Anhydrolide macrolides. 2. Synthesis and antibacterial activity of 2,3- anhydro-6-O-methyl 11,12-carbazate erythromycin A analogues

Article abstract of DOI:10.1021/jm970548p

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11,12- cyclic carbazate analogues was prepared and evaluated for antibacterial activity. These 2,3-anhydro macrolides were found to be potent antibacterial agents in vitro against macrolide-susceptible organisms including Staphylococcus aureus 6538P, Streptococcus pyogenes EES61, and Streptococcus pneumoniae ATCC6303. These compounds were also very active against some organisms that show macrolide resistance (S. aureus A5177, S. pyogenes PIU2584, and S. pneumoniae 5649). The compounds generally showed poor activity against organisms with constitutive MLS resistance. Selected compounds were evaluated in vivo in mouse protection studies. Although most of the compounds tested in vivo showed poor efficacy, two compounds, 38 and 57, were more active than clarithromycin against S. pneumoniae ATCC6303.

Full text of DOI:10.1021/jm970548p

1660
J . Med. Chem. 1998, 41, 1660-1670
An h yd r olid e Ma cr olid es. 2. Syn th esis a n d An tiba cter ia l Activity of
2,3-An h yd r o-6-O-m eth yl 11,12-Ca r ba za te Er yth r om ycin A An a logu es
George Griesgraber,* Mark J . Kramer, Richard L. Elliott, Angela M. Nilius, Patty J . Ewing, Patti M. Raney,
Mai-Ha Bui, Robert K. Flamm, Daniel T. W. Chu, J acob J . Plattner, and Yat Sun Or
Anti-Infective Discovery Research, Pharmaceutical Products Research Division, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064-3500
Received August 14, 1997
A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11,12-cyclic carbazate
analogues was prepared and evaluated for antibacterial activity. These 2,3-anhydro macrolides
were found to be potent antibacterial agents in vitro against macrolide-susceptible organisms
including Staphylococcus aureus 6538P, Streptococcus pyogenes EES61, and Streptococcus
pneumoniae ATCC6303. These compounds were also very active against some organisms that
show macrolide resistance (S. aureus A5177, S. pyogenes PIU2584, and S. pneumoniae 5649).
The compounds generally showed poor activity against organisms with constitutive MLS
resistance. Selected compounds were evaluated in vivo in mouse protection studies. Although
most of the compounds tested in vivo showed poor efficacy, two compounds, 38 and 57, were
more active than clarithromycin against S. pneumoniae ATCC6303.
Ch a r t 1
In tr od u ction
Macrolide antibiotics, like erythromycin (Chart 1),
have been extensively used in the treatment of bacterial
infections for over 40 years. They are generally effective
in the treatment of upper and lower respiratory tract
infections, and because of their safety, they are often
prescribed for children. Erythromycin however is quickly
degraded under the acidic conditions found in the
stomach to give inactive byproducts resulting in low
bioavailability. Cleavage of the acid-labile cladinose
moiety at C-3 is a common problem. Other degradation
pathways which lead to inactive compounds often
involve interaction of the hydroxyl groups at C-6 and
C-12 with the carbonyl at C-9.1 In addition to the loss
of antibacterial activity, some of these degradation
products have been shown to cause intestinal peristalsis
resulting in the gastrointestinal discomfort often as-
sociated with taking this drug.2
Recently, semisynthetic erythromycin derivatives have
been prepared which overcome some of the acid insta-
bility problems.3 Clarithromycin, the 6-O-methyl de-
rivative of erythromycin,4 has the C-6 hydroxyl blocked
which prohibits it from interacting with the C-9 carbo-
nyl. In azithromycin, the C-9 carbonyl has been re-
moved via a Beckmann rearrangement/ring expansion
of erythromycin 9-oxime.5,6 In addition to maintaining
potent activity against erythromycin-sensitive organ-
isms, these second-generation macrolides also show
increased activity against Legionella, Branhamella spp.,
and Chlamydia and Pasteurella mutocida. Azithromy-
cin also has therapeutic utility against Haemophilus
influenzae, and clarithromycin exhibits good activity
against Helicobactor pylori and has been approved in a
combination regiment for the treatment of peptic ulcer
disease.
Unfortunately, like erythromycin, both clarithromycin
and azithromycin are ineffective against organisms that
show macrolide-lincosamide-streptogramin B (MLS)
cross-resistance. Organisms with this type of resistance
are able to selectively dimethylate an adenine residue
in their ribosomal RNA. This methylation occurs in the
MLS binding region and thus confers resistance to
macrolide, lincosamide, and streptogramin B antibiotics.
Other forms of resistance include the presence of
esterases which cleave the lactone ring and macrolide
efflux mechanisms. Organisms with macrolide resis-
tance are becoming more prevalent, especially in hos-
* To whom correspondence should be addressed: George Gries-
graber, Ph.D., Dept 47N, 100 Abbott Park Rd., Abbott Park, IL 60064-
3500. E-mail: george.griesgraber@abbott.com.
S0022-2623(97)00548-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/21/1998

Anhydrolide Macrolides. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1661
Sch em e 1
Sch em e 2
pital settings. Recently, over 20% of the clinically
isolated pneumoncocci in France were found to be
resistant to macrolides, and in J apan 18-20% were
resistant.7 The incidence of macrolide resistance in
staphylococci in clinical isolates from South Africa over
a period from May 1992 to J uly 1992 was found to be
about 70%.8 Because of the increase in macrolide-
resistant bacteria, much effort has gone into developing
new macrolides with better activity against these or-
ganisms.
Recently, a series of 3-ketoclarithromycin derivatives
was developed. In this series, the cladinose sugar has
been removed and the resulting alcohol at the C-3
position was oxidized to a ketone. In addition to
maintaining good activity against erythromycin-suscep-
tible organisms, these “ketolides”, which include RU-
0049,10 and TE-802,11 also show activity against strains
that have inducible MLS resistance. This 3-keto modi-
fication also disproved the long-held belief that the
cladinose sugar was essential for antibacterial activity.
With this knowledge, we undertook a search for new
macrolide derivatives with novel modifications in this
region of the molecule.
In the companion paper, we describe a series of
clarithromycin derivatives that have been dehydrated
at the 2,3-positions.12 These compounds were further
modified by forming cyclic carbamates at the 11,12-
positions. While these compounds had increased activ-
ity against MLS-resistant organisms, the broad-spec-
trum activity was only moderate. On the basis of
previous structure-activity relationship (SAR) studies,
we felt that replacing the carbamate with a cyclic
carbazate at the 11,12-positions would give compounds
with better activity.10,13 Herein, we describe the syn-
thesis and antibacterial activity of these anhydrolide
carbazates.
carbazate 2 (39%) along with the epimeric 10(S)-
carbazate 3 (49%). We also obtained a small amount
of the pyrazoline 4 (6%) whose unique structure was
determined by X-ray crystallography. The terminal
amino group of carbazates 2 and 3 is set for further
modification. From previous studies of 11,12-carbamate
derivatives of clarithromycin14 and our experience in the
3-keto carbazate series,13 we felt that the most promis-
ing substituents on the carbazate nitrogen would consist
of an aromatic ring attached by an alkyl chain.
Reductive alkylation of 2 with hydrocinnamaldehyde
and cinnamaldehyde, in the presence of NaBH3CN and
acetic acid, gave the desired compounds 5 and 6,
respectively (Scheme 2). The epimeric 10(S)-carbazate
3 also underwent successful alkylation to give com-
pounds 7 and 8. The overall antibacterial activity of
the compounds with the natural 10(R) stereochemistry
was better than that of the 10(S) compounds (vide infra),
which is generally the case for macrolide derivatives of
this type.12,13 Because of this, we placed our emphasis
on preparing compounds in the 10(R) series (Chart 2).
Compounds 9-28 and 30-52 were prepared by reduc-
Ch em istr y
The key acylimidazolide intermediate 1 was prepared
following the procedure described in the companion
paper.12 To prepare the parent carbazate, compound 1
was treated with hydrazine in dimethylformamide,
followed by methanolysis of the 2′-acetate, to give the
mixture of products shown in Scheme 1. Chromato-
graphic separation of the mixture gave us the desired

1662 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Griesgraber et al.
Ch a r t 2
unlike the organisms with MLS resistance, these organ-
isms are susceptible to clindamycin and are probably
resistant due to a macrolide efflux mechanism. We also
tested against a strain of ampicillin-resistant Haemo-
philus influenzae to monitor activity against this Gram-
negative organism.
The parent carbazate with the natural stereochem-
istry at C-10, compound 2, has moderate antibacterial
activity against the erythromycin-susceptible organisms
but is less active than erythromycin itself. However,
compound 2 has slightly better activity than erythro-
mycin against S. aureus A5177, the strain with induc-
ible MLS resistance, and much better activity against
resistant S. pyogenes PIU2584 and S. pneumoniae 5649.
No antibacterial activity was seen against the consti-
tutively resistant strains. The compound with the 10-
epi stereochemistry (3) showed a significant decrease
in activity against all strains tested.
The alkylated carbazates generally showed much
better activity than the parent compounds 2 and 3.
Compounds 5 and 6, substituted with hydrocinnamyl
and cinnamyl, respectively, showed erythromycin-like
activity against susceptible strains and very good activ-
ity against the resistant S. aureus A5177, S. pyogenes
PIU2584, and S. pneumoniae 5649. The activity against
the constitutively resistant organisms, while still poor,
was better than that of erythromycin itself. The alky-
lated compounds with the 10(S) stereochemistry, 7 and
8, showed better activity than the parent carbazate 3,
but the overall activity is significantly lower compared
to the activity of the analogous compounds with 10(R)
stereochemistry. However, the alkylated derivatives
with 10(S) stereochemistry did show a slight improve-
ment against the constitutively resistant organisms.
The remaining carbazates (9-58) all have the natural
C-10(R) stereochemistry. The compounds generally
maintained good activity against the erythromycin-
susceptible organisms and against the resistant S.
aureus A5177, S. pyogenes PIU2584, and S. pneumoniae
5649. The best compounds against these organisms
have the hydroxy- and nitro-substituted aromatic rings
(24-26, 29-33, 34-40). While most of the compounds
tested were still inactive against the constitutively
resistant organisms, a few, especially the compounds
with the unsubstituted and halogenated aromatic rings
(10-16, 21), started to show some activity against these
organisms. There were even a few compounds identified
(24, 39, 48, 57) with increased activity against H.
influenzae.
tive alkylation of 2 with the corresponding aldehydes.
Compound 29 was prepared by reductive alkylation with
terephthalaldehyde (benzene-1,4-dicarboxaldehyde); how-
ever, the second formyl group of the starting aldehyde
undergoes reduction during the reaction to give the
hydroxymethyl compound. The amino compounds 53-
57 were prepared by reducing the corresponding nitro
compounds 34-38 using Zn in the presence of HCl.
Compound 58 was prepared by selective N-acetylation
of 57 with acetyl chloride.
We were also able to perform some modifications on
pyrazoline 4 (Scheme 3). The imine at C-9 was selec-
tively reduced with NaBH3CN to give the tetrahydro-
pyrazole 59. This in turn was subjected to reductive
alkylation to give phenylpropyl-substituted compound
60.
Resu lts a n d Discu ssion
The pyrazoline 4 had no antibacterial activity in our
screen. This was somewhat surprising considering the
similarity in structure to TE-802.11 The strain of the
fused pyrazoline and carbamate rings, perhaps, forces
the rest of the macrolide into a conformation unfavor-
able for ribosomal binding. The reduced compound 59
and the alkylated compound 60 were also very poor
antibacterial agents.
