H
H
N
N
Me
Me
H
H
O
H
O
B
NH2
– OOC
H
Me
A
OH
OH
HO
1
Figure 1 Vancomycin (1)
Commercially obtained L-tyrosine was esterified using
thionyl chloride in methanol under reflux to afford L-ty-
rosine methyl ester (2). Then, Boc-protected (R)-phenyl-
glycine 3 was coupled with L-tyrosine methyl ester (2)
using N-ethyl-N¢-(3-dimethylaminopropyl)carbodiimide
hydrochloride (1.5 equiv), 1-hydroxybenzotriazole (1
equiv), and N,N-diisopropylethylamine (3 equiv) as a base
in dichloromethane at 25 °C for 2 hours to afford com-
pound 4 in 90% yield (Scheme 1). Compound 4 was N-
deprotected using dry hydrogen chloride in ethyl acetate
at 25 °C for 12 hours to afford compound 5 in 96% yield.
The aryl ether linkage is frequently encountered both in
natural products and designed molecules. Much
chemistry3a has been extended for the construction of such
systems, particularly as they relate to vancomycin-type
structures.2a,c–e,10 These glycopeptide antibiotics are be-
coming increasingly important as clinical agents against a
growing number of drug-resistant bacterial strains and
have been the target of syntheses by several groups.3b,9,11
Although preparations of several cyclic diaryl ether sys-
tems related to vancomycin have been reported, a number
(4-Hydroxyphenyl)acetic acid (6) was protected with
dimethyl sulfate (2.5 equiv) and potassium carbonate (3
equiv) in acetone at 25 °C to afford compound 7 in 96%
yield (Scheme 2). Compound 7 was hydrolyzed in the
presence of lithium hydroxide and a mixture of methanol
and water at 25 °C to afford acid 8 in 96% yield. Acid 8
was brominated using bromine in acetic acid at 25 °C to
afford compound 9 in 95% yield. Compound 9 was again
SYNTHESIS 2009, No. 19, pp 3322–3326
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.08.2009
DOI: 10.1055/s-0029-1216937; Art ID: Z08209SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of the Model C–O–D Ring System of Vancomycin
3323
OH
OH
OH
O
O
b
NHBoc
O
+
a
HO
NH2⋅HCl
N
H
NHBoc
N
H
96%
90%
MeO
NH2
O
MeO
O
MeO
O
2
3
4
5
Scheme 1 Reagents and conditions: (a) EDCI, HOBt, DIPEA, CH2Cl2, 25 °C, 2 h; (b) dry HCl, EtOAc, 25 °C, 12 h.
protected using dimethyl sulfate (1.5 equiv) and potassi- mixture of methanol and water to give compound 12 in
um carbonate (2 equiv) in acetone at 25 °C to afford com- 96% yield (Scheme 2).
pound 10 in 96% yield. Compound 10 was treated with
potassium acetate as a base (3 equiv), PdCl2(dppf) as a
catalyst (0.05 equiv), and bis(pinacolato)diboron (1.3
equiv) in 1,2-dimethoxyethane as a solvent at 110 °C for
18 hours to yield arylboronate 11 in 90% yield. Arylbor-
onate 11 was hydrolyzed using lithium hydroxide in a
Compound 5 was coupled with compound 12 using N-eth-
yl-N¢-(3-dimethylaminopropyl)carbodiimide hydrochlo-
ride (1.5 equiv), 1-hydroxybenzotriazole (1 equiv), and
N,N-diisopropylethylamine (3 equiv) as a base in dichlo-
romethane at 25 °C for 2 hours to afford arylboronate 13
in 66% yield (Scheme 3).
OMe
OMe
OMe
OMe
Br
Br
OH
d
c
b
a
96%
95%
96%
96%
OMe
OH
OH
OMe
OH
O
O
O
O
O
6
7
8
9
10
OMe
O
B
OMe
O
B
O
f
e
O
96%
90%
OH
OMe
O
O
11
12
Scheme 2 Reagents and conditions: (a) Me2SO4, K2CO3, acetone, 25 °C, 12 h; (b) LiOH, MeOH, H2O, 25 °C, 30 min; (c) Br2, AcOH, 25 °C,
17 h; (d) Me2SO4, K2CO3, acetone, 25 °C, 3 h; (e) bis(pinacolato)diboron, KOAc, PdCl2(dppf), DME, 110 °C, 18 h; (f) LiOH, MeOH, H2O,
25 °C, 30 min.