The 2,3-anhydro 11,12-carbazates have in vitro activ-
ity similar to that of the 3-keto analogues that we had
previously prepared.13 Both classes retain activity
against erythromycin-susceptible strains and show in-
creased activity against the resistant S. aureus A5177,
S. pyogenes PIU2584, and S. pneumoniae 5649. Due
to its activity against MLS-resistant organisms, RU-004
All of the compounds were tested in vitro against a
number of Gram-positive strains including Staphy-
lococcus aureus, Streptococcus pyogenes, and Strepto-
coccus pneumoniae. Table 1 shows the antibacterial
activity against erythromycin-susceptible organisms (S.
aureus 6538P, S. pyogenes EES61, and S. pneumoniae
ATCC6303) and a number of erythromycin-resistant
strains. The resistant strains can be broken down into
different categories. Some of the organisms tested have
MLS cross-resistance. S. aureus A5177 has inducible
MLS resistance, while S. aureus A-5278, S. pyogenes
930, and S. pneumoniae 5979 have a constitutive form
of MLS resistance. S. pyogenes PIU2584 and S. pneu-
moniae 5649 are also resistant to erythromycin, but

Anhydrolide Macrolides. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1663
Sch em e 3
has been the most publicized member of the 3-keto
macrolides.9,10 This compound, which contains a 4-
quinolylpropyl side chain attached to the 11,12-carba-
zate, was prepared at Roussel-Uclaf by the group that
had done the initial research efforts in the 3-keto class
of clarithromycin derivatives. When we compare the
in vitro activity of RU-004 with its 2,3-anhydro coun-
terpart, compound 48, we see that RU-004 is slightly
more active against most of the strains tested. Where
RU-004 is clearly superior to 48 is against the consti-
tutively resistant organisms S. pyogenes 930 (RU-004
MIC ) 2 µg/mL vs 48 MIC > 64 µg/mL) and S.
pneumoniae 5979 (RU-004 MIC ) 8 µg/mL vs 48 MIC
> 64 µg/mL). RU-004 is rather unique in its increased
in vitro activity against these organisms because the
majority of compounds in both the 3-keto and 2,3-
anhydro classes lack this ability. However, RU-004 still
lacks activity against the constitutively resistant S.
aurues A-5278.
Compounds 2, 5, 15, 32, 38, 43, 48, and 57 were
evaluated for in vivo activity against the macrolide-
susceptible strains S. aureus NCTC10649M and S.
pnuemoniae ATCC6303 in mouse protection studies
following protocols described previously.15 Compounds
2, 5, 15, 32, 43, and 48 were all at least 2-fold less active
than the standard, clarithromycin, against both organ-
isms (data not shown). However, the compounds with
the 4-nitro (38)- and 4-amino (57)-substituted cinnamyl
side chains, while still 2-fold less active than clarithro-
mycin against S. aureus NCTC10649M, were much
better than clarithromycin against S. pneumoniae
ATCC6303 (Table 2). Compound 38 was approximately
2-fold more active and compound 57 was approximately
3-fold more active than clarithromycin against this
strain.
compounds from this class in vivo, and the results will
be reported in due time.
Exp er im en ta l Section
All solvents and reagents were reagent grade unless oth-
erwise noted. Elemental analyses were obtained from Rob-
ertson Laboratories, Madison, NJ . Chromatographic purifi-
cations were carried out using flash chromatography (60 mesh
silica gel, 0.04-0.063 mm; E. Merck). 1H and 13C NMR spectra
were taken in CDCl3 at 300 or 500 MHz, and chemical shifts
are reported in ppm relative to CHCl3 assigned at 7.26 and
77.0 ppm, respectively. Proton assignments were determined
from 1H-1H COSY experiments and can be found in the
Supporting Information. All final compounds, unless other-
wise noted, were analyzed by 1H NMR, 13C NMR, MS, and
elemental analysis and in general had a chemical purity of
>95% as determined by 1H NMR. 3-(2-Chlorophenyl)propanal,
3-(3-chlorophenyl)propanal, 3-(4-chlorophenyl)propanal, 3-(2,4-
dichlorophenyl)propanal, 3-(2-hydroxyphenyl)propanal, 3-(3-
hydroxyphenyl)propanal, 3-(4-hydroxyphenyl)propanal, 3-(4-
methoxyphenyl)propanal, 3-(2-nitrophenyl)propanal, 3-(3-
nitrophenyl)propanal, 3-(4-nitrophenyl)propanal, and 3-(4-
acetamidophenyl)propanal were prepared by the Pd-mediated
coupling of the corresponding aryl iodides with allyl alcohol.16
The preparation of 3-(1-benzotriazolyl)propanal, 3-(2-benzot-
riazolyl)propanal, 3-(4-phenylimidazolyl)propanal, and 3-(4-
quinolyl)propanal is described below. All other reagents were
purchased from Aldrich Chemical Co. and used without further
purification.
For in vitro studies, the minimum inhibitory concentrations
were determined by standard agar dilution methods.17
2,3-An h yd r o-5-O-d esosa m in yl-11-h yd r a zo-6-O-m eth yl-
er yth r on olid e A, 11,12-Ca r ba m a te (2). A solution of the
12-O-acylimidazolyl compound 1 (4.00 g, 5.81 mmol) dissolved
in 20 mL of DMF was treated with hydrazine (0.45 mL, 14.4
mmol, 2.5 equiv). After stirring for 30 min, the reaction
mixture was diluted with CH2Cl2 (200 mL) and washed with
5% KH2PO4 solution and H2O (3×). The organic portion was
dried with Na2SO4 and concentrated under reduced pressure
to give a white foam. This was dissolved in 50 mL of MeOH,
and the reaction mixture was left standing overnight. The
MeOH was then removed under reduced pressure. Chroma-
tography (SiO2, 10% MeOH/tert-butyl methyl ether with 1%
NH4OH) separated the 10(S)-epimer 3 (1.73 g) from the 10-
(R)-epimer 2 and the dihydropyrazole 4. A second chroma-
tography (5-10% MeOH/CH2Cl2 with 0.2% NH4OH) separated
the 10(R)-epimer 2 (1.38 g) and the dihydropyrazole 4 (0.22
g). Compound 2: CI MS m/z 612 (M + H)+; 13C NMR (CDCl3)
δ 216.9, 169.6, 155.9, 146.6, 122.9, 104.7, 83.2, 81.7, 78.9, 77.9,
70.2, 69.5, 65.7, 63.1, 48.8, 44.4, 40.3, 40.1, 37.0, 28.3, 21.7,
21.0, 19.9, 17.7, 16.9, 14.0, 12.6, 10.5. Anal. (C31H53N3O9) C,
H, N.
Con clu sion
In summary, a series of N-alkylated derivatives of 2,3-
anhydro-11-hydrazo-6-O-methylerythromycin 11,12-
cyclic carbazates was prepared and evaluated for in vitro
antibacterial activity. These compounds were generally
better than or equal to erythromycin in potency when
tested against macrolide-susceptible organisms. More
importantly, these compounds had increased activity
against the erythromycin-resistant strains S. aureus
A5177, S. pyogenes PIU2584, and S. pneumoniae 5649.
It appears that like the 3-ketolides, these 2,3-anhydro
derivatives also do not induce MLS resistance. These
compounds, however, were not very active against
organisms with constitutive MLS resistance. The en-
couraging in vivo data of compounds 38 and 57 warrant
further investigation. We are currently evaluating more
10-ep i-2,3-An h yd r o-5-O-d esosa m in yl-11-h yd r a zo-6-O-
m eth yler yth r on olid e A, 11,12-ca r ba m a te (3): CI MS m/z
612 (M + H)+; 13C NMR (CDCl3) δ 215.1, 171.9, 157.3, 144.5,
124.1, 105.2, 83.9, 83.8, 78.6, 78.3, 70.4, 69.5, 65.6, 63.7, 50.4,
45.6, 42.6, 41.0, 40.2, 36.8, 28.3, 21.2, 21.2, 21.0, 19.9, 17.4,
16.9, 11.7, 10.4, 10.4. Anal. (C31H53N3O9) C, H, N.
2,3-An h yd r o-9-d eoxo-5-O-d esosa m in yl-11-h yd r a zo-6-O-
m eth yler yth r on olid e A, 9-im in e 11,12-ca r ba m a te (4): CI

1664 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Griesgraber et al.
Ta ble 1. In Vitro Activity of 2,3-Anhydro-6-O-methyl 11,12-Carbazate Erythromycin Analogues
MIC (µg/mL)
S. aureus
S. pyogenes
S. pneumoniae
H. flu
entry
6538Pa
A5177b
A-5278c
EES61a
PIU2584d
930c
ATCC6303a
5649d
5979c
DILL
Ery A
2
3
4
5
6
7
8
9
0.2
1.56
50
3.1
1.56
50
>100
>100
>100
>100
50
100
25
50
>100
>100
25
100
50
0.03
0.25
8
32
1
32
>128
>64
>128
>128
32
32
8
16
>64
64
8
32
16
16
16
8
64
16
>64
64
0.06
0.25
8
16
1
16
>128
>64
>128
>128
64
32
16
16
>64
>64
16
32
32
4
32
>128
>128
16
8
>128
>64
8
>64
16
16
16
32
16
16
16
16
8
>100
>100
>128
0.06
0.06
2
>128
>128
>128
0.1
0.1
0.1
1
0.5
8
8
1
2
1
1
1
1
1
1
1
2
1
1
2
0.125
0.03
2
2
1
8
4
1
2
1
1
1
2
1
2
1
2
2
2
0.02
12.5
12.5
0.39
0.78
0.39
0.2
0.2
0.39
0.1
0.39
0.39
0.78
0.2
0.39
1.56
0.39
0.05
0.2
0.2
0.2
3.1
0.78
0.2
0.2
0.1
0.2
0.2
6.2
0.2
0.78
0.39
0.2
4
1
0.03
0.25
0.125
0.03
0.03
0.25
0.125
0.06
0.03
0.06
0.03
0.03
0.25
0.03
0.015
0.03
0.03
0.03
0.25
1
0.06
0.25
0.125
0.06
0.125
0.25
0.03
0.125
0.06
0.06
0.125
0.06
0.25
0.03
0.03
0.06
0.03
0.03
0.25
1
0.03
0.03
0.03
0.004
0.03
0.03
0.03
0.004
0.03
0.03
0.03
0.03
0.125
0.5
0.125
0.06
0.06
0.06
0.03
0.004
0.125
0.03
0.004
0.03
0.25
0.03
0.03
0.03
0.03
0.03
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RU-004
0.2
0.39
0.05
0.39
0.2
0.78
0.2
50
25
25
50
32
16
8
64
100
16
>100
>100
25
>64
>64
16
0.39
1.56
16
>64
8
8
64
2
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
100
>100
>100
>100
>100
100
1
0.5
0.5
2
1
1
2
2
1
2
0.5
1
0.25
1
1
0.25
1
1
0.5
0.25
1
64
0.02
0.2
0.1
0.2
3.1
0.78
0.2
0.2
0.1
0.1
0.5
0.5
0.5
1
128
>64
>128
>128
128
>128
>128
>128
128
>64
32
128
64
64
64
32
>128
>64
>128
>128
128
>128
>128
>128
>128
>64
32
4
2
4
4
32
32
4
16
4
4
8
8
8
8
8
8
2
4
16
0.5
2
0.03
0.03
0.06
0.004
0.06
0.03
0.03
0.004
0.03
0.06
0.004
0.015
0.125
0.25
0.03
0.06
0.06
0.03
0.03
0.004
0.06
0.03
0.004
0.03
0.06
0.06
0.03
0.03
0.03
0.06
>128
16
1
0.25
0.5
1
0.5
0.25
1
0.05
0.1
0.2
0.1
0.2
0.02
0.1
0.2
0.05
0.01
0.2
0.1
0.2
>128
128
128
64
1
64
0.01
>100
>100
>100
100
0.25
0.25
1
2
2
2
1
1
0.5
0.5
0.5
1
1
1
1
1
1
1
64
>128
>128
>128
32
>128
128
16
4
0.2
3.1
16
16
4
8
8
8
8
2
8
8
8
4
16
16
4
4
2
3.1
2
1
2
1
1
1
1
1
0.78
0.39
0.39
0.39
0.39
0.2
0.39
0.2
0.2
0.78
0.39
0.39
0.39
0.2
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
100
>64
>128
>128
>64
>128
>64
>64
128
128
>128
>128
128
>128
>128
>128
>64
>128
64
>64
>128
>128
>64
>128
>64
>64
>128
>128
>128
>128
>128
>128
>128
>128
>64
>128
64
0.1
0.39
0.5
0.5
1
0.2
0.1
0.78
0.39
0.2
0.2
0.78
0.39
0.2
0.39
0.2
1
1
1
1
0.2
0.2
>100
1
1
0.2
4
>100
100
0.1
>128
64
0.25
>128
16
0.004
>128
64
0.5
>128
>64
1
50
0.05
>100
0.008
2
8
a
b
S. aureus 6538P, S. pyogenes EES61, and S. pneumoniae ATCC6303: erythromycin-susceptible. S. aureus A5177: inducible MLS
resistance. c S. aureus A-5278, S. pyogenes 930, and S. pneumoniae 5979: constitutive MLS resistance. S. pyogenes PIU2584 and S.
d
pneumoniae 5649: erythromycin-resistant, clindamycin-susceptible.
MS m/z 594 (M + H)+; 13C NMR (CDCl3) δ 171.3, 166.9, 156.4,
145.1, 124.3, 105.1, 86.6, 84.6, 80.1, 79.5, 73.7, 70.8, 69.4, 65.9,
50.4, 44.8, 40.3, 40.0, 38.1, 30.8, 28.6, 26.2, 25.7, 21.8, 21.4,
19.7, 18.0, 17.9, 12.0, 12.0. Anal. (C31H51N3O8) C, H, N.
Ger er a l P r oced u r e for th e P r ep a r a tion of Alk yla ted
Ca r ba za tes 5-52. 2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-
p h en ylp r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,-
12-Ca r ba m a te (5). A solution of 2 (263 mg, 0.430 mmol)
dissolved in 5 mL of MeOH was treated with hydrocinnama-
ldehyde (280 µL, 2.13 mmol, 5 equiv) and AcOH (122 µL, 2.13
mmol, 5 equiv). The reaction mixture was stirred under N2
and monitored by TLC. After the starting material had been
consumed, NaBH3CN (200 mg) was added and additional
acetic acid was added dropwise until bromocresol green

Anhydrolide Macrolides. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1665
S. pneumoniae ATCC6303
Ta ble 2. In Vivo Efficacy of Compounds 38 and 57a,b
S. aureus NCTC10649M
entry
MIC (µg/mL)
ED50
MIC (µg/mL)
ED50
38
57
0.2
0.2
0.39
50.1 (31.7-79.2)
0.004
0.03
0.03
16.8 (9.1-31.0)
39.9 (25.6-62.3)
9.9 (6.7-14.7)
clarithromycinc
22.4-24.8 (13.3-37.9)
27.2-34.6 (20.2-52.7)
a
b
Values are ED50 reported in mg/kg/day (95% confidence interval). Mice were intraperitoneally infected with 1000 × LD50 for S.
aureus and 100 × LD50 for S. pneumoniae. Macrolides were administered orally at 1 and 5 h pi. c Values for clarithromycin represent the
range for two trials.
indicator had turned from blue to yellow. After stirring for 3
h, the reaction mixture was added to saturated NaHCO3
solution and extracted into CH2Cl2. The organic portion was
washed with H2O and brine, dried over Na2SO4, and concen-
trated under reduced pressure. Chromatography (5% MeOH/
CH2Cl2 containing 0.1% concentrated NH4OH) gave the prod-
uct as a white solid (159 mg, 51% yield): CI MS m/z 730 (M +
H)+; 13C NMR (CDCl3) δ 217.2, 169.1, 155.8, 145.9, 142.1,
128.4, 128.1, 125.5, 123.9, 104.8, 83.1, 81.5, 78.9, 77.8, 70.2,
69.6, 65.7, 57.9, 49.0, 48.0, 44.3, 40.7, 40.1, 40.0, 37.2, 33.2,
29.5, 28.1, 21.8, 21.1, 20.4, 18.2, 17.0, 14.7, 14.5, 13.0, 10.6.
Anal. (C40H63N3O9) C, H, N.
2,3-An h ydr o-5-O-desosam in yl-11-[(3-ph en yl-2-pr open yl)-
h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r ba m a te
(6). The title compound was prepared from 2 and cinnama-
ldehyde. Chromatography (4% MeOH/CH2Cl2 containing 0.2%
concentrated NH4OH) gave the product as a white foam (27%
yield): CI MS m/z 728 (M + H)+; 13C NMR (CDCl3) δ 217.5,
169.4, 156.0, 146.2, 136.9, 134.0, 128.4, 127.4, 126.7, 125.8,
123.8, 105.0, 83.3, 81.8, 79.0, 78.6, 70.3, 69.8, 65.8, 57.8, 51.0,
49.5, 44.4, 40.8, 40.2, 40.1, 37.4, 28.2, 21.8, 21.2, 20.5, 18.4,
17.1, 14.8, 14.8, 13.1, 10.4. Anal. (C40H61N3O9) C, H, N.
10-epi-2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-p h en ylp r o-
p yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r ba m -
a te (7). The title compound was prepared from 3 and
hydrocinnamaldehyde. Chromatography (5% MeOH/CH2Cl2
containing 0.2% concentrated NH4OH) gave the product as a
white foam (47% yield): CI MS m/z 730 (M + H)+; 13C NMR
(CDCl3) δ 214.9, 171.7, 156.5, 144.4, 141.7, 128.3, 128.2, 125.9,
124.3, 105.1, 83.9, 83.8, 78.6, 78.0, 70.4, 69.6, 65.6, 62.7, 50.1,
49.7, 46.0, 42.1, 41.0, 40.2, 36.8, 33.3, 29.5, 28.3, 21.4, 21.2,
20.9, 19.8, 17.5, 16.9, 11.8, 10.5, 10.4. Anal. (C40H63N3O9) C,
H, N.
10-ep i-2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-p h en yl-2-
p r op en yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (8). The title compound was prepared from 3 and
cinnamaldehyde. Chromatography (5% MeOH/CH2Cl2 con-
taining 0.2% concentrated NH4OH) gave the product as a white
foam (35% yield): CI MS m/z 728 (M + H)+; 13C NMR (CDCl3)
δ 215.0, 171.9, 156.7, 144.5, 136.8, 134.0, 128.5, 127.7, 126.5,
124.5, 124.3, 105.3, 84.2, 84.0, 78.7, 78.2, 70.5, 69.6, 65.8, 62.6,
52.3, 50.3, 46.1, 42.4, 41.1, 40.3, 37.0, 28.5, 21.5, 21.3, 20.9,
19.9, 17.5, 17.0, 11.9, 10.5, 10.4. Anal. (C40H61N3O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(p h en ylm et h yl)h y-
d r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r ba m a te (9).
The title compound was prepared from 2 and benzaldehyde.
Chromatography (5% MeOH/CH2Cl2 with 0.1% NH4OH) gave
the compound as a white powder (57% yield): CI MS m/z 702
(M + H)+; 13C NMR (CDCl3) δ 217.2, 169.3, 155.6, 146.0, 136.7,
129.2, 128.2, 127.4, 124.2, 104.9, 83.4, 81.6, 79.2, 77.3, 70.4,
69.8, 65.8, 58.6, 52.6, 49.6, 44.3, 41.1, 40.2, 40.1, 37.4, 28.3,
21.9, 21.2, 20.8, 18.4, 17.2, 14.9, 14.4, 13.1, 10.7. Anal.
(C38H59N3O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(2-p h en ylet h yl)h y-
dr azo]-6-O-m eth yler yth r on olide A, 11,12-Car bam ate (10).
The title compound was prepared from 2 and phenylacetal-
dehyde. Chromatography (4% MeOH/CH2Cl2 with 0.1% NH4-
OH) gave the compound as a white powder (37% yield): CI
MS m/z 716 (M + H)+; 13C NMR (CDCl3) δ 217.1, 169.2, 155.9,
146.1, 139.4, 128.7, 128.2, 125.9, 123.8, 104.8, 83.2, 81.6, 78.9,
77.8, 70.2, 69.6, 65.7, 58.4, 50.1, 49.1, 44.2, 40.8, 40.1, 40.0,
37.2, 34.4, 28.1, 21.8, 21.1, 20.4, 18.2, 17.0, 14.7, 14.4, 13.0,
10.7. Anal. (C39H61N3O9) C, H, N.
2,3-An h ydr o-5-O-desosam in yl-11-[(3-(1-n aph th yl)-2-pr o-
p en yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (11). The title compound was prepared from 2 and
3-(1-naphthyl)-2-propenal. Chromatography (5% MeOH/CH2-
Cl2 with 0.1% NH4OH) gave the compound as a white solid
(81% yield): CI MS m/z 778 (M + H)+; 13C NMR (CDCl3) δ
217.1, 169.3, 155.9, 146.3, 134.6, 133.4, 131.1, 130.6, 129.0,
128.1, 127.5, 125.7, 125.6, 125.4, 124.1, 123.7, 104.8, 83.3, 81.8,
79.0, 78.0, 70.2, 69.6, 65.7, 57.8, 51.1, 49.4, 44.2, 40.7, 40.1,
39.9, 37.3, 28.1, 21.5, 21.1, 20.4, 18.2, 17.0, 14.6, 12.9, 10.1.
Anal. (C44H63N3O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((4-ch lor op h en yl)-
m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (12). The title compound was prepared from 2 and
4-chlorobenzaldehyde. Chromatography (3% MeOH/CH2Cl2
with 0.1% NH4OH) gave the compound as a white solid (47%
yield): CI MS m/z 736 (M + H)+; 13C NMR (CDCl3) δ 217.5,
169.4, 155.5, 146.2, 135.3, 133.2, 130.7, 128.4, 124.0, 104.9,
83.2, 81.6, 79.2, 78.2, 70.3, 69.8, 65.8, 58.2, 51.8, 49.5, 44.4,
40.9, 40.2, 40.1, 37.4, 28.2, 21.8, 21.2, 20.7, 18.4, 17.1, 14.8,
14.6, 13.1, 10.7. Anal. (C38H58ClN3O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(2-ch lor op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (13). The title compound was prepared from 2 and
3-(2-chlorophenyl)propanal. Chromatography (3% MeOH/CH2-
Cl2 with 0.1% NH4OH) gave the compound as a white foam
(27% yield): CI MS m/z 764 (M + H)+; 13C NMR (CDCl3) δ
217.3, 169.3, 155.9, 146.1, 139.8, 133.9, 130.7, 129.3, 127.2,
126.8, 124.0, 104.9, 83.3, 81.7, 79.1, 77.9, 70.4, 69.8, 65.9, 58.1,
49.2, 48.1, 44.4, 40.9, 40.3, 40.2, 37.4, 31.1, 28.4, 27.9, 21.9,
21.2, 20.5, 18.4, 14.8, 14.6, 13.1, 10.7. Anal. (C40H62ClN3O9)
C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(3-ch lor op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (14). The title compound was prepared from 2 and
3-(3-chlorophenyl)propanal. Chromatography (3% MeOH/CH2-
Cl2 with 0.1% NH4OH) gave the compound as a white foam
(50% yield): CI MS m/z 764 (M + H)+; 13C NMR (CDCl3) δ
217.3, 169.3, 155.9, 146.0, 144.3, 134.0, 129.5, 128.6, 126.8,
125.8, 124.1, 104.9, 83.2, 81.7, 79.1, 77.9, 70.4, 69.8, 65.9, 58.0,
49.2, 47.9, 44.4, 40.8, 40.2, 37.4, 33.0, 29.4, 28.3, 21.9, 21.2,
20.5, 18.3, 17.1, 14.8, 14.6, 13.1, 10.7. Anal. (C40H62ClN3O9)
C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(4-ch lor op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (15). The title compound was prepared from 2 and
3-(4-chlorophenyl)propanal. Chromatography (10% MeOH/
tert-butyl methyl ether with 1% NH4OH) gave the compound
as a white foam (57% yield): CI MS m/z 764 (M + H)+; 13C
NMR (CDCl3) δ 217.3, 169.2, 155.8, 145.9, 140.5, 131.2, 129.8,
128.2, 124.0, 104.8, 83.0, 81.6, 78.9, 77.7, 70.2, 69.6, 65.7, 57.9,
49.0, 47.8, 44.4, 40.6, 40.1, 40.1, 37.2, 32.5, 32.5, 29.4, 28.2,
21.8, 21.1, 20.4, 18.2, 17.0, 14.7, 14.5, 13.0, 10.7. Anal.