OH
O
B
OMe
OH
O
OMe
O
B
a
O
+
O
NH
66%
N
H
O
NH2⋅HCl
O
N
H
OH
MeO
O
MeO
O
O
12
13
5
Scheme 3 Reagents and conditions: (a) EDCI, HOBt, DIPEA, CH2Cl2, 25 °C, 2 h.
Synthesis 2009, No. 19, 3322–3326 © Thieme Stuttgart · New York

3324
S. Ghosh et al.
PAPER
Methyl (S)-2-[(R)-2-(tert-Butoxycarbonylamino)-2-phenylacet-
amido]-3-(4-hydroxyphenyl)propanoate (4)
The arylboronate 13 was converted into the arylboronic
acid 14 in 90% yield using sodium periodate in acetone in
the presence of 0.1 N aqueous ammonium acetate solution
at 25 °C for 16 hours. Key ring closure of 14 to 1512 via
the intramolecular O-arylation reaction of substituted
phenol with arylboronic acid proceeded smoothly using
copper(II) acetate (1.3 equiv) and 4-(dimethylamino)pyri-
dine (5 equiv) in dichloromethane in the presence of pow-
dered 4-Å molecular sieves at 25 °C for 48 hours in 60%
yield. Compound 15 was demethylated by a procedure13
using tetrabutylammonium iodide and boron trichloride in
dichloromethane, initially at –78 °C, to afford compound
16 in 80% yield (Scheme 4).
To a suspension of L-tyrosine methyl ester (2; 6.0 g, 30.7 mmol) in
anhyd CH2Cl2 (150 mL) were added compound 3 (7.7 g, 30.7
mmol), EDCI (8.8 g, 46.0 mmol), HOBt (4.14 g, 30.7 mmol), and
DIPEA (11.78 g, 92.0 mmol) at 25 °C. The resulting mixture was
stirred at 25 °C for 2 h. The reaction mixture was quenched with
H2O (100 mL) and neutralized with 10% aq citric acid, and the
CH2Cl2 layer was separated and concentrated to give a residue. The
residue was purified by column chromatography on silica gel
(CH2Cl2–MeOH, 9:1) to afford compound 4 as an off-white solid;
yield: 11.8 g (90%).
24
Mp 68–75 °C; [a]D –15.2 (c 0.255, MeOH); Rf = 0.6 (CH2Cl2–
MeOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 9.19 (d, J = 10.0 Hz, 1 H), 7.28
(m, J = 2 Hz, 1 H), 7.27 (m, J = 7.6 Hz, 4 H), 7.17 (m, J = 7.2 Hz,
2 H), 6.91 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 8.4 Hz, 1 H), 6.60 (d,
J = 8.8 Hz, 1 H), 6.52 (d, J = 8.4 Hz, 1 H), 5.20 (m, 1 H), 4.39 (m,
1 H), 3.58 (s, 3 H), 2.85 (m, 2 H), 1.35 (s, 9 H).
13C NMR (400 MHz, DMSO-d6): d = 172.3, 170.4, 156.4, 155.2,
139.0, 130.4, 129.0, 128.5, 127.7, 127.3, 115.5, 78.8, 57.6, 55.3,
54.4, 36.3, 28.5.
In conclusion, we have herein provided a short, new, con-
cise, and practical route for the synthesis of a 16-mem-
bered macrocycle from commercially available L-
tyrosine, (R)-phenylglycine, and (4-hydroxyphenyl)acetic
acid by an intramolecular O-arylation reaction of arylbo-
ronic acid with substituted phenol. The method is mild
enough for the construction of the vancomycin-type mod-
el system.
ESI-MS: m/z = 429 [M + H+].
(3-Bromo-4-methoxyphenyl)acetic Acid (9)14
All solvents and reagents were purchased from the suppliers and
were used without further purification. All nonaqueous reactions
were performed in dry glassware under dry nitrogen atmosphere.
Organic solutions were concentrated under reduced pressure. Thin-
layer chromatography was performed on Merck precoated silica gel
60 F254 plates. 1H and 13C NMR spectra were recorded on a Varian
Gemini 400 MHz FT NMR spectrometer using DMSO-d6 as sol-
vent. The chemical shifts are reported in d ppm relative to TMS.
Mass spectra were recorded on Shimadzu LCMS-QP 800 LC/MS
and Applied Biosystems 4000 Q-trap LC/MS/MS instruments. Op-
tical rotations were measured using a Jasco P-1020 polarimeter at
24 °C. Melting points were obtained using the open capillary meth-
od and are uncorrected.