(C40H62ClN3O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(2,4-d ich lor op h e-
n yl)p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (16). The title compound was prepared from 2
and 3-(2,4-dichlorophenyl)propanal. Chromatography (5-10%
MeOH/tert-butyl methyl ether with 1% NH4OH) gave the
compound as a white foam (36% yield): CI MS m/z 799 (M +
H)+; 13C NMR (CDCl3) δ 216.9, 168.8, 155.5, 145.6, 137.9,
134.1, 131.8, 131.2, 128.6, 126.6, 123.7, 104.4, 82.8, 81.2, 78.6,
77.4, 69.9, 69.3, 65.5, 57.6, 48.8, 44.0, 40.4, 39.8, 39.7, 36.9,

1666 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Griesgraber et al.
28.1, 21.5, 20.8, 20.1, 17.9, 16.7, 14.4, 14.2, 12.7, 10.3. Anal.
(C40H61Cl2N3O9) C, H, N.
44.5, 40.9, 40.2, 40.0, 37.4, 28.3, 21.7, 21.3, 20.6, 18.4, 17.2,
14.8, 14.5, 13.0, 10.6. Anal. (C39H58N4O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((2-h yd r oxyp h en yl)-
m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (24). The title compound was prepared from 2 and
2-hydroxybenzaldehyde. Chromatography (5% MeOH/CH2Cl2
with 0.2% NH4OH) gave the compound as a white foam (55%
yield): CI MS m/z 718 (M + H)+; 13C NMR (CDCl3) δ 217.7,
169.3, 157.7, 155.6, 146.4, 129.5, 129.4, 123.5, 121.2, 119.4,
117.2, 104.9, 83.1, 82.3, 79.0, 78.1, 70.3, 69.7, 65.8, 58.5, 51.5,
49.5, 44.5, 40.5, 40.2, 37.3, 28.3, 21.8, 21.2, 20.3, 18.2, 17.0,
14.7, 14.7, 13.0, 10.6. Anal. (C38H59N3O10) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((3-h yd r oxyp h en yl)-
m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (25). The title compound was prepared from 2 and
3-hydroxybenzaldehyde. Chromatography (5% MeOH/CH2Cl2
with 0.1% NH4OH) gave the compound as a white foam (56%
yield): CI MS m/z 718 (M + H)+; 13C NMR (CDCl3) δ 217.3,
169.6, 155.9, 155.8, 146.3, 137.8, 129.9, 124.1, 121.6, 116.9,
114.9, 104.9, 83.1, 81.5, 79.2, 78.9, 70.4, 69.8, 65.8, 58.4, 52.1,
49.7, 44.5, 40.9, 40.2, 40.2, 37.4, 28.3, 22.1, 21.2, 20.7, 18.5,
17.1, 15.0, 14.6, 13.1, 10.7. Anal. (C38H59N3O10) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((4-h yd r oxyp h en yl)-
m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (26). The title compound was prepared from 2 and
4-hydroxybenzaldehyde. Chromatography (5% MeOH/CH2Cl2
with 0.2% NH4OH) gave the compound as a white foam (38%
yield): CI MS m/z 718 (M + H)+; 13C NMR (CDCl3) δ 217.4,
169.5, 155, 155.6, 146.1, 130.7, 128.3, 124.0, 115.2, 104.7, 83.2,
81.8, 79.1, 78.3, 70.3, 69.6, 65.8, 58.4, 52.0, 49.6, 44.3, 41.0,
40.3, 40.3, 37.3, 28.5, 21.9, 21.2, 20.7, 18.4, 17.1, 14.9, 14.5,
13.1, 10.7. Anal. (C38H59N3O10) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((2,5-d ih yd r oxyp h e-
n yl)m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (27). The title compound was prepared from 2
and 2,5-dihydroxybenzaldehyde. Chromatography (5% MeOH/
CH2Cl2 with 0.1% NH4OH) gave the compound as a white foam
(23% yield): CI MS m/z 734 (M + H)+; 13C NMR (CDCl3) δ
217.3, 169.6, 155.9, 155.8, 146.3, 137.8, 129.9, 124.1,121.6,
116.9, 114.9, 104.9, 83.1, 81.5, 79.2, 78.9, 70.4, 69.8, 65.8, 58.4,
52.1, 49.7, 44.5, 40.9, 40.2, 40.2, 37.4, 28.3, 22.1, 21.2, 20.7,
18.5, 17.1, 15.0, 14.6, 13.1, 10.7. Anal. (C38H59N3O11) C, H,
N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((3,4-d ih yd r oxyp h e-
n yl)m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (28). The title compound was prepared from 2
and 3,4-dihydroxybenzaldehyde. Chromatography (10% MeOH/
CH2Cl2 with 0.2% NH4OH) gave the compound as a white foam
(56% yield): CI MS m/z 734 (M + H)+; 13C NMR (CDCl3) δ
217.4, 169.5, 156.1, 146.4, 144.4, 143.3, 128.2, 124.0, 122.0,
117.0, 115.3, 104.8, 83.0, 81.8, 79.1, 78.6, 70.4, 69.7, 65.7, 58.5,
51.9, 49.7, 44.4, 40.8, 40.2, 37.4, 28.4, 22.0, 21.2, 20.7, 18.4,
17.1, 15.0, 14.7, 13.1, 10.7. Anal. (C38H59N3O11) C, H, N.
2,3-An h ydr o-5-O-desosam in yl-11-[((4-(h ydr oxym eth yl)-
ph en yl)m eth yl)h ydr azo]-6-O-m eth yler yth r on olid e A, 11,-
12-Ca r ba m a te (29). The title compound was prepared from
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(4-flu or op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (17). The title compound was prepared from 2 and
3-(4-fluorophenyl)propanal. Chromatography (3% MeOH/CH2-
Cl2 with 0.1% NH4OH) gave the compound as a white solid
(61% yield): CI MS m/z 748 (M + H)+; 13C NMR (CDCl3) δ
217.3, 169.3, 161.3, 155.9, 146.0, 137.7, 129.8, 124.1, 114.9,
104.9, 83.2, 81.6, 79.1, 77.9, 70.4, 69.8, 65.8, 58.1, 49.1, 47.9,
44.7, 40.8, 40.2, 40.1, 37.4, 32.5, 29.7, 28.2, 21.9, 21.2, 20.5,
18.3, 17.1, 14.8, 14.6, 13.1, 10.7. Anal. (C40H62FN3O9) C, H,
N.
2,3-An h ydr o-5-O-desosam in yl-11-[((4-(tr iflu or om eth yl)-
ph en yl)m eth yl)h ydr a zo]-6-O-m eth yler yth r on olid e A, 11,-
12-Ca r ba m a te (18). The title compound was prepared from
2 and 4-(trifluoromethyl)benzaldehyde. Chromatography (5%
MeOH/CH2Cl2 with 0.1% NH4OH) gave the compound as a
fluffy white solid (42% yield): CI MS m/z 770 (M + H)+; 13C
NMR (CDCl3) δ 217.5, 169.4, 155.5, 146.2, 140.9, 129.5, 125.2,
124.1, 104.9, 83.3, 81.7, 79.3, 78.2, 70.4, 69.8, 65.8, 58.3, 52.1,
49.6, 44.4, 41.0, 40.2, 40.1, 37.4, 28.3, 21.8, 21.2, 20.7, 18.4,
17.2, 14.8, 14.5, 13.1, 10.6. Anal. (C39H58F3N3O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((4-m eth oxyp h en yl)-
m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (19). The title compound was prepared from 2 and
4-methoxybenzaldehyde. Chromatography (3% MeOH/CH2Cl2
with 0.1% NH4OH) gave the compound as a white powder (32%
yield): CI MS m/z 732 (M + H)+; 13C NMR (CDCl3) δ 217.2,
169.4, 159.0, 155.6, 146.0, 130.5, 128.9, 124.2, 113.7, 104.9,
83.4, 81.6, 79.2, 78.3, 70.4, 69.8, 65.8, 58.5, 55.2, 51.9, 49.6,
44.3, 41.1, 40.2, 40.1, 37.4, 28.3, 21.9, 21.2, 20.8, 18.4, 17.2,
14.9, 14.4, 13.1, 10.7. Anal. (C39H61N3O10) C, H, N.
2,3-An h ydr o-5-O-desosam in yl-11-[(3-(4-m eth oxyph en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (20). The title compound was prepared from 2 and
3-(4-methoxyphenyl)propanal. Chromatography (10% MeOH/
tert-butyl methyl ether with 1% NH4OH) gave the compound
as a white foam (62% yield): CI MS m/z 760 (M + H)+; 13C
NMR (CDCl3) δ 217.3, 169.2, 157.7, 155.9, 146.0, 134.3, 129.4,
124.0, 113.7, 104.8, 83.2, 81.6, 79.0, 77.9, 70.3, 69.7, 65.8, 58.0,
55.2, 49.1, 48.1, 44.4, 40.8, 40.2, 40.1, 37.3, 32.4, 29.8, 28.3,
21.9, 21.2, 20.5, 18.3, 17.1, 14.8, 14.6, 13.1, 10.7. Anal.
(C41H65N3O10) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((4-p h en oxyp h en yl)-
m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (21). The title compound was prepared from 2 and
4-(phenoxyphenyl)benzaldehyde. Chromatography (5% MeOH/
CH2Cl2 with 0.1% NH4OH) gave the compound as a white foam
(73% yield): CI MS m/z 794 (M + H)+; 13C NMR (CDCl3) δ
217.3, 169.3, 157.3, 156.4, 155.5, 146.0, 131.5, 130.7, 129.5,
124.0, 122.9, 118.7, 118.6, 104.8, 83.2, 81.5, 79.1, 78.1, 70.2,
69.6, 65.7, 58.3, 51.8, 49.5, 44.3, 40.9, 40.1, 40.0, 37.3, 28.1,
21.8, 21.1, 20.6, 18.3, 17.0, 14.8, 14.4, 13.0, 10.6. Anal.
(C44H63N3O10) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((4-(m eth ylth io)p h e-
n yl)m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (22). The title compound was prepared from 2
and 4-(methylthio)benzaldehyde. Chromatography (5% MeOH/
CH2Cl2 with 0.1% NH4OH) gave the compound as a white foam
(43% yield): CI MS m/z 748 (M + H)+; 13C NMR (CDCl3) δ
217.3, 169.3, 155.5, 146.0, 137.3, 133.7, 129.7, 126.6, 124.1,
104.8, 83.3, 81.6, 79.1, 78.2, 70.3, 69.7, 65.8, 58.4, 52.0, 49.5,
44.3, 41.0, 40.2, 40.0, 37.4, 28.3, 31.9, 21.2, 20.7, 18.4, 17.1,
16.0, 14.9, 14.5, 13.1, 10.6. Anal. (C39H61N3O9S) C, H, N.
2
and terephthaldicarboxaldehyde. Chromatography (4%
MeOH/CH2Cl2 with 1% NH4OH) gave the compound as a white
foam (54% yield): CI MS m/z 732 (M + H)+; 13C NMR (CDCl3)
δ 217.3, 169.3, 155.5, 146.0, 140.2, 136.2, 129.5, 127.0, 124.1,
104.8, 83.3, 81.6, 79.1, 78.3, 70.3, 69.7, 65.7, 65.3, 58.8, 52.2,
49.5, 44.3, 41.0, 40.2, 40.1, 37.4, 28.3, 21.9, 21.2, 20.7, 18.4,
17.1, 14.9, 14.5, 13.1, 10.7. Anal. (C39H61N3O10) C, H, N.
2,3-An h ydr o-5-O-desosam in yl-11-[(3-(2-h ydr oxyph en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (30). The title compound was prepared from 2 and
3-(2-hydroxyphenyl)propanal. Chromatography (5% MeOH/
CH2Cl2 with 0.1% NH4OH) gave the compound as a white foam
(54% yield): CI MS m/z 746 (M + H)+; 13C NMR (CDCl3) δ
217.2, 169.4, 156.2, 155.3, 146.3, 130.3, 127.4, 127.2, 123.9,
120.1, 116.9, 104.9, 83.1, 82.0, 79.0, 77.9, 70.3, 69.7, 65.8, 57.4,
49.3, 45.7, 44.6, 40.5, 40.2, 40.1, 37.4, 28.3, 27.8, 26.3, 21.9,
21.2, 20.4, 18.4, 17.1, 14.8, 14.7, 13.1, 10.8. Anal. (C40H63N3O10)
C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((4-cya n op h en yl)-
m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (23). The title compound was prepared from 2 and
4-cyanobenzaldehyde. Chromatography (5% MeOH/CH2Cl2
with 0.1% NH4OH) gave the compound as a white foam (42%
yield): CI MS m/z 727 (M + H)+; 13C NMR (CDCl3) δ 217.6,
169.5, 155.5, 146.3, 142.5, 132.0, 129.9, 124.1, 118.9, 111.3,
104.9, 83.3, 81.7, 79.3, 78.1, 70.4, 69.8, 65.9, 58.1, 52.2, 49.5,

Anhydrolide Macrolides. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1667
2,3-An h ydr o-5-O-desosam in yl-11-[(3-(3-h ydr oxyph en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (31). The title compound was prepared from 2 and
3-(3-hydroxyphenyl)propanal. Chromatography (5% MeOH/
CH2Cl2 with 0.1% NH4OH) gave the compound as a white foam
(40% yield): CI MS m/z 746 (M + H)+; 13C NMR (CDCl3) δ
217.4, 170.1, 156.2, 156.0, 146.5, 143.2, 129.4, 123.8, 120.8,
115.4, 113.1, 104.8, 83.1, 81.3, 78.9, 78.5, 70.4, 69.7, 65.8, 58.3,
49.0, 48.0, 44.4, 40.7, 40.2, 40.2, 37.3, 33.0, 28.5, 28.4, 22.0,
21.2, 20.4, 18.3, 17.0, 14.9, 14.6, 13.1, 10.9. Anal. (C40H63N3O10)
C, H, N.
44.5, 40.6, 40.1, 40.1, 37.3, 33.1, 29.2, 28.2, 21.8, 21.1, 20.4,
18.2, 17.0, 14.6, 14.5, 13.0, 10.7. Anal. (C40H62N4O11) C, H,
N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(4-n itr op h en yl)-2-
p r op en yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (38). The title compound was prepared from 2
and 4-nitrocinnamaldehyde. Chromatography (4% MeOH/
CH2Cl2 with 0.1% NH4OH) gave the compound as a white foam
(48% yield): CI MS m/z 773 (M + H)+; 13C NMR (CDCl3) δ
217.6, 169.5, 156.0, 146.8, 146.3, 143.4, 131.8, 131.3, 127.2,
123.8, 123.8, 104.9, 83.2, 81.8, 79.1, 78.3, 70.3, 69.7, 65.7, 57.5,
50.8, 49.5, 44.4, 40.6, 40.2, 40.0, 37.4, 28.2, 21.7, 21.2, 20.5,
18.3, 17.1, 14.7, 14.7, 13.0, 10.5. Anal. (C40H60N4O11) C, H,
N.
2,3-An h ydr o-5-O-desosam in yl-11-[(3-(2-(5-n itr ofu r an yl))-
2-p r op en yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (39). The title compound was prepared from 2
and 5-nitro-2-furanacrolein. Chromatography (4% MeOH/CH2-
Cl2 with 0.1% NH4OH) gave the compound as a yellow solid
(67% yield): CI MS m/z 763 (M + H)+; 13C NMR (CDCl3) δ
217.6, 169.5, 155.8, 155.2, 151.4, 146.3, 132.9, 124.0, 120.1,
113.6, 110.1, 104.7, 83.3, 81.9, 79.1, 78.1, 70.2, 69.5, 65.8, 58.0,
50.3, 49.5, 44.4, 40.7, 40.2, 40.0, 37.3, 28.7, 21.7, 21.2, 20.5,
18.3, 17.2, 14.7, 14.6, 13.1, 10.7. Anal. (C38H58N4O12) C, H,
N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((2-h yd r oxy-5-n itr o-
ph en yl)m eth yl)h ydr a zo]-6-O-m eth yler yth r on olid e A, 11,-
12-Ca r ba m a te (40). The title compound was prepared from
2 and 2-nitro-5-hydroxybenzaldehyde. Chromatography (5-
10% MeOH/CH2Cl2 with 0.1% NH4OH) gave the compound as
a white foam (42% yield): CI MS m/z 763 (M + H)+; 13C NMR
(CDCl3) δ 218.3, 169.3, 164.1, 155.8, 146.7, 140.3, 125.9, 125.4,
123.5, 121.4, 117.5, 104.9, 83.1, 82.8, 79.1, 77.6, 70.3, 69.7, 65.7,
58.6, 51.5, 49.6, 44.4, 40.5, 40.2, 40.2, 37.3, 28.3, 21.7, 21.2,
2,3-An h ydr o-5-O-desosam in yl-11-[(3-(4-h ydr oxyph en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (32). The title compound was prepared from 2 and
3-(4-hydroxyphenyl)propanal. Chromatography (5% MeOH/
CH2Cl2 with 0.2% NH4OH) gave the compound as a white foam
(57% yield): CI MS m/z 746 (M + H)+; 13C NMR (CDCl3) δ
217.4, 169.3, 156.0, 154.0, 146.2, 133.8, 129.4, 124.0, 115.2,
104.8, 83.1, 79.0, 77.9, 70.4, 69.8, 65.7, 58.0, 49.2, 48.1, 44.4,
40.2, 40.1, 37.3, 32.4, 29.8, 28.3, 21.9, 21.2, 20.5, 18.3, 17.1,
14.8, 14.6, 13.1, 10.7. Anal. (C40H63N3O10) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((2-h yd r oxyn a p h th -
yl)m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (33). The title compound was prepared from 2
and 2-hydroxy-1-naphthaldehyde. Chromatography (5% MeOH/
CH2Cl2 with 0.1% NH4OH) gave the compound as a white foam
(38% yield): CI MS m/z 768 (M + H)+; 13C NMR (CDCl3) δ
217.7, 169.3, 156.3, 155.8, 146.4, 132.9, 129.7, 128.7, 128.5,
126.3, 123.7, 122.5, 121.9, 119.5, 112.0, 104.8, 83.5, 82.7, 79.1,
78.0, 70.3, 69.7, 65.7, 60.3, 49.4, 4.8, 44.5, 44.3, 40.7, 40.3, 40.2,
37.3, 29.1, 28.2, 21.9, 21.2, 20.4, 18.2, 17.1, 14.8, 14.5, 13.1,
10.6. Anal. (C42H61N3O10) C, H, N.
2,3-An h yd r o-5-O-d e sosa m in yl-11-[((4-n it r op h e n yl)-
m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (34). The title compound was prepared from 2 and
4-nitrobenzaldehyde. Chromatography (5% MeOH/CH2Cl2
with 0.1% NH4OH) gave the compound as a white powder (61%
yield): CI MS m/z 747 (M + H)+; 13C NMR (CDCl3) δ 217.7,
169.5, 155.5, 147.5, 146.4, 144.6, 130.0, 124.0, 123.4, 104.9,
83.2, 81.7, 79.2, 78.0, 70.3, 69.8, 65.8, 58.0, 51.9, 49.6, 44.5,
40.8, 40.2, 40.0, 37.4, 28.3, 21.7, 21.2, 20.6, 18.4, 17.1, 14.7,
14.6, 13.1, 10.7. Anal. (C38H58N4O11) C, H, N.
20.3, 18.1, 17.0, 14.6, 14.5, 13.0, 10.5. Anal. (C38H58N4O12
C, H, N.
)
2,3-An h ydr o-5-O-desosam in yl-11-[((4-(dim eth ylam in o)-
ph en yl)m eth yl)h ydr azo]-6-O-m eth yler yth r on olid e A, 11,-
12-Ca r ba m a te (41). The title compound was prepared from
2 and 4-(dimethylamino)benzaldehyde. Chromatography (4%
MeOH/CH2Cl2 with 0.1% NH4OH) gave the compound as a
white powder (64% yield): CI MS m/z 745 (M + H)+; 13C NMR
(CDCl3) δ 217.0, 169.3, 155.6, 150.1, 145.9, 130.2, 124.6, 124.2,
112.6, 104.8, 83.4, 81.6, 79.2, 78.4, 70.4, 69.7, 65.9, 58.7, 52.0,
49.6, 44.1, 40.7, 40.5, 40.3, 40.1, 37.4, 28.4, 22.0, 21.2, 20.8,
18.5, 17.2, 15.0, 14.4, 13.1, 10.7. Anal. (C40H64N4O9) C, H, N.
2,3-An h ydr o-5-O-desosam in yl-11-[((4-(dim eth ylam in o)-
n a p h th yl)m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A,
11,12-Ca r ba m a te (42). The title compound was prepared
from 2 and 4-(dimethylamino)-1-naphthaldehyde. Chroma-
tography (5-10% MeOH/CH2Cl2 with 0.1% NH4OH) gave the
compound as a white foam (20% yield): CI MS m/z 795 (M +
H)+; 13C NMR (CDCl3) δ 217.0, 169.4, 155.6, 151.1, 146.0,
133.7, 129.1, 127.4, 127.1, 126.2, 125.1, 124.9, 124.3, 113.2,
104.8, 83.5, 81.8, 79.2, 78.3, 70.4, 69.7, 65.9, 59.3, 50.6, 49.6,
45.2, 44.1, 41.3, 40.2, 40.1, 37.4, 28.4, 22.0, 21.2, 20.8, 18.5,
17.2, 15.0, 14.4, 13.1, 10.7. Anal. (C44H66N4O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[((4-(a cet yla m in o)-
ph en yl)m eth yl)h ydr a zo]-6-O-m eth yler yth r on olid e A, 11,-
12-Ca r ba m a te (43). The title compound was prepared from
2 and 4-acetamidobenzaldehyde. Chromatography (5% MeOH/
CH2Cl2 with 0.2% NH4OH) gave the compound as a white
powder (44% yield): CI MS m/z 759 (M + H)+; 13C NMR
(CDCl3) δ 217.3, 169.3, 168.3, 155.6, 146.1, 137.3, 133.5, 129.9,
124.0, 119.7, 104.9, 83.2, 81.7, 79.1, 78.1, 70.3, 69.7, 65.8, 58.4,
52.1, 49.6, 44.3, 41.0, 40.2, 40.1, 37.4, 28.3, 24.6, 21.9, 21.2,
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(2-n it r op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (35). The title compound was prepared from 2 and
3-(2-nitrophenyl)propanal. Chromatography (10% MeOH/CH2-
Cl2 with 1% NH4OH) gave the compound as a white foam (84%
yield): CI MS m/z 775 (M + H)+; 13C NMR (CDCl3) δ 217.4,
169.2, 155.9, 149.1, 146.2, 137.3, 133.0, 132.5, 126.9, 124.5,
123.9, 104.9, 83.3, 81.7, 79.0, 77.8, 70.3, 69.7, 65.8, 57.9, 49.3,
47.9, 44.5, 40.7, 40.3, 40.2, 37.4, 30.4, 28.9, 28.4, 21.9, 21.2,
20.5, 18.3, 17.1, 14.8, 14.7, 13.1, 10.7. Anal. (C40H62N4O11
C, H, N.