To a soln of (4-methoxyphenyl)acetic acid (8; 10 g, 60.2 mmol) in
AcOH (50 mL) was slowly added a soln of Br2 (3.3 mL, 66.2 mmol)
in AcOH (20 mL). After being stirred at 25 °C for 17 h under argon,
the solution was poured over ice and filtered. The collected precip-
itate was washed with H2O (4 × 20 mL) to provide the white solid
9; yield: 14 g (95%).
1H NMR (400 MHz, DMSO-d6): d = 12.29 (br s, 1 H), 7.43 (s, 1 H),
7.20 (d, J = 8.8 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 1 H), 3.78 (s, 3 H),
3.49 (s, 2 H).
ESI-MS: m/z = 246 [M + H+].
OH
OMe
HO
OH
O
B
OMe
B
HO
a
O
90%
O
O
NH
NH
N
H
N
H
O
O
MeO
MeO
O
O
14
13
OH
OMe
O
O
c
b
O
80%
60%
O
NH
N
O
NH
H
N
O
H
O
OMe
O
OMe
16
15
Scheme 4 Reagents and conditions: (a) NaIO4, 0.1 N aq NH4OAc, acetone, 25 °C, 16 h; (b) Cu(OAc)2, DMAP, powdered 4-Å MS, CH2Cl2,
48 h; (c) TBAI, BCl3, CH2Cl2, –78→0 °C, 2 h.
Synthesis 2009, No. 19, 3322–3326 © Thieme Stuttgart · New York

PAPER
Synthesis of the Model C–O–D Ring System of Vancomycin
3325
Methyl (3-Bromo-4-methoxyphenyl)acetate (10)
action mixture was quenched with H2O (100 mL) and neutralized
with 10% aq citric acid, and the CH2Cl2 layer was separated and
concentrated to give a residue. The residue was purified by column
chromatography on silica gel (CH2Cl2–MeOH, 9:1) to afford com-
pound 13 as an off-white solid; yield: 5.5 g (66%).
To a soln of compound 9 (10 g, 40.8 mmol) in acetone (100 mL)
were added K2CO3 (11.4 g, 81.6 mmol) and Me2SO4 (7.6 g, 61.2
mmol) at 25 °C. The mixture was stirred at the same temperature for
3 h. The reaction mixture was filtered through a pad of Celite®
which was washed with acetone (50 mL). The acetone layer was
concentrated under reduced pressure. Purification by column chro-
matography on silica gel (hexane–EtOAc, 7:3) provided aryl bro-
mide 10 as a yellow oil; yield: 10.14 g (96%).
24
Mp 85–92 °C; [a]D –17.1 (c 0.18, MeOH); Rf = 0.5 (CH2Cl2–
MeOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 9.21 (br s, 1 H), 8.71 (m, 1 H),
8.61 (m, 1 H), 7.44 (m, J = 2.8 Hz, 1 H), 7.31 (m, J = 7.6 Hz, 1 H),
7.20 (m, 5 H), 6.80 (m, 3 H), 6.61 (d, J = 8.0 Hz, 1 H), 6.53 (d,
J = 8.0 Hz, 1 H), 5.54 (m, 1 H), 4.39 (m, 1 H), 3.67 (s, 3 H), 3.58 (s,
3 H), 3.46 (m, 2 H), 2.85 (m, 2 H), 1.29 (s, 12 H).
13C NMR (400 MHz, DMSO-d6): d = 172.3, 171.9, 170.5, 163.0,
156.4, 139.1, 137.5, 133.8, 130.5, 130.4, 128.5, 128.0, 127.6, 127.1,
121.7, 115.5, 111.0, 83.5, 56.0, 55.8, 54.4, 52.3, 41.1, 36.3, 25.3,
25.0.
Rf = 0.6 (heptanes–EtOAc, 7:3).
1H NMR (400 MHz, DMSO-d6): d = 7.45 (d, J = 2.4 Hz, 1 H), 7.18
(m, 1 H), 7.02 (d, J = 8.8 Hz, 1 H), 3.78 (s, 3 H), 3.60 (s, 2 H), 3.57
(s, 3 H).
13C NMR (400 MHz, DMSO-d6): d = 172.0, 154.7, 134.1, 130.4,
128.4, 112.9, 110.6, 56.6, 52.1, 38.9.
ESI-MS: m/z = 260 [M + H+].
ESI-MS: m/z = 603 [M + H+].