)
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(3-n it r op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (36). The title compound was prepared from 2 and
3-(3-nitrophenyl)propanal. Chromatography (10% MeOH/tert-
butyl methyl ether with 1% NH4OH) gave the compound as a
white foam (92% yield): CI MS m/z 775 (M + H)+; 13C NMR
(CDCl3) δ 217.4, 169.3, 156.0, 146.1, 144.3, 135.0, 129.2, 124.1,
123.3, 121.0, 104.9, 83.3, 81.7, 79.1, 77.8, 70.4, 69.7, 65.9, 58.0,
49.2, 47.8, 44.5, 40.8, 40.3, 40.1, 37.4, 32.9, 29.4, 28.4, 21.9,
21.2, 20.5, 18.4, 17.2, 14.7, 14.6, 13.1, 10.7. Anal. (C40H62N4O11)
C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(4-n it r op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (37). The title compound was prepared from 2 and
3-(4-nitrophenyl)propanal. Chromatography (5-10% MeOH/
CH2Cl2 with 0.1% NH4OH) gave the compound as a white foam
(77% yield): CI MS m/z 775 (M + H)+; 13C NMR (CDCl3) δ
217.5, 169.2, 155.9, 150.2, 146.2, 146.0, 129.3, 124.0, 123.5,
104.8, 83.0, 81.7, 79.0, 77.7, 70.3, 69.7, 65.7, 57.8, 49.0, 47.6,
20.7, 18.4, 17.1, 14.9, 14.6, 13.1, 10.7. Anal. (C40H62N4O10
C, H, N.
)
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(4-(a cetyla m in o)-
p h en yl)p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,-
12-Ca r ba m a te (44). The title compound was prepared from
2 and 3-(4-acetamidophenyl)propanal. Chromatography (5%
MeOH/CH2Cl2 with 0.2% NH4OH) gave the compound as a
white solid (18% yield): CI MS m/z 787 (M + H)+; 13C NMR

1668 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Griesgraber et al.
(CDCl3) δ 217.2, 169.3, 155.9, 146.1, 138.2, 135.7, 128.9, 124.0,
120.0, 104.9, 83.3, 81.7, 79.1, 77.9, 70.4, 69.7, 65.9, 58.1, 49.2,
48.1, 44.4, 40.8, 40.2, 40.1, 37.4, 32.7, 29.6, 28.4, 24.5, 21.9,
21.2, 20.5, 18.3, 17.1, 14.8, 14.5, 13.1, 10.7. Anal. (C42H66N4O10)
C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(2-p yr id ylm et h yl)-
h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r ba m a te
(45). The title compound was prepared from 2 and 2-pyridi-
necarboxaldehyde. Chromatography (5% MeOH/CH2Cl2 with
0.1% NH4OH) gave the compound as a white solid (41%
yield): CI MS m/z 703 (M + H)+; 13C NMR (CDCl3) δ 217.3,
168.9, 157.2, 155.6, 149.0, 145.6, 136.2, 124.0, 122.9, 122.0,
104.7, 83.1, 81.7, 78.8, 78.0, 70.3, 69.6, 65.7, 58.5, 54.0, 49.5,
44.4, 40.8, 40.2, 40.2, 37.2, 28.3, 21.9, 21.1, 20.5, 18.3, 17.0,
14.8, 14.5, 13.1, 10.7. Anal. (C37H58N4O9‚1/2H2O) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-p yr id ylm et h yl)-
h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r ba m a te
(46). The title compound was prepared from 2 and 3-pyridi-
necarboxaldehyde. Chromatography (5-10% MeOH/CH2Cl2
with 0.1% NH4OH) gave the compound as a white solid (56%
yield): CI MS m/z 703 (M + H)+; 13C NMR (CDCl3) δ 217.5,
169.3, 155.4, 150.3, 148.8, 146.2, 136.9, 132.3, 124.0, 123.2,
104.8, 83.1, 81.7, 79.1, 77.9, 70.2, 69.7, 65.7, 58.3, 50.0, 49.5,
44.3, 40.8, 40.2, 40.0, 37.3, 28.2, 21.7, 21.1, 20.6, 18.3, 17.1,
14.7, 14.4, 13.0, 10.6. Anal. (C37H58N4O9) C, H, N.
9.90 (s, 1H), 8.82 (d, 1H), 8.14 (d, 1H), 8.00 (m, 1H), 7.73 (m,
1H), 7.59 (m, 1H), 7.26 (d, 1H), 3.44 (t, 2H), 2.97 (m, 2H).
2,3-An h ydr o-5-O-desosam in yl-11-[(3-(4-qu in olyl)pr opyl)-
h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r ba m a te
(48). The title compound was prepared from 2 and 3-(4-
quinolyl)propanal. Chromatography (10% MeOH/tert-butyl
methyl ether with 1% NH4OH) gave the compound as an off-
white foam (53% yield): CI MS m/z 781 (M + H)+; 13C NMR
(CDCl3) δ 217.4, 169.3, 156.0, 150.1, 148.4, 148.1, 146.0, 129.9,
129.0, 127.6, 126.3, 124.1, 123.9, 121.1, 104.7, 83.2, 81.7, 79.0,
77.8, 70.3, 69.5, 65.8, 57.9, 49.1, 48.1, 44.5, 40.8, 40.2, 40.1,
37.3, 29.5, 28.2, 28.2, 21.9, 21.2, 21.2, 20.4, 18.3, 17.2, 14.7,
14.6, 13.1, 10.7. Anal. (C43H64N4O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-in d olylm eth yl)h y-
dr azo]-6-O-m eth yler yth r on olide A, 11,12-Car bam ate (49).
The title compound was prepared from 2 and indole-3-
carboxaldehyde. Chromatography (5% MeOH/CH2Cl2 with
0.2% NH4OH) gave the compound as a colorless solid (60%
yield): CI MS m/z 741 (M + H)+; 13C NMR (CDCl3) δ 217.0,
169.4, 155.7, 146.1, 136.3, 127.4, 124.4, 123.5, 121.9, 119.6,
119.5, 111.7, 110.9, 104.8, 83.6, 81.7, 79.2, 78.2, 70.4, 69.8, 65.8,
59.0, 49.5, 44.1, 44.0, 41.3, 40.2, 40.0, 37.4, 28.3, 21.9, 21.2,
20.9, 18.4, 17.2, 14.9, 14.3, 13.0, 10.7. Anal. (C40H60N4O9) C,
H, N.
2-(2-(4-P h en ylim id a zolyl)eth yl)-1,3-d ioxola n e. 4-Phe-
nylimidazole (2.01 g, 14.0 mmol, 1.0 equiv) was added to a
suspension of NaH (1.17 g, 29.3 mmol, 2.1 equiv) in DMF (25
mL) at 0 °C under nitrogen. 2-(2-Bromoethyl)-1,3-dioxolane
(1.80 mL, 15.3 mmol, 1.1 equiv) was added dropwise, and the
reaction mixture was warmed to room temperature. After
stirring for 28 h, the reaction mixture was partitioned between
Et2O and brine. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. Chromatography (5%
MeOH/CH2Cl2) gave 2.15 g of the desired product as an oil
(63% yield): CI MS m/z 245 (M + H)+; 1H NMR (CDCl3) δ 7.76
(m, 2H), 7.53 (m, 1H), 7.36 (m, 2H), 7.27-7.19 (m, 2H), 4.87
(t, 1H), 4.12 (t, 2H), 3.98 (m, 2H), 3.86 (m, 2H), 2.19 (m, 2H).
2,3-An h yd r o-5-O-d esosa m in yl-11-[(4-p yr id ylm et h yl)-
h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r ba m a te
(47). The title compound was prepared from 2 and 4-pyridi-
necarboxaldehyde. Chromatography (5% MeOH/CH2Cl2 with
0.1% NH4OH) gave the compound as a white solid (44%
yield): CI MS m/z 703 (M + H)+; 13C NMR (CDCl3) δ 217.6,
169.5, 155.5, 149.8, 146.3, 145.9, 124.1, 123.9, 105.0, 83.3, 81.8,
79.3, 78.1, 70.4, 69.8, 65.9, 58.2, 51.5, 49.6, 44.5, 40.9, 40.3,
40.1, 37.5, 28.3, 21.8, 21.3, 20.7, 18.4, 17.2, 14.8, 14.5, 13.1,
10.6. Anal. (C37H58N4O9) C, H, N.
Eth yl 3-(4-Qu in olyl)p r op en oa te. A suspension of LiCl
(972 mg, 22.9 mmol, 1.2 equiv) in 60 mL of anhydrous CH3-
CN was treated with triethyl phosphonoacetate (4.55 mL, 22.9
mmol, 1.2 equiv) and DBU (3.05 mL, 20.4 mmol, 1.07). The
mixture was stirred under nitrogen until everything was in
solution. Quinoline-4-carboxyaldehyde (3.00 g, 19.1 mmol,
1.00 mmol) was then added, and the reaction mixture was
stirred for 6 h. The reaction was quenched by addition of 5%
KH2PO4 solution and then extracted into ether. The organic
portion was washed with water and brine, dried over MgSO4,
and concentrated under reduced pressure. Chromatography
(t-BuOMe) gave 4.21 g of the desired compound as a yellow
oil (97% yield): 1H NMR (CDCl3) δ 8.95 (d, 1H), 8.43 (d, 1H),
8.16 (m, 1H), 7.78 (m, 1H), 7.64 (m, 1H), 7.54 (d, 1H), 6.65 (d,
1H), 4.34 (q, 2H), 1.39 (t, 3H).
3-(4-P h en ylim id a zolyl)p r op a n a l. 2-(2-(4-Phenylimida-
zolyl)ethyl)-1,3-dioxolane (1.96 g) was dissolved in 25 mL of
acetone and treated with 20 mL of 2 N HCl. The reaction
mixture was heated to 50 °C. After 24 h, 1 mL of concentrated
HCl was added, and the heating was continued for 3 days.
After cooling, the reaction mixture was neutralized with 1 N
NaOH and extracted into 200 mL of CH2Cl2. The organic layer
was separated, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to give 300 mg of the
desired product as a white solid: CI MS m/z 201 (M + H)+; 1H
NMR (CDCl3) δ 9.81 (s, 1H), 7.75 (m, 2H), 7.53 (m, 1H), 7.36
(m, 2H), 7.27-7.19 (m, 2H), 4.28 (t, 2H), 2.99 (t, 2H).
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(4-p h en ylim id a -
zolyl)p r op yl)h yd r a zo]-6-O-m et h yler yt h r on olid e A, 11,-
12-Ca r ba m a te (50). The title compound was prepared from
2 and 3-(4-phenylimidazolyl)propanal. Chromatography (5%
MeOH/CH2Cl2 with 0.1% NH4OH) gave the compound as a
colorless solid (74% yield): CI MS m/z 796 (M + H)+; 13C NMR
(CDCl3) δ 217.5, 169.3, 156.0, 146.3, 142.0, 137.5, 134.4, 128.4,
126.4, 124.7, 123.8, 115.1, 104.9, 83.1, 81.8, 78.9, 77.5, 70.2,
69.7, 65.7, 57.6, 49.1, 44.8, 44.4, 44.3, 40.5, 40.1, 40.0, 37.3,
29.1, 28.2, 21.7, 21.1, 20.3, 18.2, 17.0, 14.6, 14.6, 13.0, 10.7.
Anal. (C43H65N5O9) C, H, N.