Methyl [4-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl]acetate (11)
HRMS (ESI): m/z [M+] calcd for C33H39BN2O8: 602.4823; found:
602.4802.
Aryl bromide 10 (10 g, 38.6 mmol), bis(pinacolato)diboron (12.60
g, 50.2 mmol), KOAc (11.3 g, 115.8 mmol), and PdCl2(dppf) (1.6
g, 1.9 mmol) were suspended in anhyd DME (100 mL, degassed by
sparging with N2) and heated to 110 °C for 18 h. H2O (50 mL) and
EtOAc (50 mL) were added. The layers were separated, and the
aqueous layer was extracted with EtOAc (2 × 100 mL). The com-
bined organic layer was dried (MgSO4), filtered, and concentrated
under reduced pressure. Purification by column chromatography on
silica gel (hexane–EtOAc, 7:3) provided arylboronate 11 as a yel-
low oil; yield: 10.62 g (90%).
5-(2-{(R)-2-[(S)-3-(4-Hydroxyphenyl)-1-methoxy-1-oxopropan-
2-ylamino]-2-oxo-1-phenylethylamino}-2-oxoethyl)-2-meth-
oxyphenylboronic Acid (14)
To a stirred soln of the boronate ester 13 (2.0 g, 3.3 mmol) in ace-
tone (60 mL) were added 0.1 N aq NH4OAc (50 mL) and NaIO4
(2.12 g, 9.9 mmol). The mixture was stirred at 25 °C for 16 h. The
reaction was monitored by TLC until there was no starting material
left. Then, EtOAc (50 mL) was added to the reaction mixture. The
EtOAc layer was separated and concentrated to afford the product
14. This was purified by column chromatography on silica gel
(CH2Cl2–MeOH, 9:1) which provided arylboronic acid 14 as an off-
white solid; yield: 1.65 g (90%).
Rf = 0.5 (heptanes–EtOAc, 7:3).
1H NMR (400 MHz, DMSO-d6): d = 7.38 (d, J = 2.4 Hz, 1 H), 7.28
(dd, J = 5.6, 10.8 Hz, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 3.68 (s, 3 H),
3.55 (s, 5 H), 1.23 (s, 12 H).
13C NMR (400 MHz, DMSO-d6): d = 172.4, 163.2, 137.7, 134.1,
126.0, 111.2, 83.5, 55.8, 52.0, 40.5, 25.2, 24.9.
24
Mp 95–100 °C; [a]D –13 (c 0.20, MeOH); Rf = 0.4 (CH2Cl2–
MeOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 9.29 (br s, 1 H), 8.84 (m, 1 H),
8.68 (m, 1 H), 7.79 (m, 1 H), 7.71 (s, 2 H), 7.54 (m, 1 H), 7.39 (m,
2 H), 7.28 (m, 3 H), 7.01 (m, 3 H), 6.69 (d, J = 8.8 Hz, 1 H), 6.61
(d, J = 8.4 Hz, 1 H), 5.63 (m, J = 8.8 Hz, 1 H), 4.40 (m, 1 H), 3.84
(s, 3 H), 3.67 (s, 2 H), 3.56 (s, 3 H), 2.90 (m, 2 H).
13C NMR (400 MHz, DMSO-d6): d = 172.3, 170.6, 170.2, 162.7,
156.4, 139.1, 136.7, 132.6, 132.1, 130.4, 129.0, 128.5, 128.4, 127.6,
127.5, 115.5, 111.6, 56.0, 55.8, 54.4, 52.3, 41.3, 36.3.
ESI-MS: m/z = 307 [M + H+].
[4-Methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]acetic Acid (12)
To a stirred soln of arylboronate 11 (10 g, 32.6 mmol) in MeOH (50
mL) and H2O (50 mL) was added LiOH (1.5 g, 65.3 mmol) at 25 °C.
The mixture was stirred at the same temperature for 30 min. Hep-
tane (80 mL) was added to the reaction mixture which was then
stirred for another 15 min. The aqueous layer was separated and was
acidified with 10% aq citric acid to pH ~4. The aqueous layer was
extracted with EtOAc (3 × 50 mL). The combined organic layer was
dried (MgSO4), filtered, and concentrated under reduced pressure to
afford compound 12 as an off-white solid; yield: 9.2 g (96%).
ESI-MS: m/z = 521 [M + H+].
HRMS (ESI): m/z [M+] calcd for C27H29BN2O8: 520.3387; found:
520.3413.
Methyl (11R,14S)-4-Methoxy-9,12-dioxo-11-phenyl-2-oxa-
10,13-diazatricyclo[14.2.2.13,7]henicosa-
Mp 105–108 °C.