Eth yl 3-(4-Qu in olyl)p r op ion a te. Ethyl 3-(4-quinolyl)-
propenoate (2.60 g) was dissolved in 20 mL of methanol, and
the reaction vessel was flushed with nitrogen. Pd/C (10%) (50
mg) was added, and the vessel was then flushed with H2. The
reaction mixture was then stirred rapidly under 1 atm of H2
pressure for 17 h. The mixture was filtered through a Celite
pad, and the filtrate was concentrated under reduced pressure.
Chromatography (50% ethyl acetate/hexane) gave 1.51 g of the
desired compound as a colorless oil (58% yield): 1H NMR
(CDCl3) δ 8.82 (d, 1H), 8.13 (d, 1H), 8.05 (m, 1H), 7.72 (m,
1H), 7.58 (m, 1H), 7.27 (d, 1H), 4.16 (q, 2H), 3.43 (t, 2H), 2.79
(t, 2H), 1.25 (t, 3H).
3-(4-Qu in olyl)p r op a n a l. Ethyl 3-(4-quinolyl)propionate
(1.51 g, 6.59 mmol, 1.0 equiv) was dissolved in 60 mL of dry
toluene, and the solution was cooled to -78 °C under nitrogen.
DIBAL-H (13.2 mL, 13.2 mmol, 2.0 equiv) was added dropwise
over 10 min; the reaction mixture was then allowed to stir for
an additional 2 h. The reaction was then quenched with a
solution containing water (0.25 mL) and acetic acid (1 mL)
dissolved in 3 mL of ether. The mixture was allowed to warm
to room temperature and then filtered. The filtrate was
concentrated under reduced pressure. Chromatography (75-
100% ethyl acetate/hexane) gave 0.79 g of the desired com-
pound as a light-yellow oil (65% yield): 1H NMR (CDCl3) δ
2-(2-(1-Ben zotr ia zolyl)eth yl)-1,3-d ioxola n e a n d 2-(2-(2-
Ben zotr ia zolyl)eth yl)-1,3-d ioxola n e. Benzotriazole (2.02 g,
17.0 mmol, 1.0 equiv) was added to a suspension of NaH (1.35
g, 33.8 mmol, 2.0 equiv) in DMF (25 mL) at 0 °C under
nitrogen. 2-(2-Bromoethyl)-1,3-dioxolane (2.00 mL, 17.0 mmol,
1.0 equiv) was added dropwise, and the reaction mixture was
warmed to room temperature. After stirring for 3 h, the
reaction mixture was partitioned between Et2O and brine. The
organic layer was dried over Na2SO4 and concentrated under
reduced pressure. Chromatography (25% EtOAc/hexanes)
gave 550 mg of 2-(2-(2-benzotriazolyl)ethyl)-1,3-dioxolane as
an oil (15% yield): CI MS m/z 220 (M + H)+; 1H NMR (CDCl3)
δ 7.85 (m, 2H), 7.37 (m, 2H), 5.00 (t, 1H), 4.88 (t, 2H), 3.99

Anhydrolide Macrolides. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1669
(m, 2H), 3.86 (m, 2H), 2.51 (m, 2H); 13C NMR (CDCl3) δ 144.4,
126.2, 118.0, 101.8, 65.2, 51.7, 33.9. The column was then
eluted with 50% EtOAc/hexanes to give 630 mg of 2-(2-(1-
benzotriazolyl)ethyl)-1,3-dioxolane as an oil (17% yield): CI
NH4OH) gave the compound as a white foam (71% yield): CI
MS m/z 745 (M + H)+; 13C NMR (CDCl3) δ 217.3, 169.1, 155.9,
146.1, 145.0, 129.7, 126.7, 126.1, 123.8, 117.9, 115.3, 104.8,
83.0, 81.6, 78.9, 77.6, 70.2, 69.6, 65.7, 57.5, 49.1, 47.5, 44.4,
40.5, 40.1, 40.0, 37.2, 28.4, 28.2, 27.7, 21.7, 21.1, 20.3, 18.2,
17.0, 14.6, 14.6, 13.0, 10.6. Anal. (C40H64N4O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(3-a m in op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (55). The title compound was prepared by reducing
compound 36 following the procedure that was used to prepare
compound 53. Chromatography (10% MeOH/CH2Cl2 with
0.1% NH4OH) gave the compound as a white foam (49%
yield): CI MS m/z 745 (M + H)+; 13C NMR (CDCl3) δ 217.2,
169.5, 155.8, 146.4, 146.0, 143.3, 129.1, 124.0, 118.9, 115.5,
112.6, 104.8, 83.3, 81.6, 79.0, 78.0, 70.3, 69.7, 65.9, 58.1, 49.2,
48.1, 4.4, 40.9, 40.3, 40.1, 37.3, 33.3, 29.3, 28.4, 21.9, 21.2, 20.5,
18.3, 17.1, 14.8, 14.6, 13.1, 10.7. Anal. (C40H64N4O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(4-a m in op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (56). The title compound was prepared by reducing
compound 37 following the procedure that was used to prepare
compound 53. Chromatography (3-5% MeOH/CH2Cl2 with
0.1% NH4OH) gave the compound as a white foam (26%
yield): CI MS m/z 745 (M + H)+; 13C NMR (CDCl3) δ 217.2,
169.1, 155.7, 145.9, 144.0, 132.1, 129.1, 123.9, 115.1, 104.8,
83.1, 81.5, 78.9, 77.8, 70.2, 69.6, 65.7, 57.9, 49.0, 48.0, 44.3,
40.7, 40.1, 40.0, 37.2, 32.3, 29.7, 28.2, 21.8, 21.1, 20.4, 18.2,
17.0, 14.7, 14.5, 13.0, 10.6. Anal. (C40H64N4O9) C, H, N.
1
MS m/z 220 (M + H)+; H NMR (CDCl3) δ 8.07 (m, 1H), 7.60
(m, 1H), 7.50 (m, 1H), 7.38 (m, 1H), 4.94 (t, 1H), 4.81 (t, 2H),
4.00 (m, 2H), 3.87 (m, 2H), 2.41 (m, 2H); 13C NMR (CDCl3) δ
146.0, 133.0, 127.2, 123.8, 120.0, 109.3, 101.6, 65.1, 43.1, 33.6.
3-(2-Ben zot r ia zolyl)p r op a n a l. 2-(2-(2-Benzotriazolyl)-
ethyl)-1,3-dioxolane (550 mg) was dissolved in 25 mL of acetone
and treated with 10 mL of 2 N HCl. The reaction mixture
was heated to 50 °C for 2 days. After cooling, the reaction
mixture was diluted with 50 mL of CH2Cl2. The organic layer
was separated, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to give 300 mg of the
desired product as a white solid: CI MS m/z 176 (M + H)+; 1H
NMR (CDCl3) δ 9.92 (t, 1H), 7.90 (m, 2H), 7.39 (m, 2H), 5.08
(t, 2H), 3.34 (m, 2H).
3-(1-Ben zot r ia zolyl)p r op a n a l. 2-(2-(1-Benzotriazolyl)-
ethyl)-1,3-dioxolane (630 mg) was dissolved in 25 mL of acetone
and treated with 10 mL of 2 N HCl. The reaction mixture
was heated to 50 °C for 2 days. After cooling, the reaction
mixture was diluted with 50 mL of CH2Cl2. The organic layer
was separated, washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to give 350 mg of the
desired product as a white solid: CI MS m/z 176 (M + H)+; 1H
NMR (CDCl3) δ 9.88 (s, 1H), 8.06 (m, 1H), 7.64 (m, 1H), 7.53
(m, 1H), 7.39 (m, 1H), 4.92 (t, 2H), 3.34 (t, 2H).
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(2-ben zotr ia zolyl-
)p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (51). The title compound was prepared from 2 and
3-(2-benzotriazolyl)propanal. Chromatography (5-10% MeOH/
tert-butyl methyl ether with 1% NH4OH) gave the compound
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(4-a m in op h en yl)-
2-p r op en yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (57). The title compound was prepared by
reducing compound 38 following the procedure that was used
to prepare compound 53. Chromatography (5% MeOH/CH2-
Cl2 with 0.2% NH4OH) gave the compound as a white powder
(58% yield): CI MS m/z 743 (M + H)+; 13C NMR (CDCl3) δ
217.3, 169.4, 156.1, 146.1, 145.8, 133.9, 127.9, 123.9, 122.0,
115.0, 104.9, 83.4, 81.7, 79.1, 78.6, 70.4, 69.7, 65.9, 58.0, 51.2,
49.5, 44.3, 40.9, 40.3, 40.0, 37.4, 28.5, 21.8, 21.2, 20.6, 18.4,
17.2, 14.8, 14.7, 13.0, 10.4. Anal. (C40H62N4O9) C, H, N.
as a colorless solid (90% yield): CI MS m/z 771 (M + H)+; 13
C
NMR (CDCl3) δ 217.2, 169.2, 156.0, 146.1, 144.4, 125.9, 125.0,
124.1, 118.0, 104.8, 83.2, 81.7, 79.1, 77.8, 70.3, 69.7, 65.9, 58.2,
54.2, 49.2, 45.7, 44.4, 40.8, 40.3, 40.1, 37.3, 28.6, 28.3, 21.9,
21.2, 20.5, 18.3, 17.2, 14.8, 14.5, 13.1, 10.7. Anal. (C40H62N6O9)
C, H; N: calcd, 10.90; found, 10.30.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(1-ben zotr ia zolyl-
)p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (52). The title compound was prepared from 2 and
3-(1-benzotriazolyl)propanal. Chromatography (3-5% MeOH/
tert-butyl methyl ether with 1% NH4OH) gave the compound
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(4-(a cetyla m in o)-
p h en yl)-2-p r op en yl)h yd r a zo]-6-O-m et h yler yt h r on olid e
A, 11,12-Ca r ba m a te (58). A solution of compound 57 (120
mg, 0.162 mmol) in 3 mL of dry CH2Cl2 was cooled to 0 °C.
Acetyl chloride (12 µL, 0.17 mmol, 1.05 equiv) was added, and
the mixture was stirred for 3 h. The reaction was then
quenched with saturated NaHCO3 solution and extracted into
CH2Cl2. The organic portion was washed with H2O and brine,
dried over Na2SO4, and concentrated under reduced pressure.
Chromatography (7-10% MeOH/CH2Cl2 with 0.1% NH4OH)
gave the compound (103 mg) as a white solid (81% yield): CI
MS m/z 785 (M + H)+; 13C NMR (CDCl3) δ 217.5, 169.4, 168.4,
156.2, 146.2, 137.5, 133.4, 132.8, 127.2, 124.8, 123.8, 119.6,
104.9, 83.3, 81.9, 79.0, 78.5, 70.3, 69.7, 65.8, 57.8, 51.1, 49.6,
44.4, 40.7, 40.2, 40.1, 37.4, 28.3, 24.6, 21.8, 21.2, 20.5, 18.4,
17.1, 14.8, 14.8, 13.0, 10.5. Anal. (C42H64N4O10) C, H, N.
9-Am in o-2,3-a n h yd r o-9-d eoxo-5-O-d esosa m in yl-11-h y-
d r a zo-6-O-m eth yler yth r on olid e A, 11,12-Ca r ba m a te (59).
A solution of 4 (318 mg, 0.536 mmol) dissolved in 10 mL of
MeOH and 1 mL of AcOH was treated with NaBH3CN (300
mg). After the mixture stirred for 24 h, another 200-mg
portion of NaBH3CN and 0.5 mL of AcOH were added. After
stirring for 3 days, the reaction mixture was added to
saturated NaHCO3 solution and extracted into CH2Cl2. The
organic portion was washed with H2O and brine, dried over
Na2SO4, and concentrated under reduced pressure to give the
product as a white solid (297 mg, 93% yield): CI MS m/z 596
(M + H)+; 13C NMR (CDCl3) δ 168.9, 158.9, 143.1, 125.9, 104.2,
83.3, 82.6, 79.2, 78.8, 78.0, 76.7, 70.4, 69.5, 65.8, 50.3, 40.3,
37.6, 37.2, 35.3, 33.3, 28.6, 26.8, 25.4, 21.1, 21.1, 20.4, 19.8,
18.1, 12.4, 12.2. Anal. (C31H53N3O8) C, H, N.
as a colorless solid (76% yield): CI MS m/z 771 (M + H)+; 13
C
NMR (CDCl3) δ 217.4, 169.2, 156.2, 146.3, 145.2, 133.5, 127.1,
123.9, 123.7, 119.6, 110.2, 104.9, 83.2, 81.8, 79.1, 77.6, 70.3,
69.7, 65.9, 57.7, 49.3, 45.6, 45.4, 44.5, 40.6, 40.2, 40.1, 37.4,
28.4, 28.1, 21.8, 21.2, 20.4, 18.3, 17.1, 14.7, 14.6, 13.0, 10.7.
Anal. (C40H62N6O9) C, H, N.
Ger er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
53-57. 2,3-An h ydr o-5-O-desosam in yl-11-[(3-(4-am in oph e-
n yl)m eth yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-
Ca r ba m a te (53). Acetyl chloride (300 µL, 4.2 mmol) was
added to 5 mL of MeOH, and the mixture was stirred for 15
min. Compound 34 (144 mg, 0.193 mmol), dissolved in 10 mL
of MeOH, was then added to the solution followed by Zn dust
(380 mg, 5.8 mmol). After the mixture stirred for 12 h, a
saturated solution of K2CO3 was added (1 mL). EtOAc (25 mL)
was then added, and the organic portion was decanted from
the solids. The organic portion was washed with H2O and
brine, dried over Na2SO4, and concentrated under reduced
pressure. Chromatography (5% MeOH/CH2Cl2 with 0.1% NH4-
OH) gave the compound (85 mg) as a white powder (62%
yield): CI MS m/z 717 (M + H)+; 13C NMR (CDCl3) δ 217.2,
169.3, 155.6, 145.9, 145.7, 130.4, 126.7, 124.1, 115.0, 104.8,
83.3, 81.5, 79.1, 78.3, 70.3, 69.7, 65.8, 58.5, 52.0, 49.6, 44.2,
41.1, 40.2, 40.1, 37.6, 28.3, 21.9, 21.2, 20.7, 18.4, 17.1, 14.9,
14.5, 13.1, 10.7. Anal. (C38H60N4O9) C, H, N.
2,3-An h yd r o-5-O-d esosa m in yl-11-[(3-(2-a m in op h en yl)-
p r op yl)h yd r a zo]-6-O-m eth yler yth r on olid e A, 11,12-Ca r -
ba m a te (54). The title compound was prepared by reducing
compound 35 following the procedure that was used to prepare
compound 53. Chromatography (5% MeOH/CH2Cl2 with 0.1%
2,3-An h yd r o-9-d eoxo-5-O-d esosa m in yl-11-h yd r a zo-9-
((3-ph en ylpr opyl)am in o)-6-O-m eth yler yth r on olide A, 11,-
12-Ca r ba m a te (60). A solution of 59 (88 mg, 0.148 mmol)
dissolved in 5 mL of MeOH was treated with hydrocinnama-

1670 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Griesgraber et al.
(7) Yoshida, R.; Kaku, M.; Kohno, S.; Ishida, K.; Mizukane, R.;
Takemura, H.; Tanaka, H.; Usui, T.; Tomona, K.; Koga, H.; Hara,
K. Trends in Antimicrobial Resistance of Streptococcus pnue-
moniae in J apan. Antimicrob. Agents Chemother. 1995, 39,
1196-1198.
(8) Gardee, Y.; Kirby, R. The Incidence of Induible Macrolide-
Lincosamide-Streptogramin B Resistance in Methicillin-Resis-
tant Staphylococci in Clinical Isolates From the Eastern Cape
Area of South Africa. Lett. Appl. Microbiol. 1993, 17, 264-268.
(9) (a) Agouridas, C.; Bonnefoy, A.; Chantot, J . F.; Le Martret, O.;
Denis, A. (Roussel-Uclaf) EP596802-A1, May 11, 1994. (b) Le
Martret, O.; Agouridas, C.; Bonnefoy, A.; Chantot, J . F.; Denis,
A. (Roussel-Uclaf) FR2697524-A1, May 6, 1994.
(10) Agouridas, C.; Benedetti, Y.; Chantot, J . F.; Denis, A.; Le
Martret, O. (Roussel-Uclaf) EP676409-A1, Oct. 11, 1995. Also
see: Agouridas, C.; Benedetti, Y.; Denis, A.; Le Martret, O.;
Chantot, J . F. 35th Interscience Conference on Antimicrobial
Agents and Chemotherapy, San Francisco, CA, Sept. 17-20,
1995; Abstr. No. F157.
(11) Asaka, T.; Kashimura, M.; Misawa, Y.; Ono, T.; Suzuki, K.;
Yoshida, H.; Yoshida, T.; Akashi, T.; Yokoo, C.; Nagate, T.;
Morimoto, S. A New Macrolide Antibiotic, TE-802; Synthesis and
Biological Properties. 35th Interscience Conference on Antimi-
crobial Agents and Chemotherapy, San Francisco, CA, Sept. 17-
20, 1995; Abstr. No. F176.
ldehyde (100 µL, 0.760 mmol, 5 equiv) and NaBH3CN (55 mg,
0.859 mmol, 6 equiv). Acetic acid was added dropwise until
bromocresol green indicator had turned from blue to yellow.
After stirring for 15 h, the reaction mixture was added to
saturated NaHCO3 solution and extracted into CH2Cl2. The
organic portion was washed with H2O and brine, dried over
Na2SO4, and concentrated under reduced pressure. Chroma-
tography (5-10% MeOH/CH2Cl2 containing 0.2% concentrated
NH4OH) gave the product as a white solid (45 mg, 43% yield):
CI MS m/z 714 (M + H)+; 13C NMR (CDCl3) δ 169.2, 159.0,
143.2, 142.2, 128.5, 128.3, 125.8, 125.7, 104.9, 85.4, 82.7, 82.6,
79.5, 78.7, 72.8, 70.4, 69.5, 65.8, 58.7, 50.2, 40.3, 37.6, 37.5,
36.0, 33.1, 33.0, 30.1, 28.7, 26.8, 25.1, 21.8, 21.1, 20.8, 20.0,
17.9, 12.5, 12.0. Anal. (C40H63N3O8‚1/2H2O) C, H, N.
Ackn owledgm en t. The authors thank Rodger Henry
for determining the crystal structure of 4. We also thank
Carmina Presto, Xiaolin Zhang, and Dr. Thomas Pagano
for their help in acquiring and interpreting NMR data.
We are indebted to Dr. J ohnathan Pease for providing
us with the advanced synthetic intermediates used to
prepare the compounds presented in this paper.
(12) Elliott, R. L.; Pireh, D.; Griesgraber, G.; Nilius, A. M.; Ewing,
P. J .; Bui, M.-H.; Raney, P. M.; Flamm, R. K.; Kim, K.; Henry,
R. F.; Chu, D. T. W.; Plattner, J . J .; Or, Y. S. Anhydrolide
Macrolides. 1. Synthesis and Antibacterial Activity of 2,3-
Anhydro-6-O-methyl 11,12-Carbamate Erythromycin A Ana-
logues. J . Med. Chem. 1998, 41, 1651-1659.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR chemical
shifts and peak assignments for compounds 2-60 (8 pages).
Ordering information is given on any current masthead page.
Refer en ces
(13) Griesgraber, G.; Or, Y. S.; Chu, D. T. W.; Nilius, A. M.; J ohnson,
P. M.; Flamm, R. K.; Henry, R. F.; Plattner, J . J . 3-Keto-11,12-
carbazate Derivatives of 6-O-methylerythromycin A. Synthesis
and In Vitro Activity. J . Antibiot. 1996, 49, 465-77.
(14) (a) Baker, W. R.; Clark, J .; Stephens, R. L.; Kim, K. H.
Modifications of Macrolide Antibiotics. Synthesis of 11-Deoxy-
11-(carboxyamino)-6-O-Methylerythromycin A 11,12-(Cyclic es-
ters) via an Intramolecular Michael Reaction of O-Carbamates
with an R,â-Unsaturated Ketone. J . Org. Chem. 1988, 53, 2340-
2345. (b) Fernandes, P. B.; Baker, W. R.; Frieberg, L. A.; Hardy,
D. J .; McDonald, E. J . New Macrolides Active against Strepto-
coccus pyogenes with Inducible or Constitutive Type of Mac-
rolide-Lincosamide-Streptogramin B Resistance. Antimicrob.
Agents Chemother. 1989, 33, 78-81.
(15) Hardy, D. J .; Swanson, R. N.; Shipkowitz, N. L.; Frieberg, L.
A.; Lartey, P. A.; Clement, J . J . In Vitro Activity and In Vivo
Efficacy of a New Series of 9-Deoxo-12-Deoxy-9,12-Epoxyerthro-
mycin A Derivatives. Antimicrob. Agents Chemother. 1991, 35,
922-928.
(16) J effery, T. Palladium-catalysed Vinylation of Organic Halides
under Solid-Liquid Phase Transfer Conditions. J . Chem. Soc.,
Chem. Commun. 1984, 1287-1289.
(1) Kurath, P.; J ones, P. H.; Egan, R. S.; Perun, T. J . Acid
Degradation of Erythromycin A and Erythromycin B. Experi-
entia 1971, 27, 362.
(2) Itoh, Z.; Nakaya, K.; Suzuki, H.; Aria, H.; Wakabayashi, K.
Erythromycin mimics Exogenous Motilin in Gastrointestinal
Contractile Activity in the Dog. Am. J . Physiol. 1984, 247,
G688-G694.
(3) (a) Zuckerman, J . M.; Kaye, K. M. The Newer Macrolides.
Azithromycin and Clarithromycin. Infect. Dis. Clin. North Am.
1995, 9 (3), 731-745. (b) Chu, D. T. W. Recent Developments
in 14- and 15-Membered Macrolides. Exp. Opin. Invest. Drugs
1995, 4 (2), 65-94. (c) Bahal, N.; Nahata, M. C. The New
Macrolide Antibiotics: Azithromycin, Clarithromycin, Dirithro-
mycin, and Roxithromycin. Ann. Pharmacother. 1992, 26 (1),
46-55.
(4) Morimoto, S.; Takahashi, Y.; Adachi, T.; Nagate, T.; Wantanabe,
Y.; Omura, S. Chemical Modifications of Erythromycins II.
Synthesis and Antibacterial Activity of O-Alkyl Derivatives of
Erythromycin A. J . Antibiot. 1990, 43, 286-305.
(5) Djokic, S.; Kobrehel, G.; Lazarevski, G. Erythromycin Series XII.
Antibacterial In Vitro Evaluation of 10-Dihydro-10-Deoxo-11-
Azaerythromycin A. J . Antibiot. 1987, 40, 1006-1015.
(6) Bright, G. M.; Nagel, A. A.; Bordner, J .; Desai, K. A.; Dibrino,
J . N.; Nowakowska, J .; Vincent, L.; Waltrous, R. M.; Sciavolino,
F. C.; English, A. R.; Retsema, J . A.; Anderson, M. A.; Brennan,
L. A.; Borovoy, R. J .; Cimochowski, C. R.; Faiella, J . A.; Girard,
A. E.; Girard, D.; Herbert, C.; Manousos, M.; Mason, R.
Synthesis, In Vitro and In Vivo Activity of Novel 9-Deoxo-9a-
Aza-9a-Homoerythromycin A Derivatives; A New Class of Mac-
rolide Antibiotics. J . Antibiot. 1988, 41, 1029-1047.
(17) Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria that Grow Aerobically; National Committee for Clinical
Laboratory Standards: Villanova, PA, 1985: M7-A, Vol. 5, No.
22.
J M970548P