1(19),3(21),4,6,16(20),17-hexaene-14-carboxylate (15)12
To a soln of arylboronic acid 14 (1.0 g, 1.9 mmol) in CH2Cl2 (100
mL) were added DMAP (1.2 g, 9.6 mmol) and powdered 4-Å mo-
lecular sieves (2.0 g), and the mixture was stirred at 25 °C for 30
min. Cu(OAc)2 (0.45 g, 2.5 mmol) was added to the mixture which
was then stirred at 25 °C for 48 h. The mixture was filtered and the
filtrate was washed successively with 5% aq KHSO4 (50 mL) and
brine (50 mL), and then dried (MgSO4). The solvent was removed
under reduced pressure, and the residue was purified by column
chromatography on silica gel (CH2Cl2–MeOH, 9:1) which provided
compound 15 as an off-white solid; yield: 0.546 g (60%).
1H NMR (400 MHz, DMSO-d6): d = 7.38 (d, J = 2.4 Hz, 1 H), 7.27
(dd, J = 8.4, 8.4 Hz, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 3.67 (s, 3 H),
2.75 (q, J = 15.6 Hz, 2 H), 1.22 (s, 12 H).
13C NMR (400 MHz, DMSO-d6): d = 173.5, 163.1, 137.6, 134.0,
126.7, 111.1, 83.5, 72.9, 55.8, 43.1, 25.0.
ESI-MS: m/z = 293 [M + H+], 315 [M + Na+].
Methyl (S)-3-(4-Hydroxyphenyl)-2-[(R)-2-{2-[4-methoxy-3-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetami-
do}-2-phenylacetamido]propanoate (13)
To a suspension of 5 (5.0 g, 13.7 mmol) in anhyd CH2Cl2 (100 mL)
were added compound 12 (4.4 g, 15.2 mmol), EDCI (4.36 g, 22.8
mmol), HOBt (2.05 g, 15.2 mmol), and DIPEA (5.85 g, 45.7 mmol)
at 25 °C. The resulting mixture was stirred at 25 °C for 2 h. The re-
24
Mp 215–220 °C; [a]D –44.8 (c 0.26, MeOH); Rf = 0.8 (CH2Cl2–
MeOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 8.58 (m, 1 H), 8.45 (m, 1 H),
7.38 (m, 2 H), 7.29 (m, 3 H), 7.23 (m, 3 H), 6.96 (m, 2 H), 6.77 (m,
Synthesis 2009, No. 19, 3322–3326 © Thieme Stuttgart · New York

3326
S. Ghosh et al.
PAPER
1 H), 6.68 (m, 1 H), 5.36 (d, J = 9.2 Hz, 1 H), 4.38 (m, 1 H), 3.79
(s, 3 H), 3.58–3.55 (m, 2 H), 3.53 (s, 3 H), 2.97–2.91 (m, 2 H).
Acknowledgment
We are grateful to the Indian Association for Cultivation Sciences,
Jadavpur for analytical support, Pfizer Ltd, and SVNIT, Surat,
India.
13C NMR (400 MHz, DMSO-d6): d = 171.9, 171.7, 169.7, 154.2,
150.0, 147.4, 139.7, 133.1, 130.6, 129.7, 128.6, 127.7, 126.8, 122.3,
121.6, 114.7, 112.8, 56.1, 55.6, 55.3, 52.7, 41.8, 35.1.
ESI-MS: m/z = 475 [M + H+].
HRMS (ESI): m/z [M+] calcd for C27H26N2O6: 474.5051; found:
References
474.5023.
(1) Glycopeptide Antibiotics; Nagarajan, R., Ed.; Marcel
Dekker: New York, 1994.
Methyl (11R,14S)-4-Hydroxy-9,12-dioxo-11-phenyl-2-oxa-
10,13-diazatricyclo[14.2.2.13,7]henicosa-
(2) (a) Sheldrick, G. M.; Jones, P. G.; Kennard, O.; Williams, D.
H.; Smith, G. A. Nature (London) 1978, 271, 223. (b) Loll,
P. J.; Bevivino, A. E.; Korty, B. D.; Axelson, P. H. J. Am.
Chem. Soc. 1997, 119, 1516. (c) McCormick, M. H.; Stark,
W. M.; Pittenger, R. C.; McGuire, G. M. Antibiot. Annu.
1955–1956, 606. (d) Harris, C. M.; Harris, T. M. J. Am.
Chem. Soc. 1982, 104, 4293. (e) Harris, C. M.; Kopecka, H.;
Harris, T. M. J. Am. Chem. Soc. 1983, 105, 6915.
(3) For reviews in the area, see: (a) Rao, A. V. R.; Gurjar, M.
K.; Reddy, K. L.; Rao, A. S. Chem. Rev. 1995, 95, 2135.
(b) Burgess, K.; Lim, D.; Martinez, C. I. Angew. Chem.
1996, 108, 1162. (c) Zhu, J. P. Synlett 1997, 133.
(4) (a) Williamson, M. P.; Williams, D. H. J. Am. Chem. Soc.
1981, 103, 6580. (b) Nagarajan, R. J. Antibiot. 1993, 46,
1181.
1(19),3(21),4,6,16(20),17-hexaene-14-carboxylate (16)13
Compound 15 (0.5 g, 1.05 mmol) and TBAI (1.0 g, 2.7 mmol) were
stirred in anhyd CH2Cl2 (10 mL) at –78 °C under N2. A 1 M soln of
BCl3 in CH2Cl2 (2.7 mL, 2.6 mmol) was added over 2 min. After 5
min, the solution was warmed to 0 °C and was stirred for 2 h. The
reaction solution was quenched with ice and H2O (20 mL), stirred
for 30 min, and partially concentrated to remove the CH2Cl2. After
H2O (10 mL) was added, the mixture was extracted with Et2O (2 ×
50 mL). The combined organic layer was washed with sat. aq NaCl
(100 mL), dried (Na2SO4), and concentrated. The residue was puri-
fied by column chromatography on silica gel (CH2Cl2–MeOH, 9:1)
which provided compound 16 as an off-white solid; yield: 0.38 g
(80%).
(5) Courvalin, P. Antimicrob. Agents Chemother. 1990, 34,
2291.
(6) Malabarba, A.; Ciabatti, R. J. Med. Chem. 1994, 37, 2988.
(7) Bois-Choussy, M.; Beugelmans, R.; Bouillon, J. P.; Zhu, J.
Tetrahedron Lett. 1995, 36, 4781.
Rf = 0.3 (CH2Cl2–MeOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 9.32 (d, J = 7.6 Hz, 1 H), 8.77
(d, J = 10.4 Hz, 1 H), 8.64 (t, J = 9.2 Hz, 1 H), 8.24 (d, J = 6.8 Hz,
1 H), 7.78 (m, 1 H), 7.44 (m, 5 H), 7.11 (m, 2 H), 6.93 (m, 1 H), 6.82
(m, 1 H), 6.65 (t, J = 8.8 Hz, 1 H), 5.45 (m, J = 8 Hz, 1 H), 4.46 (m,
1 H), 4.20 (m, 2 H), 3.53 (s, 3 H), 3.01 (t, J = 13.6 Hz, 2 H).
(8) Suzuki, Y.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett.
1989, 30, 6043.
13C NMR (400 MHz, DMSO-d6): d = 173.0, 170.0, 169.0, 154.4,
145.1, 144.9, 139.8, 134.4, 131.3, 130.5, 129.0, 128.5, 127.6, 126.9,
123.3, 122.9, 116.3, 56.3, 55.4, 52.8, 44.5, 38.5.
ESI-MS: m/z = 461 [M + H+].
HRMS (ESI): m/z [M+] calcd for C26H24N2O6: 460.4785; found:
(9) Evans, D. A.; Ellman, J. A.; DeVries, K. M. J. Am. Chem.
Soc. 1989, 111, 8912.
(10) (a) Griffith, R. S. J. Antimicrob. Chemother., Suppl. D 1984,
14, 1. (b) Williams, D. H.; Kalman, J. R. J. Am. Chem. Soc.
1977, 99, 2768.
(11) Evans, D. A.; Watson, P. S. Tetrahedron Lett. 1996, 37,
460.4773.
3251.
(12) Hitotsuyanagi, Y.; Ishikawa, H.; Naito, S.; Takeya, K.
Tetrahedron Lett. 2003, 44, 5901.
(13) Rescek, D. M.; Woodworth, G. F.; Morgan, B. P.; Coe, J. W.
J. Org. Chem. 1999, 64, 9719.
(14) Morgan, B. J.; Xie, X.; Phuan, P.-w.; Kozlowski, M. C.
J. Org. Chem. 2007, 72, 6171.
Synthesis 2009, No. 19, 3322–3326 © Thieme Stuttgart · New York